Synthesis of trisubstituted thiazoles by ligand-free palladium-catalyzed direct 5-arylation of 2,4-disubstituted thiazoles under conventional and microwave-assisted heating

Article abstract of DOI:10.1016/j.tet.2013.10.053

Trisubstituted thiazoles were synthesized with excellent yields using ligand-free, palladium-catalyzed, direct 5-arylation of 2,4-disubstituted thiazole and conventional or microwave-assisted heating. The palladium-catalyzed reaction yields were significantly influenced by LiCl additive, solvent, and heating method. The reaction times were reduced dramatically by employing microwave radiation instead of conventional heating. The synthetic methods can be applied to diverse 2,4,5-trisubstituted thiazoles by varying the aryl bromide and disubstituted thiazole reactants.

Full text of DOI:10.1016/j.tet.2013.10.053

Tetrahedron 69 (2013) 10990e10995
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Tetrahedron
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Synthesis of trisubstituted thiazoles by ligand-free palladium-
catalyzed direct 5-arylation of 2,4-disubstituted thiazoles under
conventional and microwave-assisted heating
*
Su Kang Kim, Ji-Hyun Kim, Young Chul Park, Jae Won Kim, Eul Kgun Yum
Department of Chemistry, Chungnam National University, Yusung, Daejon 305-764, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 August 2013
Received in revised form 14 October 2013
Accepted 16 October 2013
Available online 23 October 2013
Trisubstituted thiazoles were synthesized with excellent yields using ligand-free, palladium-catalyzed,
direct 5-arylation of 2,4-disubstituted thiazole and conventional or microwave-assisted heating. The
palladium-catalyzed reaction yields were significantly influenced by LiCl additive, solvent, and heating
method. The reaction times were reduced dramatically by employing microwave radiation instead of
conventional heating. The synthetic methods can be applied to diverse 2,4,5-trisubstituted thiazoles by
varying the aryl bromide and disubstituted thiazole reactants.
Keywords:
Trisubstituted thiazoles
Ligand-free
Ó 2013 Elsevier Ltd. All rights reserved.
Palladium-catalyzed
5-Arylation
2,4-Disubstituted thiazoles
1. Introduction
However, palladium-catalyzed cross-coupling reactions require
prior preparation of related organometallic derivatives and aryl-
Sulfur-containing azaheteroaromatic moieties are an important
classes of heterocyclic compounds in pharmaceuticals and organic
syntheses due to their unique biological and physical properties.1
Thiazoles are present in many natural materials2 and are potent
biologically active compounds that exhibit, e.g., antimicrobial, an-
tifungal, antihypertensive, anti-inflammatory, antitumor, and cy-
totoxic activities.3e6 Some functionalized thiazoles have found
diverse applications in materials science.7,8 The most frequently
used synthetic method of generating thiazoles is the Hantzsch
halides. Since the publication of Ohta’s reports16e18 describing the
direct arylation of heterocyclic compounds via palladium-catalyzed
CeH activation, palladium-catalyzed, direct arylation has been
shown to be a practical method for the preparation of disubstituted
thiazoles under mild conditions.19e24 Palladium-catalyzed, direct
arylation of thiazoles generally requires 5e10 mol % of palladium
catalyst associated with 5e20 mol % of mono-or bidentate phos-
phine ligands and a relatively long reaction time.21 In addition,
palladium-catalyzed sequential arylation using thiazoles25 or thi-
azole N-oxides26 is promising for the preparation of triarylated
thiazoles. Practical, one-pot sequential arylation has been demon-
strated with these reaction methods compared with other reported
stepwise CeH bond arylation methods.
Recently, the use of microwave radiation to accelerate organic
reactions has attracted considerable attention because it often re-
duces reaction times dramatically from days or hours to minutes.27
In the course of establishing a chemical compound library of bi-
ologically active thiazole derivatives,28 we needed a convenient
synthetic procedure to generate 2,4,5-trisubstituted thiazoles. In
this study, we examined and compared conventional and
microwave-assisted heating as a means of accelerating ligand-free,
palladium-catalyzed direct arylation of several 2,4-disubstituted
thiazoles for the preparation of diverse trisubstituted thiazoles.
process,9 in which an
a-haloketone is condensed with a thioamide.
Synthetic methods have also been reported for trisubstituted
thiazoles.10e14 Although the Hantzsch method is attractive for the
preparation of substituted thiazole compounds, diversification of
thiazole moieties is limited due to the requirement for elaborate
preparation of each a-haloketone and thioamide.
The palladium-catalyzed coupling reaction of a thiazole halide
with a stoichiometric amount of an arylmetal, such as the aryl-
boronic acids or arylstannane and arylzinc reagents, represents one
of the most effective strategies for synthesizing arylthiazoles.15
* Corresponding author. Tel.: þ82 428215474; fax: þ82 428218896; e-mail ad-
dress: ekyum@cnu.ac.kr (E.K. Yum).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.053

S.K. Kim et al. / Tetrahedron 69 (2013) 10990e10995
10991
2. Results and discussions
and 7). Arylation reactions employing several alkali metal carbon-
ates or acetates were also examined (Entries 3, 8e12). The reaction
using K2CO3 as the base provided relatively high yields of tri-
substituted thiazole, comparable to those obtained with Cs2CO3.
The above results show that the optimal conditions for conven-
tionally heated direct arylation of disubstituted thiazoles were
5 mol % Pd(OAc)2,1 equiv LiCl,1 equiv Cs2CO3, and DMF at 150 ꢀC for
24 h.
The microwave-assisted, palladium-catalyzed, direct arylation
of 2-methyl-4-phenyl thiazole (1) was reexamined using the above
conditions optimized for the conventionally heated reaction. Fre-
quently, microwave irradiation of chemical reactions boasts several
advantages over conventional heating, including accelerated re-
action rates and significant energy savings. Microwave irradiation
results in efficient internal heating by direct coupling of microwave
energy to the molecules (solvents, reagents, catalyst) present in the
reaction mixture. Preliminary, microwave-assisted, palladium-cat-
alyzed direct arylation reactions proceeded rapidly with high yields
of the desired product, even in the absence of the LiCl additive.
Therefore, we investigated the microwave-assisted, palladium-
catalyzed arylation of 2-methyl-4-phenylthiazole. The reaction
parameters included variations in the solvent (DMF, NMP, and
DMAc), alkali metal carbonate, and acetate base. The results are
shown in Table 2.
Starting materials (1e5) were prepared in good to excellent
yields using the Hantzsch method with
a-bromoketones and
methyl and phenylthioamide, as shown in Scheme 1. Most
palladium-catalyzed, direct arylation reactions used to generate
thiazoles use aryliodide, as opposed to the corresponding bromide
or chloride, due to the speed with which the palladium oxidative
addition occurs at low temperatures. In the current study, however,
5-bromopyrimidine was used as a model aryl halide with 2-methyl-
4-phenylthiazole (1) to optimize the reaction conditions with our
previously reported LiCl-mediated transition metal-catalyzed het-
eroannulation and N-arylation.29 The results using several palla-
dium species and bases are summarized in Table 1. Although direct
arylation of monosubstituted thiazoles using low percentages of
palladium catalyst has been reported,21 in the current study, low
yields of product and high levels of starting materials resulted from
1 mol % palladium-catalyzed direct arylation of disubstituted thi-
azoles, even after 24 h. Ligand-free, LiCl-mediated direct arylation
of 2-methyl-4-phenyl (1) required 5 mol % Pd(OAc)2 with 1 equiv of
Cs2CO3 base to reach completion within 24 h (Entries 1e5). The
same reaction conditions were also applied at 180 ꢀC with varia-
tions in reaction time (Entry 2). The results indicated incomplete
reaction after 12 h at 180 ꢀC.
S
S
N
O
Table 2
DMF
60
R
Br
Optimization of microwave-assisted, palladium-catalyzed arylation to 2,4-
disubstituted thiazole
H
N
R
R
, 1h
R
N
1. R1
2. R1
3. R1
4. R1
5. R1
=
=
=
=
=
CH3, R2 = Ph
5mol% Pd(OAc)2, 1eq K2CO3
Solvent, 180 MW, 10 min
N
Ph,
R2
=
=
=
=
4-F-Ph
Ph
S
N
N
S
N
4-F-Ph,R2
N
CH3
Ph,
R2
R2
CH3
MeO
Br
Scheme 1.
Entrya
Base
Solvent
Isolated yield (%)
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
Na2CO3
Li2CO3
KOAc
DMF
NMP
DMA
DMF
NMP
DMA
DMF
NMP
NMP
DMA
NMP
NMP
81
81
81
47
81
59
24
29
34
22
51
31
Table 1
Optimization of a conventionally heated, palladium-catalyzed 5-arylation reaction
to 2-methyl-4-phenylthiazole
N
S
N
N
Pd source, base
N
S
N
9
N
Br
1eq LiCl, DMF, 150 , 24h
10
11
12
KOAc
NaOAc
Entrya
Pd source
1 equiv LiCl
Base
Isolated
yield (%)
a
All reactions were conducted at the 1.0 mmol scale in 2 mL of solvent in
a Biotage 5-mL vial sealed with a crimp cap. Microwave radiation was supplied with
a Biotage Initiator EXP EU (400 W, 2450 MHz).
1
1 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
10 mol % Pd(OAc)2
5 mol % Pd(PPh3)4
5 mol % PdCl2(PPh3)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
5 mol % Pd(OAc)2
þ
þ
d
þ
þ
þ
þ
þ
þ
þ
þ
þ
1 equiv Cs2CO3
1 equiv Cs2CO3
1 equiv Cs2CO3
2 equiv Cs2CO3
1 equiv Cs2CO3
1 equiv Cs2CO3
1 equiv Cs2CO3
1 equiv K2CO3
1 equiv Li2CO3
1 equiv Na2CO3
1 equiv NaOAc
1 equiv KOAc
45
80
10
52
82
46
33
76
34
45
36
40
2b
3
4
5
6
7
8
9
10
11
12
The reactions employing K2CO3 as the base provided the same
81% yield of desired product, irrespective of the solvent used (En-
tries 1e3). Reactions using Cs2CO3 as the base provided the highest
yields (81%) only when NMP was used as the solvent. Other bases
(Li2CO3, Na2CO3, NaOAc, and KOAc) gave low yields in all of the
solvents. Therefore, the optimum reaction conditions for
microwave-assisted, palladium-catalyzed arylation of disubstituted
thiazoles were 5 mol % Pd(OAc)2, 1 equiv K2CO3, and NMP solvent at
180 ꢀC for 10 min. During the reaction, the internal vapor pressure
in the reaction vial was 2e4 bar, as indicated by the online monitor
of the Biotage microwave reactor.
a
All reactions were conducted at the 1.0 mmol scale in 5 mL of DMF at 150 ꢀC for
24 h in a sealed vial.
b
The reaction conditions were 150 ꢀC (80% after 24 h) and 180 ꢀC (48% after 12 h
and 80% after 24 h).
The palladium-catalyzed arylation of various disubstituted thi-
azoles using conventional heating and microwave-assisted heating
to prepare diverse trisubstituted thiazoles was examined. The re-
sults are shown in Table 3.
The reactions employing 3- or 5-heteroaromatic bromides, such
as pyrimidine, quinolone, and pyridine bromides, provided high
Increasing the percentage of palladium catalyst or the amount of
base did not improve yields of the desired products (Entries 4 and
5). Reactions using Pd(PPh)4 or Pd(PPh)2Cl2 as the palladium cat-
alyst gave moderate-to-low yields of 5-arylated thiazole (Entries 6

10992
S.K. Kim et al. / Tetrahedron 69 (2013) 10990e10995
yields of 5-heteroaryl trisubstituted thiazoles (compounds 6e8).
However, the reaction with 2-bromopyridine gave a low yield of the
desired product using both conventional and microwave-assisted
heating (compound 9). The 2-bromopyridine likely complexed
with the palladium metal. Variation of substituted phenylbromides
also gave high-to-moderate yields of trisubstituted thiazoles
(compounds 10e14). Although the yields of direct arylation to
2-methyl-4-phenylthiazoles varied with the functional group on
the phenyl moiety, substituted aryl bromides were generally ef-
fective for the direct 5-arylation of disubstituted thiazoles. Opti-
mized reaction conditions were used with various disubstituted
thiazoles and 5-bromopyrimidine, 3-bromoquinoline, and
3-bromopyridine. The microwave-assisted, direct arylation of dia-
rylthiazoles gave high yields of triarylthiazoles (compounds 15e20)
with short reaction times. The same reaction also proceeded effi-
ciently with 2,4-dimethylthiazole and 5-aryl-4-methoxy-2-
phenylthiazole. Diverse trisubstituted thiazoles (compound
21e26) were easily prepared using ligand-free, palladium-cata-
lyzed direct arylation of various disubstituted thiazoles with both
conventional and microwave-assisted heating.
Table 3
Conventional and microwave-assisted heating in the ligand-free palladium-cata-
lyzed direct arylation of disubstituted thiazoles
3. Conclusions
Conventional and microwave-assisted heating provided similar
reactivity with the same substrates, although the yields of
microwave-assisted reactions were slightly higher. However, re-
action times were reduced dramatically by employing microwave
radiation instead of conventional heating. Ligand-free, palladium-
catalyzed arylation is an effective method of producing diverse
2,4,5-trisubstituted thiazoles.
4. Experimental
4.1. Instrumentation and analysis
All 1H and 13C NMR spectra were recorded on a Jeol 400 MHz
spectrometer, and chemical shifts were referenced to tetrame-
thylsilane (TMS) as an internal standard. The infrared spectra were
obtained on Bio-Rad Laboratories/FTS-175C. The GCeMS spectra
were obtained using a Shimadzu QP 1000GC-MS. Elemental anal-
yses were carried out by Chungnam National University using an
elemental analyzer (EA-1110). Microwave-assisted reactions were
performed with an initiator instrument (EXP EU, Biotage, 400 W,
2450 MHz). Reaction temperatures were measured using infrared
sensors on the outer surface of the reaction vial. Products were
purified by flash chromatography on 230e400 mesh ASTM 60
silica gel. All base and palladium species were purchased from
SigmaeAldrich Chemical Co. Chemicals were used directly as ob-
tained from commercial sources unless otherwise noted.
4.2. Preparation of 2,4-disubstituted thiazoles
4.2.1. Methyl-4-phenylthiazole (1).30 Thioamide 0.75 g (10 mmol)
and bromoacetophenone 1.99 g (10 mmol) were dissolved 5 mL of
DMF in a 20 mL pressure tube. The reaction mixtures were sealed
and heated 1 h at 60 ꢀC in oil bath. The resulting mixture was di-
luted with saturated aqueous ammonium chloride. The product
was extracted with ethyl acetate. The ethyl acetate layer was dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
product was purified by silica gel column chromatography using
hexane:ethyl acetate. 2-Methyl-4-phenyl-thiazole was obtained in
99% yield as a white solid. Mp: 68e69 ꢀC; IR (KBr) 3054, 1583, 1432,
1186, 771 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
(2H, s, AreH), 7.43 (2H, m, AreH), 7.34 (3, m, AreH), 2.89 (3H, s,
CH3); 13C NMR (CDCl3, 100 MHz)
165.8, 155.1, 134.5, 128.6, 127.9,
126.2, 112.2, 19.3; Ms (m/z, relative intensity): 176.3 (Mþ1, 100);
d 9.11 (1H, s, AreH), 8.65
d

S.K. Kim et al. / Tetrahedron 69 (2013) 10990e10995
10993
Anal. Calcd for C10H9NS: C, 68.53; H, 5.18; N, 7.99; S,18.30; Found: C,
68.71; H, 5.02; N, 8.15; S, 18.12.
100 MHz) d 176.2, 167.7, 166.7, 162.5, 143.9, 139.2, 139.1, 138.9, 137.6,
134.5, 29.6 Ms (m/z, relative intensity): 253 (Mþ, 100), 212 (20), 185
(18); Anal. Calcd for C14H11N3S: C, 66.38; H, 4.38; N, 16.59; S, 12.66;
Found: C, 66.47; H, 4.48; N, 16.28; S, 12.77.
4.2.2. 2-(4-Fluorophenyl)-4-phenylthiazole (2). The compound 2
was obtained from 4-fluorobenzothioamide 1.55 g (10 mmol) and
bromoacetophenone 2.0 g (10 mmol) in 97% yields as a white solid.
Mp: 114e115 ꢀC; IR (KBr) 3052, 1602, 1223, 978, 685 cmꢁ1; 1H NMR
4.4. General experimental procedure for microwave-assisted
ligand-free palladium-catalyzed 5-arylation of 2,4-
disubstituted thiazole
(CDCl3, 400 MHz)
d
8.03 (2H, d, J¼7.6 Hz, AreH), 7.99 (2H, d,
J¼7.6 Hz, AreH), 7.44 (3H, t, J¼7.6 Hz, AreH), 7.35 (1H, t, J¼7.6 Hz,
AreH), 7.14 (2H, t, J¼7.6 Hz, AreH); 13C NMR (CDCl3, 100 MHz)
2-Methyl-4-phenyl thiazole (0.175 g,1.0mmol), K2CO3 (1.0mmol),
5-bromopyridine (0.318 g, 2 mmol), Pd(OAc)2 (0.05 mmol), and NMP
(2 mL) were added to a 5-mL vial. The vial was sealed with a crimp
cap and placed in a Biotage initiator microwave cavity. After irradi-
ation at 180 ꢀC for 10 min and subsequent cooling, the reaction
mixture was diluted with saturated aqueous ammonium chloride.
Products were isolated by extraction into ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, filtered, and
concentrated. Products were purified by silica gel column chroma-
tography using a hexane/ethyl acetate eluent. 2-Methyl-4-phenyl-5-
(pyrimidin-5yl)thiazole (6) was obtained in 81% yield as a yellow oil.
The following compounds (7e26) were prepared with conven-
tionally and microwave-assisted heating in the ligand-free
palladium-catalyzed general experimental procedures.
d
165.6, 165.1, 162.6, 156.3, 134.3, 130.1, 130.0, 128.7, 128.5, 128.4,
128.2, 126.4, 116.0, 115.8, 112.5. Ms (m/z, relative intensity): 255
(Mþ, 89), 134 (100), 89 (25); Anal. Calcd for C15H10FNS: C, 70.57; H,
3.95; F, 7.44 N, 5.49; S, 12.56; Found: C, 70.11; H, 4.05; F, 7.45; N,
5.30; S, 12.40.
4.2.3. 4-(4-Fluorophenyl)-2-phenylthiazole (3).31 The compound 3
was obtained from benzothioamide 1.37 g (10 mmol) and 2-bromo-
1-(4-fluorophenyl)ethanone 2.17 g (10 mmol) in 69% yields as
a white solid. Mp: 104e105 ꢀC; IR (KBr) 3052, 1602, 1480, 1224,
746 cmꢁ1
;
1H NMR (CDCl3, 400 MHz)
d
8.04 (2H, dd, J¼5.6 Hz,
J¼1.2 Hz, AreH), 7.97 (2H, dd, J¼5.6 Hz, J¼1.2 Hz, AreH), 7.45 (3H,
m, AreH), 7.41 (1H, s, AreH), 7.13 (2H, t, J¼5.6 Hz, AreH); 13C NMR
(CDCl3, 100 MHz)
d 168.0, 163.9, 161.5, 155.2, 133.6, 130.8, 130.7,
130.1, 129.0, 128.2, 128.1, 126.5, 115.7, 115.5, 112.2; Ms (m/z, relative
4.4.1. 2-Methyl-4-phenyl-5-(quinolin-3-yl)thiazole (7). The product
intensity): 255 (Mþ, 85), 134 (100), 89 (22); Anal. Calcd for
7
was obtained from 2-methyl-4-phenylthiazole and 3-
bromoquinoline. Yield: 94% (Thermal); 89% (MW). Yellow oil. IR
(KBr) 3065, 1509,1209, 735 cmꢁ1; 1H NMR (CDCl3, 400 MHz):
8.77
C
15H10FNS: C, 70.57; H, 3.95; F, 7.44 N, 5.49; S, 12.56; Found: C,
70.11; H, 4.05; F, 7.45; N, 5.30; S, 12.40.
d
(1H, d, J¼2.4 Hz, AreH), 8.11 (1H, d, J¼2.4 Hz, AreH), 8.07 (1H, d,
4.2.4. 2,4-Dimethylthiazole (4). The compound 4 was obtained
from thioamide 0.75 g (10 mmol) and bromoacetone 1.37 g
(10 mmol) in 75% yields as a colorless oil. IR (KBr) 1486, 1178,
J¼8.4 Hz, AreH), 7.72 (2H, m, AreH), 7.54 (1H, t, J¼8.4 Hz, AreH),
7.50 (2H, m, AreH), 7.28 (H, d, J¼6.2 Hz, AreH), 2.80 (3H, s, CH3); 13
C
NMR (CDCl3, 100 MHz)
d 165.0, 150.9, 150.6, 146.9, 145.7, 134.2,
743 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
6.69 (1H, s, AreH), 2.67 (3H,
165.2, 152.0,
129.8, 129.2, 128.9, 128.6, 128.2, 127.8, 127.6, 127.2, 125.7, 19.3; Ms
(m/z, relative intensity): 302 (Mþ, 100), 260 (27), 216 (21); Anal.
Calcd for C19H14N2S: C, 75.47; H, 4.67; N, 9.26; S, 10.60; Found: C,
75.22; H, 4.77; N, 9.52; S, 10.49.
s, CH3), 2.40 (3H, s, CH3), 13C NMR (CDCl3, 100 MHz)
d
112.6, 19.0, 16.9; Ms (m/z, relative intensity): 113 (Mþ, 100), 71 (89),
45 (59); Anal. Calcd for C5H7NS: C, 53.06; H, 6.23; N, 12.38; S, 28.33;
Found: C, 53.11; H, 12.22; N, 12.54; S, 28.07.
4.4.2. 2-Methyl-4-phenyl-5-(pyridin-3-yl)thiazole (8). The product
4.2.5. 4-Methoxy-2-phenylthiazole (5). The compound 5 was ob-
tained from methyl 2-bromoacetate 0.15 g (1 mmol) and benzo-
thioamide 0.14 g (1 mmol) and in 50% yields as a yellow oil. IR (KBr)
8
was obtained from 2-methyl-4-phenylthiazole (1) and 3-
bromopyridine. Yield: 85% (Thermal); 80% (MW). Yellow oil. IR
(KBr) 3066, 1486, 1152, 704 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
8.56
d
3021, 1528, 1342, 1094, 750 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
7.92
(1H, s, AreH), 8.50 (1H, d, J¼4.8 Hz, AreH), 7.56 (1H, d, J¼7.6 Hz,
(2H, m, AreH), 7.40 (3H, m, AreH), 6.06 (1H, s, AreH), 3,93 (3H, s,
AreH), 7.44 (2H, m, AreH), 7.27 (3H, m, AreH), 7.19 (1H, d, J¼7.6 Hz,
OCH3); 13C NMR (CDCl3, 100 MHz)
d
165.7, 136.4, 130.4, 130.1, 130.0,
AreH), 2.75 (3H, s, CH3); 13C NMR (CDCl3, 100 MHz)
d 164.8, 150.8,
129.6, 126.8, 126.7, 90.0, 57.8; Ms (m/z, relative intensity): 191 (Mþ,
100), 88 (48), 45 (40); Anal. Calcd for C10H9NOS: C, 62.80; H, 4.74; N,
7.32;O,8.37;S,16.77;Found:C,62.78;H,4.69;N,7.22;O,8.21;S, 28.07.
149.8, 148.7, 136.5, 134.2, 128.8, 128.4, 128.1, 128.0, 123.2, 19.2; Ms
(m/z, relative intensity): 251 (Mþ, 100), 210 (41), 166 (20); Anal.
Calcd for C15H12N2S: C, 71.40; H, 4.79; N, 11.10; S, 12.71. Found: C,
71.36; H, 4.43; N, 11.49; S, 12.72.
4.3. General experimental procedure for conventional heat-
ing in the ligand-free palladium-catalyzed 5-arylation of
2,4-disubstituted thiazoles
4.4.3. 2-Methyl-4-phenyl-5-(pyridin-2-yl)thiazole (9). The product
9
was obtained from 2-methyl-4-phenylthiazole (1) and 2-
bromopyridine. Yield: 7% (Thermal); 21% (MW). Yellow oil. IR
(KBr) 3054, 1583, 1432, 1186, 771, 700 cmꢁ1 1H NMR (CDCl3,
400 MHz)
2-Methyl-4-phenylthiazole
(0.175
g,
1.0
mmol),
;
5-bromopyrimidine (0.318 g, 2 mmol), LiCl (1.0 mmol), Cs2CO3
(1.0 mmol), 5 mol % Pd(OAc)2, and DMF (5 mL) were added in 10 mL
vial with screw cap. The vial was sealed and stirred at 150 ꢀC in oil
bath. After heating the reaction mixture at 150 ꢀC for 24 h, the
reaction mixture was diluted with saturated aqueous ammonium
chloride. The product was extracted with ethyl acetate. The ethyl
acetate layer was dried over anhydrous magnesium sulfate, filtered,
and concentrated. The product was purified by silica gel column
chromatography using hexane:ethyl acetate eluent. 2-Methyl-4-
phenyl-5-(pyrimidin-5yl)thiazole (6) was obtained in 80% yield as
d
8.57 (1H, d, J¼4.8 Hz, AreH), 7.54 (2H, m, AreH), 7.43
(1H, m, AreH), 7.37 (3H, m, AreH), 7.16 (1H, d, J¼7.6 Hz, AreH), 7.10
(1H, dd, J¼7.6 Hz, J¼4.8 Hz, AreH), 2.80 (3H, s, CH3); 13C NMR
(CDCl3, 100 MHz)
d 166.1, 151.7, 151.2, 149.6, 149.2, 136.9, 136.0,
135.4, 133.9, 129.2, 128.6, 128.4, 123.7, 122.1, 122.0, 121.1, 19.3; Ms
(m/z, relative intensity): 251 (Mþ, 100), 210 (70), 166 (40); Anal.
Calcd for C15H12N2S: C, 71.40; H, 4.79; N, 11.10; S, 12.71. Found: C,
71.38; H, 4.47; N, 11.18; S, 12.69.
4.4.4. 2-Methyl-5-(naphthalen-2-yl)-4-phenylthiazole
(10). The
a yellow oil. IR (KBr) 3045, 1494, 1149, 733 cmꢁ1
400 MHz) 9.11(1H, s, AreH), 8.65 (2H, s, AreH), 7.43 (2H, m,
AreH), 7.34 (3, m, AreH), 2.89 (3H, s, CH3); 13C NMR (CDCl3,
;
1H NMR (CDCl3,
product 10 was obtained from 2-methyl-4-phenylthiazole (1) and
2-bromonaphthalene. Yield: 55% (Thermal); 60% (MW). Yellow
solid; mp: 108e109 ꢀC; IR (KBr) 3054,1502,1182, 773, 697 cmꢁ1; 1H
d

10994
S.K. Kim et al. / Tetrahedron 69 (2013) 10990e10995
NMR (CDCl3, 400 MHz)
d
7.89 (2H, m, AreH), 7.80 (1H, d, J¼7.6 Hz,
157.6, 156.4, 152.1, 132.7, 130.8, 130.7, 130.6, 128.9, 126.9, 126.5, 115.9,
AreH), 7.47 (2H, dd, J¼4.6 Hz, J¼1.2 Hz, AreH), 7.45 (1H, t, J¼7.6 Hz
AreH), 7.40 (3H, m, AreH), 7.09 (3H, m, AreH), 2.80 (3H, s, CH3); 13
NMR (CDCl3, 100 MHz) 164.7, 151.0, 134.6, 133.7, 132.4, 129.6,
129.5, 129.4, 129.1, 128.3, 128.1, 127.3, 126.6, 126.2, 125.7, 125.4, 19.3;
Ms (m/z, relative intensity): 301 (Mþ, 100), 259 (11), 215 (39), 129
(18); Anal. Calcd for C20H15NS: C, 79.70; H, 5.02; N, 4.65; S,
10.64. Found: C, 79.64; H, 4.98; N, 4.78; S, 10.43.
115.7; Ms (m/z, relative intensity): 333 (Mþ, 100), 300 (34), 203 (24).
C
d
4.4.10. 4-(4-Fluorophenyl)-2-phenyl-5-(quinolin-3-yl)thiazole
(16). The product 16 was obtained from 4-(4-fluorophenyl)-2-
phenylthiazole (2) and 3-bromo-quinolone. Yield: 93% (Thermal);
76% (MW). Yellow solid; mp: 112e114 ꢀC; IR (KBr) 3054, 1603, 1442,
1186, 801, 700 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 8.82 (1H, d,
J¼2.0 Hz, AreH), 8.17 (1H, d, J¼2.0 Hz, AreH), 8.10 (1H, d, J¼8.4 Hz,
AreH), 8.03 (2H, m, AreH), 7.75 (2H, m, AreH), 7.57 (3H, m, AreH),
7.45 (3H, m, AreH), 7.00 (2H, t, J¼8.4 Hz, AreH); 13C NMR (CDCl3,
4.4.5. 4-(2-Methyl-4-phenylthiazol-5-yl)benzaldehyde
(11). The
product 11 was obtained from 2-methyl-4-phenylthiazole (1) and
4-bromobenzaldehyde. Yield: 64% (Thermal); 71% (MW). Yellow
solid; mp: 133e134 ꢀC; IR (KBr) 3059, 1700, 1601, 1176, 829,
100 MHz) d 166.7, 151.1, 150.5, 147.2, 135.8, 133.2, 130.9, 130.8, 130.5,
130.4, 130.1, 129.3, 128.9, 127.8, 127.5, 127.4, 126.5, 125.4, 115.7,
699 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
9.90 (1H, s, AreH), 7.80 (2H,
d, J¼8.4 Hz, AreH), 7.47 (4H, m, AreH), 7.31 (3H, m, AreH), 2.80
(3H, s, CH3); 13C NMR (CDCl3, 100 MHz)
191.5, 165.1, 151.1, 138.6,
115.5; Ms (m/z, relative intensity): 382 (Mþ, 100), 279 (33), 234 (17).
d
4.4.11. 4-(4-Fluorophenyl)-2-phenyl-5-(pyridin-3-yl)thiazole
(17). The product 17 was obtained from 4-(4-fluorophenyl)-2-
phenylthiazole (2) and 3-bromo-pyridine. Yield: 64% (Thermal);
83% (MW). White solid; mp: 122e125 ꢀC; IR (KBr) 3061, 1603, 1492,
135.4, 134.5, 130.9, 130.0, 129.9, 129.1, 128.5, 128.2, 19.3; Ms (m/z,
relative intensity): 279 (Mþ, 100), 238 (42), 208 (40); Anal. Calcd for
C
17H13NOS: C, 73.09; H, 4.69; N, 5.01 O, 5.73; S, 11.48; Found: C,
73.01; H, 4.58; N, 4.97; O, 5.65; S, 11.43.
1236, 839, 687 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 8.65 (1H, s,
AreH), 8.56 (1H, d, J¼4.4 Hz, AreH), 8.00 (2H, d, J¼6.6 Hz, AreH),
7.64 (1H, d, J¼8.8 Hz, AreH), 7.50 (2H, d, J¼8.0 Hz, AreH), 7.46 (3H,
m, Are2H, AreH), 7.26 (1H, dd, J¼8.0 Hz, J¼4.4 Hz, AreH), 7.01(2H,
4.4.6. 2-(2-Methyl-4-phenylthiazol-5-yl)benzonitrile
product 12 was obtained from 2-methyl-4-phenylthiazole (1) and
(12). The
2-bromobenzonitrile. Yield: 77% (Thermal); 80% (MW). Yellow
t, J¼8.8 Hz, AreH); 13C NMR (CDCl3, 100 MHz)
d 165.3, 162.7, 152.2,
solid; mp: 123e124 ꢀC; IR (KBr) 3061, 2227, 1497, 1179, 767 cmꢁ1
;
149.9, 149.1, 134.2, 129.0, 128.7, 128.4, 128.5, 128.4, 128.3, 116.1,
1H NMR (CDCl3, 100 MHz)
d
7.70 (1H, d, J¼1.6 Hz, AreH), 7.56 (1H,
115.9; Ms (m/z, relative intensity): 332 (Mþ, 100), 229 (32), 184 (14).
td, J¼7.6 Hz, J¼1.6 Hz, AreH), 7.44 (2H, m, J¼2.0 Hz, AreH), 7.39 (2H,
m, J¼2.0 Hz, AreH), 7.25 (3H, m, J¼2.0 Hz, AreH), 2.80 (3H, s, CH3);
4.4.12. 2-(4-Fluorophenyl)-4-phenyl-5-(pyrimidin-5-yl)thiazole
(18). The product 18 was obtained from 4-(4-fluorophenyl)-2-
phenylthiazole (3) and 5-bromo-pyrimidine. Yield: 78% (Ther-
mal): 93% (MW). White solid; mp: 181e183 ꢀC; IR (KBr) 3058, 1594,
13C NMR (CDCl3, 400 MHz)
d 165.8, 152.5, 136.2, 134.1. 133.6, 132.8,
132.1, 130.6, 129.2, 128.8, 128.7, 128.4, 128.1, 126.9, 117.4, 113.8, 19.3;
Ms (m/z, relative intensity): 276 (Mþ, 100), 238 (16), 208 (73); Anal.
Calcd for C17H12N2S: C, 73.88; H, 4.38; N, 10.14; S, 11.60; Found: C,
73.77; H, 4.51; N, 10.22; S, 11.23.
1404, 1226, 842, 701 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d 9.14 (1H, s,
AreH), 8.72 (2H, s, AreH), 8.01 (2H, dd, J¼8.4, J¼5.2 Hz, AreH), 7.53
(2H, m, AreH), 7.37 (3H, m, AreH), 7.16 (2H, t, J¼8.4 Hz, AreH); 13
C
4.4.7. 2-Methyl-4-phenyl-5-(3-(trifluoromethyl)phenyl)thiazole
(13). The product 13 was obtained from 2-methyl-4-
phenylthiazole (1) and 3-bromobenzotrifluoride. Yield: 86%
(Thermal); 85% (MW). Brown oil; IR (KBr) 3062, 1496, 1317, 1123,
NMR (CDCl3, 100 MHz) d 166.3, 162.9, 157.6, 156.5, 153.4, 133.6,
128.9, 128.8, 128.7, 128.6, 128.5, 127.1, 116.3, 116.1; Ms (m/z, relative
intensity): 333 (Mþ, 100), 212 (33), 185 (27).
801, 697 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
7.58 (1H, s, AreH), 7.54
4.4.13. 2-(4-Fluorophenyl)-4-phenyl-5-(quinolin-3-yl)thiazole
(19). The product 19 was obtained from 4-(4-fluorophenyl)-2-
phenylthiazole (3) and 3-bromo-quinoline. Yield: 63% (Thermal);
75% (MW). White solid; mp: 121e123 ꢀC; IR (KBr) 3060, 1599, 1487,
(1H, d, J¼7.6 Hz, AreH), 7.46 (3H, m, AreH), 7.40 (1H, t, J¼7.6 Hz,
AreH), 7.29 (3H, m, AreH), 2.80 (3H, s, CH3); 13C NMR (CDCl3,
100 MHz) d 164.6, 150.6, 134.4, 133.2, 132.8, 131.3, 131.1, 130.9, 130.6,
129.2, 129.0, 128.5, 128.1, 126.3, 124.6, 122.9, 19.3; Ms (m/z, relative
intensity): 319 (Mþ, 100), 278 (31), 233 (36), 208 (42), 165 (79);
Anal. Calcd for C17H12F3NS: C, 63.94; H, 3.79; F, 17.85; N, 4.39; S,
10.04; Found: C, 64.01; H, 3.88; F, 17.59; N, 4.39; S, 10.03.
1232, 839, 701 cmꢁ1 1H NMR (CDCl3, 400 MHz):
; d 8.83 (1H, d,
J¼2.4 Hz, AreH), 8.20 (1H, d, J¼8.2 Hz, AreH), 8.10 (1H, d, J¼8.4 Hz,
AreH), 8.05 (2H, m, J¼5.2 Hz, AreH), 7.70 (2H, m, AreH), 7.59 (3H, m,
AreH), 7.33 (3H, m, AreH), 7.18 (2H, t, J¼8.4 Hz, AreH). 13C NMR
(CDCl3,100 MHz) d 165.4, 165.3, 152.3, 150.6, 147.2, 135.8, 134.3, 130.0,
4.4.8. 5-(3,5-Difluorophenyl)-2-methyl-4-phenylthiazole (14). The
product 14 was obtained from 2-methyl-4-phenylthiazole (1) and
1-bromo-3,5-difluorobenzene. Yield: 30% (Thermal); 56% (MW);
Yellow solid; mp: 100e101 ꢀC; IR (KBr) 3061, 1619, 1591, 1433, 1120,
129.7, 129.4, 129.0, 128.7, 128.5, 128.4, 127.9, 127.6, 127.3, 125.5, 116.2,
116.0; Ms (m/z, relative intensity): 382 (Mþ, 100), 261 (35), 216 (25).
4.4.14. 2-(4-Fluorophenyl)-4-phenyl-5-(pyridin-3-yl)thiazole
(20). The product 20 was obtained from 4-(4-fluorophenyl)-2-
phenylthiazole (3) and 3-bromopyridine. Yield: 60% (Thermal);
73% (MW). Yellow solid; mp: 104e106 ꢀC; IR (KBr) 3060, 1583, 1477,
699 cmꢁ1; 1H NMR (CDCl3, 100 MHz)
d
7.47 (2H, m, AreH), 7.32 (3H,
m, AreH), 6.83 (2H, m, AreH), 6.74 (3H, m, AreH), 2.80 (3H, s, CH3);
13C NMR (CDCl3, 400 MHz)
164.7, 163.8, 162.1, 150.8, 135.4, 134.2,
d
129.6, 129.0, 128.5, 128.2, 112.5, 112.4, 103.4, 19.3, Ms m/z (relative
1221, 805, 687 cmꢁ1 1H NMR (CDCl3, 400 MHz)
; d 8.65 (1H, s,
intensity): 286.9 (Mþ, 100), 238.0 (54), 201.0 (55); Anal. Calcd for
AreH), 8.56 (1H, d, J¼5.4 Hz, AreH), 8.01(2H, dd, J¼8.4 Hz, J¼5.4 Hz,
AreH), 7.65 (1H, d, J¼8.4 Hz, AreH), 7.55 (2H, d, J¼3.6 Hz, AreH),
7.33 (3H, m, AreH), 7.26 (1H, m, AreH), 7.15 (2H, t, J¼8.4 Hz, AreH);
C
16H11F2NS: C, 66.88; H, 3.86; F, 13.22; N, 4.87; S, 11.16; Found: C,
66.78; H, 3.88; F, 13.35; N, 4.39; S, 11.03.
13C NMR (CDCl3, 100 MHz)
d 166.7, 163.9, 161.4, 149.9, 149.2, 136.6,
4.4.9. 4-(4-Fluorophenyl)-2-phenyl-5-(pyrimidin-5-yl)thiazole
(15). The product 15 was obtained from 4-(4-fluorophenyl)-2-
phenylthiazole (2) and 5-bromo-pyrimidine. Yield: 80% (Thermal);
88% (MW). Yellow solid; mp: 153e154 ꢀC; IR (KBr) 3052, 1602, 1497,
133.2, 130.9, 130.8, 130.4, 129.0, 126.5, 123.4, 115.7, 115.4; Ms (m/z,
relative intensity): 332 (Mþ, 100), 229 (32), 184 (14).
4.4.15. 2,4-Dimethyl-5-(pyrimidin-5-yl)thiazole (21). Theproduct21
was obtained from 2,4-dimethylthiazole (4) and 5-bromopyrimidine.
Yield: 49% (Thermal); 65% (MW). White solid; mp: 116e117 ꢀC; IR
1223, 839, 685 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d
9.15 (1H, s, AreH),
8.70 (2H, s, AreH), 8.00 (2H, s, AreH), 7.52 (2H, m, AreH), 7.47 (3H, s,
AreH), 7.05 (2H, m, AreH); 13C NMR (CDCl3, 100 MHz)
167.6, 164.0,
d
(KBr) 3066, 1483, 1178, 904, 749 cmꢁ1 1H NMR (CDCl3, 400 MHz)
;

S.K. Kim et al. / Tetrahedron 69 (2013) 10990e10995
10995
d
9.10 (1H, s, AreH), 8.74 (2H, s, AreH), 2.66 (3H, s, CH3), 2.42 (3H, s,
(CDCl3, 100 MHz)
d
161.9, 160.9, 147.8, 147.4, 133.7, 133.6, 130.5,
CH3); 13C NMR (CDCl3, 100 MHz)
d
165.5, 157.3, 156.1, 149.8, 127.3,
129.3, 128.5, 126.0, 123.7, 107.3, 58.0. Ms (m/z, relative intensity):
123.6, 19.3, 16.0. Ms (m/z, relative intensity): 191 (Mþ, 100), 150 (55),
122 (39). Anal. Calcd for C9H9N3S: C, 56.52; H, 4.74; N, 21.97; S,
16.77. Found: C, 56.33; H, 4.88; N, 21.49; S,17.30.
268 (Mþ, 92), 122 (100), 78 (8).
Acknowledgements
4.4.16. Dimethyl-5-(quinol-3-yl)thiazole (22). The product 22 was
obtained from 2,4-dimethylthiazole (4) and 3-bromopyridine.
Yield: 82% (Thermal); 73% (MW). Brown oil. IR (KBr) 3055, 1483,
This Research has been performed as a cooperation project of
project and supported by the Korea Research Institute of Chemical
Technology (KRICT).
1370, 1186, 785, 740 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d 8.97 (1H, d,
J¼2.4 Hz, AreH), 8.13 (2H, m, AreH), 7.83 (1H, d, J¼7.6 Hz, AreH),
7.73 (1H, t, J¼7.2 Hz, AreH), 7.58 (1H, t, J¼7.6 Hz, AreH), 2.73 (3H, s,
CH3), 2.53 (3H s, CH3). 13C NMR (CDCl3, 100 MHz)
d 164.4, 150.5,
References and notes
148.6, 146.9, 135.1, 129.7, 127.6, 127.4, 127.2, 125.6, 19.0, 15.9. Ms
(m/z, relative intensity): 240 (Mþ, 100), 198 (68), 154 (16). Anal.
Calcd for C14H12N2S: C, 69.97; H, 5.03; N, 11.66; S, 13.34. Found: C,
69.58; H, 5.11; N, 11.59; S, 13.72.
1. Katritziky, A. R.; Rees, C. W.; Scriven, E. F. V. Comprehensive Heterocyclic
Chemistry II; BPC Wheatons Ltd: Exeter, UK, 1996, Vol. 3, pp 310e474; and
references therein.
2. Davyt, D.; Serra, G. Mar. Drugs 2010, 8, 2755 and references therein.
3. Kashyap, S. J.; Grag, V. K.; Sharma, P. K.; Kumar, N.; Dudhe, R.; Gupta, J. K. Med.
Chem. Res. 2012, 21, 2123 and references therein.
4.4.17. 2,4-Dimethyl-5-(pyridyl-3-yl)thiazole (23). The product 23
was obtained from 2,4-dimethylthiazole (4) and 3-bromopyridine.
Yield: 60% (Thermal); 83% (MW). Yellow oil. IR (KBr) 3055, 1587,
4. Siddiqui, N.; Arshad, M. F.; Ahsan, W.; Alam, S. Int. J. Pharm. Sci. Drug Res. 2009,
1, 136 and references therein.
5. Zagade, A. A.; Senthilkumar, G. P. Pharma Chem. 2011, 3, 523 and references
therein.
6. Kamisuki, S.; Shirakawa, T.; Kugimiya, A.; Abu-Elheiga, L.; Park-Choo, H.-Y.;
Yamada, K.; Shimogawa, H.; Wakil, S.; Uesugi, M. J. Med. Chem. 2011, 54, 4923.
7. Cheruku, P.; Paptchikhine, A.; Ali, M.; Neudorfl, J.-M.; Andersson, P. G. Org. Bi-
omol. Chem. 2008, 6, 366.
8. Mallakpour, S.; Zadehnazari, A. Colloid Polym. Sci. 2013, 291, 1525.
9. (a) Hantzch. Ber. Dtsch. Chem. Ges. 1888, 21, 942; (b) Wiley, R. H.; England, D. C.;
Behr, L. C. Organic Reactions; John Wiley, 1951, Vol. 6, p 37.
10. Thomae, D.; Perspicace, E.; Xu, Z.; Henryon, D.; Schneider, S.; Hesse, S.; Kirsch,
G.; Seck, P. Tetrahedron 2009, 65, 2982.
1420, 1104, 802, 700 cmꢁ1; 1H NMR (CDCl3, 400 MHz)
d 8.64 (1H, s,
AreH), 8.53 (1H, d, J¼4.0 Hz, AreH), 7.67 (1H, d, J¼7.6 Hz, ArH), 7.31
(1H, d, J¼7.6 Hz, AreH), 2.67 (3H, s, CH3), 2.53 (3H s, CH3). 13C NMR
(CDCl3, 100 MHz)
d 164.5, 149.7, 148.6, 148.5, 136.3, 128.7, 127.5,
123.5, 19.2, 16.0. Ms (m/z, relative intensity): 190 (Mþ, 100), 148
(76), 104 (15). Anal. Calcd for C10H10N2S: C, 63.13; H, 5.30; N, 14.72;
S, 16.85. Found: C, 63.62; H, 5.49; N, 14.49; S, 16.40.
11. Dunst, C.; Knochel, P. J. Org. Chem. 2011, 76, 6972e6978.
12. Li, Z.; Ma, L.; Tang, C.; Xu, J.; Wu, X.; Yao, H. Tetrahedron Lett. 2011, 52, 5643.
13. Pereira, R.; Gaudon, C.; Iglesias, B.; Germain, P.; Gronemeyer, J.; DeLera, A. R.
Bioorg. Med. Chem. Lett. 2006, 16, 49.
14. Kim, D. K.; Choi, J. H.; An, Y. J.; Lee, H. S. Bioorg. Med. Chem. Lett. 2008, 18, 2127.
15. Hammerle, J.; Schnurch, M.; Iqbal, N.; Mihovilvic, M. D.; Stanetyy, P. Tetrahedron
2010, 66, 8051 and references therein.
16. (a) Akita, Y.; Inoue, A.; Yamamoto, K.; Ohta, A. Heterocycles 1985, 23, 2327.
17. Ohta, A.; Akita, Y.; Ohkuwa, T.; Ciba, M.; Fukunaga, R.; Miyafuji, A.; Nakata, T.;
Tani, N.; Aoyagi, Y. Heterocycles 1990, 31, 1951.
18. Aoyagi, A.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga, K.; Gohma, K.;
Komatsu, J.; Sekine, K.; Miyasuji, A.; Kunoh, J.; Honma, R.; Akita, Y.; Ohta, A.
Heterocycles 1992, 33, 257.
4.4.18. 4-Methoxy-2-phenyl-5-(pyrimidin-5-yl)thiazole
product 24 was obtained from 4-methoxy-2-phenylthiazole (5) and
(24). The
5-bromopyrimidine. Yield: 67% (Thermal); 74% (MW). Yellow solꢁid1;
mp: 169e170 ꢀC; IR (KBr) 3003, 1533, 1427, 1342, 1082, 684 cm
;
1H NMR (CDCl3, 400 MHz)
d 9.05 (2H, s, AreH), 9.02 (1H, s, AreH),
7.94 (2H, m, AreH), 7.45 (3H, m, AreH), 4.22 (3H, s, OCH3); 13C NMR
(CDCl3, 100 MHz)
d 163.5, 161.9, 156.0, 153.9, 133.4, 131.0, 129.4,
127.3, 126.2, 58.3. Ms (m/z, relative intensity): 269 (Mþ, 100), 123
(52), 69 (56).
19. Yokooji, A.; Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron 2003, 59,
5685.
4.4.19. 4-Methoxy-2-phenyl-5-(quinolin-3-yl)thiazole
(25). The
20. Turner, G. L.; Morris, J. A.; Greaney, M. F. Angew. Chem., Int. Ed. 2007, 46, 7996.
21. Roger, J.; Pozgan, F.; Doucet, H. J. Org. Chem. 2009, 74, 1179 and references
therein.
22. Dong, J. J.; Roger, J.; Verrier, C.; Martin, T.; Le Golf, R.; Hoaru, C.; Doucet, H.
Green. Chem. 2010, 12, 2053.
23. Baghbanzadeh, M.; Pilger, C.; Kappe, C. O. J. Org. Chem. 2011, 76, 6138.
24. Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc.
Jpn. 1998, 71, 467.
25. Shibahara, F.; Yamauchi, T.; Yamaguchi, E.; Murai, T. J. Org. Chem. 2012, 77, 8815.
26. Campeau, L.-C.; Bertrand-Laperie, M.; Leclerc, J.-P.; Villemure, E.; Goreisky, S.;
Fannou, K. J. Am. Chem. Soc. 2008, 130, 3276.
product 25 was obtained from 4-methoxy-2-phenylthiazole (5) and
3-bromoquinoline. Yield: 65% (Thermal); 78% (MW). White solid;
mp: 127e128 ꢀC. IR (KBr) 3021, 1528, 1342, 1094, 750, 677 cmꢁ1; 1H
NMR (CDCl3, 400 MHz)
d
9.25 (1H, d, J¼2.4 Hz, AreH), 8.45 (1H, d,
J¼2.4 Hz, AreH), 8.07 (1H, d, J¼8.0 Hz, AreH), 7.96 (2H, m, AreH),
7.82 (1H, dd, J¼7.8, J¼1.2 Hz, AreH), 7.65 (1H, m, AreH), 7.54 (1H, m,
AreH), 7.44 (3H, m, AreH), 4.25 (3H, s, OCH3). 13C NMR (CDCl3,
100 MHz) d 161.8, 161.1, 149.5, 146.6, 133.6, 131.8, 130.5, 129.5, 129.2,
27. (a) Kappe, C. O.; Dallinger, D.; Murphree, S. S. Practical Microwave Synthesis for
Organic Chemists; Wiley-VCH, GmbH & KGaA: Weinheim, Germany, 2009; (b)
Kappe, C. O. Chem. Soc. Rev. 2008, 37, 1127.
128.2, 128.1, 127.3, 125.9, 125.7, 107.7, 58.0. Ms (m/z, relative in-
tensity): 268 (Mþ, 92), 172 (100), 128 (47).
28. Suh, J. H.; Yum, E. K.; Cheon, H. G.; Cho, Y. S. Chem. Biol. Drug Des. 2012, 80, 90.
29. (a) Park, S. S.; Choi, J.-K.; Yum, E. K.; Ha, D.-C. Tetrahedron Lett. 1998, 39, 627; (b)
Chi, S. M.; Choi, J.-K.; Yum, E. K.; Chi, D. Y. Tetrahedron Lett. 2000, 41, 919; (c)
Hong, K. B.; Lee, C. W.; Yum, E. K. Tetrahedron Lett. 2004, 45, 693; (d) Hong, C.
,S.; Seo, J. Y.; Yum, E. K. Tetrahedron Lett. 2007, 48, 4831; (e) Kwon, J. K.; Cho, J.
H.; Ryu, Y. S.; Oh, S. H.; Yum, E. K. Tetrahedron 2011, 67, 4820.
30. Dongjian, Z.; Jiuxi, C.; Huilong, X.; Miaochang, L.; Jinchang, D.; Huayue, W.
Synth. Commun. 2009, 39, 2895.
4.4.20. 4-Methoxy-2-phenyl-5-(pyridin-3-yl)thiazole
(26). The
product 26 was obtained from 4-methoxy-2-phenylthiazole (5) and
3-bromopyridine. Yield: 61% (Thermal); 79% (MW). Brown solid;
mp: 68e70 ꢀC; IR (KBr) 3025, 1533, 1353, 1079, 694 cmꢁ1; 1H NMR
(CDCl3, 400 MHz)
d
8.93 (1H, d, J¼2.4 Hz, AreH), 8.44 (1H, dd,
J¼4.6 Hz, J¼1.2 Hz, AreH), 8.07 (1H, m, AreH), 7.95 (2H, m, AreH),
31. Meshram, H. M.; Kumar, D.; Aravind, D.; Prasad, V.; Ramailinga, B. Synth.
7.44 (3H, m, AreH), 7.29 (1H, m, AreH), 4.21 (3H, s, OCH3). 13C NMR
Commun. 2009, 39, 2317.