Microwave-assisted aqueous Krapcho decarboxylation

Article abstract of DOI:10.1055/s-0033-1338701

The Krapcho decarboxylation of alkyl malonate derivatives has been adapted to aqueous microwave conditions. Various salt additives were examined, and both the cation and the anion impacted the facility of the reaction. A strong correlation was found between the pKa of the anion and the reaction rate, suggesting a straightforward base-catalyzed hydrolysis. Lithium sulfate gave the best results, obviating the need for DMSO co-solvent. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338701

LETTER
▌1391
letter
Microwave-Assisted Aqueous Krapcho Decarboxylation
Microwave Krapcho Decarboxylation
Jeremy D. Mason, S. Shaun Murphree*
Department of Chemistry, Allegheny College, Meadville, PA 16335, USA
Fax +1(814)3322789; E-mail: smurphre@allegheny.edu
Received: 24.03.2013; Accepted after revision: 11.04.2013
group (e.g., 4). To that end, Krückert had reported a
straightforward procedure that involved treating an acyl
chloride with ethyl acetoacetate in the presence of magne-
sium chloride to produce a diketoester (e.g., 3), which was
Abstract: The Krapcho decarboxylation of alkyl malonate deriva-
tives has been adapted to aqueous microwave conditions. Various
salt additives were examined, and both the cation and the anion im-
pacted the facility of the reaction. A strong correlation was found
between the pKa of the anion and the reaction rate, suggesting a decarbethoxylated by refluxing for 12 hours with sodium
9
straightforward base-catalyzed hydrolysis. Lithium sulfate gave the chloride in aqueous DMSO.
best results, obviating the need for DMSO co-solvent.
In adapting Krückert’s conditions to a sealed-tube micro-
wave reactor, we found that the use of DMSO could be
Key words: cleavage, esters, hydrolysis, lithium, solvent effects
avoided, and that very good isolated yields could be
achieved by heating in water containing 1.2 equivalents of
sodium chloride for five minutes at 185 °C (Scheme 2).
Remarkably, good yields could also be obtained by brief
heating in water alone.
The Krapcho decarboxylation is a convenient protocol for
the removal of an ester moiety from an electron-deficient
carbon under mild conditions. First reported in 1967 as the
cyanide-mediated decarbethoxylation of monoalkyl mal-
1
onate derivatives (e.g., 1a → 2a), the Krapcho protocol
O
O
was later modified to a system of wet DMSO without the
need for cyanide (Scheme 1). More than 40 years after
Ph
NaCl (1.2 equiv)
O
O
2
Ph
H2O
MW
the first example, the Krapcho conditions still have
O
OEt
currency in the literature.3
1
85 °C, 5 min
86%
3
4
O
O
no salt
NaCN (2 equiv)
OEt
(
same conditions)
DMSO
160 °C, 4 h, 80%
OEt
7
6%
O
OEt
1a
2a
Scheme 2 Decarboxylation of a diactivated system
DMSO–H2O
Intrigued by the facility of this reaction, we sought to ex-
pand its scope by turning our attention to the much less re-
active malonate derivatives, with an eye toward parsing
Δ, 16 h, 80%
Scheme 1 Original Krapcho conditions
Table 1 Cation Effects
Our interest in this reaction arose from the nexus of two
research projects, one involving methodology for the syn-
thesis of 2,4-disubstituted furans requiring convenient
O
4
O
salt (1 equiv)
Ph
OEt
OEt
access to β-dicarbonyls, and the other centering about our
H O
10 °C
2
Ph
OEt
2
ongoing interest in adapting workhorse synthetic methods
O
1
5 min
5
to sealed-tube microwave conditions.
1b
2b
Previous investigators have carried out the Krapcho de-
carboxylation using microwave acceleration, as seen in
Conversion (%)a
Entry
Salt
6
Kerr’s synthesis of mersicarpine and Jung’s enantio-
1
2
3
4
5
none
NaCl
LiCl
8
17
69
7
7
specific formal total synthesis of (+)-Fawcettimine. Both
routes adapt conditions previously reported by Curran
involving wet DMF as a solvent.8
For our particular synthetic application, we required ac-
cess to β-diketones in which one substituent was a methyl
KCl
MgCl2b
7
6
NH Cl
17
SYNLETT 2013, 24, 1391–1394
4
Advanced online publication: 08.05.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
a
Determined by HPLC.
DOI: 10.1055/s-0033-1338701; Art ID: ST-2013-R0260-L
Georg Thieme Verlag Stuttgart · New York
b
Amount of MgCl used was 0.5 equiv (1 equiv chloride).
2
©

1392
J. D. Mason, S. S. Murphree
LETTER
out the factors impacting the efficiency of the reaction. Table 2 Anion Effects
We began with a survey of common cations (Table 1),
O
O
salt (1 equiv)
which showed lithium to be the most effective cation by
far. One rationale for this outcome could be the differen-
tial coordination of the cation with the carbonyl oxygen,
which in turn would be dependent upon hard–soft acid–
base (HSAB) parameters. Indeed, the facility of the decar-
boxylation using alkali metal cations correlates strongly
1
b
+
H2O, 210 °C
5 min
Ph
OEt
Ph
OH
1
2
b
5
Conv. (%)a
Entry
Salt
Ratio 2b/5
1
0
to their absolute hardness (η) values (Figure 1).
1
2
3
4
5
6
7
8
9
none
NaF
NaCl
NaBr
NaI
8
89
17
16
26
91
41
68
95
86
25
75
86
6:1
15:1
5:1
5:1
5:1
NaOAc
NaNO3
9:1
8:1
NaH PO
11:1
2:1
2
4
4
Na HPO
2
1
1
1
0
1
2
3
Na C O
4
12:1
1:1
2
2
NaHSO4
Na SO
16:1
17:1
2
4
1
Li SO
2
4
a
Figure 1 Conversion as a function of cation absolute hardness
Determined by HPLC.
In light of this trend, it is somewhat surprising that mag- served when a good anion was combined with a harder
nesium cation is so ineffective in catalyzing the reaction, cation, such as lithium (entry 13).
since its hardness value is quite high. This anomaly might
be explained by the tendency of magnesium cation to
Interesting mechanistic insight is revealed when the con-
versions are plotted against the pK values of the respec-
a
form a stabilized enolate chelate, which would be resistant
tive anions (Figure 2). In short, the facility of the Krapcho
to hydrolysis (Scheme 3). For example, Rathke and
decarboxylation correlates very strongly to the basicity of
1
1
Cowan demonstrated through NMR studies that diethyl
malonate was not significantly deprotonated by triethyl-
the anion. Thus, it would appear that one important role of
the salt additive is to modulate the pH of the reaction
medium, at least under the conditions of this study.
amine (pK = 10) in acetonitrile solution, an unsurprising
a
result given the substrate has a pK of 14. However, in the
a
presence of one equivalent of magnesium chloride, even
pyridine (pK 5) effected practically quantitative deprot-
a
onation.
O
OEt
Mg2+
R
O
R
OEt
OEt
O
Mg+
EtO
O
Scheme 3 Complexation of malonate derivatives with Mg2+
We next turned our attention to the effect of the anion (Ta-
ble 2). In examining an array of common sodium salts, we
found that not only were yields widely divergent, but so
too was the propensity of the initial ester (2b) to undergo
further hydrolysis to the corresponding acid (5). The most
effective sodium salts were sodium fluoride (entry 2) and
sodium sulfate (entry 12). A synergistic effect was ob-
Figure 2 Conversion as a function of anion pKa
Synlett 2013, 24, 1391–1394
© Georg Thieme Verlag Stuttgart · New York

LETTER
Microwave Krapcho Decarboxylation
1393
M+
Finally, the effects of reaction time, salt equivalency, and
co-solvent were studied (Table 3). Increasing the salt con-
centration enhances conversion (entry 3), but with a slight
negative impact on hydrolysis selectivity. Longer reaction
times (entry 4) also lead to higher conversions, and the
same trend with increased salt concentration is observed
O
O
O
OM
O
O
M+
–OH
EtO
OEt
EtO
OEt
OH
EtO
OEt
R
R
R
1
6
7
–OEt
(entry 5). Adding DMSO as a co-solvent (entries 6–8)
makes the decarboxylation both more rapid and more se-
lective, especially at very high DMSO–water ratios. How-
ever, DMSO alone is insufficient, as removing the salt,
even in a 9:1 DMSO–water medium, hobbles the reaction
CO2
H
O
OH
O
O
EtO
EtO
EtO
O
R
R
R
(entry 9).
2
9
8
Table 3 Effects of Other Parameters
Scheme 4 Mechanism of the Krapcho decarboxylation
Table 4 Optimized Conditions
O
O
Na2SO4
1b
+
210 °C
Ph
OEt
Ph
OH
O
O
O
2b
5
Li2SO4 (1 equiv)
EtO
OEt
OEt
H2O
210 °C
30 min
Entry
Na SO4
Time
(min)
DMSO
(vol%)
Conv.
(%)a
Ratio
2b/5
R
R
2
(
equiv)
1
2
1
2
3
4
5
6
7
8
0
1
2
1
2
1
1
1
0
15
15
15
30
30
15
15
15
15
0
0
8
6:1
16:1
13:1
14:1
11:1
20:1
20:1
90:1
7:1
Yield (%)a
Entry
1
R
Product
75
2b
87
Ph
Ph
0
87
2
3
2c
74
71
0
94
Ph
2d
0
97
O
10
50
90
90
80b
88b
90b
32b
4
2e
76
Ph
5
6
EtO2C
2f
79
NC
NC
2g
2h
63
9
7
34b
a
Unless otherwise denoted, determined by HPLC.
Determined by NMR.
b
a
Isolated yield.
Deprotected alcohol was obtained in 38% yield.
b
In sum, these data suggest a mechanism for the Krapcho
malonate derivatives in an entirely aqueous medium using
decarboxylation that proceeds through a B 2-type mech-
AC
1
2
lithium sulfate as a catalyst. This methodology realizes
a useful confluence of green reaction solvent and short
conversion times, and is therefore advantageous for high-
throughput synthesis techniques.
anism (Scheme 4). Thus, initial coordination of the ester
moiety to the cation activates the carbonyl toward attack
of hydroxide, which is generated by the mild basicity of
the anion present. Once the half-acid is formed, thermal
elimination of carbon dioxide provides the monoester.
Acknowledgment
To demonstrate the generality of the procedure, a series of
monoalkyl malonate derivatives was subjected to opti-
The authors gratefully acknowledge Allegheny College (Shanbrom
mized conditions (Table 4). Lithium sulfate was selected Fund), the Petroleum Research Fund (PRF 42382-B1), and the
as the salt additive, as it combines the best chelating prop- National Science Foundation (CCLI 0837640) for their generous
financial support of this work.
erties of the cation and an optimum pH profile of the an-
ion. We also preferred to avoid a DMSO co-solvent to
simplify workup and to achieve a greener solvent system.
Supporting Information for this article is available online at
Isolated yields are generally good, with the exception of
the tert-butyldimethylsilyl derivative (entry 7), which
suffers significant deprotection under the conditions.
http://www.thieme-connect.com/ejournals/toc/synlett. SnuIpofoipmngr irtSatnoIuipfog
r
t
iornat
References and Notes
In summary, we have developed a convenient and rapid
microwave-accelerated Krapcho decarboxylation of
(
1) Krapcho, A. P.; Glynn, G. A.; Grenon, B. J. Tetrahedron
Lett. 1967, 215.
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1391–1394

1394
J. D. Mason, S. S. Murphree
LETTER
(
(
(
2) (a) Krapcho, A. P. Synthesis 1982, 805. (b) Krapcho, A. P.
Synthesis 1982, 893.
3) Poon, P. S.; Banerjee, K. S.; Laya, M. S. J. Chem. Res. 2011,
(11) Rathke, M. W.; Cowan, P. J. J. Org. Chem. 1985, 50, 2622.
(12) Experimental Procedure: To a 2–5 mL microwave vial
were added the diethyl alkyl malonate (1.5 mmol), lithium
6
7.
sulfate (166 mg, 1.5 mmol), and deionized H O (3.0 mL).
2
4) Haines, N. R.; VanZanten, A. N.; Cuneo, A. A.; Miller, J. R.;
Andrews, W. J.; Carlson, D. A.; Harrington, R. M.; Kiefer,
A. M.; Mason, J. D.; Pigza, J. A.; Murphree, S. S. J. Org.
Chem. 2011, 76, 8131.
The vial was sealed and heated at 210 °C for 30 min (see ref.
13) after which the contents were poured into sat. NaHCO3
(10 mL) and extracted with EtOAc (2 × 15 mL). The
combined organic phases were washed sequentially with
NaHCO (15 mL) and brine (15 mL), dried over Na SO , and
(5) Murphree, S. S.; Mason, J. D.; Bean, T. G.; Perry, M. C.
Synth. Commun. 2012, 42, 1979.
3
2
4
concentrated in vacuo to yield a crude oil, which was
purified by column chromatography.
(6) Magolan, J.; Carson, C. A.; Kerr, M. A. Org. Lett. 2008, 10,
1
437.
(13) Since carbon dioxide is liberated during the reaction, 3–4
atm of residual pressure remains after the vial is cooled. The
manufacturer’s instructions for releasing this pressure
should be carefully followed before opening the vial for
aqueous workup.
(
(
(
7) Jung, M. E.; Chang, J. J. Org. Lett. 2010, 12, 2962.
8) Curran, D. P.; Zhang, Q. Adv. Synth. Catal. 2003, 345, 329.
9) Krückert, K.; Flachsbarth, B.; Schulz, S.; Hentschel, U.;
Weldon, P. J. J. Nat. Prod. 2006, 69, 863.
(10) Olah, G. A.; Lin, H. C. Synthesis 1974, 444.
Synlett 2013, 24, 1391–1394
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.