Synthesis of 1,3-diaryl-1H-benzo[g]indazoles

Article abstract of DOI:10.1016/j.tet.2012.07.011

A facile three-step synthetic route toward 1,3-diaryl-1H-benzo[g]indazoles 1a-1n starting with 3,4-dimethoxy-2-allylbenzaldehyde (6) in modest total yield is described. The facile route was carried by aldol condensation of aldehyde 6 with aryl methyl ketones 5a-5d in alkaline MeOH at reflux, Knorr pyrazole synthesis of the resulting chalcones 4a-4d with aryl hydrazines 3a-3e in EtOH at reflux followed by DDQ-mediated aromatization in toluene at reflux, and oxidative cleavage annulation of olefins 2a-2n with the one-pot combination of OsO₄/NaIO₄/HOAc in the aqueous THF at reflux.

Full text of DOI:10.1016/j.tet.2012.07.011

Tetrahedron 68 (2012) 7941e7948
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 1,3-diaryl-1H-benzo[g]indazoles
,
a
a
b
Meng-Yang Chang a , Hang-Yi Tai , Yeh-Long Chen , Ru-Ting Hsu
*
a Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
b Department of Nursing, ShuZen College of Medicine and Management, Luju, Kaohsiung 821, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2012
Received in revised form 20 June 2012
Accepted 3 July 2012
Available online 10 July 2012
A facile three-step synthetic route toward 1,3-diaryl-1H-benzo[g]indazoles 1ae1n starting with 3,4-
dimethoxy-2-allylbenzaldehyde (6) in modest total yield is described. The facile route was carried by
aldol condensation of aldehyde 6 with aryl methyl ketones 5ae5d in alkaline MeOH at reflux, Knorr
pyrazole synthesis of the resulting chalcones 4ae4d with aryl hydrazines 3ae3e in EtOH at reflux fol-
lowed by DDQ-mediated aromatization in toluene at reflux, and oxidative cleavage annulation of olefins
2ae2n with the one-pot combination of OsO4/NaIO4/HOAc in the aqueous THF at reflux.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
1H-Benzo[g]indazoles
Aldol condensation
Knorr pyrazole synthesis
One-pot combination
Oxidative cleavage annulation
1. Introduction
H N NH
2
H N NH
2 2
2
CF
3
(ref. 5b)
OH
(ref. 5c)
During the last decade, functionalized 1H-indazoles have be-
come a versatile class of compounds that have found use in drug
discovery.1 Due to the particular pharmaceutical interest concern-
ing the specific substitution pattern of 1H-indazoles, some syn-
thetic methods have been developed.2 In 1961, Knorr and Huisgen
reported the first example of substituted 1H-indazoles, and recent
developments have been characterized by transition metal-
mediated synthesis.3,4 In regard to the general preparation of
1H-indazole derivatives, there have been a few reports on the
synthesis of polycyclic benzannulated 1H-indazoles.5 The adopted
synthetic routes are described in Fig. 1. Basically, the key formation
of pyrazole skeleton presents a major challenge for constructing the
tricyclic angular 1H-benzo[g]indazole or linear 1H-benzo[f]inda-
zole. While 1H-benzo-indazoles and their derivatives with this
specific substitution pattern have been developed, new methods
for their preparation are still needed.
O
N
Me N
2
O
N
H
angular benzo[g]indazole
Ph
O
H N NH
2
HOAc
2
O
N
N
N
(ref. 5e)
(ref. 5d)
2
N
3
NH
H
linear benzo[f]indazole
Fig. 1. Synthetic routes of 1H-benzo-indazoles.
aromatization in toluene at reflux, and then (3) oxidative cleavage
annulation of 2ae2n with the combination of OsO4/NaIO4/HOAc in
the aqueous THF at reflux (Fig. 2).
2. Results and discussion
In continuation of our investigation with the one-pot combina-
tion of OsO4/NaIO4/HOAc,6a a facile three-step route is employed to
create the framework of 6,7-dimethoxy-1,3-diaryl-1H-benzo[g]
indazoles 1ae1n, starting with 3,4-dimethoxy-2-allylbenzaldehyde
(6), via (1) NaOH-mediated aldol condensation of 6 with 5ae5d in
MeOH at reflux, (2) Knorr pyrazole synthesis of the resulting 4ae4d
with 3ae3e in EtOH at reflux, followed by DDQ-mediated
The starting material, 2-allylbenzaldehyde 6, was provided
from commercially available isovanillin (7) in moderate overall
three-step yields according to the reported procedures with the
reaction sequence of O-allylation and the Claisen rearrangement
followed by O-methylation.6,7
Next, synthesis of 4ae4f was examined by the NaOH-mediated
aldol condensation of 6 with 5ae5f in MeOH. After screening
six ketones 5ae5f with different functional groups (Ar1¼a, Ph; b,
4-FePh; c, 3,4,5-(MeO)3ePh; d, 2-MeOePh; e, 2-NO2ePh; f,
4-NO2ePh), (E)-isomers 4ae4f were isolated in 25e89% yields, as
* Corresponding author. Tel.: þ886
7 3121101x2220; e-mail addresses:
mychang@kmu.edu.tw, mychang624@yahoo.com.tw (M.-Y. Chang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.011

7942
M.-Y. Chang et al. / Tetrahedron 68 (2012) 7941e7948
oxidative cleavage
annulation
reaction temperature from rt to 60 ꢀC and time from 4 to 2 h, the
MeO
MeO
desired 1a with poorer yield was observed. The possible mecha-
nism for the formation of 1a is described in Scheme 3. The initial
event may be considered as the formation of I with the proton/
oxocarbenium ions from HOAc-mediated annulation. Intermediate
II with six-membered ring is yielded via the nitrogen lone pair of
pyrazole skeleton promoted cascade-type ring-closure on the in-
termediate I. After hydrogen abstraction of III and sequential oxi-
dative dehydration of the resulting IV, the tricyclic skeleton of
1H-benzo[g]indazole 1a was produced. Under the above mentioned
one-pot combination condition, 1be1l with different electron-
withdrawing and electron-donating aryl substituents were
provided in the 60e74% yields, as shown in Table 1. The structures
of 1i and 1j were determined using single-crystal X-ray analysis
(Figs. 3 and 4).9
MeO
MeO
NH NHAr 3a~3e
2
B
A
Ar
Ar
1
1
C
N
N
N
N
Knorr
Ar
2
Ar
2
1a~1n
2a~2n
condensation
Ar = a, Ph; b, 4-F-Ph; c, 4-MeO-Ph; d, 4-Me-Ph; e, SO Tol
2
Ar = a, Ph; b, 2-F-Ph; c, 3,4,5-(MeO) -Ph; d, 2-MeO-Ph
1
2
3
Ar = a, Ph; b, 4-F-Ph; c, 4-MeO-Ph; d, 4-CHO-Ph
Claisen
Ar
1
MeO
MeO
rearrangement
MeO
MeO
5a~5d
O
7
Ar
H
ref. 6
1
aldol
O
condensation
O
6
The formation of 14 cycloadducts was confirmed through
4a~4d
spectral analysis. For example, the 1H NMR spectrum of 1c
Fig. 2. Retrosynthetic route toward benzo[g]indazoles 1ae1n.
exhibited two doublets
CH protons of the B ring. The CH protons of the A ring exhibited two
doublets
was confirmed by high-resolution mass spectrometry, which
showed a peak at m/z 411.1713 [Mþþ1].
d
7.94 (J¼9.2 Hz) and 7.32 (J¼9.2 Hz) for the
d
7.11 (J¼8.8 Hz) and 7.08 (J¼8.8 Hz). Finally, compound 1c
shown in Scheme 1. We found that 4e and 4f provided poorer yields
(25% and 38%) than the others at reflux for 5 h due to the stronger
electron-withdrawing effect of nitro group.
3. Conclusion
MeO
MeO
MeO
MeO
In summary, we have successfully presented a synthetic route
for the synthesis of 1,3-diaryl-1H-benzo[g]indazoles 1ae1n via
aldol condensation, Knorr pyrazole synthesis, and oxidative cleav-
age annulation with the one-pot combination of OsO4/NaIO4/HOAc.
This synthesis starts from simple starting material and reagents,
NaOH
MeOH
Ar
1
+
H
Ar
1
O
O
O
6
4a~4f
5a~5f
Ar = 4a, Ph (82%); 4b, 2-F-Ph (50%); 4c, 3,4,5-(MeO) -Ph (89%);
4d, 2-MeO-Ph (75%); 4e, 2-NO -Ph (25%); 4f, 4-NO -Ph (38%)
1
3
and provides
a potential methodology for chemical biology
2
2
research of combretastatin-A4 (CA4).
Scheme 1. Aldol condensation of 6 with 5ae5f.
4. Experimental section
4.1. General
Furthermore, 2ae2n (Ar2¼a, Ph; b, 4-FePh; c, 4-MeOePh; d,
4-CHOePh) were obtained as single isomers with 64e83% yield via
the treatment of 4ae4d with five arylhydrazines 3ae3e (Ar¼a, Ph;
b, 4-FePh; c, 4-MeOePh; d, 4-MeePh; e, SO2Tol) in refluxing EtOH
followed by DDQ-mediated aromatization of the resulting dihy-
dropyrazole in toluene at reflux (see Table 1 and Scheme 2).
Moreover, the Ar2 group in the N1-position of the pyrazole (C ring)
is in relative opposite configuration, as expected for the regio-
chemistry of Knorr condensation. Another regioisomer 8 was not
observed during the process.8 The protocol is broadly applicable for
the synthesis of substituted pyrazoles. The structure of 2k was
determined using single-crystal X-ray analysis.9
All other reagents and solvents were obtained from commercial
sources and used without further purification. Reactions were
routinely carried out under an atmosphere of dry nitrogen with
magnetic stirring. Products in organic solvents were dried with
anhydrous MgSO4 before concentration in vacuo. Melting points
were determined with an SMP3 melting apparatus. 1H and 13C NMR
spectra were recorded on a Varian INOVA-400 spectrometer oper-
ating at 200/400 and at 100 MHz, respectively. Chemical shifts (d)
are reported in parts per million (ppm) and the coupling constants
(J) are given in hertz. High-resolution mass spectra (HRMS) were
measured with a mass spectrometer Finnigan/Thermo Quest MAT
95XL. X-ray crystal structures were obtained with an Enraf-Nonius
FR-590 diffractometer (CAD4, Kappa CCD). Elemental analyses were
carried out with Heraeus Vario III-NCSH, Heraeus CHN-OS-Rapid
Analyzer or Elementar Vario EL III.
In particular, when the oxidative dehydrogenation of dihy-
dropyrazole skeleton with 4-methylphenyl group (Ar¼4-MeePh)
was treated with DDQ, the 4-methylphenyl group of three pyr-
azoles 2d, 2h, and 2l was further converted to 4-formylphenyl
group (Ar2¼4-CHOePh) via the benzylic oxidation. For synthesiz-
ing 2n (Ar¼SO2Tol), no benzylic oxidative product was observed in
the DDQ-mediated reaction. With the experimental results, we
envisioned that p-tolyl group with electron-donating amino group
could be easily oxidized to the benzaldehyde skeleton; therefore,
a rapid synthetic route for establishing the 4-formylphenyl group
could easily result. With the previous synthetic experience, we
attempted to construct the B ring of the tricyclic 1H-benzo[g]
indazoles 1ae1n by the useful combination of OsO4/NaIO4/HOAc
via the facile one-pot oxidative cleavage of 2ae2n and subsequent
intramolecular ring-closure. Reports in the literature have de-
scribed the improved procedure for the oxidative cleavage of ole-
fins by the OsO4/NaIO4 system.10 In order to initiate the work,
one-pot oxidative cleavage of the olefinic group of 2a was first
examined. When the reaction condition was treated at rt, 1a pro-
vided with good yields within a period of 4 h. After adjusting the
4.2. A representative synthetic procedure of compounds
4ae4f
NaOH (160 mg, 4.0 mmol) was added to a solution of skeleton 6
(2.0 mmol) in MeOH (20 mL) at rt. Then methyl aryl ketones 5ae5f
(2.1 mmol) were added to the reaction mixture. The reaction mix-
ture was stirred at reflux for 3 h. The reaction mixture was con-
centrated to yield the residue. The residue was extracted with
EtOAc (3ꢁ30 mL). The combined organic layers were washed with
brine, dried, filtered, and evaporated to afford crude product. Pu-
rification on silica gel (hexanes/EtOAc¼10:1 to 6:1) afforded com-
pounds 4ae4f.

Table 1
Synthesis of 1,3-diaryl-1H-benzo[g]indazoles 1ae1naec
OMe
OMe
MeO
MeO
1) NH NHAr 3a~3e, EtOH
OsO , NMO
2
4
4a~4d
A
B
NaIO , HOAc
2) DDQ, toluene
4
Ar
Ar
1
1
C
THF/H O
2
N
2
N
N
N
Ar
2
Ar
2a~2n
1a~1n
Entry
Product 2/yield (%)a
Product 1/yield (%)b
Entry
Product 2/yield (%)a
Product 1/yield (%)b
OMe
MeO
OMe
MeO
OMe
MeO
OMe
MeO
N
N
N
N
1
8
N
N
N
N
F
F
2a / 80
1a / 74
2b / 74
1b / 69
OMe
OMe
OMe
MeO
OMe
MeO
MeO
MeO
N
N
N
N
N
2
3
4
5
6
9
N
N
N
OHC
MeO
MeO
OHC
1d / 70
2c / 82
1c / 63
2d / 69
OMe
MeO
OMe
OMe
OMe
MeO
MeO
MeO
N
N
N
N
10
11
12
13
N
N
N
N
F
F
F
F
F
F
2e / 80
1e / 72
2f / 74
1f / 63
OMe
OMe
OMe
MeO
OMe
MeO
MeO
MeO
N
N
N
N
N
N
N
N
F
F
F
F
MeO
MeO
OHC
OHC
2g / 79
1g / 60
2h / 64
1h / 74
OMe
MeO
OMe
OMe
OMe
OMe
OMe
MeO
OMe
OMe
MeO
MeO
OMe
OMe
OMe
OMe
N
N
N
N
OMe
OMe
N
N
N
N
OMe
OMe
F
F
2i / 82
1i / 67
2j / 80
1j / 63
OMe
OMe
OMe
MeO
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
MeO
MeO
MeO
N
N
N
N
N
N
N
N
OMe
OMe
OMe
OMe
MeO
MeO
OHC
OHC
2k/ 83
1k / 69
2l / 70
1l / 70
OMe
MeO
OMe
OMe
OMe
MeO
MeO
MeO
N
N
N
N
N
N
N
7
14
N
O
O
S
S
MeO
MeO
O
O
MeO
MeO
2m / 72
1m / 66
2n / 68
1n / 73
a
For the optimal reaction conditions: (i) compounds 4ae4d (1.5 mmol, 1.0 equiv), compounds 3ae3d (1.6 mmol), EtOH (20 mL), reflux, 3 h; (ii) DDQ (2.0 mmol), toluene
(15 mL), reflux, 3 h.
b
For the optimal reaction conditions: (i) compounds 2ae2n (1.0 mmol), OsO4 (2.5% in THF, 1 mL), NMO (50% in H2O, 2.2 mmol), THF/H2O (v/v¼1:1, 20 mL), rt, 2 h; (ii) NaIO4
(1.2 mmol), rt, 1 h; (iii) HOAc (1 mL), rt, 1 h.
c
The isolated products were >95% pure as determined by 1H NMR analysis.

7944
M.-Y. Chang et al. / Tetrahedron 68 (2012) 7941e7948
OMe
OMe
MeO
MeO
Ar
1) NH NHAr 3a~3e, EtOH
2
4a~4d
Ar
1
1
2) DDQ, toluene
1
2
N
N
N
N
Ar
Ar
2
2
8
2a~2n
(No detected)
Scheme 2. Synthesis of 2ae2n.
OMe
Ph
H
O
OMe
1) OsO
4
4
MeO
MeO
OH
Ph
2) NaIO
2a
Ph
3) HOAc
N
N
N
N
I
II Ph
OMe
OMe
MeO
OH MeO
OH
-H O
2
H
1a
Fig. 4. X-ray structure of 1j.
Ph
Ph
N
N
N
N
III Ph
IV Ph
CDCl3):
d
7.93 (dd, J¼1.6, 15.6 Hz, 1H), 7.76 (dt, J¼1.6, 7.6 Hz, 1H),
Scheme 3. The possible mechanism of 2a.
7.51 (d, J¼8.8 Hz, 2H), 7.26e7.12 (m, 3H), 7.85 (d, J¼8.8 Hz, 1H),
5.98e5.88 (m, 1H), 5.01 (dq, J¼1.6, 10.4 Hz, 1H), 4.86 (dq, J¼1.6,
16.8 Hz, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 3.59 (dt, J¼1.6, 5.6 Hz, 2H);
4.2.1. 3-(6-Allyl-2,3-dimethoxy-phenyl)-1-phenyl-propenone (4a)
Yield¼82% (505 mg); colorless oil; HRMS (ESI, Mþþ1) calcd for
C20H21O3 309.1491, found 309.1489; 1H NMR (400 MHz, CDCl3):
13C NMR (100 MHz, CDCl3):
d
189.29 (d, J¼2.3 Hz), 160.93
(d, J¼251.0 Hz), 154.60, 147.22, 142.87, 136.48, 134.32, 133.47
(d, J¼9.1 Hz), 130.81 (d, J¼2.3 Hz), 127.11, 125.20 (d, J¼6.0 Hz),
124.35 (d, J¼3.1 Hz), 123.10 (2ꢁ), 116.36 (d, J¼22.8 Hz), 115.75,
110.46, 60.87, 55.66, 30.02.
d
8.03e7.98 (m, 3H), 7.59e7.47 (m, 4H), 7.35 (d, J¼15.6 Hz, 1H),
6.87 (d, J¼8.8 Hz, 1H), 6.02e5.92 (m, 1H), 5.04 (dq, J¼2.0, 10.0 Hz,
1H), 4.91 (dq, J¼2.0, 17.2 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.62
(dt, J¼2.0, 5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 190.71,
4.2.3. 3-(2-Allyl-3,4-dimethoxy-phenyl)-1-(3,4,5-trimethoxy-phe-
nyl)-propenone (4c) Yield¼89% (708 mg); yellowish solid;
mp¼125e126 ꢀC (recrystallized from hexanes and EtOAc); HRMS
(ESI, Mþþ1) calcd for C23H27O6 399.1808, found 399.1813; 1H NMR
154.50, 147.30, 142.67, 138.38, 136.58, 134.29, 132.54, 128.52 (2ꢁ),
128.47 (2ꢁ), 127.49, 122.95, 121.84, 115.85, 110.43, 60.95, 55.73,
30.08.
(400 MHz, CDCl3):
d
7.99 (d, J¼15.6 Hz, 1H), 7.50 (d, J¼8.8 Hz, 1H),
4.2.2. 3-(2-Allyl-3,4-dimethoxy-phenyl)-1-(2-fluoro-phenyl)-prope-
none (4b) Yield¼50% (326 mg); colorless oil; HRMS (ESI, Mþþ1)
calcd for C20H20FO3 327.1397, found 327.1399; 1H NMR (400 MHz,
7.28 (d, J¼15.6 Hz, 1H), 7.24 (s, 2H), 6.86 (d, J¼8.8 Hz, 1H), 6.01e5.91
(m, 1H), 5.02 (dq, J¼2.0, 10.0 Hz, 1H), 4.91 (dq, J¼2.0, 17.2 Hz, 1H),
3.92 (s, 6H), 3.91 (s, 3H), 3.90 (s, 3H), 3.80 (s, 3H), 3.61 (dt, J¼2.0,
5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 189.30, 154.48, 153.04,
147.31, 142.57 (2ꢁ), 142.16, 136.57, 134.19, 133.66, 127.53, 123.07,
121.56, 115.85, 110.40, 105.94 (2ꢁ), 60.94, 56.29 (3ꢁ), 55.71, 30.15.
4.2.4. 3-(2-Allyl-3,4-dimethoxy-phenyl)-1-(2-methoxy-phenyl)-pro-
penone (4d) Yield¼75% (507 mg); colorless oil; HRMS (ESI, Mþþ1)
calcd for C21H23O4 339.1596, found 339.1603; 1H NMR (400 MHz,
CDCl3):
d
7.78 (d, J¼15.6 Hz, 1H), 7.54 (d, J¼1.6, 7.6 Hz, 1H), 7.44
(d, J¼8.4 Hz, 1H), 7.43e7.38 (m, 1H), 7.15 (d, J¼15.6 Hz, 1H),
7.00e7.93 (m, 2H), 6.81 (d, J¼8.8 Hz, 1H), 5.93e5.83 (m, 1H), 4.96
(dq, J¼1.6, 10.4 Hz, 1H), 4.82 (dq, J¼1.6, 16.8 Hz, 1H), 3.84 (s, 3H),
3.82 (s, 3H), 3.77 (s, 3H), 3.55 (dt, J¼1.6, 5.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3):
d 193.12, 157.56, 154.05, 146.94, 141.30, 136.30,
133.71, 132.24, 129.80, 129.15, 127.20, 126.52, 122.74, 120.34, 115.42,
111.28, 110.29, 60.59, 55.41 (2ꢁ), 29.56.
4.2.5. 3-(2-Allyl-3,4-dimethoxy-phenyl)-1-(2-nitro-phenyl)-prope-
none (4e) Yield¼25% (177 mg); yellowish oil; HRMS (ESI, Mþþ1)
calcd for C20H20NO5 354.1342, found 354.1348; 1H NMR (400 MHz,
CDCl3):
d
8.18 (dd, J¼0.8, 8.4 Hz, 1H), 7.75 (dt, J¼1.2, 7.6 Hz, 1H), 7.64
(dt, J¼1.6, 7.6 Hz, 1H), 7.48 (dd, J¼1.6, 7.6 Hz, 1H), 7.45 (d, J¼8.8 Hz,
1H), 7.38 (d, J¼16.0 Hz, 1H), 6.85 (d, J¼8.8 Hz, 1H), 6.4 (d, J¼16.0 Hz,
1H), 5.77e5.67 (m, 1H), 4.86 (dq, J¼1.6, 10.0 Hz, 1H), 4.71 (dq, J¼1.6,
16.8 Hz, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 3.38 (dt, J¼1.6, 5.6 Hz, 2H);
Fig. 3. X-ray structure of 1i.
13C NMR (100 MHz, CDCl3):
d 193.28, 154.90, 147.21, 144.54, 136.46,

M.-Y. Chang et al. / Tetrahedron 68 (2012) 7941e7948
7945
136.26 (2ꢁ), 133.88, 130.33, 128.96, 126.41, 125.81, 124.42, 123.21
(2ꢁ), 115.64, 110.60, 60.95, 55.75, 30.02.
d 158.35, 153.11, 150.81, 147.45, 142.84, 136.59, 133.32, 133.04,
132.82, 128.64 (2ꢁ), 127.98, 126.79, 125.82 (2ꢁ), 125.62 (2ꢁ),
123.49, 115.39, 113.86 (2ꢁ), 110.15, 106.05, 60.79, 55.59, 55.43,
31.91.
4.2.6. 3-(2-Allyl-3,4-dimethoxy-phenyl)-1-(4-nitro-phenyl)-prope-
none (4f) Yield¼38% (268 mg); yellowish oil; HRMS (ESI, Mþþ1)
calcd for C20H20NO5 354.1342, found 354.1348; 1H NMR (400 MHz,
4.3.4. 4-[5-(2-Allyl-3,4-dimethoxy-phenyl)-3-phenyl-pyrazol-1-yl]-
benzaldehyde (2d) Yield¼69% (439 mg); yellowish oil; HRMS (ESI,
Mþþ1) calcd for C27H25N2O3 425.1865, found 425.1871; 1H NMR
CDCl3):
d
7.98 (d, J¼15.2 Hz, 1H), 7.91 (d, J¼8.8 Hz, 2H), 7.50
(d, J¼8.4 Hz, 1H), 7.35 (d, J¼15.2 Hz, 1H), 6.85 (d, J¼8.4 Hz, 1H), 6.72
(d, J¼8.8 Hz, 2H), 6.02e5.92 (m, 1H), 5.03 (dq, J¼2.0, 10.0 Hz, 1H),
4.93 (dq, J¼2.0, 17.2 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.62 (dt, J¼2.0,
(400 MHz, CDCl3):
d
9.45 (s, 1H), 7.93 (d, J¼7.2 Hz, 2H), 7.78
(d, J¼8.8 Hz, 2H), 7.52e7.43 (m, 4H), 7.39e7.35 (m, 1H), 6.89
(d, J¼8.4 Hz, 1H), 6.81 (d, J¼8.4 Hz, 1H), 6.78 (s, 1H), 5.81e5.72
(m, 1H), 4.88 (dq, J¼1.6, 10.0 Hz, 1H), 4.77 (dq, J¼1.6, 16.8 Hz, 1H),
3.90 (s, 3H), 3.85 (s, 3H), 3.30 (d, J¼4.8 Hz, 2H); 13C NMR (100 MHz,
5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 188.26, 154.15, 150.33,
147.29, 143.06, 141.03, 136.63, 134.06, 130.98 (2ꢁ), 127.97, 122.82,
121.85, 115.78, 114.24 (2ꢁ), 110.41, 60.91, 55.71, 30.12.
CDCl3): d 191.14,153.51,152.29,147.72,144.72,143.19,136.16,133.87,
4.3. A representative synthetic procedure of compounds
2ae2n
133.17, 132.49,130.32 (2ꢁ), 128.71 (2ꢁ), 128.39, 126.49,125.85 (2ꢁ),
123.29 (3ꢁ), 115.56, 110.44, 107.85, 60.84, 55.62, 31.91.
Aryl hydrazines 3ae3e (1.6 mmol) were added to a solution of
compounds 4ae4d (1.5 mmol) in EtOH (20 mL) at rt. The reaction
mixture was stirred at reflux for 3 h. The reaction mixture was
concentrated to yield the residue. The residue was extracted with
EtOAc (3ꢁ30 mL). The combined organic layers were washed with
brine, dried, filtered, and evaporated to afford crude product.
Without further purification, DDQ (450 mg, 2.0 mmol) was added
the resulting product in toluene (15 mL) at rt. The reaction mixture
was stirred at reflux for 3 h. The reaction mixture was concentrated
to yield the residue. The residue was extracted with EtOAc
(3ꢁ30 mL). The combined organic layers were washed with brine,
dried, filtered, and evaporated to afford crude product. Purification
on silica gel (hexanes/EtOAc¼8:1 to 4:1) afforded compounds
2ae2n.
4.3.5. 5-(2-Allyl-3,4-dimethoxy-phenyl)-3-(2-fluoro-phenyl)-1-
phenyl-1H-pyrazole (2e) Yield¼80% (497 mg); yellowish oil; HRMS
(ESI, Mþþ1) calcd for C26H24FN2O2 415.1822, found 415.1829; 1H
NMR (400 MHz, CDCl3):
d
8.17 (dt, J¼1.6, 7.6 Hz, 1H), 7.34e7.08
(m, 8H), 6.89 (d, J¼4.0 Hz, 1H), 6.89 (d, J¼8.4 Hz, 1H), 6.77
(d, J¼8.4 Hz, 1H), 5.81e5.70 (m, 1H), 4.90 (dq, J¼1.6, 10.0 Hz, 1H),
4.81 (dq, J¼1.6, 16.8 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.31
(d, J¼6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 160.30
(d, J¼248.3 Hz), 153.18, 147.55, 140.07, 136.38, 133.44, 131.87, 129.17
(d, J¼8.3 Hz), 128.68 (2ꢁ), 128.43, 128.10 (2ꢁ), 126.71, 124.25,
124.21, 124.01, 123.70, 116.03 (d, J¼22.0 Hz), 115.44, 110.19, 110.07,
109.97, 60.78, 55.60, 31.94.
4.3.6. 5-(2-Allyl-3,4-dimethoxy-phenyl)-1,3-bis-(2-fluoro-phenyl)-
1H-pyrazole (2f) Yield¼74% (480 mg); yellowish oil; HRMS (ESI,
Mþþ1) calcd for C26H23F2N2O2 433.1728, found 433.1733; 1H NMR
4.3.1. 5-(2-Allyl-3,4-dimethoxy-phenyl)-1,3-diphenyl-1H-pyrazole
(2a) Yield¼80% (475 mg); yellowish oil; HRMS (ESI, Mþþ1) calcd
for C26H25N2O2 397.1916, found 397.1922; 1H NMR (400 MHz,
(400 MHz, CDCl3):
d
8.15 (dt, J¼1.6, 7.6 Hz, 1H), 7.34e7.26 (m, 3H),
7.22 (dt, J¼8.0, 9.2 Hz, 1H), 7.15 (ddd, J¼0.8, 8.0, 10.8 Hz, 1H),
6.99e6.93 (m, 2H), 6.89 (d, J¼4.0 Hz, 1H), 6.87 (d, J¼8.4 Hz, 1H),
6.77 (d, J¼8.4 Hz, 1H), 5.82e5.72 (m, 1H), 4.91 (dq, J¼1.6, 10.0 Hz,
1H), 4.81 (dq, J¼1.6, 16.8 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.31 (d,
CDCl3):
d 7.94e7.91 (m, 2H), 7.46e7.42 (m, 2H), 7.36e7.18 (m, 6H),
6.89 (d, J¼8.4 Hz, 1H), 6.77 (d, J¼8.4 Hz, 1H), 6.74 (s, 1H), 5.82e5.72
(m, 1H), 4.91 (dq, J¼2.0, 10.0 Hz, 1H), 4.80 (dq, J¼2.0, 17.2 Hz, 1H),
3.88 (s, 3H), 3.83 (s, 3H), 3.30 (d, J¼6.0 Hz, 2H); 13C NMR (100 MHz,
J¼6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
161.21 (d, J¼145.6 Hz),
d
CDCl3):
d
153.15, 151.36, 147.54, 142.71, 140.14, 136.51, 133.32, 133.17,
160.28 (d, J¼248.6 Hz), 153.24, 147.57, 146.19, 142.44 (d, J¼22.2 Hz),
136.29, 133.40, 129.25 (d, J¼8.3 Hz), 128.41 (d, J¼3.8 Hz), 126.75,
125.79, 125.71, 124.24 (d, J¼3.1 Hz), 123.35, 120.94 (d, J¼12.1 Hz),
116.16, 115.94, 115.64, 115.49, 115.41, 110.22, 109.93 (d, J¼10.6 Hz),
60.77, 55.58, 31.91.
128.65 (2ꢁ), 128.61 (2ꢁ), 127.89, 126.72, 126.66, 125.74 (2ꢁ), 123.92
(2ꢁ), 123.80, 115.36, 110.19, 106.56, 60.77, 55.58, 31.92. Anal. Calcd
for C26H24N2O2: C, 78.76; H, 6.10; N, 7.07. Found: C, 78.92; H, 6.31;
N, 7.38.
4.3.2. 5-(2-Allyl-3,4-dimethoxy-phenyl)-1-(4-fluoro-phenyl)-3-
phenyl-1H-pyrazole (2b) Yield¼74% (460 mg); yellowish oil; HRMS
(ESI, Mþþ1) calcd for C26H24FN2O2 415.1822, found 415.1826; 1H
4.3.7. 5-(2-Allyl-3,4-dimethoxy-phenyl)-3-(2-fluoro-phenyl)-1-(4-
methoxy-phenyl)-1H-pyrazole (2g) Yield¼79% (526 mg); yellowish
oil; HRMS (ESI, Mþþ1) calcd for C27H26FN2O3 445.1928, found
NMR (400 MHz, CDCl3):
d
7.94e7.91 (m, 2H), 7.46e7.42 (m, 2H),
445.1932; 1H NMR (400 MHz, CDCl3):
d
8.16 (dt, J¼2.0, 7.6 Hz, 1H),
7.37e7.26 (m, 3H), 6.99e6.94 (m, 2H), 6.87 (d, J¼8.4 Hz, 1H), 6.78
(d, J¼8.4 Hz, 1H), 6.74 (s, 1H), 5.83e5.74 (m, 1H), 4.92 (dq, J¼2.0,
10.0 Hz, 1H), 4.80 (dq, J¼2.0, 17.2 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H),
7.32e7.26 (m, 1H), 7.24e7.19 (m, 3H), 7.14 (ddd, J¼0.8, 8.0, 11.2 Hz,
1H), 6.88 (d, J¼8.8 Hz, 1H), 6.87 (s, 1H), 6.81e6.77 (m, 2H), 6.76 (d,
J¼8.8 Hz, 1H), 5.83e5.73 (m, 1H), 4.91 (dq, J¼2.0, 10.0 Hz, 1H), 4.82
(dq, J¼2.0, 17.2 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.32
3.31 (d, J¼6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 161.10
(d, J¼245.6 Hz), 153.20, 151.39, 147.54, 142.74, 136.41, 136.29
(d, J¼3.1 Hz), 133.26, 132.99, 128.65, 128.61 (2ꢁ), 127.96, 126.66,
125.69 (2ꢁ), 125.66 (d, J¼8.3 Hz), 123.41, 115.58, 115.41, 115.36,
110.21, 106.46, 60.54, 55.54, 31.88.
(d, J¼6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 160.24 (d,
J¼248.0 Hz), 158.31, 153.06, 147.47, 145.69, 142.30, 136.47, 133.44,
133.38, 129.01 (d, J¼8.3 Hz), 128.44 (d, J¼3.8 Hz), 126.83, 125.48
(2ꢁ), 124.19 (d, J¼3.1 Hz), 123.70, 121.17 (d, J¼12.1 Hz), 115.98 (d,
J¼22.0 Hz), 115.40, 113.83 (2ꢁ), 110.13, 109.52 (d, J¼10.7 Hz), 60.76,
55.56, 55.38, 31.92.
4.3.3. 5-(2-Allyl-3,4-dimethoxy-phenyl)-1-(4-methoxy-phenyl)-3-
phenyl-1H-pyrazole (2c) Yield¼82% (524 mg); yellowish oil; HRMS
(ESI, Mþþ1) calcd for C27H27N2O3 427.2022, found 427.2025; 1H
4.3.8. 4-[5-(2-Allyl-3,4-dimethoxy-phenyl)-3-(2-fluoro-phenyl)-pyr-
azol-1-yl]-benzaldehyde (2h) Yield¼64% (424 mg); yellowish solid;
mp¼114e115 ꢀC (recrystallized from hexanes and EtOAc); HRMS
(ESI, Mþþ1) calcd for C27H24FN2O3 443.1771, found 443.1778; 1H
NMR (400 MHz, CDCl3):
d
7.93 (d, J¼7.2 Hz, 2H), 7.47e7.41 (m, 2H),
7.36e7.32 (m, 1H), 7.22 (d, J¼8.4 Hz, 2H), 6.87 (d, J¼8.0 Hz, 1H),
6.80e6.75 (m, 3H), 6.72 (s, 1H), 5.83e5.73 (m, 1H), 4.92 (dq, J¼2.0,
10.4 Hz, 1H), 4.80 (dq, J¼2.0, 17.2 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H),
3.78 (s, 3H), 3.31 (d, J¼5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
NMR (400 MHz, CDCl3):
7.80e7.76 (m, 2H), 7.52e7.49 (m, 2H), 7.36e7.31 (m, 1H), 7.24
d
9.95 (s, 1H), 8.17 (dt, J¼2.0, 7.6 Hz, 1H),

7946
M.-Y. Chang et al. / Tetrahedron 68 (2012) 7941e7948
(dt, J¼1.2, 7.6 Hz, 1H), 7.18e7.13 (m, 1H), 6.93 (d, J¼8.0 Hz, 1H), 6.90
(d, J¼8.4 Hz, 1H), 6.80 (d, J¼8.4 Hz, 1H), 5.80e5.70 (m, 1H), 4.87
(dq, J¼2.0, 10.0 Hz, 1H), 4.78 (dq, J¼2.0, 17.2 Hz, 1H), 3.89 (s, 3H),
3.85 (s, 3H), 3.31 (br d, J¼5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
126.41, 123.25 (2ꢁ), 123.14, 115.46, 110.39, 107.75, 102.97 (2ꢁ),
60.88, 60.77, 56.14 (2ꢁ), 55.56, 31.87.
4.3.13. 5-(2-Allyl-3,4-dimethoxy-phenyl)-3-(2-methoxy-phenyl)-1-
(4-methoxy-phenyl)-1H-pyrazole (2m) Yield¼72% (492 mg); yel-
lowish oil; HRMS (ESI, Mþþ1) calcd for C28H29N2O4 457.2127, found
d
191.07, 160.36 (d, J¼248.7 Hz), 158.51, 147.74, 147.18, 144.71, 142.80
(d, J¼2.3 Hz), 136.02, 133.98, 133.28, 130.29 (2ꢁ), 129.65
(d, J¼9.1 Hz), 128.46 (d, J¼3.0 Hz), 126.55, 124.30 (d, J¼3.8 Hz),
125.35 (2ꢁ), 123.20 (d, J¼7.5 Hz), 120.55 (d, J¼12.1 Hz),
116.11 (d, J¼21.9 Hz), 115.58, 111.18 (d, J¼9.9 Hz), 110.44, 60.81,
55.61, 31.92.
457.2133; 1H NMR (400 MHz, CDCl3):
d
8.12 (dd, J¼1.6, 7.6 Hz, 1H),
7.31 (dt, J¼1.6, 8.8 Hz, 1H), 7.22 (d, J¼8.8 Hz, 2H), 7.06e6.98 (m, 2H),
6.98 (s, 1H), 6.89 (d, J¼8.8 Hz, 1H), 6.78 (d, J¼8.8 Hz, 2H), 6.75 (d,
J¼8.8 Hz, 1H), 5.84e5.74 (m, 1H), 4.91 (dq, J¼1.6, 10.0 Hz, 1H), 4.84
(dq, J¼1.6, 16.8 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.77 (s,
4.3.9. 5-(2-Allyl-3,4-dimethoxy-phenyl)-1-phenyl-3-(3,4,5-
trimethoxy-phenyl)-1H-pyrazole (2i) Yield¼82% (598 mg); yellow-
ish oil; HRMS (ESI, Mþþ1) calcd for C29H31N2O5 487.2233, found
3H), 3.34 (br d, J¼6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 158.10,
156.91, 152.91, 147.93, 147.44, 141.71, 141.43, 136.64, 133.63, 133.47,
132.38, 128.80, 128.66, 126.89, 125.46 (2ꢁ), 120.84, 115.30, 113.75
(2ꢁ), 111.31, 110.35, 110.08, 60.89, 55.57, 55.44, 55.38, 32.00.
487.2236; 1H NMR (400 MHz, CDCl3):
d 7.32e7.19 (m, 5H), 7.15
(s, 2H), 6.89 (d, J¼8.4 Hz, 1H), 6.77 (d, J¼8.4 Hz, 1H), 6.68 (s, 1H),
5.78e5.71 (m, 1H), 4.89 (dq, J¼1.6, 10.0 Hz, 1H), 4.79 (dq, J¼1.6,
16.8 Hz, 1H), 3.95 (s, 6H), 3.89 (s, 3H), 3.88 (s, 3H), 3.82 (s, 3H), 3.28
4.4. A representative synthetic procedure of compounds
1ae1n
(d, J¼6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 153.46, 153.04,
151.22, 147.54, 142.90, 139.96, 138.11, 136.48, 133.30, 128.82, 128.68
(2ꢁ), 126.80, 126.68, 125.38, 123.99 (2ꢁ), 123.62, 115.33, 110.19,
106.51, 103.00 (2ꢁ), 60.94, 60.76, 56.21 (2ꢁ), 55.59, 31.93.
A solution of 2.5% OsO4 (1 mL, in THF) was added to a solution of
compounds 2ae2n (1.0 mmol) in the co-solvent of THF (10 mL) and
water (10 mL). NMO (50% in water, 500 mg, 2.2 mmol) was added to
the reaction mixture at rt. The reaction mixture was stirred at rt for
2 h. Then, NaIO4 (257 mg, 1.2 mmol) was added to the reaction
mixture at rt. The reaction mixture was stirred at rt for 1 h. HOAc
(1 mL) was added to the reaction mixture at rt. The reaction mix-
ture was stirred at rt for 1 h. The overall synthetic procedure had to
be monitored by TLC until the reaction was completed. Aqueous
NaHSO3 () (10%, 5 mL) was added to the reaction mixture and the
solvent was concentrated. The residue was diluted with water
(10 mL) and the mixture was extracted with EtOAc (3ꢁ20 mL). The
combined organic layers were washed with brine, dried, filtered,
and evaporated to yield crude compound. Purification on silica gel
(hexanes/EtOAc) afforded compounds 1ae1n.
4.3.10. 5-(2-Allyl-3,4-dimethoxy-phenyl)-1-(4-fluoro-phenyl)-3-
(3,4,5-trimethoxy-phenyl)-1H-pyrazole (2j) Yield¼80% (605 mg);
yellowish oil; HRMS (ESI, Mþþ1) calcd for C29H30FN2O5 505.2139,
found 505.2142; 1H NMR (400 MHz, CDCl3):
d 7.30e7.25 (m, 2H),
7.13 (s, 2H), 6.98e6.92 (m, 2H), 6.86 (d, J¼8.4 Hz, 1H), 6.77 (d,
J¼8.4 Hz, 1H), 6.68 (s, 1H), 5.79e5.70 (m, 1H), 4.89 (dq, J¼1.6,
10.0 Hz, 1H), 4.78 (dq, J¼1.6, 16.8 Hz, 1H), 3.94 (s, 6H), 3.88 (s, 3H),
3.87 (s, 3H), 3.82 (s, 3H), 3.28 (d, J¼6.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3):
d 162.36, 159.91, 153.44, 153.22, 151.26, 147.51, 142.89,
138.12, 136.35, 126.16, 133.21, 128.68, 126.61, 125.76, 125.67, 123.26,
115.58, 115.36 (2ꢁ), 110.19, 106.40, 102.92 (2ꢁ), 60.88, 60.72, 56.15
(2ꢁ), 55.53, 31.87.
4.4.1. 6,7-Dimethoxy-1,3-diphenyl-1H-benzo[g]indazole
(1a)
4.3.11. 5-(2-Allyl-3,4-dimethoxy-phenyl)-1-(4-methoxy-phenyl)-3-
(3,4,5-trimethoxy-phenyl)-1H-pyrazole (2k) Yield¼83% (642 mg);
yellowish solid; mp¼105e106 ꢀC (recrystallized from hexanes and
EtOAc); HRMS (ESI, Mþþ1) calcd for C30H33N2O6 517.2339, found
Yield¼74% (281 mg); yellowish solid; mp¼105e106 ꢀC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for
C25H21N2O2 381.1603, found 381.1610; 1H NMR (400 MHz, CDCl3):
d
8.03e7.95 (m, 4H), 7.68e7.52 (m, 7H), 7.46e7.42 (m, 1H), 7.33 (d,
517.2343; 1H NMR (400 MHz, CDCl3):
d
7.20 (d, J¼8.8 Hz, 2H), 7.13 (s,
J¼9.2 Hz, 1H), 7.07 (d, J¼9.2 Hz, 1H), 4.02 (s, 3H), 3.95 (s, 3H); 13C
2H), 6.86 (d, J¼8.4 Hz, 1H), 6.76 (d, J¼8.8 Hz, 2H), 6.75 (d, J¼8.4 Hz,
1H), 6.66 (s,1H), 5.81e5.71 (m,1H), 4.90 (dq, J¼1.6,10.0 Hz,1H), 4.80
(dq, J¼1.6, 17.2 Hz, 1H), 3.93 (s, 6H), 3.88 (s, 3H), 3.86 (s, 3H), 3.81 (s,
3H), 3.75 (s, 3H), 3.29 (d, J¼6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
NMR (100 MHz, CDCl3): d 149.46, 146.40, 144.08, 141.77, 137.92,
133.16, 129.60 (2ꢁ), 129.14, 128.96, 128.80 (2ꢁ), 128.18, 128.05 (2ꢁ),
127.54 (2ꢁ), 119.64, 118.68, 118.15, 116.85, 116.35, 113.12, 61.26,
56.39.
d
158.28, 153.39 (2ꢁ), 153.04, 150.82, 147.39, 142.80, 137.94, 136.54,
133.23, 133.18, 128.90, 126.68, 125.52 (2ꢁ), 123.51, 115.25, 113.75
(2ꢁ), 110.08, 105.93, 102.89 (2ꢁ), 60.86, 60.69, 56.13 (2ꢁ), 55.50,
55.33, 31.86. Single-crystal X-ray diagram: crystal of compound 2k
was grown by slow diffusion of EtOAc into a solution of compound
2k in CCl4 to yield colorless prism. The compound crystallizes in the
4.4.2. 1-(4-Fluoro-phenyl)-6,7-dimethoxy-3-phenyl-1H-benzo[g]in-
dazole (1b Yield¼69% (275 mg); yellowish solid; mp¼171e172 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd
for C25H20FN2O2 399.1509, found 399.1513; 1H NMR (400 MHz,
CDCl3):
7.47e7.42 (m, 1H), 7.33e7.28 (m, 3H), 7.10 (d, J¼9.2 Hz, 1H), 4.02 (s,
3H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3):
162.77 (d,
d 8.01e7.95 (m, 4H), 7.66e7.62 (m, 2H), 7.56e7.52 (m, 2H),
ꢀ
trigonal crystal system, space group R-3, a¼21.0478(6) A,
3
ꢀ
ꢀ
ꢀ
b¼21.0478(6) A,
c¼32.2300(11) A,
V¼12,365.3(7) A ,
Z¼18,
d
dcalcd¼1.373 g/cm3, F(000)¼5376, 2
q
range 1.28e26.39ꢀ, R indices
J¼247.7 Hz), 149.55, 146.55, 144.14, 138.06, 137.84, 137.80, 132.96,
129.49, 129.40, 129.01, 128.84 (2ꢁ), 128.29, 128.02 (2ꢁ), 119.59,
118.40, 117.00, 116.69, 116.47, 116.19, 113.21, 61.27, 56.38.
(all data) R1¼0.0915, wR2¼0.2338.
4.3.12. 4-[5-(2-Allyl-3,4-dimethoxy-phenyl)-3-(3,4,5-trimethoxy-
phenyl)-pyrazol-1-yl]-benzaldehyde (2l) Yield¼70% (540 mg); yel-
lowish oil; HRMS (ESI, Mþþ1) calcd for C30H31N2O6 515.2182, found
4.4.3. 6,7-Dimethoxy-1-(4-methoxy-phenyl)-3-phenyl-1H-benzo[g]
indazole
(1c) Yield¼63%
(258 mg);
yellowish
solid;
515.2187; 1H NMR (400 MHz, CDCl3):
d
9.93 (s, 1H), 7.77 (d,
mp¼152e153 ꢀC (recrystallized from hexanes and EtOAc); HRMS
J¼8.8 Hz, 2H), 7.49 (d, J¼8.8 Hz, 2H), 7.14 (s, 2H), 6.89 (d, J¼8.4 Hz,
1H), 6.80 (d, J¼8.4 Hz, 1H), 6.72 (s, 1H), 5.77e5.67 (m, 1H), 4.85 (dq,
J¼1.6, 10.0 Hz, 1H), 4.75 (dq, J¼1.6, 16.8 Hz, 1H), 3.95 (s, 6H), 3.89 (s,
3H), 3.88 (s, 3H), 3.83 (s, 3H), 3.27 (br d, J¼6.0 Hz, 2H); 13C NMR
(ESI, Mþþ1) calcd for C26H23N2O3 411.1709, found 411.1713; 1H NMR
(400 MHz, CDCl3):
d
8.02e7.99 (m, 3H), 7.94 (d, J¼9.2 Hz, 1H),
7.57e7.51 (m, 4H), 7.45e7.41 (m, 1H), 7.32 (d, J¼9.2 Hz, 1H), 7.11 (d,
J¼8.8 Hz, 2H), 7.08 (d, J¼8.8 Hz, 1H), 4.01 (s, 3H), 3.95 (s, 3H), 3.94
(100 MHz, CDCl3):
144.62, 143.25, 138.34, 136.07, 133.84, 133.08, 130.26 (2ꢁ), 128.20,
d
191.05, 153.47 (2ꢁ), 153.44, 152.15, 147.65,
(s, 3H); 13C NMR (100 MHz, CDCl3):
d 160.07, 149.40, 146.03, 144.03,
138.14, 134.69, 133.31, 128.86 (2ꢁ), 128.77 (2ꢁ), 128.58, 128.08,

M.-Y. Chang et al. / Tetrahedron 68 (2012) 7941e7948
7947
128.01 (2ꢁ), 119.66, 118.56, 117.84, 116.62, 116.46, 114.70 (2ꢁ),
137.26, 135.98, 131.37 (d, J¼3.8 Hz), 130.84 (2ꢁ), 130.46 (d,
J¼8.3 Hz), 129.29, 127.36 (2ꢁ), 124.51 (d, J¼3.8 Hz), 120.41 (d,
J¼15.1 Hz), 120.19, 119.95 (d, J¼6.8 Hz), 118.65, 117.46, 116.21 (d,
J¼22.0 Hz), 115.93, 113.26, 61.29, 56.39.
113.10, 61.25, 56.37, 55.65.
4.4.4. 4-(6,7-Dimethoxy-3-phenyl-benzo[g]indazol-1-yl)-benzalde-
hyde (1d) Yield¼70% (286 mg); yellowish solid; mp¼125e126 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd
for C26H21N2O3 409.1552, found 409.1556; 1H NMR (400 MHz,
4.4.9. 6,7-Dimethoxy-1-phenyl-3-(3,4,5-trimethoxy-phenyl)-1H-
benzo[g]indazole (1i) Yield¼67% (315 mg); yellowish solid;
mp¼160e161 ꢀC (recrystallized from hexanes and EtOAc); HRMS
(ESI, Mþþ1) calcd for C28H27N2O5 471.1920, found 471.1918; 1H
CDCl3):
d
10.16 (s,1H), 8.12 (d, J¼8.8 Hz, 2H), 8.03e7.98 (m, 4H), 7.89
(d, J¼8.8 Hz, 2H), 7.57e7.53 (m, 2H), 7.48e7.44 (m, 2H), 7.12 (d,
J¼9.2 Hz, 1H), 4.03 (s, 3H), 3.97 (s, 3H); 13C NMR (100 MHz, CDCl3):
NMR (400 MHz, CDCl3):
d 7.97 (s, 2H), 7.67e7.58 (m, 5H), 7.31 (d,
d
191.16, 149.63, 147.82, 146.63, 144.20, 137.65, 135.86, 132.75,
J¼9.2 Hz, 1H), 7.21 (s, 2H), 7.07 (d, J¼9.2 Hz, 1H), 4.01 (s, 3H), 3.98
130.86, 129.18, 128.90 (2ꢁ), 128.51 (2ꢁ), 128.03 (2ꢁ), 127.33 (2ꢁ),
(s, 6H), 3.95 (s, 3H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3):
119.56, 119.16, 118.72, 117.59, 116.02, 113.29, 61.31, 56.40.
d
153.58, 149.51, 146.37, 144.09, 141.68, 138.27, 137.96, 129.60 (2ꢁ),
129.20, 128.96, 128.72, 127.56 (2ꢁ), 119.41, 118.65, 118.02, 116.96,
116.30, 113.20 (2ꢁ), 105.31 (2ꢁ), 61.24, 60.96, 56.37, 56.28 (2ꢁ).
Anal. Calcd for C28H26N2O5: C, 71.47; H, 5.57; N, 5.95. Found: C,
71.78; H, 5.87; N, 6.12. Single-crystal X-ray diagram: crystal of
compound 1i was grown by slow diffusion of EtOAc into a solution
of compound 1i in CH2Cl2 to yield colorless prism. The compound
crystallizes in the triclinic crystal system, space group P-1,
4.4.5. 3-(2-Fluoro-phenyl)-6,7-dimethoxy-1-phenyl-1H-benzo[g]in-
dazole (1e) Yield¼72% (287 mg); yellowish solid; mp¼143e144 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd
for C25H20FN2O2 399.1509, found 399.1513; 1H NMR (400 MHz,
CDCl3):
d
7.95 (d, J¼9.2 Hz, 1H), 7.86 (dt, J¼2.0, 7.6 Hz, 1H), 7.80
(dd, J¼3.6, 9.2 Hz, 1H), 7.68e7.58 (m, 5H), 7.46e7.41 (m, 1H), 7.34
3
ꢀ
ꢀ
ꢀ
ꢀ
(d, J¼9.2 Hz, 1H), 7.31e7.25 (m, 2H), 7.07 (d, J¼9.2 Hz, 1H), 4.01 (s,
a¼9.7753(5) A, b¼11.3174(6) A, c¼11.6471(6) A, V¼1191.77(11) A ,
3H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
160.20 (d,
Z¼2, dcalcd¼1.311 g/cm3, F(000)¼496, 2
q
range 1.86e26.41ꢀ, R in-
dices (all data) R1¼0.0644, wR2¼0.1455.
J¼247.9 Hz), 149.50, 144.18, 142.09, 141.77, 137.52, 131.50 (d,
J¼3.1 Hz), 130.09 (d, J¼7.5 Hz), 129.58 (2ꢁ), 129.16, 129.06, 127.49
(2ꢁ), 124.42 (d, J¼3.8 Hz), 120.88 (d, J¼15.2 Hz), 120.06 (d,
J¼7.6 Hz), 119.26, 118.63, 116.71, 116.30, 116.11 (d, J¼21.9 Hz), 113.11,
61.25, 56.38.
4.4.10. 1-(4-Fluoro-phenyl)-6,7-dimethoxy-3-(3,4,5-trimethoxy-phe-
nyl)-1H-benzo[g]indazole (1j) Yield¼63% (307 mg); yellowish
solid; mp¼213e214 ꢀC (recrystallized from hexanes and EtOAc);
HRMS (ESI, Mþþ1) calcd for C28H26FN2O5 489.1826, found
4.4.6. 1,3-Bis-(2-fluoro-phenyl)-6,7-dimethoxy-1H-benzo[g]indazole
(1f) Yield¼63% (262 mg); yellowish solid; mp¼128e129 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd
for C25H19F2N2O2 417.1415, found 417.1422; 1H NMR (400 MHz,
489.1820; 1H NMR (400 MHz, CDCl3):
d
7.94 (d, J¼9.2 Hz, 1H), 7.95
(d, J¼9.2 Hz, 1H), 7.66e7.62 (m, 2H), 7.33e7.29 (m, 3H), 7.21 (s,
2H), 7.10 (d, J¼9.2 Hz, 1H), 4.02 (s, 3H), 3.98 (s, 6H), 3.96 (s, 3H),
3.93 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
162.84 (d, J¼247.8 Hz),
CDCl3):
d
7.94 (dd, J¼0.4, 9.2 Hz, 1H), 7.82 (dt, J¼1.6, 8.0 Hz,1H), 7.78
153.61, 149.67, 146.42, 144.15, 138.40, 138.11, 137.54, 137.51, 129.55,
129.47, 129.07, 128.27, 119.34, 118.41, 117.90, 117.23, 116.75, 116.52,
116.07, 113.30, 105.30 (2ꢁ), 61.27, 60.97, 56.36, 56.29 (2ꢁ). Anal.
Calcd for C28H25FN2O5: C, 68.84; H, 5.16; N, 5.73. Found: C, 69.10;
H, 5.32; N, 5.98. Single-crystal X-ray diagram: crystal of compound
1j was grown by slow diffusion of EtOAc into a solution of com-
pound 1j in CH2Cl2 to yield colorless prism. The compound crys-
tallizes in the monoclinic crystal system, space group P-1,
(dd, J¼3.2, 9.2 Hz, 1H), 7.66e7.60 (m, 2H), 7.45e7.39 (m, 1H),
7.31e7.23 (m, 5H), 7.07 (d, J¼9.2 Hz, 1H), 3.99 (s, 3H), 3.93 (s, 3H);
13C NMR (100 MHz, CDCl3):
d
162.75 (d, J¼247.1 Hz), 160.14 (d,
J¼247.8 Hz), 149.54, 144.20, 142.22, 137.80 (d, J¼3.1 Hz), 137.63,
131.39 (d, J¼3.8 Hz), 130.16 (d, J¼8.3 Hz), 129.35 (d, J¼8.3 Hz),
129.06, 124.42 (d, J¼3.1 Hz), 120.68 (d, J¼14.4 Hz), 119.98 (d,
J¼6.8 Hz), 119.21, 118.31, 116.81, 116.63, 116.40, 116.22, 116.11, 116.01,
113.16, 61.21, 56.33.
3
ꢀ
ꢀ
ꢀ
ꢀ
a¼9.6671(4) A, b¼11.4385(5) A, c¼11.6125(5) A, V¼1195.10(9) A ,
Z¼2, dcalcd¼1.358 g/cm3, F(000)¼512, 2
q
range 2.20e26.41ꢀ, R in-
4.4.7. 3-(2-Fluoro-phenyl)-6,7-dimethoxy-1-(4-methoxy-phenyl)-
1H-benzo[g]indazole (1g) Yield¼60% (257 mg); yellowish solid;
mp¼130e131 ꢀC (recrystallized from hexanes and EtOAc); HRMS
(ESI, Mþþ1) calcd for C26H22FN2O3 429.1615, found 429.1619; 1H
dices (all data) R1¼0.0599, wR2¼0.1151.
4.4.11. 6,7-Dimethoxy-1-(4-methoxy-phenyl)-3-(3,4,5-trimethoxy-
phenyl)-1H-benzo[g]indazole (1k) Yield¼69% (345 mg); yellowish
solid; mp¼198e199 ꢀC (recrystallized from hexanes and EtOAc);
HRMS (ESI, Mþþ1) calcd for C29H29N2O6 501.2026, found 501.2028;
NMR (400 MHz, CDCl3):
d
7.93 (dd, J¼0.8, 9.2 Hz, 1H), 7.85 (dt,
J¼2.0, 8.0 Hz, 1H), 7.79 (dd, J¼3.6, 9.2 Hz, 1H), 7.57e7.54 (m, 2H),
7.45e7.39 (m, 1H), 7.33 (dd, J¼0.8, 9.2 Hz, 1H), 7.30e7.23 (m, 2H),
7.12e7.08 (m, 2H), 7.07 (d, J¼9.2 Hz, 1H), 4.00 (s, 3H), 3.94 (s, 3H),
1H NMR (400 MHz, CDCl3):
d
7.96 (br s, 2H), 7.54 (d, J¼6.8 Hz, 2H),
7.31 (d, J¼9.2 Hz, 1H), 7.22 (s, 2H), 7.10 (d, J¼6.8 Hz, 2H), 7.07 (d,
J¼9.2 Hz,1H), 4.00 (s, 3H), 3.97 (s, 6H), 3.94 (s, 3H), 3.93 (s, 3H), 3.92
3.92 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
160.15 (d, J¼247.1 Hz),
160.10, 149.43, 144.12, 141.69, 137.72, 134.60, 131.47 (d, J¼1.9 Hz),
129.98 (d, J¼8.3 Hz), 128.97, 129.78 (2ꢁ), 124.37 (d, J¼3.7 Hz),
120.92 (d, J¼14.4 Hz), 120.06 (d, J¼7.6 Hz), 118.93, 118.51, 116.49,
116.37, 116.06 (d, J¼21.2 Hz), 114.67 (2ꢁ), 113.08, 61.20, 56.34,
55.59.
(s, 3H); 13C NMR (100 MHz, CDCl3):
d
160.04, 153.47 (2ꢁ), 149.38,
145.87, 143.93, 138.10, 138.06, 134.42, 128.80 (3ꢁ), 119.33, 118.48,
117.59, 116.69, 116.29, 114.63 (3ꢁ), 113.09, 105.12 (2ꢁ), 61.14, 60.88,
56.25, 56.17 (2ꢁ), 55.54.
4.4.12. 4-[6,7-Dimethoxy-3-(3,4,5-trimethoxy-phenyl)-benzo[g]in-
dazol-1-yl]-benzaldehyde (1l) Yield¼70% (349 mg); yellowish
solid; mp¼214e215 ꢀC (recrystallized from hexanes and EtOAc);
HRMS (ESI, Mþþ1) calcd for C29H27N2O6 499.1869, found 499.1876;
4.4.8. 4-[3-(2-Fluoro-phenyl)-6,7-dimethoxy-benzo[g]indazol-1-yl]-
benzaldehyde (1h) Yield¼74% (315 mg); yellowish solid;
mp¼146e147 ꢀC (recrystallized from hexanes and EtOAc); HRMS
(ESI, Mþþ1) calcd for C26H20FN2O3 427.1458, found 427.1462; 1H
1H NMR (400 MHz, CDCl3):
d
10.16 (s, 1H), 8.12 (d, J¼8.4 Hz, 2H),
NMR (400 MHz, CDCl3):
d
10.16 (s, 1H), 8.14e8.11 (m, 2H), 8.00 (dd,
8.03 (d, J¼8.4 Hz, 1H), 7.96 (d, J¼8.4 Hz, 1H), 7.89 (d, J¼8.4 Hz, 2H),
7.44 (d, J¼9.2 Hz,1H), 7.20 (s, 2H), 7.12 (d, J¼9.2 Hz,1H), 4.03 (s, 3H),
3.98 (s, 6H), 3.97 (s, 3H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3):
J¼0.4, 9.2 Hz,1H), 7.91e7.88 (m, 2H), 7.83 (dt, J¼2.0, 7.6 Hz,1H), 7.79
(dd, J¼3.6, 9.2 Hz,1H), 7.49e7.43 (m, 2H), 7.32e7.26 (m, 2H), 7.12 (d,
J¼9.2 Hz, 1H), 4.02 (s, 3H), 3.97 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
191.08, 153.61 (2ꢁ), 149.66, 147.71, 146.47, 144.17, 138.46, 137.67,
d
191.11, 160.18 (d, J¼247.9 Hz), 149.69, 146.51, 144.29, 143.52,
135.90, 130.81 (2ꢁ), 129.15, 128.21, 127.35 (2ꢁ), 119.31, 118.97,

7948
M.-Y. Chang et al. / Tetrahedron 68 (2012) 7941e7948
118.68, 117.68, 115.92, 113.32, 105.23 (2ꢁ), 61.27, 60.95, 56.36, 56.25
(2ꢁ).
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.07.011.
4.4.13. 6,7-Dimethoxy-3-(2-methoxy-phenyl)-1-(4-methoxy-phe-
nyl)-1H-benzo[g]indazole (1m) Yield¼66% (290 mg); yellowish oil;
HRMS (ESI, Mþþ1) calcd for C27H25N2O4 441.1814, found 441.1822;
References and notes
1. (a) Cerecetto, H.; Gerpe, A.; Gonzalez, M.; Aran, V. J.; Ochoa de Ocariz, C. Mini-
Rev. Med. Chem. 2005, 5, 869; (b) Murineddu, G.; Lazzari, P.; Ruiu, S.; Sanna, A.;
Loriga, G.; Manca, I.; Falzoi, M.; Dessi, C.; Curzu, M. M.; Chelucci, G.; Pani, L.;
Pinna, G. A. J. Med. Chem. 2006, 49, 7502.
2. For reviews on the syntheses of indazoles, see: (a) Schimdt, A.; Beutler, A.;
Snovydovych, B. Eur. J. Org. Chem. 2008, 4073; (b) Schimdt, A.; Dreger, A. Curr.
Org. Chem. 2011, 15, 1423.
1H NMR (400 MHz, CDCl3):
d
7.88 (dd, J¼0.4, 9.2 Hz, 1H), 7.71 (d,
J¼9.2 Hz, 2H), 7.57 (d, J¼8.8 Hz, 2H), 7.43 (dt, J¼2.0, 8.0 Hz,1H), 7.36
(d, J¼9.2 Hz, 1H), 7.11e7.07 (m, 4H), 7.06 (d, J¼9.2 Hz, 1H), 4.00 (s,
3H), 3.94 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d 159.91, 157.26, 149.25, 144.31, 144.07, 137.43, 134.83,
3. Huisgen, R.; Knorr, R. Naturwissenschaften 1961, 48, 716.
4. (a) Inamoto, K.; Katsuno, M.; Yoshino, T.; Arai, Y.; Hiroya, K.; Sakamoto, T. Tet-
rahedron 2007, 63, 2695; (b) Vina, D.; Olmo, E. D.; Lopez-Perez, J. L.; Feliciano,
A. S. Org. Lett. 2007, 9, 525; (c) O’Dell, D. K.; Nicholas, K. M. Heterocycles 2004,
63, 373.
131.74, 129.75, 129.91, 128.83 (2ꢁ), 122.14, 121.10, 120.81, 119.45,
118.58, 116.56, 115.68, 114.56 (2ꢁ), 112.84, 111.10, 61.17, 56.35, 55.59,
55.44.
5. (a) Shvartsberg, M. S.; Ivanchikova, I. D.; Fedenok, L. G. Tetrahedron Lett. 1994,
35, 6749; (b) Hashem, M. M.; Berlin, K. D.; Chesnut, R. W.; Durham, N. N. J. Med.
Chem. 1976, 19, 229; (c) Hojo, M.; Masuda, R.; Okada, E. Synthesis 1990, 481; (d)
Bashir, N.; Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1973, 868; (e) Adger, B. M.;
Bradbury, S.; Keating, M.; Rees, C. W.; Storr, R. C.; Williams, M. T. J. Chem. Soc.,
Perkin Trans. 1 1975, 31; (f) Saracoglu, N.; Durucasu, I.; Balci, M. Tetrahedron
1995, 51, 10979; (g) Grimshaw, J.; Mannus, D. J. Chem. Soc., Perkin Trans. 1 1977,
2096; (h) Olivera, R.; SanMartin, R.; Dominguez, E. Synlett 2000, 1028.
6. (a) Chang, M.-Y.; Wu, M.-H.; Lee, N.-C.; Lee, M.-F. Tetrahedron Lett. 2012, 53,
2125; (b) Chang, M.-Y.; Wu, M.-H. Tetrahedron Lett. 2012, 53, 3173.
7. (a) Chattopadhyay, S. K.; Biswas, T.; Maity, S. Synlett 2006, 2211; (b) Tsai, J.-C.; Li,
S.-R.; Chen, L.-Y.; Chen, P. Y.; Jhong, J. Y.; Shu, C.-J.; Lo, Y.-F.; Lin, C.-N.; Wang, E.-C.
J. Chin. Chem. Soc. 2008, 55, 1317.
8. (a) Congiu, C.; Onnis, V.; Vesci, L.; Castorina, M.; Pisano, C. Bioorg. Med. Chem.
2010, 18, 6238; (b) Gokhan-Kelekci, N.; Yabanoglu, S.; Kupeli, E.; Salgın, U.;
Ozgen, O.; Ucar, G.; Yesilada, E.; Kendi, E.; Yesilada, A.; Bilgin, A. A. Bioorg. Med.
Chem. 2007, 15, 5775; (c) Bonesi, M.; Loizzo, M. R.; Statti, G. A.; Michel, S.;
Tillequin, F.; Menichini, F. Bioorg. Med. Chem. Lett. 2010, 20, 1990; (d) Bhat, B. A.;
Dhar, K. L.; Puri, S. C.; Saxena, A. K.; Shanmugavel, M.; Qazi, G. N. Bioorg. Med.
Chem. Lett. 2005, 15, 3177; (e) Johnson, M.; Younglove, B.; Lee, L.; LeBlanc, R.;
Holt, H. J.; Hills, P.; Mackay, H.; Brown, T.; Mooberry, S. L.; Lee, M. Bioorg. Med.
Chem. Lett. 2007, 17, 5897.
4.4.14. 6,7-Dimethoxy-3-phenyl-1-tosyl-1H-benzo[g]indazole (1n)
Yield¼73% (334 mg); yellowish solid; mp¼159e160 ꢀC (recrystal-
lized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for
C26H23N2O4S 459.1379, found 459.1383; 1H NMR (400 MHz, CDCl3):
d
9.20 (dd, J¼0.8, 9.6 Hz, 1H), 8.11 (dd, J¼0.8, 8.8 Hz, 1H), 7.84e7.81
(m, 2H), 7.78 (d, J¼8.8 Hz, 1H), 7.72 (d, J¼8.4 Hz, 2H), 7.54e7.46
(m, 4H), 7.15 (d, J¼8.4 Hz, 2H), 4.08 (s, 3H), 4.01 (s, 3H), 2.31 (s, 3H);
13C NMR (100 MHz, CDCl3):
d 152.76, 149.99, 145.12, 143.21, 141.18,
134.35,131.36,130.07,129.50 (2ꢁ), 129.45,128.79 (2ꢁ),128.48 (2ꢁ),
127.85 (2ꢁ), 123.01, 122.17, 120.41, 118.51, 117.53, 114.34, 61.25,
56.35, 21.60.
Acknowledgements
The authors would like to thank the National Science Council of
the Republic of China for its financial support (NSC 99-2113-M-037-
006-MY3).
9. CCDC 884931 (2k), 878329(1i), and 878847 (1j) contain the supplementary
crystallographic data for this paper. This data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: þ44 1223 336033; e-mail: deposit@ccdc.cam.ac.
uk).
Supplementary data
10. (a) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217; (b) Nielsen, T.
E.; Meldal, M. Org. Lett. 2005, 7, 2695; (c) Nielsen, T. E.; Le Quement, S. T.;
Meldal, M. Org. Lett. 2007, 9, 2469.
Scanned photocopies of 1H and 13C NMR spectral data were
supported.