Design and synthesis of bis thiazol-2-ylidenes

Article abstract of DOI:10.14233/ajchem.2013.14329

A series of novel hitherto unreported 4,4'-[N,N'-bis(3-phenyl-4-(4- substituted phenyl)-thiazol-2(3H)-ylidene)]methylenedianiline derivatives has been synthesized by the heterocyclization between the bis-1,3-disubstituted thiourea and substituted acetophe

Full text of DOI:10.14233/ajchem.2013.14329

Asian Journal of Chemistry; Vol. 25, No. 10 (2013), 5370-5372
http://dx.doi.org/10.14233/ajchem.2013.14329
Design and Synthesis of Bis Thiazol-2-ylidenes
*
T.V. SRAVANTHI, MADHUSUDHANA REDDY POTTEM and S.L. MANJU
Organic Chemistry Division, VIT University, Vellore-632 014, India
*Corresponding author: E-mail: slmanju@vit.ac.in; sravan2512@gmail.com
(Received: 19 July 2012; Accepted: 8 April 2013)
AJC-13208
A series of novel hitherto unreported 4,4'-[N,N'-bis(3-phenyl-4-(4-substituted phenyl)-thiazol-2(3H)-ylidene)]methylenedianiline
derivatives has been synthesized by the heterocyclization between the bis-1,3-disubstituted thiourea and substituted acetophenones in
presence of iodine. Both conventional and non-conventional methods have been used for the synthesis of the targets. All the synthesized
compounds were confirmed by spectral analysis.
Key Words: Bisthiourea, Bisthiazolidenes, Ultrasonication.
diphenylene diamine, phenyl isothiocyanate, acetophenone and
substituted acetophenones. The solvents including petroleum
ether (60-80 ºC), N,N-dimethyl formamide, dichloromethane,
methanol, absolute ethanol and ethyl acetate were purchased
from SD fine Chemicals Limited and used.
INTRODUCTION
Thiazole ring unit is a common feature of many bioactive
molecules. Thiazole ring system possessing diversified types
of pharmacological activities such as antifungal1, antiinflam-
matory2, antituberculosis3, antitumor4, etc. In the recent reviews,
many examples of enhanced bioactivity of multivalent drug
molecules have been cited5. Compounds bearing more than
one thiazole ring unit also exhibit good biological activities,
the bleomycin containing 2,4'-bis thiazole system acts as an
anticancerous antibiotic and biological reports also existing
on the 5,5'-bis thiazoles6 and 2,2'-bis thiazoles7. Further, the
2-aminothiazole is a valuable pharmacophore unit present
in many bioactive compounds including thrombotic8 and
bacterial DNA-gyrase9 inhibitors that are potentially useful in
cardiac and cancer treatment. Accordingly, thiazoline deriva-
tives also possess biological activities such as antifungal10, skin
whitening properties11 and have some interesting agricultural
applications12. Recently, the synthesis of 2-amino-4-phenyl-
thiazole through the condensation reaction between aceto-
phenone and thiourea in the presence of iodine as the reagent
was reported13. We now reported the synthesis of 4,4'-[N,N'-
bis(3-phenyl-4-(4-substituted phenyl)-thiazol-2(3H)-ylidene)]-
methylenedianiline derivatives through Hantzsch thiazole con-
densation of bis-1,3-disubstituted thiourea and acetophenones
in presence of iodine followed by E1 elimination. The synthesis
of the title compound was carried out as presented in the
Scheme-I.
Melting points were determined in open capillary tubes.
Thin layer chromatography was performed using silica gel on
the glass plates. The spots were visualized under iodine
chamber and under UV light. The spectra were recorded.
General procedure
Synthesis of 4,4'-[N,N'-bis(substituted thiourea)]-
methylenedianiline (2): A mixture of diamine (1) (5 mmol)
and phenyl isothiocyanate (10 mmol) dissolved in ethanol was
refluxed for 1 h. The reaction was monitored by using TLC
(pet. ether:ethyl acetate 4:1) and found to be completed in 1 h.
The reaction mixture was cooled, solid product formed was
filtered, dried and recrystallized from ethanol/N,N'-dimethyl
formamide. Brown solid; yield 90 %; m.p. 95-97 ºC; IR (KBr,
νmax, cm-1): 3316, 3030, 1591, 1505, 1490, 1108, 930, 768; 1H
NMR δ 7.25-7.60 (m, 10H, Ar-H), 6.90-7.10 (d, 8H, Ar-H),
3.45 (S, 2H, CH2), 8.1-8.3 (s, 4H, -NH-); m/z 468.
Synthesis of 4,4'-[N,N'-bis(3,4-diphenyl-thiazol-2(3H)-
ylidene)]methylenedianiline (3i): in situ method: To a stirred
solution of acetophenone (10 mmol) in aqueous methanol (1:1)
(10 mL), potassium bromide-potassium bromate (2:1) (1 g, 5
mmol available bromine) was added, followed by drop-wise
addition of dil. HCl (1 N, 10 mL). The reaction mixture was
allowed to stir for further 90 min. To the mixture, a solution of
bisthiourea (2) (5 mmol) dissolved in DMF, added a catalytic
amount of iodine and allowed to reflux for overnight. To the
EXPERIMENTAL
All chemicals were purchased from Sigma-Aldrich
Chemical & Co. and used without purification. They included

Vol. 25, No. 10 (2013)
Design and Synthesis of Bis Thiazol-2-ylidenes 5371
PhNCS, ethanol
reflux, 1hr
S
S
Ph
Ph
N
H
N
H
N
H
N
H
H2N
NH2
(2)
(1)
a
b
c
S
S
Ph
Ph
Compound 2
N
N
N
N
Ph
Ph
(a) Phenacylbromide (5mmol acetophenone, KBr & KBrO3 (2:1, 1g, 5mmol available Br2), 1N HCl), I2, DMF,
reflux, overnight; (b) acetophenone, I2, ethanol, reflux, 2hrs; (c) acetophenone, I2, ethanol, ultrasonication, 30 mins
b
c
S
S
Compound 2
N
N
N
N
Ph
Ph
R
R
(b) 4-substituted acetophenones( R = -NH2, -Cl, -OCH3, -CH3), I2, ethanol, reflux, 2hrs;
(c) 4-substituted acetophenones( R = -NH2, -Cl, -OCH3, -CH3), I2, ethanol, ultrasonication, 30 mins
Scheme-I
mixture added 10 mL of 1 N NaOH to neutralize and the DMF
was concentrated under reduced pressure, extracted with ethyl
acetate, washed with water and dried over sodium sulphate,
concentrated to get the crude product. The reaction was moni-
tored by using TLC(Pet. ether:ethyl acetate 4:1) and found to
be completed within 3 h. The product was purified by column
chromatography.Yellowish orange solid;Yield 61 %; m.p. 104-
109 ºC; IR (KBr, νmax, cm-1): 3050, 2951, 1822, 1434, 1306,
1180, 748, 691; 1H NMR δ 7.68-7.99 (m, 20H, Ar-H), 7.55-
7.67(d, 8H, Ar-H), 4.9 (s, 2H, CH2), 5.92(s, 2H, -CH-S in
thiazolidene ring); m/z 672(m + 2).
tives (3ii-v): To study the comparison between the conven-
tional method and non-conventional method, the heterocycli-
zation were carried out by both reflux and ultrasonication
method. The time taken for the completion of the reaction and
yields obtained by conventional and non-conventional methods
are given in Table-1. The crude products obtained were puri-
fied by column chromatography and studied their spectral
analysis.
4,4'-(N,N'-Bis(3-phenyl-4-(4-amino-phenyl)-thiazol-
2(3H)-ylidene))methylenedianiline (3ii): Brown solid; m.p.
107-109 ºC; IR (KBr, νmax, cm-1): 3052, 2959, 1905, 1434,
1308, 1176, 749, 692; 1H NMR δ 7.56-7.67 (m, 10H, Ar-H),
7.68-7.70 (m, 8H, Ar-H), 7.20-7.36(m, 8H,Ar-H), 5.26(s, 2H,
CH2), 6.52 (s, 2H, -CH-S in thiazolidene ring), 8.68 (s, 4H,
-NH2); m/z 668.
Reflux method: To the ethanol solution of 2 mmol of
acetophenone, added 3 equivalent of bis thiourea compound
(2) and 2.2 equivalent of iodine, stir and allowed to reflux for
2 h. The reaction was monitored by TLC and found to be
completed within 2 h. It was made alkaline by adding 5 %
NaOH, extracted with dichloromethane (DCM). The organic
solvent was evaporated under reduced pressure. The brown
colour crude product was re-crystallized from ethanol. Brown
solid; yield 82 %; m.p. 104-109 ºC.
4,4'-(N,N'-Bis(3-phenyl-4-(4-chloro-phenyl)-thiazol-
2(3H)-ylidene))methylenedianiline (3iii): Pale yellow solid;
m.p. 74-77 ºC; IR (KBr, νmax, cm-1) 3050, 2964, 1964, 1906,
1305, 1171, 748, 695; 1H NMR δ 7.56-7.68 (m, 10H, Ar-H),
7.68-7.70 (m, 8H, Ar-H), 7.17-7.37(m, 8H,Ar-H), 5.28(s, 2H,
CH2), 6.57(s, 2H, -CH-S in thiazolidene ring); m/z 736.
4,4'-(N,N'-Bis(3-phenyl-4-(4-methyl-phenyl)-thiazol-
2(3H)-ylidene))methylenedianiline (3iv): Pale yellow solid;
m.p. 79 ºC; IR (KBr, νmax, cm-1) 3057, 2951, 1915, 1435, 1306,
1226, 748, 690; 1H NMR δ 7.56-7.70 (m, 10H, Ar-H), 7.86-
7.95 (m, 8H, Ar-H), 7.0-7.36(m, 8H,Ar-H), 3.70(S, 2H, CH2),
4.04 (s, 2H, -CH-S in thiazolidene ring), 2.51 (s, 3H,-CH3);
m/z 696.
Ultrasonication method: To the ethanol solution of 2
mmol acetophenone, added 3.0 equivalent of bisthiourea (2)
and 2.2 equivalent of iodine were ultra-sonicated in cleaning
ultrasonic bath at 45 ºC for 0.5 h. The reaction was monitored
by TLC and found to be completed within 22 min. The solvent
was evaporated under reduced pressure. The brown colour
crude product was re-crystallized from ethanol. Brown solid;
yield 88 %; m.p. 105-109 ºC.
Synthesis of 4,4'-(N,N'-bis(3-phenyl-4-(4-substituted
phenyl)-thiazol-2(3H)-ylidene))-methylenedianiline deriva-
4,4'-(N,N'-Bis(3-phenyl-4-(4-methoxy-phenyl)-thiazol-
2(3H)-ylidene))methylenedianiline (3v): Light brown solid;
TABLE-1
REACTION TIME (min) AND YIELD (%) OF THE REACTION BY CONVENTIONAL AND NON-CONVENTIONAL METHODS
Compounds
3i
3ii
77
3iii
70
3iv
67
3v
80
Yield (%)
82
80
88
22
By reflux method
Time (min)
Yield (%)
90
120
82
135
80
90
81
84
By ultrasonication
method
Time (min)
22-28
26-30
26-30
22-25

5372 Sravanthi et al.
Asian J. Chem.
m.p. 107-111 ºC; IR (KBr, νmax, cm-1) 3051, 2955, 1965, 1905,
1307, 1246, 751, 711; 1H NMR δ 7.56-7.70 (m, 10H, Ar-H),
7.85-8.01 (m, 8H, Ar-H), 6.99-7.42(m, 8H,Ar-H), 4.52(s, 2H,
CH2), 5.76(s, 2H, -CH-S in thiazolidene ring), 3.30 (s, 3H,
-O-CH3); m/z 728.
corresponding bisthiazolidenes were obtained. The mass
spectra and the proton NMR values were in agreement with
the expected products (3ii-3v). The yields and the reaction
times were compared and found the better results in non-
conventional method.
Conclusion
RESULTS AND DISCUSSION
We designed and synthesized the hitherto unreported 4,4'-
[N,N'-bis(3-phenyl-4-(4-substituted phenyl)-thiazol-2(3H)-
ylidene)]methylenedianiline derivatives in good yields by non-
conventional method using ultrasonication and moderate yield
by conventional method. This methodology has been confir-
med by the synthesis of various bisthiazolidene derivatives.
Reaction of compound bearing amino group with phenyl
isothiocyanate in presence of ethanol gives the corresponding
disubstituted thiourea14. Similarly, 4,4'-diaminodiphenyl-
methane (1) on treatment with twice the molar weight of phenyl
isothiocyanate gives the corresponding disubstituted bis thio-
urea compound (2). The disubstituted bis thiourea product
formed was collected by evaporating the solvent under reduced
pressure. The formation of bis thiourea was confirmed by IR
spectrum which showed the characterization bands at 3316
cm-1 represents the N-H stretching, the band at 1591 cm-1
represents aromatic C=C and the band at 1490 cm-1 represents
aromatic C=S. Then, the proton NMR peaks and intense
molecular ion peak at 468 in mass spectrum are also in agree-
ment with the structure of the bis thiourea compound (2).
Further, the bisthiourea (2) on treating with phenacylbromide
(prepared by treating 5 mmol of acetophenone with mixture
of potassium bromide and potassium bromate (2:1, 1 g, 5 mmol
available bromine) in the presence 1 N hydrochloric acid) in
presence of catalytic amount of iodine undergoes Hantzsch
thiazole condensation followed by E1 elimination gives corres-
ponding bisthiazolidene product (3i)15. The formation of the
bisthiazolidene product was confirmed from mass spectrum
which showed the m/z values 671. Then, the proton NMR
values was also in agreement with the 4,4'-(N,N'-bis(3,4-diphe-
nyl-thiazol-2-ylidene))methylenedianiline product (3i). To
carry out the reaction in shorter time and in convenient method,
the ethanol solution of bisthiourea (2) was treated with aceto-
phenone in presence of iodine as the reagent and allowed to
reflux the reaction mixture for 2 h. We found that the time for
completion of the reaction was reduced and yield compara-
tively higher than in the above method. Further, we carried
out the heterocyclization by non-conventional method using
ultrasonication, the reaction was found to be completed within
22 min. We finally concluded that the reaction was easily
carried out in ultrasonication method with good yield and shortest
time period. Both the conventional and non-conventional
methods were followed to carry out the heterocyclization of
bisthiourea (2) with various substituted acetophenones, the
ACKNOWLEDGEMENTS
The authors thank VIT University, Vellore for financial
support and FTIR spectra, Mr. Kiran Desai and Ms. Mini
Dhiman for NMR spectra and mass spectra.
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