Imidazole, bromination

Medium effects were found to be important. A decrease in pH favored more 7-bromination, whereas the proportion of 195 remained fairly constant. Product ratios (Scheme 59) show pH dependence similar to that of imidazole bromination (74AJC2331). In acidic media, both NBS and NIS gave mainly 7-halogeno products (65% and 50 yields, respectively), and NCS gave the 7-chloro along with smaller quantities of 3-, 2,3-, and 3,7-chlorinated species (82CJC3049). 

Imidazole brominates very readily with bromine in aqueous solution or organic solvents... 

Imidazole, 4-acetyl-5-methyl-2-phenyl-synthesis, 5, 475 Imidazole, 1-acyl-reactions, 5, 452 rearrangement, 5, 379 Imidazole, 2-acyl-synthesis, 5, 392, 402, 408 Imidazole, 4-acyl-synthesis, 5, 468 Imidazole, C-acyl-UV spectra, 5, 356 Imidazole, N-acyl-hydrolysis rate constant, 5, 350 reactions, 5, 451-453 synthesis, 5, 54, 390-393 Imidazole, alkenyl-oxidation, 5, 437 polymerization, 5, 437 Imidazole, 1-alkoxycarbonyl-decarboxylation, 5, 453 Imidazole, 2-alkoxy-l-methyl-reactions, 5, 102 thermal rearrangement, 5, 443 Imidazole, 4-alkoxymethyl-synthesis, 5, 480 Imidazole, alkyl-oxidation, 5, 430 synthesis, 5, 484 UV spectra, 5, 355 Imidazole, 1-alkyl-alkylation, 5, 73 bromination, 5, 398, 399 HNMR, 5, 353 synthesis, 5, 383 thermal rearrangement, 5, 363 Imidazole, 2-alkyl-reactions, 5, 88 synthesis, 5, 469... 

Imidazole, 2-amino-1 -methyl-4,5-diphenyl-tautomerism, 5, 368 Imidazole, 2-aroyl-mass spectra, 5, 360 synthesis, 5, 391, 402 UV spectra, 5, 356 Imidazole, 4-aroyl-synthesis, 5, 474 Imidazole, C-aroyl-UV spectra, 5, 356 Imidazole, aryl-nitration, 5, 396, 433 oxidation, 5, 433 Imidazole, 1-aryl-dipole moments, 5, 351 dearylation, 5, 449 ethylation, 5, 448 H NMR, 5, 353 hydroxymethylation, 5, 404 rearrangement, 5, 108 synthesis, 5, 390 thermal rearrangement, 5, 363 Imidazole, 2-aryl-chlorosulfonation, 5, 397 synthesis, 5, 475 Imidazole, 4-aryl-bromination, 5, 399 Imidazole, C-aryl-electrophilic substitution, 5, 432-433 nitration, 5, 433 Imidazole, N-aryl-reactions, 5, 448-449 structure, 5, 448-449 Imidazole, arylmercapto-... 

Imidazole, 4-methyl-annular tautomerism, 5, 363 association, 5, 362 boiling point, 5, 362 bromination, 5, 398 deuteration, 5, 417 diazo coupling, 5, 403 hydrogen bonding, S, 350 hydroxymethylation, 5, 404 iodination, 5, 400 kinetics, 5, 401 mass spectra, 5, 358 melting point, 5, 362 methylation, 5, 364 sulfonation, 5, 397 synthesis, 5, 479-480, 482, 484, 489 Imidazole, 5-methyl-annular tautomerism, 5, 363 Imidazole, l-methyl-4-chloro-ethylation, 5, 386 Imidazole, l-methyl-5-chloro-ethylation, 5, 386 nitration, 5, 395... 

Imidazole, 2,4,5-trichloro-1-methyl-chlorination, 5, 398 Imidazole, 2,4,5-trideutero-iodination, 5, 401 Imidazole, 1-trifiuoroacetyl-reactions, 5, 451-452 Imidazole, 2-trifiuoromethyl-hydrolysis, 5, 432 Imidazole, 2,4,5-triiodo-nitration, 5, 396 synthesis, 5, 400 Imidazole, 1,2,4-trimethyl-photolysis, 5, 377 rearrangement, 5, 378 Imidazole, 1,2,5-trimethyl-photochemical rearrangement, 5, 377 rearrangement, 5, 378 Imidazole, 1,4,5-trimethyl-bromination, 5, 399 3-oxide... 

Displacement of bromine on phenacyl halide with imidazole gives Reduction with sodium borohydride followed by displacement with 2,6-dichloro-benzyl alcohol in HMPA then produces antifungal orconazole (37). ... 

Most electrophilic substitutions in benzimidazole (31 R = H) occur primarily in the 5-position. In multiple bromination the order followed, 5 > 7 > 6,4 > 2, parallels molecular orbital calculations. In benzimidazole itself the 4(7)- and 5(6)-positions are tautomerically equivalent. Fusion of a benzene ring deactivates C-2 to electrophilic attack to such an extent that it is around 5000 times less reactive than the 2-position of imidazole. Strong electron donors at C-5 direct halogenation to the 4-position, whereas electron-withdrawing groups favor C-4 or C-6 substitution (84MI21). 

Bromination follows the same general pattern as chlorination [78JCS(P2)865] (Scheme 22). A comprehensive kinetic study has demonstrated that benzo derivatives are much less reactive than imidazole itself. Partial rate factors for the bromination of 31 (R = H) were 5-bromination, 6.37 x I07 7-bromination, 2.88 x 106. For the 7-bromination of 6-bromobenzimidazole the factor was also 2.88 x 106, confirming that... 

Treatment of 6-(2 -furanyl)imidazo[2,l-b]thiazole (65) with bromine in chloroform gave rise to products of bromination of both furan and imidazole moieties (80MI1). In the unsubstituted imidazothiazole, bromination in dimethylformamide at 80°C, or in dichloromethane at 0°C, occurred in the 5-position. Even when there are such reactive groups as 2 -furanyl or... 

Electrophilic bromination (and nitration) of pyrido[l, 2-a]benzimidazole (analogous to 132) cannot take place in the imidazole moiety. Initial substitution, using NBS as reagent, was shown to occur at the 8-position, and subsequently at C-4 and C-6 (90JOU1166). 

The 1-bromo derivatives were formed in 85-90% yields when 2-methyl (or -phenyl) - 4H - imidazo [ 2,1 - c ] [ 1,4] benzoxa (or - benzthia) zines were treated with bromine or NBS in acetic acid. Iodination with NIS or iodine monochloride occurred at C-I in the imidazole ring in 75-86% yields, but NCS failed to react (92JOC2737). 

Several modifications of procedures based on halophosphonium ion have been developed. Triphenylphosphine and imidazole in combination with iodine or bromine gives good conversion of alcohols to iodides or bromides.22 An even more reactive system consists of chlorodiphenylphosphine, imidazole, and the halogen,23 and has the further advantage that the resulting phosphorus by-product diphenylphosphinic acid, can be extracted with base during product workup. 

In a similar way, iV-bromination on the imidazole group of an imidazolide by N-bromosuccinimide increases the compound s reactivity E11],[140]... 

Miconazole nitrate was prepared by Godefori and co-workers [5-7]. Imidazole 1 was coupled with brominated 2,4-dichloroacetophenone 2 and the resulting ke-tonic product 3 was reduced with sodium borohydride to its corresponding alcohol 4. The latter compound 4 was then coupled with 2,4-dichlorotoluene by sodium borohydride in hexamethylphosphoramide (an aprotic solvent), which was then extracted with nitric acid to give miconazole nitrate. 

Phenyl methyl ketone 1 was brominated to give l-phenyl-2-bromoethanone 2. Compound 2 was treated with methylsulfonic acid to yield the corresponding methylsulfonate 3. Etherification of 3 gave the a-benzyloxy derivative 4 and compound 4 was then chlorinated to give the 2,4-dichlorinated derivatives in both aromatic ring systems 5. Compound 5 reacted with imidazole in dimethylformamide to give miconazole 6 [7], which is converted to miconazole nitrate. 

By carefully monitoring the pH of the reaction, regioselective diiodination was achieved. Treating imidazole with iodine at pH 12 furnished 2,5-diiodoimidazole. Selective reductive deiodination secured 2-iodoimidazole, which upon bromination afforded 4,5-dibromo-2-iodoimidazole [6],... 

Having appropriate substituents on the imidazole ring, Haseltine et al. were able to carry out a regioselective bromination of l-benzyl-5-methyimidazole in excellent yield [8]. 

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