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The palladium-catalyzed trifluoromethylation of aryl chlorides.

Science (New York, N.Y.) (2010-06-26)
Eun Jin Cho, Todd D Senecal, Tom Kinzel, Yong Zhang, Donald A Watson, Stephen L Buchwald
ABSTRACT

The trifluoromethyl group can dramatically influence the properties of organic molecules, thereby increasing their applicability as pharmaceuticals, agrochemicals, or building blocks for organic materials. Despite the importance of this substituent, no general method exists for its installment onto functionalized aromatic substrates. Current methods either require the use of harsh reaction conditions or suffer from a limited substrate scope. Here we report the palladium-catalyzed trifluoromethylation of aryl chlorides under mild conditions, allowing the transformation of a wide range of substrates, including heterocycles, in excellent yields. The process tolerates functional groups such as esters, amides, ethers, acetals, nitriles, and tertiary amines and, therefore, should be applicable to late-stage modifications of advanced intermediates. We have also prepared all the putative intermediates in the catalytic cycle and demonstrated their viability in the process.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
α,α,α-Trifluorotoluene, anhydrous, ≥99%
Sigma-Aldrich
α,α,α-Trifluorotoluene, ≥99%
Sigma-Aldrich
α,α,α-Trifluorotoluene solution, NMR reference standard, 0.05% in benzene-d6 (99.6 atom % D)
Sigma-Aldrich
Triethyl(trifluoromethyl)silane, 98%
Sigma-Aldrich
α,α,α-Trifluorotoluene solution, NMR reference standard, 0.05% in benzene-d6 (99.6 atom % D), NMR tube size 3 mm × 8 in.
Sigma-Aldrich
α,α,α-Trifluorotoluene solution, NMR reference standard, 0.05% in benzene-d6 (99.6 atom % D), NMR tube size 10 mm × 8 in.