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.

Cu-catalyzed aerobic C(CO)−CH3 activation of (hetero)aryl methyl ketones provides a rare tool for aldehyde formation from ketones through oxidative processes. To elucidate the detailed reaction mechanism, a combined computational and experimental study was performed. Computational study indicates a dinuclear Cu-catalyzed spin-crossover-involved mechanism explains the aldehyde formation. Meanwhile, α-mono(hydroxy)- acetophenone int1 was found to be the real active intermediate for the formation of benzaldehyde pro1 from acetophenone sub1. sub1 transforms into int1 via oxygen activation and ratedetermining Cα−H activation. The resulting dinuclear Cu complex regenerates the active Cu(I) complex through spin-crossoverinvolved disproportionation and retro oxygen activation. int1 further generates pro1 via oxygen activation, O−H activation, iodide atom transfer, 1,2-H shift, ligand rotation, spin crossover, and nucleophilic substitution. By comparison, the previously proposed reaction route

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.

Flavin-dependent catalysts are widely applied to aerobic monooxygenation/oxidation reactions. In contrast, flavin-catalyzed aerobic dioxygenation reactions exhibit higher atomic economy but are less reported, not to mention the relevant mechanistic studies. Herein, a density functional theory study on flavin-catalyzed aerobic epoxidation-oxygenolysis of alkenyl thio-esters was performed for the first time. Different from the previous mechanistic proposal, a pathway featuring two catalytic stages, monoanionic flavin-C(4a)-peroxide/oxide intermediates, and a reverse reaction sequence (epoxidation goes prior to oxygenolysis) was revealed. In comparison, the pathways involving dianionic flavin catalysts, monoanionic flavin-N(5)-(hydro)peroxide/C-(10a)-peroxide, or neutral flavin-C(4a)-hydroperoxide/hydroxide/N(5)-oxide, and the pathways where oxygenolysis goes prior to epoxidation are less favored. Epoxidation goes through intramolecular substitution of the O−O bond of anionic flavin-C(4a)

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.

Flavin-dependent catalysts are widely applied to aerobic monooxygenation/oxidation reactions. In contrast, flavin-catalyzed aerobic dioxygenation reactions exhibit higher atomic economy but are less reported, not to mention the relevant mechanistic studies. Herein, a density functional theory study on flavin-catalyzed aerobic epoxidation-oxygenolysis of alkenyl thio-esters was performed for the first time. Different from the previous mechanistic proposal, a pathway featuring two catalytic stages, monoanionic flavin-C(4a)-peroxide/oxide intermediates, and a reverse reaction sequence (epoxidation goes prior to oxygenolysis) was revealed. In comparison, the pathways involving dianionic flavin catalysts, monoanionic flavin-N(5)-(hydro)peroxide/C-(10a)-peroxide, or neutral flavin-C(4a)-hydroperoxide/hydroxide/N(5)-oxide, and the pathways where oxygenolysis goes prior to epoxidation are less favored. Epoxidation goes through intramolecular substitution of the O−O bond of anionic flavin-C(4a)