Design and Implementation of a Catalytic Electron Donor–Acceptor Complex Platform for Radical Trifluoromethylation and Alkylation

Abstract

Electron donor−acceptor (EDA) complexes can controllably generate radicals under mild conditions through selective photoexcitation events. However, unproductive reactivity from fast deactivation of the photoexcited complexes through back electron transfer has slowed the development of EDA complexes in synthetic methodology. Here, we disclose the study of EDA complexes derived from 2-methoxynaphthalene donor and acylated ethyl isonicotinate N-oxide acceptor that undergo a fast N−O bond fragmentation event upon photoexcitation. This reaction design not only overcomes the limitations of back electron transfer but also enables regeneration of the donor species, representing a rare example of EDA photochemistry in a catalytic regime. The synthetic utility is demonstrated through visible light-driven radical trifluoromethylation and Minisci alkylation reactions. The scalability of the EDA complex-promoted reaction is evidenced by the successful multigram-scale trifluoromethylation of methyl N-Boc pyrrole-2-carboxylate in a continuous flow manifold.

Radical Perfluoroalkylation Enabled by a Catalytically Generated Halogen Bonding Complex and Visible Light Irradiation

“…Five-membered nitrogen-, sulfur-and oxygenbased heteroarenes (1-5) were all well tolerated. Electron-rich arenes also reacted well under our reaction conditions (6)(7)(8)(9). Moreover, the reaction with 1,3,5-trimethoxybenzene (6) could be performed at 1 mmol scale without any loss in reactivity.…”

“…While these examples represent important advancements in the field, they are limited in the scope of the acceptor; namely N-(acyloxy)phthalimide esters, N-alkylpyridinium salts, Togni's reagent and pyridine N-oxides generated from acid chlorides and anhydrides. Furthermore, only Stephenson's method is suitable to access readily available materials 7 , while the others require further derivatization for reactivity.…”

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

“…In 2020, Stephenson and colleagues [ 14 ] employed 2-methoxynaphthalene ( 124 ) and acylated ethyl isonicotinate N -oxide obtained from 125 and trifluoroacetic acid anhydride to form EDA complexes for the preparation of trifluoromethylated product 126 ( Scheme 44 ). As a rare example of EDA photochemistry in the catalytic system, only a catalytic equivalent of the electron donor was employed in this approach.…”

Aerobic Oxidative EDA Catalysis: Synthesis of Tetrahydroquinolines Using an Organocatalytic EDA Active Acceptor

“…Examples of these systems include the use of electron-rich aromatics and amines. 10 , 11 , 15 , 16 Examples of systems using catalytic acceptors in the same manner, however, still remain rare in the literature and are limited to strong Lewis acids ( Scheme 1 b). 17 , 18 Identification of milder suitable acceptors that could act as catalysts for photo-mediated synthesis would constitute a significant contribution to the field of EDA complex-driven transformations.…”