New efficient synthesis of trisubstituted imidazolidine-2-thiones and thiazoles via vinyliminophosphoranes

Article abstract of DOI:10.1016/j.tet.2012.07.002

Isothiocyanate 6, obtained from vinyliminophosphorane 4 with CS ₂, reacted with various aliphatic primary amines to afford directly the 1,4,5-trisubstituted imidazolidine-2-thiones 5. However, the reaction of isothiocyanate 6 with aliphatic sec

Full text of DOI:10.1016/j.tet.2012.07.002

Tetrahedron 68 (2012) 7984e7990
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New efficient synthesis of trisubstituted imidazolidine-2-thiones and thiazoles via
vinyliminophosphoranes
,
,
*
Hai Xie a b, Jian-Chao Liu a, Lei Wu a, Ming-Wu Ding a
a Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan 430079, PR China
b College of Chemistry & Chemical Engineering, Shanxi Datong University, Shanxi 037009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Isothiocyanate 6, obtained from vinyliminophosphorane 4 with CS2, reacted with various aliphatic pri-
mary amines to afford directly the 1,4,5-trisubstituted imidazolidine-2-thiones 5. However, the reaction
of isothiocyanate 6 with aliphatic secondary amines provided 2,4,5-trisubstituted thiazoles 10 in good
yields.
Received 23 February 2012
Received in revised form 25 June 2012
Accepted 3 July 2012
Available online 10 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The aza-Wittig reactions of iminophosphoranes have received
increasedattentioninviewoftheirutilityinthesynthesisofnitrogen-
Imidazole and its derivatives are one of the most important
classes of heterocyclic compounds. Imidazolidine-2-thiones are
among them of constant interest owing to the occurrence of this
ring system in various biologically important compounds.1 Some
derivatives of this ring system have shown interesting biological
activities and pharmacological properties, such as anti-
hyperthyroid,2 antitumor,3 antibacterial,4 antiinflammatory,5 anti-
arthritic6 and anticytokine activities.7 Others were used as
containing heterocyclic compounds.19 Owning to its good stability,
vinyliminophosphorane may be considered to be an equivalent of the
unstable enamine. The reactions of vinyliminophosphoranes with
carbon disulfide produced otherwise not easily accessible vinyl-
isothiocyanates, which reacted further with various nucleophiles
through nucleophilic addition/intramolecular cyclization to afford
some heterocycles, such as 2-thioxo-imidazolidiones,20 imidazo[2,1-
b]-1,3,4-thiadiazol-5(6H)-ones21 and aplysinopsin-type alkaloids.22
Recently we have been interested in the synthesis of various het-
erocycles via aza-Wittig reaction, with the aim of evaluating their
biological activities.23 Hereinwewish to report a newapproach tothe
synthesis of trisubstituted imidazolidine-2-thiones and thiazole
starting from vinyliminophosphorane in a one-pot fashion.
cholesterol acyltransferase (ACAT) inhibitor,8 dopamine
ylase inhibitors,9 -amylase inhibitors.10 In ad-
-glucosidase and
b-hydrox-
a
a
dition, some imidazolidine-2-thiones are applied for promoting the
enantioselective FriedeleCrafts alkylation as organocatalysts.11
Imidazolidine-2-thiones are generally prepared by condensation
of
They could be also prepared by cyclization of some acylthioureas
with
-bromo ketones,13 or by the addition reaction between amine
a
-hydroxy ketones with ammonium thiocyanate and thiourea.12
2. Results and discussion
a
and isothiocyanates.14 Thiazole skeletons are also one of the most
important and central building blocks in medicinal and pharma-
ceutical chemistry. Many thiazoles are found in a wide variety of
biologically active substances, which show antioxidant, antitumor,
antiinflammatory, antifungal and antibacterial activities.15e18 Thi-
azole ring is also a structural motif of natural compounds, such as
vitamin B1 (thiamine), penicillin and carboxylase. Although many
synthetic methods have been reported for imidazolidine-2-thiones
and thiazoles, new method for preparing of the two heterocycles is
still desirable.
Vinyl azide 3 was prepared either from the condensation of the
a
-azidoketone 1 with aromatic aldehydes in the presence of
piperidinium acetate,24 or from the reaction of dibromide 2 with
sodium azide.25 Further Staudinger reaction of the azide 3 with
triphenylphosphine (R¼Ph) or methyldiphenylphosphine (R¼Me)
at room temperature produced vinyliminophosphorane 4 in good
yields (Scheme 1).
Initially, we selected the triphenyliminophosphorane 4a
(R¼Ph), CS2 and methylamine as the reactants (Scheme 2). After the
triphenyliminophosphorane 4a and excess CS2 was stirred in ace-
tonitrile at 40 ꢀC for 24 h, methylamine was added and the mixture
was stirred at room temperature. Finally imidazolidine-2-thione 5a
was directly obtained from the reaction mixture but in low yield
(12%), which implies the low reactivity of triphenyliminophos-
phorane 4a toward CS2. However as more reactive methyldiphenyl
* Corresponding author. Tel.: þ86 27 63158845; fax: þ86 27 67862041; e-mail
address: ding5229@yahoo.com.cn (M.-W. Ding).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.002

H. Xie et al. / Tetrahedron 68 (2012) 7984e7990
7985
Table 1
O
Preparation of imidazolidine-2-thiones 5 from methyldiphenyl iminophosphorane 4
(R¼Me)
R2CHO
NaN3
N3
R1
O
O
1
R1
R2
R3
Yielda (%)
Ph2PR
R2
R1
N=PPh2R
4
R2
R1
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-ClC6H4
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-ClC6H4
4-FC6H4
4-CH3C6H4
4-CH3OC6H4
4-CF3C6H4
Ph
Ph
Ph
Et
Et
Ph
Ph
Me
Et
79
82
80
80
84
88
86
84
87
83
84
86
82
52
46
0
N3
3
Br
O
R2
R1
n-Pr
n-Bu
i-Pr
c-C6H11
PhCH2
n-Pr
Et
Et
Et
Et
n-Pr
PhCH2
c-C6H11
Et
n-Pr
Ph
Br
2
Scheme 1. Preparation of vinyliminophosphoranes 4.
O
O
CS2
Ph
Ph
Ph
S
Ph
Ph
N=PPh2R
N C
4a,b
0
0
0
HO
Me
Ph
Ph
a
Isolated yields based on iminophosphorane 4 (R¼Me).
MeNH2
Me
N
HN
5a
S
singlet. The signals of NCH2Ph appear at 5.05 and 4.27 ppm as two
doublets. The signals attributable to the AreHs are found at
7.43e7.16 ppm as multiplets. The 13C NMR spectrum data in 5g
showed the signals of quaternary COH carbon at 93.8 ppm but no
signals of C]O carbon. The alkenyl carbon absorbs at 102.1 ppm.
The MS spectrum of 5g shows molecular ion peak at m/z 372 with
100% abundance. The formation of the imidazolidine-2-thione 5
can be rationalized in terms of an initial aza-Wittig reaction be-
tween iminophosphorane 4 and CS2 to give the vinylisothiocyanate
6 (Scheme 3). Further reaction of 6 with amine produces thiourea 7
as intermediate, then an intramolecular nucleophilic addition of
the thiourea to carbonyl group takes place to give the imidazoli-
dine-2-thione 5. The failure in preparation of compounds 5p and 5q
might be due to polymerization of the intermediate vinyl-
isothiocyanate 6p and 6q, in which R2 is a relatively electrodonating
ethyl group. In these cases, vinylisothiocyanate 6p and 6q might
produce but polymerized quickly and were not detected by TLC
detection.
Scheme 2. Preparation of compounds 5a.
iminophosphorane 4b (R¼Me) was used to react with CS2, the re-
action took place smoothly at 40 ꢀC for only 4 h and the imidazo-
lidine-2-thione 5a was obtained in 79% yield.
With the optimized condition, various methyldiphenyl imino-
phosphorane 4 (R¼Me), CS2 and aliphatic primary amine were
employed for the reaction (Scheme 3). The reaction yields are found
to relate with R1, R2 and R3 substituents (Table 1). When R1 and R2
O
O
R3NH2
CS2
R2
R1
R2
R1
N C S
N=PPh2Me
It is interesting to note that thiazoles 10 were obtained instead
when isothiocyanates 6 were allowed to react with aliphatic sec-
ondary amines (Scheme 4, Table 2). The reaction yields are also
found to relate with R1 and R2 substituents (Table 2). When R1 and
R2 are aryl groups, the reactions occurred smoothly to produce the
thiazoles 10 in 80e90% yields (10aei). However, moderate yields
(40e55%) were obtained as R1 is changed to an alkyl group (10j and
6
4
O
HO
R1
R2
R1
NHR3
R2
R3
N
HN
HN
S
S
5
7
Scheme 3. Preparation of imidazolidine-2-thiones 5.
O
O
R4R5NH
R2
S
R1
R2
R1
NH
are aryl groups, the reactions proceeded smoothly to give the
corresponding 1,4,5-trisubstituted imidazolidine-2-thione in
N C S
5
NR4R5
8
79e88% yields (5aem). However, moderate yields (46e52%) were
obtained as R1 is changed to an alkyl group (5n and 5o), and no
product was got in case that R2 is an alkyl group (5p and 5q). Finally,
when aromatic primary amine (R3¼aryl, 5r and 5s) was used, no
imidazolidine-2-thiones 5 was obtained probably due to the low
reactivity of the aromatic primary amine. The structure of 1H-im-
idazole-2(3H)-thiones 5 was confirmed by their spectrum data. For
example, the 1H NMR spectrum of 5g shows two singlets at 8.25
and 3.24 ppm due to the NH and OH, respectively, which can be
exchanged by D2O. The signals of ]CH are found at 5.46 ppm as
6
R2
O
O
R1
-H2
R1
N
S
N
R2
NR4R5
S
R4R5N
10
9
Scheme 4. Preparation of thiazoles 10.

7986
H. Xie et al. / Tetrahedron 68 (2012) 7984e7990
Table 2
Preparation of thiazoles 10
R1
R2
NR4R5
NEt2
Yielda (%)
10a
10b
Ph
Ph
Ph
Ph
88
85
N
10c
Ph
Ph
89
N
O
10d
10e
10f
Ph
Ph
Ph
4-FC6H4
81
80
86
N
O
4-CH3C6H4
4-CH3OC6H4
N(n-Pr)2
N
10g
10h
10i
Ph
4-CF3C6H4
4-CF3C6H4
Ph
90
86
84
N
Ph
N(i-Pr)2
4-ClC6H4
N
N
Fig. 1. ORTEP diagram of the crystal structure of 10b (30% thermal ellipsoids).
10j
Me
Ph
55
good yields, and easily accessible starting material, we think that
this new synthetic approach discussed here has potential in the
synthesis of many biologically and pharmaceutically active imida-
zolidine-2-thione and thiazole derivatives.
10k
10l
10m
Me
Ph
Ph
Ph
Et
Ph
N(i-Pr)2
NEt2
NPh2
40
0
0
a
Isolated yields based on iminophosphorane 4 (R¼Me).
4. Experimental
4.1. General
10k). No product was created in case that R2 is an alkyl group (10l)
or aromatic primary amines (R4, R5¼aryl) were utilized (10m). It is
deduced that higher reaction temperature is needed for aromatic
amine, but the isothiocyanate intermediate 6 might be unstable
under higher temperature. The structure of thiazoles 10 was con-
firmed by their spectrum data. For example, the 1H NMR spectrum
of 10a shows quartet at 3.51 and triplet at 1.27 ppm due to the
NCH2CH3, respectively. The signals attributable to the AreHs are
found at 8.00e7.17 ppm as multiplet. The 13C NMR spectrum data in
10a showed the signals of C]O carbon at 191.1 ppm. The MS
spectrum of 10a shows molecular ion peak at m/z 336 with 93%
abundance. Furthermore a single crystal of thiazole 10b was
obtained from the CH2Cl2 solution of 10b, and X-ray structure
analysis verified the proposed structure (Fig. 1). The formation of
thiazoles 10 can be rationalized in terms of an addition reaction
between isothiocyanates 6 and aliphatic secondary amines to give
thiourea intermediate 8. Further intramolecular Michael addition
reaction (S-attack) takes place to produce dihydrothiazole in-
termediate 9, which undergoes dehydrogenating aromatization to
give the thiazole 10 by air oxidation under the heating condition.
The above one-pot reaction provides a new efficient synthesis of
thiazoles under mild reaction condition. The reasons for the above
different selectivity are not yet very clear, however, it is deduced
that the intermediate dihydrothiazole 9 might be stable sufficiently
and easier to form to produce thiazole 10 after subsequent dehy-
drogenating aromatization.
Melting points were determined using a X-4 model apparatus
and were uncorrected. MS were measured on a Finnigan Trace MS
spectrometer. IR were recorded on a PE-983 infrared spectrometer
as KBr pellets with absorption in cmꢁ1. NMR were recorded in
CDCl3 or DMSO-d6 on a Varian Mercury 600 spectrometer and
resonances relative to TMS. Elementary analyses were taken on
a Vario EL III elementary analysis instrument. The X-ray diffraction
data were collected on a Bruker SMART AXS CCD diffractometer,
MoKa
, 2
q
¼1.86e27.50ꢀ.
4.2. Synthesis of imidazolidine-2-thione 5
4.2.1. 4-Benzylidene-5-hydroxy-1-methyl-5-phenyl imidazolidine-2-
thione (5a) A solution of methyldiphenylphosphine (0.20 g,
1 mmol) in dry CH2Cl2 (5 mL) was added dropwise to a well-stirred
solution of vinyl azides 3a (Ar1¼Ar2¼Ph, 0.25 g, 1 mmol) in CH2Cl2
(5 mL) at room temperature. After the stirring was continued for
2 h, the solvent was evaporated under reduced pressure and the
residue was added dry CH3CN (5 mL) and excess carbon disulfide
(5 mL). After the reaction mixture was stirred for 4 h at 40 ꢀC, the
solvent was removed under reduced pressure to give iso-
thiocyanate 6, which was used directly without further purification.
To a solution of crude 6 in methylene chloride (10 mL) was added
aqueous methylamine solution (0.10 g, 40%, 1.3 mmol). The mixture
was stirred for 6e7 h at room temperature and the solvent was
removed under reduced pressure, the residue was recrystallized
from methylene chloride/petroleum ether to give imidazolidine-2-
thione 5a as white solid (0.23 g, 79%). Mp: 199e200 ꢀC. 1H NMR
3. Conclusion
We have developed an efficient one-pot synthesis of tri-
(DMSO-d6, 600 MHz):
5.25 (s, 1H, ]CH), 3.35 (s, 1H, OH), 2.80 (s, 3H, CH3). 13C NMR
(DMSO-d6, 150 MHz): 178.7, 142.2, 140.9, 134.7, 128.6, 128.4, 127.8,
126.0, 125.2, 101.9, 93.1, 27.9. MS m/z (%): 296 (Mþ, 100), 279 (34),
d 10.64 (s, 1H, NH), 7.50e7.12 (m, 10H, AreH),
substituted imidazolidine-2-thiones
5 and thiazoles 10 from
vinyliminophosphoranes 3 via different cyclization reaction. Due to
the convenient practical procedure, the mild reaction condition, the
d

H. Xie et al. / Tetrahedron 68 (2012) 7984e7990
7987
219 (50), 118 (50), 91 (27). IR (KBr):
n
¼3447, 3190, 1503, 1429, 1264,
25.8, 25.0. MS: m/z (%) 364 (Mþ, 100), 331 (26), 259 (23), 205 (18),
1101, 1051 cmꢁ1. Anal. Calcd for C17H16N2OS: C, 68.89; H, 5.44; N,
9.45; S, 10.82. Found: C, 68.97; H, 5.29; N, 9.61; S, 10.73.
118 (37), 105 (59). IR (KBr):
n¼3345, 2928, 1483, 1416, 1239, 1121,
1062 cmꢁ1. Anal. Calcd for C22H24N2OS: C, 72.49; H, 6.64; N, 7.69; S,
8.80. Found: C, 72.71; H, 6.78; N, 7.77; S, 8.59.
4.2.2. 4-Benzylidene-1-ethyl-5-hydroxy-5-phenyl imidazolidine-2-
thione (5b) Operation as above with ethylamine solution (0.09 g,
1.3 mmol), compound 5b (0.25 g, 82%) was also isolated as white
4.2.7. 1-Benzyl-4-benzylideney-5-hydroxy-5-phenyl imidazolidine-
2-thione (5g) Operation as above with benzylamine (0.14 g,
1.3 mmol), compound 5g (0.32 g, 86%) was also isolated as white
solid. Mp: 187e189 ꢀC. 1H NMR (CDCl3, 600 MHz):
d 8.10 (s,1H, NH),
7.51e7.19 (m, 10H, AreH), 5.50 (s, 1H, ]CH), 3.73e3.67 (m, 1H,
NCH), 3.50 (s, 1H, OH), 3.33e3.27 (m, 1H, NCH),1.08 (t, J¼7.2 Hz, 3H,
solid. Mp: 182e184 ꢀC. 1H NMR (CDCl3, 600 MHz):
d 8.25 (s,1H, NH),
7.43e7.16 (m, 15H, AreH), 5.46 (s, 1H, ]CH), 5.05 (d, J¼15.0 Hz, 1H,
CH3). 13C NMR (DMSO-d6, 150 MHz):
d 178.1, 142.5, 141.6, 134.8,
PhCHN), 4.27 (d, J¼15.6 Hz, 1H, PhCHN), 3.24 (s, 1H, OH). 13C NMR
128.4, 128.3, 127.8, 126.0, 125.5, 101.6, 93.5, 36.9, 14.2. MS: m/z (%):
(DMSO-d6, 150 MHz): d 179.6, 142.2, 142.1, 141.1, 141.0, 137.9, 134.7,
310 (Mþ, 100), 233 (26), 205 (26), 118 (37), 105 (51). IR (KBr):
128.4, 128.3, 127.9, 127.8, 127.6, 126.4, 126.1, 125.6, 102.1, 93.8, 45.3.
n
¼3515, 3184, 1494, 1431, 1245, 1115, 1055 cmꢁ1. Anal. Calcd for
MS: m/z (%) 372 (Mþ, 100), 339 (26), 267 (23), 178 (18), 118 (37), 105
C18H18N2OS: C, 69.65; H, 5.84; N, 9.02; S, 10.33. Found: C, 69.43; H,
5.96; N, 9.21; S, 10.19.
(59). IR (KBr):
n
¼3400, 3147, 1487, 1412, 1231, 1137, 1059 cmꢁ1. Anal.
Calcd for C23H20N2OS: C, 74.16; H, 5.41; N, 7.52; S, 8.61. Found: C,
74.11; H, 5.53; N, 7.29; S, 8.72.
4.2.3. 4-Benzylidene-5-hydroxy-5-phenyl-1-propyl imidazolidine-2-
thione (5c) Operation as above with n-propylamine (0.08 g,
1.3 mmol), compound 5c (0.25 g, 80%) was also isolated as white
4.2.8. 4-(4-Chlorobenzylidene)-5-hydroxy-5-phenyl-1-propylimidazoli-
dine-2-thione (5h) Operation as above with n-propylamine (0.08 g,
1.3 mmol), compound 5h (0.30 g, 84%) was also isolated as white
solid. Mp: 134e136 ꢀC. 1H NMR (CDCl3, 600 MHz):
d 8.12 (s, 1H,
NH), 7.50e7.19 (m, 10H, AreH), 5.50 (s, 1H, ]CH), 3.62e3.57
(m, 1H, NCH), 3.35 (s, 1H, OH), 3.13e3.08 (m, 1H, NCH), 1.65e1.44
(m, 2H, CH2), 0.78 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3,
solid. Mp: 180e181 ꢀC. 1H NMR (CDCl3, 600 MHz):
d 8.22 (s, 1H, NH),
7.48e7.13 (m, 9H, AreH), 5.43 (s, 1H, ]CH), 3.71 (s, 1H, OH),
3.58e3.54 (m, 1H, NCH), 3.12e3.07 (m, 1H, NCH), 1.62e1.43 (m, 2H,
150 MHz):
d
178.0, 141.4, 139.1, 134.7, 129.0, 128.5, 127.4, 127.1,
CH2), 0.76 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
d 177.9,
125.9, 103.3, 94.1, 45.3, 22.5, 11.3. MS: m/z (%): 324 (Mþ, 100), 247
141.8, 138.9, 133.1, 132.6, 129.1, 129.0, 128.6, 125.8, 102.1, 94.1, 44.9,
(15), 219 (22), 160 (12), 118 (32), 105 (70). IR (KBr):
n
¼3446, 3146,
22.2, 11.4. MS: m/z (%) 358 (Mþ, 100), 253 (27), 247 (19), 152 (38), 125
1565, 1431, 1232, 1120, 1070 cmꢁ1. Anal. Calcd for C19H20N2OS: C,
70.34; H, 6.21; N, 8.63; S, 9.88. Found: C, 70.06; H, 6.33; N, 8.82;
S, 9.69.
(18), 105 (85). IR (KBr):
n
¼3442, 3129, 1499, 1417, 1240, 1118,
1063 cmꢁ1. Anal. Calcd for C19H19ClN2OS: C, 63.59; H, 5.34; N, 7.81; S,
8.93. Found: C, 63.69; H, 5.06; N, 7.70; S, 8.95.
4.2.4. 4-Benzylidene-1-butyl-5-hydroxy-5-phenyl imidazolidine-2-
thione (5d) Operation as above with n-butylamine (0.10 g,
1.3 mmol), compound 5d (0.27 g, 80%) was also isolated as white
4.2.9. 1-Ethyl-4-(4-fluorobenzylidene)-5-hydroxy-5-phenylimidazolid-
ine-2-thione (5i) Operation as above with ethylamine solution
(0.09 g, 1.3 mmol), compound 5i (0.28 g, 87%) was also isolated as
solid. Mp: 146e148 ꢀC. 1H NMR (CDCl3, 600 MHz):
d
8.12 (s,1H, NH),
white solid. Mp: 178e180 ꢀC.1H NMR (CDCl3, 600 MHz):
d 8.15 (s,1H,
7.50e7.16 (m, 10H, AreH), 5.50 (s, 1H, ]CH), 3.67e3.62 (m, 1H,
NCH), 3.27 (s, 1H, OH), 3.17e3.12 (m, 1H, NCH), 1.60e1.19 (m, 4H,
CH2CH2), 0.82 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz):
NH), 7.50e7.00 (m, 9H, AreH), 5.45 (s, 1H, ]CH), 3.71e3.65 (m, 1H,
NCH), 3.57 (s, 1H, OH), 3.33e3.27 (m, 1H, NCH), 1.07 (t, J¼7.2 Hz, 3H,
CH3). 13C NMR (DMSO-d6, 150 MHz):
d 178.1, 161.2, 159.6, 142.3, 141.5,
d
177.9, 141.4, 139.0, 134.6, 129.0, 128.9, 128.5, 127.4, 127.3, 127.0,
131.3,130.8,129.8,128.4,125.5,115.2,115.1,100.5, 93.5, 36.9,14.2. MS:
125.9, 103.3, 103.2, 94.2, 43.1, 31.0, 20.2, 13.6. MS: m/z (%) 338 (Mþ,
m/z (%) 328 (Mþ, 100), 223 (15), 213 (19), 136 (30), 105 (56). IR (KBr):
100), 233 (22), 194 (12), 149 (25), 118 (32), 105 (56). IR (KBr):
n
¼3322, 3221, 1509, 1424, 1246, 1117, 1058 cmꢁ1. Anal. Calcd for
n
¼3439, 3141, 1502, 1413, 1257, 1121, 1070 cmꢁ1. Anal. Calcd for
C18H17FN2OS: C, 65.83; H, 5.22; N, 8.53; S, 9.76. Found: C, 65.52; H,
5.35; N, 8.74; S, 9.59.
C20H22N2OS: C, 70.97; H, 6.55; N, 8.28, S, 9.47. Found: C, 71.06; H,
6.38; N, 8.44; S, 9.61.
4.2.10. 1-Ethyl-5-hydroxy-4-(4-methylbenzylidene)-5-phenylimidaz-
olidine-2-thione (5j) Operation as above with ethylamine aqueous
solution (0.09 g, 1.3 mmol), compound 5j (0.26 g, 83%) was also
isolated as white solid. Mp: 187e188 ꢀC. 1H NMR (CDCl3, 600 MHz):
4.2.5. 4-Benzylidene-5-hydroxy-1-isopropyl-5-phenyl imidazolidine-
2-thione (5e) Operation as above with isopropylamine (0.08 g,
1.3 mmol), compound 5e (0.27 g, 84%) was also isolated as white
solid. Mp: 183e185 ꢀC. 1H NMR (CDCl3, 600 MHz):
d
8.03 (s,1H, NH),
d 8.10 (s, 1H, NH), 7.50e7.08 (m, 9H, AreH), 5.46 (s, 1H, ]CH),
7.54e7.16 (m, 10H, AreH), 5.37 (s, 1H, ]CH), 4.11e4.07 (m, 1H,
NCH), 3.21 (s, 1H, OH), 1.35 (d, J¼7.2 Hz, 3H, CH3), 1.32 (d, J¼7.2 Hz,
3.72e3.68 (m, 1H, NCH), 3.39 (s, 1H, OH), 3.31e3.28 (m, 1H, NCH),
2.32 (s, 3H, CH3), 1.08 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (DMSO-d6,
3H, CH3). 13C NMR (DMSO-d6, 150 MHz):
d
177.3, 142.9, 142.1, 134.9,
150 MHz): d 178.0, 141.6, 135.2, 131.9, 129.0, 128.4, 128.2, 127.9,
128.4, 128.3, 128.2, 127.8, 127.5, 125.9, 125.5, 125.3, 100.9, 94.4, 46.6,
127.8, 125.4, 101.7, 93.5, 36.9, 20.8, 14.2. MS: m/z (%) 324 (Mþ, 100),
20.3. MS: m/z (%) 324 (Mþ, 100), 291 (27), 219 (21), 195 (14), 118
307 (11), 233 (15), 219 (25), 132 (29), 105 (72). IR (KBr):
n
¼3377,
(39), 105 (66). IR (KBr):
n
¼3442, 3138, 1501, 1413, 1246, 1121,
3135, 1515, 1403, 1242, 1115, 1063 cmꢁ1. Anal. Calcd for C19H20N2OS:
C, 70.34; H, 6.21; N, 8.63; S, 9.88. Found: C, 70.47; H, 6.05; N, 8.47; S,
9.93.
1061 cmꢁ1. Anal. Calcd for C19H20N2OS: C, 70.34; H, 6.21; N, 8.63; S,
9.88. Found: C, 70.38; H, 6.34; N, 8.76; S, 9.97.
4.2.6. 4-Benzylideney-1-cyclohexyl-5-hydroxy-5-phenyl imidazoli-
dine-2-thione (5f) Operation as above with cyclohexylamine
(0.12 g, 1.3 mmol), compound 5f (0.27 g, 84%) was also isolated as
4.2.11. 1-Ethyl-5-hydroxy-4-(4-methoxybenzylidene)-5-phenylimida-
zolidine-2-thione(5k) Operation as above with ethylamine solution
(0.09 g, 1.3 mmol), compound 5k (0.28 g, 84%) was also isolated as
white solid. Mp: 184e185 ꢀC. 1H NMR (CDCl3, 600 MHz):
d
8.04 (s,
white solid. Mp: 165e166 ꢀC. 1H NMR (CDCl3, 600 MHz):
d 8.16
1H, NH), 7.53e7.16 (m, 10H, AreH), 5.36 (s, 1H, ]CH), 3.78 (s, 1H,
(s, 1H, NH), 7.50e6.84 (m, 9H, AreH), 5.42 (s, 1H, ]CH), 3.79 (s, 3H,
OCH3), 3.71e3.66 (m, 2H, NCH, and OH), 3.32e3.29 (m, 1H, NCH),
OH), 3.30e3.20 (m, 1H, NCH), 2.29e1.04 (m, 10H, (CH2)5). 13C NMR
(DMSO-d6, 150 MHz):
d
177.5, 142.8, 142.4, 142.4, 134.9, 128.3, 128.2,
1.06 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (DMSO-d6, 150 MHz):
d 177.9,
128.1, 127.8, 127.6, 125.8, 125.4, 100.8, 94.3, 55.2, 30.1, 29.7, 25.9,
157.5, 141.8, 140.6, 129.2, 128.4, 128.3, 127.4, 125.5, 113.8, 113.7,

7988
H. Xie et al. / Tetrahedron 68 (2012) 7984e7990
113.7, 101.6, 93.5, 55.0, 36.8, 14.3. MS: m/z (%) 340 (Mþ, 100), 323
residue was chromatographed on a silica gel column, eluting with
petroleum ether/ethyl acetate (6:1) to afford the thiazole 10a
(0.29 g, 88%) as yellow solid. Mp: 61e63 ꢀC. 1H NMR (CDCl3,
(26), 235 (19), 148 (24), 121 (53), 105 (75). IR (KBr):
n¼3317, 3197,
1513, 1408, 1252, 1113, 1053 cmꢁ1. Anal. Calcd for C19H20N2O2S: C,
67.03; H, 5.92; N, 8.23; S, 9.42. Found: C, 67.29; H, 5.68; N, 8.07; S,
9.47.
600 MHz):
d
7.99 (d, J¼7.8 Hz, 2H, AreH), 7.47e7.17 (m, 8H, AreH),
3.51 (q, J¼7.2 Hz, 4H, 2CH2), 1.26 (t, J¼7.2 Hz, 6H, 2CH3). 13C NMR
(CDCl3, 150 MHz):
d 191.1, 166.4, 144.5, 137.2, 132.7, 131.3, 130.3,
4.2.12. 1-Ethyl-5-hydroxy-5-phenyl-4-(4-trifluoro benzylidene)imi-
dazolidine-2-thione (5l) Operation as above with ethylamine so-
lution (0.09 g, 1.3 mmol), compound 5l (0.33 g, 86%) was also
isolated as white solid. Mp: 185e187 ꢀC. 1H NMR (CDCl3,
129.8, 128.8, 128.7, 128.5, 128.2, 127.8, 127.4, 45.3, 12.5. MS: m/z (%)
336 (Mþ, 93), 307 (39), 293 (66), 215 (29), 121 (24), 105 (100). IR
(KBr):
n
¼1663, 1547, 1448, 1330, 1218, 1103, 1075 cmꢁ1. Anal. Calcd
for C20H20N2OS: C, 71.40; H, 5.99; N, 8.33; S, 9.53. Found: C, 71.61;
H, 6.12; N, 8.21; S, 9.67.
600 MHz):
d 8.38 (s, 1H, NH), 7.57e7.30 (m, 9H, AreH), 5.49 (s, 1H,
]CH), 3.85 (s, 1H, OH), 3.68e3.63 (m, 1H, NCH), 3.33e3.27 (m, 1H,
NCH), 1.04 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (DMSO-d6, 150 MHz):
4.3.2. Phenyl(5-phenyl-2-(pyrrolidin-1-yl)thiazol-4-yl) methanone
(10b) Operation as above with pyrrolidine (0.12 g, 1.3 mmol),
compound 10b (0.28 g, 85%) was also isolated as yellow crystal. Mp:
d
178.3, 145.1, 141.2, 139.1, 128.5, 128.3, 126.0, 125.7, 125.5, 125.3,
125.1, 123.5, 99.8, 93.8, 37.0, 14.1. MS: m/z (%) 378 (Mþ, 100), 273
(28), 233 (25), 186 (28), 159 (13), 105 (66). IR (KBr):
n
¼3387, 3131,
123e124 ꢀC. 1H NMR (CDCl3, 600 MHz):
d
7.95 (d, J¼7.2 Hz, 2H,
AreH), 7.45e7.14 (m, 8H, AreH), 3.54e3.46 (m, 4H, 2CH2N),
2.08e2.02 (m, 4H, 2CH2). 13C NMR (CDCl3, 150 MHz):
191.2, 164.7,
1494, 1420, 1246, 1118, 1067 cmꢁ1. Anal. Calcd for C19H17F3N2OS: C,
60.31; H, 4.53; N, 7.40; S, 8.47. Found: C, 60.43; H, 4.77; N, 7.55; S,
8.66.
d
144.8, 136.9, 132.6, 131.3, 130.1, 129.5, 128.6, 128.1, 127.8, 127.3, 49.4,
25.5. MS: m/z (%) 334 (Mþ, 100), 305 (28), 279 (11), 263 (15), 121
4.2.13. 1-Benzyl-4-benzylidene-5-(4-chlorophenyl)-5-hydroxyimidaz-
olidine-2-thione (5m) Operation as above with benzylamine (0.14 g,
1.3 mmol), compound 5m (0.33 g, 82%) was also isolated as white
(19), 105 (44). IR (KBr):
n
¼1652, 1555, 1482, 1324, 1212, 1123,
1073 cmꢁ1. Anal. Calcd for C20H18N2OS: C, 71.83; H, 5.42; N, 8.38; S,
9.59. Found: C, 71.96; H, 5.59; N, 8.16; S, 9.39.
solid. Mp: 190e191 ꢀC. 1H NMR (CDCl3, 600 MHz):
d 8.27 (s, 1H, NH),
7.35e7.16 (m, 14H, AreH), 5.44 (s, 1H, ]CH), 4.96 (d, J¼15.0 Hz, 1H,
4.3.3. (2-Morpholino-5-phenylthiazol-4-yl)(phenyl) methanone (10c)
Operation as above with morpholine (0.11 g, 1.3 mmol), compound
10c (0.31 g, 89%) was also isolated as yellow solid. Mp: 161e163 ꢀC.
PhCHN), 4.37 (d, J¼15.6 Hz, 1H, PhCHN), 3.32 (s, 1H, OH). 13C NMR
(DMSO-d6, 150 MHz):
d 179.6, 141.8, 141.7, 140.0, 137.8, 134.6, 132.9,
128.3, 128.1, 128.0, 127.8, 127.7, 127.6, 126.4, 126.2, 102.3, 93.2, 45.1.
1H NMR (CDCl3, 600 MHz):
d
7.94 (d, J¼7.8 Hz, 2H, AreH), 7.48e7.21
(m, 8H, AreH), 3.83 (t, J¼4.8 Hz, 4H, 2CH2O), 3.52 (t, J¼4.8 Hz, 4H,
2CH2N). 13C NMR (CDCl3, 150 MHz):
190.7, 1168.4, 144.3, 137.0,
MS: m/z (%) 406 (Mþ, 50), 373 (11), 267 (43), 139 (47), 118 (25), 106
(41). IR (KBr):
n
¼3294, 3193, 1478, 1409, 1230, 1133, 1070 cmꢁ1. Anal.
d
Calcd for C23H19ClN2OS: C, 67.89; H, 4.71; N, 6.88; S, 7.88. Found: C,
68.03; H, 4.70; N, 6.69; S, 7.97.
132.8, 132.0, 130.9, 130.3, 129.0, 128.4, 127.9, 66.0, 48.3. MS: m/z (%)
350 (Mþ, 100), 305 (12), 293 (38), 215 (14), 121 (11), 105 (47). IR
(KBr):
n
¼1655,1511, 1451, 1326, 1214, 1116, 1071 cmꢁ1. Anal. Calcd for
4.2.14. 1-Benzyl-4-benzylidene-5-hydroxy-5-methyl imidazolidine-
2-thione (5n) Operation as above with benzylamine (0.14 g,
1.3 mmol), compound 5n (0.16 g, 52%) was also isolated as white
C20H18N2O2S: C, 68.55; H, 5.18; N, 7.99; S, 9.15. Found: C, 68.29; H,
5.39; N, 8.03; S, 9.01.
solid. Mp: 168e170 ꢀC. 1H NMR (CDCl3, 600 MHz):
d
8.12 (s,1H, NH),
4.3.4. (5-(4-Fluorophenyl)-2-morpholinothiazol-4-yl)(phenyl) meth-
anone (10d) Operation as above with morpholine (0.11 g,
1.3 mmol), compound 10d (0.29 g, 81%) was also isolated as yellow
7.43e7.26 (m, 10H, AreH), 5.77 (s, 1H, ]CH), 5.11 (d, J¼15.6 Hz, 1H,
PhCHN), 4.83 (d, J¼15.6 Hz, 1H, PhCHN), 2.79 (s, 1H, OH), 1.51 (s, 3H,
CH3). 13C NMR (DMSO-d6, 150 MHz):
d
179.1, 141.3, 138.8, 134.9,
solid. Mp: 119e120 ꢀC. 1H NMR (CDCl3, 600 MHz):
d 7.94
128.8, 128.3, 128.0, 127.9, 127.2, 127.1, 126.6, 125.9, 99.9, 91.0, 43.9,
(d, J¼7.2 Hz, 2H, AreH), 7.50e6.93 (m, 7H, AreH), 3.83 (t, J¼4.8 Hz,
27.2. MS: m/z (%) 310 (Mþ, 26), 292 (22), 201 (22), 91 (100). IR (KBr):
4H, 2CH2O), 3.51 (t, J¼4.8 Hz, 4H, 2CH2N). 13C NMR (CDCl3,
n
¼3442, 3197, 1502, 1414, 1237, 1124 cmꢁ1
.
Anal. Calcd for
150 MHz): d 190.3, 168.2, 163.2, 161.5, 144.4, 137.0, 132.9, 131.2,
C18H18N2OS: C, 69.65; H, 5.84; N, 9.02; S, 10.33. Found: C, 69.72; H,
5.93; N, 9.19; S, 10.06.
131.0, 130.9, 130.3, 128.0, 126.9, 115.5, 115.3, 66.0, 48.3. MS: m/z (%)
368 (Mþ, 100), 311 (33), 281 (14), 233 (19), 139 (14), 105 (50). IR
(KBr):
n
¼1654, 1536, 1448, 1325, 1233, 1120, 1072 cmꢁ1. Anal. Calcd
4.2.15. 4-Benzylidene-1-cyclohexyl-5-hydroxy-5-methyl imidazoli-
dine-2-thione (5o) Operation as above with cyclohexylamine
(0.13 g, 1.3 mmol), compound 5o (0.14 g, 46%) was also isolated as
light yellow solid. Mp: 165e167 ꢀC. 1H NMR (CDCl3, 600 MHz):
for C20H17FN2O2S: C, 65.20; H, 4.65; N, 7.60; S, 8.70. Found: C, 65.34;
H, 4.77; N, 7.56; S, 8.48.
4.3.5. (2-(Dipropylamino)-5-p-tolylthiazol-4-yl)(phenyl) methanone
(10e) Operation as above with dipropylamine (0.13 g, 1.3 mmol),
compound 10e (0.29 g, 81%) was also isolated as yellow solid. Mp:
d
7.94 (s, 1H, NH), 7.37e7.23 (m, 5H, AreH), 5.68 (s, 1H, ]CH),
3.94e3.84 (m, 1H, NCH), 2.84 (s, 1H, OH), 2.55e1.21 (m, 13H, (CH2)5,
CH3). 13C NMR (DMSO-d6, 150 MHz):
176.4, 141.7, 135.2, 128.3,
d
45e47 ꢀC. 1H NMR (CDCl3, 600 MHz):
d
8.01 (d, J¼7.8 Hz, 2H, AreH),
127.8, 125.6, 98.5, 92.5, 54.0, 29.7, 27.4, 26.0, 25.1. MS: m/z (%) 302
7.48e7.04 (m, 7H, AreH), 3.39 (t, J¼7.2 Hz, 4H, 2CH2N), 2.28 (s, 3H,
(Mþ, 34), 284 (100), 202 (85), 144 (32), 128 (18), 98 (23). IR (KBr):
CH3), 1.72e1.69 (m, 4H, 2CH2), 0.94 (t, J¼7.2 Hz, 6H, 2CH3). 13C NMR
n
¼3446, 3272, 1499, 1414, 1258, 1143, 1077 cmꢁ1. Anal. Calcd for
(CDCl3, 150 MHz): d 190.8, 166.7, 144.0, 137.4, 132.5, 130.6, 130.4,
C17H22N2OS: C, 67.51; H, 7.33; N, 9.26; S, 10.60. Found: C, 67.73; H,
7.47; N, 9.36; S, 10.41.
128.9,128.8,128.4,127.7,124.9, 53.0, 20.6,11.3. MS: m/z (%) 378 (Mþ,
51), 349 (13), 307 (100), 229 (27), 135 (10), 105 (53). IR (KBr):
n
¼1661, 1544, 1449, 1329, 1216, 1105, 1017 cmꢁ1. Anal. Calcd for
4.3. Synthesis of thiazoles 10
C23H26N2OS: C, 72.98; H, 6.92; N, 7.40; S, 8.47. Found: C, 73.11; H,
6.68; N, 7.53; S, 8.21.
4.3.1. (2-(Diethylamino)-5-phenylthiazol-4-yl)(phenyl) methanone
(10a) To a solution of vinylisothiocyanate 6 prepared above in
CH3CN (10 mL) was added diethylamine (0.10 g, 1.3 mmol). The
mixture was stirred for 3 h at room temperature and then refluxed
for 4 h. The solvent was removed under reduced pressure and the
4.3.6. (5-(4-Methoxyphenyl)-2-(pyrrolidin-1-yl)thiazol-4-yl)(phenyl)
methanone (10f) Operation as above with pyrrolidine (0.12 g,
1.3 mmol), compound 10f (0.31 g, 86%) was also isolated as yellow
solid. Mp: 118e120 ꢀC. 1H NMR (CDCl3, 600 MHz):
d 7.96

H. Xie et al. / Tetrahedron 68 (2012) 7984e7990
7989
(d, J¼7.8 Hz, 2H, AreH), 7.45e6.73 (m, 7H, AreH), 3.73 (s, 3H, CH3),
3.50 (t, J¼6.6 Hz, 4H, 2CH2N), 2.04 (t, J¼6.6 Hz, 4H, 2CH2). 13C NMR
67.51; H, 7.33; N, 9.26; S, 10.60. Found: C, 67.42; H, 7.47; N, 9.42; S,
10.79.
(CDCl3, 150 MHz):
d 191.0, 164.1, 158.8, 144.0, 137.1, 132.5, 130.2,
130.1, 130.0,127.7, 123.6,113.5, 54.9, 49.3, 25.4. MS: m/z (%) 364 (Mþ,
100), 335 (13), 293 (10), 182 (8), 151 (13), 105 (47). IR (KBr):
¼1650,
1550, 1460, 1326, 1210, 1113, 1072 cmꢁ1
Anal. Calcd for
5. Crystallographic material
n
.
Compound 10b: formula C20H18N2OS, yellow crystal. The crystal
ꢀ
C21H20N2O2S: C, 69.20; H, 5.53; N, 7.69; S, 8.80. Found: C, 69.02; H,
5.67; N, 7.82; S, 8.56.
is of monoclinic, space group P2(1)/c withꢀ a¼9.0184(8) A,
3
ꢀ
ꢀ
ꢀ
b¼16.7580(14) A, c¼11.5065(10) A, ¼103.702(1) , V¼1689.5(3) A ,
b
Z¼4, Dcalcd¼1.315 g/cm3, F(000)¼704,
m
¼0.200 mmꢁ1, R¼0.0568,
4.3.7. Phenyl(2-(piperidin-1-yl)-5-(4-(trifluoromethyl) phenyl)thia-
zol-4-yl)methanone (10g) Operation as above with piperidine
(0.11 g, 1.3 mmol), compound 10g (0.35 g, 90%) was also isolated as
and wR¼0.1274 for 3311 observed reflections with I>2
s(I0). Crys-
tallographic data for 10b have been deposited in the Cambridge
Crystallographic Data Center as supplementary publication num-
bers CCDC 867736. Copies of the data may be obtained, free of
charge, on application to CCDC,12 Union Road, Cambridge, CB2 1EZ,
UK (fax: þ44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
yellow oil. 1H NMR (CDCl3, 600 MHz):
d
8.00 (d, J¼7.2 Hz, 2H,
AreH), 7.50e7.36 (m, 7H, AreH), 3.49 (t, J¼5.4 Hz, 4H, 2CH2N),
1.68e1.56 (m, 6H, 3CH2). 13C NMR (CDCl3, 150 MHz):
190.7, 168.7,
d
145.6, 136.9, 135.0, 133.0, 130.3, 128.9, 128.4, 128.0, 125.2, 65.4, 49.4,
24.9. MS: m/z (%) 416 (Mþ, 100), 387 (31), 360 (28), 282 (11), 189
Acknowledgements
(18), 105 (92). IR (KBr):
n
¼1658, 1535, 1446, 1323, 1220, 1121,
1068 cmꢁ1. Anal. Calcd for C22H19F3N2OS: C, 63.45; H, 4.60; N, 6.73;
S, 7.70. Found: C, 63.59; H, 4.73; N, 6.57; S, 7.42.
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (No. 21032001,
21172085) and the self-determined research funds of CCNU from
the colleges’ basic research and operation of MOE (No.
CCNU11C01002).
4.3.8. (2-(Diisopropylamino)-5-(4-(trifluoromethyl)phenyl)thiazol-
4-yl)(phenyl)methanone (10h) Operation as above with diisopro-
pylamine (0.13 g, 1.3 mmol), compound 10h (0.37 g, 86%) was also
isolated as yellow solid. Mp: 52e54 ꢀC. 1H NMR (CDCl3, 600 MHz):
Supplementary data
d
8.04 (d, J¼8.4 Hz, 2H, AreH), 7.54e7.40 (m, 7H, AreH), 3.87e3.82
(m, 2H, 2CHN), 1.38 (d, J¼6.6 Hz, 12H, 4CH3). 13C NMR (CDCl3,
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.07.002.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
150 MHz): d 190.7, 165.1, 145.6, 137.4, 135.3, 132.9, 130.5, 130.1, 129.1,
128.4, 127.9, 127.2, 125.2, 124.7, 51.3, 51.0, 20.5, 19.7. MS: m/z (%) 432
(Mþ, 21), 416 (69), 387 (21), 232 (29), 117 (29), 105 (100). IR (KBr):
n
¼1664, 1535, 1451, 1322, 1199, 1124, 1069 cmꢁ1. Anal. Calcd for
C23H23F3N2OS: C, 63.87; H, 5.36; N, 6.48; S, 7.41. Found: C, 63.64; H,
5.35; N, 6.49; S, 7.58.
References and notes
1. Dawood, K. M.; Abdel-Wahab, B. F. Chem. Heterocycl. Comp. 2010, 46, 255.
2. Roy, G.; Das, D.; Mugesh, G. Inorg. Chim. Acta 2007, 360, 303.
3. Congiu, C.; Cocco, M. T.; Onnis, V. Bioorg. Med. Chem. Lett. 2008, 18, 989.
4. Saeed, A.; Batool, M. Med. Chem. Res. 2007, 16, 143.
5. Cherkofsky, S. C.; Sharpe, T. R. U.S. Patent 4,190,666, 1980.
6. Sharpe, T. R.; Cherkofsky, S. C.; Hewes, W. E.; Smith, D. H.; Gregory, W. A.;
Haber, S. B.; Leadbetter, M. R.; Whitney, J. G. J. Med. Chem. 1985, 28, 1188.
7. Laufer, S. A.; Wagner, G. K.; Kotschenreuther, D. A.; Albrecht, W. J. Med. Chem.
2003, 46, 3230.
4.3.9. (4-Chlorophenyl)(5-phenyl-2-(pyrrolidin-1-yl)thiazol-4-yl)
methanone (10i) Operation as above with pyrrolidine (0.12 g,
1.3 mmol), compound 10i (0.31 g, 84%) was also isolated as yellow
solid. Mp: 146e148 ꢀC. 1H NMR (CDCl3, 600 MHz):
d 7.92
(d, J¼8.4 Hz, 2H, AreH), 7.32e7.20 (m, 7H, AreH), 3.52e3.46 (m, 4H,
2CH2N), 2.10e2.02 (m, 4H, 2CH2). 13C NMR (CDCl3, 150 MHz):
8. Higley, C. A.; Wilde, R. G.; Maduskuie, T. P.; Johnson, A. L.; Pennev, P.; Billheimer,
J. T.; Robinson, C. S.; Gillies, P. J.; Wexler, R. R. J. Med. Chem. 1994, 37, 3511.
9. Beliaev, A.; Learmonth, D. A.; Soares-da-Silva, P. J. Med. Chem. 2006, 49, 1191
and references cited therein.
d
189.7, 164.8, 144.4, 139.0, 135.6, 131.7, 131.2, 130.6, 128.9, 128.3,
128.1, 127.6, 49.5, 25.6. MS: m/z (%) 368 (Mþ, 100), 339 (27), 297
(12), 139 (61), 121 (30), 111 (54). IR (KBr):
n
¼1669, 1551, 1458, 1321,
1214, 1121, 1088 cmꢁ1. Anal. Calcd for C23H23F3N2OS: C, 65.12; H,
4.65; N, 7.59; S, 8.69. Found: C, 65.13; H, 4.47; N, 7.42; S, 8.88.
10. Balba, M.; El-Hady, N. A.; Taha, N.; Rezki, N.; Ashry, E. S. H. E. Eur. J. Med. Chem.
2011, 46, 2596.
11. Liang, X.; Fan, J.; Shi, F.; Su, W. Tetrahedron Lett. 2010, 51, 2505.
12. Maduskuie, T. P.; Wilde, R. G.; Billheimer, J. T.; Cromley, D. A.; Germain, S.;
Gillies, P. J.; Higley, C. A.; Johnson, A. L.; Pennev, P.; Shimshick, E. J.; Wexler, R. R.
J. Med. Chem. 1995, 38, 1067.
4.3.10. 1-(5-Phenyl-2-(pyrrolidin-1-yl)thiazol-4-yl)ethanone (10j)
Operation as above with pyrrolidine (0.12 g, 1.3 mmol), compound
10j (0.15 g, 55%) was also isolated as yellow oil. 1H NMR (CDCl3,
13. Zeng, R. S.; Zou, J. P.; Zhi, S. J.; Chen, J.; Shen, Q. Org. Lett. 2003, 5, 1657.
ꢁ
14. (a) Gonda, J.; Martinkova, M.; Imrich, J. Tetrahedron 2002, 58, 1611; (b) Matsuda,
600 MHz):
2.48 (s, 3H, CH3), 2.07e2.05 (m, 4H, 2CH2). 13C NMR (CDCl3,
150 MHz): 195.1,163.9,144.7,132.4,131.5,129.9,129.7,128.1,128.0,
49.4, 30.1, 25.6. MS: m/z (%) 272 (Mþ, 100), 244 (27), 217 (22), 121
d
7.48e7.32 (m, 5H, AreH), 3.49 (t, J¼6.6 Hz, 4H, 2CH2N),
K.; Yanagisawa, I.; Isomura, Y.; Mase, T.; Shibanuma, T. Synth. Commun. 1997, 27,
3565.
15. De, S.; Adhikari, S.; Tilak-Jain, J.; Menon, V. P.; Devasagayam, T. P. A. Chem-Biol.
Interact. 2008, 173, 215.
16. Gorczynski, M. J.; Leal, R. M.; Mooberry, S. L.; Bushweller, J. H.; Brown, M. L.
Bioorg. Med. Chem. 2004, 12, 1029.
d
(11), 70 (14). IR (KBr):
n
¼1687, 1557, 1483, 1352, 1278, 1146,
17. Haviv, F.; Ratajczyk, J. D.; DeNet, R. W.; Kerdesky, F. A.; Walters, R. L.; Schmidt, S.
P.; Holms, J. H.; Young, P. R.; Carter, G. W. J. Med. Chem. 1988, 31, 1719.
18. Tsuji, K.; Ishikawa, H. Bioorg. Med. Chem. Lett. 1994, 4, 1601.
19. (a) Marsden, S. P.; McGonagle, A. E.; McKeever-Abbas, B. Org. Lett. 2008, 10,
2589; (b) Lertpibulpanya, D.; Marsden, S. P.; Rodriguez-Garcia, I.; Kilner, C.
A. Angew. Chem., Int. Ed. 2006, 45, 5000; (c) Palacios, F.; Alonso, C.; Aparicio,
D.; Rubiales, G.; Santos, J. M. Tetrahedron 2007, 63, 523; (d) Alajarin, M.;
Bonillo, B.; Ortin, M.-M.; Sanchez-Andrada, P.; Vidal, A.; Orenes, R.-A. Org.
Biomol. Chem. 2010, 8, 4690; (e) Devarie-Baez, N. O.; Xian, M. Org. Lett. 2010,
12, 752.
20. (a) Ding, M. W.; Sun, Y.; Liu, X. P.; Liu, Z. J. Org. Prep. Proced. Int. 2003, 35, 391;
(b) Ding, M. W.; Fu, B. Q.; Yuan, J. Z. Heteroat. Chem. 2005, 16, 76.
21. Ding, M. W.; Fu, B. Q.; Cheng, L. Synthesis 2004, 1067.
22. Molina, P.; Fresneda, P. M.; Almendros, P. Tetrahedron Lett. 1992, 33, 4491.
23. (a) Nie, Y. B.; Wang, L.; Ding, M. W. J. Org. Chem. 2012, 77, 696; (b) Xie, H.; Yuan,
D.; Ding, M. W. J. Org. Chem. 2012, 77, 2954; (c) Nie, Y. B.; Duan, Z.; Ding, M. W.
1071 cmꢁ1. Anal. Calcd for C15H16N2OS: C, 66.15; H, 5.92; N, 10.29; S,
11.77. Found: C, 66.44; H, 5.77; N, 10.33; S, 11.97.
4.3.11. 1-(2-(Diisopropylamino)-5-phenylthiazol-4-yl)ethanone(10k)
Operation as above with diisopropylamine (0.13 g, 1.3 mmol), com-
pound 10k (0.12 g, 40%) was also isolated as yellow oil. 1H NMR
(CDCl3, 600 MHz):
d 7.51e7.34 (m, 5H, AreH), 3.82e3.78 (m, 2H,
2CHN), 2.55 (s, 3H, CH3), 1.41 (d, J¼6.6 Hz, 12H, 4CH3). 13C NMR
(CDCl3,150 MHz): d 195.1,163.9,143.6,133.0,131.3,131.0,129.9,129.8,
127.9, 51.4, 50.3, 30.3, 29.5, 20.6, 19.6. MS: m/z (%) 302 (Mþ, 43), 259
(72), 245 (90), 218 (100), 185 (22), 140 (30). IR (KBr):
¼1687, 1541,
1451, 1367, 1286, 1137, 1096 cmꢁ1. Anal. Calcd for C17H22N2OS: C,
n

7990
H. Xie et al. / Tetrahedron 68 (2012) 7984e7990
Tetrahedron 2012, 68, 965; (d) Zhong, Y.; Wang, L.; Ding, M. W. Tetrahedron
N. Y.; Liu, M. G.; Ding, M. W. J. Org. Chem. 2009, 74, 6874; (m) Huang, N. Y.;
Liang, Y. J.; Ding, M. W.; Fu, L. W.; He, H. W. Bioorg. Med. Chem. Lett. 2009, 19,
831.
2011, 67, 3714; (e) He, P.; Nie, Y. B.; Wu, J.; Ding, M. W. Org. Biomol. Chem. 2011,
9, 1429; (f) Xie, H.; Yu, J. B.; Ding, M. W. Eur. J. Org. Chem. 2011, 6933; (g) Wu, J.;
Liu, J. C.; Wang, L.; Ding, M. W. Synlett 2011, 2880; (h) He, P.; Wu, J.; Nie, Y. B.;
Ding, M. W. Eur. J. Org. Chem. 2010, 1088; (i) Li, W. J.; Liu, S.; He, P.; Ding, M. W.
Tetrahedron 2010, 66, 8151; (j) Li, W. J.; Zhao, F. F.; Ding, M. W. Synlett 2011, 265;
(k) He, P.; Wu, J.; Nie, Y. B.; Ding, M. W. Tetrahedron 2009, 65, 8563; (l) Huang,
24. (a) Knittel, D.; Hemetsberger, H.; Weidmann, H. Monatsh. Chem. 1970, 101, 157;
(b) Hemetsberger, H.; Knittel, D.; Weidmann, H. Monatsh. Chem. 1969, 100,
1599.
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25. L’abbe, G.; Hassner, A. J. Org. Chem. 1971, 36, 258.