Cyclization of Active Methylene Isocyanides with α-Oxodithioesters Induced by Base: An Expedient Synthesis of 4-Methylthio/Ethoxycarbonyl-5-acylthiazoles

Article abstract of DOI:10.1055/s-0039-1690821

Cyclization of tosylmethyl isocyanide with α-oxodithioesters in the presence of KOH is reported for the synthesis of 4-methylthio-5-acylthiazoles. Similarly, ethyl isocyanoacetate underwent cyclization with α-oxodithioesters to form 4-ethoxycarbonyl-5-acy

Full text of DOI:10.1055/s-0039-1690821

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–G
paper
A
en
K. R. Kiran et al.
Paper
Synthesis
Cyclization of Active Methylene Isocyanides with -Oxodithioesters
Induced by Base: An Expedient Synthesis of 4-Methylthio/Ethoxy-
carbonyl-5-acylthiazoles
Kuppalli R. Kirana
Toreshettahally R. Swaroop*b
Narasimhamurthy Rajeeva
Seegehalli M. Anila
Kanchugarakoppal S. Rangappa*a
Maralinganadoddi P. Sadashiva*a
C:
EtO2C
O
MeS
R2
O
N
S
N
KOH, EtOH–H2O
DBU, EtOH
N
O
+
0 °C to RT, 1 h
R2 = Ts
0 °C to RT, 1 h
R2 = CO2Et
S
S
R1
R1
11 Examples
Yield 75–86%
R1 SMe
R1 = Aryl, hetaryl
R2 = Ts, CO2Et
10 Examples
Yield 60–74%
a Department of Studies in Chemistry, University of Mysore,
Manasagangothri, Mysuru – 570 006, India
mpsadashiva@gmail.com
rangappaks@gmail.com
b Department of Studies in Organic Chemistry, University of
Mysore, Manasagangothri, Mysuru – 570 006, India
swarooptr@gmail.com
Received: 10.01.2020
Accepted after revision: 23.01.2020
Published online: 17.02.2020
ods include cyclization of N,N-diformylaryl ketone with
P2S5,17 Cu-catalyzed annulation of amine with aldehyde,18
condensation of oxime with anhydride and thiocyanide,19
Pd/Fe-catalyzed condensation of vinyl azides with KSCN,20
the Ugi reaction,21 reaction of -amido--keto esters with
Lawesson’s reagent,22 and the reaction of thiourea with
propargyl bromides.23 However, these available methods
suffer from limitations such as the use of hazardous start-
ing materials, toxic/non-ecofriendly solvents, need for high
temperature, long reaction time and tedious workup proce-
dures. Hence, more synthetic methods are required for the
synthesis of thiazole moieties.
DOI: 10.1055/s-0039-1690821; Art ID: ss-2019-n0529-op
Abstract Cyclization of tosylmethyl isocyanide with -oxodithioesters
in the presence of KOH is reported for the synthesis of 4-methylthio-5-
acylthiazoles. Similarly, ethyl isocyanoacetate underwent cyclization
with -oxodithioesters to form 4-ethoxycarbonyl-5-acylthiazoles in the
presence of DBU/EtOH. Mechanisms for the formation of thiazoles are
proposed. These thiazoles can also be obtained by Takeda reaction, in
which thiazole-4,5-anhydride is acylated with aromatic compounds fol-
lowed by esterification; however, that approach requires two steps and
suffers from the formation of a regioisomeric mixture of products.
Key words thiazole, TosMIC, ethyl isocyanoacetate, -oxodithioester,
cyclization
Notably, thiazoles unsubstituted at the 2-position can
be synthesized by the cycloaddition of isocyanide with
thiano esters,24 carbon disulfides,25 and isothiocyanates26 or
caboxymethyldithioates.27 Recently, we have reported the
synthesis of thiazoles unsubstituted at the 2-position by cy-
clization of active methylene isocyanides with aryldithio-
carboxylates (Scheme 1a)28 and xanthate esters (Scheme
1b).29 On the other hand, -oxodithioesters are a special
class of synthons30 and their synthetic properties have not
been much explored. To our knowledge, reaction of active
methylene isocyanides with -oxodithioesters has not been
reported. In continuation of our work on the development
of new synthetic methods for the synthesis of heterocyclic
compounds,31 we herein report the cyclization of some ac-
tive methylene isocyanides with -oxodithioesters (Scheme
1).
Thiazoles are among the most important members of
the azaheterocycle family. Derivatives of these ring systems
exhibit therapeutic properties including anticancer,1 anti-
microbial,2 anti-inflammatory,3 antimalarial,4 antiproto-
zoal,5 antiprion6 and psychotrophic activities.7 They also
show inhibitory action against HIV-1 NNRT,8 PIN1,9 and his-
tone acetyl transferase.10 Some of them have fluorescence11
and photochromic properties.12 In addition, they are used
in the detection of heavy metals,13 RNA duplex formation,14
and for determination of hydrophobic 1° and 2° amines.15
Thus, the aforementioned properties mark thiazoles as
privileged moieties. A selection of important drugs that are
approved by FDA with their biological activities and some
naturally occurring and synthetically important thiazole
containing molecules are given in Figure 1.
In the beginning of our study, we considered the reac-
tion of methyl 2-oxo-2-phenylethanedithioate (1) with to-
sylmethyl isocyanide (2) in the presence of various bases
(NaH, t-BuOK, KOH, K2CO3 and DBU) with EtOH as solvent
The conventional method for the synthesis of thiazoles
is the Hantzsch method,16 which involves cyclocondensa-
tion of -bromo acetophenones with thiourea. Other meth-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
K. R. Kiran et al.
Paper
Synthesis
(Table 1, entries 1–5). Among the bases, KOH was found to
be optimal. For the same reaction, variation of solvents
(THF, DMSO, acetonitrile and toluene) in the presence of
KOH base did not improve the yield (entries 6–9). Finally,
aqueous alcoholic KOH gave product in the highest yield,
82% (entry 10).
O
OH
N
S
OH
H
N
S
O
H2N
CN
N
N
H
O
Table 1 Optimization of the Synthesis of 4-Methylthio-5-phenylthi-
azolesa
Febuxostat (XO Inhibitor)
Mirabegron (antimuscarinic)
H
N
MeS
N
O
N
O
S
KOH, EtOH–H2O
0 °C to RT
O
C
S
+
N
S
Ts
N
S
O
SMe
Ph
O
Ph
N
HN
O
N
S
F3C
1
2
3
COOH
NH2
N
O
S
Entry
Solvent
Base
Yield of 3 (%)
H2N
N
Cetriaxone (antibiotic)
Riluzole (anticonvulsant)
1
2
EtOH
EtOH
EtOH
EtOH
EtOH
THF
NaH
12
t-BuOK
KOH
K2CO3
DBU
24
H
O
S
N
N
S
3
75
N
O
HN
O
O
S
S
N
N
O–
4
50
N
N
+
H
H
5
43
COOH
Phthalylsulfathiazole
(antimicrobial)
Nizatidine
(inhibits gastric acid secretion)
6
KOH
KOH
KOH
KOH
KOH
23
7
DMSO
MeCN
16
NH2
N
8
trace
trace
82
+
N
OR
N
9
toluene
S
10
EtOH–H2O
Thiamine pyrophosphate coenzyme
(decarboxylate the pyruvic acid to acetaldehyde)
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), KOH (1 mmol),
EtOH/H2O (3 mL/3 drops), 0 °C to r.t.
O
OH
N
One of the Takeda intermediates to synthesize Tachykinin antagonist
S
Thus, with the combination of KOH base and EtOH sol-
vent, we explored the potential of the reaction by taking
various substrates. To our delight, -oxodithioesters substi-
tuted with F, Cl and Br substituents formed the respective
products 3b–d in 78–84% yield (Scheme 2). The methyl 2-
(4-nitrophenyl)-2-oxoethanedithioate also underwent
smooth cyclization with 2 to form (4-(methylthio)thiazol-
5-yl)(4-nitrophenyl)methanone (3e) in 84% yield. Similarly,
substrates with electron-donating groups (Me and OMe)
also furnished the corresponding products 3g and 3h in 76
and 86% yield, respectively.
Finally, -oxodithioesters containing naphthyl and thie-
nyl groups also afforded desired thiazoles 3i and 3j in 80
and 82% yield, respectively. In the 1H NMR spectra, all com-
pounds showed a characteristic peak of thiomethyl around
 = 2.7 ppm and a characteristic peak of thiazole around  =
8.0 ppm.
O
5-Acetylthiazole-4-
carboxylic acid
Figure 1 Some significant FDA-approved drugs and naturally occurring
thiazoles
Our previous works
a.
S
S
NaH, DMF
0 °C to r.t.
C
C
+
+
R1
R1 = Ar, HetAr
R2
N
N
R1
S
S
N
R2 = Ts, CO2Et, Ar
R2
b.
R1
O
S
NaH, DMF
R
1 = Benzyl, Alkyl
R1
O
S
R2
N
R2 = Ts, CO2Et
0 °C to r.t., 10–20 min
R2
Present work
We also considered the reaction of methyl 2-oxo-2-
phenylethanedithioate (1) with ethyl isocyanoacetate (4) in
the presence of various bases (NaH, t-BuOK, KOH, K2CO3
and DBU) with EtOH as solvent (Table 2, entries 1–5).
Among the bases, DBU was found to be optimal. Performing
the reaction in various solvents (THF, DMSO, acetonitrile
c.
S
O
S
R1 = Aryl, Hetaryl
KOH, DBU, EtOH
R1
C
R2
N
+
R
2 = SMe, CO2Et
S
N
R1
0 °C to r.t., 20 min to 1 h
R2
O
Scheme 1 Our previous work and the present work
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

C
K. R. Kiran et al.
Paper
Synthesis
To establish the scope of the protocol, we investigated
the reaction of various dithioesters 1 bearing halogens (F, Cl
and Br), electron-withdrawing groups (NO2), electron-do-
nating groups (Me and OMe), naphthyl and thienyl dithio-
esters; the reactions furnished the respective ethyl 5-ac-
ylthiazole carboxylates 5a–j in 60–74% yield, respectively
(Scheme 3). Similar products can be obtained by using the
Takeda reaction, which involves Friedel–Crafts acylation of
thiazole-4,5-anhydride with aromatic compounds to give 5-
acyl-thiazole-4-carboxylic acid followed by esterification.32
To obtain 5 by using the Takeda approach requires two
steps. Furthermore, regioisomeric products are formed
during acylation. Thus, our method is superior over the
Takeda approach. All compounds were characterized by an-
alytical techniques. For instance, the NMR spectra showed
signals around  = 1.5 ppm for methyl as a triplet,  =
4.5 ppm for methylene as a quartet and around  = 8.4 ppm
for the thiazole proton as singlet.
MeS
S
N
O
R
KOH, EtOH
0 °C to RT
C
O
+
Ts
N
S
SMe
R
1
2
3
MeS
MeS
MeS
N
N
O
N
O
O
O
S
S
S
S
N
Cl
MeS
F
Br
3a (82%)
3b (80%)
3c (84%)
3d (78%)
MeS
MeS
MeS
MeS
N
N
N
N
O
O
O
O
S
S
S
S
NO2
O2N
MeO
3h (86%)
3e (84%)
3f (78%)
3g (76%)
The required substrates were synthesized by a slight
modification of the reported protocol, which involves the
MeS
MeS
N
S
N
S
O
O
N
EtO2C
S
N
O
R
S
N
C
DBU, EtOH
0 °C to RT
SMe
O
O
S
+
EtO2C
N
S
SMe
R
3i (80%)
3j (82%)
3k (80%)
1
4
5
Scheme 2 Synthesis of 4-methylthio-5-acylthiazoles 3 from -oxo-
dithioesters 1. Reagents and conditions: 1 (1 mmol), 2 (1 mmol), KOH
(2 mmol), EtOH (3 mL), 1 h.
EtO2C
O
EtO2C
O
EtO2C
EtO2C
O
N
N
N
N
O
S
S
S
S
and toluene) in the presence of DBU base did not improve
the yield (entries 6–9). Thus, DBU in ethanol was found to
be the best combination (entry 5).
F
Cl
Br
5d (65%)
5a (68%)
5b (70%)
5c (74%)
Table 2 Optimization for the Synthesis of Ethyl 5-Benzoylthiazole-4-
EtO2C
EtO2C
EtO2C
EtO2C
carboxylatea
N
N
N
N
O
O
O
O
S
S
S
S
EtO2C
N
O
S
O
C
DBU, EtOH
0 °C to RT
+
EtO2C
N
S
SMe
Ph
Ph
O2N
MeO
5g (65%)
5e (60%)
5f (67%)
5h (73%)
1
4
5
Entry
Solvent
Base
Yield of 5 (%)
EtO2C
O
N
S
N
1
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOH
EtOH
EtOH
THF
NaH
26
38
18
52
68
32
41
52
18
N
S
t-BuOK
KOH
K2CO3
DBU
O
S
EtO
O
5i (63%)
5j (62%)
Scheme 3 Synthesis of ethyl 5-acylthiazole carboxylates 5 from -oxo-
dithioesters 1. Reagents and conditions: 1 (1 mmol), 4 (1 mmol), KOH (2
mmol), EtOH (3 mL), 1 h.
DBU
DMSO
MeCN
toluene
DBU
DBU
O
O
R
S
O
I2, Pyridine
1. S8, Et3N
2. MeI
N
I
DBU
R
R
SMe
a Reaction conditions: 1 (0.5 mmol), 4 (0.5 mmol), DBU (1 mmol), EtOH (3
6
7
1
mL), 0 °C to room temperature.
Scheme 4 Synthesis of -oxodithioesters from methyl ketones
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

D
K. R. Kiran et al.
Paper
Synthesis
O
S
O
O
O
R1
SMe
S
S
N
C
C
R1
S
N
S
N
R1
KOH, DBU
KOH, DBU
R2
N
R2
N
1
R1
C
C
C
– H2O, – DBUH
– MeS
R2
R2
2/4
8
R2
9
10
11
O
O
O
O
S
R1
R1
S
N
R1
S
N
R2 = Ts
MeS
H
S
N
Ts
15
R1
C
3
R2
12
N
R2
R2
MeS
13
5 (R2 = CO2Et)
14 (R2 = Ts)
Scheme 5 Probable mechanisms for the formation of thiazoles 3 and 5
reaction of methyl ketones with iodine and pyridine to
form pyridinium salts, which were converted into -oxo-
dithioesters after treatment with sulfur and methyl iodide
in the presence of triethyl amine (Scheme 4).
(3 × 25 mL), washed with brine solution, dried over Na2SO4 and evap-
orated. The crude material was subjected to column chromatography
using hexane/EtOAc solvent system to give the desired compound.
Synthesis of 5; General Procedure
A probable mechanism for the formation thiazoles 3 and
5 is given in Scheme 5. The pathway involves reaction of ac-
tive methylene isocyanides 2 and 4 with KOH/DBU to form
the respective anions 8. Nucleophilic attack on the thiocar-
bonyl group of 1 forms anion 9. Elimination of methane-
thiolate from 9 furnishes the condensation intermediate 10.
Abstraction of another active hydrogen by KOH/DBU forms
anion 11, which is resonance stabilized to give enethiolate
12. Cyclization of 12 forms thiazole anion 13. In the latter,
the tosyl group is substituted with methanethiolate to form
thiazole 3 via the Michael addition intermediate 15, which
is formed after the protonation of 14. On the other side,
ethyl carboxylate was retained in thiazole 5. Intermediate
anion 13 was protonated from either water or alcohol to
give thiazoles 3 and 5.
A solution of DBU (1.01 mmol) in EtOH was placed in an ice bath for
10 minutes A mixture of the oxodithioate (0.51 mmol) and ethyl cya-
noacetate (0.56 mmol) in EtOH was added, the mixture was allowed
to attain r.t. The reaction was quenched with ice cooled water and the
mixture was extracted with EtOAc (3 × 25 mL), washed with brine
solution, dried over Na2SO4, and evaporated. The crude material was
subjected to column chromatography using hexane/EtOAc solvent
system to give the desired compound.
(4-(Methylthio)thiazol-5-yl)(phenyl)methanone (3a)
Yield: 82% (98 mg); yellow solid; mp 110–112 °C.
IR (KBr): 2968, 1623, 1348, 1308, 1277 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.04 (s, 1 H, Ar-H), 7.82 (t, J = 6.8 Hz,
2 H, Ar-H), 7.60 (t, J = 7.2 Hz, 1 H, Ar-H), 7.50 (t, J = 8.0 Hz, 2 H, Ar-H),
2.74 (s, 3 H, SMe).
13C NMR (100 MHz, CDCl3):  = 186.5, 176.2, 149.1, 138.6, 137.6,
132.8, 128.9, 128.7, 16.6.
HRMS (ESI): m/z [M + H]+ calcd for C11H9NOS2: 236.0198; found:
236.0190.
All reagents and solvents were purchased from commercial suppliers
and used as such. The methyl -oxo-dithioates31e and ethyl isocyano
acetate32 were prepared by following reported procedures. All the re-
actions were monitored by TLC using commercially available pre-
coated plates ( MERCK 60F254, 0.25 mm thickness) and visualized un-
der UV light. 1H and 13C NMR spectra were obtained with an AGILENT
NMR spectrometer. Chemical shift () are given in ppm using CDCl3
solvent as reference relative to TMS, coupling constant (J) values are
given in Hz, mass spectral analysis was performed with a Water-Syn-
apt G2 mass spectrometer. The single-crystal X-ray diffraction data of
the compound was generated with a Rigoku SMART Lab model, Japan,
using a Cu source at r.t. with the monochrome beam method. The
structure was established by full matrix least square methods using
SHELKS program. Melting points were determined with a SELACO
melting-point apparatus and are uncorrected.
(4-Fluorophenyl)(4-(methylthio)thiazol-5-yl)methanone (3b)
Yield: 80% (95 mg); pale-yellow solid; mp 134–136 °C.
IR (KBr): 2944, 1624, 1597, 1349, 1314 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.02 (s, 1 H, Ar-H), 7.87 (dd, J = 5.6,
3.2 Hz, 2 H, Ar-H), 7.18 (t, J = 8.8 Hz, 2 H, Ar-H), 2.74 (s, 3 H, SMe).
13C NMR (100 MHz, CDCl3):  = 184.9, 166.8 and 164.2 (J = 254 Hz),
148.8, 145.9, 138.3, 133.9, 131.5 and 131.4 (J = 9.2 Hz), 115.9 and
115.8 (J = 21 Hz), 16.5.
HRMS (ESI): m/z [M + H]+ calcd for C11H8FNOS: 254.0104; found:
254.0100.
(4-Chlorophenyl)(4-(methylthio)thiazol-5-yl)methanone (3c)
Synthesis of 3; General Procedure
Yield: 84% (98 mg); pale-yellow solid; mp 145–147 °C.
A solution of KOH (1.01 mmol) in EtOH was placed in an ice bath for
10 minutes. To the cooled solution was added a mixture of the oxo-
dithioate (0.51 mmol) and TosMIC (0.56 mmol) in EtOH, and the reac-
tion mixture was allowed to reach to r.t. The reaction was quenched
with ice-cooled water and the mixture was extracted with EtOAc
IR (KBr): 2948, 1625, 1347, 1312 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.01 (s, 1 H, Ar-H), 7.78 (d, J = 8.4 Hz,
2 H, Ar-H), 7.48 (d, J=8.4 Hz, 2 H, Ar-H), 2.74 (s, 3 H, SMe).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

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K. R. Kiran et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3):  = 185.1, 176.6, 148.9, 139.3, 138.2,
HRMS (ESI): m/z [M + H]+calcd for C12H11NO2S2: 266.0304; found:
135.9, 130.3, 129.0, 16.6.
266.0300.
HRMS (ESI): m/z [M + H]+ calcd for C11H8ClNOS2: 269.9809; found:
269.9816.
(4-(Methylthio)thiazol-5-yl)(naphthalen-2-yl)methanone (3i)
Yield: 80% (93 mg); pale-yellow solid; mp 82–84 °C.
IR (KBr): 2963, 1640, 1568, 1432, 1307 cm–1
(4-Bromophenyl)(4-(methylthio)thiazol-5-yl)methanone (3d)
.
Yield: 78% (89 mg); pale-yellow solid; mp 128–130 °C.
1H NMR (400 MHz, CDCl3):  = 8.36 (s, 1 H, Ar-H), 8.13 (s, 1 H, Ar-H),
7.93 (dd, J = 12.8, 6.8 Hz, 4 H, Ar-H), 7.63–7.55 (m, 2 H, Ar-H), 2.76 (s,
3 H, SMe).
IR (KBr): 2948, 1630, 1347, 1311, 681 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.01 (s, 1 H, Ar-H), 7.70 (dd, J = 4.8,
2.0 Hz, 2 H, Ar-H), 7.66–7.63 (m, 2 H, Ar-H), 2.74 (s, 3 H, SMe).
13C NMR (100 MHz, CDCl3):  = 186.3, 176.1, 149.0, 138.7, 135.3,
134.9, 132.3, 130.4, 129.3, 128.8, 128.5, 127.9, 127.1, 124.8, 16.6.
HRMS (ESI): m/z [M + H]+calcd for C15H11NOS2: 286.0335; found:
13C NMR (100 MHz, CDCl3):  = 185.3, 176.7, 149.0, 138.1, 136.3,
132.0, 130.4, 127.8, 16.6.
286.0332.
HRMS (ESI): m/z [M + H]+ calcd for C11H8BrNOS2: 313.9303 and
315.9283; found: 313.9301 and 315.9298.
(4-(Methylthio)thiazol-5-yl)(thiophen-2-yl)methanone (3j)
Yield: 82% (98 mg); pale-yellow solid; mp 108–110 °C.
(4-(Methylthio)thiazol-5-yl)(4-nitrophenyl)methanone (3e)
Yield: 84% (98 mg); pale-yellow solid; mp 182–185 °C.
IR (KBr): 2920, 1610, 1500, 1413, 1347 cm–1
.
IR (KBr): 2976, 1633, 1346, 1310, 1280 cm–1
1H NMR (400 MHz, CDCl3):  = 8.36 (d, J = 8.4, 2 H, Ar-H), 7.98 (t, J =
8.8 Hz, 3 H, Ar-H), 2.76 (s, 3 H, SMe).
13C NMR (100 MHz, CDCl3):  = 184.5, 178.6, 150.1, 149.7, 142.7,
137.7, 129.7, 123.9, 16.6.
HRMS (ESI): m/z [M + H]+ calcd for C11H8N2O3S2: 281.0049; found:
281.0052.
.
1H NMR (400 MHz, CDCl3):  = 8.30 (s, 1 H, Ar-H), 7.84 (d, J = 3.2 Hz,
1 H, Ar-H), 7.71 (d, J = 4.8 Hz, 1 H, Ar-H), 7.19 (t, J = 4.4 Hz, 1 H, Ar-H),
2.75 (s, 3 H, SMe).
13C NMR (100 MHz, CDCl3):  = 176.9, 175.5, 147.3, 142.4, 137.9,
133.9, 132.8, 128.2, 16.5.
HRMS (ESI): m/z [M + H]+ calcd for C9H7NOS3: 241.9763; found:
241.9769.
(4-(Methylthio)thiazol-5-yl)(pyridin-2-yl)methanone (3k)
(4-(Methylthio)thiazol-5-yl)(3-nitrophenyl)methanone (3f)
Yield: 80% (96 mg); pale-yellow solid; mp 120–122 °C.
Yield: 78% (90 mg); pale-yellow solid; mp 173–175 °C.
IR (KBr): 2970, 1646, 1560, 1480, 1365 cm–1
IR (KBr): 2987, 1644, 1351, 1323, 1277 cm–1
.
.
1H NMR (400 MHz, CDCl3):  = 8.83 (s, 1 H, Ar-H), 8.72 (d, J = 4.4 Hz,
1 H, Ar-H), 8.19 (d, J = 7.6 Hz, 1 H, Ar-H), 7.91–7.87 ( m, 1 H, Ar-H),
7.50 (dd, J = 2.4, 12.4 Hz, 1 H, Ar-H), 2.76 (s, 3 H, SMe).
13C NMR (100 MHz, CDCl3):  = 184.2, 154.7, 153.5, 150.2, 139.2,
139.1, 135.0, 128.9, 125.4, 18.2
1H NMR (400 MHz, CDCl3):  = 8.65 (s, 1 H, Ar-H), 8.47 (d, J = 8.0 Hz,
1 H, Ar-H), 8.15 (s, 1 H, Ar-H), 8.05 (d, J = 8.0 Hz, 1 H, Ar-H), 7.77–7.69
(m, 1 H Ar-H), 2.78 (s, 3 H, SMe).
13C NMR (100 MHz, CDCl3):  = 185.8, 151.4, 148.8, 140.9, 139.4,
136.2, 131.9, 128.8, 128.6, 125.5, 18.6.
HRMS (ESI): m/z [M + H]+ calcd for C10H8N2OS2: 237.0156; found:
237.0157.
HRMS (ESI): m/z [M + H]+ calcd for C11H8N2O3S2: 279.9976; found:
279.9985.
Ethyl 5-Benzoylthiazole-4-carboxylate (5a)
(4-(Methylthio)thiazol-5-yl)(p-tolyl)methanone (3g)
Yield: 68% (90 mg); mp 92–94 °C.
IR (KBr): 3051, 2946, 1616, 1414, 1350 cm–1
Yield: 76% (90 mg); pale-yellow solid; mp 80–82 °C.
.
IR (KBr): 2964, 1620, 1499, 1350, 1297 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.37 (s, 1 H, Ar-H), 7.90–7.87 (m, 2 H,
Ar-H), 7.66 (dd, J = 7.6, 1.6 Hz, 1 H, Ar-H), 7.56–7.52 (dd, J = 6.4,
1.6 Hz, 2 H, Ar-H), 4.53–4.48 (q, J = 7.2 Hz, 2 H, CH2), 1.45 (t, J = 7.2 Hz,
3 H, Me).
13C NMR (100 MHz, CDCl3):  = 186.8, 162.9, 159.4, 148.9, 143.2,
136.9, 133.6, 129.2, 128.9, 63.1, 14.1.
1H NMR (400 MHz, CDCl3):  = 8.01 (s, 1 H, Ar-H), 7.72 (d, J = 7.6 Hz,
2 H, Ar-H), 7.26 (d, J = 8.0 Hz, 2 H, Ar-H), 2.70 (s, 3 H, SMe), 2.40 (s,
3 H, Me).
13C NMR (100 MHz, CDCl3):  = 186.0, 175.7, 148.6, 143.6, 138.7,
134.9, 129.3, 129.0, 21.6, 16.5.
HRMS (ESI): m/z [M + H]+calcd for C12H11NOS2: 250.0335; found:
250.0339.
HRMS (ESI): m/z [M + H]+ calcd for C13H11NO3S: 262.0582; found:
262.0585.
(4-Methoxyphenyl)(4-(methylthio)thiazol-5-yl)methanone (3h)
Ethyl 5-(4-Fluorobenzoyl)thiazole-4-carboxylate (5b)
Yield: 86% (101 mg); pale-yellow solid; mp 116–118 °C.
Yield: 70% (91 mg); pale-yellow solid; mp 138–140 °C.
IR (KBr): 2983, 1642, 1453, 1376, 1285 cm–1
.
IR (KBr): 3025, 2951, 1736, 1631, 1406 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.03 (s, 1 H, Ar-H), 7.85 (dd, J = 5.2,
2.0 Hz, 2 H, Ar-H), 6.97 (dd, J = 4.8, 2.0 Hz, 2 H, Ar-H), 3.88 (s, 3 H,
OMe), 2.73 (s, 3 H, SMe).
1H NMR (400 MHz, CDCl3):  = 8.35 (s, 1 H, Ar-H), 7.93 (dd, J = 5.6,
5.2 Hz, 2 H, Ar-H), 7.22 (t, J = 8.8 Hz, 2 H, Ar-H), 4.53–4.48 (q, J =
7.2 Hz, 2 H, CH2), 1.45 (t, J = 7.6 Hz, 3 H, Me).
13C NMR (100 MHz, CDCl3):  = 185.0, 175.4, 163.5, 148.2, 138.7,
131.3, 130.2, 113.9, 55.5, 16.6.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

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K. R. Kiran et al.
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Synthesis
13C NMR (100 MHz, CDCl3):  = 185.2, 167.3 and 164.7 (J = 260 Hz),
163.0, 159.4, 148.7, 143.0, 133.2, 132.0, and 131.9 (J = 10 Hz), 116.4
and 116.1 (J = 30 Hz), 63.3, 14.1.
1H NMR (400 MHz, CDCl3):  = 8.36 (s, 1 H, Ar-H), 7.91 (d, J = 8.8 Hz,
2 H, Ar-H), 7.01 (d, J = 8.8 Hz, 2 H, Ar-H), 4.53–4.48 (q, J = 7.2 Hz, 2 H,
CH2), 3.90 (s, 3 H, OMe), 1.45 (t, J = 7.2 Hz, 3 H, Me).
HRMS (ESI): m/z [M + H]+ calcd for C13H10FNO3S: 280.0438; found:
13C NMR (100 MHz, CDCl3):  = 185.1, 164.1, 162.3, 159.5, 148.2,
280.0442.
143.6, 131.8, 129.5, 114.2, 63.2, 55.6, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for C14H13NO4S: 292.0638; found:
292.0635.
Ethyl 5-(4-Chlorobenzoyl)thiazole-4-carboxylate (5c)
Yield: 74% (95 mg); pale-yellow solid; mp 106–110 °C.
IR (KBr): 3033, 1648, 1453, 1363, 1308 cm–1
Ethyl 5-(2-Naphthoyl)thiazole-4-carboxylate (5h)
.
Yield: 73% (92 mg); pale-yellow solid; mp 78–80 °C.
1H NMR (400 MHz, CDCl3):  = 8.34 (s, 1 H, Ar-H), 7.83 (t, J = 8.4 Hz,
2 H, Ar-H), 7.51 (d, J = 8.4 Hz, 2 H, Ar-H), 4.49 (d, J = 7.2 Hz, 2 H, CH2),
1.44 (t, J = 7.2 Hz, 3 H, Me).
13C NMR (100 MHz, CDCl3):  = 185.5, 163.2, 159.3, 148.8, 142.9,
140.2, 135.2, 130.6, 129.3, 63.2, 14.2.
IR (KBr): 3017, 1703, 1616, 1484, 1360 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.43 (d, J = 15.6 Hz, 2 H, Ar-H), 7.99–
7.91 (m, 4 H, Ar-H), 7.67–7.58 (m, 2 H, Ar-H), 4.54–4.49 (q, J = 7.2 Hz,
2 H, CH2), 1.45 (t, J = 7.2 Hz, 3 H, Me).
HRMS (ESI): m/z [M + H]+ calcd for C13H10ClNO3S: 296.0143; found:
296.0140.
13C NMR (100 MHz, CDCl3):  = 186.7, 162.8, 159.5, 148.9, 143.4,
135.7, 134.3, 132.3, 131.3, 129.6, 129.0, 127.9, 127.3, 124.6, 124.3,
63.2, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for C17H13NO3S: 312.0689; found:
Ethyl 5-(4-Bromobenzoyl)thiazole-4-carboxylate (5d)
312.0695.
Yield: 65% (80 mg); pale-yellow solid; mp 102–104 °C.
IR (KBr): 2936, 1631, 1305, 1276, 745 cm–1
.
Ethyl 5-(Thiophene-2-carbonyl)thiazole-4-carboxylate (5i)
1H NMR (400 MHz, CDCl3):  = 8.35 (s, 1 H, Ar-H), 7.76 (d, J = 8.4 Hz,
2 H, Ar-H), 7.69 (d, J = 8.8 Hz, 2 H, Ar-H), 4.54–4.48 (q, J = 7.2 Hz, 2 H,
CH2), 1.46 (t, J = 7.6 Hz, 3 H, Me).
Yield: 63% (83 mg); pale-yellow solid; mp 96–98 °C.
IR (KBr): 3080, 1744, 1734, 1606, 1505, 1469 cm–1
.
13C NMR (100 MHz, CDCl3):  = 185.7, 163.2, 159.3, 148.8, 142.7,
135.6, 132.3, 130.7, 128.9, 63.2, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C13H10BrNO3S: 339.9638 and
341.9707; found: 339.9643 and 341.9701.
1H NMR (400 MHz, CDCl3):  = 8.58 (s, 1 H, Ar-H), 7.91 (d, J = 5.4 Hz,
1 H, Ar-H), 7.80 (d, J = 4.8 Hz, 1 H, Ar-H), 7.24 (t, J = 4.8 Hz, 1 H, Ar-H),
4.54–4.49 (q, J = 7.2 Hz, 2 H, CH2), 1.46 (t, J = 7.2 Hz, 3 H, Me).
13C NMR (100 MHz, CDCl3):  = 177.3, 162.4, 159.4, 147.6, 142.6,
142.3, 135.3, 134.1, 128.5, 63.2, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for C11H9NO3S2: 268.0097; found:
Ethyl 5-(4-Nitrobenzoyl)thiazole-4-carboxylate (5e)
268.0096.
Yield: 60% (76 mg); pale-yellow solid; mp 128–130 °C.
IR (KBr): 2952, 1634, 1532, 1409, 1303 cm–1
.
Ethyl 5-Picolinoylthiazole-4-carboxylate (5j)
1H NMR (400 MHz, CDCl3):  = 8.38 (t, J = 12 Hz, 3 H, Ar-H), 8.03 (d, J =
8.8 Hz, 2 H, Ar-H), 4.54–4.48 (q, J = 7.2 Hz, 2 H, CH2), 1.45 (t, J = 6.8 Hz,
3 H, Me).
Yield: 62% (82 mg); pale-yellow solid; mp 110–112 °C.
IR (KBr): 3067, 1756, 1782, 1623, 1534, 1480 cm–1
.
13C NMR (100 MHz, CDCl3):  = 185.3, 164.1, 159.1, 150.5, 149.5,
142.3, 141.7, 130.1, 124.1, 63.4, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C13H10N2O5S: 307.0383; found:
307.0390.
1H NMR (400 MHz, CDCl3):  = 9.01 (s, 1 H, Ar-H), 8.78 (d, J = 4.8 Hz,
1 H, Ar-H), 8.24 (d, J = 8.0 Hz, 1 H, Ar-H), 7.96–7.92 (m, 1 H, Ar-H),
7.57 (dd, J = 1.6, 12.4 Hz, 1 H, Ar-H), 4.54–4.48 (q, J = 7.2, 21.6 Hz, 2 H,
CH2), 1.47 (t, J = 7.6 Hz, 3 H, Me).
13C NMR (100 MHz, CDCl3):  = 184.9, 167.3, 162.2, 153.8, 153.7,
150.4, 139.4, 138.7, 129.7, 125.5, 64.7, 16.1.
HRMS (ESI): m/z [M + H]+ calcd for C12H10N2O3S: 263.0490; found:
Ethyl 5-(4-Methylbenzoyl)thiazole-4-carboxylate (5f)
Yield: 67% (88 mg); pale-yellow solid; mp 94–96 °C.
263.0485.
IR (KBr): 2998, 1663, 1598, 1417, 1397 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.37 (s, 1 H, Ar-H), 7.80 (d, J = 8.0 Hz,
2 H, Ar-H), 7.34 (d, J = 8.0 Hz, 2 H, Ar-H), 4.51 (d, J = 7.2 Hz, 2 H, CH2),
2.46 (s, 3 H, Ar-Me), 1.45 (t, J = 7.6 Hz, 3 H, Me).
Funding Information
13C NMR (100 MHz, CDCl3):  = 186.3, 162.6, 159.5, 148.6, 144.7,
143.5, 134.3, 129.6, 129.4, 63.1, 21.7, 14.1.
The authors are grateful to UGC-SAP DRS III for providing financial
support and IOE for instrumentation facility.()
HRMS (ESI): m/z [M + H]+ calcd for C14H13NO3S: 276.0689; found:
276.0695.
Supporting Information
Ethyl 5-(4-Methoxybenzoyl)thiazole-4-carboxylate (5g)
Supporting information for this article is available online at
Yield: 65% (84 mg); pale-yellow solid; mp 134–136 °C.
https://doi.org/10.1055/s-0039-1690821.
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IR (KBr): 3021, 1723, 1568, 1461, 1357 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

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K. R. Kiran et al.
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Synthesis
References
(17) Sheldrake, P. W.; Matteucci, M.; McDonald, E. Synlett 2006, 460.
(18) Wang, X.; Qiu, X.; Wei, J.; Liu, J.; Song, S.; Wang, W.; Jiao, N. Org.
Lett. 2018, 20, 2632.
(19) Tang, X.; Yang, J.; Zhu, Z.; Zheng, M.; Wu, W.; Jiang, H. J. Org.
Chem. 2016, 81, 11461.
(1) Smith, B.; Chang, H. H.; Medda, F.; Gokhale, V.; Dietrich, J.;
Davis, A.; Meuillet, E. J.; Hulme, C. Bioorg. Med. Chem. Lett. 2012,
22, 3567.
(2) Annadurai, S.; Martinez, R.; Canney, D. J.; Eidem, T.; Dunman, P.
M.; Abou-Gharbia, M. Bioorg. Med. Chem. Lett. 2012, 22, 7719.
(3) (a) Inamdar, G. S.; Pandya, A. N.; Thakar, H. M.; Sudarsanam, V.;
Kachler, S.; Sabbadin, D.; Moro, S.; Klotz, K. N.; Vasu, K. K. Eur. J.
Med. Chem. 2013, 63, 924. (b) Franklin, P. X.; Pillai, A. D.; Rathod,
P. D.; Yerande, S.; Nivsarkar, M.; Padh, H.; Vasu, K. K.;
Sudarsanam, V. Eur. J. Med. Chem. 2008, 43, 129.
(4) Hamzé, A.; Rubi, E.; Arnal, P.; Boisbrun, M.; Carcel, C.; Salom-
Roig, X.; Maynadier, M.; Wein, S.; Vial, H.; Calas, M. J. Med. Chem.
2005, 48, 3639.
(20) Chen, B.; Guo, S.; Guo, X.; Zhang, G.; Yu, Y. Org. Lett. 2015, 17,
4698.
(21) Kazmaier, U.; Ackermann, S. Org. Biomol. Chem. 2005, 3, 3184.
(22) Sanz-Cervera, J. F.; Blasco, R.; Piera, J.; Cynamon, M.; Ibanez, I.;
Murguia, M.; Fustero, S. J. Org. Chem. 2009, 74, 8988.
(23) Castagnolo, D.; Pagano, M.; Bernardini, M.; Botta, M. Synlett
2009, 2093.
(24) Hartman, G. D.; Weinstock, L. M. Synthesis 1976, 681.
(25) Wildeman, J.; van Leusen, A. M. Synthesis 1979, 733.
(26) (a) Suzuki, M.; Moyira, T.; Matsumoto, K.; Miyoshi, M. Synthesis
1982, 874. (b) van Nipsen, S. P. J. M.; Bregman, J. H.; van Engen,
D. G.; van Leusen, A. M.; Saikachi, H.; Kitagawa, T.; Sasaki, H.
Recl. Trav. Chim. Pays-Bas 1982, 101, 28.
(5) Verge, J. P.; Roffey, P. J. Med. Chem. 1975, 18, 794.
(6) Ghaemmaghami, S.; May, B. C.; Renslo, A. R.; Prusiner, S. B.
J. Virol. 2010, 84, 3408.
(7) Zablotskaya, A.; Segal, I.; Germane, S.; Shestakova, I.;
Domracheva, I.; Nesterova, A.; Geronikaki, A.; Lukevics, E. Chem.
Heterocycl. Compd. 2002, 38, 859.
(8) Kasralikar, H. M.; Jadhavar, S. C.; Goswami, S. V.; Kaminwar, N.
S.; Bhusare, S. R. Bioorg. Chem. 2019, 86, 437.
(9) Zhao, H.; Cui, G.; Jin, J.; Chen, X.; Xu, B. Bioorg. Med. Chem. 2016,
24, 5911.
(10) Secci, D.; Carradori, S.; Bizzarri, B.; Bolasco, A.; Ballario, P.;
Patramani, Z.; Fragapane, P.; Vernarecci, S.; Canzonetta, C.;
Filetici, P. Bioorg. Med. Chem. 2014, 22, 1680.
(11) Kubota, Y.; Tanaka, S.; Funabiki, K.; Matsui, M. Org. Lett. 2012,
14, 4682.
(12) Lvov, A. G.; Khusniyarov, M. M.; Shirinian, V. Z. J. Photochem.
Photobiol., C 2018, 36, 1.
(13) Cui, X.; Fang, X.; Zhao, H.; Li, Z.; Ren, H. Colloids Surf., A 2018,
546, 153.
(14) Gutierrez, A. J.; Froehler, B. C. Tetrahedron Lett. 1996, 37, 3959.
(15) Steinert, J.; Khalaf, H.; Keese, W.; Rimpler, M. Anal. Chim. Acta
1996, 327, 153.
(27) Oldenziel, O. H.; van Leusen, A. M. Tetrahedron Lett. 1972, 2777.
(28) Lingaraju, G. S.; Swaroop, T. R.; Vinayaka, A. C.; Kumar, K. S. S.;
Sadashiva, M. P.; Rangappa, K. S. Synthesis 2012, 44, 1373.
(29) Rajeev, N.; Swaroop, T. R.; Anil, S. M.; Bommegowda, Y. K.;
Rangappa, K. S.; Sadashiva, M. P. Synlett 2017, 28, 2281.
(30) (a) Moran, J. R.; Tapia, I.; Alcazar, V. Tetrahedron 1990, 46, 1783.
(b) Villemin, D.; Thibault-Starzyk, F. Synlett 1993, 148.
(c) Vedejs, E.; Arnost, M. J.; Dolphin, J. M.; Eustache, J. J. Org.
Chem. 1980, 45, 2601. (d) Mloston, G.; Urbaniak, K.; Gulea, M.;
Masson, S.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 2005,
88, 2582.
(31) (a) Swaroop, T. R.; Roopashree, R.; Ila, H.; Rangappa, K. S. Tetra-
hedron Lett. 2013, 54, 147. (b) Swaroop, T. R.; Ila, H.; Rangappa,
K. S. Tetrahedron Lett. 2013, 54, 5288. (c) Raghava, B.;
Parameshwarappa, B.; Acharya, A.; Swaroop, T. R.; Rangappa, K.
S.; Ila, H. Eur. J. Org. Chem. 2014, 1882. (d) Vinayaka, A. C.;
Swaroop, T. R.; Chikkade, P. K.; Rangappa, K. S.; Sadashiva, M. P.
RSC Adv. 2016, 6, 11528. (e) Kiran, K. R.; Swaroop, T. R.;
Sukrutha, K. P.; Shruthi, K. P.; Anil, S. M.; Rangappa, K. S.;
Sadashiva, M. P. Synthesis 2019, 51, 4205.
(16) (a) Hantzsch, A.; Weber, J. H. Ber. Dtsch. Chem. Ges. 1887, 20,
3118. (b) Kumar, D.; Kumar, N. M.; Patel, G.; Gupta, S.; Varma, R.
S. Tetrahedron Lett. 2011, 52, 1983.
(32) Hartman, G. D.; Weinstock, L. M. Org. Synth. 1979, 59, 183.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G