One-pot four-component synthesis of polysubstituted thiazoles via cascade Ugi/Wittig cyclization starting from odorless Isocyano(triphenylphosphoranylidene)-acetates

Article abstract of DOI:10.1016/j.tet.2020.131101

A new one-pot four-component preparation of polysubstituted thiazoles by a cascade Ugi/Wittig cyclization has been developed. The four-component reactions of the odorless isocyano(triphenylphosphoranylidene)acetates 1, aldehydes 2, amines 3 and thiocarboxylic acids 4 produced 2,4,5-trisubstituted thiazoles 5 in moderate to good yields in the presence of triethylamine. The two-component reactions between isocyano(triphenylphosphoranylidene)acetates 1 and thiocarboxylic acids 4 in the presence of triethylamine provided the corresponding 4,5-disubstituted thiazoles 6 in good yields as well.

Full text of DOI:10.1016/j.tet.2020.131101

Journal Pre-proof
One-pot four-component synthesis of polysubstituted thiazoles via cascade Ugi/Wittig
cyclization starting from odorless Isocyano(triphenylphosphoranylidene)-acetates
Zhi-Rong Guan, Zi-Ming Liu, Qin Wan, Ming-Wu Ding
PII:
S0040-4020(20)30222-2
https://doi.org/10.1016/j.tet.2020.131101
TET 131101
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 December 2019
Revised Date: 16 February 2020
Accepted Date: 2 March 2020
Please cite this article as: Guan Z-R, Liu Z-M, Wan Q, Ding M-W, One-pot four-component
synthesis of polysubstituted thiazoles via cascade Ugi/Wittig cyclization starting from odorless
Isocyano(triphenylphosphoranylidene)-acetates, Tetrahedron (2020), doi: https://doi.org/10.1016/
j.tet.2020.131101.
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Graphical Abstract
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One-Pot Four-Component Synthesis of
Polysubstituted Thiazoles via Cascade Ugi/Wittig
Cyclization Starting from Odorless Isocyano(triphenylphosphoranylidene)-acetates
Zhi-Rong Guan, Zi-Ming Liu, Qin Wan, and Ming-Wu Ding*
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Hubei International Scientific and
Technological Cooperation Base of Pesticide and Green Synthesis, Central China Normal University, Wuhan,
430079, P. R. China
O
COOR1
R5
NC
PPh3
R1O
N
R2CHO
one-pot
R4R3N
+
NEt3
S
R5COSH
R2
R3R4NH

Tetrahedron
1

One-Pot Four-Component Synthesis of Polysubstituted Thiazoles
via Cascade Ugi/Wittig Cyclization Starting from Odorless
Isocyano(triphenylphosphoranylidene)-acetates
Zhi-Rong Guan, Zi-Ming Liu, Qin Wan and Ming-Wu Ding*
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Hubei International Scientific
and Technological Cooperation Base of Pesticide and Green Synthesis, Central China Normal University,
Wuhan 430079, People’s Republic of China
mwding@mail.ccnu.edu.cn
Abstract: A new one-pot four-component preparation of polysubstituted thiazoles by a cascade Ugi/Wittig
cyclization
has
been
developed.
The
four-component
reactions
of
the
odorless
isocyano(triphenylphosphoranylidene)acetates 1, aldehydes 2, amines 3 and thiocarboxylic acids 4
produced 2,4,5-trisubstituted thiazoles 5 in moderate to good yields in the presence of triethylamine. The
two-component reactions between isocyano(triphenylphosphoranylidene)acetates 1 and thiocarboxylic
acids 4 in the presence of triethylamine provided the corresponding 4,5-disubstituted thiazoles 6 in good
yields as well.
Key words: thiazole; Ugi reaction; Wittig reaction; isocyano(triphenylphosphoranylidene)acetate;
thiocarboxylic acid
1. Introduction
Thiazoles are important heterocyclic compounds because they possess highly valuable skeletons widely
found in many biologically active compounds and pharmaceuticals[1]. A number of thiazole derivatives
have exhibited good biological activities, including antibacterial[2-3], antifungal[4], anticancer[5],
antitumor[6-7] and anti-inflammatory activities[8]. Numerous synthetic methods to thiazoles have been
developed[9-17]. For examples, some fully substituted thiazoles were prepared by copper-catalyzed
1

cyclization of α-imino-β-oxodithioesters with α-diazocarbonyls[9]. An efficient synthesis of
2,4,5-trisubstituted thiazoles was provided via the reactions of α-nitroepoxides with thioureas under mild
conditions[10]. Recently Zhu and co-workers described a method to 2,4,5-trisubstituted thiazoles by one
equivalent of thiocarboxylic acids and two equivalents of isocyanides under the presence of Yttrium
Triflate[11]. However, these methods suffer from some drawbacks such as harsh reaction conditions,
multistep synthesis and the use of the toxic transition-metal catalysts. Hence, the development of simple
and convenient synthetic method to polysubstituted thiazoles is in growing demand for synthetic organic
and pharmaceutical chemists.
Owing to their exceptional synthetic efficiency and high atom economy, isocyanide based
multicomponent reactions (IMCRs) have attracted great attention in the synthesis of diverse compounds in
the past decades[18]. Among the IMCRs, the Ugi reactions have drawn considerable interest in synthesis of
organic molecules, especially heterocyclic compounds, under mild one-pot reaction conditions[19]. The
Wittig reaction is also a powerful synthetic tool to construct carbon-carbon double bonds between
phosphorus ylide and carbonyl compounds[20]. Recently, we have reported the synthesis of new stable
Wittig reagent isocyano(triphenylphosphoranylidene)-acetates 1 and its application in one-step
four-component preparation of oxazoles (Scheme 1a)[21]. Continuing our interests in synthesis of
heterocycles via Ugi and Wittig reactions[22], herein we wish to report a new efficient synthesis of
polysubstituted thiazoles by cascade Ugi/Wittig cyclization starting from odorless
isocyano(triphenylphosphoranylidene)-acetates 1 by using thio S-acids instead of acids (Scheme 1b).
2

a) previous work: four-component synthesis of oxazoles
O
COOR1
R5
NC
R1O
N
R2CHO
R4R3N
PPh3
1
+
O
CH2Cl2
r.t.
R2
R5COOH
R3R4NH
b) this work: four-component synthesis of thiazoles in the presence of a base
O
COOR1
NC
R1O
N
NEt3
R2CHO
R4R3N
PPh3
R5
1
+
S
MeOH
r.t.
R2
R5COSH
R3R4NH
Scheme 1. One-step four-component synthesis of oxazoles and thiazoles
2. Results and discussion
Firstly, we chose the four-component reaction of isocyano(triphenylphosphoranylidene)acetate 1a,
4-trifluorobenzaldehyde 2a, diethylamine 3a, and thioacetic acid 4a as the model reaction to optimize the
reaction
condition
(Table
1).
Though
four-component
reaction
of
isocyano(triphenylphosphoranylidene)acetates 1, aldehydes, amines and acids gave oxazoles successfully
as we reported early[21], the using of thio S-acid instead of acid failed to produce the corresponding
thiazole 5a (Table 1, entry 1). We speculated that the thio S-acid was more acidic than the corresponding
acid, which might result in the decomposition of isocyano(triphenylphosphoranylidene)acetate 1. Then a
base (NEt3) was added to the reaction mixture to adjust the solution acidity. As NEt3 (0.2 equiv) was
added to the reaction system, we were pleased to find that the corresponding thiazole 5a was produced in
27% yield (entry 2). Increasing of the amount of NEt3 to 0.5 equiv promoted the yield to 58% (entry 3).
When NEt3 (1.0 equiv) was used, the best yield (90%) was obtained (entry 4). Further Increasing of the
amount of NEt3 to 2.0 equiv resulted in a relative lower yield (68%, entry 5). Changing of the solvent
from MeOH to CH2Cl2, toluene, CH3CN or DMF gave a relative lower or even no yield (0-71%, entry 6-9)
as NEt3 (1.0 equiv) was added. As CH2Cl2 was used as the solvent, the two component (between 1a and
3

4a) product 6a was also produced in minor amount (21% yield, entry 6). Finally, as the inorganic bases
(Na2CO3, K2CO3, NaOH or KOH) were used, relative lower yields (54-78%, entry 10-13) were obtained.
Therefore, the optimum reaction condition was identified (Table 1, entry 4).
Table 1. Optimization of the Reaction Conditions[a]
CF3
O
CF3
NC
H3CO
PPh3
CHO
O
1a
Additive
2a
S
N
+
Solvent
r.t.
CH3
H
N
O
N
OCH3
H3C
SH
O
O
5a
4a
3a
Additive
(equiv.)
-
Yield[b]
(%)
Entry Solvent
1
2
MeOH
MeOH
0
NEt3 (0.2)
NEt3 (0.5)
NEt3 (1.0)
NEt3 (2.0)
NEt3 (1.0)
NEt3 (1.0)
NEt3 (1.0)
NEt3 (1.0)
27
58
MeOH
MeOH
MeOH
CH2Cl2
Toluene
CH3CN
DMF
3
4
90
5
68
71(21)[c]
6
7
0
8
56
9
0
MeOH
MeOH
MeOH
MeOH
10
11
12
13
Na2CO3 (1.0)
K2CO3 (1.0)
NaOH (1.0)
KOH (1.0)
54
58
62
78
[a] General conditions: 1a (3.0 mmol), 2a (3.0 mmol), 3a (3.0 mmol), solvent (15 mL), bases (as above), then 4a (3.0 mmol),
stirred in a sealed tube for 12 h at room temperature. [b] Isolated yields based on 1a. [c] The two component (between 1a and
4a) product 6a was also produced in minor amount (21% yield).
4

Table 2. Substrate Scope of Thiazoles 5[a][b]
COOR1
R5
O
N
NC
NEt3
R4R3N
R1O
+ R3R4NH
2
+
+
R CHO
R5COSH
S
PPh3
MeOH
r.t.
R2
1
2
3
4
5
Cl
Cl
Cl
CF3
CF3
S
S
S
S
N
N
N
N
S
N
O
N
N
N
N
O
N
O
O
O
O
O
O
O
O
O
O
5b 73%
5c 91%
5a 90%
5d 83%
5e 86%
CF3
CF3
NO2
NO2
Cl
S
S
N
N
S
S
S
N
N
N
O
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
5h 80%
5f 80%
Br
5g 95%
5i 90%
5j 85%
Br
Br
Br
S
N
S
S
N
S
N
O
N
Cl
N
N
N
N
O
O
O
O
O
O
O
O
5k 89%
5n 83%
5l 82%
5m 75%
S
S
S
N
S
N
S
N
S
N
N
N
N
N
O
O
O
O
O
O
O
O
5o 72%
5p 70%
5q 78%
5r 85%
General conditions: 1 (3.0 mmol), 2 (3.0 mmol), 3 (3.0 mmol), solvent (15 mL), NEt3 (3.0 mmol), then 4 (3.0 mmol),
stirred in a sealed tube for 12 h at room temperature. [b] Isolated yields based on 1.
With the optimized conditions in hand, the substrate scope was then explored. The reactions were
carried out smoothly to give the corresponding 2,4,5-trisubstituted thiazoles 5 with different substituents
of the reactants in moderate to good yields (Table 2). Various substituted aromatic aldehydes 2 bearing
electron-withdrawing or electron-donating group were applicable for the four-component reaction. The
5

aromatic aldehydes substituted by different electron-withdrawing groups, such as chloro (5a-5d),
trifluoromethyl (5e-5h), nitro (5i-5j), and bromo (5k-5n), readily underwent the four-component reaction
to give thiazoles 5a-5n in 73-95% yields. Benzaldehyde and p-methylbenzaldehyde were also feasible in
this transformation, giving 5o and 5p in 70-72% yields. In addition, heterocyclic 2-thiophenformaldehyde
was also utilized to synthesize the corresponding thiazoles (5q-5r) in moderate to good yields (78%-85%).
Different secondary amines 3 and thio S-acids 4 may be utilized in above one-pot cyclization to prepare
thiazoles 5. As indicated in Table 2, various cyclic or acyclic acids secondary amines, and aromatic or
aliphatic thio S-acids 4 readily occur one-pot cyclization at room temperature, leading to the smooth
formation of the trisubstituted thiazoles 5. These results demonstrated the superior competency of this
strategy to access diversely trisubstituted thiazoles 5.
In the process of entry 6 on condition optimization for trisubstituted thiazoles 5, we found another
possible product. Through separation and purification, we confirmed that it was disubstituted thiazole 6a,
and its yield reached 21%. Then direct two-component reaction of ylide 1a and thio S-acid 4a was then
undertook, however, the reaction gave complex mixture in MeOH or CH2Cl2, which might be due to the
decomposition of isocyano(triphenylphosphoranylidene)acetate 1 under the acidic condition. In the
presence of 1 equiv of triethylamine to adjust the solution acidity, the reaction proceeded smoothly at
room temperature and the corresponding 4,5-disubstituted thiazole 6a was obtained in 51% (in MeOH) or
83% (in CH2Cl2) yield. We speculated that the reason might be that the polarity of dichloromethane was
smaller than that of methanol. In the two-component reaction, thiocarboxyl anion 8 was more stable in
methanol, making it less likely for thiocarboxyl anion 8 to attack isocyanide 12. In the less polar solvent
dichloromethane, thiocarboxyl anion 8 had better activity so that two-component reaction took place
smoothly. In the four-component reaction, the polar solvent methanol was more conducive to the
6

formation of imine cation 9, while thiocarboxyl anion 8 might be more active for attacking imine cation 9.
We speculated that the formation of imine cation 9 was the rate-determining step for the four-component
reaction. The other two-component reactions of ylides 1 and thio S-acids 4 were then carried out in
CH2Cl2 (Table 3). Gratifyingly, different aliphatic and aromatic thio S-acids can be used in the
two-component reactions to produce 4,5-disubstituted thiazoles 6 in moderate to good yields. As shown in
Table 3, aliphatic thio S-acids (6a-6d) and aromatic thio S-acids (6e-6s), regardless of para-substituted
thiobenzoic acids (6e-6k) or ortho-substituted thiobenzoic acids (6n-6s), were efficient for the
two-component reactions and a series of products 6 were prepared under mild reaction condition.
Table 3. Preparation of Disubstituted Thiazoles 6[a][b]
COOR1
R5
O
NEt3
N
NC
PPh3
R5COSH
R1O
+
CH2Cl2
r.t.
S
1
4
6
S
S
S
NO2
S
S
N
N
N
N
N
O
O
O
O
O
O
O
O
O
S
O
6e 94%
6a 83%
6b 79%
6c 78%
6d 75%
S
S
S
S
Cl
OCH3
Cl
OCH3
N
N
N
N
N
O
O
O
O
O
O
N
O
O
O
O
6f 89%
6g 88%
6h 87%
6i 86%
6j 88%
F
F
S
S
S
S
S
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
6k 86%
6l 85%
6m 84%
6n 72%
6o 71%
Cl
O
Cl
O
S
S
S
S
N
N
N
O
O
O
O
O
O
O
O
6p 79%
6q 70%
6r 70%
6s 71%
General conditions: 1 (3.0 mmol), solvent (15 mL), NEt3 (3.0 mmol), then 4 (3.0 mmol), stirred in a sealed tube for 12 h at
room temperature. [b] Isolated yields based on 1.
7

According to these above experiments, the plausible reaction mechanism for 2,4,5-trisubstituted
thiazoles 5 is proposed in scheme 2. The reaction involves an initial condensation between aldehyde 2,
amine 3 and thio S-acid 4 to give the iminium cation 7, with liberating of a molecule of H2O and
conjugate base of the acid 8. Then the ylide 1 undergoes a nucleophilic addition to the iminium cation 7 to
form the intermediate 9, which is attacked by conjugate base of the thio S-acid 8 via nucleophilic addition
to form the intermediate 10. Finally, an intramolecular Wittig reaction takes place through intermediate 11
to give the product 5.
Scheme 2. Possible mechanism for the formation of thiazole products 5
H2O
O
R2 R3
R1CHO R2NHR3
NEt3
N
R4 SH
R1
R4COS
8
2
3
4
7
PPh3
C
N
COOR5
1
R4COS
8
R2 R3
N
R2 R3
N
R4
S
R1
R1
O
N
PPh3
N
PPh3
COOR5
9
COOR5
10
R2
R3
R4
R3
N
N
R1
S
-Ph3PO
R5
O
R2
S
R4
N
N
R1OOC
11
COOR5
P
Ph3
5
Meanwhile, the possible reaction mechanism for disubstituted thiazoles 6 was proposed in scheme 3. In
the presence of triethylamine, deprotonation of thiocarboxylic acid 4 could converted into thiocarboxyl
anion 8. Protonation of the isocyanide ylide 1 generates the intermediate 12, which is attacked by
conjugate base of the thio S-acid 8 through nucleophilic addition to give the intermediate 13. Finally, an
intramolecular Wittig reaction takes place through intermediate 14 to produce the final product thiazoles
6.
8

Scheme 3. Possible mechanism for the formation of thiazole products 6
3. Conclusion
In conclusion, we have reported the synthesis of 2,4,5-trisubstituted thiazoles and 4,5-disubstituted
thiazoles via the four-component or two-component Ugi/Wittig reactions starting from the odorless
isocyano(triphenylphosphoranylidene)acetates 1. The method afforded a facile and efficient strategy to the
synthesis of various multisubstituted thiazoles by direct one-pot cyclization under mild condition in
moderate to good yields, which makes it significant in synthetic and medicinal chemistry.
4. Experimental
4.1 General
All experiments were carried out under an air atmosphere. Melting points were determined using an
1
X-4 model apparatus and were uncorrected. H NMR were recorded in CDCl3 on a Varian Mercury 600
spectrometer and resonances were relative to TMS. 13C {1H} NMR spectra were recorded in CDCl3 on a
Varian Mercury 600 (150 MHz) with complete proton decoupling spectrophotometers (CDCl3: 77.0 ppm).
MS were measured on a Finnigan Trace MS spectrometer. Elementary analyses were taken on a Vario EL
III elementary analysis instrument. The isocyano(triphenylphosphoranylidene)acetates 1 were prepared by
the method we reported previously[21]
.
4.2 Synthesis of trisubstituted thiazoles 5
Typical Procedure for the Synthesis of trisubstituted thiazoles 5.
A
mixture of
9

isocyano(triphenylphosphoranylidene)acetate 1 (3.0 mmol), aldehyde 2 (3.0 mmol), secondary amine 3
(3.0 mmol) and thio S-acid 4 (3.0 mmol) and triethylamine (0.30 g, 3.0 mmol) was stirred in methanol (15
mL) at room temperature. After completion of the reaction, the solvent was evaporated completely under
reduced pressure and the residue was purified by column chromatography with EtOAc/petroleum ether
(1:5) as the eluent to afford 5.
4.2.1Methyl 5-methyl-2-(morpholino(4-(trifluoromethyl) phenyl) methyl) thiazole-4-carboxylate (5a)
1
Light yellow solid (1.080 g, 90%). Mp: 78-79 °C. H NMR (CDCl3, 600 MHz) δ (ppm) 7.64 (d, J =
8.4 Hz, 2H, Ar-H), 7.60 (d, J = 8.4 Hz, 2H, Ar-H), 4.85 (s, 1H, CH), 3.91 (s, 3H, OCH3), 3.73-3.72 (m,
4H, 2OCH2), 2.73 (s, 3H, CH3), 2.52-2.45 (m, 4H, 2NCH2). 13C NMR (CDCl3, 150 MHz) δ (ppm) 168.2,
2
1
162.5, 146.7, 142.3, 140.0, 130.2 (q, JF-C = 30 Hz), 128.7, 125.7, 123.7 (q, JF-C = 270 Hz), 72.8, 66.7,
52.2, 52.0, 13.2. MS (EI, 70 eV): m/z (%) = 400 (100, M+), 315 (18), 283 (9), 255 (21), 159 (14). Anal.
Calcd for C18H19F3N2O3S: C, 53.99; H, 4.78; N, 7.00. Found: C, 53.75; H, 5.06; N, 7.23.
4.2.2Methyl 2-((4-chlorophenyl) (dibutylamino)methyl)-5-methylthiazole-4-carboxylate (5b)
1
Operation as above. White solid (0.894 g, 73%). Mp: 53-54 °C. H NMR (CDCl3, 600 MHz) δ (ppm)
7.34-7.28 (m, 4H, Ar-H), 5.17 (s, 1H, CH), 3.89 (s, 3H, OCH3), 2.74 (s, 3H, CH3), 2.54-2.49 (m, 2H,
NCH2), 2.42-2.37 (m, 2H, NCH2), 1.75-1.38 (m, 4H, 2CH2), 1.24-1.18 (m, 4H, 2CH2), 0.85 (t, J = 7.2 Hz,
6H, 2CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 170.6, 162.9, 146.1, 139.9, 137.3, 133.4, 130.2, 128.5,
68.0, 52.0, 49.9, 28.6, 20.4, 14.0, 13.3. MS (EI, 70 eV): m/z (%) = 408 (100, M+), 280 (9), 245 (21), 220
(18), 128 (11). Anal. Calcd for C21H29ClN2O2S: C, 61.67; H, 7.15; N, 6.85. Found: C, 61.96; H, 7.37; N,
6.56.
4.2.3Methyl 2-((4-chlorophenyl) (pyrrolidin-1-yl) methyl)-5-methylthiazole-4-carboxylate (5c)
1
Operation as above. White solid (0.956 g, 91%). Mp: 99-100 °C. H NMR (CDCl3, 600 MHz) δ (ppm)
7.47 (d, J = 7.8 Hz, 2H, Ar-H), 7.29 (d, J = 7.8 Hz, 2H, Ar-H), 4.71 (s, 1H, CH), 3.90 (s, 3H, OCH3), 2.72
(s, 3H, CH3), 2.52-2.48 (m, 4H, 2NCH2), 1.79-1.78 (m, 4H, 2CH2). 13C NMR (CDCl3, 150 MHz) δ (ppm)
170.4, 162.8, 146.4, 139.4, 139.2, 133.5, 129.2, 128.8, 72.2, 53.2, 52.1, 23.4, 13.3. MS (EI, 70 eV): m/z
(%) = 350 (100, M+), 280 (11), 248 (8), 220 (27), 186 (25). Anal. Calcd for C17H19ClN2O2S: C, 58.19; H,
5.46; N, 7.98. Found: C, 58.46; H, 5.18; N, 7.76.
10

4.2.4Methyl 2-((4-chlorophenyl) (morpholino)methyl)-5-methylthiazole-4-carboxylate (5d)
1
Operation as above. White solid (0.911 g, 83%). Mp: 115-116 °C. H NMR (CDCl3, 600 MHz) δ (ppm)
7.43 (d, J = 8.4 Hz, 2H, Ar-H), 7.31 (d, J = 8.4 Hz, 2H, Ar-H), 4.75 (s, 1H, CH), 3.90 (s, 3H, OCH3), 3.71
(m, 4H, 2OCH2), 2.73 (s, 3H, CH3), 2.51-2.41 (m, 4H, 2NCH2). 13C NMR (CDCl3, 150 MHz) δ (ppm)
168.8, 162.3, 146.7, 139.9, 136.9, 133.9, 129.7, 129.0, 72.7, 66.8, 52.2, 52.1, 13.3. MS (EI, 70 eV): m/z
(%) = 366 (100, M+), 281 (7), 249 (14), 221 (28), 89 (23). Anal. Calcd for C17H19ClN2O3S: C, 55.66; H,
5.22; N, 7.64. Found: C, 55.39; H, 5.03; N, 7.39.
4.2.5Methyl 2-((diethylamino)(4-(trifluoromethyl) phenyl) methyl)-5-methylthiazole-4-carboxylate(5e)
1
Operation as above. White solid (0.996 g, 86%). Mp: 96-97 °C. H NMR (CDCl3, 600 MHz) δ (ppm)
7.60-7.55 (m, 4H, Ar-H), 5.25 (s, 1H, CH), 3.89 (s, 3H, OCH3), 2.74 (s, 3H, CH3), 2.69-2.63 (m, 2H,
NCH2), 2.56-2.51 (m, 2H, NCH2), 1.01 (t, J = 7.2 Hz, 6H, 2CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm)
2
1
170.2, 162.6, 146.1, 143.1, 139.8, 129.7 (q, JF-C = 30 Hz), 128.9, 125.2, 123.8 (q, JF-C = 270 Hz), 68.1,
51.8, 43.0, 13.1, 11.0. MS (EI, 70 eV): m/z (%) = 386 (100, M+), 315 (4), 283 (17), 255 (35), 72 (12).
Anal. Calcd for C18H21F3N2O2S: C, 55.95; H, 5.48; N, 7.25. Found: C, 56.12; H, 5.70; N, 7.43.
4.2.6Methyl 2-((dibutylamino)(4-(trifluoromethyl) phenyl) methyl)-5-methylthiazole-4-carboxylate (5f)
Operation as above. Light yellow oil (1.061 g, 80%). 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.58 (d, J = 7.8
Hz, 2H, Ar-H), 7.53 (d, J = 7.8 Hz, 2H, Ar-H), 5.27 (s, 1H, CH), 3.89 (s, 3H, OCH3), 2.75 (s, 3H, CH3),
2.56-2.51 (m, 2H, NCH2), 2.43-2.38 (m, 2H, NCH2), 1.52-1.41 (m, 4H, 2CH2), 1.26-1.22 (m, 4H, 2CH2),
0.85 (t, J = 7.2 Hz, 6H, 2CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 169.8, 162.7, 146.0, 142.7, 140.0,
2
1
129.7 (q, JF-C = 30 Hz), 129.1, 125.1, 123.9 (q, JF-C = 270 Hz), 68.0, 51.8, 49.8, 28.6, 20.3, 13.8, 13.1.
MS (EI, 70 eV): m/z (%) = 442 (100, M+), 315 (9), 283 (14), 255 (16), 128 (19). Anal. Calcd for
C22H29F3N2O2S: C, 59.71; H, 6.61; N, 6.33. Found: C, 60.0; H, 6.90; N, 6.10.
4.2.7Methyl 5-methyl-2-(pyrrolidin-1-yl(4-(trifluoromethyl)phenyl)methyl)thiazole-4-carboxylate (5g)
Operation as above. Light yellow oil (1.094 g, 95%). 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.67 (d, J = 7.8
11

Hz, 2H, Ar-H), 7.58 (d, J = 8.4 Hz, 2H, Ar-H), 4.81 (s, 1H, CH), 3.90 (s, 3H, OCH3), 2.72 (s, 3H, CH3),
2.53-2.51 (m, 4H, 2NCH2), 1.81-1.80 (m, 4H, 2CH2). 13C NMR (CDCl3, 150 MHz) δ (ppm) 169.8, 162.7,
2
1
146.4, 144.6, 139.5, 129.9 (q, JF-C = 30 Hz), 128.2, 125.6, 123.9 (q, JF-C = 270 Hz), 72.4, 53.1, 52.0,
23.4, 13.2. MS (EI, 70 eV): m/z (%) = 384 (100, M+), 314 (6), 254 (13), 172 (17), 144 (19). Anal. Calcd
for C18H19F3N2O2S: C, 56.24; H, 4.98; N, 7.29. Found: C, 56.51; H, 5.19; N, 7.01.
4.2.8Methyl 2-((4-chlorophenyl) (diethylamino)methyl)-5-methylthiazole-4-carboxylate (5h)
Operation as above. White solid (0.845 g, 80%). Mp: 77-78 °C. 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.40
(d, J = 7.8 Hz, 2H, Ar-H), 7.29 (d, J = 8.4 Hz, 2H, Ar-H), 5.15 (s, 1H, CH), 3.89 (s, 3H, OCH3), 2.73 (s,
3H, CH3), 2.67-2.61 (m, 2H, NCH2), 2.56-2.50 (m, 2H, NCH2), 0.99 (t, J = 7.2 Hz, 6H, 2CH3).13C NMR
(CDCl3, 150 MHz) δ (ppm) 170.0, 162.8, 146.2, 139.8, 137.7, 133.4, 130.0, 128.6, 68.1, 52.0, 43.0, 13.3,
11.1. MS (EI, 70 eV): m/z (%) = 352 (100, M+), 281 (13), 249 (7), 221 (17), 186 (25). Anal. Calcd for
C17H21ClN2O2S: C, 57.86; H, 6.00; N, 7.94. Found: C, 58.13; H, 6.22; N, 8.12.
4.2.9Methyl 5-methyl-2-((4-nitrophenyl) (pyrrolidin-1-yl) methyl) thiazole-4-carboxylate (5i)
1
Operation as above. Light yellow solid (0.975 g, 90%). Mp: 127-128 °C. H NMR (CDCl3, 600 MHz) δ
(ppm) 8.19 (d, J = 8.4 Hz, 2H, Ar-H), 7.74 (d, J = 7.8 Hz, 2H, Ar-H), 4.88 (s, 1H, CH), 3.91 (s, 3H,
OCH3), 2.73 (s, 3H, CH3), 2.54-2.52 (m, 4H, 2NCH2), 1.83-1.82 (m, 4H, 2CH2). 13C NMR (CDCl3, 150
MHz) δ (ppm) 169.0, 162.7, 147.7, 147.3, 146.7, 139.7, 128.8, 124.0, 72.2, 53.1, 52.1, 23.4, 13.4. MS (EI,
70 eV): m/z (%) = 361 (100, M+), 292 (15), 260 (8), 232 (14), 70 (16). Anal. Calcd for C17H19N3O4S: C,
56.50; H, 5.30; N, 11.63. Found: C, 56.73; H, 5.52; N, 11.36.
4.2.10
Ethyl 5-(4-methoxyphenyl)-2-((4-nitrophenyl) (piperidin-1-yl) methyl) thiazole-4-carboxylate(5j)
1
Operation as above. Light yellow solid (1.227 g, 85%). Mp: 142-143 °C. H NMR (CDCl3, 600 MHz) δ
(ppm) 8.21 (d, J = 7.8 Hz, 2H, Ar-H), 7.67 (d, J = 7.8 Hz, 2H, Ar-H), 7.41 (d, J = 7.8 Hz, 2H, Ar-H), 6.93
(d, J = 7.8 Hz, 2H, Ar-H), 4.96 (s, 1H, CH), 4.27 (t, J = 8.4 Hz, 2H, OCH2), 3.85 (s, 3H, OCH3),
2.48-2.44 (m, 4H, 2NCH2), 1.61-1.47 (m, 6H, 3CH2), 1.21 (t, J = 6.0 Hz, 3H, CH3). 13C NMR (CDCl3,
150 MHz) δ (ppm) 170.7, 162.1, 160.3, 148.0, 147.3, 146.0, 139.0, 131.1, 129.5, 123.8, 122.5, 113.5, 72.8,
61.2, 55.3, 52.8, 25.9, 24.1, 14.1. MS (EI, 70 eV): m/z (%) = 481 (100, M+), 397 (30), 351 (9), 323 (14),
12

276 (21). Anal. Calcd for C25H27N3O5S: C, 62.35; H, 5.65; N, 8.73. Found: C, 62.64; H, 5.91; N, 8.90.
4.2.11
Ethyl 2-((4-bromophenyl) (piperidin-1-yl) methyl)-5-phenylthiazole-4-carboxylate (5k)
1
Operation as above. White solid (1.292 g, 89%). Mp: 100-101 °C. H NMR (CDCl3, 600 MHz) δ (ppm)
7.47-7.35 (m, 9H, Ar-H), 4.79 (s, 1H, CH), 4.27-4.21 (m, 2H, CH2), 2.47-2.40 (m, 4H, 2NCH2), 1.58-1.45
(m, 6H, 3CH2), 1.16 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 172.9, 162.1, 147.3,
139.5, 137.7, 131.7, 130.8, 129.8, 128.9, 128.0, 121.7, 72.9, 61.1, 52.9, 26.0, 24.3, 13.9. MS (EI, 70 eV):
m/z (%) = 484 (100, M+), 415 (13), 260 (17), 207 (13), 186 (9). Anal. Calcd for C24H25BrN2O2S: C, 59.38;
H, 5.19; N, 5.77. Found: C, 59.66; H, 5.41; N, 5.55.
4.2.12
Ethyl 2-((4-bromophenyl) (morpholino)methyl)-5-phenylthiazole-4-carboxylate (5l)
1
Operation as above. Light yellow solid (1.196 g, 82%). Mp: 82-83 °C. H NMR (CDCl3, 600 MHz) δ
(ppm) 7.50-7.40 (m, 9H, Ar-H), 4.81 (s, 1H, CH), 4.25 (t, J = 7.8 Hz, 2H, CH2), 3.72 (s, 4H, 2OCH2),
2.55-2.50 (m, 4H, 2NCH2), 1.16 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 171.2,
161.9, 147.5, 139.7, 137.2, 132.0, 130.5, 130.2, 129.8, 129.1, 128.0, 122.2, 72.9, 66.9, 61.2, 52.3, 13.9.
MS (EI, 70 eV): m/z (%) = 486 (100, M+), 401 (22), 329 (16), 188 (13), 77 (9). Anal. Calcd for
C23H23BrN2O3S: C, 56.68; H, 4.76; N, 5.75. Found: C, 56.91; H, 4.98; N, 5.90.
4.2.13
Ethyl 2-((4-bromophenyl) (diethylamino)methyl)-5-(4-chlorophenyl) thiazole-4-carboxylate (5m)
1
Operation as above. White solid (1.139 g, 75%). Mp: 90-91 °C. H NMR (CDCl3, 600 MHz) δ (ppm)
7.48-7.36 (m, 8H, Ar-H), 5.20 (s, 1H, CH), 4.26 (t, J = 7.2 Hz, 2H, OCH2), 2.72-2.66 (m, 2H, NCH2),
2.58-2.52 (m, 2H, NCH2), 1.20 (t, J = 7.2 Hz, 3H, CH3), 1.02 (t, J = 7.2 Hz, 6H, 2CH3). 13C NMR (CDCl3,
150 MHz) δ (ppm) 174.0, 161.9, 145.8, 139.7, 137.6, 135.1, 131.6, 131.1, 130.5, 129.2, 128.2, 121.7, 68.1,
61.2, 43.1, 14.0, 11.2. MS (EI, 70 eV): m/z (%) = 506 (100, M+), 434 (19), 362 (7), 155 (13), 72 (9). Anal.
Calcd for C23H24BrClN2O2S: C, 54.39; H, 4.76; N, 5.52. Found: C, 54.65; H, 4.97; N, 5.40.
4.2.14
Ethyl 5-benzyl-2-((4-bromophenyl) (piperidin-1-yl) methyl) thiazole-4-carboxylate (5n)
1
Operation as above. White solid (1.240 g, 83%). Mp: 87-88 °C. H NMR (CDCl3, 600 MHz) δ (ppm)
13

7.42-7.25 (m, 9H, Ar-H), 4.71 (s, 1H, CH), 4.52 (s, 2H, CH2), 4.40 (q, J = 7.2 Hz, 2H, OCH2), 2.38-2.29
(m, 4H, 2NCH2), 1.52-1.41 (m, 6H, 3CH2), 1.36 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ
(ppm) 171.3, 162.3, 150.5, 139.8, 139.1, 137.9, 131.6, 130.2, 128.7, 128.6, 126.8, 121.6, 72.8, 61.1, 52.9,
33.7, 25.9, 24.2, 14.3. MS (EI, 70 eV): m/z (%) = 498 (100, M+), 417 (17), 369 (9), 147 (12), 84 (19).
Anal. Calcd for C25H27BrN2O2S: C, 60.12; H, 5.45; N, 5.61. Found: C, 60.40; H, 5.57; N, 5.49.
4.2.15
Ethyl 5-methyl-2-(phenyl(pyrrolidin-1-yl) methyl) thiazole-4-carboxylate (5o)
1
Operation as above. Light yellow solid (0.713 g, 72%). Mp: 45-46 °C. H NMR (CDCl3, 600 MHz) δ
(ppm) 7.54 (d, J = 7.2 Hz, 2H, Ar-H), 7.31 (t, J = 7.2 Hz, 2H, Ar-H), 7.24 (t, J = 7.2 Hz, 1H, Ar-H), 4.75
(s, 1H, CH), 4.39 (q, J = 6.6 Hz, 2H, OCH2), 2.69 (s, 3H, CH3), 2.54-2.51 (m, 4H, 2NCH2), 1.79 (s, 4H,
2CH2), 1.37 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 170.6, 162.5, 145.7, 140.7,
139.8, 128.6, 127.9, 127.8, 72.9, 60.9, 53.2, 23.4, 14.4, 13.4. MS (EI, 70 eV): m/z (%) = 330 (100, M+),
261 (16), 215 (19), 187 (13), 91 (8). Anal. Calcd for C18H22N2O2S: C, 65.42; H, 6.71; N, 8.48. Found: C,
65.60; H, 6.49; N, 8.31.
4.2.16
Ethyl 5-methyl-2-(pyrrolidin-1-yl(p-tolyl) methyl) thiazole-4-carboxylate (5p)
1
Operation as above. White solid (0.722 g, 70%). Mp: 104-105 °C. H NMR (CDCl3, 600 MHz) δ (ppm)
7.42 (d, J = 7.8 Hz, 2H, Ar-H), 7.12 (d, J = 7.2 Hz, 2H, Ar-H), 4.70 (s, 1H, CH), 4.38 (q, J = 7.2 Hz, 2H,
OCH2), 2.69 (s, 3H, CH3), 2.53-2.49 (m, 4H, 2NCH2), 2.31 (s, 3H, CH3), 1.78 (s, 4H, 2CH2), 1.37 (t, J =
7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 171.0, 162.5, 145.6, 139.8, 137.9, 137.5, 129.3,
127.8, 72.6, 60.9, 53.2, 23.4, 21.1, 14.4, 13.4. MS (EI, 70 eV): m/z (%) = 344 (100, M+), 275 (17), 229
(14), 201 (12), 105 (9). Anal. Calcd for C19H24N2O2S: C, 66.25; H, 7.02; N, 8.13. Found: C, 66.41; H,
7.30; N, 8.00.
4.2.17
Ethyl 2-((diethylamino)(thiophen-2-yl) methyl)-5-phenylthiazole-4-carboxylate (5q)
Operation as above. Light yellow oil (0.936 g, 78%). 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.50-7.29 (m,
6H, Ar-H), 7.06-6.96 (m, 2H, Ar-H), 5.57 (s, 1H, CH), 4.27-4.24 (m, 2H, CH2), 2.72-2.58 (m, 4H,
2NCH2), 1.18 (t, J = 7.2 Hz, 3H, CH3), 1.09 (t, J = 7.2 Hz, 6H, 2CH3). 13C NMR (CDCl3, 150 MHz) δ
14

(ppm) 172.2, 162.2, 147.1, 142.1, 139.6, 130.8, 129.8, 128.9, 128.0, 127.1, 126.3, 125.7, 63.3, 61.1, 43.8,
13.9, 12.2. MS (EI, 70 eV): m/z (%) = 400 (100, M+), 328 (14), 283 (18), 255 (9), 168 (15). Anal. Calcd
for C21H24N2O2S2: C, 62.97; H, 6.04; N, 6.99. Found: C, 63.13; H, 6.26; N, 7.17.
4.2.18
Ethyl 5-phenyl-2-(piperidin-1-yl(thiophen-2-yl) methyl) thiazole-4-carboxylate (5r)
Operation as above. Light yellow oil (1.051 g, 85%). 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.49-7.29 (m,
6H, Ar-H), 7.08-6.95 (m, 2H, Ar-H), 5.19 (s, 1H, CH), 4.28-4.23 (m, 2H, CH2), 2.55-2.46 (m, 4H,
2NCH2), 1.62-1.45 (m, 6H, 3CH2), 1.18 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm)
172.1, 162.1, 147.4, 142.0, 139.5, 130.8, 129.8, 128.9, 128.0, 127.0, 126.5, 125.9, 68.2, 61.1, 52.6, 26.0,
24.3, 14.0. MS (EI, 70 eV): m/z (%) =412 (100, M+), 329 (13), 283 (12), 255 (9), 80 (17). Anal. Calcd for
C22H24N2O2S2: C, 64.05; H, 5.86; N, 6.79. Found: C, 64.26; H, 6.08; N, 6.51.
4.3 Synthesis of disubstituted thiazoles 6
Typical Procedure for the Synthesis of disubstituted thiazoles 6. To a solution of
isocyano(triphenylphosphoranylidene)acetate 1 (3.0 mmol) and triethylamine (0.30 g, 3.0 mmol) in dry
dichloromethane (15 mL) was added thio S-acid 4 (3.0 mmol) at room temperature. After completion of
the reaction, the solvent was removed under reduced pressure. The residue was purified by column
chromatography with EtOAc/petroleum ether (1:4) as eluent to give 6.
4.3.1Methyl 5-methylthiazole-4-carboxylate (6a)
1
White solid (0.391 g, 83%). Mp: 60-61 °C (lit.[23] mp 62-65 °C). H NMR (CDCl3, 600 MHz) δ (ppm)
8.59 (s, 1H, CH), 3.96 (s, 3H, OCH3), 2.82 (s, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 162.7,
149.0, 144.8, 141.6, 52.0, 12.9. MS (EI, 70 eV) m/z (%) = 157 (100, M+), 146 (21), 122 (7), 115 (13), 77
(19).
4.3.2 Ethyl 5-methylthiazole-4-carboxylate (6b)
1
Operation as above. White solid (0.405 g, 79%). Mp: 85-86 °C (lit.[24] mp 89-90 °C). H NMR (CDCl3,
600 MHz) δ (ppm) 8.59 (s, 1H, CH), 4.43 (q, J = 7.2 Hz, 2H, CH2), 2.81 (s, 3H, CH3), 1.43 (t, J = 7.2 Hz,
15

3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 162.3, 149.0, 144.5, 141.9, 61.0, 14.3, 12.9. MS (EI, 70
eV) m/z (%) = 171 (100), 168 (8), 138 (13), 136 (17), 120 (16).
4.3.3 Methyl 5-benzylthiazole-4-carboxylate (6c)
Operation as above. Light yellow oil[25] (0.545 g, 78%). 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.59 (s, 1H,
CH), 7.33-7.25 (m, 5H, Ar-H), 4.61 (s, 2H, CH2), 3.97 (s, 3H, OCH3). 13C NMR (CDCl3, 150 MHz) δ
(ppm) 162.7, 150.2, 150.1, 140.9, 139.0, 128.7, 128.6, 127.0, 52.2, 33.2. MS (EI, 70 eV): m/z (%) = 233
(100, M+), 200 (16), 171 (8), 145 (12), 102 (9).
4.3.4 Ethyl 5-benzylthiazole-4-carboxylate (6d)
1
Operation as above. White solid (0.558 g, 75%). Mp: 50-51 °C (lit.[26] mp 49-50 °C). H NMR (CDCl3,
600 MHz) δ (ppm) 8.62 (s, 1H, CH), 7.33-7.27 (m, 5H, Ar-H), 4.61 (s, 2H, CH2), 4.45 (q, J = 7.2 Hz, 2H,
CH2), 1.43 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 162.3, 150.3, 149.8, 141.3,
139.1, 128.8, 128.7, 127.0, 61.3, 33.3, 14.3. MS (EI, 70 eV): m/z (%) = 247 (100, M+), 201 (18), 146 (11),
136 (14), 91 (7).
4.3.5 Ethyl 5-(4-nitrophenyl) thiazole-4-carboxylate (6e)
1
Operation as above. White solid (0.784 g, 94%). Mp: 138-139 °C. H NMR (CDCl3, 600 MHz) δ (ppm)
8.90 (s, 1H, CH), 8.30 (d, J = 8.4 Hz, 2H, Ar-H), 7.71 (d, J = 7.8 Hz, 2H, Ar-H), 4.35 (q, J = 6.6 Hz, 2H,
CH2), 1.31 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 161.4, 152.4, 148.0, 143.5,
142.2, 136.8, 131.1, 123.2, 61.7, 14.0. MS (EI, 70 eV): m/z (%) = 278 (100, M+), 232 (15), 205 (12), 186
(20), 159 (14). Anal. Calcd for C12H10N2O4S: C, 51.79; H, 3.62; N, 10.07. Found: C, 51.53; H, 3.83; N,
10.30.
4.3.6 Methyl 5-(4-chlorophenyl) thiazole-4-carboxylate (6f)
1
Operation as above. White solid (0.676 g, 89%). Mp: 88-89 °C (lit.[27] mp 88-90 °C). H NMR (CDCl3,
600 MHz) δ (ppm) 8.79 (s, 1H, CH), 7.47-7.41 (m, 4H, Ar-H), 3.87 (s, 3H, OCH3). 13C NMR (CDCl3,
150 MHz) δ (ppm) 162.1, 151.4, 145.6, 140.8, 135.6, 131.2, 128.4, 128.2, 52.3. MS (EI, 70 eV): m/z (%)
16

= 253 (100, M+), 221 (13), 194 (15), 167 (17), 123 (32).
4.3.7Ethyl 5-(4-chlorophenyl) thiazole-4-carboxylate (6g)
1
Operation as above. White solid (0.705 g, 88%). Mp: 147-148 °C (lit.[28] mp 147-148 °C). H NMR
(CDCl3, 600 MHz) δ (ppm) 8.79 (s, 1H, CH), 7.46-7.40 (m, 4H, Ar-H), 4.33 (q, J = 7.2 Hz, 2H, CH2),
1.30 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 161.6, 151.4, 145.2, 141.3, 135.4,
131.2, 128.3, 61.4, 14.0. MS (EI, 70 eV): m/z (%) = 267 (100, M+), 221 (14), 194 (11), 167 (9), 122 (6).
4.3.8 Methyl 5-(4-methoxyphenyl) thiazole-4-carboxylate (6h)
Operation as above. White solid (0.650 g, 87%). Mp: 88-89 °C. 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.72
(s, 1H, CH), 7.48 (d, J = 8.4 Hz, 2H, Ar-H), 6.96 (d, J = 8.4 Hz, 2H, Ar-H), 3.87 (s, 3H, OCH3), 3.85 (s,
3H, OCH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 162.3, 160.4, 150.6, 147.2, 139.8, 131.3, 121.8, 113.6,
55.2, 52.2. MS (EI, 70 eV): m/z (%) = 249 (100, M+), 218 (5), 191 (14), 164 (21), 119 (18). Anal. Calcd
for C12H11NO3S: C, 57.82; H, 4.45; N, 5.62. Found: C, 57.55; H, 4.19; N, 5.44.
4.3.9Ethyl 5-(4-methoxyphenyl) thiazole-4-carboxylate (6i)
Operation as above. Light yellow oil[29] (0.679 g, 86%). 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.73 (s, 1H,
CH), 7.46 (d, J = 7.8 Hz, 2H, Ar-H), 6.95 (d, J = 7.8 Hz, 2H, Ar-H), 4.34 (q, J = 6.0 Hz, 2H, CH2), 3.85 (s,
3H, OCH3), 1.31 (t, J = 6.6 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 162.0, 160.4, 150.7,
146.8, 140.4, 131.3, 122.0, 113.6, 61.2, 55.3, 14.1. MS (EI, 70 eV): m/z (%) = 263 (100, M+), 217 (13),
190 (17), 163 (21), 149 (6).
4.3.10 Methyl 5-(p-tolyl) thiazole-4-carboxylate (6j)
Operation as above. White solid (0.615 g, 88%). Mp: 70-71 °C. 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.74
(s, 1H, CH), 7.41 (d, J = 7.8 Hz, 2H, Ar-H), 7.24 (d, J = 7.8 Hz, 2H, Ar-H), 3.87 (s, 3H, OCH3), 2.41 (s,
3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 162.3, 150.9, 147.3, 140.2, 139.5, 129.7, 128.9, 126.7,
52.2, 21.3. MS (EI, 70 eV): m/z (%) = 233 (100, M+), 201 (5), 175 (21), 146 (14), 103 (9). Anal. Calcd for
C12H11NO2S: C, 61.78; H, 4.75; N, 6.00. Found: C, 61.99; H, 4.94; N, 6.13.
17

4.3.11 Ethyl 5-(p-tolyl) thiazole-4-carboxylate (6k)
1
Operation as above. White solid (0.637 g, 86%). Mp: 78-79 °C (lit.[28] mp 81-82 °C). H NMR (CDCl3,
600 MHz) δ (ppm) 8.74 (s, 1H, CH), 7.40 (d, J = 7.8 Hz, 2H, Ar-H), 7.23 (d, J = 7.8 Hz, 2H, Ar-H), 4.33
(q, J = 7.2 Hz, 2H, CH2), 2.40 (s, 3H, CH3), 1.30 (t , J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ
(ppm) 161.8, 150.9, 146.8, 140.7, 139.3, 129.8, 128.8, 126.9, 61.2, 21.2, 14.0. MS (EI, 70 eV): m/z (%) =
247 (100, M+), 201 (5), 174 (13), 147 (24), 103 (18).
4.3.12 Methyl 5-phenylthiazole-4-carboxylate (6l)
Operation as above. White solid (0.558 g, 85%). Mp: 99-100 °C (lit.[27] mp 98-100 °C). 1H NMR (CDCl3,
600 MHz) δ (ppm) 8.77 (s, 1H, CH), 7.53-7.43 (m, 5H, Ar-H), 3.86 (s, 3H, OCH3). 13C NMR (CDCl3,
150 MHz) δ (ppm) 162.2, 151.2, 146.9, 140.5, 129.9 129.8, 129.3, 128.1, 52.2. MS (EI, 70 eV): m/z (%) =
219 (100, M+), 187 (6), 160 (25), 132 (15), 89 (9).
4.3.13 Ethyl 5-phenylthiazole-4-carboxylate (6m)
Operation as above. Light yellow oil [29] (0.587 g, 84%). 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.74 (s, 1H,
CH), 7.49-7.38 (m, 5H, Ar-H), 4.30 (q, J = 10.2 Hz, 2H, CH2), 1.26 (t, J = 10.8 Hz, 3H, CH3). 13C NMR
(CDCl3, 150 MHz) δ (ppm) 161.8, 151.2, 146.4, 141.1, 130.0, 129.9, 129.2, 128.1, 61.2, 14.0. MS (EI, 70
eV): m/z (%) = 233 (100, M+), 188 (13), 161 (23), 134 (9), 89 (14).
4.3.14 Methyl 5-(2-fluorophenyl) thiazole-4-carboxylate (6n)
1
Operation as above. White solid (0.512 g, 72%). Mp: 77-78 °C (lit.[30] mp 80-82 °C). H NMR (CDCl3,
600 MHz) δ (ppm) 8.86 (s, 1H, CH), 7.46-7.40 (m, 2H, Ar-H), 7.24-7.17 (m, 2H, Ar-H), 3.86 (s, 3H,
OCH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 161.9, 159.5 (q, 1JF-C = 240 Hz), 152.3, 142.7, 139.0, 131.7,
131.4 (q, 2JF-C = 15 Hz), 123.9, 118.1, 115.8 (q, 2JF-C = 15 Hz), 52.3. MS (EI, 70 eV): m/z (%) = 237 (100,
M+), 205 (15), 175 (8), 151 (11), 107 (14).
18

4.3.15 Ethyl 5-(2-fluorophenyl) thiazole-4-carboxylate (6o)
1
Operation as above. White solid (0.535 g, 71%). Mp: 62-63 °C (lit.[28] mp 65-66 °C). H NMR (CDCl3,
600 MHz) δ (ppm) 8.86 (s, 1H, CH), 7.45-7.39 (m, 2H, Ar-H), 7.23-7.16 (m, 2H, Ar-H), 4.31 (q, J = 7.2
Hz, 2H, CH2), 1.24 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 161.5, 159.6 (q, 1JF-C
2
2
= 255 Hz), 152.3, 143.3, 138.5, 131.7, 131.3 (q, JF-C = 15 Hz), 123.8, 118.3, 115.7 (q, JF-C = 15 Hz),
61.3, 13.9. MS (EI, 70 eV): m/z (%) = 251 (100, M+), 205 (7), 178 (13), 151 (20), 107 (9).
4.3.16 Methyl 5-(2-chlorophenyl) thiazole-4-carboxylate (6p)
Operation as above. White solid (0.600 g, 79%). Mp: 96-97 °C. 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.87
(s, 1H, CH), 7.51 (d, J = 8.4 Hz, 1H, Ar-H), 7.41-7.33 (m, 3H, Ar-H), 3.82 (s, 3H, OCH3). 13C NMR
(CDCl3, 150 MHz) δ (ppm) 161.6, 152.3, 143.0, 142.6, 133.9, 131.6, 130.5, 129.6, 129.3, 126.4, 52.3. MS
(EI, 70 eV): m/z (%) = 253 (100, M+), 222 (14), 218 (24), 167 (9), 123 (11). Anal. Calcd for
C11H8ClNO2S: C, 52.08; H, 3.18; N, 5.52. Found: C, 52.24; H, 3.07; N, 5.34.
4.3.17 Ethyl 5-(2-chlorophenyl) thiazole-4-carboxylate (6q)
1
Operation as above. White solid (0.561 g, 70%). Mp: 168-169 °C (lit.[28] mp 166-167 °C). H NMR
(CDCl3, 600 MHz) δ (ppm) 8.87 (s, 1H, CH), 7.50 (d, J = 7.8 Hz, 1H, Ar-H), 7.40-7.32 (m, 3H, Ar-H),
4.25 (q, J = 7.2 Hz, 2H, CH2), 1.17 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 161.2,
152.3, 143.6, 142.2, 134.1, 131.6, 130.4, 129.7, 129.5, 126.4, 61.2, 13.8. MS (EI, 70 eV): m/z (%) = 267
(100, M+), 231 (7), 203 (11), 166 (14), 122 (16).
4.3.18 Methyl 5-(2-methoxyphenyl) thiazole-4-carboxylate (6r)
Operation as above. White solid (0.523 g, 70%). Mp: 72-73 °C. 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.83
(s, 1H, CH), 7.36-7.24 (m, 4H, Ar-H), 3.80 (s, 3H, OCH3), 2.18 (s, 3H, OCH3). 13C NMR (CDCl3, 150
MHz) δ (ppm) 161.7, 151.9, 145.9, 142.1, 137.2, 130.0, 129.9, 129.5, 129.3, 125,4, 52.2, 20.0. MS (EI, 70
eV): m/z (%) = 249 (100, M+), 233 (7), 201 (12), 174 (15), 146 (21). Anal. Calcd for C12H11NO3S: C,
57.82; H, 4.45; N, 5.62. Found: C, 58.01; H, 4.74; N, 5.74.
19

4.3.19 Ethyl 5-(2-methoxyphenyl) thiazole-4-carboxylate (6s)
1
Operation as above. White solid (0.560 g, 71%). Mp: 138-139 °C (lit.[28] mp 142-143 °C). H NMR
(CDCl3, 600 MHz) δ (ppm) 8.83 (s, 1H, CH), 7.35-7.23 (m, 4H, Ar-H), 4.23 (q, J = 7.2 Hz, 2H, CH2),
2.18 (s, 3H, OCH3), 1.16 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 150 MHz) δ (ppm) 161.4, 151.8,
145.4, 142.6, 137.2, 129.9, 129.8, 129.2, 125.4, 61.1, 20.0, 13.8. MS (EI, 70 eV): m/z (%) = 263 (100,
M+), 247 (5), 201 (17), 174 (6), 146 (9).
Acknowledgment
We gratefully acknowledge financial support of this work by the National Natural Science Foundation of
China (No. 21572075) and the 111 Project B17019.
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22

Highlight:
one-pot four-component reactions,
mild reaction conditions,
good yields

Declaration of interests
ꢀ* The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: