Access to β-keto esters by palladium-catalyzed carbonylative coupling of aryl halides with monoester potassium malonates

Article abstract of DOI:10.1002/anie.201304072

New tricks for an old dog: The Pd-catalyzed carbonylative α-arylation of monoethyl potassium malonates with aryl bromides and reactive aryl chlorides provides a simple and direct route to aryl β-ketoesters. Because only stoichiometric amounts of carbon monoxide are employed, the method is ideal for the introduction of carbon isotopes into more complex structures. Copyright

Full text of DOI:10.1002/anie.201304072

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Chemie
DOI: 10.1002/anie.201304072
Palladium Catalysis
Access to b-Keto Esters by Palladium-Catalyzed Carbonylative
Coupling of Aryl Halides with Monoester Potassium Malonates**
Signe Korsager, Dennis U. Nielsen, Rolf H. Taaning,* and Troels Skrydstrup*
Over the past 150 years since the discovery of the acetoacetic
ester condensation by Geuther in 1863,[1] and the subsequent
extensive research into the reaction by Claisen,[2] b-keto
esters have played a prominent role in organic synthesis. Such
compounds serve as key building blocks in the synthesis of
many pharmaceuticals and natural products, providing direct
access to a wide variety of heterocycles.[3,4] A direct procedure
for accessing b-keto esters involves the acylation of diethyl
malonate, followed by partial hydrolysis and subsequent
decarboxylation of only one of the two ester groups. The
disadvantage of this method is the possibility of diacylation,
Scheme 1. Synthesis of b-keto esters by a Pd-carbonylative coupling
strategy with aryl halides. Bn=benzyl, Tf=trifluoromethanesulfonyl.
hydrolysis of both ester groups and retro-condensation,
leading to the carboxylic acid starting material.[3] On the
other hand, Wemple and co-workers reported a modified
route to b-keto esters,[5] through the acylation of monoethyl
potassium malonate with acid chlorides using a combination
of MgCl2 and Et3N,[6,7] followed by decarboxylation. Never-
theless, both methods rely on the use of reactive carboxylic
acid chlorides as reagents for these reactions, requiring their
synthesis from the carboxylic acid precursor.
An alternative and complementary approach would
involve the Pd-catalyzed carbonylative a-arylation of mono-
ethyl potassium malonate with carbon monoxide and aryl
halides (Scheme 1).[8–10] In this way, no reactive intermediates
would be required, thus simplifying the storage of the
reagents. Because of the mild reaction conditions generally
associated with Pd-catalyzed couplings, a wide scope of both
nucleophilic and electrophilic coupling partners would be
allowed. Furthermore, this method would be ideal for the
isotope labeling of the ketone group with carbon-13 and
carbon-14 arising from an isotopically labeled CO, thus
providing easy access to isotopically labeled heterocycles
that are accessible from b-keto esters.
applied with aryl iodides, and their results were generally
unpredictable in product distribution and gave variable yields.
Herein, we report an effective catalytic system based on
palladium, which promotes the carbonylative arylation of
potassium malonate monoesters with aryl bromides, aryl
triflates, and electron-deficient aryl chlorides for the mild and
selective preparation of b-keto esters. Notably, the method
relies on the use of only stoichiometric amounts of carbon
monoxide applied from an solid precursor (COgen)[12] and
delivered ex situ, thereby allowing this approach to be highly
adaptable for carbon-isotope labeling of the keto group.[9,13]
To identify an effective catalytic system for the carbon-
ylative arylation of malonates, we initially examined the
coupling of 4-bromobenzonitrile (1) with monoethyl potas-
sium malonate. In a small optimization study, we quickly
discovered that a combination of [Pd(dba)2] (dba = dibenzy-
lideneacetone) and PtBu3 promoted the carbonylative cou-
pling, allowing the isolation of b-keto ester 2 in high yield and
selectivity over carboxylic acid 3 (Scheme 2).[14,15] Moreover,
for successful coupling, this reaction required both the
addition of MgCl2 (1.2 equiv) and triethylamine (4 equiv).
The use of other magnesium salts, including MgBr2, MgSO4,
Mg(OEt)2 and Mg(OtBu2), provided less interesting results.
Exchanging MgCl2 with ZnCl2 led to a reversal in the product
distribution, exclusively generating 3. Substituting the mono-
Previously, Tanaka and Kobayashi reported a few exam-
ples of the intermolecular carbonylative arylation of malo-
nate derivatives under high CO pressure (20 atm) and at
elevated temperatures (1208C).[11] This method was only
[*] S. Korsager, D. U. Nielsen, Dr. R. H. Taaning, Prof. Dr. T. Skrydstrup
Center for Insoluble Protein Structures (inSPIN), Interdisciplinary
Nanoscience Center (iNANO) and Department of Chemistry
Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C (Denmark)
E-mail: ts@chem.au.dk
[**] We thank the Danish National Research Foundation (DNRF59), the
Villum Foundation, the Danish Council for Independent Research:
Technology and Production Sciences, the Lundbeck Foundation, the
Carlsberg Foundation, and Aarhus University for generous financial
support of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304072.
Scheme 2. Preliminary optimization studies for the carbonylative cou-
pling of 4-bromobenzonitrile (1) with the malonate monoester.
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ethyl potassium malonate with its corresponding sodium salt
or the free acid also led only to the formation of 3.
With these optimized reaction conditions in hand, we set
out to test the generality of this reaction. Gratifyingly,
a variety of aryl bromides successfully coupled to monoethyl
potassium malonate, as shown in Scheme 3. Not only
electron-rich, but also electron-poor aryl bromides proved
to work well, leading to high carbonylative-coupling yields.[16]
Ortho-substituents on the aromatic ring, such as fluorine or
methyl, were also tolerated (compounds 17 and 23). Further-
more, heterocyclic compounds were adaptable to the applied
reaction conditions, as illustrated with b-keto esters 15, 16,
and 18. For the reactions leading to the products 12 and 21, it
was necessary to heat to 1008C to obtain good coupling yields.
Unfortunately, the suitability of the coupling conditions
was short lived, as attempts with an electron-rich aryl
bromide, represented by 4, resulted only in a 20% conversion.
Further optimization was therefore undertaken with this
substrate, as shown in Table 1. Other Pd sources were first
tested and [Pd(cod)Cl2] (cod = 1,5-cyclooctadiene) led to
a small increase in conversion (entry 1), whereas [Pd2-
(cinnamyl)2Cl2] and [Pd2(allyl)2Cl2] were less effective (results
not shown). Screening different ligands revealed that 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos)
was superior, giving full conversion into the desired product
(entry 7). The use of Pd(OAc)2 as the metal source also gave
comparable results (entry 12). Finally, different solvents were
tested to identify a higher-boiling solvent than acetonitrile.
Switching to butyronitrile and dioxane furnished excellent
results, with b-keto ester 5 in both cases isolated in
a satisfactory 99% yield.
Table 1: Optimization of the carbonylative arylation of monoethyl
potassium malonates with aryl bromide 4.[a]
Entry
Ligand
Solvent
Conv. of 4[b] [%] (ratio of 5/6)
1
2
3
4
5
6
7
8
P(tBu3)HBF4
P(o-tol)3
PCy3HBF4
PPh3
CatA
dppf
Xantphos
tBu-Josiphos
dtbpf
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
nPrCN
dioxane
toluene
Me-THF
DMA
24 (>99:1)
<5
<5
16 (>99:1)
26 (>99:1)
31 (>99:1)
>95 (>99:1)
<5
9
<5
<5
10
11[c]
12[d]
13
14
15
16
17
18
dppb
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
90 (>99:1)
>95 (>99:1)
>95 (>99:1)[e]
>95 (>99:1)[e]
52 (>99:1)
>95 (60:40)
<5
DME
72 (>99:1)
[a] All reactions were run in a two-chamber system, as reported earlier.[13]
Chamber A: aryl bromide (0.5 mmol), [Pd(cod)Cl2] (0.025 mmol), ligand
(0.025 mmol), monoethyl potassium malonate (0.55 mmol), MgCl2
(0.6 mmol), Et3N (2 mmol), and MeCN (3 mL) at 808C. Chamber B:
COgen (0.75 mmol), Cy2NMe (1.5 mmol), [Pd(cod)Cl2] (0.038 mmol),
P(tBu)3HBF4 (0.038 mmol), MeCN (3 mL) at 808C for 18 h. [b] Deter-
mined by 1H NMR analysis. [c] PdCl2 was used instead of [Pd(cod)Cl2].
[d] Pd(OAc)2 was used instead of [Pd(cod)Cl2]. [e] 99% yield of isolated
b-ketoester 5. CatA=di(1-adamantyl)-n-butylphosphine, DMA=dime-
thylacetamide, DME=1,2-dimethoxyethane, dppb=1,4-bis(diphenyl-
phosphino)butane, dppf=1,1’-bis(diphenylphosphino)ferrocene,
dtbpf=1,1’-bis(di-tert-butylphosphino)ferrocene, tBu-Josiphos(2R)-1-
{(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl}-2-(diphenylphosphino)-
ferrocene.
Scheme 3. Carbonylative arylation of monoethyl potassium malonate
with aryl halides. Reaction conditions: Chamber A: Aryl bromide
(0.3 mmol), [Pd(cod)Cl2] (0.015 mmol), Xantphos (0.015 mmol),
monoethyl potassium malonate (0.33 mmol), MgCl2 (0.36 mmol), Et3N
(1.2 mmol), and dioxane (3 mL) at 808C. Chamber B: COgen
(0.45 mmol), Cy2NMe (0.9 mmol), [Pd(cod)Cl2] (0.023 mmol),
P(tBu)3HBF4 (0.023 mmol), and dioxane (3 mL) at 808C for 18 h.
[a] Yields in parentheses were obtained from reactions run with Pd-
(OAc)2. [b] Reaction run at 1008C in butyronitrile with Cy2NMe as the
base.
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Scheme 5. Example of the gram-scale synthesis of b-keto ester 2
(30 mmol scale) with low catalyst loading.
formation of the acylated malonate B: 1) direct nucleophilic
acyl substitution on the acyl complex A; 2) a transmetalation
step, involving the magnesium malonate followed by reduc-
tive elimination; 3) reductive elimination of complex A to
generate the acyl bromide, followed by a nucleophilic acyl-
substitution step. Acid-promoted decarboxylation would then
lead to the desired product.
Finally, we examined the usefulness of this method for the
synthesis of isotopically labeled aryl and heteroaryl systems
(Scheme 7). The introduction of a single site-specific carbon-
13 label into b-keto esters was shown for the synthesis of
[13C]2 by replacing COgen with 13COgen. In this way, 300 mg
of [13C]2 could be secured on a 1.5 mmol scale (92% yield).
Both b-keto ester 2 and [13C]2 were easily transformed into
a benzene ring by reaction with dimethyl acetylenedicarbox-
ylate, yielding compounds 32 and [13C]32. Reaction with (4-
bromophenyl)hydrazine led to the pyrazoles 33 and [13C]33
Scheme 4. Carbonylative arylation of monoethyl potassium malonate
with aryl halides. Reaction conditions: Chamber A: aryl halide
(0.5 mmol), [Pd(cod)Cl2] (0.025 mmol), Xantphos (0.025 mmol), mon-
oethyl potassium malonate (0.55 mmol), MgCl2 (0.6 mmol), Et3N
(2 mmol), and dioxane (3 mL) at 808C. Chamber B: COgen
(0.75 mmol), Cy2NMe (1.5 mmol), [Pd(cod)Cl2] (0.0375 mmol),
P(tBu)3HBF4 (0.0375 mmol), dioxane (3 mL) at 808C for 18 h. [a] Reac-
tion run at 1208C in diglyme with Cy2NMe as the base.
In these cases, triethylamine was substituted for Cy2NMe
(Cy = cyclohexyl), and butyronitrile was used as a higher-
boiling solvent. It should be noted in examples 24–29 that the
developed procedure can be adapted to other monoester
potassium malonates, including those with substituents in the
a-position.
As demonstrated in Scheme 4, electron-deficient aryl
chlorides can likewise be transformed into the corresponding
b-ketoesters (2, 10 and 11) in good yields. For full conversion,
it is necessary to run these reactions at elevated temperatures
(1208C), and hence diglyme was used as the solvent.[17] On the
other hand, both a benzyl chloride and an aryl triflate
functioned well under the standard conditions, as shown with
the b-keto esters 30 and 31, respectively.
The pressure was measured over the course of the
carbonylative coupling of aryl bromide 1 with monoethyl
potassium malonate (0.3 mmol scale); it showed a rapid
increase to approximately 1.9 bar, as a result of CO release.[14]
As the carbon monoxide is consumed, the reaction pressure
decreases by 0.72 bar, which corresponds to 0.3 mmol of CO
(1 equiv). Hence, decarboxylation does not take place during
the reaction; if this was the case, the reaction pressure should
remain constant at ca. 1.9 bar throughout the reaction course
(one CO provides one CO2). Instead, decarboxylation must
occur upon quenching of the reaction mixture with formic
acid.[18]
Scheme 6. Possible mechanistic scenario.
The efficiency of accessing b-keto esters on a larger scale
was next investigated. The carbonylative coupling was applied
to the synthesis of ethyl 3-(4-cyanophenyl)-3-oxopropanoate
2 on a 30 mmol scale (Scheme 5). To our delight, the catalyst
loading could be reduced to 0.5 mol% with no reduction in
the product yield. Hence, 5.4 g of b-keto ester 2 could be
isolated in 96% yield.
In Scheme 6, we provide a possible mechanism for this Pd-
catalyzed transformation. Oxidative addition into the aryl–
halide bond followed by CO insertion provides Pd–acyl
complex A. At this point three scenarios could explain the
Scheme 7. Synthesis of 13C-labeled b-keto ester 2 and the application
of 2 and [13C]2 in cyclization reactions.
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and reaction with thiourea yielded thiazoles 34 and [13C]34. In
all three examples, the C-13 labeling is incorporated in the
ring. Finally, the keto-coumarins 35 and [13C]35 were synthe-
sized in high yield by coupling the b-keto ester with
2-hydroxy-4-methoxybenzaldehyde.
[5] R. J. Clay, T. A. Collum, G. L. Karrick, J. Wemple, Synthesis
1992, 290.
[6] a) M. W. Rathke, P. J. Cowan, J. Org. Chem. 1985, 50, 2622;
b) M. W. Rathke, M. A. Nowak, Synth. Commun. 1985, 15, 1039.
[7] For a review on the use of the MgCl2/NEt3 system in organic
synthesis, see: H. F. Anwar, Synlett 2009, 2711.
In summary, the Pd-catalyzed carbonylative arylation of
potassium malonate monoesters provides a rapid route to
b-keto esters, which serve as direct precursors to important
heterocyclic compounds. The method is adaptable to
a number of aryl bromides and other substrates, including
aryl chlorides possessing electron-poor substitutents. Further-
more, this technique proves effective for carbon-isotope
labeling of biologically relevant structures, such as coumarins,
pyrazoles, thiazole, and benzene derivatives. Further work is
in progress to examine other carbonylative couplings using
the MgCl2/Et3N system for the preparation of dicarbonyl
systems such as b-ketoamides and related systems.
[8] For some recent reviews on Pd-catalyzed carbonylations, see:
a) X.-F. Wu, H. Neumann, M. Beller, Chem. Rev. 2013, 113, 1;
b) X.-F. Wu, H. Neumann, M. Beller, Chem. Soc. Rev. 2011, 40,
4986; c) J. Magano, J. R. Dunetz, Chem. Rev. 2011, 111, 2177;
d) R. Grigg, S. P. Mutton, Tetrahedron 2010, 66, 5515; e) A.
Brennfꢀhrer, H. Neumann, M. Beller, Angew. Chem. 2009, 121,
4176; Angew. Chem. Int. Ed. 2009, 48, 4114.
[9] T. M. Gøgsig, R. H. Taaning, A. T. Lindhardt, T. Skrydstrup,
Angew. Chem. 2012, 124, 822; Angew. Chem. Int. Ed. 2012, 51,
798.
[10] The Pd-catalyzed decarboxylative cross coupling of monoethyl
potassium malonate with aryl halides has been reported for the
synthesis of aryl acetic acid derivatives. However, the reaction
conditions require heating at 140 – 1508C. Y.-S. Feng, Z.-Q. Xu,
Y. Li, M. Li, H.-J. Xu, Tetrahedron 2012, 68, 2113.
[11] T. Kobayashi, M. Tanaka, Tetrahedron Lett. 1986, 27, 4745.
[12] COgen (9-methylfluorene-9-carbonyl chloride) and COware are
commercially available from Sigma–Aldrich and SyTracks.
[13] a) P. Hermange, A. T. Lindhardt, R. H. Taaning, K. Bjerglund,
D. Lupp, T. Skrydstrup, J. Am. Chem. Soc. 2011, 133, 6061; b) P.
Hermange, T. M. Gøgsig, A. T. Lindhardt, R. H. Taaning, T.
Skrydstrup, Org. Lett. 2011, 13, 2444; c) D. U. Nielsen, R. H.
Taaning, A. T. Lindhardt, T. M. Gøgsig, T. Skrydstrup, Org. Lett.
2011, 13, 4454; d) Z. Xin, T. M. Gøgsig, A. T. Lindhardt, T.
Skrydstrup, Org. Lett. 2012, 14, 284; e) K. Bjerglund, A. T.
Lindhardt, T. Skrydstrup, J. Org. Chem. 2012, 77, 3793; f) T. M.
Gøgsig, D. U. Nielsen, A. T. Lindhardt, T. Skrydstrup, Org. Lett.
2012, 14, 2536; g) M. N. Burhardt, R. H. Taaning, N. C. Nielsen,
T. Skrydstrup, J. Org. Chem. 2012, 77, 5357; h) D. U. Nielsen, K.
Neumann, R. H. Taaning, A. T. Lindhardt, A. Modvig, T.
Skrydstrup, J. Org. Chem. 2012, 77, 6155; i) A. T. Lindhardt, R.
Simonssen, R. H. Taaning, T. M. Gøgsig, G. N. Nilsson, G.
Stenhagen, C. S. Elmore, T. Skrydstrup, J. Labelled Compd.
Radiopharm. 2012, 55, 411; j) M. N. Burhardt, R. H. Taaning, T.
Skrydstrup, Org. Lett. 2013, 15, 948; k) S. Korsager, R. H.
Taaning, T. Skrydstrup, J. Am. Chem. Soc. 2013, 135, 2891; l) S.
Korsager, R. H. Taaning, A. T. Lindhardt, T. Skrydstrup, J. Org.
Chem. 2013, 78, 6112.
Experimental Section
Ethyl 3-(4-cyanophenyl)-3-oxopropanoate (2, Scheme 2): Chamber
A: In an argon-filled glovebox, 4-bromobenzonitrile (54 mg,
0.3 mmol), [Pd(cod)Cl2] (4.3 mg, 0.015 mmol), Xantphos (8.7 mg,
0.015 mmol), monoethyl potassium malonate (56.4 mg, 0.33 mmol),
MgCl2 (34 mg, 0.36 mmol), Et3N (168 mL, 1.2 mmol), and dioxane
(3.0 mL), in that order, were added to chamber A of the two-chamber
COware system.[12] The chamber was sealed with a screwcap fitted
with a Teflon seal. Chamber B (1.5 equiv CO): In an argon-filled
glovebox, HBF4·P(tBu)3 (6.5 mg, 0.023 mmol), [Pd(cod)Cl2] (6.4 mg,
0.023 mmol), 9-methyl-9H-fluorene-9-carbonyl chloride (109 mg,
0.45 mmol), dioxane (3.0 mL), and Cy2NMe (192 mL, 0.9 mmol), in
that order, were added to chamber B of the two-chamber system. The
chamber was sealed with a screwcap fitted with a Teflon seal. The
loaded two-chamber system was removed from the glovebox and
heated to 808C for 18 h. The reaction was quenched with HCO2H,
and the product was purified by flash chromatography using pentane/
CH2Cl2 (1:1!100% CH2Cl2) as eluent. This provided the titled
compound as a mixture of the enol- and keto forms as a colorless solid
1
(57 mg, 86% yield). H NMR (400 MHz, CDCl3): d = 12.55 (s, 1H),
7.86 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 5.71 (s, 1H), 4.28 (q,
J = 7.1 Hz, 2H), 3.99 (s, 1H), 1.33 (t, J = 6.9 Hz, 3H) minor enol
tautomer (characteristic peaks) 8.05 (d, J = 8.6 Hz, 2H), 7.80 (d, J =
8.6 Hz, 2H), 4.21 ppm (q, J = 7.1 Hz, 2H). 13C NMR (100 MHz,
CDCl3): d = 172.7, 168.6, 137.6, 132.3, 126.5, 118.2, 114.4, 89.7, 60.8,
14.2 ppm. HRMS C12H11NO3 [M+H+]; calculated 218.0817, found
218.0813.
[14] See the Supporting Information.
[15] The carboxylic acid 3 is possibly formed from the initial halide
displacement of the acyl PdII halide intermediate by the
magnesium enolate, which is produced from the deprotonation
of monoethyl potassium malonate. Subsequent reductive elim-
ination of the O-bound enolate to generate a mixed acid
anhydride and hydrolysis upon workup would lead to the
benzoic acid product.
[16] The CO insertion step into the Pd – aryl bond can be slow with
aromatic ring systems possessing electron-deficient substituents,
for example, in the carbonylative Suzuki – Miyaura coupling;
see: T. Ishiyama, H. Kizaki, T. Hayashi, A. Suzuki, N. Miyaura, J.
Org. Chem. 1998, 63, 4726. The good yields obtained for our
reaction suggest that the CO insertion step is effective for both
types of aryl bromides and that this step is not rate determining.
Nevertheless, we do not have a clear explanation for this
observation.
Received: May 12, 2013
Revised: June 20, 2013
Published online: July 23, 2013
Keywords: b-keto esters · carbonylation ·
.
homogeneous catalysis · isotope labeling · palladium
[1] A. Geuther, Arch. Pharm. 1863, 106, 97.
[2] R. L. Claisen, Arch. Pharm. 1887, 20, 651.
[3] For reviews on methods for accessing b-keto esters, see: a) C. R.
Hauser, B. E. Hudson, Org. React. 1942, 1, 266; b) P. L. Pollet, J.
Chem. Educ. 1983, 60, 244; c) S. Benetti, R. Romagnoli, Chem.
Rev. 1995, 95, 1065.
[4] For selected reviews on the synthesis of heterocycles from b-keto
esters, see: a) P. Langer, Chem. Eur. J. 2001, 7, 3858; b) C. Simon,
T. Constantieux, J. Rodriguez, Eur. J. Org. Chem. 2004, 4957.
[17] Aryl chlorides with electron donating groups were unreactive to
these reaction conditions at 1208C.
[18] Upon quenching of the reaction mixture with formic acid,
considerable gas evolution was observed.
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