Ring-fluorinated imidazoles

Cohen, L. A., Kirk, K. L. Photochemical decomposition of diazonium fluoroborates. Application to the synthesis of ring-fluorinated imidazoles. J. Am. Chem. Soc. 1971,93, 3060-3061. 

Other routes to fluoroimidazoles have been reported, some of which are confined to specific structural motifs. For example, methyl and fluorine substituents were used in a study of the phototranspositions of the 1-methylpyrazole ring. The nitrogen walk mechanism produced ring-fluorinated imidazoles from the ring-fluorinated pyrazoles (Fig. 3.55). ° ... 

In initial attempts to prepare ring-fluorinated imidazoles, nucleophilic displacement of activated halogens with fluoride was unsuccessful. However, if sufficiently activated, hahde exchange can occur. Thus, l-methyl-2-fluoro-4,5-dicyanoimidazole was prepared from 1-methyl-2-bromo-4,5-dicyanoimidazole by reaction with spray-dried KF in the presence of 18-crown-6 ether as catalyst. ... 

Synthesis of Ring-Fluorinated Pyrazoles Early procedures for accessing fluoropyrazoles included the photochemical Schiemann reaction that had been developed earlier for preparation of ring-fluorinated imidazoles, as discussed above. 3-Fluoro-, 4-fluoro-, and 5-fluoro-l-methylpyrazoles were obtained in low yields (Fig. 3.65). This procedure was also used to prepare 3,4-, 4,5-, and 3,5-difluoropyrazoles. An electrochemical procedure was reported that lacked generality. ... 

Kirk, K.L. Cohen, L.A. Biochemistry and pharmacology of ring-fluorinated imidazoles. In Biochemistry of the Carbon-Fluorine Bond, ACS Symposium Series No 28 Filler, R., Ed. American Chemical Society, Washington D.C., 1976 pp. 23-36. 

Yeh, H.J.C. Kirk, K.L. Cohen, L.A. Cohen, J.S. and nuclear magnetic resonance studies of ring-fluorinated imidazoles and histidines. J. Chem. Soc., Perkin Trans. 2 1975, 928-934. 

Biological Properties of Fluorinated Imidazoles The importance of the imidazole ring in biological structure and function combined with the profound effects on physicochemical properties that result from fluorine substitution combine to make fluorinated imidazoles a class of compounds with a wide range of biological... 

The Balz-Schiemann reaction has been used for the preparation of the 4-iluoro-derivatives of pyridine and 2,5-, 2,6-, and 3,5-lutidine it has also been used to obtain 5-fluoronicotinic acid, required for conversion into the corresponding pyridylmethanol via LiAlH reduction of the ethyl ester. The introduction of F into fluoroaromatic compounds has been achieved via isotopic exchange in diazonium tetrafluoroborates. U.v. irradiation of aqueous solutions of the appropriate diazonium tetrafluoroborates has been used to procure the first ring-fluorinated imidazoks, e.g. photolysis of the diazonium solution obtained by adding sodium nitrite to 2-amino-imidazole in aqueous fluoroboric acid provides 2-fluoroimidazole contaminated with only a small amount of 2-azidoimidazole, the sole product of thermal decomposition of imidazole-2-diazonium tetrafluoroborate. 

Fluorination of thiophene-2,5-dicarboxylic acitl with a sulfur tetrafluoritie-hydrogen fluoride mixture provides 2,5-bis(trifluoromethyl)thiophene in a 69% yield no fluorine addition to the thiophene ring occurs [229J. Also, imidazole mono- and dicarboxylic acids yield only the respective trifluo-romethyliinidazoles [230],... 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

Yet a further variation of this theme consists in the replacement of the bridging methylene group by sulfur to give a thiadiazepine as the central ring. The starting thiophene ether (26-3) is obtained by the nucleophilic aromatic displacement of fluorine in nitrobenzene (26-1) by the anion from imidazole-2-thiol (26-2). The nitro... 

Fluorination of perchloro bis(imine) 4 with sodium fluoride in tetramethylene sulfone at 120 JC takes place with ring formation to give the perfluoro imidazole derivatives 5-7.13... 

SAR studies have shown that a weakly basic imidazole or 1,2,4-triazole rings substituted only at the N-l position are essential for activity. The substituent must be lipophilic in character and usually contains one or more five or six membered ring systems, some of which may be attached by an ether, secondary amine or thioether group to the carbon chain. The more potent compounds have two or three aromatic substituents, which are singly or multiply chlorinated or fluorinated at positions 2, 4 and 6. These nonpolar structures give the compounds a high degree of lipophilicity, and hence membrane solubility. 

As discussed earlier (see Section 7.2), electrophilic monochlorination, -bromination and -iodination of imidazoles and 1-substituted imidazoles is difficult because of the great propensity of the molecules to polyhalogenate. Methods have, however, been developed to achieve selective halogen introduction on all ring sites. Fluorination is a special case (see below). 

Few examples are known of ring syntheses which produce fluorine-substituted imidazoles (but see Section 3.02.8.1.1(i)), and it is usual to add the fluorine to the preformed heteroaromatic ring... 

Fluorinated Purines and Benzimidazoles The importance of fluorinated purine and pyrimidine derivatives as antiviral and anticancer agents has increased the need for efficient methods for introduction of fluorine into these heterocyclic systems. This discussion will be confined to examples wherein the fluorine functionality is on the imidazole ring of purines and related compounds. A review of the substantial literature dealing with 2-fluoro-substituted purines, for example, will not be included. 

Chemical Reactivity A major consequence of fluorination of the imidazole ring is a dramatic drop in by several pH units. For example, the TpKiJs of 2-fluoro- and 4-flurohistidines were determined by NMR chemical shift titrations to be 0.9 and 2.5, respectively.A value of 6.0 is reported for histidine. 

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