Synthesis, antimicrobial activity of some new 2-amino-4-(4′- phenylsulfanyl-phenyl)-thiazole derivatives and theoretical studies of their Schiff's base

Article abstract of DOI:10.1080/714040970

2-Amino-4-(4′-phenylsulfanyl-phenyl)-thiazole (2) has been obtained from reaction of 4-chloroacetyl diphenyl sulfide (1) with thiourea. Compound (2) reacted with active methylene derivatives, e.g., diethylmalonate or ethylcyano acetate to give fused thiaz

Full text of DOI:10.1080/714040970

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis, Antimicrobial Activity of Some New
2-Amino-4-(4′-phenylsulfanyl-phenyl)-thiazole
Derivatives and Theoretical Studies of Their Schiff's
Base
Sh. H. Abdel-Hafez a
a Assiut University, Assiut, Egypt
Version of record first published: 18 Jun 2010.
To cite this article: Sh. H. Abdel-Hafez (2003): Synthesis, Antimicrobial Activity of Some New 2-Amino-4-(4′-phenylsulfanyl-
phenyl)-thiazole Derivatives and Theoretical Studies of Their Schiff's Base, Phosphorus, Sulfur, and Silicon and the Related
Elements, 178:12, 2563-2579
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Phosphorus, Sulfur, and Silicon, 178:2563–2579, 2003
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500390248060
SYNTHESIS, ANTIMICROBIAL ACTIVITY OF SOME
NEW 2-AMINO-4-(4ꢀ-PHENYLSULFANYL-PHENYL)-
THIAZOLE DERIVATIVES AND THEORETICAL
STUDIES OF THEIR SCHIFF’S BASE
Sh. H. Abdel-Hafez
Assiut University, Assiut, Egypt
(Received June 9, 2003; accepted July 1, 2003)
2-Amino-4-(4ꢁ-phenylsulfanyl-phenyl)-thiazole (2) has been obtained
from reaction of 4-chloroacetyl diphenyl sulfide (1) with thiourea.
Compound (2) reacted with active methylene derivatives, e.g., diethyl-
malonate or ethylcyano acetate to give fused thiazolo-pyrimidines (3–6)
under variable conditions. Other substituted thiazolo-pyrimidines (7–
9) also have been prepared by the reaction of (2) with some arylidine
malonitriles (benzylidinemalononitrile and ethylbenzylidinecyano-
acetate). On treatment of schiff’s bases (10a–c) with phenylisothio-
cyanate, the corresponding thiazolo-s-triazines (11a–c) were formed.
Reaction of (2) with carbon disulfide in the presence of concentrated
aqueous sodium hydroxide and DMF as solvent gave the sodium salt of
dithiocarboimidic acid which, on treatment with 1 mmol of ethyl iodide,
gave monoethylated product (12). Reaction of (12) with anthranilic acid
yielded (13). Interaction of (2) with 2 mmol of ethyl iodide afforded
the diethylated product (14) which reacted with potassium salt of an-
thranilic acid to give (15). Also, (14) reacted with o-phenylenediamine
yielded (16). The substituent effect on the stereochemistry of Schiff’s
bases (10a–c) was studied using Hyperchem (version 5). Compounds (2,
4, 6, 10b, 12, 13, 14, 15) were tested to evaluate their antimicrobial
activity.
Keywords: Antimicrobial activity; Schiff’s base; stereochemistry;
synthesis; thiazolopyrimidines
This work was carried out1–4 according to the literature on the heterocy-
cles containing thiazole rings. These are associated with a particulary
wide range of biological properties including antiprotozoal5 anticon-
vulsants activity,6 as well as with a depressant effect on the central
Address correspondence to Sh. H. Abdel-Hafez, Chemistry Department, Faculty of
Science, Assiut University, Assiut 71516, Egypt.
2563

2564
Sh. H. Abdel-Hafez
nervous system,7 antihelminthic,8 antidiabetic,9 and as inhibitors of
dihydrofolate.10 It was of interest to incorporate the moiety of thiazole
rings into the well-known antimicrobial diphenyl sulfides.11–13 We have
synthesized some heterocyclic compounds containing diphenyl sulfides
and thiazole moieties for their useful biological application. Further-
more, a search of the literature revealed the lack of information concern-
ing the stereochemistry studies of Schiff’s bases (10a–c) derivatives.14
We have applied Hyperchem (version 5)15 to evaluate the stability of
different isomers (syn or anti).
RESULTS AND DISCUSSION
Synthesis of 4-chloroacetyl diphenyl sulfide (1) was done according
to the similar method for other products given in the literature.16
The forthcoming synthesis and studies was based on 2-amino-4-(4ꢁ-
phenylsulfanyl-phenyl)-thiazole (2), which was prepared by refluxing
equimolar amounts of (1) and thiourea in absolute ethanol as modified
process to that known in literature.17 Elucidation of the structures (1)
and (2) was based on elemental analyses and spectral data.
IR spectrum of (2) displayed characteristic absorption bands at 3430–
3290 cm−1 due to ν (NH2) and 1625 cm−1 ν (C N). The absence of
absorption band for carbonyl group in spectrum of (2) supports its cyclic
structure. The mass spectrum of (2) revealed a molecular ion peak at
m/z = 284 with 40% relative abundance corresponding to the formula
C15H12N2S2.
In accord to the well-known cyclocondensation reaction of 2-amino-
thiozoles with β-bifunctional reagents to yield thiazolo [3,2-a].
Pyrimidines,18 compound (2), reacted with diethylmalonate or ethyl-
cyanoacetate to yield 3-(4ꢁ-phenylsulfanyl-phenyl)-5,7-dioxo-thia-
zolo [3,2-a]-4,5,6,7-tetrahydropyrimidine (4) and 3-(4ꢁ-phenylsulf-
anylphenyl)-5-amino-7-oxo-thiazolo[3,2-a]-4,7-dihydropyrimidine (6)
respectively.
The formation of derivatives (4, 6) may be done via cyclization
through the amino group of (2) to give the intermediates (3, 5), which
were isolated and identified. On fusion of (3, 5) over its melting points,
or fusion of (2) with the active methylene derivative products, (4, 6)
were isolated (Scheme 1). The structures of (4, 6) were assigned on the
basis of elemental analyses and spectral data (IR, 1H NMR).
Compound (2) was reacted with benzylidinemalonoitrile to give
3-(4ꢁ-phenylsulfanyl-phenyl)-5-amino-6-cyano-7-phenyl-thiazolo [3,2-
a]-4,5-dihydro-pyrimidine (7). Structure (7) was assigned on the basis
of elemental analyses and spectral data.

2565

2566

2567

2568
Sh. H. Abdel-Hafez
Interaction of ethylarylidinecyanoacetate gave 3-(4ꢁ-phenylsulfanyl-
phenyl)-5-amino-6-carboethoxy-7-phenyl-thiazolo [3,2-a]-4,5-di-hydro-
pyrimidine (9) through the formation of the intermediate 2-benzyl-
idinethylcyanoacetate-amino-4-(4ꢁ-phenylsulfanyl-phenyl)-thiazole (8),
which was separated and identified. On treatment of (2) with some
aromatic aldehydes such as (bezaldehyde, p-nitrobenzaldehyde,
N,N-dimethylaminobenzaldehyde), the corresponding 2-arylidine-
aminothiazole derivatives (10a–c) were formed. Reaction of (10a–c
)
with phenylisothiocyanate in refluxing toluene gave 6,7-disubstituted-
thiazolo [3,2-a]-s-triazine-5-thioxo-derivatives19 (11a–c) (Scheme 2).
Reaction of (2) with CS2/NaOH in dimethylformamide20 in presence
of 1 mmol ethyl iodide gave the monoethylated derivative (12) which
reacted with anthranilic acid to give (13).
The diethylated product (14) also was obtained using 2 mmol of ethyl
iodide. The structure of (14) was assigned on the basis of analytical and
spectral data. The mass spectrum of (14) revealed a molecular ion peak
at m/z = 416 with 1.5% relative abundance. This reflex the unstabil-
ity of this molecular ion under electron impact. Reaction of (14) with
anthranilic acid or o-phenylenediamine gave (15, 16) respectively21
(Scheme 3).
It was established that the Schiff’s bases are present in two forms,
i.e., anti and syn isomers.14
We have extended our study using Hyperchem (version 5) to esti-
mate the relative stability of both forms. The calculation are listed in
Table I and Figures 1–6, which reveal that the both forms are highly
related in the absence energy of substituent on benzylidine amino
groups. Introduction of different substituent on the later affect the
stability of both isomer.
Generally, the anti isomer form is more stable than the syn isomer.
Antimicrobial Activities
Some of the newly synthesized compounds (2, 4, 6, 10b, 12–15) were
screened for the antifungal activity against two species of fungi,
namely Penicillium oxalicum and Aspergillus parasiticus, and for
antibacterial activity against Gram positive bacteria (Streptococcus
and Staphylococcus aureus) and Gram negative bacteria (Serratia

Thiazole Derivatives
2569
TABLE I Theoretical Data of Compound 10a–c and the Relative Stability (ꢀE
Kcal/mol) of Two Geometrical Isomers
Compound
no.
Energy (ꢀE),
Kcal/mol (E)
Gradient
(G)
Structure
10a (syn)
10a (anti)
21.382162
0.099353
22.83859
0.094213
10b (syn)
10b (anti)
24.050827
21.764473
0.099518
0.08784
10c (syn)
10c (anti)
163.1243
26.33323
0.091080
0.092228
marcescems and Pseudomonas aeruginosa) using the filter paper disc
method.22
The results are illustrated in Table II, which revealed that compar-
ison of the antifungal activity of thiazolopyrimidine derivatives (4, 6),
quinoxaline and dithiocarbamate (13, 14) induces more fungitoxicity

2570
Sh. H. Abdel-Hafez
FIGURE 1 Stick model of the syn isomer (10a) according to the Hyperchem
calculations.
FIGURE 2 Stick model of the anti isomer (10a) according to the Hyperchem
calculations.
FIGURE 3 Stick model of the syn isomer (10b) according to the Hyperchem
calculations.

Thiazole Derivatives
2571
FIGURE 4 Stick model of the anti isomer (10b) according to the Hyperchem
calculations.
FIGURE 5 Stick model of the syn isomer (10c) according to the Hyperchem
calculations.
FIGURE 6 Stick model of the anti isomer (10c) according to the Hyperchem
calculations.

2572

Thiazole Derivatives
2573
against Aspergillus parasiticus and Penicillium oxalicum than its
parent compound 2.
Compound (14) showed the strongest inhibition activity against
Staphylococcus aureus and compounds (2, 4, 6) exhibited a moderate
activity against Streptoccus, Pseudomonas aeruginosa, and Staphylo-
coccus aureus respectively. The remaining compounds have no signif-
icant antibacterial activity. This is may be attributed to the function
group dithiocarbamate in compound (14) which works better than the
amino group alone in compound (2) and their fused derivatives (4, 6).
Experimental Procedure
The time period required for the completion of the reaction and the pu-
rity of the prepared compounds were controlled by means of TLC. Melt-
ing points were determined on Fisher-Johns melting points apparatus
and were uncorrected. Elemental analysis were performed on a Perkin-
Elmer 240 C elemental analyzer and all the results were in an accept-
able range. The characterization data of all synthesized compounds are
given in Table III. IR spectra were recorded on a Bye-Unicom SP3-100
1
spectrophotometer using KBr wafer technique. H NMR spectra were
recorded on GNM-LA 400-MHZ-NMR spectrophotometer in suitable
deuterated solvent using TMS as internal standard (chemical shifts in δ
ppm). Mass spectra were recorded on Jeol JMS-600 mass spectrometer.
4-Chloroacetyl Diphenyl Sulfide (1)
To a conical flask containing (2.00 g, 0.01 mmol) of diphenyl sulfide
and (0.85 ml, 0.01 mmol) of chloroacetyl chloride dissolved in 30 ml car-
bon dislfide, anhydrous AlCl3 (2.14 g, 0.016 mmol) was added in small
portions. The reaction mixture was stirred in an ice bath for 6 h. The
reaction mixture was evaporated under vacuum and the residue was
poured onto a mixture of ice and conc. HCl, pale yellow precipitate was
formed collected and crystallized from pet. ether 60–80◦C as a colour-
less flakes;yield (1.12 g, 0.001 mol).
Anal. Cal. for C14H11ClOS: C, 64.00; H, 4.19; Cl, 13.52; S, 12.19.
Found: C, 63.98; H, 4.10; Cl 13.41; S, 12.02.
2-Amino-4-(4ꢀ-phenylsulfanyl-phenyl)-thiozole (2)
A mixture of 1 (1 g, 0.038 mmol) and (0.28 g, 0.038 mmol) of thiourea
in 20 ml absolute ethanol was refluxed for 4 h. The clear solution was
poured onto cold sodium acetate solution and the precipitated product
was collected by filtration and crystallized from pet. ether 60–80◦ as
pale yellow crystals; yield (0.54 g, 0.001 mmol).

2574

2575

2576
Sh. H. Abdel-Hafez
Anal. Cal. for C15H12N2S2: C, 63.38; H, 4.22; N, 9.85; S, 22.53. Found:
C, 63.11; H, 4.20; N, 9.65; S, 22.29.
Reaction of (2) with Active Methylene Derivatives (4)
and (6)
General procedure. A mixture of 2 (0.035 mmol) and the correspond-
ing ester (0.04 mmol) were heated at 180◦C in an oil bath for 3 h. The
reaction mixture was allowed to cool, whereby a solid mass was formed;
this was washed several times with ether and then crystallized from
the proper solvent. Spectral data are listed in Table III; comp. 4 yield
(0.80 g, 0.002 mmol), whereas comp. 6 yield (0.82 g, 0.002 mmol).
Anal. Cal. for comp. 4 C18H12N2O2S2: C, 61.36; H, 3.40; N, 7.95; S,
18.18. Found: C, 61.10; H, 3.22; N, 7.73; S, 18.01.
Anal. Cal. for comp. 6 C18H13N3OS2: C, 61.53; H, 3.70; N, 11.96; S,
18.23. Found: C, 61.09; H, 3.40; N, 11.49; S, 18.01.
Synthesis of the Intermediates (3) and (5)
General procedure. A mixture of 2 (0.035 mmol) with excess of ester
(0.35 mmol) was heated under reflux for about 5–6 h. The reaction
mixture was then allowed to cool, triturated with ethanol and the solid
product was collected and recrystallized from the proper solvent. The
results are tabulated in Table III; comp. 3 yield (0.86 g, 0.002 mmol)
whereas comp. 5 yield (0.79 g, 0.002 mmol).
Anal. Cal. for comp. 3 C20H18N2O3S2: C, 60.30; H, 4.52; N, 7.03;
S, 16.08. Found: C, 60.12; H, 4.31; N, 6.88; S, 18.94.
Anal. Cal. for comp. 5 C18H13N3OS2: C, 61.53; H, 3.70; N, 11.96;
S, 18.23. Found: C, 61.21; H, 3.45; N, 11.78; S, 18.00.
3-(4ꢀ-Phenylsulfanyl-phenyl)-5-amino-6-cyano-7-phenyl-
thiazolo[3,2-a]-4,5-dihydropyrimidine (7)
A mixture of compound 2 (1 g, 0.035 mmol) and benzylidine malonon-
itrile (0.54 g, 0.035 mmol) was heated under reflux for 8 h in absolute
ethanol (30 ml) and 1 ml of piperidine. The reaction mixture was then
allowed to cool to room temperature, poured onto crushed ice, and neu-
tralized with conc. HCl. The precipitate was filtered and crystallized
from ethanol; yield (0.52 g, 0.001 mmol).
Anal. Cal. for C25H18N4S2: C, 68.49; H, 4.10; N, 12.78; S, 14.61. Found:
C, 68.33; H, 3.98; N, 12.55; S, 14.41.
3-(4ꢀ-Phenylsulfanyl-phenyl)-5-amino-6-carboethoxy-
7-phenyl-thiazolo [3,2-a]-4,5-dihydropyrimidine (9)
A mixture of 2 (1 g, 0.035 mmol), benzylidinethylcyanoacetate (0.70 g,
0.035 mmol) and 1 ml piperidine in (30 ml) ethanol was heated under

Thiazole Derivatives
2577
reflux for 10 h. The reaction mixture was cooled, poured onto crushed
ice, and neutralized with concn. HCl, the precipitate was isolated and
crystallized from ethanol; yield (0.86 g, 0.001 mmol).
Anal. Cal. for C27H23N3O2S2: C, 66.80; H, 4.74; N, 8.65; S, 13.19.
Found: C, 66.73; H, 4.43; N, 8.38; S, 13.00.
2-Benzylidine Ethylcyanoacetate-4-(4ꢀ-phenylsulfanyl-
pheny)-thiazole (8)
This was prepared following the preceding method for 9 with short re-
fluxing time (3 h). The product 8 crystallized from dioxane; yield (0.92 g,
0.001 mmol).
Anal. Cal. for C27H23N3O2S2: C, 66.80; H, 4.74; N, 8.65; S, 13.19.
Found: C, 66.54; H, 4.45; N, 8.33; S, 12.89.
2-Arylidineamino Thiazole Derivatives (10a–c
)
General procedure. A mixture of 2 (0.017 mmol) and the appropriate
aldehyde (0.019 mmol) such as (benzaldehyde, p-nitrobenzaldehyde,
N,N-dimethyl aminobenzaldehyde) in 20 ml absolute ethanol in the
presence of 1 ml piperidine as a catalyst was refluxed for 7–10 h. The
precipitated product was collected by filtration and crystallized from
proper solvent (cf. Table III) ; comp. 10a yield (0.72 g, 0.001 mmol), comp.
10b yield (0.77 g, 0.001 mmol), comp. 10c yield (0.73 g, 0.001 mmol).
Anal. Cal. for 10a C22H16N2S2: C, 70.96; H, 4.30; N, 7.52; S, 17.20.
Found: C, 70.81; H, 4.21; N, 7.43; S, 17.00.
Anal. Cal. for 10b C22H15N3O2S2: C, 63.30; H, 3.59; N, 10.07; S, 15.34.
Found: C, 63.10; H, 3.33; N, 9.82; S, 14.98.
Anal. Cal. for 10c C24H21N3S2: C, 69.39; H, 5.06; N, 10.12; S, 15.42.
Found: C, 69.12; H, 4.96; N, 10.00; S, 15.21.
6,7-Disubstituted-5-thioxo-thiazolo[3,2-a]-s-triazine
Derivatives (11a–c
)
General procedure. An equimolar mixture of 10a–c (0.013 mmol) and
phenylisothiocyanate in 20 ml toluene was refluxed for 4–6 h. The sol-
vent was distilled under reduced pressure, the residue washed with
small amount of ethanol followed by water and the product was crys-
tallized from the proper solvent (cf. Table III); comp. 11a yield (0.77 g,
0.001 mmol), comp. 11b yield (0.72 g, 0.001 mmol), comp. 11c yield
(0.64 g, 0.001 mmol).
Anal. Cal. for 11a C29H21N3S3: C, 68.63; H, 4.14; N, 8.28; S, 18.93.
Found: C, 68.43; H, 4.00; N, 8.02; S, 18.63.
Anal. Cal. for 11b C29H20N4O2S3: C, 63.04; H, 3.62; N, 10.14; S, 17.39.
Found: C, 62.88; H, 3.19; N, 10.01; S, 17.10.

2578
Sh. H. Abdel-Hafez
Anal. Cal. for 11c C31H26N4S3: C, 67.63; H, 4.72; N, 10.18; S, 17.45.
Found: C, 67.30; H, 4.61; N, 9.89; S, 17.13.
2-Ethyldithiocarbamate-4-(4ꢀ-phenylsulfanyl-phenyl)-
thiazole (12)
To a well-stirred, cooled (ice/water) solution of 2 (1 g, 0.035 mmol) in
dimethylformamide (5 ml) was successively added (a) aqueous 20 molar
NaOH (0.14 ml); (b) carbon disulfide (0.42 ml); (c) aqueous 20 molar
NaOH (0.211 ml) and after 30 min, ethyl iodide (0.54 g, 0.035 mmol)
was added. Stirring was continued for 2 h. The mixture was poured onto
water (50 cc) and neutrallized to litmus with 2 N hydrochloric acid. The
solid obtained was filtered washed with water and crystallized from
ethanol as orange crystals; yield (0.27 g, 0.0007 mmol).
Anal. Cal. for C18H16N2S4: C, 55.67; H, 4.12; N, 7.21; S, 32.98. Found:
C, 55.50; H, 3.89; N, 7.11; S, 32.58.
3-[4-(4ꢀ-Phenylsulfanyl-phenyl)-thiazol-2-yl)]-2-thioxo-
4-oxo-1,2,3,4-tetrahydroquinoxaline (13)
A mixture of 12 (1 g, 0.025 mmol) and anthranilic acid (0.35 g,
0.025 mmol) in dimethlformamide (20 ml) was heated under reflux for
4 h. The precipitate was filtered, washed with water, dried, and recrys-
tallized from benzene/pet. ether 60–80◦ (5:5); yield (0.51 g, 0.001 mmol).
Anal. Cal. for C23H15N3O S3: C, 62.02; H, 3.37; N, 9.43; S, 21.57.
Found: C, 61.88; H, 3.10; N, 9.18; S, 21.32.
2-Diethyldithiocarbamate-4-(4ꢀ-phenylsulfanyl-phenyl)-
thiazole (14)
To a well-stirred solution of 2 (1 g, 0.035 mmol) in dimethylformamide
(5 ml) was added (a), (b), (c), as mentioned above, for preparation of 12.
After 30 min ethyl iodide (1.09 g, 0.070 mmol) was added and stirring
continued for 2 h. The mixture was poured onto (50 cc) water, the solid
obtained was washed with water, and it was crystallized from ethanol;
yield (032 g, 0.007 mmol).
Anal. Cal. for C20H20N2 S4: C, 57.69; H, 4.80; N, 6.73; S, 30.76. Found:
C, 57.38; H, 4.60; N, 6.57; S, 30.54.
2-[4-(4ꢀ-Phenylsulfanyl-phenyl)-thiazol-2-ylamino)-4-oxo-
benzo[d][1,3]oxazin (15)
A mixture of compound 14 (1 g, 0.024 mmol), anthranilic acid (0.32 g,
0.024 mmol) in dimethylformamide (15 ml) and potassium hydroxide
(0.096 g, 0.024 mmol) in water (2 ml) was heated under reflux for 6 h.
After cooling the product was filtered, washed with water, air-dried,

Thiazole Derivatives
2579
and crystallized form ethanol-water as yellow crystals; yield (0.045 g,
0.001 mmol).
Anal. Cal. for C23H15N3O2S2: C, 64.33; H, 3.49; N, 9.79; S, 14.91.
Found: C, 64.11; H, 3.29; N, 9.49; S, 14.63.
(1H-Benzoimidazd-2-Yl)-[4-(4ꢀ-phenylsulfanyl-phenyl)-
thiazole]-amine (16)
A solution of 14 (1 g, 0.024 mmol) in 15 ml dimethyl formamide and
o-phenylenediamine (0.25 g, 0.024 mmol) was heated under reflux for
5 h. The reaction mixture was concentrated and cooled to room temper-
ature. The solid product was filtered off and crystallized from ethanol
as yellow crystals; yield (0.43 g, 0.001 mmol).
Anal. Cal. for C22H16N4S2: C, 66.00; H, 4.00; N, 14.00; S, 16.00. Found:
C, 65.84; H, 3.88; N, 13.93; S, 15.94.
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