Direct nucleophilic difluoromethylation of aromatic isoxazoles activated by electron-withdrawing groups using (difluoromethyl)trimethylsilane

Abstract

The activation of aromatic diaryl isoxazoles with strong electron-withdrawing groups, such as the nitro, triflyl, and the phenylsulfonyl groups, at the 4-position has enabled the first regio-and diastereoselective difluoromethylation at the 5-position of isoxazoles by nucleophilic addition using (difluoromethyl) trimethylsilane, Me 3 SiCF 2 H, to provide difluoromethylated isoxazolines in good yields. Conjugated styryl-4-nitroisoxazoles were also nicely converted into the corresponding CF 2 H adducts with high regio-and excellent diastereoselectivities. Since the trifluoromethylated analogs of the corresponding diaryl-isoxazolines are effective ectoparasiticides, represented by fluralaner, should a series of difluoromethylated isoxazolines be obtained, they would be of great importance as promising drug candidates in this field.Heterocycles have an extensive history and are present in a wide variety of drugs, most vitamins, many natural products, biomolecules, and biologically active compounds [1][2][3][4]. Manmade fluorinated organic compounds have become a remarkable success in the pharmaceutical industry, despite their relatively young history [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. In this context, fluorinated heterocycles have gained attention as new drug candidates over the past few decades in medicine and agro-chemistry [21][22][23][24][25][26][27][28]. Fluorinated and trifluoromethylated compounds have been well targeted in this research area [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28], and difluoromethylated compounds are next [16,[21][22][23][24][25][26][27][28]. The difluoromethyl (CF 2 H) group is known to be isosteric and isopolar to a hydroxy (OH) and thiol (SH) unit. The CF 2 H group can also act as a more lipophilic hydrogen donor than OH and NH groups through hydrogen bonding [31][32][33][34]. Thus, the difluoromethylation of biologically active molecules is an effective strategy for the design new candidates of pharmaceuticals and agrochemicals [16]. BRAVECTO™ (fluralaner) is a highly potent insect and acarid RDL and GluCl inhibitor that was just recently approved in chewable tablets for dogs against fleas and ticks [35]. A systematically large number of research disclosed that 3,5-diaryl-5-(trifluoromethyl)-2-isoxazoline unit 1 is a key skeleton for its biological activity [36][37][38]. Since 2010, our group has also made contributions to this fascinating structure by the direct late-stage trifluoromethylation of aromatic isoxazoles with Ruppert-Prakash reagent (trifluoromethyl) trimethylsilane (Me 3 SiCF 3 ) [39][40]41], and a fluorinated building block strategy based on the use of inexpensive reagents under organocatalysis with an eye on industrial purposes [36][37][38]. We are now interested in the synthesis of difluoromethyl analogs of this key structure, i.e., 3,5-diaryl-5-(difluoromethyl)-2-isoxazolines 2. More than 27,000 isoxazolines 1 with a quaternary carbon bearing a CF 3 group at the 5-position have been s...

Synthesis of N‐Nitroso CHF2‐Pyrazolines and Their Transformation into CHF2‐Isoxazolines and ‐Pyrazoles

“…[16] Indeed, heating the representative pyrazolines in chlorobenzene smoothly gave CHF 2 -isoxazolines 6d, 15d, and 16d in 55-71 % yield after column chromatography (Table 3). [17] Table 3. Synthesis of representative CHF 2 -isoxazolines 6d, 15d, and 16d.…”

Cyclopropanation of 5-(1-Bromo-2-phenyl-vinyl)-3-methyl-4-nitro-isoxazoles under Phase Transfer Catalysis (PTC) Conditions

“…We have compared the data collected for the reaction of 1 and 6 [14] with those for the reaction of 2 and malonate 5 and explained the observed difference in enantioselectivity as follows (Figure 2). Firstly, the requirement for a free -OH on the phase transfer catalyst indicates the interaction of this group with one of the two reagents involved, presumably the enolate.…”

“…Furthermore, compounds 1 have two electrophilic centers that can be selectively reacted. Enolates, which are stabilized soft nucleophiles, react at the soft electrophilic center E2, whereas hard nucleophiles such as hydroxide react exclusively at the hard electrophilic center E1 ( Figure 1) [1][2][3][4][5][6][7][8][9][12][13][14].…”

Difluoromethylation of Alkyl Bromides and Iodides with TMSCF2H

“…To date, most efforts for the incorporation of the difluoromethyl group have been focused on the construction of the C­(sp 2 )–CF 2 H bond, while synthetic routes to install a difluoromethyl group onto a sp 3 -hybridized carbon are far less developed. One of the well-known methods for the formation of the C­(sp 3 )–CF 2 H bond is the reaction of a nucleophilic difluoromethylation reagent TMSCF 2 H with activated electrophiles such as aldehydes, ketones, or imines using CsF or KO t Bu as the promoter. Notably, Xiao and co-workers reported a Ph 3 P/ICH 2 CH 2 I system which could effectively activate the hydroxyl group for nucleophilic difluoromethylation .…”