Imidazoles nitrosation

Alloxan forms an oxime (1007) which is the same compound, violuric acid, as that formed by nitrosation of barbituric acid likewise, a hydrazone and semicarbazone. Reduction of alloxan gives first alloxantin, usually formulated as (1008), and then dialuric acid (1004 R = OH) the steps are reversible on oxidation. Vigorous oxidation with nitric acid and alkaline hydrolysis both give imidazole derivatives (parabanic acid and alloxanic acid, respectively) and thence aliphatic products. Alloxan and o-phenylenediamine give the benzopteridine, alloxazine (1009) (61MI21300). 

Pyrazoles and imidazoles exist partly as anions (e.g. 108 and 109) in neutral and basic solution. Under these conditions they react with electrophilic reagents almost as readily as phenol, undergoing diazo coupling, nitrosation and Mannich reactions (note the increased reactivity of pyrrole anions over the neutral pyrrole species). 

Under alkaline conditions, alkyl nitrites nitrosate imidazoles which possess a free NH group in the 4-position (70AHC(12)103). Nitrosation of 3,5-dimethylpyrazole gives the 4-diazonium salt by further reaction of the nitroso compound with more NO". 5-Pyrazolinones are often nitrosated readily at the 4-position. 3-Alkyl-5-acetamidoisothiazoles undergo 4-nitrosation. 

Scheme 26, which recalls the classic reactions involved in the synthesis of 50 from small, common molecules, will help in following the methods used for labeling the imidazole ring of AIRs. Nitrosation with (l5N)NaN02 allowed the preparation of AIRs labeled on N-3. When methyl cyanoacetate was prepared with (i5N)KCN, AIRs labeled on the amino nitrogen were obtained. 

A benzofuran ring replaces one of the benzene rings of the biphenyl moiety present in many of the sartans in the rather more complex drug saprisartan (80-10). It is of note, further, that the acidic proton is provided in this case by a trifluorosulfo-namide instead of the more common tetrazole ring. Construction of the imidazole fragment begins by nitrosation of the (3-ketoester (79-1) by means of sodium nitrite in acid to afford the oxime (79-2). Reaction with acetyl chloride leads to the ester (79-3). Reaction of this last intermediate with the iminoether from propionitrile then affords the imidazole (79-4). 

The second arm of the scheme involves first a reaction of the (3-beta ketoester (7-1) with nitrous acid. The first product from nitrosation on the activated carbon spontaneously rearranges to afford oxime (7-2). Treatment with acetyl chloride then affords the (9-acylated oxime (7-3). Condensation of that compound with the imino ether from propionitrile leads to the formation of the imidazole (7-4). 

A rearrangement that does not fall into the pattern described in this section has been found by Cusmano and Ruccia.191 This time a 1,2,4-oxadiazole is the final product formed by nitrosation of an imidazole. What intermediates lie between the nitroso compound (103) and the final product (104) have not been determined, but the reagent is alcoholic hydrochloric acid. Other examples of this type of rearrangement are known191,192 that also resemble the nitrosopyrrole to isoxazole rearrangement.192"... 

To date, there has been no report of the nitrosation of imidazole itself. There are, however, a number of examples of nitrosation of substituted imidazoles in basic medium. The observation that such reactions do not occur with Af-substituted imidazoles implicates the imidazole anion as the likely substrate. Substitution generally occurs at C-4 or C-5 and may be accompanied by some nitration. In the presence of sodium ethoxide, pentyl nitrite nitrosates 4-phenyl-, 2-methyl-5-phenyl- and 2,5-diphenyl-imidazoles at the vacant 4- or 5-positions. The reaction apparently failed with 5-methyl-2-phenyl- and 4,5-diphenyl-imidazoles (58G463). 

Less common methods of synthesis include nitrosation of suitable alkenes in acetonitrile solution (see Section 3.02.8.1.3(ii)) <84TLI319>, cyclization of iV-alkoxy ureas <87S1058>, and specific approaches to benzimidazole oxides from quinoxaline oxides, and to imidazole oxides from oxa-diazine and pyrazine oxides <93CHE127>. 

Imidazole ring formation of acyclo C-nucleoside 543 was made by reaction of 6-chloro-l,3-dimethyl-5-nitrouracil with o-glucopyranosylamine (541), followed by catalytic hydrogenation and concomitant cyclization of 542 (67CB492). The same C-nucleoside (543) was obtained by reacting 1-amino-l-deoxy-D-glucitol (544) with 6-chloro-l,3-dimethyluracil and subsequent nitrosation and cyclization (96S459) (Scheme 145). 

These facts suggest that the imidazole ring in compounds 86, 330, 334 and 617 is first reversibly covalently hydrated in the acid medium to form 638, and then a hydrolytic ring opening occurs to provide intermediate 639. Then A -nitroso compound 640 forms and ring closes to afford l-methyl-l,2,3-triazolo[4,5-c]pyridine 637 (80KG121). The A -nitrosation occurs with nitrogen oxides formed from nitric acid reduction. 

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