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An asymmetric synthesis of N-aryl sulfinamides was achieved through copper-catalyzed coupling reactions of aryl iodides with sulfinamides. Such a kinetic resolution process provided the desired coupling products in moderate to good yields and with moderate enantioselectivities.

Transition metal catalyzed coupling reactions of aryl halides with nucleophiles are valuable methods for the formation of aryl carbon–carbon or aryl carbon–heteroatom bonds. However, little attention has been focused on the asymmetric versions of such couplings. Besides direct coupling for the formation of axial chirality, asymmetric desymmetrization and kinetic resolution are two important strategies for achieving enantioselectivity in transition metal catalyzed aryl carbon–heteroatom couplings. This account summarizes recent progress made in our group on copper- or palladium-catalyzed asymmetric aryl carbon–nitrogen/oxygen coupling reactions using asymmetric desymmetrization or kinetic resolution strategies. 1 Introduction 2 Copper-Catalyzed Asymmetric N-Arylation 2.1 N-Arylation via Asymmetric Desymmetrization 2.1.1 First Type of Desymmetric N-Arylation 2.1.2 Second Type of Desymmetric N-Arylation 2.1.3 Double N-Arylation for Spirobilactams 2.2 N-Arylation via Kinetic Resolution 3 Asymmetric O-Arylation 3.1 Palladium/Spirocyclic Diphosphine Ligand System for O-Aryl­ation via Asymmetric Desymmetrization 3.2 Palladium/Spirocyclic Diphosphine Monoxide Ligand System for O-Arylation via Asymmetric Desymmetrization 3.3 Copper/Diamine System for O-Arylation via Asymmetric Desymmetrization 4 Summary and Outlook

Copper-catalyzed (or -mediated) asymmetric coupling reactions have received significant attention over the past few years. Especially the coupling reactions of aryl or alkyl halides with nucleophiles became a very powerful tool for the formation of C–C, C–N, C–O and other carbon–heteroatom bonds as well as for the construction of heteroatom-containing ring systems. This review summarizes the recent progress in copper-catalyzed asymmetric coupling reactions for the formation of C–C and carbon–heteroatom bonds.

A series of title compounds is prepared as building blocks for functional chiral molecules.

A copper-catalyzed enantioselective N-arylation for the formation of cyano-bearing all-carbon quaternary stereocenters was developed via kinetic resolution of racemic 3-amino-2-(2-iodobenzyl)propanenitriles. The reaction afforded the desired coupling products in moderate enantioselectivity under catalysis by CuI and a BINOL-derived ligand.

The method has been successfully applied in the syntheses of selective 5-HT1A receptor agonist MKC-242 (VIIIa) and selective α1D-adrenoceptor inhibitor WB4101 (VIIIb).

The differentiation of two nucleophilic amide groups in malonamides through a copper-catalyzed enantioselective intramolecular aryl C–N coupling reaction is demonstrated based on an asymmetric desymmetrization strategy. Such a method afforded enantioenriched 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamides in high yields and moderate to good enantioselectivity.

The cyano group at the prochiral center plays a key role for the high enantioselectivity of the copper-catalyzed intramolecular N-arylation reactions to give tetrahydroquinoline and tetrahydrobenzoazepine derivatives.

Both enantiomeric products are obtained using the same catalyst but in the presence or absence of DMAP as an additive.

An enantioselective intramolecular O-arylation was achieved through desymmetrization with Pd-catalyzed coupling reactions. The intramolecular asymmetric aryl C–O coupling reactions of 2-(2-haloaryl)propane-1,3-diols led to the enantioselective formation of chiral (3,4-dihydro-2H-chromen-3-yl)methanols in good yields and high enantiomeric selectivity.

The title multicomponent reaction proceeds through an unpredicted ring-opening process of the ketenimine-imine [2 + 2] intermediate.

The first highly enantioselective protocol for preparation of indolines and tetrahydroquinolines via Cu-catalyzed asymmetric desymmetrization of 2-propanamines and 3-pentaneamines, respectively is presented.

The sequence allow a new and efficient access to a number of triazoloquinoline derivatives.

The reaction is effective starting from iodo and bromo substrates, tolerates aromatic and aliphatic substituents at the triple bond and different substituents at the nitrogen and on the aromatic ring.

The Pd-catalyzed aminocarbonylation of carbenes, in situ generated from N-tosylhydrazones, with isocyanides represents a novel access towards carboxylic amides, e.g. (III), (V), (VIII) and (X).

The copper-catalyzed tandem reaction of isocyanides with N-(2-haloaryl)propiolamides is very efficient for the synthesis of pyrrolo[3, 2-c]quinolin-4-ones. Highly reactive cyclic organocopper intermediates were proposed to be generated in the copper-catalyzed formal [3 + 2] cycloaddition reaction of isocyanides with triple bonds. Intramolecular trapping of the organocopper intermediates can lead to aryl C-C bond formation, which offered an efficient method for constructing fused pyrrole structures.

A general synthesis of 1-aryl-1-H-indazoles from o-halogenated aryl aldehydes or ketones and aryl hydrazines was described. This protocol included an intermolecular condensation and a ligand-free copper-catalyzed intramolecular Ullmann-type coupling reaction. This method was applied to a wide range of substrates to produce the indazole products in good yields.

A room-temperature cascade process for the formation of diethyl 2-aryl-3,4-dihydro-4-oxo-1,1(2H)-naphthalenedicarboxylate is described by using a combination of Michael addition and copper-catalyzed α-arylation of malonic acid derivatives. The protocol worked well for a variety of 1-(2-iodoaryl)enones and displayed great functional group compatibility.

The optimized conditions allow an efficient N-arylation of a variety of heterocycles with (het)aryl bromides and iodides.

A broad spectrum of target compounds is prepared with good yields starting from benzimidazole (I) via an intermolecular condensation followed by intramolecular C—N coupling.

The copper(I) bromide/1-(5,6,7,8-tetrahydroquinolin-8-yl)-2-methylpropan-1-one (CuBr-L3) combination catalyzed the cross-coupling reactions between aryl or heteroaryl halides and aqueous ammonia with high yields to produce primary aromatic or heteroaromatic amines at room temperature or under mild conditions.

Copper-assisted Ullmann-type coupling reactions are valuable transformations for organic synthesis. Researchers have extensively applied these reactions in both academic and industrial settings. However, two important issues, the high reaction temperatures (normally above 150 °C) and the stoichiometric amounts of copper necessary, have greatly limited the reaction scope. To solve these problems, we and other groups have recently explored the use of special ligands to promote these coupling reactions. We first showed that the structure of α-amino acids can accelerate Cu-assisted Ullmann reactions, leading to the coupling reactions of aryl halides and α-amino acids at 80−90 °C. In response to these encouraging results, we also discovered that an l-proline ligand facilitated the following transformations: (1) coupling of aryl halides with primary amines, cyclic secondary amines, and N-containing heterocycles at 40−90 °C; (2) coupling of aryl halides with sulfinic acid salts at 80−95 °C; (3) azidation of aryl...

Smac/DIABLO is a protein released from mitochondria into the cytosol in response to apoptotic stimuli. Smac promotes apoptosis at least in part through antagonizing inhibitor of apoptosis proteins (IAPs), including XIAP, cIAP-1, and cIAP-2. Smac interacts with these IAPs via its N-terminal AVPI binding motif. There has been an enormous interest in academic laboratories and pharmaceutical companies in the design of small-molecule Smac mimetics as potential anticancer agents. This task is particularly challenging because it involves targeting protein−protein interactions. Nevertheless, intense research has now generated potent, specific, cell-permeable small-molecule peptidomimetics and nonpeptidic mimetics. To date, two types of Smac mimetics have been reported, namely, monovalent and bivalent Smac mimetics. The monovalent compounds are designed to mimic the binding of a single AVPI binding motif to IAP proteins, whereas the bivalent compounds contain two AVPI binding motif mimetics tethered together throu...

Cul-catalyzed coupling reaction of vinyl halides and phenols occurs at 60-90 °C with N,N-dimethylglycine hydrochloride as the additive, giving vinyl aryl ethers in good yields. The cross-coupling products formed from o-iodophenols and vinyl iodides are converted into substituted benzofurans via an intramolecular Heck reaction.

CuI-catalyzed coupling reaction of electron-deficient aryl iodides with aliphatic primary amines occurs at 40 degrees C under the promotion of N-methylglycine. Using L-proline as the promoter, coupling reaction of aryl iodides or aryl bromides with aliphatic primary amines, aliphatic cyclic secondary amines, or electron-rich primary arylamines proceeds at 60-90 degrees C; an intramolecular coupling reaction between aryl chloride and primary amine moieties gives indoline at 70 degrees C; coupling reaction of aryl iodides with indole, pyrrole, carbazole, imidazole, or pyrazole can be carried out at 75-90 degrees C; and coupling reaction of electron-deficient aryl bromides with imidazole or pyrazole occurs at 60-90 degrees C to provide the corresponding N-aryl products in good to excellent yields. In addition, N,N-dimethylglycine promotes the coupling reaction of electron-rich aryl bromides with imidazole or pyrazole to afford the corresponding N-aryl imidazoles or pyrazoles at 110 degrees C. The possible action of amino acids in these coupling reactions is discussed.

N-Aryl alpha- or beta-amino acids, aryl amines, N-arylpyrroles, N-arylindoles, N-arylimidazoles, N-arylpyrazoles and aryl azides are prepared by CuI-catalyzed coupling reactions of aryl halides with corresponding nitrogen sources using amino acids as the promoters.