Functionalizing specific positions on a saturated alkyl molecule is a key challenge in synthetic chemistry. Herein, a ligand-controlled regiodivergent alkylations of alkyl bromides at different positions by Ni-catalyzed alkyl-alkyl cross-electrophile coupling with the second alkyl bromides has been developed. The reaction undergoes site-selective isomerization on one alkyl bromides in a controlled manner, providing switchable access to diverse alkylated structures at different sites of alkyl bromides. The reaction occurs at three similar positions with excellent chemo-and regioselectivity, representing a remarkable ligand tuned reactivity between alkyl-alkyl cross-coupling and nickel migration along the hydrocarbon side chain. This reaction offers a catalytic platform to diverse saturated architectures by alkyl-alkyl bond-formation from identical starting materials.
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.
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.
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