Job/Unit: O30894 /KAP1 Date: 09-09-13 10:48:40 Pages: 9 FULL PAPER DOI: 10.1002/ejoc.201300894 Sodium-Hydroxide-Mediated Synthesis of Highly Functionalized [1,6]- Naphthyridines in a One-Pot Pseudo Five-Component Reaction Satavisha Sarkar, [a] Deb K. Das, [a] and Abu T. Khan* [a] Keywords: Multicomponent reactions / Nitrogen heterocycles / Cyclization / Ketones / Alcohols / Thiols The synthesis of hitherto unreported 5-amino-7-alkoxy- 2-methyl-2,4-aryl-1,2-dihydro-1,6-naphthyridine-8-carbo- nitriles (4) was accomplished by a one-pot pseudo five-com- ponent reaction using aryl methyl ketones or alkyl methyl ketones, malononitrile, and alcohols in the presence of so- dium hydroxide under reflux conditions. By following an identical reaction procedure, various 5-amino-2-methyl-2,4- Introduction The construction of structurally complex and highly functionalized multi-heterocyclic skeletons is a challenging task in modern organic synthesis. [1] One of the most useful ways to achieve this goal is to use a synthetic strategy that allows the formation of several bonds in one pot. Among the various synthetic approaches, multicomponent reac- tions [2] (MCRs) have emerged as a powerful tool in combi- natorial, medicinal, and heterocyclic chemistry. [2c] These re- actions have many advantages over conventional multistep synthesis, due to their convergent and atom-economic na- ture, and to the diversity of the products of these reac- tions. [2d,2e] MCRs are environmentally benign processes as they reduce the numbers of steps, the energy consumption, and the amounts of by-products formed. Due to the numer- ous advantages of MCRs, they are well-used for the easy construction of diverse heterocyclic scaffolds. [3] Much effort has been put into designing multicomponent reactions for the synthesis of architecturally complex molecules. [2,3] 1,6- Naphthyridine derivatives, nitrogen heterocycles containing two pyridine rings, are widely distributed in nature, [4] and they are considered to be “privileged structures” in drug discovery. These compounds show a wide range of pharma- cological activities such as antitumor, [5a] antimicrobial, [5b] allosteric, [5c] and antiproliferative activities. [5d] In addition, functionalized 1,6-naphthyridines are well-known inhibitors of human cytomegalovirus [6a] and HIV-1 integrase, [6b] and are selective antagonists of 5-HT4 receptors. [6c] Due to their [a] Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India E-mail: atk@iitg.ernet.in http://shilloi.iitg.ernet.in/~chem/People/Faculty/pages/atk.html Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201300894. Eur. J. Org. Chem. 0000, 0–0 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 diaryl-7-(arylthio)-1,2-dihydro-1,6-naphthyridine-8-carbo- nitrile derivatives (6) were also synthesized from aryl methyl ketones, malononitrile, and thiophenols in the presence of sodium hydroxide in ethanol. High bond-forming efficiency, good yields, and the use of a readily available base are some of the salient features of this multicomponent reaction. immense potential, various research groups have put con- siderable effort into the synthesis of these compounds in recent times. Over the years, numerous synthetic methods [7] have been developed for the construction of 1,6-naphthyrid- ine derivatives, and these include: heterocyclization of 3,5- diarylidenepiperidin-4-one with cyanoacetamide [8a] or with malononitrile and amines, [8b] base-mediated cyclization of a N-silyl-1-aza-allyl anion with perfluoroalkenes, [9] cobalt- catalyzed intramolecular [2 + 2 + 2] cyclizations of dialk- ynylnitriles, [10] Sonogashira coupling of 2-chloroquinolines with phenyl acetylene, [11] [5+ 1] rearrangement–annulation of 2-dicyanomethylenepyridine-3-carbonitrile with aliphatic carboxylic acids, [12] and hydrolysis of dicyanomethylene- substituted alkyldihydropyridines. [13] Both intramolecu- lar [14a] and intermolecular [14b] [4 + 2] aza-Diels–Alder reac- tions have also been explored for the synthesis of fused naphthyridine derivatives. Recently Mukhopadhyay et al. [15] reported the serendipitous synthesis of highly function- alized 1,2-dihydro-1,6-naphthyridines from methyl ketones, malononitrile and amines in a one-pot multicomponent re- action involving ylidene derivatives. Some of these methods have drawbacks such as the requirement of multistep se- quences, [5d,9] the use of expensive catalysts, [10,11] or sealed- tube reaction conditions. [12] Although all of these methods are quite useful, there is still further scope to synthesize highly substituted 1,6-naphthyridine derivatives using an in- expensive catalyst. Over the years, a large number of papers have been published about the synthesis of heterocycles using the Knoevenagel product obtained from the reaction of aldehydes with malononitrile. [16] However, reports of analogous procedures using ketones are rather fewer, prob- ably due to the lower reactivity of these compounds. Ylid- ene compounds resulting from the condensation of ketones with malononitrile in the presence of a base have been found to be key intermediates for the construction of im-