Difluoromethyl Bioisostere: Examining the “Lipophilic Hydrogen Bond Donor” Concept

Abstract

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 H 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(XCFH) - log P(XCH)) 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.

Efficient Difluoromethylation of Alcohols Using TMSCF2Br as a Unique and Practical Difluorocarbene Reagent under Mild Conditions

“…[1,2] Moreover,the a-fluorine substitution of alkyl ethers shortens and strengthens the CÀO bond [3] and thus improves the in vivo oxidative stability of the ether moiety of ad rug. [5] In the past decades,d ifluoromethyl ethers have been applied in developing enzyme inhibitors/ activators,a nti-HIV agents,a ntimicrobial agents,a nd anesthetic drugs. [5] In the past decades,d ifluoromethyl ethers have been applied in developing enzyme inhibitors/ activators,a nti-HIV agents,a ntimicrobial agents,a nd anesthetic drugs.…”

Catalytic Enantioselective Synthesis of Highly Functionalized Difluoromethylated Cyclopropanes

“…First, Rh 2 ((S)-TCPTTL) 4 was tested in DCM, and the desired cyclopropane 3a was isolated in 52 %y ield as a9:1 mixture of diastereoisomers with 86 %e nantiomeric excess (entry 1). Theu se of the fluorinated analogue,namely Rh 2 ((S)-TFPTTL) 4 ,did not provide any improvement, while Rh 2 ((S)-PTAD) 4 and Rh 2 -((S)-DOSP) 4 gave the corresponding product 3a in very poor yields (entries 2-4). Pleasingly,Rh 2 ((S)-BTPCP) 4 [19] provided 3a with an excellent enantiomeric excess (97 %), albeit with am oderate diastereoisomeric ratio and yield (entry 5).…”

“…Indeed, by using either a-aryl diazoacetates or a-nitro diazoketones with Rh 2 ((S)-BTPCP) 4 as ac atalyst, a-difluoromethylated olefins were readily converted into the corresponding highly decorated cyclopropanes.T he scope of the reaction is quite broad and offers an ew access to this versatile class of compounds. Indeed, by using either a-aryl diazoacetates or a-nitro diazoketones with Rh 2 ((S)-BTPCP) 4 as ac atalyst, a-difluoromethylated olefins were readily converted into the corresponding highly decorated cyclopropanes.T he scope of the reaction is quite broad and offers an ew access to this versatile class of compounds.…”

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

“…[1] Thus,inrecent years the controlled introduction of these groups represents one of the most active areas in the development of novel synthetic methodologies. Compared with the well-known CF 3 substituent, this group bears as lightly acidic C À Hb ond, [3] which is capable of hydrogen-bonding interactions to improve the binding selectivity to specific receptors. Compared with the well-known CF 3 substituent, this group bears as lightly acidic C À Hb ond, [3] which is capable of hydrogen-bonding interactions to improve the binding selectivity to specific receptors.…”