Electrogenerated chiral 4-methoxy-2-oxazolidinones as diastereoselective amidoalkylation reagents for the synthesis of β-amino alcohol precursors

Article abstract of DOI:10.1002/1099-0690(200107)2001:13<2425::AID-EJOC2425>3.0.CO;2-2

A flexible and efficient synthesis of enantiomerically pure 4,5-substituted 2-oxazolidinones - important target molecules as precursors of pharmacologically active 2-oxazolidinones, β-amino alcohols, β-blockers and azasugar derivatives - is described. As starting materials, the enantiopure storage forms of chiral N-acyliminium ions (4RS,5S)-5-chloromethyl-4-methoxy-1,3-oxazolidin-2-one (2) and (4RS,5R)-4-methoxy-5-methyl-1,3-oxazolidin-2-one (3) were used; these are readily available from the chiral pool with the aid of electrochemical transformations. Substitution of the 4-methoxy group in building blocks 2 and 3 with a large variety of organometallic nucleophiles resulted in the trans-diastereoselective formation of enantiopure 4,5-disubstituted 2-oxazolidinones, with a high degree of flexibility in the substituent at the 4-position.

Full text of DOI:10.1002/1099-0690(200107)2001:13<2425::AID-EJOC2425>3.0.CO;2-2

FULL PAPER
Electrogenerated Chiral 4-Methoxy-2-oxazolidinones as Diastereoselective
Amidoalkylation Reagents for the Synthesis of β-Amino Alcohol Precursors
Kerstin Schierle-Arndt,[a,b] Doris Kolter,*
[a,c]
Karsten Danielmeier, and
[a]
Eberhard Steckhan[
a][†]
Keywords: Amidoalkylation / Amino alcohols / Metathesis / Nucleophilic exchange / Oxazolidinone
A flexible and efficient synthesis of enantiomerically pure
,5-substituted 2-oxazolidinones − important target mole-
cules as precursors of pharmacologically active 2-oxazolidi- group in building blocks 2 and 3 with a large variety of or-
nones, β-amino alcohols, β-blockers and azasugar derivatives ganometallic nucleophiles resulted in the trans-diastereose-
is described. As starting materials, the enantiopure storage lective formation of enantiopure 4,5-disubstituted 2-oxazolid-
forms of chiral N-acyliminium ions (4RS,5S)-5-chloromethyl- inones, with a high degree of flexibility in the substituent at
readily available from the chiral pool with the aid of electro-
4
chemical transformations. Substitution of the 4-methoxy
−
4
-methoxy-1,3-oxazolidin-2-one (2) and (4RS,5R)-4-meth-
the 4-position.
oxy-5-methyl-1,3-oxazolidin-2-one (3) were used; these are
Introduction
We accomplished this goal by the use of (4RS,5S)- or
4RS,5R)-5-chloromethyl-4-methoxy-2-oxazolidinone (2)
(
Enantiomerically pure 4,5-disubstituted 2-oxazolidinones and (4RS,5R)- or (4RS,5S)-4-methoxy-5-methyl-2-oxazoli-
are important target molecules in organic synthesis because dinone (3) as chiral building blocks. Compounds 2 and 3
of their pharmacological properties. This is not only true of are readily available from the chiral pool,[
11,12]
through use
the oxazolidinones themselves, which can act as antibiotics of electrochemical transformations as the key steps, as we
against highly resistant Gram-positive bacteria,[ but even have described elsewhere. (Scheme 1)
more of β-amino alcohols, which can be obtained from 2-
1]
oxazolidinones by basic hydrolysis. The β-amino alcohol
subunit is an important structural element in a number of
different enzyme inhibitors[ and β-blockers. In addition,
2]
[3]
ring-annulated 2-oxazolidinones are precursors of azasugar
structures, which can act as glycosidase inhibitors.[5]
For these reasons, many publications deal with the use of
chiral oxazolidinones[ in organic synthesis, especially for
[4]
6]
[7]
the formation of chiral β-amino alcohols. Important strat-
egies for their synthesis make use, for example, of amino
[
8]
[9]
acids, amino aldehydes, amino ketones or cyclic sul-
fates
[
10]
as starting materials. However, most of these
Scheme 1. Electrochemical key step in the synthesis of 2 and 3
methods are not very flexible in the choice of substituents
allowed.
The oxazolidinones 2 and 3 are chiral N,O-acetals, which
can be used as stable precursors of chiral N-acyliminium
It was therefore our goal to develop a strategy for a very
flexible and efficient synthesis of a whole class of enantio-
merically pure 2-oxazolidinones, with scope for a large
structural variety of functionalities in the 4- and 5-posi-
tions, starting from readily available building blocks.
ions. They are established as valuable amidoalkylation re-
[13]
agents.
Starting from the N,O-acetals 2 and 3, the N-
acyliminium cations are generated in situ and can react with
a variety of nucleophiles with good to excellent trans dia-
stereoselectivities.[
4,12,14]
When oxazolidinone 2 is used, fur-
[
a]
Kekul e´ -Institut für Organische Chemie und Biochemie der
Universität Bonn
ther functionalization though the chloromethyl group in the
5
-position is possible.
Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany
New address: BASF AG, Ammoniaklaboratorium,
[
[
b]
c]
In this publication we demonstrate the application of the
6
7056 Ludwigshafen, Germany
chiral N,O-acetals 2 and 3 as flexible amidoalkylation re-
agents with different types of organometallic nucleophiles.
A broad variety of substituents can be introduced into the
New address: Institut für Biotechnologie 2,
Forschungszentrum Jülich GmbH,
5
2425 Jülich, Germany
Fax: (internat.) ϩ49Ϫ(0)2461/613870
E-mail: d.kolter@fz-juelich.de
Deceased February 10th, 2000
4
-position of the oxazolidinones with good to excellent
[
†]
trans selectivities. This route produces a large variety of
Eur. J. Org. Chem. 2001, 2425Ϫ2433

WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0713Ϫ2425 $ 17.50ϩ.50/0
2425

K. Schierle-Arndt, D. Kolter, K. Danielmeier, E. Steckhan
FULL PAPER
enantiomerically pure 4,5-substituted β-amino alcohol pre- Overhauser effects or, in the case of known compounds, by
cursors.
comparison of coupling constants.
As we have shown elsewhere, organocopper reagents are
able to react with oxazolidinones 2 and 3 under BF ·OEt
3
2
catalysis conditions.[
12,14]
The best results are obtained by
Results and Discussion
the use of higher order cuprates, which permit the introduc-
One step in our previously described synthesis of enan- tion of a phenyl group in 62% yield and with 92% ds
tiopure 1 occurred with an unsatisfactory yield of 50%.
(Table 1, entry 1) and of an n-butyl group in 59% yield and
We avoided this problem by starting with chiral epichlo- with 95% ds (Table 1, entry 2).
rohydrin, which is commercially available in both enan-
Table 1. Reactions between 2 and organocopper reagents
tiomerically pure forms. This starting material can be trans-
formed in one step into the respective enantiomer of 5-chlo-
romethyl-2-oxazolidinone (1), in nearly quantitative yield, product
using potassium cyanate as nucleophile for the opening of
the epoxide (Scheme 2). The products can be isolated and
nucleophile
R
isolated
yield (%)
ds for
4a Ϫ 5a (%)
4ab
5ab
5ab
Ph
nBu
nBuCu/BF
3
Cu
2
Li
Ph
nBu
nBu
62
59
52
92
95
88
used in further reactions without purification.
3
Cu
2
Li
3
One disadvantage is the fact that only one of the three
alkyl groups of the organocopper reagent can be trans-
ferred. From this point of view, the use of RCu·DMS com-
plexes as reported by Wistrand et al. is more economical,[
but Ϫ as shown for the example of the n-butyl copper DMS
complex Ϫ the yield and diastereoselectivity are not as high
17]
(
Table 1, entry 3).
Grignard reagents are well-known as good nucleo-
philes.[ They are convenient to handle and many reagents
are commercially available. To determine the scope of the
applicability of Grignard reagents in amidoalkylations with
oxazolidinone 2, three electronically different nucleophiles
were chosen.
18]
Scheme 2. Alternative sequence forming compound S-1 or R-1
This synthesis has been described previously for racemic
5
-chloromethyl-2-oxazolidinone rac-(1), starting from ra-
[15]
cemic epichlorohydrin.
Under BF ·OEt catalysis conditions, the reactive phenyl
3
2
The stereospecific course of the epoxide transformation
was demonstrated by determination of the enantiomeric
purity of the products by means of chiral NMR shift experi-
ments and by comparison of the optical rotations of the
reaction products with literature data.[11a]
Grignard reagent reacted to give oxazolidinones 14ab in
good yield (Table 2, entry 1). Similarly, the n-butyl and allyl
Grignard reagents, which are known to be less reactive, also
give good yields (Table 2, entries 2,3 and 5). Introduction
of the phenyl and the n-butyl group by this method pro-
ceeds with high trans selectivity, but the allyl Grignard sur-
prisingly displays lower diastereoselectivity.
Oxazolidinones 2 and 3, generated by anodic methoxyl-
[16]
ation as we described earlier,
have been intensively
studied as chiral precursors of N-acyliminium ions, using
different organometallic nucleophiles in the presence of
Lewis acids. Under these conditions, it is possible to intro-
duce different substituents into the 4-position of the oxazol-
idinones by means of an amidoalkylation reaction, with re-
placement of the 4-methoxy group (Scheme 3).
Table 2. Reactions between 2 and 3 and Grignard reagents
Scheme 3. Nucleophilic exchange reaction
These nucleophilic substitutions proceed with high trans
selectivity, induced by the substituents in the 5-position of
the oxazolidinone. The relative configurations of the syn-
The use of Grignard reagents also makes it possible to
thesized products were determined with the aid of nuclear introduce the vinyl function into the 4-position of the ox-
2426
Eur. J. Org. Chem. 2001, 2425Ϫ2433

Electrogenerated Chiral 4-Methoxy-2-oxazolidinones
FULL PAPER
azolidinone with very good diastereoselectivity and in good
yield (Scheme 4). This thus establishes an easy way to ob-
tain derivatives of vinyl glycine.
Scheme 5. Synthesis of β-amino acid derivatives with Knochel
reagent
yield and with excellent diastereoselectivity (Scheme 5). We
thus established easy access to derivatives of β-amino acids
in one step.
Another way to obtain β-amino acid derivatives is based
on the Reformatsky reaction. Other Reformatsky reactions
with N-acyliminium ions and N-acylimines have already
been described.[ Accordingly, oxazolidinone 2 was treated
20]
with BrCH COOEt in the presence of activated zinc, with
2
Scheme 4. Synthesis of derivatives of vinylglycine
catalysis using TMSCl and BF ·OEt . Again, the diastereo-
3
2
selectivity was excellent and the yield was similar to that in
the case of the copper zinc organometallics. This approach
to compound 10 is easier than the use of copper zinc or-
ganometallics but not as flexible.
A comparison between the different organometallic nu-
cleophiles with respect to their reaction with the oxazolidi-
none 2 is given in Table 4.
Many organocopper reagents are prepared from the cor-
responding magnesium or lithium organometallics. Unfor-
tunately, this approach is not compatible with the presence
of most functional groups. However, copper zinc organo-
metallics of the RCu(CN)ZnX type can be prepared from
organozinc reagents by performing a transmetallation using
the soluble copper salt CuCN·2LiCl as reported by Table 4. Comparison of the different nucleophiles in amidoalkyl-
[
19]
Knochel. Since organozinc reagents tolerate a wide range ation reactions with 2
of functionalities, this method offers general access to poly-
functional reagents.
Aliphatic organozincs may conveniently be obtained by reagent
the direct insertion of activated zinc (dust) into alkyl iodides
type of
R ϭ phenyl, 4a R ϭ n-butyl, 5a R ϭ allyl, 6a
yield (%) ds (%) yield (%) ds (%) yield (%) ds (%)
in THF. It is thus possible to introduce the n-butyl and the
allyl group into the 4-position of the oxazolidinone in good
R
3
Cu
RCu/BF
yields and with very good diastereoselectivities, starting RMgX
2
Li
3
62
64
92
59
52
64
57
95
88
95
98
96
95
66
62
82
94
from n-butyl iodide or from allyl iodide (Table 3, entries RCu(CN)ZnI 72
2
Ϫ3).
Several trends in yield and stereoselectivity are obvious.
Higher order cuprates give good results. Unfortunately, they
are not very economical, as only one of the three alkyl
groups is transferred. Wistrand cuprates are more effective,
but the yields and selectivities are lower. Use of copper zinc
organometallics enables good yields and very good diaster-
eoselectivities to be achieved. These reagents can also be
used to introduce substituents with functional groups into
the 4-position of the oxazolidinones 2 and 3. In general,
Grignard reagents work quite well, many of them are com-
mercially available and they are quite easy to handle. In the
case of the allyl Grignard, however, the diastereoselectivity
is surprisingly lower.
Table 3. Reactions between 2 and copper zinc reagents
Aryl halides do not readily undergo a zinc insertion in
4-Substituted oxazolidinones are excellent starting mat-
THF, but they may be prepared by a lithium-iodine ex- erials for construction of bicyclic piperidine structures using
[
19]
change reaction. Using this method, it is possible to form the ring-closing metathesis (RCM) strategy or the Heck re-
the 4-phenyl-substituted oxazolidinone 4a in 72% yield and action. It is thus possible to produce precursors for azasu-
with 95% ds (Table 3, entry 1).
gar structures, which play an important role as inhibitors
In order to introduce functionalized alkyl groups, we gen- of glycosidases.[21]
erated a copper-zinc reagent starting from ICH COOEt.
The metathesis reaction is widely used in ring construc-
2
The reagent was obtained by insertion of zinc into the alkyl- tions, especially for pharmacologically important com-
iodine bond. The desired product 10 was obtained in 48% pounds such as epothilone.[
Eur. J. Org. Chem. 2001, 2425Ϫ2433
22]
Grubbs’
[23]
catalyst (see
2427

K. Schierle-Arndt, D. Kolter, K. Danielmeier, E. Steckhan
FULL PAPER
Scheme 7. Heck reaction
in an extremely flexible way. We have thus established a
method that allows a broad variety of substituents to be
introduced diastereoselectively into the 4-position of 2-ox-
azolidinones. This is a prerequisite for targeted syntheses of
biologically active β-amino alcohol derivatives or azasugar
precursors based on chiral oxazolidinones 2 and 3.
Experimental Section
Scheme 6. Metathesis reaction
1
General Methods: Nuclear magnetic resonance ( H NMR) spectra
were determined in the reported solvent using Bruker AC 200
Scheme 6) shows the best results.[24] We used this RCM ap-
proach starting from oxazolidinone 3 to synthesize com-
pound 13 (Scheme 6).
(
(
200 MHz), Bruker WM 250 (250 MHz) and Bruker AC 400
400 MHz) spectrometers. The same instruments were also used for
13
the measurement of
C
spectra (50.3 MHz; 62.9 MHz;
It is first necessary to synthesize compound 12. We there- 100.6 MHz). Chemical shifts are given in ppm downfield from
fore introduced the allyl group into the 4-position of the tetramethylsilane. Ϫ R values were obtained by thin layer chroma-
f
oxazolidinone by amidoalkylation with allyltrimethylsilane tography (TLC) on aluminium sheets coated with silica gel (Merck
as we have described elsewhere,[ followed by N-alkylation
(
12]
silica gel F254). Ϫ Optical rotations were measured with a
PerkinϪElmer P241 machine. Ϫ Elemental analyses were per-
formed by the central service of our Institute. Melting points are
Scheme 6, sequence A). Inversion of the reaction sequence
Ϫ N-alkylation in the first step and amidoalkylation in the
second Ϫ resulted in a decisive increase in the diastereose-
lectivity of the amidoalkylation (sequence B).
uncorrected. All solvents were dried before use. Ϫ The relative con-
1
figurations were determined by comparison of H NMR coupling
constants with those of known compounds and by measurement
of difference NOE spectra.
Cyclization took place with the aid of Grubbs’ catalyst,
and 13 was obtained in 74% yield.[
25]
Compound S-2 was obtained in 76% yield by anodic oxidation of
Another route to piperidine structures uses the Heck re-
S-1 according to the previously described method.[
11b,12]
Com-
[
26]
action.
The reaction sequence is shown in Scheme 7.
pound 3 was prepared starting from -threonine, by cyclization to
Starting once more from the N-alkylated oxazolidinone 11,
a diastereoselective amidoalkylation reaction was used to
synthesize 14. In this case, 2-bromo trimethylallylsilane was
the nucleophile. Subsequent Heck reaction in the presence
of triethylamine and palladium acetate resulted in the
formation of compounds 15 and 16 (Scheme 7).
oxazolidinone followed by electrochemical methoxylative decarb-
[12]
oxylation.
(
S)- and (R)-5-Chloromethyl-1,3-oxazolidin-2-one (1): In an alterna-
[11a]
tive to the previously described procedure,
potassium cyanate
(
0.81 g, 10 mmol) was dissolved in water (40 mL) and epichlorohy-
drin (0.46 g) was slowly added. The solution was refluxed for 15 h
and cooled to room temp. The reaction mixture was extracted with
ethyl acetate until no product remained in the water phase. The
organic phase was dried with sodium sulfate and concentrated in
vacuo. The crude product was used for further transformations.
For analytical purposes, the product was purified by flash chroma-
tography on silica gel (ethyl acetate/cyclohexane 2:1), resulting in
Conclusion
In conclusion, we have demonstrated that the readily
available enantiopure 4-methoxy-2-oxazolidinones 2 and 3
are very effective chiral amidoalkylation reagents, which
can be substituted in the 4-position with good to excellent 0.68 g (100%) of 1 as a colourless solid. Ϫ R ϭ 0.20 (ethyl acetate/
f
trans selectivities by the use of organometallic nucleophiles cyclohexane, 2:1); m.p. 65 °C.
2428
Eur. J. Org. Chem. 2001, 2425Ϫ2433

Electrogenerated Chiral 4-Methoxy-2-oxazolidinones
Compound S-1: [α]20
ϭ ϩ18 (c ϭ 2, dichloromethane). Ϫ H NMR
FULL PAPER
1
ded. After the mixture had been stirred for 5 min, oxazolidinone 2
D
(
(
(
400 MHz, CDCl
d, J ϭ 6.1 Hz, 2 H), 3.75 (dd, J ϭ 9.1, 9.1 Hz, 1 H), 4.76Ϫ4.92 temperature, the mixture was heated to room temp., the reaction
m, 1 H), 6.13 (br, NH, 1 H). Ϫ 13C NMR (100.6 MHz, CDCl
): was stopped by addition of 30 mL conc. NH
/aq. NH Cl (1:1) and
3
): δ ϭ 3.52 (ddd, J ϭ 9.1, 5.5, 1.3 Hz, 1 H), 3.68 or 3 in dry THF (5 mL) was added. After stirring for 15 h at this
3
3
4
δ ϭ 43.6, 44.5, 74.7, 159.2. Ϫ MS (70 eV, EI): m/z ϭ 135 (13.44) the solids were filtered off. The water phase was extracted three
ϩ
[
[
M ], 86 (100), 42 (45), 36 (11). Ϫ HRMS calcd. for C
4
H
6
ClNO
2
times with diethyl ether, while the combined organic phases were
/NH Cl (1:1), dried with sodium
ϩ
M ]: 135.0087, found 135.0081. Ϫ C
4
H
6
ClNO
2
(135.0): calcd. C washed with 30 mL conc. NH
3
4
3
5.44, H 4.46, N 10.33; found C 35.60, H 4.57, N 10.38.
sulfate and concentrated in vacuo. The crude product was purified
by flash chromatography on silica gel (ethyl acetate/cyclohexane).
Compound R-1: [α]20
ϭ Ϫ18 (c ϭ 3, dichloromethane).
D
Nucleophilic Exchange with Aryl Copper Zinc Reagents. ؊ General
Procedure V: The aryl iodide was dissolved in dry THF (6 mL) in
a dry Schlenk tube under argon atmosphere and cooled to Ϫ100
Nucleophilic Exchange with Organocopper Reagents of R
3
2
Cu Li
Stoichiometry. ؊ General Procedure I: In a dry Schlenk tube, the
organolithium compound was added to a suspension of CuI in dry
THF at Ϫ50 °C under argon atmosphere. After stirring for 15 min
at this temperature, the reaction mixture was cooled to Ϫ78 °C and
°
C. n-Butyllithium was added dropwise at the same temperature,
and the solution was stirred for 3 min. A solution of dry zinc iodide
dried for 1 h at 140 °C) in dry THF (2.5 mL) was added and the
(
BF
was added as a solution in dry THF. The mixture was stirred for
several hours and heated to room temp. The mixture was extracted
three times with 30 mL conc. NH /aq. NH Cl (1:1) until a clear
3 2
·OEt was added slowly. The mixture was stirred for 5 min and
reaction mixture was stirred for 5 min. A solution of lithium chlor-
ide and copper(I) cyanide in dry THF (5 mL) was added, the reac-
tion mixture was heated to Ϫ60 °C and the solution was stirred for
2
3
4
5
3 2
min. After the mixture had been cooled to Ϫ78 °C, BF ·OEt
solution was formed. The organic phase was dried with sodium
sulfate and concentrated in vacuo. The crude product was purified
by flash chromatography on silica gel (ethyl acetate/cyclohexane).
was added. After the mixture had been stirred for 5 min the oxazol-
idinone 2 in dry THF (5 mL) was added. After stirring for 15 h at
this temperature, the solution was heated to room temp., the mix-
ture was quenched by the addition of 30 mL conc. NH
1:1) and the solids were filtered off. The water phase was extracted
three times with diethyl ether, while the combined organic phases
were washed with 30 mL conc. NH /NH Cl (1:1), dried with so-
dium sulfate and concentrated in vacuo. The crude product was
purified by flash chromatography on silica gel (ethyl acetate/cyclo-
hexane).
3 4
/aq. NH Cl
Nucleophilic Exchange with Organocopper Reagents of RCu/BF
3
(
Stoichiometry. ؊ General Procedure II: In a dry Schlenk tube,
I
Cu Br·DMS was suspended in dry diethyl ether under argon atmo-
3
4
sphere and cooled to Ϫ40 °C. The organolithium compound was
added slowly at the same temperature and the reaction mixture was
stirred for 30 min. After the mixture had been cooled to Ϫ78 °C,
BF
3 2
·OEt was added dropwise. The reaction mixture was stirred
for 5 min and oxaxolidinone 2 in dry diethyl ether was added. The
(4R,5S)-5-Chloromethyl-4-phenyl-1,3-oxazolidin-2-one (4a): Gen-
mixture was stirred for several hours and heated to room temp. eral procedure I was used. Oxazolidinone 2 (0.5 g, 3 mmol) was
The reaction mixture was quenched by the addition of 30 mL conc.
treated with CuI (3.43 g, 18 mmol), phenyllithium in cyclohexane/
NH /aq. NH Cl (1:1) and the solids were filtered off. The water diethyl ether (1.8 , 15 mL 27 mmol) and BF ·OEt (0.4 mL,
3
4
3
2
phase was extracted three times with diethyl ether and the com-
bined organic phases were dried with sodium sulfate and concen-
trated in vacuo. The crude product was purified by flash chromato-
graphy on silica gel (ethyl acetate/cyclohexane).
3 mmol) in 40 mL of THF. The reaction was complete after 10 h.
Purification of the crude product on silica gel (1. ethyl acetate/
cyclohexane 1:5; 2. ethyl acetate) resulted in 0.39 g (62%) of 4a as
a colourless solid. The (4R,5S) product trans-4a was obtained in
9
2% ds.
Nucleophilic Exchange with Grignard Reagents. ؊ General Proced-
ure III: The Grignard compound was dissolved in dry THF and
cooled to Ϫ78 °C in a dry Schlenk tube under argon atmosphere.
General procedure III was also used. Oxazolidinone 2 (0.1 g,
0
1
.6 mmol) was treated with PhMgBr in THF (3 , 0.5 mL,
.5 mmol) and BF ·OEt (0.2 mL, 1.5 mmol) in 8 mL of THF. Puri-
3 2
BF ·OEt was slowly added at the same temperature, and the reac-
3
2
fication of the crude product on silica gel (ethyl acetate/cyclohexane
:3) afforded 0.08 g (64%) of 4a as a colourless solid. The (4R,5S)
tion mixture was stirred for 10 min. Oxazolidinone 2 or 3, dissolved
in dry THF, was added slowly and the reaction mixture was stirred
for 15 h at Ϫ78 °C. After heating to room temp., the reaction was
1
product trans-4a was obtained in 96% ds.
3
stopped by the addition of a conc. aq. NaHCO solution and the
General procedure V was also used. Oxazolidinone 2 (0.1 g,
solids were filtered off. The phases were separated and the water
phase was extracted three times with diethyl ether. The combined
organic phases were dried with sodium sulfate and concentrated in
vacuo. The crude product was purified by flash chromatography
on silica gel (ethyl acetate/cyclohexane).
0
.6 mmol) was treated with PhI (0.51 g, 2.5 mmol), n-butyllithium
in hexane (15%, 1.6 mL, 2.6 mmol), CuCN (0.23 g, 2.6 mmol), LiCl
0.22 g, 5.2 mmol) and BF ·OEt (0.6 mL, 4.5 mmol) in 18.5 mL of
(
3
2
THF. Purification of the crude product on silica gel (ethyl acetate/
cyclohexane 1:3) afforded 0.091 g (72%) of 4a as a colourless solid.
f
The (4R,5S) product trans-4a was obtained in 95% ds. Ϫ R ϭ 0.67
Nucleophilic Exchange with Alkyl Copper Zinc Reagents. ؊ General
Procedure IV: Zinc powder was suspended in dry THF (1 mL) in a
dry Schlenk tube under argon atmosphere, and 1,2-dibromoethane
was added. The suspension was heated to 65 °C for 1 min and
cooled to room temp. TMSCl was then added dropwise and the
suspension was stirred for 15 min. The alkyl iodide, in dry THF
2
5
(
ethyl acetate/cyclohexane 1:1); m.p. 104 °C; [α]
D
ϭ ϩ28 (c ϭ 1,
3
): δ ϭ 3.70 (dd,
1
dichloromethane). Ϫ H NMR (200 MHz, CDCl
J ϭ 10.0, 3.8 Hz, 1 H), 3.78 (dd, J ϭ 10.0, 4.8 Hz, 1 H), 4.52 (ddd,
J ϭ 5.3, 4.8, 3.8 Hz, 1 H), 4.82 (dd, J ϭ 5.3, 0.3 Hz, 1 H), 6.75 (br,
1
3
3
NH, 1 H), 7.47Ϫ7.22 (m, 5 H). Ϫ C NMR (50.2 MHz, CDCl ):
δ ϭ 39.2, 59.1, 82.7, 126.1, 128.9, 129.2, 139.1, 158.6. Ϫ MS (70 eV,
(4 mL), was added slowly and the reaction mixture was stirred for
ϩ
EI): m/z ϭ 211 (10) [M ], 176 (100), 133 (18), 105 (55), 104 (68),
4
h at room temp. In a second dry Schlenk tube, dry lithium chlor-
ϩ
9
1 (28), 77 (37). Ϫ HRMS calcd. for C10
2
H10ClNO [M ]: 211.0401,
ide and dry copper(I) cyanide were dissolved in dry THF (11 mL)
and cooled to Ϫ20 °C. The organozinc compound was slowly ad-
ded at this temperature and the reaction mixture was stirred for
found 211.0399.
(4RS,5S)-4-n-Butyl-5-chloromethyl-1,3-oxazolidin-2-one (5ab):
5
min. The solution was cooled to Ϫ78 °C and BF
3
·OEt
2
was ad- General procedure I was used. Oxazolidinone 2 (0.5 g, 3 mmol) was
Eur. J. Org. Chem. 2001, 2425Ϫ2433
2429

K. Schierle-Arndt, D. Kolter, K. Danielmeier, E. Steckhan
FULL PAPER
treated with CuI (3.43 g, 18 mmol), n-butyllithium in hexane (15%, 44.2, 54.8, 79.3, 120.1, 131.5, 158.5. Ϫ MS (70 eV, EI): m/z ϭ 176
6.5 mL, 27 mmol) and BF ·OEt
(0.4 mL, 3 mmol) in 40 mL of (1.84), 175 (0.95), 148 (17), 136 (40), 134 (100), 90 (26). Ϫ HRMS
1
3
2
ϩ
THF. The reaction was complete after 12 h. Purification of the calcd. for C
crude product on silica gel (ethyl acetate/cyclohexane 1:2) afforded
0
H
10ClNO
2
[M ]: 175.0400, found 175.0399.
7
1
Compound cis-6b: H NMR (200 MHz): δ ϭ 2.38 (m, 2 H), 3.60
d, J ϭ 5.1 Hz, 2 H), 3.67 (m, 1 H), 4.38 (m, 1 H), 5.14 (m, 1 H),
.17 (d, J ϭ 1.2 Hz, 1 H), 5.67 (m, 1 H), 6.51 (br, NH, 1 H). Ϫ
.34 g (59%) of 5a as a colourless oil. The (4R,5S) product trans-
(
5
a was obtained in 95% ds.
5
General procedure II was also used. The oxazolidinone 2 (0.25 g,
.5 mmol) was treated with CuBr·DMS (0.68 g, 3 mmol), n-butylli-
thium in hexane (15%, 1.8 mL, 3 mmol) and BF ·OEt (0.4 mL,
mmol) in 17 mL of diethyl ether. Purification of the crude prod- (4RS,5R)-4-Allyl-5-methyl-1,3-oxazolidin-2-one (8ab): General pro-
uct on silica gel (ethyl acetate/cyclohexane 1:2) afforded 0.15 g cedure III was used. Oxazolidinone 3 (0.13 g, 1.02 mmol) was
52%) of 5ab as a colourless oil. The (4R,5S) product trans-5a was
treated with C MgBr in THF (1 , 4.1 mL, 4.1 mmol) and
BF ·OEt (0.51 mL, 4.1 mmol) in 7 mL THF. Purification of the
crude product on silica gel (ethyl acetate/cyclohexane 1:1) afforded
13
C NMR (50.3 MHz, CDCl
3
): δ ϭ 40.3, 42.5, 54.1, 80.8, 119.7,
1
1
32.3, 158.4.
3
2
3
(
3 5
H
obtained in 88% ds.
3
2
General procedure III was also used. Oxazolidinone 2 (0.1 g,
0
8
.10 g (67%) of 8ab as a colourless oil. The (4R,5R) product trans-
a was obtained in 80% ds. Ϫ R ϭ 0.32 (ethyl acetate 1:1).
f
0
.6 mmol) was treated with nBuMgCl in THF (2 , 1 mL, 2 mmol)
and BF ·OEt (0.3 mL, 2.25 mmol) in 8 mL of THF. Purification
of the crude product on silica gel (ethyl acetate/cyclohexane 1:2)
3
2
1
Compound trans-8a: H NMR (250 MHz, CDCl ): δ ϭ 1.33 (d, J ϭ
3
afforded 0.07 g (64%) of 5a as a colourless oil. The (4R,5S) product 6.7 Hz, 3 H), 2.28 (m, 2 H), 3.41 (ddd, J ϭ 6.4, 6.4, 6.4 Hz, 1 H),
trans-5a was obtained in 95% ds.
4.38 (qd, J ϭ 6.7, 6.4 Hz, 1 H), 5.14 (m, 2 H), 5.57 (m, 1 H), 6.52
1
3
(
3
br, NH, 1 H). Ϫ C NMR (62.9 MHz, CDCl ): δ ϭ 20.92, 39.11,
General procedure IV was also used. Oxazolidinone 2 (0.13 g,
5
8.77, 78.33, 119.43, 132.18, 159.19. Ϫ MS (70 eV, EI): m/z ϭ 142
0
.75 mmol) was treated with nBuI (0.92 g, 5 mmol), 1,2-dibromoe-
thane (0.04 mL, 0.2 mmol), TMSCl (0.02 mL, 0.16 mmol), CuCN
0.4 g, 4.0 mmol), LiCl (0.38 g, 8.8 mmol) and BF ·OEt (0.6 mL,
.5 mmol) in 21 mL of THF. Purification of the crude product on
silica gel (ethyl acetate/cyclohexane 1:2) afforded 0.08 g (57%) of
a as a colourless oil. The (4R,5S) product trans-5a was obtained
in 98% ds. Ϫ R ϭ 0.31 (ethyl acetate/cyclohexane 1:2).
ϩ
(
17.8), 100 (100), 56 (84.3). Ϫ HRMS calcd. for C
7
H
11NO
2
[M ]
ϩ
1
41.0782, found 141.0786; for C
7 2
H12NO [M ϩ H] 142.0864,
(
4
3
2
found 142.0866.
1
Compound cis-8a: H NMR (250 MHz, CDCl
3
): δ ϭ1.30 (d, J ϭ
.5 Hz, 3 H), 2.28 (m, 2 H), 3.78 (ddd, J ϭ 6.4, 6.4, 6.4 Hz, 1 H),
.38 (qd, J ϭ 6.5 Hz, 6.4 Hz, 1 H), 5.14 (m, 2 H), 5.57 (m, 1 H),
5
6
4
f
1
3
Compound trans-5a: [α]25
1
6.52 (br, NH, 1 H). Ϫ C NMR (62.9 MHz, CDCl
3
): δ ϭ 14.88,
D
ϭ ϩ21 (c ϭ 1, chloroform). Ϫ H NMR
3
4.60, 54.93, 75.95, 119.35, 132.98, 159.19.
(
400 MHz, CDCl
3
): δ ϭ 0.86 (t, J ϭ 6.89 Hz, 3 H), 1.28 (m, 4 H),
.53 (m, 2 H), 3.57 (dd, J ϭ 11., 6.4 Hz, 1 H), 3.61 (dd, J ϭ 11.6,
.7 Hz, 1 H), 3.65 (m. 1 H), 4.29 (ddd, J ϭ 6.4, 4.7, 4.4 Hz, 1 H),
.27 (br, NH, 1 H). Ϫ 13C NMR (100.6 MHz, CDCl
): δ ϭ 13.9,
1
4
6
2
1
(
4RS,5S)-5-Chloromethyl-4-vinyl-1,3-oxazolidin-2-one (7ab): Gen-
eral procedure III was used. Oxazolidinone 2 (0.125 g, 0.75 mmol)
was treated with C MgBr in THF (1 , 2 mL, 2 mmol) and
BF ·OEt (0.3 mL, 2.25 mmol) in 8 mL of THF. Purification of the
crude product on silica gel (ethyl acetate/cyclohexane, 1:3) afforded
3
2
H
3
2.4, 27.1, 35.4, 44.2, 55.7, 80.2, 158.5. Ϫ MS (70 eV, EI): m/z ϭ
91 (2), 156 (6), 136 (30), 134 (100), 90 (11), 63 (13). Ϫ HRMS
3
2
ϩ
calcd. for C
8 2
H14ClNO [M ]: 191.0713, found 191.0713. Ϫ
0
7
.07 g (58%) of 7a as a colourless oil. The (4R,5S) product trans-
a was obtained in 94% ds.
C
4
H
6
ClNO (191.1): calcd. C 50.14, H 7.36, N 7.31; found C 50.30,
2
H 7.42, N 7.19.
1
Compound trans-7a: H NMR (400 MHz): δ ϭ 3.64 (dd, J ϭ 11.9,
Compound cis-5b: 13C NMR (100.6 MHz, CDCl
): δ ϭ 13.9, 22.4,
3
4
5
.4 Hz, 1 H), 3.68 (dd, J ϭ 11.9, 5.7 Hz, 1 H), 4.21 (dd, J ϭ 7.1,
.7 Hz, 1 H), 4.38 (ddd, J ϭ 5.7, 5.7, 4.4 Hz, 1 H), 5.23 (d, J ϭ
28.1, 28.7, 40.4, 55.0, 78.4, 158.5.
(4RS,5S)-4-Allyl-5-chloromethyl-1,3-oxazolidin-2-one (6ab): Gen-
10.1 Hz, 1 H), 5.31 (d, J ϭ 17.0 Hz, 1 H), 5.79 (ddd, J ϭ 17.0,
eral procedure III was used. Oxazolidinone 2 (0.16 g, 0.75 mmol)
was treated with C MgBr in THF (1 , 2 mL, 2 mmol) and
BF ·OEt (0.3 mL, 2.25 mmol) in 8 mL of THF. Purification of the
crude product on silica gel (ethyl acetate/cyclohexane, 1:2) afforded
10.1, 7.1 Hz, 1 H), 6.69 (br, NH, 1 H);
3 5
H
13C NMR (100.6 MHz, CDCl
58.6. Ϫ MS (70 eV, EI): m/z ϭ 162 (6), 161 (5.6), 134 (17), 126
22), 112 (100), 83 (52), 55 (96). Ϫ HRMS calcd. for C 18ClNO
3
): δ ϭ 43.7, 58.2, 80.3, 120.7, 140.2,
3
2
1
(
6
H
2
0.09 g (66%) of 6ab as a colourless oil. The (4R,5S) product trans-
ϩ
[M ]: 161.0243, found 161.0243.
6a was obtained in 82% ds.
(
4R,5R)-5-Methyl-4-vinyl-1,3-oxazolidin-2-one (9a): General pro-
General procedure IV was also used. Oxazolidinone 2 (0.13 g,
.75 mmol) was treated with C I (0.84 g, 5 mmol), 1,2-dibromo-
ethane (0.04 mL, 0.2 mmol), TMSCl (0.02 mL, 0.16 mmol), CuCN
0.4 g, 4. mmol), LiCl (0.38 g, 8.8 mmol) and BF ·OEt (0.6 mL,
.5 mmol) in 21 mL of THF. Purification of the crude product on
silica gel (ethyl acetate/cyclohexane 1:2) afforded 0.08 g (62%) of
a as a colourless oil. The (4R,5S) product trans-6a was obtained
in 95% ds. Ϫ R ϭ 0.18 (ethyl acetate/cyclohexane, 1:2).
cedure III was used. Oxazolidinone 3 (0.137 g, 1.04 mmol) was
treated with C MgBr in THF (1 , 4.2 mL, 4.2 mmol) and
BF ·OEt (0.52 mL, 4.2 mmol) in 7 mL THF. Purification of the
crude product on silica gel (ethyl acetate/cyclohexane 1:1) afforded
0
8
0
3 5
H
3 5
H
(
4
3
2
3
2
.10 g (67%) of 8ab as a colourless oil. The (4R,5R) product trans-
a was obtained in Ͼ 98% ds. Ϫ R ϭ 0.29 (ethyl acetate/cyclohex-
f
6
ane, 1:1).
f
Compound trans-6a: [α]25
(
ϭ ϩ88 (c ϭ 1, methanol). Ϫ H NMR
1
Compound trans-9a: H NMR (400 MHz, CDCl
6.2 Hz, 3 H), 3.75 (dd, J ϭ 7.2, 7.1 Hz, 1 H), 4.26 (dq, J ϭ 7.1,
1
D
3
): δ ϭ 1.39 (d, J ϭ
200 MHz): δ ϭ 2.38 (m, 2 H), 3.60 (d, J ϭ 4.7 Hz, 2 H), 3.75 (dt,
J ϭ 5.6, 5.0 Hz, 1 H), 4.38 (dt, J ϭ 5.6, 4.7 Hz, 1 H), 5.13 (ddt, 6.2 Hz, 1 H), 5.21 (d, J ϭ 17.0 Hz,1 H), 5.27 (d, J ϭ 10.1 Hz, 1
J ϭ 7.5, 1.2, 1.2 Hz, 1 H), 5.17 (d, J ϭ 1.2 Hz, 1 H), 5.67 (m, 1 H), 5.79 (ddd, J ϭ 17.0 Hz, 10.1 Hz, 7.2 Hz, 1 H), 6.52 (br, NH, 1
H), 6.73 (br, NH, 1 H). Ϫ 13C NMR (50.3 MHz, CDCl
H). Ϫ C NMR (62.9 MHz, CDCl
13
3
): δ ϭ 39.7,
3
): δ ϭ 18.92, 62.83, 78.81,
2430
Eur. J. Org. Chem. 2001, 2425Ϫ2433

Electrogenerated Chiral 4-Methoxy-2-oxazolidinones
18.82, 135.23, 159.55. Ϫ C NO ·1/5H
O (130.6) calcd. C 56.68; 15.5, 4.9, 1.5, 1 H), 4.21 (dq, J ϭ 9.4, 6.3 Hz, 1 H), 5.65 (m, 2 H),
FULL PAPER
1
6
H
9
2
2
1
3
H 7.13, N 11.02; found C 56.12, H 7.09, N 10.72.
5.15 (m, 4 H). Ϫ C NMR (100.6 MHz, CDCl
4.57, 60.66, 74.71, 118.52, 119.70, 131.50, 132.17, 157.37. Ϫ MS
70 eV, EI): m/z: 181 (0.4), 140 (100), 112 (22.1), 96 (10.7). Ϫ
3
): δ ϭ 20.47, 35.92,
4
(
Ethyl (4R,5S)-5-Chloromethyl-1,3-oxazolidin-2-one-4-carboxylate
(
10): General procedure IV was used. Oxazolidinone 2 (0.13 g,
.75 mmol) was treated with EtO CCH I (1.07 g, 5 mmol), 1,2-di-
bromoethane (0.04 mL, 0.2 mmol), TMSCl (0.02 mL; 0.16 mmol),
CuCN (0.4 g, 4. mmol), LiCl (0.38 g, 8.8 mmol) and BF ·OEt
0.6 mL, 4.5 mmol) in 21 mL of THF. Purification of the crude
product on silica gel (ethyl acetate/cyclohexane, 1:2) afforded 0.08 g
48%) of 10 as a colourless oil. The (4R,5S) product 10 was ob-
ϩ
HRMS calcd. for C10
2 3 5
H15NO [M Ϫ C H ) 140.0711, found
0
2
2
1
40.0710;
1
3
2
Compound cis-12b: H NMR (400 MHz, CDCl
.3 Hz, 3 H), 2.28 (dddt, J ϭ 14.3, 7.6, 6.7, 1.2 Hz, 1 H), 2.36
dddt, J ϭ 14.3, 6.7, 3.7, J ϭ 1.5 Hz, 1 H), 3.30 (ddd, J ϭ 9.4, 7.6,
.7 Hz, 1 H), 3.73 (ddt, J ϭ 15.5, 7.4, 1.0 Hz, 1 H), 4.21 (dq, J ϭ
.4, 6.3 Hz, 1 H), 4.60 (ddt, J ϭ 15.5, 4.9, 1.5 Hz, 1 H), 5.65 (m, 2
3
): δ ϭ 1.30 (d, J ϭ
(
6
(
(
3
9
tained in Ͼ98% ds.
1
3
H), 5.15 (m, 4 H). Ϫ C NMR (100.6 MHz, CDCl
1.82, 44.83, 57.04, 73.86, 118.24, 118.76, 132.29, 132.89, 157.37.
3
): δ ϭ 14.94,
Reformatsky Reaction: Zinc powder was suspended in dry THF
3
(
(
2 mL) in a dry Schlenk tube under argon atmosphere, and TMSCl
0.1 mL, 0.16 mmol) was added. After the mixture had been stirred
(
(
0
4RS,5R)-3-Allyl-4-(2-bromoallyl)-5-methyl-1,3-oxazolidin-2-one
14ab): General procedure VI was used. Oxazolidinone 11 (0.09 g,
for 5 min, EtO
added dropwise and the mixture was stirred for 10 min. The mix-
ture was cooled to Ϫ20 °C, BF ·OEt (0.6 mL, 4.5 mmol) was
slowly added and the solution was stirred for 5 min. The oxazolidi-
none 2 (0.1 g, 0.6 mmol), in dry THF (5 mL), was added. After
stirring for 15 h at this temperature, the solution was heated to
room temp., the mixture was quenched by the addition of conc. aq.
2 2
CCH Br (0.30 g, 5 mmol) in dry THF (2 mL) was
.50 mmol) was treated with (2-bromoallyl)trimethylsilane
0.25 mL, 1.51 mmol) and BF ·OEt (0.10 mL, 0.70 mmol) in 5 mL
dichloromethane. Purification of the crude product on silica gel
ethyl acetate/cyclohexane, 1:4) afforded 0.11 g (85%) of 14ab as a
colourless oil. The (4R,5R) product trans-14a was obtained in Ͼ
3
2
(
3
2
(
2
5
9
f D
6% ds. Ϫ R ϭ 0.18 (ethyl acetate/cyclohexane 1:4); [α] ϭ ϩ43.2
c ϭ 0.54, dichloromethane).
3
NaHCO and the solids were filtered off. The phases were separ-
(
ated and the water phase was extracted three times with diethyl
ether, which was dried with sodium sulfate and concentrated in
vacuo. The crude product was purified by flash chromatography
on silica gel (ethyl acetate/cyclohexane, 1:2). The reaction afforded
1
Compound trans-14a: H NMR (400 MHz, CDCl
3
): δ ϭ 1.30 (d,
J ϭ 6.3 Hz, 3 H), 2.42 (dd, J ϭ 14.3, 8.9 Hz, 1 H), 2.81 (ddd, J ϭ
4.3, 4.3, 0.7 Hz, 1 H), 3.54 (ddt, J ϭ 15.5, 7.4, 1.0 Hz, 1 H), 3.59
dt, J ϭ 8.9, 4.4 Hz, 1 H), 4.08 (ddt, J ϭ 15.5, 4.9, 1.5 Hz, 1 H),
.23 (qd, J ϭ 6.4, 4.4 Hz, 1 H), 5.20 (dd, J ϭ 17.3, 1.2 Hz, 1 H),
.23 (dd, J ϭ 10.1, 1.2 Hz, 1 H), 5.52 (d, J ϭ 1.7 Hz, 1 H), 5.70
1
(
4
5
0
.08 g (58%) of 10 as a colourless oil. The (4R,5S) product 10 was
obtained in Ͼ98% ds. Ϫ R ϭ 0.10 (ethyl acetate/cyclohexane, 1:2);
f
25
1
α]
D
[ ϭ ϩ13 (c ϭ 0.5, dichloromethane). Ϫ H NMR (400 MHz):
δ ϭ 1.22 (t, J ϭ 7.2 Hz, 3 H), 3.38 (m, 2 H), 3.66 (dd, J ϭ 11.6,
(
Ϫ
d, J ϭ 1.7 Hz, 1 H), 5.72 (dddd, J ϭ 17.3, 10.1, 7.6, 4.9 Hz, 1 H).
5
4
4
.9 Hz, 1 H), 3.71 (dd, J ϭ 11.6, 4.4 Hz, 1 H), 4.04 (dt, J ϭ 6.7,
.6 Hz, 1 H), 4.12 (q, J ϭ 7.2 Hz, 2 H), 4.42 (ddd, J ϭ 5.9, 4.6,
.4 Hz, 1 H), 6.44 (br, NH, 1 H). Ϫ C NMR (50.3 MHz, CDCl ):
3
13
C NMR (100.6 MHz, CDCl
4.85, 119.01, 120.90, 127.57, 131.97, 157.04. Ϫ MS (70 eV, EI):
m/z ϭ 259 (0.4), 180 (0.4), 140 (100), 112 (22.7), 96 (12.8). Ϫ
HRMS calcd. for C10
Ϫ C10 14NO Br (259.0) calcd. C 46.17; H 5.42, N 5.38; found
3
): δ ϭ 20.86, 44.18, 44.94, 59.43,
7
13
δ ϭ 14.9, 39.9, 44.4, 52.0, 62.7, 79.5, 157.9, 170.3. Ϫ MS (70 eV,
EI): m/z ϭ 142 (100), 136 (23), 134 (79), 88 (39), 71 (100). Ϫ MS
ϩ
2
H14NO Br [M ] 259.0194; found 259.0200.
H
2
ϩ
(FAB): m/z ϭ 222 [M ϩ H].
C 46.18, H 5.29, N 5.29.
Nucleophile Exchange with Allylsilane Reagents. ؊ General Proced-
ure VI: Oxazolidinone 3 or 11 was dissolved in dry dichlorome-
thane in a dry Schlenk tube under argon atmosphere and cooled
2 4
to Ϫ78 °C. At the same temperature, BF3·OEt or TiCl was added
slowly and the reaction mixture was stirred for 20 min. The allylsil-
ane reagent was added slowly and the reaction mixture was stirred
for 18 h at Ϫ78 °C. After heating to room temp., the reaction was
N-Allylation. ؊ General Procedure VII: Oxazolidinone 3, 8a or 9a
was dissolved in N,N-dimethylformamide and cooled to 0 °C. After
the mixture had been stirred for 3 h at this temperature, allyl brom-
ide was added. After stirring for 24 h at room temp. the reaction
mixture was quenched by the addition of an aqueous solution of
citric acid (5%). The mixture was extracted repeatedly with ethyl
acetate. The organic phase was dried with sodium sulfate and con-
centrated in vacuo. The crude product was purified by flash chro-
matography on silica gel (ethyl acetate/cyclohexane).
[
12]
3
stopped by the addition of saturated aq. NaHCO solution and the
solids were filtered off. The layers were separated and the water
phase was extracted four times with dichloromethane. The com-
bined organic phases were dried with magnesium sulfate and con-
centrated in vacuo. The crude product was purified by flash chro-
matography on silica gel (ethyl acetate/cyclohexane).
(
4RS,5R)-3-Allyl-4-methoxy-5-methyl-1,3-oxazolidin-2-one (11ab):
General procedure VII was used. Oxazolidinone (0.67 g,
.10 mmol) was treated with sodium hydride (spatula tip) and allyl
3
5
bromide (1.10 mL, 12.75 mmol) in 20 mL N,N-dimethylformamide.
Purification of the crude product on silica gel (ethyl acetate/cyclo-
hexane, 1:4) afforded 0.70 g (81%) of 11ab as a yellow oil. The
(
4RS,5R)-3,4-Diallyl-5-methyl-1,3-oxazolidin-2-one (12ab): General
procedure VI was used. The oxazolidinone 11 (0.13 g, 0.78 mmol)
was treated with allyltrimethylsilane (0.16 mL, 1.02 mmol) and
BF3·OEt (0.13 mL, 1.02 mmol) in 6 mL dichloromethane. Puri-
2
fication of the crude product on silica gel (ethyl acetate/cyclohex-
(
f
4R,5R) product trans-11a was obtained in 80% ds. Ϫ R ϭ 0.27
(
ethyl acetate/cyclohexane, 1:4).
ane, 1:4) afforded 0.11 g (85%) of 12ab as a colourless oil. The
1
Compound trans-11a: H NMR (400 MHz, CDCl
3
): δ ϭ 1.30 (d,
f
(4R,5R) product trans-12a was obtained in Ͼ 92% ds. Ϫ R ϭ 0.27
J ϭ 6.6 Hz, 3 H), 3.20 (s, 3 H), 3.62 (ddt, J ϭ 15.5, 7.4, 1.0 Hz, 1
H), 4.37 (qd, J ϭ 6.6, 1.7 Hz, 1 H), 4.53 (d, J ϭ 1.7 Hz, 1 H), 4.57
(ethyl acetate/cyclohexane, 1:4).
1
Compound trans-12a: H NMR (400 MHz, CDCl
3
): δ ϭ 1.30 (d, (ddt, J ϭ 15.5, 4.7, 1.5 Hz, 1 H), 5.19 (dddd, J ϭ 17.0, 10.0, 1.5,
1
3
J ϭ 6.3 Hz, 3 H), 2.20 (dddt, J ϭ 14.3, 7.6, 6.7, 1.2 Hz, 1 H), 2.36 1.0 Hz, 2 H), 5.65 (dddd, J ϭ 17.0, 10.0, 7.4, 4.7 Hz, 1 H). Ϫ
dddt, J ϭ 14.3, 6.7, 3.7, 1.5 Hz, 1 H), 3.30 (ddd, J ϭ 9.4, 7.6, NMR (100.6 MHz, CDCl ): δ ϭ 19.24, 43.86, 52.81, 74.96, 90.99,
.7 Hz, 1 H), 3.54 (ddt, J ϭ 15.5, 7.4, 1.0 Hz, 1 H), 4.09 (ddt, J ϭ 118.49, 131.87, 156.58. Ϫ MS (70 eV, EI): m/z ϭ 171 (10.7), 156
C
(
3
3
Eur. J. Org. Chem. 2001, 2425Ϫ2433
2431

K. Schierle-Arndt, D. Kolter, K. Danielmeier, E. Steckhan
Heck Reaction
FULL PAPER
(
2.0), 140 (23.7), 112 (16.7), 99 (100), 84 (22.2). Ϫ HRMS calcd.
ϩ
for C
8
H
13NO
3
[M ] 171.0893; found 171.0895.
Palladium diacetate (0.01 g, 0.37 mmol), triphenylphosphane
): δ ϭ1.35 (d, J ϭ (0.03 g, 0.04 mmol) and triethylamine (0.1 mL, 0.11 mmol) were
1
Compound cis-11b: H NMR (400 MHz, CDCl
3
6
4
.6 Hz, 3 H), 3.38 (s, 3 H), 3.62 (ddt, J ϭ 15.5, 7.4, 1.0 Hz, 1 H), added to a solution of oxazolidinone 14 in 2 mL toluene in a dry
.48 (qd, J ϭ 6.6, 1.7 Hz, 1 H), 4.57 (ddt, J ϭ 15.5, 4.7, 1.5 Hz, 1 Schlenk tube. The reaction mixture was refluxed for 16 h. Purifica-
H), 4.70 (d, J ϭ 1.7 Hz, 1 H), 5.19 (dddd, J ϭ 17.0, 10.0, 1.5,
tion of the crude product on silica gel (cyclohexane/ethyl acetate
4:1) afforded 0.05 g (72%) of 15 and 0.01 g (12%) of 16. Both prod-
ucts are solids.
1
3
1.0 Hz, 2 H), 5.65 (dddd, J ϭ 17.0, 10.0, 7.4, 4.7 Hz, 1 H). Ϫ
C
3
NMR (100.6 MHz, CDCl ): δ ϭ 18.74, 44.31, 57.46, 74.96, 88.26,
1
18.33, 132.40, 156.85.
(
1R,8aR)-1,6-Dimethyl-7-methylene-1,7,8,8a-tetrahydro-oxazolo-
(
4RS,5R)-3,4-Diallyl-5-methyl-1,3-oxazolidin-2-one (12ab): General [3,4-a]pyridin-3-one (15): R ϭ 0.40 (cyclohexane/ethyl acetate, 4:1);
f
procedure VII was used. Oxazolidinone 8a (0.220 g, 1.21 mmol)
[α]25 ϭ ϩ5.3 (c ϭ 0.33, dichloromethane).
D
was treated with sodium hydride (spatula tip) and allyl bromide
1
Compound trans-15: H NMR (400 MHz, CDCl
3
): δ ϭ 1.44 (d, J ϭ
(0.26 mL, 3.03 mmol) in 20 mL dimethylformamide. Purification of
6
2
9
4
.2 Hz, 3 H), 1.75 (d, J ϭ 1.2 Hz, 3 H), 2.20 (ddt, J ϭ 14.6, 10.8,
the crude product on silica gel (ethyl acetate/cyclohexane 1:4) af-
forded 0.13 g (58%) of 11ab as a yellow oil. Ϫ R ϭ 0.27 (ethyl
f
acetate/cyclohexane, 1:4).
.2 Hz, 1 H), 2.60 (dd, J ϭ 4.6, 3.4 Hz, 1 H), 3.49 (ddd, J ϭ 10.8,
.1, 3.4 Hz, 1 H), 4.24 (dq, J ϭ 9.1, 6.4 Hz, 1 H), 4.78 (m, 1 H),
1
3
.93 (m, 1 H), 6.50 (d, J ϭ 1.2 Hz, 1 H). Ϫ C NMR (100.6 MHz,
): δ ϭ 16.30, 18.51, 34.59, 53.63, 78.43, 110.65, 119.31,
23.45, 137.68, 153.14. Ϫ MS (70 eV, EI): m/z ϭ 179 (60.7), 164
90.7), 134 (18.6), 107 (100), 91 (18.6), 79 (50.7). Ϫ HRMS calcd.
(4RS,5R)-3-Allyl-5-methyl-4-vinyl-1,3-oxazolidin-2-one (14): Gen-
CDCl
1
(
3
eral procedure VI was used. Oxazolidinone 9a (0.08 g, 0.59 mmol)
was treated with sodium hydride (spatula tip) and allyl bromide
(0.12 mL, 1.48 mmol) in 6 mL dimethylformamide. Purification of
ϩ
for C10
H
13NO
2
[M ] 179.0946; found 179.0946, for C10
H14NO
2
the crude product on silica gel (ethyl acetate/cyclohexane 1:4) af-
ϩ
[M Ϫ H]178.0869; found 178.0867.
forded 0.08 g (77%) of 14 as a colourless oil. Ϫ R
f
ϭ 0.21 (ethyl
ϭ ϩ33.2 (c ϭ 0.85, dichlorome-
acetate/cyclohexane, 1:4). [α]2
5
(1R,8aR)-1-Methyl-6,7-dimethylene-1,7,8,8a-tetrahydro-oxazolo-
D
f
[3,4-a]pyridin-3-one (16): R ϭ 0.35 (cyclohexane/ethyl acetate, 4:1).
thane).
2
5
M.p. 100 °C; [α]
D
ϭ Ϫ35 (c ϭ 0.25, dichloromethane);
1
Compound trans-14a: H NMR (400 MHz, CDCl
J ϭ 6.2 Hz, 3 H), 3.43 (ddt, J ϭ 15.5, 7.6, 1.0 Hz, 1 H), 3.67 (dd, Compound trans-16: H NMR (400 MHz, CDCl
3
): δ ϭ 1.34 (d,
1
3
): δ ϭ 1.38 (d, J ϭ
J ϭ 7.6, 6.3 Hz, 1 H), 4.01 (ddt, J ϭ 15.5, 4.9, 1.5 Hz, 1 H), 4.16
dq, J ϭ 6.3, 6.2 Hz, 1 H), 5.12 (m, 2 H), 5.27 (m, 2 H), 5.62 (m, 13.3, 3.7 Hz, 1 H), 3.49 (ddd, J ϭ 11.3, 5.8, 3.7 Hz, 1 H), 3.54 (dt,
6.3 Hz, 3 H), 2.17 (ddt, J ϭ 13.3, 11.3, 2.2 Hz, 1 H), 2.47 (dd, J ϭ
(
2
7
H). Ϫ 13C NMR (100.6 MHz, CDCl
5.66, 118.73, 121.59, 131.72, 134.34, 157.42. Ϫ MS (70 eV, EI):
): δ ϭ 18.80, 44.62, 66.16, J ϭ 14.6, 2.2 Hz, 1 H), 4.18 (dq, J ϭ 6.3, 5.8 Hz, 1 H), 4.30 (d,
3
1
3
J ϭ 14.6 Hz, 1 H), 4.85 and 5.12 (m, 4 H). Ϫ C NMR
(100.6 MHz, CDCl ): δ ϭ 19.70, 38.30, 46.30, 60.73, 77.36, 110.74,
[M ] 167.0944; found 167.0945. Ϫ 111.97, 140.91, 142.14, 156.48. Ϫ MS (70 eV, EI): m/z ϭ 179 (62.1),
(167.1) calcd. C 64.65; H 7.84, N 8.38; found C 64.07, 164 (14.3), 134 (28.6), 120 (32.1), 107 (100), 92 (20.0), 79 (100). Ϫ
m/z ϭ 167 (51.4), 140 (44.3), 108 (25.3), 94 (82.1), 68 (100). Ϫ
HRMS calcd. for C H13NO
9 2
C
3
ϩ
9
H
13NO
2
ϩ
H 7.76, N 8.07.
2
HRMS calcd. for C10H13NO [M ] 179.0946; found 179.0946.
Metathesis Reaction
Acknowledgments
(
(
1R,8aR)-1-Methyl-1,5,8,8a-tetrahydro-oxazolo[3,4-a]pyridin-3-one
13): Oxazolidinone 12 (0.12 mg, 0.66 mmol) was dissolved in 4 mL Financial support by the Deutsche Forschungsgemeinschaft (Ste
of dried dichloromethane and Grubbs’ catalyst (0.11 mg,
227/19Ϫ2/3), the Fonds der Chemischen Industrie and BASF
0.13 mmol), also dissolved in 8 mL of dried dichloromethane, was
Aktiengesellschaft is gratefully acknowledged. K.S. and K.D. are
added. The violet solution was refluxed for 30 min. During this grateful for graduate fellowships from the federal state of North
time a colour change of the solution from violet through red to Rhine-Westphalia.
brown took place. The reaction mixture was quenched by the addi-
tion of 6 mL of an aqueous solution of citric acid (5%). The water
[
1] [1a]
S. J. Brickner, D. K. Hutchinson, M. R. Barbachyn, P. R.
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bined organic phases were dried with magnesium sulfate and con-
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cyclohexane/ethyl acetate, 4:1) afforded 0.10 mg (74%) of 13 as a
2
5
[1d]
colourless oil. Ϫ R
f
ϭ 0.15 (cyclohexane/ethyl acetate, 4:1). [α]
D
ϭ
Pharmaceutical Design 1996, 2, 175Ϫ194. Ϫ
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J. Gante, Angew. Chem. 1994, 106, 1780Ϫ1802; Angew.
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[2b]
Compound trans-13: H NMR (400 MHz, CDCl
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D. Dorsch,
6
5
.2 Hz, 3 H), 2.20 (m, 1 H), 2.25 (m, 1 H), 3.28 (ddd, J ϭ 10.3,
.6, 4.9 Hz, 1 H), 3.61 (ddd, J ϭ 18.2, 4.4, 2.2 Hz, 1 H), 4.02 (ddd,
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E. G. J. C. Warmerdam, J. Brussee, A. van der Geen, Helvet-
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3b]
(
2
4
.2 Hz, 1 H). Ϫ 1 C NMR (100.6 MHz, CDCl
3
3
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1.04, 57.06, 77.98, 123.07, 123.92, 157.17. Ϫ MS (70 eV, EI):
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HRMS calcd. for C
(153.1) calcd. C 62.73; H 7.24, N 9.14; found C 63.00,
H 7.72; N 9.29.
8 2
H11NO [M ] 153.0798; found 153.0794. Ϫ
5
09Ϫ514.
[5] [5a]
A. D. Elbein, Ann. Rev. Biochem. 1987, 56, 497Ϫ534; [5b] A.
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C H11NO
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