Synthesis of 3-alkyloxazolidin-2,4-diones using 2-chloroacetamides, carbon dioxide and 1,8-diazabicyclo[5.4.0]undecene (DBU)

Article abstract of DOI:10.1016/j.tetlet.2009.06.109

Diazabicyclo[5.4.0]undecene (DBU) reacts with carbon dioxide and N-subsititued-2-chloroacetoamides in a very simple one-step procedure, to give the corresponding 3-substituted oxazolidin-2,4-diones in excellent yields.

Full text of DOI:10.1016/j.tetlet.2009.06.109

Tetrahedron Letters 50 (2009) 5123–5125
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Tetrahedron Letters
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Synthesis of 3-alkyloxazolidin-2,4-diones using 2-chloroacetamides, carbon
dioxide and 1,8-diazabicyclo[5.4.0]undecene (DBU)
Guido Galliani b, Bruno Rindone a, Francesco Saliu a,
*
a Department of Environmental Sciences, University of Milano- Bicocca, Piazza della Scienza 1, 20126 Milano, Italy
b Chorisis, Via Roberto Lepetit 34, Gerenzano (VA), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Diazabicyclo[5.4.0]undecene (DBU) reacts with carbon dioxide and N-subsititued-2-chloroacetoamides
in a very simple one-step procedure, to give the corresponding 3-substituted oxazolidin-2,4-diones in
excellent yields.
Received 22 May 2009
Revised 20 June 2009
Accepted 23 June 2009
Available online 27 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
3-Alkyloxazolidin-2,4-diones
Carbon dioxide
DBU
Amines
Chemical synthesis
1. Introduction
2. Results and discussion
Oxazolidine-2,4-diones are used as anticonvulsants, herbicides
or chemical intermediates.1,2 TrimethadioneÒ (3,5,5- trimethylox-
azolidine-2,4-dione), ParamethadioneÒ (5-ethyl-3,5-dimethyloxa-
zolidine-2,4-dione) and MalidoneÒ (3-allyl-5-methyloxazolidine-
2,4-dione)3 are important commercial products.
The preparation of 3-substituted oxazolidin-2,4-diones employs
toxic and hazardous compounds such as phosgene and isocya-
nates.4–7 Carbon dioxide fixation8 offers a greener alternative to
this chemistry.
The ability of amidines such as 1,8-diazabicyclo[5.4.0]undecene
(DBU) to promote a new C–N bond formation in reactions involving
carbon dioxide fixation, has been described recently in the synthe-
sis of formanilide and carbanilide9, of 2,4-dihydroquinazolines10, of
1-H-quinazolines-2,4-diones11 and of N-alkyl carbamates.12
We wish to report a very easy and highly efficient procedure to
prepare 3-substituted oxazolidin-2,4-diones from primary chloro-
acetamides, by directly incorporating carbon dioxide in the pres-
ence of a stoichiometric amount of DBU. To the best of our
knowledge, it is the first example, in the preparation of these com-
pounds, of the use of carbon dioxide with an organic base and
without electrochemical methodologies.13–18
In an exploratory experiment, N-benzyl-2-chloroacetamide (3a:
X = Cl; R = benzyl), prepared via the reaction of chloroacetylchlo-
ride (2: X = Cl) with benzylamine (1: R = benzyl) (Scheme 1), was
put into an autoclave with carbon dioxide (20 bar) and a stoichi-
ometric amount of 1,8-diazabicyclo[5.4.0]undecene (DBU, 4). After
4 h at 80 °C the crude reaction mixture was separated by silica gel
chromatography and 3-benzyloxazolidin-2,4-dione (6a: R = ben-
zyl) was obtained in excellent yield (96%).
Different primary N-alkylchloroacetamides gave different 3-
alkyloxazolidin-2,4-diones (6) in excellent yields. On the contrary
N-phenylchloroacetamide (3h: R = phenyl) gave the corresponding
3-phenyloxazolidin-2,4-dione (6h: R = phenyl) in very low yield
and 3-adamantylchloroacetamide (3g: X = Cl, R = adamantyl) did
not react (Table 1).
Using amides lacking the a–chlorine atom produced carbamate
salts (5). In fact, upon performing the DBU-assisted carbonatation
of the propionamide (3: X = Me) in dichloromethane, the reaction
product showed an IR band at 1648 cmÀ1, consistent with the for-
mation of the carbamate salt (5: X = Me).24
This suggests a plausible reaction pathway involving carboxyl-
ation of the starting chloroacetamide by DBU, to form a carbamate
salt (5: X = Cl) which undergoes intramolecular SN2 cyclization,
and where the chloride ion acts as the leaving group to give (6).
If DBU is not present, no reaction of the chloroacetamide (3:
X = Cl) with CO2 is observed.
* Corresponding author. Tel.: +39 02 642813; fax: +39 02 64482839.
E-mail address: francesco.saliu@unimib.it (F. Saliu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.109

5124
G. Galliani et al. / Tetrahedron Letters 50 (2009) 5123–5125
and pyridine (10 mmol) in 150 ml of tetrahydrofuran. The solution
N
was stirred for 4 h at room temperature, then 100 mL of ethyl ace-
tate was added and the organic phase was washed three times
with 100 mL portions of water, and then it was dried over sodium
sulfate. Evaporation of the organic phase under reduced pressure
gave the N-alkyl 2-chloroacetoamides (3).
N
(4)
1) K2CO3
2) EtOAc
DBU
DBUH+Cl-
(b) 3-Alkyl-oxazolidine-2,4-dione (6): all the experiments were
carried out in a 100 mL autoclave equipped with temperature con-
trol. In a typical experiment, 2 mmol of N-alkyl-2-chloroacetoa-
mide (3) and 2 mmol of DBU (4) were dissolved in 20 mL of
acetonitrile and the solution was put in a quartz reactor which
was inserted into the autoclave. This was then charged with carbon
dioxide (99.8%), 20 bar, placed in an oil bath and left to react for the
required time at 80 °C. Then the autoclave was cooled, excess gas
was released slowly and the reaction mixture was purified by col-
umn chromatography on silica gel R = 50 eluting with dichloro-
methane–ethyl acetate 1:1.
CO2
O
O
O-DBUH+
NR
X
(5)
O
NHR
O
O
n-Pentyloxazolidine-2,4-dione: MS (EI 70 ev) m/z: 171 (M+) 156,
142, 129, 115, 102, 70,56; 1H NMR (CDCl3, d): 0.84–0.87 (m,3H),
1.25–1.32 (m,4H), 1.59–1.63 (m,2H), 3.48–3.52 (m,2H), 4.65
(s,2H); 13C NMR (CDCl3, d): 14.0 (CH3), 22.3 (CH2), 27.4 (CH2),
28.9 (CH2), 40.4 (CH2), 68.0 (CH2), 156.2 (C@O), 170.9 (C@O).
n-Hexyloxazolidine-2,4-dione: MS (EI 70 ev) m/z: 185 (M+), 170,
156, 115, 102, 70, 56; 1H NMR (CDCl3, d): 0.82–0.85(m,3H), 1.22–
1.30 (m,6H); 1.59–1.63(m,2H)); 3.48–3.52 (m,2H); 4.65 (s,2H);
13C NMR(CDCl3, d): 14.0 (CH3), 22.7 (CH2), 27.5 (CH2), 29.1 (CH2),
32.4 (CH2),40.4 (CH2), 68.0 (CH2), 156.2 (C@O), 170.9 (C@O).
Cyclohexyloxazolidine-2,4-dione: MS (EI 70 ev) m/z: 183
(M+),102; 1H NMR (CDCl3, d): 1.22–1.39 (m,4H), 1.48–73 (m,6H);
2.02–2.14 (m,1H); 3.82–3.88 (m,2H); 4.65 (s,2H); 13C NMR(CDCl3,
d): 24.6 (CH2), 22.7(CH2), 27.5(CH2), 29.1(CH2), 32.4(CH2), 40.2
(CH), 68.0 (CH2), 156.2 (C@O), 170.9 (C@O).
X
pyridine
NR
NH2R
(1)
O
(6)
(3)
Cl
X
O
(2)
Scheme 1. Synthesis of 3 alkyloxazolidin-2,4-diones.
Table 1
Yield in 3-substituted oxazolidine-2,4-diones (6)
Entry
R
Substrate
Product
Yielda (%)
1
2
3
4
5
6
7
8
Benzyl
3a
3b
3c
3d
3e
3f
6a15,17–21
6b19,22
6c19,21
6d
96
Cyclohexyl
n-Pentyl
n-Hexyl
i-Propyl
Allyl
87b
95
i-Propyloxazolidine-2,4-dione: MS (EI 70 ev) m/z: 143 (M+), 128,
102, 70, 56; 1H NMR (CDCl3, d): 1.40 (d, J = 7 Hz, 6H), 3.42–3.53
(m, 1H); 4.58 (s, 2H); 13C NMR(CDCl3, d: 19.8 (CH3), 38.2 (CH),
68.0 (CH2), 156.2 (C@O), 170.9 (C@O).
96
6e
88b
86
6f16–18,20,21
Adamantyl
Phenyl
3g
3h
6g
0b,c
5b,c
6h15–17,20,22,23
a
Acknowledgements
Isolated product, reaction time 4 h.
Reaction time 14 h.
GC yield.
b
c
A special thanks to INOXRIVA s.r.l. for providing us with stain-
less steel components and instrumental assembly for pressure con-
trol. We would also like to thank Giovanni Bosetti for technical
support, and Daniel Ehman, Emma Page, Moira Pringle and our stu-
dents Benedetto Putomatti Andrea Agnelli, Giusy Cardinale, for
their collaboration.
About 70% of DBU may be recovered by dissolving the reaction
mixture in methylene chloride and washing the resulting solution
three times with 100 mL of water. The collected aqueous extracts
are treated with solid K2CO3 and extracted with ethyl acetate.
The organic phase was dried over anhydrous sodium sulfate, fil-
tered and evaporated under reduced pressure to recover DBU.
Other bases were also tested for their ability to promote the
reaction under the same experimental conditions used with DBU:
triazabicyclodecene (TBD) gave 3-benzyloxazolidin-2,4-dione (6a)
from (3a) in 85% yield; 1,8-dimethylaminonaphthalene (DMAN)
and triethylamine were almost ineffective; no reaction was noticed
with sodium hydroxide.
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