Difluorocarbene-based [4 + 1] Cycloaddition Strategy for Synthesizing Derivatives of 5-Fluorinated Thiazoles and Oxazoles

Fuchibe, Kohei; Morota, Yuki; Miura, Takahiro; Ichikawa, Junji

doi:10.1246/cl.220212

Cited by 5 publications

(3 citation statements)

References 31 publications

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“…The sulfur or oxygen atom of N -thioacyl- or N -acylamidines 17 reacted with difluorocarbene generated from TFDA and a proton sponge catalyst, providing the corresponding [4+1] cycloaddition products 18 via thiocarbonyl or carbonyl ylide formation followed by 5- endo-trig cyclization, respectively (Scheme 11, –CF 2 – introduction). 40…”

Section: Discussionmentioning

confidence: 99%

Generation of difluorocarbenes and introduction of fluorinated one carbon units into carbonyl and related compounds

Fuchibe

Ichikawa

2023

Chem. Commun.

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Section: Discussionmentioning

confidence: 99%

Generation of difluorocarbenes and introduction of fluorinated one carbon units into carbonyl and related compounds

Fuchibe

Ichikawa

2023

Chem. Commun.

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“…The oxygen or sulfur atom in acyl or thioacyl group of amidines 66 nucleophilically attack difluorocarbene to yield zwitterionic (thio)carbonyl ylides U as intermediates, which further undergo an intramolecular nucleophilic addition (Michael‐type addition) to afford 5,5‐difluorooxazoline‐3‐amine and thiazoline‐3‐amine derivatives 67 (Scheme 19). [36] …”

Section: Synthesis Of Gem‐difluoroheterocyclesmentioning

confidence: 99%

Difluorocarbene in Cycloadditions and Annulations for the Synthesis of gem‐Difluorocarbocycles and gem‐Difluoroheterocycles

Xu,

Sun

2023

Eur J Org Chem

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Difluorocarbene is a simple, readily prepared, and versatile difluoriinated one‐carbon synthon. It can be applied as both the difluoromethylating reagent in the carbene insertion and the difluoromethylenating reagent in various cycloadditions and annulations. This concept article provides an account of applications of difluorocarbene in cycloadditions and annulations for synthesis of gem‐difluorocarbocycles and gem‐difluoroheterocycles. The synthesized gem‐difluorocarbocycles include 2,2‐difluorobicyclo[1.1.1]pentanes, 4,4‐/5,5‐difluoro‐cyclopentenes, 2,2‐difluorocyclopentanones, and 5,5‐difluorocyclopent‐2‐enones via tandem [2 + 1] cycloaddition and ring‐expansion or [4 + 1] annulations. The prepared gem‐difluoroheterocycles involve 2,2‐/3,3‐difluoro‐2,3‐dihydrofurans, 2,2‐difluoro‐2,3‐dihydrobenzofurans, 2,2‐difluoro‐2,3‐dihydrobenzothiophenes, 2,2‐difluorobenzofuran‐3(2H)‐ones, 2,2‐difluorobenzothiophen‐3(2H)‐ones, 2,2‐difluoro‐2,3‐dihydrothie‐no[2,3‐b]pyridines, 2,2‐difluorothieno[2,3‐b]pyridine‐3(2H)‐ones, 5,5‐difluorooxazolines and thiazolines, and spirocyclic 2,2‐difluorobenzo [d][1,3]aza/phosphaborol‐1‐ium‐3‐yliums via [4 + 1] annulations, 1,1‐difluoro‐1,9a‐dihydropyrido[2,1‐c][1,4]thiazines and 3,3‐difluorobenzo[e][1,4,2] oxaza/phosphaborinin‐4‐ium‐2‐uides via [5 + 1] annulations, 9,9‐difluoro‐8‐azabicyclo[5.2.0]nona‐2,4,6‐trienes via [8 + 1] annulation, 4,4‐difluorooxazolidines and 3,3‐difluoropyrrolidines via [1 + 2 + 2] annulations. Difluorocarbene generated from different readily available precursors proceeds these cycloadditions and annulations well. The substrate scopes, proposed mechanisms, selected product examples and their applications are discussed.

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“…Despite significant progress, cyclization with difluorocarbene remains a significant challenge due to the limited reaction types . Most of these processes focus on the formation of gem -difluorinated three-membered rings from [2+1] cycloadditions with alkenes or alkynes. , Other examples of cycloaddition reactions with difluorocarbene, such as [4+1] and [8+1], etc., are scarce, with limited documented success . On this basis, we expect to extend the cycloaddition of difluorocarbene to the preparation of gem -difluorinated 1,2-diazetidines via a [3+1] pathway.…”

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TBAF-Mediated [3+1] Cycloaddition of Difluorocarbene to Access gem-Difluorinated 1,2-Diazetidine Analogues as Potent Anticancer Agents

Mao,

Li,

Liu

et al. 2023

Org. Lett.

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The facile synthesis of gem-difluorinated 1,2-diazetidines was achieved by metal-free [3+1] annulation between C,N-cyclic azomethine imines with difluorocarbene. A library of 30 compounds benefiting from the TBAF-mediated cyclization process could be directly assembled in moderate to good yield under mild conditions. A plausible mechanism involving the difluorocarbene pathway was proposed based on carbene trapping and control experiments. Many compounds exhibited dramatic antiproliferative activity in 4T1, A549, and HeLa tumor cell lines.

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Difluorocarbene-based [4 + 1] Cycloaddition Strategy for Synthesizing Derivatives of 5-Fluorinated Thiazoles and Oxazoles

Cited by 5 publications

References 31 publications

Generation of difluorocarbenes and introduction of fluorinated one carbon units into carbonyl and related compounds

Generation of difluorocarbenes and introduction of fluorinated one carbon units into carbonyl and related compounds

Difluorocarbene in Cycloadditions and Annulations for the Synthesis of gem‐Difluorocarbocycles and gem‐Difluoroheterocycles

TBAF-Mediated [3+1] Cycloaddition of Difluorocarbene to Access gem-Difluorinated 1,2-Diazetidine Analogues as Potent Anticancer Agents

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