Metal- and Catalyst-Free, Formal [4 + 1] Annulation via Tandem CO/CS Functionalization: One-Pot Access to 3,5-Disubstituted/Annulated Isothiazoles

An
operationally simple and user-friendly new protocol for the
synthesis of 3,5-disubstituted/annulated isothiazoles is devised utilizing
β-ketodithioesters/β-ketothioamides and NH4OAc via CO/CS bond functionalization under metal-
and catalyst-free conditions. The strategic [4 + 1] annulation initiated
by NH4OAc is carbon-economic and relies on a sequential
imine formation/cyclization/aerial oxidation cascade forming consecutive
C–N and S–N bonds in one pot. A wide range of previously
inaccessible and synthetically challenging isothiazoles are compatible
with this transformation under nontoxic conditions with excellent
functional group tolerance. The products bear useful synthetic handles
for further functionalization.