Ultrasound aided expedient synthesis, characterization and antimicrobial studies of fluorenyl-hydrazono-thiazole derivatives

Article abstract of DOI:10.14233/ajchem.2019.22118

Ultrasound assisted facile synthesis of fluorenyl-hydrazonothiazoles (4a-d) in quantitative yields by the condensation of 2-(9H-fluoren-9-ylidene)hydrazinecarbothioamide (2) with substituted phenacyl bromides in presence of dimethyl formamide has been rep

Full text of DOI:10.14233/ajchem.2019.22118

Asian Journal of Chemistry; Vol. 31, No. 10 (2019), 2245-2248
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.22118
Ultrasound Aided Expedient Synthesis, Characterization and
Antimicrobial Studies of Fluorenyl-Hydrazono-Thiazole Derivatives
*
AVNEET PAL KAUR and DEEPIKA GAUTAM
Department of Chemistry, Sant Baba Bhag Singh University, Jalandhar-144030, India
*Corresponding author: Fax: +91 181 271155; Tel.: +91 181 2711163; E-mail: dpkgtm641@gmail.com
Received: 5 April 2019; Accepted: 19 May 2019; Published online: 30 August 2019;
AJC-19530
Ultrasound assisted facile synthesis of fluorenyl-hydrazonothiazoles (4a-d) in quantitative yields by the condensation of 2-(9H-fluoren-
9-ylidene)hydrazinecarbothioamide (2) with substituted phenacyl bromides in presence of dimethyl formamide has been reported. The
reaction of carbothioamide 2 with α-haloacids resulted in to fluorenyl-hydrazonothiazolidin-4-ones (3). The structural characterization of
the cyclized products have been established by elemental analysis and spectral data (IR, NMR and mass). The antimicrobial studies of the
synthesized compounds are also reported.
Keywords: Thiazole, Halo acid, Fluorenone, Phenacyl bromide, Antimicrobial activity.
INTRODUCTION
EXPERIMENTAL
In last few decades, heterocyclic compounds have been
found immensely useful in biological and industrial arena.
They have secured a highly remarkable position among pharma-
ceutically important natural and synthetic materials. Thiazoles
are well known heterocyclic compounds which own important
features of a variety of medicinal agents. In addition to vitamin
B1 (thiamine), the thiazole ring is found in many potent biolo-
gically active agents such as penicillins (antibacterial drugs),
sulfathiazole (antimicrobial drug), ritonavir (antiretroviral
drug) and meloxicam (anti-inflammatory drug). Compounds
containing thiazole moiety have been reported to manifest wide
spectrum of biological activities such as for treatment of
allergies [1], hypertension [2], inflammation [3], schizophrenia
[4], HIV infection [5,6], tumour [7-9] and convulsions [10-12].
The scrutiny for new biologically active analogues continues to
be a zone of intensive research in medicinal chemistry [13,14].
In the present investigations, some new fluorenyl-hydrazono-
thiazole derivatives have been synthesized under ultrasonic
conditions. The synthesis method is very fast and efficient as
the products are obtained in quantitative yields. The structures
of all the synthesized compounds have been validated with elem-
ental analysis and spectral data. All these compounds have
also been screened for their antimicrobial activities.
Fluorenone and other chemicals were procured from Merck
and were used without further purification. Melting points were
determined in a melting point apparatus in open capillaries
and are reported without any correction. Proton and carbon NMR
spectra were recorded in DMSO-d6 on BRUKER AVANCE II
400 MHz spectrometer. Tetramethylsilane (TMS) was used as
an internal standard and the chemical shifts are reported in
ppm. IR spectra were obtained on Perkin Elmer (RZX) FTIR
spectrometer and the frequencies are reported in cm-1. Euro
EA 3000 ElementalAnalyzer was employed for element analysis.
Molecular weight analysis was performed on Shimadzu GC-
MS QP 2010 Ultra spectrometer. Thin layer chromatography
(TLC) was accomplished on silica gel G coated plates and using
iodine vapours as visualizing agent. Ultrasonication experiments
were performed on Cole Parmar CPX500, 20 KHz and 500 Watt
ultrasonicator.
General procedure for synthesis of compound 2:A mixture
of 9-fluorenone (1) (1.0 mmol) and thiosemicarbazide (1.0 mmol)
in absolute ethanol (20 mL) containing 2-3 drops of conc. HCl
was stirred for 3-4 h at ambient temperature. The progress of
reaction was monitored byTLC.After the completion of reaction,
the reaction mixture was poured in to ice cold water and filtered
the crude product. The crude solid was recrystallized from ethanol.
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2246 Kaur et al.
Asian J. Chem.
2-(9H-Fluoren-9-ylidene)hydrazinecarbothioamide (2):
MHz, DMSO-d6) δ: 6.93 (s, 1H, =CH), 7.41 (d, 2H, Ar, J =
7.6 Hz), 7.52 (d, 42H, Ar, J = 7.2 Hz), 7.54-7.59 (m, 4H, ArH),
7.8-7.85 (m, 4H,ArH); 13C NMR (100 MHz, DMSO-d6) δ: 160.2,
157.4 (C=N), 147.1, 146.3, 140.2, 140.6, 138.7, 132.4, 127.6,
125.3, 123, 122.8, 121.5; Mass: m/z 387 (18 %, M+), 389 (5 %,
M+2).Anal. calcd. (found) % for C22H14N3SCl: C, 68.12 (68.27);
H, 3.64 (3.53); N, 10.83 (10.62); S, 8.27 (8.11).
Yellow crystalline solid, yield 78 %; m.p.: 198-99 ºC (Lit.
m.p. 202-203 ºC [Ref. 15,16]). IR (KBr, νmax, cm-1): 1618 (C=N),
1221 (C=S); 1H NMR (400 MHz, DMSO-d6) δ: 7.25 (t, 2H,
C6H5, J = 7.4 Hz), 7.35-7.49 (m, 4H, C6H5), 7.56 (t, 2H, C6H5,
J = 7.4 Hz), 8.51 (br, 1H, NH), 10.5 (br, 1H, NH); mass: m/z
253 (M+, 48 %).
General procedure for the synthesis of compound 3:A
mixture of carbothioamide 2 (0.005 mol), chloroacetic acid/
2-chloropropionic acid (0.005 mol), anhydrous sodium acetate
(0.8 g, 0.01 mol), glacial acetic acid (3.0 mL) and acetic anhydride
(1.0 mL) was heated under reflux for 4 h. The reaction mixture
was cooled to room temperature and then poured into ice cold
water. The resultant solid was filtered, washed with water and
recrystallized from ethanol.
(Z)-2-((9H-Fluoren-9-ylidene)hydrazono)thiazolidin-
4-one (3a): Pale yellow crystalline solid, yield 88 %, m.p.:
211-215 ºC. IR (KBr, νmax, cm-1): 1705 (C=O), 1620 (C=N);
1H NMR (400 MHz, DMSO-d6) δ: 3.84 (s, 2H, SCH2), 7.35-7.38
(m, 2H,ArH), 7.47-7.53 (m, 2H,ArH), 7.78-7.85 (m, 3H,ArH),
8.57 (d, 1H,ArH, J = 7.6 Hz), 13.13 (br, 1H, NH). 13C NMR (100
MHz, DMSO-d6) δ: 178.2 (C=O), 162.5 (C=N), 158.0 (C=N),
142.4 (thiazole-CS), 141.6, 135.6, 131.8, 130.9, 129.9, 128.3,
122.2, 120.5 (Ar-C). Mass: [M+, 293] (42 %).Anal. calcd (found)
% for C16H11N3OS: C, 65.51 (65.82); H, 3.78 (4.01); N, 14.32
(14.56); S, 10.93 (11.28).
(Z)-2-((9H-Fluoren-9-ylidene)hydrazono)-5-methyl-
thiazolidin-4-one (3b): Dark yellow solid, yield 78 %, m.p.:
202-204 ºC. IR (KBr, νmax, cm-1): 1698 (C=O), 1628 (C=N).
1H NMR (400 MHz, DMSO-d6) δ: 1.56 (q, 1H, CH3), 3.88 (d,
1H, SCH), 7.38-7.41 (m, 2H, ArH), 7.45-7.5 (m, 2H, ArH),
7.8-7.82 (m, 4H,ArH), 12.15 (br, 1H, NH). 13C NMR (100 MHz,
DMSO-d6) δ: 175.8 (C=O), 165.6 (C=N), 159.2 (C=N), 143.6
(thiazole-CS), 142.3, 139.7, 133.5, 132.6, 128.3, 126.9, 124.7,
122.6 (Ar-C), 25.8 (CH3). Mass: [M+, 307] (36 %).Anal. calcd.
(found) % for C17H13N3OS: C, 66.43 (66.66); H, 4.26 (4.53);
N, 13.67 (13.80); S, 10.43 (10.28).
2-(2-(9H-Fluoren-9-ylidene)hydrazinyl)-4-(4-nitro-
phenyl)thiazole (4c):Yellowish fluffy solid, yield 83 %, m.p.:
232-234 ºC. IR (KBr, νmax, cm-1): 1638 (C=N), 1H NMR (400
MHz, DMSO-d6) δ: 7.12 (s, 1H, =CH), 7.46 (d, 2H, Ar, J = 8.2
Hz), 7.5 (d, 2H, Ar, J = 7.8 Hz), 7.6-7.63 (m, 5H, ArH), 7.9-
7.95 (m, 3H, ArH); 13C NMR (100 MHz, DMSOd6) δ: 167.6,
159.3 (C=N), 148.3, 146.5, 143.9, 142.5, 139.8, 136.1, 129.3,
127.8, 125.2, 124, 122.2; Mass: m/z 398 (25 %, M+). Anal.
calcd. (found) for C22H14N4SO: C, 66.32 (66.57); H, 3.54 (3.73);
N, 14.06 (13.87); S, 8.05 (8.21).
2-(2-(9H-Fluoren-9-ylidene)hydrazinyl)-4-(4-bromo-
phenyl)thiazole (4d):Yellowish green solid, yield 81 %, m.p.:
220-222 ºC. IR (KBr, νmax, cm-1): 1627 (C=N), 1H NMR (400
MHz, DMSO-d6) δ: 6.89 (s, 1H, =CH), 7.5 (m, 3H, ArH), 7.65
(d, 2H, Ar, J = 7.4 Hz), 7.64-7.66 (m, 4H, ArH), 7.82-7.85 (m,
13
3H, ArH); C NMR (100 MHz, DMSO-d6) δ: 164.3, 157.4
(C=N), 146.2, 145.3, 144.8, 141.6, 140, 135.6, 130.4, 128.8,
127.3, 125.1, 121.7; Mass: m/z 432 (29 %, M+), 434 (25 %,
M+2). Anal. calcd. (found) for C22H14N3SBr: C, 61.12 (61.37);
H, 3.26 (3.54); N, 9.72 (9.88); S, 7.42 (7.22).
RESULTS AND DISCUSSION
9-Fluorenone (1) on stirring with thiosemicarbazide in
ethanol and conc. HCl at ambient temperature for 3 h furnished
2-(9H-fluoren-9-ylidene)hydrazinecarbothioamide (2). The
melting point of carbothioamide derivative 2is well in agreement
with the reported literature [15,16]. IR spectrum of compound
2 showed absorption bands at 1618 and 1221 cm-1 associated
1
with C=N and C=S functionalities, respectively. H NMR
spectrum of compound 2 exhibited broad singlets at δ 8.51
ppm and δ 10.5 ppm due to two NH groups. Finally, the mass
spectrum, showed a peak at m/z 253 (48 %) corresponding to
the molecular ion. Condensation of carbothioamide 2 with
chloroacetic acid and 2-bromopropionic acid in presence of
anhydrous sodium acetate and acetic acid furnished 2-((9H-
fluoren-9-ylidene)hydrazono)thiazolidin-4-one (3a) and 2-
((9H-fluoren-9-ylidene)hydrazono)-5-methylthiazolidin-4-one
(3b) (Scheme-I), respectively. The IR spectrum of compound
3a displayed peaks at 1705 and 1620 cm-1 due to C=O and
General procedure for the synthesis of compound 4:A
mixture of carbothioamide 2 (0.001 mol) and p-substituted
phenacyl bromide (0.001 mol) in 5 mL of DMF was kept under
ultrasonication and the progress of the reaction was monitored
with TLC. The reaction was completed in 5-8 min. After the
completion of reaction, the mixture was poured in to ice cold
water. The solid thus obtained was filtered and recrystallized
from ethanol-DMF (3:1) mixture.
2-(2-(9H-Fluoren-9-ylidene)hydrazinyl)-4-phenyl-
thiazole (4a): Pale yellow fluffy solid, yield 82 %, m.p.: 155-
157 ºC. IR (KBr, νmax, cm-1): 1632 (C=N), 1H NMR (400 MHz,
DMSO-d6) δ: 6.82 (s, 1H, =CH), 7.0 (t, 2H, C6H5, J = 7.4) 7.34-
7.44 (m, 3H, Ar), 7.51(t, 2H, C6H5, J = 6.8), 7.63-7.69 (m, 4H,
Ar), 7.77-7.85 (m, 2H, Ar); 13C NMR (100 MHz, DMSO-d6)
δ: 162.6 (C=N), 158.5 (C=N), 146.6, 145.2, 144.3, 144.1, 142.6,
136.9, 134.2, 128.5, 126.3, 122.5, 120.4; Mass: m/z 353 (16 %,
M+).Anal. calcd. (found) % for C22H15N3O2S: C, 74.76 (74.92);
H, 4.28 (4.43); N, 11.89 (12.15); S, 9.07 (9.28).
1
C=N groups, respectively. H NMR spectrum of compound
3a exhibited a singlet of two protons at δ 3.84 ppm, which
was assigned to SCH2 group of thiazolidin-4-one ring.Aromatic
protons appeared between δ 7.35-8.57 ppm. 13C NMR showed
C=O and C=N peaks at δ 178.2 and 162.5 ppm, respectively.
The mass spectrum of compound 3a exhibited molecular ion
peak at m/z 293 (42 %). The structure of compound 3b was
also similarly established spectrally.
A pilot reaction of carbothioamide 2with phenacyl bromide
was carried out under reflux conditions, grinding in neat condi-
tions and under ultrasonic conditions in different solvents. The
2-(2-(9H-Fluoren-9-ylidene)hydrazinyl)-4-(4-chloro-
phenyl)thiazole (4b): Greenish fluffy solid, yield 80 %, m.p.:
182-184 ºC. IR (KBr, νmax, cm-1): 1632 (C=N), 1H NMR (400

Vol. 31, No. 10 (2019) Ultrasound Aided Expedient Synthesis and Antimicrobial Studies of Fluorenyl-Hydrazono-Thiazole Derivatives 2247
H
O
R
S
NH
R
Cl-CH-CO2H
N
N
EtOH,
NNHCSNH2
O
3
(a) R= H
NH2NHCSNH2
EtOH, rt
(b) R= CH3
Ar
1
2
S
N
N
ArCOCH2Br
EtOH
NH
4
(a) Ar= C6H5
(b) Ar= C6H4-Cl-p
(c) Ar= C6H4-NO2-p
(d) Ar= C6H4-Br-p
Scheme-I: Synthesis of fluorenyl-hydrazonothiazole derivatives
TABLE-1
progress of the reaction was monitored by TLC and the yield
of the product was estimated and reported in Table-1. It is
clear that under ultrasonic conditions, the reaction is quick
and the yield is quantitative. Compounds 4a-d was obtained
accordingly under ultrasonic conditions. The structure of the
synthesized thiazole derivatives have been established by analy-
tical and spectral data. In 1H NMR spectrum of compound 4a,
the signal for methine CH of thiazole ring appears at δ 6.82 ppm
authenticating the formation of thiazole ring. All other protons
appear in aromatic region between δ 7.0-7.85 ppm. 13C NMR
spectrum of compound 4a displayed two peaks at δ 162.6 ppm
and δ 158.5 ppm attributed to C=N groups. Methine carbon
appeared at 120.4 ppm in carbon NMR of compound 4a. The
mass spectrum of compound 4a exhibited molecular ion peak
at m/z 353 (16 %). The structure of other fluorenyl-hydrazono-
thiazole derivatives (4b-d) was similarly assigned on the basis
of spectral data.
OPTIMIZATION OF REACTION PARAMETERS
Solvent
Ethanol
Ethanol
DMF
–
Condition
Room temp stirring
Reflux
Time (min)
Yield (%)a
120
30
15
30
15
5
30
62
65
56
68
82
Reflux
Grinding
Ultrasonic
Ultrasonic
Ethanol
DMF
aYields are reported for 4a and for others please refer experimental
section.
aeruginosa stains were employed for antibacterial screening.
For Aspergillus niger, Aspergillus fumigates and Candida
albicans strains were used for antifungal screening. Both microbial
studies were assessed by minimum inhibitory concentration
(MIC) by serial dilution method [17]. Ciprofloxacin and micona-
zole were used as reference drugs. The results of the screening
experiments are presented in Table-2.All the compounds show
bacterial inhibition in broad range. MIC values of derivatives
4b and 4d demonstrated the highest antibacterial activity.
Antimicrobial activity of compounds 3 and 4:Compounds
3and 4were assayed for their in vitro antibacterial and antifungal
activity. Staphylococcus aureus, Escherichia coli and Pseudomonas
TABLE-2
BIOLOGICAL ASSAY OF COMPOUNDS 3 AND 4
Antimicrobial activity (MIC, µg/mL)
Antibacterial activity
Compd.
Antifungal activity
S. aureus
50
E. coli
50
6.25
25
25
25
12.5
6.25
–
P. aeruginosa
A. niger
25
C. albicans
A. fumigates
3a
3b
4a
4b
4c
25
25
25
12.5
12.5
25
6.25
–
25
12.5
25
50
50
50
–
6.25
25
12.5
50
50
50
50
–
6.25
25
25
12.5
12.5
12.5
12.5
12.5
–
12.5
25
12.5
6.25
–
4d
Ciprofloxacin
Miconazole
6.25

2248 Kaur et al.
Asian J. Chem.
6. H. Chen, T. Yang, S. Wei, H. Zhang, R. Li, Z. Qin and X. Li, Bioorg.
Med. Chem. Lett., 22, 7041 (2012);
Compound 3b (MIC = 12.5 µg/mL) demonstrated very good anti-
fungal activity against A. niger, C. albicans and A. fumigates.
https://doi.org/10.1016/j.bmcl.2012.09.100.
7. R.F. George, E.M. Samir, M.N. Abdelhamed, H.A. Abdel-Aziz and
S.E-S. Abbas, Bioorg. Chem., 83, 186 (2019);
https://doi.org/10.1016/j.bioorg.2018.10.038.
8. G.S. Hassan, S.M. El-Messery, F.A.M. Al-Omary and H.I. El-Subbagh,
Bioorg. Med. Chem. Lett., 22, 6318 (2012);
https://doi.org/10.1016/j.bmcl.2012.08.095.
9. A.M.Al-O. Fatmah, S.H. Ghada, S.M. El-Messery and H.I. El-Subbagh,
Eur. J. Med. Chem., 47, 65 (2012);
Conclusion
A simple and highly efficient protocol for the synthesis
of thiazole derivatives from carbothioamide derivative and phen-
acyl bromides under ultrasonic conditions has been developed.
High yields and easy work up are benefits of the present synthetic
protocol.
https://doi.org/10.1016/j.ejmech.2011.10.023.
CONFLICT OF INTEREST
10. R. Sadashiva, D. Naral, J. Kudva, S.M. Kumar, K. Byrappa, R.M. Shafeeull
and M. Kumsig, J. Mol. Struct., 1145, 18 (2017);
https://doi.org/10.1016/j.molstruc.2017.05.066.
11. X.Q. Deng, M.X. Song, C.X. Wei, F.N. Li and Z.S. Quan, Iran. J.
Pharm. Res., 13, 459 (2014).
The authors declare that there is no conflict of interests
regarding the publication of this article.
12. K.Z. Laczkowski, K. Salat, K. Misiura,A. Podkowa and N. Malikowska,
J. Enzyme Inhib. Med. Chem., 31, 1576 (2016);
https://doi.org/10.3109/14756366.2016.1158172.
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