Direct Synthesis of α‐Aryl‐α‐Trifluoromethyl Alcohols via Nickel Catalyzed Cross‐Electrophile Coupling

• Published in: Angewandte Chemie International Edition Vol. 61; no. 47; pp. e202211732 - n/a
• Main Authors: Lombardi, Lorenzo, Cerveri, Alessandro, Giovanelli, Riccardo, Castiñeira Reis, Marta, Silva López, Carlos, Bertuzzi, Giulio, Bandini, Marco
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 21.11.2022; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Edition: International ed. in English
• Subjects: Alcohols; Catalysis; Chemistry; Chemistry, Multidisciplinary; Communication; Communications; Computer applications; Coupling; Cross-Electrophile Coupling; DFT Calculation; Functional groups; Hydrogen Atom Transfer; Hydrogen atoms; Nickel; Nickel - chemistry; Nickel Catalysis; Oxidation-Reduction; Physical Sciences; Science & Technology; Trifluoromethylation; NUCLEOPHILIC TRIFLUOROMETHYLATION; HALIDES; Hydrogen Atom Transfer; ALKYL; DFT Calculation; MECHANISMS; FLUORINATION; INDOLES; ABSTRACTION; Trifluoromethylation; Nickel Catalysis; BASIS-SETS; Cross-Electrophile Coupling; FRIEDEL-CRAFTS REACTION
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202211732

A nickel‐catalyzed reductive cross‐electrophile coupling between the redox‐active N‐trifluoroethoxyphthalimide and iodoarenes is documented. The protocol reproduces a formal arylation of trifluoroacetaldehyde under mild conditions in high yields (up to 88 %) and with large functional group tolerance (30 examples). A combined computational and experimental investigation revealed a pivotal solvent assisted 1,2‐Hydrogen Atom Transfer (HAT) process to generate a nucleophilic α‐hydroxy‐α‐trifluoromethyl C‐centered radical for the Csp2−Csp3 bond forming process. A nickel catalyzed synthesis of α‐aryl‐α‐trifluoromethyl alcohols B is presented that exploits the condensation of iodoarenes and the redox active ether A via cross‐electrophile coupling. A mechanistic study was conducted using a comprehensive computational investigation that was also supported by ad hoc control experiments and showed that the key 1,2‐HAT (Hydrogen Atom Transfer) event results in the formation of a C‐centered radical C′ that mimics the reactivity of trifluoroacetaldehyde.