further cooling for 1 h then neutralized with concentrated
aqueous sodium hydrogen carbonate and extracted with chloro-
form (3 × 20 ml). The combined extracts were dried, the solvent
evaporated and the residue chromatographed on a neutral
Al2O3 column with chloroform as the eluant to give the pyri-
dazine 2a (0.81 g; 64%) as colourless crystals, mp 88–89 ЊC
(from hexane–benzene); δH 1.62 (3H, t, J 7.2, CH2CH3), 2.84
(3H, s, 3-CH3), 4.76 (2H, q, J 7.2, CH2CH3), 7.45–7.60 (3H, m,
3Ј-, 4Ј- and 5Ј-H) and 7.80 (2H, dd, J 7.6 and 2.1, 2Ј- and 6Ј-H)
[Found: C, 61.13; H, 4.89; Cl, 12.92. C14H13ClN4 requires C,
61.65; H, 4.80; Cl, 13.00%].
b) A solution of sodium nitrite (0.07 g, 1.0 mmol) in water
(1 ml) was added dropwise at Ϫ15 ЊC to a stirred suspension of
pyrazole 7a (0.20 g, 0.95 mmol) in 36% aqueous hydrochloric
acid (40 ml). The resulting mixture was stirred at ambient tem-
perature for 1 h then heated to boiling point and allowed to
reflux for 6 h. The cooled solution was neutralized with concen-
trated aqueous sodium hydrogen carbonate and extracted with
chloroform (3 × 20 ml). The combined extracts were dried
and concentrated. Preparative thin-layer chromatography (5:1
chloroform–acetone) of the residue yielded a high Rf fraction
(0.12 g, 65%) which was identical with pyridazine 6a prepared
by method a). The low Rf fraction contained 0.04 g (16%) of the
diazonium chloride 9a (see below).
4-Chloro-1-ethyl-3-methyl-5-(4-methoxyphenyl)-1H-pyrazolo-
[3,4-c]pyridazine 2b
Aminopyrazole 1b (0.90 g, 3.5 mmol) was diazotized in exactly
the same manner as the foregoing to give, after preparative
TLC on silica gel (elution with chloroform), the pyridazine 2b
(0.51 g, 47.8%) as yellowish crystals, mp 106–107 ЊC (benzene–
hexane); δH 1.61 (3H, t, J 7.2, CH2CH3), 2.79 (3H, s, 3-CH3),
3.82 (3H, s, OCH3), 4.73 (2H, q, J 7.2, CH2CH3), 7.06 (2H, d,
J 8.6, 3Ј- and 5Ј-H) and 7.74 (2H, d, J 8.6, 2Ј- and 6Ј-H) [Found:
C, 59.89; H, 4.89; Cl, 11.92. C15H15ClN4O requires C, 59.50; H,
4.99; Cl, 11.71%].
7-Chloro-1,3-dimethyl-6-(4-methoxyphenyl)-1H-pyrazolo[4,3-c]-
pyridazine 6b
The pyridazine 6b was similarly prepared by the two forgoing
methods: using method a), pyrazole 4b (0.90 g, 3.7 mmol) was
converted into 6b (0.82 g, 76%) while reaction of pyrazole 7b
(0.90 g, 3.7 mmol) under conditions b) gave 6b (0.69 g, 64%).
The pyridazine 6b, yellow crystals, mp 186–187 ЊC (benzene–
hexane) showed δH 2.91 (3H, s, 3-CH3), 3.87 (3H, s, OCH3), 4.11
(3H, s, 1-CH3), 7.21 (2H, d, J 8.5, 3Ј- and 5Ј-H) and 7.98 (2H, d,
J 8.5, 2Ј- and 6Ј-H) [Found: C, 58.59; H, 4.69; Cl, 11.88.
C14H13ClN4O requires C, 58.23; H, 4.54; Cl, 12.28%].
4-Chloro-1-ethyl-5-hexyl-3-methyl-1H-pyrazolo[3,4-c]pyrid-
azine 2c
Following the foregoing procedure, diazotization of ami-
nopyrazole 1c (2.33 g, 10 mmol) and purified by preparative
TLC on silica gel (20:1 chloroform–acetone) gave the pyrid-
azine 2c (2.30 g, 82%) as a colourless oil; δH 0.90 (3H, t, J 8.1,
(CH2)5CH3), 1.20–1.50 (8H, m, 4 × CH2), 1.55 (3H, t, J 7.5,
CH3CH2N), 2.70 (3H, s, 3-CH3), 3.25 (2H, t, J 7.5, CH2) and
4.65 (2H, q, J 7.5, CH2N) [Found: C, 59.36; H, 7.71; Cl, 12.02.
C14H21ClN4 requires C, 59.88; H, 7.54; Cl, 12.63%].
1-Methyl-5-(1,5-dimethyl-3-phenylethynylpyrazolyl-4-azo-
methyl)-3-phenylethynylpyrazole-4-diazonium chloride 9a
A solution of sodium nitrite (0.50 g, 7.2 mmol) in water (2 ml)
was added dropwise at 0 ЊC to a stirred suspension of
aminopyrazole 7a (1.05 g, 4.9 mmol) in 36% aqueous hydro-
chloric acid (10 ml) and the resulting mixture stirred at 30–
45 ЊC for 2 h. The solution was neutralized with solid sodium
hydrogen carbonate, stirred at 20–25 ЊC for 4 h, then diluted
with water (50 ml). The resulting yellow solid was filtered off,
washed with water (5 ml) and dried in a vacuum desiccator over
phosphorus pentoxide to give the diazonium salt 9a (1.18 g,
92%); νmax/cmϪ1 (KBr) 2340 (NN) and 2230 (CC) [Found: C,
59.34; H, 3.72; Cl, 13.78. C26H21ClN8ؒHCl requires C, 60.34; H,
4.29; Cl, 13.70%].
4-Bromo-1-ethyl-3-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyrid-
azine 3a
A solution of sodium nitrite (0.35 g, 5.1 mmol) in water (3 ml)
was added dropwise at Ϫ15 ЊC to a stirred suspension of
aminopyrazole 1a (1.05 g, 5.0 mmol) in 47% aqueous hydro-
bromic acid (40 ml). The resulting mixture was stirred at 25–
28 ЊC for 1 h. After the usual work up, preparative thin-layer
chromatography (5:1 chloroform–acetone) gave the bromopyri-
dazine 3a (1.16 g, 77%), mp 97–98 ЊC (1:1 benzene–hexane);
δH 1.60 (3H, t, J 7.3, CH2CH3), 2.68 (3H, s, 3-CH3), 4.60 (2H, q,
J 7.3, CH2N), 7.40–7.61 (3H, m, 3Ј-, 4Ј- and 5Ј-H) and 7.74
(2H, dd, J 7.6 and 2.2, 2’- and 6Ј-H) [Found: C, 53.46; H, 4.03;
Br, 25.29. C14H13BrN4 requires C, 53.16; H, 4.13; Br, 25.19%].
1-Methyl-5-(1,5-dimethylpyrazol-4-ylazomethyl)pyrazole-4-
diazonium chloride 9d
By the foregoing procedure, aminopyrazole 7d (1.94 g, 1.7
mmol) was diazotized at 0 ЊC. The work up described for salt 9a
provided 2.25 g (86.2%) of the diazonium salt 9d; νmax/cmϪ1
(KBr) 2300 (NN). [Found: C, 40.11; H, 4.27; Cl, 18.48.
C10H13ClN8ؒ0.5HCl requires C, 40.18; H, 4.55; Cl, 17.79%].
7-Chloro-1,3-dimethyl-6-phenyl-1H-pyrazolo[4,3-c]pyridazine
6a
1-Methyl-6-(1,5-dimethyl-3-phenylethynylpyrazol-4-ylazo)-3-
a) A solution of sodium nitrite (0.35 g, 5.1 mmol) in water (5
ml) was added dropwise at Ϫ10 ЊC to a stirred suspension of
the 4-aminopyrazole 4a (0.90 g, 4.3 mmol) in 36% aqueous
hydrochloric acid (50 ml). The mixture was stirred at ambient
temperature for 1 h then heated to boiling point and allowed to
reflux for 2 h. The cooled reaction mixture was poured into
water (50 ml), neutralized with sodium hydrogen carbonate and
extracted with chloroform (3 × 70 ml). The combined extracts
were passed through silica gel (3 cm in length). The filtrate was
concentrated at reduced pressure to give 0.90 g (82%) of the
title compound as brown crystals. Recrystallization of the crude
product from benzene–hexane (1:1) gave an analytical sample
of the pyridazine 6a as yellow crystals, mp 175–176 ЊC; δH 2.97
(3H, s, 3-CH3), 4.28 (3H, s, 1-CH3), 7.45–7.61 (3H, m, 3Ј-,
4Ј- and 5Ј-H) and 7.90 (2H, dd, J 7.8 and 2.2, 2Ј- and 6Ј-H)
[Found: C, 60.23; H, 4.28; Cl, 13.43. C13H11ClN4 requires C,
60.35; H, 4.29; Cl, 13.70%].
phenylethynyl-1,4-dihydro-pyrazolo[4,3-c]pyrazole 10a
A stirred suspension of diazonium salt 9a (0.50 g, 0.97 mmol)
and triethylamine (10 ml) in ethanol (100 ml) was refluxed for
25 min, by which time the salt had dissolved. The cooled reac-
tion mixture was evaporated to 5 ml and diluted with ether (30
ml). The resulting brown precipitate was filtered off, washed
with water (20 ml), dried in a vacuum desiccator over potassium
hydroxide and recrystallised from chloroform and benzene
to afford yellow crystals of azo compound 10a. Subsequent
chromatography of the product on an alumina column (20 ×
100 mm, elution with chloroform) provide an analytical sample
of 10a (0.23 g, 54%), mp 246–247 ЊC; νmax/cmϪ1 (KBr) 3400
(NH) and 2230 (CC); δH 2.66 (3H, s, 5-CH3), 3.88 (3H, s,
N-CH3), 4.45 (3H, s, N-CH3), 7.30–7.41 (6H, m, Ph) and 7.51–
7.63 (4H, m, Ph) [Found: C, 70.02; H, 4.49; N, 25.34. C26H20N8
requires C, 70.26; H, 4.53; N, 25.21%].
3724
J. Chem. Soc., Perkin Trans. 1, 1999, 3721–3726