From intramolecular cyclization to intermolecular hydrolysis: TMSCF<sub>2</sub>Br-enabled carbonylation of aldehydes/ketones and amines to α-hydroxyamides

Luo, An; Sun, Shuo; Xie, Qiqiang; Huang, R. L.; Kong, Taige; Ni, Chuanfa; Hu, Jinbo

doi:10.1039/d3qo00665d

Cited by 3 publications

(2 citation statements)

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“…94 Interestingly, in the above-mentioned transformation, the reaction pathway can be changed if water is present (Scheme 37). 95 The fluorinated iminium intermediate can be trapped by water to give α-hydroxyamides as major products (instead of undergoing intramolecular cyclization).…”

Section: Bromodifluoromethyltrimethylsilanementioning

confidence: 99%

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

Xie,

2024

Acc. Chem. Res.

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

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Section: Bromodifluoromethyltrimethylsilanementioning

confidence: 99%

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

Xie,

2024

Acc. Chem. Res.

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“…Several drug-related molecules can be modified (Scheme 13b). 50 In 2019, Song's group employed ClCF 2 H as a difluorocarbene precursor, which underwent two C-F bond cleavages, as a new C1 source to react with amines. By judicious screening of different amines and reaction conditions, a variety of valuable formimidamides, benzo [d]oxazoles and benzo [d]imidazole derivatives could be successfully synthesized under transition-metal free conditions with good chemo-and stereo-selectivities (Scheme 14).…”

Section: C-n Bond Formation and C-f Functionalizationmentioning

confidence: 99%

C–F bond functionalizations via fluorinated carbenes

Li,

Luo,

Jiang

2023

Org. Chem. Front.

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Ag-catalyzed and difluorocarbene-promoted amide-ylide rearrangement: synthesis of 3-salicyloylpyridines

Yuan,

Zhou,

Wang

et al. 2025

Org. Chem. Front.

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From intramolecular cyclization to intermolecular hydrolysis: TMSCF₂Br-enabled carbonylation of aldehydes/ketones and amines to α-hydroxyamides

Abstract: A metal-free multicomponent strategy has been developed for the synthesis of various α-hydroxyamides via carbonylation of aldehydes/ketones and amines enabled by the difluorocarbene reagent TMSCF2Br (TMS = trimethylsilyl). TMS-protecting group...

Cited by 3 publications

References 95 publications

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

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

C–F bond functionalizations via fluorinated carbenes

Ag-catalyzed and difluorocarbene-promoted amide-ylide rearrangement: synthesis of 3-salicyloylpyridines

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From intramolecular cyclization to intermolecular hydrolysis: TMSCF2Br-enabled carbonylation of aldehydes/ketones and amines to α-hydroxyamides

Abstract: A metal-free multicomponent strategy has been developed for the synthesis of various α-hydroxyamides via carbonylation of aldehydes/ketones and amines enabled by the difluorocarbene reagent TMSCF2Br (TMS = trimethylsilyl). TMS-protecting group...

Cited by 3 publications

References 95 publications

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

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

C–F bond functionalizations via fluorinated carbenes

Ag-catalyzed and difluorocarbene-promoted amide-ylide rearrangement: synthesis of 3-salicyloylpyridines

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Product

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From intramolecular cyclization to intermolecular hydrolysis: TMSCF₂Br-enabled carbonylation of aldehydes/ketones and amines to α-hydroxyamides

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

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