A convenient synthesis of N-substituted 2-thioxo-1,3-thiazolidin-4-ones

Article abstract of DOI:10.1055/s-2006-926409

A convenient method was developed for the synthesis of N-substituted rhodanines based on the reaction of amines, hydrazides, or acid thiohydrazides with trithiocarbonyl diglycolic acid in the presence of dicyclohexylcarbodiimide or 1,1′-carbonyldiimidazole. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926409

1246
SHORT PAPER
A Convenient Synthesis of N-Substituted 2-Thioxo-1,3-thiazolidin-4-ones
Synthesis of
N
-Sub
l
stitute
a
d 2-Thioxo
d
-1, 3-thiazolid
i
in-4-o
m
ne
s
ir N. Yarovenko,*a Aleksandra S. Nikitina,b Igor V. Zavarzin,a Mikhail M. Krayushkin,a
Leonid V. Kovalenkob
a
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991 Moscow, Russian Federation
Fax +7(095)1355328; E-mail: yarov@mail.ioc.ac.ru
D. I. Mendeleev Russian University of Chemical Technology, 9 pl. Miusskaya, Moscow 125047, Russian Federation
b
Received 18 October 2005; revised 30 November 2005
Conceivably, the bulky sulfur atom in oxamic acid thiohy-
Abstract: A convenient method was developed for the synthesis of
drazides hinders the reaction with the carboxy group,
whereas refluxing in basic aqueous media leads to decom-
position of the starting thiohydrazide.
N-substituted rhodanines based on the reaction of amines, hy-
drazides, or acid thiohydrazides with trithiocarbonyl diglycolic acid
in the presence of dicyclohexylcarbodiimide or 1,1¢-carbonyldiimi-
dazole.
In our opinion, the process involving the reaction of amine
with an activated carboxy group as the initial step and sub-
sequent cyclization accompanied by the replacement of
the thioglycolic group, which is a good leaving group
(Scheme 2), could occur more smoothly. The carboxy
group was activated with p-toluenesulfonic acid, dicyclo-
hexylcarbodiimide or 1,1¢-carbonyldiimidazole.
Key words: oxamic acid thiohydrazides, amines, hydrazides,
rhodanines, carbodiimide, 1,1¢-carbonyldiimidazole
Rhodanines are widely used for the design of various
compounds with useful properties.1 The synthesis of anti-
tuberculosis agents based on 3-acylaminorhodanines has
attracted considerable attention.2,3 It was of interest to ex-
amine the possibility of preparing 3-thioacylaminorhoda-
nines taking into account that a number of widely used
antituberculosis drugs (for example, Protionamide-Akri,
Ethionamide, and Thioacetazonum) contain the thioamide
or thiohydrazide fragments.
O
S
S
RNH2
NHR
S
1
S
N
R
O
S
COOH
Scheme 2
Earlier, we have developed a convenient method for the
preparation of oxamic acid thiohydrazides and used the
latter for the synthesis of various heterocyclic com-
pounds.4,5 In continuation of these studies, we investigat-
ed the reaction of oxamic acid thiohydrazides with
trithiocarbonyl diglycolic acid in expectation that 3-thio-
acylaminorhodanines will be produced by analogy with
the known method.6
We have studied the reaction of trithiocarbonyl diglycolic
acid (1) with compound 2 in the presence of p-toluene-
sulfonic acid. Actually, it appeared that refluxing these re-
agents in toluene for six hours afforded rhodanine 3 in
49% yield (Scheme 3).
O
H
N
The advantage of the reactions involving trithiocarbonyl
diglycolic acid is that they allow the one-pot synthesis of
rhodanines starting from the corresponding amino-con-
taining compounds. However, our attempts to prepare the
target products according to a procedure developed for the
synthesis of 3-acylaminorhodanines (in water in the pres-
ence of a base)6 failed. It is assumed that the reaction in-
volves the replacement of the thioglycolic fragment under
the action of amine followed by cyclization to form the
thiazolidine ring (Scheme 1).7
S
N
O
S
N
O
H2N
NHPh
S
S
2
PhHN
1
TsOH
3
Scheme 3
It was found that substituted rhodanines are smoothly gen-
erated from oxamic acid thiohydrazides and trithiocar-
bonyl diglycolic acid with the use of a small excess of
dicyclohexylcarbodiimide in THF at 0 °C. An increase in
the reaction temperature led to a decrease in the yield of
rhodanines. The order of addition of the reagents was
demonstrated to have no effect on the yield of the product.
However, in spite of rather high yields of rhodanines (70–
80%), this method is not very convenient, because the
products are difficult to separate from dicyclohexylurea
that formed in the reaction.
S
S
COOH
S
S
COOH
COOH
RNH2
S
S
S
N
R
O
NHR
1
Scheme 1
SYNTHESIS 2006, No. 8, pp 1246–1248
x
x
.
x
x
.2
0
0
6
Advanced online publication: 27.03.2006
DOI: 10.1055/s-2006-926409; Art ID: Z20405SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Synthesis of N-Substituted 2-Thioxo-1,3-thiazolidin-4-ones
1247
1. 1,1′-carbonyldiimidazole,
THF, 1.5 h
O
2.
H
1. 1,1′-carbonyldiimidazole,
THF, 1.5 h
N
H2N
NHR
2a–d
reflux, 4 h
2. RNH2
4a–e
reflux, 4 h
S
N
O
S
S
N
O
S
N
O
S
S
1
R
RHN
3a–d
5a–e
O
NH
N
4a, 5a R =
2a, 3a R = Ph
2b, 3b R = p-ClC6H4
N
4d, 5d R =
N
2c, 3c R = p-OMeC6H4
4b, 5b R =
4c, 5c R =
N
O
4e, 5e R =
N
OEt
N
2d, 3d R =
Et
S
Scheme 4
A procedure for the synthesis of substituted rhodanines The proposed method allows one to prepare various N-
with the use of 1,1¢-carbonyldiimidazole proved to be substituted rhodanines in good yields from amino-con-
more convenient. The reaction was carried out in THF at taining compounds under mild conditions.
room temperature. The addition of trithiocarbonyl digly-
Table 1 Characteristic Data for Compounds 3a–d and 5a–e
colic acid to 1,1¢-carbonyldiimidazole and subsequent
storage of the reaction mixture affords, apparently, an
Product
3a
Yield (%)
Mp (°C)
acylimidazole derivative, which smoothly reacts with ox-
amic acid thiohydrazides 2a–d to give rhodanines 3a–d in
75–88% yields (Scheme 4, Table 1). When the reagents
were mixed simultaneously, resinification of the reaction
mixture occurred. It was found that a twofold excess of
1,1¢-carbonyldiimidazole should be used. When the latter
compound was used in a smaller excess, the unconsumed
starting thiohydrazide remained in the reaction mixture.
67
73
84
77
85
82
67
92
89
126–128
3b
183–184
3c
156–157
3d
167–168
5a
198–199 (Lit.6 197–198)
43–45 (Lit.8 41–45)
57–58 (Lit.9 54–55)
141–142
This is the general method for preparing various N-substi-
tuted rhodanines. This method does not require heating in
basic aqueous media, which can lead to decomposition of
the labile starting amines. The use of the modified ap-
proach made it possible to prepare the above-described
rhodanines in substantially higher yields, as well as to
synthesize compounds, which are impossible to prepare
by the reaction with trithiocarbonyl diglycolic acid in wa-
ter in the presence of a base.
5b
5c
5d
5e
149–150
a Satisfactory microanalysis obtained:
0.18; H 0.22; N 0.19; S 0.17.
C
For example, refluxing nicotinic acid hydrazides with
trithiocarbonyl diglycolic acid in water in the presence of
a base afforded nicotineaminorhodanine (5a) in 50%
yield,5 whereas the use of 1,1¢-carbonyldiimidazole led to
an increase in the yield of compound 5a to 80–85%
(Table 1). The reaction with aminocyclopropane 4c in wa-
ter produced rhodanine 5c in 3% yield, whereas the reac-
tions with allylamine (4b), 2-aminopyrimidine (4d), or 3-
amino-1,2,4-triazole (4e) did not yield rhodanines at all.
At the same time, the reactions performed in the presence
of 1,1¢-carbonyldiimidazole afforded the corresponding
rhodanines 5b–e in 80–85% yields (Table 1). The NMR
data of compounds 3 and 5 prepared are listed in Table 2.
The 1H and 13C NMR spectra were recorded on a Bruker AC-300 in-
strument in DMSO-d6. The spin-spin coupling constants (J) are giv-
en in Hz. The mass spectra were obtained on a Kratos instrument
using a direct inlet system; the ionization energy was 70 eV; the ac-
celerating voltage was 1.75 kV. The melting points were measured
on a Boetius hot-stage apparatus and are uncorrected. All reaction
mixtures were analyzed and the purity of the products was checked
by TLC (EtOAc–hexane, 1:1 as the eluent).
Oxamic acid thiohydrazides 2a–d were synthesized as described
earlier.4,5 Trithiocarbonyl diglycolic acid (1) was prepared accord-
ing to a known procedure.10
2-Thioxo-1,3-thiazolidin-4-ones 3a–d, 5a–e; General Procedure
A solution of trithiocarbonyl diglycolic acid (1; 0.12 g, 0.5 mmol)
and 1,1¢-carbonyldiimidazole (0.16 g, 1 mmol) in THF (10 mL) was
Synthesis 2006, No. 8, 1246–1248 © Thieme Stuttgart · New York

1248
V. N. Yarovenko et al.
SHORT PAPER
Table 2 Spectroscopic Data for 3a–d and 5b–e
Product 1H NMR (300.13 MHz, DMSO-d6) d, J (Hz)
13C NMR (75.47 MHz, DMSO-d6) d
MS m/z [M+]
3a
3b
3c
3d
4.2 (s, 2 H, SCH2), 7.2 (t, J = 7.6, 1 Harom para to 37.387 (CH2), 121.092 (CHarom ortho to N), 125.037 (CHarom
312
N), 7.4 (t, J = 7.6, 2 Harom ortho to N), 7.9 (d,
J = 7.6, 2 Harom meta to N), 10.7 (s, 1 H, NH)
para to N), 129.023 (CHarom meta to N), 137.775 (Carom),
169.015 (C=O), 193.623 (C=S)
4.3 (s, 2 H, SCH2), 7.5 (d, J = 8.7, 2 Harom ortho to 37.458 (CH2), 122.654 (CHarom ortho to N), 128.935 (CHarom
N), 7.9 (d, J = 8.7, 2 Harom meta to N), 10.1 (s, 1 H, meta to N, para to N), 136.806 (Carom), 169.015 (C=O), 193.623
NH) (C=S)
346
4.25 (s, 2 H, SCH2), 7.0 (d, J = 8.9, 2 Harom ortho 33.756 (CH2), 53.687 (OCH3), 116.963 (CHarom para to N),
to N), 7.65 (d, J = 8.9, 2 Harom meta to N), 10.1 (s, 123.036 (CHarom ortho to N), 131.852 (CHarom meta to N),
341
1 H, NH)
137.21 (Carom), 167.065 (C=O), 191.025 (C=S)
1.25 (t, J = 7.44, 3 H, CH3), 1.35 (t, J = 7.11, 3 H, 14.201 (CH3), 15.208 (CH3), 22.042 (CH2), 37.715 (CH2 rhod), 418
CH3), 2.7 (q, J = 4.77, 2 H, CH2), 4.15 (s, 2 H,
SCH2), 4.35 (q, J = 4.08, 2 H, OCH2), 7.0 (s, 1
Harom), 11.8 (s, 1 H, NH)
60.524 (OCH2), 114.101 (Cthioph), 119.935 (CHthioph), 137.435
(Cthioph), 143.771 (Cthioph), 156.037 (C=O), 163.490 (C=O),
164.267 (C=S), 189.335 (C=S)
5b
5c
5d
5e
3.7 (d, J = 7.44, 2 H, CH2), 4.2 (s, 2 H, SCH2), 5.2 38.248 (CH2 rhod), 47.126 (CH2N), 113.587 (CH2=CH),
(m, 2 H, =CH2), 5.9 (m, 1 H, =CH) 139.356 (CH2=CH), 168.973 (C=O), 191.345 (C=S)
173
174
212
200
1.2 (m, 4 H, CH2CH2), 1.7 (m, 1 H, NCH), 4.0 (s, 12.478 (CH2, cyclopropyl), 25.417 (CH, cyclopropyl), 38.410
2 H, SCH2) (CH2, rhod), 165.073 (C=O), 195.793 (C=S).
4.25 (s, 2 H, SCH2), 6.5 (d, J = 4.81, 1 Harom), 6.6 39.214 (CH2), 110.207 (CHarom meta to N), 157.959 (CHarom
(t, J = 4.77, 1 Harom), 8.2 (d, J = 4.8, 1 Harom
)
ortho to N), 163.353 (C=S), 168.127 (C=O)
4.25 (s, 2 H, SCH2), 7.5 (s, 1 H, N=CH)
39.487 (CH2), 145.344 (N=CH), 156.269 (C=O), 168.655
(C=S)
stirred at r.t. for 1.5 h. Then oxamic acid thiohydrazide 2a–d (0.5
mmol) or the amine 4a–e (0.5 mmol) was added, and the mixture
was refluxed for 4 h. A 2 M HCl solution (30 mL) was added, and
the mixture was extracted with EtOAc (4 × 15 mL). The combined
organic phases were dried (MgSO4) and concentrated. The residue
was recrystallized from MeCN (Tables 1 and 2).
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Synthesis 2006, No. 8, 1246–1248 © Thieme Stuttgart · New York