Scope and limitations of the TiCl 4 ‐mediated additions of isocyanides to aldehydes and ketones with formation of α‐hydroxycarboxylic acid amides

The adducts obtained from TiCl 4 and achiral ( 8 – 12 ) or chiral, nonracemic ( 13 – 22 ) isocyanides are combined with aldehydes (aromatic or aliphatic) and ketones (acetone, cyclohexanone, acetophenone) to give, after aqueous workup, α‐hydroxyamides ( 27 – 55 ) [Passerini‐type reaction]. The transformation is compatible with a variety of functional groups (aromatic and heterocyclic rings, amino, ether, ester, and amido groups, halides, and phosphonate substituents). The yields range from 14 to over 95% (with the lower values in the case of more highly functionalised isocyanides). No diastereoselectivity is observed with chiral isocyanides. If the R groups of the isocyanide (RNC) form a rather stable cation ( t ‐alkyl or benzylic), cyanohydrins may result from the reaction, rather than the N ‐substituted α‐hydroxyamides (see Scheme 2).