Quinoxaline N-Oxideに関する研究 (第3報)

Abstract

Quinoxalines substituted in 2-position and in 2- and 3-positions were submitted to N-oxidation to examine the effect of adjacent substituent on the ring nitrogen. N-Oxidation was carried out with (a) monoperphthalic acid in ether or benzene at below 10° and (b) hydrogen peroxide in acetic acid at an appropriate temperature between 60 and 100°. Results of these reactions are presented in the reaction formulae and following conclusions were drawn.1) Effect of adjacent substituent on the ring nitrogen during N-oxidation:(i) Methyl group slightly facilitates the formation of N-oxide.(ii) Primary alkyl groups like ethyl and propyl do not interfere in the formation of N-oxide but it is uncertain whether they facilitate the formation.(iii) Isopropyl group (and probably secondary alkyl groups in general) have fairly great adverse effect on the formation of N-oxide(iv) Phenyl group have some adverse effect on the formation of N-oxide but not enough to prevent its formation.(v) Alkoxyl, chloro, cyano, carbamoyl, ethoxycarbonyl, carboxy, and acyl groups have fairly great interfering action on N-oxide formation.(vi) When there are substituents in the 2- and 3-positions, result of the reaction cannot be predicted from the foregoing conclusions (i) to (v), and the reaction result seems to be determined in some cases by the correlation of the two substituents. For example, only the 4-oxide is formed from 2-quinoxalinecarboxamide (XXIX) and not 1-oxide or 1, 4-dioxide, while only the 1-oxide is formed from 3-phenyl-2-quinoxalinecarboxamide (LXXVII) and not 4-oxide or 1, 4-dioxide.2) Side reactions:(i) Alkoxy and chloro groups interfere in the formation of N-oxide but a more drastic reaction conditions in the (b) method, such as elevation of reaction temperature and prolongation of reaction time, results in the acceleration of the hydrolysis of these groups, a side reaction rather than the formation of N-oxide.(ii) Ring carbon to which carbamoyl or aryl group is bonded undergoes oxidation, with liberation of the substituent, and sometimes results in a side reaction with subsequent substitution with hydroxy group.(iii) When cyano group is present, treatment with monoperphthalic acid results in more facile change of chano group into carbamoyl group rather than N-oxidation. Consequently, treatment with hydrogen peroxide is more suitable than with monoperphthalic acid.