An official website of the United States government
Intermolecular C–H difluoromethoxylation of (hetero)arenes remains a long-standing and unsolved problem in organic synthesis. Herein, we report the first catalytic protocol employing a redox-active difluoromethoxylating reagent 1a and photoredox catalysts for the direct C–H difluoromethoxylation of (hetero)arenes. Our approach is operationally simple, proceeds at room temperature, and uses bench-stable reagents. Its synthetic utility is highlighted by mild reaction conditions that tolerate a wide variety of functional groups and biorelevant molecules. Experimental and computational studies suggest single electron transfer (SET) from excited photoredox catalysts to 1a forming a neutral radical intermediate that liberates the OCF 2 H radical exclusively. Addition of this radical to (hetero)arenes gives difluoromethoxylated cyclohexadienyl radicals that are oxidized and deprotonated to afford the products of difluoromethoxylation.
more »
« less
Redox‐Active Reagents for Photocatalytic Generation of the OCF 3 Radical and (Hetero)Aryl C−H Trifluoromethoxylation
Abstract The trifluoromethoxy (OCF3) radical is of great importance in organic chemistry. Yet, the catalytic and selective generation of this radical at room temperature and pressure remains a longstanding challenge. Herein, the design and development of a redox‐active cationic reagent (1) that enables the formation of the OCF3radical in a controllable, selective, and catalytic fashion under visible‐light photocatalytic conditions is reported. More importantly, the reagent allows catalytic, intermolecular C−H trifluoromethoxylation of a broad array of (hetero)arenes and biorelevant compounds. Experimental and computational studies suggest single electron transfer (SET) from excited photoredox catalysts to1resulting in exclusive liberation of the OCF3radical. Addition of this radical to (hetero)arenes gives trifluoromethoxylated cyclohexadienyl radicals that are oxidized and deprotonated to afford the products of trifluoromethoxylation.
more »
« less
- Award ID(s):
- 1654122
- PAR ID:
- 10075734
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 57
- Issue:
- 42
- ISSN:
- 1433-7851
- Page Range / eLocation ID:
- p. 13795-13799
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract We report copper(II) and copper(III) trifluoromethyl complexes supported by a pyridinedicarboxamide ligand (L) as a platform for investigating the role of electron transfer in C(sp2)−H trifluoromethylation. While the copper(II) trifluoromethyl complex is unreactive towards (hetero)arenes, the formal copper(III) trifluoromethyl complex performs C(sp2)−H trifluoromethylation of a wide range of (hetero)arenes. Mechanistic studies using the copper(III) trifluoromethyl complex suggest that the mechanism of arene trifluoromethylation is substrate‐dependent. When the thermodynamic driving force for electron transfer is high, the reaction proceeds through a previously unidentified single electron transfer (SET) mechanism, where an initial electron transfer occurs between the substrate and oxidant prior to CF3group transfer. Otherwise, a CF3radical release/electrophilic aromatic substitution (SEAr) mechanism is followed. These studies provide valuable insights into the role of strong oxidants and potential mechanistic dichotomy in Cu‐mediated C(sp2)−H trifluoromethylation.more » « less
-
Abstract Visible‐light capture activates a thermodynamically inert CoIII−CF3bond for direct C−H trifluoromethylation of arenes and heteroarenes. New trifluoromethylcobalt(III) complexes supported by a redox‐active [OCO] pincer ligand were prepared. Coordinating solvents, such as MeCN, afford green, quasi‐octahedral [(SOCO)CoIII(CF3)(MeCN)2] (2), but in non‐coordinating solvents the complex is red, square pyramidal [(SOCO)CoIII(CF3)(MeCN)] (3). Both are thermally stable, and2is stable in light. But exposure of3to low‐energy light results in facile homolysis of the CoIII−CF3bond, releasing.CF3radical, which is efficiently trapped by TEMPO.or (hetero)arenes. The homolytic aromatic substitution reactions do not require a sacrificial or substrate‐derived oxidant because the CoIIby‐product of CoIII−CF3homolysis produces H2. The photophysical properties of2and3provide a rationale for the disparate light stability.more » « less
-
null (Ed.)A Cu-catalyzed strategy has been developed that harnesses a radical relay mechanism to intercept a distal C-centered radical for C–C bond formation. This approach enables selective δ C–H (hetero)arylation of sulfonamides via intramolecular hydrogen atom transfer (HAT) by an N-centered radical. The radical relay is both initiated and terminated by a Cu catalyst, which enables incorporation of arenes and heteroarenes by cross-coupling with boronic acids. The broad scope and utility of this catalytic method for δ C–H arylation is shown, along with mechanistic probes for selectivity of the HAT mechanism. A catalytic, asymmetric variant is also presented, as well as a method for accessing 1,1-diaryl-pyrrolidines via iterative δ C–H functionalizations.more » « less
-
Abstract Applications of TEMPO.catalysis for the development of redox‐neutral transformations are rare. Reported here is the first TEMPO.‐catalyzed, redox‐neutral C−H di‐ and trifluoromethoxylation of (hetero)arenes. The reaction exhibits a broad substrate scope, has high functional‐group tolerance, and can be employed for the late‐stage functionalization of complex druglike molecules. Kinetic measurements, isolation and resubjection of catalytic intermediates, UV/Vis studies, and DFT calculations support the proposed oxidative TEMPO./TEMPO+redox catalytic cycle. Mechanistic studies also suggest that Li2CO3plays an important role in preventing catalyst deactivation. These findings will provide new insights into the design and development of novel reactions through redox‐neutral TEMPO.catalysis.more » « less
