Choline chloride/urea ionic liquid catalyzed a convenient one-pot synthesis of indole-3-propanamide derivatives

Article abstract of DOI:10.1080/00397911.2013.769601

A sequential three-component reaction of aromatic aldehydes with Meldrum-s acid and N-methyl indole in the presence of choline chloride/urea ionic liquid as green catalyst has been described. In this one-pot multicomponent reaction, a series of indole-3-propanamide derivatives were synthesized with good to excellent yields. This methodology shows several advantages including fast reaction, easy isolation, operational simplicity that make it a useful and attractive option for the library generation of indole-3-propanamides (5a-l) for drug discovery. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2013.769601

This article was downloaded by: [Yale University Library]
On: 29 July 2013, At: 06:16
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Choline Chloride/Urea Ionic Liquid Catalyzed a
Convenient One-Pot Synthesis of Indole-3-Propanamide
Derivatives
Eranna Siddalingamurthy a , Kittappa M. Mahadevan a & Tamatakallu O. Shrungesh Kumar a
a Department of Post Graduate Studies and Research in Chemistry, School of Chemical
Science , Kuvempu University , Shankaraghatta , Karnataka , India
Accepted author version posted online: 03 Jul 2013.
To cite this article: Synthetic Communications (2013): Choline Chloride/Urea Ionic Liquid Catalyzed a Convenient One-Pot
Synthesis of Indole-3-Propanamide Derivatives, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2013.769601
To link to this article: http://dx.doi.org/10.1080/00397911.2013.769601
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

ACCEPTED MANUSCRIPT
Choline chloride/Urea Ionic Liquid Catalyzed a Convenient One-Pot Synthesis of
Indole-3-Propanamide Derivatives
Eranna Siddalingamurthy1, Kittappa M. Mahadevan1, Tamatakallu O. Shrungesh Kumar1
1Department of Post Graduate Studies and Research in Chemistry, School of Chemical
Science, Kuvempu University, Shankaraghatta, Karnataka, India
Correspondence: K. M. Mahadevan,Department of Post Graduate Studies and Research
in Chemistry, Kuvempu University, P.G. Center Kadur, Karnataka 577548, India Tel.:
+91-9164621170; E-mail: mahadevan.kmm@gmail.com
Abstract
A sequential three-component reaction of aromatic aldehydes with Meldrum’s acid and
N-methyl indole in presence of choline chloride/urea ionic liquid as green catalyst has
been described. In this one-pot multicomponent reaction, a series of indole-3-
propanamide derivatives were synthesized with good to excellent yields. This
methodology shows several advantages including fast reaction, easy isolation and
operational simplicity makes it a useful and attractive option for the library generation of
indole-3-propanamides (5a-l) for drug discovery.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
ACCEPTED MANUSCRIPT
1

ACCEPTED MANUSCRIPT
KEYWORDS: choline chloride/urea, indole-3-propanamides, multicomponent reaction,
Meldrum’s acid.
INTRODUCTION
Indole-3-propanamide has been served as precursor to obtain several biologically active
molecules, especially for the treatment of brain disorder,[1a] tyrosine kinase inhibitors and
in specifically inhibitors of epidermal growth factor (EGF) receptor.[1b] N-aryl-3-(indol-3-
yl)propanamide shows promising immunosuppressive activity.[2a] The fact that some
indolylcarboxamides also act as anti-allergic activity.[2b] Further,indole-3-propanamide
have been tested as potential systemic and topical inflammation inhibitors.[3] Thus indole-
3-propanamides have become an important precursor for the various pharmaceutical
ingredients. Therefore there is demand for better synthetic route for the preparation of
indolylcarboxamides. Over the past decade multicomponent reactions have undoubtedly
ACCEPTED MANUSCRIPT
2

ACCEPTED MANUSCRIPT
become a versatile tool for its rapidity, diversity, efficiency and environmental amiability.
Keeping above points in mind we have chosen the multicomponent reactions between
indole, Meldrum’s acid and aldehydes to prepare the beta substituted indole-3-
propanamides.[4,5]
Ionic liquids are the versatile solvents and reagents for the synthesis of many organic
molecules because they are neither volatile nor flammable, and non toxic, can be
recovered for reuse.[6] Thus choline chloride/urea ionic liquid has been used successfully
in Knoevenagel condensation and other organic reactions.[7,8]
The indole-3-propanamides have been prepared by various methods.[1,3][11–13] All the
existing methods suffered from some technical constraints like poor yield, use of pyridine
as solvent which is toxic, sometimes formation of bisindoles was observed and
sometimes only Knoevenagel products were being observed.[6] Keeping all these in mind
and inspired by our earlier use of choline chloride/urea ionic liquid as catalyst,[9,10] and
development of new methods for the synthesis of various heterocyclic compounds,[14–25]
here we have described a more conventional, but shorter and more economical approach
i.e. one pot condensation between N-methyl indole, aldehydes and Meldrum's acid in
choline chloride/urea ionic liquid catalytic system to get Meldrum’s adduct as
intermediates (Scheme 2) followed by cleavage of the intermediate Meldrum’s adduct by
various amines to furnish medicinally important indole-3-propanamide derivatives (5a-l)
in good to excellent yields.
ACCEPTED MANUSCRIPT
3

ACCEPTED MANUSCRIPT
RESULTS AND DISCUSSION
The synthetic route to target (5a) has been outlined in the Scheme 1. It started with
mixing three component coupling of N-methyl indole, Meldrum’s acid with the phenyl
acetaldehyde in presence of choline chloride/urea ionic liquid (20 mol%) in acetonitrile
solvent to get intermediate Meldrum’s adduct under 6 hr stirring at 80o C. Later the
isolated Meldrum’s adduct in the reaction mass was treated with 3-chloro aniline (4a)
under reflux condition gave N-(3-chlorophenyl)-3-(1-methyl-1H-indol-3-yl)-4-
phenylbutanamide (5a). Here the intermediate Meldrum’s adduct formation was
confirmed by spectral data with the standard.[10] Alternatively, when Meldrum’s adduct
was treated with the same amine (4a) without isolation, we found that the conversion was
neat to give product (5a) in good yield. Thus we adopted this methodology for the
preparation of remaining indole-3-propanamides (5b-l) as given in Scheme 2.
Before choosing the choline chloride/urea ionic liquid, we examined tertiary bases like
triethyl amine (TEA) and diisopropyl ethyl amine (DIPEA). Here we found that the
reaction was sluggish, and we didn’t observe any improvement even at reflux condition.
Further, we also did notice that no product formation in the absence of bases both in
ethanol and acetonitrile solvent. Based on these results as given in Table 1, we have
chosen choline chloride/urea (IL) as basic ionic liquid in acetonitrile which could give us
better yields of indole-3-propanamides in which the choline chloride/urea catalyst found
to expedite the multicomponent condensation between N-methyl indole, aldehydes and
Meldrum’s acid to give compounds (5a-n) at reflux condition.
ACCEPTED MANUSCRIPT
4

ACCEPTED MANUSCRIPT
In order to further improve reaction condition we tried various concentration of the ionic
liquid at both room temperature and reflux temperature. Irrespective of the concentration
of IL we found the reaction did not proceed at room temperature except in the case of
(5a) where we found 50% conversion after 15 h (IL 20 mol%). Further, we have seen that
the reaction mass was charred when we use IL as solvent as well as catalyst.
Accordingly, when the reaction was carried out at 50 mol% of IL in acetonitrile solvent,
we observe that the yield was significantly increased. So after several efforts we found,
20 mol% of IL in acetonitrile was optimal to obtain good to excellent yields of indole-3-
propanamide derivatives. The details are mentioned in Table 2.
Thus, the Meldrum’s adducts formed were treated with various amine nucleophiles (4a-
h) to afford various indole-3-propanamide (5a-l). In the case of amino alcohol 4b we
found only amine is reacted with Meldrum’s adduct over alcohol. Similarly, when
Meldrum’s adduct was treated with water we found exclusively corresponding acid
products (5m & 5n). This is probably due to the presence of ionic liquid which makes
water a strong nucleophile by generating more hydroxyl anions.
Further, the meldrum’s adducts were synthesized using various aldehydes such as
aliphatic (phenyl acetaldehyde), aromatic (various benzaldehydes) and heterocyclic
(quinoline-3-carbaldehyde). In each case the formation of adduct was excellent. The
substituents like electron donating (2-ethoxy benzaldehyde) and electron withdrawing (4-
nitro benzaldehyde) groups in the benzene ring did not deter the adduct formation as well
as their yield (table 1). Altogether, this emphasizes the generality of this new procedure.
ACCEPTED MANUSCRIPT
5

ACCEPTED MANUSCRIPT
In addition, the reaction of various amines with Meldrum’s adduct to give corresponding
indole-3-propanamides (5a-l) was found to be concentration dependent. Thus, when we
used 1 equivalent of amines (4a-h) to cleave Meldrum’s adduct by refluxing at 80oC for
6hr. Along with products (5a-l) we found unreacted Meldrum’s adduct in the reaction
mixture. But at the same time when increase in the amine concentration to 4 to 5
equivalent, the Meldrum’s adduct was completely disappeared to give corresponding
indole-3-propanamides (5a-l) including side products. After several trials, we found that
1.5-2 equivalence of amines were optimum for the complete conversion with minimum
impurities. The details of the yields have been given in the Table 3.
Thus, successfully we adopted this trimolecular condensation between N-methyl indole,
Meldrum’s acid and aldehydes using choline chloride/urea (IL) ionic liquid as catalyst for
the preparation of indole-3-propanamides. This method proved to be a versatile and
general method for the preparation of various indole-3-propanamides, considering the
tolerance to diverse aldehydes and the limitations observed in reported methods.
CONCLUSION
In conclusion we have developed a versatile and general method using choline
chloride/urea (IL) as catalyst for the three component coupling of N-methyl indole,
Meldrum’s acid and aldehydes to get Meldrum’s adduct followed by reaction of amines
with this Meldrum’s adduct to get indole-3-propanamides. This is an environmentally
benign method which offers several advantages such as ease of the reaction, cheaper
ACCEPTED MANUSCRIPT
6

ACCEPTED MANUSCRIPT
catalyst and less hazardous. As well as it sustains diverse aldehydes in synthesizing
variety of indole-3-propanamides in good yields.
EXPERIMENTAL
The 1H NMR and 13C NMR spectra were recorded on a 400 MHz and 100 MHz Bruker
Spectrometer using CDCl3 or DMSO-d6 solvents and TMS as internal standard. Mass
spectra were recorded on Agilent 1200 series single quadrapole mass analyzer.The
elemental analysis was recorded in VarioMICRO CHNS elemental analyser. Melting
points were recorded (uncorrected) in Buchi Melting Point B-545 instrument. The purity
of the compounds was checked by TLC and was further purified by column
chromatography.
Preparation Of Ionic Liquid (IL)
The ionic liquid choline chloride/urea was prepared according to the procedures reported
in literature [26] by heating a mixture of choline chloride and urea with a molar ratio of 1:2
at 80 oC until a homogeneous liquid was formed.
Typical Procedure For The Preparation Of Β-Substituted Indole-3-Propanamide
Derivatives
N-(3-chlorophenyl)-3-(1-methyl-1H-indol-3-yl)-4-phenylbutanamide (5a):
To the solution of N-methyl indole (200 mg, 1.52 mmol), Meldrum’s acid (220 mg, 1.52
mmol), phenyl acetaldehyde (180 mg, 1.52 mmol) in acetonitrile (2 mL), choline
chloride-urea ionic liquid (20 mol%) was added. The resultant mixture was stirred at 80
ACCEPTED MANUSCRIPT
7

ACCEPTED MANUSCRIPT
oC. After 6hr, 3-chloro aniline (291 mg, 2.28 mmol) was added and continued the
heating. After 7hr, reaction completion was monitored by TLC which shows absence of
starting material. The reaction mixture was cooled to ambient temperature and diluted
with water (2 mL). The contents were extracted into ethyl acetate (6 x 3 mL). The organic
layer was washed with brine solution (3 mL), dried over anhydrous Na2SO4 and
concentrated to residue. The residue was further purified by column chromatography (Pet
ether and ethyl acetate system). The product collected in the gradient of 30-40% v/v to
get pure compound (450mg, 74%). Similar procedure was followed to prepare other
analogues.
Spectral Data
N-(3-Chlorophenyl)-3-(1-Methyl-1H-Indol-3-Yl)-4-Phenylbutanamide (5a)
1H NMR (400 MHz, DMSO-d6 ): δ 2.70 (d, J = 7.28 Hz, 2H), 2.95 (dd, J = 6.88, 13.4 Hz,
1H), 3.05 (dd, J = 7.64, 13.48 Hz, 1H), 3.67 (s, 3H), 3.73-3.79 (m, 1H), 6.97-7.05 (m,
2H), 7.09-7.12 (m, 5H), 7.18-7.21 (m, 2H), 7.25 (t, J = 8.08 Hz, 1H), 7.32-7.36 (m, 2H),
7.63 (d, J = 8.00 Hz, 1H), 7.73 (s, 1H), 10.05 (s, 1H). ppm; 13C NMR (100 MHz, DMSO-
d6): 32.75, 35.09, 41.76, 42.70, 110.09, 116.72, 117.88, 118.74, 119.04, 119.45, 121.43,
123.13, 126.26, 126.89, 127.17, 128.45, 129.48, 130.74, 133.39, 137.20, 140.79, 141.04,
171.0 ppm. LCMS: m/z=403.2 (M+1). Anal. Calcd. for C25H23ClN2O2: C, 74.52; H, 5.75;
N, 6.95; Found: C, 74.20; H, 5.521; N, 6.62.
ACKNOWLEDGMENTS
ACCEPTED MANUSCRIPT
8

ACCEPTED MANUSCRIPT
We are thankful to the Department of Postgraduate Studies and Research in Chemistry,
Kuvempu University, Shankaraghatta, for providing laboratory facilities and also grateful
to the Indian Institute of Science, Bangalore, for providing spectral data.
SUPPORTING INFORMATION:
Full experimental detail, 1H and 13C NMR spectra, LCMS and Elemental Analysis data
can be found via the ‘‘Supplementary Content’’ section of this article’s webpage.’’
REFERENCES
[1]
(a) Cooper, L. C.; Chicchi, G. G.; Dinnell, K.; Elliott, J. M.; Hollingworth, G. J.;
Kurtz, M. M.; Locker, K. L.; Morrsion, D.; Shaw, D. E.; Taso, K. L.; Watt, A. P.;
Williams, A. R.; Swain. C. J. 2-Aryl Indole Nk1 Receptor Antagonists: optimization of
indole substitution. Bioorg. Med. Chem. Lett. 2001, 11, 1233-1236; (b) Andrew, M. T.;
David, W. F.; Alan, J. K.; William, A. D. Tyrosine kinase inhibitors.2.synthesis of 2,2’-
dithiobis(1H-indole-3-alkanamides) and investigation of their inhibitory activity against
epidermal growth factor receptor and pp600-src protein tyrosine kinases. J. Med. Chem.
1994, 37, 598–609; (c) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Meldrum’s acid in
organic synthesis A convenient one-pot synthesis of ethyl indole propionates.
Tetrahedran Lett. 1978, 19, 1759-1762; (d) Oikawa, Y.; Hirasawa, H.; Yonemitsu, O.
Medrum’s Acid in organic synthesis. Versatile One-pot synthesis of indolepropionic
Ester via simultaneous condensation of three different carbon components, Indole
aldehydes and medrum’s acid. Chemical & pharmaceutical bulletin. 1982, 30, 3092-
3096.
ACCEPTED MANUSCRIPT
9

ACCEPTED MANUSCRIPT
[2]
(a) Francis, G.; Pascal, M.; Delphine, C.; Michael, S.; François, L.;Muriel, D.
Synthesis of N-aryl-3-(indol-3-yl)propanamides and their immunosuppressive activities.
Bioorg. Med. Chem. Lett. 2010, 20, 5203–5206; (b) Jacobs, R. T.; Brown, F. J.; Cronk, L.
A.; Aharony, D.; Buckner, C. K.; Kusner, E. J. Kirkland, K. M.; Neilson, K. L.
Substituted 3-(phenylmethyl)-1H-indole-5-carboxamides and 1-(phenylmethyl)indole-6-
carboxamides as potent, selective, orally active antagonists of the peptidoleukotrienes. J.
Med. Chem. 1993, 36, 394-409.
[3]
Duflos, M.; Nourrsson, M. R.; Brelet, J.; Courant, J.; LeBaut, B.; Brimaud, N.;
Petit, J. Y. N-Pyridinyl-indole-3-(alkyl)carboxamides and derivatives as potential
systemic and topical inflammation inhibitors. Eur. J. Med. Chem. 2001, 36, 545-553.
[4]
(a) Dardennes, E.; Gérard, S.; Petermann, C.; Sapi, J. Diastereoselective
trimolecular condensation between indole, Meldrum’s acid and chiral sugar-derived
aldehydes. Tetrahedron: Asymmetry. 2010, 21, 208–215; (b) Dardennes, E.; Kulyassa, A.
K.; Boisbrun, M.; Petermann, C.; Laronze, J. Y.; Sapi, J . Diastereocontrolled
multicomponent pathway to 3,4-heterocycle-annulated tetrahydro- -carbolines.
Tetrahedron: Asymmetry. 2005, 16, 1329–1339.
[5]
Cochard, F.; Laronze, M.; Sigaut, P.; Sapi, J.; Laronze. J. Y. Synthesis of
carbazoles by a lanced four component condensation. Tetrahedron Lett. 2004, 45, 1703-
1707.
[6]
Mols, A.; Vendra, R. J.; Axel, T. K.; Ionic liquids. Journal of Endochemisty:
Phys. Dut. Aspects. 125.
[7]
(a) Zhiying, D.; Yanlong, G.; Youquan, D. Green and moisture-stable Lewis
acidic ionic liquids (choline chloride xZnCl2) catalyzed protection of carbonyls at room
ACCEPTED MANUSCRIPT
10

ACCEPTED MANUSCRIPT
temperature under solvent-free conditions. Catalysis Commun. 2006, 7, 651–656; (b)
Yogesh, A. S.; Sunanda, B. P.; Bhushan, N. B.; Amit, R. J.; Ganapati, S. S. Synthesis of
diphenylamine-based novel fluorescent styryl colorants by knoevenagel condensation
using a conventional method, biocatalyst, and deep eutectic solvent. Org. Lett. 2010, 12,
1456-1459.
[8]
Anlian, Z.; Tao, J.; Buxing, H.; Jicheng, Z.; Ye, X.; Xiumin, M. Supported
choline chloride/urea as a heterogeneous catalyst for chemical fixation of carbon dioxide
to cyclic carbonates. Green Chem. 2007, 9, 169–172.
[9]
Harishkumar, H. N.; Mahadevan, K. M.; Kumar, H. C. K.; Satyanarayan. N. D. A
facile, Choline Chloride/Urea catalysed solid phase synthesis of coumarins via
Knoevenagel condensation.Org. Commun. 2011, 4, 9-15.
[10] Harishkumar, H. N.; Mahadevan, K. M.; Jagadeesh. N. M. Facile synthesis of 2-
(1,3-benzoxaol/benzothiazol-2-yl)-3H-benzol[f]chromen-3-one as Blue Fluorescent
Brighteners. S. Afr. J. Chem. 2012, 65, 5-9.
[11] Nemes, C.; Jeannin, L.; Sapi, J.; Laronze, M.; Seghir, H.; Auge, F.; Laronze, J. Y.
A convenient synthesis of conformationally constrained -substitued tryptophans.
Tetrahedron. 2000, 56, 5479-5492.
[12] Boisbruna, M.; Vassilevab, E.; Raoul, M.; Laronze, J. Y.; Sapi, J. A Convenient
preparation of b-acetamido substituted tryptamine derivatives. Monatshefte fur Chemie.
2003, 134, 1641–1649
[13] Cochard, F.; Sapi, J.; Laronze, J. Y. A novel and convenient access to highly
substituted spiro[pyrrolidinon-3,3-indoles]. Tetrahedron Letters. 2001, 42, 6291–6294.
ACCEPTED MANUSCRIPT
11

ACCEPTED MANUSCRIPT
[14] Rajesha.; Bhojya, N. H. S.; Harishkumar, H. N.; Hosamani, K. M.; Mahadevan,
K. M. Studies on the synthesis and fluorescent properties of long-chained 2-(5-alkyl-1, 3,
4-oxadiazol-2-yl)-3H-benzo[f]chromen-3-ones. Arkivoc. 2009, (ii), 11-19.
[15] Rajesha, G. Kiran, K. H. C.; Bhojya, N. H. S.; Mahadevan, K. M. Synthesis of
new benzocoumaryl oxadiazolyls as strong blue-green fluorescent brighteners. S. Afr. J.
Chem. 2011, 64, 88-94.
[16] Rajesha, Kiran K. H. C.; Bhojya, N. H. S.; Mahadevan, K. M. Synthesis and
fluorescence study of 2-[5-(-2-arylethenyl)-1, 3, 4-oxadiazol-2-yl]-3H-benzo[f]chromen-
3-ones. Org. Chem.: Indian J. 2012, 8(1), 34-40.
[17] Harishkumar, H. N.; Vijaykumar, H.; Mahadevan, K. M. Aqueous synthesis of N-
phenyl/alkyl-2-quinolinone-3-carboxylic acids from coumarin-3-carboxylic acids. Synth.
Commun. 2010, 40, 3281-3289.
[18] Prabhakara, V. P.; Mahadevan, K. M.; Abdul, K.; Vijaykumar, H. One pot
synthesis of 2-hydroxy pyrrolidine derivatives. Org. Commun. 2011, 4:3, 52-57.
[19] Prabhakara, V. P.; Srinivasa, A.; Mahadevan, K. M. An efficient InCl3/H2O
catalyzed one-pot stereo selective synthesis of cis-2-methyl-4-amido-1,2,3,4-
tetrahydroquinoline derivatives. Synth. Commun. 2011, 41, 2186-2194.
[20] Harishkumar, H. N.; Mahapatra, S.; Venugopala, K. N.; Mahadevan, K. M. 3-(2-
Bromoacetyl)-6-fluoro-2H-chromen-2-one. Acta Cryst. 2011, E67, 2264.
[21] Rajesha, G. Mahadevan, K. M.; Satyanarayan, N. D.; Bhojya, N. H. S. Synthesis,
antibacterial, and analgesic activity of novel 4-hydroxy-3-(phenylthio)-2H-chromen-2-
ones and 4-hydroxy-3-[imidazol/tetrazolo-2-yl)thio]-2hchromen-2-ones. Phosphorus,
Sulfur Silicon Relat. Elem. 2011, 186, 1733-1743.
ACCEPTED MANUSCRIPT
12

ACCEPTED MANUSCRIPT
[22] Rajesha, Kiran, K. H. C.; Bhojya, N. H. S.; Mahadevan, K. M. Aqueous synthesis
of coumarins using tetramethylammonium hydroxide as surfactants. Org. Chem.: Indian
J. 2011, 7(6), 365-368.
[23] Bindu, P. J.; Mahadevan, K. M.; Satyanarayan, N. D.; Ravikumar, N. T. R.
Synthesis and DNA cleavage studies of novel quinoline oxime esters. Bioorg. Med.
Chem. Lett. 2012, 22, 898-900.
[24] Bindu, P. J.; Mahadevan, K. M.; Ravikumar, N. T. R. Sm(III)nitrate-catalyzed
one-pot synthesis of furano[3,2c]-1,2,3,4-tetrahydroquinolines and DNA photocleavage
studies. J. Mol. Struct. 2012, 1020, 142-147.
[25] Kiran, K. H. C.; Mahadevan, K. M.; Prabhakara, V. P.; Srinivasa, A. One pot
synthesis of medicinally important cis-2-methyl-4-amino substituted-1,2,3,4-
tetrahydroquinoline. Chin. J. Chem. 2012, 30, 534-540.
[26] Abbott, A. P.; Capper, G.; Davies, D. L.; Rasheed, R. K.; Tambyrajah, V. Novel
solvent properties of choline chloride/urea mixtures. Chem. Comm. 2003, 70-71.
ACCEPTED MANUSCRIPT
13

ACCEPTED MANUSCRIPT
Table 1. Optimization of basic condition for the synthesis of indole-3-propanmides at 80o
C
Solvents
CAN
Catalyst
--
Result
NR
EtOH
CAN
--
NR
TEA
DIPEA
IL
<20%
<20%
<50%
75%
CAN
EtOH
CAN
IL
Note:- IL: Choline chloride /urea, NR: No reaction.
TEA: triethyl amine.
DIPEA: Diisopropyl ethyl amine.
ACCEPTED MANUSCRIPT
14

ACCEPTED MANUSCRIPT
Table 2. Optimization of reaction condition for the synthesis of indole-3 propanamides in
different concentrations of ionic liquid a
Entry
Aldehydes N-methyl Meldrum’s Ionic
Time (h)
Yieldb
(%)
Mol %
Indole
acid Mol % Liquid
mol
Mol %
1
2
3
1
1
1
1
1
1
1
1
1
as solvent
1
4
6
---
50 mol%
20 mol%
< 50
85
aAll reactions were carried out at reflux temperature.
bisolated yields.
ACCEPTED MANUSCRIPT
15

ACCEPTED MANUSCRIPT
Table 3. Physical data of indole-3-propanamide 5a-l and indole-3-propanoic acid 5m-n
analogues.
Entry
5a
R
R1
Products
Yield b
(%)
M.P/ oC
154-155
O
NH
HN
74
Cl
N
Cl
5b
5c
84
85
203-204
147-148
OH
O
NH
OH
NH
HN
N
O
O
NH
Cl
O
Cl
N
NH
HN
5d
5e
89
85
123-124
193-194
O
O
N
O
NH
O
O
N
Cl
N
O
NH
Cl
N
NH
5f
5g
5h
86
80
88
205-206
185-186
169-171
N
O
N
N
N
NH
N
NH
O
N
O
O
NH
N
O
NH
N
NH
N
ACCEPTED MANUSCRIPT
16

ACCEPTED MANUSCRIPT
HN
5i
90
90
200-202
215-218
N
O
N
NH
Cl
Cl
N
O
N
2
NO
2
5j
O
HN
N
5k
5l
91
92
200-204
210-213
O
HN
N
Cl
Cl
O
HN
N
F
O
F
5m
5n
81
84
216-217
235-237
-OH
-OH
O
O
O
O
HO
N
N
S
S
O
N
HO
N
aAll reactions were carried out at reflux temperature
bisolated yields.
ACCEPTED MANUSCRIPT
17

ACCEPTED MANUSCRIPT
Scheme 1. Preparation of N-(3-chlorophenyl)-3-(1-methyl-1H-indol-3-yl)-4-
phenylbutanamide 5a.
ACCEPTED MANUSCRIPT
18

ACCEPTED MANUSCRIPT
Scheme 2. Three component coupling to prepare indole-3-propanamide 5b-l. and indole-
3-propanoic acid analogues 5m-n.
ACCEPTED MANUSCRIPT
19