Intramolecular Pd-catalyzed carboetherification and carboamination. Influence of catalyst structure on reaction mechanism and product stereochemistry

Article abstract of DOI:10.1021/ja057489m

The intramolecular Pd-catalyzed carboetherification of alkenes affords 2-indan-1-yltetrahydrofuran products in moderate to good yield with good to excellent levels of diastereoselectivity. The stereochemical outcome of these reactions is dependent on the

Full text of DOI:10.1021/ja057489m

Published on Web 02/09/2006
Intramolecular Pd-Catalyzed Carboetherification and
Carboamination. Influence of Catalyst Structure on Reaction
Mechanism and Product Stereochemistry
Josephine S. Nakhla, Jeff W. Kampf,1 and John P. Wolfe*
Contribution from the Department of Chemistry, UniVersity of Michigan, 930 North UniVersity
AVenue, Ann Arbor, Michigan 48109-1055
Received November 2, 2005; E-mail: jpwolfe@umich.edu
Abstract: The intramolecular Pd-catalyzed carboetherification of alkenes affords 2-indan-1-yltetrahydrofuran
products in moderate to good yield with good to excellent levels of diastereoselectivity. The stereochemical
outcome of these reactions is dependent on the structure of the Pd catalyst. Use of PCy3 or P[(4-MeO)-
C6H4]3 as the ligand for Pd leads to syn-addition of the arene and the oxygen atom across the double
bond, whereas use of (()-BINAP or DPP-benzene affords products that result from anti-addition. The
catalyst-induced change in stereochemistry is likely due to a change in reaction mechanism. Evidence is
presented that suggests the syn-addition products derive from an unprecedented transannular alkene
insertion of an 11-membered Pd(Ar)(OR) complex. In contrast, the anti-addition products appear to arise
from Wacker-type anti-oxypalladation. Studies on analogous Pd-catalyzed intramolecular carboamination
reactions, which afford 2-indan-1-ylpyrrolidines that result from syn-addition, are also described.
Introduction
A strategy that provides access to both possible diastereomers
(syn-addition or anti-addition) from a single starting material
A large number of important biologically active molecules
and natural products contain subunits composed of heterocyclic
or carbocyclic rings attached by a C-C bond between two
stereogenic centers.2 Many approaches to the construction of
these moieties employ strategies in which one or both stereo-
centers are generated prior to ring closure.2-4 However, a
potentially attractive and concise alternate approach would be
to form both rings and both stereocenters in a single step via a
stereospecific addition across a carbon-carbon double bond.5
should allow for facile preparation of analogues that could be
used to optimize biological properties or probe structure/activity
relationships. In addition, this strategy would permit construction
of the desired product stereoisomer from the starting material
with the most easily accessible alkene geometry, which could
potentially decrease the length of synthetic sequences and
improve overall synthetic efficiency.
We have recently described a stereoselective method for the
construction of tetrahydrofurans and pyrrolidines via Pd-cata-
lyzed intermolecular6 carboetherification7a,b or carboamination7c,d,8
reactions between aryl bromides and γ-hydroxy or -amino
alkenes (eq 1). These reactions generate two bonds and up to
two stereocenters in one step and are believed to proceed via
intramolecular syn-alkene insertion into a Pd(Ar)(YR) complex
(e.g., 1).7b,d We reasoned that this methodology could potentially
be employed for the stereoselective construction of heterocycles
bearing attached carbocyclic rings (e.g., 4) by appending the
aryl halide moiety to the unsaturated alcohol or amine, which
would lead to the formation of two bonds, two stereocenters,
* To whom correspondence should be addressed.
(1) Author to whom correspondence regarding X-ray structure analysis should
be addressed. E-mail: jkampf@umich.edu.
(2) For examples of heterocycles bearing attached heterocycles, see: (a)
Bermejo, A.; Figadere, B.; Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.;
Cortes, D. Nat. Prod. Rep. 2005, 22, 269-303. (b) Faul, M. M.; Huff, B.
E. Chem. ReV. 2000, 100, 2407-2474. (c) Hoppe, R.; Scharf, H.-D.
Synthesis 1995, 1447-1464. (d) Koert, U. Angew. Chem., Int. Ed. Engl.
1995, 34, 298-300.
(3) For examples of heterocycles bearing attached carbocycles, see: (a) Ukiya,
M.; Akihisa, T.; Yasukawa, K.; Kasahara, Y.; Kimura, Y.; Koike, K.;
Nikaido, T.; Takido, M. J. Agric. Food Chem. 2001, 49, 3187-3197. (b)
Spinella, A.; Mollo, E.; Trivellone, E.; Cimino, G. Tetrahedron 1997, 53,
16891-16896. (c) Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N. G.;
Walton, E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.; Brooks,
J. R.; Berman, C. J. Med. Chem. 1986, 29, 2298-2315. (d) Arthur, H. R.;
Ko, P. D. S. Phytochemistry 1974, 13, 2551-2557.
(4) For representative examples of other strategies that generate attached rings
via C-C bond-forming reactions between cyclic precursors, see: (a)
Lemieux, R. M.; Meyers, A. I. J. Am. Chem. Soc. 1998, 120, 5453-5457.
(b) Lebsack, A. D.; Overman, L. E.; Valentekovich, R. J. J. Am. Chem.
Soc. 2001, 123, 4851-4852.
(5) (a) For attached-ring synthesis via pincaol-terminated Prins cyclizations,
which generate two stereocenters and one ring in a single step, see:
Overman, L. E.; Pennington, L. D. Can. J. Chem. 2000, 78, 732-738. (b)
For attached-ring synthesis via intramolecular 1,3-dipolar cycloaddition
followed by Mo-catalyzed ring cleavage, see: Tranmer, G. K.; Tam, W.
Org. Lett. 2002, 4, 4101-4104. (c) For attached-ring synthesis via Mn-
(III)-promoted oxidative cyclization reactions of malonates bearing tethered
unsaturated alcohols, see: Hulcoop, D. G.; Sheldrake, H. M.; Burton, J.
W. Org. Biomol. Chem. 2004, 2, 965-967.
(6) Both the intermolecular and intramolecular carboetherification/carboami-
nation reactions have an intramolecular component, as the heteroatom is
tethered to the alkene in both cases. In this article, the term “intermolecular
carboetherification/carboamination” is used to describe the reaction between
an aryl bromide and a γ-unsaturated alcohol/amine that is not tethered,
whereas the term “intramolecular carboetherification/carboamination”
describes reactions in which the γ-unsaturated alcohol/amine is tethered
to the aryl bromide.
(7) (a) Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc. 2004, 126, 1620-1621.
(b) Hay, M. B.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 16468-16476.
(c) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605-3608.
(d) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644-8651.
(8) For recent examples of stoichiometric Cu-promoted carboamination reac-
tions, see: Sherman, E. S.; Chemler, S. R.; Tan, T. B.; Gerlits, O. Org.
Lett. 2004, 6, 1573-1575.
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J. AM. CHEM. SOC. 2006, 128, 2893-2901
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A R T I C L E S
Nakhla et al.
alcohols and amines bearing tethered aryl halides. These
reactions afford 2-indan-1-yl tetrahydrofurans and pyrrolidines
in good yields with stereoselectivities up to >20:1. Products
resulting from syn-addition of the arene and the alcohol/amine
across the carbon-carbon double bond are formed when
catalysts bearing monodentate phosphines such as PCy3 or P[(p-
MeO)C6H4]3 are employed and likely derive from unprecedented
transannular alkene insertions of macrocyclic palladium(aryl)-
(alkoxide) or palladium(aryl)(amido) complexes (e.g., 3). In
contrast, substrates bearing tethered alcohol nucleophiles provide
products resulting from anti-addition when catalysts supported
by chelating ligands with small bite angles such as (()-BINAP
or DPP-benzene are used.15 The experiments described herein
suggest that the change in product stereochemistry likely results
from a change in reaction mechanism that is influenced by both
the structure of the Pd catalyst and the nature of the tethered
heteroatom, and are the first examples of phosphine ligand
control of syn- versus anti-oxypalladation pathways in catalytic
reactions.
and two rings in a single step (Scheme 1).9,10 However, we felt
these transformations could be quite challenging, as intermo-
lecular carboetherification reactions of internal olefins are
currently limited to substrates bearing tertiary alcohol nucleo-
philes, and intermolecular carboamination reactions provide
complex mixtures of products when acyclic internal alkenes are
employed as substrates.7
Scheme 1
Results
Intramolecular Carboetherification Reactions. In our initial
experiments we elected to explore the intramolecular carboet-
herification of Z-alkene 6 bearing a tethered primary alcohol
group because we felt that the Z-alkene geometry combined
with the high nucleophilicity of the unhindered alkoxide
(generated in situ upon reaction with NaOtBu) would help to
facilitate formation of the putative 11-membered palladium-
(aryl)(alkoxide) complex required for syn-alkoxypalladation. Our
previous studies of Pd-catalyzed intermolecular carboetherifi-
cation reactions demonstrated that the choice of phosphine
ligand had a large impact on chemical yield of the desired
tetrahydrofuran products.7a,16 Thus, our optimization studies
focused on variation of this parameter while employing other-
wise standard reaction conditions (toluene, NaOtBu, 105 °C).17
The alcohol substrate was prepared in three steps from
commercially available materials18 and was treated with catalytic
In addition to the potential synthetic utility and challenges
described above, these transformations also posed an interesting
mechanistic question. The intramolecular reactions,6 if mecha-
nistically analogous to the intermolecular reactions (eq 1), would
involve syn-alkene insertions of 11-membered palladacyclic
intermediates such as 3 (Scheme 1, Path A). Only one previous
report has described transformations that presumably involve
macrocyclic palladacycles bearing both Pd-C and Pd-hetero-
atom bonds,11 and transannular syn-alkene insertions of mac-
rocyclic palladacycles bearing internal olefins are unknown.
Alternatively, product formation could potentially occur through
other mechanistic pathways that have not been previously
observed to predominate in carboamination/carboetherification
processes involving alkenes and aryl bromides.12 For example,
a Wacker-type mechanism (Scheme 1, Path B) could generate
products resulting from anti-addition across the C-C double
bond (5).9,10 Although a priori we could not predict which
pathway would predominate, both pathways seemed potentially
viable, and we felt it might be possible to influence the
mechanistic and stereochemical course of the reactions by
varying catalyst structure.13,14
(13) (a) Through a series of deuterium labeling studies, Hayashi and co-workers
have demonstrated that the Pd(II)-catalyzed oxidative cyclization of an
o-allylphenol derivative proceeds via anti-alkoxypalladation in the presence
of LiCl, and via syn-alkoxypalladation in the absence of LiCl. However,
one of the stereocenters formed in these transformations is destroyed by
the â-hydride elimination step that terminates the catalytic cycle. Thus, in
the absence of labeled substrates, both transformations would provide
identical products. See: Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi,
Y. J. Am. Chem. Soc. 2004, 126, 3036-3037. (b) Stoltz and co-workers
have recently described experiments analogous to Hayashi et al.’s deuterium
labeling studies that provide further evidence for an accessible syn-
oxypalladation pathway in Wacker-type cyclizations of unsaturated alcohol
derivatives. See: Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am.
Chem. Soc. 2005, 127, 17778-17788. (c) For additional studies on the
effect of chloride ion concentration on the mechanistic/stereochemical
pathway of the Wacker oxidation, see: Hamed, O.; Thompson, C.; Henry,
P. M. J. Org. Chem. 1997, 62, 7082-7083 and references therein.
(14) Previously described Wacker-type cyclizations of alkenes bearing tethered
heteroatoms that afford tetrahydrofuran or pyrrolidine products generally
proceed via a Pd(II)-Pd(0) catalytic cycle. The mechanism of these
transformations involves complexation of the alkene to Pd(II) followed by
nucleophilic attack of the tethered heteroatom and â-hydride elimination
to generate the heterocyclic product. The resulting Pd(H)(X) complex
undergoes reductive elimination of HX to provide a Pd(0) complex, which
is then reoxidized to Pd(II) by an added oxidant. Catalysts employed for
these reactions generally contain halide, carboxylate, or amine ligands rather
than phosphine ligands. For further details, see: (a) Reference 13. (b)
Semmelhack, M. F.; Bodurow, C. J. Am. Chem. Soc. 1984, 106, 1496-
1498. (c) Harayama, H.; Abe, A.; Sakado, T.; Kimura, M.; Fugami, K.;
Tanaka, S.; Tamaru, Y. J. Org. Chem. 1997, 62, 2113-2122.
In this article, we describe the first examples of intramolecular
carboetherification and carboamination reactions of unsaturated
(9) Balme has described elegant studies on related intramolecular reactions of
alkenes bearing a bromoaryl group tethered to one sp2carbon and a malonate
derivative tethered to the other. These reactions proceed via Wacker-type
trans-carbopalladation of intermediate six-membered arylpalladium alkene
complexes to afford products resulting from anti-addition across the C-C
double bond. See: Bruye`re, D.; Bouyssi, D.; Balme, G. Tetrahedron 2004,
60, 4007-4017.
(10) For intramolecular Wacker-type anti-addition reactions of alkynes bearing
an alkyl(bromoaryl) group tethered to one end and an alkyl carboxylic acid
to the other, see: (a) Cavicchioli, M.; Bouyssi, D.; Gore, J.; Balme, G.
Tetrahedron Lett. 1996, 37, 1429-1432. (b) Bouyssi, D.; Balme, G. Synlett
2001, 1191-1193.
(11) For examples of Pd-catalyzed N-arylation reactions that likely proceed
through macrocyclic palladium(aryl)(amido) complexes, see: Beletskaya,
I. P.; Bessmertnykh, A. G.; Averin, A. D.; Denat, F.; Guilard, R. Eur. J.
Org. Chem. 2005, 281-305 and references therein.
(15) (()-BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; DPP-benzene
(12) In our previous studies, we have noted that the large majority of products
formed in intermolecular carboetherification and carboamination reactions
of internal alkenes derive from syn-insertion of the alkene into the Pd-
heteroatom bond of intermediate Pd(Ar)(OR) or Pd(Ar)(NRR′) complexes.
See refs 7b and 7d.
) 1,2-bis(diphenylphosphino)benzene.
(16) Hay, M. B.; Hardin, A. R.; Wolfe, J. P. J. Org. Chem. 2005, 70, 3099-3107.
(17) Further optimization experiments revealed that use of bases such as
triethylamine and potassium carbonate did not afford the desired cyclization
products.
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Pd-Catalyzed Carboetherification and Carboamination
A R T I C L E S
Table 1 a
Scheme 2 a
entry
ligand
drb
isolated yield (7 + 8) (%)
1
2
3
4
5
6
7
8
P[(p-MeO)C6H4]3
PPh3
P(o-tol)3
PCy3
DPE-Phos
DPPE
8:1
5:1
2:1
2:1
1:1
1:2
1:2
1:18
54
27
35
48
49
46
44
60
DPP-benzene
(()-BINAP
a Conditions: 1.0 equiv of 6, 2.0 equiv of NaOtBu, 1 mol % Pd2(dba)3,
4 mol % ligand (monophosphines) or 2 mol % ligand (bisphosphines),
toluene (0.1 M), 105 °C, 3-8 h. b Diastereoselectivities were determined
1
by GC and/or H NMR analysis of crude reaction mixtures.
a Conditions: 1.0 equiv of alcohol substrate, 2.0 equiv of NaOtBu, 1
mol % Pd2(dba)3, 4 mol % ligand (monophosphines) or 2 mol % ligand
(bisphosphines), toluene (0.1 M), 105 °C, 3-8 h. Diastereoselectivities were
amounts of Pd2(dba)3/phosphine ligand in the presence of excess
NaOtBu (2.0 equiv). As shown in Table 1, we were gratified
to find that Pd-catalyzed reactions of 6 proceeded to generate
the desired 2-(1-indanyl)tetrahydrofuran as a mixture of two
diastereomers (7 and 8) in moderate to good yield with
stereoselectivities dependent on catalyst structure. Use of a
catalyst composed of Pd2(dba)3 and P(o-tol)3 that provided
optimal results in intermolecular carboetherification reactions
of acyclic internal alkenes7b afforded 7 as the major diastereomer
(entry 3), which derives from syn-addition of the arene and the
alkoxide across the C-C double bond. The major side products
observed in this reaction resulted from debromination of the
starting material19 or intramolecular Heck arylation of the alkene.
After some experimentation, a mixture of Pd2(dba)3 and P[(4-
MeO)C6H4]3 was found to provide product 7 in 54% isolated
yield with 8:1 diastereoselectivity (entry 1). Use of this catalyst
system diminished the competing Heck arylation, although
competing debromination of the substrate was still problematic.
X-ray crystallographic analysis of a derivative bearing an
aminobiphenyl substituent on the aromatic ring confirmed that
the major diastereomer 7 possesses the (1S*,2S*)-relative
stereochemistry.20
1
determined by GC and/or H NMR analysis.
Scheme 3 a
a Conditions: 1.0 equiv of alcohol substrate, 2.0 equiv of NaOtBu, 1
mol % Pd2(dba)3, 4 mol % ligand (monophosphines) or 2 mol % ligand
(bisphosphines), toluene (0.1 M), 105 °C, 3-8 h. Diastereoselectivities were
1
determined by GC and/or H NMR analysis.
Surprisingly, a complete shift in the stereochemical outcome
of this reaction was observed when (()-BINAP was employed
as the ligand (entry 8). Under these conditions, the (1S*,2R*)-
diastereomer (8) was formed as the major product. This
substance derives from anti-addition of the arene and the alcohol
across the double bond and was obtained in 60% yield and 18:1
dr. Other chelating phosphine ligands with small bite angles
(e93°) such as DPPE and DPP-benzene also provided modest
selectivity for the anti-addition product.
With optimized reaction conditions in hand, we examined the
intramolecular carboetherification of several different alcohol sub-
strates with varying alkene geometries and varied degrees of
alcohol substitution. As shown in Scheme 2, the transformations
of substrates bearing primary alcohols were found to be stereo-
specific, and either diastereomer could be selectively obtained
from either the E- or Z-alkene starting materials (6 or 9) with
the appropriate choice of catalyst. For example, the (1S*,2R*)-
2-indan-1-yl tetrahydrofuran 8 was generated in 51% yield and
>20:1 dr via the Pd/PCy3-catalyzed syn-addition reaction of
E-alkene substrate 921 and was obtained in 60% yield and 18:1
dr via the Pd/(()-BINAP-catalyzed anti-addition of Z-alkene
substrate 6. Similarly, the (1S*,2S*)-isomer 7 was produced in
56% yield (15:1 dr) from 9 with DPP-benzene as ligand,22 and
54% yield (8:1 dr) from 6 with the ligand P[(p-MeO)C6H4]3.
Substrates 10 and 11 bearing tethered tertiary alcohols were
also selectively converted to products of either syn- or anti-
addition depending on catalyst structure (Scheme 3). However,
in contrast to reactions of Z-alkene primary alcohol 6, which
afforded syn-addition product 7 with most catalyst systems,
transformations of the analogous tertiary alcohol bearing a
Z-alkene (11) gave anti-addition product 12 under most condi-
(18) Complete details on the synthesis of all substrates are provided in the
Supporting Information.
(19) Aldehyde products derived from oxidation of the primary alcohol moiety
were not observed, but it is likely that these side products are not stable
under the reaction conditions.
(20) See the Supporting Information for complete details of stereochemical
assignments.
(21) Basic trialkylphosphine ligands such as tricyclohexylphosphine and trim-
ethylphosphine were employed in the form of their air-stable tetrafluo-
roborate salts. These ligands (and all other reagents employed in these
reactions) were weighed and handled in air. See: Netherton, M. R.; Fu, G.
C. Org. Lett. 2001, 3, 4295-4298.
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A R T I C L E S
Nakhla et al.
Table 2 a
tions examined. After some experimentation, the Pd/PMe3‚
HBF4-catalyzed reaction of 11 was found to provide 13,21 the
product of syn-addition across the Z-alkene, in 74% yield with
9:1 dr. Use of the ligand PCy3‚HBF4 for the Pd-catalyzed
cyclization of 11 afforded anti-addition product 12 in 78% yield
and 14:1 dr.22 Although both diastereomers 12 and 13 could be
selectively obtained from either starting material (10 or 11),
higher yields were obtained with the Z-alkene substrate 11.
To examine the possibility of stereoselectively generating
products with three stereocenters, the secondary alcohol 14
bearing an E-alkene was prepared and subjected to the carboet-
herification reaction conditions. The best results were obtained
with a catalyst composed of Pd2(dba)3/PCy3‚HBF4, which
provided a 40% isolated yield of 15 with 92:5:2:1 selectivity
favoring syn-addition across the alkene and trans-stereochem-
istry around the tetrahydrofuran ring (eq 2).23 The modest yield
can be attributed to the formation of large amounts of side
products that derive from reduction of the aryl bromide with
concomitant oxidation of the alcohol. Use of (()-BINAP for
this transformation led to complex mixtures of products; only
small amounts of the desired tetrahydrofuran derivatives were
entry
ligand
drb
isolated yield (19 + 20) (%)
1
2
3
4
5
6
7
(()-BINAP
DPE-Phos
DPPE
P(o-tol)3
Xantphos
P[(p-MeO)C6H4]3
PCy3‚HBF4
1:1
15:1
16:1
8:1
12:1
13:1
>20:1
46
49
54
47
57
68
88
a Conditions: 1.0 equiv of 18, 2.0 equiv of NaOtBu, 1 mol % Pd2(dba)3,
4 mol % ligand (monophosphines) or 2 mol % ligand (bisphosphines),
toluene (0.14 M), 105 °C, 3-10 h. b Diastereoselectivities were determined
1
by GC and/or H NMR analysis of crude reaction mixtures.
lecular carboamination reactions could also be achieved. Thus,
the Z-alkene substrate 18 bearing a tethered aniline moiety was
prepared and treated with a catalytic amount of Pd2(dba)3 and
several different phosphine ligands under reaction conditions
similar to those described above (Table 2). Interestingly, in
contrast to the results obtained in cyclizations of alcohol-contain-
ing substrate 6, all catalysts examined for the cyclization of 18
provided selectivity for formation of (1S*,2S*)-stereoisomer 19,
which derives from syn-addition across the Z-alkene. As observ-
ed in the related transformations of substrates bearing alcohol
nucleophiles, the major side products formed in these reactions
result from debromination of the starting material or intramole-
cular Heck arylation. Use of PCy3‚HBF4 (entry 7) provided the
optimal results for this transformation (88% yield, >20:1 dr)
and effectively suppressed the formation of both side products.
The intramolecular carboamination reactions also proved to
be stereospecific, as E-alkene derivative 21 underwent cycliza-
tion under optimized conditions to afford (1S*,2R*)-diastere-
omer 20, the product of syn-addition across the E-alkene, in
71% yield with >20:1 dr (eq 5). As observed with the analogous
alcohol substrates, the chemical yield obtained in the reaction
of the E-alkene was slightly lower than the yield of the reaction
of Z-alkene 18.
1
detected by H NMR analysis of crude reaction mixtures.
The cyclization of the corresponding Z-alkene 16 proceeded
in 40% yield with good selectivity (17:2:1:1 dr)24 for syn-
addition/trans-THF formation (eq 3); the two most prevalent
diastereomers both contained trans-tetrahydrofuran rings.23 As
noted above, competing oxidation/reduction of the substrate was
problematic in this system.
In contrast to the related Pd/BINAP-catalyzed transformation
of the E-alkene substrate 14, treatment of 16 with catalytic Pd2-
(dba)3/(()-BINAP provided 15 as the major diastereomer, which
results from anti-addition with trans-THF formation, albeit in
low yield (25%) (eq 4). High selectivity for anti-addition was
observed (94:6), although trans/cis-selectivity was modest (ca.
2:1).23 The major side products in this transformation resulted
from competing intramolecular Heck arylation of the starting
material.
Reactions involving aniline-bearing substrates that are branched
at C-1 proceeded with complete syn-selectivity. For example,
treatment of 22 with catalytic Pd2(dba)3/PCy3‚HBF4 afforded
product 23 in 55% yield and 5:1 diastereoselectivity (eq 6).
Interestingly, the major product diastereomer was found to
possess 2,5-trans-disubstitution around the pyrrolidine ring; the
(22) The Pd2(dba)3/BINAP catalyst system also provided the anti-addition
product as the major diastereomer, albeit in low yield. Use of BINAP as
ligand for the cyclization of 9 gave 35% yield (3:1 dr) of 7, and the
cyclization of 11 proceeded to afford 24% yield (>20:1 dr) of 12 under
similar conditions.
(23) Only the major product diastereomer is shown in eqs 2-4, 6, and 7. The
structures of the other minor diastereomers are shown in the Supporting
Information.
(24) The products were isolated in 40% yield as a 17:2:1:1 mixture of
diastereomers. However, analysis of the crude reaction mixture indicated
that the diastereomers were formed in a 9:2:1:1 ratio, suggesting that partial
resolution of the diastereomers occurred upon chromatographic purification.
Intramolecular Pd-Catalyzed Carboamination Reactions.
Having demonstrated the feasibility of intramolecular carboet-
herification reactions, we sought to determine whether intramo-
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Pd-Catalyzed Carboetherification and Carboamination
A R T I C L E S
minor diastereomer results from syn-addition with cis-pyrroli-
dine formation.23 In contrast, the analogous intermolecular
carboamination reactions of γ-(N-arylamino)alkenes have been
shown to provide generally high selectivity for the formation
of 2,5-cis-disubstituted pyrrolidine products.7c The reaction of
Z-alkene 24 proceeded in high yield (81%) but modest diaste-
reoselectivity (2:1 dr) favoring product 25, which results from
syn-addition across the alkene with cis-stereochemistry around
the pyrrolidine ring (eq 7). As seen in the reaction of 22, both
observed diastereomers resulting from the cyclization of 24
derive from syn-addition but differ in their relative stereochem-
istry about the pyrrolidine ring.23
tertiary alcohol substrates were transformed to products of syn-
addition when catalysts bearing electron-rich monodentate
ligands such as PCy3, PMe3, or P[(MeO)C6H4]3 were employed,
but reactions of these starting materials gave products of anti-
addition when chelating phosphines with small bite angles (e.g.,
BINAP, DPP-benzene, or DPPE; bite angles e 93°) were used
as supporting ligands. Notably, in carboetherification reactions
of primary and tertiary alcohols either product diastereomer
could be obtained selectively from either starting alkene
stereoisomer.
Reactions involving R-substituted alcohols catalyzed by Pd/
PCy3 or P[(MeO)C6H4]3 proceed with good to excellent levels
of selectivity for the formation of one of four possible dias-
tereomeric products; the major diastereomer results from syn-
addition with trans-THF formation. However, use of Pd/BINAP
with these substrates leads to low yields and modest selectivities.
The analogous Pd/PCy3-catalyzed reactions of R-branched
anilines proceed in good yields with very high syn-selectivity,
but give mixtures of cis- and trans-pyrrolidine products.
Mechanism of Intramolecular Carboetherification Reac-
tions That Provide syn-Addition Products. In our previous
studies on intermolecular Pd-catalyzed carboetherification and
carboamination reactions, we obtained results that were most
consistent with a mechanistic pathway involving syn-insertion
of the alkene moiety into the Pd-heteroatom bond of intermedi-
ate Pd(Ar)(OR) or Pd(Ar)(NRR′) complexes (e.g., 1).7b,d Other
mechanistic scenarios such as product formation via a Wacker-
type anti-addition or via intermolecular carbopalladation fol-
lowed by C-O or C-N bond-forming reductive elimination
were ruled out on the basis of the observed product stereo-
chemistry, the side products formed in the reactions, and the
high regioselectivity for formation of five-membered ring
products. The fact that syn-addition products are also obtained
in the intramolecular reactions suggests that a similar mechanism
may operate. However, this pathway would necessitate the
formation of 11-membered ring intermediates (e.g., 3), which
may be entropically unfavorable, and would require transannular
alkene insertion of a macrocyclic palladacycle bearing an
internal alkene, which is unprecedented.25 Thus, two plausible
mechanisms for the formation of the observed syn-addition
products of intramolecular reactions merit consideration.
Discussion
Reactivity and Stereoselectivity. The intramolecular pal-
ladium-catalyzed carboetherifications and carboaminations of
γ-hydroxy- or γ-aminoalkenes with tethered aryl bromides
provide a new, stereoselective means to generate carbocycles
bearing attached heterocycles. These reactions effect the conver-
sion of acyclic precursors to bicyclic products with formation
of two bonds, two rings, and two stereocenters in a single step.
The yields and selectivities are dependent on a number of
factors, but under optimal conditions the desired products are
obtained in moderate to good yields with good to excellent
stereocontrol.
Several trends in reactivity have been observed during the
course of these experiments. From the results described above,
it appears that the chemical yield is affected by the alkene
geometry, the nature of the heteroatom, and the degree of
substitution adjacent to the heteroatom. For example, substrates
bearing Z-alkenes are usually transformed in higher chemical
yield than the analogous E-alkenes. In addition, reactions
involving starting materials with tethered aniline nucleophiles
produce higher yields than analogous reactions of alcohol-
bearing substrates (with a similar degree of substitution). Finally,
in many cases substitution next to the heteroatom decreases
chemical yield.
As shown in Scheme 4, oxidative addition of the aryl bromide
26 to the LnPd(0) species generated in situ from Pd2(dba)3 and
a monodentate phosphine ligand, followed by coordination of
the tethered alkene, would afford the 16-electron intermediate
27, a species common to both mechanistic scenarios. This
intermediate could potentially be converted to the observed
products via a Heck-type 5-exo carbopalladation25a and depro-
tonation by NaOtBu to provide 28 (Path A), which could
undergo nucleophilic displacement of the bromide by the
The stereochemical outcome of these reactions is influenced
by both the nature of the heteroatom and the catalyst. All
substrates containing nitrogen nucleophiles that were examined
in these studies are selectively converted to products resulting
from syn-addition across the double bond. Although the catalyst
structure has an effect on the diastereoselectivity of the
pyrrolidine-forming reactions, with diastereomeric ratios varying
from 1:1 to >20:1, no catalyst examined led to selective
formation of the anti-addition product. In contrast, primary and
(25) For examples of transannular alkene insertion reactions of intermediates
bearing exocyclic alkylpalladium moieties and/or exocyclic alkenes, see:
(a) Link, J. T. Org. React. 2002, 60, 157-534. For representative examples,
see: (b) Hulin, B.; Newton, L. S.; Cabral, S.; Walker, A. J.; Bordner, J.
Org. Lett. 2004, 6, 4343-4345. (c) Fox, M. E.; Li, C.; Marino, J. P., Jr.;
Overman, L. E. J. Am. Chem. Soc. 1999, 121, 5467-5480.
9
J. AM. CHEM. SOC. VOL. 128, NO. 9, 2006 2897

A R T I C L E S
Scheme 4
Nakhla et al.
tethered alkoxide to afford 29.26 An unprecedented sp3 carbon-
oxygen bond-forming reductive elimination from Pd(II) complex
29 (with retention of configuration) would generate the observed
product 30.27,28 However, the fact that the cyclizations of
secondary alcohol substrates 14 and 16 proceed with good to
excellent stereoselectivity for trans-tetrahydrofuran formation
and syn-addition suggests that this pathway is much less likely
than the mechanism shown in Path B (see below).29 If the
reactions proceed via the mechanism outlined in Path A, the
5-exo carbopalladation event would determine both the syn/
anti-stereochemistry as well as the stereochemistry around the
THF ring. If the stereochemistry-determining event occurs via
intramolecular carbopalladation of intermediate 27 with no
communication between the alcohol and the metal, it is unlikely
that high selectivity for trans-THF formation would be ob-
served.30 In addition, Heck-type side products that would result
from slow reductive elimination following the 5-exo carbopal-
ladation are not formed in significant amounts in optimized
reactions that lead to syn-addition.
the 16-electron intermediate 27 could undergo deprotonation
followed by associative ligand substitution31 of the alkoxide for
the bromide26 to afford 11-membered palladacycle 31 in which
the alkyl group is oriented in a pseudoequatorial position.32
Formation of the 11-membered palladacycle 31 is presumably
facilitated by complexation of the alkene to the metal, which
allows for Pd-O bond formation via an effectively smaller
ring.29 Transannular insertion of the alkene into the palladium-
oxygen bond would generate 32, which could undergo C-C
bond-forming reductive elimination to form the observed product
30. Pseudoequatorial orientation of the R-substituent in the
transition state for alkene insertion would lead to the observed
products bearing trans-2,5-disubstituted tetrahydrofuran groups
and should be lower in energy than the related transition state
with axial orientation of the R-group due to developing
transannular interactions. The side products that comprise the
remainder of the mass balance in these reactions result from
oxidation of the alcohol with concomitant reduction of the aryl
bromide and are consistent with competing â-hydride elimina-
tion of 31 prior to alkene insertion. Although the experiments
described in this article cannot rule out product formation via
alkene insertion into the Pd-C bond of macrocycle 31, literature
precedent suggests that alkene insertion into the metal-
heteroatom bond of late-metal M(R)(OR) complexes is usually
more facile than insertion into the M-C bond.7,33,34
In contrast, the mechanistic pathway outlined in Scheme 4,
Path B, which is analogous to that proposed for the intermo-
lecular reactions,7b,d can account for both high syn-selectivity
and high selectivity for trans-THF formation. In this scenario,
(26) For studies on the formation of Pd(Ar)(OR) and Pd(Ar)(NR2) complexes,
see: (a) Yamashita, M.; Cuevas Vicario, J. V.; Hartwig, J. F. J. Am. Chem.
Soc. 2003, 125, 16347-16360 and references therein. (b) Widenhoefer,
R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 6504-6511 and
references therein.
Mechanism of Intramolecular Carboetherification Reac-
tions That Provide anti-Addition Products. In contrast to all
previously described intermolecular carboetherification reactions
of internal alkenes with aryl bromides,7a,b,35,36 which provide
syn-addition products, the intramolecular carboetherifications
(27) No examples of sp3 C-O bond-forming reductive elimination from Pd(II)
complexes have been previously described. One transformation that may
involve sp3 C-N bond-forming reductive elimination from a Pd(II) complex
with no syn-â-hydrogen atoms has been described by Stahl and co-workers.
See: (a) Brice, J. L.; Harang, J. E.; Timokhin, V. I.; Anastasi, N. R.; Stahl,
S. S. J. Am. Chem. Soc. 2005, 127, 2868-2869. For examples of related
sp3 carbon-heteroatom bond-forming reductive elimination from Pd(IV),
Pt(IV), and Ni(III), see: (b) Lin, B. L.; Clough, C. R.; Hillhouse, G. L. J.
Am. Chem. Soc. 2002, 124, 2890-2891 and references therein. (c) Desai,
L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542-
9543. (d) Williams, B. S.; Goldberg, K. I. J. Am. Chem. Soc. 2001, 123,
2576-2587. (e) Stahl, S. S.; Labinger, J. A.; Bercaw, J. E. Angew. Chem.,
Int. Ed. 1998, 37, 2180-2192.
(30) A mechanism involving fast and reversible carbopalladation followed by
selective Pd-heteroatom bond formation of one possible diastereomeric
intermediate could also account for the high diastereoselectivity. However,
reversible carbopalladation reactions have only been observed in complexes
lacking â-hydrogen atoms; carbopalladation is believed to be irreversible
in most other systems. The fact that oxidized/reduced side products are
observed instead of Heck-type side products also suggests this pathway is
less plausible than Path B. For lead references on reversible carbopalla-
dation, see: (a) Campora, J.; Gutierrez-Puebla, E.; Lopez, J. A.; Monge,
A.; Palma, P.; del Rio, D.; Carmona, E. Angew. Chem., Int. Ed. 2001, 40,
3641-3644. (b) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 119-122.
(28) Although related sp2C-O bond-forming reductive elimination is well-
established, reductive elimination in aryl sp2 systems has been demonstrated
to proceed via an addition/elimination mechanism similar to nucleophilic
aromatic substitution, which is not an accessible pathway for reductive
elimination to form sp3C-O bonds. For details, see ref 26b.
(31) The vast majority of ligand substitutions at 16-electron Pd(II) complexes
proceeds via an associative mechanism. The very rare examples of
dissociative ligand substitution at 16-electron Pd(II) complexes involve the
extremely bulky, monodentate, and unusually labile ligands tris(2,4,6-
trifluoromethylphenyl)phosphine and P(o-tol)3. See: (a) Bartolome, C.;
Espinet, P.; Martin-Alvarez, J. M.; Villafane, F. Eur. J. Inorg. Chem. 2004,
2326-2337. (b) Louie, J.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117,
11598-11599.
(32) Although formation of 11-membered rings is usually entropically unfavor-
able, formation of the 11-membered palladacycle 31 is presumably
facilitated by complexation of the alkene to the metal, which brings the
heteroatom closer to the complex.
(29) Palladium alkoxide formation and alkene 5-exo-insertion into a Pd-O bond
appear to be kinetically faster than 5-exo carbopalladation under our optimal
reaction conditions. As shown below, treatment of 1-bromo-2-(but-3-enyl)-
benzene with 2-methylhex-5-en-2-ol with a catalytic amount of Pd2(dba)3/
PCy3 in the presence of NaOtBu afforded only the 2-benzyltetrahydrofuran
derivative. Products derived from 5-exo-Heck cyclization of the aryl
bromide were not observed.
(33) (a) Villanueva, L. A.; Abboud, K. A.; Boncella, J. M. Organometallics
1992, 11, 2963-2965. (b) Bryndza, H. E. Organometallics 1985, 4, 406-408.
9
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Pd-Catalyzed Carboetherification and Carboamination
A R T I C L E S
Scheme 5
Scheme 6
provide products resulting from anti-addition when chelating
ligands with small bite angles (e.g., BINAP or DPP-benzene)
are employed. Formation of anti-addition products via syn-
insertion followed by reversible â-hydride elimination/reinser-
tion/σ-bond rotation processes that are occasionally observed
in the intermolecular transformations7b does not appear to be
likely in the intramolecular reactions (Scheme 5), as this
pathway would require a 7-endo-hydridopalladation of an aryl-
(hydrido)palladium alkene complex (33), which is energetically
unfavorable.37 In addition, side products that would result from
reductive elimination of 33 prior to 7-endo-hydridopalladation
are not observed; the major side products in reactions that afford
anti-addition products derive from intramolecular Heck-type
reactions (see below).
expected to inhibit the associative ligand substitution process
required for palladium alkoxide formation.31 As outlined in
Scheme 6, Path A, oxidative addition of the aryl bromide 26 to
a (L-L)Pd(0) complex followed by alkene coordination would
generate 18-electron complex 34. This coordinatively saturated
complex could not be converted to a palladium(aryl)(alkoxide)
analogous to 31 via an associative ligand substitution process,
and it is unlikely that the 11-membered palladacycle 31 would
be generated in the absence of alkene coordination, as 11-
membered ring formation is entropically unfavorable. Thus,
conversion of 34 to 31 is likely to be relatively slow.38 Instead,
a mechanistic pathway involving a Wacker-type anti-alkoxyp-
alladation may be more accessible in this system than in other
carboetherification processes. The anti-alkoxypalladation of 34
via an ordered transition state such as 35 could generate 36,
which would provide anti-addition product 37 upon C-C bond-
forming reductive elimination. The stereochemistry around the
tetrahydrofuran ring would again be dictated by nonbonding
interactions in the transition state, with a preference for
pseudoequatorial orientation of substituents. However, prior
studies have shown that differences in transition-state energies
for pseudoaxial versus pseudoequatorial orientation of the
R-substituents or the alkene moiety in related Wacker-type
cyclizations may be relatively small, as the preference for trans-
Instead, it appears likely that the change in observed product
stereochemistry arises from a fundamental change in the
mechanism through which the products are formed. This change
can be attributed to the notion that tightly chelating ligands are
(34) For other recent examples of syn-alkene insertion into late transition metal-
heteroatom bonds, see: (a) Helaja, J.; Go¨ttlich, R. J. Chem. Soc., Chem.
Commun. 2002, 720-721. (b) Tsutsui, H.; Narasaka, K. Chem. Lett. 1999,
45-46. (c) Reference 27a.
(35) Yeh, M.-C. P.; Tsao, W.-C.; Tu, L.-H. Organometallics 2005, 24, 5909-
5915.
(36) Wacker-type carbonylative carboetherifications described by Semmelhack
and Bodurow afford products resulting from anti-addition of an oxygen
atom and an ester group across an alkene. See ref 14b.
(37) Endo carbopalladation reactions are extremely rare, and 7-endo hydri-
dopalladation reactions are unknown. For lead references, see: Gibson, S.
E.; Guillo, N.; Middleton, R. J.; Thuilliez, A.; Tozer, M. J. J. Chem. Soc.,
Perkin Trans. 1 1997, 447-456 and references therein.
(38) Conversion of 34 to 31 could occur via dissociation of one arm of the
chelating ligand followed by associative substitution of alkoxide for
bromide, or by dissociation of the bromide followed by associative ligand
substitution. Either of these pathways is likely to be higher in energy than
the analogous conversion of 27 to 31.
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A R T I C L E S
Nakhla et al.
THF formation is often modest in the absence of additional
substituents.9,36
Alternatively, the products of anti-addition could derive from
Heck-type carbopalladation of 34 to generate 38, followed by
C-O bond-forming reductive elimination through an SN2 mech-
anism, which would lead to inversion of the C2 stereocenter to
provide 37. Although we cannot rule out product formation via
this mechanism, we currently favor the hypothesis involving a
Wacker-type pathway, as the sp3 C-O bond-forming reductive
elimination required for product formation via Path B is not
known to occur from Pd(II) complexes27,28 and would require
SN2 substitution to occur at a hindered secondary carbon atom
flanked by an adjacent secondary carbon stereocenter. The fact
that Heck-type side products (e.g., 39) are generated in these trans-
formations suggests that complex 38 is kinetically accessible,
but mechanistic pathway B cannot account for control of relative
stereochemistry around the tetrahydrofuran ring. The observed
selectivity for formation of trans-disubstituted tetrahydrofuran
products in the Pd/BINAP-catalyzed reaction of 16 is more con-
sistent with an ordered transition state similar to 35. Thus, al-
though 38 may be accessible under the reaction conditions, it is
not necessarily an intermediate along the pathway between 34
and 37.
nucleophilicity (anionic alkoxide versus neutral amine) on the
rate of anti-heteropalladation. In the presence of NaOtBu there
is likely a significant equilibrium concentration of highly
nucleophilic alkoxides that results from deprotonation of the
substrate alcohol.42 In contrast, deprotonation of the less acidic
aniline nucleophile would occur to a lesser extent, and hence
the concentration of anilide anion is likely to be low, which
may result in relatively slower rates of Wacker-type addition
of the nitrogen nucleophiles. The fact that yields of anti-addition
products of intramolecular carboetherification reactions decrease
(under identical conditions) with increasing steric bulk of the
alcohol nucleophile is also consistent with this notion.22,43
Conclusions
In conclusion, we have demonstrated the feasibility of a new
strategy for the stereoselective construction of products bearing
two attached rings via Pd-catalyzed carboetherification and
carboamination reactions. Depending on the structure of the
catalyst and the substrate, selectivity for either syn-addition or
anti-addition is observed. The products of syn-addition appear
to derive from unprecedented transannular alkene insertions of
unusual 11-membered Pd(Ar)(YR) intermediates. In contrast,
the products of anti-addition are consistent with reaction via a
different mechanistic pathway that may involve Wacker-type
anti-heteropalladation of the alkene. These studies represent the
first examples of phosphine ligand control of syn-insertion
versus anti-addition pathways in catalytic reactions involving
olefin oxypalladation, which allows for stereoselective construc-
tion of either of two possible product diastereomers from a given
alcohol substrate. Further studies on the scope and synthetic
applications of this new methodology are currently underway.
Mechanism and Stereochemistry of Intramolecular Car-
boamination Reactions. The intramolecular carboamination
reactions described above provide products that derive from syn-
addition of the amine and the arene across the carbon-carbon
double bond. It is likely that these transformations proceed via
a mechanism similar to that outlined above (Scheme 4, Path B)
for syn-addition reactions of alcohol substrates, which involves
a transannular alkene insertion of an 11-membered palladium-
(aryl)(amido) intermediate through transition state 40 or 41.
However, in reactions of substrates bearing tethered anilines
with R-stereocenters, the factors leading to a preference for either
trans-pyrrolidine stereochemistry (E-alkenes) or cis-pyrrolidine
stereochemistry (Z-alkenes) are more complicated than in the
related transformations of secondary alcohols, and the origin
of the observed stereochemistry is not entirely clear. One
possible explanation for these results is that pseudoequatorial
orientation of the C1-R-group (40) would minimize developing
transannular interactions in the transition state,39 but could lead
to developing A1,3-strain between the Nsp2 aryl group and the
pseudoequatorial R-substituent.40 Alternatively, pseudoaxial
orientation of the R-group (41) may minimize allylic strain at
the expense of increased unfavorable transannular interactions.
The results of the experiments shown in eqs 6 and 7 are
consistent with preferred pseudoequatorial orientation of the
substituent when the substrate contains the E-alkene geometry,
which suggests that the energetic effects of the transannular
interactions outweigh the effects of A(1,3)-strain for this system.
In contrast, there appears to be a slight preference for pseudo-
axial orientation with the Z-alkene geometry, which implies that
the transannular interactions may be lessened relative to the
degree of allylic strain in this case.41
Acknowledgment. We thank the NIH-NIGMS (GM-071650)
and the University of Michigan for financial support of this
work. J.P.W. acknowledges the Camille and Henry Dreyfus
Foundation for a New Faculty Award, Research Corporation
(39) Dosen-Micovic, L.; Lorenc, L.; Mihailovic, M. L. Tetrahedron 1990, 46,
3659-3666.
(40) (a) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841-1860. (b) Hart, D. J. J.
Am. Chem. Soc. 1980, 102, 397-398. (c) Williams, R. M.; Sinclair, P. J.;
Zhai, D.; Chen, D. J. Am. Chem. Soc. 1988, 110, 1547-1557.
(41) As noted above, our previously described intermolecular carboamination
reactions of terminal alkenes have proceeded with high stereoselectivity
for the formation of trans-2,5-disubstituted N-arylpyrrolidines, which is also
consistent with favorable pseudoaxial orientation of a C-1 substituent in
the absence of medium-ring transannular interactions. However, the effects
of E/Z-alkene geometry on the ratio of trans/cis-pyrrolidine pyrrolidine
formation have not yet been examined in intermolecular transformations.
For further details, see ref 7c.
(42) The addition of base has been observed to dramatically increase the rate
and/or yield of oxidative Wacker cyclizations of o-allylphenol derivatives.
See: (a) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2003, 42, 2892-2895. (b) Larock, R. C.; Wei, L.;
Hightower, T. R. Synlett 1998, 522-524.
(43) The rate and/or yield of Wacker cyclization reactions that afford tetrahy-
drofuran products have also been observed to decrease with increasing steric
bulk at the C1 position. See: (a) Meulemans, T. M.; Kiers, N. H.; Feringa,
B. L.; van Leeuwen, P. W. N. M. Tetrahedron Lett. 1994, 35, 455-458.
(b) Hosokawa, T.; Hirata, M.; Murahashi, S.-i.; Sonoda, A. Tetrahedron
Lett. 1976, 17, 1821-1824.
In contrast to Pd/BINAP or Pd/DPP-benzene-catalyzed reac-
tions of alcohol substrates, which provide good selectivity for
products of anti-addition, use of BINAP or DPP-benzene with
substrates bearing aniline nucleophiles results in low syn/anti
stereoselectivity. The differences in the stereochemical outcome
of these transformations may be due to the effect of heteroatom
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Pd-Catalyzed Carboetherification and Carboamination
A R T I C L E S
for an Innovation Award, and Eli Lilly for a Grantee Award.
We also thank Amgen, 3M, and Eli Lilly for additional
unrestricted support.
characterization data for all new compounds, and descriptions
of stereochemical assignments with supporting crystallographic
structural data (CIF, PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
Supporting Information Available: Experimental procedures
for synthesis of substrates and for Pd-catalyzed reactions,
JA057489M
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J. AM. CHEM. SOC. VOL. 128, NO. 9, 2006 2901