A novel and efficient synthesis of 2-aryl-2H-indazoles via SnCl 2-mediated cyclization of 2-nitrobenzylamines

Article abstract of DOI:10.1055/s-2007-986665

A mild, efficient, and novel synthesis of 2-aryl-2H-indazoles via cyclization of 2-nitrobenzylamines promoted by SnCl₂·2H ₂O has been described. This method applies to a wide scope of substrates containing electron-donating and elect

Full text of DOI:10.1055/s-2007-986665

LETTER
2509
A Novel and Efficient Synthesis of 2-Aryl-2H-indazoles via SnCl -Mediated
2
Cyclization of 2-Nitrobenzylamines
a,b
b
b
b
b
b
b
S
D
ynthesis of 2-Ary
a
l-2
H
-indaz
-
oles Qing Shi,* Guo-Lan Dou, Sai-Nan Ni, Jing-Wen Shi, Xiao-Yue Li, Xiang-Shan Wang, Hui Wu,
a
Shun-Jun Ji
a
College of Chemistry and Chemical Engineering, Key Laboratory of Organic Synthesis of Jiangsu Province, Suzhou University,
Suzhou 215123, P. R. of China
b
Department of Chemistry, Xuzhou Normal University, Xuzhou 221116, P. R. of China
E-mail: dqshi@suda.edu.cn
Received 25 June 2007
intramolecular amination of the corresponding N-aryl-N-
o-bromobenzyl)hydrazines yielded 2-substituted-2H-in-
dazoles, however, the yield of this reaction is low and the
Abstract: A mild, efficient, and novel synthesis of 2-aryl-2H-inda-
zoles via cyclization of 2-nitrobenzylamines promoted by
SnCl ·2H O has been described. This method applies to a wide
(
2
2
1
5
scope of substrates containing electron-donating and electron-with- time of the reaction is long. A one-step heterocyclization
drawing substituents.
of 2-nitrobenzylamines in the presence of KOH and alco-
hol produced 3-alkoxy-2H-indazoles, however, only one
Key words: 2-aryl-2H-indazole, 2-nitrobenzylamine, SnCl2
1
6
2
-aryl-2H-indazole was mentioned with low yield. Re-
cently, Huo reported a novel synthesis of 5,6-dihydroin-
dazolo[3,2-a]isoquinolines and their relative compounds
Indazole is well known as an aza analogue of indole, and
a number of indazole derivatives have powerful
1
7
via SnCl ·2H O as reducing agent. Although these meth-
2
2
1
ods have successfully led to a large repertoire of 2H-inda-
zole synthetic routes, many of these still suffer from
drawbacks such as unsatisfactory yields, long reaction
time, occurrence of side reactions, use of an expensive
catalyst, high temperature, and inaccessible starting
materials. Therefore, the development of more efficient
methods for the preparation of this kind of compounds is
still an active research area and there is room for further
improvement toward milder reaction conditions and im-
proved yields with a greener nature. In this paper, we wish
to describe a new route to 2-aryl-2H-indazoles through the
pharmacological activities including anti-inflammatory,
2
3
4
antitumor, anti-HIV, antidepressant, contraceptive
5
activities, anti-aggregatory, and vasorelaxant activity by
6
NO release. Recently, Aran reported some new 5-nitro-
indazole derivatives have trichomonacidal, antichagasic,
7
and antineoplastic activities. Different approaches to the
synthesis of 2-substituted indazoles have been proposed.8
The reduction of secondary 2-nitrobenzyl amines with Sn,
9
Zn, or Fe in acidic medium, produced 2-substituted inda-
1
0
zole byproduct in low yields. The direct N-alkylation
1
1
and N-arylation of indazole yielded mixtures of 1- and
-substituted indazole with poor selectivities. The reac-
tion of 2-nitrobenzylidenamines with trivalent organo-
creation of the N–N bond via a SnCl -mediated cycliza-
2
2
tion of 2-nitrobenzylamines (Scheme 1).
phosphorous reagents as deoxygenating agents resulted in In a preliminary study, N-(4-fluorophenyl)-2-nitrobenzyl-
-aryl-2H-indazoles with high yields, but the drastic con- amine (1a, Table 1), which was readily prepared by a
2
1
2
16
ditions of the reaction restrict application. The reduction literature procedure, was used to define the reaction
of 2-nitrobenzylamines and subsequent cyclization to 2- conditions for the reductive cyclization sequence. When
substituted indazoles were achieved by an electro- compound 1a was reduced with different reagents (entries
chemical method, but this method requires special equip- 1–4, Table 1), only the SnCl ·2H O/EtOH system gave
ment. Transition-metal-complex-catalyzed N–N bond the desired product 2a (50% yield). Further optimization
formation via reductive carbonylation of N-(2-nitrobenz- of the reaction conditions revealed that the use of two
ylidene)amine yielded 2H-indazoles, but this reaction per- equivalents SnCl ·2H O at 40 °C gave superior results
2
2
1
3
2
2
formed under drastic conditions (i.e., at 100 °C under 20 (entries 5–11, Table 1).
–
2
14
kg cm of CO pressure). The palladium-catalyzed
SnCl2·2H2O
EtOH, 40 °C, 2 h
N
R1
R1
H
N
R2
R2
N
NO2
1
2
Scheme 1
SYNLETT 2007, No. 16, pp 2509–2512
0
1
.1
0
.2
0
0
7
Advanced online publication: 12.09.2007
DOI: 10.1055/s-2007-986665; Art ID: W12107ST
Georg Thieme Verlag Stuttgart · New York
©

2
510
D.-Q. Shi et al.
LETTER
Table 1 Optimization of Reductive Reagent, Ratio, and Tempera-
ture in the Synthesis of 2-(4-Fluorophenyl)-2H-indazole (2a)
In order to apply this reaction to a library synthesis, vari-
ous 2-nitrobenzylamines were subjected to the reaction
conditions and representative examples are shown in
Table 2. Most of the 2-nitrobenzylamines gave the ex-
pected 2-aryl-2H-indazole products in moderate to good
yields, either bearing electron-withdrawing groups (such
as halides) or electron-donating groups (such as alkyl or
alkoxyl groups) under the same reaction conditions.
Therefore, we concluded that the electronic nature of the
substituents has no significant effects on this reaction.
However, when the aromatic groups were 2-methyl-
phenyl, 2-naphthyl and 5-quinolyl, the reactions did not
take place and the desired products were not obtained,
suggesting that steric hindrance plays a critical role in this
reaction.
Entry Reductive reagent
Ratio (1a:reduc- Temp
Yield
(%)
tive reagent)
(°C)
reflux
reflux
reflux
reflux
60
1
2
3
4
5
6
7
8
9
0
1
TiCl -Zn, THF
1:2
1:2
0
0
4
Zn-NH Cl, EtOH
4
SnCl ·2H O, HCl–EtOH 1:2
0
2
2
SnCl ·2H O, EtOH
1:2
1:2
1:2
1:2
1:1
1:3
1:4
1:5
50
56
65
47
56
39
22
23
2
2
SnCl ·2H O, EtOH
2
2
SnCl ·2H O, EtOH
40
2
2
SnCl ·2H O, EtOH
r.t.
2
2
1
All the structures of the products were characterized by H
SnCl ·2H O, EtOH
40
2
2
13
NMR, C NMR, IR, MS spectra, and elemental analy-
SnCl ·2H O, EtOH
40
19
2
2
sis. In addition, the structure of compound 2i was further
confirmed by X-ray diffraction analysis (Figure 1).20
1
1
SnCl ·2H O, EtOH
40
2
2
SnCl ·2H O, EtOH
40
2
2
18
Table 2 Synthesis of 2-Aryl-2H-indazole via SnCl -Mediated Cyclization of 2-Nitrobenzylamine
2
Entry
Substratea
Product
Yield (%)b
65
NH
F
2
2
2
2
2
2
2
2
a
b
c
d
e
f
N
N
N
N
F
N
N
N
N
NO2
N
88
40
46
85
71
75
65
H
NO2
N
Me
OMe
Br
H
Me
NO2
N
H
OMe
NO2
N
H
N
N
Br
N
N
NO2
N
Me
Me
H
NO2
Cl
Cl
Cl
Cl
N
N
g
h
H
N
NO2
Cl
Cl
N
H
N
N
NO2
Synlett 2007, No. 16, 2509–2512 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Aryl-2H-indazoles
2511
Table 2 Synthesis of 2-Aryl-2H-indazole via SnCl -Mediated Cyclization of 2-Nitrobenzylamine1 (continued)
8
2
Entry
Substratea
Product
Yield (%)b
72
Cl
Cl
N
Me
2
2
2
2
i
H
N
N
Me
Br
N
N
NO2
Cl
Cl
Cl
Cl
Cl
Cl
N
Br
F
j
k
l
70
68
60
H
NO2
Cl
Cl
N
H
N
N
F
F
N
N
NO2
N
F
H
NO2
Cl
Cl
Cl
Cl
N
2
m
N
61
H
N
OMe
NO2
OMe
a
All substrates were prepared according to the literature procedure.16
Isolated yields by crystallization.
b
In summary, a series of 2-aryl-2H-indazoles were synthe-
sized via cyclization of 2-nitrobenzylamines promoted by
SnCl . The advantages of this new method are the easily
2
accessible starting materials, convenient manipulation,
short reaction time, and moderate to high yields.
Acknowledgment
We are grateful to the National Natural Science Foundation of
China (20472062 and 20672079), the Natural Science Foundation
of Jiangsu Province (BK2006048) and the Natural Science Found-
ation of Jiangsu Education Department (06KJA15007) for financial
support.
Figure 1 The molecular structure of compound 2i
We propose the following possible mechanism
(
Scheme 2) to account for the reaction. At the first step, 1
was reduced by SnCl to 3. This nitroso compound then
2
cyclized by the nucleophilic attack of the NH group onto References and Notes
the nitroso group giving intermediate 4. Finally, the ex-
(
1) (a) Bistochi, G. A.; De Meo, G.; Pedini, M.; Ricci, A.;
pected product 2 was produced by elimination of water.
Brouilhet, H.; Bucherie, S.; Rabaud, M.; Jacquignon, P.
Farmaco Ed. Sci. 1981, 36, 315. (b) Picciola, G.; Ravenna,
F.; Carenimi, G.; Gentili, P.; Riva, M. Farmaco Ed. Sci.
Ar
1
981, 36, 1037.
N
Ar
SnCl2·2H2O
NH
H
(2) Keppler, B. K.; Hartmann, M. Met.-Based Drugs 1994, 1,
NO2
N
O
145.
(
3) (a) Sun, J.-H.; Teleha, C. A.; Yan, J.-S.; Rodgers, J. D.;
Nugiel, D. A. J. Org. Chem. 1997, 62, 5627. (b) Rodgers, J.
D.; Johnson, B. L.; Wang, H.; Greenberg, R. A.; Erickson-
Viitanen, S.; Klabe, R. M.; Cordova, B. C.; Rayner, M. M.;
Lam, G. N.; Chang, C.-H. Bio. Med. Chem. Lett. 1996, 6,
2919.
1
3
H
–
H2O
N
Ar
N
Ar
N
N
(4) Ykeda, Y.; Takano, N.; Matsushita, H.; Shiraki, Y.; Koide,
T.; Nagashima, R.; Fujimura, Y.; Shindo, M.; Suzuki, S.;
Iwasaki, T. Arzneim. Forsch. 1979, 29, 511.
OH
4
2
(5) Corsi, G.; Palazzo, G.; Germani, C.; Barcellona, P. S.;
Silvestrini, B. J. Med. Chem. 1976, 19, 778.
Scheme 2
(6) Cerecetto, H.; Gerpe, A.; Gonzalez, M.; Aran, V. J.; de
Ocarizi, C. O. Mini-Rev. Med. Chem. 2005, 5, 869.
Synlett 2007, No. 16, 2509–2512 © Thieme Stuttgart · New York

2
512
D.-Q. Shi et al.
LETTER
(
7) Aran, V. J.; Ochoa, C.; Boiani, L.; Buccino, P.; Cerecetto,
H.; Gerpe, A.; Gonzalez, M.; Montero, D.; Nogal, J. J.;
Gomez-Barrio, A.; Azqueta, A.; de Cerain, A. L.; Piro, O.
E.; Castellano, E. E. Bioorg. Med. Chem. 2005, 13, 3197.
8) Stadlbauer, W. Science of Synthesis, Vol. 12; Neier, R. R.,
Ed.; Thieme: Stuttgart, 2002, 227.
for 2 h. The reaction mixture was quenched with 3% HCl
(100 mL), filtrated, the crude product was purified by
crystallization from 95% EtOH to give the pure products 2.
(19) Representative Spectral Data for 2b
1
(
(
H NMR (400 MHz, DMSO-d ): d = 9.12 (s, 1 H, H-3), 8.10
6
(d, 2 H, J = 8.0 Hz, ArH), 7.78 (d, 2 H, J = 8.4 Hz, ArH),
7.72 (d, 2 H, J = 8.4 Hz, ArH), 7.46 (t, 1 H, J = 7.2 Hz, ArH),
7.32 (t, 1 H, J = 8.0 Hz, ArH), 7.11 (t, 1 H, J = 7.6 Hz, ArH)
9) (a) Paal, C.; Krecke, F. Chem. Ber. 1890, 23, 2640.
(
b) Paal, C. Chem. Ber. 1891, 24, 959. (c) Busch, V.;
1
3
Hartman, P. J. Prakt. Chem. 1895, 2, 404. (d) Campi, E.
M.; Habsuda, J.; Jackson, W. R.; Jonasson; Cartrin, A. M.;
McCubbin, Q. J. Aust. J. Chem. 1995, 48, 2023.
ppm. C NMR (100 MHz, DMSO-d ): d = 149.12, 140.12,
6
129.86, 128.02, 126.96, 122.64, 122.28, 121.74, 121.11,
120.42, 117.65 ppm. IR (KBr): n = 3131, 3066, 1626, 1593,
1518, 1494, 1464, 1407, 1378, 1349, 1314, 1250, 1231,
1201, 1143, 1129, 1073, 1044, 950, 907, 820, 780, 754, 685
(
10) (a) Auwers, K. V.; Schaich, W. Chem. Ber. 1921, 54, 1738.
(
b) Albini, A.; Bettinetti, G.; Minoli, G. Heterocycles 1988,
–
1
+
27, 1207. (c) Seela, F.; Bourgeois, W. Helv. Chim. Acta.
cm . MS: m/z (%) = 194 (100) [M ]. Anal. Calcd for
1991, 74, 315.
C H N : C, 80.39; H, 5.19; N, 14.42. Found: C, 80.55; H,
1
3
10
2
(
(
11) (a) Cerrada, M. L.; Elguero, J.; de la Fuente, J.; Pardo, C.;
Ramos, M. Synth. Commun. 1993, 23, 1947. (b) Rosevear,
J.; Wilshire, J. F. K. Aust. J. Chem. 1991, 44, 1097.
12) (a) Cadogan, J. I. G.; Cameron-Wood, M.; Mackie, R. K.;
Searle, R. J. G. J. Chem. Soc. 1965, 4831. (b) Armour, M.
A.; Cadogan, J. I. G.; Grace, D. S. B. J. Chem. Soc., Perkin
Trans. 1 1975, 1185. (c) Cadogan, J. I. G.; Mackie, R. K.
Org. Synth. 1968, 48, 113. (d) Varughese, D. J.; Manhas, M.
S.; Bose, A. K. Tetrahedron Lett. 2006, 47, 6795.
5.29; N, 14.26.
(20) Crystallographic data for the structure of 2i has been
deposited at the Cambridge Crystallographic Data Centre
under the deposit number CCDC-655981. Copies of
available material can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44 (1223)336033; e-mail:
deposit@ccdc.cam.ac.uk]. Crystal data for 2i: C H Cl N ;
M = 277.14, colorless block crystals, 0.43 × 0.40 × 0.32
mm, monoclinic, space group P2 /c, a = 14.234(3) Å,
b = 14.438(3) Å, c = 6.0511(15) Å, a = 90°, b = 92.338(7)°,
g = 90°, V = 1242.5(5) Å , Z = 4, D = 1.481 g cm ,
F(000) = 568, m (Mo Ka) = 0.503 mm . Intensity data were
collected on a diffractometer with graphite monochromated
Mo Ka radiation (l = 0.71073 Å) using w scan mode with
1.43° < q < 25.00°; 2183 unique reflections were measured
and 1532 reflections with I > 2s(I) were used in the
refinement. The structures were solved by direct methods
and expanded using Fourier techniques. The final cycle of
full-matrix least squares technique to R = 0.0460 and
wR = 0.1283.
1
4
10
2
2
(
(
13) Frontana-Oribe, B. A.; Moinet, C. Tetrahedron 1998, 54,
1
3
197.
14) Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1994,
9, 3375.
3
–
1
c
–
1
5
(
(
15) Song, J. J.; Yee, N. K. Org. Lett. 2000, 2, 519.
16) Mills, A. D.; Nazer, M. Z.; Haddadin, M. J.; Kurth, M. J.
J. Org. Chem. 2006, 71, 2687.
(
(
17) Kuo, C. Y.; Wu, M. J. J. Chin. Chem. Soc. 2005, 52, 965.
18) General Procedure for the Synthesis of 2-Aryl-2H-
indazoles
A solution of 2-nitrobenzylamine (3 mmol) and SnCl ·2H O
2
2
(
6 mmol) in 95% EtOH (20 mL) was allowed to stir at 40 °C
Synlett 2007, No. 16, 2509–2512 © Thieme Stuttgart · New York