An efficient and operationally convenient general synthesis of tertiary amines by direct alkylation of secondary amines with alkyl halides in the presence of Huenig’s base

Jason L Moore,Vadim A Soloshonok,Stephen M Taylor,Paul Krapcho

doi:10.3998/ark.5550190.0006.624

Jason L Moore, Vadim A Soloshonok + Show 2 more

Open Access

https://doi.org/10.3998/ark.5550190.0006.624

Copy DOI

Abstract

A general method for the direct formation of tertiary amines via direct N-alkylation of secondary amines by alkyl halides in acetonitrile in the presence of Hunig’s base is reported. In contrast to methods previously reported in the literature, this procedure is highly functional group tolerant and employs operationally convenient conditions in the absence of transition metal catalysts or solid supports and without formation of the undesired quaternary ammonium salt.

Highlights

Amines are one of the most common structural features of naturally occurring biologically active compounds and are widely used throughout the chemical industry as basic intermediates to prepare fine chemicals, pharmaceuticals, and agrochemicals.[1]
From a methodological standpoint the direct alkylation of secondary amines with alkyl halides is the most straight-forward method for the synthesis of tertiary amines.[3]. This method on a practical basis has been somewhat limited since direct N-alkylation of secondary amines often results in the formation of the quaternary ammonium salts and a mixture of the desired tertiary amine and the starting secondary amine.[3,4,5]
In an attempt to address some of these issues, Varma et al, recently reported a method for the direct formation of unfunctionalized tertiary amines via N-alkylation of primary or secondary amines by alkyl halides in aqueous media using microwave irradiation.[4]

Summary

Introduction

Amines are one of the most common structural features of naturally occurring biologically active compounds and are widely used throughout the chemical industry as basic intermediates to prepare fine chemicals, pharmaceuticals, and agrochemicals.[1]. The synthetic route we envisioned for preparation of these compounds included a two step alkylation of primary amine 2 with alkyl halide 1 through intermediate secondary amine 3. Attempts to apply the literature methods for the direct synthesis of tertiary amines utilizing our highly functionalized alkyl halides and secondary amines were unsuccessful.

Results

Conclusion