Cyclocondensation of β-(aryl/heteroaryl)methylaminoenones with thionyl chloride: A facile general approach for the synthesis of 2,4-bis(het)aryl- 5(het)aroylthiazoles

Article abstract of DOI:10.1016/j.tetlet.2013.07.079

An efficient, regioselective route to 2,4-bis(het)aryl-5(het)aroylthiazoles has been developed by cyclocondensation of thionyl chloride with novel β-(het)arylmethylaminoenones which are readily accessible by the reaction of (het)arylmethylamines with 1,3-bis(het)arylmonothio-1,3-diketones. The method allows entry to 2,4,5-trisubstituted thiazoles, with full control for the introduction of either a (het)aryl group at 2,4 positions or a (het)aroyl group at 5 position of the thiazole ring.

Full text of DOI:10.1016/j.tetlet.2013.07.079

Tetrahedron Letters 54 (2013) 5288–5292
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Tetrahedron Letters
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Cyclocondensation of b-(aryl/heteroaryl)methylaminoenones with
thionyl chloride: a facile general approach for the synthesis of
2,4-bis(het)aryl-5(het)aroylthiazoles
Toreshettahally R. Swaroop a, Hiriyakkanavar Ila b, Kanchugarakoppal S. Rangappa a,
⇑
a Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
b New Chemistry Unit, JNCASR, Jakkur, Bangalore 560 064, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, regioselective route to 2,4-bis(het)aryl-5(het)aroylthiazoles has been developed by cyclo-
condensation of thionyl chloride with novel b-(het)arylmethylaminoenones which are readily accessible
by the reaction of (het)arylmethylamines with 1,3-bis(het)arylmonothio-1,3-diketones. The method
allows entry to 2,4,5-trisubstituted thiazoles, with full control for the introduction of either a (het)aryl
group at 2,4 positions or a (het)aroyl group at 5 position of the thiazole ring.
Received 17 May 2013
Revised 11 July 2013
Accepted 12 July 2013
Available online 20 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
b-(Aryl/heteroaryl)methylaminoenones
Thiazoles
Thionyl chloride and cyclocondensation
Thiazoles are among the most commonly encountered hetero-
cycles of biological interest with many applications.1 The thiazole
ring is present in a large number of natural products; many of
them have been isolated from marine organisms, and display sig-
nificant biological activity such as cytotoxic, antifungal, antituber-
culosis, enzyme inhibitors, and peripheral analgesics.1 This
heterocyclic system is found in several marketed drugs and occu-
pies a prominent position in drug development2 for the treatment
of inflammation, hypertension, bacterial and HIV infection, herbi-
cides, and fungicides.3 Also, some thiazole derivatives have found
application as liquid crystals for ferroelectric display4 and as cos-
metic sunscreens.5
more flexible, general regioselective routes for functionalized thia-
zoles are still needed.
We have recently reported the synthesis and reaction of 1,3-
monothiodiketones 1,11 a new class of three carbon 1,3-bielectro-
philic precursors, which have not been much explored. During
the course of these studies, with a view to examine further syn-
thetic applications of these 1,3-bis(het)arylmonothiodiketones 1,
we have reacted these intermediates with various (het)arylmethyl
amines and subjected the resulting enaminones 2 to cycloconden-
sation with thionyl chloride, furnishing the corresponding 2,4-dia-
ryl/heteroaryl-5-acyl thiazoles of the general structure
3 in
moderate to good yields. The results of these studies have been re-
ported in this Letter.
Among the various methods available for substituted thiazoles,1
Hantzsch thiazole synthesis6 (or its modified versions)7 has proven
to be a powerful method for the synthesis of 2,4,5-substituted thi-
The desired enaminones 2a–j carrying
a b-(aryl/hetero-
aryl)methylamino group were obtained in excellent yields in
highly regioselective manner, by condensation of the correspond-
ing 1,3-monothiodiketones 1a–j with the appropriate (het)arylm-
ethylamines 4 in ethanol at room temperature in the presence of
acid catalyst (Scheme 2). Enaminone 2a was selected as a model
substrate for optimizing the reaction conditions for the formation
of thiazole 3a in the presence of various bases and solvents (Table 1,
Scheme 1). Thus treatment of 2a with thionyl chloride in the pres-
ence of pyridine, both as base and solvent at 0 °C under the
conditions described earlier,12 afforded the desired 4-(4-methoxy-
phenyl)-2-(4-methylphenyl)-5-benzoylthiazole 3a only in 15%
yield (Table 1, entry 1). Similarly, thiazole 3a was obtained in
low yield, when the reaction was conducted in dichloromethane
as solvent in the presence of pyridine as base (Table 1, entry 2).
azoles, involving condensation of
with thioamides. Other methods include reaction of
iles with CS2, COS, isothiocyanates, and dithiocarboxylic acids,8
and thionationcyclization of -acylaminoketones (or related pre-
a-haloketones (or its variant)
a
-aminonitr-
a
cursors) with various thionation reagents such as P2S5, H2S, Lawes-
son, or Belleau’s reagent.9 Recently 2,4,5-trisubstituted thiazoles
have also been synthesized through palladium catalyzed cross-
coupling reactions and CAH arylation.10 Despite these advances,
⇑
Corresponding author. Tel.: +91 821 2419661; fax: +91 821 2500846.
E-mail addresses: rangappaks@gmail.com, rangappaks@uni-mysore.ac.in (K.S.
Rangappa).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.079

T. R. Swaroop et al. / Tetrahedron Letters 54 (2013) 5288–5292
5289
SOCl2 (6 equiv)/base
S
N
O
O
Solvent/reaction conditions
N
H
MeO
MeO
2a
3a
Scheme 1. Synthesis of (4-(4-methoxyphenyl)-2-p-tolylthiazol-5-yl)(phenyl)methanone 3a.
However, a dramatic increase in the yield (65%) of thiazole 3a was
observed when 4-(dimethylamino)pyridine (DMAP) was used as
base instead of pyridine under similar conditions (Table 1, entry
3) probably due to enhanced base strength of DMAP. Use of other
bases such as DBU, triethylamine, afforded thiazole 3a in lower
yields (Table 1, entries 4 and 5), whereas, enaminone 2a was recov-
ered unchanged, when K2CO3 was used as base (entry 6). Dichloro-
methane was found to be the best solvent with DMAP as base for
this reaction and lower yields of thiazole 3a were obtained by
use of other solvents such as THF, acetonitrile, acetone, or dichlo-
roethane even after prolonged reaction time. Attempts to further
improve the yield of 3a by varying the reaction temperature or
time were not successful yielding only intractable reaction
mixture.
and 2-furoyl/2-thiophenecarbonyl groups at 4 and 5 positions
were obtained in higher yields from the respective enaminones
2g,h under these conditions. (Table 2, entries 7 and 8). Enaminone
2i derived from (2-thienyl)methylamine also furnished 4,5-disub-
stituted 2-(2-thienyl) thiazole 3i in 54% yield under similar condi-
tions (Table 2, entry 9). Finally, it was possible to install three
different (het)aryl groups at various positions of thiazole 3j using
this protocol, by subjecting enaminone 2j, derived from 3-(picolyl)
amine to cyclocondensation under these conditions (Table 2, entry
10). Enaminone 2k, from 2-(furyl)methylamine failed to give any
thiazole 3k yielding only unchanged enaminone 2k (Table 2, entry
11). At this stage, it is not possible to give any rational explanation
for the inertness of enaminone 2k under the described reaction
conditions.
With the optimized reaction conditions in hand, we next exam-
ined the generality and scope of the reaction for the synthesis of
other substituted thiazoles 3b–j from the respective enamines
2b–j as shown in Table 2. Thus enaminones 2b,c derived from
3,4-methylenedioxy- and 3-(trifluoromethyl)benzylamines also
underwent cyclocondensation with thionyl chloride under these
conditions, yielding the corresponding 2,4-diaryl-5-aroylthiazoles
3b,c in 58% and 55% yields respectively (Table 2, entries 2 and 3).
Similarly, enaminones 2d–f carrying a (het)aryl group such as 3-
indolyl- or 3-pyridyl moieties also furnished the (het)aryl substi-
tuted thiazoles 3d–f, although in moderate yields (Table 2, entries
4–6). On the other hand, the thiazoles 3g,h, bearing 2-furyl/thienyl
The probable mechanism for the formation of thiazoles 2 ap-
pears to be similar to that suggested earlier,12 and is depicted in
Scheme 3. Thus, the nucleophilic attack of enaminone 2 on thionyl
chloride, followed by elimination of HCl in intermediate 5 fur-
nishes sulfene intermediate 6, which on subsequent deprotonation
and intramolecular cyclization of the resulting anion 7 affords
thiazoline S-oxide anion 8. Further reaction of 8 with another mol-
ecule of thionyl chloride affords thiazoles 3 by deoxygenation
through a Pummerer intermediate 9 (Scheme 3).
In conclusion, we have reported an efficient regioselective route
to b-(het)arylmethylamino enones 2 from readily available 1,3-
bis(het)aryl-1,3-monothiodiketones 1 and utilized these enami-
nones 2, to develop a straightforward general approach for diver-
sity oriented synthesis of 2,4-bis(het)aryl-5-(het)aroyl thiazoles
3. The strategy reported herein allows us a novel entry to 2,4,5-tri-
substituted thiazoles with full control over substitution at the 2-
and 4- and 5-positions. Although the yields of thiazoles are modest
to good, the route offers a direct access to a large number of diverse
new thiazoles based on pharmaceutically relevant structures,
which would otherwise be considerably more difficult to prepare
by alternative routes. In addition, this method offers a facile regio-
selective entry to 5-(het)aroylthiazoles, thus overcoming the limi-
tations of Hantz type condensation,13 in which the mixture of
Table 1
Optimization of reaction conditions for the formation of thiazole 3a
Entry
Basea
Solvent
Time (h)
Yield (3a) (%)
1
2
3
4
5
6
Pyridine
Pyridine
DMAP
DBU
Et3N
K2CO3
Pyridine
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3
3
3
5
7
15
25
65
32
10
b
10
—
a
regioisomeric thiazoles are formed with unsymmetrical
a-
6 equiv of base.
Compound 2a was recovered unchanged.
b
halo1,3-diketones.14
R1
R1
R1
SOCl2/CH2Cl2
DMAP (6 equiv)
H2N
R3
S
N
O
4
O
O
R3
EtOH/RT/H2SO4 (Cat)
R2
1-1.5 h
0°C-RT, 3-5 h
R2
N
H
R3
H
R2
S
1a-j
2a-j
3a-j
Scheme 2. Synthesis of enaminones 2a–j from 1a–j and thiazoles 3a–j.

5290
T. R. Swaroop et al. / Tetrahedron Letters 54 (2013) 5288–5292
Table 2
Synthesis of 2,4-bis(het)aryl-5-(het)aroyl thiazoles 3a–j from enaminones 2a–j
Entry
2
Yield 2 (%)
3
Yield 3 (%)
S
N
O
O
1
85
65
N
H
MeO
MeO
2a
3a
Br
Br
O
S
N
O
O
2
3
4
79
82
58
58
55
48
O
O
O
N
H
3b
2b
OMe
OMe
CF3
S
O
O
CF3
N
N
H
3c
CN
2c
CN
OMe
OMe
S
N
O
O
OMe
OMe
N
H
N
N
2d
3d
CF3
CF3
O
N
S
N
O
N
5
70
56
O
N
H
OMe
3e
2e
N
N
S
O
O
6
7
72
78
53
68
N
N
H
2f
3f
S
S
S
N
O
O
O
O
Cl
N
H
O
O
Cl
3g
2g
O
O
S
N
OMe
8
80
75
N
H
S
S
OMe
3h
2h

T. R. Swaroop et al. / Tetrahedron Letters 54 (2013) 5288–5292
5291
Table 2 (continued)
Entry
2
Yield 2 (%)
3
Yield 3 (%)
N
N
S
N
O
O
O
9
10
11
75
54
45
0
S
N
H
S
Cl
Cl
2i
3i
O
S
O
O
72
N
H
N
N
S
S
N
3j
2j
S
S
S
N
O
N
O
O
N
55
H
O
N
2k
3k
R1
R2
R1
R2
O
S
R1
R2
O
S
R1
O
S
DMAP
SOCl2
O
O
O
Cl
O
R3
N
R3
N
R2
N
H
R3
N
H
5
R3
7
6
2
R3
O
R1
O
R1
O
S
S
SOCl2
O
S
O
Cl
R3
S
R3
O
R3
N
R2
N
R2
H
N
R2
3
9
8
Scheme 3. Probable mechanism for the formation of thiazoles 3.
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Acknowledgments
T.R.S. thanks CSIR, New Delhi for Junior and Senior Research Fel-
lowship, financial support to K.S.R. through BRNS Project (Vide No.
2009/37/40/BRNS/2266 Dated 23-11-2009) and UGC Major Re-
search Project (Vide No. 39-106/2010(SR) Dated 24-12-2010) is
greatly acknowledged.
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