Fluoromethyl Aromatics

The products ArCF2SMe are assumed to be precursors of ArCF3. Indeed, l-(tri-fluoromethyl)naphthalene is obtained in 83% yield by the reaction of l-[difluoro(methylsul-fanyl)mcthyl]naphthalene with tetrabutylammonium dihydrogen trifluoride/ l,3-dibromo-5,5-dimethylhydantoin. It should be noted that under the oxidative desulfurization conditions the electron-rich aromatic compounds can undergo ring bromination. 

The reaction of sulfur tetrafluoride with carboxylic acids (aliphatic, aromatic, and heterocyclic) is of particular importance as the most general and simplest route to trifluorotnethyl derivatives. The reaction proceeds in two steps, the first step gives acyl or aroyl fluorides 1, and then catalysis in the second step by hydrogen fluoride released in the first step results in the tri-fluoromethyl derivatives 2.41... 

In various heterocyclic compounds two types of C F bonds are hydrogenolyzed. In fluoromethyl groups, which are attached to the aromatic heterocyclic ring, the C-F bonds arc activated similarly to benzylic C-F bonds, but the degree of activation is influenced by the position relative to the heteroatom the reactivity of aromatic C-F bonds in six-membered heterocyclcs is strongly influenced by their positions relative to the heteroatom(s). 

With its doublet deriving from the four equatorial fluorines appearing at +51.6 ppm and its pentet deriving from the single axial fluorine at +77.9 ppm, both signals exhibit significant shielding compared to those of SF5-benzenoid aromatics, which appear at +62.3 and +84.1 ppm, respectively. This trend is in the same direction as that exhibited in the comparison of the fluorine chemical shifts of 2-(trifluoromethyl)pyridine (-68 ppm) with those of (tri-fluoromethyl)benzene (-63 ppm), but the SF5 difference is more dramatic. 

Aromatic systems arc fluorinated by reagents containing an O-F bond, in particular by tri-fluoromethyl hypofluorite, and acetyl hypofluoritc. Trifluoromethyl hypofluorite is a commercial reagent which is prepared by the reaction of elemental fluorine with carbon monoxide. The initial product is carbonyl fluoride 10 formed by a spontaneous and highly exothermic reaction. This product is passed through a bed of cesium fluoride which catalyzes the addition of a second mole of fluorine to give trifluoromethyl hypofluorite. 

There are several different routes to carboxamides. Usually a carboxyhc acid is converted to a more reactive intermediate, e.g. an acid chloride, which is then reacted with an amine. For practical reasons it is preferable to form the reactive intermediate in situ. We have found that arylboronic acids bearing electron-withdrawing aromatic groups, e.g. 3,4,5-trifluorophenylboronic acid, 3,4,5-F3C( H2B(OH)2, and 3,5-bis(tri-fluoromethyl)phenylboronic acid, 3,5-(CF3)2C6H3B(OH)2, act as highly efficient catalysts in the amidation of carboxylic acids with amines [167]. The catalysts are useful in the reaction of primary and secondary amines with a variety of carboxylic acids (Eq. 114). 

Table 11.9). Several alkyl side-chains were found to be effective, including aminomethyl, fluoromethyl, 2-pyridyl, 2-furanyl, and 2-thienyl. This may imply that the acetamidine side-chain is involved in hydrophobic interactions with the enzyme that can be enhanced by aliphatic and aromatic groups. The 2-furanyl and 2-thienyl groups may be able to bind in the hydrophobic pocket created by Pro336, Val338, and Phe355 in the active site of nNOS. 

Fig. 4. Mechanism proposed for inactivation of aromatic-amino-acid decaitxixylase by a-fluoromethyl-DOPA (4).

A soln. of startg. 4-aryl-1,4-dihydropyridine in DMF treated with NaCN at 60°, and stirred for 20 min - 3-methyl 5-(isopropyl) 2-(fluoromethyl)-6-methylpyridine-3,5-dicarboxylate and l-chloro-4-fluoro-2-(trifluoromethyl)benzene (Y 72%). This is the first generally applicable fragmentation-type aromatization of a Hantzsch ester under mild, basic, non-oxidative conditions. F.e.s. T. Mclnally, A.C. Tinker, J. Chem. Soc. Perkin Trans. I 1988, 1837-44. 

Small F-thiols such as the aliphatic [ F]fiuropropane-l-thiol, a PEG3-derivative ([ F]fluoro-PEG3-thiol) and an aromatic system, 4-[ F]Fluoromethyl-N-(2-mercaptoethyl) benzamide, are also useful prosthetic groups, which allow an efficient chemoselective conjugation to N-chloroacetylated peptides (Glaser et al. 2004). 

SCHEME 9.3 Six molecules approved in 2012 which contain a fluorinated aromatic or tri-fluoromethyl group. 

These include anionic polymerizations of some conjugated monomers such as -tri-fluoromethyl acrylates, fluorostyrene derivatives and 1,4-perfluoro-butadiene (17), and condensation polymerization to afford such aromatic fluoropolymers as polyarylates and aramides (18). In addition, fluorinated polyimides are on a way of evaluation for practical applications in the electronics field. 

Fluorinated amino acids and amino alcohols have shown extensive biological activity [18]. In 2008, the Bandini and Umani-Ronchi group developed an efficient Henry reaction between nitromethane and fluoromethyl ketones catalyzed by cinchona alkaloids [19]. They showed that benzoylcupreines bearing electron-withdrawing substituents at the C9 position of the catalyst structure are essential for good results (Table 29.2,14 versus 15). Remarkably, comparable levels of asymmetric induction could be obtained with both aromatic and aliphatic ketones. 

Guanidine was shown to be an efficient organocatalyst for the Friedel-Crafts-type alkylation of indoles with aromatic fluoromethyl ketones, yielding up to 98% of trifluoromethyl-indolyl-phenylethanols, potential intermediates for pharmaceutical and agrochemical synthesis [114]. 

---