The recognition of the biological activity of H2S has drawn much attention to the development of biocompatible H2S release reactions. Thiol-, particularly cysteine-triggered systems which mimic the enzymatic conversion of cysteine or homocysteine to H2S have been intensively reported recently. Herein, a density functional theory (DFT) study was performed to address the reaction mechanism of H2S release and potential amide bond formation from thionoesters and cysteine to gain deeper mechanistic insights. Three possible mechanisms were considered and we found that the one starting from the nucleophilic addition of the ionized mercapto of cysteine on thionoester to generate a dithioester intermediate (Path A) is kinetically favored over the others starting from the nucleophilic addition of the amine of cysteine to generate thionoamide intermediates (Paths B and C). Dithioester then undergoes intramolecular nucleophilic addition of an amine group and the rate-limiting water-assisted proton

The mechanism of ruthenium-catalyzed [4 + 1] annulation of benzamide and propargyl alcohol has been investigated by density functional theory calculations. The reaction undergoes N−H and C−H deprotonations by a concerted metalation-deprotonation mechanism to afford a 5- membered ruthenacyclic species, which then undergoes ring expansion by alkyne insertion to deliver a 7-membered ring intermediate. Our study focused on how the successive hydrogen migrations take place that remains unclear. The 1,2- proton migration and 1,3-proton transfer from O to C are successively finished by using acetate anion as a shuttle (a stepwise process). In contrast to the experimental proposal that the reaction experiences a Ru(II)−Ru(0)−Ru(II) transformation, our study unveiled a Ru(II)−Ru(IV)−Ru(II) transformation in the reaction. In addition, our calculations suggested that the EtO−N bond cleavage rather than the C−H activation is likely to be the rate-determining step for the entire reaction, which is

The combination of carbon monoxide with palladium chemistry has been demonstrated to be a promising tool for the synthesis of carbonyl compounds, and relative mechanistic studies are desirable to take this field one step further. In this manuscript, density functional theory calculations were performed to investigate the mechanism and origin of stereoselectivity of Pd-catalyzed cascade annulation of aryl iodide, alkene, and carbon monoxide to access the core of cephanolides B and C. It was found that the favorable mechanism proceeds via oxidative addition of Ar−I bond, migratory insertion of the CC bond, CO insertion into the Pd−(sp3) bond, Ar−H activation, and C(sp2)− C(sp2) reductive elimination. The Ar−H activation is the ratedetermining step and goes through an I-assisted outer-sphere concerted metalation−deprotonation mechanism. The CC bond insertion is irreversible and controls the stereoselectivity. In contrast, other two pathways involving the direct Ar−H activation after the

We discovered a cooperative gold/silver catalysis mechanism in the oxidative cross-coupling reaction between 1,2,4,5-tetrafluorobenzene and N-TIPS-indole, using DFT calculations. A silver(I)- catalyzed CMD mechanism is responsible for the C−H activation of 1,2,4,5-tetrafluorobenzene, and C−H acidity determines the chemoselectivity. A gold(III)-catalyzed SE2Ar mechanism is responsible for the C3−H activation of N-TIPS-indole, and arene nucleophilicity determines the chemo- and regioselectivity. The orthogonal chemoselectivity control provides a mechanistic guide for dual C−H activation reactions.

A 1,1-hydroboration of alkynylgermanes with unique transGe/B stereochemistry under transition-metal-free conditions is reported. Mechanistic studies suggest that a pathway involving α boration followed by a stepwise 1,2-Ge/H shift on the intermediate structurally lies between an alkyne−Ge+ π complex and a typical vinyl cation. The resulting Ge/B bimetallic modules, along with a Ge*/Ge/B trimetallic variant, can be conveniently transformed into trisubstituted olefins through iterative divergent cross-coupling. This work demonstrates that incorporating metalloids into classical organic reactions may offer unconventional chemical selectivity and efficient synthetic applications.

Nickel/photoredox dual catalyzed cross-coupling of aryl halides with alkylboron compounds is one of the effective methodologies for the construction of C(sp2) C(sp3) bonds. Although elegant results have been achieved by using alkyl trifluoroborates as alkyl radical precursors, the generation of alkyl radicals from readily available alkyl boronic esters is still limited due to their high oxidation potential. We disclosed here that activation of alkyl boronic esters by MeOLi is highly efficient for the generation of alkyl radicals under photocatalysis conditions. The reaction featured with a wide substrate scope, high functional group tolerance, and late-stage modification of bioactive substances. In addition, the method was also successfully extended to alkyl boronic acids. Experimental and computational mechanistic studies indicated that the crosscoupling likely proceeds via a Ni(I)-catalyzed pathway.

α-Heteroatom-substituted amides are useful as both targets and intermediates but are challenging to synthesize via conventional enolate chemistry. Herein, we describe a general and unified umpolung procedure to prepare α-heteroatom-functionalized secondary amides with various heteroatom-based nucleophiles under redox-neutral conditions. This transformation is a formal oxidation state reshuffle process from -N to -C in the hydroxamate, thereby achieving the umpolung α-heterofunctionalization of carbonyl groups without external oxidants. Regulated by the reshuffle mechanism, functionalization exclusively occurs at the α-position of the hydroxamate and precisely affords the α-functionalized amide with reliable predictability even in complex settings. Density functional theory studies support that soft enolization enabled by Mg2+/DIPEA combination is essential to facilitate the formation of the α-lactam intermediate. This represents the first general protocol to prepare α-functionalized se

The classic Curtius rearrangement provides an efficient method for converting carboxylic acids into amine derivatives but has safety concerns. Herein, we report a general and powerful method for the direct decarboxylative C–N coupling of alkyl and aryl carboxylic acids with dioxazolones in the presence of a base. A diverse array of amides, especially acylated chiral amines, can be synthesized under transition-metal-free conditions at room temperature, offering an alternative to the classic Curtius rearrangement. On the basis of mechanistic investigations, a distinctive mechanism involving multiple nucleophilic addition–eliminations, acyl transfers and a Lossen-type rearrangement is proposed for this unpredicted stereoretentive transformation.

A 1,1-hydroboration of alkynylgermanes with unique transGe/B stereochemistry under transition-metal-free conditions is reported. Mechanistic studies suggest that a pathway involving α boration followed by a stepwise 1,2-Ge/H shift on the intermediate structurally lies between an alkyne−Ge+ π complex and a typical vinyl cation. The resulting Ge/B bimetallic modules, along with a Ge*/Ge/B trimetallic variant, can be conveniently transformed into trisubstituted olefins through iterative divergent cross-coupling. This work demonstrates that incorporating metalloids into classical organic reactions may offer unconventional chemical selectivity and efficient synthetic applications.

Nickel/photoredox dual catalyzed cross-coupling of aryl halides with alkylboron compounds is one of the effective methodologies for the construction of C(sp2) C(sp3) bonds. Although elegant results have been achieved by using alkyl trifluoroborates as alkyl radical precursors, the generation of alkyl radicals from readily available alkyl boronic esters is still limited due to their high oxidation potential. We disclosed here that activation of alkyl boronic esters by MeOLi is highly efficient for the generation of alkyl radicals under photocatalysis conditions. The reaction featured with a wide substrate scope, high functional group tolerance, and late-stage modification of bioactive substances. In addition, the method was also successfully extended to alkyl boronic acids. Experimental and computational mechanistic studies indicated that the crosscoupling likely proceeds via a Ni(I)-catalyzed pathway.

α-Heteroatom-substituted amides are useful as both targets and intermediates but are challenging to synthesize via conventional enolate chemistry. Herein, we describe a general and unified umpolung procedure to prepare α-heteroatom-functionalized secondary amides with various heteroatom-based nucleophiles under redox-neutral conditions. This transformation is a formal oxidation state reshuffle process from -N to -C in the hydroxamate, thereby achieving the umpolung α-heterofunctionalization of carbonyl groups without external oxidants. Regulated by the reshuffle mechanism, functionalization exclusively occurs at the α-position of the hydroxamate and precisely affords the α-functionalized amide with reliable predictability even in complex settings. Density functional theory studies support that soft enolization enabled by Mg2+/DIPEA combination is essential to facilitate the formation of the α-lactam intermediate. This represents the first general protocol to prepare α-functionalized se

The classic Curtius rearrangement provides an efficient method for converting carboxylic acids into amine derivatives but has safety concerns. Herein, we report a general and powerful method for the direct decarboxylative C–N coupling of alkyl and aryl carboxylic acids with dioxazolones in the presence of a base. A diverse array of amides, especially acylated chiral amines, can be synthesized under transition-metal-free conditions at room temperature, offering an alternative to the classic Curtius rearrangement. On the basis of mechanistic investigations, a distinctive mechanism involving multiple nucleophilic addition–eliminations, acyl transfers and a Lossen-type rearrangement is proposed for this unpredicted stereoretentive transformation.