CAN-catalyzed microwave promoted reaction of indole with Betti bases under solvent-free condition and evaluation of antibacterial activity of the products

Article abstract of DOI:10.1080/00397911.2017.1360912

CAN-catalyzed reaction of Betti bases with indoles under microwave irradiation gives 3-(α,α-diarylmethyl)indoles. Better yield of the products, especially when one of the aryl ring is phenol were achieved. The reaction is performed in solvent-free condition. The antibacterial studies of the synthesized compounds were performed and some of the compounds showed good activity against Methicillin-resistant Staphylococcus aureus bacteria.

Full text of DOI:10.1080/00397911.2017.1360912

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
CAN-Catalyzed microwave promoted reaction
of indole with betti bases under solvent-free
condition and evaluation of antibacterial activity
of the products
Choitanya Dev Pegu, Sheikh Benazir Nasrin, Mohit L. Deb, Deep Jyoti Das,
Kandarpa K. Saikia & Pranjal K. Baruah
To cite this article: Choitanya Dev Pegu, Sheikh Benazir Nasrin, Mohit L. Deb, Deep Jyoti Das,
Kandarpa K. Saikia & Pranjal K. Baruah (2017): CAN-Catalyzed microwave promoted reaction of
indole with betti bases under solvent-free condition and evaluation of antibacterial activity of the
products, Synthetic Communications, DOI: 10.1080/00397911.2017.1360912
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1360912
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Date: 08 August 2017, At: 19:58

CAN-catalyzed microwave promoted reaction of indole with
Betti bases under solvent-free condition and evaluation of
antibacterial activity of the products
Choitanya Dev Pegu
Department of Applied Sciences, GUIST, Gauhati University, Guwahati, Assam, India
Sheikh Benazir Nasrin
Department of Applied Sciences, GUIST, Gauhati University, Guwahati, Assam, India
Mohit L. Deb
Department of Applied Sciences, GUIST, Gauhati University, Guwahati, Assam, India
Deep Jyoti Das
Department of Bioengineering and Technology, GUIST, Gauhati University, Guwahati, Assam,
India
Kandarpa K. Saikia
Department of Bioengineering and Technology, GUIST, Gauhati University, Guwahati, Assam,
India
Pranjal K. Baruah
Department of Applied Sciences, GUIST, Gauhati University, Guwahati, Assam, India
1

Address coresspondence to Pranjal K. Baruah, Department of Applied Sciences, GUIST, Gauhati
University, Guwahati, 781014, Assam, India. Tele: + 91-8876998905. Fax: + 91-3612700311. E-
mail: baruah.pranjal@gmail.com
ABSTRACT
CAN-catalyzed reaction of Betti bases with indoles under microwave irradiation gives 3-
(,-diarylmethyl)indoles. Better yield of the products, especially when one of the aryl ring is
phenol were achieved. The reaction is performed in solvent-free condition. The antibacterial
studies of the synthesized compounds were performed and some of the compounds showed good
activity against Methicillin-resistant Staphylococcus aureus bacteria.
GRAPHICAL ABSTRACT
KEYWORDS: 3-(,-diarylmethyl)indoles, Betti base, CAN-catalyzed, microwave, solvent-
free
Introduction
Ceric (IV) ammonium nitrate (CAN) is a versatile reagent in carrying out several organic
reactions. CAN is extensively used as one electron oxidant in carrying out oxidation reactions.[1]
This catalyst is air stable and easy to work with. The low cost and toxicity in addition to reasonably
good solubility in organic solvents has made it very attractive catalyst for carrying out many
2

organic reactions.[2] Many carbon-carbon and carbon-heteroatom bond forming reactions are
catalyzed by CAN.[3],[4] Use of CAN as catalyst in multicomponent reaction and green synthesis is
reviewed by Prajapati et al.[5]
Microwave technology was used by organic chemists from the later part of 1980. Since
then microwave synthesis has attracted chemists due to its faster and clean reaction over
conventional heating method. The pharmaceutical industry which require more number of
chemical compounds are greatly assisted by using microwave technology which allow quicker
access to organic compounds. The use of microwave technology in organic chemistry is
extensively reviewed in literature.[6],[7]
N-containing heterocyclic compounds are found to have several biological activities.
Indole nucleus is very important moiety in many important molecules having wide medicinal
applications.[8] Many alkaloids having indole as core unit have broad spectrum activities.[9] C-3
substituted indoles have found applications in several fields including perfumery, agrochemical,
pharmaceutical, etc. industries. Many antifungal, antibacterial, analgesic, antipyretic, anticancer,
antidiabetic compounds are found to be C-3 substituted indole derivatives.[10] When the indole
nucleus substituted with various groups or attached with other heterocyclic moieties, they are
found to affect the antioxidant properties of the resulting coumpounds.[11],[12] Naphthol and phenol
derivatives possesses several biological activity. Most of the phenolic substances have important
biological activities and are found to be the key components in the defence of plants against
herbivores and pathogens.[13] Many natural phenolic compounds may prevent cancer.[14] They have
strong antioxidant property and therefore, function as protective agents against many free radical
mediated diseases.[15]
3

Result and Discussion
The bioactivity of the 3-alkylated indoles and phenols inspired us to synthesize compounds
having both indole and aryl alohol moiety. Although considerable progress has been made in the
synthesis of these compounds, development of efficient synthesis with mild catalyst and improved
reaction condition is highly sought-after. We have observed in our previous studies that the yield
of the 3-(,-diarylmethyl)indoles from indole Mannich base is low when the aryl alcohol moiety
is phenol compared to napthol.[16] Further, reaction of the Betti base with indole under microwave
irradiation catalyzed by PTSA gave us bis(indolyl)methane through denaphtholation.[17] We thus
searched for an alternative method which would give better yield of the 3-(,-
diarylmethyl)indoles having phenol component and also prevent the C-C bond cleavage. To attain
a better method for the reaction, several catalysts were screened under microwave and thermal
condition. We observed that various Lewis acid and organocatalysts did not afford good yield of
the product. Use of Bronsted acids (e.g. HCl-2N) was also not productive. We were delighted to
find that CAN in acetonitrile as solvent gave us moderate yield. To compare the solvent affect, we
performed the reaction in different solvents and the results are presented in Table 1. However, we
observed that the optimum yield was obtained when 5 mol% of CAN was used under solvent-free
condition (entry 14, Table 1). Increase of catalyst loading did not increase the yield (entry 13,
Table 1); however, lowering of catalyst amount decreases the product yield (entry 16, Table 1).
Lowering of reaction time also diminished the yield of 3a (entry 15, Table 1).
The affect of the amine moiety on the yield of the product was also studied and obtained
best result when the amine moiety was dimethylamine rather than pyrrolidine and piperidine. In
order to screen the substrate scope we have carried out reactions using several substituted phenols
4

and naphthols. We obtained very good yield for both the phenol and naphthol derivatives. We
observed that when electron-withdrawing groups were present in the aryl ring (R1) of 1, the yield
of the 3 was better (e.g., 3f-3g, Scheme 2). However, presence of electron-donating groups on the
phenol ring increased the yield (e.g., 3b vs. 3c, Scheme 2). On the other hand, 2-methylindole gave
better yield of 3 than 1-methyl- and NH-indoles. The starting material 1 for the reaction can easily
be prepared by the 3-component method using phenol, aldehyde and amine.[18] The mechanism for
the formation of 3 is similar as described by our previous report which proceeds through the
formation of quinone methide.[18] CAN helps to eliminate the amine group by coordinating its
metal ion with the nitrogen of amine.
Bioactivity studies
Antibiotics are the substances that are produced by microorganisms most of which are
manufactured synthetically and are used in the treatment of bacterial, fungal, parasitic, and viral
infections by inhibiting their biological processes. The implementation of empiric antibiotic
therapy has led to antibiotic resistance in many microbes. The major factor for the growth of
antibiotic resistance is the spread of resistance strains of bacteria among the persons. Bacterial
infections are treated by proper use of antibiotic but overuse or misuse of them enhanced bacterial
resistance. Gram positive and gram negative bacteria can transfer antibiotic resistance gene
through horizontal gene transfer or spontaneous mutations. Development of antibiotic resistance
in pathogens has led to the development of synthetic drug molecules that are found to be effective
against many microbes. We have thus tested our compounds against various bacteria and obtained
promising result.
Antibacterial assay
5

The antibiotic sensitivity was done by well-diffusion method on Mueller Hinton agar
medium using the specified test compounds and bacterial isolates viz. E. coli, K. pneumoniae &
Methicillin-resistant Staphylococcus aureus (MRSA) isolated from clinical samples urine, sputum
and pus respectively.[19] The compounds were dissolved in 70% DMSO (1mg/ml). DMSO was
also used as the solvent control. After 18 to 24 h of incubation, the plates were examined and
diameters of the zone of inhibition measured (Figure 1) and values were recorded as shown in
Table 2.
The compounds showed no activity against E. Coli and K. Pneumonaie bacteria. The
results indicates that 3-(,-diarylmethyl)indoles with various naphthol moiety have no activity
against all the three bacterial stains studied. However the phenolic counterparts gave us promising
results. 3a showed good activity against the Staphylococcus aureus bacteria. When the methyl
group was replaced by tert-butyl (e.g. 3b) or –OMe (e. g. 3d), the compounds lost activity against
the bacteria. However substitution by –Cl group retained the activity. Substitution on the phenyl
ring also affects the biological activity of the compounds. Compound 3f with –F substitution
showed highest activity followed by 3e with –Cl, whereas compound 3g with –NO2 group showed
no activity. Interestingly, when the nitrogen of indole is substituted with a methyl group (e.g. 3i),
the compound lost its activity completely. Further ring substitution on the phenol ring made the
compounds 3k and 3l inactive against the studied bacteria. Similarly, substitution on the indole
whether on five membered (e.g. 3j) or six membered ring (e.g. 3h) also eliminates bioactivity.
Minimum inhibitory concentration (MIC) test against MRSA (Methicillin-
resistant Staphylococcus aureus)
6

MIC is defined as the lowest concentration of compound that was able to inhibit growth of
bacteria. After overnight incubation in Luria Bertani (LB) Broth, the bacterial isolates were
centrifuged at 4000 RPM for 5 min. The supernatant obtained was discarded and pellet was re-
suspended in 20 ml of normal saline and re-centrifuged at 4000 rpm for 5 min. Pellet was then
dissolved in 20 ml sterile normal saline for use in the MIC assay. Resazurin dye was prepared as
per standard protocol.[20] In a 96 well microtitre plate, the first row of the plate was filled with 100
µL of the test compound and all the wells were filled with 100 µL of LB broth. Two fold serial
dilutions were achieved transferring 100 µL from the first well to the subsequent wells such that
each well has 100 µL of sample in decreasing concentration. 10 µL of resazurin dye was added to
each well as an indicator. Finally 10 µL of the bacterial suspension was added to all the wells and
the plate was loosely wrapped with cling film to ensure that bacteria did not become dehydrated.
Each plate had two controls: i) a well with all solutions with the exception of the test compound
and ii) a well with all solutions except bacterial suspension, replaced by LB Broth. The plate was
incubated overnight at 37°C and then observed for any visible colour change. Colour change from
purple to pink or colourless was considered as positive. The lowest concentration of the test
compound at which the colour change was observed was recorded as the MIC value Table 3.[20]
Conclusion
In conclusion, we have developed a mild and efficient method to synthesize 3-(,-
diarylmethyl)indoles. The main advantage of this method is that phenol derivatives could also be
synthesized in higher yield than the previously reported methods. The biological activity study of
the synthesized compounds was done and promising results were obtained. The antibacterial
activity of the compounds were tested against clinical bacterial isolates of Escherichia coli,
Klebsiella pneumoniae & MRSA(Methicillin-resistant Staphylococcus aureus) using agar well
7

diffusion method. The zone of inhibition ranged from a maximum of 20 mm to minimum of 13
mm against MRSA. However no significant activity was observed against the gram negative
bacteria- E. coli and K. pneumoniae. Further MIC test was carried out for the biologically active
compounds. Compound 3f showed the most effective MIC value of 8.33µg/ml against selected
isolate of MRSA. Thus the present work could open up new possibility for biological activity
studies of this important class of compounds. Further, studies on improving the activity against
other resistant bacterial and fungal stains are underway and the results would be reported soon.
Experimental
General experimental procedure for the synthesis of 3
1 (1.0 mmol), 2 (1.0 mmol) and CAN (5 mol %, 27.5 mg) were irradiated in a closed vessel
inside a microwave reactor at 110C for the specified time. The progress of the reaction was
monitored by TLC. After completion of the reaction the crude mixture was purified by column
chromatography using hexane/ethyl acetate as the eluent to give the desired product 3.
Representative characterization of 3a: off white solid; Yield: 263 mg, 84 %; 1H NMR (400 MHz,
DMSO-d6): δ 10.82 (d, J = 1.0 Hz, 1H), 9.19 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.28 – 7.15 (m, 5H),
7.11 (d, J = 7.8 Hz, 1H), 7.04 (t, J = 7.3 Hz, 1H), 6.88 – 6.81 (m, 2H), 6.76 – 6.74 (m, 2H), 6.65 –
6.64 (m, 1H), 5.95 (s, 1H), 2.06 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 152.3, 144.4, 136.7,
130.1, 129.8, 128.7, 128.0, 127.4, 126.8 (2C), 125.8, 124.2, 121.1, 119.0, 118.3, 117.9, 115.0,
111.5, 40.5, 20.5; MS: m/z = 314.2 [M + H]+.
Funding
8

M. L. D. is thankful to the Science and Engineering Research Board (SERB), India, for
financial support (Grant No. SB/FT/CS-073/2014) under the Fast Track Scheme. P. K. B. is
thankful to the SERB, New Delhi, India (Grant No. SB/FT/CS-100/2012) for financial support.
References
[1] Ho, T. L. Synthesis 1973, 347.
[2] Sridharan, V.; Menendez, J. C. Chem. Rev. 2010, 110, 3805–3849.
[3] (a) Jang, H.-Y.; Hong, J.-B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004. (b)
Nair, V.; Mathew, J.; Prabhakaran, J. Chem. Soc. Rev. 1997, 26, 127.
[4] (a) Alvarez-Manzaneda, E. J.; Chabouna, R.; Alvarez, E.; Cabrera, E.; Alvarez-Manzaneda,
R.; Haidour, A.; Ramos, J. M. Synlett 2006, 1756. (b) Nair, V.; Augustine, A.; Suja, T. D.
Synthesis 2002, 2259. (c) Maiti, S.; Menéndez, J. C. Synlett 2009, 2249. (d) Varala, R.;
Sreelatha, N.; Adapa, S. R. Synlett 2006, 1549. (e) Nair, V.; Rajan, R.; Rath, N. P. Org. Lett.
2002, 4, 1575.
[5] Prajapati, N. P.; Vekariya, R. H.; Patel, H. D. Synth. Commun. 2015, 45, 2399.
[6] (a) de la Hoz, A.; Loupy, A. (Eds.) Microwaves in Organic Synthesis, 3rd ed.; Wiley-VCH:
Weinheim, 2012. (b) Sanghi, R.; Singh, V. (Eds.) Green Chemistry for Environmental
Remediation; Wiley: Hoboken, 2012. (c) Pollastri, M. P.; Devine, W. G. Microwave Synthesis.
In Green Techniques for Organic Synthesis and Medicinal Chemistry; Zhang, W., Cue, B. Eds.;
Wiley: Chichester, 2012; Ch. 12, pp 325–342. (d) Tierney, J. P.; Lidstrom, P. (Eds.) Microwave
Assisted Organic Synthesis; Blackwell Publishing Ltd: Oxford, 2009. (e) Leadbeater, N. E.
Organic Synthesis Using Microwave Heating. In Comprehensive Organic Synthesis, 2nd ed.;
Knochel, P., Molander, G. Eds.; Elsevier Ltd: Oxford, 2014; Ch. 10, Vol. 9, pp 234–286. (f)
Kappe, C. O.; Stadler, A. Microwaves in Organic and Medicinal Chemistry, 2nd ed.; Wiley:
Weinheim, 2012.
[7] (a) Baig, R. B. N.; Varma, R. S. Chem. Soc. Rev. 2012, 41, 1559. (b) Pedersen, S. L.;
Tofteng, A. P.; Malik, L.; Jensen, K. J. Chem. Soc. Rev. 2012, 41, 1826. (c) Takkellapati, S. R.
Curr. Org. Chem. 2013, 17, 2305. (d) Kappe, C. O. Chem. Soc. Rev. 2013, 42, 4977.
[8] (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1996. (b)
Juwarker, H.; Suk, J.-M.; Jeong, K.-S. Top. Heterocycl. Chem. 2010, 24, 177. (c) Barluenga, J.;
Valdes, C. Five Membered Heterocycles: Indole and Related Systems in Modern Heterocyclic
Chemistry; Wiley: New York, 2011; Vol. 1, pp 377–513. (d) Vicente, R. Org. Biomol. Chem.
2011, 9, 6469. (e) Sharma, V.; Kumar, P.; Pathak, P. J. Heterocycl. Chem. 2010, 47, 491.
[9] (a) Kaniwa, K.; Arai, M. A.; Li, X.; Ishibashi, M. Bioorg. Med. Chem. Lett. 2007, 17, 4254.
(b) Teng, M.; Zi, W.; Ma, D. Angew. Chem. Intl. Ed. 2014, 53, 1814.
9

[10] (a) Basha, A. R. Indole Alkaloids; Harwood Academic: Chichester, UK, 1998. (b) Higuchi,
K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24, 843. (c) Ishikura, M.; Yamada, K.; Abe, T. Nat.
Prod. Rep. 2010, 27, 1630. (d) Ishikura, M.; Yamada, K. Nat. Prod. Rep. 2009, 26, 803. (e)
Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73. (f) Walsh, T. F.; Toupence, R. B.;
Ujjainwalla, F.; Young, J. R.; Goulet, M. T. Tetrahedron 2001, 57, 5233. (g) Jacotot, B.; Banga,
J. D.; Pfister, P.; Mehra, M. Br. J. Clin. Pharmacol. 1994, 38, 257. (h) Reddy, B. V. S.; Reddy,
M. R.; Madan, C.; Kumar, K. P.; Rao, M. S. Bioorg. Med. Chem. Lett. 2010, 20, 7507. (i)
Chavan, R. S.; More, H. N. J. Pharm. Res. 2011, 4, 1575.
[11] (a) Lakshmi, N. V.; Thirumurugan, P.; Noorulla, K. M.; Perumal, P. T. Bioorg. Med. Chem.
Lett. 2010, 20, 5054. (b) Biradar, J. S.; Sasidhar, B. S.; Parveen, R. Eur. J. Med. Chem. 2010, 45,
4074. (c) Biradar, J. S.; Sasidhar, B. S. Eur. J. Med. Chem. 2011, 46, 6112. (d) Samadi, A.;
Soriano, E.; Revuelta, J.; Valderas, C.; Chioua, M.; Garrido, I.; Bartolomé, B.; Tomassolli, I.;
Ismaili, L.; Gonzalez-Lafuente, L.; et al. Bioorg. Med. Chem. 2011, 19, 951.
[12] (a) Yılmaz, A. D.; Coban, T.; Suzen, S. J. Enzyme Inhib. Med. Chem. 2012, 27, 428. (b)
Silveira, C. C.; Mendes, S. R.; Soares, J. R.; Victoria, F. N.; Martinez, D. M.; Savegnago, L.
Tetrahedron Lett. 2013, 54, 4926–4929.
[13] (a) Manosroi, A.; Jantrawut, P.; Ogihara, E.; Yamamotob, A.; Fukatsu, M.; Yasukawa, K.;
Tokuda, H.; Suzuki, N.; Manosroi, J.; Akihisa, T. Chem. Biodiervs. 2013, 10, 1448. (b) Wink, M.
Theor. Appl. Genet. 1988, 75, 225.
[14] Huang, W.-Y.; Cai, Y.-Z.; Zhang, Y. Nutr. Cancer 2010, 62, 1.
[15] (a) Sakihama, Y.; Mano, J.; Sano, S.; Asada, K.; Yamasaki, H. Biochem. Biophys. Res.
Commun. 2000, 279, 949. (b) Arora, A.; Nair, M. G.; Strasburg, G. M. Free Radical Biol. Med.
1998, 24, 1355. (c) Evans, C. R.; Miller, N.; Paganga, G. Trends Plant Sci. 1997, 2, 152.
[16] Deb, M. L.; Das, C.; Deka, B.; Saikia, P. J.; Baruah, P. K. Synlett 2016, 27, 2788.
[17] Deb, M. L.; Saikia, B-S.; Borah, K.; Baruah, P. K. Syn. Commun. 2016, 46, 1940.
[18] Deb, M. L.; Pegu, C. D.; Deka, B.; Dutta, P.; Kotmale, A. S.; Baruah, P. K. Eur. J. Org.
Chem. 2016, 3441.
[19] Sen, A.; Batra, A. Int. J. Curr. Pharm. Res. 2012, 4, 67.
[20] Sarker, S. D.; Nahar, L.; Kumarasamy, Y. Methods 2007, 42, 321.
10

Table 1. Optimization of the reaction condition.a
Entry
Catalyst (mol %)
Solvent
Time (min),
MW/[Thermal]
10 [180]
10 [180]
10 [180]
10 [180]
10 [180]
10 [180]
10 [180]
10 [180]
10 [180]
10 [180]
10 [180]
10 [180]
8 [90]
Yield, 3a (%)b,
MW/[Thermal]
trace [NR]c
trace [NR]
25 [trace]
33 [45]
1
2
–
–
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
Toluene
EtOH
–
3
AcOH (10)
p-TsOH (10)
TFA (10)
Thiourea (20)
FeCl3.6H2O (10)
PNBA (10)d
CAN (10)
CAN (10)
CAN (10)
CAN (10)
CAN (10)
CAN (5)
4
5
30 [37]
6
trace [NR]
20 [NR]
15 [NR]
67 [25]
7
8
9
10
11
12
13
14
15
16
25 [18]
56 [41]
28 [15]
84 [51]
–
8 [90]
84 [43]
CAN (5)
–
7 [60]
76 [40]
CAN (3)
–
8 [90]
50 [29]
11

17
18
19
20
21
Silica gel (10)
H3BO3 (10)
HCl-2N (10)
LiCl (10)
–
–
–
–
–
10 [180]
10 [180]
10 [180]
10 [180]
10 [180]
NR [NR]
trace [NR]
44 [26]
trace [NR]
trace [NR]
CuCl2 (10)
aUnless otherwise mentioned, all the reactions were performed by using 1a (1.0 mmol, 241mg), 2a (1.0 mmol, 117 mg). 110°C
was maintained for all the reactions under microwave condition. In thermal condition, reactions were carried out under reflux.
bProducts were purified by column chromatography and yields are of isolated products. cNR: no reaction. dp-Nitro benzoic acid.
12

Table 2. Calculation of zone size.
Compound code
Organism
MRSA
MRSA
MRSA
MRSA
Zone size (mm)
20
16
14
13
3f
3e
3a
3c
13

Table 3. Calculation for MIC mean value and standard error.
Drug (µg/ml)
Organism
MRSA
MRSA
MRSA
MRSA
Mean value ± standard error
8.33 ± 0
25 ± 0
3f
3e
3a
3c
25± 0
12.5 ± 0
14

Figure 1. Antibacterial test against bacterial strains. a: E. coli (ve); b: K. pneumonia (ve); c:
MRSA (+ve).
15

Scheme 1. Reaction of Betti bases with indoles.
16

Scheme 2. Substrate scope for the synthesis of 3. Reaction conditions: 1 (1.0 mmol), 2 (1.0
mmol), CAN (5 mol %, 27.5 mg) at 110°C under microwave irradiation. Products were purified
by column chromatography using silica gel (100-200 mesh) and yields are for the isolated
products.
17