Copper-catalyzed synthesis of substituted indazoles from 2-chloroarenes at low catalyst-loading

Article abstract of DOI:10.1039/c1ob05875d

An efficient and convenient access to 1-substituted indazol-3-ones 2 has been achieved throughout the intramolecular C-N bond formations of 2-chloro-benzoic acid-N′-aryl and alkyl-hydrazides employing 0.5 mol% of cuprous (I) iodide and 20 mol% of l-prolin

Full text of DOI:10.1039/c1ob05875d

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PAPER
Copper-catalyzed synthesis of substituted indazoles from 2-chloroarenes at
low catalyst-loading†
Shinji Tanimori,* Yasuyuki Kobayashi, Yasukazu Iesaki, Yuka Ozaki and Mitsunori Kirihata
Received 2nd June 2011, Accepted 8th November 2011
DOI: 10.1039/c1ob05875d
An efficient and convenient access to 1-substituted indazol-3-ones 2 has been achieved throughout the
intramolecular C–N bond formations of 2-chloro-benzoic acid-N¢-aryl and alkyl-hydrazides employing
0.5 mol% of cuprous (I) iodide and 20 mol% of L-proline as catalyst precursors under mild conditions
in moderate to excellent yields.
20 mol% of catalysts have been frequently exploited for the com-
plete consumption of starting materials, in the copper-catalyzed
Introduction
systems.9 After the several examinations based on our previous
report,7 it was eventually found that the 2-chlorobenzohydrazides
1 were also suitable substrates to be converted smoothly into 1-
substituted indazol-3-ones 2 with only 0.5 mol% of copper catalyst
in practical efficiency. Details of the results are reported below.
Substituted indazol-3-ones are present in many important phar-
maceutically active molecules.1 For instance, the indazole com-
pounds and their derivatives have been reported to exhibit
analgesic,2 antitumor,3 anticancer,4 anti-inflammatory,5 and an-
tifertility activities.6 We previously reported the synthesis of 1-
substituted indazol-3-ones from 2-iodo- and 2-bromo-benzoic
acid-N¢-aryl and alkylhydrazides, which employed 10 mol% of
cuprous(I) iodide and 20 mol% of L-proline as the pre-catalysts
at room temperature for 3 h in good to excellent yields (Scheme
1).7,8 However, decreasing the catalyst-loading under 10 mol% and
also the use of chloroarenes as substrates afforded unsatisfactory
results.7
Results and discussions
Synthesis
Table 1 shows the summary for optimization studies of the reaction
conditions to improve our previous system.7 The reaction of
2-chlorobenzoic acid-N¢-phenylhydrazide 1a in the presence of
1 mol% of cuprous (I) iodide with L-proline9d (2 mol%)10 and
potassium carbonate (2 equiv.) in dimethylsulfoxide at 70 ◦C
for 15 h gave a ring-closed product 2a in 31% yield (entry 1).
The reaction did not perform under ligand free conditions (not
shown). Gratifyingly, when 5 mol% L-proline was employed with
1 mol% of cuprous (I) iodide, the yield was increased to 67%
in the same reaction conditions (entry 2). To our delight, the
satisfactory results were observed when excess amount of L-proline
(10 and 20 mol% based on substrates) was introduced with 1 mol%
CuI to afford desired product in 75 and 79% yields, respectively
(entry 3 and 4). Organic base DBU should also be a good base
for this transformation, although prolonged reaction time was
required to accomplish the complete consumption of the starting
material (entry 5). The reaction with cesium carbonate afforded
a lower yield (62%, entry 7) and sodium t-butoxide provided
complex mixture (not shown). A more efficient and economical
conversion was realized with the use of 0.5 mol% copper catalyst
and large excess L-proline (20◦mol%) to produce indazolone 2a
in 80% yield after 24 h at 90 C (entry 8).11 To our knowledge,
these results would be the first cases for copper-mediated coupling
reactions to achieve efficient and practical carbon-heteroatom
bond formations utilizing less reactive chloroarene as coupling
partner along with a lower catalyst loading (<1 mol%) under the
mild conditions. The role of excess L-proline based on the loading
Scheme 1 Strategy to synthesize indazolones.
The employment of 2-chlorobenzohydrazides as starting materi-
als would represent some benefits. Economically, 2-chlorobenzoic
acids and derivatives, precursors of 2-chlorobenzohydrazides, are
usually less expensive than the corresponding iodo- and bromo-
derivatives. Moreover, the rich existence of their analogues with
a variety of substituents should also be attractive for diversity-
oriented synthesis. Ordinarily, iodo- and bromoarenes have been
utilized as coupling partner for the copper-catalyzed carbon-
carbon and carbon-heteroatom bond-forming reactions and
choroarenes were not nearly employed due to their significantly
low reactivity.9 Moreover, lowering the catalyst loading is also
highly desirable from a green chemistry viewpoint. Mostly, 5 to
Department of Bioscience and Informatics, Graduate School of Life and En-
vironmental Sciences, Osaka Prefecture University, 1-1 Gakuencho, Nakaku,
Sakai, Osaka, 599-8531, Japan. E-mail: tanimori@bioinfo.osakafu-u.ac.jp;
Fax: +81 72 254 9469; Tel: +81 72 254 9469
† Electronic supplementary information (ESI) available: See DOI:
10.1039/c1ob05875d
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Table 1 The intramolecular cyclization of 1a under various reaction conditionsa
Entry
Catalyst
Ligand
Base
Temp (◦ C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (0.5)
CuI (0.5)
CuI (0.5)
L-Proline (2)
L-Proline (5)
L-Proline (10)
L-Proline (20)
L-Proline (20)
L-Proline (20)
L-Proline (20)
L-Proline (20)
K2CO3
K2CO3
K2CO3
K2CO3
DBU
K2CO3
Cs2CO3
K2CO3
70
70
70
70
70
70
70
90
15
15
15
15
48
15
15
24
31
67
75
79
84
71
62
80
a All of the reactions were carried out using benzhydrazide 1a (1.0 mmol), catalyst (0.5 and 1 mmol), ligand (2–20 mmol), and base (2.0 mmol) in DMSO
(10 mL). b Isolated yield.
of copper catalyst for this system could be explained by considering
the competitive role of the hydrazide moiety in complexating the
copper ion. Such a complexation would inhibit the intramolecular
coupling. Therefore a large excess of proline is needed to ensure
the complexation of copper. The closely related phenomenon has
been argued in our previous report, where DMEDA (20 mol%)
and cuprous (I) chloride (1 mol%) were exploited as pre-catalysts
for the coupling of 2-haloaniline with a–amino acids to form
quinoxaline-2-ones.12 A control experiment without the use of
catalyst gave no desired product (not shown).
As the optimized reaction conditions were in hand, we next
investigated the cyclization reactions with a series of substituted
2-chlorobenzohydrazides to examine the generality of the condi-
Scheme 2 Simple synthesis of the key intermediates for a pharmaceutical.
tions (Table 2). Both electron-donating and electron-withdrawing
groups on aromatic rings of corresponding benzoic acid and
hydrazine moieties are feasible for this cyclization reaction. Alkyl-
substituted hydrazides also reacted effectively at the same proce-
dure (entries 7, 8 and 10). Although nitro-substituted hydrazides
1c and 1d provided complex mixtures under the optimized
conditions, to our delight, the cyclization proceeded smoothly at
room temperature to afford indazolone 2c and 2d in 93% and
55% yields, respectively (entries 3 and 4). In the latter case, a
strong electron-donating methoxy group would destabilize the
intermediacy nucleophilic nitrogen anion in the cyclization step.
The pyridine containing substrates 1k, 1l and 1m were also
accessible for this transformation to provide a novel class of
pyrazolo[3,4-b]pyridin-3-ones 2k, 2l and 2m in moderate to good
yields (entries 11, 12 and 13). Sulfonamide 1n also reacted to
give multi-substituted indazolone 2n without the use of protecting
group. Moreover, the comparable efficiencies were observed by a
comparison of Br/I and Cl as leaving groups as shown in entries
1 and 7. The scalability of this transformation has also been
demonstrated with the use of hydrazide 1a (1.30 g, 5.25 mmol) to
provide indazolone 2a (1.00 g, 90%) under the optimal conditions
(see experimental section).
synthesized easily from commercial starting materials utilizing
our protocol. The copper-mediated cyclization of hydrazides 1o,
derived from 5-fluoro-2-bromo and chlorobenzoic acids with 2-
fluorophenylhydrazine, underwent to form desired indazolone 2o
in both 58% yields. The moderate efficiency for the cyclization step
would attribute to steric bulk of ortho-substitution on hydrazine
aromatic ring. This strategy avoids a hazardous reagent and
unstable intermediate required for previous route.13
Pharmacology
In the course of our continuing study directed toward the discovery
of anti-cancer drugs,15 we tested the cytotoxic activity of all
synthesized compounds (hydrazides 1 and indazolones 2) against
HeLaS3 cell line. Most of compounds did not show significant
inhibition under 30 mM (IC50) except for hydrazides 1n (0.25 mM)
and 1o-Br (2.9 mM). Other biological studies are now under
investigation.
Conclusions
As shown in Scheme 2, indazolone 2o,13 a key intermediate
for the synthesis of (S)-5-fluoro-1-(2-fluorophenyl)-3-(piperidin-
3-ylmethoxy)-1H-indazole 3, a norepinephrine/serotonin reup-
take inhibitor for the treatment of fibromyalgia,14 has been
In conclusion, we have established a general and practical access to
substituted indazolones from readily available starting materials.
The substrate scope for this synthesis has been expanded to even
less reactive chloroarenes in this study. The improved reaction
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Table 2 Synthesis of substituted indazolone derivativesa
Entry
1
Hydrazide 1
Indazolone 2
Yieldb (%)
80 (R¢ Cl)
82 (R¢ I)
59 (R¢ Br)
2
87
93
55
3c
4c
5
6
91
86
7
83 (R¢ R¢¢ Cl)
66 (R¢ H, R¢¢ I)
80 (R¢ H, R¢¢ Br)
86 (R¢ H, R¢¢ Cl)
8
9
82
79
10
90
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Table 2 (Contd.)
Entry
11
Hydrazide 1
Indazolone 2
Yieldb (%)
66
12
80
13
14
77
65
a All the reactions were carried out using hydrazide 1 (1.0 mmol), CuI (0.0050 mmol, 0.5 mol%), L-proline (0.020 mmol, 20 mol%), K2CO3 (2.0 mmol) in
DMSO (10 mL). b Isolated yield. c The reaction was performed at room temperature.
conditions with lower copper catalyst loading (0.5 mol%) have
been realized by carefully controlled ligand loading (20 mol%).
The success of the key low loading of copper-catalyst in this
transformation would partially attributed to the use of excess
ligand. Bolm suggests that the ligand shifts equilibria away from
favorable low-coordinated copper species which otherwise would
be deactivated by aggregation.12 Structurally diverse indazolones
together with benzhydrazides as the precursors have been syn-
thesized efficiently by this process to prepare two series of small
chemical libraries. The simple synthesis of a key intermediate 2o for
a drug 3 was conducted by this protocol in mild conditions. Finally,
the novel class of strong cytotoxic compound 1n has appeared
among the libraries.
spectrometers, respectively. Proton chemical shifts (d) are relative
to tetramethylsilane (TMS, d = 0.0) as the internal standard and
expressed in parts per million. Spin multiplicities are given as
s (singlet), d (doublet), t (triplet), and m (multiplet) as well as
b (broad). Coupling constants (J) are given in hertz. Infrared
spectra were recorded on a FT-IR spectrometer. Melting points
were determined by using a Bu¨chi melting point B-540 apparatus
and are uncorrected. MS spectra were obtained on a mass
spectrometer. HR-MS was determined using JEOL JNM-AX 500
mass spectrometer.
General procedure for the preparation of acid hydrazides 1a–o
by the condensation of acid with hydrazine. To a stirred solution
of acid (5.0 mmol) in DMF (10 mL) were added EDC·HCl (1.1
g, 5.5 mmol), HOBt·H2O (0.74 g, 5.5 mmol), DMAP (31 mg,
0.25 mmol), and hydrazine (5.0 mmol) at 0 ◦C. The resulting
mixture was allowed to warm to room temperature over 24 h,
and it was diluted with EtOAc and poured into saturated NH4Cl
solution. Extractive workup with EtOAc and purification by
column chromatography afforded acid hydrzide as a white solid.
Experimental
Chemistry
General methods. Unless stated otherwise, reactions were
monitored by thin layer chromatography (TLC) on silica gel
plates (60 F254), visualizing with ultraviolet light or iodine spray.
Column chromatography was performed on silica gel (60–120
Spectral data of acid hydrazides (1a–o)
1
mesh) using hexane and ethyl acetate. H and 13C NMR spectra
2-Chloro-N¢-phenylbenzohydrazide (1a)7. Yield 90%; Rf 0.53
(hexane : AcOEt = 1 : 1); mp 152.2 ◦C; 1H NMR (400 MHz,
were determined in DMSO-d6 solution using 400 and 100 MHz
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DMSO-d6) d 10.21 (d, 1H, J = 2.7 Hz, CONH), 8.03 (d, 1H,
J = 2.7 Hz, PhNH), 7.38–7.60 (m, 4H, Ar), 7.17 (dd, 2H, J = 7.3,
7.6 Hz, Ar), 6.84 (d, 2H, J = 7.6 Hz, Ar), 6.72 (t, 1H, J = 7.3 Hz, Ar).
30.9 (2¥C), 25.7, 23.9 (2¥C); HRMS Calcd for C13H16N2OCl2:
286.0640, Found: 286.0640.
2-Chloro-5-fluoro-benzoic ◦acid N¢-4-methylphenyl-hydrazide
1
2-Chloro-4-methyl-benzoic acid N¢-phenyl-hydrazide (1b).
Yield 68%; mp 178.4 ◦C; 1H NMR (400 MHz, DMSO-d6) d 10.14
(s, 1H, CONH), 7.96 (s, 1H), 7.41 (d, 1H, J = 8.3 Hz), 7.35 (s,
1H), 7.31 (d, 1H, J = 8.0 Hz), 7.17 (t, 2H, J = 7.3 Hz), 6.86 (d, 2H,
J = 7.8 Hz), 6.73 (t, 1H, J = 7.3 Hz), 2.35 (s, 3H, Me); 13C NMR
(136 Hz, DMSO-d6)d 166.3, 149.1, 136.8, 135.0, 131.7, 129.5,
129.4, 128.7 (2¥C), 127.2, 118.6, 112.3 (2¥C), 20.4; HRMS-EI
calcd for C14H13N2OCl: 260.0717, Found: 260.0699.
(1i). Yield 69%; mp 167.0 C; H NMR (400 MHz, DMSO-
d6) d 10.25 (d, 1H, J = 2.9 Hz), 7.85 (d, 1H, J = 2.4 Hz), 7.60 (dd,
1H, J = 4.9, 9.0 Hz), 7.44 (dd, 1H, J = 2.9, 8.3 Hz), 7.38 (1H, dt,
J = 2.9, 8.3 Hz), 6.98 (d, 2H, J = 8.3 Hz), 6.77 (d, 2H, J = 8.3 Hz),
2.19 (s, 3H, Me); 13C NMR (136 Hz, DMSO-d6) d 155.8, 137.6,
136.2, 134.4, 129.9 (3C), 120.8 (3¥C), 117.3, 111.9, 104.5, 20.5;
HRMS Calcd for C14H12N2OClF: 278.0622, Found: 278.0605.
2-Chloro-5-fluoro-benzoic acid N¢-t-butyl-hydrazide (1j). Yield
79%; mp 103.3 ◦C; 1H NMR (400 MHz, DMSO-d6) d 9.91 (br s,
1H), 7.63 (dd, 1H, J = 4.9, 8.3 Hz), 7.36–7.46 (m, 2H), 4.93 (br s,
1H), 1.14 (s, 9H); 13C NMR (136 Hz, DMSO-d6) d 163.8 (C O),
161.6 (159.1), 137.34 (137.26), 131.6 (131.5), 125.72 (125.70),
118.0 (117.8), 116.5 (116.2), 54.7, 27.3 (3¥C); HRMS Calcd for
C11H14N2OClF: 244.0779, Found: 244.0829.
2-Chloro-4-nitro-benzoic acid N¢-phenyl-hydrazide (1c)16.
Yield 68%; Rf 0.63 (hexane : AcOEt = 1 : 1); mp 169.1 ◦C; 1H
NMR (400 MHz, DMSO-d6) d 10.53 (s, 1H, CONH), 8.46 (d,
1H, J = 1.7 Hz, Ar), 8.34 (d, 1H, J = 8.5 Hz, Ar), 8.19(s, 1H,
PhNH), 7.90 (d, 2H, J = 8.5 Hz, Ar), 7.25 (t, 2H, J = 7.8 Hz,
Ar), 6.92 (d, 2H, J = 7.8 Hz, Ar), 6.81 (t, 1H, J = 6.8 Hz, Ar); 13
C
NMR (136 Hz, DMSO-d6) d 164.9 (C O), 148.8, 148.6, 141.0,
131.5, 130.4, 128.9 (2¥C, Ar), 124.8, 122.5, 118.9, 112.4 (2¥C, Ar).
2,6-Dichloro-nicotinic acid N¢-phenyl-hydrazide◦ (1k). Yield
1
93%; Rf 0.45 (hexane : AcOEt = 1 : 1); mp 147.4. C; H NMR
2-Chloro-4-nitro-benzoic acid N¢-4-methoxyphenyl-hydrazide
(1d). Yield 59%; Rf 0.54 (hexane : AcOEt = 1 : 1); mp: 183.4 ◦C;
1H NMR (400 MHz, DMSO-d6) d 10.42 (s, 1H, CONH), 8.39 (d,
1H, J = 2.0 Hz, ArNH), 8.27 (dd, J = 6.0, 2.2 Hz, 1H, Ar), 7.78–
7.82 (m, 2H, Ar), 6.78–6.88 (m, 4H, Ar), 3.67 (s, 3H, MeO); 13C
NMR (136 Hz, DMSO-d6) d 164.9 (C O), 152.9, 148.5, 142.6,
141.1, 131.4, 130.4, 124.7, 122.5, 114.3 (2¥C, Ar), 113.9 (2¥C, Ar),
55.3; IR (neat): 3256 (NH), 2837 (Me), 1660 (C O), 1518, 1351
(NO2), 1239, 1037, 832 cm-1; HRMS Calcd for C14H12O4N3Cl:
321.0516, Found: 321.0338.
(400 MHz, DMSO-d6) d 10.40 (s, 1H, CONH), 8.12 (d, 1H, J =
8.0 Hz, Ar), 8.09 (br s, 1H, ArNH), 7.71 (d, 1H, J = 8.0 Hz,
Ar), 7.17 (t, 2H, J = 7.6 Hz, Ar), 6.85 (d, 2H, J = 7.8 Hz, Ar),
6.68–6.80 (m, 1H, Ar); 13C NMR (136 Hz, DMSO-d6)d 164.2
(C O), 149.8, 148.7, 146.2, 141.6, 130.7, 128.9 (2¥C, Ar), 123.8,
119.0, 112.4 (2¥C, Ar); IR (neat): 3256 (NH), 3055 (Ar), 1653
(C O), 1492, 1341, 1144, 912, 756, 691 cm-1; HRMS Calcd for
C12H9N3OCl2: 281.0122, Found: 281.0216.
2,6-Dichloro-nicoti◦nic acid N¢-4-chlorophenyl-hydrazide (1l).
Yield 77%; mp 180.3 C; 1H NMR (400 MHz, DMSO-d6) d 10.45
(s, 1H, CONH), 8.13 (dd, 1H, J = 1.5, 8.0 Hz), 7.71 (dd, 1H, J =
1.5, 8.0 Hz), 7.21 (d, 2H, J = 7.6 Hz), 6.85 (d, 2H, J = 7.6 Hz);
13C NMR (136 Hz, DMSO-d6) d 164.2, 149.9, 147.7, 146.2, 141.6,
130.5, 128.7 (2¥C), 123.8, 122.3, 113.9 (2¥C); HRMS Calcd for
C12H8N3OCl3: 314.9733, Found: 314.9837.
2,4-Dichloro-benzoic acid N¢-phenyl-hydrazide (1e)17. Yield
◦
1
84%; mp 169.1 C; H NMR (400 MHz, DMSO-d6) d 10.26 (s,
1H, CONH), 8.03 (s, 1H), 7.75 (d, 1H, J = 1.7 Hz), 7.52–7.62 (m,
2H), 7.17 (t, 2H, J = 7.6 Hz), 6.84 (d, 2H, J = 7.6 Hz), 6.73 (t, 1H,
J = 7.3 Hz); 13C NMR (136 Hz, DMSO-d6) d 165.5, 149.0, 135.0,
134.1, 131.5, 130.6, 129.4, 128.8 (2¥C), 127.5, 118.8, 112.3 (2¥C).
2,6-Dichloro-nicoti◦nic acid N¢-4-methylphenyl-hydrazide (1m).
Yield 78%; mp 145.5 C; 1H NMR (400 MHz, DMSO-d6) d 10.34
(d, 1H, J = 2.4 Hz, CONH), 8.09 (d, 1H, J = 8.0 Hz), 7.91 (br s, 1H),
7.70 (d, 1H, J = 8.0 Hz), 6.99 (d, 2H, J = 8.5 Hz), 6.76 (d, 2H, J =
8.5 Hz), 2.18 (s, 3H, Me); 13C NMR (136 Hz, DMSO-d6) d 164.1,
149.7, 146.4, 146.2, 141.6, 130.7, 129.2 (2¥C), 127.6, 123.7, 112.6
(2¥C), 20.2; HRMS Calcd for C13H11N3OCl2: 295.0279, Found:
295.0259.
2,4-Dichloro-benzoic acid N¢-(4-nitro-phenyl)-hyd◦razide (1f)18.
Yield 84%; Rf 0.43 (hexane : AcOEt = 1 : 1); mp 247.6 C; 1H NMR
(400 MHz, DMSO-d6) d 10.63 (s, 1H, CONH), 9.35 (s, 1H, Ar),
8.10 (d, 2H, J = 7.8 Hz,Ar), 7.79 (d, 1H, J = 1.7 Hz, ArNH), 7.66
(d, 1H, J = 8.3 Hz, Ar), 7.57 (dd, 1H, J = 1.7, 8.3 Hz, Ar), 6.90
(d, 2H, J = 7.8 Hz, Ar); 13C NMR (136 Hz, DMSO-d6) d 165.4
(C O), 154.5, 138.3 (2¥C, Ar), 135.5, 133.4, 131.6, 130.7, 129.5,
127.6, 126.0 (2¥C, Ar), 110.9.
2,4-Dichloro-5-sulfamoyl-benzoic acid N¢-(1-methyl-phenyl)-
hydrazide (1n). Yield 71%; Rf 0.40 (hexane : AcOEt = 1 : 1); mp
2,4-Dichloro-◦benzoic acid N¢-t-butyl-hydrazide (1g)19. Yield
91%; mp 112.9 C; 1H NMR (400 MHz, DMSO-d6) d 9.80 (br s,
1H), 7.70 (d, 2H, J = 2.0 Hz), 7.49 (dd, 1H, J = 2.0, 8.3 Hz), 7.44
(d, 1H, J = 8.3 Hz), 1.06 (s, 9H); 13C NMR (136 Hz, DMSO-d6) d
164.2, 134.6, 134.5, 131.5, 130.7, 129.1, 127.3, 54.7, 27.3 (3¥C).
◦
1
208.3 C; H NMR (400 MHz, DMSO-d6) d: 10.39 (d, 1H, J =
2.2 Hz, CONH), 8.00 (s, 1H, Ar), 7.99 (s, 1H, Ar), 7.92 (br s, 1H,
ArNH), 7.89 (br s, 2H, SO2NH2), 6.99 (d, 2H, J = 8.0 Hz, Ar),
6.73 (d, 2H, J = 8.0 Hz, Ar), 2.18 (s, 3H, Me); 13C NMR (136 Hz,
DMSO-d6) d 164.5 (C O), 146.5, 140.1, 134.4, 134.2, 132.4,
132.3, 129.3 (2¥C, Ar), 129.0, 127.6, 112.6 (2¥C, Ar), 20.2 (Me);
HRMS Calcd for C14H13N3O3Cl2: 373.0055, Found: 373.0059.
2,4-Dichloro-benzoic acid N¢-cyclohexyl-hydrazide (1h). Yield
◦
1
60%; mp 164.7 C; H NMR (400 MHz, DMSO-d6) d 9.83 (d,
1H, J = 2.7 Hz, CONH), 7.68 (d, 1H, J = 1.7 Hz), 7.48 (dd, 1H,
J = 1.7, 8.3 Hz), 7.43 (1H, d, J = 8.3 Hz), 4.94 (br s, 1H), 2.72–2.84
(m, 1H), 1.83 (d, 2H, J = 11.5 Hz), 1.63–1.76 (m, 2H), 1.50–
1.59 (d, 2H, J = 8.8 Hz), 1.02–1.28 (m, 5H); 13C NMR (136 Hz,
DMSO-d6) d 164.3, 134.6, 134.5, 131.5, 130.5, 129.1, 127.3, 57.8,
2-Chloro-5-fluoro-benzoic a◦cid N¢-2-fluorophenyl-hydrazide (1o-
1
Cl). Yield 78%; mp 145.5 C; H NMR (400 MHz, DMSO-
d6) d 10.34 (br s, 1H), 7.89 (br s, 1H), 7.61 (dd, 1H, J = 4.9,
8.8 Hz), 7.35–7.46 (m, 2H), 6.96–7.14 (m, 3H), 6.71–6.79 (m,
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1H); 13C NMR (136 Hz, DMSO-d6) d 165.04 (165.02), 161.6,
159.1, 136.55 (136.47), 136.41 (136.30), 131.84 (131.76), 125.77,
(125.74), 124.60 (124.57), 119.05 (118.99), 118.50 (118.29), 116.38
(116.13), 114.97 (114.79), 113.88 (113.85); HRMS Calcd for
C13H9N2OClF2: 282.0371, Found: 282.0374.
7.13 (d, 2H, J = 6.3 Hz, Ar), 3.82 (s, 3H, OMe); 13C NMR (136 Hz,
DMSO-d6) d 157.8 (C O), 155.8, 147.3, 137.8, 132.1, 123.7
(2¥C, Ar), 121.8, 116.9, 114.9 (2¥C, Ar), 114.1, 106.4, 55.5 (OMe);
HRMS Calcd for C14H11N3O4: 285.0749, Found: 285.0748.
6-Chloro-1-phenyl-2,3-dihydro-1H-indazol-3-one (2e)18. Yield
91%; mp 236.4 ◦C; 1H NMR (400 MHz, DMSO-d6) d 11.47 (br
s, 1H), 7.77 (s, 1H), 7.76 (d, 1H, J = 8.5 Hz), 7.67 (d, 2H, J = 7.8
Hz), 7.52 (t, 2H, J = 7.6 Hz), 7.28 (1H, t, J = 7.3 Hz), 7.16 (d, 1H,
J = 9.3 Hz); 13C NMR (136 Hz, DMSO-d6) d 156.2, 139.6, 139.3,
133.6, 129.6 (2¥C), 125.4, 122.1, 121.0 (2¥C), 120.9, 113.6, 109.9.
General procedures for the synthesis of indazole-3-ones 2a–o.
The mixture of 2-chlorobenzoic acid hydrazide (1.0 mmol), CuI
(0.95 mg, 0.005 mmol, 0.5 mol%), L-proline (23 mg, 0.20 mmol,
20 mol%), and K2CO3 (0.28 g, 2.0 mmol) in DMSO (10 mL) was
stirred at 90 ◦C for 24 h under nitrogen atmosphere. The mixture
was treated with water and the mixture was extracted three times
with ethyl acetate. The combined organic layer was washed with
water and brine and dried over magnesium sulfate. After filtration,
solvent was evaporated in vacuo to ca. 1 mL and crystallization
afforded indazole-3-ones.
6-Chloro-1-(4-nitrophenyl)-2,3-dihydro-1H-indazol-3-one (2f).
Yield 86%; colorless oil; Rf 0.20 (hexane : AcOEt = 7 : 3); 1H NMR
(400 MHz, DMSO-d6) d 11.97 (br s, 1H, NH), 8.32 (d, 2H, J =
9.0 Hz, Ar), 8.04 (s, 1H, Ar), 7.95 (d, 2H, J = 9.0 Hz, Ar), 7.80 (d,
1H, J = 8.5 Hz, Ar), 7.28 (d, 1H, J = 8.5 Hz, Ar); 13C NMR (136 Hz,
DMSO-d6) d 157.7 (C O), 144.9, 143.0, 139.4, 134.6, 125.5, 125.4
(2¥C, Ar), 122.4, 119.5 (2¥C, Ar), 115.3, 111.1; HRMS-EI Calcd
for C13H8N3O3Cl: 289.0254, Found: 289.0275.
1-Phenylindazol-3(2H)-one (2a)7,20
.
Yield 80%; Rf 0.45
(hexane : AcOEt = 7 : 3); mp 166.4 ◦C; 1H NMR (400 MHz,
DMSO-d6) d 11.29 (br s, 1H, NH), 7.76 (t, 2H, J = Ar), 7.68
(d, 2H, J = 7.8 Hz, Ar), 7.51 (t, 2H, J = 7.8 Hz, Ar), 7.45 (t, 1H,
J = 7.3 Hz, Ar), 7.25 (t, 1H, J = 7.3 Hz, Ar), 7.15 (t, 1H, J = 7.3 Hz,
Ar); IR (KBr): n 1554 (C O), 1349 (NO2), 1301, 1231, 885, 802,
753, 695 cm-1.
1-tert-Butyl-6-chloro-2,3-dihydro-1H-indazol-3-one
(2g).
Yield 83%; mp 179.3 ◦C; 1H NMR (400 MHz, DMSO-d6) d
10.80 (br s, 1H, NH), 7.74 (s, 1H), 7.68 (d, 1H, J = 8.5 Hz), 7.05
(d, 1H, J = 8.5 Hz), 1.67 (s, 9H); 13C NMR (136 Hz, DMSO-d6)
d 152.7, 139.2, 131.6, 121.6, 118.8, 112.6, 111.1, 58.8, 29.3 (3¥C);
HRMS-EI Calcd for C11H13N2OCl: 224.0717, Found: 224.0707.
A gram scale preparation of 2a. A mixture of 2-chlorobenzoic
acid hydrazide 1a (1.30 g, 5.25 mmol), CuI (5 mg, 0.026 mmol,
0.5 mol%), L-proline (120 mg, 1.05 mmol, 20 mol%), and K2CO3
(1.45 g, 10.5 mmol) in DMSO (15 mL) was stirred at 90 ◦C
for 24 h under nitrogen atmosphere. After cooling, the mixture
was treated with sat. NaHCO3 aq. (100 mL) and the mixture
was extracted eight times with ethyl acetate (30 mL¥8). The
combined organic layer was washed with water (50 mL¥3) and
brine (50 mL) and dried over magnesium sulfate. After filtration,
solvent was evaporated in vacuo to afford a crude product which
was recrystallized to provide pure 2a (0.754 g, 68%). The mother
liquid was concentrated in vacuo and the residue was subjected to
column chromatography (chloroform) afforded additional pure 2a
(0.244 g, 22%).
6-Chloro-1-cyclohexyl-2,3-dihydro-1H-indazol-3-one
(2h).
1
Yield 82%; mp 197.0; H NMR (400 MHz, DMSO-d6) d 10.77
(br s, 1H, NH), 7.67 (d, 1H, J = 7.6 Hz), 7.59 (d, 1H, J = 8.5
Hz), 6.96 (1H, dd, J = 1.7, 7.6 Hz), 4.32–4.42 (1H, m, NCH),
1.63–1.88 (m, 7H), 1.38–1.53 (m, 2H), 1.12–1.26 (m, 1H); 13C
NMR (136 Hz, DMSO-d6) d 153.9, 140.2, 131.9, 121.5, 118.9,
110.8, 108.8, 55.8, 32.0 (2¥C), 25.1, 25.0 (2¥C); HRMS-EI Calcd
for C13H15N2OCl: 250.0873, Found: 250.0873.
5-Fluoro-1-(4-methylphenyl)-2,3-dihydro-1H-indazol-3-one (2i).
Yield 79%; mp 223.4 ◦C; 1H NMR (400 MHz, DMSO-d6) d
11.25 (br s, 1H, NH), 7.01 (br s, 1H), 7.43–7.60 (m, 3H), 7.24–
7.28 (m, 3H), 2.34 (s, 3H, Me); 13C NMR (136 Hz, DMSO-d6) d
155.8, 137.6, 136.2, 134.4, 129.9 (3¥C), 120.8 (3¥C), 117.3, 111.9,
104.5, 20.5; HRMS-EI Calcd for C14H11N2OF: 242.0855, Found:
242.0854.
5-Methyl-1-p◦henyl-2,3-dihydro-1H-indazol-3-one (2b). Yield
87%; mp 226.5 C; 1H NMR (400 MHz, DMSO-d6) d 11.16 (br s,
1H), 7.63–7.72 (m, 3H), 7.46–7.56 (m, 3H), 7.29 (d, 1H, J = 8.8 Hz),
7.24 (t, 1H, J = 7.3 Hz), 2.41 (s, 3H); 13C NMR (136 Hz, DMSO-
d6) d 155.9, 140.4, 137.9, 130.1, 129.4 (2¥C), 129.3, 124.4, 120.1
(2¥C), 119.5, 115.1, 110.2, 20.6; HRMS-EI Calcd for C14H12N2O:
224.0949, Found: 224.0938.
1-tert-Butyl-5-fluoro-2,3-dihydro-1H-indazol-3-one (2j). Yield
90%; mp 172.8 ◦C; 1H NMR (400 MHz, DMSO-d6) d 10.53 (br
s, 1H, NH), 7.64 (dd, 1H, J = 3.9, 9.3 Hz), 7.31 (d, 1H, J = 8.5
Hz), 7.15 (t, 1H, J = 9.3 Hz), 1.59 (s, 9H); 13C NMR (136 Hz,
DMSO-d6) d 156.8, 154.4, 152.6, 136.5, 115.6, 113.4, 104.0, 58.5,
29.3 (3¥C); HRMS-EI Calcd for C11H13N2OF: 208.1012, Found:
208.0984.
6-Nitro-1-phenyl-2,3-dihydro-1H-indazol-3-one
(2c). Yield
◦
1
93%; Rf 0.31 (hexane : AcOEt = 7 : 3); mp 286.9 C; H NMR
(400 MHz, DMSO-d6) d 11.86 (br s, 1H, NH), 8.46 (s, 1H, Ar),
8.00 (d, 1H, J = 8.5 Hz), 7.94 (d, 1H, J = 8.5 Hz), 7.74 (d, 2H, J =
7.6 Hz, Ar), 7.59 (t, 2H, J = 7.6 Hz, Ar), 7.37 (t, 1H, J = 7.3 Hz,
Ar); 13C NMR (136 Hz, DMSO-d6) d 156.4 (C O), 147.7, 139.2,
137.8, 130.1 (2¥C, Ar), 126.5, 122.1, 121.8 (2¥C, Ar), 117.8,
114.9,106.8; IR (KBr): n 3093, 1554, 1349, cm-1; HRMS-EI Calcd
for C13H9N3O3: 255.0644, Found: 255.0605.
6-Chloro-1-phenyl-1H,2H,3H-pyrazolo[3,4-b]pyridin-3-one (2k).
Yield 66%; Rf 0.64 (hexane : AcOEt = 1 : 1); mp 236.4 ◦C; 1H NMR
(400 MHz, DMSO-d6) d 11.90 (br s, 1H, CONH), 8.25 (dd, 1H,
J = 8.4, 1.2 Hz Ar), 8.08 (d, 2H, J = 8.8 Hz, Ar), 7.51 (t, 2H, J =
7.6 Hz, Ar), 7.29 (dd, 1H, J = 8.3, 1.2 Hz, Ar), 7.57 (dt, 1H, J =
8.3, 1.3 Hz, Ar);13C NMR (136 Hz, DMSO-d6)d 154.4 (C O),
150.4, 148.5, 138.9, 133.4, 129.2 (2¥C, Ar), 124.9, 119.4 (2¥C, Ar),
116.8, 106.5; HRMS-EI Calcd for C12H8N3OCl: 245.0356, Found:
245.0327.
6-Nitro-1-(4-methoxy-phenyl)-2,3-dihydro-1H-indazol-3-one
◦
(2d). Yield 55%; Rf 0.21 (hexane : AcOEt = 7 : 3); mp 281.4 C;
1H NMR (400 MHz, DMSO-d6) d 11.70 (br s, 1H, CONH), 8.30
(s, 1H, Ar), 7.78–8.07 (m, 2H, Ar), 7.61 (d, 2H, J = 6.1 Hz, Ar),
1386 | Org. Biomol. Chem., 2012, 10, 1381–1387
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6-Chloro-1-(4-chlorophenyl)-1H,2H,3H-pyrazolo[3,4-b]pyridin-
3-one (2l). Yield 90%; mp 266.6 ◦C; 1H NMR (400 MHz,
DMSO-d6) d 11.99 (br s, 1H, NH), 8.26 (d, 1H, J = 8.0 Hz), 8.12
(d, 2H, J = 7.6 Hz), 7.57 (d, 2H, J = 7.6 Hz), 7.31 (d, 1H, J = 8.0
Hz);13C NMR (136 Hz, DMSO-d6) d 154.6, 150.5, 148.6, 137.7,
133.5, 129.2 (2¥C), 128.6, 120.6 (2¥C), 117.1, 106.8; HRMS-EI
Calcd for C12H7N3OCl2: 278.9966, Found: 278.9950.
Notes and references
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2002, 10, 2415.
2 S. R. Fletcher, E. Mclver, S. Lewis, F. Burkamp, C. Leech, G. Mason,
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3 H. Wang, H. Han and D. D. Von Hoff, Cancer Res., 2006, 66, 9722.
4 N. Kawanishi, T. Sugimoto, J. Shibata, K. Nakamura, K. Masutani,
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5 K. A. M. Abouzid and H. S. El-Abhar, Arch. Pharmacal Res., 2003,
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6 (a) B. Silvestrini and C. Y. Cheng, US Pat. 99-304042, 1999; (b) H.
Cerecetto, A. Gerpe, M. Gonzalez, V. J. Aran and C. O. de Ocariz,
Mini-Rev. Med. Chem., 2005, 5, 869.
7 S. Tanimori, Y. Ozaki, Y. Iesaki and M. Kirihata, Synlett, 2008, 1973.
8 Recent synthesis of indazolones, see: (a) M. B. Donald, W. E. Conrad,
S. James, J. S. Oakdale, J. D. Butler, M. J. Haddadin and M. J. Kurth,
Org. Lett., 2010, 12, 2524; (b) G. Dou and D. Shi, J. Comb. Chem.,
2009, 11, 1073; (c) N. Halland, M. Nazare’, O. R’kyek, J. Alonso, M.
Urmann and A. Lindenschmidt, Angew. Chem., Int. Ed., 2009, 48,
6879; (d) D. Vin˜a, E. del Olmo, J. L. Lo´pez-Pe´rez and A. San Feliciano,
Org. Lett., 2007, 9, 525; (e) W. Stadlbauer, N. Camp, in Science of
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Bellus, S. V. Ley, R. Noyori, M. Regitz, E. Schaumann, E. Shinkai, E. J.
Thomas, B. M. Trost and P. J. Reider, Thieme, Stuggart, 2002, vol. 12,
p 227.
6-Chloro-1-(4-methylphenyl)-1H,2H,3H-pyrazolo[3,4-b]pyri-
◦
1
din-3-one (2m). Yield 77%; mp 222.5 C; H NMR (400 MHz,
DMSO-d6) d 11.89 (br s, 1H, NH), 8.26 (d, 1H, J = 8.3 Hz), 7.93
(d, 2H, J = 8.5 Hz), 7.30 (d, 2H, J = 8.5 Hz), 7.25 (d, 1H, J =
8.3 Hz), 2.32 (s, 3H, Me); 13C NMR (136 Hz, DMSO-d6) d 154.2,
150.3, 148.3, 136.5, 134.1, 133.4, 129.5 (2¥C), 119.5 (2¥C), 116.5,
106.2, 20.5; HRMS-EI Calcd for C13H10N3OCl: 259.0512, Found:
259.0504.
6-Chloro-5-sulfamoyl-1-(4-methylphenyl)-2,3-dihydro-1H-inda-
zol-3-one (2n). Yield 65%; Rf 0.63 (hexane : AcOEt = 1 : 3); mp
◦
1
297.7 C; H NMR (400 MHz, DMSO-d6) d 11.80 (br s, 1H,
CONH), 8.45 (s, 1H, Ar), 7.84 (s, 1H, Ar), 7.58 (d, 2H, J = 6.6 Hz,
Ar), 7.57 (s, 2H, SO2NH2), 7.35 (d, 2H, J = 8.3 Hz, Ar), 2.36 (s,
3H, OMe); 13C NMR (136 Hz, DMSO-d6) d: 156.8 (C O), 139.3,
136.7, 135.6, 133.1, 130.2 (2¥C, Ar), 130.1, 122.5, 121.6 (2¥C, Ar),
112.6, 112.0, 20.6; IR (neat): 3382 (NH), 3277 (NH), 3032 (Ar),
1557 (C O), 1337 (S O), 1169, 997, 916, 810 cm-1; HRMS-EI
Calcd for C14H12N3O3SCl: 337.0268, Found: 337.0168.
9 Recent reviews for copper-catalyzed Ullmann-type coupling reaction,
see: (a) F. Bellina and R. Rossi, Chem. Rev., 2010, 110, 1082; (b) F.
Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2009, 48, 6954;
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639; (f) M. Kienle, S. R. Dubbaka, K. Brade and P. Knochel, Eur. J.
Org. Chem., 2007, 4166 and references cited therein.
10 When 10 mol% of L-proline was employed with 10 mol% of CuI, the
yield of 2a was 29% at room temperature for 36 h and 66% at 70 ◦C for
12 h, respectively.
11 The efficiency is even better and comparable to corresponding
iodoarene (91% yield; conditions: 10 mol% CuI, 20 mol% L-proline,
2 equiv. K2CO3 in DMSO, at 70 ◦C for 3 h) and bromoarene (62%
yield; conditions: 10 mol% CuI, 20 mol% L-proline, 2 equiv. K2CO3 in
DMSO, at room temperature for 12 h)7.
5-Fluoro-1-(2-fluorophenyl)-2,3-dihydro-1H-indazol◦-3-one (2o)13.
Yield 58%; Rf 0.35 (hexane : AcOEt = 7 : 3); mp 211.7 C; 1H NMR
(400 MHz, DMSO-d6) d 11.39 (br s, 1H, CONH), 7.59 (t, 1H, J =
7.8 Hz Ar), 7.40–7.54 (m, 3H, Ar), 7.36 (t, 1H, J = 7.3 Hz, Ar),
7.22–7.34 (m, 2H, Ar).
Pharmacology21
Cell Culture. HeLa S3 cells were cultured at 37 ◦C in a
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microplates. After overnight incubation, 0.1 mL aliquots of
medium containing serially diluted test compounds were added to
triplicate wells, and incubation was continued for 72 more hours.
Cell growth was assessed using the crystal violet staining method.22
The IC50 value was defined at the drug concentration needed
to produce a 50% reduction of growth relative to the untreated
control.
14 R. M. Schelkun and P.-W. Yuen, PCT Int. Appl. (2006), WO 2006056873
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15 S. Tanimori, T. Nishimura and M. Kirihata, Bioorg. Med. Chem. Lett.,
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16 K. Kitatani, T. Takeda and S. Hoshi, Jpn. Kokai Tokkyo Koho, 1994,
JP 06027652 A 19940204.
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20 D. L. Selwood et al., J. Med. Chem., 2001, 44, 78.
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Acknowledgements
We gratefully acknowledge Ms. Sachiko Asami, Mrs. Ikuhiro
Inada, Atsushi Isayama, and Hiroaki Ohmukai for generous
supports in some of the experiments.
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