Citric acid Mediated One-pot Regioselective Synthesis of N-Alkylated Indazoles: An Efficient Green Strategy

Trivikram Reddy G,Venkatesh Mv,Reddy Bodireddy Mohan,Gangi Reddy Nc

doi:10.21767/2471-9889.100021

Abstract

Citric acid mediated green synthetic route has been demonstrated for the regioselective synthesis of N-alkylated indazoles in good to excellent isolated yields ( ~ 78-96%) from readily available starting materials 2-methylanilines (1), NaNO2 (2) and ethyl chloroacetate (3) via diazotization, intra molecular cyclization and followed by N-alkylation in the presence of 1:1 ratio of ethanol and water in one-pot. Notably, if the substrate (1) contains – NO2 group and is reduced to – NH2 in the presence of Fe, CaCl2 in the same pot at 60-65°C for 30-40 min. The remarkable advantages of this method include cleaner reaction profile, easy to perform, high yields of products and simple work-up procedure. Besides, the reaction is step-and atom-economic and is carried out in green catalytic medium.

Highlights

Heterocyclic ring systems are frequently found in numerousOne-pot Regioselective Synthesis of N-Alkylated Indazoles: An Efficient Green Strategy
We demonstrated a biodegradable citric acid mediated green synthetic route for the regioselective synthesis of N-alkylated indazoles in good to excellent isolated yields ( ~ 7896%) from readily available starting materials 2-methylanilines (1), NaNO2 (2) and ethyl chloroacetate (3) via diazotization, intra molecular cyclization and followed by N-alkylation in the presence of 1:1 ratio of ethanol and water in a single step operation
The construction of 1H-indazole followed by N-alkylation involved in the present process which is carried out in the presence of various biodegradable α-hydroxy acidic catalysts such as malic acid, mandelic acid, tartaric acid and citric acid (1.0 equivalent) in water for about 150 min

Summary

Introduction

Heterocyclic ring systems are frequently found in numerousOne-pot Regioselective Synthesis of N-Alkylated Indazoles: An Efficient Green Strategy. Derivatives/diazo compounds/hydrazones [23,24], condensation of hydrazine to o-halo/o-alkoxy arylhydrazone [25,26]. In addition to the above methods, other intra molecular cyclizations are reported for the synthesis of indazole derivatives, for example Pd-mediated ring closure of hydrazine and hydrazone based derivatives [27,28], copper catalyzed intramolecular amination of o-haloarylcarbonyl compounds/2-halobenzohydrazides [29,30], CuI promoted cyclization of an aryl hydrazone under microwave irradiation [31], FeBr3/O2-mediated intramolecular C-H amination of arylhydrazones [32], PIFA-mediated oxidative cyclization of o-amidobenzanilides [33], Rhodium-catalyzed cyclocarbonylation of azobenzenes [34], Zinc catalyzed reductive

Methods

Results

Conclusion