B(C6F5)3-Catalyzed Direct C3 Alkylation of Indoles and Oxindoles.

Shyam Basak,Laura Winfrey,Rebecca L Melen,Alexander P Pulis,Ana Alvarez-Montoya,Louis C Morrill

doi:10.1021/acscatal.0c01141

Abstract

The direct C3 alkylation of indoles and oxindoles is a challenging transformation, and only a few direct methods exist. Utilizing the underexplored ability of triaryl boranes to mediate the heterolytic cleavage of α-nitrogen C–H bonds in amines, we have developed a catalytic approach for the direct C3 alkylation of a wide range of indoles and oxindoles using amine-based alkylating agents. We also employed this borane-catalyzed strategy in an alkylation-ring opening cascade.

Highlights

The direct C3 alkylation of indoles and oxindoles is a challenging transformation, and only a few direct methods exist
With methyl iodide, 1,2-dimethylindole and 1-methylindole are unreactive,4 2-methylindole results in mixtures of N- and Cmethylation,[5] and oxindoles undergo dialkylation at C3.3 The installation of a methyl group is a worthwhile endeavor, considering the interest of medicinal chemists in the “magic methyl effect”;6 yet only a few methods exist for the direct C3 methylation of indoles and oxindoles (Scheme 1a)
We considered if boranes could be used to cleave C(sp3)−H bonds heterolytically[13] and unveil new approaches to challenging transformations

Summary

Introduction

The direct C3 alkylation of indoles and oxindoles is a challenging transformation, and only a few direct methods exist. We have developed a new strategy for the direct C3 methylation of indoles and oxindoles (Scheme 1c). We surveyed the scope of the B(C6F5)3-catalyzed methylation of various 1,2-, 1-, and 2-substituted indoles and oxindoles and found that the reaction broadly tolerated a range of functional groups and substitution patterns

Results

Conclusion