Synthesis of a-amino nitrile

The asymmetric Strecker synthesis of a-amino nitriles from Schiff bases of a-methylbenzyl-aminc is improved by the use of trimethylsilyl cyanide, instead of hydrogen cyanide and by promotion of the transformation with a Lewis acid, preferably zinc chloride43. Thus, from the butyraldimine 2, the amino nitrile is synthesized with a yield of 98.5% and an ee of 68.5%. 

Strecker reactions provide one of the most efficient methods for the synthesis of a-amino nitriles, which are useful intermediates in the synthesis of amino acids and nitrogen-containing heterocycles. Although classical Strecker reactions have some limitations, use of trimethylsilyl cyanide (TMSCN) as a cyano anion source provides promising and safer routes to these compounds.133-351 Consequently, we focused our attention on tributyltin cyanide (Bu3SnCN), because Bu3SnCN is stable in water and is also a potential cyano anion source. Indeed, the Strecker-type reactions of aldehydes, amines, and Bu3SnCN proceeded smoothly in water (Eq. 9).1361 It should be noted that no surfactants are required in this reaction. Furthermore, Complete recovery of the toxic tin compounds is also possible in the form of bis(tributyltin) oxide after the reaction is over. Since conversion of bis(tributyltin) oxide to tributyltin cyanide is known in the literature, this procedure provides a solution to the problem associated with toxicity of tin compounds. 

S. Kobayashi, H. Ishitani, M Ueno, Facile Synthesis of a-Amino Nitriles Using Lanthanide Triflate as a Lewis Acid Catalyst Synlett. 1997,115-116. 

Corey, E. J. Grogan, M. J. Enantioselective Synthesis of a-Amino Nitriles from N-Benzhydryl Imines and HCN with a Chiral Bicyclic Guanidine as Catalyst Org Lett. 1999,1,157-160. 

Scheme 4.19 Asymmetric Strecker-type synthesis of a-amino nitriles.

S. Czemecki and J.-M. Valery, Stereochemical studies of the synthesis of a-amino-nitriles... 

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. 

For example, N-(2-hydroxyphenyl)imines 9 (R = alkyl, aryl) together with chiral zirconium catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [17], the diastereo- and/or enantioselective synthesis of homoallylic amines [18], the enantioselective synthesis of simple //-amino acid derivatives [19], the diastereo- and enantioselective preparation of a-hydroxy-//-amino acid derivatives [20] or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans, a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10)... 

Another application of high pressure in combinatorial chemistry has been reported by Matsumoto and Jenner. For the first time, uncatalysed, high-pressure (0.6 GPa) three-component Strecker synthesis of a-amino nitriles 202 was carried out in high yields by reacting aniline (200) with various ketones 201... 

Kunz H, Sager W (1987) Diastereoselective Strecker synthesis of a-amino nitriles in carbohydrate matrixes. Angew Chem 99 595-597, Angew Chem hit Ed Engl 26 557... 

Inspired by the work of Inoue, Lipton and coworkers replaced the imidazole side chain of t icZo-peptide 50, which was efficient as catalyst in cyanohydrin synthesis from aldehydes (Scheme 13.29), with a more basic guanidine moiety in order to afford a catalyst capable of accelerating proton transfer in the Strecker reaction. The modified catalyst 52 was found to be effective in the synthesis of a-amino nitriles with very high yields from aromatic and aliphatic M-benzhydiyl imines, giving enantioselectivities of up to 99% (Scheme 13.30). ... 

The Strecker reaction is one of the most atom-economical and practical carbon-carbon bond-forming reactions for the synthesis of a-amino nitriles, which can be readily transformed to a-amino acid derivatives. As a consequence of the huge demand for optically active a-amino acids, considerable effort has been devoted to the development of catalytic and... 

Most of the elementary reactions in the classic MCRs are equilibrium processes. Therefore, thermodynamic factors can significantly impact the reaction pathways in addition to the reaction kinetics. A classic example is the Strecker synthesis of a-amino nitrile 9 from aldehydes, amines, and cyanide (Scheme 15.5). The key step in this reaction is the nucleophilic addition of cyanide to the in situ formed iminium. However, condensation of a carbonyl compound with an amine leading to iminium is an equilibrium process, especially under aqueous conditions. Therefore, the desired addition reaction is in competition with direct addition of cyanide to the aldehyde, leading to cyanohydrin 10. However, since the formation of both 9 and 10 were reversible, only the more stable adduct 9 was produced at the expense of cyanohydrin 10 under thermodynamically controlled conditions. 

First of all, two examples of the change in selectivity of catalytic reactions performed in "silent" or ultrasound conditions should be recalled (for a discussion, see Ch. 4, p. 145). The classical paper by Ando 2 refers to the reaction between benzyl bromide and potassium cyanide on alumina in toluene. In the sonochemical reaction, the main product is benzyl cyanide, while in a silent condition it is the Friedel-Craft adduct. When the Strecker synthesis of a-amino nitriles from an aldehyde, potassium cyanide, and an amine in acetonitrile is performed with alumina and ultrasound, the main product (selectivity = 90%) is the a-amino nitrile. In the same conditions, except for the absence of ultrasoimd, the selectivity for the same product is only 64%. If ultrasound is used without alumina, the selectivity is 23%, and 6% if only stirring is used. 

For other example, see J. Wang, Y. Masni, M. Onaka, Eur. J. Org. Chem. 2010, 1763-1771. Synthesis of a-amino nitriles from carbonyl componnds, amines, and trimethylsUyl cyanide comparison between catalyst-free conditions and the presence of tin ion-exchanged montmoriUonite. 

R. A. Kumar, P. Thirupathi, Helv. Chim. Acta 2007, 90, 1206-1210. One-Pot three-component synthesis of a-amino nitriles catalyzed by 2,4,6-trichloro-l,3,5-triazine (cyanuric acid), (c)... 

Hajipour, A. R., Ghayeb, Y., and Sheikhan, N. (2010). Zr(HS04)4 catalyzed one-pot Strecker synthesis of a-amino nitriles from aldehydes and ketones under solvent-liee conditions. J. Iran. 

Baghbanian, S. M., Farhang, M., and Baharfar, R. (2011). One-pot three-componrait synthesis of a-amino nitriles catalyzed by nano powder Ti02 P 25. Chin. Chem. Lett., 22, 555 558. 

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