One-step efficient synthesis of pyrazolo[3,4-f]quinoline derivatives under microwave irradiation

Article abstract of DOI:10.1080/00397910903032317

A series of new pyrazolo[3,4-f]quinoline derivatives were synthesized by multicomponent reactions of equimolar amounts of aromatic aldehydes 1, barbituric acids 2 (barbituric acid or 1,3-dimethyl barbituric acid), and 5-aminoindazole 3 in mixed solvent of

Full text of DOI:10.1080/00397910903032317

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One-Step Efficient Synthesis of
Pyrazolo[3,4-f]quinoline Derivatives
Under Microwave Irradiation
Shu-Jiang Tu a , Shan-Shan Wu a , Xiao-Hong Zhang a , Zheng-Guo
Han a , Xu-Dong Cao a & Wen-Juan Hao a
a School of Chemistry and Chemical Engineering, Xuzhou Normal
University , Xuzhou, Jiangsu, China
Published online: 04 Mar 2010.
To cite this article: Shu-Jiang Tu , Shan-Shan Wu , Xiao-Hong Zhang , Zheng-Guo Han , Xu-Dong Cao
& Wen-Juan Hao (2010) One-Step Efficient Synthesis of Pyrazolo[3,4-f]quinoline Derivatives Under
Microwave Irradiation, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 40:7, 1057-1064, DOI: 10.1080/00397910903032317
To link to this article: http://dx.doi.org/10.1080/00397910903032317
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Synthetic Communications1, 40: 1057–1064, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903032317
ONE-STEP EFFICIENT SYNTHESIS OF
PYRAZOLO[3,4-f]QUINOLINE DERIVATIVES
UNDER MICROWAVE IRRADIATION
Shu-Jiang Tu, Shan-Shan Wu, Xiao-Hong Zhang,
Zheng-Guo Han, Xu-Dong Cao, and Wen-Juan Hao
School of Chemistry and Chemical Engineering, Xuzhou Normal University,
Xuzhou, Jiangsu, China
A series of new pyrazolo[3,4-f]quinoline derivatives were synthesized by multicomponent
reactions of equimolar amounts of aromatic aldehydes 1, barbituric acids 2 (barbituric acid
or 1,3-dimethyl barbituric acid), and 5-aminoindazole 3 in mixed solvent of glacial acetic
acid and ethylene glycol (2:1, v=v) without catalyst under microwave irradiation. This
one-pot protocol has the advantage of good yields (91–94%), simple workup procedure,
and short reaction times (5–6 min).
Keywords: Microwave irradiation; mixed solvent; pyrazolo[3,4-f]quinoline
INTRODUCTION
An immunostimulant could play a role in livestock production. Periods of stress
(e.g., shipping, weaning, handling, dietary changes, comingling) have been associated
with increased incidences of bacterial disease in cattle and swine.[1–3] Pyrazolo[3,4-f]
quinoline derivatives are a novel class of immunostimulant with potent in vivo effects
in a murine infection model.[4,5] Studies in side-chain structure–activity relationships
(SAR), formulation issues, and injection site toleration have been addressed, and
compounds suitable for extensive in vivo evaluation have been identified.[6] Therefore,
the synthesis of pyrazolo[3,4-f]quinoline derivatives is of great significance. However,
to the best of our knowledge, few of efficient procedures for the preparation of
pyrazolo[3,4-f]quinoline derivatives have been reported. One of the methods was
described in the literature: small pyrazolo[3,4-f]quinoline derivatives were synthesized
by the Ullmann reaction using 5-aminoindazole reactions of o-chlorobenzoic acid to
give anthranilic acids. Cyclization of these acids in sulfuric acid led to pyrazolo[3,4-f]
quinoline derivatives.[7] There are some inevitable drawbacks in these synthetic proce-
dures: multistep procedures, inconvenient materials, and narrow application scope of
substrates. Therefore, a simple, rapid, and efficient procedure is still strongly desired
for the synthesis of these important heterocyclic compounds.
Received March 18, 2009.
Address correspondence to Shu-Jiang Tu, School of Chemistry and Chemical Engineering, Xuzhou
Normal University, Xuzhou, Jiangsu, China. E-mail: laotu2001@263.net
1057

1058
S.-J. TU ET AL.
Scheme 1. Synthesis of pyrazolo[3,4-f]quinoline derivatives.
The microwave (MW)–assisted organic synthesis has been a topic of continued
studies because it could lead to easier operation and shorter reaction times than the
traditional heating methods.[8] Use of MW irradiation (MWI) for the formation of
carbon–heteroatom, especially carbon–nitrogen, bonds has been reported.[9] In
addition, the diversity potential of multicomponent reactions (MCRs) has been
recognized, and their utility in preparing libraries to screen for functional molecules
is well appreciated.[10,11]
In the context of our long-standing interest in the design and development of
heterocyclic compounds with important biological prosperities and expansion of the
libraries of pyrazolo[3,4-f]quinoline for biomedical screening, we herein report an
efficient method for the synthesis of pyrazolo[3,4-f]quinoline derivatives via reactions
of equimolar amounts of aromatic aldehydes 1, barbituric acids 2 (barbituric acid, or
1,3-dimethyl barbituric acid), and 5-aminoindazole 3 without catalyst under micro-
wave irradiation (Scheme 1).
RESULTS AND DISCUSSION
Choosing an appropriate solvent is of crucial importance for successful
MW-promoted synthesis because of the rapid rise of temperature in the reaction
mixture. To optimize the reaction solvent, the reaction of 4-bromophenylaldehyde
(1e), barbituric acid (2), and 5-aminoindazole (3) was carried out in different organic
solvents containing ethanol, ethylene glycol, glacial acetic acid, and dimethylforma-
mide (DMF) and different proportions of mixed solvents (glacial acetic acid and
ethylene glycol) in the synthesis of 4e at 120 ꢀC. All reactions were carried out at a
maximum power of 200 W. The results are summarized in Table 1.
It was shown in Table 1 that the reactions in mixed acetic acid and glycol (pre-
ferred volume ratio 2:1) gave the best results (entry 7) and these were thus chosen as
the solvents for subsequent reactions. Furthermore, to optimize the reaction tem-
perature, the same reaction was carried out using a mixed solvent of glacial acetic
acid and ethylene glycol (v=v ¼ 2:1) at the maximum power of 200 W at temperatures
ranging from 90 to 150 ꢀC in increments of 10 ꢀC. The results are shown in Table 2
(entries 1–7).
We found that the yield of product 4e was improved and the reaction time
was shortened as the temperature increased from 90 to 130 ꢀC (Table 2, entries
1–5). The yield plateaued when temperature was further increased to 140 and
150 ꢀC (Table 2, entries 6 and 7). It implied that further increase of the temperature

PYRAZOLO[3,4-f]QUINOLINE
1059
Table 1. Solvent optimization for the synthesis of 4e at 120 ꢀC under MWI
Entry
Solvent
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
EtOH
Glycol
HOAc
10
8
40
71
89
80
89
91
93
7
DMF
7
HOAc–glycol (4:1)a
HOAc–glycol (3:1)a
HOAc–glycol (2:1)a
7
7
7
aVolume ratio.
bIsolated yields.
Table 2. Temperature optimization for synthesis of 4e
Entry
Temp. (ꢀC)
Time (min)
Yielda (%)
1
2
3
4
5
6
7
90
100
110
120
130
140
150
8
8
7
7
6
6
6
89
90
92
93
95
94
93
aIsolated yields.
above 130 ꢀC has no obvious influence on this reaction. Therefore, 130 ꢀC was
chosen for all further reactions.
Under these optimized conditions [130 ꢀC, glacial acetic acid and ethylene
glycol (v=v ¼ 2:1), 200 W (maximum power)], a new type of pyrazolo[3,4-f]quinoline
derivatives 4 were synthesized via reactions of 1, 2, and 3 under microwave
irradiation (Table 3).
As shown in Table 3, this protocol could be applied not only to aromatic
aldehydes with either electron-withdrawing or electron-donating groups but also
to heterocyclic aromatic aldehydes. Those one-pot MCRs have the advantage
Table 3. Synthesis of 4 under microwave irradiation at 130 ꢀC
Entry
Compound
Ar
R
Time (min)
Yielda (%)
Mp (ꢀC)
1
2
4a
4b
4c
4d
4e
4f
3.4-CH3OC6H3
3,4-(OCH2O)C6H3
2-Thienyl
H
H
6
6
6
6
5
6
5
5
5
6
93
93
92
92
93
93
93
91
92
94
>300
>300
>300
>300
>300
>300
>300
>300
>300
>300
3
H
4
4-OCH3-C6H4
4-Br-C6H4
H
5
H
6
4-OH-3-NO2C6H3
4-CH3-sC6H4
3-NO2C6H4
H
7
4g
4h
4i
CH3
CH3
CH3
CH3
8
9
10
3,4-(OCH2O)C6H3
4-NO2-C6H4
4j
aIsolated yields.

1060
S.-J. TU ET AL.
Scheme 2. Possible mechanism of formation of pyrazolo[3,4-f]quinoline derivatives 4.
of good yields (91–94%), one step, simple workup procedure, and short
reaction times (5–6 min).
Although the detailed mechanism of the reaction remains to be fully clarified,
we reasoned their possible mechanism proceeded via a reaction sequence of conden-
sation, addition, cyclization, and dehydration (presented in Scheme 2). First, the
condensation between aromatic aldehyde 1 and barbituric acids 2 leads to intermedi-
ate 5; Michael addition between 5 and 3 would give 6, which upon intermolecular
cyclization and dehydration generates the product 4.
To test the mechanism, under the optimized conditions mentioned [130 ꢀC, gla-
cial acetic acid and ethylene glycol (v=v ¼ 2:1)], 4-bromophenylaldehyde (1e), and
5-aminoindazole (3) were added into the vessel under MWI after several minutes.
We cannot get Schiff’s base from the condensation of 1e and 3. When a mixture
of 1e and barbituric acid were added into the vessel at the same conditions, the inter-
mediate product 5e was obtained. Furthermore, the reaction of intermediate product
5e and 3 was carried out under the same conditions. The target compound was
obtained, with yield similar to the one-pot reaction. The experimental results support
the proposed mechanism.
1
In this study, all the products were characterized by infrared (IR) spectra, H
NMR, and elemental analysis. Some compounds were also characterized by 13C
NMR.
CONCLUSION
In summary, we have provided a practical, efficient, inexpensive, one-step
method for the synthesis of pyrazolo[3,4-f]quinoline derivatives that may provide
new classes of biological active for biomedical screening. An extension of this work
is currently under investigation.
EXPERIMENTAL
All reactions were carried out in a monomodal EmrysTM Creator from
Personal Chemistry, Uppsala, Sweden. Melting points were determined in open

PYRAZOLO[3,4-f]QUINOLINE
1061
capillaries and are uncorrected. IR spectra were recorded on a Tensor 27 spec-
trometer in KBr. 1H NMR (13C NMR) spectra were measured on a DPX400
spectrometer operating at 400 MHz (100 MHz), using dimethylsulfoxide (DMSO-
d6) as solvent and tetramethylsilane (TMS) as an internal standard. Elemental analy-
sis was determined by using a Perkin-Elmer 240c elemental analysis instrument.
General Procedure for the One-Pot Synthesis of Pyrazolo[3,4-f]
quinoline Derivatives Under MW Irradiation
In a 10-mL EmrysTM reaction vial, appropriate aromatic aldehydes (1 mmol),
barbituric acids (barbituric acid or 1,3-dimethyl barbituric acid) (1 mmol), and an
equimolar amount of 5-aminoindazole in the presence of glacial acetic acid (2 mL)
and ethylene glycol (1 mL) were mixed and then capped. The mixture was irradiated
by MWI at the maximum power of 200 W at 130 ꢀC. Upon completion [monitored
by thin-layer chromatography (TLC)], the reaction mixture was cooled to room tem-
perature and filtered to give the crude products, which were further purified by
recrystallization from 95% EtOH to give pure pyrazolo[3,4-f]quinoline derivatives.
Data
Compound 4a. IR (KBr): 3376 (br), 3211, 1704, 1640, 1559, 1448, 1373, 1246,
1186, 1142, 1025, 925, 813, 767 cmꢁ1.1H NMR (400 MHz, DMSO-d6): d 12.97 (s, 1H,
NH), 10.55 (s, 1H, NH), 10.28 (s, 1H, NH), 8.80 (s, 1H, NH), 8.09 (s, 1H, ArH), 7.35
(d, 1H, J ¼ 8.8 Hz, ArH), 7.13 (d, 1H, J ¼ 8.8 Hz, ArH), 7.06 (s, 1H, ArH), 6.74–6.67
(m, 2H, ArH), 5.37 (s, 1H, CH), 3.69 (s, 3H, CH3O), 3.62 (s, 3H, CH3O). 13C NMR
(100 MHz, DMSO-d6): d 162.9, 150.2, 148.1, 147.1, 145.5, 140.0, 128.1, 121.5, 119.4,
117.1, 114.2, 112.0, 111.8, 109.4, 85.4, 55.5, 37.5, 30.7. Anal. calcd. for C20H17N5O4:
C, 61.38; H, 4.38; N, 17.89. Found: C, 61.62; H, 4.27; N, 17.83.
Compound 4b. IR (KBr): 3398, 3363, 3229, 1713, 1632, 1512, 1424, 1370,
1237, 1168, 1094, 934, 804, 770 cmꢁ1.1H NMR (400 MHz, DMSO-d6): d 12.99 (s,
1H, NH), 10.56 (s, 1H, NH), 10.29 (s, 1H, NH), 8.83 (s, 1H, NH), 8.05 (s, 1H,
ArH), 7.36 (d, 1H, J ¼ 8.8 Hz, ArH), 7.14 (d, 1H, J ¼ 8.8 Hz, ArH), 6.88 (s, 1H,
ArH), 6.77–6.69 (m, 2H, ArH), 5.88 (s, 2H, CH2), 5.36 (s, 1H, CH). 13C NMR
(100 MHz, DMSO-d6): d 162.8, 150.1, 146.9, 145.4, 145.3, 141.3, 128.1, 121.4,
120.4, 117.1, 114.0, 109.5, 108.1, 107.7, 100.6, 85.4, 37.7, 30.7. Anal. calcd. for
C19H13N5O4: C, 60.80; H, 3.49; N, 18.66. Found: C, 61.01; H, 3.24; N, 18.60.
Compound 4c. IR (KBr): 3391, 3380, 3307, 1704, 1601, 1517, 1449, 1398,
1228, 1165, 1039, 928, 846, 770 cmꢁ1.1H NMR (400 MHz, DMSO-d6): d 13.04 (s,
1H, NH), 11.28 (s, 1H, NH), 10.37 (s, 1H, NH), 8.97 (s, 1H, NH), 8.16 (s, 1H,
ArH), 7.40–7.35 (m, 1H, ArH), 7.17–7.13 (m, 2H, ArH), 6.92 (d, 1H, J ¼ 2.8 Hz,
ArH), 6.80–6.78 (m, 1H, ArH), 5.77 (s, 1H, CH). 13C NMR (100 MHz, DMSO-
d6): d 162.8, 150.9, 150.1, 145.6, 128.1, 126.3, 123.8, 123.6, 121.4, 117.1, 113.2,
111.6, 111.1, 84.9, 81.0, 32.8. Anal. calcd. for C16H11N5O2S: C, 56.96; H, 3.29; N,
20.76; S, 9.50. Found: C, 57.17; H, 3.22; N, 20.69; S, 9.47.

1062
S.-J. TU ET AL.
Compound 4d. IR (KBr): 3395 (br), 3278, 1710, 1602, 1569, 1454, 1256,
1175, 929, 847, 772 cmꢁ1.1H NMR (400 MHz, DMSO-d6): d 12.97 (s, 1H, NH),
10.53 (s, 1H, NH), 10.27 (s, 1H, NH), 8.80 (s, 1H, NH), 8.00 (s, 1H, ArH), 7.35
(d, 1H, J ¼ 8.8 Hz, ArH), 7.22 (d, 2H, J ¼ 8.4 Hz, ArH), 7.13 (d, 1H, J ¼ 8.8 Hz,
ArH), 6.73 (d, 2H, J ¼ 8.8 Hz, ArH), 5.36 (s, 1H, CH), 3.63 (s, 3H, CH3O). Anal.
calcd. for C19H15N5O3: C, 63.15; H, 4.18; N, 19.38. Found: C, 63.37; H, 4.32; N,
19.31.
Compound 4e. IR (KBr): 3381, 3211, 1706, 1602, 1517, 1420, 1324, 1222,
1
1089, 928, 841, 763 cmꢁ1. H NMR (400 MHz, DMSO-d6): d 13.03 (s, 1H, NH),
10.58 (s, 1H, NH), 10.36 (s, 1H, NH), 8.95 (s, 1H, NH), 7.99 (s, 1H, ArH), 7.38
(t, 3H, J ¼ 8.4 Hz, ArH), 7.29 (d, 2H, J ¼ 8.4 Hz, ArH), 7.15 (d, 1H, J ¼ 8.8 Hz,
ArH), 5.43 (s, 1H, CH). Anal. calcd. for C18H12BrN5O2: C, 52.70; H, 2.95; N,
17.07. Found: C, 52.89; H, 2.77; N, 17.69.
Compound 4f. IR (KBr): 3277 (br), 3189, 1703, 1630, 1482, 1409, 1332, 1235,
1
1177, 1092, 931, 845, 763 cmꢁ1. H NMR (400 MHz, DMSO-d6): d 13.03 (s, 1H,
OH), 10.70 (s, 1H, NH), 10.60 (s, 1H, NH), 10.36 (s, 1H, NH), 8.91 (s, 1H, NH),
8.04 (s, 1H, ArH), 7.82 (s, 1H, ArH), 7.48 (dd, 1H, J1 ¼ 8.8 Hz, J2 ¼ 2.0 Hz, ArH),
7.39 (d, 1H, J ¼ 8.8 Hz, ArH), 7.17 (d, 1H, J ¼ 8.8 Hz, ArH), 6.96 (d, 1H, J ¼ 8.4 Hz,
ArH), 5.47 (s, 1H, CH). 13C NMR (100 MHz, DMSO-d6): d 172.0, 166.8, 162.8,
150.5, 150.1, 145.5, 138.5, 136.0, 134.5, 128.3, 121.3, 118.7, 117.2, 112.9, 84.7,
37.0, 21.0. Anal. calcd. for C18H12N6O5: C, 55.11; H, 3.08; N, 21.42. Found: C,
55.29; H, 3.24; N, 21.37.
Compound 4g. IR (KBr): 3339, 3249, 1676, 1640, 1561, 1503, 1317, 1241,
1043, 945, 832, 770 cmꢁ1.1H NMR (400 MHz, DMSO-d6): d 13.00 (s, 1H, NH),
9.16 (s, 1H, NH), 8.03 (s, 1H, ArH), 7.46–7.37 (m, 2H, ArH), 7.23 (d, 2H, J ¼ 8.0 Hz,
ArH), 6.95 (d, 2H, J ¼ 7.6 Hz, ArH), 5.48 (s, 1H, CH), 3.53 (s, 3H, CH3), 3.11 (s, 3H,
CH3), 2.15 (s, 3H, CH3). Anal. calcd. for C21H19N5O2: C, 67.55; H, 5.13; N, 18.76.
Found: C, 67.31; H, 5.34; N, 18.83.
Compound 4h. IR (KBr): 3313, 3267, 1694, 1667, 1559, 1435, 1339, 1246,
1170, 1094, 928, 773 cmꢁ1.1H NMR (400 MHz, DMSO-d6): d 13.07 (s, 1H, NH),
9.31 (s, 1H, NH), 8.17 (s, 1H, ArH), 8.05 (s, 1H, ArH), 7.95–7.92 (m, 1H, ArH),
7.85 (d, 1H, J ¼ 7.6 Hz, ArH), 7.51–7.44 (m, 3H, ArH), 5.75 (s, 1H, CH), 3.54 (s,
3H, CH3), 3.11 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6): d 162.3, 160.7,
150.7, 150.4, 145.3, 138.4, 136.1, 134.6, 128.6, 123.3, 118.6, 117.7, 113.3, 112.7,
85.2, 37.9, 29.9, 27.5, 21.0. Anal. calcd. for C20H16N6O4: C, 59.40; H, 3.99; N,
20.78. Found: C, 59.59; H, 3.85; N, 20.72.
Compound 4i. IR (KBr): 3413, 3298, 1698, 1634, 1511, 1452, 1377, 1264,
1
1178, 1024, 956, 846, 770 cmꢁ1. H NMR (400 MHz, DMSO-d6): d 13.01 (s, 1H,
NH), 9.16 (s, 1H, NH), 8.08 (s, 1H, ArH), 7.46–7.38 (m, 2H, ArH), 6.91 (s, 1H,
ArH), 6.81 (dd, 1H, J1 ¼ 8.0 Hz, J2 ¼ 1.6 Hz, ArH), 6.69 (d, 1H, J ¼ 8.0 Hz, ArH),
5.87 (s, 2H, CH2), 5.47 (s, 1H, CH), 3.53 (s, 3H, CH3), 3.13 (s, 3H, CH3). 13C
NMR (100 MHz, DMSO-d6): d 160.7, 150.7, 146.9, 145.3, 145.2, 141.3, 128.5,
121.1, 120.5, 117.6, 114.3, 112.7, 108.2, 107.6, 100.6, 85.8, 56.0, 30.7, 29.8, 27.5,

PYRAZOLO[3,4-f]QUINOLINE
1063
18.5. Anal. calcd. for C21H17N5O4: C, 62.53; H, 4.25; N, 17.36. Found: C, 62.77; H,
4.33; N, 17.29.
Compound 4j. IR (KBr): 3405, 3277, 1698, 1634, 1511, 1452, 1377, 1264,
1178, 1024, 956, 846, 770 cmꢁ1.1H NMR (400 MHz, DMSO-d6): d 13.07 (s, 1H,
NH), 9.29 (s, 1H, NH), 8.05 (d, 3H, J ¼ 8.8 Hz, ArH), 7.66 (d, 2H, J ¼ 8.4 Hz,
ArH), 7.50 (d, 1H, J ¼ 8.8 Hz, ArH), 7.44 (d, 1H, J ¼ 8.8 Hz, ArH), 5.71 (s, 1H,
CH), 3.54 (s, 3H, CH3), 3.11 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6): d
160.7, 154.2, 150.7, 145.8, 145.5, 128.9, 128.7, 123.3, 121.0, 117.8, 117.5, 116.9,
112.7, 112.6, 86.7, 84.8, 30.0, 27.5, 18.5. Anal. calcd. for C20H16N6O4: C, 59.40;
H, 3.99; N, 20.78. Found: C, 59.17; H, 3.81; N, 20.84.
ACKNOWLEDGMENTS
We are grateful for the financial support from the National Science
Foundation of China (Nos. 20372057 and 20672090), the Natural Science Foun-
dation of the Jiangsu Province (No. BK2006033), and the Elite Foundation of the
Jiangsu Province (No. 06-A-039).
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