Direct Synthesis of Thioesters from Feedstock Chemicals and Elemental Sulfur.

The development of a mild, atom- and step-economical catalytic strategy that effectively generates value-added molecules directly from readily available commodity chemicals is a central goal of organic synthesis. In this context, the thiol-ene click chemistry for carbon-sulfur (C-S) bond construction has found widespread applications in the synthesis of pharmaceuticals and functional materials. In contrast, the selective carbonyl thiyl radical addition to carbon-carbon multiple bonds remains underdeveloped. Herein, we report a carbonyl thiyl radical-based thioester synthesis through three-component coupling from feedstock aldehydes, alkenes, or alkynes and elemental sulfur by direct photocatalyzed hydrogen atom transfer. This method represents an orthogonal strategy to the conventional thiol-based nucleophilic substitution and exhibits a remarkably broad substrate scope ranging from simple commodity chemicals such as ethylene and acetylene to complex pharmaceutical molecules. This protocol can be easily extended to the synthesis of thiolactones, oligomer/polymers, and thioacids. Its synthetic utility has been demonstrated by a two-step synthesis of the drug esonarimod. Mechanistic studies indicate that the use of elemental sulfur to trap acyl radicals is both thermodynamically and kinetically favored, illustrating its great potential for the synthesis of sulfur-containing molecules.

Oxygen mediated oxidative couplings of flavones in alkaline water.

Catalyzed oxidative C-C bond coupling reactions play an important role in the chemical synthesis of complex natural products of medicinal importance. However, the poor functional group tolerance renders them unfit for the synthesis of naturally occurring polyphenolic flavones. We find that molecular oxygen in alkaline water acts as a hydrogen atom acceptor and oxidant in catalyst-free (without added catalyst) oxidative coupling of luteolin and other flavones. By this facile method, we achieve the synthesis of a small collection of flavone dimers and trimers including naturally occurring dicranolomin, philonotisflavone, dehydrohegoflavone, distichumtriluteolin, and cyclodistichumtriluteolin. Mechanistic studies using both experimental and computational chemistry uncover the underlying reasons for optimal pH, oxygen availability, and counter-cations that define the success of the reaction. We expect our reaction opens up a green and sustainable way to synthesize flavonoid dimers and oligomers using the readily available monomeric flavonoids isolated from biomass and exploiting their use for health care products and treatment of diseases.

Photomediated reductive coupling of nitroarenes with aldehydes for amide synthesis.

In view of the widespread significance of amide functional groups in organic synthesis and pharmaceutical studies, an efficient and practical synthetic protocol that avoids the use of stoichiometric activating reagents or metallic reductants is highly desirable. A straight-forward pathway to access amides from abundant chemical feedstock would offer a strategic advantage in the synthesis of complex amides. We herein disclose a direct reductive amidation reaction using readily available aldehydes and nitroarenes enabled by photo-mediated hydrogen atom transfer catalysis. It avoids the use of metallic reductants and production of toxic chemical waste. While aldehydes represent a classic class of electrophilic synthons, the corresponding nucleophilic acyl radicals could be directly accessed by photo hydrogen atom transfer catalysis, enabling polarity inversion. Our method provides an orthogonal strategy to conventional amide couplings, tolerating nucleophilic substituents such as free alcohols and sensitive functional groups to amines such as carbonyl or formyl groups. The synthetic utilization of this reductive amidation is demonstrated by the late-stage modification of complex biologically active molecules and direct access of drug molecules leflunomide and lidocaine.

Divergent functionalization of aldehydes photocatalyzed by neutral eosin Y with sulfone reagents.

While aldehydes represent a classic class of electrophilic synthons, the corresponding acyl radicals are inherently nucleophilic, which exhibits umpolung reactivity. Generation of acyl radicals typically requires noble metal catalysts or excess oxidants to be added. Herein, we report a convenient and green approach to access acyl radicals, capitalizing on neutral eosin Y-enabled hydrogen atom transfer (HAT) photocatalysis with aldehydes. The generated acyl radicals underwent SOMOphilic substitutions with various functionalized sulfones (X-SO2R') to deliver value-added acyl products. The merger of eosin Y photocatalysis and sulfone-based SOMOphiles provides a versatile platform for a wide array of aldehydic C-H functionalizations, including fluoromethylthiolation, arylthiolation, alkynylation, alkenylation and azidation. The present protocol features green characteristics, such as being free of metals, harmful oxidants and additives; step-economic; redox-neutral; and amenable to scale-up assisted by continuous-flow technology.

Visible light driven deuteration of formyl C-H and hydridic C(sp3)-H bonds in feedstock chemicals and pharmaceutical molecules.

Deuterium labelled compounds are of significant importance in chemical mechanism investigations, mass spectrometric studies, diagnoses of drug metabolisms, and pharmaceutical discovery. Herein, we report an efficient hydrogen deuterium exchange reaction using deuterium oxide (D2O) as the deuterium source, enabled by merging a tetra-n-butylammonium decatungstate (TBADT) hydrogen atom transfer photocatalyst and a thiol catalyst under light irradiation at 390 nm. This deuteration protocol is effective with formyl C-H bonds and a wide range of hydridic C(sp3)-H bonds (e.g. α-oxy, α-thioxy, α-amino, benzylic, and unactivated tertiary C(sp3)-H bonds). It has been successfully applied to the high incorporation of deuterium in 38 feedstock chemicals, 15 pharmaceutical compounds, and 6 drug precursors. Sequential deuteration between formyl C-H bonds of aldehydes and other activated hydridic C(sp3)-H bonds can be achieved in a selective manner.