A New and Efficient Access to Thiazoline-4-carboxylates and Cysteine Derivatives Incorporating Cyclopropyl Groups

Abstract

Under basic conditions (NaHCO3, MeCN), thiocarboxamides 2, including N,N-thioureas, cleanly undergo Michael addition onto 2-chloro-2-cyclopropylideneacetates 1, attacking through the sulfur, and this is followed by an intramolecular substitution to afford 5-spirocyclopropane-annelated thiazoline-4-carboxylates 4 in 37−92% yields. The thiazolines 4 are cysteine derivatives that possess a cyclopropyl or substituted cyclopropyl group in place of the gem-dimethyl-substituted β-carbon atom of penicillamine; they can be hydrolyzed to the hydrochloride salt of the amino acid 5 by heating in acid. Under acidic conditions (CH2Cl2, HCl), the Michael adducts 7 of thioamides 2 onto 1 are formed in high to virtually quantitative yields. When treated with NaHCO3 in MeCN, the adducts 7 cyclize to thiazolinecarboxylates 4 (51−82%), but in the presence of Ti(OiPr)4 they form spirocyclopropane-annelated thiazinones 8 (19−88%).