The development of enantioselective alkyl-alkyl cross-couplings with coinstantaneous formation of a stereogenic center without the use of sensitive organometallic species is attractive yet challenging. Herein, we report the intermolecular regio-and enantioselective formal hydrofunctionalizations of acrylamides, forging a stereogenic center a-position to the newly formed C sp3 -C sp3 bond for the first time. The use of a newly developed chiral ligand enables the electronicallyreversed formal hydrofunctionalizations, including hydroalkylation, hydrobenzylation, and hydropropargylation, offering an efficient way to access diverse enantioenriched amides with a tertiary a-stereogenic carbon center which is facile to racemize. This operationally simple protocol allows for the anti-Markovnikov enantioselective hydroalkylation, and unprecedented hydrobenzylation, hydropropargylation under mild conditions with excellent functional group compatibility, delivering a wide range of amides with excellent levels of enantioselectivity.Scheme 1. Alkyl-alkyl cross-coupling strategies to construct stereogenic carbon center.

A series of tunable iminium ions, generated in situ by the condensation of 4-trifluoromethyl-p-quinols with cyclic amines, can lead to the divergent synthesis of trifluoromethylated arylamines in a single step via redox-neutral isomerization. The direct α- and β-functionalization of saturated amines can be achieved regioselectively under mild conditions.

A formal [4 + 2] cyclization of easily available ketene dithioacetals with acyl chlorides has been developed. Mediated by lithium bis(trimethylsilyl)amide, a series of γ-pyrones were obtained with a broad substrate scope. This unprecedented formal [4 + 2] cyclization provides a novel mode for ketene dithioacetals as versatile synthons. The synthesized γ-pyrones could be successfully transformed to 2-aryl/amino γ-pyrones and 2,3-dihydroimidazo[1,2-a]pyridin-7(1H)-ones mainly via the cleavage of the C−S bond. Article pubs.acs.org/joc

TheC À Cbond formation via C À Sbond activation( disclosed in 2000) has received increasing attention. However, stoichiometric amounts of exogenous thiophilic reagents are generally requireda s thiolate scavengers.H erein, an ew model for the synthesis of 4-aminoquinolines, the copper(II)-catalyzed aerobic oxidative desulfitative 6p cyclization of the readily available N-arylimino ketene N,S-acetals is described. Ther eactionc an proceed efficiently under mild conditions without any exogeneous thiolate scavengers (due to the formation of disulfide as the by-product) to affordd iverse 4-aminoquinolines, ap rivileged structure motif displaying antimalarial activity,w ith aw ide range of functional groups at the C-2 to C-8 positions.Scheme 3. Preparation of ketene N,S-acetals 2x-2z,4 -aminoquinolines 3x-3z,and carbodiimide 10.

The development of enantioselective alkyl-alkyl cross-couplings with coinstantaneous formation of a stereogenic center without the use of sensitive organometallic species is attractive yet challenging. Herein, we report the intermolecular regio-and enantioselective formal hydrofunctionalizations of acrylamides, forging a stereogenic center a-position to the newly formed C sp3 -C sp3 bond for the first time. The use of a newly developed chiral ligand enables the electronicallyreversed formal hydrofunctionalizations, including hydroalkylation, hydrobenzylation, and hydropropargylation, offering an efficient way to access diverse enantioenriched amides with a tertiary a-stereogenic carbon center which is facile to racemize. This operationally simple protocol allows for the anti-Markovnikov enantioselective hydroalkylation, and unprecedented hydrobenzylation, hydropropargylation under mild conditions with excellent functional group compatibility, delivering a wide range of amides with excellent levels of enantioselectivity.Scheme 1. Alkyl-alkyl cross-coupling strategies to construct stereogenic carbon center.

In recent years, numerous methods have emerged for the synthesis of trifluoromethylated arenes based on the late-stage introduction of a trifluoromethyl group onto an aryl ring. In sharp comparison, the synthesis of trifluoromethylated arenes based on the pre-introduction of a trifluoromethyl group onto an “aromatic to be” carbon has rarely been addressed. It has been found that 4-trifluoromethyl-p-quinol silyl ethers, the readily available and relatively stable compounds, can act as dielectrophiles to be applied to multi-component reactions for the synthesis of various trifluoromethylated arenes. Catalyzed by In(OTf)3, 4-trifluoromethyl-p-quinol silyl ethers react with C-, N-, and S-nucleophiles, respectively, in a regiospecific 1,2-addition manner to generate the corresponding highly reactive electrophilic intermediates. Further reaction of the in-situ generated electrophiles with a C-nucleophile followed by spontaneous aromatization enables the construction of functionalized trifluoromethyl arenes. This three-component, double nucleophilic addition/aromatization reaction based on the pre-introduction of a trifluoromethyl group onto an “aromatic to be” carbon provides a divergent strategy for the synthesis of trifluoromethylated arenes under mild reaction conditions in a single operation.

Enantioenriched α-tertiary-α-aminoacid and αchiral-β-aminoacid derivatives play an important role in biological science and pharmaceutical chemistry. Thus, the development of methods for their synthesis is highly valuable and yet remains challenging. Herein, an unprecedented catalyst-controlled regiodivergent and enantioselective formal hydroamination of N,N-disubstituted acrylamides with aminating agents has been developed, accessing enantioenriched α-tertiary-α-aminolactam and α-chiral-β-aminoamide derivatives. Sterically-disfavored and electronically-disfavored enantioselective hydroamination of electron-deficient alkenes have been successfully tuned using different transition metals and chiral ligands. Notably, extremely hindered aliphatic α-tertiary-α-aminolactam derivatives were synthesized by CuÀ H catalyzed asymmetric CÀ N bond forming with tertiary alkyl species. Enantioenriched αchiral-β-aminoamide derivatives have been accessed by NiÀ H catalyzed anti-Markovnikov-selective formal hydroaminations of alkenes. This set of reactions tolerates a wide range of functional groups to deliver diverse αtertiary-α-aminolactam and α-chiral-β-aminoamide derivatives in good yields with high levels of enantioselectivity.

Asymmetric hydrocarbofunctionalizations of alkenes has emerged as an efficient synthetic strategy for accessing optically active molecules via carbon-carbon bond-forming process from readily available alkenes and carbo-electrophiles. Herein, we present a summary of the efforts from our group to control the regio- and enantioselectivity of hydrocarbofunctionalizations of electron-deficient alkenes with a nickel catalyst and chiral bisoxazolidine ligand. The reaction undergoes electron-reversed hydrocarbofunctionalizations acrylamides with excellent enantioselectivity. This operationally simple protocol enables the asymmetric hydroalkylation, hydrobenzylation and hydropropargylation of acrylamides. This reaction is useful for preparing a wide range of α-branched chiral amides with broad functional group tolerance.