Transition-Metal-Catalyzed Cleavage of CâN Single Bonds - Chemical

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Transition-Metal-Catalyzed Cleavage of C−N Single Bonds Kunbing Ouyang,†,‡ Wei Hao,† Wen-Xiong Zhang,*,†,§ and Zhenfeng Xi† †

Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China ‡ Institute of Chemistry, Chinese Academy of Sciences (CAS), Beijing 100190, China § State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China 2.6.1. C−N Bond Cleavage via Oxidative Addition 2.6.2. C−N Bond Cleavage via Denitrogenation 2.6.3. C−N Bond Cleavage via Ring-Opening of the Strained Ring Intermediate 2.7. Cyanamides 2.7.1. C−N Bond Cleavage via Oxidative Addition 2.7.2. C−N Bond Cleavage via Insertion/Deinsertion 2.8. Triazenes 2.9. Ureas 2.10. Thiocarbamates 3. Cleavage of Activated C−N Single Bonds 3.1. Quaternary Ammonium Salts 3.2. Diazonium Salts 3.3. Triazoles 3.4. Aziridines 3.5. 2H-Azirines 4. Summary and Outlook Author Information Corresponding Author Notes Biographies Acknowledgments Notations and Abbreviations References

CONTENTS 1. Introduction 2. Cleavage of Unactivated C−N Single Bonds 2.1. Primary Amines 2.1.1. C−N Bond Cleavage via Oxidative Addition 2.1.2. C−N Bond Cleavage via Imine or Iminium Species 2.1.3. C−N Bond Cleavage via Ammonium Species 2.2. Secondary Amines 2.2.1. C−N Bond Cleavage via Oxidative Addition 2.2.2. C−N Bond Cleavage via Imine or Iminium Species 2.2.3. C−N Bond Cleavage via Ammonium Species 2.2.4. C−N Bond Cleavage via σ-Bond Metathesis 2.3. Tertiary Amines 2.3.1. C−N Bond Cleavage via Oxidative Addition 2.3.2. C−N Bond Cleavage via Imine or Iminium Species 2.3.3. C−N Bond Cleavage via Ammonium Species 2.3.4. C−N Bond Cleavage via β-Amino Elimination 2.4. Diamines 2.4.1. C−N Bond Cleavage via Oxidative Addition 2.4.2. C−N Bond Cleavage via Imine or Iminium Species 2.5. Amides 2.5.1. Amide C−N Bond Cleavage in the R′R″NCO Unit 2.5.2. Non-Carbonyl C−N Bond Cleavage in the R′R″NCO Unit 2.6. Hydrazines

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1. INTRODUCTION The C−N bond is one of the most abundant chemical bonds and widely exists in many organic molecules and biomacromolecules. The formation and transformation of C−N bonds are among the central topics in organic chemistry, organometallic chemistry, and biochemistry.1−19 For example, both the process of making proteins from α-amino acids via the C− N bond formation and the reverse process from proteins to αamino acids via the amide C−N bond cleavage in the presence of enzymes are essential for life.20 Although transition-metalcatalyzed cleavage of inert chemical bonds such as C−H,21−36 C−C,37−41 and C−O42−45 bonds is an area of utmost importance in organic chemistry and organometallic chemistry, the cleavage of C−N bonds, especially transition-metalcatalyzed C−N bond cleavage, is less explored. The high C−

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Received: July 3, 2015

© XXXX American Chemical Society

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DOI: 10.1021/acs.chemrev.5b00386 Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 1. Annual Published Items on the Topic of Transition-Metal-Catalyzed Cleavage of C−N Single Bonds

N bond dissociation energy46 and the stability of unactivated N-containing compounds, e.g., amines, have made them the most prevalent and unreactive classes of organic compounds in synthetic organic chemistry. Therefore, it is conceivable that the C−N bond cleavage will remain a great challenge and will attract much attention in future chemistry. Transition-metal-catalyzed cleavage of the C−N single bond was initiated as early as 1980, and has become a hot topic since 2010, because it provides a mild and convenient approach to obtain good nitrogen and/or carbon sources for the synthesis of the desired products (Scheme 1). On the basis of the reported literature on transition-metal-catalyzed C−N bond cleavage, simple N-containing compounds are classified into two types (Scheme 2): (1) N-containing compounds having unactivated C−N bonds, e.g., amines, amides, hydrazines, etc., and (2) N-containing compounds having activated C−N bonds, e.g., ammonium salts, diazonium salts, triazoles, and strained azaheterocycles. Mechanistic understanding of transition-metal-catalyzed C− N bond cleavage is critical for us to accelerate the development of the related areas. It helps not only in knowing the cleaved processes, the influencing factors, and the final direction of the cleaved nitrogen or carbon sources, but also in designing the corresponding reaction to explore efficiently the nitrogen and/ or carbon sources with synthetic aims. Transition-metalcatalyzed C−N bond cleavage is classified mainly into five pathways: (1) via oxidative addition of transition-metal catalysts to C−N bond, (2) via imine or iminium species, (3) via ammonium species, (4) via β-amino elimination, (5) via insertion/deinsertion, etc. (Scheme 2). When simple Ncontaining compounds, e.g., secondary amines, tertiary amines, amides, and ammonium salts, have more than one C−N bond, selective C−N bond cleavage can be observed in these transformations. The C−N bond in a less-hindered substituent is more likely to be cleaved than a bulky C−N bond in most cases. However, the selectivity strongly relies on the substrate structure and reaction conditions. Many papers on stoichiometric metal-promoted C−N bond cleavage have been published,47−60 and we will not discuss them here because of the limited space. Since several excellent reviews have summarized transition-metal-free or transition-

Scheme 2. Main Pathways of Transition-Metal-Catalyzed Cleavage of C−N Single Bonds of Simple N-Containing Compounds

metal-catalyzed C−N bond cleavage in diazonium salts61−64 and high-strained azaheterocycles, such as aziridines,65,66 2Hazirines,66,67 and four-membered-ring azaheterocycles,68−70 only selected examples and recent works will be discussed. In this review, we will introduce transition-metal-catalyzed cleavage of both unactivated and activated C−N single bonds of simple N-containing compounds. To better understand the comprehensive review, the content is organized according to B


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realized. This reaction opens up the possibilites for the transition-metal-catalyzed C−N bond cleavage of amines. Primary allylic amines are a class of important alternatives of allylic halides and alcohol derivatives to deliver allyl units in the Tsuji−Trost reaction because of the higher atom economy and easy preparation on a large scale.18,74−77 Tian et al. developed the Pd-catalyzed coupling reactions of primary allylic amines with various nucleophiles via the cleavage of the C−N bond to prepare multiple allylic derivatives, 7−9, in good to excellent yields with exclusive selectivity (Scheme 4).78−85 These

the types of C−N bonds in different N-containing compounds and the order of the main mechanistic pathways as shown in Scheme 2.

2. CLEAVAGE OF UNACTIVATED C−N SINGLE BONDS 2.1. Primary Amines

2.1.1. C−N Bond Cleavage via Oxidative Addition. The cleavage of the C−N bond of a primary amine (R−NH2) is a challenging process because the primary NH2 group has a poor leaving ability and the two active N−H bonds have a relatively lower tolerance for functional groups. However, an ammonium ion (H3N+) produced by protonation of the NH2 group is a good leaving group owing to the decreasing strength of the C− N bond. Therefore, acid-assisted C−N bond activation by converting the NH2 group to ammonium ions provides the possibility of C−N bond cleavage of the primary amine. On the other hand, oxidative addition of an A−B bond to transition metals yielding active “A−[M]−B” is an elementary process to cleave the A−B bond in organometallic chemistry.71 Therefore, the combination of oxidative addition of a C−N bond to transition metals with acid-assisted C−N bond activation should be an effective and direct strategy to realize the cleavage of C−N bonds. An initial attempt at stoichiometric Pd(OAc)2-promoted Csp2−N bond cleavage in anilines was carried out by Fujiwara et al. in 1977 (Scheme 3).72,73 In this arylation reaction of anilines

Scheme 4. Pd-Catalyzed Coupling Reactions of Primary Allylic Amines in the Presence of B(OH)3

Scheme 3. Arylation of Olefins by Arylamines

nucleophiles include sulfonate salts, boronic acids, boronates, and ketone-stabilized phosphonium ylides. In these reactions, the NH2 group is activated by B(OH)3, and serves as a leaving group to generate allylic electrophiles.78−80 Then π-allyl−Pd intermediate 10 is produced via oxidative addition of Pd species to the C−N bond. Subsequently, 10 is attacked by the nucleophile (e.g., phosphonium ylides) to generate the intermediate 11, which then leads to the formation of phosphonium ylides 12 and the regeneration of the Pd catalyst. The subsequent one-pot Wittig reaction of 12 with formaldehyde gives α,β-unsaturated ketones 9. When hypophosphorous acids or H-phosphinic acids are used as nucleophiles, the NH2 group can be activated by these acids to facilitate allylic C−N bond cleavage with the Pd(0) species (Scheme 5).85 This reaction does not require the additional acids and yields the disubstituted phosphinic acids 13 and the sole byproduct ammonia (NH3).

with olefins providing aryl-substituted olefins 1, the aryl C−N bond of aniline is broken. A reasonable mechanism for this process involves the formation of the Ar−Pd−N species 2 by oxidative addition of ammonium ion 3 to the Pd species, a migratory insertion of alkene, and β-H elimination to yield the desired products 1. Acetic acid is crucial for this transformation to produce ammonium ion 3 from the primary amine. This reaction has a limited substrate scope and low yields (9−62%). The low efficiency is mainly owed to the formation of acetanilide 4 via the condensation reaction of anilines with acetic acid. This reaction shows the possibility of a transition metal cleaving the ammonium C−N bond by oxidative addition. Furthermore, if the Pd(II) intermediate 5 formed by β-H elimination could be converted to Pd(0) by the release of ammonium salt 6, this catalytic arylation reaction would be C


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2.1.2. C−N Bond Cleavage via Imine or Iminium Species. Imine or iminium species easily undergo hydrolysis to cleave the CN double bond.86−89 The challenge of amine C−N single bond cleavage via imine or iminium species is how to transform the amine C−N single bond to an imine CN double bond. The oxidation of the C−H bond adjoining the nitrogen atom is an effective strategy for the formation of imine or iminium species.11,16,17 Therefore, the mechanism of the amine C−N bond cleavage via imine or iminium species requires that an amine has at least one C−H bond adjoining the nitrogen atom. Although the mechanism has been well applied in tertiary amines, it is seldom explored in primary amines because of the difficulty in C−H bond oxidation of primary amines. Jiang et al. reported the C−N bond cleavage in aromatic methylamines via an aerobic oxidation in the presence of Cu salts to construct various 2,4,6-trisubstituted pyridines 19 from primary amines and ketones (Scheme 7).90 A plausible

Scheme 5. Pd-Catalyzed Coupling of Primary Allylic Amines with Hypophosphorous Acids or H-Phosphinic Acids

It is noted that the allylation of primary allylic amines with sulfonate salts is stereospecific. When BINOL is used as a ligand, α-chiral allylic sulfones 14 (R1 ≠ R3) can be achieved by stereospecific allylation from α-chiral allylic amines with good retention of the enantiomeric excess (ee) value (Scheme 6).78 Scheme 6. Pd-Catalyzed Coupling of α-Chiral Primary Allylic Amines Yielding Chiral Allylic Derivatives

Scheme 7. Cu-Catalyzed Synthesis of 2,4,6-Trisubstituted Pyridines from Primary Amines

mechanism suggests a Cu(II)-mediated single-electron oxidation and aminolysis of benzylamine form the imine 20. A reversible hydrolysis of 20 gives benzaldehyde and benzylamine. The aldehyde is confirmed to be the possible key intermediate in this reaction according to several controlled experiments. Then a Lewis acid-assisted condensation of benzaldehyde, benzylamine, and ketone gives the intermediate 21, which is readily oxidized to the final product 19. Meanwhile, the benzaldehyde is regenerated via oxidative hydrolysis under the Cu/O2 system. 2.1.3. C−N Bond Cleavage via Ammonium Species. An ammonium species is a good leaving group. Therefore, Lewis acid-assisted C−N bond cleavage by converting the NH2 group to ammonium ions provides a good pathway. Interestingly, changing the starting amine in Scheme 7 into (2-pyridylmethyl)amine (22) would give chain product 23 instead of trisubstituted pyridines 19 (Scheme 8).90 In this process, the C−N bond is cleaved via the ammonium species. The difference between aromatic methylamine and (2pyridylmethyl)amine leading to different products might be ascribed to the coordination interaction between the Cu

Analogously, the allylation reactions of α-chiral allylic amines with other nucleophiles, such as malononitriles, hydrazines, nonallylic amines, and sulfonyl hydrazides (RSO2NHNH2), also provide the highly stereospecific allylic derivatives 15− 18.81−85 In case of malononitriles, the stereospecific allylation was performed without any additives at room temperature to yield ammonia as a single byproduct.81 For sulfonyl hydrazides, this reaction proceeds via Pd-catalyzed oxidative coupling without any additives to give structurally diverse allylic sulfones 18.84 In this process, the sulfonyl hydrazide serves as a sulfonyl source by Pd-catalyzed aerobic oxidation and S−N bond cleavage with the release of N2. D


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Scheme 8. Cu-Catalyzed Synthesis of β-Pyridin-2-yl Ketones from (2-Pyridylmethyl)amine

2.2.1. C−N Bond Cleavage via Oxidative Addition. Amine exchange is an important reaction to achieve the cleavage of the C−N bond. In the early stage, Trost et al. described a Pd-catalyzed C−N bond cleavage in an amine exchange process (Scheme 10). 9 2 Treating (4,4′Scheme 10. Pd(PPh3)4-Catalyzed Amine Exchange between Secondary Amines and Primary Amines

dimethoxybenzhydryl)sorbylamine (29) with benzylamine, Pd catalysts, and acetic acid in refluxing THF could yield the benzylsorbylamine. Similar to Fujiwara’s observation,72,73 the addition of a stoichiometric amount of acetic acid is necessary for this transformation, indicating the possible existence of an ammonium intermediate. Although the catalytic mechanism was not proposed in the original paper, we consider that the C−N bond cleavage in the starting secondary amine should proceed via oxidative addition of the C−N bond to the Pd center. Hartwig et al. observed the Ni- or Pd-catalyzed exchange between allylic secondary amines and other secondary amines in 2002 (Scheme 11).93 This process would lead to the

catalyst and (2-pyridylmethyl)amine. Initially, the interaction between Cu(OTf)2 and ketone generates HOTf and affords an alkenyloxy−Cu species. The reaction of 22 with HOTf gives the ammonium species 24. Then the coordination interaction between 24 and the alkenyloxy−Cu species leads to the formation of intermediate 25, followed by an intramolecular nucleophilic attack and a C−N bond cleavage process to provide the desired product 23. In contrast to Pd-catalyzed coupling reactions of primary allylic amines with various nucleophiles, primary (αaminoalkyl)ferrocenes 26 serve as electrophiles to undergo ZnCl2-catalyzed direct substitution with various carbon, nitrogen, and sulfur nucleophiles, yielding ferrocenyl-derived compounds 27 in an enantiospecific fashion. In the presence of Lewis acid, 26 is transformed to the ammonium intermediate 28. Then a carbon cation intermediate is formed with the aid of a Lewis acid. A nucleophilic substitution affords the final products 27 (Scheme 9).91

Scheme 11. Ni- or Pd-Catalyzed Amine Exchange between Secondary Amines

Scheme 9. Direct Enantiospecific Substitution of Primary (αAminoalkyl)ferrocenes

generation of the mixed allylic amines. Complex 30 and free amine (R1NH2) could be obtained by mixing equal amounts of (DPPF)Ni(COD), CF3COOH (TFA), and an allylic amine in THF, so the cleavage of the C−N bond can be ascribed to oxidative addition of the Ni catalyst to the allylic amine. Similar to primary allylic amines acting as allyl units in the Tsuji−Trost reaction,78−85 secondary allylic amines can also deliver the allyl moiety by C−N bond cleavage. In 2007, List et al. reported the first catalytic enantioselective α-allylation reaction of α-branched aldehydes with N-benzyl allylic amine using the combined Pd/chiral Brønsted acid catalytic system (Scheme 12).94 The combination of chiral phosphoric acid with transition-metal catalysis has become a powerful tool in enantioselective reactions since the first enantioselective hydrocarboxylation of styrene derivatives catalyzed by Pd(II)

2.2. Secondary Amines

The C−N bond in secondary amines could be cleaved in the presence of transition metals. Four major pathways via oxidative addition, imine or iminium species, ammonium species, and σ-bond metathesis have been reported and will be discussed here. E


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Scheme 12. Catalytic Asymmetric α-Allylation of Aldehydes via C−N Bond Cleavage of an Allylic Amine

Scheme 13. Au/Pd/Brønsted Acid-Catalyzed Cascade Hydroamination/Allylic Alkylation Reaction

and a chiral phosphoric acid was reported.95,96 This method provides a good route for the preparation of various allylic aldehydes with all-carbon quaternary stereogenic centers. Chiral phosphoric acid 32 acts as a cocatalyst in this catalytic cycle. The condensation of an aldehyde with a secondary amine in the presence of 32 leads to the formation of phosphate salt 33, which reacts with the Pd(0) species to generate cationic πallyl−Pd complex 34. The nucleophilic attack of the enamine onto 34 would lead to the formation of α-allylated iminium ion 35, which could be hydrolyzed to the final product 31 and regenerate 32. The phosphoric acid cocatalyst plays a dual role in the catalytic cycle: (i) as proton source and (ii) as the counteranion/ligand for the cationic π-allyl−Pd intermediate. The Au/Pd/Brønsted acid ternary system for the cascade hydroamination/allylic alkylation reaction involving the C−N bond cleavage process was presented by Gong et al. (Scheme 13).97 This cascade reaction by combination of relay and cooperative catalysis affords dihydropyrroles 37 in high yields. This process could be divided into two parts. Initially, the gold catalyst coordinates to the secondary amine-bridged enyne 36 to generate intermediate 38. 38 undergoes a hydroamination to afford N-allylic enamine intermediate 39 and release the gold catalyst. Next, an allylic alkylation of 39 promoted by a Pd catalyst and a Brønsted acid via intermediate 40 leads to the formation of dihydropyrroles 37 and the regeneration of the Pd catalyst. The C−N bond of the secondary amine is cleaved through N-allylic group migration assisted by the Brønsted acid in the second catalytic cycle. 2.2.2. C−N Bond Cleavage via Imine or Iminium Species. Oxidation is an effective strategy for the C−N bond cleavage in secondary amines, and has been applied in some cases. In this strategy, the C−N single bond would initially be oxidized to a CN bond, which could be further transformed

to a CO bond. As reported by Li et al., the reaction between α-amino carbonyl compounds 41 and indoles provides 2-(1Hindol-3-yl)-2-imino carbonyls 42 in good yields in the presence of CuCl and t-BuOOH under an argon environment.98 However, under an aerobic environment, it gives 2-(1Hindol-3-yl)-2-oxo carbonyls 43 via C−N bond cleavage with the same catalytic system (Scheme 14).98 The selectivity for this reaction could be easily controlled by the reaction conditions. A wide range of 3-subsititutued indoles 42 and 43, which are valuable synthetic intermediates and important building blocks, could be obtained in good yields. On the basis of the reaction selectivity and some controlled experiments, a plausible mechanism was proposed. The reaction starts with a C−H bond oxidative deprotonation of α-amino carbonyl compounds 41 by t-BuOOH to yield imine intermediate 44. Subsequently, the in situ Friedel-Craft alkylation of indole with 44 generates 42. Finally, this product is hydrolyzed to 43 by H2O with the aid of CuCl2 and t-BuOOH in the aerobic environment. Su et al. reported the Ru-catalyzed oxidative coupling of indoles with N-methylaniline to provide 3-formylindoles 45 (Scheme 15).99 In contrast, 3-acylindoles 46 can be prepared by Fe-catalyzed acylation of indoles with N-benzylaniline (Scheme 15).99 In these two processes, N-methyl- and Nbenzylanilines act as formylation and acylation sources via Csp3−N bond cleavage, respectively. These two reactions share a similar iminium intermediate formed via the C−H bond oxidation strategy. The 13C-labeling experiments clearly showed that the carbonylic carbon atom in the formylation was from the methyl group of N-methylaniline. DDQ was employed as a dehydrogenation reagent in the acylation reaction. N-Dealkylation of secondary amines could be achieved by oxidation in the presence of a Rh catalyst. As reported by Fu et F


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Scheme 14. Oxidative Coupling of α-Amino Carbonyl Compounds

Scheme 16. Rh-Catalyzed Oxidative N-Dealkylation of Secondary Amines in Aqueous Solution

Scheme 15. Ru-Catalyzed Formylation of Indoles Using Anilines as the Carbonyl Source the C−N bonds in amines in many cases. Treating Ntosylpropargylamine 51 with a catalytic amount of AuCl3 provides various 1,3-diarylpropynes 52 in excellent yields (Scheme 17).101 This reaction tolerates a broad range of arene Scheme 17. Au-Catalyzed Synthesis of 1,3-Diarylpropynes via C−N Bond Cleavage of N-Tosylpropargylamine

al., various primary amines could be generated from secondary amines in aqueous solution under aerobic conditions (Scheme 16).100 The transformation starts with the coordination of the Rh(III) catalyst to the secondary amine. β-H elimination of 47 gives the iminium ion 48 and rhodium hydride species 49. The corresponding primary amines and carbonyl compounds are generated via hydrolysis of 48. The Rh(I) complex 50 is oxidized to Rh(III) by molecular oxygen to complete the catalytic cycle. 2.2.3. C−N Bond Cleavage via Ammonium Species. NSulfonyl compounds, such as N-benzylic and N-allylic sulfonamides, easily undergo Csp3−N bond cleavage to give the corresponding carbocations and primary sulfonamides as neutral byproducts under acidic conditions. Therefore, the employment of N-sulfonyl groups with either a Lewis acid or a Brønsted acid has been applied as an effective strategy to cleave

nucleophiles, including anisole, furan, pyrrole, phenol, 2naphthol, etc. The Lewis acid AuCl3 is supposed to promote the formation of carbocationic species 53. Tian et al. presented several Lewis acid-catalyzed C−N bond cleavages of N-benzylic and N-allylic sulfonamides as shown in Scheme 18.18,102−105 In these cases, the Lewis acids (ZnCl2 or FeCl3) accelerate the formation of carbocationic species from N-tosyl compounds. The formed carbocationic species would couple with carbon or sulfur nucleophiles in an SN1 manner to G


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cleavage in secondary amines and a consequent Csp2−N and Csp3−N bond formation to construct N-substituted pyrrole derivatives 60 and 60′ from amines and alkenyl or aryl dibromides (Scheme 20).106 A new type of cyclopentadiene−

Scheme 18. Lewis Acid-Catalyzed C−N Bond Cleavage of NTosyl Compounds

Scheme 20. Cyclopentadiene−Phosphine/Pd-Catalyzed Synthesis of Pyrrole Derivatives

afford various functional molecules, 54−57, via nucleophilic attack. These nucleophiles mainly include protic carbon nucleophiles,102 protic sulfur nucleophiles,102 alkynes,103 βketo acids,104 and arylallenes.105 In the case of β-keto acids, the Fe-catalyzed reaction provides an effective decarboxylative alkylation of β-keto acids via sequential cleavage of C−N and C−C bonds.104 In the case of alkynes103 and arylallenes,105 the two reactions proceed via the Friedel−Crafts cyclization of carbocations to afford polysubstituted indenes 55 and 57, respectively. The above-mentioned four reactions all adopt a similar reaction pathway. The process for the formation of indene derivatives 55 was taken as an example to elucidate the mechanism (Scheme 19).103 Benzyl cation 58 would first be Scheme 19. Proposed Mechanism for Lewis Acid-Catalyzed C−N Bond Cleavage of N-Tosyl Compounds phosphine ligand, L1, plays a key role in promoting the efficiency of this catalytic process. In the catalytic cycle, the sixmembered palladacycle intermediate 61 would be formed through oxidative addition, Buchwald−Hartwig amination, and oxidative addition. Then the C−N bond cleavage via a possible σ-bond metathesis would occur due to the driving force to form the aromatic pyrrole species 62. Finally, 62 couples with another amine to form the N-substituted pyrroles 60 via intermediate 63 with the regeneration of the Pd(0) species. Later, the o-NR2 iodobenzene derivative 64 and 1-bromo-2iodobenzene (65) were designed to react with an internal alkyne and a secondary amine to construct N-substituted indoles 66 and 66′, respectively (Scheme 21).107,108 In these two multicomponent reactions, intermediates 67 and 67′, which were similar to the above intermediate 61, would be formed.

generated from N-benzylic sulfonamide in the presence of FeCl3. This cation would then be attacked by the disubstituted internal alkyne to give vinyl cation 59, followed by a cyclization and an aromatization to form the indene derivatives 55. The selectivity is controlled by the R group of alkyne, as the R2 group is less capable of stabilizing a positive charge. In this catalytic cycle, FeCl3 would react with N-benzylic sulfonamide, affording [FeCl3(NHTs)]−, which would regenerate FeCl3 in the presence of H+. 2.2.4. C−N Bond Cleavage via σ-Bond Metathesis. In 2012, we reported an efficient Pd-catalyzed Csp3−N bond

2.3. Tertiary Amines

Tertiary amines are readily accessible starting materials and important building blocks in organic synthesis. Therefore, cleaving the C−N bonds in tertiary amines and applying the fragments in organic synthesis are of great significance. Compared with C(α)−H bond activation of tertiary amines, H


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Scheme 22. Synthesis of β,γ-Unsaturated Carbonyl Compounds via Pd-Catalyzed CO Insertion

Scheme 21. Synthesis of Indole Derivatives from Aryl Iodide, Alkynes, and Amines

C−N bond cleavage is more difficult because the C−N bond is stronger than the C(α)−H bond in tertiary amines. All abovementioned C−N bond cleavage strategies could be applied in the tertiary amines. Meanwhile, some other strategies have been developed as well. 2.3.1. C−N Bond Cleavage via Oxidative Addition. 2.3.1.1. C−N Bond Cleavage in an Allylic Amine. Oxidative addition of transition metals into the C−N bond in tertiary amines is a good strategy to realize the cleavage of the C−N bond. Murahashi et al. reported a Pd-catalyzed carbonylation of allylic amines to yield a variety of β,γ-unsaturated carbonyl compounds 68, which are useful precursors in organic synthesis (Scheme 22).109 The choice of phosphine ligand is crucial for this carbonylation reaction. Monodentate phosphines, including PPh3, PBu3, etc., were found ineffective for this transformation, while bidentate phosphines could promote this process. Both allylic amines 69 and 70 lead to the exclusive formation of the same product, 71, indicating that the two reactions involve the same π-allyl−Pd intermediate. The proposed catalytic cycle involves an initial oxidative addition of the allylic amine to the Pd catalyst, giving cationic π-allyl complex 72 via C−N bond cleavage of the allylic amine. Generally, the oxidative addition of allylammonium salts to Pd(0) species is convenient, but the oxidative addition of a neutral allylic amine is difficult. However, in this process, the addition of a catalytic amount of acid resulted in a reduced conversion. The exact reason is not clear. 72 is then transformed to complex 74 via σ-ally−Pd intermediate 73 with the insertion of CO.110,111 A reductive elimination of 74 gives 68 and regenerates the Pd catalyst. Alternatively, a direct nucleophilic attack of amide on the coordinated CO of 73 would afford 75, which could generate 68 via reductive elimination. Due to the structural feature an allylic amine, a π-allyl intermediate is readily generated from the allylic amine in the presence of an acid and transition-metal salts. This characteristic made it relatively easier to cleave the C−N bond. As reported by Guibé et al., an allylic amine and diallylamine could

be selectively deallylated in the presence of a Pd catalyst and NDMBA (Scheme 23).112 In the plausible catalytic cycle, the allylic amine is initially transformed to the corresponding ammonium ion in the presence of NDMBA in a reversible manner. The ammonium ion would react with the Pd(0) catalyst to afford a π-allyl−Pd(II) complex and deallylated Scheme 23. Synthesis of Amines via Selective Deallylation of Allylic Amines

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amine. The π-allyl−Pd(II) complex is then trapped by the carbanion 76 to generate the corresponding allylated derivatives. Trost et al. presented a Ni-catalyzed cross-coupling of allylic amines with boronic acids to yield allylic compounds with good regioselectivity in 1995 (Scheme 24).113 A bulky donor

Scheme 26. Pd-Catalyzed C−N Bond Cleavage of Allylic Amines via Hydrogen Bond Activation

Scheme 24. Ni-Catalyzed Coupling of Allylic Amines with Boronic Acids

proposed catalytic cycle, the coordination of Pd species to the allyl double bond in 81 yields Pd−olefin complex 84 along with the formation of a hydrogen bond between the nitrogen atom and hydrogen atom of the solvent. This hydrogen bond can activate the C−N bond, resulting in the cleavage of this C−N bond and the formation of a π-allyl−Pd complex. Further nucleophilic addition of an enamine, which is generated in situ from 82 and pyrrolidine, gives intermediate 85. Elimination of Pd species in the presence of water affords 83 and completes the catalytic cycle. Rearrangement is a common process in organic syntheses.116−120 It provides the facile pathways for the cleavage of chemical bonds. Murahashi et al. reported a Pd-catalyzed rearrangement of N-allylenamines in the presence of a catalytic amount of TFA to give unsaturated imines 86 (Scheme 27).121,122 It is noted that the employment of Pd(II) salt could not mediate this rearrangement; however, by changing the catalysts into Pd(0) catalysts such as Pd(PPh3)4, Pd(OAc)2− PPh3, and Pd2(dba)3·CHCl3−PPh3, the formation of a small amount of unsaturated imines could be observed. The yield could be strongly enhanced by addition of a catalytic amount of TFA. The reaction starts with an oxidative addition of a Pd(0)

phosphine ligand promotes the reaction at the less substituted position, while a bidentate ligand leads to C−C bond formation at the more substituted position. In this reaction, the tertiary amine could be regarded as a hard nucleophile. By coordinating to the boron center, the allylic amine would be transformed to the corresponding ammonium salt 77 in the presence of boronic acids. In the presence of the Ni catalyst, 77 is deallylated to give π-allyl−Ni complex 78 along with the formation of the corresponding secondary amine. The Lewis acid coordinates to 78, affording 79. 79 reacts with the secondary amine to give 80, which releases the final product and regenerates the Ni catalyst. In 1997, Mortreux et al. developed a Ni-catalyzed coupling reaction of allylic amines with soft nucleophiles such as active methylene compounds (Scheme 25).114 In this reaction, Scheme 25. Ni-Catalyzed Coupling Reaction of Allylic Amines with Soft Nucleophiles

Scheme 27. Pd-Catalyzed Rearrangement of NAllylenamines

Ni(DPPB)2 generated from Ni(COD)2 and DPPB is more active than the corresponding Pd systems. This observation could be explained by the higher ability of Ni species to activate an allylic substrate with a poor leaving group or lower propensity for the Ni center with a coordination of amines. Zhang et al. reported a Pd-catalyzed allylic alkylation of carbonyl compounds 82 with allylic amine 81 via C−N bond cleavage of the allylic amine (Scheme 26).115 It provides a convenient method to construct a C−C bond via catalytic allylic alkylation by using inexpensive alcohol solvents. In the J


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species to the C−N bond in the allylic enammonium ion, which is generated from the amine and acid, to form the π-allyl−Pd complex and enamines. A subsequent nucleophilic reaction of this enamine would lead to the formation of rearranged imines and the regeneration of the Pd(0) species. In the above metal-catalyzed allylic alkylation, the amino group in allylic amines only serves as the leaving group to yield the allylic reagents (Scheme 27). However, the amino group can play a dual role in serving as the leaving group and also as the nucleophile. As shown in Scheme 28, Yudin et al. reported

Scheme 29. Rh-Catalyzed/Chelate-Assisted Hydrogenolysis of Amine C−N Bonds

Scheme 28. Pd-Catalyzed Skeletal Isomerization of Cyclic Allylic Amines

such a dual role of the amino group in a Pd-catalyzed skeletal isomerization of cyclic allylic amines 87.123 In this transformation, an oxidative addition of ammonium ion species to Pd(0) gives the key π-allyl−Pd intermediate in the presence of acid. The following reductive elimination gives the rearranged allylic amines. 2.3.1.2. C−N Bond Cleavage in Other Tertiary Amines. Milstein et al. presented a Rh-catalyzed hydrogenolysis of an amine C−N bond in the aromatic aminophosphine 88 (Scheme 29).124 It is noted that this is catalytic C−N bond activation rather than C−C bond activation.125−129 The reaction starts with the insertion of Rh(I) to the Ar−CH3 bond, affording complex 90. 90 reacts with H2 to yield the hydrido chloride 91 via the release of CH4. The reductive elimination should yield the Rh(I) species 92. The exchange between the amine “arm” of 92 and the phosphine moiety of aminophosphine yields the intermediate 93 owing to the fact that a phosphine is a stronger ligand for low-valent late transition metals than an amine. Then the intramolecular C−N bond oxidative addition via C−N bond cleavage and hydrogenolysis takes place at the Rh center to give 94. The coordination of the amine arm in 94 affords 89 and regenerates the reactive Rh species 91. The driving force for the formation of 91 is the generation of two five-membered chelating rings. In 2007, Kakiuchi et al. discovered the first Ru-catalyzed Csp2−N activation/C−C coupling reaction of o-NMe2-substituted pivalophenones with organoboronates to provide the biaryls 95.130−133 Later, Snieckus et al. developed the Rucatalyzed amide-directed Csp2−N activation/C−C coupling reaction of anthranilamides with organoboronates (Scheme 30).134 The NMe2 group serves as a leaving group in this reaction, which could be a good complement to the Suzuki coupling reaction. Selective Csp2−N bond cleavage was

Scheme 30. Ru-Catalyzed Cross-Coupling Reaction of Aniline Derivatives with Organoboronates

observed in these transformations, probably due to the chelation assistance from an anchoring ketone directing group. The investigation of substrate scope showed that the substituents on the nitrogen atom do not have a significant effect while the substituents on the phenyl ring play an important role in this reaction. The coordination of the boron to the amino group is the key step for the transmetalation between Ru−NMe2 species and Ar−B(OR)2. A competitive experiment indicates the electron-withdrawing effect of the NMe2 group enhances the reactivity in the transmetalation process. The Ru intermediates in this transformation were obtained in 2009.131 Two Ru complexes, 96 and 97, could be generated by reaction of RuH2(CO)(PPh3)3 with 2 equiv of oacylanilines. It is obvious that the C−N bond of o-acylaniline is cleaved in 97 (Scheme 31). Further experiments showed the reaction of 97 with phenylboronate could yield the K


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effected by oxidative addition of the C−N bond to the Ni center.

Scheme 31. Isolation of Ru Intermediates and Proposed Mechanism for the C−N Bond Cleavage in Aniline Derivatives

Scheme 33. Ni-Catalyzed Suzuki Reaction Employing Azoles as the Leaving Group

2.3.2. C−N Bond Cleavage via Imine or Iminium Species. The oxidation of tertiary amines is a common and important process which provides new and efficient protocols for N-containing compounds.11,16,17 Among all the types of oxidative transformations of tertiary amines, the transitionmetal-catalyzed oxidation of tertiary amines, which cleaves the C−N bond, has received much attention in recent years. Some transition metals, including Fe, Cu, Ag, and Pd, could be employed in the oxidation of tertiary amines. In these cases, an iminium intermediate is usually involved. 2.3.2.1. Fe-Catalyzed C−N Bond Cleavage. Li et al. developed two synthetic methods involving the Fe-catalyzed oxidation of tertiary amines (Scheme 34).137,138 In these

corresponding product. On the basis of these results, this C−N bond cleavage reaction should proceed via the coordination/ oxidative addition/transmetalation/reductive elimination pathway. Recently, Wen et al. reported a facile synthesis of pyrido[2,1a]indoles 99 via multiple Rh/Cu-catalyzed C−H, C−C, and C−N bond cleavages of 1-(pyridin-2-yl)-1H-indoles 98 and γsubstituted propargyl alcohols (Scheme 32).135 Various

Scheme 34. Fe-Catalyzed Oxidation of Tertiary Amines

Scheme 32. Rh/Cu-Catalyzed Synthesis of Pyrido[2,1a]indoles via the Cleavage of Multiple C−H, C−C, and C−N Bonds

approaches, the tertiary amines are employed as carbon sources via their C−N bond cleavage. An oxidant, such as t-BuOOH, is required in these transformations. Methylene-bridged bis-1,3dicarbonyl compounds 102 and β-1,3-dicarbonyl aldehydes 103 could be synthesized in good yields with broad functional group tolerance. A mechanism for the generation of methylene-bridged bis1,3-dicarbonyl compounds 102 is shown in Scheme 35.137 The oxidative coupling of a 1,3-dicarbonyl compound with amine affords 104. 102 could be generated from 104 via a nucleophilic substitution reaction. Alternatively, Cope elimination of 104

functionalities are well tolerated in this transformation. Cu(OAc)2·H2O is responsible for the C−C bond cleavage of propargyl alcohols via β-C elimination, while the Rh catalyst enforces the Csp2−H bond cleavage. However, the mechanism for the C−N bond cleavage remains unclear. Robins et al. reported a Ni-catalyzed Suzuki cross-coupling reaction of triazole/imidazole-substituted purine derivatives 100 with arylboronic acids yielding 6-arylpurine 2′-deoxynucleosides 101 (Scheme 33).136 In this reaction, azoles act as leaving groups. The cleavage of the C−N bond should be L


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Scheme 35. Plausible Mechanism for Fe-Catalyzed Synthesis of Methylene-Bridged Bis-1,3-dicarbonyl Compounds

Scheme 37. Cu-Catalyzed Rearrangement of Tertiary Amines

can yield intermediate 105, which undergoes Michael addition to give 102. However, the proposed mechanism for the formation of β1,3-dicarbonyl aldehydes 103 is a little different from the mechanism in Scheme 35 according to the experimental results (Scheme 36).138 In this catalytic process, iminium 106 is

115 affords 116. Finally, a nucleophilic attack by MeOH produces the α-amino acetal 110. Huang et al. reported an efficient approach for Cu-catalyzed oxidative amination of benzoxazoles with tertiary amines to provide substituted benzoxazoles 117 in good yields (Scheme 38).140 This approach could be performed in the absence of an external base with molecular oxygen as the oxidant. This reaction combines the cleavage of the C−N bond and amination of the C−H bond, presenting the utility of tertiary amines as the nitrogen source in the C−H bond activation process. A proposed mechanism is shown in Scheme 38. The Cu catalyst is oxidized to reactive Cu species by oxygen. The

Scheme 36. Proposed Mechanism for Fe-Catalyzed Synthesis of β-1,3-Dicarbonyl Aldehydes

Scheme 38. Cu-Catalyzed Synthesis of Substituted Benzoxazoles Using Tertiary Amines as the Nitrogen Source

generated via one-electron oxidation of nitrogen, deprotonation of the C−H bond adjacent to the nitrogen atom, and a second one-electron oxidation. Then 106 is hydrolyzed to aldehyde 107, which further proceeds via aldol condensation to yield α,βunsaturated aldehyde 108. A final Michael addition promoted by an Fe catalyst affords the target product 103. Alternatively, 106 could undergo a direct aldol-type condensation and a Michael addition to give 103. 2.3.2.2. Cu-Catalyzed C−N Bond Cleavage. Loh et al. described a Cu-catalyzed rearrangement of tertiary amines 109 via the cleavage and re-formation of the C−N bond in 2010 (Scheme 37).139 This transformation provides a mild and cheap method for the direct synthesis of a variety of useful α-amino acetals 110. A plausible mechanism for this rearrangement was illustrated on the basis of trapping, control, and isotope-labeling experiments. Initially, a series of one-electron oxidations of the tertiary amine by Cu catalysts and dioxygen generate iminium ion 111, which is then coverted to enamine 112 by deprotonation. Another single-electron transfer process of 112 yields cationic radical intermediates 113 and 114, followed by nucleophilic attack of MeOH and an electron transfer process to give aziridinium ion 115. A ring-opening reaction of M


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tertiary amine would coordinate the Cu species with high Lewis acidity to give iminium ion intermediate 118 with the aid of HOAc. 118 is then hydrolyzed to the copper amide 119, which coordinates to benzoxazole to give 120. Further deprotonation and rearrangement form 121 and regenerate HOAc. The reductive elimination of 121 affords the final product 117 and regenerates the Cu catalyst to complete the catalytic cycle. A similar aerobic oxidative amidation of tertiary amines with 2-phenylacetonitrile derivatives was described by Yin et al. (Scheme 39a).141,142 This one-pot reaction involves C−C bond

Scheme 40. Synthesis of H-Pyrazolo[5,1-a]isoquinolines via Cu(II)-Catalyzed Oxidation of Tertiary Amines

Scheme 39. Synthesis of Tertiary Amides via Cu-Catalyzed Oxidative C−N Bond Cleavage

source for the synthesis of 3,3′-bisindolylmethanes 127 and 3formylindoles 128 (Scheme 41).144,145 Both C−H bond oxidation and C−N bond cleavage processes of TMEDA are involved in these reactions. The reaction begins with the coordination of TMEDA with CuCl2 to give 129. The iminium ion 130 is then generated by oxidation of a C−H bond of TMEDA. In the presence of base, a nucleophilic addition of indole occurs to give Mannich-type intermediate 131. 131 undergoes further oxidation and hydrolysis to yield 128 (pathway A). In contrast, in the absence of base, 130 could generate formaldehyde by Cu-catalyzed oxidative N-demethylation. 127 is obtained by the reaction of two indoles with one formaldehyde in the presence of CuCl2 (pathway B). The Cu-catalyzed cascade reaction of enaminones with ammonium chloride under aerobic conditions was reported by Wan et al. for the synthesis of 3,5-disubsitituted pyridine derivatives 132 (Scheme 42).146 The branched C−N and C C bonds of enaminones are cleaved, and ammonium chloride acts as the nitrogen source of the pyridine ring. In this process, enaminone is first activated by Cu salt to give 133, which would further be oxidized to peroxide intermediate 134. Then a nucleophilic attack of another enaminone leads to the formation of intermediate 135, followed by a C−C bond cleavage to yield 136. The dehydration of 136 provides iminium ion 137, which is then transformed to 138 via nucleophilic addition of an additional enaminone. Then a cyclization with an ammonium salt via double transamination gives intermediate 139. An aromatization of 139 gives 132 along with the elimination of dimethylamine. Huang et al. presented a Cu/Fe-cocatalyzed Meyer− Schuster-like rearrangement of propargylic amines under aerobic conditions to selectively yield (E)-β-aminoacrylalde-

activation, C−N bond cleavage, and C−H bond oxygenation. It is worth noting that the reaction proceeded smoothly by using only 5 mol % CuCl2 as the catalyst and molecular oxygen as the sole oxidant without any additional ligands. A wide range of tertiary amides 122 can be synthesized easily by this practical and mild method. The catalytic cycle is similar to Scheme 38, which proceeds via an iminium ion intermediate and the copper amide intermediate 119. Further reaction of 119 with a benzoyl compound, which is generated by oxidation of 2-phenylacetonitrile, leads to the formation of 122. Additionally, this aerobic oxidation reaction could also be accomplished by using CCl4 as the oxidant under a nitrogen atmosphere (Scheme 39b). The initial coordination of the tertiary amine with CCl4 in the presence of base yields iminium ion intermediates, which would be further transformed to the desired amides. Wu et al. reported a Cu/Ag-cocatalyzed three-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and a tertiary amine for the synthesis of H-pyrazolo[5,1-a]isoquinolines 123 with broad functional group tolerance (Scheme 40).143 In this three-component reaction, the Cu salts are responsible for the oxidation of an aliphatic C−H bond of the tertiary amine in the presence of air, while Ag salts are used for the intramolecular cyclization reaction of the alkyne group. Iminium ion 124 is generated from the tertiary amine by Cu salts and oxygen. Isoquinolinium-2-ylamide 125 would be formed via a AgOTf-catalyzed cyclization of benzaldehyde and sulfonohydrazide. Then an intermolecular nucleophilic attack affords the intermediate 126, followed by an elimination of the tosyl group and aromatization to give 123. Li et al. reported the Cu-catalyzed and base-switched methylenation and formylation using TMEDA as the carbon N


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Scheme 43. Synthesis of β-Aminoacrylaldehydes via Cu/FeCatalyzed Rearrangement of Propargylic Amines

Scheme 41. Cu-Catalyzed Cleavage of the C−N Bond in TMEDA

to yield intermediate 142 in the presence of Lewis acid FeCl3. A [1,3]-migration in 142 affords intermediate 143, which isomerizes to give 140. 2.3.2.3. Ag-Catalyzed C−N Bond Cleavage. Wang et al. reported the Ag-catalyzed amidation of benzoylformic acids with tertiary amines via selective C−C bond cleavage to yield αketoamides 144 (Scheme 44).148 In this process, K2S2O8 acts as Scheme 44. Ag-Catalyzed Synthesis of α-Ketoamides Using Tertiary Amines as the Nitrogen Source Scheme 42. Synthesis of Pyridines via Cleavage of the Branched C−N and CC Bonds of Enaminones

an effective oxidant. Iminium ion 145 is generated via oneelectron oxidation of nitrogen, deprotonation, and further oneelectron oxidation in the presence of an oxidant. Then hydrolysis of 145 affords the silver amide 146 with elimination of an aldehyde. The amidation of 146 with α-keto acid gives 144. The trace amount of water might be the source of the oxygen atom in the aldehyde byproduct. 2.3.2.4. Pd-Catalyzed C−N Bond Cleavage. Li et al. presented a Pd-catalyzed oxidative coupling of trialkylamines with aryl iodides to provide various alkyl/aryl ketones 147 with broad functional group tolerance (Scheme 45).149 In this process, the combination of trialkylamines and water acts as an effective carbonyl source via selective cleavage of the C−N bond. Iminium intermediate 148 is generated in the presence of the Pd catalyst, air, and ZnO. 148 then reacts with an ArPdI

hydes 140 (Scheme 43).147 The 18O-labeling experiments indicated the oxygen atom should come from water. Iminium intermediate 141 is formed via C−H bond oxidation of propargylamine by molecular oxygen. 141 is attacked by H2O O


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to the formation of 155, followed by a reductive elimination to give the amide derivatives and regenerate the Pd catalyst. 2.3.2.5. Ru- or Os-Catalyzed C−N Bond Cleavage. Laine et al. reported the alkyl exchange between tertiary amines in the presence of H2O in the early 1980s (Scheme 47).151,152 The

Scheme 45. Pd-Catalyzed Oxidative Coupling of Trialkylamines with Aryl Iodides

Scheme 47. Ru- or Os-Promoted Alkyl Exchange of Tertiary Amines

C−N bonds of tertiary amines were activated in these situations. These transformation conditions were milder than those reported for heterogeneous Pd/C catalysts.153 It should be mentioned that this alkyl exchange reaction is reversible. Although the mechanism is not clear, the exchange should involve the activation of the C−H and C−N bonds of the tertiary amines via the iminium intermediates.154−162 2.3.3. C−N Bond Cleavage via Ammonium Species. 2.3.3.1. C−N Bond Cleavage via Dealkylation in Ammonium Species. Larock et al. developed a series of electrocyclization reactions from N,N-dialkyl-o-iodoanilines and terminal alkynes to construct various substituted indole derivatives 156 in good to excellent yields (Scheme 48).163−166 In these cyclization

species, which is formed via oxidative addition of Pd(0) to ArI, to generate 149 and regenerate the Pd(0) species. Another oxidation reaction of 149 yields iminium ion 150, followed by hydrolysis to afford 147. The Pd-catalyzed aminolysis reaction of aryl esters with tertiary amines under neutral and mild conditions was reported by Bao et al. to provide a broad range of amides (Scheme 46).150 This reaction proceeds via activation of the acyl C−O Scheme 46. Pd-Catalyzed Aminolysis Reaction of Aryl Esters and Tertiary Amines

Scheme 48. Synthesis of Substituted Indoles via Cyclization of o-Alkynylanilines

processes, the Pd/Cu catalysts usually take part in the Sonogashira reaction in the first step, leading to the formation of o-alkynylaniline derivatives 157.163,164 The real cyclization process proceeded readily in the presence of I2. The mechanism involves an anti-attack of the electrophile I2 and the nitrogen of the N,N-dialkylamino group on the alkyne to afford the iodoindolium salt. An SN2 displacement by the iodide leads to the removal of a methyl group via cleavage of the C−N bond. Further investigation revealed that the electrophiles could be changed to arylsulfenyl chlorides or aryl iodides.166 Alternatively, the Pd catalysts could take part in the cyclization

bond and the C−N bond. The addition of TEMPO did not reduce the yield of the targeted amide, indicating a radical-free process. A cross-experiment showed an iminium intermediate is possible in this process. A catalytic cycle was proposed according to these results. Coordination of the Pd(0) species with aryl ester gives intermediate 151. Subsequently, an intramolecular oxidative addition via the acyl C−O bond activation affords intermediate 152. Then the tertiary amine is coordinated to the Pd(II) center to generate intermediate 153, which undergoes an alkoxide attack on the α-position of the tertiary amine to give 154 and phenol. Hydrolysis of 154 leads P


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tion of o-alkynylanilines for the synthesis of indolo[3,2c]isoquinolinones 158, the intermolecular cross-coupling of oalkynylanilines with terminal alkynes for the efficient synthesis of disubstituted 3-alkynylindoles 159 and 160, and the intermolecular cross-coupling of o-alkynylanilines with internal alkynes for the efficient synthesis of bis(heterocyclic) compounds 161. These reactions all involve the σindolylpalladium(II) ammonium intermediate. Only the possible mechanism for bis(heterocyclic) compounds is shown. An initial coordination of Pd(OAc)2 to the CC bond of o-alkynylanilines 162 and a subsequent anti-aminopalladation affords σ-indolylpalladium(II) ammonium intermediate 164. 164 acts as a Lewis acid to activate 163. A selective oxypalladation gives intermediate 165, followed by a nucleophilic attack of I− or OAc− to yield 166. The formation of ammonium salt intermediate 165 was confirmed by a mechanistic study. A final reductive elimination gives 161 and the Pd(0) species, which is then oxidized to Pd(II) to complete the catalytic cycle. The less hindered alkyl C−N bond (N−Me) would be broken in this transformation. In parallel, Liang et al. presented a Pd(II)-catalyzed tandem cyclization/C−H functionalization of o-alkynylanilines with internal alkynes to afford polycyclic functionalized indoles 167 (Scheme 50).173,174 Molecular oxygen was used as the oxidant.

process when aryl iodides are involved in this reaction, leading to the formation of an iodoindolium salt.165 Zhu et al. have reported the synthesis of indole derivatives 158−161 by a series of Pd(II)-catalyzed reactions of oalkynylanilines under aerobic oxidative conditions via C−N bond cleavage since 2012 (Scheme 49),167−172 for example, the sequential intramolecular amination/N-demethylation/amidaScheme 49. Pd-Catalyzed Synthesis of Indole Derivatives from o-Alkynylanilines

Scheme 50. Tandem Cyclization/C−H Activation of oAlkynylanilines

Useful functional groups such as halogen, ether, and alkyl were well tolerated in this process. The proposed catalytic cycle also involves the key σ-indolylpalladium(II) ammonium intermediate, which is similar to 164. Recently, a Pd-catalyzed tandem cyclization of o-alkynylanilines with 2-alkynylbromobenzenes involving the C−N bond cleavage process was reported to provide various quinolones 170 (Scheme 51).175 The proposed mechanism, which is a little different from the above Zhu mechanism,167−171 proceeds via Pd-catalyzed Cacchi cyclization of o-alkynylanilines.176,177 This reaction starts with an oxidative addition of Pd(0) to 2alkynylbromobenzenes 168, affording intermediate 171. Then 171 generates 172 via intermolecular insertion of the triple bond of 169. A subsequent intramolecular triple bond insertion yields intermediate 173, which then forms ammonium salt 174. An N-demethylation via SN2 attack in 174 gives intermediate 175, followed by a reductive elimination to form the final product 170 and regenerate the Pd(0) catalyst. Wu et al. reported the Pd-catalyzed intermolecular coupling of o-alkynylanilines, isocyanides, and silver acetate (AgOAc) to prepare 3-amidylindoles 176 with high efficiency in a one-pot procedure (Scheme 52).178−180 In this reaction, AgOAc acts not only as the reactant but also as the oxidant. When silver trifluoroacetate (AgTFA) was used as the oxidant, the Pdcatalyzed cross-coupling of o-alkynylanilines with isocyanides led to the formation of 3-cyanoindoles 177 with the removal of Q


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Scheme 51. Synthesis of 5H-Indeno[1,2-c]quinolines via C− N Bond Cleavage of o-Alkynylanilines

Scheme 52. Pd-Catalyzed Synthesis of Indole Derivatives Involving C−N Bond Cleavage

the R group. Interestingly, in the presence of water, 3amidylindoles 178 were observed. In addition, the Pd-catalyzed cross-coupling of o-alkynylanilines with trifluoromethanesulfanylamide in the presence of bismuth chloride could yield 3((trifluoromethyl)thio)indoles 179 (Scheme 52).178−180 The above four reactions all involve C−N bond cleavage via a σindolylpalladium(II) ammonium intermediate. A representative Pd-catalyzed mechanism for the synthesis of 3-cyanoindoles and 3-amidylindoles is shown in Scheme 52. σIndolylpalladium(II) ammonium intermediate 180 is generated via Pd-catalyzed cyclization, followed by the insertion of isocyanide to give 181. 181 might undergo either a direct C−N bond cleavage along with removal of the tertiary carbon cation to generate 3-cyanoindole 177 or a reductive elimination in the presence of water to afford 3-amidylindoles 178 and the Pd(0) species. The C−N bond in an ordinary tertiary amine could also be cleaved via an ammonium salt intermediate. Kuninobu and Takai et al. described an Fe-catalyzed synthesis of glycine derivatives 182 by reaction of tertiary amines with diazoacetate involving a C−N bond cleavage process (Scheme 53).181 This experimental result indicated the (ethoxycarbonyl)methyl groups should come from diazoacetate. An iminium intermediate was ruled out since no oxidant was introduced to this reaction. A mechanism was proposed according to the experimental results. Diazoacetate is activated by coordination to a Lewis acidic metal center, affording intermediate 183. 183

isomerizes to give the zwitterion 184. A nucleophilic substitution of 184 with the tertiary amine gives ammonium salt intermediate 185 with the release of N2. The protonation of 185 with EtOH and the following C−N bond cleavage via elimination of EtOR3 will generate 182. Perumal et al. reported the synthesis of 1,1-bisindolylmethanes 186 by Pd-catalyzed alkylation of indole derivatives (Scheme 54).182 The oxidative coupling of indoles with Et3N involves an aliphatic Csp3−H bond activation/C−N bond cleavage/addition process. This reaction tolerates a broad range of indole derivatives. Although the details of the mechanism are still unclear, a proposed cycle was presented. Coordination of Et3N to palladium acetate affords intermediate 187, which will give 188 via the C−H bond activation of Et3N. The acetate (OAc−) serves as an internal base in this process. The oxidative addition of 188 to an indole affords 189, which proceeds via a reductive elimination to give 190 by release of the Pd species. Protonolysis of 190 leads to the formation of the ammonium intermediate 191, in which the C−N bond would be cleaved to generate 186 in the presence of indole. R


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Scheme 55. π-Lewis Acidic Transition-Metal-Catalyzed Cyclization of o-Alkynylphenyl N,O-Acetals

Scheme 53. Fe-Catalyzed Synthesis of Glycines Involving C− N Bond Cleavage of Tertiary Amines

elimination of a Pd salt gives the indole derivatives 193 and completes the catalytic cycle. Similar to the Pd-catalyzed processes,167−180 Au-catalyzed synthesis of indole derivatives from 2-alkynylanilines having two N−H bonds has been reported.176,177,184−186 In these reactions, no C−N bond cleavage in 2-alkynylanilines was observed.185 However, when N,N-dimethylalkynylanilines were utilized, the methyl C−N bond cleavage was observed. Bertrand et al. reported the first Au-catalyzed C−N bond cleavage of N,N-dimethylalkynylanilines for the synthesis of indole derivatives 197 in 2010 (Scheme 56).187 The formation of indole-type ammonium intermediate 198 was confirmed. The methyl C−N bond is cleaved by N-methyl group migration, yielding 2-methyl-subsitituted indole derivatives 197. The ligand effect in this Au(I)-catalyzed intramolecular

Scheme 54. Derivation of Indole Using Et3N as the Carbon Source

Scheme 56. Au-Catalyzed Synthesis of Indoles from N,NDimethylalkynylanilines

2.3.3.2. C−N Bond Cleavage via Alkyl Migration in Ammonium Species. N-Substituent migration was also observed in the C−N bond cleavage of an ammonium salt intermediate. A π-Lewis acidic transition-metal-catalyzed cyclization of o-alkynylphenyl N,O-acetals 192 was reported by Nakamura et al. to afford the corresponding 2,3disubstituted indoles 193 (Scheme 55).183 The Pd(II) salt would coordinate to the alkyne 192, leading to the formation of intermediate 194. Nucleophilic attack of the nitrogen on the alkyne gives the ammonium salt intermediate 195. Migration of the R group on the nitrogen atom leads to the cleavage of the C−N bond and the formation of intermediate 196. An S


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could form β-amino acid derivatives 200 via Michael addition. In pathway B, a ligand exchange reaction affords intermediate 202. The insertion of a CC bond gives intermediate 203, which could be protonolyzed to give 200 and regenerate the Pd salts.

hydroamination of N,N-dimethyl-o-alkynylaniline derivatives was studied by Tarantelli et al.188 2.3.4. C−N Bond Cleavage via β-Amino Elimination. Ziółkowski et al. revealed a Pd-promoted C−N bond activation mode in triethylamine (Scheme 57).189 A mechanism involving

2.4. Diamines

Scheme 57. C−N Bond Activation of Trimethylamine via βAmino Elimination

2.4.1. C−N Bond Cleavage via Oxidative Addition. The C−N bonds in diamines could be effectively activated by transition metals. Aminals, as an important class of 1,1diamines, are used as electrophiles in metal-catalyzed nucleophilic addition reactions. The cleavage of a C−N bond in aminals is regarded as a convenient method because of the good leaving ability of the amino group. Murai et al. discovered a Rh-catalyzed C−N bond cleavage process of aminals in 1992 (Scheme 59).193 The reaction of aminals with hydrosilane and Scheme 59. Rh-Catalyzed C−N Bond Cleavage in Aminals

the elimination of the β-amino group in the presence of H2O was presented.190 Initially, the amine would coordinate to the Pd center with the activation of a C−H bond and the formation of a Pd−C bond. Then a nucleophilic attack of OH− from water on the α-C will generate the complex 199, which will give the Pd(0) species and the secondary amine.191 Jiang et al. reported a Pd-catalyzed C−N bond activation approach from triethylamine and acrylates for the synthesis of β-amino acid derivatives 200, which can act as versatile building blocks in synthetic organic chemistry (Scheme 58).192 The

CO in the presence of the Rh catalyst affords 204 via the incorporation of CO and the cleavage of a C−N bond. A ring expansion reaction of five-membered cyclic aminals could also take place to give the cyclic enediamine 205 with the incorporation of CO under the same reaction conditions. Although the role of CO is still unclear, it is crucial for this transformation. Huang et al. reported the highly selective Pd-catalyzed vinylation of styrene derivatives with aminals for the synthesis of linear allylic amines 206 as the exclusive E isomer. In addition, the Pd-catalyzed difunctionalization of enol ethers with aminals and alcohols was reported to afford amino acetals 207 (Scheme 60).194,195 A mechanism for the formation of amino acetals 207 is presented. The reactive Pd(0) species and a catalytic amount of acid are initially generated from Pd(II) precatalyst in the presence of 2-PrOH. The aminal would be activated by this catalytic amount of acid, giving ammonium species 208. The oxidative addition of 208 to the Pd(0) species along with the C−N bond cleavage affords the key intermediate 209. This electrophilic intermediate 209 would react with the electron-rich enol ether to give intermediate 210, followed by attack of a nucleophile to generate complex 211. Reductive elimination of 211 forms 207 and regenerates the Pd(0) species to complete the catalytic cycle. Recently, the Pd-catalyzed insertion of an allene into an aminal was reported to provide an atom-economic and convenient approach for the synthesis of 1,3-diamines 212 (Scheme 61).196 Plenty of substituents were tolerated in this process. Low catalytic loading (2.5 mol %) is needed when the reaction proceeds on the gram scale. A plausible catalytic cycle was released on the basis of the isolation and characterization of reactive intermediates. The oxidative addition of an aminal to a Pd(0) species via a C−N bond cleavage yields electrophilic cationic Pd−alkyl species 213. The terminal double bond of allene would coordinate to cationic Pd−alkyl species 213, followed by a migratory insertion of the more electron-deficient

Scheme 58. Synthesis of β-Amino Acids from Triethylamine and Acrylates

addition of HOAc was found to be necessary for this transformation; otherwise, stoichiometric PdCl2 must be used. Molecular O2 was found to be negative for this process. On the basis of the experimental results and Ziółkowski’s work,189 Jiang et al. proposed a possible mechanism. Initial coordination of Pd(II) salts to triethylamine leads to the activation of a C−H bond and the formation of a Pd−C bond. Then β-amino elimination affords intermediate 201. The desired β-amino acid could be generated from 201 via two pathways. For pathway A, 201 is activated by acid to give the secondary amine, which T


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Scheme 60. Synthesis of Allylic Amines and Amino Acetals

Scheme 62. Cu-Catalyzed Aerobic Oxidative Amination of Aminals

Scheme 61. Pd-Catalyzed Insertion of an Allene into an Aminal

aldehyde and copper catalysis. The plausible catalytic cycle starts with the reaction of the aminal with Cu(acac)2, affording copper amide 217 and iminium intermediate 218 via C−N bond cleavage. In addition, hydrolysis of 218 in the presence of Cu(acac)2 and benzoic acid gives 217. The copper amide 217 would undergo a transmetalation with arylboronic acid to form 219, followed by a reductive elimination to provide amine product 215 and a Cu(I) species. The Cu(I) species would then be oxidized to the Cu(II) catalyst by O2 to complete the catalytic cycle. Additionally, various N-alkyl linear amides 220 could be readily prepared from alkenes, aminals, and CO in the presence of a Pd catalyst under mild conditions (Scheme 63).199 Iminium species 221 could be generated in the presence of the Pd catalyst. Scheme 63. Pd-Catalyzed Hydroaminocarbonylation of Alkenes with Amines

CC bond into the Pd−C bond to afford π-allyl−Pd intermediate 214. Nucleophilic addition of a nitrogen in a diamine to 214 gives 212 and regenerates the cationic Pd species to complete the catalytic cycle. 2.4.2. C−N Bond Cleavage via Imine or Iminium Species. Additionally, the C−N bond in an aminal could be cleaved by Cu-catalyzed aerobic oxidative amination (Scheme 62).197,198 The amination reaction of various arylboronic acids and aminals with air as the oxidant and PhCO2H as the additive was achieved to yield aromatic amines 215 and 216. It is noted that the direct aerobic oxidative C−H amination of azoles with aminals can be realized via a synergistic combination of U


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Chen and Yu et al. developed an efficient method for the synthesis of 2-arylpyridines 222 by using 1,3-diaminopropane as the nitrogen source (Scheme 64).200 A gram scale amount of

Scheme 66. Synthesis of Isoquinolin-1(2H)-ones via Decarbonylative Addition of Phthalimides to Alkynes

Scheme 64. Synthesis of 2-Arylpyridines by Using 1,3Diaminopropane as the Nitrogen Source

oxidative addition to afford intermediate 227. 227 then undergoes a decarbonylation to give 228. A subsequent intermolecular insertion of alkyne to the Ni−C bond of 228 forms seven-membered nickelacycle 229, followed by a reductive elimination to generate 226 and regenerate the Ni(0) catalyst. 2.5.1.2. C−N Bond Cleavage via Acyl Migration in Ammonium Species. Similar to N−R alkyl group migration in the C−N bond cleavage in tertiary amines, the acyl groups attached to the nitrogen atom could also undergo a [1,3]migration process, resulting in the amide C−N bond cleavage. Yamamoto et al. released the intramolecular addition of amides to alkynes in o-alkynyl amides (aminoacylation or carboamination) using the PtCl2 catalyst via the migration of the acyl group.202 However, this reaction suffered from the disadvantage of deacylation. Later, Liu et al. found the Pd-catalyzed intramolecular addition could efficiently provide indoles 231 (Scheme 67).203 A mechanism involving a quaternary ammonium salt intermediate was proposed. A coordination of Pt/Pd to alkyne 230 followed by an intramolecular nucleophilic attack of the o-nitrogen atom affords intermediate 233. Subsequently, a [1,3]-migration of the acyl moiety forms intermediate 234, which then gives 3-acylindole product 231 and regenerates the metal catalysts. When M = Pt, the 3deacylated indole 232 could be generated by protonolysis of the C−Pt bond. In the case of the Pd-catalyzed process, the formyl group was found to be the best migrating group on the nitrogen, while bulky acyl groups migrate sluggishly under the standard conditions.203 2.5.1.3. C−N Bond Cleavage via Protonolysis of the Amide C−N Bond. Protonolysis of the amide C−N bond is a classical process to cleave the amide C−N bond. Zhu et al. developed an efficient approach for the synthesis of 1H-indole-3-carboxamidines 236 by Pd-catalyzed three-component coupling of isocyanides, o-alkynyltrifluoroacetanilides 235, and secondary amines (Scheme 68).204 Reactive Pd species 237 is generated in the presence of isocyanide, piperidine, and O2. Coordination of 237 to alkyne 235 followed by an intramolecular nucleophilic attack of the anilide anion gives intermediate 238. 238 gives indole derivatives 236 and Pd(0) species by reductive elimination and detrifluoroacetylation. Detrifluoroacetylation via C−N bond cleavage is promoted by an acid. Oxidation of

2-arylpyridines could be readily prepared from diverse acetophenones and 1,3-diaminopropane by this Cu-catalyzed aerobic reaction. Imine intermediate 224 was suggested to be the key intermediate in this transformation. A plausible pathway involves an initial condensation of acetophenone with 1,3diaminopropane to afford 223, which is then oxidized to 224 in the presence of Cu salt and O2. The sequential hydrolysis, condensation, elimination, and oxidation give 222. 2.5. Amides

Amides are important and readily accessible pharmaceutical precursors in organic synthesis, and their C−N cleavage reactions have received much attention in recent years. Two types of C−N bonds, including the amide C−N bond and the non-carbonyl C−N bond, are involved in an amide molecule (Scheme 65). Generally, the amide C−N bond is considered to be more reactive than the non-carbonyl C−N bond. The cleavage of both types of C−N bonds will be dicussed in this section. Scheme 65. Two Types of C−N Bonds in Amides

2.5.1. Amide C−N Bond Cleavage in the R′R″NCO Unit. 2.5.1.1. C−N Bond Cleavage via Oxidative Addition. The direct oxidative addition of the low-valent transition metals into an amide C−N bond generating the active C−M−N species provides a good strategy to cleave the amide C−N bond. The Ni-catalyzed decarbonylative addition of Narylphthalimides 225 to alkynes was achieved to afford various isoquinolin-1(2H)-ones 226 (Scheme 66).201 In this process, the cleavage of an amide C−N bond in 225 is effected by V


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Scheme 67. Pt- or Pd-Catalyzed Addition of Amides to Alkynes

Scheme 69. Synthesis of Benzimidazo[1,2-a]quinazolines Involving a C−N Bond Cleavage Process

Scheme 68. Synthesis of 1H-Indole-3-carboxamidines

The C2-olefination of indoles has attracted much interest in recent years. The N-(p-tolyl) carboxamide group was considered to be a good directing group for the C−H activation of indoles. This strategy was applied to a Rhcatalyzed oxidative C−H bond activation of indoles by Kim et al. (Scheme 70).206,207 Various alkynes and olefins could be Scheme 70. Rh-Catalyzed Synthesis of C2-Olefinated Indoles

Pd(0) to Pd(II) by O2 would finally complete the catalytic cycle. Wang et al. presented an efficient method to synthesize benzimidazo[1,2-a]quinazoline derivatives 239 (Scheme 69).205 This reaction involves a Cu-catalyzed Ullmann C−N bond formation and the cleavage of two C−N bonds. Compound 240, which is produced by a Cu-catalyzed Ullmann reaction, would undergo the base-promoted protonolysis of the amide C−N bond to give intermediate 241. Subsequently, the base would attack the N−H bond, leading to the second C−N bond cleavage and the formation of 239.

used to derivatize indoles under the Rh catalytic system. The amide C−N bond is cleaved via protonolysis of N-(p-tolyl) carboxamide directing groups. Shi et al. presented a Rh/Cu-catalyzed annulation of benzimides 242 with internal alkynes to provide multisubstituted indenones 243 (Scheme 71).208 A broad range of functional groups are tolerated, regardless of electron-withdrawing and electron-rich substituents. An amide C−N bond and an aryl C−H bond are both cleaved. This work presented W


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Scheme 71. Rh/Cu-Catalyzed Annulation of Benzimide with Internal Alkynes

Scheme 72. Ni-Catalyzed Decarboxylation of Isatoic Anhydrides with Alkenes

the first directed C−H functionalization of a benzoic ester and an alkyne. In the proposed mechanism, the C−H bond is cleaved by coordination of benzimide 242 to the cationic Rh− C species 244. The insertion of an alkyne into the Rh−C bond gives seven-membered-ring intermediate 245. An intramolecular insertion of the carbonyl group into the Rh−C bond in 245 will give 246. A transmetalation between a Cu salt and 246 gives complex 247 and regenerates the Rh catalyst. In the presence of HOAc, 247 would be transformed to indenone 243 via the release of an amine and the cleavage of the C−N bond. 2.5.1.4. C−N Bond Cleavage via Decarboxylation. Yang et al. reported a Ni-catalyzed intermolecular decarboxylative cycloaddition of isatoic anhydrides 248 with alkenes to give tricyclic quinolones 249 (Scheme 72).209 Highly reactive norbornenes substituted with both electron-donating and electron-withdrawing groups were employed in this reaction. The reactive Ni(0) species in the catalytic cycle is generated via reduction of Ni(II) salts using Zn powder. The oxidative addition of an anhydride OCO bond to the Ni(0) species affords seven-membered azanickelacycle intermediate 250, which then releases CO2 to give intermediate 251. At this time, the amide C−N bond is cleaved by decarboxylation. Coordination of 251 to norbornene produces 252, followed by an insertion of norbornene to generate seven-membered azanickelacycle 253. 249 is then formed via reductive elimination of 253, completing the catalytic cycle. 2.5.1.5. C−N Bond Cleavage via Hydrogenation. Meanwhile, some other pathways for the amide C−N bond cleavage have been developed. Ikariya et al. developed a Ru-catalyzed chemoselective hydrogenation of imides 254 leading to glutarimides 255 (Scheme 73).210 Chiral glutarimides 255 could be prepared with a high ee value in almost quantitative yields. The hydrogenated product could be further applied in the synthesis of (−)-paroxetine. The C−N bond in imides is cleaved via reductive hydrogenation. The configuration of Cp*Ru(PN) in this reaction is similar to that of the possible transition states for reductive cleavage of the C−O bond in a

Scheme 73. Ru-Catalyzed Chemoselective Hydrogenation of Imides

ketone or an epoxide.211,212 The Brønsted acidic NH2 group is the active species, which could coordinate to the CO double bond and reduce this CO bond smoothly, along with the cleavage of the C−N bond. The orientation of the two carbonyl groups plays a key role in the selectivity. 2.5.2. Non-Carbonyl C−N Bond Cleavage in the R′R″NCO Unit. Although the non-carbonyl C−N σbond in the R′R″N−CO unit is less activated than the amide C−N bond, the cleavage of this C−N bond has been studied by many research groups. 2.5.2.1. C−N Bond Cleavage via Oxidative Addition. Itami et al. described a C−N arylation of aminothiazoles 256 with arylboronic acids to efficiently construct heterobiaryls 257 (Scheme 74).213 The N-aroyl-N-benzyl units in aminothiazoles 256 were found to be crucial for this process. Various arylboronic acids were well tolerated in this reaction. A proposed mechanism for this process involves an oxidative addition to the C−N bond followed by transmetalation of arylboronic acids to generate diaryl−Pd species 258. The subsequent reductive elimination affords 257 and regenerates X


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proceeds by Csp3−N bond activation via oxidative addition and hydrogenolysis of the alkene. 2.5.2.2. C−N Bond Cleavage via Imine or Iminium Species. As discussed regarding the cleavage of a C−N bond in tertiary amines, the Csp3−N bond could be cleaved by oxidation. This strategy could also be applied in the C−N bond cleavage of amides. As presented by Chang et al., DMF and ammonia could be employed as a combined source for the cyano “CN” unit with the C−N bond cleaved under aerobic conditions (Scheme 77).216 This assumption was confirmed by isotopic incorpo-

Scheme 74. Pd-Catalyzed C−N Arylation of Aminothiazoles with Arylboronic Acids

Scheme 77. Pd-Catalyzed Cyanation of Aryl C−H Bonds Using DMF and Ammonia as a Combined “CN” Source

the Pd catalyst. The non-carbonyl Csp2−N bond is selectively cleaved in this transformation. Tobisu and Chatani et al. presented a Ni-catalyzed reaction of N-aryl amides 259 with hydroborane or diboron to provide the corresponding reduction products 260 or borylation products 261 (Scheme 75).214 It is a reductive borylative Scheme 75. Ni-Catalyzed Reductive Borylative Cleavage of Aromatic C−N Bond in N-Aryl Amides and Carbamates

ration experiments. The kinetic isotopic effect (kH/kD = 3.3) also suggested the Pd catalyst is involved only in the C−H bond activation process. A further experiment showed the reaction was completely suppressed in the presence of TEMPO, which supported an SET mechanism. Two pathways were proposed on the basis of these results. The major pathway includes an SET process in the presence of CuBr2, generating imine species 262. The attack of 262 by ammonia leads to intermediate 263. 263 could act as a CN source under the aerobic conditions with its C−N bond cleavage. The minor pathway generating the CN source from the formyl group of DMF and ammonia is also possible. Meanwhile, an alternative pathway involving intermediate 265 formed via reaction of the substrate with 264, instead of the prior-generated CN source, could not be ruled out. Similarly, DMF could be used as the carbon source in organic synthesis under aerobic conditions. As reported by Wang et al., various vinylquinolines 267 could be readily synthesized via an Fe-catalyzed C−H functionalization and C−N bond cleavage process (Scheme 78).217 Functional groups, including electrondonating and electron-withdrawing groups, are tolerated. According to the proposed mechanism, the abstraction of the hydrogen radical from 268 by the tert-butyl alcohol radical, which is generated in situ by thermal homolysis of t-BuOOH, gives intermediate 269. 269 would be oxidized to 270 in the presence of Fe3+, together with the generation of Fe2+. Fe2+ would react with t-BuOOH to give Fe3+, OH−, and t-BuO•, completing the Fe2+/Fe3+ redox process. Meanwhile, 270 would react with intermediate 271, which is generated from 266 in the presence of FeCl3, to produce intermediate 272. Then a C−N bond cleavage process assisted by FeCl3 leads to the formation of 267.

cleavage of the aromatic C−N bond in N-aryl amides and carbamates. This process provided a new strategy in electrophilic aromatic substitution, in which an amino group on an aromatic ring is employed as a removable activating and directing group. Mechanistic studies showed that the activation of the aromatic C−N bond proceeds via oxidative addition. Aubé et al. discovered the Pd-catalyzed non-carbonyl C−N bond cleavage of bridged lactams (Scheme 76).215 The sole bicyclic products were obtained via a regioselective cleavage of the C−N bond within the seven-membered ring. This reaction Scheme 76. Pd-Catalyzed C−N Bond Cleavage in Bridged Lactams

Y


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80).220 This intramolecular pathway excluded the formation of 1,2-disubstituted ethylene derivatives, which are commonly

Scheme 78. Fe-Catalyzed Synthesis of Vinylquinolines from 2-Methylquinoline Using DMF as the Carbon Source

Scheme 80. Pd-Catalyzed β C−N Bond Cleavage in a 5-exoCyclization

formed in Heck reactions. A variety of 1,1′-disubstituted ethylene derivatives 278 could be readily prepared. The plausible mechanism suggested intermediate 279 is formed via oxidative addition of 277 to the Pd(0) species. Then an intramolecular cyclization occurs, leading to the formation of intermediate 280. Intermediate 281 is generated from 280 via β-amino elimination. Protonation of 281 in the presence of Et3N produces the 1,1′-disubstituted ethylene derivatives 278 and Pd(0) species, completing the catalytic cycle.

2.5.2.3. C−N Bond Cleavage via β-Amino Elimination. Kaufmann et al. presented the first non-carbonyl C−N bond cleavage in R′R″NCO in 2002 (Scheme 79).218 By Scheme 79. C−N Bond Cleavage in Diazabicyclo[2.2.1]hept5-ene

2.6. Hydrazines

2.6.1. C−N Bond Cleavage via Oxidative Addition. Hydrazines are important building blocks in organic synthesis. Loh et al. presented the first transition-metal-catalyzed cleavage of C−N bonds in arylhydrazines in 2011 (Scheme 81).221 A Pd-catalyzed cross-coupling of arylhydrazines with olefins could generate the corresponding styrene derivatives 282. A wide range of ortho-, para-, and meta-substituted arylhydrazines with Scheme 81. Pd-Catalyzed Cross-Coupling Reaction of Arylhydrazines with Olefins

treatment of a catalytic amount of Pd(OAc)2 and AsPh3, one of the C−N bonds in diazabicyclo[2.2.1]hept-5-ene 273 would be broken. The proposed mechanism starts with a syn-addition of the [ArPdX] species to an alkene, leading to the formation of intermediate 276. In the presence of an acid and F−, the βamino elimination of 276, which is substituted with an electronpoor Ar group, would give the trans-configured compounds 274. Alternatively, this intermediate, 276, could undergo a β-H elimination to afford compound 275 in the presence of formic acid. A similar process could be achieved in the presence of a Rh catalyst and Cu(OAc)2·H2O.219 Recently, Loh’s group described an intramolecular Mizoroki−Heck reaction via a vinyl C−N bond cleavage (Scheme Z


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either electron-donating or electron-withdrawing groups could react smoothly with various olefins. The later stage of this reaction is suggested to be similar to the nature of the Heck reaction, in which an aryl−Pd complex is involved. Therefore, the formation of this aryl−Pd complex is supposed to cleave the C−N bond in arylhydrazines. This assumption was confirmed by the isolation, characterization, and further reaction of aryl− Pd complex 283 from the reaction of 4-hydrazinylbenzonitrile with a stoichiometric amount of Pd(OAc)2 and ligand L3 (Scheme 81). A plausible mechanism is shown in Scheme 82.

Scheme 83. Aerobic Pd-Catalyzed Coupling Reactions of Arylhydrazines

Scheme 82. Proposed Mechanism for Pd-Catalyzed CrossCoupling Reaction of Arylhydrazines with Olefins

The key aryl−Pd complex 285 and HOAc are formed from arylhydrazine and Pd(OAc)2.222 An oxidative addition of Pd(0) to 285 gives binuclear Pd complex 286, whose reaction with HOAc affords complexes 287 and 288. In the presence of O2, 287 would give N2, H2O, and the Pd(0) species. The Pd(0) species is subsequently oxidized to a Pd(II) species to complete the catalytic cycle. Meanwhile, 288 would react with olefin in a Heck reaction manner to generate 282 and the Pd(0) species. Chen,223 Yao,224 Liu,225and Gao and Yin226 have applied arylhydrazines in aerobic Pd-catalyzed cross-coupling reactions in the past two years (Scheme 83). The corresponding 3substituted indole derivatives 289, diaryls 290, α-C-glycosides 291, and arylphosphonates 292 could be prepared by these simple and environmentally friendly approaches. It is worth noting that the high stereoselectivity was achieved when (3R)glycals were employed, yielding pure α-C-glycosides 291. One acyl group was cleaved in this process. A mixture of both α,β-Cglycosides was obtained when (3S)-glycals were used. The plausible catalytic cycles of these reactions are similar to Loh’s mechanism,221 in which Pd(II) intermediates 285−288 are involved. Analogously, it could be imaged that arylhydrazines could be used in Suzuki cross-coupling (Scheme 84). Lu et al. reported the first Suzuki cross-coupling of N′-tosylarylhydrazines with various organoboron reagents.227 A similar strategy has also been applied by Liu and Peng et al.228 and Xu and Gao et al.229 A number of corresponding diaryls could be generated in high yields. Various N′-tosylarylhydrazines, including both electronrich and electron-poor ones, and a broad range of organoboron reagents are proven to be good partners in these transformations. A plausible mechanism by Lu et al. is shown in Scheme 84.227 Dehydrogenation of N′-tosylarylhydrazines in the presence of a base affords diazene 293, which is in equilibrium with the corresponding diazonium ion. Then an

Scheme 84. Suzuki Cross-Coupling Reaction of Arylhydrazines with Organoborons

oxidative addition of diazonium ion to the Pd catalyst leads to the formation of intermediate 294, followed by a transmetalation to yield intermediate 295. The C−N bond is cleaved in this oxidative addition process. The desired diaryl products AA


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however, the corresponding intermediate 304′ would undergo decarboxylation before the insertion of an alkene. 2.6.3. C−N Bond Cleavage via Ring-Opening of the Strained Ring Intermediate. Liu et al. reported a Rhcatalyzed addition/cyclization/ring-opening of hydrazines with alkynes for the synthesis of pyrazoles 306, which are the core of several commercial drugs (Scheme 86).232 This reaction

are then formed via reductive elimination of 295. Since both arylhydrazines and organoboron reagents are readily accessible starting materials, these coupling reactions provide convenient routes to prepare diaryls and can be regarded as a complement to the classical Suzuki cross-coupling reaction. 2.6.2. C−N Bond Cleavage via Denitrogenation. Tian et al. reported the Pd-catalyzed cross-coupling reactions of acyl hydrazides with alkenes under aerobic conditions (Scheme 85).230,231 A series of α,β-unsaturated esters 296 and 1,2-

Scheme 86. Synthesis of Pyrazoles from Hydrazines and Alkynes

Scheme 85. Reactions of Acyl Hydrazides with Alkenes

involves a C−N bond cleavage of hydrazine. A plausible mechanism for this cascade reaction was proposed. The Rh precatalyst would be activated by NaOAc at the beginning of this process. Then a deprotonation of N−H in hydrazine 305 leads to the formation of intermediate 307, which coordinates to an alkyne to afford intermediate 308. Subsequently, the sixmembered [C−Rh−O] complex 309 would be generated by an intramolecular insertion. An intramolecular nucleophilic addition in 309 will give four-membered-ring intermediate 310. A ring-opening process of 310 produces 311 by cleaving the C−N bond. The protonation of 311 gives intermediate 312 and regenerates the reactive Rh species. The cyclization of 312 proceeds via an intramolecular nucleophilic addition and dehydration to produce 306.

disubstituted alkenes 297 could be obtained with good functional group tolerance and regioselectivity. A plausible catalytic cycle for the formation of α,β-unsaturated esters 296 was described. The carbazates would react with the Pd catalyst to give 299 via intermediate 298 by releasing HCl. A reductive elimination of 299 produces compound 300 and the Pd(0) species. Another displacement of [Pd(π-allyl)Cl]2 with 300 would afford 301 as a byproduct. Meanwhile, the Pd(0) species could be oxidized to a Pd(II) species in the presence of O2 and Cu salts. The Pd(II) species would undergo another displacement with carbazates to give diazene 302 and HPdCl. The attack of the diazene on PdCl2 yields intermediate 303, which undergoes the extrusion of N2 to afford alkoxycarbonyl−Pd complex 304. In this step, the cleavage of the C−N bond occurs. An insertion of 304 into an alkene followed by a β−H elimination produces α,β-unsaturated esters 296 and HPdCl. The reductive elimination of HPdCl would release HCl to complete the catalytic cycle. The mechanism for the formation of 1,2-disubstituted alkenes 297 is similar to this process;

2.7. Cyanamides

The R2N−CN bond is not easy to break because the C−N single bond has a partial CN double bond character owing to the conjugation of the pair electron of the nitrogen atom. However, the C−N bond cleavage of cyanamides has received much attention in recent years because it has been used as an important cyanation reagent.19 Two major pathways for the C− N bond cleavage of cyanamides are included: (i) Lewis acid (LA)-activated oxidative addition and (ii) coordination/ insertion/deinsertion (Scheme 87). AB


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Scheme 87. Two Major Pathways for the C−N Bond Cleavage of Cyanamides

Scheme 89. Stoichiometric Transition-Metal-Promoted R2N−CN Bond Cleavage

Scheme 90. Transition-Metal-Catalyzed N−CN Bond Cleavage in the Presence of Et3SiH 2.7.1. C−N Bond Cleavage via Oxidative Addition. Nakao et al. reported an intramolecular amiocyanation of alkenes by cooperative Pd/boron catalysis (Scheme 88).233 A Scheme 88. Intramolecular Aminocyanation of Alkenes by Pd/Boron Catalysis

transformed to N-silylated η2-amidino complex 319 in the presence of Me2NCN, followed by the cleavage of the N−CN bond to generate 320. Dissociation of silyl isocyanide leads to 16e amido complex 321, which affords complex 322 by reacting with Et3SiH. Finally, a reductive elimination produces Me2NH and regenerates 318. This mechanism was also supported by DFT calculations.235 Beller et al. presented a general method for the cyanation of aryl- and alkenylboronic acids (Scheme 91).237 N-Cyano-4methyl-N-phenylbenzenesulfonamide (323) was employed as a cyanation reagent in this process via cleavage of the N−CN bond. This method provided a direct and mild approach to various aromatic and vinyl nitriles in high yield.238,239 A mechanism for this transformation was postulated. The reactive Rh species 324 is formed via transmetalation of the Rh precatalyst with boronic acid. Coordination of the nitrogen atom of the CN group to 324 gives 325. The insertion of Rh− Ar into the CN triple bond affords intermediate 326. 326 undergoes a rearrangement to produce reactive Rh species 327 by releasing a nitrile. In this step, the C−N bond cleavage is observed. Finally, transmetalation of 327 with boronic acid regenerates 324 and completes the catalytic cycle. 323 could also be used as a cyano source in the Rh-catalyzed directed C−H cyanation of aryl ketone oximes 328 (Scheme 92).240 Various aromatic nitriles 329 could be efficiently synthesized by this method. The reaction starts with a formation of 330 via C−H activation. The coordination of intermediate 330 to the CN group followed by an intramolecular insertion of the CN moiety into the Rh−C

large number of substituted indolines and pyrrolidines (313) could be readily furnished. It is worth noting that an enantioselective aminocyanation could be achieved by this reaction. In this catalytic process, the CN group is activated by coordination to a Lewis acid (BR3). The oxidative addition of Pd(0) to the N−CN bond gives intermediate 314, breaking the N−CN bond. Insertion of the Pd center into CC double bond affords intermediate 315, which undergoes a reductive elimination to produce 313 and regenerate the Pd(0) species. The formation of the analogous boron-coordinated cyano−Pd complex 314 was confirmed by NMR and X-ray structural analysis. 2.7.2. C−N Bond Cleavage via Insertion/Deinsertion. Nakazawa et al. discovered the photoreaction of cyanamide 316 with a stoichiometric amount of silyl−iron complex Cp(CO)2Fe(SiEt3) would lead to the formation of Et3SiCN via cleavage of the C−N bond of the cyanamide.234−236 N-Silylated η2amidino−Fe complex 317, which was formed via a 1,2rearrangement, was successfully characterized. 317 was regarded as an appropriate intermediate for this N−CN bond cleavage (Scheme 89). The employment of Et3SiH made it possible to extend the stoichiometric N−CN bond cleavage to a catalytic reaction (Scheme 90). In this catalytic process, 16e silyl complex 318 is generated by reaction of the precatalyst and Et3SiH. 318 is AC


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Scheme 91. Rh-Catalyzed Cyanation of Aryl- and Alkenylboronic Acid

Scheme 93. Intramolecular Cyanation of Styrene Derivatives via Rh-Catalyzed N−CN Bond Cleavage

biaryl compounds (Scheme 94). 242 A wide range of aryltriazenes substituted with electron-donating groups, elecScheme 94. Pd-Catalyzed Cross-Coupling Reaction of Aryltriazenes with Arylboronic Acids

Scheme 92. Rh-Catalyzed Directed C−H Cyanation of Arenes

tron-withdrawing groups, and sterically hindered groups could be tolerated. Diaryl ketone 336 could also be obtained by the carbonylative cross-coupling reaction under a CO atmosphere with a similar catalyst system. It should be noted that the addition of 1 equiv of BF3·OEt2 is crucial for this transformation. The BF3·OEt2 acts as a Lewis acid to activate the aryltriazene, enhancing the reactivity of the Csp2−N bond. The resulting aminotrifluoroborate moiety, which acts as a fluoride base, would promote the transmetalation of the boronic acid. This process gives the diaryl−Pd intermediate, which forms the diaryls via a reductive elimination.

bond generates 331. 329 is then formed along with the elimination of tosylaniline-coordinated Rh species 332, which is then transformed to the reactive Rh species in the presence of an acid to complete the catalytic cycle. Furthermore, a Rh-catalyzed intramolecular β-cyanation of styrene derivatives 333 via N−CN bond cleavage was reported to provide the corresponding nitrile products 334 (Scheme 93).241 The deuterium-labeling experiment suggested the existence of an intramolecular process, e.g., Rh(I)-mediated CN group transfer from N to the terminal alkene.

2.9. Ureas

Brown et al. reported a study on a Cu(II) ion-catalyzed solvolysis of N,N-bis(2-picolyl)ureas 337 in alcohol solvents yielding bis(2-picolyl)amine (338) and the carbamate 339 (Scheme 95).243,244 By coordination of the urea and alcohol to the Cu center, the C−N bond in the urea was activated. The nucleophilic attack of OMe on the carbonyl group leads to the C−N bond cleavage, generating methyl carbamate derivatives 339. The detailed mechanism was studied by kinetic studies. Recently, Song et al. developed a Cu-catalyzed synthesis of benzonitriles 341 from phenylacetic acids 340 and urea

2.8. Triazenes

Saeki and Tamao et al. presented a Pd-catalyzed coupling reaction of aryltriazenes 335 with arylboronic acids in the presence of BF3·OEt2 to efficiently prepare the corresponding AD


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limiting step for the whole reaction according to the kinetic isotope effect (kH/kD = 1.5). A mechanism for this reaction was proposed. The thioenolate is generated from thiocarbamate 342 in the presence of an acid, which reacts with Pd(OAc)2 to give the Pd−S-enolate intermediate 342a. The cyclopalladium species 344 is formed via electrophilic palladation, activating the aryl C−H bond. The Pd(0) species is then generated via reductive elimination of 344, along with the formation of the iminium salt 345. The Pd(0) species would be oxidized to Pd(OAc)2 by benzoquinone (BQ). An intramolecular O−N exchange between 345 and acetic acid gives intermediate 346, which then delivers 343 via C−N bond cleavage.

Scheme 95. Cu(II) Ion-Catalyzed Solvolysis of N,N-Bis(2picolyl)ureas in Alcohol Solvents

3. CLEAVAGE OF ACTIVATED C−N SINGLE BONDS 3.1. Quaternary Ammonium Salts

Many works on cleavage of “unreactive” C−N bonds have been summarized above. In fact, study of the “activated” C−N bond has been conducted for many years. A quaternary ammonium salt is one of the most common N-containing substrates in organic synthesis.247−249 In 1998, Wenkert et al. reported the first Ni-catalyzed Kumada-Corriu cross-coupling of aryltrimethylammonium iodides 347 with aryl and alkyl Grignard reagents.250 The feasibility of the C−N bond cleavage via oxidative addition of a Ni(0) species into a C−N bond of aryltrimethylammonium salts was demonstrated in this pioneering work.250,251 Then Reeves et al. reported the room temperature Pd-catalyzed cross-coupling of aryltrimethylammonium triflates 348 with aryl Grignard reagents yielding biaryls.252 Later, Wang et al. reported Fe-catalyzed crosscoupling of aryltrimethylammonium triflates 348 with alkyl Grignard reagents at room temperature (Scheme 98).253 A wide range of functionalities are tolerated in these processes. These transformations share a common mechanism which is similar to that of the Kumada−Corriu cross-coupling reaction.

245

(Scheme 96). A broad range of benzonitriles could be readily prepared by this method. The urea serves as the nitrogen Scheme 96. Cu-Catalyzed Synthesis of Benzonitriles from Phenylacetic Acids

source of the CN group in 341. However, the mechanism for C−N bond cleavage in this reaction remains unclear. 2.10. Thiocarbamates

Huang et al. reported a Pd-catalyzed intramolecular C−H bond sulfuration reaction of aryl thiocarbamates 342, which provides a facile approach to multisubstituted benz[d][1,3]oxathiol-2ones 343 (Scheme 97).246 An aryl C−H bond and an amide C−N bond were both activated in this oxidative process. The kinetic isotope effect showed the C−H bond cleavage is the rate-determining step (kH/kD = 2.7) for the Pd-mediated cycle. However, the C−N bond cleavage was suggested to be the rate-

Scheme 98. Cross-Coupling Reaction of Quaternary Ammonium Salts and Grignard Reagents

Scheme 97. Pd-Catalyzed Synthesis of Benz[d][1,3]oxathiol2-ones from Thiocarbamates

AE


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As presented in Scheme 98,253 a catalytically active [Fe(MgX)2] species is formed via reduction of Fe(acac)3 using a Grignard reagent. The reaction of this reactive species with 348 affords ArFe(OTf)(MgX)2 and NMe3. By elimination of MgX(OTf), ArFe(MgX) is generated. Then another molecule of the Grignard reagent reacts with ArFe(MgX) to give ArFe(R)(MgX)2, which undergoes a reductive elimination to yield the final product. Analogously, aryltrimethylammonium salts could be applied to Suzuki cross-coupling,254 Negishi cross-coupling,255,256 and Buchwald−Hartwig amination257 (Scheme 99). Various diaryls

Scheme 101. Pd-Catalyzed Carbonylation of Quaternary Ammonium Halides

Scheme 99. Suzuki Cross-Coupling, Negishi CrossCoupling, and Buchwald−Hartwig Amination Involving Quaternary Ammonium Salts as Electrophilic Partners

which is formed from quaternary ammonium halides in the presence of the Pd catalyst, leading to the formation of intermediate 352. Coordination of CO to 352 affords 353. Then a migratory insertion of CO gives 354, which generates MeCOI and regenerates Pd(0) via a reductive elimination. The MeCOI would react with a tertiary amine to give the desired tertiary amide. The C−N bond cleavage in the above quaternary ammonium salts proceeds via oxidative addition of the metal catalysts to the C−N bonds. However, the C−N bond can also be cleaved by elimination of ammonium salts. Li et al. described a C−H activation of phenacylammonium salts 355 and 357 (Scheme 102).261 The ammonium group was employed as a directing group in this transformation. A wide range of benzocyclopentanones 356 and ortho-olefinated acetophenones 358 with various substituents could be prepared efficiently. It should also be mentioned that the desired products could be prepared in a one-pot fashion from α-bromoacetophenones and trimethylamine under the optimal conditions. DFT and experimental studies on the mechanism of the coupling of phenacylammonium salts with diazo esters were presented. Intermediate 359 is generated from phenacylammonium salt 355 and a Rh salt via C−H bond activation. The coordination of a diazo ester to 359 gives 360, which eliminates N2 and undergoes an intramolecular insertion of the Rh−Ar bond into a carbene species to afford 361. Then the intermediate 362 would be produced by elimination of HEt3NBr in the presence of HOAc. Further migratory insertion of the Rh−C bond into the carbenoid forms intermediate 363, which would be transformed to 356 and regenerate the Rh catalyst with the aid of HOAc.

and tertiary amines could be readily prepared by these crosscoupling reactions via aryl C−C bond or C−N formation along with the cleavage of the C−N bond in arylammonium salts 347 and 348, respectively. Particularly, Watson et al. developed a Ni-catalyzed Suzuki cross-coupling of benzylic ammonium salts 349 and boronic acid to provide diarylmethanes 350 and diarylethanes 351 (Scheme 100).258 It is noted that chiral diarylethanes could be Scheme 100. Ni-Catalyzed Suzuki Coupling Reaction of Benzylic Ammonium Salts with Boronic Acids

3.2. Diazonium Salts

Diazonium salts are important building blocks and intermediates in organic synthesis.262,263 The general reactivity of diazonium aromatic cations 364 with transition metals is presented in Scheme 103. The low stability of arene cations 365, which are generated by elimination of N2 from 364, makes diazonium salts reactive in various reactions. Previous works on diazonium salts and diazo compounds as substrates in Pdcatalyzed cross-coupling reactions have been summarized in other reviews.61−64 Only a recent work in this area will be discussed. Very recently, Toste et al. reported an enantioselective 1,1arylborylation of alkenes (Scheme 104).264 The Pd-catalyzed three-component coupling of α-olefins, aryldiazonium salts, and bis(pinacolato)diboron provides the direct preparation of chiral

efficiently generated with high enantioselectivity via the Nicatalyzed Suzuki coupling reaction. In this process, an oxidative addition of the Ni catalyst to the C−N bond cleaves the Csp3− N bond of benzylic ammonium salts. The quaternary ammonium halides could be applied to the catalytic carbonylation for the synthesis of tertiary amides in the presence of Pd catalysts and CO (Scheme 101).259,260 The catalytic cycle starts with an oxidative addition of Pd(0) to MeI, AF


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Scheme 102. C−H Activation and C−N Bond Cleavage of Phenacylammonium Salts

Scheme 104. Preparation of Chiral Benzylic Boronates from Terminal Alkenes

reductive elimination gives the chiral benzylic boronates and regenerates the Pd(0) catalyst. 3.3. Triazoles

Recently, triazoles have emerged as convenient precursors of diazo species to generate the related metal azavinyl carbenes. An equilibrium between N-sulfonyltriazoles with their diazoimine tautomers makes them ideal reactants with transition metals to give highly reactive metal azavinyl carbenes (Scheme 105).265,266 Since Gevorgyan et al. reported the insertion of the

Scheme 103. General Reactivity of Diazonium Aromatic Cations with Transition Metals

Scheme 105. Triazoles as Metal Carbene Precursors

rhodium azavinyl carbene into the Si−H bond of triethylsilane (Scheme 106),267 many synthetic methods constructing new Scheme 106. Rhodium Azavinyl Carbene Insertion into a Si−H Bond

benzylic boronic esters 366 via cooperative chiral anion phase transfer and transition-metal catalysis. The enantioselectivity is determined by the chiral phosphorus ligand. As mentioned above, the diazonium salt would first be transformed to intermediate 367 via elimination of N2 and oxidative addition. A migratory insertion of alkene yields chiral Pd complex 368, which then generates 369 via β-H elimination and reinsertion. Transmetalation between 369 and B2(pin)2 followed by a AG


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C−C, C−N, and C−O bonds from triazoles have been developed (Scheme 107).265 The metal azavinyl carbenes could

Scheme 108. Rh-Catalyzed Regiospecific Ring Expansion/ Carbonylation of Aziridines

Scheme 107. Reactions of Metal Azavinyl Carbenes

Scheme 109. Pd-Catalyzed Ring-Opening of Aziridines

react with unsaturated compounds to synthesize various heterocycles via cycloaddition.268−283 Alternatively, this type of metallocarbene readily undergoes 1,1-insertion reaction with the C−H bond and 1,3-insertion reaction with the O−H or N− H bond to form a series of N-sulfonylimines and Nsulfonylamines.267,284−288 Besides, the intramolecular 1,2migration is observed in these metallocarbenes derived from alkyl-, cycloalkyl-, and alkanol-substituted sulfonyltriazoles. This 1,2-migration leads to the formation of the ring expansion/ rearrangement products.289−291

374 or azametallacyclobutane 375. Then β-H elimination of these intermediates produces intermediate 376, which undergoes reductive elimination to afford an N-tosylenamine.299 Isomerization of the N-tosylenamine forms 373. Trost et al. applied the ring-opening of vinylaziridines to the derivatization of pyrroles and indoles (Scheme 110).300 The pyrrole and indole derivatives 377 could be prepared in good yields with high regio-, chemo-, and enantioselectivity. The C− N bond in the aziridine is cleaved via oxidative addition of a Pd species to the C−N bond, generating a π-allyl−Pd cation

3.4. Aziridines

Ring expansion of aziridines provides direct access to a broad range of useful products, including lactams, lactones, thiolactones, etc., which are not readily accessible by traditional methods. Since other reviews have summarized this field,65,66 only selected former works and recent developments will be introduced here. Alper et al. have presented various Rh-catalyzed regiospecific ring expansion/carbonylation reactions of aziridines to afford βlactams since the 1980s (Scheme 108).292,293 The reactive Rh species 370 is formed via oxidative addition of the Rh center to the C−N bond. A subsequent intramolecular insertion of CO into the Rh−C bond gives intermediate 371. 372, which is generated from 371 in the presence of CO, reacts with the aziridine to produce the β-lactam and regenerate reactive species 370.294,295 Wolfe et al. described the Pd-catalyzed ring-opening of aziridines (Scheme 109).296,297 Various N-tosylketimines 373 could be synthesized by this mild method. Functionalities such as ketones, esters, and acetals are well tolerated. In this transformation, the Pd center inserts into the less hindered C− N bond, and thus leads to its cleavage. A proposed mechanism was described.298 The oxidative addition of aziridine to Pd(0) species in an SN2 manner gives either zwitterion intermediate

Scheme 110. Derivatization of Pyrroles and Indoles Involving Ring-Opening of Vinylaziridines

AH


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Pd(PPh3)4 (Scheme 112).304,305 In the catalytic cycle, the reactive Pd species 384 is generated from Pd(PPh3)4 in the

species. Therefore, the azaheterocycle serves as a nucleophile in this transformation. Doyle et al. developed several Ni-catalyzed cross-coupling reactions of aziridines with organozinc reagents (Scheme 111).301−303 The employment of an inexpensive and air-stable

Scheme 112. Synthesis of Bicyclic β-Lactams via Ring Expansion/Carbonylation of 2H-Azirines

Scheme 111. Ni-Catalyzed Negishi Cross-Coupling Reactions of Aziridines

presence of CO. 384 then promotes a C−N bond cleavage of the 2H-azirine via oxidative addition to yield π-allyl intermediate 385, which reacts with another molecule of the 2H-azirine to give intermediate 386. An intramolecular cyclization gives the bicyclic complex 387, followed by an insertion of Pd into C−N bond to generate intermediate 388. Subsequently, a ligand migration affords intermediate 389. Finally, the reductive elimination forms β-lactams and regenerates 384. A lot of studies on 2H-azirines have been reported in recent years. Novikov et al. presented several Rh- or Cu-catalyzed ringopening processes of 2H-azirines affording heterocyclic products (390 and 391) (Scheme 113).306,307 In the Cucatalyzed cycle, the coordination of the 2H-azirine to a Cu salt produces intermediate 392, which then produces vinyl nitrene intermediate 393. 393 is trapped by a diazo compound, giving intermediate 394. The following ring closure forms 395. 395 attacks 393 to give 391. Park et al. developed a rhodium carbenoid-mediated ringopening of 2H-azirines to construct substituted pyridines 396 (Scheme 114).308 A variety of 2H-azirines with both electronrich and electron-deficient substituents could react smoothly with a series of diazo compounds to give the corresponding pyridines 396. The experimental results indicate a 6π electrocyclization of 3-azatriene 398, which is formed by ringopening of 2H-azirines in the rhodium ylide 397, is involved in the formation of 396. Ohe et al. reported a Rh-catalyzed reaction of 2H-azirines with carbonyl enynes for the synthesis of furyl derivatives 399 (Scheme 115).309 Since the insertion of the Rh center into the 2H-azirine has been reported, Ohe et al. suggested that the addition of furylcarbene−Rh(II) complexes to 2H-azirines and

Ni salt and ligand/additive made these reactions convenient and mild approaches for the synthesis of amine derivatives 378−381. These reactions share a similar mechanism. The intermediate 382 would be generated from the aziridine and Ni catalyst via either an SET oxidative addition pathway or an SN2type oxidative addition pathway, followed by a Negishi-type pathway to give the corresponding product. 3.5. 2H-Azirines

2H-Azirines are important building blocks for the synthesis of heterocyclic compounds by cleavage of one of the C−N bonds. Generally, nucleophilic reagents attack the CN bond, giving a five-membered-ring product; the dihalocarbene- or rhodium carbenoid-mediated ring-opening process occurred exclusively on the C−N bond. Since recent advances in 2H-azirine chemistry, including synthesis and reactivity, have been summarized in other reviews,66,67 only selected previous examples and recent works will be introduced here. Similar to aziridines, 2H-azirines could undergo a ring expansion to afford various useful products. As reported by Alper et al., bicyclic β-lactams 383 could be generated from 2Hazirines and CO in the presence of a catalytic amount of AI


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Scheme 113. Rh- or Cu-Catalyzed Ring-Opening of 2HAzirines

Scheme 115. Synthesis of Furyl Derivatives Using a 2HAzirine as the Nucleophilic Reagent

Scheme 116. Gold-Catalyzed Synthesis of Functionalized Pyridines from 2-Propargyl-2H-azirines

Scheme 114. Synthesis of Substituted Pyridines via RingOpening of 2H-Azirines

gives charge-delocalized intermediate 404, which then forms pyridine 401 and regenerates the Au catalyst. Alternatively, intermediate 404 could be generated in a concerted manner via transition state 405.

ring-opening of 2H-azirines are the key steps in this transformation. In addition, 2H-azirines could serve as the synthetic equivalent of alkenyl nitrenes. For example, Gagoosz et al. reported a Au-catalyzed synthesis of functionalized pyridines 401 from readily accessible 2-propargyl-2H-azirine 400 (Scheme 116).310 This reaction provided an efficient, lowcatalyst-loading approach for the preparation of functionalized pyridines with high functional group tolerance. The initial coordination of the alkyne 400 to the Au catalyst promotes the 5-endo nucleophilic addition of the azirine fragment and generates aziridinium species 402. 402 is then transformed into α-imino−Au−carbene intermediate 403 via a Au-assisted ring fragmentation process (pathway A). A 1,2-H shift of 403

4. SUMMARY AND OUTLOOK Recently, transition-metal-catalyzed cleavage of C−N single bonds has become a hot area, because it provides either an excellent nitrogen source or an excellent carbon source from readily available and simple N-containing compounds to construct useful molecules. Few works in this area had been reported before 2010. However, in the past 5 years, more than 140 papers on transition-metal-catalyzed cleavage of the C−N single bonds have been published. We have reviewed the cleavage of C−N single bonds in 15 types of N-containing AJ


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Biographies

compounds catalyzed by various transition metals. Different strategies have been developed for this transformation. With detailed mechanistic studies on the cleavage of various C−N bonds, scientists have gained some insight into the nature of this process and developed many important concepts in the field of inert chemical bond activation. Generally, one molecule of a N-containing compound acts as either a carbon source or a nitrogen source in one reaction via C−N bond cleavage. The whole atom economy is low. Therefore, improvement of the atom economy of the C−N bond cleavage process will become a promising area. If only the C-containing fragment as the carbon source is incorporated into the target molecules, the C−N bond cleavage in primary amines is more atom-economical than that in other amines because only a mass of 17 amu in primary amines will be missing. Compared with secondary or tertiary amines, the C−N bond cleavage in primary amines is less explored at present, but will receive much attention in the future. If only the Ncontaining fragment as the nitrogen source is incorporated into the target molecules, the selective C(Me)−N bond cleavage in Me-substituted amines is atom-economical because only a mass of 15 amu will be missing. From the atom-economic view, the best option is to incorporate the cleaved N- and C-containing fragments into the target molecules. Only several good examples have been reported and are reviewed here. However, the atom-economical incorporation of the cleaved N- and Ccontaining fragments into the target molecules remains a great challenge. In the case of transition-metal catalysts, most of these studies on C−N single bond cleavage focus on late transition metals. Developing new catalytic systems, especially for early transition metals, to explore selective C−N bond cleavage and the atom-economical incorporation of the cleaved N- and Ccontaining fragments will be of importance. Meanwhile, studies on the transition-metal-catalyzed cleavage of CN double bonds and CN triple bonds are limited. Most of these works on the cleavage of CN double bonds focused on the oxidation reaction311,312 or the metathesis process.313−318 Few works on the transition-metal-catalyzed cleavage of the CN triple bond have been presented.319 Considering the high efficiency of new C−C or C−N bond formation via C−N bond cleavage and readily accessible Ncontaining molecules, the development of the transition-metalcatalyzed cleavage of carbon−nitrogen bonds, especially for unsaturated carbon−nitrogen bonds, remains a promising field in the future.

Kunbing Ouyang was born in 1989 in Hunan, China. She received her B.S. degree from Xiangtan University in 2010 and her Ph.D. degree from the Institute of Chemistry, Chinese Academy of Sciences, in 2015 under the direction of Professor Z. Xi and Professor W.-X. Zhang. She is currently working as a lecturer at Xiangtan University. Her current research interests focus on transition-metal-catalyzed cleavages of the Csp3−Si bond and the silyl Csp3−H bond.

Wei Hao was born in 1987 in Jiangsu Province. He received his B.S. degree from Jiangsu University in 2010. Then he joined the College of Chemistry at Peking University as a Ph.D. candidate in 2011 under the direction of Professor Z. Xi and Professor W.-X. Zhang. His research interests include the design, synthesis, and application of cyclopentadiene−phosphine ligands, and the study of transition-metalcatalyzed C−N bond activation.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

Wen-Xiong Zhang received his B.Sc. from Hunan Normal University in 1996, his M.Sc. from Guangxi Normal University in 1999, and his Ph.D. from Nankai University with Professor Li-Cheng Song in 2003.

Notes

The authors declare no competing financial interest. AK


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Dipp DMAc DME DMF DMSO DPPB DPPF DPPP DPPPen equiv glyme Het IMes IPr MTBE NMP Nu OAc OPiv OTf SET TEMPO TFA TMEDA TMS

He carried out postdoctoral research at Peking University with Prof. Zhenfeng Xi and at Riken in Japan with Prof. Zhaomin Hou. In 2007, he joined the College of Chemistry at Peking University, where he is now an Associate Professor. His research interests include metalcatalyzed C−N bond activation, rare-earth-metal-catalyzed smallmolecule activation, and carbodiimide-based organic synthesis to construct N-containing heterocycles.

Zhenfeng Xi received his B.S. degree from Xiamen University in 1983, M.S. degree from Nanjing University, Zhengzhou University, and the Henan Institute of Chemistry in 1989, and Ph.D. degree from the Institute for Molecular Sciences (IMS), Japan, in 1996 with Prof. Tamotsu Takahashi. He took an Assistant Professor position at Hokkaido University in 1997. In 1998, he joined the College of Chemistry at Peking University, where he is now a Professor. His research interests include development of organometallic reagents, study of the mechanisms of reactions involving reactive organometallic intermediates, and synthesis of functional structures.

2,6-diisopropylphenyl dimethylacetamide 1,2-dimethoxyethane dimethylformamide dimethyl sulfoxide 1,4-bis(diphenylphosphino)butane 1,1′-bis(diphenylphosphino)ferrocene 1,3-bis(diphenylphosphino)propane 1,5-bis(diphenylphosphanyl)pentane equivalent dimethoxyethane heterocycle 1,3-bis(2,4,6-trimethylphenyl)imidazolium 1,3-bis(2,6-diisopropylphenyl)imidazolium methyl tert-butyl ether N-methylpyrrolidine nucleophile acetate pivalate triflate single-electron transfer (2,2,6,6-tetramethylpiperidin-1-yl)oxyl trifluoroacetic acid tetramethylethylenediamine trimethylsilyl

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Grants 21172007 and 21372014) and the 973 Program from the National Basic Research Program of China (Grant 2012CB821600). We also thank Mr. Yue Chi, Mr. Liang Liu, Dr. Junnian Wei, and Dr. Ling Xu for useful discussions and comments on the manuscript. NOTATIONS AND ABBREVIATIONS 1,10-phen 1,10-phenanthroline acac acetylacetonate Ac2O acetic anhydride HOAc acetic acid Ad adamantyl BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl BINOL 1,1′-bi-2-naphthol Bn benzyl BQ benzoquinone Bu butyl COD cyclooctadiene Cp cyclopentadienyl Cp* η5-pentamethylcyclopentadienyl Cy cyclohexyl dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DDQ dichlorodicyanoquinone decalin decahydronaphthalene DFT density functional theory AL


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