A general strategy for C(sp3)-H functionalization with nucleophiles using methyl radical as a hydrogen atom abstractor

Abstract

Photoredox catalysis has provided many approaches to C(sp³)-H functionalization that enable selective oxidation and C(sp³)-C bond formation via the intermediacy of a carbon-centered radical. While highly enabling, functionalization of the carbon-centered radical is largely mediated by electrophilic reagents. Notably, nucleophilic reagents represent an abundant and practical reagent class, motivating the interest in developing a general C(sp³)-H functionalization strategy with nucleophiles. Here we describe a strategy that transforms C(sp³)-H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover. The resulting carbocation is functionalized by a variety of nucleophiles-including halides, water, alcohols, thiols, an electron-rich arene, and an azide-to effect diverse bond formations. Mechanistic studies indicate that HAT is mediated by methyl radical-a previously unexplored HAT agent with differing polarity to many of those used in photoredox catalysis-enabling new site-selectivity for late-stage C(sp³)-H functionalization.

Fig. 1. Prior art in nucleophilic C(sp³)–H functionalization and overview of this work.

A Current mechanisms employed for C(sp³)–H activation and subsequent functionalization. B Array of common electrophilic and nucleophilic functionalizing reagents. C Recent examples of nucleophilic C(sp³)–H functionalization^–,–. D This work. HAT=hydrogen atom transfer.

Fig. 2. Scope of C(sp³)–H fluorination (0.25 mmol scale, ¹⁹F NMR yields).

^aReaction performed using Ir(p-CF₃-ppy)₃ as photocatalyst and benzene as solvent. ^bReaction performed using Ir(p-CF₃-ppy)₃ as photocatalyst and 1,2-difluorobenzene as solvent. ^cReaction performed with 20 mol % n-Bu₄NPF₆. ^dReaction performed using Ir(p-CF₃-ppy)₃ as photocatalyst, 1,2-difluorobenzene as solvent, and abstractor 3.

Fig. 3. Scope of C(sp³)–H difluorination (0.25 mmol scale, ¹⁹F NMR yield).

See Supplementary Information for reaction details.

Fig. 4. Scope of general nucleophilic C(sp³)–H functionalization (0.25 mmol, isolated yields).

^a19F NMR yields. ^bReaction was performed without Et₃N•3HF. ^cReaction was performed without Et₃N•3HF and with 0.15 equiv. H₂O. ^dReaction performed using Ir(p-CF₃-ppy)₃ as photocatalyst, benzene as solvent, and 3.0 equiv. C(sp³)–H coupling partner.

Fig. 5. Mechanistic investigations of nucleophilic C(sp³)–H fluorination.

A Proposed catalytic cycle. B Radical trapping experiments. C Monitoring of (i) methane and (ii) methane-d₁ evolution by PhotoNMR. D Investigation of regioselectivity via competition experiments among 3°, 2° and 1 °C(sp³)–H coupling partners. E Investigation of kinetic isotope effect via parallel initial rates experiment with ethylbenzene and ethylbenzene-d₁₀. F Hammett analysis performed with the methyl radical precursor (left) and the methoxy radical precursor (right). ^aFor reaction conditions see Fig. 2 (¹⁹F NMR yields). ^bReaction performed with 1.5 equiv. TEMPO (¹H NMR yield). ^cSee Supplementary Information for details.

Fig. 6. Investigations of site-selectivity with methoxy and methyl radical in the functionalization of ibuprofen ethyl ester.

A Tunable selectivity for the C(sp³)–H functionalization of ibuprofen demonstrating favorable secondary benzylic fluorination with methoxy radical (left) and favorable tertiary benzylic fluorination with methyl radical (right). B Previous examples of site-selectivity in the C(sp³)–H functionalization of ibuprofen^,,. ^aReaction performed using abstractor 3 and standard reaction conditions described in Fig. 2. ^bReaction performed using abstractor 1 and standard reaction conditions described in Fig. 2.