Facile synthesis of bis-thiosemicarbazone derivatives as key precursors for the preparation of functionalised bis-thiazoles

Article abstract of DOI:10.3184/174751916X14639296902648

A new class of bis-thiosemicarbazones was designed and synthesised by the condensation of 2,6-diformylphenol derivatives and thiosemicarbazide using either ultrasound or conventional methods. Both thiosemicarbazone groups of these derivatives underwent a heterocyclisation process to give a series of novel bis-thiazole derivatives as major products. The structures of all the synthesised compounds were characterised by multinuclear NMR (¹H and ¹³C), IR, HRMS and elemental analyses.

Full text of DOI:10.3184/174751916X14639296902648

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 JULY, 385–392
RESEARCH PAPER 385
Facile synthesis of bis-thiosemicarbazone derivatives as key precursors for
the preparation of functionalised bis-thiazoles
Wael A.A. Arafaa,b* and Mohamed G. Badryb
aChemistry Department, College of Science, Aljouf University, P.O. Box 2014, Sakaka, Aljouf, Kingdom of Saudi Arabia
bChemistry Department, Faculty of Science, Fayoum University, 63514, Fayoum, Egypt
A new class of bis-thiosemicarbazones was designed and synthesised by the condensation of 2,6-diformylphenol derivatives and
thiosemicarbazide using either ultrasound or conventional methods. Both thiosemicarbazone groups of these derivatives underwent
a heterocyclisation process to give a series of novel bis-thiazole derivatives as major products. The structures of all the synthesised
compounds were characterised by multinuclear NMR (1H and 13C), IR, HRMS and elemental analyses.
Keywords: bis-thiosemicarbazones, bis-thiazoles, ultrasound irradiation, condensation, heterocyclisation
Thiosemicarbazones are extensively used in organic synthesis.
Their varied chemical as well as biological properties have
attracted chemists for a number of years.1,2 They are widely used
for the synthesis of sulfur- and nitrogen- containing heterocyclic
compounds such as thiazoles.3 The thiosemicarbazone functional
group, with thiocarbonyl sulfur and azomethine nitrogen donor
atoms leads to several robust complexes. These metal complexes
have been used for device applications in optical computing, optical
storage, optical information processing and telecommunications.4
In addition, they are used as selective and sensitive analytical
reagents,5 exhibit corrosion inhibition behaviour toward metal
surfaces6 and have various biological properties.7–9
Thiazole moieties represent one of the most important
scaffolds either in synthetic heterocyclic chemistry or in
the field of medicinal chemistry and drug design.10,11 These
compounds display a central role in modern synthetic organic
chemistry, especially in the application of asymmetric
synthesis.11 Thiazoles are widely encountered in numerous
pharmacologically active substances and in some naturally-
occurring compounds.12 In recent years, many thiazole
derivatives have been synthesised and screened for various
biological activities.13–19 In addition, from the data reported in
the literature, bis-heterocyclic compounds have been shown
to exhibit much better antibacterial activity than their mono-
heterocyclic analogues.20,21 Prompted by the aforementioned
literature survey and in continuation of our research work22–25
aiming to develop a straightforward and flexible synthetic
method towards functionalised heterocyclic compounds;
herein we planned to study structural variation by attaching
biologically active bis-thiazoles to the phenol moiety hoping to
get a new lead structure for further study.
2,6-diformylphenol derivatives 2a–c, were prepared
previously24 through the reaction of 4-substituted phenols 1a–c
with hexamethylenetetramine in anhydrous trifluoroacetic
acid. The precursor bis-thiosemicarbazones 3a–c were
synthesised in good yields (77–82%) by reaction of substituted
2,6-diformyl phenols 2a–c with thiosemicarbazide in ethanol
at reflux temperature for 3–4 h (Scheme 1 and 2). In order to
optimise the reaction conditions, we selected 3a as a model
compound to examine its preparation by using ultrasound
irradiation under different conditions. The optimisation of the
reaction conditions, including solvent and temperature was
then investigated. First, a small solvent screen was studied
(Table 1), we found that ethanol proved to be preeminent for
this reaction (Table 1, entry 2). Then, we conducted the reaction
at different temperatures in order to investigate their influence
on the reaction course. To our satisfaction, when the reaction
o
was carried out at 60 C in ethanol for 30 min, the product
was obtained in 96% yield (Table 1, entry 7) but the yield was
reduced to 82% under reflux conditions (Table 1, entry 1). The
important points of this reaction process include the shorter
reaction time and higher yields than the conventional method.
Table 1 Optimisation for the synthesis of thiosemicarbazone derivative 3a
Entry Solvent
Temp./°C Time/min
Method
Reflux
USa
Yield/%
82
78
Trace
20
32
80
96
96
1
2
3
4
5
6
7
8
Ethanol
Ethanol
Toluene
DCM
Ethyl acetate
Ethanol
Ethanol
Ethanol
130
r.t.
r.t.
r.t.
r.t.
40
60
80
240
30
30
30
30
30
30
30
USa
USa
USa
USa
USa
Results and discussion
USa
The synthetic strategies adopted to obtain the target compounds
are depicted in Schemes 1–5. The key intermediates
aUS, ultrasound.
S
OH
OH
H2N
H
N
N
H
N
NH2
H2N
N
NH2
O
O
H
N
S
S
2a
3a
Scheme 1 The optimisation of the model reaction.
* Correspondent. E-mail: waarafa@ju.edu.sa, waa00@fayoum.edu.eg

386 JOURNAL OF CHEMICAL RESEARCH 2016
S
OH
N
H2N
OH
OH
X
N
NH2
H
H
N
H
H2N
N
N
NH2
O
O
N
N
N
N
EtOH
S
S
TFA
X
X
2a c
−
3a c
−
1a c
−
R
O
Br
R
OH
X
R
H
H
4a,b
NaOAc
N
N
N
N
N
N
S
S
X = CH3, Br, COOH
R = H, OCH3
5a f
−
Scheme 2 Synthesis of bis-thiosemicarbazones 3a–c and bis-thiazoles 5a–f.
Under the optimised reaction conditions, a series of bis-
thiosemicarbazone derivatives 3a–c were synthesised
(Scheme 2). The molecular structure of compounds 3a–c
was confirmed on the basis of analytical and spectral data.
For example, the IR spectrum of 3a showed broad absorption
bands corresponding to the OH, NH2 and NH functionalities
at 3422–3250 cm–1, the absorption bands at 1617 and 1290 cm–1
due to CH protons, α to the sulfur atom of the thiazole ring,
in the H NMR spectrum. The presence of additional signals
1
in the aromatic region δ 7.02–7.44 was indicative of the two
benzene rings that had been incorporated into the molecule.
All the compounds, 5a–f, gave [M + H]+ ions as the base peak
and significantly stable molecular ion peaks which revealed
that they contained one mole of bis-thiosemicarbazones
3a–c per two moles of phenacyl bromides 4a,b. For example,
compound 5a exhibited a molecular ion peak at m/z 509.1213
corresponding to [M + H]+.
1
were due to C=N and C=S bonds, respectively. The H NMR
spectrum showed signals at δ 11.46 and 8.32 ppm attributed to
NH and CH=N protons, respectively. Further, in the 13C NMR
spectrum, the appearance of a signal at 141.75 ppm is most
probably due to the imine carbon atom (C=N) that confirms the
condensation. The HRMS of 3a revealed a molecular ion peak
at m/z 309.0585 corresponding to [M + H]+.
Next, the reactivity of the key intermediates 3a–c towards
ethyl chloroacetate was evaluated. Thus, the reaction of 3a–c
with ethyl chloroacetate in refluxing ethanol containing a
catalytic amount of potassium carbonate afforded the bis-
thiazolidinone derivatives 6a–c (Scheme 3). Their IR spectra
In each functional thiosemicarbazone group, the two sulfur
atoms and the two nitrogen atoms of the imine are in a trans
disposition relative to the two CH=N bonds. This configuration
is stabilised by the presence of a hydrogen bond between the
imine nitrogen and the hydrogen atom of the amide.8 Thus,
the two hydrogen atoms of the amino groups are of different
1
showed bands due to C=O at 1717–1705 cm–1. The H NMR
spectra of derivatives 6a–c showed the presence of methylene
group signals in the range δ 4.01–3.83 in addition to the presence
of OH, NH, CH=N, and aromatic protons. The formation of
bis-thiazolidinone derivatives 6a–c is assumed to proceed
through initial alkylation and intramolecular cyclisation via
elimination of ethanol. Similarly, the bis-thiosemicarbazone
derivatives 3a–c were allowed to react with chloroacetonitrile
in absolute ethanol containing triethylamine to produce the bis-
aminothiazolidines 7a–c in good yield (Scheme 3) and were
adequately characterised. The most prominent features were the
characteristic broad bands in the IR spectra at 3230–3411 cm–1,
assigned to the OH and NH2 groups; distinctive (C=N) stretches
appeared in the range 1623–1635 cm–1, also. The NH2 and CH2
1
electronic environment, a finding confirmed from their H
NMR spectra which revealed two signals for the amino protons.
For example, the 1H NMR spectrum of product 3a revealed the
presence of two singlet signals at δ 8.17 and 8.07 ppm assigned
to the NH2 protons, in addition to the signals of the NH, OH,
methine, aromatic, and methyl protons (Fig. 1).
The bis-thiosemicarbazones 3a–c were used as potential
starting materials for the synthesis of bis-thiazole derivatives
via their reaction with α-bromoketones through the
Hantzsch thiazole synthesis. Thus, cyclocondensation of bis-
thiosemicarbazones 3a–c with phenacyl bromide derivatives
4a,b in refluxing ethanol containing a catalytic amount of
anhydrous sodium acetate delivered the expected bis-thiazole
derivatives 5a–f in good to moderate yields (Scheme 2). The
formation of bis-thiazole derivatives 5a–f was clearly evident
with the disappearance of the NH2 groups of compounds
3a–c and the appearance of singlet signals around δ 7.8 ppm
1
proton resonances in the H NMR spectra appeared in the
regions δ 7.88–7.98 and 3.94–4.13 ppm, respectively.
The bis-thiazolone derivatives 8a–c were also successfully
prepared from the reaction of bis-thiosemicarbazone derivatives
3a–c with diethyl acetylenedicarboxylate in ethyl acetate at
room temperature (Scheme 3). The NMR and IR spectra, as
well as HRMS of compounds 8a–c were in agreement with
the proposed structures. The low frequency of the ester C=O

JOURNAL OF CHEMICAL RESEARCH 2016 387
Fig. 1 400 MHz 1H NMR spectrum of compound 3a in DMSO-d6.
O
OH
X
H
N
H
N
H5
OC2
N
N
S
N
N
S
Cl
N
N
N
N
N
N
O
O
S
S
N
S
S
N
K
2CO3
6a c
−
CN
OH
X
OH
H
H
H2N
N
N
NH2
N
N
N
N
Cl
H2N
NH2
S
S
TEA
X
3a c
−
7a c
−
CO2Et
OH
H
N
H
N
EtO2C
Et
CO2
Et
CO2
O
O
X
8a c
−
3, 6 8a
: X = CH3
: X = Br
: X = COOH
−
b
c
Scheme 3 Synthesis of bis-thiazole derivatives 6–8.

388 JOURNAL OF CHEMICAL RESEARCH 2016
stretching absorption is probably the result of the conjugation
of the C=C bond. The H NMR spectrum of compound 8a in
thiazines 11B or bis-thiazoles 12a–c, which could be suggested
as reaction products as outlined in Scheme 4.
1
DMSO-d6 exhibited two sharp singlets readily recognised as
arising from =CHCOOEt (δ 6.57) and CH=N (δ 8.58). A triplet
at δ 1.26 and a quartet at δ 4.23 corresponded to the presence
of the CH3 and CH2 protons of the ethyl group, respectively.
Also, the 13C NMR spectrum displayed an increase in the
number of signals of carbon atoms to 13 in agreement with the
proposed structure. As expected, the reaction could give rise
to two possible stereoisomers (E and Z); it was found that the
thermodynamically stable Z-isomer was formed selectively
over the E-isomer as characterised by the down-field shift of
their methine-group protons when compared to that of the
E-isomer.26
Our study was extended to include the synthesis of the
bis-thiazoles 12a–c as outlined in Scheme 4. Thus, the
reaction of bis-thiosemicarbazone derivatives 3a–c with
2-(4-chlorobenzylidene)malononitrile afforded, in each case,
a single isolable product as examined by TLC.27,28 In each
case, there are three possible products via different cyclisation
routes, leading to either the bis-pyrimidine-2-thiones 11A, bis-
However in all cases, we suggest that the reaction
proceeds via addition of the nucleophilic solvent (ethanol)
to the ylidenemalononitrile followed by a thiophilic attack
on the thiocarbonyl S-atom to afford intermediate 9, from
which elimination of EtOH and subsequent ring closure and
dehydrogenation ensue. The reaction product was proved, in each
case, to be a bis-thiazole 12a–c, where the spectral data (IR, MS,
1H NMR and 13C NMR spectra) were in complete agreement with
structure 12a–c but not with 11A or 11B. For example, HRMS
showed the exact molecular ion peak corresponding to [M + H]+
for derivative 12a and (M+) for derivatives 12b, c. The IR spectra
of 12a–c revealed the presence of strong cyano group bands in
the 2226–2220 cm–1 region. The successful incorporation of
the phenyl rings was indicated by the appearance of aromatic
doublets peaks at δ 7.21–7.78. Moreover, the NH protons of the
hydrazide protons appeared downfield at δ 11.03–11.12 ppm.
The 13C NMR spectra of 12a–c showed signals around 113 ppm
characteristic of cyano groups and the absence of the thiocarbonyl
carbon signals (expected at ~ 180 ppm).
H
O
CN
OH
Et
H
H
NC
H2N
N
N
NH2
+
Ar
N
N
Ar
CN
S
S
NC
..
X
Et-O-H
3a c
−
Ar
N
N
Ar
S
N
S
N
OH
OH
X
H
N
H
N
N
N
H2N
NH
..
..
2
Et
O
Et
O
NC
N
N
N
N
CN
NH2
NH2
S
S
Ar
Ar
NC
NC
NC
NC
CN
X
CN
11A
9a c
−
or
-
2EtOH
N
OH
Ar
CN
OH
Ar
NC
H
N
H
N
H
S
N
H
H
N
H
N
S
N
N
N
N
Ar
Ar
CN
CN
N
S
CN
S
NH2
H2N
X
X
11B
10a c
−
-2HCN
-2H2
OH
H
N
H
N
N
N
N
Ar
Ar
CN
S
S
9-12:a:
b:
X = CH3, Ar = 4-ClC6H4
X = Br, Ar = 4-ClC6H4
X = COOH, Ar = 4-ClC6H4
X
12a c
−
c:
Scheme 4 Synthesis of bis-thiazoles 12a–c.

JOURNAL OF CHEMICAL RESEARCH 2016 389
Conclusions
Moreover, condensation of 2,6-diformylphenols 2a–c with
cyanoacetic acid hydrazide afforded the desired bis-N-arylidene
cyanoacetic acid hydrazides 13a–c, which on treatment with
phenyl isothiocyanate and finely divided sulfur in the presence
of trimethylamine, as a basic catalyst, afforded bis-thiazole-
2-thiones 17a–c (Scheme 5). Mechanistically, the reaction
is likely to start by the addition of sulfur to the α-activated
acetonitriles 13a–c to generate the sulfur adducts 14a–c.
Nucleophilic attack of sulfur in 14a–c on phenyl isothiocyanate
afforded intermediates 15a–c which underwent ring closure via
nucleophilic attack of nitrogen atoms on the cyano groups to
give intermediates 16a–c. Rearrangement of 16a–c afforded
the isolable products 17a–c (Scheme 5).
In conclusion, this paper reports an efficient synthesis of novel
bis-thiosemicarbazones which were used as versatile precursors
for the synthesis of a new series of bis-thiazole derivatives.
These products were well characterised by NMR, HRMS and
elemental analyses. The newly synthesised compounds are
interesting both in their own right as unique molecules and
for their promising biological and pharmaceutical activities. A
study involving the antibacterial and antioxidant activities of
this new series is already in progress in our laboratory.
Experimental
All reagents were purchased from commercial suppliers and were
used without further purification. The purity of the synthesised
compounds and the times required for the completion of the
reactions were monitored by thin layer chromatography (TLC). The
melting points of the synthesised compounds were determined on an
Electrothermal IA9100 melting point apparatus and the values were
uncorrected. IR spectra were recorded on a Perkin-Elmer Spectrum
One spectrophotometer, using samples prepared as KBr discs. 1H
and 13C NMR spectra were recorded on a Bruker spectrometer at 400
and 100 MHz, respectively using dimethyl sulfoxide (DMSO-d6)
solvent and TMS as internal standard (chemical shifts expressed in
δ ppm). High resolution mass spectra measurements were recorded
on a Bruker Daltonics microTOF spectrometer with an electrospray
ioniser. Ultrasonic reactions were carried out in a Clifton Ultrasonic
Bath (2 × T2A, 300 W, DU-4) made by Nickel Electro Ltd, Weston-
super-Mare Somerset, England. The starting 2,6-diformylphenols
1a–c were prepared as previously reported.24
Identification of compounds 13a–c and 17a–c was performed
using IR, NMR, HRMS and elemental analyses. The NMR
observations reveal the appearance of two methylene protons
1
in the region 4.22–4.26 ppm in the H NMR spectra and the
presence of two cyano groups in the region 115.60–115.88
ppm in the 13C NMR spectra, confirming the formation of
bis-N-arylidene cyanoacetic acid hydrazides 13a–c. Also, the
bis-thiazole-2-thiones 17a–c were confirmed by the presence
of two NH2 and two NH groups in the region 6.31–6.71 ppm
1
and 10.01–9.93 ppm, respectively in the H NMR and two
C=S carbons at the region 188.50–189.70 ppm in the 13C NMR
spectra. In addition, the HRMS of derivative 17a showed a peak
at m/z 683.0752 corresponding to [M + Na]+. All compounds,
13a–c and 17a–c, showed satisfactory elemental analysis data
with the theoretically calculated values.
O
CN
OH
X
OH
H
H
N
N
H2N NH
EtOH
S8/NEt3
NC
N
N
CN
O
O
O
O
X
13a c
−
2a c
−
S
S
S
S
C
S
C
C
C
N
Ph
N
Ph
Ph
N
N
N
N
OH
S
H
S
OH
X
S
H
N
H
H
N
Ph
N
N
N
N
NC
N
N
CN
O
O
O
O
X
15a c
14a c
−
−
S
S
S
S
S
OH
S
H
S
OH
S
H
N
H
N
H
N
N
N
Ph
N
N
Ph
Ph
Ph
N
N
N
N
N
H2N
NH2
HN
NH
O
O
O
O
X
X
16a c
17a c
−
−
13 17a:
X = CH3
X = Br
X = COOH
−
b:
c:
Scheme 5 Synthesis of bis-thiazol-2-thiones 17a–c.

390 JOURNAL OF CHEMICAL RESEARCH 2016
Synthesis of bis-thiosemicarbazones 3a–c; general procedure
128.21, 126.05, 123.47, 111.93, 104.04 ppm; HRMS (EI) calcd for [M
+ H]+: 573.0167; found: 573.0166; Anal. calcd for C26H19BrN6OS2: C,
54.26; H, 3.33; N, 14.60; found: C, 54.29; H, 3.30; N, 14.57%.
Conventional method
A solution of 2a–c (1 mmol) and thiosemicarbazide (0.182 g, 2 mmol)
in ethanol (20 mL) was stirred at reflux for 3–4 h. The reaction was
followed by TLC analysis. The precipitate that formed while heating
was filtered off, dried and recrystallised from dioxane to produce 3a–c
(77–82%).
4-Hydroxy-3,5-bis[2-(4-phenyl-thiazol-2-yl)hydrazonomethyl]
benzoic acid (5c): Yellow crystals (ethanol); yield 80%; m.p. 255 °C;
IR nmax/cm−1 (KBr): 3211 (br, 2OH, NH), 1679 (C=O), 1611, 1595
(C=N, C=C); 1H NMR (400 MHz, DMSO-d6): 8.48 (s, 2H, 2 CH=N),
8.09 (s, 2H, 2NH), 7.86 (s, 2H, Thiazole-H5), 7.85 (s, 2H, ArH)
7.37–7.35 (m, 4H, ArH), 7.27–7.25 (m, 3H, ArH) 7.12 (s, 3H, ArH)
ppm; 13C NMR (100 MHz, DMSO-d6): 169.61, 166.50, 162.57, 150.95,
141.27, 135.68, 130.11, 128.93, 128.11, 127.63, 125.99, 120.51, 102.02
ppm; HRMS (EI) calcd for [M + H]+: calcd 539.0955; found: 539.0953;
Anal. calcd for C27H20N6O3S2: C, 59.99; H, 3.73; N, 15.55; found: C,
60.01; H, 3.70; N, 15.51%.
4-Methyl-2,6-bis {2- [4- (2-methoxyphenyl) thiazol-2-yl]
hydrazonomethyl}phenol (5d): Yellow crystals (ethanol); yield 87%;
m.p. 260 °C; IR nmax/cm−1 (KBr): 3347 (br, OH, NH), 1613, 1599 (C=N,
C=C); 1H NMR (400 MHz, DMSO-d6): 8.34 (s, 2H, 2 CH=N), 8.05–8.02
(m, 2H, 2NH), 7.41 (s, 2H, ArH), 7.38 (s, 2H, ArH), 7.32–7.28 (m, 2H,
ArH), 7.13–7.11 (M, 2H, ArH), 7.04–7.01 (m, 2H, ArH), 3.92 (s, 6H,
2OCH3), 2.31 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6):168.21,
156.55, 153.46, 143.33, 131.30, 130.29, 129.32, 123.45, 122.35, 121.20,
113.32, 111.95, 106.93, 55.92, 21.28 ppm; HRMS (EI) calcd for [M + H]+:
569.1424; found: 569.1427; Anal. calcd for C29H26N6O3S2: C, 61.03; H,
4.59; N, 14.73; found: C, 61.10; H, 4.52; N, 14.70%.
Ultrasonic irradiation method
To a solution of thiosemicarbazide (0.182 g, 2 mmol) in ethanol
(10 mL) was added the 2,6-diformylphenol derivative 2a–c (1 mmol).
The reaction mixture was irradiated with an ultrasound probe for
30 min at 60 °C (the reaction was monitored by TLC). After that time,
the precipitate was filtered off and dried to produce 3a–c in excellent
yields without any further purification.
2-Hydroxy-5-methylisophthalylidenebisthiosemicarbazide
(3a):
White crystals; yield 96%; m.p. 282 °C; IR nmax/cm−1 (KBr): 3422 (OH,
NH2), 3250 (NH), 1617, 1598 (C=N, C=C), 1290 (C=S); 1H NMR (400
MHz, DMSO-d6):11.46 (s, 2H, 2NH), 9.56 (s, 1H, OH), 8.32 (s, 2H, 2
CH=N), 8.17 (s, 2H, NH2), 8.07 (s, 2H, NH2), 7.63 (s, 2H, ArH), 2.25
(s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): 178.15, 157.13,
141.75, 130.94, 129.42, 121.27, 20.26 ppm; HRMS (EI) calcd for [M +
H]+: 309.0587; found: 309.0585; Anal. calcd for C11H14N6OS2: C, 42.56;
H, 4.55; N, 27.07; found: C, 42.58; H, 4.51; N, 27.11%.
2-Hydroxy-5-bromoisophthalylidenebisthiosemicarbazide
(3b):
4-Bromo-2,6-bis {2- [4- (2-methoxyphenyl) thiazol-2-y])
hydrazonomethyl}phenol (5e): Yellow crystals (ethanol); yield 94%;
m.p. 318 °C; IR nmax/cm−1 (KBr): 3338 (br, OH, NH), 1621, 1601
Colourless crystals; yield 98%; m.p. 310 °C; IR nmax/cm−1 (KBr):
3331 (OH, NH2), 3222 (NH), 1622, 1593 (C=N, C=C), 1299 (C=S);
1H NMR (400 MHz, DMSO-d6): 11.53 (s, 2H, N2H), 10.87 (s, 1H,
OH), 8.31 (s, 2H, 2 CH=N), 8.21 (br, 4H, 2NH2), 8.07 (s, 2H, ArH)
ppm; 13C NMR (100 MHz, DMSO-d6): 178.42, 154.20, 139.54, 131.48,
124.60, 112.88 ppm; HRMS (EI) calcd for [M + H]+: 372.9541; found:
372.9540; Anal. calcd for C10H11BrN6OS2: C, 32.01; H, 2.95; N, 22.39;
found: C, 32.11; H, 2.90; N, 22.42%.
1
(C=N, C=C); H NMR (400 MHz, DMSO-d6): 11.18 (s, 1H, OH),
8.37 (s, 2H, 2 CH=N), 7.92 (dd, J = 7.6, 1.3 Hz, 2H, ArH), 7.74 (s, 2H,
2NH), 7.35 (s, 2H, ArH), 7.34–7.28 (m, 2H, ArH), 7.10 (d, J = 8.0 Hz,
2H, ArH), 7.02 (dd, J = 11.5, 4.2 Hz, 2H, ArH), 3.89 (s, 6H, 2OCH3)
ppm; 13C NMR (100 MHz, DMSO-d6):166.43, 157.04, 154.39, 144.58,
140.50, 130.36, 129.66, 129.53, 123.82, 120.90, 112.04, 111.96, 107.85,
55.97 ppm; HRMS (EI) calcd for (M + H)+: 633.0378; found: 633.0379;
Anal. calcd for C28H23BrN6O3S2: C, 52.91; H, 3.65; N, 13.22; found: C,
52.88; H, 3.71; N, 13.17%.
2-Hydroxy-5-carboxyisophthalylidenebisthiosemicarbazide
(3c):
Colourless crystals; yield 96%; m.p. 296 °C; IR nmax/cm−1 (KBr):
3322 (br, OH, NH2, NH), 1675 (C=O), 1614, 1591 (C=N, C=C), 1286
(C=S); 1H NMR (400 MHz, DMSO-d6): 12.93 (br, 1H, COOH), 11.54
(s, 2H, 2NH), 10.37 (br, 1H, OH), 8.42 (s, 2H, 2 CH=N), 8.23 (s, 2H,
ArH), 8.21 (br, 4H. 2NH2) ppm; 13C NMR (100 MHz, DMSO-d6):
178.29, 166.80, 161.01, 141.43, 131.60, 123.32, 121.31 ppm; HRMS
(EI) calcd for [M + H]+: 339.0329; found: 339.0329; Anal. calcd for
C11H12N6O3S2: C, 38.81; H, 3.55; N, 24.69; found: C, 38.78; H, 3.59; N,
24.72%.
4-Hydroxy-3,5-bis{2-[4- (2-methoxyphenyl) -thiazol-2-yl]
hydrazonomethyl}benzoic acid (5f): Yellow crystals (ethanol) yield
83%; m.p. 210 °C; IR nmax/cm−1 (KBr): 3247 (br, 2OH, NH), 1683
1
(C=O), 1615, 1591 (C=N, C=C); H NMR (400 MHz, DMSO-d6):
11.89 (br, 2H, 2OH), 8.48 (s, 2H, 2 CH=N), 8.22 (s, 2H, ArH), 8.05 (d,
J = 6.9 Hz, 2H, ArH), 7.38 (s, 2H, ArH), 7.30 (t, J = 7.1 Hz, 2H, ArH),
7.11 (d, J = 8.3 Hz, 2H, ArH), 7.03 (t, J = 7.4 Hz, 2H, ArH), 3.93 (s, 6H,
2OCH3) ppm; 13C NMR (100 MHz, DMSO-d6):167.64, 166.60, 157.08,
146.38, 140.89, 133.63, 129.40, 129.03, 128.56, 123.05, 121.41, 120.86,
111.98, 107.62, 55.88 ppm; HRMS (EI) calcd for (M + H)+: 599.1166;
found: 599.1164; Anal. calcd for C29H24N6O5S2: C, 57.99; H, 4.03; N,
13.99; found: C, 57.94; H, 4.11; N, 14.06%.
Synthesis of bisthiazoles 5a–f; general procedure
A mixture of bis-thiosemicarbazones 3a–c (1 mmol) and the
appropriate phenacyl bromide derivative 4a or 4b (2 mmol) in ethanol
(20 mL) in the presence of anhydrous sodium acetate (3 mmol) was
heated under reflux for 5 h. The solid formed was filtered off, washed
with water (3 × 10 mL), dried and purified by recrystallisation from a
suitable solvent to give 5a–f.
Synthesis of thiazolidinone derivatives 6a–c; general procedure
A mixture of the appropriate bis-thiosemicarbazone 3a–c (1 mmol)
and ethyl chloroacetate (0.21 mL, 2 mmol) in ethanol (20 mL)
containing anhydrous potassium carbonate (0.552 g, 4 mmol) was
refluxed for 3 h (monitored by TLC). The reaction mixture was cooled
and the resulting precipitate was filtered off, washed with water
(3 × 10 mL), and recrystallised from an appropriate solvent.
4-Methyl-2,6-bis[(thiazol-4-one-2-yl)hydrazonomethyl]phenol
(6a): Yellow crystals (dioxane); yield 79%; m.p. 290 °C; IR nmax/cm−1
(KBr): 3201 (br, OH, NH), 1706 (C=O), 1631, 1575 (C=N, C=C);
1H NMR (400 MHz, DMSO-d6): 12.31 (s, 1H, OH), 11.65 (s, 1H, NH)
8.33 (s, 2H, 2 CH=N), 7.42 (s, 2H, ArH), 3.83 (s, 4H, 2CH2), 2.35 (s,
3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): 189.11, 161.54, 141.73,
154.22, 132.81, 119.89, 32.45, 21.28 ppm; HRMS (EI) calcd for [M +
H]+: 389.0491; found: 389.0495; Anal. calcd for C15H14N6O3S2: C,
46.14; H, 3.61; N, 21.52; found: C, 46.19; H, 3.57; N, 21.48%.
4-Methyl-2,6-bis[2-(4-phenylthiazol-2-yl)hydrazonomethyl]phenol
(5a): Yellow crystals (dioxane); yield 87%; m.p. 254 °C; IR nmax
/
cm−1 (KBr): 3338 (br, OH, NH), 1610, 1586 (C=N, C=C); H NMR
(400 MHz, DMSO-d6):10.86 (s, 1H, OH), 8.37 (s, 2H, 2 CH=N), 7.87
(s, 2H, 2NH), 7.85 (s, 2H, Thiazole–H5), 7.44 – 7.39 (m, 6H, ArH),
7.33–7.31 (m, 6H, ArH), 2.31 (s, 3H, CH3) ppm; 13C NMR (100 MHz,
DMSO-d6): 168.03, 154.61, 148.11, 143.52, 133.61, 132.60, 131.21,
129.11, 128.18, 126.03, 120.75, 104.31, 20.61 ppm; HRMS (EI) calcd
for [M + H]+: 509.1213; found: 509.1213; Anal. calcd for C27H22N6OS2:
C, 63.51; H, 4.34; N, 16.46; found: C, 63.48; H, 4.37; N, 16.48%.
4-Bromo-2,6-bis[2-(4-phenylthiazol-2-yl)hydrazonomethyl]phenol
1
(5b): Yellow crystals (dioxane); yield 85%; m.p. 283 °C; IR nmax
/
cm−1 (KBr): 3258 (br, OH, NH), 1602, 1583 (C=N, C=C); H NMR
(400 MHz, DMSO-d6): 11.18 (s, 1H, OH), 8.33 (s, 2H, 2 CH=N), 7.86
(s, 2H, 2NH), 7.84 (s, 2H, Thiazole-H5), 7.74 (s, 2H, ArH) 7.42–7.40
(m, 5H, ArH), 7.34–7.32 (m, 5H, ArH) ppm; 13C NMR (100 MHz,
DMSO-d6): 167.94, 154.09, 147.21, 142.2, 134.62, 130.07, 129.11,
1
4-Bromo-2,6-bis[(thiazol-4-one-2-yl)hydrazonomethyl]phenol
(6b): Brown crystals (dioxane); yield 84%; m.p. 320 °C; IR nmax/cm−1

JOURNAL OF CHEMICAL RESEARCH 2016 391
(KBr): 3231 (br, OH, NH), 1705 (C=O), 1626, 1580 (C=N, C=C);
1H NMR (400 MHz, DMSO-d6): 12.26 (s, 1H, OH), 11.70 (s, 1H, NH)
8.35 (s, 2H, 2 CH=N), 7.91 (s, 2H, ArH), 3.85 (s, 4H, 2CH2) ppm;
13C NMR (100 MHz, DMSO-d6):187.32, 160.71, 154.61, 143.22, 132.40,
119.55, 38.31 ppm; HRMS (EI) calcd for [M + H]+: 452.9439; found:
452.9436; Anal. calcd for C14H11BrN6O3S2: C, 36.93; H, 2.44; N, 18.46;
found: C, 36.89; H, 2.48; N, 18.48%.
115.61, 63.76, 21.64, 14.60 ppm; HRMS (EI) calcd for [M]+: 558.0991;
found: 558.0990; Anal. calcd for C23H22N6O7S2: C, 49.45; H, 3.97; N,
15.05; found: C, 49.42; H, 3.99; N, 15.12%.
2,6-Bis[(5-ethoxycarbonylmethylene-4H-thiazol-4-one-2-yl)
hydrazonomethyl]-4-bromophenol (8b): Brown crystals (DMF-
H2O); yield 70%; m.p. 360 °C; IR nmax/cm−1 (KBr): 3229 (br, OH, NH),
1
1711, 1688 (2C=O), 1618, 1583 (C=N, C=C); H NMR (400 MHz,
4-Hydroxy-3,5-bis[(thiazol-4-one-2-yl)hydrazonomethyl]benzoic
DMSO-d6): 12.36 (br, H, COOH), 11.54 (s, 1H, OH), 11.22 (s, 1H, NH)
8.59 (s, 2H, 2 CH=N), 7.82 (s, 2H, ArH), 6.54 (s. 2H, 2C=CH), 4.33
(q, J = 7.1 MHz, 4H, 2CH2CH3), 1.29 (t, J = 7.1 MHz, 6H, 2CH2CH3)
ppm; 13C NMR (100 MHz, DMSO-d6): 180.35, 163.87, 159.02, 154.82,
145.38, 133.40, 129.54, 120.34, 116.11, 113.50, 61.21, 14.89 ppm;
HRMS (EI) calcd for [M + Na]+: 644.9838; found: 644.9834; Anal.
calcd for C22H19BrN6O7S2: C, 42.38; H, 3.07; N, 13.48; found: C, 42.41;
H, 3.04; N, 13.50%.
acid (6c): Brown crystals (DMF); yield 75%; m.p. 353 °C; IR nmax
/
cm−1 (KBr): 3387 (br, OH, NH), 1717, 1689 (2C=O), 1629, 1584 (C=N,
C=C); 1H NMR (400 MHz, DMSO-d6): 12.79 (br, 2H, 2OH), 11.11 (s,
1H, NH) 8.39 (s, 2H, 2 CH=N), 8.28 (s, 2H, ArH), 4.01 (s, 4H, 2CH2)
ppm; 13C NMR (100 MHz, DMSO-d6): 187.84, 166.52, 161.56, 157.11,
144.27, 129.70, 127.99, 120.34, 37.31 ppm; HRMS (EI) calcd for [M
+ H]+: 419.0232; found: 419.0234; Anal. calcd for C15H12N6O5S2: C,
42.85; H, 2.88; N, 19.99; found: C, 42.82; H, 2.90; N, 19.84%.
3,5-Bis[(5-ethoxycarbonylmethylene-4H-thiazol-4-one-2-yl)
hydrazonomethyl]-4-hydroxybenzoic acid (8c): Yellow crystals
(dioxane); yield 70%; m.p. 392 °C; IR nmax/cm−1 (KBr): 3205 (br, OH,
Synthesis of aminothiazole derivatives 7a–c; general procedure
To a solution of 3a–c (1 mmol) in ethanol (20 mL) was added
triethylamine (1 mL) and the mixture was stirred for 30 min at
ambient temperature. To the resulting clear solution was added
chloroacetonitrile (0.13 mL, 2 mmol) dropwise whilst the reaction
mixture was stirred. After complete addition, the reaction mixture
was refluxed for 3–5 h (monitored by TLC). The solid that precipitated
was filtered off, washed with water (3 × 10 mL), dried and finally
recrystallised from dioxane.
2,6-Bis[(4-amino-5H-thiazol-2-ylidene)hydrazonomethyl]-4-
methylphenol (7a): Yellow crystals (dioxane); yield 74%; m.p. 233 °C;
IR nmax/cm−1 (KBr): 3230 (br, OH, NH2), 1629, 1584 (C=N, C=C);
1H NMR (400 MHz, DMSO-d6): 12.24 (s, H, OH), 8.22 (s, 2H, 2
CH=N), 7.98 (br, 4H, 2NH2), 7.23 (s, 2H, ArH), 4.13 (s, 4H, 2CH2)
ppm; 13C NMR (100 MHz, DMSO-d6): 161.43, 156.23, 152.09, 145.93,
136.35, 133.91, 120.89, 37.88, 21.57 ppm; HRMS (EI) calcd for [M +
H]+: 389.0967; found: 389.0967; Anal. calcd for C15H16N8OS2: C, 46.38;
H, 4.15; N, 28.84; found: C, 46.41; H, 4.22; N, 28.89%.
2,6-Bis[(4-amino-5H-thiazol-2-ylidene)hydrazonomethyl]-4-
bromophenol (7b): Yellow crystals (dioxane); yield 71%; m.p. 374 °C;
IR nmax/cm−1 (KBr): 3361 (br, OH, NH), 1623, 1590 (C=N, C=C);
1H NMR (400 MHz, DMSO-d6): 12.83 (s, H, OH), 8.335 (s, 2H, 2
CH=N), 7.93–7.89 (m, 6H, ArH + 2NH2), 4.02 (s, 4H, 2CH2) ppm;
13C NMR (100 MHz, DMSO-d6): 160.46, 157.70, 153.05, 147.22,
131.04, 116.39, 38.10 ppm; HRMS (EI) calcd for [M + H]+: 452.9915;
found: 452.9918; Anal. calcd for C14H13BrN8OS2: C, 37.09; H, 2.89; N,
24.72; found: C, 37.11; H, 2.85; N, 24.70%.
3,5-Bis[(4-amino-5H-thiazol-2-ylidene)-hydrazonomethyl]-4-
hydroxybenzoic acid (7c): Yellow crystals (dioxane); yield 71%; m.p.
360 °C; IR nmax/cm−1 (KBr): 3411 (br, 2OH, NH), 1687 (C=O), 1635,
1596 (C=N, C=C); 1H NMR (400 MHz, DMSO-d6): 13.72 (s, H,
COOH), 11.30 (s, 1H, OH) 8.41 (s, 2H, 2 CH=N), 8.22 (s, 2H, ArH),
7.88 (br, 4H, 2NH2), 3.94 (s, 4H, 2CH2) ppm; 13C NMR (100 MHz,
DMSO-d6): 167.93, 161.40, 155.52, 153.06, 142.71, 128.92, 126.82,
119.07, 36.92 ppm; HRMS (EI) calcd for [M]+: 418.063; found:
418.067; Anal. calcd for C15H14N8O3S2: C, 43.05; H, 3.37; N, 26.78;
found: C, 43.00; H, 3.32; N, 26.73%.
1
NH), 1722, 1695 (2C=O), 1627, 1577 (C=N, C=C); H NMR (400
MHz, DMSO-d6): 12.36 (br, H, COOH), 11.54 (S, 1H, OH), 11.22
(s, 1H, NH) 8.59 (s, 2H, 2 CH=N), 8.21 (s, 2H, ArH), 6.84 (s. 2H,
2C=CH), 4.50 (q, J = 7.1 MHz, 4H, 2CH2CH3), 1.34 (t, J = 7.1 MHz,
6H, 2CH2CH3) ppm; 13C NMR (100 MHz, DMSO-d6): 189.44, 168.71,
163.88, 161.09, 146.90, 134.87, 129.00, 128.13, 119.59, 63.71, 14.77
ppm; HRMS (EI) calcd for [M + Na]+: 611.0631; found: 611.0632;
Anal. calcd for C23H20N6O9S2: C, 46.94; H, 3.43; N, 14.28; found: C,
46.90; H, 3.48; N, 14.31%.
Synthesis of thiazoles 12a–c; general procedure
A
mixture of 3a–c (1 mmol) and 2-(4-chlorobenzylidene)
malononitrile (0.376 g, 2 mmol) in ethanol (20 mL) was refluxed
for 3–4 h (monitored by TLC). The reaction mixture was cooled
and the resulting precipitate was filtered off and recrystallised from
dioxane.
2 , 6 - B i s { [ 4 - ( p - c h l o r o p h e n y l ) -5 - c y a n o t h i a z o l - 2 -y l ]
hydrazonomethyl}-4-methylphenol (12a): Yellow crystals (dioxane);
yield 70%; m.p. 348 °C; IR nmax/cm−1 (KBr): 3220 (br, OH, NH), 2220
(CN), 1599, 1585 (C=N, C=C); 1H NMR (400 MHz, DMSO-d6): 11.78
(s, 1H, OH), 11.03 (s, 2H, NH), 8.37 (s, 2H, 2 CH=N), 7.86 (d, J = 1.3,
8.2 MHz, 4H, ArH), 7.61 (d, J = 1.4, 8.2 MHz, 4H, ArH), 7.21 (s, 2H,
ArH), 2.42 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): 166.62,
155.90, 147.90, 143.61, 135.09, 134.22, 132.80, 130.66, 129.71, 129.62,
127.28, 119.04, 113.48, 21.95 ppm; HRMS (EI) calcd for [M + H]+:
627.0344; found: 627.0348; Anal. calcd for C29H18Cl2N8OS2: C, 55.33;
H, 2.88; N, 17.80; found: C, 55.37; H, 2.79; N, 17.89%.
2 , 6 - B i s { [ 4 - ( p - c h l o r o p h e n y l ) -5 - c y a n o t h i a z o l - 2 -y l ]
hydrazonomethyl}-4-bromophenol (12b): Brown crystals (dioxane);
yield 84%; m.p. 322 °C; IR nmax/cm−1 (KBr): 3235 (br, OH, NH), 2226
(CN), 1598, 1583 (C=N, C=C); 1H NMR (400 MHz, DMSO-d6):
11.97 (s, 1H, OH), 11.12 (s, 2H, NH), 8.40 (s, 2H, 2 CH=N), 7.89 (s,
2H, ArH), 7.78 (d, J = 1.3, 8.2 MHz, 4H, ArH), 7.57 (d, J = 1.4, 8.2
MHz, 4H, ArH) ppm; 13C NMR (100 MHz, DMSO-d6): 170.21, 158.40,
149.34, 144.26, 135.20, 133.25, 134.01, 130.41, 128.94, 128.09, 122.71,
115.95, 112.83 ppm; HRMS (EI) calcd for [M]+: 691.9371; found:
691.9370; Anal. calcd for C28H15BrCl2N8OS2: C, 48.43; H, 2.18; N,
16.14; found: C, 48.48; H, 2.15; N, 16.21%.
Synthesis of bis-thiazolones 8a–c; general procedure
A mixture of 3a–c (1 mmol) and diethyl acetylenedicarboxylate
(0.3 mL, 2.2 mmol) in ethyl acetate (20 mL) was stirred for 5 h at
ambient temperature (monitored by TLC). The solid that formed was
collected by filtration and recrystallised from the indicated solvent.
2,6-Bis[(5-ethoxycarbonylmethylene-4H-thiazol-4-one-2-yl)
hydrazonomethyl]-4-methylphenol (8a): Canary yellow crystals
(dioxane); yield 88%; m.p. 372 °C; IR nmax/cm−1 (KBr): 3254 (br, OH,
3 , 5 - B i s { [ 4 - ( p - c h l o r o p h e n y l ) -5 - c y a n o t h i a z o l - 2 -y l ]
hydrazonomethyl}-4-hydroxybenzoic acid (12c): Yellow crystals
(dioxane); yield 65%; m.p. 369 °C; IR nmax/cm−1 (KBr): 3260 (br,
1
OH, NH), 2223 (CN), 1610, 1595 (C=N, C=C); H NMR (400 MHz,
DMSO-d6): 12.42 (s, 1H, COOH), 11.63 (s, 1H, OH), 11.07 (s, 2H,
NH), 8.41 (s, 2H, 2 CH=N), 8.32 (s, 2H, ArH), 7.66 (q, J = 1.1, 1.3,
8.2 MHz, 4H, ArH), 7.51 (q, J = 1.1, 1.4, 8.2 MHz, 4H, ArH) ppm;
13C NMR (100 MHz, DMSO-d6): 169.22, 166.72, 158.04, 150.78,
144.65, 135.33, 134.90, 134.11, 128.96, 128.43, 127.47, 126.46, 120.52,
113.48 ppm; HRMS (EI) calcd for [M]+: 658.0164; found: 658.0164;
Anal. calcd for C29H16Cl2N8O3S2: C, 52.81; H, 2.45; N, 16.99; found: C,
52.81; H, 2.45; N, 16.99%.
1
NH), 1721, 1691 (2C=O), 1628, 1601 (C=N, C=C); H NMR (400
MHz, DMSO-d6): 12.81 (br, H, COOH), 11.18 (S, 1H, OH), 11.06
(s, 1H, NH) 8.58 (s, 2H, 2 CH=N), 7.49 (s, 2H, ArH), 6.57 (s. 2H,
2C=CH), 4.23 (q, J = 7.1 MHz, 4H, 2CH2CH3), 2.27 (s, 3H, CH3), 1.26
(t, J = 7.1 Hz, 6H, 2CH2CH3) ppm; 13C NMR (100 MHz, DMSO-d6):
181.62, 165.09, 161.39, 158.22, 147.40, 136.58, 134.52, 131.60, 120.72,

392 JOURNAL OF CHEMICAL RESEARCH 2016
Synthesis of cyanoacetic acid hydrazide derivatives 13a–c; general
procedure
C28H21BrN8O3S4: C, 46.34; H, 2.92; N, 15.44; found: C, 46.39; H, 2.91;
N, 15.39%.
3 , 5 - B i s [ ( 4 - a m i n o - 3 - p h e n y l - 2 H - t h i a z o l - 5 - y l )
carbohydrazonomethyl]-4-hydroxybenzoic acid (17c): Yellow crystals
(dioxane); yield 75%; m.p. 178 °C; nmax/cm−1 (KBr): 3363 (br, OH,NH2,
NH), 1693, 1674 (C=O), 1622, 1583 (C=N, C=C); 1H NMR (400 MHz,
DMSO-d6): 12.33 (br, 1H, COOH), 11.01 (s, 1H, OH), 9.93 (s, 2H,
NH), 8.44 (s, 2H, 2 CH=N), 8.04 (s, 2H, ArH), 7.67 (m, 4H, ArH), 7.53
(m, 4H, ArH), 7.29 (m, 2H, ArH), 6.71 (br, 4H, NH2) ppm; 13C NMR
(100 MHz, DMSO-d6):189.57, 167.93, 164.81, 157.88, 154.60, 146.73,
142.05, 129.63, 129.02, 127.11, 125.62, 122.70, 118.95, 104.22 ppm;
HRMS (EI) calcd for [M + H]+: 689.0518; found: 689.0518; Anal. calcd
for C29H22N8O5S4: C, 50.42; H, 3.21; N, 16.22; found: C, 50.38; H, 3.20;
N, 16.18%.
A mixture of thiosemicarbazones 3a–c (1 mmol) and cyanoacetic
acid hydrazide (0.198 g, 2 mmol) in ethanol (20 mL) was heated under
reflux for 4 h. The precipitate formed after cooling was filtered off,
dried, and recrystallised from the indicated solvent.
2,6-Bis(cyanoacetylhydrazonomethyl)-4-methylphenol
(13a):
Colourless crystals (ethanol); yield 85%; m.p. 187 °C; IR nmax/cm−1
(KBr): 3211 (br, OH, NH), 2229 (CN), 1698 (C=O), 1605, 1581 (C=N,
C=C); 1H NMR (400 MHz, DMSO-d6): 11.55 (s, 1H, OH), 10.23
(s, 2H, NH), 8.43 (s, 2H, 2 CH=N), 7.40 (s, 2H, ArH), 4.22 (s, 4H,
2CH2CN), 2.42 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6):
167.31, 156. 70, 146.22, 134.23, 133.10, 120.36, 115.88, 25.71, 21.30
ppm; HRMS (EI) calcd for [M + H]+: 325.1049; found: 325.1046; Anal.
calcd for C15H14N6O3: C, 55.21; H, 4.32; N, 25.75; found: C, 55.26; H,
4.29; N, 25.81%.
We are very thankful to the Department of Organic Chemistry,
Arrhenius Lab., Stockholm University for providing laboratory
facilities.
2,6-Bis(cyanoacetylhydrazonomethyl)-4-bromophenol (13b): Yellow
crystals (dioxane–ethanol); yield 85%; m.p. 219 °C; IR nmax/cm−1 (KBr):
3223 (br, OH, NH), 2228 (CN), 1701 (C=O), 1622, 1598 (C=N, C=C);
1H NMR (400 MHz, DMSO-d6): 11.57 (s, 1H, OH), 10.60 (s, 2H, NH),
8.41 (s, 2H, 2 CH=N), 7.96 (s, 2H, ArH), 4.26 (s, 4H, 2CH2CN) ppm;
13C NMR (100 MHz, DMSO-d6): 168.06, 156.72, 146.80, 131.47, 120.08,
116.11, 115.72, 26.03 ppm; HRMS (EI) calcd for [M + H]+: 388.9998;
found: 388.9993; Anal. calcd for C14H11BrN6O3: C, 42.99; H, 2.83; N,
21.48; found: C, 42.92; H, 2.90; N, 21.52%.
Received 20 January 2016; accepted 10 April 2016
Paper 1603861 doi: 10.3184/174751916X14639296902648
Published online: 9 June 2016
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K.S. Ravindra and K.S. Ashok, J. Mol. Struct., 2015, 1094, 61.
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3,5-Bis(cyanoacetylhydrazonomethyl)-4-hydroxybenzoic acid (13c):
White crystals (dioxane–ethanol); yield 85%; m.p. 199 °C; IR nmax/cm−1
(KBr): 3321 (br, OH, NH), 2224 (CN), 1701, 1685 (C=O), 1608, 1584
4
5
Y. Tian, C. Duan, C. Zhao, X. You, T.C.W. Mak and Z.Y. Zhang, Inorg.
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1
(C=N, C=C); H NMR (400 MHz, DMSO-d6): 12.43 (s, 1H, COOH),
11.33 (s, 1H, OH), 10.64 (s, 2H, NH), 8.41 (s, 2H, 2 CH=N), 8.31 (s, 2H,
ArH), 4.23 (s, 4H, 2CH2CN) ppm; 13C NMR (100 MHz, DMSO-d6):
168.42, 168.05, 157.32, 146.88, 128.39, 120.62, 115.60, 26.09 ppm;
HRMS (EI) for [M + H]+: calcd 355.0791; found: 355.0795; Anal. calcd
for C15H12N6O5: C, 50.57; H, 3.39; N, 23.59; found: C, 50.51; H, 3.43; N,
23.66%.
6
7
K.F. Khaled, Electrochim. Acta., 2010, 55, 5375.
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Synthesis of thiazolthiones 17a–c; general procedure
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To a mixture of 13a–c (1 mmol), finely divided sulfur (0.13 g, 2 mmol),
and triethylamine (0.7 mL) in ethanol (20 mL), was added phenyl
isothiocyanate (0.4 mL, 4 mmol). The reaction mixture was heated at
45 °C for 5 h with continuous stirring. The reaction mixture was cooled
to ambient temperature, and then poured into ice water containing a
few drops of hydrochloric acid. The solid product formed was filtered
off, washed with water (3 × 10 mL), dried, and recrystallised from the
indicated solvent.
2,6-Bis[(4-amino-3-phenyl-2H-thiazol-5-yl)carbohydrazonomethyl]-
4-methylphenol (17a): Yellow crystals (dioxane); yield 68%; m.p. 253
°C; IR nmax/cm−1 (KBr): 3471 (br, OH, NH2, NH), 1683 (C=O), 1601,
1598 (C=N, C=C); 1H NMR (400 MHz, DMSO-d6): 11.21 (s, 1H, OH),
10.01 (s, 2H, NH), 8.37 (s, 2H, 2 CH=N), 7.66 (m, 4H, ArH), 7.54 (m,
4H, ArH), 7.34 (m, 2H, ArH), 7.26 (s, 2H, ArH),6.31 (br, 4H, NH2),
2.44 (s, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6): 189.70, 167.41,
158.48, 152.45, 146.75, 141.70, 135.88, 131.37, 128.48, 122.54, 119.00,
103.35, 22.61 ppm; HRMS (EI) calcd for [M + Na]+: 683.0752; found:
683.0752; Anal. calcd for C29H24N8O3S4: C, 52.71; H, 3.66; N, 16.96;
found: C, 52.68; H, 3.69; N, 16.89%.
2,6-Bis[(4-amino-3-phenyl-2H-thiazol-5-yl)carbohydrazonomethyl]-
4-bromophenol (17b): Yellow crystals (DMF–H2O); yield 66%; m.p.
298 °C; IR nmax/cm−1 (KBr): 3390 (br, OH, NH2, NH), 1685 (C=O), 1611,
1599 (C=N, C=C); 1H NMR (400 MHz, DMSO-d6): 11.23 (s, 1H, OH),
9.86 (s, 2H, NH), 8.42 (s, 2H, 2 CH=N), 7.62 (m, 4H, ArH), 7.47 (m, 4H,
ArH), 7.39 (m, 2H, ArH), 7.96 (s, 2H, ArH), 6.54 (br, 4H, NH2) ppm;
13C NMR (100 MHz, DMSO-d6):188.50, 166.53, 156.90. 152.22, 146.62,
141.91, 132.86, 129.37, 125.42, 122.80, 119.05, 115.35.104.61 ppm;
HRMS (EI) calcd for [M]+: 723.9803; found: 723.9801; Anal. calcd for