Imidazoles nitriles

Photolysis of 2,3-diphenyl-A -azirine (442) generates benzonitrile ylide (443). Irradiation in the presence of ethyl cyanoformate resulted in a mixture of the oxazoline (444) and the imidazole (445) by 1,3-dlpolar cycloaddition to the carbonyl and nitrile group, respectively (72HCA919). 

The imidazole nucleus is often found in biologically active molecules,3 and a large variety of methods have been employed for their synthesis.4 We recently needed to develop a more viable process for the preparation of kilogram quantities of 2,4-disubstituted imidazoles. The condensation of amidines, which are readily accessible from nitriles,5 with a-halo ketones has become a widely used method for the synthesis of 2,4-disubstituted imidazoles. A literature survey indicated that chloroform was the most commonly used solvent for this reaction.6 In addition to the use of a toxic solvent, yields of the reaction varied from poor to moderate, and column chromatography was often required for product isolation. Use of other solvents such as alcohols,7 DMF,8 and acetonitrile9 have also been utilized in this reaction, but yields are also frequently been reported as poor. 

Herrmann has prepared several unsymmetrical salts 7 from 1-alkyl-imidazoles (Scheme 6). The chirality was introduced, after N-alkylation of the imidazole by chloro acetonitrile, by addition of enantiomerically pure aminoalcohols onto the nitrile to form an oxazolidine ring [14],... 

Aldoximes are readily dehydrated with N, N -carbonyldiimidazole (CDI). An intermediate azolide is formed in the process under elimination of one mole of imidazole, which fragments into a nitrile through elimination of CO2 and a second mole of imid-azole.[1],[2]... 

In summary, reactions of nitronates with acid anhydrides or acyl chlorides give the O-acylated products, and reactions with acyl imidazoles, phenyl esters, acyl nitriles, and enol-lactones gives the C-acylated products, (see Eq. 5.13).25 The C/O selectivity of nitronate acylation by RCOX is qualitatively correlated with strength (pKJ of the acid HX conjugated to the leaving group X .25... 

The hydroxyl group was usually protected, because cyanohydrins have tendency to racemization or even decomposition. Vinyl ethers or acetal and acid catalysts furnish acetals [62]. Trialkylsilyl chlorides and imidazole are used to give silyl ethers [63]. Commonly used protective groups are silyl ether, ester, methoxy isopropyl (MIP) ether, and tetrahydro-pyranyl ether. ( -Protected cyanohydrins are tolerant to a wider range of cyanide/nitrile transformations and are utilized widely in the synthesis of compounds of synthetic relevance in organic chemistry. 

Another example of the remarkable reactivity of Mg actuated by our procedure is its reaction with nitriles. In this respect, the Mg resembles an alkali metal more than an alkaline earth. Benzonitrile reacts with Mg overnight, in refluxing DME, to give 2,4,6-triphenyl-l,3,5-triazine and 2,4,5-triphenylimidazole in 26 and 27% yield, respectively, based on magnesium. Jhe imidazole was shown to arise, at least in part, from the action of Mg on the triazine. The trimerization of aromatic nitriles to give symmetrical triazines is not unknown, but generally the reactions are... 

Three approaches to the synthesis of 4-amino-5-unsubstituted imidazoles (71) have been described and are summarized in Scheme 7. These are (a) reduction of 4-nitroimidazoles (72) (b) hydrolysis of carbamates and amides (73) (c) cyclization of nitrile derivatives (74). 

In the presence of Bu OK, (benzotriazole-l-yl)methyl isocyanide (BetMIC) 697 undergoes alkylation on the methylene group to give isocyanide 698. The anion derived from 698, upon its treatment with Bu OK, adds to the electron-deficient double bonds of ajl-unsaturated ketones, esters or nitriles to produce pyrroles 699. A similar reaction of isocyanide 698 with Schiff bases provides imidazoles 700. In both cases, use of unsubstituted isonitriles 697 in the reactions leads to heterocycles 699 and 700 with R1 = H (Scheme 108) <1997H(44)67>. 

Nitrile oxides add to various N-nucleophiles, bearing N-H bonds to give amidoximes. These nucleophiles comprise primary and secondary amines, amides, N-heterocycles and so on. Thus, N-unsubstituted pyrazole, imidazole, 1,2,3- and... 

The 1,3-dipoles were generated by the addition of Et3N in 20% excess. Only imidazole was basic enough to generate a nitrile oxide in the absence of triethy-lamine. Due to prototropic tautomerism, reactions of triazoles and tetrazoles led to mixtures of two isomers. With unsubstituted pyrazole and imidazole only one hydroximoylazole was formed (117). 

The reaction of 2-aminobenzimidazoles 600 with 2,3-allenenitriles led to pyrimi-dobenzimidazoles 604 via initial attack of the unsaturated nitrogen atom in the imidazole ring followed by a 1,3-H shift to form 602. Intramolecular amination of the nitrile group in 602 and a subsequent 1,3-H shift afforded the final product 604... 

A domino reaction of 1,1-diphenyl-3,3-dilithioallene (157) with benzonitrile yields both a yellow imidazole (158 R = Ph X = NH) (12%) and a colourless 5-imidazol-5-yl-l,4-dihydropyrimidine (159 R = Ph) (51%), the products, respectively, of the incorporation of three and four nitrile molecules. The proposed mechanism (Scheme 13) involves initial formation of an intermediate (160) that is the product of the interaction of three molecules of benzonitrile with l,l-diphenyl-3,3-dilithioallene (157), which cyclizes to (162 R = Ph) and then eliminates a molecule of benzonitrile to produce (161 R = Ph). Re-addition of benzonitrile at a different locus produces... 

When the temperature was raised to 210 C, undecyllmldazole was completely degradated after 15 min (Figure 8.. No imidazole ring structure was observed. The nitrile peak at 2190 cm was pronounced, and the copper oxide formation was Intense. On the other hand, PVI(1) and PVI(4) degradation was relatively mild at after 15 min (Figures 9 and 10.). It was not until the... 

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