Copper-mediated amidation of heterocyclic and aromatic C-H bonds.
ABSTRACT: A copper-mediated aerobic coupling reaction enables direct amidation of heterocycles or aromatics having weakly acidic C-H bonds with a variety of nitrogen nucleophiles. These reactions provide efficient access to many biologically important skeletons, including ones with the potential to serve as inhibitors of HMTs.
Project description:A Rh(III)-catalyzed protocol for the amidation of anilide and enamide C-H bonds with isocyanates has been developed. This method provides direct and efficient syntheses of N-acyl anthranilamides, enamine amides, and pyrimidin-4-one heterocycles.
Project description:A Cu-catalyzed aromatic C-H amidation with phthalimide under oxygen as a terminal oxidant without using additional additives has been achieved. This reaction has the broad substrate scope and shows moderate to good yields in most cases. This method is complementary to the previously reported metal-catalyzed C-H amination systems.
Project description:The rhodium-catalyzed oxidative amidation of allylic alcohols and aldehydes is reported. In situ generated [(BINAP)Rh]BF4 catalyzes the one-pot isomerization/oxidative amidation of allylic alcohols or direct amidation of aldehydes using acetone or styrene as the hydrogen acceptor. The conditions are general, affording good to excellent yields with a wide array of amine and aniline nucleophiles, and chemoselective, other alcohols do not participate in the oxidation reaction. Utilization of biphasic conditions is critical, as they promote an equilibrium between the imine/enamine byproducts and the hemiaminal, which can undergo oxidation to the amide.
Project description:Abstract In the classical amidation between aromatic ketones and amines, 2.0 equivalents of amines are necessarily required to gain satisfying yields. The specific role of the amine in the direct amidation already puzzled us for a long time. In this work, we disclosed that the amine acts as both reactant and catalyst. Specifically, the determination of reaction intermediates revealed the full mechanism, based on which, the introduction of one equivalent base in the amidation is showcased here that a high yield (?95?%) can be afforded using only 1.1?equiv. of amine. Solving the puzzle: The role of the amine in direct amidation of aromatic ketones has been investigated. Amines act as both the reactant and catalyst, as such the excess amount (two or more equivalents) of amines are required to afford reasonable conversions/yields in the classical amidation. The direct amidation of aromatic ketones has been achieved at mild reaction conditions.
Project description:A divergent cyclopropanation reaction has been accomplished via the dearomative addition of sulfur ylides to activated N-heteroarenes. A series of biologically significant molecular skeletons was obtained by the direct cyclopropanation of quinolinium zwitterions. Furthermore, a straightforward synthetic route to optically enriched cyclopropane-fused heterocycles was developed using sulfur ylides as chiral nucleophiles in the 1,4-dearomative reaction.
Project description:An efficient amidation method between readily available 1,1-dicyanoalkanes and either chiral or nonchiral amines was realized simply with molecular oxygen and a carbonate base. This oxidative protocol can be applied to both sterically and electronically challenging substrates in a highly chemoselective, practical, and rapid manner. The use of cyclopropyl and thioether substrates support the radical formation of ?-peroxy malononitrile species, which can cyclize to dioxiranes that can monooxygenate malononitrile ?-carbanions to afford activated acyl cyanides capable of reacting with amine nucleophiles.
Project description:An oxidant-free Rh(iii)-catalyzed direct amidation of alkyl dithianes via C(sp3)-H bond activation utilizing diverse and robust dioxazolone reagents is reported. The reaction hinges on use of a Cp*Rh(iii) complex in combination with an essential amino-carboxylate additive to generate usefully protected 1,3-aminoaldehyde derivatives. The scalability of the reaction was demonstrated as was a series of downstream product functionalizations, including dithiane deprotection, anion alkylation and reductive desulfurization, highlighting the general applicability of this transformation in the synthesis of novel scaffolds and building blocks.
Project description:The scope and mechanistic implications of the direct transformation of heterocyclic N-oxides to 2-trifluoromethyl-, and related perfluoroalkyl- and perfluoroaryl-substituted N-heterocycles has been studied. The reaction is effected by perfluoroalkyl- and perfluorophenyltrimethylsilane in the presence of strong base. In situ displacement of the para-fluoro substituent in the pentafluorophenyl ring and the methoxy group in 8-methoxyquinolines with additional nucleophiles allows for further site-selective refunctionalization of the N-heterocyclic products.
Project description:The generally accepted monoacyloxyboron mechanism of boron-catalysed direct amidation is brought into question in this study, and new alternatives are proposed. We have carried out a detailed investigation of boron-catalysed amidation reactions, through study of the interaction between amines/carboxylic acids and borinic acids, boronic acids and boric acid, and have isolated and characterised by NMR/X-ray crystallography many of the likely intermediates present in catalytic amidation reactions. Rapid reaction between amines and boron compounds was observed in all cases, and it is proposed that such boron-nitrogen interactions are highly likely to take place in catalytic amidation reactions. These studies also clearly show that borinic acids are not competent catalysts for amidation, as they either form unreactive amino-carboxylate complexes, or undergo protodeboronation to give boronic acids. It therefore seems that at least three free coordination sites on the boron atom are necessary for amidation catalysis to occur. However, these observations are not consistent with the currently accepted 'mechanism' for boron-mediated amidation reactions involving nucleophilic attack of an amine onto a monomeric acyloxyboron intermediate, and as a result of our observations and theoretical modelling, alternative proposed mechanisms are presented for boron-mediated amidation reactions. These are likely to proceed via the formation of a dimeric B-X-B motif (X = O, NR), which is uniquely able to provide activation of the carboxylic acid, whilst orchestrating the delivery of the amine nucleophile to the carbonyl group. Quantum mechanical calculations of catalytic cycles at the B3LYP+D3/Def2-TZVPP level (solvent = CH2Cl2) support the proposal of several closely related potential pathways for amidation, all of which are likely to be lower in energy than the currently accepted mechanism.
Project description:Chromenes, isochromenes, and benzoxathioles react with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to form stable aromatic cations that react with a range of nucleophiles. These oxidative fragment coupling reactions provide rapid access to structurally diverse heterocycles. Conducting the reactions in the presence of a chiral Brønsted acid results in the formation of an asymmetric ion pair that can provide enantiomerically enriched products in a rare example of a stereoselective process resulting from the generation of a chiral electrophile through oxidative carbon-hydrogen bond cleavage.