Synthesis of Small 3-Fluoro- and 3,3-Difluoropyrrolidines Using Azomethine Ylide Chemistry

McAlpine, Indrawan; Tran-Dubé, Michelle; Wang, Fen; Scales, Stephanie; Matthews, Jean; Collins, Michael R.; Nair, Sajiv K.; Nguyen, Mary; Bian, Jianwei; Alsina, Luis Martinez; Sun, Jianmin; Zhong, Jiaying; Warmus, Joseph S.; O’Neill, Brian T.

doi:10.1021/acs.joc.5b00853

Cited by 52 publications

(27 citation statements)

References 25 publications

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“…[11] In the present study,w ew anted to extend this strategy towards other spirocycles. In fact, all three-(5, 6), four-(2, 7-10), five- (11)(12)(13), six-(4, [14][15][16][17][18][19][20], and seven-membered-ring (21)a lkenes gave the desired spirocyclic products in good to excellent yields. Only startingm aterial wasr ecovered from the reactionm ixture.…”

Section: Resultsmentioning

confidence: 99%

“…[7][8][9] Recently,o ur group, and Juhl and co-workers, have independently developedar apid two-step approacht os pirocyclic pyrrolidines from four-membered-ring aliphatic ketones. [11][12][13] Three-and six-membered-ring (hetero)aliphatic cyclic alkenes have also been used previously, but very rarely and not systematically.T ot he best of our knowledge,c yclopropyl-containings ubstrates have been mentioned in only one patent, [14] whereas six-membered-ring (hetero)aliphatic substrates have received somewhat more attention. [11][12][13] Three-and six-membered-ring (hetero)aliphatic cyclic alkenes have also been used previously, but very rarely and not systematically.T ot he best of our knowledge,c yclopropyl-containings ubstrates have been mentioned in only one patent, [14] whereas six-membered-ring (hetero)aliphatic substrates have received somewhat more attention.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis of Spirocyclic Pyrrolidines: Advanced Building Blocks for Drug Discovery

Chalyk

Butko

Yanshyna

et al. 2017

Chemistry A European J

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In the context of drug discovery, novel spirocyclic pyrrolidines have been synthesized in two steps from common three- to seven-membered-ring (hetero)alicyclic ketones. The key transformation is a reaction between an electron-deficient exocyclic alkene and an in situ generated N-benzyl azomethine ylide. The developed method has been used to synthesize the central diamine core of the known antibacterial agents Sitafloxacin and Olamufloxacin.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis of Spirocyclic Pyrrolidines: Advanced Building Blocks for Drug Discovery

Chalyk

Butko

Yanshyna

et al. 2017

Chemistry A European J

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“…In 2014, Genung and co-workers from Pfizer developed this two-step transformation into a one-pot methodology for the formation of 2-substituted indazoles. 35 This concerted cycloaddition reaction can be used with a range of fluorinated olefins including, enol ethers, α,β-unsaturated esters, heteroaromatics, as well as electron-deficient and electron-rich styrene analogues. Both electron-rich and electron-poor ortho-nitrobenzaldehydes were shown to successfully undergo reaction with substituted anilines, aminopyridines, and aliphatic amines.…”

Section: Selectivity In Heterocycle Formationmentioning

confidence: 99%

Modern advances in heterocyclic chemistry in drug discovery

et al. 2016

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New advances in synthetic methodologies that allow rapid access to a wide variety of functionalized heterocyclic compounds are of critical importance to the medicinal chemist as it provides the ability to expand the available drug-like chemical space and drive more efficient delivery of drug discovery programs. Furthermore, the development of robust synthetic routes that can readily generate bulk quantities of a desired compound help to accelerate the drug development process. While established synthetic methodologies are commonly utilized during the course of a drug discovery program, the development of innovative heterocyclic syntheses that allow for different bond forming strategies are having a significant impact in the pharmaceutical industry. This review will focus on recent applications of new methodologies in C-H activation, photoredox chemistry, borrowing hydrogen catalysis, multicomponent reactions, regio- and stereoselective syntheses, as well as other new, innovative general syntheses for the formation and functionalization of heterocycles that have helped drive project delivery. Additionally, the importance and value of collaborations between industry and academia in shaping the development of innovative synthetic approaches to functionalized heterocycles that are of greatest interest to the pharmaceutical industry will be highlighted.

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“…McAlpine group [22] showed that vinyl difluorides could participate in 1,3-dipolar cycloaddition with a simple azomethine ylide to generate gem-difluoropyrrolidines. They tried to synthesize 2,2-difluorostyrenes with benzaldehydes and Hu's reagent, then found out that benzaldehydes with electron deficient groups gave higher yields in [3＋2] cycloaddition reactions (Scheme 16).…”

Section: Scheme 15 Julia-kocienski Reaction Of Aliphatic Aldehydesmentioning

confidence: 99%

Progress of Difluoromethyl Heteroaryl Sulfones as Difluoroalkylation Reagents

Tao¹,

Sheng²,

Bao³

et al. 2019

Chinese Journal of Organic Chemistry

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Due to the uniqueness of fluorine atom and C-F bond, difluoromethylene has special properties. As a bioisostere of an oxygen or a carbonyl group, it plays an important role in medicines, pesticides and materials. Difluoromethyl heteroaryl sulfones, represented by 2-PySO 2 CF 2 H (Hu reagent), have been developed recently as difluoromethylation reagents, and widely recognized by synthetic chemists for their ease of preparation, good functional group tolerance and universal applicability to a wide range of carbonyl compounds. Through different types of reactions such as nucleophilic substitution, nucleophilic addition, Julia-Kocienski olefination reaction, and radical-mediated difunctionalization, they introduced difluoromethyl, difluoromethylene, gem-difluoroalkene and other fluorine-containing groups into aldehydes, ketones, and heterocyclic compounds. For the first time, the synthesis of fluorine-containing organic compounds involved in various difluoromethyl heteroaryl sulfones in the past decade is reviewed from the perspective of reaction types and their application studies.

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Synthesis of Small 3-Fluoro- and 3,3-Difluoropyrrolidines Using Azomethine Ylide Chemistry

Cited by 52 publications

References 25 publications

Synthesis of Spirocyclic Pyrrolidines: Advanced Building Blocks for Drug Discovery

Synthesis of Spirocyclic Pyrrolidines: Advanced Building Blocks for Drug Discovery

Modern advances in heterocyclic chemistry in drug discovery

Progress of Difluoromethyl Heteroaryl Sulfones as Difluoroalkylation Reagents

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