Imidazole lithio

Imidazole, 1 -hydroxy-2,4,5-triphenyl-3-oxides reactions, S, 455 Imidazole, iodo-nitrodehalogenation, 5, 396-397 Imidazole, 1-iodo-reactions, S, 454 stability, S, 110 Imidazole, 2-iodo-synthesis, S, 401 Imidazole, N-iodo-, S, 393 reactions, 5, 454 Imidazole, 4-iodo-5-methyl-iodination, 5, 400 Imidazole, 2-isopropyl-4-nitro-N-nitration, 5, 351 Imidazole, 2-lithio-reactions, S, 106, 448 Imidazole, 2-mercapto-l-methyl-as antithyroid drug, 1, 171 mass spectra, 5, 358 Imidazole, 1-methoxymethyl-acylation, S, 402 Imidazole, 5-methoxy-l-methyl-reactions... 

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. ... 

The dimethylaminomethyl group (entry 9) is easily introduced by a Mannich reaction, and lithiation occurs readily at -78°C (88JOC5685). After reaction with a variety of electrophiles, hydrolysis can be performed directly with aqueous acid to give 2-substituted imidazoles in good yield. However, the 2-lithio anion 47 was found to be quite basic, despite the base-weakening effect of coordination with the amino substituent, and thus it was capable of deprotonating the 2-butyl derivative 48 as it was formed by reaction with 1-bromobutane (Scheme 42). No such side-reac-... 

Even after successful metalation at the 5-position of imidazoles, rearrangement to the more thermodynamically stable 2-lithio derivative can still occur, as was shown by the isolation of the 2-aldehyde product from the reaction of l-methyl-4,5-dibromoimidazole with n-butyllithium and DMF (Scheme 48) (81MI1). 

A similar type of transmetalation was also seen with l,2-dimethyl-5-trimethylstannylimidazole, which gave the 5-lithio derivative at -100°C, but rearranged to the 2-lithiomethyl derivative at higher temperatures [83JCS(P1)271]. However, transmetalation does not occur with Grignard reagents and 5-substituted imidazoles can be successfully prepared via this route (Scheme 49) (81 Mil 82OPP409). 

Careful choice of reaction conditions also allows 2-lithiation of imidazoles even in the presence of groups susceptible to attack by the reagent. At -100°C in THF 4,5-dicyano-l-methylimidazole forms the 2-lithio compound at -80°C butyllithium attacks one of the nitrile functions (92JHC1091). 1-Alkoxyimidazoles are lithiated by n-butyllithium (THF, -78°C) at the 2-position (98JOC12). 

The cyclic a-lithio-l,3-dithiane S-oxide 406 was generated from compound 392 with n-BuLi at —10 °C and reacted with deuterium oxide, alkyl halides, carbonyl compounds and esters to afford the corresponding products 407 as mixture of diastereomers (Scheme 106)605 - 607. (V-Acyl imidazoles were better acylating agents than esters608. However, compound 406 has not been employed properly as acyl anion. Intermediate... 

Imidazol 4,5-Dibrom-l-fethoxy-methyl)-2-lithio- E19d, 414 (Br - Li)... 

N-Alkyl-imidazoles and -benzimidazoles react with lithium or butyllithium at low temperatures to give the 2-lithio derivatives. It has been reported, though, that in the metalation of 1-methylimidazole a small amount of the 5-substituted compound is also... 

The reactions of 2-lithio- and 2-sodio-imidazoles and -benzimidazoles are not particularly novel. The compounds do, however, prove a means of introducing a variety of functional groups into the 2-position of the heterocyclic ring. Such metalation reactions at C-2 can only occur readily when there is no alternative site for the metal. Therefore, only N-substituted imidazoles are of synthetic utility, and it may be necessary to select an N-substituent which can be removed later. For this reason, benzyl (removed by reductive or oxidative methods), benzenesulfonyl (removed by ammoniacal ethanol), trityl (hydrolyzed by mild acid treatment) and alkoxymethyl (easily hydrolyzed in acid or basic medium) groups have proved useful in this context. A typical reaction sequence is shown in Scheme 136 <78JOC438l, 77JHC517). In addition, reactions with aldehydes and ketones (to form alcohols), with ethyl formate (to form the alcohol) and with carbon dioxide (to form carboxylic acids) have found application (B-76MI40701). 

Above 170 °C the amidrazone ylide (36) decomposes with loss of triethylamine and concurrent cyclization to give an 85% yield of 2-phenylbenzimidazole (Scheme 19) (B-75M140800). Poorer yields ( 40%) are obtained when N-benzyl-o-nitroaniline is pyrolyzed in the presence of iron oxalate. No doubt this last reaction is similar in many respects to the reactions shown in Scheme 2. Both 2-phenyl-imidazoles and -benzimidazoles (as well as other 2-substituted analogues) can be obtained as a result of thermal rearrangement of the 1-substituted isomers (Section 4.07.1.2.2), by radical substitution methods (Section 4.07.1.7) or via the 2-lithio derivatives (Sections 4.07.1.6, 4.07.3.7). 

Clean monochlorination of all possible ring positions in imidazole is most likely to be successful using the lithio precursors, e.g. 1-benzyl-2-lithioimidazole reacts with hexachloroethane to give l-benzyl-2-chloro-imidazole [10, 11] quenching the 2-lithio derivative of 1-tritylimidazole with chlorine, followed by deprotection gives 2-chloroimidazole in 39% yield... 

Nitroimidazoles are readily made by nitration of imidazole or 1-substituted imidazoles in concentrated sulfuric acid (see Section 7.2.1). It is much more difficult to make 2-nitroimidazoles since direct nitration is seldom observed in the 2-position. Although electrophilic nitrodehalogenation reactions, too, occur mainly at C-4(5) [1], Katritzky has recently selectively nitrodeiodinated 2,4,5-triiodoimidazole to prepare 2,4(5)-dinitro-5(4)-iodo-and 2,4,5-triiiitroimidazoles, albeit in poor yield [2], Other routes to 2-nitroimidazoles include those which react a diazonium fluoroborate with the nitrite ion, and methods which oxidize 2-amino derivatives, themselves often only available by laborious sequences. The most appealing routes to 2-nitroimidazoles are the methods which make the 2-lithio derivative and treat it with a source of nitronium ion (e.g. n-propyl nitrate or N2O4) [3-5] (see Section 7.2.2). 

AT-Methylimidazole was converted into the 2-lithio-imidazole upon treatment with a stoichiometric amount of lithium in the presence of isoprene as catalyst (20mol%) in THF at room temperature with near quantitative yield <2005T11148>. The same lithioimidazole was obtained in high yield when butyllithium <2005H(66)263> or methyllithium <2002EJI2015> were used as lithiating reagents (Schemes 79 and 80). 

As with other halogenation processes, the monoiodination of imidazole has proved to be a difficult process. A number of recent approaches have shown some success. Thus, imidazoles can be monoiodinated at C-2 via the 2-lithio derivative or Grignard reagent. With iodine and iodic acid 5-chloro-l-methylimidazole was converted to a mixture of 12.8% of the 2,4-diiodo compound and 27.5% of the 4-iodo product. The previously undescribed 2-iodoimidazole (119) has been prepared in low yield by the sequence shown in Eq. (27). ... 

The most common reactions with aldehydes and ketones reported have been those of lithio-imidazoles. The products are usually alcohols, but sometimes ketones are formed on aerial oxidation of the primary products. Access to 2-, 4-, and 5-carbinols is now readily available <94H(38)2487>. 

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