Fused quinoline heterocycles VI: Synthesis of 5H-1-thia-3,5,6-triazaaceanthrylenes and 5H-1-thia-3,4,5,6-tetraazaaceanthrylenes

Abstract

Ethyl 3-amino-4-chlorothieno[3,2-c]quinoline-2-carboxylate (4) is a versatile synthon, prepared by reacting an equimolar amount of 2,4-dichloroquinoline-3-carbonitrile (1) with ethyl mercaptoacetate (2). Ethyl 5-alkyl-5H-1-thia-3,5,6-triazaaceanthrylene-2-carboxylates 9a-c, novel perianellated tetracyclic heteroaromatics, were prepared by refluxing 4 with excess of primary amines 7a-c to yield the corresponding aminothieno[3,2-c]quinolines 8a-c. Subsequent reaction with an excess of triethyl orthoformate (TEO) furnished 9a-c. Reaction of 4 with TEO in Ac 2 O, at reflux, gave the simple acetylated compounds, thieno[3,2-c]quinolines 12 and 13. Refluxing 4 with benzylamine (7d) gave 10, and subsequent treatment with TEO gave the tetracyclic compound 11. Refluxing 13 with an excess of alkylamines 7a-d gave the thieno[3,2-c]quinolines 15. Refluxing the aminothienoquinolines 8b with an excess of triethyl orthoacetate gave thieno[3,2c]quinoline 17, while heating with Ac 2 O gave 18 and 19, with small amounts of 16. Reaction of 8a,b with ethyl chloroformate and phenylisothiocyanate generated the new 1-thia-3,5,6-triazaaceanthrylenes 20a,b and 21a,b, respectively. Diazotization of 8a-c afforded the novel tetracyclic ethyl 5-alkyl-5H-1-thia-3,4,5,6tetraazaaceanthrylene-2-carboxylates 22a-c in good yields. J. Heterocyclic Chem., 42, 567 (2005).Selectively functionalized quinolines are building blocks for the synthesis of numerous tetracyclic systems with a wide variety of biological activities [1-3]. For some time, our research has focused on the synthesis of fused heterocyclic systems, particularly those containing a quinoline nucleus, with the aim of evaluating their pharmacological and/or biological activity [4][5][6][7]. As a result of this work, we recently reported a new and useful method for the synthesis of novel tetracyclic ring systems [8][9][10][11][12]. In pharmacological studies thieno[3,4-d]-pyrimidines have been shown to possess pharmacological activities including antibacterial [13], antihypertensive [14,15], antiulcer [16], fungicidal [17], gastric acid secretion inhibitory [18], insecticidal, miticidal [17] vasodilatory [14] activity, and antiallergic activity [19]. Several thienoquinolines have attracted attention over the last decade owing to their biological activities, which include antitumor [20], drug resistance modulation [21], anti-inflammatory, immunoregulatory, analgesic and antipyretic activities [22]. In addition, some compounds show potent antianaphylactic activity [23]. Our previous work [8-12] has led to the synthesis of novel tetracyclic ring systems containing both thiophene 568Vol. 42 and pyrimidine moieties condensed with a quinoline nucleus. The newly synthesized perianellated tetracyclic compounds, pyrimidothienoquinolines and 1,2,3-triazinothienoquinolines, are promising targets for biological-activity evaluation studies, and to the best of our knowledge these ring systems are totally unexplored. We therefore report a novel, efficient and convenient synthesis of the first representati...

Novel Polycarbo-Substituted Alkyl (Thieno[3,2-c]quinoline)-2-Carboxylates: Synthesis and Cytotoxicity Studies

“…Although β-chlorovinylaldehydes such as the 2/4-chloroquinoline-3-carbaldehydes have been exploited extensively in the synthesis of angular and linear azoloquinolines [10,15], to our knowledge, there is no literature precedent for their transformation into thienoquinoline derivatives. Recourse to the literature, on the other hand, revealed a single-pot base-promoted conjugate addition–elimination of the 4-chloro-5,6-diphenyl-2 H -thiopyran-3-carbaldehyde with methyl thioglycolate and subsequent heteroannulation to afford 4 H -thieno[3,2- c ]thiopyran [16].…”

“…Likewise, thieno[3,2- c ]-quinolinones were prepared via thio-Claisen rearrangement of the corresponding 4-allylthio-1-methylquinolin-2(1 H )-ones in refluxing N , N- diethylaniline [9]. Moreover, a one-pot conjugate addition-elimination of the analogous 2,4-dichloroquinoline-3-carbonitrile with ethyl mercaptoacetate previously afforded ethyl 3-amino-4-chlorothieno[3,2- c ]quinoline-2-carboxylates [4,10]. Less traditional synthesis of 2-substituted thieno[3,2- c ]quinolines, which involves sequential amination and intramolecular palladium-catalyzed direct arylation of thiophene-3-carbaldehyde with 2-haloanilines to afford 2-arylthieno[1,3- c ]quinolines in a single-pot operation has been reported [11].…”

Recent Advances in the Synthesis of Thienoquinolines (Quinoline‐fused heterocycle)

“…[45] In 2008, Mekheimer and co-workers developed fused quinoline heterocycles, alike 3-amino-thieno[3,2-c]quinolines 67 from 2,4-dichloroquinoline-3-carbonitrile 65. [46] (Scheme 22) The reaction of compound 65 with ethyl mercapto-acetate in the presence of DMF and triethylamine resulted in 3-amino-4-chlorothieno[3,2-c]quinoline-2-carboxylate 66, [47] which further treated with various secondary amines using DMF under reflux to obtain the corresponding 3-amino substituted thieno[3,2-c] quinolines 67 in excellent yields.…”

Synthesis of 4-phenylthieno[2,3-c]quinolines via Suzuki–Miyaura cross-couplings

“…7 Two general strategies have been investigated to prepare thieno [3,2-c]quinolines. Specifically, a number of methods have accessed these heterocycles via quinoline substrates, [8][9][10][11][12] while other approaches have employed thiophene precursors. [13][14][15][16][17][18][19] In this work, we deployed robust cross-coupling methodology [20][21][22] to establish a short, modular synthetic route enabling the efficient construction of a small library of functionalized 4-phenylthieno [3,2-c]quinolines from a simple thiophene starting material.…”