Synthesis of methyl 7-aryl(hetaryl, cyclohexenyl)-10,10-dimethyl-8-oxo-7,8,9,10,11,12-hexahydrobenzo[b][1,7]phenanthroline-9-carboxylates

Abstract

Three-component condensation of quinolin-5-amine with methyl 2,2-dimethyl-4,6-dioxocyclohexane-1-carboxylate and aromatic (heteroaromatic) aldehydes or cyclohex-3-ene-1-carbaldehyde gave previously unknown 1,7-phenanthroline derivatives. The reactions in butan-1ol were characterized by 100% regioselectivity but low stereoselectivity, and mixtures of cis-and trans-isomeric methyl 7-aryl(hetaryl, cyclohexenyl)-10, 10-dimethyl-8-oxo-7,8,9,10,11,12-hexahydrobenzo[b][1,7]phenanthroline-9-carboxylates were obtained at a ratio of ~45 : 55.Reactions of amines of the quinoline series with carbonyl-containing compounds are widely used in the synthesis of phenanthrolines. We previously showed [1-4] that quinolin-6-amine reacts with aromatic aldehydes and methyl or methylene ketones (CH acids) to give various 4,7-phenanthroline derivatives. It was also found that cyclic 1,3-diketones are the most efficient reagents among CH acids [3,4]. Partly hydrogenated oxo derivatives of benzo[b][4,7]phenanthroline obtained as a result of the above reactions attract interest as analogs of natural alkaloids, enzyme inhibitors, bactericidal agents, and antibiotics [5][6][7][8].In the present work we were the first to perform three-component condensation of quinolin-5-amine (I) with methyl 2,2-dimethyl-4,6-dioxocyclohexane-1-carboxylate (II) and substituted benzaldehydes, thiophene-2-carbaldehydes, and cyclohex-3-ene-1-carbalehyde IIIa-IIIs with a view to obtain previously unknown fused 1,7-phenanthroline derivatives (structural analogs of previously synthesized benzo[b][4,7]phenanthrolines) as potential biologically active substances [9, 10]. The condensation was performed by heating equimolar amounts of the reactants in boiling butan-1-ol. Due to high reactivity of β-dicarbonyl compound II, its condensation with amine I and aldehydes III in alcoholic medium required no catalyst. Presumably, the reaction was catalyzed by proton formed via ionization of the enol tautomer of β-diketone II. As a result, the corresponding stereoisomeric 7-substituted methyl 10, 10-dimethyl-8-oxo-7,8,9,10,11,12-hexahydrobenzo[b][1,7]phenanthroline-9-carboxylates IVa-IVs and Va-Vs were formed in 37-80% yield with high regioselectivity.By analogy with our previous data [11] on the three-component condensation of naphthalen-1-amine (a carbocyclic analog of quinolin-5-amine) with aromatic aldehydes and 5,5-dimethylcyclohexane-1,3-dione (dimedone), we presumed that the fused benzo[b]-[1,7]phenanthroline system is formed via initial reaction of amine I with aldehyde III. The subsequent addition of diketone II at the C=N bond of Schiff base A yields intermediate B which undergoes HofmannMartius type rearrangement (migration of the N-alkyl substituent in aniline into aromatic ring [12]), followed by cyclocondensation of rearrangement product E.Transformation of intermediate B may also involve its hydramine fission into initial amine I and α,β-unsaturated ketone D. The exocyclic double bond in the latter is strongly activated due to conjugation with two neighboring carb...