Difluoro compound

FLUOROBIPHENYLS Fluorobiphenyls are incorporated into the analgesic and antiinflammatory dmgs diflunisal [22494-42-4] and flurbiprofen [5104-49-4]. The first is a difluoro compound and the other monofluoro. 

The best known of the hahdes are the trialkyldihalo- and triaryldihaloantimony compounds. The dichloro, dibromo, and diiodo compounds are generally prepared by direct halogenation of the corresponding tertiary stibiaes. The difluoro compounds are obtained by metathasis from the dichloro or dibromo compounds and silver fluoride. The diiodo compounds are the least stable and are difficult to obtain ia a pure state. The tri alkyl- and triaryldichloro- and dibromoantimony compounds are all crystalline soHds which are stable at room temperature that but decompose on heating ... 

The difluoro compounds, however, do not undergo this thermal decomposition. 

The recent discovery of a convenient synthesis of sulfur tetrafluoride from sulfur dichloride and sodium fluoride in acetonitrile invited the application of this reagent in fluorination reactions. Hasek, Smith and Engelhardt showed that carboxylic acids and their derivatives can be converted into trifluoromethyl derivatives and that aldehydes and ketones are converted into 5 em-difluoro compounds. They also observed that the reaction was acid... 

The preparation of e/n-difluoro compounds by the oxidative fluorodesul-furization ot 1,3-dithiolanes readily proceeds by treatment with a pyridinium polyhydrogen fluoride-Af-halo compound reagent the latter serves as a bromonium ion source [2], l,3-Dibromo-5,5-dimethylhydantoin is the most effective of several At-halo oxidants. It is believed that /V-halo compounds combine with hydrogen fluoride to generate in situ halogen fluorides, the oxidants. Formation of gem-difluorides from dithiolanes derived from ketones is efficient and rapid, even at -78 °C, whereas the reaction of dithiolanes derived from aldehydes requires higher temperature (0 °C) (equation 4). 

Methyliodobenzene difluoride cleaves aryl dithioketals. The reactions are conducted in dichloromethane solutions at 0 °C to give gem-difluoro compounds in 65-90% yields [4 (equation 6)... 

High yields (65-94%) of geminal difluoro compounds can be obtained tram diazoketones and dilute molecular fluorine [90] (equation 25)... 

Many aldehydes and ketones have been converted to g m-difluoro compounds with sulfur tetrafluoride (SF4), " including quinones, which give 1,1,4,4-tetra-fluorocyclohexadiene derivatives. With ketones, yields can be raised and the reaction temperature lowered, by the addition of anhydrous HF. Carboxylic acids, acyl chlorides, and amides react with SF4 to give 1,1,1-trifluorides. In these cases the first product is the acyl fluoride, which then undergoes the ge i-difluorination reaction ... 

Silylated diphenols such as persilylated hydroquinone 2195 react with difluoro compounds such as 2,6-difluoropyridine 2196 in the presence of CsF at 140-300 °C to give aromatic polyethers such as 2197 and the volatile Me3SiF 71 (b.p. 17°C) [11] (Scheme 14.3). 

Difluoro compounds have been prepared by treatment of carbonyl compounds with DAST. These are methyl 5-deoxy-5,5-difluoro-2,3,-0-isopropylidene-)S-D-ribofuranoside, 6-deoxy-6,6-difluoro-1,2 3,4-di-0-isopropylidene-a-D-galactopyranose, methyl 2-deoxy-2,2-difluoro-... 

Isolated yield. A, CFjOF in CCI3F at — 60 to — 80° with or without CaO B, F2 in Ar (or N2—CCI3F) at — 78° B, F2 in N2—HjO at room temperature C, Xep2-BF3 OEt2 in ether, benzene, toluene, dichloromethane, or a mixture of some of them (0° to room temperature). Yield of the deprotected compound after hydrolysis. " 2,2-Difluoro compound, Estimated from the final 2-deoxy-2-fluoroglycose. 

The 4-fluoro (518), 4-trifluoromethyl (523) and 3-chloro derivatives (522) also showed improved binding. 3,5-Disubstitution was also well tolerated (519), however the 3,4-difluoro compound (521) had the most potent inverse agonism of the series with an EC50 of 8 uM, with an average 110% maximal response and 400-fold selectivity over CB2. In addition to the crucial role of the 4-chloro substituent on the 5-phenyl ring, the 2,4-dichloro substitution on the 6-phenyl ring, which mimics that of (382), was also found to be optimal. 

Even trifluoromethylbenzene can be used as a starting material, which gives various n-difluoro compounds in one-step (Scheme 3.10) [22],... 

An impressive example for the successful use of domino reactions for the synthesis of pharmacological lead structures was described by Paulsen et al1241 Recently, the difluoro compound 57 has been identified as highly potent inhibitor of the cholesterin-ester-transferprotein (CETP), which is responsible for a transfer of cholesterin from high-density lipoprotein (HDL) to low-density lipoprotein (LDL). This clearly results in an increase of LDL and a decrease of HDL which raise the risk of coronary heart desea-ses. The core structure of 57 is now accessible efficiently by a combination of a Mukaiyama-MichaeL... 

A summary of the kinetic parameters is given in Table 11. With the exception of 3,3,3-trifluoropropyltrifluorosilane the decompositions are first-order homogeneous processes. The 2,2-difluoro compounds decompose by a four-centre transition state ... 

More conclusive evidence for the intermediacy of benzocyclopropenyl cations was obtained upon chloride/fluoride exchange of 22 with AgF in acetonitrile, which led to the chloro-fluoro derivative 278 and, ultimately, to the difluoro compound 279 in almost quantitative yield. Reaction of 22 with LiAlH AlClj afforded 2,5-diphenylbenzocyclopropene (264), while that with ethyl magnesium bromide lead to the diethyl derivative 280. Phenylmagnesium bromide and methylmagne-... 

Not unexpectedly by comparison with the monofluorinated 1-deoxynojirimycin derivatives, the 4,4-difluoro derivative 102 (Scheme 26) was found to be inactive with almond (l-glucosidase and the a-glucosidase from yeast.227 Equally inactive with these enzymes was the 3,3-difluoro compound 105 (Scheme 26).228 It is noteworthy that the 4,4-difluoro derivative of 1-deoxymannojirimycin, 103 (pAfa 5.3) turned out a good inhibitor of the (1-glucosidase from almonds (K, 45 pM, at pH 6.8 2 47 pM) and remained unprotonated and active at pH 5 (K, 92 pM 2 Kt 300 pM)227... 

The following bands of the PE spectrum of dimethyldiazirine were reported IP(v) 12.1, ZP(n+) 13.3, ZP(n ) 9.75 eV. Thus the i/r(7r)-orbital lies between the orbitals of the lone electron pairs. Interpretation of the spectrum suggested that the lone electron pairs are not so lonely, but are localized at the N atoms to only 56% and 43% respectively (73HCA1933). This effect is known, but less markedly, from (Z)-azomethane. PE spectra of the parent diazirine and the difluoro compound were also recorded. Comparison with calculated spectra gave good agreement (72JCP(57)1758). 

Merritt et al. [124,170-174] carried out some of the earliest additions of fluorine to carbon-carbon double bonds. The fluorination of cis and trans propenyl benzene in a nonpolar solvent at low temperature gave predominantly erythro and threo difluorides respectively. More recently, Rozen [175] carried out similar reactions, but used a more polar solvent (trichlorofluoro methane, chloroform and ethanol) and a very low concentration of fluorine. Thus, in the fluorination of cis and trans 3-hexene- l-ol acetate (Fig. 72), syn addition occured to give exclusively the erythro and threo difluoro compounds respectively. Corresponding results were obtained in the addition of fluorine to other alkenes, including cyclic alkenes and cyclic enones. 

Further, by using Et3N.3HF in acetonitrile as solvent, they have demonstrated that electrolysis of benzyl nitriles, carboxylic acid esters, sulphonic acid esters and ketones give the corresponding monofluoro- or difluoro-compounds, depending on anode potential in yields of 30 - 70 %. 

The activated sulphur compound PhCOCH2SPh has been shown to react in a two stage process to produce, firstly, at lower potential, the monofluoro- derivative, and then, at higher potential, the difluoro-compound, both in good yields... 

The second synthetic route to PAE containing quinoxaline units involved the reaction of an aromatic dihydroxy quinoxaline or aromatic bis(hydroxy-quinoxaline) with activated aromatic difluoro compounds (Eq. (3)) [15]. The dihydroxy quinoxaline and bis(hydroxyquinoxaline) monomers were readily prepared from the condensation of 1,2-diaminobenzene with 4,4 -dihydroxyben-zil and aromatic bis(o-diamines) with 4-hydroxybenzil, respectively. The Tgs of a series of PAE containing quinoxaline units are presented in Tables 3 and 4. For these polymers, the trend for the Tg is sulfone > carbonyl > terephthaloyl-> isophthaloyl. This trend holds for most polymer families when polymers of similar molecular weights are compared. Several polyphenylquinoxalines of the same chemical structure as those in Table 3 were also prepared by the poly-... 

Poly(arylene ether)s containing phenylimidazole units were initially prepared from the reaction of 2-phenyl-4,5-di(4-hydroxyphenyl)imidazole and various activated aromatic difluoro compounds according to Eq. (4) [20]. The dihydroxyimidazole was first prepared from the reaction of 4,4 -dimethoxyben-zil, benzaldehyde and ammonium acetate in refluxing acetic acid followed by... 

Hydrazones are transformed into gcw-difluoro compounds by treatment with a combination of 60% hydrogen fluoride/pyridine or 59% hydrogen fluoride/poly-4-vinylpyridine and N-bromosuccinimide yields are satisfactory.170 The electrochemical reaction of diarylketone hydrazones 1 in the presence of triethylamine trisfhydrogen fluoride) complex in dichloromethane solution (current density 1.3 mA cm"2) gives mainly the monofluorinated products 2 besides only very small amounts of difluorides 3.332... 

The most general and useful application of sulfur tetrafluoride is replacement of carbonyl oxygen and hydroxy groups by fluorine. The reaction has broad scope and is effective with all carbonyl and hydroxy compounds. Alcohols are converted into monofluoro derivatives 1, aldehydes, ketones and quinones into gew-difluoro compounds 2 and 3, and carboxylic acids, acid anhydrides, acid halides and amides into trifluoromethyl compounds 4. 

Ketones are less reactive than the aldehydes (see Section 8.4.2.). Ketones, e.g. 1 and 3, can be converted to the corresponding gem-difluoro compounds, e.g. 2 and 4, respectively, with (dia-lkylamino)trifluoro-A4-sulfanes at temperatures ranging from 20 to 80 C (see Table 4). 

The fluorination of ketones with DAST may result in the formation of vinyl fluorides, e.g. 5, in addition to gew-difluoro compounds. If vinyl fluorides are the desired product, this reaction can be promoted by carrying out the fluorination procedure in 1,2-dimethoxyethane in the presence of fuming sulfuric acid.51... 

Suprisingly, the treatment of furanones such as benzofuran-3(2//)-one (6) with DAST does not result in the formation of the desired gem-difluoro compound, but instead in the formation of the monofluorinated addition product 7 in good yield.52... 

Silicon trifluoromethanesulfonate 9 react with lithium fluoride even at — 30°C in diethyl ether to afford the difluoro compound 10 in 63% yield.9... 

This alkoxyfluorination leads to alkoxy fluoro and difluoro compounds. The product distribution depends on the reaction conditions. Similarly, fluoro halides are obtained in addition to alkoxy halides using a combination of boron trifluoride and alkyl hypohalite.50... 

---