title: Formation of 4H-1,2-benzoxazines by intramolecular cyclization of nitroalkanes. Scope of aromatic oxygen-functionalization reaction involving a nitro oxygen atom and mechanistic insights.
abstract: In this paper, we deal with the scope and mechanism of the strong Brønsted acid-catalyzed intramolecular cyclization reaction of methyl 3-aryl-2-nitropropionates to give 4H-1,2-benzoxazines. This reaction can be regarded as an oxygen functionalization of the aromatic ring wherein the oxygen atom is derived from the nitro group in the molecule, and it is favored by the presence of electron-withdrawing groups on the benzene ring. The reaction rate is strongly influenced by the acidity of the reaction medium, and the methyl ester group on the alpha-carbon atom with respect to the nitro group facilitates deprotonation at the alpha-position to give aci-nitro species in situ. Some correlation was found between the electron-withdrawing ability of the substituents on benzene, represented in terms of Hammett's sigma p value of the substituents, and the rate of disappearance of the starting substrate leading to the product in trifluoromethanesulfonic acid (TFSA)/trifluoroacetic acid (TFA) medium. This would be because the acidity of the alpha-proton with respect to the nitro group is influenced by the substituents on the benzene ring. Experimentally, we excluded the 6pi electrocyclization mechanism involving deprotonation of the benzyl proton of the protonated aci-nitro species. Alternative cyclization mechanisms involving equilibrating monocationic aci-nitro species bearing O-protonated ester carbonyl group and O-protonated aci-nitro species were calculated to be highly energetically unfavorable. Diprotonated or protosolvative species can reduce the activation energy significantly, and this is consistent with the observed acidity-dependent nature of the cyclization.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakamura
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohwada
mesh_terms: D000143:Acids / Q000737:chemistry; D000473:Alkanes / Q000737:chemistry*; D048588:Benzoxazines / Q000138:chemical synthesis*; D002384:Catalysis; D003500:Cyclization; D007700:Kinetics; D009574:Nitro Compounds / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000143:Acids; D000473:Alkanes; D048588:Benzoxazines; D009574:Nitro Compounds; D010100:Oxygen