Expeditive Synthesis of 4-Substituted 3-Aminopyridazines

Abstract

3-Aminopyridazines substituted at position 4 were prepared via palladium-catalysed cross-coupling reactions starting from 3-amino-4-bromopyridazines using Suzuki and Sonogashira experimental conditions.

aminopyridazine - palladium - catalysis - arylations - aryl­alkylations

References

1 Franck H. Heinisch G. Pharmacologically Active Pyridazines, In Progress in Medicinal Chemistry   Vol. 27:  Ellis GP. West GB. Elsevier; Amsterdam: 1990.  p.1-49  

2 Contreras JM. Rival YM. Chayer S. Bourguignon JJ. Wermuth CG. J. Med. Chem.  1999,  42:  730 

3 Wermuth CG. Bourguignon JJ. Schlewer G. Gies JP. Schoenfelder A. Melikian AJ. J. Med. Chem.  1987,  30:  239 

4 Wermuth CG. Schlewer G. Bourguignon JJ. Maghioros G. Bouchet M. Moire C. Kan JP. Worms P. Biziere K. J. Med. Chem.  1989,  32:  528 

5 Sitamze JM. Schmitt M. Wermuth CG. J. Org. Chem.  1992,  57:  3257 

6 Guery S. Parrot I. Rival Y. Wermuth CG. Tetrahedron Lett.  2001,  42:  2115 

7 Parrot I. Rival Y. Wermuth CG. Synthesis  1999,  1163 

8 Maes BUW. Lemiere GLF. Dommisse R. Augustyns K. Haemers A. Tetrahedron  2000,  56:  1777 

9 Estévez I. Coelho A. Ravina E. Synthesis  1999,  1666 

10 Coelho A. Ravina E. Sotelo E. Synlett  2002,  2062 

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The structures of 3a,b and 4a,b were determined by ¹H and ¹³C NMR. 3a: Yield 53%. ¹H NMR (CDCl₃, 300 MHz) δ 5.11 (d, J = 5.6 Hz, 2 H, CH ₂Ph); 7.3-7.6 (m, 8 H, ArH); 7.99 (m, 1 H, NHBn exchange with D₂O); 8.06 (m, 2 H, ArH); 8.40 (s, 1 H, H5). ¹³C NMR (CDCl₃, 300 MHz) δ 46.24 (CH₂); 118.29 (C5); 126.37 (2 CHAr); 128.27 (CHAr); 128.44 (2 CHAr); 129.29 (2 CHAr); 129.54 (2 CHAr); 129.95 (CHAr); 132.14 (C4); 135.39 (CAr); 138.00 (CAr); 149.57 (C3); 152.13 (C6). 4a: Yield 23%. ¹H NMR (CDCl₃, 200 MHz) δ 4.98 (d, J = 5.4 Hz, 2 H, CH ₂Ph); 6.42 (m, 1 H, NHBn exchange with D₂O); 7.3-7.6 (m, 10 H, ArH); 8.79 (s, 1 H, H6). ¹³C NMR (CDCl₃, 200 MHz) δ 46.56 (CH₂); 128.06 (2 CHAr); 128.25 (2 CHAr); 128.49 (2 CHAr); 129.26 (CHAr); 129.76 (2 CHAr); 130.55 (CHAr); 132.29 (C5); 133.06 (CAr); 133.34 (C4); 138.05 (CAr); 145.11 (C6); 149.46 (C3). Similar satisfactory spectral data were obtained for 3b and 4b.

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Structures of compounds 3a and 4a have been unambiguously assigned by hsqc experiments: strong correlations have been observed between C3 and CH₂Ph and between C3 and C5H for compound 3a, whereas no correlation could be observed between C3 and C6-H for compound 4a (Figure [1] ).
Representative procedure for the preparation of 5a,b from 3a,b. To a solution of 3-substituted amino-4-nitro-6-phenylpyridazine 3a,b (1.36 mmol) in acetic acid (8 mL) was added 720 mL of a 5.7 M solution of HBr-AcOH (4.10 mmol, 3 equiv). The mixture was then heated at 90 °C in a sealed tube during 3 h. The solvent was evaporated and the crude oil was purified by flash chromatography (EtOAc-hexane, 1:2). 5b: Yield 75%. ¹H NMR (CDCl₃, 200 MHz) δ 5.61 (br s, 2 H, NH ₂ exchange with D₂O); 7.3-7.5 (m, 3 H, ArH); 7.80 (s, 1 H, H5); 7.8-7.9 (m, 2 H, ArH). ESMS m/z: 250 (M⁺, ⁷⁹Br), 252 (M⁺, ⁸¹Br). Similar satisfactory spectral data were obtained for 5a.

13 Maes BUW. R’kyek O. Kosmrlj J. Lemiere GLF. Esmans E. Rozenski J. Dommisse R. Haemers A. Tetrahedron  2001,  57:  1323 

14 Maes BUW. Monsieurs K. Loones KTJ. Lemiere GLF. Dommisse R. Matyus P. Riedl Z. Hajos G. Tetrahedron  2002,  58:  9713 

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Representative procedure for Suzuki arylations. A suspension of 5a or 5b (0.60 mmol, 1 equiv), phenylboronic acid (0.69 mmol, 1.15 equiv), sodium carbonate 2 M (0.64 mL, 1.27 mmol, 2.12 equiv) in toluene (1.8 mL) and ethanol (0.2 mL) was stirred under an atmosphere of argon for 30 min. Pd(PPh₃)₄ (0.027 mmol, 0.045 equiv) was then added and the mixture was heated at 110 °C for 20 h. The toluene was removed in vacuo, the residue was diluted with H₂O and extracted with EtOAc (3 × 5 mL). The organic layers were dried over sodium sulfate, concentrated in vacuo and then purified by flash chromatography on silica gel (for compounds 6: EtOAc-hexane 1:2; for compounds 7: EtOAc-hexane 1:1, TEA 2%). Satisfactory spectral data were obtained for all new compounds. As an example 7b: mp 167-169 °C; ¹H NMR (CDCl₃, 200 MHz) δ 3.93 (s, 3 H, OCH ₃); 5.02 (br s, 2 H, NH ₂ exchange with D₂O); 7.10 (d, J = 8.3 Hz, 2 H, ArH); 7.4-7.5 (m, 5 H, ArH); 7.55 (s, 1 H, H5); 8.04 (d, J = 8.2 Hz, 2 H, ArH).

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Representative procedure for Sonogashira couplings. A mixture of 5a or 5b (0.76 mmol, 1 equiv), alkyne (1.14 mmol, 1.5 equiv), Pd(PPh₃)₂Cl₂ (0.076 mmol, 0.1 equiv), CuI (0.076 mmol, 0.1 equiv) and dry triethylamine (0.158mL, 1.14 mmol, 1.5 equiv) in dry acetonitrile (5 mL) was flushed with argon for 5 min. The reaction mixture was heated at 70 °C for 12 h. The solution was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography on silica gel (for compounds 6: EtOAc-hexane 1:3; for compounds 7: EtOAc-hexane 1:1, Et₃N 2%). Satisfactory spectral data were obtained for all new compounds. As an example 6i: ¹H NMR (CDCl₃, 200 MHz) δ 1.93 (m, 2 H, CH ₂); 2.64 (t, J = 6.9 Hz, 2 H, CH ₂ ); 3.59 (t, J = 6.8 Hz, 2 H, CH ₂); 4.49 (s, 2 H, OCH ₂Ph); 4.90 (d, J = 5.6 Hz, 2 H, NHCH ₂Ph); 5.50 (t, J = 5.6 Hz, 1 H, NH exchange with D₂O); 7.3-7.5 (m, 13 H, ArH); 7.59 (s, 1 H, H5); 8.00 (m, 2 H, ArH).