Steric and electronic factors influence regio-isomeric thiazole formations between substituted benzothioamides and ethyl bromopyruvate

Article abstract of DOI:10.1002/jhet.1644

We observed unexpected thiazole 1B formation when 2,6- dichlorobenzothioamide 1 and ethyl bromopyruvate were reacted under basic conditions at elevated temperatures in ethanol. Thiazole 1B, regio-isomeric to that expected under conventional Hantzsch condi

Full text of DOI:10.1002/jhet.1644

Month 2013 Steric and Electronic Factors Influence Regio-isomeric Thiazole Formations
Between Substituted Benzothioamides and Ethyl Bromopyruvate
Jun Liang,1 Valerie Dorman Soucy,1 Vickie Tusi,1 Yanzhou Liu,1 Birong Zhang,1 Yingjie Lai,1 Steve Magnuson,1
1
2
2
2
2
2
2
*
Bingyan Zhu, Fangdao Wang, Jinghao Gu, Qingfen Zhang, Yuan Wu, Wei Deng, and Wenqian Yang
1Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080
2ChemPartner, 998 Halei Road, Zhang Jiang Hi-tech Park, Pudong New Area, Shanghai, 201203, People’s Republic of China
*
E-mail: wqyang@chempartner.cn
Received December 15, 2011
DOI 10.1002/jhet.1644
Published online in Wiley Online Library (wileyonlinelibrary.com).
We observed unexpected thiazole 1B formation when 2,6-dichlorobenzothioamide 1 and ethyl bromopyruvate
were reacted under basic conditions at elevated temperatures in ethanol. Thiazole 1B, regio-isomeric to that
expected under conventional Hantzsch conditions, was extensively characterized and later confirmed by single
crystal X-ray structure. We carried out this transformation with several substituted benzothioamides and
found that the formation of the unexpected thiazole regio-isomer was highly dependent on the steric as well
as the electronic characteristics of the ortho-substituents on the phenyl ring. A mechanism to account for
this novel transformation was proposed.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
The synthesis of 1A has been reported in the literature, but
no experimental procedures or characterization data for the
compound were included [8]. We used the conditions
reported in literature (heating in ethanol at 80ꢀC in the
presence of pyridine) and isolated a single thiazole product
in 32% yield. We found, however, that the results of subse-
quent transformations of this compound were inconsistent
with the expected 1A chemical structure. We carried out
reduction of this material to the corresponding primary alcohol
with lithium aluminum hydride. No nuclear Overhauser effect
(NOE) [9] was observed between the thiazole C5-proton of
this alcohol and its methylene protons, suggesting that we
had not isolated the primary alcohol 1D. On the basis of mass
spectrometry and NMR data, we suspected that the correct
structure of the primary alcohol might be 1E and that we
had isolated the regio-isomeric thiazole 1B under our initial
thiazole-forming conditions.
To confirm this hypothesis, we utilized a different method
for thiazole 1A synthesis that involved a two-step process:
thioamide 1 was mixed with ethyl bromopyruvate to form,
presumably, the dihydrothiazole intermediate 1C, which,
after an extractive workup, was heated in refluxing toluene
in the presence of a catalytic amount of p-toluenesulfonic
acid to effect elimination of water. Using this two-step pro-
cess, we obtained a single thiazole product that was spectro-
scopically distinct from that produced in our original
synthesis. This new thiazole product was assigned as the
desired regio-isomer 1A. This assignment was further
Substituted thiazoles appear in many natural products
with interesting biological activities, for example,
epothilone C and D [1] and (+)-nostocyclamide [2].
They are also present in many marketed drugs, such
as pan-Src kinase inhibitor dasatinib [3] and leukotriene
D4 antagonist cinalukast [4]. Given their interesting
properties, there have been many reported methods for
thiazole synthesis over the years [5]. A notable synthetic
method, first reported by Hantzsch and co-workers
[6], involves the condensation of a thioamide and an
a-bromo-ketone to presumably form the dihydrothiazole
(also called thiazoline) intermediate, followed by
dehydration at elevated temperatures. When milder dehydra-
tion conditions are required, this can be accomplished
through the use of an activating reagent and a base, for exam-
ple, trifluoroacetic anhydride and 2,6-lutidine [7].
We discovered an unusual thiazole formation between
2,6-dichlorobenzothioamide 1 and ethyl bromopyruvate
to give exclusively thiazole 1B that was regio-isomeric
to the thiazole formed under traditional Hantzsch condi-
tions. Details of our studies are reported herein.
RESULTS AND DISCUSSION
Recently, we were interested in the synthesis of thiazole
1A (Scheme 1) for an ongoing anti-inflammatory project.
© 2013 HeteroCorporation

J. Liang, V. D. Soucy, V. Tusi, Y. Liu, B. Zhang, Y. Lai, S. Magnuson,
B. Zhu, F. Wang, J. Gu, Q. Zhang, Y. Wu, W. Deng and W. Yang
Vol 000
Scheme 1. Formation of thiazoles from 2,6-dichlorobenzothioamide 1.
supported by the reduction of the ester present in 1A to its
corresponding primary alcohol 1D and observation of an
NOE between the thiazole C5-proton and the methylene
protons. Eventually, the structures of 1A and 1B were
unequivocally confirmed by obtaining single X-ray crystal
structures of both thiazole isomers (Fig. 1).
Intrigued by this unexpected thiazole regio-isomer forma-
tion, we investigated the reaction conditions in detail to
optimize formation of the thiazole product 1B (Table 1). It
was found that the reaction went to completion when
heated for 3 days at 80ꢀC or 18 h at 120ꢀC (entries 1 and 2,
respectively). When the reaction temperature was further
raised to 150ꢀC in a sealed tube in a microwave irradiator,
the reaction was complete in 1.5 h and thiazole 1B could
be isolated in 80% yield (entry 3). We next used heating con-
ditions of 150ꢀC in a microwave irradiator and screened the
reaction with various solvents and bases. When ethanol was
replaced with n-butyl alcohol, thiazole 1B was formed as the
major product (entry 4), but a small amount of the n-butyl
ester by-product was also isolated (18% yield). The
transesterification side reaction could be completely sup-
pressed when t-butanol was used instead, giving thiazole
1B in 38% yield (entry 5). Thiazole 1B was isolated in
slightly lower yields when an aprotic solvent, such as tol-
uene, 1,4-dioxane, or DMF (entries 6–8) was used. We
also surveyed different bases, both organic and inor-
ganic, with a range of pKa values, but this led to
reduced yields of thiazole 1B (entries 9–14) relative
to when pyridine was used.
Subsequently, we utilized the optimized reaction condi-
tions outlined previously (entry 3, Table 1) to survey addi-
tional substituted benzothioamides, hoping to understand
the substrate scope of this transformation. The results are
summarized in Table 2. Assignment of thiazole regio-isomers
was based on reducing each ethyl ester to the corresponding
primary alcohol and the observation or absence of an NOE
between the thiazole C5-H and the methylene protons, as
described in Scheme 1. It is important to note that even
though isolated yields for thiazoles A and B are reported in
Table 2, we confirmed that the relative ratios of A and B
1A
1B
Figure 1. Single X-ray crystal structures of 1A and 1B. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Steric and Electronic Factors Influence Regio-isomeric Thiazole Formations
Between Substituted Benzothioamides and Ethyl Bromopyruvate
Table 1
Formation of thiazole 1B under different conditions.
Entry
Solvent
Basea
Temperature and timeb
Yield of 1Bc (%)
1
2
3
4
5
6
7
8
Ethanol
Ethanol
Ethanol
n-Butanol
t-Butanol
Toluene
1,4-Dioxane
DMF
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
DBU
Triethylamine
2,6-Lutidine
DMAP
Cs2CO3
KOtBu
Therm, 80ꢀC, 3 days
Therm, 120ꢀC, 18 h
MW, 150ꢀC, 1.5 h
MW, 150ꢀC, 1.5 h
MW, 150ꢀC, 1.5 h
MW, 150ꢀC, 1.5 h
MW, 150ꢀC, 1.5 h
MW, 150ꢀC, 1.5 h
MW, 150ꢀC, 1.5 h
MW, 150ꢀC, 1.5 h
MW, 150ꢀC, 1.5 h
MW, 150ꢀC, 1.5 h
MW, 150ꢀC, 1.5 h
MW, 150ꢀC, 1.5 h
32
37
80
42
38
26
26
19
8
9
10
11
12
13
14
8
19
23
6
10
aReactions were performed using 2.0 equiv of ethyl bromopyruvate and 3.0 equiv of base.
bThermal reaction was carried out in a sealed tube in an oil bath; reaction at 150ꢀC was conducted in a microwave irradiator.
cIsolated yield following chromatographic purification.
reflect those from the crude reaction mixtures. For the
majority of substrates, a mixture of both thiazoles A and B
was observed. Overall, the ratio of thiazole A versus B seems
to be determined by a combination of steric and electronic
factors of the phenyl substituents, particularly those at the
ortho-positions. Generally, as the steric hindrance around
the benzothioamide is reduced, the yield of the unexpected
thiazole isomer B is lower. Without any substituent (entry
12), the unexpected thiazole 12B was isolated only in small
amounts, compared with that of the expected thiazole 12A.
Steric hindrance is clearly not the only factor that determines
the ratio of the two thiazole products. For example, very
different thiazole ratios were observed for entry 2 versus
entries 5 and 6 and entry 5 versus entry 10, suggesting that
incorporation of a chloro or fluoro at the ortho-position favors
thiazole B formation. We were also interested in investigating
the thiazole formations for 2,6-dimethylbenzothioamide
with ethyl bromopyruvate (entry 4). Thiazole formation was
exceedingly sluggish for this substrate, and only small
amounts of thiazole 4A and 4B were isolated under standard
reaction conditions.
dihydrothiazole intermediate 1C (Scheme 2). Intermediate
1C was relatively stable at room temperature, and we were
able to obtain and characterize a pure sample after silica gel
column chromatography [10]. When the dihydrothiazole
intermediate 1C was heated at 150ꢀC in ethanol for 1.5 h
in a microwave irradiator, thiazole 1B was isolated as the
only product in 78% yield, suggesting that 1C is likely
an intermediate during the transformation of 1 to 1B. To
monitor the subsequent transformations of 1C to thiazole
1B, intermediate 1C was dissolved in ethanol-d6 and
pyridine-d5 in a sealed NMR tube and heated at 80ꢀC
1
inside an NMR spectrometer where H NMR spectrum
was taken every 15 min. Complete deuterium exchange
was observed for the two protons on the dihydrothiazole
ring in 1C in 1 h at 80ꢀC, even though at this point, there
was almost no thiazole product 1B formed in the reaction
mixture. This observation suggests that the dihydrothiazole
ring might be in rapid equilibrium with its open form
1F (Scheme 2). Therefore, we modified our experimental
design by replacing ethanol-d6 with CD3CD2OH to avoid
deuterium exchange. A solution of dihydrothiazole 1C in
CD3CD2OH and pyridine-d5 was divided into NMR tubes
and sealed. The tubes were heated at 120ꢀC in an oil bath,
and every 1–2 h, a tube was removed, cooled, and then
Using 2,6-dichlorobenzothioamide 1 as an example, we
sought to identify any intermediates that might form during
this transformation. Upon mixing of thioamide 1 with ethyl
bromopyruvate in the presence of pyridine in ethanol at
room temperature, a clean reaction took place to give
1
examined by H NMR and LCMS. Except for the signals
of the starting material 1C, thiazole product 1B and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Liang, V. D. Soucy, V. Tusi, Y. Liu, B. Zhang, Y. Lai, S. Magnuson,
B. Zhu, F. Wang, J. Gu, Q. Zhang, Y. Wu, W. Deng and W. Yang
Vol 000
Table 2
Isolated yields of thiazole A and B for different thioamides.
Entrya
1
Thioamide
Substrate structure
Yield of Ab (%)
Yield of Bb (%)
1
0
80
49
53
2
3
2
3
0
10
4
5
4
5
8
3
23
34
6
7
6
7
21
40
23
32
8
8
36
28
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Steric and Electronic Factors Influence Regio-isomeric Thiazole Formations
Between Substituted Benzothioamides and Ethyl Bromopyruvate
Table 2
(Continued)
Entrya
9
Thioamide
Substrate structure
Yield of Ab (%)
Yield of Bb (%)
9
32
16
I
10
11
12
10
11
12
69
55
66
17
8
6
aAll reactions were performed with 2.0 equiv of ethyl bromopyruvate and 3.0 equiv of pyridine in ethanol at 150ꢀC in a microwave irradiator.
bIsolated yield after chromatographic purification.
CH3CH2OH (presumably resulting from exchange of
(Scheme 1). But the formation of carbocation is disfavored
under basic conditions in the presence of excess pyridine.
Additionally, because the rate of dehydration depends on
the rate of carbocation formation, this elimination step is
slowed further as a result of the 2,6-dichoro substitution for
both steric and electronic reasons. The two chlorines should
force the phenyl group and dihydrothiazole ring to be out of
plane with each other. Therefore, the phenyl group is unable
to conjugate with the dihydrothiazole ring and stabilize
the carbocation intermediate during dehydration. Secondly,
the electron-withdrawing chloro-substitutions at the ortho-
positions of the phenyl group might also destabilize the
developing carbocation through inductive effect. As a result,
the excess pyridine can deprotonate the a-proton of the ke-
tone in 1F and the resulting enolate can add to the thio-imi-
date intramolecularly to give thiirane 1G, in a manner
highly reminiscent of the initial steps in Eschenmoser’s
sulfide contraction chemistry [12]. The opening of thiirane
in intermediate 1G leads to intermediate 1H in which the
CD3CD2OH with the –OCH2CH3 of ethyl ester), no other
1
signals were observed during the reaction process by H
NMR or LCMS.
A proposed mechanism to account for formation of
thiazole 1B is shown in Scheme 2. On the basis of deuterium
exchange observed when ethanol-d6 was used as reaction
solvent, we propose that dihydrothiazole 1C exists in rapid
equilibrium with its open form thio-imidate 1F, even
though the equilibrium likely favors the cyclized form 1C.
At elevated temperatures, intermediate 1C could undergo
dehydration to give thiazole 1A. It had been reported that
dehydration of dihydrothiazoles to give thiazoles most likely
occurs through a carbocation intermediate [11]. However, a
few factors might have slowed down this pathway signifi-
cantly for 1C, with an electron-withdrawing ethyl ester
group. Under acidic conditions, dihydrothiazole 1C can still
eliminate water to form thiazole 1A, as evidenced by the
82% yield of thiazole 1A in the two-step Hantzsch process
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Liang, V. D. Soucy, V. Tusi, Y. Liu, B. Zhang, Y. Lai, S. Magnuson,
B. Zhu, F. Wang, J. Gu, Q. Zhang, Y. Wu, W. Deng and W. Yang
Vol 000
Scheme 2. Proposed mechanism for the unexpected thiazole 1B formation.
Scheme 3. Reaction of thioamide 1 with bromoacetone.
thiol can undergo nucleophilic addition to the adjacent
ketone that results in thiirane 1I. Fragmentation of thiirane
ring can give rise to enamine 1J, which can cyclize to give
dihydrothiazole 1K via the nucleophilic addition of amino
group to the ketone. Elimination of water in 1K will provide
thiazole 1B. As demonstrated in Table 2, this rearrangement
leading to thiazole B formation is favored only for a couple
2,6-disubstituted benzothioamides, when the competing
dehydration pathway to give thiazole A is slowed as a
result of a combination of steric and electronic factors of
the substituents on the phenyl ring.
To further shed light on the mechanism of this
reaction, we examined thiazole formation between 2,
6-dichlorobenzothioamide 1 and bromoacetone (Scheme 3).
Under the same conditions that formed thiazole 1B,
however, only one thiazole product was formed. The struc-
ture of this product was assigned as 13, on the basis of an
NOE observed between thiazole C5-proton and protons of
the methyl group. It is apparent that the rearrangement did
not take place, and this may be explained by considering
that without the electron-withdrawing ethyl ester group in
dihydrothiazole intermediate 1C, the dehydration (through
carbocation formation) leading to thiazole 1A is more
favorable (Scheme 2). This outcome may also be explained
by comparing the relative acidity of the methylene a-protons
of the ketone in the corresponding intermediate 1F (Scheme 2)
for bromoacetone and ethyl bromopyruvate. As bromoacetone
lacks the electron-withdrawing ester group, the rearrangement
pathway leading from intermediate 1F to thiazole 1B would
be unlikely to proceed.
CONCLUSIONS
We have discovered an interesting thiazole formation
that occurred under basic conditions for certain substituted
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Steric and Electronic Factors Influence Regio-isomeric Thiazole Formations
Between Substituted Benzothioamides and Ethyl Bromopyruvate
131.60, 128.38, 127.27, 62.35, 13.99; IR (thin film) 3111, 2987,
1718, 1587, 1558, 1467, 1406, 1298, 1267, 1091, 1016,
783 cmÀ1; HRMS (ESI) m/z Calcd for C12H10Cl2NO2S 301.9804,
found 301.9804 (M+ H); Anal. Calcd for C12H10Cl2NO2S: C,
47.70; H, 3.00; N, 4.64. Found: C, 47.55; H, 2.95; N, 4.42.
Ethyl 2-(2,6-dichlorophenyl)-4-hydroxy-4,5-dihydrothiazole-4-
carboxylate (1C). A mixture of 2,6-dichlorobenzothioamide 1
(100 mg, 0.520mmol) and ethyl bromopyruvate (203 mg,
1.04mmol) in DMF (5 mL) was stirred at 20ꢀC for 3 h. The
resultant mixture was then poured in water (10 mL) and extracted
with ethyl acetate (3Â 15mL). The combined organic layers
were washed with brine (2 Â 20mL), dried over Na2SO4,
and concentrated under reduced pressure. The residue was
recrystallized from ethyl acetate/petroleum ether to give ethyl
2-(2,6-dichlorophenyl)-4-hydroxy-4,5-dihydrothiazole-4-carboxylate
benzothioamides with ethyl bromopyruvate. Compared with
the traditional Hantzsch thiazole product, the unexpected
regio-isomeric thiazole is favored only when there is
chloro-substitution or fluoro-substitution at the ortho-
positions of the benzothioamide. On the basis of our limited
mechanistic investigation, we propose that this unexpected
thiazole product is formed as a result of a combination
of steric and electronic effects of the substituents on the
benzothioamides, as well as the use of ethyl bromopyruvate
as the electrophile.
EXPERIMENTAL
(1C) (130 mg, 82% yield) as
a pale yellow solid, mp
General.
Chemicals were purchased from commercial
130–132ꢀC; 1H NMR (500 MHz, DMSO-d6) d 7.60–7.51
(m, 3H), 7.28 (brs, 1H), 4.20 (q, J = 7.0 Hz, 2H), 4.04
(d, J = 12.5 Hz, 1H), 3.51 (d, J = 12.5 Hz, 1H), 1.23
(t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) d 169.95,
165.75, 132.59, 132.27, 131.25, 128.62, 106.31, 61.43, 42.61,
13.98; IR (thin film) 3101, 3003, 1749, 1614, 1435, 1199,
1103, 1024, 947, 790 cmÀ1; HRMS (ESI) m/z Calcd for
C12H12Cl2NO3S 319.9918. Found: 301.9910 (M + H).
sources and used immediately upon arrival. H, 13C NMR, and
NOESY spectra were recorded with Bruker AVANCE III 500
(Rheinstetten, Germany) or 400-MHz UltraShield-PlusTM Digital
NMR spectrometer. Melting points were determined on a SGW-
X4 instrument from Cany Precision Instruments Co., Ltd
(Shanghai, China) and are uncorrected. IR spectra were measured
on a Shimadzu Prestigate 21 FITR spectrophotometer (Kyoto,
Japan). ESI HRMS analyses, elemental analyses, and X-ray
structure determination were performed by the Facility of
Shanghai Institute of Organic Chemistry. Thioamides (1–12)
were either purchased from commercial sources or prepared by
following published procedure [13].
1
General procedure for the synthesis of (2-(2,6-dichlorophenyl)
thiazol-4-yl)methanol (1D) and (4-(2,6-dichlorophenyl)thiazol-2-yl)
methanol (1E).
To a solution of the corresponding thiazole
ethyl ester (0.33 mmol) in THF, LiAlH4 (25 mg, 0.66 mmol) at
0ꢀC was added. After being stirred for 2 h, the reaction was
quenched by addition of water (2 mL). The resultant mixture
was extracted with ethyl acetate (3 Â 20 mL), washed with
brine (2 Â 20 mL), dried over Na2SO4, and concentrated. The
crude product was recrystallized from ethyl acetate/petroleum
ether to afford the desired product.
(2-(2,6-Dichlorophenyl)thiazol-4-yl)methanol (1D). mp 106–
109ꢀC; 1H NMR (400 MHz, CDCl3) d 7.44–7.32 (m, 4H), 4.88 (s,
2H), 2.38 (brs, 1H); 13C NMR (100 MHz, CDCl3) d 161.89,
156.71, 135.97, 132.03, 131.29, 128.22, 117.07, 61.09; IR (thin
film) 3250, 3120, 2900, 1419, 1230, 1188, 1062, 997, 786,
748 cmÀ1; HRMS (ESI) m/z Calcd for C10H8Cl2NOS 259.9704.
Found: 259.9698 (M + H).
Ethyl 2-(2,6-dichlorophenyl)thiazole-4-carboxylate (1A).
A
mixture of 2,6-dichlorobenzothioamide 1 (15 g, 73mmol) and
ethyl bromopyruvate (28.4 g, 146mmol) in DMF (200 mL) was
stirred at 20ꢀC for 14h. The resulting mixture was then poured
into water (100 mL) and extracted with EtOAc (3Â 100 mL). The
combined organic layers were washed with brine (100 mL), dried
over Na2SO4, and concentrated under reduced pressure. The
residue was dissolved in toluene (800 mL), and p-TsOH (2.0g)
was added. The resulting mixture was heated at 110ꢀC for 4 h.
The mixture was concentrated under reduced pressure, and the
residue was purified by silica gel column chromatography
eluting with EtOAc/petroleum ether (1:9) to give ethyl 2-(2,
6-dichlorophenyl)thiazole-4-carboxylate (1A) (18 g, 82% yield) as
1
a brown solid, mp 169–172ꢀC; H NMR (500MHz, MeOH-d4)
(4-(2,6-Dichlorophenyl)thiazol-2-yl)methanol (1E). mp 107–
1
109ꢀC; H NMR (400MHz, CDCl3) d 7.42–7.38 (m, 2H), 7.31
d 8.68 (s, 1H), 7.61–7.54 (m, 3H), 4.44 (q, J= 7.5 Hz, 2H), 1.43
(t, J= 7.5 Hz, 3H); 13C NMR (125 MHz, MeOH-d4) d 164.22,
162.35, 148.22, 136.89, 133.69, 132.24, 131.89, 129.68, 62.73,
14.59; IR (thin film) 3128, 2989, 1712, 1496, 1427, 1315, 1283,
1026, 989, 785 cmÀ1; HRMS (ESI) m/z Calcd for C12H10Cl2NO2S
301.9804. Found: 301.9803 (M + H).
(s, 1H), 7.28–7.24 (m, 1H), 4.98 (s, 2H), 3.48 (brs, 1H); 13C
NMR (100 MHz, CDCl3) d 171.08, 149.19, 135.84, 133.31,
130.17, 128.15, 119.36, 62.07; IR (thin film) 3226, 3188,
3089, 1421, 1340, 1182, 1068, 1033, 783, 738 cmÀ1
;
HRMS (ESI) m/z Calcd for C10H8Cl2NOS 259.9706. Found:
259.9698 (M + H).
Ethyl 4-(2,6-dichlorophenyl)thiazole-2-carboxylate (1B).
A
solution of 2,6-dichlorobenzothioamide 1 (6.0g, 29mmol), ethyl
bromopyruvate (11 g, 58mmol), and pyridine (6.8 g, 87mmol) in
EtOH (40 mL) was stirred at 80ꢀC for 3 days. After removal of
solvent under reduced pressure, the residue was partitioned
between ethyl acetate and water. The organic layer was dried over
sodium sulfate and concentrated. The crude product was purified
by silica gel chromatography eluting with ethyl acetate/petroleum
ether (1:5) to give ethyl 4-(2,6-dichlorophenyl)thiazole-2-
carboxylate (1B) (3.0 g, 32% yield) as a solid, mp 119–123ꢀC; 1H
NMR (500 MHz, DMSO-d6) d 8.30 (s, 1H), 7.65–7.34 (m, 3H),
4.42 (q, J = 7.0Hz, 2H), 1.35 (t, J = 7.0Hz, 3H); 13C NMR
(125MHz, DMSO-d6) d 159.23, 157.25, 150.68, 134.77, 132.43,
Ethyl 2-(2-chloro-6-fluorophenyl)thiazole-4-carboxylate
(2A).
This compound was prepared by following the same
1
procedure as 1A. 90% yield, mp 97–100ꢀC; H NMR (500MHz,
MeOH-d4) 8.68 (s, 1H), 7.60 (ddd, J = 8.5, 8.5, 6.0 Hz, 1H), 7.48
(dd, J = 8.5, 1.0 Hz, 1H), 7.32 (ddd, J = 9.0, 8.5, 1.0 Hz, 1H), 4.53
(q, J = 7.0 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H); 13C NMR (125MHz,
MeOH-d4) d 162.35, 162.26 (d, J = 250.9 Hz), 160.46, 148.43,
136.07 (d, J = 2.4 Hz), 134.06 (d, J = 8.8 Hz), 131.87, 127.10
(d, J = 3.3 Hz), 115.87 (d, J = 21.6 Hz), 62.72, 14.58; IR
(thin film) 3128, 2989, 1708, 1494, 1446, 1317, 1242, 1028, 993,
889, 786, 767 cmÀ1; HRMS (ESI) m/z Calcd for C12H10ClFNO2S
286.0099. Found: 286.0102 (M+ H).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Liang, V. D. Soucy, V. Tusi, Y. Liu, B. Zhang, Y. Lai, S. Magnuson,
B. Zhu, F. Wang, J. Gu, Q. Zhang, Y. Wu, W. Deng and W. Yang
Vol 000
General procedure for the synthesis of thiazoles 3A–12A,
1B–12B, and 13 under microwave conditions. A solution of
(d, J= 3.5 Hz), 14.41; IR (thin film) 3116, 2987, 1710, 1465, 1317,
1240, 1022, 991, 945, 881, 783 cmÀ1; HRMS (ESI) m/z Calcd for
C13H13FNO2S 266.0653. Found: 266.0646 (M + H).
thioamide (1.0 mmol), ethyl bromopyruvate (2.0 mmol), and
pyridine (3.0 mmol) in EtOH (2.0 mL) was stirred at 150ꢀC for
1.5 h in a microwave irradiator. After removal of solvent under
reduced pressure, the residue was partitioned between ethyl acetate
and water. The organic layer was dried over sodium sulfate and
concentrated. The crude product was purified by either flash
column chromatography with silica gel or prep-TLC eluting with
ethyl acetate/petroleum ether to give thiazole A and B, respectively.
Ethyl 4-(2-chloro-6-fluorophenyl)thiazole-2-carboxylate
Ethyl 4-(2-fluoro-6-methylphenyl)thiazole-2-carboxylate
(5B). 1H NMR (500MHz, CDCl3) d 7.60 (d, J = 1.5 Hz, 1H),
7.25 (ddd, J = 6, 7.5, 8.0 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.97
(dd, J = 8.0, 10.0Hz, 1H), 4.50 (q, J = 7.0 Hz, 2H), 2.29
(d, J = 5.5 Hz, 3H), 1.45 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 160.65 (d, J = 246.8Hz), 160.10, 157.72, 150.80,
140.20 (d, J= 1.5 Hz), 129.82 (d, J= 8.9 Hz), 125.92 (d, J=3.3Hz),
124.70 (d, J= 3.3 Hz), 122.04 (d, J= 14.6 Hz), 112.90 (d,
J= 22.8 Hz), 62.66, 20.28 (d, J= 2.4 Hz), 14.32; IR (thin film)
3107, 2981, 1714, 1446, 1417, 1300, 1249, 1091, 1018, 858,
781 cmÀ1; HRMS (ESI) m/z Calcd for C13H13FNO2S 266.0643.
Found: 266.0646 (M + H).
(2B).
mp 81–84ꢀC; 1H NMR (500 MHz, DMSO-d6) d 8.38
(s, 1H), 7.61–7.39 (m, 3H), 4.42 (q, J=7.0Hz, 2H), 1.36
(t, J= 6.5 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) d 160.32
(d, J= 249.3 Hz), 159.21, 157.31, 147.02, 133.93 (d, J=3.6Hz),
131.69 (d, J= 10.6 Hz), 127.91, 125.69 (d, J= 3.0 Hz), 121.93
(d, J= 17.4 Hz), 114.81 (d, J= 22.1 Hz), 62.31, 13.98; IR (thin film)
3113, 2987, 1718, 1608, 1570, 1473, 1417, 1298, 1265, 1093, 1014,
783 cmÀ1; HRMS (ESI) m/z Calcd for C12H10ClFNO2S 286.0099,
found 286.0101 (M + H); Anal. Calcd for C12H10ClFNO2S: C, 50.44;
H, 3.17; N, 4.90. Found: C, 50.46; H, 3.02; N, 4.72.
Ethyl 2-(2-chlorophenyl)thiazole-4-carboxylate (6A). 1H NMR
(400 MHz, DMSO-d6) d 8.71 (s, 1H), 8.21 (dd, J= 6.5, 2.7 Hz,
1H), 7.73–7.49 (m, 3H), 4.38 (q, J=7.1Hz, 2H), 1.37
(t, J=7.1Hz, 3H); 13C NMR (125 MHz, CDCl3) d 164.15, 161.52,
146.74, 132.07, 131.48, 131.22, 130.99, 130.52, 128.52, 127.18,
61.52, 14.40; IR (thin film) 3117, 2981, 1732, 1485, 1429, 1236,
1097, 1022, 987, 761, 640 cmÀ1; HRMS (ESI) m/z Calcd for
C12H11ClNO2S 268.0201. Found: 268.0194 (M + H).
Ethyl 2-(2-chloro-6-methylphenyl)thiazole-4-carboxylate
(3A).
mp 132–135ꢀC; 1H NMR (400 MHz, CDCl3) d 7.54
(s, 1H), 7.31–7.16 (m, 3H), 4.50 (q, J= 7.2 Hz, 2H), 2.15 (s, 3H),
1.45 (t, J=7.2Hz, 3H); 13C NMR (100 MHz, CDCl3) d 160.11,
157.94, 154.10, 140.13, 134.39, 133.18, 129.66, 128.46, 126.90,
124.32, 62.69, 20.80, 14.34; IR (thin film) 3107, 2984, 1720,
1445, 1292, 1261, 1089, 1016, 855, 777 cmÀ1; HRMS (ESI) m/z
Calcd for C13H13ClNO2S 282.0352. Found: 282.0350 (M + H).
Ethyl 4-(2-chloro-6-methylphenyl)thiazole-2-carboxylate
Ethyl 4-(2-chlorophenyl)thiazole-2-carboxylate (6B). 1H NMR
(400 MHz, DMSO-d6) d 8.47 (s, 1H), 7.88 (m, 1H), 7.61
(d, J=6.8Hz, 1H), 7.48 (q, J=7.0Hz, 2H), 4.44 (q, J=7.0Hz,
2H), 1.37 (t, J=7.0Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 160.05, 157.20, 154.00, 132.36, 132.07, 131.89, 130.35, 129.66,
127.07, 123.97, 62.70, 14.30; IR (thin film) 2982, 2930, 1738,
1479, 1302, 1258, 1091, 1039, 860, 758 cmÀ1; HRMS (ESI) m/z
Calcd for C12H11ClNO2S 268.0200. Found: 268.0194 (M + H).
Ethyl 2-(2,4-dichlorophenyl)thiazole-4-carboxylate
(3B).
1H NMR (400 MHz, CDCl3) d 7.60 (s, 1H), 7.24
(dd, J= 13.8, 7.9 Hz, 1H), 7.05 (d, J= 7.6 Hz, 1H), 6.96
(t, J= 8.9 Hz, 1H), 4.49 (q, J= 7.1 Hz, 2H), 2.28 (s, 3H), 1.44
(t, J=7.2Hz, 3H); 13C NMR (125 MHz, CDCl3) d 152.64, 152.26,
140.11, 134.40, 133.79, 129.30, 128.48, 126.97, 117.72, 99.82,
62.04, 20.74, 14.23; IR (thin film) 3103, 2976, 1749, 1445, 1298,
1176, 1057, 870, 820, 775 cmÀ1; HRMS (ESI) m/z Calcd for
C13H13ClNO2S 282.0351. Found: 282.0350 (M + H).
Ethyl 2-(2,6-dimethylphenyl)thiazole-4-carboxylate
(4A). 1H NMR (500 MHz, CDCl3) d 8.33 (s, 1H), 7.26–7.23
(m, 1H), 7.10–7.09 (m, 2H), 4.46 (q, J = 7.3 Hz, 2H), 2.15 (s, 6H),
1.43 (t, J = 7.3 Hz, 3H); 13C NMR (125MHz, CDCl3) d 167.42,
161.58, 147.58, 137.73, 132.78, 129.66, 128.83, 127.54, 61.49,
20.29, 14.44; IR (thin film) 3120, 2924, 1712, 1498, 1460, 1315,
1234, 1089, 1026, 985, 777 cmÀ1; HRMS (ESI) m/z Calcd for
C14H16NO2S 262.0902. Found: 262.0896 (M + H).
(7A).
mp 103–104ꢀC; 1H NMR (500 MHz, CDCl3) d 8.31
(d, J= 8.5 Hz, 1H), 8.30 (s, 1H), 7.52 (d, J=2.5Hz, 1H), 7.37
(dd, J=2.5, 8.5Hz, 1H), 4.46 (q, J= 7.0 Hz, 2H), 1.43
(t, J=7.0Hz, 3H); 13C NMR (125 MHz, CDCl3) d 163.02, 161.39,
146.84, 136.43, 132.59, 132.25, 130.28, 129.78, 128.59, 127.66,
61.60, 14.38; IR (thin film) 3431, 2969, 1724, 1423, 1375, 1206,
1097, 1026, 866, 827, 750, 630 cmÀ1; HRMS (ESI) m/z Calcd for
C12H10Cl2NO2S 301.9804. Found: 301.9804 (M + H).
Ethyl 4-(2,4-dichlorophenyl)thiazole-2-carboxylate
(7B).
mp 83–85ꢀC; 1H NMR (500 MHz, CDCl3) d 8.10
(s, 1H), 7.97 (d, J= 8.0 Hz, 1H), 7.49 (d, J=1.5Hz, 1H), 7.34
(dd, J=1.5, 8.0Hz, 1H), 4.51 (q, J= 7.0 Hz, 2H), 1.46
(t, J=7.0Hz, 3H); 13C NMR (125 MHz, CDCl3) d 1659.89,
157.36, 152.87, 134.83, 132.72, 132.61, 130.88, 130.15, 127.47,
124.13, 62.78, 14.29; IR (thin film) 3126, 2926, 1732, 1473, 1433,
1267, 1234, 1095, 1020, 858, 790 cmÀ1; HRMS (ESI) m/z Calcd
for C12H10Cl2NO2S 301.9805. Found: 301.9804 (M + H).
Ethyl 4-(2,6-dimethylphenyl)thiazole-2-carboxylate
(4B).
1H NMR (500 MHz, CDCl3) d 7.40 (s, 1H),7.21–7.18
(m, 1H), 7.10–7.08 (m, 2H), 4.50 (q, J = 7.0 Hz, 2H), 2.08
(s, 6H), 1.45 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 160.23, 157.96, 156.86, 137.49, 134.10, 128.55, 127.36,
122.70, 62.61, 20.77, 14.32; IR (thin film) 3363, 2924, 1658,
1633, 1463, 1261, 1095, 1027, 872 cm-1; HRMS (ESI) m/z Calcd
for C14H16NO2S 262.0898. Found: 262.0896 (M+ H).
Ethyl 2-(2,5-dichlorophenyl)thiazole-4-carboxylate
(8A).
mp 65–66ꢀC; 1H NMR (500 MHz, CDCl3) d 8.36
(d, J = 2.5 Hz, 1H), 8.32 (s, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.35
(dd, J = 2.5, 8.5 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 1.44
(t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 162.67,
161.36, 146.90, 133.42, 132.39, 131.65, 130.94, 130.88, 130.18,
128.90, 61.66, 14.38; IR (thin film) 3456, 2926, 1710, 1471,
1244, 1093, 1018, 947, 806, 746 cmÀ1; HRMS (ESI) m/z Calcd
for C12H10Cl2NO2S 301.9816. Found: 301.9804 (M + H).
Ethyl 2-(2-fluoro-6-methylphenyl)thiazole-4-carboxylate
(5A).
mp 77–74ꢀC; 1H NMR (500 MHz, CDCl3) d 8.35
(s, 1H), 7.32 (ddd, J = 6, 7.5, 8.0 Hz, 1H), 7.09 (d, J = 7.5 Hz,
1H), 7.00 (dd, J = 8.0, 10. 0 Hz, 1H), 4.45 (q, J = 7.0 Hz, 2H),
2.38 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 161.45, 161.13, 160.61 (d, J = 248.9 Hz), 147.44,
140.56, 131.04 (d, J = 9.4 Hz), 128.97, 126.30 (d, J = 3.0 Hz),
120.84 (d, J= 14.1 Hz), 113.06 (d, J= 20.9 Hz), 61.52, 20.45
Ethyl 4-(2,5-dichlorophenyl)thiazole-2-carboxylate
(8B).
mp 78–80ꢀC; 1H NMR (500 MHz, CDCl3) d 8.14
(s, 1H), 8.02 (d, J = 2.5 Hz, 1H)), 7.40 (d, J = 8.5 Hz, 1H), 7.27
(dd, J = 2.5, 8.5 Hz, 1H), 4.52 (q, J = 7.0 Hz, 2H), 1.47
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Steric and Electronic Factors Influence Regio-isomeric Thiazole Formations
Between Substituted Benzothioamides and Ethyl Bromopyruvate
(t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 159.87, 157.50,
152.59, 133.59, 133.12, 131.58, 131.47, 130.21, 129.59, 124.64,
62.83, 14.29; IR (thin film) 3140, 2945, 1734, 1477, 1255, 1091,
Ethyl 2-phenylthiazole-4-carboxylate (12A) [14]. 1H NMR
(500 MHz, CDCl3) d 8.16 (s, 1H), 8.02–8.00 (m, 2H), 7.47–7.45
(m, 3H), 4.45 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H); MS
1
1035, 817, 794, 770 cmÀ1
;
HRMS (ESI) m/z Calcd for
(ESI) m/z: 234.1 (M + H). The H NMR data are in agreement
C12H10Cl2NO2S 301.9814. Found: 301.9804 (M+ H).
with that reported in literature.
Ethyl 2-(2-iodophenyl)thiazole-4-carboxylate (9A). 1H NMR
(400 MHz, CDCl3) d 8.31 (s, 1H), 7.98 (dd, J= 0.8, 8.0 Hz, 1H)),
7.74 (dd, J= 1.6, 8.0 Hz, 1H), 7.44 (ddd, J=0.8, 8.0, 8.0Hz, 1H),
7.14 (ddd, J= 1.6, 8.0, 8.0 Hz 1H), 4.46 (q, J=7.0Hz, 2H), 1.43 (t,
J= 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 168.30, 161.50,
147.13, 140.43, 137.60, 131.59, 131.27, 128.70, 128.28, 96.67,
61.58, 14.42; IR (thin film) 3111, 2978, 1724, 1490, 1446, 1236,
1207, 1095, 1018, 985, 761 cmÀ1; HRMS (ESI) m/z Calcd for
C12H11INO2S 359.9554. Found: 359.9550 (M + H).
Ethyl 4-phenylthiazole-2-carboxylate (12B). mp > 320ꢀC; 1H
NMR (400 MHz, CDCl3) d 7.97–7.95 (m, 2H), 7.75 (s, 1H),
7.47–7.38 (m, 3H), 4.51 (q, J= 7.2 Hz, 2H), 1.44 (t, J=7.2Hz,
3H); 13C NMR (125 MHz, CDCl3) d 160.12, 158.21, 157.81,
133.52, 128.82, 126.72, 118.66, 62.65, 14.29; IR (thin film) 3537,
1739, 1714, 1487, 1442, 1092, 808, 761, 692 cmÀ1; HRMS (ESI)
m/z Calcd for C12H12Cl2NO3S 234.0583. Found: 234.0585 (M + H).
2-(2,6-Dichlorophenyl)-4-methylthiazole (13).
1H NMR
(500 MHz, CDCl3) d 7.34–7.32 (m, 1H), 7.32 (m, 2H), 7.25–7.19
(m, 1H), 7.03 (q, J=1.0Hz, 1H), 2.48 (d, J= 1.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 159.62, 152.11, 135.00, 131.48,
130.01, 127.09, 114.84, 16.08; IR (thin film) 3080, 2924, 1558,
Ethyl 4-(2-iodophenyl)thiazole-2-carboxylate (9B). 1H NMR
(400 MHz, CDCl3) d 7.95 (dd, J = 1.0, 8.0 Hz, 1H), 7.85
(s, 1H), 7.61 (dd, J = 1.8, 8.0 Hz, 1H), 7.42 (ddd, J = 1.0, 8.0,
8.0 Hz, 1H), 7.07 (ddd, J = 1.8, 8.0, 8.0 Hz, 1H), 4.51
(q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 160.10, 158.34, 157.48, 139.98, 138.80,
131.14, 130.14, 128.26, 123.64, 97.36, 62.73, 14.33; IR
(thin film) 3446, 2980, 1737, 1710, 1473, 1435, 1301, 1257,
1012, 759 cmÀ1; HRMS (ESI) m/z Calcd for C12H11INO2S
359.9562. Found: 359.9550 (M + H).
1521, 1429, 1236, 1190, 1105, 999, 786, 748, 704 cmÀ1
;
HRMS (ESI) m/z Calcd for C10H8Cl2NS 243.9757. Found:
243.9749 (M + H).
Single X-ray crystal structure of 2A.
Ethyl 2-o-tolylthiazole-4-carboxylate (10A).
1H NMR
(400 MHz, CDCl3) d 8.21 (s, 1H), 7.68 (d, J = 7.7 Hz, 1H),
7.30 7.20 (m, 3H), 4.43 (q, J = 7.2 Hz, 2H), 2.57 (s, 3H), 1.41
(t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 168.32,
161.62, 147.45, 136.84, 132.36, 131.37, 130.18, 129.97,
127.75, 126.09, 61.46, 21.26, 14.40; IR (thin film) 3115, 2980,
1730, 1473, 1236, 1203, 1095, 1022, 985, 761, 719 cmÀ1
;
HRMS (ESI) m/z Calcd for C13H14NO2S 248.0742. Found:
248.0740 (M + H).
Ethyl 4-o-tolylthiazole-2-carboxylate (10B).
1H NMR
Single X-ray crystal structure of 2B.
(500 MHz, CDCl3) d 7.56 (d, J= 7.5 Hz, 1H), 7.54 (s, 1H),
7.31–7.24 (m, 3H), 4.50 (q, J= 7.0 Hz, 2H), 2.42 (s, 3H), 1.45
(t, J=7.0Hz, 3H); 13C NMR (125 MHz, CDCl3) d 160.22, 158.02,
157.40, 136.34, 133.77, 130.78, 130.07, 128.70, 125.94, 122.00,
62.61, 20.91, 14.31; IR (thin film) 3105, 2980, 1735, 1450, 1300,
1244, 1089, 862, 759 cmÀ1
; HRMS (ESI) m/z Calcd for
C13H14NO2S 248.0746. Found: 248.0740 (M + H).
Ethyl 2-(2-fluorophenyl)thiazole-4-carboxylate (11A). 1H NMR
(500 MHz, CDCl3) d 8.44–8.40 (m, 1H), 8.27 (s, 1H), 7.46–7.41
(m, 1H), 7.29–7.26 (m, 1H), 7.22–7.18 (m, 1H), 4.46
(q, J= 7.0 Hz, 2H), 1.44 (t, J= 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 161.48, 161.20 (d, J= 6.1 Hz), 160.15 (d, J= 251.8 Hz),
146.93, 131.83 (d, J = 8.0 Hz), 129.39 (d, J = 1.8 Hz), 128.26
(d, J = 9.4 Hz), 124.69 (d, J = 2.6 Hz), 120.61 (d, J = 12.4 Hz),
116.02 (d, J = 20.8 Hz), 61.52, 14.38; IR (thin film) 3431,
Acknowledgments. The authors would like to thank Peter
Dragovich, Joseph Lyssikatos, Steve Staben, Nicole Blaquiere,
Gina Xiaojing Wang, Lewis Gazzard, and Jun Li for the many
helpful discussions and suggestions.
2978, 1730, 1440, 1213, 1099, 1024, 773, 744, 632 cmÀ1
;
HRMS (ESI) m/z Calcd for C12H11FNO2S 252.0495. Found:
252.0489 (M + H).
Ethyl 4-(2-fluorophenyl)thiazole-2-carboxylate (11B). 1H NMR
(500 MHz, CDCl3) d 8.33–8.29 (m, 1H), 8.02 (d, J= 1.5 Hz, 1H),
7.37–7.32 (m, 1H), 7.27–7.24 (m, 1H), 7.18–7.14 (m, 1H), 4.51
(q, J= 7.0 Hz, 2H), 1.47 (t, J= 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 161.26, 160.18, 157.20, 151.32 (d, J= 2.1 Hz), 130.42
(d, J= 2.8 Hz),130.06 (d, J= 8.2 Hz), 124.58 (d, J= 3.1 Hz), 123.55
(d, J= 14.1 Hz), 121.34 (d, J= 12.4 Hz), 115.96 (d, J=12.4Hz),
62.73, 14.32; IR (thin film) 3456, 2978, 1730, 1490, 1267, 1246,
1091, 1062, 864, 808, 767 cmÀ1; HRMS (ESI) m/z Calcd for
C12H11FNO2S 252.0496. Found: 252.0489 (M + H).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet