Expeditious, large scale preparation of ethyl (R)-5-methyl-3-oxo octanoate via a cross Claisen reaction between N-acyl oxazolidinone derivatives and the magnesium enolate of potassium ethyl malonate

Article abstract of DOI:10.1016/j.tetlet.2008.03.004

A new and efficient method for the direct conversion of N-acyl oxazolidinones to a β-keto ester is disclosed. The one-pot transformation is effected by the utilization of an excess of Lewis acid along with base and potassium ethyl malonate. This methodology has been applied to the large scale preparation of ethyl (R)-5-methyl-3-oxooctanoate.

Full text of DOI:10.1016/j.tetlet.2008.03.004

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2956–2959
Expeditious, large scale preparation of ethyl (R)-5-methyl-3-oxo
octanoate via a cross Claisen reaction between N-acyl oxazolidinone
derivatives and the magnesium enolate of potassium ethyl malonate
a,
b
c
*
Javier Magano , Thomas N. Nanninga , Derick D. Winkle
a Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA
b Bridge Organics, 311 W Washington, Vicksburg, MI 49097, USA
c Pleotint LLC, 7705 West Olive Road, West Olive, MI 49460, USA
Received 26 February 2008; accepted 3 March 2008
Available online 6 March 2008
Abstract
A new and efficient method for the direct conversion of N-acyl oxazolidinones to a b-keto ester is disclosed. The one-pot trans-
formation is effected by the utilization of an excess of Lewis acid along with base and potassium ethyl malonate. This methodology
has been applied to the large scale preparation of ethyl (R)-5-methyl-3-oxooctanoate.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: b-Keto ester; Claisen; Oxazolidinone; Magnesium enolate; Malonic acid ester
b-Keto esters are important intermediates in organic
synthesis and their preparation have attracted considerable
interest. The most traditional method is the Claisen con-
densation, where an ester displaces an alkoxy or aryloxy
group.1 Another very popular methodology is the acylation
of diethyl malonate followed by the hydrolysis and the
decarboxylation of one of the two ester groups in the acyl-
ated malonate intermediate,2 but a drawback is the poten-
tial formation of a methyl ketone by-product. Many other
methods have been developed that employ diverse
approaches3 but, unfortunately, very few of them are ame-
nable to be scaled up in a safe and cost effective manner. A
notable exception involves the use of the magnesium eno-
late of the half ester of malonic acid prepared by using
magnesium chloride and triethylamine. This has been
shown to react with acid chlorides or imidazolides to
provide b-keto esters.4
branched alkyl b-keto esters and, in particular, we were
interested in ethyl (R)-5-methyl-3-oxo-octanoate (9). The
introduction of the chiral center in the molecule was
accomplished through the Michael addition of organocop-
per species to crotonyl derivatives of oxazolidinones
(Scheme 1).5 Both the phenylglycinol and the norephe-
drin-derived oxazolidinones auxiliaries (1 and 2, respec-
tively) were successfully used to prepare enantioenriched
materials. The typical method of transforming these inter-
mediates into keto esters is shown in Scheme 2 and involves
the following: (1) the preparation of lithium peroxide; (2)
the reaction of lithium peroxide with the substrate; (3)
the reductive decomposition of the peroxy acyl intermedi-
ate as well as the excess peroxide; (4) workup in order to
achieve an anhydrous solution of the corresponding acid;
(5) activation of the acid by making, for example, an imi-
dazolide, a mixed anhydride or an N-acyl urea, and (6)
reaction with the magnesium enolate of malonic ester.6
Even though this sequence has been safely and effec-
tively performed by our group many times on 100s of
moles scale, there are several important drawbacks, such
as a tedious reaction sequence that takes several days of
As part of an on-going project in our laboratories, we
had the need for large quantities of enantioenriched x-
*
Corresponding author. Tel.: +1 860 6869021.
E-mail address: jmaganop@yahoo.com (J. Magano).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.004

J. Magano et al. / Tetrahedron Letters 49 (2008) 2956–2959
2957
O
O
O
O
O
1.
2.
n
-BuLi, THF, -40
ºC
n
-PropylMgBr
CuBr, TMEDA, THF
-55 C to -35
O
NH
R
O
N
R
O
N
R
O
3
-50 ºC
º
ºC
Ph
Cl
Ph
Ph
R = H (1), Me (2)
Not isolated
R = H (4), Me (5)
R = H (6), Me (7)
d.e.: 99.6%
(after recrystallization)
Scheme 1. The synthesis of x-branched alkyl b-keto esters.
1. CDI
2. KEM, Et3N, MgCl2
O
O
O
1. LiOOH
6 or 7
HO
EtO
2. NaHSO3
3. HCl
9
8
KEM = Potassium Ethyl Malonate
Scheme 2. Typical transformation sequence to prepare b-keto esters from N-acyl oxazolidinones.
O
O
O
O
NH
Me
+
t-BuO
O
11
Ph
10
t
-BuO
7
O
O
O
O
LDA, THF, -60
º
C
unidentified
impurity
HN
+
+
t-BuO
Ph
Me
13
12
Scheme 3. Direct conversion using the lithium tert-butyl acetate enolate.
processing to effect complete conversion, the fact that the
aqueous hydrogen peroxide and the resulting lithium deriv-
ative and acylperoxy intermediate are both high-energy
species capable of rapid decomposition, the need for
expensive reagents (N,N0-dicyclohexylcarbodiimide, 1,10-
carbonyldiimidazole) to activate the acid for displacement,
a low throughput and large amounts of waste.
There are several reports on the direct reaction of ester
enolates in order to accomplish the above conversion more
efficiently through the use of magnesium p-nitrobenzyl
malonate,7 but only in the presence of benzylic oxazolidi-
nones, or allylzinc to afford the corresponding allylic alco-
hol.8 The use of lithium tert-butyl acetate has also been
reported9 and, when tested on N-acyl oxazolidinone 7 as
a representative example, the reaction was complete in less
than 30 min at ꢀ60 °C and afforded the desired b-keto ester
11 but, also, gave up to 20% of undesired by-product 12
(Scheme 3) and up to 30% of an unidentified impurity 13.
The use of MgCl2 in the reaction gave similar results and
ZnCl2 gave a much slower reaction (no reaction at ꢀ60 °C)
with similar levels of 12. A summary of the conditions that
were screened is shown in Table 1. The low conversions
with ZnCl2 as an additive are likely due to water being
present.
Table 1
Conditions screen for the displacement of the oxazolidinone moiety in 7
with the lithium enolate of tert-butyl acetate
O
O
1.
KO
MgCl2, Et3N,
O
O
O
OEt
O
NH
Me
+
Entry Additive Enolate
Conversion T of
addition
12
(%)
13
(%)
+
CO2
7
EtO
equivalents (%)
Ph
MeCN, 80
2. HCl
ºC
9
1
2
3
4
5
None
None
MgCl2
ZnCl2
ZnCl2
2
100
60
80
40
70
ꢀ70 °C
ꢀ65 °C
20
20
30
30
20
0
10
1.15
1.44
1.44
2.3
50% recovery
83%
ꢀ60 °C to rt 20
ꢀ60 °C to rt 20
ꢀ60 °C to rt 20
Scheme 4. Direct conversion of 7 to b-keto ester 9 using the magnesium
enolate of KEM.
0

2958
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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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

J. Magano et al. / Tetrahedron Letters 49 (2008) 2956–2959
2959
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10. The recovered yield of oxazolidinone was lower than usual in this case
because the reaction temperature was run on the high end (80 °C
instead of 60 °C).