Wang resin-supported sulfonic acid-catalyzed multicomponent reaction in water leading to 4-oxo-4,5,6,7-tetrahydroindole derivatives

Article abstract of DOI:10.1080/00397911.2018.1458240

A greener approach for the synthesis of 4-oxo-4,5,6,7-tetrahydro indole derivatives has been achieved through Wang-OSO₃H-mediated three-component reaction involving dimedone, phenacyl bromide, and primary amine in water. A variety of indole der

Full text of DOI:10.1080/00397911.2018.1458240

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
Wang resin-supported sulfonic acid-catalyzed
multicomponent reaction in water leading to 4-
oxo-4,5,6,7-tetrahydroindole derivatives
Naresh Kumar Reddy Dinne, Ramamohan Mekala, S. Pulla Reddy, Ganesh
Yaddanapudi Sesha Siva & Chandrasekhar Kothapalli Bannoath
To cite this article: Naresh Kumar Reddy Dinne, Ramamohan Mekala, S. Pulla Reddy, Ganesh
Yaddanapudi Sesha Siva & Chandrasekhar Kothapalli Bannoath (2018) Wang resin-supported
sulfonic acid-catalyzed multicomponent reaction in water leading to 4-oxo-4,5,6,7-tetrahydroindole
derivatives, Synthetic Communications, 48:13, 1649-1656, DOI: 10.1080/00397911.2018.1458240
To link to this article: https://doi.org/10.1080/00397911.2018.1458240
View supplementary material
Published online: 08 Jun 2018.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

SYNTHETIC COMMUNICATIONS®
2018, VOL. 48, NO. 13, 1649–1656
https://doi.org/10.1080/00397911.2018.1458240
Wang resin-supported sulfonic acid-catalyzed
multicomponent reaction in water leading to
4-oxo-4,5,6,7-tetrahydroindole derivatives
Naresh Kumar Reddy Dinnea,b, Ramamohan Mekalaa, S. Pulla Reddya,
Ganesh Yaddanapudi Sesha Sivaa, and Chandrasekhar Kothapalli Bannoathb
aTechnology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Miyapur,
b
Hyderabad, Telangana, India; College of Engineering, Jawaharlal Nehru Technological University Anantapur,
Ananthapuramu, Andhra Pradesh, India
ABSTRACT
ARTICLE HISTORY
Received 16 December 2017
A greener approach for the synthesis of 4-oxo-4,5,6,7-tetrahydro
indole derivatives has been achieved through Wang-OSO3H-mediated
three-component reaction involving dimedone, phenacyl bromide,
and primary amine in water. A variety of indole derivatives were
prepared using this operationally simple and straight forward
methodology in acceptable yields.
KEYWORDS
Dimedone; multicomponent
reactions (MCR); phenacyl
bromide; tetrahydro indoles;
Wong-OSO3H
GRAPHICAL ABSTRACT
Introduction
Multicomponent reactions (MCRs) are one of the significant key tools that permit the
formation of several new bonds in single operation and give outstanding advantages like
convergence, operational simplicity, and facile automation.[1,2] These reactions can avoid
time consuming and costly processes for isolation and purification of intermediates of
various precursors, thereby reduced the waste generation.[3] Development of cost-effective
and environmentally benign reactions is of great importance in both medicinal and organic
chemistries as these procedures provide quick and easy access to the diversity-based
library of small organic molecules useful for new drug discovery effort. MCRs have
attracted extensive attention of researchers especially working in the area of medicinal/
pharmaceutical/organic chemistry. Indeed, MCRs have been used mostly to generate
library of small molecules having diverse substituents.[4] these libraries of potentially
CONTACT Ramamohan Mekala
ramamohanm@drreddys.com
Technology Development Centre, Custom
Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Bollaram Road, Miyapur, Hyderabad-500049, Telangana, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
© 2018 Taylor & Francis

1650
N. K. R. DINNE ET AL.
bioactive organic molecules were found to be attractive for high-throughput
pharmacological screen, leading to the identification of a pre-hit or lead molecule in a
particular therapeutic area.
Indole and its derivatives are the highest abundant heterocyclic compounds existing in
the nature and these compounds are denoted as important privileged structures in research
of drug discovery because of their ability to bind various receptors with good affinity.[5]
4,5,6,7-tetrahydroindole-4-one derivatives have great interest for their vital medicinal
activity and exhibit wide applications in pharmaceutical chemistry and as well as medicinal
chemistry. Tetrahydroindole derivatives were used as antibiotics,[6] antipsychotics,[7] anti-
proliferatives,[8] cytotoxic agents,[9] and platelet aggregation inhibitors.[10] Moreover, these
compounds are very important key intermediates in the synthesis of acetylcholine
esterase inhibitors[11] and for the preparation of several indole derivatives.[12] 4,5,6,
7-tetrahydroindole-4-one is the substructural unit and occurs in many biologically very
important alkaloids and mitomycins.[13]
In 1982, Dagher et al. synthesized 4,5,6,7-tetrahydroindole-4-one derivatives in two
steps by reacting phenacyl bromide with dimedone in presence of K2CO3 and subsequent
reaction with aniline in presence of acetic acid.[14] Later Jiang et al. and Maity et al. synthe-
sized these derivatives by reacting aryl glyoxal and 3-(aryl/aralkyl amino)-cyclohex-2-
enone.[15,16]
The above approaches to synthesize the tetrahydroindole derivatives are very useful
and efficient, however, in most of the approaches involved nonenvironmental benign
catalysts and solvents. Thus, the synthesis of 4,5,6,7-dihydroindole-4-one derivatives using
environmentally benign methodology is desirable.
We were continued the finding of a better and efficient catalysts for the synthesis of
4,5,6,7-dihydroindole-4-one derivatives in terms of recyclability, operational simplicity,
and economic viability. Recently sulfonic acid-functionalized Wang resin 2 (Wang-
OSO3H) is reported as efficient recyclable solid acid catalyst,[17] which can be handled
simply and can be easily removed by filtration from the reaction mixture.
Wang resin 2 is most often used for the attachment of organic and inorganic acids.
Wang-OSO3H is prepared by reacting Wang resin with chlorosulfonic acid (Scheme 1)
in presence of N, N-diisopropylethylamine (DIPEA).[17]
We have developed an efficient and simple three-component methodology for the syn-
thesis of 4,5,6,7-tetrahydroindole-4-one derivatives using recyclable and environmentally
benign Wang resin-supported sulfonic acid as a catalyst and water as a solvent medium
for the reaction. The Wang resin-supported sulfonic acid-catalyzed three-component reac-
tion of dimedone 3, phenacyl bromide 4, and different primary amines 5, leading to variety
of substituted 4,5,6,7-tetrahydroindole-4-one derivatives 6 (Scheme 2).
Scheme 1. Synthesis of Wang-OSO3H.

SYNTHETIC COMMUNICATIONS®
1651
Scheme 2. Synthesis 4,5,6,7-tetrahydroindole-4-one derivatives.
Results and discussion
The reaction of dimedone 3, phenacyl bromide 4a, and aniline 5a was explored under
various reaction conditions as shown in Table 1. Initially, the reaction was conducted
without catalyst in water at 90–100 °C and product 6a was isolated with 10% yield (entry 1,
Table 1). However, the product 6a yield was enhanced to 30% when amberlite was used as
catalyst in water (entry 2, Table 1), but product 6a yield was reduced to 15% when same
reaction conducted in PEG-400 instead of water (entry 3, Table 1). Product yield was
improved to 40% when amberlite was replaced with silica-supported phosphomolybdic
acid (PMA-SiO2) as a catalyst in water (entry 4, Table 1). Further, to improve the yield,
various catalysts such as silica gel, Indion resin, montmorillonite K-10 clay, and Wang-
OSO3H were screened (entries 5–8, Table 1). Among these catalysts, Wang-OSO3H-
catalyzed reaction produced 84% yield (entry 8, Table 1). Wang-OSO3H catalyst in other
solvents such as methanol, isopropyl alcohol, and PEG-400 were found to be less effective
than water (entries 9–11, Table 1).
Experiments were continued to check the effect of catalyst loading (entries 12 and 13,
Table 1) and reaction temperature (entries 14 and 15, Table 1). Reducing the catalyst load-
ing to 10 from 15% and reducing the temperature to 60–65 °C from 80–85 °C reduced the
Table 1. Optimization of reaction conditions for 4-oxo-4,5,6,7-tetrahydroindole derivatives.a
Entry
Catalyst/Loading (%w/w)
Solvent
Temp (°C)
Yield (%)b
1
2
No catalyst
Water
Water
PEG-400
Water
Water
Water
Water
Water
MeOH
IPA
PEG-400
Water
Water
Water
Water
Water
90–100
90–100
90–100
90–100
90–100
90–100
90–100
80–85
65
80–85
90–100
80–85
80–85
60–65
90–100
80–85
10
Amberlite (15%)
30
3
Amberlite (15%)
15
4
PMA-SiO2 (15%)
46
5
SiO2 (15%)
15
6
Montmorillonite K-10 clay (15%)
Indion resin (15%)
Wang-OSO3H (15%)
Wang-OSO3H (15%)
Wang-OSO3H (15%)
Wang-OSO3H (15%)
Wang-OSO3H (10%)
Wang-OSO3H (20%)
Wang-OSO3H (15%)
Wang-OSO3H (15%)
Wang-OSO3H (15%)
25
7
38
8
84
9
54
10
11
12
13
14
15
16
58
72
68
84
76
85
84, 82, 82, 80c
aReaction conditions: Dimedone 3 (1.0 equiv.), Phenacy bromide 4a (1.0 equiv.), primary amine 5a (1.0 equiv.), and catalyst in
a solvent.
c
bIsolated yields. The catalyst is recovered and reused for an additional four runs.

1652
N. K. R. DINNE ET AL.
isolated yield. While increasing the catalyst loading to 20% and increasing the temperature
to 90–100 °C did not gave significant yield improvement.
To check the recyclability and reuse of the catalyst, after completion of the reaction,
Wang-OSO3H was recovered by simple filtration and the catalyst was reused. The catalytic
activity of recovered wang-OSO3H was evaluated by subjecting the recovered catalyst
(entry 16, Table 1) to fresh substrates under optimized conditions. In the preparation of
6a, the recovered catalyst was reused for four times without significant loss in the yield
and its catalytic activity and the yields were 84, 82, 82, and 80%.
Experimental
General methods
Unless stated otherwise, reactions were performed under nitrogen atmosphere using oven-
dried glassware. Reactions were monitored by thin-layer chromatography (TLC) on silica
gel plates (60 F254), visualizing with ultraviolet light or iodine spray. Flash chromato-
graphy was performed on silica gel (100–200 mesh) using distilled hexane, ethyl acetate,
1
dichloromethane. H NMR and 13C NMR spectra were determined in CDCl3 or DMSO-
d6 solution using 400 or 100 MHz spectrometers, respectively. Proton chemical shifts (δ)
are relative to tetramethylsilane (TMS, δ ¼ 0.00) as internal standard and expressed in
ppm. Spin multiplicities are given as s (singlet), d (doublet), t (triplet), and m (multiplet)
as well as b (broad). Coupling constants (J) are given in hertz. Melting points were deter-
mined using melting point B-540 apparatus and are uncorrected. HRMS was determined
using waters LCT premier XETOF ARE-047 apparatus.
General experimental procedure for the preparation of 4-oxo-4,5,6,
7-tetrahydroindole derivatives (6a-n)
To a stirred solution of dimedone 3 (1 mmol.), phenacyl bromide 4a (1 mmol.), aniline 5a
(1 mmol.), in water (4 ml) was charged wang-OSO3H (15% w/w) at room temperature and
stirred the mixture at 80–85 °C for 4–5 h. After completion of the reaction as indicated by
TLC, cooled to room temperature, diluted with ethyl acetate (5 ml) and filtered the catalyst,
washed the catalyst with ethyl acetate (2 � 3 mL). Reaction conducted in water media using
Wong sulfonic acid resin in heterogeneous condition. After completion of the reaction, to
isolate our product from water reaction mass was diluted with ethyl acetate and filtered to
remove catalyst. Obtained filtrate is a mixture of immiscible water and ethyl acetate so our
product is in ethyl acetate layer which was separated and concentrated to get our products
(6a-n, because this is genaral procedure for preparation of 6).
Preparation of various 4-oxo-4,5,6,7-tetrahydroindole derivatives (6a-n)
Using optimized conditions, various 4-oxo-4,5,6,7-tetrahydroindole derivatives were
prepared in good to excellent yields. The phenacyl bromide and its derivatives having
groups like chloro, cyano, and methoxy were participated well in the reaction and
produced corresponding products (entries 1–4, Table 2). Aniline and its derivatives
having substituents like chloro, bromo, fluoro, and methyl also participated well in this
three-component reaction. Moreover, aliphatic amines like n-butylamine, cycloalkyl
amines like cyclopropylamine also gave corresponding products with good yields.

SYNTHETIC COMMUNICATIONS®
1653
Table 2. Synthesis of 4-oxo-4,5,6,7-tetrahydroindole derivatives under optimized conditionsa.
Entry
1
Phenacyl bromide (4)
Primary amine (5)
Product (6)
Time (h) Yield (%)b
3
91
2
3
3
84
4
81
4
5
6
4
3
3
80
89
90
(Continued)

1654
N. K. R. DINNE ET AL.
Table 2. Continued.
Entry
7
Phenacyl bromide (4)
Primary amine (5)
Product (6)
Time (h) Yield (%)b
3 85
8
4
86
9
10
3
88
11
4
87
12
4
83
(Continued)

SYNTHETIC COMMUNICATIONS®
1655
Table 2. Continued.
Entry
13
Phenacyl bromide (4)
Primary amine (5)
Product (6)
Time (h) Yield (%)b
3 89
14
3
92
aReactions were conducted using 3 (1 mmol), 4 (1 mmol), 5 (1 mmol) and 15% w/w catalyst in H2O (4 mL) at 80–85 °C.
bIsolated yields.
This Wang-OSO3H-catalyzed multicomponent methodology produced the 4-oxo-4,5,6,7-
tetrahydroindole derivatives in good yields (80–92%).
Proposed mechanism
The plausible reaction mechanism for this three-component reaction is shown in Scheme 3.
In the first step, dimedone 3 undergoes alkylation with phenacyl bromide 4 and forms tri-
keto compound A. In presence of the catalyst, primary amine 5 can attack one of the keto
groups of dimedone and followed by elimination of water molecule gives enamine B.
Scheme 3. Plausible mechanism for the formation of 6.

1656
N. K. R. DINNE ET AL.
Amino group of B can attack the carbonyl group of phenacyl bromide in presence of
catalyst and followed by elimination of water molecule gives the product 6.
Conclusion
In conclusion, Wang-OSO3H was found to be an efficient and reusable catalyst for the syn-
thesis of 4-oxo-4,5,6,7-tetrahydro indole derivatives through three-component reaction in
water. Current methodology is involved three-component reaction of variety of phenacyl
bromide, dimedone, and various primary amine compounds. This environmentally
benign, efficient, and operationally easy methodology afforded a range of 4-oxo-4,5,6,
7-tetrahydroindole derivatives in good yields (80–92%). The use of this recyclable, less
expensive, and environmentally benign catalyst in water media and good yield and wider
substrate scope of products are the key features of this methodology.
Funding
The authors would like to thank Dr. H. Rama Mohan and the management of Dr. Reddy’s Labora-
tories Limited for giving support to perform this work. We also thank the analytical department of
Dr. Reddy’s Laboratories for providing a timely support.
References
[1] Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
[2] Li, M.; Cao, H.; Wang, Y.; Lv, X. L.; Wen, L. R. Org. Lett. 2012, 14, 3470–3473.
[3] Doomling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083–3135.
[4] (a) Maiti, B.; Chanda, K.; Selvaraju, M.; Tseng, C. C.; Sun, C. M. ACS Comb. Sci. 2013, 15,
291–297; (b) Ganem, B. Acc. Chem. Res. 2009, 42, 463–472; (c) Isambert, N.; Duque,
M. M. S.; Plaquevent, J. C.; Genisson, Y.; Rodriguez, J.; Constantieux, T. Chem. Soc. Rev.
2011, 40, 1347–1357.
[5] Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893–930.
[6] Remers, W. A.; Weiss, M. J. J. Org. Chem. 1965, 30, 4381–4386.
[7] Masaguer, C. F.; Ravina, E. Tetrahedron Lett. 1996, 37, 5171–5174.
[8] Chun-Chatprasert, L.; Shannon, P. V. R. J. Chem. Soc., Perkin Trans. 1 1996, 1787–1795.
DOI:10.1039/P19960001787.
[9] Chacon-Garcia, L.; Martinez, R. Eur. J. Med. Chem. 2002, 37, 261–266.
[10] Sun, L.; Tran, N.; Liang, C.; Hubbard, S.; Tang, F.; Lipson, K.; Schreck, R.; Zhou, Y.; McMahon,
G.; Tang, C. J. Med. Chem. 2000, 43, 2633.
[11] To, Q. H.; Lee, Y. R.; Kim, S. H. Tetrahedron Lett. 2014, 70, 8108–8113.
[12] Remers, W. A.; Roth, R. H.; Gibs, G. J.; Weiss, M. J. Org. Chem. 1971, 36, 1232–1240.
[13] Nakajima, S.; Yoshida, K.; Mon, M.; Ban, Y.; Shibasaki, M. J. Chem. Soc., Chem. Commun. 1990,
468–470. DOI:10.1039/C39900000468.
[14] Dagher, C.; Hanna, R.; Terentiev, P. B.; Boundel, Y. G.; Kost, A. N.; Maskimov, B. I.
J. Hetrocyclic Chem. 1982, 19, 645–647.
[15] Jiang, B.; Li, Y.; Tu, M. S.; Wang, S. L.; Tu, S. J.; Li, G. J. Org. Chem. 2012, 77, 7497–7505.
[16] Maity, S.; Pathak, S.; Pramanik, A. Eur. J. Org. Chem. 2013, 2013, 2479–2485.
[17] Dhanunjaya Rao, A. V.; Vykunteswararao, B. P.; Bhaskarkumar, T.; Jogdand, N. R.; Kalita, D.;
Jaydeep, K. D.; Lilakar, J. K. D.; Siddaiah, V.; Sanasi, P. D.; Raghunadh, A. Tetrahedron Lett.
2015, 56, 4714–4717.