Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

Abstract

Herein, we report a pair of regioselective N1- and N2-alkylations of a versatile indazole, methyl 5-bromo-1H-indazole-3-carboxylate (6) and the use of density functional theory (DFT) to evaluate their mechanisms. Over thirty N1- and N2-alkylated products were isolated in over 90% yield regardless of the conditions. DFT calculations suggest a chelation mechanism produces the N1-substituted products when cesium is present and other non-covalent interactions (NCIs) drive the N2-product formation. Methyl 1H-indazole-7-carboxylate (18) and 1H-indazole-3-carbonitrile (21) were also subjected to the reaction conditions and their mechanisms were evaluated. The N1- and N2-partial charges and Fukui indices were calculated for compounds 6, 18, and 21 via natural bond orbital (NBO) analyses which further support the suggested reaction pathways.

Keywords

• dft
• indazole
• indazole substitution
• mechanism
• n1-substituted indazole
• n2-substituted indazole
• regioselectivity