Synthesis of Some 2-(3-Alkyl/aryl-5-trifluoromethylpyrazol-1-yl)-4-(coumarin-3-yl)thiazoles as novel antibacterial agents

Article abstract of DOI:10.1080/00397911.2015.1062986

Herein, we describe a one-pot synthesis of some novel 2-(3-alkyl/aryl-5-trifluoromethylpyrazol-1-yl)-4-(coumarin-3-yl)thiazoles (6) involving the reaction of 3-alkyl/aryl-5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazole-1-thiocarboxamides (3) with 3-bromoacetylcoumarins (5) in the presence of sodium carbonate in ethanol. Reaction of 3 with 5 in the absence of sodium carbonate, however, resulted in the formation of 2-(3-alkyl/aryl-5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-yl)-4-(coumarin-3-yl)thiazoles, which were subsequently dehydrated to 6 by refluxing in ethanol in the presence of sodium carbonate. The structure of the synthesized compounds (6) was confirmed by infrared (IR), mass, ¹H NMR, and ¹³C NMR spectra and elemental analysis data. Newly synthesized compounds (6) showed moderate to good activity against Gram-positive bacteria.

Full text of DOI:10.1080/00397911.2015.1062986

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Synthesis of some 2-(3-alkyl/aryl-5-
trifluoromethylpyrazol-1-yl)-4-(coumarin-3-yl)thiazoles
as novel antibacterial agents
Sunil Kumara, Ranjana Aggarwala & Chetan Sharmab
a Department of Chemistry, Kurukshetra University, Kurukshetra, India
b Department of Microbiology, Kurukshetra University, Kurukshetra, India
Accepted author version posted online: 23 Jun 2015.
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To cite this article: Sunil Kumar, Ranjana Aggarwal & Chetan Sharma (2015): Synthesis of some 2-(3-alkyl/aryl-5-
trifluoromethylpyrazol-1-yl)-4-(coumarin-3-yl)thiazoles as novel antibacterial agents, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1062986
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Synthesis of some 2-(3-alkyl/aryl-5-trifluoromethylpyrazol-1-yl)-4-(coumarin-3-
yl)thiazoles as novel antibacterial agents
Sunil Kumar1, Ranjana Aggarwal1, Chetan Sharma2
1Department of Chemistry, Kurukshetra University, Kurukshetra, India, 2Department of
Microbiology, Kurukshetra University, Kurukshetra, India
Corresponding Author: Sunil Kumar, E-mail: sunildhull102@gmail.com.
# Presently Assistant Prof. at NIILM University, Kaithal-136027, India.
Abstract
Herein, we describe a one-pot synthesis of some novel 2-(3-alkyl/aryl-5-
trifluoromethylpyrazol-1-yl)-4-(coumarin-3-yl)thiazoles (6) involving the reaction of 3-
alkyl/aryl-5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazole-1-thiocarboxamides (3) with
3-bromoacetylcoumarins (5) in presence of sodium carbonate in ethanol. Reaction of 3
with 5 in the absence of sodium carbonate, however, resulted in the formation of 2-(3-
alkyl/aryl-5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-yl)-4-(coumarin-3-
yl)thiazoles which were subsequently dehydrated to 6 by refluxing in ethanol in presence
of sodium carbonate. The structure of the synthesized compounds (6) was confirmed by
IR, mass, 1H, and 13C NMR spectra and elemental analyses data. Newly synthesized
compounds (6) showed moderate to good activity against Gram-positive bacteria.
KEYWORDS: 3-(2-Bromoacetyl)coumarins; 3-alkyl/aryl-5-hydroxy-5-trifluoromethyl-
4,5-dihydropyrazole-1-thiocarboxamides; 2-(3-alkyl/aryl-5-trifluoromethylpyrazol-1-yl)-
4-(coumarin-3-yl)thiazoles; Sodium carbonate; antibacterial
1

INTRODUCTION
Heterocyclic rings containing nitrogen and sulphur have been under investigation
for a long time because of their important medicinal properties. Thiazole and its
derivative are found to be associated with various biological activities, such as
antibacterial, antifungal, anthelmintic, cytotoxic, algicidal, and antithrombotic activities[1-
10] and recently, found in many applications in drug development for the treatment of
schizophrenia,[11] inflammation,[12] HIV infections,[13] and hypertension[14]
.
Much attention has been addressed to trifluoromethylated heterocyclic
compounds because they often show unique biological and physiological activities
associated with them. In particular, trifluoromethyl substituted pyrazoles and other five-
membered heterocycles have interesting biological activities viz. anti-inflammatory,
antimicrobial, antihypertensive etc.[15-20] The search for a simple and efficient access to
such compounds with a CF3 group at a specific position is one of the important goals in
this area. However, there are a limited number of regioselective syntheses of
trifluoromethyl containing heteroaromatic compounds in good yield.
Coumarin and its derivative represent one of the most active class of compounds
possessing a wide spectrum of biological activity. Many of these compounds have proved
to be active as, antibacterial,[21–24] antitumor,[25] anticoagulant,[26] antiviral,[27] and anti-
inflammatory[28-29] agents. In addition, these compounds are used as additives to food and
cosmetics.[30] Coumarin derivatives are commonly used as optical whiteners,
luminescence dyes,[31-32] active media for lasers[33] and solar collector[34]. Thus, the
2

synthesis of coumarin derivatives is still a popular research topic in organic chemistry.
Recently, we have reported the synthesis of 2-(3-alkyl/aryl-5-hydroxy-5-trifluoromethyl-
4,5-dihydropyrazol-1-yl)-4-(coumarin-3-yl)thiazole (5) which exhibited excellent level of
antibacterial and anti-inflammatory activity.[35]
Prompted by these reports and in continuation of our search for biological active
molecules comprising of 2,4-disubstituted thiazole ring,[17-20, 35-37] we have synthesized
some novel thiazoles having trifluoromethyl substituted pyrazole as well as coumarin
ring in order to investigate their biological activity.
RESULTS AND DISCUSSION
5-Hydroxy-5-trifluoromethylpyrazole-1-thiocarboxamides (3), prepared by the
condensation of thiosemicarbazide (1) with trifluoromethyl-β-diketones (2),[38-39] was
refluxed with 3-(2-bromoacetyl)coumarins (5) in ethanol in presence of small amount of
sodium carbonate to obtain 2-(3-alkyl/aryl-5-trifluoromethylpyrazol-1-yl)-4-(coumarin-3-
yl)thiazole (6). 3-(2-bromoacetyl)coumarins (5a-c) were prepared by the bromination of
3-acetylcoumarins (4a-c) with liquid bromine in chloroform. The synthetic reactions are
outlined in Scheme 1.
Recently, we have reported the synthesis of some fluorinated pyrazolylthiazoles
where the reaction of 5-hydroxy-5-trifluoromethylpyrazole-1-thiocarboxamides (3) with
α-bromomethyl ketones led to the formation of 4-aryl-2-(3-phenyl-5-
trifluoromethylpyrazol-1-yl)thiazole in refluxing ethanol, accompanied by simultaneous
3

dehydration of 4-aryl-2-(3-phenyl-5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-
yl)thiazole.[19] It was suggested that acid (HBr) generated during the synthesis of thiazole
ring facilitated the simultaneous dehydration of 4-aryl-2-(3-phenyl-5-hydroxy-5-
trifluoromethyl-4,5-dihydropyrazol-1-yl)thiazole to 4-aryl-2-(3-phenyl-5-
trifluoromethylpyrazol-1-yl)thiazole . However, in the present work presence of a strong
electron withdrawing coumarin ring instead of an aryl ring in α-bromomethyl ketones
makes 2-(3-alkyl/aryl-5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-yl)-4-
(coumarin-3-yl)thiazole (7) resistant to undergo dehydration under the conditions of
Hantzsch thiazole synthesis and formation of 2-(3-alkyl/aryl-5-hydroxy-5-
trifluoromethyl-4,5-dihydropyrazol-1-yl)-4-(coumarin-3-yl)thiazole (7) takes place,
which further may dehydrated to corresponding pyrazoles (6) on refluxing in acetic
anhydride. In this article we are describing a single step pathway to synthesize the
targeted compounds i.e. 2-(3-alkyl/aryl-5-trifluoromethylpyrazol-1-yl)-4-(coumarin-3-
yl)thiazole (6), by refluxing 5-hydroxy-5-trifluoromethylpyrazol-1-thiocarboxamides (3)
with 3-(2-bromoacetyl)coumarins (5) in ethanol in the presence of small amount of
sodium carbonate (1.0 mole equivalent). In another experiment 6 was obtained when 7
(prepared by refluxing equimolar mixture of 3 and 5 in ethanol) was refluxed in ethanol
in the presence of small amount of sodium carbonate. Generally acidic media e.g. HCl in
ethanol, acetic anhydride, SOCl2-pyridine, P2O5 in chloroform, EtOH-H2SO4 etc. have
been reported for the dehydration of hydroxypyrazoline.[18, 40-43] This report shows that
hydroxypyrazoline may be dehydrated in the presence of a weak base e.g. sodium
carbonate. Larock et al have reported dehydration of N-acyl-5-hydroxy-4,5-dihydro-1H-
pyrazoles to corresponding pyrazoles using Li2CO3 (2 equiv.) and ICl (3 equiv.).[44] To
4

the best of our knowledge this is the first report describing the dehydration of hydroxyl
pyrazoline with such a mild base like sodium carbonate (0.5 equiv.) in absolute EtOH
with excellent yields, thus providing a greener and efficient protocol with reduced
number of steps for such type of reactions. Structure of all the newly synthesized
compounds was established by spectral data such as IR, mass, NMR (1H and 13C) and
elemental analyses.
In 1H NMR spectra of 6 two singlets, of one proton intensity each, appeared at δ
7.15-7.30 and 8.38-8.48 ppm corresponding to position-4 of pyrazole ring and position-5
of thiazole ring, respectively. A singlet appeared at δ 8.5-8.6 ppm is characteristic signal
for an olefinic proton present at position-4 of coumarin ring. In 13C NMR spectra of 6,
signals at δ 109-110, 130-133 and 131-134 ppm were assigned to C4, C3 and C5 carbon of
aromatic pyrazole ring, respectively. These values are in close agreement with the
reported values for pyrazole carbons 4, 3 and 5.[18-19, 45]
ANTIBACTERIAL ACTIVITY
The in vitro antibacterial activity of five chemical compounds was evaluated by
the agar well diffusion method.[46] On the basis of maximum inhibitory activity shown
against Gram-positive bacteria, compounds namely 6a, 6b and 6f were found to be the
most effective against B. subtilis and S. aureus with zone of inhibition of 19.6, 20.4, 18.3
mm, and 22.3, 19.2, 20.6 mm, respectively, whereas other tested compounds displayed
moderate activity (Table 1). In the whole series, the MIC of various tested chemical
compounds ranged between 32 and 256 µg/ml against Gram-positive bacteria. Compound
5

6a, 6b and 6f were found to be best as they exhibit the lowest MIC of 32, 32, 64 µg/ml
against S. aureus and MIC of 32, 64, 32 µg/ml against B. subtilis (Table 2). One
compound could not be tested for antibacterial activity due to poor solubility in DMSO.
CONCLUSION
In conclusion, we have described a one-pot synthesis of some novel 2-(3-
alkyl/aryl-5-trifluoromethylpyrazol-1-yl)-4-(coumarin-3-yl)thiazoles (6) involving the
reaction of 3-alkyl/aryl-5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazole-1-
thiocarboxamides (3) with 3-bromoacetylcoumarins (5) in presence of sodium carbonate
in ethanol. Compounds 6a, 6b and 6f have shown good antibacterial activity against
Gram-positive bacteria when compared with Ciprofloxacin.
EXPERIMENTAL
Fluorinated trifluoromethyl-β-diketones (2a-d) were prepared according to the
literature procedure.[47-48] 5-Hydroxy-5-trifluoromethyl-3-aryl-4,5-dihydropyrazole-1-
thiocarboxamides (3a-d) and 6-substituted-3-bromoacetylcoumarins (5a-c) were also
synthesized according to literature procedure.[35, 38]
General procedure for the preparation of 2-(3'-alkyl/aryl-5'-trifluoromethylpyrazol-1'-
yl)-4-(coumarin-3'''-yl)thiazoles (6a-g)
An ethanolic solution (30 ml) of 3-(2-bromoacetyl)coumarin (5a) (0.53g, 2 mmol)
and 5-hydroxy-3,5-bis(trifluoromethyl)-4,5-dihydropyrazol-1-thiocarboxamide (3)
6

(0.56g, 2 mmol) was refluxed in the presence of sodium carbonate (0.11g, 1 mmol) on
water bath for 6 hr. On completion of the reaction (observed by TLC), solvent was
evaporated. The solid thus obtained was dissolved in chloroform (25 ml) and washed
with hot water (50 ml, to dissolve sodium carbonate). Separated the organic layer and
distilled off the excess solvent. It was crystallized with aqueous ethanol to afford the
targeted compound 6a.
Similarly, the other compounds 6b-g were prepared by following the same procedure.
6a: 2-(3',5'-Bis-trifluoromethylpyrazol-1'-yl)-4-(coumarin-3'''-yl)thiazole mp 190-191
oC; Yield: 79%; IR (KBr, cm-1): 1720, 1528, 1296, 1180, 1142, 1095, 957, 756; 1H NMR
(300 MHz, CDCl3, δ ppm): 8.65 (s, 1H, 4'''-H), 8.46 (s, 1H, 5-H), 7.69 (d, 1H, J=7.5 Hz,
5'''-H), 7.62 (m, 1H, 7'''-H), 7.43 (m, 2H, 8''', 6'''-H), 7.19 (s, 1H, 4'-H); 19F NMR (CDCl3,
ppm): -80.34 (5-CF3), -66.98 (3-CF3); HRMS (m/z): 431.0160 [M]+, requires 431.0163;
Anal. Calcd. for C17H7F6N3O2S: C, 47.34; H, 1.64; N, 9.74. Found C, 47.32; H, 1.61; N,
9.69.
6f: 2-(3'-(p-Bromophenyl)-5'-trifluoromethylpyrazol-1'-yl)-4-(6'''-bromocoumarin-3'''-
yl)thiazole mp 305-306 oC; Yield: 69%; IR (KBr, cm-1): 1713, 1543, 1288, 1227, 1149,
1011, 949, 818, 787; 1H NMR (300 MHz, δ ppm): 8.58 (s, 1H, 4'''-H), 8.39 (s, 1H, 5-H),
7.82 (ds, 1H, J=2.1 Hz, 5'''-H), 7.80 (d, 2H, J=8.7 Hz, 2'', 6''-H), 7.67 (ds, 1H, J=2.1 Hz,
7'''-H), 7.64 (d, 2H, J=8.7 Hz, 3'', 5''-H), 7.31 (d, 1H, J=8.7 Hz, 8'''-H), 7.22 (s, 1H, 4'-H);
7

19F NMR (CDCl3, ppm): -80.50 (5-CF3); Anal. Calcd. for C22H10Br2F3N3O2S: C, 44.25;
H, 1.69; N, 7.04. Found C, 44.24; H, 1.65; N, 6.95.
An alternative procedure for the preparation of 2-(3'-alkyl/aryl-5'-
trifluoromethylpyrazol-1'-yl)-4-(coumarin-3'''-yl)thiazoles (6) from 2-(3'-alkyl/aryl-5'-
hydroxy-5'-trifluoromethyl-4',5'-dihydropyrazol-1'-yl)-4-(coumarin-3'''-yl)thiazoles (7)
An ethanolic solution of 2-(3′-alkyl/aryl-5′-hydroxy-5′-trifluoromethyl-4′,5′-
dihydropyrazol-1′-yl)-4-(coumarin-3′′-yl)thiazole (7a, 0.898 g, 2 mmol) and Na2CO3
(0.106 g, 1 mmol) was refluxed in ethanol (20 ml) for 5 hrs. Excess of ethanol was
distilled off from the reaction mixture and added chloroform. The organic layer was
washed thoroughly (2×25 ml) with water. The organic layer thus separated was dried
over anhyd. Na2SO4. The reaction mixture was concentrated and cooled to room
temperature. Filtered and washed the solid with aqueous ethanol. On drying dehydrated
product 6a was obtained, which was confirmed by comparing its mp and 1H NMR.
ACKNOWLEDGEMENTS
We thank the CSIR, New Delhi, India for providing the financial assistance in the
form of Senior Research Fellowship to Sunil Kumar. Thanks are also due to SAIF, CDRI,
Lucknow; SAIF, Panjab University, Chandigarh, India and UCSF, USA for providing 19F
NMR, elemental analyses and HRMS spectra, respectively.
SUPPORTING INFORMATION
8

Supplemental data for this article can be accessed on the publisher’s website.
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Zanatta, N.; Martins, M.A.P. Heteroatom Chem. 2006, 17, 685-691. (ii) Bonacorso, H.
12

G.; Oliveira, M. R.; Costa, M. B.; Drekener, R. L.; daSilva, L. B.; Zanatta, N.; Martins,
M. A. P. J. Het. Chem. 2005, 42, 631-637.
43.
Bonacorso, H. G.; Wastowski, A. D.; Muniz, M. N.; Zanatta, N.; Martins, M. A.
P. Synthesis, 2002, 8, 1079-1083.
44.
45.
46.
47.
Waldo, J. P.; Mehta, S.; Larock, R. C. J. Org. Chem. 2008, 73, 6666-6670.
Song, L.; Zhu, S. J. Fluorine Chem. 2011, 111, 201-205.
Aneja, K. R.; Sharma, C.; Joshi, R. Jundishapur J. Microbiol. 2011, 4, 175-183.
Colla, A. ; Martins, M. A. P.; Clar, G.; Krimmer, S.; Fischer, P. Synthesis 1991,
483-486.
48.
(i) Siqueira, G. M.; Flores, A. F. C.; Clar, G.; Zanatta, N.; Martins, M. A. P.
Quimica Nova 1994, 17, 24-26; (ii) Flores, A. F. C.; Siqueira, G. M.; Freitag, R.; Zanatta,
N.; Martins, M. A. P. Quimica Nova 1994, 17, 298-300.
13

Table 1. In vitro antibacterial activity of chemical compounds through agar well diffusion
method
Compound
Diameter of growth of inhibition zone (mm)
S. aureus B. subtilis E. coli P. aeruginosa
19.6
20.4
14.3
15.0
18.3
15.6
24.6
22.3
19.0
16.6
16.3
20.6
16.3
23.0
-
-
6a
6b
6c
6d
6f
-
-
-
-
-
-
-
-
-
-
6g
Ciprofloxacin
24.0
21.0
a
No activity; Values, including diameter of the well (8mm), are means of three replicates
14

Table 2. Minimum inhibitory concentration (MIC) (in µg/ml) of compounds (6)
Compound
S. aureus
32
B. subtilis
32
6a
32
64
6b
128
128
64
64
6c
128
32
6d
6f
128
6.25
64
6g
Ciprofloxacin
6.25
15

Scheme 1. Synthesis of 2-(3'-alkyl/aryl-5'-trifluoromethylpyrazol-1'-yl)-4-(coumarin-3'''-
yl)thiazoles (6a-g)
16