Mannich cyanation

S)-proline-catalyzed reactions using unmodified aldehydes as nucleophiles retain the aldehyde group, and the aldehyde group of the products can be used for further transformations in the same reaction vessel. For example, one-pot Mannich-oxime formation [71b], Mannich-allylation [71c], and Mannich-cyanation [80] reactions have been demonstrated (Scheme 2.18). Mannich-type reaction products that possess an aldehyde functionality are easily epimerized during work-up and silica gel column purification. In the one-pot Mannich-cyanation reaction sequence, the cyanohydrin was obtained without epimerization at the a-position of the original aldehyde Mannich products. Thus, this one-pot sequence minimizes potential epimerization of the Mannich products. 

Scheme 2.18 One-pot Mannich-oxime formation [71b], Mannich-allylation [71c], and Mannich-cyanation [80] reactions.

Bifunctional thiourea-catalysed enantioselective Michael reaction has been achieved. The thiourea moiety and an amino group of the catalyst activated a nitroolefin and a 1,3-dicarbonyl compound, respectively afford the Michael adduct with high enantioselectivity.177,178 Thioureas work as one of the most effective and general enantioselective nitro-Mannich reaction and carbonyl cyanation catalyst.179,180... 

Extension of this reaction toward a one-pot asymmetric Mannich-hydrocyanation reaction sequence was also reported by the Barbas group [29]. In this one-pot two-step process proline-catalyzed asymmetric Mannich reaction of unmodified aldehydes with the a-imino glyoxylate was performed first, then diastereoselective in situ cyanation. The resulting /i-cyanohydroxymethyl a-amino acids were obtained with high enantioselectivity (93-99% ee) [29]. Another one-pot two-step reaction developed by Barbas et al. is the Mannich-allylation reaction in which the proline-catalyzed Mannich reaction is combined with an indium-promoted allylation [30], This one-pot synthesis was conducted in aqueous media and is the first example of a direct organocatalytic Mannich reaction in aqueous media [28, 30]. 

The corresponding /i-amino aldehydes are reduced in situ and the corresponding amino alcohols are isolated in good yield with up to >99 % ee. The Mannich reactions proceed with excellent chemoselectivity and inline formation occurs with the acceptor aldehyde at a faster rate than C-C bond-formation. Moreover, the one-pot three-component direct asymmetric cross-Mannich reaction enables aliphatic aldehydes to serve as acceptors. The absolute stereochemistry of the reaction was determined by synthesis and reveled that L-proline provides syn /i-amino aldehydes with (S) stereochemistry of the amino group. In addition, the proline-catalyzed direct asymmetric Mannich-type reaction has been connected to one-pot tandem cyanation and allylation reaction in THF and aqueous media affording functional a-amino acid derivatives [39, 42]. 

Alder, cyanation, allylation, Michael reaction, and Friedel-Crafts acylation). The same catalyst was also effective in three-component reactions such as Mannich-type reactions, Strecker, and quinoline-forming reactions. The polymer catalyst was recovered and reused many times without loss of activity (Eq. 31). 

Diformylbenzene (61) was allowed to react with the bis-Mannich base (62) of 1,4-diacetylbenzene. The reaction was carried out in DMF in the presence of a catalytic amount of sodium cyanate. 

---