Late Transition Metal-Catalyzed Hydroamination and

Review pubs.acs.org/CR

Late Transition Metal-Catalyzed Hydroamination and Hydroamidation Liangbin Huang,† Matthias Arndt,† Kaẗ he Gooßen, Heinrich Heydt, and Lukas J. Gooßen* Department of Chemistry, TU Kaiserslautern, Erwin-Schrödinger-Strasse Geb. 54, 67663 Kaiserslautern, Germany 2.4.3. Intramolecular Hydroamidation of Alkynes 2.5. Other Nitrogen Nucleophiles 2.5.1. Addition of Hydrazines to Alkynes 2.5.2. Addition of Imidates to Alkynes 2.5.3. Addition of Aldoximes to Alkynes 2.5.4. Addition of Hydrazones to Alkynes 2.5.5. Addition of Triazenes to Alkynes 2.5.6. Addition of Azides to Alkynes 2.5.7. Addition of Tetrazoles to Alkynes 2.5.8. Addition of Imines/Pyridines to Alkynes 3. Catalytic Addition of Nitrogen Nucleophiles to Allenes 3.1. Aliphatic Amines 3.1.1. Intermolecular Hydroamination of Terminal Allenes 3.1.2. Intramolecular Hydroamination of Allenes 3.2. Aliphatic and Aromatic Amines 3.2.1. Intermolecular Hydroamination of Terminal Allenes 3.3. Aromatic Amines 3.3.1. Intermolecular Hydroamination of Terminal Allenes 3.3.2. Intermolecular Hydroamination of Internal Allenes 3.3.3. Intermolecular Asymmetric Hydroamination of Allenes 3.3.4. Intramolecular Hydroamination of Allenes 3.4. Amides 3.4.1. Intermolecular Hydroamidation of Terminal Allenes 3.4.2. Intermolecular Hydroamidation of Internal Allenes 3.4.3. Intermolecular Asymmetric Hydroamidation of Allenes 3.4.4. Intramolecular Hydroamidation of Allenes 3.4.5. Intramolecular Asymmetric Hydroamidation of Allenes 3.5. Other Nitrogen Nucleophiles 3.5.1. Addition of Hydroxylamines and Hydroxylamine Ethers to Allenes 3.5.2. Addition of Hydroxylamines and Hydrazines to Allenes 3.5.3. Addition of Hydrazones to Allenes

CONTENTS 1. Introduction 1.1. Products Obtainable by Hydroaminations and Hydroamidations 1.2. Traditional Syntheses of Enamines/Imines and Enamides 1.3. Hydroamination and Hydroamidations: A Historical Overview 1.4. Potentials and Challenges in Metal-Catalyzed Hydroaminations and Hydroamidations 1.4.1. Thermodynamic and Kinetic Issues 1.4.2. Selectivity 1.4.3. Strategies To Control Reactivity and Selectivity 1.5. Catalyst Metals Used in Hydroaminations and Hydroamidations 1.6. Scope and Structure of This Review 2. Catalytic Addition of Nitrogen Nucleophiles to Unconjugated Alkynes 2.1. Ammonia 2.1.1. Intermolecular Hydroamination of Terminal Alkynes 2.2. Aliphatic Amines 2.2.1. Intermolecular Hydroamination of Terminal Alkynes 2.2.2. Intermolecular Hydroamination of Internal Alkynes 2.2.3. Intramolecular Hydroamination of Alkynes 2.3. Aromatic Amines 2.3.1. Intermolecular Hydroamination of Terminal Alkynes 2.3.2. Intermolecular Hydroamination of Internal Alkynes 2.3.3. Intramolecular Hydroamination of Alkynes 2.4. Amides 2.4.1. Intermolecular Hydroamidation of Terminal Alkynes 2.4.2. Intermolecular Hydroamidation of Internal Alkynes

© XXXX American Chemical Society

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Received: September 20, 2012

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DOI: 10.1021/cr300389u Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 3.5.4. Addition of Azides to Allenes 4. Catalytic Addition of Nitrogen Nucleophiles to Unconjugated Alkenes 4.1. Aliphatic Amines 4.1.1. Intermolecular Hydroamination of Ethylene 4.1.2. Intermolecular Hydroamination of Terminal Alkenes 4.1.3. Intermolecular Hydroamination of Internal Alkenes 4.1.4. Intermolecular Asymmetric Hydroamination of Alkenes 4.1.5. Intramolecular Hydroamination of Alkenes 4.1.6. Intramolecular Asymmetric Hydroamination of Alkenes 4.2. Aliphatic and Aromatic Amines 4.2.1. Intermolecular Hydroamination of Alkenes 4.2.2. Intramolecular Hydroamination of Alkenes 4.3. Aromatic Amines 4.3.1. Intermolecular Hydroamination of Ethylene 4.3.2. Intermolecular Hydroamination of Terminal Alkenes 4.3.3. Intermolecular Hydroamination of Internal Alkenes 4.3.4. Intermolecular Asymmetric Hydroamination of Alkenes 4.3.5. Intramolecular Hydroamination of Terminal Alkenes 4.4. Amides 4.4.1. Intermolecular Hydroamidation of Ethylene 4.4.2. Intermolecular Hydroamidation of Terminal Alkenes 4.4.3. Intermolecular Hydroamidation of Internal Alkenes 4.4.4. Intermolecular Asymmetric Hydroamidation of Alkenes 4.4.5. Intramolecular Hydroamidation of Alkenes 4.4.6. Intramolecular Asymmetric Hydroamidation of Alkenes 4.5. Other Nitrogen Nucleophiles 4.5.1. Asymmetric Addition of Hydroxylamine Esters to Alkenes 4.5.2. Addition of Hydrazines to Alkenes 4.5.3. Addition of Azides to Alkenes 4.5.4. Addition of Secondary Amine Precursors to Alkenes 5. Catalytic Addition of Nitrogen Nucleophiles to Conjugated Multiple Bonds 5.1. Aliphatic Amines 5.1.1. Hydroamination of Diynes 5.1.2. Hydroamination of Enynes 5.1.3. Hydroamination of Dienes 5.2. Aliphatic and Aromatic Amines 5.2.1. Hydroamination of Diynes 5.2.2. Hydroamination of Dienes 5.3. Aromatic Amines 5.3.1. Hydroamination of Diynes

Review

5.3.2. Hydroamination of Dienes 5.3.3. Asymmetric Hydroamination of Dienes 5.4. Amides 5.4.1. Hydroamidation of Diynes 5.4.2. Hydroamidation of Dienes 5.4.3. Asymmetric Hydroamidation of Dienes 5.5. Other Nitrogen Nucleophiles 5.5.1. Addition of Hydroxylamines and Hydrazines to Dienes 6. Reaction Cascades and Sequences 6.1. Cascade Insertions of Several C−C and C−X Multiple Bonds into N−H Bonds 6.1.1. Cascade Insertion of Diynes or Enynes into an N−H Bond 6.1.2. Cascade Insertion of Two Separate Alkynes or Alkenes into an N−H Bond 6.1.3. Insertion of an Allene and an Alkene into an N−H Bond 6.1.4. Cascade Insertion of C−C and C−O Double Bonds into an N−H Bond 6.1.5. Intramolecular Cascade Insertion of Alkenes and Alkynes into an N−H Bond 6.2. Hydroamination/Hydroamidation Followed by Further Functionalization 6.2.1. Hydroamination Followed by Hydrolysis 6.2.2. Hydroamination Followed by Nucleophilic Substitution 6.2.3. Hydroamination Followed by Dehydration 6.2.4. Hydroamination Followed by Hydrogenation 6.2.5. Hydroamination Followed by Oxidation 6.2.6. Hydroamination Followed by Nucleophilic Addition 6.2.7. Hydroamination Followed by Carbene Insertion 6.2.8. Hydroamination Followed by Allylic Alkylation 6.2.9. Hydroamination Followed by C−H Activation 6.2.10. Hydroamination Followed by Cycloaddition 6.2.11. Hydroamination Followed by Pictet− Spengler Reaction 6.2.12. Hydroamination Followed by Ring Contraction 6.2.13. Addition of Imines to Alkynes Followed by Nucleophilic Capture 6.3. In Situ Formation of Amine Groups Followed by Intramolecular Hydroamination 6.3.1. Hydroamination with N-Nucleophiles Generated by Nucleophilic Addition to Imines 6.3.2. Hydroamination with N-Nucleophiles Generated by Nucleophilic Addition to Isoquinolines 6.3.3. Hydroamination with N-Nucleophiles Generated by Nucleophilic Addition to Nitriles 6.3.4. Hydroamination with N-Nucleophiles Generated by Nucleophilic Addition to Isocyanates

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Chemical Reviews 6.3.5. Hydroamination with N-Nucleophiles Generated by Nucleophilic Addition to Aziridines 6.3.6. Hydroamination of Allenes with NNucleophiles Generated by Nucleophilic Addition to Alkynyl Aziridines 6.4. C−C Bond Formation Followed by Hydroamination or Hydroamidation 6.4.1. Sonogashira Coupling Followed by Hydroamination 6.4.2. A3 (Amine-Alkyne-Aldehyde)-Coupling Followed by Hydroamination 6.4.3. Conjugate Addition of Terminal Alkynes Followed by Hydroamidation 6.4.4. Hydroacylation Followed by Hydroamidation 6.4.5. Addition of Terminal Alkynes to Carbonyl Groups Followed by Intramolecular Hydroamination 6.4.6. Oxidative C−C Coupling Followed by Hydroamination 6.4.7. Claisen Rearrangement Followed by Hydroamidation 6.4.8. Allene Formation Followed by Hydroamination 6.4.9. Carbene Insertion Followed by Hydroamination 6.4.10. Cross-Metathesis Followed by Hydroamidation 6.5. C−Heteroatom Bond Formation Followed by Hydroamination or Hydroamidation 6.5.1. Buchwald−Hartwig-Type C−N Coupling Followed by Hydroamidation 6.5.2. C−S Coupling Followed by Hydroamination 6.5.3. Allylic or Propargylic Amination Followed by Hydroamidation 6.5.4. Click Reaction Followed by Hydroamination 6.5.5. Carbene Insertion Followed by Hydroamination 6.5.6. Hydration/Alkoxy Group Elimination Followed by Hydroamidation 7. Conclusion and Outlook 7.1. State-of-the-Art 7.2. Synthetic Challenges 7.3. Mechanistic Challenges Author Information Corresponding Author Author Contributions Notes Biographies Acknowledgments Abbreviations References

Review

and formation of a C−N and a C−H bond. Acyl, sulfonyl, or phosphinyl substituents acidify the N−H proton by 5−20 orders of magnitude and markedly reduce the nucleophilicity of the nitrogen.1 These strongly electron-withdrawing substituents fundamentally alter the reactivity of the N−H group, so that different product classes are obtained in catalytic addition reactions of amine- and amide-type substrates. Although the addition of amides and related compounds across C−C multiple bonds is sometimes also called hydroamination, such reactions appear to be more accurately designated as hydroamidations, because of the differences in substrates, reactivity, and products. In this Review, usage of the term hydroamidation is not limited to the substrate classes of amides, sulfonamides, and phosphonamides, but extended to structurally related compounds with a similar pKa range and reactivity, such as carbamates, lactams, ureas, amidines, guanidines, etc.

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1.1. Products Obtainable by Hydroaminations and Hydroamidations

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Amine, enamine/imine, or enamide moieties, as are accessible by hydroamination or -amidation reactions, are widely encountered in the scaffolds of natural products or synthetic drugs (Figure 1). Monomorine is one of the first natural products that became accessible by a synthetic sequence involving a hydroamination step.2

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Figure 1. Examples of bioactive natural products accessible via hydroamination or -amidation reactions.

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In Chinese folk medicine, extracts of the plant Carduus crispus are used for the treatment of cold, stomach ache, and rheumatism. An active ingredient of this plant, crispine A, displays cytotoxic activity and inhibits the growth of some human cancer cells.3,4 It has been synthesized via a sequence involving an intramolecular hydroamination of homopropargyl amine to generate 5,6-dihydro-8,9-dimethoxypyrrolo[2,1-a]isoquinoline, and subsequent hydrogenation.3 (−)-Epimyrtine is an alkaloid isolated from Vaccinium myrtillus, and exhibits anticancer, antibacterial, antiviral, and anti-inflammatory activity. It has been synthesized by a gold-catalyzed intramolecular 6-endo-dig hydroamidation of alkynes.5 The tricyclic piperidine alkaloid porantheridine was isolated from Corymbosa porantherida. Its key synthetic intermediate, a cis-isoxazolidine, was obtained by silver-catalyzed intramolecular allene hydroamination.6 The polyhydroxylated indolizidine swainsonine, found in the genera Polygonatum and Prosopis, is a potent inhibitor of several glycosidase enzymes, resulting in anti-HIV and anticancer activities.7,8 A formal synthesis of swainsonine involves a AuIII-catalyzed intramolecular allene hydroamidation.9 (+)-Terreusinone is a dipyrrolobenzoquinone, isolated from the algicolous marine fungus Aspergillus terreus. A key step in its synthesis consists of a gold-catalyzed intramolecular

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1. INTRODUCTION This Review examines recent developments in late transition metal-catalyzed hydroamination and -amidation reactions. A hydroamination is a reaction in which an N−H unit of a nucleophilic primary/secondary amine or ammonia is added across a C−C multiple bond with cleavage of the N−H bond C


Chemical Reviews

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Scheme 1. Enamines, Imines, and Enamides as Central Building Blocks

selective synthesis of chiral amines, amides, or amino acids, the combination of an addition of N−H nucleophiles to alkynes with an enantioselective hydrogenation of enamines/imines or enamides opens an efficient alternative to the challenging asymmetric addition of N−H nucleophiles to alkenes (see sections 4.1.4 and 4.1.6). Many metal complexes25 as well as organocatalysts26−28 are known to promote the hydrogenation of enamines or enamides. For example, Zhou et al. synthesized crispine A and other tertiary cyclic amines via iridium-catalyzed asymmetric enamine hydrogenations in 97% yield and with 90% enantiomeric excess (ee).29 β-Amino acids are obtained in high yields and ee by the organocatalytic asymmetric hydrogenation of enamines with trichlorosilane as the hydride donor and sigamide as the organocatalyst.30 Rhodium catalysts in combination with chiral phosphine ligands allow synthesizing chiral N-protected amino acids starting from enamides in high ee.31,32 Enamines/imines and enamides are versatile building blocks also for cycloadditions (3 and 4). They can be used as dienophiles in [4+2]-(hetero)cycloadditions (3), and incorporated into highly functionalized heterocycles.33,34 For example, Stevenson et al. described an yttrium-catalyzed Povarov reaction with 3-substituted imines and acyclic enamides.35 In this [4+2]-heterocycloaddition, the tetrahydroquinoline product is formed as a single regio- and diastereoisomer. N-Vinyl oxazolidinones can be used as chiral dienophiles, for example, in Eu(fod)3-catalyzed [4+2]-hetero-Diels−Alder reactions with inverse electron demand. Thus, (2S,4S)-N-2-deoxyglycosyloxazolidinones are accessible in high regio- and stereoselectivities starting from (4S)-dienophiles and β,γ-unsaturated α-ketoesters or vice versa.36 In the presence of Jacobsen’s CrIIIsalen-complex, conjugated enamides react with acroleins in an asymmetric hetero-Diels−Alder reaction to give substituted cyclohexenes in up to 95% yield and 97% ee.37 Terminal enamides are also effective synthons for constructing four-

hydroamination to give a pyrrolo[2,3-f ]indole derivative that was oxidized to the final product.10 Lansiumamide B is present in the leaves and fruits of Clausena lansium, which are used in Chinese medicine for the treatment of asthma and viral hepatitis.11 It has been obtained via the Ru-catalyzed intermolecular hydroamidation of terminal alkynes.12 Imidazo[1,2-a]pyridine is an essential motif in pharmacologically important molecules such as alpidem, which is extensively used to treat anxiety.13 A synthetic sequence involving a copper-catalyzed A3 coupling and in situ intramolecular hydroamination of the propargylaminopyridine intermediate (see Scheme 1) provides a convenient access to this compound.13 In addition to their relevance as part of bioactive naturally occurring products, enamines/imines and enamides are of substantial interest as building blocks (Scheme 1). Enamides are widely used as monomers in polymerization processes (1).14 One economically important building block for such polymerizations is N-vinylpyrrolidone (NVP), which has been produced on a technical scale since 1939 via the addition of 2-pyrrolidone to acetylene under high pressure.14−16 Radical polymerization of NVP allows the synthesis of numerous functional polymers and copolymers,17,18 for example, Kollidon, Luviskol, Sokalan, and Luvitec.19 In 2006, the world market for polyvinylpyrrolidone (PVP) had a capacity of approximately 31 000 tons.20 Some of these polymers/copolymers show remarkable physical properties. For example, they can be tuned to be highly hygroscopic, dispersing, or adhesive with a strong tendency toward film and complex formation. They are also compatible with biological systems, nontoxic, stable within a wide pH range, and soluble in hydrophilic as well as lipophilic systems. Recently, published methods also allow transforming enamides into various cyclic and linear products via lightinitiated radical processes.21−24 Enamines/imines and enamides are also used as starting materials for asymmetric hydrogenations (2). For the stereoD


Chemical Reviews

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Scheme 2. Syntheses of Enamines/Imines and Enamides

substituted enamides in the trans-position. Palladium- or copper-catalyzed C−H functionalizations of enamides, which occur at the vicinal59−61 or geminal positions of nitrogen atom,62,63 lead to functionalized enamides.

membered rings via light-initiated [2+2]-(hetero)cycloadditions (4).38−40 A further reaction mode of enamines and enamides is their addition to electrophiles (5). The chemical bond is usually formed at the vinylogous carbon rather than at the nitrogen atom of the enamine. Enamines are strong nucleophiles due to the electron-donating ability of the nitrogen, which increases the electron density at the C−C double bond. The nucleophilicity of enamides is lower because of the electronwithdrawing effect of the carbonyl group. Imines, in contrast, exhibit electrophilic properties, and nucleophilic attack occurs at the α-carbon. This process is usually catalyzed by acids or Lewis-acidic metals.41,42 Thus, Matsubara et al. described an aza-ene-type copper-catalyzed asymmetric addition of enamides to electrophiles.43−46 The resulting β-amino imines can be hydrolyzed to β-amino ketones or reduced to diamines.44,45 This method can also be applied to the addition of enamides and enecarbamates.43,46 The enantioselective aza-Henry or Mannich-type reaction of imines with silyl nitronates or silyl ethers leads to the formation of N-protected α-amino esters (6).47−49 Imines can also be diversely functionalized via nucleophilic addition reactions, which are promoted by copper, silver, and gold catalysts (see section 6.1). NHC-catalyzed annulations of α,β-unsaturated aldehydes with imines have been used to construct various N-heterocycles with exceptional enantioselectivity.50−54 Enamines have been employed in a related cyclization involving an NHC-catalyzed aza-Claisen step to give dihydropyridinones (7).55 Other reaction modes of enamides are metal-catalyzed crosscouplings (8),56−58 C−H functionalizations (9),59−63 and codimerizations (10),64 as well as Heck reactions with aryl bromides. 65 The cross-coupling of vinyl iodides with arylboronic acids leads to the same products and allows for further substitution at the enamide double bond. The ruthenium-catalyzed codimerization of N-vinyl amides and acrylates or alkynes is a mild method to derivatize non-

1.2. Traditional Syntheses of Enamines/Imines and Enamides

The versatile applications of enamines/imines and enamides described above explain the quantity of effort made toward finding general, stereoselective, and environmentally benign access to these substance classes. An overview on traditional approaches, ranging from condensations (1)66−73 with organocatalyst,74 alkyl- or phenylaluminum dichloride as mediators,75 trimethylsilyl triflate as the catalyst,76 to cross-coupling techniques (2,3),77−88 is given in Scheme 2. The disadvantages of condensations are that usually the thermodynamically favored E-products are formed, whereas the Z-isomers are inaccessible.89−91 In cross-couplings, the stereoselectivity issue is only transferred from the enamide formation to the synthesis of the vinyl halide starting materials. The oxidative amidations of olefins also yield E-configured enamides.92−109 However, in some cases, this stereoselectivity can be reverted in favor of the Z-products.110,111 Wittig reactions of amides or imides and phosphoranes or phosphonates result in the formation of enamines and enamides in good to excellent yields (4).112,113 However, the stereochemical outcome of the reaction is driven by the residues in the starting materials. Z-Enamides can also be synthesized in moderate to good yields from isocyanates or N,N-dialkyl formamides and Grignard reagents (5,6).114−116 Contemporary synthetic entries to enamides also include the Rh-catalyzed arylation of azavinyl carbenes (8),117−121 the hydrogenation of ynamides and allenamides (9),122−124 multicomponent reaction between allenes, nitriles, and carboxylic acids (10),125−127 and the isomerization of N-allylamides (11).128 A limited range of E-enamines can be obtained by E


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the addition of N-alkyl-substituted lithium amides to terminal epoxides (7).129−131 Overall, a wealth of methods is known for the synthesis of enamines/imines and enamides, but still none of them satisfies all requirements of starting material availability, operational simplicity, atom economy, and selectivity.

Scheme 5. Base-Mediated Hydroamidation of Phenylacetylene

1.3. Hydroamination and Hydroamidations: A Historical Overview

The first experimental evidence for a homogeneously catalyzed hydroamination of alkynes was provided by Kozlov in 1936.132 He reported that the addition of aniline to acetylene in the presence of mercury(II) chloride leads to N-[(1E)-ethylidene]aniline (Scheme 3, top). On this basis, Loritsch et al. developed

pressures of up to 1000 bar, a mixture of ethyl, diethyl, and triethyl amines was isolated in up to 66% yield (Scheme 6).

Scheme 3. Mercury-Catalyzed Hydroaminations of Terminal and Internal Alkynes

Scheme 6. Addition of Ammonia to Ethylene

A broad range of useful product classes are accessible by catalytic hydroaminations and hydroamidations (Scheme 7). Imines are obtained when adding primary amines to alkynes, whereas the addition of secondary amines results in the formation of enamines, which may be E- or Z-configured. In the presence of water, these products hydrolyze to the corresponding aldehydes or ketones, respectively (a, b). In contrast, enamides, as obtained when adding amides to alkynes, are hydrolytically stable and widely encountered in the scaffolds of natural products and functional materials,145 and protocols exist for the selective formation of both E- and Z-configured enamides from alkynes (a, b). Especially for the case of terminal alkynes, the regioselectivity for the formation of Markovnikov or anti-Markovnikov products can efficiently be controlled by the catalyst system. The hydroamination of alkenes leads to alkylamines, and alkylamides are formed by hydroamidation (c). The regioselectivities of intermolecular reactions are clearly much harder to control than those of their intramolecular variants (d). Intramolecular hydroaminations and hydroamidations with formation of five- or six-membered rings are catalyzed by numerous metals, and are widely used in the synthesis of N-heterocycles, for example, of indoles (e). The synthetic versatility of this reaction type is further potentiated by the ease of incorporating N−H addition steps into reaction cascades, and a wealth of such tandem or cascade reactions has been reported (see section 6).

a mercury-oxide-catalyzed hydroamination of terminal and internal alkynes with aniline (Scheme 3, bottom).133 The toxicity of mercury was not considered a stumbling block before the 1990s, and a lot of fascinating Hg chemistry was developed in the time frame of 1940−1990.134 However, the use of this toxic metal has become obsolete with the advent of modern transition metal-based catalysts and is therefore not covered in this Review. In 1992, Bergman and Livinghouse reported hydroaminations of alkynes with zirconocene and titanocene catalysts, and Marks with lanthanide catalysts.135−138 This set the stage for the development of various hydroamidation protocols using early transition metal or lanthanide catalysts (Scheme 4).139−142 Already in 1939, Reppe et al. showed that various N-vinyl compounds are accessible by adding amides and related N−H nucleophiles to acetylene in the presence of strong bases.15 This initially noncatalytic hydroamidation was later found to be enhanced by the presence of copper acetylides.16 In 1969, Möhrle et al. discovered that the sodium salts of cyclic lactams, methylacetamide, and acetanilide can also be added to phenylacetylene to give Z-configured enamides (Scheme 5).143 The first addition of amines to alkenes was reported in 1954.144 Howk and co-workers found that ammonia adds to ethylene in the presence of metallic sodium or lithium, or of the corresponding alkali metal hydrides. At 200 °C and under

1.4. Potentials and Challenges in Metal-Catalyzed Hydroaminations and Hydroamidations

The addition of N-nucleophiles across C−C double or triple bonds holds great potential as an efficient and safe way of

Scheme 4. Catalytic Methods for the Hydroamination of Alkenes and Alkynes

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Scheme 7. Products Accessible via Hydroaminations and Hydroamidations

those across C−C double bonds. This can be explained by the formation of substantially weaker π-bonds between most catalysts and alkynes as compared to alkenes. The intermediate strength of the interaction between the alkyne and the catalyst allows activating the C−C triple bond toward nucleophilic attack without inhibiting the reaction by a strong πcoordination to the metal center. Furthermore, alkynes are sterically less hindered toward attack of the nucleophile. The efficient and selective addition of amines and amides to alkenes remains a major challenge, but substantial advances have been made in recent years. 1.4.2. Selectivity. Besides achieving high catalytic activity, it is also necessary to control the chemo-, regio-, and stereoselectivity of this transformation to make it preparatively useful (Figure 2).

synthesizing enamines, imines, and enamides. In comparison to the traditional methods discussed in the last section, hydroamination and -amidation reactions have the inherent benefit of optimal atom economy, are based on readily available and inexpensive starting materials, and do not require stoichiometric amounts of coupling or dehydrating reagents. However, control of their chemo-, regio-, and stereoselectivity is essential to establish them as “green” alternatives to the known methodologies.146 As detailed below, the development of catalyst systems for achieving highly selective, efficient, and environmentally benign addition processes encounters many challenges. 1.4.1. Thermodynamic and Kinetic Issues. The addition of a nucleophile such as an amine across a C−C multiple bond is slightly exothermic or approximately thermoneutral.147,148 However, it is kinetically difficult, because the high electron density of the nucleophile and the π-electrons of the multiple bond repel each other. Therefore, a high activation barrier needs to be overcome to ensure that conversion will occur. Moreover, the high temperatures required to cross this barrier induce a shift of the equilibrium toward the starting materials because of the negative entropy associated with this reaction type.148−150 Noncatalytic hydroaminations and -amidations involve either strong acids that protonate the C−C multiple bond, thus facilitating attack by the N-nucleophile,151−153 or strong bases to deprotonate the N-nucleophile to generate strongly nucleophilic metal amides, which can add to the C−C multiple bond more easily.154−158 Metal catalysts can mimic the action of the proton in coordinating to the C−C multiple bond, thereby reducing its electron density and, thus, enabling C−N bond formation. Alternatively, they can replace the nitrogenbound proton and thus allow insertion of C−C multiple bonds. Despite the fact that alkynes have more π-electrons than alkenes, which could be expected to increase the electrostatic repulsion of the nucleophile, metal-catalyzed addition reactions across C−C triple bonds are much easier to accomplish than

Figure 2. Chemo-, regio-, and stereocontrol in addition reactions.

For a start, the chemoselectivity is not easy to control. Good functional group tolerance is the key to the broad applicability of a new method, and the presence of functional groups opens opportunities for further derivatization. Without a catalyst, N− H nucleophiles have a more profound tendency to react with electrophilic centers, for example, carbonyl groups, than with C−C multiple bonds. To ensure that hydroamination will occur, a selective hydroamination catalyst needs to preferentially coordinate to N−H nucleophiles and/or C−C multiple bonds and must not react with other functionalities. Late transition metals such as ruthenium and palladium tend to score better in terms of functional group tolerance than most G


Chemical Reviews

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Scheme 8. M-Catalyzed Hydroamination and Hydroamidation of Alkene, Allene, and Alkyne

initiating steps: (a) activation of the C−C multiple bond by πcoordination of a Lewis-acidic metal complex, followed by nucleophilic addition of the N-nucleophile; (b) initial formation of a metal−nitrogen bond, followed by insertion of the alkene/ alkyne into the M−N bond; (c) initial formation of a metal− hydride, and migratory insertion of the alkene/alkyne into the M−H bond; and (d) rearrangement of initially formed η2alkyne−metal species into vinylidene complexes, which are then attacked by the N-nucleophile. Pathway (a) is the most common. A Lewis-acidic catalyst metal activates the C−C multiple bond by withdrawing electron density, via η2-coordination of C−C multiple bonds to form the intermediate A1 or A1′. Cationic metal complexes bearing electron-poor ligands show particularly high activity. Usually, the attack of the nucleophile occurs from outside the coordination sphere of the metal, so that the metal and amine/ amide are in anti-configuration (Scheme 8, eq a). Theoretical studies revealed that the slippage from η2- to η1-coordination is crucial for nucleophilic addition, as it lowers the lowest unoccupied molecular orbital (LUMO) in energy and localizes it on the β-carbon of the η1-coordinated alkene.161,162 The hydroamination or -amidation product is liberated from intermediate A2 or A2′ by direct protonolysis or protonation at the central metal followed by reductive elimination. Both of these terminating steps usually occur with retention of the configuration, so that, overall, the addition of the N−H group proceeds with anti-selectivity. The substrates most likely to enter this pathway are electron-deficient alkenes/alkynes (i.e., terminal alkenes/alkynes, diynes, or propiolic acid derivatives) in combination with electron-rich N-nucleophiles, such as amines and N−H heterocycles. This pathway may also come to play with electron-poor N-nucleophiles including amides, sulfonamides, carbamates, lactams, or ureas in combination with various classes of alkenes including ethylene, aliphatic alkenes, styrenes, and internal alkenes, as well as allenes. Another commonly encountered mechanism is pathway (b), in which the metal catalyst first activates the N-nucleophile either by ligand exchange (typically basic amine substrates) or by oxidative addition of a low-valent transition metal to the N− H bond (usually less basic amine or amide substrates) (Scheme 8, eq b). The C−N bond is then formed by migratory insertion of the alkene/alkyne or allene into the M−N bond.163 Although alkenes are intuitively proposed by most authors to insert into M−C or M−H rather than M−N bonds, there is a growing body of evidence that especially Rh, Ir, Pt, Pd complexes can also insert coordinated alkenes into M−N bonds.164 A free

early transition metals, and the conditions employed are usually milder. However, even if the catalyst is able to selectively activate C−C multiple bonds, these transformations are often associated with several competing reactions. For example, most hydroamination catalysts also promote oligomerizations of olefins and alkynes.159 State-of-the-art catalysts favor hydroaminations over alkene/alkyne oligomerization reactions, but the related oligomerization products are often detected. Thus, hydroamination yields are mostly calculated on the basis of the N−H nucleophile, because the alkene/alkyne is added in excess. The second issue to be addressed is regioselectivity. This is particularly challenging for internal olefins or alkynes with similar substituents on both sides. For terminal alkynes, efficient strategies have been developed, particularly for terminal C−C multiple bonds, to selectively produce either Markovnikov or anti-Markovnikov addition products. For internal C−C multiple bonds, the regioselectivity can be influenced by introducing strongly electron-withdrawing or extremely bulky substituents on one side of the multiple bond.160 In intramolecular hydroaminations, the regioselectivity is mostly controlled by the preferential formation of five- or sixmembered rings. In catalytic reaction, the preferred regioselectivity strongly depends on the catalytic pathway. The third challenge in addition reactions is the control of their stereochemical outcome. Depending on whether the attack of the nucleophile occurs from the top or bottom of the C−C double or triple bond, different enantiomers/diastereomers are formed (see Figure 2). The stereochemical outcome of the reaction is influenced by factors related both to the substrate (acidity of the N−H bond, electronic properties of the C−C multiple bond, and steric bulk of the reaction partners) and to the catalyst (electronic and steric properties of the transition metal complex). One strategy to develop stereoselective hydroaminations is to design the ligand environment to efficiently block an attack to the C−C multiple bond from one side, so that the N−H addition can only occur from another. 1.4.3. Strategies To Control Reactivity and Selectivity. The addition of amines, amides, or other N−H nucleophiles across C−C multiple bonds can follow various mechanisms, and the efficiency and selectivity depend on the catalytic pathway at play (Scheme 8). The substrate combination, the catalyst system, and the conditions together determine which mechanism is most favorable. Catalytic N−H pathways can roughly be divided into four categories depending on their H


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Scheme 9. Oxidative Amination and Amidation versus Hydroamination of Alkenes

from a hydroamination or -amidation of alkenes (Scheme 9). This pathway is favored for metal catalysts with a preference for β-hydride elimination, such as palladium. With this metal, a wealth of oxidative aminations and amidations have been described,94−100 but only few redox-neutral additions of N−H nucleophiles. Another side reaction that results from the competition between β-hydride elimination and protonolysis/ reductive elimination is the conversion of alkynes to allenes. If an alkyne is converted first into the corresponding allene, the following hydroamination step will lead to the formation of allylic amines in place of the expected enamines/imines or enamides.167−171 Four strategies have been employed to suppress competing β-hydride elimination in hydroamination/-amidation processes. The first consists of using a metal with a lower tendency for βhydride elimination. Thus, platinum often effectively promotes the intermolecular hydroamidation of alkenes, when palladium catalysts exclusively give oxidative amination products.172,173 The second involves adding an excess of coordinating anions or bi- or tridentate ligands to block all coordination sites of the transition metal center and, thus, preclude metal−β-hydride interactions.174−176 Excess bulky ligands also accelerate the reductive elimination of the hydroamidation product from intermediate E before β-hydride elimination with formation of the oxidative amination products can occur. Alternatively, an acidic cocatalyst or additive can be added to facilitate the liberation of the hydroamination products via a protonolysis of intermediates E.

coordination site is necessary for C−C multiple bond coordination to metal−amido complexes. In contrast to pathway (a), this reaction type demands at least two coordination sites on the metal center, one for nitrogen nucleophile and one for C−C multiple bond. In the resulting intermediate B2 or B2′, the metal and amine/amide are in synconfiguration. Liberation of the product via protolysis again occurs with retention, so that, overall, the syn-addition products are obtained. Migratory insertions are often sensitive to steric hindrance, so that the metal is inclined to go to the less sterically hindered position. Thus, this pathway, which has been described mostly for the reaction of anilines and amides with alkenes, allenes, and alkynes, will also preferentially lead to the formation of Markovnikov products. Only with one Rh-catalyst has it been reported to give anti-Markovnikov products (see Scheme 33).165 Pathway (c) is complementary to (b) in that it involves a migratory insertion of the alkene/alkyne into an M−H rather than an M−N bond. The M−H bond is formed by oxidative addition either of a carboxylic acid additive or of an acidic N−H nucleophile, such as an amide or aromatic amine, to the metal center. This reaction mode has been described, for example, for low-valent Rh, Ir, Ru, or Pd complexes. Other methods for the generation of M−H species include the dehydrogenation of alcohols, and hydride transfer from silanes, for example, to Cu, Fe, or Co catalysts. Migratory insertion of the alkene, alkyne, or allene into the M−H bond to give intermediates C2 or C2′ is again influenced by steric factors that will usually direct the metal to the less hindered carbon atom. The subsequent reductive elimination process, in which the C−N bond forms, will thus give rise to the anti-Markovnikov product (Scheme 8, eq c). Pathway (d) has been described for ruthenium-catalyzed hydroamidations of alkynes. It also starts with the formation of an M−H species D1 followed by insertion of the alkyne, which leads to a vinyl−metal species D2. Such intermediates rearrange to the corresponding vinylidene complexes, which are susceptible to attack by the N-nucleophile in the α-C position (Scheme 8, eq d).166 This pathway usually leads to the exclusive formation of Markovnikov products with high selectivity for the syn-enamides. However, the right choice of ligands allows inverting the stereoselectivity of the process in favor of the antiMarkovnikov products. The addition of N-nucleophiles to alkenes affords alkyl− metal species, which are prone to β-hydride elimination. Such oxidative processes lead to enamine/imine or enamide products rather than the saturated amines and amides that would result

1.5. Catalyst Metals Used in Hydroaminations and Hydroamidations

Over the years, numerous metals have been found to promote the addition of N−H nucleophiles across C−C multiple bonds. Because of their inherent set of properties, the application range of the various metals is diverse and often complementary. The appeal of a catalyst system is not only determined by its performance, but also by its availability and cost, its functional group tolerance, and, last but not least, its toxicity. Thus, despite their excellent stability, activity, and carbophilicity, research on Hg and Tl-based systems has almost been abandoned because of their toxicity. Catalysts based on early transition metals, for example, Ti or Zr, or on lanthanides/ actinides display high activity in various additions of amines across C−C multiple bonds.177−180 They have widely been employed as catalysts for the hydroamination of symmetrically and unsymmetrically substituted internal and terminal alkynes/ alkenes with alkyl or aryl amines. However, their high oxophilicity renders such catalyst systems susceptible to air I


a

J

intermol.

intramol.

intermol.

intramol.

intermol.

intramol.

intermol.

intramol.

reaction type

secondary aliphatic amines, anilines, N−H heterocycles amides, sulfonamides, ureas, imidates, lactams, carbamates secondary aliphatic amines amides, ureas, sulfonamides, carbamates secondary aliphatic amines, primary anilines amides, lactams, ureas, carbamates, sulfonamides, imides

Markovnikov: Rh(cod)2BF4/DPEphos;b,c,204 anti-Markovnikov: Rh(cod)2BF4/DPEphosb,c,205 Markovnikov: AuCl/L5/AgSbF6,b,c,206 [Ir(coe)2Cl]2/L8a,c,207 Pd(OAc)2b,d,208 (AuCl)2/L9/AgBF4b,c,e,209 RhCl/L10/AgBF4a,201 [Pd(π-cinnamyl)Cl]2/dppp,b,c,211 CuI/1,10-phenb,d,212

Markovnikov: Pd(BF4)2/L7b,c,174

amides, carbamates, ureas, hydrazines

primary aliphatic amines, secondary anilines amides, (thio)carbamates, sulfonamides, amidines, phosphonamides, (thio)ureas, lactams, guanidines ammonia, secondary aliphatic amines, anilines, N−H heterocycles amides, lactams, imides, ureas, thioamides, carbamates

aliphatic amines, primary anilines, N−H heterocycles amides, carbamates, lactams, sulfonamides, ureas, sulfamidate secondary aliphatic amines, anilines, N−H heterocycles primary carbamates, sulfonamides, 2-pyridone amines, ammonium salts

selected catalyst systems five- to six-membered rings: [Rh(cod)Cl]2/L1a,181 five- to six-membered rings: AuSbF6/L2,b,182 AuCl(PPh3)/AgNTf2;a,183 larger rings: IPrAuCl/ AgOTs,b,184 PtCl2a,185 internal alkynes: AuCl/L3/AgB(C6F5)4;b,d,186 terminal alkynes; Markovnikov, AuCl/L4/ AgOTf,a,c,187 anti-Markovnikov, RuClPPh3(dppe)(MeCN)BPh3a,c,188 internal alkynes: AgNTf2;b,d,189 terminal alkynes: (E) anti-Markovnikov, [(cod)Ru(met)2]/ PnBu3;b,c,190 (Z) anti-Markovnikov, [(cod)Ru(met)2]/dcypma,c,191 five- to six-membered rings: AuCl/imidazole;a,d,192 larger rings: IPrAuCl/AgOTfa,d,193 five- to six-membered rings: AuOPNB/xylylBINAP,e,194 AuCl/L2/AgOTfb,195 branched: [Rh(cod)Cl]2/DPEphosb,196 or Josiphos;a,e,197 linear: [Pd(η3-ally)Cl]2/dppfb,c,198 branched: [Rh(cod)Cl]2/L5;b,c,e,199 linear: (AuCl)2/L5a,d,e,200,201 Markovnikov: Rh(cod)2BF4/L6;b,c,e,202 anti-Markovnikov: [Rh(cod)DPPB]BF4b,c,203

N-nucleophile

Pd0, AgI, AuI FeIII, Pd0,II, AgI, AuI,III RhI, Pd0,II, AgI, PtII, AuI,III Pd0,II, AuI FeII, ZnII, RhI, PdII, IrII, PtII, AuI FeII, CuI,II, RuI, RhI, PdII, PtII, AuI RuI,II, RhI,III, PdII, IrI, PtII Pd0,II, IrI, PtII, AuI CuII, PdII FeIII, CuII, Pd0,II, Ag, AuI Ni0, CuI,II, RhI, PdII, AuI CuI,II, PdII, AuI

CuI, RhI, PdII, AgI, IrI, AuI,III CuI, RuI,II, RhI,II, PdII, AgI, PtII, AuI,III NiII, CuI, Ru0,II,III, RhI,III, Pd0,II, IrI, PtII, AgI, AuI Re0, Ru0,II, PdII, AgI

commonly used catalyst metals

Recommended for primary N-nucleophiles. bRecommended for secondary N-nucleophiles. cOnly terminal C−C multiple bonds. dOnly internal C−C multiple bonds. eWith asymmetric induction.

conjug. multiple bonds

alkenes

allenes

alkynes

substrates

Table 1. Selected Catalysts and Commonly Used Catalyst Metals in Hydroaminations/Hydroamidations

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Scheme 10. Reaction Pathways and Product Classes Covered in This Review

promote the asymmetric intermolecular hydroamination of alkenes with heteroaromatic amines.223 Pd complexes are widely used to catalyze intramolecular hydroaminations and -amidations of alkynes. As an example, intramolecular hydroaminations of aminoalkynes represent an advantageous strategy to obtain indoles.224 In combination with chiral phosphine ligands, high enantioselectivities were reached in intermolecular hydroaminations of alkenes, 1,3-dienes, and allenes.225 Palladium is the catalyst metal of choice for C−Ccoupling/intramolecular hydroamination cascades. The strong tendency of alkyl−palladium intermediates to undergo βhydride eliminations hampers its use in intermolecular hydroaminations of alkenes, but opens a wealth of opportunities for oxidative amination processes. Pt complexes have a low tendency toward β-hydride eliminations. As a consequence, they efficiently promote intra- and intermolecular hydroaminations and -amidations not only of alkynes and allenes, but also of alkenes (see sections 4.4.2 and 4.4.5).172,173,226,227 Ru catalysts promote the addition of various nucleophiles such as water, carboxylic acids, and thiols across C−C double and triple bonds.228−236 They are particularly active catalysts for the addition of N−H nucleophiles specifically to terminal alkynes via highly regio- and stereoselective pathways involving vinylidene intermediates (see section 2.4.1). Ru catalysts also show high activity in asymmetric intermolecular hydroaminations of alkenes (Scheme 181).237 Re catalysts have recently been reported to promote some hydroamidations of terminal alkynes that are usually catalyzed by Ru systems.238,239 The use of inexpensive transition metals such as Fe, Co, Ni, and Cu in hydroamination and amidation reactions is still in its infancy. Iron has been employed to catalyze intramolecular hydroamidations of allenes and alkynes, and intermolecular hydroamidations of activated alkenes. Cobalt exhibits excellent activity in C−N bond-forming reactions of hydrazines and azides (see section 4.5). Nickel complexes have been shown to promote intermolecular hydroaminations of alkynes, 1,3-dienes, and some activated alkenes with aliphatic amines, albeit at high catalyst loadings and elevated temperatures.240−242 Copper catalysts have been used for intramolecular hydroaminations and -amidations of C−C multiple bonds. In addition, CuI shows excellent activity in the anti-Markovnikov hydro-

and moisture, and raises challenges related to functional group tolerance. Moreover, early transition metals usually do not promote the addition of amides to any type of C−C multiple bond. Because of their lower reactivity toward oxygen-containing functional groups, the use of late transition metal catalysts is desirable in particular for the late-stage functionalization of complex molecules, and many new systems have been disclosed within the past decade. Many different catalysts were developed for specific applications, so that it is not easy to predict which of them will be ideal for a given substrate combination. Table 1 can thus only serve as a rough guideline for catalyst selection. For an in-depth discussion of each catalyst system, see the corresponding section of this Review as well as the primary literature. Au213,214 and Ag complexes215,216 have intensely been studied for the hydroamidation of alkenes, allenes, and alkynes, and have been found also to promote inter- and intramolecular hydroaminations of alkynes and allenes. Gold catalysts have been reported to give extremely high turnover numbers (TON) of up to 95 000.217 Gold is a particularly efficient catalyst metal also for asymmetric addition reactions, for example, intermolecular hydroaminations and -amidations of alkenes, and hydroamidations of 1,3-dienes and allenes. Silver salts with noncoordinating anions are used to abstract halide ions from the gold catalyst and thereby to enhance its Lewis acidity. As a consequence, gold and silver catalysts are often used in combination with each other. Rh complexes show excellent activity in intermolecular hydroaminations of alkynes and alkenes, and their selectivity is high for the anti-Markovnikov addition products (see Table 2).165,205,218−220 Rhodium tolerates a particularly wide range of functional groups. In combination with chiral 2-dialkylphosphino-2′-alkoxy-1,1′-binaphthyl ligands, this metal allows efficiently synthesizing various chiral amines via asymmetric cyclizations of N−H functionalized alkenes.202 Ir complexes are similarly active in intra- and intermolecular hydroaminations of terminal alkynes and alkenes with anilines and heteroaromatic amines, and generally lead to Markovnikov products.221 Iridium complexes also catalyze intermolecular Markovnikov hydroamidations of nonactivated alkenes.207,222 Moreover, chiral Ir complexes have been found to efficiently K


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amination of aliphatic terminal alkenes with electrophilic nitrogen sources and hydride reagents (see Scheme 235).243 A related approach has been utilized also in Markovnikovselective, enantioselective hydroaminations of vinyl arenes and oxa- and azabicyclic alkenes (see Scheme 240).244,245

Scheme 12. Cope-Type Hydroamination

1.6. Scope and Structure of This Review

This Review examines recent developments in the field of hydroamination and -amidation reactions, that is, the addition of amines, amides, and related N-nucleophiles across C−C double or triple bonds. Müller et al. have previously reviewed homogeneously and heterogeneously catalyzed hydroaminations of alkenes and alkynes in 1998 and 2008 in this journal.147,246 Their focus was set on hydroamination protocols involving rare earths, early transition metals, and palladium catalysts along with Brønsted acid and base catalysts. Since then, the field of addition reactions of N-nucleophiles has become so vast that it is no longer possible to cover it comprehensively within a single review. This Review therefore exclusively studies late transition metal-catalyzed hydroaminations and hydroamidations, which are only briefly mentioned in the preceding Chemical Reviews articles, but have undergone a tremendous development within the past decade. Scheme 10 provides a structured overview of the scope of this Review. More than 400 publications on late transition metal-catalyzed addition reactions of N-nucleophiles have appeared since the 2008 review, which underlines the topicality of this field. This Review aims at comprehensively covering late transition metal-catalyzed addition reactions of N-nucleophiles to C−C multiple bonds that were disclosed after the 2008 review. Older literature is included only if it still represents the state-of-the-art in a given field. The material is structured according to the combination of N-nucleophile and C−C multiple bond classes, so that synthetic organic chemists in particular may easily navigate this Review. One substrate combination was omitted, the addition of N−H nucleophiles to Michael acceptors (Scheme 11). Formally, such reactions, which are catalyzed

respective section, and reference is given to complementary or preceding review articles, including those presented below. Doye et al. have reviewed the transition metal-catalyzed intermolecular hydroamination chemistry of alkynes, with a particular focus on titanium, up to the end of 2006.148,149 In 2013, hydroamidations catalyzed by group III−V metals, lanthanides and actinides, as well as main group metals were reviewed by Reznichenko and Hultzsch.275 These authors also briefly discuss some progress made in late transition metalcatalyzed hydroamination reactions. Alonso et al. have reviewed early and late transition metal-catalyzed hydroamination reactions of alkynes until 2004, with a focus on palladiumbased methods.276 A short review by Yamamoto covers late transition metal-catalyzed hydroaminations (but not hydroamidations) up to 2010, and is structured according to the reaction modes involved.277 Moreover, some more general reviews exist on hydrofunctionalizations of C−C multiple bonds, including the addition of N−H, O−H, S−H, P−H, and C−H nucleophiles.213,278,279

2. CATALYTIC ADDITION OF NITROGEN NUCLEOPHILES TO UNCONJUGATED ALKYNES 2.1. Ammonia

Ammonia is a particularly cheap and abundant nitrogen source, and its use in atom-economic processes for C−N bond formation is of considerable importance.280,281 It is a challenging substrate in hydroamination reactions because of its moderate nucleophilicity and strongly coordinating properties. Bond dissociation energy (BDE) calculations by Lledós and Ujaque confirmed that ammonia forms unusually strong complexes with the metal center.282 The noncatalyzed addition of ammonia to short-chain alkynes and olefins is known to proceed only under very basic, rather forcing conditions,144,283−285 that is, stoichiometric amounts of alkali metals and up to 100 bar NH3.154 2.1.1. Intermolecular Hydroamination of Terminal Alkynes. The only example of a late transition metal-catalyzed hydroamination was reported by Bertrand et al., who found that cationic AuI complexes with cyclic (alkyl)(amino)carbene ligands promote the addition of ammonia to alkynes to give the Markovnikov products. Starting from diynes, double hydroamination with ammonia using the same catalyst provides access to pyrroles (Scheme 13).286 This cationic gold complex can also fulfill the addition of ammonia to both terminal and internal allenes. Mechanistic investigations revealed that the reaction proceeds via an intermediate in which both the NH3 and the alkyne are bound to the Lewis-acidic gold complex, rather than via coordination of the alkyne and intermolecular attack of NH3 to the C−C triple bond. In view of the importance of ammonia as a feedstock for the production of nitrogen-containing molecules, continuation of this pioneering work would be of substantial interest.

Scheme 11. TM-Catalyzed Intermolecular Hydroaminations and Hydroamidations of Activated Alkenes

by various transition metals such as Pd,247−254 Cu,255−258 Ni,259−265 and Pt complexes,266 as well as heterobimetallic systems, 267 could be classified as hydroaminations or -amidations. However, we believe that they are more similar in essence to classical Michael reactions than to the additions of N-nucleophiles to nonactivated alkynes, allenes, and alkenes covered in this Review.268−272 C−N bond-forming reactions via Cope cycloadditionscycloreversions are versatile tools for constructing C−N and C−H bonds starting from alkynes, alkenes, or allenes and hydroxylamine or hydrazine derivatives. They proceed via a five-membered cyclic transition state (Scheme 12).273 The Cope-type hydroamination, a metal-free process, has been discussed in recent reviews.274 Neither reaction type is covered within this Review. At the beginning of each section, the state-of-the-art is briefly summarized for the specific C−N bond-forming reaction using catalysts other than those comprehensively discussed in the L


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Lau and co-workers reported that the regioselectivity of the hydroamination of terminal alkynes can be inverted in favor of the Markovnikov product by using a hydro(trispyrazolyl)borato-ruthenium(II) diphosphinoamino catalyst. This Ru complex allows synthesizing various E-configured tertiary enamines in moderate to good yields (Scheme 15).305 In

Scheme 13. Cationic Gold-Catalyzed Hydroamination of Alkynes with NH3

Scheme 15. Ru-Catalyzed anti-Markovnikov-Selective Addition of Secondary Amines to Terminal Alkynes 2.2. Aliphatic Amines

2.2.1. Intermolecular Hydroamination of Terminal Alkynes. Aliphatic amines are more nucleophilic than ammonia, and their catalytic addition to multiple bonds is more easily accomplished. However, in late transition metalcatalyzed hydroaminations of alkynes, they are less reactive than aromatic amines. This can be explained by their stronger coordination to the catalyst, which slows the catalytic turnover. Thus, many catalysts that are highly efficient for the intermolecular Markovnikov hydroamination of alkynes with anilines (section 2.3) are unable to promote the transformation of aliphatic amines. A uranium complex was the first metal catalyst reported to promote the anti-Markovnikov hydroamination of terminal alkynes with primary amines.287,288 After that, the intermolecular hydroamination of alkynes was dominated by early transition metal catalysts for a long time.289−293 As documented in preceding review articles, various complexes of Ti and Zr294−298 as well as of lanthanides and actinides299 efficiently promote the intermolecular hydroamination of alkynes with aliphatic amines at temperature between 60 and 100 °C. For example, bis(amidate)bis(amido)titanium complexes catalyze various intermolecular anti-Markovnikov hydroaminations of alkynes with aliphatic amines at 65 °C with up to 98% yield and >49:1 regioselectivity even on multigram scales.300,301 However, early transition metal catalysts are inactive in hydroaminations with secondary amines, because the intermediate formation of imido-metal species is crucial for catalytic turnover. In 2007, Fukumoto et al. reported a RhI-catalyzed antiMarkovnikov addition of both primary and secondary amines to terminal aliphatic alkynes as the first late transition metalcatalyzed hydroamination of aliphatic amines. The use of both trispyrazolylborate and phosphine ligands is essential to suppress undesired alkyne dimerization and to promote the formation of E-enamines (Scheme 14).302 By using a catalyst

analogy to Fukumoto’s rhodium-catalyzed hydroamination of terminal alkynes (see Scheme 14), the reaction was proposed to proceed via nucleophilic addition of the N−H nucleophile to a Ru-vinylidene intermediate. It is interesting that with the same catalyst, the analogous addition of β-diketones to 1-alkynes proceeds with Markovnikov selectivity. In 2013, Astruc et al. reported that both primary and secondary amines react with ethynylcobalticinium to give the corresponding cobalticinium trans-enamines in quantitative yields (Scheme 16).306 It is not entirely clear if the cobalt complex acts only as a substrate or also as a catalyst in this antiMarkovnikov hydroamination. Scheme 16. anti-Markovnikov Hydroamination of Ethynylcobalticinium

2.2.2. Intermolecular Hydroamination of Internal Alkynes. One of the obvious challenges of the intermolecular hydroamination of internal alkynes is achieving satisfactory regioselectivity. One way to address this is to employ alkynes containing an electron-withdrawing group, which will force the amine to attack the less electron-rich side of the π-system. However, it is difficult to differentiate such processes from traditional Michael additions, which are not covered in this Review. For example, 5 mol % of CuCl effectively promotes the addition of amines to alkynylphosphonates (Scheme 17),307 whereas the base-mediated addition of amines to alkynylphosphonates usually gives a mixture of Z- and Eisomers.308−310 E-2-(Dialkylamino)alkenyl phosphonates are formed in high selectivities in the presence of this Cu-catalyst.

Scheme 14. RhI-Catalyzed anti-Markovnikov Hydroamination of Terminal Alkynes

Scheme 17. Cu-Catalyzed Intermolecular Hydroamination of Alkynylphosphonates

generated in situ from an 8-quinolinolato rhodium complex and P(p-MeOC6H4)3, the anti-Markovnikov addition of secondary amines to aryl- and heteroaryl acetylenes was achieved in reasonable yields already at room temperature.303,304 The reaction proceeds via the vinylidene mechanism depicted in Scheme 8, eq d, which explains why it is strictly limited to terminal alkynes. M


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Scheme 18. AuI-Catalyzed Regioselective Intermolecular Hydroamination of Internal Alkynes

TONs of up to 9.6 × 104.181 A drawback common to these systems is that they are generally suitable only to make five- or six-membered N-heterocycles. The construction of sevenmembered rings remains challenging; that of four- and eightmembered rings has yet to be accomplished.312 The late transition metal-catalyzed cyclization of 6-aminohex1-yne to 6-methyl-2,3,4,5-tetrahydropyridine was systematically investigated by Müller et al. (Scheme 20).313,314 [Cu-

The regioselective addition of amines to nonactivated internal alkynes is much harder to accomplish. In 2009, the Bertrand group utilized their cationic AuI complexes with cyclic (alkyl)(amino)carbene ligands to achieve the hydroamination of terminal/internal alkynes with secondary amines in good yield and moderate regioselectivity.311 Later, the addition of a narrow range of dialkylamines to unsymmetrical internal alkynes with reasonable yields and selectivities was developed by Stradiotto et al. using a cationic AuI complex with a bulky P,N-ligand (Scheme 18).186 The C−N bond is formed preferentially at the carbon bearing the aryl substituent, with the exception of 2-alkynylpyridines, which react as Michael-type substrates. The reaction is believed to proceed via the coordination of the alkyne to an Au-amine adduct, followed by the formation of a vinyl-Au intermediate via proton transfer and alkyne insertion. The E-configured enamine is liberated stereoselectively via protodeauration. Garciá et al. reported that 0.5 mol % of (dippe)Ni(μ-H) promotes the hydroamination of diphenylacetylene with pyrrolidine at 180 °C.240 The use of NiII complexes with triphenyl phosphite ligands allowed decreasing the reaction temperature to 140 °C and extending the scope to alkyl aryl alkynes (Scheme 19).241 The yields and regioselectivities

Scheme 20. Cyclization of 5-Hexyn-1-amine with Group 8− 12 Transition Metal Catalysts

(CH3CN)4]PF6, as well as several group 12 metal salts, exhibited the highest catalytic activity. Yan et al. subsequently reported a Re(CO)5(H2O)BF4-catalyzed version of this cyclization.315 In this reaction type, a free coordination site on the transition metal center is crucial for success. One extensively used strategy to form the active catalysts in situ is to abstract an anionic ligand from neutral metal complexes using silver salts or NaBPh4. Catalyst activation is also possible by dissociation of a labile ligand from the transition metal. Messerle et al. reported a series of RhI- and IrI-catalyzed intramolecular hydroaminations of terminal alkynes (Scheme 21).316−324 Thus, cationic RhI and IrI complexes with bidentate N,P-, N,N-, or N-carbenes were shown to be efficient catalysts for the hydroamination of 4pentyn-1-amine. The same cyclization was also efficiently catalyzed with Ag complexes stabilized by bidentate ligands, such as 1-(2-(diphenylphosphino)ethyl)pyrazole.325 A bifunctional hydroxyl-aminoalkyne chemoselectively undergoes hydroamination in the presence of an NHC−CuI catalyst (Scheme 22).326 In contrast, the related hydroalkoxylation of the same substrates was promoted by a lanthanum complex.327 Silver catalyzes 5-endo-dig hydroaminations leading to 4,5dihydroisoxazoles,328 isoquinoline,329 and 1-pyrroline derivatives,330 whereas the formation of pyrroles was observed via a 5exo-dig cyclization.331 Thus, Helquist et al. reported an efficient silver-catalyzed desymmetrization of aminodiynes via hydroamination (Scheme 23).332 A variety of functionalized 1pyrroline derivatives were synthesized in 73−88% isolated yields under mild conditions. Ru-, Ir-, and Rh-complexes have also been used for 5-endo-dig hydroaminations of internal alkynes with primary amines to form 1-pyrroline derivatives.320,333,334

Scheme 19. Ni-Catalyzed Intermolecular Hydroamination of Alkynes

remain moderate, and a vast excess of the N-nucleophile is required to ensure that the reaction proceeds effectively. However, this reaction demonstrates that, in principle, inexpensive Ni can be used as the catalyst metal in such difficult hydroaminations. 2.2.3. Intramolecular Hydroamination of Alkynes. Intramolecular processes are easier to accomplish because of the close spatial proximity of the amine and C−C triple bond. Reviews on the hydroamination of alkynes provide good coverage of early work in this area.148,149 Various metals have been used to promote such reactions, including early and late transition metals and rare earths. State-of-the-art catalysts consist of RhI complexes bearing N,N- and N,P-ligands, which catalyze the intramolecular hydroamination of alkynes with N


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Scheme 21. RhI/IrI-Catalyzed Hydroamination of 4-Pentyn-1-amine

Scheme 22. Cu-Catalyzed Chemoselective Intramolecular Hydroamination of Terminal Alkynes

Scheme 25. Au-Catalyzed Intramolecular 6-endo-dig Cyclization of Internal Alkynes

Scheme 23. Ag-Catalyzed Intramolecular 5-exo-dig Hydroamination of Internal Alkynes complex exhibits better activity than the simple AuCl3 or NaAuCl4 salts toward the hydroamination of 4-pentyn-1-amine or 5-hexyn-1-amine under air at room temperature (Scheme 26).339,340 Scheme 26. Dimer-TM-Catalyzed Intramolecular Hydroamination of Terminal Alkynes

In 1987, Utimoto et al. reported an intramolecular hydroamination of alkynes catalyzed by NaAuCl4 in refluxing THF or MeCN (Scheme 24).335,336 Cationic Au(PPh3)SbF6 was also employed to construct cyclic spiroimines by intramolecular hydroamination of alkynes.337 Scheme 24. Au-Catalyzed 6-exo-dig Hydroamination of Alkynes

Transition metals on solid supports have also been employed as hydroamination catalysts. For example, Alper et al. reported in 2001 that silica-supported cis-[PdMe(Cl)(PMe3)2] catalyzes the hydroamination of 5-hexyn-1-amine with 85% conversion at 1.2 mol % loading.341 Messerle’s group used RhI complexes with N,N- or N,P-ligands anchored to glassy carbon electrodes to heterogeneously catalyze the hydroamination of 4-pentyn-1amine with high TONs (up to 96 000), which are orders of magnitude greater than those of their homogeneous counterparts.342

A convenient route for the synthesis of various charged tetracyclic isoquinolizinium hexafluoroantimonates was developed using AgSbF6/AuCl(PPh3) for the intramolecular addition of amine to alkyne (Scheme 25).338 However, stoichiometric amounts of silver were needed for generating the oxidative cyclization product. Dinuclear transition metal complexes are also efficient catalysts for the intramolecular hydroamination of terminal alkynes. Thus, the combination of a Pd dimer and HBAr4 promotes the cyclization of 4-pentyn-1-amine and 5-hexyn-1amine at 90 °C with up to 100% conversion. The AuIII-oxo

2.3. Aromatic Amines

The reactivity of aromatic amines in metal-catalyzed hydroaminations is higher as compared to aliphatic amines, because they coordinate less strongly to the metal catalysts, and are more easily transferred to the alkyne triple bond. Titanium, zirconium, lanthanides, and actinides, as well as various late transition metals, catalyze intermolecular hydroaminations of alkynes with aromatic amines.149 Thus, an impressive TON of O


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31 200 at only 50 °C was achieved for this transformation using a cationic gold complex stabilized by electron-rich, sterically demanding bis(ortho-biphenyl)cyclohexyl phosphine ligands.187 2.3.1. Intermolecular Hydroamination of Terminal Alkynes. 2.3.1.1. Primary Amines. Late transition metalcatalyzed hydroaminations of terminal alkynes with primary aromatic amines usually lead to Markovnikov products. The enamines intermediately formed rapidly tautomerize to the imines. As such, they do not usually react further to double hydroamination products. The reaction can be driven toward the dienamines by employing excess alkyne in the presence of gold complexes with electron-rich, sterically demanding ligands. Wakatsuki and co-workers introduced the first method for the addition of primary amines to terminal alkynes to give imines.343 Their decisive discovery was that the presence of amine adducts of acids with noncoordinating anions, such as NH4PF6, strongly enhances the activity of Ru3(CO)12 as a hydroamination catalyst (Scheme 27). Thus, the addition of

0.6 mol % of NH4PF6 were sufficient to obtain moderate to high yields of the desired ketimines. Related Ru-sources, such as Ru(CO)(PPh3)2(SP), Ru(CO)2(PPh3)3, Ru(CO)3(PPh3)2, and RuH2(CO)(PPh3)3, were less effective. Further improvements of the catalyst activity were achieved by using tungstophosphoric acid (H3PW12O40) as the additive instead of NH4PF6, so that only 0.1 mol % Ru(CO)(PPh3)2(SP) and 0.2 mol % H3PW12O40 were needed for the hydroamination of equimolar mixtures of phenylacetylene with various anilines in up to 99% yield. In comparison to the Wakatsuki system343 (see Scheme 27), the reaction times are rather long, but the reaction proceeds cleanly even when the alkyne is added in only stoichiometric quantities. Klein et al. found that a dinuclear ruthenium complex with a rigid double-bridged dicyclopentadienyl ligand also possesses catalytic activity for the Markovnikov-selective hydroamination of phenylacetylenes with anilines (Scheme 29).346 The reactions proceed without side product formation, albeit with only moderate catalyst turnover numbers (up to six). A detailed mechanistic study was performed to elucidate the mode of action of the dinuclear complex. The catalytically active species was characterized as {(η5-C5H3)2(SiMe2)2}Ru2(CO)3{NH2(4MeC6H4)}, which is formed from the precursor {(η5C5H3)2(SiMe2)2}Ru2(CO)3(C2H4)H+BF4− by exchange of the ethylene and the bridging hydride for 4-toluidine. Most of the transient reaction intermediates have unambiguously been characterized by crystal structure analysis or NMR. An otherwise analogous, nonbridged Ru-dimer exhibited no catalytic activity, which suggests that a bridge between the two cyclopentadienyl ligands is indispensable for the hydroamidation activity of such dimeric complexes. The first intermolecular hydroamination of alkynes catalyzed by rhodium was reported by Beller et al. (Scheme 30).347 Their

Scheme 27. Ru/Acid-Catalyzed Hydroamination of Terminal Alkynes

aniline to phenylacetylene in 50 g scale yields the Markovnikov product in 84% yield when performed in the presence of 0.1 mol % Ru3(CO)12 and 0.3 mol % NH4PF6 at 100 °C. In the absence of acid, the product was obtained in only 3% yield. The acid might have two possible effects on the hydroamination: (1) formation of the ammonium salt, which as a consequence will not coordinate to the catalyst and thus accelerate hydrogen transfer; and (2) formation of an H−M species via oxidative addition, thus leading to a change in mechanism (cf., Scheme 8, pathway c). The scope includes aliphatic and aromatic alkynes as well as methoxy-substituted alkynes. The authors propose that in analogy to studies by Lavigne et al.,344 the presence of such ammonium salts with noncoordinating anions facilitates the substitution of carbonyl ligands in Ru3(CO)12. This early system is still remarkably close to the state-of-the-art with regard to the catalyst activity. Mizushima et al. showed that ruthenium styrylphosphine (SP) complexes mediate the hydroamination of phenylacetylene with anilines to give the Markovnikov imine (Scheme 28).345 0.3 mol % of Ru(CO)2(PPh3)(SP) in combination with

Scheme 30. Rh-Catalyzed Intermolecular Hydroamination of Terminal Alkynes

cationic RhI/phosphine system catalyzed the addition of anilines to terminal alkynes under very mild reaction conditions (base- and acid-free at room temperature) to form the Markovnikov-imines in up to 99% yield. The presence of acid proved to be beneficial also in Rh-catalyzed intermolecular hydroaminations of terminal alkynes. Thus, [Cp*RhCl2]2 (0.5 mol %)/NH4PF6 (1.5 mol %) provided the Markovnikov products in excellent yields.348 Cao et al. reported a NHC-Pd-catalyzed Markovnikov hydroamination of terminal alkynes with anilines that gave up to 99% yield within 2 h (Scheme 31).349 In diethyl ether, the poor solubility of the NHC−Pd complex allowed easy recovery

Scheme 28. Ru/Styrylphosphine-Catalyzed Hydroamination of Phenylacetylene

Scheme 29. Hydroamination Catalyzed by a Dinuclear Ru Complex

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Scheme 31. NHC−Pd-Catalyzed Intermolecular Hydroamination of Terminal Alkynes

substrates in alkyne hydroaminations for three reasons. First, secondary arylamines are more nucleophilic than primary amines and coordinate more strongly to the metal, so that their transfer to the carbon center is more difficult. Second, the electrostatic repulsion between the more electron-rich secondary amines and the alkyne π-electrons is stronger. Finally, for mechanisms involving simultaneous coordination of the amine and alkyne to the metal, the greater steric bulk of the secondary amines is a disadvantage. There are, therefore, few examples of late transition metal-catalyzed hydroaminations of secondary amines. The addition of secondary amines or N-heterocycles to terminal alkynes is traditionally mediated by strong bases (KOH or CsOH). These protocols usually provide antiMarkovnikov enamines with low Z/E-selectivities.157,367,368 Early metal catalysts for this transformation involved toxic HgCl2, which led to Markovnikov products (Scheme 34).369

and reuse of the catalyst in a total of four cycles without losses in the yield. Tanaka et al. reported an efficient intermolecular hydroamination of alkynes with anilines promoted by (Ph3P)AuMe in conjunction with acidic promoters under solvent-free conditions at 70 °C (Scheme 32).350 The authors observed Scheme 32. Au/Acidic Promoter-Catalyzed Hydroamination of Terminal and Internal Alkynes

that electron-rich arylalkynes are more reactive than electronpoor derivatives. In 2009, Shi and co-workers published a more efficient system for this transformation, consisting of 0.1 mol % PPh3AuOTf/benzotriazole/H3PW12O40, which afforded the corresponding product in up to 98% yield.351 The highest turnover number of 95 000 for the intermolecular hydroamination of alkynes was achieved by Lavallo et al., who used a zwitterionic gold catalyst coordinated to a phosphine ligand bearing an noncoordinating carborane substituent.217 A cationic gold/cyclohexylbis(2′,6′-diisopropoxybiphenyl-2-yl)phosphine complex at 25 ppm loading allowed the reaction to proceed at 50 °C, with an impressive TON of 31 200.187 Other recent advances include the use of N-heterocyclic carbene-assisted AuI,352−354 AuIII porphyrins,355 and heterogeneous gold complexes356−360 for highly selective and efficient intermolecular Markovnikov hydroaminations of terminal alkynes with aryl amines. PtBr2,361 IrIII,362 heterogeneous copper,363,364 and Zn−Co complexes365 are also efficient catalysts for the intermolecular hydroamination of alkynes with anilines. The first example of an intermolecular anti-Markovnikov addition of primary anilines to terminal alkynes was achieved with a cationic RhI complex bearing iminopyridine-based bidentate nitrogen donor ligands (Scheme 33).165,366 The anti-Markovnikov E-imines were obtained with high regio- and stereoselectivity. The reaction proceeds via the vinylidene mechanism depicted in Scheme 8, pathway d. 2.3.1.2. Secondary Amines. In comparison to primary arylamines, secondary derivatives are more challenging

Scheme 34. HgCl2-Catalyzed Intermolecular Hydroamination of Terminal Alkynes

The first ruthenium-catalyzed addition of secondary amines to terminal alkynes was presented by Uchimaru et al. in 1999.370 They found that a triruthenium dodecacarbonyl catalyst promotes the addition of N-methyl aniline or Nmethyl toluidine to aryl and cycloalkenyl alkynes to selectively give the Markovnikov addition products (Scheme 35). Good Scheme 35. Ru3(CO)12-Catalyzed Hydroamination Protocol by Uchimaru

yields based on the alkyne were obtained when the reaction was performed in a 10-fold excess of the amine. The excess amine is required to reduce alkyne oligomerization and isomerization of the enamine product. The postulated reaction mechanism is displayed in Scheme 36. The catalytic cycle starts with an oxidative addition of the amine to a Ru0 center with formation of a ruthenium-amidohydride complex. Coordination of an alkyne, followed by its insertion into the Ru−N bond, gives rise to a rutheniumenamine intermediate, which releases the product via reductive elimination, regenerating the active Ru0 species. In 2012, Bhattacharjee et al. achieved a highly regio- and stereoselective anti-Markovnikov addition of azoles to terminal alkynes using a RuII-based cationic complex (Scheme 37).188

Scheme 33. Rh-Catalyzed Intermolecular anti-Markovnikov Hydroamination of Alkynes

Q


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noncatalytic Michael addition of anilines at room temperature.376

Scheme 36. Reaction Mechanism for the Ru-Catalyzed Markovnikov Hydroamination

Scheme 39. AuI-Catalyzed Hydroamination of Propiolic Acid Derivatives/Ynamides with Anilines

Scheme 37. Ru-Catalyzed anti-Markovnikov Hydroamination of Alkynes with Azoles In 2013, Liu et al. reported an efficient Ag0/carbon nanotubes-catalyzed synthesis of enamines via the hydroamination of activated alkynes with aromatic amines (Scheme 40).377 The catalyst could be recycled and reused thrice without a decrease in the yield. Under the optimal conditions, benzotriazoles can also undergo anti-Markovnikov addition to phenylacetylene with complete N1-selectivity. The mechanism was proposed to proceed via a ruthenium vinylidene intermediate as depicted in Scheme 8, pathway d. The regiocontrol of the functionalization of benzotriazoles is a challenging field due to the equilibrium between N2 and N1(N3) tautomers. Because the N2 tautomer decreases the aromaticity of benzotriazole, the N1-substituted benzotriazole is usually the dominant product.371−373 In 2009, Shi et al. reported a highly efficient approach to synthesize vinylsubstituted triazoles via gold-catalyzed Markovnikov hydroamination of alkynes with triazoles (Scheme 38).374 The benzotriazoles selectively give the N1-addition product, while the carbonyl-substituted N−H triazoles lead to the N2-addition product.

Scheme 40. Recyclable Silver-Catalyzed Intermolecular Hydroamination of Activated Alkynes

Cationic AuI complexes exhibit remarkable reactivity toward the electrophilic activation of alkynes, but overcoming the reactivity-stability dilemma of simple cationic AuI complexes is a significant challenge. Shi and co-workers synthesized 1,2,3triazole-bound cationic gold complexes with substantially improved thermal stability as compared to other known AuI complexes.351 These catalysts provided excellent yields in the challenging intermolecular hydroamination of internal alkynes with arylamines (Scheme 41). Moreover, by increasing the

Scheme 38. Au-Catalyzed Hydroamination of Alkynes with Triazoles

Scheme 41. Triazole/Au-Catalyzed Intermolecular Hydroamination of Internal Alkynes

2.3.2. Intermolecular Hydroamination of Internal Alkynes. The regiochemistry of the hydroamination of internal alkynes is determined mainly by the electronic properties of the substrates and by the steric hindrance by the substituents on the C−C triple bond. 2.3.2.1. Primary Amines. In 2009, Skrydstrup and coworkers reported a highly regioselective hydroamination of propiolic acid derivatives and ynamides, both of which feature a strongly polarized C−C triple bond, catalyzed by (PPh3)AuTf2 (Scheme 39).375 N,N-Disulfonylynamides, which are activated by two strongly electron-withdrawing groups, can undergo

catalyst loading to 10 mol %, the challenging intermolecular hydroaminations of aliphatic amines are achieved in moderate yields, and the intermolecular hydroamidations of alkyne with benzamide in 10% yield. AuSPhosNTf2 also exhibits good activity in the intermolecular hydroamination of various alkynes with amines.378 Silver-exchanged tungstophosphoric acid (AgTPA) exhibits excellent activity for the intermolecular hydroamination of alkynes with both aliphatic and aromatic amines (Scheme 42).379 R


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Scheme 42. AgTPA-Catalyzed Intermolecular Hydroamination of Alkynes

Scheme 44. Transition Metal-Catalyzed Indole Synthesis from ortho-Alkynylanilines

2.3.2.2. Secondary Amines. There are sporadic examples for the late transition metal-catalyzed intermolecular hydroamination of internal alkynes with secondary aromatic amines. A Pd(PPh3)4/benzoic acid-catalyzed coupling of aromatic amines with alkynes reported by Yamamoto et al. in fact proceeds via isomerization of the alkynes to allenes, and provides the allylic amines (Scheme 43).170,380,381 Various electron-withdrawing

Catalytic intramolecular hydroaminations of alkynes leading to five- and six-membered rings have been used to efficiently construct complex ring systems. Interestingly, many of these are endo-cyclizations. An example is the Pd-catalyzed synthesis of polycyclic lamellarin derivatives by Xu and co-workers starting from 4-alkynyl-3-aminocoumarins (Scheme 45).390

Scheme 43. Pd-Catalyzed Intermolecular Hydroamination of Internal Alkynes

Scheme 45. Pd-Catalyzed 5-endo-dig Hydroamination To Afford the Polycyclic Lamellarin Scaffold

2-Substituted 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolines are obtained by Pal’s CuI-catalyzed 5-endo-dig cyclization of 8alkynyl-1,2,3,4-tetrahydroquinolines (Scheme 46).391 Scheme 46. Copper-Catalyzed 5-endo-dig Cyclization of 8Alkynyltetrahydroquinolines

and -donating groups were tolerated on the aniline ring. The authors propose that the oxidative addition of benzoic acid to the Pd0 catalyst generates HPdOBz, which catalyzes an isomerization of the alkynes to allenes via insertion and βhydride elimination. The resulting allene inserts into the H−Pd bond to afford a π-allylpalladium species, which allylates the aromatic amine. An intramolecular version of this transformation leads to 2-substituted tetrahydroquinolines. This transformation has also been performed enantioselectively with up to 76% ee when (R,R)-RenorPhos was used as the chiral ligand.382 Bhanage et al. recently found that polymer-supported triphenylphosphine/palladium is an active heterogeneous catalyst for the related allylation of 1-phenyl-1-propyne with O- and N-nucleophiles.383 2.3.3. Intramolecular Hydroamination of Alkynes. Intramolecular hydroaminations of alkynes are catalyzed by a wide array of metals. Particularly the formation of five- and sixmembered rings proceeds well, and is possible even with simple acid catalysts.147 This reaction mode is comprehensively covered up to 2011 in Hierso’s review,224 so that this section lists only the more recent examples and new developments in the field. Indole derivatives are widely found in natural products and pharmaceuticals.384 As a result, their synthesis has intensely been studied.385,386 Indole syntheses via intramolecular hydroaminations of ortho-alkynyl anilines have been the focus of reviews published in 2006 and 2011, to which we refer for further reading on this reaction mode (Scheme 44).387−389

Kundu et al. showed that the isoquinoline ring of isoquinolino-benzazepino-indoles can be formed by CuIcatalyzed 6-endo-dig cyclization of alkynyl-benzazepino-indoles (Scheme 47).392 Scheme 47. Cu-Catalyzed 6-endo-dig Cyclization To Afford 6H-Indolo[2,3-c]isoquino[2,1-a][1]1benzazepines

Wu et al. presented a mild and efficient synthesis of 6pyrazolo[1,5-a]pyridines in the presence of a cationic gold complex (Scheme 48).393 The starting material for the hydroamination step, which proceeds in near quantitative yield, is generated from 2 equiv of hydrazine and 1 equiv of enediynones in 75−95% yields. Three publications report intramolecular hydroaminations with switchable regioselectivity, in which endo-products are S


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Scheme 48. Au-Catalyzed 6-endo-dig Cyclization To Afford Pyrazolo[1,5-a]pyridines

Scheme 51. Au- and Ag-Catalyzed Intramolecular Hydroaminations with Opposite Regioselectivity

obtained in the presence of a silver catalyst, whereas other methods give the exo-products. Thus, Wu et al. showed that in the intramolecular hydroamination of α-amino (2alkynylphenyl)methylphosphonate, a palladium catalyst leads to 5-exo-dig cyclization and provides 2,3-disubstituted 2Hisoindol-1-ylphosphonates, whereas silver triflate catalyzes a 6endo-cyclization to 2,3-disubstituted 1,2-dihydroisoquinolin-1ylphosphonates (Scheme 49).394

Scheme 52. Alkyne Hydroamination Catalyzed by Au3+/Au+, Leading to a Strongly Fluorescent Product

Scheme 49. Intramolecular Hydroamination of R-Amino-(2alkynylphenyl)-methylphosphonate

by Crabtree398 and others.399−401 Messerle et al. found that the C−N bond formation to give indoles follows an unusual pathway involving hydroalkoxylation and Lewis acid-mediated isomerization (Scheme 53).402

The regioselectivity of an intramolecular hydroamination of alkynyl-substituted, fused benzimidazoles could similarly be tuned by the catalyst system. Liu and co-workers showed that in the presence of a silver catalyst, 7-endo-dig cyclization products are obtained, and that the same substrate undergoes a noncatalytic, thermal 6-exo-dig cyclization (Scheme 50).395

Scheme 53. Ir-Catalyzed Intramolecular Indole Synthesis

Scheme 50. Regioselective Hydroamination To Synthesize Fused Benzimidazoles

2.4. Amides

2.4.1. Intermolecular Hydroamidation of Terminal Alkynes. The intermolecular addition of amides to alkynes usually requires strong bases (see Scheme 5) or Brønsted acids.403 Early transition metals do not seem to catalyze such hydroamidations, and the first example of a late transition metal-catalyzed reaction was reported as late as 1995. Watanabe et al. observed that Ru3(CO)12/tricyclohexylphosphine mediates the anti-Markovnikov additions of simple anilides to 1octyne. This catalyst was applicable only to a handful of rather special substrate combinations and called for rather extreme temperatures and the use of a pressure reactor (Scheme 54).404 In the same year, Heider et al. reported that RuCl3 mediates the addition of N-nucleophiles to acetylene even in the absence of a base (Scheme 55).405 In their process, cyclic Nnucleophiles (e.g., 2-pyrrolidone, imidazole, or succinimide) are treated with 20 bar of a 1:3 mixture of N2/acetylene at 150−160 °C to give the corresponding enamides, enimides, or enamines. Ten years later, Gooßen et al. developed catalyst systems based on bis(2-methallyl)(cycloocta-1,5-diene)ruthenium(II)

Van der Eycken et al. reported another intramolecular hydroamination with switchable regioselectivity (Scheme 51).396 In the presence of 5 mol % AuCl and 10 equiv of TFA, ortho-alkynyl anilines undergo 5-endo-dig cyclization, while the 6-exo-dig hydroamination products were produced exclusively with silver triflate as a catalyst. An intramolecular hydroamination was applied by Song et al. in 2012 to fluorescence imaging of gold ions in living cells. Their novel fluorescent probe works by photoinduced electron transfer, which is selectively blocked by gold ions (Au3+/Au+) that catalyze its 6-exo-dig cyclization to produce a strongly fluorescent product (Scheme 52).397 A recent, mechanistically interesting development in this field is the iridium-catalyzed intramolecular hydroamination of internal alkynes bearing a tethered hydroxyl group described T


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Scheme 54. First Example of Ru-Catalyzed Hydroamidation

Scheme 57. Mechanism for the Ru-Catalyzed Hydroamidation of Terminal Alkynes

Scheme 55. First Ru-Catalyzed Hydroamidation Protocol

[(cod)Ru(met)2], which resulted in dramatically improved efficiency and generality of ruthenium-catalyzed hydroamidation reactions.190 Thus, a system generated in situ from (cod)Ru(met)2, tri-n-butylphosphine, and 4-diaminopyridine (DMAP) promotes the anti-Markovnikov-selective addition of various secondary N−H nucleophiles, including amides, anilides, ureas, bislactams, and carbamates, across terminal C−C triple bonds. The substrate scope does not include primary amides. High yields and E/Z-selectivities of up to 30:1 are achieved, and various functional groups are tolerated, including alkoxycarbonyl, alkoxy, carbonyl, halo, or silane groups (Scheme 56). The mechanism of the hydroamidation was extensively studied by a combination of deuterium-labeling and control experiments, as well as kinetic and spectroscopic studies (Scheme 57).190 The catalytically active Ru0 complex is generated via reductive coupling of a phosphine and a methallyl ligand, and exchange of the 1,5-cyclooctadiene with phosphine and DMAP ligands. The catalytic cycle starts with an insertion of the Ru0 species into the amide N−H bond. An alkyne coordinates to the resulting RuII-hydride species and inserts into the Ru−H bond. The resulting RuII-vinyl complex

rearranges to a RuIV-hydride-vinylidene species via α-hydride transfer. The vinylidene group is susceptible to nucleophilic attack at the electropositive α-C-position, explaining the antiMarkovnikov selectivity of the reaction. Thus, attack of the amide at this position furnishes a RuII-enamide intermediate. Finally, reductive elimination releases the E-enamide and regenerates the original Ru0 species. On the basis of these mechanistic studies, a simplified protocol was developed, in which the same catalyst species is generated in situ from simple precursors, that is, ruthenium trichloride hydrate (RuCl3·3H2O), PnBu3, DMAP, K2CO3, and water (see Scheme 57).406 In the above protocols, the E-enamides are predominantly formed. However, upon replacing the PnBu3 and DMAP ligands with bis(dicyclohexylphosphino)methane (dcypm) and water, the stereoselectivity is inverted in favor of the Z-isomers.190 Even though performance and selectivity of this complementary protocol do not yet reach the same levels as the E-selective protocol (Z/E ratios of up to 8:1), it demonstrated for the first time that the stereochemistry of ruthenium-catalyzed hydroamidations can be efficiently controlled by the ligand

Scheme 56. Ru-Catalyzed E-Selective Addition of Secondary Amides to Terminal Alkynes

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by employing Lewis acids rather than auxiliary bases to support the insertion of the Ru catalyst into the N−H bond. Thus, a catalyst formed in situ from (cod)Ru(met)2, dcypb, and ytterbium triflate in wet DMF effectively promoted the Zselective monovinylation of primary amides (Scheme 59). Yb(OTf)3 functions as a Lewis acid, facilitating the oxidative addition to the ruthenium center, and the electron-rich and sterically demanding bidentate ligand dcypb suppresses a second vinylation of the product and controls the reaction stereochemistry in favor of the thermodynamically disfavored Z-isomer. The Z-enamides were obtained in good yields and selectivities. The scope of this reaction includes many sensitive functionalities such as ester, ether, halide, nitrile, nitro, and alkene groups. Even fragile acrylic, oxalic, malonic, or αcyanoacetic amides were efficiently converted. The reaction was also employed to synthesize a key intermediate in Castedo’s total synthesis of aristolactam.409 Because of the higher stability of E- as compared to Zenamides, the Z-enamides obtained in the above protocol can be isomerized in situ in the presence of an amine base and by raising the temperature to 110 °C (Scheme 60). Competing

environment. On the basis of spectroscopic studies, the mechanism of the Z-selective protocols is proposed to be analogous to that of the E-selective reactions (see Scheme 57). In the Ru-vinylidene intermediate, the bulky chelating phosphines seem to force the R3-substituent onto the side of the coordinated amide, so that the vinylidene substituent is attacked by the coordinated N-nucleophile from the face that carries the R3-substituent resulting in the formation of a Zenamide. A broader scope and high Z-selectivities of greater than 20:1 were reported for a bimetallic catalyst system composed of (cod)Ru(met) 2 , 1,4-bis(dicyclohexylphosphino)butane (dcypb), and ytterbium triflate (Scheme 58).191 Yb(OTf)3 Scheme 58. Z-Selective Ru-Catalyzed Addition of Secondary Amides to Terminal Alkynes

Scheme 60. Syntheses of E-Configured Enamides via Hydroamidation and Isomerization Sequence

was proposed to facilitate the oxidative addition of the N−H bond to ruthenium in the absence of an auxiliary base.191 Upon replacing the bulky bidentate phosphine ligand by P(nBu)3, the selectivity is inverted in favor of the E-configured products. Beyond amides, the substrate range includes ureas, carbamates, and even imides, in combination with numerous aliphatic and aromatic alkynes. These initial catalyst systems were unable to convert primary amides. In comparison to secondary amides, they have a lower nucleophilicity, so that more active catalysts are required. Moreover, the secondary enamide products formed in the hydroamidation should themselves be more reactive than the starting materials toward a second alkyne hydroamidation. Thus, double-vinylated products would be expected to predominate. The first catalyst system capable of overcoming these hurdles was reported in 2008.407,408 The strategy used to make the reaction selective for the monovinylated products consisted of making the acidity of the N−H bond, rather than the nucleophilicity of the amide, the selectivity-determining factor,

hydrolysis is effectively suppressed by adding 3 Å molecular sieves. The resulting hydroamidation/Z-to-E-isomerization sequence gives access to a wide range of E-configured enamides in high yields and Z/E-selectivities up to 1:20. The synthetic utility of both hydroamidation protocols was recently demonstrated by the synthesis of a family of bioactive natural products, the botryllamides C and E, alatamide, the lansiumamides A and B, and lansamide I.407,408,410 Starting

Scheme 59. anti-Markovnikov Z-Selective Addition of Primary Amides to Alkynes

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from simple, commercially available precursors, the desired products were obtained in 1−3 reaction steps in 57−98% overall yields (Schemes 61 and 62).

Scheme 63. Ru-Catalyzed Intermolecular Hydroamidation of Indolic Alkynes

Scheme 61. Syntheses of Botryllamides C and E via Hydroamidation

ligand, and the molecular sieves are replaced by the strong base potassium tert-butoxide. The substrate scope of the complementary protocols includes alkyl- and aryl-substituted alkynes, conjugated enynes, trimethylsilylacetylene, and a range of secondary thioamides bearing aromatic or aliphatic substituents. In 2007, Yudha et al. found that Re2(CO)10 is an effective catalyst for the hydroamidation of terminal alkynes with cyclic lactams (Scheme 66).238 The N−H nucleophiles add antiMarkovnikov selectively, with a moderate preference for Econfigured enamides. The products can be isomerized almost quantitatively to the thermodynamically favored E-isomer by prolonged heating. The mechanism is believed to be analogous to the Ru-based protocols with involvement of Re−vinylidene intermediates. Panda et al. reported a palladium-catalyzed intermolecular hydroamidation of electron-deficient terminal alkynes (Scheme 67).415 The transformation is highly stereoselective: primary amides produce Z-enamides, whereas secondary amides afford the E-enamides only. An intramolecular hydrogen bond between the amido proton and the carbonyl oxygen of the alkynes is believed to cause this surprising selectivity. The mild base cesium carbonate in combination with the Lewis acid FeCl3 also effectively mediates the intermolecular hydroamidation of terminal alkynes. With this procedure, some amides and sulfonamides give the anti-Markovnikov products in good to excellent yields at 150 °C.156 However, only moderate Z/E-selectivities can be reached. 2.4.2. Intermolecular Hydroamidation of Internal Alkynes. There are no examples of intermolecular hydroamidations of dialkyl alkynes. However, Kozmin et al. found that silver bis(trifluoromethylsulfonyl)imide (AgNTf2) mediates the addition of secondary amides and carbamates to the highly reactive siloxy alkynes within only 30 min at ambient temperature (Scheme 68).189 The addition exclusively gives the Markovnikov products with high selectivities for the Econfigured isomers.

Barker et al. employed the above-mentioned rutheniumcatalyzed hydroamidation of indolic alkynes in concise syntheses of igzamide and Z-coscinamide B (Scheme 63).411 Especially adapted protocols allowed extending the scope of Ru-catalyzed hydroamidations to N−H nucleophiles with substantially higher N−H acidity. This includes imides, which are more acidic (pKa(DMSO) of 2-pyrrolidone = 24.2 and of succinimide = 14.6) and less nucleophilic than amides because of the extended electron-pair delocalization over the two carbonyl groups adjacent to the nitrogen.412 The anti-Markovnikov addition of imides (pKa ≈ 15) to terminal alkynes was achieved with a catalyst system generated in situ from (cod)Ru(met)2, PnBu3, and scandium(III) triflate (Scheme 64).413 Under these conditions, the Markovnikov products are formed exclusively with a high preference for the Z-isomers. If tri(isopropyl)phosphine is used as the ligand in place of PnBu3, the stereoselectivity is inverted, and the Econfigured isomers become the major product. The scope of the two complementary reaction protocols extends to aryl- and alkyl-substituted alkynes in combination with various imines. Thioamides are ambident nucleophiles with rather acidic N− H groups [pKa(DMSO) of pyrrolidine-2-thione = 18.1]412 that can react at the nitrogen or sulfur terminus depending on whether hard or soft electrophiles are used. They are potential catalyst poisons because of their strong interaction with many late transition metals. A catalyst generated in situ from (cod)Ru(met)2, tri-n-octylphosphine (PnOc3), and molecular sieves (3 Å MS) mediates the anti-Markovnikov addition of secondary thioamides to terminal alkynes affording the Econfigured thioenamides in high yields and excellent selectivities (Scheme 65).414 The diastereoselectivity is reversed in favor of the corresponding Z-configured isomer when bis(dicyclohexylphosphino)methane (dcypm) is used as the Scheme 62. Syntheses of Lansiumamides via Hydroamidation

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Scheme 64. anti-Markovnikov Addition of Imides to Alkynes

Scheme 65. anti-Markovnikov Addition of Secondary Thioamides to Alkynes

Scheme 66. Re-Catalyzed Hydroamidation of Terminal Alkynes with Cyclic Lactams

Scheme 69. Mechanism for the Ag-Catalyzed Hydroamidation

Scheme 67. Pd-Catalyzed Intermolecular Hydroamidation of Terminal Alkynes

protodemetalation of the alkenyl−silver compound gives the product and regenerates the silver catalyst. 2.4.3. Intramolecular Hydroamidation of Alkynes. Intramolecular hydroamidations of alkynes are more easily achieved than the intermolecular versions, and numerous metal complexes have been reported to promote such reactions. Simple acids and bases often suffice as the catalysts. For example, the cyclization of (2-alkynyl)anilines or (2alkynylphenyl)ureas proceeds smoothly in the presence of KOtBu155 or TfOH.403 However, the use of late transition metals offers great benefits. Several systems, for example, based on gold, silver, or palladium, allow accessing not only five- and six-, but also the entropically unfavorable four- and sevenmembered heterocycles.213,215,216 Most substrates appear to exhibit a preference for the formation of either exo- or endocyclization products. In several recent instances, however, the catalyst determines whether endo- or exo-cyclization occurs, and there are several pairs of complementary protocols that allow accessing either product. From the examples below, rhodium appears to have a preference for endo-cyclizations. It remains

Scheme 68. Ag-Catalyzed Hydroamidation of Siloxy Alkynes

The proposed mechanism is illustrated in Scheme 69. The initial step, reversible coordination of the siloxy alkyne to the silver center, is believed to be fast. The subsequent attack of the activated alkyne by the amide proceeds via a six-membered transition state and results in a highly syn-selective addition. Subsequent release of a proton from this intermediate and X


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6-endo-dig cyclizations (Scheme 73).420 It leads to indoles, 1,2dihydroisoquinolines, and 1,4-dihydroquinolines in high yields.

unclear which factors determine whether gold-, silver-, or palladium-catalyzed intramolecular hydroaminations will proceed with exo- or endo-selectivity, and accurate predictions as to the reaction outcome are difficult to make because subtle differences in the substrate structure or counterion in the catalyst have profound effects. The choice of the metal catalyst also influences whether ring closure occurs via the amide nitrogen or oxygen. Late transition metals often activate the amides by intermediate formation of metal−amido complexes, thereby increasing the reactivity of the nitrogen nucleophile toward C−C multiple bonds. 2.4.3.1. Terminal Alkynes: 4-exo versus 5-endo Cyclization. The 4-exo cyclizations are rarely observed due to the considerable ring strain in the products. Au(PPh3)Cl/Ag2CO3 catalyzes the 5-endo cyclization of N′-substituted N-(2alkynylphenyl)ureas to indole-1-carboxamides (Scheme 70).416 The reaction proceeds in water under microwave irradiation within 10 min.

Scheme 73. Ru-Catalyzed Intramolecular endo-Selective Hydroamidation of Terminal Alkynes

As expected for a reaction that proceeds via Ru-vinylidene intermediates, it does not extend to internal alkynes. Interestingly, the scope of this cyclization includes not only sulfonamides and amides, but also unprotected anilines. 2.4.3.2. 5-endo versus 6-exo Cyclization. Ureas may undergo either 5-endo or 6-exo cyclization, depending on which nitrogen atom forms the new bond to the alkyne carbon. In the protocol reported by the Asensio group in 2010, the selectivity depends on the substrate electronics. Thus, the same NHC−gold complex catalyzes the selective 6-exo cyclization of substituted (2-ethynylphenyl)ureas, whereas it leads to 5-endo cyclization when the substrates contain a more electrondeficient pyridine in place of the benzene ring (Scheme 74).421 As an alternative to hydroamination, a possible mechanism involving hydration of the alkynes to form the corresponding ketones followed by condensation cannot be ruled out for the 6-exo cyclization pathway.422 2.4.3.3. 5-exo versus 6-endo Cyclization. In 1990, Tamaru and co-workers reported that 5-exo cyclization of O-propargyl carbamates to the corresponding oxazolidinones is not only mediated by base, but also by CuI (R3 = p-toluenesulfonyl) and AgI catalysts (R3 = acyl) (Scheme 75).423 The carbamates may also be formed in situ from propargylic alcohols and ptoluenesulfonyl isocyanate, then cyclized to the oxazolidinones using 1 mol % copper iodide and 5 mol % Et3N as the catalyst.424 Amidines obtained by reaction of imidoyl chlorides with prop-2-yn-1-amines undergo gold-catalyzed 5-exo cyclization to afford imidazole derivatives (Scheme 76).425 A methylene-bridged diimidazolyl RhI dicarbonyl complex is an effective catalyst for the 6-endo cyclization of selected orthoalkynylanilines to give a range of benzo(dipyrroles), isoquinolines, and 1,8-dihydropyrrolo[3,2-g]indoles (Scheme 77).426 Besides the diacetamides, nonsubstituted diamines also react in good yields. With ruthenium as a catalyst metal, the cyclization of alkynyl anilides can be directed to different products by the ligand system. Saá et al. showed that whereas the 6-endo product 1,4dihydroquinoline is formed with CpRuCl(PPh3)2 (cf., Scheme 73), in the presence of a RuCl2(p-cymene) 2-methylindole is formed via 5-exo cyclization followed by isomerization (Scheme 78).420,427 2.4.3.4. 6-exo versus 7-endo Cyclization. A cationic gold complex obtained by chloride abstraction from Au(PPh)3Cl by Ag+ catalyzes the 6-exo cyclization of Boc-protected aminoalkynes to the corresponding piperazines (Scheme 79).428

Scheme 70. Cationic Gold-Catalyzed 5-endo-Selective Intramolecular Hydroamidation

A palladium-catalyzed 5-endo cyclization of homopropargylic sulfonamides was reported by Rutjes et al. (Scheme 71, top).417 Scheme 71. Pd- or Ag-Catalyzed Cyclization of Homopropargylic Sulfonamides

Partial racemization of the chiral center occurred. A high ee was conserved in a similar transformation catalyzed by silver, as reported by Jarvo and co-workers (Scheme 71, bottom).418 A ruthenium complex was shown by Grotjahn et al. to be applicable to the 5-endo cyclization of tosamides, amidines, and primary/secondary aromatic amines (Scheme 72).419 The proposed mechanism involves attack of the N−H nucleophile on a vinylidene intermediate. The Ru-catalyzed intramolecular hydroamidation of aromatic alkynyl amides by the Saá group is another example for 5- and Scheme 72. Ru-Catalyzed 5-endo-Selective Intramolecular Hydroamination To Give Indoles

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Scheme 74. AuI-Catalyzed 6-exo- or 5-endo-Selective Intramolecular Hydroamidation

Scheme 75. CuI- or AgI-Catalyzed 5-exo-Selective Intramolecular Hydroamidation

Scheme 78. Ru-Catalyzed Selective 5-exo and 6-endo Cyclization

Scheme 79. Cationic AuI-Catalyzed 6-exo-Selective Intramolecular Hydroamidation to the Piperazines Scheme 76. AuI-Catalyzed 5-exo-Selective Intramolecular Hydroamidation of Amidines

Scheme 80. Cationic AuI-Catalyzed 7-endo-Selective Intramolecular Hydroamidation Czekelius et al. found that 7-endo cyclization occurred in the presence of a gold complex bearing electron-rich phosphines or NHCs activated by silver tetrafluoroborate. The intramolecular hydroamidation of 1,4-diynes provided oxazepines exclusively, rather than the thermodynamically favored 6-exo cyclization products (Scheme 80).429 Unprotected primary amines and carboxamides (i.e., benzamides and trifluoroacetamides) failed to react under the same conditions. Takemoto et al. reported a complementary set of methods also for 6-exo- versus 7-endo-selective intramolecular hydroamidations of certain α-propargylamino amides (Scheme 81).430 Whereas bismuth triflate promotes 6-exo-cyclization, PtCl2 catalyzes the formation of 1,4-diazepanone derivatives via 7-endo cyclization. 2.4.3.5. 7-exo versus 8-endo Cyclization. No examples for 8-endo-selective intramolecular hydroamidations have been reported to date. Gold−triethynylphosphine complexes catalyze the 7-exo cyclization of p-toluenesulfonyl-protected aminoalkynes (Scheme 82).431 Thus, Sawamura reported that with

Scheme 81. 6-exo- and 7-endo-Selective Intramolecular Hydroamidations

semihollow-shaped triethynylphosphine as a ligand for gold, a variety of azepine and benzazepine derivatives could be obtained that are difficult to access by other methods.

Scheme 77. RhI-Catalyzed 6-endo-Selective Intramolecular Dihydroamination/Dihydroamidation

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Scheme 82. AuI-Catalyzed 7-exo-Selective Intramolecular Hydroamidation

2.4.3.6. Internal Alkynes: 4-exo versus 5-endo Cyclization. In the presence of hydroamidation catalysts, 5-amidoalkynes cyclize easily to the 5-endo products, whereas the corresponding 4-exo cyclization is more difficult to achieve. The 5-endoselective intramolecular hydroamidation of 2-alkynyl anilides, in particular, has found widespread application for the synthesis of indole derivatives. Various catalyst systems are known, including copper salts,432 palladium salts,433 RhI/BINAP,434 or Pd/Cu bimetallic system.435 These are covered in the recent review about synthesis of indoles.387,388 New contributions appear regularly, for example, the cyclization of 2-alkynylanilines catalyzed by Hg(OTf)2,436 and by a homogeneous silver catalyst (Scheme 83).437

Rossom and Hill reported the TBAF mediated 5-endo-dig cyclization and deprotonation of the N-tosamide to form the pyrrole ring (Scheme 85).439 The palladium catalyst could achieve the intramolecular hydroamidation to afford the corresponding N-tosyl-2,5-diaryl-2-pyrroline derivatives. The reaction sequence can be considered to commence with an initial 5-endo-dig cyclization upon deprotonation of the Ntosamide, followed by deprotection through elimination of sulfinic acid, and finally tautomerization leads to formation of the pyrrole ring. Substituted pyrroles can be obtained by Au/Ag or Aucatalyzed intramolecular 5-endo-dig hydroamidation/elimination reactions of homopropargyl amine derivatives. The groups of Aponick and Akai both reported a version involving dehydration (Scheme 86, top),440,441 and Kimper and coworkers presented a related protocol with dehydrofluorination (Scheme 86, bottom).442

Scheme 83. HgII and AgI 5-endo-Selective Intramolecular Hydroamidation of Alkynes to Indoles

Scheme 86. AuI/AgI or AuIII-Catalyzed 5-endo-Selective Hydroamidation of Homopropargyl Amides

Nakamura’s cyclization of 2-alkynylanilides with sulfonyl group migration is a remarkable variation of this old reaction. The sulfonyl group originally attached to the aniline nitrogen migrates to the 3-position in the AuIII-catalyzed version, whereas InIII catalysis results in its migration to the 6-position (Scheme 84).438 A mechanistic rationale for the differences between Au and In was not provided.

An interesting sequence to efficiently access trisubstituted pyrroles from simple N-sulfonyl propargylamines involves a dimeric RhI-catalyzed head-to-tail dimerization, followed by AuIII-catalyzed 5-endo-selective intramolecular hydroamidation of the resulting homopropargylic amides (Scheme 87).443 Gouault et al. showed that with gold(III) oxide catalysts, equilibrium enol formation is completely suppressed and stereogenic centers of α-amino-ynone derivatives are conserved in the hydroamidation step (Scheme 88).444 In contrast, full racemization of the chiral center in the pyrrolin-4-one products was observed when instead using an AuCl catalyst under nonbasic conditions. In 2013, the same group achieved the total synthesis of (−)-epimyrtine through the related AuI-catalyzed

Scheme 84. Sulfonyl Group Migration in AuIII- or InIIICatalyzed Hydroamidations

Scheme 85. Pd- or Base-Mediated Hydroamidation of Homopropargyl Amides

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Scheme 87. AuIII-Catalyzed Intramolecular Hydroamidation To Afford Trisubstituted Pyrroles

Scheme 88. Au-Catalyzed Hydroamidation of α-Aminoynone Derivatives

Scheme 90. 5-endo versus 6-exo Intramolecular Hydroamination

6-endo-cyclization of β-amino-ynone derivatives, for which basic conditions were not needed.5 A Pd- or base-mediated intramolecular hydroamidation of difluoropropargyl amides to gem-difluoro β- and γ-lactams was reported by Fustero and Hammond (Scheme 89).445 β-Lactams

In 2012, Chan et al. reported a AgOAc-catalyzed intramolecular hydroamidation of 1-(2-(sulfonylamino)phenyl)prop-2-yn-1-ols to afford Z-2-methylene-1-sulfonylindolin-3ols with high regioselectivity under mild conditions (Scheme 91).449,450

Scheme 89. Intramolecular Hydroamination of Difluoropropargyl Amides

Scheme 91. AgI-Catalyzed 5-exo-Selective Hydroamidation of Alkynes

were obtained via palladium-catalyzed 4-exo-dig cyclization, whereas γ-lactams were obtained in the presence of TBAF. The gem-difluoro moiety should incline the α-position for intramolecular nucleophilic attack by the nitrogen atom. It was proposed that the initial alkyne activation occurs via coordination of Pd0 with C−C triple bond, the process of which increases the p character of the alkyne carbons, resembling an sp2-like hybridization. This pseudohybridization could favor 4-exo-dig cyclization. 2.4.3.7. 5-endo versus 6-exo Cyclization. Acetamidines may undergo 5-endo versus 6-exo cyclization, depending on which nitrogen atom forms the new bond to the alkyne carbon. The intramolecular hydroamidation of N-(ortho-alkynyl)aryl-N′substituted trifluoroacetamidines and bromodifluoroacetamidines by Wu et al. demonstrates that transition metal catalysts are able to invert the usual selectivity of the cyclization (Scheme 90).446 Whereas base promotes the 6-exo-selective addition of the other amidine N−H across the C−C triple bond, the gold catalyst gives only 5-endo hydroamination products in analogy to the examples discussed above. 2.4.3.8. 5-exo versus 6-endo Cyclization. For 6-amidoalkynes, the regioselectivity of the hydroamidation is more complex. Typically, these substrates undergo 5-exo cyclization in the presence of hydroamidation catalysts,447,448 but the examples below show that 6-endo cyclization may occur for certain substrates using a range of metal catalysts, including Cu, Ag, Au/Ag, and Pd catalysts.

In the examples below, the 6-endo cyclization products are obtained selectively. Interestingly, all start from aryl-substituted alkynes and contain a CO, SO2, or P(O)OR group that is part of the newly formed ring. This would seem to imply that the selectivity is substrate-dependent, and that for this reversible reaction type, the greater delocalization and lower ring strain in the resulting 6-endo products as compared to 5exo products may be contributing factors toward this endo selectivity. In 2007, Pal and co-workers achieved a CuI-catalyzed 6-endodig cyclization of 2-alkynyl benzenesulfonamides to give 2H1,2-benzothiazine 1,1-dioxides at 140 °C in DMF. The same hydroamidation proceeded within 5 min at 80 °C when replacing CuI by 15 mol % AgSbF6 and 3 equiv of Et3N in ethanol (Scheme 92).451 The Pal group went on to report AgNO3/DMF as a less costly and moisture-sensitive alternative to AgSbF6.452 Scheme 92. CuI- or AgI-Catalyzed 6-endo-Selective Cyclization of 2-Alkynyl Benzenesulfonamides

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the open-chain ether and the 6-endo products for the cyclic ether derivative. Takemoto et al. also utilized AuI-catalyzed 6endo-dig hydroamidations of (2-alkynyl)benzyl carbamates to synthesize various 1,2-dihydroisoquinolines including the nitidine alkaloids.460 Starting from acyclic propargylic amide derivatives,461−464 the choice of the catalyst appears to be the main factor dictating the selectivity for 5-exo or 6-endo cyclization. Pd(OAc)2 has been shown by Bäckvall et al. to catalyze the 5-exo-selective intramolecular hydroamidation of a variety of substituted propargyl ureas, thioureas, carbamates, and thiocarbamates. The reaction is highly effective for the synthesis of fivemembered heterocycles including oxazolidinones, oxazolidinethiones, imidazolidinones, and imidazolidinethiones (Scheme 97).461,462 In contrast, RhII complexes lead to the 6-endo-dig products starting from either propargyl guanidines or ureas. Thus, Looper et al. used two different dimeric RhII complexes to catalyze the formation of dihydropyrimidinones and eneguanidines (Scheme 98).463,464 The same propargyl guanidines undergo 5-exo-selective hydroamidation in the presence of AgOAc/AcOH instead of RhII as a catalyst (Scheme 99, path a).463 This reaction type can also be performed with in situ formation of the guanidine by addition of the propargylic amine to a carbodiimide.465 Such hydroamidations have been applied to the total synthesis of (+)-saxitoxin,466 S-(−)-crambidine,467 and (−)-cyclooroidin.468 Propargyl ureas (X = O) are generally prepared in situ from the propargylic amines and isocyanates. For R4 = aryl, the product undergoes an additional isomerization of the double bond (Scheme 99, path b).469 When R4 is a tosyl residue, silver(I) catalyzes a 5-exo-selective intramolecular hydroamidation of the propargylic amines and isocyanates to the 2imidazolones (Scheme 99, path b′).470 The same N-tosyl substrates give oxazolidin-2-imines following 5-exo-addition of the urea oxygen to the alkyne when a cationic gold complex is used instead of AgOTf (Scheme 99, path c).470 In contrast, cationic gold catalyzes the 6-endo-addition of the urea nitrogen to the alkyne, affording the corresponding N-aryl or alkyl substrates with formation of 3,4-dihydropyrimidin-2(1H)-ones (Scheme 99, path d).471 On the basis of these examples, it is hard to predict either the N/O- or the exo/endo selectivity for this substrate class when using silver or gold catalysts. It would be interesting to see whether endo products could be obtained when using rhodium catalysts (cf., Scheme 98). 2.4.3.9. 6-exo versus 7-endo Cyclization. Takemoto et al. reported a hydroamidation in which the 6-exo versus 7-endo selectivity could be controlled by the catalyst system.430 Whereas 6-exo hydroamidation of the phenylpropargyl amine substrates occurs in the presence of a cationic gold complex,183 a PtCl2 catalyst selectively gives the 7-endo cyclization products (Scheme 100), in analogy to the hydroamidation of terminal

In their Au/Ag-catalyzed cyclization of alkynyl ureas, Kundu et al. observed a strong counterion effect on the chemoselectivity (Scheme 93).453 Thus, 6-endo-dig N-cyclization occurred in the presence of AuI/AgOTf, whereas AuI/AgNO3 led to 6-endo-dig O-cyclization. Scheme 93. Counterion Effect in AuI/AgI-Catalyzed Chemoselective Cyclization

The 6-endo-dig cyclization products are selectively obtained also in the palladium-catalyzed intramolecular hydroamidation of N-alkyl-o-ethynylbenzamides reported by Sashida et al. (Scheme 94).454 The same catalyst was also able to convert the structurally related phosphonamides under slightly modified conditions (Scheme 94).455,456 Scheme 94. PdII-Catalyzed 6-endo-Selective Intramolecular Hydroamidation

In the hydroamidation of o-alkynylbenzyl carbamates by Catalán et al., a clear substrate dependence of the endo/exo selectivity of the cyclization step was observed (Scheme 95).457,458 With gradually increasing numbers of α-fluorine atoms, the ratio of 5-exo to 6-endo cyclization was shifted from 40:60 for CH3 to 80:20 for CF3. Very similar substrates gave the opposite regioselectivity with the same cationic gold catalyst in the example by Fujii and Ohno (Scheme 96).182,459 In this case, ring strain in the product appears to be the main contributor to this selectivity, the expected 5-exo hydroamidation products being obtained for

Scheme 95. Substrate-Dependent Regioselectivity Affected by the Fluorinated Residue

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Scheme 96. Substrates Control the Regioselectivity of Intramolecular Hydroamidation

A related process was employed by Liu et al. to synthesize substituted pyrroles from the corresponding N-phthalyl alkynylaziridines (Scheme 104).476 The mechanism was elucidated on the basis of deuterium labeling experiments. As in the example above, addition of the aziridine nitrogen to the gold-activated alkyne followed by ring opening leads to a cationic alkenyl-AuI intermediate, which undergoes 1,2-hydrogen migration and deauration to generate the pyrrole product. Related processes were described by the Hou and Davies groups.477,478 Starting from N-tosyl alkynylaziridines, the regioselectivity is determined by the counterion on the gold catalyst (Scheme 105).479 Only in the presence of the extremely weakly coordinating triflate counterion does the reaction follow a pathway involving an 1,2-aryl shift in the alkenyl-Au I intermediate to afford the 2,4-substituted pyrrole, whereas the slightly more strongly coordinating tosylate is sufficient to move the preference toward a 1,2-hydrogen shift, resulting in the 2,5-substituted pyrrole. A similar reaction reported by Aguilar and co-workers involves an intramolecular hydroamidation of internal alkynes with opening of a cyclopropane instead of an aziridine ring (Scheme 106).184 This NHC−gold-catalyzed reaction proceeds only for substrates bearing a donor−acceptor substituent (respectively, −OMe, −CONR) on the cyclopropane ring, and leads to seven-membered cyclic dienamides.

Scheme 97. Pd-Catalyzed Cyclization of Propargylic Ureas, Thioureas, Carbamates, and Thiocarbamates

alkynes (cf., Scheme 81).185 This methodology was applied to a straightforward synthesis of the caprazamycin core. Caprazamycins are lipo-nucleoside antibiotics, which show antibacterial activity against, for example, Mycobacterium tuberculosis. Mitchell reported a palladium-catalyzed 7-endo-selective hydroamidation leading to 3-benzazepinones (Scheme 101).472 This palladium-catalyzed transformation is limited to alkyl-substituted alkynes. Liu’s complementary 7-endo cyclization of 2-(1-alkynyl)phenylacetamides, which bear an aryl substituent on the alkyne group, requires an Au/Ag catalyst (Scheme 101).473 A similar 7-endo-dig hydroamidation in the presence of 10 mol % Pd(PhCN)2Cl2 in THF at 60 °C provides access to the 1,3-dihydro-2H-3-benzazepin-2-one scaffold (Scheme 102).474 2.4.3.10. Cycloisomerizations. Starting from propargylic acyl aziridines, intramolecular hydroamidations proceed with 5endo cyclization and rearrangement of the three-membered ring to the corresponding pyrroles. Ph3PAuCl/AgOTf was shown to be an efficient catalyst for this reaction type. Zhang et al. employed fused bicyclic aziridines as the substrates, and proposed a mechanism that starts with activation of the C−C triple bond by AuI coordination. The subsequent 5-endoselective addition of the aziridine nitrogen to the activated alkyne leads to a nitrogen-centered cation, which then undergoes ring-opening by cleavage of the N−C2 bond. The resulting spirocyclic intermediate bearing an allylic cation finally rearranges to the fused pyrrole through a Wagner−Meerwein process (Scheme 103).475

2.5. Other Nitrogen Nucleophiles

The coordination of soft, strongly Lewis acidic late transition metals strongly activates the C−C multiple bonds enabling not only the attack of primary or secondary amines and amides but also of various other nitrogen nucleophiles. Hydrazines and imidates with N−H moieties react via the usual hydroamidation mechanisms. Late transition metals also promote intramolecular C−N bond formations from alkynes and nitrogen nucleophiles without N−H bonds. Such transformations, which are not true hydroaminations but mechanistically related, are unknown for early transition metals or rare earth metals. 2.5.1. Addition of Hydrazines to Alkynes. Fukumoto et al. utilized the TpRh(C2H4)2/P(2-furyl)3 (Tp = tris-pyrazolyl

Scheme 98. Rh-Catalyzed 6-endo-Selective Cyclization of Propargylic Ureas and Guanidines

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Scheme 99. AgI- and Au/Ag-Catalyzed Cyclization of Propargylic Ureas and Guanidines

Scheme 103. AuI-Catalyzed Cyclization of Propargylic Aziridines

Scheme 100. Au- or Pt-Catalyzed Intramolecular Hydroamidation of Propargyl Amines

Scheme 101. Pd- and Au/Ag-Catalyzed 7-endo-Selective Intramolecular Hydroamidations

Scheme 102. Pd-Catalyzed Intramolecular 7-endo-dig Hydroamidation of Alkynes ruthenium-vinylidene species, as described for the hydramination of primary and secondary amines (cf., Scheme 14). When the TpRuCl(PPh3)2 complex was applied in the same reaction instead of the Rh-based system, the corresponding nitriles were obtained.481 In this case, an additional proton migration step leads to a zwitterionic complex, which undergoes deamination (Scheme 108). This method allows converting various alkynes bearing functional groups such as ethers, silyl ethers, amines, nitriles, chlorides, tosylates, thiophenes, and pyridines in high yields. The Markovnikov hydrohydrazination of terminal alkynes with substituted hydrazines can be mediated by titanium,482−484 rhodium, and iridium485 catalysts. The Bertrand group used

borate) system for the anti-Markovnikov addition of N,Ndimethylhydrazine to terminal alkynes, which leads to the selective formation of hydrohydrazination products (Scheme 107).480 This reaction involves an intermolecular attack of the nonsubstituted hydrazine nitrogen at the α-carbon atom of a AE


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Scheme 104. Cationic Gold-Catalyzed Cycloisomerization of Alkynyl Aziridines

Scheme 105. Counterion Effects in AuI-Catalyzed Hydroamidations of Alkynyl Aziridines

Scheme 106. AuI-Catalyzed Cycloisomerization of 2-Alkynyl Cyclopropanamides

shown in Scheme 13 for the hydrohydrazination of alkynes with anhydrous hydrazines at 100 °C.487 In 2014, Hashmi et al. reported the room-temperature hydrohydrazination of alkynes in the presence of saturated abnormal N-heterocyclic carbene ligands (Scheme 109).488 Scheme 109. Au-Catalyzed Markovnikov Addition of Nonsubstituted Hydrazine to Terminal Alkynes

Scheme 107. Rh-Catalyzed anti-Markovnikov Hydrohydrazination of Terminal Alkynes

Scheme 108. Synthesis of Nitriles via Addition of N,NDimethylhydrazine to Alkynes

Pyrazole derivatives can also be efficiently synthesized by a gold-catalyzed 5-endo-dig cyclization (Scheme 110).489 It was suggested that the intramolecular hydroamidation leads to a Scheme 110. Pyrazole Formation from Propargyl Hydrazides under the Influence of a Gold Catalyst

cationic gold catalysts to achieve the Markovnikov addition of hydrazine to terminal alkynes, diynes, and allenes.486,487 In contrast, the addition of nonsubstituted hydrazine to alkynes remains relatively unexplored. One example was published by Bertrand et al. using a CAAC−AuI complex as AF


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gold-substituted pyrazoline intermediate, which is followed by a double elimination of both hydrogen chloride and the tosylate anion. A 1,2-hydride shift and the release of the gold catalyst give the final product. A similar FeCl3-catalyzed chemoselective synthesis of 3,4,5- and 1,3,5-pyrazoles was recently reported,490 which involves propargylic substitution combined with a [1,5]sigmatropic shift. In 2013, Coeffard and Greck reported the gold-catalyzed synthesis of chiral aza-proline derivatives by 5-exo-dig cyclization of enantio-enriched α-hydrazino esters containing an alkyne group (Scheme 111).491 In the presence of 5 mol % Ph3PAuCl/AgBF4, the ring closure product can be obtained in 62−82% yield at room temperature.

Scheme 113. Au-Catalyzed Cyclization of 2Alkynylbenzaldoximes

Scheme 114. Ag-Catalyzed Cyclization of o-Alkynylaryl Aldoxime Derivatives

Scheme 111. Au-Catalyzed Intramolecular 5-exo-Cyclization of Alkynes with Hydrazino Esters

2.5.4. Addition of Hydrazones to Alkynes. In 2010, Nakamura and co-workers reported the intramolecular hydroamination of propynyl hydrazones through N−N bond cleavage to synthesize the corresponding 3-aminoacrylonitriles in good to high yields (Scheme 115).499 First, the copper-activated

2.5.2. Addition of Imidates to Alkynes. In 2006, Shin and Hashmi independently reported the gold-catalyzed intramolecular cyclization of alkynes with trichloroacetimidates.492,493 Catalyst loadings around 2−5 mol % of different cationic gold complexes were required to give the cyclization product under mild conditions. The substrate scope is limited to intramolecular terminal alkynes. An Ag(py)2OTf complex was also found to be effective for the cyclization of internal and terminal alkynes with imidates (Scheme 112).494

Scheme 115. Cu-Catalyzed Intramolecular Hydroamination of Propynyl Hydrazones

Scheme 112. Ag-Catalyzed Intramolecular 5- or 6-exoCyclization of Alkynes with Imidates

alkyne moiety undergoes nucleophilic attack by the sp3 nitrogen atom of the hydrazone group to generate a cyclized intermediate. Next, N−N bond cleavage followed by hydrogen absorption affords a vinyl-Cu intermediate. Finally, protodemetalation gives rise to the β-amino acrylonitriles. 2.5.5. Addition of Triazenes to Alkynes. Triazenes can also attack the C−C triple bond through AgI-catalyzed N−N bond cleavage or an intramolecular cyclization without cleavage of any N−N bond. In 2014, Yu and Huang reported the first synthesis of indoles from alkynyl triazenes in the presence of silver (Scheme 116).500

2.5.3. Addition of Aldoximes to Alkynes. In contrast to the previously described reactions, imines and the following substrate classes do not contain a N−H moiety. In consequence, these compounds cannot undergo hydroamination/hydroamidation reactions in a classic manner. The transition metal-mediated cyclization of alkynes containing a nucleophile in proximity to the C−C triple bond has been extensively used to synthesize N- or O-heterocycles.213 Shin et al. reported the efficient cyclization of 2alkynylbenzaldoxime derivatives to afford the corresponding isoquinoline-N-oxides in the presence of a IMesAuOTf complex under mild reaction conditions (Scheme 113).495,496 In the AgI-catalyzed cyclization reaction of o-alkynylaryl aldoxime derivatives, a dramatic substituent effect was observed (Scheme 114).497,498 When R represents an alkyl or allyl group, the AgI-catalyzed reaction in DMA at 110 °C affords isoquinolines in good to excellent yields.498 In contrast, isoquinolin-1(2H)-ones are obtained in moderate to high yields at room temperature in DMF, when R equals an acetyl group.497

Scheme 116. Ag-Catalyzed Cyclization of Alkynyl Triazenes

In the absence of a metal catalyst, 2-alkynlylaryl triazenes undergo thermal cycloaddition with elimination of triethylamine to afford cinnoline derivatives (Scheme 117).501−503 In contrast, in the presence of a CuCl catalyst, 2H-indazole aldehydes are formed.504 AG


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Scheme 117. Selective Cyclization of Alkynyl Triazenes

Scheme 120. Ag-Catalyzed Intermolecular Hydroazidation of Alkynes

2.5.6. Addition of Azides to Alkynes. It has been shown by Toste et al. that azides can serve as nucleophiles in an addition reaction if the alkyne has been activated by a cationic AuI complex (Scheme 118).505 In this reaction, the gold catalyst

indicated that the free hydroxyl group plays a significant role in the chemoselectivity of the hydroazidation. The authors suggested a silver-catalyzed activation of the alkyne via formation of silver acetylides. 2.5.7. Addition of Tetrazoles to Alkynes. In the presence of strong bases, aryltetrazoles are easily converted to the corresponding N-arylcyanamides. In 2013, Wang et al. reported an Ag-catalyzed intermolecular hydroamination of bromoalkynes with tetrazoles to generate Z-N-(2-bromo-1vinyl)-N-arylcyanamides (Scheme 121).512

Scheme 118. Au-Catalyzed Cyclization of Homopropargyl Azides

Scheme 121. Ag-Catalyzed Hydroamination of Alkynes with Tetrazoles

serves both as a π-acid and an electron donor allowing the activation of the alkyne and the extrusion of N2, respectively. In this way, tri- and tetrasubstituted pyrroles can be synthesized starting from homopropargyl and cyclobutyl azides. Hiroya et al. reported the PtCl4-catalyzed cyclization of homopropargyl azide derivatives to form pyrroles, using ethanol as solvent and 2,6-di-tert-butyl-4-methylpyridine as the base.506 DFT calculation of the Au- and Pt-catalyzed intramolecular cyclization of homopropargyl azides indicates that the isomerization of 2H-pyrrole to 1H-pyrrole is an intermolecular process in which a second 2H-pyrrole is responsible for a proton shift.507 Moreover, TMS-azides can react with alkynes to vinyl-azides that can be further converted into nitriles, amides, or tetrazoles (Scheme 119). When the reaction is carried out in the presence of Ag2CO3, terminal alkynes can be converted to alkyl and aryl nitriles by cleavage of the C−C triple bond.508 Furthermore, Jiao reported the synthesis of amides starting from internal diaryl alkynes in a PPh3AuCl-catalyzed reaction.509 Echavarren applied a gold-mediated protocol for the synthesis of tetrazoles starting from terminal alkynes.510 Bi and co-workers reported the Ag2CO3-catalyzed hydroazidation of alkynes to synthesize 2-azidoallyl alcohols in good to excellent yields (Scheme 120).511 The control experiments

The Z- and E-N-cyano enamines can be selectively obtained in good yields in the absence or presence of K2CO3 via a silvermediated 1,2-addition of aryltetrazoles with alkyl propiolates (Scheme 122).513 A subsequent allenoate isomerization of the Z- to the E-isomer can be performed using 2 equiv of K2CO3. Scheme 122. Ag-Catalyzed Hydroamination of Alkyl Propiolates

2.5.8. Addition of Imines/Pyridines to Alkynes. In 1999, Larock et al. reported the synthesis of isoquinolines and pyridines via copper- or silver-catalyzed cyclization of aryl-,

Scheme 119. Transformations Involving Au-Catalyzed Hydroazidation of Alkynes

AH


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alkenyl-, and alkyl-substituted iminoalkynes (Scheme 123).514,515 This transformation proceeds via a palladium-

Scheme 126. Transition Metal-Catalyzed 5-exo or 6-endo Cyclization of N-Propargylamino Pyridines

Scheme 123. Cu-Catalyzed Cyclization of Iminoalkynes

catalyzed Sonogashira-coupling and subsequent copper-catalyzed cyclization of the resulting iminoalkynes. Control experiments indicate that the hydrogen atom in the 4-position of the isoquinoline originates from the tert-butyl group of the imine rather than from the solvent. Similar results can also be observed with silver as the catalyst.516,517 This synthetic strategy was applied in the synthesis of β- and γ-carbolines518 and the total synthesis of the isoquinoline alkaloid decumbenine B.515 Additionally, the group of Gevorgyan reported the coppercatalyzed cycloisomerization of acyclic and cyclic alkynyl imines to afford pyrroles and fused heterocycles, respectively (Scheme 124).519,520

iminoimidazoazines in the presence of silver (Scheme 126, path c).528,529 The 6-endo hydroamination of 9-propargyladenine gives rise to tricyclic purine derivatives (Scheme 126, path d).530 Propargylic derivatives of N-containing heterocycles have been extensively used as building blocks in the synthesis of fused heterocycles. Hoveyda et al. converted enantiomerically enriched bicyclic amides into the corresponding indolizinones using 5 mol % copper iodide at 80 °C in CH3CN (Scheme 127,

Scheme 124. Cu-Catalyzed Cycloisomerization of Alkynyl Imines

Scheme 127. Transition Metal-Catalyzed Cyclization of Propargylic Derivatives

The same group synthesized a series of 5−6−5 tricyclic heteroaromatic skeletons by double cycloisomerization of bisalkynylpyrimidines (Scheme 125).521,522 This transformation Scheme 125. Cu-Catalyzed Double Cycloisomerization

path a).531 Sarpong and co-workers obtained indolizines, pyrrolones, and indolizinone heterocycles via a PtII-catalyzed tandem cycloisomerization/1,2-migration of pyridine propargylic alcohol derivatives (Scheme 127, path b).532 A metal-free cycloisomerization/1,2-migration of isoquinoline propargylic alcohol derivatives was used for the synthesis of two natural products, 3-demethoxyerythratidinone and (±)cocculidine.533 Gevorgyan et al. developed a gold-mediated alkyne-vinylidene isomerization and a concomitant 1,2-shift of hydrogen, silyl, or stannyl groups to synthesize fused pyrroloheterocycles from diverse propargyl-substituted heterocycles under mild conditions (Scheme 127, path c).534,535 A complementary cyclization of pyridine propargylic derivatives without 1,2migration was developed, using silver as the catalyst under baseand ligand-free conditions (Scheme 127, path d).536,537

was used as a key step in the highly diastereoselective total synthesis of (±)-tetraponerine T6. Qu and co-workers reported a similar transformation with catalytic amounts of copper, in which purine-fused tricyclic structures are obtained from Npropargyl-adenine.523 Chioua et al. reported a silver-catalyzed cycloisomerization of readily available N-(prop-2-yn-1-yl)pyridine-2-amines as a new synthetic pathway for the regioselective synthesis of substituted 3-methylimidazo[1,2-a]pyridines (Scheme 126, path a).524−526 Under oxygen atmosphere, in the presence of silver, the oxidation product, imidazo[1,2-a]-pyridine-3-carbaldehyde, can be obtained in moderate to good yields (Scheme 126, path b).527 The 5-exo cyclization leads to dihydroimidazo[1,2a][1,3,5]triazin-4(6H)-ones in the presence of copper and to AI


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In the presence of PtI2, pyridine-terminated propargylic esters can be selectively cyclized, leading to substituted indolizines (Scheme 128).538 In this reaction, the pyridine

Scheme 130. Aminoisoquinoline Synthesis via Au-Catalyzed Condensation/Hydroamination

Scheme 128. Pt-Catalyzed 5-exo or 6-endo Cyclization of Propargylic Esters

Following condensation of a ketone with a primary amine, an alkynyl-substituted secondary imine is obtained, which also undergoes a hydroamination-type reaction. The reaction proceeds in the presence of AgOTf or AuCl/AgOTf/PPh3 catalysts, and leads to pyrrole products (Scheme 132).552−555 A catalyst consisting of 10 mol % FeCl3 was also shown to be effective at a reaction temperature of 60 °C. Thus, a variety of tetra- and pentasubstituted pyrroles as well as fused pyrrole derivatives were constructed in good to excellent yields.556

moiety behaves analogously to an imine. The initial 5-exo versus 6-endo cyclization of the acyl group and the activated alkyne of a propargylic ester depends on the electronic effects of the substituents and can be controlled by the ratio of 1,3- to 2,3-disubstituted indolizines. A number of examples exist in which the 2-alkynyl imine is formed in one pot by condensation of an alkynyl ketone and ammonia or an equivalent, and subsequent catalytic addition of the imine to the alkyne (Scheme 129). Thus, pyrrole derivatives

3. CATALYTIC ADDITION OF NITROGEN NUCLEOPHILES TO ALLENES Allenes are highly versatile synthetic synthons in preparative organic chemistry due to the high reactivity of their cumulated double bonds. As compared to intermolecular additions to allenes, intramolecular nucleophilic additions with transition metals received much more attention.557 Especially gold, silver, and platinum catalysts have been extensively used in the addition of nitrogen nucleophiles to allenes due to their soft and carbophilic character.214,558 Late transition metals have been extensively used in intermolecular hydroaminations of allenes with anilines and aliphatic secondary amines. As a complementary strategy, the early transition metals could promote the intermolecular hydroamination of allenes with primary aliphatic amines.559 Bases and various transition metals can mediate the intramolecular hydroamidation of allenes, while intermolecular processes require Au or Pd complexes as the catalysts. Especially gold complexes are known to catalyze intermolecular hydroamidation of internal allenes.

Scheme 129. Condensation/Hydroamination of (2Ethynylphenyl)alkanones in the Presence of Ammonia

3.1. Aliphatic Amines

3.1.1. Intermolecular Hydroamination of Terminal Allenes. In 2010, Widenhoefer and co-workers reported a (dppf)PtCl2/AgOTf-catalyzed intermolecular hydroamination of monosubstituted allenes with secondary alkylamines at 80 °C to form allylic amines in high yields (Scheme 133).560 Already in 2007, Yamamoto and co-workers achieved the first gold-catalyzed hydroamination of allenes with morpholine as the only amine source using a Ar3PAuCl/AgOTf system at 80 °C.561 Aromatic amines can also perform a intermolecular hydroamination with monosubstituted, 1,1-, and 1,3-disubstituted allenes in the presence of a mixture of [P(tBu)2-obiphenyl]AuCl/AgOTf.562 Employing a mixture of a NHC−AuI complex and KB(C6F5)4 leads to in situ formation of a cationic gold species, which exhibits a high reactivity for intermolecular hydroamination of allenes with a variety of primary and secondary amines (Scheme 134).563 This NHC−gold complex also allows the use of ammonia (cf., Scheme 13)286 or hydrazine for hydroaminations of alkynes and allenes.486,487

are obtained by condensation of (2-ethynylphenyl)alkanones and ammonia followed by hydroamination.539,540 This strategy also serves to efficiently access other heterocycles such as pyrido[3,4-c]thiazoles,541 pyrido[3,4-b]indoles,542 pyrrolo[1,2a]pyrazines,543,544 and isoquinolines.545 A variation of the above sequence consists of the AgIcatalyzed reaction of o-alkynyl aldehydes with amines, yielding fused isoquinolines, naphthyridines, and thienopyridines.546,547 An AuIII-mediated condensation/hydroamination process developed by Chen starts from 2-alkynyl benzamides and ammonium acetate and gives access to pharmaceutically interesting 1-aminoisoquinolines (Scheme 130).548 The condensation between alkynyl ketones or aldehydes and hydrazines leads to hydrazones, which cyclize in the presence of copper iodide to afford pyrazole derivatives (Scheme 131).549,550 This strategy has been used to synthesize 2,7disubstituted pyrazolo[1,5-a]pyridines from enediynones and hydrazine.551 However, stoichiometric amounts of CuCl are needed for the transformation (cf., Scheme 48). AJ


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Scheme 131. Condensation/Hydroamination of Alkynyl Aldehydes or Ketones and Hydrazines

Scheme 132. Pyrrole Synthesis via Condensation/Tautomerization to the Enamide and Hydroamination

stabilizing ligand allowed this reaction type to proceed at 80 °C within only 12 h. The resulting dihydropyrrole, a key intermediate in the synthesis of the bioactive (αS,2R)-(2,5dihydro-1H-pyrrol-2-yl)glycine, was isolated in 78% yield (Scheme 136).192

Scheme 133. Pt-Catalyzed Intermolecular Hydroamination of Allenes

Scheme 136. Au-Catalyzed Intramolecular Hydroamination of α-Aminoallene

Scheme 134. Intermolecular Hydroamination of Allenes Catalyzed by a Cationic Au-Complex

3.2. Aliphatic and Aromatic Amines

3.2.1. Intermolecular Hydroamination of Terminal Allenes. The first intermolecular Markovnikov hydroamination of allenes was reported with equimolar amounts of PtII and HgII salts.572,573 In 1995, Cazes et al. demonstrated the palladiumcatalyzed addition of amines to allenes in the presence of triethylammonium iodide via a Pd−H species.574,575 On the basis of the same strategy, Yamamoto and co-workers extended the scope of intermolecular hydroaminations of allenes by using Pd0/acetic acid catalyst systems (Scheme 137).576 The authors

3.1.2. Intramolecular Hydroamination of Allenes. AgI salts and HgCl2 are widely employed for intramolecular hydroamination reactions of allenes to generate five- or sixmembered heterocycles (Scheme 135).564,565 Notably, such a

Scheme 137. Pd-Catalyzed Intermolecular Hydroamination of Allenes

Scheme 135. Ag/Hg-Catalyzed Intramolecular Hydroamination of Allenes

protocol can also be applied for the synthesis of chiral products if chiral allenes or chiral auxiliaries are used.566−568 Copper salts are also known to be efficient catalysts for the hydroamination of allenylamines to 3-pyrrolines or 2-alkenylpyrrolidines.569 The Au-catalyzed intramolecular hydroamination of unprotected α-aminoallenes generally requires long reaction times of several days and relatively forcing conditions (see Scheme 160).570,571 In 2013, Krause et al. showed that imidazole as AK


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proposed that the reaction is initiated by the oxidative addition of acetic acid to Pd0. The allene inserts into a Pd−H species to form a π-allylpalladium intermediate, which undergoes reductive elimination to yield the final product. Schmidt and co-workers synthesized a series of Pd II complexes, which have shown excellent activity in intermolecular hydroaminations of 3-methyl-1,2-butadiene (Scheme 138).577,578 They found that the final product was afforded via isomerization of the kinetic branched intermediate.

Scheme 140. AgF-Catalyzed Intermolecular Hydroamination of Allenes

Scheme 138. Pd-Catalyzed Intermolecular Hydroamination of Allenes at Room Temperature

provide excellent regioselectivities for the branched product and high ee (see section 3.3.3). The Breit group reported a new catalytic system, which provides a N2- versus N1-selective coupling of benzotriazoles with allenes (Scheme 142).196 This work is the first example of N2-selective hydroamination of allenes with benzotriazoles using a rhodium/DPEphos system. In sharp contrast, the rhodium/JoSPOphos system provides the N1-allylation product exclusively. Isotopic labeling and stoichiometric experiments indicate that a Rh−H species is formed by oxidative addition toward the N−H bond of benzotriazoles, followed by migratory insertion, amination, and reductive elimination to yield the final product. Breit et al. also reported a [Rh(cod)Cl]2/DPEphos system, which efficiently promotes the hydroamination of allenes with anilines to afford the branched allylic amine in good yield (Scheme 143).197 Using chiral ligands instead of DPEphos, a high ee and an increase of the yield by 25% can be observed (see section 3.3.3). Similarly, hydroaminations of C-(tetra-Oacetyl-β-D-galactopyranosyl)allene with various aromatic primary amines can be achieved with a palladium complex in yields up to 42%.582 In 2010, Kimber’s group reported an intermolecular hydroamination of allenamides with arylamines using the well-known π-acidic properties of cationic gold complexes, which provides an efficient method to synthesize E-enamide derivatives (Scheme 144).583 3.3.2. Intermolecular Hydroamination of Internal Allenes. In 2006, Yamamoto and co-workers reported the first gold-catalyzed intermolecular hydroamination of internal allenes (Scheme 145).584,585 The reaction is conducted in the presence of 10 mol % AuBr3 at ambient temperature. In addition, when allenes with axial chirality were used, the products were obtained in high ee values. This strongly supported that a gold−amine complex was formed, instead of a π-allyl gold complex. The reaction might be initiated by a coordination of the allene to the gold−amine complex to form the intermediate C, followed by allene insertion and protodeauration to the final product. However, in 2013, Toste and Bergman found that gold−amide intermediates were unreactive to π-bonds, which suggested the hydroamination of π-bonds took place via an outer-sphere mechanism.586 3.3.3. Intermolecular Asymmetric Hydroamination of Allenes. In 2012, Breit and co-workers reported a RhI/ Josiphos system for the first intermolecular asymmetric hydroamination of allenes with anilines (Scheme 146).197 First mechanistic studies on the base of deuterium-labeling

To enhance the activity of the PdII complexes, they designed a series of alicyclic 3-iminophosphine ligands. Employing these ligands in the hydroamination of 1,1-dimethylallene, cyclohexylallene, benzylallene, and selected aryl allenes with alkyl amines yielded the branched substituted allylamine product with nearly quantitative conversions at ambient temperature in less than 1 h. Using phenylallene and 1,1-diphenylallene with secondary amines under the same conditions, the linear hydroamination product can be obtained with high selectivity (Scheme 139).579 Under the same conditions, aniline derivatives selectively led to the kinetic Markovnikov product.580 Scheme 139. Regioselective Intermolecular Hydroamination of Allenes

In 2014, Guo et al. reported the silver-catalyzed intermolecular hydroamination of 9-allenyl-9H-purines with primary anilines and secondary aliphatic amines (Scheme 140).581 It provides an efficient and regioselective approach to get 9alkenyl-9H-purines with functionalized side chains. Besides the hydroamination of N-allenes, the authors also describe the hydrocarboxylation of various aliphatic and aromatic carboxylic acids in the presence of 2 mol % Ag2CO3 or AgF (1 equiv). 3.3. Aromatic Amines

3.3.1. Intermolecular Hydroamination of Terminal Allenes. In 2013, Breit and co-workers reported a Pd-catalyzed regio- and stereoselective intermolecular hydroamination of imidazole and benzimidazole derivatives with monosubstituted allenes (Scheme 141).198 The PdII/dppf system gives rise to linear products with a high regioselectivity and high E/Z selectivity, while a RhI/Josiphos system was reported as well to AL


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Scheme 141. Pd- and Rh-Catalyzed Hydroamination of Allenes with Imidazoles

Scheme 142. Rh-Catalyzed N-Selective Hydroamination of Allenes with Benzotriazoles

experiments suggested that the oxidative addition of aniline to RhI leads to the formation of a RhIII−H intermediate. After hydrometalation of the allene, the corresponding π-allyl-Rh complex undergoes reductive elimination to afford branched allylic amines. The same RhI/Josiphos system was also used to extend this procedure to imidazoles and benzimidazoles as the amine coupling partners (cf., Scheme 141). 3.3.4. Intramolecular Hydroamination of Allenes. Hashmi et al. reported the 7-exo-trig cyclization of unprotected aniline derivatives with an allene side chain in the presence of an IPrAu complex (Scheme 147).193 Synthetically useful 1,5benzoxazepines and 1,4-benzodiazepines are easily formed.

Scheme 143. Rh-Catalyzed Intermolecular Hydroamination of Allenes

Scheme 144. Au-Catalyzed Intermolecular Hydroamination of Allenamides

Scheme 147. Au-Catalyzed 7-exo-trig Hydroamination of Allenes Scheme 145. First Au-Catalyzed Intermolecular Hydroamination of Internal Allenes

The intramolecular hydroamination of allenes with unprotected indoles as the nucleophiles proceeds under microwave irradiation in the presence of 5 mol % Pd(PPh3)4 (Scheme 148).587 Control experiments support that the Scheme 148. Pd-Catalyzed Intramolecular Hydroamination of Allene with Indole

Scheme 146. Rh-Catalyzed Intermolecular Asymmetric Hydroamination of Allenes with Anilines

reaction is initiated by the oxidative addition of indole to Pd0. After the insertion of the allene group into the Pd−H species, the corresponding π-allyl-PdII complex undergoes reductive elimination with release of the product and regeneration the corresponding active Pd0 species. AM


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Scheme 149. Pd-Catalyzed Intermolecular Hydroamidation of Terminal Allenes

3.4. Amides

the amount of n-pentoxyallene from large excess (70 equiv) to 5 equiv. On the basis of the NHC/gold-catalyzed intermolecular hydroamidation of allenes200 and dinuclear gold complexcatalyzed intramolecular asymmetric hydroamidation of allenes,194,591−597 Widenhoefer et al. developed an asymmetric version of the hydroamidation of allenes with N-nonsubstituted carbamates based on a dinuclear gold complex and accompanying silver salts. This catalyst system provides asymmetric allylic amines in excellent yields and up to 92% ee (Scheme 152).201

3.4.1. Intermolecular Hydroamidation of Terminal Allenes. In 1997, Yamamoto et al. reported a Pd-catalyzed intermolecular hydroamidation of allenes with sulfonamides to give allylic amines (Scheme 149).576 Unfortunately, under the described reaction conditions, a mixture of hydroamidation and dihydroamidation products is usually obtained. The catalytically active species in this process is a Pd−H species as described before (see Scheme 43). 3.4.2. Intermolecular Hydroamidation of Internal Allenes. In 2008, Widenhoefer employed a NHC−gold complex in intermolecular hydroamidations of allenes with primary carbamates (Scheme 150, top).200 A similar cationic

Scheme 152. Au-Catalyzed Intermolecular Asymmetric Hydroamidation of Allenes

Scheme 150. Au-Catalyzed Intermolecular Hydroamidation of Allenes

Breit et al. reported a Rh-catalyzed intermolecular asymmetric hydroamidation of terminal allenes with the relatively acidic N-nucleophile 2-pyridone (Scheme 153).199 Depending on the choice of the phosphine ligand, the N- versus Ochemoselectivity was excellent and enantioselectivities were high. Strong electron-withdrawing groups on the 2-pyridone can accelerate the reaction and require lower catalyst loadings, while electron-rich 2-pyridones only give moderate yields even in the presence of 5 mol % rhodium catalyst. 2-Pyridones substituted in the 3-, 4-, and 5-positions reacted smoothly to give the N-allylated products, whereas 6-chloropyridone gave only the O-allylated product, presumably for steric reasons. 3.4.4. Intramolecular Hydroamidation of Allenes. Intramolecular hydroamidations of allenes were initially performed mostly using silver tetrafluoroborate as catalyst. The selective 5- or 6-endo-trig cyclization affords 2,5-dihydro1H-pyrroles,598,599 tetrahydro-1H-pyrrolo[1,2-c]oxazol-3-ones, or 3,6-dihydro-1H-pyridones, respectively (Scheme 154).600 Starting from allenyl sulfonamides, the use of silver nitrate allows for 5-endo-trig hydroamidation in acetone at room temperature (Scheme 155).601 By contrast, the use of tert-

gold catalyst was reported to promote intermolecular hydroamidations of allenes with sulfonamides to generate N-allylic amides (Scheme 150, bottom).588 The reaction is highly regioselective for both 1,1- and 1,3-disubstituted or trisubstituted allenes. 3.4.3. Intermolecular Asymmetric Hydroamidation of Allenes. In 2012, Rhee et al. reported the first palladiumcatalyzed intermolecular asymmetric hydroamidation of monosubstituted allenes (Scheme 151).589 This reaction provides an efficient access to chiral N,O-acetals by the enantioselective hydroamidation of alkoxyallenes. Later, the formation of cyclic N,O-acetals was also demonstrated by a cascade hydroamidation with concomitant ring-closing metathesis.590 It is worth mentioning that the change of the ligand could decrease

Scheme 151. Pd-Catalyzed Intermolecular Asymmetric Hydroamidation

AN


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Scheme 153. Rh-Catalyzed Intermolecular Asymmetric Hydroamidation of Terminal Allenes

Scheme 154. Ag-Catalyzed Intramolecular 5- or 6-endo-trig Hydroamidation of Allenes

Scheme 157. Au-Catalyzed Intramolecular Hydroamidation of Allenes

butoxide as a base in DMSO provides the aromatic 3-methoxy2-phenylpyrrole in 71% yield.

catalyst. Ongoing work extended the substrate scope to internal allenes by using AuI and AuCl3 as catalysts.604 In 2005, Yamamoto et al. reported the Pd(PPh3)4/PPh3catalyzed isomerization of alkynes to allenes in benzene at 100 °C, followed by intramolecular hydroamidation of the in situ formed allenes, which are tethered with a protected amino group (Scheme 158, top).605 Later, the same group extended this strategy to afford six-membered lactams (Scheme 158, bottom).606

Scheme 155. Ag or Base-Promoted Intramolecular 5-endotrig Hydroamidation

Scheme 158. Pd-Catalyzed Intramolecular Hydroamidation of in Situ Formed Allenes

The first cyclization of N-monosubstituted allenic carboxamides was reported by Brandsma et al. in 2002 (Scheme 156).602 In the presence of AgI salts, dihydrofuran and dihydropyrrole derivatives can be formed via attack of the oxygen or nitrogen atom to the allene functionality.

Liu et al. described a palladium-catalyzed intramolecular hydroamidation of N-(γ-allenyl)tosylamides (Scheme 159).607 In a mechanistic sense, the active XPd−H catalyst is formed in situ by the oxygen promoted oxidation of isopropyl alcohol to acetone. This XPd−H species does not suffer a possible reductive elimination of H−X, but allene inserts into XPd−H species to form a π-allyl−PdII intermediate. Reductive elimination leads to the hydroamidation products and formation of a Pd0 species, which is readily reoxidized by molecular oxygen to close the catalytic cycle. Recent progress in the development of new catalyst systems was achieved by using gold as the preferred metal for the transition metal-catalyzed intramolecular hydroamidation of allenes. In 2004, Krause et al. reported the AuCl3-catalyzed intramolecular hydroamidation and hydroamination of allenes to achieve the corresponding 3-pyrrolines in good to excellent yields. The amine protecting group has a significant influence on the reactivity and chirality of the transformation (Scheme 160).570 The same group later found that the low activity of the unprotected α-aminoallenes could be enhanced by AuCl (Scheme 160).571 Mechanistic investigations suggest that the AuI complex is the catalytically active species, even when AuCl3 was used as precursor. Lipshutz and Krause showed that a

Scheme 156. Selective O- or N-Cyclization of Allenic Carboxamides

In 1998, Yamamoto et al. reported the PdII/acetic acidcatalyzed 5- or 6-exo-dig cyclization of allenes to form pyrrolidines and piperidines in good to excellent yield (Scheme 157).603 The authors suggested that an in situ generated Pd0 species oxidatively added to the N−H bond, followed by the allene insertion, reductive elimination, and regeneration of the AO


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Scheme 162. AuI-Catalyzed Intramolecular Hydroamidation of N-Allenyl Carbamates

Scheme 159. Pd-Catalyzed Aerobic Intramolecular Hydroamidation of Allenes

Broggini group by 5- and 6-exo-trig hydroamidation of allenamides using 5 mol % AuCl3 as the catalyst in refluxing acetonitrile (Scheme 163). Scheme 163. AuCl3-Catalyzed Intramolecular Hydroamidation of Allenamides

Scheme 160. AuCl3-Catalyzed Intramolecular Cyclization of Aminoallenes Bates and co-workers used the concept of the intramolecular hydroamidation of allenes in the stereoselective gold-catalyzed synthesis of the natural product swainsonine, which represents a potential mannosidase inhibitor (Scheme 164).9 Scheme 164. AuCl3-Catalyzed Synthesis of the Natural Product Swainsonine

micellar AuBr3 catalyst is able to promote this transformation at room temperature in water, and that the catalyst was highly activity and recyclable.608 In 2005, Lee and co-workers reported the high activity of AuCl3 as catalyst for the conversion of 4-allenylazetidin-2-ones to the corresponding bicyclic β-lactams (Scheme 161).609

In 2009, a NHC−AuI complex was used by the Widenhoefer group to catalyze the diastereoselective dihydroamidation of N,N′-disubstituted ureas with an allenyl moiety bonded to the N-alkyl chain to generate the corresponding bicyclic imidazolidin-2-ones in good yield (Scheme 165).612 The

Scheme 161. AuCl3-Catalyzed Intramolecular Hydroamidation of 4-Allenyl-2-azetidinones

Scheme 165. Au-Catalyzed Intramolecular Dihydroamidation of Allenes

Widenhoefer et al. developed the AuI-catalyzed intramolecular 6-exo-trig hydroamidation of carbamates with an allenyl moiety at the 5′ position of the aliphatic chain yielding 2-alkenyl-piperidine derivatives (Scheme 162).195 This catalyst also allows the efficient intramolecular hydroalkoxylation of γhydroxy and δ-hydroxy allenes to form the corresponding oxygen heterocycles in good yield with high exo-selectivity and hydroarylation of 2-allenyl indoles to yield 4-vinyl-tetrahydrocarbazoles. The synthesis of 2-vinylimidazolidin-4-ones610 and 2-vinyl2,3-dihydroquinazolin-4(1H)-ones611 was achieved by the

reaction proceeds in two steps via the hydroamidation of the allene and the subsequent hydroamidation of the in situ generated alkenyl gold species toward the bicyclic product, hexahydroimidazo[1,5-a]pyridine-3(2H)-ones. The ytterbium- or gold-catalyzed intramolecular hydroamidation of cyclopropane-1,1-dicarboxylates bearing a N−O nucleophile at the periphery of the allenyl unit was reported by Shi et al. in 2011 (Scheme 166).613 After initial activation of the allene by ytterbium(III) triflate, the attack of the N-nucleophile results in a cyclopropane ring opening under formation of a C− AP


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Scheme 166. Intramolecular Hydroamidation of Vinylidenecyclopropane Diesters

Scheme 169. Pd-Catalyzed Intramolecular Asymmetric Hydroamidation of in Situ Generated Allenes

C triple bond. In the presence of a AuI catalyst and water, a second reaction step takes place affording the ketone functionality by hydration of the C−C triple bond. Bebbington et al. reported the synthesis of six-membered cyclic sulfamidates by the AuI-catalyzed intramolecular allene hydroamidation (Scheme 167).614 The reaction allows the formation of quaternary, N-substituted carbon centers in high yields, and it presents the first example for the hydroamidation of allenic sulfamidates.

extended the asymmetric hydroamidation of C−C triple bonds to hydroalkoxylations and hydrocarbonations of alkynes to generate the corresponding nitrogen-, oxygen-, and carbocycles in good yields and enantioselectivities.618 The first asymmetric version of the gold-catalyzed hydroamidation of allenes was reported in 2007 by Toste and coworkers (Scheme 170).194 The discovery of a significant Scheme 170. Au-Catalyzed Asymmetric Intramolecular Hydroamidation of Allenes

Scheme 167. Au-Catalyzed Hydroamidation of Allenic Sulfamidates

The Kang group reported the synthesis of a variety of piperidine derivatives via FeIII-catalyzed intramolecular hydroamidation of sulfonamides bearing an allenic subunit (Scheme 168).615 Using Fe(OTf)3 in chlorobenzene at 10 °C, different

counterion effect led to the development of active phosphine AuI-bis-p-nitrobenzoate catalysts. These dinuclear AuI complexes allow the enantioselective synthesis of various vinylsubstituted pyrrolidines and piperidines. On the basis of this finding, Widenhoefer and Gade used bis(gold)-phosphine complexes and also trinuclear gold complexes for the intramolecular asymmetric hydroamidation of a broad variety of allenes.591−593,619 The combination of silver complexes with optically active anionic ligands derived from oxophosphorus(V) acids was also used for the enantioselective hydroamidation of sulfonamides and led to moderate ee values.594

Scheme 168. Fe-Catalyzed Intramolecular Hydroamidation of Allenes


3.5.1. Addition of Hydroxylamines and Hydroxylamine Ethers to Allenes. A regio- and stereoselective strategy for the formation of different chiral heterocycles, such as N-hydroxy-2,5-dihydro-1H-pyrroles, 4,5-dihydroisoxazoles, and 3,6-dihydro-2H-1,2-oxazines, was reported by Krause and co-workers in 2009 (Scheme 171).620 In case of Ononsubstituted hydroxylamine units, the intramolecular amination reaction proceeds chemoselectively by attack of the nitrogen atom to the allene moiety in a 5- or 6-endo-trig cyclization manner. If allenic hydroxylamine ethers are used as substrates, the chemoselectivity is shifted either toward the dihydroisoxazoles in the presence of a cationic gold precatalyst, or to the dihydrooxazines by using N-Boc-protected precursors. Later, the same group used this method for the intramolecular 5-endo-hydroamination of primary amines with an allene moiety to construct azafuranomycin analogues in good yields.621 3.5.2. Addition of Hydroxylamines and Hydrazines to Allenes. Usually, the enantioselectivity of a given reaction can

substituted piperidine derivatives can be obtained in good selectivities and yields. At higher temperatures, the double bond directly isomerizes to give the thermodynamically more favored trisubstituted C−C double bond products. Meanwhile, FeIII can also promote the intramolecular hydroalkoxylation of allenyl alcohols.615 3.4.5. Intramolecular Asymmetric Hydroamidation of Allenes. In 2004, the Yamamoto group reported an asymmetric hydroamidation of in situ generated allenes using palladium catalysts in combination with chiral P-ligands (Scheme 169).616,617 It was suggested that the reaction is initiated by a Pd-catalyzed isomerization of the alkyne substrate to allene, followed by an enantioselective allylic alkylation mediated by the palladium-hydride species, which is formed by oxidative addition of PhCOOH into Pd0. Later, the same group AQ


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modular approach for the synthesis of substituted allyl azide derivatives (Scheme 174).626 In contrast to alcohols and

Scheme 171. Au-Catalyzed Cyclization of Chiral Hydroxylamines

Scheme 174. Intermolecular Au-Catalyzed Hydroazidation of Allenes

amines, the easily available nucleophilic sodium azide or TMSN3 does not have the necessary proton for the required protonolysis of the intermediate vinyl-gold complex. Therefore, the volatile, toxic, and explosive HN3 must be used and has to be cautiously generated in situ from TMSN3 in the presence of TFA.

be influenced by a chiral ligand bound to the transition metal catalyst. In 2007, the Toste group found a new strategy toward asymmetric transition metal-catalyzed intramolecular cyclizations of allenes that employs chiral counterions.595,596,622 They showed that a dinuclear gold complex in combination with the chiral silver salt (S)-TriPAg effectively mediates the intramolecular asymmetric hydroamination of allenes with hydrazines and hydroxylamines (Scheme 172).597

4. CATALYTIC ADDITION OF NITROGEN NUCLEOPHILES TO UNCONJUGATED ALKENES 4.1. Aliphatic Amines

Because of the unfavorable competition between weakly coordinating alkenes and strongly coordinating aliphatic amines, the hydroamination of nonactivated alkenes with aliphatic amines is very difficult to achieve. It is understandable that the intermolecular version is much more challenging as compared to the intramolecular version. Some early transition metal catalysts such as zirconium, 180 lanthanum, and magnesium complexes are active catalysts for the enantioselective intramolecular hydroamination of alkenes.177,627 Catalyst systems based on rare-earth metals such as lanthanum complexes give the intermolecular Markovnikov hydroamination of nonactivated alkenes in excellent yields with moderate enantioselectivities.628,629 Late transition metals, as well as heavier group II complexes and ytterbium catalysts,630,631 are able to give the linear tertiary amines via anti-Markovnikov hydroamination of styrenes with amines. They could also promote the enantioselective intramolecular hydroamination of alkenes to generate five- or six-membered chiral amines. 4.1.1. Intermolecular Hydroamination of Ethylene. The first examples of transition metal-catalyzed homogeneous hydroamination reactions were reported by Coulson in 1971 (Scheme 175).632 Both RhI and RhIII complexes can effectively

Scheme 172. Chiral Counterion-Induced Enantioselective Cyclization of Allenes

Mechanistic studies revealed that the overall transformation is first order to the allene and the catalyst reagent and zero order with regard to the nucleophiles. Control experiments indicate that the rate-limiting step consists of the allene activation.623 Recently, Shapiro and Rauniyar found that dithiophosphoric acids could promote the intramolecular asymmetric hydroamidation of allenes and 1,3-dienes without metal catalysts. The reaction proceeds via addition of the acid catalyst to the all-carbon π-system, followed by nucleophilic displacement of the resulting dithiophosphate intermediate.624 3.5.3. Addition of Hydrazones to Allenes. The cycloisomerization of β-allenyl hydrazones catalyzed by a cationic gold species was reported by Fensterbank and co-workers (Scheme 173).625 This intramolecular cyclization of alkyl- and

Scheme 175. First Rh-Catalyzed Hydroamination of Alkene

Scheme 173. Au-Catalyzed Intramolecular Hydroamination of β-Allenyl Hydrazones

catalyze the hydroamination of ethylene with secondary aliphatic amines. Poli et al. found that a RhI species is the active catalyst for the hydroamination of ethylene.633 4.1.2. Intermolecular Hydroamination of Terminal Alkenes. In 1999, Beller and co-workers reported the first transition metal-catalyzed anti-Markovnikov hydroamination of styrenes. They use a catalyst species generated in situ from cationic [Rh(cod)2]BF4 and PPh3 (Scheme 176).218,219 Control experiments indicate that the anti-Markovnikov hydroamination proceeds via protonolysis of an alkyl−rhodium intermediate, rather than via hydrogenation of an enamine formed in situ. Although it is difficult to prevent the formation of

aryl-substituted allenes provides an efficient access to multisubstituted N-aminopyrroles under mild conditions with microwave irradiation. A subsequent intramolecular 1,2-alkyl or -aryl migration occurs in this selective hydroamination process to give access to aromatic heterocyclic compounds. 3.5.4. Addition of Azides to Allenes. In 2014, the goldcatalyzed addition of azides to allenes was reported as a AR


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Scheme 176. anti-Markovnikov Selective Hydroamination of Styrenes

Scheme 178. Rh-Catalyzed Intermolecular Hydroamination of Allyl Imines

oxidative anti-Markovnikov hydroamination products,107,108 the use of morpholine leads to a higher yield of the hydroamination product as compared to other amines. The role of the morpholine may be to coordinate to the rhodium center through its oxygen atom, thereby stabilizing the alkyl−rhodium complex and inhibiting β-hydride elimination. Hartwig and co-workers used a cationic rhodium complex that can be easily activated by addition of DPEphos ligand to achieve a regioselective hydroamination of vinylarenes with various secondary amines (Scheme 177).205 An excess of DPEphos ligand increases the yield of the hydroamination product, while the closely related Xantphos and DBFphos give little or no hydroamination product. Scheme 177. Rh-Catalyzed anti-Markovnikov Hydroamination of Vinylarenes Scheme 179. (η6-Styrene)-ruthenium-Catalyzed antiMarkovnikov Hydroamination

The efficiency of the anti-Markovnikov hydroamination of vinylarenes with secondary amines could be further improved and extended to the hydroamination of α-methylstyrenes.220 The anti-Markovnikov products can be obtained in up to 96% yield and up to >99% selectivity, in the presence of 5 mol % [Ru(cod)(2-methylallyl)2], 7 mol % 1,5-bis-diphenylphosphinopentane (DPPPent), and 10 mol % TfOH. Both the ligand and the acid are essential for these transformations. In contrast to activated alkenes such as styrenes, 1,3-dienes, or strained cyclic olefins, electronically nonactivated and unstrained 1-alkenes have low tendency to undergo hydroamidations and especially hydroaminations. The main reason is the low affinity of 1-alkenes toward transition metals, so that they cannot compete for coordination sites with amines, which are much stronger donor ligands. Hull et al. have incorporated a Lewis-basic, coordinating imine functional group into the alkenes, which directs the alkene moiety toward the metal center and induces hydroamination reactivity (Scheme 178).204 Moreover, the metallacyclic intermediate promotes hydroamination over β-hydride elimination. The reaction affords 1,2diamines in good to excellent yields and high diastereoselectivities. Other Lewis-basic groups, such as amines, amides, and imides, were unsuccessful in this context. In addition, (η6-styrene)-ruthenium complexes were later found to promote the anti-Markovnikov hydroamination in a different way (Scheme 179).634 The control experiments strongly indicate that these transformations occur via nucleophilic attack on an in situ formed η6-vinylarene complex and exchange of the anti-Markovnikov product with a second vinylarene. Shibata et al. achieved the anti-Markovnikov addition of cyclic aliphatic secondary amines to styrenes

using [Ru(benzene)Cl2]2/AgOTf/DPPPent [DPPPent = 1,5bis(diphenylphosphino)pentane] as catalysts.237 4.1.3. Intermolecular Hydroamination of Internal Alkenes. The palladium-catalyzed addition of secondary amines to dihydrofurans and dihydropyrans to form α-amino tetrahydrofurans and -pyrans was reported by Hill et al. in 2001 (Scheme 180).635 K2Pd(SCN)4 proved to be the best among Scheme 180. Pd-Catalyzed Hydroamination of Dihydrofurans and Dihydropyrans

various PdII catalysts. The use of an excess of KSCN increases the yield, which suggests that the unusual anion might stabilize the reaction intermediates. 4.1.4. Intermolecular Asymmetric Hydroamination of Alkenes. Using (η 6-arene)−metal complexes as chiral templates, Shibata et al. reported the first enantioselective hydroamination of styrenes with secondary alkylamines (Scheme 181).237 The asymmetric anti-Markovnikov products were generated in moderate yields and enantiomeric excess values. AS


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Scheme 181. Ru-Catalyzed Intermolecular Asymmetric antiMarkovnikov Hydroamination

Scheme 183. Pd-Catalyzed Intramolecular Hydroamination of Vinyl Ether

were not observed. A variety of functional groups, such as hydroxy, halogen, cyano, and carboalkoxy groups, are tolerated by this hydroamination catalyst system. Mechanistic investigations on the hydroamination of secondary amines showed that the Rh−C bond cleavage is the rate-limiting step, which could also be observed with Pd, Pt, and Ir.643 Hollis and coworkers found that CCC−NHC Rh and Ir pincer complexes are also efficient and stable catalysts for such cyclization reactions.644 In the RhI-catalyzed intramolecular hydroamination of nonactivated alkenes with primary amines, the authors found that the nucleophilic addition of the amine toward the coordinated olefin is the rate-limiting step. Usually, basic nitrogen nucleophiles, such as alkylamines, are not suitable as substrates for such reactions because they are strong ligands and inactivate the catalyst via coordination to the electrophilic transition metal center. The main difference between RhI- and PdII-catalyzed hydroaminations is that alkenes coordinated to RhI are less electrophilic than alkenes coordinated to PdII. Thus, more nucleophilic amines are expected to react with the rhodium-bound alkenes, whereas less nucleophilic amines should attack the palladium-bound alkenes (Scheme 185).645 In 2006, Hartwig and co-workers reported the first intramolecular anti-Markovnikov hydroamination of nonactivated olefins (Scheme 186). 203 The reaction proceeds selectively in the presence of [Rh(cod)(DPPB)]BF4 in good yields. Kuwata and Ikariya reported a series of iridium-pyrazole bifunctional catalysts for the intramolecular hydroamination of nonactivated alkenes (Scheme 187).646,647 The authors proposed two mechanistic pathways and emphasized the importance of the β-nitrogen group in the bifunctional pyrazole/pyrazolato complexes A regardless of which mechanism is operative. More mechanistic details were presented by DFT calculations,648 and the catalyst system for this type of intramolecular hydroamination was expanded to RhI and IrI complexes with bifunctional pyrazolyl-1,2,3-triazolyl ligands.649 Gold-catalyzed hydroamidations with carboxamide derivatives and sulfonamides have been extensively studied (see section 4.4). However, gold catalysis is less established for the hydroamination of alkenes. In 2008, Widenhoefer et al. reported the first gold-catalyzed intramolecular hydroamination of nonactivated alkenes with ammonium salts (Scheme 188).650 In 2010, Sakurai and Kitahara reported moisture- and airstable gold nanoclusters stabilized by a poly(N-vinyl-2pyrrolidone) polymer as versatile catalysts for the intramolecular cycloaddition of primary amines to nonactivated alkenes.651 The authors proposed that O2 is initially adsorbed to the gold surface to form the electron-deficient reactive site. Roesky et al. recently described the high catalytic activity of bimetallic Au-based nanoparticles (Au−M where M = Pt, Pd, Cu, Ni) for the Markovnikov hydroamination of 2,2diphenylpent-4-en-1-amine to the five-membered product.652 A zinc-catalyzed intramolecular hydroamination of nonactivated alkenes was reported by Roesky and co-workers. With an air- and moisture-stable aminotroponiminate zinc methyl

4.1.5. Intramolecular Hydroamination of Alkenes. In comparison with the hydroamination of alkynes, the hydroamination of nonactivated olefins remains challenging, although the attack of nucleophiles across olefins complexed to PtII has been known for more than a century.636 In an early publication, Zambonelli et al. discovered that platinum can promote the cyclization of 4-pentenyl-amine.637,638 A number of γ- and σamino olefins can be used for an intramolecular hydroamination in the presence of [PtCl2(C2H4)]2 to form the corresponding pyrrolidine derivatives in moderate to good yields (Scheme 182).639 The catalyst system shows excellent Scheme 182. Mechanism of the Pt-Catalyzed Intramolecular Hydroamination of Alkenes

functional group tolerance and low moisture sensitivity. Control experiments supported a mechanism initiated by the formation of platinum amine complex trans-I. C−N bond formation presumably occurs via intramolecular ligand exchange followed by outer-sphere attack of the adjacent amine of the olefin II to form III. Deprotonation/chloride displacement of species III followed by an intermolecular protonolysis of the Pt−C bond of trans-IV leads to the intermediate VI. In the last step, trans-I is regenerated by ligand exchange and the product is released. Westcott et al. reported a ligand-free PdI2-catalyzed intramolecular hydroamination of 3-(vinyloxy)propylamine at room temperature (Scheme 183).640 Pd−P and Pd−N complexes supported on SiO2, Al2O3, and TiO2 were also shown to catalyze the hydroamination of this substrate.641 In 2008, Hartwig and co-workers reported several RhIcatalyzed hydroaminations of nonactivated alkenes with primary and secondary alkylamines (Scheme 184).642 Following this method, cyclic amines can be obtained in excellent yields. Side-products from the competitive oxidative amination AT


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Scheme 184. Rh-Catalyzed Intramolecular Hydroamination of Alkenes with Secondary Amines

Scheme 185. RhI-Catalyzed Intramolecular Hydroamination of Alkenes with Primary Amines

Scheme 188. Au-Catalyzed Hydroamination of Olefins with Ammonium Salts

isolated yields were obtained when the reactions were carried out in 1,4-dioxane in the presence of 10 mol % of the catalyst.

Scheme 186. Rh-Catalyzed Intramolecular anti-Markovnikov Hydroamination of Olefins

Scheme 189. Zn-Catalyzed Intramolecular Hydroamination of Alkenes

Scheme 187. Ir-Ligand Bifunctional Catalysts in Hydroamination of Alkenes The Lewis acid-assisted hydroamination is usually incompatible with primary aliphatic amines as substrates. This may be caused by the strong affinity of the nitrogen atom toward the metal center, which is not counteracted by the steric hindrance of a substituent. In 2014, Hannedouche et al. reported an intramolecular hydroamination of primary aliphatic alkenyl amines using a well-defined four-coordinate FeII complex as catalyst (Scheme 190).655 Stoichiometric experiments indicate that this transformation proceeds via a stepwise σ-insertion of the alkene into an iron−amido bond. A kinetic isotope effect (KIE) of kH/kD = 3 indicates that the N−H(D) bond cleavage in the aminolysis step is the rate-limiting step. 4.1.6. Intramolecular Asymmetric Hydroamination of Alkenes. In 2010, Buchwald et al. reported the first late transition metal-catalyzed enantioselective intramolecular hydroamination of nonactivated olefins using Rh(cod)2BF4 with Cy-Mop-type ligands (Scheme 191).202 Various enantioenriched pyrrolidines were smoothly synthesized in up to 91% ee. The gold-catalyzed asymmetric intramolecular hydroamination was extensively investigated by Michon et al. Mononuclear AuI complexes bearing BINOL-based chiral phosphoramidite ligands gave good conversions and moderate ee values.656

complex they were able to achieve a reactivity superior to those of previously reported homogeneous zinc complexes.653 Li et al. used ZnI2 to catalyze the hydroamination of 4penten-1-amine derivatives (Scheme 189).654 Up to 95% AU


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Scheme 190. FeII-Catalyzed Intramolecular Hydroamination of Primary Aliphatic Alkenyl Amines

Scheme 193. Ligand-Free Pt-Catalyzed Intramolecular Hydroamination of Alkenes

Scheme 194. Ligand-Free Ir-Catalyzed Intramolecular Hydroamination of Alkenes

Scheme 191. Rh-Catalyzed Asymmetric Hydroamination of Terminal Alkenes

that the reductive elimination from IrIII with Ir−C bond cleavage is the rate-limiting step.661 4.3. Aromatic Amines

4.3.1. Intermolecular Hydroamination of Ethylene. The precatalyst PtBr2 is extensively used for the hydroamination of ethylene. In 2004, Brunet and co-workers reported the first platinum-catalyzed hydroamination of ethylene with arylamines.662 The authors claimed that the basicity of the amine substrates is critical for the transformation. For less basic amines, much higher TONs were observed. Reacting ethylene with the weakly basic 2-chloroaniline and the PtBr2/H+ catalyst (1.0 mol %) for 3 days at 150 °C gave Nethyl-2-chloroaniline in nearly quantitative yield (Scheme 195).

4.2. Aliphatic and Aromatic Amines

4.2.1. Intermolecular Hydroamination of Alkenes. The anti-Markovnikov hydroamination of styrene with secondary aliphatic amines is achieved by using Ru and Rh complexes (see section 4.1.2). In 2008, Gunnoe et al. reported the first coppercatalyzed anti-Markovnikov hydroamination of styrenes with anilines and aliphatic amines using 5 mol % of a monomeric CuI−amido complex as the catalyst (Scheme 192).657 However, the scope of alkenes is limited to styrenes containing a strong electron-withdrawing group in the para position.

Scheme 195. First Pt-Catalyzed Hydroamination of Ethylene with Arylamines

Scheme 192. Cu-Catalyzed anti-Markovnikov Hydroamination of Electron-Deficient Styrenes After this seminal work, Poli663−669 and others670−677 made significant contribution to the Pt- or Rh-catalyzed hydroamination of ethylene with aromatic amines. Leitner calculated a variety of iridium and rhodium complexes with pincer ligands with DFT methods to gain insight into a possible catalytic cycle for the hydroamination of ethylene with ammonia. The results indicated that the computationally active iridium catalyst could promote the hydroamination of ethylene with ammonia.678−680 Ruthenium complexes were also shown to be effective catalysts for the hydroamination of ethylene with both anilines and aliphatic amines.681,682 4.3.2. Intermolecular Hydroamination of Terminal Alkenes. In contrast to Rh- and Ru-catalyzed (see chapter 4.1.2) intermolecular hydroaminations of vinylarenes with aliphatic amines, palladium-catalyzed transformations form the Markovnikov products exclusively (Scheme 196).683,684 Mechanistic studies indicated that these transformations involve an insertion of the C−C double bond into a Pd−H species, followed by an external nucleophilic attack of the amine to a η3benzyl complex.685−687 Furthermore, the combination of Pd(O2CCF3)2, DPPF, and TfOH could effectively promote the hydroamination of vinylarenes with arylamines.688

4.2.2. Intramolecular Hydroamination of Alkenes. In 2010, Stradiotto et al. reported the intramolecular hydroamination of primary and secondary alkyl or aryl amines tethered to α-olefins. The ligand-free Pt-complexes such as PtCl2 and (cod)PtCl2 were used as effective precatalysts for this intramolecular hydroamination (Scheme 193).658 Later, Shi and co-workers described that a highly effective NHC−platinum complex gives similar hydroamination products in up to 99% yield.659 In 2009, the commercially available [Ir(cod)Cl]2 was shown to be an efficient precatalyst for the intramolecular hydroamination of several nonactivated alkenes at relatively low loadings (typically 0.25−5.0 mol % Ir) and without other assisting ligands or cocatalysts (Scheme 194).660 This reaction proceeds with high chemoselectivity from benzyl protected amines. In contrast, N−Boc derivatives did not react. Subsequent mechanistic studies by Stradiotto et al. suggest AV


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4.3.4. Intermolecular Asymmetric Hydroamination of Alkenes. In 1997, Togni et al. reported the first intermolecular enantioselective hydroamination of alkenes (Scheme 200).691

Scheme 196. Pd-Catalyzed Intermolecular Hydroamination of Vinylarenes

Scheme 200. First Ir-Catalyzed Asymmetric Intermolecular Hydroamination of Alkenes

In 2014, Grubbs and co-workers reported a two-step, onepot anti-Markovnikov hydroamination strategy employing a sequence of oxidative and reductive cycles (Scheme 197).689

An Ir/diphosphine system was shown to effectively promote the reaction of norbornene with aniline in up to 95% ee. Furthermore, a remarkable effect of fluoride ions on the activity and selectivity was observed. Later, Zhou and Hartwig achieved a dramatic increase in turnover numbers and enantioselectivity for the conversion of various arylamines with norbornene by utilizing KHMDS instead of fluoride as a base.692 Shibata et al. accomplished the intermolecular asymmetric hydroamination of nonactivated alkenes (Scheme 201).223 In this transformation, the pyridine group is essential for the oxidative addition of Ir to the N−H bond due to its directing effect.

Scheme 197. Pd-Involved anti-Markovnikov Hydroamination of Olefins

Styrenes or aliphatic olefins and either primary or secondary aromatic amines are suitable substrates for this transformation. Additionally, a variety of functionalities, such as ethers, esters, aryl halides, alkyl halides, and nitro groups, were tolerated at the olefin. Currently, the intermolecular hydroamination of nonactivated olefins suffers from the large excess of olefin required. Hartwig and co-workers recently reported an Ir-catalyzed intermolecular hydroamination of nonactivated olefins with indoles (Scheme 198).222 With 4 equiv of olefin, the products

Scheme 201. Ir-Catalyzed Asymmetric Hydroamination of Alkenes with Heteroaromatic Amines

Hartwig and co-workers reported the first palladiumcatalyzed asymmetric intermolecular hydroamination of styrenes using (R)-BINAP as the ligand (Scheme 202).683 Later, Hu and Hii, respectively, reported a series of 4,4′-disubstituted BINAP and SEGPhos ligands for this transformation and achieved ee values up to 85%.693,694

Scheme 198. Ir-Catalyzed Intermolecular Hydroamination of Olefins with Indoles

Scheme 202. Pd-Catalyzed Intermolecular Asymmetric Hydroamination of Styrene were formed in moderate to good yields. Mechanistic investigations revealed that olefin insertion into an Ir−N bond is the rate-limiting step of this transformation. 4.3.3. Intermolecular Hydroamination of Internal Alkenes. Various transition metal catalysts can promote the hydroamination of norbornylene with anilines (Scheme 199). Most of these transformations can be divided into two major mechanistic pathways. One is initiated by the oxidative addition of the low-valent transition metal to the N−H bond of anilines, which was first demonstrated by Casalnuov.690 The second one goes through a carbocation mechanism.153

Transition metal-catalyzed intermolecular asymmetric hydroaminations of alkenes with alkylamines are relatively unexplored as compared to those mediated by rare earth metal catalysts.695 At this stage, a single example has been reported by Hartwig and co-workers using Pd(OCOCF3)2 and (R,R)-EtFerroTANE.688 4.3.5. Intramolecular Hydroamination of Terminal Alkenes. Knowles et al. reported a photoredox-catalyzed intramolecular hydroamination of olefins involving aminium radical cations (Scheme 203).696 The proposed mechanism contains four steps: (a) amine oxidation via electron transfer; (b) turnover-limiting C−N bond formation; (c) a second single-electron transfer step to reduce the carbon-centered radical; and (d) proton transfer with release of the final N-aryl heterocyclic products.

Scheme 199. Transition Metal-Catalyzed Hydroamination of Norbornene

AW


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Scheme 203. Visible-Light Photoredox Protocol for the Intramolecular Hydroamination of Aryl Olefins

Scheme 205. Scope of the Pt-Catalyzed Hydroamidation of Vinyl Arenes

The proposed reaction mechanism of these Pt-catalyzed hydroamidations is illustrated in Scheme 206. The catalytic Scheme 206. Postulated Mechanism for the Pt-Catalyzed Hydroamidation of Vinyl Arenes

4.4. Amides

Pd, Pt, Au, and Ir complexes are used for intermolecular hydroamidation of alkenes with Markovnikov selectivity. No example is available so far for the anti-Markovnikov hydroamidation of alkenes. It is worth mentioning that metal halides in combination with triflate salts or metal triflates are used as catalysts for Markovnikov hydroamidation of alkenes; the in situ generated protic acid might function as the catalytically active species.272,697 4.4.1. Intermolecular Hydroamidation of Ethylene. The first example of a hydroamidation of nonactivated alkenes was reported in 2004 by Widenhoefer and co-workers.698 In their initial protocol, a catalyst generated in situ from [PtCl2(C2H4)]2 and triphenylphosphine mediated the Markovnikov-selective addition of benzamides and carbamates to ethylene and propylene. Limbach et al. later used a cationic platinum bromide complex supported by tridentate NHC ligands to achieve the hydroamidation of ethylene with various amides (Scheme 204).699

cycle starts with an outer-sphere attack of the amide to a platinum−olefin π-complex, resulting in the formation of a zwitterionic platinum-alkyl intermediate. Loss of HCl from this intermediate followed by protonolysis of the Pt−C bond releases the N-alkyl-amide with regeneration of the catalytically active Pt-species. The authors reason that the high Markovnikov selectivity of the platinum-catalyzed hydroamidation of vinyl arenes might result from the zwitterionic character of the metal−olefin interaction, which places substantial positive charge on the benzylic carbon atom. Almost at the same time, Tilley reported the PtII-catalyzed intermolecular hydroamidation of aliphatic terminal alkenes with sulfonamides to generate N-alkyl-substituted sulfonamides in excellent yield (Scheme 207).226 Kinetic studies indicated that the attack of a sulfonamide on the Pt-activated olefin is the rate-determining step.

Scheme 204. NHC−Pt Complex-Catalyzed Intermolecular Hydroamidation of Ethylene

Scheme 207. Pt-Catalyzed Intermolecular Hydroamidation of Alkenes with Sulfonamides

4.4.2. Intermolecular Hydroamidation of Terminal Alkenes. Later, Widenhoefer’s [PtCl2(C2H4)]2 system698 was extended to the reaction of vinyl arenes. For these transformations, the electron-poor tris(4-trifluoromethylphenyl)phosphine proved to be the optimal ligand. The reactions were performed in mesitylene at 140 °C, tolerating electronrich, electron-poor, and hindered styrene derivatives, to afford the products in good yields (Scheme 205).172,173 Control experiments suggest that the hydroamidation of vinyl arenes is reversible at temperature above 140 °C.

The combination of an NHC-amidate-alkoxide palladium catalyst with p-TsOH displays high catalytic activity toward intermolecular hydroamidation of vinyl arenes (Scheme 208).700 In comparison to the Brønsted acid-catalyzed hydroamidation of styrenes,701 this protocol efficiently suppresses the dimerization of the vinyl arene.702 Unfortunately, the substrate scope is limited to halide-substituted and electron-rich vinyl arenes due to the fast reduction of palladium or gold complexes. The turnover number of palladium- or goldAX


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Scheme 208. Pd-Catalyzed Intermolecular Hydroamidation of Vinyl Arenes with Sulfonamides

Scheme 210. Au-Catalyzed Intermolecular Hydroamidation of Nonactivated Alkenes

catalyzed intermolecular hydroamidations could be increased by addition of CuCl2 as shown by Corma et al.258,703 The environmentally friendly and inexpensive FeCl3 was recently shown to not require any ligand or cocatalyst in catalyzing the intermolecular hydroamidation of styrenes with p-toluenesulfonamide.704 On the basis of the palladium-catalyzed aerobic hydroamidation of allenes,607 Liu et al. reported the inter- and intramolecular hydroamidation of styrenes with N-fluorodibenzenesulfonimide (NFSI) in the presence of the bidentate ligand bathocuproine (Scheme 209).705 The ligand is essential for the

Ir-catalyzed intermolecular hydroamidation of terminal alkenes and bicyclo-alkenes with arylamides and sulfonamides to afford the N-alkylamides in high yields (Scheme 211).207 Again, the large amount of olefin required for the process might limit its further application. Scheme 211. Ir-Catalyzed Intermolecular Hydroamidation of Nonactivated Alkenes

Scheme 209. Pd-Catalyzed Markovnikov Selective Hydroamidation of Alkenes with NFSI

4.4.3. Intermolecular Hydroamidation of Internal Alkenes. In 1998, Yamamoto et al. reported the first example for the hydroamidation of methylenecyclopropanes to afford allylamides (Scheme 212).706 On the basis of the deuteriumScheme 212. First Hydroamination of Methylenecyclopropanes

labeling experiments, the authors proposed the following reaction mechanism. A Pd−D intermediate is formed by an oxidative addition of the N-deutero imide to the in situ formed Pd0 species. The C−C double bond migratory insertion into the Pd−D bond, followed by the proximal bond cleavage and migration, formed the π-allylpalladium intermediate. Finally, product and Pd0 are generated by C−N bond reductive elimination. Later, Shi et al. extended the amide scope for this ringopening hydroamidation to sulfonamides.707 In 2005, the Yamamoto group showed that both cyclic amides and primary amines can be used for the hydroamidation or hydroamination of methylenecyclopropanes (Scheme 213).708 The first hydroamidation of cyclopropenes to afford the corresponding allylic amides in good yields was reported by Yamamoto et al. (Scheme 214).709 The same catalyst system also promotes the intermolecular hydrocarbonation of cyclopropene with carbon nucleophiles. The authors suggest that this type of transformation is initiated by oxidative addition of the Pd 0 species to the C−C bond to generate a palladacyclobutene intermediate.

formation of the Pd−H species during the aerobic alcohol oxidation process. The authors suggest that the alkylpalladium intermediate, formed by styrene insertion into the Pd−H species, is oxidized to PdIV by NFSI. Finally, reductive elimination of the C−N bond from the PdIV center generates the Markovnikov hydroamidation product and regenerates the PdII catalyst. In this PdII-to-PdIV oxidation process, the deactivation of the Pd catalyst is decreased by controlling the formation of Pd-black. In 2009, the Widenhoefer group reported a cationic gold complex-catalyzed intermolecular hydroamidation of nonactivated alkenes (Scheme 210).206 A variety of nonactivated terminal alkenes including ethylene were converted to the corresponding intermolecular Markovnikov hydroamidation products at or below 100 °C in excellent yields. However, a vast amount of alkene (10 equiv) is essential for good yields, and only cyclic ureas are suitable amide substrates. Nevertheless, the synthesis of N-alkylamides by intermolecular hydroamidation of nonactivated alkenes still remains a significant challenge. In 2012, the Hartwig group reported an AY


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Scheme 213. Pd-Catalyzed Hydroamidation of Methylenecyclopropanes with Cyclic Amides

takes places in a regioselective manner, and the products display E-configuration only in the case of α-phenyl-substituted vinylcyclopropanes. 4.4.4. Intermolecular Asymmetric Hydroamidation of Alkenes. The gold-catalyzed intermolecular asymmetric hydroamidation of nonactivated alkenes was reported by Widenhoefer et al. (Scheme 218).206 In this protocol, the Markovnikov

Scheme 214. Pd-Catalyzed Intermolecular Hydroamidation of Cyclopropene

Scheme 218. Au-Catalyzed Intermolecular Asymmetric Hydroamidation of Nonactivated Alkenes

In 2009, Pahadi and Tunge reported a similar Pd(PPh3)4catalyzed intermolecular hydroamidation of vinyl ethers. The authors proposed that palladium was oxidized by the relatively acidic sulfonamide to afford a palladium hydride species, which initiated this transformation (Scheme 215).710

hydroamidation products were afforded in good yields and ee values. The scope is limited to aliphatic alkenes, and an excess amount of alkene is required to obtain acceptable yields. 4.4.5. Intramolecular Hydroamidation of Alkenes. One of the early examples of intramolecular hydroamidations of nonactivated alkenes was reported by Sanford and Groves in 2004 using a Rh−H species as catalyst (Scheme 219).713 They

Scheme 215. Pd-Catalyzed Intermolecular Hydroamidation of Vinyl Ethers

Scheme 219. Rh-Mediated Intramolecular anti-Markovnikov Hydroamidation of Terminal Alkenes

In contrast to the palladium-catalyzed hydroamidation of cyclopropenes,706−708 the application of a cationic gold complex leads to the formation of the corresponding pyrrolidine derivatives (Scheme 216).711 The homoallylic sulfonamide, formed by intermolecular ring-opening hydroamidation, is the key intermediate for the finally intramolecular 5-endo hydroamidation. Scheme 216. Au-Catalyzed Inter- and Intramolecular Dihydroamidation of Cyclopropanes

proposed a three-step reaction cycle, whereby a terminal olefin is hydrofunctionalized in an anti-Markovnikov manner: (1) The olefin inserts reversibly into a Rh−H species, (2) reductive elimination of the corresponding hydroamidation product, and (3) regeneration of the active RhI−H species. The antiMarkovnikov selectivity is dictated by the insertion of the olefin, which forms the less substituted and less sterically hindered metal−alkyl intermediate. These consequent steps open the access to pyrrolidine derivatives in moderate yields and with a quite remarkable Sn2/E2 ratio. At the beginning of 2006, Widenhoefer et al. reported the intramolecular hydroamidation of alkenyl carbamates in the presence of [Au{P(tBu)2(o-biphenyl)}]Cl and AgOTf (Scheme 220).714 This transformation tolerates labile carbamates and all kinds of substitution patterns leading to Markovnikov hydro-

The hydroamidation of nonactivated vinylcyclopropanes with sulfonamides to afford homoallylic amides in the presence of 10 mol % AuPPh3OTf was reported in 2007 by Togni’s group (Scheme 217).712 In this reaction, the ring-opening process Scheme 217. Au-Catalyzed Intermolecular Hydroamidation of Vinylcyclopropanes

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Scheme 220. Au-Catalyzed Intramolecular Hydroamidation of Alkenyl Carbamates

Scheme 223. NHC−Au-Catalyzed Intramolecular Hydroamidation of Alkenes

amidation products selectively. Later, the same system was applied for the intramolecular hydroamidation of carboxamides leading to the corresponding heterocycles in moderate to high yield.715 In 2010, Toste synthesized alkyl−AuI complexes through a AuI-promoted intramolecular addition of various amide nucleophiles to olefins (Scheme 221).716 Deuterium labeling

Scheme 224. Intramolecular Hydroamidation Catalyzed by an Acyclic Aminooxycarbene−Au Complex

Scheme 221. Protodeauration of Alkyl−Au Complexes acyclic diaminocarbenes (ADC), which show significant distortion from the coplanarity and have been engaged as ligands for gold catalysis in numerous transformations, acyclic aminooxycarbenes (AAOCs) can maintain their coplanarity. Therefore, olefins without gem-dialkyl substituents, which are less reactive and more challenging, could also be converted into the corresponding cyclic products in good yields, although higher catalyst loadings were required. The group of Sakurai accomplished the intramolecular hydroamidation of alkenes with toluenesulfonamides in EtOH under aerobic and basic conditions (Scheme 225).651,725,726

experiments and X-ray crystal structures supported the proposed anti-addition of the nucleophile to a gold-activated alkene. The protonolysis of C(sp2)−Au bonds is a fast and efficient step.717,718 However, attempted protodeauration of the alkyl−AuI complexes affords the starting olefins.719 Nevertheless, the cleavage of an alkyl−AuI bond could be achieved under reductive conditions. Another contribution to this field was reported by Che and He, respectively (Scheme 222).720,721 Terminal olefins bearing

Scheme 225. Au Cluster-Catalyzed Intramolecular Hydroamidation of Alkenes

Scheme 222. Au-Catalyzed Intramolecular Hydroamidation of Terminal Olefins

tosylated amide or carbamate groups were found sufficiently reactive, affording the corresponding cyclic lactams or carbamates in moderate to good yields, although high metal loadings were required. Besides sterically hindered, electron-rich phosphines such as P(tBu)2(o-biphenyl), which were engaged before, highly sterically hindered N-heterocyclic carbenes, which are strong σ-donors, are also particularly effective ligands for goldcatalyzed hydroamidation reactions. In 2006, Widenhoefer et al. reported the intramolecular 5-exo-hydroamidation of Nalkenyl ureas catalyzed by an NHC−Au complex in the presence of silver triflate allowing the formation of the corresponding N-heterocycles at room temperature in excellent yields (Scheme 223).722,723 In 2011, Hong et al. reported the acyclic aminooxycarbene (AAOCs)−gold-catalyzed hydroamidation of alkenyl ureas with high efficiency (Scheme 224).724 In contrast to the bulky

The oxygen is adsorbed by the Au-cluster giving rise to a cationic site on the gold cluster surface. D-labeling experiments indicate that the EtOH participated in the protonolysis of the C−Au bond by hydrogen abstraction from the ethyl-group forming the desired product and releasing the free gold cluster. In 2012, Shi and co-workers reported a cationic goldcatalyzed cascade process involving intramolecular hydroamidation and ring-opening of sulfonamide-substituted methylenecyclopropyl carbinols (Scheme 226).727 With this method, various isoxazolidine derivatives are accessible in good to excellent yields. In 2006, the first palladium-catalyzed cyclization of amidoalkenes was reported by Michael (Scheme 227).174 Because of the strong tendency of the alkyl-palladium species to BA


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Scheme 226. Au-Catalyzed Intramolecular Hydroamidation To Construct Five-Membered N,O-Heterocycles

Scheme 229. Pt-Catalyzed Intramolecular Hydrohydrazination of Alkenes

alkene. On the basis of control experiments and stoichiometric reactions of the isolated intermediates, the authors proposed a mechanism that involves N−H activation, followed by insertion of the alkene into the Pt−N bond. In the final step, the protonation of the cyclized alkyl−Pt complex by an additional hydrazide releases the cyclization product and regenerates the catalyst. In 2008, the Trost group reported a ruthenium-catalyzed intramolecular hydroamidation of in situ formed α,β-unsaturated ketones, isomerized from propargylic alcohols in the presence of a Ru catalyst to afford the corresponding functionalized pyrrolidine or piperidine derivatives in good yields (Scheme 230).728 It was proposed that the active catalyst

Scheme 227. Pincer Pd-Complex-Catalyzed Intramolecular Hydroamidation of Alkenes

undergo β-hydride elimination, the authors employed a tridentate ligand to block free coordination sites at the Pdcenter, thus steering the reactivity toward a desired protonation of the C−Pd bonds affording various N-heterocycles. The use of coordinating solvents, such as THF, MeCN, or Et2O, completely inhibits the reaction by occupying all free coordination sites at the palladium center. Later, Michael showed that the same catalytic system could be applied for the synthesis of 2,6-disubstituted piperazines via diastereoselective 6-exo-trig cyclization demonstrating its synthetic potential (Scheme 228, top).175 The same group

Scheme 230. Ru-Catalyzed Isomerization/Cyclization of in Situ Formed α,β-Unsaturated Ketones

Scheme 228. Pd-Catalyzed Hydroamidation To Form (Top) Piperazine Derivatives and (Bottom) Morpholine Derivatives promotes a 1,2-hydrogen shift from the propargylic alcohols to generate vinyl-metal species A. The final product is formed through protonolysis of A followed by a Michael addition. This transformation displays good functional group tolerance and a broad scope. As compared to expensive Rh, Au, and Pd complexes, Takaki and co-workers showed that cheap and nontoxic FeCl3 displays also high activity toward the intramolecular hydroamidation of amino-olefins under mild conditions (Scheme 231).729 The Scheme 231. FeCl3-Catalyzed Intramolecular Hydroamidation of Amino-Olefins

recently developed a one-pot procedure to transform Cbzprotected aziridines and allyl alcohols to the corresponding 2,3,5-trisubstituted morpholine derivatives with high diastereoselectivity and excellent yields (Scheme 228, bottom).176 In 2010, Michael et al. developed a Pt-catalyzed intramolecular hydrohydrazination reaction of terminal alkenes, opening a novel route to cyclic hydrazines, which are desirable building blocks for biologically active compounds and ligands (Scheme 229).227 This transformation occurs in the presence of a dicationic Pt-catalyst and AgOTf in DMF and represents the first metal-catalyzed addition of a hydrazine N−H bond to an

formation of the corresponding pyrrolidine and piperidine derivatives occurs in good to excellent yields, and this strategy is not limited to terminal alkenes only but is also suitable for internal alkenes and styrene derivatives. In 2010, Sawamura et al. reported a Cu−Xantphos system that catalyzed the intramolecular 5- or 6-exo-cyclization of terminal olefins substituted with an amine or amide substituent. BB


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The reaction proceeds in alcoholic solvents, and the corresponding piperidines and pyrrolidines are formed in good to excellent yields (Scheme 232).730 This system can also be applied to intramolecular hydroaminations of allylic alcohols to obtain unprotected hydroxylated piperidine and pyrrolidine derivatives.731

Scheme 234. Cu-Catalyzed Asymmetric Intramolecular Hydroamidation of Aromatic N-Sulfonamides

Scheme 232. Cu-Catalyzed Intramolecular Hydroamination of Nonactivated Alkenes

Scheme 235. Proposed Catalytic Cycle for Cu-Catalyzed Asymmetric Hydroamination of Alkenes 4.4.6. Intramolecular Asymmetric Hydroamidation of Alkenes. Various gold complexes exhibit strong activity toward intramolecular hydroamidation of alkenes (Schemes 220−225). In 2012, Mikami et al. used dinuclear gold complexes with chiral phosphoric acid to achieve enantioselective intramolecular hydroamidations of N-allenyl urea, although the ee values are moderate (Scheme 233).732 The authors showed that dinuclear gold complexes significantly accelerate the cyclization process via proximal and bimetallic activation of both the alkene and the urea. In 2012, the Chemler group reported an enantioselective copper-catalyzed 5-exo-trig cyclization of aromatic N-sulfonyl-2allylamines to afford chiral 2-methylindolines under oxidative conditions (Scheme 234).733 The reaction is initiated by enantioselective aminocupration of the alkene to generate an alkyl−copper intermediate. The following homolysis affords a CuI species and a carbon radical, which abstracts a H atom from 1,4-cyclohexadiene. The copper catalyst is then in situ reoxidized by MnO2.

4.5.2. Addition of Hydrazines to Alkenes. In 2004, Carreira et al. reported a novel CoIII-catalyzed olefin hydrohydrazination reaction affording a variety of Markovnikov alkyl hydrazides (Scheme 236).735 The authors hypothesized that the olefin inserts into the in situ hydrido-cobalt species to form an alkyl−Co intermediate, followed by an addition of the N N electrophile. Subsequent reaction of the cobalt hydrazide complex with silane affords the hydrohydrazination product and regenerates the Co−H species. Notably, the olefin conjugation to an aromatic ring was found to have a significant accelerating effect on the rate of the Co-catalyzed hydrohydrazination reaction. Later, the same group improved the reaction conditions and expanded the substrate scope by changing the catalytic system to [Mn(dpm)3].736 In 2005, Carreira and co-workers applied a Co-catalyzed hydrohydrazination of dienes and enynes in a synthesis of allylic and propargylic hydrazines.737


4.5.1. Asymmetric Addition of Hydroxylamine Esters to Alkenes. In 2013, Miura and Buchwald independently reported the copper-catalyzed enantioselective hydroamination of alkenes with O-benzoylhydoxylamines in the presence of hydrosilanes (Scheme 235).244,245,734 Various terminal and internal olefins are tolerated in this transformation, forming the corresponding enantioenriched tertiary amines in moderate to excellent yields. They postulated that the LnCu−H intermediate is the key catalytic species in this transformation. In the first step, the alkene inserts into the Cu−H bond of the LnCu−H species to generate the corresponding alkyl−Cu complex. The following oxidative addition of an electrophilic amine leads to the corresponding CuIII intermediate. Reductive elimination releases the desired product and regenerates the CuI catalyst.

Scheme 233. Au−Au Complex-Catalyzed Enantioselective Intramolecular Hydroamidation of Alkenes

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Scheme 236. Co-Catalyzed Intermolecular Hydrohydrazination of Alkenes

4.5.3. Addition of Azides to Alkenes. The direct addition of HN3, TMSN3, or NaN3 to olefins is an efficient method to obtain alkyl azides.738−743 However, the scope of olefins was limited to styrenes or activated alkenes. These limitations were overcome by Carreira et al., who developed a Co-catalyzed intermolecular hydroazidation of nonactivated olefins using a catalyst that is generated in situ from ligands and CoII-salts (Scheme 237).744−746

of methanol and supercritical CO2, the latter being an attractive, green medium (Scheme 239).748 It is a direct and convenient method to construct β-amino acid derivatives in high yields. Scheme 239. Pd-Catalyzed Intermolecular Hydroaminations of Alkenes with Tertiary Amines

Scheme 237. Co-Catalyzed Intermolecular Hydroazidation of Olefins with TsN3 Complementary to various N-containing nucleophiles used for the hydroamination process, electrophilic N sources were used for the one-pot hydroamination of terminal aliphatic alkenes to form anti-Markovnikov tertiary alkyl amines (Scheme 240).243 Interestingly, when styrene is used as the Scheme 240. Cu-Catalyzed Intermolecular anti-Markovnikov Hydroamination of Alkenes In 2012, Boger and co-workers developed a FeIII/NaBH4mediated hydroazidation of nonactivated olefins with NaN3, which proceeds exclusively via Markovnikov addition (Scheme 238).747 Besides NaN3, a range of free radical scavengers, such Scheme 238. Fe-Mediated Intermolecular Hydroazidation of Olefins with NaN3

substrate, the Markovnikov hydroamination product is selectively formed.749 This switch of regioselectivity has been explained by a reinsertion of the alkene into a copper−hydride bond generating an energetically more stable α-bound Cu species.750 This strategy provides an efficient way to perform an anti-Markovnikov hydroamination of aliphatic alkenes751,752 alternatively to the Rh- or Ru-catalyzed anti-Markovnikov hydroamination of styrenes discussed above.205,220,237

5. CATALYTIC ADDITION OF NITROGEN NUCLEOPHILES TO CONJUGATED MULTIPLE BONDS The addition of nucleophiles to conjugated multiple bonds meets another significant problem related to the control of regioselectivity. It is not too surprising that there are comparably few reports about the hydroamination and -amidation of conjugated multiple bonds. The addition of nitrogen nucleophiles to conjugated diynes can be achieved with late transition metal catalysts, such as copper or gold complexes.753−755 If enynes are used as substrates for hydroamination or hydroamidation reactions, the first addition occurs regioselectively at the triple bond with subsequent addition to the double bond.756 Intramolecular hydroaminations and hydroamidations to 1,3-dienes can be achieved with various metal catalysts and even under metal-free conditions.138

as OH, SCN, Cl, CN, NHCONH2, NO, and TEMPO, are available to capture the alkyl radical intermediates formed during the functionalization reaction. 4.5.4. Addition of Secondary Amine Precursors to Alkenes. It is generally accepted that PdII complexes can be effectively reduced to Pd0 in the presence of tertiary amines to form the corresponding secondary amines via C−N bond activation. Jiang et al. reported the intermolecular hydroamination of activated alkenes with tertiary amines in a mixture BD


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Nevertheless, a selective intermolecular hydroamination and -amidation of 1,3-dienes is still a challenge, which may soon be overcome by using late transition metal catalysts.210

Scheme 243. Cu-Catalyzed 5-exo-dig Cyclization of Enynamines

5.1. Aliphatic Amines

5.1.1. Hydroamination of Diynes. In 1972, Chalk and coworkers reported the copper-catalyzed hydroamination of 1,3butadiynes with benzylamine (Scheme 241).753 However, the high reaction temperature and the restricted substrate scope prevent an industrial broad application. Scheme 244. Ni-Catalyzed Intermolecular Hydroamination of 1,3-Dienes

Scheme 241. Cu-Catalyzed Intermolecular Hydroamination of 1,3-Butadiynes

The PdII-3-iminophosphine (3IP) complexes can catalyze the hydroamination of 1,3-dienes and allenes with secondary aliphatic amines, but the narrow substrate scope of this transformation has so far precluded further applications.757 5.2. Aliphatic and Aromatic Amines

5.2.1. Hydroamination of Diynes. In 2010, Hua et al. reported the copper-catalyzed intermolecular hydroamination of 1,3-butadiynes to form 1,2,5-trisubstituted pyrrole derivatives. The transformation occurs via intramolecular hydroamination of an amino enyne intermediate (Scheme 245).754

5.1.2. Hydroamination of Enynes. In 1998, Yamamoto et al. reported the first intermolecular stereoselective hydroamination of conjugated enynes in the presence of a palladium(0)/acid catalytic system (Scheme 242).756 It was supposed that AcOH underwent oxidative addition to Pd0 followed by ligand exchange to generate the R2NPd−H species. Hydroamination of enynes gave the allenyl amine, which undergoes a consecutive hydroamination step to form the final product. In 2003, Gabriele et al. demonstrated that CuCl2 and PdI2 exhibit high reactivity in the cycloisomerization of Z-(2-en-4ynyl)amines to form the corresponding substituted pyrroles (Scheme 243).208 CuCl2 displays good activity for the cycloisomerization of substrates substituted at the C-3 position, while the PdI2/KI system was found to be superior in the reaction of enynamines not substituted at the C-3 position. 5.1.3. Hydroamination of Dienes. In 2002, Hartwig and co-workers reported the nickel-catalyzed hydroamination of 1,3-dienes with aliphatic amines to form allylic amines. The combination of DPPF, Ni(cod)2, and acids forms an active catalyst system, which can be used for this transformation (Scheme 244).242

Scheme 245. Cu-Catalyzed Intermolecular Hydroamination of 1,3-Butadiynes

The copper-mediated dihydroamination of 1,3-butadiyne with amines has been widely used for the synthesis of pyrrolic

Scheme 242. Pd-Catalyzed Intermolecular Hydroamination of Enynes

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hydroamination of nonactivated 1,3-dienes with anilines, using a novel catalytic system consisting of Pd(cod)Cl2 and DPEphos to give the 1,4-hydroamination products.766 Using this catalytic system, both cyclic and acyclic 1,3-dienes can be converted. Alternatively, a cationic ruthenium complex in combination with HBF4·OEt2 at 60 °C can promote the addition of aniline to acyclic 1,3-dienes in moderate yields.682 5.3.3. Asymmetric Hydroamination of Dienes. In 2001, Hartwig et al. reported the palladium-catalyzed intermolecular asymmetric hydroamination of cyclohexadiene with anilines to afford the allylic amines in good yields and high enantioselectivities (Scheme 249).225 Both electron-withdrawing and

macrocycles, which are important due to their biological and electron-conducting properties.758−761 5.2.2. Hydroamination of Dienes. Several transition metal catalysts have been used for the regioselective intermolecular hydroamination of 1,3-dienes to afford allylic amines. Some are effective for aliphatic amines,242,757 while others are useful for the aromatic ones.682,684,762−764 However, there is still lack of a general system that allows the addition of both aryl and alkyl amines to 1,3-dienes in good yields.765 Meek and co-workers applied a carbodicarbene (CDC)−Rh complex in the hydroamination of 1,3-dienes with aryl and alkyl amines. The corresponding products were isolated in up to 97% yield and with >98:2 regioselectivity (Scheme 246).210 Generally, the (CDC)−Rh-catalyzed hydroamination of 1,3-dienes with alkyl amines requires higher reaction temperatures as compared to aryl amines.

Scheme 249. Pd-Catalyzed Intermolecular Asymmetric Hydroamination of 1,3-Dienes

Scheme 246. Rh-Catalyzed Intermolecular Hydroamination of 1,3-Dienes

5.3. Aromatic Amines

electron-donating substituents on the arenes are well tolerated. Moreover, the reaction can be done at room temperature, but a long reaction time (up to 120 h) is required for achieving satisfactory results.

5.3.1. Hydroamination of Diynes. Kramer et al. reported the gold-catalyzed intermolecular hydroamination of polarized conjugated diynes producing 2,5-disubstituted pyrrole derivatives in good to excellent yields (Scheme 247).755 It is worth

5.4.1. Hydroamidation of Diynes. Kundu and co-workers employed a copper/phenanthroline system for the catalytic hydroamidation of conjugated diynes (Scheme 250).212 Fair to

5.4. Amides

Scheme 250. Cu-Catalyzed Hydroamidation of 1,3-Diynes

Scheme 247. Au-Catalyzed Intermolecular Hydroamination of 1,3-Diynes

mentioning that electron-rich pyrroles are usually difficult to synthesize. Furthermore, the 1,2,5-trisubstituted pyrroles can be obtained in moderate yields at relatively low temperatures. 5.3.2. Hydroamination of Dienes. In 2001, Ozawa and co-workers described the hydroamination of 1,3-dienes with aniline in the presence of palladium complexes supported by sp2-hybridized phosphorus compounds (Scheme 248).762 The [Pd(η3-allyl)Cl]2/Xantphos system was found to be an effective catalyst for the intermolecular hydroamination of cyclic 1,3dienes.684,763,764 In 2014, the Beller group reported the

good yields and excellent E-selectivities of N-alkenynes can be obtained when acyclic amides are used as N−H nucleophiles together with 10 mol % of the copper catalyst, whereas moderate Z-selectivities of N-alkenynes were observed when lactams were used as N-nucleophiles under similar reaction conditions. Notably, the copper catalyst achieves the selective addition of only one amide group to the diyne. In 2013, the Banwell group reported the consecutive AuIcatalyzed intramolecular hydroamidation of diynes to obtain pyrimido[1,6-a]indol-1(2H)-one derivatives in good yields (Scheme 251).767 5.4.2. Hydroamidation of Dienes. In 2006, He and coworker reported the first gold-catalyzed intermolecular hydroamidation of 1,3-dienes with sulfonamides and carbamates at room temperature (Scheme 252).768 Later, the Ujaque group studied the mechanism of AuI-phosphine-catalyzed hydroamidation of 1,3-dienes by density functional methods.769 It was found that the PPh3AuOTf species first undergoes ligand

Scheme 248. Pd-Catalyzed Intermolecular Hydroamination of 1,3-Dienes

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sulfonamides, and carboxamides. This method gives access to corresponding allylic amides in good yields and high regioselectivity (Scheme 254).772

Scheme 251. Au-Catalyzed Double Hydroamidation of Alkynes

Scheme 254. Cu/Bi-Catalyzed Intermolecular Hydroamidation of 1,3-Dienes

Scheme 252. Au-Catalyzed Intermolecular Hydroamidation of 1,3-Dienes

A significant acceleration effect of bidentate phosphine ligands was observed for the copper-catalyzed intermolecular hydroamidation of cyclic dienes (Scheme 255).773 This Cu(OTf)2/dppe system smoothly promotes the intermolecular Markovnikov hydroamidation of vinylarenes and norbornene with sulfonamides.

substitution between the triflate ligand and one diene, followed by nucleophilic attack of the benzyl carbamates to the activated 1,3-dienes. The authors proposed that the triflate anion can act as a proton shuttle mediating the tautomerization of benzyl carbamate and assisting protonolysis of the C−Au bond. Later, Nájera et al. found an intermolecular hydroamidation of 1,3-dienes with sulfonamides in the presence of a catalyst loading as low as 0.1 mol % [(PhO)3P]AuCl/AgOTf at room temperature.770 Besides 1,3-dienes, nonactivated alkenes are also suitable for this transformation. Terminal alkenes undergo Markovnikov hydroamination, while dienes are hydroaminated regioselectively at the less substituted double bond. Intermolecular hydroamidation of 1,3-dienes can be accomplished by using only AgOTf as the catalyst at 85 °C or room temperature.771 In 2014, Beller et al. reported the first palladium-catalyzed intermolecular hydroamidation of 1,3-dienes with amides and sulfonamides to afford the corresponding allylamides in high yield (Scheme 253).211 This method tolerates various functional groups and shows excellent regioselectivity. Matsunaga and Shibasaki et al. disclosed a Bi(OTf)3/ Cu(MeCN)4PF6 bimetallic catalyst system for the intermolecular hydroamidation of 1,3-dienes with carbamates,

Scheme 255. Cu-Catalyzed Intermolecular Hydroamidation of Cyclic Dienes

In 2010, Yamamoto et al. reported the intramolecular hydroamidation of dienyl sulfonamides to generate the corresponding five- and six-membered vinylene-type heterocycles (Scheme 256, path a).774 The cyclization products can be obtained in excellent yields at room temperature. Later, the same group used bulky carbaboranylmercuric salts to selectively activate terminal alkenes (Scheme 256, path b).775 Following this strategy, the intramolecular hydroamidation of 1,3-dienes gives access to homoallylic amine derivatives in good to excellent yields with high regioselectivity. The Yeh group demonstrated that a cationic gold complex also shows high catalytic activity for intramolecular hydroamidations of cyclo-1,3-dienes (Scheme 257).776 Hexahydroindole derivatives can be obtained in good yield in the presence of 5 mol % Ph3PAuCl/AgOTf at 80 °C. The authors reasoned

Scheme 253. Pd-Catalyzed Intermolecular Hydroamidation of 1,3-Dienes

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Scheme 256. Hg(OTf)2-Catalyzed Intramolecular Hydroamidation of 1,3-Dienes

Scheme 259. Lewis or Brønsted Acid-Catalyzed Intramolecular Hydroamidation of 1,3-Dienes

Brønsted acids usually generate allylic amines as mentioned above due to the formation of η2-allyl complexes and the stability of these allyl cationic intermediates. In 2013, the Michael group accomplished the 5-exo-1,2-addition of dienes by using a pincer palladium catalyst to give homoallylic amine derivatives in good to excellent yields (Scheme 260).779 The Scheme 257. Au-Catalyzed Intramolecular Hydroamidation of Cyclo-1,3-dienes

Scheme 260. Pincer Palladium-Catalyzed Intramolecular Hydroamidation of 1,3-Dienes

that the AuI species coordinates to the 1,3-diene at the double bond adjacent to the arylsulfonamide to generate a η2-alkene Au complex followed by an anti-attack of the sulfonamide at the terminal position of the 1,3-diene, forming a fused bicyclic ring with a newly formed Au−C bond at the allylic position. The final product is formed by sequential allylic rearrangement of the η1-allyl-Au complex and protodemetalation. In 2011, Ramachary et al. observed a competition between intra- and intermolecular hydroamidation in the presence of 5 mol % Ph3PAuCl/AgOTf in toluene at 100 °C (Scheme 258).777 This is one of the few examples of intramolecular hydroamidations of anilines. A plausible mechanism for the formation of the phenanthridine products starts with a rather unusual intermolecular hydroamidation of the 1,3-diene moiety followed by [4 + 2] cycloadditions. The product selectivity was mainly controlled by the nature of the substituent at the nitrogen group. A variety of transition metals, such as silver triflate, cationic gold complexes, BINAP−Cu(OTf)2, FeCl3, and InBr3, are effective for intramolecular hydroaminations of conjugated acyclic aminodienes to afford allylic amines (Scheme 259).778 Lewis acids such as iodine and Brønsted acid TfOH increase the activity for hydroamidation of 1,3-dienes. Among various catalysts, (triphenylphosphine)gold(I) triflate and TfOH provide the best results. One major challenge in hydroamidations of dienes is the control of the regioselectivity. Transition metal catalysts and

observed regioselectivity arises from a 1,4-aminopalladation to form the less-substituted η1-allyl complex, then followed by the SE2′ protonation of the ally-Pd intermediate. Homoallylic alcohols can also react as pseudodienes. Thus, 2,5-dihydro-1H-pyrroles and 1,2-dihydroquinolines can be effectively synthesized by Cu(OTf)2-catalyzed intramolecular cyclization of homoallylic amino alcohols under mild conditions (Scheme 261).780 Scheme 261. Cu-Catalyzed Hydroamidation of in Situ Formed 1,3-Dienes

5.4.3. Asymmetric Hydroamidation of Dienes. The Katsumura group developed an asymmetric 6-endo-cyclization to afford chiral 2-piperidinones using a Pd2(dba)3/(S)-BINAP system (Scheme 262).781

Scheme 258. Competition between Intra- and Intermolecular Hydroamidation

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oxidative C−H activation,786 and carboxylate-assisted ruthenium-catalyzed alkyne annulations by C−H/Het−H bond functionalizations.787 In many of these processes, late transition metals are used to mediate the hydroamination or hydroamidation steps. As illustrated in Scheme 265, the cascade reactions involving late transition metal-catalyzed hydroaminations or -amidations can be divided into four categories: (1) Processes that are initiated by hydroamination or -amidation steps that give rise to reactive intermediates, such as enamides that undergo follow-up reactions such as nucleophilic additions, C−H functionalizations, oxidative or reductive processes, or C−C bond cleavages. (2) Processes in which the N−H reagent consecutively adds to two or more π-bonds. (3) Processes in which N−H reagents are initially formed, for example, via a nucleophilic addition of a X−H group across imines, nitriles, or N-heterocycles and then undergo intra- or intermolecular hydroaminations or -amidations. (4) Catalytic cross-couplings between N-sources and C−C multiple bonds leading to N−H functionalized alkenes or alkynes, which subsequently undergo intramolecular hydroaminations or -amidations. It is not always easy to decide whether or not a reaction cascade involves a true hydroamination or -amidation step, that is, an addition of an N−H group across a multiple bond. In many cases, different mechanistic pathways have been postulated for seemingly related procedures, some of which involve catalytic additions of N−H groups across double bonds, others leading to very similar intermediates or products via alternative pathways that do not explicitly mention hydroamination or -amidation steps. We have decided to apply a rather liberal interpretation of the terms hydroamination and -amidation throughout this section, and thus to include reactions in which the C−N bond formation may, but need not in all instances, be rationalized by a hydroamination or -amidation process.

Scheme 262. Pd-Catalyzed Asymmetric 6-endo Cyclization of Dienamides

Another asymmetric intramolecular hydroamidation of 1,3dienes was reported by Toste et al. by using a dinuclear gold complex as catalyst (Scheme 263).209 The rate and selectivity of Scheme 263. Au-Catalyzed Asymmetric Intramolecular Hydroamidation of 1,3-Dienes

this transformation are enhanced by adding potential Brønsted acids. Control experiments indicated that these two products are formed through two different mechanisms. In the first case, the gold catalyst coordinates to a diene, thus facilitating an intramolecular nucleophilic addition. Protodemetalation of the newly formed complex leads to the product a. In the second pathway, gold coordinates to menthol, thus increasing its Brønsted acidity, which then protonates the dienes. The following cyclization of the nucleophile leads to product b. 5.5. Other Nitrogen Nucleophiles

5.5.1. Addition of Hydroxylamines and Hydrazines to Dienes. Hartwig et al. extended their [Pd(η3-allyl)Cl]2/ Xantphos system to the hydroamination of aliphatic dienes with hydrazine and hydroxylamine derivatives. The system is able to form allylamine products at the more hindered site in high yields under mild conditions (Scheme 264).782,783 Scheme 264. Pd-Catalyzed Intermolecular Hydroamination of 1,3-Dienes with Hydrazines

6.1. Cascade Insertions of Several C−C and C−X Multiple Bonds into N−H Bonds

6.1.1. Cascade Insertion of Diynes or Enynes into an N−H Bond. The reaction of enediynes with anilines leads to the formation of diarylamines via a reaction cascade initiated by addition of the amino groups. Liu and co-workers employed a cationic ruthenium complex to synthesize anilines, phenols, or ethers in high yields from enediynes and various nucleophiles such as anilines, water, alcohols, acetylacetones, pyrroles, or dimethyl malonate (Scheme 266).788 This reaction concept can also be used to access bicyclic structures from 1,2-dietynylbenzenes with tethered nucleophiles (Scheme 267).789 Besides cationic ruthenium complexes, platinum dichloride is also a good catalyst for this reaction. Fujii and Ohno reported another example of a hydroamination/cyclization cascade using a cationic gold complex (Scheme 268).790−792 The reaction gives access to various benzo[a]carbazoles, benzo[c]indoles, as well as azepino- or oxepino-indole derivatives, and even polycyclizations have been demonstrated. A related gold-catalyzed cascade cyclization of 1,6-diynes, triggered by an intramolecular nucleophilic addition reaction, was also employed to construct other monocyclic and bridged bicyclic products.793,794

6. REACTION CASCADES AND SEQUENCES Reaction cascades containing transition metal-catalyzed hydroaminations open a wealth of opportunities for the synthesis of complex molecules, especially structures containing nitrogen heterocycles. Such reactions have extensively been employed in organic synthesis, for example, for accessing core structures of alkaloids.784 Part of this material is covered in reviews on other elemental steps within cascade reactions, carbo- and heterocyclization of oxygen- and nitrogen-containing electrophiles,785 C−C, C−O, and C−N bond formation via RhIII-catalyzed BI


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Scheme 265. Transition Metal-Catalyzed Cascade Reactions Involving Hydroamination or Hydroamidation Steps

Scheme 266. Ru-Catalyzed Nucleophilic Addition to Enediynes

Scheme 268. Au-Catalyzed Cascade Hydroamination/ Cyclization

Scheme 267. Ru-Catalyzed Hydroamination/Cyclization of 1,2-Dietynylbenzenes

the higher is the activity of the catalyst system. AuPtBu3NTf2 (5 mol %) in acetonitrile at 80 °C catalyzes the transformation of anilines and alkynes (4 equiv) to dienamines with up to 99% yield. AuI-catalyzed tandem cyclization reactions of various 1,6diyne derivatives, tethered to nitrogen or oxygen groups, have been reported by the group of Fiksdahl (Scheme 271).793 The reactions are triggered by N-nucleophiles, such as amine, amide, and sulfonamide functionalities. Depending on the substrate, the catalytic system, and reaction conditions, different regioisomers of monocyclic and bridged bicyclic heterocyclic products were obtained.797 In 2014, Wan et al. reported an efficient synthesis of fused pyrroles via hydroamination/cyclization of 2-alkynyl-propiolates, and primary amines (Scheme 272).798 According to the proposed mechanism, the enamine intermediates formed in the hydroamination step are further converted into vinyl silver intermediates, which cyclize to the products in good yields.

In 2007, Li and co-workers reported a mixed intra- and intermolecular double hydroamination that proceeds in one pot under mild conditions without solvent (Scheme 269).795 Control experiments support a mechanism in which the intermolecular hydroamination precedes the intramolecular endo-cyclization to the indole. In 2010, Corma et al. presented a gold(I)-catalyzed double intermolecular hydroamination (Scheme 270).796 The better electron-donating and more hindered is the phosphine ligand, BJ


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and regioselectivities. It is believed that the reaction proceeds via a cobalt-mediated oxidative coupling of the diyne moiety to yield a cobaltacyclopentadiene intermediate followed by proton transfer and formation of an N-coordinated cobaltacyclopentene complex. Reductive valence tautomerization and release of the cobalt mediator with Fe(NO3)3 furnishes the dienamide product. A nickel complex catalyzes a cascade involving alkyne/allene rearrangement, intermolecular hydroamination, insertion of the second alkyne residue, and rearomatization (Scheme 274).800 Pyrroles and furans bearing various secondary amino groups can be accessed this way. 6.1.2. Cascade Insertion of Two Separate Alkynes or Alkenes into an N−H Bond. In 2012, a silver-catalyzed double insertion of internal alkynes into an N−H bond was reported by Zhu et al. (Scheme 275).801 Solely the ratio of the alkynes to the anilines determines whether simple hydroamination products are formed or two molecules of the alkyne insert into the N−H bond. The reaction is strictly limited to phenylpropiolic acid esters. A similar double hydroamination followed by imine− enamine tautomerization and cycloisomerization was reported by Qian et al. It allows synthesizing 1,5-benzodiazepines from ortho-phenylenediamines and terminal alkynes (Scheme 276).802 Double hydroamination gives rise to dienamine intermediates, which then tautomerize to the enamines and cycloisomerize with formation of the seven-membered diazepine ring. N-Substituted o-phenylenediamines and terminal alkynes were found to be suitable substrates for constructing 1,5-benzodiazepines under the same conditions.803 On the basis of this strategy, fused tricyclic benzo[b][1,4]diazepines can be accessed in good yields. For activated alkynes such as ethyl propiolate, the functionalized 1,5-benzodiazepine is formed even without catalyst, whereas nonactivated alkynes require the presence of a gold catalyst.804 In contrast, in the presence of a copper catalyst, ortho-phenylenediamines and terminal alkynes undergo another hydroamination cascade to form quinoxalines instead of 1,5-benzodiazepines.805 Lei and Lu reported an intramolecular hydroamidation of ynamides followed by an intermolecular coupling with α,βunsaturated carbonyl compounds in the presence of a palladium catalyst to generate 1,3-oxazolidin-2-ones, imidazolidin-2-ones, or lactams (Scheme 277).806 The cyclization products are obtained in good yields and high chemo- and stereoselectivities via an alkyne aminopalladation/alkene insertion/protonolysis cascade. Lu807 and others808,809 used related strategies for coupling 2alkynylanilines and α,β-unsaturated carbonyl compounds to give indole derivatives (Scheme 278). This transformation is also effectively mediated by gold810 or rhodium(I) catalysts.434 In 2010, the Patil group reported a related synthesis that is initiated by a gold-catalyzed intramolecular hydroamination. The intermediately formed vinyl-gold species reacts with an exocyclic enol ether, which itself is formed via gold-catalyzed cyclization of alkynols to give indoles bearing cyclic ethers (Scheme 279).811 6.1.3. Insertion of an Allene and an Alkene into an N− H Bond. Trost and co-workers reported ruthenium-catalyzed syntheses of pyrrolidines and piperidines from allenes and enones (Scheme 280).812 The ruthenium catalyst coordinates to the allene and enone moiety to form the ruthenacycle intermediate, which is attacked by the secondary amine to generate a ruthenium enolate species. Protonation gives the

Scheme 269. AuCl3-Catalyzed Double Hydroamination of oAlkynylanilines with Terminal Alkynes

Scheme 270. AuI-Catalyzed Double Intermolecular Hydroamination of Terminal Alkynes

Scheme 271. Au-Catalyzed Cascade Hydroamination/ Cyclization of 1,6-Diynes

Scheme 272. Fused Pyrrole Synthesis via Ag-Mediated Hydroamination/Cyclization Cascade

A cobalt-mediated, regio- and stereoselective synthesis of dienamides from α,ω-diynes and amides proceeding via a hydroamidation process was reported by Vollhardt and coworkers (Scheme 273).799 In the presence of 1 equiv of (η5cyclopentadienyl)bis(η2-ethene)cobalt(I), the amides were found to add to terminal and internal diynes in good yields BK


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Scheme 273. Co-Mediated Syntheses of Dienamides

Scheme 274. Ni-Catalyzed Hydroamination/Cyclization of 1,6-Diynes

transformation is so far restricted to nonsubstituted acrolein in combination with allenes bearing simple hydrocarbon substituents. Because allenes are more reactive than α,βunsaturated aldehydes, acrolein needs to be used in 15-fold excess to suppress homocoupling of the allene. 6.1.4. Cascade Insertion of C−C and C−O Double Bonds into an N−H Bond. In 2014, Kanai et al. reported an N−H bond addition to a C−C and a C−O double bond to generate indole derivatives. The reaction proceeds via intramolecular amidocupration of an allene, followed by asymmetric addition of the chiral allyl−Cu species formed in situ to an aldehyde or ketone (Scheme 282).814 Aromatic, heteroaromatic, and aliphatic aldehydes and ketones are suitable substrates for constructing 2-(2-hydroxyethyl)indole scaffolds in this efficient and enantioselective process. 6.1.5. Intramolecular Cascade Insertion of Alkenes and Alkynes into an N−H Bond. In 2005, Kozmin et al. reported the double cyclization of 1,5-enynes bearing nitrogenbased nucleophiles (Scheme 283).815 It is believed that the gold catalyst activates the alkyne triple bond for nucleophilic attack

Scheme 275. Ag-Catalyzed Sequential Hydroamination of Internal Alkynes

cyclization products in good to excellent yields. The range of nitrogen nucleophiles is limited to secondary aliphatic amines. Amides and sulfonamides are not suitable for this transformation. Lu et al. disclosed a palladium-catalyzed intramolecular hydroamidation of allenes affording vinyl-PdII intermediates, which then undergo intermolecular addition to α,β-unsaturated aldehydes. This reaction cascade yields 1,3-oxazolin-2-ones substituted in the 3-position with an aldehyde- and alkenecontaining side chain (Scheme 281).813 The scope of this

Scheme 276. Au-Catalyzed Double Hydroamination/Tautomerization/Cycloisomerization

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Scheme 277. Pd-Catalyzed N−H Bond Insertion into a C−C Triple Bond/C−C Double Bond

In 2007, an efficient gold-catalyzed hydroamidation/cycloisomerization process starting from 1,6-enynes was reported by the Michelet group (Scheme 284).816 The scope for the nitrogen nucleophiles ranges from tosamides, ethyl, or benzyl carbamates to arylamines containing electron-withdrawing groups. The reaction provides good to excellent yields of the substituted secondary carbo- and heterocyclic amines. In 2010, Wang et al. utilized a cationic gold complex to activate amidoalkynyl indoles (Scheme 285).817 The amide nucleophile adds across the indole double bond, then the alkyne inserts into the Au−C bond, and the fused polycyclic 2,3-dihydro-indole product is liberated by hydrodeauration. This transformation was also employed to synthesize the akuammiline alkaloid minfiensine.

Scheme 278. Pd-Catalyzed Hydroamidation Involving One Alkyne and One Activated Alkene

Scheme 279. Au-Catalyzed Hydroalkoxylation/ Hydroamination of Alkynols and 2-Alkynylanilines

6.2. Hydroamination/Hydroamidation Followed by Further Functionalization

In this reaction type, a hydroamination or hydroamidation process generates a reactive intermediate in situ, which is susceptible to further transformations, such as C−C or C− heteroatom bond formations (Scheme 265). 6.2.1. Hydroamination Followed by Hydrolysis. The most commonly encountered reaction cascade containing a nucleophilic substitution step is the hydroamination of alkynes followed by the hydrolysis of the resulting enamines or imines with formation of ketones. The overall process is synthetically equivalent to the often harder to control direct hydration of alkynes. There are few recent examples for this established transformation. In 2002, Yamamoto et al. disclosed a palladium-catalyzed hydroamination/hydrolysis cascade that allows converting internal alkynes to ketones in near quantitative yield (Scheme 286a). 171 As the amine component, 2-aminophenol is employed. A chelating coordination of the phenolic OHfunction is essential in the hydroamination process. This reaction concept was extended to the intermolecular hydroamination/C−C bond cleavage of diynes to yield imines and 1,3-benoxazoles (Scheme 286b).818 In 2011, the Urabe group reported an efficient synthesis of butyrolactones via Rh-catalyzed intramolecular debenzylative hydroamination of molecules bearing both a benzylamino and a chloroacetylene moiety (Scheme 287).819 It was suggested that the rhodium catalyst promotes the intramolecular aminometalation to give the benzylammonium salt intermediate, which is attacked by water to cleave the benzylic C−N bond. Hydrolysis of chlorovinyl rhodium intermediate affords the lactam. The reaction proceeds best with chloroalkynes; other haloacetylenes tend to decompose under the reaction conditions. 6.2.2. Hydroamination Followed by Nucleophilic Substitution. The hydroamidation of 2-alkynyl-aminobenzenes bearing a hydroxymethyl group leads to indoles, which can be further derivatized in situ by nucleophilic substitution with amines and hydrolysis of the amide group (Scheme 288).820

Scheme 280. Addition of an N−H Group to an Allene Followed by an Alkene Insertion

Scheme 281. Pd-Catalyzed N−H Addition to Allenes and α,β-Unsaturated Aldehydes

by the alkene resulting in 6-endo-dig ring closure, thereby generating a positive charge that induces the nucleophilic attack by the amide nitrogen with 5-endo-trig cyclization to generate an alkenyl−Au intermediate. Subsequent proton-initiated demetalation releases the gold catalyst and liberates the fused pyrrolidine product. The reaction was also shown to work with 1,5-enynes bearing oxygen-based nucleophiles. BM


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Scheme 282. Cu-Catalyzed N−H Addition to an Allene Followed by CO Insertion

been used in the total synthesis of (−)-rhazinilam and the first asymmetric total synthesis of (−)-rhazinicine. 6.2.3. Hydroamination Followed by Dehydration. The hydroamination or -amidation of propargyl alcohol derivatives leads to the formation of hydroxyl enamines or enamides, respectively, which easily undergo dehydration to form the conjugated 1,3-dienes or heterocycles (Scheme 292). This reactivity opens opportunities for several follow-up steps as detailed below. 6.2.3.1. Hydroamidation Followed by Dehydration. In the presence of 2 mol % CuCl2, γ-N-Boc- or N-tosyl-4-amino-1-yn3-ols undergo intramolecular hydroamidation followed by dehydration to form pyrroles (Scheme 293).825,826 Ag and Pd complexes were also reported to be efficient catalysts for this elegant pyrrole synthesis.827,828 In 2013, Sahoo and co-workers reported a simple protocol for the formation of E-allyl-gem-dipyrazoles via an α-attack of pyrazole on the transiently formed allene pyrazole (Scheme 294).829 6.2.3.2. Hydroamination Followed by Dehydration and Condensation. Bandini et al. reported an efficient synthesis of tricyclic 6H-azepino[1,2-α]indoles from N-3-oxoalkyl-3-(2aminophenyl)prop-2-yn-1-ols via a cascade hydroamination/ dehydration/condensation sequence mediated by a silver/gold system (Scheme 295).830 Control experiments suggest that a cationic gold species inserts into the electron-rich C−C double bond to give a nucleophilic vinyl-Au intermediate, which undergoes an intramolecular condensation reaction with the ketone closing the seven-membered ring. 6.2.3.3. Hydroamidation Followed by Double Dehydration. In 2012, Chan et al. reported an efficient synthesis of 2alkynylindole derivatives via a silver-catalyzed hydroamidation/ isomerization sequence. A 2-ethylideneindolin-3-ol was confirmed to be the key intermediate (Scheme 296).831 6.2.4. Hydroamination Followed by Hydrogenation. Hydroamination/reduction cascade processes are widely applicable to the synthesis of secondary and tertiary amines. For instance, a chiral gold complex together with a Brønsted acid can be used as catalysts for the synthesis of enantiomerically enriched secondary amines,832 and enantioselective intramolecular hydroamination/transfer hydrogenation processes were used to access tetrahydroquinolines with excellent ee values (Scheme 297).833 In other protocols, molecular hydrogen834 or inexpensive zinc835 were used as the reducing agent.836 6.2.5. Hydroamination Followed by Oxidation. In 2013, Ye and co-workers reported an oxidative cyclization of homopropargyl amides in the presence of a cationic gold catalyst and m-CPBA as the oxidant (Scheme 298).837 The reaction is believed to involve a 5-endo-dig amination yielding a vinyl-Au intermediate, which is transformed into an iminium species by protonolysis. Oxidation of the iminium intermediate yields the γ-lactam product. Notably, the reaction proceeds with

Scheme 283. Au-Catalyzed Hydroamidation of 1,5-Enynes

Scheme 284. Au-Catalyzed Intermolecular Hydroamidation of 1,6-Enynes

Scheme 285. Au-Catalyzed Cascade Cyclization of Alkynylindoles

Intramolecular versions of this strategy were utilized by the Bandini group in their synthesis of 1H-[1,4]oxazino[4,3a]indoles (n = 1)821 and by Hashmi et al. in a synthesis of 1H-imidazo[1,5-α]indol-3(2H)-ones (Scheme 289).822 A combination of a gold-catalyzed hydroamination with an intramolecular stereoselective allylic alkoxylation allows converting 3-(2-aminophenyl)prop-2-yn-1-ol bearing an allylic alcohol moiety at the amino function into (3S)-3-vinyl-3,4dihydro-1H-[1,4]oxazino[4,3-a]indoles in high yield and ee value up to 98%. The reaction cascade is catalyzed by a cationic gold catalyst with an (S)-DTBM-segphos ligand (Scheme 290).823 A hydroamidation/nucleophilic substitution/elimination process was utilized to construct the bicyclic indolizinone skeleton by gold-catalyzed intramolecular 6-exo-dig hydroamidation/aromatization (Scheme 291).824 This strategy has BN


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Scheme 286. Pd-Catalyzed Synthesis of Ketones by Intermolecular Hydroamination/Hydrolysis Reaction

The protocol provides an efficient and simple approach to the synthesis of γ,δ-alkynyl-β-amino acid derivatives in moderate to good yields. Unfortunately, the scope of the method is still limited to combinations of secondary aliphatic amines, terminal aromatic alkynes, and activated alkynes. The reaction proceeds via an intermolecular hydroamination of the propiolate with the amine to give an enamine, which is attacked by the terminal alkyne. A similar reaction sequence can also be performed using 2 equiv of terminal alkyne rather than two different ones. In 2013, an effective synthesis of tetrasubstituted propargylic amines was reported, which proceeds via intermolecular hydroamination of terminal alkynes followed by nucleophilic addition, using a second equivalent of the terminal alkyne as the nucleophile (Scheme 301).842 Besides copper catalysts, zinc complexes with bidentate Nligands also mediate this cascade hydroamination/alkynylation process.843 The propargylic tertiary amine products are not accessible from ketones in a way analogous to that propargylic secondary amines are easily obtained via couplings of aldehydes with amines and alkynes.844−847 This underlines the synthetic utility of the outlined process. 6.2.6.1.2. Amino- or Amidoalkynes and Nucleophiles. The combination of an intramolecular hydroamination with the addition of external nucleophiles is an efficient strategy to access cyclic amines. In 2009, Hammond and Xu reported a CuBr-catalyzed sequence to furnish alkynylated N-heterocycles in excellent yields using microwave irradiation (Scheme 302).848 This intramolecular hydroamination/nucleophilic addition cascade was extended to various nucleophiles such as TMSCN, TMSCF3, and phosphinates to give α-CN-, α-CF3-, and αPO(OR)2-substituted N-heterocycles with ring sizes of 5−7 (Scheme 302).849−853

Scheme 287. Rh-Catalyzed Hydroamination/Hydrolysis in the Synthesis of Butyrolactams

conservation of the stereochemistry when using chiral propargylic amines. This synthetic strategy also extends to the synthesis of γ-lactones from homopropargyl alcohols.838 6.2.6. Hydroamination Followed by Nucleophilic Addition. The hydroamination of alkynes with amines would lead to the formation of enamines and imines, which can act as the electrophilic precursors for a second addition reaction (Scheme 299, paths a and b). Usually, two of the three functionalities involved in the process originate from one substrate. This kind of cascade hydroamination/nucleophilic addition process has been employed to synthesize functionalized five- to seven-membered N-heterocycles. There are only a few examples in which the three functionalities all result from different molecules, and linear products are formed (Scheme 299, path c). 6.2.6.1. Hydroamination Followed by Intermolecular Nucleophilic Addition. 6.2.6.1.1. Activated Alkynes, Terminal Alkynes, and Amines. In 2008, Jiang and Li reported an ligand free three-component coupling of amines, alkynes, and propargylic acid esters in the presence of 5 mol % CuBr2 (Scheme 300).839−841

Scheme 288. Functional Indole Synthesis via Pd-Catalyzed Hydroamination/Intermolecular Substitution

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Scheme 289. Au-Catalyzed Hydroamidation/Intramolecular Nucleophilic Substitution

Scheme 290. Au-Catalyzed Hydroamination/Enantioselective Intramolecular Allylic Alkoxylation

Scheme 291. Au-Catalyzed Hydroamidation/Nucleophilic Substitution/Elimination

Scheme 292. Cascade Process Containing Hydroamination and Dehydration

finally hydroarylation to form the products. This reaction was successfully performed on a 5 g scale (Scheme 303).854 A hydroamination/nucleophilic addition/hydroarylation cascade was also used in the synthesis of dihydroquinoline from an aniline and 2 equiv of the same terminal alkyne or one terminal and one internal alkyne (Scheme 304).855,856 In the latter case, the internal alkyne undergoes intermolecular hydroamination, and the terminal alkyne adds to the enamine intermediate. A hydroarylation step completes the reaction cascade. Related syntheses of dihydroquinolines from aniline derivatives and terminal alkynes are also promoted by AgBF4/HBF4857 or zincammonium salts as catalysts.858 This reaction concept was extended to less nucleophilic amides by Liu et al. (Scheme 305).859 Thus, bicyclic lactams, that is, pyrrolo[1,2-a]quinolin-1(2H)-ones, were synthesized via a hydroamidation/nucleophilic addition/hydroarylation sequence in the presence of a AuBr3/AgSbF6 catalyst within 4 h in toluene at 120 °C. Unfortunately, only phenylacetylene derivatives could be used as the terminal alkyne component. Similar intramolecular hydroamination/nucleophilic addition sequences were also used for internal alkynes. An efficient and regioselective PtII-catalyzed cascade synthesis of multipsubstituted indolines and tetrahydroquinolines was reported involving a reaction pathway via intramolecular hydroamination

Scheme 293. Synthesis of Pyrrole Derivatives via CuCatalyzed Cyclization/Dehydration

Scheme 294. Ag-Catalyzed Addition of Pyrazole to in Situ Formed Allenes

The above intramolecular hydroamination/nucleophilic addition sequence can be extended by a hydroarylation step. Thus, Liu and Che reported the synthesis of multisubstituted pyrrolo[1,2-a]quinolines from aminoalkynes and terminal alkynes. The reaction cascade involves the generation of enamines by gold-catalyzed hydroamination, followed by a gold-catalyzed nucleophilic addition of a terminal alkyne, and BP


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Scheme 295. Fused Indole Synthesis via Au-Catalyzed Hydroamination/Dehydration/Condensation

Scheme 296. 2-Alkynylindole Synthesis via Ag-Catalyzed Hydroamidation/Double Dehydration

Scheme 297. Au-Catalyzed Hydroamination/Hydrogenation Cascade

6.2.6.2. Hydroamination Followed by Intramolecular Nucleophilic Addition. Cyclic structures can also be accessed by intermolecular hydroaminations combined with intramolecular nucleophilic addition sequences. In 2010, the Patil group reported a gold-catalyzed cascade process involving either double hydroamination or hydroamination/hydroarylation sequences to yield N-containing heterocycles in good to excellent yields (Scheme 307).784,861 It was proposed that goldcatalyzed Markovnikov hydroamination addition leads to an enamine intermediate, which is attacked by a tethered nitrogenor carbon-nucleophile. This elegant reaction is presently limited to terminal alkynes. Intramolecular hydroamidations combined with further intramolecular steps result in the formation of bi- or polycyclic molecules. Dixon described a highly enantioselective cascade consisting of a AuI-catalyzed intramolecular 5-exo-dig hydroamidation followed by a phosphoric acid-promoted enantioselective hydroarylation process that gives access to complex sulfonamide scaffolds (Scheme 308).862−865 Another process that combines a hydroamination with a hydroarylation was reported in 2011 by Liu et al. In the presence of a cationic AuI catalyst, pyrrole- or indolesubstituted anilines were coupled with alkynes to give pyrrolo[1,2-a]quinoxalines in moderate to excellent yields (Scheme 309).866 Terminal and internal alkynes are both suitable substrates for this reaction. Related processes have also been reported starting with a hydroalkoxylation or acyloxylation followed by hemiaminal formation catalyzed by platinum or gold systems.867−870 On the basis of this strategy, Liu and Patil have respectively developed various efficient syntheses of fused N-containing heterocycles.871−878

Scheme 298. Au-Catalyzed Cycloisomerization/Oxidation of Homopropargyl Amides

Scheme 299. Transition Metal-Catalyzed Cascade Hydroamination/Nucleophilic Addition

of an aminoalkyne followed by addition of an 1,3-diketone and condensation steps (Scheme 306).860 BQ


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Scheme 300. Synthesis of β-Amino Acids via Cu-Catalyzed Hydroamination/Nucleophilic Addition

Scheme 301. Propargylic Amine Synthesis via Cu-Catalyzed Hydroamination/Alkynylation

Scheme 305. Pyrroloquinolinone Synthesis via Au-Catalyzed Hydroamidation/Nucleophilic Addition/Arylation Cascade

Scheme 302. Cu-Catalyzed Intramolecular Hydroamination/ Nucleophilic Addition

Scheme 306. Indoline and Tetrahydroquinoline Synthesis via Pt-Catalyzed Hydroamination/Addition/Condensation

Scheme 303. Pyrroloquinoline Synthesis via Au-Catalyzed Hydroamination/Nucleophilic Addition/Hydroarylation

6.2.7. Hydroamination Followed by Carbene Insertion. Propargyl alcohol derivatives bearing a nucleophile in an appropriate position can be transformed to cyclic α,βunsaturated carbene complexes in the presence of electrophilic transition metal catalyst.879−882 In the presence of suitable nucleophiles, these carbene intermediates can be further converted into vicinal bis-heterocyclic compounds. This reactivity was exploited by the Ferreira group in a highly selective Pt-catalyzed double heterocyclization reaction of propargylic ethers yielding oxygen- and nitrogen-containing vicinal bis-heterocycles (Scheme 310).883

The ruthenium-mediated 5-exo-dig cyclization of pent-2-en4-yn-1-amines gives rise to (2-pyrrolyl)carbenoid intermediates, which react with water, alcohols, and anilines with insertion into the H−X bonds to give functionalized pyrroles. This reaction requires only low catalyst loadings and proceeds at only 50 °C (Scheme 311).884 6.2.8. Hydroamination Followed by Allylic Alkylation. In 2012, Gond and co-workers reported a high-yielding

Scheme 304. Dihydroquinoline Synthesis via Au-Catalyzed Hydroamination/Nucleophilic Addition/Hydroarylation

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This concept was recently extended to the synthesis of various spiro-hemiaminals and spiro ketals (Scheme 316).894 In 2007, Porco and co-workers reported the silver-catalyzed cycloisomerization/[3+2] dipolar cycloaddition cascade of N-2alkynylbenzylidene-glycinates to afford the pyrrolo[2,1-a]isoquinolines-3-carboxylates in moderate to good yields (Scheme 317).895 In the first step of the reaction sequence, an azomethine ylide intermediate is generated by addition of the imine to the alkyne, which then undergoes a dipolar [3+2] cycloaddition reaction with electron-withdrawing alkynes. 6.2.11. Hydroamination Followed by Pictet−Spengler Reaction. In 2012, Yadav et al. reported a domino hydroamination/Pictet−Spengler reaction of 2-(4-tosylaminobut-1ynyl)aniline with aldehydes using a cationic gold complex as the catalyst to produce 1-aryl-N-tosyl-2,3,4,5-tetrahydropyrido[4,3b]indole derivatives in good yields (Scheme 318).896 It was suggested that an intramolecular hydroamination reaction leads to an isotryptamine intermediate, which undergoes condensation with the aldehyde to generate the N-sulfonyliminium species. Finally, a gold-mediated nucleophilic addition of the indole moiety to the C−N double bond produces the pyridoindole derivative. 6.2.12. Hydroamination Followed by Ring Contraction. In another reaction sequence described by Patil et al., a hydroamination is preceded by condensation of prop-2ynamines with 2-aminobenzaldehydes to the corresponding alkynylimines. PPh3AuOTf catalyzes their cyclization by intramolecular addition of the aniline-N−H to the C−C triple bond to give 1,4-benzodiazepines, which undergo goldcatalyzed ring contraction to the 3-aminoquinoline derivatives (Scheme 319).897 6.2.13. Addition of Imines to Alkynes Followed by Nucleophilic Capture. In the addition of HX-type nucleophiles to imines, the reactivity of the intermediates is analogous to that of X−CRR′−N−H compounds, which can be expected to be capable of undergoing hydroamination reactions. This reaction type has found many applications in synthesis. In 2005, Asao and co-workers reported the silvercatalyzed coupling between 1-(2-ethynylphenyl)methanimines and carbon nucleophiles to generate 1,2-dihydroisoquinolines (Scheme 320).898,899 Following this pioneering discovery, silver, copper, gold, indium, iron, nickel, and even catalystfree systems were developed for this type of transformation. In the absence of a metal catalyst, HCCl3 used in 5-fold excess is also suitable as a C−H nucleophile to produce 1,2dihydroisoquinolines.900 However, the substrates are limited to terminal alkynes. Later, a PdCl2(PPh3)2/dppe catalyst was developed that tolerates a broad range of substrates and gives the heterocycles in good to excellent yields.901 Other nucleophiles, such as TMSCF3,902,903 diethylphosphite,904,905

Scheme 307. Au-Catalyzed Hydroamination Followed by Hydroarylation/Hydroamination

pyrrolidine synthesis via a hydroamination/allylic alkylation cascade (Scheme 312).885 A gold-catalyzed intramolecular hydroamination gives the N-allylic enamine intermediate, which undergoes allylic alkylation under the cooperative catalysis of a Pd-complex and a Brønsted acid. 6.2.9. Hydroamination Followed by C−H Activation. In 2009, Verma and Larock reported a reaction cascade consisting of an intermolecular hydroamination and a concomitant cyclization with C−H activation to construct indolo- or pyrrolo[2,1-α]isoquinolines from 1-halo-2-ethynylbenzenes and indoles or pyrroles (Scheme 313).886 The reaction is catalyzed by a Cu-complex bearing a 1hydroxymethylbenzotriazole ligand. Similar cascade processes initiated by hydroamination or -amidation steps followed by C−H activation have been widely used to construct various heterocycles.887−889 A cascade consisting of a hydroamination and an intermolecular C−H activation was utilized in an efficient synthesis of tricyclic pyrrolidine derivatives from indoline and 2 equiv of a terminal alkyne in the presence of a cationic ruthenium catalyst (Scheme 314).890−892 The mechanism is believed to involve the formation of a ruthenium acetylide from a ruthenium hydride and 2 equiv of the alkyne. An intermolecular hydroamination reaction furnishes a ruthenium vinyl intermediate, which undergoes ortho C−H activation, sequent alkyne insertion, and migratory insertion of the C−C double bond with migration of the ruthenium. The resulting alkyl-ruthenium intermediate possesses no β-hydrogens, which would give rise to elimination, allowing its σ-bond metathesis with the terminal alkyne with liberation of the product and regeneration of the catalyst. 6.2.10. Hydroamination Followed by Cycloaddition. The combination of an intramolecular hydroamidation with a hetero-Diels−Alder reaction allows the synthesis of the bicyclic hemiaminals. Thus, pyrano[2,3-b]pyrroles were synthesized by Xu et al. from N-alkynyl-N-tosyl-amines and 2-oxopent-3enolates via a gold-catalyzed hydroamidation followed by the Ga(OTf)3-catalyzed hetero-Diels−Alder reaction of the resulting 2,3-dihydro-1H-pyrrols (Scheme 315).893

Scheme 308. Synthesis of Fused Indole Derivatives via Au-Catalyzed Hydroamidation/Hydroarylation Cascade Reaction

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Scheme 309. Pyrrolo[1,2-a]quinoxalines Synthesis via Au-Catalyzed Hydroamination/Hydroarylation

2H-Isoindolo-1-ylphosphonates can be accessed via this cascade using a bimetallic catalyst system consisting of FeCl3 and PdCl2 from 2-alkynylbenzaldehyde, aniline, and phosphites.916 A similar strategy for the synthesis of substituted pyrazolo[5,1-a]isoquinolines was developed by Peng et al. They used N-allyl-ynamide as the nucleophile to activate 2alkynylbenzaldehyde tosylhydrazone for the addition across the alkyne C−C triple bond, leading to isoquinoline skeletons. The reaction proceeded under cocatalysis of silver triflate and palladium acetate.917 The synthesis of isoquinolines on the basis of this strategy was reported by a number of research groups, with many contributions by the group of Wu.918−927 In 2009, Wu et al. reported a silver-mediated [3+2]cyclization/hydroamination process that generates 1,2-dihydroisoquinolines in good to excellent yields from various terminal alkynes and N′-(2-alkynylbenzylidene)hydrazide (Scheme 321, path a).918,919 A complementary process for the synthesis of pyrazolo[5,1-a]isoquinolines makes use of either carbonyl compounds such as aldehydes or ketones or their O-silyl enolates and proceeds in the presence of a silver catalyst under redox-neutral conditions (Scheme 321, path c).920,921 Instead of using the carbonyl compound directly, the reagents can be generated in situ from secondary/tertiary amines or alcohols in the presence of air as the oxidant and a catalyst based on silver, copper, or palladium (Scheme 321, paths b and h).922−924 Later, electron-rich alkynes, such as Nallyl ynamides (Scheme 321, path d), and electron-poor alkynes, such as dimethyl acetylenedicarboxylates (Scheme 321, path g), were shown to react with N′-(2alkynylbenzylidene)hydrazides to furnish the corresponding annulation products.917,925 Fused spirooxindoles (Scheme 321, path e) and 1-(indol-3-yl)-2-aminoisoquinolinium triflates (Scheme 321, path f), respectively, can be synthesized in good to excellent yields by cyclization of N′-(2alkynylbenzylidene)hydrazide with methylene-indolinones and indoles. 926,927 Furthermore, N′-(2-alkynylbenzylidene)-

Scheme 310. Pt-Catalyzed Vicinal Bis-heterocyclization of Alkynes

Scheme 311. Synthesis of Pyrroles by Ru-Catalyzed Cyclization/Nucleophilic Addition Cascade Reactions

imidazoles,906 indoles,907,908 in situ formed zinc reagent,909 ketones,910−913 α,β-unsaturated ketones,914 and allyltributylstannanes,911,912 are able to smoothly add to the 1-(2ethynylphenyl)methanimines and thus to initiate the cascade cyclization. A mixture of 2-alkynylaldehydes, amines, and sodium borohydride gives the 1-nonsubstituted dihydroisoquinoline derivatives in the presence of 2−5 mol % AgOTf in good to excellent yields.915

Scheme 312. Au/Pd-Catalyzed Hydroamination/Allylic Alkylation

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Scheme 313. Cu-Catalyzed Hydroamination/Intramolecular C−H Activation

322, paths b and c).931,932 A control experiment with radical scavengers suggests that the reaction involves a radical N−O cleavage process. The cascade reaction of 2-alkynylbenzaldoxime and an arylsulfonyl chloride in the presence of 10 mol % AgOTf affords 4-(arylsulfonyl)isoquinolines in moderate to good yields (Scheme 322, path f).933 In the reaction of alkynylbenzaldehyde oxime with arylsulfonyl chlorides to give 1-[(trifluoromethyl)thio]isoquinolines, AgSCF3 was found to be the most reactive catalyst (Scheme 322, path f).934 The silver-catalyzed cascade reaction of carbodiimides or isocyanides with 2-alkynylbenzaldehyde oximes via 6-endo-cyclization gives convenient access to 1-(isoquinolin-1-yl)ureas and N(isoquinolin-1-yl)formamides (Scheme 322, paths d and e).935,936

Scheme 314. Ru-Catalyzed Hydroamination/Intermolecular C−H Activation/Cyclization of Indoline

6.3. In Situ Formation of Amine Groups Followed by Intramolecular Hydroamination

6.3.1. Hydroamination with N-Nucleophiles Generated by Nucleophilic Addition to Imines. In 2009, Xu et al. reported a related copper(I)-catalyzed cascade reaction between dimethyl 2-prop-2-ynylmalonates and N-tosyl imines (Scheme 323).937 The N−H equivalent is generated by addition of the C−H acidic to the imine moiety and adds across the terminal alkyne in 5-exo-dig cyclization to afford 2methylenepyrrolidines. Asymmetric reaction variants, in which the nucleophilic addition to Boc- or Cbz-imines is mediated by chiral organocatalysts, allow the synthesis of spiro[pyrrolidin-3,2′oxindole],938 piperidines,939 and trisubstituted pyrrolidines940 in high yields and ee values. A related nitro-Mannich/ hydroamidation/nitro-group elimination cascade allows the one-pot synthesis of 2,5-disubstituted pyrroles from N-tosyl imines and 4-nitrobut-1-ynes using a combination of KOtBu and AuCl3.941 Unprotected imines can be analogously converted via nucleophilic addition/hydroamination cascades. In the presence of copper bromide, [(2-alkylidenamino)phenyl]prop-n-yl-1-ols are smoothly converted to ring-fused bicyclic indoles via nucleophilic addition of the OH group to the imine moiety followed by an intramolecular hydroamination reaction (Scheme 324).942 The synthesis of the imine can be combined into a one-pot procedure with the subsequent nucleophilic addition/hydro-

Scheme 315. Au-Catalyzed Hydroamidation/Hetero-Diels− Alder Reaction

hydrazide was also shown to react with benzyne or dimethyl cyclopropane-1,1-dicarboxylate to generate H-pyrazolo[5,1-a]isoquinolines 9 28 or tetrahydro-1H-pyridazino[6,1-a]isoquinolines, respectively.929 In mechanistically related reactions, Wu et al. utilized 2alkynylbenzaldehyde oximes as the starting materials to construct 1,2-dihydroisoquinoline derivatives (Scheme 322) via a AgOTf/Yb(OTf)3 cocatalyzed process (Scheme 322, path a).930 Alkylidenecyclopropanes with high ring tension and 1(cyclopropylidenemethyl)-2-alkynyl)benzenes were found to react with 2-alkynylbenzaldehyde oxime in the presence of 10 mol % AgOTf to afford derivatives of benzo[8]annulen-7(6H)ones or 1-(cyclopropyl)isoquinolines, respectively (Scheme

Scheme 316. Au-Catalyzed Synthesis of Spiroaminals via Hydroamination/Hetero-Diels−Alder Reaction

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Scheme 317. Ag-Catalyzed Cycloisomerization/[3+2] Cycloaddition Reaction

gold or silver catalysts (Scheme 325).546,547,943−949 In combination with chiral Brønsted acids such as (R)-(−)-1,1′binaphthyl-2,2′-diyl hydrogen phosphate derivatives, PPh3AuMe promotes the addition to imine in high ee of up to 96%.943 A similar reaction under metal-free conditions was described for the synthesis of tetrahydroisoquinoline skeletons from 2-vinylbenzaldehydes and amino alcohols involving an aza-Michael reaction.950 Related imine condensation/nucleophilic addition/hydroamination cascades have also been used for coupling Ntosylamides bearing aldehyde and alkynylmethyl groups with 1,2-diamines in the presence of a copper catalyst. Moreover, the scaffold of biological active 7,8-dihydroimidazo[1,2-a]pyrazines (Scheme 326) was obtained in a single step in reasonable yields from N-alkynylmethylindoles or pyrroles bearing formyl groups in 2-position.951 In 2012, Wu et al. reported a silver-catalyzed nucleophilic addition/rearrangement/hydroamination cascade for the synthesis of isoquinolines (Scheme 327).952 It is believed to be initiated by the addition of a 2-isocyanoacetate to a 2alkynylbenzaldehyde under basic conditions to form a dihydrooxazole intermediate, which rearranges to an enamide intermediate. The latter undergoes a silver-catalyzed 6-exo-dig hydroamidation, and the resulting enamide extrudes carbon monoxide to form the isoquinoline product. 6.3.2. Hydroamination with N-Nucleophiles Generated by Nucleophilic Addition to Isoquinolines. The addition of nucleophiles to isoquinolines also gives rise to intermediates that are capable of undergoing hydroamination reactions. In 2008, Yadav et al. reported a reaction cascade that allows the coupling of isoquinolines first with C−H or P−H nucleophiles and then with acetylene dicarboxylic acid esters to form substituted 1,2-dihydroquinolines in one step (Scheme 328).953 If terminal alkynes are employed as C−H nucleophiles, a gold catalyst is required, whereas the reaction proceeds without any catalyst for indoles.954,955 6.3.3. Hydroamination with N-Nucleophiles Generated by Nucleophilic Addition to Nitriles. A bimetallic Au/ Zn catalyst system enables reaction cascades initiated with the addition of nitrogen nucleophiles to nitriles followed by an intramolecular hydroamination process to give 2-aminopyrroles (Scheme 329).956 The zinc salt activates the nitriles and promotes the addition of anilines or aliphatic amines to the C− N triple bonds, and the gold catalyst mediates the subsequent hydroamination step. Unfortunately, N-substituted products are often obtained as a mixture with the nonsubstituted derivatives. The addition of alcohols to nitriles followed by intramolecular hydroamination of alkynes with the resulting imidates was found to be catalyzed by a hydroplatinum complex (Scheme 330). This way, various 3-substituted 1alkyoxyisoquinolines and isoquin-1(2H)-ones were synthesized from alkynylbenzonitrile in moderate yields (Scheme 330).957

Scheme 318. Au-Catalyzed Hydroamination/Pictet− Spengler Reaction

Scheme 319. Au-Catalyzed Condensation/Hydroamination/ Ring Contraction Sequence

Scheme 320. Transition Metal-Catalyzed Imine Addition/ Nucleophilic Capture

amination cascade. Thus, various fused isoquinoline derivatives were synthesized directly from 2-alkynylaldehydes and amines bearing another nucleophile β- or γ-position in the presence of BV


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Scheme 321. Cyclization Reactions Starting from N′-(2-Alkynylbenzylidene)hydrazide

Scheme 322. Ag-Catalyzed Hydroamination Cascades Starting from 2-Alkynyl Benzaldehyde Oximes

Scheme 323. 2-Methylenepyrrolidine Synthesis via Nucleophilic Addition/Hydroamidation

6.3.4. Hydroamination with N-Nucleophiles Generated by Nucleophilic Addition to Isocyanates. In 2009, Yanada et al. utilized PtCl2 as a Lewis acid catalyst to synthesize

macrocyclic indole-carbamates, indole-ureas, indole-phosphoranes, and related compounds via a cascade process from arylalkynes bearing amide groups. The reaction cascade is BW


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Scheme 324. Fused Indoles Synthesis via Cu-Catalyzed Nucleophilic Addition/Hydroamination

Scheme 327. Isoquinoline Synthesis via 2Alkynylbenzaldehyde-isocycanoacetate Condensation/ Hydroamination Cascade

Scheme 325. Transition Metal-Catalyzed Condensation/ Nucleophilic Addition/Hydroamination

Scheme 328. Au-Catalyzed Nucleophilic Addition to Isoquinoline/Hydroamination

initiated by a Hoffmann rearrangement, followed by nucleophilic addition of alcohols, amines, or certain Wittig reagents to generate the corresponding N−H nucleophiles, which undergo intramolecular hydroamidation with formation of the cyclic products (Scheme 331).958,959 6.3.5. Hydroamination with N-Nucleophiles Generated by Nucleophilic Addition to Aziridines. The addition of H−X nucleophiles to N-tosyl aziridines or azetidines also results in nitrogen nucleophiles that can undergo hydroamidation reactions. Under basic conditions, the OH-group of propargylic alcohols reacts with these substrates under ring opening, and the N−H group thus generated adds to the alkyne moiety in the presence of 2 mol % of Ag(cod)2PF6 as catalyst (Scheme 332).960 A broad range of six- to eight-membered N,O-unsaturated heterocycles were obtained in high yields. The nature of the alkynes determines the regioselectivity of the hydroamidation step. Terminal propargyl alcohols mostly undergo endo-dig cyclization, whereas exo-dig cyclization predominates for internal alkynes. In 2010, Shi et al. reported a gold-catalyzed cyclization of 2(2-ethynylphenyl)aziridines with electron-rich arenes to

produce 3,4-dihydroisoquinolines in high yields and stereoselectivities (Scheme 333).961 According to the proposed mechanism, the cationic gold catalyst promotes the ring opening of the aziridines by a nucleophilic attack of the arenes to generate a 2-aryl-2-(ethynyl)ethaneamine intermediate, which undergoes 6-exo-dig hydroamidation followed by isomerization to give the dihydroquinoline product.962 The reaction is so far limited to electron-rich arenes, which have to be used in large excess to facilitate the initiating C−H activating step. 6.3.6. Hydroamination of Allenes with N-Nucleophiles Generated by Nucleophilic Addition to Alkynyl Aziridines. Alkynyl-substituted N-tosyl aziridines bearing aryl groups undergo complex rearrangements in the presence of silver or gold catalysts. The group of Pale demonstrated that these compounds are stereoselectively converted into 1azaspiro[4.5]decane derivatives with gold(I) catalyst via a

Scheme 326. Cu-Catalyzed Condensation/Addition/Hydroamination Cascade

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Scheme 329. Aminopyrrole Synthesis via a Au/Zn-Catalyzed Nucleophilic Addition/Hydroamination

Scheme 330. Pt-Catalyzed Alcohol Addition to Nitriles Followed by Hydroamidation

Scheme 334. AuI-Catalyzed Intramolecular Hydroarylation/ Isomerization/Hydroamination Cascade of Aziridinyl Alkynes

Scheme 331. Pt-Catalyzed Hoffmann Rearrangement/ Nucleophilic Addition/Hydroamidation Cascade

heterocycles. The reaction cascade gives convenient access to spiro-tetrahydro-1H-β-carbolines in high yields under mild conditions (Scheme 335).965 N-Aryl-2-alkynylazetidines are also suitable substrates for cascades initiated by ring openings via intermolecular hydroarylations (Scheme 336).966 A gold catalyst with a bulky phosphine ligand promotes the alkynylazetidine ring opening to generate an eight-membered allene-amine intermediate, which undergoes an intramolecular hydroamination yielding pyrrolo[1,2-a]indoles in good to excellent yields.

Scheme 332. Ag-Catalyzed Aziridine/Azetidine RingOpening/Hydroamidation Cascade

6.4. C−C Bond Formation Followed by Hydroamination or Hydroamidation

The ease with which intramolecular hydroaminations and -amidations proceed in the presence of various metal catalysts has triggered the development of numerous cascade reactions in which these substrates are generated in situ via catalytic coupling reactions. Thus, various protocols have been disclosed in which amino-substituted alkynes are generated via Sonogashira, Tsuji−Trost, A3 (amine-alkyne-aldehyde), or other coupling reactions and are directly cyclized via catalytic hydroaminations or hydroamidations.

hydroarylation/rearrangement/hydroamidation cascade.963,964 In Scheme 334, a representative example of these transformations is depicted. This reaction concept can also be used to convert indoles bearing alkynylaziridine side chains into interesting polycyclic

Scheme 333. Au-Catalyzed Nucleophilic Addition/Hydroamination Cascade of Aziridinyl Alkynes with Electron-Rich Arenes

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Scheme 335. Spiro-tetrahydro-β-carbolines Synthesis via Hydroarylation/Isomerization/Hydroamidation

obtained using the same method when starting from sulfonamide and malonate derivatives. A similar strategy can be used for the synthesis of 1,2,3,4tetrahydro-β-carbolines (pyridoindoles) from a 2-alkynylaminobenzene, an aldehyde, and a secondary amine. If the amine contains appropriate functionalities, such as R3 = CH2OH or CO2R, the A3-coupling/hydroamination product could further be transformed into a 1,2,3,4-tetrahydro-carboline derivative under basic or acidic conditions (Scheme 341).1005 Four-component couplings/cyclizations utilizing 2-ethynylbenzaldehyde, paraformaldehyde, a secondary amine, and t BuNH 2 afford 3-(aminomethyl)isoquinolines (Scheme 342).1006 It was suggested that following A3-coupling, t BuNH2 reacts with the 2-ethynylbenzaldehyde to form the imine, which acts as the nucleophile to attack the A3-coupling intermediate. Similar copper-catalyzed four-component couplings of 2alkynylbenzaldehydes, paraformaldehyde, and secondary amines followed by treatment with a diamine, yielding tricyclic isoquinoline derivatives, were described by the group of Ohno and Fujii (Scheme 343).1007 The imine moiety formed in situ from the diamine and A3-coupling intermediate is attacked intramolecularly by the primary amino group, which triggers the hydroamination cascade. In certain cases, the products obtained by A3-coupling/ hydroamination undergo further C−C bond-forming cyclization under the reaction conditions. Thus, Ohno and co-workers described a reaction sequence in which indole-fused tetracyclic 1,4-diazepine derivatives are directly obtained from 2ethynylanilines, secondary amines, and aldehydes by coppercatalyzed A3-coupling followed by intramolecular hydroamination and N-arylation (Scheme 344).1008 A reaction sequence involving gold-catalyzed A3-coupling of aliphatic aldehydes or ketones, alkynes, and acylhydrazines, followed by an intramolecular hydroamidation, leads to polysubstituted dihydropyrazoles (Scheme 345).1009 When starting from 1,2-dialkynylbenzene substrates, the dihydropyrazoles cyclize further in a hydroarylation process, leading to fused tricyclic heterocycles. 6.4.3. Conjugate Addition of Terminal Alkynes Followed by Hydroamidation. 2,4-Disubstituted pyrroles are accessible by Pd-catalyzed conjugate addition of a terminal alkyne to an N-Boc-aminomethylpropiolate, followed by intermolecular hydroamidation and double-bond migration (Scheme 346).1010 The reaction tolerates moisture and can be performed at ambient temperature. Both aromatic and aliphatic terminal alkynes are transformed to the corresponding pyrroles in good to excellent yields.

Scheme 336. Au-Catalyzed Alkynylazetidine Ring-Opening/ Hydroarylation/Hydroamination Cascade

6.4.1. Sonogashira Coupling Followed by Hydroamination. Table 2 presents some illustrative examples for one-pot Sonogashira coupling/hydroamination sequences. Copper and palladium are the most commonly used catalysts. Various five- or six-membered rings are conveniently accessible by this strategy. 6.4.2. A3 (Amine-Alkyne-Aldehyde)-Coupling Followed by Hydroamination. The coupling reaction between aldehydes, alkynes, and amines, commonly called A3-coupling, is a convenient approach to propargylamines and other functionalized products.846,987 In 2010, Gevorgyan et al. reported a copper-catalyzed A3-coupling/hydroamination cascade to afford fused imidazo-heterocycles (Scheme 337).13 After this seminal work, a range of other catalysts such as copper nanoparticles,988 CuSO4/TsOH,989 CuSO4/glucose,990 Cu/Mn bimetallic system,991 CuI/NaHSO4·SiO2,992 and InBr3993 were shown to catalyze this reaction sequence. An extension of such aldehyde-amine-alkyne coupling/ hydroamination cascades to heteroaryl aldehydes using a gold catalyst was presented by Liu and co-workers in 2007. This process provides efficient and atom-economical access to substituted indolizin-1-amines (Scheme 338).994,995 Later, the expensive gold catalyst was replaced by cheaper transition metals such as AgBF4,996 CuI,997 and Fe(acac)3.998 When 2-aminobenzaldehydes, secondary amines, and terminal alkynes were used for the copper-catalyzed A3-coupling, the in situ formed propargylamine intermediate can undergo selective cyclization to afford 3-aminoindolines999 or 2substituted quinolines (Scheme 339).1000 A mechanistic study revealed that the oxidation state of copper and the substitution pattern of the amine determine the selectivity of the cyclization reaction.1001 Ohno and Fujii started from Ts-ethynylaniline to construct 2-(aminomethyl)-indoles based on the A3-coupling/hydroamidation strategy (Scheme 340).1002 CuBr also catalyzes the A3-coupling/hydroamination of numerous other cyclic or acyclic secondary amines and aldehydes (paraformaldehyde, aliphatic or aromatic aldehydes).1003,1004 Benzo[e][1,2]thiazine and indene motifs are BZ


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Table 2. Sonogashira Cross-Couplings Followed by Hydroaminations or Hydroamidations

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Scheme 337. Fused Imidazo-heterocycle Synthesis via Cu-Catalyzed A3-Coupling/Hydroamination

convenient entry to the pyrrole skeleton. At this stage, only aromatic alkynes can be converted. 6.4.7. Claisen Rearrangement Followed by Hydroamidation. Polysubstituted pyrroles can also be synthesized by a one-pot reaction sequence that consists of a catalytic Claisen rearrangement, followed by an amine condensation and a hydroamination step. In the presence of a silver/gold catalyst, pentasubstituted pyrroles are obtained. Silver catalyzes the propargyl-Claisen rearrangement, and gold promotes the 5-exodig intramolecular hydroamination reaction (Scheme 351, left).1016,1017 With another set of conditions, similar propargyl vinyl ethers can also be transformed into 1,2-dihydropyridines. In this transformation, gold catalyzes the propargyl-Claisen rearrangement, and a Brønsted acid promotes the 6-endo-dig cyclization. Similar α-allenyl-β-enaminone intermediates can be obtained via gold-catalyzed Claisen rearrangement of propargyl vinyl ethers and condensation with amines. They subsequently undergo intramolecular 5-exo-dig hydroamidation to the corresponding pyrrole products (Scheme 351, right).1018,1019 In 2008, a RhI-catalyzed amino-Claisen rearrangement/ intramolecular hydroamination cascade was presented, which provides a high-yielding synthetic entry to 2,3-disubstituted indoles (Scheme 352).1020 The active catalyst [Rh(CO)(Ph3P)2]OCH(CF3)2 is generated in situ from RhH(CO)(Ph3P)3 and TFIP. It promotes the rearrangement of phenyl propargyl amines into allenylanilines that easily undergo intramolecular hydroamination with selective formation of the corresponding indole rings. 6.4.8. Allene Formation Followed by Hydroamination. In 2013, Kang et al. utilized a copper-mediated condensation of terminal alkynes with aldehydes to generate aminosubstituted allenes, which under the forcing reaction conditions undergo intramolecular hydroamination with formation of 3,4-dihydropyrroles (Scheme 353).1021 In analogous reaction cascades, amino-substituted allenes suitable for intramolecular hydroamination reactions were generated in situ by condensation of N-tosylhydrazones bearing amino groups with terminal alkynes1022,1023 or of aminosubstituted terminal alkynes with alkyl or aryl N-tosylhydrazones.1024 Zhou et al. employed both strategies for the synthesis of 2-substituted indoles in the presence of CuBr (Scheme 354).1023,1024

Scheme 338. Indolizin-1-amines Synthesis via Au-Catalyzed A3-Coupling/Hydroamination

6.4.4. Hydroacylation Followed by Hydroamidation. 2,3-Dihydro-1-N-tosylquinolin-4(1H)-one derivatives (azaisoflavanones) have efficiently been synthesized via gold-catalyzed annulation of 2-tosylaminobenzaldehyde and arylalkynes (Scheme 347).1011 The authors proposed that the hydroacylation proceeds via an amino group-assisted catalytic C−H activation of the aldehyde followed by alkyne insertion to form an α,β-unsaturated ketone.1012 This intermediate then undergoes intramolecular hydroamidation to the azaisoflavanone product. 6.4.5. Addition of Terminal Alkynes to Carbonyl Groups Followed by Intramolecular Hydroamination. Aminoalkynes suitable for intramolecular hydroamination reactions can also be generated in situ by adding terminal alkynes to aminoaryl-substituted carbonyl compounds. Thus, 1(2-aminophenyl)alkanones react with various terminal alkynes in the presence of AgOTf to give 2,4-disubstituted quinolines in good to high yield (Scheme 348).1013 Such nucleophilic addition/hydroamination/dehydration reactions are also mediated by NHC−Au complexes.855 A catalyst system consisting of a AuI catalyst, p-anisidine, and a chiral Brønsted acid was used to synthesize quinolines from 2aminobenzaldehydes and terminal alkynes via a nucleophilic addition/hydroamination/dehydration process (Scheme 349).1014 The quinolines were in situ hydrogenated with Hantsch ester to the corresponding tetrahydroquinolines in high ee. 6.4.6. Oxidative C−C Coupling Followed by Hydroamination. In 2013, the Lei group presented a silver-mediated oxidative C−C coupling between terminal alkynes and βenamino esters followed by an intramolecular hydroaminationtype step (Scheme 350).1015 This sequence provides a

Scheme 339. 3-Aminoindolines or Quinolines Synthesis via Cu-Catalyzed A3-Coupling/Hydroamination

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Scheme 340. 2-(Aminomethyl)-indoles Synthesis via Cu-Catalyzed A3-Coupling/Hydroamination Cascades

Scheme 341. Cu-Catalyzed A3-Coupling/Hydroamination and Follow-Up Steps

Scheme 342. Isoquinoline Synthesis via Cu-Catalyzed A3-Coupling/Condensation/Hydroamination

Scheme 343. Tricyclic Isoquinolines Synthesis via Cu-Catalyzed A3-Coupling/Condensation/Nucleophilic Addition/ Hydroamination

Scheme 345. Au-Catalyzed A3-Reaction/Hydroamination/ Hydroarylation Cascade

Scheme 344. Indole-Fused 1,4-Diazepine Synthesis via CuCatalyzed A3-Coupling/Hydroamination/N-Arylation

6.4.9. Carbene Insertion Followed by Hydroamination. The C−H bond of terminal alkynes is even more reactive toward carbenoids than amine N−H bonds. Thus, alkynylated anilines or anilides react with diazoacetates with formation of carboxylatemethyl-substituted alkynes that undergo intramoCC


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mol %) and 10 mol % CuI, the reaction sequence works well with anilines and amides, resulting in good yields of the corresponding N-aryl- or N-acyl indoles. Beside Pd and Cu, Ni(cod)2/dpppf was recently shown to be another effective system for this type of transformation (Scheme 358).1031 Pd also catalyzes this type of transformation with hydrazines in place of the amines. C−N coupling between 2alkynylhaloarenes and hydrazines followed by hydroamination leads to 1-aminoindole products in good to excellent yields under mild conditions (Scheme 359).1032 6.5.2. C−S Coupling Followed by Hydroamination. In 2010, Chen et al. found that the CuI/DMEDA catalytic system could also be used in the C−S coupling/hydroamination sequence to synthesize fused nitrogen/sulfur heterocycles (Scheme 360).1033 Under the basic conditions (TBAF), dehydrohalogenation of the 1,1-dibromoalkene starting materials yields 1-bromoalkynes, which then undergo C−S coupling and hydroamination to give the imidazol[2,1-b]-thiazole products. Recently, another C(sp)−S coupling followed by 5endo-dig cyclization was used to construct [1,3]thiazolo[3,2a]benzimidazoles from terminal alkynes and 1H-benzimidazole2-thiol or dihydropyrimidine-2-thione.1034 Both reactions require a stoichiometric amount of copper salt as oxidant. 6.5.3. Allylic or Propargylic Amination Followed by Hydroamidation. Intermediates able to undergo hydroamidation reactions are also obtained by allylic amination of alkynyl-substituted allylic alkoxy-derivatives. Liang et al. used a gold catalyst for a tandem allylic amidation/hydroamidation starting with tosyl amide that leads directly to polysubstituted (fused) pyrroles (Scheme 361).1035 The process starts directly from the allylic alcohols, but requires 15 equiv of TsNH2. The synthesis of substituted pyrroles via Pd-catalyzed amination of alkynyl-substituted allylic acetates requires 4 equiv of an aromatic or aliphatic amine (Scheme 362).1036 In 2012, Tu et al. reported a mechanistically related pyrrole synthesis from alkynyl-substituted allyl chloroacetates and anilines or aliphatic amines (Scheme 363).1037 An allylic amination furnishes the alkynyl amine, which undergoes intramolecular 5-exo-dig hydroamination with formation of a tetrahydropyrrole intermediate. Both double bonds migrate into the ring, so that aromatic pyrroles are finally obtained in reasonable yields. Various N-heterocycles such as 9H-pyrrolo[1,2-a]indole, 3Hpyrrolo[1,2-a]indole, and 1H-pyrrolo[1,2-a]indole derivatives were shown to be accessible by silver-catalyzed propargylic amination/hydroarylation or propargylic arylation/hydroamination cascades (Scheme 364).1038 A copper-catalyzed propargylic amination/hydroamination/oxidative aromatization cascade was used to synthesize 2,4-disubstituted or 2,4,6trisubstituted pyrimidines from propargyl alcohols and amidines in moderate to good yields (Scheme 364).1039 6.5.4. Click Reaction Followed by Hydroamination. 2Tosylimino-2,3-dihydroindoles are accessible through a cascade starting with a CuI-catalyzed click reaction involving cyclo-

Scheme 346. Pyrrole Synthesis via Pd-Catalyzed Conjugate Addition/Hydroamidation/Double-Bond Migration Cascade

Scheme 347. Azaisoflavanone Synthesis via Au-Catalyzed Hydroacylation/Hydroamidation

lecular 5-endo-dig hydroaminations/hydroamidations to form 2substituted indoles in reasonable to high yields (Scheme 355).1025 6.4.10. Cross-Metathesis Followed by Hydroamidation. In 2007, Fustero and co-worker reported a metathesis/ hydroamidation cascade, which allows the synthesis of 2,5substituted pyrrolidines or piperidines (Scheme 356).1026,1027 The reaction is mediated by a Grubbs catalyst of the second generation in combination with BF3·OEt2. Microwave irradiation significantly accelerates this cascade process. A related metathesis/intramolecular hydroamidation cascade catalyzed by a Ru/Au system has been used to access dihydroquinoline derivatives.777 6.5. C−Heteroatom Bond Formation Followed by Hydroamination or Hydroamidation

6.5.1. Buchwald−Hartwig-Type C−N Coupling Followed by Hydroamidation. Cu-catalyzed couplings of halogen-substituted enynes with amines have been used to generate enaminoalkyne intermediates, which directly undergo intramolecular hydroamidation. Thus, in 2006, Buchwald et al. reported CuI/DMEDA-catalyzed reactions of (1Z)-1-halobut1-en-3-ynes with either tert-butyl carbamate or bis(tertbutyloxycarbonyl)hydrazine that proceed via amination of the vinyl halide followed by 5-endo- or 5-exo-dig cyclization, respectively, to afford pyrrole or pyrazole derivatives (Scheme 357).1028 When a similar reaction is applied to 2-alkynylhaloarenes, indole products are obtained. Ackermann and co-workers reported in 2009 that a 5 mol % Pd(OAc)2/N-heterocyclic carbene system catalyzes the formation of indoles with steric demanding substituents, for instance, bulky alkyl amines, in good to excellent yields in toluene at 105−120 °C.1029 The scope includes less nucleophilic anilines as well as alkyl amines. Later, the same group succeeded in replacing the expensive palladium catalyst with the cheap CuI without any ligand.1030 In the presence of N,N′-dimethylethylenediamine (DMEDA) (30

Scheme 348. Synthesis of 2- or 2,4-Substituted Quinolines via Ag-Catalyzed Addition/Hydroamination/Dehydration

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Scheme 349. Tetrahydroquinoline Synthesis via Au-Catalyzed Nucleophilic Addition/Hydroamination/Dehydration/ Hydrogenation

Scheme 352. Indole Synthesis via RhI-Catalyzed AminoClaisen/Hydroamination Cascade

Scheme 350. Synthesis of Substituted Pyrroles by AgMediated Oxidative Coupling/Hydroamination

Scheme 353. 3,4-Dihydropyrrole Synthesis via Cu-Mediated Allene Formation/Hydroamination addition of sulfonyl azides, generally tosyl azide, to 2-alkynyl anilines, followed by loss of N2. The aromatic amino group then adds across the reactive ketenimine intermediate to give the 2-tosylimino-2,3-dihydroindole (Scheme 365).1040−1044 Several variations of click reaction/hydroamination cascades have been disclosed, in which nucleophiles react with in situ formed triazole intermediates to form cyclic and linear products.117,120,1045,1046 6.5.5. Carbene Insertion Followed by Hydroamination. In 2008, Wang et al. reported a copper-catalyzed cyclization of (2-alkynylphenyl)diazoacetate with incorporation of an aniline derivative (Scheme 366).1047 According to the proposed mechanism, the diazo function releases nitrogen with formation of a carbenoid intermediate that inserts into the N− H bond of the aniline. Interestingly, the hydroamination selectivity changes from 6-endo-dig to 5-exo-dig when employing the amine in excess. This way, the corresponding isoindoles (following double bond migration) or dihydroisoquinolines are obtained in good to excellent yields. 6.5.6. Hydration/Alkoxy Group Elimination Followed by Hydroamidation. In 2007, Floreancig et al. reported a gold-catalyzed sequence for the synthesis of piperidines bearing

Scheme 354. Cu-Catalyzed Allene Formation/ Hydroamination Cascade

ketone side chains that starts from propargylic or homopropargylic ethers (Scheme 367).1048,1049 Mechanistic studies suggest that the reaction is initiated by the hydration of the

Scheme 351. Pyrroles via Au-Catalyzed Claisen Rearrangement/Hydroamidation

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Scheme 355. Indole Synthesis via Cu-Catalyzed Carbene C−H Insertion/Hydroamination Cascade

Scheme 356. Synthesis of 2,5-Substituted Pyrrolidines via Ru-Catalyzed Metathesis/Hydroamidation

Scheme 357. Cu-Catalyzed C−N Coupling/Hydroamidation Sequences

Scheme 358. Indole Synthesis via Transition Metal-Catalyzed C−N Bond Formation/Hydroamination from orthoAlkynylhaloarenes

Scheme 359. Pd-Catalyzed 1-Aminoindole Formation from 2-Alkynylhaloarenes and Hydrazines

Scheme 360. Cu-Catalyzed C−S Coupling/Hydroamination

Scheme 361. Pyrrole Synthesis via an Au-Catalyzed Allylic Amidation/Hydroamidation Sequence

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economic. One can thus expect that hydroaminations and hydroamidations will gradually replace efficient but less sustainable synthetic strategies such as cross-couplings or Wittig reactions.

Scheme 362. Pyrroles Synthesis via Pd-Catalyzed Allylic Amination/Hydroamination

7.1. State-of-the-Art

Particular progress has been achieved in anti-Markovnikovselective hydroamidations of alkynes affording synthetically meaningful enamides, in which the regio- and stereoselectivity can efficiently be controlled by the catalyst system. State-of-theart systems for Z-selective hydroamidations are (cod)Ru(met)2/(dcypb) catalysts with the Lewis acidic ytterbium triflate cocatalyst, which provide Z-enamides in up to 99% yield and with Z/E ratios of up to 40:1.190 The E-configured products can be obtained using (cod)Ru(met)2/DMAP in up to 99% yield and 30:1 selectivity.191 Another remarkable development is the greatly enhanced regioselectivity in hydroaminations of internal alkynes. Greater than 20:1 ratios in favor of the 1-aryl enamines were achieved in the hydroamination of aryl alkyl alkynes with aliphatic secondary amines using a cationic AuI complex with a bulky P,N-ligand.186 In hydroaminations of alkenes, early transition metals are still state-of-the-art, but especially the (DPEphos)Rh(cod)BF4 systems are approaching the selectivities and reactivities of early transition metals. The example of hydroamination of nonactivated alkenes with secondary amines illustrates this, because the sole Markovnikov isomer can be obtained in up to 93% yield with only 1 mol % catalyst.204 As compared to other catalysts, late transition metals show the best activity in alkene hydroamidations. Among them, both [Ir(coe)2Cl]2 and cationic AuI are able to promote the intermolecular hydroamidation of nonactivated alkenes in good yields but require the use of more than 10 equiv of alkene.207 [PtCl2(C2H4)]2 catalyzes the hydroamidation of vinyl arenes with a range of amides in up to 85% yield,172 and that of nonactivated alkenes with sulfonamides in up to 95% yield.226 The asymmetric hydroamination and -amidation of alkenes and allenes has undergone a rapid development. Asymmetric catalysts are mainly composed of Au, Rh, and Ir complexes.1050 For example, Rh(cod)2BF4 with Cy-Mop-type ligands catalyzes the asymmetric intramolecular hydroamination of alkenes in up to 92% yield and 91% enantiomeric excess. Only moderate ee values were obtained in the asymmetric intramolecular hydroamidation of alkenes catalyzed by a cationic Au complex with a chiral phosphoric acid ligand. [Ir(coe)2Cl]2/chiral phosphine and cationic AuI/chiral phosphine complexes are the best asymmetric catalysts for intermolecular hydroaminations and hydroamidations, respectively. [Rh(cod)Cl]2/ Josiphos-catalyzed intermolecular asymmetric hydroaminations of allenes with anilines gave chiral allylic amines in up to 92% yield and 90% ee. Meanwhile, dinuclear AuI/chiral phosphine complexes were shown to promote the intermolecular asymmetric hydroamidation of internal allenes in up to 99%

Scheme 363. Pyrrole Synthesis via Pd-Catalyzed Allylic Amination/Hydroamination/Isomerization

Scheme 364. Propargylic Substitution/Hydroamination Cascades

alkyne, elimination of the alkoxy group, followed by an intramolecular addition of the N−H group to the activated double bond.

7. CONCLUSION AND OUTLOOK This Review demonstrates that late transition metal-catalyzed additions of N−H nucleophiles to alkenes, alkynes, and allenes have attracted tremendous attention over the past decade. During this period, hydroaminations and hydroamidations have evolved into broadly applicable methodologies that give convenient access to various product classes of considerable synthetic value. State-of-the-art reactions often proceed with high chemo-, regio-, and stereoselectivity, at low temperatures, and under mild conditions. The starting materials, alkynes/ alkenes and amines/amides, are readily available in great structural diversity, and the reaction concept is inherently atom-

Scheme 365. 2-Tosylimino-2,3-dihydroindole Synthesis via Cu-Catalyzed Click Reaction/Hydroamination Cascade

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Scheme 366. Isoindole or Dihydroisoquinoline Synthesis via Cu-Catalyzed Carbenoid N−H Insertion/Hydroamination Cascade

the use of Lewis acids rather than auxiliary bases as cocatalysts shifted the reactivity-determining factor from the nucleophilicity to the acidity of the amine substrate. Another unmet challenge is the development of efficient protocols for anti-Markovnikov hydroamination reactions that allow accessing linear aliphatic amines from terminal alkenes and amines or ammonia. The key toward achieving this goal is to find a catalyst system that efficiently activates the N−H bond, promotes the insertion of a simple alkene, and is then still able to reductively eliminate the product. All of these steps are known individually, but their combination demands that the catalysts display a complex and seemingly diverging set of properties. Markovnikov-selective intermolecular hydroaminations or -amidations of alkenes, as well as the hydroamidations of alkynes, are still in their infancy. For alkyne substrates, a complementary set of Markovnikov- and anti-Markovnikovselective protocols based on ruthenium catalysts with orthogonal ligand systems has recently been developed for the addition of carboxylic acids to terminal alkynes. This raises confidence that not only the stereo- but also the regioselectivity of alkyne hydroaminations or -amidations can be controlled by ligands. This field certainly merits further attention. Internal enamides, as would result from such Markovnikovselective hydroamidations, could be hydrogenated in high yields and enantioselectivities using know catalysts to give valuable chiral nitrogen compounds. Asymmetric versions of hydroaminations or -amidations of alkenes would lead to the same product class in only one step. To date, such reactions have been described only intramolecularly or for rather special substrate combinations, however, and there is much room for improvement. Because of the abundance of chiral amino groups in biologically active molecules, the development of intermolecular asymmetric hydroaminations is a particularly worthwhile research area. The above-mentioned gold-catalyzed intermolecular hydroamination of terminal alkynes with anilines is one of the few examples of a hydroamination process that proceeds with an industrially interesting catalyst loading. Many of the protocols presented in this Review still require large amounts of expensive catalysts, and there is much room for improvement. However, mechanistically related addition reactions, such as gold-catalyzed hydrations of alkynes (TON of up to 107),1051 nurture the hope that a similar efficiency might be possible also for hydroaminations and -amidations. A key element in addressing this challenge consists of the rational design of ligands specifically for hydroamination or hydroamidation reactions. For example, phosphine ligands with a rigid framework containing a Lewis-basic functional group have been shown to significantly improve the TON of hydroaminations by enhancing the anti-addition of the nucleophiles to the alkynes.1052 The use of customized ligands might lead to

Scheme 367. Au-Catalyzed Hydration/Alkoxy Group Elimination/Hydroamidation

yield and 92% ee. Various chiral N-containing heterocycles were constructed utilizing AuI/chiral phosphine complexes or cationic gold complexes with chiral phosphoric acid ligands. Another outstanding achievement in late transition metalcatalyzed hydroaminations is the high TON. The TON of 95 000, achieved in an intermolecular hydroamination of terminal alkynes and anilines with a gold complex, illustrates how efficient such reactions may become.217 Another rapidly developing area is that of cascade reactions. Imines, imides, enamides, and enamines are all structures with high intrinsic reactivity, and their formation can easily be combined with follow-up reaction steps leading to synthetically valuable products. There is a great diversity of catalysts, and on the basis of current knowledge, it is still hard to predict which system will be the best for a given application. However, a few rules begin to emerge: When aiming at reactions initiated by an intramolecular hydroamination or -amidation of alkynes followed by further functionalization of enamines or enamides, gold, platinum, and silver complexes, especially cationic gold(I), Pd(OAc)2, or copper(I)/base, are versatile catalysts. When the cascade process is initiated by a cross-coupling and followed by intramolecular hydroamination or -amidation, palladium and copper catalysts such as palladium(0)/phosphine complexes are commonly used. Although hundreds of such reactions have already been developed, this research area has only started to evolve, and one can expect numerous creative reaction cascades to be disclosed in the upcoming years. 7.2. Synthetic Challenges

Despite all progress achieved, a number of obstacles still need to be overcome. One such challenge is the use of ammonia as a substrate for hydroaminations. The gold-catalyzed hydroamination of alkynes/allenes with ammonia discussed in this Review is a first important step in this direction.286 The long way toward an efficient and atom-economic synthesis of amines from ammonia and alkynes is well worth pursuing. The key difficulty here is that the products of such reactions, primary amines, will always be more nucleophilic than ammonia itself. It may be possible to surmount this challenge using a concept similar to that employed for the selective addition of primary amides to terminal alkynes, even in the presence of the more nucleophilic secondary amide reaction products. In this case, CH


Chemical Reviews

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Biographies

breakthroughs in both the efficiency and the selectivity of many N−H additions across C−C double and triple bonds. It is certainly worthwhile directing research activities toward this goal. 7.3. Mechanistic Challenges

Various mechanisms of hydroaminations have been proposed, but only very few extensive mechanistic studies have been performed to assess the validity of the mechanistic assumptions made. For the ruthenium-catalyzed hydroamidations of alkynes, the proposed mechanism was revised several times until finally a detailed mechanism was established with substantially enhanced complexity as compared to the initial draft. Just recently, the origin of the reversal of stereochemistry in these reactions could be pinpointed, so that a rational ligand design has become possible. The mechanism of intramolecular hydroaminations or -amidations of alkenes has extensively been explored. Usually, the cleavage of C−M (M = Rh, Ir, Pd, Fe, Au) bond by either protonation or aminolysis of the C−M bond was found to be the rate-determining step. In-depth spectroscopic and theoretical investigations would be welcome also for a detailed study of the late transition metalcatalyzed hydroaminations. For example, the origin of the regioselectivities (e.g., 6-endo vs 5-exo) in intramolecular hydroaminations tends not to be fully understood. The mechanisms are often rather tentative. Comparative studies of the proposed pathways should be conducted to aid the rational development of selective catalyst systems. This would be of particular interest for the desirable reversal of the hydroamination or -hydroamidation selectivity toward the Markovnikov products. Inntermolecular N−H addition reactions are mechanistically very diverse and far from being fully understood. Hartwig et al. found that the migratory insertion of alkenes into the Ir−N bond was the rate-limiting step for the specific case of an intermolecular hydroamination of alkenes with indoles. In contrast, the suggested pathway for hydroamination or -amidation via a migratory insertion of the alkyne into the M−N bond (pathway c in Scheme 8) has not yet been validated,163,164 nor is it clear which steps are likely to be limiting for a given set of catalysts. M−amide and M−amido species are easily formed under mild conditions, so that numerous potential applications might arise from a better understanding of such processes.1053

Liangbin Huang was born in 1986 in Hubei province of China and received his B.S. in 2008 from Beijing University of chemical technology. He earned his Ph.D. in 2013 from South China University of technology, where he worked on transition metal-catalyzed oxidative functionalization of alkenes with Prof. Huanfeng Jiang. He is currently a postdoctoral fellow at the TU Kaiserslautern with Prof. L. J. Gooßen.

Matthias Arndt was born in 1983 in Koblenz, Germany. In 2003, he started to study chemistry at the TU Kaiserslautern. In 2008 he joined the group of Professor L. J. Gooßen, finished his diploma work in the same year, and received his Ph.D. in organic chemistry in June 2012 for his research on hydroamidation and carboxylation reactions of terminal alkynes. During his studies he participated in the Sokrates/

AUTHOR INFORMATION

Erasmus exchange program and was a scholar holder of the

Corresponding Author

*Tel.: (+49) 631-205-2046. Fax: (+49) 631-205-3921. E-mail: [email protected].

Landesgraduiertenförderung Rheinland-Pfalz. In August 2012 he joined Clariant, a globally leading specialty chemicals company

Author Contributions †

based in Switzerland. Currently he holds a position as manager of a

Notes

R&D laboratory located in Frankfurt-Hoechst and focuses on the

The authors declare no competing financial interest.

synthesis and development of new surfactants.

L.H. and M.A. contributed equally.

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Chemical Reviews

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Lukas Gooßen studied Chemistry at the universities of Bielefeld, Michigan, and UC Berkeley. He was awarded a Ph.D. in 1997 for research on N-heterocyclic carbene complexes supervised by W. A. Herrmann, TU Munich, and pursued postdoctoral research with K. B. Sharpless, Scripps Research Institute. He began his professional career as an industrial chemist at Bayer AG in 1999, but moved back to academia to the group of M. T. Reetz, MPI for Coal Research for his Habilitation, and further to RWTH Aachen. Since 2005, he is professor at the TU Kaiserslautern. His research is devoted to the development of novel concepts for C−C and C−heteroatom bond formation. He has authored over 120 publications and 25 patents. Recent awards include the Jochen-Block award of the DECHEMA, the Carl-Duisberg Award of the GDCh, the Novartis Young Investigator Award, and the AstraZeneca Award in Organic Chemistry (2008).

Käthe Gooßen, née Baumann, studied chemistry at the University of Durham (UK) and moved to the group of Prof. J. A. Murphy at the University of Strathclyde (Glasgow, UK) for her Ph.D. studies on palladium-catalyzed alkaloid syntheses. Between 1999 and 2006, she worked for Bayer AG, first in Leverkusen as head of laboratory in Central Research in the fluorine chemistry group, then in Chemical Development Pharma at Bayer Healthcare in Wuppertal, and from 2005 on in strategic planning at Bayer Schering Pharma. During parental leave in 2006−2011 she has been active in the Gooßen group, and alongside, completed an M.Sc. in Toxicology at the TU Kaiserslautern. She is presently a member of the Systematic Reviews

ACKNOWLEDGMENTS We thank the DFG (SFB-TRR 88 “3MET”) and the Alexandervon-Humboldt foundation (fellowship to L.H.) for financial support.

group of the German Surgical Society at the University of Heidelberg.

ABBREVIATIONS Ac acetyl Ar aryl Bn benzyl BINOL 1,1′-bi-2-naphthol Boc tert-butyloxycarbonyl Bz benzoyl CAAC cyclic(alkyl)(amino)carbene Cbz benzyloxycarbonyl cod 1,5-cyclooctadiene Cp cyclopentadiene Cp* 1,2,3,4,5-pentamethylcyclopentadiene Cy cyclohexyl dba dibenzylideneacetone DBFphos 4,6-bis(diphenylphosphino) dibenzofuran DBU 1,8-diazabicyclo-[5.4.0]undec-7-ene DCE 1,2-dichloroethane DCM dichloromethane dipea N,N-diisopropylethylamine Dipp 2,6-di-iso-propylphenyl dippe 1,2-ethanediylbis[di(propan-2-yl)phosphane] DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMEDA tetramethylethylenediamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DPEphos bis[(2-diphenylphosphino)phenyl]methane

Heinrich Heydt obtained his first degree in chemistry at University of Saarbrücken. For his Ph.D. studies, he moved to the Technical University of Kaiserslautern, where he worked on the reactivity of diazo compounds, in relation to their carbene chemistry, and their cycloaddition behavior under the supervision of Manfred Regitz. Since 1976, he has worked as a senior lecturer in the department of Organic Chemistry at the TU Kaiserslautern. His research is concerned with the synthesis and reactivity of low-coordinated phosphorus compounds, for instance phosphaalkenes, phosphaalkynes, and phosphaheterocycles. He is author and co-author of more than 120 publications, review articles, and book contributions. He is also member of the editorial board of the RÖ MPP Chemielexikon. He is officially retired but still active writing publications. CJ


Chemical Reviews dppe dppf dppp dr ee equiv er Et EDG EWG Fmoc IMes Ind i-Pr IPr JohnPhos KHMDS L Naph m Me MS Ms μW n-Bu NHC n-Oct n-Pent n-Pr Ns NTf2 OPNB OTf o-tol p p-cymene Ph PMB PMP p-Tol p-Ts Py rac-BINAP rt Sphos TBAF t-Bu TEMPO Tf TFA THF TIPS TM TMEDA TMS Tp Ts Xantphos

Review

xylxylBINAP (R)-(+)-2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl

1,2-bis(diphenylphosphino)ethane 1,1′-bis(diphenylphosphino)ferrocene 1,3-bis(diphenylphosphino)propane diastereomeric ratio enantiomeric excess equivalents enantiomeric ratio ethyl electron-donating group electron-withdrawing group 9-fluorenylmethoxycarbonyl 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene indenyl iso-propyl N,N′-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (2-biphenyl)di-tert-butylphosphine potassium bis(trimethylsilyl)amide ligand naphthyl meta methyl molecular sieves methanesulphonyl microwaves n-butyl N-heterocyclic carbene n-octyl n-pentyl n-propyl 4-nitrophenylsulfonyl bis(trifluoromethylsulfonyl)amide p-nitrobenzonate trifluoromethanesulfonate 2-methylphenyl para 1-methyl-4-(1-isopropyl)benzene phenyl para-methoxybenzyl para-methoxyphenyl 4-methylphenyl para-toluenesulfonyl pyridine (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene room temperature 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl tetra-n-butylammonium fluoride tert-butyl 2,2,6,6-tetramethylpiperidine-1-oxyl trifluoromethanesulfonyl trifluoroacetic acid tetrahydrofuran triisopropylsilyl transition metal N,N,N′,N′-tetramethylethylendiamine trimethylsilyl trispyrazolylborate tosyl 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

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