1.2.4.5- tetrasubstituted imidazoles

This transformation can also be carried out under solvent-free conditions in a domestic oven using acidic alumina and ammoniiun acetate, with or without a primary amine, to give 2,4,5-trisubstituted or 1,2,4,5-tetrasubstituted imidazoles, respectively (Scheme 15A) [69]. The automated microwave-assisted synthesis of a library of 2,4,5-triarylimidazoles from the corresponding keto-oxime has been carried out by irradiation at 200 ° C in acetic acid in the presence of ammonium acetate (Scheme 15B) [70]. Under these conditions, thermally induced in situ N - O reduction occurs upon microwave irradiation, to give a diverse set of trisubstituted imidazoles in moderate yield. Parallel synthesis of a 24-membered library of substituted 4(5)-sulfanyl-lff-imidazoles 40 has been achieved by adding an alkyl bromide and base to the reaction of a 2-oxo-thioacetamide, aldehyde and ammonium acetate (Scheme 15C) [71]. Under microwave-assisted conditions, library generation time was dramatically re-... 

The synthesis of imidazoles is another reaction where the assistance of microwaves has been intensely investigated. Apart from the first synthesis described since 1995 [40-42], recently a combinatorial synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles has been described on inorganic solid support imder solvent-free conditions [43]. Different aldehydes and 1,2 dicarbonyl compounds 42 (mainly benzil and analogues) were reacted in the presence of ammonium acetate to give the trisubstituted ring 43. When a primary amine was added to the mixture, the tetrasubstituted imidazoles were obtained (Scheme 13). The reaction was done by adsorption of the reagent on a solid support, such as silica gel, alumina, montmorillonite KIO, bentonite or alumina followed by microwave irradiation for 20 min in an open vial (multimode reactor). The authors observed that when a non-acid support was used, addition of acetic acid was necessary to obtain good yields of the products. 

A modification of this reaction by Orm et al. [16] included an a-diketone, an amine and an aldehyde that react with ammonia to afford a tetrasubstituted imidazole (Scheme 4). Microwave heating was used to substantially decrease the reaction time. 

Scheme 4 Model reaction of the imidazole synthesis via the modified Radziszewski method to afford tetrasubstituted imidazoles [16]...

Gelens E, De Kanter FJJ, Schmitz RF et al (2006) Efficient library synthesis of imidazoles using a multicomponent reaction and microwave irradiation. Mol Divers 10(1) 17-22 Acke DRJ, Orru RVA, Stevens CV (2006) Continuous synthesis of tri- and tetrasubstituted imidazoles via a multicomponent reaction under microreactor conditions. QSAR Comb Sci 25(5-6) 474-483... 

Balalaie, S. and Arabanian, A., One-pot synthesis of tetrasubstituted imidazoles catalyzed by zeolite HY and silica gel under microwave irradiation, Green Chem., 2000,2, 274-276. 

Balalaie, S., Hashemi, M.M. and Akhbari, M., A novel one-pot synthesis of tetrasubstituted imidazoles under solvent-free conditions and microwave irradiation, Tetrahedron Lett., 2003, 44, 1709-1711. 

Balalaie, S., Al abaman, A. and Hashtroudi, M.S., Zeolite HY and silica gel as new and efficient heterogenous catalysts for the synthesis oftriarylimidazoles under microwave irradiation, Monatsh. Chem., 2000,131,945— 948 Balalaie, S. and Arabanian, A., One-pot synthesis of tetrasubstituted imidazoles by zeolite HY and silica gel under microwave irradiation, Green Chem., 2000, 2, 274-276. 

Scheme 2.32. Solid-phase synthesis of tetrasubstituted imidazoles.

The imidazole derivative, prochloraz, has a peculiar feature compared to the azole derivatives. The nitrogen atom in the 1-position of the imidazole is bonded to a carbamoyl group and not to alkyl. This compound, which is regarded as a tetrasubstituted urea, has a very broad spectrum and can be used in cereals both as a seed dressing and a foliar fungicide (9). 

In the reaction of 179 with 3,5-dimethyl pyrazole anion, the hexasubstitution product is formed in 72%, with 8-9% of disubstitution and 18-22% of the tetrasubstitution product. With 3,5-dimethyl-4-nitropyrazole anion and imidazole anion, the hexasubstitution products are formed quantitatively228. 

Claiborne CF, Liverton NJ, Nguyen KT (1998) An efficient synthesis of tetrasubstituted imidazoles from A-(2-oxo)-amides. Tetrahedron Lett 39 8939-8942... 

Nagarapu L, Apuri S, Kantevari S (2007) Potassium dodecatugstocobaltate trihydrate (K5CoW12O40-3H2O) a mild and efficient reusable catalyst for the one-pot synthesis of 1, 2, 4, 5-tetrasubstituted imidazoles under conventional heating and microwave irradiation. J Mol Catal A Chem 266 104-108... 

Mohammadizadeh MR, Hasaninejad A, Bahramzadeh M (2009) Trifluoroacetic acid as an efficient catalyst for one-pot, four-component synthesis of 1, 2, 4, 5-tetrasubstituted imidazoles under microwave-assisted, solvent-free conditions. Synth Commun 39 3232-3242... 

The four-component, two-step synthesis of tetrasubstituted imidazoles 259 is described in Scheme 45 [90]. Initially, all the four components were heated together resulting, however, in lower yields because of the competing formation of... 

The reaction of amines with 1,2-diketo substrates led to a variety of substituted imidazole derivatives. Treatment of various substituted anilines 88 with glyoxals 89 gave the imine intermediate 90, which was then cyclized to the 1-arylimidazoles 91 with paraformaldehyde and ammonium chloride under acidic conditions <0382661>. A one-pot, three-component condensation of benzil 92, benzonitrile derivatives and primary amines on the surface of silica gel under solvent-free conditions and microwave irradiation provided tetrasubstituted imidazoles 93<03TL1709>. 

Tetrasubstituted imidazoles (xxviii) were also obtained in high yields by a one-pot, three-component condensation of benzyl, benzonitrile derivatives and 1° amines on the surface of silica gel under solvent free microwave condition [2]. 

The previous cycloaddition reaction discussed is believed to proceed through an aldimine anion (19). Such delocalized anions can also be generated by treatment of suitable aldimines with a strong base. Subsequent cyclocondensation with a nitrile produces imidazoles [25-28]. The 2-azaallyl lithium compounds (19) are made by treatment of an azomethine with lithium diiso-propylamide in THF-hexane ( 5 1) (Scheme 4.2.9) [29. To stirred solutions of (19) one adds an equimolar amount of a nitrile in THF at —60°C. Products are obtained after hydrolysis with water (see also Section 2.3). If the original Schiff base is disubstituted on carbon, the product can only be a 3-imidazoline, but anions (19) eliminate lithium hydride to give aromatic products (20) in 37-52% yields (Scheme 4.2.9). It is, however, not possible to make delocalized anions (19) with R = alkyl, and aliphatic nitriles react only veiy reluctantly. Examples of (20) (Ar, R, R, yield listed) include Ph, Ph, Ph, 52% Ph, Ph, m-MeCeUi, 50% Ph, Ph, p-MeCeUi, 52% Ph, Ph, 3-pyridyl, 47% Ph, Ph, nPr, 1% [25]. Closely related is the synthesis of tetrasubstituted imidazoles (22) by regioselective deprotonation of (21) and subsequent reaction with an aryl nitrile. Even belter yields and reactivity are observed when one equivalent of potassium t-butoxide is added to the preformed monolithio anion of (21) (Scheme 4.2.9) [30]. 

Recently, Nakamura et al. successfully synthesized a regioisomer of kealiiquinone (Scheme 11) [50]. l-Methyl-2-phenylthio-lff-imidazole 44 was first converted into the 5-substituted imidazole 45, then the benzylic hydroxyl group in 45 was protected by a ferf-butyldimethylsilyl (TBDMS) group, and bromination with N-bromosuccinimide gave the bromide 46. Lithiation by ferf-butyllithium at the 4-position of 46 followed by trapping with 3,4-dimethoxy-2-(methoxymethoxy)benzaldehyde gave the tetrasubstituted imidazole 47 as a diastereomeric mixture. Acetylation of the hydroxy group of 47... 

The cycloaddition of the mesoionic isoxazole (228) to an iV-(phenylmethylene)benzene sulfonamide provides a versatile entry to 1,4,5-tri- and 1,2,4,5-tetrasubstituted imidazoles which form via eUmination of carbon dioxide and benzenesulfinic acid. The mesoionic (228) are masked 1,3-dipoles ( munchones ) (Equation (70)) <9UCR(S)188,93JCS(P2)i5ii>. 

Microwave irradiation has been employed in several published syntheses of substituted imidazoles. Microwave irradiation of aldehydes 87 and TV-substituted a-amino acid amides 88 under solvent-free conditions led to substituted imidazolidin-4-ones 89 <04H(63)1165>. A simple, high yielding synthesis of 2,4,5-trisubstituted imidazoles 91 have been prepared from diketone 90 with aromatic aldehydes in the presence of excess ammonium acetate in acetic acid under microwave irradiation <04OL1453>. Condensation of benzoin 92, aromatie aldehydes, amines and ammonium acetate in the presence of silica gel under microwave irradiation and solvent-free conditions led to tetrasubstituted imidazoles 93 <04H(63)87>. 

Tetrasubstituted oxazolium perchlorates or methyl sulfates on heating with ammonium acetate in acetic acid are readily converted into the corresponding tetrasubstituted imidazoles (172) in good yields.321... 

The unusual condensation of 2-bromoalkylidene malonitrile (66) with 4,5-dihydroimidazole-2-thione (67) gave a substituted 2,3-dihydro-l/7-pyrrolo[l,2-a]imidazole (68) in moderate yield <84TL390l>. A general synthesis of these systems is shown by the intramolecular cyclization reaction of l,3,4,5-tetrasubstituted-2-aminopyrrole (69) to give the corresponding pyrrolo[l,2-a] imidazole derivative (70) in good yield <86JHC393>. Both of these reactions are shown in Scheme 10. 

Tetrasubstituted imidazoles have been prepared in high yield by one-pot three-component condensation of benzil, benzonitrile derivatives, and primary amines adsorbed on silica gel without solvent (Scheme 10.87) [169]. Under irradiation conditions yields range from 58 to 92% (8 min). 

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