Trifluoromethylation of arylboronic acids by Cu-mediated CF3 radicals


The incorporation of fluorine atoms into pharmaceutical molecules has long been in the medicinal chemist’s book of tricks to improve metabolic stability. The number of recent publications focusing on development of new methodologies for novel fluorination  and trifluoromethyl reactions only reflect the importance of such transformations.

Despite significant progress in the development of trifluoromethylation methodologies, and more recently with the Cu-catalysed trifluoromethylation of boronic acids, many transformations are still limited by either the cost of reagents, high temperature, strong acids / bases or limited scope.

Following on Melanie Sanford’s excellent JACS communication earlier this year, Melanie is back with a further publication addressing the scope and methodology of the trifluoromethylation of arylboronic acids with CF3 radicals. Key advantages to the publication is the generation of a practical source of CF3 radicals under mild conditions.

The CF3 radicals are generated in situ from of readily available NaSO2CF3 (Langlois’ reagent) and tert-butyl hydroperoxide (TBHP) and can undergo Cu-mediated trifluoromethylation with a range of boronic acids.

After an extensive evaluation of copper salts, CuCl proved to work well on reactions with no protodeborylation observed under the mild reaction conditions (Figure 2)

Figure 2

Both electron-rich and electron-neutral boronic acids are tolerated under the conditions described in the publication. However, Melanie reports that electron-deficient boronics acids led to moderate to poor yields. Further Cu screening for electron-deficient boronic acids led to the substitution of CuCl for (MeCN)4CuPF6 and addition of NaHCO3 (acceleration of the transmetalation rate) resulting in an improved yield (Figure 3).

Figure 3

From the scope of the reaction, it is worth noting that sterically hindered boronic acids are tolerated and the reaction compatible with a range of functional groups (esters, ketones, phenols).

Overall, a very mild and general approach for the Cu-catalysed trifluoromethylation of arylboronic acids, demonstrating the feasibility of a radical pathway.