Highly Selective Trifluoromethylation of 1,3‐Disubstituted Arenes through Iridium‐Catalyzed Arene Borylation

Abstract

The old one two: A sequential iridium-catalyzed borylation and copper-catalyzed trifluoromethylation of arenes is described (see scheme; Pin = pinacol). The reaction is conducted under mild reaction conditions and tolerates a variety of functional groups. The advantages of this tandem procedure are demonstrated by the late-stage trifluoromethylation of a number of biologically active molecules.

Improving Transformations Through Organotrifluoroborates

“…Over the last decade, Cu-catalyzed electrophilic [54][55][56], nucleophilic [57,58], and radical trifluoromethylations [59] of various boronic acids have been demonstrated. Electrophilic trifluoromethylation protocols have been extended to both aryltrifluoroborates and arylboronic esters [60,61]. Recently, progress toward the cost-effectiveness and substrate scope expansion for the conversion of organotrifluoroborates to the corresponding trifluoromethylated substructures has been made.…”

Merging Visible-Light Photocatalysis and Transition-Metal Catalysis in the Copper-Catalyzed Trifluoromethylation of Boronic Acids with CF3I

“…This demonstrates the complementarity of this method to many other Cu-catalyzed trifluoromethylation protocols. 5a,5c,5f Furthermore, it provides additional evidence against the possibility of aryl iodide intermediates in this transformation.…”

“…1 As such, the development of mild and versatile synthetic methods for generating carbon–CF 3 bonds has become a field of intense research effort. Over the past 3 years, a variety of Pd 2,3 and Cu 4,5 -based cross-coupling protocols have been developed for the trifluoromethylation of aryl halides, aryl boronic acids, and aromatic carbon– hydrogen bonds. As exemplified in Scheme 1a/b for the Cu-promoted trifluoromethylation of boronic acids, these transformations typically involve “CF 3 − ” 4c,4e,4l,5i or “CF 3 + ” 4f,5d,e reagents and are believed to proceed via nucleophilic or electrophilic transfer of the CF 3 group to the Cu center, respectively.…”

“…In some cases, temperatures greater than 100 °C 2b,3a,b,4d and/or strong acids or bases (TFA 3a or t BuOK 4j ) are necessary. Other methods require expensive trifluoromethylating reagents (e.g., S -(trifluoromethyl)thiophenium salts, 3a,4f,5d Togni’s reagent, 5b,5e,5g or TESCF 3 ). 3b,5a Finally, many protocols exhibit limited substrate scope/generality.…”

“…Other methods require expensive trifluoromethylating reagents (e.g., S -(trifluoromethyl)thiophenium salts, 3a,4f,5d Togni’s reagent, 5b,5e,5g or TESCF 3 ). 3b,5a Finally, many protocols exhibit limited substrate scope/generality. 3c,5a,b …”