Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

Abstract

A straightforward method that enables the formation of biologically attractive trifluoromethyl ketones from readily available methyl esters using the potent greenhouse gas fluoroform (HCF₃, HFC-23) was developed. The combination of fluoroform and KHMDS in triglyme at -40 °C was effective for this transformation, with good yields as high as 92%. Substrate scope of the trifluoromethylation procedure was explored for aromatic, aliphatic, and conjugated methyl esters. This study presents a straightforward trifluoromethylation process of various methyl esters that convert well to the corresponding trifluoromethyl ketones. The tolerance of various pharmacophores under the reaction conditions was also explored.

Keywords: HFC-23; fluoroform; greenhouse gas; trifluoromethyl ketones; trifluoromethylation.

Scheme 1

Chemistry of the CF₃ anion generated from HCF₃. a) Decomposition of the trifluoromethyl anion to difluorocarbene and fluoride. b) A hemiaminaloate adduct of CF₃ anion to DMF. c) Formation of the [P4-t-Bu]H⁺ CF₃ anion salt. d) Encapsulation of K⁺ by glymes. Transformation of esters to trifluoromethyl ketones.

Figure 1

Trifluoromethyl ketones. a) Hydrolysis of trifluoromethyl ketones. b) Selected examples of biologically active trifluoromethyl ketones.

Scheme 2

Trifluoromethylation of esters by HCF₃ by a) Russell and Roques (1998), b) Prakash and co-workers (2012), c) Szymczak and co-workers (2018), d) Han, Lian and co-workers (2019), and e) our group in this work.

Scheme 3

Substrate scope of esters 1 for trifluoromethylation by HCF₃ under the optimized conditions. ^aDetermined by ¹⁹F NMR of the crude 2 with trifluorotoluene as an internal standard. ^bIsolated yield. ^cIsolated yield of gram-scale reaction by using 1 g of substrate.