Regioselective synthesis of 1-arylindazoles via N-arylation of 3-trimethylsilylindazoles

Article abstract of DOI:10.1016/j.tetlet.2005.03.157

The copper(II)-catalyzed cross-coupling reaction of 3- trimethylsilylindazoles bearing substituents on the benzene ring with arylboronic acids regioselectively gave the corresponding 1-aryl-3- trimethylsilylindazoles and no 2-aryl isomers were formed at all. Moreover, the trimethylsilyl group of the resulting indazoles was easily removed by treatment with ethanolic KOH to give 1-arylindazoles.

Full text of DOI:10.1016/j.tetlet.2005.03.157

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3771–3774
Regioselective synthesis of 1-arylindazoles via N-arylation of
-trimethylsilylindazoles
3
Yoshiyuki Hari, Yoshimichi Shoji and Toyohiko Aoyama*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho, Nagoya 467-8603, Japan
Received 9 February 2005; revised 17 March 2005; accepted 18 March 2005
Available online 8 April 2005
Abstract—The copper(II)-catalyzed cross-coupling reaction of 3-trimethylsilylindazoles bearing substituents on the benzene ring
with arylboronic acids regioselectively gave the corresponding 1-aryl-3-trimethylsilylindazoles and no 2-aryl isomers were formed
at all. Moreover, the trimethylsilyl group of the resulting indazoles was easily removed by treatment with ethanolic KOH to give
1
-arylindazoles.
Ó 2005 Elsevier Ltd. All rights reserved.
Indazole derivatives have attracted much attention for
their pharmaceutical activities, for example, anti-inflam-
matory, anti-tumor, anti-HIV, anti-depressant, contra-
ceptive activities, etc. Many methods for the synthesis
2
of substituted indazoles have been developed to date.
by reaction with aldehydes in the presence of cesium
1
2
fluoride. We considered that 3-trimethylsilylindazoles
would also be useful as substrates for the regioselective
N-arylation at the 1-position of an indazole nucleus
owing to steric hindrance of the bulky trimethylsilyl
group. In this letter, the synthesis of 1-arylindazoles
from 3-trimethylsilylindazoles through regioselective
N-arylation is described.
1
However, it would be difficult to regioselectively intro-
duce a substituent to an indazole nucleus, and for
instance, N-arylation of indazoles generally gives a
3
–5
mixture of 1-arylindazoles and its 2-aryl isomers. To
overcome the problem, recently, Pd-catalyzed cycliza-
As reaction conditions of the N-arylation of trimethylsi-
lylindazoles, we chose a copper(II)-catalyzed cross-cou-
pling reaction with arylboronic acids in consideration of
0
6
tion reactions of N-aryl-N -(o-bromobenzyl)hydrazines
0
7
and N-aryl-N -(o-bromophenyl)hydrazones in situ pre-
pared from o-bromobenzaldehyde and arylhydrazines
giving 1-arylindazoles have been reported. To the best
of our knowledge, there is no report concerning regio-
selective N-arylation of indazoles bearing substituents
3
its easy operation and the mild reaction conditions. The
1
3,14
results of the reaction are summarized in Table 1.
As
expected, reaction of 3-trimethylsilylindazole 1 with
phenylboronic acid at room temperature smoothly pro-
ceeded and the desired 1-phenyl-3-trimethylsilylindazole
8
,9
on the benzene ring.
6a was obtained in 94% yield (entry 1). In this reaction,
We have already developed various new reactions using
trimethylsilyldiazomethane (Me SiCHN ) and its lith-
no 2-phenyl isomer could be detected. Similarly, the
reaction of 1 with various arylboronic acids such as
4-methyl-, 4-methoxy-, 4-bromo-, and 2-methyl-phenyl
3
2
1
0
ium salt (Me SiC(Li)N ). For example, recently, we
3
2
have found a facile, one-pot synthesis of 3-trimethylsilyl-
indazoles by [3+2]cycloaddition reaction of Me Si-
C(Li)N2 with benzynes prepared in situ from
halobenzenes. In addition, the resulting 3-trimethyl-
silylindazole 1 was found to be easily converted to ind-
azoles bearing a hydroxymethyl unit at the 3-position
ones
1-arylindazoles 6b–e in high yields as the sole product,
successfully
afforded
the
corresponding
3
1
5
respectively (entries 2–5). 5,6-Dimethyl-3-trimethyl-
silylindazole 2 also gave the corresponding 1-phenyl
derivative 6f (entry 6). It is presumed that introduction
of a substituent to the 7-position of indazole would lead
to poor regioselectivity for N-arylation because of the
steric hindrance of the substituent. In fact, when
1
1
7
-methylindazole 7g was reacted with phenylboronic
Keywords: N-Arylation; Arylboronic acid; Indazoles; Regioselectivity;
Silyl compounds.
acid under the same conditions as shown in Table 1, a
mixture of 1- and 2-phenylindazoles (8g and 9g) was
obtained in 92% yield, in which the 2-phenyl isomer 9g
*
Corresponding author. Tel./fax: +81 52 836 3439; e-mail: aoyama@
phar.nagoya-cu.ac.jp
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.157

3772
Y. Hari et al. / Tetrahedron Letters 46 (2005) 3771–3774
a
Table 1. Copper(II)-catalyzed N-arylation of 3-trimethylsilylindazoles
R1
R1
SiMe3
N
ArB(OH)2 (2.0 eq.)
Cu(OAc)2 (1.5 eq.)
SiMe3
N
N
Ar
R2
R2
R3
R3
N
pyridine (2.0 eq.)
MS 4Å, CH2Cl2
rt, air, 10-37 h
H
R4
R4
1
-5
6a-k
1
R
2
R
3
R
4
R
b
Entry
Substrate
Ar
Yield (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
1
1
1
1
1
2
3
3
3
4
5
5
Ph
94 (6a)
88 (6b)
86 (6c)
93 (6d)
93 (6e)
93 (6f)
97 (6g)
H
H
4-Tolyl
4-MeO–Ph
4-Br–Ph
2-Tolyl
Ph
H
H
H
H
H
H
H
H
H
Me
Me
Me
Br
Ph
Ph
c
H
84 (6g)
H
4-MeO–Ph
Ph
Ph
99 (6h)
82 (6i)
98 (6j)
95 (6k)
10
11
12
H
MeO
MeO
MeO
MeO
4-Br–Ph
a
b
c
The 2-aryl isomer was not obtained in all cases.
Isolated yield.
Cu(OAc)
2
(0.1 equiv) was used. The reaction was carried out under O
2
atmosphere instead of air and the reaction time was 45 h.
R
SiMe3
N
N
Ph
N
+
N
N
H
N
H
R
PhB(OH)2 (2.0 eq.)
Cu(OAc)2 (1.5 eq.)
8g, 8l
Me
Me
1
(0.6 mmol)
7a (0.6 mmol)
N
+
R
N
pyridine (2.0 eq.)
MS 4Å, CH2Cl2
rt, air, 17-22 h
H
4-tolylB(OH)2 (0.6 mmol), Cu(OAc)2 (0.7 mmol)
pyridine (0.9 mmol), MS 4Å, CH Cl
Me
N
Ph
g, 9l
2
2
N
7
7
g : R = H
l : R = I
rt, air, 2 d
9
(
92 %, 8g:9g = 4:7 from 7g)
80 %, 8l:9l = 6:1 from 7l)
(
SiMe3
N
N
Scheme 1.
N
+
8b
4
-tolyl
N
4
-tolyl
N
4-tolyl
(32 %, 8b:9b = 2:1)
6
b (68 %)
N
9b
was predominantly formed (8g:9g = 4:7) as shown in
Scheme 1. Moreover, even N-phenylation of 3-iodo-7-
methylindazole 7l with the bulky substituent at the 3-po-
sition gave a mixture of 1- and 2-phenylindazoles (8l and
Scheme 2.
9
l) in 80% yield though the former 8l was predominant.
and 9b (32% yield, 8b:9b = 2:1). These results suggest
that the trimethylsilyl group may cause not only sup-
pression of N-arylation at the 2-position by its steric
hindrance but also acceleration of the reaction rate of
N-arylation at the 1-position presumably due to the
electronic effect of the silicon atom.
Thus, examination using 7-substituted 3-trimethylsilyl-
indazoles was carried out (entries 7–12). Surprisingly,
the N-arylation of 7-methyl-3-trimethylsilylindazole 3
with arylboronic acids smoothly proceeded to afford
only 1-aryl derivatives 6g and 6h in high yield, respec-
tively (entries 7 and 9). Similarly, 7-bromo-3-trimethylsi-
lylindazole 4 and 4,7-dimethoxy-3-trimethylsilylindazole
Finally, the trimethylsilyl group of 6 was easily removed
by treatment with ethanolic KOH to give 1-arylind-
5
tives 6i–k (entries 10–12). The use of a catalytic amount
also selectively gave the corresponding 1-aryl deriva-
1
6,17
azoles 8 in good to high yields (Scheme 3).
of copper(II) acetate under O atmosphere was applic-
2
able in this reaction, though prolonged reaction time
was required (entry 8).
R1
R1
SiMe3
R2
R2
R3
1
0 % KOH / EtOH
Next, a competitive experiment was carried out to inves-
tigate the role of the trimethylsilyl group (Scheme 2). A
mixture of 3-trimethylsilylindazole 1 (0.6 mmol) and
indazole 7a (0.6 mmol) was treated with phenylboronic
acid (0.6 mmol) in the presence of copper(II) acetate to
preferentially give 6b (68% yield) with a mixture of 8b
N
N
Ar
N
R3
reflux, 1-19 h
(62-97 %)
N
R4
R4
Ar
6
a-k
8a-k
Scheme 3.

Y. Hari et al. / Tetrahedron Letters 46 (2005) 3771–3774
3773
1
(hexane). H NMR (270 MHz, CDCl
7
In conclusion, we have found that N-arylation of 3-trim-
3
) d: 0.50 (9H, s),
.20 (1H, dd, J = 8 and 8 Hz), 7.31–7.42 (2H, m), 7.52
ethylsilylindazoles with arylboronic acid proceeds in a
completely regioselective fashion and the resulting 1-
aryl-3-trimethylsilylindazoles can be easily converted
to 1-arylindazoles. Moreover, we have revealed that
the trimethylsilyl group at the 3-position of indazoles
accelerates the reaction rate of N-arylation at the
(
J = 8 Hz). C NMR (68 MHz, CDCl
2H, d, J = 8 Hz), 7.75 (3H, d, J = 8 Hz), 7.87 (1H, d,
1
3
3
) d: ꢀ0.6, 110.4,
1
1
20.9, 122.0, 122.8, 126.3, 126.4, 129.3, 131.0, 139.0, 140.2,
48.5. IR (nujol) m: 1504, 1250 cm . MS (EI) m/z 266
ꢀ1
+
(M ), 251. Anal. Calcd for C H N Si: C, 72.13; H, 6.81;
N, 10.52. Found: C, 71.99; H, 6.94; N, 10.18.
1
6
18
2
1
-position.
1
4. Selected data for the other 1-aryl-3-trimethylsilylindazoles
6
1
b–k. Compound 6b: H NMR (270 MHz, CDCl ) d: 0.49
3
(
7.40 (3H, m), 7.61 (2H, d, J = 8 Hz), 7.70 (1H, d,
9H, s), 2.42 (3H, s), 7.18 (1H, dd, J = 8 and 8 Hz), 7.30–
Acknowledgements
1
J = 8 Hz), 7.86 (1H, d, J = 8 Hz). Compound 6c:
H
NMR (270 MHz, CDCl ) d: 0.48 (9H, s), 3.44 (3H, s), 7.04
This work was financially supported by a Grant-in-Aid
for Scientific Research (KAKENHI) (to T.A.), a Grant-
in-Aid from The Fujisawa Foundation (to Y.H.), and a
Grant-in-Aid for Research in Nagoya City University
3
(
dd, J = 8 and 8 Hz), 7.59–7.65 (3H, m), 7.86 (1H, d,
2H, d, J = 8 Hz), 7.18 (1H, dd, J = 8 and 8 Hz), 7.37 (1H,
1
J = 8 Hz). Compound 6d: H NMR (270 MHz, CDCl
.49 (9H, s), 7.21 (1H, dd, J = 8 and 8 Hz), 7.40 (1H, dd,
J = 8 and 8 Hz), 7.63 (4H, s), 7.69 (1H, d, J = 8 Hz), 7.86
3
) d:
0
(
to Y.H.).
1
(
1H, d, J = 8 Hz). Compound 6e: H NMR (270 MHz,
CDCl ) d: 0.49 (9H, s), 2.12 (3H, s), 7.15–7.37 (7H, m),
3
1
References and notes
. For a review. Br a¨ se, S.; Gil, C.; Knepper, K. Bioorg. Med.
Chem. 2002, 10, 2415–2437.
7.88 (1H, d, J = 8 Hz). Compound 6f:
270 MHz, CDCl ) d: 0.48 (9H, s), 2.39 (6H, s), 7.31
(1H, dd, J = 8 and 8 Hz), 7.45–7.58 (4H, m), 7.73 (2H, d,
H NMR
(
3
1
2
3
1
J = 8 Hz). Compound 6g: H NMR (270 MHz, CDCl ) d:
3
. Stadlbauer, W. In Science of Synthesis; Fleming, I., Ed.;
Georg Thieme: Stuttgart, 2002; Vol. 12, pp 227–324.
. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron
Lett. 1998, 39, 2941–2944.
0.47 (9H, s), 2.09 (3H, s), 7.08–7.10 (2H, m), 7.44–7.48
(5H, m), 7.70–7.74 (1H, m). Compound 6h: H NMR
(270 MHz, CDCl ) d: 0.46 (9H, s), 2.09 (3H, s), 3.88 (3H,
3
1
s), 6.98 (2H, d, J = 9 Hz), 7.06–7.08 (2H, m), 7.38 (2H, d,
J = 9 Hz), 7.69–7.70 (1H, m). Compound 6i: H NMR
1
4
. (a) Fedorov, A. Y.; Finet, J.-P. Tetrahedron Lett. 1999, 40,
2747–2748; (b) Barton, D. H.; Finet, J.-P.; Khamsi, J.
Tetrahedron Lett. 1987, 28, 887–890.
3
(270 MHz, CDCl ) d: 0.50 (9H, s), 7.06 (1H, dd, J = 8 and
8 Hz), 7.48–7.52 (5H, m), 7.57 (1H, d, J = 8 Hz), 7.84 (1H,
d, J = 8 Hz). Compound 6j: H NMR (270 MHz, CDCl )
1
3
5
6
7
8
. L o´ pez-Alvarado, P.; Avenda n˜ o, C.; Men e´ ndez, J. C. J.
Org. Chem. 1995, 60, 5678–5682.
. Song, J. J.; Yee, N. K. Tetrahedron Lett. 2001, 42, 2937–
d: 0.41 (9H, s), 3.66 (3H, s), 3.93 (3H, s), 6.38 (1H, d,
J = 8.1 Hz), 6.67 (1H, d, J = 8 Hz), 7.32 (1H, dd, J = 8 and
8 Hz), 7.42 (2H, dd, J = 8 and 8 Hz), 7.57 (2H, d,
1
2
940.
J = 8 Hz). Compound 6k: H NMR (270 MHz, CDCl
3
)
. Cho, C. S.; Lim, D. K.; Heo, N. H.; Kim, T.-J.; Shim, S.
C. Chem. Commun. 2004, 104–105.
. Very recently, highly regioselective N-arylation at the 1-
position of indazole and 3-chloroindazole by reaction with
halobenzenes has been reported. Antilla, J. C.; Baskin, J.
M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69,
d: 0.41 (9H, s), 3.71 (3H, s), 3.94 (3H, s), 6.42 (1H, d,
J = 8 Hz), 6.70 (1H, d, J = 8 Hz), 7.44–7.56 (4H, m).
15. Under the same reaction conditions as shown in entry 2 of
Table 1, the reaction of indazole with 4-tolylboronic acid
has been reported to give a mixture of 1- and 2-(4-tolyl)-
indazole (9:2) in 88% yield. See Ref. 3.
5
578–5587.
16. Typical procedure. A solution of 1-phenyl-3-trimethyl-
silylindazole 6a (42.8 mg, 0.16 mmol) in 10% ethanolic
9
. Highly regioselective N-arylation at the 1-position of 3-
iodoindazole by reaction with arylboronic acids has been
reported. Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron
Lett. 2000, 41, 9053–9057.
2
KOH (1 ml) was refluxed for 6 h. After dilution with H O,
the mixture was extracted with AcOEt. The organic
extracts were washed with 1 N KHSO , H O, and brine,
4
2
1
0. (a) For reviews. Shioiri, T.; Aoyama, T. In Science of
Synthesis; Fleming, I., Ed.; Georg Thieme: Stuttgart, 2002;
Vol. 4, pp 569–577; (b) Shioiri, T.; Aoyama, T. J. Synth.
Org. Chem. Jpn. 1996, 54, 918; (c) Shioiri, T.; Aoyama, T.
In Advances in the Use of Synthons in Organic Chemistry;
Dondoni, A., Ed.; JAI Press Ltd.: London, 1993; Vol. 1,
pp 51–101.
2 4
dried over Na SO , and concentrated in vacuo. The
residue was purified by column chromatography (Fuji
Silysia, BW-200) using hexane–AcOEt (9:1) as an eluent to
give 1-phenylindazole 8a (27.8 mg, 89%). Mp 80 °C
1
8
(hexane) (lit. mp 78 °C).
17. Selected data for the other 1-arylindazoles 8b–k. Com-
pound 8b: Ref. 5. Compound 8c: H NMR (270 MHz,
1
1
1
1
1. Shoji, Y.; Hari, Y.; Aoyama, T. Tetrahedron Lett. 2004,
3
CDCl ) d: 3.87 (3H, s), 7.05 (2H, d, J = 8 Hz), 7.20 (1H,
4
5, 1769–1771.
2. Hari, Y.; Shoji, Y.; Aoyama, T. Synthesis 2004, 1183–
186.
dd, J = 8 and 8 Hz), 7.40 (1H, dd, J = 8 and 8 Hz), 7.58–
7.66 (3H, m), 7.79 (1H, d, J = 8 Hz), 8.17 (1H, s).
1
1
Compound 8d: H NMR (270 MHz, CDCl ) d: 7.21–
3
3. Typical procedure. A mixture of 1 (56.7 mg, 0.30 mmol),
phenylboronic acid (73.1 mg, 0.60 mmol), copper(II) ace-
tate (81.7 mg, 0.45 mmol), pyridine (48.5 ll, 0.60 mmol),
7.26 (1H, m), 7.40 (1H, dd, J = 8 and 8 Hz), 7.63 (4H, s),
7.69 (1H, d, J = 8 Hz), 7.86 (1H, d, J = 8 Hz), 8.20 (1H, s).
1
Compound 8e: H NMR (270 MHz, CDCl
s), 7.20–7.25 (2H, m), 7.33–7.40 (5H, m), 7.81 (1H, d,
) d: 2.12 (3H,
3
˚
and activated molecular sieves 4 A (400 mg) in CH Cl
(
2
2
1
2.0 ml) was stirred under air at rt for 28 h. After filtration
J = 8 Hz), 8.20 (1H, s). Compound 8f:
(270 MHz, CDCl ) d: 2.38 (3H, s), 2.40 (3H, s), 7.33
(1H, dd, J = 7 and 7 Hz), 7.49–7.55 (4H, m), 7.72 (2H, d,
H NMR
Ò
of the mixture through a pad of Celite , the filtrate was
concentrated in vacuo. The residue was purified by column
chromatography (Fuji Silysia, BW-200) using hexane–
3
1
J = 7 Hz), 8.06 (1H, s). Compound 8g:
(270 MHz, CDCl ) d: 2.12 (3H, s), 7.08–7.13 (2H, m),
7.44–7.48 (5H, m), 7.65 (1H, d, J = 7 Hz), 8.15 (1H, s).
H NMR
Et O (10:1) as an eluent to give 1-phenyl-3-trimethylsilyl-
indazole 6a (74.6 mg, 94%). Compound 6a: mp 52 °C
2
3

3774
Y. Hari et al. / Tetrahedron Letters 46 (2005) 3771–3774
1
Compound 8h: H NMR (270 MHz, CDCl
s), 3.89 (3H, s), 6.99 (2H, d, J = 9 Hz), 7.09–7.12 (2H, m),
.39 (2H, d, J = 9 Hz), 7.63–7.66 (1H, m), 8.13 (1H, s).
3
) d: 2.12 (3H,
s), 6.41 (1H, d, J = 8 Hz), 6.90 (1H, d, J = 8 Hz), 7.35–7.47
(3H, m), 7.56 (2H, d, J = 8 Hz), 8.23 (1H, s). Compound
1
7
8k: H NMR (270 MHz, CDCl ) d: 3.73 (3H, s), 3.94 (3H,
3
1
Compound 8i: H NMR (270 MHz, CDCl
dd, J = 7 and 8 Hz), 7.48–7.52 (5H, m), 7.59 (1H, d,
3
) d: 7.07 (1H,
s), 6.42 (1H, d, J = 8 Hz), 6.70 (1H, d, J = 8 Hz), 7.45 (1H,
d, J = 9 Hz), 7.55 (1H, d, J = 9 Hz), 8.22 (1H, s).
18. Borsche, W.; Diacont, K. Liebigs Ann. Chem. 1934, 510,
287–297.
J = 7 Hz), 7.77 (1H, d, J = 8 Hz), 8.20 (1H, s). Compound
j: H NMR (270 MHz, CDCl ) d: 3.70 (3H, s), 3.94 (3H,
1
8
3