N-methylimidazole-promoted efficient synthesis of functionalized 1,3-oxazoline-2-thiones under solvent-free conditions

Article abstract of DOI:10.1055/s-2008-1078403

An efficient synthesis of ethyl 2-thioxo-2,3-dihydro-1,3-oxazole-5- carboxylates or ethyl 5-methyl-2-thioxo-2,3-dihydro-1,3-oxazole-4-carboxylates, under solvent-free conditions, is described via reaction between ammonium thiocyanate, acid chlorides, and

Full text of DOI:10.1055/s-2008-1078403

LETTER
1287
N-Methylimidazole-Promoted Efficient Synthesis of Functionalized
1,3-Oxazoline-2-thiones under Solvent-Free Conditions
N
-Methy
s
limidazol
s
e-Promote
a
d
S
ynthesis of Fu
Y
nctionalized 1,3-
O
a
xazoline-2
v
Chemistry Department, Tarbiat Modares University, P. O. Box 14115-175, Tehran 18716, Iran
Fax +98(21)82886544; E-mail: yavarisa@modares.ac.ir
Received 12 February 2008
thiones.1,2 Syntheses of 1,3-oxazoline-2-thiones have
been reported using condensation of either thiocyanic
acid3–6 or isothiocyanates7 with an a-hydroxycarbonyl
substrate, or condensation of thiophosgene with an ami-
Abstract: An efficient synthesis of ethyl 2-thioxo-2,3-dihydro-1,3-
oxazole-5-carboxylates or ethyl 5-methyl-2-thioxo-2,3-dihydro-
1,3-oxazole-4-carboxylates, under solvent-free conditions, is de-
scribed via reaction between ammonium thiocyanate, acid chlo-
rides, and ethyl bromopyruvate or ethyl 2-chloroacetoacetate in the noketone.8 The balance of reactivity of a-hydroxycarbon-
presence of N-methylimidazole.
yl systems with thiocyanic acid toward the formation of
either 1,3-oxazolidine-2-thione or 1,3-oxazoline-2-thione
Key words: oxazole, ethyl bromopyruvate, N-methylimidazole,
ammonium thiocyanate, benzoyl chloride, ethyl 2-chloroacetoace-
tate
has been reported recently.9,10
As part of our current studies on the development of new
routes in heterocyclic synthesis,11–13 we report an efficient
synthetic route to functionalized 1,3-oxazoline-2-thiones.
Thus, the reaction of ammonium thiocyanate (1), acid
chlorides 2, ethyl bromopyruvate (3) in the presence of N-
methylimidazole (20 mol%), under solvent-free condi-
tions, produced ethyl 2-thioxo-2,3-dihydro-1,3-oxazole-
5-carboxylates 4 in good yields14 (Scheme 1).
1,3-Oxazoline-2-thiones possess a simple heterocyclic
frame which has been barely explored compared to its
nonaromatic counterpart 1,3-oxazolidine-2-thione, with
only relatively simple precursors related to a-hydroxyke-
tones having been converted into 1,3-oxazoline-2-
N
2, 4
R
Yield (%) of 4
S
N
O
O
a
b
Ph
85
95
Me
CO2Et
N
O
NH4SCN
+
+
Br
4-MeC6H4
R
R
Cl
O
solvent-free, r.t.
4-BrC6H4
4-ClC6H4
4-O2NC6H4
c
d
e
75
70
85
CO2Et
1
2
3
f
g
t-Bu
Et
83
86
Scheme 1
N
O
N
NMe
O
S
3
+
C
R
S
1
2
R
R
N
N
NMe
5
6
O
S
O
S
NMe
N
N
S
NMe
O
R
N
N
N
NMe
O
R
N
4
O
O
_
EtO2C
N
_
HBr
NMe
EtO2C
Br
CO2Et
7
8
9
Scheme 2
SYNLETT 2008, No. 9, pp 1287–1288
x
x.
x
x.
2
0
0
8
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1078403; Art ID: D05208ST
© Georg Thieme Verlag Stuttgart · New York

1288
I. Yavari et al.
LETTER
N
N
S
2, 11
R
Yield (%) of 11
O
O
O
O
Me
a
b
c
d
Ph
85
80
76
75
NH4SCN
+
+
N
O
R
OEt
R
Cl
4-MeC6H4
4-BrC6H4
4-O2NC6H4
solvent-free, r.t.
Cl
EtO2C
Me
1
2
10
11
Scheme 3
(5) Kapsomenos, G. S.; Akrivos, P. D. D. Can. J. Chem. 1988,
66, 2835.
(6) Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1998, 63, 551.
(7) Gonzalez-Romero, C.; Martinez-Palou, R.; Jimenez-
Vazquez, H. A.; Fuentes, A.; Jimenez, F.; Tamariz, J.
Heterocycles 2007, 71, 305.
(8) Bobosik, V.; Piklerova, A.; Maretvon, A. Collect. Czech.
Chem. Commun. 1983, 48, 3421.
(9) Tatibouët, A.; Lawrence, S.; Rollin, P.; Holman, G. D.
Synlett 2004, 1945.
(10) Leconte, N.; Silva, S.; Tatibouët, A.; Rauter, A. P.; Rollin, P.
Synlett 2006, 301.
(11) Yavari, I.; Mirzaei, A.; Moradi, L. Helv. Chim. Acta 2006,
89, 2825.
(12) Yavari, I.; Sabbaghan, M.; Hossaini, Z. Synlett 2006, 2501.
(13) Yavari, I.; Souri, S. Synlett 2007, 2969.
(14) General Procedure for the Preparation of Compounds 4
and 11: A stirred mixture of ammonium isothiocyanate
(0.15 g, 2 mmol) and acid chloride 2 (2 mmol) was warmed
at about 90 °C in a water bath for 5 min and ethyl
bromopyruvate (0.39 g, 2 mmol) or ethyl 2-chloroaceto
acetate (0.33 g, 2 mmol) was added slowly. The mixture was
allowed to cool to r.t. and N-methylimidazole (0.032 g, 20
mol%) was added. The reaction mixture was stirred for 12 h
and extracted with Et2O (2 mL) to afford the pure title
compounds.
The structures of compounds 4a–g were assigned by a
1
consideration of their IR, H NMR, 13C NMR spectro-
scopic and mass spectrometric data. The 1H NMR spectra
of 4a–g exhibited characteristic signals for methine (d =
7.52–7.64 ppm) protons. The 13C NMR spectra of the 1,3-
oxazoline-2-thione ring system of 4a showed signals at
d = 118.4 (CH), 139.8 (C), 156.6 (C=O), 176.7 (C=O),
and 178.1 (C=S) ppm. The mass spectra of 4a–g displayed
the molecular ion peaks at appropriate m/z values.
A tentative mechanism for this transformation is proposed
in Scheme 2. The reaction starts with the formation of
isothiocyanate 5, followed by addition of N-methylimida-
zole and formation of the 1:1 adduct 6, which is subse-
quently attacked by ethyl bromopyruvate to produce 7.
Intermediate 7 subsequently undergoes cyclization and
loss of N-methylimidazole to generate 4.
To extend our knowledge of this reaction, we performed
the reaction between ethyl 2-chloroacetoacetate (10), am-
monium thiocyanate, and acid chlorides 2 in the presence
of N-methylimidazole (20 mol%). This reaction led to the
formation of ethyl 3-aroyl-5-methyl-2-thioxo-2,3-dihy-
dro-1,3-oxazole-4-carboxylates 11 in good yields14
(Scheme 3).
Compound 4a: pale yellow crystals; yield: 0.38 g (85%); mp
129–131 °C. IR (KBr): 1724, 1631, 1585, 1518, 1470 cm–1.
1H NMR: d = 1.45 (t, 3J = 7.2 Hz, 3 H, Me), 4.46 (q, 3J = 7.2
Hz, 2 H, OCH2), 7.52 (t, 3J = 7.8 Hz, 2 H, 2 × CH), 7.61 (t,
3J = 6.1 Hz, 1 H, CH), 7.65 (s, 1 H, CH), 7.52 (d, 3J = 6.1 Hz,
2 H, 2 × CH). 13C NMR: d = 14.6 (Me), 63.0 (OCH2), 118.4
(CH), 128.9 (2 × CH), 130.5 (2 × CH), 133.8 (CH), 134.9
(C), 139.8 (C), 156.6 (C=O), 176.7 (C=O), 178.1 (C=S). EI–
MS: m/z = 227 (10) [M+], 121 (20), 105 (100), 77 (90), 57
(30), 51 (64), 45 (36). Anal. Calcd for C13H11NO4S (277.29):
C, 56.31; H, 4.00; N, 5.05. Found: C, 56.30; H, 4.03; N, 5.00.
Compound 11a: white powder; yield: 0.49 g (85%); mp
140–142 °C. IR (KBr): 1720, 1635, 1582, 1510, 1475 cm–1.
1H NMR: d = 1.38 (t, 3J = 7.2 Hz, 3 H, Me), 2.68 (s, 3 H, Me),
4.34 (q, 3J = 7.2 Hz, 2 H, OCH2), 7.48 (t, 3J = 7.5 Hz, 2 H,
2 × CH), 7.58 (t, 3J = 7.5 Hz, 1 H, CH), 8.31 (d, 3J = 7.5 Hz,
2 H, 2 × CH). 13C NMR: d = 13.8 (Me), 14.1 (Me), 62.0
(OCH2), 110.4 (C), 128.4 (2 × CH), 129.9 (2 × CH), 133.1
(CH), 134.8 (C), 155.5 (C), 160.6 (C=O), 176.1 (C=O),
177.5 (C=S). EI–MS: m/z = 291 (15) [M+], 186 (78), 105
(100), 77 (48), 45 (48). Anal. Calcd for C14H13NO4S
(291.32): C, 57.72; H, 4.50; N, 4.81. Found: C, 57.76; H,
4.54; N, 4.80.
Compounds 11a–d were again fully characterized accord-
1
13
ing to their elemental analyses and IR, H NMR and C
NMR spectra.
In conclusion, the reaction between ethyl bromopyruvate
or ethyl 2-chloroacetoacetate, ammonium thiocyanate,
and acid chlorides in the presence of N-methylimidazole
(20 mol%) leads to the functionalized 2-thioxo-2,3-dihy-
dro-1,3-oxazoles in good yields. This procedure has the
advantage that the reaction is performed under neutral
conditions, and the starting materials can be used without
any preactivation or modification.
References and Notes
(1) Willems, J. F.; Vandenberghe, A. Bull. Soc. Chim. Belg.
1961, 70, 745.
(2) Lacasse, G.; Muchowki, J. M. Can. J. Chem. 1972, 50, 3082.
(3) Bradscher, C. K.; Jones, W. J. J. Org. Chem. 1967, 32, 2079.
(4) Guimon, C.; Pfister-Guillouzo, G.; Arbelot, M.; Chanon, M.
Tetrahedron 1974, 30, 3831.
Synlett 2008, No. 9, 1287–1288 © Thieme Stuttgart · New York

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