Synthesis of diazabicyclo compounds possessing an a-nitrolactam framework Haruyasu Asahara a,b , Shota Takeda a , Kazuhiko Saigo a,b , Nagatoshi Nishiwaki a,b,⇑ a School of Environmental Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan b Research Center for Material Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan article info Article history: Received 16 February 2015 Revised 18 March 2015 Accepted 23 March 2015 Available online 28 March 2015 Keywords: Bicyclic compound Michael addition Nitroacetate Pseudo-intramolecular process abstract Diazabicyclo compounds possessing an a-nitrolactam framework were directly synthesized upon treatment of a-nitro-d-keto esters with diamines. This reaction proceeds via pseudo-intramolecular process. In this process, the formation of ammonium nitronate is a key step, by which the amino group and the ketone carbonyl group are in close proximity to cause the imine formation efficiently. The follow- ing tandem bicyclization constructs 1,7-diaza-3-nitro-2-oxobicyclic systems having two aryl groups at the 4- and 6-positions. Ó 2015 Published by Elsevier Ltd. The pseudo-intramolecular reaction (PIR) is one of the useful synthetic protocols, which facilitates the efficient synthesis of poly- functionalized compounds from the substrate having both acidic hydrogen and functionalities. 1 In the PIR, the highly acidic substrate immediately forms the salt with amine. When the amine is liberated under equilibrium, the electrophilic substrate, and the nucleophilic amine are in closed together. The spatial proximity of the reactants (the intimate pair) enhances the reactivity, and consequently, the reaction proceeds like an intramolecular process although it actually proceeds in intermolecular process (Scheme 1). Indeed, a-nitro-d-keto nitrile also serves as one of the suitable substrates for the PIR to afford vicinally functionalized 1,4-dihydropyridines, 2 pyridazines, 3 and diazabicyclo compounds 2,4 upon treatment with amines, hydrazines, and diamines, respectively. These results prompted us to apply the PIR to a-nitro-d-keto esters 2, which promisingly affords diazabicyclo compounds having an a-nitrolac- tam framework. The bicyclic compounds including an a-nitrolactam framework are often found in biologically active compounds such as calcitonin gene-related peptide receptor antagonists 5 and H 3 histamine receptor. 6 In addition, the stable enolate anion of the a-nitrolactam serves as the good nucleophile to facilitate the introduction of the lactam framework, 7 and the easy leaving ability of the nitro group facilitates the formation of C–C double bond as a result of elim- ination of a nitrous acid. 8 The a-nitrolactam is generally prepared by lithiation of the corresponding lactam using lithium diisopropy- lamide followed by nitration using propyl nitrate. 9 As the other preparative methods for the a-nitrolactam framework, the ring closure of a-nitro-c-amino esters 10 and the condensation of a-ni- tro-a,b-unsaturated aldehyde with azalactone accompanied by the ring expansion 11 are also known. With regard to construction of the bicyclic structures, two rings are constructed stepwise, 5,6 and direct preparative method with single experimental manip- ulation has not been reported to our best of knowledge. Hence, the PIR is considered to be a promising method for the synthesis of bicyclic a-nitrolactams. a-Nitro-d-keto esters 2, the substrates for the PIR, were easily prepared by two steps (Scheme 2). Firstly, the crossed aldol con- densations of benzaldehydes with acetophenones were conducted http://dx.doi.org/10.1016/j.tetlet.2015.03.100 0040-4039/Ó 2015 Published by Elsevier Ltd. ⇑ Corresponding author. Tel.: +81 887 57 2517; fax: +81 887 57 2520. E-mail address: nishiwaki.nagatoshi@kochi-tech.ac.jp (N. Nishiwaki). + RNH 2 RNH 2 H FG H FG _ N R H 2 FG H FG H NH R intimate pair Scheme 1. The concept of pseudo-intramolecular reaction (PIR). Tetrahedron Letters 56 (2015) 2504–2507 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet