Investigations on imidazoles 98. Reactions of nitrohaloimidazoles with amino acids

Abstract

Three groups of biologically active amino acids containing the imidazole nucleus within their structure are known. These are the irreplaceable amino acid histidine [2], the biosynthetic precursor of the purine nucleotides 4(5)-amino-5(4)-imidazolecarboxamide and its antagonists [3][4][5][6][7], and 1-carboxyalkylimidazoles [8][9][10][11] in which a nitrogen atom is common to both amino acid and imidazole.N-Substituted amino acids in which one hydrogen atom of the amino group is replaced by imidazole residue have not been described in the literature. With the aim of obtaining this type of compound we have studied the reaction of 5-chloro-1-methyl-4-nitro-(I), 5-bromo-1,2-dimethyl-4-nitro-(I1), and 4-chloro-1-methyl-5-nitroimidazoles (III) with a series of aliphatic and aromatic amino acids (glycine, valine, 13-alanine, y-aminobutyric, paminophenylacetic, and m-and o-aminobenzoic acids).The reaction of nitrohaloimidazoles I and II with amino-acids proceeds readily on heating the components in water or in n-butanol in the presence of potassium hydroxide and leads to formation of the corresponding Nimidazolyl-substituted amino acids IV -IX (in 65-80% yield).The reaction of 5-halo-4-nitroimidazoles I and II with anthranilic acid proceeds with significantly more difficulty. It occurs only under the conditions of the Ullman reaction, i.e. on extended boiling in amyl alcohol in the presence of sodium bicarbonate and cuprous chloride catalyst. The more reactive 4-chloro-l-methyl-5-nitroimidazole III reacts with anthranilic acid without a catalyst. Yields of the N-imidazolyl-substituted anthranilic acids X -XII were 61-72%.The esters of certain N-imidazolylamino acids (especially anthranilic) XIII -XVI are of particular interest. Acid X is readily esterified in methanol in the presence of hydrogen chloride with formation of methyl ester XIII (in 90% yield). Acid XI, which is similar in structure, under the same conditions forms methyl ester XIV in 20% yield. Ester XIV was obtained in high yield (86%) by the reaction of acid XI with dimethyl sulfate in DMF in the presence of potassium carbonate.N-(1-Methyl-5-nitro-4-imidazolyl)anthranilic acid XII as its potassium salt was esterified With dimethyl sulfate and alkyl halides (CH3I, C2H5I) in DMF. The methyl XV and ethyl XVI esters were obtained in this way in 61-65% yield. Samples of ester XV obtained by the different methods proved to be identical. *For Part 97 see [1].

Reactions of halonitroimidazoles with nucleophiles (review)

“…The reaction of 5-halo-4-nitroimidazoles 13 with the sodium salts of CH acids leads to the formation of 4-nitro-5-imidazolyl CH acids 76 [81]. The reaction of 4-bromo-5-nitroimidazole 74 with trifluoromethylcopper, resulting in the synthesis of 2-cyano-1-methyl-5-nitro-4-trifluoromethylimidazole 80, was described in [12].…”

“…NH 2 NH 2 4-Halo-5-nitroimidazoles enter into reaction similarly with N-nucleophiles. The reactions of compounds 52 with ammonia [55], amines [14,19,22,58], amino alcohols [19,59], amino acids [60], and derivatives of imidazole with a free NH group [20,59] An unusual reaction with N-nucleophiles, during which not only the halogen atom but also the NO 2 group is substituted by the N-nucleophile fragment, was described in the series of halonitro derivatives of imidazole and 2,2'-diimidazole. Thus, 4,4',5,5'-tetraphenylamino-2,2'-diimidazole was obtained when 4,4'-dibromo-5,5'-dinitro-2,2'-diimidazole was boiled in aniline [66].…”

“…5-Halo-4-nitroimidazoles 13 react with ammonia [55], primary [16-18, 21, 56] and secondary [14,19,[56][57][58] amines, dialkylaminoalkylamines [16,17,20,56], amino alcohols [19,59], aminophenols [21], amino acids [60], and heterocyclic compounds containing a free NH group [20,57]. A large series of 5-amino-4-nitroimidazole derivatives 41-43 were synthesized as a result of these reactions.…”