An efficient one pot synthesis and antimicrobial activity of novel S-alkylisothiosemicarbazone and imidazolidinone derivatives of pyrazole carbaldehyde

Article abstract of DOI:10.3184/174751912X13459883792770

S-Alkylisothiosemicarbazone and imidazolidinone derivatives were synthesised from pyrazole 4-carbaldehyde in a one pot reaction. The synthesised compounds were characterized by IR, 1H NMR, 13C NMR, mass and elemental analysis. Most of the synthesised compounds showed antimicrobial activity against S. Aureus, B. subtilis, E. coli, P. aeruginos, A. Niger and C. albicans.

Full text of DOI:10.3184/174751912X13459883792770

590 RESEARCH PAPER
OCTOBER, 590–594
JOURNAL OF CHEMICAL RESEARCH 2012
An efficient one pot synthesis and antimicrobial activity of novel
S-alkylisothiosemicarbazone and imidazolidinone derivatives of pyrazole
carbaldehyde
Sachin V. Patila, Nitin D. Gaikwadb and Vivek D. Bobadea*
aDepartment of Chemistry, H.P.T Arts and R.Y.K. Science College, Nashik 422005, India
bDepartment of Chemistry, K.T.H.M. College, Nashik 422005, India
S-Alkylisothiosemicarbazone and imidazolidinone derivatives were synthesised from pyrazole 4-carbaldehyde in a
1
one pot reaction. The synthesised compounds were characterized by IR, H NMR, 13C NMR, mass and elemental
analysis. Most of the synthesised compounds showed antimicrobial activity against S. Aureus, B. subtilis, E. coli,
P. aeruginos, A. Niger and C. albicans.
Keywords: one pot, S-alkylisothiosemicarbazone, imidazolidinone, ethyl chloroacetate, alkyl bromides, pyrazole 4-carbaldehyde
Test microorganisms
Pyrazole, imidazolidinone and isothiosemicarbazone deriva-
tives show varied biological activities and are therefore of
considerable interest for drug discovery. On this basis, we
have studied the design and synthesis of new molecules which
combine the nucleus of pyrazole and thiazolidinone as well as
pyrazole and isothiosemicarbazone in one molecular frame-
work in anticipation that such compounds might show
enhanced biological activity.1–12 The literature revealed that
pyrazole derivatives of barbituric acid, thiobarbituric acid,
some activated nitriles, and acetophenones showed antimicro-
bial activities.13 In continuation of our work14–17 on the synthesis
of new derivatives with a combination of different heterocyclic
rings as possible antimicrobial agents, we report here the
synthesis of some new S-alkyl isothiosemicarbazone and
imidazolidinone derivatives of pyrazole carbaldehyde. From
substituted acetophenones 1a–e the intermediate pyrazole
carbaldehydes 2a–e were synthesised by known literature
methods.18,19 Two different series of pyrazole aldehyde deriva-
tives (3a–j and 4a–k) were synthesised and screened for their
antimicrobial activity.
All the synthesised compounds were screened for their in vitro
antibacterial activity against the standard strains B. subtilis (2250),
S. aureus (2079), E. coli (2109) and P. aeruginosa (2036) and for their
antifungal activity against C. albicans (3471) and A. niger (545). All
the strains were obtained from the microbial type culture collection
(MTCC) at the NCIM, Pune, India.
Primary screening
The antibacterial activity of all the newly synthesised compounds
was estimated by the agar-well diffusion assay technique.20 A 24 h old
bacterial culture of all test microorganisms were used as the inoculum,
which was adjusted to 0.5 McFarland standard (1.5 × 108 CFU/mL).
The stock solutions of all test compounds (100 µg mL−1) were
prepared by dissolving 100 µg of the test compound in DMSO (1 mL).
Chloramphenicol and DMSO were used as positive and negative
controls, respectively.
20 mL of molten and cooled MHA and 320 µl of each test bacterial
culture were mixed (separate flasks were used for each bacterial
culture) and poured in sterilised and labelled Petri plates. The wells of
6 mm were punched in the solidified Petri plates, aseptically. 50 µL
from stock solutions of all compounds as well as controls were added
to each well of labelled Petri plates and incubated at 35 °C for 24 h.
The diameter of the zone of growth inhibition around each well was
measured after incubation using a Vernier caliper.
For the antifungal activity, sliced potatoes were placed with 500 mL
of distilled water in a pan and boiled for 30 min until a spoon could
pierce them. The mixture was then filtered while hot and broth was
again placed in a pan with the rest of the distilled water. Dextrose was
dissolved in distilled water and weighed agar was added to the broth
and heated to boiling. The medium thus obtained was sterilised in a
pressure cooker for 30 min. The sterilised medium (15 mL) was pipet-
ted out into flat Petri plates. When it solidified, 15 mL of warm seeded
agar was applied over it. The seeded agar was made by cooling
the medium to 40 °C and then adding a spore suspension to the
seeded medium. The spores were obtained from 10 days culture of
C. albicans and A. niger species. The final inoculum size was adjusted
to 1 × 106 spore mL−1. Nystatin and DMSO were used as positive and
negative controls, respectively.
Experimental
Chemicals were purchased from Aldrich Chemical Co. Reactions
were monitored and purity of the products was checked by TLC using
Merck 60 F-254 silica gel plates with visualisation by UV light.
Melting points were determined on a Buchi Melting Point B-545
apparatus. The IR spectra of the compounds were recorded on a
Nicolet 6700 FT-IR spectrometry using KBr pellets. 1H NMR spectra
were recorded on a Bruker spectrometer at 300 MHz and 75 MHz
(13C NMR) in CDCl3. Chemical shifts were recorded in parts ppm
downfield from tetramethylsilane. Mass spectra were recorded using
a MS-3200Q. CHN Analysis was done on an HOSLI CH- analyser.
Column chromatography was performed on silica gel (230–400 mesh)
supplied by Acme Chemical Co. The chemicals and solvents used
were laboratory grade and were purified as per literature methods.
Antimicrobial activity
For antibacterial activity the solid media used for the study were
Muller-Hinton agar (Hi media) MHA of the following composition,
beef infusion (300 g L−1), casein acid hydrolysate (17.5 g L−1), starch
(1.5 g mL−1), agar-agar (17 g L−1) and sterilised distilled water
(1000 mL) adjusted to pH 7.4. and soyabean casein digest agar
(SCDA; casein enzymatic hydrolysate (17.0 g L−1), papain digest of
soyabean 3.0 (g L−1), NaCl 5.0 (g L−1), dipotassium phosphate (2.5 g
L−1) and distilled water (1000 mL), adjusted to pH 7.3) were used for
biological assays.
For antifungal activity the solid media used for the study were
potato dextrose agar (Hi media) of the following composition potato
(250 g), dextrose (10g), agar-agar (20g), sterilised distilled water
(100 mL) adjusted to pH 7.3.
Before the solidification of agar, the plate was tilted to ensure
that coverage was even. These Petri plates were then put into the
refrigerator upside down to prevent condensation of moisture. A con-
centration 100 µg mL−1 of the synthesised compounds were prepared
by dissolving the required quantity of compounds in DMSO.
Sterilised Whatman filter paper number 541 discs were prepared by
cutting 6 mm diameter with a cork borer and were spread individually
with a needle and planted upon the chilled seeded medium. The
culture plates were then incubated for 24 to 72 h at 37 °C and the
inhibition zone around each disc was measured from the centre of
the disc. The diameter of growth inhibition zone was calculated by a
Vernier caliper.
Synthesis of pyrazole 4-carbaldehyde (2a–e)
The compounds 2a–e were synthesised from different substituted ace-
tophenones 1a–e using literature protocol18,19 as shown in Scheme 1.
* Correspondent. E-mail: v_bobade31@rediffmail.com

JOURNAL OF CHEMICAL RESEARCH 2012 591
Synthesis of isothiosemicarbazone derivatives (3a–j)
1-((3-(4-Nitrophenyl)1-phenyl-1H-pyrazol-4-yl)methyleneamino)-
2-ethylisothio urea (3f): M.p. 176 °C, yield: 80%, 1H NMR δ (300 MHz,
CDCl3): 9.8 (bs, 2H, NH2), 9.3 (s, 1H, pyrazolyl H), 8.5 (s, 1H,
CH=N), 8.38 (d, 2H, J = 8.2 Hz), 8.03 (d, 2H, J = 8.2 Hz), 7.4–7.7 (m,
A suspension of thiosemicarbazide (5 mmol) and alkyl bromide
(5 mmol) in ethanol (20 mL) was refluxed until the solid was com-
pletely dissolved. To this, aldehyde (5 mmol) was added and the heat-
ing was continued for 1 h. The progress of the reaction was monitored
by TLC (ethyl acetate: hexane, 4:6). After completion, the reaction
mixture was cooled at room temperature and poured into ice-cold
water. The solid product obtained was filtered, washed with water and
purified by column chromatography.
5H), 3.4 (q, 2H, J = 7.1 Hz, S–CH2), 1.3 (t, 3H, J = 7.1 Hz, CH3). 13
C
NMR δ (75 MHz, CDCl3): 162.62 (C=S), 150.540 (CH=N), 150.767,
139.335, 133.749 (2C), 131.542, 130.01 (2C), 129, 128.421, 128.121
(2C), 122.896, 119.431 (2C), 117.142, 22.85 (S–CH2), 15.61 (CH3)
Anal. Calcd for C19H18N6O2S C, 57.85; H, 4.60; N, 21.31. Found: C,
57.79; H, 4.72; N, 21.25%.
1-((3-(4-Nitrophenyl)1-phenyl-1H-pyrazol-4-yl)methyleneamino)-
2-propylisothiourea (3g): M.p. 180 °C, yield: 83%, 1H NMR δ (300 MHz,
CDCl3): 9.8 (bs, 2H, NH2), 9.4 (s, 1H, pyrazolyl H), 8.6 (s, 1H,
CH=N), 8.38 (d, 2H, J = 8.2 Hz), 8.03 (d, 2H, J = 8.2 Hz), 7.4–7.7
(m, 5H), 3.4 (t, 2H, J = 7.1 Hz,S–CH2), 1.7 (m, 2H, CH2), 1.0 (t, 3H,
J = 7.1 Hz,CH3). 13C NMR, δ (75 MHz, CDCl3): 162 (C=S), 150.45
(CH=N), 150.92, 140, 134.10 (2C), 131.624, 130.52 (2C), 129.2,
128.54, 128 (2C), 123.01, 119.132 (2C), 117.142, 22.58 (S–CH2),
14.50 (CH3), 13.54 (CH2) MS (EI, 70 eV): m/z (%) = 408 (M+, 100),
409 (M+1, 25). Anal. Calcd for C20H20N6O2S, C, 58.81; H, 4.94; N,
20.57. Found: C, 58.75; H, 4.86; N, 20.45%.
Synthesis of imidazolidinone derivatives (4a–k)
A mixture of (5 mmol) of pyrazole carbaldehyde, thiosemicarbazide
(5 mmol), ethyl chloroacetate (5 mmol), alkyl bromide (5 mmol) and
triethyl amine (two drops) was refluxed in ethanol (20 mL) for about
30 minutes. The reaction was monitored by TLC (ethyl acetate:
hexane, 3:7). After completion, the reaction mixture was cooled and
poured into crushed ice. The precipitate obtained was filtered, washed
with water and purified by column chromatography.
1-((1,3-Diphenyl-1H-pyrazol-4-yl)methyleneamino)-2-butylisothio-
urea (3a): M.p. 121 °C, yield: 75%, IR (cm−1): 3200 (NH2), 3020
1
(Aromatic CH), 1615 (C=N), 1600, 1500, 1228, 504, 754, 705. H
NMR δ (300 MHz, CDCl3): 9.3 (s, 1H, pyrazolyl H), 9.1 (bs, 2H,
NH2), 8.5 (s, 1H, CH=N), 7.3–7.9 (m, 9H), 3.3 (t, J = 6.8 Hz, 2H, S–
CH2), 1.7 (m, 2H, CH2), 1.4 (m, 2H, CH2), 0.9 (t, J = 7.1 Hz, 3H,CH3).
13C NMR δ (75 MHz, CDCl3): 162.5 (N=C-S), 150.35 (CH=N), 150.6,
140.43, 130 (2C), 131.245, 129.10 (2C), 130.03 (2C), 125.54, 125.05,
123.03, 119.54 (2C), 117.142, 22.569 (S–CH2), 16.684 (CH2), 16,
15.657. MS (EI, 70 eV): m/z (%) = 377 (M+, 100), 378 (M+1, 42).
Anal. Calcd for C21H23N5S, C, 66.81; H, 6.14; N, 18.55. Found: C,
66.75; H, 6.20; N, 18.50%.
1-((3-(4-Nitrophenyl)1-phenyl-1H-pyrazol-4-yl)methyleneamino)-
2-butylisothiourea (3h): M.p. 192 °C, yield: 78%, 1H NMR δ (300 MHz,
CDCl3): 9.5 (bs, 2H, NH2), 9.4 (s, 1H, pyrazolyl H), 8.6 (s, 1H,
CH=N), 8.38 (d, 2H, J = 8.2 Hz), 8.03 (d, 2H, J = 8.2 Hz), 7.4–7.7 (m,
5H), 3.3 (t,2H, J = 7.1 Hz, S–CH2), 1.6 (m, 2H, CH2), 1.4 (m, 2H,
CH2), 0.9 (t, 3H, J = 7.1 Hz, CH3). 13C NMR δ (75 MHz, CDCl3):
162.62 (C=S), 150.540 (CH=N), 150.767, 139.335, 133.749 (2C),
131.542, 130.01 (2C), 129, 128.421, 128.121 (2C), 122.896, 119.431
(2C), 117.142, 22.11 (S–CH2), 14 (CH3), 13.21 (CH2), 12.35 (CH2)
Anal. Calcd for C21H22N6O2S C, 59.70; H, 5.25; N, 19.89. Found: C,
59.65; H, 5.15; N, 19.78%.
1-((3-(4-Bromophenyl)1-phenyl-1H-pyrazol-4-yl)methyleneamino)-
2-ethylisothiourea (3i): M.p. 178 °C, yield: 72%, 1H NMR δ (300 MHz,
CDCl3): 9.85 (bs, 2H, NH2), 9.3 (s, 1H, pyrazolyl H), 8.45 (s, 1H,
CH=N), 7.9 (d, 2H, J = 8.3 Hz), 7.8 (d, 2H, J = 8.3 Hz), 7.3–8.2 (m,
5H, ArH), 3.4 (q,2H, J = 7.1 Hz, S–CH2), 1.3 (t, 3H, J = 7.1 Hz, CH3).
13C NMR δ (75 MHz, CDCl3): 162.784 (C=S), 150.018 (CH=N),
150.767, 139.335, 131.749 (2C), 131.245, 130.360 (2C), 129.551
(2C), 127.689, 127.353, 122.896, 119.431 (2C), 117.142, 22.11 (S–
CH2), 15 (CH3). MS (EI, 70 eV): m/z (%) = 427 (M+, 100), 429 (M+2,
100) 428 (M+1, 21). Anal. Calcd for C19H18BrN5S, C, 53.28; H, 4.24,
N, 16.35. Found: C, 53.38; H, 4.29; N, 16.31%.
1-((1-Phenyl-3-(4-methyl-phenyl)-1H-pyrazol-4-yl)methylene-
amino)-2-ethyl isothio urea (3b): M.p. 113 °C, yield: 65%, IR (cm−1):
3200–3210 (NH2), 3010 (Aromatic CH), 1616 (C=N), 1600, 1510,
1235, 510, 750, 708. 1H NMR δ (300 MHz, CDCl3): 9.8 (bs, 2H, NH2),
9.3 (s, 1H, pyrazolyl H), 8.4 (s, 1H, CH=N), 7.6 (d, 2H, J = 8.1 Hz),
7.9 (d, 2H, J = 8.1 Hz), 7.3–7.8 (m, 5H), 3.1 (q, J = 7.1 Hz, 2H,
S–CH2), 1.3 (t, 3H, J = 7.1 Hz, CH3), 2.4 (s, 3H, Ar-CH3). 13C NMR
δ (75 MHz, CDCl3): 162.021 (C=S), 150 (CH=N), 151.01, 139.01,
128.6 (2C), 131, 127.11 (2C), 129 (2C), 125, 123.8, 122.5, 118 (2C),
117.142, 22.50 (S–CH2), 14 (CH3), 23.380 (CH3-Ar). MS (EI, 70 eV):
m/z (%) = 363 (M+, 100), 364 (M+1, 27). Anal. Calcd for C20H21N5S
C, 66.09; H, 5.82; N, 19.27. Found: C, 66.15; H, 5.75; N, 19.35%.
1-((1-Phenyl-3-(4-methyl-phenyl)-1H-pyrazol-4-yl)methyleneamino)-
2-butylisothio urea (3c): M.p. 141 °C, yield: 68%, 1H NMR δ (300 MHz,
CDCl3): 9.3 (s, 1H, pyrazolyl H), 9.2 (bs, 2H, NH2), 8.5 (s, 1H,
CH=N), 7.6 (d, 2H, J =8.1 Hz), 7.9 (d, 2H, J = 8.1 Hz), 7.3–7.8 (m,
5H), 3.3 (t, 2H, J = 7.1 Hz, S–CH2), 2.4 (s, 3H, Ar-CH3), 1.7 (m, 2H,
CH2), 1.4 (m, 2H, CH2), 0.9 (t, 3H, J = 7.1 Hz, CH3). 13C NMR δ
(75 MHz, CDCl3): 162.462 (C=S), 150 (CH=N), 151.07, 139, 128.87
(2C), 131, 127.82 (2C), 129 (2C), 125.5, 122.852, 122.663, 118.87
(2C), 116.60, 23.45 (CH3-Ar), 22.05 (S–CH2), 15.80 (CH3), 14.87
(CH2), 12 (CH2). MS (EI, 70 eV): m/z (%) = 391 (M+, 100), 392 (M+1,
32). Anal. Calcd for C22H25N5S, C, 67.49; H, 6.44; N, 17.89. Found: C,
67.60; H, 6.35; N, 17.79%.
1-((3-(3,5-Bis(trifluoromethyl)phenyl-1H-pyrazol-4-yl)methylene-
1
amino)-2-ethylisothiourea (3j): M.p. 182 °C, yield: 69%, HNMR δ
(300 MHz, CDCl3): 9.85 (bs, 2H, NH2), 9.3 (s, 1H, pyrazolyl H), 8.45
(s, 1H, CH=N), 8.3 (s, 2H, ArH), 7.9 (s, 1H, ArH), 7.4–7.8 (m, 5H,
ArH phenyl), 3.4 (q, 2H, J = 7.1 Hz, S–CH2), 1.3 (t,3H, J = 7.1 Hz,
CH3). 13C NMR δ (75 MHz, CDCl3): 162.95 (N=C-S), 150.305
(CH=N), 149, 139.5, 135, [133.122, 132.682, 132.242, 131.794
(q, 2C, J = 33 Hz)], 130.15 (2C), 128.9, 128.544 (2C), 127.680,
123, 120.1 (2C), 117.524, [125.135, 121.51, 117.88, 114.252 (q, 2C
J = 272 Hz)], 22.356 (S–CH2), 15.241 (CH3). MS (EI, 70 eV): m/z (%)
= 485 (M+, 100), 487 (M+2, 10) 486 (M+1, 15). Anal. Calcd for
C21H17F6N5S: C, 51.96; H, 3.53; N, 14.43. Found: C, 51.90; H, 3.59;
N, 14.49%.
1-((3-(4-Chlorophenyl)1-phenyl-1H-pyrazol-4-yl)methyleneamino)-
2-heptylisothio urea (3d): M.p. 190 °C, yield: 77%, IR (cm−1): 3220
1
(NH2), 3015 (Aromatic CH), 1610 (C=N), 1500, 1235, 510, 705. H
3-((3,5-Bis(trifluoromethyl)phenyl)-1-phenyl-1H-pyrazol-4-yl)meth-
yleneamino)-1-ethyl-2-thioimidazolidin-4-one (4a): M.p. 125 °C, yield:
70%, IR (cm−1): 3015 (Aromatic CH), 1610 (C=N), 1680 (C=O), 1055
(C=S), 1230, 500. 1H NMR δ (300 MHz, CDCl3): 8.5 (s, 1H, pyrazolyl
H), 8.4 (s, 1H, CH=N), 8.3 (s, 2H, ArH), 7.9 (s, 1H, ArH), 7.4–7.8 (m,
5H, ArH phenyl), 3.9 (q, 2H, J = 7.1 Hz, CH2-N), 3.7 (s, 2H, CH2,
imidazolidinone ring), 1.1 (t, 3H, J = 7.1 Hz, CH3). 13C NMR δ
(75 MHz, CDCl3): 171.95 (C=S), 163.17 (C=O), 149.805 (CH=N),
149.561,139.106, 134.771, [133.254, 132.809, 132.364, 131.919 (q,
2C, J = 33 Hz)], 129.658 (2C), 128.864, 128.544 (2C), 127.735,
122.9, 119.508 (2C), 117.524, [125.06, 121.435, 117.809, 114.182 (q,
2C, J = 272 Hz], 38.743 (CH2 imidazolidinone ring), 33.05 (N–CH2),
29.53. MS (EI, 70 eV): m/z (%) = 525 (M+, 100), 527 (M+1, 27). Anal.
Calcd for C23H17F6N5OS: C, 52.57; H, 3.26; N, 13.33. Found: C, 52.48;
H, 3.68; N, 13.25%.
3-((3,5-Bis(trifluoromethyl)phenyl)-1-phenyl-1H-pyrazol-4-yl)
methyleneamino)-1-isopropyl-2-thioimidazolidin-4-one (4b): M.p.
220 °C, yield: 69%, IR (cm−1): 3010 (Aromatic CH), 1600 (C=N),
1685 (C=O), 1055 (C=S), 500. 1H NMR δ (300 MHz, CDCl3): 8.5 (s,
1H, pyrazolyl H), 8.4 (s, 1H, CH=N), 8.3 (s, 2H, ArH), 7.9 (s, 1H,
ArH), 7.4–7.8 (m, 5H, ArH phenyl), 4.8–4.85 (m, 1H, CH–N), 3.7
(s, 2H, CH2 imidazolidinone ring), 1.5 (d, 6H, J = 6.8 Hz, 2CH3).
NMR δ (300 MHz, CDCl3): 9.6 (bs, 2H, NH2), 9.3 (s, 1H, pyrazolyl
H), 8.5 (s, 1H, CH=N), 7.7 (d, 2H, J = 8.3 Hz), 7.8 (d, 2H, J = 8.3 Hz),
7.3–7.7 (m, 5H), 3.4 (t, 2H, J = 7.1 Hz, S–CH2), 1.4–1.7 (m, 10 H,
5CH2), 0.9 (t, 3H, J = 7.1 Hz, CH3). 13C NMR δ (75 MHz, CDCl3):
162 (C=S), 149.8 (CH=N), 150.51, 139, 131 (2C), 131.5, 129.91 (2C),
129.04 (2C), 127, 126.05, 122.05, 119 (2C), 117, 22.62 (S–CH2),
15.71 (CH2), 15.05 (CH2), 14.02, 13.5, 13, 12.11. MS (EI, 70 eV): m/z
(%) = 453 (M+, 100), 454 (M+1, 20), 455 (M+2, 35). Anal. Calcd for
C24H28ClN5S C, 63.49; H, 6.22; N, 15.42. Found: C, 63.34; H, 6.35; N,
15.39%.
1-((3-(4-Chlorophenyl)1-phenyl-1H-pyrazol-4-yl)methyleneamino)-
2-butylisothio urea (3e): M.p. 225 °C, yield: 69%, 1H NMR δ (300 MHz,
CDCl3): 9.6 (bs, 2H, NH2), 9.3 (s, 1H, pyrazolyl H), 8.5 (s, 1H,
CH=N), 7.7 (d, 2H, J = 8.3 Hz), 7.8 (d, 2H, J = 8.3 Hz), 7.4–7.7 (m,
5H), 3.4 (t, 2H, J = 7.1 Hz, S–CH2), 1.7 (m, 2H, CH2), 1.4 (m, 2H,
CH2), 0.9 (t, 3H, J = 7.1 Hz, CH3). 13C NMR δ (75 MHz, CDCl3):
162 (C=S), 150.05 (CH=N), 150.8, 139, 131 (2C), 131.52, 130 (2C),
129.64 (2C), 127.01, 125.94, 123.05, 119.431 (2C), 117, 22.011
(S–CH2), 15.0 (CH3), 12.5 (CH2), 13.41 (CH2). MS (EI, 70 eV): m/z
(%) = 411 (M+, 100), 413 (M+2, 33), 412 (M+1, 20) Anal. Calcd for
C21H22ClN5S C, 61.23; H, 5.38; N, 17.00. Found: C, 61.15; H, 5.43; N,
17.26%.

592 JOURNAL OF CHEMICAL RESEARCH 2012
13C NMR δ (75 MHz, CDCl3): 171.9 (C=S), 163.15 (C=O), 149.70
(CH=N), 149.52, 139.02, 134.62,[133.254, 132.809, 132.364, 131.919
(q, 2C, J = 33 Hz)], 129.66 (2C), 128.745, 128.40 (2C), 127.691,
122.85, 119.48 (2C), 117.420, [125.06, 121.435, 117.809, 114.182 (q,
2C, J = 272 Hz)], 38.83 (CH2 imidazolidinone ring), 32.121 (N–CH),
28.15 (2CH3). MS (EI, 70 eV): m/z (%) = 539 (M+, 100), 540 (M+1,
32)Anal. Calcd for C24H19F6N5OS: C, 53.43; H, 3.55; N, 12.98. Found:
C, 53.31; H, 3.65; N, 12.89%.
3-((3,5-Bis(trifluoromethyl)phenyl)-1-phenyl-1H-pyrazol-4-yl)
methyleneamino)-1-propyl-2-thioimidazolidin-4-one (4c): M.p. 180 °C,
yield: 72%, 1H NMR δ (300 MHz, CDCl3): 8.48 (s, 1H, pyrazolyl H),
8.46 (s, 1H, CH=N), 8.3 (s, 2H, ArH), 7.9 (s, 1H, ArH), 7.4–7.8 (m,
5H, ArH phenyl), 3.8 (t, 2H, J = 7.4 Hz, N–CH2), 3.7 (s, 2H, CH2
imidazolidinone ring), 1.8 (m, 2H, CH2), 0.9 (t, 3H, J = 7.4 Hz, CH3).
13C NMR δ (75 MHz, CDCl3): 171.80 (C=S), 163.2 (C=O), 149.791
(CH=N), 149.432, 139.11, 134.651, [133.254, 132.809, 132.364,
131.919 (q, 2C,J = 33 Hz)], 129.4 (2C), 128.912, 128.624 (2C),
127.660, 122.6, 119.81 (2C), 117.5, [(125.06, 121.435, 117.809,
114.182, q, 2C, J = 272 Hz], 38.5 (imidazolidinone ring), 31.1 (N–
CH2), 25.05 (CH2), 23.16 (CH3). MS (EI, 70 eV): m/z (%) = 539 (M+,
100), 540 (M+1, 32). Anal. Calcd for C24H19F6N5OS: C, 53.43; H,
3.55; N, 12.98. Found: C, 53.34; H, 3.40; N, 13.01%.
3-((3,5-Bis(trifluoromethyl)phenyl)-1-phenyl-1H-pyrazol-4-yl)
methyleneamino)-1-hexyl-2-thioimidazolidin-4-one (4d): M.p. 118 °C,
yield: 71%, 1H NMR δ (300 MHz, CDCl3): 8.48 (s, 1H, pyrazolyl H),
8.46 (s, 1H, CH=N), 8.3 (s, 2H, ArH), 7.9 (s, 1H, ArH), 7.4–7.8 (m,
5H, ArH phenyl), 3.8 (t, 2H, J = 7.1 Hz, N–CH2), 3.7 (s, 2H, CH2
imidazolidinone ring), 1.7 (m, 2H, CH2), 1.3 (m, 6H, 3CH2), 0.9
(t, 3H, J = 7.1 Hz, CH3). 13C NMR δ (75 MHz, CDCl3): 171.95
(C=S), 163.17 (C=O), 149.805 (CH=N), 149.561, 139.106, 134.771,
[(133.254, 132.809, 132.364, 131.919 q, 2C, J = 33 Hz)] 129.5 (2C),
128.9, 128.6 (2C), 127.71, 122.50, 119.410 (2C), 116.9, [(125.06,
121.435, 117.809, 114.182, q, 2C, J = 272 Hz)], 38.91 (CH2 imidaz-
olidinone ring), 32.01 (N–CH2), 24.45 (CH2), 20.92, 17.6, 15.09,
12.15. Anal. Calcd for C27H25F6N5OS: C, 55.76; H, 4.33; N, 12.04.
Found: C, 55.68; H, 4.28; N, 12.40%.
3-((3-(4-Nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)methyleneamino)-
1-ethyl-2-thioimidazolidin-4-one (4e): M.p. 160 °C, yield: 71%, IR
(cm−1): 3010 (Aromatic CH), 1600 (C=N), 1685 (C=O), 1050 (C=S),
1350, 1535 (NO2). 1H NMR δ (300 MHz, CDCl3): 8.6 (s, 1H, pyrazo-
lyl H), 8.5 (s, 1H, CH=N), 8.34 (d, 2H, J = 8.2 Hz), 8.06 (d, 2H,
J = 8.2 Hz), 7.3–7.8 (m, 5H, ArH), 3.9 (q, 2H, 7.1 Hz, N–CH2), 3.7 (s,
2H, CH2 imidazolidinone ring), 1.1 (t, 3H, J = 7.1 Hz, CH3). 13C NMR
δ (75 MHz, CDCl3): 171.95 (C=S), 162.5 (C=O), 152 (CH=N),
150.87, 139.7, 134.12 (2C), 130.6, 130.21 (2C), 129.8, 128.6, 128.350
(2C), 123, 118.61 (2C), 117, 38.6 (CH2 imidazolidinone ring), 32.51
(N–CH2), 28 (CH3). MS (EI, 70 eV): m/z (%) = 434 (M+, 100), 435
(M+1, 30). Anal. Calcd for C21H18N6O3S: C, 58.05; H, 4.18; N, 19.34.
Found: C, 58.15; H, 4.09; N, 19.42%.
J = 6.8 Hz, CH2-N), 1.3–1.7 (m, 8H, 4 CH2), 0.9 (t, J = 7.1 Hz, 3H,
CH3). 13C NMR δ (75 MHz, CDCl3): 171.6 (C=S), 162 (C=O), 151
(CH=N), 150.69, 140.1, 130.9 (2C), 131.33, 130 (2C), 128.85 (2C),
127.8, 127, 123.01, 119.56 (2C), 116, 38.60 (CH2 imidazolidinone
ring), 33.619 (N–CH2), 28.95 (CH2), 25.61 (CH2), 23, 22.5, 16.01. MS
(EI, 70 eV): m/z (%) = 523 (M+, 100), 525 (M+2, 97), 524 (M+1, 21).
Anal. Calcd for C25H26BrN5OS: C, 57.25; H, 5; N, 13.35. Found: C,
57.10; H, 4.95; N, 13.1%.
3-((1,3-Diphenyl-1H-pyrazol-4-yl)methyleneamino)-1-ethyl-2-
1
thioimidazolidin-4-one (4i): M.p. 136 °C, yield: 64%, H NMR δ
(300 MHz, CDCl3): 8.5 (s, 1H, pyrazolyl H), 8.4 (s, 1H, CH=N), 7.3–
7.9 (m, 5H, ArH), 3.8 s (s, 2H, CH2 imidazolidinone ring), 3.9 (q, 2H,
J = 7.1 Hz, N–CH2), 1.3 (t, 3H, J = 7 Hz, CH3).13C NMR δ (75 MHz,
CDCl3): 170 (C=S), 162 (C=O), 152.01 (CH=N), 150.5, 140, 132.05
(2C), 131.5, 128.12 (2C), 129.810 (2C), 127, 123, 122.5, 118.6 (2C),
117, 38.05 (CH2 imidazolidinone ring), 32.5 (N–CH2), 29 (CH3). MS
(EI, 70 eV): m/z (%) = 389 (M+, 100), 390 (M+1, 23). Anal. Calcd for
C21H19N5OS: C, 64.76; H, 4.92; N, 17.98. Found: C, 64.70; H, 4.89; N,
17.90%.
3-((1-Phenyl-3-p-tolyl-1H-pyrazol-4-yl)methyleneamino)-1-ethyl-
1
2-thioimidazolidin-4-one (4j): M.p. 173 °C, yield: 69%, H NMR δ
(300 MHz, CDCl3): 8.5 (s, 1H, pyrazolyl H), 8.4 (s, 1H, CH=N), 7.6
(d, 2H, J = 8.3 Hz), 7.9 (d, 2H, J = 8.3 Hz), 7.3–7.8 (m, 5H, ArH), 3.8
(s, 2H, CH2 imidazolidinone ring), 3.9 (q, 2H, J = 7.1 Hz, N–CH2),
1.3 (t, 3H, J = 7 Hz, CH3), 2.3 (s, 3H, CH3, Ar-CH3).13C NMR δ
(75 MHz, CDCl3): 170 (C=S), 161 (C=O), 152.05 (CH=N), 151,
139.5, 129 (2C), 130.85, 129 (2C), 129.70 (2C), 124.85, 122.77,
123.01, 119 (2C), 118.01, 38.5 (CH2 imidazolidinone ring), 32.7 (N–
CH2), 25.5 (CH3), 24.420 (CH3-Ar). MS (EI, 70 eV): m/z (%) = 403.05
(M+, 100), 404.11 (M+1, 23). Anal. Calcd for C22H21N5OS: C, 65.49;
H, 5.25; N, 17.36. Found: C, 65.40; H, 5.21; N, 17.30%.
3-((3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)methyleneamino)-
1
1-ethyl-2-thioimidazolidin -4-one (4k): M.p. 185 °C, yield: 72%, H
NMR δ (300 MHz, CDCl3): 8.5 (s, 1H, pyrazolyl H), 8.4 (s, 1H,
CH=N), 7.7 (d, 2H, J = 8.4 Hz), 7.6 (d, 2H, J = 8.4 Hz), 7.3–7.5
(m, 5H, ArH), 3.8 (s, 2H, CH2 imidazolidinone ring), 3.9 (q, 2H, J =
7.1 Hz, N–CH2), 1.3 (t, 3H, J = 7.1 Hz, CH3). 13C NMR δ (75 MHz,
CDCl3): 170 (C=S), 162.89 (C=O), 151 (CH=N), 150.5, 140, 132
(2C), 131.7, 128.8 (2C), 129.6 (2C), 127, 126.6, 122.8, 118.8 (2C),
117.142, 37.78 (CH2 imidazolidinone ring), 32.5 (N–CH2), 29.760
(CH3).MS (EI, 70 eV): m/z (%) = 423.05 (M+, 100), 425.11 (M+1, 25).
Anal. Calcd for C21H18ClN5OS: C, 59.50; H, 4.28; N, 16.52. Found: C,
59.59; H, 4.21; N, 16.59%.
Results and discussion
The synthesis of target isothiosemicarbazones (3a–j) is
depicted in Scheme 1. Treatment of thiosemicarbazide with
the appropriate alkyl bromide in ethanol gave alkyl isothio-
semicarbazide salt intermediates which were then condensed
with pyrazole carbaldehyde to afford compounds 3a–j. One
pot reaction of pyrazole carbaldehyde, thiosemicarbazide,
ethyl chloroacetate and alkyl bromide afforded imidazolidi-
none derivatives 4a–k (Scheme 2).
3-((3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)methyleneamino)-
1
1-propyl-2-thioimidazolidin-4-one (4f): M.p. 190 °C, yield: 68%, H
NMR δ (300 MHz, CDCl3): 8.5 (s, 1H, pyrazolyl H), 8.4 (s, 1H,
CH=N), 7.8 (d, 2H, J = 8.6 Hz), 7.7 (d, 2H, J = 8.6 Hz), 7.3–7.6 (m,
5H, ArH), 3.8 (s, 2H, CH2 imidazolidinone ring), 1.8 (m, 2H, CH2),
0.9 (t, 3H, J = 7.1 Hz, CH3), 3.9 (q, 2H, J = 7.1 Hz, N–CH2). 13C NMR
δ (75 MHz, CDCl3): 171.784 (C=S), 162.183 (C=O), 152.018 (CH=N),
150.767, 139.335, 131.749 (2C), 131.245, 130.360 (2C), 129.551
(2C), 127.689, 127.353, 122.896, 119.431 (2C), 117.142, 38.583 (CH2
imidazolidinone ring), 32.569 (N–CH2), 29.187 (CH2), 26.542 (CH3).
MS (EI, 70 eV): m/z (%) = 481 (M+, 100), 483 (M+2, 98), 482 (M+1).
Anal. Calcd for C22H20BrN5OS: C, 54.78; H, 4.18; N, 14.52. Found: C,
54.60; H, 4.28; N, 14.48%.
1
The IR and H NMR spectra of compounds (3a–j) were
1
consistent with the assigned structures. The H NMR spectra
of these compounds showed a singlet at 8.5–8.6 ppm for the
CH=N proton, while NH2 protons appeared at 9.5–9.8 ppm as
a broad singlet. In IR spectra, the bands in the region of 3450–
3100 cm−1 are due to NH2. The typical bands of v(C=N) and
v(C=C) appeared between 1680 and 1565 cm−1 while the C–H
stretching band appeared at 705–710 cm−1. The 1H NMR spec-
tra of compounds (4a–k) showed a singlet at 8.4–8.6 ppm for
the CH=N proton while CH2 protons of the imidazolidinone
ring appeared between 3.7 and 3.9 ppm. In the IR spectra
of compounds (4a–k), the C=N and C=C stretching bands
appeared in the region 1550–1650 cm−1 while C=O of amide
and C=S stretching band appeared in the range of 1670–
1685 cm−1 and 1050–1055 cm−1 respectively.
3-((3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)methyleneamino)-
1
1-ethyl-2-thioimidazolidin -4-one (4g): M.p. 171 °C, yield: 72%, H
NMR δ (300 MHz, CDCl3): 8.5 (s, 1H, pyrazolyl H), 8.4 (s, 1H,
CH=N), 7.8 (d, 2H, J = 8.6 Hz), 7.7 (d, 2H, J = 8.6 Hz), 7.3–7.6
(m, 5H, ArH), 3.8 s (s, 2H, CH2 imidazolidinone ring), 3.9 (q, 2 H,
J = 7.1 Hz, N–CH2), 1.3 (t, 3 H, J = 7.1 Hz, CH3). 13C NMR δ
(75 MHz, CDCl3): 171.8 (C=S), 162.10 (C=O), 152 (CH=N), 150.7,
139, 131.6 (2C), 132, 131.60 (2C), 128.9 (2C), 127.6, 127, 123.1,
118.89 (2C), 116, 37.80 (CH2 imidazolidinone ring), 32.01 (N–CH2),
28.78 (CH3). Anal. Calcd for C21H18BrN5OS: C, 53.85; H, 3.87; N,
14.95. Found: C, 53.78; H, 3.79; N, 14.87%.
Antimicrobial screening
3-((3-(4-Bromophenyl)-1-phenyl-1H-pyrazol-4-yl)methyleneamino)-
1-Hexyl-2-thioimidazolidin -4-one (4h): M.p. 140 °C, yield: 73%, 1H
NMR δ (300 MHz, CDCl3): 8.5 (s, 1H, pyrazolyl H), 8.4 (s, 1H,
CH=N), 7.8 (d, 2H, J = 8.6 Hz), 7.7 (d, 2H, J = 8.6 Hz), 7.3–7.6
(m, 5H, ArH), 3.8 (s, 2H, CH2 imidazolidinone ring), 3.9 (t, 2H,
All the compounds synthesised were tested for antibacterial
activity against B. subtilis (2250), S. aureus (2079), E. coli (2109)
and P. aeruginosa (2036) and antifungal activity against
C. albicans (3471) and A. niger (545) at 100 µg mL−1 in DMSO,

JOURNAL OF CHEMICAL RESEARCH 2012 593
Scheme 1 Synthesis of S-alkyl isothiosemicarbazone derivatives.
Compd
3a
H
3b
4-CH3
Et
3c
3d
4-Cl
3e
3f
4-NO2
Et
3g
3h
3i
4-Br
Et
3j
3,5-Bis CF3
Et
R
4-CH3
n-Butyl
4-Cl
4-NO2
4-NO2
n-Butyl
R1
n-Butyl
n-Heptyl
n-Butyl
n-Propyl
Scheme 2 Synthesis of imidazolidinone derivatives.
Compd
4a
3,5-Bis CF3
Et
4b
4c
4d
4e
4-NO2
Et
4f
4g
4-Br
Et
4h
4-Br
4i
4j
4-CH3
Et
4k
4-Cl
Et
R
3,5-Bis CF3
Isopropyl
3,5-Bis CF3
n-Propyl
3,5-Bis CF3
n-Hexyl
4-Br
H
R1
n-Propyl
n-Hexyl Et
Table 1 Antimicrobial activity of synthesised compounds (3a–j and 4a–k)
Compound
S. aureus
E. coli
B. subtilis
P. aeruginosa
A. niger
C. albicans
3a
20.2
22.1
22
16.3
16
14.5
14.5
14.6
18
13.1
10
–
18
–
16.6
16
–
16
16.4
12.4
12
10.5
10
14.8
8
7.9
–
–
3b
20.2
20.1
17
3c
–
15
3d
15.4
15
–
–
8
10
3e
17.4
15
15.1
12
11.2
12
9.5
10.5
11
10
–
14.9.
15.1
–
–
–
12
NA
29.14
3f
11
10.8
10.9
–
3g
–
10.3
9.9
7.9
7.6
10
–
8.6
10
7.9
12
11.8
13.8
–
16.5
13.4
NA
24.68
3h
–
9.9
12
3i
–
3j
9
–
–
4a
–
–
–
4b
10.1
9.5
8.9
11
8.9
–
–
–
4c
–
–
4d
8.0
9
–
–
14.3
14.4
16.7
–
NA
30.11
–
–
4e
9.5
11.5
12
8.6
–
4f
15.4
15
4g
–
–
4h
15
11.8
16
15.6
13.8
21.12
NA
4i
16
10
8
9.1
21.96
NA
4j
18
4k
15
Nystatin
NA
32.8
Chloramphenicol
Zone diameter of growth inhibition in mm.
NA, not applicable; –, inactive. Chloramphenicol (100 µg/disc) and Nystatin (100 µg/disc) were used as reference; synthesised com-
pounds (100 µg/disc)

594 JOURNAL OF CHEMICAL RESEARCH 2012
using agar diffusion method. Known antibiotics Chloramphen-
icol and Nystatin were used for comparison. Most of the com-
pounds were found to be active against gram positive and gram
negative bacteria as well as both the fungi species as shown in
Table 1. Both isothiosemicarbazone (3a–j) and imidazolidi-
none derivatives (4a–k) showed enhanced antimicrobial activ-
ity with an electron donating group (CH3) on the phenyl ring
as compared to electron withdrawing groups (Cl, Br, NO2 and
CF3).
References
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Conclusions
In the present work we have successfully synthesised new
S-alkyl isothiosemicarbazone and imidazolidinone derivatives.
Most of the synthesised compounds showed good biological
activity against bacteria like B. subtilis, S. aureus, E. coli and
P. aeruginosa and against fungi like C. albicans and A. niger.
Based on the results, it can be concluded that these new
pyrazole aldehyde derivatives could serve as lead molecules
for further development of new antimicrobial agents.
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Received 3 June 2012; accepted 10 August 2012
Paper 1201351 doi: 10.3184/174751912X13459883792770
Published online: 28 September 2012

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