Synlett 2003(10): 1482-1484
DOI: 10.1055/s-2003-40831
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Expeditive Synthesis of 4-Substituted 3-Aminopyridazines

Maryline Bourotte, Nadia Pellegrini, Martine Schmitt*, Jean-Jacques Bourguignon
Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081 CNRS/ULP, Université Louis Pasteur, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch-Graffenstaden, France
Fax: +33(3)90244310; e-Mail: schmitt@pharma.u-strasbg.fr;
Further Information

Publication History

Received 26 March 2003
Publication Date:
24 July 2003 (online)

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.

    References

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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.

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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).