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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Palladium-Catalyzed Difluorocarbene Transfer Enabled Divergent Synthesis of γ-Butenolides and Ynones from Iodobenzene and Terminal Alkynes

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(2), С. 1722 - 1731

Опубликована: Янв. 4, 2024

Herein, we report a ligand-controlled palladium-catalyzed method that enables the synthesis of ynones and γ-butenolides with excellent regioselectivity from same set readily available aryl iodides, acetylenes, BrCF2CO2K. In this reaction, [PdII]═CF2 does demonstrate electrophilicity can generate CO when reacting H2O. It is environmentally friendly safe compared to traditional methods, current protocol us afford in high yields functionality tolerance. Moreover, esters also be obtained corresponding phenols alcohols utilizing strategy. The success late-stage functionalization bioactive compounds further illustrates synthetic utility material development drug discovery.

Язык: Английский

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Oxygen Migration–Defluorination Strategy Enables the Aminocarbonylation of Enaminones with o-Aminobenzamides and CF₂Br₂

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Фев. 24, 2025

The development of different concept approaches and user-friendly carbonyl surrogates for aminocarbonylation is highly desirable. Herein, we report the photocatalytic enaminones with easily available o-aminobenzamides CF2Br2 through an oxygen migration-defluorination strategy. reaction features switchable transformation construction carbamoyl-substituted enol products allows expedient synthesis fully substituted maleimides under mild conditions.

Язык: Английский

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Photochemically Mediated Ring Expansion of Indoles and Pyrroles with Chlorodiazirines: Synthetic Methodology and Thermal Hazard Assessment

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(31)

Опубликована: Июнь 9, 2023

We demonstrate that arylchlorodiazirines serve as photo-activated halocarbene precursors for the selective one-carbon ring expansion of N-substituted pyrroles and indoles to corresponding pyridinium quinolinium salts. Preliminary investigations indicate same strategy also enables conversion pyrazoles pyrimidinium The N-substituent substrate plays an essential role in: (1) increasing scope by preventing product degradation, (2) enhancing yields suppressing co-product inhibition, (3) activating azinium products towards subsequent synthetic manipulations. This latter point is illustrated subjecting salts four complementary partial reductions, which provide concise access ring-expanded with different degrees increased C(sp

Язык: Английский

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Triftosylhydrazone in Single-Atom Skeletal Editing

Accounts of Chemical Research, Год журнала: 2024, Номер unknown

Опубликована: Дек. 16, 2024

ConspectusIn the past decade, single-atom skeletal editing, which involves precise insertion, deletion, or exchange of single atoms in core skeleton a molecule, has emerged as promising synthetic strategy for rapid construction diversification complex molecules without laborious de novo processes. Among them, carbene-initiated editing is particularly appealing due to ready availability and diverse reactivities carbene species. The initial endeavors modify heteroarenes through carbon-atom insertion could date back 1881, when Ciamician Denstedt described conversion pyrroles pyridines by trapping haloform-derived free carbene. Despite its potential value, general applicability this one-carbon seen limited progress poor yields harsh reaction conditions. Significant advances via were achieved only 3 years Levin, Ball, Xu, Song, Glorius, others. hallmark these approaches facile halocyclopropanation followed regioselective ring opening facilitated expulsion halide ion. Consequently, specially designed α-halocarbene precursors, such haloform derivatives, α-halodiazoacetates, chlorodiazirines, α-chlorodiazo oxime esters, can be employed achieve Ciamician–Denstedt-type editing. This not limits types functional groups installed on expansion products but also prevents their widespread adoption, especially late-stage contexts. enduring quest develop environmentally friendly versatile superior group compatibility, application diversifications investigation mechanistic insights into carbon reactions remain fundamental objective.In our over 5 years, we have developed o-trifluoromethylbenzenesulfonylhydrazones (named Triftosylhydrazones) operationally safe easily decomposable diazo surrogates explored various challenging catalytic transfer reactions. Recently, put great efforts expanding scope unlocking triftosylhydrazones precursors Since 2018, realized range acyclic 1,3-dicarbonyls with silver carbenes access 1,4-dicarbonyls, proceeding cyclopropanation/ring-opening process. Inspired results, recently demonstrated series transition-metal-catalyzed highly selective medicinally interesting like pyrroles, indoles, 1,2-diazoles carbenic insertion. We then strained three-membered nitrogen- oxygen-containing heterocycles single-carbon atoms. In Account, present an overview achievements heterocycles, organized based three situ-generated key intermediates, cyclopropane, N-ylide, O-ylide from focus scopes, features, applications. hope that Account will provide valuable contribute development new methodologies both chemistry fields.

Язык: Английский

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Copper-Catalyzed Radical Addition of Alkynols to Synthesize Difluoroheterocyclic Compounds

Organic Letters, Год журнала: 2023, Номер 25(15), С. 2733 - 2738

Опубликована: Апрель 6, 2023

A convenient method for the synthesis of fluorine-containing heterocyclic compounds was developed by a copper-catalyzed free radical addition reaction alkynol and ethyl bromodifluoroacetate. This strategy involves molecular lactone exchange ethynyl alcohol The is characterized easy availability raw materials, good stereochemical selectivity, simple operation. More importantly, valuable tetrasubstituted E-configurated alkenes various vinyl C-Br bonds difluoromethylene-containing functionalized heterocycles can be obtained this method.

Язык: Английский

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One‐Carbon Ring Expansion of Indoles and Pyrroles: A Straightforward Access to 3‐Fluorinated Quinolines and Pyridines

Angewandte Chemie International Edition, Год журнала: 2023, Номер 63(5)

Опубликована: Дек. 12, 2023

Abstract 3‐Fluorinated quinolines and pyridines are prevalent pharmacophores, yet their synthesis is often challenging. Herein, we demonstrate that dibromofluoromethane as bromofluorocarbene source enables the one‐carbon ring expansion of readily available indoles pyrroles to structurally diverse 3‐fluorinated pyridines. This straightforward protocol requires only a short reaction time ten minutes can be performed under air atmosphere. Preliminary investigations reveal this strategy also applied other valuable azines by using different 1,1‐dibromoalkanes bromocarbene sources.

Язык: Английский

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Pd‐Catalyzed Synthesis of Aryl Esters Involving Difluorocarbene Transfer Carbonylation

European Journal of Organic Chemistry, Год журнала: 2024, Номер 27(10)

Опубликована: Фев. 14, 2024

Abstract A Pd‐catalyzed three‐component intermolecular reaction between aryl halides, ClCF 2 COONa and phenols is developed. series of benzoates were synthesized in up to 84 % yield via difluorocarbene transfer carbonylation. It devoted acquiring the targeted products by construction new C−C, C=O C−O bonds a one‐pot, one‐step process. The feature this method includes use readily available starting materials, showing outstanding resistance spatial obstruction simple operation procedure with mild conditions. Therefore, makes methodology useful alternative other schemes typically used for synthesis esters.

Язык: Английский

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Difluorocarbene-induced [1,2]- and [2,3]-Stevens rearrangement of tertiary amines

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

Опубликована: Июнь 5, 2024

The [1,2]- and [2,3]-Stevens rearrangements are one of the most fascinating chemical bond reorganization strategies in organic chemistry, they have been demonstrated a wide range applications, representing fundamental reaction tactic for synthesis nitrogen compounds community. However, their applicabilities limited by scarcity efficient, general, straightforward methods generating ammonium ylides. Herein, we report general difluorocarbene-induced tertiary amine-involved stemmed from situ generated difluoromethyl ylides, which allows versatile amines bearing either allyl, benzyl, or propargyl groups, resulting corresponding products under same conditions with way. Broad substrate scope, simple operation, mild late-stage modification natural highlight advantages this strategy, meanwhile, rearrangement is believed to bring opportunities transformations ylides assembly valuable amino acids. This will further enrich repertoire difluorocarbene species, facilitate development reactions involving salts, provide an avenue type reactions.

Язык: Английский

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Base-controlled selective cleavage of the C–F bond of difluorocarbene for the divergent assembly of indolizines

Organic Chemistry Frontiers, Год журнала: 2024, Номер 11(15), С. 4214 - 4218

Опубликована: Янв. 1, 2024

A [3 + 1 1] cascade annulation reaction for the divergent construction of trisubstituted indolizines using sulfoxonium ylides, BrCF 2 CO Me and pyridinium salts as readily available substrates has been developed.

Язык: Английский

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