CuII-hydrotalcite catalyzed one-pot three component synthesis of 2H-indazoles by consecutive condensation, C-N and N-N bond formations

Article abstract of DOI:10.1039/c2cy20590d

An efficient and straightforward synthesis of 2H-indazoles is achieved from 2-bromobenzaldehydes, primary amines and sodium azide through consecutive condensation, C-N and N-N bond formations, catalyzed by a novel heterogeneous Cu^II-HT catalyst. The recoverable heterogeneous Cu^II-HT catalyst exhibited an impressive activity for the title reaction without any additives (expensive ligands, etc.). Heterocyclization proceeds through C-N and N-N bond formation, which is the key step to deliver the desired 2H-indazole scaffold. A series of structurally diverse 2H-indazoles were prepared in good to excellent yields from easily accessible starting materials by employing this protocol.

Full text of DOI:10.1039/c2cy20590d

Catalysis
Science & Technology
View Article Online
View Journal | View Issue
PAPER
CuII–hydrotalcite catalyzed one-pot three component
synthesis of 2H-indazoles by consecutive condensation,
C–N and N–N bond formations†
Cite this: Catal. Sci. Technol., 2013,
3, 654
Avvari N. Prasad, Rapelli Srinivas and Benjaram M. Reddy*
An efficient and straightforward synthesis of 2H-indazoles is achieved from 2-bromobenzaldehydes,
primary amines and sodium azide through consecutive condensation, C–N and N–N bond
formations, catalyzed by a novel heterogeneous CuII–HT catalyst. The recoverable heterogeneous
CuII–HT catalyst exhibited an impressive activity for the title reaction without any additives (expensive
ligands, etc.). Heterocyclization proceeds through C–N and N–N bond formation, which is the key
Received 22nd August 2012,
Accepted 15th October 2012
step to deliver the desired 2H-indazole scaffold.
A series of structurally diverse 2H-indazoles
DOI: 10.1039/c2cy20590d
were prepared in good to excellent yields from easily accessible starting materials by employing this
protocol.
www.rsc.org/catalysis
devoted towards 2H-indazoles, such as (1) 2-halophenyl acetylenes
with hydrazines by using a Pd-catalyst and palladium-catalyzed
1. Introduction
Over the past decades, there has been great interest in the
synthesis of heterocyclic compounds. Among the numerous
heterocycles, the indazole ring system has been receiving
significant attention due to its pronounced biological activity.
Captivatingly, in the field of drug discovery, the indazole
scaffolds received a lot of interest because they act as efficient
bioisosteres of indoles and benzimidazoles,1,2 and constitute
the key subunit in various drug substances with a broad range
of biological properties, including anti-inflammatory, anti-
depressant,3 antitumor,4 HIV protease inhibition,5 anti-
microbial6 and contraceptive activities.7 In heterocyclic
intramolecular amination of the corresponding N-aryl-N-
(o-bromobenzyl) hydrazines,19 (2) Fe-catalyzed intramolecular
N–N bond formation from aryl azides,20 (3) reaction of highly
functionalized zinc reagents with aryldiazonium salts,21 (4)
[3+2] dipolar cycloaddition of arynes and sydnones,8 (5) reaction
of sodium hydride or DBU catalyzed 2-nitrobenzyl triphenyl-
phosphonium bromide with aryl isocyanates,22 and (6) Baylis–
Hillman adducts of 2-cyclohexen-1-one by using DDQ oxidation,23
and also the feasibility of further elaboration of 2H-indazoles
using Suzuki–Miyaura and Sonogashira couplings.24
However, most of the existing methods exhibit several draw-
backs, such as the formation of regioisomers, requirement of
additives (expensive phosphine ligands, etc.) and low functional
group tolerance, and also these methods require several steps
to synthesize the starting materials. Furthermore, most of these
methods are homogeneous in nature. Therefore, there is a need
for novel, proficient and selective approaches to synthesize
2H-indazoles by using readily available starting materials or
precursors. To the best of our knowledge, there is only one
instance of the multicomponent reaction (MCR) for obtaining
2H-indazoles through a different approach.25 As part of our
on-going research programme, stimulated by the development
of MCRs by using heterogeneous catalysts, the present investi-
gation was undertaken. The reported novel heterogeneous
Cu–Al hydrotalcites (CuII–HTs) offer numerous advantages,
such as being inexpensive and recoverable, and having a simple
workup procedure.
chemistry, the indazole unit has been recognized as
a
‘‘privileged structure’’, and it is an important pharmacophore
in medicinal chemistry.8–16
Although a number of methods were known for the prepara-
tion of indazoles, most of the existing approaches are targeted
to 1H-indazoles or mixture of 1H- and 2H-indazoles.17 In
addition, 2H-indazoles are less studied as compared to
1H-indazoles due to the difficulty in their preparation. Hence,
the formation of 2H-indazoles still remains a challenging
task.18 Recently, several promising synthetic routes have been
Inorganic and Physical Chemistry, CSIR - Indian Institute of Chemical Technology,
Uppal Road, Hyderabad, 500607, India. E-mail: bmreddy@iict.res.in,
mreddyb@yahoo.com; Fax: +91 40 2716 0921; Tel: +91 40 27191714
† Electronic supplementary information (ESI) available: Additional characteriza-
tion studies supporting the results which include 1H NMR, 13C NMR, FTIR and
MS data of isolated compounds. See DOI: 10.1039/c2cy20590d
c
654 Catal. Sci. Technol., 2013, 3, 654--658
This journal is The Royal Society of Chemistry 2013

View Article Online
Paper
Catalysis Science & Technology
2. Experimental section
2.1 Preparation of CuII–hydrotalcite (CuII–HT) catalysts
A series of CuII–HT catalysts were synthesized by adopting a
coprecipitation method. In a typical procedure, a mixture
solution containing the requisite quantities of Cu(NO3)2Á6H2O
and Al(NO3)3Á9H2O (Cu/Al mole ratios = 1 : 1, 2 : 1, 3 : 1,
2.5 : 1, and 4 : 1; all chemicals are Fluka, AR grade) precursors
were dissolved separately and mixed together. A base mixture
solution (1 : 1 volume of 2 M NaOH and 1 M Na2CO3) was also
prepared separately in distilled water. Both mixture solutions
were added slowly and simultaneously to a beaker containing
double distilled water with vigorous stirring until the pH of the
solution reached B9. The pH was maintained constantly
throughout the addition. Later, the obtained precipitates were
filtered off, washed thoroughly with distilled water until free
from anion impurities (pH = 7) and then oven dried at 100 1C
for 12 h. The synthesized catalysts were characterized by X-ray
diffraction, FT-infrared, thermogravimetry and other techni-
ques. There results could be found in the ESI.†
Scheme 1 Synthesis of 2H-indazoles using the CuII–HT catalyst.
In the initial experiments, the reaction of 2-bromobenzalde-
hyde (1.5 mmol), aniline (1.8 mmol) and sodium azide (2 mmol)
was investigated as the model reaction for optimization of
reaction parameters such as, mole ratio of CuII–HTs, solvent
and the temperature to synthesize 2H-indazoles; and the
obtained results are summarized in Table 1. A preliminary
reaction was also carried out to identify the best catalyst system
using DMSO as the reaction medium at 120 1C temperature
with catalytic amounts of CuII–HTs containing various Cu : Al
mole ratios. As can be seen from Table 1, the 3 : 1 mole ratio
CuII–HT catalyst exhibited an impressive activity and enriched
regioselectivity towards the desired 2H-indazole (Table 1, entry 5).
Gratifyingly, the CuII–HTs with 4 : 1 and 2.5 : 1 (Cu : Al) mole
ratios also showed better yields of 82% and 76%, respectively
(Table 1, entries 2 and 4). However, the yields were lower than
that of the 3 : 1 mole ratio CuII–HT catalyst. Trace amounts of
products including some by-products and longer reaction times
were noticed in the absence of the CuII–HT catalyst (Table 1,
entry 6), and also we observed different spots in the TLC in the
presence of catalyst under solvent-free conditions (Table 1,
entry13).
2.2 Synthesis of 2H-indazoles
All chemicals employed in this study were commercially available
and used without further purification. A mixture of 2-bromo-
benzaldehyde (1.5 mmol), primary amine (1.8 mmol), sodium
azide (2 mmol) and catalytic amounts of CuII–HT (20 mg) in
dimethylsulfoxide (DMSO) (1.5 mL) were stirred at 120 1C
temperature for an appropriate time. After completion of the
reaction, as indicated by thin layer chromatography (TLC), the
reaction mixture was centrifuged to separate the catalyst. The
reaction mixture was poured into EtOAc (30 mL) and washed
with distilled water (3 Â 20 mL), and the combined layers were
dried over anhydrous Na2SO4, concentrated in vacuum and
purified by column chromatography on 60–120 mesh silica gel,
using ethyl acetate and hexane as the eluent (1 : 9) to afford the
pure 2H-indazoles.
Table 1 Optimization of reaction conditions for synthesis of 2H-indazolesa
Catalyst mole
Entry ratio (Cu : Al)
3. Results and discussion
Solvent
Temp. (1C) Yieldb (%)
1
2
3
4
5
6
7
8
CuII–HT (1 : 1)
CuII–HT (4 : 1)
CuII–HT (2 : 1)
DMSO
DMSO
DMSO
120
120
120
120
120
120
120
65
40
80
120
65
120
110
80
45
82
62
76
91
From an ecological perspective, the MCRs arose as powerful
strategies that allow multiple bond formation events taking
place in a single vessel, and exhibit economy of steps and often
atom economy, selectivity and low levels of by-product genera-
tion.26 Heterocyclic frameworks were well constructed by using
these MCRs from readily available starting materials. Interest-
ingly, the CuII–HTs exhibited good catalytic activity for various
organic transformation reactions.27 Very recently, we have also
reported the one-pot MCR for the synthesis of b-hydroxy
1,4-disubstituted 1,2,3-triazoles by using the CuII–HT hetero-
geneous catalyst.28 Herein, we report an MCR of 2-bromo-
benzaldehydes, primary amines and sodium azide with catalytic
amounts of CuII–HT to produce 2H-indazoles through con-
secutive condensation, C–N and N–N bond formations
(Scheme 1). In this the C–N and N–N bond formation is the
crucial step for heterocyclization to deliver the 2H-indazole
scaffold.
CuII–HT (2.5 : 1) DMSO
CuII–HT (3 : 1)
—
DMSO
DMSO
DMF
c
—
78
72
15
68
42
64
CuII–HT (3 : 1)
CuII–HT (3 : 1)
CuII–HT (3 : 1)
CuII–HT (3 : 1)
CuII–HT (3 : 1)
CuII–HT (3 : 1)
CuII–HT (3 : 1)
CuII–HT (3 : 1)
CuII–HT (3 : 1)
CuII–HT (3 : 1)
Methanol
Dichloromethane
Acetonitrile
o-Xylene
Tetrahydrofuran
—
Toluene
Benzene
Water
9
10
11
12
13
14
15
16
d
—
58
28
71
100
a
Reagents and reaction conditions: 2-bromobenzaldehyde (1.5 mmol),
aniline (1.8 mmol), sodium azide (2 mmol), catalyst (20 mg) and solvent
(1.5 mL); unless otherwise mentioned, stirred at 120 1C temperature for
6 h. Yields of isolated products. Catalyst-free condition, stirred at
120 1C temperature for more than 24 h. Solvent-free condition, stirred
b
c
d
at 120 1C temperature for more than 24 h.
c
This journal is The Royal Society of Chemistry 2013
Catal. Sci. Technol., 2013, 3, 654--658 655

View Article Online
Catalysis Science & Technology
Paper
Table 2 Synthesis of 2H-indazoles from diverse 2-bromobenzaldehydes, various
After identifying the most efficient catalyst (Table 1), we
further screened different solvents in order to enhance the
reaction rates. Among the various solvents we examined,
the reaction performed well in DMSO, which was found to be
the most appropriate solvent for synthesis of desired 2H-indazoles
with excellent yields (Table 1, entry 5). We have also observed
better results with various solvents namely, dimethylform-
amide (DMF), methanol (MeOH), acetonitrile, tetrahydrofuran
(THF) and water (Table 1, entries 7, 8, 10, 12 and 16).
Unexpectedly, much lower yields were observed with dichloro-
methane (Table 1, entry 9). Among different solvents that are
screened, nonpolar solvents (Table 1, entries 11, 12 and 15) are
found to be not suitable for the title reaction compared to polar
solvents, and the polar solvents resulted in good to excellent
yields of the desired products.
Having the optimized reaction conditions (catalyst, solvent,
temperature and additive-free) in hand, we extended the scope
of the reaction by using various 2-bromobenzaldehydes, struc-
turally diverse amines (aliphatic, aromatic and heteroaromatic)
and sodium azide as illustrated in Table 2. Furthermore,
reactions of most of the substrates with several aromatic
amines bearing electron neutral and -donating as well as
electron-withdrawing groups were performed smoothly and
the corresponding 2H-indazoles are attained in good to excellent
yields. Interestingly, good yields were observed with hetero-
aromatic amines such as 2-aminopyridine (Table 2, entry 2).
Fascinatingly, the reaction of 2-bromobenzaldehydes with steri-
cally hindered aliphatic amines such as 1-adamantyl amine
produced good yields (Table 2, entries 11 and 12). Remarkably,
the substituted 2-bromobenzaldehydes reacted with amines
(aliphatic and aromatic) resulting the corresponding 2H-indazoles
in moderate to good yields. However, these yields were slightly
lower than those attained from 2-bromobenzaldehyde.
We studied a wide range of amines having both electron-
donating and electron-withdrawing groups. In the case of
aromatic amines having a methoxy group at the para position,
there is insignificant effect and produced excellent yields, when
compared to the methoxy group at the ortho position (Table 2,
entries 6 and 10). This determines the ability of steric hindrance
of ortho substituents. Conversely, 3,4-dimethylaniline provided
better yields than p-toluidine (Table 2, entries 3 and 4). How-
ever, sterically hindered aromatic amines such as 4-bromo-2,6-
dimethylaniline produced corresponding 2H-indazole yields of
only 38% and 32% with 2-bromobenzaldehyde and 5-fluoro2-
bromobenzaldehyde, respectively (Table 2, entries 14 and 15).
Additionally, we carried out catalyst recycling experiments by
using 2-bromobenzaldehyde, aniline and sodium azide as the
model reaction. Interestingly, the used CuII–HT catalyst exhibited
the same activity and selectivity in terms of the desired product up
to three cycles since there is no metal leach.
primary amines and sodium azidea
Time Yieldb
Entry Aldehyde Amine
Product
(h)
(%)
1
6
91
2
3
4
5
7
7
82
86
79
38
8
10
6
8
11
10
9
86
72
78
81
70
87
78
86
7
8
9
10
11
12
13
10
8
11
10
14
15
16
38
20
24
32
0
On the basis of our investigation and earlier studies,20,25,28
the plausible mechanism is shown in Scheme 2. The one-pot
multicomponent coupling reaction involves first the formation
of the N-(2-bromobenzylidene)amine intermediate. In the next
stage, the bromide is replaced with azide in the presence of
the CuII–HT catalyst and results N-(2-azidobenzylidene)amine.
16
No product
a
Reagents and reaction conditions: 2-bromobenzaldehyde (1.5 mmol),
aniline (1.8 mmol), sodium azide (2 mmol), catalyst (20 mg) and solvent
(1.5 mL); unless otherwise mentioned, stirred at 120 1C temperature
b
for 6 h. Yields of isolated products.
c
656 Catal. Sci. Technol., 2013, 3, 654--658
This journal is The Royal Society of Chemistry 2013

View Article Online
Paper
Catalysis Science & Technology
3 Y. Ykeda, N. Takano, H. Matsushita, Y. Shiraki, T. Koide,
R. Nagashima, Y. Fujimura, M. Shindo, S. Suzuki and
T. Iwasaki, Arzneim. Forsch., 1979, 29, 511–520.
4 (a) G. A. Bistochi, G. De Meo, M. Pedini, A. Ricci,
H. Brouilhet, S. Bucherie, M. Rabaud and P. Jacquignon,
Farmaco, Ed. Sci., 1981, 36, 315–333; (b) G. Picciola,
F. Ravenna, G. Carenini, P. Gentili and M. Riva, Farmaco,
Ed. Sci., 1981, 36, 1037–1056.
5 B. K. Keppler and M. Hartmann, Met.-Based Drugs, 1994,
1(2–3), 145–149.
6 (a) J.-H. Sun, C. A. Teleha, J.-S. Yan, J. D. Rodgers and
D. A. Nugiel, J. Org. Chem., 1997, 62, 5627–5629; (b) J. D.
Rodgers, B. L. Johnson, H. Wang, R. A. Greenberg,
S. Erickson-Viitanen, R. M. Klabe, B. C. Cordova, M. M.
Rayner, G. N. Lam and C.-H. Chang, Bioorg. Med. Chem.
Lett., 1996, 6, 2919–2924.
7 G. Corsi, G. Palazzo, C. Germani, P. S. Barcellona and
B. Silvestrini, J. Med. Chem., 1976, 19, 778–783.
Scheme 2 A plausible reaction mechanism for 2H-indazoles formation with the
CuII–HT catalyst.
8 C. Wu, Y. Fang, R. C. Larock and F. Shi, Org. Lett., 2010, 12,
2234–2237.
9 P. G. Wyatt, A. L Gill, G. Saxty and R. Apaya, WO
2005014554, 2005.
10 J. Arnold, D. R. Artis, C. Hurt, P. N. Ibrahim, H. Krupka,
J. Lin, M. V. Milburn, W. Wang and C. Zhang, WO
2005009958, 2005.
In the resulting intermediate, the azide is activated by the
CuII–HT catalyst and the desired 2H-indazole product is formed
through intramolecular cyclization with N–N bond formation
by simultaneous attack of the activated azide by the N-atom of
benzylideneamine.
11 M. H. Chen, J. B. Doherty, L. Liu, S. Natarajan and
R. M. Tynebor, WO 2005026128, 2005.
4. Conclusions
12 H.-C. Zhang, C. K. Derian, D. F. McComsey, K. B. White,
H. Ye, L. R. Hecker, J. Li, M. F. Addo, D. Croll, A. J. Eckardt,
C. E. Smith, Q. Li, W.-M. Cheung, B. R. Conway, S. Emanuel,
K. T. Demarest, P. Andrade-Gordon, B. P. Damiano and
B. E. Maryanoff, J. Med. Chem., 2005, 48, 1725–1728.
13 S. Andreonati, V. Sava, S. Makan and G. Kolodeev, Pharmazie,
1999, 54, 99–101.
14 M. D. Angelis, F. Stossi, K. A. Carlson, B. S. Katzenellenbogen
and J. A. Katzenellenbogen, J. Med. Chem., 2005, 48, 1132–1144.
15 X. Li, S. Chu, V. A. Feher, M. Khalili, Z. Nie, S. Margosiak,
V. Nikulin, J. Levin, K. G. Sprankle, M. E. Tedder, R. Almassy,
K. Appelt and K. M. Yager, J. Med. Chem., 2003, 46, 5663–5673.
16 H.-J. Boehm, M. Boehringer, D. Bur, H. Gmuender,
W. Huber, W. Klaus, D. Kostrewa, H. Kuehne,
T. Luebbers, N. Meunier-Keller and F. Mueller, J. Med.
Chem., 2000, 43, 2664–2674.
17 (a) P. Lopez-Alvarado, C. Avendano and J. C. Menendez,
J. Org. Chem., 1995, 60, 5678–5682; (b) P. Y. S. Lam, C. G.
Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T. Chan and
A. Combs, Tetrahedron Lett., 1998, 39, 2941–2944; (c) A. Y.
Fedorov and J.-P. Finet, Tetrahedron Lett., 1999, 40,
2747–2748; (d) R. M. Claramunt, J. Elguero and R. Garceran,
Heterocycles, 1985, 23, 2895–2906; (e) For one successful
example, see: D. J. Slade, N. F. Pelz, W. Bodnar, J. W. Lampe
and P. S. Watson, J. Org. Chem., 2009, 74, 6331–6334.
In conclusion, we report for the first time, to the best of our
knowledge, that CuII–HT is an efficient heterogeneous catalyst
for the synthesis of 2H-indazoles. We have developed a novel,
simple and proficient protocol for three component (2-bromo-
benzaldehydes, primary amines and sodium azide) consecutive
condensation, C–N and N–N bond formations as a one-pot
MCR. Additionally, the CuII–HT catalyst can be readily recovered
and reused for at least three runs without any significant loss of
activity. It has the potential for large scale applications also.
Acknowledgements
ANP and RS thank Council of Scientific and Industrial Research
(CSIR), New Delhi, for Senior Research Fellowships. The
authors thank the Department of Science and Technology
(DST), New Delhi, Govt. of India (SERC Scheme: SR/S1/PC-63/
2008), for financial support of this work.
Notes and references
1 (a) A. Schmidt, A. Beutler and B. Snovydovych, Eur. J. Org.
Chem., 2008, 4073–4095; (b) L. A. Clutterbuck, C. G. Posada,
C. Visintin, D. R. Riddal, B. Lancaster, P. J. Gane,
J. Garthwaite and D. L. Selwood, J. Med. Chem., 2009, 52,
2694–2707.
´
18 N. Halland, M. Nazare, O. R’kyek, J. Alonso, M. Urmann and
A. Lindenschmidt, Angew. Chem., Int. Ed., 2009, 48,
6879–6882.
19 J. J. Song and N. K. Yee, Org. Lett., 2000, 2, 519–521.
2 J. Elguero, in Comprehensive Heterocyclic Chemistry, ed.
A. R. Katritzky and C. W. Rees, Pergamon Press, New York,
1984, vol. 5, p. 167.
c
This journal is The Royal Society of Chemistry 2013
Catal. Sci. Technol., 2013, 3, 654--658 657

View Article Online
Catalysis Science & Technology
Paper
20 B. J. Stokes, C. V. Vogel, L. K. Urnezis, M. Pan and 26 (a) B. M. Reddy and M. K. Patil, Chem. Rev., 2009, 109,
T. G. Driver, Org. Lett., 2010, 12, 2884–2887.
21 B. Haag, Z. Peng and P. Knochel, Org. Lett., 2009, 11,
4270–4273.
22 A. Taher, S. Ladwa, S. T. Rajan and G. W. Weaver, Tetra-
hedron Lett., 2000, 41, 9893–9897.
23 K. Y. Lee, S. Gowrisankar and J. N. Kim, Tetrahedron Lett.,
2005, 46, 5387–5391.
24 Y. Fang, C. Wu, R. C. Larock and F. Shi, J. Org. Chem., 2011,
76, 8840–8851.
2185–2208; (b) M. K. Patil, A. N. Prasad and B. M. Reddy,
Curr. Org. Chem., 2011, 15, 3961–3985; (c) B. Thirupathi,
R. Srinivas, A. N. Prasad, J. K. P. Kumar and B. M. Reddy,
Org. Process Res. Dev., 2010, 14, 1457–1463.
27 (a) M. L. Kantam, S. Laha, J. Yadav, P. R. Likhar,
B. Sreedhar, S. Jha, S. Bhargava, M. Udayakiran and
B. Jagadeesh, Org. Lett., 2008, 10, 2979–2982;
(b) K. Namitharan, M. Kumarraja and K. Pitchumani,
Chem.–Eur. J., 2009, 15, 2755–2758.
25 M. R. Kumar, A. Park, N. Park and S. Lee, Org. Lett., 2011, 13, 28 A. N. Prasad, B. Thirupathi, G. Raju, R. Srinivas and
3542–3545.
B. M. Reddy, Catal. Sci. Technol., 2012, 2, 1264–1268.
c
658 Catal. Sci. Technol., 2013, 3, 654--658
This journal is The Royal Society of Chemistry 2013