A General One-Pot Protocol for Hindered N-Alkyl Azaheterocycles from Tertiary Carboxylic Acids

Abstract

In this letter, we report a general one-pot strategy that utilizes three elementary steps (decarboxylative hydrazination, Boc deprotection, and heterocycle condensation) to regioselectively prepare hindered C(sp 3 ) substituted pyrazoles and triazoles. The operational simplicity of this sequence and ubiquity of tertiary carboxylic acids allow rapid access to hindered N-alkyl azaheterocycles that will be useful to practitioners of medicinal chemistry and agro-chemistry.

Decarboxylation‐Initiated Intermolecular Carbon‐Heteroatom Bond Formation

“…Alkyl radicals generated via photolytic decarboxylation of aliphatic carboxylic acids were shown to add to nitrogen‐heteroatom π‐bonds of nitrosoarenes [362] and azodicarboxylates, [363–367] permitting the synthesis of alkyl hydroxylamine and hydrazine derivatives, respectively (Scheme 84).…”

Decarboxylative N-Alkylation of Azoles through Visible-Light-Mediated Organophotoredox Catalysis

“…This approach enables the installation of various primary, secondary, and tertiary alkyl groups onto the nitrogen atom of nitrogen-based nucleophiles, including azoles. Although a few examples of tertiary alkylation were demonstrated, the scope of alkyl fragments was restricted . Against this background, Baran and co-workers expanded the synthetic toolbox by employing electrochemical generation of carbocations from aliphatic carboxylic acids to achieve N-alkylation of azoles (Scheme B) …”

The Direct Decarboxylative N-Alkylation of Azoles, Sulfonamides, Ureas, and Carbamates with Carboxylic Acids via Photoredox Catalysis

“…We were encouraged by recent work from Baran and co-workers wherein they utilized electrochemistry to generate carbocation intermediates from secondary and tertiary carboxylic acids which were then trapped by azoles (Figure D) . This precedent is a significant departure from all previous methods for decarboxylative N -alkylation because it relies on the inherent nucleophilicity and electrophilicity of the coupling partners to forge the C–N bond . However, there are a few inherent challenges with electrochemical procedures that have limited their adoption in the industrial setting relative to photoredox transformations .…”

“…18 This precedent is a significant departure from all previous methods for decarboxylative N-alkylation because it relies on the inherent nucleophilicity and electrophilicity of the coupling partners to forge the C−N bond. 19 However, there are a few inherent challenges with electrochemical procedures that have limited their adoption in the industrial setting relative to photoredox transformations. 20 Namely, the ability of photoredox catalysis to generate reactive intermediates (whether radical or carbocation) under mild conditions and greater familiarity with the photochemical reaction setup has led to broad adoption of photoredox-catalyzed transformations by many industrial organizations.…”