1780
B. U. W. Maes et al. / Tetrahedron 56 (2000) 1777–1781
H-20); LRMS (EI): 189, 161, 133, 120; HRMS (EI): Mϩ,
found 189.0708, C10H8FN3 requires 189.0702.
EtOAc (50 mL) was added and the suspension was placed in
an ultrasonic bath for a few minutes. The mixture was
filtered over Celite and washed thoroughly with EtOAc
and the filtrate evaporated under reduced pressure to
dryness. The residue was purified by flash column chroma-
tography on silica gel. The obtained product was solved in
EtOAc (50 mL) and a saturated KF solution in water
(100 mL) was added. The two phase system was mag-
netically stirred overnight and filtered. The organic layer
washed with NaOH (50 mL, 1 M), dried over MgSO4 and
evaporated under reduced pressure to dryness.
3-Amino-6-(4-methylthiophenyl)pyridazine (5). Reaction
time: 8 h (starting from 1a and 1b); yield: 75% (from 1a)
and 73% (from 1b); eluent for flash column chromato-
graphy: EtOAc–MeOH (98:2); mp 171ЊC (white); nmax
(KBr): 3406, 3282, 3113 (br), 1649, 1595, 1451, 1142,
1096, 821 cmϪ1; dH (DMSO-d6): 2.52 (s, 3H, SCH3), 6.44
(s, 2H, NH2), 6.85 (d, 1H, J9.3 Hz, H-4), 7.34 (d, 2H,
J8.7 Hz, H-30), 7.78 (d, 1H, J9.2 Hz, H-5), 7.91 (d,
2H, J8.5 Hz, H-20); LRMS (EI): 217, 202, 189, 174,
161, 148, 133; HRMS (EI): Mϩ, found 217.0669,
C11H11N3S requires 217.0674.
The following compounds were prepared in this manner.
3-Amino-6-(2-furanyl)pyridazine (9). Reaction time: 20 h
(starting from 1a), 39 h (starting from 1b); yield: 89% (from
1a) and 99% (from 1b); eluent for flash column chromato-
graphy: CH2Cl2–MeOH (97:3); mp 134ЊC (yellow); nmax
(KBr): 3313 (br), 3156 (br), 1638, 1496, 1464, 1158,
1002, 842, 732 cmϪ1; dH (DMSO-d6): 6.52 (s, 2H, NH2),
6.62 (dd, 1H, J3.4, 1.7 Hz, H-40), 6.84 (d, 1H, J9.3 Hz,
H-4), 6.97 (dd, 1H, J3.4, 0.8 Hz, H-30), 7.61 (d, 1H,
J9.3 Hz, H-5), 7.77 (dd, 1H, J1.8, 0.8 Hz, H-50);
LRMS (EI): 161, 133, 104, 92; HRMS (EI): Mϩ, found
161.0582, C8H7N3O requires 161.0589.
3-Amino-6-(4-methoxyphenyl)pyridazine (6). Reaction
time: 5 h (starting from 1a and 1b); yield: 78% (from 1a)
and 92% (from 1b); eluent for flash column chromato-
graphy: EtOAc; mp 171ЊC (white); nmax (KBr): 3415,
3294, 3109 (br), 1650, 1609, 1512, 1457, 1281, 1249,
1176, 1031, 826 cmϪ1; dH (DMSO-d6): 3.79 (s, 3H,
OCH3), 6.35 (s, 2H, NH2), 6.85 (d, 1H, J9.3 Hz, H-4),
7.00 (d, 2H, J8.7 Hz, H-30), 7.74 (d, 1H, J9.3 Hz,
H-5), 7.88 (d, 2H, J8.7 Hz, H-20); LRMS (EI): 201, 173,
158, 145, 132, 117; HRMS (EI): Mϩ, found 201.0902,
C11H11N3O requires 201.0902.
3-Amino-6-(2-thienyl)pyridazine (10). Reaction time:
30 h (starting from 1a), 107 h (starting from 1b); yield:
96% (from 1a) and 87% (from 1b); eluent for flash column
chromatography: CH2Cl2–MeOH (98:2); mp 139ЊC
(yellow); nmax (KBr): 3447, 3347, 3415, 3094, 1628,
1461, 1429, 1132, 841, 821, 722, 697, 681 cmϪ1; dH
(DMSO-d6): 6.49 (s, 2H, NH2), 6.83 (d, 1H, J9.3 Hz, H-
4), 7.12 (dd, 1H, J5.0, 3.5 Hz, H-40), 7.51 (dd, 1H, J5.2,
1.0 Hz, H-50), 7.56 (dd, 1H, J3.7, 1.1 Hz, H-30), 7.79 (d,
1H, J9.3 Hz, H-5); LRMS (EI): 177, 149, 121, 108;
HRMS (EI): Mϩ, found 177.0333, C8H7N3S requires
177.0361.
3-Amino-6-(3-trifluoromethylphenyl)pyridazine (7). Reac-
tion time: 20 h (starting from 1a and 1b); yield: 81% (from
1a) and 80% (from 1b); eluent for flash column chromato-
graphy: CH2Cl2–MeOH (98:2); mp 141ЊC (white); nmax
(KBr): 3354 (br), 3306 (br), 3124 (br), 1645, 1603, 1464,
1337, 1265, 1175, 1133, 1069, 1048, 845, 808, 702 cmϪ1
;
dH (DMSO-d6): 6.63 (s, 2H, NH2), 6.90 (d, 1H, J9.4 Hz,
H-4), 7.71 (t, 1H, J7.6 Hz, H-50), 7.75 (br d, 1H, J
7.8 Hz, H-40 or H-60), 7.96 (d, 1H, J9.3 Hz, H-5), 8.27
(br d, 1H, J7.5 Hz, H-40 or H-60), 8.32 (br s, 1H, H-20);
LRMS (EI): 239, 220, 211, 183, 170; HRMS (EI): Mϩ,
found 239.0670, C11H8F3N3 requires 239.0670.
3-Amino-6-(3-thienyl)pyridazine (8). Reaction time: 25 h
(starting from 1a and 1b); yield: 74% (from 1a) and 91%
(from 1b); eluent for flash column chromatography:
EtOAc–MeOH (98:2); mp 163ЊC (white); nmax (KBr):
3409, 3282, 3090, 1647, 1454, 1411, 1135, 847, 792,
760 cmϪ1; dH (DMSO-d6): 6.39 (s, 2H, NH2), 6.81 (d, 1H,
J9.2 Hz, H-4), 7.60 (dd, 1H, J5.0, 2.9 Hz, H-40), 7.69
(dd, 1H, J5.0, 1.4 Hz, H-50), 7.73 (d, 1H, J9.2 Hz, H-5),
7.96 (dd, 1H, J2.9, 1.4 Hz, H-20); LRMS (EI): 177, 149,
121, 108; HRMS (EI): Mϩ, found 177.0362, C8H7N3S
requires 177.0361.
Acknowledgements
We thank Prof. Dr M. Claeys and H. Van den Heuvel for
high resolution mass spectrometry measurements. Ing. J.
Aerts, K. Amssoms, T. Jonckers, R. Philippeth and Ing. J.
Verreydt for technical assistance. Bert U. W. Maes thanks
the foundation ‘Rosa Blanckaert’ for a grant.
References
1. This work was presented at the Sigma–Aldrich Organic
Synthesis Meeting, De Haan, Belgium, 3/12/98-4/12/98 and at
the 17th ICHC, Vienna, Austria, 1/8/99-6/8/99.
General procedure for the synthesis of 3-amino-6-
(hetero)arylpyridazines (9–10) via Stille cross-coupling
2. Wermuth, C.-G. J. Heterocycl. Chem. 1998, 35, 1091.
´
3. Wermuth, C.-G. Actual. Chim. Ther. 1985, 12, 3.
A
mixture of 3-amino-6-halopyridazine (1a or 1b,
ˇ
2.55 mmol), PdCl2(PPh3)2 (0.168 g, 0.24 mmol), THF
(6 mL) and organostannane (3.5 mmol) was flushed with
N2 for 5 min under magnetic stirring. The reaction mixture
was stirred and heated under reflux (temperature of oil
bath85ЊC) under a N2 atmosphere until the starting
material has disappeared. After cooling, the reaction
mixture was evaporated under reduced pressure to dryness.
4. Tisler, M.; Stanovnik, B. Adv. Heterocycl. Chem. 1990, 49, 385.
5. Frank, H.; Heinisch, G. In Progress in Medicinal Chemistry,
Ellis, G. P., West, G. B., Eds.; Elsevier: Amsterdam, 1990; Vol. 27,
pp 1–49.
6. Frank, H.; Heinisch, G. In Progress in Medicinal Chemistry,
Ellis, G. P., Luscombe, D. K., Eds.; Elsevier: Amsterdam, 1992;
Vol. 29, pp 141–183.