Thiazole-based chemosensor III: Synthesis and fluorescence sensing of CH3CO2- based on inhibition of ESIPT

Article abstract of DOI:10.1016/j.tet.2010.07.007

Novel fluorogenic sensors based on urea derivative of 2-(2′- aminophenyl)-4-phenylthiazole (4 and 5) were prepared and used for recognition of anions with similar basicity and surface charge density. Chemosensor 4 was found to be highly selective to aceta

Full text of DOI:10.1016/j.tet.2010.07.007

Tetrahedron 66 (2010) 7097e7103
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Thiazole-based chemosensor III: synthesis and fluorescence sensing
of CH3COꢀ2 based on inhibition of ESIPT
*
Aasif Helal, Hong-Seok Kim
Department of Applied Chemistry, Kyungpook National University, Daegu 702-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Novel fluorogenic sensors based on urea derivative of 2-(20-aminophenyl)-4-phenylthiazole (4 and 5)
were prepared and used for recognition of anions with similar basicity and surface charge density.
Chemosensor 4 was found to be highly selective to acetate ion over other anions. The selectivity was
related to the structure matching between the host and the guest. The evaluation of the chemosensors’
interaction with anions was performed by UVevis and fluorescence titration. This acetate binding affinity
was further tuned by varying the acidity of the NeH proton of the urea moiety in chemosensor 5.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 27 May 2010
Received in revised form 1 July 2010
Accepted 2 July 2010
Available online 24 July 2010
Keywords:
2-(20-Aminophenyl)thiazole
Urea
Fluorescence sensing
Acetate anion
ESIPT
1. Introduction
indicator of organic decomposition in marine sediments.5 Several
anion sensors having strong affinity and selectivity for acetate an-
There exists a large interest in the development of artificial
neutral receptors for anions due to their medicinal and environ-
mental potential applications.1 Such molecules should be able to
behave as hydrogen-bond donors toward the envisaged anion,
giving rise to a complex that is stable in solution. Beside mere
electrostatic interactions, hydrogen-bonds are directional, a fea-
ture, which allows the design of receptors capable of differentiating
between anions with different geometries and hydrogen-bonding
requirements. Neutral receptors that contain NeH fragments can
act as hydrogen-bond donors for the anion. One of the most fre-
quently employed neutral receptor containing the NeH fragment is
urea. In fact, urea can donate two hydrogen bonds in a parallel
fashion, and so it is complementary to Y-shaped oxoanions, such as
carboxylates. One of the first examples of anion complexation by
urea-based receptors was reported by Wilcox and Hamilton who
characterized the receptoreanalyte interaction through 1H NMR
experiments.2 In particular, the carboxylate anions exhibit specific
biochemical behaviors in the enzymes and antibodies3 and are also
critical components of numerous metabolic processes.4 So the
recognition and sensing of acetate ion is considered to be more
important than the other biologically functional anions. Acetate
production and oxidation rate has been frequently used as an
ions are reported based on phenylhydrazone and benzimidazole
moiety.6
During the last few years, much attention has been focused on
the fluorescent sensing because of the high sensitivity and selec-
tivity of this method.7 In cell and tissues, fluorescent probes are
generally distributed inhomogeneously. As a consequence their
fluorescence intensity is dependent on the local concentration of
the sensors as well as on other factors, such as illumination in-
tensity, optical path length, and bleaching. In order to eliminate
the effects of these factors a ratiometric sensor that exhibits
a spectral shift upon reaction or binding to the analyte of interest is
generally used. In the case of ratiometric sensors the ratio between
the two emission intensities can be used to evaluate the analyte
concentration. In this respect, dual fluorescence probes exhibiting
two well separated emission bands in organic solvents are of
particular interest, since they provide a reliable ratiometric signal
independent of the probe concentration.8 Excited-state intra-
molecular proton transfer (ESIPT) is very effective for the design of
probes with dual fluorescence. ESIPT results in the formation of
two tautomeric forms in the excited state of the probe: N
*
- enol
and T
*
- keto forms.9 ESIPT is one of the most well known photo-
physical process occurring in o-hydroxy-benzoxazole, benzimid-
azole, and benzothiazole.10 It is expected that replacement of the
oxygen atom in the oxazole ring with a sulfur atom to form a thi-
azole ring increases the polarizabilities of the molecule and in-
troduces interesting novel spectral-luminescent properties that
* Corresponding author. E-mail address: kimhs@knu.ac.kr (H.-S. Kim).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.007

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A. Helal, H.-S. Kim / Tetrahedron 66 (2010) 7097e7103
S
N H N
N H
S
iii, iv
i
O
NH 2
X
N
95%
NO 2
S
2: X = NO2
3: X = NH2
4: R = H (90%)
5: R = CF3 (93%)
1
ii
R
Scheme 1. Synthesis of chemosensors 4 and 5. Reagents and conditions: (i) 2-bromoacetophenone, EtOH, reflux, 2 h; (ii) 10% Pd/C, H2, MeOH, 6 h; (iii) phenyl isocyanate, dioxane,
reflux, 12 h; (iv) 4-trifluoromethylphenyl isocyanate, dioxane, reflux, 2 h.
are essential for practical applications of the luminophores. For-
mation of an intramolecular hydrogen bond in these compounds
promotes luminescence intensity and results in abnormally large
Stokes shifts.11
339 nm, which is attributed to the pep transition favored by the
*
planar orientation enforced by the intramolecular hydrogen
bonding (Fig. 1).12,13 It shows that the Fꢀ and the CH3COꢀ2 (10 equiv)
only produce a blue shift with slight decrease in the absorbance
spectra at 339 nm. No other anions (Clꢀ, Brꢀ, Iꢀ, ClOꢀ4 , NOꢀ3 , H2PO4ꢀ,
HSOꢀ4 ) produce any significant change in absorption.
Previously we already exploited the inhibition of ESIPT for cation
sensing and ratiometric fluoride sensing in 2-hydroxyphenylthi-
azole.12 To prepare an ESIPT-based anion chemosensor, the sensor
moiety should form an intramolecular hydrogen bond in the ground
state with the adjacent hydrogen-bonding acceptor and the acidity
of the receptor should be weak enough to avoid the deprotonation of
the sensor upon interactionwith the basic anions, such as CH3COꢀ2 or
Fꢀ, yet it should be strong enough to induce a fast rate of ESIPT.
Therefore we introduced a urea group, which is a good hydrogen-
bonding donor and can bind efficiently with the Y-shaped anion,
such as acetate. Moreover we have appended an electron-with-
drawing substituent (eCF3) to the urea framework in order to po-
larize the NeH bonds and to increase their hydrogen-bond donor
tendencies. Therefore, the strongest interactions are expected to
occur between highly basic anions and highly acidic urea fragments.
0.6
4
339 nm
-
F
-
OAc
0.4
331 nm
0.2
0.0
2. Results and discussion
Chemosensors 4 and 5 were prepared as described in Scheme 1
starting from thionation of 2-nitrobenzamide with Lawesson’s re-
agent. The Hantzsch condensation of 2-nitrobenzthioamide with
2-bromoacetophenone in dry ethanol gave 2 in good yield.
Hydrogenation of the latter with 10% Pd/C in methanol afforded 2-
(20-aminophenyl)-4-phenylthiazole 3 that was used for the prep-
aration of 4 and 5 without further purification. The structures of 4
and 5 were confirmed by 1H NMR, 13C NMR, and elemental analysis.
The binding and recognition abilities of 4 and 5 toward various
anions in dry CH3CN were studied by UVevis and fluorescence
spectroscopy. The receptor 4 produces an absorption band at
275
300
325
Wavelength (nm)
350
375
Figure 1. UVevis spectra of 4 (50 m
M) upon addition of 10 equiv of Fꢀ and CH3CO2ꢀ
anions.
Spectrophotometric titration was carried out by slow addition of
the tetrabutylammonium acetate to a dry CH3CN solution of 4. The
addition of the Y-shaped CH3COꢀ2 produces a slight blue shift from
0.0
b
a
0.6
0-10 eq
-0.2
-0.4
339 nm
0.4
331 nm
313 nm
0.2
-0.6
339 nm
-0.8
0.0
275
0
1
2
Equiv. of TBA OAc
3
-
4
300
325
Wavelength (nm)
350
375
+
Figure 2. (a) UVevis spectra of 4 (50 m
M) upon successive addition of CH3COꢀ2 (0e10 equiv) in CH3CN. (b) Normalized absorbance changes at 339 nm versus equiv of TBAþOAcꢀ added.

A. Helal, H.-S. Kim / Tetrahedron 66 (2010) 7097e7103
7099
500
400
300
200
100
0
The fluorescence responses of 4 with different anions were
recorded in dry acetonitrile with excitation at 339 nm i.e., the ab-
sorption band maximum of 4 for the purpose of avoiding specific
solvent effects.14 From Figure 3 it can be seen that only CH3COꢀ2
produces a new enhanced peak at 479 nm on binding with 4, while
complexation with the Fꢀ produces a small change in the emission
spectra. None of any other anions produce any noticeable change in
the emission spectra.
Spectrofluorimetric titrations were also investigated with an
excitation at 339 nm. The sensor 4 undergoes ESIPT and produces
a normal emission at 389 nm (Form A) and a tautomer emission of
556 nm (Form B). On the slow addition of CH3COꢀ2 , the peaks at 389
and 556 nm disappears and a new peak is formed at 479 nm (Form
C) as shown in Scheme 2 and Figure 4.
The ESIPT is inhibited by the hydrogen bonding of the urea NeH
with the CH3COꢀ2 , which causes fluorescence enhancement that
results in the formation of emission peak between the normal and
tautomer emissions burying the normal emission and quenching
the tautomer emission with an isoemission point at 556 nm
(Fig. 4a). The peak at 479 nm showed a linear enhancement with
the increase of acetate ion concentration when the ratio of acetate
ion and 4 concentrations is below or equal to the ratio of 1:1. When
the ratio has reached 1:1, however, higher acetate ion concentra-
tion did not lead to any further emission enhancement (Fig. 4b).
This is supported by the Job’s plot of 4 with CH3COꢀ2 , which also
indicates the formation of a ratio of 1:1 complex (Fig. 5). From this
titration experiment, the association constant of 4 with CH3COꢀ2 in
CH3CNwascalculatedtobe1.2ꢁ104 Mꢀ1 (error limitꢂ10%)15 (Table 1).
-
OAc
479 nm
-
-
-
-
4, Cl , Br , I , ClO ,
4
-
-
-
NO , HSO ,
3
4
F
-
H PO
2
.
4
350
400
450
500
550
600
650
Wavelength (nm)
Figure 3. Fluorescence spectra of 4 (50
ions in CH3CN (lex¼339 nm).
mM) upon addition of 10 equiv of various an-
500
400
300
200
100
0
Scheme 2. The possible ESIPT in
stoichiometry.
4 a 1:1 binding
and binding of CH3COꢀ2 in
339 to 331 nm with decrease in absorbance (Fig. 1). The presence of
a well defined isosbestic point at 313 nm indicates that only one
acetate anion can form hydrogen bonds with the urea subunit of 4
during the entire titration. This intermolecular hydrogen bond for-
mation can disturb the intramolecular hydrogen bonding and de-
stroy the rigidity of the molecule, so the blue shift and decrease in
the absorption band at 339 nm is observed.14a Moreover the ab-
sorption band at 339 nm linearly decreased, up to 1 equiv of CH3CO2ꢀ
addition (Fig. 2a and b), indicating the formation of a 1:1 complex.
0.0
0.2
0.4
0.6
0.8
1.0
-
[OAc ]/([OAc ]+[4])
-
Figure 5. Fluorescence Job’s plot of 4 (100
m
M) with CH3COꢀ2 (100
mM) in CH3CN.
500
0-10 eq
C
1.0
b
479 nm
479 nm
a
400
300
0.8
0.6
0.4
0.2
0.0
200
556 nm
100
B
389 nm
A
0
350
0
1
2
3
4
400
450
500
550
600
650
Wavelength (nm)
Figure 4. (a) Changes in fluorescence spectra of 4 (50
m
M) upon successive addition of CH3COꢀ2 (0e10 equiv) in CH3CN. (lex¼339 nm) (b) Normalized fluorescence changes at
479 nm versus equiv of TBAþOAcꢀ added.

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A. Helal, H.-S. Kim / Tetrahedron 66 (2010) 7097e7103
Table 1
Photophysical properties and association constants of 4 and 5 in CH3CN
a
Sensor
UVevis (nm, log
3
)
Fluorescence (nm)
Host
Association constant Ka (Mꢀ1
)
Host
OAcꢀ
Fꢀ
OAcꢀ
479
Fꢀ
OAcꢀ
Fꢀ
4
317 (3.61)
339 (3.70)
317 (3.61)
331 (3.63)
314 (3.67)
339 (3.66)
389 (N
*
)
389
480
556
Ndb
1.2ꢁ104
4.2ꢁ102
556 (T
*
)
5
317 (3.68)
336 (3.76)
317 (3.66)
388 (3.59)
390 (N
*
)
473
2.5ꢁ104
Ndb
553 (T )
*
N
*
¼normal emission, T ¼tautomer emission.
*
a
Calculated from fluorescence titration, error estimated to be ꢂ10%.
b
Not determined.
The reason for the high selectivity of CH3COꢀ2 over Fꢀ, Clꢀ, Brꢀ,
Iꢀ, H2POꢀ4 , NO3ꢀ, ClO4ꢀ, and HSOꢀ4 is related to the configuration of
the CH3COꢀ2 matching with the chemosensor and the alkalescence
of the anion, as well as the acidity of urea NeH protons in che-
mosensor. Because acetate anion is a Y-shaped oxyanion and planar
triangular with the angle of OeCeO is about 120ꢃ, the distance of
the two oxygen atoms may fit to two hydrogen atoms on recogni-
tion sites of the receptor 4 (Scheme 2). This increases its binding
affinity than the fluoride ion though the latter has smaller size and
higher basicity (Table 1 and Fig. 6). This is also confirmed by the
geometry optimized structure according to the density functional
theory using B3LYP/6-31G(d), which shows that there exists
a strong hydrogen-bond, with bond length of 1.61 and 2.05 Å be-
tween the NeH of the urea and the acetate oxygen (Fig. 7). More-
over, the angle of OePeO in H2POꢀ4 is about 108ꢃ (tetrahedral
configuration), and the distance of two oxygen atoms of acetate ion
is longer than that of the H2POꢀ4 , and so two oxygen atoms of H2POꢀ4
could not match well with two hydrogen atoms of 4.6a The alka-
lescence of acetate anion is also stronger than the other halide
anions (Clꢀ, Brꢀ, Iꢀ). Thus appropriate multiple hydrogen bonding
interactions and high alkalescence cause high affinity for CH3CO2ꢀ
over other anions.
150
Figure 7. Optimized structure (B3LYP/6-31G) of 4-CH3CO2ꢀ
.
556 nm
120
1 equiv of CH3COꢀ2 is added. Further addition only causes broad-
ening of the peak.
90
0-10 eq
For the 1H NMR titration spectrum, two effects are responsible
for the spectral changes upon NeH/anion hydrogen bond for-
mation: (a) through-bond effects, which increase the electron
density of the phenyl ring and promote upfield shifts in the case of
480 nm
60
Ha
(
Dd¼0.07), Hb
(
Dd¼0.23), and Hc Dd¼0.06), and (b) through-
(
space effects, which polarize the CeH bond in proximity to hy-
drogen bonds, creating a partial positive charge on the proton, and
causing a downfield shifts in the case of Hd (Dd¼0.06), He (Dd¼0.5),
and Hf (Dd¼0.05).
30
389 nm
0
Deprotonation of the NeH proton of urea shows that the elec-
tron density of the phenyl para position is enhanced as shown in
Scheme 3. This indicates that the acidity of this kind of chemo-
sensors can be tuned by changing the electronic property of the
substituent at the para position.
400
450
500
550
600
650
Wavelength (nm)
Figure 6. Changes in fluorescence spectra of 4 (50
(0e10 equiv) in CH3CN (lex¼339 nm).
m
M) upon successive addition of Fꢀ
Thus by introducing an electron-withdrawing substituent (CF3)
at the para position of the phenyl ring, the acidity and thus the
hydrogen-bond donor property of the NeH moiety is increased.
Similarly UVevis titration was carried out by the slow addition
of tetrabutylammonium acetate salt to a dry CH3CN solution of 5.
The addition of the CH3COꢀ2 produces a blue shift from 336 to
317 nm with decrease in absorbance (Fig. 9). The presence of a well
defined isosbestic point at 307 nm indicates that during the entire
titration only one CH3COꢀ2 can form hydrogen bonds with the urea
More evidences for the notion that the formation of hydrogen
bonds between urea NeH and CH3COꢀ2 came from 1H NMR titration
carried in DMSO-d6. From Figure 8 we can see that both the NeH
signals shift downfield over the course of the titration from
d 9.58 to
10.37 and 10.40 to 10.85. However, the NeH signals were ob-
d
servable throughout the titration, and were consistent with a hy-
drogen-binding process, and not deprotonation, involving the
receptor. The downfield shift of the NeH protons take place till

A. Helal, H.-S. Kim / Tetrahedron 66 (2010) 7097e7103
7101
Figure 8. Partial 1H NMR spectra of 4 with CH3CO2ꢀ in DMSO-d6.
S
S
S
-
A
O
N
N
O
N
N
O
N
H
N
H
H
H
N
N
N
+
4
HA
Scheme 3. Resonance representation of the deprotonated form of 4.
Thus by increasing the acidity and the hydrogen bonding affinity of
the urea moiety, the fluorescence intensity and the binding ca-
pacity with the anion is enhanced (Table 1).
An absorbance study of 5, with 1 equiv of Fꢀ, produces a new
red-shifted band at 388 nm, which matches well with the absorp-
tion band formed from tetrabutylammonium hydroxide by depro-
tonation. This imply that highly basic Fꢀ causes the deprotonation
of 5 (Fig. 11), leading to a red-shift in the absorbance spectra,
making it an acidebase reaction, and so the association constant
(Ka) cannot be calculated.16,17
Figure 9. Changes in UVevis spectra of 5 (50
(0e10 equiv) in CH3CN.
m
M) upon successive addition of CH3CO2ꢀ
subunit of 5. This intermolecular hydrogen bond formation with the
anion can disturb the intramolecular hydrogen bond more strongly
than 4, leading to the destruction of the molecular rigidity so there
is a larger blue shift and more decrease in the absorbance on ace-
tate binding as compared to 4 (Table 1).14a
The receptor 5 undergoes ESIPTand produces a normal emission
at 390 nm and tautomer emission at 553 nm when excited at
336 nm (Fig. 10). On slow addition of CH3COꢀ2 , a new peak is formed
at 473 nm that buries both the normal and tautomer emissions.
Figure 10. Changes in fluorescence spectra of 5 (50
CH3COꢀ2 (0e10 equiv) in CH3CN (lex¼336 nm).
mM) upon successive addition of

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A. Helal, H.-S. Kim / Tetrahedron 66 (2010) 7097e7103
EtOAc. The organic layer was dried over anhydrous sodium sulfate
and concentrated. The residue was purified using SiO2 column
chromatography (EtOAcehexane, 1:2) to give 1 in 82% yield. Mp:
153e155 ꢃC (CH2Cl2ehexane); 1H NMR
d
7.48 (d, J¼7.2 Hz, 1H), 7.59
(t, J¼7.2 Hz, 1H), 7.72 (t, J¼4.0 Hz, 1H), 7.99 (d, J¼8.0 Hz, 1H), 9.92 (s,
1H, NH), 10.21 (s, 1H, NH); 13C NMR
124.4, 128.5, 129.9, 133.8,
d
138.8, 145.6, 198.9. Anal. Calcd for C7H6N2O2S: C, 46.14; H, 3.32; N,
15.38; S, 17.60; found: C, 46.26; H, 3.32; N, 15.27; S, 17.62.
4.1.2. 2-(20-Nitrophenyl)-4-phenylthiazole (2). A mixture of
1
(182 mg, 0.99 mmol) and 2-bromoacetophenone (244 mg, 1.2 mmol)
in ethanol (15 mL) was refluxed for 2 h. The solvent was removed
under vacuoand the residuewas washed with water, neutralized with
1 N NaOH solution, and extracted with EtOAc. The organic layer was
dried over anhydrous sodium sulfate and concentrated. The residue
was purified using SiO2 column chromatography (EtOAcehexane,1:9)
to give 2 in 95% yield. Mp: 66e67 ꢃC (CH2Cl2ehexane); 1H NMR
(CDCl3)
d
7.36 (t, J¼6.4 Hz,1H), 7.43 (d, J¼7.6 Hz, 2H), 7.53 (t, J¼7.6 Hz,
2H), 7.58 (s,1H), 7.78e7.73 (m, 3H), 7.93 (d, J¼7.2 Hz); 13C NMR (CDCl3)
Figure 11. UVevis spectra of 5 (50 mM) upon addition of 10 equiv of various anions in
CH3CN.
d
114.6,124.1,126.4,127.0,128.5,128.8,130.4,131.0,132.0,133.8,148.7,
156.5, 161.6. Anal. Calcd for C15H10N2O2S: C, 63.81; H, 3.57; N, 9.92; S,
11.36; found: C, 63.64; H, 3.51; N, 9.87; S, 11.42.
3. Conclusion
4.1.3. 1-Phenyl-3-(2-(4-phenylthiazol-2-yl)phenyl)urea (4). A solu-
tion of 2 (146 mg, 0.80 mmol) in methanol (10 mL) was hydrogenated
with 10% Pd/C under hydrogen atmosphere for 6 h. After the catalyst
was removed by filtration through the Celite pad, the filtrate was
concentrated and dried to give crude amino product 3. Without fur-
ther purification, to the solution of the crude amine (100 mg,
0.39 mmol)indioxane(15 mL)phenyl isocyanate(72 mg, 0.60 mmol)
was added and refluxed for 12 h. The solid precipitated on cooling the
reaction mixture was filtered and dried to give 4 in a 90% yield. Mp:
In this study, we have developed a chemosensor that can se-
lectively detect acetate anion from anions with similar basicity and
surface charge density such as Fꢀ and H2PO4ꢀ. An investigation of
the binding patterns of chemosensors by a series of structurally
different anions provided this very important information that the
chemosensor preferred structure matching anions, such as acetate.
We also tuned the acidity of the NeH in the urea moiety by in-
troducing an electron withdrawing group that not only increased
the fluorescence, but also enhanced the binding ability.
220e222 ꢃC (DMSO); 1H NMR
d
6.99 (t, J¼7.4 Hz,1H), 7.17 (t, J¼7.6 Hz,
1H), 7.31 (t, J¼8.0 Hz, 2H), 7.38 (t, J¼7.0 Hz, 1H), 7.46 (t, J¼7.6 Hz, 3H),
7.51 (d, J¼8.0 Hz, 2H), 7.90 (d, J¼7.6 Hz,1H), 8.10 (d, J¼8.0 Hz, 3H), 8.24
4. Experimental section
4.1. General methods
(s,1H), 9.57 (s,1H, NH),10.41 (s,1H, NH); 13C NMR
d 115.3,119.4,119.5,
121.6, 122.0, 123.0, 123.6, 127.3, 129.3, 129.7, 129.9, 131.5, 134.3, 137.9,
140.8, 153.8, 155.4, 167.8. Anal. Calcd for C22H17N3OS: C, 71.14; H, 4.61;
N, 11.31; S, 8.63; found C, 70.78; H, 4.75; N, 10.95; S, 8.30.
Melting points were determined using a Standford Research
System model Opti Melt- MPA100 melting point apparatus and are
uncorrected. 1H and 13C NMR spectra were recorded on a Bruker
AM-400 FT-NMR spectrometer using Me4Si as the internal stan-
dard. Unless otherwise specified, DMSO-d6 was used as NMR sol-
vent. UVevis absorption spectra were determined on a Shimadzu
UV-1650PC spectrophotometer. Fluorescence spectra were mea-
sured on a Shimadzu RF-5301 fluorescence spectrometer equipped
with a xenon discharge lamp, 1 cm quartz cells. All of the mea-
surements were carried out at 298 K. 1H NMR titrations were run
with a Bruker AM-400 FT-NMR spectrometer (400 MHz) at con-
centration levels of 4.5 mM concentrations, with aliquots of
a 45 mM (nBu)4NþXꢀ salts solution added. Association constants
were calculated from fluorescence titration according to the liter-
ature procedure.15 Analytical grade acetonitrile was purchased
from Merck and dried with calcium hydride. All other materials
used for synthesis were purchased from Aldrich Chemical Co. and
used without further purification. The solutions of anions were
prepared from their tetrabutylammonium salts of analytical grade,
and then subsequently diluted to prepare working solutions.
Structure of 4 with acetate was optimized using density functional
theory with B3-LYP functional at the 6-31G (d,p) basis set.18
4.1.4. 1-Trifluoromethylphenyl-3-(2-(4-phenylthiazol-2-yl)phenyl)
urea (5). 4-(Trifluoromethyl)phenyl isocyanate (90 mg, 0.48 mmol)
was added to the solution of the crude amine 3 (100 mg,
0.39 mmol) in dioxane (15 mL) and refluxed for 2 h. The solid
precipitated on cooling the reaction mixture was filtered and dried
to give 5 in 93% yield. Mp: 250e251 ꢃC (DMSO); 1H NMR
d 7.21 (t,
J¼6.0 Hz, 1H), 7.38 (t, J¼8.0 Hz, 1H), 7.46 (t, J¼8.0 Hz, 3H), 7.68 (dt,
J¼8.5, 12.0 Hz, 4H), 7.92 (d, J¼8.0 Hz, 1H), 8.09 (m, 3H), 8.25 (s, 1H),
8.10 (d, J¼8.0 Hz, 3H), 10.00 (s, 1H, NH), 10.52 (s, 1H, NH); 13C NMR
d
114.9, 118.4, 121.3, 122.1, 122.6, 123.5, 126.2, 126.4, 126.7, 128.7,
129.1, 129.3, 130.9, 133.7, 136.8, 143.9, 152.9, 154.8, 167.0. Anal. Calcd
for C23H16F3N3OS: C, 62.86; H, 3.67; N, 9.56; S, 7.30; found C, 62.39;
H, 3.61; N, 9.41; S,7.42.
Acknowledgement
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded by
the Ministry of Education, Science and Technology (20100010070).
4.1.1. 2-Nitrobenzthioamide (1). Lawesson’s reagent (608 mg,
1.5 mmol) was added to a solution of 2-nitrobenzamide (200 mg,
1.23 mmol) in dry THF (15 mL) and refluxed for 1 h. The reaction
mixture was evaporated in vacuo. The residue was then washed
with saturated solution of sodium bicarbonate and extracted with
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.07.007.

A. Helal, H.-S. Kim / Tetrahedron 66 (2010) 7097e7103
7103
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