Transition-Metal (Cu, Pd, Ni)-Catalyzed Difluoroalkylation via Cross-Coupling with Difluoroalkyl Halides

Accounts of Chemical Research, Journal Year: 2018, Volume and Issue: 51(9), P. 2264 - 2278

Published: Aug. 22, 2018

Difluoroalkylated compounds play a remarkably important role in life and materials sciences because of the unique characteristics difluoromethylene (CF2) group. In particular, precise introduction CF2 group at benzylic position can dramatically improve biological properties corresponding molecules. As consequence, difluoroalkylation aromatic has become powerful strategy modulating bioactivities organic However, efficient strategies to selectively synthesize difluoroalkylated arenes had been very limited before 2012. Traditional synthetic methods this regard suffer from either harsh reaction conditions or narrow substrate scope, significantly restricting their widespread applications, particularly for late-stage bioactive To overcome these limitations, straightforward route access valuable skeletons is direct (CF2R) onto rings through transition-metal-catalyzed cross-coupling. instability some metal species, which are prone protonation, dimerization, and/or generation other unknown byproducts, it difficult control catalytic cycle suppress side reactions. context, we proposed use low-cost widely available difluoroalkyl halides as fluoroalkyl sources reactions via Account, summarize our major efforts on copper-, palladium-, nickel-catalyzed difluoroalkylations aromatics with sources. Four modes reactions, including nucleophilic difluoroalkylation, electrophilic radical metal-difluorocarbene coupling (MeDiC), have demonstrated careful modulation systems. Among MeDiC represents new mode fluoroalkylation. These processes enable variety aryl arylboron reagents under mild conditions. A wide range halides, activated (Cl/BrCF2R, R = π system), unactivated (BrCF2R, alkyl, H), especially inert inexpensive industrial chemical chlorodifluoromethane (ClCF2H), applicable providing facile routes diverse (hetero)arenes. halide-based also be applied prepare alkenes, alkynes, alkanes feature impressive advantages over conventional synthesis terms efficiency, functional tolerance, structural diversity. molecules offers good opportunities development medicinal agents without need multistep de novo syntheses.

Language: Английский

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Mechanisms of Nickel-Catalyzed Cross-Coupling Reactions

Trends in Chemistry, Journal Year: 2019, Volume and Issue: 1(9), P. 830 - 844

Published: Sept. 13, 2019

Language: Английский

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Late-stage difluoromethylation: concepts, developments and perspective

Chemical Society Reviews, Journal Year: 2021, Volume and Issue: 50(14), P. 8214 - 8247

Published: Jan. 1, 2021

This review describes the conceptual advances that have led to multiple difluoromethylation processes making use of well-defined CF₂H sources.

Language: Английский

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Sequential C–F bond functionalizations of trifluoroacetamides and acetates via spin-center shifts

Science, Journal Year: 2021, Volume and Issue: 371(6535), P. 1232 - 1240

Published: March 5, 2021

Defluorinative functionalization of readily accessible trifluoromethyl groups constitutes an economical route to partially fluorinated molecules. However, the controllable replacement one or two fluorine atoms while maintaining high chemoselectivity remains a formidable challenge. Here we describe general strategy for sequential carbon-fluorine (C-F) bond functionalizations trifluoroacetamides and trifluoroacetates. The reaction begins with activation carbonyl oxygen atom by 4-dimethylaminopyridine-boryl radical, followed spin-center shift trigger C-F scission. A chemoselectivity-controllable two-stage process enables generation difluoro- monofluoroalkyl radicals, which are selectively functionalized different radical traps afford diverse products. mechanism origin were established experimental computational approaches.

Language: Английский

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Radical Retrosynthesis

Accounts of Chemical Research, Journal Year: 2018, Volume and Issue: 51(8), P. 1807 - 1817

Published: Aug. 2, 2018

ConspectusIn The Logic of Chemical Synthesis, E. J. Corey stated that the key to retrosynthetic analysis was a "wise choice appropriate simplifying transforms" (Corey, J.; Cheng, X.-M. Synthesis; John Wiley: New York, 1989). Through lens "ideality", chemists can identify opportunities lead more practical, scalable, and sustainable synthesis. percent ideality synthesis is defined as [(no. construction rxns) + (no. strategic redox rxns)]/(total no. steps) × 100. A direct consequence designing "wise" or "ideal" plans new transformations often need invention. For example, if functional group interconversions are be avoided, one faced with prospect directly functionalizing C–H bonds (Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976; Brückl, T.; et al. Acc. Res. 2012, 45, 826). If protecting groups minimized, methods testing limits chemoselectivity require invention (Baran, S.; Nature 2007, 446, 404; Young, I. Nat. 2009, 1, 193). Finally, extraneous manipulations eliminated, generating skeletal result (Burns, N. Z.; Angew. Chem., Int. Ed. 48, 2854). Such analyses applied total have seen an explosion interest in recent years. Thus, it interplay aspirational demands available influence inspire ingenuity. Corey's sage advice holds true when endeavoring complex molecule synthesis, but together tenets avoiding concession steps leads most strategically tactically optimal route (Hendrickson, B. Am. 1975, 97, 5784; Gaich, Org. 2010, 75, 4657).Polar disconnections intuitive underlie much logic. Undergraduates exposed multistep taught assemble organic molecules through combination positively negatively charged synthons because, after all, opposites attract. Indeed, employed two-electron C–C bond forming reactions today those based upon either classical cross-coupling (e.g., Suzuki, Negishi, Heck) polar additions (aldol, Michael, Grignard). These mainstay modern revolutionized way constructed due their robust predictable nature. In contrast, radical chemistry sparsely covered beyond basic principles chain processes (i.e., halogenation). historical perception radicals somewhat uncontrollable species does not help situation. As result, synthetic prone make radical-based during first-pass analyses.Recent use one-electron (RCC) has been fueled by realization uniquely chemoselective profiles they uncover for dramatically general, such couplings proceed relying on innate preferences substrate (innate RCC) interception mediator (usually transition metal) achieve programmed RCC. This Account presents series case studies illustrating inherent tactical advantages employing both types cross-couplings variety disparate settings. Thematically, clear disconnections, while considered intuitive, serve enable syntheses feature minimal chemistry, interconversions, nonstrategic fluctuations.

Language: Английский

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Selective C–F Functionalization of Unactivated Trifluoromethylarenes

Journal of the American Chemical Society, Journal Year: 2019, Volume and Issue: 141(33), P. 13203 - 13211

Published: Aug. 1, 2019

Fluorinated organic molecules are pervasive within the pharmaceutical and agrochemical industries due to range of structural physicochemical properties that fluorine imparts. Currently, most abundant methods for synthesis aryl–CF2 functionality have relied on deoxyfluorination ketones aldehydes using expensive poorly atom economical reagents. Here, we report a general method aryl–CF2R aryl–CF2H compounds through activation corresponding trifluoromethyl arene precursors. This strategy is enabled by an endergonic electron transfer event provides access radical anions lie outside catalyst reduction potential. Fragmentation these reactive intermediates delivers difluorobenzylic radicals can be intercepted alkene feedstocks or hydrogen provide diverse array difluoalkylaromatics.

Language: Английский

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Copper Catalyzed C(sp³)–H Bond Alkylation via Photoinduced Ligand-to-Metal Charge Transfer

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(7), P. 2729 - 2735

Published: Feb. 12, 2021

Utilizing catalytic CuCl2 we report the functionalization of numerous feedstock chemicals via coupling unactivated C(sp3)-H bonds with electron-deficient olefins. The active cuprate catalyst undergoes Ligand-to-Metal Charge Transfer (LMCT) to enable generation a chlorine radical which acts as powerful hydrogen atom transfer reagent capable abstracting strong electron-rich bonds. Of note is that chlorocuprate an exceedingly mild oxidant (0.5 V vs SCE) and proposed protodemetalation mechanism offers broad scope olefins, offering high diastereoselectivity in case endocyclic alkenes. Cu reduction through LMCT enables highly HAT operationally simple economical protocol.

Language: Английский

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Copper‐Catalyzed Radical Cross‐Coupling of Redox‐Active Oxime Esters, Styrenes, and Boronic Acids

Angewandte Chemie International Edition, Journal Year: 2018, Volume and Issue: 57(47), P. 15505 - 15509

Published: Oct. 8, 2018

A visible-light-driven, copper-catalyzed three-component radical cross-coupling of oxime esters, styrenes, and boronic acids has been developed. Key steps this protocol involve catalytic generation an iminyl from a redox-active ester subsequent C-C bond cleavage to generate cyanoalkyl radical. Upon its addition styrene, the newly formed benzylic undergoes coupling with boronic-acid-derived ArCuII complex achieve 1,1-diarylmethane-containing alkylnitriles.

Language: Английский

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Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry

Chemistry - A European Journal, Journal Year: 2018, Volume and Issue: 25(18), P. 4590 - 4647

Published: Nov. 2, 2018

Nonconjugated hydrocarbons, like bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, triptycene, and cubane are a unique class of rigid linkers. Due to their similarity in size shape they useful mimics classic benzene moieties drugs, so-called bioisosteres. Moreover, also fulfill an important role material sciences as linear linkers, order arrange various functionalities defined spatial manner. In this Review article, recent developments usages these special, rectilinear systems discussed. Furthermore, we focus on covalently linked, nonconjugated arrangements discuss the physical chemical properties differences individual well application medicinal sciences.

Language: Английский

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A Radical Approach to Anionic Chemistry: Synthesis of Ketones, Alcohols, and Amines

Journal of the American Chemical Society, Journal Year: 2019, Volume and Issue: 141(16), P. 6726 - 6739

Published: April 3, 2019

Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of foundational importance to the practice organic synthesis. After placing this work in proper historical context, Article reports development, full scope, a mechanistic picture for strikingly different way forging such functional groups. Thus, carboxylic acids, once converted redox-active esters (RAEs), can be utilized as formally nucleophilic coupling partners with other derivatives (to produce ketones), imines benzylic amines), or aldehydes alcohols). The reactions uniformly mild, operationally simple, and, case ketone synthesis, broad scope (including several applications simplification synthetic problems parallel synthesis). Finally, an extensive study synthesis is performed trace elementary steps catalytic cycle provide end-user clear understandable rationale selectivity, role additives, underlying driving forces involved.

Language: Английский

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