A novel one-pot, three-component synthesis of 5-imino-2,3,5,8- tetrahydropyrazolo[1,2-a]pyridazin-1-one derivatives

Article abstract of DOI:10.1055/s-0028-1088070

It was found that the zwitterionic intermediate obtained from the addition of isocyanides to dimethyl acetylenedicarboxylate could react with 1,3-dipolar compounds under mild conditions to produce 5-imino-2,3,5,8-tetrahydropyrazolo[1, 2-a]pyridazin-1-one

Full text of DOI:10.1055/s-0028-1088070

PAPER
1689
A Novel One-Pot, Three-Component Synthesis of 5-Imino-2,3,5,8-tetrahydro-
pyrazolo[1,2-a]pyridazin-1-one Derivatives
S
ynthesis of 5-Im
o
ino-2,3, 5,8-tetrahy
Q
dropyrazolo[1,2-
a
i
]pyrida
a
zin-1-one
D
nerivatives ,a Ming-Jin Fan,b Yong-Xin Xie,a Lu-Yong Wu,a Yun Shi,a Yong-Min Liang*a,b
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, P. R. of China
b
Fax +86(931)8912582; E-mail: liangym@lzu.edu.cn
Received 28 October 2008; revised 6 January 2009
Abstract: It was found that the zwitterionic intermediate obtained
from the addition of isocyanides to dimethyl acetylenedicarboxylate
could react with 1,3-dipolar compounds under mild conditions to
produce 5-imino-2,3,5,8-tetrahydropyrazolo[1,2-a]pyridazin-1-one
derivatives in high yields. A plausible mechanism was also dis-
cussed for this process.
O
N
O
COOMe
N
CHCl3
C
+
N C
+
N
N
reflux, 12 h
C
COOMe
N
COOMe
COOMe
4a
Key words: isocyanide, dimethyl acetylenedicarboxylate, multi-
component reactions, 1,3-dipolar compounds, 5-imino-2,3,5,8-tet-
rahydropyrazolo[1,2-a]pyridazin-1-one
1a
2a
3a
Scheme 1
Table 1 Reaction of tert-Butyl Isocyanide (1a) with Dimethyl Acet-
ylenedicarboxylate (2a) and 2-Benzylidene-5-oxopyrazolidin-2-ium-
1-ide (3a) under Various Conditionsa
Multicomponent reactions (MCRs) have become increas-
ingly important in the last 150 years. Compared with two-
component reactions, multicomponent reactions are espe-
cially valuable. They have attracted considerable interest
owing to their simple experimental procedures, one-pot
character, and exceptional synthetic efficiency. Particu-
larly, the isocyanide multicomponent reaction (IMCR)
has occupied a major position in multicomponent reac-
tions in recent years.1–3 There are many reactions reported
in the literature that involve isocyanides and dimethyl
acetylenedicarboxylate.4–9 The reactive 1:1 zwitterionic
intermediate, formed by the addition of an isocyanide to
dimethyl acetylenedicarboxylate, has since been identi-
fied.10 In studying the reactions of zwitterionic intermedi-
ates, we found that zwitterionic intermediates obtained
from isocyanide 1a and dimethyl acetylenedicarboxylate
(2a) could react with 1,3-dipolar compound 3a to produce
4a in good yield (80%, Scheme 1). This one-pot, three-
component reaction gave a new and convenient way for
the synthesis of 5-imino-2,3,5,8-tetrahydropyrazolo[1,2-
a]pyridazin-1-one derivatives and pyrazolo[1,2-a]py-
Entry
Temp
reflux
reflux
reflux
r.t.
Solvent
CCl4
Yieldb (%)
1
2
3
4
5
6
7
33
50
60
52
80
0
toluene
CH2Cl2
CHCl3
CHCl3
THF
reflux
reflux
reflux
MeCN
0
a Reaction conditions: t-BuNC (1.0 equiv), DMAD (1.0 equiv), 2-
benzylidene-5-oxopyrazolidin-2-ium-1-ide (1.0 equiv).
b Isolated yield.
flux (Table 1, entries 4 and 5). Therefore, all the following
reactions were carried out in chloroform at reflux.
ridazine ring systems11 under mild conditions. In this pa- In subsequent research, it was found that aromatic alde-
per, we presented our detailed investigations on this type hydes, regardless of electron-donating or electron-with-
of reaction.
drawing substituents on the phenyl ring, participated in
this process with high efficiency (Table 2). The products
4 were obtained in good or excellent yields. We also
found that electron-deficient aldehydes performed much
better than electron-rich ones. For example, the reaction
of 4-methylbenzaldehyde and 4-methoxybenzaldehyde
resulted in lower yields of the corresponding products
(Table 2, entries 7 and 8). The position of the substituents
on the aromatic ring has no significant effect on this trans-
formation. Reactions of aromatic aldehydes, such as 4-
chlorobenzaldehyde and the sterically congested 3-bro-
mobenzaldehyde could also produce the corresponding
products in high yields (Table 2, entries 2 and 6). To ex-
Firstly, we conducted the reaction in various solvents at
different temperatures to increase the product yield and
reduce the reaction time. Of all of the solvents tested, such
as dichloromethane, chloroform, carbon tetrachloride, tet-
rahydrofuran, acetonitrile, and toluene, chloroform was
found to be the best. The reaction could also take place at
room temperature, but the yield was lower than that at re-
SYNTHESIS 2009, No. 10, pp 1689–1693
Advanced online publication: 27.04.2009
DOI: 10.1055/s-0028-1088070; Art ID: F22408SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
9

1690
B. Qian et al.
PAPER
plore the scope of this reaction further, other isocyanides
were utilized and the results were acceptable (Table 2, en-
tries 11–14). Other acetylenic esters were also tried, but
no conversion was observed in their reactions (Table 2,
entries 15 and 16).
Table 2 Reaction of Isocyanides 1 with Acetylenic Esters 2 and 1,3-
Dipolar Compounds 3a
R1
O
O
N
N
CHCl3
R1
R2
C
C
COOMe
N
N
+
N C
+
R2
COOMe
reflux, 12 h
N
R3
2
R3
1
3
4
Entry R1
R2
R3
Ph
Product Yieldb (%)
Figure 1 X-ray crystal structure of 4a
1
2
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Cy
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
H
4a
4b
4c
4d
4e
4f
80
77
72
67
85
79
35
33
70
69
71
70
63
68
4-ClC6H4
4-BrC6H4
4-O2NC6H4
3-ClC6H4
3-BrC6H4
4-MeC6H4
4-MeOC6H4
3-MeC6H4
3-MeOC6H4
Ph
COOMe
C
COOMe
+
O
N
3
N
R1
N
C
R1
N
C
R3
+
C
COOMe
4
COOMe
5
3
1
2
5
6
7
4g
4h
4i
R1
O
N
R1
N
O
N
N
8
N
9
N
COOMe
COOMe
COOMe
COOMe
R3
10
11
12
13
14
15
16
4j
R3
6
4
4k
4l
Scheme 2
Cy
4-O2NC6H4
Ph
Bn
4m
4n
4o
4p
followed by attack of the 1,3-dipolar compound 3 result-
ing in the formation of 6, which can produce the heterocy-
clic system 4.
Bn
4-O2NC6H4
Ph
c
t-Bu
t-Bu
–
Another reaction using 3-hydroxy-3-methyl-N¢-(4-ni-
trobenzylidene)butanehydrazide (7), an acyclic acylhy-
drazone was also tried. Unfortunately, the product with a
cyclic structure was not obtained, but a linear compound
dimethyl 2-[(tert-butylimino)methyl]-3-[1-(3-hydroxy-3-
methylbutanoyl)-2-(4-nitrobenzylidene)hydrazinyl]fu-
marate (8) was formed (Scheme 3).
c
Ph
Ph
–
a Reagents and conditions: R1NC 1 (1.0 equiv), acetylenic ester 2 (1.0
equiv), 1,3-dipolar compound 3 (1.0 equiv), CHCl3, reflux, 12 h.
b Isolated yield.
c No reaction.
The structures of 4 were deduced from their IR, 1H NMR,
and 13C NMR spectra and elemental analysis. In addition,
the NMR-based structure was further confirmed by X-ray
crystallographic analysis of 4a (Figure 1).12
O
N
COOMe
NH
HO
MeOOC
CHCl3
reflux, 12 h
N
C
COOMe
Although we have not established the mechanism of this
reaction in an experimental manner, a possible explana-
tion is proposed in Scheme 2. On the basis of the well-es-
tablished chemistry of isocyanides,1–3,13,14 it is reasonable
to assume that the functionalized pyrazoles 4 may result
from initial addition of the isocyanide 1 to acetylenedicar-
boxylate 2 and subsequent formation of the 1:1 adduct 5,
N C +
+
C
N
O
N
COOMe
O2N
HO
1a
2a
7
8
NO2
Scheme 3
Synthesis 2009, No. 10, 1689–1693 © Thieme Stuttgart · New York

PAPER
Synthesis of 5-Imino-2,3,5,8-tetrahydropyrazolo[1,2-a]pyridazin-1-one Derivatives
1691
Crystal data:12 C21H25N3O5, Mw = 399.44, T = 294(2) K,
l = 0.71073 Å, P21/c, a = 9.6832(19) Å, b = 11.0308(19) Å,
c = 12.041(2) Å, a = 68.267(3)°, b = 85.804(3)°, g = 64.363(2)°,
V = 1071.3(3) Å3, Z = 2, Dcalcd = 1.238 mg/m3, m = 0.089 mm–1,
F(000) = 424. Crystal size 0.28 × 0.25 × 0.22 mm, independent re-
flections 3953 [Rint = 0.0159], reflections collected 5669, refine-
ment method, full-matrix least-squares on F2, goodness-of-fit on F2
1.234, final R indices [I > 2s(I)] R1 = 0.0455, wR2 = 0.1026, R in-
dices (all data) R1 = 0.0687, wR2 = 0.1132, extinction coefficient
0.012(2), Largest diff. peak and hole 0.179 and –0.149 e·Å–3.
The structure of 8 was deduced from its IR, 1H NMR, and
13C NMR spectra and elemental analysis. In addition, the
NMR-based structure was further confirmed by X-ray
crystallographic analysis of 8 (Figure 2).15
In conclusion, we have developed a novel one-pot, three-
component synthesis of 5-imino-2,3,5,8-tetrahydropyra-
zolo[1,2-a]pyridazin-1-one derivatives. The simple start-
ing materials, no need for catalysts, and good yields of the
products are the main advantages of this method. Our fu-
ture studies will focus on the application of these prod-
ucts.
Dimethyl 8-(tert-Butylimino)-5-(4-chlorophenyl)-1-oxo-2,3,5,8-
tetrahydro-1H-pyrazolo[1,2-a]pyridazine-6,7-dicarboxylate
(4b)
White solid; mp 135 °C.
IR (KBr): 3317, 2923, 1730, 1274, 1088 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.27 (s, 1 H), 7.39–7.37 (d, J = 8.0
Hz, 2 H), 7.20–7.18 (d, J = 8.0 Hz, 2 H), 3.66 (s, 3 H), 3.49–3.47
(m, 2 H), 3.45 (s, 3 H), 2.33–2.30 (t, J = 6.0 Hz, 2 H), 1.39 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 175.8, 167.2, 167.0, 149.8, 145.0,
134.8, 131.9, 129.0, 114.7, 90.3, 54.9, 52.3, 51.4, 51.3, 46.5, 30.4,
30.1.
Anal. Calcd for C21H24ClN3O5: C, 58.13; H, 5.58; N, 9.68. Found:
C, 58.15; H, 5.57; N, 9.65.
Dimethyl 5-(4-Bromophenyl)-8-(tert-butylimino)-1-oxo-2,3,5,8-
tetrahydro-1H-pyrazolo[1,2-a]pyridazine-6,7-dicarboxylate
(4c)
White solid; mp 139–140 °C.
IR (KBr): 3326, 2988, 1717, 1239, 1090 cm–1.
Figure 2 X-ray crystal structure of 8
1H NMR (400 MHz, CDCl3): d = 8.20 (s, 1 H), 7.45–7.43 (d, J = 8.0
Hz, 2 H), 7.20–7.18 (d, J = 8.0 Hz, 2 H), 3.77 (s, 3 H), 3.37–3.35
(m, 2 H), 3.33 (s, 3 H), 1.96–1.93 (t, J = 6.0 Hz, 2 H), 1.28 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 172.7, 165.5, 163.5, 149.8, 145.0,
134.6, 132.4, 131.9, 122.9, 90.2, 59.0, 52.2, 45.9, 38.8, 38.6, 31.7,
30.4.
The acetylenecarboxylates were commercially available. Isocya-
nides and 1,3-dipolar compounds were prepared by literature proce-
dures.16,17 Melting points were determined on a microscopic
apparatus and without correction. Column chromatography was
1
carried out on silica gel; petroleum ether = PE. H NMR spectra
were recorded at 300 MHz or 400 MHz in CDCl3 and 13C NMR
spectra were recorded at 75 MHz or 100 MHz in CDCl3. A Nicolet
AVATAR 360 FT-IR spectrophotometer was used for IR spectra.
Anal. Calcd for C21H24BrN3O5: C, 52.73; H, 5.06; N, 8.78. Found:
C, 52.74; H, 5.05; N, 8.75.
Dimethyl 8-(tert-Butylimino)-5-(4-nitrophenyl)-1-oxo-2,3,5,8-
tetrahydro-1H-pyrazolo[1,2-a]pyridazine-6,7-dicarboxylate
(4d)
Orange solid; mp 102–104 °C.
IR (KBr): 3380, 2922, 1734, 1203, 1094 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.40 (s, 1 H), 8.29–8.27 (d, J = 6.0
Hz, 2 H), 7.46–7.44 (d, J = 6.0 Hz, 2 H), 3.67 (s, 3 H), 3.49–3.45
(m, 5 H), 2.36–2.32 (t, J = 6.0 Hz, 2 H), 1.40 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 175.8, 167.1, 166.8, 150.2, 147.8,
143.6, 140.1, 129.0, 124.1, 116.1, 89.7, 55.1, 51.7, 51.5, 46.8, 30.5,
30.1.
Dimethyl 8-Imino-1-oxo-2,3,5,8-tetrahydro-1H-pyrazolo[1,2-
a]pyridazine-6,7-dicarboxylates 4a–n; General Procedure
To a magnetically stirred soln of acetylenedicarboxylate 2 (3 mmol)
and 1,3-dipolar derivative 3 (3 mmol) in anhyd CHCl3 (4 mL) was
added a soln of the appropriate isocyanide 1 (3 mmol) in anhyd
CHCl3 (6 mL) at r.t. over 5 min. The mixture was then stirred and
heated at reflux for 12 h. The solvent was removed under reduced
pressure and the residue was purified by flash column chromatogra-
phy (silica gel, PE–EtOAc) to give final products.
Dimethyl 8-(tert-Butylimino)-1-oxo-5-phenyl-2,3,5,8-tetrahy-
dro-1H-pyrazolo[1,2-a]pyridazine-6,7-dicarboxylate (4a)
Recrystallization (PE–EtOAc); yellow solid; mp 113 °C.
IR (KBr): 3367, 2954, 1729, 1204, 1093 cm–1.
Anal. Calcd for C21H24N4O7: C, 56.75; H, 5.44; N, 12.61. Found: C,
56.75; H, 5.43; N, 12.59.
Dimethyl 8-(tert-Butylimino)-5-(3-chlorophenyl)-1-oxo-2,3,5,8-
tetrahydro-1H-pyrazolo[1,2-a]pyridazine-6,7-dicarboxylate
(4e)
White solid; mp 138–140 °C.
IR (KBr): 3312, 2956, 1738, 1278, 1066 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.87 (s, 1 H), 7.62–7.60 (d, J = 6.0
Hz, 1 H), 7.60–7.58 (d, J = 6.0 Hz, 1 H), 7.32–7.23 (m, 1 H), 4.54
(s, 1 H), 4.21–4.19 (m, 1 H), 4.02–3.94 (m, 1 H), 3.90 (s, 3 H), 3.79
1H NMR (300 MHz, CDCl3): d = 8.24 (s, 1 H), 7.40–7.39 (m, 3 H),
7.27–7.24 (m, 2 H), 3.66 (s, 3 H), 3.51–3.46 (t, J = 7.5 Hz, 2 H),
3.42 (s, 3 H), 2.34–2.30 (t, J = 6.0 Hz, 2 H), 1.39 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 176.1, 167.4, 167.2, 149.8, 146.5,
133.5, 128.9, 128.7, 127.8, 114.1, 90.6, 54.8, 51.4, 51.3, 46.5, 30.5,
30.3.
Anal. Calcd for C21H25N3O5: C, 63.14; H, 6.31; N, 10.52. Found: C,
63.13; H, 6.33; N, 10.51.
Synthesis 2009, No. 10, 1689–1693 © Thieme Stuttgart · New York

1692
B. Qian et al.
PAPER
(s, 3 H), 2.84–2.80 (t, J = 6.0 Hz, 1 H), 2.63–2.57 (m, 1 H), 1.06 (s,
9 H).
Anal. Calcd for C22H27N3O5: C, 63.91; H, 6.58; N, 10.16. Found: C,
63.92; H, 6.60; N, 10.15.
13C NMR (75 MHz, CDCl3): d = 186.2, 163.3, 159.2, 145.7, 139.7,
139.0, 137.9, 134.8, 131.0, 129.7, 127.4, 125.8, 53.5, 53.4, 52.8,
50.4, 37.6.
Dimethyl 8-(tert-Butylimino)-5-(3-methoxyphenyl)-1-oxo-
2,3,5,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazine-6,7-dicarbox-
ylate (4j)
Yellow solid; mp 88–90 °C.
IR (KBr): 3280, 2952, 1731, 1207, 1094 cm–1.
Anal. Calcd for C21H24ClN3O5: C, 58.13; H, 5.58; N, 9.68. Found:
C, 58.14; H, 5.59; N, 9.66.
Dimethyl 5-(3-Bromophenyl)-8-(tert-butylimino)-1-oxo-2,3,5,8-
tetrahydro-1H-pyrazolo[1,2-a]pyridazine-6,7-dicarboxylate
(4f)
1H NMR (400 MHz, CDCl3): d = 7.43–7.39 (m, 2 H), 7.29–7.22 (m,
2 H), 7.16–7.14 (d, J = 8.0 Hz, 1 H), 3.84 (s, 3 H), 3.55–3.36 (m, 5
H), 3.18–3.16 (m, 2 H), 2.35 (s, 3 H), 1.43 (s, 9 H).
White solid; mp 142–144 °C.
IR (KBr): 3310, 2957, 1735, 1276, 1067 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.07 (s, 1 H), 7.71–7.69 (d, J = 6.0
Hz, 1 H), 7.39–7.24 (m, 2 H), 4.52 (s, 1 H), 4.19–4.13 (m, 1 H),
3.98–3.90 (m, 1 H), 3.85 (s, 3 H), 3.74 (s, 3 H), 2.83–2.75 (t,
J = 12.0 Hz, 1 H), 2.58–2.52 (m, 1 H), 1.00 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 169.0, 163.5, 161.5, 142.6, 140.8,
138.3, 137.6, 129.5, 128.5, 127.7, 124.2, 86.0, 58.2, 52.5, 37.6,
33.5, 30.1, 29.5, 27.65.
Anal. Calcd for C22H27N3O6: C, 61.53; H, 6.34; N, 9.78. Found: C,
61.52; H, 6.32; N, 9.80.
Dimethyl 8-(Cyclohexylimino)-1-oxo-5-phenyl-2,3,5,8-tetrahy-
dro-1H-pyrazolo[1,2-a]pyridazine-6,7-dicarboxylate (4k)
Yellow solid; mp 113 °C.
IR (KBr): 3425, 2927, 1723, 1270, 1070 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.40–7.29 (m, 5 H), 4.94 (s, 1 H),
3.90 (s, 3 H), 3.64–3.53 (m, 5 H), 3.25–3.17 (t, J = 12.0 Hz, 1 H),
2.04–1.97 (m, 2 H), 1.86–1.71 (m, 2 H), 1.57–1.26 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 174.0, 165.7, 163.5, 138.5, 138.3,
133.1, 131.4, 129.5, 129.3, 63.6, 60.7, 54.2, 52.7, 52.4, 34.7, 33.4,
33.1, 25.8, 23.8, 23.7.
13C NMR (75 MHz, CDCl3): d = 186.2, 163.2, 159.1, 145.8, 140.0,
138.9, 138.1, 133.9, 130.4, 129.9, 126.3, 122.9, 53.6, 53.4, 52.9,
50.5, 37.6.
Anal. Calcd for C21H24ClN3O5: C, 52.73; H, 5.06; N, 8.78. Found:
C, 52.75; H, 5.04; N, 8.77.
Dimethyl 8-(tert-Butylimino)-1-oxo-5-(4-tolyl)-2,3,5,8-tetrahy-
dro-1H-pyrazolo[1,2-a]pyridazine-6,7-dicarboxylate (4g)
Yellow solid; mp 80–83 °C.
IR (KBr): 3328, 2955, 1730, 1269, 1039 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.28–7.20 (m, 4 H), 4.88 (s, 1 H),
3.83 (s, 3 H), 3.62–3.36 (m, 5 H), 2.35 (s, 3 H), 1.81–1.78 (t, J = 6.0
Hz, 2 H), 1.36 (s, 9 H).
Anal. Calcd for C23H27N3O5: C, 64.93; H, 6.40; N, 9.88. Found: C,
64.90; H, 6.38; N, 9.90.
Dimethyl 8-(Cyclohexylimino)-5-(4-nitrophenyl)-1-oxo-2,3,5,8-
tetrahydro-1H-pyrazolo[1,2-a]pyridazine-6,7-dicarboxylate
(4l)
Orange solid; mp 90 °C.
IR (KBr): 3266, 2932, 1729, 1214, 1098 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.79–8.76 (d, J = 9.0 Hz, 1 H),
8.28–8.26 (d, J = 6.0 Hz, 2 H), 7.46–7.43 (d, J = 9.0 Hz, 2 H), 3.67
(s, 3 H), 3.52–3.46 (m, 5 H), 2.39–2.35 (t, J = 6.0 Hz, 2 H), 2.04–
2.01 (m, 3 H), 1.76–1.50 (m, 4 H), 1.42–1.30 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 173.2, 169.0, 161.5, 138.7, 130.0,
129.3, 129.2, 127.6, 127.0, 86.1, 63.1, 59.0, 52.3, 46.2, 33.4, 29.4,
29.1, 21.2.
Anal. Calcd for C22H27N3O5: C, 63.91; H, 6.58; N, 10.16. Found: C,
63.93; H, 6.56; N, 10.17.
Dimethyl 8-(tert-Butylimino)-5-(4-methoxyphenyl)-1-oxo-
2,3,5,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazine-6,7-dicarbox-
ylate (4h)
Yellow solid; mp 92–94 °C.
IR (KBr): 3319, 2957, 1709, 1275, 1066 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.32–7.27 (m, 2 H), 6.93–6.89 (m,
2 H), 4.88 (s, 1 H), 3.86 (s, 3 H), 3.80 (s, 3 H), 3.66–3.36 (m, 5 H),
3.36–3.32 (m, 1 H), 1.83–1.73 (m, 1 H), 1.36 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 173.7, 167.2, 167.0, 149.9, 147.7,
140.6, 140.2, 129.2, 124.0, 115.6, 84.0, 53.4, 51.6, 51.2, 46.3, 33.2,
30.0, 25.3, 24.3.
Anal. Calcd for C23H27N4O7: C, 58.72; H, 5.57; N, 11.91. Found: C,
58.73; H, 5.56; N, 11.93.
13C NMR (100 MHz, CDCl3): d = 173.2, 164.7, 159.9, 131.2, 130.5,
129.4, 128.4, 124.7, 114.0, 90.8, 62.8, 59.1, 55.2, 52.3, 46.2, 35.4,
30.5, 29.1.
Dimethyl 8-(Benzylimino)-1-oxo-5-phenyl-2,3,5,8-tetrahydro-
1H-pyrazolo[1,2-a]pyridazine-6,7-dicarboxylate (4m)
Yellow solid; mp 156 °C.
IR (KBr): 3430, 2950, 1726, 1272, 1081 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.42–7.20 (m, 10 H), 4.96 (s, 2 H),
4.67 (s, 1 H), 3.91 (s, 3 H), 3.63–3.58 (m, 4 H), 3.44–3.36 (m, 1 H),
2.03–1.94 (m, 1 H), 1.25–1.00 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 172.0, 165.4, 163.4, 142.2, 140.0,
132.8, 129.7, 129.3, 128.2, 127.1, 126.4, 63.9, 56.7, 52.7, 46.1,
29.7.
Anal. Calcd for C22H27N3O6: C, 61.53; H, 6.34; N, 9.78. Found: C,
61.50; H, 6.35; N, 9.79.
Dimethyl 8-(tert-Butylimino)-1-oxo-5-(3-tolyl)-2,3,5,8-tetrahy-
dro-1H-pyrazolo[1,2-a]pyridazine-6,7-dicarboxylate (4i)
Yellow solid; mp 83–84 °C.
IR (KBr): 3279, 2955, 1728, 1269, 1039 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.30–7.26 (m, 2 H), 7.07–7.02 (m,
2 H), 3.86 (s, 1 H), 3.66 (s, 3 H), 3.50–3.46 (t, J = 8.0 Hz, 2 H), 3.42
(s, 3 H), 2.36 (s, 3 H), 2.34–2.30 (t, J = 8.0 Hz, 2 H), 1.37 (s, 9 H).
Anal. Calcd for C24H23N3O5: C, 66.50; H, 5.35; N, 9.69. Found: C,
66.35; H, 5.30; N, 9.76.
13C NMR (100 MHz, CDCl3): d = 176.1, 167.4, 167.3, 149.8, 146.8,
138.5, 133.5, 129.6, 128.6, 124.8, 114.0, 90.8, 54.8, 52.3, 51.4,
51.3, 46.6, 30.5, 21.4.
Dimethyl 8-(Benzylimino)-5-(4-nitrophenyl)-1-oxo-2,3,5,8-tet-
rahydro-1H-pyrazolo[1,2-a]pyridazine-6,7-dicarboxylate (4n)
Orange solid; mp 86–88 °C.
Synthesis 2009, No. 10, 1689–1693 © Thieme Stuttgart · New York

PAPER
Synthesis of 5-Imino-2,3,5,8-tetrahydropyrazolo[1,2-a]pyridazin-1-one Derivatives
1693
IR (KBr): 3287, 2950, 1730, 1214, 1101 cm–1.
Acknowledgment
1H NMR (300 MHz, CDCl3): d = 8.28–8.25 (d, J = 9.0 Hz, 2 H),
7.59–7.57 (d, J = 6.0 Hz, 2 H), 7.35–7.24 (m, 5 H), 5.05–4.95 (m, 2
H), 4.76 (s, 1 H), 3.92 (s, 3 H), 3.62–3.41 (m, 5 H), 2.17–2.04 (m, 1
H), 1.26–1.01 (m, 1 H).
The authors thank the NSF-20621091 and the ‘Hundred Scientist’
from the Chinese Academy of Sciences for the financial support of
this work.
13C NMR (75 MHz, CDCl3): d = 171.3, 164.9, 163.1, 148.5, 141.5,
139.6, 130.3, 128.2, 127.1, 126.6, 124.2, 63.3, 56.7, 52.8, 46.1,
29.4.
References
(1) Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810.
(2) Dömling, A. Chem. Rev. 2006, 106, 17.
(3) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
(4) Ahmadi, E.; Ramazani, A.; Haghighi, M. N. Tetrahedron
Lett. 2007, 48, 6954.
Anal. Calcd for C24H22N4O7: C, 60.25; H, 4.63; N, 11.71. Found: C,
60.44; H, 4.71; N, 11.58.
3-Hydroxy-3-methyl-N¢-(4-nitrobenzylidene)butanehydrazide
(7)
(5) Zinner, G.; Moderhack, D.; Kliegel, W. Chem. Ber. 1969,
4-Nitrobenzaldehyde (167 mg, 1.1 mmol) was added to a soln of
5,5-dimethylpyrazolidin-3-one (105 mg, 0.9 mmol) in MeOH (5
mL). The mixture was stirred at r.t. for 2 h. The precipitate was fil-
tered and washed with acetone to give the product (146 mg, 55%)
as a yellow solid; mp 140 °C.
102, 2536.
(6) (a) Nair, V.; Nair, J. S.; Vinod, A. U.; Rath, N. P. J. Chem.
Soc., Perkin Trans. 1 1997, 3129. (b) Nair, V.; Nair, J. S.;
Vinod, A. U. Synthesis 2000, 1713. (c) Nair, V.; Bindu, S.;
Balgopal, L. Tetrahedron Lett. 2001, 42, 2043. (d) Nair, V.;
Vinod, A. U. Chem. Commun. 2000, 1019.
(7) Yadav, J. S.; Reddy, S. B. V.; Shubashree, S.; Shadiv, K.;
Naidu, J. J. Synthesis 2004, 2376.
(8) (a) Nair, V.; Vinod, A. U. J. Org. Chem. 2001, 66, 4427.
(b) Nair, V.; Vinod, A. U.; Nair, J. S.; Sreekanth, A. R.; Rath,
N. P. Tetrahedron Lett. 2000, 41, 6675. (c) Nair, V.; Vinod,
A. U.; Ramesh, R.; Menon, R. S.; Varma, R. L.; Mathew, S.;
Chiaroni, A. Heterocycles 2002, 58, 147. (d) Nair, V.;
Mathen, J. S.; Vinod, A. U.; Varma, R. L. Chem. Lett. 2001,
30, 738.
(9) (a) Yavari, I.; Adib, M.; Sayahi, M. H. J. Chem. Soc., Perkin
Trans. 1 2002, 2343. (b) Yavari, I.; Nasiri, F.; Moradi, L.;
Djahaniani, H. Tetrahedron Lett. 2004, 45, 7099.
(10) Winterfeldt, E.; Schumann, D.; Dillinger, H. J. Chem. Ber.
1969, 102, 1656.
IR (KBr): 3399, 2972, 1665, 1519, 1343 cm–1.
1H NMR (400 MHz, CDCl3): d = 10.37 (s, 1 H), 8.29–8.27 (d,
J = 8.0 Hz, 2 H), 7.95 (s, 1 H), 7.85–7.83 (t, J = 8.0 Hz, 2 H), 4.27
(s, 1 H), 3.01 (s, 2 H), 1.39 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 176.1, 148.6, 142.0, 139.3, 127.8,
124.1, 69.6, 43.3, 29.6.
Dimethyl 2-[(tert-Butylimino)methyl]-3-[1-(3-hydroxy-3-meth-
ylbutanoyl)-2-(4-nitrobenzylidene)hydrazinyl]fumarate (8)
To a magnetically stirred soln of acetylenedicarboxylate 2a (3
mmol) and butanehydrazide 7 (3 mmol) in anhyd CHCl3 (4 mL) was
added a soln of the appropriate isocyanide 1a (3 mmol) in anhyd
CHCl3 (6 mL) at r.t. in 5 min. The mixture was then stirred and heat-
ed at reflux for 12 h. The solvent was removed under reduced pres-
sure and the residue was purified by flash column chromatography
(silica gel PE–EtOAc) to give the final product (56%), which was
recrystallized (PE–EtOAc) to give a yellow solid; mp 120 °C.
(11) Adib, M.; Koloogani, S. A.; Abbasi, A.; Bijanzadeh, H. R.
Synthesis 2007, 3056.
(12) The atomic coordinates for 4a have been deposited at the
Cambridge Crystallographic Data Centre (deposition
number CCDC 702357). The coordinates can be obtained on
request from the Director Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK, e-mail:
deposit@ccdc.cam.ac.uk, fax: +44(1223)336033.
(13) Adib, M.; Sayahi, M. H.; Rahbari, S. Tetrahedron Lett.
2005, 46, 6545.
(14) Walborsky, H. M.; Periasamy, M. P. In The Chemistry of
Functional Groups, Supplement C; Patai, S.; Rappaport, Z.,
Eds.; Wiley: New York, 1983, Chap. 20, 835–837.
(15) The atomic coordinates for 8 have been deposited at the
Cambridge Crystallographic Data Centre (deposition
number CCDC 713140). The coordinates can be obtained on
request from the Director Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK, e-mail:
deposit@ccdc.cam.ac.uk, fax: +44(1223)336033.
(16) (a) Hosseini-Sarvari, M.; Sharghi, H. J. Org. Chem. 2006,
71, 6652. (b) Janza, B.; Studer, A. Org. Lett. 2006, 8, 1875.
(17) (a) Taylor, E. C.; Haley, N. F.; Clemens, R. J. J. Am. Chem.
Soc. 1981, 103, 7743. (b) Perri, S. T.; Slater, S. C.; Toske,
S. G.; White, J. D. J. Org. Chem. 1990, 55, 6037.
(c) Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
10778. (d) Suárez, A.; Downey, C. W.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 11244. (e) Shintani, R.; Hayashi, T.
J. Am. Chem. Soc. 2006, 128, 6330. (f) Sibi, M. P.; Stanley,
L. M.; Nie, X.; Venkatraman, L.; Liu, M.; Jasperse, C. P.
J. Am. Chem. Soc. 2007, 129, 395.
IR (KBr): 3451, 2977, 2072, 1681, 1344 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.29–8.26 (d, J = 9.0 Hz, 2 H),
7.89–7.86 (d, J = 9.0 Hz, 2 H), 5.68 (s, 1 H), 4.23 (s, 1 H), 3.76–3.74
(d, J = 6.0 Hz, 6 H), 3.22–3.17 (d, J = 15.0 Hz, 1 H), 2.96–2.91 (d,
J = 15.0 Hz, 1 H), 1.49–1.45 (d, J = 12.0 Hz, 9 H), 1.34 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 174.9, 170.6, 167.4, 161.0, 148.3,
140.2, 139.3, 127.9, 123.9, 69.5, 62.5, 58.9, 53.4, 52.8, 51.8, 43.9,
30.0, 29.5, 29.1.
Anal. Calcd for C23H30N4O8: C, 56.32; H, 6.16; N, 11.42. Found: C,
56.31; H, 6.18; N, 11.41.
Crystal data:15 C23H30N4O8, Mw = 490.51, T = 296(2) K,
l = 0.71073 Å, P21/c, a = 8.7460(10) Å, b = 12.8442(15) Å,
c = 24.154(3) Å, a = 94.182(6)°, b = 99.607(5)°, g = 97.892(6)°,
V = 2637.2(5) Å3, Z = 4, Dcalcd = 1.235 mg/m3, m = 0.094 mm–1,
F(000) = 1040. Crystal size 0.24 × 0.23 × 0.21 mm, independent
reflections 9524 [Rint = 0.0284], reflections collected 13760, refine-
ment method, full-matrix least-squares on F2, goodness-of-fit on F2
0.873, final R indices [I > 2s(I)] R1 = 0.0502, wR2 = 0.1301, R in-
dices (all data) R1 = 0.1274, wR2 = 0.1615, extinction coefficient
0.012(2), Largest diff. peak and hole 0.160 and –0.175 e·Å–3.
Synthesis 2009, No. 10, 1689–1693 © Thieme Stuttgart · New York