Synthesis of heteroannulated 3-nitro- and 3-aminopyridines by cyclocondensation of electron-rich aminoheterocycles with 3-nitrochromone Viktor O. Iaroshenko a, b, * , Satenik Mkrtchyan a, c , Ashot Gevorgyan a, c , Marcelo Vilches-Herrera a , Dmitri V. Sevenard d , Alexander Villinger a , Tariel V. Ghochikyan c , Ashot Saghiyan c , Vyacheslav Ya. Sosnovskikh e , Peter Langer a, f, * a Institut f€ ur Chemie, Universit€ at Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany b National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33 01033, Ukraine c Faculty of Chemistry, Yerevan State University, Alex Manoogian 1, 0025 Yerevan, Armenia d Hansa Fine Chemicals GmbH, BITZ, Fahrenheitstrasse 1, 28359 Bremen, Germany e Department of Chemistry, Ural State University, 51 Lenina Ave., 620083 Ekaterinburg, Russia f Leibniz-Institut f€ ur Katalyse e. V. an der Universit€ at Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany article info Article history: Received 7 April 2011 Received in revised form 15 June 2011 Accepted 27 June 2011 Available online 2 July 2011 Keywords: Chromones Cyclocondensation Aminoheterocycles Anilines Purine isosteres Regioselectivity abstract 3-Nitrochromone reacts with electron-rich aminoheterocycles (in glacial acetic acid at reflux) and ani- lines (in a mixture of DMF and TMSCl at 100e140  C) to give a variety of hetero(carbo)annulated 3- nitropyridines. The reaction, involving a formal [3þ3] cyclocondensation, proceeds in high yields and appears not to be influences greatly by the nature of the 1,3-C,N-dinucleophile as seen from the thorough scope study. The synthetic utility of the products was demonstrated by their conversion into the cor- responding 3-aminopyridine derivatives. An NMR study and X-ray crystallographic analysis are reported. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Nitrogen containing heterocycles are of considerable pharma- cological relevance. 1 Heteroannulated pyridines attracted signifi- cant attention because of their various pharmacological activities. 2,3 3-Nitro- and 3-aminopyridines, their heteroannulated analogues, 4 and functionalized quinolines represent attractive lead structures for drug discovery. 5 We have been particularly interested in purine-type scaffolds I containing electron-withdrawing sub- stituents (EWG) at the 1-position of the purine core structure. We believe that such structures represent promising patterns for the development of inhibitors of adenosine deaminase (ADA), since some 3-nitropyridines are known to undergo hydration at the 4- position to form stable Meisenheimer type hydrates. 6 3- Nitropyridines as well as their heteroannulated analogues un- dergo, depending on the pH of the solution, a reaction with water to give stable hydrates. In the case of 5,6-bicyclic systems, these hy- drates II are expected to be promising scaffolds for the de- velopment of ADA transition state mimetics (Fig. 1). On the other hand, 3-substituted chromones (3-acyl-, 7 3- methoxalyl-, 8 3-cyanochromones 9 ) are used as valuable synthetic intermediates in the preparation of pharmacologically relevant products and new heterocyclic systems. Introduction of an electron-withdrawing group into the 3-position of chromones radically changes the reactivity of the pyrone ring toward nucleo- philic reagents and opens up a broad synthetic scope of this im- portant oxygen-containing heterocyclic system. Being essentially gem-activated alkenes, 3-substituted chromones exhibit a variety of in vivo N H EWG N R EWG R OH H H 2 O I II Het Het Fig. 1. 5,6-Bicyclic systems as promising scaffolds for the development of ADA tran- sition state mimetics. * Corresponding authors. Tel.: þ49 381 4986410; fax: þ49 381 49864112; e-mail addresses: viktor.iaroshenko@uni-rostock.de (V.O. Iaroshenko), peter.langer@uni- rostock.de (P. Langer). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2011.06.101 Tetrahedron 68 (2012) 2532e2543