Synthesis of the chiral α,β-unsaturated N-acyl-oxazolidin-2-ones by wittig reaction

Article abstract of DOI:10.1080/10426500490468155

A new, universal, and versatile method has been developed for the synthesis of the chiral α,β-unsaturated N-acyl-oxazolidin-2-ones 4 based on the Wittig reaction of the triphenylphosphonium salt 7 derived from the (R)-3-(2-Chloro-acetyl)-5,5-dimethyl-4-ph

Full text of DOI:10.1080/10426500490468155

This article was downloaded by: [RMIT University]
On: 06 October 2013, At: 02:04
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the Related
Elements
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/gpss20
SYNTHESIS OF THE CHIRAL α,β-UNSATURATED N-ACYL-
OXAZOLIDIN-2-ONES BY WITTIG REACTION
Manouchehr Mamaghani a , Khalil Tabatabaeian a & Abed Badrian a
a University of Guilan, Rasht, Iran
Published online: 16 Aug 2010.
To cite this article: Manouchehr Mamaghani , Khalil Tabatabaeian & Abed Badrian (2004) SYNTHESIS OF THE CHIRAL α,β-
UNSATURATED N-ACYL-OXAZOLIDIN-2-ONES BY WITTIG REACTION, Phosphorus, Sulfur, and Silicon and the Related Elements,
179:7, 1347-1353, DOI: 10.1080/10426500490468155
To link to this article: http://dx.doi.org/10.1080/10426500490468155
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 179:1347–1353, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490468155
SYNTHESIS OF THE CHIRAL α,β-UNSATURATED
N-ACYL-OXAZOLIDIN-2-ONES BY WITTIG REACTION
Manouchehr Mamaghani, Khalil Tabatabaeian,
and Abed Badrian
University of Guilan, Rasht, Iran
(Received October 16, 2003)
A new, universal, and versatile method has been developed for the syn-
thesis of the chiral α,β-unsaturated N-acyl-oxazolidin-2-ones 4 based
on the Wittig reaction of the triphenylphosphonium salt 7 derived from
the (R)-3-(2-Chloro-acetyl)-5,5-dimethyl-4-phenyl-oxazolidin-2-one 6.
Keywords: Chiral auxiliaries; oxazolidin-2-one; Wittig reaction
One of the most popular and reliable methods of asymmetric synthe-
sis has proved to be via stoichiometric chiral auxiliaries.1 The role of
chiral auxiliaries in asymmetric synthesis for the preparation of ho-
mochiral molecules is now firmly established in organic synthesis.2 In
this area the versatile oxazolidin-2-one based chiral auxiliaries 1 de-
velopd by Evans et al. has been widely used for the preparation of
highly functionalized homochiral molecules.3 Recently Davies et al.
reported the synthesis and application of Quats 2 and SuperQuats 3
which had the advantage of completely clean removal and recycling of
the auxiliary while maintaining effective stereocontrol in a variety of
reactions.4
The authors are grateful to Guilan University Research Council for financial support
of our research program.
Address correspondence to Manouchehr Mamaghani, Department of Chemistry, Fac-
ulty of Sciences, University of Guilan, Rasht, Iran. E-mail: m-chem41@guilan.ac.ir
1347

1348
M. Mamaghani et al.
This methodology generally involves coupling the auxiliary to an acyl
fragment which is then chemically derivatized to afford ideally a sin-
gle diastereoisomer with one or more new stereocenters. Subsequent
cleavage and purification of the transformed acyl fragment affords the
desired homochiral product and the chiral auxiliary which may be re-
cycled as required.5
The α,β-unsaturated N-acyl-oxazolidin-2-ones 5, are important ac-
ceptor reactants in many type of transformations. The use of chiral
auxiliary attached to an activated alkene in alkylation and conjugate
additions, cyclization, and cycloaddition reactions of attached N-acyl
moieties has been briefly described.6 The most popular method of N-
acylation of oxazolidin-2-one is the reaction of its Li salt (generated
with BuLi at −78◦C ) with an acyl chloride (Scheme 1).5b
SCHEME 1
Generally, this procedure leads to N-acyl-oxazolidin-2-ones in good
yields, but there are some limitations: 1) Acryloyl derivatives tend
to polymerize under these conditions; 2) β,γ -unsaturated carboxylic-
acid derivatives isomerize to the α,β-unsaturated compounds; 3) the
method is not applicable to carboxylic acids, which do not form stable
acid halides; 4) due to the basicity of the lithiated oxazolidinone group,
substrates with relatively acidic H-atoms or with a propensity for elimi-
nation cannot be employed; and 5) the use of Ri at −78◦C is not desirable
from an economic point of view (at least in larg-scale application).7,8
To circumvent these limitations, we report our results on the use of
Wittig reaction as an alternative method for preparation of the α,β-
unsaturated N-acyl-oxazolidin-2-ones.
RESULTS AND DISCUSSION
The (R)-4-phenyl-5,5-dimethyl oxazolidin-2-ones 4 is readily available
from the ꢀR -phenylglycine according to the Davies protocol.9 N-Acylation
of this auxiliary was achieved via deprotonation with BuLi followed

Oxazolidin-2-Ones
1349
by quenching with chloroacetylchloride. This gave the ꢀR -3-(2-chloro-
acetyl)-5,5-dimethyl-4-phenyl-oxazolidin-2-one 6 in 93% yield, which
was then treated with PPh3 in the presence of KI.
It is known that α-haloamides can be reduced in some cases when
reacted with PPh3.10 The interaction of compound 6 with PPh3 under
heating in ethanolic or dioxane solutions proceeds with low yields and
in some cases is accompanied by the formation of side products.11 We
succeeded in finding of reaction conditions which afford phosphonium
salt 7 in 85% yield (Scheme 2).
SCHEME 2
The Wittig reaction is one of the most powerful methods for the prepa-
ration of carbon-carbon double bonds12 and is used as a key step in this
synthesis. The required alkylidenephosphorane was prepared by de-
protonation of phosphonium salt 7. We searched for a strong base that
work efficiently and eliminate the hydrogen halide to produce the corre-
sponding ylide.13 When the mixture of benzaldehyde and phosphonium
salt 7 treated either with DBU or with NaOH in aq. THF at 0◦C gave
only exocyclic cleavage and regeneration of auxiliary 4 in 95% yield. Af-
ter testing several bases, it was found that NaH is a very effective base
for the Wittig reaction and no exocyclic cleavage occurs in this process.
Our results are shown in Table I.

1350
M. Mamaghani et al.
TABLE I Products Obtained from the Wittig Reaction of
Phosphonium Salt 7 with Several Aldehydes
Entry
Aldehyde
R1
Yield 5(%)a,b
a
b
c
d
e
f
Benzaldehyde
Acetaldehyde
Ph
Me
80
73
82
84
77
78
82
75
4-chlorobenzaldehyde
4-nitrobenzaldehyde
4-methylbenzaldehyde
4-methoxybenzaldehyde
4-pyridinecarbaldehyde
3-pyridinecarbaldehyde
4-Cl-C6H5
4-NO2-C6H5
4-Me-C6H5
4-OMe-C6H5
4-Py
g
h
3-Py
aAll products were analyzed by comparison of their physical and
spectroscopic data (1H NMR, IR) with those of authentic samples.
bYields are based on isolated products.
1H NMR spectroscopic analysis of each of the products indicated that
the generated ylide was particularly stable and yielded the E isomer of
5 as a major product.
In conclution the results presented in this communication show that
the Wittig reaction is a very useful and effective method for the prepa-
ration of α,β-unsaturated N-acyl-oxazolidin-2-ones.
EXPERIMENTAL SECTION
Chemicals were purchased from Merck and Fluka. Melting points were
measured on an Electrothermal 9100 apparatus. Elemental analyses
were performed using a Heraeus CHN-O-Rapid analyzer. These re-
sults agreed favorably with the calculated values. IR spectra were de-
1
termined on a Shimadzo IR-470 spectrometer. H NMR spectra were
recorded on a 500 MHz Bruker DRX-500 in CDCl3 as solvent and TMS
as internal standard. Preparative thin layer chromatography was pre-
pared from Merck Kieselgel 60 H, F254, Art No 7730. GC was carried out
using Buck Scientific 910 (capillary column, MXT-5, 15 m). All solvents
used were dried and distilled according to standard procedures.
ꢀR
General Procedure for the Synthesis of -3-(2-Chloro-
acetyl)-5,5-dimethyl-4-phenyl-oxazolidin-2-one 6
n-Buthyllithium (1.3 M, 38.8 mL, 52 mmol) was added dropwise via
syringe to a stirred solution of the auxiliary 4 (9.5 g, 50 mmol) in THF
(300 mL) at −78◦C under nitrogen atmosphere and the mixture allowed
to stir for 15 min. Chloroacetylchloride (5.3 mL, 56 mmol) was added at

Oxazolidin-2-Ones
1351
−78◦C and the reaction stirred at this temperature for 30 min, then al-
lowed to warm to room temperature over 2 h. Saturated NH4Cl (aq.) was
added and the reaction extracted with ethyl acetate (3×). The combined
organic extracts were washed with NaHCO3 (aq.), brine, dried (MgSO4),
and evaporated to give the title compound 6 as a white solid, (12.4 g,
93%, m.p. = 123–125◦C), (Found: C, 58.25; H, 5.33; Cl, 13.15; N, 5.33
C13H14ClNO3 requires C, 58.32; H, 5.27; Cl, 13.24; N, 5.23%), IR (film,
cm−1); 1780, 1720, 1360, 1340, 700, [α]D26 = +45.9 (c 1 in CHCl3),1H
NMR (CDCl3, δ); 1.05 (s, 3H), 1.67 (s, 3H), 4.21 (s, 2H), 5.30 (s, 1H),
7.10–7.30 (m, 5H).
General Procedure for the Synthesis of Phosphonium
Salt 7
KI (7.64 g, 46 mmol) and Ph3P were added to a solution of 6 (10.70 g,
40 mmol) in DMF at 0◦C. The reaction mixture was kept at 0–7◦C for 2–
3 days and then poured into a 30% aqueous solution of KI (100 mL) and
then kept at the same temperature for 8 h. After adding water (100 mL)
the residue was kept until crystallization occurred. The product was
filtered off, recrystallized from chloroform-ether, and dried over P4O10
to give the title compound 7 as a solid, (26.40 g, 85%, m.p. > 300◦C),
(Found: C, 59.85; H, 4.76; N, 2.30 C31H29INO3P requires C, 59.92; H,
4.70; N, 2.25%), IR (film, cm−1); 3010, 1785, 1722, 1364, 1347, 1H NMR
(CDCl3, δ); 1.11 (s, 3H), 1.70 (s, 3H), 2.28 (s, 2H), 5.43 (s, 1H), 7.10–7.64
(m, 15H).
General Procedure for the Wittig Reactions
To a stirred solution of NaH (0.12 g, 5 mmol, prepared from 0.22g of
sodium hydride mineral oil dispersion by several washings with dry
hexane) in CH2Cl2 (15 mL) the phosphonium salt 7 (3.1 g, 5 mmol)
was added at room temperature. After stirring for 30 min, a solution of
the aldehyde (5 mmol) in CH2Cl2 (10 mL) was added to the resulting
red ylide solution. Stirring was continued for 12 h at the same tem-
perature, and then the mixture poured into large excess of ice-water
mixture and extracted with ether. The ethereal layer was washed with
water and brine, dried over MgSO4, and evaporated in vacuo to provide
a crude product. This product was purified by column chromatography
(petroleum ether/ethyl acetate 3:2) to give adducts in 73–84% yield. The
isolated yield for each product is given in parentheses and IR, 1H NMR
data for the compounds 5a–h are given below.
5a: white solid (80%, m.p. 149–150◦C), (Found: C, 74.80; H, 5.93; N,
4.33 C20H19NO3 requires C, 74.75; H, 5.97; N, 4.36%), IR (film, cm−1);

1352
M. Mamaghani et al.
1771, 1682, 1615, [α]D26 = +25.9◦ (c 1 in CHCl3), 1H NMR (CDCl3, δ); 1.04
(s, 3H), 1.65 (s, 3H), 5.24 (s, 1H), 7.20–7.64 (m, 10H), 7.80 (d, J15.8, 1H),
8.07 (d, J15.8, 1H).
5b: white solid (73%, m.p. 104–105◦C), (Found: C, 69.39; H, 6.73; N,
5.33 C15H17NO3 requires C, 69.48; H, 6.61; N, 5.40%), IR (film, cm−1);
1769, 1687, 1618, [α]D26 = −82.5◦ (c 1 in CHCl3), H NMR (CDCl3, δ);
1
0.99 (s, 3H), 1.60 (s, 3H), 1.93 (d, J5.4, 3H), 5.14 (s, 1H), 7.02–7.40 (m,
7H).
5c: white solid (82%, m.p. 165–166◦C), (Found: C, 67.45; H, 5.13; N,
3.88 C20H18ClNO3 requires C, 67.51; H, 5.10; N, 3.94%), IR (film, cm−1);
1776, 1687, 1619, [α]D26 = +36.8◦ (c 1 in CHCl3), 1H NMR (CDCl3, δ); 1.06
(s, 3H), 1.68 (s, 3H), 5.28 (s, 1H), 7.10–7.64 (m, 9H), 7.86 (d, J15.9, 1H),
8.16 (d, J15.9, 1H).
5d: pale yellow solid (84%, m.p. 173–175◦C), (Found: C, 65.58; H,
4.93; N, 7.72 C20H18N2O5 requires C, 65.57; H, 4.95; N, 7.65%), IR (film,
cm−1); 1780, 1690, 1620, [α]D26 = −45.9 (c 1 in CHCl3), 1H NMR (CDCl3,
δ); 1.08 (s, 3H), 1.70 (s, 3H), 5.30 (s, 1H), 7.10–8.15 (m, 11H).
5e: white solid (77%, m.p. 141–142◦C), (Found: C, 75.15; H, 6.38; N,
4.23 C21H21NO3 requires C, 75.20; H, 6.31; N, 4.18%), IR (film, cm−1);
1770, 1680, 1613, [α]D26 = +35.4◦ (c 1 in CHCl3), H NMR (CDCl3, δ);
1
1.03 (s, 3H), 1.64 (s, 3H), 2.37 (s, 3H), 5.23 (s, 1H), 7.20–7.66 (m, 9H),
7.78 (d, J15.6, 1H), 8.03 (d, J15.6, 1H).
5f: white solid (78%, m.p. 157–158◦C), (Found: C, 71.80; H, 5.97; N,
4.15 C21H21NO4 requires C, 71.78; H, 6.02; N, 3.99%), IR (film, cm−1);
1777, 1685, 1619, [α]D26 = +55.9◦ (c 1 in CHCl3), H NMR (CDCl3, δ);
1
1.07 (s, 3H), 1.67 (s, 3H), 3.70 (s, 3H), 5.28 (s, 1H), 7.21–7.65 (m, 9H),
7.84 (d, J15.8, 1H), 8.11 (d, J15.8, 1H).
5g: pale yellow solid (82%, m.p. 163–165◦C), (Found: C, 70.82; H,
5.72; N, 8.55 C19H18N2O3 requires C, 70.79; H, 5.63; N, 8.69%), IR (film,
cm−1); 1778, 1689, 1621, [α]D26 = −64.6◦ (c 1 in CHCl3), 1H NMR (CDCl3,
δ); 1.07 (s, 3H), 1.72 (s, 3H), 5.33 (s, 1H), 7.10–8.61 (m, 11H).
5h: pale yellow solid (75%, m.p. 143–145◦C), (Found: C, 70.83; H,
5.71; N, 8.51 C19H18N2O3 requires C, 70.79; H, 5.63; N, 8.69%), IR (film,
cm−1); 1777, 1690, 1625 [α]D26 = −56.6◦ (c 1 in CHCl3), 1H NMR(CDCl3,
δ); 1.06 (s, 3H), 1.74 (s, 3H), 5.35 (s, 1H), 7.10–8.60 (m, 11H).
REFERENCES
[1] a) S. G. Davies, Aldrichimica Acta, 23, 39 (1990); b) W. Oppolzer, Pure and Appl.
Chem., 60, 39 (1988); c) D. Enders and H. Eichenauer, Angew. Chem., Int. Ed. Engl.,
15, 549 (1976); d) A. I. Meyers, G. Knaus, and K. Kamata, J. Am. Chem. Soc., 96,
268 (1974).

Oxazolidin-2-Ones
1353
[2] a) G. Procter, Asymmetric Synthesis (Oxford University Press, Oxford, 1996);
b) R. E. Gawley and J. Aube, Principles of Asymmetric Synthesis, Tetrahedron
Organic Chemistry Series, vol. 14, edited by J. E. Baldwin and P. D. Magnus (Elsevier
Ps, Oxford, 1996); c) J. Seyden-Penne, Chiral Auxiliaries and Ligands for Asymmet-
ric Synthesis (Wiley, New York, 1995).
[3] D. A. Evans, Aldrichimica Acta, 15, 23 (1982).
[4] a) S. G. Davies and H. J. Sanganee, Tetrahedron: Asymmetry, 6, 671 (1995); b) S. G.
Davies, G. J. M. Doisneau, J. C. Prodger, and H. J. Sanganee, Tetrahedron Lett., 35,
2369 (1994); c) S. G. Davies, G. J. M. Doisneau, J. C. Prodger, and H. J. Sanganee,
Tetrahedron Lett., 35, 2373 (1994).
[5] a) D. A. Evanes, T. C. Britton, and J. A. Ellman, Tetrahedron Lett., 28, 6141 (1987);
b) D. A. Evanes, M. D. Ennis, and D. J. Mathre, J. Am. Chem. Soc., 104, 1737 (1982).
[6] a) A. Studer, Synthesis, 793 (1996); b) H. Kunz and K. Ruck, Angew. Chem. Int. Ed.
Engl., 105, 355 (1993) c) J. K. Whitesell, Chem. Rev., 92, 953 (1992); d) W. Oppolzer,
Tetrahedron, 43, 1969 (1987); e) D. Seebach, R. Imwinkelried, and T. Weber, in
Modern Synthetic Methods, edited by R. Sheffold (Springer Verlag, Berlin, 1986),
pp. 125–259; f) K. Drauz, A. Kleemann, and J. Martenes, Angew. Chem. Int. Ed.
Engl., 94, 590 (1982).
[7] T. Hintermann and D. Seebach, Helv. Chim. Acta, 81 (1998).
[8] a) K. C. Nicolaou, M. W. Harter, J. L. Gunzer, and A. Nadin, Liebigs Ann./Recueil,
1283 (1997); b) H. Pommer, Angew. Chem., 89, 437 (1977); c) H. Pommer, Angew.
Chem. Int. Ed. Engl., 16, 423 (1977).
[9] a) S. G. Davies, H. J. Sanganee, and P. Szolcsanyi, Tetrahedron, 55, 3337 (1999);
b) S. D. Bull, S. G. Davies, et al., Synlett, 517 (1998).
[10] H. Kagoshima, Y. Hashimoto, D. Oguro, T. Kutsuna, and K. Saigo, Tetrahedron Lett.,
39, 1203 (1998).
[11] H. E. Zaugg, Synthesis, 181 (1984).
[12] A. S. Fisyuk and N. V. Poendaev, Molecules, 7, 124 (2002).
[13] a) D. J. Ager, I. Prakash, and D. R. Schaad, Chem. Rev., 96, 835 (1996); b) D.
Seebach, K. Beck, and A. Studer, in Modern Synthetic Methods, edited by B. Ernst
and C. Leuman (VHCA, Basel/VCH, Weinheim, 1995), pp. 1–178; c) A. Studer, T.
Hintermann, and D. Seebach, Hevl. Chim. Acta, 78, 1185 (1995).