Diastereoselective approach to substituted oxazolidinones from Morita-Baylis-Hillman adducts

Article abstract of DOI:10.1080/00397910903534023

We disclose herein a new strategy for the diastereoselective preparation of 4- and 4,5-substituted oxazolidinones from Morita-Baylis-Hillman adducts. The strategy is based on an intramolecular cyclization involving a nucleophilic attack of an alkoxide ion

Full text of DOI:10.1080/00397910903534023

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Diastereoselective Approach to
Substituted Oxazolidinones from
Morita–Baylis–Hillman Adducts
Patrícia Rezende a , Paulo H. S. Paioti a & Fernando Coelho a
a Laboratory of Synthesis of Natural Products and Drugs, Department
of Organic Chemistry , Chemistry Institute, University of Campinas ,
Campinas, Brazil
Published online: 15 Dec 2010.
To cite this article: Patrícia Rezende , Paulo H. S. Paioti & Fernando Coelho (2010) Diastereoselective
Approach to Substituted Oxazolidinones from Morita–Baylis–Hillman Adducts, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:2, 227-242, DOI: 10.1080/00397910903534023
To link to this article: http://dx.doi.org/10.1080/00397910903534023
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Synthetic Communications1, 41: 227–242, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903534023
DIASTEREOSELECTIVE APPROACH TO SUBSTITUTED
OXAZOLIDINONES FROM MORITA–BAYLIS–HILLMAN
ADDUCTS
´
Patrıcia Rezende, Paulo H. S. Paioti, and Fernando Coelho
Laboratory of Synthesis of Natural Products and Drugs, Department of
Organic Chemistry, Chemistry Institute, University of Campinas,
Campinas, Brazil
We disclose herein a new strategy for the diastereoselective preparation of 4- and 4,5-
substituted oxazolidinones from Morita–Baylis–Hillman adducts. The strategy is based
on an intramolecular cyclization involving a nucleophilic attack of an alkoxide ion to the
carbonyl group of a carbamate. The latter is prepared from a Curtius rearrangement having
Morita–Baylis–Hillman adduct as substrate. The oxazolidinones were prepared in six steps
with an overall yield of 18% and 49%.
Keywords: Curtius rearrangement; heterocycles; Morita–Baylis–Hillman; oxazolidinones
INTRODUCTION
Oxazolidinones (Fig. 1) are five-membered heterocycles that have many
synthetic applications and important biological effects. Thanks to the efforts of
Evans et al.[1–6] these heterocycles have been successfully used as chiral auxiliaries
in many asymmetric organic transformations[7–12] and in aldol condensation reac-
tions,[13–15] Diels–Alder reactions,[16–19] alkylations,[20–23] Michael additions,[24–26]
and electrophilic aminations.[27–29]
In addition to the synthetic relevance of oxazolidinones, this type of compound
also presents strong antibacterial activity. At present, there is a medical need for the
discovery of new classes of antibiotics because of the appearance of several multidrug-
resistent microorganisms. Ozaxolidinones are a new class of synthetic antibiotics dis-
covered in the seventies and represent the only new type of antibiotics licensed in the
USA by the Food and Drug Administration in the past 30 years.[30–32] Linezolid
(Zyvox1) is an example of a successful commercial oxazolidinone antibiotic (Fig. 2).
The combination of synthetic usefulness with the pharmacological activity of
the oxazolidinones has stimulated efforts to develop alternatives for the synthesis
of this class of compounds.[33–35] Conventionally, oxazolidinones can be synthesized
Received July 20, 2009.
Address correspondence to Fernando Coelho, Laboratory of Synthesis of Natural Products and
Drugs, Department of Organic Chemistry, Chemistry Institute, University of Campinas, P.O. Box
6154, Campinas 13084-971, SP, Brazil. E-mail: coelho@iqm.unicamp.br
227

228
P. REZENDE, P. H. S. PAIOTI, AND F. COELHO
Figure 1. Oxazolidinone core and the most usual oxazolidinone chiral auxiliaries.
Figure 2. Oxazolidinone-based antibiotic.
by the treatment of a,b-difunctionalized compounds such as b-aminoalcohols,
oxiranes, and aziridines with phosgene,[36] carbonates,[33–35] isocyanates,[37–39] or
the mixture of carbon monoxide and oxygen via oxidative carbonylation,[40–45]
respectively. Strategies based on solid–state chemistry have already been employed
for the preparation of oxazolidinones.[46] Despite the great diversity of methodolo-
gies, some of them have drawbacks. For example, the use of carbonates and oxida-
tive carbonylations are not ecofriendly because of the risk associated with explosion
hazards using CO=O2 mixtures or the necessity of poisonous phosgene or carbon
monoxide involved in the synthesis.[47–49] The synthesis of oxazolidinones from
aziridines and carbon dioxide requires high temperatures and has the drawback of
polymer formation.[50]
The importance of oxazolidinones in pharmaceutical chemistry and organic
synthesis calls for the availability of as many alternative methods to prepare these
key compounds as possible. The Morita–Baylis–Hillman reaction (MBH) is an
amazing chemical transformation that allows access to a new r C-C bond.[51–59]
This reaction affords multifunctionalized products, which have already been used
as starting materials for the synthesis of several advanced synthetic intermediates
and natural products.[60–67]
Some years ago, during the synthesis of intermediates for the preparation of
alkaloids using MBH adducts, we needed to selectively remove a secondary protect-
ing group in the presence of a primary one. To accomplish this transformation,
isocyanate 1 was treated with SnCl4 at room temperature. To our delight, the
oxazolidinone 2 was the only product detected (Scheme 1).[68]
Because of the synthetic and biological relevance of oxazolidinones, we decided
to evaluate the scope of this synthetic methodology. Oxazolidinones could be
promptly prepared using the MBH reaction using the sequence proposed in the
retrosynthetic analysis depicted in Scheme 2.

OXAZOLIDINONES FROM MORITA–BAYLIS–HILLMAN
229
Scheme 1. Synthesis of oxazolidinone 2 from MBH reaction.
Scheme 2. Retrosynthetic analysis for the preparation of oxazolidinones from MBH adducts.
Both oxazolidinones (4- and 4,5-substituted) can be prepared from a common
intermediate (3) by treatment with NaH in tetrahydrofuran (THF). The alkoxides
generated under these experimental conditions can make a nucleophilic attack on
the carbonyl group to furnish both regioisomeric oxazolidinones. Carbamate 3
can be prepared from carboxylic acid 4 by a Curtius rearrangement. Finally, acid
4 can be obtained from different MBH adducts.
We disclose herein the results achieved in the preparation of 4- and 4,5-
substituted oxazolidinones employing the synthetic strategy proposed previously.
RESULTS AND DISCUSSION
Our work begins with the preparation of MBH adducts 5 and 6, synthesized
according a methodology well established in our laboratory (Scheme 3).[69,70]
Subsequently, the hydroxyl groups of the adducts were protected by treatment with
tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) in dichloromethane to
furnish the corresponding silyl ethers in 90% and 99% yield, respectively.
The silylated adducts were then treated with LiOH in a mixture of CH3CN–
H2O (3:1) at 50 ꢀC to afford the corresponding carboxylic acid in almost quantitative
yield for both cases. Acids 4a=4b were prepared in three steps with overall yields of
80 and 93%, respectively.
The Curtius rearrangement is an efficient method to add a nitrogen atom to a
given compound. An isocyanate is formed as intermediate of this reaction, which
in turn can be transformed into several different functional groups (amines,
carbamates, etc).[71] Acids 4a/b were initially treated with ethyl chloroformate at
5 ꢀC in the presence of triethylamine for 5 min. Afterward, a tiny amount of an aque-
ous solution of NaN3 was added to the reaction medium to provide the intermediate
acylazides, after 2 h of vigorous stirring. The solvent was removed, and the acyla-
zides were thermally rearranged by refluxing them in toluene for 2 h to afford the
ene-isocyanates. The entire sequence of reactions was performed without any

230
P. REZENDE, P. H. S. PAIOTI, AND F. COELHO
Scheme 3. Preparation of silylated acids from MBH adducts.
purification steps. The only procedure used between each step was simply solvent
removal. After evaporation, the crude ene-isocyanates were refluxed in anhydrous
t-butanol to give ene-carbamates 9 and 10. The carbamates were submitted to the
next step without purification, since they were demonstrated to be unstable when
exposed to silica-gel chromatography. Thus, the crude ene-carbamates were directly
treated with borane at 0 ꢀC, and the resulting solution was stirred for 16 h at room
temperature. Finally, a solution of NaOH was added, followed by a careful addition
of H2O2 to give the carbamates 11 and 12, in 37 and 69% overall yields (Scheme 4).
Because of the presence of the Boc protecting group, the measure of the coup-
1
ling constants of the carbinolic hydrogen on the H NMR spectra of 11 and 12
was unconclusive, and no data concerning the relative stereochemistry of these com-
pounds could be provided at this stage of our synthetic sequence. This issue forced
us to finish the synthesis and determine the relative stereochemistries of 3a and 3b
indirectly by measurig the coupling constants after cyclization (oxazolidinones).
Compounds 11 and 12 were separatedly treated with tetrabutylammonium
fluoride (TBAF) in THF at 0 ꢀC to give the corresponding carbamate-diols 3a and
3b in 87 and 98% yields, respectively. Finally, a solution of diols in anhydrous
THF was treated with an excess of NaH at room temperature to provide a mixture
Scheme 4. Preparation of carbamates from Curtius rearrangement of MBH adducts.

OXAZOLIDINONES FROM MORITA–BAYLIS–HILLMAN
231
Scheme 5. Synthesis of 4- and 4,5-substituted oxazolidinones.
of regioisomeric oxazolidinones that were easily separated by silica-gel column
chromatography (Scheme 5).
The regioisomeric oxazolidinones 13 and 14 were obtained in 69% yield in a
regioisomeric ratio of 1:1.5 (13:14), while regioisomeric oxazolidinones 15 and 16
were obtained in 79% yield with a ratio of 1:2 (15:16).
To determine the stereochemistry of our oxazolidinones, some nuclear Over-
hauser effect (nOe) experiments were carried out. The 1H NMR spectrum of 13 does
not show a regioisomeric mixture (Fig. 3). A doublet centered at 5.68 ppm
(J ¼ 5.2 Hz) was atributted to the carbinolic hydrogen. A multiplet centered at
Figure 3. Stereochemical determination of oxazolidinone 13.

232
P. REZENDE, P. H. S. PAIOTI, AND F. COELHO
3.94 ppm was attributed to the hydrogen attached to the C-N bond in the
five-membered ring. The correlation spectroscopy (COSY) spectrum clearly shows
that both hydrogens are coupled, another coupling is centered at 3.94 ppm, and the
hydrogen is centered at 3.67 ppm. According Futagawa et al., trans-4,5-substituted
oxazolidinones have a coupling constant between the vicinal hydrogens ranging from
4 to 6 Hz, while the vicinal coupling constant for the cis isomer varies between 9 and
10 Hz.[72] Based on these experimental data, we can unambigously assume that
oxazolidinone 13 is trans and also that the stereochemistry of diol 3a should be
syn (for the major isomer) (Fig. 3).
1
The H NMR spectrum of oxazolidinone 14 shows a mixture of diastereoi-
somers in a ratio of 5:1. An absorption centered at 5.02 ppm, as a doublet
(J ¼ 4.5 Hz), was attributed to the carbinolic hydrogen of the major diastereoisomer,
and the absorption centered at 4.84 ppm (J ¼ 6.9 Hz) was attributed to the minor
diastereoisomer. An absorption centered at 4.12 ppm, as a multiplet, was attributed
to the hydrogen directly attached to C-N bond. When the doublet centered at
5.02 ppm was irradiated, an increment of 1.21% in the multiplet centered at
4.12 ppm was observed. However, a huge increment of 11.27% was observed
when the doublet at 4.84 ppm was irradiated. These data strongly suggest that the
hydrogen at 4.84 ppm is on the same side as that appearing at 4.12 ppm and on
the opposite side of the hydrogen centered at 5.02 ppm (Fig. 4).
Based on these data, the relative stereochemistry of the major diastereoisomers
was determined to be anti and that of minor one to be syn. Besides, the coupling con-
stant (J ¼ 6.9 Hz) of the latter diastereoisomer is compatible with data described by
Donohoe et al. for a structurally related syn-oxazolidinone.[73]
The same experimental procedure was employed to determine the relative stereo-
chemistries of oxazolidinones 15 and 16. Oxazolidinone 15 appears as a mixture of
1
diastereoisomers in an 8:1 ratio (measured by H NMR from the crude reaction
medium; after chromatographic purification, the minor diastereoisomer is no longer
detected). The carbinolic hydrogen of the minor isomer appears as doublet centered
at 5.72ppm (J ¼ 8 Hz), while this absorption for the major isomer appears also as doub-
let centered at 5.36ppm (J ¼ 5.1 Hz). According Futagawa, we can assume the relative
stereochemistry of the major isomer is trans, while that of the minor one is cis (Fig. 5).
Unfortunately, oxazolidinone 16 was obtained as a mixture of stereoisomers,
without any diastereoselectivity. The relative stereochemistry of both stereoisomers
was attributed using the same procedure as already described for 14 and by compari-
son with data available in literature (Fig. 6).[73]
Figure 4. Determination of the relative stereochemistry of diastereoisomers 14.

OXAZOLIDINONES FROM MORITA–BAYLIS–HILLMAN
233
Figure 5. Stereochemical determination of isomers cis- and trans-15.
Figure 6. Determination of the relative stereochemistry of 16.
CONCLUSIONS
In summary, we have described a new approach to synthesize oxazolidinones
from MBH adducts. Two new 4-substituted and two new 4,5-substituted oxazolidi-
nones were prepared in six steps with overall yields of 18 and 49%. The diastereo-
selectivity obtained is very good for most cases. The method allows the preparation
of several oxazolidinones with different substitution patterns on the aromatic ring,
simply by changing the aldehyde used in the MBH reaction step. We believe
that the sequence described herein is a valuable alternative for the preparation of
oxazolidinones using an easy-to-handle and easy-to-obtain starting material.
EXPERIMENTAL
The following procedures are representative for all compounds prepared in this
work. All the reagents were purchased from specialized suppliers with analytical
1
purity and were utilized without previous purification, unless noted. The H and
13C spectra were recorded on a Varian instrument at 250 MHz and 68.5 MHz,
respectively, or on an Inova instrument at 500 MHz and 125 MHz, respectively.
The mass spectra were recorded using a Micromass (Manchester, UK) QT instru-
ment ESI-QT with 5000 mass resolution and 50 ppm mass accuracy in the turnover
frequency (TOF) mass analyzer. Infrared (IR) spectra were obtained with a Nicolet

234
P. REZENDE, P. H. S. PAIOTI, AND F. COELHO
Impact 410. Manipulations and reactions were not performed under dry atmo-
spheres or employing dry solvents, unless otherwise specified. Purification and
separations by column chromatography were performed on silica gel, using normal
or flash chromatography. Thin-layer chromatography (TLC) visualization was
achieved by spraying with 5% ethanolic phosphomolybdic acid and heating. An
ultrasonic cleaner, Unique model GA 1000 (1000 W, 25 kHz), was used to perform
MBH reactions. Ice was added occasionally to avoid increasing the temperature of
the water bath of the ultrasonic cleaner, which was maintained between 35 and 40 ꢀC.
General Experimental Protocol for the Preparation of the
Morita–Baylis–Hillman Adducts
A mixture of 1 mmol of aldehyde, 1.3 mmol of methyl acrylate, and 0.65 mmol
of 1,4-diazabicyclo[2.2.2]octane (DABCO) was sonicated (1000 W, 25 kHz) until com-
plete disappearance of starting material (monitoring by TLC). The ultrasound bath
temperature was constantly monitored and kept at 30–40 ꢀC during the reaction,
through ice addition or by using a refrigerated circulator. After the reaction time,
the mixture was evaporated under reduced pressure to remove the excess of acrylate.
The residue was diluted with dichlorometane or ethyl acetate (30 mL). The organic
solution was washed with 10% aqueous HCl (2 ꢁ 10 mL), saturated NaHCO3
(20 mL), and brine (20 mL) and dried over Na2SO4. After filtration and solvent
removal, the residue was filtered through a pad of silica gel to afford the corresponding
MBH adducts (5 and 6) in good to excellent yield, respectively 90 and 95%.
Methyl 2-[hydroxy(2-thienyl)methyl]acrylate (5). A yellow oil; 90% yield;
IR (film): n 3445, 2952, 1715 (C O), 1632 (C C) cmꢂ1; 1H NMR (300 MHz, CDCl3):
d 7.25 (1H, t, J ¼ 3.2 Hz), 6.96 (d, 2H, J ¼ 3.4 Hz), 6.36 (1H, s), 5.96 (1H, s), 5.77
(1H, s), 3.75 (3H, s), 3.48 (1H, sl, OH); 13C NMR (75 MHz, CDCl3): d 166.4,
145.6, 141.1, 126.7, 126.1, 125.2, 124.6, 69.5, 52.0; HRMS (Mþ) calcd. for
C9H10O3S 198.03507; found 198.03501.
=
=
Methyl 2-((3-chlorophenyl)(hydroxy)methyl)acrylate (6). A yellow oil;
ꢂ1
=
=
95% yield; IR (film): n 3452, 1711 (C O), 1624 (C C), 1433, 1282, 1151, 1041cm
;
1H NMR (250 MHz, CDCl3): d 3.16 (1H, s, OH), 3.71 (3H, s), 5.49 (1H, s), 5.84
(1H, s), 6.34 (1H, s), 7.24 (3H, m), 7.36 (1H, s); 13C NMR (62.5 MHz, CDCl3): d
166.6, 143.4, 141.4, 134.3, 129.7, 127.9, 126.7, 124.8, 72.6, 52.1; Anal. calcd. for
C11H11ClO3: C, 58.29%; H, 4.89%. Found: C, 58.27%; H, 4.88%.
General Procedure for the Preparation of Silylated MBH Adducts
A mixture of 1 mmol of MBH adduct, 2 mmol of triethylamine, and dichloro-
methane as solvent was stirred for 10 min. Then, 1.3 mmol of TBSOTf was added
at room temperature, under an inert atmosphere, and the resulting mixture was
stirred until complete disappearance of starting material (monitoring by TLC). Then,
the reaction mixture was diluted with dichloromethane (20 mL), and the organic layer
was washed with brine and a saturated solution of NaHCO3 and dried over MgSO4.
The solvent was evaporated under reduced pressure. The residue was purified by
silica-gel column chromatography using hexane=ethyl acetate as eluent.

OXAZOLIDINONES FROM MORITA–BAYLIS–HILLMAN
235
Methyl 2-[(tert-butyldimethylsilyloxy)(2-thienyl)methyl]acrylate (7). A
=
=
colorless oil; 90% yield; (film): n 2954, 2930, 2857, 1723 (C O), 1632 (C C), 1256,
1082, 838, 778 cmꢂ1; H NMR (300 MHz, CDCl3): d 7.19 (1H, dd, J ¼ 0.8 Hz and
1
J ¼ 5.0 Hz), 6.95 (1H, dd, J ¼ 0.6 Hz and J ¼ 3.0 Hz), 6.90 (1H, dd, J ¼ 3.5 Hz and
J ¼ 5.0 Hz), 6.29 (1H, s), 6.14 (1H, t, J ¼ 1.1 Hz), 5.90 (1H, s), 3.74 (3H, s), 0.9
(9H, s), 0.09 (3H, s), 0.01 (3H, s); 13C NMR (75 MHz, CDCl3): d 165.9, 147.1,
143.3, 126.1, 124.4, 124.2, 124.0, 68.4, 51.8, 25.8, 18.3, ꢂ2.7, ꢂ4.9. HRMS (ESI,
m=z): calcd. for C15H24O3SSi [M þ H]þ 313.1288; found 313.1280.
Methyl 2-[(tert-butyldimethylsilyloxy)(3-chlorophenyl)methyl]acrylate
=
(8). Colorless oil; 99% yield; IR (film): n 3453, 2954, 2861, 1714 (C O), 1629
1
(C C), 1576, 1475, 1004, 939, 740, 671, 520, 450, 426 cmꢂ1; H NMR (250 MHz,
=
CDCl3): d 7.35 (1H, s), 7.26–7.19 (3H, m), 6.28 (1H, t, J ¼ 2.6 Hz), 6.10 (1H, t,
J ¼ 3.1 Hz), 5.58 (1H, s), 3.69 (3H, s), 0.88 (9H, s), 0.06 (3H, s), ꢂ0.08 (3H, s); 13C
NMR (75 MHz, CDCl3): d 166.1, 144.8, 143.4, 133.9, 129.3, 127.5, 127.0, 125.2,
124.4, 72.1, 51.7, 46.7, 25.7, 18.1, ꢂ5.0. HRMS (ESI, m=z): calcd. for C17H25ClO3Si
[M þ Na]þ 366.1153; found 366.1141.
Hydrolysis of MBH Adducts: Preparation of Silylated Acids 4a/b
The silylated MBH adducts were treated with LiOH (10 equiv.) in a mixture of
CH3CN–H2O (1:1) (1 mmol of adduct = 20 mL of solution), at 50–60 ꢀC. After com-
plete disappearance of starting material (monitoring by TLC), the residue was con-
centrated under reduced pressure and diluted with ethyl acetate. The organic layer
was washed with brine and dried over NaSO4. The solvent was evaporated to afford
the crude acids, which are used for the next step without additional purification.
2-[(tert-Butyldimethylsilyloxy)(2-thienyl)methyl]acrylic acid (4a). Yellow
=
oil; 99% yield; IR (film): n 3355 (COOꢂH1), 3213, 2959, 2931, 2857, 1691 (C O),
;
1H NMR (300 MHz, CDCl3): d 7.21
=
1627 (C C), 1459, 1259, 1212, 837 cm
(1H, dd, J ¼ 0.9 Hz and J ¼ 5.1 Hz), 6.95 (1H, d, J ¼ 3.4 Hz), 6.91 (1H, d, J ¼ 5.0 Hz),
6.90 (1H, d, J ¼ 5.0 Hz), 6.45 (1H, s), 6.23 (1H, s), 5.87 (1H, s), 0.92 (9H, s), 0.11
(3H, s), 0.03 (3H, s); 13C NMR (75 MHz, CDCl3): d 170.4, 146.8, 142.6, 126.8,
126.3, 124.8, 124.5, 68.3, 25.7, 18.2, ꢂ5.0. HRMS (ESI, TOF): calcd. for
C16H22O3SSi [M þ Na]þ 321.0951; found 321.0883.
2-[(tert-Butyldimethylsilyloxy)(3-chlorophenyl)methy])acrylic acid (4b).
=
Colorless oil; 99% yield; IR (film): n 3056 (COOH), 2953, 2929, 2855, 1695 (C O),
1
1629 (C C), 1470, 1429, 1254, 1074, 837 cmꢂ1; H NMR: d 7.39 (1H, s), 7.35–7.22
=
(3H, m), 6.48 (1H, s), 6.26 (1H, s), 5.58 (1H, s), 0.93 (9H, s), 0.11 (3H, s), ꢂ0.03
(3H, s); 13C NMR (75 MHz, CDCl3): d 170.7, 144.4, 142.7, 133.9, 129.4, 127.6,
127.0, 125.1, 71.7, 25.7, 18.1, ꢂ5.0. HRMS (ESI, m=z): calcd. for C16H23NO3ClSi
[M þ Na]þ 349.0918; found 349.1003.
General Procedure for the Curtius Rearrangement and Hydroboration
To a solution of 1 mmol of acid in acetone (5 mL) at 0 ꢀC, 1.5 mmol of ethyl
chloroformate and 2 mmol of triethylamine were added. After 45 min (analysis by

236
P. REZENDE, P. H. S. PAIOTI, AND F. COELHO
TLC showed the complete disappearance of starting material), 1.5 mmol of sodium
azide dissolved in a small amount of water was added with vigorous stirring, and the
resulting mixture was stirred vigorously for 2 h. After that, the mixture was diluted in
cold dichloromethane, and the organic layer was washed with cold distilled water
and brine and dried over anhydrous Na2SO4. The solvent was evaporated, and the
residue was dissolved in anhydrous toluene (15 mL) and refluxed for 2 h. Then, the
solvent was evaporated, and the residue was dissolved in anhydrous t-butanol and
refluxed for 12 h. After that, the solvent was evaporated to give the crude
ene-carbamates (9) and (10), which were used immediately in the next step, without
purification.
To a stirred solution of 1 mmol of ene carbamates (9) and (10) in anhydrous
THF (10 mL), at 0 ꢀC, under an inert atmosphere, 7 mmol of BH3 ꢃ S(CH3)2
(1 mol=Lꢂ1 in THF) were added slowly. After the addition, the reaction medium
was warmed to room temperature and stirred for 16 h. The temperature of the result-
ing solution was then lowered to 0 ꢀC. A solution of NaOH (5 mL, 3 mol Lꢂ1) was
added, followed by the careful addition (drop by drop) of 30% H2O2 (5 mL). The
mixture was stirred for 45 min at 0 ꢀC and for 45 min at room temperature. After
this time, a saturated solution of NaHCO3 (10 mL) was added, and the mixture
was extracted with ethyl acetate. The organic layer was successively washed with a
saturated solution of NaHCO3, distilled water, and brine and dried over Na2SO4.
The solvent was removed under reduced pressure. The products (11 and 12) were
used in the next steps without purification.
tert-Butyl
[2-(tert-butyl-dimethyl-silanyloxy)-1-(hydroxymethyl)-2-
(2-thienyl)-ethyl] carbamate (11). Colorless oil; 37% overall yield; 1H NMR
(300 MHz, CDCl3): d 7.22 (1H, m), 6.95 (2H, m), 5.4 (1H, s, NH), 5.21 (1H, d,
J ¼ 3.3 Hz), 3.96 (1H, dd, J ¼ 2.7 Hz and J ¼ 11.7 Hz), 3.77 (1H, m), 3.68 (2H, d,
J ¼ 6.0 Hz), 3.52 (1H, dd, J ¼ 3.6 Hz and J ¼ 11.7 Hz), 1.47 (9H, s), 1.42 (9H, s),
0.94 (9H, s), 0.90 (9H, s), 0.12 (3H, s), 0.10 (3H, s), ꢂ0.007 (3H, s), ꢂ0.08 (3H, s);
13C NMR (75 MHz, CDCl3): d 145.1, 126.7, 126.1, 124.7, 124.1, 123.5, 74.0, 70.0,
62.6, 61.5, 58.3, 57.3, 28.4, 25.8, 18.1, ꢂ4.96.
tert-Butyl [2-(3-chlorophenyl)-2-tert-butyl-dimethyl-silanyloxy-1-
(hydroxymethyl)ethyl] carbamate (12). Colorless oil; 69% overall yield; IR
=
(film): n 3452 (OH), 3329, 2953, 2937, 2855, 1699 (C O), 1503, 1474, 1364, 1258,
1127, 1102, 1070, 837, 775 cmꢂ1; 1H NMR (300 MHz, CDCl3): d 7.37–7.19 (4H, m),
5.45 (1H, d, J ¼ 7.7 Hz), 5.13 (1H, sl), 4.91 (1H, sl), 3.82 (1H, dd, J ¼ 2.8 Hz
and J ¼ 11.6 Hz), 3.73–3.43 (3H, m), 1.47 (9H, s), 0.90 (9H, s), 0.08 (3H, s), 0.06
(3H, s), ꢂ0.08 (3H, s), ꢂ0.13 (3H, s); 13C NMR (75 MHz, CDCl3): d 155.6, 144.04,
143.3, 134.3, 134.0, 129.6, 129.4, 127.6, 127.5, 126.5, 126.1, 124.4, 124.0, 79.6, 72.7,
62.6, 60.9, 56.6, 28.3, 25.7, 18.1, ꢂ4.6, ꢂ5.2.
General Procedure for the Desilylation of the Aminoalcohols
To a solution of 1 mmol of protected aminoalcohols in THF (10 mL), 2.5 mmol
of tetrabutylamonium fluoride (TBAF) were slowly added under an inert atmos-
phere, at 0 ꢀC. After that, the reaction medium was stirred for 2 h at room tempera-
ture. Then, the solvent was evaporated under reduced pressure, and the residue was

OXAZOLIDINONES FROM MORITA–BAYLIS–HILLMAN
237
dissolved in ethyl acetate. The organic layer was washed with a saturated solution of
amonium chloride (NH4Cl), distilled water, and brine and dried over Na2SO4. Then,
the solvent was evaporated to afford the unprotected aminoalcohols 3a and 3b in
87% and 98% yields, respectively. Both aminoalcohols were used for the next step
without purification.
Preparation of the 4- and 4,5-Substituted Oxazolidinones
A solution of 1 mmol of aminoalcohol 3a in THF (10 mL) was added to a sus-
pension of 2.5 mmol of NaH under an inert atmosphere. After that, the reaction
medium was stirred for 16 h at room temperature. After this time, a solution of
ammonium chloride (NH4Cl) was added, and the resulting solution was extracted
with ethyl acetate. The organic layer was washed with a 5% solution of HCl
(10 mL), a saturated solution of NaHCO3(10 mL), and brine and dried over Na2SO4.
The solvent was evaporated under reduced pressure to afford a mixture of regioi-
somers in 69% yield. The regioisomers were separated on silica gel to afford the
oxazolidinones 13 and 14 in a proportion of 2:3, respectively.
(4-(Hydroxymethyl)-5-(2-thienyl)-1,3-oxazolidin-2-one (13). Colorless oil;
1
IR (film): n 3378, 2955, 2929, 2856, 1735, 1522, 1347, 1112, 704 cmꢂ1; H NMR
(300 MHz, CDCl3): d 7.5 (1H, dd, J ¼ 1.1 Hz and J ¼ 6.1 Hz), 7.22 (1H, d,
J ¼ 3.3 Hz), 7.06 (1H, dd, J ¼ 3.6 Hz and J ¼ 5.2 Hz), 5.68 (1H, d, J ¼ 5.2 Hz), 3.94
(1H, m), 3.67 (2H, m); 13C NMR (75 MHz, CDCl3): d 161.0, 143.1, 128.2, 127.8,
127.6, 77.5, 63.5; HRMS (ESI, m=z): calcd. for C8H9NO3S 199.0303; found
200.0308 [M þ H]þ.
4-[Hydroxy(2-thienyl)methyl]-1,3-oxazolidin-2-one (14). Colorless oil;
IR (film): n 3319, 2922, 2852, 1736, 1475, 1415, 1240, 1036 cmꢂ1 1H NMR
;
(300 MHz, CDCl3): d 7.28 (1H, dd, J ¼ 4.2 Hz and J ¼ 7.2 Hz), 6.99 (2H, m),
6.80–6.60 (1H, s, NH, diastereoisomers), 5.02 (1H, d, J ¼ 4.5 Hz, major diastereo-
isomer), 4.84 (1H, d, J ¼ 6.9 Hz, minor diastereoisomer), 4.5–4.3 (1H, m, HC-N,
OH), 4.12 (2H, m, CH2); 13C NMR (75 MHz, CDCl3): d 160.5, 142.6, 127.5,
125.5, 124.7, 70.3, 66.2, 57.8; HRMS (ESI, m=z): calcd. for C8H9NO3S 199.0303;
found 200.0421 [M þ H]þ.
A solution of 1 mmol of aminoalcohol 3b in THF (10 mL) was added to a sus-
pension of 2.5 mmol of NaH, under an inert atmosphere. After that, the reaction
medium was stirred for 16 h at room temperature. After this time, a solution of
ammonium chloride (NH4Cl) was added, and the resulting solution was extracted
with ethyl acetate. The organic layer was washed with a 5% solution of HCl
(10 mL), saturated solution of NaHCO3(10 mL), and brine and dried over Na2SO4.
The solvent was evaporated under reduced pressure to afford a mixture of regioi-
somers with 79% yield. The regioisomers were separated in silica gel to afford the
oxazolidinones 15 and 16 in a proportion of 1:2, respectively.
4-(Hydroxymethyl)-5-(3-chlorophenyl)-1,3-oxazolidin-2-one (15). Colorless
oil; IR (film): 3305, 2970, 2937, 2913, 2876, 1740, 1601, 1572, 1433, 1041, 739 cmꢂ1
;
1H NMR (300 MHz, CDCl3): d 7.28 (4H, m), 6.63 and 6.24 (1H, sl, NH, diastereo-
isomers), 5.72 (1H, d, J ¼ 8.0 Hz, minor diastereoisomer), 5.36 (1H, d, J ¼ 5.1 Hz,

238
P. REZENDE, P. H. S. PAIOTI, AND F. COELHO
major diastereoisomer), 3.83 (3H, m, N-CH and CH2); 13C NMR (62.5 MHz,
CDCl3): d 164.3, 140.6, 130.5, 129.2, 79.2, 63.0, 61.9. HRMS (ESI, m=z) calcd. for
C10H10ClNO3 227.0349; found [M þ H]þ 228.0344.
4-[Hydroxy(3-chlorophenyl)methyl]-1,3-oxazolidin-2-one (16). Colorless
oil; IR (film): n 3423, 3309, 2958, 2921, 2859, 1736, 1593, 1568, 1474, 1417, 1237,
1
1029, 730 cmꢂ1; H NMR (300 MHz, CDCl3) (diastereoisomers): d 7.28 (4H, m),
6.45 and 6.27 (1H, s, NH); 4.81 (1H, d, J ¼ 4.2 Hz), 4.59 (1H, d, J ¼ 7.2 Hz), 4.40
(1H, m), 4.25 (2H, m), 4.05 (3H, m); 13C NMR (75 MHz, CDCl3) (diastereoisomers):
d 160.7, 160.0, 141.2, 134.9, 130.2, 130.09, 128.9, 128.4, 126.8, 126.2, 124.8, 124.1,
75.3, 72.6, 66.6, 65.9, 58.2, 57.8. HRMS (ESI, m=z) calcd. for C10H10ClNO3
227.0349; found [M þ H]þ 228.0344.
ACKNOWLEDGMENTS
P. R. and P. H. S. P. thank FAPESP for fellowships. F. C. thanks FAPESP for
financial support and CNPq for financial support and a research fellowship.
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