An easy access to 4,5-disubstituted thiazoles via base-induced click reaction of active methylene isocyanides with methyl dithiocarboxylates

Article abstract of DOI:10.1055/s-0031-1290762

An efficient synthesis of 4,5-disubstituted thiazoles via base-induced cyclization of active methylene isocyanides such as tosylmethyl isocyanide, ethyl isocyanoacetate, and arylmethyl isocyanides with methyl arene- and hetarenecarbodithioates is reported

Full text of DOI:10.1055/s-0031-1290762

PAPER
▌1373
paper
An Easy Access to 4,5-Disubstituted Thiazoles via Base-Induced Click
Reaction of Active Methylene Isocyanides with Methyl Dithiocarboxylates
Easy Access to 4,5-Disubstituted Thiazoles
Gejjalagere S. Lingaraju, Toreshettahally R. Swaroop, Ajjampura C. Vinayaka, Kothanahally S. Sharath Kumar,
Marilinganadoddi P. Sadashiva,* Kanchugarakoppal S. Rangappa*
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
Fax +91(821)2500846; E-Mail: rangappaks@gmail.com; E-Mail: rangappaks@uni-mysore.ac.in; E-Mail: mpsadashiva@gmail.com
Received: 17.01.2012; Accepted after revision: 24.02.2012
synthesis from both the point of view of yield and gener-
Abstract: An efficient synthesis of 4,5-disubstituted thiazoles via
ality of the various isocyanides in the protocols. Despite
base-induced cyclization of active methylene isocyanides such as
these procedures, novel methods that allow more substit-
uent diversity on the thiazole ring remain in demand.
tosylmethyl isocyanide, ethyl isocyanoacetate, and arylmethyl iso-
cyanides with methyl arene- and hetarenecarbodithioates is report-
ed. This synthesis could be a new click chemistry reaction, since it Therefore, as a part of our research aimed at the develop-
is simple, rapid, and often avoids purification steps. In addition, this
method allow us a clear and general synthesis of novel 4,5-diaryl-
thiazoles.
ment of new synthetic methods for biologically important
heterocyclic compounds,20 we report herein a general pro-
tocol for the synthesis of thiazoles (Scheme 2) with vari-
ous functionalities at the 4-position and with the 2-
position remaining unsubstituted. To achieve this process,
Keywords: thiazole, isocyanide, cyclization, dithioester, click re-
action
we selected base-induced cyclization of active methylene
isocyanides with dithioesters21.
Thiazoles have eminent interest because of their potential
Reaction of tosylmethyl isocyanide (2a) with methyl ben-
as bioactive compound and versatile synthons for natural
zodithioate (1a) (Scheme 1) was investigated as a model
products and drugs in pharmaceuticals. Thiazole deriva-
reaction in the presence of various solvent and base com-
tives exhibit significant biological properties such as anti-
binations; the results are summarized in Table 1.
bacterial,1 anti-inflammatory,2 antihypertensive,3 anti-
HIV,4 antitumor,5 and antihyperlipidemic6 activities. Par-
ticularly, thiazoles unsubstituted at the 2-position play an
important role in nature. For instance, the thiazolium ring
present in vitamin B1 serves as an electron sink and its co-
enzyme form is important for the decarboxylation of α-
keto acids.7
C:
S
N
N
S
O
S
O
O
SMe
S
base
O
+
solvent
0 °C to r.t.
Furthermore, isocyanide cyclization reactions provide
useful methods for the synthesis of several nitrogen het-
erocycles.8 They often give thiazoles unsubstituted at 2-
position,9 which are not easily available by other methods
developed by Hantzsch,10 Cook and Heilborn,11 and sev-
eral other groups.12 One of the most widely used methods
is the Hantzsch synthesis, which entails the reaction of α-
halo carbonyl compounds with thioureas or thioamides.
Relatively recent novel methods involve the oxidation of
thiazoline/thiazolidine,13 Ugi reaction,14 thioacylation-
cycloisomerization of 4-aminobut-2-ynoic acid esters/
amides,15 treatment of aryl (diformylamino)methyl ketones
with phosphorus pentasulfide,16 alkylation-cyclization of
propargyl bromides with thioureas,17 treatment of α-ami-
do-β-keto esters with Lawesson’s reagent,18 and others.19
1a
2a
3a
Scheme 1 Base-induced cyclization of tosylmethyl isocyanide (2a)
with methyl benzodithioate (1a)
Table 1 Optimization of Reaction Conditions for the Synthesis of
5-Phenyl-4-tosylthiazole (3a)
Yielda (%)
Entry
Solvent
Base (equiv)
Time
b
1
2
3
4
5
6
7
8
THF
DBU (2)
DBU (2)
NaOH (2)
t-BuOK (2)
NaH (2)
NaH (2)
NaH (2)
NaH (2)
48 h
48 h
10 h
9 h
–
DMF
DMF
DMF
DMF
THF
31
55
58
90
70
54
46
For the synthesis of 4,5-disubstituted thiazoles, a few
methods involving the cyclization of α-metalated methyl
isocyanides with carbon disulfide,9a,b thiono esters,9c iso-
thiocyanates,9d,e and carboxymethyl dithioates9f have been
reported. These methods have limits to their application in
10 min
8 h
MeCN
benzene
14 h
16 h
SYNTHESIS 2012, 44, 1373–1379
Advanced online publication: 05.04.2012
DOI: 10.1055/s-0031-1290762; Art ID: SS-2012-N0058-OP
© Georg Thieme Verlag Stuttgart · New York
a Isolated yields.
b No reaction.
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1374
G. S. Lingaraju et al.
PAPER
Our initial attempt to effect the cyclization of 2a with 1a proved to be the most effective, allowing cyclization of 2a
in the presence of DBU as a base in tetrahydrofuran at with 1a to afford 3a in 90% yield in 10 minutes (entry 5).
room temperature failed to give the cyclized product 3a Use of sodium hydride in other solvents such as tetrahy-
even after a prolonged reaction time; only 1a was recov- drofuran, acetonitrile, and benzene (entries 6–8) gave
ered (Table 1, entry 1). Then, we observed progress in the only moderate or low yields of 3a.
reaction on replacing tetrahydrofuran by N,N-dimethyl-
formamide, which gave 3a in 31% yield (entry 2). This
S
S
NaH/DMF
0 °C to r.t.
C:
N
may be due to the stabilization of activated 2a by N,N-di-
methylformamide. The use of sodium hydroxide as a base
in N,N-dimethylformamide proved to be effective, fur-
nishing 3a in 55% yield (entry 3), probably due to an in-
crease in reactivity of activated 2a with enhanced base
strength in the reaction. Thereafter, we decided to increase
the reactivity of 2a by using strong bases, with N,N-di-
methylformamide as the solvent of choice. When reaction
was effected using potassium tert-butoxide, 3a was ob-
tained in 58% yield (entry 4). Finally, sodium hydride
R1
R1
+
R2
N
SMe
R2
3–6
1
2
2a, R2 = Ts
3a–h
4a–d
5a–q
6a–d
2b, R2 = CO2Et
2c, R2 = Ph
2d, R2 = 4-FC6H4
Scheme 2 Sodium hydride induced cyclization of isocyanides with
dithioesters
Table 2 Synthesis of 4,5-Disubstituted Thiazoles 3–6 from Dithioesters and Isocyanides
R1
R2
Productc
Yielda (%)
Entry
Dithioester
Isocyanide
Time (min)
3a9f
3b9f
3c9f
3d9f
3e
90b
95b
91b
84
1
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
2c
2c
2c
2c
2c
2d
2d
2d
2d
Ph
Ts
10
12
12
15
15
20
20
15
10
20
15
10
25
30
30
30
30
25
25
20
25
25
20
2
4-MeOC6H4
4-MeC6H4
Ts
3
Ts
4
4-ClC6H4
Ts
92b
93b
85
90b
40
50
44
42
80
84
83
85
90
78
83b
88
90
5
3,4-(MeO)2C6H3
3,4,5-(MeO)3C6H2
thiophen-2-yl
1-methylindol-3-yl
Ph
Ts
6
Ts
3f
7
1g
1h
1a
1b
1f
Ts
3g
8
Ts
3h
4a9g
4b
9
CO2Et
CO2Et
CO2Et
CO2Et
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4-MeOC6H4
3,4,5-(MeO)3C6H2
1-methylpyrrol-2-yl
Ph
4c
1i
4d
5a22
5b
5c
1a
1b
1c
1e
1f
4-MeOC6H4
4-MeC6H4
Ph
Ph
3,4-(MeO)2C6H3
3,4,5-(MeO)3C6H2
1-methylindol-3-yl
1-methylpyrrol-2-yl
Ph
Ph
5d
5e
Ph
1g
1i
Ph
5f
Ph
5g
6a
6b
6c
1a
1b
1f
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-MeOC6H4
3,4,5-(MeO)3C6H2
1-methylpyrrol-2-yl
91b
93
1i
6d
a Isolated yields.
b Purified by crystallization (EtOAc–hexane).
c Known compounds are indicated by their literature reference.
Synthesis 2012, 44, 1373–1379
© Georg Thieme Verlag Stuttgart · New York

PAPER
Easy Access to 4,5-Disubstituted Thiazoles
1375
Using the optimized reaction conditions, we next studied tions, they furnished 5-aryl- or 5-hetaryl-substituted 4-(4-
the reaction of 2a with various dithioesters 1a–h, with a fluorophenyl)thiazoles in high yields (entries 20–23).
view to examining the generality and scope of this cycli-
zation reaction (Scheme 2, Table 2, entries 1–8). Thus, cy-
clization is compatible with various benzodithioates 1a–f
bearing electron-donating and -withdrawing substituents
and also with hetarenecarbodithioates 1g,h, affording the
product 5-aryl- or 5-hetaryl-substituted 4-[(4-methylphe-
A plausible mechanism for the sodium hydride induced
formation of thiazoles 3–6 from dithioesters 1 and active
methylene isocyanides 2 is shown in Scheme 3. Thus, in
the presence of sodium hydride, the anion 7 formed by the
abstraction of an acidic proton from the active methylene
group of 2, attacks dithioester 1 to give unstable interme-
nyl)sulfonyl]thiazoles 3a–h in 84–95% yields (entry 1–8).
diate 8. In the presence of sodium hydride, the carbanion
Interestingly, all dithioesters 1a–h furnished thiazoles in
9 formed by the abstraction of a proton from 8 is in equi-
librium with the enethiolate ion 10. Subsequent intramo-
comparable yields and short reaction time.
Notably, some products were sufficiently pure for analyt- lecular cyclization of 10 affords thiazoles 3–6.
ical characterization after crystallization from ethyl ace-
tate and hexane. It is important to highlight that
S
C
–
C
1
compounds 3a–d were obtained by Oldenziel and
van Leusen from the reaction of tosylmethyl isocyanide
with carboxymethyl dithioates in the presence of potassi-
um hydroxide in tert-butyl alcohol in 48–79% yields.9f
Whereas the present method afforded the same com-
pounds in 84–95% yields, which indicates that our proto-
col is effective in comparison to the earlier reported
method.
NaH
N
R2
N
R1
2
S
C
N
R2
8
7
–
R1
R2
–
S
C
N
9
3–6
R1
R2
To further probe the efficiency of the reaction for the syn-
thesis of ester-substituted thiazoles, the cyclization of eth-
yl isocyanoacetate (2b) with 1a was examined. Thus,
reaction of 2b with 1a under the reaction conditions de-
scribed afforded the cyclized product ethyl 5-phenylthia-
zole-4-carboxylate (4a) in 40% yield (entry 9). Similarly,
reaction of 1b,f,i gave 5-aryl- and 5-hetaryl-substituted
ethyl thiazole-4-carboxylates in 42–50% yields (entries
9–12).
10
Scheme 3 Plausible mechanism for the formation of thiazoles 3–6
from 2
In summary, we have developed an efficient general pro-
tocol for the synthesis of 4,5-disubstituted thiazoles from
easily prepared dithioesters and activated methylene iso-
cyanides. The methodology allows different functional-
ities (tosyl, alkoxycarbonyl, aryl) at the 4-position of the
thiazole ring. The procedure described here is simple and
rapid. Some of the products isolated according to this pro-
tocol are sufficiently pure for analytical characterization,
thus avoiding the need of purification from column chro-
matography. Hence, this reaction could be a new click
chemistry reaction. To the best of our knowledge, the syn-
thesis of thiazoles from arylmethyl isocyanides is the first
example of this type in isocyanide cyclization reactions.
Further application of this methodology is under way in
our laboratory.
However, our attempts to improve the yield of 4a were
unsuccessful using alternative bases (t-BuOK, DBU,
NaOH, etc.) under different conditions and yielded either
the unreacted benzodithioate 1a or an intractable reaction
mixture at higher temperatures. At this stage, we attribute
the moderate yields of 5-aryl- and 5-hetaryl-substituted
ethyl thiazole-4-carboxylates to the lower reactivity of the
ethyl isocyanoacetate enolate ion.
To further introduce a point of diversity at the 4-position
of the thiazole ring, this protocol was elaborated to the cy-
clization of arylmethyl isocyanides with dithioesters un-
der the conditions described. It should be noted that
cyclization reactions of arylmethyl isocyanides for the
construction of thiazole rings have not been previously re-
ported, to best of our knowledge. The desire arylmethyl
isocyanides were prepared by dehydration of the corre-
sponding N-benzylformamides.23 Thus, when 1a was re-
acted with benzyl isocyanide (2c) under standard reaction
conditions, 4,5-diphenylthiazole (5a) was obtained in
The starting materials were commercially available and used as re-
ceived without further purification. The dithioesters 1a–i were pre-
pared by following a known procedure.21 Reactions were monitored
by TLC using precoated sheets of silica gel G/UV-254 of 0.25 mm
thickness (Merck 60F254) using UV light for visualization. The
melting points were determined on Selaco melting point apparatus
and are uncorrected. 1H and 13C NMR spectra were recorded on an
NMR spectrometer operating at 400 and 100 MHz, respectively, us-
ing the residual solvent peaks as reference relative to SiMe4. Mass
80% yield (entry 13). Similarly other dithioesters 1b–f,g,i spectra were recorded using electrospray ionization (ESI) mass
spectrometry. The C, H, and N analysis were performed using CE-
400 CHN analyzer. Infrared spectra were recorded on Shimadzu
FT-IR model 8300 spectrophotometer.
underwent smooth cyclization with 2c under the opti-
mized reaction conditions, affording the respective 5-aryl-
or 5-hetaryl-substituted 4-phenylthiazoles in overall high
yields (entries 14–19).
4-[(4-Methylphenyl)sulfonyl]-5-phenylthiazole (3a); Typical
Procedure
A soln of dithioester 1a (3.0 mmol) and TosMIC (2a, 3.0 mmol) in
DMF (8 mL) was added dropwise to a stirring suspension of NaH
Also, when dithioesters 1a,b,d,f,i reacted with 4-fluoro-
benzyl isocyanide (2d) under the standard reaction condi-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1373–1379

1376
G. S. Lingaraju et al.
PAPER
(6 mmol) in DMF (8 mL) at 0 °C. The resulting mixture was stirred
at r.t. for 10–30 min (TLC monitoring). It was then poured into sat.
NH4Cl soln (100 mL). The mixture was extracted with EtOAc
(3 × 50 mL), washed with H2O (2 × 50 mL) and brine (50 mL),
dried (anhyd Na2SO4), and concentrated in vacuo. The crude prod-
uct 3a were purified either by crystallization (EtOAc–hexane). In
general the products were purified by crystallization (EtOAc–hex-
ane) or column chromatography (silica gel, hexane–EtOAc, 8:2)
(see Table 2).
5-(3,4-Dimethoxyphenyl)-4-[(4-methylphenyl)sulfonyl]thiazole
(3e)
Yellow solid; yield: 1.03 g (92%); mp 139–141 °C.
IR (KBr): 3030, 2955, 2852, 1986, 1913, 1840, 1789, 1728, 1597,
1523, 1473, 1442, 1384, 1265, 1172, 1118, 1026, 960, 829, 763,
682, 570, 540 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.65 (s, 1 H), 7.77 (d, J = 8 Hz, 2
H), 7.26 (t, J = 5.6 Hz, 2 H), 7.13 (d, J = 2 Hz, 1 H), 7.10 (dd, J =
8.4, 2.4 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 3.94 (s, 3 H), 3.91 (s, 3
H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 151.2, 150.5, 148.5, 144.5, 144.2,
137.7, 129.5, 128.3, 127.9, 123.4, 120.2, 113.9, 110.7, 56.5, 55.9,
21.6.
4-[(4-Methylphenyl)sulfonyl]-5-phenylthiazole (3a)
Yellow solid: yield: 0.84 g (90%); mp 149–151 °C.
IR (KBr): 3035, 2951, 2850, 1940, 1886, 1797, 1620, 1396, 1323,
1230, 1145, 1037, 960, 810, 748, 694, 582, 505 cm–1.
MS: m/z = 376 [M + H]+.
1H NMR (400 MHz, CDCl3): δ = 8.70 (s, 1 H), 7.77 (d, J = 6.8 Hz,
2 H), 7.54–7.44 (m, 5 H), 7.27 (d, J = 8.0 Hz, 2 H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 151.7, 148.5, 144.5, 144.4, 140.1,
Anal. Calcd for C18H17NO4S2: C, 57.48; H, 4.56; N, 3.73. Found: C,
57.26; H, 4.78; N, 3.92.
137.7, 130.9, 129.5, 128.9, 128.4, 125.0, 21.4.
MS: m/z = 316 [M + H]+.
4-[(4-Methylphenyl)sulfonyl]-5-(3,4,5-trimethoxyphenyl)thia-
zole (3f)
Brownish solid; yield: 1.09 g (93%); mp 101–103 °C.
Anal. Calcd for C16H13NO2S2: C, 60.93; H, 4.15; N, 4.44. Found: C,
61.09; H, 4.26; N, 4.34.
IR (KBr): 3038, 2956, 2840, 1985, 1913, 1842, 1790, 1718, 1567,
1532, 1478, 1424, 1364, 1269, 1176, 1128, 1026, 960, 829, 763,
682, 570, 541 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.67 (s, 1 H), 7.76 (d, J = 8.4 Hz,
2 H), 7.27 (d, J = 8.4 Hz, 2 H), 6.75 (s, 2 H), 3.90 (s, 3 H), 3.86 (s,
6 H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.6, 152.8, 151.3, 149.0, 144.6,
139.4, 138.8, 137.5, 129.5, 128.4, 122.9, 108.2, 60.9, 56.2, 21.6.
MS: m/z = 406 [M + H]+.
5-(4-Methoxyphenyl)-4-[(4-methylphenyl)sulfonyl]thiazole (3b)
Yellow solid; yield: 0.99 g (95%); mp 181–183 °C.
IR (KBr): 3035, 2952, 2850, 1967, 1940, 1917, 1890, 1867, 1789,
1604, 1454, 1392, 1296, 1257, 1196, 1083, 1026, 940, 794, 648,
574, 532 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.65 (s, 1 H), 7.78 (d, J = 8.0 Hz,
2 H), 7.48 (d, J = 8.4 Hz, 2 H), 7.27 (d, J = 8.0 Hz, 2 H), 6.96 (d,
J = 8.4 Hz, 2 H), 3.87 (s, 3 H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 160.9, 151.4, 148.2, 144.5, 137.7,
131.9, 129.5, 128.4, 1200, 113.7, 55.3, 21.6.
Anal. Calcd for C19H19NO5S2: C, 56.28; H, 4.72; N, 3.45. Found: C,
56.48; H, 4.96; N, 3.62.
MS: m/z = 346 [M + H]+.
4-[(4-Methylphenyl)sulfonyl]-5-(thiophen-2-yl)thiazole (3g)
Brownish sticky liquid; yield: 0.78 g (85%).
Anal. Calcd for C17H15NO3S2: C, 59.11; H, 4.38; N, 4.05. Found: C,
59.28; H, 4.25; N, 4.16.
IR (KBr): 3026, 2968, 2860, 1976, 1903, 1860, 1799, 1748, 1597,
1523, 1473, 1442, 1384, 1265, 1172, 1118, 1026, 960, 829, 763,
682, 567, 547 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.66 (s, 1 H), 7.79 (d, J = 8.0 Hz,
2 H), 7.56 (t, J = 1.2 Hz, 1 H), 7.51 (t, J = 1.2 Hz, 1 H), 7.27 (d, J =
8.0 Hz, 2 H), 7.13 (q, J = 4.4 Hz, 1 H), 2.41 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 151.7, 150.1, 144.7, 137.3, 132.0,
129.7, 129.6, 129.4, 128.3, 127.7, 127.8, 21.6.
MS: m/z = 322 [M + H]+.
5-(4-Methylphenyl)-4-[(4-methylphenyl)sulfonyl]thiazole (3c)
Off-white solid; yield: 0.90 g (91%); mp 141–143 °C.
IR (KBr): 3033, 2953, 2850, 1951, 1913, 1801, 1597, 1531, 1473,
1384, 1234, 1184, 1083, 1037, 1018, 964, 910, 806, 698, 655, 570,
536 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.66 (s, 1 H), 7.79 (d, J = 8.4 Hz,
2 H), 7.43 (d, J = 8.4 Hz, 2 H), 7.26 (t, J = 7.2 Hz, 4 H), 2.42 (s, 3
H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 151.6, 148.5, 144.5, 144.4, 140.1,
137.7, 130.3, 129.5, 128.9, 128.4, 125.0, 21.6, 21.3.
Anal. Calcd for C14H11NO2S3: C, 52.31; H, 3.45; N, 4.36. Found: C,
52.09; H, 3.58; N, 4.53.
MS: m/z = 330 [M + H]+.
1-Methyl-3-{4-[(4-methylphenyl)sulfonyl]thiazol-5-yl}-1H-in-
dole (3h)
Brownish solid; yield: 0.97 g (90%); mp 157–159 °C.
Anal. Calcd for C17H15NO2S2: C, 61.98; H, 4.59; N, 4.25. Found: C,
61.65; H, 4.72; N, 4.43.
IR (KBr): 3045, 2978, 2849, 1996, 1913, 1860, 1789, 1728, 1597,
1543, 1493, 1442, 1384, 1265, 1172, 1138, 1026, 980, 829, 763,
682, 580, 536 cm–1.
5-(4-Chlorophenyl)-4-[(4-methylphenyl)sulfonyl]thiazole (3d)
Brownish solid; yield: 0.87 g (84%); mp 180–182 °C.
1H NMR (400 MHz, CDCl3): δ = 8.66 (s, 1 H), 7.90 (s, 1 H), 7.77
(d, J = 8.4 Hz, 2 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1
H), 7.31 (t, J = 8.4 Hz, 1 H), 7.20 (t, J = 4.8 Hz, 3 H), 3.90 (s, 3 H),
2.35 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.1, 147.1, 144.2, 138.2, 137.8,
136.8, 132.8, 129.4, 128.1, 127.2, 122.6, 120.8, 119.0, 109.9, 101.7,
33.3, 21.5.
IR (KBr): 3033, 2958, 2856, 1990, 1963, 1882, 1789, 1620, 1593,
1415, 1396, 1319, 1296, 1265, 1184, 1145, 1087, 1014, 964, 817,
694, 667, 657, 648, 590, 536 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.71 (s, 1 H), 7.75 (d, J = 8.4 Hz,
2 H), 7.49–7.42 (m, 4 H), 7.25 (d, J = 8.4 Hz, 2 H), 2.41 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 152.2, 149.3, 144.8, 142.6, 137.3,
136.2, 131.8, 129.6, 128.5, 128.4, 126.5, 21.6.
MS: m/z = 369 [M + H]+.
MS: m/z = 350 [M + H]+.
Anal. Calcd for C19H16N2O2S2: C, 61.93; H, 4.38; N, 7.60. Found:
C, 61.81; H, 4.61; N, 7.43.
Anal. Calcd for C16H12ClNO2S2: C, 54.93; H, 3.46; N, 4.00. Found:
C, 55.17; H, 3.63; N, 3.77.
Synthesis 2012, 44, 1373–1379
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Easy Access to 4,5-Disubstituted Thiazoles
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Ethyl 5-Phenyl-1,3-thiazole-4-carboxylate (4a)
Yellow viscous liquid; yield: 0.38 g (40%).
Anal. Calcd for C15H11NS: C, 75.91; H, 4.67; N, 5.90. Found: C,
76.02; H, 4.76; N, 6.12.
IR (KBr): 3036, 2958, 2850, 2823, 1738, 1712, 1586, 1432, 1368,
5-(4-Methoxyphenyl)-4-phenylthiazole (5b)
1203, 876, 762 cm–1.
Yellow gum; yield: 0.68 g (84%).
1H NMR (400 MHz, CDCl3): δ = 9.06 (s, 1 H), 7.79 (d, J = 6.8 Hz,
2 H), 7.41–7.51 (m, 3 H), 4.30 (q, J = 6.0 Hz, 2 H), 1.29 (t, J = 6.0
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.1, 152.5, 132.6, 129.9, 129.2,
128.7, 128.2, 119.0, 114.8, 60.9, 55.8, 14.1.
IR (KBr): 3040, 2957, 2850, 2830, 1722, 1623 1597, 1433, 1372,
1288, 1203, 1134, 1066, 861, 755 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.77 (s, 1 H), 7.55 (d, J = 8.8 Hz,
2 H), 7.32–7.25 (m, 5 H), 6.86 (d, J = 8.8 Hz, 2 H), 3.82 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.6, 150.4, 150.1, 134.8, 132.8,
130.9, 128.9, 128.2, 127.6, 123.9, 114.2, 55.2.
MS: m/z = 234 [M + H]+.
Anal. Calcd for C12H11NO2S: C, 61.78; H, 4.75; N, 6.00. Found: C,
60.78; H, 4.08; N, 5.80.
MS: m/z = 268 [M + H]+.
Anal. Calcd for C16H13NOS: C, 71.88; H, 4.90; N, 5.24. Found: C,
71.64; H, 5.15; N, 5.41.
Ethyl 5-(4-Methoxyphenyl)-1,3-thiazole-4-carboxylate (4b)
Yellow gum; yield: 0.46 g (50%).
IR (KBr): 3029, 2951, 2857, 2834, 1741, 1709, 1588, 1402, 1378,
5-(4-Methylphenyl)-4-phenylthiazole (5c)
Brownish gum; yield: 0.63 g (83%).
1193, 854, 798 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.05 (s, 1 H), 7.68 (d, J = 8.4 Hz,
2 H), 7.05 (d, J = 8.4 Hz, 2 H), 4.28 (q, J = 6.0 Hz, 2 H), 3.23 (s, 3
H), 1.29 (t, J = 6.0 Hz, 3 H).
3C NMR (100 MHz, CDCl3): δ = 168.0, 160.6, 152.5, 128.5, 124.9,
119.0, 114.8, 60.9, 55.8, 14.1.
IR (KBr): 3025, 2957, 2840, 1722, 1597, 1433, 1372, 1288, 1203,
1124, 1059, 967, 891, 735 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.79 (s, 1 H), 7.54 (d, J = 8.0 Hz,
2 H), 7.30–7.23 (m, 5 H), 7.13 (d, J = 8.8 Hz, 2 H), 2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.7, 149.7, 138.2, 134.7, 133.1,
129.5, 129.4, 128.9, 128.3, 127.9, 126.8, 21.2.
MS: m/z = 264 [M + H]+
Anal. Calcd for C13H13NO3S: C, 59.30; H, 4.98; N, 5.32. Found: C,
60.15; H, 4.68; N, 5.20.
MS: m/z = 252 [M + H]+.
Anal. Calcd for C16H13NS: C, 76.46; H, 5.21; N, 5.57. Found: C,
76.64; H, 5.82; N, 5.23.
Ethyl 5-(3,4,5-Trimethoxyphenyl)thiazole-4-carboxylate (4c)
Viscous liquid; yield: 0.41 g (44%).
5-(3,4-Dimethoxyphenyl)-4-phenylthiazole (5d)
Yellow gum; yield: 0.75 g (85%).
IR (KBr): 3035, 2958, 2850, 2835, 2820, 1735, 1722, 1597, 1433,
1372, 1288, 1203, 1124, 1066, 881, 785 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.76 (s, 1 H), 7.26 (d, J = 7.6 Hz,
2 H), 4.29 (q, J = 9.2 Hz, 2 H), 3.96 (s, 3 H), 3.17 (s, 6 H), 1.26 (t,
J = 9.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.8, 153.1, 152.5, 139.2, 128.2,
128.0, 118.8, 104.6, 60.9, 55.8, 14.1.
IR (KBr): 3023, 2965, 2863, 2830, 2816, 1722, 1597, 1433, 1372,
1288, 1203, 1124, 1066, 894, 756 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.77 (s, 1 H), 7.55 (dd, J = 8.4, 1.6
Hz, 2 H), 7.32–7.25 (m, 3 H), 6.96 (dd, J = 8.4, 2.0 Hz, 1 H), 6.82
(t, J = 8.4 Hz, 2 H), 3.89 (s, 3 H), 3.66 (s, 3 H).).
13C NMR (100 MHz, CDCl3): δ = 150.4, 150.2, 149.1, 148.8, 134.8,
132.9, 129.0, 128.2, 127.7, 124.1, 122.3, 112.7, 11.3, 55.8, 55.7.
MS: m/z = 323 [M + H]+.
Anal. Calcd for C15H17NO5S: C, 55.71; H, 5.30; N, 4.33. Found: C,
55.86; H, 5.72; N, 4.63.
MS: m/z = 298 [M + H]+.
Anal. Calcd for C17H15NO2S: C, 68.66; H, 5.08; N, 4.71. Found: C,
68.83; H, 5.29; N, 4.98.
Ethyl 5-(1-Methyl-1H-pyrrol-2-yl)thiazole-4-carboxylate (4d)
Yellow viscous liquid; yield: 0.29 g (42%).
4-Phenyl-5-(3,4,5-trimethoxyphenyl)thiazole (5e)
Greenish gum; yield: 0.85 g (90%).
IR (KBr): 3035, 2958, 2850, 1735, 1722, 1597, 1433, 1372, 1288,
1203, 1124, 1066, 881, 785, 725 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.87 (s, 1 H), 6.71 (d, J = 2.0 Hz,
1 H), 6.32 (dd, J = 3.6, 1.6 Hz, 1 H), 6.23 (d, J = 3.0 Hz, 1 H), 4.34
(q, J = 6.0 Hz, 2 H), 3.17 (s, 3 H), 1.32 (t, J = 5.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 189.9, 152.2, 139.9, 137.7, 120.9,
109.9, 105.1, 58.3, 34.1, 22.9.
IR (KBr): 3036, 2960, 2836, 2836, 2820, 1722, 1597, 1433, 1372,
1288, 1203, 1124, 1066, 896, 732 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.79 (s, 1 H), 7.56 (d, J = 7.6 Hz,
2 H), 7.34–7.25 (m, 3 H), 6.55 (s, 2 H), 3.87 (s, 3 H), 3.70 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 153.3, 150.6, 138.2, 134.7, 132.9,
129.0, 128.2, 127.9, 126.9, 106.9, 104.0, 60.9, 56.0.
MS: m/z = 328 [M + H]+.
MS: m/z = 237 [M + H]+.
Anal. Calcd for C11H12N2O2S: C, 55.91; H, 5.12; N, 11.86. Found:
C, 56.15; H, 5.40; N, 12.26.
Anal. Calcd for C18H17NO3S: C, 66.03; H, 5.23; N, 4.28. Found: C,
66.23; H, 5.06; N, 4.45.
4,5-Diphenylthiazole (5a)
1-Methyl-3-(4-phenylthiazol-5-yl)-1H-indole (5f)
Yellow gum; yield: 0.56 g (80%).
Yellowish-brown gum; yield: 0.66 g (78%).
IR (KBr): 3032, 2955, 2851, 1722, 1597, 1433, 1372, 1288, 1203,
1124, 1066, 956, 881, 785, 682 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.79 (s, 1 H), 7.53–7.48 (m, 2 H),
7.34 (s, 5 H), 7.00–6.95 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.7, 161.2, 151.0, 149.6, 131.6,
130.8, 129.6, 128.8, 128.4, 115.4, 115.1.
MS: m/z = 238 [M + H]+.
IR (KBr): 3036, 2959, 2852, 1722, 1670, 1597, 1433, 1372, 1295,
1288, 1203, 1124, 1066, 861, 756 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.89 (s, 1 H), 7.65 (dd, J = 8.0, 3.8
Hz, 2 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.35 (d, J = 8.4 Hz, 2 H), 7.28
(s, 1 H), 7.27–7.24 (m, 2 H), 7.08 (t, J = 7.6 Hz, 2 H), 3.78 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.5, 150.2, 136.9, 135.3, 135.1,
134.0, 128.7, 128.5, 128.2, 127.5, 126.8, 122.3, 120.1, 109.4, 32.9.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1373–1379

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G. S. Lingaraju et al.
PAPER
MS: m/z = 291 [M + H]+.
13C NMR (100 MHz, CDCl3): δ = 163.6, 161.1, 152.3, 151.2, 130.9,
129.5, 129.5, 129.4, 124.0, 121.5, 115.5, 115.3, 112.2, 108.6, 34.0.
MS: m/z = 259 [M + H]+.
Anal. Calcd for C18H14N2S: C, 74.45; H, 4.86; N, 9.65. Found: C,
74.86; H, 5.10; N, 9.85.
Anal. Calcd for C14H11FN2S: C, 65.10; H, 4.29; N, 10.84. Found: C,
65.30; H, 4.56; N, 11.05.
5-(1-Methyl-1H-pyrrol-2-yl)-4-phenylthiazole (5g)
Off-white solid; yield: 0.59 g (83%); mp 99–101 °C.
IR (KBr): 3035, 2958, 2850, 1886, 1612, 1415, 1338, 1269, 1222,
1157, 1130, 1103, 1083, 964, 829, 740, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.87 (s, 1 H), 7.51 (d, J = 6.8 Hz,
2 H), 7.33–7.30 (m, 3 H), 6.71 (d, J = 2 Hz, 1 H), 6.32 (dd, J = 3.6,
1.6 Hz, 1 H), 6.23 (t, J = 3.2 Hz, 1 H), 3.17 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 152.2, 152.0, 134.7, 128.5, 127.8,
127.6, 123.8, 123.8, 121.7, 112.1, 108.4, 34.1.
Acknowledgement
G.S.L. gratefully acknowledges financial support (Grant F. No. 37-
456/2009[SR]) from the University Grants Commission, New
Delhi, India and one of the authors T.R.S. thanks the Council of
Scientific and Industrial Research, New Delhi, India for a Junior
Research Fellowship.
MS: m/z = 241 [M + H]+.
Anal. Calcd for C14H12N2S: C, 69.97; H, 5.03; N, 11.66. Found: C,
70.12; H, 5.26; N, 11.83.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.omnorinIftangonmSorniuifIatoprtngiSutpor
4-(4-Fluorophenyl)-5-phenylthiazole (6a)
Yellow gum; yield: 0.67 g (88%).
References
IR (KBr): 3055, 2968, 2859, 1958, 1722, 1597, 1433, 1372, 1288,
1203, 1124, 1100, 1066, 831, 735 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.79 (s, 1 H), 7.53–7.48 (m, 2 H),
7.54 (s, 5 H), 7.00–6.95 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 163.6, 151.0, 149.6, 131.6,
130.73, 130.7, 129.6, 128.8, 128.4, 115.3, 115.1.
MS: m/z = 256 [M + H]+.
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70.78; H, 4.26; N, 5.68.
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4-(4-Fluorophenyl)-5-(4-methoxyphenyl)thiazole (6b)
Yellow gum; yield: 0.77 g (90%).
IR (KBr): 3035, 2958, 2850, 2830, 1722, 1597, 1433, 1372, 1288,
1203, 1124, 1100, 1066, 841, 725 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.76 (s, 1 H), 7.53–7.49 (m, 2 H),
7.24 (s, J = 8.8 Hz, 2 H), 6.98 (m, 2 H), 6.87 (d, J = 8.8 Hz, 2 H),
3.83 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.5, 161.1, 159.7, 150.5, 149.1,
132.7, 130.9, 130.7, 130.6, 123.7, 115.3, 115.1, 114.3, 55.2.
MS: m/z = 286 [M + H]+.
Anal. Calcd for C16H12FNOS: C, 67.35; H, 4.24; N, 4.91. Found: C,
67.84; H, 4.46; N, 5.19.
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4-(4-Fluorophenyl)-5-(3,4,5-trimethoxyphenyl)thiazole (6c)
Brownish solid; yield: 0.91 g (91%); mp 95–98 °C.
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IR (KBr): 3033, 2955, 2856, 2830, 2820, 1722, 1597, 1433, 1372,
1288, 1203, 1124, 1100, 1066, 821, 736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.79 (s, 1 H), 7.57–7.53 (m, 2 H),
7.01 (m, 2 H), 6.53 (s, 2 H), 3.88 (s, 3 H), 3.72 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 163.6, 161.2, 153.4, 150.7, 149.4,
138.3, 132.8, 130.8, 130.7, 126.7, 115.3, 115.1, 106.9, 60.9, 56.2.
MS: m/z = 346 [M + H]+.
Anal. Calcd for C18H16FNO3S: C, 62.59; H, 4.67; N, 4.06. Found:
C, 62.42; H, 4.96; N, 4.36.
4-(4-Fluorophenyl)-5-(1-methyl-1H-pyrrol-2-yl)thiazole (6d)
Off-white solid; yield: 0.71 g (93%); mp 90–92 °C.
IR (KBr): 3031, 2952, 2850, 1994, 1924, 1894, 1643, 1589, 1450,
1354, 1307, 1226, 1130, 1002, 902, 833, 767, 671 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.83 (s, 1 H), 7.50–7.47 (m, 2 H),
6.98 (t, J = 8.8 Hz, 2 H), 6.72 (d, J = 1.6 Hz, 1 H), 6.30 (d, J = 1.6
Hz, 1 H), 6.23 (t, J = 3.2 Hz, 1 H), 3.17 (s, 3 H).
Synthesis 2012, 44, 1373–1379
© Georg Thieme Verlag Stuttgart · New York

PAPER
Easy Access to 4,5-Disubstituted Thiazoles
1379
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1373–1379