A novel and efficient one-pot synthesis of furo[3′,4′:5,6]pyrido[2,3-c]pyrazole derivatives using organocatalysts

Article abstract of DOI:10.1016/j.tet.2007.12.053

A novel approach to one-pot synthesis of dihydrofuro[3′,4′:5,6]pyrido[2,3-c]pyrazole and indeno[2′,1′:5,6]pyrido[2,3-c]pyrazole derivatives have been investigated using organocatalysts that are recyclable. This new protocol has the advantages of environme

Full text of DOI:10.1016/j.tet.2007.12.053

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2425e2432
www.elsevier.com/locate/tet
A novel and efficient one-pot synthesis of furo[30,40:5,6]pyrido[2,3-c]-
pyrazole derivatives using organocatalysts
c
b
b
a,
Chun-Ling Shi a, Da-Qing Shi b, , Sung Hong Kim , Zhi-Bin Huang , Shun-Jun Ji , Min Ji
*
*
a College of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, Nanjing, Jiangsu 210096, PR China
b College of Chemistry and Chemical Engineering, Key Laboratory of Organic Synthesis of Jiangsu Province, Suzhou University, Suzhou 215123, PR China
c Analysis Research Division, Daegu Center, Korea Basic Science Institute, Daegu 702-701, South Korea
Received 1 August 2007; received in revised form 20 December 2007; accepted 25 December 2007
Available online 4 January 2008
Abstract
A novel approach to one-pot synthesis of dihydrofuro[30,40:5,6]pyrido[2,3-c]pyrazole and indeno[20,10:5,6]pyrido[2,3-c]pyrazole derivatives
have been investigated using organocatalysts that are recyclable. This new protocol has the advantages of environmental friendliness, higher
yield, low cost, as well as convenient operation. The catalytic efficiency of various small organocatalysts such as L-proline, trans-4-
hydroxy-L-proline, L-thiaproline, cinchonidine, (þ)-cinchonine, and DL-2-phenylglycine has also been studied.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Molecular frameworks for the development of dihydro-
furo[3,4-b]pyridines have also been described.15 However, there
is no report about the synthesis of dihydrofuro[30,40:5,6]-
pyrido[2,3-c]pyrazole derivatives, which may show potential
pharmaceutical activities.
Small organic molecules like cinchona alkaloids, L-proline,
and its derivatives are readily commercially available catalysts
and have been used in various transformations with excellent
yields.16 L-Proline has been found to be very effective in en-
amine based direct catalytic asymmetric aldol,17 Mannich,18
Michael,19 DielseAlder,20 a-amination reactions, and Knoe-
venagel type reaction,20,21 and unsymmetric Biginelli reac-
tion.22 More recently, L-proline and its derivatives have been
used in multi-component unsymmetric Hantzsch reaction.23
Therefore, we are interested in investigating of the activity
of L-proline as well as other small organocatalysts in synthesis
of dihydrofuro[30,40:5,6]pyrido[2,3-c]pyrazole derivatives.
Pyrazolopyridines have received more and more attention
in the recent years. Pharmaceutical researches of this kind of
compounds have been reported, such as a potent cyclin depen-
dent kinase 1 (CDK1) inhibitor,1 HIV reverse transcriptase in-
hibitors,2 CCR1 antagonists,3 protein kinase inhibitors,4 and
inhibitors of cGMP degradation, together with several herbi-
cidal and fungicidal activities.5 Numerous methods for the
synthesis of pyrazolopyridines in the last twenty years have
been reported with respect to their different structures.6
Furopyridines is one of the ‘privileged medicinal scaffolds’,
which are used for the development of pharmaceutical agents
of various applications. Compounds with this motif show
a wide range of pharmacological activities such as antipsy-
chotic,7 antiproliferative,8 anticonvulsant,9 antianaphylactic,10
and anthelmintic11 activities and can be used as calcium influx
promoters,12 HIV-1 non-nucleoside reverse transcriptase in-
hibitors,13 and acetylcholinesterase inhibitors.14
2. Results and discussion
In order to get 3-methyl-1-phenyl-4-substituted-4,8-dihy-
drofuro[30,40:5,6]pyrido[2,3-c]pyrazole derivatives (4), we de-
scribe here a facile three-component reaction in the presence
* Corresponding authors.
E-mail address: dqshi@263.net (D.-Q. Shi).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.053

2426
C.-L. Shi et al. / Tetrahedron 64 (2008) 2425e2432
R
O
O
H3C
H3C
5a-5f
+
O
+
RCHO
O
N
N
EtOH, 80 °C
N
Ph
NH2
O
N
Ph
N
H
1
2
3
4
Scheme 1. Synthesis of dihydrofuro[30,40:5,6]pyrido[2,3-c]pyrazole derivatives catalyzed by organocatalysts.
Table 3
The effect about amounts of L-proline when synthesizing 4a in ethanol at
of organocatalysts (5aef) using 5-amino-1-phenyl-3-methyl-
pyrazole (1), aldehyde (2), and tetronic acid (3) as starting
materials in EtOH at refluxing temperature (Scheme 1).
To optimize the reaction temperature, the reaction of
5-amino-1-phenyl-3-methylpyrazole (1), 4-methylbenzalde-
hyde (2a), and tetronic acid (3), was studied in EtOH in the
presence of 10 mol % L-proline, at different temperatures
such as room temperature, 50 ꢀC, and 80 ꢀC, respectively.
The results are summarized in Table 1.
80 ꢀC
Entry Amounts of L-proline (mol %) Reaction time (h) Isolated yield (%)
1
2
3
4
5
10
15
20
3
91
96
94
95
1.5
1.5
1.5
was used and the reaction was carried out in refluxing ethanol.
As shown in Table 4 the catalytic effects of 5a, 5b, and 5c
were similar, while 5d, 5e, and 5f gave lower yields. The
presence of a secondary nitrogen and carboxylic acid at
2-position in the catalysts led to good yields of products, while
Table 1
Temperature optimization for the synthesis of 4a in EtOHa
Entry Reaction temperature (ꢀC) Reaction time (h) Isolated yield (%)
1
2
3
rt
3
84
93
96
50
80
2
1.5
a
L-Proline (10 mol %) was used as catalyst.
Table 4
Study of catalytic efficiency of different organocatalysts over the reaction
synthesizing 4aa
As shown in Table 1, the reaction at 80 ꢀC proceeded in
highest yield and shortest reaction time among three reaction
temperatures tested. Therefore, 80 ꢀC was chosen for this
reaction.
Entry
1
Catalyst
None
Reaction time (h)
2
Isolated yield (%)
68
COOH
To find the optimal solvent for this reaction, the synthesis of
4a was carried out at refluxing temperature using EtOH, water,
acetone, CHCl3, DMF, HOAc, etc. as solvents, respectively. It
is shown in Table 2 that the reactions with EtOH as solvent
resulted in shorter reaction time and higher yield than other
solvents. So EtOH was chosen as the solvent of this reaction.
2
3
4
5
1.5
1.5
1.5
2
96
90
89
70
N
H
5a
S
COOH
N
H
5b
HO
COOH
N
H
Table 2
Solvent optimization for 10 mol % L-proline catalyzed synthesis of 4a at
refluxing temperature
5c
Ph
H2N
HO
COOH
Entry
Solvent
Reaction time (h)
Isolated yield (%)
5d
1
2
3
4
5
6
7
EtOH
Water
1.5
2
96
90
87
81
88
87
79
H
Acetone
CHCl3
DMF
2
2.5
1.5
1.5
3
N
H
6
2
2
78
79
HOAc
CH3CN
5e
N
To optimize the catalyst loading, 5 mol %, 10 mol %,
15 mol %, and 20 mol % of L-proline was tested, respectively.
The results are summarized in Table 3. A 10 mol % loading of
L-proline was sufficient to push the reaction forward and
5 mol % of L-proline was not enough. Higher amounts of
L-proline did not lead to significant change in the reaction
yields.
H
N
HO
7
H
N
5f
a
Reaction conditions: 5-amino-1-phenyl-3-methylpyrazole (1 mmol), 4-
methylbenzaldehyde (1 mmol) and tetronic acid (1 mmol), catalyst
10 mol %, EtOH, 80 ꢀC, stirring.
The catalytic efficiency of other organocatalysts in this re-
action was also studied. In all cases 10 mol % of the catalyst

C.-L. Shi et al. / Tetrahedron 64 (2008) 2425e2432
2427
Table 6
L-Proline catalyzed synthesis of 7
DL-phenylglycine (5d) with a primary amino group, and (þ)-
cinchonine (5e), cinchonidine (5f) with a tertiary amino group,
respectively, gave lower yields. These results indicate that the
presence of secondary nitrogen may be essential for better cat-
alytic activity. Replacing CH2 (5a) by S (5b) and with CHOH
(5c) did not affect yields significantly. Therefore it was con-
cluded that L-proline was the best among the six catalysts in
this study.
Product
R
Reaction time (h)
Isolated yield (%)
7a
7b
7c
7d
7e
7f
4-ClC6H4
4-FC6H4
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
90
95
93
92
96
97
91
95
94
95
92
93
91
92
92
85
87
4-CH3OC6H4
4-OHC6H4
4- CH3C6H4
4-NO2C6H4
3,4-OCH2OC6H3
3,4-Cl2C6H3
Thiophen-2-yl
3,4-(CH3O)2C6H3
4-(CH3)2NC6H4
2,4-Cl2C6H3
2-NO2C6H4
Pyridin-3-yl
4-BrC6H4
Under these optimized reaction conditions (2 mL EtOH,
80 ꢀC, 10 mol % L-proline), a series of 3-methyl-1-phenyl-4-
substituted-4,8-dihydrofuro[30,40:5,6]pyrido[2,3-c]pyrazole deri-
vatives (4) were synthesized. The results are summarized in
Table 5.
7g
7h
7i
7j
1
7k
7l
1
0.5
0.5
0.5
0.5
2
7m
7n
7o
7p
7q
Table 5
L-Proline catalyzed synthesis of 4
CH3(CH2)2
CH3CH2
Product
R
Reaction time (h)
Isolated yield (%)
2
4a
4b
4c
4d
4e
4f
4-CH3C6H4
4-BrC6H4
1.5
1
96
90
97
94
95
96
97
97
96
91
93
92
94
94
61a
59a
4-OHC6H4
3,4-OCH2OC6H3
4-CH3OC6H4
4-ClC6H4
1
conditions. Compare aliphatic aldehydes with others, reaction
times were longer, and products were obtained in lower yields
by column chromatography.
1
1.5
1
4g
4h
4i
4-FC6H4
3-ClC6H4
1
Apart from the mild conditions of the process and its excel-
lent results, the simplicity of product isolation and the possibil-
ity to recycle the reaction solution offer a significant advantage.
Because L-proline is soluble only with EtOH and the solution of
desired products is little in EtOH, the products can be directly
separated by cooling to room temperature and filtering after
the reaction is completed. The remaining reaction solution can
be recycled. Studies using 1, 2a, and 3 as model substrates
showed that the recovered reaction solution could be succes-
sively recycled in subsequent reactions without any decrease
of yields (Table 7). It is shown that reaction solution has been
recycled sixth rounds, catalytic efficiency of L-proline in reac-
tion solution not be decreased even in the seventh round.
1.5
1.5
1.5
1
4-NO2C6H4
3,4-Cl2C6H3
2-ClC6H4
4j
4k
4l
2,4-Cl2C6H3
Thiophen-2-yl
Pyridin-3-yl
CH3(CH2)2
CH3CH2
1.5
2
4m
4n
4o
4p
a
2
3
3
Aromatization products.
To expand the scope of the present method, 1,3-indane-
dione 6 was examined to replace tetronic acid 3. This is par-
ticularly attractive because compounds with indenopyridine
motifs show a wide range of biological activities such as
calcium antagonistic,24 antioxidant,25 antihistamine, and anti-
depressant,26 and also act as phosphodiesterase (PDE) inhibi-
tors,27 NK-1, and dopamine receptor ligands.28 To our delight,
under the above optimized conditions, the reactions proceeded
smoothly. A series of indeno[20,10:5,6]pyrido[2,3-c]pyrazole
derivatives 7 were obtained (Scheme 2) in excellent yields.
The results are summarized in Table 6.
As shown in Tables 5 and 6, this protocol can be applied not
only to the aromatic aldehydes with either electron-withdraw-
ing groups (such as nitro and halide groups) or electron-donat-
ing groups (such as hydroxyl and alkoxyl groups), but also to
heterocyclic and aliphatic aldehydes under the same
Table 7
Studies on the reuse of reaction solution in the preparation of 4a
Round
1
2
3
4
5
6
7
Yield (%)
96
95
94
95
96
94
95
All the products 4 and 7 were characterized by mp, IR, and
1H NMR spectra as well as HRMS. The structure of 4e was
further confirmed by X-ray diffraction analysis.29 The molec-
ular structure 4e is shown in Figure 1.
We propose a possible mechanism for the L-proline cata-
lyzed synthesis of furo[30,40:5,6]pyrido[2,3-c]pyrazole deriva-
tives 4 (Scheme 3). We suggest that, L-proline catalyze the
R
O
O
O
H3C
H3C
L-proline
+
RCHO
+
N
N
EtOH, 80 °C
N
Ph
NH2
N
Ph
N
1
2
6
7
Scheme 2. Synthesis of indeno[20,10:5,6]pyrido[2,3-c]pyrazole derivatives 7 catalyzed by L-proline.

2428
C.-L. Shi et al. / Tetrahedron 64 (2008) 2425e2432
formation of iminium ion 8 in a reversible reaction with the
aldehyde. The higher reactivity of the iminium ion compared
to the carbonyl species could facilitate Knoevenagel condensa-
tion between aldehyde 2 and tetronic acid 3, via intermediate 9
and after the elimination of L-proline, 10 might be produced as
an intermediate. The addition of 10 to 5-amino-3-methyl-1-
phenylpyrazole 1 then could furnish the intermediate product
11, which upon intermolecular cyclization and dehydration
would give rise to products 4.
3. Conclusion
In conclusion, we have developed a simple three-compo-
nent reaction of an aldehyde, 5-amino-3-methyl-1-phenylpyr-
azole, and either tetronic acid or 1,3-indanedione for the
synthesis of furo[30,40:5,6]pyrido[2,3-c]pyrazole and inden-
o[20,10:5,6]pyrido[2,3-c]pyrazole derivatives using organocata-
lysts that are recyclable. This new method has the advantages
of good yields, convenient procedure, and environmentally
friendly reaction conditions.
4. Experimental
Figure 1. ORTEP diagram of 4e.
4.1. General
Melting points are uncorrected. Infrared spectra were re-
corded on a Tensor 27 spectrometer in KBr with absorption
O
COO-
N+
O
1
in cmꢁ1. H NMR spectra were recorded on a Bruker DPX
3
H
R
8
O
400-MHz spectrometer as DMSO-d6 solution. J values are in
hertz. Chemical shifts are expressed in d downfield from inter-
nal tetramethylsilane. Mass spectra were obtained using TOF-
MS instrument. X-ray crystallographic analysis was performed
with a Smart-1000 CCD diffractometer.
O
R
H
2
H
N
O
COO-
COOH
H
N
H
O
O
R
9
4.2. General procedure for the L-proline catalyzed synthesis
of furo[30,40:5,6]pyrido[2,3-c]pyrazole derivatives 4 and
indeno[20,10:5,6]pyrido[2,3-c]pyrazole derivatives 7
O
O
R
H
O
A mixtureof5-amino-3-methyl-1-phenylpyrazole1 (1 mmol),
aldehyde 2 (1 mmol), tetronic acid 3 or 1,3-indanedione
6 (1 mmol), L-proline (10 mol %), and EtOH (2 mL) in
a 10 mL round bottom flask was stirred at 80 ꢀC for given times.
After completion of the reaction, the reaction mixture was
cooled to room temperature. The precipitate was collected by
filtration and purified by recrystallization from EtOH and
DMF or was extracted with CH2ClCH2Cl and the extract was
purified with column chromatography using acetone/petroleum
ether (60:90) 1:5 as the eluents (when aliphatic aldehydes were
used) to give products 4 or 7.
10
R
O
O
H3C
H3C
N
N
N
NH2
N
Ph
NH2
O
Ph
1
11
R
R
O
O
O
H3C
H3C
4.2.1. 3-Methyl-1-phenyl-4-(4-methylphenyl)-4,8-
O
N
N
N
Ph
N
H
dihydrofuro[30,40:5,6]pyrido[2,3-c]pyrazole (4a)
N
Ph
N
H
OH
1
Mp: 222e224 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.81
12
4
(s, 3H, CH3), 2.27 (s, 3H, CH3), 4.80 (d, J¼16.0 Hz, 1H, CH2),
4.86 (d, J¼16.0 Hz, 1H, CH2), 4.88 (s, 1H, CH), 7.10
(d, J¼8.0 Hz, 2H, ArH), 7.16 (d, J¼8.0 Hz, 2H, ArH),
7.40e7.47 (m, 2H, ArH), 7.52e7.56 (m, 3H, ArH), 10.20
H2O
Scheme 3. Possible mechanism of furo[30,40:5,6]pyrido[2,3-c]pyrazole deriva-
tives 4.

C.-L. Shi et al. / Tetrahedron 64 (2008) 2425e2432
2429
(s, 1H, NH). IR (KBr): 3322, 3046, 2921, 2864, 1720, 1641,
1591, 1539, 1474, 1436, 1392, 1357, 1222, 1133, 1101,
1063, 1020, 843, 760, 698 cmꢁ1. HRMS [found: m/z
357.1479 (Mþ), calcd for C22H19N3O2: M, 357.1477].
J¼16.0 Hz, 1H, CH2), 4.98 (s, 1H, CH), 7.31 (d, J¼8.0 Hz,
2H, ArH), 7.37 (d, J¼8.0 Hz, 2H, ArH), 7.41e7.45 (m, 1H,
ArH), 7.52e7.56 (m, 4H, ArH), 10.28 (s, 1H, NH). IR
(KBr): 3303, 3061, 2847, 1718, 1639, 1591, 1540, 1474,
1390, 1342, 1255, 1163, 1101, 1064, 1019, 910, 836, 788,
4.2.2. 3-Methyl-1-phenyl-4-(4-bromophenyl)-4,8-dihydrofuro-
760, 697 cmꢁ1. HRMS [found: m/z 377.0914 (Mþ), calcd
35
[30,40:5,6]pyrido[2,3-c]pyrazole (4b)
for C21H ClN3O2: M, 377.0931].
16
1
Mp: 238e240 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.81
(s, 3H, CH3), 4.82 (d, J¼16.0 Hz, 1H, CH2), 4.87 (d, J¼
16.0 Hz, 1H, CH2), 4.97 (s, 1H, CH), 7.25 (d, J¼8.0 Hz, 2H,
ArH), 7.41e7.45 (m, 1H, ArH), 7.50e7.56 (m, 6H, ArH),
10.28 (s, 1H, NH). IR (KBr): 3304, 3060, 2936, 2847, 1719,
1639, 1591, 1538, 1474, 1391, 1340, 1221, 1131, 1101,
1063, 1022, 834, 760, 696 cmꢁ1. HRMS [found: m/z
4.2.7. 3-Methyl-1-phenyl-4-(4-fluorophenyl)-4,8-dihydrofuro-
[30,40:5,6]pyrido[2,3-c]pyrazole (4g)
1
Mp: 249e250 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.81
(s, 3H, CH3), 4.81 (d, J¼16.0 Hz, 1H, CH2), 4.87 (d,
J¼16.0 Hz, 1H, CH2), 4.98 (s, 1H, CH), 7.11e7.15 (m, 2H,
ArH), 7.33 (dd, J1¼8.4 Hz, J2¼5.6 Hz, 2H, ArH), 7.40e7.44
(m, 1H, ArH), 7.52e7.56 (m, 4H, ArH), 10.26 (s, 1H, NH).
IR (KBr): 3296, 3064, 2943, 2858, 1718, 1641, 1599, 1542,
1476, 1391, 1343, 1256, 1156, 1102, 1065, 1027, 855, 798,
762, 698 cmꢁ1. HRMS [found: m/z 361.1228 (Mþ), calcd
for C21H16FN3O2: M, 361.1227].
421.0225 (Mþ), calcd for C21H BrN3O2: M, 421.0226].
79
16
4.2.3. 3-Methyl-1-phenyl-4-(4-hydroxyphenyl)-4,8-
dihydrofuro[30,40:5,6]pyrido[2,3-c]pyrazole (4c)
1
Mp: 258e260 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.81
(s, 3H, CH3), 4.79 (d, J¼16.0 Hz, 1H, CH2), 4.81 (s, 1H, CH),
4.85 (d, J¼16.0 Hz, 1H, CH2), 6.68 (d, J¼8.0 Hz, 2H, ArH),
7.05 (d, J¼8.0 Hz, 2H, ArH), 7.41 (t, J¼8.0 Hz, 1H, ArH),
7.51e7.58 (m, 4H, ArH), 9.24 (s, 1H, OH), 10.17 (s, 1H,
NH). IR (KBr): 3293, 1725, 1641, 1592, 1543, 1479, 1387,
1357, 1253, 1218, 1137, 1100, 1066, 1024, 845, 797, 766,
697 cmꢁ1. HRMS [found: m/z 359.1264 (Mþ), calcd for
C21H17N3O3: M, 359.1270].
4.2.8. 3-Methyl-1-phenyl-4-(3-chlorophenyl)-4,8-dihydrofuro-
[30,40:5,6]pyrido[2,3-c]pyrazole (4h)
1
Mp: 168e170 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.82
(s, 3H, CH3), 4.82 (d, J¼16.0 Hz, 1H, CH2), 4.90 (d,
J¼16.0 Hz, 1H, CH2), 5.00 (s, 1H, CH), 7.26e7.28 (m, 2H,
ArH), 7.33e7.37 (m, 2H, ArH), 7.41e7.45 (m, 1H, ArH),
7.53e7.59 (m, 4H, ArH), 10.30 (s, 1H, NH). IR (KBr):
3144, 2966, 1746, 1651, 1596, 1544, 1474, 1394, 1365,
4.2.4. 3-Methyl-1-phenyl-4-(benzo[d][1,3]dioxol-5-yl)-4,8-
dihydrofuro[30,40:5,6]pyrido[2,3-c]pyrazole (4d)
1264, 1135, 1111, 1066, 1025, 995, 862, 786, 687 cmꢁ1
.
1
35
16
Mp: 268e270 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.84
HRMS [found: m/z 377.0937 (Mþ), calcd for C21H ClN3O2:
M, 377.0931].
(s, 3H, CH3), 4.79 (d, J¼16.0 Hz, 1H, CH2), 4.86 (d, J¼
16.0 Hz, 1H, CH2), 4.87 (s, 1H, CH), 5.97 (d, J¼2.0 Hz, 2H,
CH2), 6.73e6.76 (m, 1H, ArH), 6.81e6.84 (m, 2H, ArH),
7.40e7.44 (m, 1H, ArH), 7.52e7.58 (m, 4H, ArH), 10.22 (s,
1H, NH). IR (KBr): 3327, 2946, 2874, 2788, 1718, 1645,
1592, 1533, 1474, 1436, 1393, 1358, 1250, 1220, 1138,
1101, 1062, 1022, 927, 845, 795, 754, 693 cmꢁ1. HRMS
[found: m/z 387.1230 (Mþ), calcd for C22H17N3O4: M,
387.1219].
4.2.9. 3-Methyl-1-phenyl-4-(4-nitrophenyl)-4,8-dihydrofuro-
[30,40:5,6]pyrido[2,3-c]pyrazole (4i)
1
Mp: 228e230 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.81
(s, 3H, CH3), 4.85 (d, J¼16.0 Hz, 1H, CH2), 4.90 (d,
J¼16.0 Hz, 1H, CH2), 5.18 (s, 1H, CH), 7.31 (d, J¼8.0 Hz,
2H, ArH), 7.37 (d, J¼8.0 Hz, 2H, ArH), 7.41e7.45 (m, 1H,
ArH), 7.52e7.56 (m, 4H, ArH), 10.28 (s, 1H, NH). IR
(KBr): 3303, 3061, 2847, 1718, 1639, 1591, 1540, 1474,
1390, 1346, 1255, 1132, 1102, 1064, 1021, 912, 861, 766,
703 cmꢁ1. HRMS [found: m/z 388.1159 (Mþ), calcd for
C21H16N4O4: M, 388.1172].
4.2.5. 3-Methyl-1-phenyl-4-(4-methoxyphenyl)-4,8-
dihydrofuro[30,40:5,6]pyrido[2,3-c]pyrazole (4e)
1
Mp: 230e232 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.81
(s, 3H, CH3), 3.73 (s, 3H, OCH3), 4.80 (d, J¼16.0 Hz, 1H,
CH2), 4.86 (d, J¼16.0 Hz, 1H, CH2), 4.88 (s, 1H, CH), 6.68
(d, J¼8.0 Hz, 2H, ArH), 7.18 (d, J¼8.0 Hz, 2H, ArH),
7.40e7.44 (m, 1H, ArH), 7.52e7.63 (m, 4H, ArH), 10.19 (s,
1H, NH). IR (KBr): 3318, 3030, 2942, 2855, 1725, 1646,
1593, 1536, 1473, 1390, 1358, 1255, 1216, 1136, 1101,
1063, 1020, 904, 843, 794, 759, 697 cmꢁ1. HRMS [found:
m/z 373.1412 (Mþ), calcd for C22H19N3O3: M, 373.1426].
4.2.10. 3-Methyl-1-phenyl-4-(3,4-dichlorophenyl)-4,8-
dihydrofuro[30,40:5,6]pyrido[2,3-c]pyrazole (4j)
1
Mp: 244e246 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.83
(s, 3H, CH3), 4.83 (d, J¼16.0 Hz, 1H, CH2), 4.89 (d,
J¼16.0 Hz, 1H, CH2), 5.05 (s, 1H, CH), 7.29 (dd, J1¼
8.4 Hz, J2¼2.0 Hz, 1H, ArH), 7.42e7.46 (m, 1H, ArH),
7.55e7.59 (m, 6H, ArH), 10.34 (s, 1H, NH). IR (KBr):
3270, 3048, 2947, 2867, 1721, 1646, 1592, 1528, 1472,
1392, 1359, 1254, 1164, 1099, 1065, 901, 888, 794,
4.2.6. 3-Methyl-1-phenyl-4-(4-chlorophenyl)-4,8-dihydrofuro-
[30,40:5,6]pyrido[2,3-c]pyrazole (4f)
1
Mp: 223e224 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.81
688 cmꢁ1. HRMS [found: m/z 411.0533 (Mþ), calcd for
35
(s, 3H, CH3), 4.82 (d, J¼16.0 Hz, 1H, CH2), 4.87 (d,
C21H Cl2N3O2: M, 411.0541].
15

2430
C.-L. Shi et al. / Tetrahedron 64 (2008) 2425e2432
4.2.11. 3-Methyl-1-phenyl-4-(2-chlorophenyl)-4,8-
[found: m/z 307.1310 (Mþ), calcd for C18H17N3O2: M,
307.1321].
dihydrofuro[30,40:5,6]pyrido[2,3-c]pyrazole (4k)
1
Mp: 258e260 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.77
(s, 3H, CH3), 4.84 (d, J¼16.0 Hz, 1H, CH2), 4.88 (d,
J¼16.0 Hz, 1H, CH2), 5.39 (s, 1H, CH), 7.31 (d, J¼8.0 Hz,
2H, ArH), 7.40e7.45 (m, 2H, ArH), 7.51e7.57 (m, 5H,
ArH), 10.32 (s, 1H, NH). IR (KBr): 3240, 3050, 2928, 1719,
1643, 1592, 1526, 1470, 1391, 1359, 1260, 1138, 1103,
4.2.16. 3-Methyl-1-phenyl-4-ethylfuro[30,40:5,6]pyrido-
[2,3-c]pyrazole (4p)
Mp: 186e188 ꢀC. 1H NMR (DMSO-d6, 300 MHz): d 1.33 (t,
J¼6.0 Hz, 3H, CH3), 2.79 (s, 3H, CH3), 3.44e3.46 (m, 2H,
CH2), 5.43 (s, 2H, CH2), 7.38 (t, J¼6.9 Hz, 1H, ArH), 7.56e
7.61 (m, 2H, ArH), 8.17 (d, J¼6.0 Hz, 2H, ArH). IR (KBr):
3044, 2939, 1761, 1587, 1513, 1489, 1429, 1329, 1200, 1099,
1075, 1029, 757 cmꢁ1. HRMS [found: m/z 293.1151 (Mþ),
calcd for C17H15N3O2: M, 293.1164].
1066, 1020, 905, 836, 754, 695 cmꢁ1. HRMS [found: m/z
35
16
377.0926 (Mþ), calcd for C21H ClN3O2: M, 377.0931].
4.2.12. 3-Methyl-1-phenyl-4-(2,4-dichlorophenyl)-4,8-
dihydrofuro[30,40:5,6]pyrido[2,3-c]pyrazole (4l)
1
Mp: 254e256 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.78
4.2.17. 3-Methyl-1-phenyl-4-(4-chlorophenyl)indeno-
(s, 3H, CH3), 4.84 (d, J¼16.0 Hz, 1H, CH2), 4.88 (d,
J¼16.0 Hz, 1H, CH2), 5.39 (s, 1H, CH), 7.35 (d, J¼8.0 Hz,
1H, ArH), 7.39 (d, J¼1.6 Hz, 1H, ArH), 7.44 (d, J¼8.0 Hz,
1H, ArH), 7.51e7.59 (m, 5H, ArH), 10.37 (s, 1H, NH). IR
(KBr): 3320, 3062, 2924, 1722, 1644, 1590, 1538, 1470,
1392, 1358, 1255, 1132, 1102, 1021, 912, 848, 796,
[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7a)
1
Mp: 271e272 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.98
(s, 3H, CH3), 7.41 (t, J¼8.0 Hz, 1H, ArH), 7.58e7.64 (m, 8H,
ArH), 7.74 (t, J¼8.0 Hz, 1H, ArH), 7.96 (d, J¼8.0 Hz, 1H,
ArH), 8.27 (d, J¼8.0 Hz, 2H, ArH). IR (KBr): 3054, 2923,
1710, 1596, 1572, 1503, 1461, 1436, 1383, 1325, 1245,
696 cmꢁ1. HRMS [found: m/z 411.0533 (Mþ), calcd for
1201, 1119, 1083, 1014, 942, 866, 833, 767, 689 cmꢁ1
.
35
16
C21H Cl2N3O2: M, 411.0541].
15
HRMS [found: m/z 421.0984 (Mþ), calcd for C26H ClN3O:
35
M, 421.0982].
4.2.13. 3-Methyl-1-phenyl-4-(thiophen-2-yl)-4,8-dihydrofuro-
[30,40:5,6]pyrido[2,3-c]pyrazole (4m)
4.2.18. 3-Methyl-1-phenyl-4-(4-fluorophenyl)indeno-
1
Mp: 276e278 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.96
[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7b)
1
(s, 3H, CH3), 4.81 (d, J¼16.0 Hz, 1H, CH2), 4.87 (d,
J¼16.0 Hz, 1H, CH2), 5.31 (s, 1H, CH), 6.94e6.96 (m, 1H,
ArH), 7.01 (d, J¼3.2 Hz, 1H, ArH), 7.35 (d, J¼4.8 Hz, 1H,
ArH), 7.43 (t, J¼7.2 Hz, 1H, ArH), 7.51e7.57 (m, 4H, ArH),
10.33 (s, 1H, NH). IR (KBr): 3290, 3088, 3066, 2853, 1724,
1641, 1592, 1540, 1474, 1390, 1356, 1252, 1144, 1101, 1021,
907, 849, 797, 701 cmꢁ1. HRMS [found: m/z 349.0878 (Mþ),
calcd for C19H15N3O2S: M, 349.0885].
Mp: 256e257 ꢀC. H NMR (DMSO-d6, 400 MHz): d 2.02
(s, 3H, CH3), 7.38e7.44 (m, 3H, ArH), 7.60e7.66 (m, 6H,
ArH), 7.76 (t, J¼7.2 Hz, 1H, ArH), 8.00 (d, J¼7.2 Hz, 1H,
ArH), 8.28 (d, J¼8.0 Hz, 2H, ArH). IR (KBr): 2932, 2834,
1710, 1608, 1559, 1510, 1463, 1439, 1384, 1327, 1246,
1201, 1177, 1122, 1094, 1035, 952, 834, 770, 690 cmꢁ1
.
HRMS [found: m/z 405.1278 (Mþ), calcd for C26H16FN3O:
M, 405.1277].
4.2.14. 3-Methyl-1-phenyl-4-(pyridin-3-yl)-4,8-dihydrofuro-
4.2.19. 3-Methyl-1-phenyl-4-(4-methoxyphenyl)indeno-
[30,40:5,6]pyrido[2,3-c]pyrazole (4n)
[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7c)
1
1
Mp: 194e196 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.80
Mp: 222e224 ꢀC. H NMR (DMSO-d6, 400 MHz): d 2.02
(s, 3H, CH3), 4.83 (d, J¼16.0 Hz, 1H, CH2), 4.89 (d,
J¼16.0 Hz, 1H, CH2), 5.05 (s, 1H, CH), 7.37 (dd,
J1¼8.0 Hz, J2¼4.0 Hz, 1H, ArH), 7.42e7.46 (m, 1H, ArH),
7.53e7.57 (m, 3H, ArH), 7.68e7.70 (m, 1H, ArH), 8.44
(dd, J1¼4.8 Hz, J2¼3.2 Hz, 1H, ArH), 8.57 (d, J¼2.0 Hz,
1H, ArH), 10.33 (s, 1H, NH). IR (KBr): 3435, 3379, 3152,
3058, 2996, 1743, 1706, 1640, 1599, 1542, 1505, 1477,
1430, 1392, 1365, 1285, 1265, 1165, 1102, 1028, 842, 782,
699 cmꢁ1. HRMS [found: m/z 344.1287 (Mþ), calcd for
C20H16N4O2: M, 344.1273].
(s, 3H, CH3), 3.88 (s, 3H, OCH3), 7.09 (d, J¼8.0 Hz, 2H,
ArH), 7.40 (t, J¼7.2 Hz, 1H, ArH), 7.49 (d, J¼8.0 Hz, 2H,
ArH), 7.55e7.63 (m, 4H, ArH), 7.72 (t, J¼7.2 Hz, 1H, ArH),
7.94 (d, J¼8.0 Hz, 1H, ArH), 8.27 (d, J¼8.0 Hz, 2H, ArH).
IR (KBr): 3069, 3020, 1716, 1606, 1560, 1509, 1462, 1437,
1383, 1325, 1248, 1201, 1160, 1121, 1085, 1016, 954, 839,
763, 697 cmꢁ1. HRMS [found: m/z 417.1480 (Mþ), calcd for
C27H19N3O2: M, 417.1477].
4.2.20. 3-Methyl-1-phenyl-4-(4-hydroxyphenyl)indeno-
[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7d)
1
4.2.15. 3-Methyl-1-phenyl-4-propylfuro[30,40:5,6]pyrido-
[2,3-c]pyrazole (4o)
Mp: 316e318 ꢀC. H NMR (DMSO-d6, 400 MHz): d 2.03
(s, 3H, CH3), 6.91 (d, J¼8.0 Hz, 2H, ArH), 7.35e7.41 (m, 3H,
ArH), 7.53e7.62 (m, 4H, ArH), 7.71 (t, J¼8.0 Hz, 1H, ArH),
7.92 (d, J¼8.0 Hz, 1H, ArH), 8.27 (d, J¼8.0 Hz, 2H, ArH),
9.88 (s, 1H, OH). IR (KBr): 3231, 3067, 2961, 2920, 1694,
1593, 1500, 1435, 1382, 1332, 1274, 1200, 1119, 1087, 997,
849, 767, 685 cmꢁ1. HRMS [found: m/z 403.1317 (Mþ), calcd
for C26H17N3O2: M, 403.1321].
1
Mp: 168e169 ꢀC. H NMR (DMSO-d6, 300 MHz): d 1.04
(t, J¼6.0 Hz, 3H, CH3), 1.70e1.77 (m, 2H, CH2), 2.78 (s, 3H,
CH3), 3.40e3.43 (m, 2H, CH2), 5.43 (s, 2H, CH2), 7.38 (t,
J¼7.5 Hz, 1H, ArH), 7.56e7.61 (m, 2H, ArH), 8.17 (d,
J¼6.0 Hz, 2H, ArH). IR (KBr): 2959, 1758, 1593, 1514,
1492, 1442, 1200, 1105, 1071, 1037, 764 cmꢁ1. HRMS

C.-L. Shi et al. / Tetrahedron 64 (2008) 2425e2432
2431
4.2.21. 3-Methyl-1-phenyl-4-(4-methylphenyl)indeno-
4.2.26. 3-Methyl-1-phenyl-4-(3,4-dimethoxyphenyl)indeno-
[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7e)
[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7j)
1
1
Mp: 217e218 ꢀC. H NMR (DMSO-d6, 400 MHz): d 2.01
Mp: 230e231 ꢀC. H NMR (DMSO-d6, 400 MHz): d 2.09
(s, 3H, CH3), 3.79 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 7.09e
7.14 (m, 2H, ArH), 7.19 (s, 1H, ArH), 7.42 (t, J¼8.0 Hz, 1H,
ArH), 7.57e7.65 (m, 4H, ArH), 7.75 (t, J¼8.0 Hz, 1H, ArH),
7.99 (d, J¼8.0 Hz, 1H, ArH), 8.28 (d, J¼8.0 Hz, 2H, ArH). IR
(KBr): 2936, 2838, 1703, 1606, 1550, 1487, 1463, 1444, 1381,
1328, 1247, 1195, 1158, 1138, 1086, 1022, 966, 920, 856, 801,
762, 729, 686 cmꢁ1. HRMS [found: m/z 447.1584 (Mþ), calcd
for C28H21N3O3: M, 447.1583].
(s, 3H, CH3), 2.46 (s, 3H, CH3), 7.36 (d, J¼8.0 Hz, 2H, ArH),
7.42e7.45 (m, 3H, ArH), 7.59e7.65 (m, 4H, ArH), 7.75 (t,
J¼8.0 Hz, 1H, ArH), 7.99 (d, J¼8.0 Hz, 1H, ArH), 8.29 (d,
J¼8.0 Hz, 2H, ArH). IR (KBr): 2916, 1714, 1556, 1498,
1437, 1383, 1325, 1247, 1199, 1120, 767, 727, 698 cmꢁ1
.
HRMS [found: m/z 401.1533 (Mþ), calcd for C27H19N3O:
M, 401.1528].
4.2.22. 3-Methyl-1-phenyl-4-(4-nitrophenyl)indeno-
[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7f)
4.2.27. 3-Methyl-1-phenyl-4-(4-dimethylaminophenyl)-
1
Mp: 318e319 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.99
indeno[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7k)
1
(s, 3H, CH3), 7.43 (t, J¼8.0 Hz, 1H, ArH), 7.59e7.65 (m, 4H,
ArH), 7.77 (t, J¼8.0 Hz, 1H, ArH), 7.88 (d, J¼8.0 Hz, 2H,
ArH), 8.01 (d, J¼8.0 Hz, 1H, ArH), 8.28 (d, J¼8.0 Hz,
2H, ArH), 8.41 (d, J¼8.0 Hz, 2H, ArH). IR (KBr): 3061,
1708, 1566, 1519, 1503, 1438, 1384, 1347, 1245, 1200,
1120, 996, 949, 837, 767, 692 cmꢁ1. HRMS [found: m/z
432.1203 (Mþ), calcd for C26H16N4O3: M, 432.1222].
Mp: 241e242 ꢀC. H NMR (DMSO-d6, 400 MHz): d 2.09
(s, 3H, CH3), 3.04 (s, 6H, N(CH3)2), 6.84 (d, J¼8.0 Hz, 2H,
ArH), 7.41 (d, J¼8.0 Hz, 3H, ArH), 7.57e7.64 (m, 4H, ArH),
7.73 (t, J¼8.0 Hz, 1H, ArH), 7.96 (d, J¼8.0 Hz, 1H, ArH),
8.29 (d, J¼8.0 Hz, 2H, ArH). IR (KBr): 3017, 2893, 2816,
1705, 1617, 1561, 1511, 1479, 1462, 1442, 1370, 1325,
1232, 1194, 1156, 1125, 1085, 1020, 945, 849, 815, 768,
729, 701 cmꢁ1. HRMS [found: m/z 430.1783 (Mþ), calcd
for C28H22N4O: M, 430.1794].
4.2.23. 3-Methyl-1-phenyl-4-(benzo[d][1,3]dioxol-5-yl)-
indeno[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7g)
1
Mp: 221e222 ꢀC. H NMR (DMSO-d6, 400 MHz): d 2.02
4.2.28. 3-Methyl-1-phenyl-4-(2,4-dichlorophenyl)indeno-
(s, 3H, CH3), 6.17 (s, 2H, OCH2O), 6.99 (d, J¼8.0 Hz, 1H,
ArH), 7.07 (d, J¼8.0 Hz, 1H, ArH), 7.12 (s, 1H, ArH), 7.38
(t, J¼8.0 Hz, 1H, ArH), 7.53e7.61 (m, 4H, ArH), 7.69 (t,
J¼8.0 Hz, 1H, ArH), 7.90 (d, J¼8.0 Hz, 1H, ArH), 8.25 (d,
J¼8.0 Hz, 2H, ArH). IR (KBr): 3074, 2881, 1714, 1560,
1503, 1440, 1383, 1324, 1238, 1195, 1118, 1081, 1043, 996,
942, 819, 805, 763, 730, 701 cmꢁ1. HRMS [found: m/z
431.1264 (Mþ), calcd for C27H17N3O3: M, 431.1270].
[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7l)
1
Mp: 182e184 ꢀC. H NMR (DMSO-d6, 400 MHz): d 2.00
(s, 3H, CH3), 7.43 (t, J¼8.0 Hz, 1H, ArH), 7.59e7.67 (m, 6H,
ArH), 7.78 (t, J¼8.0 Hz, 1H, ArH), 7.91 (s, 1H, ArH), 8.03 (d,
J¼8.0 Hz, 1H, ArH), 8.27 (d, J¼8.0 Hz, 2H, ArH). IR (KBr):
3076, 2930, 1717, 1593, 1562, 1504, 1473, 1435, 1383, 1321,
1306, 1247, 1198, 1159, 1124, 1102, 1084, 1030, 995, 947,
873, 829, 791, 760, 728, 687 cmꢁ1. HRMS [found: m/z
455.0587 (Mþ), calcd for C26H Cl2N3O: M, 455.0592].
35
15
4.2.24. 3-Methyl-1-phenyl-4-(3,4-dichlorophenyl)-
indeno[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7h)
4.2.29. 3-Methyl-1-phenyl-4-(2-nitrophenyl)indeno-
1
Mp: 192e194 ꢀC. H NMR (DMSO-d6, 400 MHz): d 2.01
[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7m)
1
(s, 3H, CH3), 7.41 (t, J¼8.0 Hz, 1H, ArH), 7.56e7.63 (m, 5H,
ArH), 7.74 (t, J¼8.0 Hz, 1H, ArH), 7.83 (d, J¼8.0 Hz, 1H,
ArH), 7.91 (s, 1H, ArH), 7.96 (d, J¼8.0 Hz, 1H, ArH), 8.26
(d, J¼8.0 Hz, 2H, ArH). IR (KBr): 3065, 2928, 1713, 1567,
1504, 1472, 1436, 1377, 1323, 1308, 1245, 1203, 1181, 1119,
1084, 1035, 954, 895, 832, 766, 727, 688 cmꢁ1. HRMS
[found: m/z 455.0586 (Mþ), calcd for C26H1535Cl2N3O: M,
455.0592].
Mp: 274e276 ꢀC. H NMR (DMSO-d6, 400 MHz): d 1.94
(s, 3H, CH3), 7.43 (t, J¼7.2 Hz, 1H, ArH), 7.58e7.66 (m, 4H,
ArH), 7.72e7.77 (m, 2H, ArH), 7.90 (t, J¼8.0 Hz, 1H, ArH),
7.92e8.02 (m, 2H, ArH), 8.29 (d, J¼8.0 Hz, 2H, ArH), 8.40
(d, J¼8.0 Hz, 1H, ArH). IR (KBr): 3063, 2922, 1711, 1593,
1568, 1504, 1436, 1420, 1382, 1353, 1248, 1204, 1121,
1083, 997, 951, 874, 850, 763, 726, 692 cmꢁ1. HRMS [found:
m/z 432.1218 (Mþ), calcd for C26H16N4O3: M, 432.1222].
4.2.25. 3-Methyl-1-phenyl-4-(thiophen-2-yl)indeno-
4.2.30. 3-Methyl-1-phenyl-4-(pyridin-3-yl)indeno-
[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7i)
[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7n)
1
1
Mp: 232e233 ꢀC. H NMR (DMSO-d6, 400 MHz): d 2.09
Mp: 216e217 ꢀC. H NMR (DMSO-d6, 400 MHz): d 2.00
(s, 3H, CH3), 7.28e7.30 (m, 1H, ArH), 7.39e7.43 (m, 2H,
ArH), 7.58e7.63 (m, 4H, ArH), 7.74 (t, J¼8.0 Hz, 1H, ArH),
7.90 (d, J¼7.2 Hz, 1H, ArH), 7.95 (d, J¼7.2 Hz, 1H, ArH),
8.25 (d, J¼8.0 Hz, 2H, ArH). IR (KBr): 3104, 3076, 3017,
1704, 1562, 1499, 1434, 1380, 1320, 1246, 1192, 1117,
1082, 1030, 990, 942, 904, 859, 806, 770, 752, 720,
686 cmꢁ1. HRMS [found: m/z 393.0917 (Mþ), calcd for
C24H15N3OS: M, 393.0936].
(s, 3H, CH3), 7.42 (t, J¼8.0 Hz, 1H, ArH), 7.58e7.64 (m,
5H, ArH), 7.74 (t, J¼8.0 Hz, 1H, ArH), 7.98 (d, J¼8.0 Hz,
1H, ArH), 8.04 (d, J¼8.0 Hz, 1H, ArH), 8.27 (d, J¼8.0 Hz, 2H,
ArH), 8.76e8.78 (m, 2H, ArH). IR (KBr): 3344, 3057,
2929, 1712, 1595, 1559, 1502, 1419, 1383, 1326, 1308,
1247, 1190, 1152, 1119, 1084, 1028, 995, 948, 907, 869,
765, 753, 728, 688 cmꢁ1. HRMS [found: m/z 388.1316
(Mþ), calcd for C25H16N4O: M, 388.1324].

2432
C.-L. Shi et al. / Tetrahedron 64 (2008) 2425e2432
Chem. 1989, 32, 945; (f) Lynch, B. M.; Khan, M. A.; Teo, H. C.; Pedrotti,
F. Can. J. Chem. 1988, 66, 420.
4.2.31. 3-Methyl-1-phenyl-4-(4-bromophenyl)indeno-
[20,10:5,6]pyrido[2,3-c]pyrazole-5-one (7o)
7. New, J. S.; Christopher, W. L.; Yevich, J. P.; Butler, R.; Schlemmer, R.;
Francis, J.; VanderMaelen, C. P.; Cipollina, J. A. J. Med. Chem. 1989,
32, 1147.
8. Bukoski, R. D.; Bo, J.; Xue, H.; Bian, K. J. Pharmacol. Exp. Ther. 1993,
265, 30.
1
Mp: 274e275 ꢀC. H NMR (DMSO-d6, 400 MHz): d 2.01
(s, 3H, CH3), 7.42 (t, J¼8.0 Hz, 1H, ArH), 7.53 (d, J¼8.0 Hz,
2H, ArH), 7.58e7.64 (m, 4H, ArH), 7.76 (d, J¼8.0 Hz, 3H,
ArH), 7.99 (d, J¼8.0 Hz, 1H, ArH), 8.27 (d, J¼8.0 Hz, 2H,
ArH). IR (KBr): 3051, 2922, 1712, 1594, 1569, 1503, 1460,
1436, 1383, 1325, 1245, 1200, 1120, 1092, 1011, 942, 866,
9. Paronikyan, E. G.; Oganisyan, A. K.; Noravyan, A. S.; Paronikyan, R. G.;
Dzhagatspanyan, I. A. Pharm. Chem. J. 2002, 36, 413.
10. Wagner, G.; Prantz, J. Pharmazie 1993, 48, 250.
831, 767, 727, 690 cmꢁ1. HRMS [found: m/z 465.0461
11. Jeschke, P.; Harder, A.; Etzel, W.; Gau, W.; Goehrt, A.; Benet-Buchholz,
J.; Thielking, G. Bioorg. Med. Chem. Lett. 2005, 15, 2375.
12. Gerster, P.; Riegger, C.; Fallert, M. Arzneim.-Forsch. 1987, 37, 309.
13. Wishka, D. G.; Graber, D. R.; Seest, E. P.; Dolak, L. A.; Han, F.; Watt, W.;
Morris, J. J. Org. Chem. 1998, 63, 7851.
79
16
(Mþ), calcd for C26H BrN3O: M, 465.0477].
4.2.32. 3-Methyl-1-phenyl-4-propylindeno[20,10:5,6]pyrido-
[2,3-c]pyrazole-5-one (7p)
14. Marco, J. L.; Carreiras, M. C. Mini-Rev. Med. Chem. 2003, 3, 578.
15. (a) Geurtsen, B.; De Bie, D. A.; Van der Plas, H. C. Tetrahedron 1989, 45,
6519; (b) Frissen, A. E.; Marcelis, A. T. M.; Buurman, D. G.; Pollmann,
C. A. M.; Van der Plas, H. C. Tetrahedron 1989, 45, 5611.
16. (a) Chandrasekhar, S.; Reddy, N. S.; Sultana, S. S.; Narsihmulu, C.;
Reddy, K. V. Tetrahedron 2006, 62, 338e345; (b) Li, H.; Wang, B.;
Deng, L. J. Am. Chem. Soc. 2006, 128, 732; (c) Poulsen, T. B.; Bernardy,
L.; Bell, M.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2006, 45, 1.
17. (a) Rasalkar, M. S.; Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. J. Mol.
Catal. A: Chem. 2005, 235, 267; (b) Alcaide, B.; Almendros, P.; Luna, A.;
Torres, M. S. J. Org. Chem. 2006, 71, 4818.
Mp: 146e148 ꢀC. 1H NMR (DMSO-d6, 300 MHz):
d 1.03e1.05 (m, 3H, CH3), 1.68e1.70 (m, 2H, CH2), 2.51e
2.52 (m, 2H, CH2), 2.67 (s, 3H, CH3), 7.33 (t, J¼3.0 Hz,
1H, ArH), 7.32e7.34 (m, 2H, ArH), 7.35e7.42 (m, 3H,
ArH), 7.88 (d, J¼6.0 Hz, 1H, ArH), 8.25 (d, J¼6.0 Hz, 2H,
ArH). IR (KBr): 3075, 2959, 1704, 1572, 1503, 1463, 1425,
1389, 1334, 1268, 1194, 1145, 1091, 963, 768, 727, 690 cmꢁ1
.
4.2.33. 3-Methyl-1-phenyl-4-ethylindeno[20,10:5,6]pyrido-
[2,3-c]pyrazole-5-one (7q)
18. (a) Bogevig, A.; Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Jorgensen,
K. A. Angew. Chem., Int. Ed. 2002, 41, 1790; (b) Janey, J. M.; Hsiano, Y.;
Armstrong, J. D., III. J. Org. Chem. 2006, 71, 390.
Mp: 207e208 ꢀC. 1H NMR (DMSO-d6, 300 MHz):
d 1.33e1.35 (m, 3H, CH3), 2.56e2.61 (m, 2H, CH2), 2.72
(s, 3H, CH3), 7.41e7.43 (m, 1H, ArH), 7.59e7.61 (m, 3H,
ArH), 7.71e7.76 (m, 2H, ArH), 7.94 (d, J¼6.0 Hz, 1H,
ArH), 8.26 (d, J¼6.0 Hz, 2H, ArH). IR (KBr): 2977, 2934,
1703, 1573, 1503, 1463, 1428, 1385, 1334, 1276, 1194,
19. (a) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bogevig, A.; Jorgensen,
K. A. J. Am. Chem. Soc. 2002, 124, 827; (b) Kotrusz, P.; Toma, S.
Molecules 2006, 11, 197.
20. (a) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew. Chem.
2003, 115, 4365; (b) Kotrusz, P.; Toma, S. Arkivoc 2006, 100.
21. Hossein, A. O.; Elham, R.; Majid, M. H. J. Chem. Res. 2006, 246.
22. (a) Yadav, J. S.; Kumar, S. P.; Kondaji, G.; Rao, R. S.; Nagaiah, K.
Chem. Lett. 2004, 33, 1168; (b) Mabry, J.; Ganem, B. Tetrahedron
Lett. 2006, 47, 55.
23. Kumar, A.; Maurya, R. A. Tetrahedron 2007, 63, 1946.
24. Safak, C.; Simsek, R.; Altas, Y.; Boydag, S.; Erol, K. Boll. Chim. Farm.
1997, 136, 665.
1162, 1063, 941, 910, 811, 753, 727 cmꢁ1
.
Acknowledgements
We are grateful to the National Natural Science Foundation
of China (20472062 and 20672079), the Natural Science
Foundation of Jiangsu Province (BK2006048), and the Natural
Science Foundation of Jiangsu Education Department
(06KJA15007) for financial support.
25. Bisenieks, E.; Uldrikis, J.; Kirule, I.; Tirzite, G.; Dubur, G. Khim. Getero-
tsikl. Soedin. 1982, 1528.
26. (a) Augstein, J.; Ham, A. L.; Leeming, P. R. J. Med. Chem. 1972, 15, 466;
(b) Kunstmann, R.; Lerch, U.; Gerhards, H.; Leven, M.; Schacht, U.
J. Med. Chem. 1984, 27, 432; (c) Kunstmann, R.; Fischer, G. J. Med.
Chem. 1984, 27, 1312.
References and notes
27. Rentzea, C.; Meyer, N.; Kast, J.; Plath, P.; Koenig, H.; Harreus, A.;
Kardorff, U.; Gerber, M.; Walter, H. Ger. Offen. DE 4301426 A1 21,
1994; Chem. Abstr. 1994, 121, 133986.
1. Huang, S.; Lin, R.; Yu, Y.; Lu, Y.; Connolly, P. J.; Chiu, G.; Li, S.;
Emanuel, S. L.; Middleton, S. A. Bioorg. Med. Chem. Lett. 2007, 17, 1243.
2. Saggar, S. A.; Sisko, J. T.; Tucker, T. J.; Tynebor, R. M.; Su, D. S.;
Anthony, N. J. U.S. Patent Appl. US 2,007,021,442, 2007.
28. (a) De Wit, T.; Van Emelen, K.; Maertens, F.; Hoornaert, G. J.;
Compernolle, F. Tetrahedron Lett. 2001, 42, 4919; (b) Van Emelen, K.;
De Wit, T.; Hoornaert, G. J.; Compernolle, F. Tetrahedron 2002, 58, 4225.
29. Crystallographic data for the structures of 4e has been deposited at the
Cambridge Crystallographic Data Centre, deposit number is CCDC-
670361.Copies of available material can be obtained free of charge on ap-
plication to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44
1223 336 033; e-mail: deposit@ccdc.cam.ac.uk). The single-crystal
growth was carried out in EtOH and DMF solutions at rt. Intensity data
were collected on a Smart-1000 diffractometer with graphite monochro-
3. Zhang, P.; Pennell, A. M. K.; Wright, J. J. K.; Chen, W.; Leleti, M. R.; Li,
Y.; Li, L.; Xu, Y. PCT Int. Appl. WO 2007002293, Chemocentryx, USA.
4. Chiu, G.; Li, S.; Connolly, P. J.; Middleton, S. A.; Emanuel, S. L.; Huang,
S.; Lin, R.; Lu, Y. PCT Int. Appl. WO 2006130673, Janssen Pharmaceu-
tica, N.V., Belgium.
5. Feurer, A.; Luithle, J.; Wirtz, S.; Koenig, G.; Stasch, J.; Stahl, E.;
Schreiber, R.; Wunder, F.; Lang, D. PCT Int. Appl. WO 2004009589,
Bayer Healthcare AG, Germany.
˚
mated Mo Ka radiation (l¼0.71073 A) using the u scan mode with
2.05ꢀ<q<25.05ꢀ. Crystal data for 4e: empirical formula C22H19N3O3, color-
less, crystal dimension 0.35ꢂ0.33ꢂ0.25 mm, monoclinic, space group
6. (a) Chen, T.; He, H. Huaxue Tongbao (in Chinese) 2005, 68 w040/1; (b)
Diaz-Ortiz, A.; De la Hoz, A.; Langa, F. Green Chem. 2000, 2, 165; (c)
Krygowski, T. M.; Anulewicz, R.; Cyranski, M. K.; Puchala, A.; Rasala,
D. Tetrahedron 1998, 54, 12295; (d) Sanghvi, Y. S.; Larson, S. B.; Robins,
R. K.; Revankar, G. R. Nucleosides Nucleotides 1989, 8, 887; (e) Sanghvi,
Y. S.; Larson, S. B.; Willis, R. C.; Robins, R. K.; Revankar, G. R. J. Med.
ꢀ
˚
˚
˚
P21/n, a¼11.5496(9) A, b¼12.5051(10) A, c¼13.3867(11) A, a¼90 ,
3
b¼107.2830(10)ꢀ, g¼90ꢀ. V¼1846.1(3) A , Mr¼373.40, Z¼4, Dc¼
˚
1.343 Mg/m3, m(Mo Ka)¼0.091 mmꢁ1, F(000)¼784, S¼1.027, R1¼
0.0696, wR2¼0.1515.