Project description:A method for remote radical C-H alkynylation and amination of diverse aliphatic alcohols has been developed. The reaction features a copper nucleophile complex formed in situ as a photocatalyst, which reduces the silicon-tethered aliphatic iodide to an alkyl radical to initiate 1,n-hydrogen atom transfer. Unactivated secondary and tertiary C-H bonds at β, γ, and δ positions can be functionalized in a predictable manner.
Project description:The direct cyanomethylation of unactivated sp3 C-H bonds of aliphatic amides was achieved via palladium catalysis assisted by a bidentate directing group with good functional group compatibility. This process represents the first example of the direct cross-coupling of sp3 C-H bonds with acetonitrile. Considering the importance of the cyano group in medicinal and synthetic organic chemistry, this reaction will find broad application in chemical research.
Project description:Pd(0)-catalyzed intermolecular arylation of sp(3) C-H bonds has been achieved using PR(3)/ArI. This protocol can be used to arylate a variety of aliphatic carboxylic acid derivatives, including a number of bioactive drug molecules. The use of fluorinated aryl iodides also allows for the introduction of fluorine into a molecule of interest.
Project description:Cobalt-catalysed sp(2) C-H bond functionalization has attracted considerable attention in recent years because of the low cost of cobalt complexes and interesting modes of action in the process. In comparison, much less efforts have been devoted to the sp(3) carbons. Here we report the cobalt-catalysed site-selective dehydrogenative cyclization of aliphatic amides via a C-H bond functionalization process on unactivated sp(3) carbons with the assistance of a bidentate directing group. This method provides a straightforward synthesis of monocyclic and spiro β- or γ-lactams with good to excellent stereoselectivity and functional group tolerance. In addition, a new procedure has been developed to selectively remove the directing group, which enables the synthesis of free β- or γ-lactam compounds. Furthermore, the first cobalt-catalysed intermolecular dehydrogenative amination of unactivated sp(3) carbons is also realized.
Project description:A general efficient regioselective cobalt catalyzed carbonylation of unactivated C(sp3)-H bonds of aliphatic amides was demonstrated using atmospheric (1-2 atm) carbon monoxide as a C1 source. This straightforward approach provides access to α-spiral succinimide regioselectively in a good yield. Cobalt catalyzed sp3 C-H bond carbonylation is reported for the first time including the functionalization of (β)-C-H bonds of α-1°, 2°, 3° carbons and even internal (β)-C-H bonds. Our initial mechanistic investigation reveals that the C-H activation step is irreversible and will possibly be the rate determining step.
Project description:Intermolecular Ritter-type C-H amination of unactivated sp(3) carbons has been developed. This new reaction proceeds under mild conditions using readily available reagents and an inexpensive source of nitrogen (acetonitrile). A broad scope of substrates can be aminated with this method since many functional groups are tolerated. This reaction also allows for the direct, innate C-H amination of a variety of hydrocarbons such as cyclohexane without the need of prefunctionalization or installation of a directing group.
Project description:An intermolecular radical based distal selectivity in appended alkyl chains has been developed. The selectivity is maximum when the distal carbon is γ to the appended group and decreases by moving from γ → δ → ε positions. In -COO- linked alkyl chains, the same distal γ-selectivity is observed irrespective of its origin, either from the alkyl carboxy acid or alkyl alcohol. The appended groups include esters, N-H protected amines, phthaloyl, sulfone, sulfinimide, nitrile, phosphite, phosphate and borate esters. In borate esters, boron serves as a traceless directing group, which is hitherto unprecedented for any remote Csp3 -H functionalization. The selectivity order follows the trend: 3° benzylic > 2° benzylic > 3° tertiary > α to keto > distal methylene (γ > δ > ε). Computations predicted the radical stability (thermodynamic factors) and the kinetic barriers as the factors responsible for such trends. Remarkably, this strategy eludes any designer catalysts, and the selectivity is due to the intrinsic substrate reactivity.
Project description:The mechanism and origins of site-selectivity of Rh2(S-tfpttl)4-catalyzed C(sp3)-H bond aminations were studied using density functional theory (DFT) calculations. The synergistic combination of the dirhodium complex Rh2(S-tfpttl)4 with tert-butylphenol sulfamate TBPhsNH2 composes a pocket that can access both tertiary and benzylic C-H bonds. The nonactivated tertiary C-H bond was selectively aminated in the presence of an electronically activated benzylic C-H bond. Both singlet and triplet energy surfaces were investigated in this study. The computational results suggest that the triplet stepwise pathway is more favorable than the singlet concerted pathway. In the hydrogen atom abstraction by Rh-nitrene species, which is the rate- and site-selectivity-determining step, there is an attractive π-π stacking interaction between the phenyl group of the substrate and the phthalimido group of the ligand in the tertiary C-H activation transition structure. By contrast, such attractive interaction is absent in the benzylic C-H amination transition structure. Therefore, the DFT computational results clearly demonstrate how the synergistic combination of the dirhodium complex with sulfamate overrides the intrinsic preference for benzylic C-H amination to achieve the amination of the nonactivated tertiary C-H bond.
Project description:A direct oxidative C-H amination affording 1-acetyl indolecarboxylates starting from 2-acetamido-3-arylacrylates has been achieved. Indole-2-carboxylates can be targeted with a straightforward deacetylation of the initial reaction products. The C-H amination reaction is carried out using a catalytic Pd(II) source with oxygen as the terminal oxidant. The scope and application of this chemistry is demonstrated with good to high yields for numerous electron-rich and electron-poor substrates. Further reaction of selected products via Suzuki arylation and deacetylation provides access to highly functionalized indole structures.
Project description:Although Pd(OAc)2-catalysed alkoxylation of the C(sp3)-H bonds mediated by hypervalent iodine(iii) reagents (ArIX2) has been developed by several prominent researchers, there is no clear mechanism yet for such crucial transformations. In this study, we shed light on this important issue with the aid of the density functional theory (DFT) calculations for alkoxylation of butyramide derivatives. We found that the previously proposed mechanism in the literature is not consistent with the experimental observations and thus cannot be operating. The calculations allowed us to discover an unprecedented mechanism composed of four main steps as follows: (i) activation of the C(sp3)-H bond, (ii) oxidative addition, (iii) reductive elimination and (iv) regeneration of the active catalyst. After completion of step (i) via the CMD mechanism, the oxidative addition commences with an X ligand transfer from the iodine(iii) reagent (ArIX2) to Pd(ii) to form a square pyramidal complex in which an iodonium occupies the apical position. Interestingly, a simple isomerization of the resultant five-coordinate complex triggers the Pd(ii) oxidation. Accordingly, the movement of the ligand trans to the Pd-C(sp3) bond to the apical position promotes the electron transfer from Pd(ii) to iodine(iii), resulting in the reduction of iodine(iii) concomitant with the ejection of the second X ligand as a free anion. The ensuing Pd(iv) complex then undergoes the C-O reductive elimination by nucleophilic attack of the solvent (alcohol) on the sp3 carbon via an outer-sphere SN2 mechanism assisted by the X- anion. Noteworthy, starting from the five coordinate complex, the oxidative addition and reductive elimination processes occur with a very low activation barrier (ΔG ‡ 0-6 kcal mol-1). The strong coordination of the alkoxylated product to the Pd(ii) centre causes the regeneration of the active catalyst, i.e. step (iv), to be considerably endergonic, leading to subsequent catalytic cycles to proceed with a much higher activation barrier than the first cycle. We also found that although, in most cases, the alkoxylation reactions proceed via a Pd(ii)-Pd(iv)-Pd(ii) catalytic cycle, the other alternative in which the oxidation state of the Pd(ii) centre remains unchanged during the catalysis could be operative, depending on the nature of the organic substrate.