Microwave-assisted base-catalyzed cyclization and nucleophilic substitution of o-azidobenzanilides to synthesize 1,2-disubstituted indazol-3-ones

Article abstract of DOI:10.1080/00397910802663386

A series of 1,2-disubstituted indazol-3-ones were synthesized by microwave-assisted base-catalyzed cyclization and nucleophilic substitution of o-azidobenzanilides. Among five tested reaction conditions, the cyclization of o-azidobenzanilides catalyzed by

Full text of DOI:10.1080/00397910802663386

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Microwave-Assisted Base-
Catalyzed Cyclization and
Nucleophilic Substitution
of O-Azidobenzanilides to
Synthesize 1,2-Disubstituted
Indazol-3-ones
Arthur Y. Shaw a , Yi-Ru Chen a & Chia-Hua Tsai a
a Department of Chemistry , Tamkang University ,
Tamsui, Taiwan
Published online: 26 Jun 2009.
To cite this article: Arthur Y. Shaw , Yi-Ru Chen & Chia-Hua Tsai (2009)
Microwave-Assisted Base-Catalyzed Cyclization and Nucleophilic Substitution of
O-Azidobenzanilides to Synthesize 1,2-Disubstituted Indazol-3-ones, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:15, 2647-2663, DOI: 10.1080/00397910802663386
To link to this article: http://dx.doi.org/10.1080/00397910802663386
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Synthetic Communications1, 39: 2647–2663, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802663386
Microwave-Assisted Base-Catalyzed Cyclization
and Nucleophilic Substitution
of O-Azidobenzanilides to Synthesize
1,2-Disubstituted Indazol-3-ones
Arthur Y. Shaw, Yi-Ru Chen, and Chia-Hua Tsai
Department of Chemistry, Tamkang University, Tamsui, Taiwan
Abstract: A series of 1,2-disubstituted indazol-3-ones were synthesized by
microwave-assisted base-catalyzed cyclization and nucleophilic substitution of
o-azidobenzanilides. Among five tested reaction conditions, the cyclization
of o-azidobenzanilides catalyzed by sodium hydride in DMF, sequentially
followed by the nucleophilic substitution under microwave irradiation, exhibited
the optimal results. Moreover, compared to the counterparts prepared by conven-
tional heat, this method demonstrated a more expeditious and efficient process to
establish a diversified 1,2-disubstituted indazol-3-one library for high-throughput
biological screening.
Keywords: Base-catalyzed cyclization, indazol-3-one, microwave-assisted
INTRODUCTION
Although the indazol-3-one skeleton is not found in naturally occurring
compounds, many synthetic indazol-3-one derivatives have gained a
great deal of attention because of their promising pharmacological
properties, such as anti-asthmatic,[1] anti-inflammatory,[2] anticancer,[3]
antihyperlipidemic,[4] and antipsychotic[5] activities. Additionally, they
are potential analgesics for the antagonism of transient receptor potential
vanilloid 1 (TRPV1).[6] As a result, the indazol-3-one structure seems to
Received August 28, 2008.
Address correspondence to Arthur Y. Shaw, Department of Chemistry,
Tamkang University, Tamsui 251, Taiwan. E-mail: shaw299@mail.tku.edu.tw
2647

2648
A. Y. Shaw, Y.-R. Chen, and C.-H. Tsai
be a versatile scaffold for the design of a variety of pharmacologically
active compounds. So far, several protocols access to 2-substituted
indazol-3-one derivatives, including the base-catalyzed cyclization of
o-azidobenzanilides,[7] the high-pressure transition-metal-catalyzed carbo-
nylation of azobenzenes,[8] the cyclization of o-arylhydrazinobenzoic
acids,[9] and the reduction cyclization of o-nitrobenzanilides.[10] More
recently, the PIFA-mediated oxidative cyclization of o-amidobenzanili-
des was developed by Correa et al.[11] Nevertheless, none of the synthetic
approaches mentioned were carried out under microwave irradiation. To
develop an expeditious and efficient process for the synthesis of
1,2-disubstituted indazol-3-one derivatives, we take advantage of
microwave-assisted, base-catalyzed cyclization of o-azidobenzanilides,
sequentially followed by nucleophilic substitution to generate a series
of 1,2-disubstituted indazol-3-ones.
RESULTS AND DISCUSSION
The overall synthetic routes to 1,2-disubstituted indazol-3-ones in this
study are summarized in Scheme 1. All tested o-azidobenzanilides 3a–j
were readily prepared as indicated in Table 1.
First of all, we took 3a and benzyl bromide as our model reaction in
several conditions to examine the feasibility of the microwave-assisted,
based-catalyzed cyclization of o-azidobenzanilides. As shown in Table 2,
the cyclization of 3a was carried out by the treatment of 1.2 equiv of
sodium hydride in anhydrous dimethylformamide (DMF) under micro-
wave irradiation for 1.5 min. Without workup, 1.05 equiv of benzyl
Scheme 1. Reagents and conditions: (a) (i) NaNO2, HCl=H2O, 5ꢀC; (ii) NaN3,
H2O, 5ꢀC to rt; (b) (i) SOCl2, DMF (cat), reflux, 1.5 h; (ii) ArNH2, NEt3,
DCM, rt; (c) (i) NaH, DMF, heat or microwave irradiation; (ii) Ar’CH2Br, rt
or microwave irradiation.

Microwave-Assisted Cyclization of Indazol-3-ones
2649
Table 1. Chemical structures of 2-azidobenzanilides 3a–j
Entry
Ar
Yield (%)
3a
3b
3c
3d
3e
3f
Phenyl
Pyridin-4-yl
4-Methylphenyl
4-Methoxyphenyl
4-(Dimethylamino)phenyl
4-Chlorophenyl
4-Bromophenyl
4-Cyanophenyl
4-Nitrophenyl
3,4,5-Trimethoxyphenyl
95
90
85
88
85
92
84
79
74
87
3g
3h
3i
3j
bromide was added to the mixture and irradiated for a further 30 s to
afford 4a with 94% yield (entry 3).
Similarly, the reaction carried out in the presence of NaH in
anhydrous dimethyl sulfoxide (DMSO) gave 90% yield of 4a (Table 2,
Table 2. Reaction conditions of microwave-assisted cyclization of
o-azidobenzanilide
Entry
Base
Solvent
MW (Watt)
Time (min)
Yield (%)
1
2
3
4
5
KOH
NaOEt
NaH
NaH
NaH
EtOH
EtOH
DMF
DMSO
THF
80
80
80
80
20
20
2
2
10
20
25
94
90
37
300

2650
A. Y. Shaw, Y.-R. Chen, and C.-H. Tsai
entry 4). However, as the reaction solvent was replaced by anhydrous
tetrahydrofuran (THF) to irradiate in the range of 80 W to 300 W, the
yield turned out to be less than those of DMF and DMSO (4a in 37%
yield, Table 2, entry 5). This discrepancy might be attributed to the poor
solubility of NaH in THF as well as THF’s lower dielectric loss (e, 0.348)
for efficient microwave irradiation. Furthermore, neither pottassium
hydroxide (KOH) nor NaOEt in ethanol (EtOH) was a suitable base in
microwave-assisted conditions, with 20% (Table 2, entry 1) and 25%
(Table 2, entry 2) yields, respectively. These findings were in accordance
with the cyclization of o-azidobenzanilides mediated by thermal heating,
with poor yield reported in the literature.[7] The proposed mechanism of
the sequential base-catalyzed cyclization and nucleophilic substitution to
generate 1,2-disubstituted indazol-3-one is depicted in Scheme 2.
In the presence of a strong base, o-azidobenzanilide was deproto-
nated as the resonance stabilized anions (5 and 5a). Following by the
assisted loss of the nitrogen molecule contributed by o-azido group, the
cyclization of intermediate 5a to obtain 2-substituted indazol-3-one (6)
was accomplished. Without stopping the reaction, the nucleophilic sub-
stitution of intermediate (6) was further performed by the treatment of
benzyl bromide to give desired 1,2-disubstituted indazol-3-one (4a).
With the optimized reaction condition in hand, we next tested the
scope of this protocol by varying 4-substituted benzyl bromides to carry
out nucleophilic substitution in the second step of the reaction. As shown
in Table 3, all products (4a–f) obtained under microwave irradiation
exhibited good yields with reduced reaction time as compared to the
counterparts prepared by the conventional heat.
Scheme 2. Proposed mechanism of 1,2-disubstituted indozol-3-one (4a)
preparation.

Microwave-Assisted Cyclization of Indazol-3-ones
2651
Table 3. Chemical structures of 1,2-disubstituted indozol-3-one derivatives 4a–f
Conventional heat
Microwave irradiation
Entry
Ar0
Time (h)
Yield (%)
Time (min)
Yield (%)
4a
4b
4c
4d
4e
4f
Phenyl
6
6
6
6
6
6
88
71
68
76
87
76
2
94
85
84
88
92
84
4-Fluorophenyl
4-Chlorophenyl
4-Bromophenyl
4-Methylphenyl
4-Nitrophenyl
1.5
1.5
1.5
2
1.5
Later, various o-azidobenzanilides (3b–j, Table 1) bearing both
electron-donating and electron-withdrawing groups on the aryl moiety
were further examined under microwave irradiation. As summarized in
Table 4, the desired products (4g–o) were easily obtained with good yield.
To further investigate the compatibility of nucleophilic aromatic sub-
stitution adopted by this protocol, we chose 1-fluoro-4-nitrobenzene as a
model reaction. As shown in Scheme 3, the reaction was carried out to
obtain the desired product (4p) with 87% isolated yield.
In conclusion, we have successfully synthesized a series of 1,2-
disubstituted indazol-3-ones by sequential microwave-assisted, base-
catalyzed cyclization and nucleophilic substitution in good yields. This
expeditious and efficient process approach could be applied to establish
a library of diversified 1,2-disubstituted indazol-3-ones for high-
throughput biological screening.
Typical Procedure for the Synthesis of N,N-Disubstituted Indozol-3-one
Derivatives
Conventional Heat Method
2-Azido-N-phenylbenzamide (238 mg, 1.0 mmol) was added to a suspen-
sion of NaH (60% dispersion in mineral oil, 48 mg, 1.2 mmol) in dry
DMF (3.0 ml). The reaction mixture was stirred at 60ꢀC for 5 h. The

2652
A. Y. Shaw, Y.-R. Chen, and C.-H. Tsai
Table 4. Chemical structures of 1,2-disubstituted indozol-3-one derivatives
derivatives 4g–o
Conventional heat Microwave irradiation
Entry
Ar
Time (hr) Yield (%) Time (min) Yield (%)
4g
4h
4i
Pyridin-4-yl
4-Methylphenyl
4-Methoxyphenyl
4-(Dimethylamino)phenyl
4-Chlorophenyl
4-Bromophenyl
4-Cyanophenyl
4-Nitrophenyl
3,4,5-Trimethoxyphenyl
6.5
6
4.5
4.5
6
6
6
6
5
46
73
90
86
53
78
73
71
85
1.5
1.5
1.5
1.5
2
2
2
2
1.5
84
88
93
92
72
87
79
87
93
4j
4k
4l
4m
4n
4o
reaction mixture was cooled to room temperature, and then benzyl
bromide (180 mg, 1.05 mmol) was added. The mixture was stirred for
an additional 1 h. The solvent was removed under reduced pressure,
and the residue was charged with dichloromethane (DCM) (10 ml), then
washed with water (10 ml) and brine (10 ml). The organic layer was dried
over MgSO4, evaporated in vacuo, and purified by flash chromatography
on silica gel (ethyl acetate–hexane ¼ 3=7) to obtain 4a (264 mg, 88%).
Scheme 3. Preparation of 1,2-diaryl indazol-3-one (4p).

Microwave-Assisted Cyclization of Indazol-3-ones
2653
Microwave Irradiation Method
Microwave irradiation experiments were demonstrated using a single-
mode microwave instrument, Discover Benchmate (CEM Focused
Synthesis System, NC). Experiments were carried out in sealed micro-
wave process vials at 80 W with the temperature of 50 to 60ꢀC for the
time indicated in each case.
EXPERIMENTAL
Chemical reagents and organic solvents were purchased from TCI,
Aldrich, and Alfa Aesar unless otherwise mentioned. Melting points were
determined on a Fargo MP-2D instrument Nuclear magnetic resonance
spectra (1H and 13C NMR) were measured on a Bruker AC-300 instru-
ment. Chemical shifts (d ) are reported in parts per million (ppm) relative
to the tetramethylsilane (TMS) peak. Mass spectra (MS) were obtained
by EI and FAB on a Jeol JMS-700 instrument. Flash column chromato-
graphy was performed with silica gel (230–400 mesh). Elemental analysis
was carried out on a Heraeus Vario EL-III C, H, N analyzer.
2-Azidobenzoic Acid (2)
A solution of sodium nitrite (4.75 g, 69 mmol) in H2O (63 mL) was added
to a solution of anthranilic acid (10 g, 73 mmol) in H2O (125 mL) and
conc. HCl (125 mL) at 5ꢀC under N2 and then stirred for 10 min. This
solution was then added dropwise over 25 min to a stirred solution of
sodium azide (4.2 g, 65 mmol) and sodium acetate (105 g, 0.77 mol) in
H2O (125 mL) at ꢁ5ꢀC. The resulting mixture was stirred at 0ꢀC for
5 min, warmed to room temperature, and stirred for a further 90 min.
The resulting precipitate was filtered, washed with H2O (200 mL) and
hexanes (200 mL), and dried under reduced pressure to yield the desired
azide (8.68 g, 73%). 1H NMR (300 MHz, d4-MeOH) d 7.24 (t, J ¼ 8.6 Hz,
1 H), 7.33 (d, J ¼ 8.1 Hz, 1 H), 7.59 (t, J ¼ 7.6 Hz, 1 H), 7.87 (dd, J ¼ 7.8,
1.3 Hz, 1 H) ppm.
2-Azido-N-phenylbenzamide (3a)
A mixture of 2-azidobenzoic acid (1.63 g, 10.0 mmol), thionyl chloride
(4.76 g, 40.0 mmol), and DMF (0.5 ml) in DCM (30 ml) was stirred under
reflux for 2 h. The reaction mixture was cooled to room temperature, eva-
porated in vacuo, and dried with a high vacuum pump to obtain crude

2654
A. Y. Shaw, Y.-R. Chen, and C.-H. Tsai
2-azidobenzoyl chloride. Without purification, 2-azidobenzoyl chloride
and aniline (0.93 g, 10.0 mmol) were dissolved in an ice-bath with DCM
(20 ml). Triethylamine (1.2 g, 12.0 mmol) was added slowly to the solu-
tion, and the resulting mixture was stirred for 18 h. The reaction mixture
was washed with saturated NaHCO3 (20 ml), water (10 ml), and brine
(10 ml); dried over MgSO4; and evaporated in vacuo to get the crude
product, followed by the purification with silica-gel chromatography
(hexane=ethyl acetate 7=3) to afford 2-azido-N-phenylbenzamide
(2.26 g, 9.5 mmol, 95% yield) as a solid. Mp 133–134ꢀC. (lit.[12] 134ꢀC).
1H NMR (300 MHz, CDCl3) d 7.16 (t, J ¼ 7.4 Hz, 1 H), 7.24 (dd,
J ¼ 7.9, 7.4 Hz, 2 H), 7.35 (d, J ¼ 7.8 Hz, 2 H), 7.53 (dd, J ¼ 7.8, 7.4 Hz,
1 H), 7.68 (d, J ¼ 7.9 Hz, 2 H), 8.26 (d, J ¼ 7.9 Hz, 1 H), 9.38 (s, 1 H)
ppm. 13C NMR (75 MHz, CDCl3) 118.5, 120.5, 124.5, 125.2, 129.0,
132.1, 132.6, 136.8, 138.0, 162.9 ppm.
2-Azido-N-(pyridin-4-yl)benzamide (3b)
Compound 3b was synthesized from the procedure described for com-
1
pound 3a as a solid. Mp 144.5–145.5ꢀC. H NMR (300 MHz, CDCl3) d
7.23 (d, J ¼ 6.9 Hz, 1 H), 7.31 (dd, J ¼ 7.3, 6.9 Hz, 1 H), 7.57 (dd,
J ¼ 7.6, 7.3 Hz, 1 H), 7.61 (d, J ¼ 4.9 Hz, 2 H), 8.19 (J ¼ 7.6 Hz, 1 H),
8.51 (d, J ¼ 4.9 Hz, 2 H), 9.62 (s, 1 H) ppm. 13C NMR (75 MHz, d6-DMSO)
113.7, 119.6, 125.0, 128.4, 129.5, 132.0, 137.0, 145.6, 150.5, 165.7 ppm.
2-Azido-N-p-tolylbenzamide (3c)
Compound 3c was synthesized from the procedure described for com-
pound 3a as a solid. Mp 128ꢀC (lit.[1] 130ꢀC). 1H NMR (300 MHz,
CDCl3) d 2.34 (s, 3 H), 7.17 (d, J ¼ 8.3 Hz, 2 H), 7.25 (d, J ¼ 7.6 Hz, 1
H), 7.32 (dd, J ¼ 7.9, 7.5 Hz, 1 H), 7.52 (d, J ¼ 7.6, 7.5 Hz, 1 H), 7.54
(d, J ¼ 8.3 Hz, 2 H), 8.24 (d, J ¼ 7.9 Hz, 1 H), 9.24 (s, 1 H) ppm. 13C
NMR (75 MHz, CDCl3) 21.1, 118.6, 120.7, 125.5, 129.7, 132.8, 132.9,
134.3, 135.5, 136.9, 162.7 ppm.
2-Azido-N-(4-methoxyphenyl)benzamide (3d)
Compound 3d was synthesized from the procedure described for com-
1
pound 3a as a solid. Mp 119–120ꢀC (lit.[1] 120ꢀC). H NMR (300 MHz,
CDCl3) d 3.81 (s, 3H), 6.89 (d, J ¼ 8.8 Hz, 2H), 7.25 (m, 2H), 7.51 (d,
J ¼ 7.8 Hz, 1 H), 7.58 (d, J ¼ 8.8 Hz, 2 H), 8.23 (d, J ¼ 7.8 Hz, 1 H),

Microwave-Assisted Cyclization of Indazol-3-ones
2655
9.21 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3) 55.6, 114.2, 118.6, 122.4,
125.4, 125.5, 131.2, 132.4, 132.7, 136.9, 156.7, 162.6 ppm.
2-Azido-N-(4-(dimethylamino)phenyl)benzamide (3e)
Compound 3e was synthesized from the procedure described for com-
pound 3a as a solid. Mp 117–119.7ꢀC. 1H NMR (300 MHz, CDCl3)
d 2.94 (s, 6 H), 6.75 (d, J ¼ 6.8 Hz, 2 H), 7.31 (m, 1 H), 7.52 (d, J ¼ 6.8 Hz,
2 H), 7.65 (m, 2 H), 8.24 (d, J ¼ 7.8 Hz, 1 H), 9.11 (s, 1 H) ppm. 13C NMR
(75 MHz, d6-DMSO) 40.5, 112.6, 119.5, 121.0, 124.9, 128.9, 129.4, 129.5,
131.3, 136.6, 147.3, 163.7 ppm.
2-Azido-N-(4-chlorophenyl)benzamide (3f)
Compound 3f was synthesized from the procedure described for com-
1
pound 3a as a solid. Mp 115.5ꢀC (lit.[1] 117ꢀC). H NMR (300 MHz,
CDCl3) d 7.26 (d, J ¼ 7.5 Hz, 1H), 7.32 (dd, J ¼ 7.9, 7.5 Hz, 1H), 7.33
(d, J ¼ 6.9 Hz, 2H), 7.54 (dd, J ¼ 7.9, 7.5 Hz, 1H), 7.63 (d, J ¼ 6.9 Hz,
2H), 8.26 (d, J ¼ 7.9 Hz, 1H), 9.38 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3) 118.4, 121.6, 124.9, 125.1, 128.8, 129.2, 131.9, 132.7, 136.5,
136.8, 162.8 ppm.
2-Azido-N-(4-bromophenyl)benzamide (3g)
Compound 3 g was synthesized from the procedure described for com-
pound 3a. Mp 125ꢀC. 1H NMR (300 MHz, CDCl3) d 7.26 (d, J ¼ 7.5 Hz,
Hz, 1 H), 7.32 (dd, J ¼ 7.9, 7.5 Hz, 1 H), 7.33 (d, J ¼ 6.8 Hz, 2 H), 7.52
(dd, J ¼ 7.9, 7.5 Hz, 1 H), 7.61 (d, J ¼ 6.8 Hz, 2 H), 8.26 (d, J ¼ 7.9 Hz,
1 H), 9.38 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3) 117.0, 118.5,
122.0, 124.9, 125.3, 131.9, 132.2, 132.9, 136.9, 137.1, 162.8 ppm.
2-Azido-N-(4-cyanophenyl)benzamide (3h)
Compound 3h was synthesized from the procedure described for com-
pound 3a. Mp 133.7ꢀC. 1H NMR (300 MHz, CDCl3) d 7.31 (d,
J ¼ 7.5 Hz, 1H), 7.35 (d, J ¼ 8.0 Hz, 1H), 7.57 (d, J ¼ 7.5 Hz, 1H), 7.63
(d, J ¼ 7.9 Hz, 2H), 7.81 (d, J ¼ 7.9 Hz, 2H), 8.27 (d, J ¼ 8.0 Hz, 1H),
9.65 (s, 1H) ppm. 13C NMR (75 MHz, d6-DMSO) 105.6, 118.2, 119.6,
125.0, 127.2, 128.5, 129.5, 130.0, 132.6, 136.9, 143.1, 165.3 ppm. HRMS
(M þ 1)þ for C14H10N5O 264.0880; found 264.0884.

2656
A. Y. Shaw, Y.-R. Chen, and C.-H. Tsai
2-Azido-N-(4-nitrophenyl)benzamide (3i)
Compound 3i was synthesized from the procedure described for
1
compound 3a. Mp 161.5ꢀC (lit.[1] 160ꢀC). H NMR (300 MHz, CDCl3)
d 7.27 (d, J ¼ 8.1 Hz, 1 H), 7.30 (d, J ¼ 8.1 Hz, 1H), 7.61 (t, J ¼ 7.9 Hz,
1H), 7.86 (d, J ¼ 5.0 Hz, 2H), 8.24 (d, J ¼ 5.0 Hz, 2H), 8.28 (d, J ¼ 7.9 Hz,
1 H), 9.23 (s, 1 H) ppm. 13C NMR (75 MHz, d6-DMSO) 119.3, 119.5,
124.9, 125.0, 128.3, 129.6, 132.1, 137.1, 142.6, 145.1, 165.3 ppm.
2-Azido-N-(3,4,5-trimethoxyphenyl)benzamide (3j)
Compound 3j was synthesized from the procedure described for
1
compound 3a. Mp 141.4–141.7ꢀC. H NMR (300 MHz, CDCl3) d 3.76
(s, 3H), 3.89 (s, 6H), 6.98 (s, 2H), 7.19 (d, J ¼ 8.1 Hz, 1H), 7.29 (dd,
J ¼ 8.1 Hz, 7.6 Hz, 1H), 7.56 (dd, J ¼ 7.8, 7.6 Hz, 1H), 8.24 (d, J ¼ 7.8 Hz,
1H), 9.23 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3) 50.1, 60.9, 98.1,
118.5, 125.3, 128.3, 131.9, 132.7, 134.1, 134.8, 136.8, 153.2, 162.9 ppm.
HRMS (M)þ for C16H16N4O4 328.1172; found 328.1172.
1-Benzyl-2-phenyl-1H-indazol-3(2H)-one (4a)
A 5-ml microwave process vial was charged with a stir bar. To the vessel
containing a suspension of NaH (60% dispersion in mineral oil, 48mg,
1.2 mmol) in dry DMF (3.0 ml), 2-azido-N-phenylbenzamide (238mg,
1.0 mmol) was added. The reaction vessel was sealed, and the mixture was
subsequently heated in a microwave reactor at 80W for 1 min. Following
by the addition of benzyl bromide (180 mg, 1.05mmol), the mixture was
heated by microwave irradiation at 80W for an additional 30 s. After this
time, the solvent was removed under reduced pressure, and the residue
was charged with DCM (10ml) and washed with water (10ml) and brine
(10 ml). Subsequently, the organic layer was dried over MgSO4, evaporated
in vacuo, and purified by flash chromatography on silica gel (ethyl acetate–
hexane ¼ 3=7) to obtain 4a (319 mg, 94%) as a solid. Mp 128ꢀC. 1H NMR
(300 MHz, CDCl3) d 4.74 (s, 2H), 6.88 (d, J ¼ 6.5 Hz, 2H), 7.14 (t,
J ¼ 7.3 Hz, 1H), 7.17 (dd, J ¼ 7.3, 6.5 Hz, 2H), 7.23 (t, J ¼ 7.2 Hz, 1H),
7.27 (d, J ¼ 7.6 Hz, 1H), 7.32 (d, J ¼ 7.6 Hz, 1H), 7.54 (d, J ¼ 7.3 Hz, 2H),
7.56 (dd, J ¼ 7.7, 7.6 Hz, 1 H), 7.59 (d, J ¼ 7.3 Hz, 2 H), 7.82 (d, J ¼ 7.7 Hz,
Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3) 55.1, 113.5, 120.1, 123.2, 124.1,
124.8, 126.6, 128.5, 128.9, 129.4, 132.6, 133.5, 135.5, 150.3, 162.7 ppm. MS
(M)þ calcd. for C20H16N2O 300; found 300. HRMS (M)þ calcd. for
C20H16N2O 300.1263; found 300.1268. Anal. calcd. for C20H16N2O: C,
79.98; H, 5.37; N, 9.33. Found: C, 79.29; H, 5.36; N, 9.04.

Microwave-Assisted Cyclization of Indazol-3-ones
2657
1-(4-Fluorobenzyl)-2-phenyl-1H-indazol-3(2H)-one (4b)
Compound 4b was synthesized from the procedure described for
1
compound 4a. Mp 137.5–137.8ꢀC. H NMR (300 MHz, CDCl3) d 4.72
(s, 2 H), 6.81 (d, J ¼ 7.5 Hz, 2 H), 6.83 (s, 2 H), 7.23 (t, J ¼ 7.1 Hz, 1 H),
7.34 (m, 2 H), 7.56 (dd, J ¼ 7.9, 7.5 Hz, 1 H), 7.58 (m, 3 H), 7.62 (d,
J ¼ 7.5 Hz, 1 H), 7.83 (d, J ¼ 7.9 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3) 54.3, 113.4, 115.3, 115.6, 120.3, 123.4, 123.9, 124.9, 126.6,
129.1, 129.5, 130.6, 132.7, 135.4, 150.1, 161.2, 162.7, 164.5 ppm. MS
(M)þ calcd. for C20H15FN2O 318; found 318. HRMS (M)þ calcd. for
C20H15FN2O 318.1168; found 318.1168. Anal. calcd. for C20H15FN2O:
C, 75.46; H, 4.75; N, 8.80. Found: C, 75.43; H, 5.27; N, 8.26.
1-(4-Chlorobenzyl)-2-phenyl-1H-indazol-3(2H)-one (4c)
Compound 4c was synthesized from the procedure described for
1
compound 4a. Mp 145.7–146ꢀC. H NMR (300 MHz, CDCl3) d 4.72 (s,
2 H), 6.79 (d, J ¼ 6.6 Hz, 2 H), 7.09 (d, J ¼ 6.6 Hz, 2 H), 7.21 (t, J ¼ 7.6 Hz,
1 H), 7.29 (dd, J ¼ 7.6, 7.3 Hz, 2 H), 7.55 (m, 2 H), 7.57 (d, J ¼ 7.9 Hz, 1 H),
7.59 (d, J ¼ 7.3 Hz, 2 H), 7.83 (d, J ¼ 7.9 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3) 54.2, 120.1, 123.8, 124.8, 126.6, 128.6, 129.1, 129.8,
130.2, 131.7, 132.3, 132.7, 134.4, 135.3, 150.0, 162.6 ppm. MS (M)þ calcd.
for C20H15ClN2O 334; found 334. HRMS (M)þ calcd. for C20H15ClN2O
334.0873; found 334.0871. Anal. calcd. for C20H15ClN2O: C, 71.75; H,
4.52; N, 8.37. Found: C, 75.45; H, 4.86; N, 8.34.
1-(4-Bromobenzyl)-2-phenyl-1H-indazol-3(2H)-one (4d)
Compound 4d was synthesized from the procedure described for
1
compound 4a. Mp 159ꢀC. H NMR (300 MHz, CDCl3) d 4.70 (s, 2 H),
6.74 (d, J ¼ 6.6 Hz, 2 H), 7.27 (d, J ¼ 6.6 Hz, 2 H), 7.22–7.35 (m, 3 H),
7.55–7.60 (m, 5 H), 7.84 (d, J ¼ 7.9 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3) 54.4, 111.3, 120.2, 122.8, 123.5, 123.9, 124.9, 126.6, 129.5,
130.5, 131.7, 132.3, 132.8, 135.4, 150.1, 162.7 ppm. MS (M þ 2 Li)þ calcd.
for C20H15N2OLi2 390; found 390. HRMS (M)þ calcd. for C20H15BrN2O
378.0368; found 378.0367. Anal. Calcd. for C20H15BrN2O: C, 63.34; H,
3.99; N, 7.39. Found: C, 63.67; H, 3.65; N, 7.64.
1-(4-Methylbenzyl)-2-phenyl-1H-indazol-3(2H)-one (4e)
Compound 4e was synthesized from the procedure described for
compound 4a. Mp 117.7ꢀC. 1H NMR (300 MHz, CDCl3) d 2.24 (s,

2658
A. Y. Shaw, Y.-R. Chen, and C.-H. Tsai
3H), 4.71 (s, 2H), 6.76 (d, J ¼ 7.9 Hz, 2H), 6.93 (d, J ¼ 7.9 Hz, 2H), 7.19
(t, J ¼ 7.3 Hz, 1 H), 7.29 (dd, J ¼ 7.6, 7.3 Hz, 2 H), 7.53 (m, 3 H), 7.62 (d,
J ¼ 7.6 Hz, 2 H), 7.82 (d, J ¼ 7.8 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3) 21.3, 54.8, 113.6, 120.1, 123.1, 124.1, 124.7, 126.5, 128.8, 129.2,
129.4, 130.4, 132.6, 135.5, 138.3, 150.3, 162.7 ppm. MS (M)þ calcd.
for C21H18N2O 314; found 314. HRMS (M)þ calcd. for C21H18N2O
314.1419, found 314.1416. Anal. calcd. for C21H18N2O: C, 80.23; H,
5.77; N, 8.91. Found: C, 80.04; H, 5.91; N, 8.47.
1-(4-Nitrobenzyl)-2-phenyl-1H-indazol-3(2H)-one (4f)
Compound 4f was synthesized from the procedure described for
1
compound 4a. Mp 195–197ꢀC. H NMR (300 MHz, CDCl3) d 4.84 (s,
2H), 7.05 (d, J ¼ 8.7 Hz, 2H), 7.25 (dd, J ¼ 7.9, 7.5 Hz, 1H), 7.32
(d, J ¼ 8.7 Hz, 1H), 7.36 (m, 1H), 7.51 (d, J ¼ 7.5 Hz, 1H), 7.66
(d, J ¼ 8.7 Hz, 2H), 7.59 (m, 2H), 7.84 (d, J ¼ 7.9 Hz, 1H),
8.01 (d, J ¼ 8.7 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3) 54.2, 113.1,
120.1, 123.7, 123.8, 123.9, 125.1, 126.9, 129.7, 129.8, 130.1, 133.1,
135.1, 140.5, 148.1, 149.8, 162.6 ppm. MS (M þ 2 Li)þ calcd. for
C20H15N3O3Li2 357; found 357. HRMS (M)þ calcd. for C20H15N3O3
345.3514; found 345.1114. Anal. calcd. for C20H15N3O3: C, 69.56; H,
4.38; N, 12.17. Found: C, 69.56; H, 4.62; N, 12.01.
1-Benzyl-2-(pyridin-4-yl)-1H-indazol-3(2H)-one (4g)
Compound 4 g was synthesized from the procedure described for
1
compound 4a. Mp 149.6–149.9ꢀC. H NMR (300 MHz, CDCl3) d 4.75
(s, 2 H), 6.86 (d, J ¼ 7.2 Hz, 2 H), 7.12 (d, J ¼ 7.2 Hz, 2 H), 7.14 (m,
1 H), 7.25 (dd, J ¼ 8.2, 7.3 Hz, 1 H), 7.31 (d, J ¼ 8.2 Hz, 1 H), 7.61 (dd,
J ¼ 7.5, 7.3 Hz, 1 H), 7.65 (d, J ¼ 6.5 Hz, 2 H), 7.81 (d, J ¼ 7.5 Hz, 1
H), 8.71 (d, J ¼ 6.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3) 56.3,
114.2, 116.2, 120.0, 123.9, 125.1, 128.7, 128.9, 129.0, 132.5, 133.7,
143.0, 151.1, 151.5, 163.3 ppm. MS (M)þ calcd. for C19H15N3O 301;
found 301. HRMS calcd. for C19H15N3O 301.1215; found 301.1214.
Anal. calcd. for C19H15N3O: C, 75.73; H, 5.02; N, 13.94. Found: C,
75.08; H, 4.98; N, 14.03.
1-Benzyl-2-p-tolyl-1H-indazol-3(2H)-one (4h)
Compound 4h was synthesized from the procedure described for
compound 4a. Mp 169.7ꢀC. 1H NMR (300 MHz, CDCl3) d 2.41 (s,

Microwave-Assisted Cyclization of Indazol-3-ones
2659
3 H), 4.73 (s, 2 H), 6.91 (d, J ¼ 7.2 Hz, 2 H), 7.13 (d, J ¼ 7.4 Hz, 2 H), 7.17
(m, 2 H), 7.22 (d, J ¼ 7.2 Hz, 1 H), 7.30 (d, J ¼ 8.3 Hz, 2 H), 7.47 (d,
J ¼ 8.3 Hz, 2 H), 7.52 (dd, J ¼ 7.9, 7.2 Hz, 1 H), 7.83 (d, J ¼ 7.9 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3) 21.3, 54.8, 113.3, 120.1, 123.0,
124.3, 124.8, 128.4, 128.5, 128.8, 130.1, 132.5, 132.8, 133.7, 136.6,
150.1, 162.6 ppm. MS (M)þ calcd. for C21H18N2O 314, found 314.
HRMS (M)þ calcd. for C21H18N2O 314.1419; found 314.1425. Anal.
calcd. for C21H18N2O: C, 80.23; H, 5.77; N, 8.91. Found: C, 79.95; H,
5.84; N, 8.88.
1-Benzyl-2-(4-methoxyphenyl)-1H-Indazol-3(2H)-one (4i)
Compound 4i was synthesized from the procedure described for
compound 4a. Mp 155.3ꢀC. 1H NMR (300 MHz, CDCl3) d 3.85 (s,
3H), 4.72 (s, 2H), 6.89 (d, J ¼ 6.7 Hz, 2H), 7.02 (d, J ¼ 8.8 Hz, 2H),
7.13 (d, J ¼ 6.7 Hz, 2H), 7.15 (d, J ¼ 8.3 Hz, 1H), 7.18 (dd, J ¼ 8.2,
7.8 Hz, 1H), 7.25 (d, J ¼ 8.3 Hz, 1H), 7.46 (d, J ¼ 8.8 Hz, 2H), 7.56 (d,
J ¼ 8.2 Hz, 1H), 7.83 (d, J ¼ 7.8 Hz, 1H) ppm. 13C NMR (75 MHz,
CDCl3) 54.6, 55.7, 113.1, 114.7, 119.8, 122.9, 124.6, 126.2, 128.1, 128.4,
128.5, 128.7, 132.4, 133.8, 149.8, 158.5, 162.6 ppm. MS (M)þ calcd. for
C21H18N2O2 330; found 330. HRMS (M)þ calcd. for C21H18N2O2
330.1368; found 330.1446. Anal. calcd. for C21H18N2O2: C, 76.34; H,
5.49; N, 8.48. Found: C, 76.45; H, 5.23; N, 8.39.
1-Benzyl-2-(4-(dimethylamino)phenyl)-1H-indazol-3(2H)-one (4j)
Compound 4j was synthesized from the procedure described for
compound 4a. Mp 127.6ꢀC. 1H NMR (300 MHz, CDCl3) d 3.00 (s,
6H), 4.72 (s, 2H), 6.82 (d, J ¼ 7.1 Hz, 2H), 6.95 (d, J ¼ 7.2 Hz, 2H),
7.13–7.16 (m, 3H), 7.18 (d, J ¼ 7.2 Hz, 2H), 7.36 (d, J ¼ 7.1 Hz, 2H),
7.51 (d, J ¼ 7.7 Hz, 1H), 7.85 (d, J ¼ 7.7 Hz, 1H) ppm. 13C NMR
(75 MHz, CDCl3) 40.8, 54.2, 112.8, 119.6, 119.8, 122.6, 123.9, 124.6,
126.5, 128.3, 128.5, 128.6, 132.0, 134.3, 149.4, 149.8, 162.4 ppm. MS
(M)þ calcd. for C22H21N3O 343; found 343. HRMS (M)þ calcd. for
C22H21N3O 343.4216; found 345.1683. Anal. calcd. for C22H21N3O: C,
76.94; H, 6.16; N, 12.24. Found: C, 76.62; H, 6.30; N, 11.79.
1-Benzyl-2-(4-chlorophenyl)-1H-indazol-3(2H)-one (4k)
Compound 4k was synthesized from the procedure described for com-
1
pound 4a. Mp 127.3ꢀC. H NMR (300 MHz, CDCl3) d 4.72 (s, 2H),

2660
A. Y. Shaw, Y.-R. Chen, and C.-H. Tsai
6.86 (d, J ¼ 7.2 Hz, 2 H), 7.12 (dd, J ¼ 7.7, 7.2 Hz, 2 H), 7.24 (d,
J ¼ 7.2 Hz, 2 H), 7.29 (d, J ¼ 8.4 Hz, 1 H), 7.49 (d, J ¼ 8.8 Hz, 2 H),
7.56 (d, J ¼ 8.4 Hz, 1 H), 7.60 (d, J ¼ 8.8 Hz, 2 H), 7.81 (d, J ¼ 7.7 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3) 55.3, 113.6, 119.9, 123.4, 124.8,
125.0, 128.5, 128.6, 128.8, 129.6, 131.9, 132.9, 133.2, 134.1, 150.5,
162.8 ppm. MS (M)þ calcd. for C20H15ClN2O 334; found 334. HRMS
(M)þ calcd. for C20H15ClN2O 334.0873; found 334.0873. Anal. calcd.
for C20H15ClN2O: C, 71.75; H, 4.52; N, 8.37. Found: C, 71.62; H,
4.66; N, 8.30.
1-Benzyl-2-(4-bromophenyl)-1H-indazol-3(2H)-one (4l)
Compound 4 l was synthesized from the procedure described for com-
1
pound 4a. Mp 120.5ꢀC. H NMR (300 MHz, CDCl3) d 4.72 (s, 2H),
6.86 (d, J ¼ 7.3 Hz, 2H), 7.13 (dd, J ¼ 7.7, 7.3 Hz, 2 H), 7.18 (d,
J ¼ 7.3 Hz, 2 H), 7.31 (d, J ¼ 8.4 Hz, 1H), 7.49 (d, J ¼ 8.8 Hz, 2H), 7.58
(d, J ¼ 8.4 Hz, 1H), 7.62 (d, J ¼ 8.8 Hz, 2 H), 7.82 (d, J ¼ 7.7 Hz, 1H)
ppm. 13C NMR (75 MHz, CDCl3) 55.1, 113.3, 119.3, 119.6, 123.2,
124.6, 124.8, 128.3, 128.6, 129.3, 131.7, 132.7, 132.9, 133.8, 135.4,
150.2, 162.5 ppm. MS (M þ 2 Li)þ calcd. for C20H15N2OLi2 390, found
390. HRMS (M)þ calcd. for C20H15BrN2O 378.0368; found 378.0365.
Anal. calcd. for C20H15BrN2O: C, 63.34; H, 3.99; N, 7.39. Found:
63.01; H, 4.25; N, 7.96.
4-(1-Benzyl-3-oxo-1H-indazol-2(3H)-yl)benzonitrile (4m)
Compound 4m was synthesized from the procedure described for com-
1
pound 4a. Mp 200.3ꢀC. H NMR (300 MHz, CDCl3) d 4.73 (s, 2 H),
6.83 (d, J ¼ 7.3 Hz, 2 H), 7.14 (d, J ¼ 7.7 Hz, 2 H), 7.24 (d, J ¼ 7.9 Hz,
2 H), 7.34 (d, J ¼ 7.9 Hz, 1H), 7.62 (t, J ¼ 7.9 Hz, 1 H), 7.77 (m, 4H),
7.81 (d, J ¼ 7.9 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3) 56.2, 109.2,
114.0, 118.8, 119.9, 123.0, 123.9, 125.1, 128.7, 128.8, 128.9, 132.6,
133.5, 133.6, 139.7, 151.2, 163.1 ppm. MS (M)þ calcd. for C21H15N3O
325; found 325. HRMS (M)þ calcd. for C21H15N3O 325.1215; found
325.1211. Anal. calcd. for C21H15N3O: C, 77.52; H, 4.65; N, 12.91.
Found: C, 77.04; H, 4.64; N, 12.97.
1-Benzyl-2-(4-nitrophenyl)-1H-indazol-3(2H)-one (4n)
Compound 4n was synthesized from the procedure described for com-
1
pound 4a. Mp 172.9ꢀC. H NMR (300 MHz, CDCl3) d 4.75 (s, 2H),

Microwave-Assisted Cyclization of Indazol-3-ones
2661
6.82 (d, J ¼ 7.1 Hz, 2 H), 7.14 (d, J ¼ 7.1 Hz, 2 H), 7.21 (m, 2 H), 7.35 (d,
J ¼ 8.2 Hz, 1 H), 7.64 (d, J ¼ 8.2 Hz, 1 H), 7.81 (m, 1 H), 7.83 (d,
J ¼ 9.1 Hz, 2 H), 8.38 (d, J ¼ 9.1 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3) 56.3, 114.1, 119.8, 122.6, 124.1, 125.2, 128.7, 128.9, 132.4,
133.8, 141.3, 144.9, 151.3, 163.2 ppm. MS (M þ 2 Li)þ calcd. for
C20H15N3O3Li2 357; found 357. HRMS (M)þ calcd. for C20H15N3O3
345.3514; found 345.1118. Anal. calcd. for C20H15N3O3: C, 69.56; H,
4.38; N, 12.17. Found: C, 69.27; H, 4.38; N, 12.15.
1-Benzyl-2-(3,4,5-trimethoxyphenyl)-1H-indazol-3(2H)-one (4o)
Compound 4o was synthesized from the procedure described for com-
1
pound 4a. Mp 139.4ꢀC. H NMR (300 MHz, CDCl3) d 3.86 (s, 6 H),
3.88 (s, 3 H), 4.76 (s, 2 H), 6.78 (s, 2 H), 6.95 (d, J ¼ 7.2 Hz, 2 H),
7.14–7.28 (m, 5 H), 7.57 (t, J ¼ 8.2 Hz, 1 H), 7.85 (d, J ¼ 8.2 Hz, 1 H)
ppm. 13C NMR (75 MHz, CDCl3) 55.4, 55.5, 61.3, 102.4, 113.3, 119.9,
123.4, 124.8, 128.7, 128.8, 131.1, 132.9, 134.1, 136.9, 150.2, 153.8,
162.8 ppm. MS (M þ 2 Li)þ calcd. for C23H22N2O4Li2 402; found 402.
HRMS (M)þ calcd. for C23H22N2O4 390.1580; found 390.1583. Anal.
calcd. for C23H22N2O4: C, 70.75; H, 5.68; N, 7.17. Found: C, 70.38; H,
5.82; N, 7.01.
1-(4-Nitrophenyl)-2-phenyl-1H-indazol-3(2H)-one (4p)
Compound 4p was synthesized from the procedure described for com-
pound 4a. Mp 149.6–150ꢀC. 1H NMR (300 MHz, CDCl3) d 7.16 (t,
J ¼ 7.5 Hz, 1 H), 7.34 (d, J ¼ 7.2 Hz, 2 H), 7.35–7.37 (m, 2 H), 7.45 (d,
J ¼ 7.2 Hz, 2 H), 7.55 (d, J ¼ 8.9 Hz, 2 H), 7.58 (d, J ¼ 7.7 Hz, 1 H),
7.96 (d, J ¼ 7.7 Hz, 1 H), 8.22 (d, J ¼ 8.9 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3) 111.8, 118.4, 123.0, 123.8, 124.5, 125.0, 125.4, 126.5,
129.3, 133.9, 135.8, 145.9, 147.8, 148.6, 162.9 ppm. MS (M)þ calcd. for
C19H13N3O3 331; found 331. HRMS (M)þ calcd. for C19H13N3O3
331.0957; found 331.0963. Anal. calcd. for C19H13N3O3: C, 68.88; H,
3.95; N, 12.68. Found: C, 68.75; H, 4.11; N, 12.58.
ACKNOWLEDGMENT
Financial support from the National Science Council of the Republic of
China (NSC 96-2113-M-032-007-MY2) is gratefully acknowledged.

2662
A. Y. Shaw, Y.-R. Chen, and C.-H. Tsai
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