1535-67-7Relevant articles and documents
Difluoromethyl bioisostere: Examining the lipophilic hydrogen bond donor concept
Zafrani, Yossi,Yeffet, Dina,Sod-Moriah, Gali,Berliner, Anat,Amir, Dafna,Marciano, Daniele,Gershonov, Eytan,Saphier, Sigal
, p. 797 - 804 (2017)
There is a growing interest in organic compounds containing the difluoromethyl group, as it is considered a lipophilic hydrogen bond donor that may act as a bioisostere of hydroxyl, thiol, or amine groups. A series of difluoromethyl anisoles and thioanisoles was prepared and their druglike properties, hydrogen bonding, and lipophilicity were studied. The hydrogen bond acidity parameters A (0.085-0.126) were determined using Abraham's solute 1H NMR analysis. It was found that the difluoromethyl group acts as a hydrogen bond donor on a scale similar to that of thiophenol, aniline, and amine groups but not as that of hydroxyl. Although difluoromethyl is considered a lipophilicity enhancing group, the range of the experimental Δlog P(water-octanol) values (log P(XCF2H) - log P(XCH3)) spanned from -0.1 to +0.4. For both parameters, a linear correlation was found between the measured values and Hammett σ constants. These results may aid in the rational design of drugs containing the difluoromethyl moiety.
SRN1 Substitutions of Halogenoperfluoroalkanes (CF3Br or CF2Cl2) under Pressure
Wakselman, Claude,Tordeux, Marc
, p. 793 - 794 (1984)
Radical chain fluoroalkylation of arenethiolates by CF3Br or CF2Cl2, performed under slight pressure in a glass apparatus, gives aryl polyfluoromethyl sulphides.
SYNTHESIS OF BROMODIFLUOROMETHYL PHENYL SULFIDE, SULFOXIDE AND SULFONE
Burton, Donald J.,Wiemers, Denise M.
, p. 573 - 582 (1981)
Sodium thiophenoxide reacts with dibromodifluoromethane to give bromodifluoromethyl phenyl sulfide.Peracid oxidation of the sulfide gives the corresponding sulfoxide and sulfone.The formation of the sulfide is suggested to proceed via attack of thiophenoxide on halogen to produce difluorocarbene.Capture of carbene by thiophenoxide followed by a second positive halogen abstraction reaction yields the sulfide, PhSCF2Br.The use of excess sodium thiophenoxide yields difluorobis(thiophenyl)methane, (PhS)2CF2, via a similar mechanistic scheme.
Synthesis of α-Difluoromethyl Aryl Ketones through a Photoredox Difluoromethylation of Enol Silanes
Arseniyadis, Stellios,Cambeiro, Xacobe C.,Selmi-Higashi, Elias,Zhang, Jinlei
supporting information, p. 4239 - 4243 (2021/06/28)
We report here an efficient and highly straightforward access to α-difluoromethylated ketones through a visible light-mediated difluoromethylation of readily available enol silanes. The method, which takes advantage of the polyvalence of Hu's reagent, N-tosyl-S-difluoromethyl-S-phenylsulfoximine, used here as a CHF2 radical precursor under catalytic photoredox conditions, is practical, scalable, and provides the corresponding α-CHF2 ketones in good to excellent yields.
Regio- and chemoselectivity in S- and O- difluoromethylation reactions using diethyl (bromodifluoromethyl)phosphonate
Amir, Dafna,Binyamin, Iris,Drug, Eyal,Fridkin, Gil,Gershonov, Eytan,Marciano, Daniele,Redy-Keisar, Orit,Yehezkel, Lea,Zafrani, Yossi
, (2021/09/08)
The effective difluoromethylations of various S- and O- based- nucleophiles, presenting a wide range of pKa values, using diethyl(bromodifluoromethyl) phosphonate (1) under basic conditions is described. These reactions, which rely on the quantitative generation of difluorocarbene formed through the hydrolysis of 1, were found to be effective only once the starting materials had pKa values of less than ca. 11. Importantly, in cases in which the substrates held two or three nucleophilic centers this feature was successfully implemented to achieve a high chemo- or regioselective difluoromethylation of the center exhibiting the lowest pKa value and the highest polarizability.
A Unified Strategy for the Synthesis of Difluoromethyl- And Vinylfluoride-Containing Scaffolds
Duchemin, Nicolas,Buccafusca, Roberto,Daumas, Marc,Ferey, Vincent,Arseniyadis, Stellios
supporting information, p. 8205 - 8210 (2019/10/16)
Here, we report a general method for the synthesis of quaternary and tertiary difluoromethylated compounds and their vinylfluoride analogues. The strategy, which relies on a two-step sequence featuring a C-selective electrophilic difluoromethylation and either a palladium-catalyzed decarboxylative protonation or a Krapcho decarboxylation, is practical, scalable, and high yielding. Considering the generality of the method and the attractive properties offered by the difluoromethyl group, this approach provides a valuable tool for late-stage functionalization and drug development.
