Investigations into Transition-Metal-Catalyzed Arene Trifluoromethylation Reactions

Abstract

Trifluoromethyl-substituted arenes and heteroarenes are widely prevalent in pharmaceuticals and agrochemicals. As a result, the development of practical methods for the formation of aryl–CF3 bonds has become an active field of research. Over the past five years, transition metal catalyzed cross-coupling between aryl–X (X = halide, organometallic, or H) and various “CF3” reagents has emerged as a particularly exciting approach for generating aryl–CF3 bonds. Despite many recent advances in this area, current methods generally suffer from limitations such as poor generality, harsh reaction conditions, the requirement for stoichiometric quantities of metals, and/or the use of costly CF3 sources. This Account describes our recent efforts to address some of these challenges by: (1) developing aryl trifluoromethylation reactions involving high oxidation state Pd intermediates, (2) exploiting AgCF3 for C–H trifluoromethylation, and (3) achieving Cu-catalyzed trifluoromethylation with photogenerated CF3•.

Copper-Catalyzed Trifluoromethylation of Alkoxypyridine Derivatives

“…This effect is more pronounced when a trifluoromethyl group is introduced, evidenced by the surge in the number of FDA-approved CF 3 -group containing drugs in recent years [ 7 , 8 , 9 ]. There are multiple approaches for the establishment of the trifluoromethyl group, including nucleophilic, radical, and electrophilic routes [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Our objective was to systematically study the copper-catalyzed trifluoromethylation [ 24 ] of alkoxypyridine derivatives and their benzologs that could serve as useful building blocks in medicinal chemistry.…”

Copper-Catalyzed Monofluoroalkylation of Allyl Phosphates with Nucleophilic Ethyl 2-Fluoro-2-(trimethylsilyl)acetate

“…Fluorine-containing compounds have been widely used in the fields of materials, pharmaceuticals, and agrochemicals because the introduction of fluorine or fluorinated moieties into organic compounds usually has a significant impact on their lipophilicity, metabolic stability, and bioavailability. − Therefore, there is a growing demand for fluorinated organic compounds from both academia and industry, and the need to develop new synthetic methods for fluorinated organic compounds has become more urgent. − Fluorinated compounds are mainly obtained by fluorination and fluoroalkylation of organic compounds, wherein the monofluoroalkylation can introduce both fluorine atoms and other groups in a one-step reaction. − …”

“…−191.1 to −191.4 (m) 13. C{ 1 H} NMR (151 MHz, chloroformd) δ 169.1 (d, J = 23.7 Hz), 136.6, 133.1, 132.9, 128.9, 127.5, 127.1, 125.4 (d, J = 3.7 Hz), 123.3, 88.3 (d, J = 186.4 Hz), 61.7, 36.1 (d, J = 21.2 Hz), 14.2.…”

“…J = 7.1 Hz, 3H).19 F NMR (564 MHz, chloroform-d) δ −114.6, −191.3 (dt, J = 49.4, 24.8 Hz) 13. C{ 1 H} NMR (151 MHz, chloroform-d) δ 169.2 (d, J = 23.7 Hz), 133.0, 127.8, 127.7, 122.0 (dd, J = 3.5, 2.3 Hz), 115.5, 115.3, 88.3 (d, J = 186.6 Hz), 61.6, 36.0 (d, J = 21.3 Hz), 14.2.…”

“…The product (55 mg, 63%) as a colorless oil was purified with silica gel chromatography (petroleum ether:ethyl acetate = 20:1). 1 H NMR (400 MHz, chloroform-d) δ 7.55 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 6.56 (d, J = 15.9 Hz, 1H), 6.30 (dt, J = 15.8, 7.2 Hz, 1H), 5.02 (ddd, J = 48.7, 6.8, 4.6 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 2.96−2.73 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H).19 F NMR (376 MHz, chloroform-d) δ −62.6, −191.2 (dt, J = 49.1, 24.7 Hz) 13.…”