Acid and base catalyzed Davis–Beirut reaction: experimental and theoretical mechanistic studies and synthesis of novel 3-amino-2H-indazoles

Abstract

The Davis-Beirut reaction, which provides an efficient synthesis of 2H-indazoles and, subsequently, indazolones, is shown to proceed rapidly from o-nitrosobenzaldehyde and primary amines under both acid or base catalysis. Experimental and theoretical evidence in support of a reaction mechanism is provided in which o-nitrosobenzylidine imine is a pivotal intermediate in this N,N-bond forming heterocyclization reaction. The Davis-Beirut reaction is also shown to effectively synthesize a number of novel 3-amino-2H-indazole derivatives.

N–N Bond Formation between Primary Amines and Nitrosos: Direct Synthesis of 2-Substituted Indazolones with Mechanistic Insights

“…7 Reactive 2 is a reagent for 2 H -indazole synthesis, and its generation involves a straightforward photochemical transformation from o -nitrobenzyl alcohol 1 . 8 That said, practical applications of 2 are limited because of poor bench stability; i.e., it is prone to air oxidation to o -nitrobenzoic acid. 9 Recently, we discovered that base treatment can deprotect o -nitrobenzyl compounds, generating o -nitrosobenzaldehyde ( 2 ).…”

Synthesis of indazole motifs and their medicinal importance: An overview

“…The Davis-Beirut reaction shows the synthesis of 2H-indazoles from o-nitroso benzaldehyde and primary amines under both acid and base catalysis. This reaction synthesizes a number of novel 3-amino-2H-indazole derivatives (Scheme-51) [65]. Similarly 3-cyano-2H-indazole N-oxides has been synthesized it gives the trypanocidal and leishmanocidal activities of each derivative.…”

Copper(I) Complex of Dihydro Bis(2‐Mercapto Benzimidazolyl) Borate as an Efficient Homogeneous Catalyst for the Synthesis of 2H‐Indazoles and 5‐Substituted 1H‐Tetrazoles

“…[32][33][34][35][36][37][38][39][40][41] In recent years, literature reports in regards to enabling certain regioselective synthetic paths towards 2H-indazoles have appeared. [1,[42][43][44][45][46][47][48][49][50][51][52][53][54] A common way for the formation of highly regioselective 2H-indazoles is based on the intramolecular coupling of properly pre-functionalized substrates including 2halobenzaldehydes. [55][56][57][58][59][60] This eco-efficient one-pot approach includes consecutive CÀ N and NÀ N bonds formation with extrusion of N 2 to corresponding 2H-indazoles.…”