Development of a decarboxylative palladation reaction and its use in a Heck-type olefination of arene carboxylates

Article abstract of DOI:10.1021/ja027523m

The development of a palladium-catalyzed decarboxylative coupling reaction of arene carboxylates with olefinic substrates is described. The optimized procedure for decarboxylative palladation employs Pd(O₂CCF₃)₂ as catalys

Full text of DOI:10.1021/ja027523m

Published on Web 08/29/2002
Development of a Decarboxylative Palladation Reaction and Its Use in a
Heck-type Olefination of Arene Carboxylates
Andrew G. Myers,* Daisuke Tanaka, and Michael R. Mannion
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received July 1, 2002
We describe the development of a palladium-catalyzed decar-
boxylative coupling reaction of arene carboxylates with olefinic
substrates. The process can be viewed as proceeding by an initial
Ar-SE reaction, depicted in Scheme 1, involving ipso attack of an
electrophilic Pd(II) intermediate on an arene carboxylate to form
an arylpalladium(II) species with loss of carbon dioxide. This
intermediate is then proposed to react with an olefinic substrate by
steps common to the Heck coupling process.1
15-18). Our experiments suggest that at least one ortho substituent
is necessary for successful decarboxylative palladation to occur
(vide infra). Many o,o-disubstituted benzoic acids were effective
substrates; the coupling reactions of the sterically hindered mesi-
tylene carboxylic acid (entries 7 and 8) are particularly noteworthy.
Several alkenes were used successfully as Heck reaction partners,
including styrene, acrylates, (E)-ethyl crotonate (entry 4), and,
notably, cyclohexenone (entries 5, 8).2
The primary pathway mitigating decarboxylative palladation in
those cases where this was not the major course of reaction was an
apparent C-H insertion or ortho-palladation reaction, a pathway
that was especially prevalent among substrates lacking ortho
substituents, those with a single ortho substituent, and in certain
heteroaromatic systems. For example, p-anisic acid was observed
to form the isocoumarin derivative 3,3 while 2-benzofurancarboxylic
acid reacted by a slightly different sequence to form trans,trans-
2,3-distyrylbenzofuran (4) (see also Table 1, entry 18 and Sup-
porting Information). Use of 5% DMSO-DMF as solvent was found
to maximize the decarboxylative coupling pathway relative to C-H
insertion (e.g., 1b f 2b, 70% yield, whereas in DMF alone the
isocoumarin 5 was the major product).
Scheme 1
A large number of palladium sources, as well as other metals,
were screened for their ability to promote the decarboxylative
coupling of 2,4,5-trimethoxybenzoic acid (1a) with styrene. After
many unsuccessful experiments, we discovered that warming of
1a and styrene (1.2 equiv) in the presence of potassium carbonate
(5 equiv), palladium(II) trifluoroacetate (0.15 equiv), and copper-
(II) trifluoroacetate (hydrate, 2 equiv) in DMSO (85 °C, 12 h) led
to the formation of the coupling product trans-2,4,5-trimethox-
ystilbene (2a) in 82% yield. These conditions did not translate well
with other, less electron-rich carboxylic acid substrates, which could
be recovered unchanged from the reaction mixture, pointing toward
a problem in the decarboxylation step. Two critical reaction
parameters were identified whose modification led to a more general
and efficient method. First, the use of the additive silver(I) carbonate
(3 equiv), in lieu of K2CO3 and Cu(O2CCF3)2, was found to
dramatically improve the efficiency of the decarboxylation reaction.
This additive presumably functions as both a base and a stoichio-
metric oxidant and is believed to prolong the lifetime of the active
catalyst. The second critical parameter proved to be the reaction
solvent. The optimum reaction medium was found to be 5% DMSO
in DMF. Use of either solvent alone led to dramatically reduced
yields of coupling products (vide infra).
Under these presently optimal reaction conditions (0.2 equiv of
Pd(O2CCF3)2, 3 equiv of Ag2CO3, 5% DMSO-DMF), a wide range
of arene carboxylates was found to undergo efficient Heck-type
decarboxylative coupling with olefinic substrates between 80 and
120 °C (0.5-3 h reaction time, Table 1). Reactions could be
conducted in the air (all entries, Table 1), under nitrogen, or under
pure oxygen without discernible differences and were unaffected
by small amounts of water. Good coupling yields were obtained
with many electron-rich carboxylic acid substrates (entries 1-6),
as well as substrates with electron-withdrawing substituents such
as fluoro, chloro, bromo, and nitro (entries 9-14). Certain
heterocyclic carboxylic acids were also effective substrates (entries
Evidence supporting the proposed mechanism for the decar-
1
boxylative coupling process was gained from H NMR studies of
the reaction of 1a with Pd(O2CCF3)2 (1.2 equiv) in pure DMSO-d6
(eq 1). Heating these reactants at 80 °C for 1 h led to the evolution
of CO2 (precipitate formed in lime water) and the disappearance
of resonances associated with 1a. Peaks for a new intermediate,
with arene resonances upfield of those of 1a, were identified (72%
yield based on an internal standard). This intermediate was assigned
as the arylpalladium(II) species 7, a proposal supported by the
finding that addition of styrene (1.5 equiv, 23 °C) led to rapid (<3
min) formation of the coupling product 2a (73%; quantitative based
on 7) with simultaneous precipitation of a solid presumed to be
Pd(0). Further evidence for the assignment of the observed
intermediate as the arylpalladium(II) species was obtained by
treating 7 with excess trifluoroacetic acid (10 equiv) followed by
heating (70 °C, 12 h), leading to quantitative protonolysis to give
1,2,4-trimethoxybenzene. 1H NMR analysis confirmed that the rate
of decarboxylation of 1a was much faster in DMF-d7 containing
small amounts of DMSO-d6 than it was in either solvent alone.
These observations, coupled with those concerning the competing
ortho-palladation reaction discussed above, point toward the unique
effectiveness of low concentrations of DMSO in DMF in the
decarboxylative coupling process. Although speculative at this point,
* To whom correspondence should be addressed. E-mail: myers@
chemistry.harvard.edu.
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J. AM. CHEM. SOC. 2002, 124, 11250-11251
10.1021/ja027523m CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Decarboxylative Olefination Reactionsa
our findings. Among these is the electrophilic decarboxylation of
electron-rich acids to form organomercurials by Hg(II) salts,5 the
Pesci reaction, a hemidecarboxylation of phthalic acids by mercury
salts,6 the decarboxylative substitution of unsaturated acids by Br2,7
+ 9
NBS,8 NO2
,
and H+,10 and palladium-catalyzed Heck-type
couplings of aromatic acid chlorides,11 anhydrides,12 and p-
nitrophenyl esters13 with various olefinic substrates. An important
distinction between our work and earlier palladium-catalyzed
processes is that the latter are proposed to evolve carbon monoxide,
not carbon dioxide as in our work, a proposal which we have
validated experimentally in the case of coupling of acid chlorides
and olefins (Supporting Information). The primary novelty of the
discovery we report is the decarboxylative palladation reaction, a
step which might be productively utilized in ways beyond the
coupling described, for example, in a palladium-catalyzed protio-
decarboxylation reaction of aromatic carboxylic acids or in alterna-
tive C-C bond-forming processes.14
Acknowledgment. Financial support from the National Science
Foundation is gratefully acknowledged. D.T. acknowledges financial
support from Dainippon Pharm. Co. Ltd (Japan), and M.R.M.
acknowledges an NSERC Postdoctoral Fellowship.
Supporting Information Available: Experimental procedures,
spectral data for new compounds (2d, 2g-r, and 4-6), and additional
experimental results (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
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a Conditions: acid (1 equiv), alkene (1.5 equiv), Pd(O2CCF3)2 (0.2 equiv),
Ag2CO3 (3 equiv), 5% DMSO-DMF, 120 °C, except as noted. b Reaction
conducted at 80 °C. c The bis-olefinated product 6 was also formed in 35%
yield.
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Although the transformation we describe is new, there are many
important precedents which must be cited to appropriately reference
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