Exploration and Optimization of an Efficient One-pot Sequential Synthesis of Di/tri-substituted Thiazoles from α-Bromoketones, Thioacids Salt, and Ammonium Acetate

Article abstract of DOI:10.1002/jhet.2446

Exploration of scope of an optimized one-pot sequential procedure for preparing of 2,4-di- and 2,4,5-tri-substituted thiazoles has been accomplished. The synthesis was performed by the initial formation of a β-keto-thioester intermediate from nucleophilic substitution of α-bromoketones with thioacid potassium salts, followed by treatment with ammonium acetate and one equivalent of acetic acid in toluene to form imine intermediate eventually leading to cyclization yielding thiazoles. This procedure should be highlighted with a flexible way to control the substitution pattern around thiazole ring by choosing appropriately substituted α-bromoketones even containing acid labile functionality and thioacid potassium salts, and thus its applicability is very wide.

Full text of DOI:10.1002/jhet.2446

Month 2015 Exploration and Optimization of an Efficient One-pot Sequential Synthesis
of Di/tri-substituted Thiazoles from α-Bromoketones, Thioacids Salt, and
Ammonium Acetate
*
Eeda Venkateswararao, Hitesh B. Jalani, Manickam Manoj, and Sang-Hun Jung
College of Pharmacy and Istitute of Drug Research and Development, Chungnam National University, Daejeon 305-764,
Republic of Korea
*
E-mail: jungshh@cnu.ac.kr
Additional Supporting Information may found in the online version of this article.
Received January 29, 2015
DOI 10.1002/jhet.2446
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
Exploration of scope of an optimized one-pot sequential procedure for preparing of 2,4-di- and 2,4,5-tri-
substituted thiazoles has been accomplished. The synthesis was performed by the initial formation of a β-
keto-thioester intermediate from nucleophilic substitution of α-bromoketones with thioacid potassium salts,
followed by treatment with ammonium acetate and one equivalent of acetic acid in toluene to form imine
intermediate eventually leading to cyclization yielding thiazoles. This procedure should be highlighted with
a flexible way to control the substitution pattern around thiazole ring by choosing appropriately substituted
α-bromoketones even containing acid labile functionality and thioacid potassium salts, and thus its applica-
bility is very wide.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
around thiazole ring as well as the efficiency to construct
the sterically congested thiazole analogs.
Thiazole derivatives are one of the most important classes
of five-membered heterocyclic scaffolds used in a variety of
applications. Their analogs have attracted continuing inter-
est over the years due to their broad pharmacological appli-
cations such as anticancer [1–5], antiinflammatory [1,4–6],
antihypertensive [5–7], anticonvulsant [8], antifungal [9–14],
antibacterial [12,14–19] anti-HIV [4–6,20], and psychotro-
pic activities [5]. Recently, 2-aminothiazole analogs have
been identified in the treatment of diabetes [8] and tubercu-
losis [9]. Apart from biological properties, films of conju-
gated polyaminothioazole have recently demonstrated
electrochemical properties with high thermal stability [10].
Accordingly, various methods for the preparation of thi-
azoles have been reported. Among them the most widely
used methods for the synthesis of thiazoles include
Hantzsch’s cyclocondensation of thiourea with α-
haloketones/α-tosylketone [21], the reaction of α-
thiocyanate ketone compounds with aromatic or aliphatic
amine hydrochlorides [22], and one-pot reaction of isothio-
cyanates, amidines/guanidines, and 2-halomethylene com-
pounds [23]. Dubs et al. [24] previously reported similar
kind of efficient one-pot thiazole synthesis, but they did
not optimize and investigate the scope of the reaction with
various substrates, in particular containing sensitive groups
like esters. Thus there is still a necessity to demonstrate the
flexibility of their method to control the substitution pattern
RESULTS AND DISCUSSION
In this regard, we modified Dubs thiazole synthesis and
explored the scope of this method for the construction of
2,4- or 2,4,5-substituted thiazoles from simple commer-
cially available α-bromoketones, thioacid potassium salts,
and ammonium acetate as shown in Scheme 1. Initial
attempt was started by reacting 2-bromoacetophenone (1a)
and commercially available potassium thioacetate (2a) in
THF at ambient temperature to give β-keto-thioester interme-
diate 5, which was isolated and confirmed its structure, and
then this intermediate without isolation was further treated
with ammonium acetate 3 and one equivalent of acetic acid
at reflux to give the desired thiazole 4a [25] (Table 1). The re-
action was monitored by thin layer chromatography, which
showed characteristic yellow spot with different Rf value
from those of starting materials. Reactions conducted without
acetic did not produce the desired product, implying that
Brønsted acid is required for the cyclization.
In order to optimize the reaction conditions, we per-
formed the reaction in different solvents such as THF
(81%), DMF (72%), acetonitrile (68%), and toluene
(83%). Although the reaction in toluene gave the satisfac-
tory yield, the dual solvent system was discovered to
improve the yield. The initial reaction proceeded smoothly
© 2015 HeteroCorporation

E. Venkateswararao, H. B. Jalani, M. Manoj, and S.-H. Jung
Vol 000
Scheme 1. One-pot synthesis of di/tri-substituted thiazoles. [Color figure can
be viewed in the online issue, which is available at wileyonlinelibrary.com.]
In order to observe the effect of substituent’s on the para
position of bromoacetophenone 1, substituents were varied
from electron donating to electron withdrawing groups as
shown in entry 1 to 6 in Table 1. It was observed that 2-
bromoacetophenone containing electron donating groups
such as methyl (entry 2, 4b, 87%) and methoxy (entry 3,
4c, 85%) produced slightly lowered yield compared to
bromoacetophenone containing strong electron withdraw-
ing groups like nitro (entry 5, 4e, 98%) and trifluoro (entry
6, 4f, 95%). Chloro substituent gave moderate influence as
in THF, and subsequent addition of an equal volume of
toluene in second stage led to the highest yield of the com-
pound 4a (88%). With this optimized route, we screened
the scope of this procedure with other α-bromoketones
and thioacids as shown in Table 1.
Table 1
Synthesis of di/tri-substituted thiazoles from, α-bromoketones, thioacid salts, and ammonium acetate.
Entry
1
α-Halo ketone
Thio acid salt
CH3COSK
Product no.
Product/yield
4a [21e]
2
3
CH3COSK
CH3COSK
4b [26]
4c [27]
4
5
6
7
CH3COSK
CH3COSK
CH3COSK
CH3COSK
4d [26]
4e [28]
4f
4g [29]
(Continued)
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Synthesis of Di/tri-substituted Thiazoles
Table 1
(Continued)
Entry
8
α-Halo ketone
Thio acid salt
PhCOSK
Product no.
Product/yield
4h [21e]
9
PhCOSK
PhCOSK
PhCOSK
PhCOSK
PhCOSK
PhCOSK
4i [30]
4j [26,30]
4k [21e]
4l [28]
4m [31]
4n
10
11
12
13
14
15
CH3COSK
4o [32]
(Continued)
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E. Venkateswararao, H. B. Jalani, M. Manoj, and S.-H. Jung
Vol 000
Table 1
(Continued)
Entry
16
α-Halo ketone
Thio acid salt
CH3COSK
Product no.
Product/yield
4p [28]
17
18
PhCOSK
PhCOSK
4q [30]
4r [33]
19
20
21
22
CH3COSK
PhCOSK
PhCOSK
CH3COSK
4s
4t
4u [34]
4v [34]
23
24
CH3COSK
PhCOSK
4w
4x
shown in entry 4 (4d, 90%). The electronic withdrawing
property of substituents obviously enhances the yield
possibly due to the acceleration of initial step and imine
formation, although the substituents are located at para
position of phenyl ring of bromoacetophenone 1. Increas-
ing size of aromatic ring as shown in bromoacety-
lnaphthalene did not influence the formation of thiazole
as shown in 4g (entry 7, yield 86%).
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To observe the effect of structural variation of thioacid 2,
replacement of thioacetic acid with the bulkier thiobenzoic
acid in this procedure did not alter the yield in the formation
of di-substituted thiazole analogs (entry 8–14, 4h–n). Thus
the various thioacid 2 could be applied in this procedure.
To confirm the steric effect of α-bromoketone substrates,
the primary bromoacetophenones were replaced with sec-
ondary bromoacetophenones as shown in entry 15–18 in
Table 1, which produced the sterically more congested
2,4,5-tri-substituted thiazole analogs. The yields of these
analogs as shown in preparation of 4o (R2¼Ph, yield
76%), 4p (R2¼CH3, yield 71%), 4q (R2¼CH3, yield
75%), and 4r (R2¼Ph, yield 80%) were little lowered by
the existence of R2 substituents rather than their kind. This
influence might be the result of reduced formation of inter-
mediate 5 due to increased steric congestion of secondary
bromide compared to primary bromoacetophenones.
To gain insight into the sensitivity of the reaction, esters
(entry 19,20,21,22) were subjected to these conditions, which
is considered as one of the most sensitive groups in this reac-
tion condition. The reactions were moderately proceeded as
shown in the formation of 4s (yield 32%), 4t (yield 38%),
4u (yield 68%), and 4v (yield 62%), Thus, this procedure
can be used with α-boromoketones containing acid labile func-
tional groups. In addition, we have prepared fused thiazoles 4w
(yield 46%) and 4x (yield 32%) from α-bromocyclohexanone,
with moderate yields under the same conditions.
This one-pot sequential procedure for the preparation
of thiazole 4 may be explained with the following mech-
anistic interpretation as shown in Scheme 2. Initial nucle-
ophilic substitution reaction of α-bromoketone 1 with
potassium thioactate 2 results in the formation of thio-
ester intermediate 5, which was isolated and confirmed
as stable intermediate with high yield in stepwise opera-
tion. The carbonyl function of thio-ester intermediate 5 is
then protonated and converted to 6 by the treatment of am-
monium acetate 3 and transformed to β-imino-thioester 7,
which was rearranged to give 8. The thio-ester carbonyl
of 8 is protonated by acetic acid and then undergoes a nucle-
ophilic attack by amino group and thereby results into the
concomitant Robinson–Grabrial cyclodehydration to form
9 and eventually to afford the desired thiazoles 4.
CONCLUSION
In conclusion, we have demonstrated an efficient one-
pot sequential method for the preparation of di/tri-
substituted thiazoles from readily available materials like
α-boromoketones, thio-acid salt and ammonia. This proce-
dure is attractive due to its wide applicability, its facile
conditions and no requirement of expensive metal catalyst
and microwave usage. Most importantly, this procedure
should be highlighted with flexible way to control the
substitution pattern around thiazole ring by choosing
appropriately substituted α-bromoketones even containing
acid labile functionality and thioacid potassium salts.
GENERAL EXPERIMENTAL INFORMATION
All reactions were carried out under atmospheric pres-
sure. Solvents were purified by standard techniques with-
1
out special instructions. H and 13C NMR spectra were
recorded on JEOL, JNM-AL-400 (Alice) (400 MHz for
1H, 100 MHz for 13C) spectrometer. CDCl3 and TMS were
used as a solvent and an internal standard, respectively.
The chemical shifts are reported in ppm downfield (δ) from
TMS; the coupling constants J is given in Hz. The peak
patterns are indicated as follows: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; and bs, broad singlet.
TLC was carried out on SiO2 (silica gel 60 F254, Merck),
and the spots were located with UV light, dragon dwarf re-
agent or 1% aqueous KMnO4. Flash chromatography was
carried out on silica gel 60 (0.040–0.063 mm). The starting
materials 1, 2 and 3 are commercially available.
GENERAL SYNTHETIC PROCEDURE FOR
SYNTHESIS OF THIAZOLES
An oven-dried clean round-bottom flask with a magnetic
bar was charged with substituted 2-bromoacetophenone (1,
1.0 equivalent) and potassium salt of thioacid derivative (2,
1.0 equivalent) in 10 mL of THF at ambient temperature.
The reaction mixture was sealed under nitrogen gas stirred
for 3h. After the disappearance of starting materials on
TLC, one equivalent of acetic acid and ammonium acetate
(3, 3 equivalents) and 10mL of toluene were added. The
reaction mixture was refluxed for 6h. The solvent was re-
moved under reduced pressure, and the residue obtained
was purified using flash column chromatography (eluent;
hexanes: ethyl acetate) to afford desired thiazole (4)
derivatives.
Scheme 2. Plausible reaction mechanism for thiazole formation. [Color
figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
2-Methyl-4-phenylthiazole (4a).
1H NMR (CDCl3) δ
7.88 (d, J = 8.29Hz, 2H) 7.42 (t, J =7.68 Hz, 2 H) 7.30–
7.37 (m, 2 H) 2.74–2.82 (s, 3 H); 13C NMR (CDCl3) δ
165.88, 155.17, 134.55, 128.73, 127.98, 126.33, 112.27,
19.38. HRMS calculated for C10H9NS: m/z 170.0456,
Found: 170.0459.
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E. Venkateswararao, H. B. Jalani, M. Manoj, and S.-H. Jung
Vol 000
2-Methyl-4-p-tolylthiazole (4b).
1H NMR (CDCl3) δ
7.39–7.50 (m, 6H); 13C NMR (CDCl3) δ 172.95, 168.15,
155.07, 133.94, 133.57, 132.99, 130.21, 128.98, 128.91,
127.71, 127.61, 126.61, 112.91. HRMS calculated for
C15H10ClNS: m/z 271.0222, Found: 271.0225.
7.77 (d, J = 7.56Hz, 2 H) 7.19–7.27 (m, 3 H) 2.70–2.86
(m, 3H) 2.36–2.42 (m, 3H); 13C NMR (CDCl3) δ
165.73, 155.24, 137.80, 131.83, 129.42, 126.21, 111.48,
21.28, 19.37. HRMS calculated for C11H11NS: m/z
189.0612, Found: 189.0666.
4-(4-Nitrophenyl)-2-phenylthiazole (4l).
1H NMR
(CDCl3) δ 8.31 (m, J= 8.78 Hz, 2H) 8.17 (m, J= 8.54 Hz,
2 H) 7.99–8.11 (m, 2 H) 7.68 (s, 1H) 7.40–7.56 (m, 3 H);
13C NMR (CDCl3) δ 168.84, 153.83, 147.34, 140.30,
133.22, 130.57, 129.08, 126.99, 126.70, 124.22, 115.99.
HRMS calculated for C15H10N2O2S: m/z 282.0463,
Found: 282.0469.
4-(4-Methoxyphenyl)-2-methylthiazole (4c).
1H NMR
(CDCl3) δ 7.73–7.88 (m, 2 H) 7.17 (s, 1 H) 6.94 (d,
J =8.78 Hz, 2 H) 3.84 (s, 3H) 2.76 (s, 3 H); 13C NMR
(CDCl3) δ 165.71, 159.46, 154.94, 127.59, 114.06,
110.50, 55.33, 19.35. HRMS calculated for C11H11NOS:
m/z 205.0561, Found: 205.0563.
2-Phenyl-4-(4-(trifluoromethyl)phenyl)thiazole (4m).
1H
4-(4-Chlorophenyl)-2-methylthiazole (4d).
1H NMR
NMR (CDCl3) δ 7.98–8.15 (m, 4H) 7.70 (d, J=8.54Hz,
2H) 7.59 (s, 1H) 7.42–7.52 (m, 3 H); 13C NMR (CDCl3) δ
168.43, 154.72, 133.45, 130.34, 129.02, 126.65, 126.62,
126.02, 125.81, 125.76, 125.71, 114.39. HRMS calculated
for C16H10F3NS: m/z 305.0486, Found: 305.0489.
(CDCl3) δ 7.81 (m, J = 8.54Hz, 2 H) 7.38 (m, J = 8.54Hz,
2 H) 7.30 (s, 1 H) 2.77 (s, 3 H); 13C NMR (CDCl3) δ
166.17, 153.96, 133.72, 133.02, 128.88, 127.57, 112.62,
19.35. HRMS calculated for C10H8ClNS: m/z 209.0066,
Found: 209.0069.
4-(Naphthalen-2-yl)-2-phenylthiazole (4n).
1H NMR
2-Methyl-4-(4-nitrophenyl)thiazole (4e). 1H NMR (CDCl3)
δ 8.28 (m, J=9.02Hz, 2H) 8.05 (m, J=8.78Hz, 2H) 7.54
(s, 1H) 2.80 (s, 3H); 13C NMR (CDCl3) δ 166.85, 152.72,
140.34, 126.83, 124.20, 115.89, 19.38. HRMS calculated
for C10H8N2O2S: m/z 220.030, Found: 220.0308.
(CDCl3) δ 8.55 (s, 1H) 7.99–8.15 (m, 3 H) 7.79–7.99 (m,
3 H) 7.60 (s, 1 H) 7.40–7.56 (m, 5 H); 13C NMR (CDCl3)
δ 168.07, 156.24, 133.75, 133.66, 133.22, 131.81,
130.15, 128.99, 128.49, 128.41, 127.74, 126.70, 126.38,
126.16, 125.53, 124.36, 113.07. HRMS calculated for
C19H13NS: m/z 287.0769, Found: 287.0773.
2-Methyl-4-(4-(trifluoromethyl)phenyl)thiazole (4f).
1H
NMR (CDCl3) δ 7.93–8.09 (m, 2 H) 7.61–7.77 (m, 2 H)
7.42–7.49 (m, 1 H) 2.78 (s, 3 H); 13C NMR (CDCl3) δ
166.42, 153.62, 137.71, 129.51, 126.46, 125.73, 125.68,
114.16, 19.36. HRMS: calculated for C11H8F3NS: m/z
243.0330, Found 243.0334.
2-Methyl-4,5-diphenylthiazole (4o). 1H NMR (CDCl3) δ
7.42–7.61 (m, 2 H) 7.15–7.39 (m, 8 H) 2.77 (s, 3 H); 13C
NMR (CDCl3) δ 163.82, 149.47, 134.95, 132.42, 132.22,
129.58, 129.02, 128.66, 128.27, 127.93, 127.65, 19.22.
HRMS calculated for C16H13NS: m/z 251.0769, Found:
251.0774.
2-Methyl-4-(naphthalen-2-yl)thiazole (4g).
1H NMR
2,5-Dimethyl-4-phenylthiazole (4p). 1H NMR (CDCl3) δ
7.58–7.66 (m, 2 H) 7.42 (t, J =7.68 Hz, 2 H) 7.33 (d,
J = 7.32Hz, 1 H) 2.67 (s, 3 H) 2.51 (s, 3H); 13C NMR
(CDCl3) δ 161.78, 150.52, 135.12, 129.19, 128.53,
127.42, 19.06, 12.53. HRMS calculated for C11H11NS:
m/z 189.0612, Found: 189.0615.
(CDCl3) δ 8.43 (s, 1 H) 7.74–8.00 (m, 4 H) 7.36–7.56 (m,
3 H) 2.82 (s, 3 H); 13C NMR (CDCl3) δ 166.10, 155.10,
133.65, 133.09, 131.80, 128.40, 127.69, 126.35, 125.29,
124.26, 112.72, 19.44. HRMS calculated for C14H11NS:
m/z 225.0612, Found: 225.0612.
2,4-Diphenylthiazole (4h). 1H NMR (CDCl3) δ 7.96–
8.10 (m, 4H) 7.42–7.50 (m, 6 H) 7.31–7.40 (m, 1 H); 13C
NMR (CDCl3) δ 167.88, 156.29, 134.53, 133.77, 130.06,
128.94, 128.19, 126.46, 112.64. HRMS calculated for
C15H11NS: m/z 237.0612, Found: 237.0614.
5-Methyl-2,4-diphenylthiazole (4q). 1H NMR (CDCl3) δ
7.91–8.01 (m, 2 H) 7.68–7.78 (m, 2H) 7.33–7.49 (m,
6 H) 2.61 (s, 3 H); 13C NMR (CDCl3) δ 163.71, 152.05,
135.18, 133.88, 129.67, 128.87, 128.69, 128.44, 127.63,
126.35, 12.78. HRMS calculated for C16H13NS: m/z
251.0769, Found: 251.0772.
2-Phenyl-4-p-tolylthiazole (4i). 1H NMR (CDCl3) δ 8.04
(dd, J = 7.80, 1.71Hz, 2 H) 7.89 (d, J = 8.05Hz, 2H) 7.35–
7.53 (m, 4 H) 2.40 (s, 3H); 13C NMR (CDCl3) δ 167.72,
156.38, 138.02, 133.84, 131.82, 129.99, 129.44, 128.91,
126.61, 126.36, 111.89, 21.33. HRMS calculated for
C16H13NS: m/z 251.0679, Found: 251.0782.
2,4,5-Triphenylthiazole (4r). 1H NMR (CDCl3) δ 8.04
(dd, J = 7.73, 1.77 Hz, 2 H) 7.62 (dd, J = 7.08, 2.51Hz,
2 H) 7.29–7.53 (m, 11H); 13C NMR (CDCl3) δ 165.58,
150.86, 135.02, 133.68, 132.12, 130.05, 129.66, 129.18,
128.96, 128.78, 128.34, 128.21, 127.88, 126.48. HRMS
calculated for C21H15NS: m/z 313.0925, Found: 313.0925.
Ethyl 5-benzyl-2-methylthiazole-4-carboxylate (4s). 1H NMR
(400MHz, CHLOROFORM-d) δ 7.27–7.35 (m, 4H), 7.20–
7.24 (m, 1H), 4.41 (d, J=7.07Hz, 2H), 4.19 (s, 2H), 2.49 (s,
3H), 1.40 (t, J=7.20Hz, 4H); 13C NMR (100MHz,
CHLOROFORM-d) δ 163.6, 158.6, 148.2, 138.0, 137.4,
128.9, 128.6, 128.5, 126.7, 61.2, 33.0, 14.2. HRMS
calculated for C14H15NO2S: m/z 261.0823, Found: 261.0826.
4-(4-Methoxyphenyl)-2-phenylthiazole (4j).
1H NMR
(CDCl3) δ 8.00–8.08 (m, 2 H) 7.93 (d, J = 8.78Hz, 2 H)
7.39–7.50 (m, 3 H) 7.31–7.36 (m, 1 H) 6.98 (d,
J =9.02 Hz, 2H) 3.86 (s, 3 H); 13C NMR (CDCl3) δ
167.71, 159.68, 156.13, 133.87, 129.95, 128.90, 127.75,
127.56, 126.59, 114.10, 110.90, 55.36. HRMS calculated
for C16H13NOS: m/z 267.0718, Found: 267.0720.
1
4-(4-Chlorophenyl)-2-phenylthiazole (4k). H NMR (CDCl3)
δ 8.03 (dd, J= 7.68, 2.07Hz, 2 H) 7.94 (d, J=8.54Hz, 2H)
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Ethyl 5-benzyl-2-phenylthiazole-4-carboxylate (4t).
1H
NMR (300 MHz, CHLOROFORM-d) δ 7.74–8.00 (m,
2H), 7.28–7.50 (m, 6H), 7.14–7.27 (m, 2H), 4.14–4.49
(m, 4H), 1.29–1.46 (m, 3H); 13C NMR (100MHz,
CHLOROFORM-d) δ 161.6, 147.1, 138.8, 129.9, 128.9,
128.8, 128.5, 126.5, 126.1, 126.1, 60.9, 33.1, 14.3.
HRMS calculated for C19H17NO2S: m/z 323.0980,
Found: 323.0983.
Ethyl 2-phenylthiazole-4-carboxylate (4u).
1H NMR
(CDCl3) δ 8.17 (s, 1 H) 7.93–8.09 (m, 2 H) 7.36–7.55 (m,
3 H) 4.47 (q, J =7.08 Hz, 2 H) 1.45 (t, J= 7.12 Hz, 3 H);
13C NMR (CDCl3) δ 128.11, 127.80, 126.96, 31.95,
29.72, 22.72, 14.16. HRMS calculated for C12H11NO2S:
m/z 233.0510, Found: 233.0515.
Ethyl 2-methylthiazole-4-carboxylate (4v).
1H NMR
(CDCl3) δ 8.04 (s, 1 H) 4.43 (q, J =7.08 Hz, 2H) 2.77
(s, 3 H) 1.41 (t, J = 7.12Hz, 4 H); 13C NMR (CDCl3) δ
166.88, 161.50, 146.94, 127.31, 61.40, 19.29, 14.28.
HRMS calculated for C7H9NO2S: m/z 171.0354, Found:
171.0354.
[11] Wardkhar, W. W.; Youssef, M. M.; Hamed, I. F.; Ouf, A. S.
J Chin Chem Soc 2008, 55, 1133.
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Chem 2008, 478, 633.
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2007, 128, 127.
2-Methyl-6-phenyl-4,5,6,7-tetrahydrobenzo[d]thiazole (4w). 1H
NMR (400 MHz, CHLOROFORM-d) 7.31–7.36 (m,
2H), 7.22–7.29 (m, 3H), 2.93–3.10 (m, 3H), 2.78–2.92
(m, 2H), 2.70 (s, 3H), 2.14–2.22 (m, 1H), 1.97–2.10
(m, 1H); 13C NMR (100 MHz, CHLOROFORM-d) δ
145.3, 128.7, 128.1, 126.9, 126.6, 41.1, 31.1, 30.0,
26.4, 18.8. HRMS calculated for C14H15NS: m/z
229.0925, Found: 229.0925.
[14] Anjali, R. M. Asian J Chem 1999, 11, 427.
[15] Tsuji, K.; Ishikawa, H. Bioorg Med Chem Lett 1994, 4, 1601.
[16] Kaspady, M.; Narayanaswamy, K. V.; Raju, M.; Rao, K. G.
Lett Drug Desg Discov 2009, 6, 21.
[17] Vicini, P.; Geronikaki, A.; Incerti, M.; Busonera, B.; Poni, G.;
Cabras, A. C.; Lacolla, P. Bioorg Med Chem 2003, 11, 4785.
[18] Ma, Z.; Zhang, X.; Bai, L.; Zheng, Y.; Yang, G. Modern Appl
Sci 2011, 5, 207.
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E. A. Carbohydr Res 2010, 345, 1135.
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Zappalā, M.; Balzarini, J.; De Clercq, E.; Pannecouque, C.; Witvrouw, M.
Bioorg Med Chem Lett 2001, 11, 1793.
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Garcia-Egido, E.; Wong, S. Y. F.; Warrington, B. H. Lab Chip 2002, 2,
31; (c) Lin, P. Y.; Hou, R. S.; Wang, H. M.; Kang, I. J.; Chen, L. C. J Chin
Chem Soc 2009, 56, 455; (d) Arutyunyan, S.; Nefzi, A. J Comb Chem
2010, 12, 315; (e) Kumar, D.; Kumar, N. M.; Patel, G.; Gupta, S.; Varma,
R. S. Tetrahedron Lett 2011, 52, 1983.
[22] (a) Baily, N.; Dean, A. W.; Judd, D. B.; Middlemiss, D.;
Storer, R.; Watson, S. P. Bioorg Med Chem Lett 1996, 6, 1409; (b) Kear-
ney, P. C.; Fernandez, M. J OrgChem 1998, 63, 196; (c) Rudolp, J. Tetra-
hedron 2000, 56, 3161; (d) Schantl, J. G.; Lagoja, I. M. Synth Commun
1998, 28, 1451; (e) Aoyama, T.; Murata, S.; Arai, I.; Araki, N.; Takido, T.;
Suzuki, Y.; Kodomari, M. Tetrahedron 2006, 62, 3201.
2,6-Diphenyl-4,5,6,7-tetrahydrobenzo[d]thiazole (4x).
1H
NMR (400 MHz, CHLOROFORM-d) δ 7.88–7.95 (m,
2H), 7.22–7.46 (m, 8H), 2.87–3.17 (m, 5H), 2.17–2.28
(m, 1H), 2.01–2.15 (m, 1H); 13C NMR (100MHz,
CHLOROFORM-d) 165.4, 151.1, 145.3, 133.8, 129.8,
128.9, 128.9, 128.7, 126.9, 126.6, 126.4, 126.4, 41.1,
31.4, 30.2, 26.8. HRMS calculated for C19H17NS: m/z
291.1082, Found: 291.1086.
Acknowledgments. We gratefully acknowledge the Priority
Research Centers Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of
Education, Science and Technology (2009-0093815) and the
Institute of Drug Research and Development Centre, Chungnam
National University (CNU) Daejeon for the financial support to
this work.
[23] Jalani, H. B.; Pandya, A. N.; Pandya, D. H.; Sharma, J. A.;
Sudarsanam, V.; Vasu, K. K.; Tetrahedron Lett 2013, 53, 5403.
[24] Dubs, P.; Stuessi, R. Synthesis 1976, 696.
[25] Optimized procedure for the preparation of 4a: An oven dried
clean round bottom flask with a magnetic bar was charged with 2-
bromoacetophenone (1, 250 mg, 1.0 equivalent) and potassium salt of
thioacetic acid (2, 143 mg, 1.0 equivalent) in 10 mL of THF at ambient
temperature. The reaction mixture was sealed under nitrogen gas stirred
for 3 h. After the disappearance of starting materials on TLC, a 1equiv-
alent of acetic acid (1 mL) and ammonium acetate (3, 290 mg, 3 equiv-
alents) and 10 mL of toluene were added. The resulting reaction mixture
was refluxed for 6 h. The solvent was removed under reduced pressure,
and the residue obtained was purified via flash column chromatography
(eluent; hexanes: ethyl acetate) to afford desired thiazole 4a in 88%
yield.
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