DMSO as a Methine Source in TFA-Mediated One-Pot Tandem Regioselective Synthesis of 3-Substituted-1-Aryl-1 H-Pyrazolo-[3,4- b]quinolines from Anilines and Pyrazolones

Article abstract of DOI:10.1021/acs.joc.0c02696

An acid-mediated and DMSO participant one-pot tandem synthesis of 3-substituted-1-aryl-1H-pyrazolo-[3,4- b]quinoline from readily available anilines and pyrazolones was achieved. This method enables regioselective construction of the valuable heterocycles under transition-metal and oxidant-free conditions in which DMSO acts as a methine source as well as solvent making this process an environmentally benign approach. A broad range of diversely substituted aryl amines and pyrazolines are successfully employed in this reaction to access a series of pyrazolo[4,3-c]quinolones through a novel cascade mechanism. Furthermore, the application and mechanistic studies of the present methodology also demonstrated.

Full text of DOI:10.1021/acs.joc.0c02696

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Article
DMSO as a Methine Source in TFA-Mediated One-Pot Tandem
Regioselective Synthesis of 3‑Substituted-1-Aryl‑1H‑Pyrazolo-
[3,4‑b]quinolines from Anilines and Pyrazolones
Pushpendra Yadav, Annapurna Awasthi, Sabapathi Gokulnath, and Dharmendra Kumar Tiwari*
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ABSTRACT: An acid-mediated and DMSO participant one-pot tandem synthesis of 3-substituted-1-aryl-1H-pyrazolo-[3,4-
b]quinoline from readily available anilines and pyrazolones was achieved. This method enables regioselective construction of the
valuable heterocycles under transition-metal and oxidant-free conditions in which DMSO acts as a methine source as well as solvent
making this process an environmentally benign approach. A broad range of diversely substituted aryl amines and pyrazolines are
successfully employed in this reaction to access a series of pyrazolo[4,3-c]quinolones through a novel cascade mechanism.
Furthermore, the application and mechanistic studies of the present methodology also demonstrated.
Scheme 1. DMSO as the Methylene Source in the Synthesis
of Various Important Heterocycles (eq. i−vi) along with the
Present Study (eq. vii)
INTRODUCTION
■
Pyrazoloquinolines,1,2 including pyrazolo[3,4-b]quinolines,2
are considered an important class of N-containing heterocycles
frequently encountered in various natural products and
pharmaceuticals that display a wide range of biological
activities, such as antiviral, antimicrobial, oncogenic Ras, and
lowering of serum cholesterol, FLT3-mediated disorders, and
anticancer activities.3 In addition, the pyrazolo[3,4-b]quinoline
derivatives have found great application in materials chemistry
as blue or green light emitters with electron-transporting
properties. They are widely used as fluorescent molecular
probe and electroluminescent materials. Owing to the wide
range of applications, the development of any straightforward,
efficient, and environmentally benign approach for the
synthesis of the pyrazoloquinoline skeletons from easily
accessible starting materials would be highly desirable.
In the recent past, the DMSO-participated reactions have
found extensive applications in assembling a varied range of
biologically important heterocycles. In addition to being an
oxidant and most commonly used solvent, it is increasingly
used as a source of −O, −Me, −SMe, −CH2SMe, SO2Me,
−CH2, −CHO, and −CN under various conditions.4 Moreover,
the use of DMSO as a carbon source has received much
attention in recent years.5−11 For example, Zhang and co-
workers first reported the copper-catalyzed synthesis of
quinazolines from amidines and DMSO in the presence of
excess amount of select flour (Scheme 1, eq (i).6 We recently
reported a transition metal free synthesis of 3-ketoquinolines
from readily available acetophenones, anthranils, and DMSO
via sequential one-carbon homologation/conjugate addition/
annulation cascade reaction (Scheme 1, eq (ii).7 Recently,
Singh and co-workers explored DMSO as a methine source in
K2S2O8 mediated synthesis of quinolines from readily available
acetophenones and anilines (Scheme 1, eq (iii).8 In this
Received: November 11, 2020
Published: January 11, 2021
https://dx.doi.org/10.1021/acs.joc.0c02696
© 2021 American Chemical Society
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a
connection, Wu et al. have well exploited DMSO as a building
block to construct various medicinally relevant heterocycles.
An important example among them is the iodine mediated
synthesis of pyrrolo[2,1-a]isoquinolines from acetophenones,
1,2,3,4-tetrahydroisoquinoline (THIQ), and DMSO. Further-
more, mechanistic studies revealed that DMSO served as a
methylene source in this reaction (Scheme 1, eq (iv).9 Using
DMSO as a carbon source Wu and co-workers again developed
a 1,3-dipolar cycloaddition reaction of stabilized pyridinium
salts with dimethyl sulfoxide in the presence of trifluoroacetic
acid, K2S2O8, and trimethylethylenediamine (TMEDA) to
access indolizidine indolizine derivatives (Scheme 1, eq (v).10
Guo and co-workers have a continuing interest in this
emerging area of research. Recently, they demonstrated
DMSO intervened one-pot tandem synthesis of 3-(methyl-
thiomethyl)-chroman-4-ones from hydroxyl acetophenone in
the presence of an oxidant. In this reaction, DMSO not only
acted as a solvent but also serves as the source of methylene
and −CH2SMe groups (Scheme 1, eq vi).11 Although all these
versatile approaches demonstrate the application of DMSO as
a methine source to construct wide range of heterocycles but
the requirement of transition metals and oxidants are the few
drawbacks associated with these methodologies. Furthermore,
most of the literature reported methodologies are with
acetimidamide, activated ketones, alkynes, and aromatic
amines. In this regard, the reaction of DMSO with amide is
not much explored. Our current research is focused on the
development of new methodologies for the synthesis of
biologically important heterocycles.12 As a continuation of
the same research program which uses DMSO specifically as a
carbon synthon,7,13 we report herein, TFA mediated DMSO
activation approach in the synthesis of 3-substituted-1-aryl-1H-
pyrazole-[3,4-b]quinolines from readily available anilines and
pyrazolines. This newly developed transition metal and oxidant
free reaction proceeds through in situ generations of imine/
enamine followed by one carbon homologation and elimi-
nation to form azadiene which subsequently undergoes
intramolecular cyclization reaction cascades in a single pot to
access a wide range of 3-substituted-1-aryl-1H-pyrazole-[3,4-
b]quinolines. Notably, the DMSO activation in pyrazolone is
not known to date.
Table 1. Optimization of Reaction Conditions
b
en.
additives
K2S2O8
solvent
temp (°C)
yields (%)
a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
120
140
120
120
120
120
120
140
90
120
120
120
120
120
120
120
n.o.
a
K2S2O8
p-TsOH·H2O
TfOH
MsOH
aq. HCl
TFA
TFA
TFA
TFA
TFA
n.o.
a
52
36
48
n.o
a
a
a
a
81
b
77
71
c
d
62
e
81
f
TFA
TFA
TFA
TFA
80
g
48
trace
trace
trace
DMA
NMP
TFA
a
Reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), additive (2.5
b
equiv), solvent (3.0 mL) at 120 °C, and 12 h in a sealed tube. When
c
reaction was stirred at 140 °C. When reaction was stirred at 90 °C..
d
e
When 1.5 equiv of TFA was used. When 3.5 equiv of TFA was used.
f
g
Reaction time 24 h. Reaction time 6 h.
With promising results in hand, we focused on optimizing
reaction conditions. Initially, various acids such as TfOH,
MsOH, and aq. HCl were tested. However, all of them resulted
in poor yields of desired product 3aa (entries 4−6).
Gratifyingly, a substantial increment in the yield (81%) of
desired product (3aa) was observed when the reaction was
performed in the presence of TFA (2.5 equiv) at 120 °C for 12
h in a sealed tube (entry 7). Further increasing or decreasing
the reaction temperature away from 120 °C did not improve
the product yield (entries 8−9). We found that the amount of
TFA noticeably influenced the yield of desired product 3aa.
Decreasing the amount of TFA to 1.5 equiv. furnished the
desired product in 62% yield (entry 10), whereas increasing
the amount of TFA to 3.5 equiv. did not markedly improve the
efficiency and furnished the desired 3aa in similar yield (entry
11). Subsequently, the reaction time was optimized, no change
in the efficiency of the reaction was observed by extending the
reaction time to 24 h rather a significant impact on the reaction
yield (48%) was noted when the reaction time was decreased
to 6 h (entries 12−13). To further improve the yield of desired
product several solvents such as DMF, DMA, and NMP were
tested as one carbon source10 but all of them furnished the
desired product only in trace amount (entries 14−16).
The substrate scope of present methodology was sub-
sequently assessed, and the optimized reaction conditions were
found to be compatible with a broad range of variously
substituted anilines (1a−1q) and pyrazolones (2a−2c), as
shown in Schemes 2 and 3. The electronic properties of the
substituents on the aromatic ring of anilines appeared to have
negligible impact on the efficiency of this reaction. Anilines
bearing electron-neutral (e.g., 4-H, 4-Me, 3−4-dimethyl, 2-
ethyl, 4-isopropyl, 4-butyl, and 4-pentyl), electron-rich (e.g., 4-
OMe, 2-OMe, 4,5-di-OMe, 3,5-di-OMe, phenoxy, 2,3-
OCH2O, and 3,4-OCH2CH2O) and electron-deficient (e.g.,
RESULTS AND DISCUSSION
■
To initiate our investigation, we chose aniline (1a) and 5-
methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (2a) as a
model substrate for this one-pot tandem reaction, and the
details are summarized in Table 1. On the basis of our previous
experiences in DMSO activation chemistry, we initially treated
aniline (1a,1.0 mmol) and pyrazolone (2a,1.2 mmol) in the
presence of K2S2O8 (2.5 equiv) in DMSO (3.0 mL) at room
temperature however did not afford the desired product (Table
1, entry 1). Further increasing the reaction temperature to 140
°C was also found to be unsuccessful (entry 2). To our delight,
when the reaction was carried out in the presence of p-TsOH·
H2O (2.5 equiv) in a sealed tube at 120 °C for 12 h, the
product 3aa was obtained in 52% yield as a sole product. It is
worth mentioning that under these conditions the expected
products 3aa′ was not observed even in a trace amount. At this
stage, the structure of pyrazoloquinoline (3aa) was confirmed
by various spectroscopic techniques and the final proof for the
exact structure was obtained by single-crystal X-ray structure of
one of the derivatives 3lb (vide infra).
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a b
,
Taking into consideration the potential importance of the of
the pyrazolo[3,4-b]quinoline in medicinal and material
chemistry, the practicality of present methodology was further
extended by establishing a gram scale synthesis wherein, 3 lb
was prepared in 79% yield from aniline (1l) and pyrazolone
(2b) under optimized reaction conditions (Scheme 4). This
Scheme 2. Substrate Scope with Different Anilines
a
Scheme 4. Gram Scale Synthesis and X-ray Structure of 3
b
lb
a
Reaction Conditions: 10.0 mmol scale, 12 h in a sealed tube.
ORTEP diagram of 3 lb
b
result clearly indicates that there is not much loss of efficiency
during the scale-up process. The structure of 3lb was
unambiguously confirmed by single X-ray analysis (see SI for
detailed X-ray crystallography data).14
The synthetic utility of the present methodology was further
evaluated (Scheme 5). For example, 6- methyl-1,3-diphenyl-
a
Reaction conditions: Anilines (1.0 mmol), pyrazolones (1.2 mmol),
TFA (2.5 mmol), DMSO (3.0 mL), 120 °C, 12 h, in a sealed tube.
Scheme 5. Synthetic Utility
b
Isolated yield of product.
a b
,
Scheme 3. Substrate Scope with Different Pyrazolones
1H-pyrazolo[3,4-b]quinoline (3ba) on treatment with NBS in
the presence of catalytic amount of AIBN (2,2′-azoisobutyr-
onitrile) furnished 6-(bromomethyl)-1,3-diphenyl-1H-
pyrazolo[3,4-b]quinoline (4) in 75% yield. The compound 4,
is known for its chromophore acceptor property and also
serves as an advance intermediate for the synthesis of
macrocyclic pyrazoloquinoline (5) which is widely used as
bright signaling fluorescent probes, electrontransfer (PET),
and intramolecular charge-transfer (ICT) processes.
To support the reaction mechanism various controlled
experiments were conducted (Scheme 6). In order to confirm
the involvement of radical pathway, initial reaction was
performed in the presence of TEMPO under standard
conditions leading the formation of 3aa in 62% yield,
suggesting that no radical species is operative in this process
(Scheme 6a). Furthermore, N-tosyl aniline (6) under standard
conditions failed to initiate the reaction, clearly indicating that
reaction is proceeding through imine formation (Scheme 6b).
Similarly 2,5-dimethyl aniline (7) on reaction with pyrazolone
under standard condition did not afford the desired product
3aa, suggesting the annulation of aniline at ortho position is
involved. To verify the carbon source in this reaction, 1a and
2a were reacted with methyl phenyl sulfoxide (PhSOMe; 8)
under standard conditions leading to the formation of desired
3aa in 55% yield (Scheme 6c). However, no product formation
was observed when diphenyl sulfoxide (Ph2SO; 9) was used as
a solvent (Scheme 6d). These experiments demonstrated that
DMSO was the methylene source in this reaction. To shed
more light on the reaction mechanism a deuterium labeling
experiment was conducted where in 1a and 2a when treatedin
DMSO-d6 under standard conditions furnished 3aa-d in 80%
a
b
Reaction conditions: 1.0 mmol scale, 12 h, in a sealed tube. Isolated
yield of product.
4-Br, 2-Br, 4-F, 4-Cl, and 3-Cl) groups at aromatic ring of
anilines effectively participated in this tandem reaction to
furnish the desired products (3aa−3sa) in excellent yields
(72−84%). Furthermore, anilines bearing halogen substituents
on the aromatic ring (F, Cl, and Br) reacted smoothly under
the optimized conditions, affording products in 72−76% yields
(3oa−3sa) which offered the opportunity of further function-
alization.
The scope of this methodology was further evaluated with
respect to different pyrazolones (2b−2d) (Scheme 3). The
pyrazolone bearing isopropyl, phenyl and 3-methoxy-phenyl
groups at C5 positions (2b−2d) effectively reacted with
various anilines containing both electron withdrawing (F, Br,
CF3, and −COCH3) and electron-donating (methoxy and
dimethoxylene) groups at ring system to form the desired
pyrazolo[3,4-b]quinolines in very high yields.
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purification. All experiments were carried out in sealed tubes. All the
solvents used for the reaction were distilled before use. The product
purification by column chromatography was accomplished using silica
gel 100−200 mesh. Analytical TLC was performed with Merck silica
gel 60 F254 plates, and the products were visualized by UV detection.
1H, 13C NMR spectra were recorded on Avance III, Bruker at 400
MHz, 101 and 376 MHz spectrometers, respectively, using CDCl3. In
Scheme 6. Controlled Experiments
1
the Experimental Section, the H NMR chemicals shift are expressed
in the form of ppm (δ) relative to δ = 7.26 for CDCl3 whereas
13C{1H} NMR chemical shifts are expressed relative to δ = 77.00.
Multiplicities in the 1H NMR spectra are described as s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, and bs = broad singlet;
coupling constants are reported in Hz. HRMS and Electron Spray
Ionization (ESI) (m/z) spectra were recorded on Agilent
Technologies 6530 Accurate-Mass Q-TOF LC/MS.
Preparation of 4-Isopropyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-
one (2b). A mixture of ethyl 4-methyl-3-oxopentanoate (3.17 g, 0.02
mol) and phenylhydrazine (2.16 g, 0.02 mol) was dissolved in acetic
acid (20.0 mL). The reaction was refluxed at 120 °C for 8 h. The
reaction temperature was cooled down to room temperature and
quenched with cold aq. NaHCO3 solution. Once the mixture was
neutralized the reaction mixture was then diluted with ethyl acetate
(60.0 mL). The organic layer was washed with water (20 mL),
sodium bicarbonate (20 mL), and brine (20 mL). The organic layer
was further dried over anhydrous sodium sulfate and solvent was
evaporated under reduced pressure to get crude product which was
purified by coloumn chromatography using 10% (ethyl acetate/
hexane) on 100−200 mesh silica gel to get the product 2b in 3.6 g, in
90% yield as white solid. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J =
8.0 Hz, 2H), 7.38 (t, J = 7.7 Hz, 2H), 7.16 (t, J = 7.2 Hz, 1H), 3.42 (s,
2H), 2.78 (hept, J = 13.7, 6.8 Hz, 1H), 1.24 (d, J = 6.8 Hz, 6H);
13C{1H} NMR (101 MHz, CDCl3) δ 170.6, 164.3, 138.1, 128.7,
yield with 100% deuteration at the C-4 position confirmed by
1H NMR analyses.
On the basis of the above results and previous reports,11
a
possible reaction mechanism for this transformation is
proposed in (Scheme 7). Initially, aniline 1a on condensation
Scheme 7. Proposed Reaction Mechanism
124.9, 118.8, 39.8, 30.7, 20.0; HRMS (ESI) m/z calcd for C12H15N2O
[M + H] is 203.1179, found 203.1177.
2,5-Diphenyl-2,4-dihydro-3H-pyrazol-3-one (2c). The compound
2c was prepared from ethyl 3-oxo-3-phenylpropanoate and phenyl-
hydrazine following the same experimental procedure given for the
1
compound 2b. H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.2 Hz,
2H), 7.68−7.59 (m, 2H), 7.35−7.29 (m, 5H), 7.11 (t, J = 7.4 Hz,
1H), 3.67 (s, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.2, 154.7,
138.0, 130.7, 130.6, 128.8, 128.8, 125.9, 125.2, 118.9, 39.5; HRMS
(ESI) m/z calcd for C15H13N2O [M + H] is 237.1022, found
237.1022.
2-(3-Methoxyphenyl)-5-phenyl-2,4-dihydro-3H-pyrazol-3-one
(2d). The compound 2d was prepared from ethyl 3-(3-methox-
yphenyl)-3-oxopropanoate and phenylhydrazine following the same
experimental procedure given for the compound 2b.1H NMR (400
MHz, CDCl3) δ 7.99 (d, J = 8.2 Hz, 2H), 7.45 (t, J = 7.8 Hz, 2H),
7.40−7.34 (m, 2H), 7.30 (d, J = 8.3 Hz, 2H), 7.24 (t, J = 7.3 Hz, 2H),
7.02 (d, J = 8.1 Hz, 2H); 3.89 (s, 3H), 3.82 (s, 2H); 13C{1H} NMR
(101 MHz, CDCl3) δ 170.2, 159.9, 154.5, 138.1, 132.1, 129.9, 128.8,
125.3, 119.08, 118.7, 116.6, 110.8, 55.4, 39.7; HRMS (ESI) m/z calcd
for C16H15N2O2 [M + H] is 267.1128, found 267.1120.
with pyrazolone in the presence of TFA furnished the imine
(c) which isomerizes to more stable pyrazole (D). However,
DMSO was activated under acidic condition to generate an
electrophilic thionium ion (E) which reacts with pyrazole (D)
to form the intermediate (F). The intermediate (F) on
elimination of −MeSH provided the azadiene intermediate
(G). The azadiene intermediate on annulation furnished the
intermediate (H) which subsequently aromatizes to form the
desired 3aa.
Experimental Procedure for the Synthesis of 3-Methyl-1-phenyl-
1H-pyrazolo[3,4-b]quinolone (3aa). A solution of aniline (1a, 1.0
mmol, 0.09 mL), 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one
(2a, 1.2 mmol, 0.21 g), trifluoroacetic acid (2.5 mmol, 0.19 mL), and
DMSO (3.0 mL) in a sealed tube was placed in preheated oil bath
(120 °C). The reaction mixture was then allowed to attain room
temperature and then diluted with ethyl acetate (10 mL). The organic
layer was washed with water (10 mL), sodium bicarbonate (10 mL),
and brine (10 mL). The organic layer was further dried over
anhydrous sodium sulfate and solvent was evaporated under reduced
pressure to get the crude product which was purified by coloumn
chromatography using 5% ethyl acetate/hexane mixture on 100−200
mesh silica gel to get the product 3aa as a pale yellow liquid 0.21 g in
CONCLUSIONS
■
In summary, we have developed herein an atom-economical,
transition metal, and oxidant-free DMSO activation for the
synthesis of pyrazolo[3,4-b]quinolone from easily accessible
starting materials in the presence of an acid. This reaction
worked well with variously substituted anilines and pyrazo-
lones. As a result, a series of fused pyrazolo[3,4-b]quinolones
were prepared to reflect the generality of this method. DMSO
assumes a dual role in this process because it acts as a solvent
and methine source, making the present methodology
environmentally benign.
1
81% yield. H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.42 (d, J =
EXPERIMENTAL SECTION
General Information. All reagents were purchased from Sigma-
Aldrich, Alfa Aesar, and local venders and were used without further
8.2 Hz, 2H), 8.09 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.72−
7.66 (m, 1H), 7.47 (t, J = 7.9 Hz, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.19
(d, J = 6.8 Hz, 1H), 2.68 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3)
■
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δ 150.4, 148.3, 143.4, 139.93, 130.6, 129.6, 129.1, 129.0, 128.8, 124.9,
124.1, 124.1, 120.1, 118.3, 12.8; HRMS (ESI) m/z calcd for
C17H14N3 [M + H] is 260.1182, found 260.1177.
yellow stickey solid. H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.1
Hz, 2H), 8.39 (s, 1H), 8.05 (d, J = 9.4 Hz, 1H), 7.53 (t, J = 7.8 Hz,
2H), 7.44 (dd, J = 9.4, 2.6 Hz, 1H), 7.28−7.22 (m, 1H), 7.17 (d, J =
2.5 Hz, 1H), 3.94 (s, 3H), 2.73 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 155.9, 149.6, 144.7, 142.7, 140.0, 130.1, 129.0, 127.6, 124.8,
124.7, 124.5, 119.8, 118.3, 105.1, 55.5, 12.8; HRMS (ESI) m/z calcd
for C18H16N3O [M + H] is 290.1288, found 290.1285.
3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone (3ba). Pu-
rified by column chromatography on silica gel (petroleum ether/ethyl
acetate = 95/5) to afford 3ba as a pale yellow semisolid (213 mg,
78%), 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.45 (s, 2H), 8.10
(d, J = 8.7 Hz, 1H), 7.72 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.54 (t, J =
7.6 Hz, 2H), 7.28−7.24 (m, 1H), 2.75 (s, 3H), 2.55 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 150.0, 146.8, 143.3, 139.9, 133.8, 133.4,
129.0, 128.9, 128.4, 127.5, 124.9, 124.2, 120.2, 118.4, 21.5, 12.8;
HRMS (ESI) m/z calcd for C18H16N3 [M + H] is 274.1339, found
274.1338.
8-Methoxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone
(3ia). Purified by column chromatography on silica gel (petroleum
ether/ethyl acetate = 97/3) to afford 3ia (237 mg, yield = 82%) as a
colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.50 (d, J =
8.1 Hz, 2H), 7.58 (d, J = 8.5 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.40
(t, J = 7.9 Hz, 1H), 7.28−7.22 (m, 1H), 7.11 (d, J = 7.5 Hz, 1H), 4.13
(s, 3H), 2.77 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 154.8,
149.6, 143.2, 140.6, 139.9, 129.7, 129.1, 125.1, 124.8, 123.9, 120.9,
119.9, 118.5, 108.2, 56.2, 12.8; HRMS(ESI) m/z calcd for
C18H16N3O [M + H] is 290.1288, found 290.1285.
3,6,8-Trimethyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone (3ca).
Purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 96/4) to afford 3ca (253 mg, 82%), as a pale yellow
1
solid; mp 97−99 °C. H NMR (400 MHz, CDCl3) δ 8.63 (dd, J =
8.7, 1.1 Hz, 1H), 8.33 (s, 1H), 7.57−7.52 (m, 3H), 7.46 (s, 1H),
7.27−7.23 (m, 1H), 2.84 (s, 3H), 2.73 (s, 3H), 2.51 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 149.5, 146.2, 143.0, 140.4, 135.9, 133.2,
133.0, 128.9, 128.6, 125.3, 124.2, 124.0, 119.2, 117.9, 21.5, 18.4, 12.8;
HRMS (ESI) m/z calcd for C19H18N3 [M + H] is 288.1495, found
288.1493.
5,6-Dimethoxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone
(3ja). Purified by column chromatography on silica gel (petroleum
ether/ethyl acetate = 96/4) to afford 3ja (260 mg, yield = 84%) as a
white solid; mp 209−211 °C. 1H NMR (400 MHz, CDCl3) δ 8.32 (d,
J = 8.1 Hz, 2H), 8.19 (s, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.30 (s, 1H),
7.15−7.11 (m, 1H), 7.01 (s, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 2.58 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 153.9, 149.9, 148.5, 146.0,
142.8, 140.1, 129.0, 127.2, 124.7, 120.0, 119.9, 116.7, 106.9, 105.5,
56.2, 55.9, 12.7; HRMS (ESI) m/z calcd for C19H18N3O2 [M + H] is
320.1394, found 320.1394.
5,7-Dimethoxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone
(3ka). Purified by column chromatography on silica gel (petroleum
ether/ethyl acetate = 97/3) to afford 3ka (261 mg, yield = 82%) as a
white sticky solid. 1H NMR (800 MHz, CDCl3) δ 8.88 (s, 1H), 8.56
(d, J = 8.6 Hz, 2H), 7.65 (t, J = 8.1 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H),
6.50 (s, 1H), 4.11 (s, 3H), 4.09 (s, 3H), 2.81 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 162.5, 156.9, 150.9, 150.5, 143.9, 139.9, 129.0,
124.9, 124.8, 120.2, 115.7, 113.5, 98.5, 96.0, 55.7, 55.6, 12.6; HRMS
(ESI) m/z calcd for C19H18N3O2 [M + H] is 320.1394, found
320.1396.
8-Ethyl-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone (3da).
Purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 96/4) to afford 3da as a white solid (221 mg, yield =
1
77%); mp 112−114 °C. H NMR (400 MHz, CDCl3) δ 8.62 (d, J =
8.2 Hz, 2H), 8.53 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 6.8
Hz, 1H), 7.54 (t, J = 7.7 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.25 (t, J =
7.4 Hz, 1H), 3.39 (q, J = 7.5 Hz, 2H), 2.76 (s, 3H), 1.48 (t, J = 7.5
Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 149.8, 146.9, 143.2,
142.1, 140.3, 129.8, 128.9, 128.8, 127.0, 124.4, 124.1, 124.0, 119.3,
118.00, 25.2, 14.5, 12.8; HRMS (ESI) m/z calcd for C19H18N3 [M +
H] is 288.1495, found 288.1495.
6-Isopropyl-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone
(3ea). Purified by column chromatography on silica gel (petroleum
ether/ethyl acetate = 96/4) to afford 3ea as a yellow oil (214 mg,
1
yield = 75%); H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8.3 Hz,
3-Methyl-1-phenyl-1H-[1,3]dioxolo[4,5-g]pyrazolo[3,4-b]-
quinolone (3la). Purified by column chromatography on silica gel
(petroleum ether/ethyl acetate = 95/5) to afford 3la (252 mg, yield =
83%) as a yellow semisolid. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J
= 8.2 Hz, 2H), 8.17 (s, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.31 (s, 1H),
7.21−7.16 (m, 1H), 7.04 (s, 1H), 6.03 (s, 2H), 2.61 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 152.1, 149.7, 147.1, 146.5, 142.7, 140.0,
128.9, 127.7, 124.7, 121.0, 120.0, 116.6, 104.5, 102.9, 101.8, 53.4,
12.6; HRMS (ESI) m/z calcd for C18H14N3O2 [M + H] is 304.1081,
found 304.1084.
1H), 8.43 (s, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.72 (s, 1H), 7.68 (d, J =
9.0 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.27−7.24 (m, 1H), 3.11 (sep, J
= 13.7, 6.9 Hz, 1H), 2.72 (s, 3H), 1.37 (d, J = 6.9 Hz, 6H); 13C{1H}
NMR (101 MHz, CDCl3) δ 150.2, 147.2, 144.3, 143.1, 140.0, 130.9,
129.0, 128.9, 128.6, 127.1, 124.7, 124.6, 124.1, 120.5, 119.9, 118.2,
33.8, 23.7, 12.7; HRMS (ESI) m/z calcd for C20H20N3 [M + H] is
302.1652, found 302.1647.
6-Butyl-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone (3fa).
Purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 95/5) to afford 3fa as a colorless oil (245 mg, yield =
77%); 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8.3 Hz, 2H), 8.46
(s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.62 (d, J = 9.1 Hz,
1H), 7.53 (t, J = 7.8 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 2.82 (t, J = 7.7
Hz, 2H), 2.75 (s, 3H), 1.76−1.69 (m, 2H), 1.45−1.39 (m, 2H), 0.96
(t, 6.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 150.3, 147.3,
143.2, 140.0, 138.6, 132.5, 129.2, 129.0, 128.8, 128.6, 126.8, 124.7,
124.2, 120.4, 119.9, 118.3, 35.4, 33.2, 22.3, 13.9, 12.7; HRMS (ESI)
m/z calcd for C21H22N3 [M + H] is 316.1808, found 316.1806.
3-Methyl-6-pentyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone (3ga).
Purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 96/4) to afford 3ga as a colorless oil (260 mg, yield =
79%); 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.43 (s, 2H), 8.08
(d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.51 (t, J =
7.8 Hz, 2H), 7.24−7.20 (m, 1H), 2.77 (t, J = 7.7 Hz, 2H), 2.71 (s,
3H), 1.75−1.65 (m, 2H), 1.38−1.30 (m, 4H), 0.88 (t, J = 6.4 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 149.98, 146.98, 143.28,
139.92, 138.69, 132.69, 129.09, 129.0, 128.3, 126.8, 124.8, 124.1,
120.0, 118.3, 35.7, 31.4, 30.7, 22.5, 14.0, 12.7; HRMS (ESI) m/z calcd
for C22H24N3 [M + H] is 330.1965, found 330.1962.
3-Methyl-1-phenyl-7,8-dihydro-1H-[1,4]dioxino[2,3-g]pyrazolo-
[3,4-b]quinolone (3ma). Purified by column chromatography on
silica gel (petroleum ether/ethyl acetate = 97/3) to afford 3ma (260
1
mg, yield = 82%) as a colorless oil. H NMR (400 MHz, CDCl3) δ
8.68 (s, 1H), 8.39 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 9.3 Hz, 1H), 7.46
(t, J = 7.9 Hz, 2H), 7.32 (d, J = 9.3 Hz, 1H), 7.22−7.17 (m, 1H),
4.45−4.39 (m, 2H), 4.35−4.30 (m, 2H), 2.66 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 149.4, 144.2, 143.3, 139.9, 136.9, 136.4, 129.1,
128.8, 124.8, 123.9, 122.6, 121.38, 120.0, 118.6, 117.5, 117.2, 64.7,
64.4, 12.7; HRMS (ESI) m/z calcd for C19H16N3O2 [M + H] is
318.1237, found 318.1237.
3-Methyl-6-phenoxy-1-phenyl-1H-pyrazolo[3,4-b]quinolone
(3na). Purified by column chromatography on silica gel (petroleum
ether/ethyl acetate = 97/3) to afford 3na (277 mg, yield = 79%) as a
1
yellow oil. H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 8.3 Hz, 2H),
8.32 (s, 1H), 8.16 (d, J = 9.3 Hz, 1H), 7.61−7.56 (m, 3H), 7.44 (t, J =
7.7 Hz, 2H), 7.36 (d, J = 2.4 Hz, 1H), 7.32−7.28 (m, 1H), 7.22 (t, J =
7.4 Hz, 1H), 7.16 (d, J = 8.2 Hz, 2H), 2.71 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 156.7, 153.5, 149.8, 145.0, 142.8, 139.8, 130.4,
129.9, 128.9, 128.3, 125.1, 124.7, 124.4, 123.7, 119.8, 119.3, 118.4,
113.5, 12.6; HRMS (ESI) m/z calcd for C23H18N3O [M + H] is
352.1444, found 352.1443.
6-Methoxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone
(3ha). Purified by column chromatography on silica gel (petroleum
ether/ethyl acetate = 97/3) to afford 3ha (240 mg, yield = 83%) as a
2662
https://dx.doi.org/10.1021/acs.joc.0c02696
J. Org. Chem. 2021, 86, 2658−2666

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone
(3oa). Purified by column chromatography on silica gel (petroleum
ether/ethyl acetate = 97/3) to afford 3oa (253 mg, yield = 75%) as a
133.6, 133.1, 129.1, 128.9, 128.3, 127.4, 124.6, 123.9, 120.0, 116.8,
28.5, 21.8, 21.4; HRMS (ESI) m/z calcd for C20H20N3 [M + H] is
302.1652, found 302.1652.
1
yellow semisolid. H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.40
3-Isopropyl-8-methoxy-1-phenyl-1H-pyrazolo[3,4-b]quinolone
(3ib). Purified by column chromatography on silica gel (petroleum
ether/ethyl acetate = 95/5) to afford 3ib (241 mg, yield = 76%) as a
red color oil. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.58 (d, J =
8.2 Hz, 2H), 7.58 (dd, J = 13.0, 5.5 Hz, 3H), 7.41 (t, J = 7.9 Hz, 1H),
7.28 (t, J = 7.3 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 4.15 (s, 3H), 3.59
(hept, J = 7.0 Hz, 1H), 1.62 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (101
MHz, CDCl3) δ 154.8, 151.8, 149.9, 140.4, 140.2, 130.1, 129.1, 128.9,
125.0, 124.8, 123.9, 121.2, 120.9, 120.0, 117.1, 108.3, 56.2, 28.6, 21.9;
HRMS (ESI) m/z calcd for C20H20N3O [M + H] is 318.1601, found
318.1599.
(d, J = 8.2 Hz, 2H), 8.07 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 7.3 Hz, 1H),
7.57−7.45 (m, 3H), 7.22 (t, J = 7.4 Hz, 1H), 2.74 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 150.3, 148.8, 143.8, 139.6, 130.5, 129.8,
129.1, 128.9, 127.9, 125.2, 123.4, 123.1, 120.1, 119.1, 12.8; HRMS
(ESI) m/z calcd for C17H13BrN3 [M + H] is 338.0287, found
338.0285.
5-Bromo-3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone
(3pa). Purified by column chromatography on silica gel (petroleum
ether/ethyl acetate = 97/3) to afford 3pa (267 mg, yield = 76%) as a
1
yellow solid; mp 166−168 °C. H NMR (400 MHz, CDCl3) δ 8.93
(s, 1H), 8.39 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 8.7 Hz, 1H), 7.56 (d, J =
8.6 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.22 (d, J = 7.4 Hz, 1H), 2.74
(s, 3H), 2.60 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 149.9,
147.5, 143.7, 139.7, 134.2, 133.4, 129.4, 129.01, 128.1, 125.1, 123.9,
123.8, 120.1, 119.0, 23.8, 12.8; HRMS (ESI) m/z calcd for
C18H15BrN3 [M + H] is 352.0444, found 352.0441.
3-Isopropyl-1-phenyl-1H-[1,3]dioxolo[4,5-g]pyrazolo[3,4-b]-
quinolone (3 lb). Purified by column chromatography on silica gel
(petroleum ether/ethyl acetate = 97/3) to afford 3 lb (262 mg, yield
= 79%) as a white crystalline solid; mp 175−177 °C. H NMR (400
1
MHz, CDCl3) δ 8.37 (d, J = 7.8 Hz, 2H), 8.26 (d, J = 2.7 Hz, 1H),
7.44 (t, J = 7.9 Hz, 2H), 7.30 (d, J = 1.8 Hz, 1H), 7.16 (dd, J = 9.0,
5.7 Hz, 1H), 7.02 (d, J = 2.9 Hz, 1H), 6.00 (s, 2H), 3.40 (hept, J = 6.9
Hz, 1H), 1.46 (d, J = 7.0 Hz, 6H); 13C{1H} NMR (101 MHz,
CDCl3) δ 152.0, 151.3, 150.0, 146.8, 146.4, 140.0, 128.9, 128.1, 124.6,
120.8, 120.1, 115.0, 104.4, 102.9, 101.8, 28.5, 21.8; HRMS (ESI) m/z
calcd for C20H18N3O2 [M + H] is 332.1394, found 332.1391.
6-Fluoro-3-isopropyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone
(3qb). Purified by column chromatography on silica gel (petroleum
ether/ethyl acetate = 97/3) to afford 3qb (223 mg, yield = 73%) as a
6-Fluoro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone (3qa).
Purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 96/4) to afford 3qa (202 mg, yield = 73%) as a yellow
1
semisolid. H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.47 (d, J =
8.2 Hz, 2H), 8.20 (dd, J = 10.0, 5.3 Hz, 1H), 7.58 (dd, J = 14.6, 7.8
Hz, 4H), 7.34−7.27 (m, 1H), 2.78 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 158.7 (d, J = 245.6 Hz), 149.9, 145.1, 142.8, 139.7,
130.9 (d, J = 8.9 Hz), 129.0, 128.7, 124.0 (d, J = 9.9 Hz), 123.9, 121.4
(d, J = 26.6 Hz), 119.9, 118.6, 111.0 (d, J = 21.7 Hz), 12.6; HRMS
(ESI) m/z calcd for C17H13FN3 [M + H] is 278.1088, found
278.1088.
6-Chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone (3ra).
Purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 96/4) to afford 3ra (211 mg, yield = 72%) as a pale
yellow solid. 1H NMR(400 MHz, CDCl3) δ 8.47 (d, J = 8.4 Hz, 2H),
8.36 (s, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.67
(dd, J = 9.2, 1.6 Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.30 (t, J = 7.3 Hz,
1H), 2.73 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 150.3, 146.4,
143.2, 139.7, 131.4, 130.3, 129.4, 129.0, 128.5, 127.2, 125.0, 124.3,
119.9, 118.6, 12.7; HRMS (ESI) m/z calcd for C17H13ClN3 [M + H]
is 294.0793, found 294.0793.
1
pale yellow solid; mp 129−131 °C. H NMR (400 MHz, CDCl3) δ
8.47 (s, 1H), 8.41 (d, J = 8.2 Hz, 2H), 8.07 (dd, J = 8.9, 5.3 Hz, 1H),
7.52−7.42 (m, 4H), 7.22−7.14 (m, 1H), 3.46 (hept, J = 7.0 Hz, 1H),
1.49 (d, J = 7.0 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 158.7
(d, J = 245.8 Hz), 151.5, 150.4, 145.1, 139.9, 131.0 (d, J = 8.9 Hz),
129.1, 129.1, 129.0, 124.9, 123.9 (d, J = 9.8 Hz), 121.5, 121.2, 120.1,
117.3, 111.1 (d, J = 21.7 Hz), 28.5, 21.8; HRMS (ESI) m/z calcd for
C19H17FN3 [M + H] is 306.1401, found 306.1401.
6-Methyl-1,3-diphenyl-1H-pyrazolo[3,4-b]quinolone (3bc). Puri-
fied by column chromatography on silica gel (petroleum ether/ethyl
acetate = 97/3) to afford 3bc (271 mg, yield = 81%) as a yellow solid,
1
mp 175−177 °C. H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.60
(d, J = 8.3 Hz, 2H), 8.14 (d, J = 7.9 Hz, 2H), 8.07 (d, J = 8.8 Hz, 1H),
7.72 (s, 1H), 7.61−7.56 (m, 5H), 7.50 (t, J = 7.3 Hz, 1H), 7.31 (t, J =
7.3 Hz, 1H), 2.54 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
150.6, 146.8, 144.3, 139.9, 134.0, 133.5, 132.6, 129.9, 129.0, 128.9,
128.5, 127.5, 127.4, 125.2, 124.8, 120.5, 116.4, 21.5; HRMS (ESI) m/
z calcd for C23H18N3 [M + H] is 336.1495, found 336.1493.
6,8-Dimethyl-1,3-diphenyl-1H-pyrazolo[3,4-b]quinolone (3cc).
Purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 97/3) to afford 3cc (286 mg, yield = 82%) as a yellow
solid; mp 178−180 °C. 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H),
8.71 (s, 2H), 8.15 (d, J = 7.8 Hz, 2H), 7.60−7.55 (m, 5H), 7.51−7.45
(m, 2H), 7.28 (t, 6.6 Hz, 1H), 2.84 (s, 3H), 2.49 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 149.9, 146.0, 144.0, 140.3, 135.9, 133.6,
133.2, 132.8, 129.9, 128.9, 128.9, 128.8, 127.3, 125.3, 124.7, 124.6,
119.8, 115.9, 21.5, 18.3; HRMS (ESI) m/z calcd for C24H20N3 [M +
H] is 350.1652, found 350.1652.
7-Chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone (3sa).
Purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 97/3) to afford 3sa (211 mg, yield = 76%) as a
1
semisolid. H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.49 (d, J =
8.1 Hz, 2H), 8.13 (d, J = 8.7 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.58
(t, J = 8.3 Hz, 3H), 7.32 (t, J = 7.4 Hz, 1H), 2.84 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 150.3, 148.8, 143.9, 139.7, 132.4, 130.1,
129.1, 128.1, 127.1, 125.2, 124.1, 122.3, 120.2, 118.8, 118.5, 12.8;
HRMS (ESI) m/z calcd for C17H13ClN3 [M + H] is 294.0793, found
294.0791.
3-Isopropyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone (3ab). Puri-
fied by column chromatography on silica gel (petroleum ether/ethyl
acetate = 97/3) to afford 3ab (227 mg, yield = 79%) as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.44 (d, J = 8.3 Hz, 2H),
8.10 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.73−7.64 (m,
1H), 7.47 (t, J = 7.7 Hz, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 6.5
Hz, 1H), 3.49 (hept, J = 7.0 Hz, 1H), 1.51 (d, J = 7.0 Hz, 6H);
13C{1H} NMR (101 MHz, CDCl3) δ 152.1, 150.4, 147.9, 140.0,
8-Methoxy-1,3-diphenyl-1H-pyrazolo[3,4-b]quinolone (3ic). Pu-
rified by column chromatography on silica gel (petroleum ether/ethyl
acetate = 96/4) to afford 3ic (274 mg, yield = 78%) as a yellow oil.
1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.63 (d, J = 8.1 Hz, 2H),
8.16 (d, J = 7.8 Hz, 2H), 7.59 (dd, J = 13.2, 7.7 Hz, 5H), 7.50 (t, J =
7.5 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.12
(d, J = 7.5 Hz, 1H), 4.14 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3)
δ 155.0 150.1, 144.3, 140.5, 140.0, 132.6, 130.9, 129.1, 129.1, 129.0,
127.5, 125.8, 125.3, 124.3, 121.0, 120.4, 116.7, 108.5, 56.2; HRMS
(ESI) m/z calcd for C23H18N3O [M + H] is 352.1444, found
352.1443.
130.7, 130.3, 129.1, 129.0, 128.6, 124.9, 124.1, 123.9, 120.3, 117.0,
28.6, 21.8; HRMS (ESI) m/z calcd for C19H18N3 [M + H] is
288.1495, found 288.1494.
3-Isopropyl-6-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinolone
(3bb). Purified by column chromatography on silica gel (petroleum
ether/ethyl acetate = 97/3) to afford 3bb (229 mg, yield = 76%) as a
1
yellow solid, mp 117−119 °C. H NMR (400 MHz, CDCl3) δ 8.43
(s, 1H), 8.42 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 8.8 Hz, 1H), 7.59 (s,
1H), 7.46 (dd, J = 17.8, 9.5 Hz, 3H), 7.15 (dd, J = 9.5, 5.2 Hz, 1H),
3.44 (hept, J = 6.9 Hz, 1H), 2.44 (s, 3H), 1.48 (d, J = 7.0 Hz, 6H);
13C{1H} NMR (101 MHz, CDCl3) δ 151.8, 150.3, 146.7, 140.01,
6-Bromo-1,3-diphenyl-1H-pyrazolo[3,4-b]quinolone (3oc). Puri-
fied by column chromatography on silica gel (petroleum ether/ethyl
acetate = 97/3) to afford 3oc (287 mg, yield = 72%) as a red color
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solid; mp 127−129 °C. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H),
8.55 (d, J = 8.1 Hz, 2H), 8.15 (s, 1H), 8.11 (d, J = 7.7 Hz, 2H), 8.04
(d, J = 9.1 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.561−7.55 (m, 5H),
7.51 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 150.8, 146.6, 144.6, 139.7, 134.2, 132.3, 130.8, 130.6,
129.9, 129.2, 129.1, 129.1, 127.5, 125.7, 125.6, 120.7, 117.8, 116.9;
HRMS (ESI) m/z calcd for C22H15BrN3 [M + H] is 400.0444, found
400.0442.
1,3-Diphenyl-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]quinoline
(3sc). Purified by column chromatography on silica gel (petroleum
ether/acetone = 94/6) to afford 3sc (295 mg, yield = 76%) as a thick
oil. 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.60 (d, J = 8.1 Hz,
2H), 8.39 (s, 1H), 8.31 (d, J = 9.0 Hz, 1H), 8.17 (d, J = 7.5 Hz, 2H),
7.96 (d, J = 8.6 Hz, 1H), 7.63 (q, J = 7.2 Hz, 4H), 7.56 (t, J = 7.4 Hz,
1H), 7.38 (t, J = 7.4 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ
151.5, 148.9, 144.8, 139.6, 132.27, 132.1, 130.2, 129.4, 129.2, 129.1,
127.4 (d, J = 4.7 Hz), 127.4, 126.4, 126.2 (q, J = 2.7 Hz), 123.7 (q, J =
272 Hz), 120.8, 117.3; HRMS (ESI) m/z calcd for C23H15F3N3 [M +
H] is 390.1213, found 390.1213.
1-(1,3-Diphenyl-1H-pyrazolo[3,4-b]quinolin-6-yl)ethan-1-one
(3tc). Purified by column chromatography on silica gel (petroleum
ether/acetone = 95/5) to afford 3tc (283 mg, yield = 78%) as a semi-
sticky solid. 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.55 (d, J =
7.3 Hz, 3H), 8.27 (d, J = 9.0 Hz, 1H), 8.11 (d, J = 7.1 Hz, 3H), 7.62−
7.54 (m, 5H), 7.35 (t, J = 7.3 Hz, 1H), 2.72 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3) 196.9, 151.4, 149.7, 144.6, 139.5, 132.9, 132.8,
132.0, 131.9, 129.3, 129.2, 129.1, 129.0, 128.7, 127.4, 125.7, 123.3,
120.6, 117.0, 26.48; HRMS (ESI) m/z calcd for C24H18N3O [M + H]
is 364.1444, found 364.1449.
anhydrous sodium sulfate, and the solvent was evaporated under
reduced pressure to get the crude product which was purified by
column chromatography using 100−200 mesh silica gel to obtain the
product 3lb as a white solid crystalline solid 2.54 g, in 77% yield.
3-Methyl-1-phenyl-1H-pyrazolo[3,4-b]quinoline-4-d (3aa-d). Pu-
rified by column chromatography on silica gel (petroleum ether/ethyl
acetate = 97/3) to afford 3aa-d (208 mg, yield = 80%) as a yellow oil.
1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.1 Hz, 2H), 8.05 (d, J =
8.7 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.46
(t, J = 7.9 Hz, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H),
2.63 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 150.3, 148.1,
143.3, 139.9, 130.5, 128.9, 128.9, 128.7, 124.8, 123.9, 123.9, 120.0,
118.2, 12.7; HRMS (ESI) m/z calcd for C17H13DN3 [M + H] is
261.1245, found 261.1242.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02696.
1H and 13C NMR data, and X-ray Crystallography Data
(PDF)
Accession Codes
CCDC 2032763 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
3-(3-Methoxyphenyl)-6-methyl-1-phenyl-1H-pyrazolo[3,4-b]-
quinolone (3bd). Purified by column chromatography on silica gel
(petroleum ether/acetone = 95/5) to afford 3bd (288 mg, yield =
1
79%) as a pale yellow solid, mp 120−122 °C. H NMR (400 MHz,
AUTHOR INFORMATION
CDCl3) δ 8.78 (s, 1H), 8.63 (d, J = 8.2 Hz, 2H), 8.09 (d, J = 8.8 Hz,
1H), 7.73 (t, J = 8.0 Hz, 3H), 7.61 (t, J = 7.9 Hz, 3H), 7.52 (t, J = 7.9
Hz, 1H), 7.34 (t, J = 7.3 Hz, 1H), 7.07 (dd, J = 8.2, 2.2 Hz, 1H), 3.98
(s, 3H), 2.56 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.1,
150.6, 146.8, 144.1, 139.9, 134.0, 133.9, 133.4, 130.0, 129.8, 128.9,
128.4, 127.5, 125.2, 124.7, 120.5, 119.9, 116.3, 114.5, 112.8, 55.4,
21.4; HRMS (ESI) m/z calcd for C24H20ON3 [M + H] is 366.1601,
found 366.1602.
■
Corresponding Author
Dharmendra Kumar Tiwari − Molecular Synthesis and Drug
Discovery Laboratory, Center of Biomedical Research
(CBMR), Sanjay Gandhi Post-Graduate Institute of Medical
Sciences Campus, Lucknow 226014, Uttar Pradesh, India;
orcid.org/0000-0002-0978-4177; Email: dktiwari@
cbmr.res.in, dkt80.org@gmail.com
Experimental Procedure for the Synthesis of 6-(Bromomethyl)-
1,3-diphenyl-1H-pyrazolo[3,4-b]quinolone (4). To a solution of 3ba
(0.335 g, 1.0 mmol) in dry CCl4 (6.0 mL) were added NBS (0.18 g,
1.0 mmol) and AIBN (0.02 g, 0.10), and the reaction mixture was
allowed to reflux for 6 h. After that the reaction was cooled down to
room temperature. The mixture was filtered through a pad of
diatomaceous earth and the organic layer was washed with water (1 ×
5.0 mL) and brine (1 × 5.0 mL). The organic layer was further dried
over anhydrous sodium sulfate, and the solvent was evaporated under
reduced pressure to get a crude product which was purified by
coloumn chromatography (5% ethyl acetate and hexane) using 100−
200 mesh silica gel to get the product 4 as a yellow sticky solid 310
Authors
Pushpendra Yadav − Molecular Synthesis and Drug Discovery
Laboratory, Center of Biomedical Research (CBMR), Sanjay
Gandhi Post-Graduate Institute of Medical Sciences Campus,
Lucknow 226014, Uttar Pradesh, India; Department of
Chemistry, Institute of Science, Banaras Hindu University,
221005 Varanasi, Uttar Pradesh, India
Annapurna Awasthi − Molecular Synthesis and Drug
Discovery Laboratory, Center of Biomedical Research
(CBMR), Sanjay Gandhi Post-Graduate Institute of Medical
Sciences Campus, Lucknow 226014, Uttar Pradesh, India;
Department of Chemistry, Institute of Science, Banaras Hindu
University, 221005 Varanasi, Uttar Pradesh, India
Sabapathi Gokulnath − School of Chemistry, Indian Institute
of Science Education and Research (IISER),
1
mg in 75% yield. H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.60
(d, J = 8.3 Hz, 2H), 8.14 (d, J = 6.9 Hz, 3H), 7.96 (s, 1H), 7.79 (d, J =
8.9 Hz, 1H), 7.64−7.59 (m, 4H), 7.53 (t, J = 7.3 Hz, 1H), 7.36 (t, J =
7.3 Hz, 1H), 4.69 (s, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ
150.9, 147.7, 144.4, 139.7, 133.6, 132.3, 131.7, 130.8, 129.7, 129.1,
129.0, 129.0, 128.8, 127.4, 125.5, 124.2, 120.6, 116.7, 33.5. HRMS
(ESI) m/z calcd for C23H17BrN3 [M + H] is 414.0600, found
414.0601.
Gram Scale Synthesis of 3-Isopropyl-1-phenyl-1H-[1,3]dioxolo-
[4,5-g]pyrazolo[3,4-b]quinolone (3lb). A solution of aniline (1l, 1.37
g, 10.0 mmol), 3-isopropyl-1-phenyl-4,5-dihydro-1H-pyrazole (2b,
12.0 mmol, 2.4 g), trifluoroacetic acid (25.0 mmol, 1.9 mL), and
DMSO (30.0 mL) in a sealed tube was placed in a preheated oil bath
(120 °C). The reaction mixture was then allowed to attain room
temperature and then diluted with ethyl acetate (100 mL). The
organic layer was washed with water (50 mL), sodium bicarbonate
(50 mL), and brine (5 mL). The organic layer was further dried over
Thiruvananthapuram 695 551, Kerala, India; orcid.org/
0000-0001-9299-5217
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02696
Author Contributions
The manuscript was written through the contributions of all
authors. All authors have approved the final version of the
manuscript.
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1656−1660. (e) Szlachcic, P.; Kucharek, M.; Jarosz, B.; Danel, A.;
Stadnicka, K. Facile and Regioselective Synthesis of Substituted 1H-
Pyrazolo[3,4-b]quinolines from 2-Fluorobenzaldehydes and 1H-
Pyrazol-5-amines. J. Heterocycl. Chem. 2017, 54, 1729−1745.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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Authors are thankful to Science and Engineering Research
Board (SERB) New Delhi for financial support in the form of
Core Research Grant (File No: CRG/2020/000801). P.Y.
thanks the University Grant Commissions (UGC), New Delhi
(India) for the award of research fellowship. A.A. thanks
Council of Scientific and Industrial Research (CSIR), New
Delhi for fellowship. P.Y. and A.A. gratefully acknowledge the
Banaras Hindu University (BHU) for PhD registration. The
authors are thankful to the Director CBMR for infrastructure.
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