An alternative approach toward 2-aryl-2H-pyrazolo[4,3-c]-quinolin-3-ones by a multistep synthesis

Article abstract of DOI:10.1016/j.tetlet.2009.10.123

A series of 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones derivatives 6 and 7 was conveniently prepared. A multistep synthesis was carried out starting from dichloro- and bromoanilines (1a-b) and diethyl 2-(ethoxymethylene)malonate using a slightly modified Go

Full text of DOI:10.1016/j.tetlet.2009.10.123

Tetrahedron Letters 51 (2010) 478–481
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An alternative approach toward 2-aryl-2H-pyrazolo[4,3-c]-quinolin-3-ones
by a multistep synthesis
*
*
Marisa J. López Rivilli, Elizabeth L. Moyano , Gloria I. Yranzo
INFIQC, Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Cordoba, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2009
Revised 26 October 2009
Accepted 27 October 2009
Available online 6 November 2009
A series of 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones derivatives 6 and 7 was conveniently prepared. A
multistep synthesis was carried out starting from dichloro- and bromoanilines (1a–b) and diethyl 2-(eth-
oxymethylene)malonate using a slightly modified Gould-Jacobs reaction. In this work we present a novel
chlorination strategy to prepare quinoline derivatives 4 in excellent yields as key intermediates in the
synthesis of the target compounds. Several reaction conditions were evaluated to optimize the formation
of pyrazoloquinolinone nucleus. Differences in chemical behavior of both chloroquinolinones 4a–b with
aryl and benzyl-hydrazines are also discussed.
Dedicated to Professor Gloria I. Yranzo
Ó 2009 Elsevier Ltd. All rights reserved.
Benzodiazepines (BDZs) are the drugs of choice in the pharmaco-
therapy of anxiety and related emotional disorders. These
compounds act via the benzodiazepine receptor site (BzR) on the
The multistep synthesis described here involves classical,7,8
novel, and alternative steps. The optimization of the whole meth-
odology allowed us to afford different compounds in each step in
good to very good yields.
c-aminobutyric acid receptor complex (GABAA). The central recep-
tors located in the neuronal tissues are functionally linked to a GA-
BAA receptor chloride ionophore complex and are apparently
located in the synaptic membranes. Central BDZ receptors mediate
classical pharmacological properties of the widely used benzodiaze-
pines.1 Ligands interacting with BzR have intrinsic activity ranging
from agonists (anxiolytic, hypnotic, and anticonvulsant agents),
through antagonists (without efficacy), to inverse agonists (procon-
vulsant and anxiogenic agents).2 BzR includes not only substances
with a benzodiazepine structure but also those chemically diverg-
ing, and they mediate a broad variety of pharmacological actions.3
Since the discovery of chlordiaxepoxide and diazepam,4 1,4-benzo-
diazepines have been an important source of research. However,
these anxioselective compounds have shown undesirable side ef-
fects and the design and development of truly innovative drugs are
further required. Thus, the study of 2-aryl-2,5-dihydropyrazol-
o[4,3-c]quinoline-3-ones as high affinity BzR ligands has been an
interesting contribution to the development of new bioactive com-
pounds.5 The absence of adverse effects found in benzodiazepine
structures and the wide spectrum of the biological activity observed
contribute to constituting pyrazoloquinolinone nucleus as an
important structural target. We studied the synthesis of this type
of compounds on the basis of the rationalization of the common
structural requirements for binding to BzR (Fig. 1).6
We also discuss the effect of the reaction conditions in the last
path to prepare both benzyl-pyrazoloquinolinones derivatives: 2-
benzyl-7,9-dichloro-2H-pyrazolo[4,3-c]quinolin-3-one (6d) and
2-benzyl-8-bromo-2H-pyrazolo[4,3-c]quinolin-3-one (7d). Here,
1-benzyl-isomer products (6e and 7e) were also obtained and the
regioselectivity of the reaction depends on the nature of the start-
ing quinolinone.
All pyrazoloquinolinones were prepared through the synthesis
outlined in Scheme 1.
Diethyl 2-((phenylamino)methylene)malonates 2a,b were pre-
pared by the nucleophilic reaction of aromatic amines 1a,b and
diethyl 2-(ethoxymethylene)malonate by a Gould–Jacobs cycliza-
tion according to the procedure in the literature.9 Without purifica-
tion, malonates 2a,b were thermally cyclized in diphenylether
(DPE)10,11 to give ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylates
3a,b. Several attempts were made to optimize this reaction. Refluxin
DPE (at 257 °C) led to the decomposition of the solvent and to a high
contamination of the final products. Using the same solvent at
R´
N
N
O
R
N
H
* Corresponding authors. Tel./fax: +54 351 4334170 (E.L.M.).
E-mail addresses: lauramoy99@hotmail.com, lauramoy@fcq.unc.edu.ar (E.L.
Moyano).
Figure 1. General
derivatives.
structure of 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.123

M. J. López Rivilli et al. / Tetrahedron Letters 51 (2010) 478–481
479
R1
R1
R1
O
O
O
O
R2
R3
R2
R3
R2
R3
DPE
220-230 °C
OEt
OEt
EtO
OEt
120-130 °C
+
N
O
NH2
N
H
EtO
H
EtO
O
3 a-b
1 a R1= Cl R2= H R3= Cl
1 b R1= H R2= Br R3= H
2 a-b
SOCl2/DMFcat.
79 °C
R4
R4
N
N
Cl
R1 Cl
O
N
N
R2
R3
O
Br
O
OEt
For 4a
For 4b
Cl
N
H
N
4 a-b
NH2-NHR4 (5a-d)
NH2-NHR4 (5a-d)
N
H
DMF, 130-140 °C
DMF, 130-140 °C
6a, R4= phenyl
7a, R4= phenyl
6b, R4= p-methoxyphenyl
6c, R4= p-fluorophenyl
6d, R4= benzyl
7b, R4= p-methoxyphenyl
7c, R4= p-fluorophenyl
7d, R4= benzyl
Scheme 1. Multistep synthesis of pyrazoloquinolinones 6a–d and 7a–d.
180–210 °C, the reaction was cleaner but the yields were too low
(25–30%). At 220–230 °C, and with strict control of the temperature,
compounds 3a and 3b were prepared in good yields, 78% and 71%,
respectively, calculated from aniline precursor. Compound 3a was
not reported in the literature whereas 3b was prepared from
diethyl-4-bromoanilinomethylenemalonate (2b) in 57% yield12
showing that our procedure was found to be more efficient.
Dihydroquinoline-3-carboxylates were inert to react with
hydrazines to give the expected pyrazoloquinolinones 6 and 7.
For this reason the halogenation of quinolines was achieved to pre-
pare chloroderivatives which could react with nucleophilic hydra-
zines. Numerous attempts were made to obtain compounds 4.
First, the reported halogenation treatments using an excess of
POCl3 (0.04 mol of 3a and 0.27 mol of POCl3)8a at reflux tempera-
ture did not lead to the corresponding 4-chloroquinoline, and the
starting quinolinone was recovered. When 3a was treated with
PCl5 (10% of mol of 3a) and POCl3 (excess) in a range of tempera-
ture from 0 to 25 °C,13 a mixture of products was obtained without
the quantitative formation of the compound 4a. NMR analysis of
the crude showed that, in addition to product 4a, a quinoline-3-
carboxilic acid derivative was formed. The formation of this acid
could result from the hydrolysis of a quinoline-3-carbonyl chloride
obtained as intermediate in the halogenation process.
One of the possible difficulties to obtain chloroderivatives 4 was
the tendency of these compounds to undergo hydrolysis and re-
establish the starting quinolinone. Having this in mind, the reac-
tion was then carried out in SOCl2 (excess) at reflux temperature
with catalytic amount of DMF. After 1.5 h the crude was exhaus-
tively evaporated without additional workup. We were pleased
to discover that the solid thus prepared (P98% yield) was chloro-
quinoline 4a in excellent conditions to be used in the next step.
This protocol was adopted in the chlorination of quinoxalined-
iones,14 however, there are no precedents of their utilization in the
chlorination of quinolinones. We examined this methodology for
the preparation of 4b. In this case, the reaction yielded a quantita-
tive conversion (100% yield) within 2 h. In our reactions, it was ob-
served that the use of DMF was not mandatory and analogous
excellent yields were obtained in the absence of this catalyst.
Optimization of the chlorination step was crucial for the suc-
cessful development of this synthetic methodology since the chlo-
roderivatives thus prepared were stable enough to allow the
reaction with different hydrazines.
Table 1
Yields of pyrazoloquinolinones 6 and 7
Compound
R1
R2
R3
R4
Yielda
6a
6b
6c
6d
7a
7b
7c
7d
7e
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
H
H
H
H
H
Phenyl
71b
40c
40c
15c
53b
35c
50c
10d
9d
p-Methoxyphenyl
p-Fluorophenyl
Benzyl
Phenyl
p-Methoxyphenyl
p-Fluororophenyl
Benzyl
Benzyl
a
b
c
Isolated product.
Reactions with free phenylhydrazine.
Reactions with hydrazine monohydrochloride.
Reactions with hydrazine dihydrochloride.
d
philic substitution of the chlorine atom by the hydrazine derivative
followed by cyclization10 confirmed once again its usefulness for
the goal proposed. In all reactions, anhydrous DMF was used as sol-
vent and cyclizations were complete over 1-2 h at 130–140 °C. In
the case of cyclizations with hydrazine monohydrochloride (5b,c)
and benzylhydrazine dihydrochloride (5d), a previous neutraliza-
tion with sodium methoxide solution (12.5% w/v) was needed.
All pyrazoloquinolinones were isolated in good to very good
yields (35–71%), except in the case of benzylderivatives where
the yields did not overcome 15%. To the best of our knowledge,
all compounds are new except 6a.15
To test the effect of hydrochloride salt or hydrazine-free nucle-
ophiles in the yield of the reaction, pyrazoloquinolinone 7a was
synthesized from phenylhydrazine and phenylhydrazine monohy-
drochloride. It was surprising to find that better yield (62%) was
achieved when monohydrochloride salt was used, probably due
to stabilization of hydrazine as nucleophilic species.
When the cyclization reaction of chloroquinolines 4a,b was per-
formed using benzylhydrazine dihydrochloride and 2 equiv of
methoxide (NaOMe) as base, one isomer (N-1) of these structures,
derivatives 6e and 7e, was obtained in addition to the awaited
products (6d and 7d) (Scheme 2). For a thorough characterization
of isomers N-1 and N-2, a careful isolation of compounds 6d, 7d,
and 7e was achieved. Although many attempts were made to af-
ford isolated 6e, it was not obtained and such compound was iden-
tified from a mixture with 6d.
Chloroquinolines 4a,b were cyclized with aryl (5a–c)- and ben-
zyl (5d)-hydrazines to afford pyrazoloquinolinones 6a–d and
7a–d, respectively (Table 1).15 The reaction consisting of a nucleo-
1H NMR experiments showed similar signals for isomers 7d and
7e. 13C NMR analysis of both compounds showed a significant dif-

480
M. J. López Rivilli et al. / Tetrahedron Letters 51 (2010) 478–481
117.5 ppm was found for the same C-9b in compound 7e. A com-
R1 Cl
O
plete elucidation of the structures was achieved by spectroscopic
techniques of 1D NMR ROESY and 2D NMR HMBC and HSQC (
Fig. 2). Thus, in the ROESY experiment, two significant signals
(5.86 ppm and 8.53 ppm) corresponding to the interaction be-
tween methylene protons (H-10) and proton H-9 were found for
isomer 7e. This correlation indicated a spatial approach (spatial
distance <2.5 Å) between both types of hydrogen. ROESY analysis
of 7d did not show a signal corresponding to this type of interac-
tion, but a signal assigned to the interaction of amine proton with
protons H-4 and H-6 was observed. HMBC analysis of compound
7d showed correlations between methylene protons (H-10) and
the carbonylic carbon signal at position 3. In the case of isomer
7e, a signal corresponding to the interaction of H-10 and C-9 was
observed. For isomer 7e, HMBC spectra showed correlations be-
tween methylene protons 10 and the bridge C-9a.
R2
R3
O
N
4 a-b
via A
via B
H
N
NH
NH2
NH2
O
5d
R1 HN
O
R1
N
N
R2
R3
R2
R3
O
O
N
These findings allowed us to confirm the structures of pyrazol-
oquinolinones 7d and 7e.
N
NH
R1
N
R1
N
N
It is evident that the presence of these isomers relates to the ali-
phatic nature of the hydrazine substrate since, in the case of aro-
matic hydrazines, only one pyrazoloquinolinone was obtained. In
the reactions performed with aromatic hydrazines (5a–c), the pri-
mary amino group displaced the halogen following the mechanism
described in, via A, Scheme 2, whereas in the reactions with ben-
zylhydrazine, both amino groups (primary and secondary) could
substitute the chlorine atom. In all experiments with quinoline
4a, isomer 6d was mostly found while in the cyclizations of 4b,
the ratio of isomers 7d and 7e showed variations (Table 2). Thus,
in the case of dichloride derivative 4a, the relationship of 6d:6e
was equal to 82:18, whereas in the case of the bromide derivative
4b the relationship of 7d:7e equaled 47:53.
R2
R3
O
R2
R3
O
N
H
Isomer N-2
Isomer N-1
6e R1 = Cl, R2 = H, R3 = Cl
7e R1 = H , R2 = Br, R3 = H
6d R1 = Cl, R2 = H, R3 = Cl
7d R1 = H , R2 = Br, R3 = H
Scheme 2. Formation of pyrazoloquinolinones isomers N-1 and N-2.
The small amount of isomer 6e in the reaction mixture could be
rationalized if we analyzed the structure of the starting material
4a. In this case the halogenated substituent at position 9 could in-
hibit the nucleophilic substitution by the N-2 of the hydrazine to
form the pyrazolone ring (via B). Therefore, the initial displace-
ment of chlorine by the primary amino group of hydrazine fol-
lowed by cyclization (via A) seems more favorable. When R1 = H
(4b), the two types of cyclization are equally possible.
1´
1´
N
3
NH
N
N
2
2
1
1
3
9
Br
O
Br
9 a
O
9 b
9 b
4
5
6
N
H
N
7d
Isomer N-2
7e
Isomer N-1
Encouraged by this result, we decided to study different condi-
tions so as to form pyrazoloquinolinone isomers. Thus, when
1 equiv of sodium methoxide was used in the neutralization of
benzylhydrazine dihydrochloride, the relationship of isomers
6d:6e remained unaltered (81:19) and the relation of the isomers
7d:7e amounted to 31:69. The steric impediment of substrate 4a
to form isomer 6e was also demonstrated. The increase in the
Figure 2. Diagnostic HMBC (black arrow) and ROESY (red arrow) correlations for
compounds 7d and 7e.
ference in the shifts of signal due to carbon at position 9b (C-9b)
(Fig. 2). In the case of 7d, the signal appeared at 140.5 ppm, a typ-
ical shift found for iminic carbons, while a vinylic signal at
Table 2
Relative ratio of isomers N-1 and N-2 determined by 1H NMR
Ph
Ph
N
Ph
N
Ph
N
NH
NH
Cl
N
Cl
N
N
Br
O
O
Br
O
O
Substrate
Base, equivalents
Time (h)
Cl
N
N
Cl
N
N
H
H
7e
7d
6e
6d
4a
4b
NaOMea, 2
NaOMea, 1
TEAb, 2
1.5
1.5
4
82
81
87
68
—
—
—
—
18
19
13
32
—
—
—
—
—
—
—
—
43
31
28
—
—
—
—
—
57
69
72
100
TEAb, 1
4
NaOMea, 2
NaOMea, 1
TEAb, 2
1.5
1.5
4
TEAb, 1
4
a
Solution 12.5% w/v.
Anhydrous triethylamine.
b

M. J. López Rivilli et al. / Tetrahedron Letters 51 (2010) 478–481
481
amount of isomer 7e may result from the first deprotonation of
References and notes
secondary amine and the favored displacement of halogen from
the N-2 nucleophilic centre. When triethylamine (TEA) was used
as base, the relative ratio of isomers for each pyrazoloquinolinone
was modified. Thus, in the case of the reaction of 4a, by using
2 equiv of TEA, the formation of isomer 6d in the amount similar
to that of the reactions with sodium methoxide was favored. When
only 1 equiv of base was employed, the proportion of isomer 6e in-
creased due to a better deprotonation of N-2 in the hydrochloride
salt. In the reactions of substrate 4b, the effect of TEA as base was
particularly noticeable. Thus, by using 1 equiv of base, isomer 7d
was not detected, and the reaction gave rise selectively and exclu-
sively to regioisomeric pyrazoloquinolinone 7e. It should be noted
that the reactions with TEA were completed in 4 h, whereas the
transformations with NaOMe were completed in 1.5 h.
These results show that the regiochemistry of the reaction de-
pends on the nature of the base reagent and on the amount em-
ployed in the neutralization of the starting hydrazine. A similar
behavior was found in the reaction of 3-acyl-4-methoxy-quinoli-
nones with N-substituted hydrazines to prepare 2,5-dihydro-4H-
pyrazolo[4,3-c]quinolinones.16 Here the regioselectiviy of the reac-
tion changes markedly if free hydrazine or hydrazine hydrochloride
is used as a base. On the other hand, a regioselective behavior was
analyzed in the synthesis of pyrazolo[4,3-c]pyrrolo[3,2-f]quinolin-
3-one derivatives where the use of methylhydrazine favored the
N-1-methyl isomer and the use of arylhydrazines exclusively fa-
vored N-2-aryl isomers.17,18
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In conclusion, we have prepared pyrazolo[4,3-c]quinolin-3-
ones (6,7) in a multistep protocol from simple anilines. This novel
approach involved a simple and convenient halogenation of quin-
olinone-3-carboxylates (3a,b) with SOCl2 to obtain the key inter-
mediate precursors (4a,b) of the target compounds. With the
present methodology, the regioselectivity achieved in the last
cyclization step when arylhydrazines were used is worth noting.
In this case, N-1 isomers were obtained, whereas in the reaction
with benzylhydrazines, isomers N-1 and N-2 were synthesized.
15. Representative procedure to prepare 7,9-dichloro-2-phenyl-2H-pyrazolo[4,3-
c]quinolin-3(5H)-one (6a): Aniline 1a (3 mmol) and diethyl(ethoxy-
methylene)-malonate (3 mmol) were mixed and heated at 120–130 °C for
5.5 h to give malonate 2a. This compound was treated with diphenylether
(DPE, 10 mL) at 220–230 °C for 4 h to afford quinolone 3a (78% yield). Then, 3a
(0.8 mmol) was mixed with thionyl chloride (0.5 mL) and a drop of DMF at
reflux temperature for 1 h to give chloroquinolines 4a. Thionyl chloride excess
was removed by evaporation and co-evaporation with dichloromethane
(3 ꢀ 10 mL). Pyrazoloquinolinones 6a was obtained by reaction between 4a
(0.8 mmol) and phenylhydrazine 5a (1 mmol) in DMF at 130–140 °C. This
compound was obtained as a yellow solid after a column chromatographic
purification process (71% yield), mp > 310 °C dec. 1H NMR (400.16 MHz,
[(CD3)2SO]), d (ppm): 7.20 (t; J = 7.3 Hz; 1H); 7.46 (t; J = 7.6 Hz and J = 8.2 Hz;
2H); 7.67 (d; J = 1.8 Hz; 1H); 7.75 (d, J = 1.8 Hz; 1H); 8.21 (d; J = 8.3 Hz; 2H);
8.77 (s; 1H); 12.1 (s; 1H). 13C (100.04 MHz, TFA), d (ppm): 107.7; 116.0; 117.6;
118.6; 124.3; 127.3; 128.7; 131.4; 133.5; 138.1; 139.7; 139.8; 141.1; 160.9. MS
(EI): m/z (%) = 330 [M+] (73), 294 (80), 300 (15), 259 (7), 223 (20), 196 (33), 161
(27), 77 (100). HMRS (ESI+): calcd for C16H10N3Cl2O 330.0201; found 330.0204.
See the Supplementary data.
Acknowledgments
Financial support from CONICET and SECyT-UNC is gratefully
acknowledged.
Supplementary data
16. Savini, L.; Massarelli, P.; Corti, P.; Pellerano, C.; Bruni, G.; Romeo, M. R. Il
Farmaco 1993, 48, 1675–1679.
17. Chimichi, S.; Boccalini, M.; Matteucci, A. Tetrahedron 2008, 64, 9275–9279.
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Biggio, G. Bioorg. Med. Chem. 2005, 13, 3531–3541.
Supplementary data (general procedures, additional experi-
mental descriptions, NMR, HMRS and MS analysis of all products
are presented) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2009.10.123.