Selective N2-Alkylation of 1H-Indazoles and 1H-Azaindazoles

Abstract

A general and selective procedure for the N2-alkylation of 1H-indazoles and 1H-azaindazoles is presented. Promoted by either trifluoromethanesulfonic acid or copper(II) triflate, diverse 1H-indazoles/azaindazoles are selectively alkylated with varied primary, secondary, and tertiary alkyl 2,2,2-trichloroacetimidates at the N2-nitrogen to afford the corresponding 2-alkyl-2H-indazoles/azaindazoles. Forty-one examples are included along with a discussion of reaction optimization, scope, and mechanism.

Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir

“…With a scalable assembly method of indazole 16 in hand, the subsequent N -methylation was examined (Scheme C, top). Using trimethyloxonium tetrafluoroborate (Me 3 O·BF 4 , known as Meerwein’s reagent) gave the best result compared with other methylation reagents, such as methyl iodide, dimethyl sulfate, dimethyl carbonate, and methyl 2,2,2-trichloroacetimidate. , The present reaction conditions using Me 3 O·BF 4 could suppress the generation of side-products 19 and 20 to an acceptable level. It has been reported that the regioselectivity between two nitrogen atoms on the indazole depends on the nature of the alkylating reagents .…”