Efficient synthesis of 2-thioxo-1,3-thiazolanes from primary amines, CS2, and ethyl bromopyruvate

Article abstract of DOI:10.1007/s00706-008-0953-x

An efficient synthesis of 2-thioxo-1,3-thiazolanes is described via reaction of carbon disulfide, ethyl bromopyruvate, and primary amines.

Full text of DOI:10.1007/s00706-008-0953-x

Monatsh Chem 139, 1479–1482 (2008)
DOI 10.1007/s00706-008-0953-x
Printed in The Netherlands
Efficient synthesis of 2-thioxo-1,3-thiazolanes from primary amines,
CS2, and ethyl bromopyruvate
Issa Yavari, Samereh Seyfi, Zinatossadat Hossaini, Maryam Sabbaghan, Faezeh Shirgahi-Talari
Chemistry Department, Tarbiat Modares University, Tehran, Iran
Received 16 April 2008; Accepted 22 April 2008; Published online 9 July 2008
# Springer-Verlag 2008
Abstract An efficient synthesis of 2-thioxo-1,3-thia-
zolanes is described via reaction of carbon disulfide,
ethyl bromopyruvate, and primary amines.
Therefore, synthesis of these compounds received
considerable attention. General methods for their
synthesis involve the reaction of an amine with cost-
ly and toxic reagents, such as thiophosgene or iso-
thiocyanate [16]. As part of our current studies on
the development of new routes in heterocyclic syn-
thesis [17–20], we describe an efficient procedure
for the direct synthesis of functionalized cyclic thio-
carbamates from the reaction of CS2 and ethyl bro-
mopyruvate (2) in the presence of primary amines 1
at room temperature (Scheme 1).
Keywords 1,3-Thiazolane; Benzylamine; Ethyl bromopyru-
vate; Carbon disulfide; Primary amines.
Introduction
During the last few decades, a central objective in
synthetic organic chemistry has been to develop ef-
ficient syntheses of biologically active compounds
with potential application in the pharmaceutical or
agrochemical industries. In this context, the solvent-
free approach is simple with amazing versatility.
The reactions occur under mild conditions and
usually require easier work-up procedures and sim-
pler equipment. Moreover, it may allow access to
compounds that require harsh reaction conditions
under traditional approaches or when the yields
are too low to be of practical convenience [1–3].
Dithiocarbamates have received considerable atten-
tion due to their numerous biological activities [4–7]
and their pivotal role in agriculture [8–10], and as
linkers in solid-phase organic synthesis [11–13].
Dithiocarbamates are also widely used in medicinal
chemistry and have found application in the treat-
ment of cancer [14, 15].
Results and discussion
The reaction of 1 with 2 in the presence of CS2
led to 2-thioxo-1,3-thiazolanes 3 in 80–90% yields
(Scheme 1). Structures of compounds 3a–3i were
assigned by IR, 1H NMR, 13C NMR, and mass spec-
tral data. Because of the presence of an estereogenic
center in these molecules, the hydrogen atoms of the
CH2 and OCH2 groups are diastereotopic. Thus,
1
the H NMR spectra of 3a–3i exhibited characteris-
tic multiplets for CH2 and OCH2 moieties. The car-
bonyl and thiocarbonyl resonances in the 13C NMR
spectra of 3a–3i appear at about 170 (C¼O) and 198
(C¼S) ppm. The mass spectra of these compounds
displayed the molecular ion peak at appropriate m=z
values.
A tentative mechanism for this transformation is
proposed in Scheme 2. It is conceivable that the
initial event is the formation of the 1:1 adducts 4
Correspondence: Issa Yavari, Chemistry Department, Tarbiat
Modares University, PO Box 14115-175, Tehran, Iran.
E-mail: yavarisa@modares.ac.ir

1480
I. Yavari et al.
paratus. IR Spectra: Shimadzu IR-460 spectrometer; in cmꢀ1
.
1H and 13C NMR Spectra: Bruker DRX-500-Avance instru-
ment; in CDCl3 at 500.1 and 125.7 MHz; ꢀ in ppm, J in Hz.
EI-MS (70 eV): Finnigan MAT-8430 mass spectrometer; m=z.
Elemental analyses (C, H, and N): Heraeus CHN-O-Rapid
analyzer; the results were in good agreement with the calcu-
lated values.
General procedure for the preparation of compounds 3
Primary amine 1 (2 mmol) was added to a mixture of
0.76 g CS2 (10 mmol) and 0.39 g ethyl bromopyruvate 2
(2 mmol) at rt. The reaction mixture was then stirred for
12 h. The product was separated by column chromatogra-
phy (SiO2; n-hexane=AcOEt 10=1) to afford the pure title
compounds.
Ethyl 3-butyl-4-hydroxy-2-thioxo-1,3-thiazolane-4-
carboxylate (3a, C10H17NO3S2)
Pale yellow powder, mp 125–127ꢁC, yield 0.45 g (86%);
IR (KBr): ꢁꢀ¼ 3224, 1738, 1614, 1531, 1430, 1334, 1194,
1157 cmꢀ1; EI-MS: m=z (%) ¼ 263 (Mþ, 5), 115 (85), 148
(56), 147 (32), 57 (100), 45 (48); 1H NMR: ꢀ ¼ 0.89 (3H, t,
3J ¼ 7.4 Hz, Me), 1.23–1.29 (2H, m, CH2), 1.32 (3H, t,
3J ¼ 7.2 Hz, Me), 1.47–1.50 (1H, m, CH), 1.63–1.66 (1H,
CH), 3.58–3.66 (1H, m, CH), 3.67 (1H, d, 2J ¼ 12.0 Hz,
CH), 4.15–4.37 (2H, m, OCH2), 5.75 (1H, s, OH) ppm;
13C NMR: ꢀ ¼ 13.4 (Me), 13.8 (Me), 20.0 (CH2), 29.2
(CH2), 37.8 (CH2), 46.1 (CH2), 64.2 (OCH2), 95.9 (C),
169.6 (C¼O), 196.8 (C¼S) ppm.
Scheme 1
2
m, CH), 3.33 (1H, d, J ¼ 12.0 Hz, CH), 3.36–3.42 (1H, m,
Ethyl 3-(2-hydroxyethyl)-4-hydroxy-2-thioxo-1,3-thiazolane-
4-carboxylate (3b, C8H13NO4S2)
Pale yellow powder, mp 116–118ꢁC, yield 0.43g (86%);
IR (KBr): ꢁꢀ¼ 3192, 1740, 1588, 1489, 1439, 1354, 1185,
1200 cmꢀ1; EI-MS: m=z (%) ¼ 251 (Mþ, 15), 149 (86), 135
(64), 103 (65), 73 (95), 45 (100); 1H NMR: ꢀ ¼ 1.36 (3H, t, 3J ¼
7.2 Hz, Me), 3.33 (1H, d, 2J ¼ 11.0Hz, CH), 3.69–3.74 (2H, m,
Scheme 2
2
NCH2), 3.79 (1H, d, J ¼ 11.0 Hz, CH), 3.94–3.99 (1H, m,
CH), 4.25–4.30 (1H, m, CH), 4.32–4.36 (2H, m, OCH), 4.56
3
(1H, s, OH), 4.67 (1H, t, J ¼ 5.3 Hz, OH) ppm; 13C NMR:
from CS2 and amine 1, which are subsequently
attacked by ethyl bromopyruvate to produce 5.
Intermediate 5 undergoes HBr elimination and cycli-
zation reaction to generate 3.
In conclusion, the reaction of primary alkyl amines
with CS2 in the presence of ethyl bromopyruvate led
to 2-thioxo-1,3-thiazolanes in excellent yields. The
present procedure has the advantage that the reaction
is performed under neutral conditions, and the start-
ing material can be used without any activation or
modification.
ꢀ ¼ 14.0 (Me), 38.2 (CH2), 48.9 (CH2), 59.2 (OCH2), 63.6
(OCH2), 96.4 (C), 168.6 (C¼O), 198.5 (C¼S) ppm.
Ethyl 3-benzyl-4-hydroxy-2-thioxo-1,3-thiazolane-4-
carboxylate (3c, C13H15NO3S2)
Colorless crystals, mp 120–122ꢁC, yield 0.53 g (90%);
IR (KBr): ꢁꢀ¼ 3200, 1747, 1591, 1483, 1431, 1342, 1204,
1151cmꢀ1; EI-MS: m=z (%) ¼ 297 (Mþ, 38), 181 (40), 149
(78), 148 (94), 91 (100), 77 (46), 45 (68); 1H NMR: ꢀ ¼ 1.00
(3H, t, 3J ¼ 7.2 Hz, Me), 3.33 (1H, d, 2J ¼ 12.0Hz, CH), 3.31–
2
3.38 (1H, m, CH), 3.70 (1H, d, J ¼ 12.0Hz, CH), 3.86–3.92
2
(1H, m, CH), 4.41 (1H, d, J ¼ 15.4Hz, CH), 4.97 (1H, s,
OH), 5.46 (1H, d, 2J ¼ 12.0Hz, CH), 7.23–7.26 (3H, m,
3CH), 7.31 (2H, d, 3J ¼ 7.5 Hz, 2CH) ppm; 13C NMR:
ꢀ ¼ 13.5 (Me), 37.9 (CH2), 48.3 (CH2), 64.2 (OCH2), 94.8
(C), 127.9 (CH), 128.3 (2CH), 128.7 (2CH), 135.1 (C),
169.5 (C¼O), 198.8 (C¼S) ppm.
Experimental
Compounds 1, 2, and CS2 were obtained from Fluka and
used without further purification. Mp Electrothermal-9100 ap-

Efficient synthesis of 2-thioxo-1,3-thiazolanes
1481
(CH2), 55.3 (MeO), 64.2 (OCH2), 94.8 (C), 113.7 (2CH),
127.2 (C), 130.1 (2CH), 159.3 (C), 169.6 (C¼O), 198.5
(C¼S) ppm.
Ethyl 3-(2-chlorobenzyl)-4-hydroxy-2-thioxo-1,3-thiazolane-
4-carboxylate (3d, C13H14ClNO3S2)
Pale yellow powder, mp 163–165ꢁC, yield 0.49g (75%); IR
(KBr): ꢁꢀ¼ 3215, 1738, 1489, 1471, 1429, 1340, 1395,
1145 cmꢀ1; EI-MS: m=z (%) ¼ 331 (Mþ, 15), 182 (75), 149
(56), 125 (64), 112 (45), (84); 1H NMR: ꢀ ¼ 1.12 (3H, t,
Ethyl 3-(1-naphthylmethyl)-4-hydroxy-2-thioxo-1,3-
thiazolane-4-carboxylate (3h, C17H17NO3S2)
2
3J ¼ 7.2 Hz, Me), 3.42 (1H, d, J ¼ 12.1Hz, CH), 3.64–3.71
Pale yellow powder, mp 124–126ꢁC, yield 0.60g (87%);
IR (KBr): ꢁꢀ¼ 3214, 1720, 1601, 1512, 1410, 1340, 1225,
1100cmꢀ1; EI-MS: m=z (%) ¼ 347 (Mþ, 10), 206 (54), 199
(58), 141 (100), 127 (48), 45 (84); 1H NMR: ꢀ ¼ 1.12 (3H, t,
(1H, m, CH), 3.81 (1H, d, 2J ¼ 12.1Hz, CH), 3.96–4.05 (1H,
2
m, CH), 4.90 (1H, d, J ¼ 16.4Hz, CH), 5.04 (1H, s, OH),
5.21 (1H, d, 2J ¼ 16.4Hz, CH), 7.19 (2H, t, 3J ¼ 7.6 Hz, 2CH),
7.32 (1H, d, 3J ¼ 7.5 Hz, CH), 7.38 (1H, d, 3J ¼ 7.6 Hz,
CH) ppm; 13C NMR: ꢀ ¼ 13.5 (Me), 37.8 (CH2), 45.6
(CH2), 64.2 (OCH2), 95.2 (C), 126.5 (CH), 128.7 (CH), 129.2
(CH), 129.3 (CH), 132.3 (C), 132.7 (C), 169.0 (C¼O), 198.9
(C¼S) ppm.
2
3J ¼ 7.2 Hz, Me), 3.45 (1H, d, J ¼ 11.9Hz, CH), 3.56–3.64
(1H, m, CH), 3.80 (1H, d, 2J ¼ 11.9Hz, CH), 3.94–4.00 (1H,
2
m, CH), 5.01 (1H, d, J ¼ 15.2Hz, CH), 5.89 (1H, s, OH),
5.27 (1H, d, 2J ¼ 15.2 Hz, CH), 6.68 (1H, t, 3J ¼ 7.2 Hz, CH),
3
3
7.36 (1H, t, J ¼ 7.5Hz, CH), 7.56 (1H, t, J ¼ 7.6 Hz, CH),
3
3
7.60 (1H, t, J ¼ 7.5 Hz, CH), 7.75 (1H, d, J ¼ 7.6 Hz, CH),
3
3
7.88 (1H, d, J ¼ 7.6 Hz, CH), 8.07 (1H, t, J ¼ 7.5 Hz, CH)
ppm; 13C NMR: ꢀ ¼ 13.8 (Me), 35.4 (CH2), 49.3 (CH2), 64.2
(OCH2), 94.8 (C), 121.6 (CH), 122.5 (CH), 125.2 (CH), 125.9
(CH), 126.3 (C), 126.4 (CH), 127.7 (CH), 128.8 (CH), 133.7
(C), 134.0 (C), 169.2 (C¼O), 197.1 (C¼S) ppm.
Ethyl 3-(4-methylbenzyl)-4-hydroxy-2-thioxo-1,3-thiazolane-
4-carboxylate (3e, C14H17NO3S2)
Pale yellow powder, mp 129–131ꢁC, yield 0.53g (85%); IR
(KBr): ꢁꢀ¼ 3195, 1741, 1590, 1481, 1433, 1345, 1200,
1150 cmꢀ1; EI-MS: m=z (%) ¼ 311 (Mþ, 15); 162 (85), 149
1
(45), 105 (100), 91 (44), 45 (68); H NMR: ꢀ ¼ 1.05 (3H, t,
3J ¼ 7.2 Hz, Me), 2.31 (3H, s, Me), 3.35 (1H, d, 2J ¼ 12.0 Hz,
Ethyl 3-phenyl-4-hydroxy-2-thioxo-1,3-thiazolane-4-
carboxylate (3i, C12H13NO3S2)
CH), 3.43–3.46 (1H, m, CH), 3.70 (1H, d, 2J ¼ 12.0Hz, CH),
2
Pale yellow powder, mp 134–136ꢁC, yield 0.58g (83%); IR
(KBr): ꢁꢀ¼ 3196, 1734, 1620, 1524, 1500, 1314, 1162,
1104cmꢀ1; EI-MS: m=z (%) ¼ 283 (Mþ, 5), 206 (65), 135
3.93–3.97 (1H, m, CH), 4.45 (1H, d, J ¼ 15.2Hz, CH), 4.94
2
(1H, s, OH), 5.42 (1H, d, J ¼ 15.2Hz, CH), 7.08 (2H, d,
3
3J ¼ 8.1 Hz, 2CH), 7.23 (2H, d, J ¼ 8.1 Hz, 2CH) ppm; 13C
1
NMR: ꢀ ¼ 13.9 (Me), 21.0 (Me), 37.8 (CH2), 48.1 (CH2), 64.1
(OCH2), 94.7 (C), 128.7 (2CH), 128.9 (2CH), 132.0 (C), 137.6
(C), 169.6 (C¼O), 198.6 (C¼S) ppm.
(86), 148 (66), 77 (100), 45 (84); H NMR: ꢀ ¼ 1.30 (3H, t,
3J ¼ 7.2 Hz, Me), 4.18–4.29 (2H, m, OCH2), 4.31 (1H, d,
2J ¼ 11.5 Hz, CH), 4.41 (1H, d, 2J ¼ 11.5 Hz, CH), 6.81
3
(2H, t, J ¼ 8.2 Hz, 2CH), 7.00 (1H, s, OH), 7.18 (1H, t,
3
3J ¼ 8.2 Hz, CH), 7.45 (2H, d, J ¼ 8.2 Hz, 2CH) ppm; 13C
Ethyl 3-(4-chlorobenzyl)-4-hydroxy-2-thioxo-1,3-thiazolane-
4-carboxylate (3f, C13H14ClNO3S2)
NMR: ꢀ ¼ 14.2 (Me), 35.6 (CH2), 61.6 (OCH2), 92.4 (C),
115.3 (2CH), 119.1 (CH), 128.9 (2CH), 145.8 (C), 166.8
(C¼O), 197.8 (C¼S) ppm.
Pale yellow crystals, mp 153–155ꢁC, yield 0.56 g (85%);
IR (KBr): ꢁꢀ¼ 3220, 1745, 1589, 1480, 1430, 1339, 1201,
1152 cmꢀ1; EI-MS: m=z (%) ¼ 331 (Mþ, 10), 182 (85), 149
1
(57), 125 (100), 111 (85), 45 (62); H NMR: ꢀ ¼ 1.08 (3H, t,
2
3J ¼ 7.2 Hz, Me), 3.37 (1H, d, J ¼ 12.0Hz, CH), 3.51–3.58
References
2
(H, m, CH), 3.72 (1H, d, J ¼ 12.0 Hz, CH), 3.97–4.04 (1H,
1. Fringuelli F, Girotti R, Pizzo F, Vaccaro L (2006) Org Lett
8:2487
2. Yusubov MS, Wirth T (2005) Org Lett 7:519
3. Shibahara F, Nozaki K, Hiyama TJ (2003) J Am Chem
Soc 125:8555
4. Caldas ED, Hosana Conceicu¨a M, Miranda MCC, Souza
L, Lima JF (2001) J Agric Food Chem 49:4521
5. Erian AW, Sherif SM (1999) Tetrahedron 55:7957
6. Beji M, Sbihi H, Baklouti A, Cambon A (1999) J Fluorine
Chem 99:17
2
m, CH), 4.47 (1H, d, J ¼ 15.5Hz, CH), 4.93 (1H, s, OH),
5.35 (1H, d, 2J ¼ 15.5Hz, CH), 7.23 (2H, d, 3J ¼ 7.8 Hz,
2CH), 7.29 (2H, d, 3J ¼ 7.8 Hz, 2CH) ppm; 13C NMR:
ꢀ ¼ 13.5 (Me), 37.9 (CH2), 47.6 (CH2), 64.3 (OCH2), 94.7
(C), 128.3 (2CH), 129.9 (2CH), 133.7 (C), 133.8 (C), 169.5
(C¼O), 198.8 (C¼S) ppm.
Ethyl 3-(4-methoxybenzyl)-4-hydroxy-2-thioxo-1,3-
thiazolane-4-carboxylate (3g, C14H17NO4S2)
Pale yellow powder, mp 150–152ꢁC, yield 0.52g (80%);
IR (KBr): ꢁꢀ¼ 3219, 1744, 1584, 1475, 1395, 1335, 1198,
1149 cmꢀ1; EI-MS: m=z (%) ¼ 327 (Mþ, 5), 178 (85), 149
7. Goel A, Mazur SJ, Fattah RJ, Hartman TL, Turpin JA,
Huang M, Rice WG, Appella E, Inman JK (2002) Bioorg
Med Chem Lett 12:767
8. Mizuno T, Nishiguchi I, Okushi T, Hirashima T (1991)
Tetrahedron Lett 32:6867
9. Rafin C, Veignie E, Sancholle M, Postal D, Len C, Villa P,
Ronco G (2000) J Agric Food Chem 48:5283
10. Len C, Postal D, Ronco G, Villa P, Goubert C,
Jeufrault E, Mathon B, Simon H (1997) J Agric Food
Chem 45:3
1
(66), 121 (64), 107 (85), 45 (62); H NMR: ꢀ ¼ 1.05 (3H, t,
2
3J ¼ 7.2 Hz, Me), 3.31 (1H, d, J ¼ 12.0Hz, CH), 3.46–3.49
2
(1H, m, CH), 3.67 (1H, d, J ¼ 12.0Hz, CH), 3.76 (3H, s,
MeO), 3.94–3.97 (1H, m, CH), 4.41 (1H, d, 2J ¼ 15.2 Hz,
CH), 4.98 (1H, s, OH), 5.39 (1H, d, 2J ¼ 15.4 Hz, CH),
6.81 (2H, d, 3J ¼ 8.2 Hz, 2CH), 7.27 (2H, d, 3J ¼ 8.2 Hz,
2CH) ppm; 13C NMR: ꢀ ¼ 13.5 (Me), 37.9 (CH2), 47.8

1482
I. Yavari et al.
15. Elgemeie GH, Sayed SH (2001) Synthesis:1747
16. Chin-Hsien W (1981) Synthesis:622
17. Yavari I, Hosseini N, Moradi L (2008) Monatsh Chem
139:133
18. Yavari I, Zare H (2007) Monatsh Chem 138:787
19. Yavari I, Hossaini Z, Sabbaghan M, Ghazanfarpour-
Darjani M (2007) Monatsh Chem 138:677
20. Habibi H, Mousavifar L, Yavari I, Yazdanbakhsh MR
(2007) Monatsh Chem 138:603
11. Morf P, Raimondi F, Nothofer HG, Schnyder B, Yasuda
A, Wessels JM, Jung TA (2006) Langmuir 22:658
12. McClain A, Hsieh YL (2004) J Appl Polym Sci 92:218
13. Dunn AD, Rudorf WD (1989) Carbon Disulphide in
Organic Chemistry. Ellis Harwood, Chichester, UK,
p 226
14. Ronconi L, Marzano C, Zanello P, Corsini M, Miolo G,
Macca C, Trevisan A, Fregona D (2006) J Med Chem
49:1648