Catalyst free sequential one-pot reaction for the synthesis of 3-indole propanoates/propanoic acid/propanamides as antituberculosis agents

Article abstract of DOI:10.1002/jccs.202000386

A highly efficient catalyst free one pot four component synthesis of highly functionalized three-substituted indole derivatives has been reported. Thus, sequential catalyst free condensation of readily available aldehydes with Meldrum's acid followed by Michael addition of indole resulting three carbon component condensed product and concurrent decarboxylation by the nucleophilic attack of ethanol/water/amines affords three-indole propanoates/propanoic acid/propanamides in affordable yields. Further, synthesized compounds and standard drugs were evaluated against Mycobacterium tuberculosis H37Rv strain by Alamar blue assay method. Majority of the compounds exhibited the superior activity and specifically compound 4d has MIC 1.6 μg/ml, which is better than the reference drugs used.

Full text of DOI:10.1002/jccs.202000386

Received: 8 September 2020
DOI: 10.1002/jccs.202000386
Revised: 12 December 2020
Accepted: 12 December 2020
C O M M U N I C A T I O N
Catalyst free sequential one-pot reaction for the synthesis
of 3-indole propanoates/propanoic acid/propanamides
as antituberculosis agents
Narasimhamurthy Rajeev1 | Kothanahally S. Sharath Kumar1
|
Yadaganahalli K. Bommegowda1 | Kanchugarakoppal S. Rangappa2
Marilinganadoddi P. Sadashiva1
|
1Department of Studies in Chemistry,
Abstract
University of Mysore, Mysuru, India
2Institution of Excellence, University of
Mysore, Mysuru, India
A highly efficient catalyst free one pot four component synthesis of highly
functionalized three-substituted indole derivatives has been reported. Thus,
sequential catalyst free condensation of readily available aldehydes with
Meldrum's acid followed by Michael addition of indole resulting three carbon
component condensed product and concurrent decarboxylation by the nucleo-
philic attack of ethanol/water/amines affords three-indole propanoates/
propanoic acid/propanamides in affordable yields. Further, synthesized com-
pounds and standard drugs were evaluated against Mycobacterium tuberculosis
H37Rv strain by Alamar blue assay method. Majority of the compounds
exhibited the superior activity and specifically compound 4d has MIC
1.6 μg/ml, which is better than the reference drugs used.
Correspondence
Marilinganadoddi P. Sadashiva,
Department of Studies in Chemistry,
University of Mysore, Manasagangotri,
Mysuru 570006, India.
Email: mpsadashiva@gmail.com
Kanchugarakoppal S. Rangappa,
Institution of Excellence, University of
Mysore, Vijnana Bhavan, Manasagangotri,
Mysuru, 570006, India.
Email: rangappaks@gmail.com,
rangappaks@yahoo.com
K E Y W O R D S
indole, Meldrum's acid, Michael addition, multicomponent and tuberculosis
1 | INTRODUCTION
natural compounds,10 antimicrobial agents,11 and functional
materials.12 Tuberculosis is becoming leading infectious
One-pot multicomponent coupling reactions have
become an important tool for the synthesis of a wide vari-
ety of pharmaceuticals and agrochemicals. The advances
in the field of drug discovery1–4 have majorly dependent
on improved reaction conditions in which a numerous
parallel reaction could be done.5,6 Soon these one pot
multicomponent processes become necessary to shift
toward more green processes.7
cause of death in adults surpassing human immunodefi-
ciency virus.13 Indole-3-propionic acid (IPA) is the first
microbiome-derived metabolite produced by the gut
microbiota has potential to impact Mycobacterium tuber-
culosis both in vitro and in vivo. IPA is the deamination
product of essential aromatic amino acid tryptophan
(Trp) (Figure 1) and thus a close structural analog of this
amino acid and mimics Trp. Negatu et al.14 have hypoth-
esized that anti-Mycobacterium tuberculosis activity of
IPA is by blocking Trp biosynthesis through allosteric
inhibition of TrpE activity.
Three-substituted indole represent an important class
of heterocyclic compounds, due to its presence in a num-
ber of pharmaceutical products,8 agrochemicals,9 bioactive
In view of the potential antitubercular activity of IPA,
many simple and high yielding protocols have been devel-
oped for the synthesis of three-substituted indole
Narasimhamurthy Rajeev and Kothanahally S. Sharath Kumar
contributed equally to this work.
J Chin Chem Soc. 2021;68:39–44.
http://www.jccs.wiley-vch.de
© 2020 The Chemical Society Located in Taipei & Wiley-VCH GmbH
39

40
RAJEEV ET AL.
SCHEME 1 Synthesis of ethyl 3-(4-cyanophenyl)-
3-(6-methoxy-1H-indol-3-yl) propanoate (4a)
FIGURE 1 Structures of Indole-3-propionic acid (IPA) and
aromatic amino acid(L-Tryptophan)
TABLE 1 Catalyst free one pot synthesis of 4a under different
derivatives. Yonemitsu and coworkers15 have first reported
the trimolecular condensation of indole with Meldrum's
acid and aldehyde for the synthesis of three-substituted
indoles. Later they have applied the same strategy16 for
the synthesis of various ethyl-3-indole propanoates. In
both the attempts they have reported two step synthesis of
ethyl-3-indole propanoates, more importantly ethanolysis
of the condensed product (6) formed from the first step
was achieved in the presence of pyridine (toxic)17 and used
copper as a catalyst to accelerate the decarboxylation pro-
cess and the major concern is limited substrate scope,
which only produce ethyl-3-indole propanoates.
Based on these reports many research groups have
attempted for the enantioselective synthesis of three-
substituted indole derivatives using various catalysts and
additives like Cu(OTf)2,18–20 oxazoline based metal
complexes,21,22 scandium(III) complexes,23–27 copper,28
Cu(ClO4)2Á6H2O,29 pyridine complexes,30,31 chiral
thioureas,32 TiCl4 derivatives,33 Yb(OTf)3,34 rhodium
complexes,35 zinc,36 nano materials,37,38 and chiral phos-
phoric acid.39 It is noteworthy to mention that, none of
the above mentioned methods reported the synthesis of
3-indole propanoic acid and propanamide derivatives in
one pot operation using aldehyde, Meldrum's acid, and
indole as three carbon components.
reaction conditions
Sl. noa
Solvent
DMF
Time (hr)
Temp. (ꢀC)
80
Yieldb
76
1
5
5
5
5
4
6
5
5
5
5
5
5
2
DMF
90
85
3
DMF
100
92
4
DMF
110
90
5
DMF
100
86
6
DMF
100
91
7
1,4-Dioxane
Acetonitrile
THF
100
84
8
100
86
9
100
80
10
11
12
Toluene
Benzene
DMA
100
81
100
82
100
78
aIndole, aldehyde, and Meldrum's acid were stirred in DMF for 12 hr.
bIsolated yield.
Our continuing efforts and interests in developing
multi component reactions for the synthesis of various
heterocycles40–44 prompted us to investigate the simple
approach to produce structurally diversified three-
substituted indole derivatives through adaptable one-pot
multicomponent reactions. Here, we report an experi-
mentally simple and high yielding protocol for the syn-
thesis of 3-indole propanoates/propanoic acid/
propanamide derivatives via one-pot operation. To the
best of our knowledge, we are the first to attempt the cat-
alyst free synthesis of 3-indole propanoic acid/
propanamides in one-pot operation.
SCHEME 2 Synthesis of indole-3-propanoates/propanoic acid/
propanamides
4-cyanobenzaldehyde (2a) and 6-methoxy-indole (1a)
(Scheme 1) in polar aprotic solvent dimethylformamide
(DMF). After the examination of the reaction by thin
layer chromatography (TLC) for 12 hr at room tempera-
ture we have noticed the formation of condensation prod-
uct (6) in excellent yield. Later in the same reaction
mixture we have tried ethanolysis of condensed product
using ethanol as a nucleophile without any catalyst and
additives by heating the reaction mixture at 80ꢀC. The
reaction was monitored by TLC for 5 hr and reaction
yielded the appropriate ethyl-3-indole propanoate (4a)
with 76% yield (Table 1, entry 1). We observed that
increase in temperature of the reaction mixture would
2 | RESULTS AND DISCUSSION
To optimize the reaction condition, we initially selected
the condensation reaction of Meldrum's acid (3),

RAJEEV ET AL.
41
TABLE 2 Synthesis of three-substituted indole derivatives (4a-n)
Sl. noa
1
2
Nu
4
T (hr)
Yieldb (%)
1
EtOH
5
92
2
3
4
EtOH
EtOH
EtOH
5
5
6
91
90
88
1a
1b
5
6
H2O
H2O
6
5
85
91
1b
1b
7
8
2e
H2O
H2O
6
5
87
90
9
H2O
H2O
6
8
6
86
85
90
10
11
2e
1c
1c
1b
12
13
2i
6
6
91
89
2g
14
1b
2i
7
84
aIndole (1 eq), Meldrum's acid (1.05 eq), Aldehyde (1.05 eq), DMF (10 V) Nucleophile (1.1 eq).
bIsolated yield.

42
RAJEEV ET AL.
enhance yield up to 92% in 5 hr (Table 1, entry 2 and 3),
further increase in temperature of the reaction and vari-
ation in reaction time does not improve the product
yield (Table 1, entry 4–6). We then selected the optimal
temperature and time by changing the solvent, thus
the reaction was screened in various solvents viz 1,4
dioxane, acetonitrile, tetrahydrofuran (THF), toluene,
benzene, and dimethylacetamide gave decreased yield of
4a (Table 1, entry 7–12).
With the optimized reaction condition in hand, we
went on to synthesize different ethyl-3-indole propa-
noates (Scheme 2) using different indole and aliphatic/
aromatic aldehyde derivatives bearing both electron
donating and electron withdrawing substituents, interest-
ingly all of them gave a moderate to good yield (Table 2,
entry 1–4). To explore the generality of the protocol and
to extend our study, we used the optimized condition to
react the condensation product (6) with different nucleo-
philes like water and amines. Surprisingly both the
nucleophiles are efficient in affecting the decarboxylation
of condensed product without any catalyst/additives.
Water produced corresponding indole propanoic acid in
excellent yield (Table 2, entry 5–10) and both primary
and secondary amines underwent reaction smoothly to
give respective indole propanamides in good yield
(Table 2, entry 11–14).
As we have mainly focused on screening small
molecules for different biological activities,45–50 all the
synthesized compounds 4(a-n) were screened for anti-
Mycobacterium tuberculosis activity by Alamar Blue assay
method.51 Majority of the compounds exhibited the good
activity against the H37Rv strain, their Minimum Inhibi-
tory concentration (MIC) are evaluated experimentally
and their values are tabulated in the Table 3. The in vitro
studies indicated that eight compounds (4j, 4i, 4b, 4c, 4d,
4n, 4k, and 4l) have good to excellent activity, while the
rest showed lower inhibition against Mycobacterium
tuberculosis in comparison with the standard.
The possible mechanism looks to be simple
(Scheme 3), which involves the aldol condensation
followed by the Michael addition of indole to produce
condensed product (6), which undergoes decarboxylation
in presence of different nucleophiles (ethanol, water, and
amines) to give the desired products with the liberation
of acetone as a byproduct.
3 | EXPERIMENTAL
General procedure for the synthesis of 3-indole propanoates/
propanoic acid/propanamides (4a-n).
TABLE 3 MIC values of compounds (4a-n) against
Mycobacterium tuberculosis H37Rv strain
The mixture of Indole (2 mmol), Meldrum's acid
(2.1 mmol), and aldehyde (2.1 mmol) were dissolved in
DMF (20 ml) and stirred for 12 hr at room temperature.
The disappearance of the starting materials and the for-
mation of the condensation product were monitored by
TLC, after the completion of the reaction, to the same
reaction mixture the nucleophile (2.2 mmol) was added
and the reaction mixture was heated to 100ꢀC and stirred
for 5 hr. After the completion of reaction monitored by
TLC, water (25 ml) was added to the reaction mixture
and extracted with ethyl acetate (25 ml × 2). The com-
bined organic layer was washed in water (25 ml), brine
(25 ml), dried over anhydrous sodium sulfate, and
Compounds
MIC
25
Compounds
MIC
12.5
3.12
3.12
3.12
3.12
25
4a
4h
4b
3.12
6.25
1.6
4i
4c
4j
4d
4k
4e
50
4l
4f
12.5
25
4m
4g
4n
6.25
6.25
Pyrazinamide
3.12
Streptomycin
Note: MIC values are in μg/ml.
SCHEME 3 Possible mechanism for the formation of
3-indole propanoates/propanoic acid/propanamides

RAJEEV ET AL.
43
[2] S. Jagadish, M. Hemshekhar, S. K. Naveen Kumar, K. S.
Sharath Kumar, M. S. Sundaram, K. S. Girish, K. S. Rangappa,
Toxicol. Appl. Pharmacol. 2017, 334, 167.
[3] S. Jagadish, N. Rajeev, S. K. Naveen Kumar, K. S. Sharath
Kumar, M. Manoj Paul, M. P. Hegde, K. S. Sadashiva, K. S. R.
Girish, Mol. Cell. Biochem. 2016, 414, 137.
[4] N. Snehal, M. Raghunandan, K. Jinsha, K. S. Sujeeth Kumar,
G. Sharath Kumar, S. S. S. K. Vidya, B. Choudhary, Molecules
2020, 25, 4499.
concentrated under reduced pressure to get crude prod-
ucts, which were purified by column chromatography
using 10% ethyl acetate in hexane.
3.1 | Anti-TB activity using Alamar
blue dye
[5] S. Ding, N. S. Gray, X. Wu, Q. Ding, P. G. Schultz, J. Am.
Chem. Soc. 2002, 124, 1594.
The antimycobacterial activity of compounds was
screened for M. tuberculosis (H37 RV strain), ATCC No-
27294, using microplate Alamar Blue assay (MABA). For
the outer perimeter of the well in 96 well plate, 200 μl of
sterile deionized water was added (to minimized evapora-
tion of medium in the test wells during incubation),
100 μl of the Middlebrook 7H9 broth, and serial two-fold
dilution of synthesized compounds were added to the
each well (100–0.2 μg/ml). After addition, plates were
covered and sealed with parafilm and incubated at 37ꢀC
for 5 days. Once completion of the incubation, added
25 μl of freshly prepared 1:1 mixture of Almar Blue
reagent and 10% tween 80 to the plate and incubated for
24 hr at the same temperature. The appearance of the
blue color in the well indicated as no bacterial growth
and appeared pink color as growth. The lowest concen-
tration of drug, which prevented the color change from
blue to pink was defined as MIC of the compound.
[6] K. Wang, D. Kim, A. Domling, J. Comb. Chem. 2010, 12, 111.
[7] M. C. Bryan, B. Dillon, L. G. Hamann, G. J. Hughes, M. E.
Kopach, E. A. Peterson, M. Pourashraf, I. Raheem, P.
Richardson, D. Richter, H. F. Sneddon, J. Med. Chem. 2013,
56, 6007.
[8] S. Hanessian, E. Stoffman, X. Mi, P. Renton, Org. Lett. 2011,
13, 840.
[9] A. Andreani, M. Rambaldi, J. Het. Chem. 1988, 25, 1519.
[10] X. Zhang, T. Mu, F. Zhan, L. Ma, G. Liang, Angew. Chem.
2011, 50, 6164.
[11] S. Mostafa, M. Adel, K. El-Dean, A. Mostafa, H. Reda, J. Chin.
Chem. Soc. 2019, 66, 218.
[12] K. K. Lo, K. H. Tsang, W. K. Hui, N. Zhu, Chem. Commun.
2003, 2704.
[13] WHO, Global Tuberculosis Report, World Health Organization,
Geneva, Switzerland 2017.
[14] D. A. Negatu, J. J. J. Liu, M. Zimmerman, F. Kaya, V. Dartois,
C. C. Aldrich, M. Gengenbacher, T. Dick, Antimicrob. Agents
Chemother. 2018, 62, e01571.
[15] Y. Oikawa, H. Hirasawa, O. Yonemitsu, Tetrahedron Lett.
1978, 19, 1759.
[16] Y. Oikawa, H. Hirasawa, O. Yonemitsu, Chem. Pharm. Bull.
1982, 30, 3092.
4 | CONCLUSIONS
In conclusion, we have demonstrated a straight forward,
mild and high yielding protocol for the synthesis of 3-indole
propanoates/propanoic acid/propanamides. The main
advantages of this protocol are one-pot operation and the
reaction does not demand a catalyst or additive to accelerate
the decarboxylation process to produce the title compounds.
All the compounds are evaluated for their antitubercular
activity against Mycobacterium tuberculosis H37Rv stain.
Among the compounds, 4d was found to be a more potent
than the standards with MIC of 1.6 μg/ml. These molecules
open a new avenue for the development of active anti-TB
drug candidates in the future.
[17] L. J. Pollock, I. Finkelman, A. J. Arieff, Arch. Intern. Med.
1943, 71, 95.
[18] A. Schatz, R. Rasappan, M. Hager, A. Gissibl, O. Reiser, Chem-
istry 2008, 14, 7259.
[19] W. Zhuang, T. Hansen, K. A. Jorgensen, Chem. Commun.
2001, 347.
[20] J. Wu, D. Wang, F. Wu, B. Wan, J. Org. Chem. 2013, 78,
5611.
[21] J. Zhou, M. C. Ye, Z. Z. Huang, Y. Tang, J. Org. Chem. 2004,
69, 1309.
[22] M. C. Ye, B. Li, J. Zhou, X. L. Sun, Y. Tang, J. Org. Chem.
2005, 70, 6108.
[23] Y. Liu, D. Shang, X. Zhou, X. Liu, X. Feng, Chemistry 2009, 15,
2055.
[24] E. L. Armstrong, H. K. Grover, M. A. Kerr, J. Org. Chem. 2013,
78, 10534.
ACKNOWLEDGMENTS
All authors are grateful to the Institute of excellence,
University of Mysore, Mysuru for spectral analysis. MPS
thanks UGC-SAP-DRS-III for financial assistance.
[25] J. Oelerich, G. Roelfes, Org. Biomol. Chem. 2015, 13, 2793.
[26] Y. Liu, X. Zhou, D. Shang, X. Liu, X. Feng, Tetrahedron 2010,
66, 1447.
[27] A. Viola, L. Ferrazzano, G. Martelli, S. Ancona, L. Gentilucci,
A. Tolomelli, Tetrahedron 2014, 70, 6781.
[28] B. Mohammad, K. Ali, B. Zohreh, T. Zahara, M. Mohamad,
J. Chin. Chem. Soc. 2019, 66, 674.
[29] J. Zhou, Y. Tang, J. Am. Chem. Soc. 2002, 124, 9030.
[30] P. K. Singh, V. K. Singh, Org. Lett. 2008, 10, 4121.
REFERENCES
[1] K. S. Sharath Kumar, A. Hanumappa, M. Hegde, K. H.
Narasimhamurthy, S. C. Raghavan, K. S. Rangappa, Eur.
J. Med. Chem. 2014, 81, 341.

44
RAJEEV ET AL.
[31] L. Jeannin, T. Nagy, E. Vassileva, J. Sapi, J.-Y. Laronze, Tetra-
hedron Lett. 1995, 36, 2057.
[32] H. Jiang, M. W. Paixao, D. Monge, K. A. Jorgensen, J. Am.
Chem. Soc. 2010, 132, 2775.
Kumari, N. Kumari, R. Uijjayinee, G. Radha, D. Depina, P.
Monica, H. Ananda, S. K. Subhas, S. Mrinal, J. P.
Charbonnier, C. Bibha, K. Mantelingu, S. C. Raghavan,
FEBS J. 2018, 285, 3959.
[33] A. Renzetti, E. Dardennes, A. Fontana, P. De Maria, J. Sapi, S.
Gerard, J. Org. Chem. 2008, 73, 6824.
[34] F. Epifano, S. Genovese, O. Rosati, S. Tagliapietra, C.
Pelucchini, M. Curini, Tetrahedron Lett. 2011, 52, 568.
[35] T. Goto, Y. Natori, K. Takeda, H. Nambu, S. Hashimoto, Tetra-
hedron: Asymmetry 2011, 22, 907.
[36] A. Palmieri, M. Petrini, J. Org. Chem. 2007, 72, 1863.
[37] N. Kobra, S. P. Seyedeh, J. Chin. Chem. Soc. 2020, 67,
1303.
[38] W. Xiaobo, P. Wan-Xi, J. Chin. Chem. Soc. 2020, 67, 2129.
[39] P. Bachu, T. Akiyama, Chem. Commun. 2010, 46, 4112.
[40] K. H. Narasimhamurthy, S. Chandrappa, K. S. Sharath
Kumar, K. B. Harsha, H. Ananda, K. S. Rangappa, RSC Adv.
2014, 4, 34479.
[47] H. Ananda, K. S. Sharath Kumar, M. Nishana, M. Hegde, S.
Mrinal, B. Raghava, C. Bibha, S. C. Raghavan, K. S. Rangappa,
Mol. Cell. Biochem. 2017, 426, 149.
[48] H. Ananda, K. S. Sharath Kumar, M. S. Sudhanva, R. Shobith,
K. S. Rangappa, Mol. Cell. Biochem. 2018, 449, 137.
[49] Y. R. Girish, K. S. Sharath Kumar, H. S. Manasa, S.
Shashikanth, J. Chin. Chem. Soc. 2014, 61, 1175.
[50] K. S. Sharath Kumar, H. Ananda, V. Maruthai, M. Hegde,
Y. R. Girish, T. R. Byregowda, S. Rao, S. C. Raghavan, K. S.
Rangappa, Bioorg. Med. Chem. Lett. 2015, 25, 3616.
[51] K. G. Vindya, Dukanya, K. Mantelingu, K. S. Rangappa, J.
Chin. Chem. Soc. 2020, 67, 1453.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
[41] G. S. Lingaraju, T. R. Swaroop, A. C. Vinayaka, K. S. Sharath
Kumar, M. P. Sadashiva, K. S. Rangappa, Synthesis 2012, 44,
1373.
[42] K. H. Narasimhamurthy, S. Chandrappa, K. S. Sharath Kumar,
T. R. Swaroop, K. S. Rangappa, Chem. Lett. 2013, 42, 1073.
[43] K. S. Sharath Kumar, T. R. Swaroop, K. B. Harsha, K. H.
Narasimhamurthy, K. S. Rangappa, Tetrahedron Lett. 2012, 53,
5619.
[44] Y. R. Girish, K. S. Sharath Kumar, U. Muddegowda, N. K.
Lokanath, K. S. Rangappa, S. Shashikanth, RSC Adv. 2014, 4,
55800.
[45] H. Ananda, K. S. Sharath Kumar, M. Hegde, K. S. Rangappa,
Mol. Cell. Biochem. 2016, 420, 141.
How to cite this article: Rajeev N, Sharath
Kumar KS, Bommegowda YK, Rangappa KS,
Sadashiva MP. Catalyst free sequential one-pot
reaction for the synthesis of 3-indole propanoates/
propanoic acid/propanamides as antituberculosis
agents. J Chin Chem Soc. 2021;68:39–44. https://
doi.org/10.1002/jccs.202000386
[46] V. V. Supriya, H. A. Swarup, G. Vidya, K. G. Vindya, R.
Virginie, N. Mridula, J. Franklin, K. S. Sharath Kumar, R.