Mendeleev Communications Electronic Version, Issue 2, 2001 (pp. 43–84) New approach to [a]-fused fluoroquinolones: the synthesis of 5-oxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinolines Elizaveta Tsoi,a Valerii N. Charushin,*a Emiliya V. Nosova,a Galina N. Lipunovaa and Alexey V. Tkachevb a Department of Organic Chemistry, Urals State Technical University, 620002 Ekaterinburg, Russian Federation. Fax: + 7 3432 74 0458; e-mail: charushin@prm.uran.ru b N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russian Federation. Fax: +7 3832 34 4752; e-mail: atkachev@nioch.nsc.ru 10.1070/MC2001v011n02ABEH001323 The reaction of N-(ethoxycarbonyl)methyl substituted ethyl 6,7-difluoro-, 6,7,8-trifluoro- and 5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline- 3-carboxylates with methyl methacrylate results in the [3 + 2] adducts, hexahydropyrrolo[1,2-a]quinolones, which can be precursors of [a]-fused fluoroquinolones.Among the tricyclic N1–C2 fused fluoroquinolones, compounds with excellent antimicrobial and other kinds of biological activity have been found.1–3 A common strategy for the synthesis of this type of fused fluoroquinolones is based on condensation reactions of appropriately substituted heterocyclic synthons A–C (Scheme 1).In particular, pyrrolo[1,2-a]quinolones were obtained by the intramolecular condensation of cyclic derivatives of ethyl 3-amino-2-benzoyl acrylates A.2 The second approach is based on the ring closure reactions of appropriate C2-substituted quinolones B.4 The first successful example of using the nucleophilic substitution of hydrogen at C2 in fluoroquinolones C for the construction of [a]-fused tricyclic systems was performed through intramolecular addition of the Grignard reagent followed by oxidation of the intermediate ó-adduct.5 Later we reported a new approach towards pyrazolo[1,5-a]quinolones via the [3 + 2] annelation resulting from the reaction of 1-amino- 6-fluoro-4-quinolones with â-diketones.6 A similar synthetic route to the same heterocyclic system of pyrazoloquinolones was developed by D.Barrett and co-workers via the tandem addition reaction of N-aminoquinolones with alkyl acrylates and other activated alkenes under basic condition.7,8 We report here the extension of this [3 + 2] annelation methodology based on tandem addition reactions.However, instead of the =N–NHR moiety, we used the CH-active N-(ethoxycarbonyl) methyl fragment in fluoroquinolones 1a–c to generate nucleophilic species. We found that the reaction of ethyl 6,7-difluoro-, 6,7,8- trifluoro- and 5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3- carboxylates 1a–c with methyl methacrylate proceeds smoothly in an anhydrous DMF solution in the presence of sodium hydride and affords 5-oxo-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinolines 2a–c in 50–61% yields (Scheme 2).The 1H NMR spectroscopy of reaction products 2a–c† revealed that the mixtures of three stereomers were obtained in all cases in a ratio of approximately 2.5:1:trace. The major isomers were separated by silica gel column chromatography followed by crystallisation from hexane.The relative configuration of substituents in major diastereomers 2a and 2b was determined by NMR spectroscopy. The proton–proton coupling 3JH-4,H-3a » 14 Hz for both compounds demonstrates the anti-periplanar (trans-) position of H-4 and H-3a, whereas the cis-arrangement of the pairs C-10 and H-3a, H-1 and H-2â is evident from the nuclear Overhauser effects (NOE, Scheme 3).Although the NOE for 2c have not been measured, it is clear that the stereostructure of 2c is just the same due to similarities of its spectral NMR characteristics to those of 2a,b. In conclusion, note that the reaction discovered provides an alternative route to fused pyrrolo[a]quinoline derivatives, the key intermediates for potential fluoroquinolone antibacterials.Moreover, compounds 2a–c are of interest as novel representatives of the tricyclic fluoroquinolone system bearing the bridge-headed nitrogen atom and having structural similarities to natural alkaloids. X NH O O OEt F F N O OEt O H Z YH F N O OEt O C A B C Scheme 1 † The 1H and 19F NMR spectra were recorded in CDCl3 solutions on Bruker WP-250 and Bruker WP-80-SY instruments (250 MHz for 1H and 75 MHz for 19F).Homonuclear 1H–1H Overhauser effects for compounds 2a,b and the 13C NMR spectrum of 2a in CDCl3 were obtained on a Bruker DRX-500 spectrometer (500 MHz for 1H and 125 MHz for 13C). Mass spectra were recorded using a Varian MAT 311A spectrometer. 1,4-Di(ethoxycarbonyl)-3-methoxycarbonyl-3-methyl-7,8-difluoro-5-oxo- 1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline 2a.A solution of ethyl N-(ethoxycarbonyl)methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate 1a (0.35 g, 1mmol) in dry DMF (5ml) was treated with sodium hydride (60% dispersion in oil) (50 mg, 1.2 mmol) and stirred for 15 min. Methyl methacrylate (0.33 ml, 3 mmol) was added to the reddish reaction mixture, which was allowed to stand at room temperature for 24 h (until 1a disappeared and the solution became yellowish green).The reaction mixture was diluted with 10 ml of water; the pH of the solution was adjusted to 7.0 with 6% hydrochloric acid; and the contents were extracted with dichloromethane. The organic layers were washed with water, dried (Na2SO4) and evaporated. The oily residue was treated with diethyl ether–hexane to give 2a (0.27 g, 61%) as a yellow powder.Major individual diastereoisomer 2a was isolated as a colourless powder by silica gel column chromatography (eluent: hexane–ethyl acetate, 10:1) followed by crystallisation from hexane to yield 0.13 g (30%), mp 102– 103 °C. 1H NMR, d: 1.21 (t, 3H, Me, 3J 7.2 Hz), 1.33 (t, 3H, Me, 3J 7.2 Hz), 1.35 (s, 3H, Me), 1.85 (dd, 1H, 2-Há, 2J2-Há,2-Hâ 13.4 Hz, 3J2-Há,1-H 6.4 Hz), 3.08 (dd, 1H, 2-Hâ, 2J2-Hâ,2-Há 13.4Hz, 3J2-Hâ,1-H 9.0 Hz), 3.46 (d, 1H, 4-H, 3J4-H,3a-H 14.4 Hz), 3.70 (s, 3H, OMe), 4.19 (q, 2H, OCH2, 3J 7.2 Hz), 4.30 (q, 2H, OCH2, 3J 7.2 Hz), 4.38 (d, 1H, 3a-H, 3J3a-H,4-H 14.4 Hz), 4.48 (dd, 1H, 1-H, 3J1-H,2-Há 6.4 Hz, 3J1-H,2-Hâ 9.0 Hz), 6.17 (dd, 1H, 9-H, 3J9-H,8-F 11.9 Hz, 4J9-H,7-F 6.1 Hz), 7.51 (dd, 1H, 6-H, 3J6-H,7-F 10.2 Hz, 4J6-H,8-F 9.0 Hz). 13C NMR, d: 14.0 (C-18), 14.02 (C-15), 21.94 (C-10), 40.51 (C-2, 1J2-C,2-H 139.0 and 133.6 Hz), 52.19 (C-12), 52.32 (C-3), 55.56 (C-4, 1J4-C,4-H 131.5 Hz), 59.37 (C-1, 1J1-C,1-H 150.7 Hz), 61.39 (C-17), 61.63 (C-14), 67.39 (C-3a, 1JC-3a,3a-H 145.9 Hz), 101.22 (C-9, 1JC-9,9-H 162.7 Hz), 113.12 (C-5a), 116.08 (C-6, 1J6-C,6-H 166.8 Hz), 143.46 (C-7, 1J7-C,7-F 242.2 Hz), 145.32 (C-9a), 157.77 (C-8, 1J8-C,8-F 257.6 Hz), 167.33 (C-16), 172.29 (C-13), 173.46 (C-11), 186.55 (C-5). 19F NMR, d: 125.11 (ddd, 7-F, 3J7-F,8-F 22.0 Hz, 3J7-F,6-H 12.7 Hz, 4J7-F,9-H 9.8 Hz), 151.70 (ddd, 8-F, 3J8-F,7-F 22.0 Hz, 3J8-F,9-H 9.8 Hz, 4J8-F,6-H 5.9 Hz). MS, m/z: 439 (10%, M+), 366 (100), 339 (25), 320 (20), 267 (40).Mendeleev Communications Electronic Version, Issue 2, 2001 (pp. 43–84) This work was supported in part by the US Civilian Research and Development Foundation (award no.REC-005) and the Russian Foundation for Basic Research (grant no. 00-03-32785a). References 1 I. Segawa, M. Kitano, K. Kazuno, M. Tsuda, I. Shirahase, M. Ozaki, M. Matsuda and M. Kise, J.Heterocycl. Chem., 1992, 29, 1117. 2 D. T. W. Chu and A. K. Claiborne, J. Heterocycl. Chem., 1987, 24, 1537. 3 Y. Ito, H. Kato, S. Yasuda, N. Yagi, T. Yoshida and T. Suzuki, Japanese Patent, 117388, C07d, 1992 (Chem. Abstr., 1992, 117, 111597d). 4 G. A. Mokrush ina, E. V. Nosova, G.N. Lipunova and V. N. Ch arushin, Zh. Org. Khim., 1999, 35, 1447 (Russ. J. Org. Chem., 1999, 35, 1413). 5 M. C. Sch roeder and I. S. Kiely, J. Heterocycl. Chem., 1988, 25, 1769. 6 O. N. Chupakhin, Y. A. Azev, S. G. Alekseev, S. V. Shorshnev, E. V. Tsoi and V. N. Charushin, Mendeleev Commun., 1992, 151. 7 D. Barrett, H. Sasaki, T. Kinoshita and K. Sakane, Chem. Commun., 1996, 61. 8 D. Barrett, H. Sasaki, T. Kinoshita, A. Fujikawa and K. Sakane, Tetrahedron, 1996, 52, 8471. Scheme 2 Reagents and conditions: i, DMF, NaH, room temperature, 24 h; ii, H2O, pH 7 (6% HCl).N F F X Y O COOEt COOEt N F F X Y O O O H H Há Hâ H O O Me O O 1 2 3 4 5 6 3a 5a 7 8 9 9a 10 11 12 13 14 15 16 17 18 H2C Me COOMe 1a–c 2a–c a X = Y = H b X = H, Y = F c X = Y = F i, ii Compounds 2b,c were obtained analogously. 2b (major isomer): yield 0.145 g (32%), mp 106–107 °C. 1H NMR, d: 1.23 (t, 3H, Me, 3J 7.1 Hz), 1.32 (t, 3H, Me, 3J 7.1 Hz), 1.32 (s, 3H, Me), 1.80 (dd, 1H, 2-Há, 2J2-Há,2-Hâ 13.4 Hz, 3J2-Há,1-H 6.3 Hz), 3.11 (dd, 1H, 2-Hâ, 2J2-Hâ,2-Há 13.4 Hz, 3J2-Hâ,1-H 9.5 Hz), 3.55 (d, 1H, 4-H, 3J4-H,3a-H 14.5 Hz), 3.71 (s, 3H, COOMe), 4.18 (q, 2H, OCH2, 3J 7.1 Hz), 4.25 (d, 1H, 3a-H, 3J3a-H,4-H 14.5 Hz), 4.29 (q, 2H, OCH2, 3J 7.1 Hz), 4.95 (dd, 1H, 1-H, 3J1-H,2-Há 6.3 Hz, 3J1-H,2-Hâ 9.5 Hz), 7.46 (ddd, 1H, 6-H, 3J6-H, 7-F 9.9 Hz, 4J6-H,8-F 8.1 Hz, 5J6-H,9-F 2.1 Hz). 19F NMR, d: 148.33 (dd, 7-F, 3J7-F,8-F 22.0 Hz, 3J7-F,6-H 9.8 Hz), 149.35 (ddd, 8-F, 3J8-F,7-F 22.0 Hz, 3J8-F,9-F 17.1 Hz, 4J8-F,6-H 8.3 Hz), 151.60 (ddd, 9-F, 3J9-F,8-F 17.1 Hz, 4J9-F,7-F 6.8 Hz, 5J9-F,6-H 2.4 Hz). MS, m/z: 457 (M+, 10%), 384 (100), 338 (15), 306 (20), 285 (25), 252 (25), 238 (30).For 2c (major isomer): yield 0.155 g (33%), mp 104–105 °C. 1H NMR, d: 1.27 (t, 3H, Me, 3J 7.1 Hz), 1.35 (t, 3H, Me, 3J 7.1 Hz), 1.35 (s, 3H, Me), 1.81 (dd, 1H, 2-Há, 2J2-Há,2-Hâ 13.4 Hz, 3J2-Há,1-H 6.7 Hz), 3.11 (dd, 1H, 2-Hâ, 2J2-Hâ,2-Há 13.4 Hz, 3J2-Hâ,1-H 9.2 Hz), 3.61 (d, 1H, 4-H, 3J4-H, 3a-H 14.0 Hz), 3.74 (s, 3H, OMe), 4.26 (q, 2H, OCH2, 3J 7.1 Hz), 4.28 (q, 1H, 3a-H, 3J3a-H,4-H 13.7 Hz), 4.38 (q, 2H, OCH2, 3J 7.1 Hz), 5.01 (dd, 1H, 1-H, 3J1-H,2-Há 6.7 Hz, 3J1-H,2-Hâ 9.5 Hz). 19F NMR, d: 141.86 (m, 1F), 147.26 (m, 1F), 158.56 (m, 1F), 172.59 (m, 1F). MS, m/z: 475 (M+, 10%), 402 (100), 388 (18), 374 (15), 296 (15), 270 (18), 256 (28). Scheme 3 Homonuclear 1H–1H Overhauser effects for compounds 2a and 2b. EtOOC N F F H O COOEt H H Há Hâ H COOMe CH3 1 2 3 4 3a 2a 1% 4% 4% 6% EtOOC N F F F O COOEt H H Há Hâ H COOMe CH3 1 2 3 4 3a 2b 1% 4% 5% 5% 2% 6% Received: 18th May 2000; Com. 00/1649