Imidazole formation formamide

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). 

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). ... 

Since formamide is a weak nucleophile, the use of imidazole or 4-dimethylaminopyridine (DMAP) is necessary for acyl transfer to formamide via an activated amide (imidazolide) or acylpyridinium ion. As Scheme 22 illustrates, the reaction starts with the oxidative addition of aryl bromide 152 to Pd(0) species, followed by CO insertion to form acyl-Pd complex 154. Imidazole receives the aroyl group to form imidazolide 155 and liberates HPdBr species. Then, imidazolide 155 reacts with formamide to form imide 156. Finally, decarbonylation of imide 156 gives amide 157. In fact, the formations of imidazolide intermediate 155 and imide 156 as well as the subsequent slow transformation of imide 156 to amide 157 by releasing CO were observed. This mechanism can accommodate the CO pressure variations observed during the first few hours of aminocarbonylation. When the reaction temperature (120 °C) was reached, a fast drop of pressure occurred. This corresponds to the formation of the intermediary imide 156. Then, the increase of pressure after 3 h of reaction was observed. This phenomenon corresponds to the release of CO from imide 156 to form amide 157. ... 

The formation of oxazoles may begin to predominate if conditions in which the imidazole ring is formed preferentially (large excess of formamide at 180°-200°C, or passage of a stream of ammonia at 150°-175°C for 4-6 hours)66 are not maintained. This situation is also favored by the use of sulfuric acid as the condensing medium.67... 

Imidazole, itself, is prepared in 60% yield from the reaction of bromoacetaldehyde (as the glycol acetal), formamide, and ammonia at 180°C.70 The initial step in the formation of imidazoles from a-haloketones is replacement of the halogen by an hydroxy group.65 From the stage of acyloin formation it is assumed 61 that the following reaction path is followed ... 

Applicability of the reaction sequence to the preparation of 2-substituted imidazoles rests on the use of more complex amides than formamide. This constitutes a severe limitation to the process since it has only proved possible to substitute acetamide in a few cases, with the formation of 2-methylimidazoles. Nevertheless, the method still has many applications in the preparation of 4- and 5-substituted imidazoles. Best results are obtained if a large excess of formamide is used at 180-200 °C, or passage of a stream of ammonia at 150-175 C for 4-6 hours is maintained. The use of sulfuric acid as a condensing agent is also of value. Should these conditions not be adhered to then oxazoles may be formed preferentially. 

Related reactions include the formation of the 2-cyano compounds (190) when 1,2-dimethyl-5-nitroimidazole is heated with nitrosyl chloride or an AT-oxide, and when 2-methyl-l-(o-nitrophenyl)imidazoles (191) cyclize under the influence of iron(II) oxalate (Scheme 98) (74JCS(P1)1970). The last reaction product is contaminated by a large amount of amine reduction product ( 64%) but there is also some cyclization with the 4-methyl isomer of (191). In the presence of trimethylamine, 2-cyanomethylbenzimidazole condenses with acetone to give the unsaturated derivative (192 Scheme 99) (77CPB3087). Neither 2-methylimidazole nor 2-methylbenzimidazole reacts with formamide in the presence of phosphoryl chloride. 

The susceptibility of 1,3,5-triazine to nucleophilic attack with ring opening makes it a synthetically useful equivalent of formate, or formamide, particularly for the synthesis of other heterocycles, such as imidazoles and triazoles (see above). Despite the high susceptibility of 1,2,4-triazines to nucleophilic addition, 3-substituted-6-methoxy-l,2,4-triazines can be successfully lithiated. ... 

In summary, GTP cyclohydrolase II appears to catalyze an ordered reaction that starts with the formation of a covalent guanyl adduct (15). This is followed by the hydrolytic opening of the imidazole ring (16, 17) and the hydrolysis of the resulting formamide-type intermediate (18, 19) the latter two reactions depend on the Zn ion acting as a Lewis acid, which sequentially activates two water molecules (17, 19) that attack first the imidazole carbon atom 8 of the covalent guanyl adduct 17 and then the formamide motif of the covalent intermediate 19. 

Ammonium citrate tribasic Ammonium fluoborate Ammonium-12-molybdosilicate Ammonium phosphomolybdate Basic blue 9 Bromodichloromethane t-ButyIdimethylsilyl imidazole Chromium chloride (ous) Dimethyl acetamide Dimethyl formamide Ethoxydiglycol acetate Ethyl acetate Ethylbenzene Ethyl formate Ferric sulfate Formic acid Heptane Hexamethylenetetramine Isopropyl ether Methyl cyclohexane 2,7-Naphthalenediol ... 

Compounds with a strong tendency for hydrogen-bond formation, such as urea, formamide, acetamide, and imidazole... 

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