Copper-Catalyzed Cross-Coupling of Benzylic C–H Bonds and Azoles with Controlled N-Site Selectivity

Abstract

Azoles are important motifs in medicinal chemistry, and elaboration of their structures via direct N−H/C−H coupling could have broad utility in drug discovery. The ambident reactivity of many azoles, however, presents significant selectivity challenges. Here, we report a copper-catalyzed method that achieves site-selective cross-coupling of pyrazoles and other N−H heterocycles with substrates bearing (hetero)benzylic C−H bonds. Excellent N-site selectivity is achieved, with the preferred site controlled by the identity of co-catalytic additives. This cross-coupling strategy features broad scope for both the N−H heterocycle and benzylic C−H coupling partners, enabling application of this method to complex molecule synthesis and medicinal chemistry.

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

“…However, this regioselectivity is opposite to that obtained when copper catalysis is employed for N -alkylation via a reductive elimination mechanism, highlighting the complementarity of this decarboxylative protocol . We attribute the observed regioselectivity for exclusive N 2 -alkylation to be due to formation of the kinetic product, which would be favored under our proposed S N 1-type reaction pathway . Notably, the transformation also tolerated more highly nitrogenated heteroarenes, such as purine and xanthine systems, which have significant relevance to the pharmaceutical industry ( 34 – 36 , 46–76% yield).…”

“…13 We attribute the observed regioselectivity for exclusive N 2 -alkylation to be due to formation of the kinetic product, which would be favored under our proposed S N 1-type reaction pathway. 24 Notably, the transformation also tolerated more highly nitrogenated heteroarenes, such as purine and xanthine systems, which have significant relevance to the pharmaceutical industry (34− 36, 46−76% yield).…”

Recent Advances in Non-Precious Metal Catalysis

“…Stahl's group reported a notable protocol of Cu-catalyzed C−N cross couplings between benzylic C−H bonds and azoles with controlled N-site selectivity. 40 With TBACl as an additive, kinetic products with N 2 regioselectivity were predominantly formed. However, if a Lewis acid (such as TMSOTf or BF 3 • OEt 2 ) was employed instead of TBACl, the thermodynamically favored N 1 regioselective product was observed as the major species (Scheme 28).…”

Cu-Catalyzed C(sp3)–N Coupling and Alkene Carboamination Enabled by Ligand-Promoted Selective Hydrazine Transfer to Alkyl Radicals

“…Normally, the amination of alkyl radicals under Cu catalysis could be categorized into three major types: (1) conjugated radicals underwent facile 1e-oxidation by Cu II to afford stabilized carbocations, which would then capture an N-nucleophile to form the C–N bond (Scheme a). Such processes were usually seen in the difunctionalization of styrenyl alkenes , and oxidative amination of benzylic C–H bonds . (2) For radicals that were less easily oxidized, Cu III species was often proposed to form by capturing the radical, and the C–N bonds were made through reductive elimination, ,− , although other ambiguous Cu II pathways have also been envisioned − (Scheme b).…”