The Palladium-Catalyzed Trifluoromethylation of Aryl Chlorides

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. Herein, 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 also have prepared all the putative intermediates in the catalytic cycle and demonstrated their viability in the process.

Palladium‐Catalyzed Decarbonylative Trifluoromethylation of Acid Fluorides

“…These reactivity features make this a complimentary method to Buchwald's procedure with ArCl 9. While 2‐phenylbenzoyl fluoride 1 b gave 82 % conversion to the desired ArCF 3 product 2 b with our protocol, the corresponding 2‐phenyl aryl chloride generated much less of 2 b with Buchwald's method in our tests (BrettPhos: <5 % conversion, RuPhos: 34 % conversion).…”

“…As such, Buchwald's catalytic Pd 0 /Pd II ‐catalyzed trifluoromethylation of aryl chlorides is a major accomplishment 9. We report herein our studies to widen the precursor pool for trifluoromethylation from aryl chlorides or bromides9, 10 to underexplored and easily accessible aryl carboxylic acid derivatives, that is, acid fluorides. …”

“…Moreover, several equivalents of fluoride salt additive are generally required to activate the transmetalating agent, such as R 3 SiCF 3 , and even the smallest parts per million quantities of moisture introduced by these salts can cause catalyst decomposition 4e, 8. As such, Buchwald's catalytic Pd 0 /Pd II ‐catalyzed trifluoromethylation of aryl chlorides is a major accomplishment 9. We report herein our studies to widen the precursor pool for trifluoromethylation from aryl chlorides or bromides9, 10 to underexplored and easily accessible aryl carboxylic acid derivatives, that is, acid fluorides.…”

Palladium-Mediated Organofluorine Chemistry

“…Buchwald's group succeeded in performing a catalytic cycle by using BrettPhos or RuPhos as supporting ligands in which the reductive elimination is the slowest step. 60 Kinetic experiments carried out on the isolated intermediates [PdArCF 3 (BrettPhos)]…”

Regioselective trifluoromethylation of N-heteroaromatic compounds using trifluoromethyldifluoroborane activator

“…Most current processes for accessing CF 3 containing molecules are performed by carboxy or trichloromethyl group substitution using hazardous fluorinating reagents under harsh reaction conditions 6 . Cross-coupling reactions between organohalides [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] or boronic acids (or their esters) [25][26][27][28][29][30][31][32][33][34] and trifluoromethylating reagents are another common approach. Although CF 3 groups can be regioselectively introduced to aromatic rings in cross-coupling reactions, requirement of multiple steps for the preparation of aryl halides and boronic acids/esters and generation of stoichiometric amounts of metal salts decrease synthetic efficiency.…”