Nickel-catalyzed allylic defluorinative alkylation of trifluoromethyl alkenes with reductive decarboxylation of redox-active esters

Lü, Xi; Wang, Xiaoxu; Gong, Tian‐Jun; Pi, Jing-Jing; He, Shuai; Fu, Yao

doi:10.1039/c8sc04335c

Cited by 187 publications

(48 citation statements)

References 95 publications

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“…Previously, the defluorinative S N 2′ reaction of 1-(trifluoromethyl)alkenes with different nucleophiles with or without a catalyst offers a straightforward access to substituted gem-difluoroalkenes 71 . The electrophilic alkyl halides or aliphatic RAE, were also successfully coupled with 1-(trifluoromethyl) alkenes in the presence of a nickel catalyst and stoichiometric amount of zinc reductant 72,73 .…”

Section: Decarboxylative Vinylationmentioning

confidence: 99%

Manganese-mediated reductive functionalization of activated aliphatic acids and primary amines

et al. 2020

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Alkyl carboxylic acids as well as primary amines are ubiquitous in all facets of biological science, pharmaceutical science, chemical science and materials science. By chemical conversion to redox-active esters (RAE) and Katritzky’s N-alkylpyridinium salts, respectively, alkyl carboxylic acids and primary amines serve as ideal starting materials to forge new connections. In this work, a Mn-mediated reductive decarboxylative/deaminative functionalization of activated aliphatic acids and primary amines is disclosed. A series of C-X (X = S, Se, Te, H, P) and C-C bonds are efficiently constructed under simple and mild reaction conditions. The protocol is applicable to the late-stage modification of some structurally complex natural products or drugs. Preliminary mechanistic studies suggest the involvement of radicals in the reaction pathway.

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Section: Decarboxylative Vinylationmentioning

confidence: 99%

Manganese-mediated reductive functionalization of activated aliphatic acids and primary amines

et al. 2020

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“…In designing a synthetically useful method for synthesising sp 3 -rich chiral amines and derivatives to meet the increased demand in drug discovery, we innovated an operationally facile reaction using easily synthesised enamides with readily available and batch-stable alkyl halides under reductive conditions. Our group devoted efforts to develop olefin reductive alkylation reactions 26 – 30 . Nowadays, olefin reductive hydroalkylation has been one of the most appealing methods for alkyl–alkyl formation 31 – 35 .…”

Section: Introductionmentioning

confidence: 99%

Catalytic asymmetric reductive hydroalkylation of enamides and enecarbamates to chiral aliphatic amines

et al. 2021

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To increase the reliability and success rate of drug discovery, efforts have been made to increase the C(sp3) fraction and avoid flat molecules. sp3-Rich enantiopure amines are most frequently encountered as chiral auxiliaries, synthetic intermediates for pharmaceutical agents and bioactive natural products. Streamlined construction of chiral aliphatic amines has long been regarded as a paramount challenge. Mainstream approaches, including hydrogenation of enamines and imines, C–H amination, and alkylation of imines, were applied for the synthesis of chiral amines with circumscribed skeleton structures; typically, the chiral carbon centre was adjacent to an auxiliary aryl or ester group. Herein, we report a mild and general nickel-catalysed asymmetric reductive hydroalkylation to effectively convert enamides and enecarbamates into drug-like α-branched chiral amines and derivatives. This reaction involves the regio- and stereoselective hydrometallation of an enamide or enecarbamate to generate a catalytic amount of enantioenriched alkylnickel intermediate, followed by C–C bond formation via alkyl electrophiles.

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“…To explain the results in Fig. 2, we propose a tertiary carbon radical is generated and participates in the crucial C-C bond formation step [72][73][74][75] . The oxidative addition of alkyl bromides to low-valent Ni catalysts usually takes place through a cascade of single electron transfer and alkyl radical generating steps 76 .…”

Section: Resultsmentioning

confidence: 97%

Migratory functionalization of unactivated alkyl bromides for construction of all-carbon quaternary centers via transposed tert-C-radicals

et al. 2020

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Despite remarkable recent advances in transition-metal-catalyzed C(sp3)−C cross-coupling reactions, there remain challenging bond formations. One class of such reactions include the formation of tertiary-C(sp3)−C bonds, presumably due to unfavorable steric interactions and competing isomerizations of tertiary alkyl metal intermediates. Reported herein is a Ni-catalyzed migratory 3,3-difluoroallylation of unactivated alkyl bromides at remote tertiary centers. This approach enables the facile construction of otherwise difficult to prepare all-carbon quaternary centers. Key to the success of this transformation is an unusual remote functionalization via chain walking to the most sterically hindered tertiary C(sp3) center of the substrate. Preliminary mechanistic and radical trapping studies with primary alkyl bromides suggest a unique mode of tertiary C-radical generation through chain-walking followed by Ni–C bond homolysis. This strategy is complementary to the existing coupling protocols with tert-alkyl organometallic or -alkyl halide reagents, and it enables the expedient formation of quaternary centers from easily available starting materials.

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Nickel-catalyzed allylic defluorinative alkylation of trifluoromethyl alkenes with reductive decarboxylation of redox-active esters

Abstract: Synthesis of functionalized gem-difluoroalkenes was achieved through nickel-catalyzed allylic defluorinative alkylation of trifluoromethyl alkenes with reductive decarboxylation of redox-active esters.

Cited by 187 publications

References 95 publications

Manganese-mediated reductive functionalization of activated aliphatic acids and primary amines

Manganese-mediated reductive functionalization of activated aliphatic acids and primary amines

Catalytic asymmetric reductive hydroalkylation of enamides and enecarbamates to chiral aliphatic amines

Migratory functionalization of unactivated alkyl bromides for construction of all-carbon quaternary centers via transposed tert-C-radicals

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