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Chemistry Letters Vol.37, No.10 (2008)
Facile Synthesis of Alkyl 1-Oxo-3-phenyl-1H-indene-2-carboxylate
through Palladium-catalyzed Carboalkoxylation from 2-Bromo-3-phenylinden-1-ones
Eul Kgun Yum,1 Woul Seong Park,2 Se Hoan Kim,2 Seung Kyu Kang,2
Sung Soo Kim,2 and Jin Hee Ahnꢀ2
1Department of Chemistry, Chungnam National University, Yuseong, Daejeon 305-764, Korea
2Drug Discovery Division, Korea Research Institute of Chemical Technology,
Yuseong, Daejeon 305-600, Korea
(Received August 5, 2008; CL-080762; E-mail: jhahn@krict.re.kr)
Palladium-catalyzed carboalkoxylation of 2-bromo-3-
phenylindenones in various alcoholic solvents afforded diverse
alkyl 1-oxo-3-phenyl-1H-indene-2-carboxylates in high yields.
Table 1. Carboalkoxylation of 2-bromo-3-phenylinden-1-one
under diverse reaction conditions
3 mol% PdII
O
O
6 mol% Ligand
1.2 equiv Base
CO (10 atm)
MeO
MeO
O
Br
OEt
Palladium-catalyzed carbonylation reaction of aryl or vinyl
halides is considered a valuable method for the synthesis of
carboxylic acid derivatives,1 and has been applied to the prepa-
ration of several biologically active substances.2 In the course of
our medicinal chemistry program, the alkyl 1-oxo-3-phenyl-1H-
indene-2-carboxylate (1) (Figure 1) and their N-oxide deriva-
tives were identified as an agonist of peroxisome proliferators-
activated receptor ꢀ (PPARꢀ), which is a promising target for
treatment of diabetes.3
Furthermore, indenone moieties have been shown to be
useful starting materials toward preparing biologically active
molecules such as C-nor-D-homosteroids,4 estrogen-binding
receptors,5 angiotensin II receptor antagonists,6 etc.7 Due to
the structural interests, many synthetic methods of indenone
have been developed using Friedel–Crafts,8 Grignard,9 super-
acid,10 and organometallic11 reaction conditions. We tried to
synthesize indenone compounds 1 by a known method,12
however encountered problems in terms of decomposition of
ꢁ-keto-ester intermediate under acidic conditions. Therefore,
we examined palladium-catalyzed carboalkoxylation with 2-
bromoindenone derivatives. To the best of our knowledge, no
organometallic carboalkoxylation of indenones has been
reported in the literature. Now, we wish to report a facilez
synthetic method for obtaining alkyl 1-oxo-3-phenyl-1H-in-
dene-2-carboxylate from 2-bromo-3-phenylinden-1-one through
palladium-catalyzed carboalkoxylation.
Ph
Ph
EtOH, 125 oC, 4 h
(1a)
Isolated
yield (%)
Entrya
PdII
Ligand
Base
1
2
3
4
5
6
7
8
9
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(dppf)
PdCl2(dppf)
PdCl2(dppf)
PdCl2
—
—
—
—
dppf
dppf
dppf
Ph3P
—
Et3N
Na2CO3
CsF
CsF
CsF
KF
CsF
CsF
CsF
43
43
85
85
85
70b
84
PdCl2
PdCl2
89
<5
92
10
11
Pd(OAc)2
Pd(OAc)2
Ph3P
—
CsF
CsF
<5
aAll reactions were examined with 1 mmol scale. bStaring
material was recovered (20%).
product (i.e., debrominated indenone). When CsF was used as
a base, yield was improved to 85% (Entry 3). Introduction of
PdCl2(dppf) as a catalyst exhibited similar yield of 85% with
PdCl2(PPh3)2 (Entries 4 and 5).
The reaction using KF14 as a base gave 70% yield of ethyl
1-oxo-3-phenyl-1H-indene-2-carboxylate with 20% remaining
starting material (Entry 6). Finally, we examined several reac-
tions using PdCl2 and Pd(OAc)2 catalyst. The reactions provided
high yields of ethyl 1-oxo-3-phenyl-1H-indene-2-carboxylate
with PPh3 ligand (84–92%, Entries 7–11). From the results,
we assumed that the palladium(II) species did not have signifi-
cant influence on carboalkoxylation of indenones, but the yield
of product was significantly influenced by use of base and phos-
phine ligand. The optimum conditions for the carboalkoxylation
were found to be of 3 mol % of PdII, 6 mol % of phosphine li-
gand, 1.2 equiv of CsF respectively and with a specific alcoholic
solvent. Palladium-catalyzed carboalkoxylation using 6-subsuti-
tuted 2-bromo-3-phenylindenone was examined with several
alcoholic solvents under the optimum reaction conditions. The
results are summarized in Table 2. The reactions using ethyl
alcohol as a solvent gave the corresponding ethyl esters in high
yield of 85% (Entries 1 and 2). Similarly reaction using isopro-
pyl alcohol also provided the desired product in 87% (Entry 3).
Furthermore, the reaction using sterically hindered t-butyl
As a model, we investigated a catalytic carboalkoxylation
of 2-bromo-6-methoxy-3-phenylinden-1-one13 in ethyl alcohol
under 10 atmospheres of CO in the presence of PdII and base.
The results are summarized in Table 1. We used PdII catalysts
such as PdCl2, PdCl2(PPh3)2, Pd(dppf), and Pd(OAc)2, which
could be converted to Pd0 species in the reaction medium. In
the presence of PdCl2(PPh3)2 catalyst, using Et3N or Na2CO3
as a base, the desired product was produced in low yields of
43% (Entries 1 and 2) along with significant amount of by-
O
R
O
R = OH, OMe, C6H5(CH2)nO
R1 = Alkyl
OR1
Ph
(1)
Figure 1.
Copyright Ó 2008 The Chemical Society of Japan
Yum, Eul Kgun
