Imidazole 1,5-disubstituted

The photorearrangement of pyrazoles to imidazoles is probably analogous, proceeding via iminoylazirines (82AHC(30)239) indazoles similarly rearrange to benzimidazoles (67HCA2244). 3-Pyrazolin-5-ones (56) are photochemically converted into imidazolones (57) and open-chain products (58) (70AHC(ll)l). The 1,2- and 1,4-disubstituted imidazoles are interconverted photochemically. 

Imidazol-2-ylidene and its N,N -disubstituted derivatives as stable carbenes 99ACR913. 

Acylation of 2-aroylimidazoles 492 gave 1-acyl-4,5-disubstituted imidazoles 493, whose cyclocondensation with hydrazine hydrate gave (88JIC784) imidazotriazines 494. 

Reaction of a-isocyano-a, / -unsaturated sulfones with primary aliphatic amines affords 1,5-disubstituted imidazoles 59 (equation 56)48. The reaction of aromatic amines such as aniline is too slow to be of practical use. Results of the preparation of 59 are listed in Table 5. 

PREPARATION OF 2,4-DISUBSTITUTED IMIDAZOLES 4-(4-METHOXYPHENYL)-2-PHENYL-lH-IMID AZOLE... 

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. 

We found that the optimal reaction protocol was to add a solution of a-bromo ketone in THF to the amidine in aqueous THF in the presence of potassium bicarbonate under vigorous reflux. Using this procedure, 2,4-disubstituted imidazoles were isolated in excellent yields with >95% purity without column chromatography. Aromatic and aliphatic a-halo ketones participate in this reaction with a variety of aromatic amidines, as indicated in Table 1. Particularly noteworthy is that reactions involving pyridylamidines or chloroacetone are substantially more robust using this process (entries 3 and 4). We have successfully used this protocol on a multi-kilogram scale. 

N-silylated imines 509 react with the Li salts of tosylmethylisonitriles to give 4,5-disubstituted imidazoles in moderate yields [93]. Acetylation of N-trimethylsilyl imines 509 with acetyl chloride and triethylamine affords 72-80% of the aza-dienes 510 these undergo readily Diels-Alder reactions, e.g. with maleic anhydride at 24 °C to give 511 [94] or with dimethyl acetylenedicarboxylate to give dimethyl pyridine-3,4-dicarboxylates [94] (Scheme 5.29). 

Benzofuroxans 65 can be transformed into the imidazol-fV-oxides 66 or 2,2-disubstituted imidazole-iVjA -dioxides 64... 

Similarly, heterocyclic amines such as imidazole were added to pyrimidines 57 with moderate to high regioselectivity to produce mainly 4,5-disubstituted pyrimidines 58 after a 1,3-hydride shift along with small amounts of the 2,5-disubstituted isomers 59 . 

Analogously, 5-tributylstannylimidazole 29 was easily obtained from the regioselective deprotonation of 1,2-disubstituted imidazole 28 at C(5) followed by treatment with tributyltin chloride [24]. In the presence of 2.6 equivalents of LiCl, the Stille reaction of 29 with aryl triflate 30 afforded the desired 1,2,5-trisubstituted imidazole 31 with 2,6-di-tert-butyl-4-methylphenol (BHT) as a radical scavenger. Reversal of the nucleophile and electrophile of the Stille reaction also provided satisfactory results. For example, the coupling reaction of 5-bromoimidazole 33, derived from imidazole 32 via a regioselective bromination at C(5), and vinylstannane 34 produced adduct 35 [24],... 

Anodic oxidation of JV,iV-disubstituted trifluoroethanimidamide 45 in dry and in aqueous acetonitrile gave the imidazole 46 and quinoneimine 47 as the reaction products (Scheme 24). The constant current electrolysis on a glassy carbon anode and a platinum cathode was performed in an undivided cell [74]. 

In many cases the synthesis of NHC complexes starts from iV,A/ -disubstituted azolium salts. Imidazolium salts as precursors for imidazolin-2-ylidenes are generally accessible by two ways complementing each other (i) nucleophilic substitution at the imidazole heterocycle or (ii) a multicomponent reaction building up the heterocycle with the appropriate substituents in a one-pot reaction. 

Veerabhadraiah et al. (89SUL167) treated 4,5-disubstituted 2-mercapto-imidazoles with 3-(a>-bromoacetyl)coumarins and obtained ketones that on subsequent cyclization with PPA furnished 2,5,6-trisubstituted imidazo[2,l-h]thiazoles 38. 

A base-mediated condensation of an isocyanide and an isothiocyanate gives 4,5-disubstituted thiazoles, as first reported by Matsumoto et al. in 1982 [73]. In subsequent work by Solomon et al., a regioisomeric imidazole was observed as a side-product due to the flexibility of the route that allows facile introduction of a substituent on the exocyclic nitrogen atom [74]. Baxendale et al. [75] explored this reaction under microfiow conditions (Scheme 33). 

Methimazole Methimazole, l-methyl-2-imidazolthiol (25.2.5), is synthesized by reacting aminoacetic aldehyde diethylacetal with methylisothiocyanate and snbseqnent hydrolysis of the acetal group of the resulting disubstituted urea derivative 25.2.4 by a solution of sulfuric acid, during which a simultaneous cyclization reaction takes place, forming the imidazole ring of the desired methimazole [15,16]. 

Because of the electron withdrawing effect of the extra nitrogen atom, the deprotonation of 1,5-disubstituted 1,2,3-triazoles at the 4-position is a more facile process than that for the related imidazoles, and the metalation of 1,5-diphenyl-l, 2,3-triazole occurred readily, as was shown by the isolation of the 4-methyl derivative in 99% yield (7ICJC1792). A different result was observed in the case of a 5-methyl group, however, where lateral metalation was found to be the preferred mode of reaction (Scheme 63) (71CJC1792). 

Cycloaddition reactions of A -(phenylmethylene)benzenesulfonamide with meso-ionic oxazolones 311 produces 2,5-disubstituted imidazoles 313 in a highly regio-selective process via cycloreversion of cycloadduct 312 and subsequent loss of benzenesulhnic acid. 

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