A copper-catalyzed three-component reaction of dithioacetals with diazo ketones and ketimines.

A copper-catalyzed three-component reaction of dithioacetals with diazo-ketones and ketimines has been reported. This reaction proceeds via trapping of the highly active sulfur ylide species, which are generated from thioacetal and carbene intermediates, with isatin-derived ketimine, providing an efficient protocol for the synthesis of acyclic thioacetal derivatives and medium-sized sulfur-containing heterocycles in good to high yields under mild reaction conditions with a broad substrate scope.

Recent Advances in Catalytic Alkyne Transformation via Copper Carbene Intermediates.

As one of the abundant and inexpensive metals on the earth, copper has demonstrated broad applications in synthetic chemistry and catalysis. Among these copper-catalyzed advances, copper carbenes are versatile and reactive intermediates that can mediate a variety of transformations, which have attracted much attention in the past decades. The present review summarizes two different reaction models that take place between a copper carbene intermediate and alkyne species, including the cross-coupling reaction of copper carbene intermediate with terminal alkyne, and the addition of copper carbene intermediate onto the C-C triple bond. This article will cover the profile from 2010 to 2021 by placing emphasis on the detailed catalytic models and highlighting the synthetic applications offered by these practical and mild methods.

Generation of Diazomethyl Radicals by Hydrogen Atom Abstraction and Their Cycloaddition with Alkenes.

A general catalytic methodology for the synthesis of pyrazolines from α-diazo compounds and conjugated alkenes is reported. The direct hydrogen atom transfer (HAT) process of α-diazo compounds promoted by the tert-butylperoxy radical generates electrophilic diazomethyl radicals, thereby reversing the reactivity of the carbon atom attached with the diazo group. The regiocontrolled addition of diazomethyl radicals to carbon-carbon double bonds followed by intramolecular ring closure on the terminal diazo nitrogen and tautomerization affords a diverse set of pyrazolines in good yields with excellent regioselectivity. This strategy overcomes the limitations of electron-deficient alkenes in traditional dipolar [3+2]-cycloaddition of α-diazo compounds with alkenes. Furthermore, the straightforward formation of the diazomethyl radicals provides umpolung reactivity, thus opening new opportunities for the versatile transformations of diazo compounds.

AgI -Catalyzed Reaction of Enol Diazoacetates and Imino Ethers: Synthesis of Highly Functionalized Pyrroles.

An unprecedented AgI -catalyzed efficient method for the coupling of imino ethers and enol diazoacetates through a [3+2]-cycloaddition/C-O bond cleavage/[1,5]-proton transfer cascade process is reported. The general class of imino ethers that includes oxazolines, benzoxazoles and benzimidates are applicable substrates for these reactions that provide direct access to fully substituted pyrroles with uniformly high chemo- and regioselectivity. High variability in substitution at the pyrrole 2-, 5- and N-positions characterizes this methodology that also presents an entry point for further pyrrole diversification via facile modification of resulting N-functional pyrroles.

Strain-Induced Nucleophilic Ring Opening of Donor-Acceptor Cyclopropenes for Synthesis of Monosubstituted Succinic Acid Derivatives.

1,2,3-Trisubstituted donor-acceptor cyclopropenes (DACPs) generated in situ from enoldiazo compounds react with nucleophiles to form α-substituted succinic acid derivatives in high yields. Initial dirhodium(II) carboxylate catalysis rapidly converts enoldiazo-acetates or -acetamides to DACPs that undergo catalyst-free Favorskii ring opening with amines, and also with anilines, alcohols, and thiols, when facilitated by catalytic amounts of 4-dimethylaminopyridine (DMAP). This methodology provides easy access to mixed esters and amides of monosubstituted succinic acids, including derivatives of naturally occurring compounds. It also affords dihydrazide, dihydroxamic acid, and diamide derivatives, as well as α-substituted tetrahydropyridazine-3,6-diones in high yields. Attempts to generate optically enriched DACPs were not successful because their populations having the R and S configurations formed with a chiral dirhodium catalyst are quite similar, and the loss of enantiocontrol likely originates from the DACP ring forming step which is reversible with its intermediate metal carbene.

Chiral 3-Acylglutaric Acid Derivatives from Strain-Induced Nucleophilic Retro-Claisen Ring-Opening Reactions.

A nucleophilic retro-Claisen ring-opening of donor-acceptor cyclobutenes, formed with high stereocontrol by [3 + 1]-cycloaddition of TIPS-protected enoldiazoacetates with α-acyl sulfur ylides, has been developed. Removal of the TIPS group to form the isolable ß-keto ester precedes the strain-induced ring-opening. Various amines, alcohols, thiols, and amino acid derivatives are effective nucleophiles, and their products are formed in very high yields via stoichiometric reactions. The chirality of the reactant donor-acceptor cyclobutenes is fully retained in the ring-opening reactions. The 3-acylglutaric acid products are converted to various valuable structures, including amido-diols, γ-aminobutyric acid (GABA) derivatives, and heterocycles.

Transient-axial-chirality controlled asymmetric rhodium-carbene C(sp2)-H functionalization for the synthesis of chiral fluorenes.

In catalytic asymmetric reactions, the formation of chiral molecules generally relies on a direct chirality transfer (point or axial chirality) from a chiral catalyst to products in the stereo-determining step. Herein, we disclose a transient-axial-chirality transfer strategy to achieve asymmetric reaction. This method relies on transferring point chirality from the catalyst to a dirhodium carbene intermediate with axial chirality, namely a transient-axial-chirality since this species is an intermediate of the reaction. The transient chirality is then transferred to the final product by C(sp2)-H functionalization reaction with exceptionally high enantioselectivity. We also generalize this strategy for the asymmetric cascade reaction involving dual carbene/alkyne metathesis (CAM), a transition-metal-catalyzed method to access chiral 9-aryl fluorene frameworks in high yields with up to 99% ee. Detailed DFT calculations shed light on the mode of the transient-axial-chirality transfer and the detailed mechanism of the CAM reaction.

Brønsted Acid Catalyzed Friedel-Crafts-Type Coupling and Dedinitrogenation Reactions of Vinyldiazo Compounds.

The direct Friedel-Crafts-type coupling and dedinitrogenation reactions of vinyldiazo compounds with aromatic compounds using a metal-free strategy are described. This Brønsted acid catalyzed method is efficient for the formation of α-diazo ß-carbocations (vinyldiazonium ions), vinyl carbocations, and allylic or homoallylic carbocation species via vinyldiazo compounds. By choosing suitable nucleophilic reagents to selectively capture these intermediates, both trisubstituted α,ß-unsaturated esters, ß-indole-substituted diazo esters, and dienes are obtained with good to high yields and selectivity. Experimental insights implicate a reaction mechanism involving the selective protonation of vinyldiazo compounds and the subsequent release of dinitrogen to form vinyl cations that undergo intramolecular 1,3- and 1,4- hydride transfer processes as well as fragmentation.

Chiral donor-acceptor azetines as powerful reactants for synthesis of amino acid derivatives.

Coupling reactions of amines and alcohols are of central importance for applications in chemistry and biology. These transformations typically involve the use of a reagent, activated as an electrophile, onto which nucleophile coupling results in the formation of a carbon-nitrogen or a carbon-oxygen bond. Several promising reagents and procedures have been developed to achieve these bond forming processes in high yields with excellent stereocontrol, but few offer direct coupling without the intervention of a catalyst. Herein, we report the synthesis of chiral donor-acceptor azetines by highly enantioselective [3 + 1]-cycloaddition of enoldiazoacetates with aza-ylides and their selective coupling with nitrogen and oxygen nucleophiles via 3-azetidinones to form amino acid derivatives, including those of peptides and natural products. The overall process is general for a broad spectrum of nucleophiles, has a high degree of electronic and steric selectivity, and retains the enantiopurity of the original azetine.

Synthesis of Chiral Tetrasubstituted Azetidines from Donor-Acceptor Azetines via Asymmetric Copper(I)-Catalyzed Imido-Ylide [3+1]-Cycloaddition with Metallo-Enolcarbenes.

The all-cis stereoisomers of tetrasubstituted azetidine-2-carboxylic acids and derivatives that possess three chiral centers have been prepared in high yield and stereocontrol from silyl-protected Z-γ-substituted enoldiazoacetates and imido-sulfur ylides by asymmetric [3+1]-cycloaddition using chiral sabox copper(I) catalysis followed by Pd/C catalytic hydrogenation. Hydrogenation of the chiral p-methoxybenzyl azetine-2-carboxylates occurs with both hydrogen addition to the C=C bond and hydrogenolysis of the ester.

Copper-catalyzed [4+1]-annulation of 2-alkenylindoles with diazoacetates: a facile access to dihydrocyclopenta[b]indoles.

A copper-catalyzed [4+1]-annulation of 2-vinylindoles with diazoacetates has been developed that provides a straightforward access to the dihydrocyclopenta[b]indoles bearing two contiguous all-carbon quaternary centers in good yields. Mechanistic studies indicate that the reaction goes through a concerted and asynchronous annulation process via the key zwitterionic intermediate.

Copper-catalyzed carbene/alkyne metathesis terminated with the Buchner reaction: synthesis of dihydrocyclohepta[b]indoles.

A copper-catalyzed selective cascade reaction of alkyne-tethered diazo compounds is reported for the direct and efficient construction of dihydrocyclohepta[b]indole skeletons under mild reaction conditions. A vinyl copper carbene is the key intermediate, which is generated in situ via carbene/alkyne metathesis (CAM) and terminated with the Buchner reaction.

Enantioselective Oxidative Cyclization/Mannich Addition Enabled by Gold(I)/Chiral Phosphoric Acid Cooperative Catalysis.

An enantioselective Mannich-type reaction of 3-butynol and nitrones is described, which affords dihydrofuran-3-ones in good yields and with excellent enantioselectivities. The reaction is initiated by gold-catalyzed alkyne oxidation and modification of the resulting gold carbene species with a tethered hydroxy group to form enolate species; the reaction terminates with an enantioselective Mannich-type addition with the assistance of chiral phosphoric acid (CPA) and hydrogen bonding. This novel pattern of alkyne transformation involving chemical bond cleavage, and a fragment modification and reassembly process, provides an atom- and step-economic method, and is the first example of cooperative asymmetric catalysis in gold-catalyzed alkyne oxidations via an α-oxo gold carbene route.

Syntheses of Tetrahydropyridazine and Tetrahydro-1,2-diazepine Scaffolds through Cycloaddition Reactions of Azoalkenes with Enol Diazoacetates.

Catalyst-dependent [4 + 2]-cycloaddition reactions of azoalkenes from α-halohydrazones with enol diazoacetates have been developed. A [4 + 2]-cycloaddition of enol diazoacetates with in situ formed azoalkenes produces tetrahydropyridazinyl-substituted diazoacetates promoted by only Cs2CO3. In contrast, donor-acceptor cyclopropenes, which are formed in situ from enol diazoacetates by Rh2(OAc)4-catalyzed dinitrogen extrusion, undergo [4 + 2]-cycloaddition with azoalkenes to yield bicyclo[4.1.0]tetrahydropyridazines. These stable cycloaddition products undergo subsequent one-step transformations to form 6-alkylidenetetrahydropyridazines and 4,5,6,7-tetrahydro-1,2-diazepine derivatives in good yields.

Transition-Metal-Free Fluoroarylation of Diazoacetamides: A Complementary Approach to 3-Fluorooxindoles.

An efficient transition-metal-free fluoroarylation reaction of N-aryl diazoacetamides with NFSI (N-fluorobenzenesulfonimide) is described. This reaction directly provides 3-fluorooxindole derivatives in yields of 67-93% with high selectivity via a carbene-free process under mild reaction conditions.

NaI-Mediated Acetamidosulphenylation of Alkenes with Nitriles as the Nucleophiles: A Direct Access to Acetamidosulfides.

An example of a transition-metal-free, direct, and efficient acetamidosulphenylation reaction of alkenes using nitriles as the nucleophiles via a radical process is presented. This reaction shows a broad substrate scope and high regioselectivity and provides straightforward access to acetamidosulfide derivatives in moderate to high yields.

Oxime-mediated facile access to 5-methylisoxazoles and applications in the synthesis of valdecoxib and oxacillin.

A palladium-catalyzed efficient synthesis of 5-methylisoxazoles via oxime-mediated functionalization of unactivated olefins is described. The reaction affords a variety of 5-methylisoxazoles in moderate to good yields. To further demonstrate the utility of the method, the rapid synthesis of valdecoxib and oxacillin is reported.