Synthesis of arylacetic acid derivatives from diethyl malonate using in situ formed palladium(1,3-dialkylimidazolidin-2-ylidene) catalysts

Article abstract of DOI:10.1016/j.tetlet.2004.06.012

The in situ prepared three component system Pd(OAc)₂/1,3- bis(alkyl) imidazolinium halide LHX (1-5)/Cs₂CO₃ catalyses the arylation of diethyl malonate efficiently with accompanying dealkoxycarbonylation. Imidazolinium salts with bulky benzyl and alkoxyethyl groups were found to be the most efficient and afforded α-arylacetates in high yields when employing a wide variety of substrates.

Full text of DOI:10.1016/j.tetlet.2004.06.012

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5823–5825
Synthesis of arylacetic acid derivatives from diethyl malonate using
in situ formed palladium(1,3-dialkylimidazolidin-2-ylidene)
catalysts
a
a
b
b,
*
€
ꢀ
Ismail Ozdemir, Murat Yigit, Engin Cßetinkaya and Bekir Cßetinkaya
aDepartment of Chemistry, In€on€u University, 44069 Malatya, Turkey
bDepartment of Chemistry, Ege University, Bornova, 35100 Izmir, Turkey
Received 8 April 2004; revised 22 May 2004; accepted 3 June 2004
Abstract—The in situ prepared three component system Pd(OAc)2/1,3-bis(alkyl) imidazolinium halide LHX (1–5)/Cs2CO3 catalyses
the arylation of diethyl malonate efficiently with accompanying dealkoxycarbonylation. Imidazolinium salts with bulky benzyl and
alkoxyethyl groups were found to be the most efficient and afforded a-arylacetates in high yields when employing a wide variety of
substrates.
Ó 2004 Elsevier Ltd. All rights reserved.
Transition metal-catalyzed cross-coupling is a versatile
and highly useful transformation, which yields a variety
of organic compounds.1 For example, arylation of alk-
enes (Mizoroki–Heck reaction),2 arylboronic acids
(Suzuki–Miyaura reaction),3 aldeydes,4 ketones,5
acetates6 and malonates7 are very often employed. In the
past few years, many attempts have been made to
develop effective palladium complexes for the a-aryla-
tion of carbonyl compounds.8 However, despite sub-
stantial improvements, significant limitations still exist.
For instance, aryl chlorides containing electron-donat-
ing groups have proved problematic. Moreover, the use
of Pd and phosphine ligands limit the attraction of these
methods for certain applications: the phosphine ligands
require air-free handling to prevent their oxidation and
are comparatively difficult to make or rather expensive
to purchase.
direct introduction of an acetic acid ester moiety into an
aromatic ring using palladium-catalyzed reactions.6a
In one approach, a convenient synthesis developed by
Kondo et al. involved the Pd2(dba)3/PBut3 mediated
coupling of diethyl malonate with aryl iodides or bro-
mides at 120 °C in the presence of 10 equiv of Cs2CO3
and gave fair to good yields.10 In this area, aryl chlo-
rides, which are the most attractive class of substrate
due to their low cost and ready availability, have not
exhibited noteworthy reactivity. Thus, it is desirable to
find less costly alternatives and/or operationally simple
procedures.
It has been previously disclosed that N-heterocyclic
carbene (NHC) ligands serve as excellent supporting
ligands in the Pd-catalyzed arylation and olefination of
aryl halides.11–13 It is worth noting that ‘in situ’ forma-
tion of the NHC complex by deprotonation of the imid-
azol(in)ium salt led to significantly better results than
the use of the preformed complex. The success of these
processes as well as the recent report by Kondo et al.10
prompted us to examine whether in situ generated NHC
ligands could be used for other C–C bond forming
reactions. Herein, we report a mild, practical, Pd-cata-
lyzed arylation of malonates using air-stable Pd(OAc)2
as the catalyst, 1,3-bis(alkyl) imidazolinium halides
(LHX) as the NHC ligand precursor, Cs2CO3 as the
base and dioxane as the solvent; the reactions can be
Arylacetic acid derivatives are important structural units
frequently found in analgesics and antiinflammatory
drugs.9 Various approaches have been studied for the
synthesis of a-aryl acetates using coupling reactions and
recently significant progress has been made involving the
Keywords: Arylations; Palladium catalysts; NHC complexes; Diethyl
malonate.
* Corresponding author. Tel.: +90-2323881092; fax: +90-2323881036;
e-mail: bekircetinkaya@hotmail.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.012

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5824
I. Ozdemir et al. / Tetrahedron Letters 45 (2004) 5823–5825
R1
R1
1.5% Pd(OAc)2/LHX
Cs2CO3
dioxane, 80 0C
R2
R2
CH2CO2Et
X
CH2(CO2Et)2
+
R1
R1
Scheme 1.
OMe
OMe
OMe
OMe
OMe
N
+
N
N
OEt
N
N
+
N
OMe
N
+
N
Cl-
Cl-
- OMe
OMe
Cl-
Cl-
+
+
Cl
N
N
OMe
OMe
OMe
OMe
OMe
5
1
2
3
4
Scheme 2. Imidazolinium salts (LHX) used.
performed without protection from air or moisture
(Scheme 1). 1,3-Bis(alkyl)imidazolinium chlorides, LHX
(Scheme 2, 1–5) were prepared according to the litera-
ture.14
(80 °C), shorter reaction times and lower base loadings
than previous work using Pd2(dba)3/PBut3 as catalyst.
The procedure is simple and does not require induction
periods. Secondly, the scope of this reaction is broad
and includes aryl chlorides that are activated or deacti-
vated and 2,6-disubstituted aryl bromide (entries 36–40).
Thirdly, all complexes led to good conversions at low
catalyst concentration (1.5 mol %). Although not dra-
matic, consistent differences in yields were observed in
the reactions according to the ligand precursors 1–5.
Table 1 summarizes our results from screening the five
imidazolinium salts LHX, for a variety of substrates
that undergo arylation accompanied by decarboxylation
to form arylacetic acid esters. Several trends are readily
apparent. Firstly, the use of saturated NHC ligand
precursors (1–5) allowed lower reaction temperatures
a
Table 1. Arylation of diethyl malonate catalyzed by Pd(OAc)2/LHX (1–5)/Cs2CO3
Entry
R1
R2
X
LHX
Time (h)
Yield (%)b;c;d
1
2
3
4
5
H
H
H
H
H
H
H
H
H
H
I
I
I
I
I
1
2
3
4
5
24
24
24
24
24
93
91
89
96
95
6
H
H
H
H
H
COMe
COMe
COMe
COMe
COMe
Br
Br
Br
Br
Br
1
2
3
4
5
24
24
24
24
24
89
87
86
91
89
7
8
9
10
11
12
13
14
15
H
H
H
H
H
NO2
NO2
NO2
NO2
NO2
Br
Br
Br
Br
Br
1
2
3
4
5
24
24
24
24
24
87
85
83
89
88
16
17
18
19
20
H
H
H
H
H
CHO
CHO
CHO
CHO
CHO
Br
Br
Br
Br
Br
1
2
3
4
5
24
24
24
24
24
90
88
87
94
91
21
22
23
24
25
H
H
H
H
H
H
H
H
H
H
Br
Br
Br
Br
Br
1
2
3
4
5
48
48
48
48
48
85
83
81
87
84

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I. Ozdemir et al. / Tetrahedron Letters 45 (2004) 5823–5825
5825
Table 1 (continued)
Entry
R1
R2
X
LHX
Time (h)
Yield (%)b;c;d
26
27
28
29
30
H
H
H
H
H
COMe
COMe
COMe
COMe
COMe
Cl
Cl
Cl
Cl
Cl
1
2
3
4
5
24
24
24
24
24
92
89
85
93
90
31
32
33
34
35
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
Cl
Cl
Cl
Cl
Cl
1
2
3
4
5
24
24
24
24
24
85
83
81
87
84
36
37
38
39
40
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Br
Br
Br
Br
Br
1
2
3
4
5
24
24
24
24
24
85
83
89
91
95
a Reaction conditions: 1.0 mmol of ArX, 1.0 mmol diethyl malonate, 2 mmol Cs2CO3, 1.5 mol % Pd(OAc)2, 3 mol % LHX, dioxane (3 mL).
b Purity of compounds was determined by NMR and yields were based on aryl halides.
c All reactions were monitored by TLC.
d Temperature 80 °C; reaction times were not optimized.
metallics 2000, 19, 741–748; (c) Zapf, A.; Beller, M. Chem.
Eur. J. 2001, 7, 2908–2915.
Presumably, the bulkier and potentially hemilabile
ligands derived from 4 and 5 are more effective in
stabilizing the Pd complex. Bis(trimethoxybenzyl)
substituted precursors such as 2 and 3 gave relatively
poor yields compared with 1, 4 and 5. Control experi-
ments revealed that no reaction was observed in the
absence of the NHC ligand precursors.
3. (a) Mathews, C. J.; Smith, P. J.; Welton, T. J. Mol. Catal.
A: Chem. 2003, 206, 77–82; (b) Heiden, M.; Pleino,
H. Chem. Eur. J. 2004, 10, 1789–1797; (c) Walker, S. D.;
Barder, T. I.; Martinelli, J. R.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2004, 43, 1871–1876.
4. Terao, Y.; Fukuoka, Y.; Satoh, T.; Miura, M.; Nomura,
M. Tetrahedron Lett. 2002, 43, 101–104.
In conclusion, five imidazolinium salts, LHX, as pre-
cursors of 1,3-dialkyl substituted NHC ligands were
evaluated in Pd-catalyzed cross-coupling reactions of
aryl halides with diethyl malonate with accompanying
dealkoxycarbonylation. The reaction was found to
proceed with high conversion (up to 96%) in relatively
short reaction times and at low temperatures to give the
desired arylacetic esters. It is also possible to run the
reaction catalytically under an oxygen atmosphere
without significant loss of yield.
5. (a) Gaertzen, O.; Buchwald, S. L. J. Org. Chem. 2002, 67,
465–475; (b) Lee, S.; Beare, N. A.; Hartwig, J. F. J. Am.
Chem. Soc. 2001, 123, 8410–8411.
6. (a) Jorgensen, M.; Lee, S.; Liu, X.; Wokowski, J.
P.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 12557–
12565; (b) Moradi, W. A.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7996–8002.
7. (a) Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67,
541–555; (b) Wokowski, J. P.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2002, 41, 4289–4291.
8. (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36,
234–245; (b) Lloyd-Jones, G. C. Angew. Chem., Int. Ed.
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9. Dannhardt, G.; Kiefer, W. Eur. J. Med. Chem. 2001, 36,
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Acknowledgements
10. Kondo, Y.; Inamoto, K.; Uchiyama, M.; Sakamoto,
T. Chem. Commun. 2001, 2704–2705.
We thank the Technological and Scientific Research
€
Council of Turkiye TUBITAK (TUBITAK COST D17)
_
€
€
and Inonu University Research Fund (BAP 2002/23) for
€
€
11. (a) Bohm, V. P. W.; Gstottmayr, C. W. K.; Weskamp,
T.; Herrmann, W. A. J. Organomet. Chem. 2000, 595, 186–
€ €
financial support of this work.
€
190; (b) Furstner, A.; Leitner, A. Synlett 2001, 290–292.
€
€
€
12. Gurbuz, N.; Ozdemir, I.; Demir, S.; Cßetinkaya, B. J. Mol.
Catal. A: Chem. 2004, 209, 23–28.
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