A-Benzylimidazole

With the sodium derivative of benzyl alcohol, dibenzyl ether was obtained in 63% yield, accompanied by 24% of A-benzylimidazole. Formation of the latter compound results from the reaction of the benzyl sulfonate with imidazol sodium in competition with the second step of the ether synthesis (b). 

These reactions correspond to the transformation of sodium benzylalcoholate with benzenesulfonic acid imidazolide, leading to A/-benzylimidazole[10] (see also references [11] and [12]) ... 

The imidazole-fused deoxynojirimycin analogue 113 and its C-2 epimer were obtained by cyclization of 112 and its C-2 epimer (Scheme 23). The latter epimers were the major and minor products, respectively, from addition of lithiated A -benzylimidazole to 2,3 4,S-di-0-isopropylidene-D-arabinose followed by acetylation. ... 

The well-known application of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine as a diene in inverse electron demand Diels-Alder cyclizations was adapted for the synthesis of purines <1999JA5833>. The unstable, electron-rich dienophile 5-amino-l-benzylimidazole was generated in situ by decarboxylation of 5-amino-l-benzyl-4-imidazolecarboxylic acid under mildly acidic conditions (Scheme 54). Collapse of the Diels-Alder adduct by retro-Diels-Alder reaction and elimination of ethyl cyanoformate, followed by aromatization by loss of ammonia, led to the purine products. The reactions proceeded at room temperature if left for sufficient periods (e.g., 25 °C, 7 days, 50% yield) but were generally more efficient at higher temperatures (80-100 °C, 2-24 h). The inverse electron demand Diels-Alder cyclization of unsubstituted 1,3,5-triazine was also successful. This synthesis had the advantage of constructing the simple purine heterocycle directly in the presence of both protected and unprotected furanose substituents (also see Volume 8). 

In the case of the trinuclear [ t-N1,C2-bzimAu]3 (bzim = benzylimidazolate), in addition to the extended structures that form with other metals (see Section 6.3), it also forms supramolecular networks, acting as an electron donor with small organic acids [48]. For example, it reacts with TCNQ (tetracyanoquinodimethane) giving rise to a columnar structure in which each TCNQ molecule is sandwiched between two units of the trinuclear complex in a face-to-face manner. Thus, the repetition of this pattern leads to a stacking of the type (Au3)(Au3)( t-TCNQ)(Au3)... 

The imidazo[4,5- ]triazepines 529 were synthesized in a single-pot reaction of 4-amino-l-benzylimidazole-5-carbal-dehyde 528 with 1,2-dimethylhydrazine dihydrochloride and trimethyl or triethyl orthoformate using the corresponding alcohol as the solvent (Scheme 271) <2004JME1044, 2004NN263, CHEC-III(13.14.7T1)419>. 

Most usual oxidizing agents act normally with imidazole aldehydes and ketones but l-benzylimidazole-2-carbaldehyde is reportedly somewhat resistant to selenium dioxide oxidation. Reduction of ketone functions under Clemmensen and Wolfi-Kischner conditions is usually successful. Zinc dust and acetic acid reduce acetyl groups to a mixture of secondary alcohol and ethyl borohydride gives the alcohol exclusively (B-76MI40701). 

While removal of an AT-alkyl substituent is not always a feasible process benzyl groups can be removed by reduction with sodamide or by catalytic hydrogenolysis. If such reductive methods fail, an oxidation with chromium trioxide in acid may be successful. Other groups are not so readily displaced, but a procedure involving transalkylation with benzyl chloride followed by debenzylation can be employed to convert 1-methylimidazole into imidazole (Scheme 137). The reaction is capable of extension and operates because the quaternary salt is in equilibrium with both 1-alkylimidazoles and the alkyl halides. Under conditions in which the more volatile alkyl halide can escape from the system the 1-benzylimidazole builds up. 

On the other hand, 9-benzyl-2-(tritluoromethyl)hypoxanthinc (18) is prepared by acylation of 5-amino-l-benzylimidazole-4-carboxamide with trifluoroacetic anhydride and subsequent heating of the intermediate. A number of dehydration agents fail to effect this ring closure. ... 

Benzyl-5-chloroimidazole cannot be readily made by benzylation of 4(5)-chloroimidazole the other isomer (1,4) is the major product. Nor is chlorination of 1-benzylimidazole a feasible alternative. (See (Chapters 7 and 8.)... 

Imidazole sodium salt (0.90 g, 10 mmol), acetonitrile (4.3 ml) and methyl iodide (0.62 ml) are mixed with stirring at —25°C in a closed reaction vessel [5], The vessel is kept in the bath while its temperature is raised to 20°C in about 1 h. Stirring is then continued at 20°C (72 h). The solvent is removed in vacuo at 20°C, the residue is extracted into dichloromethane (3 x 8 ml), the solvent is again removed. The resulting product (0.80 g, 98%) is distilled in a ball-tube, bio 200°C. Similarly prepared is l-benzylimidazole (94%). 

A mixmre of aqueous formaldehyde (d 1.08, 25 ml) and 1-benzylimidazole (15.8 g, 0.1 mol) is heated in a sealed glass tube at 150°C (3 h). After cooling, the mixture is treated with water (200 ml) and extracted with dichloromcthane (3 X 30 ml). The organic extracts are washed with water (2 x 50 ml), dried... 

To a solution of 1-methylimidazole (5g, 61 mmol) in acetonitrile (60 ml) is added sequentially benzoyl chloride (7.1 ml, 8.6 g, 61 mmol) and triethylamine (8.5 ml, 6.2 g, 61 mmol). After 15h at 25°C the triethylamine hydrochloride is filtered off, the acetonitrile is rotary evaporated, and the residue is boiled (30 min) with aqueous sodium carbonate. Continuous extraction with chloroform of the alkaline solution yields, after removal of the dried solvent, an oil which is distilled to give a pale yellowish liquid (4.2 g, 37%), bi 149°C. Similarly prepared are ethyl l-methylimidazole-2-carboxylate (bo.os 60°C), 2-bcnzoyl-l-phenylimidazole (61%, b2 210°C) and 2-benzoyl-1-benzylimidazole (68%, m.p. 66°C). 

The alkylation of imidazole with 1-propanol gave a 40% conversion of imidazole, N-n-propylimidazole was a sole product. The alkylation of imidazole with benzyl alcohol gave a low yield of l-benzylimidazole(2%). 

Sardana, S. and Madan, A.K. (2003) Topological models for prediction of antihypertensive activity of substituted benzylimidazoles. J. Mol Struct. (Theochem), 638, 41-49. 

---