Alkynes hydroamination reactions

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. 

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]. 

Cyclization reactions triggered by intermolecular alkyne hydroamination reactions provide straightforward access to structurally diverse heterocyclic motifs as summarized in a recent general [5] and specialized [202] review. 

Organometallic complexes of the /-elements have been reported that will perform both intra-and intermolecular hydroamination reactions of alkenes and alkynes, although these lie outside of the scope of this review.149-155 Early transition metal catalysts are not very common, although a number of organometallic systems exist.156-158 In these and other cases, the intermediacy of a metal imido complex LnM=NR was proposed.159,160 Such a species has recently been isolated (53) and used as a direct catalyst precursor for N-H addition to alkynes and allenes (Scheme 35).161,162... 

Similar to the addition of secondary phosphine-borane complexes to alkynes described in Scheme 6.137, the same hydrophosphination agents can also be added to alkenes under broadly similar reaction conditions, leading to alkylarylphosphines (Scheme 6.138) [274], Again, the expected anti-Markovnikov addition products were obtained exclusively. In some cases, the additions also proceeded at room temperature, but required much longer reaction times (2 days). Treatment of the phosphine-borane complexes with a chiral alkene such as (-)-/ -pinene led to chiral cyclohexene derivatives through a radical-initiated ring-opening mechanism. In related work, Ackerman and coworkers described microwave-assisted Lewis acid-mediated inter-molecular hydroamination reactions of norbornene [275]. 

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

The cationic gold complex with CAAC ligand 29 can also catalyze the unprecedented hydroamination reaction of alkynes and allenes using ammonia [59, 60]. It was also demonstrated that it can catalyze the simple hydroamination reaction. It... 

The excellent ability of late transition metal complexes to activate alkynes to nucleophilic attack has made them effective catalysts in hydroamination reactions. The gold(l)-catalyzed cyclizations of trichloroacetimidates 438, derived from homopropargyl alcohols, furnished 2-(trichloromethyl)-5,6-dihydro-4f/-l,3-oxazines 439 under exceptionally mild conditions (Equation 48). This method was successfully applied to compounds possessing aliphatic and aromatic groups R. With R = Ph, cyclization resulted in formation of 439 with complete (Z)-stereoselectivity <2006OL3537>. 

Finally, though not strictly a hydroamination reaction, the asymmetric addition of alkynes to imines with a copper-bis(oxazoline) complex is worth briefly mentioning.[144] The nature of the ionic liquid cation has a strong effect on the enantioselectivity of the reaction and it appears that a good balance between hydrophobicity and acidity play an important role with best results obtained with [C4Ciim][Tf2N]. 

Transition metal-catalyzed addition of heteroatom-hydrogen bonds to alkynes in syntheses of cyclic amines and pyrroles by hydroamination reactions, in syntheses of O-heterocycles by hydroalkoxylation of alkynes, and in syntheses of S- and Se-heterocycles 04CRV3079. 

As discussed in the previous sections, hydrosilylation and hydroamination reactions can be catalyzed by essentially the same catalysts under very similar reaction conditions due to the similarity in their reaction mechanisms. Hence, both reactions can be performed in one synthetic procedure as a one-pot sequence. Although less explored than hydrosilylation of C-C multiple bonds, organolanthanide-catalyzed hydrosilylation of imines is a facile straightforward process [172,173]. Imines, in particular cyclic imines, are readily available via organolanthanide-catalyzed hydroamination of alkynes. Roesky and coworkers have demonstrated that A-silylated saturated heterocycles can be smoothly obtained (38) and (39) utilizing the bis(phosphinoamide)methanide complex 12 (Fig. 8) [57,58]. The higher reactivity of aminoalkynes in the hydroamination process makes this method a valuable alternative to aminoalkene hydroamination. 

Group 4 metal based catalysts have been studied intensively in hydroamination reactions involving alkynes and allenes [77 81], but (achiral) hydroamination reac tions involving aminoalkenes were only recently reported [82 84]. The reactivity of these catalysts is significantly lower than that of rare earth, alkali, and alkaline earth metal based catalysts. In most instances, gem dialkyl activation [37] of the aminoalk ene substrate is required for catalytic turnover. 

Hydroamination reactions involving alkynes and enantiomerically pure chiral amines can produce novel chiral amine moieties after single pot reduction of the Schiffbase intermediate 82 (Scheme 11.27) [123]. Unfortunately, partial racemiza tion ofthe amine stereocenter was observed with many titanium based hydroamina tion catalysts, even in the absence of an alkyne substrate. No racemization was observed when the sterically hindered Cp 2TiMe2 or the constrained geometry catalyst Me2Si(C5Me4)(tBuN)Ti(NMe2)2 was used in the catalytic reaction. Also, the addition of pyridine suppressed the racemization mostly. 

Hydroamination reactions of alkynes provide an alternate route to arylhydrazones that can be utilized in the Fischer indole synthesis. Treatment of arylhydrazine 99 with alkyne 100 in the presence of catalyst system comprised of titanium tetrachloride and /-butylamine afforded arylhydrazone intermediate 101 which underwent a Fischer cyclization to give 1,2,3-trisubstituted indole 102 as a single regioisomer <04TL9541>. A similar titanium-catalyzed hydroamination reaction was utilized to prepare tryptamine derivatives <04TL3123>. 

The formation of alkyne oligomers that are concomitantly formed in the hydroamination reactions catalyzed by the thorium complexes indicates that two possible different complexes can be considered as active, conceivably with inter-conversion causing the occurrence of the two parallel processes. The discernment between these two most probable mechanistic pathways to find the key organometallic intermediate, responsible for the hydroamination process, was achieved by kinetic and thermodynamic studies (Scheme 5). The first pathway proposed the insertion of an alkyne into a metal-imido (M=N) bond, as observed for early transition metal complexes [101]. The second pathway suggested the insertion of an alkyne into a metal-amido bond, as found in some lanthanide compounds [39, 58, 84, 85]... 

The hydroamination reaction is the addition of an N-H bond across the G=G or C=C bonds of an alkene or alkyne. This is a highly atom-economical method of preparing substituted amines that are attractive targets for organic synthesis and the pharmaceutical industry. Different homogeneous catalysts have been utilized for hydroamination reactions. However, the heterogeneous catalysts for this kind of reactions have received less attention. 

The Zn-Zn bonded complex [( -Cp )2Zn2] has been found to catalyse the inter-and intra-molecular hydroamination reactions of alkynes. Thus, alkyne PhC=CH reacted with 2,4,6-(Me)3CgH2NH2 to afford ketimine [2,4,6-(Me)3CgH2]N=C(Me)Ph in the presence of PhN+Me2H B(CgE5). ... 

The hydroamination of alkynes catalyzed by group 4 complexes were some of the first transition-metal-catalyzed hydroamination reactions. One example of these reactions is shown in Equation 16.84. The reactions only occur with hindered amines and are slow. Nevertheless, the reactions occur m high yield and, in the absence of air, the catalysts are stable indefinitely. An early intramolecular reaction catalyzed by CpTiClj to form a cyclic enamine is shown in Equation 16.85. Reactions with internal alkynes occur to form products with Markovnikov regiochemistry. ° As described in more detail below, tliese reactions occur by [2+2] additions of the alkyne to an intermediate metal-imido complex. 

The hydroamination of alkenes and alkynes has been of longstanding interest in organometallic chemistry [26]. Much of the early work in this area focused on early transition metal or lanthanide metal catalyst systems. However, much recent progress has been made in late-metal catalyzed hydroamination chemistry, and several interesting hydroamination reactions that afford nitrogen heterocycles have been developed using palladium catalysts. 

Palladium-catalyzed intramolecular hydroamination reactions of alkynes that afford pyrrolidine derivatives were initially reported by Yamamoto in 1998 [27] and have been the subject of detailed investigation over the past ten years [28]. In a... 

Although Pd-catalyzed intramolecular hydroamination reactions of alkynes have been known for ten years, analogous transformations of unactivated alkenes have only recently been developed [33]. Key to the success of these studies was the use of a cationic palladium complex bearing a pyridine-derived P-N-P pincer ligand (29). For example, treatment of 26 with catalytic amounts of 29, AgB F4, and Cu(OTf)2 led to the formation of pyrrolidine 27 in 88% yield with 4 1 dr (Eq. (1.13)). Detailed mechamstic studies have indicated these transformations proceed via alkene coordination to the metal complex followed by outer-sphere aminopaUadation to provide 28. Protonolysis ofthe metal-carbon bond with acid generated in situ leads to formation of the product with regeneration of the active catalyst. 

Recently, transition metal-catalyzed hydroamination reaction of alkynes with hydrazines was used to generate aryl hydrazones, highly reactive and versatile intermediates in a subsequent metal-catalyzed Fischer indole synthesis. Thus, Odom first reported a 3 + 2 synthesis of 1,7-fused, di-, and tri-substituted indoles 285 featuring the Ti(IV)-catalyzed hydroamination of various alkynes 283 with... 

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. 

I 75 Transition-Metal-Catalyzed Hydroamination Reactions Table 15.4 Group 4 metal-catalyzed intermolecular hydroamination of terminal alkynes. 

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