Efficient Synthesis of α‐Trifluoromethyl Carboxylic Acids and Esters through Fluorocarboxylation of <i>gem</i>‐Difluoroalkenes

Yoo, Woo‐Jin; Kondo, Junpei; Rodríguez‐Santamaría, José A.; Nguyen, Thanh V. Q.; Kobayashi, Shū

doi:10.1002/ange.201902779

Cited by 18 publications

(4 citation statements)

References 54 publications

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“…The previously formed 4CzPEBN • – ( E 1/2 (P/P • – ) = −1.69 V vs SCE, Figure S1 ) should be able to reduce the benzylic radical ( E 1/2 red = −1.60 V vs SCE for the phenylethyl radical) 17 to accomplish the photoredox catalytic cycle and afford the carbanion of ethylbenzene. It is well-known that this anion can be readily captured by CO 2 , 18 generating the final product after protonation. Overall, CO 2 formally inserts into the benzylic C–H bond without the addition of any sacrificial reagent ( Scheme 3 ).…”

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confidence: 99%

Photocarboxylation of Benzylic C–H Bonds

et al. 2019

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The carboxylation of sp 3 -hybridized C–H bonds with CO 2 is a challenging transformation. Herein, we report a visible-light-mediated carboxylation of benzylic C–H bonds with CO 2 into 2-arylpropionic acids under metal-free conditions. Photo-oxidized triisopropylsilanethiol was used as the hydrogen atom transfer catalyst to afford a benzylic radical that accepts an electron from the reduced form of 2,3,4,6-tetra(9H-carbazol-9-yl)-5-(1-phenylethyl)benzonitrile generated in situ . The resulting benzylic carbanion reacts with CO 2 to generate the corresponding carboxylic acid after protonation. The reaction proceeded without the addition of any sacrificial electron donor, electron acceptor or stoichiometric additives. Moderate to good yields of the desired products were obtained in a broad substrate scope. Several drugs were successfully synthesized using the novel strategy.

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confidence: 99%

Photocarboxylation of Benzylic C–H Bonds

et al. 2019

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“…In 2019, Kobayashi and co‐workers developed a simple and straightforward procedure for the fluorocarboxylation of gem‐ difluoroalkenes 63 . [ 27 ] This catalyst‐ and additive‐free protocol, proceeding in the presence of nucleophilic CsF and CO 2 , was facilitated by the presence of polar solvents such as DMSO (Figure 20). Although providing useful yields at atmospheric pressure of CO 2 , the reaction efficiency became excellent at 20 atm.…”

Section: Metal/base‐promoted Alkene Carboxylative Functionalizations With Co2mentioning

confidence: 99%

Tandem Functionalization‐Carboxylation Reactions of π‐Systems with CO₂

et al. 2021

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The tandem catalytic functionalization/carboxylation of double as well as triple carbon‐carbon bonds with CO2 represent an emerging research area in synthetic organic methodology. In particular, the combination of mild reaction conditions, stoichiometric acceptor/donorless conditions (visible light photoredox catalysis) and chiral catalysts contributed to a rapid development of this intriguing research area capable of creating chemical diversity/ complexity from readily available unsaturated hydrocarbons and CO2 as a C1‐buinding block. The most recent developments in the field have been collected in the present review article and organized, based on the different sets of π‐systems/intermediates/reactive partners employed (i.e., nickelalactones, organo‐halides) as well as synthetic strategies (i.e., visible‐light photo redox catalysis).

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“…Bonnet–Delpon and co-workers already demonstrated that gem -difluoroalkene-derivatized artemisinins exhibit prolonged in vivo antimalarial activity through replacement of the carbonyl group 5 . Moreover, gem -difluoroalkenes can be transformed to various organofluorine motifs 6 , 7 such as trifluoromethyl 8 – 10 , difluoromethyl 11 – 14 , monofluoroalkenyl 15 – 18 , and difluoromethylenyl 19 , 20 groups for late-stage functionalization. Conventionally, Wittig- or Horner-Wadsworth-Emmons-type olefination and S N 2’ reactions of vinyl trifluoromethyl compounds are widely employed to construct the gem -difluoroalkene moiety 7 , 21 , 22 .…”

Section: Introductionmentioning

confidence: 99%

2,2-difluorovinyl benzoates for diverse synthesis of gem-difluoroenol ethers by Ni-catalyzed cross-coupling reactions

Chan

Lee

et al. 2021

Nat Commun

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Abstractgem-Difluoroalkene is a bioisostere of carbonyl group for improving bioavailability of drug candidates. Herein we develop structurally diverse 2,2-difluorovinyl benzoates (BzO-DFs) as versatile building blocks for modular synthesis of gem-difluoroenol ethers (44 examples) and gem-difluoroalkenes (2 examples) by Ni-catalyzed cross coupling reactions. Diverse BzO-DFs derivatives bearing sensitive functional groups (e.g., C = C, TMS, strained carbocycles) are readily prepared from their bromodifluoroacetates and bromodifluoroketones precursors using metallic zinc as reductant. With Ni(COD)2 and dppf [1,1’-bis(diphenylphosphino)ferrocene] as catalyst, reactions of BzO-DFs with arylboronic acids and arylmagnesium/alkylzinc reagents afforded the desired gem-difluoroenol ethers and gem-difluoroalkenes in good yields. The Ni-catalyzed coupling reactions features highly regioselective C(vinyl)–O(benzoate) bond activation of the BzO-DFs. Results from control experiments and DFT calculations are consistent with a mechanism involving initial oxidative addition of the BzO-DFs by the Ni(0) complex. By virtue of diversity of the BzO-DFs and excellent functional group tolerance, this method is amenable to late-stage functionalization of multifunctionalized bioactive molecules.

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Efficient Synthesis of α‐Trifluoromethyl Carboxylic Acids and Esters through Fluorocarboxylation of gem‐Difluoroalkenes

Cited by 18 publications

References 54 publications

Photocarboxylation of Benzylic C–H Bonds

Photocarboxylation of Benzylic C–H Bonds

Tandem Functionalization‐Carboxylation Reactions of π‐Systems with CO₂

2,2-difluorovinyl benzoates for diverse synthesis of gem-difluoroenol ethers by Ni-catalyzed cross-coupling reactions

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Efficient Synthesis of α‐Trifluoromethyl Carboxylic Acids and Esters through Fluorocarboxylation of gem‐Difluoroalkenes

Cited by 18 publications

References 54 publications

Photocarboxylation of Benzylic C–H Bonds

Photocarboxylation of Benzylic C–H Bonds

Tandem Functionalization‐Carboxylation Reactions of π‐Systems with CO2

2,2-difluorovinyl benzoates for diverse synthesis of gem-difluoroenol ethers by Ni-catalyzed cross-coupling reactions

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Tandem Functionalization‐Carboxylation Reactions of π‐Systems with CO₂