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A Facile and Efficient Synthesis of 3Aryloxazolidin-2-ones from Isocyanates and Epoxides Promoted by MgI2 Etherate
Xingxian Zhang , Wei Chen , Chengfeng Zhao , Cheng Li , Xiang Wu & Wei Z. Chen
a a a a a a a

College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang, P. R. China Available 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, 40:24, 3654-3659 To link to this article: http://dx.doi.org/10.1080/00397910903470525

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Synthetic Communications1, 40: 36543659, 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

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We described a mild and efcient 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 efcient 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-Ph4SbI[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 difcult 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 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 efciently catalyze Mukaiyama-type aldol of aldehydes with trimethylsilyl 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, efcient 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

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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 25). 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 811) 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

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Ar C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 C6H5 2-Me-5-ClC6H3 2-MeC6H4 4-ClC6H4 4-NO2C6H4 4-ClC6H4 2,3-Me2C6H3 C6H5 4-ClC6H4 C6H5 2-Me-5-ClC6H3 2-MeC6H4 4-ClC6H4

R CH2Cl CH2Cl CH2Cl CH2Cl CH2Cl CH2Cl CH2Cl CH2Cl CH2Cl CH2Cl CH2Cl CH3 CH3 CH2OPh CH2OPh CH2Cl CH2Cl CH2Cl CH2Cl

MgX2 MgI2 MgI2 MgI2 MgI2 MgI2 MgI2 MgI2 MgI2 MgI2 MgI2 MgI2 MgI2 MgI2 MgI2 MgI2 MgBr2 MgBr2 MgBr2 MgBr2

Amounts of MgX2b <5 10 15 20 25 30 50 50 50 50 50 50 50 50 50 50 50 50 50

Time (h) 8 10 10 10 3 3 2 5 4 3 4 1 2 4 5 5 6 7 8

Product N.Ad 1a 1a 1a 1a 1a 1a 1b 1c 1d 1e 1f 1g 1h 1i 1a 1b 1c 1d

Yield (%)c N.A 18 32 42 51 71 92 82 85 79 68 82 78 91 70 78 67 73 66

a The reaction was carried out by the addition of aryl isocyanate (5 mmol) to the mixture of epoxide (6 mmol) and MgX2 etherate in reuxing THF. b Relative to aryl isocyanate. c Isolated yield by silica gel ash chromatography. d Not available.

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Scheme 1. Plausible mechanism for the cycloaddition of isocyanate with epoxide.

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desired products in high yield (Table 1, entries 12 and 13). Moreover, the cycloaddition 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 etherate, MgBr2 etherate and MgCl2 etherate were compared under parallel reaction conditions (50 mol % of catalyst) in the reaction of phenyl isocyanate with epichlorohydrin, respectively. MgCl2 etherate is almost inactive and MgBr2 etherate is less effective in terms of substrate conversion and yield. Moreover, the cycloaddition of various isocyanates with epichlorohydrin was further studied in the presence of MgBr2 etherate (Table 1, entries 1619). The lower yield of the parent cycloaddition promoted by MgBr2 etherate was obtained 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 base activation of Lewis acid.[10] A plausible mechanism of this reaction is proposed in Scheme 1. All the compounds were characterized by 1H NMR spectra, FT-IR spectra and by comparison with known compounds. In conclusion, we have rstly 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 operationally convenient. The details of this reaction and its extension to the cycloaddition of epoxides with other heterocumulenes are now under investigation.

EXPERIMENTAL For product purication by ash column chromatography, silica gel (200$300 mesh) and light petroleum ether (PE, b.p. 60$90  C) were used. 1H 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.

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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 ash chromatographic purication 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 104.3105.4 (lit.[5] 103  C). tmax (KBr)=cm1 1739 (C=O). 1H NMR (500 MHz, CDCl3) d 3.733.81 (m, 2H), 3.96 (dd, J 6.0, 9.0 Hz, 1H), 4.17 (t, J 9.0 Hz, 1H), 4.854.88 (m, 1H), 7.147.18 (m, 1H), 7.377.40 (m, 2H), 7.54 (dd, J 1.0, 8.5 Hz, 2H). Compound 1b. Mp 76.777.9  C. tmax (KBr)=cm1 1748 (C=O). 1H NMR (500 MHz, CDCl3) d 2.25 (s, 3H), 3.72 (dd, J 3.5, 12.0 Hz, 1H), 3.77 (dd, J 6.0, 9.0 Hz, 1H), 3.82 (dd, J 5.0, 12.0 Hz, 1H), 4.00 (t, J 9.0 Hz, 1H), 4.894.94 (m, 1H), 7.19 (dd, J 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], 224 (35), 180 (78), 145 (55), 117 (100), 77 (10). Found (HRMS): m=z 259.0187 (C11H11Cl2NO2), Calc. 259.0167. Compound 1c. Mp 56.857.8  C. tmax (KBr)=cm1 1731 (C=O). 1H NMR (500 MHz, CDCl3) d 2.32 (s, 3H), 3.77 (dd, J 3.5, 11.5 Hz, 1H), 3.813.86 (m, 2H), 4.06 (t, J 9.0 Hz, 1H), 4.894.94 (m, 1H), 7.227.29 (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 2], 225 (62) [M], 190 (88), 146 (100), 118 (96). Found (HRMS): m=z 225.0562 (C11H12ClNO2), Calc. 225.0557. Compound 1d.[11] Mp. 131.8132.5  C. tmax (KBr)=cm1 1743 (C=O). 1H NMR (500 MHz, CDCl3) d 3.743.81 (m, 2H), 3.94 (dd, J 6.0, 9.0 Hz, 1H), 4.15 (t, J 9.0 Hz, 1H), 4.864.91 (m, 1H), 7.337.36 (m, 2H), 7.487.51 (m, 2H). Compound 1e.[12] Mp. 150.4152.4  C. tmax (KBr)=cm1 1759 (C=O). 1H NMR (500 MHz, CDCl3) d 3.823.84 (m, 2H), 4.05 (dd, J 6.0, 9.0 Hz, 1H), 4.26 (t, J 9.0 Hz, 1H), 4.965.01 (m, 1H), 7.75 (dd, J 2.0, 7.0 Hz, 2H), 8.28 (dd, J 2.0, 7.0 Hz, 2H). Compound 1f.[11] Mp. 104.5106.3  C. tmax (KBr)=cm1 1741 (C=O). 1H NMR (500 MHz, CDCl3) d 1.54 (d, J 6.5 Hz, 3H), 3.60 (dd, J 7.5, 8.5 Hz, 1H), 4.09 (t, J 8.5 Hz, 1H), 4.774.82 (m, 1H), 7.32 (dd, J 2.0, 7.0 Hz, 2H), 7.48 (dd, J 2.0, 7.0 Hz, 2H). Compound 1g. Mp 70.971.9  C. tmax (KBr)=cm1 1739 cm1 (C=O). 1H NMR (500 MHz, CDCl3) d 1.54 (d, J 6.5 Hz, 3H), 2.19 (s, 3H), 2.30 (s, 3H), 3.49 (dd, J 7.0, 9.0 Hz, 1H), 3.98 (t, J 8.0 Hz, 1H), 4.814.85 (m, 1H),

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7.077.09 (m, 1H), 7.127.14 (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 intensity): 205 (55) [M], 176 (28), 161 (22), 132 (100), 117 (57), 77 (18). Found (HRMS): m=z 205.1107 (C12H15NO2), Calc. 205.1103. Compound 1h.[5] Mp. 139.0139.7  C. tmax (KBr)=cm1 1739 (C=O). 1H NMR (500 MHz, CDCl3) d 4.08 (dd, J 6.0, 9.0 Hz, 1H), 4.194.25 (m, 3H), 4.975.01 (m, 1H), 6.916.92 (m, 2H), 7.00 (t, J 7.5 Hz, 1H), 7.16 (t, J 7.5 Hz, 1H), 7.297.32 (m, 2H), 7.387.41 (m, 2H), 7.577.59 (m, 2H). Compound 1i.[13] Mp. 158.6159.6  C. tmax (KBr)=cm1 1737 (C=O). 1H NMR (500 MHz, CDCl3) d 4.05 (dd, J 6.0, 9.0 Hz, 1H), 4.17 (t, J 9.0 Hz, 1H), 4.22 (d, J 5.0 Hz, 2H), 4.965.01 (m, 1H), 6.896.91 (m, 2H), 7.00 (t, J 7.5 Hz, 1H), 7.287.32 (m, 2H), 7.337.36 (m, 2H), 7.517.54 (m, 2H).

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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 1,2epoxides 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 heterocumulenes with oxiranes catalyzed by organotin iodide-Lewis base complex. J. Org. Chem. 1986, 51, 2177.

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Downloaded by [210.212.206.4] at 21:41 18 July 2011

6. Fujiwara, M.; Baba, A.; Tomohisa, Y.; Matsuda, H. Cycloaddition reaction of 2,3disubstituted oxiranes with isocyanates by highly activated catalyst; Ph4SbIBu3SnI. 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 efcient allylation of aldehydes with allyltributylstannane promoted by MgI2 etherate. Synlett. 2008, 1, 6568; (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. Zoa, L.-Z.; Tadeusz, U. Novel methods of preparation of 2-oxazolidones. Org. Prep. Proc. Inter. 1971, 3(1), 14. 13. Idris, J. J. The reaction of carbonyl chloride with 1,2-epoxides. J. Chem. Soc. 1957, 2735.