Facile synthesis of 1H-pyrazolo[1,2-a]pyridazine-5,8-dione derivatives by a one-pot, three-component reactions

Article abstract of DOI:10.1016/j.tet.2009.10.114

Protonation of the highly reactive 1:1 intermediate produced in the reaction between alkyl or aryl isocyanides and electron-deficient acetylenic esters with 3,6-dihydroxypyridazine, leads to a vinylisonitrilium cation, which undergoes an addition reaction

Full text of DOI:10.1016/j.tet.2009.10.114

Tetrahedron 66 (2010) 259–264
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Tetrahedron
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Facile synthesis of 1H-pyrazolo[1,2-a]pyridazine-5,8-dione derivatives
by a one-pot, three-component reactions
,
b
c
Mohammad Bagher Teimouri a , Farideh Mansouri , Reihaneh Bazhrang
*
a Petrochemical Department, Iran Polymer and Petrochemical Institute, PO Box 14965-115, Tehran, Iran
b Faculty of Chemistry, Firouzabad Branch, Islamic Azad University, Firouzabad, Iran
c Department of Chemistry, Payame Noor University (PNU) of Abhar, Abhar, Zanjan, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 August 2009
Received in revised form 14 October 2009
Accepted 29 October 2009
Available online 3 November 2009
Protonationof the highly reactive1:1 intermediate producedinthereactionbetween alkyl orarylisocyanides
and electron-deficient acetylenic esters with 3,6-dihydroxypyridazine, leads to a vinylisonitrilium cation,
which undergoes an addition reaction with the conjugate base of the 3,6-dihydroxypyridazine to produce
dialkyl 3-(alkyl or arylamino)-5,8-dioxo-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-1,2-dicarboxylates in
good yields at room temperature.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Dialkyl acetylenedicarboxylate
Isocyanide
Multicomponent reaction
3,6-Dihydroxypyridazine
1H-Pyrazolo[1,2-a]pyridazine
1. Introduction
small molecule peptidomimetics 2 (Scheme 1).20,21 To the best of
our knowledge, there are only a few reports19,22,23 on cycloaddition
The design and development of convergent strategies to syn-
thesize diverse arrays of drug-like compounds for biological
screening is an important objective in contemporary chemical
biology and medicinal chemistry. In this context, multicomponent
reactions (MCRs) are attractive to many organic and pharmaceuti-
cal chemists, as these reactions allow construction of basic and
important compounds that serve as molecular skeletons for many
naturally occurring products and biologically active substances in
a single step.1
entries into the fused 1H-pyrazolo[1,2-a]pyridazine-5,8-dione ring
system involving ring synthesis by formation of two bonds from
[3þ2] atom fragments ([CCCþNN]). All these cycloaddition re-
actions employ a two-component condensation between maleic
hydrazide and an a,b-unsaturated aldehyde. To date, we know of no
published report concerning the synthesis of pyrazolo[1,2-a]pyr-
idazine ring systems, which proceed via the formation of three new
bonds (one C]C and two C–N bonds) by a [CþCCþNN] annulation
strategy.
Nitrogen-containing heterocycles have received a great deal of
interest in the biological and medicinal sciences and this justifies
continuing efforts in the development of new efficient and
mild synthetic strategies.2–6 Among a large variety of nitrogen-
containing heterocyclic compounds, heterocycles containing
a bridgehead hydrazine functionality have received considerable
attention because of their pharmacological properties and clinical
applications.7–19 For example, 1-hydroxy-, 1-amino- and 1-hydra-
zino-2,3-dihydro-1H-pyrazolo[1,2-a]pyridazine-5,8-diones 1 were
reported to possess anti-inflammatory, analgesic, anti-hypoxic and
anti-pyretic properties.19 Furthermore, pyrazolidine compounds
have been converted into azaproline amino acids, which have been
studied upon incorporation into traditional peptides as well as
O
O
Z
R1
R2
N
N
N
N
CBzHN
R3
CO2Me
H
O
O
Z = -OH, -NHR4, -NHNHBz
1
2
Scheme 1. Some biologically active 1H-pyrazolo[1,2-a]pyridazine-5,8-diones.
Extensive work has been done by many groups on the
reactivities of 1,4-dipoles derived from activated acetylenic
compounds and isocyanides.24–26 Recently, these highly reactive
* Corresponding author. Tel.: þ98 21 44580000; fax: þ98 21 44580023.
E-mail address: m.teimouri@ippi.ac.ir (M.B. Teimouri).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.114

260
M.B. Teimouri et al. / Tetrahedron 66 (2010) 259–264
Table 1
Three-component condensation reactions of isocyanides, dialkyl acetylenedicarboxylates, and 3,6-dihydroxypyridazine
OH
R
CO2R'
C
O
O
H
N
Acetone
rt, 48 h
N
N
O
H
H
R
N
C
+
+
N
N
C
OR'
CO2R'
OH
CO2R'
H
3
4
6
5
Entry
1
R
R0
Product
Yielda (%)
CH3
H
N
O
CH3
CH3
CO2CH3
H3C
H3C
H3C
H
CH3
CH3
N
N
83
H
6a
CO CH
H
H
2
3
O
O
H
N
H
H
N
N
2
3
4
86
81
72
CO2CH3
CO CH
2
3
6b
O
O
H
N
H
H
CH3
CH3
N
N
CO2CH3
CO CH
H
2
3
6c
O
O
O
H
N
O
O
CH3
O
H
N
N
CO2CH3
H3C
O
H
CO CH
H
2
3
6d
H C CH3
CH3
CH3
CH3
H 3
N
O
H3C
H3C
H
CH3CH2
CH3CH2
5
80
N
N
CH3
CH3
CO2CH2CH3
CH3
H
6e
CO CH CH
H
2
2
3
O
O
H3C
HN
CH3
CH3
CH3
H
H
6
81
N
N
CO2CH2CH3
CO CH CH
H
2
2
3
6f
O
O
H
N
H
H
N
N
CH3CH2
H3C
7
8
83
76
CO2CH2CH3
CO CH CH
H
H
2
2
3
6g
O
O
CH3
H
N
CH3
CH3
CO2C(CH3)3
H3C
H
H
N
N
H C
H C
3H3C
3H3C
CO C(CH )
3 3
2
6h
O
O
H
N
H3C
H
H
N
N
9
79
CO2C(CH3)3
CO C(CH )
H C
3H3C
H
2
3 3
6i
O

M.B. Teimouri et al. / Tetrahedron 66 (2010) 259–264
261
Table 1 (continued)
Entry
R
R0
Product
H3C
Yielda (%)
CH3
O
H3C
HN
CH3
CO2C(CH3)3
H
10
84
H C
N
N
3H3C
CH3
H
CO C(CH )
3 3
H
H
2
6j
O
O
O
O
H
N
H3C
CH3
O
O
H
11
70
H C
N
N
3H3C
CO2C(CH3)3
H3C
H
6k
CO C(CH )
3 3
2
O
a
Refers to purified yield.
1,4-dipolar intermediates have been captured by suitable CH–,24
NH–,25 and OH-acids26 substrates. These studies have led to
a number of interesting carbon–carbon bond forming reactions and
heterocyclic constructions.
156.9, 163.3 and 168.9 ppm. Partial assignment of these resonances
is given in Experimental section.
The structural assignments made on the basis of the 1H and 13
C
NMR spectra of compounds 6a was supported by measurement of
its IR spectra. The IR spectrum of 6a showed strong absorptions at
1749, 1706, 1683 and 1657 cmꢀ1 due to the carbonyls and the amino
group at 3150 cmꢀ1 as a weak broad band.
Indeed, our group has long had an interest in developing new
reactions as well as expanding the scope of existing MCRs to rapidly
accessdrug-like motifs. Inconnectionwith ourrecent interestaimed
at the development of efficient protocols for the preparation of bio-
logically active heterocycles via isocyanide-based multicomponent
reactions involving acidic substrates,27 in this report the facile syn-
thesis of some new pyrazolopyridazine heterocycles is described.
3,6-Dihydroxypyridazine is a very interesting heterocyclic com-
pound, which has two rather acidic protons.28 In the present study,
this was used advantageously in the formation of polyfunctional
pyrazolopyridazine derivatives incorporating the 1H-pyrazolo[1,2-
The scope and limitations of this three-component reaction
were explored by using three dialkyl acetylenedicarboxylates and
six alkyl or aryl isocyanides. The results show that the three-com-
ponent reaction is quite general with dialkyl acetylenedicarboxy-
lates affording the expected pyrazolopyridazines 6 in good yields.
Note that even moderate yields are synthetically useful because
these reactions form complex structures and a number of bonds are
formed. Also, we examined the scope of reactive isocyanides in the
three-component reaction. As shown in Table 1, a variety of struc-
turally diverse alkyl or aryl isocyanides are used in this protocol
with excellent results.
a]pyridazine-5,8-dione substructure via
a
three-component
condensation reaction of isocyanides.
The mechanism of this reaction has not been established
experimentally, a likely mechanism for the formation of these
heterocycles 6 is shown in Scheme 2. In a first step, nucleophilic
attack of the isocyanide on to the acetylenic ester and subsequent
protonation of the highly reactive 1:1 zwitterionic intermediate by
OH-acid (3,6-dihydroxypyridazine) affords the vinylisonitrilium
cation 7. Then, vinylisonitrilium cation 7 could undergone addition
reactions with the nitrogen atom of the conjugate base of the OH-
acid 8 on the two possible electrophilic sites (1,2-addition and
1,4-conjugate addition) to produce two possible intermediates 9
and 10 in equilibrium with each other. These intermediates can
then cyclise under the reaction conditions employed to produce
the dialkyl 3-(alkyl or arylamino)-5,8-dioxo-5,8-dihydro-1H-pyr-
azolo[1,2-a]pyridazine-1,2-dicarboxylates 6.
2. Results and discussion
The one-pot, three-component condensation reactions of alkyl
or aryl isocyanides 3 with dialkyl acetylenedicarboxylates 4 in the
presence of 3,6-dihydroxypyridazine 5 proceeded at room tem-
perature in dry acetone and were complete after 48 h to afford
corresponding dialkyl 3-(alkyl or arylamino)-5,8-dioxo-5,8-dihy-
dro-1H-pyrazolo[1,2-a]pyridazine-1,2-dicarboxylates 6 in 70–86%
yields and the full results are summarized in Table 1. 1H and 13C
NMR spectra of the crude products clearly indicated the formation
of fused pyrazolopyridazine 6. Any other products could not be
detected by NMR spectroscopy.
The structures of the products 6a–k were deduced from their
elemental analyses and IR, 1H NMR and 13C NMR spectra. For
example, the 1H NMR spectrum of 6a exhibited four single sharp
lines readily recognized as arising from tert-butyl (dH 1.44 ppm),
two methoxy protons (dH 3.70 and 3.76 ppm), and allylic methine
3. Conclusion
(
dH 5.60 ppm) along with two doublets for the two vinylic methines
In summary, the one-pot, three-component condensation re-
action of isocyanides with dialkyl acetylenedicarboxylates in
presence of 3,6-dihydroxypyridazine can be successfully applied to
the synthesis of dialkyl 3-(alkyl or arylamino)-5,8-dioxo-5,8-dihy-
dro-1H-pyrazolo[1,2-a]pyridazine-1,2-dicarboxylates derivatives.
The method is simple, starts from readily accessible commercial
reagents, and provides biologically interesting pyrazolopyridazine
derivatives in good yields without any other additive to promote
the reaction. Moreover, it is worth noting that two C–N and one
C]C bonds were formed with concomitant creation of a fused
pyrazolopyridazine ring in this one-pot, three-component process.
of pyridazine residue (dH 6.86 and 6.94 ppm, J¼10.1 Hz). A fairly
broad singlet (dH 8.55 ppm) was observed for the NH group. The
presence of an amine proton was confirmed by exchange with D2O.
The chemical shift of the NH group indicates that this moiety must
have participated in a six-membered intramolecular hydrogen
bond formation with the vicinal carbonyl group as shown in Table 1.
The 1H decoupled 13C NMR spectrum of 6a showed 13 distinct
resonances, which confirmed the proposed structure. The charac-
teristic signal due to the allylic methine carbon was discernible at dC
81.3 ppm and four carbonyl groups were resonated at dC 153.1,

262
M.B. Teimouri et al. / Tetrahedron 66 (2010) 259–264
OH
O
CO2R'
C
CO2R'
N
N
N
N
R
N
C
+
+
R
N
C
C
CH
C
CO2R'
CO2R'
7
8
OH
OH
1,4-addition
1,2-addition
O
O
O
NR
H
NR
C
H
CO2R'
CO2R'
N
N
N
N
CO2R'
O
CO2R'
10
9
R
O
H
N
O
H
H
N
N
OR'
CO2R'
H
O
6
Scheme 2.
4. Experimental
4.1. General
diethyl ether and crystallized from CH2Cl2:n-hexane (1:4) to give 6a
as yellow powder (0.140 g, 83%). Mp 164–166 ꢁC (dec); Rf (30%
EtOAc/n-hexane) 0.55; IR (KBr) (nmax, cmꢀ1): 3150 (N–H), 1749,
1706, 1683 and 1657 (C]O), 1597 and 1554 (C]C); dH (400 MHz,
CDCl3) 1.44 (9H, s, C(CH3)3), 3.70 and 3.76 (6H, 2 s, OCH3), 5.60 (1H,
s, NCH), 6.86 and 6.94 (2H, 2 d, J¼10.2 Hz, CH]CH), 8.55 (1H, br s,
NH/O]C); dC (100.6 MHz, CDCl3) 168.9 and 163.3 (2ꢂCO2Me),
156.9 and 153.1 (2ꢂN–C]O), 149.1 (N–C]C), 135.9 and 134.8
(CH]CH), 81.3 (N–C]C), 62.8 (N–CH), 57.4 (CMe3), 53.1 and 51.2
(2ꢂOCH3), 29.9 (CMe3); Anal. Calcd for C15H19N3O6 (337.32): C,
53.41; H, 5.68; N, 12.46%. Found: C, 53.46; H, 5.71; N, 12.43%.
Melting points were measured on a Bu¨chi 535 apparatus and are
uncorrected. Elemental analyses were performed using an ele-
mentar vario EL III instrument. FTIR Spectra were recorded on
a Bruker Equinox-55 spectrometer. 1H and 13C NMR spectra were
recorded on a Bruker DRX-400 Avance spectrometer at 400.13 and
100.77 MHz, respectively, with CDCl3 as solvent. Chemical shifts are
reported in parts per million relative to TMS as internal reference. The
solvents, 3,6-dihydroxypyridazine, dimethyl and diethyl acetyle-
nedicarboxylates, cyclohexyl and 1,1,3,3-tetramethylbutyl isocyanides
used in this work were purchased from Merck and the 2,6-dime-
thylphenyl, tert-butyl isocyanide, and di-tert-butylacetylenedi-
carboxylate were obtained from Fluka (Buchs, Switzerland). The
benzyl isocyanide and ethyl isocyanoacetate were obtained from
Aldrich chemical company. All reagents were used without further
purification.
4.2.1. Dimethyl 3-(cyclohexylamino)-5,8-dioxo-5,8-dihydro-1H-pyr-
azolo[1,2-a]pyridazine-1,2-dicarboxylate
(6b). Yellow
powder
(0.160 g, 86%); mp 182–184 ꢁC (dec); Rf (30% EtOAc/n-hexane) 0.53;
IR (KBr) (nmax, cmꢀ1): 3073 (N–H),1744,1707,1682 and 1655 (C]O),
1600 and 1550 (C]C); dH (400 MHz, CDCl3) 1.22–1.70 (10H, m, 5
CH2), 3.70 and 3.78 (6H, 2 s, 2 ꢁCH3), 4.40 (1H, m, NHCH), 5.57 (1H, s,
NCH), 6.90 and 6.96 (2H, 2 d, J¼10.1 Hz, CH]CH), 8.50 (1H, d,
J¼5.1 Hz, NH/O]C); dC (100.6 MHz, CDCl3) 169.1 and 162.8
(2ꢂCO2Me), 156.8 and 153.0 (2ꢂN–C]O), 149.2 (N–C]C), 135.6
and 135.1 (CH]CH), 77.9 (N–C]C), 62.8 (N–CH), 53.9 (NH–CH),
53.0 and 51.3 (2ꢂOCH3), 33.7, 33.1, 25.4, 24.2 and 24.1 (5ꢂCH2);
Anal. Calcd for C17H21N3O6 (363.36): C, 56.19; H, 5.83; N, 11.56%.
Found: C, 56.26; H, 5.80; N, 12.01%.
4.2. Typical procedure for preparation of dimethyl 3-(tert-
butylamino)-5,8-dioxo-5,8-dihydro-1H-pyrazolo[1,2-
a]pyridazine-1,2-dicarboxylate (6a)
To a magnetically stirred solution of 3,6-dihydroxypyridazine
(0.056 g, 0.5 mmol) and tert-butyl isocyanide (0.042 g, 0.5 mmol) in
dry acetone (40 mL) was added dropwise a mixture of dimethyl
acetylenedicarboxylate (0.071 g, 0.5 mmol) in acetone (2 mL) at
room temperature over 10 min via a syringe. The reaction mixture
was stirred at room temperature for 48 h. The solvent was removed
under reduced pressure and the solid residue was washed with
4.2.2. Dimethyl
azolo[1,2-a]pyridazine-1,2-dicarboxylate
(0.151 g, 81%); mp 190–192 ꢁC (dec); Rf (30% EtOAc/n-hexane) 0.56;
IR (KBr) (nmax, cmꢀ1): 3132 (N–H),1748,1710,1680 and 1660 (C]O),
1609 and 1558 (C]C); dH (400 MHz, CDCl3) 3.74 and 3.81 (6H, 2 s,
3-(benzylamino)-5,8-dioxo-5,8-dihydro-1H-pyr-
(6c). Yellow powder

M.B. Teimouri et al. / Tetrahedron 66 (2010) 259–264
263
2
ꢁCH3), 4.38 and 4.42 (2H, AB system, J¼14.8 Hz, NHCH2Ph), 5.61
(2ꢂOCH2), 51.3 (NH–CH), 33.7, 33.1, 25.4, 24.2 and 24.1 (5ꢂCH2),
14.3 and 14.1 (2ꢂCH3); Anal. Calcd for C19H25N3O6 (391.41): C,
58.30; H, 6.44; N, 10.74%. Found: C, 58.34; H, 6.47; N, 10.80%.
(1H, s, NCH), 6.88 and 6.95 (2H, 2 d, J¼10.0 Hz, CH]CH), 7.28–7.41
(5H, m, C6H5), 8.54 (1H, br s, NH/O]C); dC (100.6 MHz, CDCl3)
169.3 and 162.7 (2ꢂCO2Me), 156.9 and 152.8 (2ꢂN–C]O), 149.0
(N–C]C), 138.1 and 135.4 (CH]CH), 135.1 (Cipso), 128.4 (Cmeta),
127.3 (Cpara),127.1 (Cortho), 77.8 (N–C]C), 62.9 (N–CH), 53.5 and 51.2
(2ꢂOCH3), 43.5 (NH–CH2); Anal. Calcd for C18H17N3O6 (371.34): C,
58.22; H, 4.61; N, 11.32%. Found: C, 58.30; H, 4.58; N, 11.35%.
4.2.7. Di-tert-butyl 3-(tert-butylamino)-5,8-dioxo-5,8-dihydro-1H-
pyrazolo[1,2-a]pyridazine-1,2-dicarboxylate (6h). Yellow powder
(0.160 g, 76%); mp 157–159 ꢁC (dec); Rf (30% EtOAc/n-hexane) 0.64;
IR (KBr) (nmax, cmꢀ1): 3142 (N–H),1744,1712, 1661 and 1623 (C]O),
1604, 1543 (C]C); dH (400 MHz, CDCl3) 1.18 (9H, s, NC(CH3)3), 1.25
and 1.40 (18H, s, 2ꢂOC(CH3)3), 5.60 (1H, s, NCH), 6.93 and 6.96 (2H,
2 d, J¼10.1 Hz, CH]CH), 8.50 (1H, br s, NH/O]C); dC (100.6 MHz,
4.2.3. Dimethyl 3-[(ethoxycarbonyl)methylamino]-5,8-dioxo-5,8-di-
hydro-1H-pyrazolo[1,2-a]pyridazine-1,2-dicarboxylate (6d). Yellow
powder (0.133 g, 72%); mp 153–155 ꢁC (dec); Rf (30% EtOAc/n-
hexane) 0.63; IR (KBr) (nmax, cmꢀ1): 3204 (N–H), 1741, 1736, 1701,
1667 and 1661 (C]O), 1602 and 1554 (C]C); dH (400 MHz, CDCl3)
1.20 (3H, t, J¼7.1 Hz, CH2CH3), 3.72 and 3.79 (6H, 2 s, 2 ꢁCH3), 4.15–
4.22 (4H, m, CH2CH3 and NHCH2CO), 5.66 (1H, s, NCH), 6.89 and
6.94 (2H, 2 d, J¼10.1 Hz, CH]CH), 8.89 (1H, br s, NH/O]C); dC
(100.6 MHz, CDCl3) 169.8, 168.5 and 163.8 (2ꢂCO2Me and CO2Et),
156.9 and 153.2 (2ꢂN–C]O), 148.8 (N–C]C), 136.0 and 133.7
(CH]CH), 82.3 (N–C]C), 62.1 (N–CH), 61.9 (OCH2), 53.2 and 51.5
(2ꢂOCH3), 44.2 (NH–CH2), 14.1 (CH3); Anal. Calcd for C15H17N3O8
(367.31): C, 49.05; H, 4.66; N, 11.44%. Found: C, 48.97; H, 4.70; N,
11.45%.
t
CDCl3) 168.8 and 162.8 (2ꢂCO2 Bu), 156.7 and 152.4 (2ꢂN–C]O),
149.0 (N–C]C), 135.7 and 134.7 (CH]CH), 80.3 (N–C]C), 79.8 and
79.3 (2ꢂOCMe3), 62.5 (N–CH), 57.3 (NCMe3), 30.3 (NCMe3), 29.9
and 29.8 (2ꢂOCMe3); Anal. Calcd for C21H31N3O6 (421.48): C, 59.84;
H, 7.41; N, 9.97%. Found: C, 59.90; H, 7.45; N, 9.95%.
4.2.8. Di-tert-butyl 3-(cyclohexylamino)-5,8-dioxo-5,8-dihydro-1H-
pyrazolo[1,2-a]pyridazine-1,2-dicarboxylate (6i). Yellow powder
(0.177 g, 79%); mp 205–207 ꢁC (dec); Rf (30% EtOAc/n-hexane) 0.61;
IR (KBr) (nmax, cmꢀ1): 3201 (N–H), 1735, 1709, 1648 and 1620
(C]O), 1587, 1550 (C]C); dH (400 MHz, CDCl3) 1.17–2.06 (10H,
m, 5 CH2), 1.30 and 1.46 (18H, 2 s, 2ꢂOC(CH3)3), 4.38 (1H, m,
NHCH), 5.58 (1H, s, NCH), 6.94 and 6.97 (2H, 2 d, J¼10.1 Hz,
CH]CH), 8.54 (1H, br s, NH/O]C); dC (100.6 MHz, CDCl3) 169.2
4.2.4. Diethyl 5,10-dioxo-3-[(1,1,3,3-tetramethylbutyl)amino]-5,8-di-
hydro-1H-pyrazolo[1,2-a]pyridazine-1,2-dicarboxylate (6e). Yellow
powder (0.169 g, 80%); mp 190–192 ꢁC (dec); Rf (30% EtOAc/n-
hexane) 0.55; IR (KBr) (nmax, cmꢀ1): 3180 (N–H), 1744, 1706, 1678
and 1660 (C]O), 1588, 1548 (C]C); dH (400 MHz, CDCl3) 1.06 (9H,
s, C(CH3)3), 1.21 and 1.26 (6H, 2 t, 3JHH¼7.0 Hz, 2 ꢁCH2CH3), 1.48 and
1.53 (6H, 2 s, C(CH3)2), 1.78 and 2.03 (2H, AB system, 2JHH¼15.1 Hz,
CH2), 4.15–4.21 (4H, m, 2 ABX3 overlapping systems, 2 OCH2CH3),
5.58 (1H, s, NCH), 6.89 and 6.97 (2H, 2 d, J¼10.1 Hz, CH]CH), 8.51
(1H, s, NH/O]C); dC (100.6 MHz, CDCl3) 169.9 and 163.3
(2ꢂCO2Et), 157.1 and 153.2 (2ꢂN–C]O), 149.5 (N–C]C), 136.5 and
134.7 (CH]CH), 81.9 (N–C]C), 62.6 (N–CH), 62.2 and 62.1
(2ꢂOCH2), 60.1 (CMe2), 50.0 (CH2), 31.8 (CMe2), 30.8 (CMe3) 29.1
(CMe3) 14.5 and 14.1 (2ꢂCH3); Anal. Calcd for C21H31N3O6 (421.48):
C, 59.84; H, 7.41; N, 9.97%. Found: C, 59.90; H, 7.39; N, 10.00%.
t
and 163.1 (2ꢂCO2 Bu), 156.6 and 151.9 (2ꢂN–C]O), 148.8 (N–
C]C), 135.6 and 134.6 (CH]CH), 80.2 (N–C]C), 80.0 and 79.7
(2ꢂOCMe3), 62.4 (N–CH), 51.5 (NH–CH), 33.7, 33.2, 25.3, 24.3,
24.1 (5ꢂCH2), 29.9 and 29.7 (2ꢂOCMe3); Anal. Calcd for
C23H33N3O6 (447.52): C, 61.73; H, 7.43; N, 9.39%. Found: C, 61.68;
H, 7.40; N, 9.41%.
4.2.9. Di-tert-butyl
3-[(2,6-dimethylphenyl)amino]-5,8-dioxo-5,8-
dihydro-1H-pyrazolo[1,2-a]pyridazine-1,2-dicarboxylate (6j). Yellow
powder (0.197 g, 84%); mp 214–216 ꢁC (dec); Rf (30% EtOAc/n-
hexane) 0.60; IR (KBr) (nmax, cmꢀ1): 3176 (N–H), 1745, 1714, 1681
and 1648 (C]O), 1588, 1501 (C]C); dH (400 MHz, CDCl3) 1.24 and
1.41 (18H, s, 2ꢂOC(CH3)3), 2.21 (6H, s, 2ꢂCH3), 5.58 (1H, s, NCH),
6.84 and 6.92 (2H, 2 d, J¼10.1 Hz, CH]CH), 8.53 (1H, br s, NH/
t
O]C); dC (100.6 MHz, CDCl3) 169.2 and 163.1 (2ꢂCO2 Bu),156.6 and
4.2.5. Diethyl 3-[(2,6-dimethylphenyl)amino]-5,8-dihydro-1H-pyr-
azolo[1,2-a]pyridazine-1,2-dicarboxylate
152.1 (2ꢂN–C]O), 148.9 (N–C]C), 135.6 and 135.0 (CH]CH),
131.4, 131.0, 129.8 and 123.2 (aromatic carbons), 80.4 (N–C]C), 80.1
and 79.9 (2ꢂOCMe3), 62.5 (N–CH), 29.9 and 29.7 (2ꢂOCMe3), 18.8
(C6H3Me2); Anal. Calcd for C25H31N3O6 (469.53): C, 63.95; H, 6.65;
N, 8.95%. Found: C, 64.02; H, 6.60; N, 9.00%.
(6f). Yellow
powder
(0.167 g, 81%); mp 205–207 ꢁC (dec); Rf (30% EtOAc/n-hexane) 0.51;
IR (KBr) (nmax, cmꢀ1): 3170 (N–H), 1736, 1710, 1681 and 1657 (C]O),
1594, 1540 (C]C); dH (400 MHz, CDCl3) 1.22 and 1.25 (6H, 2 t,
3JHH¼7.0 Hz, 2 ꢁCH2CH3), 2.19 (6H, s, 2 CH3), 4.16–4.22 (4H, m, 2
ABX3 overlapping systems, 2 OCH2CH3), 5.68 (1H, s, NCH), 6.87 and
6.98 (2H, 2 d, J¼10.0 Hz, CH]CH), 8.61 (1H, br s, NH/O]C); dC
(100.6 MHz, CDCl3) 168.8 and 162.2 (2ꢂCO2Et), 156.7 and 152.8
(2ꢂN–C]O), 149.1 (N–C]C), 135.6 and 134.9 (CH]CH), 131.4,
130.8, 129.7 and 123.1 (aromatic carbons), 81.0 (N–C]C), 62.9
(N–CH), 62.2 and 60.2 (2ꢂOCH2), 18.7 (C6H3Me2), 14.3 and 13.9
(2ꢂCH3); Anal. Calcd for C21H23N3O6 (413.42): C, 61.01; H, 5.61; N,
10.16%. Found: C, 60.96; H, 5.63; N, 10.20%.
4.2.10. Di-tert-butyl
3-[(ethoxycarbonyl)methylamino]-5,8-dioxo-
5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-1,2-dicarboxylate
(6k). Yellow powder (0.158 g, 70%); mp 170–172 ꢁC (dec); Rf (30%
EtOAc/n-hexane) 0.67; IR (KBr) (nmax, cmꢀ1): 3180 (N–H), 1748,
1734, 1705, 1672 and 1652 (C]O), 1602 and 1532 (C]C); dH
(400 MHz, CDCl3) 1.19 (3H, t, J¼7.1 Hz, CH2CH3), 1.25 and 1.41
(18H, s, 2ꢂOC(CH3)3), 4.16–4.22 (4H, m, CH2CH3 and NHCH2CO),
5.63 (1H, s, NCH), 6.88 and 6.96 (2H, 2 d, J¼10.1 Hz, CH]CH),
8.70 (1H, br s, NH/O]C); dC (100.6 MHz, CDCl3) 169.5, 168.3
and 163.8 (2ꢂCO2tBu and CO2Et), 156.1 and 152.9 (2ꢂN–C]O),
148.7 (N–C]C), 135.7 and 133.7 (CH]CH), 81.9 (N–C]C), 80.5
and 80.0 (2ꢂOCMe3), 62.3 (N–CH), 62.0 (OCH2), 43.9 (NH–CH2),
29.9 and 29.8 (2ꢂOCMe3), 14.1 (CH3); Anal. Calcd for C21H29N3O8
(451.47): C, 55.87; H, 6.47; N, 9.31%. Found: C, 55.93; H, 6.50; N,
9.34%.
4.2.6. Diethyl
3-(cyclohexylamino)-5,8-dihydro-1H-pyrazolo[1,2-
a]pyridazine-1,2-dicarboxylate (6g). Yellow powder (0.163 g, 83%);
mp 218–220 ꢁC (dec); Rf (30% EtOAc/n-hexane) 0.60; IR (KBr) (nmax
,
cmꢀ1): 3125 (N–H), 1744, 1708, 1670 and 1614 (C]O), 1588, 1533
(C]C); dH (400 MHz, CDCl3) 1.21–2.18 (10H, m, 5 CH2),1.21 and 1.23
3
(6H, 2 t, JHH¼7.0 Hz, 2 ꢁCH2CH3), 4.10–4.23 (4H, m, 2 ABX3 over-
lapping systems, 2 OCH2CH3), 4.38 (1H, m, NHCH), 5.59 (1H, s,
NCH), 6.86 and 6.93 (2H, 2 d, J¼10.0 Hz, CH]CH), 8.57 (1H, d,
J¼5.0 Hz, NH/O]C); dC (100.6 MHz, CDCl3) 170.0 and 162.7
(2ꢂCO2Et), 156.8 and 152.8 (2ꢂN–C]O), 149.1 (N–C]C), 135.6 and
135.0 (CH]CH), 78.0 (N–C]C), 62.5 (N–CH), 62.1 and 60.4
Acknowledgements
We would like to thank Iran Polymer and Petrochemical Institute
(IPPI) Research Council for the financial support.

264
M.B. Teimouri et al. / Tetrahedron 66 (2010) 259–264
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