Preparation of 1,3-Thiazolidine-2-thiones by Using Potassium Ethylxanthate as a Carbon Disulfide Surrogate

Article abstract of DOI:10.1055/s-0037-1612124

A simple procedure is presented for preparing 1,3-thiazolidine-2-thiones by using potassium ethylxanthate and the corresponding β -amino alcohols as the starting materials in the presence of ethanol.

Full text of DOI:10.1055/s-0037-1612124

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
Z. Lu et al.
Letter
Synlett
Preparation of 1,3-Thiazolidine-2-thiones by Using Potassium
Ethylxanthate as a Carbon Disulfide Surrogate
Zheng Lu
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1-9
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5-8
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S
S
CS2 free
9 examples
up to 96% yield
Yong-Qing Yang*
Weixiang Xiong
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8
6
9-
9
9
5
6
HO
NH2
R2
R1
S
NH
R2
R1
K S
O
*
*
EtOH
R1, R2 = H, alkyl or aryl
School of Pharmacy, Jiangsu University,
No. 301 Xuefu Road, Zhenjiang, Jiangsu
Province 212013, P. R. of China
yqy@ujs.edu.cn
Received: 12.11.2018
Accepted after revision: 17.01.2019
Published online: 21.02.2019
In our previous researches, we found that potassium
ethylxanthate [KSC(S)OEt] can be employed to form chiral
1,3-oxazolidine-2-thiones 3 from vicinal amino alcohols in
good to excellent yields (Scheme 1).11 On a further detailed
study of this reaction, we found that the major byproducts
generated for some substrates were the 1,3-thiazolidine-2-
thiones 2. This eventually became a good starting point for
the development of a new approach for the synthesis of 1,3-
thiazolidine-2-thiones 2, as reported below.
DOI: 10.1055/s-0037-1612124; Art ID: st-2018-w0738-l
Abstract A simple procedure is presented for preparing 1,3-thiazoli-
dine-2-thiones by using potassium ethylxanthate and the correspond-
ing -amino alcohols as the starting materials in the presence of etha-
nol.
Key words thiazolidinethiones, chiral auxiliaries, potassium ethylxan-
thate, green chemistry, heterocycles, amino alcohols
S
KSCSOEt
(5.0 equiv)
1,3-Thiazolidine-2-thiones are a class of compounds
that are extensively studied in organic chemistry. They are
used as chiral auxiliaries in asymmetric aldol addition in
modern asymmetric syntheses,1 and they can be used as
precursors to -lactams (through oxidation and extrusion
of SO2)2 or alkenes (induced by benzyne).3 They can also be
used as twisted amides to induce asymmetric acylation of
secondary alcohols,4 or as sulfur donor in the preparation of
heterotricyclic compounds5a,b or 2-methylthiiranes.5c
Among these applications, their use as chiral auxiliaries is
the most familiar. In the formation of two adjacent chiral
carbon centers by asymmetric aldol condensation, 1,3-thi-
azolidine-2-thiones can act as powerful chiral auxiliaries
that can be readily removed at a later stage.6 Furthermore,
they can be easily removed after their use in asymmetric al-
dol reactions, and they can provide high diastereoselectivi-
ties in acetate-type aldol reactions.7 However, the use of
1,3-thiazolidine-2-thiones has been limited by difficulties
in their preparation. Carbon disulfide (CS2) is an essential
reagent for building these heterocycles from vicinal amino
alcohols1g,6a,8 or aziridines;9 however, because it is volatile
and highly flammable, CS2 is classified as a highly hazard-
ous solvent according to the solvent-selection guides of
pharmaceutical companies.10
S
NH
R2
R1
our current work
our previous work
R3
R4
EtOH, 100 °C
sealed, N2, 24 h
HO
R4
R3
NH2
R2
R1
2
KSCSOEt
(2.5 equiv)
S
1
O
R4
R3
NH
R2
R1
EtOH, reflux, 1 h
3
Scheme 1 Formation of 1,3-thiazolidine-2-thiones 2 and 1,3-oxazoli-
dine-2-thiones 3 from vicinal amino acids 1 and potassium ethylxan-
thate
Using (2R)-2-amino-2-phenylethanol (1a) as a standard
substrate, we investigated the reaction conditions for the
synthesis of (4R)-4-phenyl-1,3-thiazolidine-2-thione (2a)
to (4R)-4-phenyl-1,3-oxazolidine-2-thione (3a) in various
ratios by mixing 1a with KSC(S)OEt in EtOH and refluxing
in an oil bath heated to 100 °C.
As shown in Table 1, when 2.5 equivalents of KSC(S)OEt
were employed and the mixture was refluxed for one hour,
3a was isolated exclusively in 88% yield (Table 1, entry 1).
However, when the reaction period was extended to eight
hours, the yield of 3a fell significantly and 2a was isolated
in 29% yield (entry 2). On extending the reaction time to 18
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
Z. Lu et al.
Letter
Synlett
Table 1 Optimization of the Conditions for the CS2-Free Conversion of
(R)-2-phenylglycinol (1a) into the 1,3-Thiazolidine-2-thione 2a and the
1,3-Oxadiazoline-2-thione 3a in the Presence of Potassium Ethylxan-
thate
mized conditions, a multigram-scale preparation was found
to be feasible and gave an equally good outcome in terms of
the yield and selectivity to that of the small-scale prepara-
tion (entry 14).
Having identified the optimal conditions, we next ex-
amined the scope of the reaction with respect to the use of
various vicinal amino alcohols 1 for the synthesis of 1,3-thi-
azolidine-2-thiones 2 (Scheme 2). Nine amino alcohols
with different substituents 1a–i generally provided the cor-
responding products 2 in good to excellent yields, except for
1f and 1h. The chiral centers of amino alcohols 1a–g and 1i
were retained in the corresponding 1,3-thiazolidine-2-thi-
ones. It was clear that the substituents had significant im-
pact on this reaction. Appropriate substituent on the car-
bon adjacent to nitrogen in the amino acid increased the
yield of the 1,3-thiazolidine-2-thiones (compare 2c with 2a,
2b, 2d, 2e, and 2i). However, when R1 (or R2) was a tertiary
alkyl group rather than a methyl group or a primary or sec-
ondary alkyl group, the oxazolidine-2-thione was formed
in preference to the 1,3-thiazolidine-2-thione 2f. The strain
induced by a fused ring also increased the difficulty of
forming the five-membered heterocyclic ring (2g). When
R3 = R4 = Me, no 1,3-thiazolidine-2-thione was formed at all,
and the oxazolidine-2-thione 3h was isolated exclusively.
S
S
S
NH
O
NH
HO
NH2
KSCSOEt
+
solvent, reflux
1a
2a
3a
Entry
KSC(S)OEt
(equiv)
Solvent
Time (h)
Yield (%)
of 2a
Yield (%)
of 3a
1a
2a
2.5
2.5
1.5
2.5
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
–
1
8
0
29
11
45
51
26
37
82
74
78
80
48
7
88
52
58
7
3a
8
4a
18
18
18
18
24
24
24
24
24
24
24
5ab
24
37
0
6c
7d
8abe
9abe
10abe
11abe
12abe
13abe
14bef
EtOH
i-PrOH
PrOH
BuOH
DMF
10
3
2
S
6
NH2
R2
R1
HO
R4
R3
KSCSOEt
EtOH
S
NH
R2
R1
3
R4
R3
DMSO
EtOH
12
7
1
2
82
S
S
S
a The reaction was carried out on a 1.0 mmol scale of amino alcohol 1a
(concentration 0.5 mol/L).
X
NH
Ph
S
NH
Bn
S
NH
b Under N2.
c The reaction was carried out on a 1.0 mmol scale of amino alcohol 1a
(concentration 0.1 mol/L)..
2a X = S 82%
3a X = O 10%
2b 83%
2c 55%
d No solvent.
e The reaction was carried out in an autoclave.
f The reaction was carried out on a 15.0 mmol scale of amino alcohol 1a
(concentration 0.5 mol/L).
S
S
S
X
NH
S
NH
S
NH
hours, the yield of 2a improved further to 45% (entry 4). In-
creasing the amount of KSC(S)OEt to 5.0 equivalents result-
ed in a slightly increase in the yield of 2a (entry 5). When
the reaction was carried out in more-dilute solution, 3a was
formed in preference to 2a (entry 6). With no solvent, no 3a
was detected and 2a was isolated in poor yield (entry 7).
Then the reaction was carried out in an autoclave under N2,
2a was obtained in 82% yield, although 3a was also isolated
in 10% yield (entry 8). To examine the effect of the solvent,
several polar solvents were screened. The reaction proceed-
ed fairly well in the protic solvents i-PrOH, PrOH, and BuOH
(entries 9–11), although the yields were not as good as that
in ethanol. On the other hand, yields in the aprotic solvent
DMF or DMSO were poor (entries 12 and 13). Because 2a is
a useful chiral auxiliary in stereoselective synthesis, the
ability to prepare this compound on a multigram scale is
pivotal for the practicability of our method. Under the opti-
2d 85%
2e 96%
2f X = S 35%
3f X = O 65%
S
S
S
N
S
NH
S
X
NH
2g 47%
2h X = S 0%
3h X = O 80%
2i 86%
Scheme 2 Screening of the scope of formation of 1,3-thiazolidine-2-
thiones 2. An autoclave was charged with the amino alcohol 1 (1.0
mmol, 0.5 mol L–1) and potassium ethylxanthate (5.0 equiv) then
flushed with N2 for 5 min and heated at 100 °C in an oil bath for 24 h.
To explore the mechanism of our CS2-free synthesis of
1,3-thiazolidine-2-thiones (2), we used two isomers with
different geometries as substrates (Scheme 3). When
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

C
Z. Lu et al.
Letter
Synlett
(1S,2R)-1-aminoindan-2-ol (1j) was used under the stan-
dard conditions, (3aS,8aR)-3,3a,8,8a-tetrahydro-2H-inde-
no[1,2-d][1,3]oxazole-2-thione12 (3j) was isolated in 59%
yield and none of the corresponding 1,3-thiazolidine-2-thi-
one 2j was detected. However, trans-1-amino-2-indanol
(1k) gave cis-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]-
oxazole-2-thione7c (2k) in 18% yield, and none of the corre-
sponding 1,3-oxazolidine-2-thione 3k was isolated. These
results clearly show that the geometry of the vicinal amino
alcohol is intimately involved in the formation of the het-
erocycle, which provided strong proof for our proposed
mechanism (see below).
S
K S
O
S
S
NH
R2
R1
NH2
R2
HO
R4
HO
R4
R3
R1
R3
1
A
S
S
S
S
S
-
R4
R3
HS
NH
R2
R1
HS
S
K S
O
NH
R2
O
NH
R2
R1
O
R4
R4
O
S
R1
R3
S
R3
HS
D
C
B
S
S
– SH
S
S
NH
O
NH
NH2
HO
KSCSOEt
EtOH
+ SH
HS
O
+
S
S
1j
NH
2j
3j
NH
S
O
R2
R1
R2
R1
R3
0%
59%
R4
R4
R3
S
S
2
3
NH2
HO
S
NH
O
NH
KSCSOEt
EtOH
Scheme 4 Plausible mechanism for the formation of 1,3-thiazolidine-
2-thiones 2 and 1,3-oxazolidine-2-thiones 3 from vicinal amino alcohols
and KSC(S)OEt
+
1k
2k
3k
18%
0%
form products 3 and disfavoring the intermolecular nucleo-
philic attack on ethylxanthate to form intermediate C. The
fact that 3a can be converted into 2a in excellent yield in the
presence of an excess of hydrosulfide and KSC(S)OEt
(Scheme 5) supports this mechanism and indicates that the
transformation of 2 into intermediate B is reversible. (This
step is irreversible in Le Corre’s mechanism.8b) As is shown
in our mechanism, both the amount of potassium ethylxan-
thate and the steric hindrance around the hydroxy group
control the chemoselectivity of the reaction. Smaller
amounts of KSC(S)OEt and more steric hindrance of the hy-
droxy group favor products 3; otherwise, products 2 are the
major products.
Scheme 3 The effect of the geometry, as demonstrated by 1-amino-2-
indanols
We therefore proposed the plausible mechanism shown
in Scheme 4; this was inspired by Le Corre and co-workers’
mechanism8b for the formation of 1,3-thiazolidine-2-thi-
ones from amino alcohols and CS2 under basic conditions.
Initially, the ethylxanthate reacts with the amine group
to give dithiocarbamate A in equilibrium with B. If R3 ≠ H
and R4 ≠ H, a subsequent nucleophilic attack on the thiocar-
bonyl group affords the oxazolidine-2-thione 3 (see Scheme
2, 2h), for the following reasons. First, steric hindrance on
carbon adjacent to the oxygen atom prevent further xan-
thation. Secondly the gem-dialkyl effect, known as the
Thorpe–Ingold effect,13 favors the formation of a five-mem-
bered ring.14 However, if R3 = R4 = H, another ethylxanthate
ion can react with the oxyanion to form the xanthate dith-
iocarbamate C in equilibrium with intermediate D. Nucleo-
philic attack on the thiocarbonyl group then affords the 1,3-
thiazolidine-2-thione 2. The order of yields of the 1,3-thi-
azolidine-2-thiones from the corresponding amino alcohol
is as follows: R1 (or R2) = 2° C > Me > 1° C ≈ Ph > 3° C
(Scheme 2, 1a–f, 1i). Steric hindrance generated by R1 or R2
favors the formation of a five-membered ring. However,
when R1 = tert-Bu (1i), product 3 is favored over product 2.
This might be because the bulky substituent pushes the
thiocarbamate group away, causing it to lean toward the
oxyanion in intermediate B, thereby favoring ring closure to
S
S
NaSH⋅H2O (2.0 equiv)
KSCSOEt (2.0 equiv)
O
NH
S
NH
EtOH, N2, sealed
reflux, 24 h
2a
3a
85%
Scheme 5 Transformation of (3a) into (4R)-4-phenyl-1,3-oxazolidine-
2-thione (2a)
In summary, we have developed a CS2-free approach to
the preparation of 1,3-thiazolidine-2-thiones from vicinal
amino alcohols in the presence of potassium ethylxanthate
as a CS2 surrogate.15 Common chiral 1,3-thiazolidine-2-thi-
ones were conveniently prepared in this manner, which
should permit a broadening of their use in modern organic
synthesis. Meanwhile, we found that 1,3-oxazolidine-2-thi-
ones can be converted into 1,3-thiazolidine-2-thiones in
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

D
Z. Lu et al.
Letter
Synlett
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viding a deeper understanding of the formation of chiral
auxiliaries from vicinal amino alcohols.
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Funding Information
Financial support was provided by the National Natural Science Foun-
dation of China (21572118 and 21572080) and Jiangsu University
(10JDG042 and 14JDG018).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612124.
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Phenyl-1,3-oxazolidine-2-thione; Typical Procedure
Potassium ethylxanthate (802 mg, 5.0 mmol) was rapidly added
to a suspension of (2R)-2-amino-2-phenylethanol (1a; 137 mg,
1.0 mmol) in absolute EtOH (2.0 mL) in a 20 mL autoclave. The
autoclave was flushed with N2 for 5 min, then sealed and heated
in an oil bath at 100 °C for 24 h. It was then cooled to r.t. and the
mixture was transferred to a 50 mL round-bottomed flask and
concentrated under reduced pressure to remove the alcohol.
H2O (10 mL) was added to the slurry, and the mixture was
extracted with EtOAc (3 × 30 mL). The organic phases were
combined, washed with brine (30 mL), dried (Na2SO4), and con-
centrated to give a crude product that was purified by flash
chromatography [silica gel, EtOAc–PE (1:3)] to afford 2a and 3a.
2a8b
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Watanabe, S.-i.; Iwamura, T.; Muraoka, O.; Tanabe, G. Angew.
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Ed. 2008, 47, 4224.
Off-white solid; yield: 160 mg (0.82 mmol, 82%); mp 123–
125 °C [Lit.8b 124–125 °C (aq EtOH)]; Rf = 0.3 (EtOAc–PE, 1:3),
22
[]D –205.8 (c 1.03, CHCl3) [Lit. –209.32 (c 0.35, CHCl3)]. IR
(KBr): 3132, 2923, 1489, 1452, 1258, 1050, 941, 759 cm–1 1H
.
NMR (400 MHz, CDCl3):  = 7.62 (br s, 1 H), 7.46–7.36 (m, 5 H),
5.32 (t, J = 8.0 Hz, 1 H), 3.86 (dd, J = 11.2, 8.0 Hz, 1 H), 3.52 (dd, J
= 11.2, 8.0 Hz, 1 H). 13C NMR (101 MHz, CDCl3):  = 201.6, 138.0,
129.4, 129.2, 126.3, 67.5, 41.6. ESI-MS: m/z = 196.0 [M + H]+.
3a8b,11
White solid; yield: 18 mg (0.10 mmol, 10%); mp 120.0–120.4 °C
(Lit.8b 121–122 °C); Rf = 0.3 (EtOAc–PE, 1:3); []D20 –78.5 (c 0.20,
CHCl3) [Lit.8b –79.3 (c 0.21, CHCl3)]. IR (KBr): 3436, 1525, 1170,
969, 701 cm–1. 1H NMR (400 MHz, CDCl3):  = 7.95–7.50 (br s, 1
H), 7.45–7.36 (m, 3 H), 7.34–7.30 (m, 2 H), 5.12 (dd, J = 8.8, 7.6
Hz, 1 H), 5.00 (t, J = 8.8 Hz, 1 H), 4.49 (dd, J = 9.2, 7.2 Hz, 1 H). 13
C
NMR (101 MHz, CDCl3):  = 189.6, 137.9, 129.2, 129.0, 126.2,
77.6, 60.1. ESI-MS: m/z = 178.0 [M–H]–.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D