Synthesis and antimicrobial study of 1,2,4-triazole, quinazoline and benzothiazole derivatives from 1-naphthoylisothiocyanate

Article abstract of DOI:10.3184/030823410X12707543946812

1-Naphthoylisothiocyanate (1) is used as a building block in the synthesis of 1,2,4-triazole, quinazoline, benzothiazole and thiourea derivatives. The antimicrobial activity of some of the synthesised compounds was tested.

Full text of DOI:10.3184/030823410X12707543946812

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 219
APRIL, 219–221
Synthesis and antimicrobial study of 1,2,4-triazole, quinazoline and
benzothiazole derivatives from 1-naphthoylisothiocyanate
Magdy M. Hemdan*, Amin F. Fahmy and Amira A. El-Sayed
Department of Chemistry, Faculty of Science, Ain Shams University, 11566 Abbasia, Cairo, Egypt
1-Naphthoylisothiocyanate (1) is used as a building block in the synthesis of 1,2,4-triazole, quinazoline, benzothiazole
and thiourea derivatives. The antimicrobial activity of some of the synthesised compounds was tested.
Keywords: 1-naphthoylisothiocyanate 1,2,4-triazoles, quinazolines, benzothiazoles
In view of the significant pharmacological activities associated
with the derivatives of 1,2,4-triazole,1,2 quinazoline,3,4 and
thiourea.5,6 Our previous investigations on utilisation of aroyl
isothiocyanates7–10 afforded many different sizes heterocyclic
rings. In the present work, we use 1-naphthoylisothiocyanate
(l) and nitrogen nucleophilies as building blocks to synthesise
some new derivatives of 1,2,4-triazoles, in addition, to quin-
azoline, benzothiazole and thiourea derivatives. We aimed to
synthesise these heterocycles bearing a lipophilic naphthalene
moiety (hydrocarbon moiety) in order to enhance their
biological activity.
triazole derivative 5 can be explained on the basis of attack the
amino group of thiosemicarbazide at isothiocyanato carbon
atom followed by cyclisation of the non isolable intermediate
thiourea derivative with removal a molecule of H2S. The
spectroscopic data correspond very well with its structure.
(see Experimental).
As shown in Scheme 2, reaction of isothiocyanate 1 with
anthranilic acid in acetonitrile gave thiourea derivatives 6.
Heating of compound 6 with acetic anhydride afforded quin-
azoline derivative 7. The spectra of compounds 6 and 7 are
consistent with their structures. The MS gave further highlight
on the assigned structures of 7 since it displayed the molecular
ion peaks. Unfortunately, the MS of 6 did not show the molec-
ular ion peak, however, its MS peaks correspond very well
with its proposed structure.
Refluxing of isothiocyanate 1 with 2-aminothiophenol in
acetonitrile produced benzothiazole derivative 9 in a one-pot
reaction. The formation of compound 9 presumably formed
via cyclisation of the non isolable thiourea derivatives
8a. However, reaction of 1 with 2-aminophenol, or o-
phenylenediamine, did not give the expected benzoxazole nor
benzimidazole rings, instead they afforded the corresponding
thiourea derivatives 8b,c. The spectra are consistent with these
structures.
Results and discussion
The new derivatives were prepared following the reaction
sequences depicted in Schemes 1 and 2. Treatment of 1-
naphthoylisothiocyanate (1) with phenylhydrazine in acetoni-
trile, yielded 1,2,4-triazole derivative 2 in one-pot reaction
(Scheme 1). The formation of 2 can be visualised on the basis
of cyclocondensation of phenylhydrazine with isothiocyanate
1. The structure of compound 2 was elucidated from its
spectroscopic data (see experimental).
The reaction of isothiocyanate 1 with benzoylhydrazine, in
acetonitrile produced the corresponding thiourea derivatives 3.
Cyclisation of compounds 3 was achieved with polyphosphoric
acid (PPA) to remove a molecule of water from N-4 and
benzoyl carbonyl group to give 1,2,4-triazole derivatives 4.
The spectroscopic data were consistent with the structures.
Treatment of isothiocyanate 1 with thiosemicarbazide in
dry acetonitrile led to release of H2S gas during the reaction
progress, and leave a product formulated as 1,2,4-triazole
derivatives 5 in one-pot reaction (Scheme 1). The formation of
Biological activitiy
The antimicrobial screening of some of the synthesised com-
pounds was done using the agar diffusion assay. The possible
antimicrobial activities of compounds 2, 4, 5, 7 and 9 were
investigated to four standard organisms including the Gram-
positive bacteria, Bacillus subtilis and, the gram-negative
Scheme 1
* Correspondent. E-mail: mhemdan39@hotmail.com

220 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 2
Table 1 Antimicrobial activities of selected compounds
Experimental
General
No
Inhibition zone diameter (mm/mg sample)
Melting points were determined in open capillary tubes on a Gallen-
kemp melting point apparatus and were uncorrected. The elemental
analysis was done on Perkin-Elemer 2400 CHN elemental analyser.
The IR spectra recorded on FTIR Maltson (infinity series) spectrom-
Bacillus Escherichia
Candida Saccharomyces
subtills
coli
albcans
cereviseae
(Fungus)
(G+)
(G−)
(Fungus)
1
Control
0
0
0
0
eters as KBr discs. The H NMR spectra were measured on Varian
DMSO
Gemini 300 MHz instrument with chemical shift (δ) expressed in ppm
downfield from TMS as internal standard, in DMSO-d . Mass spectra
were recorded on Shimadzu GC-MS, QP 1000 EX inst6rument operat-
ing at 70 eV. TLC carried out the monitoring of the progress of all
reactions and homogeneity of the synthesised compounds. TLC were
determined using TLC aluminum sheets silica gel F254 (Merck).
1-Naphthoylisothiocyanate (1): The of solution of 1-naphthoyl
chloride (3 mmole) in dry acetonitrile (30 mL) and solid ammonium
thiocyanate (3 mmole) was stirred for half an hour at room tempera-
ture.13 The precipitated ammonium chloride was filtered off to give a
clear solution of 1-naphthoyl isothiocyanate (1).
2
12
12
13
15
13
26
–
13
12
13
16
13
31
–
11
12
13
28
13
–
13
15
13
16
15
–
4
5
7
9
Tc
Am
20
20
0, no activity (inhibition zone < 7mm); weak activity (7–10 mm);
moderate activity (11–15); strong activity (> 15 mm); solvent,
DMSO (6 mm).
Reaction of isothiocyanate 1 with the different nucleophiles; general
procedure
bacteria, Esherichia coli, in addition to pathogenic fungi Can-
dida albicans and the unicellar yeast fungus Saccharomyes
cereviseae. The obtained results presented in Table 1.
Standard discs of tetracycline (Tc) (antibacterial agent),
amphotericin B (Am) (antifungal agent) served as positive
controls for antimicrobial activity but filter discs impregnated
with 10 µL of DMSO were used as a negative control.
Data in Table 1 emphasised the fact that the chemical agents
2, 4, 5, 7 and 9 exhibited various degree of activities against
Gram positive bacteria, Gram negative bacteria and fungi.
Against Bacillus subtilis ( Gram +ve rod) all the tested com-
pounds show moderate activity (12–15 mm). For Esherichia
coli (Gram –ve rod ) all the tested compounds also show a
moderate activity (12–13 mm) except compound 7 which
shows strong activity (16 mm). With respect to Candida alb-
cans and Saccharomyces cereviseae all the tested compounds
show moderate activity (11–15 mm) except compound 7 which
shows strong activity (28 mm) and (16 mm) respectively.
To a solution of isothiocyanate 1 (3 mmole) in dry acetonitrile
(50 mL), phenylhydrazine, benzoyl hydrazine, thiosemicarbazide,
anthranilic acid, o-aminothiophenol, o-aminophenol, or o-phenylene-
diamine, (3 mmole) was added. The reaction mixture was refluxed for
2–3 hours (TLC), cooled to room temperature. The precipitated solid
was washed with ethanol, and crystallised from a suitable solvent to
give the corresponding compounds.
5-(Naphthalen-1-yl)-1-phenyl-1H-1,2,4-triazole-3(2H)-thione (2):
85% yield; pale yellow crystals; m.p. 262–264 °C (acetic acid); IR
(KBr) υ: 3111 (NH), 1553 (C=N), 1253 (C=S) cm−1; 1H NMR (DMSO-
d6) δ: 7.47 (d, J = 7.5 Hz,1H), 7.56 (d, J = 6.9 Hz, 1H), 7.60–7.70
(m, 4H), 7.99–8.18 (m, 5H), 8.70 (d, J = 8.4 Hz, 1H), 14.3 (br. s, 1NH,
exchangeable with D2O); MS (70eV) m/z (%): 303 (M+., 100), 305
(M+. +2, 8), 304 (M+..+1, 23), 302 (M+.-H) (55), 243 (12), 168 (6), 153
(15), 127 (11) 91 (69), 77 (16). Anal. Calcd for C18H N S (303.38):
C, 71.26; H, 4.32; N, 13.85. Found: C 71.17; H, 4.27; 1N3 , 313.78%.
N-(2-Benzoylhydrazinethiocarbonyl)-1-naphthamide (3): 82%
yield; colorless crystals; m.p. 188–190 °C (acetic acid); IR (KBr) υ:
3295, 3198, 3100 (NH),1666 (C=O), 1166 (C=S) cm−1; 1H NMR
(DMSO- d ) δ: 7.43 (d, J = 6.9 Hz, 2H), 7.63–7.72 (m, 4H), 8.04–8.25
(m, 5H), 8.686 (d, J = 8.4 Hz, 1H), 9.2, 10.3, 13.3 (br. s, 3NH, exchange-
able with D2O);MS (70 eV) m/z (%): 349 (M+, 9), 351(M+. +2, 1), 350
(M+. +1, 3), 316 (9), 213 (3), 155 (100), 127 (53), 105 (46), 77 (47).
Anal. Calcd for C19H N O2S (349.41): C, 65.31; H, 4.33; N, 12.03.
Found: C, 65.23; H, 41.5263; N, 11.97%.
Conclusion
The introduction of hydrocarbon moiety (naphthalene moiety)
to the synthesised 1,2,4-triazole, quinazoline and benzothia-
zole, ring systems augments the antimicrobial action apprecia-
bly. The lipophilic property of the hydrocarbon moiety, favours
the permeation of the compounds through lipoid barriers in the
fungal cell membrane. The greater antibacterial and antifungal
activities of compound 7 than the other compounds might be
attributed to its more planar and compact structure. This pre-
sumption is supported by the earlier observations that compact
size and planarity of a molecule often enhance its pesticidal
properties.11,12
N-(5-Thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-1-naphthamide
(5): 86% yield; colorless crystals; m.p. > 300 °C (DMF); IR (KBr) υ:
3327, 3268, 3113 (NH)1648 (C=O), 1561 (C=N), 1144 (C=S) cm−1;
1H NMR (DMSO-d6) δ: 7.59–7.64 (m, 3H), 7.82–7.85 (m, 3H),
8.20–8.23 (m, 1H), 6.80 (br s, 2NH, exchangeable), 12.40 (br s, 1NH,
exchengeable); MS (70 eV) m/z (%): 270 (M+., 6), 272 (M+. +2, 1), 271
(M+. +1, 1), 269 (M+. -H) (2), 155 (100), 127 (58), 101 (3), 60 (39); ).

JOURNAL OF CHEMICAL RESEARCH 2010 221
Anal. Calcd for C13H10N4OS (270.31): C, 57.76; H, 3.73; N, 20.73.
Found: C, 57.67; H, 3.70; N, 20.65%.
90 °C for 1h. Cool, a solid product was obtained filtered off and
recrystallised from dimethylformamide 79% yield; pale yellow crys-
tals; m.p. 232–234°C; IR (KBr) υ: 3228 (NH), 1684 (C=O), 1633
(C=O), 1258 (C=S) cm−1; 1H NMR (DMSO- d6) δ: 7.55–7.86 (m, 4H),
7.87–8.12 (m, 6H), 8.15–8.16 (m, 1H), 12.50, (br s, 1NH, exchange-
able ); MS (70eV) m/z (%): 332 (M+., 20), 334 (M+. + 2, 3), 333 (M+. +
1, 4), 304 (9), 155 (100), 127(57), 77(9). Anal. Calcd for C19H12N2O S
(332.38): C, 68.66; H, 3.64; N, 8.43; found C 68.58; H, 3.621;
N, 8.37.
2-[3-(1-Naphthoyl)thioureido]benzoic acid (6): 92% yield; yellow
crystals; m.p. 242–245 °C (acetic acid); IR (KBr) υ: 3300–2850 (br.
OH), 3221, 3121 (NH), 1709 (C=O), 1681 (C=O), 1262 (C=S) cm−1;
MS (70eV) m/z (%): 350 (M+., 0), 333 (M+. –OH) (12), 198 (5), 197
(42), 171 (20), 170 (11), 137 (36), 155 (94), 127 (100), 93 (5), 77 (23),
64 (28). Anal. Calcd for C H14N2O S (350.39): C, 65.13; H, 4.03;
N, 7.99. Found: C 65.04; H,139 .97; N,37.93.
N-(1,3-Benzothiazol-2-yl)-1-naphthamide (9): 79% yield; grey
crystals; m.p. 164–166 °C (benzene–ethanol); IR (KBr) υ: 3176 (NH),
1681(C=O), 1549 (C=N) cm−1; 1H NMR (DMSO- d6) δ: 7.37 (d, 1H,
J = 7.8 Hz), 7.46–7.48 (m, 1H), 7.63–7.66 (m, 3H), 7.8 (d, 1H, J =
7.5 Hz), 7.93 (d, 1H, J = 7.2 Hz ), 8.04–8.07 (m, 2H), 8.1 (d, 1H, J =
8.1 Hz), 8.3 (m, 1H), 12.40, (br. s, 1NH, exchangeable); MS (70 eV)
m/z (%): 304 (M+., 21), 305 (M+.+ 1, 6), 276 (M- CO) (21), 155 (100),
127 (90), 77 (5); ). Anal. Calcd for C H12N2OS (304.37): C, 71.03;
H, 3.97, N, 9.20. Found: C 70.99; H, 31.98 3; N, 9.13.
Measurement of antimicrobial activity using diffusion disc method:
A filter paper sterilised disc saturated with measured quantity of the
sample is placed on plate containing solid bacterial medium (nutrient
agar broth) or fungal medium (Dox’s medium) which have been
heavily seeded with the spore suspension of the tested organism. The
diameter of the clear zone of inhibition of surrounding the sample is
taken as a measure of the inhibitory power of the sample against the
particular test organism.14
N-(2-Hydroxyphenylthiocarbamoyl)-1-naphthamide (8b): 89%
yield; yellow crystals; m.p. 198–190 °C (acetic acid); IR (KBr) υ:
3391 (OH), 3258, 3100 (NH),1655 (C=O), 1145 (C=S) cm−1; MS
(70eV) m/z (%): 322 (M+., 3), 323 (M+. + 1, 1), 305 (M+. – OH, 0.6),
288 (7), 260 (3), 170 (5), 155 (100), 127 (61); Anal. Calcd for
C H N O2S (322.38): C, 67.06; H, 4.38; N, 8.69. Found: C 67.14;
H1,84.3149;2N, 8.59.
N-(2-Aminophenylthiocarbamoyl)-1-naphthamide (8c): 93% yield;
pale yellow crystals; m.p. 208–210 °C (DMF); IR (KBr) υ: 3220,
3163 (NH), 1668 (C=O), 1151 (C=S) cm−1; MS (70eV) m/z (%): 321
(M+., 5), 322 (M+. + 1, 1), 288 (11), 287 (6), 259 (7), 170 (4), 155
(100), 127 (85). Anal. Calcd for C18H15N OS (321.40): C, 67.27;
H, 4.70; N, 13.07. Found: C 67.33; H, 4.63;3N, 12.71.
Received 16 February 2010; accepted 22 March 2010
Paper 101007 doi: 10.3184/030823410X12707543946812
Published online: 29 April 2010
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