Synthesis of 2-substitued 3-aroylindenes via palladium-catalyzed carbonylative cyclization of diethyl 2-(2-(1-alkynyl)phenyl)malonates with aryl halides

Article abstract of DOI:10.1021/ol061019v

The palladium-catalyzed reaction of readily accessible diethyl 2-(2-(1-alkynyl)phenyl)malonates with aryl halides under a balloon pressure of CO produced 2-substitued 3-aroylindenes in good yields. The reaction is believed to proceed via cyclization of th

Full text of DOI:10.1021/ol061019v

ORGANIC
LETTERS
2006
Vol. 8, No. 14
3053-3056
Synthesis of 2-Substitued
3-Aroylindenes via Palladium-Catalyzed
Carbonylative Cyclization of Diethyl
2-(2-(1-Alkynyl)phenyl)malonates with
Aryl Halides
Xin-Hua Duan,† Li Na Guo,† Hai-Peng Bi,† Xue-Yuan Liu,† and Yong-Min Liang*,†,‡
−
State Key Laboratory of Applied Organic Chemistry, Lanzhou UniVersity, Lanzhou
730000, P. R. China, and State Key Laboratory of Solid Lubrication, Lanzhou Institute
of Chemical Physics, Chinese Academy of Science, Lanzhou 730000, P. R. China
liangym@lzu.edu.cn
Received April 27, 2006
ABSTRACT
The palladium-catalyzed reaction of readily accessible diethyl 2-(2-(1-alkynyl)phenyl)malonates with aryl halides under a balloon pressure of
CO produced 2-substitued 3-aroylindenes in good yields. The reaction is believed to proceed via cyclization of the alkyne containing a proximate
nucleophilic center promoted by an acylpalladium complex.
The transition metal-catalyzed cyclization of alkynes has
recently proven to be a powerful method for the construction
of a variety of carbo- and heterocycles.1 Among them, the
palladium-catalyzed carbonylative cyclization of alkynes
bearing proximate nucleophilic centers with use of unsatur-
ated organic halides/triflates in the presence of carbon
monoxide has also been shown to be extremely effective for
the synthesis of ketone-containing isoquinolines,2 indoles,3
and benzofurans.4 Such reactions could generate one carbon-
heteroatom bond and two carbon-carbon bonds in a single
synthetic operation. However, the corresponding reactions
with carbon nucleophiles to give three carbon-carbon
bonded species are rare.
Very recently, we described a convenient approach to the
synthesis of 2,3-disubstituted indenes from diethyl 2-(2-(1-
alkynyl)phenyl)malonates and a wide variety of organic
halides (Scheme 1).5 Our continuing interest in the synthesis
of indenes derivatives by this chemistry as well as the
valuable biological activity6 exhibited by some substituted
indenes (their metallocene complexes may also be utilized
to catalyze olefin polymerization)7 led us to investigate the
extension of the methodology to the synthesis of substituted
* Address correspondence to this author. Fax: +86-931-8912582.
Phone: +86-931-8912593.
† Lanzhou University.
‡ Chinese Academy of Science.
(1) For some recent reviews, see: (a) Cacchi, S.; Fabrizi, G. Chem. ReV.
2005, 105, 2873. (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV.
2004, 104, 3079. (c) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285.
(d) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127.
(2) (a) Dai, G.; Larock, R. C. Org. Lett. 2002, 4, 193. (b) Dai, G.; Larock,
R. C. J. Org. Chem. 2002, 67, 7042.
(3) (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Moro, L. Eur. J. Org. Chem.
1999, 1137. (b) Cacchi, S.; Fabrizi, G.; Pace, P.; Marinelli, F. Synlett 1999,
620. (c) Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F. Tetrahedron
1994, 50, 437.
(4) (a) Arcadi, A.; Cacchi, S.; Rosario, M. D.; Fabrizi, G.; Marinelli, F.
J. Org. Chem. 1996, 61, 9280. (b) Hu, Y.; Zhang, Y.; Yang, Z.; Fathi, R.
J. Org. Chem. 2002, 67, 2365.
(5) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. J. Org.
Chem. 2006, 71, 3325.
10.1021/ol061019v CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/17/2006

Scheme 1
Table 2. Palladium-Catalyzed Carbonylative Cyclization of
Diethyl 2-(2-(2-Phenylethynyl)phenyl)malonate with Aryl
Halidesa
indenes. Herein, we wish to report a successful synthesis of
2-substitued 3-aroylindenes by the palladium-catalyzed car-
bonylative cyclization of diethyl 2-(2-(1-alkynyl)phenyl)-
malonates with aryl halides in the presence of CO (Scheme
2).
time
(h)
isolated
entry
ArX (2)
Ar (3a)
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
p-ClC6H4I
24 p-ClC6H4 (3aa)
p-CH3O2CC6H4I 24 p-CH3O2CC6H4 (3ab)
83 (0)
90 (0)
75 (0)
83 (0)
52 (7)
42 (6)
61 (0)
51 (0)
89 (0)
85 (0)
62 (0)
78 (15)
65 (0)
15 (22)
p-NO2C6H4I
p-CF3C6H4I
p-CH3C6H4I
p-CH3OC6H4I
PhI
m-CH3C6H4I
m-ClC6H4I
m-NO2C6H4I
o-CH3C6H4I
24 p-NO2C6H4 (3ac)
24 p-CF3C6H4 (3ad)
48 p-CH3C6H4 (3ae)
48 p-CH3OC6H4 (3af)
24 Ph (3ag)
48 m-CH3C6H4 (3ah)
24 m-ClC6H4 (3ai)
24 m-NO2C6H4 (3aj)
48 o-CH3C6H4 (3ak)
Scheme 2
o-CH3O2CC6H4I 24 o-CH3O2CC6H4 (3al)
2-iodothiophene 48 2-thienyl (3am)
p-NO2C6H4Br
48 p-NO2C6H4 (3ac)
Initially, we started out our investigation of the reaction
by using 1.0 equiv of diethyl 2-(2-(2-phenylethynyl)phenyl)-
malonate (1a; 0.2 mmol), 1.2 equiv of 4-chloroiodobenzene
under a balloon pressure of CO employing 5 mol % of Pd-
(PPh3)4 and 2.0 equiv of K2CO3 in DMF at 100 °C for 24 h,
reaction conditions that were used in our earlier palladium-
catalyzed synthesis of 2,3-disubstituted indenes.5 The desired
product, diethyl 3-(4-chlorobenzoyl)-2-phenyl-1H-indene-
1,1-dicarboxylate (3aa), was formed in only a 34% isolated
a All reactions were carried out under the optimal conditions reported in
the text. b The numbers in parentheses are the isolated yields of the
corresponding 2-phenyl 3-arylindenes 4a.
yield, the other diethyl 3-(4-chlorophenyl)-2-phenyl-1H-
indene-1,1-dicarboxylate (4aa) was also isolated in 52% yield
(Table 1, entry 1). 2-Phenyl 3-arylindene 4aa was formed
without incorporation of CO by a process reported previously
by us.5 Tri-n-butylamine and KOAc were ineffective (Table
1, entries 2 and 3). When KOt-Bu was used as the base,
only the 2-phenyl 3-arylindene 4aa was isolated (Table 1,
entry 4).
Table 1. Optimization of the Palladium-Catalyzed
Carbonylative Cyclization of Diethyl
2-(2-(2-Phenylethynyl)phenyl)malonate and
4-Chloroiodobenzenea
Changing the solvent from DMF to DMSO did not
enhance the yield of 3aa or the selectivity between the two
indene products (Table 1, entry 5). Using acetonitrile as the
solvent at 80 °C led to cleaner reaction, affording the desired
product 3aa in 22% yield with none of the side product 4aa
(Table 1, entry 6). Fortunately, the yield increased to 83%
.
when the catalyst Pd2(dba)3 CHCl3 was employed instead of
Pd(PPh3)4 (Table 1, entry 7). Other palladium catalysts tested,
such as Pd(dba)2 and Pd(OAc)2/PPh3, were less effective
(Table 1, entries 8 and 9). The optimum reaction conditions
thus far developed employ 1.0 equiv of 1a, 1.2 equiv of the
aryl halide, 5 mol % of Pd2(dba)3‚CHCl3, and 2.0 equiv of
K2CO3 in CH3CN at 80 °C under a balloon pressure of CO.
palladium
catalysis
temp isolated yield
solvent (°C)
entry
base
of 3aa (%)b
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
K2CO3
DMF
100
100
100
100
34 (52)
no reaction
no reaction
0 (65)
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3‚CHCl3 K2CO3
Pd(dba)2
Pd(OAc)2/PPh3
(n-Bu)3N DMF
KOAc DMF
KOt-Bu DMF
K2CO3
K2CO3
DMSO 100
20 (35)
22 (0)
83 (0)
55 (0)
15 (0)
(6) (a) Kikuchi, T.; Tottori, K.; Uwahodo, Y.; Tanaka, H.; Ichikawa,
H.; Ono, Y.; Nakai, S. PCT Int. Appl. 9621449, 1996; Chem. Abstr. 1996,
125, 204539. (b) Mederski, W.; Dorsch, D.; Wilm, C.; Osswald, M.;
Schmitges, C.-J.; Christadler, M. Ger. Offen. 19711785, 1998; Chem. Abstr.
1998, 129, 275905. (c) Dillard, R.; Hagishita, S.; Ohtani, M. PCT Int. Appl.
9603120, 1996; Chem. Abstr. 1996, 125, 341826. (d) Kouznetsov, V. V.;
Puentes, C. O.; Bohorquez, A. R. R.; Zacchino, S. A.; Sortino, M.; Gupta,
M.; Vazquez, Y.; Bahsas, A.; Amaro-Luis, J. Lett. Org. Chem. 2006, 3,
300.
CH3CN
CH3CN
CH3CN
CH3CN
80
80
80
80
K2CO3
K2CO3
a Reactions were carried out on a 0.2 mmol scale in 2.0 mL of solvent
under CO at 100 °C or 80 °C with 1.0 equiv of 1a, 1.2 equiv of 2a, 2.0
equiv of base, and 0.05 equiv of [Pd]. b The numbers in parentheses are
the isolated yields of the corresponding 2-phenyl 3-arylindene 4aa.
(7) Spaleck, W.; Antberg, M.; Dolle, V.; Klein, R.; Rohmann, J.; Winter,
A. New J. Chem. 1990, 14, 499.
3054
Org. Lett., Vol. 8, No. 14, 2006

Table 3. Palladium-Catalyzed Carbonylative Cyclization of
Diethyl 2-(2-(1-Alkynyl)phenyl)malonates with Methyl
4-Iodobenzoatea
Table 4. Palladium-Catalyzed Carbonylative Cyclization of
Ethyl Acetate Alkynes with Methyl 4-Iodobenzoatea
time
(h)
isolated
entry
E
3b
yield (%)b
time
(h)
isolated
entry
R1
3b
yield (%)b
1
2
SO2Ph (1g)
CN (1h)
24
24
3gb
3hb
55 (0)
65 (0)
1
2
3
4
5
p-CH3OC6H4 (1b)
p-NO2C6H4 (1c)
p-BrC6H4 (1d)
1-cyclohexenyl (1e)
n-pentyl (1f)
24
24
24
24
24
3bb
3cb
3db
3eb
3fb
80 (0)
93 (0)
85 (0)
70 (0)
60 (0)
a All reactions were carried out under the optimal conditions reported in
the text. b The numbers in parentheses are the isolated yields of the
corresponding 2-phenyl 3-arylindenes.
a All reactions were carried out under the optimal conditions reported in
the text. b The numbers in parentheses are the isolated yields of the
corresponding 2-substitued 3-arylindenes.
We have also investigated the reactions of diethyl malonate
alkynes containing different R1 groups at the end of the triple
bond with an aryl iodide. With methyl 4-iodobenzoate,
diethyl malonate alkynes with an electron-withdrawing group
or an electron-donating group on the benzene ring were
employed in the reaction, and the corresponding products
were isolated in high yields (Table 3, entries 1-3). Diethyl
malonate alkyne 1e bearing a 1-cyclohexenyl group afforded
the corresponding 2-substitued 3-aroylindene 3eb in a good
yield of 70% (Table 3, entry 4). Diethyl malonate alkyne 1f
containing an n-pentyl group afforded the desired product
3fb in a 60% yield (Table 3, entry 5).
Furthermore, ethyl acetate alkynes with different electron-
withdrawing groups, such as ethyl 2-(2-(2-phenylethynyl)-
phenyl)-2-(phenylsulfonyl)acetate (1g) and ethyl 2-cyano-
2-(2-(2-phenylethynyl)phenyl)acetate (1h), have also been
allowed to react with methyl 4-iodobenzoate to afford
moderate yields of the desired products 3gb and 3hb (Table
4, entries 1 and 2).
To extend the general applicability of this carbonylative
cyclization reaction, the reaction of diethyl malonate alkyne
1a with various aryl halides was carried out under the above-
optimized conditions, and the results are summarized in Table
2. Aryl iodides bearing an electron-withdrawing group or
an electron-donating group in the para, meta, and ortho
positions afforded the corresponding multiply substituted
indenes 3a in moderate to good yields (Table 2, entries 1-6
and 8-12). Aryl iodides bearing an electron-withdrawing
group in the para position usually led to good yields of the
2-phenyl 3-aroylindenes (Table 2, entries 1-4). When
4-methyliodobenzene and 4-iodoanisole were employed in
the reaction with substrate 1a (Table 2, entries 5 and 6), the
corresponding products 3ae and 3af were isolated in 52%
and 42% yields along with low yields of the side products
diethyl 2-phenyl-3-p-tolyl-1H-indene-1,1-dicarboxylate (4ae)
and diethyl 3-(4-methoxyphenyl)-2-phenyl-1H-indene-1,1-
dicarboxylate (4af). Iodobenzene also afforded 3ag in
satisfactory yield (Table 2, entry 7). The reactions of 1a and
aryl iodides with an electron-withdrawing group, such as a
Cl or NO2 group in the meta position, afforded the desired
products 3ai and 3aj in high yields (Table 2, entries 9 and
10). 3-Methyliodobenzene gave a modest yield of the indene
product 3ah (Table 2, entry 8). Aryl iodides bearing an
electron-withdrawing group or an electron-donating group
in the ortho position have also proven successful. For
example, the reaction of 2-methyliodobenzene and methyl
2-iodobenzoate produced 62% and 78% yields of the desired
products, respectively (Table 2, entries 11 and 12). In
addition, the use of 2-iodothiophene also afforded the indene
3am in 65% yield (Table 2, entry 13). In most of these
reactions, only a very small amount of or no 2-phenyl-3-
arylindene 4a was isolated. Thus, these reactions exhibit good
reaction selectivities. Unlike aryl iodides, aryl bromides such
as 4-bromonitrobenzene gave the low yield of diethyl 3-(4-
nitrobenzoyl)-2-phenyl-1H-indene-1,1-dicarboxylate (3ac)
and poor selectivity (Table 2, entry 14).
The mechanism shown in Scheme 3 is proposed for this
process. It is similar to mechanisms proposed in previously
Scheme 3
Org. Lett., Vol. 8, No. 14, 2006
3055

reported palladium-catalyzed syntheses of isoquinolines,2
indoles,3 benzofurans,4 and furans.8 It consists of the fol-
lowing key steps: (1) oxidative addition of the aryl halide
to the Pd(0) catalyst, followed by CO insertion,9 (2)
coordination of the resulting acylpalladium intermediate 6
to the alkyne triple bond to form complex 7,2,3,4,8 (3) insertion
of the alkyne in the aroyl palladium complex 7 to form a
vinylic palladium intermediate, 8, (4) generation of a
carbanion by the base, (5) intramolecular nucleophilic attack
of the carbanion on the vinylic palladium intermediate to
afford a palladacyclic intermediate, 10,10 and (6) reductive
elimination of the intermediate to furnish the indene and
regenerate the Pd(0) catalyst. One competing process is
cyclization of the starting material diethyl malonate alkynes
promoted by an arylpalladium intermedate 5 to afford
2-substitued 3-arylindenes.5
In summary, an efficient, palladium-catalyzed synthesis
of 2-substitued 3-aroylindenes has been developed. A variety
of aryl iodides undergo this process, giving the desired
products in moderate to good yields with good reaction
selectivities. In particular, three carbon-carbon bonds are
formed in a single operative step.
Acknowledgment. We thank the NSF (NSF-20021001,
NSF-20572038) and the “Hundred Scientist Program” from
the Chinese Academy of Sciences for financial support.
Supporting Information Available: Typical experimen-
tal procedure and characterization for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(8) Arcadi, A.; Rossi, E. Tetrahedron Lett. 1996, 37, 6811.
(9) Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434.
(10) Zhang, D.; Yum, E. K.; Liu, Z.; Larock, R. C. Org. Lett. 2005, 7,
4963.
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