Synthesis of 3-Substituted Indoles Using Deep Eutectic Solvent and Ultrasound

Full text of DOI:10.1080/00304948.2021.1875775

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Synthesis of 3-Substituted Indoles Using Deep
Eutectic Solvent and Ultrasound
Dnyaneshwar T. Nagre, Amol U. Khandebharad, Swapnil R. Sarda, Bharat K.
Dhotre & Brijmohan R. Agrawal
To cite this article: Dnyaneshwar T. Nagre, Amol U. Khandebharad, Swapnil R. Sarda, Bharat
K. Dhotre & Brijmohan R. Agrawal (2021) Synthesis of 3-Substituted Indoles Using Deep Eutectic
Solvent and Ultrasound, Organic Preparations and Procedures International, 53:3, 278-283, DOI:
10.1080/00304948.2021.1875775
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
2021, VOL. 53, NO. 3, 278–283
https://doi.org/10.1080/00304948.2021.1875775
EXPERIMENTAL PAPER
Synthesis of 3-Substituted Indoles Using Deep Eutectic
Solvent and Ultrasound
Dnyaneshwar T. Nagrea, Amol U. Khandebharadb , Swapnil R. Sardab, Bharat K.
Dhotrec , and Brijmohan R. Agrawalb
b
aDepartment of Chemistry, RMIG College, Jalna, India; Department of Chemistry, JES College, Jalna,
c
India; Department of Chemistry, Swami Vivekanand College, Mantha, Jalna, India
ARTICLE HISTORY Received 1 April 2020; Accepted 30 September 2020
Deep eutectic solvents (DESs) are a class of ionic liquids (ILs) successfully implemented
for many organic transformations.1,2 Several reports have shown the immense potential
of using ILs with ultrasound, as the blend of these two practices can fulfill several
important criteria of green chemistry.3–8
Indoles are key heterocyclic systems, present in naturally-occurring compounds such
as tryptophan, serotonin, melatonin, tryptamine, and plant growth hormones, as well as
synthetic materials.9 Their varied biological activities have made them of much interest.
In the development of the latter, an important focus of research has been on functional-
ization at the C-3 position.10 Numerous reports have been published on the synthesis of
3-substituted indoles by using such techniques as the electrochemical approach,11 such
catalysts as copper(II) sulfonato salen,12 Zn(II) salen,13 2-pyrrolecarbaldiminato-Cu(II)
15
complexes,14
hybrid
nanoparticles
H5PW10V2O40@VOx/SBA-15-NH2,
H3PW12O40/SBA-15,16 L-proline,17 PEG-400,18 PEG-200,19 tetrabutylammonium fluor-
ide,20 and such ILs as tetrabutylammonium glycinate.21
In continuation of our work on the use of easily available catalysts and extending the
ideas of green methods,22–25 we now report the synthesis of 3-substituted indole deriva-
tives by utilizing the synergetic effect of ultrasound and the DES formed by choline
chloride and urea (ChCl: urea) (Scheme 1).
As a model, we chose to optimize the reaction of benzaldehyde (1 mmol), malononi-
trile (1 mmol) and indole (1 mmol) at 60 ꢀC. Our results are summarized in Table 1.
We found that the simple Lewis acids FeCl3 and AlCl3 gave poor results, forming the
product in 7-8 hours with very low yield (Table 1, entries 1, 2). Using the concepts of
hydrogen bond donors (HBD) and acceptors (HBA), we prepared our DES by taking
combinations of choline chloride (ChCl) with such different HBD as glucose, glycerol,
oxalic acid and succinic acid, obtaining the results shown in Table 1, entries 4-8. We
further observed that a mixture of ChCl and urea gave good results (entry 8, 75% in
2 hrs). We conclude that the enhanced yield in entry 8 is due to the specific suitability
of the HBD and HBA combination, and the mild basicity of the urea is likely to be a
key factor in this.
CONTACT Amol U. Khandebharad
amolkhandebharad@gmail.com
Department of Chemistry, JES College, Jalna,
MS, India
ß 2021 Taylor & Francis Group, LLC

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
279
Scheme 1. The model reaction for the synthesis of 3-substituted indole derivatives.
Table 1. Optimization of reaction conditions.a
Entry
Catalyst
Solvent
yieldb
Time
1
2
3
4
5
6
7
8
FeCl3
AlCl3
ChCl
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Water
MeOH
DMF
DMSO
CH3CN
DCM
THF
Toulene
Solvent-free
Solvent-free
Solvent-free
Solvent-free
NR
15
NR
NR
35
18
NR
75
70
55
40
42
30
25
10
15
80
80
60
88
8 hr
7.5 hr
8 hr
8 hr
5 hr
5 hr
8 hr
2 hr
1 hr
3 hr
5 hr
5 hr
6 hr
8 hr
3 hr
6 hr
ChCl:Glucose (2:1)
ChCl:Glycerol ( 1:2)
ChCl: Oxalic acid (1:1)
ChCl:Succinic acid (1:1)
ChCl:Urea (1:2)
ChCl:Urea (1:2)
ChCl:Urea (1:2)
ChCl:Urea (1:2)
ChCl:Urea (1:2)
ChCl:Urea (1:2)
ChCl:Urea (1:2)
ChCl:Urea (1:2)
ChCl:Urea (1:2)
9
10
11
12
13
14
15
16
17
18
19
20
ChCl:Urea (1:2)
40 min
40 min
60 min
25 min
ChCl:Urea (1:2) (10 mol%)
ChCl:Urea (1:2) (5 mol%)
ChCl:Urea (1:2) (10 mol%)C
aReaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol) and indole (1 mmol) and 20 mol% of catalyst in
10 mL of solvent heated at 60 ꢀC.
ChCl: Second component ratio is given in mol:mol, and this formed DES was used in mol%.
NR: No Reaction.
bIsolated yield.
cModel reaction carried out in the ultrasonic bath.
We examined a variety of solvents and found good results with polar protic ones
(entries 8-10). However, a surprising and noteworthy result was observed when the
reaction was performed in solvent-free conditions, providing an 80% yield in just
40 min. (entry 17). Focusing next on the amount of DES catalyst, we found the optimal
amount to be 10 mol%, providing 80% yield in 40 min. Finally, the model reaction was
carried out under ultrasonic irradiation (entry 20). This reduced the reaction time to
25 min and gave an 88% yield. This result inspired us to use a variety of different alde-
hydes in our optimized protocol (Scheme 2), and the results are summarized in Table 2.
The yields were uniformly very good (mean 88%) and did not seem to be overly sensi-
tive to the presence of substituent groups. The products were known compounds, iden-
tified by matching their melting points with literature values given in the references
cited in the table. Some representative spectra are provided in the Experimental section.

280
D. T. NAGRE ET AL.
Scheme 2. Synthesis of 3-substituted indoles by using DES and ultrasound.
Table 2. Synthesis of 3-indole derivativesa
Entry
R
Time (min)
Yield (%)c
mp (ꢀC)ref
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-methoxy
H
4-chloro
2-chloro
2-nitro
3,4-C4H4
4-methyl
4-nitro
4-bromo
4-fluoro
30
25
20
25
60
30
45
45
25
20
94
88
90
85
80
92
82
85
90
92
160-162 (160-162)15
80-82 (79-80)15
70-72 (73-74)14
112-114 (113-115)15
134-136 (135-137)15
70-72 (73-75)14
209-211 (209-211)16
160-162 (160-162)15
178-180 (178-180)15
66-68 (65-66)14
4j
aReaction conditions: aldehyde (1 mmol), malononitrile (1 mmol) and indole (1 mmol) in 10 mol% DES (ChCl:urea) under
ultrasonic irradiation
bIsolated yield
The DES could be easily isolated during work-up of the reaction (see Experimental sec-
tion). The recovered DES could be used for the next run.
In summary, we have demonstrated the synthesis of 3-substituted indoles using a
deep eutectic solvent and ultrasound. Their substitution patterns and potential for fur-
ther modification make these indoles attractive as building blocks for organic synthesis.
Given their utility and potential, it is our expectation that these compounds will find
further exploitation in chemical reactions, now that they will be readily available. We
further expect that our particular combination of DES and ultrasound will find other
useful applications.
Experimental section
All reagents were obtained from Sigma Aldrich. The reactions were monitored on TLC
using pre-coated plates (silica gel on aluminum, Merck). Ethyl acetate and n-hexane
were used as eluting solvents. Visualization of spots on TLC plates was accomplished
with UV light and by staining in an I2 chamber. Chemicals used were SD Fine or
Sigma Aldrich and were used without further purification. Melting points were meas-
1
ured in open glass capillaries and are uncorrected. H NMR specta were recorded on a
Varian 300 MHz instrument in CDCl3 using TMS as the internal standard. An Equitron
ultrasonic cleaner of 50 kHz and 170 w was used for ultrasonication.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
281
Preparation of the DES Choline Chloride:Urea
The preparation of DESs by the combination of choline chloride with urea, glucose, gly-
cerol, oxalic acid and succinic acid were carried out according to reported methods.29–33
The prepared clear solution of a given DES was used without purification as shown in
Table 1.
General Procedure for the Synthesis of 3-substituted indole derivatives
A mixture of malononitrile (1 mmol), aromatic aldehyde (1 mmol), and indole (1 mmol)
was placed in a 10 mL borosilicate round bottom flask containing 10 mol% of the DES
prepared by the combination of ChCl:urea (1:2), then it was subjected to ultrasound
irradiation for the specific time mentioned in Table 2. Progress of the reaction was
monitored by TLC (ethyl acetate/n-hexane ¼ 1:9). After completion of the reaction,
10 mL DCM was added to the reaction mass to extract the desired product. The DCM
layer was subjected to evaporation under vacuum to get the final product. The obtained
crude product was purified by recrystallization from absolute ethanol. The DES could
be easily isolated after extraction of the product owing to its immiscibility in DCM. The
products were characterized by a comparison of their melting points with literature val-
ues, as specified in Table 2. For the sake of completeness, some representative spectra
are provided below.
2-((1H-Indol-3-yl)(4-methoxyphenyl)methyl)malononitrile (4a)
1H NMR (300 MHz; CDCl3): 7.99 (s, 1H, NH), 7.36–7.28 (m, 4H, ArH), 7.13 (t, 1H,
ArH), 7.04 (t, 1H, ArH), 6.90 (d, 2H, ArH), 4.91 (d, 1H, CH), 4.64 (d, 1H, CH), 3.71
(s, 3H, OCH3) ppm
13C NMR (75 MHz; CDCl3): 28.7, 43.64, 55.28, 108.15, 110.95, 112.45, 112.76, 114.30,
118.28, 120.15, 121.80, 126.16, 128.61, 129.11, 133.71, 135.36, 159.14.ppm
2-((1H-Indol-3-yl)(phenyl)methyl)malononitrile (4b)
1H NMR (300 MHz; CDCl3): 8.27 (s, 1H, NH), 7.36-7.45 (m, 7H, ArH), 7.19-7.29 (m,
2H, ArH), 7.00 (t, 1H, ArH), 4.94 (d, 1H, CH), 4.45 (d, 1H, CH) ppm
13C NMR (75 MHz; CDCl3): 28.79. 139.34, 136.19, 128.75, 128.12, 127.90, 126.01,
122.87, 121.79, 119.03, 118.68, 114.19, 112.48, 111.80, 42.59 ppm
2–((1H–Indol–3–yl)(4–nitrophenyl)methyl)malononitrile(4h)
1H NMR (300 MHz; CDCl3):11.31 (s, 1H, NH), 8.24 (d, 2H, ArH), 7.80 (d, 2H, ArH),
7.59 (s, 1H, ArH), 7.47 (d, 1H, ArH), 7.39 (d, 1H, ArH), 7.09 (t, 1H, ArH), 6.97–6.93
(m, 1H, ArH), 5.97 (d, 1H, CH), 5.49 (d, 1H, CH) ppm
13C NMR (75 MHz; CDCl3): 28.18, 41.93, 111.27, 111.89, 113.57, 118.42, 119.23,
121.96, 123.20, 123.96, 125.76, 129.50, 136.15, 146.68 147.10 ppm

282
D. T. NAGRE ET AL.
Acknowledgment
We are thankful to Dr. J. D. Kabra, Principal, J.E.S. College, Jalna, India, for providing laboratory
facilities and for his kind support in the completion of this work.
ORCID
Amol U. Khandebharad
http://orcid.org/0000-0003-3679-8336
Bharat K. Dhotre
http://orcid.org/0000-0002-4161-897X
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