Partly hydrogenated 2-[5-methyl(bromo, nitro)furan-2-yl]-substituted furo [3,2-c]quinolines, pyrano-[3,2-c]quinolines, and 4-ethoxyquinolines were synthesized by the imino Diels-Alder (Povarov) reaction. Cycloadditions of these compounds with maleic, citraconic, and dibromomaleic anhydrides, as well as with acryloyl, methacryloyl, and cinnamoyl chlorides led to the formation of substituted epoxyisoindolo[2,1-a]-quinolines and -quinolinecarboxylic acids. Oxidation of the double C=C bond in the adducts, esterification of the carboxy group, and aromatization of the 7-oxabicycloheptene fragment were accomplished.We previously synthesized 4-substituted 6-R-2-furyltetrahydroquinolines and those fused at the C 3 -C 4 bond and studied their [4 + 2]-cycloaddition reactions with maleic anhydride and acryloyl chloride [1-3] and the effect of electronic properties of the R substituents in the aryl fragment on the cyclization of N-furfurylideneanilines with vinyl ethers and vinyl amides to the corresponding tetrahydroquinolines (Povarov reaction) [4,5].The goal of the present work was to study the behavior of N-furfurylideneanilines with different substituents in position 5 of the furan ring in the Povarov reaction and reveal general relations holding in the cycloaddition of 2-furyltetrahydroquinolines thus obtained with maleic, citraconic, and dibromomaleic anhydrides, as well as with substituted acryloyl chlorides. N-Furfurylideneanilines I were synthesized by condensation of the corresponding 5-substituted furan-2-carbaldehydes with ortho-and para-substituted anilines. Compounds I were brought into cycloadditions with dihydrofuran, dihydropyran, and ethyl vinyl ether (Scheme 1). The reactions were carried out in diethyl ether or benzene at 0-20°C in the presence of boron trifluoride-diethyl ether complex (5 mol %).We previously showed that electron-withdrawing substituents in the aniline fragment reduce the yield of furyl-substituted tetrahydroquinolines [1]. In the present work we found that increase in the electronacceptor power of the substituent R 3 in the furan ring favors formation of cycloaddition products II. Schiff base Ic having a hydroxy group in the ortho-position of the benzene ring was considerably less active in the Povarov reaction. According to the 1 H NMR data, 5-nitrofuryl-substituted tetrahydroquinoline IIf was formed as an equimolar mixture of two stereoisomers differing by mutual arrangement of the 5-nitrofuryl substituent and fused tetrahydrofuran ring. The coupling constants for the cis isomer of IIf are J 4, 3a = 2.7, J 3a, 9b = 7.4 Hz, and for the trans isomer, J 4, 3a = 5.4, J 3a, 9b = 10.1 Hz. Tetrahydroquinolines III and IV were reported by us previously [1, 2].2-Furyl-substituted tetrahydroquinolines IIa, IIcIIe, III, and IV readily reacted with maleic anhydride at 0-5°C, following the Diels-Alder pattern (Scheme 2), to produce mixtures of stereoisomeric exo-tetrahydrofurano-(Va, Vc-Ve), tetrahydropyrano-(VI), and 4-ethoxyisoindolo[2,1-a]quinolinecarboxylic acids (VII). In the reactions with f...
were obtained for the first time from 8-aminoquinolines using the Povarov reaction. Various oxidizing agents were shown to effect the elimination of the substituent at C(4) with subsequent aromatization of the tetrahydroquinoline fragment.The Povarov reaction (the acid-catalyzed [4+2] cycloaddition of electron-rich alkenes to N-arylazomethines) is commonly used for the synthesis of substituted tetrahydroquinolines and, judging from the rising number of publications, is now experiencing a rebirth of interest [1-3]. Nevertheless, there have been only a few examples of the preparation of 2-furyl-1,2,3,4-tetrahydroquinolines by this method [4][5][6] and there is only one example of the use of an 8-aminoquinoline in the Povarov reaction [7]. This paucity is related primarily to the acidophobic nature of the furan fragment and, secondarily, to passivation of the acid catalysts. The behavior of 2-furyltetrahydroquinolines in the presence of oxidizing agents has also not been studied extensively and apparently is complex.2 -Furyltetrahydroquinolines 2a,b, 3, and 4 used as the starting compounds in this work were obtained by the Povarov reaction from the corresponding furfurylideneanilines 1a,b and electron-rich alkenes (dihydrofuran, 3,4-2H-dihydropyran, and N-vinyl-2-pyrrolidone) in the presence of boron trifluoride etherate as described in our previous work [8]. The hydrogenated quinolines 2-4 are cis addition adducts.
A procedure was developed for the synthesis of hydrogenated furyl substituted furo[3,2 c]quinolines, pyrano[3,2 c]quinolines, and 4 ethoxy and 4 (2 oxopyrrolidin 1 yl)quinolines. The reactions of these compounds with acryloyl chloride and maleic anhydride produce epoxyisoindolo[2,1 a]quinoline derivatives through successive acylation at the quino line nitrogen atom and intramolecular exo [4+2] cycloaddition at the furan moiety.We have synthesized 1 the previously unknown epoxy oxoisoindolo[2,1 a]tetrahydroquinolines 1 containing electron donating substituents R by intramolecular cy clization of 3 metallyl substituted N aryl 3a,6 epoxy tetrahydroisoindol 1 ones under the action of phospho ric acid in 37-67% yields (Scheme 1).Intramolecular cyclization of epoxyisoindolones containing electron withdrawing substituents R (see Scheme 1) in the N aryl fragment requires higher tem peratures and, as a result, is accompanied by aromatiza tion to give isoindoloquinolines 1´. 1 Epoxy compounds 1 are promising synthons for the synthesis of derivatives containing the isoindo lo[2,1 a]tetrahydroquinoline moiety. Methods for the syn thesis of the latter compounds are scarce and involve many steps. 2 It was found that isoindolo[2,1 a]tetra hydroquinolines have antihypoxic properties and inhibit human topoisomerase. 3,4In the present study, we developed a new synthetic approach to compounds 1 based on the [4+2] cycloaddi tion reaction of 4 substituted or 3,4 fused 2 furyltetra hydroquinolines with activated alkenes.2 Furyl substituted tetrahydroquinolines required for this investigation were synthesized from furfurylidene anilines 2 and alkenes containing the N or O vinyl frag ment by the Povarov reaction in the presence of Lewis acids (LA). 5-8 This reaction was widely used for the syn thesis of substituted tetrahydroquinolines, 9-13 including 2 furyl derivatives 7,11,12 (18-41% yields). To optimize this process involving 2 furyl substituted tetrahydroquino lines 3-5, we studied the influence of the nature of the catalyst and the solvent and the electronic effects of the substituents in the aryl moiety of furfurylideneanilines 2. Scheme 1 1: R = 3 Me, 3 Pr i , 1 Et; 1´: R = 1 Cl, 3 Cl, 3 F
Quinoline derivatives R 0410Product Structure in the Reaction of Dimethyl Acetylenedicarboxylate with 2-Furyl-1,2,3,4-tetrahydroquinolines. -(ZUBKOV, F. I.; ZAITSEV, V. P.; ORLOVA, A. A.; PEREGUDOV, A. S.; MIKHAILOVA, N. M.; VARLAMOV, A. V.; Russ.
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