Synlett 2016; 27(20): 2747-2755
DOI: 10.1055/s-0036-1588637
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© Georg Thieme Verlag Stuttgart · New York

Metal-Catalyzed Decarboxylative Fluoroalkylation Reactions

Brett R. Ambler, Ming-Hsiu Yang, Ryan A. Altman*
  • Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, USA   Email: raaltman@ku.edu
Further Information

Publication History

Received: 22 August 2016

Accepted after revision: 06 October 2016

Publication Date:
25 October 2016 (eFirst)

Abstract

Metal-catalyzed decarboxylative fluoroalkylation reactions enable the conversion of simple O-based substrates into biologically relevant fluorinated analogues. Herein, we present decarboxylative methods that facilitate the synthesis of trifluoromethyl- and difluoroketone-containing products. We highlight key mechanistic aspects that are critical for efficient catalysis, and that inspired our thinking while developing the reactions.

1 Introduction

2 Copper-Catalyzed Decarboxylative Trifluoromethylation Reactions

2.1 Net Trifluoromethylation of Alcohols

2.2 Mechanism of Decarboxylation Impacts Functional-Group Tolerance

2.3 Allylic Trifluoromethylation Enabled by Activation Protocol

2.4 Generation of Iodide Intermediate Required for Benzylic Trifluoromethylation

2.5 Ligand-Controlled Regiodivergent Trifluoromethylation of Propargylic Electrophiles

2.6 Summary

3 Palladium-Catalyzed Decarboxylative Alkylation of α,α-Difluoroketone Enolates

3.1 Convergent Routes towards α,α-Difluoroketones

3.2 Palladium-Catalyzed Decarboxylative Benzylation of α,α-Difluoroketone Enolates

3.3 Palladium-Catalyzed Decarboxylative Allylation of α,α-Difluoroketone Enolates

3.4 Summary