ORIGINAL

Abstract

Trifluoromethyl groups [CF\(_{3}\)] are a common motif in drug molecules due to their resistance to oxidation and enhancement of pharmacokinetic parameters. Despite this interest, site-specific introduction of [CF\(_{3}\)] groups to aromatic rings remains a challenge for synthesis. One strategy to regioselectively introduce a trifluoromethyl group into an aromatic ring is to leverage highly selective cobalt-catalyzed C(sp\(^{2}\)–H) borylation followed by sequential trifluoromethylation. Herein, two novel trifluoromethylation reagents – (tetramethylpyrazine)tris(trifluoromethyl)copper [(TMPZ)Cu(CF\(_{3}\))\(_{3}\)] and (4-dimethylaminopyridine)tris(trifluoromethyl)copper [(DMAP)Cu(CF\(_{3}\))\(_{3}\)] – have been synthesized, isolated, and characterized by X-ray crystallography. Both copper complexes are active for trifluoromethylation of arylboronic acids utilizing substoichiometric amounts of copper. In addition to these novel reagents, previously reported reagents were tested in the development of a process-friendly technique that utilizes catalytic copper. Optimization studies led to the development of a method for copper-catalyzed trifluoromethylation of arylboronic acids with s-(trifluoromethyl) dimesitylsulfonium trifluoromethanesulfonate. This trifluoromethylation reagent was first reported by the MacMillan lab and can be synthesized in one step. Interestingly, both electron-rich and electron-deficient arylboronic acids are tolerated by this protocol. Preliminary experimental evidence suggests that this process occurs through a single electron transfer pathway with the formation of a CuCF\(_{3}\) intermediate. However, the potential for other competing mechanisms is discussed. Efforts toward establishing structure activity relationships with various trifluoromethylation reagents will also be presented.