Stop-Flow Microtubing Reactor-Assisted Visible Light-Induced Hydrogen-Evolution Cross Coupling of Heteroarenes with C(sp³)–H Bonds

Abstract

The synthesis of valuable alkyl-substituted heteroarenes from abundant and inexpensive feedstocks under mild conditions is attractive and highly desirable in pharmaceutical and natural product synthesis. Minisci-type cross dehydrogenative coupling between heteroarenes and C­(sp3)–H bonds offers direct access to these important scaffolds in a step-economic manner. Herein, assisted by stop-flow microtubing reactors, an operationally simple protocol for the visible light-induced hydrogen-evolution cross coupling of heteroarenes with unactivated C­(sp3)–H bonds was developed in a metal- and external oxidant-free manner. A wide range of alkylated heteroarenes was generated with common feedstock chemicals, including ethane. Mechanistic studies indicated that photoredox-induced hydrogen atom transfer processes followed by dehydrogenative rearomatization delivered the desired coupling products. The merits of this strategy were further demonstrated by the late-stage functionalization of various complex bioactive molecules.

Photoexcited Direct Amination/Amidation of Inert Csp3–H Bonds via Tungsten–Nickel Catalytic Relay

“…According to previous reports, − a plausible catalytic cycle is proposed (Scheme F). Under irradiation, photoexcitation of the photocatalyst would produce the triplet excited state.…”

“…For different substituted cyclohexanes, the amidation reaction occurred on the ring with high selectivity (46−51). Functional groups such as alkyl (46, 47), vinyl (48), and aryl (50) were all tolerated. Finally, we explored the CCNC of a simple alkane.…”

Phototriggered Self-Catalyzed Three-Component Minisci Reaction: A Route to β-C(sp3) Heteroarylated Alcohols/Ethers

“… In view of the high pharmaceutical importance of heteroarylethyl alcohol and its derivatives, methods that can directly functionalize heterocyclic substructures to generate medicinally valuable structural analogues are highly desirable. Minisci-type reactions constitute one of the most powerful synthetic strategies for building up complexity around basic heteroarenes . In this context, site-selective Minisci-type heteroarylation occurring at the position of α-C­(sp 3 ) and δ-C­(sp 3 ) of aliphatic alcohols has been greatly developed via the photoredox catalysis and 1,5-hydrogen-atom transfer strategy .…”

Hydrogen-Evolution Allylic C(sp3)–H Alkylation with Protic C(sp3)–H Bonds via Triplet Synergistic Brønsted Base/Cobalt/Photoredox Catalysis

“…Inspired by these elegant works, we envisioned that merging photoredox with cobalt catalysis could be a promising strategy to achieve oxidant-free allylic C(sp 3 )−H alkylation with protic C(sp 3 )−H feedstocks. In light of our ongoing interests in visible-lightinduced C(sp 3 )−H functionalization, 45,46 herein, we developed a mild protocol of hydrogen-evolution allylic C(sp 3 )−H alkylation with protic C(sp 3 )−H feedstocks enabled by a triplet synergistic Brønsted base/cobalt/photoredox catalysis (Figure 1D). 47 A wide range of branched α-olefins were tolerated in this strategy.…”