Rapid microwave assisted synthesis of 3-substituted 4-thioxo-oxazolidin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2006.04.050

The microwave assisted thionation of 3-substituted 4-imino-oxazolidin-2-ones with hydrogen sulfide in dichloromethane-pyridine afforded 3-substituted 4-thioxo-oxazolidin-2-ones.

Full text of DOI:10.1016/j.tetlet.2006.04.050

Tetrahedron Letters 47 (2006) 4241–4243
Rapid microwave assisted synthesis of 3-substituted
4-thioxo-oxazolidin-2-ones
Thomas Kurz,* Mehdi Khankischpur and Khalid Widyan
Institute of Pharmacy, University of Hamburg, Bundesstrasse 45, 20146 Hamburg, Germany
Received 9 February 2006; revised 6 April 2006; accepted 7 April 2006
Available online 9 May 2006
Abstract—The microwave assisted thionation of 3-substituted 4-imino-oxazolidin-2-ones with hydrogen sulfide in dichloromethane–
pyridine afforded 3-substituted 4-thioxo-oxazolidin-2-ones.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
idin-2-ones with hydrogen sulfide in the presence of pyr-
idine in dichloromethane or THF.1,2
4-Functionalized oxazolidin-2-ones have found applica-
tions as drugs and agrochemicals.1,2 While 3-arylamino-
4-thioxo-oxazolidin-2-ones (I) display potent fungicidal
activity, the corresponding 3-alkoxy(arylalkloxy) deriva-
tives (II) are inactive.1,2 In the course of our research
directed to the synthesis and biological activity of
4-functionalized oxazolidin-2-ones, we became inter-
ested in the microwave assisted synthesis of 3-aryl(aryl-
alkyl)-4-thioxo-oxazolidin-2-ones.2,3 Interestingly, an
intensive literature research revealed that the title com-
pounds (III) have not been prepared till now (Fig. 1).
Although a Beilstein search refers to two patents con-
taining 3-aryl(arylalkyl)-4-thioxo-oxazolidin-2-ones (III),
the isomeric 2-thioxo-oxazolidin-4-ones are in fact
described.4,5 Compounds I and II are commonly
prepared by treatment of 3-substituted 4-imino-oxazol-
Microwave assisted syntheses have become an impor-
tant tool in organic and medicinal chemistry. Due to
higher yields, clean reactions and short reaction times,
microwave assisted reactions often offer a considerable
advantage over conventional heating.6 We herein report
the rapid microwave assisted synthesis of previously
unreported 3-substituted 4-thioxo-oxazolidin-2-ones
(5a–k) starting from 3-substituted 4-imino-oxazolidin-
2-ones (4a–k).
2. Results and discussion
Substrates 4a–k have been prepared by reacting cyano-
hydrins (1) subsequently with 1,10-carbonyl-diimidazole
or 1,10-carbonyl-di-(1,2,4-triazole) and primary amines
via carbamates (3) in 51–72% yields (Scheme 1, Table
1).7,8
O
O
O
Ph
NH
Microwave assisted thionation of 4a–k was accomplished
within only 1.5–6 min by reacting substrates 4a–k with a
saturated solution of hydrogen sulfide in dry dichloro-
methane/pyridine. A simple aqueous workup procedure
followed by filtration through a short silica gel column
and recrystallization from an appropriate solvent
afforded the target compounds 5a–k in 54–70% yield
(Scheme 2, Table 2).9
O
N OR3
S
O
N
R3
O
N
R1
R1
Ph
R2
II
Figure 1. 3-Substituted 4-thioxo-oxazolidin-2-ones.
R2
III
S
S
I
Keywords: Microwave assisted synthesis; Thionation; Hydrogen
sulfide; 4-Imino-oxazolidin-2-ones; 4-Thioxo-oxazolidin-2-ones.
In all cases, the completion of the reaction was moni-
tored by IR spectroscopy. While the IR spectra of the
starting materials 4a–k showed two characteristic
*
Corresponding author. Tel.: +49 40 42838 3467; fax: +49 40 42838
6573; e-mail: kurz@chemie.uni-hamburg.de
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.050

4242
T. Kurz et al. / Tetrahedron Letters 47 (2006) 4241–4243
In summary, we have developed a practical and rapid
O
method for the microwave assisted thionation of 3-
substituted 4-imino-oxazolidin-2-ones using hydrogen
sulfide in dichloromethane/pyridine to obtain previously
unreported 3-aryl-, 3-alkyl-, and 3-arylalkyl-substituted
4-thioxo-oxazolidin-2-ones.
N
X
N
OH
H2N-R3
O
CDI or CDT
CH2Cl2
R1
R2
R1
CN
CN
R2
1
2
O
O
H
N R3
N R3
NH
Et3N
O
References and notes
O
R1
R1
CN
1. Sternberg, J. A.; Adams, J. B. (DuPont de Nemours) 1992,
EP 503798; Chem. Abstr. 1993, 118, 80921u.
R2
R2
X: N, CH
4a-k
3
2. Widyan, K.; Kurz, T. Synthesis 2005, 8, 1340–1344.
3. Kurz, T.; Widyan, K. Org. Lett. 2004, 6, 4403–4405.
4. Taber, R. C.; Brooker, L. G. S. (Estman Kodak Co.) Brit.
1,112,034 (Cl C 09b) 01 May 1968; Chem. Abstr. 1969, 70,
12858e.
Scheme 1. Synthesis of 4-imino-oxazolidin-2-ones (4a–k).
5. Jenkins, P. W.; Brooker, L. G. S. (Kodak-Pathe) Fr.
1,400,756 (Cl G 03c) 28 May 1965; Chem. Abstr. 1966, 64,
30052f.
6. (a) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250;
(b) Wathey, B.; Tiemey, J.; Lidstro¨m, P.; Westman, J.
Drug Discovery Today 2002, 7, 373–380; (c) Lidstro¨m, P.;
Tierney, J.; Wathey, Bernard; Westman, J. Tetrahedron
2001, 57, 9225–9283.
Table 1. 3-Substituted 4-imino-oxazolidin-2-ones (4a–k)
4
R1
R2
R3
Yield [%]
a
b
c
d
e
f
1-Naphthyl
CH3
CH3
Ph
Ph
H
H
H
H
H
H
H
H
3-F–Ph
4-CH3–Bn
4-F–Bn
2-Cl–Bn
2-F–Bn
3-Cl–Bn
2-CH3–Bn
4-Cl–Bn
CH3
64
72
69
51
65
66
67
58
59
62
61
Ph
7. Kurz, T.; Widyan, K.; Khankischpur, M. Synthesis, in press.
8. The novel analogs 4e–k have been purified by column
chromatography using EtOAc–hexane (3:7) as an eluent.
Analytically pure products have been obtained after
recrystallization from EtOAc/hexane. For the synthesis of
5,5-disubstituted 4-imino-oxazolidin-2-ones (4j,k) 1,10-car-
bonyl-di-(1,2,4-triazole) and catalytic amounts of DMAP
have been used for the activation of cyanohydrines 1.
Experimental data for compound 4e. 3-(2-Fluorobenzyl)-4-
imino-5-phenyl-oxazolidin-2-one: Colorless solid (65%).
g
h
i
4-CH3–Ph
4-CH3O–Ph
2,4-Cl–Ph
4-Cl–Ph
CH3
H
CH3
CH3
j
2-Cl–Bn
4-CH3–Ph
k
O
O
Mp 82.6ꢁC; IR (KBr): m = 1781, 1667 cmꢀ1 1H NMR
;
H S, CH Cl -pyridine
3
2
2
2
3
(DMSO-d6) d (ppm): 4.74–4.83 (m, 2H), 6.14 (s, 1H), 7.16–
7.23 (m, 2H), 7.32–7.38 (m, 2H), 7.40–7.47 (m, 5H); 13C
NMR (DMSO-d6) d (ppm): 37.55, 79.75, 115.81, 124.82,
127.66, 129.36, 129.72, 129.77, 129.90, 129.98, 134.30,
134.92, 155.96, 161.65; Anal. Calcd for C16H13FN2O2: C,
67.60; H, 4.61; N, 9.85. Found: C, 67.46; H, 4.93; N, 9.91.
9. General procedure for the microwave-assisted synthesis of
5a–k. 0.5 mmol of 4a–k and 5 mL of a saturated solution of
hydrogen sulfide in dry dichloromethane–pyridine were
O
N R
O
N R
microwave
1
1
R
R
S
NH
2
2
R
R
5a-k
4a-k
Scheme 2. Thionation of 4-imino-oxazolidin-2-ones.
added into
a 10 mL glass pressure microwave tube
Table 2. 3-Substituted 4-thioxo-oxazolidin-2-ones (5a–k)
equipped with a magnetic stirrer bar. The tube was closed
with a silicon septum and the reaction mixture was
subjected to microwave irradiation for the indicated time
using parameters a or b (Table 2). The reaction mixture was
allowed to cool to room temperature and was transferred to
a round bottomed flask. The solvent was evaporated,
diethylether (20 mL) was added and the mixture was
washed with 1 M hydrochloric acid (3 · 10 mL). The
organic layer was dried over MgSO4, filtered, and the
solvent was evaporated. The remaining residues were
purified by filtration through a short silica gel column
(3 cm) with CH2Cl2–hexane (3:1) as an eluent. Crystalliza-
tion from Et2O–hexane provided 5a–k as pure pale yellow
solids. Microwave assisted reactions were carried out using
a CEM microwave reactor model Discover. Parameters a;
for compounds 5a,d–h: Discover mode; power: 250 W;
ramp time: 30 s; hold time as indicated in Table 2;
temperature: 40 ꢁC; pressure: 2 bar; PowerMax-cooling
mode. Parameters b; for compound 5b,c,i–k: Discover
mode, power: 300 W; ramp time: 30 s hold time as indicated
in Table 2; temperature: 50 ꢁC; pressure: 2 bar; PowerMax-
cooling mode.
5
R1
R2
R3
Yield [%] Hold time
(min)
a
b
c
d
e
f
1-Naphthyl
CH3
CH3
Ph
Ph
H
H
H
H
H
H
H
H
H
3-F–Ph
4-CH3–Bn 65
4-F–Bn
2-Cl–Bn
2-F–Bn
3-Cl–Bn
2-CH3–Bn 70
4-Cl–Bn
CH3
54
1a
3a
70
62
68
61
5.5a
2a
2a
Ph
2a
g
h
i
4-CH3–Ph
4-CH3O–Ph
2,4-Cl–Ph
4-Cl–Ph
CH3
2.5a
2.5a
5a
68
68
55
54
j
CH3 2-Cl–Bn
CH3 4-CH3–Ph
5.5a
5a
k
a See Ref. 9 for more detailed conditions.
absorption bands at 1760–1795 cmꢀ1 (C@O) and 1664–
1686 cmꢀ1 (C@N), the IR spectra of 4-thioxo-oxazoli-
din-2-ones (5a–k) showed two new absorption bands
at 1789–1811 cmꢀ1 (C@O) and 1215–1230 cmꢀ1 (C@S).

T. Kurz et al. / Tetrahedron Letters 47 (2006) 4241–4243
4243
Experimental data for compounds 5a–k. 3-(3-Fluorophenyl)-
5-naphth-1-yl-4-thioxo-oxazolidin-2-one (5a): Pale yellow
solid (54%). Mp 138 ꢁC; IR (KBr): m = 1811, 1223 cmꢀ1; 1H
NMR (DMSO-d6) d (ppm): 7.24 (s, 1H), 7.43–7.51 (m, 2H),
7.59–7.74 (m, 5H), 7.83–7.85 (m, 1H), 8.05–8.16 (m, 3H);
13C NMR (DMSO-d6) d (ppm): 87.35, 115.73, 115.97,
117.40, 123.40, 124.66, 125.86, 126.74, 127.73, 129.27,
130.23, 131.01, 131.41, 133.81, 134.87, 154.93, 161.19,
203.41; Anal. Calcd for C19H12FNO2S: C, 67.64; H, 3.59;
N, 4.15. Found: C, 67.41; H, 3.66; N, 4.13.
(ppm): 46.30, 89.70, 126.75, 128.06, 128.33, 129.24, 130.21,
130.94, 133.57, 134.60, 137.09, 155.91, 203.33; Anal. Calcd
for C16H12ClNO2S: C, 60.47; H, 3.81; N, 4.41. Found: C,
60.55; H, 4.02; N, 4.36.
3-(2-Methylbenzyl)-4-thioxo-5-p-tolyl-oxazolidin-2-one (5g):
Pale yellow solid (70%). Mp 120 ꢁC; IR (KBr): m = 1792,
1230 cmꢀ1 1H NMR (DMSO-d6) d (ppm): 2.33 (s, 3H),
;
2.38 (s, 3H), 4.98–5.08 (m, 2H), 6.46 (s,1H), 7.07–7.09 (m,
1H), 7.15–7.24 (m, 3H), 7.26–7.34 (m, 4H); 13C NMR
(DMSO-d6) d (ppm): 19.32, 21.17, 44.70, 89.65, 126.27,
126.41, 127.93, 127.99, 129.82, 130.71, 131.82, 132.48,
135.94, 139.85, 156.02, 203.69; Anal. Calcd for
C18H17NO2S: C, 69.43; H, 5.50; N, 4.50. Found: C, 69.36;
H, 5.71; N, 4.36.
5-Methyl-3-(4-methylbenzyl)-4-thioxo-oxazolidin-2-one (5b):
Colorless solid (65%). Mp 54 ꢁC; IR (KBr): m = 1810,
1221 cmꢀ1 1H NMR (DMSO-d6) d (ppm): 1.58–1.60 (d,
;
J = 7.03 Hz, 3H), 2.27 (s, 3H), 4.91 (s, 2H), 5.41–5.46 (q,
J = 6.78 Hz, 1H), 7.14–7.24 (m, 4H); 13C NMR (DMSO-d6)
d (ppm): 19.71, 21.03, 46.39, 85.88, 128.15, 129.48, 131.76,
137.54, 155.87, 206.14; Anal. Calcd for C12H13NO2S: C,
61.25; H, 5.57; N, 5.95. Found: C, 61.37; H, 5.76; N, 5.96.
3-(4-Fluorobenzyl)-5-methyl-4-thioxo-oxazolidin-2-one (5c):
Colorless solid (70%). Mp 57 ꢁC; IR (KBr): m = 1790,
3-(4-Chlorobenzyl)-5-(4-methoxyphenyl)-4-thioxo-oxazolidin-
2-one (5h): Pale yellow solid (68%). Mp 120 ꢁC; IR (KBr):
1
m = 1784, 1225 cmꢀ1; H NMR (DMSO-d6) d (ppm): 3.77
(s, 3H), 5.00–5.08 (m, 2H), 6.37 (s, 1H), 6.97–7.00 (m, 2H),
7.30–7.34 (m, 2H), 7.40–7.46 (m, 4H); 13C NMR (DMSO-
d6) d (ppm): 46.26, 55.63, 89.64, 114.68, 129.01, 129.80,
130.20, 129.04, 133.01, 133.79, 155.81, 160.72, 203.61; Anal.
Calcd for C17H14ClNO3S: C, 58.71; H, 4.06; N, 4.03.
Found: C, 58.36; H, 4.06; N 3.66.
1226 cmꢀ1 1H NMR (DMSO-d6) d (ppm): 1.59–1.61 (d,
;
J = 7.02 Hz, 3H), 4.91–4.99 (m, 2H), 5.41–5.46 (q,
J = 7.02 Hz, 1H), 7.15–7.21 (m, 2H), 7.38–7.43 (m, 2H);
13C NMR (DMSO-d6) d (ppm): 19.62, 45.93, 85.98, 115.63,
115.85, 130.39, 130.47, 155.84, 160.87, 206.22; Anal. Calcd
for C11H10FNO2S: C, 55.22; H, 4.21; N, 5.85. Found: C,
55.32; H, 4.39; N, 5.82.
5-(2,4-Dichlorophenyl)-3-methyl-4-thioxo-oxazolidin-2-one
(5i): Pale yellow solid (68%). Mp 88 ꢁC; IR (KBr):
m = 1802 cmꢀ1 1H NMR (DMSO-d6) d (ppm): 3.30 (s,
;
3H), 6.51 (s, 1H), 7.54–7.71 (m, 2H), 7.76–7.77 (d,
J = 2.26 Hz, 1H); 13C NMR (DMSO-d6) d (ppm): 30.00,
86.33, 127.96, 129.85, 130.44, 133.44, 134.26, 135.81,
155.65, 201.50; Anal. Calcd for C10H7Cl2NO2S: C, 43.50;
H, 2.56; N, 5.07. Found: C, 43.41; H, 2.60; N, 5.02.
3-(2-Chlorobenzyl)-5-phenyl-4-thioxo-oxazolidin-2-one (5d):
Pale yellow solid (62%). Mp 110 ꢁC; IR (KBr): m = 1798,
1231 cmꢀ1 1H NMR (DMSO-d6) d (ppm): 5.08–5.17 (m,
;
2H), 6.50 (s, 1H), 7.29–7.38 (m, 3H), 7.46–7.53 (m, 6H); 13
C
NMR (DMSO-d6) d (ppm): 45.00, 89.76, 127.79, 128.21,
128.59, 129.25, 129.88, 129.96, 130.23, 131.49, 132.20,
134.58, 155.76, 203.38; Anal. Calcd for C16H12ClNO2S:
C, 60.47; H, 3.81; N, 4.41. Found: C, 60.20; H, 3.95; N,
4.42.
3-(2-Chlorobenzyl)-5-(4-chlorophenyl)-5-methyl-4-thioxo-
oxazolidin-2-one (5j): Pale yellow solid (55%). Mp 90 ꢁC;
IR (KBr): m = 1793, 1215 cmꢀ1 1H NMR (DMSO-d6) d
;
(ppm): 2.09 (s, 3H), 5.04–5.13 (m, 2H), 7.11–7.13 (m, 1H),
7.29–7.37 (m, 2H), 7.48–7.60 (m, 5H); 13C NMR (DMSO-
d6) d (ppm): 26.15, 45.03, 93.65, 127.47, 128.12, 128.70,
129.52, 129.60, 130.97, 131.84, 134.07, 136.48, 154.42,
206.23; Anal. Calcd for C17H13Cl2NO2S: C, 55.75; H,
3.58; N, 3.82. Found: C, 55.57; H, 3.61; N, 3.79.
3-(2-Fluorobenzyl)-5-phenyl-4-thioxo-oxazolidin-2-one (5e):
Pale yellow solid (68%). Mp 102 ꢁC; IR (KBr): m = 1789,
1227 cmꢀ1 1H NMR (DMSO-d6) d (ppm): 5.07–5.15 (m,
;
2H), 6.44 (s, 1H), 7.18–7.26 (m, 2H), 7.36–7.46 (m, 7H); 13
C
NMR (DMSO-d6) d (ppm): 41.35, 89.55, 124.94, 128.05,
129.25, 130.12, 130.20, 130.41, 130.49, 134.62, 134.67,
155.71, 159.16, 203.10; Anal. Calcd for C16H12FNO2S: C,
63.77; H, 4.01; N, 4.65. Found: C, 63.65; H, 4.30; N, 4.62.
3-(3-Chlorobenzyl)-5-phenyl-4-thioxo-oxazolidin-2-one (5f):
Pale yellow solid (61%). Mp 81 ꢁC; IR (KBr): m = 1801,
5,5-Dimethyl-4-thioxo-3-p-tolyl-oxazolidin-2-one (5k): Pale
yellow solid (54%). Mp 122 ꢁC; IR (KBr): m = 1804,
1217 cmꢀ1 1H NMR (DMSO-d6) d (ppm): 1.73 (s, 6H),
;
2.37 (s, 3H), 7.33–7.38 (m, 4H); 13C NMR (DMSO-d6) d
(ppm): 20.75, 23.04, 26.53, 92.81, 127.51, 129.60, 131.12,
139.15, 153.96, 209.74; Anal. Calcd for C12H13NO2S: C,
61.25; H, 5.57; N, 5.95. Found: C, 61.15; H, 5.61; N,
5.86.
1230 cmꢀ1 1H NMR (DMSO-d6) d (ppm): 5.07 (s, 2H),
;
6.46 (s, 1H), 7.33–7.47 (m, 9H); 13C NMR (DMSO-d6) d