An efficient, microwave-assisted, one-pot synthesis of novel 5,6,7,8-tetrahydroquinoline-3-carbonitriles

J. Serb. Chem. Soc. 76 (6) 823–830 (2011) JSCS–4162 UDC 547.831+547.592+547.447:542.913 Original scientific paper An efficient, microwave-assisted, one-pot synthesis of novel 5,6,7,8-tetrahydroquinoline-3-carbonitriles DIPTI K. DODIYA*, HARESH K. RAM, AMIT R. TRIVEDI and VIRESH H. SHAH Department of Chemistry, Saurashtra University, Rajkot-360 005, Gujarat, India (Received 2 July 2010, revised 9 January 2011) Abstract: An efficient, microwave-assisted synthesis of novel 2-alkoxy-5,6,7,8-tetrahydroquinoline-3-carbonitriles, which have not hitherto been reported, via reactions of cyclohexanone and arylidene malononitriles in the corresponding alcohols in presence of sodium is described. All the newly synthesized compounds were characterized by the IR, 1H-NMR, 13C-NMR and mass spectrescopic techniques and by elemental analyses. The newly synthesized compounds were evaluated for their antibacterial and antifungal activities. Keywords: 2-alkoxytetrahydroquinoline-3-carbonitriles; quinoline-3-carbonitriles; one-pot synthesis; microwave-assisted synthesis; cyclohexanone; arylidene malononitriles. INTRODUCTION As a privileged fragment, quinoline is a ubiquitous subunit in many quinoline-containing natural products with remarkable biological activities. Members of this family have wide applications in medicinal chemistry, being used as antimalarial, anti-inflammatory, antiasthmatic, antibacterial, antihypertensive and tyrosine kinase inhibiting agents.1 Because of their importance as substructures in a broad range of natural and designed products, significant efforts continue to be directed into the development of new quinoline-based structures.2 Among quinoline derivatives, tetrahydroquinolines are an important structural subunit of natural products and many tetrahydroquinoline derivatives exhibit interesting biological and pharmaceutical activities,3 including anti-HIV,4,5 anticancer,6 antimalarial,7 cholesteryl ester transfer protein inhibitors,8 anti-diabetic,9 etc. Consequently, synthetic methodologies for preparing tetrahydroquinoline derivatives have attracted considerable interest and several methods offering good results have been reported. However, most of them describe the synthesis of * Corresponding author. E-mail: doi: 10.2298/JSC100702071D 823 Available online at www.shd.org.rs/JSCS/ _________________________________________________________________________________________________________________________________________ 2011 Copyright (CC) SCS 824 DODIYA et al. the 1,2,3,4-tetrahydroquinoline nucleus,10–12 and concise methods to access usefully functionalized 5,6,7,8-tetrahydroquinolines are scarce in the literature.13 Recently, 5,6,7,8-tetrahydroquinolines have drawn considerable attention due to their interesting pharmacological applications as RET tyrosine kinase inhibitors,14 anti-HIV,15,16 anti-fungal,17 anti-cancer18 and C5a receptor antagonists agents.19 The development of simple synthetic routes for widely used organic compounds from readily available reagents is one of the major tasks in organic synthesis. Application of microwave irradiation in achieving this task has been the focus of considerable attention in recent years and is becoming an increasingly popular technology.20,21 In view of these observations and as part of a continuing effort in our laboratory towards the development of new methods for the expeditious synthesis of biologically relevant heterocyclic compounds,22 herein, a simple and efficient microwave-assisted synthesis of functionalized novel 2-alkoxy-5,6,7,8-tetrahydroquinoline-3-carbonitriles, which are also structurally relevant to recently reported bioactive 5,6,7,8-tetrahydroquinolines,16–19 is described (Fig. 1). Fig. 1. Examples of some bioactive 5,6,7,8-tetrahydroquinolines structurally relevant to the synthesized 5,6,7,8-tetrahydroquinoline-3-carbonitriles. All the newly synthesized compounds 3a–j were evaluated for their antibacterial and antifungal activity. The biological activity of the synthesized compounds was compared with reference standard drugs. Available online at www.shd.org.rs/JSCS/ _________________________________________________________________________________________________________________________________________ 2011 Copyright (CC) SCS EFFICIENT SYNTHESIS OF 5,6,7,8-TETRAHYDROQUINOLINES 825 RESULTS AND DISCUSSION Chemistry There are very few reports in literature for the synthesis of 2-alkoxypyridine-3-carbonitriles,23,24 but most of them do not describe the synthesis of fused pyridines or benzo-fused pyridines, i.e., quinolines. During an extensive literature survey, only one such synthesis of benzothiepino-fused 2-alkoxy-pyridine-3-carbonitriles was found.25 Herein, the efficient and rapid microwave-assisted one-pot synthesis of functionalized novel 2-alkoxy-5,6,7,8-tetrahydroquinoline-3-carbonitriles, which have not hitherto been reported, via the reactions of cyclohexanone, arylidene malononitriles in the corresponding alcohol in the presence of sodium is reported. The arylidene malononitriles 2 were prepared following a reported literature procedure.26 Treatment of cyclohexanone 1 with arylidene malononitriles 2 in the corresponding alcohol in the presence of sodium under microwave irradiation at 300 W afforded the 2-alkoxy-5,6,7,8-tetrahydroquinoline-3-carbonitriles 3a–j in excellent yields (88–95 %) in a very short time (Scheme 1) as compared to conventional heating, which results in lower yields after longer reaction times (5– –10 h). Scheme 1. Microwave-assisted synthesis of 2-alkoxy-5,6,7,8-tetrahydroquinoline-3-carbonitriles. The proposed mechanism27 involves Michael addition between 1 and 2 to generate intermediate A, followed by nucleophilic alkoxide attack at one of the nitrile groups of A with dehydration and subsequent dehydrogenation to give the tetrahydroquinoline 3 (Scheme 2). All the newly synthesized 2-methoxy- and 2-ethoxy-5,6,7,8-tetrahydroquinolines 3a–j were characterized by IR, 1H-NMR, 13C-NMR, mass spectroscopy Available online at www.shd.org.rs/JSCS/ _________________________________________________________________________________________________________________________________________ 2011 Copyright (CC) SCS 826 DODIYA et al. and elemental analyses (Supplementary material). The IR spectra of 3a–j revealed the appearance of confirmatory bands characteristics of the stretching vibrations of the –CN and C=N groups at 2231–2225 cm–1 and 1635–1566 cm–1, respectively. Furthermore, asymmetric and symmetric stretching vibration bands of the ether (C–O–C) linkage were also present in the IR spectra in the range of 1296–1263 cm–1 and 1097–1018 cm–1, respectively, which confirmed the presence of 2-alkoxy groups. The 1H-NMR spectra of compounds 3a–e showed confirmatory signals in the δ range 3.75–3.80 ppm as a singlet for (–OCH3), while the 1H-NMR spectra of compounds 3f–j revealed signals at δ 1.27–1.44 ppm as a triplet for the (–CH2–CH3) and signals at δ 4. (...truncated)