Experimental and Theoretical Analyses of Azulene Synthesis from Tropones and Active Methylene Compounds: Reaction of 2-Methoxytropone and Malononitrile

• Published in: Journal of organic chemistry Vol. 77; no. 12; pp. 5318 - 5330
• Main Authors: Machiguchi, Takahisa, Hasegawa, Toshio, Yamabe, Shinichi, Minato, Tsutomu, Yamazaki, Shoko, Nozoe, Tetsuo
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 15.06.2012; Amer Chemical Soc
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; azulene; chemical reactions; chemical structure; Chemistry; Chemistry, Organic; Condensed benzenic and aromatic compounds; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; imines; Kinetics and mechanisms; Lewis bases; nuclear magnetic resonance spectroscopy; Organic chemistry; Physical Sciences; Preparations and properties; Reactivity and mechanisms; Science & Technology; THERMAL CYCLOADDITION REACTIONS; QUINONES; 3-BROMO-1,5-AZULENEQUINONE; ZUR KENNTNIS; DERIVATIVES; Reaction intermediate; One pot reaction; Nitrile; Furan derivatives; NMR spectrometry; Oxygen heterocycle; Meisenheimer complex; Azulene derivatives; Anions; Amine; Reaction mechanism; Malononitrile; Aromatic compound; Chemical synthesis; Low temperature; Theoretical study; Imine; Active methylene compound; Cyclization; Density functional method; Carboxamide; Detection; Nucleophilic substitution; Tropones; Nucleophilic addition; Dinitrile; Successive reaction
• ISSN: 0022-3263; 1520-6904; 1520-6904
• DOI: 10.1021/jo300693n

A representative azulene formation from an active troponoid precursor (2-methoxytropone) and an active methylene compound (malononitrile) has been analyzed both experimentally and theoretically. 2H-Tracer experiments using 2-methoxy[3,5,7-2H3]tropone (2-d 3) and malononitrile anion give 2-amino-1,3-dicyano[4,6,8-2H3]azulene (1-d 3) in quantitative yield. New and stable 2H-incorporated reaction intermediates have been isolated, and main intermediates have been detected by careful low-temperature NMR measurements. The detection has been guided by mechanistic considerations and B3LYP/6-31(+)G(d) calculations. The facile and quantitative one-pot formation of azulene 1 has been found to consist of a number of consecutive elementary processes: (a) The troponoid substrate, 2-methoxytropone (2), is subject to a nucleophilic substitution by the attack of malononitrile anion (HC(CN)2 –) to form a Meisenheimer-type complex 3, which is rapidly converted to 2-troponylmalononitrile anion (5). (b) The anion 5 is converted to an isolable intermediate, 2-imino-2H-cyclohepta[b]furan-3-carbonitrile (6), by the first ring closure in the reaction. (c) A nucleophilic addition of the second HC(CN)2 – toward the imine 6 at the C-8a position produces the second Meisenheimer-type adduct 7. (d) The second ring closure leads to 1-carbamoyl-1,3-dicyano-2-imino-2,3-dihydroazulene (11). A base attacks the imine 11, which results in generation of a conjugate base 12 of the final product, azulene 1.