Imidazole ring amidines

However, more-rigorous treatment (5% acetic acid, 100°C, 17 hours) opened the imidazole ring and produced /V -cyclohexyl-a-formylaminoacetamidine (57), characterized as the crystalline picrate. Amidine 57 produced no dye in the Bratton-Marshall assay. The same behavior can be expected from AIR (46), although the product of hydrolytic ring-opening was not actually isolated. On the other hand, it was observed that a solution of AIRs (0.2 mM in 0.01-M ammonium hydroxide) prepared by biosynthesis, when stored at 4°C, did not change appreciably within a day. A decrease in the concentration of AIRs of about 30% occurred within a month. 

Cimetidine contains an imidazole ring comparable to histamine, a sulfur atom (thioether group) in the side-chain, and a terminal functional group based upon a guanidine (see Section 4.5.4). Ranitidine bears considerable similarity to cimetidine, but there are some important differences. The heterocycle is now furan rather than imidazole, and the guanidine has been modified to an amidine (see Section 4.5.4). A newer drug, nizatidine, is a variant on ranitidine with a thiazole heterocyclic ring system. 

There is one report of reductive cleavage of the imidazole ring. Treatment of 122 with sodium dithionate in aqueous ammonia yielded amidine 123, which on hydrolysis with acid gave 124. Compound 124 was obtained directly on reduction with sodium dithionate in aqueous ethanolic sodium bicarbonate (83JHC1003). 

Setzt man als Amidin-Komponente Amino-hetarene (z. B. 2-Amino-pyridine, 2- bzw. 4-Amino-pyrimidine) ein, so erhalt man Imidazole, bei denen liber die Positionen 1 und 2 des Imidazol-Rings ein heterocyclischer Ring anelliert ist96 98 ... 

The thioamide function also provides the entry for the construction of a fused imidazole ring, though the sequence is somewhat more complex due to the need to form a new carbon-carbon bond. Reaction of the thioamide (18-1) with methylamine proceeds to give the corresponding amidine this is transformed into a good leaving group by conversion to the A-nitroso derivative (18-2) by treatment with nitrous... 

An electron-deficient carbon bearing a trifluoromethyl group becomes part of an imidazole ring when Schiff bases (18) made from amidines and hexa-fluoroacetonc are reduced by tin(U) chloride (Scheme 2.2.7). The 5-fluoro-4-trifluoromethylimida2olcs (19) are isolated in 58-65% yields [9-11]. The fluoro substituents in the 5-position are readily displaced by nucleophiles such as alkoxy or cyanide, thereby extending the versatility of these syntheses [9j. 

Reaction of 2,6-di-f-butyl-5-nitroimidazo[2,l-Zj][l,3,4]thiadiazole (83) with sodium bicarbonate or with ammonium hydroxide in the presence of sodium dithionite results in the cleavage of the imidazole ring and alfords the respective 5-f-butyl-2-pivaloylamino-l,3,4-thiadiazole (84) or its amidine derivative (85) <83JHC1003>. 

Other difunctional nucleophiles may bring about annelation in a like fashion for example amidines from imidazole rings [174,179] ... 

This has been found true to the extent that radioactive formate has been found to be an excellent precursor of radioactive histidine in yeast and that it furnishes only 1 carbon of the molecule, namely the amidine carbon of the imidazole ring. Incorporation of formate into histidine has also been observed in human liver slices. This observe tion is in harmony with the knowledge that histidine is an essential amino acid for the rat and various other mammals, but not for man. ... 

The presence of a sulfur atom on the amidine carbon of the imidazole ring makes possible two tautomeric modifications, the imidazolethiol and imidazolethione structures (VI)... 

Methyl /3-hydroxypropionimidates (12) (prepared from ethylene cyanohydrin, methanol, and HO) condense with aminoacetaldehyde dimethylacetal (13) to yield an amidine hydrochloride (14) which undergoes ring closure to an imidazole.87 Applications of this reaction have been used in the synthesis of 2-phenylimidazole and its 4-alkyl derivatives,88 some new 2-mercaptoimidazoles,89 and isohistamine .90 Isohistamine [2-(2 -aminoethyl)imidazole], originally reported in error by Jones,01 was prepared in 50% yield by an adaptation of the method of Ellinger and Goldberg92 and proved by NMR spectroscopy to be the authentic compound. The compound prepared... 

There is one example in which part of the amidine system is a C—N bond in a heterocyclic ring. The enamino ketone condensation products (42) of 3-amino-l,2,4-oxadiazoles and 1,3-dicarbonyl compounds cyclize in basic medium to form 60-80% yields of imidazoles. The driving force for this reaction is provided by the well-established, general attack of a nucleophilic centre in the side-chain at N-2 of the heterocyclic ring, but it is unusual in that a carbon nucleophile (rather than an oxygen or nitrogen species) is implicated (Scheme 23). 

Claisen rearrangement of the adduct (43) formed when a propiolate ester and an aryl aldoxime combine leads to imidazole-4-carboxylates in 61-72% yields. This reaction also proceeds by ring closure of an amidine (44 Scheme 24) (80AHC(27)241). 

Reactions of imidoylaziridines (49) (amidine-type compounds), which ring open and cyclize in the presence of such reagents as oxalyl chloride or ethanolic HCl, provide further examples of 1,5-bond formation (Scheme 26). The products, though, are reduced imidazoles, being triketoimidazolidines (50) and 2-imidazolines (51), respectively (77JOC847). 

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