Expedited microwave-assisted N-alkylation of isatins utilizing DBU

Carly A Jordan,Krystyna B Wieczerzak,Kyle J Knisley,Daniel M Ketcha

doi:10.3998/ark.5550190.p008.205

Abstract

The N-alkylation of a variety of isatins with alkyl or benzylic halides can be effected under microwave irradiation in ethanol using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base. The conditions employed allow for the expedited synthesis of such substrates wherein the products precipitate from the reaction mixture in high yields and high purity after simple filtration. As will be described, microwave irradiation provides a relatively rapid means of effecting N-alkylations of isatin with a variety of benzylic halides, propargyl bromide and ethyl bromoacetate in times ranging from 10-25 min at 140 C in closed vials. This report involves the first reported use of DBU for this purpose, and in contrast to other methods, allows for the facilitated isolation of pure products while avoiding extractive or chromatographic purification steps.

Highlights

Increased attention is being devoted to exploiting the chemistry[1,2] and bioactivity[3] of the highly diversifiable isatin nucleus.[4,5] The “privileged”[6] nature of this scaffold and its central role as progenitor to other classes of biologically active heterocycles,[7,8] provides incentive for the development of expedient protocols for the embellishment of this core structure, especially in terms of N-alkylation.[9]
In devising highly efficient and rapid solution phase methodologies for the parallel preparation of diverse isatins, it was envisaged that the use of a soluble base under microwave conditions might constitute a useful expedient
Since it appeared that the N-alkylation of isatin had yet to be conducted under microwave irradiation using DBU, it was decided to examine the use of this basic catalyst in ethanol (EtOH) under microwave irradiation in a CEM Discover microwave (300 watts)

Summary

Introduction

Increased attention is being devoted to exploiting the chemistry[1,2] and bioactivity[3] of the highly diversifiable isatin nucleus.[4,5] The “privileged”[6] nature of this scaffold and its central role as progenitor to other classes of biologically active heterocycles,[7,8] provides incentive for the development of expedient protocols for the embellishment of this core structure, especially in terms of N-alkylation.[9].

Results

Conclusion