Synthetic protocol toward fused pyrazolone derivatives via a michael addition and reductive ring closing strategy

Article abstract of DOI:10.1021/jo5005795

A new class of pyrazolo[3,4-c]pyridine-3,7-dione and pyrazolo[3,4-d] azepine-3,7-dione scaffolds was synthesized via a Michael addition and reductive cyclization strategy. These fused heterocycles were accessed from simple starting materials such as nitroolefins and 3-ethoxycarbonyl(methylene) pyrazoline-5-one. The pyrazolo-fused heterocycles were obtained in good overall yields.

Full text of DOI:10.1021/jo5005795

Note
pubs.acs.org/joc
Synthetic Protocol toward Fused Pyrazolone Derivatives via a
Michael Addition and Reductive Ring Closing Strategy
Nikita Parekh,†,‡ Joice Thomas,† Jubi John,† Radhika Kusurkar,‡ Wim M. De Borggraeve,†
and Wim Dehaen*,†
†
Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
‡
Department of Chemistry, University of Pune, Pune 411 007, India
S
* Supporting Information
ABSTRACT: A new class of pyrazolo[3,4-c]pyridine-3,7-
dione and pyrazolo[3,4-d]azepine-3,7-dione scaffolds was
synthesized via a Michael addition and reductive cyclization
strategy. These fused heterocycles were accessed from simple
starting materials such as nitroolefins and 3-ethoxycarbonyl-
(methylene)pyrazoline-5-one. The pyrazolo-fused heterocycles
were obtained in good overall yields.
he design and synthesis of novel N-heterocyclic moieties
tion,9c nucleophilic addition of conjugated azoalkenes and
Thas always been an interesting and challenging task for pyrazolinones,9d and palladium-catalyzed carbonylation.9e Only
a few asymmetric transformations using pyrazolone derivatives
as nucleophiles in Michael addition reactions have been
reported.10−13 Other reports on Michael addition of
pyrazolones are reactions with maleimides,14a benzylidene
malononitriles,14b and acyclic aliphatic α,β-unsaturated keto-
nes,14c an organocatalytic amination of pyrazolone,14d and a
one-pot sequential Michael addition/dearomative bromina-
tion.14e
organic chemists as these cores have found wide applications,
most importantly in medicinal chemistry.1 Heterocycles
containing pyrazolone rings belong to a class of molecules
that have been well-studied because of their diverse applications
in drug molecules,2a−c agrochemicals,2d,e voltage-sensitive
dyes,2f,g extraction, and separation of metal ions2h to name a
few. Particularly, they are attractive targets in the field of
medicinal chemistry and drug discovery.3 A literature survey
revealed the presence of a pyrazolone core in a number of
promising pharmaceuticals that exhibit a broad range of
biological properties such as antibacterial,4a antiviral,4b and
anti-inflammatory4c activity. Some examples are edaravone (1),
a potent drug used in the treatment of brain ischemia;5
dipyrone (2), which possesses analgesic and antipyretic
properties;6 2-arylpyrazolo[3,4-c]quinolin-4-ones (3), which
function as adenosine receptor antagonists;7 and pyrazolopyr-
idinedione derivatives (4), which are effective for the treatment
of idiopathic pulmonary fibrosis8 (Figure 1).
It is a well-known fact that pyrazolin-5-ones can exist in
various tautomeric forms.15 Figure 2 shows the different
Figure 2. Possible tautomeric forms of ethyl 5-hydroxy-1-phenyl-1H-
pyrazole-3-carboxylate.
Several reports have appeared on the reactivity of pyrazolone
derivatives in Michael addition, 1,5-migration/Michael additio-
n,9a condensation and substitution reactions,9b C−H activa-
tautomers of ethyl 5-hydroxy-1-phenyl-1H-pyrazole-3-carbox-
ylate. The 1H NMR spectrum revealed the presence of a
mixture of tautomers in CDCl3 and a single tautomer in
DMSO.16 To the best of our knowledge, the pyrazole-3-
carboxylate has never been used as a nucleophile in Michael
additions.
A careful literature study showed that pyrazolones have been
used for the Michael addition reaction, although further
derivatization of the Michael adducts remains unexplored. We
envisaged the use of substituted 5-hydroxy-N-phenyl-1H-
pyrazole-3-carboxylate 2a as a nucleophile for Michael addition
to β-nitrostyrene. This Michael adduct could be then subjected
Received: March 11, 2014
Published: May 5, 2014
Figure 1. Bioactive molecules containing a pyrazolone unit.
© 2014 American Chemical Society
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Note
to a reductive cyclization strategy to furnish a novel class of
heterocycles with a pyridone ring fused to pyrazolone. Herein
we disclose our success in the design and synthesis of pyridone-
fused pyrazolones via a Michael addition−reductive cyclization
pathway (Scheme 1).
Scheme 2. Plausible Reaction Pathway for the Formation of
3a
Scheme 1. Strategy toward Pyridone-Fused Pyrazolones
Intermediate B subsequently abstracts a proton from the
protonated base, after which a C−N tautomeric shift produces
the desired Michael adduct 3a.
Having the optimized protocol in hand (Table 1, entry 6) we
examined the substrate generality with substituted nitroolefins
1a−g and pyrazolones 2a−c (Table 2). The electronic
We initiated our studies of the Michael addition with the use
of β-nitrostyrene (1a) and ethyl 4,5-dihydro-1-phenyl-1H-
pyrazol-5-one-3-carboxylate (2a) using various bases, as
summarized in Table 1. A model reaction was done using 1.0
a
Table 1. Base Evaluation of Michael Addition Reaction
Table 2. DABCO-Mediated Michael Addition of Nitroolefins
a
1a−g and Pyrazolones 2a−c
b
entry
base
equiv
time (h)
yield (%)
1
2
3
4
5
6
7
DMAP
DMAP
−
0.1
1
12
4
52 (incomplete)
64
−
1
12
4
no reaction
pyridine
85
TEA
1
12
4
45
b
entry
olefin 1
pyrazolone 2
product 3
yield (%)
DABCO
DABCO
1
92
1
2
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2a
2b
2c
2a
2c
3a
3b
3c
3d
3e
3f
92
81
85
80
85
74
81
90
76
77
0.1
12
62 (incomplete)
a
Reaction conditions: 1a (0.5 mmol) and 2a (0.5 mmol) in DCM (2
mL) at 25 °C. Isolated yields.
b
3
4
5
equiv of both nitrostyrene 1a and N-substituted pyrazolone 2a
in the presence of a catalytic amount of DMAP in
dichloromethane at room temperature. The reaction was
found to be incomplete even after 12 h, but the desired
Michael adduct 3a was isolated in 52% yield (Table 1, entry 1).
When the base loading was increased to 1 equiv, the reaction
time decreased to 4 h and the desired product was obtained in
64% isolated yield (Table 1, entry 2). It was also observed that
the reaction failed to proceed in the absence of base (Table 1,
entry 3). We were pleased to observe a clean reaction with 85%
yield when pyridine was used as the base (Table 1, entry 4). A
low yield (45%) was observed when triethylamine was used as
the base (Table 1, entry 5). On the other hand, DABCO
mediated the reaction in excellent yield (Table 1, entry 6).
Lowering the base loading made the reaction sluggish (Table 1,
entry 7), probably as a result of catalyst deactivation by
nitronate formation with the product. Although comparable
results were obtained using pyridine and DABCO, it was
desirable to use less toxic, environmentally more friendly
DABCO as the base to mediate the Michael reaction.
6
7
1a
1a
1g
1g
3g
3h
3i
8
9
10
3j
a
Reaction conditions: 1 (0.5 mmol) and 2 (0.5 mmol) in DCM (2
b
mL) at 25 °C. Isolated yields.
properties did not much influence the reaction rate, and the
reactions of 1b and 1c with 2a afforded the products 3b and 3c
in excellent yields. Moreover, aliphatic and heteroaromatic
nitroalkenes 1d and 1e gave the corresponding nitro adducts
3d and 3e. When α,β-disubstituted nitroalkene 1f was used, 1H
NMR analysis of the crude reaction mixture showed the
presence of diastereomers (1:0.9). After column purification we
could only isolate a single diastereomer in a slightly lower yield
(Table 2, entry 6). N-Methyl-substituted pyrazolone 2b (Table
2, entry 7) also readily participated in the reaction, giving an
81% yield of 3g. The insertion of one −CH2− unit in the
pyrazolone (Table 2, entry 8) was also tolerated well in the
reaction. The Michael additions with sterically hindered
nitroalkene 1g (Table 2, entries 9 and 10) showed very good
diastereoselectivity (>99%), affording the adducts 3i and 3j in
good yields.
On the basis of these results, a plausible mechanism for the
efficient formation of Michael adduct 3a is illustrated in Scheme
2. In the first step, deprotonation of pyrazalone 2a by the base
leads to carbanion A, which then undergoes an intermolecular
Michael addition to nitroolefin 1a to afford intermediate B.
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Note
Table 3. Reductive Cyclization of Michael Adducts 3a−ga
Scheme 3. Synthesis of a Seven-Membered Fused Heterocycle and a Tetracyclic Fused System
It is important to note that for all of the Michael adducts
shown in Table 2, distinct line broadening in the H NMR
solvent at reflux temperature afforded the corresponding
product 4a in 69% isolated yield (Table 3). However, the
one-pot reductive cyclization strategy using zinc/acetic acid
gave a low yield of product 4a, which was difficult to separate
from excess zinc. Therefore, the scope of Michael adducts was
studied using the optimized protocol as shown in Table 3. By
this procedure, we successfully prepared fused pyrazolo[3,4-
c]pyridine-3,7-diones 4a−g from Michael adducts 3a−g in
satisfactory overall yields (Table 3). Surprisingly, a single
diastereomer 4f was obtained in 65% isolated yield starting
from the Michael adduct 3f. This presumably arises through
deprotonation of 3f, giving a nitronate that upon reduction
gives a single diastereomeric amine. From the NMR experi-
ments we were able to confirm the product 4f to have the trans
geometry (see the Supporting Information).
Seven-membered heterocycles form an important framework
in many biologically active drugs.17 Key examples that belong
to this class include diazepam, dibenzazepine, and oxcarbaze-
pine. The present methodology provides an interesting access
toward fused seven-membered heterocycles (Scheme 3). We
started from the above-synthesized Michael adduct 3h, which
1
spectrum was typically observed for benzylic and methylene
protons. This most likely is due to the simultaneous presence of
several tautomers that are in dynamic equilibrium on the time
scale of the NMR experiment (intermediate exchange regime).
1
The H NMR spectrum in the presence of DABCO proved to
be simpler because of an increase in the rates of these dynamic
processes (fast exchange). In all of the structural formulas, for
simplicity we have written only the −NH tautomer.
Starting from Michael adducts 3a, we proceeded with the
reduction of the nitro group to an amine followed by
intramolecular cyclization. A few reduction methods to give
the corresponding amines were tried, including NaBH4/NiCl2,
Raney Ni/H2, zinc/acetic acid, and Pd/H2. In practice, isolation
of the amine was difficult because of low solubility during the
NaBH4/NiCl2 procedure, which uses MeOH as the solvent. By
using either Raney Ni/H2 or zinc/acetic acid we were able to
reduce the nitro compound to an amine effectively. The
prepared amine was then subjected to cyclization without
further purification. Further optimization in 3:2 toluene/AcOH
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Note
Scheme 4. Synthetic Utility of Michael Adduct 3a
1. The compound ethyl 5-hydroxy-1-phenyl-1H-pyrazole-3-car-
boxylate (2a) can exist in several tautomeric forms (A−C) in
solution. NMR spectra for 2a in DMSO-d6, CDCl3, and CDCl3
with DABCO were recorded.
underwent reductive cyclization to form substituted pyrazolo-
[4,3-d]azepine-3,7-dione heterocycle 4h in 51% isolated yield.
Michael adduct 3i could easily undergo reduction to the
corresponding amine, but the formation of the targeted
compound 4i failed (Scheme 3). In order to force the
cyclization we tried using the more acidic CF3COOH instead
of CH3COOH as well as using a high-boiling solvent such as
xylene. Unfortunately, these attempts also did not furnish the
cyclized product. A possible explanation could be that the
conformation of the molecule is such that the ester and the
amine functionalities are too far away from each other to allow
cyclization. It was thought that Michael adduct 3j in which a
methylene group is inserted between the ester and pyrazolone
unit would bring some flexibility so as to facilitate cyclization.
We were indeed able to synthesize the tetracyclic fused
pyrazolone compound 4j in satisfactory yield.
2. In DMSO-d6, it exist in one tautomeric form i.e either B or C;
in CDCl3, mixture of two tautomer i.e A and B/C; in CDCl3-
DABCO its B/C.
3. The 1H NMR and 13C NMR spectra for compound 2a in
CDCl3, DMSO-d6, and CDCl3 with DABCO are below.
4. For convenience, we present the −NH tautomeric form
(structure C) for all of the compounds.
We decided to investigate the further utility of these Michael
adducts by introducing an additional point of diversity. The
primary amine from 3a was transformed into secondary amine
5 using standard conditions via imine formation followed by
reduction. Secondary amine 5 without any purification was
subjected to cyclization in toluene/AcOH to give the desired
fused six-membered pyrazolopyridinone 6 in 49% overall yield
(Scheme 4) with increased solubility in organic solvents.
In conclusion, we have developed a facile methodology for
the synthesis of novel fused pyrazolo[3,4-c]pyridine-3,7-diones
via Michael addition followed by reductive cyclization starting
from pyrazolones and nitroalkenes. In the case where two
stereocenters are present, the reaction occurs in a diaster-
eoselective manner. Interestingly, we were also successful in
building pyrazolo[3,4-d]azepine-3,7(4H,8H)-dione and rigid
tetracyclic substituted pyrazolone derivatives and in introducing
an additional point of diversity by reductive amination prior to
cyclization.
Synthetic Procedures and Characterization Data. Syntheses
of 1 and 2. The nitroalkenes18 (1a−g) and pyrazolone derivatives19
(2a−c) were prepared according to literature methods.
General Procedure for the Synthesis of Michael Adducts (3a−j).
Pyrazolone 2 (1 mmol), nitroalkene 1 (1 mmol), and DABCO (1
mmol) were stirred in dry DCM (5 mL) under N2 at room
temperature for 4 h. The reaction progress was monitored by TLC.
When the reaction was complete, the DCM was evaporated off. The
crude sample was purified by column chromatography on silica gel
(with petroleum ether/ethyl acetate as the eluent) to afford the
corresponding Michael adduct 3.20
Ethyl 4-(2-Nitro-1-phenylethyl)-5-oxo-1-phenyl-2,5-dihydro-1H-
pyrazole-3-carboxylate (3a). ((E)-2-Nitrovinyl)benzene (1a) (100
mg, 0.67 mmol), ethyl 2,5-dihydro-5-oxo-1-phenyl-1H-pyrazole-3-
carboxylate (2a) (156 mg, 0.67 mmol), DABCO (75 mg, 0.67
mmol), and DCM (5 mL) were used. The product was obtained as a
light-yellow solid (242 mg) in 92% yield. Mp 41−43 °C; Rf 0.30
(hexane/ethyl acetate = 6:4); MS (EI) m/z 381 (M+); HRMS (EI)
1
calcd for C20H19N3O5 381.1324, found m/z 381.1325; H NMR (400
MHz, CDCl3 with DABCO) δ 9.3 (bs, 1H), 7.74 (d, 2H, J = 8.0 Hz),
7.47 (d, 2H, J = 7.6 Hz), 7.40−7.36 (m, 2H), 7.28−7.17 (m, 4H),
5.55−5.52 (m, 1H), 5.46−5.44 (m, 1H), 5.0 (dd, 1H, J = 12.1, 6.3
Hz), 4.35 (q, 2H, J = 7.0 Hz), 1.35 (t, 3H, J = 7.3 Hz); 13C NMR (100
MHz, CDCl3 with DABCO) δ 163.6, 157.5, 141.2, 140.2, 139.2, 132.1,
129.4, 129.1, 128.8, 128.4, 127.9, 126.6, 126.4, 123.8, 100.8, 77.8, 60.6,
39.2, 14.3.
Ethyl 4-(1-(4-Methoxyphenyl)-2-nitroethyl)-5-oxo-1-phenyl-2,5-
dihydro-1H-pyrazole-3-carboxylate (3b). 1-Methoxy-4-((E)-2-
nitrovinyl)benzene (1b) (100 mg, 0.56 mmol), ethyl 2,5-dihydro-5-
oxo-1-phenyl-1H-pyrazole-3-carboxylate (2a) (129 mg, 0.56 mmol),
DABCO (62 mg, 0.56 mmol), and DCM (5 mL) were used. The
product was obtained as a green solid (184 mg) in 81% yield. Mp 48−
50 °C; Rf 0.23 (hexane/ethyl acetate = 6:4); MS (EI) m/z 411 (M+);
HRMS (EI) calcd for C21H21N3O6 411.1453, found m/z 411.1449; 1H
NMR (300 MHz, CDCl3 with DABCO) δ 8.42 (bs, 1H), 7.82−7.78
(m, 2H), 7.43−7.38 (m, 4H), 7.27−7.23 (m, 1H), 6.82 (d, 2H, J = 8.6
Hz), 5.64−5.57 (m, 1H), 5.42−5.36 (m, 1H), 4.92 (dd, 1H, J = 12.1,
6.2 Hz), 4.40−4.32 (m, 2H), 3.76 (s, 3H), 1.37 (t, 3H, J = 7.0 Hz);
EXPERIMENTAL SECTION
■
General Experimental Methods. NMR spectra were acquired on
commercial instruments (300 and 400 MHz), and chemical shifts (δ)
are reported in parts per million (ppm) referenced to tetramethylsilane
(1H) or the internal (NMR) solvent signal (13C). Mass spectra (EI, 70
eV ionization energy) were acquired. Exact mass measurements were
performed in the EI mode at a resolution of 10 000 and also on a
quadrupole orthogonal acceleration time-of-flight mass spectrometer.
Samples were infused at 3 μL/min, and spectra were obtained in
positive (or negative) ionization mode with a resolution of 15 000
(fwhm) using leucine enkephalin to lock the mass. Melting points (not
corrected) were determined using a Reichert Thermovar apparatus.
For column chromatography, 70@230 mesh silica 60 (E. M. Merck)
was used as the stationary phase. Chemicals received from commercial
sources were used without further purification. Solvents used in
reactions were used as received.
Important Notes.
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Note
13C NMR (75 MHz, CDCl3 with DABCO) δ 163.8, 158.3, 158.3,
140.4, 139.5, 133.6, 129.0, 128.9, 126.3, 123.9, 113.8, 100.6, 78.1, 60.6,
55.3, 38.9, 14.5.
7.22−7.13 (m, 3H), 5.37−5.26 (m, 2H), 5.03 (dd, 1H, J = 9.1, 3.7
Hz), 4.32−4.25 (m, 2H), 3.55 (s, 3H), 1.31 (t, 3H, J = 7.3 Hz); 13C
NMR (75 MHz, CDCl3 with DABCO) δ 163.3, 155.8, 140.7, 137.9,
128.4, 127.8, 126.8, 101.9, 78.1, 60.7, 39.2, 33.7, 14.4.
Ethyl 4-(1-(4-(Methoxycarbonyl)phenyl)-2-nitroethyl)-5-oxo-1-
phenyl-2,5-dihydro-1H-pyrazole-3-carboxylate (3c). Methyl 4-((E)-
2-nitrovinyl)benzoate (1c) (53 mg, 0.25 mmol), ethyl 2,5-dihydro-5-
oxo-1-phenyl-1H-pyrazole-3-carboxylate (2a) (60 mg, 0.25 mmol),
DABCO (29 mg, 0.25 mmol), and DCM (5 mL) were used. The
product was obtained as a yellow semisolid (96 mg) in 85% yield. Rf
0.24 (hexane/ethyl acetate = 6:4); MS (EI) m/z 439 (M+); HRMS
Ethyl 2-(2,5-Dihydro-4-(2-nitro-1-phenylethyl)-5-oxo-1-phenyl-
1H-pyrazol-3-yl)acetate (3h). ((E)-2-Nitrovinyl)benzene (1a) (200
mg, 1.34 mmol), ethyl 2-(2,5-dihydro-5-oxo-1-phenyl-1H-pyrazol-3-
yl)acetate (2c) (330 mg, 1.34 mmol), DABCO (150 mg, 1.34 mmol),
and DCM (10 mL) were used. The product was obtained as a yellow
solid (420 mg) in 90% yield. Mp 100−102 °C; Rf 0.26 (hexane/ethyl
acetate = 6:4); MS (EI) m/z 395 (M+); HRMS (EI) calcd for
1
(EI) calcd for C22H21N3O7 439.1379, found m/z 439.1377; H NMR
1
C21H21N3O5 395.1481, found m/z 395.1476; H NMR (600 MHz,
(300 MHz, CDCl3 with DABCO) δ 9.1 (bs, 1H), 7.96−7.93 (m, 2H),
7.77 (d, 2H, J = 8.1 Hz), 7.56 (d, 2H, J = 8.2 Hz) 7.41 (t, 2H, J = 7.5
Hz), 7.27−7.22 (m, 1H), 5.65−5.58 (m, 1H), 5.51−5.46 (m, 1H),
4.99 (dd, 1H, J = 11.8, 5.9 Hz), 4.38−4.31 (m, 2H), 3.88 (s, 3H), 1.35
(t, 3H, J = 7.1 Hz); 13C NMR (75 MHz, CDCl3 with DABCO) δ
167.0, 163.7, 158.6, 146.8, 140.3, 139.5, 129.8, 128.9, 128.5, 128.0,
126.5, 124.0, 99.4, 77.3, 60.7, 52.1, 39.5, 14.5.
CDCl3 with DABCO) δ 8.6 (bs, 1H); 7.73 (d, 2H, J = 8.1 Hz), 7.42−
7.36 (m, 4H), 7.28 (t, 2H, J = 8.1 Hz), 7.20−7.15 (m, 2H), 5.35 (dd,
1H, J = 12.4, 8.8 Hz), 4.99−4.96 (m, 1H), 4.74−4.72 (m, 1H), 4.04−
4.02 (m, 2H), 3.5 (s, 2H), 1.58 (t, 3H, J = 7.3 Hz); 13C NMR (150
MHz, CDCl3 with DABCO) δ 170.9, 156.8, 144.6, 140.8, 139.7, 132.2,
129.4, 129.2, 128.8, 128.5, 127.9, 126.7, 125.3, 122.8, 77.8, 60.9, 39.9,
34.6, 14.1.
Ethyl 2,5-Dihydro-4-(1-nitropentan-2-yl)-5-oxo-1-phenyl-1H-pyr-
azole-3-carboxylate (3d). (E)-1-nitropent-1-ene (1d) (25 mg, 1.74
mmol), ethyl 2,5-dihydro-5-oxo-1-phenyl-1H-pyrazole-3-carboxylate
(2a) (50 mg, 1.74 mmol), DABCO (24 mg, 1.74 mmol), and DCM
(4 mL) were used. The product was obtained as a yellow viscous oil
(59 mg) in 80% yield. Rf 0.34 (hexane/ethyl acetate = 6:4); MS (EI)
m/z 347 (M+); HRMS (EI) calcd for C17H21N3O5 347.1481, found m/
Ethyl 2,5-Dihydro-4-(1,2,3,4-tetrahydro-2-nitronaphthalen-1-yl)-
5-oxo-1-phenyl-1H-pyrazole-3-carboxylate (3i). 1,2-Dihydro-3-nitro-
naphthalene (1g) (46 mg, 0.26 mmol), ethyl 2,5-dihydro-5-oxo-1-
phenyl-1H-pyrazole-3-carboxylate (2a) (61 mg, 0.26 mmol), DABCO
(29 mg, 0.26 mmol), and DCM (3 mL) were used. The product was
obtained as a light-yellow solid (81 mg) in 76% yield. Mp 80−82 °C;
Rf 0.35 (hexane/ethyl acetate = 6:4); MS (EI) m/z 407 (M+); HRMS
1
z 347.1485; H NMR (300 MHz, CDCl3 with DABCO) δ 9.6 (bs,
1
(EI) calcd for C22H21N3O5 407.1481, found m/z 407.1476; H NMR
1H), 7.73−7.70 (m, 2H), 7.41−7.35 (m, 2H), 7.26- 7.22 (m, 1H),
5.11−5.03 (m, 1H), 4.61 (dd, 1H, J = 11.4, 5.6 Hz), 4.37 (q, 2H, J =
7.1 Hz), 3.90−3.85 (m, 1H), 1.89−1.82 (m, 1H), 1.64−1.57 (m, 1H),
1.39 (t, 3H, J = 7.0 Hz), 1.33−1.25 (m, 2H), 0.87 (t, 3H, J = 7.1 Hz);
13C NMR (75 MHz, CDCl3 with DABCO) δ 164.1, 158.1, 140.5,
(600 MHz, CDCl3 with DABCO) δ 7.86 (d, 2H, J = 7.5 Hz) 7.40 (t,
2H, J = 7.8 Hz), 7.27−7.22 (m, 1H), 7.09−7.04 (m, 4H), 6.36 (bs,
1H), 5.71 (ddd (observed as dt), 1H, J = 11.1, 11.2, 3.4 Hz), 5.14−
5.12 (m, 1H), 4.25 (q, 2H, J = 6.8 Hz), 3.15−3.00 (m, 2H), 2.54−2.44
(m, 2H), 1.24 (t, 3H, J = 7.1 Hz); 13C NMR (150 MHz, CDCl3 with
DABCO) δ 163.6, 158.9, 140.8, 139.6, 138.3, 134.5, 128.9, 128.8,
128.7, 128.3, 127.8, 126.3, 126.1, 125.6, 123.5, 101.6, 87.1, 60.5, 39.7,
29.3, 28.4, 14.3.
Ethyl 2-(2,5-Dihydro-4-(1,2,3,4-tetrahydro-2-nitronaphthalen-1-
yl)-5-oxo-1-phenyl-1H-pyrazol-3-yl)acetate (3j). 1,2-Dihydro-3-ni-
tronaphthalene (1g) (50 mg, 0.28 mmol), ethyl 2-(2,5-dihydro-5-
oxo-1-phenyl-1H-pyrazol-3-yl)acetate (2c) (70 mg, 0.28 mmol),
DABCO (32 mg, 0.28 mmol), and DCM (2 mL) were used. The
product was obtained as a yellow solid (92 mg) in 77% yield. Mp 41−
43 °C; Rf 0.31 (hexane/ethyl acetate = 6:4); MS (EI) m/z 421 (M+);
HRMS (EI) calcd for C23H23N3O5 421.1637, found m/z 421.1640; 1H
NMR (300 MHz, CDCl3) δ 7.63 (d, 2H, J = 7.9 Hz), 7.36 (t, 2H, J =
7.9 Hz), 7.26−6.99 (m, 5H), 5.41 (bs, 1H), 4.61−4.58 (bs, 1H), 4.21
(q, 2H, J = 7.1 Hz), 3.61 (bs, 2H), 3.12−2.94 (m, 2H), 2.58−2.30 (m,
2H), 1.30 (t, 3H, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3 with
DABCO) δ 171.2, 156.7, 144.9, 139.9, 137.7, 134.7, 129.6, 128.7,
128.1, 126.4, 125.9, 125.1, 122.4, 99.4, 87.1, 60.9, 39.4, 34.5, 29.2, 28.3,
14.2.
General Procedure for Reductive Cyclization (4a−h and 4j). To a
stirred solution of Michael adduct 3 (1 mmol) in acetic acid (5 mL)
was added zinc dust (10 mmol). The reaction mixture was stirred for 2
h at room temperature. After completion of the reaction, the reaction
mixture was filtered through Celite. The filtrate was concentrated and
subjected to cyclization by addition of 3:2 toluene/acetic acid and
refluxing at 120 °C for 24 h. The reaction mixture was concentrated,
and the residue was quenched with saturated NaHCO3 solution and
further washed with organic solvents such as DCM and Et2O. The
residue was concentrated to afford the pure product (4a−g) or
purification was done by column chromatography using 95:5 EtOAc/
MeOH as the eluent (4h and 4j).21
2,4-Diphenyl-5,6-dihydro-1H-pyrazolo[3,4-c]pyridine-3,7(2H,4H)-
dione (4a). Michael adduct 3a (54 mg) was used. The product was
obtained as a white solid (32 mg) in 69% overall yield (two steps). Mp
>250 °C (compound decomposes above 250 °C); MS (EI) m/z 305
(M+); HRMS (EI) calcd for C18H15N3O2 305.1164, found m/z
305.1166; 1H NMR (300 MHz, DMSO-d6) δ 12.14 (bs, 1H), 7.78 (d,
2H, J = 7.7 Hz), 7.48 (t, 3H, J = 7.5 Hz), 7.33−7.26 (m, 3H), 7.22−
7.14 (m, 3H), 4.19 (s, 1H), 3.79 (dd, 1H, J = 12.8, 4.7 Hz), one proton
139.6, 128.8, 126.3, 123.7, 101.3, 79.3, 60.6, 34.9, 34.1, 20.9, 14.5, 14.1.
Ethyl 2,5-Dihydro-4-(2-nitro-1-(thiophen-2-yl)ethyl)-5-oxo-1-phe-
nyl-1H-pyrazole-3-carboxylate (3e). 2-((E)-2-nitrovinyl)thiophene
(1e) (33 mg, 0.22 mmol), ethyl 2,5-dihydro-5-oxo-1-phenyl-1H-
pyrazole-3-carboxylate (2a) (50 mg, 0.22 mmol), DABCO (24 mg,
0.22 mmol), and DCM (5 mL) were used. The product was obtained
as a yellow viscous oil (70 mg) in 85% yield. Rf 0.31 (hexane/ethyl
acetate = 6:4); MS (EI) m/z 387 (M+); HRMS (EI) calcd for
1
C18H17N3O5S 387.0888, found m/z 387.0880; H NMR (300 MHz,
CDCl3 with DABCO) δ 9.76 (bs, 1H), 7.68 (bs, 2H), 7.35−7.33 (m,
2H), 7.27−7.21 (m, 1H), 7.10−7.09 (m, 1H), 6.94−6.87 (m, 2H),
5.60−5.59 (bm, 1H), 5.44−5.40 (bm, 1H), 5.07 (dd, 1H, J = 12.2, 6.6
Hz), 4.34 (q, 2H, J = 7.1 Hz), 1.36−1.32 (m, 3H); 13C NMR (75
MHz, CDCl3 with DABCO) δ 163.4, 156.8, 144.5, 140.01, 138.9,
134.7, 132.2, 131.7, 128.8, 126.8, 124.5, 124.0, 123.6, 101.3, 78.2, 60.8,
34.8, 14.4.
Ethyl 4-(2-Nitro-1-phenylpropyl)-5-oxo-1-phenyl-2,5-dihydro-1H-
pyrazole-3-carboxylate (3f). ((E)-2-nitroprop-1-enyl)benzene (1f)
(100 mg, 0.61 mmol), ethyl 2,5-dihydro-5-oxo-1-phenyl-1H-pyrazole-
3-carboxylate (2a) (142 mg, 0.61 mmol), DABCO (68 mg, 0.61
mmol), and DCM (5 mL) were used. The product was obtained as an
off-white solid (179 mg) in 74% yield as a single diastereomer. Mp
151−153 °C; Rf 0.33 (hexane/ethyl acetate = 6:4); MS (EI) m/z 395
(M+); HRMS (EI) calcd for C21H21N3O5 395.1481, found m/z
1
395.1487; H NMR (300 MHz, CDCl3 with DABCO) δ 7.72−7.66
(m, 4H), 7.43−7.30 (m, 2H), 7.27−7.17 (m, 4H), 6.20−6.14 (m, 1H),
5.09 (d, 1H, J = 11.4 Hz), 4.42−4.36 (m, 2H), 1.43−1.38 (m, 6H);
13C NMR (75 MHz, CDCl3 with DABCO) δ 163.9, 157.9, 141.8,
140.3, 139.6, 128.9, 128.6, 128.2, 128.1, 126.8, 126.4, 126.3, 124.4,
123.7, 101.8, 84.8, 60.5, 19.8, 14.5.
Ethyl 2,5-Dihydro-1-methyl-4-(2-nitro-1-phenylethyl)-5-oxo-1H-
pyrazole-3-carboxylate (3g). ((E)-2-Nitrovinyl)benzene (1a) (43
mg, 0.29 mmol), ethyl 2,5-dihydro-1-methyl-5-oxo-1H-pyrazole-3-
carboxylate (2b) (50 mg, 0.29 mmol), DABCO (33 mg, 0.29
mmol), and DCM (6 mL) were used. The product was obtained as a
greenish-yellow solid (76 mg) in 81% yield. Mp 54−56 °C; Rf 0.29
(hexane/ethyl acetate = 1:9); MS (EI) m/z 319 (M+); HRMS (EI)
1
calcd for C15H17N3O5 319.1168, found m/z 319.1164; H NMR (300
MHz, CDCl3 with DABCO) δ 9.57 (bs, 1H), 7.36−7.28 (m, 2H),
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The Journal of Organic Chemistry
Note
overlapped with the solvent peak; 13C NMR (75 MHz, CDCl3) δ
163.2, 157.6, 143.9, 141.8, 140.9, 128.2, 127.6, 127.5, 125.7, 123.8,
123.0, 102.6, 48.3, 34.5.
3.59 (s, 3H), 3.29 (m, 1H, merged in the H2O peak); 13C NMR (150
MHz, DMSO-d6) δ 161.8, 148.6, 142.4, 140.1, 128.0, 127.5, 126.3,
101.1, 54.9, 48.6, 34.6.
4-(4-Methoxyphenyl)-2-phenyl-5,6-dihydro-1H-pyrazolo[3,4-c]-
pyridine-3,7(2H,4H)-dione (4b). Michael adduct 3b (60 mg) was
used. The product was obtained as a gray solid (35 mg) in 72% overall
yield (two steps). Mp >260 °C (compound decomposes above 260
°C); MS (ESI) m/z 358 ([M + Na]+); HRMS (ESI) calcd for
2,4-Diphenyl-1,2,4,5,6,8-hexahydropyrazolo[3,4-d]azepine-3,7-
dione (4h). Michael adduct 3h (65 mg) was used. The product was
obtained as a white solid (26 mg) in 51% overall yield (two steps). Mp
>280 °C (compound decomposes above 280 °C); MS (EI) m/z 319
(M+); HRMS (EI) calcd for C19H17N3O2 319.1320, found m/z
1
C19H17N3O3 358.1167 ([M + Na]+), found m/z 358.1162; H NMR
1
319.1323; H NMR (600 MHz, MeOD) δ 7.61 (d, 2H, J = 7.5 Hz),
(400 MHz, MeOD) δ 7.92 (d, 2H, J = 7.6 Hz); 7.39−7.16 (m, 5H),
6.79 (d, 2H, J = 8.5 Hz), 4.08−4.07 (m, 1H), 3.88 (dd, 1H, J = 12.3,
5.0 Hz), 3.73 (s, 3H), 3.46 (dd, 1H, J = 12.3, 2.2 Hz); 13C NMR (100
MHz, MeOD) δ 166.9, 161.4, 161.0, 159.7, 142.8, 141.9, 136.6, 129.8,
129.4, 126.1, 123.4, 114.5, 101.9, 55.6, 50.9, 36.2.
7.44 (t, 2H, J = 7.5 Hz), 7.31−7.27 (m, 3H), 7.22−7.19 (m, 3H), 4.06
(bs, 1H), 3.92−3.77 (m, 3H), 3.56−3.52 (m, 1H); 13C NMR (150
MHz, DMSO-d6) δ 173.1, 162.3, 144.8, 142.5, 141.5, 128.1, 127.9,
127.8, 127.4, 125.2, 121.2, 117.6, 47.3, 41.6, 37.5.
2-Phenyl-2,3,4,6,6a,7,8,12b-octahydronaphtho[2,1-b]pyrazolo-
[4,3-d]azepine-1,5-dione (4j). Michael adduct 3j (70 mg) was used.
The product was obtained as a light-brown solid (32 mg) in 56%
overall yield (two steps). Mp >250 °C (compound decomposes above
250 °C); MS (EI) m/z 345 (M+); HRMS (EI) calcd for C21H19N3O2
345.1477, found m/z 345.1478; 1H NMR (300 MHz, MeOD) δ 7.73−
7.72 (m, 2H), 7.48−7.50 (m, 2H), 7.35−7.33 (m, 1H), 7.16−7.13 (m,
4H), 4.18 (d, 1H, J = 7.1 Hz), 3.87−3.86 (m, 2H), 3.20 (d, 1H, J = 7.3
Hz), 3.10−3.01 (m, 2H), 2.34−2.31 (m, 1H), 2.07−2.04 (m, 1H); 13C
NMR (75 MHz, MeOD) δ 175.2, 159.9, 131.9, 130.2, 129.8, 128.8,
127.7, 127.6, 127.0, 126.8, 126.5, 120.1, 53.9, 52.9, 42.6, 29.2, 28.2.
Synthesis of 6-Benzyl-2,4-diphenyl-5,6-dihydro-1H-pyrazolo[3,4-
c]pyridine-3,7(2H,4H)-dione (6). To a stirred solution of nitro adduct
3a (50 mg) in methanol (10 mL) was cautiously added a 50% (w/w)
aqueous slurry of Raney nickel (100 mg). The reaction mixture was
stirred under a H2 balloon at rt for 24 h. The reaction mixture was
filtered through a pad of Celite, and the pad was rinsed with MeOH
(10 mL). The filtrate was concentrated under reduced pressure to give
a quantitative yield of the amine as a white solid.
Methyl 4-(3,7-Dioxo-2-phenyl-2,3,4,5,6,7-hexahydro-1H-
pyrazolo[3,4-c]pyridin-4-yl)benzoate (4c). Michael adduct 3c (50
mg) was used. The product was obtained as an brown solid (29 mg) in
70% overall yield (two steps). Mp >250 °C (compound decomposes
above 250 °C); MS (ESI) m/z 386 ([M + Na]+); HRMS (ESI) calcd
1
for C20H17N3O4 386.1116 ([M + Na]+), found m/z 386.1110; H
NMR (300 MHz, MeOD) δ 8.20 (d, 2H, J = 7.7 Hz), 7.82 (d, 2H, J =
8.2 Hz), 7.39 (d, 2H, J = 8.2 Hz), 7.27 (t, 2H, J = 7.5 Hz), 7.16−7.14
(m, 1H), 6.98 (t, 1H, J = 7.1 Hz), 3.9 (bs, 1H), 3.82 (s, 3H), 3.71 (dd,
1H, J = 12.4, 5.1 Hz), 3.34−3.29 (m, 1H); 13C NMR (75 MHz,
MeOD) δ 166.3, 164.1, 161.2, 150.7, 142.2, 141.6, 128.6, 128.1, 128.0,
127.9, 127.1, 122.2, 118.4, 96.4, 51.9, 48.1, 35.5.
2-Phenyl-4-propyl-5,6-dihydro-1H-pyrazolo[3,4-c]pyridine-3,7-
(2H,4H)-dione (4d). Michael adduct 3d (50 mg) was used. The
product was obtained as an off-white solid (26 mg) in 69% overall
yield (two steps). Mp >270 °C (compound decomposes above 270
°C); MS (EI) m/z 271 (M+); HRMS (EI) calcd for C15H17N3O2
1
271.1320, found m/z 271.1316; H NMR (400 MHz, MeOD) δ 7.55
(d, 2H, J = 7.8 Hz), 7.38 (t, 2H, J = 7.8 Hz), 7.28 (d, 1H, J = 7.6 Hz),
3.57 (dd, 1H, J = 12.8, 5.0 Hz), 3.35 (dd, 1H, J = 12.8, 3.3 Hz), 2.85
(bs, 1H), 1.68−1.65 (m, 1H), 1.50−1.42 (m, 3H), 0.94 (t, 3H, J = 7.2
Hz); 13C NMR (100 MHz, MeOD) δ 165.8, 156.8, 141.1, 139.6,
129.6, 127.8, 124.8, 95.5, 47.3, 36.3, 31.5, 21.4, 14.5.
To the stirred solution of the amine (42 mg, 0.12 mmol, 1 equiv) in
methanol (5 mL) were added benzaldehyde (14 mg, 0.13 mmol, 1.1
equiv) and molecular sieves (nos. 5−6) at room temperature. The
reaction mixture was heated at 60 °C for 6 h. After completion of the
reaction, the reaction mass was cooled to room temperature, and to it
was added sodium cyanoborohydride (38 mg, 0.60 mmol, 5 equiv).
Further, the reaction mass was stirred for 24 h at rt. The reaction was
quenched by addition of water, and the aqueous layer was extracted
with ethyl acetate. The organic layer was dried over MgSO4 and
concentrated. Without any further purification, it was subjected to
cyclization in 3:2 toluene/acetic acid by refluxing for 24 h. The
reaction mixture was concentrated and washed with a saturated
solution of NaHCO3. The pure compound was precipitated in
petroleum ether. The product was obtained as a light-brown solid (24
mg) in 49% overall yield (three steps). Mp >140 °C (compound
decomposes above 140 °C); MS (EI) m/z 395 (M+); HRMS (EI)
2-Phenyl-4-(thiophen-2-yl)-5,6-dihydro-1H-pyrazolo[3,4-c]-
pyridine-3,7(2H,4H)-dione (4e). Michael adduct 3e (50 mg) was used.
The product was obtained as a white solid (31 mg) in 75% overall
yield (two steps). Mp >280 °C (compound decomposes above 280
°C); MS (EI) m/z 311 (M+); HRMS (EI) calcd for C16H13N3O2S
1
311.0728, found m/z 311.0725; H NMR (300 MHz, DMSO-d6) δ
12.47 (bs, 1H), 7.79 (d, 2H, J = 7.7 Hz), 7.63 (bs, 1H), 7.46 (t, 2H, J =
7.7 Hz), 7.30−7.29 (m, 2H), 6.92 (bs, 1H), 6.82 (bs, 1H) 4.44 (s,
1H), 3.77−3.78 (m, 1H), 1H merged in the DMSO-d6 water peak; 13
C
NMR (75 MHz, DMSO-d6) δ 162.7, 157.4, 148.5, 140.9, 140.5, 128.3,
126.4, 124.3, 124.1, 123.4, 120.6, 101.6, 48.9, 30.4.
1
(4S,5R)-5-Methyl-2,4-diphenyl-5,6-dihydro-1H-pyrazolo[3,4-c]-
pyridine-3,7(2H,4H)-dione (4f). Michael adduct 3f (60 mg) was used.
The product was obtained as a white solid (31 mg) in 65% overall
yield as single diastereomer (two steps). Mp >280 °C (compound
decomposes above 280 °C); MS (EI) m/z 319 (M+); HRMS (EI)
calcd for C25H21N3O2 395.1633, found m/z 395.1634; H NMR (300
MHz, MeOD) δ 7.79 (d, 2H, J = 6.6 Hz), 7.43−7.27 (m, 6H), 7.16−
6.99 (m, 7H), 4.74 (d, 1H, J = 14.7 Hz), 4.38 (d, 1H, J = 14.5 Hz),
4.16 (s, 2H), 3.94 (d, 1H, J = 10.1 Hz), 3.47 (d, 1H, J = 12.1 Hz); 13C
NMR (75 MHz, MeOD) δ 163.9, 159.8, 143.1, 143.0, 140.3, 137.8,
136.3, 132.5, 131.0, 130.5, 130.2, 129.8, 129.4, 129.3, 128.8, 128.6,
128.2, 127.7, 123.9, 102.5, 56.6, 50.5, 36.4.
1
calcd for C19H17N3O2 319.1320, found m/z 319.1321; H NMR (400
MHz, DMSO-d6) δ 11.44 (bs, 1H), 7.77 (d, 2H, J = 8.5 Hz), 7.66 (bs,
1H), 7.49 (t, 2H, J = 7.6 Hz), 7.35−7.28 (m, 3H), 7.23−7.16 (m, 3H),
4.04 (s, 1H), 3.66−3.63 (m, 1H), 1.27 (d, 3H, J = 6.6 Hz); 13C NMR
(100 MHz, DMSO-d6) δ 160.6, 149.5, 142.8, 141.6, 138.6, 128.9,
128.2, 127.5, 126.5, 126.4, 121.9, 100.9, 55.4, 40.9, 22.9. Assignment of
stereochemistry: From the NOESY experiment we concluded that the
methyl protons are correlated with the benzylic proton (see the
NOESY spectrum on p S23 in the Supporting Information).
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of the novel precursors. This material
is available free of charge via the Internet at http://pubs.acs.org.
2-Methyl-4-phenyl-5,6-dihydro-1H-pyrazolo[3,4-c]pyridine-3,7-
(2H,4H)-dione (4g). Michael adduct 3g (50 mg) was used. The
product was obtained as a white solid (19 mg) in 52% overall yield
(two steps). Mp >250 °C (compound decomposes above 250 °C);
MS (EI) m/z 243 (M+); HRMS (EI) calcd for C13H13N3O2 243.1007,
found m/z 243.1001; H NMR (600 MHz, DMSO-d6) δ 10.99 (bs,
1H), 7.32 (bs, 1H), 7.27 (t, 2H, J = 7.4 Hz), 7.19 (t, 1H, J = 7.4 Hz),
7.10 (d, 2H, J = 7.4 Hz), 4.10 (bs, 1H), 3.72 (dd, 1H, J = 12.4, 4.7 Hz),
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wim.dehaen@chem.kuleuven.be.
1
Notes
The authors declare no competing financial interest.
5343
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The Journal of Organic Chemistry
Note
(16) The 1H NMR spectrum is provided in the Supporting
Information for reference.
(17) Reekie, T. A.; Kavanagh, M. E.; Longworth, M.; Kassiou, M.
ACKNOWLEDGMENTS
■
The Erasmus Exchange ProgramExperts II is acknowledged
for the the award of a fellowship to N.P. We thank the
University of Leuven and the FWO-Vlaanderen for financial
support and the University of Pune for the collaboration with
the Erasmus Exchange Program.
Synthesis 2013, 45, 3211.
(18) (a) Vallejos, G.; Fierro, A.; Rezende, M.; Sepulveda-Bozaand, S.;
Reyes-Parada, M. Bioorg. Med. Chem. 2005, 13, 4450−4451.
(b) Naveen, T.; Maity, S.; Sharma, U.; Maiti, D. J. Org. Chem. 2013,
78, 5949−5954.
(19) (a) Graham, B.; Porter, H. D.; Weissberger, A. J. Am. Chem. Soc.
1949, 71, 983−988. (b) Ochi, H.; Miyasaka, T. Chem. Pharm. Bull.
1983, 31, 1228−1234. (c) Bianchini, R.; Bonanni, M.; Corsi, M.;
Infantino, A. Tetrahedron 2012, 68, 8636−8644.
REFERENCES
■
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1
after column purification showed a complex H NMR spectrum, but
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1
the spectrum was simplified and was easy to interpret. The H NMR
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1
correspond to DABCO) showed good splitting in H NMR spectrum
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