Synlett 2002(12): 2062-2064
DOI: 10.1055/s-2002-35567
LETTER
© Georg Thieme Verlag Stuttgart · New York

Pyridazines. Part 30: [1] Palladium-Catalysed Synthesis of 5-Substituted 6-Phenyl-3(2H)-pyridazinones Asissted by a Retro-Ene Transformation

Alberto Coelho, Enrique Raviña, Eddy Sotelo*
Laboratorio de Química Farmacéutica, Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, España
Fax: +34(98)1594912; e-Mail: [email protected];
Further Information

Publication History

Received 25 September 2002
Publication Date:
20 November 2002 (online)

Abstract

The efficient one-pot functionalization, through pal­ladium-catalysed reactions, of position 5 of the 6-phenyl-3(2H)-pyridazinone system has been performed using a retro-ene-assisted fragmentation. This route allows access through a short synthetic sequence to several pharmacologically useful 3(2H)-pyridazinones.

    References

  • 1 For the previous paper in this series, see: Sotelo E. Fraiz N. Yañez M. Terrades V. Laguna R. Cano E. Raviña E. Bioorg. Med. Chem.  2002,  10:  2873 
  • 2 Frank H. Heinisch G. Pharmacologically Active Pyridazines, In Progress in Medicinal Chemistry   27:  Ellis GP. West GB. Elsevier; Amsterdam: 1990.  p.1-49  
  • 3 Raviña E. García-Mera G. Santana L. Orallo F. Calleja JM. Eur. J. Med. Chem.  1985,  20:  475 
  • 4 Raviña E. Terán C. Dominguez N. Masaguer CF. Arch. Pharm. (Weinheim)  1991,  324:  455 
  • 5 Gil Longo J. Laguna R. Verde I. Castro M. Orallo F. Fontenla J. Calleja JM. Raviña E. Terán C. J. Pharm. Sci.  1993,  82:  286 
  • 6 Laguna R. Montero A. Cano E. Raviña E. Sotelo E. Estévez I. Acta Pharmaceutica Hungarica  1996,  66:  S43 ; Chem. Abstr. 1997, 126, 165993
  • 7 Laguna R. Rodriguez-Liñares B. Cano E. Estévez I. Raviña E. Sotelo E. Chem. Pharm. Bull.  1997,  45:  1151 
  • 8 Montero-Lastres A. Fraiz N. Cano E. Laguna R. Estévez I. Raviña E. Biol. Pharm. Bull.  1999,  22:  1376 
  • 9 Sotelo E. Fraiz N. Yañez M. Laguna R. Cano E. Brea J. Raviña E. Bioorg. Med. Chem. Lett.  2002,  10:  1575 
  • 10 Estévez I. Coelho A. Raviña E. Synthesis  1999,  1666 
  • 11 Coelho A. Sotelo E. Estévez I. Raviña E. Synthesis  2001,  871 
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16

Representative Procedure for Preparation of Compound 2. A mixture of 1 (2.64 g, 0.105 mmol) and 35% formaldehyde (0.828 mL, 0.105 mmol) was flushed with argon for 5 min. The suspension was stirred and heated under reflux (oil bath 110 °C) under argon until the starting material had disappeared (24 h). The mixture was cooled and the suspension was concentrated to dryness under reduced pressure. The obtained solid was purified by column chromatography on silica gel (EtOAc-hexanes, 1:2). Physical and spectral data for compound 2: Yield: 89%, mp 237-238 °C. IR (KBr): 3100-3000, 1642 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 7.55-7.40 (m, 5 H, Ph), 5.58 (d,
J = 8.1 Hz, 2 H, CH2), 4.74 (t, J = 8.1 Hz, 1 H, OH).
13C NMR (CDCl3, 300 MHz): δ = 159.6, 147.0, 134.9, 133.4, 131.7, 130.0, 129.6, 128.6, 77.1. HRMS (Autospec Micromass): m/z calcd for C11H9 BrN2O2 (M+): 279.9847. Found: 279.9859.

18

Representative Procedure for Suzuki Arylations on Compound 2. A mixture of 2 (0.45 g, 1.6 mmol), arylboronic acid (1.6 mmol), Pd(PPh3)4 (0.036 g, 0.032 mmol) and Na2CO3 (0.67 g, 6.4 mmol) in 18 mL of 3:1 DME-H2O was flushed with argon for 5 min. The mixture was stirred and heated under reflux (oil bath 120 °C) under argon until the starting material had disappeared. The mixture was cooled and the solution was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel.

19

Representative Procedure for Sonogashira Couplings on Compound 2. A mixture of 2 (0.28 g, 1.0 mmol), acetylene derivative (1.5 mmol), Pd(PPh3)2Cl2 (0.03 g, 0.01 mmol), CuI (0.01 g, 0.01 mmol) and anhyd triethylamine (0.282 mL, 2.0 mmol) in 10 mL of DMF was flushed with argon for
5 min. The reaction mixture was stirred and heated (oil bath 55 °C) under argon until the starting material had dis-appeared. The reaction mixture was cooled and the solution was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel.

20

Selected Physical and Spectral Data for Representative Compounds 3. 3a: Yield: 90%. IR (KBr): 3100-2923, 1668, 1589 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 11.58 (br s, 1 H, NH), 7.38-7.20 (m, 10 H, phenyl), 7.01 (s, 1 H, H4). 3b: Yield: 78%., IR (KBr): 3500-2924, 1642 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 11.40 (br s, 1 H, NH), 7.41-7.29 (m, 5 H, phenyl), 7.18 (d, J = 8.0 Hz, 2 H, phenyl), 7.06 (d, J = 8.0 Hz, 2 H, phenyl), 7.01 (s, 1 H, H4), 2.33 (s, 3 H, CH3). 3c: Yield: 78%. IR (KBr): 3500-2924, 1642 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 11.65 (br s, 1 H, NH), 7.40-7.30 (m, 5 H, Arom), 7.16 (d, J = 8.4 Hz, 2 H, Arom), 7.05 (d, J = 8.4 Hz, Arom), 6.97 (s, 1 H, H4). 3e: Yield: 70%. IR (KBr): δ = 3000-3100, 2136, 1654 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 12.46 (br s, 1 H), 7.73 (m, 2 H, Arom), 7.42 (m, 3 H, Arom), 7.13 (s, 1 H), 0.16 (s, 9 H, 3 × CH3). 3f: Yield: 86%. IR (KBr): 3100, 1680 cm-1. 1H NMR (MeOD, 300 MHz): δ = 13.18 (br s, 1 H, NH), 7.75 (m, 2 H, Arom), 7.47 (m, 3 H, Arom), 7.16 (s, 1 H, H4), 4.35 (s, 2 H, CH2), 3.34 (t, 1 H, J = 1.6 Hz, OH). 3g: Yield: 81%. IR (KBr): 3246-2885, 2236, 1667, 1053 cm-1. 1H NMR (MeOD, 300 MHz): δ = 12.40 (br s, 1 H, NH), 7.70-7.64 (m, 2 H, Arom), 7.42-7.37 (m, 3 H, Arom), 7.17 (s, 1 H, H4), 5.35 (s, 1 H, CH), 3.52 (m, 4 H, 2 × OCH2), 1.15 (m, 6 H, 2 × CH3). 3h: Yield: 86%. IR (KBr): 1669, 1092 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 12.68 (br s, 1 H, NH), 7.43 (m, 5 H, Arom), 7.11 (s, 1 H, H4), 6.45 (dd, 1 H, J = 10.9, 17.2 Hz, CH=CH2), 5.87 (d, 1 H, J = 17.2 Hz, CH=CH2), 5.50 (d, 1 H, J = 10.9 Hz, CH=CH2).