An efficient synthesis of 2H-indazoles via reductive cyclization of 2-nitrobenzylamines induced by low-valent titanium reagent

Article abstract of DOI:10.1016/j.tet.2012.03.043

An efficient and improved synthesis of 2H-indazoles via reductive cyclization of 2-nitrobenzylamines induced by low-valent titanium reagent (TiCl₄/Zn) is described. In this reaction triethylamine (TEA) was used to control the pH value. This met

Full text of DOI:10.1016/j.tet.2012.03.043

Tetrahedron 68 (2012) 3851e3855
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An efficient synthesis of 2H-indazoles via reductive cyclization of
2-nitrobenzylamines induced by low-valent titanium reagent
*
Fang Sun, Xian Feng, Xuan Zhao, Zhi-Bin Huang, Da-Qing Shi
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and improved synthesis of 2H-indazoles via reductive cyclization of 2-nitrobenzylamines
induced by low-valent titanium reagent (TiCl4/Zn) is described. In this reaction triethylamine (TEA)
was used to control the pH value. This method has the advantages of easily accessible starting materials,
convenient manipulation, higher yield, shorter reaction time, and wider substrate scope.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 4 November 2011
Received in revised form 5 March 2012
Accepted 13 March 2012
Available online 17 March 2012
Keywords:
2H-Indazole
2-Nitrobenzylamine
Reductive cyclization
Low-valent titanium reagent
1. Introduction
synthetic routes, many of these still suffer from drawbacks such as
unsatisfactory yields, long reaction time, and occurrence of side
Indazole is well known as an aza analogue of indole. The inda-
zole unit has been found in pharmaceutical materials with a broad
range of biological properties including antitumor,1 anti-HIV,2 an-
tidepressant,3 antimicrobial,4 anti-inflammatory,5 and contracep-
tive activities.6 Considering the potent bioactivities of compounds
containing 2H-indazole core, the development of new strategies for
the efficient synthesis of 2H-indazole is needed. To construct this
intriguing 2H-indazole scaffold, several synthetic methods have
been developed from different starting materials.7 Among them,
reductive cyclization of 2-nitrobenzylamine attracts more attention
because diverse starting materials are readily available. The re-
duction of 2-nitrobenzylamines with Sn, Zn, or Fe in acidic me-
dium,8 produced 2-substituted indazole byproduct in low yields.
The reduction of 2-nitrobenzylamines and subsequent cyclization
to 2-substituted indazoles were achieved by an electrochemical
method, but this method requires special equipment.9 A one-pot
heterocyclization of 2-nitrobenzylamines in the presence of KOH
and alcohol produced 3-alkoxy-2H-indazoles, however, only one 2-
aryl-2H-indazole was mentioned with low yield.10 Recently we
reported the improved synthesis of 2-aryl-2H-indazoles via re-
ductive cyclization of 2-nitrobenzylamines promoted by
SnCl2$2H2O,11 This method has the advantages of a wide scope of
substrates, however, the yields were unsatisfied. Although these
methods have successfully led to a large repertoire of 2H-indazole
reactions. Therefore, the development of more efficient methods
for the preparation of this kind of heterocyclic compounds is still an
active research area.
Low-valent titanium reagents have an exceedingly high ability
to promote reductive coupling reaction of carbonyl compounds and
are attracting increasing interest in organic synthesis.12 Many other
functional groups can also be coupled.13 Recently, we have focused
on the synthesis of heterocyclic compounds such as quinazolin-
4(3H)-ones,14 pyrroles,15 quinazoline-2,4-diones,16 naphtho[1,2-e]
[1,3]oxazine,17 benzothiazole,18 and pyrrolo[1,2-a]quinazolin-
5(1H)-one19 induced by low-valent titanium reagent. However,
most of the reported reactions mediated by a low-valent titanium
reagent have been carried out in the presence of acid. Quite sur-
prisingly, base controlled reactions with low-valent titanium re-
agents have not stimulated much interest so far. Recently, we
reported the synthesis of indazol-3(2H)-ones form 2-
nitrobenzamides induced by a low-valent titanium reagent in the
presence of base (TEA),20 in this paper we would like to describe
a convenient base (TEA)-controlled protocol for the synthesis of
2H-indazoles induced by low-valent titanium reagent (Scheme 1).
Scheme 1. Synthesis of 2H-indazole 2.
* Corresponding author. E-mail address: dqshi@263.net (D.-Q. Shi).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.043

3852
F. Sun et al. / Tetrahedron 68 (2012) 3851e3855
Table 2
2. Results and discussion
Synthesis of 2H-indazoles 2 induced by low-valent titanium reagent
Entry R1
R2
Ar
Compound Yield Literature11
On the basis of our previous experience, 4-chloro-N-(2-
nitrobenzyl)aniline 1a as a model substrate was investigated to
establish the feasibility of the strategy and to optimize the reaction
conditions for the synthesis of 2-(4-chlorophenyl)-2H-indazole
(2a) (Scheme 2).
(%)
yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-ClC6H4
2a
2b
2c
2d
2e
2f
83
89
81
87
83
86
80
85
88
82
75
80
78
85
79
86
79
90
77
78
83
87
79
75
72
d
d
d
88
40
46
65
85
71
d
61
d
72
65
d
60
68
70
d
d
d
d
d
d
d
3-CH3OC6H4
3-Cle4-FC6H3
C6H5
4-CH3C6H4
4-CH3OC6H4
4-FC6H4
4-BrC6H4
3-Cle4-CH3C6H3 2i
3,4-OCH2OC6H3
3-CH3OC6H4
4-ClC6H4
2g
2h
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
2j
2k
2l
3-Cle4-CH3C6H3 2m
C6H5
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w
2x
Scheme 2. Model reaction.
3-CH3C6H4
3-Cle4-FC6H3
4-FC6H4
4-BrC6H4
3-ClC6H4
As shown in Table 1, we briefly examined the effect of different
low-valent titanium systems and pH values on the success of the
cyclization step. When substrate 1a was reduced by TiCl4/Zn and no
base was added, no desired product 2a was detected (Table 1, entry
1). When substrate 1a was reduced with different low-valent tita-
nium reagents in TEA and pH¼8 (Table 1, entries 2e6), TiCl4/Zn
gave the best result of synthesis of 2a (83% yield) (Table 1, entry 2).
To further optimize reaction conditions, a similar test was carried
out at pH value ranging from 5 to 9 with an increment of 1 each
time. The yield of product 2a was increased as pH value was in-
creased from 5 to 8 (Table 1, entries 7e9 and 2). However, a further
increase of pH value to 9 failed to improve the yield of product 2a
(Table 1, entry 10). Therefore, TEA and pH¼8 was chosen as the
reaction condition for all further synthesis of 2H-indazoles.
CH3O CH3O 4-CH3OC6H4
CH3O CH3O 3-ClC6H4
CH3O CH3O 4-BrC6H4
CH3O CH3O 4-FC6H4
CH3O CH3O 3-CH3C6H4
CH3O CH3O 3-Cle4-CH3C6H3 2y
Table 1
Optimization of reaction conditions for the synthesis of 2a
Entry
TiCl4/M
Base/pH value
Isolated yield (%)
1
2
3
4
5
6
7
8
9
TiCl4/Zn
TiCl4/Zn
TiCl4/Fe
TiCl4/Sm
TiCl4/Mg
TiCl4/Al
TiCl4/Zn
TiCl4/Zn
TiCl4/Zn
TiCl4/Zn
No base/2
TEA/8
TEA/8
TEA/8
TEA/8
TEA/8
TEA/5
TEA/6
TEA/7
TEA/9
0
83
37
66
45
78
60
67
74
76
Fig. 1. The crystal structure of compound 2w.
According to literature,20 we suppose the following mechanism
to explain this reaction. TiCl4 is reduced by zinc dust to give low-
valent titanium species. In the initial step, 2-nitrobenzylamine 1
was reduced by low-valent titanium reagent to 2-
nitrosobenzylamine 3 in the presence of TEA. 2-Nitrosobenzyl-
amine 3 then cyclized by the nucleophilic attack of the NH group
onto the nitroso group giving intermediate 4. Finally, the expected
product 2 was produced by elimination of water in the presence of
TEA (Scheme 3).
10
In order to apply this reaction to a library synthesis of 2H-
indazoles, various 2-nitrobenzylamines were subjected to the re-
action conditions and the results are summarized in Table 2.
As shown in Table 2, it can be seen that the proposed cyclization
process proved to be suitable for substrates in which the 2-
nitrobenzylamine was substituted with either electron-withdraw-
ing group (such as halide group) or electron-donating group (such
as methoxyl group). Also the reactions proved to be effective for
substrates in which the N-aryl was substituted by not only aryl
groups with either electron-withdrawing groups (such as halide
groups) but also to electron-donating groups (such as alkyl groups).
To show the merit of the present work in comparison with
reported results in the literature, we compared results of
SnCl2$2H2O with reported reducing agent11in the synthesis of 2-
aryl-2H-indazoles. As shown in Table 2, the TiCl4/Zn/TEA system
can act as a suitable reducing agent with respect to reaction times
and yields of the products.
The structures of all products 2 were characterized by IR, 1H
NMR spectral data as well as HRMS analysis. The structure of 2w
was further confirmed by X-ray diffraction analysis.21 The molec-
ular structure of 2w is shown in Fig. 1.
Scheme 3. Proposed mechanism for the synthesis of 2H-indazoles.

F. Sun et al. / Tetrahedron 68 (2012) 3851e3855
3853
3. Conclusion
J¼6.0 Hz, 1H, ArH), 8.12e8.16 (m, 1H, ArH), 8.36e8.38 (m, 1H, ArH),
9.16 (s, 1H, C3eH). HRMS [found: m/z 246.0358 (Mþ), calcd for
C13H385ClFN2: M, 246.0360].
In summary, a series of 2-aryl-2H-indazoles were synthesized
via reductive cyclization of 2-nitrobenzylamines induced by low-
valent titanium reagent in the presence of TEA. The advantages of
this new method are the easily accessible starting materials, con-
venient manipulation, shorter reaction time, and higher yields, and
wider substrate scope.
4.2.4. 2-Phenyl-2H-indazole (2d). Mp: 84e85 ꢂC (lit.11 84e85 ꢂC).
IR (KBr) n: 3066, 1626, 1593, 1518, 1494, 1464, 1407, 1378, 1349,
1314, 1250, 1231, 1201, 1143, 1129, 1073, 1044, 950, 907, 820, 780,
754, 685 cmꢀ1. 1H NMR (300 MHz, DMSO-d6): dH 7.11 (t, J¼5.7 Hz,
1H, ArH), 7.32 (t, J¼6.0 Hz, 1H, ArH), 7.46 (t, J¼5.4 Hz, 1H, ArH),
7.59 (t, J¼5.7 Hz, 2H, ArH), 7.72 (d, J¼6.6 Hz, 1H, ArH), 7.77 (d,
J¼6.3 Hz, 1H, ArH), 8.10 (d, J¼6.0 Hz, 2H, ArH), 9.12 (s, 1H, C3eH).
HRMS [found: m/z 194.0843 (Mþ), calcd for C13H10N2: M,
194.0844].
4. Experimental section
4.1. General
Tetrahydrofuran (THF) was distilled from sodium/benzophe-
none immediately prior to use. All the reactions were conducted
under N2 atmosphere. Melting points are uncorrected. IR spectra
were recorded on Varian F-1000 spectrometer in KBr with ab-
4.2.5. 2-(4-Methylphenyl)-2H-indazole (2e). Mp: 96e98 ꢂC (lit.11
97e98 ꢂC). IR (KBr)
n: 3039, 2946, 1624, 1522, 1453, 1418, 1392,
1378, 1346, 1311, 1258, 1230, 1196, 1146, 1126, 1108, 1047, 1017, 953,
822, 791, 756, 738 cmꢀ1. 1H NMR (300 MHz, DMSO-d6): dH 2.39 (s,
3H, CH3), 7.09 (t, J¼6.0 Hz, 1H, ArH), 7.30 (t, J¼5.1 Hz, 1H, ArH),
7.38 (d, J¼6.3 Hz, 2H, ArH), 7.71 (d, J¼6.6 Hz, 1H, ArH), 7.77 (d,
J¼6.6 Hz, 1H, ArH), 7.96 (d, J¼6.3 Hz, 2H, ArH), 9.02 (s, 1H, C3eH).
HRMS [found: m/z 208.1002 (Mþ), calcd for C14H12N2: M,
208.1000].
sorptions in cmꢀ1 1H NMR and 13C NMR were determined on
.
Varian Inova-300 MHz spectrometer in DMSO-d6 or CDCl3 solution.
J values are in hertz. Chemical shifts are expressed in parts per
million downfield from internal standard TMS. HRMS analyses
were carried out using TOF-MS or GCT-TOF instrument. X-ray dif-
fractions were recorded on a Siemens P4 diffractometer.
4.2. General procedure for the synthesis of 2H-indazoles 2
4.2.6. 2-(4-Methoxyphenyl)-2H-indazole (2f). Mp: 124e126 ꢂC
(lit.11 123e124 ꢂC). IR (KBr)
n: 3010, 2959, 2836, 1626, 1609, 1520,
TiCl4 (0.44 mL, 4 mmol) was added dropwise using a syringe to
a stirred suspension of zinc powder (0.52 g, 8 mmol) in freshly
distilled anhydrous THF (10 mL) at room temperature (rt) under
a dry N2 atmosphere. After completion of the addition, the mixture
was refluxed for 2 h. The suspension of the low-valent titanium
reagent formed was cooled to rt, and then, 5 mL TEA was added; the
pH was about 8 (the pH value was determined by pH test paper). A
solution of 2-nitrobenzylamines (1) (1 mmol) in THF (3 mL) was
added dropwise. The reaction mixture was stirred at rt for 30 min.
After this period, the thin layer chromatography (TLC) analysis of
the mixture showed the reaction to be completed. The reaction
mixture was quenched with 18% HCl (15 mL) and extracted with
ClCH2CH2Cl (3ꢁ40 mL). The combined extracts were washed with
water (3ꢁ40 mL) and dried over anhydrous Na2SO4. After evapo-
ration of the solvent under reduced pressure, the crude product
was purified by recrystallization from 95% ethanol to give pure 2H-
indazoles (2).
1458, 1437,1396, 1382, 1340, 1315,1302,1244,1177, 1127, 1108, 1046,
1028, 952, 837, 810, 779, 754, 729 cmꢀ1. 1H NMR (300 MHz, CDCl3):
dH 3.87 (s, 3H, CH3O), 7.02 (d, J¼6.3 Hz, 2H, ArH), 7.11 (t, J¼4.8 Hz,
1H, ArH), 7.32 (J¼5.1 Hz, 1H, ArH), 7.70 (d, J¼6.6 Hz, 1H, ArH),
7.791e7.81 (m, 3H, ArH), 8.31 (s, 1H, C3eH). HRMS [found: m/z
224.9050 (Mþ), calcd for C14H12N2O: M, 224.9050].
4.2.7. 2-(4-Fluorophenyl)-2H-indazole (2g). Mp: 102e103 ꢂC (lit.11
102e104 ꢂC). IR (KBr)
n: 3062, 1627, 1520, 1456, 1434, 1382, 1294,
1234, 1203, 1156, 1129, 1097, 1042, 1008, 951, 839, 816, 793, 779,
752 cmꢀ1. 1H NMR (300 MHz, CDCl3): dH 7.05 (t, J¼5.1 Hz, 1H, ArH),
7.12e7.18 (m, 2H, ArH), 7.26 (t, J¼6.0 Hz, 1H, ArH), 7.63 (d, J¼6.0 Hz,
1H, ArH), 7.71 (d, J¼6.3 Hz,1H, ArH), 7.77e7.79 (m, 2H, ArH), 8.26 (s,
1H, C3eH). HRMS [found: m/z 212.0748 (Mþ), calcd for C13H9FN2:
M, 212.0750].
4.2.8. 2-(4-Bromophenyl)-2H-indazole (2h). Mp: 148e149 ꢂC (lit.11
148e150 ꢂC). IR (KBr)
n: 3062, 1627, 1520, 1456, 1434, 1382, 1294,
4.2.1. 2-(4-Chlorophenyl)-2H-indazole (2a). Mp: 140e141 ꢂC (lit.7h
1234, 1203, 1156, 1129, 1097, 1042, 1008, 951, 839, 816, 793, 779,
752 cmꢀ1. 1H NMR (300 MHz, CDCl3): dH 7.12 (t, J¼5.1 Hz, 1H, ArH),
7.33 (t, J¼4.8 Hz, 1H, ArH), 7.64 (d, J¼6.0 Hz, 2H, ArH), 7.69 (d,
J¼6.6 Hz, 1H, ArH), 7.78 (t, J¼5.1 Hz, 3H, ArH), 8.37 (s, 1H, C3eH).
HRMS [found: m/z 271.9945 (Mþ), calcd for C13H799BrN2: M,
271.9949].
141e142 ꢂC). IR (KBr)
n: 1623, 1496, 1377, 1200, 1090, 949, 824,
751 cmꢀ1
.
1H NMR (300 MHz, DMSO-d6): dH 7.11 (t, J¼5.1 Hz, 1H,
ArH), 7.30e7.34 (1H, m, ArH), 7.65 (d, J¼3.0 Hz, 2H, ArH), 7.70 (d,
J¼6.0 Hz, 1H, ArH), 7.76 (d, J¼6.3 Hz, 1H, ArH), 8.12 (d, J¼6.3 Hz, 2H,
ArH), 9.11 (s, 1H, C3eH). HRMS [found: m/z 228.0451 (Mþ), calcd for
C13H395ClN2: M, 228.0454].
4.2.9. 2-(3-Chloro-4-methylphenyl)-2H-indazole (2i). Mp: 133e135
4.2.2. 2-(3-Methoxyphenyl)-2H-indazole (2b). Mp: 46e47 ꢂC. IR
ꢂC (lit.11 133e135 ꢂC). IR (KBr)
n: 3057, 2942, 1628, 1606, 1580, 1520,
(KBr)
n
: 3010, 2960, 2837, 1625, 1599, 1485, 1383, 1325, 1261, 1162,
1499, 1446, 1415, 1377, 1336, 1275, 1231, 1208, 1149, 1128, 1058, 963,
877, 842, 811, 778, 709 cmꢀ1. 1H NMR (300 MHz, DMSO-d6): dH 2.41
(s, 3H, CH3), 7.10e7.14 (m, 1H, ArH), 7.31e7.35 (m, 1H, ArH), 7.58 (d,
J¼6.3 Hz, 2H, ArH), 7.77 (d, J¼6.3 Hz, 1H, ArH), 8.01 (dd, J1¼1.5 Hz,
1038, 861, 781, 679 cmꢀ1. 1H NMR (300 MHz, DMSO-d6): dH 3.87 (s,
3H, CH3O), 7.01 (d, J¼6.0 Hz,1H, ArH), 7.10 (t, J¼5.1 Hz,1H, ArH), 7.31
(t, J¼4.8 Hz, 1H, ArH), 7.48 (t, J¼5.4 Hz, 1H, ArH), 7.65e7.67 (m, 2H,
ArH), 7.71 (d, J¼6.6 Hz, 1H, ArH), 7.76 (d, J¼6.3 Hz, 1H, ArH), 9.11 (s,
1H, C3eH). 13C NMR (75 MHz, DMSO-d6): dC 55.5, 105.8, 112.3, 113.7,
117.5,121.0,121.8,122.2,122.4,126.9,130.6,141.1,148.9,160.2. HRMS
[found: m/z 224.0951 (Mþ), calcd for C14H12N2O: M, 224.0950].
J2¼6.3 Hz, 1H, ArH), 8.20 (d, J¼1.5 Hz, 1H, ArH), 9.16 (s, 1H, C3eH).
35
HRMS [found: m/z 242.0610 (Mþ), calcd for C14
H ClN2: M,
11
242.0611].
4.2.10. 2-(3,4-Methylenedioxyphenyl)-2H-indazole (2j). Mp: 114e116
ꢂC. IR (KBr)
: 3036, 2915, 2805, 1625, 1605, 1590, 1508, 1488,
1365, 1309, 1288, 1253, 1223, 1183, 1158, 1094, 1065, 930, 894, 865,
810, 780 cmꢀ1. 1H NMR (300 MHz, DMSO-d6): dH 6.12 (s, 2H, OCH2O),
7.06 (s, 2H, ArH), 7.26 (s,1H, ArH), 7.50e7.65 (m, 4H, ArH), 8.95 (s,1H,
4.2.3. 2-(3-Chloro-4-fluorophenyl)-2H-indazole (2c). Mp: 130e132
n
ꢂC. IR (KBr)
n
: 3065, 1627, 1504, 1380, 1262, 1064, 956, 857,
755 cmꢀ1
.
1H NMR (300 MHz, DMSO-d6): dH 7.12 (t, J¼5.1 Hz, 1H,
ArH), 7.33 (t, J¼4.8 Hz, 1H, ArH) , 7.64e7.72 (m, 2H, ArH), 7.77 (d,

3854
F. Sun et al. / Tetrahedron 68 (2012) 3851e3855
C3eH). 13C NMR (75 MHz, DMSO-d6): dC 101.9, 102.0, 108.6, 113.8,
117.3, 120.8, 121.5, 122.0, 122.3, 126.5, 134.6, 146.9, 148.1, 148.6. HRMS
[found: m/z 239.0815 (MþH)þ, calcd for C14H11N2O2: MþH,
239.0821].
7.68(s, 1H, ArH), 7.72 (d, J¼6.9 Hz, 1H, ArH), 7.83e7.86 (m, 2H, ArH),
8.29 (s, 1H, C3eH). HRMS [found: m/z 246.0360 (Mþ), calcd for
C13H385ClFN2: M, 246.0360].
4.2.18. 2-(4-Bromophenyl)-5-chloro-2H-indazole (2r). Mp: 150e152
4.2.11. 5-Chloro-2-(3-methoxyphenyl)-2H-indazole (2k). Mp: 97e
ꢂC (lit.11 150e152 ꢂC). IR (KBr)
n: 3066, 1587, 1510, 1485, 1418, 1371,
98 ꢂC (lit.11 97e99 ꢂC). IR (KBr)
n
: 3065, 2959, 2834, 1608, 1593,
1335, 1313, 1292, 1196, 1137, 1049, 1005, 952, 925, 852, 827, 801, 766,
724, 693 cmꢀ1. 1H NMR (300 MHz, CDCl3): dH 7.26 (d, J¼6.0 Hz, 1H,
ArH), 7.64e7.66 (m, 3H, ArH), 7.71 (d, J¼6.6 Hz, 1H, ArH), 7.77 (d,
J¼8.0 Hz, 2H, ArH), 8.32 (s, 1H, C3eH). HRMS [found: m/z 305.9561
(Mþ), calcd for C13H879Br35ClN2: M, 305.9559].
1513, 1483, 1438, 1369, 1337, 1311, 1271, 1225, 1193, 1161, 1095, 1050,
1039, 966, 927, 867, 808, 771, 729 cmꢀ1. 1H NMR (300 MHz, DMSO-
d6): dH 3.88 (s, 3H, CH3O), 7.02e7.04 (m, 1H, ArH), 7.28e7.31 (m, 1H,
ArH), 7.49 (t, J¼5.1 Hz, 1H, ArH), 7.66 (d, J¼6.0 Hz, 2H, ArH), 7.77 (d,
J¼6.9 Hz, 1H, ArH), 7.85 (d, J¼1.2 Hz, 1H, ArH), 9.11 (s, 1H, C3eH).
35
HRMS [found: m/z 258.0560 (Mþ), calcd for C14
H
ClN2O: M,
4.2.19. 5-Chloro-2-(3-chlorophenyl)-2H-indazole (2s). Mp: 142e144
11
258.0560].
ꢂC (lit.11 143e144 ꢂC). IR (KBr)
n
: 3073, 1591, 1510, 1483, 1462,
1443, 1396, 1370, 1332, 1304, 1229, 1200, 1090, 1077, 1049, 925,
868, 835, 798, 747, 719, 695 cmꢀ1 1H NMR (300 MHz, CDCl3): dH
4.2.12. 5-Chloro-2-(4-chlorophenyl)-2H-indazole (2l). Mp: 142e144
ꢂC. IR (KBr) : 2925, 1513, 1259, 1191, 1046, 805, 715 cmꢀ1. 1H NMR
.
n
7.27 (d, J¼3.6 Hz, 1H, ArH), 7.39 (d, J¼5.4 Hz, 1H, ArH), 7.46 (t,
J¼5.4 Hz, 1H, ArH), 7.74e7.66 (m, 2H, ArH), 7.38 (t, J¼6.0 Hz, 1H,
ArH), 7.77 (d, J¼5.4 Hz, 1H, ArH), 7.95 (s, 1H, ArH), 8.34 (s, 1H,
C3eH). HRMS [found: m/z 262.0065 (Mþ), calcd for C13H385Cl2N2: M,
262.0069].
(300 MHz, DMSO-d6): dH 7.30 (d, J¼6.0 Hz, 1H, ArH), 7.66 (d,
J¼6.0 Hz, 2H, ArH), 7.76 (d, J¼6.0 Hz, 1H, ArH), 7.86 (s, 1H, ArH), 8.11
(d, J¼6.3 Hz, 2H, ArH), 9.11 (s, 1H, C3eH). 13C NMR (75 MHz, DMSO-
d6): dC 100.8, 107.4, 112.6, 116.1, 119.6, 120.3, 120.8, 121.2, 125.4,
133.5, 145.7, 147.0, 147.5. HRMS [found: m/z 262.0069 (Mþ), calcd
for C14H385Cl2N2: M, 262.0065].
4.2.20. 5,6-Dimethoxy-2-(4-methoxyphenyl)-2H-indazole (2t). Mp:
186e188 ꢂC. IR (KBr)
n
: 3060, 2960, 2835, 1608, 1595, 1513, 1485,
1439, 1369, 1377, 1311, 270, 1225, 1193, 1161, 1095, 1049, 1038, 965,
730, 867, 808, 770, 730, 693 cmꢀ1 1H NMR (300 MHz, CDCl3): dH
4.2.13. 5-Chloro-2-(3-chloro-4-methylphenyl)-2H-indazole
(2m). Mp: 160e162 ꢂC (lit.11 159e161 ꢂC). IR (KBr)
n
: 3094, 2988,
.
2950,1601,1581,1511,1446,1416,1380,1364,1334,1304,1274,1231,
1205, 1195, 1150, 1059, 1049, 994, 931, 877, 866, 848, 817, 806, 767,
734, 711, 693 cmꢀ1. 1H NMR (300 MHz, CDCl3): dH 2.35 (s, 3H, CH3),
7.17 (dd, J1¼1.5 Hz, J2¼7.2 Hz, 1H, ArH), 7.28 (d, J¼6.3 Hz, 1H, ArH),
7.57 (s, 2H, ArH), 7.62 (d, J¼6.9 Hz, 1H, ArH), 7.84 (s, 1H, ArH), 8.21
3.85 (s, 3H, CH3O), 3.92 (s, 3H, CH3O), 3.96 (s, 3H, CH3O), 6.89 (s, 1H,
ArH), 7.00 (d, J¼6.0 Hz, 2H, ArH), 7.05 (s, 1H, ArH), 7.73 (d, J¼5.4 Hz,
2H, ArH), 8.11 (s, 1H, C3eH). 13C NMR (75 MHz, CDCl3): dC 56.0, 56.4,
96.3, 97.5, 115.0, 117.6, 119.7, 122.1, 134.7, 146.7, 148.7, 152.2, 159.1.
HRMS [found: m/z 284.1161 (Mþ), calcd for C16H16N2O3: M,
284.1161].
(s, 1H, C3eH). HRMS [found: m/z 276.0220 (Mþ), calcd for
35
C14
H Cl2N2: M, 276.0221].
10
4.2.21. 2-(3-Chlorophenyl)-5,6-dimethoxy-2H-indazole
143e144 ꢂC. IR (KBr)
: 3135, 3011, 2960, 2835, 1625, 1592, 110,
1483, 1460, 1440, 1385, 1370, 1330, 1305, 1229, 1200, 1090, 1075,
1050, 920, 860, 834, 898, 746, 720, 694 cmꢀ1 1H NMR (300 MHz,
CDCl3): dH 3.84 (s, 3H, CH3O), 3.88 (s, 3H, CH3O), 6.76 (s, 1H, ArH),
6.94 (s, 1H, ArH), 7.20 (d, J¼6.0 Hz, 1H, ArH), 7.31 (t, J¼6.3 Hz, 1H,
ArH), 7.62 (d, J¼6.0 Hz,1H, ArH), 7.81 (s,1H, ArH), 8.12 (s,1H, C3eH).
13C NMR (75 MHz, CDCl3): dC 56.1, 95.9, 97.0, 117.9, 118.0, 120.4,
(2u). Mp:
4.2.14. 5-Chloro-2-phenyl-2H-indazole (2n). Mp: 143e145 ꢂC (lit.11
143e144 ꢂC). IR (KBr)
: 3063, 1627, 1596, 1509, 1462, 1405, 1371,
1323, 1298, 1286, 1230, 1199, 1177, 1140, 1072, 1051, 954, 930, 898,
872, 809, 769, 753, 728, 696 cmꢀ1 1H NMR (300 MHz, CDCl3): dH
7.24e7.26 (m, 1H, ArH), 7.42 (t, J¼5.4 Hz, 1H, ArH), 7.53 (t, J¼5.7 Hz,
2H, ArH), 7.68 (s, 1H, ArH), 7.73 (d, J¼6.6 Hz, 1H, ArH), 7.88 (d,
J¼6.0 Hz, 2H, ArH), 8.35 (s, 1H, C3eH). HRMS [found: m/z 228.0452
(Mþ), calcd for C13H935ClN2: M, 228.0454].
n
n
.
.
127.1, 135.5, 141.7, 147.1, 149.0, 152.6. HRMS [found: m/z 288.0661
35
(Mþ), calcd for C15
H ClN2O2: M, 288.0665].
13
4.2.15. 5-Chloro-2-(3-methylphenyl)-2H-indazole (2o). Mp: 97e98
ꢂC (lit.11 97e99 ꢂC). IR (KBr)
n
: 3030, 2921, 1626, 1606, 1590, 1508,
1489, 1364, 1309, 1288, 1253, 1223, 1173, 1158, 1141, 1093, 1059,
1050, 930, 893, 865, 810, 780, 732, 695 cmꢀ1 1H NMR (300 MHz,
4.2.22. 2-(4-Bromophenyl)-5,6-dimethoxy-2H-indazole (2v). Mp:
156e158 ꢂC. IR (KBr)
: 2957, 2834, 1628, 1520, 1456, 1435, 1383,
1292, 1234, 1204, 1156, 1130, 1096, 1040, 1007, 950, 815, 794, 779,
752, 765 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 3.93 (s, 3H, CH3O),
3.97 (s, 3H, CH3O), 6.86 (s, 1H, ArH), 7.02 (s, 1H, ArH), 7.60 (d,
J¼6.6 Hz, 2H, ArH), 7.72 (d, J¼6.0 Hz, 2H, ArH), 8.16 (s, 1H, C3eH).
13C NMR (75 MHz, CDCl3): dC 56.1, 59.9, 97.0, 117.9, 119.2, 120.5,
n
.
DMSO-d6): dH 2.43 (s, 3H, CH3), 7.28e7.30 (m, 2H, ArH), 7.46e7.50
(m, 1H, ArH), 7.77 (d, J¼6.6 Hz, 1H, ArH), 7.84e7.87 (m, 2H, ArH),
.
7.92 (s, 1H, ArH), 9.05 (s, 1H, C3eH). HRMS [found: m/z 242.0610
35
(Mþ), calcd for C14
H ClN2: M, 242.0611].
11
121.5, 132.8, 139.7, 147.0, 148.9, 152.5. HRMS [found: m/z 332.0160
79
4.2.16. 5-Chloro-2-(3-chloro-4-fluorophenyl)-2H-indazole (2p). Mp:
140e141 ꢂC (lit.11 140e142 ꢂC). IR (KBr)
: 3093, 1627, 1599, 1548,
1517, 1453, 1427, 1373, 1337, 1310, 1271, 1259, 1235, 1194, 1127,
1067, 1049, 965, 932, 877, 859, 804, 761, 716, 692 cmꢀ1 1H NMR
(300 MHz, DMSO-d6): dH 7.30e7.34 (m, 1H, ArH), 7.65 (t,
J¼6.6 Hz, 1H, ArH), 7.76 (t, J¼5.4 Hz, 1H, ArH), 7.86 (s, 1H, ArH),
8.10e8.13 (m, 1H, ArH), 8.34e8.36 (m, 1H, ArH), 9.14 (s, 1H,
C3eH). HRMS [found: m/z 279.9969 (Mþ), calcd for C13H375Cl2FN2:
M, 279.9970].
(Mþ), calcd for C15
H BrN2O2: M, 332.0160].
13
n
4.2.23. 2-(4-Fluorophenyl)-5,6-dimethoxy-2H-indazole (2w). Mp:
106e108 ꢂC. IR (KBr)
: 3060, 3135, 3010, 2955, 2836, 1625, 1520,
1456, 1434, 1382, 1294, 1234, 1203, 1155, 1129, 1098, 1044, 950, 840,
815, 792, 751 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 3.91 (s, 3H,
.
n
.
CH3O), 3.95 (s, 3H, CH3O), 6.86 (s, 1H, ArH), 7.02 (s, 1H, ArH), 7.16 (t,
J¼6.3 Hz, 2H, ArH), 7.76e7.79 (m, 2H, ArH), 8.11 (s, 1H, C3eH). 13
C
NMR (75 MHz, CDCl3): dC 56.1, 95.9, 97.1, 116.4, 116.7, 117.7, 119.5,
121.9, 122.0, 137.1,146.9, 148.7,152.3, 160.1,163.3. HRMS [found: m/z
273.1034 (MþH)þ, calcd for C15H14FN2O2: MþH, 273.1039].
4.2.17. 5-Chloro-2-(4-fluorophenyl)-2H-indazole (2q). Mp: 133e135
ꢂC (lit.11 134e135 ꢂC). IR (KBr)
n
: 1609, 1517, 1431, 1404, 1370, 1292,
1238, 1197, 1153, 1095, 1050, 1010, 954, 930, 867, 831, 803, 769, 729,
695 cmꢀ1 1H NMR (300 MHz, CDCl3): dH 7.21e7.27 (m, 3H, ArH),
4.2.24. 5,6-Dimethoxy-2-(3-methylphenyl)-2H-indazole (2x). Mp:
.
110e112 ꢂC. IR (KBr)
n: 3030, 2921, 2835, 1625, 1605, 1590, 1508,

F. Sun et al. / Tetrahedron 68 (2012) 3851e3855
3855
4. Li, X.; Chu, S.; Feher, V. A.; Khalili, M.; Nie, Z.; Margosiak, S.; Nikulin, V.; Levin, J.;
Sparankle, K. G.; Fedder, M. E.; Almassy, R.; Appelt, K.; Yager, K. M. J. Med. Chem.
2003, 46, 5663e5673.
5. (a) Bistochi, G. A.; De Meo, G.; Pedini, M.; Ricci, A.; Brouilhet, H.; Bucherie, S.;
Rabaud, M.; Jacquignon, P. Farmaco Ed. Sci. 1981, 36, 315e333; (b) Picciola, G.;
Ravenna, F.; Carenini, G.; Gentili, P.; Riva, M. Farmaco Ed. Sci. 1981, 36,
1037e1056.
1488,1365,1309,1288,1253,1223,1173,1158,1142,1094,1059,1051,
930, 894, 865, 810, 780, 732, 695 cmꢀ1.1H NMR (300 MHz, CDCl3): dH
2.43 (s, 3H, CH3), 3.91 (s, 3H, CH3O), 3.95 (s, 3H, CH3O), 6.86 (s, 1H,
ArH), 7.05 (s, 1H, ArH), 7.13 (d, J¼5.4 Hz, 1H, ArH), 7.34 (t, J¼6.0 Hz,
1H, ArH), 7.57 (d, J¼6.0 Hz, 1H, ArH), 7.69 (s, 1H, ArH), 8.18 (s, 1H,
C3eH). 13C NMR (75 MHz, CDCl3): dC 21.7, 56.1, 96.0, 97.2,117.3,117.5,
119.5,121.1,128.1,139.9,140.7,146.7,148.62,152.18. HRMS [found: m/
z 269.1285 (MþH)þ, calcd for C16H17N2O2: MþH, 269.1290].
6. Corsi, G.; Palazzo, G.; Germani, C.; Barcellona, P. S.; Silvestrini, B. J. Med. Chem.
1976, 19, 778e783.
7. (a) Albini, A.; Bettinetti, G.; Minoli, G. Heterocycles 1988, 27, 1207e1216; (b)
Seela, F.; Bourgeois, W. Helv. Chim. Acta 1991, 74, 315e322; (c) Cerrada, M. L.;
Elguero, J.; de le Fuente, J.; Pardo, C.; Ramos, M. Synth. Commun. 1993, 23,
1947e1952; (d) Rosevear, J.; Wilshire, J. F. K. Aust. J. Chem. 1991, 44, 1097e1114;
(e) Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1994, 59, 3375e3380; (f)
Song, J. J.; Yee, N. K. Org. Lett. 2000, 2, 519e521; (g) Sawant, D.; Kumar, R.;
Maulik, P. R.; Kundu, B. Org. Lett. 2006, 8, 1525e1528; (h) Wu, C.; Fang, Y.;
Larock, R. C.; Shi, F. Org. Lett. 2010, 12, 2234e2237; (i) Haag, B.; Peng, Z.; Kno-
chel, P. Org. Lett. 2009, 11, 4270e4273; (j) Halland, N.; Nazare, M.; Rkyek, O.;
Alonso, J.; Urmann, M.; Lindenschmidt, A. Angew. Chem., Int. Ed. 2009, 48,
6879e6882; (k) Stokes, B. J.; Vogel, C. V.; Urnezis, L. K.; Pan, M.; Driver, T. G. Org.
Lett. 2010, 12, 2884e2887; (l) Kumar, M. R.; Park, A.; Park, N.; Lee, S. Org. Lett.
2011, 13, 3542e3545.
4.2.25. 2-(3-Chloro-4-methylphenyl)-5,6-dimethoxy-2H-indazole
(2y). Mp: 121e123 ꢂC. IR (KBr)
n
: 3028, 2920, 2832, 1628, 1607,
1590, 1508, 1480, 1365, 1310, 1288, 1250, 1223, 1176, 1154, 1142,
1094, 1045, 930, 897, 868, 788, 734 cmꢀ1 1H NMR (300 MHz,
.
DMSO-d6): dH 2.35 (s, 3H, CH3), 3.79 (s, 3H, CH3O), 3.82 (s, 3H,
CH3O), 6.95e7.00 (m, 2H, ArH), 7.50 (s, 1H, ArH), 7.86 (s, 1H, ArH),
8.05 (s, 1H, ArH), 8.80 (s, 1H, C3eH). 13C NMR (75 MHz, DMSO-d6):
dC 24.4, 60.8, 60.9,100.9,102.7,114.7,122.6,123.0,124.6,125.5,137.4,
8. (a) Paal, C.; Krecke, F. Chem. Ber. 1890, 23, 2640e2641; (b) Paal, C. Chem. Ber.
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J. Chem. 1995, 48, 2023e2033.
139.1, 144.5, 151.3, 153.5, 157.4. HRMS [found: m/z 303.0895
35
(MþH)þ, calcd for C16
H ClN2O2: M, 303.0900].
16
9. Frontana-Oribe, B. A.; Moinet, C. Tetrahedron 1998, 54, 3197e3206.
10. Mills, A. D.; Nazer, M. Z.; Haddadin, M. J.; Kurth, M. J. J. Org. Chem. 2006, 71,
2687e2689.
Acknowledgements
11. Shi, D. Q.; Dou, G. L.; Ni, S. N.; Shi, J. W.; Li, X. Y.; Wang, X. S.; Wu, H.; Ji, S. J.
Synlett 2007, 2509e2512.
12. (a) McMurry, J. E. Acc. Chem. Res. 1974, 7, 281e286; (b) McMurry, J. E. Acc. Chem.
We acknowledge the financial support from the Foundation of
the Natural Science Foundation of China (No. 21072144), the Major
Basic Research Project of the Natural Science Foundation of the
Jiangsu Higher Education Institutions (No. 10KJA150049), A Project
Funded by the Priority Academic Project Development of Jiangsu
Higher Education Institutions and the Foundation of Key Laboratory
of Organic Synthesis of Jiangsu Province (No. JSK0812).
Res. 1983, 16, 405e411; (c) McMurry, J. E. Chem. Rev. 1989, 89, 1513e1524.
€
13. (a) Lenoir, D. Synthesis 1989, 883e897; (b) Furstner, A.; Bogdanovi, B. Angew.
Chem., Int. Ed. 1996, 35, 2442e2469; (c) Shi, D. Q.; Chen, J. X.; Chai, W. Y.; Chen,
W. X.; Kao, T. Y. Tetrahedron Lett. 1993, 34, 2863e2864.
14. Shi, D. Q.; Rong, R. C.; Wang, J. X.; Zhuang, Q. Y.; Wang, X. S.; Hu, H. W. Tet-
rahedron Lett. 2003, 44, 3199e3201.
15. (a) Shi, D. Q.; Dou, G. L.; Shi, C. L.; Li, Z. Y.; Ji, S. J. Synthesis 2007, 3117e3124;
(b) Dou, G. L.; Shi, D. Q. J. Comb. Chem. 2008, 10, 810e813.
16. Shi, D. Q.; Dou, G. L.; Li, Z. Y.; Ni, S. N.; Li, X. Y.; Wang, X. S.; Wu, H.; Ji, S. J.
Tetrahedron 2007, 63, 9764e9773.
Supplementary data
17. Shi, D. Q.; Rong, S. F.; Dou, G. L.; Wang, M. M. J. Comb. Chem. 2010, 12, 25e30.
18. Shi, D. Q.; Rong, S. F.; Dou, G. L. Synth. Commun. 2010, 40, 2302e2310.
19. Zhao, X.; Shi, D. Q. J. Heterocycl. Chem. 2011, 48, 634e638.
Supplementary data related to this article can be found in the
online version, at doi:10.1016/j.tet.2012.03.043.
20. Dou, G. L.; Shi, D. Q. J. Comb. Chem. 2009, 11, 1073e1077.
21. Crystallographic data for the structures of 2w have been deposited at the
Cambridge Crystallographic Data Centre, deposit number is CCDC 869942.
Copies of available material can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44 1223 336 033;
e-mail: deposit@ccdc.cam.ac.uk).The single-crystal growth was carried out
in ethanol solutions at rt. Intensity data were collected on a Siemens P4
References and notes
1. (a) Keppler, B. K.; Hartmann, M. Met.-Based Drugs 1994, 1, 145e150; (b) Baraldi,
P. G.; Balboni, G.; Pavani, M. G.; Spalluto, G.; Tabrizi, M. A.; Clercq, E. D.; Bal-
zarini, J.; Bando, T.; Sugiyama, H.; Romagnoli, R. J. Med. Chem. 2001, 44,
2536e2543; (c) Qian, S. J.; Cao, J.; Yan, Y.; Sun, M.; Zhu, H.; Hu, Y.; He, Q.; Yang,
B. Mol. Cell Biochem. 2010, 345, 13e21.
2. (a) Sun, J. H.; Teleha, C. A.; Yan, J. S.; Rodgers, J. D.; Nugiel, D. A. J. Org. Chem.
1997, 62, 5627e5629; (b) Rodgers, J. D.; Johnson, B. L.; Wang, H.; Greenberg, R.
A.; Erickson-Viitanen, S.; Klabe, R. M.; Cordova, B. C.; Rayer, M. M.; Lam, G. N.;
Chang, C. H. Bioorg. Med. Chem. Lett. 1996, 6, 2919e2924.
diffractometer with graphite monochromated Mo
71075 A) using the
K
a
radiation
<25.50ꢂ.Crystal data for 2w:
empirical formula C15H13FN2O2, yellow, crystal dimension 0.75ꢁ0.30ꢁ0.
(
l
¼0.
u q
scan mode with 3.02ꢂ<
ꢀ
ꢀ
ꢀ
20 mm, orthorhombic, space group Pbca, a¼11.5483(18) A, b¼13.452(2) A,
3
ꢀ
c¼33.213(5) A,
a
¼90ꢂ,
b
¼90ꢂ,
g
¼90ꢂ. V¼5159.4(14) A , Mr¼272.27, Z¼16,
ꢀ
Dc¼1.402 Mg/m3,
m
(Mo K
a
)¼0.104 mmꢀ1, F(000)¼2272, S¼1.275, R1¼0.1070,
3. Ikeda, Y.; Takano, N.; Matsushita, H.; Shiraki, Y.; Koide, T.; Nagashima, R.; Fu-
jimura, Y.; Shindo, M.; Suzuki, S.; Iwasaki, T. Arzneim.-Forsch. 1979, 29, 511e520.
wR2¼0.2372.