ORGANIC
LETTERS
2010
Vol. 12, No. 18
4102-4105
Facile Formation of N-Acyl-oxazolidinone
Derivatives Using Acid Fluorides
Corinna S. Schindler, Patrik M. Forster, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Zu¨rich, Wolfgang-Pauli-Strasse 10,
8093 Zu¨rich, Switzerland
Received July 21, 2010
ABSTRACT
i
A mild method is presented for the formation of N-acylated oxazolidinones that employs acid fluorides and mild bases, such as Pr2NEt and
NEt3. Optimized reaction conditions for two types of substrates have been developed utilizing either the oxazolidinone itself or the corresponding
in situ generated O-silyloxazolidinones resulting in the formation of the desired N-acylated products in high yields of up to 98%.
As a class of compounds, oxazolidinones have shown a wide
range of biological activity, including antidepressant, antihis-
taminic, antifungal, antihypertensive, and antibacterial activity.1
The inhibition of bacterial protein biosynthesis by substituted
oxazolidinones was first discovered at E.I. DuPont de Nemours
and Co. in 1983 and represented the only new class of synthetic
antimicrobial agents introduced into clinical practice between
the 1970s and 2000.2 In addition, substituted oxazolidinones
were also found to be active cholesterol-absorption inhibitors.3
Functionalized chiral oxazolidin-2-ones have been used as
versatile chiral precursors in the asymmetric syntheses of various
biologically active natural products.4 In organic synthesis,
substituted oxazolidin-2-ones5 are the most successful chiral
auxiliaries; these were first employed by Evans in 19816 and
have since seen application in a vast variety of asymmetric
transformations ranging from enolate alkylations to aldol and
Diels-Alder reactions. Herein we report a mild method to form
N-acylated oxazolidinone derivatives using acid fluorides. Acid
fluorides are easily prepared and undergo reaction readily under
i
mild conditions (i.e., Pr2NEt, NEt3) with the corresponding
oxazolidinones to form the desired imide derivatives. The acid
fluorides are conveniently obtained following a procedure
developed by Oliver and Oyelere7 and proved to be stable upon
storage at -20 °C for several days. The reaction of various
amino acid derived acid fluorides with a variety of commercially
available oxazolidinones generally provided the corresponding
N-acylated products in good to excellent yields (Scheme 1,
Table 1, 72-98%).
(1) (a) Genin, M. J.; Hutchinson, D. K.; Allwine, D. A.; Hester, J. B.;
Emmert, D. E.; Garmon, S. A.; Ford, C. W.; Zurenko, G. E.; Hamel, J. C.;
Schaad, R. D.; Stapert, D.; Yagi, B. H.; Friis, J. M.; Shobe, E. M.; Adams,
W. J. J. Med. Chem. 1998, 41, 5144. (b) Jandu, K. S.; Barrett, V.; Brockwell,
M.; Cambridge, D.; Farrant, D. R.; Foster, C.; Giles, H.; Glen, R. C.; Hill,
A. P.; Hobbs, H.; Honey, A.; Martin, G. R.; Salmon, J.; Smith, D.; Woollard,
P.; Selwood, D. L. J. Med. Chem. 2001, 44, 681. (c) Iwama, S.; Segawa,
M.; Fujii, S.; Ikeda, K.; Katsumura, S. Bioorg. Med. Chem. Lett. 1998, 8,
3495. (d) 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. J. Med. Chem. 1996, 39, 673.
(e) Barbachyn, M. R.; Hutchinson, D. K.; Brickner, S. J.; Cynamon, M. H.;
Klemens, S. P.; Glickman, S. E.; Grega, K. C.; Hendges, S. K.; Toops,
D. S.; Ford, C. W.; Zurenko, G. E. J. Med. Chem. 1996, 39, 680.
(2) Slee, A. M.; Wuonola, M. A.; McRipley, R. J.; Zajac, I.; Zawada,
M. J.; Bartholomew, P. T.; Gregory, W. A.; Forbes, M. Antimicrob. Agents
Chemother. 1987, 31, 1791.
Reactions involving chiral ꢀ-amino alcohols or their N-
substituted derivatives and either phosgene or diethyl carbonate
(3) (a) Dugar, S.; Kirkup, M. P.; Clader, J. W.; Lin, S. I.; Rizvi, R.;
Snow, M. E.; Davis, H. R.; McCombie, S. W. Bioorg. Med. Chem. Lett. 1995,
5, 2947. (b) Kværnø, L.; Ritter, T.; Werder, M.; Hauser, H.; Carreira, E. M.
Angew. Chem., Int. Ed. 2004, 43, 4653. (c) Ritter, T.; Kværnø, L.; Werder,
M.; Hauser, H.; Carreira, E. M. Org. Biomol. Chem. 2005, 19, 3514.
(4) For examples, see: Nicolaou, K. C.; Snyder, S. A. Classics in Total
Synthesis II: More Targets, Strategies, Methods; Wiley-VCH: Weinheim, 2003.
(5) (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96,
835. (b) Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997,
30, 1.
(6) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
10.1021/ol1016977 2010 American Chemical Society
Published on Web 08/13/2010