Efficient synthesis of 5-substituted thiazolidin-2-ones from xanthates and tert-butyl N-allylcarbamates

Article abstract of DOI:10.1016/j.tet.2013.10.031

A series of 5-substituted thiazolidin-2-ones with various functional groups was synthesized efficiently via a radical addition of xanthates and tert-butyl N-allylcarbamates and subsequent 88% HCO₂H-catalyzed cyclization. The mechanism of the acid-catalyzed cyclization was proposed as well.

Full text of DOI:10.1016/j.tet.2013.10.031

Tetrahedron 69 (2013) 10272e10278
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of 5-substituted thiazolidin-2-ones from
xanthates and tert-butyl N-allylcarbamates
,b,
Zhongyan Huang a, Jiaxi Xu a
*
a State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science, Beijing University of Chemical
Technology, Beijing 100029, China
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2013
Received in revised form 25 September 2013
Accepted 10 October 2013
Available online 17 October 2013
A series of 5-substituted thiazolidin-2-ones with various functional groups was synthesized efficiently
via a radical addition of xanthates and tert-butyl N-allylcarbamates and subsequent 88% HCO2H-cata-
lyzed cyclization. The mechanism of the acid-catalyzed cyclization was proposed as well.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Thiazolidin-2-one
Cyclization
Xanthate
Carbamate
Radical addition
1. Introduction
well.8 Benzothiazolone derivatives were prepared via the reaction
of a-haloanilines with potassium O-alkyl xanthates and subsequent
Thiazolidin-2-one unit has been found in many natural products
and it plays a very important role in both pharmaceutical and or-
ganic synthetic chemistry. Thiazolidin-2-one derivatives show an-
ticancer,1 anti-HIV activities,2 and bactericidal, pesticidal, anti
convulsant, and antiinflammatory activities.3 One thiazolidin-2-
one derivative (Fosthiazate) was used as one of safe insecticides
in agriculture in America.4 Thus, synthesis and biological in-
vestigation of thiazolidin-2-one derivatives have caught many
chemists’ attention.
Recently, several methods for the preparation of thiazolidin-2-
one derivatives have been developed. The direct methods are cy-
clization of aminoethanols or aminoethanethiols with carbonyl
reactants under the catalysis of selenium,5a K2CO3,5b CDI,5c Mont-
morillonite,5d or pyridine.5e Substituted 4-spirothiazolidin-2-ones
were prepared from cycloalkanones, mercaptoacetic acid, and
ammonium carbonate in refluxing benzene.6 While substituted 5-
spirothiazolidin-2-ones were synthesized via a one-pot three
component condensation of enamines, sulfur, and isocyanates.7
Several substituted thiazolidin-2-ones were synthesized via the
acidic hydrolysis of the corresponding 2-iminothiazolidines as
oxidation/other treatment.9 In addition, the reduction of S-(2-
alkoxycarbonylaminoalkyl)O-ethyl xanthates with NaBH4 gave
rise to a mixture of substituted thiazolidin-2-ones and thiazolidine-
2-thiones.10 Recently, Shen’s and our groups reported a convenient
synthesis of thiazolidin-2-ones from thiazolidine-2-thiones.11
Although several synthetic methods have been reported to
prepare thiazolidin-2-one derivatives till now, most of them are not
general and practical and some of them even have to use toxic
catalysts or reactants, such as selenium, phosphorus, haloethanols,
and so on. In addition, to the best of our knowledge, most of the
vicinal amino mercaptans are commercially unavailable and they or
their derivatives are uncomfortably odorous.5e11 Very recently, we
prepared substituted taurines and homotaurines by the performic
acid oxidation of S-1-phthalimidoalkyl O-ethyl dithiocarbonates,
which were synthesized from the corresponding xanthates and
olefins.12 Similarly, S-1-tert-butoxycarbonylaminoalkan-2-yl O-
ethyl dithiocarbonates can be synthesized and considered as
starting materials for the synthesis of thiazolidin-2-ones via
deprotection of tert-butoxycarbonyl (Boc) and intramolecular cy-
clization. Thus, we hope to use abundantly available xanthates and
tert-butyl N-allylcarbamates as starting materials to synthesize 5-
substituted thiazolidin-2-ones via a radical addition and sub-
sequent cyclization. Herein, we present our efficient synthesis of 5-
substituted thiazolidin-2-ones.
* Corresponding author. Tel./fax: þ86 10 64435565; e-mail address: jxxu@mail.
buct.edu.cn (J. Xu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.031

Z. Huang, J. Xu / Tetrahedron 69 (2013) 10272e10278
10273
2. Results and discussion
HCl (Table 1, entry 12). However, the products 3a and 4 were ob-
tained in yields of 69% and 2%, respectively, when the reaction
mixture was heated to reflux in acetonitrile for 12 h (Table 1, entry
13). Increasing concentration of hydrochloric acid resulted in the
yield decrease of 3a and the yield increase of 4 (Table 1, entries
14e16). The yields of products 3 and 4 were improved slightly,
compared with those in acetonitrile, when the reaction was carried
out in THF and DMSO under the catalysis of 12 mol/L HCl (Table 1,
entries 17 and 18). When equivalent of anhydrous formic acid was
used as the acidic catalyst, trace of 3a was detected in acetonitrile
(Table 1, entry 19). But the yield of 3a increased sharply when
15 equiv of formic acid was added (Table 1, entry 20). When 88%
formic acid (15 equiv) was used as the catalyst in acetonitrile, 3a was
obtained as sole product in a good yield of 82% (Table 1, entry 21).
However, when the reaction was conducted in 88% formic acid,
products 3a and 4 were obtained in 36% and 2% yields, respectively
(Table 1, entry 22). Acetic acid cannot catalyze the cyclization due to
its weak acidity (Table 1, entries 23 and 24). The results indicate that
middle strong acids can catalyze the cyclization reaction for the
synthesis of 5-substituted thiazolidin-2-ones and formic acid, es-
pecially 88% formic acid, is more efficient catalyst than the others.
Different xanthates 1 were readily obtained via the reaction of
potassium O-ethyl xanthate and the corresponding haloalkanes.12
They reacted with tert-butyl N-allylcarbamate to afford the ad-
duct dithiocarbonates 2 in satisfactory to good yields (Table 2)
except for S-(1-tert-butoxycarbonylamino-5-ethoxy-4-ethoxycar
bonyl-5-oxo)pentan-2-yl O-ethyl dithiocarbonate (2c), S-[1-tert-
S-1-tert-Butoxycarbonylamino-4-phthalimidobutan-2-yl O-ethyl
dithiocarbonate (2a) was first prepared via a radical addition of O-
ethyl S-phthalimidomethyl dithiocarbonate (1a) and tert-butyl N-
allylcarbamate in the presence of dilauroyl peroxide (DLP) as a radi-
cal initiator and selected to optimize cyclization conditions. The cy-
clization reaction did not occur when the dithiocarbonate 2a was
refluxed in acetonitrile ora mixture of acetonitrile and water for 24 h,
indicating that the amide group in the carbamate moiety is a poor
nucleophile to attack the xanthate group (Table 1, entries 1 and 2).
When we used NaBH4 to catalyze the cyclization, 5-phthalimido
ethylthiazolidin-2-one (3a) and 5-phthalimidoethylthiazolidine-2-
thione (4) were obtained in separated yields of 46% and 17%, re-
spectively (Table 1, entry 3). Attempt to abstract the hydrogen at the
carbamate group with base, such as Na2CO3, NaH, or NaOH, to realize
the cyclization failed (Table 1, entries 4e6). Neither product 3a nor 4
was observed when 2a was deprotected the Boc (tert-butox-
ycarbonyl) group via treatment with 30% TFA (F3CCO2H) in
dichloromethane (DCM) and neutralized with NaOH (Table 1, entry
7). However, products 3a and 4 were obtained in low yields when
a solution of the dithiocarbonate 2a in acetonitrile was refluxed in
the presence of TFA (Table 1, entries 8 and 9). Considering that TFA
can catalyze the hydrolysis of acetonitrile and may be consumed in
refluxing acetonitrile, the cyclization reaction was also conducted in
THFand nonhydrolyzable DMSO, respectively (Table 1, entries 10 and
11). The yield of 4 was improved in THF, while the yield of 3a in-
creased to 53% in DMSO. To further evaluate the efficiency of other
acids in the cyclization, hydrochloric acid in different concentration
was tested. No reaction occurred when the reaction was conducted
at room temperature in acetonitrile under the catalysis of 1 mol/L
butoxycarbonylamino-4-(benzothiazol-2-yl)]butan-2-yl
O-ethyl
dithiocarbonate (2g), and S-[1-tert-butoxycarbonylamino-4-(6-
methylpyridin-2-yl)]butan-2-yl O-ethyl dithiocarbonate (2h)
(Table 2, entries 3, 7, and 8) in relatively low yields due to the steric
hindrance or the less stable radical precursors. Most of the adduct
dithiocarbonates
2 were cyclized to the corresponding 5-
substituted thiazolin-2-ones 3 in good yields under the catalysis
of 88% formic acid in acetonitrile (Table 2). The Boc group was re-
moved under acidic conditions. The generated amino group is
easily converted to ammonium salt, which can slow down the cy-
clization, in the presence of strong acids. This is the main reason
why the cyclization occurs in the presence of middle strong acids
and requires refluxing usually for 12 h. The concentrated hydro-
chloric acid can catalyze hydrolysis of acetonitrile and is consumed.
Table 1
Optimization for the synthesis of thiazolidin-2-one 3a
Entry Catalyst
(equiv vs 2a)
Solvent
(5 mL)
Temp
Reaction Yield (%)
time (h)
3a
4
Table 2
1
2
d
MeCN
MeCN/H2O
(4:1, v/v)
THF
MeCN
THF
Reflux 24
Reflux 24
0
0
0
0
Synthesis of 5-substituted thiazolin-2-ones
allylcarbamate
3 from xanthates 1 and tert-butyl
d
3
4
5
6
7
NaBH4 (2 equiv)
Na2CO3 (2 equiv)
NaH (1.5 equiv)
NaOH (2 equiv)
(1) TFA
rt
12
6
46
0
0
0
0
17
0
0
0
0
Reflux
Reflux
Reflux
rt
2
1
H2O
(1) DCM
12
(2) Aq NaOH
8
9
TFA (1 equiv)
TFA (3 equiv)
TFA (15 equiv)
TFA (15 equiv)
HCl (1 mol/L, 1 mL)
HCl (1 mol/L, 1 mL)
HCl (2 mol/L)
HCl (6 mol/L, 1 mL)
HCl (12 mol/L, 1 mL)
HCl (12 mol/L, 1 mL)
HCl (12 mol/L, 1 mL)
HCO2H (1 equiv)
HCO2H (15 equiv)
MeCN
MeCN
THF
DMSO
MeCN
MeCN
Reflux 24
Reflux 24
Reflux 15
100 ꢀC 20
25
35
35
53
0
69
35
11
12
28
23
trace
74
82
36
trace
trace
2
3
17
3
0
2
Entry
1
R
2 Yield (%)
3 Yield (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
PhthNCH2
MeO2CCH2
(EtO2C)2CH
MeCOCH2
PhCOCH2
NCCH2
76
85
42
74
84
72
82
89
73
72
80
85
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
rt
24
Reflux 12
HCl (2 mol/L) Reflux 12
2
MeCN
MeCN
THF
DMSO
MeCN
MeCN
Reflux 12
Reflux 12
Reflux 15
100 ꢀC 20
Reflux 24
Reflux 12
Reflux 12
24
23
8
2
0
2
0
2
0
7
8
1g
1h
32
35
78
81
88% HCO2H (15 equiv) MeCN
88% HCO2H
AcOH (15 equiv)
AcOH (15 equiv)
88% HCO2H
MeCN
MeCN/H2O
(4:1, v/v)
Reflux
2
Reaction conditions for the preparation of 2: 1 (2.0 mmol) and tert-butyl N-allyl-
carbamate (378 mg, 2.4 mmol) were refluxed in DCE (2 mL) in the presence of DLP.
Reaction conditions for the synthesis of 3: 2 (1.0 mmol) and 88% HCOOH (784 mg,
15.0 mmol) were refluxed in MeCN (5 mL) for 12 h.
Reflux 24
Reflux 24
0

10274
Z. Huang, J. Xu / Tetrahedron 69 (2013) 10272e10278
However, formic acid cannot (verified by 1H NMR analysis). This
may be another reason why low cyclization yields were obtained
under the catalysis of 12 mol/L HCl in acetonitrile.
Recently, many best-selling and newly approved drugs contain
the fluorine atom. The introduction of the fluorine atom leads to
change in properties of compounds, which make the molecules
more stable in metabolism and display better membrane perme-
ability.13 Trifluoromethylation is one of the most efficiently method
to introduce the fluorine atom into molecules and catches many
chemists’ attention. Therefore, the introduction of trifluoromethyl
into thiazolidin-2-one derivatives will increase their potential ap-
plication. We used xanthate 1i as trifluoromethylating reagent to
react with tert-butyl N-allylcarbamate, producing adduct dithio-
carbonate 2i in a good yield of 86%. Under the same conditions, 5-
(2,2,2-trifluoroethyl)thiazolidin-2-one (3i) was obtained in a yield
of 84%. Meanwhile, 2-phenylethyl formate, rather than 2-
phenylethanol, was obtained as byproduct in a yield of 72%
(Scheme 1).
Scheme 3. Attempt to the S/O transformation of thiazolidine-2-thione 4.
It was reported that 2-ethoxybenzothiazoline derivatives can be
converted to the corresponding benzothiazolidin-2-one derivatives
under the catalysis of TFA, but 2-methylthiothiazolonaphthyridine
required strong base (such as NaOMe) for the similar trans-
formation (Scheme 4).14 The different electron-withdrawing abili-
ties of the ethoxy and methylthio groups may be the main reason.
That is, only strong nucleophiles can attack the C]N bond in
alkylthiothiazoles due to the weak electron-withdrawing alkylthio
group, while weak nucleophiles can attack the C]N bond in
alkoxythiazoles because of the stronger electron-withdrawing
alkoxy group. Thus, when the alkylthio group is used to replace
the alkoxyl group in dithiocarbonates 2, the cyclization product
would be 2-alkylthiothiazoles rather than thiazolidin-2-ones. To
verify the analysis, butyl phthalimidomethyl trithiocarbonate (1k)
was designed and prepared and further reacted with tert-butyl N-
allylcarbamate to afford an adduct product 2k, which was subjected
to the cyclization under the optimal conditions, heated to reflux in
the presence of 88% formic acid in acetonitrile for 12 h, to give rise
to 2-butylthio-5-phthalimidoethylthiazolidine (5) in 72% yield as
expected and thiazolidin-2-one 3a in 2% yield (Scheme 5).
Scheme 1. Synthesis of 5-(2,2,2-trifluoroethyl)thiazolidin-2-one (3i).
S
S
N
TFA
R
O
R
OEt
S
EtOH
N
H
To extend the application of the method, tert-butyl N-allyl-N-
benzylcarbamate was selected as the olefin precursor to react with
O-ethyl S-2-phthalimidomethylxanthate (1a) to afford S-(1-N-
N
N
S
N
CH3ONa
DMF
S
O
N
H
benzyl-tert-butoxycarbonylamino-4-phthalimido)butan-2-yl
O-
ethyl dithiocarbonate (2j) in a good yield of 84%, which was
cyclized to 3-benzyl-5-phthalimidoethylthiazolidin-2-one (3j) in
a good yield 80% under the catalysis of 88% formic acid in aceto-
nitrile for 2 h (Scheme 2). The reaction time was shortened to 2 h
because the secondary amino group shows higher nucleophilicity
than the primary one. Thus, the method can be utilized to syn-
thesize 3,5-disubstituted thiazolidin-2-ones.
Scheme
4. Transformations
of
2-ethoxybenzothiazolines
and
2-
methylthiothiazolonaphthyridine to the corresponding benzothiazolidin-2-one
derivatives.
SBu
S
S
N
S
PhthNCH2
PhthNCH2
NHBoc
S
3k
72%
88% HCOOH
S
SnBu
NHBoc
+
O
MeCN
PhthNCH2S
1k
SnBu DLP, DCE
reflux
PhthNCH2
reflux, 12h
2k
26%
NH
2%
3a
Scheme 5. Cyclization of trithiocarbonate 2k.
Scheme 2. Synthesis of 3,5-disubstituted thiazolidin-2-one (3j).
On the basis of the above experimental results (Schemes 1e5),
the plausible mechanism of the cyclization reaction is proposed
and depicted in Scheme 6. The carbamate group in dithiocar-
bonates 2 is hydrolyzed under acidic conditions under heating to
generate intermediates A and tert-butyl carbocation. Water attacks
tert-butyl carbocation to give rise to tert-butanol, which was ap-
proved by isolated tert-butanol from the reaction mixture. The in-
termediates A further generate intermediates B after releasing
carbon dioxide. The generated amino group in the intermediates B
exists in an equilibrium between the free amino group and its
ammonium form. The free amino group attacks the protonated
thiocarbonyl group to form intermediates C. The intermediates C
can further undergo two different pathways to yield thiazolidine-2-
thiones 4 (pathway 1) or thiazolidin-2-ones 3 (pathway 2). In
pathway 1, after a proton on the nitrogen transfers to the oxygen
In our acid-catalyzed cyclization, interestingly, thiazolidin-2-
ones, rather than thiazolidine-2-thiones, were obtained. This pro-
moted us to investigate the cyclization mechanism of dithiocar-
bonates 2. We first assumed that thiazolidine-2-thiones were
generated initially via an intramolecular aminolysis of the xanthate
group by the amino group generated by the acidic deprotection of
the Boc group and they were converted into thiazolidin-2-ones
under acidic aqueous conditions. To verify our assumption, the
byproduct 4 was treated under the cyclization conditions, refluxed
in 88% formic acid in acetonitrile. However, no reaction occurred.
That is, no S/O transformation of thiazolidine-2-thione 4 was ob-
served (Scheme 3). The result indicates that thiazolidin-2-ones
were generated during cyclization, rather than from the S/O
transformation of thiazolidine-2-thiones.

Z. Huang, J. Xu / Tetrahedron 69 (2013) 10272e10278
10275
catalyzed intramolecular cyclization. The mechanism of the
acid-catalyzed cyclization was investigated and proposed. Com-
pared with previous methods, the current approach shows many
advantages, such as available diverse xanthates and tert-butyl N-
allylcarbamates as starting materials, environment-friendly cata-
lyst, and good functional group tolerance.
OH
H2O
- H+
S
OEt
S
S
S
OEt
OEt
S
H+
H
O
S
H
+
H
N
H
N
R
N
R
O
R
O
A
O
2
+OH
O
- CO2
+SH
OEt
4. Experimental section
4.1. General
S
S
HS
S
H+
H+
- H+
OEt
NH2
S
S
OEt
S
OEt
NH2
R
R
+NH3
R
NH2
R
C
B
Route 1
Route 2
Melting points were determined with a melting point apparatus
and are uncorrected. 1H NMR spectra were recorded at 400 MHz in
CDCl3 with TMS as the internal standard. 13C NMR spectra were
recorded at 101 MHz in CDCl3. IR spectra were determined directly.
HRMS spectra were recorded with an LC/MSD TOF mass spec-
trometer. TLC analysis was performed on glass pre-coated silica
+SH
S
HS
S
+OH
H2S+
S
O
- EtOH
- H+
S
S
NH
NH
NH
R
NH
R
R
R
4
D
E
- H2S
O
+OH
gel (10e40
mm) plate. Spots were visualized with UV light or
H
O
H
O+
NH
H
O
H
O
O
O
H
O
HO+
S
HOOCH
R
iodine. Column chromatography was performed on silica gel
(200e300 mesh). All xanthates 1 were prepared according to the
reported methods.12,16
S
O
NH
- EtOH
R
+NH
S
S
S
+NH
N
R
R
R
F
G
J
H
I
EtOH
H2O
H
H
O
H
EtO+
S
4.2. General procedure for the synthesis of S-alkyl O-ethyl
xanthates 2
H
H
H
+OH
NH
EtO
S
OEt
+OEt
HO+
N
O+
H
- EtOOCH
R
-EtOH
O
S
O
H
NH
O
H
NH
S
S
R
R
N
R
R
HCO2H
K
A mixture of xanthate 1 (2 mmol) and tert-butyl N-allylcarba-
mate (378 mg, 2.4 mmol) in 1,2-dichloroethane (2 mL) was
degassed by vacuumized, then filled with nitrogen. The solution
was then heated to reflux and dilauroyl peroxide (DLP)
(1.25e10 mol %, 10e80 mg) was added portionwise per hour. The
reaction was monitored by TLC until complete disappearance of the
xanthate 1. After evaporation of the solvent, the residue was
chromatographed on a silica gel column (petroleum ether/ethyl
acetate: 15/1 to 3/1, v/v) to afford the addition product 2.
- H+
O
HCO2H
+ EtOH
HCO2Et
S
NH
R
3
Scheme 6. Plausible mechanism of the acid-catalyzed reaction of S-(1-tert-butox-
ycarbonylaminoalkan-2-yl) O-ethoxy dithiocarbonates.
atom, the intermediates C convert to intermediates D, which re-
lease a molecule of ethanol followed by deprotonation to produce
byproducts thiazolidine-2-thiones 4. However, the proton on the
nitrogen transfers to the thiol group, resulting in the formation of
intermediates E, which release gaseous hydrogen sulfide to yield 2-
ethoxythiazolidines F. The pathway 2 is favorable than the pathway
1 because hydrogen sulfide gas can escape from the reaction mix-
ture, promoting transformation from the intermediates C to E to F.
The weak nucleophile formic acid can attack the intermediates F,
protonated alkoxythiazolidines, to produce intermediates G. After
a proton transfer, releasing ethanol, and another proton transfer,
the intermediates G are converted to intermediates J. The released
ethanol attacks the protonated carbonyl group of the intermediates
J to give rise to final thiazolidin-2-ones 3 with releasing ethyl for-
mate and the subsequent deprotonation. The formation of the
byproduct 2-phenylethyl formate in Scheme 1 supports our pro-
posed formation mechanism of thiazolidin-2-ones 3. In addition,
for the formation of thiazolidin-2-ones 3, another possibility is
through a sequence of direct water attack of the intermediates F,
proton transfer, releasing ethanol, and deprotonation. In this pos-
sibility, ethyl formate is generated via formic acid-catalyzed ester-
ification.15 It is impossible to distinguish these two possible
formation processes. Possibly thiazolidin-2-ones 3 are generated
via dual processes.
4.2.1. S-(1-tert-Butoxycarbonylamino-4-phthalimidobutan-2-yl)O-
ethyl dithiocarbonate (2a).12b The reaction was complete after ad-
dition of 25 mol % of DLP. Yellow oil; yield: 649 mg, 74%. Rf¼0.17
(petroleum ether/ethyl acetate¼5/1, v/v). 1H NMR (CDCl3, 400 MHz)
(d, ppm) 1.40 (t, J¼7.1 Hz, 3H, CH3), 1.43 (s, 9H, 3CH3), 2.00 (ddt,
J¼14.1, 7.8, 7.3 Hz, 1H in CH2), 2.13 (ddt, J¼14.1, 7.7, 6.5 Hz, 1H in
CH2), 3.45e3.57 (m, 2H, CH2), 3.78e3.94 (m, 3H, CH2 & CH), 4.61 (q,
J¼7.1 Hz, 2H, CH2), 4.87 (br s, 1H, NH), 7.72 (dd, J¼5.5, 3.1 Hz, 2H,
ArH), 7.85 (dd, J¼5.5, 3.1 Hz, 2H, ArH). 13C NMR (CDCl3, 101 MHz) (
d,
ppm) 13.7, 28.3, 30.4, 35.6, 43.3, 49.3, 70.2, 79.6, 123.2, 132.1, 133.9,
155.9, 168.2, 213.7.
4.2.2. S-(1-tert-Butoxycarbonylamino-5-methoxy-5-oxopentan-2-yl)
O-ethyl dithiocarbonate (2b). The reaction was complete after
addition of 15 mol % of DLP. Yellow oil; yield: 598 mg, 85%.
Rf¼0.38 (petroleum ether/ethyl acetate¼5/1, v/v). 1H NMR
(CDCl3, 400 MHz) (
d
, ppm) 1.42 (t, J¼7.1 Hz, 3H, CH3), 1.43 (s, 9H,
3CH3), 1.89 (dddd, J¼14.5, 8.6, 7.6, 6.3 Hz, 1H in CH2), 2.11 (dddd,
J¼14.5, 8.6, 8.4, 6.3 Hz, 1H in CH2), 2.48 (ddd, J¼15.0, 8.6, 6.3 Hz,
1H in CH2), 2.54 (ddd, J¼15.0, 8.6, 6.3 Hz, 1H in CH2), 3.37 (dt,
J¼13.5, 6.3 Hz, 1H in CH2), 3.49 (dt, J¼13.5, 5.8 Hz, 1H in CH2),
3.68 (s, 3H, CH3), 3.87 (dddd, J¼8.4, 7.6, 6.3, 5.8 Hz, 1H, CH), 4.65
(q, J¼7.1 Hz, 2H, CH2), 4.86 (br s, 1H, NH). 13C NMR (CDCl3,
101 MHz) (d, ppm) 13.7, 26.5, 28.3, 31.2, 43.6, 51.1, 51.7, 70.2, 79.5,
155.8, 173.1, 213.2. IR (nmax, cmꢁ1) 3368, 1737, 1715, 1516, 1219,
3. Conclusion
1050. HRMS (ESI) calcd for
374.1072; found 374.1069.
C
14H25NNaO5S2 [MþNa]þ m/z
In summary, we have developed a convenient and practical
protocol for the synthesis of 5-substituted thiazolidin-2-ones
with various functional groups via a radical addition reaction of
xanthates with tert-butyl N-allylcarbamates and subsequent acid-
4.2.3. S-(1-tert-Butoxycarbonylamino-5-ethoxy-4-ethoxycarbonyl-
5-oxopentan-2-yl)O-ethyl dithiocarbonate (2c). The reaction was
complete after addition of 25 mol % of DLP. Yellow oil; yield:

10276
Z. Huang, J. Xu / Tetrahedron 69 (2013) 10272e10278
368 mg, 42%. Rf¼0.37 (petroleum ether/ethyl acetate¼5/1, v/v). 1H
5.8 Hz, 1H, CH), 4.64 (q, J¼7.1 Hz, 2H, CH2), 4.95 (br s, 1H, NH), 7.35
(t, J¼7.6 Hz, 1H, ArH), 7.45 (t, J¼8.0 Hz, 1H, ArH), 7.83 (d, J¼7.6 Hz,
NMR (CDCl3, 400 MHz) (
d
, ppm) 1.26 (t, J¼7.1 Hz, 3H, CH3), 1.27 (t,
J¼7.1 Hz, 3H, CH3), 1.40 (t, J¼7.1 Hz, 3H, CH3), 1.43 (s, 9H, 3CH3), 2.11
(ddd, J¼14.5, 8.0, 5.6 Hz, 1H in CH2), 2.41 (ddd, J¼14.5, 8.8, 8.0 Hz,
1H in CH2), 3.41e3.51 (m, 2H, CH2), 3.66 (dd, J¼8.0, 5.6 Hz, 1H, CH),
3.87 (dddd, J¼8.8, 8.0, 6.4, 5.6 Hz, 1H, CH), 4.19 (q, J¼7.1 Hz, 4H,
2CH2), 4.63 (q, J¼7.1 Hz, 2H, CH2), 4.85 (br s, 1H, NH). 13C NMR
1H, ArH), 7.96 (d, J¼8.0 Hz, 1H, ArH). 13C NMR (CDCl3, 101 MHz) (
d,
ppm) 13.7, 28.3, 30.8, 31.4, 43.7, 51.1, 70.2, 79.6, 121.4, 122.5, 124.8,
125.9, 135.1, 153.1, 155.8, 170.2, 213.0. IR (nmax, cmꢁ1) 3340, 3055,
1711, 1515, 1220, 1049. HRMS (ESI) calcd for C19H27N2O3S3 [MþH]þ
m/z 427.1184; found 427.1184.
(CDCl3, 101 MHz) (d, ppm) 13.7, 13.9, 14.0, 28.3, 30.1, 43.8, 49.5, 49.8,
61.6, 61.7, 70.3, 79.5, 155.8, 168.7, 168.9, 212.7. IR (nmax, cmꢁ1) 3389,
1731, 1513, 1220, 1048. HRMS (ESI) calcd for C18H32NO7S2 [MþH]þ
m/z 438.1620; found 438.1613.
4.2.8. S-[1-tert-Butoxycarbonylamino-4-(6-methylpyridin-2-yl)bu-
tan-2-yl]O-ethyl dithiocarbonate (2h). The reaction was complete
after addition of 25 mol % of DLP. Yellow oil; yield: 269 mg, 35%.
Rf¼0.12 (petroleum ether/ethyl acetate¼5/1, v/v). 1H NMR (CDCl3,
4.2.4. S-(1-tert-Butoxycarbonylamino-5-oxohexan-2-yl)O-ethyl di-
thiocarbonate (2d). The reaction was complete after addition of
15 mol % of DLP. Yellow oil; yield: 496 mg, 74%. Rf¼0.30 (petroleum
400 MHz) (
d
, ppm) 1.41 (t, J¼7.1 Hz, 3H, CH3),1.43 (s, 9H, 3CH3), 2.01
(dddd, J¼14.5, 8.8, 8.4, 6.5 Hz, 1H in CH2), 2.19 (dddd, J¼14.5, 8.0,
7.8, 6.2 Hz, 1H in CH2), 2.53 (s, 3H, CH3), 2.88 (ddd, J¼13.5, 8.0,
6.5 Hz,1H in CH2), 2.96 (ddd, J¼13.5, 8.4, 6.2 Hz,1H in CH2), 3.42 (dt,
J¼13.0, 6.2 Hz, 1H in CH2), 3.50 (dt, J¼13.0, 5.8 Hz, 1H in CH2), 3.87
(dddd, J¼8.8, 7.8, 6.2, 5.8 Hz, 1H, CH), 4.63 (q, J¼7.1 Hz, 2H, CH2),
5.05 (br s, 1H, NH), 6.94 (d, J¼7.7 Hz, 1H, ArH), 6.97 (d, J¼7.7 Hz, 1H,
ether/ethyl acetate¼5/1, v/v). 1H NMR (CDCl3, 400 MHz) (
d, ppm)
1.42 (t, J¼7.1 Hz, 3H, CH3), 1.43 (s, 9H, 3CH3), 1.82 (ddt, J¼14.5, 7.6,
7.3 Hz, 1H in CH2), 2.05 (ddt, J¼14.5, 8.5, 7.3 Hz, 1H in CH2), 2.14 (s,
3H, CH3), 2.64 (t, J¼7.3 Hz, 2H, CH2), 3.37 (dt, J¼13.4, 6.2 Hz, 1H in
CH2), 3.47 (dt, J¼13.4, 5.8 Hz, 1H in CH2), 3.82 (dddd, J¼8.5, 7.6, 6.2,
ArH), 7.47 (t, J¼7.7 Hz, 1H, ArH). 13C NMR (CDCl3, 101 MHz) (
d, ppm)
5.8 Hz, 1H, CH), 4.64 (q, J¼7.1 Hz, 2H, CH2), 4.86 (br s, 1H, NH). 13
C
13.7, 24.3, 28.3, 31.3, 35.2, 43.7, 51.2, 70.0, 79.3, 119.9, 120.8, 136.7,
155.8,157.9,160.0, 213.5. IR (nmax, cmꢁ1) 3343, 3136,1711, 1511,1217,
1049. HRMS (ESI) calcd for C18H29N2O3S2 [MþH]þ m/z 385.1620;
found 385.1613.
NMR (CDCl3, 101 MHz) (d, ppm) 13.7, 25.0, 28.3, 30.0, 40.5, 43.6,
51.2, 70.2, 79.6, 155.9, 207.5, 213.4. IR (nmax, cmꢁ1) 3359, 1711, 1514,
1223, 1050. HRMS (ESI) calcd for C14H25NNaO4S2 [MþNa]þ m/z
358.1123; found 358.1122.
4.2.9. S-(1-tert-Butoxycarbonylamino-4,4,4-trifluorobutan-2-yl)O-
ethyl dithiocarbonate (2i). The reaction was complete after addition
of 15 mol % of DLP. Pale yellow oil 726 mg, 86% yield. Rf¼0.26
(petroleum ether/ethyl acetate¼10/1, v/v). 1H NMR (CDCl3,
4.2.5. S-(1-tert-Butoxycarbonylamino-5-oxo-5-phenylpentan-
2-yl) O-ethyl dithiocarbonate (2e). The reaction was complete
after addition of 20 mol % of DLP. Yellow oil; yield: 668 mg, 84%.
Rf¼0.40 (petroleum ether/ethyl acetate¼5/1, v/v). 1H NMR
400 MHz) (d, ppm) 1.44 (s, 9H, 3CH3), 2.42e2.56 (m, 2H, CH2), 3.12
(CDCl3, 400 MHz) (
d
, ppm) 1.40 (t, J¼7.1 Hz, 3H, CH3), 1.43 (s, 9H,
(t, J¼7.2 Hz, 2H, CH2), 3.28e3.35 (m, 1H in CH2), 3.46e3.53 (m, 1H in
CH2), 3.95e3.99 (m, 1H, CH), 4.75e4.86 (m, 3H, CH2 & NH), 7.24 (d,
J¼7.2 Hz, 2H, ArH), 7.25 (t, J¼7.2 Hz, 1H, ArH), 7.33 (t, J¼7.7 Hz, 2H,
3CH3), 2.01 (ddt, J¼14.4, 8.5, 7.3 Hz, 1H in CH2), 2.24 (ddt, J¼14.4,
7.6, 7.3 Hz, 1H in CH2), 3.18 (t, J¼7.3 Hz, 2H, CH2), 3.42 (ddd,
J¼13.4, 6.2 Hz, 1H in CH2), 3.54 (ddd, J¼13.5, 5.8 Hz, 1H in CH2),
3.94 (dddd, J¼8.5, 7.6, 6.2, 5.8 Hz, 1H, CH), 4.61 (dq, J¼15.5, 7.1 Hz,
1H in CH2), 4.63 (dq, J¼15.5, 7.1 Hz, 1H in CH2), 4.92 (br s, 1H, NH),
7.46 (t, J¼7.6 Hz, 2H, ArH), 7.56 (t, J¼7.6 Hz, 1H, ArH), 7.95 (d,
ArH). 13C NMR (CDCl3, 101 MHz) (
d, ppm) 28.2, 29.5, 34.4, 35.7 (q,
JCeF¼28.9 Hz, CH2CF3), 44.6, 74.2, 79.9,125.6 (q, JCeF¼278.9 Hz, CF3),
126.8, 128.6, 128.8, 136.9, 155.8, 211.4. IR (nmax, cmꢁ1) 3349, 3065,
3029,1712, 1250, 1155, 1060. HRMS (ESI) calcd for C18H24F3NNaO3S2
[MþNa]þ m/z 446.1047; found 446.1051.
J¼7.6 Hz, 2H, ArH). 13C NMR (CDCl3, 101 MHz) (
d, ppm) 13.7, 25.0,
28.3, 40.5, 43.6, 51.1, 70.2, 79.5, 155.8, 207.4, 213.3. IR (nmax, cmꢁ1
)
3359, 3045, 1706, 1687, 1511, 1217, 1048. HRMS (ESI) calcd for
C
4.2.10. S-[(1-N-Benzyl-tert-butoxycarbonylamino-4-phthalimido)
butan-2-yl]O-ethyl dithiocarbonate (2j). The reaction was complete
after addition of 25 mol % of DLP. Pale yellow oil 888 mg, 84% yield.
Rf¼0.35 (petroleum ether/ethyl acetate¼5/1, v/v). 1H NMR (CDCl3,
19H27NNaO4S2 [MþNa]þ m/z 420.1279; found 420.1281.
4.2.6. S-(1-tert-Butoxycarbonylamino-4-cyanobutan-2-yl)O-ethyl
dithiocarbonate (2f). The reaction was complete after addition of
20 mol % of DLP. Yellow oil; yield: 458 mg, 72%. Rf¼0.14 (petroleum
400 MHz) (
d
, ppm) 1.40 (t, J¼7.1 Hz, 3H, CH3), 1.42 [1.49 (Rotamer)]
(s, 9H, 3CH3), 1.95 (ddt, J¼14.4, 7.6, 7.2 Hz, 1H in CH2), 2.14 (s, 1H in
CH2), 3.41 (dd, J¼14.4, 7.6 Hz, 1H in CH2), 3.51 [3.72 (Rotamer)] (s,
1H, CH), 3.76 (dd, J¼14.4, 6.4 Hz, 1H in CH2), 3.84 (s, 1H in CH2), 3.94
(s, 1H in CH2), 4.47e4.60 (m, 2H, CH2), 4.59 (q, J¼7.1 Hz, 2H, CH2),
7.19e7.31 (m, 5H, ArH), 7.72 (dd, J¼5.5, 3.1 Hz, 2H, ArH), 7.84 (dd,
ether/ethyl acetate¼5/1, v/v). 1H NMR (CDCl3, 400 MHz) (
d, ppm)
1.43 (t, J¼7.1 Hz, 3H, CH3), 1.44 (s, 9H, 3CH3), 2.01 (dddd, J¼14.5, 8.5,
7.6, 6.2 Hz,1H in CH2), 2.15 (dddd, J¼14.5, 8.8, 7.8, 6.2 Hz,1H in CH2),
2.54 (ddd, J¼15.5, 7.8, 6.2 Hz, 1H in CH2), 2.62 (ddd, J¼15.5, 8.5,
6.2 Hz, 1H in CH2), 3.42 (dt, J¼13.8, 6.3 Hz, 1H in CH2), 3.49 (dt,
J¼13.8, 6.0 Hz,1H in CH2), 3.92 (dddd, J¼8.8, 7.6, 6.3, 6.0 Hz,1H, CH),
4.66 (q, J¼7.1 Hz, 2H, CH2), 4.86 (br s, 1H, NH). 13C NMR (CDCl3,
J¼5.5, 3.1 Hz, 2H, ArH). 13C NMR (CDCl3, 101 MHz) (
d, ppm) 13.6
[14.0 (Rotamer)], 28.3 [26.8 (Rotamer)], 30.2 [30.8 (Rotamer)], 35.7,
47.6 [47.8 (Rotamer)], 49.3, 50.2 [50.9 (Rotamer)], 70.0, 80.2 [80.4
(Rotamer)], 123.1, 127.1, 127.7, 128.4, 132.0, 133.8, 138.2, 155.8, 168.0,
213.2 [213.5 (Rotamer)]. IR (nmax, cmꢁ1) 3474, 3062, 3029, 1772,
1713, 1225, 1049. HRMS (ESI) calcd for C27H32N2NaO5S2 [MþNa]þ
m/z 551.1650; found 551.1647.
101 MHz) (d, ppm) 13.7, 15.0, 27.4, 28.3, 43.1, 50.6, 70.6, 79.9, 118.8,
155.9, 212.0. IR (nmax, cmꢁ1) 3354, 3053, 2248, 1707, 1512, 1224,
1048. HRMS (ESI) calcd for C13H23N2O3S2 [MþH]þ m/z 319.1150;
found 319.1146.
4.2.7. S-[4-(Benzothiazol-2-yl)-1-tert-butoxycarbonylaminobutan-
2-yl]O-ethyl dithiocarbonate (2g). The reaction was complete after
addition of 25 mol % of DLP. Yellow oil; yield: 273 mg, 32%. Rf¼0.25
(petroleum ether/ethyl acetate¼5/1, v/v). 1H NMR (CDCl3, 400 MHz)
4.3. General procedure for the synthesis of 5-substituted
thiazolidin-2-ones 3
To a solution of xanthate 2 (1 mmol) in acetonitrile (5 mL) was
added 88% formic acid (784 mg, 15 mmol). The resulting solution
was heated to reflux for 12 h. After removal of the solvent, the
residue was purified by column chromatography on silica gel (pe-
troleum ether/ethyl acetate: 3/1 to 1/2, v/v) to afford thiazolidin-2-
one 3 in good yield.
(d
, ppm) 1.40 (t, J¼7.1 Hz, 3H, CH3), 1.44 (s, 9H, 3CH3), 2.19 (dddd,
J¼14.5, 8.8, 7.6, 6.2 Hz, 1H in CH2), 2.38 (dddd, J¼14.5, 9.2, 8.8,
6.4 Hz, 1H in CH2), 3.27 (ddd, J¼15.2, 8.8, 6.4 Hz, 1H in CH2), 3.34
(ddd, J¼15.2, 9.2, 6.2 Hz, 1H in CH2), 3.43 (dt, J¼13.6, 6.3 Hz, 1H in
CH2), 3.55 (dt, J¼13.6, 5.8 Hz, 1H in CH2), 3.98 (dddd, J¼8.8, 7.6, 6.3,

Z. Huang, J. Xu / Tetrahedron 69 (2013) 10272e10278
10277
4.3.1. 5-(2-Phthalimidoethyl)thiazolidin-2-one (3a). White solid;
mp: 171e172 ꢀC; yield: 226 mg, 82%. Rf¼0.27 (petroleum ether/
(ddd, J¼16.0, 7.6, 6.8 Hz, 1H in CH2), 3.37 (ddd, J¼10.1, 5.2, 1.2 Hz, 1H
in CH2), 3.82 (ddd, J¼10.1, 7.2, 0.6 Hz, 1H in CH2), 3.93 (ddt, J¼9.2,
ethyl acetate¼2/1, v/v). 1H NMR (CDCl3, 400 MHz) (
d
, ppm)
5.2, 7.2 Hz,1H, CH), 6.40 (br s, 1H, NH). 13C NMR (CDCl3,101 MHz) (
d,
2.11e2.24 (m, 2H, CH2), 3.36e3.40 (m, 1H, CH), 3.76e3.85 (m, 4H,
2CH2), 6.42 (br s, 1H, NH), 7.74 (dd, J¼5.2, 3.0 Hz, 2H, ArH), 7.85 (dd,
ppm) 15.2, 31.3, 45.0, 48.2, 118.3, 174.2. IR (nmax, cmꢁ1) 3268, 2246,
1680, 1075. HRMS (ESI) calcd for C6H9N2OS [MþH]þ m/z 157.0436;
found 157.0426.
J¼5.2, 3.0 Hz, 2H, ArH). 13C NMR (CDCl3, 101 MHz) (
d, ppm) 34.4,
35.6, 44.1, 48.5, 123.3, 131.8, 134.1, 168.2, 175.1. IR (nmax, cmꢁ1) 3349,
3054, 1769, 1707, 1088, 1049. HRMS (ESI) calcd for C13H13N2O3S
[MþH]þ m/z 277.0647; found 277.0643.
4.3.7. 5-[2-(Benzothiazol-2-yl)ethyl]thiazolidin-2-one (3g). Orange
solid; mp: 98e99 ꢀC; yield: 206 mg, 78%. Rf¼0.15 (petroleum ether/
ethyl acetate¼1/1, v/v). 1H NMR (CDCl3, 400 MHz) (
d, ppm) 2.42
4.3.2. Methyl 3-(2-oxothiazolidin-5-yl)propanoate (3b). Brown oil;
yield: 168 mg, 89%. Rf¼0.13 (petroleum ether/ethyl acetate¼2/1, v/
(dddd, J¼14.4, 8.4, 7.6, 6.8 Hz, 1H in CH2), 2.43 (dddd, J¼14.4, 9.6,
8.6, 6.0 Hz,1H in CH2), 3.21 (ddd, J¼15.8, 8.6, 6.8 Hz,1H in CH2), 3.26
(ddd, J¼15.8, 7.6, 6.0 Hz,1H in CH2), 3.38 (ddd, J¼10.1, 5.2, 0.8 Hz,1H
in CH2), 3.77 (dd, J¼10.1, 7.2, 0.6 Hz, 1H in CH2), 3.97 (ddt, J¼9.6, 8.4,
7.2, 5.2 Hz, 1H, CH), 6.23 (br s, 1H, NH), 7.37 (dt, J¼8.0, 0.8 Hz, 1H,
ArH), 7.46 (dt, J¼8.0, 1.2 Hz, 1H, ArH), 7.84 (d, J¼8.0 Hz, 1H, ArH),
v). 1H NMR (CDCl3, 400 MHz) (
d
, ppm) 2.07 (dddd, J¼14.5, 8.6, 7.2,
6.4 Hz, 1H in CH2), 2.14 (dddd, J¼14.5, 8.8, 7.6, 6.8 Hz, 1H in CH2),
2.43 (ddd, J¼16.0, 7.6, 6.4 Hz, 1H in CH2), 2.49 (ddd, J¼16.0, 8.6,
6.8 Hz, 1H in CH2), 3.33 (ddd, J¼10.1, 5.2, 0.8 Hz, 1H in CH2), 3.70 (s,
3H, CH3), 3.75 (ddd, J¼10.1, 7.2, 0.6 Hz, 1H in CH2), 3.87 (ddt, J¼8.8,
7.96 (d, J¼8.0 Hz, 1H, ArH). 13C NMR (CDCl3, 101 MHz) (
d, ppm) 31.6,
5.2, 7.2 Hz,1H, CH), 6.39 (br s,1H, NH). 13C NMR (CDCl3,101 MHz) (
d,
34.7, 45.8, 48.5, 121.5, 122.6, 124.9, 126.0, 135.0,153.1, 169.4, 174.9. IR
ppm) 30.5, 31.4, 45.9, 48.7, 51.8, 172.8, 175.1. IR (nmax, cmꢁ1) 3255,
1732, 1681, 1076. HRMS (ESI) calcd for C7H12NO3S [MþH]þ m/z
190.0538; found 190.0531.
(
nmax, cmꢁ1) 3351, 3209, 3071, 1677, 1074. HRMS (ESI) calcd for
C
12H13N2OS2 [MþH]þ m/z 265.0469; found 265.0463.
4.3.8. 5-[2-(6-Methylpyridin-2-yl)ethyl]thiazolidin-2-one
(3h). Orange solid; mp: 87e88 ꢀC; yield: 180 mg, 81%. Rf¼0.28
(petroleum ether/ethyl acetate¼1/2, v/v). 1H NMR (CDCl3,
4.3.3. Diethyl[(2-oxothiazolidin-5-yl)methyl]malonate
(3c). Colorless solid; mp: 68e69 ꢀC; yield: 201 mg, 73%. Rf¼0.49
(petroleum ether/ethyl acetate¼1/2, v/v). 1H NMR (CDCl3,
400 MHz) (
d
, ppm) 2.18 (ddt, J¼14.4, 6.4, 7.6 Hz, 1H in CH2), 2.26
400 MHz) (
d
, ppm) 1.28 (t, J¼7.1 Hz, 3H, CH3), 1.29 (t, J¼7.1 Hz, 3H,
(dddd, J¼14.4, 8.4, 7.2, 6.0 Hz, 1H in CH2), 2.52 (s, 3H, CH3), 2.81
(ddd, J¼16.2, 7.6, 6.0 Hz,1H in CH2), 2.88 (ddd, J¼16.2, 7.2, 6.4 Hz,1H
in CH2), 3.34 (dd, J¼10.1, 6.4 Hz, 1H in CH2), 3.71 (dd, J¼10.1, 7.2 Hz,
1H in CH2), 3.87 (dddd, J¼8.4, 7.6, 7.2, 6.4 Hz, 1H, CH), 5.96 (br s, 1H,
NH), 6.94 (d, J¼7.6 Hz, 1H, ArH), 7.00 (d, J¼7.6 Hz, 1H, ArH), 7.49 (t,
CH3), 2.32 (ddd, J¼14.2, 9.0, 7.2 Hz, 1H in CH2), 2.40 (ddd, J¼14.2,
9.2, 5.6 Hz,1H in CH2), 3.34 (ddd, J¼10.1, 5.6, 0.9 Hz, 1H in CH2), 3.50
(dd, J¼9.0, 5.6 Hz, 1H, CH), 3.76 (dd, J¼10.1, 7.2, 0.6 Hz, 1H in CH2),
3.86 (ddt, J¼9.2, 5.6, 7.2 Hz, 1H, CH), 4.17e4.26 (m, 4H, 2CH2), 6.23
(br s, 1H, NH). 13C NMR (CDCl3, 101 MHz) (
d
, ppm) 13.9, 14.0, 34.4,
J¼7.6 Hz, 1H, ArH). 13C NMR (CDCl3, 101 MHz) (
d, ppm) 24.4, 35.4,
44.4, 48.7, 49.8, 61.8, 61.9, 168.4, 168.5, 174.7. IR (nmax, cmꢁ1) 3330,
3244, 1729, 1682, 1215,1065, 1030. HRMS (ESI) calcd for C11H18NO5S
[MþH]þ m/z 276.0906; found 276.0902.
35.9, 46.5, 48.7,119.8,121.0,136.8,158.0,159.3,175.3. IR (nmax, cmꢁ1
)
3239, 3061, 1678, 1075. HRMS (ESI) calcd for C11H15N2OS [MþH]þ
m/z 223.0905; found 223.0898.
4.3.4. 5-(3-Oxobutyl)thiazolidin-2-one (3d). Colorless oil; yield:
125 mg, 72%. Rf¼0.16 (petroleum ether/ethyl acetate¼1/1, v/v). 1H
4.3.9. 5-(2,2,2-Trifluoroethyl)thiazolidin-2-one (3i). White solid;
mp: 98e100 ꢀC; yield: 155 mg, 84%. Rf¼0.28 (petroleum ether/ethyl
NMR (CDCl3, 400 MHz) (
d, ppm) 1.98 (dddd, J¼14.4, 7.6, 7.2, 6.4 Hz,
acetate¼2/1, v/v). 1H NMR (CDCl3, 400 MHz) (
d, ppm) 2.52e2.72 (m,
1H in CH2), 2.11 (dddd, J¼14.4, 9.6, 7.6, 6.0 Hz,1H in CH2), 2.17 (s, 3H,
CH3), 2.56 (ddd, J¼16.4, 7.2, 6.0 Hz,1H in CH2), 2.63 (ddd, J¼16.4, 7.6,
6.4 Hz, 1H in CH2), 3.31 (ddd, J¼10.1, 5.2, 1.2 Hz, 1H in CH2), 3.73
(ddd, J¼10.1, 7.2, 0.6 Hz, 1H in CH2), 3.88 (dddd, J¼9.6, 7.6, 7.2,
2H, CH2), 3.44 (dd, J¼10.4, 6.4 Hz, 1H in CH2), 3.80 (dd, J¼10.4,
7.2 Hz, 1H in CH2), 4.10 (tt, J¼7.2, 6.4 Hz, 1H, CH), 6.66 (br s, 1H, NH).
13C NMR (CDCl3, 100 MHz) (
d
, ppm) 39.1 (q, JCeF¼28.6 Hz, CH2CF3),
39.5 (q, JCeF¼2.8 Hz, CHS), 48.3, 125.2 (q, JCeF¼278.7 Hz, CF3), 174.7.
IR (nmax, cmꢁ1) 3225, 3086, 1678, 1254, 1146, 1068. HRMS (ESI)
calcd for C5H7F3NOS [MþH]þ m/z 186.0200; found 186.0196.
5.2 Hz, 1H, CH), 6.16 (br s, 1H, NH). 13C NMR (CDCl3, 101 MHz) (
d,
ppm) 29.1, 30.0, 40.7, 46.1, 48.8, 175.0, 207.1. IR (nmax, cmꢁ1) 3245,
1677, 1075. HRMS (ESI) calcd for C7H12NO2S [MþH]þ m/z 174.0589;
found 174.0581.
4.3.10. 2-Benzyl-5-(2-phthalimidoethyl)thiazolidin-2-one (3j). The
reaction was heated to reflux for 2 h. Colorless oil; yield: 311 mg,
85%. Rf¼0.32 (petroleum ether/ethyl acetate¼2/1, v/v). 1H NMR
4.3.5. 5-(3-Oxo-3-phenylpropyl)thiazolidin-2-one
(3e). Colorless
crystals; mp: 167e169 ꢀC; yield: 188 mg, 80%. Rf¼0.19 (petroleum
(CDCl3, 400 MHz) (
d, ppm) 2.03 (dddd, J¼14.4, 8.6, 7.2, 6.4 Hz, 1H in
ether/ethyl acetate¼1/1, v/v). 1H NMR (CDCl3, 400 MHz) (
d, ppm)
CH2), 2.09 (dddd, J¼14.4, 7.6, 7.4, 6.8 Hz,1H in CH2), 3.20 (dd, J¼10.1,
6.0 Hz, 1H in CH2), 3.59 (dddd, J¼8.6, 7.6, 7.2, 6.0 Hz, 1H, CH), 3.64
(dd, J¼10.1, 7.2 Hz, 1H in CH2), 3.72 (ddd, J¼14.0, 7.2, 6.8 Hz, 1H in
CH2), 3.76 (ddd, J¼14.0, 7.4, 6.4 Hz,1H in CH2), 4.41 (d, J¼15.0 Hz,1H
in CH2), 4.54 (d, J¼15.0 Hz, 1H in CH2), 7.23e7.36 (m, 5H, ArH), 7.73
(dd, J¼5.2, 3.0 Hz, 2H, ArH), 7.83 (dd, J¼5.2, 3.0 Hz, 2H, ArH). 13C
2.18 (dddd, J¼14.4, 8.6, 7.6, 6.4 Hz, 1H in CH2), 2.31 (dddd, J¼14.4,
9.2, 7.8, 6.0 Hz, 1H in CH2), 3.11 (ddd, J¼16.4, 7.8, 6.4 Hz, 1H in CH2),
3.19 (ddd, J¼16.4, 8.6, 6.0 Hz, 1H in CH2), 3.38 (dd, J¼10.1, 5.2, 1.2 Hz,
1H in CH2), 3.78 (dd, J¼10.1, 7.2, 0.6 Hz, 1H in CH2), 3.99 (dddd,
J¼9.2, 7.6, 7.2, 5.2 Hz, 1H, CH), 5.92 (br s, 1H, NH), 7.48 (t, J¼7.6 Hz,
2H, ArH), 7.58 (t, J¼7.6 Hz, 1H, ArH), 7.96 (d, J¼7.6 Hz, 2H, ArH). 13
C
NMR (CDCl3, 101 MHz) (
d, ppm) 34.7, 35.5, 39.3, 48.5, 53.1, 123.3,
NMR (CDCl3, 101 MHz) (
d
, ppm) 29.7, 35.8, 46.4, 48.9, 128.0, 128.7,
127.8, 128.0, 128.8, 131.8, 134.1, 135.8, 168.1, 171.1. IR (nmax, cmꢁ1
)
133.4, 136.5, 174.8, 198.6. IR (nmax, cmꢁ1) 3308, 3228, 3045, 1677,
1660, 1088, 1050. HRMS (ESI) calcd for C12H14NO2S [MþH]þ m/z
236.0745; found 236.0742.
3464, 3058, 3030, 1771, 1711, 1674, 1214, 1043. HRMS (ESI) calcd for
C
20H19N2O3S [MþH]þ m/z 367.1116; found 367.1118.
4.3.11. 5-(2-Phthalimidoethyl)thiazolidine-2-thione
(4). White
4.3.6. 5-(2-Cyanoethyl)thiazolidin-2-one (3f). Orange solid; mp:
71e72 ꢀC; yield: 133 mg, 85%. Rf¼0.14 (petroleum ether/ethyl
solid; mp: 112e113 ꢀC. Rf¼0.56 (petroleum ether/ethyl acetate¼1/2,
v/v). 1H NMR (CDCl3, 400 MHz) (
d
, ppm) 2.16 (ddt, J¼15.0, 7.6,
acetate¼1/1, v/v). 1H NMR (CDCl3, 400 MHz) (
d
, ppm) 2.12 (dddd,
6.8 Hz, 1H in CH2), 2.21 (ddt, J¼15.0, 8.4, 6.8 Hz, 1H in CH2), 3.74 (dd,
J¼11.2, 4.8 Hz, 1H in CH2), 3.80 (t, J¼6.8 Hz, 1H in CH2), 3.81 (t,
J¼6.8 Hz, 1H in CH2), 3.94 (ddt, J¼8.4, 4.8, 7.6 Hz, 1H, CH), 4.12 (dd,
J¼14.4, 8.0, 7.2, 6.8 Hz, 1H in CH2), 2.18 (dddd, J¼14.4, 9.2, 7.6,
6.4 Hz, 1H in CH2), 2.49 (ddd, J¼16.0, 8.0, 6.4 Hz, 1H in CH2), 2.56

10278
Z. Huang, J. Xu / Tetrahedron 69 (2013) 10272e10278
J¼11.2, 7.6 Hz, 1H in CH2), 7.43 (br s, 1H, NH), 7.75 (dd, J¼5.2, 3.0 Hz,
2H, ArH), 7.86 (dd, J¼5.2, 3.0 Hz, 2H, ArH). 13C NMR (CDCl3,
After removal of the solvent, the residue was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate: 4/1, v/
v) to afford 2-butylthio-5-(2-phthalimidoethyl)thiazoline (3k) as
pale yellow oil 63 mg, 72% yield. Rf¼0.35 (petroleum ether/ethyl
101 MHz) (d, ppm) 33.9, 35.4, 47.9, 55.8, 123.4, 131.8, 134.2, 168.2,
201.2. IR (nmax, cmꢁ1) 3294, 3054, 1769, 1708, 1087, 1048. HRMS
(ESI) calcd for
293.0414.
C
13H13N2O2S2 [MþH]þ m/z 293.0418; found
acetate¼3/1, v/v). 1H NMR (CDCl3, 400 MHz) (
d, ppm) 0.92 (t,
J¼7.2 Hz, 3H, CH3), 1.42 (hextet, J¼7.2 Hz, 2H, CH2), 1.62e1.70 (m,
2H, CH2), 1.92e2.08 (m, 2H, CH2), 3.05 (dt, J¼12.8, 7.2 Hz, 1H in
CH2), 3.10 (dt, J¼12.8, 7.6 Hz, 1H in CH2), 3.74 (ddd, J¼13.6, 8.0,
6.4 Hz, 1H in CH2), 3.78 (ddd, J¼13.6, 7.2, 6.8 Hz, 1H in CH2),
3.84e3.90 (m, 1H, CH), 4.08 (dd, J¼14.8, 4.0 Hz, 1H in CH2), 4.18 (dd,
J¼14.8, 7.6 Hz, 1H in CH2), 7.75 (dd, J¼5.2, 3.0 Hz, 2H, ArH), 7.87 (dd,
4.3.12. Phenethyl formate.15 Colorless liquid; yield: 109 mg, 72%.
Rf¼0.56 (petroleum ether/ethyl acetate¼10/1, v/v). 1H NMR (CDCl3,
400 MHz) (
d
, ppm) 2.97 (t, J¼7.2 Hz, 2H, CH2), 4.38 (t, J¼7.2 Hz, 2H,
CH2), 7.21e7.25 (m, 3H, ArH), 7.31 (t, J¼7.2 Hz, 2H, ArH), 8.03 (s, 1H,
CH). 13C NMR (CDCl3, 101 MHz) (
128.8, 137.3, 160.9.
d
, ppm) 34.9, 64.3, 126.7, 128.5,
J¼5.2, 3.0 Hz, 2H, ArH). 13C NMR (CDCl3, 101 MHz) (
d, ppm) 13.5,
21.8, 31.2, 32.4, 34.7, 36.1, 50.5, 69.3, 123.3, 131.9, 134.0, 165.1, 168.2.
IR (nmax, cmꢁ1) 3464, 1767, 1711, 1030. HRMS (ESI) calcd for
4.4. Synthesis of trithiocarbonate 2k and acid-catalyzed cy-
clization reaction
C
17H21N2O2S2 [MþH]þ m/z 349.1044; found 349.1043.
Acknowledgements
Butanethiol (902 mg, 10 mmol), carbon disulfide (761 mg,
10 mmol), and THF (5 mL) were placed in 25 mL round-bottomed
flask. A solution of KOH (561 mg, 10 mol) in 3 mL of water was
added dropwise under stirring at room temperature. The resulting
solution was stirred at room temperature for a further 15 min. Then
the solution was added slowly into a solution of N-(chloromethyl)
phthalimide (1.96 g, 10 mmol) in acetone (10 mL). The reaction
mixture was stirred for 30 min. After removal of the solvent, the
residue was diluted with ethyl acetate (100 mL). The solution was
washed sequentially with water (2ꢂ50 mL) and saturated brine
(2ꢂ50 mL), dried over anhydrous Na2SO4, and the solvent was re-
moved by rotary evaporation, the residue was recrystallized from
a mixture of petroleum ether and ethyl acetate to give S-[(1-tert-
butoxycarbonylamino-4-phthalimido)butan-2-yl] S0-butyl trithio-
carbonate (1k) as yellow crystals 2.86 g, 88% yield, mp: 89e91 ꢀC.
This work was supported by the National Basic Research Pro-
gram of China (No. 2013CB328905) and the National Natural Sci-
ence Foundation of China (Project No 20973013).
Supplementary data
Copies of the 1H NMR and 13C NMR spectra of all key in-
termediates and final products are available. Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.10.031. These data include MOL files and InChiKeys of the
most important compounds described in this article.
References and notes
Lit.17 89e91 ꢀC. 1H NMR (CDCl3, 400 MHz) (
d, ppm) 0.93 (t, J¼7.2 Hz,
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3H, CH3), 1.42 (hextet, J¼7.2 Hz, 2H, CH2), 1.64e1.72 (m, 2H, CH2),
3.37 (t, J¼7.2 Hz, 2H, CH2), 5.65 (s, 2H, CH2), 7.75 (dd, J¼5.2, 3.0 Hz,
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166.6, 220.8.
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(
d
, ppm) 0.92 (t, J¼7.1 Hz, 3H, CH3), 1.38e1.45 (m, 2H, CH2), 1.43 (s,
9H, 3CH3), 1.61e1.68 (m, 2H, CH2), 2.04 (ddt, J¼15.0, 8.0, 7.2 Hz, 1H
in CH2), 2.15 (ddt, J¼15.0, 8.6, 7.2 Hz, 1H in CH2), 3.31 (t, J¼7.2 Hz,
2H, CH2), 3.48e3.58 (m, 2H, CH2), 3.77e3.93 (m, 2H, CH2), 4.31 (ddt,
J¼8.6, 6.0, 7.2 Hz, 1H, CH), 4.82 (br s, 1H, NH), 7.72 (dd, J¼5.5, 3.1 Hz,
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101 MHz) (d, ppm) 13.5, 22.0, 28.3, 29.8, 30.3, 35.5, 36.7, 43.1, 49.6,
79.6, 123.2, 132.0, 133.9, 168.1, 223.2. IR (nmax, cmꢁ1) 3367, 1773,
1713, 1167, 1050. HRMS (ESI) calcd for C22H30N2NaO4S3 [MþNa]þ m/
z 505.1265; found 505.1267.
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0.25 mmol) in acetonitrile (2.5 mL) was added 88% formic acid
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