Nonprecious Metals Catalyzing Hydroamination and CâN Coupling

Review pubs.acs.org/OPRD

Nonprecious Metals Catalyzing Hydroamination and C−N Coupling Reactions Simona M. Coman and Vasile I. Parvulescu* Department of Organic Chemistry, Biochemistry and Catalysis, Faculty of Chemistry, University of Bucharest, Bdul Regina Elisabeta 4-12, Bucharest 030016, Romania ABSTRACT: This review highlights the recent achievements in replacing precious-metal-based catalysts with nonpreciousmetal-based catalysts in two important syntheses: hydroamination and C−N coupling reactions. The reported improvements are discussed in direct relation to the nature of the ligands, catalyst preparation methods, and the selection of other additives. Syntheses using ligand-free catalysts are also analyzed.

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INTRODUCTION The catalytic formation of carbon−nitrogen bonds has been the subject of intense research in recent years because of its multiple applications. In particular, the identification of efficient chemical synthesis protocols was suggested as a strategy to bypass biosynthetic pathways in the production of substitutes for natural products and related structures.1 Most of the protocols dealing with such syntheses are carried out in the presence of expensive noble metals. However, the replacement of these catalysts with nonprecious metals is highly demanded. The price of the noble metals is almost 1000 times higher than that of the nonprecious metals, which has a direct effect on the price of the products synthesized with these catalysts (Figure 1).2 Therefore, improvements in the field can be obtained by correct identification of the metal and in direct relation to the ligands, catalyst preparation methods, and selection of other additives. The aim of this review is to highlight achievements reported to date in the replacement of precious-metal catalysts with nonprecious-metal catalysts in two important reactions providing C−N bonds, namely, hydroamination and direct C−N coupling.

the olefin/alkyne with the metal center will reduce the electron density in the π system, thus allowing the nucleophilic attack of the amine nitrogen atom. In this way, the formation of moreelectrophilic complexes or charged intermediates may allow the hydroamination of alkenes, alkynes, dienes, and allenes even under metal-free catalytic conditions, albeit in the presence of an acid with a certain strength.16 In addition, the coexistence of a strong Brønsted acid function has the role of accelerating the rate-determining step in this reaction. The role of the acidic promoter was explained through the protonolysis of the precatalyst to yield cationic complexes, which may act as the active catalysts involved in the mechanism. On this basis, bifunctional catalysts combining a soft Lewis acidic function to activate the alkene with a strong Brønsted acid function were reported to provide high catalytic activities, especially for electron-rich anilines, which react more readily under these conditions.17 The literature mentions several catalytic routes for hydroamination reactions, including both homogeneous and heterogeneous catalysis.18,19 Particularly, under homogeneous catalysis these reaction may occur via (i) hydroamination of olefins through oxidative addition of an amine to a late transition metal (Pd, Ru, Rh, Ir) complexed by a phosphine ligand or to different complexes of early transition metals, including rare-earth elements;20,21 (ii) amination of olefins via an alkaline-metal or lanthanide compound (Li, Na, Ln);22,23 (iii) a radical mechanism for the alkaline-metal-catalyzed hydroamination of α-methylstyrene with aziridine;18 (iv) hydroamination of alkynes via metal (U, Zr, Ti) imide species; and (v) Lewis acid-catalyzed hydroamination of olefins and alkynes using metal salts or cationic metal complex catalysts.24,25 In particular, the use of transition metals for such a purpose requires a capacity to coordinate olefins. This allows activation of the olefin towards attack by nucleophiles, such as amines, to generate σ-alkyl complexes.26 However, the process is limited by the ability of the metal to coordinate the olefin.

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HYDROAMINATION General Considerations. Hydroamination represents the direct addition of amines to C−C multiple bonds, leading to amines, imines, and enamines (Schemes 1 and 2).3−5 It has become a very useful synthetic route for the production of pharmaceuticals, various bulk and fine chemicals, and a consistent number of intermediates.6 This is largely due to the fact that hydroamination is 100% atom-economical and inexpensive and uses readily available materials. As a result, this has led to an extensive number of publications reporting on hydroamination.7−13 However, hydroamination requires the presence of a catalyst because both the amine component and the alkene/alkyne component are considered to be electron-rich. As a result, the direct coupling is kinetically unfavorable.9,13In addition, the intermolecular process requires activated alkenes such as vinyl arenes or acrylic acid derivatives14,15 The presence of a Lewis acid center may facilitate this reaction, since the interaction of © 2015 American Chemical Society

Special Issue: Non-precious Metal Catalysis Received: January 7, 2015 Published: April 16, 2015 1327

DOI: 10.1021/acs.oprd.5b00010 Org. Process Res. Dev. 2015, 19, 1327−1355

Organic Process Research & Development

Review

Figure 1. Price evolution of (a) noble and (b) non-noble metals.

Scheme 1. Hydroamination of alkenes and alkynes

observations based on a kinetic analysis of intramolecular alkene hydroamination,27 the activation barriers for alkene insertion are 16.7 kcal mol−1 for Ca and 21.0 kcal mol−1 for Mg, while those for protonolysis of the aminoalkane are 8.6 kcal mol−1 for Ca and 19.8 kcal mol−1 for Mg. Additional gas-phase computational studies of this system taking into consideration the characteristics the group IIA elements confirmed their specificity in this reaction and suggested a different behavior than a simply “lanthanide mimetic”.27 A very similar behavior in the alkaline-earth metal series was reported for iminoanilide [{N^N}M(X)(THF)n] alkyl (X = CH(SiMe3)2) and amide (X = N(SiMe3)2) complexes of Ca, Sr, and Ba.29 Cyclohydroamination of 1-amino-2,2-dimethyl-4pentene occurred with rates that paralleled the change in the metal size (Ca > Sr > Ba), and the intermolecular hydroamination of styrene exhibited anti-Markovnikov regiospecificity. Main-Group-Metal Catalysts (Groups IIIA−VA). The recent interest in the area of frustrated Lewis pairs has attracted hydroamination reactions as well. Frustrated Lewis pairs correspond to compounds or mixtures containing a Lewis acid and a Lewis base that, because of steric hindrance, cannot combine to form an adduct. They may involve metal complexes such as Al(C6F5)3·(PhMe)30 or can be metal-free like B(C6F5)3· (PhMe). For the case of hydroamination, the Lewis base is directly replaced by the amine, as was demonstrated in a recent study involving arylamines and alkynes. The reaction can proceed stoichiometrically (Scheme 4) or catalytically.31 This hydroamination strategy also proved to be effective for substituted diphenylamines, where the yields of the desired product exceeded 70%. In all cases the regioselectivity was in favor of the Markovnikov isomers. Common Lewis acid catalysts such as AlCl3, GaCl3, and InBr3 were reported to catalyze the hydroaminations of alkenes

Scheme 2. Synthesis of enamines from hydroamination of alkynes

The aim of this subchapter is to offer a critical analysis of hydroamination reactions using non-noble-metal-based homogeneous/heterogeneous Lewis/Brønsted catalysts. On the basis of this analysis, the chapter will provide a short overview of the synthesis of amines, imines, and enamines from unsaturated substrates. Homogeneous Catalytic Hydroamination. Lewis Acid Catalysts. s-Block Elements. From the main-group metals of group IIA, homoleptic [M{N(SiMe3)2}2]2 amides and [M{CH(SiMe3)2}2]2 alkyls (M = Ca, Sr) were reported to catalyze the anti-Markovnikov addition of amines to vinyl arenes, whereas related magnesium and barium analogues proved ineffective for the same reactions (Scheme 3).23,27 The trend in reactivity has been rationalized as a consequence of a rather delicate balance between the polarity of the M−N/M−C bond and the polarizability of the alkaline-earth metal in the highly polarized transition-state structure for olefin insertion into the M−N/M−C bond.28 This is also associated with a greater degree of coordinative saturation at the electrophilic metal center and determines an increase in the energy of the transition state of the rate-determining alkene insertion step. As a direct consequence, the decrease in the metal ionic radius leads to lower reaction rates. The order for the intermolecular hydroamination of vinyl arenes, dienes, and alkynes is Ca > Sr > Ba > Mg. Thus, large variations in cation size and resultant charge density produce dramatic effects on the reactivity across the series of M 2+ cations. According to experimental 1328



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Scheme 3. Anti-Markovnikov addition of amines to vinyl arenes on homoleptic [M{N(SiMe3)2}2]2 amide and [M{CH(SiMe3)2}2]2 alkyl precatalysts:27 (A) catalysts; (B) [M{N(SiMe3)2}2]2-mediated hydroamination of vinyl arenes with benzylamine and piperidine; (C) alkaline-earth-mediated addition of piperidine to vinyl arenes

Scheme 4. Stoichiometric hydroaminations in the presence of B(C6F5)331

with sulfonamides or aromatic amines.32−34 Besides hydroamination, as a result of the strong acidity of these Lewis acids, side reactions such as alkylation may occur, affecting the selectivity (Scheme 5). This behavior was confirmed even by reactions with weaker Lewis acids such as FeCl3. It is noteworthy that for a large family of aniline derivatives (except aniline itself), FeCl3 led to superior selectivities and yields of the hydroaminated products compared with the case with AlCl3 as the catalyst.35 AlCl3 is a stronger Lewis acid than the halides of the next group IIIA elements (GaCl3 and InCl3).36 Very interestingly, in spite of the differences in acidity, there are reports indicating much superior activity of GaCl3 and InCl3 compared with AlCl3 in hydroamination of phenylacetylene with 2,4-dichloroaniline

(Scheme 6).36 While AlCl3 afforded only traces of the product, GaCl3 and InCl3 formed the product in high yields, giving the Markovnikov hydroamination product (Scheme 6a). As shown in Scheme 6a, the activity of these halides correlates very well with the quadrupolar coupling constant of 35Cl. Additional arguments were provided by density functional theory (DFT) studies, which explained this mechanism by coordination of the alkyne to GaCl3, subsequent nucleophilic attack of the amine at the coordination π complex to generate a zwitterionic intermediate, and the final aniline-assisted proton transfer process to produce the Markovnikov product.36 The role of LiAlH4 in the second step was to reduce the imine produced by the hydroamination to the corresponding amine. 1329



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Scheme 5. Hydroamination of alkenes with aromatic amines35

Scheme 6. (A) Hydroamination of phenylacetylene with 2,4-dichloroaniline and subsequent reduction of the imine to the amine;36 (B) Variation of the conversion as a function of the quadrupolar coupling constant

between GaCl3/InCl3 and AlCl3, the most active catalysts were InBr3 and InI3, whereas InCl3 exhibited only poor activity.41 BiCl3 was also investigated in hydroamination reactions, and its catalytic performance was close to those of the Lewis acids FeCl3 and AlCl3.35 Early- and Middle-Transition-Metal Catalysts (Groups IIIB−VIIB). Group IIIB Transition-Metal Catalysts. Although it is often associated with the f-block elements because of its +III oxidation state, yttrium is differentiated by its ionic radius. Therefore, the design of reported yttrium complex catalysts considered this specific particularity, and neutral Y(III) dialkyl complexes bounded by tridentate N−,N,N monoanionic methylthiazole− or benzothiazole−amidopyridinate ligands are typical examples. These yttrium complexes, and especially their cationic forms obtained by activation with the Lewis acid Ph3C+[B(C6F5)4]−, were found to be good candidate catalysts for intramolecular hydroamination/cyclization reactions (Scheme 8).42 Complexes of yttrium with a chiral siliconlinked tridentate amidoindenyl ligand were synthesized as well. These are able to catalyze the intramolecular hydroamination of unactivated olefins with very high ee’s (Scheme 9).43 Group IVB Transition-Metal Catalysts (Ti, Zr, Hf). The Lewis acid TiCl4 catalyzes the intermolecular hydroamination of vinyl arenes with a high tolerance to a range of functional groups (Scheme 10) and allows the synthesis of a tetrahydroisoquinoline derivative.44 Like for AlCl3, working with TiCl4 is not always very simple and imposes many precautions. The stabilization of isolated titanium ions with the preservation of the catalytic activity requires specific ligands. Although from the same IVB group, zirconium and hafnium exhibit higher stabilities in different media. However, metal

This behavior suggested that organogallium complexes may indeed act as efficient Lewis acids for molecular catalysis of hydroamination.37 Indeed, the complex of gallium(III) with the ligand 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene (Ga1, Scheme 7) undergoes reversible addition of alkynes.38 Scheme 7. Complex of gallium(III) with the ligand 1,2bis[(2,6-diisopropylphenyl)imino]acenaphthene (Ga1)39

It was also demonstrated that the same complex serves well as a Markovnikov-selective catalyst for the hydroamination of alkynes with various anilines.39 The investigation of these complexes also confirmed the differences observed in hydroaminations using gallium and aluminum chlorides. The digallium compound Ga1, in contrast to the corresponding Al complex, can add less-activated alkynes, including HCCH and HCCPh, while aluminum generates stronger Al−C bonds during the addition process.40 The effect of the halide anion was checked for a series of indium compounds in the hydroamination of phenylacetylene with p-toluidine. In close relation to differences observed 1330



Review

Scheme 8. (A) Metal-to-ligand hydride migration; (B) Intramolecular hydroamination of primary and secondary amino alkenes over Y(III)−tridentate N−,N,N monoanionic methylthiazole− or benzothiazole−amidopyridinate complexes42

Scheme 9. Asymmetric intramolecular hydroamination of unactivated olefins with silicon-linked tridentate amidoindenyl Y(III) complexes43

solve this problem, dimethyltitanocene, [Cp2TiMe2], was proposed as catalyst precursor. In the presence of an arbitrary amine, it loses methane to form the catalytically active titanium−bisamide or titanium−imido complex. Indeed, this system was reported to catalyze the hydroamination of diphenylacetylene to th e corresp on ding N-(1,2diphenylethylidene)aniline imine.49 Also, the increase in steric bulk around the cyclopentadienyl ligands allowed hydroamination with alkylamines that are not sterically bulky, but at the price of a decrease in regioselectivity.50 Electronically

complexes based on titanium, zirconium, or hafnium are often utilized for hydroamination of various substrates where the reaction occurs via an imido−metal intermediate, and the deactivation is caused by their polymerization.45 [CpTiCl3] was the first titanium complex reported to catalyze the intramolecular hydroamination of aminoalkynes,46−48 but intermolecular hydroaminations using this catalyst were not successful. Changing to bisamide complexes of titanium, such as [Cp2Ti(NHC6H5)2],49 led to good performances, but recovery of the catalyst was difficult. To 1331



Review

Scheme 10. Intermolecular hydroamination of vinyl arenes catalyzed by TiCl444

Scheme 11. Titanium-based systems with (A) N,N-chelating, (B) N,O-chelating, and (C) 2-pyridonato ligands58

protonation rates (Scheme 12).47 Unsymmetrical substituted alkynes preferentially gave the anti-Markovnikov products.

biased alkynes or bulky alkylamines resulted in the formation of the anti-Markovnikov isomers, whereas arylamines led to the Markovnikov isomers.51 N-heterocyclic carbenes (NHCs) have attracted much interest as ligands in many important catalytic reactions52 as a consequence of their very good σ-donor properties, chemical robustness, and ability to modulate either electronic or stereochemical properties.53 However, these characteristics are not always relevant for the NHC complexes of early transition metals, as is the case of group IVB elements. Titanium-based systems are more prevalent for the intermolecular hydroamination of alkynes with primary amines.5 More recently, N,N- and N,O-chelating ligands (Scheme 11A,B) have been used to prepare hydroamination catalysts for such reactions, where very high selectivities for the anti-Markovnikov isomers were reported.54−56 However, there are also many examples of using these catalysts for the intermolecular hydroamination of alkenes. (2Aminopyridinato)titanium complexes generated in situ from [Ti(NMe2)4] and 2-(methylamino)pyridine were indicated as efficient catalysts for the regioselective hydroaminoalkylation of styrenes.57 2-Pyridonatotitanium complexes (Scheme 11C)58 showed similar performances. In addition, these ligands can be associated with zirconium and hafnium as well. Hydroamination reactions catalyzed by zirconocene bisamides, Cp2Zr(NHR)2, were first applied in reactions with more reactive alkynes and allene, leading to enamines and imines.59 When Cp2Zr(NHR1)(R2) (R1 = 2-MeC6H4, 2,6-i-Pr2C6H3; R2 = CH2CH2CMe3) or Cp2ZrNAr (Ar = 2,6-dimethylphenyl) NHC complexes were used, the regioselectivity in the catalytic intermolecular hydroamination with primary amines was high for the reaction with both aryl- and alkylacetylenes. However, an erosion in the catalytic reaction was attributed to a complex interplay of metallacycle formation, retro-cycloaddition, and

Scheme 12. Catalytic hydroamination via imido−Zr intermediates47

The importance of the catalyst regeneration, as the critical step, was mentioned for [Zr{N,N-bis[(2,4-di-tert-butylphenoxy6-yl)methyl]imidazolium}(NMe2)(THF)Br] and [Zr(N,N-bis{[2,4-bis(2-phenylpropan-2-yl)phenoxy-6-yl]methyl}imidazolium)(NMe2)(THF)Br] complexes. They react with 2,2-diphenylpent-4-en-1-amine to perform internal hydroamination.53 Further achievements in designing zirconium NHC complexes allowed their use as catalysts for hydroamination of alkenes in intramolecular hydroamination. Thus, sterically crowded tris(amidate)mono(amido) complexes are among the amidates of the group IVB elements showing activity in such hydroaminations.60 Amidate ligands can adopt a variety of coordination modes when binding. They react with 2,2diphenylpent-4-en-1-amine to perform internal hydroamination,46 generating a four-membered metallacycle (Scheme 13). 1332



Review

Scheme 13. Cyclohydroamination in the presence of sterically crowded tris(amidate)mono(amido)zirconium complexes60

complexes, the rates for hydroamination/cyclization of unactivated aminoalkenes to yield pyrrolidines or piperidines (Scheme 14A,B) varied in the order I > Br > Cl, demonstrating that in this way the density of the electrons on the metal could be further controlled. The effect of the halogen in zirconium-based hydroamination catalysis is also evident from reports using very simple catalysts such as bis(cyclopentadienyl)zirconium chloride hydride (Schwartz reagent).62 This reacts with linear 1-alkenes to produce 1-alkylzirconocene chloride. However, for these catalysts the intermolecular N-methylamination requires a further activation of the amine that may be achieved in the presence of N-methylhydroxylamine-O-sulfonic acid, which is easily obtained from hydroxylamine-O-sulfonic acid and produces nitrogen electrophiles that lead to exclusive antiMarkovnikov selectivity. The reaction is fast, and its efficiency has been proved for a large number of substrates.62 In addition, amination of 9-O-benzylquinine- and D-mannose-derived substrates (Scheme 15A,B) demonstrated the utility of the method for the synthesis of complex molecules. Further modification of the electron density on the metal can be achieved by stabilization of neutral Zr(IV) and Hf(IV) dimethyl complexes by unsymmetrical dianionic {N,C,N′} pincer ligands (Scheme 16).63 Such a combination was reported to translate into systems having a better balance between stability and reactivity, as has been demonstrated for intramolecular hydroamination/cyclization of primary and secondary aminoalkenes at room temperature. f-Element Metal Catalysts. Organolanthanide complexes are known to be highly active hydrofunctionalization catalysts. They are also highly efficient hydroamination catalysts, where they can act either as metallocene (1−3) or non-metallocene (4 and 5) structures (Scheme 17).64 Among these, homoleptic [Ln{N(SiMe3)2}3] amido complexes 4 and 5 (Ln = lanthanide)

These complexes have a variety of steric and electronic properties in the distal backbone position (R1, Scheme 13) as well as on the nitrogen-bound aryl substituent (R2, Scheme 13), affording the cyclohydroamination of 2,2-diphenylpent-4-en-1amine in high yields.60 In addition to the structure of the ligand, the activity the NHC−group IVB metal complexes in hydroamination reactions is also influenced by the halogen, as was demonstrated for [Zr(1,3-bis(3′-butylimidazol-2′-ylidene)-2-phenylene)(dimethylamido)X2] (X = Cl, Br, I) and [Hf(1,3-bis(3′butylimidazol-2′-ylidene)-2-phenylene)(dimethylamido)X2] (X = Cl, Br, I) pincer complexes (Scheme 14C).61 With these Scheme 14. (A, B) Hydroamination/cyclization of unactivated aminoalkenes on Zr or Hf pincer complexes to yield (A) pyrrolidines or (B) piperidines;61 (C) Structure of the precatalysts (M = Zr, Hf)

Scheme 15. Amination of (A) 9-O-benzylquinine-derived and (B) D-mannose-derived substrates62

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Scheme 16. Intramolecular hydroamination of primary and secondary aminoalkenes catalyzed by Zr(IV) or Hf(IV) {N,C,N′} pincer complexes63

Scheme 17. Hydroamination catalysts as metallocene (structures 1−3) or non-metallocene (4 and 5) structures64

Scheme 18. Intramolecular hydroamination/cyclization of aminoalkenes leading to chiral heterocycles71

enabling the synthesis of chiral amines from simple, readily available prochiral substrates in a single step. Besides these advantages, organolanthanide-based catalysts are somewhat sensitive to oxygen and water. As for the transformations mediated by alkaline-earth metals, the effect of the ionic radius on the reaction kinetics of organolanthanide(III) hydroamination catalysis has been welldemonstrated, and the reaction tends to proceed at lower rates with decreasing metal ionic radius.27 Oxazolines represent another class of ligands associated with the application of f elements in Lewis acid catalysis. The most commonly used are the bis(oxazolinyl)methane and pyridinebis(oxazoline) ligands.70 However, a chiral bis(oxazolinylphenyl)amide (BOPA) ligand has been reported as well.71 With the amido precursors [Ln{N(SiMe3)2}3],72 it generates bis(amido) complexes [Ln(R-BOPA){N(SiMe3)2}2] (Scheme 18). All of these lanthanide complexes were active towards the intramolecular hydroamination/cyclization of aminoalkenes, leading to chiral heterocycles (Scheme 18).

are versatile agents for a variety of organic transformations, which can be either intermolecular or intramolecular in character.65−67 Intermolecular vinyl arene hydroamination proceeds on these catalysts in good isolated yields with excellent anti-Markovnikov regioselectivity that is attributed to the electrophilic lanthanide center.66 The stereoelectronic tunability of organolanthanide coordination spheres by variation of the metal ionic radius and ancillary ligands is often a key optimization variable in organolanthanide-catalyzed hydroamination. The high electrophilicity of these Lewis acid catalysts also allows facile olefin insertion that permeates hydroamination/cyclization reactions, where the rate increases with larger Ln3+ ionic radius (La > Sm > Lu).64 Another attractive reaction of these catalysts is the aminoallene cyclization leading to exclusive diastereoselectivity in the formation of trans-2,5-disubstituted pyrrolidines and cis-2,6disubstituted piperidines.68,69 Enantioselective hydroamination with moderate ee (over 40%) can also be achieved with chiral organolanthanide catalysts (structures 3 and 5; Scheme 17), 1334



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The incorporation of an additional donor between the oxazoline moieties afforded catalysts with much improved reactivity and selectivity. Spectroscopic investigations under both catalytic and pseudocatalytic conditions confirmed the ability of the complexes to invoke stereoselectivity.73 Ytterbium is the penultimate element in the lanthanide series, and it shows a relative stability of the +2 oxidation state due to this position. In contrast to many f elements, it may generate heteroleptic Yb(II)−amide species such as those supported by amidinate and 1,3,6,8-tetra-tert-butylcarbazol-9-yl ligands, [2-MeOC 6 H 4 NC(t-Bu)N(C 6 H 3 -i-Pr 2 -2,6)]Yb[N(SiMe3)2](THF) and [1,3,6,8-t-Bu4C12H4N]Yb[N(SiMe3)2](THF)n (n = 1, 2), respectively.74 They are efficient precatalysts for the intermolecular hydroamination of styrene with pyrrolidine to give exclusively the anti-Markovnikov monoaddition product (Scheme 19). Very similar behavior in the same reactions was reported for Yb(II) iminoanilide alkyl (X = CH(SiMe3)2) and amide (X = N(SiMe3)2) complexes of the form [{N^N}M(X)(THF)n].29

However, these Lewis acid catalysts are not active enough for primary aliphatic amines, which exhibit a greater binding affinity towards the metal center than electron-deficient amines. A solution for these substrates is the use of well-defined lowcoordinate iron(II) complexes.76 They showed activity in the cyclohydroamination of primary aliphatic alkenylamines as an effect of the predilection for electronegative ligands, and the stabilization of the low-coordinate iron(II) alkyl complexes by β-diketiminate ligands accounts for this. Depending on the reaction conditions (temperature, concentration, solvent, additives), the reaction may afford the hydroamination product, the oxidative amination product, or the reduced product (Scheme 21). Iron(II) complex catalysts were also reported in intermolecular formal hydroamination of unactivated alkenes using electrophilic O-benzoyl-N-hydroxylamines as the nitrogen source and cyclopentylmagnesium bromide as the reducing agent.77 The regioselectivity was total for the Markovnikov hydroamination product using iminopyridine bi- and tridentate ligands (Scheme 22). More elaborated catalysts such as Knolker’s iron complex expanded the scope of the reactions using iron(III) complexes to synthesis of more complex molecules.78 Although not really catalytic, ethynylcobalticenium may interact with amine-terminated dendrimers to produce transenamine dendrimers.79 From a practical point of view, this method allows the introduction of the cobalticenium group onto dendrimers and the synthesis of heterobimetallic dendrimers. In contrast to cobalt, pincer-type ligands were indicated to generate nickel complexes that can catalyze hydroamination of olefins. 80 Complexes of the type [(POCsp3OP)NiX] (Scheme 23) are stable for X = OSiMe3 and can follow the lanthanide chemistry in this reaction.80 Other ligands to synthesize nickel complexes for various hydroamination reactions have been investigated. The behavior of [(diphos)Ni](OTf)2 was investigated in the hydroamination of activated alkenes and alkynes, and [(dippe)NiCl2] was tested in the hydroamination of phenylacetylene with pyrrolidine, while [((PhO) 3 P) 2 Ni(COD) 2 ], [((PhO) 3 P) 2 NiCl 2 ], [((OEt)3P)2NiCl2], [(R3P)2Ni(COD)2], and [(R3P)2NiCl2] were studied in the hydroamination of alkynes.81 These studies gathered additional information on the role of the acidity in this reaction. Better yields were obtained with π-acidic phosphines, while the use of less acidic or even σ-donating ligands gave lower conversions and/or higher yields for the undesired hydrogenation byproducts.81 Accordingly, the best yields were achieved with the [((OEt)3P)2NiCl2] catalyst. Group IB and IIB Transition-Metal Catalysts. Cu(I) was largely investigated in C−N coupling reactions.82−87 Even in a very simple structure like CuBr or CuCl, it may catalyze alkyne hydroamination. More complicated reactions such as that of 2amino-N′-phenylbenzohydrazide with 3-phenylpropynal diethyl acetal to produce 1-arylpyrazolo[5,1-b]quinazolin-9(1H)-one derivatives are also possible (Scheme 24). However, this reaction additionally requires the presence of a mild base such as Cs2CO3, Na2CO3, NaHCO3, or Et3N.88 Asymmetric hydroamination is an even more challenging reaction. Most asymmetric hydroaminations are limited to the addition of arylamines to simple β-unsubstituted styrene derivatives.14,89,90 In the case of copper, the very high ee’s of the asymmetric reactions are associated with the participation of copper hydride (CuH) intermediates (Scheme 25B).91−96 BINAP, SEGPHOS, and DTBM-SEGPHOS ligands (Scheme

Scheme 19. Intermolecular hydroamination of styrene with pyrrolidine over heteroleptic Yb(II)−amide precatalysts74

Late-Transition-Metal Complexes (Groups VIIIB, IB, and IIB). Late-transition-metal complexes are much more easily handled and functional-group-tolerant than early-transitionmetal complexes. While catalysts based on early transition metals predominantly afford anti-Markovnikov products, intermolecular alkyne hydroaminationd catalyzed by late transition metals typically generate Markovnikov products. Group VIIIB Transition-Metal Catalysts. The intramolecular hydroamination of electron-deficient amines was found to occur in high yields on iron(III) chloride in the absence of any electron modifier.75 In the presence of either FeCl3 or FeCl3· 6H 2 O, but also of Cu(OTf) 2 , 2,2-dimethyl-1-(4toluenesulfonylamino)pent-4-ene underwent an intramolecular hydroamination to give 2,4,4-trimethyl-1-(4-toluenesulfonyl)pyrrolidine with an efficiency superior to that with any other conventional transition-metal catalyst (Scheme 20). The Scheme 20. Intramolecular hydroamination of 2,2-dimethyl1-(4-toluenesulfonylamino)pent-4-ene75

presence of water did not prevent the reaction. However, iron salts of other anions such as NO3 −, SO 4 2−, or acetylacetonate exhibited no activity in this reaction. The nature of the solvent is also very important. The reaction goes well in 1,2-dichloroethane and hexane but is blocked by coordinative solvents such as benzene, 1,4-dioxane, tetrahydrofuran, 2-propanol, dimethyl sulfoxide, and N,N-dimethylformamide.75 1335



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Scheme 21. Cyclohydroamination of 2,2-diphenylpent-4-en-1-amine catalyzed by a β-diketiminatoiron(II) alkyl complex76

Scheme 22. Markovnikov hydroamination of unactivated alkenes with electrophilic O-benzoyl-N-hydroxylamines:77 (A) ligands; (B) catalytic performances

Scheme 23. Complexes of the type [(POCsp3OP)NiX]80

oxa- and azabicyclic alkenes with PMHS and O-benzoylhydroxylamines in the presence of CuCl as the precatalyst, LiO-tBu as the base, and 1,2-bis[(2R,5R)-2,5-diphenylphospholano]ethane ((R,R)-Ph-BPE) as the ligand (Scheme 27B).97 The ability to establish control of both the regio- and enantioselectivity for the intermolecular additions of amines to alkenes with unactivated substrates is also very provocative. A recent report indicated that such a goal can be achieved with a Cu(OAc)2/CF3-1,2-bis(diphenylphosphino)benzene mixture in the presence of LiOtBu as the base and PMHS as the hydride source. An enantioselective alternative of this reaction was also reported using CuCl as the catalyst with either (S,S)-MeDuPhos (L1) or (R,R)-Ph-BPE (L2) as the ligand (Scheme 28).14,98 This enabled the hydroamination of a variety of α,βsubstituted styrenes with a range of N,N-dialkylhydroxylamines as the electrophilic amine sources.

25A) were used in conjunction with polymethylhydrosiloxane (PMHS) or diethoxymethylsilane hydride reagents. The insertion of an alkene into a chiral-ligand-bound LCuIH species (I) generates an alkylcopper complex (II) (Scheme 26). This step is followed by oxidative addition of an electrophilic amine source and subsequent reductive elimination with the enantioselective formation of the C−N bond. Other examples of asymmetric reactions involving CuH intermediates include the enantioselective hydroamination of

Scheme 24. Hydroamination of 3-phenylpropynal diethyl acetal with 2-amino-N′-phenylbenzohydrazide88

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Review

Scheme 25. Asymmetric intermolecular hydroamination of alkenes on copper catalysts96

complexes, the position of the distinctive electron is concerted with the coordination of the ligand. Therefore, the synthesis of such complexes requires a rational design. The reaction mechanism is also controlled by the properties of the complexes. For the alkaline-earth metals and f elements, where the ligands are merely connected via a M−N bond, the first step is insertion of the CC or CC bond into the M−N bond, which is followed by rapid protonolysis by the amine substrate. The hydroamination reaction catalyzed by early- andmiddle-transition-metal complexes takes place via an intermediate imido species that reacts in the next step with the CC or C C bond. In an opposite way, late-transition-metal catalysts first activate the CC or CC bond, leading to a complex that generates the C−N bond after the interaction with amine. Brønsted Acid Catalysts. Brønsted acid-catalyzed hydroaminations were quite recently reported.102 By the use of catalysts such as triflic acid, sulfuric acid, trifluoroacetic acid, or other forms of proton catalysts, both intra- and intermolecular hydroamination reactions can be accomplished under relatively mild conditions. The coordination of substrates with Brønsted acids may catalyze reactions involving unsaturated systems. The reactions occur through the formation of more-electrophilic complexes or charged intermediates. Studies of hydroamination of dienes and allenes demonstrate that to achieve this goal under metalfree catalytic conditions, the presence of an acid with a certain strength is necessary.16 As an example, the reaction could be carried out in the presence of dithiophosphoric acids, while phosphoric acid and phosphoramide organocatalysts failed to promote the hydroamination. Other homogeneous Bronsted acids such as sulfamic acid103 were also efficient. However, the scope of this reaction is limited. First of all, this route suffers from harsh reaction conditions and difficulty in the separation of the product. Moreover, in the presence of a Brønsted acid, the hydroamination of olefins with aliphatic amines does not occur under mild conditions, which has been assumed to be a result of the leveling effect of the amine. On the contrary, the acid can catalyze hydroamination with arylamines, but in addition, significant amounts of hydroarylation product are formed in combination with the desired hydroamination product.104 The catalytic effect of the Brønsted acid is more efficient in intermolecular reactions of less basic reagents with N−H

Scheme 26. Mechanism of the intermolecular asymmetric hydroamination of alkenes on copper catalysts96

Cu(I) catalysts have been reported for hydroaminations leading to the synthesis of more complex molecules such as Nalkylated α,β-unsaturated ketonitrones (Scheme 29).99 Such reactions are better catalyzed by CuI, although they are also possible with CuBr and CuCl. Zinc complexes have also been investigated in such reactions. Organozinc complexes with phenalenyl (PLY) ligand backbones, [N(Cy),O-PLY-ZnMe]2 (A) and [N(Cy),N(Cy)-PLYZnMe] (B), are examples of such catalysts. They were tested in the hydroamination of unactivated primary and secondary aminoalkenes in the presence of an externally added activator (Scheme 30).100 Isolation of the intermediates indicated that the reaction involves transamination followed by insertion of the olefin moiety into the metal−amide bond.101 Conclusions on Hydroaminations Using Homogeneous Lewis Acid Catalysts. The literature is growing in examples of hydroaminations using homogeneous non-noble-metal Lewis acid catalysts. The large majority of these reported catalysts are either metal halides or metal complexes. Hydroamination in the presence of metal halides involves as a first step the interaction of the Lewis acid with the amine. This is followed by the reaction with the alkene/alkyne leading to the product. In this series, obviously bromide and iodide are more efficient ligands compared with fluoride and chloride. In the case of metal 1337



Review

Scheme 27. Enantioselective Cu(I)-catalyzed formal hydroamination of oxabenzonorbornadiene with (A) morpholino benzoate and various ligands or (B) various O-benzoylhydroxylamines and (R,R)-Ph-BPE as the ligand97

Scheme 28. Asymmetric hydroamination of α,β-substituted styrenes with a range of N,N-dialkylhydroxylamines98

styrene, were reported.102 However, the formation of side products represents an important drawback in these reactions as well. Brønsted acids also catalyze intramolecular hydroaminations. In the intramolecular hydroamination of N-benzyl-2,2-diphe-

bonds, such as amides, carbamates, and sulfonamides, allowing intermolecular additions of these reagents to alkenes.102 On this basis, a series of hydroaminations using triflic acid, such as the addition of p-toluenesulfonamide to norbornene, cyclohexene, and cyclooctene and the addition of benzamide to 1338



Review

Scheme 29. π-Acidic metal-catalyzed hydroamination of alkynes with propargyloxyamines99

Scheme 30. Cyclo/hydroamination of unactivated alkenes on complexes A and B100

ensure the activation of the CC double bond in one aspect and to maintain the reactivity of amino groups on the other, is very important.105 Inorganic acids exhibited poor behavior in this reaction. Keggin-type heteropoly acids belong to the same category of Brønsted acids.106 Intermolecular hydroamination of unactivated olefins with sulfonamides, amides, and benzyl carbamate proceed efficiently in the presence of environmentally benign silicotungstic acid or molybdophosphoric acid catalysts. The addition products are obtained under mild conditions in air (Scheme 32). Catalytic amounts of a Brønsted or Lewis acid in ionic liquids were found to provide higher selectivity and yields than the same acid in classical organic solvents in this reaction.107 The ionic liquid increased the acidity of the medium and stabilized ionic intermediates through the formation of supramolecular aggregates. Then the simple addition of TfOH to the supported ionic liquid phase was also indicated to promote the intermolecular hydroamination.108 Brønsted Base Catalysts. Homogeneous Brønsted base catalysts have also been reported as metal-free catalysts in hydroamination reactions. The addition of N-heterocycles to phenylacetylene was first reported using CsOH·H2O,109 but soluble KOt-Bu and CsOt-Bu led to higher reaction rates in such internal hydroaminations (Scheme 33).110 Further investigations demonstrated the ability of the base to mediate the addition of electron-rich N-heterocycles (indoles and pyrroles) to alkynes.111−113 The reaction of imidazole with 3-ethynylthiophene leading to (E)/(Z)-1-(2-(thiophen-3-yl)vinyl)-1H-imidazoles (Scheme 34) is a particular example of the general reaction (Scheme 35), which allows the synthesis of natural product intermediates. All of these reactions are catalyzed by KOH with a good control of the Z/E ratio (Schemes 34 and 35).114,115

nylpent-4-en-1-amine, a large number of such acids were tested, including inorganic (H2SO4, H3PO4, HNO3) and organic acids, and only triflic acid, methanesulfonic acid, and trifluoroacetic acid led to acceptable yields (Scheme 31).105 This result in fact demonstrates that in addition to the strength of the Brønsted acid, the capacity of the acid to bear a balanced Lewis acidity, to Scheme 31. Intramolecular hydroamination of N-benzyl-2,2diphenylpent-4-en-1-amine using Brønsted acids105

1339



Review

Scheme 32. Hydroamination of unactivated olefins with nitrogen nucleophiles over Keggin-type heteropoly acids106

which is of high interest for practical applications;117 (ii) their acidity is strong enough to effectively promote a multitude of catalytic reactions in high yields, including reactions forming C−heteroatom bonds. Hydroamination reactions fall into this category. Metal triflate catalysis is discussed separately from homogeneous and heterogeneous catalysis as a consequence of the fact that they can catalyze reactions under both homogeneous and heterogeneous conditions. For such catalysts, biphasic catalysis methodology may economically improve the hydroamination reactions, especially because of the simple and complete separation of the product from the catalyst. To date, a large number of metal triflates (Ga, Yb, Pr, In, Bi, Cu, Fe, Sc, Ag, and Zn) have been investigated in hydroamination reactions. Accordingly, the literature contains many examples of intra- and intermolecular hydroaminations of a high variety of substrates catalyzed by metal triflates, including reactions involving aliphatic and aromatic amines.118−130 A very important characteristic of the triflate catalysts is their potential use in multiple reactions. As examples, In(OTf)3 and Zn(OTf)2 showed activities in hydroamination of phenylacetylene with p-toluidine,41 and Zn(OTf)2 also showed activity

Scheme 33. Na-, K-, and Cs-mediated internal hydroamination reactions110

Hydroamination on Metal Triflates. Metal triflates have received special attention as Lewis acids catalysts over the last two decades.116 Two characteristics make the interest for them so special: (i) compared with metal halides, they are tolerant of water and oxygen impurities and also afford reusable catalysts,

Scheme 34. Hydroamination of 3-ethynylthiophene with imidazole114,115

1340



Review

Scheme 35. Synthesis of (Z)- and (E)-styryl enamines114,115

in reactions of protected propargylamines with primary amines, leading to the synthesis of imidazoles (Scheme 36).131 Another

in the intermolecular hydroamination of unactivated alkenes with aniline,124 In(OTf)3 in the hydroamination of phenylacetylene with different aromatic amines and the intramolecular hydroamination of sulfonamide-substituted 1,1-vinylidenecyclopropane diesters,125,126 and Bi(OTf)3 in hydroamination of aminoalkene and aminoallene compounds with some enophiles.127 In the same reaction, Cu(OTf)2 demonstrated very good stability, working for longer reaction times, while Fe(OTf)2,3 and Sc(OTf)3 provided moderate yields and Zn(OTf)2 and TfOH were sluggish. Zn(OTf)2 catalyzed the synthesis of indoles by hydrohydrazination of terminal alkynes and the hydroamination of 1-octyne with aniline,128 the hydroamination of different vinyl arenes and anilines,129 the reaction of N-acylpropargylamides and amines,131 and hydroamination of arylalkynes.130 An example of the cooperation among a complex compensated by triflate, the ligand of the complex, and HOTf was also reported for the intermolecular hydroamination of vinyl arenes with aliphatic amines.90 Pure HOTf catalyzed the intramolecular hydroamination of N-(2cyclohex-2′-enyl-2,2-diphenylethyl)-p-toluenesulfonamide.135 In addition to triflate, bis(trimethylsilyl)amide represents another anion strong enough to activate rare-earth elements for hydroamination reactions involving unactivated alkenes.136 Hydroamination under Heterogeneous Catalysis. Heterogeneous catalytic hydroamination represents a practical alternative to homogeneous catalysis since it may allow easier separation of the product and recycling of the catalyst as well as transfer of the reaction to flow conditions. Reports published to date indicate that the heterogeneous attempts in fact used all of the active elements identified in homogeneous catalysis. However, the integration of these elements into a solid network provides a more versatile route to carry out the hydroamination reaction, and several classes of materials have shown even better performances. Main-Group-Metal Catalysts. It was reported early on that ammonia adds to alkynes at 300−350 °C in the presence of a silica or alumina catalyst, while amines require a zinc or cadmium acetate catalyst.137,138 In modern heterogeneous catalysis, acid catalysis with aluminum is associated with zeolites.139 They represent a huge number of structures in which the catalytic properties of the solid are controlled by the positions of Al atoms in the entire framework (T sites, zeolite rings, or channel/cavity systems).140 Another specificity of zeolites consists of the fact that in these structures aluminum coexists in both Lewis acidic and Brønsted acidic sites (Scheme 39). As in the case of homogeneous catalysis, hydroamination requires zeolites with strong accumulated acidity. The initial hydroaminations using H-BEA or ZSM-5 zeolites indicated their capability to protonate isobutene to give the correspond-

Scheme 36. Hydroamination of protected propargylamines with primary amines, leading to the synthesis of imidazoles131

interesting application of Zn(OTf)2 is the hydroamination of 2,5-dihydrofuran with aniline, leading to compounds that may serve as intermediates in further reactions (Scheme 37).132 Scheme 37. Hydroamination of 2,5-dihydrofuran with aniline132

When water is used as the solvent or even under solvent-free conditions, other complex molecules such as 1,3-oxazine derivatives can be effectively synthesized via a hydroamination approach. Yb(OTf)3 catalyzed such reactions in satisfactory yields when acetylenedicarboxylates, aromatic or aliphatic amines, and formaldehyde were used as substrates (Scheme 38).123 Copper triflates were reported as catalysts for intermolecular reactions between vinyl arenes and amines119,120 or allenylamines.121 Copper was also used in combination with silver salts.133 Intermolecular reactions of unactivated olefins and nitrogen compounds of moderate nucleophilicity were carried out successfully in the presence of a copper halide, a silver salt, and a phosphane ligand. In spite of the fact that pure triflic acid showed rather poor efficiency in hydroamination,134 mechanistic investigations demonstrated that in its presence the coordination of the amine to a copper cationic complex generates a Brønsted acid that is the prominent catalytic species. This result raises the question of whether hydroamination on these catalysts is a true metal-catalyzed process or the metal simply generates a Brønsted acid.133 The use of the pure triflate catalysts overcomes these problems, and many successful examples have been reported. Ga(OTf)3 was tested in the direct reductive amination of aldehydes,122 Yb(OTf)3 in the hydroamination of acetylene dicarboxylates with aliphatic and aromatic amines,123 Pr(OTf)3 1341



Review

Scheme 38. Synthesis of 1,3-oxazine derivatives using acetylene dicarboxylates, aromatic or aliphatic amines, and formaldehyde123

ing tert-butyl carbenium ion, which can further react with ammonia or an amine.141,142 On less acidic zeolites such as Y, MOR, or LTA, the hydroamination of activated olefins (e.g., methyl acrylate) with aromatic amines (i.e., an aza-Michael addition) resulted in moderate conversions, which fits very well with the electronwithdrawing properties of the amine functional group (Scheme 40).143,144 The addition of the nucleophile occurs via a conjugate addition, and thus, anti-Markovnikov selectivity is

Scheme 39. Lewis and Brønsted acidic sites in zeolites

1342



Review

Scheme 40. Hydroamination of activated olefins with aromatic amines over zeolites143,144

Scheme 41. Hydroamination of α,β-ethylenic compounds with amines on TiO2-nanoparticle-stabilized 12-tungstophosphoric acid in SBA-15 (reproduced with permission from ref 149; copyright 2014 Wiley-VCH Verlag GmbH & Co. KGaA)

Figure 2. Hydroamination of styrene with aniline and substituted anilines in the presence of scandium triflate-based catalysts.152

determinant for this reaction and how is it correlated to the selectivity for the Markovnikov or anti-Markovnikov products. Early-Transition-Metal-Based Catalysts. Oxides were utilized in this reaction either because of their Brønsted acid properties or as a support for complex or more acidic structures. Pure TiO2 nanoparticles were also reported to catalyze hydroamination reactions, creating hybrid TiO2− polyaniline core−shell nanoparticles via the hydroamination of methacrylic acid with aniline.148

expected. Further exchange of these zeolites with sodium induced low basicity and complete deactivation. The same adduct (e.g., anti-Markovnikov) was the major product in the conjugate addition of α,β-unsaturated carbonyl compounds on montmorillonite clay.145 Using unactivated substrates and exchanged Brønsted acid sites the reaction was accompanied by a change in the selectivity in favor of the Markovnikov regioisomers.146,147 However, in spite of the sustained effort, it is still unclear which kind of acidity is 1343



Review

Scheme 42. Hydroamination of phenylacetylene with 4-isopropylaniline on double metal cyanides163

Hydroamination of α,β-ethylenic compounds with amines on TiO2-nanoparticle-stabilized 12-tungstophosphoric acid (TPA) in SBA-15 was also reported (Scheme 41). The catalysts were prepared by wet impregnation of TPA/TiO2 nanoparticles into the SBA-15 and afforded total chemoselectivity for the antiMarkovnikov product (i.e., the monoaddition product) without any leaching of the active species.149 Nanocrystalline zirconosilicates and titanosilicates with the MFI framework structure showed activity in the synthesis of amino esters by the hydroamination reaction of methyl acrylates and amines that was well-correlated with the acidity of these materials.150 Similar reactions were carried out on a variety of crystalline heterogeneous catalysts such as Al/Zrsubstituted nanocrystalline ZSM-5, conventional M-ZSM-5 (M = Zr, Al), and Zr-substituted amorphous mesoporous catalysts (Zr-SBA-15 and Zr-KIT-6).151 Scandium triflate was encapsulated in mesoporous UVM-7 silica, and its catalytic performance in the hydroamination of styrene with aniline and substituted anilines was compared with those of different zeolites (Beta and mordenites), scandium triflate, and physical mixtures prepared under ultrasound irradiation.152 The conversion was mainly controlled by the strength of the acid sites and their accessibility, while the selectivity appeared to be controlled by the Lewis/Brønsted acid site ratio (Figure 2). Lewis acid catalysts directed the reactions mainly to the formation of the Markovnikov adducts and Brønsted acid catalysts to the anti-Markovnikov adducts. Among the different physical mixtures, those of scandium triflate with the mesoporous scandium triflate embedded in a UVM-7 structure provided better conversions with good selectivity for the Markovnikov adduct. The results were attributed to better dispersion of scandium triflate during the preparation of the physical mixtures. Late-Transition-Metal-Based Catalysts. Ionic exchange of zeolites (H-BEA) with Cu(I) or Zn(II) led to catalysts with catalytic activities higher than that of the corresponding homogeneous Zn(CF3SO3)2 catalyst but smaller than that of the parent BEA zeolite.20,117,153,154 The activity of ionexchanged heterogeneous catalysts was assigned to residual protons in the material.155 In fact, the reaction was supposed to be initiated by the Lewis acidic metal sites, while the presence of the protons enhances the reaction rate.156 Mesoporous AlSBA-15 was also exchanged with Cu(II), affording the hydroamination of terminal alkynes with aromatic amines.157 Also, montmorillonite K-10 was exchanged with Cu(II) and Zn(II) for the same reaction.147 Cation-exchange resins (Amberlyst-15, Nafion) in ethanol158 or in ionic liquids were also found to be recyclable systems for hydroamination reactions of alkenes and vinylpyridines with

several amides, sulfonamides, carbamates, and aromatic amines as nitrogen nucleophiles.159 Hydroamination of several alkenes by cyclohexylamine was also catalyzed by a series of metal salt nanoparticles (NiCl2, AlCl3, CoCl2, FeCl3, CuCl2, and ZnCl2) supported on chiral mesoporous silica.160,161 The size of the metal salt nanoparticles (>10 nm) allowed a strong interaction with the support, resulting in catalyst stability. Other materials such as the double metal cyanide (DMC) of Zn behave as recyclable catalysts for hydroamination of phenylacetylene with 4-isopropylaniline.162 The activity of these materials was ascribed to Lewis acidic zinc sites in a pseudo-octahedral environment with four or five cyanide ligands surrounding the Zn (Scheme 42).163 Additives in the synthesis of these catalysts also have an important effect, and yields as high as 92% have been achieved with polyethers such as poly(tetramethylene ether) glycol. Immobilization of triflic acid on silica has also been shown to catalyze the hydroamination of alkenes with sulfonamides.164 Hydroamination under Ball Mill Conditions. Solventfree reactions are gaining importance in green chemistry. Among other techniques, ball mills have the advantages of more effective activation and mixing of the substrates.165,166 Besides these, the ability to work solvent-free, especially for organic syntheses, makes this method extremely attractive. Very recently the intramolecular cyclization/hydroamination of 2-alkynylanilines to give indoles in a planetary ball mill was reported (Scheme 43).166 The reaction was performed in the Scheme 43. Ball mill intramolecular cyclization/ hydroamination of 2-alkynylanilines to give indoles in the presence of Lewis acid catalysts166

absence of any solvent using different cheap, readily accessible Lewis acid catalysts (CoCl2·6H2O, CuCl2·2H2O, FeCl3·6H2O, ZnBr2, InBr3, Sc(OTf)3, Y(OTf)3). The reaction was possible even in the absence of any catalyst, albeit in low yields. There are also examples in which attempts to conduct hydroaminations in solution have either failed or given very low conversions. This is the case in the synthesis of N1344



Review

Scheme 44. Ball mill intermolecular synthesis of N-sulfonylguanidines:167 (A) coupling of trifluoromethylsulfonamide with different carbodiimides; (B) coupling of p-tolyl- and p-chlorophenylsulfonamide with different carbodiimides

sulfonylguanidines, which is normally blocked by the poor nucleophilicity of sulfonamides. However, experiments carried out under ball mill conditions showed that trifluoromethylsulfonamide can react with carbodiimides under these conditions in the absence of any catalyst (Scheme 44A).167 More complex substrates such as p-tolylsulfonamide or p-chlorosulfonamide require the presence of a catalyst, with simple CuCl being sufficient to produce very high yields (Scheme 44B).

Part of the recent developments were inspired by the Buchwald−Hartwig as well as the classic Ullman reaction (copper-catalyzed arylation) and the related Goldberg reaction (copper-catalyzed N-arylation of amides), in which C−C and C−N couplings are achieved in the presence of Cu(I) catalysts.214,215 However, the Ullman and Goldberg reactions are also associated with some drawbacks, including the necessity to use high temperatures, highly polar solvents, and often large amounts of copper reagents, which have prevented these reactions from being employed to their full potential. To solve these drawbacks, the recent copper-catalyzed C−N couplings use homogeneous catalysts in which less-expensive bidentate ligands such as phenanthrolines, 216,217 diamines,213,218 imines,219,220 amino acids and derivatives,221,222 picoline- and pyrrole-2-carboxylic acid,223,224 diketones,225,226 β-keto esters,227 salicylamides,228 bis(2,2,6,6-tetramethyl-3,5heptanedionate),229 etc., lower the overall synthesis procedure costs while still leading to very good yields of the desired products. Kinetic studies coupled with DFT calculations indicated for these systems that the reaction mechanism is indeed highly dependent on the ligand but also on the aryl halide and the nucleophile.230 Diamines may have an additional role, namely, to act as mass-transfer promoters, accelerating the reaction rate.230 Scheme 45 shows examples of such C−N coupling reactions catalyzed by Cu(I)−diamine ligands.231,232 Phosphine ligands have also been used in conjuction with Cu(I), as the air-stable complex [Cu(PPh3)3Br] (prepared from CuBr2 and PPh3 in methanol) was used to catalyze the amination of aryl iodides with anilines (Scheme 46, bottom).233,234 In addition, phosphine oxime A (Scheme 46, top) can efficiently catalyze the coupling of aryl iodides with alkylamines or N−H heterocycles as a ligand not only to Cu(I) but also to Cu2O.235 Although more complex, the 3,4diphosphinidenecyclobutene ligands B (Scheme 46, top) enabled the coupling of aniline and morpholine with unactivated aryl chlorides at a moderate temperature.236 Other ligands such as N,N′-bis(2,6-diisopropylphenyl)-1,4diaza-1,3-butadiene showed a coordination versatility that was the result of the NC−CN backbone and its strong σdonating and π-accepting properties.237 [(Cl2NN)Cu−OtBu] is an active catalyst for the catalytic intermolecular C−H amination with simple, unactivated alkylamines (Scheme 47). It can be produced from a βdiketiminatodicopper chloride following a simple protocol.238 Another group of copper catalysts investigated in the Narylation reactions of diverse amines and N-containing

■

C−N CROSS-COUPLING Cross-coupling is a very powerful route to generate aryl− carbon and aryl−heteroatom covalent bonds and may occur following different routes: (i) cross-coupling of Grignard reagents with organic halides;168−170 (ii) the reaction of aryl halides with alk-1-enylboranes (the Suzuki−Miyaura reaction);171 (iii) coupling of an organotin compound with a variety of organic electrophiles (Migita−Kosugi−Stille coupling);72,172,173 (iv) the formation of carbon−carbon bonds between terminal alkynes and aryl or vinyl halides in the presence of Cu(I) (Sonagashira coupling);174 and (v) the reaction of an unsaturated halide (or triflate) with an alkene in the presence of a base (Mizoroki−Heck reaction).175,176 Among these, the formation of C−N bonds has elicited a large interest in the synthesis of compounds with pharmaceutical, cosmetic, agrochemical, and optical-device applications.177−184 and thus has received a great industrial and academic attention in the past two decades.185 Initiated by Migita et al.186 using aminostannanes, the amination of aryl halides is mostly known as the Buchwald−Hartwig reaction.187−192 It represents a palladium-mediated cross-coupling procedure193,194 and occurs under homogeneous catalytic conditions in the presence of strong bases, aprotic and/or polar and nonpolar solvents, and different ligands.195−201 Homogeneous Copper-Catalyzed C−N Cross-Coupling Reactions. Although palladium demonstrated its efficiency, more recent literature also contains reports of nonprecious metals as catalysts that can replace noble metals in C−N cross-coupling processes. Among the metals mentioned to be in competition with palladium are copper,202−207 nickel,208,209 and, more recently, iron.210−212 Besides the price, the replacement of palladium by other metals is also recommended by its incompatibility with some functional groups, such as 1- and 2-amides and substrates where there is a free OH or NH directly bound to the aromatic ring that contains the halide or sulfonate.213 1345



Review

Scheme 45. Cu(I)-catalyzed C−N coupling reactions in the presence of diamine ligands213

1346



Review

Scheme 45. continued

Scheme 46. (top) Structures of ligands A and B;235,236 (bottom) C−N coupling catalyzed by [Cu(PPh3)3Br]233

of N′,N″-dibenzylmalonamide and N′,N″- dibutylmalonamide followed by cleavage of the malonyl group were obtained in very good yields.243 Besides CuI, ligand-free N-arylations244−246 were reported on copper carbonate and copper sulfate.247 Ligand-free reactions have been also applied in the synthesis of biologically active compounds.248 The literature contains reports of a broad variety of nucleophiles that have been successfully used in homogeneous copper-mediated cross-coupling reactions to form C(aryl)−N bonds: amines, anilines, amides, imides, ureas, carbamates, and sufonamides as well as aromatic heterocycles (imidazoles, pyrazoles, triazoles, tetrazoles, benzimidazoles, indazoles).231,248 Excellent yields were obtained under relatively mild conditions by the coupling of aryl halides with amides and N-heterocycles,

heterocycles with aryl and heteroaryl bromides are the (2aminoarenethiolato)copper(I) complexes shown in Scheme 48.239,240 These catalysts are thermally stable and soluble in common organic solvents, and depending on the substrate, they allow the synthesis of targeted products in moderate to good yields. Several “ligand-free” reactions have also been reported for the N-arylation of aromatic N-heterocycles catalyzed by copper compounds, where the role of a strong base (KOt-Bu) was indicated to be very important.241 The amination of primary amines to give triarylamines is one of the examples. The conversion of aniline and the selectivity for triarylamines also depended on the nature of the copper precursor.242 Thus, aromatic amines based on ligand-free CuI-catalyzed N-arylation 1347



Review

Scheme 47. Catalytic intermolecular C−H amination of unactivated alkylamines in the presence of [(Cl2NN)Cu−OtBu]238

(compared with DMSO, dioxane, etc.).252 The addition of water had a positive effect, as seen in several cases. Coppercatalyzed amination in N,N-dimethylethanolamine is a mild and practical method to prepare amine derivatives from 2- and 3halothiophenes, 2,5-dihalothiophenes, and halobithiophenes.250 Obviously, the reaction of unactivated halothiophenes with aliphatic amines under mild conditions is not easy. Water is an attractive solvent for many applications, especially when it can be associated with the possibility of low metal and ligand loadings. 4,7-Dipyrrolidinyl-1,10-phenanthroline was identified as an efficient ligand for coppercatalyzed selective aromatic N-arylation in water. N-Arylation of indoles, imidazoles, and purines afforded moderate to excellent yields (>95%) with complete selectivity over aliphatic amines.253 Pyrrole-2-carbohydrazides represent another example of ligands that can be used for the Cu-catalyzed amination of aryl halides with amines in water. A variety of aryl bromides or iodides were aminated under microwave irradiation or conventional heating without protection by an inert gas.254 The low cost, reduced flammability, reduced toxicity, recyclability, easy degradability, and miscibility with a wide variety of organic solvents recommend poly(ethylene glycol) (PEG) and its solutions as interesting green solvent systems.255 These properties were also demonstrated by copper iodide in PEG-400, which catalyzed the amination of aryl halides with ammonia.256 Along with the choice of the ligand and the solvent, an important component of the C−N cross-coupling reaction is the nature of the base (e.g., carbonate, phosphate, alkaline hydroxide, alkoxide, inorganic fluoride, or silylamide), which plays an important role in the evolution of the reaction as it is involved in the deprotonation of the N substrate.257 Nonpolar and aprotic solvents are able to dissolve all of the reactants except for the base. Heterogeneous Copper-Catalyzed C−N Cross-Coupling Reactions. For the conversion of simple, active substrates by ligand-free approaches, transferring this crosscoupling reaction from homogeneous to heterogeneous

Scheme 48. (2-Aminoarenethiolato)copper(I) complexes239,240

which was efficiently catalyzed using small quantities of copper. Moreover, the reaction of a variety of substituted indoles with aryl iodides was explored. Reactions of carbazole, 7-azaindole, and 5-cyano- and 5-aminoindole proceeded in high yields (over 80%).249 In contrast to palladium catalysis, copper-type coupling reactions tolerate atmospheric oxygen, while the reaction temperatures and reaction times are comparable to those in the palladium-catalyzed processes.248 Macrocyclization using amides and aryl bromides is also possible using Cu-catalyzed C−N coupling, and both inter- and intramolecular N-arylation reactions were successfully achieved.248 Cu(I) exhibited a higher activity in this reaction (yields of over 90%), and iodide appeared to be the most efficient anion in the series I−, Cl−, SCN−. Except for CuO and CuCl2, which exhibited very low activities, Cu(0) and Cu(II) salts (sulfate, acetate, aceylacetonate, methoxide) afforded low to moderate yields (

Nonprecious Metals Catalyzing Hydroamination and CâN Coupling

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