A facile and efficient synthesis of 3-aryloxazolidin-2-ones from isocyanates and epoxides promoted by MgI2 etherate

Article abstract of DOI:10.1080/00397910903470525

We described a mild and efficient procedure for the synthesis of 3-aryloxazolidin-2-ones via the cycloaddition of isocyanates with epoxides in the presence of MgI₂ etherate (MgI₂(OEt2)_n) in good yields. Copyright

Full text of DOI:10.1080/00397910903470525

This article was downloaded by: [New York University]
On: 19 February 2015, At: 14:49
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
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
A Facile and Efficient Synthesis of 3-
Aryloxazolidin-2-ones from Isocyanates
and Epoxides Promoted by MgI2 Etherate
Xingxian Zhang a , Wei Chen a , Chengfeng Zhao a , Cheng Li a , Xiang
Wu a & Wei Z. Chen a
a College of Pharmaceutical Sciences, Zhejiang University of
Technology , Hangzhou, Zhejiang, P. R. China
Published online: 09 Nov 2010.
To cite this article: Xingxian Zhang , Wei Chen , Chengfeng Zhao , Cheng Li , Xiang Wu & Wei
Z. Chen (2010) A Facile and Efficient Synthesis of 3-Aryloxazolidin-2-ones from Isocyanates and
Epoxides Promoted by MgI2 Etherate, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:24, 3654-3659, DOI: 10.1080/00397910903470525
To link to this article: http://dx.doi.org/10.1080/00397910903470525
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

Synthetic Communications1, 40: 3654–3659, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903470525
A FACILE AND EFFICIENT SYNTHESIS OF
3-ARYLOXAZOLIDIN-2-ONES FROM ISOCYANATES
AND EPOXIDES PROMOTED BY MgI2 ETHERATE
Xingxian Zhang, Wei Chen, Chengfeng Zhao, Cheng Li,
Xiang Wu, and Wei Z. Chen
College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou, Zhejiang, P. R. China
We described a mild and efficient procedure for the synthesis of 3-aryloxazolidin-2-ones
via the cycloaddition of isocyanates with epoxides in the presence of MgI2 etherate
(MgI2 . (OEt2)n) in good yields.
Keywords: Epoxide; isocyanate; MgI2 etherate; oxazolidinone
INTRODUCTION
A number of 5-substituted oxazolidinones are shown to have high potency as
biologically active molecules and are widely used in the pharmaceutical industry.[1]
Consequently, much attention and extensive study have been focused on the
synthesis of oxazolidinones. The cycloaddition of isocyanates with epoxides is one
of the most useful and efficient method for preparation of oxazolidin-2-ones. A
variety of catalysts have been investigated, such as quaternary ammonium salts,[2]
LiBr=n-Bu3PO or LiBr=HMPA,[3] LiCl=DMF,[4] n-Bu3SnI-Ph3PO,[5] n-Bu3SnI-Ph4-
SbI[6] and lanthanide chlorides.[7] However, vigorous reaction temperatures, reactive
polar solvents and a long reaction time are required, so they are accompanied by
undesirable reactions such as the trimerization of isocyanates. In addition, many
of these reagents are rather expensive and difficult to be handled especially on a
large scale. From the viewpoints above, the development of less expensive, environ-
mentally benign, and easily handled promoters for the cycloaddition of isocyanates
with epoxides is still highly desirable. Due to its abundant, inexpensive and nontoxic
character, Lewis acidic Mg(II) catalyst has been widely utilized into the various
organic reactions.[8] In our previous paper,[9] we have demonstrated that MgI2
etherate could efficiently catalyze Mukaiyama-type aldol of aldehydes with trimethyl-
silyl enolates and allylation of aldehydes with allylstannane. We herein wish to
report the preliminary results on the catalytic reactivity of MgI2 etherate for the
mild, efficient and regioselective cycloaddition of isocyanates with epoxides.
Received August 6, 2009.
Address correspondence to Xingxian Zhang, College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou, 310032, P. R. China. E-mail: zhangxx@zjut.edu.cn
3654

OXAZOLIDIN-2-ONES ISOCYANATES AND EPOXIDES MgI2
3655
At the onset of this work, we investigated various reaction conditions with
the model reaction of phenyl isocyanate with epichlorohydrin promoted by freshly
prepared MgI2 etherate (1.0 M in Et2O=Benzene 1:2).[9b] The results are summarized
in Table 1.
We studied the effect of amounts of MgI2 etherate on the reaction yields. It
has been found that only diphenyl urea was given when using less than 5 mol% of
MgI2 etherate (Table 1, ntry 1). When using less than 25 mol% of MgI2 etherate,
the reaction gave low yield of desired product (Table 1, entries 2–5). By increasing
the amount of MgI2 etherate, the yield of cycloadduct was obviously improved. The
reaction gave the desired product in 92% yield in the presence of 50 mol% of
MgI2 etherate (Table 1, entry 7). However, no increased yield was found in the
presence of 100 mol% of MgI2 etherate. Furthermore, the cycloaddition of a
variety of isocyanates with epichlorohydrin has been investigated (Table 1, entries
8–11) and proceeded smoothly at 65 ꢀC to provide the desired products in good
yields. The cycloaddition of propylene oxide with isocyanates also provided the
Table 1. The cycloaddition of isocyanates with epoxides promoted by MgX2 etheratea
Time (h) Product Yield (%)c
b
Entry
Ar
R
MgX2 Amounts of MgX2
1
2
C6H5
C6H5
C6H5
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH3
MgI2
MgI2
MgI2
MgI2
MgI2
MgI2
MgI2
MgI2
MgI2
MgI2
MgI2
MgI2
MgI2
MgI2
MgI2
MgBr2
MgBr2
MgBr2
MgBr2
<5
10
15
20
25
30
50
50
50
50
50
50
50
50
50
50
50
50
50
8
10
10
10
3
N.Ad
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
N.A
18
32
42
51
71
92
82
85
79
68
82
78
91
70
78
67
73
66
3
4
C6H5
C6H5
5
6
C6H5
C6H5
3
7
2
8
2-Me-5-ClC6H3
2-MeC6H4
4-ClC6H4
4-NO2C6H4
4-ClC6H4
2,3-Me2C6H3
C6H5
5
9
4
10
11
12
13
14
15
16
17
18
19
3
4
1
CH3
2
1g
1h
1i
CH2OPh
CH2OPh
CH2Cl
CH2Cl
CH2Cl
CH2Cl
4
4-ClC6H4
C6H5
5
5
1a
1b
1c
1d
2-Me-5-ClC6H3
2-MeC6H4
4-ClC6H4
6
7
8
aThe reaction was carried out by the addition of aryl isocyanate (5 mmol) to the mixture of epoxide
(6 mmol) and MgX2 etherate in refluxing THF.
bRelative to aryl isocyanate.
cIsolated yield by silica gel flash chromatography.
dNot available.

3656
X. ZHANG ET AL.
Scheme 1. Plausible mechanism for the cycloaddition of isocyanate with epoxide.
desired products in high yield (Table 1, entries 12 and 13). Moreover, the cycload-
dition of 2-phenoxymethyl oxirane with phenyl isocyanates underwent effectively
in the presence of MgI2 etherate (Table 1, entry 14) to give the desired product
in 91% yield. To examine the halide anion effect, halogen analogs of MgI2 ethe-
rate, MgBr2 etherate and MgCl2 etherate were compared under parallel reaction
conditions (50 mol % of catalyst) in the reaction of phenyl isocyanate with epi-
chlorohydrin, respectively. MgCl2 etherate is almost inactive and MgBr2 etherate
is less effective in terms of substrate conversion and yield. Moreover, the cycload-
dition of various isocyanates with epichlorohydrin was further studied in the pres-
ence of MgBr2 etherate (Table 1, entries 16–19). The lower yield of the parent
cycloaddition promoted by MgBr2 etherate was obtained under the same con-
dition. Apparently, the unique reactivity of MgI2 etherate is attributed to the dis-
sociative character of iodide counterion and a more Lewis acidic cationic [MgI]þ
species as a result of Lewis base activation of Lewis acid.[10] A plausible mech-
anism of this reaction is proposed in Scheme 1. All the compounds were character-
ized by 1H NMR spectra, FT-IR spectra and by comparison with known
compounds.
In conclusion, we have firstly demonstrated that the unique reactivity of MgI2
etherate in the cycloaddition of isocyanates with epoxides. This catalytic system is
advantagenous in that they are mild, give high yield of products, and are operation-
ally convenient. The details of this reaction and its extension to the cycloaddition of
epoxides with other heterocumulenes are now under investigation.
EXPERIMENTAL
For product purification by flash column chromatography, silica gel (200ꢁ300
1
mesh) and light petroleum ether (PE, b.p. 60ꢁ90 ꢀC) were used. H NMR spectra
were taken on a Bruker Avance-500 spectrometer with TMS as an internal standard
and CDCl3 as solvent. FT-IR was recorded on a Bruker Tensor 27 spectrometer.
Melting points were measured on BUCHI B-540 and uncorrected.

OXAZOLIDIN-2-ONES ISOCYANATES AND EPOXIDES MgI2
3657
The Representative Procedure for the Synthesis of Oxazolidin-2-ones
To a stirred solution of freshly prepared MgI2 etherate (2.5 mmol) in
THF (10 mL) was added dropwise epichlorohydrin (552 mg, 6 mmol) followed by
cycloaddition of phenyl isocyanate (595 mg, 5 mmol) at room temperature. After
addition, the reaction mixture was allowed to warm to 65 ꢀC and continued to be
stirred for 2 hours. The resulting homogeneous reaction mixture was quenched
with saturated Na2SO3 aqueous solution. Extractive workup with CH2Cl2 and
flash chromatographic purification of the crude product on silica gel gave the
5-chloromethyl-3-phenyloxazolidin-2-one 1a (970 mg) in 92% yield.
Spectroscopic Data for Selected Products (Table 1)
Compound 1a. Mp 104.3–105.4 (lit.[5] 103 ꢀC). tmax (KBr)=cmꢂ1 ¼ 1739
(C O). 1H NMR (500 MHz, CDCl3) d 3.73–3.81 (m, 2H), 3.96 (dd, J ¼ 6.0,
=
9.0 Hz, 1H), 4.17 (t, J ¼ 9.0 Hz, 1H), 4.85–4.88 (m, 1H), 7.14–7.18 (m, 1H),
7.37–7.40 (m, 2H), 7.54 (dd, J ¼ 1.0, 8.5 Hz, 2H).
1
Compound 1b. Mp 76.7–77.9 ꢀC. tmax (KBr)=cmꢂ1 ¼ 1748 (C O). H NMR
=
(500 MHz, CDCl3) d 2.25 (s, 3H), 3.72 (dd, J ¼ 3.5, 12.0 Hz, 1H), 3.77 (dd, J ¼ 6.0,
9.0 Hz, 1H), 3.82 (dd, J ¼ 5.0, 12.0 Hz, 1H), 4.00 (t, J ¼ 9.0 Hz, 1H), 4.89–4.94 (m,
1H), 7.19 (dd, J ¼ 8.5, 9.5 Hz, 2H), 7.23 (s, 1H). 13C NMR (125 MHz; CDCl3): d
17.4, 45.0, 50.0, 71.7, 126.6, 128.4, 131.8, 132.4, 134.6, 136.5, 155.1. M=z: (relative
intensity): 259 (12) [M]þ, 224 (35), 180 (78), 145 (55), 117 (100), 77 (10). Found
(HRMS): m=z 259.0187 (C11H11Cl2NO2), Calc. 259.0167.
1
Compound 1c. Mp 56.8–57.8 ꢀC. tmax (KBr)=cmꢂ1 ¼ 1731 (C O). H NMR
=
(500 MHz, CDCl3) d 2.32 (s, 3H), 3.77 (dd, J ¼ 3.5, 11.5 Hz, 1H), 3.81–3.86 (m, 2H),
4.06 (t, J ¼ 9.0 Hz, 1H), 4.89–4.94 (m, 1H), 7.22–7.29 (m, 4H). 13C NMR (125 MHz,
CDCl3): d 17.7, 45.1, 50.2, 71.6, 126.6, 126.9, 128.3, 131.3, 135.5, 135.9, 155.4. M=z:
(relative intensity): 227 (20) [M þ 2]þ, 225 (62) [M]þ, 190 (88), 146 (100), 118 (96).
Found (HRMS): m=z 225.0562 (C11H12ClNO2), Calc. 225.0557.
1
Compound 1d.[11] Mp. 131.8–132.5 ꢀC. tmax (KBr)=cmꢂ1 ¼ 1743 (C O). H
=
NMR (500 MHz, CDCl3) d 3.74–3.81 (m, 2H), 3.94 (dd, J ¼ 6.0, 9.0 Hz, 1H), 4.15 (t,
J ¼ 9.0 Hz, 1H), 4.86–4.91 (m, 1H), 7.33–7.36 (m, 2H), 7.48–7.51 (m, 2H).
1
Compound 1e.[12] Mp. 150.4–152.4 ꢀC. tmax (KBr)=cmꢂ1 ¼ 1759 (C O). H
=
NMR (500 MHz, CDCl3) d 3.82–3.84 (m, 2H), 4.05 (dd, J ¼ 6.0, 9.0 Hz, 1H), 4.26
(t, J ¼ 9.0 Hz, 1H), 4.96–5.01 (m, 1H), 7.75 (dd, J ¼ 2.0, 7.0 Hz, 2H), 8.28 (dd,
J ¼ 2.0, 7.0 Hz, 2H).
Compound 1f.[11] Mp. 104.5–106.3 ꢀC. tmax (KBr)=cmꢂ1 ¼ 1741 (C O). H
1
=
NMR (500 MHz, CDCl3) d 1.54 (d, J ¼ 6.5 Hz, 3H), 3.60 (dd, J ¼ 7.5, 8.5 Hz, 1H),
4.09 (t, J ¼ 8.5 Hz, 1H), 4.77–4.82 (m, 1H), 7.32 (dd, J ¼ 2.0, 7.0 Hz, 2H), 7.48 (dd,
J ¼ 2.0, 7.0 Hz, 2H).
Compound 1g. Mp 70.9–71.9 ꢀC. tmax (KBr)=cmꢂ1 ¼ 1739 cmꢂ1 (C O). H
1
=
NMR (500 MHz, CDCl3) d 1.54 (d, J ¼ 6.5 Hz, 3H), 2.19 (s, 3H), 2.30 (s, 3H),
3.49 (dd, J ¼ 7.0, 9.0 Hz, 1H), 3.98 (t, J ¼ 8.0 Hz, 1H), 4.81–4.85 (m, 1H),

3658
X. ZHANG ET AL.
7.07–7.09 (m, 1H), 7.12–7.14 (m, 2H). 13C NMR (125 MHz; CDCl3): d 14.0, 20.2,
20.6, 54.7, 70.4, 123.9, 126.2, 129.5, 134.4, 135.9, 138.4, 156.5. M=z: (relative inten-
sity): 205 (55) [M]þ, 176 (28), 161 (22), 132 (100), 117 (57), 77 (18). Found (HRMS):
m=z 205.1107 (C12H15NO2), Calc. 205.1103.
1
Compound 1h.[5] Mp. 139.0–139.7 ꢀC. tmax (KBr)=cmꢂ1 ¼ 1739 (C O). H
=
NMR (500 MHz, CDCl3) d 4.08 (dd, J ¼ 6.0, 9.0 Hz, 1H), 4.19–4.25 (m, 3H),
4.97–5.01 (m, 1H), 6.91–6.92 (m, 2H), 7.00 (t, J ¼ 7.5 Hz, 1H), 7.16 (t, J ¼ 7.5 Hz,
1H), 7.29–7.32 (m, 2H), 7.38–7.41 (m, 2H), 7.57–7.59 (m, 2H).
1
Compound 1i.[13] Mp. 158.6–159.6 ꢀC. tmax (KBr)=cmꢂ1 ¼ 1737 (C O). H
=
NMR (500 MHz, CDCl3) d 4.05 (dd, J ¼ 6.0, 9.0 Hz, 1H), 4.17 (t, J ¼ 9.0 Hz, 1H),
4.22 (d, J ¼ 5.0 Hz, 2H), 4.96–5.01 (m, 1H), 6.89–6.91 (m, 2H), 7.00 (t, J ¼ 7.5 Hz,
1H), 7.28–7.32 (m, 2H), 7.33–7.36 (m, 2H), 7.51–7.54 (m, 2H).
ACKNOWLEDGMENTS
This work was supported by Zhejiang Province Natural Science Foundation of
China (Project Y4100692) and Zhejiang Province Undergraduate Innovative
Program.
REFERENCES
1. (a) Park, C.-H.; Brittelli, D. R.; Wang, C. L.-J.; Marsh, F. D.; Gregory, W. A.; Wuonola,
M. A.; McRipley, R. J.; Eberly, V. S.; Slee, A. M.; Forbes, M. Antibacterials synthesis
and structure-activity studies of 3-aryl-2-oxooxazolidines. 4. multiply-substituted aryl
derivatives. J. Med. Chem. 1992, 35, 1156; (b) Brickner, S. J.; Hutchinson, D. K.;
Barbachyn, M. R.; Manninen, P. R.; Ulanowicz, D. A.; Garmon, S. A.; Grega, K. C.;
Hendges, S. K.; Toops, D. S.; Ford, C. W.; Zurenko, G. E. Synthesis and antibacterial
activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the
potential treatment of multidrug-resistant gram-positive bacterial infections. J. Med.
Chem. 1996, 39, 673; (c) Selvakumar, N.; Srinivas, D.; Khera, M. K.; Kumar, M. S.;
Mamigi, R. N. V. S.; Sarnaik, H.; Charavaryamath, C.; Rao, B. S.; Raheem, M. A.;
Das, J.; Iqbal, J.; Rajagopalan, R. Synthesis of conformationally constrained analogues
of Linezolid: Structure-activity relationship (SAR) studies on selected novel tricyclic
oxazolidinones. J. Med. Chem. 2002, 45, 3953; (d) Barbachyn, M. R.; Ford, C. W.
Oxazolidinone structure-activity relationships leading to linezolid. Angew. Chem., Int.
Ed. 2003, 42, 2010.
2. Speranza, G. P.; Peppel, W. J. Preparation of substituted 2-oxazolidones from 1,2-
epoxides and isocyanates. J. Org. Chem. 1958, 23, 1922.
3. Herweh, J. E.; Kauffman, W. J. 2-Oxazolidones via the lithium bromide catalyzed
reaction of isocyanates with epoxides in hydrocarbon solvents. Tetrahedron Lett. 1971,
12, 809.
4. Herweh, J. E.; Foglia, T. A.; Swern, D. Synthesis and nuclear magnetic resonance spectra
of 2-oxazolidones. J. Org. Chem. 1968, 33, 4029.
5. Shibata, I.; Baba, A.; Iwasaki, H.; Matsuda, H. Cycloaddition reaction of heterocumu-
lenes with oxiranes catalyzed by organotin iodide-Lewis base complex. J. Org. Chem.
1986, 51, 2177.

OXAZOLIDIN-2-ONES ISOCYANATES AND EPOXIDES MgI2
3659
6. Fujiwara, M.; Baba, A.; Tomohisa, Y.; Matsuda, H. Cycloaddition reaction of 2,3-
disubstituted oxiranes with isocyanates by highly activated catalyst; Ph4SbI–Bu3SnI.
Chem. Lett. 1986, 1963.
7. Qian, C.-T.; Zhu, D.-M. A facile synthesis of oxazolidinones via lanthanide – catalyzed
cycloaddition of epoxides with isocyanates. Synlett. 1994, 129.
8. Zhang, X.-X.; Li, W.-D. The synthetic applications of Lewis acidic Mg(II). Chinese J.
Org. Chem. 2003, 23, 1185.
9. (a) Zhang, X.-X. Mild and efficient allylation of aldehydes with allyltributylstannane
promoted by MgI2 etherate. Synlett. 2008, 1, 65–68; (b) Li, W.-D.; Zhang, X.-X.
Chemoselective aldol reaction of silyl enolates catalyzed by MgI2 etherate. Org. Lett.
2002, 4, 3485.
10. (a) Denmark, S. E.; Stavenger, R. A. Asymmetric catalysis of aldol reactions with
chiral Lewis bases. Acc. Chem. Res. 2000, 33, 432; (b) Denmark, S. E.; Wynn, T. Lewis
base activation of Lewis acids: Catalytic enantioselective allylation and propargylation
of aldehydes. J. Am. Chem. Soc. 2001, 123, 6199.
11. Wu, H.-Y.; Ding, J.-C.; Liu, Y.-K. Samarium triiodide catalyzed cycloaddition of
epoxides with isocyanates: A facile synthesis of oxazolidinones. J. Indian Chem. Soc.
2003, 80(1), 36.
12. Zofia, L.-Z.; Tadeusz, U. Novel methods of preparation of 2-oxazolidones. Org. Prep.
Proc. Inter. 1971, 3(1), 1–4.
13. Idris, J. J. The reaction of carbonyl chloride with 1,2-epoxides. J. Chem. Soc. 1957, 2735.