A Facile One-Step Multi-Component Approach toward the Synthesis of 3-(2-Amino-4-Thiazolyl)Coumarins by using Trimethylsilyl Isothiocyanate and their Antioxidant and Anti-Inflammatory Activity

Article abstract of DOI:10.1080/10426507.2014.990016

A multi-component synthesis of 3-(2-amino-4-thiazolyl)coumarins has been reported from 3-(2-bromoacetyl)-2H-chromen-2-ones primary amines and using commercially available trimethylsilyl isothiocyanate. The structures of newly synthesized compounds were ch

Full text of DOI:10.1080/10426507.2014.990016

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A Facile One-Step Multi-Component
Approach toward the Synthesis of 3-
(2-Amino-4-Thiazolyl)Coumarins by
using Trimethylsilyl Isothiocyanate and
their Antioxidant and Anti-Inflammatory
Activity
Raj Kumar Ramagiria, Rajeswar Rao Vedulaa & Murali Krishna
Thupuranib
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a Department of Chemistry, National Institute of Technology,
Warangal, 506004, Andhra Pradesh, India
b Department of Biotechnology, Chaithanya Postgraduate College
(Autonomous), Kishanpura, Hanamkonda, Andhra Pradesh, India
Accepted author version posted online: 01 Apr 2015.
To cite this article: Raj Kumar Ramagiri, Rajeswar Rao Vedula & Murali Krishna Thupurani
(2015) A Facile One-Step Multi-Component Approach toward the Synthesis of 3-(2-Amino-4-
Thiazolyl)Coumarins by using Trimethylsilyl Isothiocyanate and their Antioxidant and Anti-
Inflammatory Activity, Phosphorus, Sulfur, and Silicon and the Related Elements, 190:9, 1393-1397,
DOI: 10.1080/10426507.2014.990016
To link to this article: http://dx.doi.org/10.1080/10426507.2014.990016
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Phosphorus, Sulfur, and Silicon, 190:1393–1397, 2015
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2014.990016
A FACILE ONE-STEP MULTI-COMPONENT APPROACH
TOWARD THE SYNTHESIS OF
3-(2-AMINO-4-THIAZOLYL)COUMARINS BY USING
TRIMETHYLSILYL ISOTHIOCYANATE AND THEIR
ANTIOXIDANT AND ANTI-INFLAMMATORY ACTIVITY
Raj Kumar Ramagiri,1 Rajeswar Rao Vedula,1
and Murali Krishna Thupurani2
1Department of Chemistry, National Institute of Technology, Warangal 506004,
Andhra Pradesh, India
2Department of Biotechnology, Chaithanya Postgraduate College (Autonomous),
Kishanpura, Hanamkonda, Andhra Pradesh, India
GRAPHICAL ABSTRACT
Abstract A multi-component synthesis of 3-(2-amino-4-thiazolyl)coumarins has been re-
ported from 3-(2-bromoacetyl)-2H-chromen-2-ones primary amines and using commercially
available trimethylsilyl isothiocyanate. The structures of newly synthesized compounds were
characterized by their analytical and spectral data. All the title compounds were screened
for antioxidant and anti-inflammatory activity. Among the screened compounds, 4b exhibited
highest free radical scavenging activity and also 4b was found to be effective in inhibiting the
protein denaturation at all tested concentrations.
Keywords Trimethylsilyl isothiocyanate; coumarin; multi-component reaction; primary
amines
INTRODUCTION
Synthetically prepared substituted thiazoles are known to possess pharmacological
properties1–3 including antitumoral4 and antimicrobial5 activities and also other applications
such as liquid crystals, cosmetic sunscreens.6,7 Coumarin and its derivatives show antibac-
terial,8,9 antifungal,10,11 herbicidal,12 antitumoral13, cytotoxic,14 and anti-HIV activity.15,16
The compounds containing the coumarin motif are widely used as luminescent materials.17
Received 13 August 2014; accepted 16 November 2014.
Address correspondence to Raj Kumar Ramagiri, Department of Chemistry, National Institute of Technology,
Warangal 506004, Andhra Pradesh, India. E-mail: rajeswarnitw@gmail.com
1393

1394
R. K. RAMAGIRI ET AL.
They also act as anticoagulants,18 free radical scavengers,19 antioxidant20, lipoxygenase,21
and cyclooxygenase inhibitors.22
In the literature, numerous methods were reported for the preparation of 4-substituted
2-amino thiazoles based on Hantzsch-type23 condensation of alpha halo carbonyl
compounds with various thioureas. In this paper, we report a novel method for the
development of 2-amino thiazolyl coumarins using commercially available trimethylsi-
lyl isothiocyanate (TMSNCS), along with readily available primary amines and
3-(2-bromoacetyl)-2H-chromen-2-ones via multi-component approach.
RESULTS AND DISCUSSIONS
Chemistry
Condensation of 3-(2-bromoacetyl)-2H-chromen-2-one 1, TMSNCS 2 with different
primary amines 3 in ethanol gave the corresponding 3-(2-amino-4-thiazolyl)coumarins 4
in good yields. All the synthesized compounds are new and not reported in the literature
except compounds 4c and 4d (Scheme 1). In the literature, these two compounds were
synthesized using different methods24 and their melting points were found identical with
newly synthesized compounds.
Scheme 1 Scheme for the preparation of 3-(2-amino-4-thiazolyl)coumarins 4a-i using TMSNCS.
The mechanism for the formation of product was discussed in Scheme 2. In this
procedure, we have modified the known Hantzsch method for thiazole synthesis involving
the reaction of TMSNCS, primary amines and 3-(2-bromoacetyl)-2H-chromen-2-ones.
We tried to develop the present a novel one pot multi-component synthesis of the title
compounds using TMSNCS. This procedure may find extensive applications in the synthesis
of a wide variety of substituted thiazoles. The structures of compounds 4a-i were confirmed
by their IR, 1H NMR, and 13C NMR spectral data. The 1H NMR spectrum of 4a in CDCl3
showed thiazole proton as singlet at 7.76, C4 proton of coumarin as singlet at 8.63 and
NH proton appeared as singlet at 10.24 δ ppm. In the 13C NMR spectrum of 4a the
thiazole and carbonyl carbon resonates at 110.1 and 164.5 δ ppm, respectively. The mass
spectrum of 4a exhibited the [M+H]+ peak at m/z 365. When exposed to ethanol, TMSNCS
rapidly releases isothiocyanic acid25 5 which could react with the compound 1 to form the
respective thiocyanate26 6. Then 6 reacts with primary amines to give the end products. (Full
1
characterization and sample H and 13C NMR spectra are presented in the Supplemental
Materials, Figure S 1–S 4)

MULTI-COMPONENT SYNTHESIS OF 3-(2-AMINO-4-THIAZOLYL)COUMARINS
1395
Scheme 2 plausible mechanism for the formation of 3-(2-amino-4-thiazolyl)coumarin 4a-i.
BIOLOGICAL ACTIVITY
Results
DPPH Radical Scavenging Activity. Among the screened compounds, 4b ex-
hibited highest free radical scavenging activity. On the other hand 4g and 4h were proven
to possess significant antioxidant properties. The results were compared with known stan-
dard BHA. The inhibition percentage of the compounds 4a, 4c, 4d, 4e, 4f, 4g, 4h, 4i at
150 μg/mL.
Anti-inflammatory Activity. Among the various compounds tested, 4b was found
to be effective in inhibition of protein denaturation of all tested concentrations. The high-
est inhibition percentage 93% was obtained at 150 μg/mL and compared with standard
Diclofenac sodium 96% at 20 μg/mL concentration. On the other hand, 4g and 4h also
showed significant inhibition of protein denaturation. The percentage of inhibition noticed
for 4a, 4c, 4d, 4e, 4f, 4g, 4h, 4i at 150 μg/mL concentrations are 80, 52, 39, 59, 79, 89,
85, and 76, respectively. However, inhibition concentration IC50 of 4b was found to be less
than 50 μg/mL (Figures S5 and S6 Supplemental Materials).
CONCLUSION
This paper reports an efficient, one-pot three component method for the synthesis of 3-
(2-amino-4-thiazolyl)coumarins by TMSNCS in good yields. The experimental conditions
are simple, inexpensive, with easy work up and cleaner reaction profiles. The antioxidant
and anti-inflammatory activities of the synthesized compounds were evaluated. Among
them, 4b, 4g, and 4h showed good antioxidant as well as anti-inflammatory activities and
emerged as potential molecules for further development.

1396
R. K. RAMAGIRI ET AL.
EXPERIMENTAL
All the reagents and solvents were pure and purchased from commercial sources and
were used without further purification unless otherwise stated. 3-(2-Bromo-acetyl)-2H-
chromen-2-ones were prepared by the literature procedure.29 Melting points were deter-
mined in open capillaries with a ‘Cintex’ melting point apparatus (Mumbai, India) and were
uncorrected. CHN analysis was carried out by Carlo Erba EA 1108 automatic elemental
analyzer. The purity of the compounds was checked by TLC plates (E. Merck Mumbai, In-
dia). IR spectra were recorded on a thermo Nicolet Nexus 670 Q8 instrument (KBr pellets).
1H NMR spectra were recorded on a Bruker WM-400 spectrometer in δ ppm using TMS
as the standard. Mass spectra (EI-MS) were determined on a Perkin Elmer spectrometer
(SCIEX API-2000, ESI) at 12.5 eV.
General Procedure for 4a-i
A mixture of 3-(2-bromoacetyl)-2H-chromen-2-one 1 (1 mmol), trimethylsilyl isoth-
iocyanate 2 (1 mmol) and primary amine 3 (1 mmol) in ethanol (10 mL) was refluxed.
After completion of the reaction, the reaction mixture was cooled, filtered, and solid was
recrystallized from methanol. Complete characterization of 4b–4h and sample spectra for
4a and 4b are presented in the Supplemental Materials (Figures S1–S4).
8-Methoxy-3-(2-(p-tolylamino)thiazol-4-yl)-2H-chromen-2-one
(4a).
Color: yellow; mp: 172–174 oC; Yield: 87(%); IR (KBr) υ (cm−1): 1538 ( C C), 1603
(-C N), 1708 (lactone C O), 3316 ( NH); 1H NMR (400 MHz, DMSO-d6) δ (ppm):
2.28 (s, 3H, methyl), 3.94 (s, 3H, methoxy), 7.18 (d, 2H, J = 8 Hz, Ar-H), 7.30-7.36 (m,
2H, Ar-H), 7.47–7.50 (m, 1H, Ar-H), 7.62 (d, 2H, J = 8.4 Hz, Ar-H), 7.76 (s, 1H, thiazole),
8.63 (s, 1H, C-4 of coumarin), 10.24 (s, 1H, N-H); 13C NMR (DMSO-d6) δ (ppm): 20.8,
50.2, 110.1, 113.1, 119.1, 119.7, 120.3, 121.1, 124.3, 130, 133.4, 137.6, 138.8, 142.5, 144,
146.9, 159.1, 164.5; ESI-MS m/z (%): 365[M+H]+; Anal. Calcd (%) for C20H16N2O3S:
C, 65.92; H, 4.43; N, 7.69. Found: C, 65.90; H, 4.47; N, 7.60.
SUPPLEMENTARY DATA
Figures S1–S6 can be accessed on the publisher’s website at
http://dx.doi/10.1080/10426507.2014.990016
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