Synthesis of indenes by the palladium-catalyzed carboannulation of internal alkynes

Article abstract of DOI:10.1021/ol051907a

(Chemical Equation Presented) A number of highly substituted indenes have been prepared in good yields by treating functionally substituted aryl halides with various internal alkynes in the presence of a palladium catalyst. The reaction is believed to proceed by regioselective arylpalladation of the alkyne and subsequent nucleophilic displacement of the palladium in the resulting vinylpalladium intermediate.

Full text of DOI:10.1021/ol051907a

ORGANIC
LETTERS
2005
Vol. 7, No. 22
4963-4966
Synthesis of Indenes by the
Palladium-Catalyzed Carboannulation of
Internal Alkynes
Daohua Zhang, Eul Kgun Yum, Zhijian Liu, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received August 8, 2005
ABSTRACT
A number of highly substituted indenes have been prepared in good yields by treating functionally substituted aryl halides with various
internal alkynes in the presence of a palladium catalyst. The reaction is believed to proceed by regioselective arylpalladation of the alkyne and
subsequent nucleophilic displacement of the palladium in the resulting vinylpalladium intermediate.
The indene ring system is present in drug candidates
possessing interesting biological activities1 and metallocene
complexes utilized to catalyze olefin polymerization.2 The
importance of indenes has stimulated the development of a
number of approaches for the synthesis of the indene ring
system, including the reduction/dehydration of indanones,3
the cyclization of phenyl-substituted allylic alcohols,4 and
the ring expansion of substituted cyclopropenes.5 Although
these classic methods are quite effective for the synthesis of
simple indenes, they have certain drawbacks in the prepara-
tion of highly substituted indenes, such as the strong acid
medium required, the lengthy reaction sequences involved
and the low tolerance for functionality. These drawbacks
have prompted us to develop a general synthesis of indenes
utilizing palladium-catalyzed annulation methodology.
The palladium-catalyzed annulation of alkynes has proven
to be extremely effective for the synthesis of a wide variety
of carbocycles and heterocycles.1 For example, we have
successfully employed this annulation chemistry for the
synthesis of indoles,6 benzofurans,7 isocoumarins,8 isoquino-
lines,9 carbolines,10 indenones11 and polycyclic aromatic
hydrocarbons.12 The palladium-catalyzed synthesis of these
carbocycles and heterocycles has tremendous advantages
over traditional annulation methods. For example, only
catalytic amounts of palladium are employed, a wide number
of important organic functional groups are readily tolerated,
and the palladium catalyst is quite stable to air and moisture.
(4) Miller, W.; Pittman, C. J. Org. Chem. 1974, 39, 1955.
(5) Yoshida, H.; Kato, M.; Ogata, T. J. Org. Chem. 1985, 50, 1145.
(6) For reviews, see: (a) Larock, R. C. J. Organomet. Chem. 1999, 576,
111. (b) Larock, R. C. Pure Appl. Chem. 1999, 71, 435.
(7) (a) Larock, R. C.; Yum, E. K.; J. Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652.
(8) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. J. Org.
Chem. 1995, 60, 3270.
(9) Larock, R. C.; Doty, M. J.; Han, X. J. Org. Chem. 1999, 64, 8770.
(10) (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 1998, 63, 5306. (b)
Dai, G.; Larock, R. C. J. Org. Chem. 2003, 68, 920. (c) Huang, Q.; Larock,
R. C. J. Org. Chem. 2003, 68, 980.
(1) (a) Kikuchi, T.; Tottori, K.; Uwahodo, Y. PCT Int. Appl. 9621449,
1996; Chem. Abstr. 1996, 125, 204539. (b) Mederski, W.; Dorsch, D.; Wilm,
C.; Osswald, M.; Schmitges, C. Ger. Offen. 1971785, 1998; Chem. Abstr.
1998, 129, 275905. (c) Dillard, R.; Hagishita, S.; Ohtani, M. PCT Int. Appl.
9603120, 1996; Chem. Abstr. 1996, 125, 341826. (d) Senanayake, C.;
Roberts, F.; DiMichele, L.; Ryan, K.; Liu, J.; Fredenburgh, L.; Foster, B.
Tetrahedron Lett. 1995, 36, 3993.
(2) Spaleck, W.; Antberg, M.; Dolle, V.; Klein, R.; Rohmann, J.; Winter,
A. New J. Chem. 1990, 14, 499.
(3) (a) Prough, J.; Alberts, A.; Deanna, A.; Gilfillian, J.; Huff, R.; Smith,
J.; Wiggins, J. J. Med. Chem. 1990, 33, 758. (b) Ikeda, S.; Chatani, N.;
Kajikawa, Y.; Ohe, K.; Murai, S. J. Org. Chem. 1992, 57, 2. (c) Becker,
C.; McLaughlin, M. Synlett 1991, 642.
(11) (a) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67, 9318. (b)
Zhang, H.; Larock, R. C. J. Org. Chem. 2003, 68, 5132.
(12) Larock. R. C.; Doty, M. J.; Cacchi, S. J. Org. Chem. 1993, 58,
4579.
10.1021/ol051907a CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/27/2005

Furthermore, the base-promoted Pd-catalyzed annulation of
alkynes is especially useful for preparing acid-sensitive sub-
stances, such as indenes.13 We herein wish to report a new
synthesis of indenes by the palladium-catalyzed carboannu-
lation of internal alkynes by functionally substituted aryl
halides.
Initial studies were aimed at finding the optimal reaction
conditions for the palladium-catalyzed carbonannulation of
internal alkynes. Our investigation began with the reaction
of diethyl (2-iodophenyl)malonate (1) and 4,4-dimethyl-2-
pentyne (2) (Scheme 1). The reaction was first attempted
The reactions of 1 with symmetrical alkynes, such as
4-octyne and diphenyl acetylene, afforded good yields of the
desired products (entries 2 and 3). The annulation process
is highly regioselective for alkynes containing tertiary alkyl,
trimethylsilyl, or phenyl groups, yielding a single regioisomer
with the more sterically demanding group in the 2-position
of the indene ring (entries 1 and 4-6). The assignment of
regiochemistry is based on analogy with our earlier indole
work.7 In the case of entry 5, a much lower yield (40%) of
the indene product was isolated when KOAc was used rather
than K2CO3.
This process tolerates considerable functionality. For
example, the reaction of 1 with 3-phenyl-2-propyn-1-ol
afforded a 51% yield of a single regioisomer (entry 6). The
reactivity of other functionally substituted aryl halides has
also been examined. Aryl halides bearing two electron-
donating groups, such as 8, still work well with 4,4-dimethyl-
2-pentyne, affording 74% of the desired indene product (entry
7). Interestingly, when aryl bromide was employed, a 46%
yield of the corresponding indene can be obtained (entry 8).
Meanwhile, aryl halides with different electron-withdrawing
groups have also been allowed to react with various internal
alkynes to afford moderate yields of the desired products
(entries 9-11). Several bases, such as KOAc, NaOAc,
K2CO3 and Na2CO3, have been employed in these reactions
and K2CO3 gave the highest yield of the desired annulation
products.
Scheme 1
using 1 equiv of diethyl (2-iodophenyl)malonate (1) (0.25
mmol), 5 equiv of 4,4-dimethyl-2-pentyne, 5 mol % of
Pd(OAc)2 as the catalyst, 1 equiv of n-Bu4NCl, and 2 equiv
of KOAc in 1 mL of DMF at 80 °C. This reaction provided
a 49% yield of the desired indene 2 in 24 h with a small
amount of material which appeared to arise by multiple inser-
tion of the alkyne. To minimize the formation of the multiple-
insertion products, the concentration of the reactants was
lowered by employing 5 mL of DMF as the solvent. This
reaction furnished an 86% yield of the indene product without
any side products, but the reaction took 48 h to reach
completion.
The mechanism shown in Scheme 2 is proposed for this
annulation process. It consists of the following key steps:
Scheme 2
Using 5 mol % of PPh3 as a ligand in this reaction did
not increase the yield of the desired product. The use of other
bases, such as K2CO3, Na2CO3, or organic amine bases,
drastically reduced the yield of the desired product. Other
Pd catalysts, such as PdCl2, PdCl2(PPh3)2, Pd(PPh3)4 and
Pd3(dba)2‚CHCl3, have also been employed in this annulation
reaction. None of them gave a higher yield than Pd(OAc)2.
LiCl was examined as an alternative to n-Bu4NCl, and the
yield was comparable to the corresponding reaction using
n-Bu4NCl. When less than 5 equiv of 4,4-dimethyl-2-pentyne
were used, the reactions were slower and the yields were
lower, presumably due to the extreme volatility of this
alkyne.
On the basis of the above optimization efforts, the
combination of 1 equiv of diethyl (2-iodophenyl)malonate
(1) (0.25 mmol), 5 equiv of internal alkyne, 5 mol % of
Pd(OAc)2, 1 equiv of n-Bu4NCl, and 2 equiv of KOAc in 5
mL of DMF at 80 °C for 2 d gave the best result (Table 1,
entry 1). Having gained an understanding of the factors that
influence the carboannulation process, we explored the scope
and limitation of this method. Further carboannulation results
are summarized in Table 1.
(1) oxidative addition of the aryl halide to the Pd(0) cat-
alyst, (2) arylpalladium coordination to the alkyne and
subsequent insertion of the alkyne to form a vinylic pallad-
ium intermediate, (3) generation of a carbanion by the
base, (4) intramolecular nucleophilic attack of the carbanion
on the vinylic palladium intermediate to afford a pallada-
cyclic intermediate, and (5) reductive elimination of the
(13) (a) Larock, R. C.; Doty, M. J.; Tian, Q.; Zenner, J. M. J. Org. Chem.
1997, 62, 7536. (b) Larock, R. C.; Tian, Q. J. Org. Chem. 1998, 63, 2002.
(c) Huang, Q.; Larock, R. C. J. Org. Chem. 2003, 68, 7342.
4964
Org. Lett., Vol. 7, No. 22, 2005

Table 1. Palladium-catalyzed Carboannulation of Internal Alkynes by Aryl Halidesa
a The reactions were run under the following conditions, unless otherwise specified: 0.25 mmol of the aryl halide, 1.25 mmol of the alkyne, 5 mol % of
Pd(OAc)2, 0.25 mmol of n-Bu4NCl, 0.50 mmol of KOAc stirred in 5 mL of DMF at 80 °C under an N2 atmosphere for 48 h. b 0.25 mmol of LiCl was used
instead of n-Bu4NCl. c 0.50 mmol of the alkyne was used. d 0.50 mmol of K2CO3 was used instead of KOAc.
intermediate to furnish the indene and regenerate the Pd(0)
catalyst.
The oxidative addition of aryl halides to Pd(0) is well-
known and integral to a wide variety of Pd(0)-catalyzed
processes.14 Subsequent syn-addition of the arylpalladium
compound to the alkyne has also been established for the
analogous palladium-catalyzed hydroarylation process15 and
assumed in many other alkyne insertion processes.16 The high
regioselectivity for unsymmetrical alkynes is probably due
(14) Rodd, E. H. Chemistry of Carbon Compounds; Elsevier: Amster-
dam, 1954; Vol. III, p 82.
Org. Lett., Vol. 7, No. 22, 2005
4965

to the steric hindrance present in the developing carbon-
carbon bond. Alkyne insertion occurs so as to generate the
least steric strain in the vicinity of the shorter developing
carbon-carbon bond, rather than the longer carbon-pal-
ladium bond (Figure 1).
palladacycles, a closely related heterocyclic arylpalladium
amide has been reported and shown to undergo analogous
thermal reductive elimination to form the corresponding
aromatic heterocycle.17 It stands to reason that analogous
carbon-containing palladacycles would behave similarly.
The reactions proceed under relatively mild reaction
conditions and generally give good yields. This annulation
process exhibits excellent regioselectivity and is particularly
well suited for the synthesis of hindered 2-substituted
indenes.
Acknowledgment. We gratefully acknowledge the Na-
tional Science Foundation and the donors of the Petroleum
Research Fund, administrated by the American Chemical
Society, for partial support of this research and Johnson
Matthey, Inc., and Kawaken Fine Chemicals Co. Ltd. for
generous donations of palladium salts.
Figure 1. Steric effects on the regiochemistry of alkyne insertion.
Supporting Information Available: General experimen-
tal procedures and characterization data for all starting
materials and products. This material is available free of
charge via the Internet at http://pubs.acs.org.
Analogous regiochemistry is also observed in all of our
previously reported annulation chemistry.6 The subsequent
steps of this process are presumed to be palladacycle
formation and subsequent reductive elimination. Although
we have no actual proof of the intermediacy of such
OL051907A
(17) (a) Negishi, E. Pure Appl. Chem. 1992, 64, 323. (b) Trost, B. M.;
Shi, Y. J. Am. Chem. Soc. 1992, 114, 791. (c) Beydoun, N.; Pfeffer, M.
Synthesis 1990, 729.
(18) (a) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 8232.
(b) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 8451.
(15) (a) Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434. (b)
Tsuji, J. Palladium Reagents and Catalysts; John Wiley & Sons: New York,
1995, 5.
(16) (a) Arcadi, A.; Cacchi, S.; Marinelli, F.; Nardelli, M. Gazz. Chim.
Ital. 1986, 116, 725. (b) Cacchi, S. Pure Appl. Chem. 1990, 62, 713.
4966
Org. Lett., Vol. 7, No. 22, 2005