A general and efficient approach to 2H-indazoles and 1H-pyrazoles through copper-catalyzed intramolecular N-N bond formation under mild conditions

Article abstract of DOI:10.1039/c1cc13908h

A new efficient copper-catalyzed intramolecular amination reaction has been developed to readily synthesise a wide variety of multi-substituted 2H-indazole and 1H-pyrazole derivatives from easily accessible starting materials under mild conditions. A highly selective ligand for estrogen receptor β was prepared in three steps by employing this method. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc13908h

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COMMUNICATION
A general and efficient approach to 2H-indazoles and 1H-pyrazoles through
copper-catalyzed intramolecular N–N bond formation under mild conditionsw
Jiantao Hu, Yongfeng Cheng, Yiqing Yang and Yu Rao*
Received 30th June 2011, Accepted 22nd July 2011
DOI: 10.1039/c1cc13908h
A new efficient copper-catalyzed intramolecular amination reaction
has been developed to readily synthesise a wide variety of multi-
substituted 2H-indazole and 1H-pyrazole derivatives from easily
accessible starting materials under mild conditions. A highly
selective ligand for estrogen receptor b was prepared in three steps
by employing this method.
we proposed that the desired 2-aryl-2H-indazole products
could be obtained through the intramolecular cyclization of
N-aryl-imines with azide activation by copper.
Accordingly, a model study was initiated with 2-azido-
benzaldehyde and 4-methoxyaniline as substrates to test our
hypothesis (Table 1). First, a variety of copper salts were
tested as potential catalysts in DCM at 40 1C following
imine intermediate formation. After overnight reaction, only
a little amount of desired product 2 was observed. Among
them, copper(I) iodide was better than the other copper
catalysts. In terms of the solvent system and catalyst loading,
it was found that THF, 1,4-dioxane and toluene were superior
over DCM and a small catalyst amount, e.g. 0.05 or 0.10
equiv. of CuI, can promote the reaction as effectively as higher
catalyst loadings. Then, we turned our attention to other
factors affecting the reaction. Gratifyingly, further optimizations
Indazole derivatives play an increasingly important role in modern
drug discovery.1 Having been recognized as a privileged structure
in medicinal chemistry,2 the indazole scaffold constitutes the key
moiety in many drug substances with a broad range of pharmaco-
logical activities including anticancer,3 anti-inflammatory,4
antidepressant,5 anti-HIV,6 and contraceptive7 activities. Despite
the importance of indazoles in pharmaceutical development, only
a limited number of approaches for the regioselective synthesis of
N-substituted indazoles are available today. Most existing methods
provide the thermodynamically favored 1H-indazole or mixtures of
1H- and 2H-indazoles with low regioselectivities.8,9 Compared with
1H-indazoles, 2H-indazoles have been much less studied partly
due to the difficulty in their preparation. Recently several promising
synthetic routes to 2H-indazoles have been reported,10 however
there are disadvantages in using those methods such as limitations
of substrate scope, elevated temperatures and the requirement for
precious palladium. Thus, further development of new, efficient,
and general methods toward synthesis of 2H-indazoles using
readily available precursors under mild reaction conditions is quite
appealing. Herein, we report a novel synthesis of 2H-indazoles
and 1H-pyrazoles through the formation of the N(1)–N(2)
bond via a copper-catalyzed intramolecular amination reaction.
There are only very few cases of transition-metal-catalyzed
direct N–N bond formation in the literature. Recently iron has
been used to build up N–N bonds for synthesis of 2H-pyrazoles.11
Although copper complexes have been well established as
N-atom transfer reagents from azides to mediate C–H amination
reactions using azides as the N-atom precursor,12 a copper-based
system for N–N bond formation with aromatic or vinyl
azide functional groups has rarely been reported. During the
course of our research on the synthesis of 2-aryl-2H-indazoles,
Table 1 Optimization of the reaction conditions
Yielda
(%)
Entry Catalyst
Condition
1
2
3
4
5
6
7
8
1.0 eq. CuCl
1.0 eq. CuBr
1.0 eq. Cul
1.0 eq. CuBr2 40 1C, DCM, 12 h
1.0 eq. CuCl2 40 1C, DCM, 12 h
1.0 eq. Cu(Otf)2 40 1C, DCM, 12 h
40 1C, DCM, 12 h
40 1C, DCM, 12 h
40 1C, DCM, 12 h
2.2
2.4
6.6
4.5
1.9
6.1
5.8
6.6
35
39
30
31
22
1.0 eq. Cul
1.0 eq. Cul
1.0 eq. Cul
1.0 eq. Cul
0.5 eq. Cul
0.2 eq. Cul
0.1 eq. Cul
0.05 eq. Cul
0.1 eq. Cul
0.1 eq. Cul
0.1 eq. Cul
0.1 eq. Cul
0.1 eq. Cul
0.1 eq. Cul
0.1 eq. Cul
0.1 eq. Cul
0.1 eq. Cul
0.1 eq. Cul
rt, DCM, 12 h
40 1C, DCM, 12 h
40 1C, THF, 12 h
40 1C, 1,4-dioxane, 12 h
40 1C, THF, 12 h
40 1C, THF, 12 h
40 1C, THF, 12 h
40 1C, THF, 12 h
40 1C, THF, 1.0 eq. pyridine, 2 h
40 1C, THF, 1.0 eq. Et2NH, 2 h
40 1C, THF, 1.0 eq. Et3N, 2 h
40 1C, THF, 1.0 eq. DABCO, 2 h
40 1C, THF, 1.0 eq. TMEDA, 2 h
40 1C, THF, 0.5 eq. TMEDA, 2 h
40 1C, THF, 0.2 eq. TMEDA, 2 h
40 1C, 1,4-dioxane, 1.0 eq. TMEDA, 2 h 79
rt, THF, 1.0 eq. TMEDA, 4 h
0 1C, THF, 1.0 eq. TMEDA, 8 h
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
27
38
50
75
70
90
94b
61
Department of Pharmacology and Pharmaceutical Sciences,
School of Life Sciences and School of Medicine, Tsinghua University,
Beijing 100084, China. E-mail: yrao@mail.tsinghua.edu.cn
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc13908h
91
81
a
b
Conversion ratio. Isolated yield. ArNH2 = 4-methoxyaniline.
c
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Chem. Commun., 2011, 47, 10133–10135 10133

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revealed the addition of different nitrogen-containing bases,
especially tertiary amines such as Et3N, DABCO, TMEDA and
DBU can significantly increase product yields and accelerate
reaction rates.13 For example, in the case of TMEDA, the yield
of product 2 was improved up to 90% and the reaction time was
shortened to two hours. As to the amount of additives, around
0.50 equivalent of amines gave the best results. In particular,
lower temperatures, such as room temperature, only have a slight
effect on yields and a small influence on the time required for
the completion of reaction. Typically the reaction will go to
completion within two hours in a fast and clean manner at 40 1C
with Et3N or TMEDA as additives. Entry 20 in Table 1 was found
to be the best condition for the preparation of 2H-indazole 2.
Having identified the optimal condition, we set out to
explore the scope for this intramolecular cyclization reaction.
As shown in Table 2, a wide variety of di- and tri-substituted
2H-indazoles was smoothly prepared in good to excellent
yields. The scope of the N substituents was found to be
impressively broad. The ortho-, meta- and para-substituted
aryl groups as well as the electron-sufficient and electron-
deficient aryl groups were well tolerated, including functional
groups such as fluoride and trifluoromethyl moieties (Table 2,
compounds 4, 6, 16, 19). In comparison with other substrates,
para-nitro aniline gave relatively lower yields (compounds 5
and 21), which may be because of its strong electron-
withdrawing nature. Especially noteworthy is the synthesis
of 2H-indazoles containing 3-substituents (Table 2, compounds
20–28), since it is difficult to access those compounds by
existing methods. Besides aromatic amines, heteroaromatic
and benzylic amines were also employed as substrates to
construct the corresponding products 7 and 9 in high yields.
As illustrated in Table 3, this new method was further
applied in the synthesis of 1H-pyrazoles. A variety of
1,3-disubstituted and 1,3,4-trisubstituted 1-aryl-1H-pyrazole
derivatives were successfully prepared. Overall meta- and
para-substituted aryl groups gave better yields than ortho-
substituted aryl groups (Table 3, compounds 34, 36), which
may be in part due to less steric hindrance. Notably, sterically
hindered amines like naphthalen-1-amine provided 1H-pyrazole
products in excellent yields (Table 3, compounds 43, 44).
Being generally consistent with the synthesis of 2H-indazole,
the reaction for 1H-pyrazole showed great reactivity, broad
functional group tolerance and satisfactory yields as well.
Shown in Scheme 1 is a further application of our method in
the synthesis of biologically important small molecules, in
which a highly selective ligand for estrogen receptor b14 was
prepared readily in three steps by employing this approach.
Table 2 Reaction scope of 2H-indazole synthesis. Reaction conditions:
(a) 0.1 eq. CuI, 0.5 eq. TMEDA, THF, rt, 4 h or 40 1C, 2 h; (b) 0.1 eq.
CuI, 0.5 eq. Et3N, THF, rt, 4 h or 40 1C, 2 h
Table 3 Reaction scope of 1H-pyrazole synthesis
Yield
Cond.(%) Product
Yield
Cond.(%)
Product
3 a
97
94
57
16a
17a
18a
73
90
96
Product
Yield (%) Product
Yield (%)
4 a
5 a
29 83
38 91
6 a
7 a
85
81
19a
20b
80
82
30 80
31 46
32 34
33 85
39 81
40 66
41 97
42 93
8 a
93
21b
66
9 a
10a
11a
93
91
94
22b
23b
24b
67
85
84
34 42
35 87
43 89
44 81
45 88
12a
13a
93
97
25b
26b
66
72
36 45
37 44
14a
15a
70
70
27b
28b
83
79
c
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10134 Chem. Commun., 2011, 47, 10133–10135

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Scheme 1 Synthesis of a selective ligand for estrogen receptor b.
Reaction conditions: (a) (1) AcOH/EtOH; (2) 0.1 eq. CuI, 0.5 eq.
TMEDA, THF, 40 1C, 2 h, 42%; (b) 1.0 eq. NCS, THF, 40 1C, 2 h,
85%; (c) 10 eq. NaOH, THF/H2O (2 : 1), 15 min, 95%.
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Scheme 2 Plausible mechanism.
The possible mechanism is illustrated in Scheme 2.
Although the addition of tertiary amines is critical, their role
is still not very clear.15 Two pathways are likely involved in
this reaction. In path A, tertiary amines may purely act as
ligands to fine tune the catalytic ability of copper iodide. After
forming azide-copper(I) complex II, intramolecular cyclization
gave intermediate III. Then, the emission of N2 and dissociation
of copper catalyst furnished the final product VI. In path B,
firstly, the nucleophilic addition of tertiary amines to the imine I
gave a zwitterionic intermediate IV. Upon activation of the
azide group by copper(I), the nucleophilic nitrogen will add to
the electrophilic azide to produce the intermediate V. Following
this intramolecular N–N bond formation, elimination of the
tertiary amines and N2 afforded the desired product VI.
In conclusion, a concise, two-step protocol has been developed
for the rapid synthesis of functionalized 2H-indazoles and
1H-pyrazoles from easily accessible starting materials under
mild conditions. This method has been found to be generally
useful for the preparation of a wide variety of 2H-indazole and
1H-pyrazole derivatives some of which are difficult to make via
conventional approaches. The reaction demonstrates excellent
reactivity, broad functional group tolerance and high yields,
which has been further exemplified in one synthetic application.
By employing a combination of CuI and tertiary amines, we have
developed a highly efficient catalyst system for this intra-
molecular N–N bond formation reaction. Further investigations
into the mechanism and synthetic applications of this method are
currently underway.
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This work was supported by the national ‘973’ grant from the
Ministry of Science and Technology (grant # 2011CB965300) and
Tsinghua University 985 Phase II funds. We thank Prof. Y. F. Tang
and Prof. L. Liu (Tsinghua University) for helpful discussions.
13 Other amines such as pyridine, Et2NH and DMAP can also
improve the reaction.
14 M. D. Angelis, F. Stossi, K. A. Carlson, B. S. Katzenellenbogen
and J. A. Katzenellenbogen, J. Med. Chem., 2005, 48, 1132.
15 Other additives such as K2CO3, CsCO3 and tBuOK, etc., had also
been tested. The observations found that those bases cannot
improve the reactions as amines did, which may suggest that the
additives might need to be either potential ligands for copper or be
directly involved in the formation of intermediates.
Notes and references
1 (a) W. Stadlbauer, in Science of Synthesis, vol. 12, Georg Thieme,
Stuttgart, 2002, pp. 227–310; (b) V. Minkin, D. Garnovskii,
J. Elguero, A. Katritzky and O. Denisko, Adv. Heterocycl. Chem.,
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10133–10135 10135