Imidazoles formation

The synthesis of eprosartan mesylate (6) by SmithKline Beecham Pharmaceuticals is described in Scheme 9.9. The synthesis of the precursors 43 and 45 were required for imidazole formation. Thus, valeronitrile (40) was converted to the imidate salt 41 with... 

An example demonstrating the effect of temperature on product formation is the case of alpha methylene ketones. The latter react in methanol solution at -70 °C with sulfur (S/ketone = 8) in the presence of ammonia and piperidine giving 2H-imidazoles, 4, in high yield (14). However, a diminished yield of this type of product results when the temperature is raised to 0 °C. Interestingly, in the case of 2H-imidazole formation, sulfur is promoting the oxidation of ketone without being incoroorated into the product. 

Formation mechanisms of imidazoles in the Maillard reaction are not as well understood as those of other heterocyclic compounds. The role of a-amino carbonyl fragments as intermediates in imidazole formation was suggested in the reaction of sucrose and ammonia (43). In a study of a L-rhamnose/ammonia model system, which produced fifty-two imidazoles, it was proposed that an amino-hydroxy fragment was responsible for imidazole... 

N.R. Jena et al., Reaction of hypochlorous acid with imidazole Formation of 2-chloro- and 2-oxoimidazoles. J. Comput. Chem. 29, 98-107 (2008)... 

Imidazole formation runs closely parallel to oxazole formation.243 That the A-alkyl groups are derived from the amino acid was shown by the use of [2-13C]Gly and Ala. 

In the reaction of a-diketones with formamide and formaldehyde at 180°-200°C, no a-hydroxyketones can be detected during the reaction,65 and hence formaldehyde cannot be acting as a reducing agent. It seems then that imidazole formation must be due to generation of ammonia from formamide and subsequent reaction between the diketone, ammonia, and formaldehyde. The advantage of this method over the older Radziszewski synthesis lies in the reduced decomposition of the diketone with consequent reduction in side, reactions which normally produce mixtures of imidazoles. 

Whereas a-amino ketones readily form imidazoles with formamide, they are often not easy to prepare. Accordingly, they can be replaced by precursors, a-oximino ketones, which can be reduced either by dithionite or using catalytic mehods in formamide at 70-100 °C. Ring closure can then be achieved by raising the temperature (Scheme 80). When a-ketol esters are used it appears that the imidazole formation may in this instance proceed by way of the oxazole. A further special case is the formation of 4,5-disubstituted imidazoles from 1-chloro-l,2-epoxides and formamide. One recent example of an application of Bredereck s method is the synthesis of the imidazolepropanol (144) from 3-bromo-2-methoxytetra-hydropyran (Scheme 81) (80AHC(27)241). 

There has been considerable literature pertaining to imidazole formation from pyrimidines, pyrazines and triazines (70AHC(12)103,80AHC(27)241,b-73MI40801>. 

Unlike formamidine, acetamidine and benzamidine react with both aromatic and aliphatic a-hydroxyketones to give imidazoles exclusively. It has been suggested that aryl groups favour the enolic form (2) of the tautomeric mixture, resulting in the formation of oxazoles as major products. Aliphatic groups favour the keto form (1), from which imidazoles are derived. That amidines more complex than formamidine favour imidazole formation may be a consequence of steric hindrance to reaction of the enolic hydroxy groups with the amidine carbon in (2). The general reaction has been used to prepare such compounds as 4,5-dipropyl imidazole (25% yield from tris(formylamino)-methane and 5-hydroxyoctan-4-one), and a variety of 2-imidazolones and 2-aminoimidazoles [8]. The fact that oxazoles can be converted into imidazoles with some ease extends the applicability of this reaction. 

There are considerable data available on imidazole formation by ring contractions of pyrimidines, pyrazincs and triazines [15, 43, 59-61]. Few of the reactions, however, have synthetic potential except perhaps for the thermolytic conversions of azidopyrimidines and azidopyrazines into 1-cyano-substituled imidazoles, and the reactions of chloropyrimidines and chloropyrazines with potassium amide in liquid ammonia to give 4- and 2-cyanoimidazoles, respectively. Ring contractions of quinoxaline 1-oxides may also have some applications. 

The use of a-dicarbonyl compounds with ammonia and an aldehyde continues as a common synthetic method. " Thus a series of 2-aryl-5-trifluoromethyl-4-phenylimidazoles (2) have been prepared from the previously unknown 3,3,3-trifluoro-l-phenylpropane-l,2-dione monohydrate (1) as shown in Eq. (1). As an extension of earlier studies of imidazole formation by the action of ammonia on reducing oligosaccharides, Richards ... 

A tandem Kornblum ox/daf/on/imidazole formation reaction was used during the preparation of new fluorescent nucleotides by B. Fischer and co-workers.The adenosine monophosphate free acid was mixed with 10 equivalents of 2-bromo-(p-nitro)-acetophenone and dissolved in DMSO. The required pH value was maintained with the addition of DBU which also served as a base. The Kornblum oxidation of the alkyl halide yielded the glyoxal, which reacted in situ with the aromatic amine to form the desired imidazole derivative. 

Novel fluorescent ATP analogues where the two tertiary carbons of the etheno-moiety of A A -etheno adenosine have been modified by the introduction of a /7-nitro or a / -amino-phenyl group and a hydroxy moiety (100) have been prepared via a Kornblum oxidation reaction and imidazole formation. These compounds exhibited relative stability towards type II ATPDase. ... 

Nucleoside Pyrophosphates. - The synthesis of 8-aryl-3-P-o-ribofuranosylimiazo[2,l-i]purine 5 -phosphates (122) from AMP or ATP has been described. To access these fluorescent nucleotide derivatives, a combination of Kornblum oxidation reaction and imidazole formation was employed. For this conversion, the appropriate adenosine phosphate, present in its free acid form, was treated with p-nitro-acetophenone in DMSO in the presence of DBU. Treatment of a 5-(chloroethyl)-4-(triazole-l-yl)pyrimidine-nucleoside with benzylhydrazine offered the 6,6-bicyclic pyrimido-pyradazin-7-one, the precursor to (123). This triphosphate was used as a substrate for DNA polymerases. ... 

Cyclising dehydration of an a-acylamino-carbonyl-compound is particularly important for oxazoles, and can be adapted for thiazole or imidazole formation. 

Latterly a superior method for producing the (trifluoromethyl)-l,3,4-oxadiazines (199) rapidly (6 h), and in high yields (72-97%), has been found which involves treating the a-(trifluoro-acetyl)hydrazones (197) with trifluoroacetic acid at room temperature <90S493>. The reaction is successful with a range of A-mono- (197 R = Bu , R = Me) and A,A-dialkylated hydrazones, with the exception of the A-/-butyl-hydrazone which suffers de-/-butylation. However, cyclization of the /-butyl derivative is possible in warm (50 °C) acetic acid higher temperatures have to be avoided in order to prevent imidazole formation. 

Imidazoles. - Formation. Treatment of the dipiperidinium salt CsHioN=CHCH=NC5Hio 2Br with 7V-arylbenzamidines affords mixtures of the imidazolines (279) and (280), Compound (281) is one of the products... 

Keto aldehyde (99) is best made by the a-functionalisation approach (Chapter 23), and imidazole formation occurs with Zn(OH)2 as catalyst. Nitration at the right position occurs with nitric acid and a final condensation with benzaldehyde gives (96). 

Imidazoles.—Formation. Several new syntheses of imidazoles from isocyanides have been reported these include the formation of 1-alkyl-imidazoles (396) by the action of primary amines on 2-isocyano-2-tosylstyrene, PhCH=C-(NOTos, the cyclization of the enamine Me2NCH=C(NC)C02Me to compound (397) in the presence of methyl iodide,and the preparation of the ethers or thioethers (398) from isocyano-cyanides R CH(NC)CN by their reaction with alcohols or thiols R XH, respectively.Aromatic aldehydes are converted into 2-aryl-4,5-dichloroimidazoles (399) by the combined action of cyanogen and hydrochloric acid. 5-Acetyl-4-methylimidazole (400) results when form-amido-acetylacetone, AC2CHNHCHO, is heated with formamide and formic acid. Exhaustive chlorination of tetramethyldithio-oxamide leads to the tri-chloro-imidazolium cation (401). ... 

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