Density functional theory (DFT) calculations have been conducted to unravel the mechanisms and chemoselectivities of Au-catalyzed diazo-based couplings with phenyl unsaturated aliphatic alcohols: the propargyl alcohol Ba resulting in the [4 + 1]-cycloaddition product P4a and the allyl alcohol Db giving the [2,3]-σ rearrangement species P5b. P4a formation involves a catalyst interaction with phenyldiazoacetate, N2 release, a hydroxyl O nucleophilic attack of Ba, a [1,4]-H shift, coordination isomerization, 5-endo-dig cyclization, a [4,1]-H shift and a H2O-assisted [1,3]-H shift. After the [4,1]-H shift, the slightly less favorable five-membered ring-opening possibly follows to afford trace P5a ([2,3]-σ rearrangement product), which would be kept in solution due to subsequent irreversible evolution. In addition, the Ba-involved chemoselectivity was probed and explained as follows: (i) both large HIJhydroxyl)⋯C(carbene) electrostatic repulsion and strong three-membered ring strain involved

Reactions of thiocarboxylic acids and dithiocarbamate-terminal amines provide a linker-traceless method for amide bond formation under mild conditions, whereas the reaction mechanism is not clear. A systematic study was performed herein with density functional theory (DFT) calculations to elucidate the detailed mechanism, the substitution effect on the proposed CS2-releasing 1,3-acyl transfer and the differences between CS2- and CO2-releasing 1,3-acyl transfer. Relevant results indicate that this type of reaction proceeds via the nucleophilic addition of an in situ generated dithiocarbamic acid on thiocarboxylic acid, H2S elimination, rate-determining 1,3-acyl transfer and CS2 release. For the generation of secondary amides via the 1,3-acyl transfer, a thiocarboxylic acid- or dithiocarbamic acid-assisted pathway, in which both the carbonyl group and amide nitrogen are activated, is the most favored. For the generation of tertiary amides, MeOH-assisted carbonyl-activation is the most fa

Pd-catalyzed C(sp3)−H activation/alkylation of 2-tert-butylaryl halides with alkyl halides and CH2Br2 represents an advantageous strategy for the C−H functionalization with halogens as traceless directing groups. Several possible mechanisms were proposed for the reactions, but no further evidence was available to judge their relative feasibilities. Herein, a mechanistic study was performed with the aid of density functional theory (DFT) methods. Calculations indicate that the coupling of aryl bromides with alkyl chlorides is likely to generate alkylated benzocyclobutenes via aryl−Br oxidative addition on Pd(0) catalysts, C(sp3)−H activation, alkyl−Cl oxidative addition, aryl−alkyl reductive elimination, aryl−H activation, and aryl−C(sp3) reductive elimination. The coupling of aryl iodides with CH2Br2 is likely to generate indane derivatives via aryl−I oxidative addition, C(sp3)−H activation, alkyl−Br oxidative addition, aryl−CH2Br reductive elimination, alkyl−Br oxidative addition, C(s

A novel boron ester-catalyzed amidation reaction of carboxylic acids and amines with unprecedented functional group tolerance was recently reported. To gain deeper insights into this reaction, a computational study with density functional theory methods was performed in this manuscript. Calculations indicate that the amidation starts with the condensation of carboxylic acids with the boron ester catalyst. The resulting monoacyloxylated boron species further undergoes the carboxylic acid-assisted nucleophilic addition with amines to generate the amide product and a monohydroxyboron species. The condensation of the carboxylic acid with the monohydroxyboron species with the assistance of an amine regenerates monoacyloxylated boron species to finish the catalytic cycle. The rate-determining step is catalyst regeneration and the amine-coordinated monohydroxyboron species is the resting state in the catalytic cycle. The present results are consistent with the previous NMR study and the obser

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)