Microwave Heating Effects Rapid and Selective Decarboalkoxylation of Mono-Alkylated Malonates and β-Ketoesters

Article abstract of DOI:10.1002/adsc.200390033

Brief microwave irradiation of mono-alkylated malonates and β-ketoesters at 160-200 °C in wet DMF induces smooth and selective decarboalkoxylation. Observations suggest that this reaction occurs by nucleophilic attack of water at the ester carbonyl carbon (hydrolysis) followed by decarboxylation of the resulting acid. The process occurs despite the absence of traditional acid, base or nucleophile catalysts or reagents.

Full text of DOI:10.1002/adsc.200390033

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Microwave Heating Effects Rapid and Selective
Decarboalkoxylation of Mono-Alkylated Malonates and
b-Ketoesters
Dennis P. Curran,* Qisheng Zhang
Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USA
Fax: ( ‡ 1)-412-624-9861, e-mail: curran@pitt.edu
Received: November 21, 2002; Accepted: December 27, 2002
yield by heating in diphenyl ether at 250 8C (bath
Abstract: Brief microwave irradiation of mono-
alkylated malonates and b-ketoesters at 160 ±
[
7]
temperature) for 8 min. There was little room to
maneuver in optimizing the yield since shorter times or
lower temperatures reduced the conversion while
longer times or higher temperatures resulted in exten-
sive decomposition.
2
00 8C in wet DMF induces smooth and selective
decarboalkoxylation. Observations suggest that this
reaction occurs by nucleophilic attack of water at the
ester carbonyl carbon (hydrolysis) followed by
decarboxylation of the resulting acid. The process
occurs despite the absence of traditional acid, base
or nucleophile catalysts or reagents.
MEMO
OH
EtO2C
microwave
OSi(i-Pr)2Rf8h2
Keywords: acetoacetic ester synthesis; decarboalk-
oxylation; hydrolysis; malonic ester synthesis; micro-
wave heating
N
H
O
1
Rf8h2 = C8F17CH2CH2
MEMO
OH
O
OSi(i-Pr)2Rf8h2
ꢀ1a†
+
N
H
O
The alkylation of malonate esters, b-ketoesters and
related molecules followed by decarboalkoxylation is a
proven strategy for regioselective alkylation adjacent to
carbonyl groups.[ Limitations in this process reside
mainly in the decarboalkoxylation reaction. Classical
2
minor product
O
1]
2
8 2
OSi(i-Pr) Rf h
[
2]
methods call for exposure of substrates to strong acid,
3
a major product
strong base[ or both, and hydrolysis and decarboxyla-
tion are often accomplished in two distinct steps. Direct
decarboalkoxylations promoted by nucleophiles or
3]
O
O
[
4]
metal salts (for example, the Krapcho reaction ) have
replaced classical methods for many applications, but
long reaction times at high temperatures are still
DMF/H O
2
EtO
OSi(i-Pr)2Rf8h2
1
60 °C, 3 min
microwave
[
5]
needed. Recent reports of microwave-promoted de-
carboxylations reduce reaction times but still employ
4
a
Rf8h2 = C8F17CH2CH2
ꢀ
1b†
[
6]
acids, bases or metal salts to promote the reaction.
O
Here we report new conditions for decarboalkoxylation
that are the essence of simplicity: decarboalkoxylation
takes place upon microwave irradiation of a substrate in
wet DMF with no added reagents or catalysts. The
reaction is selective for mono-alkylated malonates and
b-ketoesters.
OSi(i-Pr)2Rf8h2
3a
The discovery of this microwave-induced decarboal- In an attempt to improve this transformation, we irra-
koxylation emanated from a failed experiment. We have diated 1 in a microwave reactor under several different
previously reported that thermal cyclization of enamide conditions varying time, temperature and solvent. Most
1
to pyridone 2 (Equation 1a) occurred in a modest 50% reactions were not especially clean and pyridone 2 was a
Adv. Synth. Catal. 2003, 345, No. 3
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1615-4150/03/34503-329 ± 332 $ 17.50+.50/0
329

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Dennis P. Curran, Qisheng Zhang
minor product at best. However, under several condi- Table 1. Microwave-promoted dealkoxylcarbonylation in
wet DMF.
tions, a new product was formed and this was readily
O
O
H2O (2.4 equiv.)
DMF, microwave
O
isolated and identified as ketone 3a. Speculating that
this ketone might arise by retro-Claisen reaction of 1 to
give ketoester 4a followed by decarboalkoxylation, we
heated authentic 4a in a microwave reactor and indeed
found that 3 was formed (Equation 1b). After a brief
optimization of solvent, temperature and time, we found
that microwave heating of 4a in a sealed tube in wet
DMF at 160 8C for 3 min cleanly provided ketone 3a,
which was isolated in 89% yield after flash chromatog-
raphy.
R1
OR3
R2
R1
R2
Entry
1
Substrate
Temperature [ C] Time [min] Product Yield [%]
O
EtO2C
OPG [a] 4a
160
160
3
3
3a
3b
89%
82%
O
O
2
4b
Ph
OEt
CO2Et
CO2Et
Ph
3
4
4c
160
20
3c
92%
84%
96%
95%
CO2Me
CO2Me
4d
4e
160
180
20
30
3d
3e
The generality of the procedure was tested by micro-
waving a variety of malonates and b-ketoesters 4b ± i in
wet DMFat temperatures varying from 160 to 200 8C for
CO2Et
CO2Et
5
Ph
CO2Me
3
± 30 min. The results of this series of experiments are
6
7
Ph
CO Me
4f
180
200
30
20
3f
2
summarized in Table 1. The indicated yields of 3a ± h are
after flash chromatographic isolation, but in most cases
the crude product after simple aqueous work-up to
remove the DMF was sufficiently clean (>90% by GC
analysis) for further use. The reaction showed good
generality for unsubstituted and monosubstituted mal-
onates and ketoesters. However, the time and temper-
ature depend significantly on the substitution pattern.
The unalkylated ketoester 4b in entry 2 suffers decar-
boalkoxylation over 3 min at 160 8C while its mono-
alkylated derivatives 4g and 4h (entries 7 and 8) require
O
O
Ph
OEt
4g
3g
91%
84%
Ph
O
O
8
9
Ph
OEt
4
h
200
160
20
20
3h
MeO2C
MeO2C
4i
+
4i
decomposition
CO2Bn
[
a]
PG = Si(i-Pr)2(CH2CH2C8F17).
2
0 min at 200 8C. A simple control experiment showed is proposed because of the difference in reactivity
the importance of microwave heating. When a mixture between mono- and dialkylated substrates. However,
of 4c in wet DMF was heated at 160 8C for 25min in an
direct (or water-promoted) attack of water on the keto
oil bath, only 5% conversion to ketoester 3c was form cannot be ruled out. The ketene mechanism[ is
observed by GC. Contrast this to the microwave experi- unusual but was considered because of the low reactivity
ment (entry 3), where complete conversion was ob- of the dialkylated substrates (these cannot form ke-
11]
served in 20 min.
tenes). In all three pathways, thermaldecarboxylation of
These reaction conditions are not effective for dialky- the intermediate b-carbonyl acid completes the trans-
lated ketoesters and malonates. For example, heating of formation.
4
i (entry 9) for 20 min at 160 8C returned mostly starting
Two lines of evidence suggest that the ketene pathway
material along with some decomposition products. is not operating. First, water is required for substrate
Under comparable conditions, monoalkylated malo- conversion; 4c was recovered largely unchanged after
nates 4c and 4d (entries 3 and 4) gave clean products. As heating in rigorously dry DMF under the conditions in
these results imply, it is indeed possible to conduct a Table 1. Second, heating of 4c in dry DMF in the
selective decarboalkoxylation of a monoalkylated mal- presence of dihydropyran or cyclohexanone to trap
onate in the presence of a dialkylated malonate. For intermediate ketenes again returned starting material.
example, microwaving a 1/1 mixture of 4e and its Both experiments also gave traces of decarboalkoxy-
dialkylated analogue {[Ph(CH ) ] C(CO Et) } at 180 8C lated product 3c, which we presume arose by reaction
[
8]
2
3 2
2
2
for 30 min resulted in 94% conversion (GC) of mon- with adventitious water.
alkylated 4e to 3e while the dialkylated precursor was
largely unchanged.
To differentiate between the hydrolysis and deal-
kylation mechanisms, we conducted a competition
Scheme 1 shows the three mechanistic pathways that experiment on a mixture of diethyl malonate 4e and
[
9]
we have considered for this transformation: ester dimethyl malonate 4f. If hydrolysis is occurring, then
hydrolysis by nucleophilic attack of water on the these two substrates will be consumed at similar rates.
carboxy carbon of the ester, ester dealkylation by However, the ethyl ester 4e should be considerably less
nucleophilic attack of water on the alcohol carbon of reactive than the methyl ester 4f if dealkylation is the
the ester, and alcohol elimination to form an acylketene path. We mixed 4e and 4f in a 1/1 ratio in wet DMF and
followed by nucleophilic attack of water. In both the microwaved the mixture at 180 8C. The conversion of
hydrolysis and dealkylation mechanisms, activation by both precursors was followed by GC as a function of
[
10]
enol formation and intramolecular hydrogen bonding
time, and the results are shown in Table 2. The dimethyl
330
Adv. Synth. Catal. 2003, 345, 329 ± 332

Decarboalkoxylation of Mono-Alkylated Malonates and b-Ketoesters
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of evidence suggest that standard hydrolysis of the
substrate (possibly in its enol form) by water is followed
by thermal decarboxylation of the resulting acid. These
reactions are convenient and atom economical, and the
mild conditions suggest the potential for broad scope.
hydrolysis
H
O
O
O
OH
OR3
OH
O
O
H O
2
R1
OR3
R1
R1
OR3
R2
R2
R2
3
O
O
CO2
R OH
O
R2
R1
OH
R1
R2
Experimental Section
dealkylation
Typical Experimental Procedure
H
O
O
2
H O
O
O
Diethyl benzylmalonate 4c (25.0 mg, 0.1 mmol), H O (4.3 mg,
2
R1
OR3
0.24 mmol) and DMF (2 mL) were heated in a sealed tube at
160 8C with stirring for 20 min in a CEM Discover microwave
reactor. The reaction mixture was then cooled to room
temperature and diluted with ether (20 mL) and water
(5mL). The layers were separated and the ether layer was
further washed with H O (2 mL Â 3), dried over MgSO and
R1
OR3
R2
R2
H
CO2
O
O
O
+
R OH2
3
R2
+
R3OH
R1
O
R1
R2
2
4
concentrated under vacuum. The residue was purified by
column chromatography (hexanes/Et O ˆ 5:1) on silica gel to
2
acylketene formation
afford 3c as a colorless oil; yield: 16.4 mg (92%).
H
3
O
O
OR3
R OH
O
R1
OR3
R1
O
Acknowledgements
R2
R2
CO2
O
O
O
O
We thank the National Institutes of Health for funding this work.
We are especially grateful to the CEM Corporation for
providing the microwave reactor. We thank Mr. Jonathan Tripp
for providing compounds 4d and 4i.
O
C
R2
R1
R1
R1
OH
R2 H O
R2
2
Scheme 1.
References and Notes
Table 2. Effects of the alkoxy substituent on the rate of
dealkoxylcarbonylation reaction.
H2O (2.4 equiv.)
[1] a) H. O. House, Modern Synthetic Reactions, 2nd edn.,
W. A. Benjamin Inc., New York, 1972; b) A. C. Cope,
H. L. Holmes, H. O. House, Org. React. 1957, 9, 108.
4e
+
4f
3e
+
3f
microwave, 180 °C
[
2] a) D. Landini, F. Rolla, J. Org. Chem. 1982, 47, 145;
b) C. R. Schmid, Tetrahedron Lett. 1992, 33, 757.
Time [min]
at 180 °C
Conversion [%]
4e
4f
4f/4e
1.03
1.13
1.28
1.11
0[a]
2
25.9
27.8
34.9
68.5
26.8
31.5
44.8
75.6
[3] a) K. L. Kaestle, M. K. Anwer, T. K. Audhya, G. Gold-
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Furuta, J. Matsuo, T. Kurata, J. Org. Chem. 1991, 56,
4
20
5
757.
[
a]
The time (about 45 seconds) for the mixture to
reach 180 °C is not counted. However, entry 1
shows that significant conversion occurs during
this period.
[4] A. P. Krapcho, Synthesis 1992, 805.
[
5] For reviews on microwave assisted organic synthesis, see:
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Strauss, R. W. Trainor, Aust. J. Chem. 1995, 48, 1665;
c) L. Perreux, A. Loupy, Tetrahedron 2001, 57, 9199; c)
for practical and safety considerations regarding sol-
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wave Synthesis, CEM Publishing, Matthews, NC, 2002.
6] a) A. Loupy, P. Pigeon, M. Ramdani, P. Jacquault, J.
Chem. Res. (S) 1993, 36; b) J. P. Barnier, A. Loupy, P.
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Chem. Res., (S) 2000, 42.
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reactive than the diethyl malonate 4e. The diesters were
consumed not only by decarboalkoxylation but also by
transesterificaton to make the mixed diester (not
shown). These observations are consistent with the
hydrolysis mechanism, not the dealkylation mechanism.
In summary, malonic esters and b-ketoesters are
decarboxylated by brief microwave heating in wet
DMF in the absence of traditional reagents or catalysts.
The reaction occurs readily with monoalkylated deriv-
atives but not with dialkylated derivatives. Several lines
[
Adv. Synth. Catal. 2003, 345, 329 ± 332
331

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Dennis P. Curran, Qisheng Zhang
[
7] Q. Zhang, A. Rivkin, D. P. Curran, J. Am. Chem. Soc.
002, 124, 5774.
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2
[
[
2
9] For mechanistic studies on hydrolysis of b-ketoesters and
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J. M. Eldridge, E. G. E .Jahngen, Jr., A. J. Lovey, W. P.
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Adv. Synth. Catal. 2003, 345, 329 ± 332