The first enantioselective [3+2] cycloaddition of epoxides to arylisocyanates: Asymmetric synthesis of chiral oxazolidinone phosphonates

Article abstract of DOI:10.1016/j.tetasy.2010.10.028

A [3+2] cycloaddition of diethyl 1,2-oxiranephosphonate to aryl isocyanates catalyzed by lanthanide cations is described. The reaction is highly regioselective and 5-substituted 2-oxazolidinone phosphonates are obtained with a regioselectivity greater than 95:5 with respect to the 4-substituted regioisomer, and in up to 84% yield. When 20 mol % of Pybox-Yb³⁺ is used as a catalyst, enantiomerically enriched products are obtained in up to 75% ee, depending on the reaction conditions, and the nature of the isocyanate. Low temperatures benefit asymmetric induction, but have an adverse effect on the regioselectivity for para-substituted aryl isocyanates.

Full text of DOI:10.1016/j.tetasy.2010.10.028

Tetrahedron: Asymmetry 21 (2010) 2746–2752
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The first enantioselective [3+2] cycloaddition of epoxides to
arylisocyanates: asymmetric synthesis of chiral oxazolidinone phosphonates
⇑
⇑
Maria Teresa Barros , Ana Maria Faísca Phillips
REQUIMTE, Department of Chemistry, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Quinta da Torre, 2829-516 Caparica, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
A [3+2] cycloaddition of diethyl 1,2-oxiranephosphonate to aryl isocyanates catalyzed by lanthanide cat-
ions is described. The reaction is highly regioselective and 5-substituted 2-oxazolidinone phosphonates
are obtained with a regioselectivity greater than 95:5 with respect to the 4-substituted regioisomer,
and in up to 84% yield. When 20 mol % of Pybox-Yb3+ is used as a catalyst, enantiomerically enriched
products are obtained in up to 75% ee, depending on the reaction conditions, and the nature of the iso-
cyanate. Low temperatures benefit asymmetric induction, but have an adverse effect on the regioselec-
tivity for para-substituted aryl isocyanates.
Received 19 October 2010
Accepted 27 October 2010
Available online 20 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
yphosphonates as antibacterials, nucleoside phosphonate ana-
logues as antivirals, and bisphosphonates as drugs for the
The oxazolidinone unit is rarely present in natural products, but
compounds with this unit have many applications.1–3 Oxazolidi-
nones are often used as chiral auxiliaries for a variety of asymmet-
ric synthetic transformations4 (the so-called Evans’ auxiliaries), as
protecting groups for 1,2-amino alcohols, and as building blocks in
polymers. In recent years 5- and 4,5-disubstituted oxazolidinones
have attracted a lot of attention because they are one of a few
new classes of antibiotics that have been discovered in the past
30 years, after the quinolones.5,6 In 2000, Linezolid of Pharmacia/
Pfizer became the first to be commercialized.
This and related antibacterials are active against numerous
Gram-positive organisms, including methicillin-resistant Staphylo-
coccus aureus (MRSA), vancomycin-resistant enterococci (VRE) and
penicillin- and cephalosporin-resistant Streptococcus pneumoniae.
The treatment of mycobacterial infections, which place at risk im-
muno-compromised populations, is a potential area of applica-
tion.7 These antibiotics inhibit bacterial protein synthesis, do not
exhibit cross-resistance, and can be administered orally as well
as intravenously. The synthesis of analogues is an active area of re-
search. Modifications of the rings, ring-substituents, as well as the
C-5 side chain, have given rise to libraries of compounds8,9 in a
search for higher activity, lower toxicity, or better properties. The
absolute configuration at C-5 is critical for the biological activity.9
We have been interested in biologically active phosphonate
derivatives for a few years,10,11 and the possibility of a phosphoryl
substituent at C-5 seemed to be an attractive option. Many
phosphonates have applications in medicine, such as epox-
treatment of numerous bone diseases. Only a few examples of oxa-
zolidinone phosphonate derivatives could be found in the litera-
ture. Wyatt et al. converted a 2-amino-1-hydroxyphosphonate
into the corresponding oxazolidinone using 1,10-carbonyldiimidaz-
ole, as a means to elucidate the stereochemistry of the parent
phosphonate.12 Jung et al. have synthesized a few biologically ac-
tive oxazolidinone phosphonates via a multi-step synthesis, with
the phosphoryl group separated from the ring by a three or more
atom tether.13–15 Starting from the oxazolidinone ring, it is also
possible to obtain N-(phosphonomethyl)oxazolidinones, via reac-
tion with phosphorus trichloride and formaldehyde.16,17 We
decided to try an approach using the 1,3-cycloaddition of epoxides
to isocyanates, a reaction that to the best of our knowledge has not
been applied in phosphonate chemistry.
A number of halides are known to catalyze the 1,3-cycloaddi-
tion of simple epoxides to isocyanates: tetraalkylammonium ha-
lides,18,19 LiBr-OPPh3,20 n-Bu-SnI Lewis base complexes,21 and
lanthanide chlorides.22 Also, Pd2(dba)3ꢀCHCl3 and trialkyl phos-
phite can also be used to convert substituted vinyl oxiranes stere-
oselectively to cis-oxazolidinones.23 Some of these methods
require high temperatures and trimerization or polymerization of
the isocyanate may occur as a side reaction. To the best of our
knowledge, no catalytic asymmetric versions have been reported.
Herein we report our results on the synthesis of enantiomerically
enriched oxazolidinone phosphonates B (Fig. 1) with potential
biological activity.
2. Results and discussion
⇑
Corresponding authors. Tel.: +351 212948300; fax: +351 212948550.
E-mail addresses: mtbarros@dq.fct.unl.pt (M.T. Barros), amfp@dq.fct.unl.pt (Ana
As
a test reaction, the [3+2] cycloaddition of phenyl
isocyanate to diethyl 1,2-epoxyphosphonate, a simple terminal
Maria Faísca Phillips).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.028

M. T. Barros, A. M. F. Phillips / Tetrahedron: Asymmetry 21 (2010) 2746–2752
2747
corresponding proton on a carbon atom attached to nitrogen, a less
electronegative atom, which in similar 4-substituted oxazolidinon-
es appears near 4.5 ppm.25 In 31P NMR spectra, a single signal was
observed for the oxazolidinone phosphonate. In 1H NMR spectra,
two additional small multiplets centered at 4.41 and 4.72 ppm
could usually be seen, suggesting that the other regioisomer may
have formed albeit in low amounts: usually 65%. There were no
other signals present that could help identify this substance, which
was difficult to separate chromatographically from the oxazolidi-
none, another indication of structural similarity.
F
O
O
R
O
N
N
O
N
O
NHAc
OR
OR
P
O
A: Linezolid
B: Targets
Figure 1.
It is generally thought19,22 that the mechanism of the reaction
with halides involves ring opening to form a 1,2-alkoxy halide,
which subsequently adds to the isocyanate, a process which would
be facilitated by epoxide coordination to the metal. This mecha-
nism is supported by computational studies.26 The chlorohydrin
found in reaction mixtures is consistent with this type of mecha-
nism. However, it was also found that if the reactions were allowed
to proceed longer than their endpoints, more chlorohydrin is
formed.
As for the nature of the metal, the hard Lewis acid TiCl4 gave
only the halohydrin after 3 h of reflux, and there was no reaction
when SnCl2 was used as a catalyst. However, BiCl3 gave 28% of
the oxazolidinone under the same conditions. Catalyst RuCl3 also
worked in this transformation, but its activity was low (entry 2).
The lanthanides, which are mild Lewis acid catalysts, are highly
oxophilic anions and usually attain association-dissociation equi-
libria rapidly in ligand substitution reactions;27 due to the liability
of the Ln–O bond, product dissociation is also fast. All the lantha-
nide chlorides that we tested, irrespective of their position in the
periodic table, were active in this [3+2] cycloaddition. The triflate
(entry 11) did not yield the desired product, which supports the
theory that the reaction between epoxides and isocyanates is initi-
ated by the reaction of a chloride ion at the epoxy ring. Both the
anhydrous and the hydrated metal chlorides yielded a product.
The hydrated catalysts reacted faster, for example, CeCl3 versus
epoxyphosphonate analogous to the well-known antibiotic fosfon-
omycin, was selected. The required substrate could be obtained in
high yield by a modification of the method of Sturtz and Pondaven-
Raphalen,24 with t-BuOK in t-BuOH being used to cyclize the inter-
mediate halohydrin obtained from the reaction of diethyl allyl
phosphonate with NaOCl formed from bleach-HCl. When the epox-
yphosphonate and isocyanate were mixed in the absence of a cat-
alyst, there was no reaction at room temperature, or even after
refluxing for 3 h in dichloromethane. Tetrabutylammonium alkyl
halides did not give the desired [3+2] cycloadducts either. How-
ever, several metal halides were found to catalyze the reaction,
with different degrees of success. The results obtained are shown
in Table 1. The reactions were regioselective: the 5-substituted
2-oxazolidinone was obtained in preference to the 4-substituted
regioisomer, either with none or with some b-chlorohydrin, in a ra-
tio that varied with the nature of the metal and the reaction condi-
tions. The regiochemistry of the product is in accordance with that
expected, considering the inductive effect of the phosphonate
group and the steric effects on the terminal epoxide. The 1H NMR
spectrum of the compound has a multiplet at 5.49 ppm due to
the methine proton, whose corresponding carbon atom is attached
to the oxygen. A chemical shift of greater than 5 ppm is consistent
with 2-oxazolidinones substituted at the 5-position by electron
withdrawing groups. It is further downfield than the signal of the
Table 1
Screening of potential metal catalysts for the [3+2] cycloaddition of epoxyphosphonate 1 to arylisocyanates
O
P
O
P
Cl
O
P
O
O
O
Catalyst
OEt
OEt
OEt Ar-N=C=O
OEt
OEt
OEt
N
Solvent; reflux
OH
Ar
4
1
2
3
Entry
Catalyst
Reagents
Conditionsa
Resultsb
Epoxide (mmol)
Isocyanate (R, mmol)
Metal (mmol)
Solvent
Time (h)
Conv. (%)
Oxazolidinonec (%)
Chlorohydrin (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
TiCl4
RuCl3
SnCl2
BiCl3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
Ph, 1.10
Ph, 1.10
Ph, 0.95
Ph, 1.10
Ph, 0.95
Ph, 1.00
Ph, 1.00
Ph, 1.00
Ph, 1.20
Ph, 1.00
Ph, 0.81
Ph, 0.94
Ph, 1.00
Ph, 1.50
pMeO–C6H4, 1.30
pAc–C6H4–, 1.00
Ph, 1.0
0.47
0.50
0.47
0.50
0.50
0.54
0.50
0.50
0.25
0.50
0.99
0.50
0.43
0.47
0.50
0.50
0.50
Toluene
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3
20
3
3
3
2.5
1
3
5
1
2
1
1
3
3
2
1
100
14
0
70
48
100
99.6
100
95
12
23
100
83
97
100
88
90
0
14
0
28
100 (52)
0
0
42
7
21
1.4
17
18
0
0
26
0
CeCl3
41
CeCl3ꢀ7H2O
SmCl3ꢀ6H2O
SmCl3ꢀ6H2O
SmCl3ꢀ6H2O
TbCl3
Yb(OTf)3
YbCl3ꢀ6H2O
YbCl3ꢀ6H2O
YbCl3ꢀ6H2O
SmCl3ꢀ6H2O
SmCl3ꢀ6H2O
SmCl3ꢀ6H2O
79 (62)
98.2 (59)
83 (76)
75
12
0
74 (66)
83
97 (74)
100 (84)
58 (40)
90
0
0
30
0
a
The reactions were performed with a concentration of 0.22 mmol/mL with respect to the phosphonate.
Percentages were determined from signal ratios in 31P NMR spectra; values within brackets represent the yields of the compounds isolated after column chromatography,
b
with respect to the initial amount of epoxyphosphonate reacted.
c
Reaction products contained about 5% of the 4-substituted oxazolidinone.

2748
M. T. Barros, A. M. F. Phillips / Tetrahedron: Asymmetry 21 (2010) 2746–2752
CeCl3ꢀ7H2O and TbCl3 (entries 5, 6 and 10). A rate enhancement in
lanthanide-catalyzed reactions in the presence of water has been
described previously.28 In a hetero Dields–Alder reaction catalyzed
by lanthanide bis-trifluoromethanesulfonylamide, the addition of
water to the reaction mixture resulted in an increase in both chem-
ical yield and enantioselectivity. Catalyst SmCl3ꢀ6H2O gave the
oxazolidinone almost quantitatively after 1 h, which was isolated
in 60% yield, and YbCl3ꢀ6H2O in 3 h, isolated in 74% yield. When
the catalyst loading was lowered from 50 to 25 mol % (entry 9)
the reaction took longer as expected but other unidentified prod-
ucts also started to form.
The synthesis of more elaborated oxazolidinones was then at-
tempted using different arylisocyanates. The reactions of aryl iso-
cyanate containing either an electron withdrawing or an electron
donating substituent in the para position of the ring were slower
than those of phenylisocyanate under the same conditions (cf. en-
tries 15–17). The reactions were also regioselective, and the 4-
substituted oxazolidinone was formed in less than 5% of the total
amount that was converted.
Once metals suitable to catalyze the reaction were found, a few
chiral ligands were tested in order to obtain enantiomerically en-
riched oxazolidinones. There have been a few reports on the suc-
cessful use of C2-symmetrical bis(oxazolines) as chiral ligands for
lanthanide ion-catalyzed reactions.27,29 We have been interested
in this type of ligand for some time,30 and so we decided to try
some (Fig. 2) to induce chirality in the epoxyphosphonate to oxa-
zolidinone phosphonate transformation. When a 1:1 mixture of
epoxyphosphonate/phenyl isocyanate was refluxed for 3.5 h in
the presence of a 1:1 complex of A/Yb3+, 10% of the substrate con-
verted into 6% product and 4% of an unidentified substance as
determined by 31P NMR spectroscopy. On the other hand,
20 mol % of Nishiyama’s Pybox ligand B converted 79% (74% iso-
lated) of the epoxyphosphonate into a product with 36% ee in
4.5 h. The larger bite size might be responsible for the increased
efficiency of this ligand to complex the large lanthanide cation.
The iso-propyl analogue C catalyzed a similar conversion (74%,
66% isolated yield) in 5 h, but this product was racemic. Some
organocatalysts were also tested: 50 mol % of proline yielded no
product after 3 h at rt, while with 20 mol % of quinine E refluxing
in CH2Cl2 or in toluene for the same period, only starting material
was recovered. Quininium chloride F was more promising. In
CH2Cl2 at rt there was no reaction after 17 h, but in refluxing tolu-
ene, after 23 h, there was 44% conversion of the starting material
into 29% oxazolidinone and 15% of an unidentified substance when
20 mol % of F was added.
Since B–Yb3+ was the most efficient catalyst for this transforma-
tion, the remaining experiments were carried out with this catalyst
system. The first step was then to find an optimum solvent. The re-
sults in Table 2 show that the best turnover is obtained in dichlo-
romethane. The reaction, as indicated in the equation in Figure 3,
was then optimized with respect to the catalyst loading, tempera-
ture and other experimental conditions and the results are summa-
rized in Table 3. The transformation was possible not only at reflux
but also with temperatures as low as 13 °C. At 0 °C the reaction was
slowed down to such an extent that other unidentified products
started to form preferentially (entry 16). A greater ligand to metal
ratio did not alter the results significantly (entries 1 and 2).
Increasing the amount of catalyst from 20 to 40 or 50 mol % sped
up the reaction with no benefit with regards to the asymmetric
induction (entries 3, 4, 21 and 22). In MeCN the reaction was faster,
but the ee was lower (cf. entries 7/8). When the temperature was
lowered the enantioselectivity went up by as much as 20% (entries
1, 7, and 20) to a maximum of 63%. When the concentration of iso-
cyanate was increased, the conversion did not vary (entries 6 and
9, or 16 and 17) indicating that the slow step of the reaction is
the reaction of chloride ion with the epoxide ring. However, more
oxazolidinone was formed in the same period of time. Hence, the
stepwise addition of isocyanate led to a faster formation of oxazo-
lidinone than when it was added all at once.
Manual hourly additions (Methods B, or E) or additions twice dai-
ly (Method C) resulted in the formation of greater amounts of oxazo-
lidinone over a shorter period of time (entries 6 and 20). In the first
case (entry 6), with a single addition, after 17 h at rt, the conversion
was 70%, but of this only 38% was oxazolidinone. On the other hand,
entry 16 shows that even at 13 °C, with only 47% conversion, there is
already the same amount of oxazolidinone present after 5 h, when
the addition of isocyanate is carried out in a stepwise fashion. Leav-
ing the reagents simply stirring for a longer period of time does not
yield more oxazolidinone because the isocyanate polymerizes with
time. These reactions were repeated a few times and gave similar re-
sults. It was also for this reason that isocyanate could not be used as
the limiting reagent in these syntheses. If the additions of isocyanate
are too far apart in time (entries 13 and 14), full conversion is possi-
ble, but the product racemizes slowly in time. It also appears that
high concentrations of isocyanate may depress the ee (entries 6
and9). Whenthesetworeactionswereperformed, theroomtemper-
ature differed by 6 °C only, so the large 20% difference in ee suggests
that when a large number of isocyanate molecules are present, com-
plexation to the metal may result in the formation of a less pro-
nounced chiral environment.
O
O
O
O
O
O
N
N
COOH
N
H
N
N
N
N
N
N
Ph
Ph
Ph
Ph
D
A
B
C
H
HO
Cl-
N
H
N
HO
MeO
MeO
N
N
E
F
Figure 2. Chiral ligands and catalysts screened.

M. T. Barros, A. M. F. Phillips / Tetrahedron: Asymmetry 21 (2010) 2746–2752
2749
Table 2
Since water-soluble phosphonic acids usually exhibit higher
biological activity than their esterified analogues, it is of interest
to convert the oxazolidinone phosphonates into the corresponding
phosphonic acids. This could be done with TMSBr, followed by
hydrolysis of the TMS esters formed with H2O, as shown in
Figure 4.
Effect of the nature of the solvent on catalytic turnovera
Solvent
Temp (°C)
Time (h)
Conv.b (%)
Yieldb (%)
CH2Cl2
Toluene
Tol/CH2Cl2
DMF
THF
CH2Cl2
50
120
50
50
80
5
5
3
3
3
5
94
100
94
52
80
84
20
72
0
60
95
c
d
3. Conclusions
50
100
a
The reactions were performed on a scale of 0.18 mmol of epoxyphosphonate,
We have shown that it is possible to synthesize 5-substituted 2-
oxazolidinone phosphonates from epoxyphosphonates via a [3+2]
cycloaddition to aryl isocyanates, catalyzed by lanthanide cations.
The regioselectivity of the reactions is very high, giving products in
95:5 ratio with respect to the 4-substituted regioisomer. Due to the
current interest in oxazolidinone antibiotics, methods leading to
chiral derivatives could become very useful synthetic tools. Here,
asymmetric induction was possible via Pybox-Yb3+ catalysis. With
20 mol % catalyst at 13 °C, ees of up to 75% were obtained. Unfor-
tunately when para-substituted aryl isocyanates were used, partic-
ularly one with an electron rich methoxy substituent, the
regioselectivity of the reaction dropped to nearly 2.5:1 in favour
of the desired product. Isocyanate side reactions became a problem
at low temperatures, preventing full conversion of the phospho-
nate into oxazolidinone, but this can be overcome by stepwise
addition of isocyanate to the reaction mixture.
with 1.0 equiv of phenyl isocyanate in 0.8 mL solvent and 20 mol % of YbCl3ꢀH2O
and of PyBox.
b
Determined from area ratios in 31P NMR spectra.
A 3:2 ratio was used.
Metal/ligand 40:40 mol %.
c
d
Therefore, in order to obtain a high yield of oxazolidinone with a
high ee, the reaction should be performed at low temperature, that
is, rt or lower, with stepwise hourly addition of isocyanate. Since
manual additions over long periods of time are not practical, the
process should be automated. Alternatively the reaction may be
stopped after a few hours, the enantiomerically enriched product
isolated, and unreacted phosphonate recovered and recycled. When
higher temperatures are used, that is, refluxing at 40 °C, conversion
into oxazolidinone is smooth, but the ee only goes up to 40%.
Other more substituted isocyanates were then tested in the
[3+2] cycloaddition reaction. Under reflux conditions, the regiose-
lectivity was similar to the racemic series, and the 5-substituted
isomers 4a and 4b formed preferentially with more than 95% selec-
tivity. For 4b the asymmetric induction was only 27%. When the
temperature was lowered, the regioselectivity of the reaction
dropped considerably with the para-substituted aryl isocyanates.
With the p-acyl derivative, the reactions had a regioselectivity of
3:1 in favor of the 5-substituted oxazolidinone 4c, and the major
regioisomer, which could be isolated, was found to have formed
with fairly high ees, of up to 75%. However, the reactions were very
slow, not only due to deactivation brought about by the electron
withdrawing substituent, but probably also due to the fact that
the isocyanate was rather insoluble in the solvent used. At room
temperature, after 17 h, there was only 63% conversion even with
an excess of isocyanate. The minor regioisomer could be identified
by a signal in the 31P NMR spectrum at 16.80 ppm, and by two mul-
tiplets at 4.57–4.75 ppm in the 1H NMR spectrum. The remaining
signals coincided with those of the major isomer. The p-methoxy
substituted aryl isocyanates were more reactive but the reactions
were far less regioselective, giving up to 2:1 of 4b/5b. However
the products were very difficult to separate on silica gel, and the
ees were not determined. Regioisomer 5b could be identified by
a singlet in the 31P NMR spectrum at 16.97 ppm, and by multiplets
at 4.35–4.45 ppm and 4.63–4.75 ppm in the 1H NMR spectrum.
4. Experimental
4.1. General
The reactions were performed under an argon atmosphere. The
reagents were obtained from commercial suppliers and used with-
out further purification. The solvents were purified by standard
methods and distilled before use. For column chromatography,
Merck silica gel 60 (230–400 mesh) was used. Thin layer chroma-
tography was performed on silica gel plates Merck 60 F254. NMR
spectra were obtained with a Bruker AR X400 NMR spectrometer
or a Bruker Avance 400 MHz spectrometer. Chemical shifts are rel-
ative to TMS. 31P NMR chemical shifts are relative to phosphoric
acid, used as external standard. The multiplicity of signals in 13C
NMR spectra was determined with a DEPT experiment. Two-
dimensional spectra (COSY 45, HMQC) were used to help with
structural determinations whenever it was necessary. IR spectra
were obtained with a Perkin Elmer Spectrum 1000 FT-IR spectro-
photometer and
spectrophotometer.
a
Perkin–Elmer Spectrum BX FT-IR
Elemental analysis was performed on a Thermo Finnigan
Elemental Analyser 1112 series, by the Laboratory for External Ser-
vices of CQFB-Lab Associado/REQUIMTE, of the Department of
YbCl3·H2O
Ligand
Cl
O
P
O
P
O
*
O
O
P
O
O
O
OEt
OEt
OEt
OEt
Ar-N=C=O
OEt
N
O
OEt
*
N
Ar
P
Solvent
OH
Ar
OEt
EtO
1
2a-c
3
4a-c
5a-c
a
b
c
: Ar = Ph
: Ar = p-MeOC6H4-
: Ar = p-AcC6H4-
O
O
N
Ligand =
N
N
Ph
Ph
PyBox
Figure 3.

Table 3
Asymmetric [3+2] cycloaddition of epoxyphosphonate 1 to arylisocyanates catalyzed by Yb3+–Pybox complexes
No
Reagentsa
Conditions
Methodc
A
Resultsb
Epoxide (mmol)
Ar
Isocyanate (mmol)
Metal/ligand (mmol)
Temp (°C)
Time (h)
Conv. (%)
Major product and yieldd,e (%)
Chlorohydrin (%)
eef (%)
1
2
3
4
5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
Ph
Ph
Ph
Ph
2a, 1.0
2a, 1.0
2a, 1.0
2a, 1.0
2b, 1.0
2a, 1.0
2a, 1.0
2a, 1.0
2a, 4.0
2b, 1.0
2b, 4.0
2c, 2.4
2a, 4.5
2a, 6.0
2a, 1.5
2a, 3.25
2a, 1.0
2a, 3.0
2a, 3.0
2a, 1.0
2a, 2.25
2a, 2.25
2b, 2.25
2c, 2.25
0.2/0.2
0.2/0.4
0.5/0.5
0.2/0.2
0.2/0.2
0.2/0.2
0.2/0.2
0.2/0.2
0.2/0.2
0.2/0.2
0.2/0.2
0.2/0.2
0.2/0.2
0.2/0.2
0.2/0.2
0.2/0.2
0.2/0.2
0.2/0.2
0.2/0.2
0.2/0.2
0.44/0.44
0.2/0.2
0.2/0.2
0.2/0.2
50
4.5
4.5
5
79
82
100
96
100
70
83
94
62
82
50
63
87
100
53
18
34
35
47
47
71
57
49
41
4a
4a
4a
4a
4b
4a
4a
4a
4a
4b
4b
4c
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
75
72
4
10
5
10
10
27
44
27
0
15
0
0
0
0
38
36
ND
ND
27
60
63
47
40
ND
ND
75
14
0
95 (42)
84 (75)
5
p-MeOC6H4
Ph
Ph
Ph
16.5
17
42
42
17
17
17
17
65
4 d
6
90
38
31
67
6
Rt
A
7
8g
9
Ph
62
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
p-MeOC6H4
p-MeOC6H4
p-AcC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
44:17 (17)
32:18 (44)
7:30 (12)
87
C
90
47
7
30
32
44
40
D
B
A
6
0
4
3
3
7
4
0
46
ND
ND
ND
ND
57
39
50
ND
73
0
13
6
3.8
3.8
15.5
5
8
8
B
E
67 (49)
57
34:15
4:13
Ph
p-MeOC6H4
p-AcC6H4
8
8
2
24
a
b
c
d
e
f
Reactions were performed in CH2Cl2 with a concentration of 0.22 mmol/mL with respect to the phosphonate.
Percentages were determined from signal ratios in 31P NMR spectra.
Addition of isocyanate: Method A, single addition; B, stepwise, 50 mol % initially, then 25 mol % hourly; C, 75 mol% twice daily; D, 25 mol % hourly; E, the insoluble solid isocyanate was added in portions at hourly intervals.
Values include up to 5% of the other regioisomer unless otherwise stated.
Values within brackets represent the yields of the compounds isolated after column chromatography.
Determined by HPLC on a chiral column.
g
Reaction performed in MeCN.

M. T. Barros, A. M. F. Phillips / Tetrahedron: Asymmetry 21 (2010) 2746–2752
2751
O
P
O
O
P
O
O
O
O
O
O
P
H2O, MeCN
40-50 C
MeCN
rt, Ar
OEt
OEt
OSiMe3
OSiMe3
OH
OH
Me3SiBr
∗
∗
N
N
N
°
Ph
Ph
Ph
3
6
7
Figure 4.
Chemistry, FCT, UNL. For HPLC analysis, a Merck Hitachi instru-
ment equipped with a Chiralpak AD-H column from Daicel, and a
Merck-Hitachi-4250 UV–Vis detector were used.
3114, 1741, 1600, 1554, 1540, 1505, 1445, 1329, 1316, 1254,
1217, 1096, 1041, 1022, 985, 758, 692 cmꢂ1 31P NMR (CDCl3,
;
161.9 MHz): d 16.98 ppm; 1H NMR (CDCl3, 400 MHz): d 1.32 (t, J
7.0 Hz, 3H, CH3), 1.35 (t, J 7.0 Hz, 3H, CH3), 3.84 (superimposed
ddd, JHP 5.9 Hz, JHH 9.7, 12.2 Hz, 1H, CHHN), 3.95 (ddd, JHH 3.1,
9.3 Hz, JHP 6.4 Hz, 1H, CHHN), 4.12–4.33 (m, 4H, 2 ꢁ CH2OP), 5.48
(td, JHH 3.0, 11.9 Hz, JHP 11.9 Hz, 1H, PCH), 7.07 (t, J 7.3 Hz, 1H,
Ph-H), 7.30 (t, J 7.6 Hz, 2H, Ph-H), 7.46 (d, J 7.8 Hz, 2H, Ph-H)
ppm; 13C NMR (CDCl3, 100.6 MHz): d 16.35 (s, 2 ꢁ CH3), 42.21 (d,
JCP 9.1 Hz, CH2N), 63.27 (s, POCH2), 63.71 (s, POCH2), 68.59 (d, J
165.3 Hz, PCH), 118.7 (s, CH, Ph-C), 123.7 (s, CH, 2 ꢁ Ph-C), 129.0
(s, CH, 2 ꢁ Ph-C), 137.6 (s, Cq, Ph-C), 151.9 (s, Cq, (NCOO) ppm.
Anal. Calcd for C13H18O5NPꢀ11 4H2O (322.53): C, 48.41; H, 6.33; N,
4.34. Found: C, 47.47; H, 5.99; N, 3.97. HPLC: CHIRALCEL AD-H col-
umn, hexane/2-propanol = 90:10, flow rate 1.0 ml/min, tr1 (ma-
jor) = 7.6, tr2 (minor) = 9.2 min.
4.2. General procedure for the metal-catalyzed synthesis of
racemic oxazolidinones
The metal and the epoxide dissolved in solvent, in the propor-
tions indicated in Table 1, were transferred to a reaction vessel
and stirred under argon. The isocyanate was added, and the mix-
ture was refluxed for the period of time indicated in Table 1. The
resulting suspension was then cooled, diluted with solvent, and
the reaction was quenched with HCl (1 M). The product was ex-
tracted three times with CHCl3. The combined extracts were
washed once with water, and the solution was filtered through
anhydrous sodium sulfate, and the solvent was removed on a ro-
tary evaporator to give the crude product, which was purified by
chromatography on silica gel.
4.6. Diethyl N-(4-methoxyphenyl)-2-oxo-oxazolidin-5-
ylphosphonate 4b
4.3. General procedure for the enantioselective synthesis of
oxazolidinones
The oxazolidinone was prepared from diethyl 1,2-oxi-
ranephosphonate and 4-methoxyphenyl isocyanate with
YbCl3ꢀ6H2O and 2,6-bis[(4R)-4-phenyl-2-oxazolidinyl]pyridine as
described under the general procedure. The crude product was
purified by column chromatography (silica gel, EtOAc/hex-
ane = 2:1) to give the product, as a white solid, which in the case
of the chiral reactions was an inseparable mixture of regioisomers;
mp 118–119 °C. IR (KBr): 3247, 3197, 3130, 3067, 2986, 2956,
2846, 1739, 1603, 1548, 1515, 1470, 1442, 1418, 1396, 1370,
The metal and the ligand, in the proportions indicated in Table 3,
were transferred to the reaction vessel, and solvent was added. The
mixture was refluxed under argon for 1 h. The mixture was then
cooled to the temperature indicated, and the epoxide dissolved
in solvent was added, followed by the isocyanate. The reaction
mixture was then stirred under argon, at the required temperature,
for the period of time indicated in Table 3. The resulting suspen-
sion was then cooled, diluted with solvent, and the reaction was
quenched with HCl (1 M). The product was extracted three times
with CHCl3. The combined extracts were washed once with water,
the solution was filtered through anhydrous sodium sulfate, and
the solvent was removed on a rotary evaporator to give the crude
product, which was purified by chromatography on silica gel.
1314, 1297, 1231, 1215, 1181, 832, 745, 721 cmꢂ1 31P NMR
;
(CDCl3, 161.9 MHz): d 17.12 ppm; 1H NMR (CDCl3, 400 MHz): d
1.25–1.50 (m, 6H, 2 ꢁ CH3), 3.75 (s, 3H, OCH3), 3.75–3.90 (m,
superimposed, 1H, CH2N), 3.90–4.06 (m, 1H, CH2N), 4.12–4.35
(m, 4H, 2 ꢁ POCH2), 5.43 (td, 1H, J 2.7, 12.0 Hz, PCH), 6.82 (d, 2H,
J 8.8 Hz, 2 ꢁ Ar-H), 7.30 (d, J 7.24 Hz, 2 ꢁ ArH) ppm; 13C NMR
(CDCl3, 100.6 MHz): d 16.36 (s, 2 ꢁ CH3), 42.31 (d, JCP 10.3 Hz,
CH2N), 55.45 (s, OCH3), 63.20 (d, JCP 5.9 Hz, POCH2), 63.54 (d, JCP
6.2 Hz, POCH2), 68.62 (d, JCP 164.7 Hz, PCH), 114.2 (s, CH, 2 ꢁ Ar-
C), 120.6 (s, CH, 2 ꢁ Ar-C), 130.5 (s, Cq, Ar-C), 152.2 (s, Cq, Ar-C),
156.1 (NCOO) ppm. Anal. Calcd for C14H20O6NPꢀH2O (347.304): C,
48.42; H, 6.39; N, 4.03. Found: C, 46.52; H, 6.02; N, 3.73. HPLC:
CHIRALCEL AD-H column, hexane/2-propanol = 90:10, flow rate
1.0 ml/min, tr1 (major) = 14.8, tr2 (minor) = 19.1 min.
4.4. Diethyl 1-chloro-2-hydroxyethylphosphonate 3
This substance, which was found to be present in many reaction
mixtures as shown in the tables, had the following spectroscopic
data: 31P NMR (CDCl3, 161.9 MHz): 20.09 ppm; 1H NMR (CDCl3):
d 1.31 (t, 6H, J 7.1 Hz, 2 ꢁ CH3) 3.69 (dq, 1H, J 5.9, 9.6, 11.5 Hz,
CHHCl), 3.83 (dq, 1H, J 2.9, 6.4, 11.6 Hz, CHHCl), 4.09 (td, 1H, J
2.9, 9.4 Hz, PCH), 4.80–4.25 (m, 4H, 2 ꢁ CH2OP), 4.34 (s, 1H, OH)
ppm; 13C NMR (CDCl3, 100.6 MHz): d 16.35 (s, 2 ꢁ CH3), 45.10 (d,
J 11 Hz, CH2), 63.12 (d, J 5.6 Hz, POCHH), 63.40 (d, J 5.4 Hz, POCHH),
68.75 (d, J 160.1 Hz, PCH) ppm. The spectroscopic data of this com-
pound agrees with the published data.31
4.7. Diethyl N-(4-acetylphenyl)-2-oxo-oxazolidin-5-
ylphosphonate 4c
The oxazolidinone was prepared from diethyl 1,2-oxi-
ranephosphonate and phenyl isocyanate with YbCl3ꢀ6H2O and
2,6-bis[(4R)-4-phenyl-2-oxazolidinyl]pyridine as described under
the general procedure. The crude product was purified by column
chromatography (silica gel, DCM/hexane/MeOH = 5:5:1) to give 4c
as a white solid; mp 113.5–114 °C. IR (KBr): 3241, 3178, 3104,
3056, 2987, 1752, 1682, 1597, 1537, 1513, 1458, 1410, 1359,
1315, 1273, 1249, 1230, 1211, 1182, 1093, 1049, 1026, 994, 956,
4.5. Diethyl N-phenyl-2-oxo-oxazolidin-5-ylphosphonate 4a
The oxazolidinone was prepared from diethyl 1,2-oxi-
ranephosphonate and phenyl isocyanate with YbCl3ꢀ6H2O and
2,6-bis[(4R)-4-phenyl-2-oxazolidinyl]pyridine as described under
the general procedure. The crude product was purified by column
chromatography (silica gel, CHCl3/acetone = 12:1 or CHCl3/ace-
tone = 12:1 followed by EtOAc/hexane = 2:1) to give the product
as a white solid; mp 79–80 °C. IR (KBr): 3243, 3216, 3188, 3160,
855, 828, 800, 757, 722 cmꢂ1 31P NMR (CDCl3, 161.9 MHz): d
;
16.63 ppm; 1H NMR (CDCl3): d 1.31 (t, 3H, J 6.9 Hz, CH3), 1.34 (t,
3H, J 7.0 Hz, CH3), 2.54 (s, 3H, Ac-CH3), 3.79–3.84 (m, 1H, CH2N),

2752
M. T. Barros, A. M. F. Phillips / Tetrahedron: Asymmetry 21 (2010) 2746–2752
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3.90–3.96 (m, 1H, CH2N), 4.19 (quint, 4H, 2 ꢁ OCH2), 5.45 (td, J 2.9,
11.4 Hz, 1H, PCHO), 7.54 (d, J 8.6 Hz, 2 ꢁ CH, Ph-H), 7.90 (d, J
8.6 Hz, 2 ꢁ CH, Ph-H) ppm; 13C NMR (CDCl3, 100.6 MHz): d 16.40
(s, 2 ꢁ CH3), 26.39 (s, COCH3), 42.16 (s, (d, JCP 9.1 Hz, CH2N),
63.34 (s, POCH2), 63.77 (s, POCH2), 69.00 (d, J 166.0 Hz, PCH),
117.9 (s, 2 ꢁ CH, Ph-C), 129.8 (s, 2 ꢁ CH, Ph-C), 132.5 (s, Cq, Ph-
C), 142.1 (s, Cq, Ph-C), 151.7 (s, Cq, NCOO), 196.9 (s, CO) ppm. Anal.
Calcd for C15H20O6NPꢀH2O (359.315): C, 50.14; H, 6.17; N, 3.90.
Found: C, 47.20; H, 6.11; N, 3.57. HPLC: CHIRALCEL AD-H column,
hexane/2-propanol = 90:10, flow rate 1.0 ml/min, tr1 (ma-
jor) = 31.8, tr2 (minor) = 37.8 min.
4.8. N-Phenyl-2-oxo-oxazolidin-5-ylphosphonic acid 7
Diethyl N-phenyl-2-oxo-oxazolidin-5-ylphosphonate (0.042 g,
0.140 mmol) was dissolved in acetonitrile (0.71 mL) and bromotri-
methylsilane was added (0.18 mL, 1.40 mmol). The solution was
stirred at room temperature for 24 h. Water (0.040 mL, 2.22 mmol)
was added and the solution was stirred for 1 h at 40–50 °C. The sol-
vent and volatiles were then removed under reduced pressure and
the product was dried to give an oil: 0.038 g, 41%. 31P NMR (CDCl3,
161.9 MHz): d 12.11 ppm; 1H NMR (D2O): d 3.70–3.85 (m, 1H,
CHHN), 3.85–4.06 (m, 1H, CHHN), 5.13 (br t, J 9.7 Hz,b 1H, CHO),
7.04–7.14 (m, 1H, Ph-H), 7.24–7.39 (m, 4H, Ph-H) ppm; 13C NMR
(D2O, 100.6 MHz): d 44.05 (s, CH2), 71.64 (d, JCP 158.0 Hz, PCO),
120.5 (s, Ph-C), 124.8 (s, Ph-C), 129.6 (s, Ph-C), 137.7 (s, Ph-C),
155.5 (s, NCOO) ppm.
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Acknowledgment
A.M.F.P. thanks the financial support (SFRH/BCC/15809/2206) of
Fundação para a Ciência e Tecnologia, MCTES.
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