Pyridazines. Part 26: [1] Efficient and Regioselective Pd-Catalysed Arylation of 4-Bromo-6-chloro-3-phenylpyridazine

Abstract

The regioselective arylation at position 4 of 4-bromo-6-chloro-3-phenylpyridazine has been performed using a Suzuki cross-coupling reaction. This route allows access to a wide-ranging series of pharmacologically useful pyridazine derivatives and confirms the usefulness of chloropyridazines as a masking group for the carbonyl moiety in cross-coupling reactions involving 5-bromo-3(2H)-pyridazinones.

arylations - palladium - catalysis - pyridazine

References

1 For the previous paper in this series, see: Efficient and selective deprotection of phar-macologically useful 2-MOM-pyridazinones using Lewis acids in: Sotelo E. Coelho A. Raviña E. Tetrahedron Lett.   2001.  43:  p.8633 

2a Frank H. Heinisch G. In Pharmacologically Active Pyridazines Part 1, Progressing Medicinal Chemistry   Ellis GP. West GB. Elsevier; Amsterdam: 1990.  p.271 

2b Frank H. Heinisch G. In Pharmacologically Active Pyridazines Part 2, Progress in Medicinal Chemistry   Chap. 29:  Ellis GP. Luscombe DK. Elsevier; Amsterdam: 1992.  p.141 

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11 Minato A. Suzuki K. Tamao K. Kumada M. J. Chem. Soc., Chem. Commun.  1984,  511 

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18 Coelho A. Sotelo E. Estevez I. Raviña E. Synthesis  2001,  6:  871 

19

4-Bromo-6-chloro-3-phenylpyridazine 2: 89%, mp: 111-112 °C (dec.), iso-PrOH. IR (KBr): 1590, 1480 cm^-1. ¹H NMR (DMSO-d₆, 300 MHz): 8.44 (s, 1 H, CH), 7.70 (m, 2 H, Aromatics), 7.54 (m, 3 H, Aromatics) ppm.

20 Suzuki A. In Recent Advances in the Cross-coupling Reactions of Organoboron Deri-vatives with Organic Electrophiles, Perspectives in Organopalladium Chemistry for the XXI Century   Tsuji J. Elsevier; Amsterdam: 1999.  p.145 

21

Cross-coupling Reactions, General Procedure: 5-Bromo-3-chloro-6-phenylpyridazine 2 (0.25 g, 0.93 mmol) was mixed with the arylboronic acid (0.93 mmol), Pd(PPh₃)₄ (5 mg, 0.006 mmol) and Na₂CO₃ (0.49 g, 5.08 mmol) in 30 mL of a 3:1 mixture of DME-H₂O. The mixture was flushed with argon for 5 min and then stirred and heated at reflux (oil bath 90 °C) under argon until the starting material had disappeared (8-12 h). The mixture was allowed to cool and concentrated to dryness under reduced pressure. The residue was extracted into CH₂Cl₂ (3 × 20 mL), dried (Na₂SO₄) and then purified by column chromatography on silica gel to afford the 6-chloropyridazines 3, which were recrystallised from the appropriate solvent (Table).
Selected physical and spectral data for compounds 3. 3a: 90%, mp: 111-112 °C (dec.), iso-PrOH. IR (KBr): 1563, 1092, 695 cm^-1. ¹H NMR (DMSO-d ₆, 300 MHz): 8.61 (s, 1 H, CH), 8.23 (m, 2 H, Aromatics), 7.79 (m, 2 H, Aromatics), 7.57 (m, 6 H, Aromatics) ppm. 3b: 95%, mp: 126-127 °C, iso-PrOH. IR (KBr): 1559, 1089, 696 cm^-1. ¹H NMR (DMSO-d ₆, 300 MHz): 8.54 (s, 1 H, CH), 8.14 (d, J = 8.0 Hz, 2 H, Aromatics), 7.76 (m, 2 H, Aromatics), 7.55 (m, 3 H, Aromatics), 7.37 (d, J = 8.0 Hz, 2 H, Aroma tics), 2.38 (s, 3 H, CH₃) ppm. 3d: 95%, mp: 150-152 °C iso-PrOH. IR (KBr): 1560, 1090, 697 cm^-1. ¹H NMR (DMSO-d ₆, 300 MHz): 8.39 (s, 1 H, CH), 8.08 (d, J = 8.8 Hz, 2 H, Aromatics), 7.61 (m, 2 H, Aromatics), 7.41 (m, 3 H, Aromatics), 6.97 (d, J = 8.8 Hz, 2 H, Aromatics), 3.70 (s, 3 H, OCH₃) ppm.

22a Gronowitz S. Lawitz K. Chem. Scr.  1983,  22:  265 

22b Gronowitz S. Stevens MFG. J. Chem. Soc., Perkin Trans. 1  1994,  3311 

23

3(2H)-Pyridazinones 4 were prepared heating at reflux 3a-f in neat acetic acid during 3-7 h. 4a: 86%, mp: 178.5-180.6 °C, Acetonitrile. IR (KBr): 3000, 1668, 1589cm^-1. ¹H NMR (DMSO-d ₆, 300 MHz): 11.58 (bs, 1 H, NH), 7.38-7.20 (m, 10 H Aromatics), 7.01 (s, 1 H, H₄) ppm. 4e: 84%, mp: 235.0-235.5 °C, iso-PrOH. IR (KBr): 3000, 1662, 1580 cm^-1.
¹H NMR (DMSO-d ₆, 300 MHz): 12.05 (bs, 1H, NH), 7.48-7.33 (m, 7 H, 5 H Aromatics + 1 H furan + H₄), 6.28 (dd,
J = 3.5, 1.8 Hz, 1 H, furan), 5.64 (d, J = 3.5 Hz, 1 H; furan) ppm.

24

Aminopyridazines 5 were prepared heating at reflux 3a-f in presence of the appropriate amine (3 equivalents) in ethanol (24-72 h). 3,4-Diphenyl-6-(2-methoxyethylamino)pyrid-azine 5a: 78%, (72 h) mp: 199-201 °C, iso-PrOH. IR (KBr): 3000, 1590 cm^-1. ¹H NMR (DMSO-d ₆, 300 MHz): 7.69-7.21 (m, 10 H, Aromatics), 6.94 (s, 1 H, H₄), 3.64 (t, J = 7.1 Hz, 2 H, CH₂), 3.35 (s, 3 H, CH₃), 3.29 (t, J = 7.1 Hz, 2 H, CH₂) ppm.

25

Hydrazinopyridazines 6 were prepared heating at reflux 3a-f in presence of 3 equivalents of hydrazine hydrate in ethanol (3-4 h). 3,4-Diphenyl-6-hydrazinopyridazine 6a: 89%, mp: 153-155 °C, iso-PrOH. [28] IR (KBr): 3500-300, 1576 cm^-1. ¹H NMR (CDCl₃, 300 MHz): 8.12 (m, 3 H, Aromatics), 7.67 (m, 2 H, Aromatics), 7.54 (s, 1 H, CH), 7.51 (m, 6 H, Aromatics), 6.08 (2, 1 H, NH), 3.48 (s, 2 H, NH₂) ppm.

26

Pyridazines 7 were prepared by reductive dechlorination of 3a-f (HCOONH₄/Pd-C, MeOH). 3,4-diphenylpyridazine 7a: 88%, mp: 106-107 °C, iso-PrOH. [29] IR (KBr): 1590 cm^-1. ¹H NMR (DMSO-d ₆, 300 MHz): 9.21 (d, J = 5.2 Hz, 1 H, CH), 7.50 (d, J = 5.2 Hz, 1 H, CH), 7.46 (m, 10 H, Aromatics) ppm.

27

Complete details of the synthesis and spectral characteristics of the compounds obtained will be published elsewhere in a full paper. All compounds gave satisfactory microanalytical (C, H, N ± 0.4%) and spectral data (¹H, ¹³C, FTIR, MS). Yields given correspond to isolated pure compounds.

28 Abdel-Motti FM. Abdel-Megeid FME. Zaki ME. Shamrokh AH. Egypt. J. Pharm. Sci.  1998,  38:  87 

29 Meresz O. Foster-Verner PA. J. Chem. Soc., Chem. Commun.  1972,  16:  950