Two-faced reactivity of alkenes: cis- versus trans-aminopalladation in aerobic Pd-catalyzed intramolecular Aza-Wacker reactions

Article abstract of DOI:10.1021/ja070424u

A number of different Pd^II catalyst systems have been reported recently for the Wacker-type aerobic oxidative cyclization of alkenes bearing tethered nitrogen nucleophiles. This study examines the stereochemistry of the aminopalladation step wi

Full text of DOI:10.1021/ja070424u

Published on Web 04/18/2007
Two-Faced Reactivity of Alkenes: cis- versus
trans-Aminopalladation in Aerobic Pd-Catalyzed
Intramolecular Aza-Wacker Reactions
Guosheng Liu and Shannon S. Stahl*
Contribution from the Department of Chemistry, UniVersity of WisconsinsMadison,
1101 UniVersity AVenue, Madison, Wisconsin 53706
Received January 19, 2007; E-mail: stahl@chem.wisc.edu
Abstract: A number of different PdII catalyst systems have been reported recently for the Wacker-type
aerobic oxidative cyclization of alkenes bearing tethered nitrogen nucleophiles. This study examines the
stereochemistry of the aminopalladation step with five different catalyst systems: Pd(OAc)2/DMSO (A),
PdX2/pyridine [X ) OAc (B), O2CCF3 (C)], Pd(IMes)(O2CCF3)2(OH2) (D), and Pd(O2CCF3)2/(-)-sparteine
(E). Use of a stereospecifically deuterated cyclopentene substrate reveals that four of the five catalyst
systems (A, B, C, and E) promote exclusive cis-aminopalladation of the alkene, whereas both cis- and
trans-aminopalladation occur with the N-heterocyclic-carbene (NHC) catalyst system. If stoichiometric
Brønsted base (NaOAc, Na2CO3) is added to the latter reaction conditions, however, only cis-aminopal-
ladation is observed. The identity of the nitrogen nucleophile also affects the aminopalladation pathway,
with results ranging from exclusively cis- to exclusively trans-aminopalladation. These results have important
implications for ongoing efforts to develop enantioselective methods for Pd-catalyzed oxidative amination
of alkenes.
Introduction
examples of this principle and find widespread use in the
synthesis of oxygen and nitrogen heterocycles.3 For example,
The prominence of nitrogen-containing heterocycles in natural
products and biologically active molecules has prompted con-
siderable efforts toward their synthesis. One powerful synthetic
strategy consists of electrophile-promoted cyclization of alkenes
bearing tethered amines or amides (eq 1).1 Effective electrophiles
various pyrrolidine derivatives can be accessed via PdII-catalyzed
cyclization of δ,ꢀ-unsaturated amine derivatives (Scheme 1).
The aminopalladated intermediate 2 commonly undergoes
â-hydride elimination to produce oxidative amination products
such as 3; however, a number of alternative products, such as
4-6 (Scheme 1), can be prepared by modifying the reaction
conditions.4,5
Renewed interest in Pd-catalyzed oxidative heterocyclization
reactions has been stimulated recently by the identification of
new Pd catalysts and reaction conditions compatible with
(2) For selected recent examples, see: (a) Schlummer, B.; Hartwig, J. F. Org.
Lett. 2002, 4, 1471-1474. (b) Bender, C. F.; Widenhoefer, R. A. J. Am.
Chem. Soc. 2005, 127, 1070-1071. (c) Bender, C. F.; Widenhoefer, R. A.
Chem. Commun. 2006, 4143-4144. (d) Zhang, J.; Yang, C.-G.; He, C. J.
Am. Chem. Soc. 2006, 128, 1798-1799. (e) Takemiya, A.; Hartwig, J. F.
J. Am. Chem. Soc. 2006, 128, 6042-6043. (f) Rosenfeld, D. C.; Shekhar,
S.; Takemiya, A.; Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179-
4182. (g) Bender, C. F.; Widenhoefer, R. A. Org. Lett. 2006, 8, 5303-
5305. (h) Han, X.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45,
1747-1749.
(3) For leading references, see: (a) Hegedus, L. S. J. Mol. Catal. 1983, 19,
201-211. (b) Wolfe, J. P.; Thomas, J. S. Curr. Org. Chem. 2005, 9, 625-
655. (c) Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106, 4644-4680. (d)
Tietze, L. F.; Sommer, K. M.; Zinngrebe, J.; Stecker. F. Angew. Chem.,
Int. Ed. 2005, 44, 257-259.
(4) For example, see: (a) Tamaru, Y.; Hojo, M.; Higashimura, H.; Yoshida,
Z.-I. J. Am. Chem. Soc. 1988, 110, 3994-4002. (b) Alexanian, E. J.; Lee,
C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127, 7690-7691. (c) Michael,
F. E.; Cochran, B. M. J. Am. Chem. Soc. 2006, 128, 4246-4247.
(5) In most cases, reactions of this type employ amine nucleophiles bearing
electron-withdrawing groups (amides, sulfonamides, carbamates, etc.). In
order to avoid modifying the nomenclature for each type of nucleophile,
we use generic terms such as “aminopalladation” and “oxidative amination”
to describe these reactions.
range from strong Brønsted acids to main-group (e.g., selenium,
halogens) and transition-metal reagents (mercury, gold and
palladium),1,2 and the reactions generally proceed via intramo-
lecular nucleophilic attack on an electrophile-activated alkene
intermediate, 1 (eq 1). The use of transition-metal electrophiles
in alkene heterocyclization reactions is attractive because facile
cleavage of the metal-carbon bond often enables the metal
electrophile to be regenerated and used catalytically. Palladium-
catalyzed “Wacker-type” heterocylizations represent prominent
(1) (a) Bartlett, P. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: New York, 1984; Vol. 3, pp 411-454. (b) Cardillo, G.; Orena, M.
Tetrahedron 1990, 46, 3321-3408. (c) Frederickson, M.; Grigg, R. Org.
Prep. Proced. Int. 1997, 29, 33-62. (d) Frederickson, M.; Grigg, R. Org.
Prep. Proced. Int. 1997, 29, 63-115. (e) Wirth, T. Angew. Chem., Int. Ed.
2000, 39, 3740-3749.
9
6328
J. AM. CHEM. SOC. 2007, 129, 6328-6335
10.1021/ja070424u CCC: $37.00 © 2007 American Chemical Society

Two-Faced Reactivity of Alkenes
A R T I C L E S
Table 1. Palladium(II) Catalyst Systems Employed in Direct-Dioxygen-Coupled Intramolecular Oxidative Amination Reactions
entry
catalysts
solvent
additive
abbreviation
1
2
3
4
5
Pd(OAc)2
Pd(OAc)2/pyridine
Pd(O2CCF3)2/pyridine
Pd(IMes)(O2CCF3)2(OH2)a
Pd(O2CCF3)2/(-)-sparteine
DMSO
toluene
toluene
toluene
toluene
NaOAc (2 equiv)
Pd(OAc)2/DMSO (A)
Pd(OAc)2/py (B)
Pd(O2CCF3)2/py (C)
Pd(IMes)(O2CCF3)2/BzOH (D)
Pd(O2CCF3)2/sp (E)
3 A° MS, Na2CO3 (2 equiv)
benzoic acid (20 mol %)
3 A° MS, DIPEAb (2 equiv)
b
a IMes ) N,N′-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (see below). DIPEA ) diisopropylethylamine.
Scheme 1. Pyrrolidine Products Accessible via Intramolecular
Aminopalladation of Alkenes
discovered that Pd(OAc)2 in dimethylsulfoxide (DMSO) cata-
lyzes aerobic oxidative heterocyclization reactions in the absence
of cocatalysts.8 The presence of stoichiometric base (NaOAc)
often enhances the yield of these reactions (Table 1, entry 1).8b
Our group demonstrated that Pd(OAc)2/pyridine (1:2) in toluene
(entry 2) is one of the most efficient catalyst systems available
for oxidative heterocyclization; turnover rates up to 70 h-1 were
observed for intramolecular oxidative amination of alkenes.9
Stoltz and co-workers later modified this catalyst system, using
Pd(O2CCF3)2/pyridine (1:4), 3 Å molecular sieves, and Na2-
CO3 (entry 3), to promote several different heterocyclization
reactions, including oxidative aminations.10 More recently, Pd
catalysts bearing a single N-heterocyclic-carbene ligand (entry
4) have been utilized for intramolecular oxidative heterocy-
clizations.11
Scheme 2. Simplified Catalytic Cycle for Direct-Dioxygen-Coupled
Pd-Catalyzed Intramolecular Oxidative Amination of Alkenes
The simplicity of these catalyst systems, together with the
prominent use of well-defined ancillary ligands, raises the
prospect of enantioselective oxidative amination reactions.
Aminopalladation of the alkene forms a new stereocenter
adjacent to the nitrogen atom (step I, Scheme 2), and this
stereocenter is retained in the product if â-hydride elimination
proceeds away from this center, as in the formation of 9 (step
II). Thus far, however, only one successful example of asym-
metric Pd-catalyzed aerobic oxidative amination of alkenes has
been identified: Yang and co-workers reported that the Pd(O2-
CCF3)2/sp catalyst system (Table 1, entry 5) catalyzes tandem
oxidative bicyclization reactions as shown in eq 2.12 The
conditions for these reactions resemble those reported previously
by Stoltz et al. for related oxidative heterocylizations of phenol
substrates (e.g., eq 3).10,13c,14
efficient dioxgen-coupled turnover.6 These reactions differ from
earlier examples7 because they often employ ligand-stabilized
Pd catalysts and they undergo dioxygen-coupled turnover
without requiring benzoquinone, CuII, or other redox-active
cocatalysts. We have been particularly interested in oxidative
amination reactions, and a simplified catalytic cycle for a
representative reaction is shown in Scheme 2: aminopalladation
of the alkene, followed by â-hydride elimination, generates the
heterocyclic product 9 and a reduced Pd catalyst (steps I and
II, Scheme 2). The reduced catalyst is then oxidized directly
by molecular oxygen to regenerate the PdII catalyst (steps III
and IV).
Despite this progress, the scope of asymmetric Wacker-type
heterocyclizations remains quite narrow. Because of this limita-
tion, we sought a better mechanistic understanding of Pd-
(8) For leading references, see: (a) Larock, R. C.; Hightower, T. R. J. Org.
Chem. 1993, 58, 5298-5300. (b) Larock, R. C.; Hightower, T. R.; Hasvold,
L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584-3585. (c) van
Benthem, R. A. T. M.; Hiemstra, H.; Michels, J. J.; Speckamp, W. N. J.
Chem. Soc., Chem. Commun. 1994, 357-359. (d) van Benthem, R. A. T.
M.; Hiemstra, H.; Longarela, G. R.; Speckamp, W. N. Tetrahedron Lett.
1994, 35, 9281-9284.
(9) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem., Int. Ed. 2002, 41, 164-
166.
A variety of catalyst systems have been employed in
intramolecular oxidative amination reactions of this type
(Table 1). The groups of Larock and Hiemstra simultaneously
(10) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem.,
Int. Ed. 2003, 42, 2892-2895.
(11) (a) Mun˜iz, K. AdV. Synth. Catal. 2004, 346, 1425-1428. (b) Rogers, M.
M.; Wendlandt, J. E.; Guzei, I. A.; Stahl, S. S. Org. Lett. 2006, 8, 2257-
2260.
(6) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400-3420.
(12) Yip, K. T.; Yang, M.; Law, K. L.; Zhu, N. Y.; Yang, D. J. Am. Chem.
Soc. 2006, 128, 3130-3131.
(13) (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. (c) Trend, R. M.; Ramtohul, Y. K.;
Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778-17788.
(7) (a) Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am.
Chem. Soc. 1978, 100, 5800-5807. (b) Hegedus, L. S.; Allen, G. F.; Olsen,
D. J. J. Am. Chem. Soc. 1980, 102, 3583-3587. (c) Hegedus, L. S.;
McKearin, J. M.; J. Am. Chem. Soc. 1982, 104, 2444-2451. (d) Ba¨ckvall,
J. E.; Hopkins, R. B. Tetrahedron Lett. 1988, 29, 2885-2888.
9
J. AM. CHEM. SOC. VOL. 129, NO. 19, 2007 6329

A R T I C L E S
Liu and Stahl
Scheme 3. Possible Outcomes for Pd-Catalyzed Oxidative
Cyclization of (E)-10
Table 2. Results for Palladium-Catalyzed Aerobic Oxidative
Cyclization of (E)-10a
catalyzed aerobic oxidative amination reactions, particularly with
respect to the stereochemistry-determining aminopalladation step
(step I, Scheme 2). Early fundamental studies of aminopalla-
dation reactions demonstrated that amine nucleophiles react with
Pd-alkene complexes via external attack on the coordinated
alkene (eq 4)15 in a manner that reflects the general mechanistic
model for electrophile-promoted nucleophilic additions to
alkenes (eq 1). More recently, however, we16 and others17 have
observed that certain Pd-catalyzed couplings of alkenes and
nitrogen nucleophiles proceed via cis-aminopalladation, an
outcome consistent with alkene insertion into a Pd-N bond
(eq 5).18 The stereochemistry of the aminopalladation step has
entry
Pd catalyst
yield (E)-12 (%)b
1
2
3
4
5
Pd(OAc)2/DMSO (A)
Pd(OAc)2/py (B)
Pd(O2CCF3)2/py (C)
Pd(IMes)(O2CCF3)2/BzOH (D)
Pd(O2CCF3)2/sp (E)
85 (10)
92
70
17 (68)
<4 (90)
a All reactions performed at 80 °C for 15 h, 0.1 mmol scale. bNMR yield
(internal standard ) 1,3,5-tri-tert-butylbenzene); recovered (E)-10 in
parentheses.
of additives (e.g., Brønsted acids) or by changing the identity
of the nitrogen nucleophile. These results complement important
recent insights into oxypalladation reactions19 and provide a
valuable framework for the pursuit of asymmetric oxidative
aminocyclization reactions.
Results and Discussion
profound implications for the rational development of asym-
metric oxidative heterocylization reactions, and in the present
study, we evaluate the full spectrum of reported Pd catalysts
that promote intramolecular aerobic oxidative amination of
alkenes (Table 1). Through the use of suitable substrate probes,
we find that cis-aminopalladation is generally favored in these
reactions; however, the pathway can be altered by the presence
Stereochemical Outcome for the Oxidative Cyclization of
a trans-Disubstituted Alkene. We initiated this study by
investigating the oxidative cyclization of the phenyl-substituted
alkene substrate (E)-10 (Scheme 3). The possible products of
this heterocyclization reaction provide mechanistic insights into
the aminopalladation step: formation of (E)-12 would arise from
initial cis-aminopalladation (cis-AP) of the alkene followed by
syn-â-hydride elimination from intermediate 11a, whereas (Z)-
12 would arise from a sequence initiated by trans-aminopalla-
dation (trans-AP) of (E)-10 (Scheme 3).20
Substrate (E)-10 was subjected to oxidative cyclization
conditions for each of the five catalyst systems shown in Table
1, and the results are summarized in Table 2. The sole product
observed from these reactions is (E)-12, indicating that the
reactions proceed via cis-aminopalladation of the alkene (cf.
Scheme 3). This product is formed in good yield with catalyst
systems A-C, but only low yields are obtained with catalyst
systems D and E, together with significant amounts of recovered
starting material.
(14) For asymmetric oxidative cyclization reactions that employ benzoquinone
as the oxidant, see: (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. (d) Arai,
M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123,
2907-2908. (e) Shinohara, T.; Arai, M. A.; Wakita, K.; Arai, T.; Sasai,
H. Tetrahedron Lett. 2003, 44, 711-714.
(15) (a) Åkermark, B.; Ba¨ckvall, J. E. Siirala-Hanse´n, K.; Sjo¨berg, K.; Zetterberg,
K. Tetrahedron Lett. 1974, 15, 1363-1366. (b) Åkermark, B.; Ba¨ckvall,
J. E.; Hegedus, L. S.; Zetterberg, K.; Siirala-Hanse´n, K.; Sjo¨berg, K. J.
Organomet. Chem. 1974, 72, 127-138. (c) Hegedus, L. S.; Allen, G. F.;
Waterman, E. L. J. Am. Chem. Soc. 1976, 98, 2674-2676. (d) Ba¨ckvall,
J. E. Acc. Chem. Res. 1983, 16, 335-342. (e) Ba¨ckvall, J. E.; Bjo¨rkman,
E. E. Acta Chem. Scand. B 1984, 38, 91-93.
(16) (a) Brice, J. L.; Harang, J. E.; Timokhin, V. I.; Anastasi, N. R.; Stahl, S.
S. J. Am. Chem. Soc. 2005, 127, 2868-2869. (b) Liu, G.; Stahl, S. S. J.
Am. Chem. Soc. 2006, 128, 7179-7181.
(17) (a) Isomura, K.; Okada, N.; Saruwatari, M.; Yamasaki, H.; Taniguchi, H.
Chem. Lett. 1985, 385-388. (b) Ney, J. E.; Wolfe, J. P. Angew. Chem.,
Int. Ed. 2004, 43, 3605-3608. (c) Ney, J. E.; Wolfe, J. P. J. Am. Chem.
Soc. 2005, 127, 8644-8651. (d) Nakhla, J. S.; Kampf, J. W.; Wolfe, J. P.
J. Am. Chem. Soc. 2006, 128, 2893-2901.
(18) No well-defined examples of alkene insertion into a Pd-N bond are
currently known, but examples of alkene insertion into other transition-
metal amido complexes have been reported: (a) Cowan, R. L.; Trogler,
W. C. Organometallics 1987, 6, 2451-2453. (b) Casalnuovo, A. L.;
Calabrese, J. C.; Milstein, D. J. Am. Chem. Soc. 1988, 110, 6738-6744.
(c) Cowan, R. L.; Trogler, W. C. J. Am. Chem. Soc. 1989, 111, 4750 -
4761. (d) Gagne´, M. R.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1992,
114, 275-294. (e) Zhao, P.; Krug, C.; Hartwig, J. F. J. Am. Chem. Soc.
2005, 127, 12066-12073.
Investigation of the cis alkene (Z)-10 under similar conditions
led to lower yields and a more complicated product mixture
(19) For related Wacker-type cyclizations involving cis-oxypalladation, see ref.
13c and Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem.
Soc. 2004, 126, 3036-3037.
(20) Anti-â-hydride elimination reactions have been implicated in a number of
Heck-type reactions, but the substrates possess unique structural properties
and the examples are extremely rare relative to the ubiquitous cases of
syn-â-hydride elimination. For a leading reference describing reactions that
proceed via (formal) anti-elimination, see: Ikeda, M.; El Bialy, S. A. A.;
Yakura, T. Heterocycles 1999, 51, 1957-1970.
9
6330 J. AM. CHEM. SOC. VOL. 129, NO. 19, 2007

Two-Faced Reactivity of Alkenes
A R T I C L E S
Table 3. Results for Palladium-Catalyzed Aerobic Oxidative
Cyclization of (Z)-10a
15 can arise from alkene isomerization of the initially formed
product 14. The stereospecifically labeled substrate trans-3-d-
13 can be used to gain insights into the stereochemical course
of the oxidative cyclization reaction (Scheme 4). Cis-amino-
palladation of the alkene will result in the Pd atom lying on the
opposite face of the cyclopentane ring from the deuterium atom.
Following â-hydride elimination (and, potentially, alkene
isomerization), the products 3-d-14 and 3-d-15 will retain the
deuterium label in its original position. In contrast, trans-
aminopalladation of trans-3-d-13 will result in either loss or
migration of the deuterium atom in the products 14 and trans-
2-d-15, respectively. The latter results arise from â-deuteride
elimination from the trans-aminopalladation intermediate in
which the Pd atom is adjacent to the deuterium atom on the
same face of the five-membered ring.
yield (%)b
entry
Pd catalysts
(Z)-10
(E)-10
(Z)-12
(E)-12
1
2
3
4
Pd(OAc)2/DMSO (A)
Pd(OAc)2/py (B)
Pd(O2CCF3)2/py (C)
Pd(IMes)(O2CCF3)2/
BzOH (D)
31
<5
12
21
0
25
32
34
0
16
18
22
10
0
38
31
5
Pd(O2CCF3)2/sp (E)
80
10
0
0
a All reactions performed at 80 °C for 15 h, 0.1 mmol scale. bNMR yield
(internal standard ) 1,3,5-tri-tert-butylbenzene).
Synthesis of the stereospecifically deuterium-labeled substrate
trans-3-d-13 was accomplished by the multistep sequence shown
in Scheme 5.22 Two key steps in this process are displacement
of tosylate by deuteride (LiBEt3D, step c) and the Ireland-
Claisen rearrangement (step e), both of which proceed ste-
reospecifically.23
(Table 3). With catalyst systems A-C, both product isomers,
(E)-12 and (Z)-12, were obtained. These results do not neces-
sarily reflect the stereochemistry of the aminopalladation step,
however, because isomerization of the cis alkene (Z)-10 into
the more stable trans isomer, (E)-10, was observed with three
of the catalyst systems (A, D, and E). No isomeric starting
material was detected in the reactions with catalyst systems B
and C, but we cannot exclude the possibility that alkene
isomerization occurs. For example, the lack of (E)-10 might
simply reflect its rapid consumption under the reaction condi-
tions to produce (E)-12. The complexities associated with the
reaction of (Z)-10 prevent us from drawing mechanistic conclu-
sions concerning the aminopalladation of this substrate.
The results obtained from the aerobic oxidative cyclization
of (E)-10 (Table 2) suggest that each of the five catalyst systems
promotes cis-aminopalladation of the alkene. The presence of
an aryl substituent on the alkene, however, might raise questions
concerning the generality of this mechanistic pathway. Further-
more, because of the low product yields obtained with catalyst
systems D and E and the complex product mixtures in the
reaction of (Z)-10, we sought a less problematic substrate probe
to evaluate the stereochemical course of these reactions.
Stereochemical Outcome for the Oxidative Cyclization of
a Deuterium-Labeled Substrate. Introduction of a deuterium
atom with appropriate regio- and stereochemistry into an
oxidative cyclization substrate can provide a means to probe
the pathway for aminopalladation of the alkene.21 The cyclo-
pentene derivative 13 (eq 6) undergoes efficient Pd-catalyzed
oxidative cyclization under aerobic conditions to form the cis-
fused [3.3.0] bicyclic product 14.8a,9,11b Formation of byproduct
Oxidative cyclization of trans-3-d-13 with four of the five
catalyst systems resulted in moderate to good yields of the
bicylic products; a relatively low yield was obtained with the
fifth Pd/(-)-sparteine catalyst system E, even though the catalyst
loading was increased to 10 mol %24 (Table 4). For catalyst
systems A, B, C, and E, only the cis-aminopalladation products
were obtained.25 In contrast, the N-heterocyclic-carbene-based
catalyst system D produced a nearly equal mixture of products
arising from cis- and trans-aminopalladation. Enhanced levels
of the alkene isomerization product 15 were observed with
catalyst systems C, D, and E.
The results in Table 4 have been rationalized on the basis of
the aminopalladation pathways shown in Scheme 4. An alterna-
tive possible mechanism for formation of the product 14
involves allylic C-D activation to form a π-allyl-PdII intermedi-
ate followed by C-N bond formation via nucleophilic attack
of the sulfonamide on the allyl fragment (Scheme 6).26 Several
observations argue against this pathway. For example, predomi-
nant formation of 3-d-14 would require allylic C-H activation
(22) For synthesis details of deuterium-labeling substrates, see the Supporting
Information.
(23) For a detailed experimental description and compound-characterization data,
see the Supporting Information.
(24) The low yield obtained with the Pd/(-)-sparteine catalyst might reflect
the fact that chelating ligands tend to inhibit Pd-catalyzed oxidative
heterocyclization. In addition, this result could arise from selective oxidation
of a single enantiomer of trans-3-d-13 (i.e., kinetic resolution of this
substrate). Analysis of the product mixture by chiral SFC (Chiralcel OD-
H), however, reveals that kinetic resolution of the substrate can only partly
account for the low yield: the reaction of 13 catalyzed by the Pd/(-)-
sparteine catalyst system produces 14 in 27% yield/44% ee and 15 in 17%
yield/71% ee. We were unable to resolve the recovered starting material
(56%) by chiral SFC.
(25) A reviewer correctly noted that the stereochemical course of the reaction
could be influenced by the presence of a deuterium kinetic isotope effect
on the â-hydride elimination step. In order to address this possibility, we
also prepared the diastereomeric substrate, cis-3-d-13. Oxidation cyclization
of this substrate with the Pd(OAc)2/DMSO and Pd(OAc)2/py catalyst
systems confirms that the reaction proceeds via cis-aminopalladation. For
full details, see the Supporting Information.
(21) For previous examples of the use of deuterium-labeled substrates to probe
the stereochemistry of palladium-catalyzed reactions with alkenes, see refs
13c, 19, and (a) Grennberg, H.; Simmon, V.; Ba¨ckvall, J.-E. J. Chem. Soc.,
Chem. Commun. 1994, 265-266. (b) Lautens, M.; Ren, Y. J. Am. Chem.
Soc. 1996, 118, 9597-9605. (c) Kisanga, P.; Widenhoefer, R. A. J. Am.
Chem. Soc. 2000, 122, 10017-10026. (d) Goj, L. A.; Widenhoefer, R. A.
J. Am. Chem. Soc. 2001, 123, 11133-11147. (e) Qian, H.; Widenhoefer,
R. A. J. Am. Chem. Soc. 2003, 125, 2056-2057. (f) Franze´n, J.; Ba¨ckvall,
J.-E. J. Am. Chem. Soc. 2003, 125, 6056-6057. (g) Hay, M. B.; Wolfe, J.
P. J. Am. Chem. Soc. 2005, 127, 16468-16476.
(26) Formation of a π-allyl-PdII species via C-H activation from the 3-position
of trans-3-d-13 is expected to be unproductive because formation of the
cis-fused bicyclic product would require cis-reductive elimination of the
C-N bond. It has been shown that attack of “soft” nucleophiles such as
sulfonamide on π-allyl-Pd species generally occurs via external (i.e., trans)
attack on the π-allyl fragment: Trost, B. M.; Van Vranken, D. L. Chem.
ReV. 1996, 96, 395-422.
9
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A R T I C L E S
Liu and Stahl
Scheme 4. Possible Outcomes for Pd-Catalyzed Oxidative Cyclization of trans-3-d-13
Scheme 5. Synthesis of the Deuterium-Labeled Substrate trans-3-d-13a
a Reaction conditions: (a) (i) Pb(OAc)4, HOAc/H2O, (ii) p-MeC6H4SO2Cl, Et3N, Me3NHCl, CH2Cl2 (39%, two steps); (b) (i) K2CO3, MeOH, (ii)
t-BuMe2SiCl, imidazole (85%, two steps); (c) LiBEt3D, THF (88%); (d) (i) TBAF, THF, (ii) Ac2O, pyridine (70%, two steps); (e) LDA, t-BuMe2SiCl, THF
(73%); (f) LiAlH4, Et2O (91%); (g) (i) MeSO2Cl, Et3N, CH2Cl2, (ii) K2CO3, p-MeC6H4SO2NH2, DMF (81%, two steps).
Table 4. Sterochemical Outcome for the Oxidative Cyclization of the Deuterium-Labeled Substrate trans-3-d-13a
product ratiob
entry
Pd catalysts
time (h)
yieldb (%)
cis-AP 3-d-14/3-d-15
trans-AP 14/trans-2-d-15
1
2
3
4
5
Pd(OAc)2/DMSO (A)
Pd(OAc)2/py (B)
Pd(O2CCF3)2/py (C)
Pd(IMes)(O2CCF3)2/BzOH (D)
Pd(O2CCF3)2/sp (E)c
15
15
15
72
72
70
84
85
60
37d
100:0
98:2
88:12
43:8
37:12
59:41
b
a All reactions performed at 80 °C; 5 mol % Pd; 0.1 mmol scale. Determined by 1H NMR spectroscopy (internal standard ) 1,3,5-trimethoxybenzene).
d
c10 mol % Pd. 45% starting material recovered.
Scheme 6. Possible π-Allyl-Pd Mechanism for the Oxidative
Cyclization of trans-3-d-13
conditions (eq 7). Attempts to use 16 as a substrate, how-
ever, resulted in nearly quantitative recovery of the starting
material.
to occur followed by an unusual cis-reductive elimination of
the C-N bond.26 The isomeric product 3-d-15 is not readily
explained by a π-allyl mechanism. Finally, if the reaction
proceeds via a π-allyl mechanism, the isomeric substrate 16
should convert readily to 14 under the oxidative cyclization
The oxidative cyclization of trans-3-d-13 was also investi-
gated with the PdCl2/benzoquinone catalyst system originally
reported by Hegedus and co-workers.7c Although multiple
isomeric products were obtained, the major products, 3-d-14
9
6332 J. AM. CHEM. SOC. VOL. 129, NO. 19, 2007

Two-Faced Reactivity of Alkenes
A R T I C L E S
Table 5. Sterochemical Outcome for the Oxidative Cyclization of
the Deuterium-Labeled Substrate trans-3-d-17a
product
time
(h)
yield
(%)b
ratiob
entry
Pd catalysts
3-d-18/3-d-19
1
2
3
4
Pd(OAc)2/DMSO (A)
Pd(OAc)2/py (B)
Pd(O2CCF3)2/py (C)
Pd(IMes)(O2CCF3)2/BzOH (D)
24
24
24
32
74
91
86
78
100:0
100:0
90:10
82:18
b
a All reactions performed at 80 °C; 5 mol % Pd; 33 µmol scale. NMR
yield, the product ratio was determined by NMR.
Figure 1. Effect of additives on the aminopalladation stereochemistry in
the oxidative cyclization of trans-3-d-13 catalyzed by 5 mol % (IMes)Pd-
(O2CCF3)2(OH2) (* - not determined). Reaction conditions: trans-3-d-13
(0.05 mmol), Pd catalyst (2.5 µmol), additive (AcOH and BzOH, 20 mol
%; CF3CO2H, 1 equiv; Na2CO3, 2 equiv), O2 (1 atm), toluene (0.5 mL),
80 °C, 72 h.
NHC-Pd catalysts for intramolecular oxidative amination
reactions, the highest product yields were observed with BzOH
as an additive. Nevertheless, we decided to reinvestigate the
oxidative cyclization of trans-3-d-13 with the NHC-Pd catalyst
under various conditions: in the presence of base (NaOAc, Na2-
CO3), with Brønsted acids of differing pKa values, and in the
absence of additives. As shown in Figure 1, products arising
from both cis- and trans-aminopalladation are obtained both in
the absence of additives and in the presence of exogenous acid.
The relative ratio of cis/trans aminopalladation decreases with
increasing acid strength, ranging from approximately 2:1 in the
absence of additives to 1:2 in the presence of trifluoroacetic
acid. The overall yield is similar (approximately 60%) in the
absence of additives and in the presence of acetic and benzoic
acids. A considerably lower yield (13%) is obtained when the
reaction is performed with trifluoroacetic acid. In the presence
of added base (NaOAc, Na2CO3), only products derived from
a cis-aminopalladation pathway are observed, and the overall
yield is slightly higher than that in the presence of acid.
Stereochemical Modulation of the Aminopalladation Path-
way: Substrate Effects. The influence of acid and base
additives on the stereochemistry of the aminopalladation step
raised the possibility that variation of the substrate pKa could
also influence the stereochemical course of the reaction. We,
therefore, investigated the oxidative cyclization of trans-3-d-
17, which possesses a p-nitrobenzenesulfonyl group (Ns) on
the nitrogen atom, and trans-3-d-20, which features a tosyl-
substituted carboxamide nucleophile. Both of these substrates
are more acidic than the parent tosylamide substrate trans-3-
d-13. Representative pKa values for these groups in DMSO
are 15.1 (TsNH2),29 13.9 (NsNH2),29 and approximately 9
(RCONHTs).30
and 3-d-15, were those resulting from cis-aminopalladation of
the alkene.27 We also detected a small amount (10%) of
isomerized starting material after the reaction was complete.
The precise origin of minor product 2-d-14 is not known;
however, this species probably arose from isomerization of
trans-2-d-15.
Stereochemical Modulation of the Aminopalladation Path-
way: Additive Effects. The results in Table 4 reveal that
aminopalladation of trans-3-d-13 proceeds with high stereose-
lectivity with four of the five catalyst systems; only the catalyst
bearing an N-heterocyclic carbene (NHC) ligand, (IMes)Pd(O2-
CCF3)2(OH2), yields products arising from both cis- and trans-
aminopalladation. The origin of the latter divergent result was
not immediately apparent; however, upon further analysis of
the reaction conditions for the five different catalyst systems,
we recognized that the NHC-coordinated catalyst is the only
one that operates under acidic conditions (in the presence of
BzOH). The other four catalyst systems possess exogenous
Brønsted base (A, C, and E) or employ a basic anionic ligand
coordinated to Pd (acetate; B).28 In our original investigation
The reaction of trans-3-d-17 yields heterocyclic product(s)
that arise exclusively from cis-aminopalladation of the alkene
(Table 5), even with the N-heterocyclic-carbene-coordinated
catalyst in the presence of BzOH (entry 4). In all cases, the
yields were slightly higher than those observed with the
tosylamide substrate trans-3-d-13.
(27) In a recent study of PdII-catalyzed oxidative cyclization of o-allylphenols,
Hayashi et al. observed primarily trans-oxypalladation of the alkene under
the same conditions (see ref 19 for details).
(28) In our mechanistic studies of Pd(OAc)2/py-catalyzed aerobic alcohol
oxidation, we obtained NMR spectroscopic evidence that an acetate ligand
serves as an internal base to promote formation of a PdII-alkoxide species:
Steinhoff, B. A.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2004, 126,
11268-11278.
(29) Ludwig, M.; Pytela, O.; Vecera, M. Collect. Czech. Chem. Commun. 1984,
49, 2593-2601.
(30) The pKa value of this substrate was not found; however, the pKa of TsN-
t
(H)CO2 Bu is 8.5. See: Koppel, I.; Koppel, J.; Degerbeck, F.; Grehn, L.;
Ragnarsson, U. J. Org. Chem. 1991, 56, 7172-7174.
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A R T I C L E S
Liu and Stahl
Table 6. Sterochemical Outcome for the Oxidative Cyclization of the Deuterium-Labeled Substrate trans-3-d-20a
product ratiob
trans-AP 21/trans-2-d-22
entry
Pd catalysts
time (h)
yieldb (%)
cis-AP 3-d-21/3-d-22
1
2
3
4
5
Pd(OAc)2/DMSO (A)
Pd(OAc)2/py (B)
Pd(O2CCF3)2/py (C)
Pd(IMes)(O2CCF3)2/BzOH (D)
Pd(IMes)(O2CCF3)2/Na2CO3 (F)
24
24
24
32
32
73
47
83
74
34
100:0
4:7
14:2
22:24
32:1
85:4
78:6
41:13
65:2
b
a All reactions performed at 80 °C; 5 mol % Pd; 33 µmol scale. NMR yield, the product ratio was determined by NMR.
The results of the oxidative cyclization of trans-3-d-20 are
more complex. Use of the Pd(OAc)2/DMSO catalyst system
results in exclusive formation of the trans-aminopalladation
product 21 (Table 6). With each of the other catalyst systems,
including the NHC-coordinated catalyst with both acid and
base additives, the oxidative cyclization of trans-3-d-20 yields
products arising from both cis- and trans-aminopalladation.
in the presence of acid (AcOH, BzOH, and TFA) (Figure 1);
the selectivity shifts toward trans-aminopalladation with in-
creasing acid strength. In contrast, use of stoichiometric base
in the reaction (NaOAc or Na2CO3) leads to exclusive cis-
aminopalladation of the alkene.
The precise origin of the preference for cis- or trans-
aminopalladation is not known; however, the following mecha-
nistic considerations provide the basis of ongoing investig-
ations. Trans-aminopalladation presumably arises from a mech-
anism resembling classical electrophile-promoted addition of
nucleophiles to alkenes (top pathway, Scheme 7; cf. eq 1):
coordination of the alkene to the electrophilic PdII center,
nucleophilic attack by the sufonamide nucleophile, and depro-
tonation of the zwitterionic intermediate 24. Cis-aminopalla-
dation probably arises from formation of a PdII-sulfonamidate
intermediate followed by alkene insertion into the Pd-N bond
(bottom pathway, Scheme 7).18,37 Formation of the Pd-amidate
species 25 liberates 1 equiv of HX and, therefore, should be
Analysis and Implications. In this study, we have probed
the Wacker-type oxidative cyclization of sulfonamide-substituted
aminoalkenes with several different Pd catalysts. The results
reveal that these reactions generally favor cis- rather than trans-
aminopalladation. This outcome is noteworthy because it
contradicts widespread assumptions concerning the stereochem-
ical course of such reactions. In recent studies, for example,
the term “Wacker-type reaction” has been used as a mechanistic
synonym for trans-heteropalladation of an alkene,17b,d,31 or trans-
heteropalladation of the alkene was simply assumed.32 Such
prevailing assumptions probably reflect the impact of elegant
early studies by Stille, Ba¨ckvall, Åckermark, Hegedus, and
others who reported definitive examples of trans-heteropalla-
dation of alkenes through isotopic labeling experiments and
fundamental reactivity studies of Pd-alkene complexes.33 These
results were countered by Henry, however, who argued that data
for the Wacker process itself were most consistent with cis-
hydroxypalladation of ethylene.34,35
(33) For leading references, see ref 15 and (a) Stille, J. K.; James, D. E. J.
Organomet. Chem. 1976, 108, 401-408. (b) James, D. E.; Hines, L. F.;
Stille, J. K. J. Am. Chem. Soc. 1976, 98, 1806-1809. (c) Ba¨ckvall, J. E.;
Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264-
265. (d) Stille, J. K.; Divakaruni. R. J. Am. Chem. Soc. 1978, 100, 1303-
1304. (e) Ba¨ckvall, J. E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem.
Soc. 1979, 101, 2411-2416. (f) Stille, J. K.; Divakaruni, R. J. Organomet.
Chem. 1979, 169, 239-248. (g) Kurosawa, H.; Majima, T.; Asada, N. J.
Am. Chem. Soc. 1980, 102, 6996-7003. (h) Andell, O. S.; Ba¨ckvall, J. E.
J. Organomet. Chem. 1983, 244, 401-407. (i) Ba¨ckvall, J. E.; Heumann,
A. J. Am. Chem. Soc. 1986, 108, 7107-7108. (j) Åkermark, B.; So¨derberg,
B. C.; Hall, S. S. Organometallics 1987, 6, 2608-2610.
Recent studies by several laboratories, including our own,
have provided increasing support for the viability of cis-
heteropalladation of alkenes, including both oxy-13c,19,21g,31 and
aminopalladation.16,17 The present study provides the first
systematic analysis of intramolecular Wacker-type oxidative
amination. Although cis-aminopalladation of the alkene is
generally favored in these reactions, trans-aminopalladation is
also possible and can predomimate, depending on the identity
of the substrate, the catalyst, and/or the reaction conditions.36
The energy barriers associated with cis- and trans-aminopalla-
dation appear to be especially finely balanced with the NHC-
Pd catalyst system (Figure 1). Products are observed from both
cis- and trans-aminopalladation in the absence of additives and
(34) For extensive analysis of the mechanistic pathway of the parent Wacker
process, see: Henry, P. M. Palladium Catalyzed Oxidation of Hydrocar-
bons; D. Reidel Publishing Co.: Boston, 1980.
(35) (a) Henry, P. M. J. Am. Chem. Soc. 1966, 88, 1595-1597. (b) Gragor,
N.; Henry, P. M.; J. Am. Chem. Soc. 1981, 103, 681-682. (c) Wan, W.
K.; Zaw, K. Henry, P. M. J. Mol. Catal. 1982, 16, 81-87. (d) Wan,
W. K.; Zaw, K.; Henry, P. M. Organometallics 1988, 7, 1677-1683.
(e) Zaw, K.; Henry, P. M. J. Org. Chem. 1990, 55, 1842-1847. (f)
Hamed, O.; Thompson, C.; Henry, P. M. J. Org. Chem. 1997, 62, 7082-
7083. (g) Hamed, O.; Henry, P. M. Organometallics 1997, 16, 4903-
4909.
(36) The apparent discrepancy between our observations (which favor cis-
aminopalladation reactions) and the early studies of Pd-mediated alkene
amination (which favor trans-aminopalladation reactions; ref 15) undoubt-
edly reflects differences between the substrates (sulfonamides vs alky-
lamines) and/or reaction conditions (catalytic vs precomplexation of the
alkene at low temperature followed by addition of stoichiometric amine
nucleophile).
(37) Another mechanism that could account for cis-aminopalladation of an alkene
involves a six-membered electrocyclic transition state (see below). See ref
16a.
(31) (a) Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc. 2004, 126, 1620-1621.
(b) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 762-763.
(32) For example, see ref 4b and (a) Lei, A.; Lu, X.; Liu, G. Tetrahedron Lett.
2004, 45, 1785-1788. (b) Streuff, J.; Ho¨velmann, C. H.; Nieger, M.; Mun˜iz,
K. J. Am. Chem. Soc. 2005, 127, 14586-14587.
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6334 J. AM. CHEM. SOC. VOL. 129, NO. 19, 2007

Two-Faced Reactivity of Alkenes
A R T I C L E S
Scheme 7. Primary Steps Associated with Intramolecular Trans- and Cis-Aminopalladation of Alkenes
favored in the presence of a Brønsted base (and disfavored
by the presence of acid). The trans-aminopalladation also
requires the loss of HX (i.e., 24 f 8′); however, this step occurs
after the C-N bond has formed, and the zwitterionic inter-
mediate 24 should be much more acidic than the free sulfona-
mide. Thus, strong exogenous base is probably not needed to
form 8′.
Several other observations can be rationalized by these
mechanisms. Increasing the acidity of the sulfonamide nucleo-
phile by using the Ns rather than the Ts derivative (17 and
13, respectively) leads to exclusive cis-aminopalladation by
the NHC-Pd catalyst, even in the presence of benzoic acid
(Table 5, entry 4). This result possibly arises from more facile
formation of the Pd-N(Ns)R species analogous to 25 in
Scheme 7.
The stereoselectivity for cyclization of the tosyl-substituted
carboxamide substrate 20 is less readily understood. With this
substrate, we observe mostly (but not exclusively) cis-amino-
palladation of the alkene with catalyst systems operating in
toluene (B, C, D, and F). The anion arising from deprotonation
of the carbonyl/sulfonyl imide in 20 is more stable than a
sulfonamidate anion and, thus, might undergo more facile
ionization of the Pd-N bond, resulting in the formation of some
trans-aminopalladation product. Exclusive trans-aminopallada-
tion of the alkene is observed with the Pd(OAc)2/DMSO catalyst
system (A). In DMSO, acetate is a sufficiently strong base to
deprotonate the imide of 20 in solution,38 without requiring
stabilization of the nitrogen anion by coordination to the metal
center. Good solvation of the imide anion by the polar solvent
DMSO could account for preferential alkene activation by PdII,
which leads to trans-aminopalladation. Further work will be
needed to test these hypotheses.
The results of this study have important implications for the
development of enantioselective Pd-catalyzed oxidative cycliza-
ton reactions. The highest levels of enantioselectivity un-
doubtedly will be observed when only a single aminopal-
ladation pathway is operating, and knowledge of the mechanism
for the stereochemistry-determining aminopalladation step will
play an important role in guiding rational catalyst design efforts.
Acknowledgment. We thank Lauren Huffman for assistance
with 2H NMR spectroscopy and Michelle M. Rogers for
preparation of the NHC-Pd catalyst and chiral SFC analysis
of products obtained in the reactions catalyzed by the (-)-
sparteine-Pd complex. We are grateful to the NIH (R01
GM67173) for financial support of this work.
Supporting Information Available: Experimental procedures
and spectroscopic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
JA070424U
(38) The pKa of acetic acid in DMSO is 12.3: Maran, F.; Celadon, D.; Severin,
M. G.; Vianello, E. J. Am. Chem. Soc. 1991, 113, 9320-9329.
9
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