Bromination of imidazole

More recent studies of the kinetics of bromination of imidazoles coordinated to cobalt(III) have implied that, in aqueous solution, proton-abstraction from a Wheland intermediate is rate-determining at acidic pH values. In more nearly neutral conditions bromine addition becomes rate-... 

The bromination of imidazole derivatives is more complicated. Imidazole, treated with an equimolecular amount of bromine in chloroform, yields, after removal of solvent and boiling the residue with water, 2,4,5-tribromoimidazole hydrobromide, ammonium bromide, and a very small amount of 4,5-dibromoimidazole.92... 

Linda93 was able to isolate an orange complex in the bromination of imidazole, which proved to be a dicoordinate complex of unipositive bromine. The bromination of imidazole should proceed according to Scheme 1. 

With bromine in chloroform imidazole forms a complex, (C3H4N2)2Br Bra , in which two imidazoles are joined to a bromonium cation through the N-3 atoms 1-methylimidazole behaves in the same way. During the bromination of imidazoles there can be considerable ring degradation which is enhanced by an increase in acidity of the medium. Such reactions, which are initiated by electrophilic bromination, will be further discussed as oxidations (Section 4.07.1.4.8)... 

There has been considerable study of the bromination of imidazoles" and benzimidazoles. " Determination of the rate laws and isotope effects provide evidence that the bromination of imidazole (and other azoles)... 

Imidazole, and 1-alkyl-imidazoles, are brominated with remarkable ease at all free nuclear positions. It is, at first sight, somewhat surprising that such relatively mild conditions allow bromination of imidazole at C-2, but it must be remembered that the neutral imidazole, not its protonic salt (cf. nitration and sulfonation), is available for attack, thus electrophilic addition of bromine to imine nitrogen, then addition of bromide at C-2 and dually elimination of hydrogen bromide may be the key to the 2-bromination. 

Bromination of Aromatic Compounds. Phenols, anilines, and other electron-rich aromatic corrqiounds can be monobromi-nated using NBS in DMF with higher yields and higher levels of para selectivity than with Br2 iV-TrimethyIsilylanilines and aromatic ethers are also selectively brominated by NBS in CHCI3 or ecu. A-Substituted pyrroles are brominated with NBS in THF to afford 2-bromopyrroles (1 equiv) or 2,5-dibromopyrroles (2 equiv) with high selectivity, whereas bromination with Br2 affords the thermodynamically more stable 3-bromopyrroles. The use of NBS in DMF also achieves the controlled bromination of imidazole and nitroimidazole. Thiophenes are also selectively brominated in the 2-position using NBS in acetic acid-chloroform. ... 

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... 

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). 

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]. 

The apparently first kinetic study of a metal-assisted electrophilic substitution in a Co(III) complex is recent. The bromination of Co(NH3)5imidH is complicated by the presence of different bromine species in solution (Brj, HOBr and Brj"). In addition, successive brominations of the coordinated imidazole occur. Rate data can be interpreted in terms of reaction of the conjugate base of the Co(III) complex with Brj, and a suggested mechanism for the first steps is (Rq = Co(NH3)5 ")... 

An iminoether bond forms the link between large parts of the molecule in yet another of the unusual conazoles. Bromination of 2,4-dichloropropiophenone (59-1) affords the corresponding bromide (59-2). Treatment with imidazole displaces the activated halogen atom to afford the intermediate (59-3). The second major fragment... 

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]. 

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