Strategic atom replacement enables regiocontrol in pyrazole alkylation.

Abstract

Pyrazoles are heterocycles commonly found as key substructures in agrochemicals and medicinally active compounds alike^1,2. Despite their pervasiveness, established methods fall notably short in delivering complex pyrazoles selectively due to issues of differentiation during either assembly or N-functionalization³. This is a direct consequence of a dominant synthetic strategy that attempts to control selectivity-determining bonds between poorly differentiated starting materials. To overcome this longstanding challenge, we here describe a prototypical example of an alternative conceptual approach, 'strategic atom replacement', in which we synthesize N-alkyl pyrazoles from isothiazoles. The net forward transformation is a 'swap' of the isothiazole sulfur atom with a nitrogen atom and its associated alkyl fragment to deliver the alkylated pyrazole^4,5. Linking the two azoles is an orphaned heterocycle class, 1,2,3-thiadiazine-S-oxides, whose synthetic potential has yet to be tapped⁶. By proceeding through these unusual heterocycles, the typical selectivity and separation challenges associated with exclusively bond-based pyrazole preparations are circumvented, and even minimally differentiated peripheral substituents can be discriminated to afford isomerically pure products.