Chemoenzymatic Preparation of 1-Heteroarylethanamines of Low Solubility

Both enantiomers of biologically and pharmaceutically interesting benzofuran‐, benzothiophen‐, and phenylfuran‐based 1‐heteroarylethanamines were prepared at close to theoretical yields by using Candida antarctica lipase B (Novozym 435) catalyzed (R)‐selective N‐acylation with isopropyl butanoate (enantiomeric ratio E > 200). The use of N‐methyl‐2‐pyrrolidinone (NMP) as a cosolvent (1:30) in isopropyl butanoate solved the problem of low solubility of the compounds. Instability of the heterocyclic ring systems against traditional acid‐ and base‐catalyzed hydrolysis was solved by using Candida antarctica lipase A as a commercial CAL‐A‐CLEA preparation for deprotection of the N‐acylated (R) enantiomers in water. The slow, highly enantioselective (E > 200) hydrolyses of racemic butanamides was also observed in the presence of Novozym 435. Both enantiomers of seven 1‐heteroarylethanamines were prepared by starting from the ketones. Enantiopurity was introduced by Candida antarctica lipase B catalyzed (R)‐selective N‐acylation. Low solubility issues were solved by the use of N‐methylpyrrolidine as a cosolvent. (R)‐Butanamides were deprotected by Candida antarctica lipase A catalyzed hydrolysis in water, to yield the (R)‐amines.