The kinetics and mechanism of the electrophilic substitution of heteroaromatic compounds. Part XLVII. Nitration of phenylisoxazoles

Abstract

3-Methyl-5-phenylisoxazole undergoes nitration as the conjugate acid at the para-position of the phenyl group. 5-Methyl-3-phenylisoxazole undergoes nitration as the conjugate acid at the rneta-position and also as the free base at the para-position of the phenyl group. Standard ratesfor nitration at 25 "C and H,, -6.6 are calculated and the influence of the charged and neutra I isoxazolyl substituents is discussed.WHEREAS alkylisoxazoles undergo nitration at the 4position of the heterocyclic ring, phenylisoxazoles are frequently substituted in the benzene ring. The precise orientation of such nitrations has been a matter of some controversy : Kochetkov and Khomutova reported that 5-phenylisoxazole (1) with H2S04-HNO, yields both 5-fi-nitrophenyl-(2) and 4-nitro-5-phenyl-isoxazole (3), but Lynch and Shiu claim3 that (2) is the sole mononitro-product and that is further nitrated to (4). 3,5-Diphenylisoxazole is reported to yield the para,para' dinitro-derivative. 3-Phenylisoxazole was first stated to yield the para-nitro-derivative, but reinvestigation 5a indicated that a mixture of 3-metn-and S-$ara-nitrophenyl derivatives was formed with H2S0,-HNO, but the 4-nitro-compound with HNO,-Ac,O.Recently the nitration of 3,5-diphenylisoxazole has been reinvesti-gated5b and found to give the 5-fi-nitrophenyl and the 3-m-nitrophenyl-5-fi-nitrophenyl analogues in mixed acid but the 4-nitro-derivative in acetic anhydride.Following our work 011 the nitration of 3,5-dimethylisoxazole,G we have now investigated preparatively and kinetically the nitration of 3-niethyl-5-phenylisoxazole ( 5 ) , 5-methyl-3-phenylisoxazole (6), and the corresyonding N-methyl cations (8) and (10) which serve as models for the protonated species (7) and (9), respectively. The methylphenylisoxazoles (5) and (6) were prepared by standard methods ; the methoperchlorates (8), (la), (lo),

Direct nitration of five membered heterocycles

“…Pyrazoles Acetyl nitrate has been employed to nitrate pyrazoles at one of the nitrogen atoms and subsequent rearrangement at 140 ºC has been observed to give 3-or 5-nitropyrazoles, sometimes as a mixture. 40 Pyrazole (12) on treatment with our nitrating system following method B gave a 41% yield of the 3,4-dinitrated derivative (13) while N-methylpyrazole under the same reaction condition gave a 65% yield of the 3-nitro product (13). This orientation was confirmed by nOe experiments (Scheme 5) ( Table 3).…”

“…The nitration of some of these heterocycles, for example pyrazoles and imidazoles 11 , isoxazoles 12,13 and isothiazoles 12 has been studied kinetically. Previous efforts to find milder nitration conditions for direct nitration have included use of cerium (IV) ammonium nitrate 14 , montmorillonite impregnated with bismuth nitrate 15 and nitrations with dinitrogen pentoxide 16,17 .…”