Regio- and stereoselective synthesis of functionalized oxazolidin-2-ones from the reaction of α-epoxyketones with urea

Article abstract of DOI:10.1007/s00706-007-0820-1

A regio- and stereoselective synthesis of functionalized 4,5-disubstituted oxazolidin-2-ones is reported with moderate to good yields from the reaction of α-epoxyketones with urea in the presence of p-toluenesulfonic acid as the catalyst.

Full text of DOI:10.1007/s00706-007-0820-1

Monatsh Chem 139, 663–667 (2008)
DOI 10.1007/s00706-007-0820-1
Printed in The Netherlands
Regio- and stereoselective synthesis of functionalized oxazolidin-2-ones
from the reaction of a-epoxyketones with urea
Farzad Nikpour, Sajjad Mohebbi, Touraj Paibast, Mahdi Beigvand
Department of Chemistry, Faculty of Sciences, University of Kurdistan, Sanandaj, Iran
Received 21 September 2007; Accepted 30 September 2007; Published online 21 April 2008
# Springer-Verlag 2008
Abstract A regio- and stereoselective synthesis of
functionalized 4,5-disubstituted oxazolidin-2-ones is
reported with moderate to good yields from the reac-
tion of ꢀ-epoxyketones with urea in the presence of
p-toluenesulfonic acid as the catalyst.
size or to modify such compounds are developed
and exploitation of non-toxic molecules and sim-
ple reagents with good reaction yields could be of
interest.
Keywords Regioselective; Stereoselective; ꢀ-Epoxyketones;
Oxazolidin-2-ones; Heterocycles.
Results and discussion
Here, we wish to report an easy strategy, which
allows the regio- and stereoselective preparation of
4,5-disubstituted oxazolidin-2-ones 2, based on the
reaction of the ꢀ-epoxyketones 1 with urea as
promising starting materials, in the presence of a
catalytic amount of p-toluenesulfonic acid (PTSA)
in DMF (Scheme 1). The results are summarized in
Table 1.
As shown in Table 1, the majority of the pre-
pared and isolated compounds are cis-isomers.
Furthermore, we found that when electron-donating
groups are present on Ar2, both of the reaction rates
and the reaction yields increase; however, electron-
withdrawing groups on Ar2 cause no reaction. The
plausible mechanisms are proposed in Scheme 2. It
seems that in an acid mediated in a polar solvent,
such as DMF, the acid mediated reaction begins with
the formation of transition state 3 (Path A). Ring
opening of 3 followed by rotation of the Cꢀ–Cꢁ
bond produces the intermediate 4. Cyclization of 4
under the same reaction conditions leads to the syn-
thesis of the cis-oxazolidin-2-ones 2. The trans-iso-
mers might be obtained through the formation of the
Introduction
Functionalized chiral oxazolidin-2-ones (Evans’ chi-
ral auxiliaries) have often been used as versatile chi-
ral synthons in asymmetric syntheses of biologically
active compounds or their synthetic intermediates.
They are chiral auxiliaries in many important asym-
metric syntheses [1] and used as interesting biolog-
ically active compounds themselves [2]. Owing to
the potent activity of oxazolidin-2-ones, consider-
able attention has been focused on their synthesis
[3]. They are generally prepared from chiral 1,2-
amino alcohols or their precursors chiral ꢀ-amino-
acids with a carbonyl source, such as phosgene [4]
(or diphosgene) and dialkyl carbonates [5] (or alkyl
chloroformates). Also, intramolecular nitrene inser-
tion of alkyl azidoformates has been reported [6].
It is still important that effective methods to synthe-
Correspondence: Farzad Nikpour, Department of Chemistry,
Faculty of Sciences, University of Kurdistan, P.O. Box 66315-
416, Sanandaj, Iran. E-mail: fnikpour@uok.ac.ir

664
F. Nikpour et al.
Scheme 1
Table 1 Reaction of ꢀ-epoxyketones 1a–1l with urea in the
presence of PTSA in DMF
pathway A is the more liable route for carrying out
the reaction. The results also show regioselectivity
on the Cꢁ atom. In fact, in the absence of an acid
catalyst, nucleophilic attack may occur on both Cꢀ
and Cꢁ atoms of an ꢀ-epoxyester [7], however, in the
case of ꢀ-epoxyketones, Cꢁ is more reactive than Cꢀ
against nucleophiles and in acid catalyst solution
which ring opening of epoxides achieves through
cation formation, Cꢁ–O bond breaking is liable for
beginning and progression of the reaction. Thus, the
reactions are carried out with high regioselectivity in
acidic solution and no 7 is obtained (Scheme 3).
Besides, instability of the Cꢁ-cation in the presence
of electron-withdrawing groups on Ar2, causes no
reaction to occur.
Ar1
Ar2
Time= Conversion=
h
Yield 2=
a
b
%
%
cis trans
a
b
c
d
e
f
g
h
i
Ph
Ph
Ph
4-Me
4-Me
5
4
4
5
3
5
4
3
3
7
7
7
82
45 24
56 20
100
100
80
100
85
85
84
90
–
4-Me
4-MeO Ph
4-MeO 4-MeO
4-Br
Ph
80
73 trace
77
–
–
Ph
60 trace
74 trace
55 trace
3-Me
2-MeO
2-MeO
2-Cl
3-NO2
4-NO2
Ph
4-Me
Ph
Ph
68
–
–
–
–
–
–
j
k
l
–
–
The reactions were carried out in DMF as an ex-
cellent polar-aprotic solvent. It is water miscible,
therefore, in the work-up process, it is simple to re-
move the solvent, the residual urea, and PTSA by
washing of the reaction mixture in water.
4-Me
–
a
Based on consumed ꢀ-epoxyketones. b Isolated yield based
on consumed ꢀ-epoxyketones
open-carbocation 5 and cyclization of the intermedi-
ate 6 (Path B). Since the major products are cis-iso-
mers, formation of the transition state 3 through the
The identification and characterization of the
products were carried out by means of their physical
and spectroscopic data. The IR spectra of compounds
Scheme 2

Regio- and stereoselective synthesis of functionalized oxazolidin-2-ones
665
Scheme 3
Hz. Mass spectra were recorded with a Finnigan-MAT 8430
mass spectrometer operating at an ionization potential of
70eV. The synthesis of the ꢀ-epoxyketones was achieved by
using the published method [9].
2 in comparison with the ꢀ-epoxyketones 1 show a
CO-stretching of carbamate carbonyl in about ꢂꢀ¼
1740–1725cmꢀ1 and a shift of the CO-stretching of
the ketone carbonyl to higher frequency due to the
ring expansion and loss of the epoxide ring strain.
The stereochemistry of the major products was
identified as cis. Based on our previous investigation
on the synthesis of 1,3-dioxolanes [8] from 1, the
coupling-constants of C4–H and C5–H in the cis-iso-
mer are larger than of those in the trans-isomer. Also,
in cis-orientation, C4–H and C5–H (especially C4–
H) appear in lower field in comparison with those
in trans-orientation, because of the anisotropic effect
of C4-aryl and C5-aroyl groups. It also was observed
General reaction procedure
In a 10 cm3 round bottom flask, 1 mmol ꢀ-epoxyketones
1a–1i was dissolved in 2 cm3 of DMF and 0.1 mmol PTSA
was added. To this solution, 0.15 g urea (2.5 mmol) was
added and the mixture was heated at 60–70 ꢁC for the times
indicated in Table 1. The mixture was washed with cold-
water (three times) to remove solvent and the residues of
urea and PTSA. The products were separated and purified
by thin-layer chromatography on 20ꢂ20 plates of silicagel
60 GF254 with n-hexane=EtOAc as eluent.
cis-5-Benzoyl-4-phenyloxazolidin-2-one (cis-2a, C16H13NO3)
IR (liquid film): ꢂꢀ¼ 3465 (NH), 1726 (CO-carbamate), 1687
1
that the NH-signal in H NMR appears in ꢃ ¼ 3.5–
(CO-ketone) cmꢀ1
;
1H NMR (250MHz, CDCl3): ꢃ ¼ 8.51
4.2 instead of 6–7 ppm. It can be confirmed by ex-
change of the NH-proton in the presence of D2O,
which causes disappearance of the NH-signal. Prob-
ably, the aryl group in the C4-position is perpendic-
ular to the NH-bond; thus, the shielding effect of the
aryl group causes the NH-signal to appear at higher
field. Two CO-peaks are observed in the 13C NMR
spectrum at about ꢃ ¼ 197 and 165–160 ppm related
to ketone and carbamate carbonyl groups. Also, in
all cases molecular ion-peaks with low abundances
appear in the mass spectra.
3
3
(d, JHH ¼ 7.2 Hz, 2H–Ar), 8.04 (dd, JHH ¼ 7.8, 7.0 Hz,
3
2H–Ar), 7.78–7.70 (m, 4H–Ar), 7.55 (dd, JHH ¼ 7.5,
4JHH ¼ 1.6 Hz, 2H–Ar), 6.76 (d, JHH ¼ 2.8 Hz, C5–H), 6.09
3
3
(d, JHH ¼ 2.8 Hz, C4–H), 4.17 (bs, NH) ppm; 13C NMR
(69.2 MHz, CDCl3): ꢃ ¼ 197.8, 160.9, 135.1, 134.2, 133.5,
129.7, 129.4, 129.þ3, 128.6, 127.9, 78.2, 75.4ppm; MS (EI):
m=z (%) ¼ 267 (M ꢃ, 5), 239 (9), 224 (10), 223 (8), 208 (19),
105 (100), 77 (62).
trans-5-Benzoyl-4-phenyloxazolidin-2-one (trans-2a,
C16H13NO3)
IR (liquid film): ꢂꢀ¼ 3456 (NH), 1721 (CO-carbamate), 1686
1
3
(CO-ketone) cmꢀ1; H NMR (CDCl3): ꢃ ¼ 8.04 (dd, JHH
¼
In conclusion, a simple synthesis route is de-
scribed for the regio- and stereoselective synthesis
of functionalized oxazilidine-2-ones with moderate
to good yields from the reaction of ꢀ-epoxyketones
with urea in the presence of PTSA as catalyst. The
reactions were carried out under mild conditions and
in one-pot without separation and purification of the
intermediates.
4
3
6.7, JHH ¼ 1.6 Hz, 2H–Ar), 7.57 (dd, JHH ¼ 8.0, 7.5Hz,
3
2H–Ar), 7.27–7.24 (m, 4H–Ar), 7.08 (dd, JHH ¼ 7.5 Hz,
4JHH ¼ 1.6 Hz, 2H–Ar), 6.29 (d, JHH ¼ 2.0 Hz, C5–
3
H), 5.62 (d, JHH ¼ 2.0 Hz, C4–H), 3.68 (bs, NH) ppm; 13C
3
NMR (CDCl3): ꢃ ¼ 197.3, 160.4, 134.7, 133.8, 133.0, 129.3,
128.9, 128.9, 128.1, 127.4, 76.6, 75.0ppm; MS (EI): m=z
þ
(%) ¼ 267 (M ꢃ, 3), 239 (8), 224 (7), 223 (5), 208 (15),
105 (100), 77 (72).
cis-5-Benzoyl-4-(4-methylphenyl)oxozolidin-2-one (cis-2b,
C17H15NO3)
Experimental
IR (liquid film): ꢂꢀ¼ 3445 (NH), 1727 (CO-carbamate), 1686
1
3
Melting points were measured with an Electrothermal 9100
apparatus. IR spectra were measured with a Shimadzu IR-460
spectrometer. NMR spectra were recorded with a Bruker
DRX-250 AVANCE instrument (250.1 MHz for 1H and
62.9MHz for 13C). Chemical shifts are given in ppm (ꢃ) rela-
tive to internal TMS, and coupling constants J are reported in
(CO-ketone) cmꢀ1; H NMR (CDCl3): ꢃ ¼ 8.03 (dd, JHH
¼
4
3
8.0 Hz, JHH ¼ 1.5 Hz, 2H–Ar), 7.70 (dd, JHH ¼ 7.2 Hz,
4JHH ¼ 1.5 Hz, 1H–Ar), 7.58 (dd, JHH ¼ 8.0, 7.2 Hz, 2H–
3
3
3
Ar), 7.05 (d, JHH ¼ 8.0 Hz, 2H–Ar), 6.96 (d, JHH ¼ 8.0 Hz,
2H–Ar), 6.25 (d, 3JHH ¼ 3.0 Hz, C5–H), 5.61 (m, C4–H), 3.67
(d, JNH ¼ 6.5 Hz, NH), 2.31 (s, CH3) ppm; 13C NMR
3

666
F. Nikpour et al.
(CDCl3): ꢃ ¼ 197.4, 160.4, 138.8, 134.6, 133.7, 129.9, 129.2,
128.8, 127.4, þ126.4, 76.7, 75.0, 21.2 ppm; MS (EI): m=z
(%) ¼ 281 (M ꢃ, 4), 253 (4), 237 (13), 222 (15), 105 (100),
cis-5-(4-Bromobenzoyl)-4-phenyloxozolidin-2-one (cis-2f,
C16H12BrNO3)
IR (liquid film): ꢂꢀ¼ 3205 (NH), 1742 (CO-carbamate),
1
1684 (CO-ketone) cmꢀ1; H NMR (CDCl3): ꢃ ¼ 7.41, 7.36
91 (67), 77 (31).
3
(2d, JHH ¼ 8.5 Hz, 4H–Ar), 7.17–7.11 (m, 5H–Ar), 6.31 (d,
3JHH ¼ 3.0 Hz, C5–H), 5.55 (bs, C4–H), 3.84 (bs, NH) ppm;
13C NMR (CDCl3): ꢃ ¼ 196.0, 164.2, 132.3, 131.1, 129.9,
129.1, 128.7, 128.1, 127.6, 126.9, 77.0, 74.5ppm; MS (EI):
trans-5-Benzoyl-4-(4-methylphenyl)oxozolidin-2-one (trans-
2b, C17H15NO3)
IR (liquid film): ꢂꢀ¼ 3460 (NH), 1719 (CO-carbamate), 1686
þ
þ
1
3
m=z (%) ¼ 347 ([M ꢃþ 2], 2), 345 (M ꢃ, 2), 304 (8), 302 (7),
(CO-ketone) cmꢀ1; H NMR (CDCl3): ꢃ ¼ 7.90 (dd, JHH
¼
¼
4
3
4
185 (100), 183 (98), 104 (53), 77 (45).
8.2 Hz, JHH ¼ 1.5 Hz, 2H–Ar), 7.53 (dd, JHH ¼ 7.7, JHH
3
1.5 Hz, 1H–Ar), 7.33 (d, JHH ¼ 8.2 Hz, 2H–Ar), 7.28 (d,
3JHH ¼ 7.7 Hz, 2H–Ar), 7.16 (d, JHH ¼ 8.0 Hz, 2H–Ar), 6.17
3
Acknowledgements
(d, 3JHH ¼ 2.5 Hz, C5–H), 5.33 (m, C4–H), 3.89 (bs, NH), 2.33
(s, CH3) ppm; 13C NMR (CDCl3): ꢃ ¼ 198.1, 159.4, 138.6,
134.3, 133.4, 129.2, 129.0, 128.6, 127.0, 126.4, 75.4, 75.3,
We are grateful to the University of Kurdistan Research
Council for the partial support of this work.
þ
21.2ppm; MS (EI): m=z (%) ¼ 281 (M ꢃ, 5), 253 (6), 237
(10), 222 (9), 105 (100), 91 (77), 77 (23).
References
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Mp 93–95ꢁC from n-hexane. IR (KBr): ꢂꢀ¼ 3375 (NH), 1736
(CO-carbamate), 1679 (CO-ketone) cmꢀ1; 1H NMR (CDCl3):
3
3
ꢃ ¼ 8.00 (d, JHH ¼ 7.8 Hz, 2H–Ar), 7.36 (d, JHH ¼ 7.8 Hz,
3
3
2H–Ar), 7.25 (d, JHH ¼ 5.5 Hz, 2H–Ar), 7.09 (d, JHH
¼
5.5 Hz, 2H–Ar), 6.14 (d, JHH ¼ 3.0 Hz, C5–H), 5.72 (dd,
3
3JNH ¼ 7.2 Hz, JHH ¼ 3.0 Hz, C4–H), 3.65 (d, JNH ¼ 7.2 Hz,
NH), 2.47, 2.16 (2s, 2CH3) ppm; 13C NMR (CDCl3):
ꢃ ¼ 197.2, 166.2, 145.7, 133.7, 131.3, 129.9, 129.1, 128.6,
128.0, 127.5,þ77.2, 75.0, 21.9, 19.3ppm; MS (EI): m=z
(%) ¼ 295 (M ꢃ, 3), 267 (1), 236 (5), 150 (21), 119 (100),
3
3
105 (14), 91 (77), 77 (23).
cis-5-(4-Methoxybenzoyl)-4-phenyloxozolidin-2-one (cis-2d,
C17H15NO4)
IR (liquid film): ꢂꢀ¼ 3455 (NH), 1720 (CO-carbamate), 1673
1
3
(CO-ketone) cmꢀ1; H NMR (CDCl3): ꢃ ¼ 8.06 (d, JHH
¼
3
7.0 Hz, 2H–Ar), 7.30 (d, JHH ¼ 8.2 Hz, 2H–Ar), 7.26 (d,
3JHH ¼ 7.5 Hz, 2H–Ar), 7.11 (dd, JHH ¼ 7.2, JHH
¼
3
4
3
1.5 Hz, 1H–Ar), 7.08 (d, JHH ¼ 7.0 Hz, 2H–Ar), 6.28 (d,
3JHH ¼ 2.5 Hz, C5–H), 5.56 (bs, C4–H), 3.93 (s, OCH3),
3.75 (bs, NH) ppm; 13C NMR (CDCl3): ꢃ ¼ 195.3, 164.7,
160.5, 133.8, 129.9, 129.3, 128.9, 128.1, 127.5, 114.5, 76.8,
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´
´
´
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þ
74.6, 55.7 ppm; MS (EI): m=z (%) ¼ 297 (M ꢃ, 1), 254 (27),
253 (7), 135 (100), 107 (17), 105 (18), 77 (44).
cis-5-(4-Methoxybenzoyl)-4-(4-methoxyphenyl)oxozolidin-2-
one (cis-2e, C18H17NO5)
IR (liquid film): ꢂꢀ¼ 3450 (NH), 1719 (CO-carbamate), 1676
´
Galeazzi R, Orena M, Gonzalez-Rosende ME, Sepulveda-
1
3
(CO-ketone) cmꢀ1; H NMR (CDCl3): ꢃ ¼ 8.07 (d, JHH
¼
¼
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3
8.5 Hz, 2H–Ar), 7.05–7.00 (m, 4H–Ar), 6.77 (d, JHH
3
8.5 Hz, 2H–Ar), 6.23 (d, JHH ¼ 3.0 Hz, C5–H), 5.54 (dd,
3
3JNH ¼ 6.5, JHH ¼ 3.0 Hz, C4–H), 3.94 and 3.77 (2s,
3
2CH3O), 3.88 (d, JNH ¼ 6.5 Hz, NH) ppm; 13C NMR
(CDCl3): ꢃ ¼ 196.1, 164.7, 160.5, 131.3, 128.9, 126.5, 125.1,
118.7, 114.5, 113.5, 77.2, 74.6, 55.6, 55.2ppm; MS (EI): m=z
´
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(%) ¼ 284 (M ꢃ-HNCO, 5), 283 (4), 177 (13), 135 (100), 107
´
´
(47), 92 (41), 77 (35).
62:6392

Regio- and stereoselective synthesis of functionalized oxazolidin-2-ones
667
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