Pyridines fluoromethyl

Ethyl substitution at the imidazole 5-position (469) was found to increase potency over the unsubstituted analogue (468), while methyl substitution (470) had a slightly deleterious effect on binding (Table 6.41). Chloro (491), bromo (492), cyano (493) and fluoromethyl (494) substitution at this position were all well tolerated (Table 6.43). Introduction of a chloro-substituted pyridine (475) in place of the more usual / -chlorophenyl group (470) resulted in a slight loss of affinity for the CBi receptor, as did replacement of the p-chloro group of (470) with bromo (471), fluoro (472) and in particular, met-hoxy (473). Trifluoromethyl substitution (474) however, was well tolerated. 

Treatment 2,3-dichloro-5-(trichloromethyl)pyridine in anhydrous hydrogen fluoride with mercury(II) oxide (red) at room temperature for 22 hours provides 2,3-dichloro-5-(tri-fluoromethyl)pyridine in 98% yield.59... 

A neutral diazo compound can be considered as both a nucleophile and an electrophile. Thus, it can be substituted by the combination of an electrophilic moiety and a nucleophilic moiety (X+ Nu ") (Scheme 8). In practice, the diazomethyl group is transformed to the fluoromethyl group by treatment with hydrogen fluoride/pyridine mixture (70 30 w/w) (X = H Nu = F), or to the halofluoromethyl group by addition of A-halosuccinimide in the same medium (X = Cl, Br, I Nu = F), e.g. formation of l.16 The reaction can be performed on secondary diazo alkanes, diazo ketones or diazo esters.16 90 316... 

Schlosser and co-workers have reported the shift of lithium in lithiated l-bromo-3-(tri-fluoromethyl)benzene 2,fa Quenching at — 100 C gives exclusively the product derived from 2, whereas after 2 hours at — 75 C, arene 2 is completely converted into less basic 3. A lithium-iodine exchange takes place in lithiated 2-chloro-3-iodo-6-(trifluoromethyl)pyridine 4, which at —85 C is totally converted into the less basic isomer 5.7 These rearrangements have been discussed in terms of a base-catalyzed halogen dance or halogen-shuffling mechanism. 

Table 1 Fluoromethyl Ketones by Reaction of Hydrogen Fluoride/Pyridine with Diazomethyl Ketones1 44 1...

The fluorine chemical shifts of a few 2- and 4-fluoromethyl pyridines and quinolines are available. The 4-substituted isomers appear to exhibit the shielding (relative to the phenyl and naphthyl analogs) that would be expected based on pyridine s electron-withdrawing hyperconjugative n-ocp impact (Scheme 3.84) (see Section 2.2.1.1). 

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. 

It is possible to halogenate selectively at the methyl position of alkylpyridines to give halogenoalkylpyridines. Low to moderate yields of fluoromethylpyridines are obtained on fluorination of 2- and 4-methyl pyridines with (V-fluoro-bis[(trifluoromethyl)sulfonyl]imide 52 in the presence of sodium carbonate in dichloromethane <1996T15>. 2-Methylpyridine is fluorinated in 20% yield and 4-methylpyridine in 72% yield under these conditions. Reagent 52 also effects the selective fluorination of 2,4,6-collidine to give the 2-fluoromethylated product in moderate yield (Equation 35). 

As discussed above, simple alcohols are not usually fluorinated with sulfur tetrafluoride with good results. For example, the attempted synthesis of 2-(fluoromethyl)furan and l-fluoro-2-phenylethanc from (2-furyl)mcthanol and 2-phcnylethanol at — 50 C in the presence of triethylamine or pyridine as a hydrogen fluoride scavenger gives the desired products in yields of only 20 and 35%, respectively.- ... 

Since Cd(CF3)2DME is ordinarily vastly superior to Hg(CF3)2 as a tii-fluoromethylating agent, it seems only reasonable to assume that trifluoromethyl zinc compounds might well be even more effective. Diligand Zn(CF3)2 complexes have been prepared by a number of routes, including the reactions of Zn(CH3)2 with Hg(CF3)2 (87) orCF3I (88) in basic solvents like pyridine, dimethoxyethane, and acetonitrile. 

Interest in close auialogs of fen-amates is illustrated by 8-tri-fluoromethyl phenothiazine-1-carboxylic acid (XIV) (an S-bridged analog) and the acetic acid homologs. Heterocyclic analogs are exemplified by several pyrimidine (XV) and pyridine (XVI) 7 iso-sters. Replacement of the carbox-resulted in a slightly less active but posit is noteworthy that the optimal activity O... 

For halothane (CFj—CHClBr), the C—Cl and C—Br vibrations are hardly affected by pyridine at room temperature. In accordance with the results of our low temperature study the C—H bond becomes more acidic and the C—Cl and C—Br bonds less associable because of the presence of the fluoromethyl group. 

Recently reported by Cottet and Schlosser regioselective synthesis of tri-fluoromethyl pyridines and -quinolines" " " is based on the trifluoromethylation of iodoheteroarynes using CF3Si(CH3)3/KF/CuI system originally applied by Urata and Fuchikami for trifiuromethylation of aryl halides." Trifluoromethyl copper in this... 

An oxazole-alkene Diels-Alder reaction has also been used to synthesize a tri-fluoromethylated pyridine related to pyridoxol. 5-Ethoxy-4-(trifluoromethyl)-2-oxazolecarboxylic acid 41 decarboxylated and then reacted with acrylic acid to give the expected 3-hydroxy-2-(trifluoromethyl)pyridine-4-carboxylic acid 42 in 63% yield (Fig. 3.13)." The electron-withdrawing trifluoromethyl group of 41 strongly modulates its reactivity, however, and it does not react with ethyl acrylate or A-phenyl maleimide. 

Owing to the presence of a CN group in the jS position (2-pyridyl sulfide 28), anodic fluorination in the presence of a base yields a bicyclic heterocycle (2-fluor-othieno[2,3-Z2]pyridine 30). Perhaps, the first step of the reaction is anodic mono-fluorination of 2-pyridyl sulfide to a fluoromethyl-pyridyl sulfide. In basic media, the... 

One can further reduce the 2-(difluoromethyl)pyridines to the corresponding dihydropyridines which can be dehydrofluorinated to give the 2-(fluoromethyl)pyridines. For instance, the 2-(difluoromethyl)-6-(trifluoromethyl)pyridine 23 can be reduced with sodium borohydride to a mixture of 1,2-... 

Another interesting discovery is that the diesters of the 2-(difluoromethyl)-6-(trifluoromethyl)- and the 2-(fluoromethyl)-6-(trifluoromethyl)pyridines can be selectively hydrolyzed on the ester group adjacent to either the difluoromethyl or the fluoromethyl group by using one equivalent of an alkaline base in a refluxing aqueous alcoholic solvent or by using excess alkaline base at room temperature. However, refluxing the diesters in an excess amounts of alkaline solution does produce the diacids (Scheme VII). 

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