Imidazole 5- fluoro

Imidazole, 2-fluoro-l-methyl-pK., 5, 384 (B-76MI4070I, 70AHC(I2)I03, 80AHC(27)24I)... 

Imidazole, 2-fluoro-4-methyl-pKa, 5, 386 <80AHC(27)241, 70AHC(12)103) Imidazole, 4-fluoro-l-methyl-p K 5, 384 (B-76MI40701, 70AHC(12)103, 80AHC(27)241)... 

This technique has been applied to the synthesis of fluormated dopamine and other compounds of biological significance Fluoroheterocycles such as fluoro-imidazoles [JJ, 36] and fluoropyrazoles [37] can also be prepared by the photo Balz-Schiemann technique (equation 9) Photochemically induced in situ fluoro dediazoniation can also be applied to arenediazonium fluorides in hydrogen fluo nde-pyndine media Thus, o-fluoroanisole is obtained in 73% yield at 20 °C after I8h [dS]... 

Kirk and Cohen (1969, 1971, 1973 Kirk et al., 1973) successfully applied the photo-fluoro-de-diazoniation method for the introduction of fluorine into imidazole and its derivatives with various substituents (e.g., histidine) 2- and 4-fluoroimi-dazole had not previously been synthesized by other methods. 2-Fluoroimidazole, in contrast to the 4-isomer, is easily hydrolyzed in water (Kirk et al., 1973). 

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. 

Thus, perfluoroalkylated imidazoles are obtained in excellent to good yields (Scheme 3.7) [16, 17]. Similarly, a hindered phenolate anion provides a fluoro-alkylated dimeric product in high yield (Scheme 3.8) [173. 

Eluorine-18 was also used as a tool for the study of the base promoted HF elimination from 4-fluoro-4-(4 -nitrophenyl)butan-2-one [62] (Scheme 3). The F KIEs values were respectively 1.0037,1.0047 and 1.0013 with formate, acetate or imidazole used as the base. The size of the fluorine KIEs corresponds to 5 -15 % of the estimated maximum for complete C-F bond breakage and is consistent with a postulated ElcB-E2 Hke or ElcBjp mechanism. 

The most important applications of the in situ photochemical fluorodediazoniation start from heterocyclic amines for which the diazonium tetrafluoroborates are impossible to isolate. In this way, fluorinated imidazoles,123-253,254-257 261 benzimidazoles,262 pyrazoles,254-256,262 indazoles,158 thiazoles,259 and triazoles259-262 have been prepared (Table 4). Some of these are the precursors of biologically active compounds such as fluoro-substituted histidines or histamines,123,253-257,258 or 5-fluoro-l/ -D-ribofuranosylimidazole-4-carboxamide.261... 

Fluoro-phenyl)- E8e, 486 (2-Ar-imidazol + HNO,) 5-(2-Fluoro-phenyl)-3-(4-methoxy-phenoxy)- E8c. 488 (2-F —Ar —CO —Cl 4-5-OAr-tctra7ol) 3-(4-Fluoro-phenyI)-5-inetbyl- ... 

Allyloxy-(2,5-dihydro-imidazol-2- I )-,inuilo] 6 fluoro 1 lutliioi o methyl- E16a/1. 290 (OH - OR)... 

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