Modified Mg: Al hydrotalcite in the synthesis of oxazolidin-2-ones

Article abstract of DOI:10.1039/b418848a

The modified Mg: Al (3: 1) hydrotalcite has been found to be an efficient catalyst in the conversion of carbamates into oxazolidin-2-ones under mild reaction conditions. A wide variety of oxazolidin-2-ones were obtained with excellent chemical yield. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b418848a

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C O M M U N I C A T I O N
Modified Mg : Al hydrotalcite in the synthesis of oxazolidin-2-ones
Agnieszka Cwik,a Aliz Fuchs,b Zolta´n Hell,*a Ildiko´ Bo¨jto¨s,a Do´ra Halmaia and
Petra Bombiczc
a Department of Organic Chemical Technology, Budapest University of Technology and
Economics, H-1521, Budapest, Hungary. E-mail: zhell@mail.bme.hu
b Research Group for Organic Chemical Technology, Hungarian Academy of Sciences, H-1521,
Budapest, Hungary
c Institute of Structural Chemistry, Chemical Research Center, Hungarian Academy of Sciences,
H-1525, Budapest, Hungary
Received 16th December 2004, Accepted 25th January 2005
First published as an Advance Article on the web 10th February 2005
The modified Mg : Al (3 : 1) hydrotalcite has been found to
be an efficient catalyst in the conversion of carbamates into
oxazolidin-2-ones under mild reaction conditions. A wide
variety of oxazolidin-2-ones were obtained with excellent
chemical yield.
We investigated first the cyclization of (2-hydroxy-propyl)-
carbamic acid ethyl ester 1b in the presence of different types
of HT catalysts under similar reaction conditions (Scheme 1,
Table 1). The applied species were rehydrated, calcined and non-
activated Mg : Al 3 : 1 hydrotalcites. The non-activated HT, with
carbonate as the compensating anions showed low activity. The
calcined HT gave a very poor yield. It seems that the Lewis basic
sites (O2−), obtained by the calcination of HT are not efficient
in this reaction. For comparison purposes the known solid base
KF/aAl2O3 has also been used. The reaction with KF/aAl2O3
gave a very good yield, but the use of the quite toxic KF in
organic synthesis should be avoided. The results showed that
the modified HT, obtained by decarbonylation and rehydration
showed the highest activity in this reaction.
Oxazolidin-2-ones are important compounds in both pharma-
ceutical1 and synthetic organic chemistry. They are widely used
as chiral auxiliaries in numerous asymmetric syntheses2 and are
applied in the synthesis of a number of valuable natural products,
antibiotics, and other compounds with immunosuppressant,
antihistaminic, antifungal, antihypertensive, antiallergic, or an-
tibacterial activities.3
Numerous synthetic methods have been described in the
literature for the preparation of oxazolidin-2-ones such as
cyclization of alkyl or aryl carbamates using either acidic4
or basic5 catalysts, cyclization of triphenylphosphonium salts6
or N-nitroso compounds,7 and carbonylation of 2-amino-
ethanols using phosgene,8 diphosgene,9 triphosgene,10 urea11 and
cyanates,12 or oxidative carbonylation of 2-amino-ethanols with
selenium13 or palladium catalysts.14 The use of these compounds
is undesirable because they are often hazardous (e.g. phosgene,
cyanates), the processes often require very low and very high
temperature15 and lead to the production of a vast amount of
toxic wastes. For these reasons, much attention has been paid to
the development and use of new, non-toxic catalysts.
Nowadays the use and design of environmental-friendly solid
acid and solid base catalysts has become an important research
target, which is mainly due to their useful properties like
high versatility, easy treatment and work-up, mild experimental
conditions, high yield and selectivity, they are inexpensive
and often reusable. Hydrotalcites (HT), the anionic layered
double hydroxides (LDHs) can be applied as adsorbents, anion-
exchangers and basic catalysts. These materials can be des-
cribed by the formula, [M(II)(1−x)M(III)x(OH)2]x+(Ax/mm−)·nH2O,
where M(II) is a divalent ion like Mg, Cu, Ni, Co, Mn, Zn; M(III)
is a trivalent ion like Al, Fe, Cr, Ga; A is the compensating anion
like OH−, Cl−, NO3−, CO32−, SO42−, and x is in the range of 0.1–
0.33. In general, the activation of HT consists of two steps.
First, HT upon thermal treatment at 450–500 ◦C form a highly
active Mg(Al)O mixed oxide that exhibits strong Lewis basicity,
which is used for catalyzing various organic reactions.16,17 In
the second step the calcined catalyst is rehydrated which, due
to its so-called memory effect, results the restoration of the
original HT structure with OH− groups, giving a Brønsted type
catalyst.18,19 The applicability of the different hydrotalcites, due
to the different nature and strength of their basic sites, is largely
investigated in various organic synthesis.
Scheme 1
The enhanced catalytic activity of this catalyst is attributed
to the presence of OH groups, generated during rehydration
of the thermally activated hydrotalcite, forming Brønsted basic
sites. The synthetic applications of rehydrated hydrotalcite have
been recently reported e.g. in aldol,18 Knoevenagel20 and Michael
reactions.21
We explored the effect of solvent on the reaction yield. As
shown in Fig. 1, toluene proved to be the most efficient among
the solvents tested. In ethanol the conversion after 5 h was only
8%, while in dioxane it was 16%.
Fig. 2 shows the conversion of (2-hydroxy-propyl)-carbamic
acid ethyl ester 1b in toluene at 20 ◦C, 80 ◦C and 110 ◦C in the
presence of rehydrated HT. Since the yield of the oxazolidin-2-
one increased dramatically at 110 ◦C and reached 89% after 5 h
while in the reaction at room temperature (20 ◦C) and at 80 ◦C
after 5 h only 9% and 25% conversion was observed, respectively,
Table 1 Comparison of modified Mg : Al (3 : 1) hydrotalcite with
several heterogeneous catalysts in the synthesis of 5-methyl-oxazolidin-
2-one 2ba
Entry
Solid catalyst
Yield (%)b
1
2
3
4
Rehydrated Mg : Al HT
Calcined Mg : Al HT
Non-activated Mg : Al HT
KF/aAl2O3
88
20
48
82
In this paper we describe the development of an environmen-
tally friendly, simple and convenient, catalytic method for the
cyclization of carbamates with activated hydrotalcite Mg : Al
(3 : 1) which gave the expected oxazolidin-2-ones in excellent
yields.
a General conditions: carbamate 5 mmol, catalyst 0.13 g, toluene (10 ml),
110 ◦C, 5 h. b Determined by 1H NMR.
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 6 7 – 9 6 9
9 6 7
©

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Table 2 Conversion of carbamates to oxazolidin-2-ones with activated
hydrotalcite Mg : Al (3 : 1)
2
R
Rꢀ
Yield (%)a
a
b
H
H
H
(
CH3
H
H
H
83
)-
89 (86)b
c
d
e
f
(
)-C2H5
95
96
91
91
(S)-C2H5
(R)-Ph
(S)-PhCH2
H
Fig. 1 Conversion of (2-hydroxy-propyl)-carbamic acid ethyl ester 2b
in different solvents.
a Based on 1H NMR. b Recycled hydrotalcite.
literature yet. The structural identity of this compound was
1
determined by H and 13C NMR analysis, furthermore by a
single crystal X-ray structural study.
There are two chemically the same but crystallographically
independent molecules in the asymmetric unit (Fig. 3) organised
by a pseudo inversion centre that can be found between the 2-
oxazolidinone moieties of the molecules. Inversion symmetry
cannot be realised because the absolute configuration of both
molecules are the same: C71, C81, and C72, C82 are all R.
Flack x parameter24 is −0.14(17). The distance between the
atoms concerned by least-squares fitting of the 17 heavy atoms
of the independent molecules is 0.2(4). The participating atoms
in the strong N–H · · · O and O–H · · · O type intermolecular
interactions ofthe twomolecules are accordinglythe same(N11–
Fig. 2 Time course of the yield of 5-methyl-oxazolidin-2-one 2b over
modified Mg : Al (3 : 1) hydrotalcite in toluene at various temperatures.
◦
◦
˚
˚
H11N · · · O22 1.97 A 170 ; N12–H12N · · · O21 2.23 A 145 ;
it seems that in this case there is mostly the reaction temperature
which determines the yield and the nature of the solvent is less
important.
Next we investigated the cyclization of a wide range of alkyl
or aryl substituted carbamates 1a–f (Scheme 1). The reactions
were carried out in the presence of a catalytic amount of HT
in boiling toluene for 5 h. The appropriate oxazolidinones 2a–f
were obtained with excellent yields, as represented in Table 2.
The overall yields were above 80%.
◦
˚
˚
O31–H31O · · · O21 2.07 A 154 ; O32–H32O · · · O22 1.96 A
160◦), while weak C–H · · · O secondary interactions are different
◦
◦
◦
◦
˚
˚
˚
˚
(C21–H21 · · · O31 2.43 A 136 ; C22–H22 · · · O41 2.53 A 131 ;
C61–H61 · · · O42 2.56 A 167 ; C71–H71 · · · O32 2.44 A 145 ;
◦
˚
C82–H82 · · · O21 2.48 A 143 ).
In the reaction of optically active carbamates 1d,e,f the cor-
responding oxazolidin-2-ones 2d,e,f were formed stereospecif-
ically. The optical purity was determined by comparing the
optical rotation of the products with the literature value.
Furthermore, the synthesis of 2-thiazolidinone 4 from (2-
mercapto-ethyl)-carbamic acid ethyl ester 3 was also successfully
performed under similar conditions (Scheme 2) in 50% yield.
Fig. 3 ORTEP diagram23 at 50% probability level showing the two
crystallographically independent molecules in the asymmetric unit
(residues are identified by the last number of the label). Residue 1 is
presented in white, residue 2 with gray octant shaded heavy atoms.
The reuseability of the catalyst was studied through the
reaction of (2-hydroxy-propyl)-carbamic acid ethyl ester 2b.
The catalyst was recovered from the reaction mixture by simple
filtration, then it was successfully reused without significant loss
of activity after washing it with toluene and being heated for 1 h
at 120 ◦C (see Table 2, 2b).
In summary the results show that the cyclization of carba-
mates in the presence of activated Mg : Al (3 : 1) hydrotalcite is
an efficient, environmentally friendly synthesis of oxazolidin-2-
ones. Several advantages, such as high catalytic activity, simply
Scheme 2
In the reaction of [(1R,2R)-2-hydroxy-1-hydroxymethyl-2-(4-
nitro-phenyl)-ethyl]-carbamic acid ethyl ester under the same
conditions we obtained the mixture of 6 and 7 in a 4 : 1 ratio
(Scheme 3).
The two products were separated by simple recrystallization
from ethyl acetate. Compound 6 has been known only in the
racemic form.22 Compound 7 has not been described in the
Scheme 3
9 6 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 6 7 – 9 6 9

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work-up, reuseability of the catalyst avoiding the problem of
disposing of concentrated basic solutions, use of harmless
reagents, can make this procedure a useful and attractive
alternative of synthesis of oxazolidin-2-ones.†
The financial support of the Hungarian Scientific Research
Fund (OTKA T-037757) is gratefully acknowledged.
ray Crystallography.27 Anisotropic full-matrix least-squares refinement28
on F2 for all non-hydrogen atoms yielded R1 = 0.0452 and wR2
=
0.0867 for 3290 [I > 2r(I)] and R1 = 0.0478 and wR2 = 0.0885
for all (3716) intensity data, goodness-of-fit = 0.909; the maximum
and mean shift/esd 0.000 and 0.000). Number of parameters is 335.
The maximum and minimum residual electron density in the final
difference map was 0.200 and −0.246 e A−3. Hydrogen atomic positions
˚
were located in difference maps. Hydrogen atoms were included in
structure factor calculations but they were not refined. CCDC reference
number 258502. See http://www.rsc.org/suppdata/ob/b4/b418848a/
for crystallographic data in .cif or other electronic format.
Notes and references
† General procedure for the preparation of oxazolidin-2-ones. The carba-
mates 1 were synthesized by alkoxycarbonylation of the corresponding
aminoalcohols with EtO2CCl using the method reported by Wu and
Shen.5c Thus, 5 ml (50 mmol) EtO2CCl was dropped into an ice-mixture
of 50 mmol aminoalcohol and 25 g (0.25 mol) KHCO3 in 40 ml water
under vigorous stirring. After the addition was complete, the cooling
bath was removed. The reaction mixture was stirred at rt for 1.5 h, then
it was extracted with EtOAc (4 × 25 ml). The combined organic phases
were washed with brine and water, dried over anhydrous magnesium
sulfate then the solvent was removed to give the pure carbamate 1.
Selected data of (2-hydroxy-propyl)-carbamic acid ethyl ester (1b): 4.12 g
(57%) white oil, 1H NMR (300 MHz, CDCl3) d (ppm): 1.16 (t, J = 7.5,
3H), 1.27 (t, J = 9 Hz, 3H), 2.99–3.19 (m, 2H), 3.91–3.98 (m, 1H), 4.10
(q, J = 10.5 Hz, 2H), 5.58 (bs, 1H).
1 (a) J. A. Tucker, D. A. Allwine, K. C. Grega, M. R. Barbachyn,
J. L. Klock, J. L. Adamski, S. J. Brickner, D. K. Hutchinson, C. W.
Ford, G. E. Zurenko, R. A. Conradi, P. S. Burton and R. M. Jensen,
J. Med. Chem., 1998, 41, 3727; (b) A. Mai, M. Artico, M. Esposito,
G. Sbardella, S. Massa, O. Befani, P. Turini, V. Giovannini and B.
Mondovi, J. Med. Chem., 2002, 45, 1180.
2 (a) For reviews, see:D. A. Evans, Aldrichima Acta, 1982, 15, 23;
(b) D. J. Ager, I. Prakash and D. R. Schaad, Aldrichima Acta, 1997,
30, 3; (c) For examples, see:D. A. Evans, J. Bartroli and T. L. Shih,
J. Am. Chem. Soc., 1981, 103, 2127; (d) K. C. Nicolaou, T. Gaulfield,
H. Kataoka and T. Kumazawa, J. Am. Chem. Soc., 1988, 110, 7910;
(e) D. A. Evans, J. R. Gage and J. L. Leighton, J. Am. Chem. Soc.,
1992, 114, 9434; (f) D. A. Evans, A. S. Kim, R. Metternich and V. J.
Novack, J. Am. Chem. Soc., 1998, 120, 5921.
3 (a) D. J. Ager, J. Prakash and D. R. Schaad, Aldrichimica Acta, 1997,
30, 3; (b) S. Katsumura, S. Iwama, T. Matsuda, T. Tant, S. Fujii and
K. Ikeda, Bioorg. Med. Chem. Lett., 1993, 3, 2703; (c) P. Ten Holte,
B. C. J. Van Esseveldt, L. Thijs and B. Zwanenburg, Eur. J. Org.
Chem., 2001, 2965; (d) D. A. Walsh and J. M. Yanni, US patent
5,086,055, 04 Feb. 1992 (Chem. Abstr., 1992, 116, 188072r); (e) B.
Bozdogan and P. C. Appelbaum, Int. J. Antimicrob. Agents, 2004, 23,
113.
[(1R,2R)-2-Hydroxy-1-hydroxymethyl-2-(4-nitro-phenyl)-ethyl]-carbamic
acid ethyl ester (5): 7.37 g (81%) light-yellow solid, mp: 107 ◦C, 1H
NMR (300 MHz, CDCl3) d (ppm): 1.18 (t, J = 7.2 Hz, 3H), 3.54–3.57
(m, 1H), 3.72–3.75 (m, 2H), 3.83–3.86 (m, 2H), 3.91 (q, J = 7 Hz, 2H),
0.89 (bs, 1H), 5.08 (bs, 1H), 7.63 (d, J = 8.5 Hz, 2H), 8.18 (d, J =
8.5 Hz, 2H).
In a typical condensation reaction, hydrotalcite (0.13 g) was added to
the mixture of carbamate (5 mmol) and toluene (10 ml) under argon.
The mixture was stirred at 110 ◦C for 5 h. Then the catalyst was filtered
out, washed with toluene and the filtrate was evaporated. The residue, if
necessary, was purified by column chromatography or recrystallized to
give the corresponding oxazolidin-2-ones. The known products were
characterized by comparing the 1H NMR, IR spectroscopy, optical
rotations and melting points data with those reported in the literature.
The spectral and physical data of the known compounds were identical
with those reported in the literature.
4 K. Ru¨ck-Braun, A. Stamm, S. Engel and H. Kunz, J. Org. Chem.,
1997, 62, 967.
5 (a) N. Lewis, A. McKillop, R. J. K. Taylor and R. J. Watson,
Synth. Commun., 1995, 25, 561; (b) H.-J. Kno¨lker and T. Braxmeier,
Tetrahedron Lett., 1998, 39, 9407; (c) Y. Wu and X. Shen, Tetrahedron:
Asymmetry, 2000, 11, 4359.
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Perkin Trans. 1, 1993, 5.
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and T. Sugai, Synlett., 2000, 2, 189.
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M. Kamada, I. Hayakawa, T. Akiba and S. Terashima, Tetrahedron
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11 W. J. Close, J. Am. Chem. Soc., 1951, 73, 95.
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13 N. Sonoda, G. Yamamoto, K. Natsukawa, K. Kondo and S. Murai,
Tetrahedron Lett., 1975, 1969.
Selected data of 5-methyl-oxazolidin-2-one (2b): oil, IR (neat) 3320, 1740,
1
1260 cm−1, H NMR (500 MHz, CDCl3) d (ppm): 1.44 (d, J = 6 Hz,
3H), 3.20 (t, J = 7.5 Hz, 1H), 3.71 (t, J = 8 Hz, 1H), 4.77–4.80 (m, 1H),
6.52 (bs, 1H); 13C NMR (75 MHz, CDCl3) d (ppm): 20.6, 47.0, 72.8,
159.8.
Spectral data of new compounds:
(4R,5R)-5-(4-Nitrophenyl)-4-hydroxymethyl-1,3-oxazolidin-2-one (6):
light-yellow solid, mp: 120 ◦C, IR (KBr): 3335, 1746, 1550, 1315, cm−1
;
1H NMR (300 MHz, methanol-d4) d (ppm): 3.78 (s, 2H), 4.29–4.31 (m,
1H), 5.6 (d, J = 4.2 Hz, 1H), 7.66 (dd, J1 = 3 Hz, J2 = 7.2 Hz, 2H), 8.29
(dd, J1 = 1.8 Hz, J2 = 8.1 Hz, 2H); 13C NMR (75 MHz, methanol-d4) d
(ppm): 59.1, 67.8, 74.4, 124.5, 128.9, 149.1, 149.4, 159.5. [a]2D5 = +1.46
(c = 1, MeOH). C10H10N2O5 Anal. Calcd. C 50.42, H 4.2, N 11.76,
Found C 50.02, H 3.98, N 11.54%.
14 B. Gabriele, R. Mancuso, G. Salerno and M. Costa, J. Org. Chem.,
2003, 68, 601.
15 J. Das, Synth. Commun, 1988, 18, 907.
16 E. Suzuki, M. Okamoto and Y. Ono, J. Mol. Catal, 1990, 61, 283.
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60.
4R-(1R-Hydroxy-(4-nitrophenyl)-methyl)-1,3-oxazolidin-2-one (7): white
solid, mp: 175–177 ◦C, IR (KBr): 3335, 1746, 1550, 1315, cm−1; 1H NMR
(300 MHz, methanol-d4) d (ppm): 4.15–4.19 (m, 2H), 4.31–4.35 (m, 1H),
4.81–4.89 (m, 1H), 7.66–7.70 (m, 2H), 8.25 (dd, J1 = 1.8 Hz, J2 = 7.8 Hz,
2H); 13C NMR (75 MHz, methanol-d4) d (ppm): 59.1, 63.8, 80.1, 124.5,
127.7, 148.1, 149.5, 159.8. [a]2D5 = +8.25 (c = 1, MeOH). C10H10N2O5
Anal. Calcd. C 50.42, H 4.2, N 11.76, Found C 50.18, H 3.96, N 11.52%.
Single crystal X-ray diffraction of compound (7). Single crystals of
(7) were grown from the mixture of toluene and acetone, and were
recrystallized from toluene by controlled solvent evaporation technique
at room temperature. Crystal data: C10H10N2O5, Fwt.: 238.20, size:
0.75 × 0.67 × 0.52 mm, crystal system: monoclinic, space group P21,
18 K. K. Rao, J. S. Gravelle, J. M. Fraile and F. Figueras, J. Catal., 1998,
173, 115.
19 F. Cavani, F. Trifiro and A. Vaccari, Catal. Today, 1991, 11, 173.
20 M. L. Kantam, B. M. Choudary, Ch. V. Reddy, K. K. Rao and F.
Figueras, Chem. Commun., 1998, 1003.
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Figueras, J. Mol. Catal. A, 1999, 146, 279.
22 Z. Hamersak, D. Sepac, D. Ziher and V. Sunjic, Synthesis, 2003, 3,
375.
23 (a) PLATONA. L. Spek, Acta Crystallogr., Sect. A, 1990, 46, C-34;
(b) Windows implementation by L. J. Farrugia, Dept. of Chemistry,
University of Glasgow, UK. 1998.
◦
˚
˚
˚
a = 5.600(1) A, b = 24.290(2) A, c = 7.740(1) A, a = c = 90.00 , b =
◦
3
˚
96.240(4) , V = 1046.6(2) A , T = 93(2) K, Z = 4, F(000) = 496, Dx =
1.512 Mg m−3, l = 1.059 mm−1. A crystal of prism shape was mounted on
a glass fibre. Cell parameters were determined by least-squares of 3150
reflections in the range of 3.6378 ≤ h≤ 72.1250◦. Intensity data were
collected on a Rigaku R-AXIS RAPID image plate diffractometer25
24 H. D. Flack, Acta Crystallogr., Sect. A, 1983, 39, 876–881.
25 CrystalClear v. 1.3.5., Rigaku Corp., 2000.
˚
(graphite monochromator; Cu-Ka radiation, k = 1.54178 A at 93(2)
K in the range 3.64 ≤ h≤ 71.78◦. A total of 19078 reflections were
collected of which 3716 were unique [Rint = 0.0989, Rr = 0.0906]; 3290
reflections were more intense than 2r(I). Completeness to 2h = 0.951.
Numerical absorption correction was applied. The structure was solved
by direct methods.26 Neutral atomic scattering factors and anomalous
scattering factors were taken from the International Tables for X-
26 G. M. Sheldrick, SHELXS-97 Program for Crystal Structure Solu-
tion, University of Go¨ttingen, Germany, 1997.
27 International Tables for X-ray Crystallography, vol. C, ed. A. J. C. Wil-
son, Kluwer Academic Publishers, Dordrecht, 1992.
28 G. M. Sheldrick, SHELXL-97 Program for Crystal Structure Refine-
ment, University of Go¨ttingen, Germany, 1997.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 9 6 7 – 9 6 9
9 6 9