Cyanation of Imines Strecker Reaction

The combination of Me2AlCN and BINOL 97 (1.2 equiv) also induced the cyana-tion of imines derived from benzaldehyde, affording the Strecker products in up to 70% ee [94]. Finally, N-allylbenzaldimines have been reported to react with HCN in the presence of chiral ammonium salt catalysts [95, 96]. 

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One of the most important approaches to a-amino acids is based on the Strecker reaction. Although there are already a number of catalytic asymmetric variants, the cyanation of imines still challenges modem organic chemists. 

The cyanation of imines, generally known as the Strecker reaction, has been one of the most aggressively studied transformations of asymmetric catalysis over the past several years. Very recent efforts in this area have resulted in the discovery of several highly efficient catalytic systems capable of providing a-ami-... 

The potential substrates for the Strecker reaction fall into two categories ald-imines (derived from aldehydes, for which cyanide addition results in formation of a tertiary stereocenter) and ketoimines (derived from ketones, for which addition results in a quaternary stereocenter). As in the case of carbonyl cyanation, significant differences are observed between the substrate subclasses. To date, while a few catalyst systems have been found to display broad substrate scope with respect to aldimine substrates, successful Strecker reactions of ketoimines have been reported in only two cases. As is the case for all asymmetric catalytic methodologies, the breadth of the substrate scope constitutes a crucial criterion for the application of the Strecker reaction to a previously unexplored substrate. 

The catalytic asymmetric cyanation of imines-the Strecker reaction-represents one of the most direct and viable methods for the asymmetric synthesis of a-amino... 

Furthermore, Rueping and coworkers applied their reaction conditions to the cyanation of ketimines [54]. The use of A-benzylated imines derived from aryl-methyl ketones generally gave comparable yields, but lower enantioselectivities. However, this method furnished Strecker products bearing a quaternary stereogenic center, which are valuable intermediates for the preparation of optically active a,a-disubstituted a-amino acids. 

The Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

Strecker reactions are among the most efficient methods of synthesis of a-amino nitriles, useful intermediates in the synthesis of amino acids [73] and nitrogen-containing heterocycles such as thiadiazoles, imidazoles, etc. [74]. Although classical Strecker reactions have some limitations, use of trimethylsilyl cyanide (TMSCN) as a source of cyano anion provides promising and safer routes to these compounds [73b,75]. TMSCN is, however, readily hydrolyzed in the presence of water, and it is necessary to perform the reactions under strictly anhydrous conditions. BusSnCN [76], on the other hand, is stable in water and a potential source of cyano anion, and it has been found that Strecker-type reactions of aldehydes, amines, and BuaSnCN proceed smoothly in the presence of a catalytic amoimt of Sc(OTf)3 in water [77]. No surfactant was needed in this reaction. The reaction was assumed to proceed via imine formation and successive cyanation (it was confirmed that imine formation was much faster than cyanohydrin ether formation under these reaction conditions) again the dehydration process (imine formation) proceeded smoothly in water. 

Strecker reaction to establish a new stereocenter is subject to asymmetric induction, capable of creating either a tertiary" or quaternary carbon atom in the presence of 59. The peptido-imine 60 proves to be an excellent ligand for the Ti(IV)-mediated cyanation of aldimines. On catalysis of the bicyclic guanidine 61 the addition of HCN to A-benzhydrylaldimines affords a-amino nitrile derivatives with moderate to good ee. ... 

Discovered in the middle of the 19th century, the Strecker reaction is one of the earliest atom-economic multicomponent reactions. Amino nitriles were simply obtained from ammonia, hydrogen cyanide and an aldehyde. These products are important intermediates for the synthesis of natural and unnatural a-aminoacids. Due to the ever-increased demand for enantioenri-chied a-aminoacids, the asymmetric Strecker reaction has emerged as a viable synthetic method. Since the first report published in 1996, the catalytic enantioselective cyanation of preformed imines was intensively studied and several excellent reviews were devoted to this topic. ... 

Recent developments in the catalytic asymmetric cyanation of ketimines. (c) T. Vilaivan, W. Bhanthumnauin, Y. Sritana-Anant, Curr. Org. Chem. 2005, 9, 1315-1392. Recent advances in catalytic asymmetric addition to imines and related C=N systems, (d) S. J. Connon, Angew. Chem. Int. Ed. 2008,47,1176-1178. The catalytic asymmetric Strecker reaction ketimines continue to join the fold. 

Strecker reaction A robust heterogeneous self-supported chiral titanium cluster (SCTC) catalyst applied both in batch and continuous mode [44] enabled imine cyanation as well as a three-component Strecker reaction using the corresponding aldehydes and amines under continuous flow conditions in a PBR giving aminonitriles enantiomeric excess values of up to 98%. 

Using a-unbranched aldimines for the asymmetric Strecker reaction under PTC, somewhat lower ee s and yields were obtained than with branched analogues. These results can be ascribed to the partial imine hydrolysis and uncatalyzed cyanation of primary and secondary aldimines under PTC [44]. Therefore, N-arylsulfonyl a-amido sulfones 78 were employed for in situ generation of the imines species (Table 30.9). With catalyst 76, generally higher yields and higher enantioselectivities were obtained for various primary and secondary aliphatic N-arylsulfonyl a-amido sulfones 78. 

Asymmetric phase-transfer catalytic addition of cyanide to C=N, C=0, and C=C bonds has been recently explored, which has been demonstrated to be an efficient method toward the synthesis of a series of substituted chiral nitriles. In this context, Maraoka and coworkers disclosed an enantioselective Strecker reaction of aldimines by using aqueous KCN [140]. In this system, the chiral quaternary ammonium salts (R)-36e bearing a tetranaphthyl backbone were found to be remarkably efficient catalysts (Scheme 12.25). Subsequently, this phase-transfer-catalyzed asymmetric Strecker reaction was further elaborated by use of a-amidosulfones as precursor of N-arylsulfonyl imines. Interestingly, the reaction could be conducted with a slight excess of potassium cyanide [141] or acetone cyanohydrin [40] as cyanide source, and good to high enantioselectivities were observed. In contrast, the asymmetric phase-transfer-catalytic cyanation of aldehydes led to the cyanation products with only moderate enantioselectivity [142]. 

Strecker-type reaction of TMS cyanide with chiral sulfinimines gives diastereoselective cyanations at the imine carbon, at —78 °C in DMF, using simple metal-free Lewis base catalysts such as tetraalkylammonium carboxylates.73... 

Kobayashi et al. disclosed reversed chemoselectivity of lanthanide Lewis acid over conventional Lewis acid in cyanation reaction. The comparitive reaction was performed with equimolar mixture of aldehydes, imines, and TMSCN, affording Strecker-type product exclusively with 20mol% of Yb(OTf)3 [10]. In sharp contrast, SnCU required more than a stoichiometric amount of reagent and gave cyanohydrin preferentially (Table 13.15). 

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