Imidazole, 4-methyl-, bromination

Cyclopentadienium (cation), and aza-analogs, antiaromaticity, 56, 347 Cyclopenta(4]imidazole, topological charge stabilisation, 56, 348 2//-Cyclopenta[c]pyridazine, 2-methyl-, bromination, chlorination, 59, 302-3... 

A third example comes from Clyne et al. [358] and concerns the axial chiral binaphthyl backbone [359,360], itself known from phosphorus chemistry [361]. The synthesis starts from the trifluoromethylsulfonato substituted binaphthyl with a Kumada coupling reaction [291,292] with methytmagnesiumbromide. Oxidation with NBS yields the methyl brominated derivative that can be attached to the imidazole ring. Subsequent methylation results in the bis-imidazolium salt that is deprotonated to the bis-carbene and coordinated to the transition metal halide (Pd, Ni), a rather straightforward reaction sequence (see Figure 3.113). The overall yield for the four-step reaction to the bis-imidazolium salt is surprisingly good (65%). 

The difficulty of monobrominating benzimidazole and its 1-substituted derivatives mirrors the state of affairs with the uncondensed imidazoles. Electrophilic bromination occurs at first in the 5-position, then at C-7, but excess brominating agent often substitutes all available positions on the fused benzene ring [23]. It has been found, though, that NBS supported on silica gel forms the 2-bromobenzimidazole (67%) in the first instance [32]. The same compound can also be made from 2-benzimidazolone, and it should be readily available via the 2-anion formed by reaction of an Al-protected benzimidazole with LDA, n-butyllithium or t-butyllithium. Hydroxymethyl and A -(dialkylamino)methyl protecting groups would appear to be the best choices [24, 25]. 

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... 

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). 

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. 

When l-methyl-2-(2 -furyl)imidazole (7) was brominated under conditions that either protonate or complex the azole nitrogen, substitution was directed mainly into the furan nucleus. Bromine only enters the imidazole ring in neutral organic solvents (89CHE1168) (Scheme 2) In 6-(2 furan yl)-imidazo[2,l-b]thiazole and some of its methyl derivatives, both furan-5-and imidazole-4-positions were brominated (80MI1). 

A benzisoxazole moiety provides the nucleus of an anticonvulsant agent whose structure differs markedly from the traditional agents in this class. The synthesis starts with a compound (61-1) that incorporates a preformed benzisoxazole. Bromination proceeds on the position adjacent to the carboxylic acid (61-2). This intermediate loses carbon dioxide on heating, leaving behind the bromomethyl derivative (61-3). Displacement of the halogen with the ion from the reaction of imidazole with sodium hydride yields the alkylation product (61-4). The short side chain is then methylated by successive treatment with a base and methyl idodide to afford zoniclezole (61-5) [64]. 

---