Synthesis of 2-selenoxo-1,3-thiazolidin-4-ones and 2-selenoxo-1,3- thiazinan-4-ones from isoselenocyanates

Article abstract of DOI:10.3987/COM-05-10435

2-Selenoxo-1,3-thiazolidin-4-ones (selenorhodanines) (7a-h) and 2-selenoxo-1,3-thiazinanes (8a-c) can easily be synthesized in a one-pot procedure from aryl isoselenocyanates and α- and β-mercapto carboxylic acids, respectively.

Full text of DOI:10.3987/COM-05-10435

HETEROCYCLES, Vol. 65, No. 8, 2005
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HETEROCYCLES, Vol. 65, No. 8, 2005, pp. 1903 - 1915
Received, 28th April, 2005, Accepted, 5th July, 2005, Published online, 7th July, 2005
SYNTHESIS OF 2-SELENOXO-1,3-THIAZOLIDIN-4-
ONES AND 2-SELENOXO-1,3-THIAZINAN-4-ONES
FROM ISOSELENOCYANATES
Geoffroy L. Sommen,1 Anthony Linden, and Heinz Heimgartner*
Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse
190, CH-8057 Zürich, Switzerland; E-mail: heimgart@oci.unizh.ch
Abstract – 2-Selenoxo-1,3-thiazolidin-4-ones (selenorhodanines) (7a-h)
and 2-selenoxo-1,3-thiazinanes (8a-c) can easily be synthesized in a one-
pot procedure from aryl isoselenocyanates and α- and β-mercapto
carboxylic acids, respectively.
INTRODUCTION
During the last 25 years, organoselenium chemistry underwent a spectacular mutation: from an
exotic area of science, practised by a few specialists, it became a relatively well-mastered
methodology widely used by organic chemists. The key to this success is that a fair number of
selenium based reagents and reactions have been discovered, which allow specific
transformations to be performed selectively and often under mild conditions. The interest in
selenium-containing compounds has increased not only because of their remarkable reactivities
and chemical properties2–8 but also because of their pharmaceutical applications.9–16
Organoselenium compounds are now an important class of biologically active products.17,18
Shamberger15 widely evidenced the importance of selenium in biology, in human health,19 in
cancer chemoprevention,20 in food,21–23 and in plants.24,25
Many syntheses of selenium-containing heterocycles involve the use of toxic selenium
reagents, which are often difficult to handle and to store. On the other hand, isoselenocyanates
are very useful starting materials26 since they are easy to prepare27 and are relatively stable.

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HETEROCYCLES, Vol. 65, No. 8, 2005
We have shown that they are the reagents of choice for the preparation of selenium-containing
heterocycles such as 1,3-selenazole[5,4-b]pyridines,28 selenet-2(2H)-imines,29 1,3-selen-
azoles,30,31 imidazole diselenides,32 6H-[5,1,3]benzoselenadiazocines,33 and 1,2,3-selena-
diazoles.34
Rhodanine derivatives (2-thioxo-1,3-thiazolidin-4-ones) have been extensively investigated.
They exhibit various biological activities,35 e.g., antidiabetic,36 antibacterial, fungicidal,
antiparasitic, and antituberculous.37,38 On the other hand, there were no reports on the
synthesis of 2-selenorhodanine derivatives until the recent work of Tejchman and Korohoda.39
As in several other reports, the C=Se bond was introduced by the use of highly toxic hydrogen
selenide. The key step of this method is the substitution of a MeS group or a R(Me)N group by
HSe in various derivatives of imidazolidine,40a 1,3-thiazolidine,40b 1,3-thiazoline,40c,41 and
pyridine.42
Recently, we have described the synthesis of 2-imino-1,3-selenazolidines (3, n = 2),43 2-imino-
1,3-selenazinanes (3, n = 3),43 and 1,3-selenazolidin-4-ones (5)44 from isoselenocyanates by
the nucleophilic attack of a primary amine and a carbon nucleophile, respectively (Scheme 1).
To the best of our knowledge, only a few articles concerning the nucleophilic attack of a thiol on
isothiocyanates have been published45–50 and even less involving isoselenocyanates.51,52 For
this reason, we investigated the reactions of mercapto carboxylic acids with isoselenocyanates
with the aim of preparing selenaheterocycles by a subsequent cyclization of the initially formed
adducts.
Scheme 1
H
H
N
HN
N
Cl
H2N (CH2)n Cl
Ar
(CH2)n
Et3N
(CH2)n-1
N
Se
Se
CH2Cl2
Ar
2
3
Ar
N
C
Se
1
X
NC
NC
X
NC
X
ClCH2CO2R
Ar
Se
N
Ar
N
Se
Et3N / DM F
O
4
5

HETEROCYCLES, Vol. 65, No. 8, 2005
1905
RESULTS AND DISCUSSION
The reactions of aryl isoselenocyanates (1a-e) with equimolar amounts of 2-mercaptoacetic
acid (6a) in a mixture of ethanol and water occurred already at room temperature. Typically, the
reactions were completed after 3–4 h (TLC control). After aqueous workup and recrystallization
of the precipitate from EtOH, 2-selenoxo-1,3-thiazolidin-4-ones (7a-e), i.e., selenorhodanines,
were obtained as orange crystals in good to excellent yields (Scheme 2, Table 1). In the NMR
spectra (CDCl3), the CH2 group appears as a singlet at 3.85–4.26 ppm (1H) and at 37.3–38.2
ppm (13C), respectively. The characteristic absorptions of C(4)=O and C(2)=Se are observed at
171.8–173.8 ppm and at 200.2–205.5 ppm. The CI-MS spectra (NH3) show the [M+H]+ peak as
the base peak, in addition to an intensive [M+NH4]+ peak, and all products gave correct
elemental analyses for C, H, N, and S.
Scheme 2
X
S
EtOH / H 2O
rt / 3-12 h
HS
COOH
O
Se
Ar
N
C
Se
X
+
N
Ar
1
6
7 , 8
- H2O
H
N
S
COOH
Ar
X
Se
A
Finally, the structure of 7a was established unambiguously by X-Ray crystallography (Figure 1).
The 1,3-thiazolidine ring is almost planar, and the attached atoms Se, O(4), and C(6) deviate
only slightly from this plane. On the other hand, the benzene ring at N(3) is twisted out of this
plane and is oriented almost orthogonal to the plane of the heterocycle with a dihedral angle
between these planes of 71.7(1)°).
Analogously, the reaction of 4-methoxyphenyl isoselenocyanate (1c) with 2-mercaptopropanoic
acid (6b) gave 2-(4-methoxyphenyl)-5-methylselenorhodanine (7f) in 74% yield.

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HETEROCYCLES, Vol. 65, No. 8, 2005
Table 1. Synthesis of Thiazolidinones (7a-f) and Thiazinanones (8a-c) from Isoselenocyanates
Isoselenocyanate (1)
Mercapto Acid (6)
Products
Yield (%) [Time,h]
O
N
NCSe
7a
HS
COOH
96 [3]
S
Se
a
a
a
O
Me
N
Me
NCSe
NCSe
7b
7c
7d
HS
HS
HS
COOH
COOH
COOH
91 [3]
93 [4]
S
b
c
Se
O
MeO
N
MeO
S
a
Se
O
N
Me
Me
Me
Me
NCSe
56 [12]
S
Se
a
a
d
e
O
Br
N
Br
NCSe
NCSe
89 [3]
74 [6]
7e
7f
HS
HS
COOH
COOH
S
Se
O
Me
Me
MeO
N
MeO
S
Se
c
b
c
c
O
N
HS
NCSe
8a
8b
82 [12]
63 [12]
COOH
S
Se
a
b
O
N
HS
HS
Me
Me
NCSe
NCSe
COOH
COOH
S
Se
O
Cl
N
Cl
8c
60 [12]
S
c
f
Se

HETEROCYCLES, Vol. 65, No. 8, 2005
1907
Figure 1. ORTEP plot53 of the molecular structure of 7a (arbitrary numbering of the atoms; 50%
probability ellipsoids)
Furthermore, the corresponding reactions of 1a, b, and f with 3-mercaptopropanoic acid (6c)
afforded the 2-selenoxo-1,3-thiazinan-4-ones (8a-c), i.e., the six-membered homologues of
1
selenorhodanines (Scheme 2, Table 1). In the H-NMR spectra of 8a-c, the two CH2 groups
resonate at ca. 2.75 and 3.50 ppm, whereas their 13C-signals appear at ca. 33.5 and 45.0 ppm.
The chemical shifts of C(4)=O and C(2)=Se (ca. 173 and 204 ppm, respectively) are almost
unaffected by the ring size (cf. 7a-f).
A reaction mechanism for the formation of 7 and 8 is proposed in Scheme 2. The nucleophilic
mercapto group undergoes an addition to the isoselenocyanate (1) to give a
(seleno)(thio)carbamate A as an intermediate. It is worth mentioning that no additional base is
needed to catalyze the reaction. The subsequent cyclization of A' occurs almost
instantaneously with loss of water to afford the selenorhodanines (7) in a one-pot-reaction. In
the case of the sterically crowded isoselenocyanate (1d), a longer reaction time of 12 h is
needed. Similarly, in the case of the reactions of 1a, b, and f with 3-mercaptopropanoic acid
(6c), the starting material had been consumed complete only after 12 h.
It is noteworthy that the ring closure of A/A’ occurs exclusively via nucleophilic attack of the N-
atom at the carboxylic group. None of the corresponding 2-imino-1,3-selenathiolanone or its
homologue has been detected, in contrast to the previously described formation of 2-imino-1,3-

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HETEROCYCLES, Vol. 65, No. 8, 2005
selenazolidines and 2-imino-1,3-selenazinanes (3),43 2-arylaminoselenazolo[5,4-b]pyrid-ines,28
1H-5-selena-1,3,6-triazaaceanthrylenes,54 and 6H-[5,1,3]benzoselenadiazocines.33 On the
other hand, in the reaction of 2-aminobenzonitrile with phenyl isoselenocyanate, the
intermediate selenourea derivatives undergo a cyclization by nucleophilic attack of the N-atom
at the nitrile group, which leads to 4-phenylaminoquinazoline-2(1H)-selones.55
In conclusion, the reaction of isoselenocyanates (1) with α- or β-mercaptocarboxylic acids is a
novel, rapid and efficient synthesis of 2-selenoxo-1,3-thiazolidine-4-ones (7, selenorhodanines)
and 2-selenoxo-1,3-thiazinan-4-ones (8).
EXPERIMENTAL
General remarks. TLC: silica gel 60 F254 plates (0.25 mm, Merck). Column chromatography
(CC): silica gel 60 (0.040–0.063 mesh, Merck). Melting points: Büchi B-540 apparatus, in a
1
capillary, uncorrected. H-NMR (300 MHz) and 13C-NMR (75 MHz) spectra: Bruker ARX-300
instrument, in CDCl3; chemical shifts in ppm, coupling constants J in Hz. EI-MS and CI-MS:
Finnigan SSQ-700 or MAT-90 instrument; EI mode: 70 eV; CI mode: NH3 as carrier gas.
Starting materials. 2-Mercaptoacetic acid (6a), 2-mercaptopropanoic acid (6b), 3-mercapto-
propanoic acid (6c), and formanilid are commercially available (Fluka). Isoselenocyanates (1)
were prepared according to Barton’s procedure, which starts from formamides.27 N-(4-
Chlorophenyl)-, N-(4-bromophenyl)-, N-(4-methoxyphenyl)-, N-(4-methylphenyl)-, and N-(2,6-
dimethylphenyl)formamide were prepared from the respective commercial aniline and 95%
formic acid by using a slightly modified procedure.56 The solution was heated to reflux for 30
min and evaporated to dryness in vacuo. The residue was dissolved in Et2O and washed with
dilute acetic acid (5%), water, and aqueous NaHCO3 (5%). The aqueous layer was extracted
with Et2O, the combined organic extracts were dried with MgSO4 and evaporated under
reduced pressure. The crude products were purified by recrystallization using a mixture of EtOH
and water.
Synthesis of 2-Selenoxo-1,3-thiazolidin-4-ones (7a-f) and 2-Selenoxo-1,3-thiazinan-4-
ones (8a-c). General Procedure. A round bottom flask equipped with a condenser and a
magnetic stirrer was charged with an aryl isoselenocyanate (1.0 mmol) in 20 mL of a mixture of
EtOH and water (2:1). The respective mercapto carboxylic acid was then added dropwise. The

HETEROCYCLES, Vol. 65, No. 8, 2005
1909
mixture was stirred at rt for several hours (see table) before being poured onto 50 mL of cold
water. After 2 h of stirring, the precipitate formed was filtered and purified, if necessary, by
recrystallization from EtOH.
1
3-Phenyl-2-selenoxo-1,3-thiazolidin-4-one (7a). Orange plates, mp 217–219°C (EtOH). H-
NMR: 4.26 (s, CH2); 7.40 (d, J = 8.2, 2 arom. H); 7.59–7.67 (m, 3 arom. H). 13C-NMR: 38.2
(CH2); 128.6 (2 arom. CH); 129.1 (3 arom. CH); 136.5 (1 arom. C); 173.8 (CO); 205.5 (CSe). CI-
MS: 275 (26, [M+NH4]+), 258 (100, [M+H]+). Anal. Calcd for C9H7NOSSe: C, 42.19; H, 2.75; N,
5.47; S, 12.52. Found: C, 42.20; H, 2.75; N, 5.42; S, 12.40.
3-(4-Methylphenyl)-2-selenoxo-1,3-thiazolidin-4-one (7b). Orange crystals, mp 201–203°C
1
(EtOH). H-NMR: 2.42 (s, Me); 3.90 (s, CH2); 7.10, 7.35 (AA’BB’, J = 8.2, 4 arom. H). 13C-
NMR: 21.3 (Me); 37.4 (CH2); 128.0 (2 arom. CH); 130.3 (2 arom. CH); 133.2, 140.0 (2 arom. C);
173.2 (CO); 203.3 (CSe). CI-MS: 289 (31, [M+NH4]+), 272 (100, [M+H]+). Anal. Calcd for
C10H9NOSSe: C, 44.45; H, 3.36; N, 5.18; S, 11.87. Found: C, 44.30; H, 3.21; N, 5.03; S, 11.78.
3-(4-Methoxyphenyl)-2-selenoxo-1,3-thiazolidin-4-one (7c). Orange crystals, mp 182–184°C
1
13
(EtOH). H-NMR: 3.85 (s, MeO); 3.89 (s, CH2); 7.03, 7.14 (AA’BB’, J = 8.2, 4 arom. H). C-
NMR: 37.3 (CH2); 55.4 (MeO); 114.9 (2 arom. CH); 128.2 (1 arom. C); 129.4 (2 arom. CH);
160.3 (1 arom. C); 173.3 (CO); 203.6 (CSe). CI-MS: 305 (32, [M+NH4]+), 288 (100, [M+H]+).
Anal. Calcd for C10H9NO2SSe: C, 41.96; H, 3.17; N, 4.89; S, 11.20. Found: C, 42.23; H, 3.33; N,
4.88; S, 11.12.
3-(2,6-Dimethylphenyl)-2-selenoxo-1,3-thiazolidin-4-one (7d). Orange crystals, mp 123–125°C
1
13
(EtOH). H-NMR: 2.10 (s, 2 Me); 3.95 (s, CH2); 7.18–7.33 (m, 3 arom. H). C-NMR: 117.5 (2
Me); 37.3 (CH2); 127.5 (1 arom. CH); 127.9 (2 arom. CH); 130.0, 136.1 (2 arom. C); 173.2 (CO);
200.2 (CSe). CI-MS: 303 (60, [M+NH4]+), 286 (100, [M+H]+). Anal. Calcd for C11H11NOSSe: C,
46.48; H, 3.90; N, 4.93; S, 11.28. Found: C, 46.33; H, 4.12; N, 5.00; S, 11.32.
3-(4-Bromophenyl)-2-selenoxo-1,3-thiazolidin-4-one (7e). Orange crystals, mp 111–113°C
1
13
(EtOH). H-NMR: 3.92 (s, CH2); 7.11, 7.67 (AA’BB’, J = 8.1, 4 arom. H). C-NMR: 37.4 (CH2);
123.3 (1 arom. C); 130.0 (2 arom. CH); 132.9 (2 arom. CH); 138.5 (1 arom. C); 171.8 (CO);

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HETEROCYCLES, Vol. 65, No. 8, 2005
203.8 (CSe). CI-MS: 353 (35, [M+NH4]+), 336 (100, [M+H]+). Anal. Calcd for C9H6NOBrSSe: C,
32.26; H, 1.80; N, 4.18; S, 9.57. Found: C, 32.41; H, 2.02; N, 3.98; S, 10.00.
3-(4-Methoxyphenyl)-5-methyl-2-selenoxo-1,3-thiazolidin-4-one (7f). Orange crystals, mp 133–
1
135°C (EtOH). H-NMR: 1.78 (d, J = 7.3, Me); 3.81 (s, MeO); 4.11 (q, J = 7.2, CH); 6.88, 7.22
(AA’BB’, J = 8.2, 4 arom. H). 13C-NMR: 17.5 (Me); 46.7 (CH); 55.4 (MeO); 114.7 (2 arom. CH);
127.3 (2 arom. CH); 129.4, 159.1 (2 arom. C); 174.4 (CO); 204.2 (CSe). CI-MS: 319 (46,
[M+NH4]+), 302 (100, [M+H]+). Anal. Calcd for C11H11NO2SSe: C, 44.00; H, 3.69; N, 4.67; S,
10.68. Found: C, 43.79; H, 3.82; N, 4.33; S, 11.00.
1
3-Phenyl-2-selenoxo-1,3-thiazinan-4-one (8a). Orange crystals, mp 152–154°C (EtOH). H-
13
NMR: 2.76, 3.55 (2t, J = 6.9, 2 CH2); 7.36–7.58 (m, 5 arom. H). C-NMR: 33.3, 45.3 (2 CH2);
125.0 (1 arom. CH); 126.2 (2 arom. CH); 128.8 (2 arom. CH); 139.6 (1 arom. C); 172.6 (CO);
204.2 (CSe). CI-MS: 288 (100, [M+NH4]+), 272 (54, [M+H]+). Anal. Calcd for C10H9NOSSe: C,
44.45; H, 3.36; N, 5.18; S, 11.87. Found: C, 44.32; H, 3.12; N, 5.34; S, 12.01.
3-(4-Methylphenyl)-2-selenoxo-1,3-thiazinan-4-one (8b). Orange crystals, mp 164–166°C
1
13
(EtOH). H-NMR: 2.73, 3.53 (2t, J = 6.9, 2 CH2); 7.12, 7.38 (AA’BB’, J = 8.1, 4 arom. H). C-
NMR: 20.2 (Me); 33.6, 45.0 (2 CH2); 128.9 (2 arom. CH); 130.8 (2 arom. CH); 134.4, 139.9 (2
arom. C); 174.0 (CO); 203.8 (CSe). CI-MS: 303 (100, [M+NH4]+), 286 (67, [M+H]+). Anal. Calcd
for C11H11NOSSe: C, 46.48; H, 3.90; N, 4.93; S, 11.28. Found: C, 46.45; H, 4.12; N, 5.13; S,
11.07.
3-(4-Chlorophenyl)-2-selenoxo-1,3-thiazinan-4-one (8c). Orange crystals, mp 163–165°C
(EtOH). 1H-NMR: 2.72 (t, J = 6.9, CH2); 3.45 (t, J = 7.0, CH2); 7.22, 7.38 (d, J = 8.1, 4 arom. H).
13C-NMR: 33.1, 45.0 (2 CH2); 129.9 (2 arom. CH); 132.5 (2 arom. CH); 133.1, 138.3 (2 arom.
C); 173.4 (CO); 204.0 (CSe). CI-MS: 323 (100, [M+NH4]+), 306 (44, [M+H]+). Anal. Calcd for
C10H8NOClSSe: C, 39.42; H, 2.65; N, 4.60; S, 10.53. Found: C, 39.22; H, 2.85; N, 4.34; S,
11.11.
X-Ray Crystal-Structure Determination of 7a (see Table 2 and Figure 1).57 All measurements
were performed on a Nonius KappaCCD area-detector diffractometer58 using graphite-
monochromated MoK radiation (λ 0.71073 Å) and an Oxford Cryosystems Cryostream 700
α

HETEROCYCLES, Vol. 65, No. 8, 2005
1911
cooler. The data collection and refinement parameters are given in Table 2, and a view of the
molecule is shown in Figure 1. Data reduction was performed with HKL Denzo and Scalepack.59
The intensities were corrected for Lorentz and polarization effects, and an absorption correction
based on the multi-scan method60 was applied. The structure was solved by direct methods
using SIR92,61 which revealed the positions of all non-H-atoms. All non-H-atoms were refined
anisotropically. All of the H-atoms were placed in geometrically calculated positions and refined
using a riding model where each atom was assigned a fixed isotropic displacement parameter
with a value equal to 1.2Ueq of its parent atom. The refinement of the structure was carried out
2
2
2 2
on F using full-matrix least-squares procedures, which minimized the function Σw(F – F ) . A
o
c
correction for secondary extinction was applied. Neutral atom scattering factors for non-H-
atoms were taken from ref.62a, and the scattering factors for H-atoms were taken from ref.63
Anomalous dispersion effects were included in F ;64 the values for ƒ’ and ƒ” were those of ref.62b
c
The values of the mass attenuation coefficients are those of ref.62c All calculations were
performed using the SHELXL97 program.65
ACKNOWLEDGMENTS
We thank the analytical services of our institute for NMR and MS spectra and elemental
analyses, and Mr. B. Bürgi for his assistance with the determination of the crystal structure.
Financial support of this work by the Dr. Helmut Legerlotz-Foundation and F. Hoffmann-La
Roche AG, Basel, is gratefully acknowledged.
REFERENCES AND NOTES
1.
2.
Postdoctoral stay at the University of Zürich, 2004–2005.
H. J. Reich, ‘Organoselenium Chemistry’, Top. Curr. Chem., Vol. 208, ed. by T. Wirth,
Springer Verlag, Berlin, 2000.
3.
4.
T. Wirth, Tetrahedron, 1999, 55, 1.
‘Organoselenium Chemistry, A Practical Approach’, ed. by T. G. Back, Oxford University
Press, Oxford, 1999.
5.
6.
V. P. Litvinov and V. D. Dyachenko, Russ. Chem. Rev., 1997, 66, 923.
C. Paulmier, ‘Selenium Reagents and Intermediates in Organic Synthesis’, Pergamon
Press, Oxford, 1986.

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HETEROCYCLES, Vol. 65, No. 8, 2005
Table 2. Crystallographic Data of Compound (7a)
Crystallized from
Empirical formula
MeCN
C H NOSSe
9 7
-1
Formula weight [g mol ]
Crystal color, habit
Crystal dimensions [mm]
Temperature [K]
256.12
orange, plate
0.05 × 0.15 × 0.15
160(1)
Crystal system
monoclinic
Space group
P2 /c
1
Z
4
Reflections for cell determination
2θ range for cell determination [°]
19295
4–60
Unit cell parameters
a [Å]
b [Å]
c [Å]
β [°]
12.9370(3)
5.6096(1)
12.7020(4)
93.493(2)
920.09(4)
1.849
3
V [Å ]
-3
D [g cm ]
x
-1
µ(MoKα) [mm ]
4.259
Scan type
φ and ω
60
2θ
[°]
(max)
Transmission factors (min; max)
Total reflections measured
Symmetry independent reflections
Reflections with I > 2σ(I)
0.640; 0.816
27219
2683
2202
Reflections used in refinement
Parameters refined
2683
119
Final R(F) [I > 2σ(I) reflections]
0.0315
0.0717
1.071
2
wR(F ) (all data)*
Goodness of fit
Secondary extinction coefficient
0.0033(8)
0.001
Final ∆
/σ
max
-3
∆ρ (max; min) [e Å ]
0.69; -0.62
*
2
2
2
-1
2
2
w = [σ (F ) + (0.0312P) + 0.4892P] , where P = (F +2F )/3
o
o
c

HETEROCYCLES, Vol. 65, No. 8, 2005
1913
7.
8.
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