Microwave-assisted Transition Metal-catalyzed Coupling Approach to Indazole Diversity

Article abstract of DOI:10.1002/bkcs.11698

Diverse mono or biaryl substituents were introduced to indazole moieties under microwave-assisted palladium-catalyzed coupling reactions with isomeric bromoindazoles and aryl boronic acids. 1,3-Disubstituted indazoles were also obtained by C?C or C?N coupling of monosubstituted indazoles with functionalized terminal alkenes and arylhalides. Facile introduction of diverse substituents to indazoles showed useful synthetic approach for creating indazole compound library to discover biologically active small molecules.

Full text of DOI:10.1002/bkcs.11698

Article
DOI: 10.1002/bkcs.11698
BULLETIN OF THE
Y. J. Oh and E. K. Yum
KOREAN CHEMICAL SOCIETY
Microwave-assisted Transition Metal-catalyzed Coupling Approach
to Indazole Diversity
*
Yoo Jin Oh and Eul Kgun Yum
Department of Chemistry, Chungnam National University, Daejon 34134, South Korea.
*E-mail: ekyum@cnu.ac.kr
Received December 13, 2018, Accepted February 7, 2019
Diverse mono or biaryl substituents were introduced to indazole moieties under microwave-assisted
palladium-catalyzed coupling reactions with isomeric bromoindazoles and aryl boronic acids.
1,3-Disubstituted indazoles were also obtained by C C or C N coupling of monosubstituted indazoles
with functionalized terminal alkenes and arylhalides. Facile introduction of diverse substituents to inda-
zoles showed useful synthetic approach for creating indazole compound library to discover biologically
active small molecules.
Keywords: Indazole, Diversity microwave, Transition metal, Coupling reaction
Introduction
catalyzed cross coupling with an isomeric haloindazole
moiety under microwave heating. This synthetic approach
affords functionally diversified indazoles for creating poten-
tially bioactive compound library.
Microwave heating has been applied to various chemistry
fields, such as nanotechnology, solid state, and organic syn-
thesis.1 In particular, microwave-assisted organic synthesis
(MAOS) has demonstrated potential for speeding up small
molecule organic synthesis.2–4 The high-speed organic syn-
thetic method could be utilized to synthesize new small het-
erocyclic compounds for drug discovery.5–8
Many natural and synthetic indazole derivatives exhibit
various biological activities, including anticancer, antibac-
terial, antiprotozoal, anti-inflammatory, inhibition of protein
kinase, HIV protease, nitric oxide synthase, and mono-
amine oxidase.9,10 The molecular shape and electrostatic
distribution of indazole moieties contribute extensively to
binding affinity, making indazoles especially active in
enzyme and receptor recognition mechanisms.
Results and Discussion
Many aryl-substituted indazole derivatives are potential
pharmaceuticals.9,10 Initially, we optimized microwave-
assisted, palladium-catalyzed coupling reaction conditions
using N-Boc-6-bromo-1H-indazole and phenylboronic acid
with a variety of Pd catalysts, bases, and solvents. The
reaction conditions are shown in Table 1. The coupling
product 6-phenyl-1H-indazole was obtained with a depro-
tected Boc group. The reaction was performed with differ-
ent palladium-based catalysts, with Pd(PPh3)2Cl2 yielding
the best results (Table 1, entries 1–3). The use of Na2CO3
as a base afforded greater yields than reactions employing
Many synthetic methods involving indazoles utilize ther-
mal or transition metal-catalyzed indazole formation to cre-
ate useful organic compounds.11–19
Table 1. Optimization of aryl-coupling with N-Boc
−6-bromoindazole with phenylboronic acid.
Recently, palladium–catalyzed coupling methods have
shown essential synthetic tools for functionalization and
formation of variety heterocycles.20–22 Our reported
microwave-assisted copper or palladium-catalyzed diversifi-
cation of heterocycles boasts significant advantages over
conventional heating.23–27 In drug discovery research,
establishment of functionally diversified small molecule
compound library is very efficient way to find biologically
active substances with biomolecular targets.28,29 Indazole
moieties contain two aromatic rings with different elec-
tronic configurations, which could be functionalized at mul-
tiple positions. Thus, diversification using an isomeric
Entry
Pd source
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
Pd(OAc)2
Pd (PPh3)4
Na2CO3
Na2CO3
Na2CO3
K2CO3
Cs2CO3
Na2CO3
Na2CO3
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
EtOH
34
73
93
85
83
NR
94
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
haloindazole moiety may be
a promising synthetic
Dioxane:
approach for discovering new biologically active com-
pounds. In this study, we examined palladium or copper-
EtOH (4:1)
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K2CO3 or Cs2CO3 (entries 3–5). Furthermore, although
reactions performed in dioxane or a mixed solvent
(Dioxane:EtOH = 4:1) gave similarly high yields, the
mixed solvent was selected for further use due to the
greater solubility of arylboronic acid and base.
Pd(PPh3)2Cl2, 4 equiv arylborornic acids, 4 equiv Na2CO3
with mixed solvents (Dioxane: EtOH: H2O = 6:2:1). The
3,6-diaryl coupled indazole and yields were shown in
Table 3.
The reactions using methoxy pyridinylboronic acids pro-
vided high yields of 3,6-diaryl coupled indazoles without
any significant reactivity different with positional methoxy
group of pyridine (2a and 2b). The reaction using
3-thiophenylboronic acid also gave good yields of diary-
lated product (2c). The reactions using different functional
group substituted phenylboronic acids provided good yields
of diaryl coupled products (2d–2i) without any significant
different electronic substitution effects of phenylboronic
acids.
We investigated 1,3-diarylated indazoles formation using
3-arylsubstituted indazole and substituted arylhalides with
copper catalyzed N-arylation based on our previously estab-
lished reaction conditions.24 The optimal conditions for N-
arylation of indazole were 1.5 equiv Cs2CO3 and 10 mol %
Cu2O in DMA at 200ꢀC. Diverse N-arylated indazole prod-
ucts and yields are shown in Table 4.
The N-arylation of 3-thiophenylindazole was performed
with different substituted phenyl bromides. The reaction
using methyl or methoxy substituted phenyl bromides pro-
vided moderate yield of 1,3-diaryl indazoles with slightly
decrease with electron donation groups of phenyl halides.
The reaction using 3-phenylindazole and 2-bromopyridine
or 3-bromobenzothiophene also gave reasonable yield of
1,3-diaryl coupled desired product. Additionally, the reac-
tions using 3-benzothiophenyl or 3-pyridyl indazole with
The ary–aryl coupling with N-Boc protected isomeric
bromoindazoles and arylboronic acids were examined
under established optimization conditions. The synthesized
monoaryl indazoles and yields are shown in Table 2.
The positional isomeric aryl substituted indazole products
were obtained with free NH indazoles. The reactions using
N-Boc 3-bromoindazole with carbo, thio, and aza, arylboro-
nic acid provided excellent yields of 3-arylindazoles (com-
pound 1a–1d). From aryl-aryl coupling results, the variation
of heteroatom in heteroarylboronic acids did not change
yields of aryl coupled products. The reactions using 4–6
positional isomeric bromoindazoles with various arylboronic
acid gave very high yields of 4–6 aryl substituted indazoles
(compound 1e–1p). The coupling reaction proceeded very
well with many different aromatic boronic acids, such as
phenyl, thiophenyl, benzothiophenyl, and pyridinyl boronic
acids.
Furthermore, we explored palladium-catalyzed coupling
reaction conditions using N-Boc 3,6-dibromoindazole and
arylboronic acid for double arylated indazoles. The optimi-
zation of double arylation conditions are 10 mol %
Table 2. Synthesis of diverse monoarylated indazoles under
palladium-catalyzed aryl-coupling with 3–6 isomeric
N-Boc-bromoindazoles.
Table 3. Synthesis of 3,6-diarylated indazoles under
palladium-catalyzed diaryl-coupling reaction.
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Coupling Approach to Indazole Diversity With Microwave Heating
KOREAN CHEMICAL SOCIETY
Table 4. Synthesis of 1,3-diarylated indazoles by
copper-catalyzed N-arylation with 3- arylindazoles with
arylbromides.
of products. Probably the coupling reactions were influ-
enced with steric bulky effect of benzothiophene.
To introduce double bond to indazole moiety, we finally
examined Heck coupling conditions with N-benzyl
3-iodoindazoles with functional group containing terminal
alkenes. The optimal Heck reaction conditions were 1 mol
% Pd(PPh3)2Cl2, 2 equiv TEA, and DMF at 120ꢀC. The
alkene coupled products and yields are shown in Table 5.
The reaction using various different electronic substituted
N-benzyl 3-iodoindazole and terminal double bond sub-
strates provided 80–99% yields of 1,3-dialkyl indazoles.
The aryl -alkene coupling reactions proceeded excellent
yields without any electronic effects for benzyl or functio-
nalized alkene substrates, such as methyl acrylate, styrene,
and vinyl ketones.
Conclusion
Diverse aryl, vinyl, and N-aryl coupling reactions with
indazoles were performed with arylboronic acids, functio-
nalized terminal alkenes, and aryl halides by microwave-
assisted palladium or copper catalysis. Diverse isomeric
mono or disubstituted indazoles were easily prepared within
60 min with excellent yields. This microwave-assisted bond
formation could be extended to prepare diversely functiona-
lized indazoles for drug discovery research.
Experimental Section
Instrumentation and Analysis. Bruker Fourier 300 (Bil-
lerica, MA, USA), 500 MHz spectrometers were used for
recording 1H and 13C NMR spectra of products. Waters
ACQVI (UPLC) SQD 2 (Milford, MA, USA) was used to
obtain LC–MS spectra. All microwave-assisted reactions
were performed with an initiator instrument (EXP EU, Bio-
tage, 400 W, 2450 MHz). Flash column chromatography
on 230-400-mesh ASTM 60 silica gel was used for prod-
ucts purification. All chemical species were purchased from
Sigma-Aldrich Chemical Co (St. Louis, USA), TCI
(Tokyo, Japan), and Alfa Aesar (Lancs, UK).
substituted aryl bromide also provided 1,3-diaryl
substituted indazoles. The results showed that reactions
using nitrogen contain heterocycles had similar reactivity
with benzene ring, but the reaction using the
3-benzothiophenyl substituted indazole provided low yield
Table 5. Synthesis of 1,3-dialkylated indazoles by
palladium-catalyzed heck reaction with N-benzyl 3-iodoindazoles
and alkenes.
General Procedure for Microwave-assisted Palladium-
catalyzed Aryl-Aryl Coupling Reactions27. tert-Butyl
3-bromo 1H-indazole-1-carboxylate (0.5 mmol), Na2CO3
(0.5 mmol), boronic acid (1.0 mmol), Pd(PPh3)2Cl2 (1 mol
%), and 1,4-dioxane: ethanol = 4:1 (5 mL) were added to
10 mL vial. The vial was sealed with a crimp cap and
placed in a Biotage initiator microwave cavity. After the
reaction vial was irradiated at 140 ꢀC for 30 min, the
microwave reactor was cooled with air. Product was sepa-
rated with ethyl acetate and saturated aqueous NH4Cl solu-
tion. The organic layer was dried with anhydrous sodium
sulfate, filtered, and concentrated. Products were purified
by silica gel column chromatography using a hexane: ethyl
acetate = 4:1.
1
3-Phenyl-1H-indazole (1a). Yield (92%), brown oil, H
NMR (300 MHz, CDCl3) δ 11.63 (s, 1H), 8.05–7.99
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(m, 3H), 7.57–7.48 (m, 2H), 7.48–7.40 (m, 1H), 7.35 (ddd,
J = 7.9, 6.7, 1.0 Hz, 1H), 7.26–7.21 (m, 1H), 7.21–7.14
(m, 1H); 13C NMR (125 MHz, CDCl3) δ 145.7, 141.7,
133.6, 129.0, 128.2, 127.8, 126.8, 121.4, 121.1, 121.0,
110.3; MS(m/z): 194.62 (M + 1).
(dd, J = 7.1, 0.9 Hz, 1H), 4.00 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 167.0, 144.3, 140.6, 134.2, 134.2,
130.2, 129.4, 128.5, 127.1, 121.7, 120.8, 115.3, 109.6,
52.3; MS(m/z): 224.26 (M + 1).
5-(Thiophen-3-yl)-1H-indazole (1i). Yield (99%),
brown solid, mp: 245–247 ꢀC; 1H NMR (300 MHz,
CDCl3) δ 8.11 (s, 1H), 7.96 (s, 1H), 7.68 (dd, J = 8.7,
1.6 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.46–7.40 (m, 3H);
13C NMR (75 MHz, CDCl3) δ 142.5, 133.1, 132.3, 126.7,
126.6, 126.4, 114.0, 102.7, 99.4, 93.2, 87.8; MS(m/z):
200.26 (M + 1).
5-(Benzo[b]thiophen-3-yl)-1H-indazole (1j). Yield
(99%), brown solid, mp: 179ꢀC; 1H NMR (300 MHz,
CDCl3) δ 8.17 (s, 1H), 8.00–7.84 (m, 3H), 7.69–7.56 (m,
2H), 7.46–7.35 (m, 3H); 13C NMR (75 MHz, CDCl3) δ
140.7, 139.5, 138.2, 138.0, 135.2, 129.2, 128.5, 124.5,
124.4, 123.7, 123.3, 123.0, 122.9, 120.7, 110.0; MS(m/z):
250.32 (M + 1).
3-(Thiophen-3-yl)-1H-indazole (1b). Yield (92%),
1
brown solid, mp: 90–94ꢀC; H NMR (300 MHz, CDCl3) δ
11.77 (s, 1H), 7.96 (dd, J = 8.2, 1.1 Hz, 1H), 7.84 (dd,
J = 3.0, 1.1 Hz, 1H), 7.78–7.71 (m, 1H), 7.45 (dd, J = 5.0,
3.0 Hz, 1H), 7.36–7.29 (m, 1H), 7.25–7.10 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 141.7, 141.5, 134.6, 127.0,
127.0, 126.3, 122.4, 121.4, 120.9, 120.9, 110.4; MS(m/z):
200.73 (M + 1).
3-(Benzo[b]thiophen-3-yl)-1H-indazole (1c). Yield
1
(93%), brown solid, mp: 120–122ꢀC; H NMR (300 MHz,
CDCl3) δ 11.86 (s, 1H), 8.44 (dt, J = 7.1, 3.5 Hz, 1H),
8.01–7.90 (m, 1H), 7.90–7.81 (m, 2H), 7.38 (tt, J = 7.1,
3.5 Hz, 2H), 7.31–7.22 (m, 1H), 7.14 (ddd, J = 8.1, 6.9,
1.0 Hz, 1H), 7.02 (dd, J = 8.1, 1.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 141.3, 141.1, 140.4, 138.0, 129.2,
127.0, 125.5, 124.9, 124.7, 124.4, 122.7, 122.0, 121.3,
120.9, 110.3; MS(m/z): 250.70 (M + 1).
5-(6-Methoxypyridin-3-yl)-1H-indazole (1k). Yield
1
ꢀ
(97%), white solid, mp: 184–185 C; H NMR (300 MHz,
CDCl3) δ 10.35 (s, 1H), 8.45 (d, J = 2.6 Hz, 1H), 8.17 (s,
1H), 7.90 (t, J = 1.2 Hz, 1H), 7.86 (dd, J = 8.5, 2.6 Hz,
1H), 7.60 (d, J = 1.2 Hz, 2H), 6.87 (d, J = 8.5 Hz, 1H),
4.03 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.4, 145.1,
137.8, 135.3, 131.3, 130.4, 126.6, 118.7, 110.9, 110.3,
106.3, 53.6, 29.7; MS(m/z): 225.25 (M + 1).
3-(6-Methoxypyridin-3-yl)-1H-indazole (1d). Yield
(82%), pale yellow solid, mp: 138–139ꢀC; 1H NMR
(500 MHz, CDCl3) δ 10.84 (s, 1H), 8.83 (d, J = 2.4 Hz,
1H), 8.22 (dd, J = 8.6, 2.4 Hz, 1H), 8.00 (d, J = 8.2 Hz,
1H), 7.50 (d, J = 8.2 Hz, 1H), 7.44 (ddd, J = 8.1, 6.7,
1.0 Hz, 1H), 7.26 (ddd, J = 8.1, 6.7, 1.0 Hz, 1H), 6.93 (d,
J = 8.6 Hz, 1H), 4.06 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 164.0, 145.5, 143.1, 141.6, 137.9, 127.6, 127.0, 123.1,
5-(Benzo[d][1,3]dioxol-5-yl)-1H-indazole (1l). Yield
1
(93%), white solid, mp: 207–209ꢀC; H NMR (300 MHz,
CDCl3) δ 8.05 (s, 1H), 7.79 (s, 1H), 7.49 (q, J = 8.8 Hz,
2H), 7.06–6.98 (m, 2H), 6.83 (d, J = 7.9 Hz, 1H), 5.94 (s,
2H); 13C NMR (75 MHz, CDCl3) δ 148.2, 146.9, 146.4,
135.9, 135.6, 134.7, 127.1, 120.8, 110.2, 108.7, 108.0,
101.2, 31.0, 30.0; MS(m/z): 238.25 (M + 1).
121.6,
120.9,
111.3,
110.0,
53.7;
MS(m/z):
225.68 (M + 1).
4-(Benzo[b]thiophen-3-yl)-1H-indazole (1e). Yield
1
(98%), purple solid, mp: 150–151ꢀC; H NMR (300 MHz,
6-Phenyl-1H-indazole (1m). Yield (99%), yellow solid,
mp: 128–131ꢀC; 1H NMR (300 MHz, CDCl3) δ 10.19
(s, 1H), 8.18 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.67 (d,
J = 7.4 Hz, 3H), 7.53–7.39 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 141.2, 140.9, 140.7, 134.4, 128.9, 127.8, 127.6,
127.6, 121.8, 121.3, 107.9, MS(m/z): 194.24 (M + 1).
6-(3-Methoxyphenyl)-1H-indazole (1n). Yield (96%),
CDCl3) δ 8.05 (s, 1H), 8.02–7.92 (m, 1H), 7.89–7.79 (m,
1H), 7.60 (s, 1H), 7.56–7.46 (m, 2H), 7.39 (m, 3H); 13C
NMR (75 MHz, CDCl3) δ 140.6, 138.0, 135.5, 134.9,
129.3, 127.2, 124.8, 124.7, 124.4, 123.2, 122.9, 121.5,
109.1; MS(m/z): 250.32 (M + 1).
4-(Thiophen-3-yl)-1H-indazole (1f). Yield (78%),
1
1
brown oil; H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H),
yellow solid, mp: 68–72ꢀC; H NMR (300 MHz, CDCl3) δ
7.65 (dd, J = 3.0, 1.4 Hz, 1H), 7.54 (dd, J = 5.0, 1.3 Hz,
1H), 7.52–7.49 (m, 1H), 7.49–7.44 (m, 2H), 7.34 (dd,
J = 6.6, 1.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 140.6,
138.0, 135.5, 127.2, 124.8, 124.7, 124.4, 123.2, 122.9,
121.5, 109.1; MS(m/z): 200.26 (M + 1).
Methyl 4-(1H-indazol-4-yl)benzoate (1g). Yield (88%),
pink oil; 1H NMR (500 MHz, CDCl3) δ 7.55–7.43 (m,
3H), 7.36–7.25 (m, 3H), 7.06–6.98 (m, 1H), 3.92 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 159.9, 141.2, 132.1, 129.9,
128.6, 127.2, 121.0, 120.6, 114.1, 113.4, 55.4, 29.7, 23.2;
MS(m/z): 252.38 (M + 1).
10.99 (s, 1H), 8.17 (d, J = 1.1 Hz, 1H), 7.83 (dd, J = 8.4,
0.9 Hz, 1H), 7.68 (q, J = 1.1 Hz, 1H), 7.51–7.35 (m, 2H),
7.30–7.25 (m, 1H), 7.21 (d, J = 1.9 Hz, 1H), 6.96 (ddd,
J = 8.2, 2.6, 1.0 Hz, 1H), 3.91 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 160.0, 142.9, 140.8, 140.3, 134.6,
129.9, 122.6, 121.4, 121.1, 120.2, 113.5, 112.9, 108.0,
55.4, MS(m/z): 244.26 (M + 1).
6-(6-Methoxypyridin-3-yl)-1H-indazole (1o). Yield
1
(97%), yellow solid, mp: 166–167ꢀC; H NMR (300 MHz,
CDCl3) δ 11.26 (s, 1H), 8.50 (d, J = 2.5 Hz, 1H), 8.15 (s,
1H), 7.91–7.79 (m, 2H), 7.63 (s, 1H), 7.36 (dd, J = 8.4,
1.5 Hz, 1H), 6.87 (d, J = 8.6 Hz, 1H), 4.05 (s, 3H); 13C
NMR (75 MHz, CDCl3δ 163.8, 145.3, 140.8, 137.9, 136.9,
134.9, 130.3, 122.5, 121.5, 120.8, 111.0, 107.45, 53.7;
MS(m/z): 225.25 (M + 1).
4-(3-Methoxyphenyl)-1H-indazole (1h). Yield (79%),
1
white solid, mp: 180–181ꢀC; H NMR (500 MHz, CDCl3)
δ 10.48 (s, 1H), 8.28–8.19 (m, 3H), 7.84–7.78 (m, 2H),
7.60–7.55 (m, 1H), 7.51 (dd, J = 8.4, 7.0 Hz, 1H), 7.32
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Coupling Approach to Indazole Diversity With Microwave Heating
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6-(4-Methoxyphenyl)-1H-indazole (1p). Yield (93%),
121.13, 108.74, 108.67, 108.02, 107.98, 107.61, 101.26,
101.21; MS(m/z): 385.35 (M + 1).
1
white solid, mp: 178–179ꢀC; H NMR (300 MHz, CDCl3)
δ 10.36 (s, 1H), 8.10 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H),
7.63–7.54 (m, 3H), 7.40 (d, J = 8.4 Hz, 1H), 7.00 (d,
J = 8.4 Hz, 2H), 3.86 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 159.4, 140.10, 138.4, 135.0, 133.8, 128.6, 121.3,
121.0, 114.3, 107.1, 104.2, 55.4; MS(m/z): 244.26 (M + 1).
Diethyl 4,40-(1H-indazole-3,6-diyl)dibenzoate (2e).
1
Yield (64%), yellow oil; H NMR (300 MHz, CDCl3) δ
8.72 (s, 1H), 8.36 (d, J = 10.0 Hz, 1H), 8.22 (d,
J = 7.9 Hz, 1H), 8.16–8.08 (m, 2H), 7.85 (d, J = 7.8 Hz,
1H), 7.73 (s, 1H), 7.66–7.53 (m, 3H), 7.27 (d, J = 2.3 Hz,
1H), 4.53–4.38 (m, 4H), 1.44 (qd, J = 8.1, 7.6, 4.2 Hz, 6H);
13C NMR (75 MHz, CDCl3) δ 151.54, 141.67, 141.18,
134.56, 133.59, 131.78, 131.27, 131.12, 129.31, 128.91,
128.64, 128.52, 128.12, 127.24, 121.62, 119.36, 115.73,
112.53, 110.56, 61.16, 61.05, 14.37, 14.30; MS(m/z):
414.46 (M + 1).
Synthesis of Diarylated Indazoles (2a-2i) with
Microwave-assisted Palladium-catalyzed Aryl-Aryl Cou-
pling reactions27. tert-Butyl 3,6-dibromo 1H-indazole-
1-carboxylate (0.5 mmol), Na2CO3 (2.0 mmol), arylboronic
acid (2.0 mmol), Pd(PPh3)2Cl2 (10 mol %), and
1,4-dioxane: ethanol:water = 6:2:1 (5 mL) were added to
10 mL vial. After the reaction mixture was heated at 120
ꢀC for 40 min, product was purified with same work-up
procedure for monoaryl coupling reaction conditions.
Dimethyl 4,40-(1H-indazole-3,6-diyl)dibenzoate (2f).
1
Yield (78%), colorless oil; H NMR (300 MHz, CDCl3) δ
8.23 (d, J = 8.2 Hz, 2H), 8.12 (d, J = 7.7 Hz, 2H),
7.98–7.89 (m, 3H), 7.77 (d, J = 9.5 Hz, 1H), 7.63 (s, 1H),
7.27–7.22 (m, 2H), 3.99 (s, 3H), 3.93 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 173.98, 173.74, 148.30, 146.82,
145.68, 145.16, 140.01, 137.87, 130.26, 130.17, 129.97,
129.40, 127.26, 123.25, 121.43, 121.22, 119.56, 119.34,
109.09, 108.52, 108.20, 103.78, 102.16, 37.56, 36.13;
MS(m/z): 386.41 (M + 1).
3,6-Bis(6-methoxypyridi-3-yl)-1H-indazole (2a). Yield
1
(91%), yellow oil, H NMR (500 MHz, CDCl3) δ 8.84 (d,
J = 2.3 Hz, 1H), 8.52–8.46 (m, 1H), 8.23 (dd, J = 8.6,
2.4 Hz, 1H), 8.06 (dd, J = 8.5, 0.8 Hz, 1H), 7.90 (dd,
J = 8.6, 2.6 Hz, 1H), 7.66 (d, J = 1.2 Hz, 1H), 7.45 (dd,
J = 8.5, 1.5 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 6.90 (dd,
J = 8.6, 0.8 Hz, 1H), 4.06 (s, 3H), 4.04 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 176.04, 172.14, 158.61, 155.51,
152.35, 143.82, 140.25, 137.86, 136.37, 135.13, 132.57,
131.08, 122.52, 121.14, 120.61, 111.32, 102.17, 30.08,
29.68; MS(m/z): 332.36 (M + 1).
3,6-Bis(3-methoxyphenyl)-1H-indazole (2g). Yield
(67%), yellow solid, mp: 150.8–151.3ꢀC; 1H NMR
(300 MHz, CDCl3) δ 7.85 (dt, J = 7.2, 1.1 Hz, 2H), 7.77
(d, J = 2.7 Hz, 2H), 7.47 (t, J = 7.8 Hz, 3H), 7.28 (d,
J = 1.0 Hz, 1H), 7.23–7.12 (m, 3H), 3.95 (s, 3H), 3.94 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 160.05, 159.97,
146.14, 143.07, 141.17, 135.15, 134.63, 129.97, 129.84,
127.22, 121.63, 120.18, 120.03, 119.47, 114.29, 113.42,
112.79, 112.21, 110.29, 55.39, 55.29; MS(m/z):
330.14 (M + 1).
3,6-Di-p-tolyl-1H-indazole (2h). Yield (67%), yellow
oil; 1H NMR (300 MHz, CDCl3) δ 8.06 (t, J = 8.5 Hz,
1H), 7.96 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H),
7.48 (d, J = 10.2 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H),
7.33–7.28 (m, 2H), 7.07 (d, J = 4.3 Hz, 1H), 2.46 (s, 3H),
2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 145.77,
142.43, 140.19, 138.24, 138.08, 137.37, 130.65, 130.05,
129.85, 129.65, 129.55, 128.58, 127.50, 127.40, 121.47,
121.37, 120.10, 115.10, 107.85, 21.34, 21.15; MS(m/z):
298.15 (M + 1).
3,6-Bis(2-methoxypyridin-4-yl)-1H-indazole
(2b).
1
Yield (83%), pale yellow oil; H NMR (500 MHz, CDCl3)
δ 8.30 (dd, J = 5.0, 1.9 Hz, 1H), 8.23 (dd, J = 5.0, 1.9 Hz,
1H), 8.04 (dd, J = 7.3, 2.0 Hz, 1H), 7.90–7.83 (m, 1H),
7.78–7.68 (m, 2H), 7.41 (dd, J = 8.5, 1.4 Hz, 1H),
7.12–6.99 (m, 2H), 4.08 (s, 3H), 4.02 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 160.96, 155.43, 154.13, 146.88,
145.99, 138.93, 136.87, 133.92, 132.13, 121.74, 120.03,
117.16, 112.44, 111.49, 107.58, 106.07, 96.89, 11.82,
11.42; MS(m/z): 332.36 (M + 1).
6-(Thiophen-2-yl)-3-(thiophen-3-yl)-1H-indazole (2c).
1
Yield (65%), brown oil; H NMR (300 MHz, CDCl3) δ
8.04 (d, J = 8.5 Hz, 1H), 7.88 (dd, J = 2.9, 1.2 Hz, 1H),
7.78–7.75 (m, 1H), 7.73 (d, J = 4.0 Hz, 1H), 7.71 (s, 1H),
7.56 (dq, J = 7.0, 2.9, 2.3 Hz, 3H), 7.49 (ddt, J = 8.0, 5.0,
2.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) 151.01, 143.85,
137.15, 134.84, 129.31, 128.84, 127.39, 121.87, 121.66,
121.17, 112.43, 109.92, 109.04, 107.81, 107.63; MS(m/z):
282.38 (M + 1).
3,6-Bis(3-fluoro-4-methoxyphenyl)-1H-indazole (2i).
1
Yield (77%), yellow solid, mp: 194.5–195.8ꢀC; H NMR
(300 MHz, CDCl3) δ 8.03 (d, J = 8.5 Hz, 1H), 7.80–7.71
(m, 2H), 7.52 (s, 1H), 7.46–7.40 (m, 1H), 7.40–7.35 (m,
1H), 7.10 (dt, J = 12.2, 8.6 Hz, 2H), 6.88 (dd, J = 5.4,
3.0 Hz, 1H), 3.98 (s, 3H), 3.96 (d, J = 2.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 165.58, 165.00, 153.82, 143.86,
143.26, 141.76, 137.46, 137.11, 136.72, 130.25, 130.22,
129.73, 128.92, 127.34, 127.13, 125.82, 123.84, 119.86,
113.81, 113.20, 111.97, 45.72, 45.01; MS(m/z):
366.37 (M + 1).
3,6-Bis(benzo[d][1,3]dioxol-5-yl)-1H-indazole
(2d).
1
Yield (61%), yellow solid, mp: 182.1–183.3ꢀC; H NMR
(300 MHz, CDCl3) δ 8.01 (d, J = 8.5 Hz, 1H), 7.79 (d,
J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.53–7.50 (m, 3H), 7.42 (dd,
J = 8.5, 1.5 Hz, 1H), 7.16–7.11 (m, 2H), 7.02–6.98 (m,
1H), 6.94 (d, J = 8.7 Hz, 1H), 6.06 (s, 4H), 6.04 (s, 2H);
13C NMR (75 MHz, CDCl3) δ 149.45, 149.28, 148.21,
148.15, 147.72, 147.36, 146.21, 146.10, 145.56, 144.45,
143.48, 142.96, 129.61, 129.45, 127.52, 127.33, 121.32,
General Procedure for Microwave-promoted Copper-
catalyzed N-Arylation Reaction24,26,27
.
3-(Thiophen-
Bull. Korean Chem. Soc. 2019
© 2019 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
5

BULLETIN OF THE
Article
Coupling Approach to Indazole Diversity With Microwave Heating
KOREAN CHEMICAL SOCIETY
3-yl)-1H-indazole (0.5 mmol), bromobenzene (0.55 mmol),
Cs2CO3 (0.75 mmol), Cu2O (10 mol %), and DMA (5 mL)
were added to a 10 mL vial. The vial was sealed with a
crimp cap and placed in a Biotage initiator microwave cav-
(m, 4H), 7.32 (dd, J = 7.9, 6.9 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 146.1, 141.9, 139.0, 134.5, 133.2, 132.4, 128.9,
128.4, 127.8, 127.2, 125.5, 124.9, 123.0, 122.9, 122.3,
122.1, 121.6, 119.6, 110.7; MS(m/z): 326.42 (M + 1).
1-(3-Methoxyphenyl)-3-(6-methoxypyridin-3-yl)-1H-
ꢀ
ity. After the reaction vial was heated at 200 C for 1 h,
1
product was purified with same work-up procedure for
monoaryl coupling reaction conditions using a hexane:
ethyl acetate = 50:1 solvent.
indazole (3g). Yield (53%), white solid, mp: 89–91ꢀC; H
NMR (300 MHz, CDCl3) δ 8.87 (q, J = 2.2 Hz, 1H), 8.28
(dq, J = 7.2, 2.2 Hz, 1H), 8.07–8.02 (m, 1H), 7.87–7.82
(m, 1H), 7.49 (m, 2H), 7.43–7.36 (m, 2H), 7.36–7.30 (m,
1H), 7.00–6.91 (m, 2H), 4.06 (s, 3H), 3.93 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 164.1, 160.6, 145.7, 145.7,
143.3, 141.1, 140.3, 138.1, 130.2, 127.3, 123.0, 122.2,
121.2, 115.0, 112.6, 111.3, 111.0, 108.8, 55.6, 53.7;
MS(m/z): 331.38 (M + 1).
1-Phenyl-3-(thiophen-3-yl)-1H-indazole
(3a)
was
obtained with 71% yields as a pink solid. mp: 81–82ꢀC;1H
NMR (300 MHz, CDCl3) δ 8.06 (d, J = 8.1 Hz, 1H), 7.90
(dd, J = 2.9, 1.3 Hz, 1H), 7.83–7.72 (m, 4H), 7.55 (t,
J = 7.8 Hz, 2H), 7.50–7.42 (m, 2H), 7.42–7.26 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 142.3, 140.1, 134.3, 129.5,
127.2, 127.1, 126.7, 126.0, 123.2, 123.0, 122.5, 122.0,
121.4, 110.7, 29.8; MS(m/z): 276.36 (M + 1).
3-(6-Methoxypyridin-3-yl)-1-(p-tolyl)-1H-indazole
(3h). Yield (55%), red solid, mp: 102ꢀC; 1H NMR
(300 MHz, CDCl3) δ 8.83 (dd, J = 2.4, 0.8 Hz, 1H), 8.25
(dd, J = 8.6, 2.4 Hz, 1H), 8.01 (dt, J = 8.2, 1.0 Hz, 1H),
7.74 (dt, J = 8.6, 0.9 Hz, 1H), 7.70–7.59 (m, 2H), 7.45
(dd, J = 8.4, 6.9 Hz, 1H), 7.40–7.24 (m, 3H), 6.90 (dd,
J = 8.6, 0.8 Hz, 1H), 4.02 (s, 3H), 2.44 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 164.0, 145.6, 143.0, 140.3, 138.1,
137.5, 136.8, 130.1, 127.1, 123.0, 122.9, 122.7, 122.0,
121.2, 111.3, 110.8, 53.7, 21.1; MS(m/z): 315.38 (M + 1).
1-(6-Methoxynaphthalen-2-yl)-3-(6-methoxypyridin-
3-yl)-1H-indazole (3i). Yield (42%), brown solid, mp:
109–110ꢀC; 1H NMR (300 MHz, CDCl3) δ 8.89 (d,
J = 2.4 Hz, 1H), 8.31 (dd, J = 8.6, 2.4 Hz, 1H), 8.14 (s,
1H), 8.08 (d, J = 8.2 Hz, 1H), 7.98–7.91 (m, 2H), 7.86 (t,
J = 8.2 Hz, 2H), 7.53–7.49 (m, 1H), 7.38–7.32 (m, 1H),
7.29–7.24 (m, 2H), 6.95 (d, J = 8.6 Hz, 1H), 4.07 (s, 3H),
3.99 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.0, 158.0,
145.7, 143.3, 140.5, 138.1, 135.6, 133.3, 129.4, 129.0,
128.2, 127.3, 122.9, 122.8, 122.6, 122.1, 121.3, 120.6,
119.9, 111.3, 110.8, 105.9, 55.4, 53.7; MS(m/z):
381.44 (M + 1).
3-(Benzo[b]thiophen-3-yl)-1-(3-methoxyphenyl)-1H-
indazole (3j). Yield (48%), yellow oil; 1H NMR
(300 MHz, CDCl3) δ 8.61 (dt, J = 7.6, 1.6 Hz, 1H), 8.02
(d, J = 8.1 Hz, 1H), 7.99–7.91 (m, 2H), 7.86 (d,
J = 8.4 Hz, 1H), 7.53–7.38 (m, 6H), 7.33–7.23 (m, 1H),
6.94 (m, 1H), 3.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
160.5, 142.0, 141.3, 140.3, 139.7, 137.8, 130.2, 128.7,
127.4, 125.6, 124.9, 124.8, 124.7, 124.2, 122.6, 122.0,
121.5, 115.0, 112.3, 110.9, 108.8, 55.6; MS(m/z):
356.45 (M + 1).
1-(3-Methoxyphenyl)-3-(thiophen-3-yl)-1H-indazole
1
(3b). Yield (59%), brown oil; H NMR (500 MHz, CDCl3)
δ 8.09 (dd, J = 8.1, 1.0 Hz, 1H), 7.93 (dd, J = 3.0, 1.2 Hz,
1H), 7.86–7.80 (m, 2H), 7.54–7.42 (m, 3H), 7.44–7.26 (m,
3H), 6.95 (dd, J = 8.1, 2.5 Hz, 1H), 3.93 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 160.5, 142.2, 141.2, 140.1,
134.2, 130.2, 127.3, 127.1, 126.0, 123.2, 122.5, 122.0,
121.3, 115.1, 112.5, 110.9, 108.8, 55.6; MS(m/z):
306.39 (M + 1).
3-(Thiophen-3-yl)-1-(p-tolyl)-1H-indazole (3c). Yield
(65%), white solid, mp: 95ꢀC; 1H NMR (300 MHz, CDCl3)
δ 8.05 (dt, J = 8.2, 1.1 Hz, 1H), 7.88 (dt, J = 2.5, 1.2 Hz,
1H), 7.79 (dd, J = 5.0, 1.1 Hz, 1H), 7.73 (dd, J = 8.2,
1.2 Hz, 1H), 7.69–7.61 (m, 2H), 7.50–7.40 (m, 2H),
7.38–7.27 (m, 3H), 2.44 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 141.9, 140.1, 137.6, 136.6, 134.4, 131.8, 130.0,
127.0, 125.9, 123.0, 122.9, 122.3, 121.7, 121.3, 110.7,
21.1; MS(m/z): 290.39 (M + 1).
1-(3,4-Dimethoxyphenyl)-3-(thiophen-3-yl)-1H-
indazole (3d). Yield (39%), brown oil; 1H NMR
(300 MHz, CDCl3) δ 8.05 (d, J = 8.2 Hz, 1H), 7.91–7.87
(m, 1H), 7.80 (d, J = 5.0 Hz, 1H), 7.68 (d, J = 8.5 Hz,
1H), 7.52–7.38 (m, 2H), 7.30 (d, J = 7.6 Hz, 3H), 7.03 (d,
J = 8.2 Hz, 1H), 3.96 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 149.7, 148.1, 141.8, 140.4, 134.3, 133.3, 127.1, 127.0,
126.0, 122.7, 122.4, 121.8, 121.3, 115.4, 111.3, 110.6,
107.9, 56.2, 56.2; MS(m/z): 336.42 (M + 1).
1-(6-Methylpyridin-2-yl)-3-phenyl-1H-indazole (3e).
Yield (61%), brown solid, mp: 93–94ꢀC; 1H NMR
(300 MHz, CDCl3) δ 8.96 (dt, J = 8.6, 1.0 Hz, 1H),
8.10–7.99 (m, 3H), 7.95 (d, J = 8.2 Hz, 1H), 7.69 (t,
J = 7.9 Hz, 1H), 7.60–7.49 (m, 3H), 7.49–7.39 (m, 1H),
7.36–7.29 (m, 1H), 6.98 (d, J = 7.5 Hz, 1H), 2.65 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 156.9, 153.8, 146.9, 140.4,
138.5, 133.1, 128.9, 128.6, 128.0, 127.7, 124.0, 122.7,
121.0, 119.1, 115.9, 110.5, 24.3; MS(m/z): 285.35 (M + 1).
1-(Benzo[b]thiophen-3-yl)-3-phenyl-1H-indaz-ole (3f).
3-(Benzo[b]thiophen-3-yl)-1-(p-tolyl)-1H-indazole (3k).
Yield (45%), white solid, mp: 173–175ꢀC; 1H NMR
(500 MHz, CDCl3) δ 8.64 (d, J = 7.8 Hz, 1H), 8.05 (d,
J = 8.3 Hz, 1H), 7.98 (d, J = 7.8 Hz, 2H), 7.83 (d,
J = 8.3 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.55–7.43 (m,
3H), 7.41 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 7.5 Hz, 1H),
2.49 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 141.7, 136.6,
134.3, 130.0, 129.9, 129.2, 129.1, 127.2, 125.3, 124.8,
124.7, 124.6, 124.5, 122.9, 122.5, 121.8, 121.4, 110.7,
68.7, 21.1; MS(m/z): 340.45 (M + 1).
1
Yield (43%), yellow oil; H NMR (300 MHz, CDCl3) δ
8.13 (d, J = 8.1 Hz, 1H), 8.11–8.05 (m, 2H), 7.98–7.90
(m, 2H), 7.68 (s, 1H), 7.60–7.50 (m, 3H), 7.49–7.40
Bull. Korean Chem. Soc. 2019
© 2019 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
6

BULLETIN OF THE
Article
Coupling Approach to Indazole Diversity With Microwave Heating
(E)-Benzyl
KOREAN CHEMICAL SOCIETY
3-(Benzo[b]thiophen-3-yl)-1-(3-isopropoxyphenyl)-1H-
3-(1-(3-fluorobenzyl)-1H-indazol-3-yl)-
indazole (3l). Yield (42%), colorless oil; 1H NMR
(300 MHz, CDCl3) δ 8.62–8.44 (m, 1H), 7.93 (dt, J = 8.2,
1.0 Hz, 1H), 7.88–7.84 (m, 2H), 7.81–7.75 (m, 1H),
7.44–7.35 (m, 3H), 7.35–7.30 (m, 3H), 7.22–7.15 (m, 1H),
6.83 (dt, J = 7.6, 2.1 Hz, 1H), 4.57 (h, J = 6.0 Hz, 1H),
1.32 (d, J = 6.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
158.9, 141.9, 141.3, 140.3, 139.7, 137.8, 130.2, 128.8,
127.4, 125.5, 124.9, 124.8, 124.7, 124.2, 122.5, 122.0,
121.5, 114.8, 114.1, 111.0, 110.6, 70.3, 22.1; MS(m/z):
384.50 (M + 1).
acrylate (4e). Yield (93%), white solid, mp: 85–86ꢀC; H
NMR (500 MHz, CDCl3) δ 8.06 (d, J = 16.3 Hz, 1H),
7.97–7.92 (m, 1H), 7.47–7.31 (m, 7H), 7.29–7.21 (m, 2H),
7.00–6.88 (m, 3H), 6.84 (d, J = 16.3 Hz, 1H), 5.59 (s, 2H),
5.29 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 166.9, 164.0,
162.0, 140.9, 140.4, 138.6 (d, JCF = 6.6 Hz), 136.3, 136.1,
130.5 (d, JCF = 8.3 Hz), 128.6, 128.3, 128.3, 127.1, 123.0,
122.7 (d, JCF = 2.7 Hz), 122.4, 120.9, 119.2, 115.0 (d,
JCF = 21.1 Hz), 114.0 (d, JCF = 22.0 Hz), 109.8, 66.4,
52.8; MS(m/z): 386.43 (M + 1).
1
General Procedure for Microwave-assisted Palladium-
catalyzed Alkene Coupling reaction27. N-Benzyl-3-iodo-
1H-indazole (0.5 mmol), methyl acrylate (1.5 mmol),
Pd(PPh3)2Cl2(1 mol %), TEA (1.0 mmol), and DMF
(3 mL) were added to a 5 mL vial. After the reaction vial
was heated at 120 C for 30 min, product was purified with
same work-up procedure for monoaryl coupling reaction
conditions using a hexane: ethyl acetate = 10:1.
(E)-Methyl 3-(1-benzyl-1H-indazol-3-yl)acrylate (4a).
Yield (99%) white solid; mp: 89–90ꢀC; 1H NMR
(500 MHz, CDCl3) δ 8.07 (d, J = 16.2 Hz, 1H), 7.96 (dt,
J = 8.1, 1.0 Hz, 1H), 7.44–7.37 (m, 2H), 7.37–7.22 (m,
6H), 6.83 (d, J = 16.2 Hz, 1H), 5.64 (s, 2H), 3.87 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 167.6, 140.9, 140.1, 136.1,
128.8, 128.0, 127.2, 126.9, 123.0, 122.3, 120.8, 118.8,
110.0, 53.5, 51.8, 29.7; MS(m/z): 292.34 (M + 1).
(E)-Ethyl 3-(1-benzyl-1H-indazol-3-yl)acrylate (4b).
Yield (89%), white solid, mp: 82–83ꢀC; 1H NMR
(300 MHz, CDCl3) δ 8.03 (d, J = 16.3 Hz, 1H), 7.94 (dt,
J = 8.2, 1.0 Hz, 1H), 7.39–7.33 (m, 2H), 7.31–7.17 (m,
6H), 6.78 (d, J = 16.3 Hz, 1H), 5.60 (s, 2H), 4.29 (q,
J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 167.1, 140.9, 140.2, 136.1, 135.9,
128.8, 128.0, 127.2, 126.9, 123.0, 122.2, 120.8, 119.4,
110.0, 60.5, 53.4, 14.4; MS(m/z): 306.37 (M + 1).
(E)-Ethyl 3-(1-(3-fluorobenzyl)-1H-indazol-3-yl)acry-
1
late (4f). Yield (99%), white solid, mp: 73–74ꢀC; H NMR
(500 MHz, CDCl3) δ 8.05 (d, J = 16.3 Hz, 1H), 7.98 (dt,
J = 8.2, 1.0 Hz, 1H), 7.46–7.33 (m, 2H), 7.33–7.24 (m,
2H), 7.04–6.94 (m, 2H), 6.91 (dt, J = 9.4, 2.1 Hz, 1H),
6.82 (d, J = 16.3 Hz, 1H), 5.62 (s, 2H), 4.33 (q,
J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR
ꢀ
(125 MHz, CDCl3) δ 167.1, 164.0, 162.0, 140.7 (d, JCF
53.6 Hz), 138.6 (d, JCF = 6.7 Hz), 135.7, 130.4 (d, JCF
=
=
8.3 Hz), 127.1, 123.0, 122.7 (d, JCF = 2.8 Hz), 122.4,
120.9, 119.7, 115.0 (d, JCF = 21.2 Hz), 114.2 (d, JCF
=
22.2 Hz), 109.7, 60.6, 52.8, 14.4; MS(m/z):
324.36 (M + 1).
(E)-Ethyl 3-(1-(3-methylbenzyl)-1H-indazol-3-yl)acry-
1
late (4g). Yield (89%), colorless oil; H NMR (500 MHz,
CDCl3) δ 8.06 (d, J = 16.3 Hz, 1H), 7.98 (dt, J = 8.2,
1.0 Hz, 1H), 7.41 (d, J = 3.8 Hz, 2H), 7.30–7.26 (m, 1H),
7.22 (t, J = 7.6 Hz, 1H), 7.13–7.02 (m, 3H), 6.81 (d,
J = 16.3 Hz, 1H), 5.60 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H),
2.32 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 167.2, 140.9, 140.1, 138.6, 136.0,
128.8, 128.7, 127.9, 126.8, 124.3, 123.0, 122.2, 121.1,
120.8, 119.3, 110.0, 60.5, 53.5, 21.4, 14.4; MS(m/z):
320.39 (M + 1).
(E)-Methyl
3-(1-(4-(tert-butyl)benzyl)-1H-indazol-
(E)-1-(3-Methoxybenzyl)-3-styryl-1H-indazole
(4c).
3-yl)acrylate (4h). Yield (99%), yellow oil; 1H NMR
(300 MHz, CDCl3) δ 8.03 (d, J = 16.2 Hz, 1H), 7.93 (d,
J = 8.1 Hz, 1H), 7.42–7.28 (m, 4H), 7.28–7.21 (m, 1H),
7.16 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 16.2 Hz, 1H), 5.58
(s, 2H), 3.84 (s, 3H), 1.27 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 167.6, 151.0, 140.9, 140.0, 136.2, 133.1, 127.0,
126.8, 125.7, 123.0, 122.2, 120.7, 118.7, 110.1, 53.1, 51.7,
34.5, 31.3; MS(m/z): 348.45 (M + 1).
Yield (81%), white solid, mp: 70–71ꢀC; 1H NMR
(500 MHz, CDCl3) δ 8.08 (d, J = 8.2 Hz, 1H), 7.67–7.60
(m, 2H), 7.59–7.48 (m, 2H), 7.45–7.36 (m, 4H), 7.34–7.30
(m, 1H), 7.25 (td, J = 8.0, 2.3 Hz, 2H), 6.86–6.82 (m, 2H),
6.80 (t, J = 1.9 Hz, 1H), 5.61 (s, 2H), 3.77 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 159.9, 142.7, 141.0, 138.3,
137.4, 130.7, 129.8, 128.7, 127.8, 126.7, 126.5, 122.4,
121.2, 120.2, 119.4, 113.1, 112.9, 109.7, 60.4, 55.2, 53.0;
MS(m/z): 340.43 (M + 1).
Acknowledgments. This work was financially supported
by the research fund of Chungnam National University.
(E)-4-(1-(3-Methoxybenzyl)-1H-indazol-3-yl)but-3-en-
1
2-one (4d). Yield (80%), yellow oil; H NMR (500 MHz,
CDCl3) δ 7.98 (dq, J = 8.3, 0.8 Hz, 1H), 7.89 (d,
J = 16.6 Hz, 1H), 7.43–7.39 (m, 2H), 7.30–7.26 (m, 1H),
7.24 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 16.6 Hz, 1H),
6.85–6.80 (m, 2H), 6.77 (t, J = 2.1 Hz, 1H), 5.61 (s, 2H),
3.76 (s, 3H), 2.45 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
198.7, 160.0, 141.1, 140.2, 137.5, 135.2, 129.9, 128.3,
127.0, 123.0, 122.5, 120.9, 119.4, 113.2, 113.1, 110.1,
55.2, 53.4, 27.0; MS(m/z): 367.37 (M + 1).
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Coupling Approach to Indazole Diversity With Microwave Heating
KOREAN CHEMICAL SOCIETY
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