Alkyne hydroamination catalysts

Allene hydroamination is less commonly explored, even though the thermodynamic profile of the reaction is comparable to alkyne hydroamination [40]. Intermolecular allene hydroamination has been established using group 4 catalysts in combination with reactive arylamine substrates [8, 41]. The more reactive aforementioned alkyne hydroamination catalyst 7 has been shown to be usefiil for allene hydroamination catalysis in an intermolecular manner, even with less reactive, sterically less demanding alkylallene substrates. In this case, only the branched product is observed (Table 15.5). These results show good selectivity for the branched product, and recent results show that even heteroatom-substituted allenes can be tolerated with this precatalyst [42]. 

An investigation comparing different hydroamination catalysts for the conversion of enamine alkynes to pyrroles is illustrated in Scheme 12.26 46 In this test, different... 

Later, Arcadi showed that /J-keto-imines react with alkynes intramolecularly to give pyrroles. The intermolecular animation with aniliaes was later developed by Hayashi and Tanaka using a cationic Au(I) catalyst to form imines (equation 27). More recently, Arcadi etal. developed an intramolecular version for the cyclization of o-alkynylanilines to form indoles (equation 28) and Li reported a double intra- and intermolecular hydroamination to obtain A-vinylindoles. " O-Substituted hydroxylamines can also undergo this type of transformation to dihydroisoxazole derivatives. " " Tandem sequences that involve a first alkyne-hydroamination step with anilines have been recently developed " " and are similar to the previonsly discnssed additions with phenols that access isoflavone skeletons. 

Scheme 15.3 General alkyne hydroamination reaction with Zr catalyst (top) and general [2+2] cycloaddition catalytic cycle (bottom).

Figure 15.2 Recent group 4 catalysts for alkyne hydroamination.

Alkyne hydroamination has been extensively reviewed [3, 4, 10] and important contributions using late transition metals have been realized to give the Markovnikov-type products most typically. Interestingly, in 2007, Fukumoto reported a tris(pyrazolyl borate)rhodium(l) complex for the anti-Markovnikov hydroamination of terminal aUcynes with both primary and secondary amine substrates, although yields with primary amines are always reduced compared to those with secondary amines (Scheme 15.26). Desirable functional group tolerance is also noteworthy for this regioselective hydroamination catalyst [187]. 

Indeed, Cu can be used in combination with tungstophosphoric acid to realize solvent-free acid-catalyzed hydroarylation and hydroamination of alkynes to give the Markovnikov products with a variety of arylamines [211]. Furthermore, gold catalysts have been used extensively with acid additives for a variety of amine and protected amine substrates [120,212]. More recently, Bertrand [189] was able to illustrate the useful apphcation of his [(CAACjAulBlCgFj) complex for intermolecular alkyne hydroamination with both primary and secondary amines (Table 15.14). 

While regioselectivity is not catalyst controlled, as illustrated in Table 15.14, reactivity is observed across a broad range of substrates, although widely varying reaction concbtions must be used. Notably, only bulky primary amines have been reported here. Interestingly, alkyne hydroamination with secondary amines gives enamines as useful reactive intermediates for the synthesis of allenes (Scheme 15.32) [189]. 

In 1999, Doye disclosed that dimethyltitanocene is a catalyst widely applicable to intermolecular hydroamination of alkynes with primary aryl- and alkylamines [302]. In the case of unsymmetrically substituted alkynes, the reaction occurs with high re-gioselectivity, forming the anti-Markovnikov products exclusively (Scheme 14.127). Kinetic studies suggest that the reaction mechanism involves the formation of a Ti-imido complex as the catalytically active species. Doye further developed a tandem Ti-catalyzed protocol of alkyne hydroamination and imine reduction, affording secondary amines in a fully catalytic one-pot reaction [303]. 

The catalytic activity of 4 in intermolecular hydroamination of alkynes by anilines as well as in the intramolecular alkene and alkyne hydroamination has been reported [40]. The results show that in the presence of ]PhNMe2H+][B(CgF5) ], 4 could catalyze these reactions very efficiently (2.5 mol% catalyst, 20 - 80 °C). It was su ested that the Cp moiety was protonolyzed to give Cp H, which was identified by NMR. In most cases, excellent yields were achieved, indicating a possible high potential of Zn-Zn-bonded complexes for catalytic organic transformations. As the presumed mechanism is not discussed further, it is hitherto unclear whether a Zn species is prevalent in the catalytic cycle. 

Af,Af-diethylgeranyIamjne, a precursor to (—)-menthol is achieved via the hydroamination of this substrate with lithium catalysts on an industrial scale [98]. A single example of intermolecular alkyne hydroamination also exists. Thus, piperidene undergoes addition to diphenylacetylene in the presence of 10 mol% [Sr CH(SiMe3)2 2(THF)2] at 60 °C in CgDe solution over a period of 17 h a 10 1 mixture of syn- and antf-addition products are isolated consistent with an isomerization event occurring under the reaction conditions [98]. 

Furthermore, this follow-up study also illustrated the broad applicability of DMCs for the hydroamination of various substrate molecules [37]. Zn-Co-DMCs could catalyze the hydroamination reaction of both aromatic and aliphatic alkynes with aromatic as well as aliphatic amines, a rare trait in heterogeneous hydroamination catalysts. 

In 2010, Monge et al. reported a one-pot tandem reaction by combining bifunctional thiourea and Au complex [77], affording dihydropynole derivatives in moderate yields and high enantioselectivities. The reaction was based on a bifunctional thiourea-catalyzed Mannich-type reaction and a subsequent Au-catalyzed alkyne hydroamination and isomerization of propargylated malononitrile and N-Boc-protected imines (Scheme 9.72). Notably, acidic additive proved cracial to prevent deactivation of the gold catalyst and enhance the reactivity and selectivity. 

More recently, neutral zirconium-based catalysts capable of performing reactions with both primary and secondary amines in intra- [55-57] and intermolecular [57, 58] reactions were reported. The imido mechanism is obviously impossible, and an insertion mechanism, similar to the lanthanide-like mechanism shown in Scheme 2 was proposed [55]. The isolation of an insertion intermediate in an intermolecular alkyne hydroamination reaction is compelling evidence in favor of the insertion mechanism [58]. 

Only a limited number of organoactinide catalysts have been investigated for the hydroamination/cyclization of aminoalkenes (Fig. 4, Table 2) [55, 96-98]. The constrained geometry catalysts 11-An (An = Th, U) show high activity comparable to the corresponding rare earth metal complexes and can be applied for a broad range of substrates [55, 96, 97]. The ferrocene-diamido uranium complex 12 was also catalytically active for aminoalkene cyclization, but at a somewhat reduced rate [98]. Mechanistic studies suggest that the actinide-catalyzed reaction occurs via a lanthanide-like metal-amido insertion mechanism and not via an imido mechanism (as proposed for alkyne hydroaminations), because also secondary aminoalkenes can be cyclized [55, 98]. 

Fig. 13 Group 4 metal catalysts for alkyne hydroamination (Ar = 2,6-Me2C6H3) [41, 179,...

The increased Markovnikov selectivity in the hydroamination of aliphatic terminal alkynes with aniline derivatives seems to be universal for a number of titanium-based hydroamination catalysts, such as Ind2TiMe2 (49) [184], the di-(pyrrolyl) amine complex 50 [186, 187], and the di(pyrrolyl)methane complex 51 [188]. The bis(amidate) titanium complex 43 exhibited enhanced catalytic activity compared to titanocene catalysts, thus combining high a ri-Markovnikov selectivity with high catalytic activity [191]. 

The formation of a bis(guanidinate)-supported titanium imido complex has been achieved in different ways, two of which are illustrated in Scheme 90. The product is an effective catalyst for the hydroamination of alkynes (cf. Section V.B). It also undergoes clean exchange reactions with other aromatic amines to afford new imide complexes such as [Me2NC(NPr )2]2Ti = NC6F5. ... 

The guanidinate-supported titanium imido complex [Me2NC(NPr02l2Ti = NAr (Ar = 2,6-Me2C6H3) (cf. Section IILB.2) was reported to be an effective catalyst for the hydroamination of alkynes. The catalytic activity of bulky amidinato bis(alkyl) complexes of scandium and yttrium (cf. Section III.B.l) in the intramolecular hydroamination/cyclization of 2,2-dimethyl-4-pentenylamine has been investigated and compared to the activity of the corresponding cationic mono(alkyl) derivatives. 

---