Photoredox Activation of Anhydrides for the Solvent-Controlled Switchable Synthesis of gem-Difluoro Compounds

Abstract

The incorporation of the gem-difluoromethylene (CF₂ ) group into organic frameworks is highly sought due to the influence of this unit on the physicochemical and pharmacological properties of molecules. Herein we report an operationally simple, mild, and switchable protocol to access various gem-difluoro compounds that employs chlorodifloroacetic anhydride (CDFAA) as a low-cost and versatile fluoroalkylating reagent. Detailed mechanistic studies revealed that electron-transfer photocatalysis triggers mesolytic cleavage of a C-Cl bond generating a gem-difluoroalkyl radical. In the presence of alkene, this radical species acts as a unique intermediate that, under solvent-controlled reaction conditions, delivers a wide range of gem-difluorinated γ-lactams, γ-lactones, and promotes oxy-perfluoroalkylation. These protocols are flow- and batch-scalable, possess excellent chemo- and regioselectivity, and can be used for the late-stage diversification of complex molecules.

Keywords: Anhydrides; Late-Stage Functionalization; Photoredox; Radical Mechanisms; gem-Difluoro Compounds.

Scheme 1

Existing and new reaction modes of halogenated anhydrides. A) Divergent synthesis in photocatalysis. B) Notable examples of gem‐difluoromethylene (CF₂) containing biorelevant structures. C) Established and new activation modes of anhydrides. D) Photoredox activation of CDFAA for the switchable synthesis of gem‐difluoro cyclic and acyclic compounds.

Scheme 2

Reaction scope. A) Scope of γ‐lactams. B) Scope of γ‐lactones. [a] General conditions I: olefin (1 equiv), fac‐Ir(ppy)₃ (1 mol%), CDFAA (2 equiv), MeCN (0.03 M), blue LEDs, rt, 12 h, isolated yields. [b] X‐Ray figures were created with the CYLview 2.0 Software, Legault, C. Y., Sherbrooke University 2020 (www.cylview.com). Hydrogen atoms were omitted for clarity. [c] Solvent EtCN (0.03 M). [d] Solvent iPrCN (0.03 M). [e] General conditions II: olefin (1 equiv), fac‐Ir(ppy)₃ (1 mol%), CDFAA (2 equiv), DMF (0.17 M), blue LEDs, rt, 12 h, isolated yields. [f] Reaction conducted for 24 h.

Scheme 3

Late‐stage functionalization of complex molecules. [a] General conditions I. [b] General conditions II. [c] General conditions III.

Scheme 4

A) Gram‐scale synthesis. [a,b] 4‐tert‐Butylstyrene (10 mmol), fac‐Ir(ppy)₃ (0.1 mmol), CDFAA (20 mmol), MeCN (300 mL) or DMF (60 mL), blue LEDs, rt, 24 h, isolated yield. [c] 4‐tert‐Butylstyrene (20 mmol), fac‐Ir(ppy)₃ (0.2 mmol), CDFAA (40 mmol), DMF (60 mL), flow rate=0.3 mL min⁻¹, τ _R=2.74 h, isolated yields. B) Adaptive functionality from 1 and 2. [d] 1 (0.5 mmol), pentylamine (0.6 mmol), THF (1 mL), rt, 16 h. [e] 1 (0.5 mmol), LiAlH₄ (2.5 mmol), THF (1 mL), rt, 2 h. [f] 2 (0.5 mmol), 1 mL 30 % NH₄OH, rt, 12 h. [g] 2 (0.5 mmol), Et₃N (0.55 mmol), pyrrolidine (0.55 mmol), 1 mL MeOH/THF (1 : 4), rt, 12 h. [h] 1 (0.5 mmol), LiAlH₄ (2.5 mmol), THF (1 mL), rt, 4 h. [i] 2 (0.5 mmol), PhLi (2.5 mmol), Et₂O (1.5 mL), 0 °C to rt, 6 h.

Scheme 5

Mechanistic studies towards formation of 1 and 2. A) Proposed mechanism (for details, see Supporting Information, pages S50–S51). B) Spectroscopic studies. C) Competition experiments. D) Screening of different anhydrides. E) Control experiments. General reaction conditions: 4‐tert‐butylstyrene (1 equiv), fac‐Ir(ppy)₃ (1 mol%), CDFAA (2 equiv) in MeCN or DMF, 12 h, GC yields. [a] For structure I‐14, see Supporting Information, page S51. [b] Extension coefficients for CDFAA are multiplied by 10 times for representation reasons. [c] Reaction was performed under air. [d] Acetonitrile‐d ₃ was used as solvent. [e] Ethenyl‐2,2‐d ₂‐benzene (1 equiv) was used as olefin. [f] H₂O¹⁸ (2 equiv, 97 atom % ¹⁸O) was added in the reaction mixture after the irradiation under argon and stirred for 30 min. Incorporation of ¹⁸O was not observed either in GC‐MS or in NMR. Relative Gibbs free‐energies (ΔG) were calculated at 298 K at the CPCM(Solvent)/M06‐2X/GD3/def2‐TZVP//M06‐2X/GD3/def2‐TZVP level of theory.

Scheme 6

Mechanistic studies towards formation of 3. A) Proposed mechanism for oxy‐perfluoroalkylation of olefins. B) Key experiments. C) Competition experiments. D) Oxy‐perfluoroalkylation scope. General conditions: 4‐tert‐butylstyrene (1 equiv), fac‐Ir(ppy)₃ (1 mol%), CDFAA (2 equiv), toluene (0.17 M), blue LEDs, rt, 12 h, GC yields. [a] For structure I‐17, see Supporting Information, page S52. [b] Reaction was performed under air. [c] See Supporting Information for details, page S47. Relative Gibbs free‐energies (ΔG) were calculated at 298 K at the CPCM(Solvent)/M06‐2X/GD3/def2‐TZVP//M06‐2X/GD3/def2‐TZVP level of theory.