Efficient Palladium-catalyzed Amination and Alkylation of 3-Iodo-6-arylpyridazines

Isabelle Parrot; Guillaume Ritter; Camille G. Wermuth; Marcel Hibert

doi:10.1055/s-2002-32595

LETTER

Efficient Palladium-catalyzed Amination and Alkylation of 3-Iodo-6-arylpyridazines

Isabelle Parrot, Guillaume Ritter, Camille G. Wermuth, Marcel Hibert*
Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081 CNRS/ULP, Université Louis Pasteur, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch Cedex, France
Fax: +33(390)244310; e-Mail: mhibert@pharma.u-strasbg.fr;

Abstract

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Abstract

A simple and efficient amination and alkylation of 3-iodo-6-arylpyridazines has been performed using palladium-catalyzed cross coupling reaction. This new route allows access to a wide-ranging series of pharmacologically useful pyridazine derivatives.

Key words

amination - palladium - catalysis - pyridazine

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References

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General Procedure for Amination. Method A: A mixture of 3-iodo-6-arylpyridazine 1 (X = I) (1 equiv), amine 2 (2.4 equiv), and sodium tert-butoxide (1.25 equiv) in dioxane was flushed with argon for 30 min under magnetic stirring. Then, PdCl₂(dppf) (0.05 equiv) and dppf (0.05 equiv) were added and the mixture was heated at 80 °C for 6 h. The dioxane was removed under reduced pressure and the residue was diluted with water, and extracted with EtOAc. The organic layer was washed with brine and concentrated under reduced pressure to give a crude product, which was purified by HPLC.
Method B: The procedure is the same as in Method A except for the amounts of 3-iodo-6-arylpyridazine 1 (2 equiv), and amine 2 (1 equiv). Method C: The procedure is the same as in Method A except for the work up. The dioxane was removed under reduced pressure, the residue diluted with water, and extracted with EtOAc. The organic layer was washed with brine and concentrated under reduced pressure to give a crude product which was dissolved in EtOAc, without further purification. Gaseous HCl was bubbled into the solution for 2 min, and the mixture was stirred at r.t. for 1 h. The chlorhydrate was then filtered and washed with ether.

General Procedure for Alkylation: In a first step a solution of trialkylborane was prepared. To a solution of 9-borabicyclo[3.3.1]borane 0.5 M in THF (2 equiv) under argon was added dropwise a solution of vinyl 4 (1 equiv) in THF. The mixture was stirred at r.t. for 4 h, and heated at reflux for 1 h.
The 3-iodo-6-arylpyridazine 1 (1 equiv) was added to a solution of K₃PO₄ (3 equiv) dissolved in a small amount of DMF:H₂O 6:2. This mixture was flushed with argon for 30 min under magnetic stirring. Then, PdCl₂(dppf) (0.05 equiv), dppf (0.05 equiv), and the trialkylborane solution were added and the mixture was heated at 70 °C for 6 h. The solvent was removed under reduced pressure, the residue diluted with water, and extracted with EtOAc. The organic layer was washed with brine and concentrated under reduced pressure to give a crude product which was purified by HPLC. [23]

All compounds were isolated and collected by a reverse phase high pressure liquid chromatography column (Gilson C18), equilibrated with 90% A (0.1% trifluoroacetic acid in H₂O) 1% solvent B (0.1% trifluoroacetic acid in MeOH) and eluting at 1 mL/min using a 10-95% gradient of solvent B in 50 min.
Selected data for: Benzyl-(4-ethyl-6-phenyl-pyridazin-3-yl)-amine(3b): colorless oil, ¹H NMR (CDCl₃, 200 MHz): δ = 1.36 (t, 3 H, J = 7.2 Hz), 2.68 (m, 2 H), 4.76 (s, 2 H), 6.95 (s, 1 H, H_-NH-), 7.26-7.64 (m, 8 H), 7.80 (s, 1 H), 7.80 (m, 2 H); ¹³C NMR (CDCl₃, 75 MHz): δ = 11.7, 22.6, 46.2, 123.5, 126.3, 127.6, 128.2, 128.9, 129.2, 131.7, 135.8, 138.3, 151.4, 155.6; SM (ES): m/z (%) = 290.18(100) [M + H]⁺.
Benzyl-[6-(2-methoxy-phenyl)-5-methyl-pyridazin-3-yl]-amine(3c): white solid, ¹H NMR (CD₃OD, 200 MHz): δ = 2.36 (s, 3 H), 4.00 (s, 3 H), 4.80 (s, 2 H), 5.25 (s, 1 H), 7.28-7.73 (m, 10 H); ¹³C NMR (CD₃OD, 75 MHz): δ = 22.4, 49.8, 59.3, 115.5, 125.2, 125.5, 128.4, 131.9, 132.2, 133.0, 134.5, 136.4, 136.7, 139.5, 150.7, 154.1, 158.9; SM (ES: m/z (%) = 306.19(100) [M + H]⁺, 328.05(15) [M + Na]⁺.
Benzyl-bis-[6-(2-methoxy-phenyl)-5-methyl-pyridazin-3-yl]-amine(3d): white solid, ¹H NMR (CDCl₃, 200 MHz): δ = 2.20 (s, 6 H), 3.81 (s, 6 H), 5.65 (s, 2 H), 6.99-7.10 (m, 2 H), 7.32-7.45 (m, 11 H), 7.62 (s, 2 H); ¹³C NMR (CDCl₃, 75 MHz): δ = 19.4, 52.5, 55.8, 111.3, 114.8, 121.4, 123.8, 127.7, 129.1, 131.5, 133.1, 139.8, 148.2, 149.1, 158.4; SM (ES): m/z (%) = 504.30(100) [M + H]⁺. N -1-Ethyl- N -1-[6-(2-methoxy-phenyl)-5-methyl-pyri-dazin-3-yl]-ethane-1,2-diamine(3e): colorless oil, ¹H NMR (CDCl₃, 200 MHz): δ = 1.27 (t, 3 H, J = 7.0 Hz), 2.15 (s, 3 H), 2.98 (m, 2 H), 3.30 (m, 2 H), 3.79 (s, 3 H), 3.98 (m, 2 H), 6.97-7.21 (m, 3 H), 7.29-7.52 (m, 2 H); ¹³C NMR (CDCl₃, 75 MHz): δ = 11.4, 19.4, 39.3, 44.2, 45.8, 55.8, 110.1, 111.4, 121.5, 130.7, 132.4, 136.1, 150.6, 154.8, 158.9; SM (ES): m/z (%) = 287.22(100) [M + H]⁺.
N ′-Ethyl- N -[6-(2-methoxy-phenyl)-5-methyl-pyridazin-3-yl]- N -[6-(2-methoxy-phenyl)-pyridazin-3-yl]-ethane-1,2-diamine(3f): colorless oil, ¹H NMR (CDCl₃, 200 MHz): δ = 1.34 (t, 3 H, J = 7.1 Hz), 2.35 (s, 6 H), 3.14 (m, 2 H), 3.54 (m, 2 H), 3.77 (t, 2 H, J = 7.4 Hz), 3.86 (s, 6 H), 4.83 (s, 1 H), 7.07-7.11 (m, 4 H), 7.38 (m, 2 H), 7.60 (m, 2 H), 8.04 (s, 2 H); ¹³C NMR (CDCl₃, 75 MHz): δ = 10.8, 18.8, 44.6, 46.3, 46.7, 55.5, 111.2, 111.4, 121.3, 124.8, 129.7, 130.6, 133.3, 146.2, 155.7, 156.9; SM (ES): m/z (%) = 485.32(100) [M + H]⁺.
N -1-Ethyl- N -1-[6-(2-methoxy-phenyl)-5-methyl-pyri-dazin-3-yl]-ethane-1,2-diamine(3g): pale yellow oil,
¹H NMR (CDCl₃, 200 MHz): δ = 1.13 (t, 3 H, J = 7.1 Hz), 2.05 (s, 3 H), 2.71 (t, 2 H, J = 6.3 Hz), 2.94 (m, 2 H), 3.56 (t, 2 H, J = 6.4 Hz), 3.76 (s, 3 H), 5.28 (s, 2 H), 6.54 (s, 1 H), 6.94-7.07 (m, 2 H), 7.32-7.39 (m, 2 H); ¹³C NMR (CDCl₃, 75 MHz): δ = 14.5, 19.1, 41.2, 44.1, 48.6, 55.8, 111.1, 114.4, 121.2, 125.2, 130.5, 131.5, 137.0, 148.3, 154.4, 158.3; SM (ES): m/z (%) = 387.26(100) [M + H]⁺.
3-[2-(1-Benzylpiperidin-4-yl)ethylamino]-5-methyl-6-(2-methoxyphenyl)pyridazine(3h): pale orange oil, ¹H NMR (CDCl₃, 200 MHz): δ = 1.28-1.43 (m, 3 H), 1.56-1.63 (m, 2 H), 1.69 (d, 2 H, J = 11.7 Hz), 1.93 (t, 2 H, J = 11.3 Hz), 2.22 (s, 3 H), 2.87 (d, 2 H, J = 11.7 Hz), 3.38-3.45 (m, 2 H), 3.48 (s, 2 H), 3.77 (s, 3 H), 5.15 (t, 1 H, J = 5.6 Hz), 6.96-7.19 (m, 4 H), 7.36-7.48 (m, 6 H); ¹³C NMR (CDCl₃, 75 MHz): δ = 19.7, 28.6, 30.6, 33.7, 39.0, 52.3, 55.5, 60.9, 111.0, 121.3, 129.3, 130.1, 130.6, 131.2, 131.8, 136.3, 139.6, 156.7, 162.2, 162.7; SM (ES): m/z (%) = 417.29(100) [M + H]⁺.
Ethyl 11-(4-Ethyl-6-phenyl-pyridazin-3-yl)-undec-anoate(3i): colorless oil, ¹H NMR (CDCl₃, 75 MHz): δ = 1.22-1.61 (m, 22 H), 2.28 (t, 2 H, J = 7.4 Hz), 2.73 (m, 2 H), 3.00 (t, 2 H, J = 7.8 Hz), 4.11 (m, 2 H), 7.47-7.50 (m, 3 H), 7.59 (s, 1 H), 8.07 (m, 2 H); ¹³C NMR (CDCl₃, 75 MHz):
δ = 13.6, 14.6, 22.4, 23.1, 24.8, 25.3, 26.8, 27.8, 29.4, 29.5, 29.6, 29.8, 30.0, 32.6, 33.1, 34.8, 35.1, 60.5, 123.1, 127.3, 129.2, 129.9, 135.3, 137.8, 151.7, 174.0; SM (ES): m/z (%) = 397.34(100) [M + H]⁺. tert -Butyl {3-[6-(2-Methoxy-phenyl)-5-methyl-pyri-dazin-3-yl]-propyl}-carbamate(3j): pale yellow oil,
¹H NMR (CDCl₃, 200 MHz): δ = 1.43 (s, 9 H), 2.06-2.21 (m, 4 H), 2.40 (s, 3 H), 3.23 (t, 2 H, J = 6.6 Hz), 3.80 (s, 3 H), 7.02-7.42 (m, 4 H), 7.80 (s, 1 H); ¹³C NMR (CDCl₃, 75 MHz): δ = 19.6, 28.7, 29.6, 30.6, 39.8, 55.9, 79.3, 111.3, 121.4, 130.8, 131.0, 131.5, 132.7, 139.0, 155.2, 156.2, 157.7, 158.5; SM (ES): m/z (%) = 358.25(100) [M + H]⁺.