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

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.

pyridazinone - ene-adducts - palladium - catalysis

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 

12 Sotelo E. Raviña E. Synlett  2002,  223 

13a Zára-Kaczián E. Mátyus P. Heterocycles  1993,  36:  519 

13b Haider N. Heinisch G. J. Chem. Soc., Perkin Trans. 1  1988,  401 

13c Haider N. Geinisch G. Heterocycles  1989,  29:  1309 

14 Greene T. Wuts GPM. Protective Groups in Organic Synthesis   3rd ed.:  Wiley; New York: 1999.  p.632 

15 Sotelo E. Coelho A. Raviña E. Tetrahedron Lett.  2001,  42:  8633 

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.

17 Ripoll J. Vallé Y. Synthesis  1993,  3:  659 

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).