Sep-Oct 2001
A Revision of the Alcoholysis and Alkanethiolysis of 3-Amino-6-chloropyridazine
1217
-1 1
3-Amino-6-propylthiopyridazine (7).
This compound was prepared with a reaction time of 53 hours;
cm ; H nmr (DMSO-d ): δ 6.85 (d, J = 9.3 Hz, 1H, H-4 or H-5),
6
6.82 (d, J = 9.3 Hz, 1H, H-4 or H-5), 5.84 (br s, 2H, NH ), 4.28
(q, J = 7.0 Hz, 2H, OCH ), 1.31 ppm (t, J = 7.0 Hz, 3H, CH );
C nmr (DMSO-d ): δ 158.75 (C-3 or C-6), 157.37 (C-3 or C-6),
119.50 (C-4 or C-5), 119.04 (C-4 or C-5), 61.37 (OCH ), 14.41
2
2
3
yield: 89%; eluent for flash column chromatography: CHCl -
3
13
6
EtOH (95:5); mp 76 °C (lit 77-78 °C) [21] (white); ir (KBr): ν
2
3406, 3320, 3199, 2961, 2929, 2869, 1635, 1597, 1533, 1452,
ppm (CH ); ms (ESI): 112, 83, 67 (100%), 54; hrms (ESI) for
-1
1
3
1237, 1156, 1102, 1054, 1024, 832, 675, 637, 460 cm ; H nmr
(DMSO-d ): δ 7.19 (d, J = 9.3 Hz, 1H, H-5), 6.70 (d, J = 9.3 Hz,
+
C H N O [M+H] : calcd 140.0824, found 140.0813.
6
10 3
6
1H, H-4), 6.20 (br s, 2H, NH ), 3.06 (t, J = 7.3 Hz, 2H, SCH ),
2
2
3-Amino-6-propoxypyridazine (4).
1.62 (h, J = 7.3 Hz, 2H, CH ), 0.96 ppm (t, J = 7.3 Hz, 3H, CH );
2
3
This compound was prepared with a reaction time of 14 hours;
yield: 81%; eluent for flash column chromatography: EtOAc; mp
75 °C (white); ir (KBr): ν 3397, 3325, 3204, 2967, 2944, 2885,
1634, 1617, 1482, 1462, 1365, 1290, 1185, 1127, 1105, 1061,
13
C nmr (DMSO-d ): δ 158.67 (C-3), 149.64 (C-6), 127.95 (C-4
6
or C-5), 115.01 (C-4 or C-5), 32.11 (SCH ), 22.26 (CH ), 13.10
2
2
ppm (CH ); ms (ESI): 128, 127, 111, 110, 100, 96 (100%), 95,
3
+
79, 47; hrms (ESI) for C H N S [M+H] : calcd 170.0752,
7
12 3
-1
1
971, 842, 562, 478 cm ; H nmr (DMSO-d ): δ 6.86 (d, J = 9.3
6
found 170.0746.
Hz, 1H, H-4 or H-5), 6.82 (d, J = 9.3 Hz, 1H, H-4 or H-5), 5.83
Synthesis of 3-Amino-6-phenylthiopyridazine (9) via
Thiophenolysis of 3-Amino-6-chloropyridazine (1).
(br s, 2H, NH ), 4.17 (t, J = 6.7 Hz, 2H, OCH ), 1.71 (h, J ≈ 7Hz,
2
2
13
2H, CH ), 0.95 ppm (t, J = 7.5 Hz, 3H, CH ); C nmr (DMSO-
2
3
d ): δ 158.91 (C-3 or C-6), 157.37 (C-3 or C-6), 119.49 (C-4 or
6
A mixture of 3-amino-6-chloropyridazine (1) (0.630 g, 4.86
mmol), sodium thiophenolate (2.83 g, 21.4 mmol) and 20 ml dry
dioxane was stirred and heated under reflux (temperature of oil
bath = 112 °C) under a nitrogen atmosphere for 60 hours. After
cooling the crude reaction mixture was poured into 100 ml
C-5), 119.02 (C-4 or C-5), 67.20 (OCH ), 21.74 (CH ), 10.26
2
2
ppm (CH ); ms (ESI): 112 (100%), 83, 67; hrms (ESI) for
3
+
C H N O [M+H] : calcd 154.0980, found154.0971.
7
12 3
General Procedure for the Synthesis of 5-7 via Alkanethiolysis.
H O/150 ml EtOAc. The organic layer was separated, dried over
2
A mixture of 3-amino-6-chloropyridazine (1) (0.630 g, 4.86
mmol), sodium alkanethiolate (21.4 mmol) and 20 ml ethanol
was stirred and heated under reflux (temperature of oil bath = 100
°C) under a nitrogen atmosphere until starting material has disap-
peared as judged by TLC and/or DCI-MS. After cooling the
crude reaction mixture was evaporated under reduced pressure to
dryness. Water (200 ml) was added. The inorganic phase was
extracted with EtOAc (6 x 100 ml). The combined organic
MgSO and evaporated to dryness. The residue was purified by
flash column chromatography on silica gel with EtOAc as eluent
4
(the mixture was brought on column dissolved in CH Cl ) yield-
2
2
ing 9 (0.97 g, 98%) as a white solid; mp 132 °C (lit. 139-140 °C)
[21] (white); ir (KBr): ν 3303, 3164, 1633, 1587, 1537, 1450,
-1
1
1189, 1154, 1081, 1026, 834, 747, 638, 550, 510, 455 cm ; H
nmr (DMSO-d ): δ 7.38-7.25 (m, 5H, Ph), 7.12 (d, J = 9.2 Hz,
6
1H, H-5), 6.73 (d, J = 9.2 Hz, 1H, H-4), 6.52 ppm (br s, 2H,
extraction fractions were dried over MgSO and evaporated
13
4
NH ); C nmr (DMSO-d ): δ 160.24 (C-3), 150.26 (C-6),
2
6
under reduced pressure. The residue was purified by flash col-
umn chromatography on silica gel. The following compounds
were prepared in this manner:
134.52 (C-1'), 131.57 (C-3',5'), 131.20 (C-4'), 130.17 (C-2',6'),
128.21 (C-4 or C-5), 116.00 ppm (C-4 or C-5); ms (ESI): 204
+
(100%), 109, 71; hrms (ESI) for C
204.0595, found 204.0576.
H
N S [M+H] : calcd
10 10
3
3-Amino-6-methylthiopyridazine (5).
This compound was prepared with a reaction time of 53 hours;
yield: 90%; eluent for flash column chromatography: EtOAc; mp
115 °C (lit 117-118 °C) [19] (white); ir (KBr): ν 3307, 3162,
Acknowledgements.
We thank J. Aerts, W. Bollaert, R. Philippeth, J. Schrooten, W.
Van Dongen, V. Van Heurck, W. Van Lierde, N. Verhaert and J.
Verreydt for technical assistance and Prof. Dr. E. Esmans for the
use of his MS facilities. Bert U. W. Maes is grateful for a grant
from the foundation 'Rosa Blanckaert'.
-1 1
2922, 1638, 1598, 1454, 1161, 1107, 834, 639, 545, 457 cm ; H
nmr (DMSO-d ): δ 7.20 (d, J = 9.3 Hz, 1H, H-5), 6.70 (d, J = 9.3
6
13
Hz, 1H, H-4), 6.19 (br s, 2H, NH ), 2.48 ppm (s, 3H, SCH );
C
2
3
nmr (DMSO-d ): δ 158.55 (C-3), 150.17 (C-6), 126.97 (C-4 or C-
6
5), 115.02 (C-4 or C-5), 13.10 ppm (SCH ); ms (ESI): 127, 110,
3
+
100 (100%), 79, 49, 47; hrms (ESI) for C H N S [M+H] : calcd
5
8 3
REFERENCES AND NOTES
142.0439, found 142.0435.
3-Amino-6-ethylthiopyridazine (6).
[1] G. B. Barlin, J. Heterocyclic Chem., 35, 1205 (1998) and
references cited therein.
[2] B. U. W. Maes, G. L. F. Lemière, R. Dommisse, K.
Augustyns and A. Haemers, Tetrahedron, 56, 1777 (2000).
[3] P. Fitton and E. A. Rick, J. Organomet. Chem., 28, 287
(1971).
[4] J. H. Clark, J. P. English, G. R. Jansen, H. W. Marson, M.
M. Rogers and W. E. Taft, J. Am. Chem. Soc., 80, 980 (1958).
[5] E. Steck, R. Brundage and L. Fletcher, J. Am. Chem. Soc.,
76, 3225 (1954).
[6] J. Druey, K. Meier and K. Eichenberger, Helv. Chim. Acta,
37, 121 (1954).
This compound was prepared with a reaction time of 53 hours;
yield: 99%; eluent for flash column chromatography: CHCl -
EtOH (95:5); mp 46 °C (lit 46-48 °C) [21] (yellow-brown); ir
(KBr): ν 3406, 3303, 3161, 2977, 2926, 1632, 1597, 1445, 1364,
3
-1
1
1260, 1163, 1105, 1052, 835, 798, 670, 638 cm ; H nmr
(DMSO-d ): δ 7.19 (d, J = 9.2 Hz, 1H, H-5), 6.72 (d, J = 9.2 Hz,
6
1H, H-4), 6.22 (br s, 2H, NH ), 3.09 (q, J = 7.3 Hz, 2H, SCH ),
2
2
13
1.26 ppm (t, J = 7.3 Hz, 3H, CH ); C nmr (DMSO-d ): δ
3
6
158.64 (C-3), 149.47 (C-6), 127.88 (C-4 or C-5), 114.98 (C-4 or
C-5), 24.41 (SCH ), 14.51 ppm (CH ); ms (ESI): 127, 110, 100
2
3
(100%), 96, 95, 79, 68, 61, 49; hrms (ESI) for C H N S
[M+H] : calcd 156.0595, found 156.0580.
[7] J. W. Mason and D. L. Aldous, in The Chemistry of
Heterocyclic Compounds, Vol 28, R. N. Castle, ed, John Wiley and
6
10 3
+