COMMUNICATION
DOI: 10.1002/chem.201301033
Synthesis of Arylacetates from Benzylic Alcohols and Oxalate Esters through
Decarboxylative Coupling
Matthias F. Grꢀnberg and Lukas J. Gooßen*[a]
The development of sustainable methodologies for
carbon–carbon bond formation is among the key objectives
in modern organic synthesis. Catalytic cross-coupling reac-
tions have proven to be efficient and versatile tools for as-
sembling even complex molecular structures.[1] In classical
redox-neutral cross-coupling reactions, carbon electrophiles,
for example, aryl halides [Eq. (1); X=halide], are regiospe-
cifically coupled with carbon nucleophiles, for example, or-
ganometallic compounds (M=main-group metal). Along
example is the Tsuji–Trost allylation (R2 =allyl).[7] The two
above approaches are combined in catalytic decarboxylation
reactions of allyl carboxylates [Eq. (4); R2 =allyl].[8] The
allyl carboxylate substrates provide both the electrophilic
allyl group and the carbon nucleophile that is masked ini-
tially, but liberated at the Pd catalyst by extrusion of CO2,
which is the only byproduct generated in the overall process.
This attractive reaction type was discovered by Saegusa and
Tsuji et al.[9] and has been led to synthetic maturity by the
research groups of Tunge,[10] Stoltz[11] and others.[8] Unfortu-
nately, an extra step is required to preform the starting ma-
terial, which often generates a lot of waste. Moreover, the
reaction is known only for allylic and benzylic esters. How-
ever, recent reports by the research groups of both Garg
and Shi, that aryl carboxylates (R2 =aryl) can undergo oxi-
dative additions to catalyst metals that are capable of medi-
ating decarboxylative processes indicate that this attractive
concept may soon become more generally applicable,
maybe even to biaryl synthesis.[6,12]
À
with the C C coupling products, byproducts are formed re-
sulting from the leaving groups, usually metal salts. Within
the last decade, several strategies have been developed to
overcome the major limitations of this concept, that is, the
necessity to generate sensitive organometallic reagents in an
extra reaction step, the use of environmentally questionable
organohalides, and the formation of salt waste.
To the best of our knowledge, there is still no example of
a regiospecific intermolecular decarboxylative cross-cou-
pling reaction between an alcohol and either a carboxylic
acid or ester [Eq. (5); R3 =H or alkyl].[13] We envisioned
À
that this kind of C C coupling should be achievable by com-
bining a reversible transesterification between an alcohol
and an appropriate alkyl carboxylate with a catalytic decar-
boxylation of the resulting ester. In the overall process, CO2
and an alcohol would be the only byproducts. As a first ex-
ample of such a process, we herein disclose a synthesis of a-
arylacetic acid esters from benzylic alcohols and diethyl oxa-
late (Scheme 1).
a-Arylacetic acids are an important product class because
many of its members possess unique biological and pharma-
ceutical activities (Figure 1).[14] Well-known representatives
include the nonsteroidal anti-inflammatory drugs, diclofenac
and indomethacin, and the antihistamine, olopatadine. Aryl-
acetic acids are also versatile intermediates used, for exam-
ple, in the synthesis of agrochemicals like spiromesifen and
pinoxaden.
One of these strategies consists in replacing traditional
with decarboxylative coupling reactions, which draw on car-
boxylate salts rather than organometallic reagents as the
carbon nucleophiles [Eq. (2)].[2] This reaction type has
found application, for example, in syntheses of biaryls[3] and
arylketones[4] and for the introduction of either allyl or
benzyl groups.[5] Another strategy involves using carboxy-
lates in the place of organohalides in cross-coupling reac-
tions with organometallic reagents [Eq. (3)].[6] A prominent
The overall reaction (Scheme 1, top), in which CO2 and
ethanol are the only byproducts, compares favorably with
classical arylacetic acid syntheses such as the hydrolysis of
benzyl cyanides and the transition metal catalyzed carbon-
[a] M. F. Grꢀnberg, Prof. Dr. L. J. Gooßen
Department of Chemistry, University of Kaiserslautern
Erwin-Schrçdinger-Strasse 54, 67663 Kaiserslautern (Germany)
Fax : (+49)631-205-3921
AHCTUNGTRENNUNG
ylation of benzylic halides or alcohols.[15] It is also a valuable
alternative to modern arylacetic acid syntheses, involving,
Supporting information for this article is available on the WWW
for example, the oxidative carbonylation of toluene,[16] the
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!