Tetrahedron 73 (2017) 164e171

Contents lists available at ScienceDirect

Tetrahedron
journal homepage: www.elsevier.com/locate/tet

One-pot synthesis of highly functionalized pyrano[2,3-c]

pyrazole-4,40 -diacetate and 6-oxo-pyrano[2,3-c]pyrazole
derivatives catalyzed by urea
Wenbo Li, Reyhangul Ruzi, Keyume Ablajan*, Zulpiya Ghalipt
Key Laboratory of Oil & Gas Fine Chemicals, Ministry of Education & Xinjiang Uyghur Autonomous Region, College of Chemistry and Chemical Engineering,
Xinjiang University, Urumqi 830046, PR China

a r t i c l e i n f o a b s t r a c t

Article history: A facile one-pot, multicomponent protocol for the synthesis of 1,4-dihydro-pyrano[2,3-c]pyrazole de-
Received 22 September 2016 rivatives using a urea catalyst is reported. This transformation proceeds via a four-component reaction of
Received in revised form ethyl acetoacetate, a hydrazine, 3-oxo-pentanedioic acid dimethyl ester, and malononitrile. The bifunc-
21 November 2016
tional nature of urea means that it catalyzes many steps in this transformation, including domino
Accepted 28 November 2016
Available online 30 November 2016
Knoevenagel condensation, Michael addition, and ring opening and closing reactions. This synthetic
method has several advantages, including good yield, simple work-up, harmless by-products, and simple
purification.
Keywords:
Urea-catalyzed
© 2016 Elsevier Ltd. All rights reserved.
Pyrano[2,3-c]pyrazole
Multi-component reaction
One-pot synthesis

1. Introduction recognition of a lead structure to the production of large libraries of

Pyrazoles are a key class of bioactive heterocycles that have
become increasingly important to the pharmaceutical, chemical,
and agricultural industries over recent decades.1 In particular,
pyrazolones, a common group of pyrazole derivatives, have been
industrially important for more than a century. 4H-Pyran is a
structural unit in many bioactive molecules,2 and is often the focus
of drug synthesis owing to the variety of pharmacological and
physiological activities of the resulting compounds.3,4 Many types
of bioactive molecules with broad medicinal and agrochemical
applications contain both pyran and pyrazole rings such as pyrano
[2,3-c]pyrazoles. The pyrano[2,3-c]pyrazole heterocyclic scaffold is
an important substructure5 showing anti-cancer,6 anti-inflamma-
tory,7 anti-microbial,8 hypoglycaemic,11 analgesic,9 and Chk1 ki-
nase inhibitory properties;10 it is also used in biodegradable
agrochemicals.12
Multicomponent reactions (MCRs) are the most efficient one-
pot route to achieving structural diversity.13,14 MCRs provide a
rapid and powerful method for synthesizing versatile heterocy-
cles.15 They are also useful for drug discovery, from the initial
* Corresponding author.
E-mail address: ablajan209@hotmail.com (K. Ablajan).
analogs.16 The use of MCRs in green synthesis has been reviewed
recently.17 For example, the FeCl3-catalyzed one-pot synthesis of
spiro[indolo-3,100 -indeno[1,2-b]quinolin]-trione derivatives via a
three-component reaction results in the formation of three bonds
in a single step.18
MCRs have been developed to prepare many heterocycles, such
as dihydrocoumarins, quinolines, furans, and pyrroles, by using
aldo-X reagents and a-oxoketene dithioacetals as substrates.19
Developing green, efficient synthetic methods for generating new
pyrano[2,3-c]pyrazoles is a major challenge in organic synthesis.20
Some approaches using heterogeneous catalysts, such as amberlyst
A21,21 ZrO2 nanoparticles,22 and magnetically recoverable CuFe2O4
nanoparticles,23 for the one-pot synthesis of pyrano[2,3-c]pyr-
azoles have been reported.
Although these methods are effective, they require expensive
catalysts. To minimize the cost of the reaction and reduce the
number of intermediate purification steps, a one-pot multicom-
ponent reaction was developed that has a simple work-up, is
environmentally safe, has a minimum number of steps, is easily
automated, and can generate a variety of products.24,25 Recent
methods for the synthesis of pyrano[2,3-c]pyrazoles include re-
actions in aqueous media,26 under microwave irradiation,27 and
under solvent-free conditions.28

http://dx.doi.org/10.1016/j.tet.2016.11.067
0040-4020/© 2016 Elsevier Ltd. All rights reserved.
 W. Li et al. / Tetrahedron 73 (2017) 164e171 165

A direct one-pot multicomponent reaction for access to variably Table 1

substituted pyrano[2,3-c]pyrazole derivatives has been devel- Optimization of reaction conditions for the synthesis of 5a.

oped.29,30 This green and efficient protocol uses a one-pot

condensation of ethyl acetoacetate, a hydrazine, a symmetrical
aliphatic ketone, and malononitrile with urea as a catalyst, in 80%
EtOH (Scheme 1).

2. Results and discussion

Initially, we optimized the four-component reaction to generate Entry Solvent Catalyst Time (h) Yielda (%)
dimethyl 2,20 -(6-amino-5-cyano-3-methyl-1-phenyl-1,4-dihydro-
1 CH3CN Urea 4 38
pyrano[2,3-c]pyrazol-4,4-diyl)diacetate (5a). First, we used EtOH as 2 CH2Cl2 Urea 4 28
the solvent and equimolar amounts of ethyl acetoacetate, a hy- 3 THF Urea 4 34
drazine, 3-oxo-pentanedioic acid dimethyl ester, and malononitrile. 4 H2O Urea 5 53
The optimal catalyst for the synthesis of compound 5a was chosen 5 EtOH Urea 5 68
6 80%EtOH Urea 4 81
from standard organocatalysts including HDBAC (hexadecyl
7 80%EtOH Ureab 4 56
dimethyl benzyl ammonium chloride), Et3N, L-proline, TEBA (ben- 8 80%EtOH Ureac 4 81
zyltriethylammonium chloride), pyrrolidine, pyridine, TsOH (p- 9 80%EtOH Uread 6 81
toluenesulfonic acid) and DBU (1,8-diazabicyclo[5.4.0]undec-7- 10 80%EtOH Ureae 4 29
ene) (Table 1). Using HDBAC (20 mol %) as the catalyst at 80  C in 11 80%EtOH HDBAC 4 74
12 80%EtOH Et3N 4 68
80% EtOH for 4 h led to desired product 5a in 74% yield (Table 1, 13 80%EtOH L-proline 4 63
entry 11). Et3N, L-proline, TEBA, pyrrolidine, pyridine, TsOH, and 14 80%EtOH TEBA 4 62
DBU at the same concentration catalyzed the reaction to afford the 15 80%EtOH pyrrolidines 4 50
desired product in 10%e68% yield (Table 1, entries 12e18). The 16 80%EtOH pyridine 4 55
17 80%EtOH TsOH 4 10
highest yield of product 5a (81%) was obtained under similar
18 80%EtOH DBU 4 48
conditions using 20 mol % urea (Table 1, entry 6). The reaction 19 80%EtOH N/A 6 10
without a catalyst yielded a negligible amount of product, even a
Isolated yields: after filtration and wash with 75% EtOH.
after 6 h (Table 1, entry 19). Based on these results, urea was b
10 mol% catalyst.
selected as the most suitable catalyst for the reaction. c
30 mol% catalyst.
d
The optimal solvent for the synthesis of product 5a was chosen The reaction time prolonged to 6 h.
from CH3CN, CH2Cl2, THF, H2O, EtOH, and 80% EtOH (Table 1). Low
e
Reaction performed at 40  C.

yields of product 5a were obtained with CH3CN, CH2Cl2, or THF as

the solvent (Table 1, entries 1e3). Reactions in H2O and EtOH gave
higher yields than those in other organic solvents (Table 1, entries
4e5). The reactions in EtOH had the highest yield of 81%. This may
be due to EtOH and water forming an azeotropic system, which is
ideal for the formation of the product.
Further optimization focused on the reaction temperature and
time in the presence of catalytic urea (Table 1, entries 6, 9, and 10).
The reaction at 80  C for 4 h was chosen as the optimal conditions. A
further decrease or increase in temperature showed no great
improvement in the yield (Table 1, entries 6 vs 10). Increasing the
reaction time to 6 h did not affect the yield of 5a (Table 1, entries 6
vs 9). Finally, the effects of catalyst loading were investigated. The
product was obtained in 56% yield using 10 mol % urea as a catalyst
(Table 1, entry 7). Under similar conditions, increasing urea loading
to 30 mol % did not change the reaction yield substantially (Table 1,
entry 8), and 20 mol % urea was chosen as the optimal amount of
catalyst.
Based on the optimized reaction conditions (Table 1, entry 6),
products 5ae5p were generated in good yields (Table 2). The
products were tolerant of aryl hydrazines containing electron-
donating or electron-withdrawing groups. For instance, the treat-
ment of hydrazine 2f bearing electron-donating groups with 3-oxo-
Scheme 1. Synthesis of pyrano[2,3-c]pyrazole-4,40 -diacetate and 6-oxo-pyrano[2,3-c]
pyrazole derivatives.
pentanedioic acid dimethyl ester (3ae3b) and malononitrile (4)
provided desired products 5e and 5m in 81% and 82% yield,
respectively. The reactions of hydrazines 2 bearing electron-
withdrawing groups, compounds 3ae3b, and malononitrile affor-
ded products 5d, 5f, 5g, 5k, 5l, 5n, and 5p with yields of 70%e76%.
The reactions to produce 5d, 5f, 5g, 5k, 5l, 5n, and 5p took longer
because of the deactivation of the hydrazine by the electron-
withdrawing group.
The structures of 5ae5p were confirmed by 1H NMR, 13C NMR,
IR spectroscopy, and mass spectrometry. The structure of repre-
sentative compound 5e was determined by single-crystal X-ray
diffraction (Fig. 1, see Supplementary Data for more details).
The crystal structure of 5e is an infinite helical chain running
along the a-axis, bound via hydrogen bonds (Fig. 2). All active
hydrogen atoms participate in intermolecular hydrogen bond for-
mation [N(3)eH(3B)/O(9) and N(7)eH(7B)/O(4)]. Basic crystal-
lographic parameters are given in the Supporting Information.
A plausible reaction mechanism for the formation of compound 5
is provided in Scheme 2. Ethyl acetoacetate 1 and hydrazine 2 undergo
an addition reaction and cyclocondensation to form intermediate A.
Subsequently, the tautomerization of intermediate A with urea forms
intermediate B by hydrogen bonding. Simultaneously, deprotonation
of 4 in the presence of the catalyst produces the malononitrile anion in
situ, which participates in Knoevenagel condensation with 3 to give
intermediate C. Michael addition of intermediate B to intermediate C
results in intermediate D in the presence of urea. The proton-transfer
ability of urea is clearer in the formation of E; the proton transfer in
the presence of the catalyst increases the electronegativity of the
carbonyl group oxygen in intermediate E, facilitating electrophilic
addition. Finally, intermediate E undergoes intramolecular cycliza-
tion to form desired product 5.
166 W. Li et al. / Tetrahedron 73 (2017) 164e171

Table 2
One-pot synthesis of pyrano[2,3-c]pyrazole derivatives.a

a
Isolated yields.
 W. Li et al. / Tetrahedron 73 (2017) 164e171
Fig. 1. Structure of compound 5e obtained by X-ray diffraction.
Fig. 2. Crystal structure of 5e. Dotted lines indicate hydrogen bonds.
Reaction scope studies used ethyl cyanoacetate instead of
malononitrile. The structure was expected to be compound 7, but
single-crystal X-ray diffraction showed that compound 6 was ob-
tained, and our experimental results indicated that ethyl cyanoa-
cetate did not participate in the reaction (Scheme 3).
Compounds 6ae6d were obtained via the three component
reaction of ethyl acetoacetate, a hydrazine, and 3-oxo-pentanedioic
acid dimethyl ester with urea in 80% EtOH (Table 3).
The structures of 6ae6d were confirmed by 1H NMR, 13C NMR,
IR spectroscopy, and mass spectrometry. The purification steps for
these products were filtration and thorough washing with 75%
EtOH, followed by recrystallization from 95% EtOH to afford the
pure product. The structure of compound 6 was confirmed by X-ray
diffraction of 6b (Fig. 3, see Supplementary Data for more details).
The methylene carboethoxy group is attached to C-4 of the 4H-
pyran ring. The spectral data also support the assigned structure.
Scheme 4 shows a reaction mechanism for the formation of
compound 6 catalyzed by urea. Ethyl acetoacetate 1 and hydrazine
2 form intermediate A. Deprotonation of intermediate A in the
167
Scheme 2. Proposed mechanism for the formation of compound 5.
presence of the urea catalyst forms intermediate anion B, which
undergoes Knoevenagel condensation with 3-oxo-pentanedioic
acid dimethyl ester 3 to give intermediate C. A proton shift occurs in
intermediate C, resulting in the loss of a water molecule in the
presence of the catalyst. Intermediate D undergoes further intra-
molecular cyclization via the attack of the OH oxygen on the
carboxyl carbon, leading to the formation of intermediate E. Finally,
target product 6a is formed by the loss of a MeOH molecule.
3. Conclusions
A highly efficient one-pot procedure for the synthesis of 1,4-
dihydro-pyrano[2,3-c]pyrazole derivatives was developed. In
addition, pyrano[2,3-c]pyrazol-6-one compounds were synthe-
sized under the same reaction conditions from three components.
The method meets all the criteria of green chemistry and provides
the products in good yields. Furthermore, products were purified
by re-crystallization, and column chromatography was avoided
entirely.
4. Experimental
4.1. General information
All solvents and reagents were analytical grade and obtained
from TCI, Alfa, and Acros, and used without further purification.
Melting points were recorded in open-ended capillaries and were
uncorrected. 1H NMR and 13C NMR spectra were recorded on a
400 MHz spectrometer (Avance II, Bruker). Chemical shifts (d) are
reported in ppm relative to TMS as the internal standard, and were
recorded in DMSO-d6 or CDCl3 as solvents. The IR spectra were
recorded on an IR spectrophotometer (Spectrum II, PerkinElmer).
The mass spectra were determined on a mass spectrometer (LCQ
Fleet, Thermo Fisher Scientific). Electrospray ionization mass
spectrometry and high-resolution mass spectrometry were per-
formed on a mass spectrometer (LTQ Orbitrap XL, Thermo Fisher
Scientific).
4.2. General procedure for the one-pot synthesis of multi-
substituted 1,4-dihydro-pyrano[2,3-c]pyrazole derivatives (5ae5p)
Ethyl acetoacetate (1, 0.5 mmol), substituted hydrazine (2,
0.5 mmol), and 80% EtOH (10 mL) were placed in a 25 mL round
168 W. Li et al. / Tetrahedron 73 (2017) 164e171
Scheme 3. Synthesis of 6-oxo-pyrano[2,3-c]pyrazole derivatives 6.
Table 3
Three-component synthesis of 1,6-dihydro-pyrano[2,3-c]pyrazole derivatives.a
a
Isolated yields.
bottom flask. The reaction mixture was heated at 80  C for
5e10 min. 3-Oxo-pentanedioic acid dimethyl ester (3, 0.5 mmol),
malononitrile (4, 0.5 mmol), and urea (20 mol %) were added to the
reaction mixture, which was heated at the same temperature for
4e5 h. After the reaction was complete (monitored by TLC), the
mixture was cooled to room temperature. The mixture was allowed
to stand for 1e2 days, during which time large amounts of pre-
cipitate formed. The precipitate was filtered and washed thor-
oughly with 70% EtOH. The crude product was recrystallized from
95% EtOH. Characterization data for compounds 5 are given below.
4.2.1. Dimethyl 2,20 -(6-amino-5-cyano-3-methyl-1-phenyl-1,4-di-
hydropyrano[2,3-c]pyrazole-4,4-diyl) diacetate (5a)
White crystal, mp: 182e183  C; IR (KBr): 3460, 3338, 3219 (br s,
NH2), 2957 (C-H), 2196 (CN), 1724, 1654, 1520, 1441 (C]C, C]N),
1333, 1236, 1159, 1030 (C-O, C-N), 763, 514 cm1; 1H NMR
(400 MHz, CDCl3, d ppm): 7.58e7.62 (m, 2H, Ar-H), 7.41e7.45 m (m,
2H, Ar-H), 7.26e7.31 (m, 1H, Ar-H), 4.73 (s, 2H, NH), 3.56 (s, 6H,
2OCH3), 2.82e2.84 (m, 4H, 2CH2), 2.35e2.36 (m, 3H, CH3); 13C NMR
(100 MHz, CDCl3, d ppm): 169.5, 169, 159.7, 144.8, 144.1, 137.4, 129.2,
126.8, 121.4, 117.9, 97, 64.3, 60.4, 51.6, 44.3, 43.9, 37, 36.8, 14.3, 13.9;
HRMS (ESI) m/z calcd for C20H21N4O5 [MþH]þ 397.1507, found
Fig. 3. Structure of compound 6b obtained by X-ray diffraction.
Scheme 4. Proposed mechanism for the formation of compound 6a.
397.1505.
4.2.2. Dimethyl 2,20 -(6-amino-5-cyano-1,3-dimethyl-1,4-dihydro-
pyrano[2,3-c]pyrazole-4,4-diyl) diacetate (5b)
Light yellow soild, mp: 161e162  C; IR (KBr): 3444, 3235 (br s,
NH2), 2960 (C-H), 2177 (CN), 1710, 1646, 1553, 1431 (C]C, C]N),
1333, 1257, 1155, 1031 (C-O, C-N), 789, 508 cm1; 1H NMR
(400 MHz, CDCl3, d ppm): 4.72 (s, 2H, NH), 3.63 (s, 3H, CH3), 3.54 (s,
6H, 2CH3), 2.77e2.79 (m, 4H, 2CH2), 2.24e2.25 (m, 3H, CH3); 13C
NMR (100 MHz, CDCl3, d ppm): 169.6, 159.7, 144.2, 118.1, 95.1, 64.3,
60.3, 51.6, 44.2, 43.9, 43.8, 37.0, 36.9, 33.8, 14.0, 13.9; HRMS (ESI) m/z
calcd for C15H19N4O5 [MþH]þ 335.1350, found 335.1349.
4.2.3. Dimethyl 2,20 -(6-amino-5-cyano-3-methyl-1,4-dihydropy-
rano[2,3-c]pyrazole-4,4-diyl) diacetate (5c)
White solid, mp: 203e205  C; IR (KBr): 3446, 3316 (br s, NH,
NH2), 2953 (C-H), 2198 (CN), 1735, 1644, 1596, 1438, (C]C, C]N),
1396, 1256, 1149, 1073 (C-O, C-N), 986, 762, 543 (N-H) cm1; 1H
NMR (400 MHz, DMSO, d ppm): 11.98 (s, 1H, NH), 6.75 (s, 2H, NH),
3.40 (s, 6H, 2CH3), 2.77 (t, J ¼ 13.9 Hz, 4H, 2CH2), 2.20e2.22 (m, 3H,
CH3); 13C NMR (100 MHz, CDCl3, d ppm): 169.7, 161.8, 155.2, 135.3,
119.6, 96.5, 59.5, 58.6, 51.2, 44.3, 40.3, 40.1, 36.3, 36.0, 13.8, 11.0;
HRMS (ESI) m/z calcd for C14H17N4O5 [MþH]þ 321.1194, found
321.1196.
4.2.4. Dimethyl 2,20 -(6-amino-1-(4-chlorophenyl)-5-cyano-3-
methyl-1,4-dihydropyrano[2,3-c] pyrazole-4,4-diyl)diacetate (5d)
White solid, mp: 182e184  C; IR (KBr): 3458, 3336, 3222 (br s,
NH2), 2956 (C-H), 2196 (CN), 1653, 1517, 1489, 1440 (C]C, C]N),
 W. Li et al. / Tetrahedron 73 (2017) 164e171
1336, 1236, 1162, 1096 (C-O, C-N), 830, 577 cm1; 1H NMR
(400 MHz, CDCl3, d ppm): 7.54e7.59 (m, 2H, Ar-H), 7.53e7.59 (m,
2H, Ar-H), 4.76 (s, 2H, NH), 3.56 (s, 6H, 2OCH3), 2.79e2.88 (m, 4H,
2CH2), 2.34e2.36 (m, 3H, CH3); 13C NMR (100 MHz, CDCl3,
d ppm):169.5, 168.9, 159.5, 159.4, 145.1144.2, 135.9, 132.3, 129.2,
122.2, 117.8, 97.3, 64.3, 60.4, 51.7, 44.2, 43.8, 43.7, 36.9, 36.7, 14.2,
13.9; HRMS (ESI) m/z calcd for C20H20N4O5Cl [MþH]þ 431.1116,
found 431.1117.
4.2.5. Dimethyl 2,20 -(6-amino-5-cyano-3-methyl-1-(p-tolyl)-1,4-
dihydropyrano[2,3-c] pyrazole-4,4-diyl)diacetate (5e)
White solid, mp: 188e189  C; IR (KBr): 3460, 3221 (br s, NH2),
2958 (C-H), 2194 (CN), 1726, 1652, 1525, 1442 (C]C, C]N), 1395,
1235, 1113, 1028 (C-O, C-N), 816, 511 cm1; 1H NMR (400 MHz,
CDCl3, d ppm): 7.44e7.48 (m, 2H, Ar-H), 7.21e7.26 (m, 2H, Ar-H),
4.74 (s, 2H, NH), 3.55 (s, 6H, 2OCH3), 2.83e2.84 (m, 4H, 2CH2),
2.34e2.37 (m, 6H, 2CH3); 13C NMR (100 MHz, CDCl3, d ppm): 169.5,
169.0, 159.7, 159.6, 144.6, 144.4, 144.0, 136.8, 134.8, 129.7, 121.4,
118.0, 96.8, 64.2,60.3, 51.6, 44.4, 44.0, 43.9, 37.0, 36.8, 29.7, 21.0,
14.2, 13.9; HRMS (ESI) m/z calcd for C21H23N4O5 [MþH]þ 411.1663,
found 411.1661.
4.2.6. Dimethyl 2,20 -(6-amino-1-(2-chlorophenyl)-5-cyano-3-
methyl-1,4-dihydropyrano[2,3-c] pyrazole-4,4-diyl) diacetate (5f)
White solid, mp: 148e149  C; IR (KBr): 3436, 3342, (br s, NH2),
2956 (C-H), 2185 (CN), 1728, 1655, 1537, 1401 (C]C, C]N), 1332,
1215, 1152, 1015 (C-O, C-N), 887, 775 cm1; 1H NMR (400 MHz,
CDCl3, d ppm): 7.26e7.52 (m, 1H, Ar-H), 7.26e7.52 (m, 3H, Ar-H),
4.63 (s, 2H, NH), 3.56 (s, 6H, 2OCH3), 2.82e2.85 (m, 4H, 2CH2),
2.37 (t, J ¼ 5.1 Hz, 6H, 2CH3); 13C NMR (100 MHz, CDCl3, d ppm):
169.5, 169.0, 159.6, 159.5, 145.2, 145.0, 144.2, 135.9, 132.2, 129.2,
122.2, 117.8, 97.3, 64.1, 60.4, 51.6, 44.2, 43.8, 43.7, 36.9, 36.7, 14.2,
13.9; HRMS (ESI) m/z calcd for C20H20N4O5Cl [MþH]þ 431.1116,
found 431.1117.
4.2.7. Dimethyl 2,20 -(6-amino-5-cyano-3-methyl-1-(4-nitrophen-
yl)-1,4-dihydropyrano[2,3-c] pyrazole- 4,4-diyl) diacetate (5g)
Yellow soild, mp: 187e188  C; IR (KBr): 3431, 3342 (br s, NH2),
2981 (C-H), 2189 (CN), 1735, 1655, 1517, 1440 (C]C, C]N), 1337,
1232, 1158, 1064 (C-O, C-N), 749, 578 cm1; 1H NMR (400 MHz,
CDCl3, d ppm): 8.28 (d, J ¼ 8.8 Hz, 2H, Ar-H), 7.82e7.91 (m, 2H, Ar-
H), 4.83 (s, 2H, NH), 3.16e3.93 (m, 6H, 2OCH3), 2.75e2.90 (m, 4H,
2CH2), 2.37 (t, J ¼ 4.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3,
d ppm): 169.0, 162.4, 159.9, 159.4, 145.2, 144.0, 133.5, 123.2, 123.1,
117.8, 116.1, 115.9, 96.9, 64.7, 60.3, 44.3, 37.1, 29.6, 14.2, 13.9; HRMS
(ESI) m/z calcd for C20H20N5O7 [MþH]þ 442.1357, found 442.1358.
4.2.8. Diethyl2,20 -(6-amino-5-cyano-3-methyl-1-phenyl-1,4dihy-
dropyrano[2,3-c]pyrazole-4,4-diyl) diacetate (5h)
White soild, mp: 181e182  C; IR (KBr): 3385, 3315 (br s, NH2),
2981 (C-H), 2191 (CN), 1705 (COO), 1654, 1519, 1492, 1446 (C]C, C]
N), 1393, 1279, 1148, 1070 (C-O, C-N), 749, 577 cm1; 1H NMR
(400 MHz, CDCl3, d ppm): 7.56e7.58 (m, 2H, H-Ar), 7.39e7.44 (m,
2H, H-Ar), 7.25e7.30 (m, 1H, H-Ar), 4.79 (s, 2H, NH2), 3.96e4.01 (q,
J ¼ 7.1 Hz, 4H, 2OCH2), 2.81 (m, 4H, 2CH2) 2.37 (s, 3H, CH3),
1.05e1.09 (m, 6H, 2CH3); 13C NMR (100 MHz, CDCl3, d ppm): 169.1,
159.6, 145.2, 144.1, 137.4, 129.2, 126.9, 121.4, 117.9, 96.9, 64.6, 60.4,
44.5, 37.2, 14.3; HRMS (ESI) m/z calcd for C22H25N4O5 [MþH]þ
425.1820, found 425.1816.
4.2.9. Diethyl 2,20 -(6-amino-5-cyano-1,3-dimethy-1,4dihydro-
pyrano[2,3-c]pyrazole-4,4-diyl) diacetate (5i)
Yellow soild, mp: 167.5e167.7  C; IR (KBr): 3548, 3312, 3142, (br
s, NH2), 2981 (C-H), 2193 (CN), 1729 (COO), 1670, 1556, 1481,1438
(C-C, C-N), 1399, 1261, 1163, 1028 (C]O, C]N), 619, 523 cm1; 1H
169
NMR (400 MHz, CDCl3, d ppm): 4.72 (s, 2H, NH2), 3.99 (q, 4H,
2OCH2), 3.97 (s, 3H, CH3), 2.81 (m, 4H, 2CH2), 2.37 (s, 3H, CH3), 1.09
(td, J ¼ 7.1, 3.1 Hz, 6H, 2CH3); 13C NMR (100 MHz, CDCl3, d ppm):
169.1, 159.6, 144.7, 143.2, 118.2, 95, 64.7, 60.3, 60.1, 45, 44.4, 37.2,
34.4, 33.7, 33.6, 29.3, 14.1, 13.9; HRMS (ESI) m/z calcd for C17H23N4O5
[MþH]þ 363.1663, found 363.1661.
4.2.10. Diethyl 2,20 -(6eamino-5ecyano-3emethyl-1,4-dihydro-
pyrano [2,3-c]pyrazole-4,4-diyl)diacetate (5j)
Milk white solid, mp: 186e187  C; IR (KBr): 3444, 3334 (br s,
NH, NH2), 2988 (C-H), 2196 (CN), 1727 (COO), 1644, 1595, 1483, 1444
(C-C, C-N), 1393, 1250, 1156, 1033 (C]O, C]N), 753, 543 (N-H)
cm1; 1H NMR (400 MHz, DMSO, d ppm): 11.98 (s, 1H, NH), 6.72 (s,
2H, NH2), 3.81e3.86 (m, 4H, 2OCH2), 2.50e2.76 (m, 4H, 2CH2), 2.23
(s, 3H, CH3), 2.81 (m, 4H, 2CH2), 2.37 (s, 3H, CH3), 0.95 (m, 6H,
2CH3); 13C NMR (100 MHz, DMSO, d ppm): 169.1, 161.7, 155.2, 135.7,
119.7, 96.2, 59.5, 59.0, 44.9, 40.3, 40.1, 39.9, 39.7, 39.4, 39.2, 39.0,
36.5, 13.8, 11.1; HRMS (ESI) m/z calcd for C16H21N4O5 [MþH]þ
349.1507, found 349.1504.
4.2.11. Diethyl 2,20 -(6-amino-1-(4echlorophenyl)-5-cyano-3-
methyl-1,4-dihydropyrano[2,3-c]pyrazole-4,4-diyl) diacetate (5k)
White solid, mp: 191e192  C; IR (KBr): 3386, 3315 (br s, NH2),
2982(C-H), 2193 (CN), 1655, 1517, 1442,1442 (C]C, C]N), 1393,
1277, 1147, 1013 (C-O, C-N), 831, 625 cm1; 1H NMR (400 MHz,
DMSO, d ppm): 7.75e7.77 (m, 2H, Ar-H), 7.50e7.52 (m, 2H, Ar-H),
7.17 (s, 2H, NH), 3.84e3.90 (m, 4H, 2OCH2), 2.49e2.86 (m, 4H,
2CH2), 2.27 (s, 3H, CH3), 0.91e1.05 (m, 6H, 2CH3); 13C NMR
(100 MHz, DMSO, d ppm): 169.1, 160, 145.7, 144.4, 136.4, 130.3,
129.5, 121.1, 118.6, 97.6, 59.7, 44.4, 40.3, 40.1, 39.9, 39.7, 39.5, 39.3,
39.0, 37.0, 14.2, 13.8; HRMS (ESI) m/z calcd for C22H24N4O5Cl
[MþH]þ 459.1430, found 459.1426.
4.2.12. Diethyl 2,20 -(6-amino-1-(2-chlorophenyl)-5-cyano-3-
methyl-1,4-dihydropyrano[2,3-c] pyrazole- 4,4-diyl) diacetate (5l)
White solid, mp: 190e192  C; IR (KBr): 3319, 3188 (br s, NH2),
2979 (C-H), 2196 (CN), 1736, 1651, 1583, 1527 (C]C, C]N), 1398,
1258, 1149, 1033 (C-O, C-N), 762, 580 cm1; 1H NMR (400 MHz,
CDCl3, d ppm): 7.49e7.51 (m, 1H, Ar-H), 7.37e7.42 (m, 3H, Ar-H),
4.87 (s, 2H, NH), 3.97e4.02 (m, 4H, 2OCH2), 2.82 (m, 4H, 2CH2),
2.38 (s, 3H, CH3), 1.10e1.13 (t, 6H, 2CH3); 13C NMR (100 MHz, CDCl3,
d ppm): 169.1, 159.5, 146.1, 145.3, 134.3, 131.6, 130.5, 130.3, 129.3,
127.6, 118.0, 95.8, 64.5, 60.4, 44.7, 37.6, 14.3, 14.0; HRMS (ESI) m/z
calcd for C22H24N4O5Cl [MþH]þ 459.1430, found 459.1429.
4.2.13. Diethyl 2,20 -(6-amino-5-cyano-3-methyl-1-(p-tolyl)-1,4-
dihydropyrano[2,3-c] pyrazole-4,4-diyl) diacetate (5m)
White solid, mp: 176e178  C; IR (KBr): 3406, 3315 (br s, NH2),
2975 (C-H), 2194 (CN), 1734, 1648, 1502, 1465 (C]C, C]N), 1391,
1297, 1144, 1096 (C-O, C-N), 818, 780 cm1; 1H NMR (400 MHz,
CDCl3, d ppm): 7.45 (t, J ¼ 6.9 Hz, 2H, Ar-H), 7.20 (d, J ¼ 8.2 Hz, 2H,
Ar-H), 4.79 (s, 2H, NH), 3.96e4.01 (q, 4H, 2OCH2), 2.81 (m, 4H,
2CH2), 2.35e2.37 (d, J ¼ 1.5 Hz, 6H, 2CH3), 1.05e1.25 (td, J ¼ 7.1,
3.4 Hz, 6H, 2CH3); 13C NMR (100 MHz, CDCl3, d ppm): 169, 159.8,
144.8, 143.9, 136.8, 134.9, 129.7, 121.4, 118.0, 96.7, 64.6, 60.4, 44.5,
37.3, 21, 14.3, 13.9; HRMS (ESI) m/z calcd for C23H27N4O5 [MþH]þ
439.1976, found 439.1980.
4.2.14. Diethyl 2,20 -(6-amino-5-cyano-3-methyl-1-(4-nitrophen-
yl)-1,4-dihydropyrano[2,3-c] pyrazole- 4,4-diyl)diacetate (5n)
Light yellow soild, mp: 185e186  C; IR (KBr): 3399, 3326, 3209
(br s, NH2), 2988 (C-H), 2191 (CN), 1740, 1664, 1519, 1400 (C]C, C]
N), 1342, 1242, 1193, 1052 (C-O, C-N), 853, 751 cm1; 1H NMR
(400 MHz, CDCl3, d ppm): 8.27e8.29 (m, 2H, Ar-H), 7.85e7.87 (m,
2H, Ar-H), 4.82 (s, 2H, NH), 3.98e4.03 (q, 4H, 2OCH2), 2.77e2.86 (m,
170 W. Li et al. / Tetrahedron 73 (2017) 164e171
4H, 2CH2), 2.37 (s, 3H, CH3), 1.10 (td, J ¼ 7.1, 3.7 Hz, 6H, 2CH3); 13C
NMR (100 MHz, CDCl3, d ppm): 168.9, 159.2, 147.0, 145.2, 142.3,
125.0, 119.9, 117.4, 98.7, 64.8, 60.5, 44.0, 36., 14.4, 13.9; HRMS (ESI)
m/z calcd for C22H24N5O7 [MþH]þ 470.1670, found 470.1669.
4.2.15. Diethyl 2,20 -(6-amino-5-cyano-1,3-diphenyl-1,4-dihydro-
pyrano[2,3-c]pyrazole-4,4-diyl) diacetate (5o)
White crystal, mp: 169e171  C; IR (KBr): 3431, 3342 (br s, NH2),
2981 (C-H), 2189 (CN), 1735, 1655, 1517, 1440 (C]C, C]N), 1337,
1232, 1158, 1064 (C-O, C-N), 749, 578 cm1; 1H NMR (400 MHz,
CDCl3, d ppm): 7.70 (d, J ¼ 7.8 Hz, 2H, Ar-H), 7.46 (dd, J ¼ 8.6, 5.7 Hz,
4H, Ar-H), 7.33 (t, J ¼ 7.4 Hz, 2H, Ar-H), 7.28 (s, 2H, Ar-H), 4.82 (s, 2H,
NH), 4.01e4.06 (m, 4H, 2OCH2), 2.66 (d, J ¼ 14.8 Hz, 2H, CH2), 2.57
(d, J ¼ 14.9 Hz, 2H, CH2), 1.11e1.40 (m, 6H, 2CH3); 13C NMR
(100 MHz, CDCl3, d ppm): 169.1, 159.5, 149.2, 143.9, 137.2, 133.6,
129.1, 128.9, 128.4, 127.0, 121.5, 117.8, 98.0, 64.6, 60.3, 44.7, 37.2,
14.0; HRMS (ESI) m/z calcd for C27H27N4O5 [MþH]þ 487.1976, found
487.1975.
4.2.16. Diethyl 2,20 -(6-amino-5-cyano-1-(4-fluorophenyl)-3-me-
thyl-1,4-dihydropyrano[2,3-c] pyrazole- 4,4-diyl)diacetate (5p)
White crystal, mp: 183e185  C; IR (KBr): 3413, 3317 (br s, NH2),
2982 (C-H), 2195 (CN), 1735, 1647, 1526, 1440 (C]C, C]N), 1340,
1270, 1145, 1095 (C-O, C-N), 835, 603 cm1; 1H NMR (400 MHz,
CDCl3, d ppm): 7.51e7.58 (m, 2H, Ar-H), 7.07e7.15 (m, 2H, Ar-H),
4.71 (s, 2H, NH), 3.87e4.13 (m, 4H, 2OCH2), 2.74e2.88 (m, 4H,
CH2), 2.36 (d, J ¼ 7.2 Hz, 3H,CH3), 1.08 (td, J ¼ 7.1, 3.8 Hz 6H, 2CH3);
13
C NMR (100 MHz, CDCl3, d ppm): 169.0, 162.4, 159.9, 159.4, 145.2,
144.0, 133.5, 123.2, 123.1, 117.8, 116.1, 115.9, 96.9, 64.7, 60.3, 44.3,
37.1, 29.6, 14.2, 13.9; HRMS (ESI) m/z calcd for C22H24N4O5F [MþH]þ
443.1725, found 443.1724.
4.3. General procedure for the three-component one-pot synthesis
of multi-substituted 6(1H)-oxo-pyrano[2,3-c]pyrazole derivatives
(6ae6d)
Ethyl acetoacetate (1, 0.5 mmol), substituted hydrazine (2,
0.5 mmol), and 80% EtOH (10 mL) were stirred at 80  C for
5e10 min. 3-Oxo-pentanedioic acid dimethyl ester (3, 0.5 mmol)
and urea (20 mol %) were added to the reaction mixture, which was
heated at the same temperature for 4e5 h. After the reaction was
complete (monitored by TLC), the mixture was cooled to room
temperature. The mixture was allowed to stand and large amounts
of precipitate formed. The precipitate was filtered and washed
thoroughly with 70% EtOH. The crude product was recrystallized
from 95% EtOH. Characterization data for compounds 6 are given
below.
4.3.1. Methyl 2-[1,3-dimethyl-6(1H)-oxo-pyrano[2,3-c]pyrazole-4-
yl]acetate (6a)
Light yellow soild, mp: 136e138  C; IR(KBr): 3436 2929 (C-H),
1752, 1603, 1579, 1439 (C]C, C]N, C]O), 1352, 1221, 1131, 1030 (C-
O, C-N), 753, 566 cm1; 1H NMR (400 MHz, CDCl3 d ppm): 5.86 (s,
1H, NH), 3.78 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.68 (d, J ¼ 6.8 Hz,
2H), 2.39 (d, J ¼ 6.8 Hz, 1H), 2.38 (m, 1H); 13C NMR (100 MHz, CDCl3
d ppm): 168.8, 159.7, 151.3, 148.1, 142.5, 106.2, 99.9, 52.7, 38.6, 38.3,
33.6, 14.2; HRMS (ESI) m/z calcd for C11H13N2O4 [MþH]þ 237.0867,
found 237.0869.
4.3.2. Methyl 2-[3-methyl-1-phenyl-6(1H)-oxo-pyrano[2,3-c]py-
razole-4-yl]acetate (6b)
Light yellow soild, mp: 133e134  C; IR(KBr): 3468 2932 (C-
H),1875, 1621, 1555, 1489 (C]C, C]N, C]O), 1338, 1234, 1151, 1055
(C-O, C-N), 847, 540 cm1; 1H NMR (400 MHz, CDCl3, d ppm): 7.83
(d, J ¼ 8.9 Hz, 2H, Ar-H), 7.46 (d, J ¼ 8.8 Hz, 2H, Ar-H), 5.96 (s, 1H, C]
CH), 3.79 (s, 3HOCH3), 3.73 (d, J ¼ 6.8 Hz, 2H, CH2), 2.47 (s, 3H, CH3);
13
C NMR (100 MHz, CDCl3, d ppm): 168.7, 159.2, 150.3, 147.9, 143.8,
136.7, 129.3, 127.3, 120.8, 107.1, 101.5, 52.7, 38.3, 14.4; HRMS (ESI) m/
z calcd for C16H15N2O4 [MþH]þ 299.1026, found 299.1023.
4.3.3. 1-(4-chlorophenyl)-methyl 2-[3-methyl-6(1H)-oxo-pyrano-
[2,3-c]pyrazole-4-yl]acetate (6c)
Yellow soild, mp: 145e147  C; IR (KBr): 3439, 2952 (C-H), 1751,
1601, 1549, 1486, 1387 (C]C, C]N, C]O), 1339, 1219, 1170, 1050 (C-
O, C-N), 823, 495 cm1; 1H NMR (400 MHz, CDCl3, d ppm): 7.83 (d,
J ¼ 9.0 Hz, 2H, Ar-H), 7.46 (d, J ¼ 9.0 Hz, 2H, Ar-H), 5.96 (s, 1H, C]
CH), 3.78 (s, 3H, OCH3), 3.73 (d, J ¼ 6.6 Hz, 2H, CH2), 2.47 (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3, d ppm): 168.7, 159.1, 150.4, 147.9,
144.2, 135.3, 132.8, 129.5, 121.7, 107.3, 101.7, 52.8, 38.4, 14.4; HRMS
(ESI) m/z calcd for C16H14N2O4Cl [MþH]þ 333.0637, found 333.0635.
4.3.4. Methyl 2-[3-methyl-1-(p-tolyl)-6(1H)-oxo-pyrano[2,3-c]
pyrzole-4-yl]acetate (6d)
Yellow soild, mp: 126e128  C; IR (KBr): 3438, 2951 (C-H), 1775,
1603, 1550, 1429, 1388 (C]C, C]N, C]O), 1340, 1218, 1171, 1051 (C-
O, C-N), 813, 520 cm1; 1H NMR (400 MHz, CDCl3, d ppm):
7.70e7.72 (m, 2H, Ar-H), 7.26e7.29 (m, 2H, Ar-H), 5.94 (t, J ¼ 0.8 Hz,
1H, C]CH), 3.75 (dd, J ¼ 14.3, 13.5 Hz, 3H, OCH3), 3.73 (m, 2H, CH2),
2.48 (d, J ¼ 3.7 Hz, 3H, CH3), 2.4 (s, 3H, CH3); 13C NMR (100 MHz,
CDCl3, d ppm): 168.1, 159.4, 150.2, 147.9, 143.6, 137.3, 134.3, 129.9,
120.8, 107.0, 101.4, 52.7, 38.4, 21.0; HRMS (ESI) m/z calcd for
C17H17N2O4 [MþH]þ 313.1183, found 313.1179.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 21462041), Natural Science Foundation
for Distinguished Young Scholars of Xinjiang Uyghur Autonomous
Region (No. Qn2015jq002), and the Tianshan Talent Cultivation
Project of Xinjiang Uyghur Autonomous Region.
Supplementary data
Copies of 1H and 13C NMR spectra for all products. Supple-
mentary data associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2016.11.067. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
References
1. a Varvounis G. Adv Heterocycl Chem. 2009;98:143e224;
b Schmidt A, Dreger A. Curr Org Chem. 2011;15:1423e1463;
c Fustero S, Roman R, Sanz-Cervera JF, Simon FA, Bueno J, Villanova SJ. J Org
Chem. 2008;73:8545e8552.
2. Hatakeyama S, Ochi N, Numata H, Takano S. J Chem Soc Chem Comun. 1988;17:
1202e1204.
3. a Demont EH, Harrity JPA. Org Lett. 2006;8:5597e5600;
b Fischer C, Rohr F. J Am Chem Soc. 2003;125:7818e7819;
c Azizian J, Hatamjafari F. J Heterocycl Chem. 2006;43:1349e1352;
d Nair V, Biju AT, Vinod AU, Suresh E. Org Lett. 2005;7, 5139e5412.
4. Sun W, Cama DE, Birzin ET, et al. Bioorg Med Chem Lett. 2006;16:1468e1472.
5. a Stachulski AV, Berry NG, Low ACL, et al. J Med Chem. 2006;49:1450e1454;
b Ablajan K, Maimaiti Z. Synth Commun. 2012;42:1959e1966;
c Wang LJ, Ablajan K, Feng J. Ultrason Sonochem. 2015;22:113e118.
6. Kuo SC, Huang LJ, Nakamura H. J Med Chem. 1984;27:539e544.
7. Zaki MEA, Saliman HA, Hickal OA, Rashad AEZ. Naturforsch, C Biosci. 2006;61:
1e5.
8. Smith WP, Sollis LS, Howes DP, Cherry CP, Starkey DI, Cobley NK. J Med Chem.
1998;41:787e797.
9. EI-Tamany ES, EI-Shahed FA, Mohamed BH. J Serb Chem Soc. 1999;64:9e18.
10. Foloppe N, Fisher LM, Howes R, Potter A, Robertson AGS, Surgenor AE. Bioorg
Med Chem. 2006;14:4792e4802.
11. Mohamed NR, Khaireldin NY, Fahmy AF, El-Sayed AA. Der Pharma Chem.
2010;2:400e417.
 W. Li et al. / Tetrahedron 73 (2017) 164e171
12. Junek H, Aigner H. Chem Ber. 1973;106:914e921.
13. Ruijter E, Scheffelaar R, Orru RVA. Angew Chem Int Ed. 2011;50:6234e6246.
14. Sebastian B, van B, Sander S, Westermann B. Chem Soc Rev. 2013;42:
4948e4962.
15. Jiang B, Rajale T, Wever W, Tu SJ, Li GG. Chem Asian J. 2010;5:2318e2335.
16. Paul S. Med Chem Commun. 2012;3:1189.
17. Razvan CC, Eelco R, Romano VAO. Green Chem. 2014;16:2958e2975.
18. Mondal A, Mukhopadhyay C. ACS Comb Sci. 2015;17:404e408.
19. a Palanisamy, R.; Lai, B. B.; Gu, Y. I. Chem RecDOI: 10.1002/tcr.201600042; b
Liu CH, Zhou L, Jiang D, Gu YL. Asian J Org Chem. 2016;5:367e372.
20. a Zou Y, Hu Y, Liu H, Shi D. ACS Comb Sci. 2012;16:129e143;
b Litvinov YM, Shestopalov A, Rodinovskaya LA, Shestopalov AM. J Comb Chem.
2009;11:914e919;
c Sohal HS, Goyal A, Sharma R, Khare R, Kumar S. Eur J Chem. 2013;4:450e453;
d Shaabani A, Sarvary A, Rezayan AH, Keshipour S. Tetrahedron. 2009;65:
3492e3495;
e Koohshari M, Dabiri M, Salehi P. RSC Adv. 2014;4:10669e10671.
21. Bihani M, Bora PP, Bez G, Askari H. ACS Sustain Chem Eng. 2013;1:440e447.
22. Saha A, Payra S, Banerjee S. Green Chem. 2015;17:2859e2866.
23. Pradhan K, Pau S, Das AR. Catal Sci Technol. 2014;4:822e831.
171
24. a Alcaide B, Almendros P, Aragoncillo C, Callejo R, Ruiz MP, Torres MR. J Org
Chem. 2012;77:6917e6928;
b Terret NK, Gardner M, Gordon DW, Kobylecki RJ, Steel J. Tetrahedron.
1995;51:8135e8173;
c Ramon DJ, Yus M. Angew Chem Int Ed. 2005;44:1602e1634;
d Doling A. Chem Rev. 2006;106:17;
e Liu J, Lei M, Hu L. Green Chem. 2012;14:840e846.
25. a Uig I. Pure Appl Chem. 2001;73:187e191;
b Weber L. Curr Opin Chem Biol. 2000;4:295e302;
c Domling A. Curr Opin Chem Biol. 2002;6:306e313;
d Alizadeh A, Rostamnia S, Hu ML. Synlett. 2006:15921594.
26. a Jin TS, Wang AQ, Cheng ZL, Zhang JS, Li TS. Synth Commun. 2005;35:137e143;
b Prasanna P, Perrumal S, Menendez JC. Green Chem. 2013;15:1292e1299.
27. a Zhou JF, Tu SJ, Zhu HQ, Zhi SJ. Synth Commun. 2002;32:3363e3366;
b Peng Y, Song G, Dou R. Green Chem. 2006;8:573e575.
28. a Chaudhary JM, Ankita K. Green Chem Lett Rev. 2012;5:1;
b Ren Z, Cao W, Tong W, Jin Z. Synth Commun. 2005;35:2509e2513.
29. Keyume A, Esmayil Z, Wang LJ, Feng J. Tetrahedron. 2014;70:3976e3980.
30. a Ablajan K, Wang LJ, Kelimu Y, Feng J. Mol Divers. 2013;17:693e700;
b Feng J, Ablajan K, Sali A. Tetrahedron. 2014;70:484e489.