An approach to synthesis of 3-Aryl-2-oxazolidinones and in situ 'click' assembly of 1,2,3-triazole oxazolidinones

Article abstract of DOI:10.2174/157017810791112414

A facile and efficient addition of isocyanates with epoxides in the presence of MgI₂ etherate was reported in good yields. The corresponding 2-oxazolidinone could be easily converted into 1,2,3-triazole-oxazolidinone by click reaction in excell

Full text of DOI:10.2174/157017810791112414

226
Letters in Organic Chemistry, 2010, 7, 226-228
An Approach to Synthesis of 3-Aryl-2-Oxazolidinones and In Situ ‘Click’
Assembly of 1,2,3-Triazole Oxazolidinones
Xingxian Zhang*, Cheng Li, Wei Chen and Xiang Wu
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, P. R. China
Received July 09, 2009: Revised December 30, 2009: Accepted January 10, 2010
Abstract: A facile and efficient addition of isocyanates with epoxides in the presence of MgI2 etherate was reported in
good yields. The corresponding 2-oxazolidinone could be easily converted into 1,2,3-triazole-oxazolidinone by click
reaction in excellent yield.
Keywords: Isocyanate, epoxide, oxazolidinone, MgI2 etherate, click reaction.
INTRODUCTION
RESULTS AND DISCUSSION
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 addition of
isocyanates with epoxides is one of the most useful and
efficient method for preparation of 2-oxazolidinones. A
variety of catalysts have been investigated, such as
quaternary ammonium salts [2], LiBr/n-Bu3PO or
LiBr/HMPA [3], LiCl/DMF [4], Lewis bases [5], Lewis
acids [6], n-Bu3SnI-Ph3PO [7], n-Bu3SnI-Ph4SbI [8] and
lanthanide chlorides [9]. 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,
environmentally benign, and easily handled promoters for
the addition 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 in the various organic reactions [10]. In our previous
paper [11], we have demonstrated that MgI2 etherate could
efficiently catalyze Mukaiyama-type aldol of aldehydes with
trimethylsilyl enolates and allylation of aldehydes with
allylstannane. Herein we will report an efficient and highly
regioselective addition of aryl isocyanates with epoxides
promoted by MgI2 etherate under mild reaction condition
(Scheme 1).
The initial reaction was carried out using phenyl
isocyanate with epichlorohydrin promoted by 50 mol% of
freshly prepared MgI2 etherate in THF. After stirring at 65
°C for 2.0 h, the desired cycloadduct was afforded in 92%
yield. Furthermore, addition of various aryl isocyanates with
epoxides has been examined. The results are summarized in
Table 1. As shown in Table 1, the reaction of various aryl
isocyanates with epichlorohydrin proceeded smoothly and
provided the desired products in good yields (Table 1. entries
1-5). The addition of aryl isocyanates and propylene oxide
also provided the desired products in high yield (Table 1.
entries 6 and 7). Moreover, the addition of 2-phenoxymethyl
oxirane with phenyl isocyanate or 4-methylphenyl
isocyanate underwent effectively in the presence of MgI2
etherate (Table 1. entries 8 and 9) to give the desired product
in 91% and 94% yield, respectively. To examine the halide
anion effect, halogen analogs of MgI2 etherate, MgBr2
etherate and MgCl2 etherate were compared under parallel
reaction conditions (50 mol % of catalyst) in the reaction of
various aryl isocyanates with epichlorohydrin (Table 1.
entries 10-13). MgCl2 etherate is almost inactive and MgBr2
etherate provided the lower yield under the same condition.
Apparently, the unique reactivity of MgI2 etherate is
attributed to the dissociative character of iodide counterion
and a more Lewis acidic cationic [MgI]+ species as a result
of Lewis baseactivation of Lewis acid [12].
The further application of these readily prepared 2-
oxazolidinones, the structural modification of 2-
oxazolidinones was investigated. The oxazolidinones 1a
reacted with 1, 2, 4-triazole and benzotriazole with the
treatment of KOH in DMF to give the product in 73% and
65% yield based on the recovery of substrate 1a, respectively
[13] (Scheme 2).
O
O
MgI2 (OEt2)n
Ar
N
C
O
+
Ar
N
O
R
THF
Among the known isosteres for an amide group, 1,2,3-
triazoles have recently gained increasing attention in drug
discovery since the introduction of the concept of “click”
chemistry by Sharpless [14, 15]. 1,2,3-triazoles serve as rigid
linking units that can mimic the topological and electronic
features of an amide bond. However, unlike amides, triazoles
are extremely stable to hydrolysis and oxidative/reductive
R
1a-1i
Scheme 1. MgI2•(OEt2)n-promoted addition of aryl isocyanates
with epoxides.
*Address correspondence to this author at the College of Pharmaceutical
Sciences, Zhejiang University of Technology, Hangzhou, 310032, P. R.
China; Fax: 86-(0)571-88320320; E-mail: zhangxx@zjut.edu.cn
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

An Approach to Synthesis of 3-Aryl-2-Oxazolidinones
Letters in Organic Chemistry, 2010, Vol. 7, No. 3
227
Table 1. The Addition of Isocyanates with Epoxides Promoted by MgX2 Etherate
a
Entry
Ar
R
MgX2
Time (h)
Productb
Yield(%)c
Refs.
1
2
C6H5
2,3-Me2C6H3
3,4,5-F3C6H2
4-ClC6H4
4-BrC6H4
4-ClC6H4
2-Me-5-ClC6H3
C6H5
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH3
MgI2
MgI2
2
4
2
3
4
1
2
4
1
5
6
8
5
1a
1b
1c
1d
1e
1f
92
90
83
79
78
82
78
91
94
78
67
66
68
[7]
[13]
[13]
[16]
[13]
[16]
[13]
[7]
3
MgI2
4
MgI2
5
MgI2
6
MgI2
7
CH3
MgI2
1g
1h
1i
8
CH2OPh
CH2OPh
CH2Cl
CH2Cl
CH2Cl
CH2Cl
MgI2
9
4-MeC6H4
C6H5
MgI2
[13]
[7]
10
11
12
13
MgBr2
MgBr2
MgBr2
MgBr2
1a
1b
1d
1e
2,3-Me2C6H3
4-ClC6H4
4-BrC6H4
[13]
[16]
[13]
a50 mol% of MgX2 etherate was used respectively.
bAll products were identified by their 1H NMR and IR spectra.
cYields of products isolated by flash column chromatography.
N
O
N
HN
N
O
KOH, n-Bu4NBr, DMF
73%
O
N
N
N
2
N
O
H
N
O
Cl
N
N
1a
N
O
N
N
KOH, n-Bu4NBr, DMF
65%
N
3
Scheme 2. Preparation of 5-triazole-oxazolidinone.
conditions. In our preliminary experiments, we succeded to
fulfill the conversion of oxazolidinone 1 to the triazole-
oxazolidinone 5 by click reaction in 85-88% yield over the
two steps (Scheme 3), which provided a facile and effective
route to acquire the novel triazole-oxazolidinone derivatives.
In conclusion, we have firstly demonstrated that the
unique reactivity of MgI2 etherate in the addition of
isocyanates with epoxides. This catalytic system is
advantagenous in that they are mild, give high yield of
products, and are operationally convenient. A click reaction
Ph
5H2O(10 mol%)
O
O
O
CuSO4
NaN3
ascorbic acid(10 mol%)
N
O
N
O
N
O
DMF
90%
N
1:1 MeOH-H2O
95-98%
Cl
N
N3
N
R
R
R
1
4
5
Ph
5a R = H
5b R = 3,4,5-F3
5c R = 2,3-Me2
Scheme 3. Synthesis of 1,2,3-triazole-oxazolidinone by click reaction.

228 Letters in Organic Chemistry, 2010, Vol. 7, No. 3
Zhang et al.
[6]
[7]
[8]
[9]
Braun, D.; Weinert, J. Reaction of epoxides with isocyanates, II.
Preparation and characterization of 2-oxazolidinones. Liebigs Ann.
1979, 200.
protocol demonstrated a convenient approach toward a
library of active 1,2,3-triazole-oxazolidinone derivatives in
the search for future therapeutic antibiotics.
Shibata, I., Baba, A.; Iwasaki, H.; Matsuda, H. Cycloaddition
reaction of heterocumulenes with oxiranes catalyzed by organotin
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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.
Qian, C. -T.; Zhu, D. -M. A facile synthesis of Oxazolidinones via
Lanthanide –catalyzed cycloaddition of epoxides with isocyanates.
Synlett, 1994, 129.
GENERAL EXPERIMENTAL PROCEDURE
General
For
product
purification
by
flash
column
chromatography, silica gel (200~300 mesh) and light
o
1
[10]
[11]
Zhang. X. -X.; Li, W. -D. The synthetic applications of Lewis
acidic Mg(ꢀ). Chin. J. Org. Chem., 2003, 23, 1185.
petroleum ether (PE, b.p. 60~90 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.
(a) Zhang, X, -X. MgI2 Etherate-promoted allylation of aldehydes:
simple and efficient synthesis of homoallylic alcohols Lett. Org.
Chem. 2007, 4, 246. (b) Li, W. -D.; Zhang. X. -X. Chemoselective
aldol reaction of silyl enolates catalyzed by MgI2 etherate. Org.
Lett. 2002, 4, 3485.
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reactions with chiral Lewis bases. Acc. Chem. Res. 2000, 33, 432.
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[12]
[13]
The Representative Procedure for the Synthesis of 2-
oxazolidinones
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 addition 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 2-oxazolidinone 1a (970 mg) in 92%
yield.
Spectroscopic Data for Selected Products (Table 1): compound
1b: Mp. 97.5-98.5 °C; IR (KBr) 1735 cm-1 (C=O); 1H NMR
(CDCl3) ꢁ 2.19 (s, 3H), 2.30 (s, 3H), 3.75-3.82 (m, 1H), 3.83 (dd, J
= 2.0, 6.0 Hz , 2H), 4.03 (t, J = 9.0 Hz, 1H), 4.89-4.94 (m, 1H),
7.09 (dd, J = 2.5, 6.5 Hz , 1H), 7.12-7.16 (m, 2H) ppm. compound
1c: Mp 73.0-73.8 °C; IR (KBr) 1736 cm-1 (C=O); 1H NMR (CDCl3)
ꢁ 3.77-3.85 (m, 2H), 3.94 (dd, J = 5.0, 9.5 Hz , 1H), 4.17-4.21 (m,
1H), 4.93-4.98 (m, 1H), 7.00-7.06 (m, 1H), 7.27-7.31 (m,1H) ppm;
EI-MS: 265 ([M]+, 22), 267 ([M+2]+, 8),186 (100), 166(31), 158
(63). compound 1e: Mp 125.0-127.2 °C; IR (KBr) 1738 cm-1
1
(C=O); H NMR (CDCl3) ꢁ 3.74-3.80 (m, 2H), 3.91 (dd, J = 6.0,
9.0 Hz, 1H), 4.13 (t, J = 9.0 Hz, 1H), 4.85-4.90 (m, 1H), 7.41-7.44
(m, 2H), 7.46-7.49 (m, 2H) ppm. compound 1g: Mp 43.4-44.0 °C;
IR (KBr) 1748 cm-1 (C=O); 1H NMR (CDCl3) ꢁ 1.54 (d, J = 6.5Hz,
3H), 2.26 (s, 3H), 3.50 (dd, J = 6.5, 8.5 Hz, 1H), 3.98 (t, J = 8.0
Hz, 1H), 4.80-4.86 (m, 1H), 7.20-7.22 (m, 3H)ppm. compound 1i:
ACKNOWLEDGEMENTS
1
Mp 126.5-127.5 °C; IR (KBr) 1745 cm-1 (C=O); H NMR (CDCl3)
This work was supported by Zhejiang University of
Technology Younger Scholars Program and Zhejiang
Provincial Undergraduate Innovative Experimental Program.
ꢁ 2.33 (s, 3H), 4.03 (dd, J = 6.0, 9.0 Hz , 1H), 4.14-4.23 (m, 3H),
4.95 (dd, J = 4.5, 9.0 Hz , 1H), 6.90 (d, J = 8.0 Hz , 2H), 6.99 (t, J
= 7.5 Hz , 1H), 7.18 (d, J = 8.5 Hz , 2H), 7.29 (dd, J = 7.5, 8.0 Hz ,
2H), 7.44 (d, J = 8.5 Hz , 2H) ppm. compound 2: Mp 115.4-115.7
1
°C; IR (KBr) 1740 cm-1 (C=O); H NMR (CDCl3) ꢁ 4.01 (dd, J =
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