reactivity of carbon centered nucleophile with electrophile

However, productively engaging a nucleophilic carbon-centered radical with a nucleophilic functionalizing reagent presents an inherent challenge due to polarity matching 3, 6, 14, 15, 16, 17. Nucleophilic reagents represent an abundant and practical reagent class, and offer an opportunity to access functional group compatibility complementary to that provided by electrophilic reagents. Electrophilic reagents are often strong oxidants, expensive to purchase, or require multi-step synthesis, posing limitations to their use in certain contexts 12, 13. While strategies for the homolytic cleavage of C(sp 3)–H bonds have been highly enabling, radical functionalization in these methodologies is dominated by electrophilic reagents (e.g., Selectfluor TM for fluorination, peroxides for alkoxylation, azodicarboxylates for amination, and electron-deficient arenes for C–C bond formation) (Fig. In contrast to hydride abstraction, HAT can offer a mild and versatile approach to C(sp 3)–H cleavage through the conversion of C(sp 3)–H bonds to radical intermediates 7, 9. Nevertheless, access to a carbocation from a C(sp 3)–H bond represents a valuable disconnection due to the versatility of the functionalization step, which can be general for a variety of heteroatom and carbon-centered nucleophiles in their native state. Among these tactics, hydride abstraction has seen limited development as a result of the requirement for strong Lewis acids, which are often incompatible with desirable substrates and functionalization reagents 5. Chemists have identified multiple strategies for C(sp 3)–H bond cleavage: oxidative addition with a transition metal, concerted C(sp 3)–H insertion, heterolytic cleavage via deprotonation or hydride abstraction, and homolytic cleavage via hydrogen atom transfer (HAT) (Fig. While significant progress has been made in this area, interfacing the cleavage of strong bonds with diverse and useful functionalization remains an outstanding challenge. 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(sp 3)–H functionalization.Ĭatalytic methods for C(sp 3)–H functionalization are of broad value for the construction of synthetic building blocks from feedstock chemicals and for the late-stage derivatization of complex molecules 1. 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. Here we describe a strategy that transforms C(sp 3)–H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover.

Notably, nucleophilic reagents represent an abundant and practical reagent class, motivating the interest in developing a general C(sp 3)–H functionalization strategy with nucleophiles. While highly enabling, functionalization of the carbon-centered radical is largely mediated by electrophilic reagents. Photoredox catalysis has provided many approaches to C(sp 3)–H functionalization that enable selective oxidation and C(sp 3)–C bond formation via the intermediacy of a carbon-centered radical.

Reactivity of carbon centered nucleophile with electrophile