Divergent functionalization of alkenes enabled by photoredox activation of CDFA and α-halo carboxylic acids

Abstract

Herein we present our studies on the solvent-controlled difunctionalization of alkenes utilizing chlorodifluoroacetic acid (CDFA) and α-halo carboxylic acids for the synthesis of γ-lactones, γ-lactams and α,α-difluoroesters. Mechanistic insights revealed that photocatalytic reductive mesolytic cleavage of the C-X bond delivers elusive α-carboxyl alkyl radicals. In the presence of an olefin molecule, this species acts as a unique bifunctional intermediate allowing for stipulated formation of C-O, C-N and C-H bonds on Giese-type adducts via single electron transfer (SET) or hydrogen atom transfer (HAT) events. These protocols exhibit great efficiency across a broad spectrum of readily available α-halo carboxylic acids and are amenable to scalability in both batch and flow. To demonstrate the versatility of this concept, the synthesis of (±)-boivinianin A, its fluorinated analog and eupomatilone-6 natural products was successfully accomplished.

Scheme 1. Introduction: (A) (bio)isostere of the CF₂ group; (B) notable examples of gem-difluoro (CF₂) containing biorelevant structures; (C) philicity trend of ˙CF₂R free radicals; (D) our photoredox methods to access fluorinated compounds from alkenes.

Scheme 2. Reaction scope: [a] conditions 1: alkene (1 equiv.), fac-Ir(ppy)₃ (1 mol%), CDFA (2 equiv.), DMF (0.5 M), blue LEDs, rt, 12 h. [b] Conditions 2: alkene (1 equiv.), fac-Ir(ppy)₃ (1 mol%), CDFA (2 equiv.), MeCN (0.17 M), Boc anhydride (2 equiv.), blue LEDs, rt, 24 h. [c] Conditions 3: alkene (1 equiv.), photocatalyst (1 mol%), CDFA (2 equiv.), VII (2 equiv.), alcohol : MeCN (1 : 1 v/v), blue LEDs, rt, 12 h; (A) scope of γ-lactams. (B) Scope of γ-lactones. (C) Scope of α,α-difluoroesters.

Scheme 3. Reaction scope: [a] conditions 1: alkene (1 equiv.), fac-Ir(ppy)₃ (1 mol%), acid (2 equiv.), DMF (0.5 M), blue LEDs, rt, 12 h; [b] conditions 2: alkene (1 equiv.), fac-Ir(ppy)₃ (1 mol%), acid (2 equiv.), MeCN (0.17 M), Boc anhydride (2 equiv.), blue LEDs, rt, 24 h; (A) scope of α-halo carboxylic acids; (B) natural product synthesis.

Scheme 4. Proposed mechanism: (A) proposed mechanism; (B) mechanistic studies towards formation of 1 and 2; (C) control experiments; (D) batch and flow scale-up. [a] Conditions 1: alkene (1 equiv.), fac-Ir(ppy)₃ (1 mol%), CDFA (2 equiv.), DMF (0.5 M), blue LEDs rt, 12 h; [b] conditions 2: alkene (1 equiv.), fac-Ir(ppy)₃ (1 mol%), CDFA (2 equiv.), MeCN (0.17 M), Boc anhydride (2 equiv.), blue LEDs, rt, 12 h; [c] alkene (10 mmol), fac-Ir(ppy)₃ (0.1 mmol), CDFA (20 mmol), DMF (10 mL), blue LEDs, rt, 24 h, isolated yields; [d] alkene (20 mmol), fac-Ir(ppy)₃ (0.2 mmol), CDFA (40 mmol), DMF (20 mL), flow rate = 0.3 mL min⁻¹, τ_R = 2 h, isolated yields.