2,2-difluorovinyl benzoates for diverse synthesis of gem-difluoroenol ethers by Ni-catalyzed cross-coupling reactions

Abstract

Abstractgem-Difluoroalkene is a bioisostere of carbonyl group for improving bioavailability of drug candidates. Herein we develop structurally diverse 2,2-difluorovinyl benzoates (BzO-DFs) as versatile building blocks for modular synthesis of gem-difluoroenol ethers (44 examples) and gem-difluoroalkenes (2 examples) by Ni-catalyzed cross coupling reactions. Diverse BzO-DFs derivatives bearing sensitive functional groups (e.g., C = C, TMS, strained carbocycles) are readily prepared from their bromodifluoroacetates and bromodifluoroketones precursors using metallic zinc as reductant. With Ni(COD)2 and dppf [1,1’-bis(diphenylphosphino)ferrocene] as catalyst, reactions of BzO-DFs with arylboronic acids and arylmagnesium/alkylzinc reagents afforded the desired gem-difluoroenol ethers and gem-difluoroalkenes in good yields. The Ni-catalyzed coupling reactions features highly regioselective C(vinyl)–O(benzoate) bond activation of the BzO-DFs. Results from control experiments and DFT calculations are consistent with a mechanism involving initial oxidative addition of the BzO-DFs by the Ni(0) complex. By virtue of diversity of the BzO-DFs and excellent functional group tolerance, this method is amenable to late-stage functionalization of multifunctionalized bioactive molecules.

Identification of Isosteric Replacements of Glycosyl Domain of Ligands by Data Mining

“…Although considerable ribose modi cation/replacement protocols have been elaborated for variety of applications, few of them speci cally address the necessity ribose replacement from molecular interactions perspective, meaning the identi cation of proper ribose bioisosteres remain the trial-and-error circle. Given the importance the bioisosterism in contemporary medicinal chemistry practice [49] and wide application [50,51], for the rst time, we have developed a cheminformatics work ow to mine the PDB for isosteric replacements of biologically important phosphate [52]. Besides the classical isosteres of phosphate, such as carboxylate, sulfone or sulfonamide [53], unexpected replacements that do not conserve charge or polarity, such as aryl, aliphatic, or positively charged groups were found.…”

Nickel-Catalyzed Cross-Electrophile Coupling Reactions between Allylic Acetates and gem-Difluorovinyl Tosylate

“…On the other hand, normal cross-coupling reactions between gem -difluorovinyl tosylate/iodide and the aryl metal reagent (or between aryl halides and the gem -difluorovinyl metal reagent) provide a new pathway to access gem -difluoroolefins (Figure a). Despite the achievements made, these methods have an obvious disadvantage, that is, to require preactivated metal reagents.…”

Access to gem-Difluoroalkenes via Organic Photoredox-Catalyzed gem-Difluoroallylation of Alkyl Iodides

“…Accordingly, researchers have made substantial efforts in developing various versions of gem -difluoroolefination reaction . Among them, gem -difluoroolefination of carbonyl, diazo, or its precursor substrates with fluorine reagents, including Hg­(CF 3 ) 2 , TMSCF 2 Br, TMSCF 3 , ClCF 2 H gas, and 2-bromo-2,2-difluoroacetates, represented a direct approach . However, most of these methods suffered from some limitations, such as low atom economy, unavailable raw materials, and/or harsh reaction conditions.…”

“…The crude product was purified by flash column chromatography using silica gel and a gradient of ethyl acetate and petroleum ether (ratio = 1:50) to afford the title product as a colorless oil (40.4 mg, 53%); 1 H NMR (400 MHz, CDCl 3 ) δ 7.20 (d,J = 8.4 Hz,2H),6.88 (d,J = 8.8 Hz,2H), 4.05 (d, J = 10.0 Hz, 2H), 3.81 (s, 3H), 2.65 (t, J = 12.0 Hz, 2H), 2.40−2.36 (m, 2H), 1.62 (d, J = 13.2 Hz, 2H), 1.44 (s, 9H), 1.40−1.35 (m, 1H), 1.32−1.00 (m, 2H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 158. 9,155.0,153.5 (dd,J = 287.3,284.1 Hz),129.4 (t,J = 3.2 Hz),125.9 (dd,J = 3.8,2.8 Hz),114.1,91.9 (dd,J = 21.3,13.5 Hz),79.3,55.4,44.1,35.6,34.6 (t,J = 2.2 Hz),32.1,29.8,28.6,25.1;19 F NMR (376 MHz, CDCl 3 ) δ −92.60 (d, J = 47.0 Hz, 1F), −92.86 (d, J = 47.0 Hz, 1F); IR ν max 2928, 2853, 1731, 1694, 1611, 1515, 1423, 1246, 1170, 1037, 3-(3,3-Difluoro-2-(4-methoxyphenyl)allyl)oxetane (3ag). The crude product was purified by flash column chromatography using silica gel and a gradient of ethyl acetate and petroleum ether (ratio = 1:20) to afford the title product as a colorless oil (34.1 mg, 71%); 1 H NMR (400 MHz, CDCl 3 ) δ 7.15 (d,J = 8.4 Hz,2H),6.88 (d,J = 8.8 Hz,2H), 4.65 (dd, J = 7.6, 6.0 Hz, 2H), 4.33 (t, J = 6.0 Hz, 2H), 3.80 (s, 3H), 3.00 (p, J = 7.2 Hz, 1H), 2.75 (dt, J = 7.6, 2.4 Hz, 2H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 159.1, 154.0 (dd, J = 287.3, 285.0 Hz), 129.5 (t, J = 3.0 Hz), 125.2 (dd, J = 4.0, 2.5 Hz), 114.2, 90.0 (dd, J = 2157, 14.9 Hz), 76.9, 55.3, 34.0 (t, J = 2.3 Hz), 32.0 (d, J = 1.2 Hz); 19 F NMR (376 MHz, CDCl 3 ) δ −91.62 (d, J = 45.2 Hz, 1F), −92.16 (d, J = 45.2 Hz, 1F); IR ν max 2960,2870,...…”

“…The crude product was purified by flash column chromatography using silica gel and a gradient of ethyl acetate and petroleum ether (ratio = 1:100) to afford the title product as a colorless oil (44.4 mg, 69%); 1 H NMR (400 MHz, CDCl 3 ) δ (mixture of two diastereomers) = δ 7.23 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 3.81, 2.71−1.57 (m, 6H), 116−1.10 (m, 2H), 0.89−0.49 (m, 13H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ (mixture of two diastereomers) = δ 158. 9,158.7,153.9 (dd,J = 285.6,283.6 Hz),129.8 (t,J = 2.8 Hz),129.5 (t,J = 3.1 Hz),126.3 (t,J = 2.4 Hz),114.0,113.9,90.9 (dd,J = 20.5,14.7 Hz),55.4,47.8,40.7,38.0,37.0,36.0,35.4,32.6,31.5,29.4,26.7,25.3,24.4,24.0,22.9,21.7,20.8;19 F NMR (376 MHz, CDCl 3 ) major: δ −92.76 (d,J = 47.8 Hz,1F), −92.78 (d,J = 47.4 Hz,1F), minor: −93.24 (d,J = 48.6 Hz,1F), −93.76 (d,J = 48.6 Hz,1F); IR ν max 2955,2842,1770,1758,1514,1456,…”