A Journey of the Development of Privileged Difluorocarbene Reagents TMSCF₂X (X = Br, F, Cl) for Organic Synthesis

Accounts of Chemical Research, Год журнала: 2024, Номер 57(5), С. 693 - 713

Опубликована: Фев. 14, 2024

ConspectusAs fluorine has played an increasingly important role in modulating the physical, chemical, and biological properties of organic molecules, selective introduction atom(s) or fluorinated moieties into target molecules become a powerful tool development new pharmaceuticals, agrochemicals, functional materials. In this context, difluoromethylene (CF2) difluoromethyl (CF2H) groups are special interest because their ability to serve as bioisosteres ethereal oxygen atoms hydroxyl (OH) thiol (SH) groups, respectively. Difluorocarbene is one most versatile reactive intermediates incorporate CF2 CF2H groups; however, before 2006, previously known difluorocarbene reagents suffered from several drawbacks such using ozone-depleting substances (ODSs), difficult-to-handle reagents, harsh reaction conditions having narrow substrate scope and/or low yields. Moreover, reactivity generated different precursors (reagents) was often unpredictable, since generation (activation modes) various different, these may mismatch those required for subsequent difluorocarbene-involved transformations. Therefore, environmentally friendly well investigation mechanistic insights reactions, been highly desirable.In Account, we summarize our contributions applications synthesis 2006. We have developed seven including 2-chloro-2,2-difluoroacetophenone (1), chlorodifluoromethyl phenyl sulfone (2), S-difluoromethyl-S-phenyl-N-tosylsulfoximine (3), difluoromethyltri(n-butyl)ammonium chloride (4), (chlorodifluoromethyl)trimethylsilane (TMSCF2Cl, 5), (bromodifluoromethyl)trimethylsilane (TMSCF2Br, 6), (trifluoromethyl)trimethylsilane (TMSCF3, 7). journey, realized key factor ideal reagent that can be used broad range is, should allow activation modes species, under basic/acidic/neutral conditions, at wide temperatures, solvents, which compatible with Among all silanes TMSCF2X (X = Br, F, Cl) stood out privileged ones, paves avenue further developing chemistry. particular, TMSCF2Br recognized "all-rounder": applied almost common more importantly, also enables many other novel transformations cannot achieve, thanks its unique structure rich releasing conditions. It expected commercial availability now, chemistry will accelerated years come.

Язык: Английский

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Single-atom skeletal editing of 2H-indazoles enabled by difluorocarbene

Science China Chemistry, Год журнала: 2023, Номер 66(7), С. 1975 - 1981

Опубликована: Май 11, 2023

Язык: Английский

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Nickel-catalyzed regiodivergent hydrosilylation of α-(fluoroalkyl)styrenes without defluorination

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 28, 2024

The fluoroalkyl-containing organic molecules are widely used in drug discovery and material science. Herein, we report ligand regulated nickel(0)-catalyzed regiodivergent hydrosilylation of α-(fluoroalkyl)styrenes without defluorination, providing an atom- step-economical synthesis route two types fluoroalkyl substituted silanes with exclusive regioselectivity. anti-Markovnikov addition products (β-fluoroalkyl silanes) formed monodentate phosphine ligand. Noteworthy, the bidentate promote generation more challenging Markovnikov (α-fluoroalkyl tetrasubstituted saturated carbon centers. This protocol features easy available starting materials commercially nickel catalysis, a wide range substrates excellent structure divergent undergo variety transformations. Comprehensive mechanistic studies including inverse kinetic isotope effects demonstrate regioselectivity controlled by through α-CF3 intermediate. DFT calculations reveal distinctive mechanism involving open-shell singlet state, which is crucial for generating intricate tetra-substituted products. authors defluorination.

Язык: Английский

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Visible-light-promoted desulfonylative radical difluoroalkylation between difluoroenol silyl ethers and difluoroalkyl sulfones to construct functionalized aryltetrafluoroethane derivatives

Organic Chemistry Frontiers, Год журнала: 2024, Номер 11(5), С. 1444 - 1449

Опубликована: Янв. 1, 2024

A visible-light-promoted desulfonylative radical difluoroalkylation between difluoroenol silyl ethers and difluoroalkyl sulfones has been developed.

Язык: Английский

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[Ph₄P]⁺[Cu(CF₂H)₂]⁻: A Powerful Difluoromethylating Reagent Inspired by Mechanistic Investigation

Angewandte Chemie International Edition, Год журнала: 2022, Номер 61(42)

Опубликована: Авг. 29, 2022

Abstract The quest of the active species in copper‐mediated difluoromethylation aryl halides led to discovery a powerful difluoromethylating reagent [Ph 4 P] + [Cu(CF 2 H) ] − . Complex was able difluoromethylate variety electrophiles including electron‐deficient and electron‐rich iodides, heteroaryl activated bromides, chloride bromides with directing group, as well other such alkenyl iodide, benzyl allyl alkyl carbonates acid chloride. In addition, presence an oxidant, complex reacted various lithium n butyl arylboronic pinacol esters, alkyne heteroarene. Moreover, could transmetalate difluoromethyl metals [CuCl [(DPPF)PdCl ].

Язык: Английский

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Copper-Catalyzed Hydroamination of gem-Difluoroalkenes Access to Diversified α-Difluoromethyl Amines

Organic Letters, Год журнала: 2023, Номер 25(3), С. 533 - 537

Опубликована: Янв. 13, 2023

The difluoromethyl group (CF2H) is of great importance in medicinal chemistry. We report herein an efficient method for the synthesis diversified α-difluoromethyl amines through copper-catalyzed hydroamination gem-difluoroalkenes, where C-N bond formed via a α-CF2H transition-metal intermediate. This new reaction proceeds Cu-H insertion to gem-difluoroalkenes and gives valuable alkyl-CF2H-containing compounds, which overcome much more challenged β-F elimination from α-fluoroalkyl organocopper species. exhibits broad substrate scope with readily available starting materials commercial catalysis.

Язык: Английский

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Controllable Fluorocarbon Chain Elongation: TMSCF₂Br-Enabled Trifluorovinylation and Pentafluorocyclopropylation of Aldehydes

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(3), С. 1806 - 1812

Опубликована: Янв. 9, 2024

Controllable fluorocarbon chain elongation (CFCE) is a promising yet underdeveloped strategy for the well-defined synthesis of structurally novel polyfluorinated compounds. Herein, direct and efficient trifluorovinylation pentafluorocyclopropylation aldehydes are described by using TMSCF

Язык: Английский

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Catalytic Asymmetric Difluoroalkylation Using In Situ Generated Difluoroenol Species as the Privileged Synthon

Advanced Science, Год журнала: 2024, Номер 11(14)

Опубликована: Фев. 6, 2024

A robust and practical difluoroalkylation synthon, α,α-difluoroenol species, which generated in situ from trifluoromethyl diazo compounds water the presence of dirhodium complex, is disclosed. As compared to presynthesized difluoroenoxysilane formed difluoroenolate under basic conditions, this difluoroenol intermediate displayed versatile reactivity, resulting dramatically improved enantioselectivity mild conditions. demonstrated catalytic asymmetric aldol reaction Mannich reactions with ketones or imines chiral organocatalysts, quinine-derived urea, phosphoric acid (CPA), respectively, relay catalysis strategy provides an effective platform for applying fluorination chemistry. Moreover, method features a novel 1,2-difunctionalization process via installation carbonyl motif alkyl group on two vicinal carbons, complementary protocol metal carbene gem-difunctionalization reaction.

Язык: Английский

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Transition‐Metal‐Free Controllable Single and Double Difluoromethylene Formal Insertions into C−H Bonds of Aldehydes with TMSCF₂Br

Angewandte Chemie International Edition, Год журнала: 2022, Номер 62(7)

Опубликована: Дек. 15, 2022

We have developed a new strategy for controllable single and double difluoromethylene (CF2 ) formal insertions into C-H bonds of aldehydes with nearly full selectivity under transition-metal-free conditions. The key to the success CF2 lies in well-defined formation 2,2-difluoroenolsilyl ether 2,2,3,3-tetrafluorocyclopropanolsilyl intermediates using difluorocarbene reagent TMSCF2 Br (TMS=trimethylsilyl). These two can react various electrophiles including proton sources halogenation reagents, allowing access diverse arrays ketones containing tetrafluoroethylene units. first synthesis relatively stable ethers has been achieved, which offers platform explore other unknown chemical space.

Язык: Английский

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Synthesis of Trifluoromethylated Alkenes: Hypervalent Iodine Meets High‐Valent Copper

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(33)

Опубликована: Июнь 13, 2023

The first trifluoromethylation of vinylbenziodoxolones (VBX) is reported herein. synthetic method based on the use bench-stable, high-valent copper(III) species, and reaction can be initiated under thermal conditions and/or irradiation (365 nm) giving access to trifluoromethylated alkenes in a stereoselective fashion. Various VBX reagents derived from tyrosine, cysteine, small peptides, thiols amides used as precursors. obtained could further functionalized by reduction or epoxidation double bond. Furthermore, applied large-scale batch/flow synthesis conducted visible light irradiation.

Язык: Английский

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