Synthesis of Novel Quinoline Analogues of Nimesulide: An Unusual Observation Lingam Venkata Reddy, a Mamatha Nakka, a Alishetty Suman, a Soumen Ghosh, b Madeleine Helliwell, c Khagga Mukkanti, a Alok Kumar Mukherjee, b and Sarbani Pal d * a Center for Chemical Science and Technology, IST, JNTH University, Kukatpally, Hyderabad 500085, India b Department of Physics, Jadavpur University, Kolkata 700032, India c Department of Chemistry, University of Manchester, Manchester M13 9PL, England d Department of Chemistry, MNR Degree and PG College, Kukatpally, Hyderabad 500072, India *E-mail: sarbani277@yahoo.com Received March 10, 2010 DOI 10.1002/jhet.618 Published online 22 February 2011 in Wiley Online Library (wileyonlinelibrary.com). Reduction of nimesulide followed by treating the N-acyl derivative of resulting arylamine with Vils- meier-Haack reagent provided novel 2-chloro-3-formylquinoline derivatives. The construction of quino- line ring using Vilsmeier-Haack reagent afforded an unexpected compound, N-(2-chloro-3-formyl-7- phenoxy quinolin-6-yl)formamide, in addition to the expected product. The structure of this unexpected quinoline derivative was established via single-crystal X-ray analysis and its formation could be explained by an unprecedented N-S bond cleavage under Vilsmeier-Haack reaction conditions. The 2- chloro-3-formylquinoline derivatives obtained were converted to a number of corresponding Schiff bases with potential pharmacological importance. J. Heterocyclic Chem., 48, 555 (2011) INTRODUCTION Nimesulide, a preferential COX-2 inhibitor, is a non- carboxylic acid nonsteroidal anti-inflammatory drug (NSAID) that has been in clinical use for treatment of pain for more than 20 years [1]. Several derivatives of nimesulide have shown antiviral, anticancer [2] and COX-2 inhibiting [3] properties. 2-Chloroquinoline derivatives, on the other hand, have shown a range of biological activities [4,5]. Thus combining nimesulide with 2-chloroquinoline in a single molecule would pro- vide new chemical entities of potential pharmacological interest (Fig. 1). In continuation to our interest in the synthesis and biological activity of nimesulide deriva- tives [6], we decided to prepare a series of novel mole- cules A for in vitro pharmacological studies. Herein, we report for the first time the synthesis of a series of hybrid molecules structurally related to both nimesulide and 2-chloroquinoline. Although different methods have been reported [7] for the construction of a quinoline ring, the approach of employing an aromatic primary amine i.e., CACAN unit as the nucleophilic nitrogen donating component and an electrophilic three carbon unit, usually carbonyl compounds, is of particular interest. For example, most of the classical routes to quinoline e.g., Skraup, Doeb- ner-von Miller, Combes and Conrad-Limpach syntheses are based on this strategy. We anticipated that this strat- egy would be beneficial in our study because the required aniline component could be readily prepared. However, to construct the quinoline ring possessing the desired functional groups we opted for the Vilsmeier- Haack cyclization of acetanilides leading to the 2- chloro-3-formylquinoline derivatives [8,9]. Our interest in 2-chloro-3-formylquinoline moiety stem from the fact that it can be utilized for further [b]-annelation to afford a wide variety of rings and for various functional group inter conversions. Our synthesis of novel quinoline ana- logues structurally related to nimesulide is shown in Scheme 1. RESULTS AND DISCUSSION The nimesulide was converted to the corresponding aromatic amine via reduction of its nitro group follow- ing a known procedure [6]. The primary amine was then converted to the corresponding N-acetyl derivative 1, V C 2011 HeteroCorporation May 2011 555