Our former endeavors1c,d in generating diverse benzo[b]-
furan-3-carboxylic esters (3) (a, Scheme 1) using Pd
chemistry encouraged us to further explore this cascade PdII
chemistry for constructing the benzofuran-3-carboxylic acids
(2) (b, Scheme 1) directly from the o-hydroxyarylacetylenes
(1). This approach was initially investigated in a model study
by using stoichiometric amounts of Pd reagent and ligand.
R3OH (a, Scheme 1) could not simply be replaced by H2O
in order to generate carboxylic acids since the CO is readily
oxidized into formic acid in the presence of H2O, leading to
the palladium bleeding,5 which is indeed consistent with our
observation.
Table 1. Optimization of the Conditions
In the absence of the alcohol, our most efficient conditions
to generate benzo[b]furan-3-carboxylic esters (3) (a, Scheme
1) in the solution phase1c could not produce any acid 2a
(Table 1, entry 1), whereas the conditions we optimized for
synthesis of the 3 (a, Scheme 1) on solid phase1d did result
in the generation of the corresponding acid 2a in a low yield
(30%) with o-acetyloxyarylacetylene 3a (29%) as an unusual
byproduct (Table 1, entry 2). To increase the yield and
suppress this side reaction, various PdII species, counter-
anions, ligands, bases, and solvents were systematically
investigated (Table 1).
The solvent effect was first studied (Table 1, entries 2-5),
and CH3CN was found to provide the best result in
comparison with DMF, THF, or benzene.
Notably, bases other than the CsOAc (Table 1, entries 1,
6-9), such as organic bases selected for avoiding side
product 3a, blocked the reactions.
Among various PdII species investigated (Table 1, entries
10-13), Pd(CH3CN)2Cl2 was found to be the most reactive.
Various ligands were tested (Table 1, entries 14-19).
Obviously, electron-rich ligands are not favorable for in-
creasing the reactivity of the cationic PdII species. Finally,
2-PyPPh2, a highly efficient ligand for PdII-catalyzed Reppe
carbonylation,6 proved outstanding in our case, the yield of
2a dramatically being increased up to 70% and the byproduct
3a notably being suppressed to less than 10% (Table 1, entry
19).
To make the PdII species more cationic so as to further
increase its reactivity, AgOTs was added to extract Cl- from
the Pd(CH3CN)2Cl2 by forming AgCl and exchange Cl- with
a noncoordinating OTs-, which is a superior counteranion
for PdII.6,7 As a result, the side product 3a was completely
suppressed and the yield of 2a was increased to 80% (Table
1, entry 20). Similarly, AgBF4 was also tested, and a
comparable result was obtained (Table 1, entry 21). Further
reaction studies were performed by using a commercially
available cationic Pd(CH3CN)4(BF4)2 in the absence of any
silver salts, a satisfactory yield of 70% was achieved.
However, 10% of byproduct 3a was generated. Therefore,
based on our investigation, silver salt did play an important
role in suppressing the side reaction of acetylation.
By using the optimized conditions (Table 1, entry 20),
various o-hydroxyarylacetylenes with different substitution
patterns were transformed into their corresponding benzo-
[b]furan-3-carboxylic acids (2a-2g, Table 2), all in good
yields, which proved the significance of this novel method.
Many oxidants, such as O2, 1,4-benzoquinone, DDQ, Fe-
(OTs)3, CuCl2, Cu(OAc)2, CBr4, etc., were tried in order to
turn over the Pd0 back to PdII. Currently, the best result (40%
yield) was achieved by using Pd(CH3CN)4(BF4)2 (5%) and
1,4-benzoquinone (2 equiv).
(5) Fenton, D. M.; Steinwand, P. J. J. Org. Chem. 1974, 39, 701.
(6) (a) Drent, E.; Arnoldy, P.; Budzelaar, P. H. M. J. Orangomet. Chem.
1994, 475, 57. (b) Drent, E.; Arnoldy, P.; Budzelaar, P. H. M. J. Orangomet.
Chem. 1993, 455, 247.
(7) (a) Tsuji, J. Acc. Chem. Res. 1973, 6, 8. (b) Oi, S.; Nomura, M.;
Aiko, T.; Inoue, Y. J. Mol. Catal. A: Chem. 1997, 115, 289.
During our model study, two observations came to our
attention: one was the acetylation of substrate 1a (Table 1)
as a major side reaction, and the other was that bases other
than AcO- hardly promoted any formation of the product
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Org. Lett., Vol. 7, No. 13, 2005