1//-Imidazole products

The dimer 43, which is piezo-, photo-, and thermochromic, is formed together with two 4//-imidazole products on hexacyanoferrate(IIl) oxidation of a p-phenylene-bis-1//-imidazole precursor. ... 

It has been reported151 that, under the influence of ultraviolet radiation, aqueous solutions of formaldehyde and ammonium salts produce imidazole products. It is possible that the irradiation catalyzes... 

UV spectroscopy has been applied to studies of 2,4,5-triarylimidazole radicals, imi-dazolones and various thioimidazoles. In addition, the rates of hydrolysis, alcoholysis and aminolysis of imidazolides such as 1-acetylimidazole can be determined readily since such azolides show characteristic intense absorptions at wavelengths longer than those of the imidazole products. In the C-acyl- and C-aroyl-imidazoles, those which have the carbonyl group attached at C-2 exhibit a bathochromic shift of about 20 nm, while in m- and p-substituted 2-aroylimidazoles intense absorptions (log,o e 3.5-4.3) appear in the 295-309 nm region, with slightly less intense peaks at about 233-266 nm (74CRV279). 

Although synthesis of the desired acyclic precursors may not always be a simple procedure, there is a host of reactions of suitably functionalized 1,2-diaminoalkanes which give uncondensed imidazole products. Many of these are related to some of the foregoing preparations of benzimidazoles. For example, when the /3-glucopyranosylamine (20) is treated in sulfuric acid with an acetylating mixture, the imidazole product (21) is formed in good yield (Scheme 10). 

The reaction of dimethylformamide diethyl acetal with the carbanion which forms when the isocyanide (31) is metalated gives an alkene (32) which reacts with methyl iodide to give an imidazole product (79LA1444). In the presence of base, 2-isocyanoalkane nitriles (33) react with alcohols, thiols or hydrogen sulfide to form imidazoles which have an oxygen or sulfur substituent at C-5 (Scheme 16) (79LA1602). 

In addition to the reactions of diaminomaleonitrile shown in Scheme 11 there are also some examples of photochemical transformations which lead to imidazole products. The initial reaction isomerizes the cw-dinitrile to the trans form which then forms a 5-aminoimidazole-4-carbonitrile via the iminoazetine (34). There are a number of related reactions, although the photochemical isomerization of enaminonitriles (35) probably involves an azirine intermediate (Scheme 17) (8UOC2872). 

Treatment of the imidoyl chloride (106) with triethylamine yields the nitrile ylide (107), which undergoes cycloaddition with a variety of reagents giving imidazole products. With ethyl cyanoformate a mixture of esters is obtained with 2,4-xylyl cyanate the 4-aryloxy... 

A novel oxazole to imidazole transformation occurs when the oxazole (168) reacts with the imidoyl chloride (169) in the presence of phosphoryl chloride. The process probably involves an initial quaternization of the oxazole with subsequent ring opening of the oxazolium salt to form a ketimine (170). Intramolecular nucleophilic attack then leads to the imidazole product (Scheme 96). 

Both pyrazine iV-oxides and 2,3-dihydropyrazines rearrange photochemically to imidazoles. Irradiation of the 2,5-disubstituted oxides (187) gives mixtures of the imidazole products (188, 189), probably through the intermediacy of oxaziridine intermediates (Scheme 109). 

When faced with the challenge of writing a monograph on the synthesis of imidazoles and benzimidazoles, one is immediately aware that although there are general methods available for the bicyclic compounds, the contrary is true for imidazoles themselves. Indeed, it is necessary to consider a number of widely divergent processes each time a synthesis is contemplated. For this reason I have divided the synthetic approaches arbitrarily into methods which make specific bonds in the imidazole product, those which transform another heterocycle, and those which start with the preformed imidazole ring. 

Suitably substituted 1,2-diamines and derivatives can by cyclized into 2H-imidazoles either by photolytic or thermal treatment in the presence of base. The 2/f-imidazole products, however, cannot always be thermally isomerized to the 1/f-isomers. The migratory aptitudes of 2-substituents have been shown to lie in the order methyl[Pg.15]

The earliest method of this type was the old Marckwald synthesis (1] in which a suitable a-aminocarbonyl compound is cyclized with cyanate, thiocyanate or isothiocyanatc. More recent modifications have employed the acetals of the a-amino aldehyde or ketone or an a-amino acid ester. The two-carbon fragment can also be provided by cyanamide, a thioxamate, a carbodiimidc or an imidic ester. When cyanates, thiocyanates or isothiocyanates are used, the imidazolin-2-ones or -2-thiones (1) are formed initially, but they can be converted into 2-unsubstituted imidazoles quite readily by oxidative or dehydrogenative means (Scheme 4.1.1). The chief limitations of the method arc the difficulty of making some a-aminocarbonyls and the very limited range of 2 substituents which are possible in the eventual imidazole products. The method is nonetheless valuable and widely used, and typically condenses the hydrochloride of an a-amino aldehyde or ketone (or the acetals or ketals), or an a-amino-)6-ketoester with the salt of a cyanic or thiocyanic acid. Usually the aminocarbonyl hydrochloride is warmed in aqueous solution with one equivalent of sodium or potassium cyanate or thiocyanate. An alkyl or aryl isocyanate or isothiocyanate will give an A-substituted imidazole product (2), as will a substituted aminocarbonyl compound (Scheme 4.1.1) [2-4]. 

Such reactions can be extended to other isocyanides which are prone to a-metallation (Scheme 4.2.2). Thus, p-tolylthiomethyl isocyanide, which forms a more nucleophilic anion than TOSMIC, reacts with a variety of nitriles to give imidazole products [8]. Nitriles are added at —75°C to the monoanions formed from a variety of thiomethyl isocyanides (butyl lithium in THF-hexane at —75°C). The process is completed by allowing the reaction mixtures to come to 0°C, followed by treatment with water (method A). Alternatively, a THF solution of equimolar proportions of the isocyanide and the nitrile... 

To a solution of betmip [22] (2.5 g, 6.1 mmol) in THF (100 ml) is added cycloheptylamine (0.69 g, 6.1 mmol). The mixture is refluxed (12h) before adding benzil (1.3 g, 6.1 mmol) and refluxing for a further 16h. The mixture is cooled, diluted with diethyl ether (100 ml) and washed twice with 2 m KOH (25 ml) to remove benzotriazole. The crude imidazole product is purified by... 

Investigation of the mechanism of these reactions has suggested ways in which the yields can be improved. Acidic conditions (pH 2) will prevent Cannizzaro rearrangement of any glyoxal-type species and also serve to hydrolyse any Schiff bases which result from side reactions of aldehyde and amine. Conditions should be adjusted so that the rate of hydrolysis of linear products is equal to the rate of cyclocondensation, allowing accumulation of the imidazole products. From glyoxal, formaldehyde and ammonium chloride the yield of imidazole can be inereased to 85% by careful control of the conditions. With an appropriate alkylammonium chloride, 1-substituted imidazoles are also accessible (e.g. 1-methyl (56%), 1-isopropyl (46%), 1-cyclohexyl (49%), 1-n-butyl (55%), 1-t-butyl (25%)). The process may have some applications, but yields drop off with branched alkyl compounds [22 j. Imidazolium salts are also available under similar conditions when two molar equivalents of a primary alkylamine are used [23]. 

The imidazole product also has a 2-methyl substiment o -Bromoketal as substrate. 

Photochemical transformations of pyrimidines can also give rise to some imidazole products. For example, in benzene or methanol, photolysis of a number of substituted 1-oxides yielded small quantities of imidazoles " " (Eq. 20). These reactions have been explained by involving oxaziridines, 1,2,4-oxadiazepines, or zwitterions as possible intermediates. 

Reactions with /cr/-butylchlorodimethylsilane to give /ert-butyldimethylsilylcyclopropyl ethers are generally performed in dimethylformamide in the presence of imidazole. Product formation under these conditions occurs without racemization when optically active cyclopropanes are used thus, ( —)-methyl (15,2/ )-cw-l-hydroxy-2-methylcyclopropanecarboxylate gave the corresponding ( —)-(15,2R)-m-l-siloxy ester 2. ... 

Suitable substituted 1,2-diamines and derivatives can be cyclized to 2 f-imidazoles, either photo-lytically or by thermolysis in the presence of a base <87S547, 87TL4605, 89JCS(Pl)2035>. The 2H-imidazole products cannot be isomerized to the 1//-isomers either thermally, or by boiling with acetic acid (Scheme 131) <87S547>. 

Among the cycloaddition reactions which lead to imidazole products is the [3 + 2] cycloaddition of imines to 2-azaallenyl radical cations (derived from azirines by photolysis) which yields 1-substituted imidazoles <91AG(E)1336,93CB543). Similar addition of 2-azallyl anions (made by deprotonation of A-alkylated Schilf bases) to aromatic nitriles can give rise to either 3-imidazolines or imidazoles depending on the substitution pattern in the azaallyl species (229) <83CB492>. These reactions have been reviewed (Scheme 164) <90CHE1>. 

Base-induced ring-opening of pyrimidines, or nitrene formation (as in the pyrolysis of azido-pyrimidines) can give imidazoles (see CHEC-I). There are also a few examples of photochemical ring contraction. For example, 4-heteroaryl substituted 1,4- (or 3,4-)dihydropyrimidines give some imidazole products (Equation (76)) <83RTC364>. 

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