1- Substituted imidazoles, reaction

Substituted imidazoles can be acylated at the 2-position by acid chlorides in the presence of triethylamine. This reaction proceeds by proton loss on the (V-acylated intermediate (241). An analogous reaction with phenyl isocyanate gives (242), probably via a similar mechanism. Benzimidazoles react similarly, but pyrazoles do not (80AHC(27)24l) cf. Section 4.02.1.4.6). 

Alkyl radicals produced by oxidative decarboxylation of carboxylic acids are nucleophilic and attack protonated azoles at the most electron-deficient sites. Thus imidazole and 1-alkylimidazoles are alkylated exclusively at the 2-position (80AHC(27)241). Similarly, thiazoles are attacked in acidic media by methyl and propyl radicals to give 2-substituted derivatives in moderate yields, with smaller amounts of 5-substitution. These reactions have been reviewed (74AHC(i6)123) the mechanism involves an intermediate cr-complex. 

A wider range of C-substituted imidazoles is commercially available, and the combination of these with the reaction shown in Scheme 2.1-2 permits the formation of many different possible starting materials. In some cases, however, it may still be necessary to carry out synthesis of the heterocycle from first principles. For reasons of space, this topic is not covered here. 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

The mechanism of the reaction has not been eiuddated. Presumably iodine eliminates the imidazole ring from N-substituted imidazole derivatives such as clotrimazole, and this then couples with diazotized sulfanilic acid to yield an azo dye. 

Note The reaction is very specific for N-substituted imidazole derivatives. In serum investigations the detection limit was 50 ng clotrimazole per milliliter serum. The reagent can be employed on silica gel, kieselguhr and Si 50000 layers. 

With sUght modifications of these conditions it is possible to prepare mono N-substituted imidazoles (Scheme 5), the reaction working well with aliphatic amines but not with many aromatic amines. The imsymmetrical... 

Gade and Bellemin-Laponnaz have reported the synthesis, in good yields, of chiral oxazoline-imidazoliums salts 10a (Scheme 8) obtained by reaction of 2-bromo-4(S)-t-butyl oxazoline with several mono-N-substituted imidazoles [16]. Similaly an imidazolium salt 10b bearing a paracyclophane substituent was prepared by Bolm [17]. 

Table 20-1. N-Substituted imidazoles and triazoles prepared by transfer reactions of azolides A—F with tertiary alcohols of the triphenylmethanol type and analogues.

The microwave activation of Michael additions in the preparation of N-substituted imidazoles afforded excellent yields in very short reaction times under mild reaction conditions, Scheme 10.9. Basic clays (Li+, Cs+) exchanged montmorillonites were found to be very active and selective catalysts for the Michael addition of imidazole and ethyl acrylate [54]. 

Me Capra in particular proposed n> that the chemiluminescence reactions of a large number of organic compounds had this concerted dioxetane decomposition step as key reaction in the production of electronically excited products, namely acridinium salts 25,26,27) indolylperoxides 28>, activated oxalic esters 29>, diphenyl carbene 30>, tetrakis-dimethylamino-ethylene 31 32>, lucigenin 33>, and substituted imidazoles 23>. 

The synthesis of the furan-imidazole derivatives, shown in Scheme 2, were also described by Wang et al. [34]. Reaction of 4-(dimethylamino)benzalde-hyde (20) with trimethylsilylcyanide (TMS)-CN in the presence of Znl2 produced the TMS cyanohydrin 21. Compound 21 was treated with LDA followed by the addition of 3,4,5-trimethoxybenzaldehyde to give the benzoin intermediate 22. Oxidation with CUSO4 in aqueous pyridine, followed by reaction with 3-furaldehyde in acetic acid, produced the substituted imidazole 23. 

The first total syntheses of these compounds were by Hibino and coworkers [91,92] and utilized palladium(0)-catalyzed coupling of 135 and 136 to produce indole-substituted imidazole 137 in 82% yield (Fig. 39). (A similar approach to closely related compounds was reported by Achab and coworkers at about the same time as the first report by Hibino) [93]. Ester 137 was hydrolyzed in near quantitative yield by reaction with sodium car-... 

Acke DRJ, Orru RVA, Stevens CV (2006) Continuous synthesis of tri- and tetra-substituted imidazoles via a multicomponent reaction under microreactor conditions. QSAR Comb Sci 25 474-483 Antes J, Tuercke T, Marioth E, Lechner F, Scholz M, Schntirer F, Krause HH, Lobbecke S (2001) In Matlosz M, Ehrfeld W, Baselt JP (eds) IMRET 5 Proceedings of the Fifth International Conference on Microreaction Technology. Springer Berlin New York Heidelberg, pp 446 153 Barrow D, Cefai J, Taylor S (1999) Shrinking to fit. Chem Ind 15 591-594 Bradley D (1999) Chemical Reduction. Eur Chem 1 17-20 Chambers RD, Spink RCH (1999) Microreactors for Elemental Flourine. Chem Comm 10 883-884... 

Steric factors play an important role in reactions of bromomethylaqua-cobaloxime with substituted imidazoles - 1-methylimidazole reacts at approximately the same rate as imidazole itself, but the presence of an alkyl substituent in the 2-position of the incoming imidazole reduces the rate dramatically (72). 

Two tautomeric equilibria have been considered for substituted imidazoles, that between 2-imidazolone 3 and its 2-hydroxyimidazole tautomer 4 [268] and also that between the 1H and 3H tautomers of 4-nitroimidazole, 6 and 5, respectively [269, 270], Karelson et al. used the D02 model with a spherical cavity of 2.5 A radius and found 2-imidazolone to be better solvated than its tautomer by 7.7 kcal/mol at the AMI level. [The asterisk in D02 indicates that the reaction field... 

Acetylated Meldrum s acid 172 and a-aminoesters 173 have been used as the building blocks to prepare the substituted imidazoles 174, which are then cyclized to give optically active dihydro products 175 <20030L3907> (Scheme 7). A modified four-component LJgi reaction has been used to prepare dihydro products 177 from the intermediate functionalized imidazole 176, isonitriles, and amines (Equation 24) <2005EJ04670>. 

The imidazole ring is often found in biologically active molecules and is as such important in medicinal chemistry [16]. An interesting route for the production of substituted imidazoles is the Debus-Radziszewski reaction. This is a three-component reaction of a diketone, an amine and an aldehyde to form trisubstituted imidazoles (Scheme 3). 

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-... 

In a recent study, Fernandez-Bertran et al. used mechanochemical reactions to prepare a number of hemin complexes with amino acids such as arginine, histidine, lysine, methionine and tryptophan. The basic amino acids react with the hemin peripheral propionic acid groups, while arginine is also able to form a pentacoordinated complex at the Fe(III) centre. The reactions were followed by IR and Mossbauer spectroscopies [77a]. The solid-state reaction of hemin with KCN, Na2S and various substituted imidazoles has also been investigated [77b]. 

There are many heterocyclic molecules in which 1,3,4-thiadiazoles are fused to other ring systems. For example, Molina et al. developed a procedure for building a thiadiazole ring on to a properly substituted imidazole moiety (Scheme 29). Reaction of l-amino-2-methylthio-4-phenylimidazole (161) with triphenylphosphine dibromide in dry benzene furnished the 2-methylthio-4-phenyl-l-triphenylphosphoranylidenamino imidazole (162) in a 95% yield. With aroyl chlorides at elevated temperature, this gave the 2-aryl-6-phenylimidazo[2,l-Z ][l,3,4]thiadiazoles (164) in yields between 50% and 70% via the imidoyl chloride intermediate (163) which could be isolated and shown to cyclize to the thiadiazole. The method developed for the imidazole ring was also applicable to the thiadiazolotriazine ring system <88H(27)1935). 

---