An efficient synthesis of pyrazolo[3,4-b]quinolin-5(6H)-one derivatives in ionic liquid

Article abstract of DOI:10.1002/jhet.538

A series of 4-aryl-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-pyrazolo[3,4-b] quinolin-5(6H)-ones were synthesized via the three-component reaction of aromatic aldehydes, 5,5-dimethyl-1,3-cyclohexandione and 5-amino-3-methyl-1- phenylpyrazole in ionic liquid

Full text of DOI:10.1002/jhet.538

308
An Efficient Synthesis of Pyrazolo[3,4-b]quinolin-5(6H)-one
Derivatives in Ionic Liquid
Vol 48
Da-Qing Shia* and Fang Yangb
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
People’s Republic of China
bCollege of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou 221116,
People’s Republic of China
*E-mail: dqshi@suda.edu.cn
Received November 9, 2009
DOI 10.1002/jhet.538
Published online 10 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
A series of 4-aryl-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-pyrazolo[3,4-b]quinolin-5(6H)-ones were
synthesized via the three-component reaction of aromatic aldehydes, 5,5-dimethyl-1,3-cyclohexandione
and 5-amino-3-methyl-1-phenylpyrazole in ionic liquid without using any catalyst. This protocol has the
advantages of easier work-up, milder reaction conditions, short reaction time, and environmentally be-
nign procedure.
J. Heterocyclic Chem., 48, 308 (2011).
INTRODUCTION
Room temperature ionic liquids, especially those
based on 1-alkyl-3-methylimidazolium cations, have
shown great promise as an attractive alterative to con-
ventional organic solvents, and more attention has been
currently focused on organic reactions promoted by
ionic liquids [7]. They are nonvolatile, recyclable, non-
explosive, easily operable, and thermally robust [8].
There are many reports concerning the applications of
ionic liquid in organic reactions, such as Friedel-Crafts
reactions [9], Diels-Alder reactions [10], Heck reactions
[11], Pechmann condensatios [12], Biginelli reactions
[13], Beckmann rearrangements [14], and other reactions
[15]. As part of our current studies on the developments
of new routes to heterocyclic system in ionic liquid
[16], we herein described a facile synthesis of pyra-
zolo[3,4-b]quinolin-5(6H)-one derivatives by the three-
component reaction of aromatic aldehyde, 5,5-dimethyl-
1,3-cyclohexandione and 5-amino-3-methyl-1-phenyl-
pyrazole in ionic liquid without using any catalyst
(Scheme 1).
Pyrazole derivatives exhibit pharmacological activities
such as hypotensive, antibacterial, antiinflammatory, and
antitumor properties. In particular, condensed pyrazole
are known for various biological activities, e. g. pyra-
zolo[3,4-b]quinolines have exhibited potential antiviral
[1], antimalarial [2], and serum cholesterol lowering
activities. A number of methods are available for the
synthesis of pyrazolo[3,4-b]quinolines[3], the most effi-
cient and commonly used method involves the reaction
of aromatic aldehyde, 1,3-dicarbonyl compound and
aminopyrazole in organic solvent such as EtOH [4]. All
the reported methods of their synthesis have limitations
of poor yields, difficult workups, and effluent pollution.
Multicomponent reactions (MCRs) in which multiple
reactions are combined into one synthetic operation
have been used extensively to form carbon–carbon
bonds in the synthetic chemistry [5]. Such reactions
offer a wide range of possibilities for the efficient con-
struction of highly complex molecules in a single proce-
dural step, thus avoiding the complicated purification
operations and allowing savings of both solvents and
reagents. In the past decade there has been tremendous
development in three- and four-component reactions and
great efforts continue to be made for developing new
MCRs [6].
RESULTS AND DISCUSSION
Choosing an appropriate solvent is of crucial impor-
tance for the successful organic synthesis. To search for
the optimal reaction solvent, the reaction of 4-hydroxy-
benzaldehyde (1a) 5,5-dimethyl-1,3-cyclohexandione (2)
C
V
2010 HeteroCorporation

March 2011 An Efficient Synthesis of Pyrazolo[3,4-b]quinolin-5(6H)-one Derivatives in Ionic Liquid
309
Scheme 1
Table 2
The synthesis of 4a-k in ionic liquid [bmim]Br.
Entry
Ar
Time (h)
Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-HOC6H4
4-CH3C6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2
1.5
2
98
95
95
94
93
90
78
79
85
68
86
2
and 5-amino-3-methyl-1-phenylpyrazole (3) was exam-
ined using a variety of ionic liquids 3-butyl-1-methyl-
imidazolium bromide ([bmim]Br), [bmim]BF4, 3-propyl-
1-methylimidazolium bromide ([pmim]Br), and conven-
tional reaction solvents; DMF, acetic acid, acetone, and
ethanol, at different reaction temperature for the synthe-
sis of the pyrazolo[3,4-b]quinolin-5(6H)-one (4a). The
results are summarized in Table 1.
2.5
3.5
4
2-NO2-5-ClC6H3
3,4-Cl2C6H3
2,4-Cl2C6H3
4-CH3OC6H4
3,4-OCH2OC6H3
4-(CH3)2NC6H4
4.5
3
4j
4k
4
3
It can be seen from the Table 1 that the best result
was obtained when the reaction was carried out in
[bmim]Br at 90ꢀC (Table 1, entry 1). [bmim]Br was
chosen as the solvent for all further reactions as it is
environmentally friendly and the toxic organic reagents
can be avoided. Under these optimized reaction condi-
shown in Scheme 2, which suffers nucleophilic attack to
give the Michael adduct [A]. The intermediate [A] then
isomerizates, cyclizes, dehydrates and subsequently
losses a hydrogen molecule to afford the fully aromat-
ized compound. This type of hydrogen loss is well
documented [17].
tions,
a series of pyrazolo[3,4-b]quinolin-5(6H)-one
In summary, we have developed an efficient three-
component reaction of aromatic aldehydes, 5,5-dimethyl-
1,3-cyclohexanedione and 5-amino-3-methyl-1-phenyl-
pyrazole for the synthesis of pyrazolo[3,4-b]quinolne-
5(6H)-one derivatives using ionic liquid as solvent.
Compared to the previous methods, this new protocol
has the advantages of easier work-up, milder reaction
conditions, short reaction time, and environmentally
benign procedure.
derivatives 4 were synthesized. The results are summar-
ized in Table 2.
As shown in Table 2, this protocol could be applied
to the aromatic aldehydes with either electron-withdraw-
ing groups (such as halide groups) or electron-donating
groups (such as alkyl and alkoxyl groups). The products
were different from those literature reported. The
reaction of 5-amino-3-methyl-1-phenylpyrazole with
dimedone and aromatic aldehyde in ethanol afforded 4-
aryl-7,7-dimethyl-4,7,8,9-tetrahydro-6H-pyrazolo[3,4-b]
quinolin-5-one[4a]. The structures of the products were
established on the spectroscopic data (IR, 1H NMR,
and HRMS).
EXPERIMENTAL
Commercial solvents and reagents were used as received.
Melting points are uncorrected. IR spectra were recorded on a
FTIR Temsor 27 spectrometer in KBr with absorptions in
.
cmꢁ1 1H NMR was determined on Bruker DPX-400 MHz
spectrometer in DMSO-d6 solution. J values are in Hz. Chemi-
cal shifts are expressed in ppm downfield from internal stand-
ard TMS. HRMS data were obtained using Micromass TOF-
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 2. The reaction occurs via an initial formation
of the a,b-unsaturated ketone, from the condensation of
aldehyde and 5,5-dimethyl-1,3-cyclohexanedione as
Scheme 2
Table 1
Solvent optimization for the synthesis of 4a.
Reaction
Reaction
Isolated
Entry
Solvent
temperature (ꢀC) time (h) yield (%)
1
2
3
4
5
6
7
[bmim]Br
[bmim]BF4
[pmim]Br
DMF
90
90
2
2
2
8
8
8
8
98
94
90
100
93
20
HOAc
acetone
ethanol
100
Reflux
Reflux
52
n. r.
39
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

310
D.-Q. Shi and F. Yang
Vol 48
MS instrument. Starting materials used were obtained from
Alfa Aesar and used without further purification. Ionic liquids
were prepared according to the stardard method [18].
4-(5-Chloro-2-nitrophenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihy-
dro-1H-pyrazolo[3,4-b]quinolin-5(6H)-one (4f). Mp: 193–
194ꢀC; IR (potassium bromide): 3077, 2959, 1677, 1599,
1573, 1519, 1479, 1458, 1389, 1378, 1296, 1261, 986, 926,
General procedure for the synthesis of pyrazolo[3,4-
b]quinolne-5-one derivatives 4. A dry 50 mL flask was
charged with aromatic aldehyde 1 (1 mmol), 5,5-dimethyl-1,3-
cyclohexandione 2 (1 mmol), 5-amino-3-methyl-1-phenyl-pyr-
azole 3 (1 mmol), and ionic liquid [bmim]Br (2 mL). The mix-
ture was stirred at 90ꢀC for 1.5–4.5 h to complete the reaction
(monitored by TLC), then 5 mL water was added. The solid
was filtered off and washed with water. The crude product was
purified by recrystallization from the mixture of DMF and
ethanol to give 4.
845, 762, 690 cmꢁ1 1H NMR (DMSO-d6) d: 1.02 (s, 3H,
;
CH3), 1.11 (s, 3H, CH3), 1.85 (s, 3H, CH3), 2.44 (d, J ¼ 16.4
Hz, 1H, CH), 2.59 (d, J ¼ 16.4 Hz, 1H, CH), 3.23 (s, 2H,
CH2), 7.39 (t, J ¼ 7.6 Hz, 1H, ArH), 7.60 (t, J ¼ 7.6 Hz, 2H,
ArH), 7.72 (s, 1H, ArH), 7.88 (dd, J1 ¼ 1.2 Hz, J2 ¼ 8.8 Hz,
1H, ArH), 8.25 (d, J ¼ 8.0 Hz, 2H, ArH), 8.38 (d, J ¼ 8.8
Hz, 1H, ArH); HRMS [Found: m/z: 460.1327 (Mþ); Calcd for
C25H3251ClN4O3: M 460.1302].
4-(3,4-Dichorophenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-
1H-pyrazolo[3,4-b]quinolin-5(6H)-one (4g). Mp: 179–181ꢀC;
IR (potassium bromide): 3063, 2954, 1685, 1597, 1567, 1508,
1468, 1383, 1355, 1291, 1265, 985, 925, 884, 863, 809, 791,
4-(4-Hydroxyphenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-
1H-pyrazolo[3,4-b]quinolin-5(6H)-one (4a). Mp: 277–279ꢀC;
IR (potassium bromide): 3304, 2957, 1666, 1613, 1594, 1571,
1557, 1512, 1472, 1455, 1433, 1385, 1265, 1124, 820, 758, 688
755, 690 cmꢁ1
.
1H NMR (DMSO-d6) d: 1.09 (s, 6H, 2 ꢂ
1
cmꢁ1; H NMR (DMSO-d6) d: 1.07 (s, 6H, 2 ꢂ CH3), 1.87 (s,
CH3), 1.89 (s, 3H, CH3), 2.53 (s, 2H, CH2), 3.22 (s, 2H, CH2),
7.32ꢃ7.40 (m, 2H, ArH), 7.59 (t, J ¼ 7.6 Hz, 2H, ArH), 7.68
(d, J ¼ 1.6 Hz, 1H, ArH), 7.74 (d, J ¼ 8.4 Hz, 1H, ArH),
8.2þ3 (d, J ¼ 8.0 Hz, 2H, ArH); HRMS [Found: m/z: 449.1093
(M ); Calcd for C25H3215Cl2N3O: M 449.1062].
3H, CH3), 2.51 (s, 2H, CH2), 3.19 (s, 2H, CH2), 6.84 (d, J ¼
8.4 Hz, 2H, ArH), 7.06 (d, J ¼ 8.4 Hz, 2H, ArH), 7.35 (t, J ¼
7.6 Hz, 1H, ArH), 7.57 (t, J ¼ 7.6 Hz, 2H, ArH), 8.24 (d, J ¼
8.4 Hz, 2H, ArH), 9.60 (s, 1H, OH); HRMS [Found: m/z:
397.1790 (Mþ); Calcd for C25H23N3O2: M 397.1790].
4-(2,4-Dichorophenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-
1H-pyrazolo[3,4-b]quinolin-5(6H)-one (4h). Mp: 127–129ꢀC;
IR (potassium bromide): 3052, 2957, 1677, 1592, 1562, 1508,
1484, 1383, 1291, 1264, 985, 910, 860, 846, 813, 778, 755,
4-(4-Methylphenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-
pyrazolo[3,4-b]quinolin-5(6H)-one (4b). Mp: 184–186ꢀC; IR
(potassium bromide): 3021, 2953, 1677, 1591, 1560, 1499,
1470, 1455, 1438, 1415, 1386, 1367, 1355, 1305, 1263, 1232,
1
693 cmꢁ1. H NMR (DMSO-d6) d: 1.06 (s, 3H, CH3), 1.10 (s,
1
1180, 908, 803, 752, 690 cmꢁ1; H NMR (DMSO-d6) d: 1.06
3H, CH3), 1.88 (s, 3H, CH3), 2.55 (s, 2H, CH2), 3.24 (s, 2H,
CH2), 7.36–7.43 (m, 2H, ArH), 7.56–7.61 (m, 3H, ArH), 7.81
(d, J ¼ 1.6 Hz, 1H, ArH), 8.24þ(d, J ¼ 8.0 Hz, 2H, ArH);
HRMS [Found: m/z: 449.1082 (M ); Calcd for C25H3215Cl2N3O:
M 449.1062].
4-(4-Methoxyphenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-
pyrazolo[3,4-b]quinolin-5(6H)-one (4i). Mp: 138–140ꢀC; IR
(potassium bromide): 3021, 2953, 1677, 1591, 1560, 1499,
1455, 1386, 1305, 1263, 982, 908, 803, 752, 690 cmꢁ1 1H
;
NMR (DMSO-d6) d: 1.08 (s, 6H, 2 ꢂ CH3), 1.81 (s, 3H,
CH3), 2.42 (s, 3H, CH3), 2.51 (s, 2H, CH2), 3.21 (s, 2H, CH2),
7.16 (d, J ¼ 8.0 Hz, 2H, ArH), 7.27 (d, J ¼ 8.0 Hz, 2H,
ArH), 7.36 (t, J ¼ 7.6 Hz, 1H, ArH), 7.58 (t, J ¼ 8.0 Hz, 2H,
ArH), 8.24 (d, J ¼ 8.0 Hz, 2H, ArH); HRMS [Found: m/z:
411.1926 (Mþ); Calcd for C26H25N3O2: M 411.1947].
(s, 6H, 2 ꢂ CH3), 1.83 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.43
(s, 2H, CH2), 3.15 (s, 2H, CH2), 7.04 (d, J ¼ 8.0 Hz, 2H,
ArH), 7.19–7.23 (m, 3H, ArH), 7.44 (t, J ¼ 7.6 Hz, 2H, ArH),
8.18 (d, J ¼ 8.0 Hz, 2H, ArH); HRMS [Found: m/z: 395.2012
(Mþ); Calcd for C26H25N3O: M 395.1998].
4-(4-Fluorophenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-
pyrazolo[3,4-b]quinolin-5(6H)-one (4c). Mp. 172–174ꢀC; IR
(potassium bromide): 3062, 2955, 1679, 1596, 1562, 1509,
1470, 1455, 1381, 1308, 1260, 1232, 1093, 912, 848, 814,
753, 690 cmꢁ1
;
1H NMR (DMSO-d6) d: 1.08 (s, 6H, 2 ꢂ
CH3), 1.83 (s, 3H, CH3), 2.51 (s, 2H, CH2), 3.21 (s, 2H, CH2),
7.27–7.38 (m, 5H, ArH), 7.58 (t, J ¼ 8.0 Hz, 2H, ArH), 8.24
(d, J ¼ 7.6 Hz, 2H, ArH); HRMS [Found: m/z: 399.1735
(Mþ); Calcd for C25H22FN3O: M 399.1747].
4-(4-Chlorophenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-
pyrazolo[3,4-b]quinolin-5(6H)-one (4d). Mp: 180–183ꢀC; IR
(potassium bromide): 2955, 1680, 1595, 1558, 1509, 1489,
1455, 1386, 1264, 1234, 982, 910, 859, 844, 810, 791, 752,
4-(3,4-Methylenedioxyphenyl)-3,7,7-trimethyl-1-phenyl-7,8-
dihydro-1H-pyrazolo[3,4-b]quinolin-5(6H)-one (4j). Mp: 175–
177ꢀC; IR (potassium bromide): 3059, 2955, 1672, 1621,
1598, 1557, 1506, 1489, 1381, 1365, 1291, 1255, 987, 934,
690 cmꢁ1
;
1H NMR (DMSO-d6) d: 1.08 (s, 6H, 2 ꢂ CH3),
907, 886, 876, 810, 788, 752 cmꢁ1 1H NMR (DMSO-d6) d:
;
1.84 (s, 3H, CH3), 2.51 (s, 2H, CH2), 3.21 (s, 2H, CH2), 7.32–
7.39 (m, 3H, ArH), 7.52–7.60 (m, 4H, ArH), 8.24 (d, J ¼ 8.0
Hz, 2H, ArH); HRMS [Found: m/z: 415.1434 (Mþ); Calcd for
C25H3252ClN3O: M 415.1451].
4-(4-Bromophenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-
pyrazolo[3,4-b]quinolin-5(6H)-one (4e). Mp: 188–189ꢀC; IR
(potassium bromide): 2954, 1679, 1591, 1558, 1511, 1498,
1486, 1455, 1386, 1367, 1305, 1263, 981, 909, 858, 842, 806,
1.07 (s, 6H, 2 ꢂ CH3), 1.93 (s, 3H, CH3), 2.51 (s, 2H, CH2),
3.19 (s, 2H, CH2), 6.12 (d, J ¼ 8.0 Hz, 2H, OCH2O), 6.72 (d,
J ¼ 7.6 Hz, 1H, ArH), 6.89 (s, 1H, ArH), 7.00 (d, J ¼ 8.0 Hz,
1H, ArH), 7.36 (t, J ¼ 7.2 Hz, 1H, ArH), 7.58 (t, J ¼ 7.6 Hz,
2H, ArH), 8.24 (d, J ¼ 8.0 Hz, 2H, ArH); HRMS [Found: m/z:
425.1727 (Mþ); Calcd for C26H23N3O3: M 425.1739].
4-(4-Dimethylaminophenyl)-3,7,7-trimethyl-1-phenyl-7,8-dihy-
dro-1H-pyrazolo[3,4-b]quinolin-5(6H)-one
(4k). Mp:
194–
751, 690 cmꢁ1
;
1H NMR (DMSO-d6) d: 1.08 (s, 6H, 2 ꢂ
196ꢀC; IR (potassium bromide): 2954, 1687, 1612, 1598,
1567, 1514, 1506, 1490, 1473, 1385, 1364, 1283, 1260, 983,
CH3), 1.84 (s, 3H, CH3), 2.51 (s, 2H, CH2), 3.21 (s, 2H, CH2),
7.27 (d, J ¼ 8.0 Hz, 2H, ArH), 7.37 (t, J ¼ 7.2 Hz, 1H, ArH),
7.58 (t, J ¼ 7.6 Hz, 2H, ArH), 7.67 (d, J ¼ 8.0 Hz, 2H, ArH),
8.2þ4 (d, J ¼ 8.0 Hz, 2H, ArH); HRMS [Found: m/z: 459.0961
(M ); Calcd for C25H7229BrN3O: M 459.0946].
947, 816, 804, 766, 692 cmꢁ1 1H NMR (DMSO-d6) d: 1.07
;
(s, 6H, 2 ꢂ CH3), 1.92 (s, 3H, CH3), 2.51 (s, 2H, CH2), 2.99
(s, 6H, (CH3)2N), 3.18 (s, 2H, CH2), 6.78 (d, J ¼ 8.4 Hz, 2H,
ArH), 7.09 (d, J ¼ 8.4 Hz, 2H, ArH), 7.35 (t, J ¼ 7.6 Hz, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011 An Efficient Synthesis of Pyrazolo[3,4-b]quinolin-5(6H)-one Derivatives in Ionic Liquid
311
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C27H28N4O: M 424.2263].
Acknowledgment. Financial support from the Foundation of
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet