Halogenation of imidazoles

The results of halogenations of imidazole and its derivatives have provided a host of complicated but mechanistically interesting results. 

Halogen atoms in the 2-position of imidazoles, thiazoles and oxazoles (542) undergo nucleophilic substitution reactions. The conditions required are more vigorous than those used, for example, for a- and y-halogenopyridines, but much less severe than those required for chlorobenzene. Thus in compounds of type (542 X = Cl, Br) the halogen atom can be replaced by the groups NHR, OR, SH and OH (in the last two instances, the products tautomerize see Sections 4.02.3.7 and 4.02.3.8.1). 

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). 

Halogenation of 106 with triphenylphosphine, iodine, and imidazole provided the iodo derivative 109. On treatment with lithium aluminum hydride, 109 was converted into two endocyclic alkenes, 110 and di-O-isopro-pylidenecyclohexanetetrol, in the ratio of 2 1. Oxidation of 110 with dimethyl sulfoxide - oxalyl chloride afforded the enone 111.1,4-Addition of ethyl 2-lithio-l,3-dithiane-2-carboxylate provided compound 112. Reduction of 112 with lithium aluminum hydride, and shortening of the side-chain, gave compound 113, which was converted into 114 by deprotection. ... 

B. Iddon, Metallation and Metall-Halogen Exchange Reactions of Imidazoles, Hctcrocycles 23, 417-443 (1985). 

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]. 

Also, psudo-P-D-mannopyranose (115) has been synthesized from 99 by the following reactions [28], Halogenation of 99 with triphenylphosphine, imidazole and iodine gave 1 L-4-0-benzyl-3-deoxy-3-iodo-1,2 5,6-di-0-isopropylidene-a//o-inositol (106), m.p. 77.4 °C, [oc]p° —30.1° (chloroform). Treatment of 106 with lithium aluminium hydride-resulted in a formation of two endocyclic olefins (107) and (108) in an approximately 1 2 ratio. Oxidation of 108with dimethyl sulfoxide and oxalyl chloride gave the enone (109) as a syrup, [a] 0 —68.11° (chloroform). Stereoselective... 

Grimmett, M. R., Advances in Imidazole Chemistry, 12, 103 27, 241 Electrophilic Substitution in the Azines, 47, 325 Halogenation of Heterocycles I. Five-member ed Rings, 57, 291 II. Six and Seven-numbered Rings, 58, 271 III. Heterocycles Fused to Other Aromatic and Heteroaromatic Rings, 59, 245. 

An enantiospecific synthesis of negstatin I (52) was accomplished efficiently with a sequence involving two C-imidazolide anion transformations. The first was coupling of a suitably protected carbohydrate intermediate with N-tritylimidazole. Direct monobromination of imidazole (51a, X = Y = H) was not feasible, except by selective halogen-metal exchange and reprotonation of dibromo intermediate (51b, X = Y = Br) [95TL6721], Introduction of the pendant acetic acid function was accomplished by C-allylation of 51c. 

Substitution generally occurs first at the 4-position, but further reaction at other available nuclear positions takes place readily, especially in the imidazole series. In 1-substituted imidazoles, C(5) is slightly more reactive than C(4). When halogenation of the nucleus involves electrophilic attack on anions of type 155, the 4-position of imidazole is... 

The complexity of individual halogenation mechanisms has become clear in more recent years from the diverse isomer distributions observed under different reaction conditions. Quantitative product studies are beginning to make a welcome appearance, but kinetic studies are almost wholly lacking. The recent kinetic work on the iodination of imidazole may signal the onset of improvement in this aspect. On the theoretical side, much attention has been given to the several possible quantum mechanical approximations applicable to heterocyclic substitution. Here again the lack of ample quantitative... 

Imidazole, itself, is prepared in 60% yield from the reaction of bromoacetaldehyde (as the glycol acetal), formamide, and ammonia at 180°C.70 The initial step in the formation of imidazoles from a-haloketones is replacement of the halogen by an hydroxy group.65 From the stage of acyloin formation it is assumed 61 that the following reaction path is followed ... 

The Wallach synthesis79 involves ring closure of an iV,jV -disubsti-tuted oxamide with PC15 to give a chlorine-containing compound, which, on reduction with hydriodic acid, yields a 1-substituted imidazole. The method has been adapted for the formation of halogen-substituted imidazoles.8 ° 8 2... 

Nuclear magnetic resonance spectroscopy has been used to determine product ratios from photoisomerization reactions of 1,4,5-trimethylimidazole,227 to determine substituent positions,228-231 and, in general, to study structural problems.123,124,138-139,217, 231-240 Studies of NMR spectra of the halogenation products of imidazoles show that the 4-halogenated compound is formed initially.230... 

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