Org. Synth. 2002, 79, 146
DOI: 10.15227/orgsyn.079.0146
FORMATION OF γ-KETO ESTERS FROM β-KETO ESTERS: METHYL
5,5-DIMETHYL-4-OXOHEXANOATE
[
Hexanoic acid, 5,5-dimethyl-4-oxo-, methyl ester
]
Submitted by Matthew D. Ronsheim, Ramona K. Hilgenkamp, and Charles K. Zercher
1
.
Checked by Scott E. Denmark and Gregory L. Beutner.
1. Procedure
CAUTION! Neat
diethylzinc
may ignite on exposure to air and reacts violently with water. It must be handled
and reacted under
nitrogen.
2 The reaction solvent must
be dried and distilled prior to use and all glassware and syringes must be thoroughly
dried.
An oven-dried, 3-L, three-necked, round-bottomed flask equipped
with a magnetic stirring bar is charged with
1000
mL of freshly distilled methylene chloride
(Note 1). One of the outer two necks of the flask is equipped
with a gas inlet adapter attached to a nitrogen source and
the other with a septum connected through a needle
to a bubbler (Notes 2,
3). A 125-mL pressure-equalizing
addition funnel capped with a septum is placed
in the center neck of the flask with the stopcock closed. The
funnel is charged with
12.1 mL (150
mmol) of methylene iodide
(Note 4)
dissolved in
75 mL of distilled methylene
chloride
. The solution is stirred under nitrogen
for 1 hr and the flask is cooled in an ice-water bath. Using
a syringe,
15.4 mL
(150 mmol) of neat diethylzinc
(Note 5) is added
to the
methylene chloride
through the septum
(Note 6). The stopcock
of the addition funnel is opened carefully and the
methylene iodide
solution is allowed
to drip into the
diethylzinc
solution over the course of 30 min (Note 7). After the reaction
is stirred for an additional 10 min,
8.0 mL
(50 mmol) of methyl 4,4-dimethyl-3-oxopentanoate
is added to the flask over a period of 15 sec through the septum
using a syringe
(Note 8). The reaction
mixture is stirred for 45 min (Note 9), the septum
is removed, and the reaction is quenched through the careful addition of
125 mL of saturated aqueous ammonium chloride
(Notes 10, 11).
Stirring is maintained for an additional 10 min, at which time the reaction mixture
is transferred to a 2-L separatory funnel. The lower organic
layer is withdrawn and placed in a large, round-bottomed flask.
The
methylene chloride
is
removed using a rotary evaporator
(Note 12)
and the residue is diluted with
500 mL of
diethyl ether
and placed in the separatory
funnel. It is washed successively with
125-mL
portions of saturated aqueous sodium bicarbonate
,
1 M aqueous sodium thiosulfate
solution (Note 13), deionized water and brine.
The aqueous washings are extracted with
diethyl
ether (3 × 150 mL) and the combined organic
layers are dried over
50 g of anhydrous sodium
sulfate
prior to concentration under reduced pressure. The product
is purified by vacuum distillation from anhydrous potassium
carbonate (58°C, 1 mm) to give
methyl
5,5-dimethyl-4-oxo-hexanoate
(7.63-8.09 g, 89-94% yield) as a clear liquid (Notes 14, 15).
2. Notes
1.
Methylene chloride,
reagent grade, was obtained from Pharmco Products, Inc.
and was distilled from
phosphorus pentoxide
prior to use.
Benzene
can
be substituted for
methylene chloride
in the chain extension reaction with similar results; however the use of
benzene
in the reaction has not been
independently checked.
2.
The first step of the chain extension reaction mechanism has been
shown to be enolate formation, the by-product of which is
ethane
gas. The
nitrogen line should be attached to a large
adapter to provide adequate venting of the gas.
3.
The checkers used a sidearm
vacuum adapter
fitted with a septum and connected to a nitrogen manifold. The third neck was stoppered.
4.
Methylene iodide
was obtained from Lancaster Synthesis, Inc.
, and used
without further purification. Distillation of the
methylene
iodide
from
copper
prior to use does not lead to increased product yield or purity.
5.
Three equivalents of the carbenoid (EtZnCH
2I) are necessary
for the clean formation of the product. One of the equivalents serves to facilitate
formation of the enolate, while a second equivalent provides the methylene group that
is incorporated into the product. However, if the reaction is performed with only
two equivalents, significant amounts of starting material and a second product,
methyl 2,4,4-trimethyl-3-oxopentanoate
,
are generated in the reaction.
6.
Diethylzinc was
obtained from Aldrich Chemical Company, Inc.
, and
used without further purification. If the reaction flask has been carefully flushed
with
nitrogen, there should be very little smoke evident when
the
zinc
reagent is added.
Diethylzinc
can be added
with the syringe tip placed below the surface of the solvent rather than above it.
7.
Formation of the
zinc carbenoid
is exothermic and potentially explosive.
3 The
ice bath should
be present in order to control the reaction temperature, and
methylene
iodide
should be added gradually rather than all at once. During
the addition of the
methylene iodide
,
or shortly thereafter, the reaction mixture should develop a cloudy, white appearance.
8.
Methyl 4,4-dimethyl-3-oxopentanoate
was obtained from Lancaster Synthesis, Inc.
, and used
without further purification.
9.
Disappearance of the starting material may be monitored by thin
layer chromatography (R
f = 0.6, 2:1
hexane:
ethyl
acetate). It is important that the reaction time not be extended past the
point when all of the β-keto ester is consumed, because long exposure to the
zinc carbenoid
has been shown
to result in substrate decomposition and reduced yields.
10.
Addition of the aqueous solution is exothermic and should, therefore,
be carried out over the course of a few minutes. The checkers found that the initial
internal temperature was 5-6°C which rose to 10°C upon addition of the first few mL
of quench solution.
11.
The checkers found that addition of
150
mL of 2 N aqueous hydrochloric acid
rather
than
125 mL of saturated aqueous ammonium
chloride
does not alter the yield or purity of the product.
12.
Methylene chloride
is exchanged for
diethyl ether
,
since removal of the
zinc
salts formed as reaction by-products is facilitated by use of an extraction solvent
that is less dense than water.
13.
The checkers found that washing the organic extracts with
sodium thiosulfate
solution was necessary
to obtain a colorless product.
14.
The NMR spectra were as follows and were consistent with those
reported in the literature:
4
1H
NMR (500 MHz, CDCl
3) δ: 1.16 (s, 9 H), 2.57 (t,
2 H, J = 6.36), 2.81 (t, 2 H, J = 6.36), 3.67 (s, 3 H)
;
13C NMR (125
MHz, CDCl
3) δ: 26.4, 27.8, 31.4,
43.9, 51.7, 173.5, 214.4
;
IR (neat) 2970, 2874,
1741, 1707, 1366, 1204, 1167,
1087
. MS: (EI) 172.1
(0.23), 155.1 (0.43), 141.1 (16), 115.0 (100),
57.1 (64)
. Anal. Calcd. for C
9H
16O
3:
C, 62.75; H, 9.36. Found: C, 62.42; H, 9.38
15.
The checkers found that distillation from
anhydrous
potassium carbonate
is required in order to obtain
a clear, analytically pure sample. Simple distillation yields a slightly yellow liquid
which is free from major contamination, but not analytically pure.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
A variety of methods have been reported for the preparation of γ-keto esters.
Although strategies in which the ketone and ester functionalities are assembled from
different sources are frequently used,
5
reactions that promote the insertion of a single methylene unit between the carbonyl
functionalities of readily accessible β-keto esters are very attractive. The
formation and fragmentation of 2-carboxycyclopropyl alcohols have been central to
this methodological development.
6
Three complementary strategies have been implemented for the formation of γ-keto
esters through these functionalized cyclopropyl alcohols.
7
While each of the three methods provided access to γ-keto esters, the multiple
steps and/or poor yields of the transformations serve to discourage their widespread
applicability. The submitters have developed a simple and efficient one-step method
for the formation of γ-keto esters from β-keto esters that appears to proceed
through a similar
cyclopropyl alcohol
intermediate.
8 Exposure
of an α-unsubstituted β-keto ester to a 1:1 mixture of
diethylzinc
and
methylene iodide
results
in its clean and rapid conversion to the chain-extended keto ester. This
zinc-mediated
process has two distinct advantages over the previously reported chain-extension methods.
The most obvious advantage is that no additional steps are required for the formation
of the intermediate enol ether or for the cleavage of the protected
cyclopropyl
alcohol
. Secondly, utilization of
diethylzinc
is operationally much simpler than preparation and application of the
zinc-copper
couple reported by Sagio.
7h
The
zinc-mediated reaction tolerates a variety of functionality
in the β-keto ester. In fact, the method described above has been applied successfully
to β-keto amides
9 and β-keto
phosphonates.
10 Unsubstituted
β-keto esters, amides and phosphonates have been chain-extended in yields that
ranged from 58% to 98% (Table I). The primary limitation to this method is the inefficiency
with which α-substituted esters and amides undergo methylene insertion. The
zinc carbenoid
must be employed
in at least a threefold excess in order to fully convert β-keto ester to products
and to avoid the formation of α-methylated β-keto esters. Side products
that result from an intermolecular reaction are observed on occasion. For example,
the preparation of
ethyl 4-oxo-4-phenylbutanoate
from
ethyl benzoylacetate
on a 50-mmol scale proceeded in only 70% isolated yield because of a competing intermolecular
reaction.
TABLE
PRODUCTS OF ZINC CARBENOID-MEDIATED CHAIN EXTENSION REACTIONS
(a) 50-mmol scale with 4 equiv of carbenoid; (b) isolated yield after chromatographic
purification of a 1-mmol scale reaction; (c) 5 equiv of carbenoid; (d) 4 equiv of
carbenoid; (e) 6 equiv of carbenoid.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
Methyl 5,5-dimethyl-4-oxohexanoate:
Hexanoic
acid, 5,5-dimethyl-4-oxo-, methyl ester (9); (34553-32-7)
Diethylzinc: FLAMMABLE LIQUID:
Zinc, diethyl-
(8, 9); (557-20-0)
Methylene iodide:
Methane, diiodo-
(8, 9); (75-11-6)
Methyl 4,4-dimethyl-3-oxopentanoate:
Pentanoic
acid, 4,4-dimethyl-3-oxo-, methyl ester (9); (55107-14-7)
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