Oxidative cyclizations in a nonpolar solvent using molecular oxygen and studies on the stereochemistry of oxypalladation

Article abstract of DOI:10.1021/ja055534k

Oxidative cyclizations of a variety of heteroatom nucleophiles onto unactivated olefins are catalyzed by palladium(II) and pyridine in the presence of molecular oxygen as the sole stoichiometric oxidant in a nonpolar solvent (toluene). Reactivity studies of a number of N-ligated palladium complexes show that chelating ligands slow the reaction. Nearly identical conditions are applicable to five different types of nucleophiles: phenols, primary alcohols, carboxylic acids, a vinylogous acid, and amides. Electronrich phenols are excellent substrates, and multiple olefin substitution patterns are tolerated. Primary alcohols undergo oxidative cyclization without significant oxidation to the aldehyde, a fact that illustrates the range of reactivity available from various Pd(II) salts under differing conditions. Alcohols can form both fused and spirocyclic ring systems, depending on the position of the olefin relative to the tethered alcohol; the same is true of the acid derivatives. The racemic conditions served as a platform for the development of an enantioselective reaction. Experiments with stereospecifically deuterated primary alcohol substrates rule out a "Wacker-type" mechanism involving anti oxypalladation and suggest that the reaction proceeds by syn oxypalladation for both mono- and bidentate ligands. In contrast, cyclizations of deuterium-labeled carboxylic acid substrates undergo anti oxypalladation.

Full text of DOI:10.1021/ja055534k

Published on Web 11/15/2005
Oxidative Cyclizations in a Nonpolar Solvent Using Molecular
Oxygen and Studies on the Stereochemistry of
Oxypalladation
Raissa M. Trend, Yeeman K. Ramtohul, and Brian M. Stoltz*
Contribution from The Arnold and Mabel Beckman Laboratories of Chemical Synthesis,
DiVision of Chemistry and Chemical Engineering, California Institute of Technology,
1200 East California BouleVard, MC 164-30, Pasadena, California 91125
Received August 12, 2005; E-mail: stoltz@caltech.edu
Abstract: Oxidative cyclizations of a variety of heteroatom nucleophiles onto unactivated olefins are
catalyzed by palladium(II) and pyridine in the presence of molecular oxygen as the sole stoichiometric
oxidant in a nonpolar solvent (toluene). Reactivity studies of a number of N-ligated palladium complexes
show that chelating ligands slow the reaction. Nearly identical conditions are applicable to five different
types of nucleophiles: phenols, primary alcohols, carboxylic acids, a vinylogous acid, and amides. Electron-
rich phenols are excellent substrates, and multiple olefin substitution patterns are tolerated. Primary alcohols
undergo oxidative cyclization without significant oxidation to the aldehyde, a fact that illustrates the range
of reactivity available from various Pd(II) salts under differing conditions. Alcohols can form both fused and
spirocyclic ring systems, depending on the position of the olefin relative to the tethered alcohol; the same
is true of the acid derivatives. The racemic conditions served as a platform for the development of an
enantioselective reaction. Experiments with stereospecifically deuterated primary alcohol substrates rule
out a “Wacker-type” mechanism involving anti oxypalladation and suggest that the reaction proceeds by
syn oxypalladation for both mono- and bidentate ligands. In contrast, cyclizations of deuterium-labeled
carboxylic acid substrates undergo anti oxypalladation.
Introduction
ment of racemic oxidase-type reactions that feature electrophilic
Pd(II), some examples of which are shown in Figure 1, although
Oxidation is one of the most fundamental and important
processes in nature. It has also become one of the most effective
ways for chemists to induce asymmetry in organic transforma-
tions for the production of enantioenriched materials.1 Most
enantioselective oxidations involve the transfer of a heteroatom,
commonly oxygen, to a substrate in a manner analogous to that
of oxygenase metalloenzymes. In contrast, there is a significant
lack of asymmetric two-electron oxidations that do not involve
heteroatom transfer. This second mode of oxidation is similar
to oxidase-type enzymatic reactions for which oxygen atoms
instead act as electron and proton acceptors in substrate
oxidation.
they are much less prevalent.3 Such reactions require the
recycling of Pd(0) to Pd(II) by a stoichiometric oxidant. Ideally,
such a process would take advantage of the most abundant and
inexpensive oxidant, molecular oxygen (O2). In fact, one of the
early systems developed for the catalytic oxidation of secondary
alcohols by Pd(II) employed O2 directly as the only stoichio-
metric oxidant.4 The use of DMSO as solvent also has enabled
racemic O2-coupled Pd(II)-catalyzed oxidative cyclizations of
olefin-appended nucleophiles, such as phenols, alcohols, acids,
and tosylamides, as well as alcohol oxidations to ketones and
aldehydes.5 Two other reoxidation systems include the tradi-
tional Wacker process that employs a copper cocatalyst in the
presence of O2 and the use of the organic oxidant benzoquinone
as a stoichiometric oxidant. Racemic cyclization reactions have
also been developed using these reoxidants.6,7
The ability of palladium (Pd) to serve as both a nucleophile
(Pd(0)) and an electrophile (Pd(II)) has led to an explosion in
Pd(0)-catalyzed reactions that have become indispensable to
organic chemistry.2 This property has also led to the develop-
(3) For reviews, see: (a) Stoltz, B. M. Chem. Lett. 2004, 33, 362-367. (b)
Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400-3420. (c) Sigman, M.
S.; Schultz, M. J. Org. Biomol. Chem. 2004, 2, 2551-2554. (d) For a recent
review of Pd-catalyzed alcohol oxidation, see: Muzart, J. Tetrahedron 2003,
59, 5789-5816. (e) Trost, B. M. Acc. Chem. Res. 1990, 23, 34-42. (f)
Hegedus, L. S. Tetrahedron 1984, 40, 2415-2434. (g) Hosokawa, T.;
Murahashi, S.-I. Acc. Chem. Res. 1990, 23, 49-54. (h) Semmelhack, M.
F.; Kim, C.; Zhang, N.; Bodurow, C.; Sanner, M.; Dobler, W.; Meier, M.
Pure. Appl. Chem. 1990, 23, 2035-2040. (i) Tsuji, J. Palladium Reagents
and Catalysts; John Wiley & Sons Ltd.: Chichester, UK, 1995; pp 125-
527. (j) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285-2309. (k)
Wolfe, J. P.; Thomas, J. S. Curr. Org. Chem. 2005, 9, 625-655.
(4) Blackburn, T. F.; Schwartz, J. J. Chem. Soc., Chem. Commun. 1977, 157-
158.
(1) (a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; Wiley & Sons: New York, 2000; pp 231-280. (b) Katsuki,
T. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley & Sons: New
York, 2000; pp 287-325. (c) Jacobsen, E. N. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
1999; Vol. 2, pp 607-618. (d) For a recent review of advances in transition
metal catalyzed oxidation, see: Punniyamurthy, T.; Velusamy, S.; Iqbal,
J. Chem. ReV. 2005, 105, 2329-2364.
(2) (a) Tsuji, J. Palladium Reagents and Catalysis; John Wiley & Sons Ltd.:
Chichester, UK and Hoboken, NJ, 2004. (b) Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed; Wiley & Sons: New
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3453-3516.
9
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Oxidative Cyclizations and Stereochemistry of Oxypalladation
A R T I C L E S
Figure 2. An oxidase-type kinetic resolution of secondary alcohols.
Table 1. Optimization of Pd Source
entry
Pd source
additive
time
yieldb
1
2
3
4
5
6
7
8
Pd(nbd)Cl2
PdCl2
none
none
none
none
Na2CO3
none
none
24 h
24 h
24 h
60 min
20 min
24 h
24 h
24 h
24 h
5 h
7%
27%
76%
87%
95%
25%
NR
Figure 1. Prototypical Pd(II)-catalyzed dehydrogenation reactions.
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd2(dba)3
Pd black
none
Despite these advances in racemic Pd(II)-catalyzed oxidation
reactions, many do not meet the ideal criteria for enantioselectiVe
reactions of employing only O2 as the stoichiometric oxidant
in a noncoordinating solvent. Instead, the necessary use of
cocatalysts, organic oxidants, or DMSO has complicated the
development of asymmetric oxidase-type reactions. For example,
the use of copper/O2 introduces a secondary catalytic cycle and
another metal that could compete with Pd for the chiral ligand.
The benzoquinone system requires the removal of stoichiometric
amounts of organic compounds,8 and benzoquinone itself can
act as a ligand.9,10 In addition, DMSO is a highly donating
solvent that could interfere with the coordination of a chiral
ligand to Pd. Despite the obstacles presented by the traditional
oxidation systems, seminal works by Hosokawa and Mura-
hashi,11 Hayashi,12 Sasai,13 and Ba¨ckvall9 established the
potential of enantioselective Pd(II)-catalyzed oxidative cycliza-
tions and dialkoxylations.14
none
NR
9
Pd(TFA)2
Pd(TFA)2
none, no O2
24%
10c
Na2CO3, Hg0
84%d
a With 5 mol % of Pd source, 20 mol % of pyridine, 500 mg/mmol of
MS3Å, 1 atm O2, toluene (0.1 M), 80 °C. b Isolated yield. c With 5 mol %
of (pyridine)2Pd(TFA)2, 10 mol % of pyridine, 2 equiv of Na2CO3, 30 equiv
of Hg0. d Conversion determined by GC.
With the requirement that O2 be the only stoichiometric
oxidant, we began to address the lack of enantioselective
oxidase-type catalysis with the development of the Pd(II)-
catalyzed asymmetric dehydrogenation of secondary alcohols
illustrated in Figure 2.15,16 This oxidation effects a kinetic
resolution to provide enantioenriched alcohol and was the first
example of an asymmetric oxidase-type reaction in that it
employs O2 as the terminal oxidant. The basis for this chemistry
was another racemic Pd(II)-catalyzed alcohol oxidation reported
in 1999 by Uemura and co-workers.17 Significantly, the reaction
used only O2 in a noncoordinating solvent (toluene) and was
accelerated by the presence of a ligand (pyridine). We subse-
quently initiated an effort to apply our enantioselective alcohol
oxidation to the development of asymmetric versions of
reactions such as those shown in Figure 1. In line with this
(5) (a) For examples of phenol cyclizations, see: Larock, R. C.; Wei, L.;
Hightower, T. Synlett 1998, 522-524. (b) For examples of alcohol
cyclizations, see: Ro¨nn, M.; Ba¨ckvall, J.-E.; Andersson, P. G. Tetrahedron
Lett. 1995, 36, 7749-7752. (c) For examples of acid cyclizations, see:
Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298-5300. (d)
For examples of tosylamide cyclizations, see: Larock, R. C.; Hightower,
T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584-
3585 and references therein. (e) For examples of primary and secondary
alcohol oxidation to aldehydes and ketones, see: Peterson, K. P.; Larock,
R. C. J. Org. Chem. 1998, 63, 3185-3189.
(6) For examples of racemic systems that employ the copper/O2 system, see
(a) phenol cyclizations: Hosokawa, T.; Ohkata, H.; Moritani, I. Bull. Chem.
Soc. Jpn. 1975, 48, 1533-1536. (b) Alcohol cyclizations: Hosokawa, T.;
Hirata, M.; Murahashi, S.-I.; Sonoda, A. Tetrahedron Lett. 1976, 21, 1821-
1824.
(7) For examples of racemic systems that employ benzoquinone, see (a) aniline
cyclizations: Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L.
J. Am. Chem. Soc. 1978, 100, 5800-5807. (b) For oxidative carbon-carbon
bond forming aryl/olefin cyclizations, see: Zhang, H.; Ferreira, E. M.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2004, 43, 6144-6148.
(8) In contrast, reactions that are solely aerobic produce only H2O or H2O2 as
byproducts.
(14) For examples of non-oxidative Pd(II)-mediated enantioselective catalysis,
see: (a) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999,
121, 5450-5458. (b) El-Qisairi, A.; Hamed, O.; Henry, P. M. J. Org. Chem.
1998, 63, 2790-2791. (c) Zhang, Q.; Lu, X. J. Am. Chem. Soc. 2000, 122,
7604-7605. (d) Overman, L. E.; Remarchuk, T. P. J. Am. Chem. Soc. 2002,
124, 12-13.
(15) (a) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725-
7726. (b) Bagdanoff, J. T.; Ferreira, E. M.; Stoltz, B. M. Org. Lett. 2003,
5, 835-837. (c) Caspi, D. D.; Ebner, D. C.; Bagdanoff, J. T.; Stoltz, B. M.
AdV. Synth. Catal. 2004, 346, 185-189. (d) For conditions employing
chloroform and air, see: Bagdanoff, J. T.; Stoltz, B. M. Angew. Chem.,
Int. Ed. 2004, 43, 353-357. (e) Trend, R. M.; Stoltz, B. M. J. Am. Chem.
Soc. 2004, 126, 4482-4483.
(16) For a similar system, see: (a) Jensen, D. R.; Pugsley, J. S.; Sigman, M. S.
J. Am. Chem. Soc. 2001, 123, 7475-7476. (b) Mueller, J. A.; Jensen, D.
R.; Sigman, M. S. J. Am. Chem. Soc. 2002, 124, 8202-8203. (c) Jensen,
D. R.; Sigman, M. S. Org. Lett. 2003, 5, 63-65. (d) Mandal, S. K.; Jensen,
D. R.; Pugsley, J. S.; Sigman, M. S. J. Org. Chem. 2003, 68, 4600-4603.
(e) Mueller, J. A.; Sigman, M. S. J. Am. Chem. Soc. 2003, 125, 7005-
7013. (f) Mandal, S. K.; Sigman, M. S. J. Org. Chem. 2003, 68, 7535-
7537.
(17) (a) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999,
64, 6750-6755. (b) Uemura has used similar conditions for the ring
cleavage of tert-cyclobutanols: Nishimura, T.; Ohe, K.; Uemura, S. J. Am.
Chem. Soc. 1999, 121, 2645-2646. (c) Related heterogeneous conditions
that use a hydrotalcite solid support have been developed: Kakiuchi, N.;
Maeda, Y.; Nishimura, T.; Uemura, S. J. Org. Chem. 2001, 66, 6620-
6625.
(9) (a) Thorarensen, A.; Palmgren, A.; Itami, K.; Ba¨ckvall, J.-E. Tetrahedron
Lett. 1997, 38, 8541-8544. (b) Itami, K.; Palmgren, A.; Thorarensen, A.;
Ba¨ckvall, J.-E. J. Org. Chem. 1998, 63, 6466-6471. (c) Cotton, H. K.;
Verboom, R. C.; Johansson, L.; Plietker, B. J.; Ba¨ckvall, J.-E. Organome-
tallics 2002, 21, 3367-3375.
(10) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem.
Soc. 2005, 127, 6970-6971.
(11) (a) Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S.-I. J. Am. Chem. Soc.
1981, 103, 2318-2323. (b) Hosokawa, T.; Okuda, C.; Murahashi, S.-I. J.
Org. Chem. 1985, 50, 1282-1287.
(12) (a) Uozumi, Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997, 119, 5063-
5064. (b) Uozumi, Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071-
5075. (c) Uozumi, Y.; Kyota, H.; Kato, K.; Ogasawara, M.; Hayashi, T. J.
Org. Chem. 1999, 64, 1620-1625.
(13) Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001,
123, 2907-2908.
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A R T I C L E S
Trend et al.
Table 2. Oxidative Cyclizations with Substituted Pyridyl and Alkyl Amine Ligands
a With 5 mol % of LnPd(TFA)2, 500 mg/mmol of MS3Å, 1 atm O2, toluene (0.1 M), 80 °C. b Conversion determined by GC. c Pd black precipitate was
observed in the reaction mixture. d For entries 6, 7, 10, and 11, 20 mol % of excess ligand was added.
goal, we recently communicated the extension of Uemura’s
conditions to the cyclizations of heteroatoms and electron-rich
indoles onto pendant olefins, as well as an asymmetric version
of the former reaction.18,19 This work established that hetero-
atom-olefin cyclizations that use O2 as the sole oxidant could
be amenable to asymmetric catalysis. We now report the full
details regarding the development of these racemic and asym-
metric heterocyclizations, an expanded substrate scope for both,
and deuterium-labeling studies that establish the stereochemistry
of oxypalladation for two types of substrates. On the basis of
our results, we offer a rationale for the difficulty in developing
the asymmetric reaction in this system specifically. As recent
work by Hayashi, Wolfe, Sanford, White, Stahl, Sigman, and
others has also shown, our studies further demonstrate that
oxidase-type catalysis by Pd(II) is both advantageously versatile
in terms of reactivity and frustratingly promiscuous in terms of
mechanism.
led to the discovery that the electron-deficient palladium(II)
trifluoroacetate (Pd(TFA)2) was most effective for producing 2
in good yield after reasonable reaction time (entry 4). A number
of exogenous bases were examined with the hope that proton
consumption would accelerate the reaction (not shown, see
Supporting Information). Sodium carbonate exerts the most
positive effect to give 95% yield in under 30 min (entry 5).
Pd(0) sources were found to be poor catalysts for the reaction:
Pd2(dba)3 resulted in the formation of a small amount of product,
along with palladium black (entry 6), and palladium black itself
gave no reaction (entry 7). No cyclization occurred in the
absence of any palladium (entry 8). O2 is necessary for good
reactivity, although there appears to be a background reaction
that leads to cyclization since the product is formed in greater
than 5% yield (entry 9). The presence of 30 equiv of elemental
mercury slowed the cyclization, but did not prevent reaction
altogether, which contraindicates colloidal Pd or Pd nanopar-
ticles as the relevant catalytic species (entry 10).20
Results and Discussion
Although pyridine had been a competent ligand during our
optimization studies, we carried out a small ligand screen of
other nitrogen-containing ligands.21 Each LnPd(TFA)2 complex
was synthesized separately and characterized, rather than
generated in situ, to limit uncertainty regarding the catalyst or
catalyst precursor. Reactions were performed with no additive,
40 mol % excess ligand, and both excess ligand and Na2CO3.
As shown in Table 2, substituted pyridyls that are less
coordinating than pyridine, whether due to electronic or steric
reasons, result in the precipitation of Pd black. Bidentate
nitrogen-containing ligands, such as 2,2′-dipyridyl (entry 6), 4,7-
dimethyl-1,10-phenanthroline (entry 7), TMEDA (entry 10), or
TMPDA (entry 11), significantly slow the reaction. Weak
alkylamine donors result in the precipitation of Pd black
Reaction Development. The Effect of Palladium X-
Ligand, Exogenous Base, and Nitrogen-Containing Ligand
on Reaction Rate. Our initial aim was to establish Pd(II)-
catalyzed conditions for racemic aerobic cyclizations to which
a chiral ligand eventually could be introduced. Thus, we began
our investigation of aerobic oxidative cyclizations with 2-(1,2-
dimethyl-1-propenyl)phenol (1) using a variety of palladium-
(II) salts, pyridine, O2, and MS3Å in toluene at 80 °C (Table
1). These conditions are modeled after Uemura’s alcohol
oxidation conditions,17a which, as stated above, were also
employed as a starting point for our oxidative kinetic resolution
chemistry.15a Surprisingly, Pd(nbd)Cl2, which is the most
effective catalyst for the kinetic resolution chemistry, was
ineffective for the cyclization of 1 to dihydrofuran 2 (entry 1).
Treatment of 1 with a range of palladium(II) salts (entries 1-4)
(20) (a) Anton, D. R.; Crabtree, R. H. Organometallics 1983, 2, 855-859. (b)
Foley, P.; DiCosimo, R.; Whitesides, G. M. J. Am. Chem. Soc. 1980, 102,
6713-6725.
(21) For an example of a Pd-catalyzed phenol/olefin cyclization using an
N-heterocyclic carbene ligand, see: Mun˜iz, K. AdV. Synth. Catal. 2004,
346, 1425-1428.
(18) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem.,
Int. Ed. 2003, 42, 2892-2895.
(19) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578-9579.
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Oxidative Cyclizations and Stereochemistry of Oxypalladation
A R T I C L E S
Table 3. Oxidative Cyclizations of Phenolsa
a With 5 mol % of Pd(TFA)2, 20 mol % of pyridine, 2 equiv of Na2CO3, 500 mg/mmol of MS3Å, 1 atm O2, toluene (0.1 M), 80 °C. b The starting
material was used as a 3.6:1 mixture of olefin isomers. c With 2 mol % of Pd(TFA)2, 8 mol % of pyridine.
Table 4. Oxidative Cyclizations of Primary Alcoholsa
(entries 8, 9, and 11). Although some rate enhancement was
observed for the nicotinate derivatives (entries 4 and 5), pyridine
offered the best combination of reactivity, catalyst stability, and
availability.
Cyclizations of Phenols and Primary Alcohols. Under our
optimized conditions, oxidative cyclization of a variety of
substituted phenols occurs readily with 5 mol % of Pd(TFA)2,
20 mol % of pyridine, 2 equiv of Na2CO3, and 500 mg of 3 Å
molecular sieves/mmol substrate at 0.1 M concentration in
toluene under a balloon of oxygen (Table 3). Workup involves
simple filtration through a pad of silica gel. Cyclizations of
electron-rich phenols are facile and provide excellent yields in
under 30 min (entries 1-4, 7-10). An electron-deficient phenol
(9) serves as an excellent substrate as well, albeit with slower
a With 5 mol % of Pd(TFA)2 20 mol % of pyridine, 2 equiv of Na2CO3,
reaction time (entry 5). In contrast, a p-bromo-substituted
500 mg/mmol of MS3Å, 1 atm O2, toluene (0.1 M), 80 °C. b The starting
substrate (11, entry 6) appears to undergo alternate reaction
pathways leading to decomposition, possibly via oxidative
addition to Pd(0). Cyclization onto a tetrasubstituted olefin (21)
proceeds in good yield (entry 11), as does cyclization of a
disubstituted olefin (23, entry 12). A dihydropyran (26) is
available under identical conditions (entry 13). Finally, high
yields and reasonable rates persist with reduced catalyst loading
(2 mol %, entry 14). For terminal olefin substrate 27, reaction
does not take place, most likely because exo cyclization occurs
that then leaves no â-hydrogens to be eliminated from the
presumed Pd-alkyl intermediate.
In addition to phenols, we have investigated primary alcohol/
olefin oxidative cyclizations. Remarkably, these reactions
proceed to the heterocyclic ethers with, in most cases, little or
no oxidation to the aldehyde under our optimized conditions
(Table 4). In addition to benzyl alcohol 28, cyclopentene (30
and 32) and cyclohexene (34) derivatives provide moderate to
material was used as a mixture of E and Z olefins. c Isolated with 7% of
the aldehyde. d Isolated with 7% of an olefin isomer. e Isolated as a 5:2.3:1
mixture of 35/olefin isomer/aldehyde.
excellent yields of spirocycles (31) and fused ring systems (33,
35). The mode of oxidative reactivityscyclization versus alcohol
oxidationsappears dependent not only on the substrate (i.e.,
primary vs secondary alcohols) but also on the specific
palladium source (cf. Uemura’s work17).
Cyclizations of Carboxylic Acids and Derivatives. A
range of carboxylic acid and carboxylic acid derivatives
were synthesized and subjected to our optimized condi-
tions. For some carboxylic acid derivatives (36, 38, 40, and 44),
the addition of an inorganic base was found to be unnecessary,
and exposure simply to 5 mol % of Pd(TFA)2, 20 mol % of
pyridine, 500 mg of MS3Å/mmol substrate and 1 atm O2 in
toluene at 80 °C led to the oxidatively cyclized products
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A R T I C L E S
Trend et al.
alcohol/olefin,5a,6a,23 and carboxylic acid/olefin5c,24,25 cyclizations
have been achieved before under Pd(II)/oxidant catalysis, our
conditions differentiate themselves by meeting the criteria for
extension to an asymmetric version: simplicity, capacity to
accommodate a chiral ligand, and active catalysis in a nonco-
ordinating solvent. Without a system of this type, the develop-
ment of a direct aerobic asymmetric cyclization would be less
feasible.
Table 5. Oxidative Cyclizations of Carboxylic Acids and
Derivativesa
Elaboration of Racemic Conditions to an Asymmetric
Version. A number of chiral ligands were screened with the
conditions established for the racemic cyclizations, including
typical chiral ligands, such as bisoxazolines, as well as less
common frameworks for catalysis, such as brucine (not shown,
see Supporting Information). As we observed during the
development of our oxidative kinetic resolution chemistry,15a
the natural product (-)-sparteine was by far the most successful
at inducing asymmetry in the cyclization. Treatment of 1 with
Pd(TFA)2 in the presence of (-)-sparteine, MS3Å, and O2 in
toluene led to a 72% conversion to 76% enantioenriched
dihydrobenzofuran (+)-2 after 36 h (eq 1).26
a With 5 mol % of Pd(TFA)2, 20 mol % of pyridine, MS3Å, 1 atm O2,
toluene, 80 °C. b The starting material was used as a mixture of E:Z olefins.
c With 10 mol % of pyridine, 2 equiv of LiOAc. d Z:E 3:1. e With 10 mol
% of Pd(TFA)2, 40 mol % of pyridine. f With 10 mol % of Pd(TFA)2, 40
mol % of pyridine, 2 equiv of Na2CO3. g Isolated with 6% of an olefin
isomer.
Optimization of the Asymmetric Reaction: Screen of
Palladium Sources. With (-)-sparteine as the most enantiose-
lective candidate to emerge from the chiral ligand screen, we
set out to increase selectivity through an optimization of Pd(II)
source and basic additive. This seemed essential in light of what
we had observed during the development of the racemic reaction
(cf. Table 1), as well as with the kinetic resolution chemistry.15a,27
Pd(II) halide sources provided product in some cases, but with
degradation of enantiomeric excess (Table 6, entries 1-2, 4-5).
Pd(OAc)2 is more effective at inducing asymmetry, but at the
expense of conversion (entry 6). The extent of asymmetric
induction varied surprisingly in the presence of different Pd(II)
sources. For example, Pd(COD)Cl2 results in only 10% ee (entry
2), whereas Pd(TFA)2 provides 76% ee (entry 7). It is remark-
able that this change has such a large effect on enantioselec-
tivity.28 Pd(TFA)2 remained the optimal catalyst, and it was
found that by using the complex of Pd(TFA)2 and (-)-sparteine
directly rather than generating it in situ led to slightly improved
and more reliable results (entry 8). Generally, more electron-
deficient Pd sources were more selective in the cyclization.
(Table 5, entries 1-3, 5). Benzoic acids (36) and amides
(38, 40) are cyclized in good to excellent yields (entries
1-3). A â-keto ester (42) undergoes cyclization as a vinyl-
ogous acid to form a heterocycle (43) rather than a carbo-
cycle (entry 4). Primary acid derivatives react to form spiro-
cycles (45) or fused bicyclic systems (47 and 49), depending
on the position of the olefin (entries 5-7). The cyclization of
derivatives 46 and 48 is more facile with double the catalyst
loading and is accelerated by the presence of 2 equiv of
Na2CO3.
Reaction Scope and Limitations. The high yields, usually
brief reaction times, and range of substrates that are character-
istic of this aerobic Pd-catalyzed oxidative cyclization demon-
strate the utility of the simple reaction conditionssPd, ligand,
base, O2, and solvent. Nearly identical conditions are applicable
to five different types of nucleophiles: phenols, primary
alcohols, carboxylic acids, a vinylogous acid, and amides.
Electron-rich phenols are excellent substrates, and multiple
olefin substitution patterns are tolerated. Primary alcohols
undergo oxidative cyclization without significant oxidation to
the aldehyde, a fact that illustrates the range of reactivity
available from various Pd(II) salts under differing conditions.
In addition to the cyclization of a benzylic alcohol, nonbenzylic
alcohols can form both fused and spirocyclic ring systems; the
same is true of the acid derivatives. Undoubtedly the range of
alcohol substrates could be increased.22 While phenol/olefin,
(23) Semmelhack, M. F.; Kim, C. R.; Dobler, W.; Meier, M. Tetrahedron Lett.
1989, 30, 4925-4928.
(24) Åkermark, B.; Larsson, E. M.; Oslob, J. D. J. Org. Chem. 1994, 59, 5729-
5733.
(25) A similar cyclization of sulfonamides was recently reported: Fix, S. R.;
Brice, J. L.; Stahl, S. S. Angew. Chem., Int. Ed. 2002, 41, 164-166.
(26) With 10 mol % of Pd(TFA)2, 40 mol % of ligand, 500 mg/mmol MS3Å,
0.41 equiv of tridecane internal GC standard, 1 atm O2, toluene (0.1 M),
80 °C. Conversion and enantiomeric excess were determined by GC.
(27) Attempted cyclization under the chloroform-based rate-enhanced conditions
for oxidative kinetic resolution ((sp)PdCl2 (5 mol %), (-)-sparteine (7 mol
%), Cs2CO3 (0.4 equiv), CHCl3 (0.1 M), O2 (1 atm, balloon), 25 °C) resulted
in no reaction.
(28) A similar, albeit less dramatic counterion effect was observed in the
oxidative kinetic resolution of secondary alcohols; see ref 15a and Nielsen,
R. J.; Keith, J. M.; Stoltz, B. M.; Goddard, W. A., III. J. Am. Chem. Soc.
2004, 126, 7967-7974.
(22) For a recent review of Pd-catalyzed reactions of alcohols to form ether
linkages, see: Muzart, J. Tetrahedron 2005, 61, 5955-6008.
9
17782 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Oxidative Cyclizations and Stereochemistry of Oxypalladation
A R T I C L E S
Table 8. Aryl Ether Formation and Attempted Suppression
Table 6. Optimization of Pd Source and Additive for the
Asymmetric Oxidative Cyclization
entry
Pd source
additive
time
convb
eeb
1
2
3
4
5
Pd(nbd)Cl2
Pd(COD)Cl2
PdCl2
Pd(CH3CN)2Cl2
PdBr2
Pd(OAc)2
Pd(TFA)2
(sp)Pd(TFA)2
Pd(OTf)2(CH3CN)4
(sp)Pd(TFA)2
none
none
none
none
none
none
none
none
36 h
36 h
36 h
36 h
36 h
36 h
36 h
36 h
160 h
36 h
36 h
68%
30%
2%
12%
10%
12%
12%
8%
51%
76%
77%
16%
76%
81%
entry
additive
time
(
+
)-8:50b
ee of (+
)-8c
1a
2
3
amberlyst 15 resin (10 mol %)
TsOH‚H2O (10 mol %)
TsOH‚H2O (100 mol %)
none
24 h
24 h
80 h
16 h
5:3
3:1
6:1
2:1
87%
81%
50%
86%
53%
32%
18%
72%
83%
20%
53%
87%
6
4
7
d
8c
9
a With 10 mol % of (sp)Pd(TFA)2, 100 mol % of (-)-sparteine, 500
mg/mmol of MS3Å, 1 atm O2, toluene (0.1 M), 80 °C. b Measured by H
1
none
Na2CO3
Ca(OH)2
10e
11e
NMR. c Measured by GC.
(sp)Pd(TFA)2
transformed with high selectivity to give (+)-8 in 90% ee and
57% yield (entry 2). tert-Butylphenol 5 and p-methylphenol
3 do not react quickly but are obtained with good levels
of enantiomeric excess (entries 3 and 4). p-Acylphenol 9
cyclizes, but with low percent enantiomeric excess, perhaps
indicative of a change in mechanism for this less electron-rich
substrate.
a With 10 mol % of Pd source, 40 mol % of (-)-sparteine, 500 mg/
mmol of MS3Å, 1 atm O2, toluene (0.1 M), 80 °C. b Conversion measured
by GC or by 1H NMR. c With 30 mol % of (-)-sparteine. d sp ) (-)-
sparteine. e With 10 mol % of (sp)Pd(TFA)2, 100 mol % of (-)-sparteine.
Table 7. Pd-Catalyzed Asymmetric Aerobic Oxidative Cyclizationa
Unfortunately, the highly enantioenriched p-methoxy dihy-
drobenzofuran (+)-8 is produced with a dimeric aryl ether
byproduct (50, Table 8). This byproduct could form via
palladation ortho to the phenol, followed by coupling to another
molecule of substrate. The addition of various acids suppressed
the formation of the byproduct, perhaps by decomposing the
postulated palladium aryl species, but also depressed the
enantioselectivity of the cyclization (entry 3).
While the asymmetric oxidative cyclization conditions that
we have developed are not yet general, we have established
that it is possible to adapt a direct dioxygen-coupled racemic
reaction to aerobic asymmetric catalysis, which had not been
achieved previously for this class of reaction. In conjunction
with our work on the oxidative kinetic resolution of secondary
alcohols, the asymmetric cyclization chemistry makes signifi-
cant headway into the realm of enantioselective oxidase-type
chemistry.
Mechanistic Investigations. Deuterium-Labeling Studies
of Primary Alcohol Substrates in the Presence of a Mono-
dentate Ligand. We hypothesized that the sluggishness of the
asymmetric cyclization could be attributed to the difference in
ligand denticity between pyridine and (-)-sparteine. In fact, in
our screen of nitrogen-containing ligands (Table 2), the de-
creased reactivity of all the bidentate ligands confirmed that
(-)-sparteine was not uniquely deactivating. We thus wished
to gain an understanding of the mechanism of the cyclization,
and whether a change from a mono- to a bidentate ligand would
involve a change in mechanism. One commonly proposed
mechanism for Pd(II)-catalyzed cyclizations involves activation
of the olefin by Pd(II) followed by anti nucleophilic attack, that
is, anti oxypalladation; indeed, this was our original hypoth-
esis.18,31 The resulting Pd-alkyl intermediate would then
undergo â-hydrogen elimination. Such a mechanism is remi-
a With 10 mol % of (sp)Pd(TFA)2, 100 mol % of (-)-sparteine, 2 equiv
of Ca(OH)2, 500 mg/mmol of MS3Å, 1 atm O2, toluene (0.1 M), 80 °C.
b Isolated yield. c Measured by GC.
However, switching the anion from trifluoroacetate to triflate
resulted in degradation of the catalyst (formation of Pd black).
In addition to palladium source, a basic additive affects reaction
rate and selectivity. Best results occur with Ca(OH)2, the
presynthesized (sp)Pd(TFA)2 complex, and 1 equiv of (-)-
sparteine (entry 11).
Asymmetric Oxidative Cyclization of Phenol Substrates.
Under the optimized conditions, phenol 1 was cyclized
to provide dihydrobenzofuran (+)-2 in 81% ee and 87%
isolated yield (Table 7, entry 1).29 Application of these condi-
tions to other substrates that reacted successfully under the
racemic conditions proved difficult.30 p-Methoxyphenol 7 is
(30) Tetrasubstituted olefin-containing phenol 21, which is Hayashi’s most
selectively cyclized substrate,12a fails to cyclize under our optimized
conditions.
(31) (a) Ref 3g and references therein. (b) Coleman, J. P.; Hegedus, L. S.
Principles and Applications of Organometallic Chemistry; University
Science Books: Mill Valley, CA, 1980; pp 401-424.
(29) The absolute stereochemistry was determined by comparison of the optical
rotation with that reported for (-)-2, by Uozumi and Hayashi, ref 12c (see
Supporting Information for rotation data). We report the absolute stereo-
chemistry of (+)-8, (-)-6, (+)-4, and (-)-10 by analogy to this substrate.
9
J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17783

A R T I C L E S
Trend et al.
niscent of that proposed by Ba¨ckvall, Stille, and Kurosawa for
the Wacker oxidation of ethylene to acetaldehyde.32 A second
possible mechanism is supported by recent reports from Hayashi
and Wolfe that find certain heteroatom/olefin cyclizations
catalyzed by Pd(II) occur with syn oxypalladation.33 Wolfe
further suggests that this involves an olefin insertion into a
Pd(II)-heteroatom bond.34-36 This pathway is analogous to the
alternative mechanism for the Wacker oxidation proposed by
Henry and others that involves syn oxypalladation.37 A third
mechanism entails allylic C-H activation by Pd(II) to form an
intermediate π-allyl species that would then undergo reductive
elimination with the heteroatom nucleophile.9,38,39
that â-hydrogen elimination would only occur when the Pd atom
and eliminated H or D atom are syn to each other.41 The
presence or absence of a deuterium label in the product would
then differentiate mechanistic pathways. Although a π-allyl
mechanism could be difficult to unambiguously rule out with
our test substrate, we hoped to at least distinguish syn from
anti oxypalladation.42
We set out to differentiate these mechanisms by synthesizing
stereospecifically deuterium-labeled substrates and observing
the products of the cyclization in the presence of a mono- and
bidentate ligand. Deuterium-labeled alcohols trans-3-d-53 and
cis-3-d-53 were designed such that oxidative cyclization would
result in retention or elimination of the label. Recently, during
the course of this work, Hayashi and co-workers reported a
similar study for the oxidative cyclization of olefin-appended
phenols by Pd(II); in those examples, syn oxypalladation occurs
exclusively except in the presence of additional chloride ion.33a
We chose to focus on primary alcohols because of the interesting
dichotomy between oxidative cyclization and alcohol oxidation
and because a study of this type had not yet been carried out
for this substrate class.
Treatment of trans-3-d-53 with 10 mol % of (pyridine)2Pd-
(TFA)2, 20 mol % of pyridine, 2 equiv of Na2CO3, 1 atm O2,
and 500 mg/mmol of MS3Å in toluene at 80 °C for 3 h provided
3-d-54 along with olefin isomer 3-d-55 in a 4:1 ratio and 95%
overall yield (Scheme 1). Likewise, reaction of the cis isomer
(cis-3-d-53) under the same conditions led to the formation of
a 1:0.7 mixture of undeuterated 54 and cis-2-d-55 in nearly
quantitative yield. Reaction of cis-3-d-53 in the absence of Na2-
CO3 leads to a nearly identical result.43 The stereochemistry of
1
cis-2-d-55 was confirmed by H NMR homodecoupling and
Stereospecific deuterium incorporation into primary alcohol
substrates could be effected with the Diels-Alder reaction
shown in eqs 2 and 3 that completed the relatively straightfor-
ward synthesis of trans- and cis-3-d-53.40 We assumed the
constraints that a cis 6-5 fused ring system would form, and
NOE experiments.40 Reexposure of the product mixture (54 and
cis-2-d-55) to the same reaction conditions and an additional
10 mol % of starting material (cis-3-d-53) for 4 h resulted in
an identical ratio of products in 90% isolated yield. Comparison
1
2
of the H and H NMR spectra of the products of the above
reactions with those formed from undeuterated cyclohexene 53
confirmed the presence or absence of a deuterium label.40
The mechanistic origin of the products, illustrated for the cis
diastereomer (cis-3-d-53), is shown in Scheme 2. For compari-
son, all three possible pathways are shown. Path A involves
anti nucleophilic attack of the Pd-coordinated olefin by the
pendant alcohol or alkoxide. Subsequent â-hydrogen elimination
would lead to the deuterium-labeled product 3-d-54, but this
product is not observed (vide supra, Scheme 1). In Path B, oxy-
palladation entails allylic C-H(D) activation and subsequent
reductive elimination to Pd(0) upon formation of the C-O bond.
The stereochemistry of the reductive elimination would likely
be anti.44 Further, unless selective C-D activation occurs, a
mixture of labeled and unlabeled products would be expected;
instead, a single product is observed. In Path C, a Pd-alkoxide
undergoes syn oxypalladation followed by syn â-deuterium
elimination to provide the observed major product, 54. Reinser-
(32) (a) Ba¨ckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem.
Commun. 1977, 264-265. (b) Ba¨ckvall, J.-E.; Åkermark, B.; Ljunggren,
S. O. J. Am. Chem. Soc. 1979, 101, 2411-2416. (c) James, D. E.; Hines,
L. F.; Stille, J. K. J. Am. Chem. Soc. 1976, 98, 1806-1809. (d) Stille, J.
K.; Divakaruni, R. J. Am. Chem. Soc. 1978, 100, 1303-1304. (e) Majima,
T.; Kurosawa, H. J. Chem. Soc., Chem. Commun. 1977, 610-611.
(33) For systems containing oxygen nucleophiles, see: (a) Hayashi, T.;
Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126,
3036-3037. (b) Hay, M. B.; Hardin, A. R.; Wolfe, J. P. J. Org. Chem.
2005, 70, 3099-3107. For systems containing nitrogen nucleophiles, see:
(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.
(34) Ba¨ckvall and co-workers have characterized computationally the reactivity
of nucleophiles toward cis migration, or olefin insertion, in (π-olefin)Pd-
(II) complexes and found that the HOMO-LUMO gap between the π*
olefin orbital and a Pd-OH nucleophile is too large for migration to be
frontier controlled. Rather, the process is charge controlled, and likely does
not occur through a concerted, four-center transition state as in true olefin
insertion reactions of Pd-CH3 or Pd-H nucleophiles. See: (a) Ba¨ckvall,
J.-E.; Bjo¨rkman, E. E.; Pettersson, L.; Siegbahn, P. J. Am. Chem. Soc. 1984,
106, 4369-4373. (b) Ba¨ckvall, J.-E.; Bjo¨rkman, E. E.; Pettersson, L.;
Siegbahn, P. J. Am. Chem. Soc. 1985, 107, 7265-7267.
(35) For experimental evidence of insertion of tetrafluoroethylene into a Pt-O
bond, see: Bryndza, H. E. Organometallics 1985, 4, 406-408.
(36) For a recent example of olefin insertion into a rhodium amide, see: Zhao,
P.; Krug, C.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 12066-12073.
(37) (a) Francis, J. W.; Henry, P. M. Organometallics 1991, 10, 3498-3503.
(b) Francis, J. W.; Henry, P. M. Organometallics 1992, 11, 2832-2836.
(c) Zaw, K.; Henry, P. M. Organometallics 1992, 11, 2008-2015. (d)
Hamed, O.; Henry, P. M. Organometallics 1997, 16, 4903-4909. (e)
Hamed, O.; Thompson, C.; Henry, P. M. J. Org. Chem. 1997, 62, 7082-
7083. (f) Hamed, O.; Henry, P. M.; Thompson, C. J. Org. Chem. 1999,
64, 7745-7750. (g) ten Brink, G.-J.; Arends, I. W. C. W.; Papadogianakis,
G.; Sheldon, R. A. Appl. Catal., A 2000, 194-195, 435-442. (h) Nelson,
D. J.; Li, R.; Brammer, C. J. Am. Chem. Soc. 2001, 123, 1564-1568.
(38) For evidence supporting this mechanism in intermolecular examples, see:
(a) Grennberg, H.; Simon, V.; Ba¨ckvall, J.-E. J. Chem. Soc., Chem.
Commun. 1994, 265-266. (b) Grennberg, H.; Ba¨ckvall, J.-E. Chem.sEur.
J. 1998, 4, 1083-1089.
(41) Examples of anti â-hydrogen elimination under various conditions have
been reported, but involve aromatization or the formation of highly
conjugated systems. See: (a) Toyota, M.; Ilangovan, A.; Okamoto, R.;
Masaki, T.; Arakawa, M.; Ihara, M. Org. Lett. 2002, 4, 4293-4296. (b)
Lautens, M.; Fang, Y.-Q. Org. Lett. 2003, 5, 3679-3682. (c) Hughes, C.
C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41, 1569-1572. (d) Hennessy,
E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 12084-12085.
(42) For a study that attempts to differentiate between oxypalladation and a
π-allyl route for a Pd(II)-catalyzed cyclization, see: Zanoni, G.; Porta, A.;
Meriggi, A.; Franzini, M.; Vidari, G. J. Org. Chem. 2002, 67, 6064-6069.
(43) After 5.5 h, 89% yield of a 1:0.75 mixture of 54 and cis-2-d-55 was
obtained.
(39) Trost has shown that Pd(TFA)2 will form π-allyl complexes by C-H
activation of olefins in acetone: Trost, B. M.; Metzner, P. J. J. Am. Chem.
Soc. 1980, 102, 3572-3577.
(44) For a Pd(II)-π-allyl electrophile, a primary alcohol (or alkoxide) would
fall into the class of “soft” nucleophiles, the conjugate acids of which as
defined by Trost have a pKa < 25. See: Trost, B. M.; Van Vranken, D. L.
Chem. ReV. 1996, 96, 395-422.
(40) See Supporting Information for details.
9
17784 J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005

Oxidative Cyclizations and Stereochemistry of Oxypalladation
A R T I C L E S
Scheme 1. Cyclization of Deuterium-Labeled Primary Alcohol
Substrates with Pyridine as Ligand
intramolecular nucleophilic attack of this intermediate (63)
would not lead to 24. The π-allyl intermediate that could lead
to cyclization (64) could be expected to arise from terminal
olefin 62 as well (Scheme 3); both starting materials would lead
to the same cyclized product (24). Instead, treatment of 62 with
our standard racemic conditions leads to a complex mixture after
several hours and less than 5% of 24. It may be that allylic or
benzylic C-H activation does occur, but is not productive for
cyclization.
To explore whether the large effect of Pd(II) source on
reactivity originated from a change in mechanism, the cycliza-
tion of cis-3-d-53 was carried out under the same reaction
conditions but in the presence of (pyridine)2PdCl2 (eq 4).51 The
initial cyclization product (55) was identical to that obtained
under the conditions employing (pyridine)2Pd(TFA)2; however,
the olefin isomer cis-2-d-55 was now the major product. The
cyclic ethers were obtained along with aldehyde cis-3-d-65 in
74% overall yield after 20 h. The formation of ether 55 and
ether cis-2-d-55 implies that syn oxypalladation still occurs,
contrary to what Hayashi observed for a similar phenol substrate,
for which anti oxypalladation dominates upon the addition of
chloride ion.33a The formation of aldehyde cis-3-d-65 likely
occurs from a common alkoxide intermediate and highlights
the effect that subtle changes in reaction conditions can have
on the mode of oxidation.
tion of the Pd-D intermediate to the product olefin accounts
for formation of the observed minor product, cis-2-d-55.45 The
fact that an identical product mixture is obtained upon reexpo-
sure of the products to the reaction conditions supports the
occurrence of reinsertion before dissociation of the product
olefin from the Pd-D fragment.46 Finally, because the Pd0 inter-
mediate in Path B cannot easily account for the formation of
olefin isomer cis-2-d-55, we favor syn oxypalladation Path C.
The remaining steps of the catalytic cycle involve reprocess-
ing of Pd(II) by molecular oxygen. On the basis of earlier work
by Murahashi and Takehira,3g,47 Uemura has proposed that this
occurs by insertion of O2 directly into the [PdII]-H to form a
Pd-hydroperoxide intermediate.17a Stahl has elaborated the
details of a mechanism for aerobic oxidation catalysis by Pd-
(II) that entails reductive elimination of HX from [PdII]-H to
form Pd(0), which is then oxidized by O2 in the formation of a
Pd-peroxo intermediate.48,49 In any case, these steps and those
outlined in Scheme 2 proceed through Pd(II) and Pd(0)
intermediates; however, we cannot definitively rule out a process
involving Pd(IV).50
Deuterium-Labeling Studies of Primary Alcohol Sub-
strates in the Presence of a Bidentate Ligand. The deuterium-
labeled alcohol substrates trans-3-d-53 and cis-3-d-53 were then
cyclized under conditions that employed dipyridyl as a bidentate
ligand. Treatment of both trans-3-d-53 and cis-3-d-53 with 10
mol % of (dipyridyl)Pd(TFA)2, Na2CO3 (2 equiv), 1 atm O2,
and 500 mg/mmol of MS3Å in toluene at 80 °C led to the
formation of the same major products (3-d-54 and 54, respec-
tively) observed with the conditions that use pyridine (Scheme
4). None of the olefin isomer was observed; instead, a small
amount of aldehyde (trans-3-d-65 and cis-3-d-65) was formed
We strove to further discount the π-allyl mechanism (Path
B, Scheme 2) by comparing the reactivity of two phenol
substrates. As shown in Scheme 3, a phenol with a disubstituted
pendant olefin (23) cyclizes in good yield to provide dihy-
drobenzofuran 24. The most likely π-allyl species to form from
23 would involve activation of a benzylic proton (63), but
(50) In one scenario, oxidative activation of an allylic C-H bond could lead to
a Pd(IV)-alkyl intermediate for the formation of a Pd(II) π-allyl species,
or reductive elimination upon formation of the C-O bond could lead to a
Pd(II) intermediate. In another scenario, Pd(II) could undergo oxidative
activation of an O-H bond to form a Pd(IV)-alkoxide, although this is
unlikely in the presence of base. Although such pathways cannot be ruled
out, the recently reported Pd oxidation reactions proposed to involve Pd-
(IV) also involve strong oxidizing agents, such as PhI(OAc)2 and I2. For
recent articles invoking Pd(IV) in Pd-catalyzed oxidative processes, see:
(a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126,
2300-2301. (b) Dick, A. R.; Kampf, J. W.; Sanford, M. S. Organometallics
2005, 24, 482-485. (c) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am.
Chem. Soc. 2005, 127, 7690-7691. (d) Yoneyama, T.; Crabtree, R. H. J.
Mol. Catal. A 1996, 108, 35-40. (e) For a related Pd-catalyzed iodination
system, see: Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005,
44, 2112-2115.
(45) The difference in the product ratios formed from the trans and cis isomers
could be accounted for by an isotope effect in the reinsertion step.
Possibilities include slower reinsertion for the [Pd]-H bound olefin than
for the [Pd]-D bound olefin, faster dissociation for the [Pd]-H bound
olefin, faster reductive elimination of HX before dissociation or reinsertion,
or faster coordination and insertion of O2 into the [Pd]-H bond, if turnover
of the catalyst occurs by that mechanism. At this time, we cannot rule out
any of or distinguish among these possibilities.
(46) Because both [Pd]-D and [Pd]-H are formed, reinsertion after [Pd]
dissociates from product 54 would lead to scrambling of the isotopic label.
(47) Takehira, K.; Hayakawa, T.; Orita, H. Chem. Lett. 1985, 1835-1838 and
references therein.
(48) (a) Stahl, S. S.; Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am. Chem.
Soc. 2001, 123, 7188-7189. (b) Steinhoff, B. A.; Stahl, S. S. Org. Lett.
2002, 4, 4179-4181.
(49) Keith, J. M.; Nielsen, R. J.; Oxgaard, J.; Goddard, W. A., III. J. Am. Chem.
Soc. 2005, 127, 13172-13179.
(51) The catalyst was generated in situ by heating (CH3CN)2PdCl2 and all other
reagents except the substrate for 15 min before addition of the substrate.
9
J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17785

A R T I C L E S
Trend et al.
Scheme 2. Three Oxypalladation Pathways
Scheme 3. Attempted Cyclization of a Terminal Olefin-Appended
Phenol
Scheme 4. Cyclization of Deuterium-Labeled Primary Alcohol
Substrates with Dipyridyl as Ligand
for both starting material diastereomers.52 Both diastereomers
were slower to cyclize in the presence of (dipyridyl)Pd(TFA)2
than in the presence of (pyridine)2Pd(TFA)2. The reaction of
trans-3-d-53 under the asymmetric conditions using (-)-
sparteine led only to oxidation to the aldehyde. The major
product distribution from cyclization in the presence of both a
mono- and bidentate ligand is the same. Presumably, the
aldehyde forms via â-hydrogen elimination from a common
alkoxide intermediate before oxypalladation can occur.
On the basis of the results outlined above, we propose that,
at least for the alcohol substrates, reaction under mono- or
bidentate ligated conditions occurs by a similar pathway. The
difference in reaction rate could arise from the degree to which
each ligand can stabilize intermediates under otherwise identical
reaction conditions. A neutral monodentate ligand such as
pyridine can dissociate when necessary to free a coordination
site for the substrate while maintaining charge-neutral interme-
diates (67-69, Scheme 5, A). When dipyridyl is used, neutral
ligand dissociation may be more difficult due to chelation, and
instead, an anionic ligand must dissociate, resulting in charged
intermediates (71 and 73, Scheme 5, B). Such intermediates
may be higher in energy under the reaction conditions, which
in turn results in decreased reactivity.53 (-)-Sparteine (cf.
Scheme 4) not only leads to the same limitation but also prevents
cyclization, perhaps due to steric congestion at Pd that prevents
formation of a Pd-O-olefin chelate (71).
(53) We cannot rule out the possibility that the reaction with dipyridyl as ligand
proceeds through similar intermediates with slow, partial dissociation of
one of the dipyridyl nitrogen atoms. The reaction with (-)-sparteine as
ligand is much less likely to undergo partial dissociation due to its structural
rigidity.
(52) The identity of the aldehyde was confirmed by oxidation of the alcohol by
another method; see Supporting Information.
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Oxidative Cyclizations and Stereochemistry of Oxypalladation
A R T I C L E S
Scheme 5. Comparison of Reaction Pathways with a Monodentate and Bidentate Ligand
Scheme 6. Cyclization of Deuterium-Labeled Carboxylic Acid
Substrates with Pyridine as Ligand
stereochemistry of oxypalladation, but may play a role in catalyst
decomposition.
Although the reasons for the change in product distribution
at this point remain unclear, geometrical constraints, pKa
differences, or differences in nucleophilicity between an acid
and an alcohol are all possibilities. The additional unsaturation
in the forming lactone could make geometrically unfavorable
the Pd-O-olefin chelate that would precede syn oxypalladation.
Whatever the case, these results confirm the versatility and
undiscriminating reactivity of Pd(II) catalysts in oxidation
reactions. As demonstrated by these results and the accumulating
evidence from several groups, generalizations about reactivity
and mechanism that span different substrates and different
reaction conditions are difficult to make for palladium-catalyzed
oxidation reactions.
Summary and Conclusion
Although an extension of these mechanistic conclusions to
the racemic and asymmetric phenol cyclizations may be tenuous,
the same scenario would account for the slowness of the
reactions catalyzed by ((-)-sparteine)Pd(TFA)2 relative to
(pyridine)2Pd(TFA)2. Hayashi and co-workers’ results also
support this conclusion. Their system undergoes syn oxypalla-
dation in the presence of a bidentate ligand with a dicationic
Pd(II) catalyst in methanol using benzoquinone as the terminal
oxidant.33a The higher dielectric solvent and dicationic catalyst
may facilitate the formation of the charged intermediates shown
in Scheme 5B, whereas our toluene-based conditions slow their
formation. Because most of the chiral ligands that are effective
in inducing asymmetry are bidentate, the mechanistic implication
of the results described above is that selectivity and good
reactivity will be difficult to attain in the Pd(II)/toluene/O2
system.
In summary, we have demonstrated that oxidase-type cy-
clizations of several different nucleophiles onto pendant olefins
can be achieved in excellent yields under simple conditions.
Reactivity is highly dependent on Pd(II) source, basic additive,
and ligand. Several different types of cyclic systems are
attainable, including aryl and alkyl bicycles, as well as fused
and spirocyclic motifs. These cyclizations are part of an ongoing
effort to develop enantioselective oxidase-type reactions using
Pd(II) catalysis and molecular oxygen. To this end, the racemic
conditions we developed were suitable for extension to an
enantioselective cyclization that uses the chiral ligand (-)-
sparteine. While the asymmetric oxidative cyclization conditions
that we have developed are not yet general, we have established
that it is possible to adapt a direct dioxygen-coupled racemic
reaction to aerobic asymmetric catalysis, which had not before
been achieved for this class of reaction. In conjunction with
our work on the oxidative kinetic resolution of secondary
alcohols, the asymmetric cyclization chemistry is a significant
stride into the arena of enantioselective oxidase-type chemistry.
Stereospecifically deuterated primary alcohol substrates were
used to probe the stereochemistry of oxypalladation and to gain
insight into the mechanism of cyclization. Contrary to the
common mechanistic proposal for reactions of this type (i.e.,
“Wacker cyclization” or anti oxypalladation), reaction of the
primary alcohol substrates appears to occur via syn oxypalla-
dation. This is in agreement with more recent reports from
Hayashi and Wolfe on related systems. Neither the presence of
chloride anion nor the use of a bidentate instead of a mono-
dentate ligand changes the stereochemistry of oxypalladation.
The implications for the asymmetric reaction are that bidentate
ligands may destabilize the intermediates necessary for a syn
Deuterium-Labeling Studies of Carboxylic Acid Sub-
strates. Alcohols trans-3-d-53 and cis-3-d-53 were oxidized40
to the corresponding carboxylic acid derivatives (trans-3-d-74
and cis-3-d-74) and subjected to the cyclization conditions that
employ pyridine (Scheme 6). Both were slow to cyclize, and
formation of Pd black was observed; nevertheless, some product
1
2
was obtained and analyzed by H and H NMR. In contrast to
the alcohol substrates, the formation of unlabeled lactone 75
from trans-3-d-74 and labeled lactone 3-d-75 from cis-3-d-74
indicates that cyclization of the acid proceeds through anti
oxypalladation. The olefin isomer arising from reinsertion was
not observed. Cyclization of trans-3-d-74 in the absence of Na2-
CO3 resulted in greatly diminished yield (4% yield after 24 h)
of the same product (75) but slower formation of Pd black,
which indicates that the inorganic base does not affect the
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J. AM. CHEM. SOC. VOL. 127, NO. 50, 2005 17787

A R T I C L E S
Trend et al.
oxypalladation pathway; thus reactivity is decreased relative to
the conditions employing a monodentate ligand. On the other
hand, similarly deuterated carboxylic acid substrates react in
the opposite sense, that is, via anti oxypalladation.
As contemporary work in this rapidly developing, recently
reborn field continues to demonstrate, oxidase-type catalysis by
Pd(II) is highly versatile and adaptable to a variety of applica-
tions.54 Our studies reported herein emphasize the subtleties of
reactivity and mechanism in this field. Further development of
dehydrogenation reactions using Pd(II) and molecular oxygen,
racemic and asymmetric, is ongoing.
Acknowledgment. The authors wish to thank the NIH-
NIGMS (R01 GM65961-01), Bristol-Myers Squibb Company
and the American Chemical Society (graduate fellowship to
R.M.T.), the University of California TRDRP (postdoctoral
fellowship to Y.K.R.), the Dreyfus Foundation, Merck Research
Laboratories, Research Corporation, Abbott Laboratories, Pfizer,
Amgen, GlaxoSmithKline, Lilly, and Johnson and Johnson for
generous financial support. Drs. Eric Ferreira, Jonathan Owen,
and Andrew Waltman are acknowledged for helpful discussions.
Supporting Information Available: Full experimental details
and characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(54) (a) Sohn, J.-H.; Waizumi, N.; Zhong, H. M.; Rawal, V. H. J. Am. Chem.
Soc. 2005, 127, 7290-7291. (b) Garg, N. K.; Caspi, D. D.; Stoltz, B. M.
J. Am. Chem. Soc. 2005, 127, 5970-5978. (c) Tietze, L. F.; Sommer, K.
M.; Zinngrebe, J.; Stecker, F. Angew. Chem., Int. Ed. 2004, 44, 257-259.
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