Pd‐Catalyzed Selective Carbonylation of <i>gem</i>‐Difluoroalkenes: A Practical Synthesis of Difluoromethylated Esters

Liu, Jiawang; Yang, Ji; Ferretti, Francesco; Jackstell, Ralf; Beller, Matthias

doi:10.1002/ange.201813801

Cited by 17 publications

(3 citation statements)

References 84 publications

(23 reference statements)

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“…Exemplarily, we first carried out the Pd-catalyzed alkoxycarbonylation of gem -difluoroallylic aryl ether 3 without further optimizations. Taking advantage of the specific phosphine ligand L1 with built-in-base functions 68 , 69 , the corresponding product 61 was obtained in 73% yield with high regioselectivity for the linear product. Furthermore, under-reported reaction conditions 70 , 3 underwent highly regioselective hydroformylation using simple Co 2 (CO) 8 as the pre-catalyst (87% yield, l / b > 20/1).…”

Section: Resultsmentioning

confidence: 99%

3,3-Difluoroallyl ammonium salts: highly versatile, stable and selective gem-difluoroallylation reagents

Spannenberg

et al. 2021

Nat Commun

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The selective synthesis of fluorinated organic molecules continues to be of major importance for the development of bioactive compounds (agrochemicals and pharmaceuticals) as well as unique materials. Among the established synthetic toolbox for incorporation of fluorine-containing units, efficient and general reagents for introducing -CF2- groups have been largely neglected. Here, we present the synthesis of 3,3-difluoropropen-1-yl ammonium salts (DFPAs) as stable, and scalable gem-difluoromethylation reagents, which allow for the direct reaction with a wide range of fascinating nucleophiles. DFPAs smoothly react with N-, O-, S-, Se-, and C-nucleophiles under mild conditions without necessity of metal catalysts with exclusive regioselectivity. In this way, the presented reagents also permit the straightforward preparation of many analogues of existing pharmaceuticals.

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Section: Resultsmentioning

confidence: 99%

3,3-Difluoroallyl ammonium salts: highly versatile, stable and selective gem-difluoroallylation reagents

Spannenberg

et al. 2021

Nat Commun

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“…A selective carbonylation of gem-difluoroalkenes using a Pd-basedcatalyst system generated ,-difluoromethylated esters (Scheme 41A). 88 Template…”

Section: Scheme 40 Selective -Hydride Elimination To Avoid the Loss Of Fluorinementioning

confidence: 99%

Fluorine-Retentive Strategies for the Functionalization of gem-Difluoroalkenes

Sorrentino

Altman

2021

Synthesis

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gem-Difluoroalkenes are readily available fluorinated building blocks, and the fluorine-induced electronic perturbations of the alkenes enables a wide array of selective functionalization reactions. However, many reactions of gem-difluoroalkenes result in a net C–F functionalization to generate monofluorovinyl products or addition of F to generate trifluoromethyl-containing products. In contrast, fluorine-retentive strategies for the functionalization of gem-difluoroalkenes remain less generally developed, and is now becoming a rapidly developing area. This review will present the development of fluorine-retentive strategies including electrophilic, nucleophilic, radical, and transition metal catalytic strategies with an emphasis on key physical organic and mechanistic aspects that enable reactivities.

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“…The transition metal or photocatalytic addition-elimination of nucleophiles or free radicals to gem-difluoroalkenes could lead to monofluoro-alkenes (Scheme 1a). [36][37][38][39][40][41][42][43][44] While nucleophiles or free radicals could also add directly to gemdifluoroalkenes without fluorine elimination, giving difluoromotifs (Scheme 1b). [45][46][47] Moreover, novel strategies have been reported by taking advantage of gem-difluoroalkenes as reliable trifluoromethyl (CF3) precursors through F + /Faddition initialized cascade reactions (Scheme 1c).…”

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confidence: 99%

Synthesis of Bioactive Fluoropyrrolidines via Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides

Bao

et al. 2021

Preprint

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Chiral pyrrolidinyl units are important building blocks in biologically active natural products and drugs, thereupon, searching approaches for the synthesis of diverse structured pyrrolidine derivatives is of great importance. Meanwhile, owing to the special physicochemical properties of fluorine atoms, the introduction of fluorine containing groups into small molecules often change their activities to a great extent. Herein, we reported an efficient route to chiral 3,3-difluoro- and 3,3,4-trifluoropyrrodinyl derivatives by Cu(I)-catalyzed enantioselective 1,3-dipolar cycloaddition of azomethine ylides with less active 1,1-difluoro- and 1,1,2-trifluoroalkenes. A series of new fluorinated pyrrolidines have been prepared in high yields (up to 96%) and excellent stereoselectivities (up to > 20:1 dr and 97% ee), and these unique structural blocks could be readily introduced into some natural compounds and pharmaceuticals. Additionally, antifungal activity investigation against four common plant funguses showed that some products possess general and high biological activities (up to 93% inhibition rate), the comparison with the antifungal activities of corresponding non-fluorinated compounds (low to 13% inhibition rate) revealed that the fluorine atoms at pyrrolidinyl rings play a crucial role in the antifungal activity, which prove the special properties of fluorine atoms in organic molecules.

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Pd‐Catalyzed Selective Carbonylation of gem‐Difluoroalkenes: A Practical Synthesis of Difluoromethylated Esters

Cited by 17 publications

References 84 publications

3,3-Difluoroallyl ammonium salts: highly versatile, stable and selective gem-difluoroallylation reagents

3,3-Difluoroallyl ammonium salts: highly versatile, stable and selective gem-difluoroallylation reagents

Fluorine-Retentive Strategies for the Functionalization of gem-Difluoroalkenes

Synthesis of Bioactive Fluoropyrrolidines via Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides

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