Convenient synthesis of oxazolidinones by the use of halomethyloxirane, primary amine, and carbonate salt

Article abstract of DOI:10.1021/jo0501644

Primary amines reacted with carbonate salts (Na₂CO₃, K₂CO₃, Cs₂CO₃, and Ag ₂CO₃) and halomethyloxiranes in the presence of a base such as DBU or TEA to give oxazolidinones in high yields. The use of K ₂CO₃ among these carbonate gave the best yield in this synthesis. A reaction mechanism was proposed that the oxazolidinone was obtained from an oxazinanone intermediate via a bicyclo[2.2.1] intermediate. The present reaction can be widely applied to convenient synthesis of useful N-substituted oxazolidinones and chiral oxazolidinones.

Full text of DOI:10.1021/jo0501644

SCHEME 1
Convenient Synthesis of Oxazolidinones by
the Use of Halomethyloxirane, Primary
Amine, and Carbonate Salt
Yumiko Osa, Yuka Hikima, Yoko Sato, Kouichi Takino,
Yoshihiro Ida, Shuichi Hirono, and Hiroshi Nagase*
School of Pharmaceutical Sciences, Kitasato University,
5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan
yields were not always high. As an improved method to
overcome the defects, cyclic carbamate synthesis by use
of carbon dioxide dissolved in protic solvents containing
amines and oxiranes was reported by Toda et al.9 When
primary amines reacted with halomethyloxiranes and a
large amount of carbon dioxide under neutral conditions,
six-membered cyclic carbamates of oxazinanones were
formed.10 They proposed a reaction mechanism by which
the ammonium carbamate intermediate reacted with
oxirane. They also used 2-(1-haloalkyl)oxirane and pri-
mary amine in the presence of cesium carbonate (Cs2-
CO3) and proposed a mechanism by which carbon dioxide
derived from Cs2CO3 reacted with the intermediate (2-
alkyl-3-aminomethyloxirane) to form oxazolidinone.11
However, these reactions did not give a high yield of
oxazolidinone.
nagaseh@pharm.kitasato-u.ac.jp
Received January 26, 2005
Primary amines reacted with carbonate salts (Na2CO3, K2-
CO3, Cs2CO3, and Ag2CO3) and halomethyloxiranes in the
presence of a base such as DBU or TEA to give oxazolidi-
nones in high yields. The use of K2CO3 among these
carbonate gave the best yield in this synthesis. A reaction
mechanism was proposed that the oxazolidinone was ob-
tained from an oxazinanone intermediate via a bicyclo[2.2.1]
intermediate. The present reaction can be widely applied to
convenient synthesis of useful N-substituted oxazolidinones
and chiral oxazolidinones.
We have recently found a simple method to synthesize
oxazolidinone derivatives using primary amine and ha-
lomethyloxirane in the presence of various carbonate
salts. The reaction is shown in Scheme 1.
At the beginning of our research, we used allylamine
(1a, 2 molar equiv), which reacted with halomethyl-
oxirane (2, 2 molar equiv, bromomethyloxirane 2a, and
chloromethyloxirane 2b) in the presence of potassium
carbonate or silver carbonate (1 molar equiv) in methanol
at room temperature to afford oxazolidinone in 45% yield.
The structure of N-allyl-5-hydroxymethyloxazolidin-2-one
Oxazolidinones can be used as the precursors of
naturally occurring amino alcohols and amino acids
which have been synthesized by a variety of methods.1
In addition, they are useful as chiral auxiliaries2 in
asymmetric synthesis.1a Recently, some oxazolidinone
derivatives such as DUP-105,3 DUP-721,3 and linezolid
(Zyvox)3b,4 have attracted much interest as monodrug- or
multidrug-resistant antibacterial agents.5 Early synthe-
sis of oxazolidinones was carried out via the reactions of
1,2-amino alcohols and phosgene or its derivatives6 or
amino alcohols with carbon dioxide under high pressure.7
Recently, carbohydrate derivatives were also used in the
synthesis of oxazinanone and oxazolidinone.8 However,
these methods required multiple steps, and the total
(6) (a) Newman, M. S.; Kutner, A. J. J. Am. Chem. Soc. 1951, 73,
4199-4204. (b) Lubell, W.; Rapoport, H. J. Org. Chem. 1989, 54, 3824-
3831. (c) Bonner, M. P.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113,
1299-1308. (d) Palomo, C.; Berree, F.; Lindent, A.; Villalgordo, J. M.
J. Chem Soc., Chem. Commun. 1994, 1861-1862. (e) Efskind, J.;
Romming, C.; Undheim, K. J. Chem. Soc., Perkin Trans. 1 1999, 1677-
1684.
(7) (a) Lynn. J. W. U. S. Patent 2,975,187, 1961; Chem. Abstr. 1961,
55, 16568. (b) Steele, A. B. U. S. Patent 2,868,801, 1959; Chem. Abstr.
1959, 53, 10261.
(8) (a) Hu, N. X.; Aso, Y.; Otsubo, T.; Ogura, F. J. Chem. Soc., Chem.
Commun. 1987, 1447-1448. (b) Lewis, N.; McKillop, A.; Taylor, R. J.
K.; Watson, R. J. Synth. Commun. 1995, 25, 561-568. (c) Li, G.;
Lenington, S.; Willis, S.; Kim, S. H. J. Chem. Soc., Perkin Trans. 1
1998, 1753-1754. (d) Feroci, M.; Inesi, A.; Mucciante, V.; Rossi, L.
Tetrahedron Lett. 1999, 40, 6059-6060. (d) Tanimori, S.; Kirihata, M.
Tetrahedron Lett. 2000, 41, 6785-6788. (e) Casadei, M. A.; Feroci, M.;
Inesi, A.; Rossi, L.; Sotgiu, G. J. Org. Chem. 2000, 65, 4759-4761. (f)
Caggiano, L.; Davies, J.; Fox, D. J.; Moody, D. C.; Warren, S. Chem.
Commun. 2003, 1650-1651. (g) Dinsmore, C. J.; Mercer, S. P. Org.
Lett. 2004, 6, 2885-2888. (i) Ella-Menye, J.-R.; Sharma, V.; Wang, G.
J. Org. Chem. 2005, 70, 463-469.
(9) (a) Toda, T. Chem. Lett. 1977, 957-958. (b) Saito, N.; Hatakeda,
K.; Ito, S.; Asano, T.; Toda, T. Heterocycles 1981, 15, 905-906. (c) Toda,
T. Nippon Kagaku Kaishi 1982, 2, 282-288. (d) Saito, N.; Hatakeda,
K.; Ito, S.; Asano, T.; Toda, T. Bull. Chem. Soc. Jpn. 1986, 59, 1629-
1631. (e) Toda, T.; Kitagawa, Y. Angew. Chem., Int. Ed. Engl. 1987,
26, 334-335. (f) Saito, N.; Hatakeda, K.; Ito, S.; Asano, T.; Namai, Y.;
Toda, T. Agric. Biol. Chem. 1987, 51, 1193-1194.
(10) (a) Asano, T.; Saito, N.; Ito, S.; Hatakeda, K.; Toda, T. Chem.
Lett. 1978, 311-312. (b) Saito, N.; Hatakeda, K.; Ito, S.; Asano, T.;
Toda, T. Nippon Kagaku Kaishi 1986, 9, 1196-1201.
(11) Yoshida, M.; Ohshima, M.; Toda, T. Heterocycles 1993, 35, 623-
626.
* To whom correspondence should be addressed. Tel: +81-3-5791-
6372. Fax: +81-3-4442-5707.
(1) (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835-875. (b) Dyen, M. E.; Swern, D. Chem. Rev. 1967, 67, 197-246.
(2) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127-2129. (b) Evans, D. A. Aldrichim. Acta 1982, 15, 23-32.
(c) Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D.
J.; Bartroli, J. Pure. Appl. Chem. 1981, 53, 1109-1127.
(3) (a) Gregory, W. A.; Brittelli, D. R.; Wang, C.-L. J.; Wuonola, M.
A.; McRipley, R. J.; Eustice, D. C.; Eberly, V. S.; Bartholomew, P. T.;
Slee, A. M.; Forbes, M. J. Med. Chem. 1989, 32, 1673-1681. (b)
Gordeev, M. F. Curr. Opin. Drug Discovery Devel. 2001, 4, 450-461.
(c) Slee, A. M.; Wuonola, M. A.; McRipley, R. J.; Zajac, I.; Zawada, M.
J.; Bartholomew, P. T.; Gregory, W. A.; Forbes, M. Antimicrob. Agents
Chemothr. 1987, 31, 1791-1797.
(4) (a) Bolmstrom, A.; Ballow, C. H.; Qwarnstrom, A.; Biedenbach,
D. J.; Jones, R. N. Clin. Microbiol. Infec. 2002, 8, 791-800. (b)
Barbachyn, M. R.; Ford, C. W. Angew. Chem., Int. Ed. 2003, 42, 2010-
2023. (c) Wang, G.; Hollingsworth, R. I. Tetrahedron: Asymmetry 2000,
11, 4429-4432.
(5) Barbachyn, M. R.; Toops, D. S.; Grega, K. C.; Hendges, S. K.;
Ford, C. W.; Zurenko, G. E.; Hamel, J. C.; Shaadt, R. D.; Stapert, D.;
Yagi, B. H.; Buysse, J. M.; Demyan, W. F.; Kilburn, J. O.; Glickman,
S. E. Bioorg. Med. Chem. Lett. 1996, 6, 1009-1014.
10.1021/jo0501644 CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/11/2005
J. Org. Chem. 2005, 70, 5737-5740
5737

TABLE 1. Conversion Conditions of Six-Membered
Ring 4b to Five-Membered Ring 3b
also gave 3b in 96% yield (run 4), but by the use of TEA
instead of K2CO3 4b was quantitatively recovered (run
5). When 1 equiv of DBU was added after addition of 3
equiv of TEA to the reaction solution, 3b was obtained
in quantitative yield (run 6). The above results showed
that the ring contraction reaction from six-membered
cyclic carbamate to five-membered cyclic carbamate
perfectly proceeded in the presence of K2CO3 or DBU but
did not occur in the presence of only TEA. These results
mean that a strong base or a basic condition is necessary
to form 3b.
Furthermore, total molecular energy calculation of
compounds 3b and 4b was carried out by the use of
Merck Molecular Force Field (MMFF94).15 The total
energy of 3b is 31.2 kcal/mol and that of 4b is 34.1 kcal/
mol. Therefore, the calculation result shows that oxazo-
lidinone is more stable than oxazinanone. This result also
supports that the six-membered ring is an intermediate
of the reaction process. Wang et al. also reported six-
membered ring oxazinanone was converted to more stable
5-membered ring oxazolidinone under base conditions
and heating,8i which gave supporting evidence in our
present conversion.
Based on the above discussion, a reaction mechanism
is proposed as depicted in Scheme 2. Two routes (I and
II) are supposed to form an intermediate D. In route I,
first, primary amine 1 attacks the C-X bond of halo-
methyloxirane 2 to afford an intermediate A. Subse-
quently, a carbonate ion attacks A to form the intermedi-
ate D. In route II, 1 attaches the oxirane ring of 2 to give
intermediate B. As oxirane ring 2 may be more electro-
philic than the C-X bond in the case of an attack of the
alkoxide ion,16 a first attack of amine 1 to the oxirane
ring may be reasonably considered.16,17 Subsequently, the
resulting alkoxide ion of intermediate B attacks the
carbon atom of the halomethyl group to form C. Next,
the carbonate ion attacks the oxirane ring C to afford
the intermediate D. Then the resulting amino nitrogen
attacks the carbonyl group in D to cyclize intramolecu-
larly to a six-membered ring of oxazinanone (4). In the
mechanism, the intermediate D can cyclize only to six-
membered oxazinanone, not five-membered oxazolidi-
none. Two routes III and IV are considered as the
conversion process of oxazolidinone (3) from compound
4. In route III, the alkoxide ion in intermediate E under
strong basic condition attacks intramolecularly the car-
bonyl carbon to give a bicyclo[2.2.1] intermediate F, which
is subsequently converted to a five-membered ring of
oxazolidinone 3. In route IV, a methoxide ion generated
from methanol under strong basic condition attacks the
carbonyl carbon of the oxazinanone (intermediate G) to
open a ring structure. The resulting alkoxide ion (in-
tramolecularly) attacks the carbon of intermediate H to
form compound 3. However, it is considered that the
intramolecular attack in route III may be more favorable
(entropy) than the intermolecular one of the methoxide
molar ratio
yield (%)
4b/1bb/
base
(equiv)
recovery
runa K2CO3/base
reaction
3b
4b
1
2
3
4
5
6
1:0:0:0
2:2:1:0
2:2:1:0
1:0:0:5
1:0:0:5
1:0:0:4
reflux, o.n.c
100
rt, stirring, o.n. 94
reflux, 2 hr
reflux, 5.5 hr
reflux, o.n.
quant
DBU
TEA
96
100
TEA (3), reflux, o.n.
quant.
DBU (1)
a All reactions were carried out in MeOH. b 1b ) NH2CH2-Ph.
c o.n. ) overnight.
(3a) obtained from allylamine (1a) was determined, in
detail, using 1H NMR, 13C NMR, 1H-1H decoupling,
NOE, and LSPD12 and also was supported by X-ray
analysis.13 Furthermore, it was confirmed that the carbon
of the carbonate salt was introduced at the 2-position in
3a by the reaction using isotopic Ag213CO3 (98% atomic
purity of 13C) instead of K2CO3.
To elucidate the reaction mechanism and increase the
yields, the IR spectrum of the reaction mixture, which
was obtained by the reaction of molar ratios of K2CO3 (1
mol), benzylamine (instead of allylamine because of its
high boiling point compared with that of allylamine), and
bromomethyloxirane (2 mol) in methanol at 0 °C, was
measured. We found the bands at 1680 and 1730 cm-1
in the reaction mixture. The former band is assigned14
to a six-membered cyclic carbamate of oxazinanone,
which was also reported by Toda et al.9e The latter band
corresponds to a five-membered cyclic carbamate of
oxazolidinone. The spot of oxazinanone in TLC (the value
of Rf was 0.47; chloroform/methanol ) 10:1) diminished
with the reaction time. On the other hand, the spot of
oxazolidinone in TLC (the value of Rf was 0.58; chloroform/
methanol ) 10:1) enlarged with the reaction time. These
facts support that oxazinanone is an unstable intermedi-
ate (kinetic product) in the reaction.
For further confirmation of oxazinanone formation in
the reaction process, the isomerization of N-benzyl-5-
hydroxyoxazinanone (4b) to N-benzyl-5-hydroxymethyl-
oxazolidinone (3b) was examined as shown in Table 1.
When only 4b was refluxed in methanol, 3b was not
obtained and 4b was recovered (run 1). On the other
hand, the reaction conditions (even if at room tempera-
ture) for oxazolidinone synthesis in the presence of K2-
CO3 gave 3b in 94% yield (run 2). These facts showed
that K2CO3 is necessary for the conversion of 4b to 3b.
Furthermore, under reflux for 2 h, 3b was obtained
quantitatively (run 3). The use of DBU instead of K2CO3
(12) (a) Takeuchi, S.; Uzawa. J.; Seto, H.; Yonehara, H, Tetrahedron
Lett. 1977, 34, 2943-2946. (b) Seto, H.; Sasaki. T.; Yonehara, H.;
Uzawa, J. Tetrahedron Lett. 1978, 10, 923-926. (c) LSPD (long range
selective proton decouple) was used to detect the ring protons adjacent
to the oxygen and nitrogen atoms linked to carbonyl carbon.
(13) Osa, Y.; Sato, Y.; Hatano, A.; Takeda, K.; Takino, K.; Takay-
anagi, H. Anal. Sci. 2003, 19, x17-x18.
(15) (a) Halgren, T. A. J. Am. Chem. Soc., 1992, 114, 7827-7843.
(b) Halgren, T. A. J. Comput. Chem. 1996, 17, 490-519.
(16) Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic
Chemistry; Oxford University Press: Oxford, 2001.
(17) The textbook of organic chemistry (for example, the book written
by Warren16) described the oxirane ring of epichlorohydrin is more
electrophilic than the C-Cl bond with alkoxide. Therefore, the carbon-
ate ion was reacted with the oxirane ring of epibromohydrin.
(14) The Aldrich Library of FT-IR Spectra, Edition II; Aldrich:
Milwaukee, 1997.
5738 J. Org. Chem., Vol. 70, No. 14, 2005

SCHEME 2
TABLE 2. Reaction Conditions for Synthesis of 3b
SCHEME 3
molar ratio
yield of
3b (%)
run
X
1b/2/K2CO3/TEA
reaction
1
2
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
1:1:1:1
rt, o.n.a
reflux, o.n.
rt, o.n.
rt, o.n.
rt, o.n.
reflux, o.n.
reflux, o.n.
rt, o.n.
reflux, o.n.
reflux, o.n.
28
37
29
61
68
76
83
58
88
81
1:1:1:1
3
1:2:2:2
4
1:3:1:1
5
1:5:5:5
ion in route IV. Therefore, we think route III may be more
reasonable. Compound 4 will be formed as a kinetic
product and 3 can be obtained as a thermodynamic
product.
6
1:5:5:0
7
1:5:5:5
8
1:10:10:10
1:10:10:10
1:5:5:5
9
10
The difference between our mechanism and that of
Toda was mainly the reaction intermediate. In the Toda
mechanism,11 the carbamate anion was formed by react-
ing 2-(1-haloalkyl)oxirane and amine with CO2 derived
from Cs2CO3 to open the epoxide in the alkaline medium
and the resulting alkoxide ion attacks at the C-X carbon
to give an epoxy ring. However, as carbonate (Cs2CO3)
could not be converted to CO2 under the strong basic
condition using CsOH, CO2 could not be produced to form
the carbamate ion. In our mechanism, the carbonate ion,
not the carbamate anion, attacks the halomethyloxirane
directly.
Furthermore, the reactivity (nucleophilicity) of the
carbonate ion was confirmed by the reaction of 2,3-
epoxypropyl 4-methoxyphenyl ether (5) and K2CO3.
Though the reaction of 5 and K2CO3 (dried in vacuo at
120 °C for 10 h) in anhydrous DMF gave no products
under the anhydrous condition, the addition of TEA to
the solution containing 5 and K2CO3 in anhydrous DMF
under anhydrous condition afforded a diol (6) which was
obtained by hydrolysis of the carbonate intermediate I
in 43% yield18 (Scheme 3). The preparation of the product,
diol (6), suggests attack of the carbonate ion to oxirane
in the presence of a base.
On the basis of the above proposed reaction mechanism
as shown in Scheme 2, we examined optimization of the
reaction conditions. In Scheme 2, the excess of reagents
for primary amine was expected to increase the yields,
and strong basic condition would be needed for formation
for the alkoxide ion to attack the carbonyl carbon (E, F)
and reflux condition would be able to convert the six-
membered ring, oxazinanone, to the five-membered ring,
oxazolidinone, easily. Table 2 shows various conditions
to optimize various molar ratios of the reagents and
temperature. The high yield of N-benzyl-5-hydroxy-
a o.n. ) overnight.
methyloxazolidin-2-one (3b) (more than 80% yield) was
obtained under the conditions of a large mole ratio (more
than 5 molar equiv) of halomethyloxirane, K2CO3 in
methanol in the presence of more than 5 mol base (TEA;
triethylamine or DBU; 1,8-diazabicyclo[5.4.0]undec-7-
ene) per mole of amine under reflux (runs 7, 9, and 10).
The use of one molar ratio of 1b, 1 or 2 molar ratio of
2b, K2CO3, and TEA gave a low yield of 3b (runs 1 and
3), and the yield of 3b did not increase even under reflux
(37%, run 2). Excess amounts (5 or 10 molar ratios) of
2a, K2CO3, and TEA to benzylamine 1b at room temper-
ature gave 3b in 68% and 58% yields (runs 5 and 8) and
the yields increased to 83 and 88% under reflux (runs 7
and 9). In the absence of TEA as a base, the yield of 3b
was lower than that in run 7 (run 6). It suggested that
the addition of a strong base increased the yield of 3b in
comparison between runs 6 and 7. The use of chloro-
methyloxirane 2b instead of bromomethyloxirane 2a gave
almost the same yield of 3b (81% yields in the case of 2b
(run 10) and 83% in the case of 2a (run 7)). Thus, we
were able to optimize the reaction conditions for oxazo-
lidinones on the basis of our reaction mechanism. Pure
product 3 was rationally identified on the basis of IR,
NMR, elemental analysis, and mass spectra.
Several kinds of carbonate salts were examined to
obtain 3 as shown in Table 3. Na2CO3, Cs2CO3, and Ag2-
CO3 (runs 2, 4, and 6) gave more than 75% yields of 3b.
At the beginning of our study,19 we examined various
primary amines of propyl, isopropyl, n-butyl, heptyl, and
cyclohexyl groups. When the reaction conditions of pri-
(19) Osa, Y.; Sato, Y.; Oshimoto, M.; Takino, K.; Takeda, A.;
Takayanagi, H. 44th Symposium of J. Synth. Org. Chem., Jpn, Kanto
Branch, Niigata, 2002, Abstract pp 123-124.
(18) Tanzer, W.; Muller, H.; Wintzer, J.; Fedtke, M. Makromol.
Chem. 1987, 188, 2857-2863.
J. Org. Chem, Vol. 70, No. 14, 2005 5739

TABLE 3. The Yield of 3b Using Various Carbonate
Salts
nucleus (Scheme 4). The results support route I in the
reaction mechanism (Scheme 2) because route II will
retain the S-configuration to give S-oxazolidinone in the
use of S-chloromethyloxirane. Accordingly, the synthesis
of oxazolidinone is supposed to proceed via route I.
In conclusion, the present synthetic method is char-
acterized by a simple procedure, mild reaction conditions,
high reaction yield, and high selectivity and will be useful
to produce various kinds of N-substituted-5-hydroxy-
methyloxazolidin-2-one and chiral oxazolidinone. The
five-membered ring compound, oxazolidinone, is more
stable than the six-membered ring compound, oxazi-
nanone.
molar ratio
1b/2a/
yield of
3b (%)
runa M2CO3 M2CO3/TEA
reaction
1
2
3
4
5
6
K2CO3
1:5:5:5
1:5:5:5
1:5:5:5
1:5:5:5
1:5:5:5
1:5:5:5
reflux, under Ar, o.n.b
reflux, under Ar, o.n.
reflux, under Ar, o.n.
reflux, under Ar, o.n.
reflux, under Ar, o.n.
reflux, dark, under Ar, o.n.
83
77
28
82
25
75
Na2CO3
Rb2CO3
Cs2CO3
Li2CO3
Ag2CO3
Experimental Section
a All reactions were carried out in MeOH. b o.n. ) overnight.
General Procedure for Oxazolidinone. Primary amine (1
mmol ratio) was added to methanol (5 mL) containing an excess
amount of halomethyloxirane (5 or 10 mmol ratio), K2CO3 (5 or
10 mmol ratio), and TEA (5 or 10 mmol ratio) under reflux
overnight. After the solution was cooled to room temperature,
the reaction mixture was filtered for removing the solidified,
unreacted carbonate salts. Then, the organic layer was evapo-
rated and the residue was solved in AcOEt. The organic layer
was washed with NaCl aq and dried using Na2SO4. The solvent
was evaporated in vacuo. The residue was isolated by silica gel
column chromatography with chloroform/methanol (10:1).
N-Benzyl-5-hydroxymethyloxazolidin-2-one (3b): yield
88% as a pale yellow solid; mp 69-70 °C; IR (film) 3200-3620,
1
1730 cm-1; H NMR (600 MHz, CDCl3) δ 3.32 (1H, dd, J ) 6.5,
8.0 Hz), 3.44 (1H, dd, J ) 8.0. 10.0 Hz), 3.62 (1H, dd, J ) 13.0,
4.0 Hz), 3.85 (1H, dd, J ) 13.0, 3.0 Hz), 4.38, 4.48 (d, 1H, J )
15.0 Hz), 4.58 (1H, m, J ) 6.5, 10.0, 4.0, 3.0 Hz), 7.25-7.38 (5H,
m); 13C NMR (150 MHz, CDCl3) δ 45.1, 47.9, 62.6, 73.5, 127.7,
127.8, 128.6, 135.4, 156.2; MS (FAB) m/z 208 (M + H)+. Anal.
Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.59;
H, 6.32; N, 7.01.
N-Benzyl-5-hydroxyoxazinan-2-one (4b). To a methanol
(4 mL) solution of bromomethyloxirane 2a (171 µL, 2.0 mmol)
was added benzylamine (218 µL, 2.0 mmol). The reaction
mixture was bubbled through CO2 for 5 h and stirred overnight.
The reaction mixture was evaporated in vacuo, and then the
yellow residue was purified by silica gel column chromatography
with chloroform/ethyl acetate (5:1) to give the pure product 4b
(163 mg, 39% unoptimized yield) as a pale yellow solid: mp 114-
FIGURE 1.
SCHEME 4
115 °C; IR (KBr) 3200-3620, 1678 cm-1 1H NMR (600 MHz,
;
CDCl3) δ 3.17 (1H, ddd, J ) 12.0, 3.0 Hz), 3.38 (1H, dd, J )
12.0, 4.0 Hz), 4.10 (1H, m), 4.20 (1H, dd, J ) 3.0, 12.0 Hz), 4.23
(1H, dd, J ) 2.5, 12.0 Hz), 4.43, 4.61 (1H, d, J ) 15.0 Hz), 7.24-
7.32 (5H, m); 13C NMR (150 MHz, CDCl3) δ 51.4, 52.7, 61.2, 70.5,
127.8, 128.1, 128.8, 136.2, 153.5; MS (EI) m/z 207 (M)+. Anal.
Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.62;
H, 6.41; N, 6.66.
mary amine 1 (2 equiv), bromomethyloxirane 2a (2
equiv), and Ag2CO3 or K2CO3 (1 equiv) in methanol
stirring overnight at room temperature were used, 36-
50% yields of the corresponding oxazolidinones were
obtained based on each amine. Application of similar
optimum reaction conditions to benzylamine will give
higher yield of oxazolidinones. The use of aniline as
aromatic amine is now under study.
We also applied chiral halomethyloxirane to a synthe-
sis for chiral oxazolidinones to confirm which route the
reaction selected, I or II. The reactions of (S)-chloro-
methyloxirane (7) with benzylamine (1b) and p-bro-
mobenzylamine (1c) under similar conditions to the above
method to give oxazolidinones 8 and 9 were carried out
(Scheme 4). The stereo structure of N-(p-bromobenzyl)-
5-hydroxymethyloxazolidin-2-one (9) was confirmed by
means of X-ray analysis (Figure 1).20 In this reaction, the
S-configuration of the oxirane ring inverted to the R-
configuration at the 5-position of the oxazolidinone
(R)-N-(p-Bromobenzyl)-5-hydroxymethyloxazolidin-2-
one (9). p-Bromobenzylamine hydrochloride 1c (100 mg, 0.45
mmol) was removed by washing with NaOH aq: yield 82% as
prisms; mp 109-110 °C (crystallized from ethyl acetate); [R]21
D
1
) -12.5 (c 0.933, MeOH); IR (film) 3200-3620, 1729 cm-1; H
NMR (600 MHz, CDCl3) δ 3.32 (1H, dd, J ) 7.0, 8.0 Hz), 3.40
(1H, dd, J ) 8.0. 10.0 Hz), 3.57 (1H, dd, J ) 12.0, 4.0 Hz), 3.83
(1H, dd, J ) 12.0, 5.0 Hz), 4.32, 4.37 (1H, d, J ) 15.0 Hz), 4.55
(1H, dt, J ) 10.0, 7.0, 5.0, 4.0 Hz), 7.13, 7.45 (1H, d, J ) 8.0
Hz); 13C NMR (150 MHz, CDCl3) δ 45.0, 47.7, 62.9, 73.5, 121.9,
129.7, 131.9, 134.6, 157.9; MS (FAB) m/z 285, 287 (M)+. Anal.
Calcd for C11H12NO3Br: C, 46.18; H, 4.23; N, 4.90. Found: C,
46.16; H, 4.28; N, 5.09.
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
(20) X-ray data was deposited in the Cambridge Crystallographic
Data Centre in CIF format as CCDC 269747 for 9.
JO0501644
5740 J. Org. Chem., Vol. 70, No. 14, 2005