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J. Magano et al. / Tetrahedron Letters 49 (2008) 2956–2959
Conversion to the KetoEster
at 16 hours at 80 ºC using 2 eq. KEM
Conversion to the KetoEster
at 16 hours at 80 ºC using 2 eq. KEM
100
90
80
70
60
50
40
100
95
90
1.4 equiv
2.0 equiv.
2.5 equiv.
0
1
2
3
Mole Equivalents of Triethylamine per
KEM
1
1.5
2
2.5
3
Mole equivalents MgCl2 per KEM
Fig. 1. Optimization results for the direct conversion of 7 to 9 using KEM.
In view of the above results, we turned our attention to
the direct reaction of the N-acyl oxazolidinones with the
dianion of the half ester of malonic acid (Scheme 4).4 To
our delight, the reaction gave high conversion and a very
good yield of b-keto ester 9 after acidic workup under sim-
ple conditions. In addition, the chiral oxazolidinone could
be recovered in high purity and fair yield after precipitating
it out from hexanes.
After optimizing the reaction conditions, it was found
that the desired ratio of reagents is 2 equiv of potassium
ethyl malonate (KEM), 3 equiv of triethylamine and
4 equiv of MgCl2. Under these conditions, the reaction is
nearly complete in 16 h at 80 °C. It was speculated that
the reason for needing 2 equiv of KEM was due to the fact
that the CO2 from the imidazolide solution might form the
carbonate adduct of KEM. This was confirmed through
additional experiments that showed that when the vessel
was purged with nitrogen gas, the reaction proceeded at
a faster rate than when CO2 was added to the tank. Also,
it is noteworthy to point out that a reaction carried out
at 100 °C under 10 psi of pressure did not seem to have a
faster rate. The results of the study are shown in Figure 1
for N-acyl oxazolidinone 7.
liquor), followed by a 60 L isopropanol wash (discarded).
The solids were dried at 45 °C resulting in 10 kg (50%
recovery) of 90% pure oxazolidinone 10.10 The filtrates
were concentrated and the product was distilled under
vacuum (boiling point range: 40–60 °C at 0.1 mm of Hg)
to give 19.6 kg (83% yield) of b-keto ester 9.
In conclusion, we have developed an efficient method for
the preparation of ethyl (R)-5-methyl-3-oxo-octanoate by a
novel methodology that simplifies the process when N-acyl
oxazolidinones are used as starting materials. This protocol
has been demonstrated on pilot plant scale to produce
multi-kilogram quantities of this important intermediate
to support our research projects. Further applications of
this methodology will be reported in due course.
Acknowledgments
We would like to thank Drs. Sally Gut, Cheryl
Hayward, Kevin Henegar, Russ Linderman, John Ragan,
and Peter Wuts for reviewing this manuscript.
References and notes
In order to illustrate the feasibility of this technology, a
typical experimental procedure is as follows:
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Cameron, A. G.; Hewson, M. I. Tetrahedron Lett. 1984, 25, 2267; (c)
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228; (c) Dubois, J. E.; Hennequin, F.; Durand, M. Bull. Soc. Chim. Fr.
1963, 4, 791; (d) Sato, T.; Itoh, T.; Fujisawa, T. Chem. Lett. 1982, 10,
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1977, 2, 282; (f) Bram, G.; Vilkas, M. Bull. Soc. Chim. Fr. 1964, 5,
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(h) Dessert, A. M.; Halverstadt, I. F. J. Am. Chem. Soc. 1948, 70,
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4. Clay, R. J.; Collom, T. A.; Karrick, G. L.; Wemple, J. Synthesis 1993,
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8593.
6. (a) Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.; Mulhern, T.
A.; Grote, T. M.; Huckabee, B. K.; Hendrickson, V. S.; Franklin, L.
C.; Granger, E. J.; Karrick, G. L. Org. Proc. Res. Dev. 1997, 1, 26; (b)
Shioiri, T.; Hayashi, K.; Hamada, Y. Tetrahedron 1993, 49, 1913; (c)
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To a stirred mixture containing 34 kg (117 moles) of N-
acyl oxazolidinone 7 and 40 kg (235 moles) of ethyl malon-
ate potassium salt in 230 kg of acetonitrile was added 45 kg
(470 moles) of magnesium chloride in portions while keep-
ing the temperature below 30 °C. The slurry was diluted
with 24 kg (235 moles) of triethylamine and heated to
80 °C for 20 h. After cooling to 10 5 °C, the reaction
was quenched by the addition of a cooled mixture of
140 L of water and 80 kg of 35% aqueous hydrochloric
acid. The lower layer was separated and the upper layer
was diluted with 90 kg of ethyl acetate. The organic layer
was washed with a solution of aqueous sodium bicarbonate
(20.2 kg), water (120 L) and water (60 L). The organic
solvents were removed by vacuum distillation, 400 L of
hexanes was added and the distillation was resumed until
a volume of about 100 L remained. After cooling to
10 °C for 1 h, the resulting slurry was filtered and the cake
was washed with 60 L hexane(wash saved with the original