Mendeleev Communications Electronic Version, Issue 4, 1998 (pp. 129–168) 1,3,4-Oxa(thia)diazino [i,j]-annelated quinolines: a new type of key intermediate in the synthesis of tricyclic fluoroquinolones Galina N. Lipunova, Emiliya V. Nosova, Valerii N. Charushin,* Larisa P. Sidorova and Olga M. Chasovskikh Department of Organic Chemistry, Urals State Technical University, 620002 Ekaterinburg, Russian Federation.Fax: +7 3422 44 0458; e-mail: mike@htf.ustu.ru The synthesis of new derivatives of 1,3,4-oxa(thia)diazino[6,5,4-i,j]quinolines, which have a structure that is very similar to the ofloxacin skeleton, by intramolecular cyclizations of ethyl 3-(R-carbonylhydrazino)- and 3-(R-thiocarbonylhydrazino)-substituted 2-polyfluorobenzoyl acrylates, is described. 6-Fluoroquinolones are a well-known class of fully synthetic antibacterials.During the last decade an enormous amount of data on their structural modifications have been accumulated in the literature.1–4 Condensed derivatives of 6-fluoro-4-oxo- 1,4-dihydroquinoline-3-carboxylic acid are of special interest since some of them possess not only antibacterial, but also antiviral and anticancer activity.1,5–7 The most important representatives of condensed fluoroquinolones are ofloxacin and its active enantiomer levofloxacin which are characterized chemically by a tricyclic structure of 7-oxo-2,3-dihydro- 7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid.2–4 We have recently described a new approach to the synthesis of pentacyclic fluoroquinolones which is based on intramolecular cyclizations of 3-(azol-2-yl)hydrazino substituted 2-(polyfluorobenzoyl) acrylates.8,9 In continuation of our studies on the reactions of 3-hydrazino substituted 2-(polyfluorobenzoyl)- acrylates we wish to report on the synthesis of novel derivatives of 9,10-difluoro-7-oxo-7H-pyrido[1,2,3-d,e][1,3,4]-benzoxa(thia)- diazine-6-carboxylic acids.These tricyclic 1,3,4-oxadiazinoand 1,3,4-thiadiazino[6,5,4-i,j] annelated quinolines have a very similar skeleton to ofloxacin and can be regarded as aza- and thia-analogues.Moreover, derivatives of 1,3,4-thiadiazino[i,j] fused quinolines represent a new heterocyclic system, and seem to be a new type of key intermediate in the synthesis of tricyclic fluoroquinolones. We have found that heating ethyl 3-hydrazino-2-polyfluorobenzoyl acrylates 1a–h, bearing pyridin-3-carbonyl, pyridin- 4-carbonyl or cycloalkylaminocarbonyl substituents at N(2), in toluene or acetonitrile in the presence of KF for 1–3 h, is sufficient to cause nucleophilic displacement of two fluorine atoms, thus affording derivatives of 7-oxo-7H-pyrido[1,2,3- d,e][1,3,4]-benzoxa(thia)diazine-6-carboxylic acids 3a–h in 48–87% yields (Scheme 1).† Starting materials 1a–h were obtained in high yields (70–90%) from the reaction of ethyl 3- ethoxy-2-[tetra(penta)fluorobenzoyl]acrylates with hydrazides of nicotinic or isonicotinic acids and cycloalkylaminosubstituted thiosemicarbazides in dry toluene or ethanol at room temperature.All compounds 1a–h gave satisfactory elemental analysis, NMR and mass spectroscopic data.Tricyclic compounds 3a–h are formed through the intermediate bicyclic fluoroquinolones 2a–h. This path is substantiated by 1H and 19F NMR studies which revealed the formation of mixtures of 2a–d and 3a–d during the course of the reaction. Individual quinolone 2a (X = H, Y = O, R = pyridin-4-yl) could be isolated in 40% yield only in one case, i.e. on heating acrylate 1a in toluene for 1 h.‡ Refluxing 2a in toluene for 2 h gave tricyclic derivative 3a in 85% yield.However, we failed to obtain compounds 2e–h since their cyclizations into tricyclic quinolones 3e–h proceed much faster than those of 1a–d. X F F F F O COOEt NHNH C R Y – HF 1a–h X F F F N O COOEt C R Y 2a–h NH – HF X F F Y N O COOEt 3a–h N R a X = H, Y = O, R = pyridin-4-yl b X = H, Y = O, R = pyridin-3-yl c X = F, Y = O, R = pyridin-4-yl d X = F, Y = O, R = pyridin-3-yl e X = H, Y = S, R = hexamethylenimin-1-yl f X = H, Y = S, R = pyrrolidin-1-yl g X = F, Y = S, R = hexamethylenimin-1-yl h X = F, Y = S, R = pyrrolidin-1-yl Scheme 1 C(13) C(12) C(11) C(10) C(9) C(8) C(7) C(6) C(5) C(4) C(3) C(2) C(1) S(1) N(1) N(2) N(3) F(1) F(2) F(3) O(1) O(2) O(3) C(14) C(15) C(16) C(17) C(18) C(19) Figure 1 Molecular structure of compound 3g.Numeration of atoms does not correspond to the IUPAC nomenclature. Selected bond lengths/Å and angles/° for compound 3g: S(1)–C(1) 1.77(1), S(1)–C(3) 1.74(1), F(1)– C(4) 1.35(1), F(2)–C(5) 1.33(1), F(3)–C(6) 1.34(1), O(1)–C(8) 1.24(1), N(1)–C(1) 1.27(1), N(2)–C(2) 1.40(1), N(2)–C(10) 1.34(1), N(3)–C(1) 1.38(1), C(2)–C(3) 1.42(1), C(2)–C(7) 1.40(1), C(3)–C(4) 1.40(1), C(4)– C(5) 1.38(1), C(5)–C(6) 1.35(1), C(6)–C(7) 1.42(1), C(7)–C(8) 1.49(1), C(8)–C(9) 1.46(1), C(9)–C(10) 1.37(1), C(9)–C(11) 1.49(1); C(1)–S(1)– C(3) 99.1(5), C(2)–N(2)–C(10) 120.1(7), C(1)–N(3)–C(14) 123.3(8), S(1)– C(1)–N(1) 128.7(7), S(1)–C(1)–N(3) 113.1(7), N(1)–C(1)–N(3) 118.1(9), N(2)–C(2)–C(3) 118.5(8), N(2)–C(2)–C(7) 119.4(8), C(3)–C(2)–C(7) 122.1(8), S(1)–C(3)–C(2) 125.3(7), S(1)–C(3)–C(4) 118.5(7), C(2)–C(3)– C(4) 116.1(9), F(1)–C(4)–C(3) 116.4(9), F(1)–C(4)–C(5) 120.3(9), C(3)– C(4)–C(5) 123.2(9), F(2)–C(5)–C(4) 117.8(9), F(2)–C(5)–C(6) 123.2(9), C(4)–C(5)–C(6) 119.0(9), F(3)–C(6)–C(5) 116.0(8), F(3)–C(6)–C(7) 121.4(8), C(5)–C(6)–C(7) 122.5(9), C(2)–C(7)–C(6) 116.9(8), C(2)– C(7)–C(8) 122.4(8), C(6)–C(7)–C(8) 120.7(8), O(1)–C(8)–C(7) 122.1(9), O(1)–C(8)–C(9) 124.6(9), C(7)–C(8)–C(9) 113.3(8), C(8)–C(9)–C(10) 120.3(8), C(8)–C(9)–C(11) 125.7(8), C(10)–C(9)–C(11) 114.0(8), N(2)– C(10)–C(9) 124.5(8).Mendeleev Communications Electronic Version, Issue 4, 1998 (pp. 129-168) Evidence for the structure of compounds 3a–h is provided by 1H, 19F NMR and mass spectroscopic data, as well as by the X-ray analysis performed for the compound 3g.§ X-Ray analysis of compound 3g¶ revealed that it represents a fused tricyclic system bearing three fluorine atoms, ethoxycarbonyl and azacycloheptane substituents (Figure 1).The † General procedure for the synthesis of 9,10-difluoro-7-oxo- 7H-2-[pyridin-3(4)-yl]pyrido[1,2,3-d,e][1,3,4]-benzoxa(thia)diazine-6- carboxylic acid 3a–d: (a) A solution of ethyl 3-[(pyridin-4-yl)- hydrazido]-2-(tetrafluorobenzoyl)acrylate 1a (0.5 g, 1.2 mmol) in dry toluene (20 ml) was kept under reflux for 2 h.The reaction solution was filtered at the end of the reaction. The filtrate was evaporated and the precipitate obtained was recrystallized from propan-2-ol to yield 3a (0.25 g, 56%), mp 244–246 °C. 1H NMR ([2H6]DMSO) d: 1.30 (t, 3H, Me), 4.23 (q, 2H, OCH2CH3), 7.63 (dd, 1H, 8-H, 3J 11 Hz, 4J 7.5 Hz), 7.88 (dd, 2H, 2',6'-H, 3J 4.5 Hz, 4J 1.5 Hz), 8.56 (s, 1H, 5-H), 8.85 (dd, 2H, 3',5'-H, 3J 4.5 Hz, 4J 1.5 Hz); 19F NMR ([2H6]DMSO) d: 154.24 (dd, 1F, 10-F, 3JFF 22 Hz, 4JFH 7.5 Hz), 134.51 (dd, 1F, 9-F, 3JFF 22 Hz, 3JFH 11 Hz); m/z: 371 (50%, M+), 326 (51), 299 (100). 3b, mp 216–218 °C (propan-2-ol). 1H NMR ([2H6]DMSO) d: 1.30 (t, 3H, Me), 4.23 (q, 2H, OCH2CH3), 7.64 (dd, 1H, 8-H, 3J 10.4 Hz, 4J 7.6 Hz), 7.67 (ddd, 1H, 5'-H, 3J5'-H,6'-H 8.1 Hz, 3J5'-H,4'-H 4.9 Hz, 5J5'-H,2'-H 0.8 Hz), 8.32 (ddd, 1H, 6'-H, 3J6'-H,5'-H 8.1 Hz, 4J6'-H,4'-H 2.3 Hz, 4J6'-H,2'-H 1.5 Hz), 8.57 (s, 1H, 5-H), 8.85 (dd, 1H, 4'-H, 3J4'-H,5'-H 4.9 Hz, 4J4'-H,6'-H 2.3 Hz), 9.14 (dd, 1H, 2'-H, 5J2'-H,5'-H 0.8 Hz, 4J2'-H,6'-H 1.5 Hz); 19F NMR ([2H6]DMSO) d: 154.24 (dd, 1F, 10-F, 3JFF 22 Hz, 4JFH 7.6 Hz), 134.66 (dd, 1F, 9-F, 3JFF 22 Hz, 3JFH 10.4 Hz); m/z: 371 (82%, M+), 326 (73), 299 (100). 3c, mp 238–240 °C (acetonitrile). 1H NMR ([2H6]DMSO) d: 1.28 (t, 3H, Me), 4.22 (q, 2H, OCH2CH3), 7.85 (dd, 2H, 2',6'-H, 3J 4.6 Hz, 4J 1.5 Hz), 8.47 (s, 1H, 5-H), 8.84 (dd, 2H, 3',5'-H, 3J 4.6 Hz, 4J 1.5 Hz); 19F NMR ([2H6]DMSO) d: 160.59 (dd, 1F, 9-F, 3J 20.2 Hz, 3J 21.4 Hz), 151.43 (dd, 1F, 10-F, 3J 21.4 Hz, 4J 6.0 Hz), 146.19 (dd, 1F, 8-F, 3J 20.2 Hz, 4J 6.0 Hz); m/z: 389 (40%, M+), 344 (45), 317 (100), 240 (36), 213 (34), 185 (34). (b) A solution of 1d (0.5 g, 1.17 mmol) and KF (0.14 g, 2.33 mmol) in acetonitrile (10 ml) was kept under reflux for 2 h.The precipitate of 3d obtained after cooling the reaction solution to room temperature was filtered off, washed with water and recrystallized from ethanol (0.35 g, 76%), mp 226–228 °C. 1H NMR ([2H6]DMSO) d: 1.29 (t, 3H, Me), 4.23 (q, 2H, OCH2CH3), 7.65 (ddd, 1H, 5'-H, 3J5'-H,6'-H 8.1 Hz, 3J5'-H,4'-H 4.8 Hz, 5J5'-H,2'-H 0.9 Hz), 8.32 (ddd, 1H, 6'-H, 3J6'-H,5'-H 8.1 Hz, 4J6'-H,4'-H 2.3 Hz, 4J6'-H,2'-H 1.5 Hz), 8.50 (s, 1H, 5-H), 8.86 (dd, 1H, 4'-H, 3J4'-H,5'-H 4.8 Hz, 4J4'-H,6'-H 2.3 Hz), 9.12 (dd, 1H, 2'-H, 5J2'-H,5'-H 0.9 Hz, 4J2'-H,6'-H 1.5 Hz); 19F NMR ([2H6]DMSO) d: 160.77 (dd, 1F, 9-F, 3J 20.2 Hz, 3J 21.3 Hz), 151.42 (dd, 1F, 10-F, 3J 21.3 Hz, 4J 5.5 Hz), 146.31 (dd, 1F, 8-F, 3J 20.2 Hz, 4J 5.5 Hz); m/z: 389 (34%, M+), 344 (30), 317 (100), 240 (29), 213 (33), 185 (27).General procedure for the synthesis of 2R-substituted ethyl 9,10-difluoro-8-X-7-oxo-7H-pyrido[1,2,3-d,e][1,3,4]-benzothiadiazine- 6-carboxylates 3e–h.A solution of 1f (0.8 g, 1.9 mmol) in dry toluene (10 ml) was kept under reflux for 1 h. The precipitate of 3f obtained after cooling the reaction solution to room temperature was filtered off and recrystallized from DMSO (0.36 g, 48%), mp 250–251 °C. 1H NMR ([2H6]DMSO) d: 1.29 (t, 3H, Me), 1.85–2.10 (m, 4H, 3',4'-H), 3.40–3.65 (m, 4H, 2',5'-H), 4.24 (q, 2H, OCH2CH3), 7.80 (dd, 1H, 8-H, 3J 10.8 Hz, 4J 8.5 Hz), 8.37 (s, 1H, 5-H); 19F NMR ([2H6]DMSO) d: 137.8 (dd, 1F, 9-F, 3JFF 22.3 Hz, 3JFH 10.8 Hz), 132.2 (dd, 1F, 10-F, 3JFF 22.3 Hz, 4JFH 8.5 Hz); m/z: 379 (73%, M+), 334 (15), 308 (17), 307 (100), 238 (25). 3e, mp 172–175 °C (acetone). 1H NMR ([2H6]DMSO) d: 1.29 (t, 3H, Me), 1.69–1.73 (m, 4H, 4',5'-H), 1.73–1.90 (m, 4H, 3',6'-H), 3.56–3.70 (m, 4H, 2',7'-H), 4.24 (q, 2H, OCH2CH3), 7.78 (dd, 1H, 8-H, 3J 10.8 Hz, 4J 9.0 Hz), 8.37 (s, 1H, 5-H); 19F NMR ([2H6]DMSO) d: 137.8 (dd, 1F, 9-F, 3JFF 23.5 Hz, 3JFH 10.8 Hz), 132.1 (dd, 1F, 10-F, 3JFF 23.5 Hz, 4JFH 9.0 Hz); m/z: 407 (100%, M+), 362 (22), 335 (86), 265 (11), 238 (49). 3g, mp 171–173 °C (acetone). 1H NMR ([2H6]DMSO) d: 1.28 (t, 3H, Me), 1.61–1.75 (m, 4H, 4',5'-H), 1.75–1.90 (m, 4H, 3',6'-H), 3.56–3.70 (m, 4H, 2',7'-H), 4.22 (q, 2H, OCH2CH3), 8.33 (s, 1H, 5-H); 19F NMR ([2H6]DMSO) d: 162.41 (dd, 1F, 9-F, 3J9-F,8-F 20.2 Hz, 3J9-F,10-F 23.2 Hz), 140.93 (dd, 1F, 8-F, 3J8-F,9-F 20.2 Hz, 4J8-F,10-F 9.8 Hz), 129.63 (dd, 1F, 10-F, 3J10-F,9-F 23.2 Hz, 4J10-F,8-F 9.8 Hz); m/z 425 (100%, M+), 380 (15), 353 (67), 283 (11), 256 (57). 3h, mp 230–231 °C (ethanol). 1H NMR ([2H6]DMSO) d: 1.28 (t, 3H, Me), 1.85–2.01 (m, 4H, 3',4'-H), 3.40–3.57 (m, 4H, 2',5'-H), 4.22 (q, 2H, OCH2CH3), 8.24 (s, 1H, 5-H); 19F NMR ([2H6]DMSO) d: 163.69 (dd, 1F, 9-F, 3J9-F,8-F 20.4 Hz, 3J9-F,10-F 23.2 Hz), 142.12 (dd, 1F, 8-F, 3J8-F,9-F 20.4 Hz, 4J8-F,10-F 9.3 Hz), 131.05 (dd, 1F, 10-F, 3J10-F,9-F 23.2 Hz, 4J10-F,8-F 9.3 Hz); m/z 397 (63%, M+), 352 (12), 324 (100), 256 (24).tricyclic system is nearly planar, the dihedral angle between planes of the quinoline fragment and the fused six-membered thiadiazine ring being 3.1°. The azacycloheptane fragment adopts a chair conformation, with the N(3), C(14), C(16) and C(17) atoms almost coplanar and deviations of the C(15), C(18) and C(19) atoms from this average plane of –0.64, 0.89 and 1.17 Å, respectively. References 1 Quinolone Antibacterial Agents, eds.D. C. Hoope and J. S. Wolfson, ASM, Washington, 1993. 2 D. Bouzard, in Antibiotics and Antiviral Compounds, eds. K. Krohn, H. A. Rirst and H. Maag, VCH, Weinheim, 1993. 3 G. A. Mokrushina, V. N. Charushin and O.N. Chupakhin, Khim.- Pharm. Zh., 1995, 9, 5 (in Russian). 4 U. Petersen, S. Bartel, K.-D. Bremm, T. Himmler, A. Krebs and T. Schenke, Bull. Soc. Chim. Belg., 1996, 105, 683. 5 S. Schneider, M. Ruppelt, M. Schriewer, T. J. Schulze and R. Neumann, European Pat. 563,734, C07D (Chem. Abstr., 1994, 120, 134497x). 6 D. T. W. Chu, R. Hallas, J. J. Clement, J. J. Alder, E. McDonald and J.J. Platner, Drugs Expl. Clin. Res., 1992, 18, 275. 7 D. J. Dorgan and D. W. Gottschall, GB Pat., 27,201,C07D (Chem. Abstr., 1997, 127, 176444c). 8 G. N. Lipunova, G. A. Mokrushina, E. V. Nosova, L. I. Rusinova and V. N. Charushin, Mendeleev Commun., 1997, 109. 9 E. V. Nosova, G. N. Lipunova, G. A. Mokrushina, O. M. Chasovskikh, L. I. Rusinova, V. N. Charushin and G. G. Alexandrov, Zh.Org. Khim., 1998, 34, 436 (in Russian). ‡ Ethyl 1-(pyridin-4-carbonyl)amino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinolin- 3-carboxylate 2a. A solution of ethyl 3-[2-(pyridin-4-carbonyl)- hydrazino-1]-2-(tetrafluorobenzoyl)acrylate 1a (0.8 g, 1.9 mmol) in dry toluene (12 ml) was refluxed for 1 h. The reaction solution was then immediately filtered, evaporated and the precipitate obtained recrystallized from propan-2-ol to yield quinolone 2a (0.3 g, 40%), mp 142–144 °C. 1H NMR ([2H6]DMSO) d: 1.30 (t, 3H, Me), 4.26 (q, 2H, OCH2CH3), 7.87 (dd, 2H, 2',6'-H, 3J 4.4 Hz, 4J 1.5 Hz), 8.04 (ddd, 1H, 5-H, 3JHF 10.2 Hz, 4JHF 8.0 Hz, 5JHF 2.1 Hz), 8.81 (s, 1H, 2-H), 8.87 (dd, 2H, 3',5'-H, 3J 4.4 Hz, 4J 1.5 Hz); 19F NMR ([2H6]DMSO) d: 151.13 (ddd, 1F, 7-F, 3J7-F,6-F 23.2 Hz, 3J7-F,8-F 19.2 Hz, 4JFH 8.0 Hz), 148.66 (ddd, 1F, 8-F, 3J8-F,7-F 19.2 Hz, 4J8-F,6-F 4.6 Hz, 5JFH 2.1 Hz), 136.32 (ddd, 1F, 6-F, 3J6-F,7-F 23.2 Hz, 3JFH 10.2 Hz, 4J6-F,8-F 4.6 Hz).§ The authors would like to thank Dr. G. Alexandrov for the X-ray analysis. ¶ Experimental X-ray crystallographic data for 3g were obtained on a Syntex-P21 diffractometer (l MoKa, graphite monochromator, q/2qscan, 2qmax = 60°). The structure was solved by a direct method and refined by a full-matrix least-squares method in an anisotropic approximation using programs SHELX-93 to R = 0.076 (wR2 = 0.187) for 2128 independent reflections with F2 > 3s(I); GOOF = 1.203. Empirical formula C19H18F3N3O3S, monoclinic crystals, space group P21/c, a = 6.913(5) Å, b = 12.532(8) Å, c = 21.32(2) Å, b = 91.06(6)°, V = 1847(3) Å3, dcalc = 1.530 g cm–3, Z = 4, m = 0.232mm–1. Full lists of bond angles, bond lengths and thermal parameters have been deposited at the Cambrige Crystallographic Data Centre (CCDC). For detail, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 1998. Any request to the CCDC should quote full literature citation and the reference number 1135/27. Received: Moscow, 19th May 1998 Cambridge, 18th June 1998; Com. 8/04513E