Convenient DABCO-catalyzed one-pot synthesis of multi-substituted pyrano[2,3-c]pyrazole dicarboxylates

Article abstract of DOI:10.1016/j.tet.2014.04.088

We developed an efficient and simple one-pot synthesis of functionalized multi-substituted 2,4-dihydro-pyrano[2,3-c]pyrazole dicarboxylates from β-ketoesters, hydrazine, dimethyl acetylenedicarboxylate and malononitrile in EtOH. This four-component one-pot reaction carried out in the presence of DABCO catalyst showed advantages over a one-pot three-component method in its simple procedure, high yield and low toxicity.

Full text of DOI:10.1016/j.tet.2014.04.088

Accepted Manuscript
Convenient DABCO-catalyzed one-pot synthesis of multi-substituted pyrano[2,3-
c]pyrazole dicarboxylates
Ablajan Keyume, Zeynepgul Esmayil, Liju Wang, Feng Jun
PII:
S0040-4020(14)00622-X
10.1016/j.tet.2014.04.088
TET 25538
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 December 2013
Revised Date: 28 April 2014
Accepted Date: 28 April 2014
Please cite this article as: Keyume A, Esmayil Z, Wang L, Jun F, Convenient DABCO-catalyzed one-pot
synthesis of multi-substituted pyrano[2,3-c]pyrazole dicarboxylates, Tetrahedron (2014), doi: 10.1016/
j.tet.2014.04.088.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
Convenient DABCO-catalyzed one-pot
synthesis of multi-substituted pyrano[2,3-
c]pyrazole dicarboxylates
Leave this area blank for abstract info.
Ablajan Keyume*, Zeynepgul Esmayil, Liju Wang, Feng Jun
CO2CH3
COOCH3
CO2CH3
R1
N
R1
COOCH3
CN
CO2CH3
R1COCH2CO2R2
CN
DABCO
EtOH
+
or
+
CH2(CN)2
HN
NH2NHR3
N
N
NH2
O
NH2
O
CO2CH3
R3

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Convenient DABCO-catalyzed one-pot synthesis of multi-substituted pyrano[2,3-
c]pyrazole dicarboxylates
Ablajan Keyume*, Zeynepgul Esmayil, Liju Wang, Feng Jun
Key Laboratory of Oil & Gas Fine Chemicals, Ministry of Education & Xinjiang Uyghur Autonomous Region, College of
Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We developed an efficient and simple one-pot synthesis of functionalized multi-substituted 2,4-
dihydro-pyrano[2,3-c]pyrazole dicarboxylates from β-ketoesters, hydrazine, dimethyl acetylene
dicarboxylate and malononitrile in EtOH. This four-component one-pot reaction carried out in
the presence of DABCO catalyst showed advantages over a one-pot three-component method in
its simple procedure, high yield and low toxicity.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
Pyrano[2,3-c]pyrazole
Acetylene dicarboxylate
Multi-component reaction
One-pot synthesis
DABCO
1. Introduction
carbon bond can undertake various active roles in organic
reactions for the facile and efficient production of various
heterocyles.10 For example, the reaction of alkynes with O-
acetyl- or O-benzoyl-substituted anilines yields the
corresponding quinolines.11 Highly functionalized 1,4-
pyranonaphthoquinone has been prepared from the reaction of
aniline, diethylacetoacetylene, hydroxyl-naphthalene-1,4-dione
and an aldehyde under microwave irradiation without the use of
a solvent or catalyst.12 An atom-economic method for the one-
pot synthesis of substituted 4H-chromene, 4H-pyran and oxepine
derivatives has been developed using a reaction involving three
components: 1,3-diketones, diethyl acetylenedicarboxylate and
malononitrile.13 Multicomponent domino reactions in aqueous
media catalyzed by L-proline have recently been developed for
the synthesis of functionalized 4H-pyrano[2,3-c]pyrazoles.14
Variations of, or an increase in the number of the various
functional groups in the pyran or pyrazole ring may modify the
biological properties of the resulting compounds.
Pyrazole and pyran are both cyclic structural units found in
many different natural and synthetic products that exhibit a wide
range of biological activities.1 Pyran-containing compounds
exhibit analgesic, anticoagulant and anticancer effects.2 4H-
Chromenes contain skeletons similar to pyran. They are
widespread in nature and are pharmacologically potent, being
employed as drugs, pigments and in cosmetics.3 Many types of
bioactive drugs with broad medicinal and agrochemical
applications contain both pyran and pyrazole rings,4 and both
structures are present in pyran[2,3-c]pyrazole and its derivatives,
which exhibit various biological activities and pharmacological
properties.5 Therefore, much research has focused on the
synthesis and bioactivities of compounds containing these
structural units.
One-pot, multicomponent reactions (MCRs) constitute a
powerful class of synthetic methods owing to their short reaction
times, high efficiencies and unique selectivities.6 They can form
several chemical bonds simultaneously.7 The carbon-carbon
triple bond is one of the most important structural units in the
formation of different rings via its reaction with different active
substances. Acetylenedicarboxylate has recently been
extensively used in the one-pot formation of various heterocyclic
systems.8 The pharmaceutical and biological importance of
multi-substituted dihydropyrano[2,3-c]pyrazoles has led to the
investigation of many synthetic approaches.9 The triple carbon-
Pyrazol-5-one, malononitrile, β-ketoesters and hydrazine are
important intermediates that are widely used in the synthesis of
functionalized and novel organic compounds.15 Many recent
studies have reported the one-pot synthesis of pyrano[2,3-
c]pyrazoles in the presence of different catalysts.16 Acetylene
dicarboxylate has been little used in the synthesis of novel
bioactive compounds, but it is considered here in the important
task of developing a direct, convenient, economic and efficient

2
Tetrahedron
ACCEPTED MANUSCRIPT
CO2CH3
multicomponent one-pot method for the synthesis of novel
COOCH3
CN
H3C
pyrano[2,3-c]pyrazole compounds.
HN
2. Results and discussion
N
O
NH2
To establish the optimal reaction conditions for the synthesis of
multi-substituted pyrano[2,3-c]pyrazol dicarboxylates, our initial
experiments were focused on a one-pot reaction involving
pyrazol-5-one, malononitrile and dimethyl acetylene-
dicarboxylate. For a low risk and eco-friendly process, both
EtOH and water are used as the preferred solvents for all of the
optimization experiments. All of the reactions were performed
via heating at 50 ºC for the appropriate time period. Compound
4a was obtained in low to moderate yields in the presence of
DBU, DDC, KOH, CH3COONa, HOAc, L-proline or piperidine
as the catalyst. Interestingly, 4a was obtained in a high yield
using DABCO (20 % mol) as a catalyst in EtOH rather than in
water (Table 1). The yield decreased when the reaction
proceeded at room temperature or over 50 ºC. According to
experimental results, the protocol described in Scheme 1 is
applicable to a different type of pyrazole-5-ones. The detailed
experimental results obtained with this three-component one-pot
reaction were listed in Table 2. Based on these results, a reaction
stirring in EtOH with 20 % mol DABCO catalyst was selected as
the optimal condition for the three-component synthesis of other
compounds.
4a
Fig. 1 Structure of compound 4a.
In comparison to the three-component one-pot reaction, for
the four-component reaction, four reactants, including β-
ketoesters, hydrazine, dimethyl acetylenedicarboxylate and
malononitrile underwent a reaction to yield the target compound
without preparing pyrazol-5-one. Similar to the above
optimization, the catalysts, solvents and temperature used in the
four-component reaction for the synthesis of compound 4a were
also investigated to optimize the reaction conditions (Table 1). It
is important to note that when the reaction was carried out in
EtOH using DABCO as the catalyst, the yield of product 4a
reached 88 %. However, the yield of compound 4a decreased
when the reaction was attempted in water using the same catalyst.
In addition, some by-products mixed with 4a were formed when
water or EtOH was used as the solvent at room temperature or
under refluxing conditions in the presence of the DABCO
catalyst.
CO2CH3
R1COCH2CO2R2
NH2NHR3
CH2(CN)2
+
CO2CH3
H3C
+
+ H3CO2C
COOCH3
CN
H3C
HN
CO2CH3
+
DABCO
EtOH
DABCO
+
CH2(CN)2
N
°
C
EtOH, 50
N
N
CO2CH3
NH2
O
O
H
CO2CH3
CO2CH3
COOCH3
4a
2
3
1
R1
COOCH3
CN
R1
Scheme 1. Three-component one-pot reaction for the synthesis of
compound 4a.
CN
or
N
HN
N
N
NH2
O
NH2
O
R3
4a~4e
Table 1. Optimization of reaction conditions involving catalyst and
solvent screening for the synthesis of 4a.
4f~4m
Scheme 2. Four-component one-pot reaction for the synthesis of
compounds 4a-m.
Entry
catalyst
yield of 4a (%)
(20 mol %)
solvent
t (h)
A a
B b
Next, all of the compounds were prepared via the four-
component one-pot reaction due to the short reaction time,
simple procedure and atom efficiency of this method. Although
the four-component reaction appears simple and convenient, the
product was not formed when the four reactants were mixed
together, despite using a similar method to the three-component
one-pot reaction. Therefore, the dropwise addition of a mixture
of acetylene diacetate and malononitrile into a mixture of
methyl/ethyl acetoacetate and hydrazine in ethanol under stirring
and heating at 50 ºC to produce the final product in high yield.
1
Piperidine
Pyrrolidine
KOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH2Cl2
MeCN
MeOH
H2O
2 h
2 h
2 h
2 h
2 h
2 h
2 h
1 h
1 h
1 h
1 h
1 h
50
45
20
25
65
35
20
35
50
65
50
80
60
30
25
30
70
45
25
45
2
3
4
CH3COONa
L-proline
DBU
5
6
7
DDC
8
DABCO
DABCO
DABCO
DABCO
DABCO
9
65
10
11
12
72
55
88
After having established the optimal reaction conditions, the
effect of the type of β-ketoesters and hydrazine was examined.
The reaction yield and reaction time indicated that hydrazine
hydrate increased the reaction rate more than phenyl hydrazine
or substituted phenyl hydrazine (Table 2). While phenyl
hydrazine or substituted phenyl hydrazine participate in the
reaction, the completion of the reaction required more time, and
the yield of product decreased. The results listed in Table 2 also
EtOH
a Isolated yields for the three-component one-pot reaction.
b Isolated yields for the four-component one-pot reaction.

3
indicated that 3-oxo aliphatic acid methyl ester afforded slightly
higher yields compared to methyl benzoyl acetate. Methyl β-
ketoesters resulted in slightly higher yields than that of ethyl β-
ketoesters (not shown). The results obtained in the three- and
four-component reactions were summarized in Table 2.
respectively. Then, the Michael addition of intermediate C to
ACCEPTED MANUSCRIPT
intermediate B resulted in an intermediate D in the presence of
DABCO. Next, the intramolecular nucleophilic attack of the
oxygen to one of the nitrile group afforded intermediate E.
Finally, subsequent isomerization occurred in the pyran and
pyrazole rings produced the final compound 4.
Table 2. One-pot synthesis of dihydropyrano[2,3-c]pyrazoles.
OH
O
H
N
H
C
% yieldb
H3CO2C
CO2CH3
OR2
R1
+
5
NC
CN
Entry Product R1
R2
R3
+
N
2
Aa / Bb
3
NH2 NH2
6
1
4a
4b
4c
4d
4e
4f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
85
80
83
85
75
82
80
76
80
82
78
70
75
/
/
/
/
/
/
/
/
/
/
/
/
/
90
85
88
92
82
87
85
83
85
88
82
80
80
CO2CH3
COOCH3
2
Et
H
COOCH3
R1
R1
R1
N
N
CO2CH3
3
n-Pro
iso-Pro
Ph
H
CN
NC
4
H
B
N
N
N
+
H+
5
H
C
NC
N
N
N
OH
N
O
H
H
H
O
6
Me
Me
Ph
D
A
C
N
7
4g
4h
4i
Me
8
Et
Ph
N
9
n-Pro
iso-Pro
Ph
Ph
CO2CH3
CO2CH3
CO2CH3
R1
COOCH3
H
R1
10
11
12
13
4j
Ph
COOCH3
CN
R1
N
COOCH3
CN
CN
4k
4l
Ph
Me
o-ClPh
p-ClPh
HN
N
C
N
4m
Me
N
N
N
NH2
O
O
NH
O
H
a Isolated yields for the three-component one-pot reaction.
H+
E
4
H
b Isolated yields for the four-component one-pot reaction.
Scheme 3. Proposed reaction mechanism for the DABCO catalyzed
one-pot synthesis of multi-substituted pyrano[2,3-c]pyrazole
dicarboxylates.
1
The structures of 4a~4m were confirmed by H NMR, 13C
NMR, MS and IR spectroscopy. The detailed data and associated
spectra were provided in the supporting information. The
structure of representative compound 4a was precisely
determined by single crystal X-ray analysis (Fig. 2). (See the
supporting information for more details).
Conclusion
We report a novel and convenient one-pot synthesis of multi-
substituted pyrano[2,3-c]pyrazole dicarboxlate derivatives using
three-component and four-component reactions. The four-
component reactions proceeded smoothly and resulted in good to
excellent yields. Our one-pot method offers several advantages,
including short reaction time, simple experimental procedure and
no toxic byproducts. The products are interesting nitrogen and
oxygen heterocyclic molecules containing two carboxyl groups.
4. Experimental
4.1. General information
All of the solvents were purified and dried prior to use. The
chemicals used in this study were analytical grade and purchased
from TCI, Alfa and Acros. The melting points were measured in
1
open capillary tubes and are uncorrected. The H and 13C NMR
spectra were recorded on
a Bruker INOVA–400 NMR
instrument at 400 MHz and 100 MHz using TMS as an internal
standard and DMSO-d6 as the solvent. The chemical shifts were
given in parts per million (d scale), and the coupling constants
were given in Hertz. Infrared (IR) spectra were recorded on a
BRUKER–EQUINOX55 spectrophotometer using KBr pellets.
ESI-MS spectra and HRMS data were obtained using a TOF-MS
spectrometer.
Figure 2. ORTEP diagram for the molecular structure of compound
4a.
A detailed reaction mechanism catalyzed by DABCO for the
formation of pyrano[2,3-c]pyrazole dicarboxylate were shown in
Scheme 3. The role of DABCO might just simply be serving as
an effective general base. Initially, spontaneous condensation of
methyl β-ketoesters with the hydrazine formed pyrazole-5-one,
and the Michael addition of malononitrile to dimethyl acetylene
dicarboxylate led to the formation of intermediate B,
4.2 General procedure for the three-component one-pot
synthesis of multi-substituted pyrano[2,3-c] pyrazole
dicarboxylates (4)

4
Tetrahedron
H) cm-1; ESI-MS m/z: 335 [M+H]+, 275, 261; HRMS (ESI) calcd
DABCO (20 % mmol) was added to a mixture of pyrazol-5-
ACCEPTED MANUSCRIPT
for C15H19N4O5 [M+H]+ 335.1277, found 335.1353.
one (2 mmol), dimethyl acetylenedicarboxylate (2 mmol) and
malononitrile (2 mmol) in 10 mL of EtOH. The reaction mixture
was heated at 50 ºC for 30–60 min. After the reaction was
completed, the mixture was cooled to room temperature. After 5
mL of water was added, the resulting clear solution was
maintained at room temperature for one additional day resulting
in the precipitation of large quantities of crystals. White or
colorless crystals were obtained via filtration with successive
washing with water and ethyl acetate. The pure product was
obtained by recrystallization in 80 % EtOH.
4.3.4. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-3-
isopropyl-2,4-dihydro-2,4-dihydro pyrano[2,3-c] pyrazole- 4-
carboxylate (4d). White crystals; mp: 218–220 ºC. 1H NMR (400
MHz, DMSO-d6): 12.30 (s, 1H, NH), 7.09 (s, 2H, NH2), 3.64 (s,
3H, OCH3), 3.42 (s, 3H, OCH3), 3.04 (d, 1H, J=15.2 Hz, CH2a),
2.90 (d, 1H, J=15.2 Hz, CH2b), 2.87 (m, 1H, J=6.8 Hz, CH), 1.19
(d, 3H, J=6.8 Hz, CH3), 1.09 (d, 3H, J=6.8 Hz, CH3); 13C NMR
(100 MHz, DMSO-d6): 172.5, 169.2, 161.7, 154.0, 145.4, 119.0,
92.6, 55.9, 52.8, 51.1, 43.6, 24.9, 21.7, 21.3; IR (KBr) ν: 3351,
3172 (brs, NH2), 2980, 2954 (C-H), 2195 (C≡N), 1731 (COO),
1662, 1602, 1495, 1408 (C=C, C=N), 1241, 1154, 1137, 1016
(C-O, C-N), 697, 629 (N-H) cm-1; ESI-MS m/z: 335 [M+H]+,
275, 261. HRMS (ESI) calcd for C15H19N4O5 [M+H]+ 335.1277,
found 335.1327.
4.3 General procedure for the four-component one-pot
synthesis of multi-substituted pyrano[2,3-c] pyrazole
dicarboxylates (4)
An
EtOH
(5
mL)
solution
containing
dimethyl
4.3.5. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-3-
acetylenedicarboxylate (2 mmol), malononitrile (2 mmol) and
DABCO (20 % mmol) was added dropwise within 5 min to a
stirred mixture of ethyl acetoacetate (2 mmol) and hydrazine (2
mmol) in EtOH (5 mL) at room temperature. Then, the reaction
mixture was stirred at 50 ºC for 30–60 min. After completion of
the reaction, a white or colorless crystal was obtained using a
method similar to one mentioned above.
phenyl-2,4-dihydropyrano[2,3-c]pyrazole-4-carboxylate
(4e).
1
White crystals; mp: 212–214 ºC. H NMR (400 MHz, DMSO-
d6): 12.82 (s, 1H, NH), 7.50–7.25 (m, 5H, C6H5), 7.24 (s, 2H,
NH2), 3.64 (s, 3H, OCH3), 3.36 (s, 3H, OCH3), 2.88 (d, 1H,
J=15.2 Hz, CH2a), 2.59 (d, 1H, J=15.2 Hz, CH2b); 13C NMR (100
MHz, DMSO-d6): 172.6, 169.0, 161.6, 154.9, 139.0, 129.2,
128.7, 127.9, 118.5, 95.3, 55.7, 52.9, 51.1, 43.4; IR (KBr) ν:
3306, 3183 (brs, NH, NH2), 2955 (C-H), 2193 (C≡N), 1731
(COO), 1641, 1599, 1500, 1407 (C=C, C=N), 1241, 1156, 1031
(C-O, C-N), 768, 688, 636 (C6H5) cm-1; ESI-MS m/z: 369
[M+H]+, 309, 295. HRMS (ESI) calcd for C18H17N4O4 [M+H]+
369.1121, found 369.1143.
4.3.1. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-3-
methyl-2,4-dihydropyrano[2,3-c] pyrazole-4-carboxylate (4a).
White crystals, mp: 212–214 ºC. H NMR (400 MHz, DMSO-
1
d6): 12.25 (s, 1H, NH), 7.08 (s, 2H, NH2), 3.65 (s, 3H, OCH3),
3.44 (s, 3H, OCH3), 3.06 (d, 1H, J=15.2 Hz, CH2a), 2.91 (d, 1H,
J=15.2 Hz, CH2b), 2.12 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6): 172.0, 169.2, 161.7, 154.5, 135.8, 119.0, 94.2, 55.8,
52.8, 51.2, 43.4, 10.3. IR (KBr) ν: 3322, 3173 (brs, NH, NH2),
2958 (C-H), 2196 (C≡N), 1733 (COO), 1662, 1601, 1497, 1409
(C=C, C=N), 1252, 1155, 1073, 1022 (C-O, C-N), 717, 580 (N-
H) cm-1; ESI-MS m/z: 307 [M+H]+, 247, 233; HRMS (ESI) calcd
for C13H15N4O5 [M+H]+ 307.0964, found 307.0995.
4.3.6. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-1,3-
dimethyl-4H-pyrano[2,3-c] pyrazole-4-carboxylate (4f). White
1
crystals; mp: 152–154 ºC. H NMR (400 MHz, DMSO-d6): 7.31
(s, 2H, NH2), 3.65 (s, 3H, OCH3), 3.57 (s, 3H, OCH3), 3.44 (s,
3H, CH3), 3.05–2.91 (dd, 2H, J=15.2 Hz, CH2), 2.01 (s, 3H,
CH3); 13C NMR (100 MHz, DMSO-d6): 171.8, 169.2, 160.5,
144.3, 142.0, 118.1, 92.8, 56.7, 52.8, 51.2, 44.2, 33.3, 12.9;
IR (KBr) ν: 3403, 3325, 3218 (brs, NH2), 2956 (C-H), 2199
(C≡N), 1736 (COO), 1663, 1561, 1437, 1403 (C=C, C=N), 1240,
1010 (C-O, C-N) cm-1; ESI-MS m/z: 321 [M+H]+; HRMS (ESI)
calcd for C14H16N4O5 [M+H]+ 321.1120, found 321.1155.
4.3.2. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-3-
ethyl-2,4-dihydropyrano[2,3-c] pyrazole-4-carboxylate (4b).
White crystals; mp: 232–234 ºC. H NMR (400 MHz, DMSO-
1
d6): 12.27 (s, 1H, NH), 7.09 (s, 2H, NH2), 3.64 (s, 3H, OCH3),
3.43 (s, 3H, OCH3), 3.05 (d, 1H, J=15.2 Hz, CH2a), 2.91 (d, 1H,
J=15.2 Hz, CH2b), 2.49 (q, 2H, CH2), 1.09(t, 3H, CH3); 13C NMR
(100 MHz, DMSO-d6): 172.3 (C1), 169.2, 161.7, 154.4, 141.1,
119.0, 93.5, 55.8, 52.8, 51.1, 43.5, 17.9, 12.5; IR (KBr) ν: 3321,
3280, 3169 (brs, NH, NH2), 2955 (C-H), 2196 (C≡N), 1732
(COO), 1662, 1598, 1498, 1410 (C=C, C=N), 1249, 1155, 1020
(C-O, C-N), 727, 585 (N-H) cm-1; ESI-MS m/z: 321 [M+H]+;
HRMS (ESI) calcd for C14H16N4O5 [M+H]+ 321.1120, found
321.1146.
4.3.7. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-1-
phenyl-3-methyl-4H-pyrano[2,3-c] pyrazole-4-carboxylate (4g).
White crystal; mp: 192–194 ºC. 1H NMR (400 MHz, DMSO-d6):
7.75–7.34 (m, 5H, C6H5), 7.49 (s, 2H, NH2), 3.71(s, 3H, OCH3),
3.47 (s, 3H, OCH3), 3.12–2.98 (dd, J=15.6 Hz, CH3), 2.14 (s,
3H, CH3); 13C NMR (100 MHz, DMSO-d6): 171.5, 169.3, 160.4,
144.6, 144.0, 137.1, 129.3, 126.4, 119.9, 118.1, 95.5, 56.5, 55.9,
53.0, 51.3, 43.9, 18.5, 13.1; IR (KBr) ν: 3440, 3337, 3226 (brs,
NH2), 2952 (C-H), 2193 (C≡N), 1737 (COO), 1702 (COO),
1646, 1521, 1444, 1395 (C=C, C=N), 1233, 1007 (C-O, C-N),
756, 696 cm-1; ESI-MS m/z: 383 [M+H]+, 405 [M+Na]+; HRMS
(ESI) calcd for C19H19N4O5 [M+H]+ 383.1254, found 383.1277.
4.3.3. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-3-
propyl-2,4-dihydropyrano[2,3-c] pyrazole-4-carboxylate (4c).
1
White crystals; mp: 237–239 ºC. H NMR (400 MHz, DMSO-
d6): 12.25(s, 1H, NH), 7.09(s, 2H, NH2), 3.63(s, 3H, OCH3),
3.43(s, 3H, OCH3), 3.04(d, 1H, J=15.2 Hz, CH2a), 2.45(m, 2H,
CH2), 2.91(d, 1H, J=15.2 Hz, CH2b), 1.51 (m, 2H, CH2), 0.85(t,
3H, CH3); 13C NMR (100 MHz, DMSO-d6): 172.4 (C1), 169.2,
161.7, 154.4, 139.6, 119.0, 93.9, 55.8, 52.8, 51.1, 43.4, 26.4,
20.9, 13.4; IR (KBr) ν: 3321, 3173 (brs, NH2), 2954 (C-H), 2195
(C≡N), 1730 (COO), 1720 (COO), 1661, 1595, 1495, 1408
(C=C, C=N), 1246, 1156, 1070, 1016 (C-O, C-N), 722, 580 (N-
4.3.8. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-1-
phenyl-3-ethyl-4H-pyrano[2,3-c]pyrazole-4-carboxylate
(4h).
1
White crystals; mp: 148–150 ºC. H NMR (400 MHz, DMSO-
d6): 7.77–7.34 (m, 5H, C6H5), 7.49 (s, 2H, NH2), 3.70 (s, 3H,
OCH3), 3.45 (s, 3H, OCH3), 3.10 (d, 1H, J=15.6 Hz, CH2a), 2.98
(d, 1H, J=15.6 Hz, CH2b), 2.50 (m, 2H, CH2), 1.17 (t, 3H, CH3);
13C NMR (100 MHz, DMSO-d6): 171.8, 169.3, 160.4, 149.2,
144.0, 137.2, 129.3, 126.4, 119.9, 118.1, 94.9, 56.6, 53.1, 51.3,
43.9, 40.0, 38.8, 20.3, 11.7; IR (KBr) ν: 3439, 3341, 3231 (brs,

5
cm-1; ESI-MS m/z: 445 [M+H]+. HRMS (ESI) calcd for
NH2), 2978, 2957 (C-H), 2195 (C≡N), 1739 (COO), 1707
(COO), 1648, 1578, 1519, 1440, 1398 (C=C, C=N), 1249, 1135,
1069, 1013 (C-O, C-N), 763, 691 cm-1. ESI-MS m/z: 397
[M+H]+. HRMS (ESI) calcd for C20H21N4O5 [M+H]+ 397.1434,
found 397.1477.
ACCEPTED MANUSCRIPT
C24H21N4O5 [M+H]+ 445.1590, found 445.1528.
4.3.12. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-1-
(o-chlorophenyl)-3-propyl-2,4-dihydropyrano[2,3-c]pyrazole- 4-
carboxylate (4 l). White crystals, mp: 188–190 ºC. 1H NMR (400
MHz, DMSO-d6): 7.70–7.52 (m, 4H, o-Cl-C6H4), 7.30 (s, 2H,
NH2), 3.72 (s, 3H, CH3), 3.46 (s, 3H, OCH3), 3.13 (d, 1H, J=15.6
4.3.9. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-1-
phenyl-3-propyl-4H-pyrano[2,3-c] pyrazole- 4-carboxylate (4i).
Hz, CH2a), 2.96 (d, 1H, J=15.6 Hz, CH2b), 2.14 (s, 3H, CH3); 13
C
1
White crystals; mp: 156–158 ºC. H NMR (400 MHz, DMSO-
d6): 7.33–7.78 (m, 5H, C6H5), 7.51 (s, 2H, NH2), 3.69 (s, 3H,
OCH3), 3.46 (s, 3H, OCH3), 3.10 (d, 1H, J=15.6 Hz, CH2a), 2.99
(d, 1H, J=15.6 Hz, CH2b), 2.48 (m, 2H, CH2), 1.61 (m, 2H, CH2),
0.93 (t, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): 171.8 (C1),
169.2, 160.4, 148.0, 143.9, 137.5, 129.3, 126.4, 119.9, 118.1,
95.16, 56.6, 53.01, 51.3, 43.9, 28.9, 20.4, 13.7; IR (KBr)
ν: 3490, 3356, 3194 (brs, NH2), 2957 (C-H), 2194 (C≡N), 1727
(2COO), 1658, 1596, 1520, 1454, 1396 (C=C, C=N), 1246, 1006
(C-O, C-N), 745, 684 cm-1; ESI-MS m/z: 411 [M+H]+. HRMS
(ESI) calcd for C21H23N4O5 [M+H]+ 411.1590, found 411.1566.
NMR (100 MHz, DMSO-d6): 171.6 (C1), 169.2, 160.4, 145.2,
145.1, 133.7, 131.2, 130.7, 130.2, 129.7, 128.2, 118.2, 93.9,
56.7, 53.0, 51.3, 44.3, 13.1; IR (KBr) ν: 3449, 3315, 3172 (brs,
NH2), 2198 (C≡N), 1736 (COO), 1664, 1582, 1538, 1436, 1399
(C=C, C=N), 1241, 1138, 1092, 1018 (C-O, C-N) cm-1; ESI-MS
m/z: 417 [M+H]+. HRMS (ESI) calcd for C19H18N4O5 [M+H]+
417.0887, found 417.0890.
4.3.13. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-1-
(p-chlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-4-
1
carboxylate (4m). White crystals; mp: 208–210 ºC. H NMR
(400 MHz, DMSO-d6): 7.80 (d, 2H, J=9.2 Hz, p-Cl-C6H4), 7.54
(d, 2H, J=9.2 Hz, p-Cl-C6H4), 7.52 (s, 2H, NH2), 3.70 (s, 3H,
CH3), 3.46 (s, 3H, OCH3), 3.12 (d, 1H, J=15.6 Hz, CH2a), 2.98
(d, 1H, J=15.6 Hz, CH2b), 2.14 (s, 3H, CH3); 13C NMR (100
MHz, DMSO-d6): 171.4 (C1), 169.2, 160.3, 145.1, 144.1, 135.9,
130.5, 129.2, 121.2, 118.0, 95.7, 56.5, 53.1, 51.3, 43.9, 13.1; IR
(KBr) ν: 3411, 3329, 3229 (brs, NH2), 2955 (C-H), 2196 (C≡N),
1722 (COO), 1659, 1591, 1523, 1393 (C=C, C=N), 1237, 1161,
1092, 1025 (C-O, C-N) cm-1; ESI-MS m/z: 417 [M+H]+. HRMS
(ESI) calcd for C19H18N4O5 [M+H]+ 417.0887, found 417.0967.
4.3.10. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-1-
phenyl-3-isopropyl-4H-pyrano[2,3-c]pyrazole-4-carboxylate
(4j). White crystals; mp: 182–184 ºC. 1H NMR (400 MHz,
DMSO-d6): 7.51 (s, 2H, NH2), 7.34–7.76 (m, 5H, C6H5), 3.70 (s,
3H, OCH3), 3.45 (s, 3H, OCH3), 3.10 (d, J=15.2 Hz, CH2a), 2.98
(d, J=15.2 Hz, CH2b), 2.80 (m, 1H, J=6.8 Hz, CH), 1.24 (d, 3H,
J=6.8 Hz), 1.12 (d, 3H, J=6.8 Hz); 13C NMR (100 MHz, DMSO-
d6): 172.0 (C1), 169.2, 160.3, 153.5, 143.5, 137.1, 129.3, 126.4,
120.0, 118.1, 94.2, 56.7, 53.0, 51.3, 44.0, 26.6, 22.2, 21.7; IR
(KBr) ν: 3388, 3318, 3209 (brs, NH2), 2971 (C-H), 2200 (C≡N),
1748 (COO), 1725 (COO), 1663, 1598, 1520, 1456, 1396 (C=C,
C=N), 1228, 1166, 1091, 1000 (C-O, C-N), 754, 691 cm-1; ESI-
MS m/z: 411 [M+H]+. HRMS (ESI) calcd for C21H23N4O5
[M+H]+ 411.1590, found 411.1559.
Acknowledgements
This work was supported by the Natural Science Foundation of
China (No. 21162028), the Natural Science Foundation of the
Xinjiang Science Technology Agency (No. 2009 211A02) and
the Tianshan Talent Cultivation Project of Xingjiang Uyghur
Autonomous Region.
4.3.11. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-
1,3-diphenyl-4H-pyrano[2,3-c] pyrazole-4-carboxylate (4k).
1
White crystals; mp: 220–224 ºC. H NMR (400 MHz, DMSO-
d6): 7.36–7.87 (m, 10H, 2C6H5), 7.64 (s, 2H, NH2), 3.70 (s, 3H,
OCH3), 3.40 (s, 3H, OCH3), 2.97 (d, 1H, J=15.6 Hz, CH2); 13C
NMR (100 MHz, DMSO-d6): 172.0, 169.0, 160.3, 147.4, 144.5,
136.9, 132.5, 129.5, 128.7, 128.5, 127.7, 127.0, 120.4, 117.7,
95.9, 56.6, 53.1, 51.2, 44.0; IR (KBr) ν: 3401, 3323, 3210 (brs,
NH2), 2954 (C-H), 2200 (C≡N), 1736 (COO), 1657, 1596, 1520,
1454, 1401 (C=C, C=N), 1240, 1074, 997 (C-O, C-N), 755, 688
Supplementary Material
Supplementary data associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/j.tet.
References and notes
1. (a) Fischer, D. S.; Allan, G. M.; Bubert, C; Vicker, N;
Smith, A.; Tutill, H. J.; Purohit, A.; Wood, L.; Packham,
G.; Mahon, M. F.; Reed, M. J.; Potter, B. V. J. Med. Chem.
2005, 48, 5749–5770; (b) Yang, Y. S.; Li, Q. S.; Sun, S.;
Zhang, Y. B.; Wang, X. L.; Zhang, F.; Tang, J. F.; Zhu, H.
L. Bioorg. Med. Chem. 2012, 20: 6048–6058.
2. (a) Cingolani, G. M.; Gualtteri, F.; Pigin, M. J. Med. Chem.
1961, 12, 531. (b) Wu, J. Y. C.; Fong, W. F.; Zhang, J. X.;
Leung, C. H.; Kwong, H. L.; Yang, M. S.; Li,D.; Cheung,
H. Y. Eur. J. Pharmacol. 2003, 473, 9–17.
3. (a) Bian, L.; Xu, J.; Xie, L.; Chen, J.; Deng, H.; Shao, M.;
Ding, T.; Zhang, H.; Cao, W. Tetrahedron, 2013, 69,
6121–6128; (b) Cui, S.; Wang, J.; Wang, Y. Tetrahedron,
2008, 64, 487–492; (c) Dong, Z. H.; Liu, X. H.; Feng, J.
H.; Wang, M.; Lin, L. L.; Fen, X. M. Eur. J. Org. Chem.
2011, 137–142; (d) Moon, D.; Kim, M.; Kang, S.; Choi,
Y.; Park, S.; Kim, G. Cancer Lett. 2010, 292, 111–118; (e)
Sabry, N. M.; Mohamed, H. M.; Khattab, E. S. A. E. H.;
Motlaq, S. S.; El-Agrody, A. M. Eur. J. Med. Chem. 2011,
46, 765–772; (f) Costa, M.; Proenca, F. Tetrahedron 2011,
67, 1799–1804; (g) Yao, C.; Jiang, B.; Li, T.; Qin, B.;
Feng, X.; Zhang, H.; Wang, C.; Tu, S. Bioorg. Med. Chem.
Lett. 2011, 21, 599–601.
4. (a) Foloppe, N.; Fisher, L. M.; Howes, R.; Potter, A.;
Robertson, A. G.; Surgenor, A. E. Bioorg. Med. Chem,
2006, 14, 4792–4802; (b) Abdelrazek, F. M.; Metz, P.;
Kataeva, O.; Jäger, A.; El-Mahrouky, S. F. Arch Pharm
(Weinheim). 2007, 340, 543–548; (c) La Motta, C.; Sartini,
S.; Tuccinardi, T.; Nerini, E.; Da Settimo, F.; Martinelli, A.
J. Med. Chem., 2009, 52, 964–975.
5. Karthikeyan, K.; Veenus Seelan, T.; Lalitha, K. G.;
Perumal, P. T. Bioorg. Med. Chem. Lett. 2009, 19, 3370–
3373.
6. (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168–3210; (b) Kappe, C. O. Acc. Chem. Res. 2000, 33,
879–888; (c) Domling, A. Chem. Rev. 2006, 106, 17–89;

6
Tetrahedron
ACCEPTED MANUSCRIPT
(d) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed.
2004, 43, 46–58.
12. Bremner, W. S.; Organ, M. G. J. Comb. Chem. 2006, 9,
14–16.
7. (a) Tietze, L. F. Chem. Rev. 1996, 96, 115–135; (b)
Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112,
3083–3135; (c) Han, Y.; Wu, Q.; Sun, J.; Yan, C.–G.
Tetrahedron 2012, 68, 8539–8544.
13. (a) Boominathan, M.; Nagaraj, M.; Muthusubramanian, S.;
Krishnakumar, R. V. Tetrahedron 2011, 67, 6057–6064; (b)
Kazemi, B.; Javanshir, S.; Maleki, A.; Safari, M.; Khavasi,
H. R. Tetrahedron Lett., 53, 2012, 6977-6981.
8. Asghari, S.; Habibi, A. K. Tetrahedron 2012, 68, 8890–
8898.
14. Prasanna, P.; Perumal, S.; Menendez, J. C. Green Chem.
2013, 15, 1292–1299.
9. (a) Guo, R. Y.; An, Z. M.; Mo, L. P.; Yang, S. T.; Liu, H.
X.; Wang, S. X.; Zhang, Z. H. Tetrahedron, 2013,
69, 9931–9938; (b) Ablajan, K.; Maimaiti, Z. Synth.
Commun. 2012, 42, 1959–1966; (c) Bakthadoss, M.;
Kannan, D.; Selvakumar, R. Comm. Commun., 2013, 49,
10947–10949; (d) Parmar, N. J.; Barad, H. A.; Pansuriya,
B. R.; Talpada, N. P. RSC Adv., 2013, 3, 8064–8070.
10. (a) Pal, S.; Khan, M. N.; Karamthulla, S.; Abbas, S. J.;
Choudhury, L. H. Tetrahedron Lett. 2013, 54, 5434–5440.
(b) Pericherla, K.; Kumar, A.; Jha, A. Org. Lett. 2013, 15,
4078–4081; (c) Feng, X.; Wang, Q.; Lin, W.; Dou, G.-L.;
Huang, Z.-B.; Shi, D.-Q. Org. Lett. 2013, 15, 2542–2545;
(d) Chinchilla, R.; Nájera, C. Chem. Rev. 2013.
15. (a) Shestopalov, A. M.; Emeliyanova, Y. M.; Shestopalov,
A. A.; Rodinovskaya, L. A.; Niazimbetova, Z. I.; Evans, D.
H. Org. Lett. 2002, 4, 423–425; (b) Wu, B.; Chen, J. Li, M.;
Zhang, J.; Xu, X.; Ji, S.; Wang, X. Eur. J. Org. Chem.
2012, 7, 1318–1327; (c) Shaabani, A.; Sarvary, A.;
Rezayan, A. H.; Keshipour S. Tetrahedron, 65, 2009,
3492–3495.
16. (a) Khurana, J. M.; Nand, B.; Kumar. S. Synth. Commun.
2011, 41, 405–410; (b) Elinson, M. N.; Dorofeev, A. S.;
Miloserdov, F. M.; Nikishinh, G. I. Mol. Divers, 2099, 13,
47–52; (c) Redkin, R. G.; Shemchuk, L. A.; Chernykh, V.
P. ;Shishkin, O. V.; Shishkina, S. V. Tetrahedron 2007, 63,
11444–11450; (d) Dania, A.; Parewa, V.; Jain, A. K.;
Rathor, K. S. Green Chem. 2011, 13, 2135–2145.
11. Liu, X. Y; Ding, P.; Huang. J. S.;, Che, C. M. Org. Lett.,
2007, 9, 2645–2648

ACCEPTED MANUSCRIPT
Supporting Information
Convenient DABCO-catalyzed one-pot synthesis of multi-substituted
pyrano[2,3-c]pyrazole dicarboxylates
Ablajan, Keyume*, Zeynepgul Esmayil, Liju Wang and Feng Jun
Key Laboratory of Oil & Gas Fine Chemicals Ministry of Education& Xinjiang Uyghur Autonomous
Region, College of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, P. R.
China.
E-mail: ablajan209@hotmail.com
CONTENTS
1. General information.................................................................................................................S2
2. General procedure for the preparation of compounds 4a-4m..................................................S2
3. Physical and spectroscopic data for compounds 4a-4m.....................................................S3-S8
4. 1H NMR, 13C NMR, IR and MS spectra...........................................................................S8-S32
5. X-ray crystallographic data for compound 4a.................................................................S33-S40
1

ACCEPTED MANUSCRIPT
1. General information
All of the solvents were purified and dried prior to use. The chemicals used in this study were analytical grade
and purchased from TCI, Alfa and Acros. The melting points were measured in open capillary tubes and are
1
uncorrected. The H and 13C NMR spectra were recorded on a Bruker INOVA–400 NMR instrument at 400
MHz and 100 MHz using TMS as an internal standard and DMSO-d6 as the solvent. The chemical shifts were
given in parts per million (d scale), and the coupling constants were given in Hertz. Infrared (IR) spectra were
recorded on a BRUKER–EQUINOX55 spectrophotometer using KBr pellets. ESI-MS spectra and HRMS data
were obtained using a TOF-MS spectrometer.
2. General procedure for the preparation of compounds 4a-4m
(1) General procedure for the three-component one-pot synthesis of multisubstituted pyrano[2,3-c]
pyrazole dicarboxylates (4)
DABCO (20 % mmol) was added to a mixture of pyrazol-5-one (2 mmol), dimethyl acetylenedicarboxylate (2
mmol) and malononitrile (2 mmol) in 10 mL of EtOH. The reaction mixture was heated at 50 ºC for 30–60 min.
After the reaction was completed, the mixture was cooled to roomtemperature. After 5 mL of water was added,
the resulting clear solution was maintained at room temperature for one additional day resulting in the
precipitation of large quantities of crystals. White or colorless crystals were obtained via filtration with
successive washing with water and ethyl acetate. The pure product was obtained by recrystallization in 80 %
EtOH.
(2) General procedure for the four-component one-pot synthesis of multisubstituted pyrano[2,3-c]
pyrazole dicarboxylates (4)
An EtOH (5 mL) solution containing dimethyl acetylenedicarboxylate (2 mmol), malononitrile (2 mmol) and
DABCO (20 % mmol) was added dropwise within 5 min to a stirred mixture of ethyl acetoacetate (2 mmol) and
hydrazine (2 mmol) in EtOH (5 mL) at room temperature. Then, the reaction mixture was stirred at 50 ºC for
30–60 min. After completion of the reaction, a white or colorless crystal was obtained using a method similar to
one mentioned above.
2

ACCEPTED MANUSCRIPT
3. Physical and spectroscopic data for compounds 4a-4m
CO2CH3
COOCH3
H3C
HN
CN
N
NH2
O
4.3.1.
Methyl
6-amino-5-cyano-4-(methoxycarbonylmethyl)-3-methyl-2,4-dihydropyrano[2,3-c]
1
pyrazole-4-carboxylate (4a). White crystals, mp: 212–214 ºC. H NMR (400 MHz, DMSO-d6): 12.25
(s, 1H, NH), 7.08 (s, 2H, NH2), 3.65 (s, 3H, OCH3), 3.44 (s, 3H, OCH3), 3.06 (d, 1H, J=15.2 Hz,
CH2a), 2.91 (d, 1H, J=15.2 Hz, CH2b), 2.12 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): 172.0,
169.2, 161.7, 154.5, 135.8, 119.0, 94.2, 55.8, 52.8, 51.2, 43.4, 10.3. IR (KBr) ν: 3322, 3173 (brs, NH,
NH2), 2958 (C-H), 2196 (C≡N), 1733 (COO), 1662, 1601, 1497, 1409 (C=C, C=N), 1252, 1155, 1073,
1022 (C-O, C-N), 717, 580 (N-H) cm-1; ESI-MS m/z: 307 [M+H]+, 247, 233; HRMS (ESI) calcd for
C13H15N4O5 [M+H]+ 307.0964, found 307.0995.
CO2CH3
COOCH3
CN
H3CH2C
HN
N
NH2
O
4.3.2.
Methyl
6-amino-5-cyano-4-(methoxycarbonylmethyl)-3-ethyl-2,4-dihydropyrano[2,3-c]
pyrazole-4- carboxylate (4b). White crystals; mp: 232–234 ºC. 1H NMR (400 MHz, DMSO-d6): 12.27
(s, 1H, NH), 7.09 (s, 2H, NH2), 3.64 (s, 3H, OCH3), 3.43 (s, 3H, OCH3), 3.05 (d, 1H, J=15.2 Hz,
CH2a), 2.91 (d, 1H, J=15.2 Hz, CH2b), 2.49 (q, 2H, CH2), 1.09(t, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6): 172.3 (C1), 169.2, 161.7, 154.4, 141.1, 119.0, 93.5, 55.8, 52.8, 51.1, 43.5, 17.9, 12.5; IR
(KBr) ν: 3321, 3280, 3169 (brs, NH, NH2), 2955 (C-H), 2196 (C≡N), 1732 (COO), 1662, 1598, 1498,
1410 (C=C, C=N), 1249, 1155, 1020 (C-O, C-N), 727, 585 (N-H) cm-1; ESI-MS m/z: 321 [M+H]+;
HRMS (ESI) calcd for C14H16N4O5 [M+H]+ 321.1120, found 321.1146.
CO2CH3
COOCH3
CN
H3CH2CH2C
HN
N
NH2
O
4.3.3.
Methyl
6-amino-5-cyano-4-(methoxycarbonylmethyl)-3-propyl-2,4-dihydropyrano[2,3-c]
1
pyrazole-4-carboxylate (4c). White crystals; mp: 237–239 ºC. H NMR (400 MHz, DMSO-d6):
12.25(s, 1H, NH), 7.09(s, 2H, NH2), 3.63(s, 3H, OCH3), 3.43(s, 3H, OCH3), 3.04(d, 1H, J=15.2 Hz,
CH2a), 2.45(m, 2H, CH2), 2.91(d, 1H, J=15.2 Hz, CH2b), 1.51 (m, 2H, CH2), 0.85(t, 3H, CH3); 13C
NMR (100 MHz, DMSO-d6): 172.4 (C1), 169.2, 161.7, 154.4, 139.6, 119.0, 93.9, 55.8, 52.8, 51.1,
43.4, 26.4, 20.9, 13.4; IR (KBr) ν: 3321, 3173 (brs, NH2), 2954 (C-H), 2195 (C≡N), 1730 (COO),
1720 (COO), 1661, 1595, 1495, 1408 (C=C, C=N), 1246, 1156, 1070, 1016 (C-O, C-N), 722, 580
(N-H) cm-1; ESI-MS m/z: 335 [M+H]+, 275, 261; HRMS (ESI) calcd for C15H19N4O5 [M+H]+
335.1277, found 335.1353.
3

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
CH3
H3C
CN
HN
N
NH2
O
4.3.4. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-3-isopropyl-2,4-dihydro-2,4-dihydro
1
pyrano [2,3-c]pyrazole-4-carboxylate (4d). White crystals; mp: 218–220 ºC. H NMR (400 MHz,
DMSO-d6): 12.30 (s, 1H, NH), 7.09 (s, 2H, NH2), 3.64 (s, 3H, OCH3), 3.42 (s, 3H, OCH3), 3.04 (d,
1H, J=15.2 Hz, CH2a), 2.90 (d, 1H, J=15.2 Hz, CH2b), 2.87 (m, 1H, J=6.8 Hz, CH), 1.19 (d, 3H, J=6.8
Hz, CH3), 1.09 (d, 3H, J=6.8 Hz, CH3); 13C NMR (100 MHz, DMSO-d6): 172.5, 169.2, 161.7, 154.0,
145.4, 119.0, 92.6, 55.9, 52.8, 51.1, 43.6, 24.9, 21.7, 21.3; IR (KBr) ν: 3351, 3172 (brs, NH2), 2980,
2954 (C-H), 2195 (C≡N), 1731 (COO), 1662, 1602, 1495, 1408 (C=C, C=N), 1241, 1154, 1137, 1016
(C-O, C-N), 697, 629 (N-H) cm-1; ESI-MS m/z: 335 [M+H]+, 275, 261. HRMS (ESI) calcd for
C15H19N4O5 [M+H]+ 335.1277, found 335.1327.
CO2CH3
COOCH3
CN
C6H5
HN
N
NH2
O
4.3.5.
Methyl
6-amino-5-cyano-4-(methoxycarbonylmethyl)-3-phenyl-2,4-dihydropyrano[2,3-c]
1
pyrazole-4-carboxylate (4e). White crystals; mp: 212–214 ºC. H NMR (400 MHz, DMSO-d6): 12.82
(s, 1H, NH), 7.50–7.25 (m, 5H, C6H5), 7.24 (s, 2H, NH2), 3.64 (s, 3H, OCH3), 3.36 (s, 3H, OCH3),
2.88 (d, 1H, J=15.2 Hz, CH2a), 2.59 (d, 1H, J=15.2 Hz, CH2b); 13C NMR (100 MHz, DMSO-d6): 172.6,
169.0, 161.6, 154.9, 139.0, 129.2, 128.7, 127.9, 118.5, 95.3, 55.7, 52.9, 51.1, 43.4; IR (KBr) ν: 3306,
3183 (brs, NH, NH2), 2955 (C-H), 2193 (C≡N), 1731 (COO), 1641, 1599, 1500, 1407 (C=C, C=N),
1241, 1156, 1031 (C-O, C-N), 768, 688, 636 (C6H5) cm-1; ESI-MS m/z: 369 [M+H]+, 309, 295.
HRMS (ESI) calcd for C18H17N4O4 [M+H]+ 369.1121, found 369.1143.
CO2CH3
COOCH3
CN
H3C
N
N
NH2
O
CH3
4.3.6. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-1,3-dimethyl-4H-pyrano[2,3-c] pyrazole-
1
4-carboxylate (4f). White crystals; mp: 152–154 ºC. H NMR (400 MHz, DMSO-d6): 7.31 (s, 2H,
NH2), 3.65 (s, 3H, OCH3), 3.57 (s, 3H, OCH3), 3.44 (s, 3H, CH3), 3.05–2.91 (dd, 2H, J=15.2 Hz,
CH2), 2.01 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): 171.8, 169.2, 160.5, 144.3, 142.0, 118.1,
92.8, 56.7, 52.8, 51.2, 44.2, 33.3, 12.9; IR (KBr) ν: 3403, 3325, 3218 (brs, NH2), 2956 (C-H), 2199
(C≡N), 1736 (COO), 1663, 1561, 1437, 1403 (C=C, C=N), 1240, 1010 (C-O, C-N) cm-1; ESI-MS m/z:
321 [M+H]+; HRMS (ESI) calcd for C14H16N4O5 [M+H]+ 321.1120, found 321.1155.
4

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
H3C
N
CN
N
NH2
O
C6H5
4.3.7. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-1-phenyl-3-methyl-4H-pyrano[2,3-c]
1
pyrazole- 4-carboxylate (4g). White crystal; mp: 192–194 ºC. H NMR (400 MHz, DMSO-d6):
7.75–7.34 (m, 5H, C6H5), 7.49 (s, 2H, NH2), 3.71(s, 3H, OCH3), 3.47 (s, 3H, OCH3), 3.12–2.98 (dd,
J=15.6 Hz, CH3), 2.14 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): 171.5, 169.3, 160.4, 144.6,
144.0, 137.1, 129.3, 126.4, 119.9, 118.1, 95.5, 56.5, 55.9, 53.0, 51.3, 43.9, 18.5, 13.1; IR (KBr) ν:
3440, 3337, 3226 (brs, NH2), 2952 (C-H), 2193 (C≡N), 1737 (COO), 1702 (COO), 1646, 1521, 1444,
1395 (C=C, C=N), 1233, 1007 (C-O, C-N), 756, 696 cm-1; ESI-MS m/z: 383 [M+H]+, 405 [M+Na]+;
HRMS (ESI) calcd for C19H19N4O5 [M+H]+ 383.1254, found 383.1277.
CO2CH3
COOCH3
CN
H3CH2C
N
N
NH2
O
C6H5
4.3.8.
Methyl
6-amino-5-cyano-4-(methoxycarbonylmethyl)-1-phenyl-3-ethyl-4H-pyrano[2,3-c]
1
pyrazole-4-carboxylate (4h). White crystals; mp: 148–150 ºC. H NMR (400 MHz, DMSO-d6):
7.77–7.34 (m, 5H, C6H5), 7.49 (s, 2H, NH2), 3.70 (s, 3H, OCH3), 3.45 (s, 3H, OCH3), 3.10 (d, 1H,
J=15.6 Hz, CH2a), 2.98 (d, 1H, J=15.6 Hz, CH2b), 2.50 (m, 2H, CH2), 1.17 (t, 3H, CH3); 13C NMR
(100 MHz, DMSO-d6): 171.8, 169.3, 160.4, 149.2, 144.0, 137.2, 129.3, 126.4, 119.9, 118.1, 94.9,
56.6, 53.1, 51.3, 43.9, 40.0, 38.8, 20.3, 11.7; IR (KBr) ν: 3439, 3341, 3231 (brs, NH2), 2978, 2957
(C-H), 2195 (C≡N), 1739 (COO), 1707 (COO), 1648, 1578, 1519, 1440, 1398 (C=C, C=N), 1249,
1135, 1069, 1013 (C-O, C-N), 763, 691 cm-1. ESI-MS m/z: 397 [M+H]+. HRMS (ESI) calcd for
C20H21N4O5 [M+H]+ 397.1434, found 397.1477.
CO2CH3
COOCH3
CN
H3CH2CH2C
N
N
NH2
O
C6H5
4.3.9. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-1-phenyl-3-propyl-4H-pyrano[2,3-c]
1
pyrazole- 4-carboxylate (4i). White crystals; mp: 156–158 ºC. H NMR (400 MHz, DMSO-d6):
7.33–7.78 (m, 5H, C6H5), 7.51 (s, 2H, NH2), 3.69 (s, 3H, OCH3), 3.46 (s, 3H, OCH3), 3.10 (d, 1H,
J=15.6 Hz, CH2a), 2.99 (d, 1H, J=15.6 Hz, CH2b), 2.48 (m, 2H, CH2), 1.61 (m, 2H, CH2), 0.93 (t, 3H,
CH3); 13C NMR (100 MHz, DMSO-d6): 171.8 (C1), 169.2, 160.4, 148.0, 143.9, 137.5, 129.3, 126.4,
119.9, 118.1, 95.16, 56.6, 53.01, 51.3, 43.9, 28.9, 20.4, 13.7; IR (KBr) ν: 3490, 3356, 3194 (brs, NH2),
5

ACCEPTED MANUSCRIPT
2957 (C-H), 2194 (C≡N), 1727 (2COO), 1658, 1596, 1520, 1454, 1396 (C=C, C=N), 1246, 1006
(C-O, C-N), 745, 684 cm-1; ESI-MS m/z: 411 [M+H]+. HRMS (ESI) calcd for C21H23N4O5 [M+H]+
411.1590, found 411.1566.
CH3
CO2CH3
COOCH3
H3C
CN
N
N
NH2
O
C6H5
4.3.10. Methyl 6-amino-5-cyano-4-(methoxycarbonylmethyl)-1-phenyl-3-isopropyl-4H-pyrano[2,3-c]
1
pyrazole-4-carboxylate (4j). White crystals; mp: 182–184 ºC. H NMR (400 MHz, DMSO-d6): 7.51 (s,
2H, NH2), 7.34–7.76 (m, 5H, C6H5), 3.70 (s, 3H, OCH3), 3.45 (s, 3H, OCH3), 3.10 (d, J=15.2 Hz,
CH2a), 2.98 (d, J=15.2 Hz, CH2b), 2.80 (m, 1H, J=6.8 Hz, CH), 1.24 (d, 3H, J=6.8 Hz), 1.12 (d, 3H,
J=6.8 Hz); 13C NMR (100 MHz, DMSO-d6): 172.0 (C1), 169.2, 160.3, 153.5, 143.5, 137.1, 129.3,
126.4, 120.0, 118.1, 94.2, 56.7, 53.0, 51.3, 44.0, 26.6, 22.2, 21.7; IR (KBr) ν: 3388, 3318, 3209 (brs,
NH2), 2971 (C-H), 2200 (C≡N), 1748 (COO), 1725 (COO), 1663, 1598, 1520, 1456, 1396 (C=C,
C=N), 1228, 1166, 1091, 1000 (C-O, C-N), 754, 691 cm-1; ESI-MS m/z: 411 [M+H]+. HRMS (ESI)
calcd for C21H23N4O5 [M+H]+ 411.1590, found 411.1559.
CO2CH3
COOCH3
CN
C6H5
N
N
NH2
O
C6H5
4.3.11.
Methyl
6-amino-5-cyano-4-(methoxycarbonylmethyl)-1,3-diphenyl-4H-pyrano[2,3-c]
1
pyrazole- 4-carboxylate (4k). White crystals; mp: 220–224 ºC. H NMR (400 MHz, DMSO-d6):
7.36–7.87 (m, 10H, 2C6H5), 7.64 (s, 2H, NH2), 3.70 (s, 3H, OCH3), 3.40 (s, 3H, OCH3), 2.97 (d, 1H,
J=15.6 Hz, CH2); 13C NMR (100 MHz, DMSO-d6): 172.0, 169.0, 160.3, 147.4, 144.5, 136.9, 132.5,
129.5, 128.7, 128.5, 127.7, 127.0, 120.4, 117.7, 95.9, 56.6, 53.1, 51.2, 44.0; IR (KBr) ν: 3401, 3323,
3210 (brs, NH2), 2954 (C-H), 2200 (C≡N), 1736 (COO), 1657, 1596, 1520, 1454, 1401 (C=C, C=N),
1240, 1074, 997 (C-O, C-N), 755, 688 cm-1; ESI-MS m/z: 445 [M+H]+. HRMS (ESI) calcd for
C24H21N4O5 [M+H]+ 445.1590, found 445.1528.
CO2CH3
H3C
N
COOCH3
CN
N
NH2
O
C6H4-Cl-o
4.3.12.
Methyl
6-amino-5-cyano-4-(methoxycarbonylmethyl)-1-(o-chlorophenyl)-3-propyl-2,4-
1
dihydropyrano[2,3-c]pyrazole-4-carboxylate (4 l). White crystals, mp: 188–190 ºC. H NMR (400
MHz, DMSO-d6): 7.70–7.52 (m, 4H, o-Cl-C6H4), 7.30 (s, 2H, NH2), 3.72 (s, 3H, CH3), 3.46 (s, 3H,
6

ACCEPTED MANUSCRIPT
OCH3), 3.13 (d, 1H, J=15.6 Hz, CH2a), 2.96 (d, 1H, J=15.6 Hz, CH2b), 2.14 (s, 3H, CH3); 13C NMR
(100 MHz, DMSO-d6): 171.6 (C1), 169.2, 160.4, 145.2, 145.1, 133.7, 131.2, 130.7, 130.2, 129.7,
128.2, 118.2, 93.9, 56.7, 53.0, 51.3, 44.3, 13.1; IR (KBr) ν: 3449, 3315, 3172 (brs, NH2), 2198 (C≡N),
1736 (COO), 1664, 1582, 1538, 1436, 1399 (C=C, C=N), 1241, 1138, 1092, 1018 (C-O, C-N) cm-1;
ESI-MS m/z: 417 [M+H]+. HRMS (ESI) calcd for C19H18N4O5 [M+H]+ 417.0887, found 417.0890.
CO2CH3
COOCH3
CN
H3C
N
N
NH2
O
C6H4-Cl-p
4.3.13.
Methyl
6-amino-5-cyano-4-(methoxycarbonylmethyl)-1-(p-chlorophenyl)-3-methyl-2,4
1
-dihydropyrano[2,3-c]pyrazole-4-carboxylate (4m). White crystals; mp: 208–210 ºC. H NMR (400
MHz, DMSO-d6): 7.80 (d, 2H, J=9.2 Hz, p-Cl-C6H4), 7.54 (d, 2H, J=9.2 Hz, p-Cl-C6 H4), 7.52 (s, 2H,
NH2), 3.70 (s, 3H, CH3), 3.46 (s, 3H, OCH3), 3.12 (d, 1H, J=15.6 Hz, CH2a), 2.98 (d, 1H, J=15.6 Hz,
CH2b), 2.14 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): 171.4 (C1), 169.2, 160.3, 145.1, 144.1,
135.9, 130.5, 129.2, 121.2, 118.0, 95.7, 56.5, 53.1, 51.3, 43.9, 13.1; IR (KBr) ν: 3411, 3329, 3229 (brs,
NH2), 2955 (C-H), 2196 (C≡N), 1722 (COO), 1659, 1591, 1523, 1393 (C=C, C=N), 1237, 1161, 1092,
1025 (C-O, C-N) cm-1; ESI-MS m/z: 417 [M+H]+. HRMS (ESI) calcd for C19H18N4O5 [M+H]+
417.0887, found 417.0967.
7

ACCEPTED MANUSCRIPT
4. 1H NMR, 13C NMR, IR and MS spectra of compounds 4a-4m
CO2CH3
COOCH3
CN
H3C
HN
N
NH2
O
4a
CO2CH3
COOCH3
H3C
CN
HN
N
NH2
O
4a
8

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
H3C
HN
CN
N
NH2
O
4a
a=3.59580614634598390e-004, t0=-1.86816612587017870e-001(TurboSpray), subtracted(0.033to0.050min), Smoothed, Smoothe
233.0672
3.8e4
307.0995
3.6e4
3.4e4
CO2CH3
3.2e4
3.0e4
COOCH3
CN
H3C
HN
2.8e4
2.6e4
2.4e4
2.2e4
2.0e4
1.8e4
1.6e4
1.4e4
1.2e4
1.0e4
8000.0
6000.0
4000.0
2000.0
0.0
247.0866
N
NH2
O
4a
100
150
200
250
300
350
400
450
500
550
m/z, Da
600
650
700
9

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
H3CH2C
HN
CN
N
NH2
O
4b
CO2CH3
COOCH3
CN
H3CH2C
HN
N
NH2
O
4b
10

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
H3CH2C
HN
CN
N
NH2
O
4b
+TOFMS: 0.267minfromSample196(2-5-168)of 201307.wiff
a=3.59580614634598390e-004, t0=-1.86816612587017870e-001(TurboSpray), subtracted(0.033to0.050min)
321.1210
3.4e4
3.2e4
3.0e4
2.8e4
2.6e4
2.4e4
2.2e4
2.0e4
1.8e4
1.6e4
1.4e4
1.2e4
1.0e4
8000.0
6000.0
4000.0
2000.0
0.0
CO2CH3
COOCH3
H3CH2C
HN
CN
N
NH2
O
4b
247.0858
261.0967
250
100
150
200
300
350
400
450
500
550
m/z, Da
600
650
700
11

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
H3CH2CH2C
HN
CN
N
NH2
O
4c
CO2CH3
COOCH3
H3CH2CH2C
HN
CN
N
NH2
O
4c
12

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
H3CH2CH2C
HN
CN
N
NH2
O
4c
+TOFMS: 0.267minfromSample195(2-5-167)of 201307.wiff
a=3.59580614634598390e-004, t0=-1.86816612587017870e-001(TurboSpray), subtracted(0.017to0.033min), Smoothed, Smoothe
335.1353
4.0e4
3.8e4
3.6e4
3.4e4
3.2e4
3.0e4
CO2CH3
2.8e4
COOCH3
CN
H3CH2CH2C
HN
2.6e4
2.4e4
2.2e4
2.0e4
1.8e4
1.6e4
1.4e4
1.2e4
1.0e4
8000.0
6000.0
4000.0
2000.0
N
NH2
O
4c
261.1028
100
150
200
250
300
350
400
450
500
550
m/z, Da
600
650
700
13

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
CH3
H3C
CN
HN
N
NH2
O
4d
CO2CH3
COOCH3
CH3
H3C
CN
HN
N
NH2
O
4d
14

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
CH3
H3C
CN
HN
N
NH2
O
4d
+TOFMS: 0.284minfromSample194(2-4-166)of 201307.wiff
a=3.59580614634598390e-004, t0=-1.86816612587017870e-001(TurboSpray), subtracted(0.033to0.050min), Smoothed, Smoothe...
335.1296
3.8e4
3.6e4
3.4e4
3.2e4
3.0e4
CO2CH3
COOCH3
CH3
2.8e4
2.6e4
2.4e4
2.2e4
2.0e4
1.8e4
1.6e4
1.4e4
1.2e4
1.0e4
8000.0
6000.0
4000.0
2000.0
261.0998
H3C
CN
HN
N
NH2
O
4d
100
150
200
250
300
350
400
450
500
550
m/z, Da
600
650
700
7
15

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
C6H5
HN
CN
N
NH2
O
4e
CO2CH3
COOCH3
CN
C6H5
HN
N
NH2
O
4e
16

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
CN
C6H5
HN
N
NH2
O
4e
+TOFMS: 0.267minfromSample202(2-6-192)of 201307.wiff
a=3.59580614634598390e-004, t0=-1.86816612587017870e-001(TurboSpray), subtracted(0.033to0.050min)
369.1143
5.2e4
5.0e4
4.8e4
4.6e4
4.4e4
CO2CH3
4.2e4
4.0e4
3.8e4
3.6e4
3.4e4
3.2e4
3.0e4
2.8e4
2.6e4
2.4e4
2.2e4
2.0e4
1.8e4
1.6e4
1.4e4
1.2e4
1.0e4
8000.0
6000.0
4000.0
2000.0
0.0
COOCH3
CN
C6H5
HN
295.0821
N
NH2
O
4e
309.1004
100
150
200
250
300
350
400
450
500
550
m/z, Da
600
650
700
17

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
H3C
N
CN
N
NH2
O
CH3
4f
CO2CH3
COOCH3
CN
H3C
N
N
NH2
O
CH3
4f
18

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
H3C
N
CN
N
NH2
O
C6H5
4g
CO2CH3
COOCH3
H3C
N
CN
N
NH2
O
C6H5
4g
19

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
H3C
N
CN
N
C6H5
NH2
O
4g
a=3.59580614634598390e-004, t0=-1.86816612587017870e-001(TurboSpray), subtracted(0.017to0.033min), Smoothed, S
383.1254
4.4e4
4.2e4
4.0e4
3.8e4
CO2CH3
3.6e4
COOCH3
CN
H3C
N
3.4e4
3.2e4
3.0e4
2.8e4
2.6e4
2.4e4
2.2e4
2.0e4
1.8e4
1.6e4
1.4e4
1.2e4
1.0e4
8000.0
6000.0
4000.0
2000.0
N
NH2
O
C6H5
4g
405.1137
100
150
200
250
300
350
400
450
500
550
m/z, Da
600
650
20

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
H3CH2C
N
CN
N
NH2
O
C6H5
4h
CO2CH3
COOCH3
CN
H3CH2C
N
N
NH2
O
C6H5
4h
21

ACCEPTED MANUSCRIPT
CO2CH3
COOCH3
CN
H3CH2C
N
N
NH2
O
C6H5
4h
+TOFMS: 0.267minfromSample201(2-5-174)of 201307.wiff
a=3.59580614634598390e-004, t0=-1.86816612587017870e-001(TurboSpray), subtracted(0.033to0.050min)
397.1377
5.7e4
5.5e4
CO2CH3
5.0e4
COOCH3
H3CH2C
N
4.5e4
4.0e4
3.5e4
3.0e4
2.5e4
2.0e4
1.5e4
1.0e4
5000.0
0.0
CN
N
NH2
O
C6H5
4h
100
150
200
250
300
350
400
450
500
550
m/z, Da
600
650
700
22