Ultrasound-assisted synthesis of diversely functionalized tetrahydro-1H-Indole-4(5H)-one using Br?nsted base silica sodium carbonate (SSC) as a catalyst under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2016.1189575

An ultrasound-promoted, environmentally benign, efficient procedure has been developed for the synthesis of biologically active tetrahydro-1H-indol-4(5H)-one using heterogeneous Br?nsted base silica sodium carbonate (SSC) as a catalyst under solvent-free conditions. In comparison to the conventional methods, this efficient green protocol provides remarkable advantages such as good to excellent yields, shorter reaction time, low cost, and easy workup procedure and bypasses the use of hazardous transition-metal catalysts and organic solvents.

Full text of DOI:10.1080/00397911.2016.1189575

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Ultrasound Assisted Synthesis of Diversely
Functionalized Tetrahydro-1H-Indole-4(5H)-one
Using Brønsted Base Silica Sodium Carbonate
(SSC) as a Catalyst Under Solvent-Free Conditions
Vijay Vilas Shinde, Seung Min Lee, Jeong Su Oh, Kwon Taek Lim & Yeon Tae
Jeong
To cite this article: Vijay Vilas Shinde, Seung Min Lee, Jeong Su Oh, Kwon Taek Lim & Yeon
Tae Jeong (2016): Ultrasound Assisted Synthesis of Diversely Functionalized Tetrahydro-1H-
Indole-4(5H)-one Using Brønsted Base Silica Sodium Carbonate (SSC) as a Catalyst Under
Solvent-Free Conditions, Synthetic Communications
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Date: 01 June 2016, At: 03:17

Ultrasound assisted synthesis of diversely functionalized tetrahydro-1H-indole-
4(5H)-one using Brønsted base silica sodium carbonate (SSC) as a catalyst under
solvent-free conditions
Vijay Vilas Shinde1, Seung Min Lee2, Jeong Su Oh1, Kwon Taek Lim1, Yeon Tae Jeong1
1Department of Image Science and Engineering, Pukyong National University, Busan,
Republic of Korea, 2LED Convergence Engineering Department, Specialized Graduate
School Science and Technology Convergence , Pukyong National University
Corresponding author. Yeon Tae Jeong, E-mail: ytjeong@pknu.ac.kr
Abstract
An ultrasound promoted an environmentally benign and efficient procedure has been
developed for the synthesis of biologically active tetrahydro-1H-indol-4(5H)-one using
heterogeneous Brønsted base silica sodium carbonate (SSC) as a catalyst under solvent-
free condition. In comparison to the conventional methods, this efficient green protocol
provides remarkable advantages such as good to excellent yields, shorter reaction time,
low cost, easy work-up procedure and bypass for use of hazardous transition metal
catalysts and organic solvent.
GRAPHICAL ABSTRACT
1

KEYWORDS: Silica sodium carbonate (SSC), Brønsted base, tetrahydro-1H-indol-
4(5H)-one, Ultrasound, solvent-free
INTRODUCTION
Polysubstituted indole derivatives represent an important class of nitrogen
containing heterocycles ubiquitous in a number of biologically active natural
products. As a representative of this class of compounds, the tetrahydro-1H-indol-
4(5H)-one scaffold serving as a valuable starting material for indole-based
compounds.[1–5] In addition, derivatives bearing this core are of considerable
pharmacological interest and possess an array of biological activities including
HSP90 inhibition,[6] soluble guanylate cyclase inhibition,[7] kv 1.5 blocking,[8] anti-
psychotic,[9] GABAA-α[9] receptor ligands,[10] antiproliferation and aurora kinase
inhibition.[11] Indolone is a prominent structural unit found in several natural
products and pharmaceutically active compounds and acts as a precursor to
indole.[12–14, 38–39]
Owing to their versatile biological activities, extensive synthetic efforts have been
devoted for the construction of polysubstituted indole. The classical methods such
as the Fischer-type indole synthesis [15] provide rapid access to substituted indole
from phenylhydrazine and an aldehyde or ketone compounds. Furthermore there
are several methods available for the synthesis of indole derivatives using transition
metal as a catalyst for instance, radical cyclization,[16] nickel-catalyzed
alkylation,[17] palladium-catalyzed C–H functionalization[18-19] reactions. On the
2

other hand, recently non-metal catalyzed method also has been developed for the
synthesis of substituted indoles from cyclic 1,3-dicarbonyl, amine and nitroolefins
involving intramolecular cyclization.[20]
Although the known methodologies have convenient protocols with good to high
yields, the reported methods still suffered from shortcomings, such as long reaction
times, expensive catalyst, low yields, toxic solvents, high temperature and the use
of non-recyclable catalysts. Thus, the development of efficient and
environmentally benign protocol using a recyclable catalyst and solvent-free
condition for the synthesis of tetrahydro-1H-indol-4(5H)-one derivatives is still
desirable and in demand.
The use of green solvents [21–22] or solvent-free [23] conditions, non classical energy
sources such as microwaves, [24] ultrasound [25–27] and infrared, [28] eco-friendly
reagents and catalysts [29] are among the alternatives to improve the greenness of
the synthesis of indoles. Ultrasound-assisted organic synthesis is a green approach
and a superior technique employed for the organic reactions leading to suppression
of side products, improved rate of reaction, milder conditions and easier handling
and formation of pure products in prominent yields.[30–31] Moreover ultrasound
promoted, especially when either one of the substrates or the products is a liquid
and can be used as the solvent of the reaction are particularly welcome.
3

In the recent years, heterogeneous catalysts have found increased application in an
organic synthesis[32] as they are efficient, easily recovered and recycled. In this
context silica sodium carbonate (SSC) is synthetically useful as an efficient
Brønsted base was found in organic reactions. Because sodium carbonate is
inorganic Brønsted base, it is widely used as a catalyst in the organic reactions.
Nevertheless, it is easily soluble in aqueous medium, so that reuse and separation
from the reaction mixture are tedious and inconvenient. On the other hand silica
sodium carbonate (SSC) is silica supported Brønsted base (Fig. 1). The unique
feature of SSC, over conventional basic catalysts is ease of handling, stability,
recyclability, cost effective, tunable Brønsted basicity. It could be successively
[33–34]
used in multicomponent reactions
.
In the last few years we have developed greener methodologies to prepare novel
heterocyclic compounds combining two or more of the Green Chemistry
Principles, using heterogeneous catalysts under solvent-free conditions and energy-
efficient protocols.[35–36] Herein, we wish to report a simple and useful synthetic
protocol, ultrasound assisted synthesis of tetrahydro-1H-indol-4(5H)-one by
employing SSC as a catalyst through one-pot three-component condensation
reaction of nitroolefin (
1), cyclic 1,3-diketones (2) and amine (3) under solvent-
free condition at 60 °C as shown in (Scheme 1).
RESULT AND DISCUSSION
4

Initially, to investigate the reaction conditions, we carried out the reaction between
1-fluoro-4-((E)-2-nitrovinyl)benzene (1a, 1 mmol), 5,5-dimethylcyclohexane-1,3-
dione (2a, 1mmol) and 3-methoxybenzenamine (3a, 1 mmol) in the absence of the
catalyst under solvent-free condition as a model. In the absence of catalyst we
could not isolate any desired product even after 14 h stirring (Table 1, entry 1).
After that we investigated by utilizing different catalysts under both conventional
heating and ultrasonication conditions without solvent. Catalysts such as FeCl3,
Y(OAc)3.H2O, GaBr3, and sodium carbonate either completely impede the reaction
or diminish the yield of the product (Table 1, entries 2–5). In order to develop a
viable approach, the model reaction was investigated by employing different silica
supported heterogeneous catalyst such as CAN-SiO2, BF3.SiO2, TiO2-SiO2,
FeCl3.SiO2, Cu(OTf)2.SiO2 and ZnCl2.SiO2 and obtained moderate product yields
(Table 1, entries 6–11). Subsequently the reaction was performed in the presence
of SSC and we obtain the desired product (4a) in high yield (Table 1, entry 12).
Moreover, The optimal molar loading of SSC was determined by performing the
model reaction using 2, 2.5, 3, 3.5, 4 and 4.5 mol % of SSC in neat condition and
53, 62, 75, 80, and 89% yields were obtained, respectively; (Table 1, entries 13–18).
Increasing the amount of catalyst above 4 mol % had no effect on yield and
reaction time. The effect of solvent on the model reaction was studied in both
conventional and ultrasonication conditions using 4 mol % of SSC in different
solvents. The reaction was also studied at varying temperature (40, 50, 60 and 80
°C). The optimum conversion of reactants to product was achieved when reaction
5

was under solvent-free condition at 60 °C. Further the frequency of ultrasonication
bath was also studied with 10KHz, 20KHz, 30KHz and 40KHz. It showed that
20KHz frequency was sufficient for this reaction. One more reaction was carried
out using plain silica as a catalyst to find out the exact role of silica in the reaction
system. But we haven't observed any product formation even after 12 h of reaction
time. So the role of silica as heterogenous support in this modified silica supported
catalyst is demonstrated (Table 1, entry 29). Hence, the product yield and the rate
of reaction, both are mutually dependent on the nature and quantity of the catalyst,
frequency of ultrasonication.
The recyclability of the SSC catalyst was also established by running the same
model reaction in five cycles with recovered SSC and obtained 4a in 89, 87, 85,
85, and 83% product yield. This proved that efficiency of the catalyst can be used
for the multiple usage purpose without much loss of its efficiency (Table1, entry
12). From all these observations (Table1), we concluded that 4 mol % of the SSC
catalyst, 60 °C and solvent-free conditions under ultrasonication (20 KHz) are best
optimized conditions for this synthesis of tetrahydro-1H-indol-4(5H)-one
derivative (4a-4ac).
In order to explore the scope and limitations of the SSC catalysis, the protocol was
extended to other examples, under the optimized conditions. To our delight, we
found this transformation to be very general for a wide range of amine, conjugated
nitroolefins and two cyclic 1,3-dicarbonyl, providing easy access to densely
6

substituted tetrahydro-1H-indol-4(5H)-one derivatives 4. Aromatic as well as
aliphatic amines displayed good reactivity in this reaction. On the other hand a
different functional groups substituted at the aromatic ring of the nitroolefin were
tolerated. We also employed two different cyclic 1,3-dicarbonyl substrates, such as
5,5-dimethylcyclohexane-1,3-dione and cyclohexane-1,3-dione, producing
tetrahydro-1H-indol-4(5H)-one in good to excellent yields.
To further demonstrate the advantage of this method, we attempted to scale-up
synthesis of tetrahydro-1H-indol-4(5H)-one (4a
nitrovinyl)benzene (1a) with 5,5-dimethylcyclohexane-1,3-dione (2a) and 3-
methoxybenzenamines (3a . These reagents were subjected to the reaction under
) use of 1-fluoro-4-((E)-2-
)
ultrasonication for 50 min. and 86% yield was afforded (Scheme 2).
Presumably the reaction seems to proceed through following mechanistic pathway
as presented in (Fig. 2). The catalyst SSC appears to play a key role as Brønsted
base in the reaction and accelerates the reaction to helps in the formation of the
intermediate β-enamino carbonyl (
nitroolefin ( ) to give intermediate B. Intermediate
of aldehyde ( ) by Nef reaction followed by intramolecular cyclization leading to
the final products 4a-4ac.
A)
which then undergoes Michael reaction with
1
B
undergoes in-situ formation
C
CONCLUSION
7

Silica sodium carbonate (SSC), proved to be an effective, selective and reusable
catalyst for the green synthesis of tetrahydro-1H-indol-4(5H)-one derivatives
under ultrasonic in solvent-free condition. Besides, being a simple procedure, the
SSC catalyst was easily recycled and reused. The use of solvent-free condition
allows the use of sonication to accelerate the reaction from hours to only a few
minutes. The low toxicity of SSC allied to an atom-economic reaction. The bypass
the solvents and use of sonication are features which make this new, silica
supported sodium carbonate protocol, a green alternative method to access
tetrahydro-1H-indol-4(5H)-one selectively.
EXPERIMENTAL
Chemicals were purchased from Aldrich and Alfa Aesar Chemical Companies. NMR
spectra were recorded in parts per million (ppm) in CDCl3 on a Jeol JNM ECP 400 NMR
instrument using TMS as internal standard. Mass spectra were recorded on a Jeol JMS-
700 mass spectrometer. All melting points were determined using open capillaries on an
Electrothermal-9100 (Japan) instrument.
Two Step Preparation Of SSC
STEP-1
Silica sodium carbonate was prepared by adopting the literature K. Eskandari, B. Karami
et al. [34]. To a 250mL round bottom flask equipped with a reflux condenser, in which
the hose interface was connected to a pot of water, 10 g of silica gel 60 (63–200 μm) that
was previously dried at 120 °C for 6 h was added. Then 40 mL of thionyl chloride was
8

added dropwise to this flask which was perched in an ice bath (caution). After the
addition of thionyl chloride, the reaction mixture was removed from the ice bath and
stirred for 0.5 h in room temperature and 48 h under reflux conditions. Afterwards, the
reaction mixture was filtrated to obtain silica chloride.
STEP-2
To a stirred 250 mL round bottom flask containing 10 g of sodium bicarbonate and 25
mL of n-hexane under reflux conditions, 10 g of silica chloride (after drying at 120 °C
for 6 h) was added. After 24 h, the reaction mixture was filtrated to separate the catalyst
and the solid product was washed with 50 mL of distilled water ten times, using 5 mL
each time until filtrate became quite neutral, in order to remove the remaining sodium
bicarbonate. Finally, dryid at 100 °C for 12 h, to afford SSC.
General Procedure For The Synthesis Of Tetrahydro-1H-Indol-4(5H)-One At
Ultrasound (4a-4c)
To a 10 mL vessel was added nitroolefins (1, 1 mmol), cyclic 1,3-dicarbonyl (2, 1mmol),
amine (3, 1 mmol) and SSC (4 mol%), the reaction was carried out under ultrasound (20
KHz). The resulting solution was sonicated with an US probe for the time indicated in
Table 2. The progress of reactions were checked by thin layer chromatography (TLC)
using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was
washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated,
and the crude product was purified by flash column chromatography on silica gel
(200−300mesh) with ethyl acetate and hexane as eluent to afford the product 4. The SSC
9

catalyst was reused by the way of addition of ethyl acetate to the reaction mixture and
filtration followed by drying in a vacuum oven every time. The spectral and analytical
data of the model representative compound is given here:
3-(4-Fluorophenyl)-6,7-Dihydro-1-(3-Methoxyphenyl)-6,6-Dimethyl-1H-Indol-4(5H)-
One (4a)
Yield 89 %; off-white solid; Mp: 130-132; 1H NMR (400 MHz, CDCl3): δ = 1.10 (s, 6H,
2CH3), 2.42 (s, 2H, CH2), 2.67 (s, 2H, CH2), 3.86 (s, 3H, OCH3), 6.84(s, 1H, ArH), 6.87
(s, 1H, ArH), 6.92 (d, J=7.7 Hz, 1H, ArH), 6.97 (d, J=8.4 Hz, 1H, ArH), 7.03 (t, J=8.6
Hz, 2H, ArH), 7.41 (t, J=8.1 Hz, 1H, ArH), 7.63-7.66 (m, 2H, ArH), 13C NMR (100 MHz,
CDCl3): δ = 28.53, 35.44, 37.53, 53.23, 55.70, 111.50, 113.51, 114.72, 114.93, 117.18,
117.55, 121.79, 124.31, 130.37, 130.45, 139.58, 143.51, 160.84, 163.31 (C-F, d, J = 246
Hz), 193.84; HRMS (ESI, m/z): calcd for C23H22FNO2 (M+H+) 363.1634, found:
363.1633.
ACKNOWLEDGMENTS
This work was supported by the Development of R&D Professionals on LED
Convergence Lighting for Shipbuilding/Marine plant And Marine Environments (Project
No: N0001363) funded by the Ministry of TRADE, INDUSTRY & Energy (MOTIE,
Korea).
SUPPORTING INFORMATION
10

Full experimental detail, 1H and 13C NMR spectra, HRMS data for all compounds. This
material can be found via the “Supplementary Content” section of this article’s webpage.
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13

Table 1. Optimization of reaction conditions in the synthesis of 4aa
Entry
Catalyst (mol%) Solvent
Tem Conventional
p
Ultrasound (20 KHz)
Time
(min)
840
Yieldb
Time(min Yieldb (%)
)
(°C)
60
(%)
-
1
2
3
-
Neat
Neat
300
156
152
-
FeCl3 (5)
60
280
30
35
55
50
Y(OAc)3.H2O 3 Neat
(5)
60
260
4
GaBr3 (5)
Neat
Neat
Neat
Neat
Neat
60
60
60
60
60
60
60
245
200
245
290
324
270
190
45
50
60
55
45
35
45
122
110
91
55
65
70
61
58
60
62
5
Na2CO3 (5)
CAN-SiO2 (5)
BF3.SiO2 (5)
TiO2-SiO2 (5)
6
7
80
8
123
140
90
9
FeCl3.SiO2 (5) Neat
10
Cu(OTf)2.SiO2
(5)
Neat
11
ZnCl2.SiO2 (5)
SSC (5)
Neat
Neat
60
60
266
190
50
70
110
45
55
12c
89, 87, 85,
14

85, 83
53
13
14
15
16
17
18
19
20
SSC (2)
SSC (2.5)
SSC (3)
SSC (3.5)
SSC (4)
SSC (4.5)
SSC (4)
SSC (4)
Neat
Neat
Neat
Neat
Neat
Neat
H2O
60
60
60
60
60
60
60
251
240
230
292
190
190
310
251
40
45
51
65
70
70
60
22
65
60
62
58
75
52
80
78
89
78
89
146
139
76
[bmim][Cl 60
]
34
21
SSC (4)
SSC (4)
SSC (4)
SSC (4)
SSC (4)
SSC (4)
SSC (4)
SSC (4)
Silica gel (5)
Toluene
Ethanol
Neat
60
60
40
50
80
60
60
60
60
263
253
285
240
190
240
150
140
720
35
55
62
65
68
52
62
65
NR
141
112
110
90
42
67
72
74
82
61
84
86
NR
22
23
24
Neat
25 d
26 e
27 f
28
Neat
55
Neat
78
Neat
65
Neat
55
29
Neat
720
aReaction between 1-fluoro-4-((E)-2-nitrovinyl)benzene (1a, 1 mmol), 5,5-
dimethylcyclohexane-1,3-dione (2a, 1mmol) and 3-methoxybenzenamine (3a, 1 mmol);
bIsolated yield; cCatalyst was reused five times; d, e and f Ultrasonication reactions carried
out with 10, 30 and 40KHz frequency respectively.
15

Table 2. Ultrasound-assisted synthesis of tetrahydro-1H-indol-4(5H)-one
derivativesa
Entry
1
R
R1
R2
Product
4a
Time (min) Yield (%)d
4-F
4-F
4-F
4-F
CH3
CH3
CH3
CH3
3-OCH3C6H4
4-CH3C6H4
3-CH3C6H4
2-CH3C6H4
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
3-OCH3C6H4
3,4-CH3C6H3
2,5-CH3C6H3
3,5-CH3C6H3
2-CH3C6H4
3-CH3C6H4
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
45
35
40
42
51
50
22
35
42
53
36
32
40
36
46
30
89
2
88
4b
4c
3
88
4
87
4d
4e
5
3,4-OCH3 CH3
3,4-OCH3 CH3
88
6
88
4f
7
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
H
92
4g
8
90
4h
4i
9
87
10
11
12
13
14
15
16
85
4j
87
4k
4l
92[39]
87
CH3
CH3
H
4m
4n
4o
89[39]
87
H
86
4p
16

17
18
19
20
21
22
23
24
H
H
3,4-CH3C6H3
2,5-CH3C6H3
4-OCH3C6H4
4-CH3C6H4
3-OCH3C6H4
2-CH3C6H4
3-CH3C6H4
2,3-dihydro-1H-
indene-5yl
48
52
50
42
55
36
50
25
84
85
84
89
87
87
87
88
4q
4r
4s
H
H
4-OCH3
4-OCH3
4-OCH3
4-OCH3
4-OCH3
H
CH3
CH3
CH3
CH3
CH3
CH3
4t
4u
4v
4w
4x
25
26
27
28
4-FC6H4
4-OCH3
H
CH3
CH3
CH3
CH3
cyclohexyl
39
40
58
25
79
4y
cyclohexyl
82
4z
3-methoxypropyl
Ph
76
4ab
4ac
H
92[20,39]
aReaction of nitroolefins (1, 1 mmol), cyclic 1,3-dicarbonyl (2, 1 mmol) and amine (3, 1
mmo), catalyzed by SSC under ultrasonication at 60 °C.; dYields of pure products
isolated by column chromatography.
17

Table 3. Comparison of the results obtained for 4ac using SSC versus the methods
reported in the literature
Entry Catalyst
Reaction condition
Time Yield
(%)a
Ref.
1
2
L-proline (10 mol%)
H2O, 60 °C
H2O, 50 °C
12 h
06 h
85
85
[20]
[39]
Carbonaceous
materials(10 mg)
SSC
3
Neat, Ultracsonication,
60 °C
25
92
This
min
work
a Isolated yield
18

Scheme 1. Synthesis of tetrahydro-1H-indol-4(5H)-one derivative catalyzed by SSC.
19

Scheme 2. Scale-up Synthesis of tetrahydro-1H-indol-4(5H)-one (4a)
20

Figure 1. Silica sodium carbonate.
21

Figure 2 Plausible mechanism for the formation of tetrahydro-1H-indol-4(5H)-one
derivatives.
22