Unexpected rearrangement; A novel route to 3-thiazoline

Article abstract of DOI:10.1055/s-0030-1260184

An unexpected and novel rearrangement was discovered and used to synthesize a series of 3-thiazoline derivatives. The structures of the new compounds were determined by HRMS, IR, NMR and X-ray analyses. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1260184

PAPER
3133
Unexpected Rearrangement; A Novel Route to 3-Thiazoline
Unexpected
R
earra
i
ngeme
n
nt; A Novel
g
R
oute to 3-T
r
hiazolin
u
e
i Liu, Baoxiang Zhao,* Yonghai Li, Liangwen Zheng, Jinting Liu
Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, P. R. of China
Fax +86(531)88564464; E-mail: bxzhao@sdu.edu.cn
Received 29 April 2011; revised 19 July 2011
CO2Et
Abstract: An unexpected and novel rearrangement was discovered
and used to synthesize a series of 3-thiazoline derivatives. The
structures of the new compounds were determined by HRMS, IR,
NMR and X-ray analyses.
N
O
S
S
Ph
Ph
CO2Et
K2CO3
3A
+
HS
Key words: rearrangement, amino acids, synthesis, thiazoline, X-
ray
Br
EtOH
reflux
NH2
1a
2
CO2Et
N
3a
Thiazoline rings had been found in a large number of nat-
ural products with biological activities, and have been
studied extensively.1 Thiazolines have also been used as
building blocks in pharmaceutical drug discovery2 be-
cause some thiazoline derivatives present interesting ac-
tivities such as anti-HIV, anti-cancer, antimitotic, and
antibiotic effects.3 New procedures for preparing such
compounds have attracted the attention of many research-
ers,4 especially for 3-thiazolines. For example, 2,4,5-tri-
methyl-3-thiazoline (TMT), a component of fox feces, has
been widely used as an odorant to induce innate fear be-
havior in rats and mice.5 In contrast to 2-thiazolines, the
methods available for synthesizing 3-thiazoline deriva-
tives are limited. Standard synthetic routes to 3-thiazo-
lines involve the Asinger reaction, in which a-
mercaptoketone, aldehyde, and ammonia react together at
high temperature, or through modified Asinger reactions.6
However, for these methods, byproducts are typically pro-
duced that are not easy to separate, and the 4-position of
3-thiazolines cannot be substituted by an ester group.
There are a few reports on the synthesis of alkyl-substitut-
ed 3-thiazoline-carboxylates by a MnO2-mediated oxida-
tion reaction of thiazolidines. For 3-thiazolines
substituted by an ester group, there has only been one
study; in this case, the substitution occurred at the 2-posi-
tion.7
Scheme 1 The reaction of a-bromoacetophenone and ethyl L-cy-
steine ester
tained. In this paper, this intriguing discovery is dis-
cussed.
It was reported that methyl (3R)-5-phenyl-1,4-thiazane-3-
carboxylate can be obtained by the reaction of a-bromo-
acetophenone with methyl L-cysteine ester in a solution of
potassium hydroxide in methanol, followed by sodium
borohydride mediated reduction.10 In our study, as shown
in Scheme 1, when the reaction of a-bromoacetophenone
(1a) and ethyl L-cysteine ester (2) was conducted with po-
tassium carbonate instead of potassium hydroxide under
reflux in ethanol for one hour, the unexpected product 3a
was found with a yield of 60%, rather than the expected
product 3A. The structure of 3a was deduced from the
HRMS, IR, and NMR spectroscopic data. The mass spec-
tra displayed molecular ion peaks at m/z values consistent
with 3a (m/z [M + H]+ calcd for C13H16NO2S: 250.0902;
found: 250.0905). The IR spectrum indicated the presence
of C=O and C=N bonds from the existence of peaks at
1736 and 1631 cm–1, respectively. The 1H NMR spectrum
of compound 3a showed a singlet signal arising from a
methyl group appearing at d = 1.98 ppm. Signals from
one methylene pair were observed at d = 4.45 and
4.54 ppm as doublet peaks with a geminal coupling of
15.6 Hz. Similarly, by using this method and starting from
2-bromo-1-(4-chlorophenyl)ethanone, compound 3b was
obtained with a yield of 63%. For further structure eluci-
dation of compound 3b, two-dimensional NMR spectros-
copy (COSY) were also obtained. The protons of the CH2
in the ethyl group had strong and weak correlations with
protons appearing at d = 1.27 and 4.42 ppm, respectively,
which were unambiguously assigned to the CH3 in the
ethyl group and H-5cis in the 3-thiazoline ring. The corre-
lations of H-5cis in the 3-thiazoline ring with the protons
of the CH2 in the ethyl group could be seen by long dis-
tance coupling.
Investigations aimed at discovering and developing anti-
cancer reagents have been carried out in our laboratory,8
and these have especially focused on the synthesis of nov-
el, structurally diverse small molecules. In order to ex-
pand our small molecule library, a method to obtain 1,4-
thiazine derivatives was designed that involved the con-
densation of cysteine and 1-aryl-2-bromoethanones,
which were typically used to build heterocycle com-
pounds.9 However, during the synthesis, an unexpected
product, 3-thiazoline, instead of 1,4-thiazine, was ob-
SYNTHESIS 2011, No. 19, pp 3133–3137
x
x.
x
x
.
2
0
1
1
Advanced online publication: 24.08.2011
DOI: 10.1055/s-0030-1260184; Art ID: H45611SS
© Georg Thieme Verlag Stuttgart · New York

3134
Y. Liu et al.
PAPER
To further investigate the reaction, other substituted a- not successful. Thus, derivatives such as carbohydrazone
bromoacetophenones were used. The reactions of ethyl L- were then investigated. Fortunately, a single crystal of the
cysteine ester (2) with a series of a-bromoacetophenone derivative of 3-thiazoline, (E)-N¢-benzylidene-2-methyl-
derivatives 1b–h and a-bromoacetofuran (1i) were carried 4-phenyl-2,5-dihydrothiazole-2-carbohydrazide
(5a),
out as shown in Scheme 2, and the yields were about 50– which was synthesized from 3a, was successfully ob-
69% (Table 1). The reaction of bromomethyl ketones in- tained. In the approach, compound 3a reacted with hydra-
stead of 1-aryl-2-bromoethanones was also carried out zine hydrate to afford compound 4a; the latter then
but, unfortunately, none of the desired product was ob- reacted with benzaldehyde to give compound 5a
tained. To our knowledge, except for our studies, ester (Scheme 4). The molecular view of 5a11 is shown in
substitutions at the 2-position of 3-thiazolines 3a–i has not Figure 1. Based on the X-ray analysis of 5a, the structure
previously been reported.
of 3a was thus confirmed.
Ph
CO2Et
O
CO2Et
K2CO3
N
+
Br
H2N
S
N
R
EtOH
reflux
R
HN
SH
CO2Et
H2NHNOC
O
N2H4⋅H2O
1
2
3
N
PhCHO
EtOH
N
S
N
S
EtOH
reflux
S
Scheme 2 Synthesis of 3-thiazoline derivatives
Table 1 Synthesis of 3-Thiazoline Derivatives
Ph
Ph
Ph
3a
4a
5a
Scheme 4 Synthesis of carbohydrazone 5a
Entry
R
Time (h) Product Yield (%)
1
2
3
4
5
6
7
8
9
Ph
1
3a
3b
3c
3d
3e
3f
60
63
60
50
57
57
69
56
54
4-ClC6H4
4-MeOC6H4
4-NO2C6H4
3-NO2C6H4
4-MeC6H4
4-(t-Bu)C6H4
4-MeO-3-NO2C6H3
2-furyl
0.8
1.5
1
1
1
1
3g
3h
3i
1
Figure 1 X-ray crystal structure of compound 5a
1.5
To explain the unexpected formation of the 3-thiazoline
ring, a mechanism for the reaction is proposed, as shown
in Scheme 5. The expected six-membered-ring product
(3A) was initially formed by the dehydration of interme-
diate 6. Compound 3A then tautomerizes to 7 and the a-
hydrogen next to the ester group is removed by potassium
ethoxide (generated from potassium carbonate and eth-
anol),12 which induces cleavage of C–S bond to form 8.
Intermediate 8 is converted into 9 by reaction with potas-
sium hydrocarbonate (formed from potassium carbonate
and ethanol).12 A 1,3-hydrogen shift then forms an imino
ester 10, which is conjugated with the enethiol. Addition
of the thio moiety to the imine generates the racemic
enamine 11. Double bond migration around the five-
membered-ring finally generates the product 3a. Attempts
were made to isolate the proposed intermediate 3A, how-
ever, this was unsuccessful.
Interestingly, when 2-bromo-1-phenylbutan-1-one (1j)
was used as starting material, two compounds were ob-
tained in 1:1 ratio, which were diastereomers arising from
different groups on C2 and C5 (Scheme 3). The mixture
could be easily separated by column chromatography on
silica gel to obtain two stereoisomers, which were racemic
because of the C2 chirality.
O
CO2Et
N
HS
Br
S
K2CO3
+
EtOH
reflux
H2N
CO2Et
1j
2
3j
Scheme 3 Reaction of 2-bromo-1-phenylbutan-1-one (1j) and ethyl
L-cysteine ester (2)
To support the mechanism, NMR experiments were car-
ried out, however, the NMR spectra were too complex to
provide any valuable information. LC-MS was also em-
ployed to obtain mass spectra at different reaction time-
To determine the exact structure of these novel and unex-
pected compounds, a single crystal of product 3 would
clearly have been ideal, unfortunately, the experiment was
Synthesis 2011, No. 19, 3133–3137 © Thieme Stuttgart · New York

PAPER
Unexpected Rearrangement; A Novel Route to 3-Thiazoline
3135
CO2Et
S
CO2Et
CO2Et
O
CO2Et
NH2
K2CO3
– H2O
N
HN
HN
HS
+
Ph
EtOH
reflux
S
S
Br
1a
Ph
Ph
Ph
Ph
OH
3A
7
6
2
CO2Et
CO2Et
CO2Et
CO2Et
HN
HN
N
EtOK
1,3-H shift
HN
KHCO3
S
SH
SH
SK
Ph
Ph
Ph
10
11
9
8
CO2Et
N
K2CO3 + EtOH
KHCO3 + EtOK
S
Ph
3a
Scheme 5 Proposed mechanism of the reaction
HRMS: m/z [M + H]+ calcd for C13H16NO2S: 250.0902; found:
250.0905.
points, which might support the proposed mechanism.
Samples taken during the initial stage of the reaction
(20 min) and analyzed by HRMS gave signals at m/z =
268.1012 and 250.1000, which are consistent with inter-
mediate 6 and either 3A or 3a, respectively.
Ethyl 4-(4-Chlorophenyl)-2-methyl-2,5-dihydrothiazole-2-car-
boxylate (3b)
Yield: 63%; yellow oil.
IR (KBr): 1734 (C=O), 1636 (C=N) cm–1.
In conclusion, an unexpected and novel rearrangement in
the reaction of a-bromoacetophenone and ethyl L-cysteine
ester in the presence of potassium carbonate was discov-
ered and used to synthesize a series of new 3-thiazoline
derivatives. The study provides a simple and versatile
method for the synthesis of relatively rare 3-thiazolines.
1H NMR (400 MHz, CDCl3): d = 1.27 (t, J = 7.2 Hz, 3 H, CH3), 1.97
(s, 3 H, CH3), 4.17–4.26 (m, 2 H, CH2), 4.42 (d, J = 15.6 Hz, 1 H,
SCHAHB), 4.45 (d, J = 15.6 Hz, 1 H, SCHAHB), 7.42 (d, J = 8.6 Hz,
2 H, ArH), 7.85 (d, J = 8.6 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 171.4, 168.9, 137.7, 131.5, 129.9
(2C), 128.9 (2C), 88.9, 61.9, 44.0, 27.4, 14.0.
HRMS: m/z [M + H]+ calcd for C13H15ClNO2S: 284.0512; found:
284.0505.
Thin-layer chromatography (TLC) was carried out on silica gel 60
F254 plates (Merck KGaA). H NMR spectra were recorded with
1
Bruker Avance 300 (300 MHz) and 400 (400 MHz) spectrometers,
using CDCl3 or DMSO as solvents and tetramethylsilane (TMS) as
internal standard. Melting points were determined with an XD-4
digital micro melting point apparatus. IR spectra were recorded
with an Avtar 370 FT-IR (Termo Nicolet) spectrophotometer. LC-
MS measurements were carried out using a C18 column (2.1 × 150
mm, 5 mm) from Agilent. HRMS spectra were recorded with a Q-
TOF6510 spectrograph.
Ethyl 4-(4-Methoxyphenyl)-2-methyl-2,5-dihydrothiazole-2-
carboxylate (3c)
Yield: 60%; yellow oil.
IR (KBr): 1732 (C=O), 1605 (C=N) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.28 (t, J = 6.8 Hz, 3 H, CH3), 1.99
(s, 3 H, CH3), 3.89 (s, 3 H, OCH3), 4.16–4.30 (m, 2 H, CH2), 4.44
(d, J = 15.2 Hz, 1 H, SCHAHB), 4.53 (d, J = 15.2 Hz, 1 H, SCHAHB),
6.96 (t, J = 8.8 Hz, 2 H, ArH), 7.88 (d, J = 8.8 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 171.8, 169.3, 162.2, 130.3 (2C),
125.8, 114.0 (2C), 88.8, 61.7, 55.4, 44.0, 27.5, 14.0.
Preparation of Ethyl 2,5-Dihydrothiazole-2-carboxylate Deriv-
atives 3a–j; General Procedure
2-Bromo-1-phenylethanone (1 mmol), L-cysteine ethyl ester (1.1
mmol), K2CO3 (4 mmol), and absolute EtOH (50 mL) were added
to a flask and the mixture was stirred and heated to reflux under N2
(the reaction was monitored by TLC until complete). The mixture
was then filtered and the filtrate was concentrated under reduced
pressure. The residue was purified by flash chromatography on sil-
ica gel (EtOAc–petroleum ether) to obtain the product.
HRMS: m/z [M + H]+ calcd for C14H18NO3S: 280.1007; found:
280.1001.
Ethyl 2-Methyl-4-(4-nitrophenyl)-2,5-dihydrothiazole-2-car-
boxylate (3d)
Yield: 50%; yellow solid; mp 71–73 °C.
IR (KBr): 1731 (C=O), 1639 (C=N) cm–1.
Ethyl 2-Methyl-4-phenyl-2,5-dihydrothiazole-2-carboxylate
1H NMR (300 MHz, CDCl3): d = 1.28 (t, J = 7.2 Hz, 3 H, CH3), 1.99
(s, 3 H, CH3), 4.17–4.31 (m, 2 H, CH2), 4.47 (d, J = 15.6 Hz, 1 H,
SCHAHB), 4.55 (d, J = 15.6 Hz, 1 H, SCHAHB), 8.07 (d, J = 8.7 Hz,
2 H, ArH), 8.30 (d, J = 8.7 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 171.0, 168.2, 149.5, 138.6, 129.6
(2C), 123.8 (2C), 89.0, 62.1, 44.1, 27.3, 14.0.
(3a)
Yield: 60%; yellow solid; mp 54–56 °C.
IR (KBr): 1736 (C=O), 1631 (C=N) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.27 (t, J = 6.9 Hz, 3 H, CH3), 1.98
(s, 3 H, CH3), 4.17–4.27 (m, 2 H, CH2), 4.45 (d, J = 15.6 Hz, 1 H,
SCHAHB), 4.54 (d, J = 15.6 Hz, 1 H, SCHAHB), 7.41–7.52 (m, 3 H,
ArH), 7.89 (dt, J = 6.3, 1.5 Hz, 2 H, ArH).
HRMS: m/z [M + H]+ calcd for C13H15N2O4S: 295.0753; found:
295.0755.
13C NMR (100 MHz, CDCl3): d = 171.6, 170.0, 133.2, 131.5, 128.7
(2C), 128.6 (2C), 89.0, 61.8, 44.2, 27.5, 14.0.
Synthesis 2011, No. 19, 3133–3137 © Thieme Stuttgart · New York

3136
Y. Liu et al.
PAPER
Ethyl 2-Methyl-4-(3-nitrophenyl)-2,5-dihydrothiazole-2-car-
boxylate (3e)
Yield: 57%; yellow oil.
IR (KBr): 1734 (C=O), 1640 (C=N) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.28 (t, J = 7.1 Hz, 3 H, CH3), 1.99
(s, 3 H, CH3), 4.18–4.28 (m, 2 H, CH2), 4.49 (d, J = 15.5 Hz, 1 H,
SCHAHB), 4.56 (d, J = 15.5 Hz, 1 H, SCHAHB), 7.65 (t, J = 8.0 Hz,
1 H, ArH), 8.26 (dt, J = 8.0, 0.8 Hz, 1 H, ArH), 8.36 (ddd, J = 8.0,
2.0, 0.8 Hz, 1 H, ArH), 8.71 (t, J = 2.0 Hz, 1 H, ArH).
1H NMR (400 MHz, CDCl3): d = 1.27 (t, J = 7.2 Hz, 3 H, CH3), 1.97
(s, 3 H, CH3), 4.13–4.28 (m, 2 H, CH2), 4.35 (d, J = 15.4 Hz, 1 H,
SCHAHB), 4.43 (d, J = 15.4 Hz, 1 H, SCHAHB), 6.54 (dd, J = 3.5,
1.5 Hz, 1 H, ArH), 6.99 (d, J = 3.5 Hz, 1 H, ArH), 7.59 (d, J =
1.5 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 171.4, 160.5, 148.3, 145.6, 115.2,
112.1, 88.9, 61.9, 43.4, 27.3, 14.0.
HRMS: m/z [M + H]+ calcd for C11H14NO3S: 240.0694; found:
240.0689.
13C NMR (100 MHz, CDCl3): d = 171.1, 168.0, 148.4, 134.7, 134.3,
(2S,5R)-Ethyl 5-Ethyl-2-methyl-4-phenyl-2,5-dihydrothiazole-
2-carboxylate (3jcis)
Yield: 27%; yellow oil.
IR (KBr): 1734 (C=O), 1633 (C=N) cm–1.
129.8, 125.9, 123.5, 88.9, 62.1, 44.0, 27.3, 14.0.
HRMS: m/z [M + H]+ calcd for C13H15N2O4S: 295.0753; found:
295.0741.
Ethyl 2-Methyl-4-(p-tolyl)-2,5-dihydrothiazole-2-carboxylate
(3f)
Yield: 57%; yellow solid; mp 52–53 °C.
IR (KBr): 1739 (C=O), 1632 (C=N) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.26 (t, J = 7.2 Hz, 3 H, CH3),
1.96 (s, 3 H, CH3), 2.40 (s, 3 H, CH3), 4.15–4.25 (m, 2 H, CH2),
4.42 (d, J = 15.6 Hz, 1 H, SCHAHB), 4.51 (d, J = 15.6 Hz, 1 H,
SCHAHB), 7.24 (d, J = 8.4 Hz, 2 H, ArH), 7.77 (d, J = 8.4 Hz, 2 H,
ArH).
1H NMR (400 MHz, CDCl3): d = 0.96 (t, J = 7.3 Hz, 3 H, CH3),
1.29 (t, J = 7.1 Hz, 3 H, CH3), 1.64–1.75 (m, 1 H, SCHAHB), 1.90–
1.99 (m, 1 H, SCHAHB), 1.96 (s, 3 H, CH3), 4.16–4.30 (m, 2 H,
CH2), 5.01 (dd, J = 9.8, 3.0 Hz, 1 H, SCH), 7.42–7.48 (m, 3 H,
ArH), 7.81 (d, J = 6.5 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 173.2, 171.9, 133.0, 130.6, 129.1
(2C), 128.8 (2C), 87.1, 62.6, 61.8, 28.6, 28.3, 14.0, 11.6.
HRMS: m/z [M + H]+ calcd for C15H20NO2S: 278.1215; found:
278.1208.
13C NMR (100 MHz, CDCl3): d = 171.7, 169.9, 141.9, 130.5, 129.4
(2S,5S)-Ethyl 5-Ethyl-2-methyl-4-phenyl-2,5-dihydrothiazole-
(2C), 128.6 (2C), 88.9, 61.8, 44.2, 27.5, 21.5, 14.0.
2-carboxylate (3jtrans
)
HRMS: m/z [M + H]+ calcd for C14H18NO2S: 264.1058; found:
264.1034.
Yield: 27%; yellow solid; mp 57–59 °C.
IR (KBr): 1735 (C=O), 1637 (C=N) cm–1.
Ethyl 4-[4-(tert-Butyl)phenyl]-2-methyl-2,5-dihydrothiazole-2-
carboxylate (3g)
Yield: 69%; yellow oil.
IR (KBr): 1735 (C=O), 1609 (C=N) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.26 (t, J = 7.1 Hz, 3 H, CH3), 1.34
[s, 9 H, C(CH3)3], 1.96 (s, 3 H, CH3), 4.15–4.25 (m, 2 H, CH2), 4.43
(d, J = 15.3 Hz, 1 H, SCHAHB), 4.53 (d, J = 15.3 Hz, 1 H, SCHAHB),
7.46 (d, J = 8.4 Hz, 2 H, ArH), 7.82 (d, J = 8.4 Hz, 2 H, ArH).
1H NMR (400 MHz, CDCl3): d = 0.96 (t, J = 7.2 Hz, 3 H, CH3),
1.26 (t, J = 7.1 Hz, 3 H, CH3), 1.61–1.72 (m, 1 H, SCHAHB), 1.88–
2.04 (m, 1 H, SCHAHB), 1.95 (s, 3 H, CH3), 4.15–4.26 (m, 2 H,
CH2), 5.07 (dd, J = 8.7, 3.2 Hz, 1 H, SCH), 7.42–7.48 (m, 3 H,
ArH), 7.75 (d, J = 6.4 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 173.3, 172.0, 132.9, 130.8, 129.3
(2C), 128.9 (2C), 86.4, 63.3, 61.7, 28.9, 28.3, 14.0, 12.7.
HRMS: m/z [M + H]+ calcd for C15H20NO2S: 278.1215; found:
278.1210.
13C NMR (100 MHz, CDCl3): d = 171.7, 169.8, 155.0, 130.4, 128.5
(2C), 125.6 (2C), 89.0, 61.7, 44.2, 35.0, 31.2 (3C), 27.5, 14.0.
Preparation of (E)-N¢-Benzylidene-2-methyl-4-phenyl-2,5-dihy-
drothiazole-2-carbohydrazide (5a); General Procedure
HRMS: m/z [M + H]+ calcd for C17H24NO2S: 306.1528; found:
306.1515.
Ethyl 2-methyl-4-phenyl-2,5-dihydrothiazole-2-carboxylate (3a; 1
mmol) and absolute EtOH (25 mL) were added to a flask, then hy-
drazine hydrate (5 mL) was added and the mixture was stirred and
heated to reflux under N2 (the reaction was monitored by TLC).
Upon completion, the mixture was concentrated under reduced
pressure, deionized H2O (10 mL) was added and the aqueous layer
was extracted with EtOAc (3 × 15 mL). The combined organic ex-
tracts were dried over anhydrous MgSO4, filtered, and evaporated.
The equivalent amount of benzaldehyde (1 mmol) and EtOH (20
mL) were added to the residue, and the mixture was heated to reflux
for 4 h. The mixture was concentrated to remove a portion of EtOH
under reduced pressure, then the mixture was kept overnight and the
formed solid was collected by filtration and washed with EtOH to
obtain the product 5a. A sample for X-ray analysis was prepared by
evaporating a solution of 5a in EtOH.
Ethyl 4-(4-Methoxy-3-nitrophenyl)-2-methyl-2,5-dihydrothiaz-
ole-2-carboxylate (3h)
Yield: 56%; yellow solid; mp 99–101 °C.
IR (KBr): 1739 (C=O), 1618 (C=N) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.27 (t, J = 7.1 Hz, 3 H, CH3), 1.96
(s, 3 H, CH3), 4.03 (s, 3 H, OCH3), 4.17–4.26 (m, 2 H, CH2), 4.41
(d, J = 15.4 Hz, 1 H, SCHAHB), 4.49 (d, J = 15.4 Hz, 1 H, SCHAHB),
7.15 (d, J = 8.8 Hz, 1 H, ArH), 8.12 (dd, J = 8.8, 2.2 Hz, 1 H, ArH),
8.34 (d, J = 2.2 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 171.3, 167.4, 155.0, 139.5, 134.2,
126.0, 125.7, 113.5, 88.8, 62.0, 56.9, 43.8, 27.4, 14.0.
HRMS: m/z [M + H]+ calcd for C14H17N2O5S: 325.0858; found:
325.0851.
(E)-N¢-Benzylidene-2-methyl-4-phenyl-2,5-dihydrothiazole-2-
carbohydrazide (5a)
Yield: 56%; yellow solid; mp 212–214 °C.
IR (KBr): 3225 (NH), 1677 (C=O), 1638 (C=N) cm–1.
Ethyl 4-(Furan-2-yl)-2-methyl-2,5-dihydrothiazole-2-carboxy-
late (3i)
Yield: 54%; yellow oil.
IR (KBr): 1733 (C=O), 1638 (C=N) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.82 (s, 3 H, CH3), 4.58 (d, J =
16.2 Hz, 1 H, SCHAHB), 4.64 (d, J = 16.2 Hz, 1 H, SCHAHB), 7.43–
7.46 (m, 3 H, ArH), 7.51–7.60 (m, 3 H, ArH), 7.66–7.69 (m, 2 H,
Synthesis 2011, No. 19, 3133–3137 © Thieme Stuttgart · New York

PAPER
Unexpected Rearrangement; A Novel Route to 3-Thiazoline
3137
ArH), 8.05 (d, J = 7.7 Hz, 2 H, ArH), 8.47 (s, 1 H, =CH), 10.68 (s,
(5) (a) Endres, T.; Fendt, M. J. Exp. Biol. 2009, 212, 2324.
1 H, NH).
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13C NMR (100 MHz, DMSO-d6): d = 170.4, 168.0, 149.3, 134.1,
132.8, 131.5, 130.1, 128.9 (2C), 128.7 (2C), 128.4 (2C), 127.0 (2C),
90.8, 42.2, 29.5.
HRMS: m/z [M + H]+ calcd for C18H18N3OS: 324.1171; found:
324.1168.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
We are grateful for the financial support from the National Natural
Science Foundation of China (90813022 and 20972088).
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Synthesis 2011, No. 19, 3133–3137 © Thieme Stuttgart · New York