Ultrasound promoted mild and facile onepot, three component synthesis of 2Hindazoles by consecutive condensation, CN and NN bond formations catalysed by copperdoped silica cuprous sulphate (CDSCS) as an efficient heterogeneous nanocatalyst

Article abstract of DOI:10.1016/j.ultsonch.2016.07.026

An ultrasonic promoted facile and convenient one-pot three-component procedure for the synthesis of 2H-indazole derivatives using copper-doped silica cuprous sulphate (CDSCS) as a heterogeneous nano-catalyst has been described. In this approach, ultrasonic mediated reaction of different substituted 2-bromobenzaldehydes, structurally diverse primary amines, and tetrabutylammonium azide (TBAA) as an azide source in the presence of CDSCS in DMSO at room temperature furnishes 2H-indazoles in good to excellent yields. Utilizing ultrasonic irradiation techniques provided the dramatic improvements in terms of higher yields and shorter reaction times compared with conventional heating method.

Full text of DOI:10.1016/j.ultsonch.2016.07.026

Accepted Manuscript
Ultrasound promoted mild and facile one-pot, three component synthesis of
2H-indazoles by consecutive condensation, C-N and N-N bond formations cat-
alysed by copper-doped silica cuprous sulphate (CDSCS) as an efficient heter-
ogeneous nano-catalyst
Mohammad Navid Soltani Rad
PII:
S1350-4177(16)30267-X
DOI:
http://dx.doi.org/10.1016/j.ultsonch.2016.07.026
ULTSON 3324
Reference:
Ultrasonics Sonochemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 June 2016
13 July 2016
27 July 2016
Please cite this article as: M.N.S. Rad, Ultrasound promoted mild and facile one-pot, three component synthesis of
2H-indazoles by consecutive condensation, C-N and N-N bond formations catalysed by copper-doped silica cuprous
sulphate (CDSCS) as an efficient heterogeneous nano-catalyst, Ultrasonics Sonochemistry (2016), doi: http://
dx.doi.org/10.1016/j.ultsonch.2016.07.026
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Ultrasound promoted mild and facile one-pot, three component synthesis
of 2H-indazoles by consecutive condensation, C-N and N-N bond formations
catalysed by copper-doped silica cuprous sulphate (CDSCS) as an efficient
heterogeneous nano-catalyst
Mohammad Navid Soltani Rad
Medicinal Chemistry Research laboratory, Department of Chemistry, Shiraz University of
Technology, Shiraz 71555-313, Iran
Phone: +98-71-37261392; Fax: +98-71-37354523
E-mails: soltani@sutech.ac.ir; nsoltanirad@gmail.com
Abstract:
An ultrasonic promoted facile and convenient one-pot three-component procedure for the
synthesis of 2H-indazole derivatives using copper-doped silica cuprous sulphate (CDSCS) as a
heterogeneous nano-catalyst has been described. In this approach, ultrasonic mediated
reaction of different substituted 2-bromobenzaldehydes, structurally diverse primary amines,
and tetrabutylammonium azide (TBAA) as an azide source in the presence of CDSCS in DMSO
at room temperature furnishes 2H-indazoles in good to excellent yields. Utilizing ultrasonic
irradiation techniques provided the dramatic improvements in terms of higher yields and
shorter reaction times compared with conventional heating method.
Keywords: Ultrasound, One-pot three component, 2H-indazole, Heterogeneous nano-catalyst,
Tetrabutylammonium azide (TBAA)
1. Introduction
Now a day, it is well realized that indazole and its related derivatives display a broad variety
of biological activities. In this connection, the approved drugs such as lonidamine, bendacort,
bendazac, granisetron, benzydamine, APINACA, axitinib and gamendazole were known to
involve the indazole cores in their molecular scaffolds (Fig. 1) [1]. In addition to above
1

indazole-based approved drugs, other indazole derivatives were found to exhibit diverse
biological activities like anti-tumour [2], anti-HIV [3], anti-microbial [4], anti-depressant [5],
anti-platelet [6], neuroprotective sodium channel modulator [7], selective ligands for
imidazoline I2 [8], estrogen [9] and 5-HT1A [10] receptors. Moreover, in the field of modern
drug design and discovery, indazoles are known as useful bioisosters for indoles and
benzimidazoles [11]. Indazole derivatives are also utilised in many industries including as
optoelectronic chromophores used in fabrication of devices like OLEDs [12], dye-pigments
[13] and agricultural purposes [14].
Despite the unique and remarkable medicinal profile of indazoles; however, a few facile and
efficient approaches for the regioselective synthesis of N-substituted indazoles have been
developed so far [15]. Nevertheless, most established protocols were devoted to achieve
thermodynamically favoured 1H-indazole or complex mixture of 1H- and 2H-indazoles; whilst
the facile and regioselective synthesis of 2H-indazoles is still remaining challenge [16].
O
Cl
Me
N
O
Me
O
OH
Cl
O
O
HO
Me
N
Me
N
N
N
N
N
N
N
H
N
O
CO2H
CO2H
O
Bendazac
(anti-inflammatory)
Granisetron
(antiemetic)
Bendacort
(glucocorticoid)
Lonidamine
(antineoplastic)
O
OH
O
N
NH
N
NH
N
N
N
N
Cl
N
F3C
S
N
O
NMe2
Cl
MeHN
Axitinib
(tyrosine kinase inhibitor)
O
Gamendazole
(male contraception)
APINACA
(cannabinoid receptors agonist)
Benzydamine
(analgesic)
Fig.1. The structure of approved drugs having indazole cores and their corresponding pharmaceutical properties
To alleviate the problems associate with regioselectivity between 1H- vs 2H-indazoles, many
useful approaches have been emerged in literatures to provide definite regioselective
synthetic routes towards 2H-indazoles, comprising (i) base-catalysed reaction of 2-
nitrobenzyl triphenylphosphonium bromide with Ar-N=C=O [17], (ii) reductive N-cyclisation
of 2-nitroarylidine catalyzed by Rh complex [18], (iii) [3+2] sydnones and arynes
2

cycloaddition [19], (iv) Pd-catalysed reaction of 2-halophenylacetylene with hydrazine [20],
(v) Fe-catalysed N–N bond formation from ArN3 [21], (vi) DDQ–oxidised reaction of hydrazine
+
-
and Baylis–Hillman adducts [22] and (vii) reaction of organozinc reagent with ArN2 BF4 [23].
Despite the usefulness of the above protocols to access 2H-indazoles, however most of the
existing methods are accompanied with several drawbacks such as requirement of multistep
procedures for synthesis of starting materials, the use of precious metals or expensive ligands,
non-regioselectivity, low tolerance of functionalities, harsh reaction conditions and non-
recyclable catalysts.
In the last decade, the use of copper-based catalysts has extensively promoted the synthesis
of 2H-indazoles. Among the copper catalysed synthesis of 2H-indazoles, the approaches in
which generate 2-azidoimine have been privileged since utilizing the readily available starting
materials. In this regard, the intramolecular N-N coupling reaction of the in situ generated 2-
azidoimine through one-pot two-step process using CuO nanoparticles [24] or CuI-TMEDA
[25] were reported to acquire 2H-indazoles. Moreover, the one-pot three component
reactions (3CR) of 2-halobenzaldehydes, amines and sodium azide were established under
Cu-based catalysts involving CuI-TMEDA [26] Cu(II)-hydrotalcite [27] Cu-complexed
functionalised silica/starch composite [28] and nano-sized Cu2O [29]. Notwithstanding of
apparent profitableness of above protocols, however they still envisaged some disadvantages
such as long reaction times, almost the homogeneity of the catalysts in media (except that of
lit.[27, 28]), failure in recycling the catalyst and agglomeration of the nano-catalyst.
Undoubtedly, in recent years, the multi-component reactions (MCRs) have proved to be a
powerful tool in organic chemistry offers incredible features such as ability to assemble a
plenty of complex structures from simple and available starting materials, ease of
experimental procedures, quantitative yields, lower environmental costs and atom economy
[30].
3

Heterogeneous catalysts have received the particular attention owing to their remarkable
economic and environmental benefits. Exploiting the heterogeneous catalysts often provides
the simple experimental procedures, mild reaction conditions, recovery and reusability of the
catalyst, the minimization of undesirable chemical wastes, and the production of large
quantities of products by using a small amount of catalyst. Thus, the application of
heterogeneous catalysts has an exact superiority over homogeneous catalyst [31].
Ultrasound-assisted organic synthesis has proved as a clean and advantageous approach in
organic synthesis especially in the field of heterocyclic chemistry [32]. The ultrasonic effect
induces very high local pressure and temperatures inside the bubbles (acoustic cavitation
phenomenon) and enhances mass transfer and turbulent flow in the liquid [33]. This unique
property of ultrasonic decisively affects the chemical reactivity through dissipation of energy.
On the other hand, compared to conventional thermal heating, ultrasound irradiation has
some important advantages: ultrasonification largely enhances the reaction rate and reduces
the reaction times, improves yields, minimizes side product formation by providing the
activation energy in micro environment, easier manipulation, increased selectivity, using
small amounts of solvents, mild reaction condition and offers environmentally friendly and
sustainable synthetic processes [34].
Silica-based catalysts are extremely important type of catalysts possessing the numerous
advantages such as mild reaction conditions, cheapness, non-corrosive properties, high yields
and selectivity, ease of handling, reusability by a simple flash filtration and also ease of
preparation. Recently, we have reported the synthesis, characterization, and application of
copper-doped silica cuprous sulfate (CDSCS) as an efficient heterogeneous nano-catalyst for
various organic transformations [35-38]. In light of the unique biological activities of 2H-
indazoles and also in continuation of our ongoing research in utilizing CDSCS in organic
synthesis, hereby we would like to report an ultrasound promoted one pot, three component
synthesis of 2H-indazoles through consecutive condensation, C-N and N-N bond formations
4

catalysed by CDSCS (Scheme 1). To the best of our knowledge, this approach is the first
example of the synthesis of 2H-indazoles through a one-pot multicomponent coupling under
ultrasonic irradiation and the use of tetrabutylammonium azide (TBAA) [CAS NO: 993-22-6]
as an azide source.
CHO
Br
N3
CDSCS
R1
R1
N R2
R2
NH2
N
)))), DMSO, r.t.
N
1
2
3
(TBAA)
R1 = H, F,...
R2 = alkyl, aryl, ...
CDSCS:
SiO2
OSO3Cu
Scheme 1. Synthesis of 2H-indazoles using CDSCS as a catalyst under ultrasonic irradiation.
2. Experimental
2.1. General
High-purity chemicals were purchased from Merck, Fluka, and Sigma-Aldrich. The fresh
CDSCS was prepared due to our reported procedure [35]. Solvents were purified by using of
standard procedures. Reactions were followed by TLC using SILG/UV 254 silica-gel plates.
Column chromatography was performed on silica gel 60 (0.063-0.200 mm, 70-230 mesh;
ASTM). Melting points were measured using Electrothermal IA 9000 melting point apparatus
in open capillary tubes and are uncorrected. IR spectra were obtained using a Shimadzu FT-
IR-8300 spectrophotometer. Ultrasonication was performed using a horn sonicator, Misonix
model S-4000 (Qsonica LLC, Newtown, CT.) with a standard titanium tip diameters of ½”
1
working at 20 kHz that was immersed directly into the reaction mixture. H- and 13C-NMR
spectrum was recorded on Brüker Avance-DPX-250/400 spectrometer operating at 250/62.5
MHz, respectively. Chemical shifts are given in δ relative to tetramethylsilane (TMS) as an
internal standard, coupling constants J are given in Hz. Abbreviations used for 1H NMR signals
are: s = singlet, d = doublet, t = triplet, m = multiplet. GC/MS was performed on a Shimadzu
5

GC/MS-QP 1000-EX apparatus (m/z; rel.%). Elemental analyses were performed on a Perkin–
Elmer 240-B micro-analyzer.
2.2. Ultrasound promoted synthesis of 2H-indazole derivatives; General Procedure. In
an open-capped cylindrical pyrex-glass (50 mL), was added a mixture of an appropriate 2-
bromobenzaldehyde (10 mmol), proper primary amine (12 mmol), TBAA (15 mmol), and
CDSCS (0.3 g, 0.05 mol%) in DMSO (10 mL) and the mixture was kept at room temperature
and irradiated at 60W power (cup horn: 20 kHz) in ultrasonic apparatus. The progress of the
reaction was monitored by TLC. After completion of the reaction (Table 5), then the reaction
mixture was filtered to separate the catalyst and catalyst was washed with EtOAc (3 × 50 mL).
The filtrate was then mixed with water (100 mL). The separated organic layer was washed
with water (2 × 100 mL). Afterward, the organic layer was dried over anhydrous Na2SO4 and
evaporated. The crude product was then purified by column chromatography on silica gel
eluting with a mixture of n-hexane/EtOAc.
2.2.1. 2-Phenyl-2H-indazole (3a) [24]. White solid; yield: 1.79 g (92%); mp 81–82 °C; IR
1
(KBr): 3100, 2945, 1652, 1567, 1470 cm–1; H NMR (250 MHz, CDCl3): δ = 7.16 (t, 1H, J = 7.8
Hz), 7.39 (t, 1H, J = 7.8 Hz), 7.48- 7.51 (m, 3H), 7.73 (d, 1H, J = 8.5 Hz), 7.81-7.86 (m, 2H), 7.97
(d, 1H, J = 8.5 Hz), 8.46 (s, 1H); 13C NMR (250 MHz, CDCl3): δ = 118.78, 120.84, 121.07, 121.79,
122.90, 123.34, 127.41, 128.77, 130.12, 141.86, 150.26; MS (EI): m/z (%) = 194 (15.7) [M+];
Anal. Calcd for C13H10N2: C, 80.39; H, 5.19; N, 14.42. Found: C, 80.30; H, 5.12; N, 14.49.
2.2.2. 2-p-Tolyl-2H-indazole (3b) [24]. Yellow solid; yield: 1.87 g (90%); mp 101–102 °C; IR
(KBr): 3065, 2958, 1633, 1538, 1447 cm–1; 1H NMR (250 MHz, CDCl3): δ = 2.26 (s, 3H), 7.11 (t,
1H, J = 7.5 Hz), 7.19 (t, 1H, J = 7.5 Hz), 7.29 (d, 2H, J = 8.6 Hz), 7.59 (d, 1H, J = 8.3 Hz), 7.80-7.89
(m, 3H), 8.49 (s, 1H); 13C NMR (250 MHz, CDCl3): δ = 22.60, 118.24, 120.93, 121.49, 122.71,
123.07, 126.82, 127.18, 131.36, 138.76, 139.50, 150.01; MS (EI): m/z (%) = 208 (16.5) [M+];
Anal. Calcd for C14H12N2: C, 80.74; H, 5.81; N, 13.45. Found: C, 80.83; H, 5.92; N, 13.59.
2.2.3. 2-(4-Methoxyphenyl)-2H-indazole (3c) [24]. Brown solid; yield: 2.04 g (91%); mp 132–
1
133 °C; IR (KBr): 3045, 2961, 1629, 1560, 1453, 1187 cm–1; H NMR (250 MHz, CDCl3): δ =
3.57 (s, 3H), 6.91 (d, 2H, J = 8.2 Hz), 7.15-7.22 (m, 2H), 7.42-7.48 (m, 2H), 7.89 (d, 2H, J = 8.2
Hz), 8.37 (s, 1H); 13C NMR (250 MHz, CDCl3): δ = 53.97, 115.72, 118.07, 120.75, 121.08,
6

122.45, 122.86, 123.16, 127.23, 134.91, 150.12, 159.90; MS (EI): m/z (%) = 224 (14.2) [M+];
Anal. Calcd for C14H12N2O: C, 74.98; H, 5.39; N, 12.49. Found: C, 75.06; H, 5.31; N, 12.59.
2.2.4. 2-Mesityl-2H-indazole (3d) [26]. Pale-yellow oil; yield: 1.49 g (63%); IR (film): 3050,
2974, 1622, 1567, 1468 cm–1; 1H NMR (250 MHz, CDCl3): δ = 1.90 (s, 6H), 2.38 (s, 3H), 6.87 (s,
2H), 7.18-7.29 (m, 2H), 7.78-7.85 (m, 2H), 7.91 (s, 1H); 13C NMR (250 MHz, CDCl3): δ = 17.85,
22.16, 118.09, 120.98, 122.52, 122.76, 125.11, 126.68, 129.47, 135.81, 137.90, 139.73, 150.03;
MS (EI): m/z (%) = 236 (18.7) [M+]; Anal. Calcd for C16H16N2: C, 81.32; H, 6.82; N, 11.85.
Found: C, 81.47; H, 6.91; N, 11.98.
2.2.5. 2-(Naphthalen-1-yl)-2H-indazole (3e) [24]. White foam; yield: 2.10 g (86%); IR (KBr):
3100, 2956, 1635, 1582, 1469 cm–1; 1H NMR (250 MHz, CDCl3): δ = 7.21 (t, 1H, J = 7.9 Hz), 7.44
(t, 1H, J = 7.9 Hz), 7.54-7.62 (m, 5H), 7.71-7.75 (m, 2H), 7.86 (d, 1H, J = 8.1 Hz), 7.97 (d, 1H, J =
8.1 Hz), 8.32 (s, 1H); 13C NMR (250 MHz, CDCl3): δ = 118.37, 120.59, 122.71, 122.96, 123.58,
124.77, 125.39, 126.02, 126.90, 127.15, 127.74, 128.81, 129.70, 130.22, 135.07, 138.12,
149.93; MS (EI): m/z (%) = 244 (21.4) [M+]; Anal. Calcd for C17H12N2: C, 83.58; H, 4.95; N,
11.47. Found: C, 83.50; H, 5.06; N, 11.51.
2.2.6. Ethyl 4-(2H-indazol-2-yl)benzoate (3f) [26]. Pale-yellow solid; yield: 2.10 g (79%); mp
120–121 °C; IR (KBr): 3037, 2964, 1730, 1610, 1542, 1458 cm–1; 1H NMR (250 MHz, CDCl3): δ
= 1.60 (t, 3H, J = 7.0 Hz), 4.57 (q, 2H, J = 7.0 Hz), 7.15 (t, J = 8.1 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H),
7.78-7.86 (m, 2H), 7.94-8.05 (m, 2H), 8.14 (d, 2H, J = 8.2 Hz), 8.38 (s, 1H); 13C NMR (250 MHz,
CDCl3): δ = 15.12, 60.27, 118.54, 120.03, 120.76, 121.29, 123.40, 126.61, 127.90, 129.52,
131.82, 144.10, 151.07, 166.75; MS (EI): m/z (%) = 266 (19.4) [M+]; Anal. Calcd for
C16H14N2O2: C, 72.16; H, 5.30; N, 10.52. Found: C, 72.05; H, 5.18; N, 10.65.
2.2.7. 2-(Pyridin-2-yl)-2H-indazole (3g) [24]. Yellow solid; yield: 1.82 g (93%); mp 105–106
°C; IR (KBr): 3047, 2959, 1598, 1513, 1436 cm–1; 1H NMR (250 MHz, CDCl3): δ = 7.15 (t, 1H, J =
7.5 Hz), 7.30-7.38 (m, 2H), 7.70 (t, 1H, J = 7.5 Hz), 7.86-7.90 (m, 2H), 7.96 (d, 1H, J = 8.0 Hz),
8.07 (d, 1H, J = 8.0 Hz), 8.51 (s, 1H); 13C NMR (250 MHz, CDCl3): δ = 114.35, 118.54, 120.91,
121.40, 122.39, 122.94, 123.88, 127.80, 138.42, 148.71, 150.67, 151.74; MS (EI): m/z (%) =
195 (13.7) [M+]; Anal. Calcd for C12H9N3: C, 73.83; H, 4.65; N, 21.52. Found: C, 73.95; H, 4.70; N,
21.60.
2.2.8. 2-(3,5-Dichlorophenyl)-2H-indazole (3h). Yellow solid; yield: 2.16 g (82%); mp 122–
1
123 °C; IR (KBr): 3051, 2960, 1638, 1527, 1472, 1094 cm–1; H NMR (250 MHz, CDCl3): δ =
7.10-7.18 (m, 2H), 7.33-7.42 (m, 3H), 7.59 (d, 1H, J = 8.4 Hz), 7.87 (d, 1H, J = 8.4 Hz), 8.41 (s,
7

1H); 13C NMR (250 MHz, CDCl3): δ = 116.28, 118.96, 120.30, 120.74, 122.70, 123.85, 127.33,
128.14, 136.23, 142.01, 149.93; MS (EI): m/z (%) = 262 (35.9) [M+]; Anal. Calcd for
C13H8Cl2N2: C, 59.34; H, 3.06; N, 10.65. Found: C, 59.45; H, 2.94; N, 10.72.
2.2.9. 2,2'-(4,4'-Oxybis(4,1-phenylene))bis(2H-indazole) (3i). White solid; yield: 3.62 g (90%);
1
mp 246–247 °C; IR (KBr): 3080, 2977, 1636, 1520, 1458, 1227 cm–1; H NMR (250 MHz,
DMSO-d6): δ = 6.90-7.01 (m, 4H), 7.15 (t, 2H, J = 7.8 Hz), 7.38 (t, 2H, J = 7.8 Hz), 7.63-7.74 (m,
6H), 7.80 (d, 2H, J = 8.1 Hz), 8.52 (s, 2H); 13C NMR (250 MHz, DMSO-d6): δ = 116.12, 118.60,
120.89, 121.47, 122.37, 122.91, 123.20, 126.79, 136.04, 147.33, 151.61; MS (EI): m/z (%) =
402 (31.6) [M+]; Anal. Calcd for C26H18N4O: C, 77.59; H, 4.51; N, 13.92. Found: C, 77.71; H, 4.58;
N, 13.84.
2.2.10. 2-Butyl-2H-indazole (3j) [24]. Colorless oil; yield: 1.06 g (61%); IR (film): 3049, 2967,
2837, 1624, 1524, 1469 cm–1; 1H NMR (250 MHz, CDCl3): δ = 0.87 (t, 3H, J = 7.0 Hz), 1.42-1.49
(m, 2H), 1.87-1.93 (m, 2H), 4.18 (t, 2H, J = 7.0 Hz), 7.10 (t, 1H, J = 7.6 Hz), 7.38 (t, 1H, J = 7.6
Hz), 7.68 (d, 1H, J = 8.3 Hz), 7.85 (d, 1H, J = 8.3 Hz), 8.04 (s, 1H); 13C NMR (250 MHz, CDCl3): δ
= 12.96, 20.66, 33.05, 53.78, 117.91, 120.47, 121.82, 122.17, 123.04, 127.31, 149.80; MS (EI):
m/z (%) = 174 (14.8) [M+]; Anal. Calcd for C11H14N2: C, 75.82; H, 8.10; N, 16.08. Found: C,
75.71; H, 8.18; N, 16.15.
2.2.11. 2-(3-Phenylpropyl)-2H-[1,3]dioxolo[4,5-f]indazole (3k) [26]. Pale-yellow solid; yield:
1
2.38 g (85%); mp 117–118 °C; IR (KBr): 3046, 2973, 1625, 1539, 1446, 1230 cm–1; H NMR
(250 MHz, CDCl3): δ = 2.41-2.47 (m, 2H), 2.70 (t, 2H, J = 7.4 Hz), 4.23 (t, 2H, J = 7.4 Hz), 5.68 (s,
2H), 6.90-7.01 (m, 2H), 7.12 (s, 1H), 7.23-7.41 (m, 4H), 8.01 (s, 1H); 13C NMR (250 MHz,
CDCl3): δ = 30.18, 32.95, 53.27, 95.01, 106.34, 111.49, 117.87, 122.44, 126.70, 128.05, 128.91,
141.20, 145.86, 146.79, 150.06; MS (EI): m/z (%) = 280 (20.3) [M+]; Anal. Calcd for
C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.97; H, 5.89; N, 10.11.
2.2.12. 2-(4-Ethylphenyl)-2H-[1,3]dioxolo[4,5-f]indazole (3l) [26]. Pale-yellow solid; yield: 2.34
1
g (88%); mp 161–162 °C; IR (KBr): 3050, 2982, 1614, 1536, 1461, 1223 cm–1; H NMR (250
MHz, CDCl3): δ = 1.34 (t, 3H, J = 7.3 Hz), 2.62 (q, 2H, J = 7.3 Hz), 5.73 (s, 2H), 7.13 (s, 1H), 7.24
(s, 1H), 7.36-7.43 (m, 2H), 7.80 (d, 2H, J = 8.5 Hz), 8.12 (s, 1H); 13C NMR (250 MHz, CDCl3): δ =
16.14, 28.87, 97.05, 107.66, 111.50, 118.81, 120.01, 120.74, 129.37, 138.49, 143.76, 146.90,
147.72, 150.19; MS (EI): m/z (%) = 266 (18.9) [M+]; Anal. Calcd for C16H14N2O2: C, 72.16; H,
5.30; N, 10.52. Found: C, 72.30; H, 5.41; N, 10.62.
8

2.2.13. 5-Fluoro-2-phenyl-2H-indazole (3m) [24]. Yellow solid; yield: 1.91 g (90%); mp 135–
1
136 °C; IR (KBr): 3029, 2960, 1681, 1547, 1453, 1279 cm–1; H NMR (250 MHz, CDCl3): δ =
7.20 (d, 1H, J = 7.8 Hz), 7.41 (d, 1H, J = 7.8 Hz), 7.63-7.68 (m, 3H), 7.84-7.90 (m, 3H), 8.27 (s,
1H); 13C NMR (250 MHz, CDCl3): δ = 104.58, 118.15, 120.32, 120.81, 121.98, 123.01, 128.30,
129.76, 140.79, 148.10, 158.47; MS (EI): m/z (%) = 212 (13.6) [M+]; Anal. Calcd for C13H9FN2:
C, 73.57; H, 4.27; N, 13.20. Found: C, 73.49; H, 4.34; N, 13.31.
2.2.14. 2-(3,4-Dimethylphenyl)-5-fluoro-2H-indazole (3n) [24]. Yellow solid; yield: 1.99 g
1
(83%); mp 106–107 °C; IR (KBr): 3042, 2960, 1618, 1535, 1465, 1203 cm–1; H NMR (250
MHz, CDCl3): δ = 2.45 (s, 3H), 2.50 (s, 3H), 6.95-7.04 (m, 2H), 7.37-7.43 (m, 2H), 7.60 (d, 1H, J =
7.9 Hz), 7.79 (s, 1H), 8.16 (s, 1H); 13C NMR (250 MHz, CDCl3): δ = 20.23, 20.79, 104.06, 118.49,
119.01, 120.17, 120.94, 121.88, 122.58, 130.70, 137.12, 138.25, 138.71, 147.34, 158.10; MS
(EI): m/z (%) = 240 (19.3) [M+]; Anal. Calcd for C15H13FN2: C, 74.98; H, 5.45; N, 11.66. Found:
C, 75.10; H, 5.54; N, 11.74.
2.2.15. Ethyl 4-(5-fluoro-2H-indazol-2-yl)benzoate (3o) [26]. Pale-yellow solid; yield: 2.27 g
1
(80%); mp 118–119 °C; IR (KBr): 3039, 2954, 1726, 1621, 1547, 1430, 1198 cm–1; H NMR
(250 MHz, CDCl3): δ = 1.56 (t, 3H, J = 7.4 Hz), 4.51 (q, 2H, J = 7.4 Hz), 7.16-7.31 (m, 3H), 7.52-
7.69 (m, 2H), 8.02 (d, 2H, J = 8.2 Hz), 8.26 (s, 1H); 13C NMR (250 MHz, CDCl3): δ = 14.95, 61.74,
103.6, 119.54, 120.08, 120.62, 120.97, 122.71, 130.23, 131.55, 143.70, 147.82, 158.29, 167.31;
MS (EI): m/z (%) = 284 (14.4) [M+]; Anal. Calcd for C16H13FN2O2: C, 67.60; H, 4.61; N, 9.85.
Found: C, 67.75; H, 4.48; N, 9.96.
3. Results and discussion
To optimize the reaction conditions, we examined the 3CR of 2-bromobenzaldehyde, aniline,
and TBAA in the presence of catalytic amount of CDSCS as a sample reaction. In view of the
immense importance of the solvent role in reaction progress, we first focused our attention on
the choice of an appropriate solvent. For this purpose, we investigated the influence of various
traditional solvents normally used in organic reactions (Table 1)
As can be seen from Table 1, the impact of several solvents involving polar protic, polar
aprotic, nonpolar and a room temperature ionic liquid was assessed for preparation of 2-
phenyl-2H-indazole (3a). Among the evaluated solvents, the use of DMSO gained the best
result in terms of reaction time and yield, therefore this solvent was utilised for all next
studied reactions (Table 1, entry 1). In addition, DMF, MeCN, THF and NMP also acquired good
yields of 3a (Table 1, entries 2-5). Whereas, nonpolar solvents such as toluene and p-xylene
9

(Table 1, entries 6 and 7) resulted the low yields of 3a. Moreover, protic solvents like water,
ethanol and PEG 400 afforded the moderate yields of the corresponding 2H-indazole.
Surprisingly, [bmim]Br as a room temperature ionic liquid failed to yield the product after
irradiation for 4h (Table 1, entry 11). In general, polar aprotic solvents achieve better yields of
2H-indazoles.
Table 1
Effect of solvents in synthesis of 2-phenyl-2H-indazole. a
CHO
CDSCS
TBAA
N
H2N
)))) (60W), solvent, r.t.
N
Br
3a
Entry
1
2
3
4
5
6
7
8
Solvent
DMSO
DMF
MeCN
THF
Time (h)
Yield b (%)
1
1.5
2.5
2
1.5
5
5
2.5
3
92
80
75
66
78
27
30
54
48
50
NRc
NMP
Toluene
p-Xylene
EtOH
H2O
PEG 400
9
10
11
3.5
4
[bmim]Br
a Reaction conditions: 2-bromobenzaldehyde (10 mmol), aniline (12 mmol), TBAA
(15 mmol), CDSCS (0.3 g), and solvent (10 mL).
b Isolated yield.
c No reaction.
After identifying the proper solvent and the persistence of finding the other optimal
conditions, the influence of ultrasound power intensity on the sample reaction was screened.
In this regard, the sample reaction was carried out at different irradiation powers in the range
of 20 to 80 W (Table 2).
As shown in Table 2, without exposing the reaction to ultrasound irradiation, the reaction
was not achieved at all even after stirring for 48h at room temperature (Table 2, entry 1).
However, as expected, the increase of ultrasonic power led to relatively higher yields of 3a in
shorter reaction time. The maximum yield of 3a was obtained when the power was set to 60
W for an hour. The increased yield associated with increasing irradiation power, is attributed
to abundance of active cavitation bubbles which result in higher maximum collapse
temperature and accelerated the respective reaction. Moreover, by increasing the ultrasonic
power (>70W) no apparent improvement was observed.
10

Table 2
The influence of ultrasonic irradiation on the synthesis of 2-phenyl-2H-indazole. a
CHO
CDSCS
TBAA
N
H2N
)))) (power), DMSO, r.t.
N
Br
3a
Entry
1
2
3
4
5
6
7
Power (W)
Time (h)
Yield b (%)
0
48
7
5
3
2
1
1
1
NRc
44
50
66
78
92
91
91
20
30
40
50
60
70
80
11
a Reaction conditions: 2-bromobenzaldehyde (10 mmol), aniline (12 mmol), TBAA
(15 mmol), CDSCS (0.3 g), and DMSO (10 mL).
b Isolated yield.
c No reaction.
In another study, we investigated the relation between loading amounts of catalyst and
reaction progress (Table 3). As shown in Table 3, the catalyst has undeniable role in reaction
advancement, thus, in the absence of an active catalyst the reaction was failed to achieved at
all (Table 3, entry 1). By increasing the loading catalyst amount, the reaction yields were
gradually increased. An impressive activity of catalyst and the maximum yield of desired 3a
were observed when the loading catalyst amount was reached to 0.05 mol% (Table 3, entry
6). Practically, the yield remained unchanged when the used catalyst amount exceeded more
than 0.05 mol% (Table 3, entries 7 and 8).
Table 3
Effect of catalyst loading in synthesis of 2-phenyl-2H-indazole. a
CHO
CDSCS (xmol%)
TBAA
N
H2N
)))) (60W), DMSO, r.t.
N
Br
3a
Entry
CDSCS (mol%)
Time (h)
Yield b (%)
1
2
3
4
5
6
7
8
0
8
4
3
2.5
2
1
1
1
NR c
52
58
63
76
92
92
90
0.01
0.02
0.03
0.04
0.05
0.06
0.07
a Reaction conditions: 2-bromobenzaldehyde (10 mmol), aniline (12 mmol), TBAA
(15 mmol), catalyst (xmol%), and DMSO (10 mL).
b Isolated yield.
c No reaction.
11

Table 4
Effect of catalyst type in synthesis of 2-phenyl-2H-indazole. a
CHO
Catalyst
TBAA
N
H2N
)))) (60W), DMSO, r.t.
N
Br
3a
Entry
catalyst
CuCl2
CuO
Cu2O
Cu(OAc)2
CuI
CuI-TMEDA C
CDSCS
CuSO4.5H2O
Time (h)
Yield b (%)
1
2
3
4
5
6
7
8
4
3
3
2.5
2
1
1
4
56
60
64
60
72
80
92
54
a Reaction conditions: 2-bromobenzaldehyde (10 mmol), aniline (12 mmol), TBAA
(15 mmol), catalyst, and DMSO (10 mL).
b Isolated yield.
c N,N,N’,N’-tetramethylethylenediamine.
In order to ascertain the catalytic potency of CDSCS in synthesis 2H-indazole under
ultrasonic irradiation, we assayed the model reaction using other used copper catalysts under
the optimized condition (Table 4). As depicted in Table 4, a higher yield of 3a was obtained
when CDSCS was employed (Table 4, entry 7). In addition to CDSCS, the combination of CuI-
TMEDA [26] afforded a good yield of 3a. Using the other catalysts, the satisfactory yields of
the corresponding product were afforded, however the reactions required longer reaction
time for completion. In general, it seems that Cu(I)-catalysts demonstrate better catalytic
activity compared with Cu(II)-catalysts in 2H-indazole synthesis under ultrasonic irradiation.
With the optimal reaction conditions in hand, we screened the versatility and the scope of
this protocol to other 2-bromobenzaldehyde and primary amine derivatives (Table 5). We
have also undertaken the synthesis of 2H-indazoles utilising CDSCS as a catalyst under
conventional heating protocol (DMSO at 120° C) and compared the results with ultrasonic
mediated protocols. As illustrated in Table 5, the dramatic improvements in terms of higher
yields and shorter reaction times were observed compared with conventional heating
method.
12

Table 5
The synthesized 2H-indazoles using CDSCS under ultrasonic irradiation. a
b
Entry
Product a
Sonication
Conventional c
Product
No.
Time
(h)
Yield d
(%)
Time
(h)
Yield d
(%)
1
2
3
4
3a
3b
3c
3d
1.0
92
90
91
63
12
8
85
N
N
N
1.0
79
Me
N
N
0.75
1.5
5
80
N
OMe
Me
10
51
N
Me
N
Me
5
3e
1.0
86
7
64
N
N
6
7
8
3f
1.5
1.5
1.5
79
93
82
9
58
81
75
N
N
CO2Et
N
3g
3h
N
7
N
Cl
Cl
10
N
N
9
3i
2.0
90
61
85
88
90
83
11
12
8
82
60
80
76
78
74
N
N
N
N
O
10
11
12
13
14
3j
1.5
N
N
O
3k
3l
0.75
1.0
N
O
O
N
10
6
N
O
N
F
3m
3n
0.75
0.5
N
N
Me
6
F
N
Me
N
F
15
3o
1.0
87
7
80
N
N
CO2Et
a All products were characterized by 1H and 13C NMR, IR, CHN, and MS analysis.
b
Reaction conditions: 2-bromobenzaldehydes (10 mmol), amines (12 mmol), TBAA (15 mmol), CDSCS
(0.3 g), DMSO (10 mL), power (60 W), room temperature.
c Reaction conditions: 2-bromobenzaldehydes (10 mmol), amines (12 mmol), TBAA (15 mmol), CDSCS (0.3
g), DMSO (10 mL), heat (120 °C).
d Isolated yield.
Using ultrasonic technique, in most cases, the reaction times shortened to around an hour or
less and yields almost enhanced to excellent or quantitative amounts. Therefore, the results in
13

Table 5 confirm the advantage of ultrasonic method over conventional thermal method. This
ultrasonic promoted protocol works well with structurally diverse aliphatic, aromatic, and
heteroaromatic amines and tolerates different functional groups to afford the corresponding
2H-indazoles in good to excellent yields. The aromatic amines bearing electron-rich
substituents were efficiently applied in the current protocol (Table 5, entries 2-4, 12 and 14).
In addition, the sterically hindered amines like 2,4,6-trimethylbenzenamine was also
successfully converted to the corresponding 2H-indazole in 63% yield (Table 5, entry 4).
Heteroaromaic amines such as 2-aminopyridine was efficaciously applied under the
optimized condition to afford 3g in almost quantitative yield (Table 5, entry 7).
Aromatic amines with electron-deficient group such as CO2Et provided the corresponding
products 3f and 3o in 79 and 87% yields, respectively (Table 4, entries 6 and 15). The
reaction of 4,4'-oxydibenzenamine with two equivalents of 2-bromobenzaldehyde afforded 3i
in an excellent yield (Table 5, entry 9). Under optimized reaction conditions, diverse aliphatic
amines were readily reacted with 2-bromoaldehydes to produce the favourable yields of 3j
and 3k (Table 5, entries 10 and 11). Furthermore, 6-bromobenzo[d][1,3]dioxole-5-
carbaldehyde and 2-bromo-5-fluorobenzaldehyde were efficiently transformed to 2H-
indzoles 3k-3o under ultrasonic irradiation (Table 5, entries 11-15).
In addition to ultrasonic irradiation and catalytic performance of CDSCS which are main
factors that influenced in progression of reaction; however, it is worthy to be mentioned that
TBAA not only behaves as an azide source but also because of its phase transfer catalytic
(PTC) nature can extensively promote the reaction.
The recoverability and reusability of heterogeneous catalyst is the important benefits and
superiority over homogeneous catalysts from both environmental and economical
standpoints. Thus, the recyclability and reusability of CDSCS were assessed under the
optimized reaction conditions (Table 6). To this end, after the completion of the reaction, the
catalyst was recycled from the reaction mixture through a sintered glass funnel and washed
14

successively with EtOAc (2 × 50 mL). The catalyst was then dried in a vacuum oven at 60 °C
and tested for several sequential runs. The obtained results in Table 6 clearly confirm that
CDSCS is a recyclable and reusable catalyst without any significant loss of its activity. In
addition, the ICP analysis has demonstrated the reusability of the catalyst with extremely
negligible desorption of active copper species from CDSCS. Based on the ICP analysis, the
amount of leached copper from CDSCS is estimated about 0.006% after five consecutive runs
which is an extremely negligible amount.
Table 6
The reusability of CDSCS for synthesis of 2-phenyl-2H-indazole under ultrasonic irradiation. a
CHO
CDSCS
TBAA
N
H2N
)))) (60W), DMSO, r.t.
N
Br
3a
Run no. b
1
Time (h)
1
Yield c (%)
92
2
3
4
5
1
92
91
90
87
1.25
1.25
1.5
a
Reaction conditions: 2-bromobenzaldehyde (10 mmol), aniline (12 mmol), TBAA (15 mmol),
recovered CDSCS (0.3 g), DMSO (10 mL).
b The entry number corresponds to the trial number.
c Isolated yield.
Due to literatures [24-29], a plausible mechanism for the preparation of 2H-indazole
derivatives via one-pot 3CR of 2-bromobenzaldehydes, amines, and TBAA using CDSCS under
ultrasonic irradiation was suggested (Scheme 2). According to this mechanism, a consecutive
condensation, C–N and N–N bond formations were happened for synthesis of 2H-indazoles
using the current protocol. The mechanism for synthesis of 2-phenyl-2H-indazole as a sample
compound is shown in Scheme 2. Initially, the reaction occurred through the condensation of
2-bromobenzaldehyde with aniline to form the imine (I) as the main intermediate. The in situ
generation of imine was evidently confirmed at the early stage of the reaction which simply
can be identified by thin layer chromatography (TLC) or gas chromatography (GS) techniques
through the comparison with pre-synthesized imine or provided authentic sample. In
15

continuation, TBAA was reacted with imine (I) in the presence of CDSCS to afford the
intermediate (II) followed by reductive elimination to azide-copper complex (III) through C-N
bond formation. Afterward, N-N bond formation via the intramolecular cyclization of (III)
resulted in intermediate (IV). Eventually, the elimination of N2 gas and dissociation of the
catalyst led to 2H-indazole (V) as the ultimate product.
CHO
))))
N
H2N
- H2O
(I)
Br
Br
N2
N
n-Bu4N3
N
SiO2
CuO3SO
(V)
))))
))))
N
SiO2
CuO3SO
N
N
N
N
N
(II)
N
(IV)
SiO2
CuO3SO
N
))))
))))
N
SiO2
CuO3SO
N
N N
(III)
Scheme 2 . A plausible mechanism for the synthesis of 2H-indazole derivatives
4. Conclusion
In conclusion, we have developed an ultrasound promoted facile and convenient one-pot
three-component procedure for the synthesis of 2H-indazole derivatives through consecutive
condensation, C–N and N–N bond formations using CDSCS as a heterogeneous nano-catalyst.
Utilizing ultrasonic irradiation techniques provided the dramatic improvements in terms of
higher yields and shorter reaction times compared with conventional heating method in
current research. The advantageous of this ultrasonic promoted approach involves the high
yields of products, short reaction times, mild reaction conditions, low catalyst loading, using
available precursors, ease of operation, the simplicity of separation, not requiring any
16

supplementary ligand, reusability of the catalyst minimization of by-products and chemical
wastes. To the best of our knowledge, this method is the first example of one-pot 3CR of 2H-
indazole through ultrasonic irradiation utilizing TBAA as a nitrogen source and CDSCS as a
heterogeneous nano-catalyst.
Acknowledgment
The author wish to thank Shiraz University of Technology research council for partial support
of this work.
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21

N
N
SiO2
CuO3SO
) ) )
)
NH2
))))
(CDSCS)
CHO
Br
NH
N3
(TBAA)
22

Highlights
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•
•
•
•
Ultrasound promoted facile three-component procedure to access 2H-indazoles.
Under ultrasonic irradiation, the yields dramatically increased.
Under ultrasonic irradiation, the reaction times considerably shortened.
CDSCS is highly active and selective nano-catalyst for 2H-indazole synthesis.
Reusability and inexpensive nature of the catalyst.
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