ARTICLE Synthesis of novel hexahydroquinolines and 6‐amino‐2‐ oxopyridine‐3,5‐dicarbonitriles incorporating sulfamethoxazole via [3 + 3] annulation Amr M. Abdelmoniem | Mohamed Gamal Mohamed Abdelrahman | Said Ahmed Soliman Ghozlan | Ismail A. Abdelhamid Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt Correspondence Ismail A. Abdelhamid, Department of Chemistry, Faculty of Science, Cairo University, PO 12613 Giza, Egypt. Email: ismail_shafy@yahoo.com Abstract Cyclic enaminone and cyanoacetamide derivative with incorporated sulfa- methoxazole moiety were prepared. Their reactions with arylidenema- lononitrile derivatives in ethanol or pyridine/piperidine at reflux yielded the corresponding hexahydroquinoline and 6‐amino‐2‐oxopyridine‐3,5‐ dicarbonitrile derivatives incorporating sulfamethoxazole. The mechanism and structural elucidation of products were discussed. 1 | INTRODUCTION Sulfamethoxazole is a chemotherapeutic drug that exhibits a wide range of pharmacological and biological activities that include antimicrobial [1–5] and anticancer agents. [6,7] Also, it is used in the treatment of urinary tract infec- tions. [1,8] In addition, pyridine derivatives have attracted a particular interest over the past years due to their various biological activities, including antiviral, [9] antihista- minic, [10] antihypertensive, [11] anti‐inflammatory agents, [12] and antitumors. [13] Furthermore, quinolines are unique fused six‐membered heterogeneous pharmaco- logical compounds that offered a wide range of activities such as antibacterial, antitumor, anti‐inflammatory, anti‐ asthmatic, antimalarial, antituberculosis, and antihyper- tensive properties. [14–19] On the other hand, due to the excellent mechanical characteristics of quinolines, they have found significant use in electronics, optoelectronics, and polymer chemistry. [20,21] Self‐hierarchical assembly of quinoline copolymers into meso‐ and nano‐structures enhanced greatly their photonic and electronic features. [22] Hexahydroquinolines exhibited potent and promising cytotoxic, antibacterial, myorelaxant, calcium channel modulatory, and neuroprotective activities. [23–28] 1,4‐ Dihydropridines have emerged as important derivatives that selectively prohibit L‐type calcium channels and act as well as one of the most common therapeutic agents for the treatment of cardiovascular diseases, including hypertension. [29,30] 2 | RESULTS AND DISCUSSION In continuation to our interest in the C─C bond forma- tion reactions, [31–45] the possibility of [3 + 3] atom combi- nation reaction of the cyclic enamine incorporating sulfamethoxazole with α,β‐unsaturated nitriles through Michael addition reaction was studied. First, the cyclic enamine 3 was prepared via the reaction of dimedone 1 with sulfamethoxazole 2 according to the procedure reported in the literature by us [33–35,44–46] and by others [47] (Scheme 1). The Michael addition reaction of the cyclic enamine 3 with arylidenemalononitriles 4a‐e was then investigated. In principle, for this type of reac- tion, there are two possible isomeric structures for the product. The product is either 4‐aminohexahy- droquinoline‐3‐carbonitrile 6 that results from initial addition of NH to the activated double bond in com- pound 4 to give 5 that readily cyclizes to 6 (pathway A) or 2‐aminohexahydroquinoline‐3‐carbonitrile 8 that results from the initial addition of enamine CH to the activated double bond in compound 4 to yield 7 that Received: 11 May 2019 Revised: 13 August 2019 Accepted: 27 August 2019 DOI: 10.1002/jhet.3737 J Heterocyclic Chem. 2019;1–9. © 2019 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/jhet 1