Send Orders for Reprints to reprints@benthamscience.net Current Organocatalysis, 2014, 1, 87-106 87 Organocatalysed Cyanations of Carbonyl Compounds Dina Murtinho and Maria Elisa da Silva Serra* Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, Coimbra 3004-535, Portugal Abstract: One of the most important carbon-carbon bond forming reactions in organic synthesis is the cyanation of car- bonyl compounds. The resulting cyanohydrins are key building blocks for many other important compounds, namely, α- hydroxy acids, α-hydroxy ketones, primary and secondary β-hydroxy amines, α-hydroxy esters and α-amino acids, which are essential in areas such as fine chemistry, agrochemicals and pharmaceuticals. Cyanohydrin synthesis can be catalyzed by enzymes, metal complexes, inorganic and organic compounds. The initial synthetic methods have been extensively ex- plored however the organocatalyzed reaction has been referred to in more limited extent. In this paper we will review the cyanation of aldehydes and ketones in the presence of organocatalysts, addressing both the formation of racemic and non- racemic cyanohydrins. Keywords: Aldehydes, asymmetric, benzaldehyde, cyanation, cyanohydrin, ethylcyanoformate, ketones, organocatalysts, trimethylsilylcyanide, trimethylsilylcyanohydrins. 1. INTRODUCTION The cyanation of aldehydes and ketones constitutes one of the fundamental carbon-carbon bond forming reactions in organic synthesis [1]. The asymmetric version of these reac- tions is of particular interest since chiral cyanohydrins and aminonitriles are precursors of other important compounds, namely, α-hydroxy acids, α-hydroxy ketones, primary and secondary β-hydroxy amines, α-hydroxy esters and α-amino acids, among others, (Scheme 1) [2, 3]. O R 1 R 2 CN OH R 1 R 2 OH R 1 R 2 OH O OH R 1 R 2 OR 3 O O R 2 OH NH 2 R 1 R 2 OH O OH R 1 R 2 NH 2 organocatalyst X CN Scheme 1. *Address correspondence to this author at the Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, 3004-535 Coimbra, Portugal; Tel: 00351239854480; Fax: 00351239827703; E-mail: melisa@ci.uc.pt The majority of the synthetic methods used for the prepa- ration of cyanohydrins involve the addition of cyanide to a carbonyl compound in the presence of Lewis acids, Lewis bases, metal alkoxides, bifunctional compounds and inor- ganic salts as catalysts. The existing literature describing these methods is extensive and has been the object of many reviews [1-5]. However, the use of organocatalysts for the cyanation of carbonyl compounds has only been referred to in a limited extent. Accordingly, this review will focus on the cyanation of aldehydes and ketones in the presence of organocatalysts, addressing both the formation of racemic and non-racemic cyanohydrins. 2. CHIRAL ORGANOCATALYSTS 2.1. Cyclopeptides Classically, the preparation of chiral cyanohydrins was achieved by using enzymes as catalysts. In an attempt to mimic these processes chiral peptides have been used to catalyse the cyanation reaction. The first asymmetric synthe- sis of this type, catalysed by a cyclic peptide, was reported by Inoue and co-workers in 1979 [6]. Although, the ee ob- tained for the addition of hydrogen cyanide to benzaldehyde was low (<10%), it was possible to conclude that the cyclic peptides originated products with higher ee than linear pep- tides, as a consequence of presenting a more rigid structure. Later on, Inoue’s group reported the use of cyclo[(S)- phenylalanyl-(S)-histidyl] (1) and other cyclic dipeptides for the cyanation of benzaldehyde [7, 8], aliphatic aldehydes [9], transcyanohydrination [10] and several substituted benzalde- hydes [11]. The best result, 90% ee, was obtained for the cyanation of benzaldehyde with 2 mol% of 1, using HCN as cyanide source. Using optimized conditions, 2 equiv of HCN, 2 mol% of catalyst, toluene as solvent (instead of benzene) and lower- ing the reaction temperature to -20°C, benzaldehyde was cyanated in 97% yield and 97% ee. Extending the scope of 2213-3380/14 $58.00+.00 © 2014 Bentham Science Publishers