Synthesis of indenes by the transition metal-mediated carboannulation of alkynes

Article abstract of DOI:10.1021/jo0620563

The synthesis of highly substituted indenes has been achieved by three different transition metal-mediated methods. The first method involves the palladium-catalyzed carboannulation of internal alkynes. The second method utilizes a two-step approach, which involves first the palladium/copper- catalyzed cross-coupling of terminal alkynes with appropriately functionalized aryl halides, followed by copper-catalyzed intramolecular cyclization. The third method involves intermolecular palladium-catalyzed arylation of the arylalkynes formed in the first step of the second method.

Full text of DOI:10.1021/jo0620563

Synthesis of Indenes by the Transition Metal-Mediated
Carboannulation of Alkynes
Daohua Zhang, Zhijian Liu, Eul K. Yum, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
Larock@iastate.edu
ReceiVed October 4, 2006
The synthesis of highly substituted indenes has been achieved by three different transition metal-mediated
methods. The first method involves the palladium-catalyzed carboannulation of internal alkynes. The
second method utilizes a two-step approach, which involves first the palladium/copper-catalyzed cross-
coupling of terminal alkynes with appropriately functionalized aryl halides, followed by copper-catalyzed
intramolecular cyclization. The third method involves intermolecular palladium-catalyzed arylation of
the arylalkynes formed in the first step of the second method.
Introduction
drawbacks in the preparation of highly substituted indenes,
namely the strong acid medium sometimes required, the lengthy
reaction sequences often involved, and the low tolerance for
important organic functionality. These drawbacks have prompted
us to develop a general synthesis of indenes utilizing palladium-
and copper-catalyzed annulation methodologies.
Transition metal-catalyzed annulation processes have proven
very useful in organic synthesis.6 The palladium-catalyzed
annulation of alkynes is particularly effective for the synthesis
of a wide variety of carbocycles and heterocycles.7 We have
successfully employed such annulation chemistry for the
synthesis of indoles,8 benzofurans,9 isocoumarins,10 isoquino-
lines,11 carbolines,12 indenones,13 and polycyclic aromatic
The indene ring system is present in drug candidates
possessing interesting biological activities1 and metallocene
complexes utilized in the catalysis of olefin polymerization.2
Consequently, a number of approaches to the synthesis of the
indene ring system have been developed, including the reduc-
tion/dehydration of indanones,3 the cyclization of phenyl-
substituted allylic alcohols,4 and the ring expansion of substituted
cyclopropenes.5 Although these classical methods are quite
effective in synthesizing simple indenes, they have certain
(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.;
Edward Roberts, F.; DiMichele, L.; Ryan, K.; Liu, J.; Fredenburgh, L.;
Foster, B. Tetrahedron Lett. 1995, 36, 3993.
(2) (a) Spaleck, W.; Antberg, M.; Dolle, V.; Klein, R.; Rohmann, J.;
Winter, A. New J. Chem. 1990, 14, 499. (b) Foster, P.; Chien, J. C. W.;
Rausch, M. D. Organometallics 1996, 15, 2404. (c) Kim, D. H.; Lee, J.
A.; Lee. B. Y.; Chung, Y. K. J. Organomet. Chem. 2005, 690, 1822.
(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.
(6) (a) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. T. Chem. ReV.
1996, 96, 935. (b) Rubin, M.; Sromek, A. W.; Gevorgyan, V. Synlett 2003,
2265.
(7) For reviews, see: (a) Larock, R. C. J. Organomet. Chem. 1999, 576,
111. (b) Larock, R. C. Pure Appl. Chem. 1999, 71, 435.
(8) (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.
(9) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. J. Org.
Chem. 1995, 60, 3270.
(10) Larock, R. C.; Doty, M. J.; Han, X. J. Org. Chem. 1999, 64, 8770.
(11) (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.
(4) Miller, W.; Pittman, C. J. Org. Chem. 1974, 39, 1955.
(5) Yoshida, H.; Kato, M.; Ogata, T. J. Org. Chem. 1985, 50, 1145.
10.1021/jo0620563 CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/09/2006
J. Org. Chem. 2007, 72, 251-262
251

Zhang et al.
SCHEME 1
On the basis of the above optimization efforts, the combina-
tion 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 days 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 limitations
of this method. Further carboannulation results are summarized
in Table 1.
hydrocarbons.14 The palladium-catalyzed synthesis of these
carbo- and heterocycles has major advantages over traditional
annulation methods. For example, only catalytic amounts of
palladium are employed, and the palladium catalyst is quite
stable to air and moisture. Most important organic functional
groups are readily accommodated. The base-promoted Pd-
catalyzed annulation of alkynes is especially useful for preparing
acid-sensitive substances.15 Recently, we have communicated
our preliminary results on the synthesis of indenes by the
palladium-catalyzed carboannulation of internal alkynes by
appropriately functionalized aryl halides.16 Herein, we wish to
report the full details of that synthesis of indenes, plus additional
approaches to indenes employing terminal alkynes plus copper-
and palladium-catalyzed processes.
The reactions of 1 with symmetrical alkynes, such as 4-octyne
and diphenyl acetylene, afforded good yields of the desired
products (Table 1, entries 2 and 3). The results with the dialkyl
acetylene are significant, since such alkynes have not always
afforded particularly good results in analogous Pd-catalyzed
annulation chemistry. The annulation process is highly regi-
oselective 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
(Table 1; entries 1, 4, and 5). The assignment of regiochemistry
is based on analogy with our earlier indole work.8 In entry 5, a
much lower yield (40%) of the indene product was isolated when
KOAc was used as the base instead of K2CO3.
Results and Discussion
This process should tolerate considerable functionality. For
example, the reaction of compound 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. The aryl halide 8 bearing two electron-
donating methoxy groups reacts with 4,4-dimethyl-2-pentyne
to afford a 74% yield of the desired indene (entry 7). Interest-
ingly, when aryl bromide 10 was employed, a 46% yield of the
corresponding indene could still be obtained (entry 8). Aryl
halides with electron-withdrawing groups other than esters have
also been allowed to react with various internal alkynes to afford
moderate yields of the desired products (Table 1; entries 9-14).
Several bases, such as KOAc, NaOAc, K2CO3, and Na2CO3,
have been employed in many of these reactions and K2CO3
generally gave the highest yield of the desired annulation
products (entries 9, 10, and 12). With certain alkynes, these
latter functionally substituted aryl iodides gave back substantial
amounts of the starting aryl halides for reasons that are not
immediately obvious.
Synthesis of Indenes by the Palladium-Catalyzed Car-
boannulation of Internal Alkynes. Our initial studies were
aimed at finding the optimal reaction conditions for the
palladium-catalyzed carbonannulation of internal alkynes (Scheme
1). Our investigation began with the reaction of diethyl
(2-iodophenyl)malonate (1) and 4,4-dimethyl-2-pentyne. The
reaction was first attempted 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% isolated yield of the desired indene
2 in 24 h, alongside a small amount of material, which appeared
to arise by multiple insertion of the alkyne. To minimize the
formation of multiple-insertion products, the concentration of
the reactants was lowered by using 5 mL of DMF as the solvent.
That reaction furnished an 86% yield of the indene product
without any side products, but the reaction took 48 h to reach
completion.
Additional reaction parameters were also studied. Using 5
mol % of PPh3 as a ligand in this latter 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. When
less than 5 equiv of 4,4-dimethyl-2-pentyne were used, the
reactions were slower, and the yields were lower.
The mechanism shown in Scheme 2 is proposed for this
annulation process. It consists of the following key steps: (1)
oxidative addition of the aryl halide to the Pd(0) catalyst, (2)
arylpalladium coordination to the alkyne and insertion of the
alkyne to form a vinylic palladium intermediate, (3) generation
of a carbanion by the base, (4) intramolecular nucleophilic attack
of the carbanion on the vinylic palladium intermediate to afford
a palladacyclic intermediate, and (5) reductive elimination of
the 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.17
Subsequent syn-addition of the resulting arylpalladium com-
pound to internal alkynes has been widely employed in
analogous palladium-catalyzed hydroarylation processes18 and
(12) (a) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67, 9318. (b)
Zhang, H; Larock, R. C. J. Org. Chem. 2003, 68, 5132.
(13) Larock, R. C.; Doty, M. J.; Cacchi, S. J. Org. Chem. 1993, 58,
4579.
(14) (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.
(15) Rodd, E. H. Chemistry of Carbon Compounds; Elsevier: Amsterdam,
1954; Vol. III, p 82.
(17) (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; p 5.
(16) Zhang, D.; Yum, E. K.; Liu, Z.; Larock, R. C. Org. Lett. 2005, 7,
4963.
(18) (a) Arcadi, A.; Cacchi, S.; Marinelli, F.; Nardelli, M. Gazz. Chim.
Ital. 1986, 116, 725. (b) Cacchi, S. Pure Appl. Chem. 1990, 62, 713.
252 J. Org. Chem., Vol. 72, No. 1, 2007

Transition Metal-Mediated Carboannulation
TABLE 1. Palladium-Catalyzed Carboannulation of Internal Alkynes by Aryl Halidesa
a All 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, and 0.50 mmol of KOAc were 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 were employed. d 0.50 mmol of K2CO3 was used instead of KOAc.
assumed in many other alkyne insertion processes.19 The high
regioselectivity for unsymmetrical alkynes is probably due 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 developing carbon-carbon bond,
rather than the longer carbon-palladium bond (Figure 1).
J. Org. Chem, Vol. 72, No. 1, 2007 253

Zhang et al.
SCHEME 2
SCHEME 3
SCHEME 4
Analogous regiochemistry is also observed in all of our
previous reported annulation chemistry.7 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 palladacycles, a closely related
heterocyclic arylpalladium amide has been reported and shown
to undergo analogous thermal reductive elimination to form the
corresponding aromatic heterocycle.20 It stands to reason that
analogous carbon-containing palladacycles would behave simi-
larly.
SCHEME 5
this latter cyclization. Best results were obtained when the
substituent was an aromatic ring bearing electron-withdrawing
substituents.
FIGURE 1. Steric effects on the regiochemistry of alkyne insertion.
Synthesis of Indenes by the Copper(I)-Catalyzed Car-
boannulation of Alkynes. We have also attempted to achieve
the annulation of terminal alkynes utilizing this same methodol-
ogy (Scheme 3). However, the reactions have only afforded
acetylenic coupling products in high yields.
Preliminary efforts to cyclize the resulting diethyl [2-(1-
octynyl)phenyl]malonate (16) by applying different Pd catalysts
or bases gave poor results, suffering either low yields or no
cyclization product at all (Scheme 4). The use of a strong base,
such as t-BuOK or NaH, appeared essential to formation of the
cyclization product 17 as noted later. However, a large amount
of diethyl 2-[(1-octynyl)phenyl]malonate (16) was recovered in
all cases.
The cyclization of diethyl [2-(1-octynyl)phenyl]malonate (16)
appears to involve intramolecular nucleophilic attack of a
carbanion on the carbon-carbon triple bond. This type of
cyclization has been achieved previously by several different
methods. For example, Cacchi and Arcadi have observed the
carbocyclization of N-substituted malonanilides using a sto-
ichiometric amount of NaH.21 The nature of the substituent
linked to the acetylenic moiety was crucial for the success of
Balme has reported an intramolecular cyclization of terminal
alkynes in the presence of 20 mol % of Pd(dppe)2 and 1.1 equiv
of t-BuOK in THF as the solvent.22 This procedure afforded a
mixture of methylene cyclopentanes and methyl cyclopentenes.
In a subsequent paper, Balme described a copper-catalyzed
intramolecular cyclization using catalytic amounts of t-BuOK
and CuI.23 Compared to the previous palladium-catalyzed
cyclization method, this procedure provided the desired meth-
ylene cyclopentanes in good yields at lower reaction tempera-
tures and in shorter reaction times. However, when this copper-
catalyzed cyclization was applied to disubstituted alkynes,
stoichiometric amounts of both t-BuOK and CuI were essential
in order to afford reasonable yields of the desired cyclization
products.
Inspired by the preceding work, we have examined a similar
copper-catalyzed intramolecular cyclization procedure in an
attempt to cyclize diethyl [2-(1-octynyl)phenyl]malonate (16)
(Scheme 5). Indeed, the use of stoichiometric amounts of CuI
and t-BuOK afforded the desired cyclization product in a 78%
yield when run in THF at 80 °C for 3 h. On the basis of the
success of this copper-mediated intramolecular cyclization, we
herein wish to report a two-step procedure for the carboannu-
lation of terminal alkynes by appropriately functionalized aryl
halides. The procedure involves the palladium/copper-catalyzed
(19) (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.
(20) 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.
(22) Monteiro, N.; Gore, G.; Balme, G. Tetrahedron 1992, 48, 10103.
(23) Bouyssi, D.; Monteiro, N.; Balme, G. Tetrahedron Lett. 1999, 40,
1297.
(21) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Manna, F.; Pace, P. Synlett 1998,
446.
254 J. Org. Chem., Vol. 72, No. 1, 2007

Transition Metal-Mediated Carboannulation
SCHEME 6
cross-coupling of terminal alkynes with aryl halides, followed
by copper-catalyzed intramolecular cyclization.
Next we explored the annulation of terminal alkynes contain-
ing a sterically demanding substituent. The cross-coupling of
3,3-dimethyl-1-butyne with diethyl (2-iodophenyl)malonate (1)
furnished diethyl [2-(3,3-dimethyl-1-butynyl)phenyl]malonate
(30) in an excellent yield (entry 8). Subsequent cyclization of
malonate 30 was slow and gave the corresponding cyclization
product 31 in only a moderate yield. This result is reasonable
considering the steric hindrance of the bulky tert-butyl group.
An attempt to cyclize diethyl [2-(trimethylsilylethynyl)phenyl]-
malonate (32) did not afford any cyclization product, and 82%
of the coupling intermediate was recovered. Using stoichiometric
amounts of both t-BuOK and CuI only resulted in formation of
the desilylation product diethyl (2-ethynylphenyl)malonate (44)
(Scheme 7).
Initial studies were aimed at finding the optimal reaction
conditions for both the coupling and cyclization steps. With
regard to the cross-coupling step, we found that the standard
Sonogashira coupling procedure24 often afforded somewhat
higher yields of the coupling products than the procedure
described in Scheme 3. In addition, Sonogashira coupling
proceeds at a lower reaction temperature and shorter reaction
times. On the basis of these results, we chose the Sonogashira
coupling as the standard method for the initial cross-coupling
step.
Next, we focused our attention on finding the best reaction
conditions for the cyclization step. The reaction was first
attempted using diethyl [2-(1-octynyl)phenyl]malonate (16, 0.25
mmol), 1.1 equiv of t-BuOK, and 1 equiv of CuI in 5 mL of
THF at 80 °C for 3 h. As noted earlier, this reaction provided
a 78% yield of the desired cyclization product 17 (Scheme 5).
The reaction afforded an even higher 85% yield of the desired
product when 5 mol % of t-BuOK, and 2 mol % of CuI were
used. Interestingly, a 26% yield of the desired product was
isolated when 1 equiv of t-BuOK and no CuI were employed.
The reaction was also carried out by using diethyl [2-(1-octynyl)-
phenyl]malonate (16, 0.25 mmol), 1.1 equiv of t-BuOK, and 1
equiv of CuI in other organic solvents, such as DMF, DMSO,
and t-BuOH, and all of these reactions provided lower yields
of the desired product. A reaction with 5 mol % of t-BuOK
and 2 mol % of CuI at 55 °C afforded an excellent 96% yield
of the desired product. An analogous reaction at 30 °C resulted
in lower yields. Thus, the optimum reaction conditions devel-
oped involve 1 equiv of diethyl [2-(1-octynyl)phenyl]malonate
(16, 0.25 mmol), 5 mol % of t-BuOK, and 2 mol % of CuI in
5 mL of THF at 55 °C for 2 h.
On the basis of the above optimization study, a two-step
procedure has thus been developed for the synthesis of indenes
by the carboannulation of terminal alkynes using suitably
functionalized aryl halides. The procedure involves the pal-
ladium/copper-catalyzed Sonogashira coupling of terminal
alkynes with aryl halides, followed by copper-catalyzed in-
tramolecular cyclization of the intermediate alkyne (Scheme 6).
A variety of indene derivatives have been synthesized by
employing this methodology. The results are summarized in
Table 2.
Both the coupling and cyclization reactions of diethyl (2-
iodophenyl)malonate (E ) CO2Et) (1) with terminal alkynes
bearing a long chain alkyl substituent afforded excellent yields
of the desired products (entries 1 and 2). This two-step
annulation methodology also tolerates a variety of functional
groups in the terminal alkyne, including a methoxy (entry 3), a
hydroxy (entry 4), an ester (entry 5), a diethoxyacetal (entry
6), and a cyano group (entry 7).
SCHEME 7
Terminal alkynes bearing a carbocyclic ring have also been
subjected to this annulation process. Both the coupling and
cyclization reactions of diethyl (2-iodophenyl)malonate (1) with
cyclohexyl acetylene (entry 10) or 1-ethynylcyclohexene (entry
11) provided the desired products in high yields. The coupling
of diethyl (2-iodophenyl)malonate (1) with phenyl acetylene
proceeded very well to give a 98% yield of the cross-coupled
product 38 (entry 12). However, subsequent cyclization afforded
the desired product 39 in only a moderate 61% yield. Terminal
alkynes bearing an electron-deficient or electron-rich aromatic
ring have also been allowed to react with diethyl (2-iodophenyl)-
malonate (1) to afford good yields of the desired products
(entries 13 and 14), although the former gave significantly lower
yields in both steps.
The reactivity of other appropriately functionalized aryl
halides has also been examined (entries 15-20). Both the cross-
coupling and cyclization reactions of 1-octyne and ethyl cyano-
(2-iodophenyl)acetate (45) afforded high yields of the desired
products (entry 15). The cross-coupling of cyclohexyl acetylene
with 45 gave a 76% yield of ethyl cyano[2-(cyclohexylethynyl)-
phenyl]acetate (48), alongside a small amount of the cyclization
product 49 (entry 16). The ethyl cyano[2-(cyclohexylethynyl)-
phenyl]acetate (48) was then allowed to react with catalytic
amounts of t-BuOK and CuI to generate the desired cyclization
product 49 in 78% yield. A high yield of ethyl 1-cyano-2-
phenyl-1H-indene-1-carboxylate (50) was obtained as the sole
product under the Sonogashira conditions, when 45 and phenyl
acetylene were employed (entry 17). While the Sonogashira
reaction of halide 51 and phenylacetylene proceeded smoothly,
the cyclization of ethyl [2-(phenylethynyl)phenyl](phenylsul-
fonyl)acetate (52) was very slow under our normal reaction
conditions and gave only a very low yield of the desired product
(24) Sonogashira, K. ComprehensiVe Organic Synthesis; Pergamon:
Oxford, 1990; Vol. 3, p 521.
J. Org. Chem, Vol. 72, No. 1, 2007 255

Zhang et al.
TABLE 2. Two-Step Annulation of Terminal Alkynes by Functionally Substituted Aryl Halidesa
256 J. Org. Chem., Vol. 72, No. 1, 2007

Transition Metal-Mediated Carboannulation
Table 2 (Continued)
a All reactions were run under the following reaction conditions, unless otherwise specified. Sonogashira coupling: 0.25 mmol of the aryl halide, 0.375
mmol of the alkyne, 2 mol % of PdCl2(PPh3)2, and 1 mol % of CuI were stirred in 3 mL of NEt3 at 55 °C for 2 h. Cu-catalyzed cyclization: 0.25 mmol of
the intermediate, 5 mol % of t-BuOK, and 2 mol % of CuI in 5 mL of THF were stirred at 55 °C for 2 h. b A 21% yield of the intermediate 26 was recovered.
c The Cu-catalyzed cyclization was run for 12 h. d An 82% yield of the alkyne 32 was recovered. e A 6% yield of 49 was isolated. f The reaction was run
for 12 h. g 1.1 Equiv of t-BuOK and 1 equiv of CuI were used, and the reaction was run at 80 °C.
SCHEME 8
53 (entry 18). Even the use of stoichiometric amounts of both
t-BuOK and CuI and an elevated temperature afforded only a
modest 36% yield of indene 53.
activated triple bond to afford a vinylic copper intermediate,
and (4) protonation of the resulting vinylic copper intermediate
to furnish the indene and regenerate the copper catalyst and the
tert-butoxide (Scheme 8).
The cross-coupling of phenyl acetylene with ethyl (2-
iodophenyl)acetate (54) or 1-iodo-2-(phenylsulfonylmethyl)-
benzene (56) provided high yields of the desired cross-coupling
products (entries 19 and 20). However, subsequent cyclization
did not provide any of the desired indene products, even using
stoichiometric amounts of both t-BuOK and CuI and an elevated
temperature. The inertness of the intermediates 55 and 57 toward
intramolecular cyclization can no doubt be attributed to the
reduced acidity of the methylene hydrogens in these intermedi-
ates compared to the methyne hydrogen in the other intermedi-
ates bearing two electron-withdrawing groups.
The copper-catalyzed intramolecular cyclization presumably
proceeds via (1) generation of a carbanion by the tert-butoxide,
(2) coordination of the copper tert-butoxide to the alkyne triple
bond, which activates the triple bond toward nucleophilic attack,
(3) intramolecular nucleophilic attack of the carbanion on the
Synthesis of Indenes via Palladium-Catalyzed Cyclization
of Diethyl 2-[2-(1-Alkynyl)phenyl]malonate by Organic
Halides. Our group has recently reported an efficient synthesis
of 3,4-disubstituted isoquinolines by the palladium-catalyzed
cross-coupling of o-(1-alkynyl)benzaldimines and organic ha-
lides (Scheme 9).11b,25 This method involves the intramolecular
nucleophilic attack of a nitrogen atom on the triple bond
promoted by coordination of a σ-aryl-, σ-allyl-, or σ-alkynylpal-
ladium complex. This successful utilization of o-(1-alkynyl)-
benzaldimines as precursors for the synthesis of 3,4-disubstituted
isoquinolines and our continuing interest in palladium-catalyzed
intramolecular cyclizations prompted us to explore analogous
methodology for the synthesis of indenes. Following the
(25) Dai, G.; Larock, R. C. Org. Lett. 2001, 3, 4035.
J. Org. Chem, Vol. 72, No. 1, 2007 257

Zhang et al.
SCHEME 9
SCHEME 10
SCHEME 11
completion of our work on this chemistry, Liang et al. reported
very similar work on the synthesis of indenes by the palladium-
catalyzed coupling of diethyl [2-(1-alkynyl)phenyl]malonates
and aryl halides.26 Herein, we wish to report the synthesis of
2,3-diarylindenes by the palladium-catalyzed arylation of aryl-
alkynes bearing a neighboring carbon nucleophile by various
aryl halides.
to 3 equiv gave a slightly lower 82% yield of the desired product
than the reaction using 5 equiv of K2CO3. The yield was much
lower when less than 3 equiv of K2CO3 were used.
The starting 2-(1-alkynyl)phenylmalonates have been pre-
pared by Sonogashira coupling of diethyl (2-iodophenyl)-
malonate (1) with various terminal alkynes (Scheme 10). For
example, diethyl 2-(phenylethynyl)phenylmalonate (38) was
isolated in a 98% yield when diethyl (2-iodophenyl)malonate
(1) was treated with phenylacetylene in the presence of 2 mol
% of PdCl2(PPh3)2 and 1 mol % of CuI in NEt3.
We next focused our attention on finding optimal reaction
conditions for the palladium-catalyzed intermolecular cross-
coupling of alkyne 38 with ethyl p-iodobenzoate (Scheme 10,
step 2). The reaction was first attempted using our optimum
reaction conditions for the synthesis of 3,4-disubstituted
isoquinolines.11b,25 The reaction was run using diethyl 2-(phe-
nylethynyl)malonate (38) (0.25 mmol), 5 equiv of ethyl 4-io-
dobenzoate, 5 mol % of Pd(PPh3)4, and 5 equiv of K2CO3 in
5 mL of DMF at 100 °C. After 3 h, the reaction afforded a
68% yield of the desired arylation product 58, alongside a small
amount of material, which appeared to arise by homo-coupling
of the aryl halide. To minimize formation of the homo-coupling
product, the amount of the aryl halide was decreased to 3 equiv.
That reaction furnished a 77% yield of the desired product and
a reduced amount of the homo-coupling product. Any further
reduction in the amount of ethyl 4-iodobenzoate resulted in a
much lower yield of the desired product.
The effect of different palladium catalysts on the outcome
of the reaction has also been studied. Pd(PPh3)4 gave a higher
yield of the desired product than other palladium catalysts
studied [Pd(OAc)2, PdCl2, PdCl2(PPh3)2, and Pd2(dba)3‚CHCl3].
Decreasing the amount of Pd(PPh3)4 to 2 mol % provided the
desired product in an improved 86% yield.
Other inorganic bases were examined as an alternative to K2-
CO3 [KOAc, Na2CO3, and Cs2CO3], and the yields were
generally lower than the reaction using K2CO3 as the base. The
use of organic bases, such as NEt3 and pyridine, did not afford
any of the desired product. Decreasing the amount of K2CO3
When other organic solvents, such as DMSO and THF, were
used, the reaction provided lower yields of the desired product.
Raising the reaction temperature to 120 °C gave a 59% yield
of the desired product and a large amount of homo-coupling
product from the aryl iodide substrate was isolated. The reaction
afforded an 84% yield of the desired product when the reaction
was run at 80 °C. However, the reaction took 9 h to reach
completion. On the basis of these optimization efforts, the
combination of diethyl [2-(phenylethynyl)phenyl]malonate (38,
0.25 mmol), 3 equiv of the aryl halide, 2 mol % of Pd(OAc)2,
and 5 equiv of K2CO3 in 5 mL of DMF at 100 °C for 3 h gave
the best result.
Having gained an understanding of the factors that influence
the arylation process, we have explored the scope and limitations
of this methodology (Scheme 11). The results are summarized
in Table 3.
The reactions of diethyl [2-(phenylethynyl)phenyl]malonate
(38) with ethyl p-, m-, and o-iodobenzoates afforded the desired
indenes in good yields, indicating that there is no significant
steric effect in this reaction (Table 3, entries 1-3). Similarly
p- and m-iodonitrobenzenes reacted with alkyne 38 to give high
yields of the desired products (entries 4 and 5). On the other
hand, the reaction of o-iodonitrobenzene with alkyne 38 gave
none of the desired arylation product for reasons that are not
obvious and produced significant amounts of diethyl 2-phenyl-
1H-indene-1,1-dicarboxylate (39) (entry 6). The reactions of p-
and m-(trifluoromethyl)iodobenzenes with alkyne 38 generated
the desired products in good yields, while o-(trifluoromethyl)-
iodobenzene gave only a 53% yield of the desired product
(entries 7-9). The lower yield of the desired product can
presumably be attributed to the steric hindrance of the bulky
ortho-substituted trifluoromethyl group.
The reactions of other electron-deficient aryl iodides with
alkyne 38 also proceeded well, providing high yields of the
desired indene derivatives (entries 10 and 11). None of the
(26) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu, X.-L.; Liang, Y.-M. J.
Org. Chem. 2006, 71, 3325.
258 J. Org. Chem., Vol. 72, No. 1, 2007

Transition Metal-Mediated Carboannulation
TABLE 3. Palladium-catalyzed Cyclization of Diethyl
2-(phenylethynyl) Phenylmalonate (38) using Various Organic
Halides (Scheme 11)a
SCHEME 12
SCHEME 13
significant amounts of byproduct 39 were observed. The reaction
of 2-iodothiophene and alkyne 38 afforded a moderate 64% yield
of the desired indene product (entry 13).
The reactivity of relatively electron-rich aryl halides has also
been examined. Iodobenzene has been allowed to react with
diethyl [2-(phenylethynyl)phenyl]malonate (38) to give a 72%
yield of the desired indene (entry 14). The p-, m-, and
o-iodotoluenes reacted with alkyne 38 to afford the desired
arylation products, but the yields are slightly lower than the
reactions of the electron-deficient aryl halides (entries 15-17).
When a strong electron-rich aryl halide, such as p-iodoanisole,
was employed in this arylation reaction, only a 14% yield of
the desired arylation product was isolated (entry 18). In this
reaction, a significant amount of byproduct 69 was isolated.
The formation of indene 69 is due to a competitive intermo-
lecular cross-coupling process in which aryl-aryl exchange
between the palladium center and the phosphine ligand in the
organopalladium(II) complex27 produces a phenylpalladium(II)
complex (Scheme 12), which subsequently produces the ob-
served side product.
Arylation using bromobenzene is nearly as effective as
iodobenzene providing the desired arylation product in a good
yield (entry 19). However, the reaction of chlorobenzene with
alkyne 38 afforded only the reduction product 39 in a 71% yield
(entry 20). On the other hand, attaching an electron-withdrawing
nitro substituent to the chlorobenzene facilitated formation of
the desired arylation product, although the 34% yield is still
relatively low (entry 21). The reaction of phenyl triflate failed
to produce any arylation product and once again afforded indene
39 in a 38% yield (entry 22).
We have also investigated the reactions of other organic
halides. For example, allyl bromide reacted with alkyne 38 to
yield an inseparable mixture of diethyl 3-allyl-2-phenyl-1H-
indene-1,1-dicarboxylate (74, 51% yield) and diethyl 2-allyl-
2-[2-(phenylethynyl)phenyl]malonate (75, 41% yield, entry 23).
1
The yields were determined by H NMR spectroscopy. The
formation of alkyne 75 probably proceeds by a competitive SN2
reaction, but it might also involve direct malonate anion attack
on the expected π-allylpalladium intermediate. Using diallyl
carbonate as an alternative source of allyl moiety only resulted
in the formation of alkyne 75 in an 86% yield (entry 24). Crotyl
chloride has also been subjected to this reaction. This reaction
gave a high yield of the corresponding allylic-substituted alkyne,
instead of the desired indene product (entry 25).
a All reactions were run under the following conditions, unless otherwise
specified: 0.25 mmol of the alkyne 38, 0.75 mmol of the aryl halide, 2
mol % of Pd(OAc)2, 5 equiv of K2CO3 stirred in 5 mL of DMF at 100 °C
for 3 h. b The reaction was run for 12 h. c A 17% yield of 69 was isolated.
d A 55% yield of 39 was isolated. e The yield was determined by 1H NMR
spectroscopy.
Vinylic halides, such as methyl E-3-iodoacrylate and ethyl
Z-3-iodoacrylate, failed to produce any of the desired indene
(27) (a) Kong, K. C.; Cheng, C. H. J. Am. Chem. Soc. 1991, 113, 6313.
(b) Goodson, E. F.; Wallow, I. T.; Novak, M. B. J. Am. Chem. Soc. 1997,
119, 12441.
desired arylation product was isolated when 3-iodopyridine was
subjected to the palladium-catalyzed arylation (entry 12). Again,
J. Org. Chem, Vol. 72, No. 1, 2007 259

Zhang et al.
SCHEME 14
TABLE 4. Palladium-Catalyzed Arylation of Various Arylalkynes
(Scheme 13)a
SCHEME 15
entry
E
R1
alkyne
R2X
product % yield
1
2
3
4
5
6
7
8
CO2Et (CH2)5CH3
CO2Et (CH2)5CH3
CO2Et (CH2)5CH3
CO2Et 1-cyclohexenyl 36 p-EtO2CC6H4I
CO2Et 1-cyclohexenyl 36 p-O2NC6H4I
CO2Et 1-cyclohexenyl 36 p-CH3COC6H4I
16 p-EtO2CC6H4I
16 p-O2NC6H4I
16 p-H3COC6H4I
77
78
79
80
81
82
83
84
61
63
9
83
87
78
53
42
CN
(CH2)5CH3
46 p-EtO2CC6H4I
52 p-EtO2CC6H4I
SO2Ph Ph
a All reactions were run under the following conditions, unless otherwise
specified: 0.25 mmol of the alkyne, 0.75 mmol of the aryl halide, 2 mol %
of Pd(OAc)2, and 5 equiv of K2CO3 were stirred in 5 mL of DMF at
100 °C for 3 h.
halide to the Pd(0) catalyst, (3) coordination of the resulting
organopalladium(II) intermediate to the alkyne triple bond to
form an organopalladium π-complex, which activates the triple
bond toward nucleophilic attack, (4) intramolecular nucleophilic
attack of the carbanion on the activated carbon-carbon triple
bond to afford a vinylic palladium intermediate, and (5)
reductive elimination to form the arylation product and regener-
ate the Pd(0) catalyst. The observation that the yields of the
reactions employing electron-deficient aryl halides are generally
higher than those utilizing electron-deficient aryl halides can
be explained by this mechanism. The arylpalladium(II) inter-
mediates derived from electron-deficient aryl halides more
strongly coordinate to the alkyne triple bond, making the alkyne
triple bond more prone to nucleophilic attack by the carbanion.
Liang has reported a similar mechanism,26 but one involving
trans addition of the arylpalladium intermediate to alkyne. This
seems highly unlikely and is inconsistent with the many other
reports of the backside attack of a nucleophile on an alkyne
complexed to an arylpalladium intermediate.11b,25,28
products, but gave back large amounts of the starting alkyne
38 (entries 26 and 27). The reaction of [4-(iodomethylene)-
cyclohexyl]benzene resulted in a complex mixture with no
obvious indene product (entry 28). The reactions of alkynyl
iodides with alkyne 38 did not generate any of the desired
indenes either (entries 29-31). A large amount of black oily
1
material was obtained in each case, and the corresponding H
NMR spectrum was unrecognizable. On the other hand, a
moderate yield of the desired 3,4-disubstituted isoquinoline was
obtained (56%) in our earlier palladium-catalyzed cross-coupling
of o-(1-alkynyl)benzaldimines and 1-iodo-1-decyne.11b,25
The reactivity of other arylalkynes bearing potential carbanion
centers has also been examined (Scheme 13). For example, a
malonate-containing arylalkyne bearing a long chain alkyl group
on the end of the acetylene has been allowed to react with
various aryl halides to furnish the desired indene products (Table
4, entries 1-3). The reactions of electron-deficient halides have
given much higher yields than the reaction of the electron-rich
halide p-iodoanisole. This observation is consistent with the
results reported in Table 3. The arylalkyne 36 bearing a
cyclohexenyl group on the end of the acetylene has also reacted
with various aryl halides to generate the desired indene
derivatives in good yields (entries 4-6). Arylalkynes bearing
different electron-withdrawing functional groups have also been
subjected to this arylation reaction, and the reactions have
afforded the desired arylation products in moderate yields
(entries 7 and 8).
Interestingly, a double arylation product 85 (Scheme 15) has
been isolated in a low yield when 1,2-diiodobenzene was
allowed to react with diethyl [2-(phenylethynyl)phenyl]malonate
(38). The formation of polycycle 85 is presumably due to
subsequent intramolecular cyclization of the expected intermedi-
ate 86 bearing an iodophenyl group resulting in organopalladium
species 88, which subsequently undergoes reductive elimination
to provide the double arylation product 85 (Scheme 16).29
(28) (a) Cacchi, S.; Fabrizi, G.; Moro, L. J. Org. Chem. 1997, 62, 5327.
(b) Cacchi, S.; Fabrizi, G.; Moro, L.; Pace, P. Synlett 1997, 1367. (c) Wei,
L.-M.; Lin, C.-F.; Wu, M.-J. Tetrahedron Lett. 2000, 41, 1215. (d) Hu, Y.;
Zhang, Y.; Yang, Z.; Fathi, R. J. Org. Chem. 2002, 67, 2365.
(29) For analogous intramolecular arylations, see: (a) Campeau, L.-C.;
Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581. (b)
Parisien, M.; Damien, V. Fagnou, K. J. Org. Chem. 2005, 70, 7578.
We propose the mechanism shown in Scheme 14 for this
process. It consists of the following key steps: (1) generation
of a carbanion by the base, (2) oxidative addition of the aryl
260 J. Org. Chem., Vol. 72, No. 1, 2007

Transition Metal-Mediated Carboannulation
SCHEME 16
SCHEME 17
SCHEME 18
A Heck type reaction analogous to our earlier work on
isoquinolines11c,30 has also been examined employing diethyl
[2-(oct-1-ynyl)phenyl]malonate (16) and ethyl acrylate (Scheme
17). The reaction yielded the desired olefinic indene product
89 in 36% yield, alongside a large amount of the direct
cyclization product 17. No further work has been carried out
on optimizing this interesting process. Presumably, compound
89 is formed through a palladium(II) pathway (Scheme 18). The
Pd(II) catalyst coordinates with the alkyne triple bond of the
carbanion intermediate 90 to form a palladium complex 91.
Cyclization of the palladium complex 91 provides a vinylic
palladium intermediate 92. Subsequent cis addition of interme-
diate 92 to the carbon-carbon double bond of the acrylate
affords an alkylpalladium intermediate 93, which undergoes
â-hydride elimination to furnish the olefinic indene 89 and Pd-
(0). The Pd(0) generated can be reoxidized back to PdBr2 by
the Cu(OAc)2 oxidant present in the reaction mixture.
Conclusions
In conclusion, three different synthetic methods have been
developed for preparing substituted indenes by the metal-
mediated carboannulation of alkynes. The first method involves
a palladium-catalyzed carboannulation of internal alkynes. The
reactions proceed under relatively mild conditions, tolerate
significant functionality, and generally give good yields. This
annulation process exhibits excellent regioselectivity and is
particularly suited for the synthesis of hindered indenes. The
(30) Huang, Q.; Larock, R. C. Tetrahedron Lett. 2002, 43, 3557.
J. Org. Chem, Vol. 72, No. 1, 2007 261

Zhang et al.
General Procedure for the Copper-Catalyzed Intramolecular
Cyclization to Indenes. To a solution of the alkyne (0.25 mmol)
in THF (5 mL) were added CuI (0.005 mmol) and t-BuOK (0.0125
mmol). The reaction mixture was allowed to stir at 55 °C for 2 h.
The mixture was cooled to room temperature, diluted with ether,
and then washed with satd aq NH4Cl. The organic layer was dried
over anhydrous MgSO4, filtered, and then concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel to afford the desired product.
Diethyl 2-n-Hexyl-1H-indene-1,1-dicarboxylate (17) (Table 2,
entry 1). Purification by flash chromatography (hexane/EtOAc)
afforded the indicated compound in a 96% yield as a pale yellow
oil: 1H NMR (CDCl3) δ 0.91 (m, 3 H), 1.25 (t, J ) 7.2 Hz, 6 H),
1.35 (m, 6 H), 1.66 (m, 2 H), 2.51 (m, 2 H), 4.21 (m, 4 H), 6.63
(t, J ) 1.8 Hz, 1 H), 7.26 (m, 3 H), 7.57 (m, 1 H); 13C NMR
(CDCl3) δ 14.2, 14.3, 22.9, 28.1, 28.7, 29.5, 30.0, 62.1, 72.2, 120.8,
125.0, 125.4, 128.8, 130.0, 140.9, 144.7, 148.5, 168.5; IR (CHCl3,
cm-1) 3048, 2983, 1758, 1471; HRMS calcd for C21H28O4
334.1988, found 334.1994.
General Procedure for the Palladium-Catalyzed Arylation
of Arylalkynes Bearing Various Carbon Nucleophiles. To a
solution of the arylalkyne (0.25 mmol) in DMF (5 mL) were added
Pd(PPh3)4 (0.005 mmol), K2CO3 (1.25 mmol), and the aryl halide
(0.75 mmol). The reaction mixture was allowed to stir at 100 °C
for 3 h. The mixture was cooled to room temperature, diluted with
ether, and washed with satd aq NH4Cl. The organic layer was dried
over anhydrous MgSO4, filtered and then concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel to afford the desired product.
second synthetic method for indene derivatives has been
accomplished in high yields by the cross-coupling of terminal
alkynes with functionally substituted aryl halides, followed by
copper-catalyzed intramolecular cyclization. This process toler-
ates various functionality in the terminal alkynes and provides
a convenient, general route to prepare 2-substituted indenes. The
third synthesis of highly substituted indenes involves the
palladium-catalyzed cross-coupling of arylalkynes bearing strong
electron-withdrawing functional groups with various aryl ha-
lides. This process involves both arylation and cyclization of
the arylalkynes in a single step and is particularly suited for
the synthesis of 2,3-diarylindenes bearing electron-deficient aryl
groups in the 3-position.
Experimental Section
General Procedure for the Palladium-Catalyzed Carboan-
nulation of Internal Alkynes. To a solution of aryl halide (0.25
mmol) in DMF (5 mL) were added the alkyne (0.50-1.25 mmol),
Pd(OAc)2 (0.0125 mmol), LiCl (0.25 mmol) or n-Bu4NCl (0.25
mmol), and the appropriate base (0.5 mmol). The reaction mixture
was allowed to stir at 80 °C for 48 h. The resulting mixture was
diluted with diethyl ether and washed with satd aq NH4Cl. The
organic layer was dried over anhydrous MgSO4, filtered, and then
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel to afford the desired
product.
Diethyl 2-tert-Butyl-3-methyl-1H-indene-1,1-dicarboxylate (2)
(Table 1, entry 1). Purification by flash chromatography (hexane/
EtOAc) afforded the indicated compound in an 86% yield as a pale
yellow oil: 1H NMR (CDCl3) δ 1.16 (t, J ) 7.2 Hz, 6 H), 1.36 (s,
9 H), 2.29 (s, 3 H), 4.13 (m, 4 H), 7.13 (dt, J ) 1.2, 7.5 Hz, 1 H),
7.19 (d, J ) 7.8 Hz, 1 H), 7.31 (dt, J ) 1.6, 7.5 Hz, 1 H), 7.47 (dt,
J ) 0.6, 7.5 Hz, 1 H); 13C NMR (CDCl3) δ 13.5, 14.1, 30.3, 34.4,
61.6, 70.9, 118.5, 122.3, 125.6, 128.5, 137.6, 140.7, 147.6, 149.1,
169.1; IR (CHCl3, cm-1) 2928, 2908, 1757, 1736, 1223, 1055;
HRMS calcd for C20H26O4 330.1831, found 330.1835.
General Procedure for the Sonogashira Coupling of Terminal
Alkynes and Functionally Substituted Aryl Halides. To a solution
of aryl halide (0.25 mmol) in Et3N (3 mL) was added Pd(OAc)2
(0.005 mmol), CuI (0.0025 mmol), and the alkyne (0.375 mmol).
The reaction mixture was allowed to stir at 55 °C for 2 h. The
mixture was then cooled to room temperature, and filtered. The
filtrate was concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel to afford
the desired product.
Diethyl [2-(Oct-1-ynyl)phenyl]malonate (16) (Table 2, entry
1). Purification by flash chromatography (hexane/EtOAc) afforded
the indicated compound in a 95% yield as a pale yellow oil: 1H
NMR (CDCl3) δ 0.87 (t, J ) 7.2 Hz, 3 H), 1.25-1.32 (m, 10 H),
1.44 (m, 2 H), 1.59 (m, 2 H), 2.41 (t, J ) 7.2 Hz, 2 H), 4.21 (m,
4 H), 5.30 (s, 1 H), 7.24 (m, 2 H), 7.41 (m, 2 H); 13C NMR (CDCl3)
δ 14.1, 19.6, 22.6, 28.6, 28.7, 31.4, 55.7, 61.8, 78.2, 95.9, 124.6,
127.8, 127.9, 128.4, 132.0, 134.6, 168.3; IR (CHCl3, cm-1) 3058,
2982, 1751, 1734, 1266; HRMS calcd for C21H28O4 344.1988, found
344.1992.
Diethyl 3-[4-(Ethoxycarbonyl)phenyl]-2-phenyl-1H-indene-
1,1-dicarboxylate (58) (Table 3, entry 1). Purification by flash
chromatography (hexane/EtOAc) afforded the indicated compound
in an 86% yield as a pale yellow oil: 1H NMR (CDCl3) δ 1.09 (t,
J ) 7.2 Hz, 6 H), 1.37 (t, J ) 7.2 Hz, 3 H), 4.14 (m, 4 H), 4.35 (q,
J ) 7.2 Hz, 2 H), 7.17 (m, 5 H), 7.25 (m, 1 H), 7.34 (m, 2 H),
7.39 (d, J ) 8.4 Hz, 2 H), 7.69 (dd, J ) 1.2, 7.6 Hz, 1 H), 8.00 (d,
J ) 8.4 Hz, 2 H); 13C NMR (CDCl3) δ 13.8, 14.4, 61.1, 62.1, 73.0,
121.1, 124.8, 126.9, 127.6, 127.7, 128.8, 129.6, 129.7, 130.3, 134.7,
139.1, 140.9, 141.8, 144.0, 144.4, 166.4, 168.0; IR (CHCl3, cm-1
)
3065, 2982, 1718, 1275; HRMS calcd for C30H28O6 484.1886, found
484.1895.
Acknowledgment. We gratefully acknowledge the National
Science Foundation and the donors of the Petroleum Research
Fund, administrated by the American Chemical Society, for
partial support of this research and Johnson Mathey Inc. and
Kawaken Fine Chemicals Co. Ltd. for generous donations of
palladium salts.
Supporting Information Available: General experimental
procedures and characterization data for all new starting materials
and products. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0620563
262 J. Org. Chem., Vol. 72, No. 1, 2007