Imidazoles chlorination

Nucleophilic attack at ring carbon atoms is well known with suitably substituted 2//-imidazoles chlorine atoms at C-4 or C-2 can be replaced by nucleophiles (Scheme 55) <83BSB78l, 84AHC(35)375>. 

Uses. Uses of sulfuryl chloride include the manufacture of chlorophenols, eg, chlorothymol for use as disinfectants. It is also used in the manufacture of alpha-chlorinated acetoacetic derivatives, eg, CH2COCHCICOOC2H3, which ate precursors for important substituted imidazole dmgs,... 

Imidazole, 4,5-dibromo-l-methyl-synthesis, S, 399 Imidazole, 4,5-di-t-butyl-synthesis, S, 483 X-ray diffraction, S, 350 Imidazole, 4,5-dichloro-chlorination, S, 398 synthesis, S, 398, 473 Imidazole, 4-(3,4-dichlorophenyl)-nitration, 5, 433 Imidazole, 4,5-dicyano-hydrolysis, S, 435-436 synthesis, S, 461, 472, 487 Imidazole, 4,5-dicyano-1-vinyl-synthesis, S, 387 Imidazole, 4,5-dihydro-mass spectra, 5, 360 Imidazole, 4-(dihydroxybutyl)-synthesis, S, 484 Imidazole, 4,5-diiodo-nitration, S, 396 synthesis, S, 400 Imidazole, 2,4-diiodo-5-methyl-iodination, S, 400 Imidazole, 1,2-dimethyl-anions... 

Imidazole, l-ethoxymethyl-2,4,5-tribromo-lithiation, S, 416 Imidazole, 2-ethyl-chlorination, S, 398 Imidazole, 4-ethyl-synthesis, S, 484 Imidazole, N-ethyl-synthesis, S, 108... 

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... 

Imidazole-5-carboxamide, l-methyl-4-nitro-mass spectra, 5, 359 Imidazole-4-carboxanilide, 1-methyl-synthesis, 5, 435 Imidazolecarboxylic acid, vinyl-polymers, 1, 281 Imidazole-2-carboxylic acid chlorination, 5, 398 mass spectra, 5, 360 synthesis, 5, 474... 

Imidazole with [Cr(CO)jCNCCl3] gives a simple product of substitution of three chlorine atoms followed by deprotonation, [Cr(CO)jCNC(im)3] (95JOM(489)27). The product reacts further with o-propylamine and pyrrolidine to give amino(alkylideneamino)carbenes 36 and 37, respectively. 

Nafimidone (93), an anticonvulsant compound, also contains an imidazole moiety It seems to have been discovered by accident during a search for antifungal agents Its synthesis is straightforward involving displacement with imidazole of the activated chlorine atom of chloro-methyl-p-naphthylketone (92) [32]... 

Another common reaction is the chlorination of alkenes to give 1,2-dihaloalka-nes. Patell et al. reported that the addition of chlorine to ethene in acidic chloroalu-minate(III) ionic liquids gave 1,2-dichloroethane [68]. Under these conditions, the imidazole ring of imidazolium ionic liquid is chlorinated. Initially, the chlorination occurs at the 4- and 5-positions of the imidazole ring, and is followed by much slower chlorination at the 2-position. This does not affect the outcome of the alkene chlorination reaction and it was found that the chlorinated imidazolium ionic liquids are excellent catalysts for the reaction (Scheme 5.1-39). 

Generally, PS containing amine groups are synthesized by condensation of chlorinated PS with amines. These type of resins are widely used as anionic resins.[8] PSs containing imidazol rings have antistatic properties and are used as additives to make dyeing of synthetic fiber materials easy [9] (Scheme [3]). 

Tetrahydroimidazo[5,l-c][l,2,4]triazine 474 was prepared (79KGS1540) by treating imidazole derivatives 472 or 473 with hydrazine. Compound 473 was obtained by reaction of the respective imidazole with 1,2-dibromoethane or by the reaction of the alcohol derivative 471 with phosphorus tribromide. On the other hand, chlorination of471 with thionyl chloride gave 472 (Scheme 100). 

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... 

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). 

The introduction of chlorinated porphyrins (10) allowed for hydrogen peroxide to be used as terminal oxidant [62], These catalysts, discovered by Mansuy and coworkers, were demonstrated to resist decomposition, and efficient epoxidations of olefins were achieved when they were used together with imidazole or imidazo-lium carboxylates as additives, (Table 6.6, Entries 1 and 2). 

Phosphazene polymers can act as biomaterials in several different ways [401, 402,407]. What is important in the consideration of skeletal properties is that the -P=N- backbone can be considered as an extremely stable substrate when fluorinated alcohols [399,457] or phenoxy [172] substituents are used in the substitution process of the chlorine atoms of (NPCl2)n> but it becomes highly hydrolytically unstable when simple amino acid [464] or imidazole [405-407] derivatives are attached to the phosphorus. In this case, an extraordinary demolition reaction of the polymer chain takes place under mild hydrolytic conditions transforming skeletal nitrogen and phosphorus into ammonium salts and phosphates, respectively [405-407,464]. This opens wide perspectives in biomedical sciences for the utilization of these materials, for instance, as drug delivery systems [213,401,405,406,464] and bioerodible substrates [403,404]. 

Because free or esterified imidazole(4,5)-acetates 745 are currently accessible only via a rather tedious multistep synthesis via (4,5)hydroxymethylimidazole [224— 226], it seemed obvious to react amidines such as isobutyraminidine-HCl 742 with commercially available methyl or ethyl 4-chloroacetoacetates 743a, b to obtain 745 directly in one step. Because of the low reactivity of the 4-chlorine in 743, however, reaction of 743, e.g. with isobutyramidine-HCl 742 in the presence of sodium methylate in methanol, affords exclusively 2-isopropyl-6-chloromethyl-pyri-midin-4-one 744 [227], whereas treatment of 743b with NaOEt in EtOH gives, in the absence of amidines, 2,5-bis(ethoxycarbonyl)cyclohexane-l,4-dione in nearly quantitative yield [228, 229]. 

Another -activation of amino acids for peptide synthesis is achieved by preparing sulfenamides from sulfenylimidazoles. A sulfenylimidazole is formed in situ from the sulfenyl chloride (prepared from the disulfide and chlorine) and imidazole, which reacts further with an amino acid ester to give a sulfenamide in high yield. Conversion of such sulfenamides with IV-acyl amino acids by means of triphenylphosphine affords dipeptides with racemization of less than 0.5%.[481... 

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. 

With chlorinated quinones. New heterocycles containing 1,2-dihydro-imidazo [l,2- ]imidazol-3-one 405 or 1/7-imi-dazo[l,2- ]pyrazole moieties were obtained via charge-transfer interaction of creatinine or 3-aminopyrazole with some 7i-deficient compounds such as 2,3-dichloro-5,6-dicyano-l,4-benzoquinone, 2,3,5,6-tetrachloro-l,4-benzoquinone, 2,3-dichloro- or 2,3-dicyano-1,4-naphthoquinone, and 3,4,5,6-tetrachloro-l,2-benzoquinone (Equation 183) C1996BSB159, 2001HC0541, 2000PS1>. 

Chlorination of the antacid cimetidine leads to the formation of four major DBFs cimetidine sulfoxide, 4-hydroxyhnethyl-5-methyl-7//-imidazole, 4-chloro-5-methyl-7//-imidazole, and a product proposed to be either a jS- or (5-sulfam. The formation of the last three products resulted from unexpected reactions and more substantial structural changes than those t3q)ically observed in chlorination [93]. 

Econazole Econazole, l-[2,4-dichloro-p-[(4-chlorobenzyl)oxy]phenethyl]-imidazole (35.2.8), is an analog of myconazole. It differs in the presence of a single chlorine atom in the benzyl part of the molecule, and it is synthesized in the same manner, except that it uses 4-chlorobenzylchloride in the last stage instead of 2,4-dichlorobenzylbromide [22-24]. 

Butoconazole Bntoconazole, l-[4-(4-chlorophenyl)-2-[(2,6-dichlorophenyl)thio]butyl]-IH-imidazole (35.2.12), is synthesized from 4-chlorobenzylmagnesium bromide, which is reacted with epichloridrine to make 4-(4 -chlorophenyl)-l-chlorobutan-2-ol (35.2.10), which is reacted with imidazole in the presence of sodium to make 4-(4 -chlorophenyl)-l-(lH-imidazolyl)butanol-2 (35.2.11). The hydroxyl group in the last is replaced with a chlorine atom npon reaction with thionyl chloride, which is then by the reaction with 2,6-dichlorothiophenol bntoconazole [27,28], is obtained. 

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