Syntheses of isochromenes and naphthalenes by electrophilic cyclization of acetylenic arenecarboxaldehydes

Article abstract of DOI:10.1021/jo0524573

Highly substituted IH-isochromenes, isobenzofurans, and pyranopyridines can be prepared by allowing o-(1-alkynyl)arenecarboxaldehydes and ketones to react with I₂, ICl, NIS, Br₂, NBS, p-O₂NC ₆H₄SCl, or PhSeBr and various alcohols or carbon-based nucleophiles at room temperature. Naphthyl ketones and iodides are also readily prepared by the reaction of 2-(1-alkynyl)arenecarboxaldehydes with I₂ and simple olefins or alkynes.

Full text of DOI:10.1021/jo0524573

Syntheses of Isochromenes and Naphthalenes by Electrophilic
Cyclization of Acetylenic Arenecarboxaldehydes
Dawei Yue, Nicola Della Ca´, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
ReceiVed NoVember 29, 2005
Highly substituted 1H-isochromenes, isobenzofurans, and pyranopyridines can be prepared by allowing
o-(1-alkynyl)arenecarboxaldehydes and ketones to react with I2, ICl, NIS, Br2, NBS, p-O2NC6H4SCl, or
PhSeBr and various alcohols or carbon-based nucleophiles at room temperature. Naphthyl ketones and
iodides are also readily prepared by the reaction of 2-(1-alkynyl)arenecarboxaldehydes with I2 and simple
olefins or alkynes.
Introduction
easily synthesized by the electrophilic cyclization of appropriate
functionally substituted alkynes using iodine-, bromine-, sulfur-,
and selenium-containing electrophiles under exceptionally mild
reaction conditions (Scheme 1).
The electrophilic cyclization of functionally substituted
alkenes has provided an extremely useful route to a wide variety
of heterocyclic and carbocyclic compounds, which have proven
useful as intermediates in the synthesis of natural products and
pharmaceuticals.1 Analogous chemistry of alkynes has been far
less studied, although it would appear to be a very promising
route to an extraordinary range of useful, functionally substituted
heterocycles and carbocycles.2 Our recent work and that of
others have indicated that benzofurans,3 benzothiophenes,4
isoquinolines,5 indoles,3c,6 isocoumarins,7 isoindolinones,8 poly-
cyclic aromatics,9 and a number of other heterocycles10 can be
(6) (a) Yue, D.; Larock, R. C. Org. Lett. 2004, 6, 1037. (b) Barluenga,
J.; Trincado, M.; Rubio, E.; Gonza´lez, J. M. Angew. Chem., Int. Ed. 2003,
42, 2406. (c) Amjad, M.; Knight, D. W. Tetrahedron Lett. 2004, 45, 539.
(7) (a) Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936. (b) Bellina,
F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron 2001, 57, 2857. (c)
Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron Lett. 2001, 42,
2859.
(8) Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 1432.
(9) (a) Yao, T.; Campo, M. A.; Larock, R. C. Org. Lett. 2004, 6, 2677.
(b) Yao, T.; Campo, M. A.; Larock, R. C. J. Org. Chem. 2005, 70, 3511.
(c) Goldfinger, M. B.; Crawford, K. B.; Swager, T. M. J. Am. Chem. Soc.
1997, 119, 4578. (d) Goldfinger, M. B.; Swager, T. M. J. Am. Chem. Soc.
1994, 116, 7895.
(1) (a) Lotagawa, O.; Inoue, T.; Taguchi, T. ReV. Heteroatom Chem.
1996, 15, 243. (b) Frederickson, M.; Grigg, R. Org. Prep. Proc. Int. 1997,
29, 33. (c) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321.
(2) (a) Drenth, W. In Chemistry of Triple-Bonded Functional Groups;
Patai, S., Ed.; J. Wiley: Chichester, U.K., 1994; Vol. 2, pp 873-915. (b)
Schmid, G. H. In Chemistry of the Carbon-Carbon Triple Bond; Patai, S.,
Ed.; J. Wiley: Chichester, U.K., 1978; Vol. 1, pp 275-341. (c) Larock, R.
C. In Acetylene Chemistry; Diederich, F., Stang, P. J., Tykwinski, R. R.,
Ed.; Wiley-VCH: Weinheim, Germany, 2005; pp 51-99.
(3) (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett
1999, 1432. (b) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70,
10292. (c) Yao, T.; Yue, D.; Larock, R. C. J. Comb. Chem. 2005, 7, 809.
(4) (a) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (b) Hessian,
K.; Flynn, B. Org. Lett. 2003, 5, 4377. (c) Flynn, B. L.; Verdier-Pinard, P.;
Hamel, E. Org. Lett. 2001, 5, 651.
(10) (a) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Perkin
Trans. 1 2002, 622. (b) Arcadi, A.; Cacchi, S.; Giuseppe, S. D.; Fabrizi,
G.; Marinelli, F. Org. Lett. 2002, 4, 2409. (c) Djuardi, E.; McNelis, E.
Tetrahedron Lett. 1999, 40, 7193. (f) Marshall, J. A.; Yanik, M. M. J. Org.
Chem. 1999, 64, 3798. (d) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli,
F.; Moro, L. Synlett 1999, 1432. (e) Knight, D. W.; Redfern, A. L.; Gilmore,
J. J. Chem. Soc., Chem. Commun. 1998, 2207. (f) Redfern, A. L.; Gilmore,
J. Synlett 1998, 731. (g) Ren, X.-F., Konaklieva, M. I.; Shi, H.; Dicy, H.;
Lim, D. V.; Gonzales, J.; Turos, E. J. Org. Chem. 1998, 63, 8898. (h) Bew,
S. P.; Knight, D. W. J. Chem. Soc., Chem. Commun. 1996, 1007. (i) El-
Taeb, G. M. M.; Evans, A. B.; Jones, S.; Knight, D. W. Tetrahedron Lett.
2001, 42, 5945. (j) Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org.
Lett. 2005, 7, 763. (k) Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005,
127, 12230. (l) Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005, 70,
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10.1021/jo0524573 CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/06/2006
J. Org. Chem. 2006, 71, 3381-3388
3381

Yue et al.
TABLE 1. Iodocyclization of 2-(Phenylethynyl)benzaldehyde
SCHEME 1
solvent
MeOH (equiv)
I2 (equiv)
base (equiv)
yield (%)
CH2Cl2
CH
DMF
CH
CH
CH
1.2
1.2
1.2
1.2
1.2
2.0
2.0
-
1.2
1.2
1.2
1.2
1.2
2.5
2.5
2.5
K2CO3(1.0)
K2CO3(1.0)
K2CO3(1.0)
KHCO3 (1.0)
Et3N
K2CO3(1.0)
K2CO3(2.0)
K2CO3(2.0)
88
40
trace
70
Not long ago, Yamamoto reported an interesting cyclization
of acetylenic aldehydes to 1-alkoxy-1H-isochromenes catalyzed
by Pd(OAc)2 (eq 1).11 The Pd(II) salt employed was claimed to
80
78
68
CH
MeOH
exhibit a dual role as both a Lewis acid and a transition-metal
catalyst. Recently, a similar preparation of 4-iodo-1H-iso-
chromenes has been achieved upon reaction of bis(pyridine)-
iodonium tetrafluoroborate (IPy2BF4) and HBF4 with the same
acetylenic carbonyl precursors in the presence of various
nucleophiles (eq 2).12 The use of expensive IPy2BF4 together
While KHCO3 provided a slightly lower yield of the desired
product than K2CO3, NEt3 proved to be totally ineffective and
none of the desired product was detected. Although CH2Cl2 is
not a good solvent for K2CO3, the presence of K2CO3 was
crucial for a clean, high-yielding reaction. K2CO3 is presumed
to neutralize the byproduct HI of the electrophilic cyclization,
which can also react with the acetylenic aldehyde and generate
the corresponding pyrilium salt.15 Increasing the amount of
methanol from 1.2 equiv to using MeOH as the solvent actually
resulted in a lower yield. Using 1.2 equiv of I2 has proven to
be enough to achieve a high yield. Further increasing the amount
of I2 did not give any better yield. Based on the above
optimization efforts, the combination of 1.2 equiv of nucleophile,
1.0 equiv of K2CO3, and 1.2 equiv of I2 and using CH2Cl2 as
the solvent at room temperature gave the best results. This
procedure has been used as our standard reaction conditions
for subsequent electrophilic cyclizations.
To explore the scope of this cyclization, other commercially
available iodine, bromine, phosphorus, sulfur, and selenium
electrophiles have also been used in this process under similar
reaction conditions. The results are summarized in Table 2. It
has been found that I2, NIS, ICl, NBS, PhSeBr, and p-O2NC6H4-
SCl are all good electrophiles for the reaction of 2-(phenyl-
ethynyl)benzaldehyde (1) and MeOH, providing decent yields
of the desired cyclization products (entries 1-7). The strong
electrophile Br2 also readily reacted with aldehyde 1 to generate
the desired cyclization product (entry 5). However, the reaction
is not clean and only 21% of the desired product was obtained.
Electrophiles, such as tert-butylsulfinyl chloride and diphen-
ylphosphinous chloride (Ph2PCl), did not react with aldehyde
1, and none of the desired product was observed (entries 8 and
9).
with B(OMe)3 or toxic, strongly acidic HBF4, and the relatively
complicated stepwise procedure employed have certain draw-
backs synthetically. Furthermore, the full scope of this cycliza-
tion has yet to be reported.
We simultaneously found that this three-component reaction13
proceeds smoothly by using the simple electrophiles ICl, NIS,
Br2, NBS, p-O2NC6H4SCl, and PhSeBr to generate the corre-
sponding iodine-, bromine-, sulfur-, and selenium-substituted
heterocycles in high yields under very mild reaction conditions.14
Herein, we wish to report further details on this efficient
approach to heterocycles and carbocycles involving electrophilic
cyclization using a range of electrophiles and nucleophiles.
Results and Discussion
Our initial studies were aimed at finding optimal reaction
conditions for the electrophilic cyclization of the o-(1-alkynyl)-
benzaldehydes. Our investigation began with the reaction of
o-(phenylethynyl)benzaldehyde (1), methanol, and I2 (eq 3,
Table 1).
The reaction was first attempted using 0.25 mmol of
o-(phenylethynyl)benzaldehyde (1), 1.2 equiv of methanol, 1.0
equiv of K2CO3, and 1.2 equiv of I2 in CH2Cl2 at room
temperature. Iodocyclization proceeded smoothly and provided
an 88% yield of the desired product 2. Other solvents, such as
CH3CN and DMF, were also investigated and proved to be far
less effective. KHCO3 and NEt3 were also investigated as bases.
To further explore the scope of this chemistry, various
nucleophiles have been tested in this process using 2-(phenyl-
ethynyl)benzaldehyde (1) and I2. Alcohols, such as MeOH,
n-BuOH, t-BuOH and 2-iodobenzyl alcohol, all react well and
provide good to excellent yields of the desired iodocyclization
products (entries 1 and 10-12). The reaction with t-BuOH
provided only a modest yield due apparently to the steric
hindrance of the tert-butyl group or perhaps dehydration of this
alcohol (entry 11).
(11) (a) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am.
Chem. Soc. 2002, 124, 764. (b) Nakamura, H.; Ohtaka, M.; Yamamoto, Y.
Tetrahedron Lett. 2002, 43, 7631.
(12) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonza´lez, J. M.
J. Am. Chem. Soc. 2003, 125, 9028.
(13) For a recent review on multicomponent reactions, see: Do¨mling,
A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
Nucleophiles other than alcohols have also been examined
under our standard cyclization conditions. While the reaction
using N,N-dimethylaniline as the nucleophile provided an
(14) For a previous communication, see: Yue, D.; Della Ca´, N.; Larock,
R. C. Org. Lett. 2004, 6, 1581.
(15) Tovar, J. D.; Swager, T. M. J. Org. Chem. 1999, 64, 6499.
3382 J. Org. Chem., Vol. 71, No. 9, 2006

Electrophilic Cyclization of Acetylenic Arenecarboxaldehydes
TABLE 2. Electrophilic Cyclization of Acetylenic Aldehydes, Ketones, and Iminesa
J. Org. Chem, Vol. 71, No. 9, 2006 3383

Yue et al.
Table 2 (Continued)
3384 J. Org. Chem., Vol. 71, No. 9, 2006

Electrophilic Cyclization of Acetylenic Arenecarboxaldehydes
Table 2 (Continued)
J. Org. Chem, Vol. 71, No. 9, 2006 3385

Yue et al.
Table 2 (Continued)
a The reactions were run under the following conditions, unless otherwise specified. While stirring a solution of 2.5 mL of CH2Cl2 containing 0.25 mmol
of the alkyne, 0.30 mmol of the nucleophile, and 0.25 mmol of K2CO3, 0.30 mmol of electrophile was added, and the resulting mixture was further stirred
at room temperature until the total disappearance of the starting material upon TLC analysis. b The reaction was run on a 1.0 mmol scale; the 0.25 mmol
scale reaction provides an 88% yield of compound 2. c A 25% yield of O-trapping product was also observed. d This yield was determined by 1H NMR
spectroscopic analysis due to the apparent instability of the product. e 1 equiv of KF was added. f A 45% yield of adduct formed by direct addition of
p-O2NC6H4SCl to the triple bond.
excellent yield of the cyclization product (entry 13), those using
phenol, thiophene, N-methylindole, 5,5-dimethyl-1,3-cyclohex-
anedione, and 1,3-cyclohexanedione only afforded modest yields
of the desired cyclization products (entries 14-18). The reaction
with phenol provided both carbon- and oxygen-trapping products
(entry 14). The reactions which have produced carbon coupling
products were highly regioselective. The 1,3-diketone reactions
gave enol trapping products, plus some aldol product in the case
of 5,5-dimethyl-1,3-cyclohexanedione (entries 17 and 18). The
reaction with the trimethylsilyl enol ether of acetophenone did
not afford the desired cyclization product under our standard
reaction conditions; only the aldol condensation product was
observed. However, adding 1 equiv of KF as a promoter greatly
affected the reaction pathway, affording a 63% yield of the
desired cyclization product (entry 19). Other nucleophiles, such
as benzofuran, benzylthiol, Meldrum’s acid, and 1-methoxy-2-
methyl-1-(trimethylsilyloxy)propene failed to react under our
standard reaction conditions, and none of the desired products
were observed (entries 20-23). Thiols did not prove to be useful
nucleophiles, perhaps due to oxidation to disulfides by iodine.
Primary and secondary amines have also been used as nucleo-
philes, but none of the expected products were formed.
To further examine the generality of this chemistry, acetylenic
aldehydes bearing different substituents on the carbon-carbon
triple bond were synthesized in high yields by palladium/copper-
catalyzed coupling of the appropriate o-bromoarenecarboxal-
dehydes and the corresponding terminal alkynes.16 The resulting
acetylenic aldehydes were then allowed to react under our
standard electrophilic cyclization conditions to afford the
corresponding 1H-isochromene products. Alkynes bearing an
alkyl and a vinylic substituent on the triple bond also react well
and provide the desired electrophilic cyclization products in good
yields, when methanol and N,N-dimethylaniline are used as the
nucleophiles (entries 24, 25, 27, 28, and 30). 4,5-Dimethoxy-
2-(phenylethynyl)benzaldehyde (25) also underwent smooth
iodocyclization, providing a quantitative yield of the MeOH-
trapped product (entry 31).
Pyridinecarboxaldehyde derivatives 30 and 32 have also been
allowed to react under our standard cyclization conditions using
MeOH as a nucleophile and I2 or ICl as electrophiles. The
electron-deficient aromatic ring of these aldehydes did not affect
cyclization. We still obtained the desired iodocyclization
products using aldehyde 30 and either I2 or ICl in 70% and
64% yields, respectively (entries 35 and 36). The presence of
an electron-donating group on the aromatic ring on the distal
end of the carbon-carbon triple bond greatly enhanced the
cyclization, and a 96% yield of the desired cyclization product
was obtained when pyridinecarboxaldehyde 32 was employed
(entry 37).
Besides aromatic carboxaldehydes, vinylic carboxaldehyde
34 has also been examined under our standard iodocyclization
conditions. Using I2 and methanol, a 1:1 mixture of 5- and
1
6-membered ring products was observed by H NMR spectro-
scopic analysis (entry 38). Using NIS and n-BuOH, a mixture
was again obtained, but this time the 5-membered ring product
was favored by a 7:1 ratio (entry 39). The ratio of 5- to
6-membered ring products thus varies depending on the nu-
cleophile and electrophile used in the reaction.
We have also investigated the possibility of carrying out a
double iodocyclization, which might be quite useful for the quick
assembly of systems with extended conjugation. Compound 39
underwent smooth iodocyclization to afford the double cycliza-
tion product in a 75% yield (entry 40). In all cases where we
have compared results, these reactions with readily available,
inexpensive iodine have given higher yields than the corre-
sponding process using the expensive iodonium salt and HBF4
reported by Barluenga.12
We have also examined the cyclization of a ketone-containing
alkyne. Ketone 41 has been allowed to react with I2 and
methanol under our standard reaction conditions (entry 41). This
reaction proceeded smoothly to provide a 90% yield of a 5-exo-
dig cyclization product, rather than the 6-membered ring ether
formed by the electrophilic cyclization of analogous benzalde-
hyde derivatives. The use of K2CO3 in our standard procedure
provides very mild basic conditions and avoids the acid-initiated,
partial decomposition of this cyclization product described by
Barluenga.12
Interestingly, we were unable to get high yields of the desired
iodocyclization products when we employed our reagents in a
stepwise manner analogous to that described by Barluenga.12
Instead, an unreactive solid, presumed to be the pyrilium salt,15
was generated. Based on this observation, a possible mechanism
for our process is proposed in Scheme 2. We believe that these
cyclizations proceed by anti attack of the electrophile and the
carbonyl to produce a pyrilium intermediate. Before it forms
an insoluble precipitate,15 the pyrilium intermediate is im-
mediately trapped by the nucleophile present in the reaction
mixture.
Besides the successful use of PhSeBr as an electrophile (entry
6, Table 2), we have also been able to extend this cyclization
chemistry to sulfur electrophiles. Thus, aryl-, alkyl-, and vinylic-
substituted acetylenes undergo cyclization and provide sulfur-
substituted isochromenes in 60-74% yields, respectively (entries
7, 26, and 29). The reaction of aldehyde 25 and p-O2NC6H4-
SCl afforded only a 51% yield of the desired cyclization product,
alongside a 45% yield of the product of simple addition of the
electrophile to the carbon-carbon triple bond (entry 32).
Rather unstable 2-ethynylbenzaldehyde (28) and 2-(trimeth-
ylsilylethynyl)benzaldehyde (29) have also been employed as
aldehydes, but they did not undergo cyclization when MeOH
and I2 were used (entries 33 and 34). The reactions were messy,
and unidentifiable mixtures were observed instead.
Recently, a number of new naphthalene synthesis have been
reported, which involve alkyne cyclizations.17 For example,
Barluenga et al. have reported that IPy2BF4, o-alkynyl-
substituted carbonyl compounds, and alkynes react to give
(16) (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter
5, pp 203-229. (b) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467.
3386 J. Org. Chem., Vol. 71, No. 9, 2006

Electrophilic Cyclization of Acetylenic Arenecarboxaldehydes
SCHEME 2
SCHEME 4
SCHEME 3
4). Using the palladium-catalyzed annulation of an internal
alkyne developed in our group,21 we have been able to convert
compound 2 to 48 in a 92% yield. Compound 2 is also readily
oxidized to 4-iodoisocoumarin 49 in an 81% yield by using PCC
(Scheme 4).
Conclusions
1-iodonaphthalene derivatives and the reaction with alkenes
instead of acetylenes afforded related naphthyl ketone deriva-
tives.17d Our studies have shown that the same substituted
naphthalenes can be synthesized in high yields comparable to
those obtained by Barluenga employing our I2 procedure and
alkenes or alkynes as the trapping reagent (Scheme 3). The use
of the more sophisticated iodonium reagent IPy2BF4 employed
by Barluenga17d for this same process is not necessary. These
reactions are believed to proceed through a similar pyrilium
intermediate, which is trapped by the alkene or alkyne. Once
again, the use of readily available, easily handled I2 greatly
simplifies the procedure developed by Barluenga.17d
We believe that this approach to heterocycles should prove
quite useful in synthesis, particularly when one considers that
there are many ways to transform the resulting halogen, sulfur
and selenium functionalities into other substituents. For instance,
the resulting heterocyclic iodides should be particularly useful
intermediates in many palladium-catalyzed processes, such as
Sonogashira,16 Suzuki,18 Stille,19 and Heck20 cross-couplings.
For instance, compound 2 has been treated under standard Heck
and Suzuki conditions, providing the corresponding coupling
products 46 and 47 in 99% and 79% yields respectively (Scheme
Efficient syntheses of a variety of substituted oxygen-
containing heterocycles and carbocycles have been developed
using the electrophilic cyclization of acetylene-containing
aldehydes and ketones, and the generality of this process has
been explored. This method accommodates various functional
groups and affords substituted heterocycles in good to excellent
yields. The resulting iodoheterocycles are readily elaborated to
more complex compounds by using known organopalladium
chemistry. Although Barluenga12,17d reported similar reactions
using o-(1-alkynyl)benzaldehydes and IPy2BF4 plus HBF4, we
have been able to extend the above chemistry to polycyclic
compounds and bisisochromenes using readily available, inex-
pensive, easily handled I2 as the iodine source, and we have
generally obtained cleaner and higher yielding reactions. We
have also shown that electrophiles, such as ICl, NIS, NBS, Br2,
p-O2NC6H4SCl ,and PhSeBr, can be used in this chemistry.
(18) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (b) Lloyd-
Williams, P.; Giralt, E. Chem. Soc. ReV. 2001, 30, 145. (c) Suzuki, A. In
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: Weinheim, 1998; pp 49-97. (d) Miyaura, N. Chem. ReV.
1995, 95, 2457.
(19) (a) Negishi, E.; Dumond, Y. Handb. Organopalladium Chem. Org.
Synth. 2002, 1, 767. (b) Kosugi, M.; Fugami, K. Handb. Organopalladium
Chem. Org. Synth. 2002, 1, 263. (c) Kosugi, M.; Fugami, K. J. Organomet.
Chem. 2002, 653, 50.
(17) For metal-catalyzed synthesis of naphthalenes, see: (a) Asao, N.;
Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc.
2002, 124, 12650. (b) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J.
Am. Chem. Soc. 2003, 125, 10921. (c) Asao, N.; Kasahara, T.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2003, 42, 3504. For the iodonium ion-prompted
synthesis of naphthalenes, see: (d) Barluenga, J.; Vazquez-Villa, H.;
Ballesteros, A.; Gonza´lez, J. M. Org. Lett. 2003, 5, 4121. (e) Barluenga,
J.; Va´zquez-Villa, H.; Ballesteros, A.; Gonza´lez, J. M. AdV. Synth. Catal.
2005, 347, 526.
(20) (a) Crisp, G. T. Chem. Soc. ReV. 1998, 27, 427. (b) Brase, S.; De
Meijere, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; pp 99-166. (c) Palladium
Reagents in Organic Synthesis; Heck, R. F., Ed.; Academic Press: San
Diego, 1985; pp 276-287.
(21) Larock, R. C.; Doty, M. J.; Han, X. J. Org. Chem. 1999, 64, 8770.
J. Org. Chem, Vol. 71, No. 9, 2006 3387

Yue et al.
Experimental Section
Acknowledgment. We thank the donors of the Petroleum
Research Fund, administered by the American Chemical Society,
the National Institute of General Medical Sciences (GM070620),
and the National Institutes of Health (KU Chemical Methodolo-
gies and Library Development Center of Excellence, P50
GM069663) for financial support of this research. We also thank
Johnson Matthey, Inc., and Kawaken Fine Chemicals Co., Ltd.,
for donations of palladium salts. We thank Dr. Xiaoxia Zhang
for help in the preparation of this manuscript.
1
General Methods. H and 13C NMR spectra were recorded at
300 and 75.5 MHz or 400 and 100 MHz, respectively. Thin-
layer chromatography was performed using commercially pre-
pared 60-mesh silica gel plates, and visualization was effected
with short wavelength UV light (254 nm) or a basic KMnO4
solution [3 g of KMnO4 + 20 g of K2CO3 + 5 mL of NaOH (5%)
+ 300 mL of H2O]. All melting points are uncorrected. Low-
resolution mass spectra were recorded on a triple quadrupole mass
spectrometer. High-resolution mass spectra were recorded on a
double focusing magnetic sector mass spectrometer using EI at 70
eV.
Supporting Information Available: General experimental
procedures and spectral data for all previously unreported starting
materials and products. This material is available free of charge
via the Internet at http://pubs.acs.org.
Reagents. All reagents were used directly as obtained com-
mercially unless otherwise noted.
JO0524573
3388 J. Org. Chem., Vol. 71, No. 9, 2006