Hydroamination Alkyne

Indium-Catalyzecl Alkyne Hydroamination (AHA) 153 Table 6.3 Turnover frequencies (TOFs) for the reaction of Equation 6.9 at 50% conversion. 

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 10 [2 + 2] Cycloaddition mechanism for alkyne hydroamination catalysis...

Indoles can also be prepared directly from o-chlorophenyl-2-alkyl alkynes and primary amines via a tandem alkyne hydroamination/Buchwald-Hartwig iV-arylation sequence, as illustrated for the conversion of 7 to 8 via intermediate enamine 9. ... 

While early efforts in rare earth systems focused on cyclohydroamination, pioneering contributions in group 4 catalyzed hydroamination catalysis focused on intermolecular reactions [8]. However, owing to the aforementioned thermodynamic problems associated with intermolecular alkene hydroamination and mechanistic hmitations (see later discussion), early efforts focused on alkyne hydroamination with a variety of primary amines. 

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

Intramolecular alkyne hydroamination reactions, while being some of the most common hydroamination investigations early on in reaction development [28], are now rarely investigated. This is in part due to the observation that many metal systems, and indeed even strong acid, can catalyze this transformation. Thus, such reactions are rarely useful probes for identifying unique and promising reactivity trends. 

Figure 15.2 Recent group 4 catalysts for alkyne hydroamination.

Some recent reports of new complexes for alkyne hydroamination catalysis (Figure 15.2) include 1 [29] and 2 [30], where the latter has been shown to be particularly useful for five-, six-, and even seven-membered ring formation (Scheme 15.4). 

Scheme 15.5 Alkyne hydroamination with anti-Markovnikov seiectivity.

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]. 

Alkyne hydroamination has been investigated since the earliest days of this transformation. Pioneering work by Barluenga and coworkers [183-186] established that toxic mercury and thaUium salts could be used for this desirable transformation. 

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]. 

Scheme 1530 Rh-catalyzed intermolecular alkyne hydroamination with arylamines.

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). 

Table 15.14 Intermolecular alkyne hydroamination with CAAC-Au complex.

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]. 

Scheme 15.32 Synthesis of allene by alkyne hydroamination with secondary amine.

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