Three-component one-pot synthesis of indeno[2',1':5,6]pyrido[2,3-d]pyrazole derivatives in aqueous media

Article abstract of DOI:10.1002/jccs.200900075

Aseries of indeno[2',1':5,6]pyrido[2,3-d]pyrazoles was synthesized by the three-component reaction of aldehyde, 5-amino-3-methyl-1-phenylpyrazole and 1,3-indenedione in the presence of SDS in aqueous media. The structures were characterized by IR, ^1<

Full text of DOI:10.1002/jccs.200900075

504
Journal of the Chinese Chemical Society, 2009, 56, 504-509
Three-component One-pot Synthesis of
Indeno[2¢,1¢:5,6]pyrido[2,3-d]pyrazole Derivatives in Aqueous Media
Da-Qing Shia,b* (
), Jing-Wen Shib (
) and Hao Yaob (
)
aCollege of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Organic Synthesis of
Jiangsu Province, Soochow University, Suzhou 215123, P. R. China
bCollege of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou 221116, P. R. China
A series of indeno[2¢,1¢:5,6]pyrido[2,3-d]pyrazoles was synthesized by the three-component reaction
of aldehyde, 5-amino-3-methyl-1-phenylpyrazole and 1,3-indenedione in the presence of SDS in aqueous
media. The structures were characterized by IR, 1H NMR, high resolution mass spectra and were further
confirmed by X-ray diffraction analysis.
Keywords: Indeno[2¢,1¢:5,6]pyrido[2,3-d]pyrazole; Three-component reaction; Aqueous media.
INTRODUCTION
The need to reduce the amount of toxic waste and by-
a Diels-Alder reaction using combined Lewis acid and SDS
catalysis. Mori et al.9 reported the method to greatly im-
prove the enantioselectivity of lipase-catalyzed hydrolysis
of racemic butyl propanoates in an aqueous buffer solution
using SDS as an additive. Vashchenko et al.10 reported pal-
ladium-catalyzed Suzuki cross-coupling reaction in the
presence of SDS. Recently, Sharma et al.11 reported an effi-
cient synthesis of 1,3-diaryl-2,3-dihydro-1,5-benzothiaze-
pines by the reaction of 1,3-diaryl-2-propenones and 2-
aminothiophenol in water catalyzed by SDS.
products arising from chemical processes requires increas-
ing emphasis on the use of less toxic and more environmen-
tally compatible materials in the design of new synthetic
methods.1 One of the most promising approaches uses wa-
ter as the reaction medium.2 Breslow,3 who showed that hy-
drophobic effects could strongly enhance the rate of sev-
eral organic reactions, rediscovered the use of water as a
solvent in organic reactions in the 1980s. In recent years,
there has been increasing recognition that water is an at-
tractive medium for many organic reactions.4 The aqueous
medium with respect to organic solvents is less expensive,
less dangerous and more environmentally friendly. Gener-
ally, the low solubiblity5 of most reagents in water is not an
obstacle to the reactivity, which on the contrary, is reduced
with the use of cosolvents.
Pyrazolopyridines have received more and more at-
tention in recent years. Pharmaceutical research into these
kinds of compounds have been reported, such as a potent
cyclin dependent kinase 1 (CDK1) inhibitor,12 HIV reverse
transcriptase inhibitorts,13 CCR1 antagonists,14 protein
kinase inhibitors,15 and inhibitors of cGMP degradation,
together with several herbicidal and fungicidal activities.16
On the other hand, indenopyridine compounds have shown
a wide range of biological activities such as calcium antag-
onistic,17 antioxidant,18 antihistamine and antidepressant
activities,19 and have also acted as phosphodiesterase (PDE)
inhibitors,20 and NK-1 and dopamine receptor ligands.21
Recently, several approaches have been developed for the
synthesis of the indeno[2¢,1¢:5,6]pyrido[2,3-d]pyrazole de-
rivatives by three-component reaction of aldehyde, 1,3-
indenedione and 5-amino-3-methyl-1-phenyl pyrazole in
DMF22 or in ethanol catalyzed by L-proline.23 However,
they were reacted in organic solvents22,23 or had low yields.22
Based on our previous studies on the use of water as solvent
for carrying out carbon-carbon bond forming reactions un-
Multi-component reactions (MCRs), in which multi-
ple reactions are combined into one synthetic operation
have been used extensively to form carbon-carbon bonds in
synthetic chemistry.6 Such reactions offer a wide range of
possibilities for the efficient construction of highly com-
plex molecules in a single procedural step, thus avoiding
the complicated purification operations and allowing sav-
ings of both solvents and reagents. In the past decade there
has been tremendous development in three- and four-com-
ponent reactions and great efforts continue to be made to
develop new MCRs.7
Sodium dodecyl sulfate (SDS) is an anionic surfactant
and has been used in organic synthesis. Otto et al.8 reported

Synthesis of Indeno[2¢,1¢:5,6]pyrido[2,3-d]pyrazole
J. Chin. Chem. Soc., Vol. 56, No. 3, 2009 505
Scheme I
der heterogeneous catalysis,24 we now report the synthesis
of indeno[2¢,1¢:5,6]pyrido[2,3-d]pyrazole derivatives (Scheme
I) in aqueous media.
ther confirmed by crystal X-ray analysis. Fig. 1 shows an
X-ray crystal structure of compound 4b. The most impor-
tant geometric features of this new compound 4b are listed
in Table 2.
RESULTS AND DISCUSSION
Though the detailed mechanism of this reaction has
not been clarified yet, the formation of 4 can be explained
by the possible mechanism presented in Scheme II. The re-
action occurs via an initial formation of the a,b-unsatu-
When aromatic aldehyde 1, 1,3-indenedione 2 and
5-amino-3-methyl-1-phenylpyrazole 3 were stirred for 4-
13 h at 90 °C in aqueous medium in the presence of SDS,
3-methyl-1-phenyl-4-aryl-5-oxoindeno[2¢,1¢:5,6]pyrido[2
,3-d]pyrazole 4 was obtained in good yields. The results are
summarized in Table 1.
Table 1 shows the results using a series of substituted
aromatic aldehydes that undergo the reaction to give high
yields (90-98%) of the products. This procedure does not
require the use of any organic solvent. In this reaction SDS
is necessary. If SDS is not added the reaction takes a long
time and the yield will be very low. The role of the SDS is to
form micelles. This protocol could be applied to the aro-
matic aldehydes with either electron-withdrawing groups
(such as nitro and halide groups) or electron-donating groups
(such as alkyl, hydroxy and alkoxyl groups).
The structures of products 4 were identified by IR, 1H
Fig. 1. Molecular structure of 4b.
NMR and HRMS. The structure of compound 4b was fur-
Table 1. Synthesis of indeno[2¢,1¢:5,6]pyrido[2,3-d]pyrazoles in aqueous media
Entry
R
Reaction Time (h) Yield (%)
m.p. (°C)
Lit. m.p. (°C)
4a
4b
4c
4d
4e
4f
4-CH3OC6H4
3,4-OCH2OC6H3
4-HOC6H4
3,4-(CH3O)2C6H3
4-(CH3)2NC6H4
4-ClC6H4
8
6
6
7
130
4
7
5
9
120
130
2
4
4
96
97
92
95
98
98
95
93
90
98
97
98
88
86
224-226
223-225
> 300
229-231
244-246
273-275
276-278
183-185
200-202
> 300
224-22522
223-22422
316-31823
230-23123
241-24223
269-27023
274-27622
182-18423
192-19423
318-31923
232-23323
216-21723
207-20823
146-14823
4g
4h
4i
4-BrC6H4
2,4-Cl2C6H3
3,4-Cl2C6H3
4-NO2C6H4
Thiophen-2-yl
Pyridin-3-yl
CH3CH2
4j
4k
4l
233-235
212-214
202-204
142-144
4m
4n
CH3CH2CH2

506 J. Chin. Chem. Soc., Vol. 56, No. 3, 2009
Shi et al.
Table 2. Crystal data and structure refinement for compound 4b
Empirical formula
Formula weight
Temperature
C27H17N3O3
431.44
193(2) K
Wavelength
Crystal system
Space group
0.710730 Å
Triclinic
P-1
Unit cell dimensions
a = 8.8305(14) Å
b = 10.0706(16) Å
c = 12.6909(17) Å
1019.9(3) Å3
2
a = 71.707(12)°
b = 72.455(13)°
g = 81.468(15)°
Volume
Z
Density (calculated)
Absorption coefficient
F (000)
1.405 Mg/m3
0.094 mm-1
448
Crystal size
Theta range for data collection
Index ranges
0.30 mm ´ 0.25 mm ´ 0.18 mm
3.13° to 25.35°
-10 £ h £ 10, -12 £ k = 12, -13 £ l £ 15
10081
3704 [R(int) = 0.0574]
Full-matrix Least-squares on F2
3704/0/300
Reflections collected
Independent reflections
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final Rindices [I > 2 signa (I)]
R indices (all data)
Largest diff. peak and hole
1.108
R1 = 0.0660, wR2 = 0.1340
R1 = 0.1049, wR2 = 0.1518
0.285 and -0.222 eÅ-3
rated ketone from the condensation of aldehyde and 1,3-in-
denedione as shown in Scheme II, which suffers nucleo-
philic attack to give the Michael adduct [A]. The intermedi-
ate [A] then isomerizates, cyclizes, dehydrates and subse-
quently loses a hydrogen molecule to afford the fully aro-
matized compound.
In summary, we developed an efficient three-compo-
nent reaction of an aromatic aldehyde, 3-methyl-1-phenyl-
5-aminopyrazole and 1,3-indenedione for the synthesis of
indeno[2¢,1¢:5,6]pyrido[2,3-d]pyrazole derivatives using
Scheme II

Synthesis of Indeno[2¢,1¢:5,6]pyrido[2,3-d]pyrazole
J. Chin. Chem. Soc., Vol. 56, No. 3, 2009 507
water as reaction medium. Compared with previous meth-
ods, this new protocol has the advantages of simple opera-
tion, higher yields, low cost and is an environmentally be-
nign procedure.
8.4 Hz, 2H, ArH), 7.90 (d, J = 7.6 Hz, 1H, ArH), 7.70-7.67
(m, 1H, ArH), 7.61-7.51 (m, 4H, ArH), 7.41-7.34 (m, 3H,
ArH), 6.88 (d, J = 8.0 Hz, 2H, ArH), 2.01 (s, 3H, CH3);
HRMS: Calcd for C26H17N3O2: 403.1321, found 403.1317.
3-Methyl-1-phenyl-4-(3,4-dimethoxyphenyl)-5-oxoin-
deno[2¢,1¢:5,6]pyrido[2,3-d]pyrazole (4d)
EXPERIMENTAL SECTION
Melting points were determined with a TX-5 micro-
scopic melting-point apparatus and are uncorrected. IR
spectra were recorded on a Tensor 27 spectrometer in KBr.
1H NMR spectra were measured on a Bruker DPX-400
MHz spectrometer using TMS standard and DMSO-d6 as
solvent. High resolution mass spectra were obtained using
a TOF-MS instrument.
IR (KBr) n (cm-1): 3053, 2938, 1703, 1606, 1549,
1510, 1463, 1381, 1287, 1261, 1195, 1122, 965, 815, 762,
750, 729; 1H NMR (DMSO-d6) d: 8.29 (d, J = 8.0 Hz, 2H,
ArH), 7.99 (d, J = 7.2 Hz, 1H, ArH), 7.77-7.74 (m, 1H,
ArH), 7.63-7.61 (m, 4H, ArH), 7.65-7.57 (m, 1H, ArH),
7.21 (s, 1H, ArH), 7.11 (s, 2H, ArH), 3.88 (s, 3H, CH3O),
3.78 (s, 3H, CH3O), 2.09 (s, 3H, CH3); HRMS: Calcd for
C28H21N3O3: 447.1583, found 447.1599.
Typical procedure for preparation of indeno[2¢,1¢:5,6]-
pyrido[2,3-d]pyrazole (4) derivatives
3-Methyl-1-phenyl-4-(4-dimethylaminophenyl)-5-oxo-
A mixture of aromatic aldehyde 1 (2 mmol), 1,3-in-
denedione 2 (2 mmol), 3-methyl-1-phenyl-5-aminopyra-
zole 3 (2 mmol) and SDS (0.2 g) in H2O (10 mL) was
stirred for 4-13 h at 90 °C, then cooled to room tempera-
ture. The crystalline powder formed was collected by filtra-
tion and washed with water. The crude products were puri-
fied by recrystallization from DMF to give 4.
indeno[2¢,1¢:5,6]pyrido[2,3-d]pyrazole (4e)
IR (KBr) n (cm-1): 3017, 1705, 1616, 1561, 1531,
1510, 1441, 1370, 1292, 1232, 1194, 1020, 992, 815, 768,
729, 701; 1H NMR (DMSO-d6) d: 8.28 (d, J = 8.0 Hz, 2H,
ArH), 7.95 (d, J = 7.2 Hz, 1H, ArH), 7.74-7.70 (m, 1H,
ArH), 7.63-7.56 (m, 4H, ArH), 7.40-7.39 (m, 3H, ArH),
6.83 (d, J = 8.4 Hz, 2H, ArH), 3.04 (s, 6H, (CH3)2N), 2.13
(s, 3H, CH3); HRMS: Calcd for C28H22N4O: 430.1794,
found 430.1783.
3-Methyl-1-phenyl-4-(4-methoxyphenyl)-5-oxoindeno -
[2¢,1¢:5,6]pyrido[2,3-d]pyrazole (4a)
IR (KBr) n (cm-1): 2932, 1710, 1608, 1559, 1510,
1463, 1438, 1384, 1327, 1292, 1246, 1201, 1152, 1035,
834, 786, 757, 727; 1H NMR (DMSO-d6) d: 8.28 (d, J = 8.0
Hz, 2H, ArH), 7.97 (d, J = 7.2 Hz, 1H, ArH), 7.75-7.71 (m,
1H, ArH), 7.64-7.57 (m, 4H, ArH), 7.51-7.41 (m, 3H, ArH),
7.10 (d, J = 8.4 Hz, 2H, ArH), 3.89 (s, 3H, CH3O), 2.04 (s,
3H, CH3); HRMS: Calcd for C27H19N3O2: 417.1477, found
417.1474.
3-Methyl-1-phenyl-4-(4-chlorophenyl)-5-oxoindeno-
[2¢,1¢:5,6]pyrido[2,3-d]pyrazole (4f)
IR (KBr) n (cm-1): 3054, 1711, 1653, 1597, 1557,
1461, 1383, 1270, 1179, 1084, 952, 867, 835, 767, 728; 1H
NMR (DMSO-d6) d: 8.27 (d, J = 8.0 Hz, 2H, ArH), 7.98 (d,
J = 7.6 Hz, 1H, ArH), 7.77-7.73 (m, 3H, ArH), 7.64-7.52
(m, 6H, ArH), 7.44-7.40 (m, 1H, ArH), 2.00 (s, 3H, CH3);
HRMS: Calcd for C26H1635ClN3O: 421.0982, found
421.0976.
3-Methyl-1-phenyl-4-(benzo[d][1,3]dioxol-5-yl)-5-oxo-
indeno[2¢,1¢:5,6]pyrido[2,3-d]pyrazole (4b)
3-Methyl-1-phenyl-4-(4-bromophenyl)-5-oxoindeno-
IR (KBr) n (cm-1): 3075, 2879, 1715, 1594, 1560,
1504, 1483, 1382, 1239, 1196, 1160, 1138, 1106, 1045,
942, 820, 764, 730; 1H NMR (DMSO-d6) d: 8.24 (d, J = 8.0
Hz, 2H, ArH), 7.85 (d, J = 7.2 Hz, 1H, ArH), 7.67-7.50 (m,
5H, ArH), 7.37-7.35 (m, 1H, ArH), 7.10-7.06 (m, 2H, ArH),
6.97 (d, J = 8.0 Hz, 1H, ArH), 6.97 (s, 2H, OCH2O), 1.93
(s, 3H, CH3); HRMS: Calcd for C27H17N3O3: 431.1270,
found 431.1264.
[2¢,1¢:5,6]pyrido[2,3-d]pyrazole (4g)
IR (KBr) n (cm-1): 3053, 1711, 1594, 1569, 1503,
1460, 1435, 1383, 1269, 1200, 1178, 1082, 952, 866, 831,
766, 726; 1H NMR (DMSO-d6) d: 8.27 (d, J = 8.0 Hz, 2H,
ArH), 7.98 (d, J = 7.6 Hz, 1H, ArH), 7.77-7.73 (m, 3H,
ArH), 7.64-7.56 (m, 4H, ArH), 7.53-7.42 (m, 3H, ArH),
2.00 (s, 3H, CH3); HRMS: Calcd for C26H1679BrN3O:
465.0477, found 465.0493.
3-Methyl-1-phenyl-4-(4-hydroxyphenyl)-5-oxoindeno-
3-Methyl-1-phenyl-4-(2,4-dichlorophenyl)-5-oxoindeno-
[2¢,1¢:5,6]pyrido[2,3-d]pyrazole (4c)
[2¢,1¢:5,6]pyrido[2,3-d]pyrazole (4h)
IR (KBr) n (cm-1): 3364, 3073, 1688, 1612, 1593,
1511, 1463, 1440, 1385, 1292, 1272, 1197, 1083, 836, 764,
731; 1H NMR (DMSO-d6) d: 9.89 (s, 1H, OH), 8.26 (d, J =
IR (KBr) n (cm-1): 2953, 1708, 1596, 1566, 1506,
1465, 1382, 1249, 1200, 1122, 996, 788, 767, 754, 727; 1H
NMR (DMSO-d6) d: 8.27 (d, J = 8.0 Hz, 2H, ArH), 8.01 (d,

508 J. Chin. Chem. Soc., Vol. 56, No. 3, 2009
Shi et al.
J = 8.0 Hz, 1H, ArH), 7.92 (s, 1H, ArH), 7.79-7.75 (m, 1H,
ArH), 7.66-7.60 (m, 6H, ArH), 7.44-7.40 (m, 1H, ArH),
1.98 (s, 3H, CH3); HRMS: Calcd for C26H1535Cl2N3O:
455.0592, found 455.0585.
(m, 3H, CH3).
3-Methyl-1-phenyl-4-propyl-5-oxoindeno[2¢,1¢:5,6]pyr-
ido[2,3-d]pyrazole (4n)
IR (KBr) n (cm-1): 2957, 1705, 1572, 1502, 1382,
1194, 1145, 1065, 753, 689; 1H NMR (DMSO-d6) d: 8.25-
8.23 (m, 2H, ArH), 7.86-7.85 (m, 1H, ArH), 7.69-7.58 (m,
5H, ArH), 7.40-7.39 (m, 1H, ArH), 2.65 (s, 3H, CH3), 2.52-
2.51 (m, 2H, CH2), 1.68-1.66 (m, 2H, CH2), 1.03-1.02 (m,
3H, CH3).
3-Methyl-1-phenyl-4-(3,4-dichlorophenyl)-5-oxoindeno-
[2¢,1¢:5,6]pyrido[2,3-d]pyrazole (4i)
IR (KBr) n (cm-1): 3064, 1710, 1673, 1593, 1565,
1545, 1498, 1465, 1386, 1326, 1310, 1243, 1197, 1084,
951, 895, 837, 768, 756, 726; 1H NMR (DMSO-d6) d: 8.24
(d, J = 8.0 Hz, 2H, ArH), 7.91-7.81 (m, 3H, ArH), 7.71-
7.69 (m, 1H, ArH), 7.61-7.54 (m, 5H, ArH), 7.41-7.39 (m,
1H, ArH), 1.93 (s, 3H, CH3); HRMS: Calcd for
C26H1535Cl2N3O: 455.0592, found 455.0586.
ACKNOWLEDGEMENT
We are grateful to the Foundation of the Key Labora-
tory of Biotechnology on Medical Plants of Jiangsu Prov-
ince and the Foundation of the Key Laboratory of Organic
Synthesis of Jiangsu Province for financial support.
3-Methyl-1-phenyl-4-(4-nitrophenyl)-5-oxoindeno-
[2¢,1¢:5,6]pyrido[2,3-d]pyrazole (4j)
IR (KBr) n (cm-1): 3062, 1708, 1591, 1566, 1519,
1504, 1437, 1383, 1346, 1290, 1245, 1180, 1153, 1084,
996, 914, 865, 850, 767, 728, 718; 1H NMR (DMSO-d6) d:
8.42 (d, J = 8.0 Hz, 2H, ArH), 8.29 (d, J = 8.0 Hz, 2H,
ArH), 8.04 (d, J = 7.2 Hz, 1H, ArH), 7.90 (d, J = 8.4 Hz,
2H, ArH), 7.80-7.77 (m, 1H, ArH), 7.66-7.59 (m, 4H,
ArH), 7.46-7.42 (m, 1H, ArH), 2.00 (s, 3H, CH3); HRMS:
Calcd for C26H16N4O3: 432.1222, found 432.1220.
3-Methyl-1-phenyl-4-(thiophen-2-yl)-5-oxoindeno-
[2¢,1¢:5,6]pyrido[2,3-d]pyrazole (4k)
Received April 10, 2008.
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d: 8.78-8.77 (m, 2H, ArH), 8.27 (d, J = 7.6 Hz, 2H, ArH),
8.04 (d, J = 8.0 Hz, 1H, ArH), 7.99 (d, J = 7.6 Hz, 1H,
ArH), 7.75 (t, J = 8.0 Hz, 1H, ArH), 7.64-7.58 (m, 5H,
ArH), 7.42 (t, J = 7.6 Hz, 1H, ArH), 2.01 (s, 3H, CH3).
3-Methyl-1-phenyl-4-ethyl-5-oxoindeno[2¢,1¢:5,6]pyri-
do[2,3-d]pyrazole (4m)
IR (KBr) n (cm-1): 2968, 1704, 1585, 1500, 1384,
1193, 1129, 755; 1H NMR (DMSO-d6) d: 8.25 (d, J = 7.6
Hz, 2H, ArH), 7.94 (d, J = 7.6 Hz, 1H, ArH), 7.76-7.71 (m,
2H, ArH), 7.60-7.58 (m, 3H, ArH), 7.41-7.34 (m, 1H,
ArH), 2.71 (s, 3H, CH3), 2.62-2.56 (m, 2H, CH2), 1.33-1.27
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