8968
M. Bakavoli et al. / Tetrahedron Letters 47 (2006) 8965–8968
evaporated under reduced pressure and the residue was
crystallized from water to give 2e as white needles.
EIMS m/z 193 (M+), Anal. Calcd for C8H11N5O: C,
49.73; H, 5.74; N, 36.25. Found: C, 49.47; H, 5.49; N,
36.54.
1
Yield (68%), mp: 204 ꢁC, H NMR (100 MHz, acetone-
d6): d 2.12 (s, 3H, CH3), 2.47 (s, 3H, CH3), 2.56 (s, 3H,
CH3), 10.12 (s, 1H, NH), IR (KBr disc) m 3300, 2990,
2220, 1691, 1662, 1547 cmꢀ1, EIMS m/z 206 (M+), Anal.
Calcd for C10H10N2O3: C, 58.25; H, 4.89; N, 13.59.
Found: C, 58.17; H, 4.73; N, 13.66.
4.2. 5-Amino-1,2-dihydro-4-(2,3-dihydro-5-methyl-3-oxo-
1H-pyrazol-4-yl)pyrazol-3-one 4b
Reaction of 2b or 2d with hydrazine: (note: for the reac-
tion of 2d only 2 equiv of hydrazine hydrate is used)
recrystallized from DMF/methanol (1:3) a pale yellow
powder, yield (73% for 2b, 62% for 2d), mp: 318–
1
3. General procedure for the preparation of furo[3,4-d]-
pyridazines 3c,e
320 ꢁC (dec), H NMR (100 MHz, DMSO-d6): d 2.13
(s, 3H, CH3), 5.71 (s, 2H, NH2), 7.12 (s, 1H, NH),
8.50–10.50 (3H, 3NH), UV (MeOH) kmax 252 nm, IR
(KBr disc) m 3400, 3250, 2994, 1640 cmꢀ1, EIMS m/z
194 (M+), Anal. Calcd for C7H9N5O2: C, 43.08; H,
4.62; N, 35.9. Found: C, 42.71; H, 4.79; N, 35.96.
Hydrazine hydrate (1 ml) was added to a mixture of 2c,e
(5 mmol) in ethanol (5 ml) and TFA (0.5 ml). The reac-
tion mixture was then refluxed for 5–6 h. The resulting
solid material was filtered off and washed with water
(10 ml) and ethanol (5 ml) to afford the pure products
3c,e.
4.3. 4-(3,5-Dimethyl-1H-pyrazol-4(5H)-ylidene)pyrazol-
idine-3,5-dione 4c
3.1. 7-Amino-4,5-dimethylfuro[3,4-d]pyridazin-1(2H)-one
3c
Hydrazine hydrate 98% (1.2 ml) was added to a solution
of 2c (2 mmol) in ethanol (8 ml), DMF (2 ml) and TFA
(0.5 ml). The reaction mixture was heated under reflux
for 18 h. The solvent was then evaporated to dryness
under reduced pressure and the residue washed with
chloroform (10 ml), and then subjected to column
chromatography using ethyl acetate–MeOH (90/10%)
to give 0.09 g (23%) of compound 4c as a yellow powder.
Reaction of 2c with hydrazine: pale yellow powder, yield
1
(47%), mp: 278 ꢁC, H NMR (100 MHz, DMSO-d6): d
2.20 (s, 3H, CH3), 2.40 (s, 3H, CH3), 6.88 (s, 2H,
NH2), 10.6 (s, 1H, NH), IR (KBr disc) m 3300, 2990,
1647 cmꢀ1, EIMS m/z 179 (M+), Anal. Calcd for
C8H9N3O2: C, 53.63; H, 5.06; N, 23.45. Found: C,
53.45; H, 5.12; N, 23.38.
1
mp: 189 ꢁC, H NMR (100 MHz, pyridine-d5): d 1.35
(d, J = 6.9 Hz, 3H, CH3), 2.17 (s, 3H, CH3), 5.42 (q,
J = 6.9 Hz, 1H, CH), 6.50 (s, 3H, 3NH), IR (KBr disc)
m 3300, 3400, 2990, 1696, 1676 cmꢀ1, EIMS m/z 195
(M+1), Anal. Calcd for C8H10N4O2: C, 49.48; H, 5.19;
N, 28.85. Found: C, 49.28; H, 5.25; N, 28.64.
3.2. N-(1-Amino-4,5-dimethylfuro[3,4-d]pyridazin-7-yl)-
acetamide 3e
Reaction of 2e with hydrazine hydrate, yellow powder,
1
yield (65%), mp: 260 ꢁC, HNMR (100 MHz, DMSO-
d6): d 2.38 (s, 3H, CH3), 2.56 (s, 3H, CH3), 2.64 (s, 3H,
CH3), 7.25 (s, 2H, NH2), 11.13 (s, 1H, NH), IR (KBr disc)
m 3300, 2990, 1680, 1650, 1600 cmꢀ1, EIMS m/z 220
(M+), Anal. Calcd for C10H12N4O2: C, 54.54; H, 5.49;
N, 25.44. Found: C, 54.62; H, 5.41; N, 25.32.
References and notes
1. Stearns, B. A.; Anker, N.; Arruda, J. M.; Campbell, B. T.;
Chen, C.; Cramer, M.; Hu, T.; Jiang, X.; Park, K.; Ren,
K. K.; Sablad, M.; Santini, A.; Schaffhauser, H.; Urbanb,
M. O.; Munoz, B. Bioorg. Med. Chem. Lett. 2004, 14,
1295.
2. Malinka, W.; Redzicka, A.; Lozach, O. IL Farmaco 2004,
59, 457.
3. Inel, S.; Jones, C.; Gretir, C. O. Tetrahedron 1984, 40,
3979.
4. General procedure for the preparation of aminobi-
pyrazoles 4a–b
Hydrazine hydrate (10–12 ml) was added to a solution
of 2a, 2b or 2d (30 mmol) in acetonitrile (12 ml), ethanol
(6 ml) and TFA (1 ml). The reaction mixture was heated
under reflux for 20–24 h. The resulting solid material
was then filtered off and washed with 10 ml of cold eth-
anol to give pure 4a–b.
4. Mosby, W. L. J. Chem. Soc. 1957, 3997.
5. Watanuki, S.; Sakamoto, S.; Harada, H.; Kikuchi, K.;
Kuramochi, T.; Kawaguchi, K.; Okazaki, T.; Tsukamoto,
S. Heterocycles 2004, 62, 127, and references cited therein.
6. Cuadro, A. M.; Elguero, J.; Navarro, P. Chem. Pharm.
Bull. 1985, 33, 2535.
7. Mardin, M.; Seuter, F.; Perzborn, E.; Schlossmann, K.;
Mayer, D.; Fiedler, V. (Bayer, A.-G.) Ger. Offen. DE
3,308,881 (Cl. A61K31/415), 13 September 1984, Appl. 12
March 1983 (Chem. Abstr. 1984, 101, 222712b).
8. Bayer, A.-G. Jpn. Kokai Tokyo Koho Jp 59,175,469
[84,175,469] (Cl. C07D231/20), 04 October 1984, DE
Appl. 3,308,881, 12 March 1983 (Chem. Abstr. 1985, 102,
56154v).
4.1. 5-Amino-1,2-dihydro-4-(3,5-dimethyl-1H-pyrazol-4-
yl)pyrazol-3-one 4a
Reaction of 2a with hydrazine: white powder, yield
1
(63%), mp: 315 ꢁC (dec) H NMR (100 MHz, DMSO-
d6): d 2.03 (s, 6H, 2CH3), 5.56 (s, 2H, NH2), 8.5–10.5
(3H, 3NH), 13C NMR (125 MHz, DMSO-d6) d 12.34,
80.47, 107.83, 142.84, 157.92, 170.61, UV (H2O) kmax
9. Igarashi, T.; Sakurai, K.; Oi, T.; Obara, H.; Ohya, H.;
Kamada, H. Free Radical Biol. Med. 1999, 26, 1339.
10. Jones, G. J. Am. Chem. Soc. 1956, 78, 159.
243 nm, IR (KBr disc) m 3300, 3100, 2990, 1633 cmꢀ1
,