Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

Lukáš Marek; Jiří Váňa; Jan Svoboda; Jiří Hanusek

doi:10.3762/bjoc.19.61

Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

Beilstein J Org Chem. 2023 Jun 9:19:808-819. doi: 10.3762/bjoc.19.61. eCollection 2023.

Authors

Lukáš Marek¹, Jiří Váňa¹, Jan Svoboda¹, Jiří Hanusek¹

Affiliation

¹ Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, CZ532 10 Pardubice, Czech Republic.

Abstract

Reactions of thiobenzamide or thioacetamide with 4-bromo-1,1-dimethyl-1,4-dihydroisoquinoline-3(2H)-one, 4-bromoisoquinoline-1,3(2H,4H)-dione and two α-bromo(phenyl)acetamides were examined under various conditions (base, solvent, thiophile, temperature) and structure/medium features that influence product distribution (Eschenmoser coupling reaction, Hantzsch thiazole synthesis and elimination to nitriles) were identified. The key factor that enables the successful Eschenmoser coupling reaction involves the optimum balance in acidity of nitrogen and carbon atoms of the intermediary α-thioiminium salts.

Keywords: Eschenmoser coupling reaction; Hantzsch thiazole synthesis; isoquinolin-4-ones; primary thioamides; structure–reactivity relationships.