Fused Quinoline Heterocycles IV: First Synthesis of Four Heterocyclic Ring Systems of 1H-5-Thia-1,2,3,6-Tetraazaacephenanthrylenes and 1H-5-Thia-1,3,6-Triazaacephenanthrylenes

Abstract

Reaction of 4-alkylamino-2-chloroquinoline-3-carbonitriles 4a-e with an equimolecular amount of ethyl mercaptoacetate gave, in each case, the corresponding ethyl 4-alkylamino-3-aminothieno[2,3-b]quinoline-2-carboxylates 7a-e. Diazotization of 7a-e afforded the novel tetracyclic ring system ethyl 1-alkyl-1H-5-thia-1,2,3,6-tetraazaacephenanthrylene-4-carboxylates 8a-e. Refluxing 7a-e with an excess of triethyl orthoformate yields the new ethyl 1-alkyl-1H-5-thia-1,3,6-triazaacephenanthrylene-4-carboxylates 9a-e. Reacting 9b, c, as example, with an excess of cyclohexylamine (2a) in boiling DMF furnished the corresponding amides 10a, b in good yields.We have reported in previous parts 1-3 of this series on the synthesis of novel tetracyclic ring systems, containing the quinoline skeleton, with potential pharmaceutical activity, such as pyrazolotriazinoquinolines 1,2 and pyrrolopyrimidoquinolines. 3 Fused heterocycloquinolines are a large group of polyheterocycles with diverse, interesting biological activities. They are reported to possess significant antiinflammatory, 4,5 antitumor, 6,7 antibacterial 8,9 and potent Bradykinin (BK) B 1 and B 2 receptor antagonist properties. 10 Moreover, some of the sulfur-containing fused quinolines and particularly thienoquinolines have recently drawn much attention due to their considerable biological and pharmacological activities as antitumor, 11 antibacterial, 11,12 drug resistance modulators, 13 memory enhancers, 14 antiinflammatorics, immunoregulators, analgesics and antipyretics. 15 Others are reported to exhibit good antiallergics 16 and antianaphylactic activities. 17Because of these findings, our interest was focused on investigating efficient and convenient routes to construct the novel title ring systems. To the best of our knowledge, however, there are only few literature reports about the synthesis of linear, anellated pyrimidothienoquinolines 18-20 and 1,2,3-triazinothienoquinolines. 16,20 Moreover, a survey on the synthesis of perianellated tetracyclic pyrimidothienoquinoline and 1,2,3-triazinothienoquinoline ring systems revealed that these ring systems have been largely ignored. In connection with our ongoing program of synthesis of pharmacologically interesting new heterocyclic systems containing the quinoline moiety, 1,21-24 we now succeeded in the synthesis of the first representatives of so far not accessible tetracyclic systems, namely ethyl 1-alkyl-1H-5-thia-1,2,3,6-tetraazaacephenanthrylene-4-carboxylates and ethyl 1-alkyl-1H-5-thia-1,3,6-triazaacephenanthrylene-4-carboxylates.In the syntheses presented in this paper, the conveniently available 2,4-dichloroquinoline-3-carbonitrile (1) 1 is employed as starting material. It is known that the chlorine atom in the 4-position of 1 is more labile than that in the 2-position and is more easy to displace using nucleophiles, 25 therefore, 1 was reacted with alkylamines 2 in order to obtain the required key intermediate 4 for subsequent thiophene ring closure. Reaction of 1 with an excess of the appropriate alkylamin...

Novel applications of the hypervalent iodine chemistry. Synthesis of thiazolo-fused quinolinones

“…6 In fact, the synthesis and the activity of a number of natural products with fused quinoline heterocyclic skeletons have been reported. 7 In particular, we considered that the thiazole moiety, which is present in a number of important natural products (epothilone, 8 althiomycin, 9 bistramide C, 10 sulfomycin I 11 ), in antibiotics (cystothiazole 12 ) and, notably, in thiamine (vitamin B) inter alia, would be an interesting and promising substructure to be included in our target molecules.…”

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

“…CH), 1700 (CO, ester), 1680 (CO, amide) cm -1 ; 1 H NMR (DMSO-d 6 ): δ = 1.39 (t, 3H, J = 7Hz, CH 3 ), 1.49-1.67 (m, 8H, H aliph ), 2.16 (m, 2H, H aliph ), 2.28 (s, 3H, CH 3 ), 4.30 (br, 1H, H aliph ), 4.43 (q, 2H, J = 7Hz, CH 2 ), 7.0 (s, 2H, NH 2 ), 7.20 (t, 1H arom , J = 8Hz), 7.52 (t, 1H arom , J = 8Hz), 7.69 (d, 1H arom , J = 8Hz), 7.81 (d, 1H arom , J = 8Hz), MS: m/z (%) = 411 (M + , 19), 364 (2), 329 (100), 314 (78), 287 (23), 286 (11), 266 (19), 252 (18), 239 (22), 215 (30), 197 (13), 128 (7), 82 (2), 55 (25).…”

“…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].…”

Regioselective Synthesis of Thieno[3,2‐b]quinolones by Acylation/Two‐Fold Buchwald–Hartwig Reactions

“…Quinolines annulated to other heterocycles have recently drawn much attention, due to their considerable pharmacological and biological activities In this context, thienoquinolines are of considerable current interest as they possess anti‐bacterial, anti‐inflammatory and anti‐tumor properties . Moreover, they are immunoregulators, drug resistance modulators, memory enhancers, as well as analgesics and antipyretics , . The quinolone substructure, contained in thienoquinolones, shows many of the attributes of an ideal antibiotic, combining high potency, a broad spectrum of activity, good bioavailability and a potentially low incidence of side‐effects .…”