Room-Temperature Alkyl-Alkyl Suzuki Cross-Coupling of Alkyl Bromides that Possess -- Hydrogens

Reaction Scheme

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.

Substrates

Procedure

In a nitrogen-filled glovebox, an oven-dried resealable test tube equipped with a magnetic stir bar was charged with KF (116 mg, 2.0 mmol) and hexyl 3- chlorobenzoate (241 mg, 1.0 mmol). A premixed solution of [(allyl)PdCl]2 (11.0 mg, 0.03 mmol) and BrettPhos (48.3 mg, 0.09 mmol) in dioxane (3.3 mL) and TESCF3 (376 �L, 2.0 mmol) were added to it. The tube was then sealed with a screw-cap, taken out of the glovebox, and placed into a preheated oil bath at 120 o C with vigorous stirring. After 12 h the tube was removed from the oil bath and allowed to cool to room temperature. The reaction mixture was then diluted with diethyl ether, filtered through a plug of silica gel to remove all solids, concentrated in vacuo, and purified via the Biotage SP4 (silica-packed 25 g snap cartridge) to give the title compound as a colorless oil in 85% yield (232 mg).

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Materials

     
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