Benzimidazoles bromination

Benzimidazole, 2-amino-5-bromo-l-methyl-diazo coupling, 5, 429 Benzimidazole, 2-amino-6-bromo-1 -methyl-diazo coupling, 5, 429 Benzimidazole, 2-amino-1-ethyl-alkylation, 5, 438 Benzimidazole, 2-amino-1-methyl-acylation, 5, 438 bromination, 5, 429 tautomerism, 5, 368 Benzimidazole, 4-amino-2-methyl-diazo coupling, 5, 429 Benzimidazole, 2-aroyl-mass spectra, 5, 360 Benzimidazole, 1-aryl-metallation, 5, 448 reactions... 

The finding that the anthelmintic thiazoloimidazole levamisole showed immunoregulatory activity spurred further investigation of this heterocyclic system. Synthesis of a highly modified analogue starts by displacement of bromine in keto ester 149 by sulfur in substituted benzimidazole 148. Cyclization of the product (150), leads initially to the carbinol 151. Removal of the ester group by saponification in base followed by acid-catalyzed dehydration of the carbinol affords the immune regulator tilomisole (152) [28]. 

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). 

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). 

Path b, on the contrary, is preferred in the bromination of benzimidazole, since the reactive positions 4 and 5 are blocked by the benzene ring. Under similar conditions, N-methylbenzimidazole, which has no reactive positions, gives a 1 1 complex of the w-donor type.93... 

Ribose may be identified through the benzimidazole from ribonic acid, 2-(D-n6o-tetrahydroxybutyl)benzimidazole52 53 54 and its picrate and hydrochloride. However, caution must be used at two points in this procedure. In the first place, the customary oxidation of ribose with alkaline hypoiodite produces both ribonic and arabonic acids, the latter being formed by the alkali-induced epimerization of the former. While this epimerization may be avoided by using a buffered oxidizing mixture such as bromine-barium benzoate,65 there is, in the second place, further risk of epimerization during the condensation of the aldonic acid with o-phenylenediamine, particularly if there is insufficient acid present.9 10-11... 

V-Bromosuccinimide (NBS) supported on silica is a versatile reagent for controlled bromination of a variety of heterocyclic compounds. Indole, carbazole, benzimidazole,... 

Scheme 8.8. Partial rate factors for bromination benzimidazole, 5-bromobenimidazole, and indazole.

In a medium of bromine in acetic acid and nitric-sulfuric mixture the benzimidazole derivatives are nitrated only to position 4 [102], In this case the bromine is introduced into the position 5 or 6 (Scheme 2.10). 

The dibromo derivatives 125a and 126a have been prepared by reaction of the unsubstituted amine 125c and the methanesulphonate salt of 126c with excess bromine in acetic acid. Amines 125b and 126b have been converted to the isothiocyanates 125 and 126 by reaction with thiophosgene in a biphasic chloroform-bicarbonate system. The radiochemical purity and the specific radioactivity of the isothiocyanate 125 were 99.9% and 27.4 Ci mmol -1, respectively. The benzimidazole isothiocyanate 126 has been prepared with >95% radiochemical purity and with specific activity of 16.3 Ci mmol -1. 

Benzimidazoles, 2,3-dihydro-, by Nu addition at C-2, 56, 203 Benzimidazole, 2-fluoro-, 59, 272 Benzimidazole, 1-methyl-, ring expansion to chloroquinoxalines, 59, 305 Benzimidazole, l-methyl-2-(5 -methyl-2 -thienyl)-, bromination, 57, 319 Benzimidazole 3-oxides, chloro-deoxygenation, 59, 270 Benzimidazoles, 2-perfluoroalkyl-, 60, 25 Benzimidazoles, 2-(l-pyridinio)-, 60, 204 Benzimidazoles, 2-(2-pyridinioethyl)-, elimination reactions, 60, 246 Benzimidazoles, tetrafluoro-, 59, 14 Benzimidazole-2-carboxylic ester 3-oxide, 7-nitro-5-trifluoromethyl-, 60, 17 Benzimidazolium salts, l-amino-3-alkyl-, reaction with activated acetylenes, 56, 138... 

Lopez-Rodriguez and co-workers prepared a number of serotonin 5-HTia receptor ligands using palladium catalysis [133]. The Spanish group used both DPPP- and BINAP-based systems to couple bromine-substituted benzimidazoles with piperazines. For example, the reaction of the protected heterocycle below with M-methylpiperazine proceeds in excellent yield, Eq. (166). 

Oxidation of certain heteroaromatic Y-oxides has been reported to give dimers of type C, e.g., the dimer (135b) obtained on heating an aqueous solution of benzimidazole 3-oxide in a sealed tube in the presence of oxygen.219 A similar 2,2 -dimer was formed when 2-(2-naphthyl)thioindoxyl-1,1 -dioxide was oxidized with bromine or potassium ferricyanide.220... 

While the rr-densities predict greater reactivity to electrophilic attack at C-2 in the imidazole anion, localization energies suggest an order of reactivity of C-4 > C-2. Use of the CNDO/2 method predicts the order of electrophilic substitution in benzimidazole to be5= 7>6>4>2, whereas the observed order (for aqueous bromination) is 5>7>6,4,2 (78JCS(P2)865). Predictions of preferential nucleophilic attack at C-2 are confirmed by experiment. Table 2 lists rr-electron densities in benzimidazole. 

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