Mechanistic studies of wacker-type intramolecular aerobic oxidative amination of alkenes catalyzed by Pd(OAc)2/pyridine

Article abstract of DOI:10.1021/jo102338a

Wacker-type oxidative cyclization reactions have been the subject of extensive research for several decades, but few systematic mechanistic studies of these reactions have been reported. The present study features experimental and DFT computational studies of Pd(OAc)₂/pyridine-catalyzed intramolecular aerobic oxidative amination of alkenes. The data support a stepwise catalytic mechanism that consists of (1) steady-state formation of a Pd^II-amidate-alkene chelate with release of 1 equiv of pyridine and AcOH from the catalyst center, (2) alkene insertion into a Pd-N bond, (3) reversible β-hydride elimination, (4) irreversible reductive elimination of AcOH, and (5) aerobic oxidation of palladium(0) to regenerate the active trans-Pd(OAc)₂(py)₂ catalyst. Evidence is obtained for two energetically viable pathways for the key C-N bond-forming step, featuring a pyridine-ligated and a pyridine-dissociated Pd^II species. Analysis of natural charges and bond lengths of the alkene-insertion transition state suggest that this reaction is best described as an intramolecular nucleophilic attack of the amidate ligand on the coordinated alkene.

Full text of DOI:10.1021/jo102338a

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Mechanistic Studies of Wacker-Type Intramolecular Aerobic Oxidative
Amination of Alkenes Catalyzed by Pd(OAc)2/Pyridine
Xuan Ye, Guosheng Liu,† Brian V. Popp, and Shannon S. Stahl*
Department of Chemistry, University of Wisconsin;Madison, 1101 University Avenue, Madison,
Wisconsin 53706, United States. †Current address: State Key Laboratory of Organometallics Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 354 Fenglin Road, Shanghai,
China, 200032
stahl@chem.wisc.edu
Received November 30, 2010
Wacker-type oxidative cyclization reactions have been the subject of extensive research for several
decades, but few systematic mechanistic studies of these reactions have been reported. The present
study features experimental and DFT computational studies of Pd(OAc)2/pyridine-catalyzed intra-
molecular aerobic oxidative amination of alkenes. The data support a stepwise catalytic mechanism
that consists of (1) steady-state formation of a PdII-amidate-alkene chelate with release of 1 equiv
of pyridine and AcOH from the catalyst center, (2) alkene insertion into a Pd-N bond, (3) reversible
β-hydride elimination, (4) irreversible reductive elimination of AcOH, and (5) aerobic oxidation of
palladium(0) to regenerate the active trans-Pd(OAc)2(py)2 catalyst. Evidence is obtained for two
energetically viable pathways for the key C-N bond-forming step, featuring a pyridine-ligated and a
pyridine-dissociated PdII species. Analysis of natural charges and bond lengths of the alkene-
insertion transition state suggest that this reaction is best described as an intramolecular nucleophilic
attack of the amidate ligand on the coordinated alkene.
Introduction
attention, with recent efforts focused especially on the devel-
opment of new synthetic transformations (e.g., 1,2-difunction-
alization of alkenes),2-6 enantioselective reactions,7,8 and
Palladium-catalyzed intramolecular aza-Wacker reactions
provide access to a number of nitrogen-containing hetero-
cycles such as pyrrolidine, piperazine, oxazolidin-2-one,
pyridine, pyrimidyldione and urea deriviatives.1 These het-
erocyclization reactions have been a subject of considerable
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DOI: 10.1021/jo102338a
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Published on Web 01/20/2011
J. Org. Chem. 2011, 76, 1031–1044 1031
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Ye et al.
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methods compatible with the use of molecular oxygen as the
terminal oxidant.9
SCHEME 1. Intramolecular Aerobic Oxidative Amination of
Alkenes Catalyzed by Pd(OAc)2/Pyridine12
Seminal early work by Hegedus10 and others11 demonstrated
that weakly coordinating nitrogen nucleophiles, especially sul-
fonamides, are particularly compatible with intramolecular
oxidative amination reactions (e.g., eq 1). Early examples
of these reactions used benzoquinone or CuCl2 as the
stoichiometric oxidant.10b Later, the groups of Larock11d
and Hiemstra11c demonstrated that molecular oxygen can be
used as an effective oxidant if the reaction is carried out in
DMSO as the solvent (eq 2).
the stoichiometric oxidant and achieves unprecedented cat-
alytic activity for such reactions. The p-toluenesulfonyl (Ts)
group proved to be the most effective nitrogen substituent.
Substrates bearing the p-nitrophenylsulfonyl (Ns) or Cbz
(PhCH2OC(O)-) groups were also effective, albeit requiring
somewhat longer reaction time. The reaction proceeds well
with aromatic and aliphatic tosylamides and tolerates wide
variations in solvent polarity, ranging from DMSO to heptane.
Nonpolar solvents permit the reaction to be performed at sig-
nificantly reduced catalyst loading. With 0.2 mol % of
Pd(OAc)2 and 0.4 mol % of pyridine in p-xylene, the
hexenyltosylamide substrate reacted with a turnover rate of
70 h-1 during the first 2 h of the reaction, and turnover numbers
up to 250-300 were attained. These values are significantly
higher than those observed with previous catalyst systems.10,11
Moreover, this catalyst system has served as the starting
point for the development of enantioselective oxidative
heterocyclization reactions.2b,13b,13c
Despite the extensive history of Pd-catalyzed oxidative
amination reactions, systematic mechanistic investigations
have been quite limited. The stereochemical course of the
C-N bond-forming step, aminopalladation of alkene, has
been a focus of some attention, and evidence for both
cis-2a,4b,15 and trans-aminopalladation10a,16 pathways has
been obtained (Scheme 2). A recent study from our group
demonstrated that the Pd(OAc)2/pyridine-catalyzed intramole-
cular aerobic oxidative amination reactions (cf. Scheme 1)
proceed exclusively via cis-aminopalladation of the alkene,
consistent with alkene insertion into a palladium-nitrogen
bond (Scheme 2).17 Here, we present experimental and
computational studies that provide insight into other important
aspects of the catalytic mechanism of Pd(OAc)2/pyridine-
catalyzed aerobicoxidativeintramolecularaminationofalkene.
Results include determination of the turnover-limiting step
and catalyst resting state, insights into the reversibility of
catalytic steps, including those that take place after the
turnover-limiting step, and the impact of O2 pressure on
the catalyst stability. These results and their implications
for Pd-catalyzed oxidative heterocyclization reactions are
presented below.18
In 2002, we reported the use of a very simple and efficient
Pd(OAc)2/pyridine catalyst system for the intramolecular
oxidative amination of alkenes to produce pyrrolidine and
pyrroline heterocycles in high yield (Scheme 1).12,13 This
catalyst system, originally reported by Uemura and co-workers
for alcohol oxidation,14 is capable of using molecular oxygen as
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5741. (b) Harayama, H.; Abe, A.; Sakado, T.; Kimura, M.; Fugami, K.;
Tanaka, S.; Tamaru, Y. J. Org. Chem. 1997, 62, 2113–2122. (c) Shinohara,
T.; Arai, M. A.; Wakita, K.; Arai, T.; Sasai, H. Tetrahedron Lett. 2003, 44,
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(7) For a general review on this subject, see: Chemler, S. R. Org. Biomol.
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T. P. J. Am. Chem. Soc. 2001, 124, 12–13.
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Int. Ed. 2004, 43, 3400–3420. (b) Stoltz, B. M. Chem. Lett. 2004, 33, 362–367.
(c) Sigman, M. S.; Schultz, M. J. Org. Biomol. Chem. 2004, 2, 2551–2554.
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Z. J. Org. Chem. 1988, 53, 5731–5741. (c) van Benthem, R. A. T. M.;
Hiemstra, H.; Longarela, G. R.; Speckamp, W. N. Tetrahedron Lett. 1994,
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Peterson, K. P. J. Org. Chem. 1996, 61, 3584–3585. (e) Harayama, H.;
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SCHEME 2. Possible Pathways for Intramolecular Aminopalladation of Alkenes
Results and Discussion
Kinetics Studies: Substrate and Catalyst Effects. Intramo-
lecular aerobic oxidative heterocyclization of (Z)-4-hexenyl-
tosylamide 1 is catalyzed by Pd(OAc)2/pyridine (2:8 mol %)
(eq 3), and the reaction proceeds to completion within 5 h at
80 °C.19,20 A computer-interfaced gas-uptake apparatus
was used to probe the kinetics of the catalytic reac-
tion by monitoring the change in oxygen pressure within a
sealed, temperature-controlled reaction vessel. The reac-
tion time-course exhibits a monotonic decrease in pres-
sure (Figure 1), and the lack of an induction period
allowed us to obtain much of our kinetic data via initial-rate
methods.
FIGURE 1. Representative kinetic time-course for Pd(OAc)2/pyr-
idine catalyzed intramolecular oxidative amination of (Z)-4-hex-
enyltosylamide obtained by gas-uptake methods. Data sampling
occurred at a rate of 1 s-1 (not all data are shown). Conditions:
[Pd(OAc)2] = 2.0 mM, [pyridine] = 8.0 mM, [amide] = 100 mM,
4.0 mL of toluene, initial pO2 = 700 Torr, 80 °C.
The initial kinetic studies focused on the influence of the
concentration of the primary reaction components (tosylamide,
O2 ,and catalyst) on the initial turnover rate. The data revealed
saturation rate dependences on the tosylamide (Figure 2A)
and catalyst (Figure 2B) concentrations. The rate depen-
dence on the O2 pressure was found to be dependent on the
Pd(OAc)2/pyridine ratio. At a Pd/py ratio of 1:4, no depen-
dence on O2 pressure was observed above 300 Torr
(Figure 3A). At a Pd/py ratio of 1:2, an apparent O2
dependence was observed, and the rate observed at the max-
imum pressure of the reaction vessel was approximately 2-fold
higher than the rate observed in the reaction with a 1:4 Pd/py
ratio (Figure 3B). In the reaction with Pd/py =1:2, signifi-
cant quantities of palladium black were observed at lower O2
pressures.
Pd/py ratio of approximately 1:1-1:1.5 (Figure 4A) and
beyond which significant inhibition is observed. A rate
dependence on [acetic acid] concentration is also observed.
The catalytic turnover rate maximizes at a 1:1 ratio of added
acetic acid to Pd(OAc)2 (Figure 4B).
If excess pyridine is added to the reaction mixture (120 mM;
10-240 equiv relative to Pd(OAc)2), the initial rate exhibits a
square-root dependence on [Pd(OAc)2] (Figure 5A). This result
contrasts the hyperbolic dependence observed when the
catalyst concentration is varied at a constant py/Pd ratio of
4:1 (Figure 2B). The rate dependence on [Pd(OAc)2] changes
again if both pyridine and acetic acid are added to thereaction
mixture (120 and 5 mM, respectively). Under these conditions,
a linear dependence of the rate on [Pd(OAc)2] is observed
(Figure 5B).
Electronic Effects. A series of para-substituted benzene-
sulfonamides (p-X = OMe, H, CH3, Cl, NO2) were used to
examine electronic effects on the catalytic turnover rate. The
Hammett plot (Figure 6) reveals that electron-rich substrates
react more rapidly than those bearing electron-withdrawing
groups, and a linear fit of the data exhibits a slope (F) of -0.22.
These results expand upon the qualitative data acquired with
the p-CH3 and -NO2 derivatives (cf. Scheme 1), which
showed that the Ns-substituted derivative required a longer
reaction time.
Pyridine and Acetic Acid Effect. The initial turnover rates
exhibit a sharp dependence on [pyridine] that maximizes at a
(18) For an analogous study of aerobic oxidative amination reactions,
catalyzed by an N-heterocyclic carbene-PdII catalyst system, see the follow-
ing: (a) Rogers, M. M.; Wendlandt, J. E.; Guzei, I. A.; Stahl, S. S. Org. Lett.
2006, 8, 2257–2260. (b) Ye, X.; Stahl, S. S. Unpublished results.
(19) (Z)-4-Hexenyltosylamide was selected instead of (E)-4-hexenyltosy-
lamide as the model substrate for this mechanistic study because cis-alkenes
usually afford better yields in palladium-catalyzed aerobic oxidative amina-
tion reactions, possibly due to better coordinating ability of cis-alkene to the
palladium center.
(20) In our original report of Pd(OAc)2/pyridine-catalyzed intramolecu-
lar aerobic oxidative amination of alkenes, a 1:2 ratio of Pd(OAc)2/pyridine
was employed. However, in the present study, a 1:4 ratio of Pd(OAc)2/
pyridine was used as the standard catalyst mixture because the palladium
catalyst is more stable and less susceptible to decomposition in the presence
of 4 equiv of pyridine ligand.
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FIGURE 2. (A) Dependence of the initial rate on amide concentration. The curve fit results from a nonlinear least-squares fit to a hyperbolic
function of [amide]. Conditions: [Pd(OAc)2] = 2.0 mM, [pyridine] = 8.0 mM, [amide] = 0-240 mM, 4.0 mL of toluene, initial pO2 = 700 Torr,
80 °C. (B) Dependence of the initial rate on catalyst concentration, where the “catalyst” is a 4:1 mixture of pyridine and Pd(OAc)2. Conditions:
[Pd(OAc)2] = 0-12.0 mM, [pyridine] = 0-48.0 mM [amide] = 100 mM, 4.0 mL of toluene, initial pO2 = 700 Torr, 80 °C.
FIGURE 3. (A) Dependence of the initial rate on the initial oxygen pressure (with Pd/py ratio of 1/4). Conditions: [Pd(OAc)2]=2.0 mM, [pyridine]=
8.0 mM, [tosylamide]=100 mM, 4.0 mL of toluene, initial pO2=300-700 Torr, 80 °C. (B) Dependence of the initial rate on the initial oxygen pressure (with
Pd/py ratio of 1/2). Conditions: [Pd(OAc)2]=2.0 mM, [pyridine]=4.0 mM, [tosylamide]=100 mM, 4.0 mL of toluene, initial pO2=300-700 Torr, 80 °C.
FIGURE 4. (A) Dependence of the initial rate on pyridine concentration with the [Pd(OAc)2] held constant. Conditions: [Pd(OAc)2]=2.0 mM, [pyridine]=
0-10 mM, [amide]=100 mM, 4.0 mL of toluene, initial pO2=700 Torr, 80 °C. (B) Dependence of the initial rate on acetic acid concentration. Conditions:
[Pd(OAc)2]=2.0 mM, [pyridine]=8.0 mM, [amide]=100 mM, [AcOH]=0-100 mM, 4.0 mL of toluene, initial pO2=700 Torr, 80 °C.
FIGURE 5. (A) Dependence of the initial rate on the square root of Pd(OAc)2 concentration in the presence of a large excess of pyridine.
Conditions: [pyridine] = 120 mM, [amide] = 100 mM, 4.0 mL of toluene, initial pO2 = 700 Torr, 80 °C. (B) Dependence of the initial rate
on the concentration of Pd(OAc)2 in the presence of excess pyridine and acetic acid. Conditions: [pyridine] = 120 mM, [AcOH] = 5 mM,
[amide] = 100 mM, 4.0 mL of toluene, initial pO2 = 700 Torr, 80 °C.
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FIGURE 6. Hammett plot derived from the relative initial rates of
catalytic oxidative amination conducted with a series of para-
substituted benzenesulfonamides. Conditions: [Pd(OAc)2] = 2.0 mM,
[pyridine] = 8.0 mM, [amide] = 100 mM, 4.0 mL of toluene, initial
pO2 = 700 Torr, 80 °C.
FIGURE 8. Dependence of the initial O2 uptake rate on amide
concentration. NH- vs ND-labeled tosylamides. Conditions:
[Pd(OAc)2] = 2.0 mM, [pyridine] = 8.0 mM, [amide] = 0-240
mM, 4.0 mL of toluene, initial pO2 = 700 Torr, 80 °C.
experiments demonstrate that this isotopic scrambling takes
place exclusively in an intramolecular fashion. No intermo-
lecular deuterium scrambling was observed when the reaction
was carried out with a 1:1 mixture of CH3- and CD3-labeled
tosylamide (eq 6).21
FIGURE 7. Dependence of the initial O2 uptake rate on amide
concentration. CH3- vs CD3-labeled tosylamides. Conditions:
[Pd(OAc)2] = 2.0 mM, [pyridine] = 8.0 mM, [amide] = 0-240
mM, 4.0 mL of toluene, initial pO2 = 700 Torr, 80 °C.
Kinetic Isotope Effects and Isotopic Labeling Studies.
Kinetic isotope effects were determined by comparing the
independent rates of reaction for tosylamide substrates
bearing terminal CH3- and CD3- groups (eq 4, Figure 7),
as well as NH- vs ND-labeled tosylamides (eq 5, Figure 8).
Small, secondary kinetic isotope effects were evident in both
cases (1.20 ( 0.05 and 1.15 ( 0.05, respectively).
The partially deuterated tosylamide substrates 2 and 3
were utilized to probe the intramolecular kinetic iso-
tope effect associated with β-hydride versus β-deuteride
elimination from the palladium-alkyl intermediate 4
(Scheme 3).22 1H NMR spectroscopic analysis of final
product mixtures reveals an approximately 3:1 distribu-
tion between β-hydride elimination and β-deuteride elim-
ination products.
The prospect of reversible aminopalladation was exam-
ined with substrate 5, which features two symmetrical
alkenes with isotopically substituted methyl groups
(eq 7). Two limiting scenarios are possible with this sub-
strate: (1) if aminopalladation is reversible, the ratio of
cyclic products 6 and 7 could approach 3:1, as dictated by
the relative rates of β-H versus β-D elimination; (2) if
aminopalladation is irreversible, the yield of 6 and 7 should
be identical (Scheme 4). When this reaction was performed,
(21) The intramolecular nature of deuterium scrambling into the β-vinyl
position of the pyrrolidine product has been independently confirmed by
crossover experiment with 1:1 mixture of CD3-labeled tosylamide and all-
protio pyrrolidine products. For a detailed experimental description, see the
Supporting Information.
Deuterium incorporation (∼20%) into the β-vinyl posi-
tion was observed in the reaction of CD3-labeled tosylamide
(eq 4). The scrambling of deuterium label into the internal
vinylic position suggests the β-hydride elimination from
the palladium-alkyl intermediate is reversible. Crossover
(22) For detailed experimental description, see the Supporting Informa-
tion.
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SCHEME 3. Intramolecular Selectivity between β-Hydride and β-Deuteride Elimination
a 1.04:1 ratio of 6/7 was obtained, implicating irreversible
aminopalladation.
SCHEME 4. Probing the Reversibility of Aminopalladation of
Alkene with Diene Substrate 5
77 equiv relative to Pd(OAc)2) into a solution of the catalyst
(1:2.2 Pd(OAc)2/py) results in essentially no change of the
chemical shifts associated with the coordinated and free pyr-
idine at temperatures ranging from -40 to þ40 °C.22
Catalytic Mechanism Based on Experimental Observa-
tions. Intramolecular aerobic oxidative amination of alkenes
catalyzed by Pd(OAc)2/pyridine proceeds via a PdII/Pd0
catalytic cycle in which palladium(II)-mediated substrate
oxidation and aerobic oxidation of the catalyst occur in
two independent, sequential stages. The kinetic studies
described above, which reveal no dependence of the rate
on [O2] and a dependence on [catalyst] and [amide],
indicate that a step associated with PdII-mediated sub-
strate oxidation is turnover-limiting. Consistent with this
proposal, trans-(py)2Pd(OAc)2 has been identified as the
catalyst resting state, and this species is capable of pro-
moting kinetically competent stoichiometric substrate
oxidation in the absence of molecular oxygen.
1H NMR Spectroscopic Studies: Characterization of the
1
Catalyst Resting State. H NMR spectroscopic studies were
The catalytic cycle shown in Scheme 5 illustrates a me-
chanism that is consistent with all of the experimental data
presented above. Key features of this mechanism include (1)
a two-step sequence for formation of the palladium(II)
amidate-alkene chelate 9, via release of 1 equiv of pyr-
idine and acetic acid (steps i and ii); (2) turnover-limiting
alkene insertion into Pd-N bond (step iii); (3) β-hydride
elimination from the alkylpalladium(II) intermediate 10
(step iv); and (4) dissociation of product and reductive
elimination of AcOH (both included in step v). Reoxida-
tion of a pyridine-ligated Pd0 species completes the cata-
lytic cycle (step vi).
conducted to gain insight into the identity of the catalyst
resting state. trans-(py)2Pd(OAc)2 forms upon the addi-
tion of 2 equiv of pyridine to Pd(OAc)2 and was previously
characterized in our mechanistic study of Pd(OAc)2/pyr-
idine-catalyzed aerobic alcohol oxidation.23 Two sets of
pyridine 1H resonances are observed if more then 2 equiv
of pyridine are present, corresponding to coordinated and
free pyridine. Titration of (Z)-4-hexenyltosylamide (from 0 to
(23) (a) Steinhoff, B. A.; Stahl, S. S. Org. Lett. 2002, 4, 4179–4181.
(b) Steinhoff, B. A.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2004, 126,
11268–11278.
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SCHEME 5. Proposed Catalytic Mechanism for Pd(OAc)2/
Pyridine-Catalyzed Aerobic Oxidative Intramolecular Amination
of Alkenes
as a trimer in nonpolar solvents,24 and the presence of coordi-
nating ligands lead to the formation of lower nuclearity Pd
species that are probably more electrophilic and/or reac-
tive with organic substrates.25 In addition, pyridine can
stabilize the palladium(0) intermediate 12, either by pre-
venting aggregation or enhancing the reaction rate be-
tween 12 and molecular oxygen.23 At high concentrations,
however, pyridine inhibits the catalytic turnover rate because it
competes with the substrate for coordination sites at the Pd
center.26
The addition of excess AcOH strongly inhibits the cataly-
tic turnover rates at high concentrations (Figure 4B). This
observation is readily explained by a competition between
alkene insertion into the palladium-amidate bond (k3,
Scheme 5) and protonation of palladium amidate intermedi-
ate 9 (k-2, Scheme 5). Elevated [AcOH] will favor proton-
ation of 9 and lead to inhibition of catalytic turnover. The
origin of the small, but noticeable, beneficial effect of AcOH
at low concentrations (Pd/AcOH = 1:1) is less certain but may
be related to the ability of AcOH to promote the pyridine-
dissociation equilibrium in step i via hydrogen bonding to
the pyridine (Figure 4B).27
The proposed turnover-limiting alkene insertion into a
Pd-Namidate bond (k3, Scheme 5) is consistent with the
observed Hammett correlation (Figure 6). Alkene insertion
into the Pd-N bond is expected to be more facile with more-
electron-rich (i.e., nucleophilic) amidates.28 β-Hydride elim-
ination (step iv, Scheme 5) takes place after the turnover-
limiting step, and therefore, the proposed mechanism is
consistent with the small secondary kinetic isotope effect
determined by comparing independent rates of tosylamide
substrates bearing terminal CH3- versus CD3- groups
(Figure 7).
The isotope-labeling studies reveal three key features of
the reaction: (1) β-hydride elimination is reversible (cf. eq 4,
Scheme 3); (2) deuterium scrambling among the three vinyl
positions occurs exclusively in an intramolecular fashion (cf.
eq 6); and (3) aminopalladation of alkene is irreversible
(cf. Scheme 4). All three observations are accommodated
by the proposed mechanism in Scheme 5. Turnover-limiting
alkene insertion into the palladium-amidate bond renders
the overall aminopalladation of alkene irreversible, and the
exclusively intramolecular deuterium scrambling suggests
that the product dissociation is irreversible.
The precise nature and sequence of the first two steps
(Scheme 5, steps i and ii) cannot be established from the
available data; however, reversible formation of intermedi-
ate 9 is consistent with the small N-H/N-D isotope effect
(Figure 8), and it rationalizes the inhibitory effect of pyridine
and AcOH. The amidate-alkene chelate 9 is the starting
point for cis-aminopalladation of the alkene.17
This mechanism also accounts for the variable [catalyst]
dependence observed under different reaction conditions:
hyperbolic dependence with a 1:4 Pd/py catalyst system;
half-order dependence in the presence of excess pyridine
(py/Pd > 10:1); and first-order dependence in the presence
of excess pyridine and AcOH (Figure 2B, Figure 5). Nearly
identical kinetic behavior was characterized previously for
Pd(OAc)2/pyridine-catalyzed alcohol oxidation.20 These ob-
servations are attributed to the kinetic influence of the small
pre-equilibrium and/or steady-state quantities of pyridine
and AcOH, whose concentrations will be directly propor-
tional to the concentration of the Pd intermediates, 8 and 9,
respectively. If sufficient quantities of pyridine and AcOH
are added to ensure that a constant excess concentration of
these species is present, a first-order dependence on [Pd(OAc)2]
is observed. A more thorough discussion of this effect has
been presented previously,20 and rate laws, based on
steady-state and pre-equilibrium formation of intermedi-
ates 8 and 9, are presented in the Supporting Information.
The neutral ligand, pyridine, plays a key role in the
stabilization and aerobic oxidation of palladium(0). At a
pyridine/Pd ratio <4:1 (e.g., 2:1), the catalytic turnover rate
exhibits an O2 dependence and significant palladium-black
formation is observed (Figure 3B), indicating a competition
between catalyst oxidation and decomposition upon forma-
tion of palladium(0). The beneficial rate effect of pyridine,
which maximizes at a ∼1:1-1:1.5 Pd/pyridine ratio (Figure 4A),
probably reflects several factors. Palladium acetate exists
(25) In a recent demonstration of this principle, pyridine ligands have
been shown to activate Pd-carboxylate catalysts toward C-H activation in
the aerobic oxidative coupling of o-xylene: Izawa, Y.; Stahl, S. S. Adv. Synth.
Catal. 2010, 352, 3223–3229.
(26) The apparent kinetic dependence on [O2] when the reaction is carried
out in the presence of 1:2 Pd:py (Figure 3B) reflects the fact that at low [O2]
the catalyst decomposes more rapidly, thereby removing active catalyst from
the reaction mixture. At higher [O2], the catalyst is more stable, and the
higher concentration of active catalyst contributes to a faster rate. The O2-
pressure effects on catalyst stablility have been analyzed in considerable
detail in the following: Steinhoff, B. A.; Stahl, S. S. J. Am. Chem. Soc. 2006,
128, 4348–4355.
(27) A similar “up/down” dependence on [AcOH] has also been observed
by Sigman and co-workers in Pd(IiPr)(OAc)2(H2O)-catalyzed aerobic alco-
hol oxidation. In this case, the observation was attributed to a balance
between the relative rate of HOAc-inhibited alcohol oxidation and HOAc-
promoted palladium catalyst regeneration by O2. See: Mueller, J. A.; Goller,
C. P.; Sigman, M. S. J. Am. Chem. Soc. 2004, 126, 9724–9734.
(28) For insights into electronic effects on alkene insertion into Pd-N
bonds, see: (a) Hanley, P. S.; Markovic, D.; Hartwig, J. F. J. Am. Chem. Soc.
2010, 132, 6302–6303. (b) Neukom, J. D.; Perch, N. S.; Wolfe, J. P. J. Am.
Chem. Soc. 2010, 132, 6276–6277.
(24) Stephenson, T. A.; Morehouse, S. M.; Powell, A. R.; Heffer, J. P.;
Wilkinson, G. J. Chem. Soc. 1965, 3632–3640.
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Ye et al.
JOCFeatured Article
FIGURE 9. Lowest free energy pathways for formation of aminopalladative intermediates with and without pyridine ligation. All reactions
are relative to trans-(py)2Pd(OAc)2 þ 1M; free py and 1/2[AcOH]2.
SCHEME 6. Calculated Energies for Alternative Aminopalladation
Transition States
Computational Studies. With the mechanistic framework
in Scheme 5 as a starting point, we performed computational
studies of the oxidative amination mechanism using density
functional theory (DFT) methods in order to gain further
insights into the energetics of the reaction pathway. These
studies employed trans-(py)2Pd(OAc)2 as the catalyst with a
model substrate, (Z)-4-hexenylmesylamide 1M (eq 8), in
which the experimental toluenesulfonyl group was replaced
with a methanesulfonyl group in the computational studies
(note: for experimental compounds modeled by computed
analogues differing only in the identity of the sulfonyl group,
we use the experimental compound number with an “M”
suffix for the computed structure). The calculations were
performed using the B3LYP functional, and the experimen-
tal solvent, toluene, was described with a continuum solvent
model. Free energies (the only energies discussed here) were
calculated for all intermediates and transition states at 80 °C.29
All calculated free energies presented below are reported
relative to the energy of trans-(py)2Pd(OAc)2 þ 1M.30
FIGURE 10. Ball-and-stick models with bond-length metrics for
the Pd-amidate-alkene intermediates 9M and K2-16M and alkene
The experimental studies indicate that aminopalladation
of the alkene is the turnover-limiting step of the catalytic
cycle. The PdII-amidate-alkene chelate 9M is the starting
point for the aminopalladation step, and the calculated
insertion transition states 13 AP-TS and 17AP-TS
.
pathway for formation of this species from trans-(py)2Pd-
(OAc)2 þ 1M is presented in the Supporting Information.
Two energetically similar pathways were identified
for alkene insertion into the palladium-amidate bond,
a pyridine-ligated and pyridine-dissociated pathway
(29) For further computational details, see the Experimental Section and
Supporting Information.
(30) For stuctures lacking pyridine or AcOH, the energies account for the
presence of free py and 0.5 equiv of [AcOH]2, respectively.
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FIGURE 11. Low energy pathways for the β-hydride elimination and AcOH-reductive elimination. All reactions are relative to (py)2Pd(OAc)2
þ 1M; free py and 1/2[AcOH]2: (A) pyridine-ligated pathway; (B) pyridine-dissociated pathway.
(Figure 9). The first pathway reflects the proposed me-
chanism in Scheme 5 and proceeds via transition state
13AP-TS for C-N bond formation, in which pyridine is
coordinated to the PdII center (Scheme 5, solid line).
Alkene insertion into the Pd-N bond exhibits a barrier
of 22.0 kcal/mol. In the other pathway, pyridine dissoci-
ates from the Pd center to form a PdII-amidate-alkene
species with a κ2-acetate ligand, K2-16M. Subsequent
alkene insertion via the pyridine-dissociated transition state
17AP-TS exhibits a much lower barrier, ΔGq = 14.7 kcal/mol
(ΔΔGq = -7.3 kcal/mol). In this pathway, pyridine dis-
sociation from PdII via [15/py]TS is calculated to be the
rate-limiting step, with a calculated barrier slightly higher
(1.2 kcal/mol) than transition state 13AP-TS. The pyridine-
ligated alkyl-PdII metallacycle 10M is 4.9 kcal/mol higher
in energy than the corresponding pyridine-dissociated species
18M, which has a K2-acetate ligand.
Several other aminopalladation transition states were
considered in the course of these studies, but all proved to be
higher in energy than those shown in Figure 9. For example, a
transition-state isomer of 13AP-TS, in which the amidate
nitrogen atom and alkene are trans to acetate and pyridine
J. Org. Chem. Vol. 76, No. 4, 2011 1039

Ye et al.
SCHEME 7. Refined Catalytic Mechanism for Pd(OAc)2/
Pyridine-Catalyzed Aerobic Oxidative Intramolecular Amination
JOCFeatured Article
ligands, respectively, is 2.3 kcal/mol higher in energy
(Scheme 6, iso-13AP-TS). In addition, pathways that proceed
via a six-membered C-N bond-forming transition state, in
which a sulfonyl oxygen atom is coordinated to the PdII
center, proved to be much higher in energy (>35 kcal/mol;
see Scheme 6).29
of Alkenes
The metrical parameters for the Pd-amidate-alkene inter-
mediates 9M and K2-16M and the alkene insertion transition
states 13AP-TS and 17AP-TS are shown in Figure 10. The bond
lengths together with the calculated natural charges for these
species are consistent with a reaction pathway that can be
described as an intramolecular nucleophilic attack of the ami-
date ligand onto a PdII-activated alkene. For example,
transition state 13AP-TS features a lengthened carbon-carbon
˚
bond relative to 9M (1.42 vs 1.39 A, respectively), and the
alkene is unsymmetrically coordinated to the palladium center in
13AP-TS, reflecting a progression toward the 5-exo-trig
cyclization transition-state geometry. Natural charges
(NC) on the alkene reflect a highly polarized carbon-
carbon bond, NC = -0.38 and þ0.07 for the terminal and
internal carbon atoms of the alkene, respectively.29 In addition,
the palladium-coordinated nitrogen atom of the sulfonamide
has substantial negative charge in 13AP-TS/NC = -0.86.
The experimental data reveal that β-hydride elimination
and subsequent AcOH-reductive-elimination take place
after the turnover-limiting step in the catalytic mechanism.
Nevertheless, these are important steps in the overall
reaction.31,32 The “pyridine-ligated” intermediate 10M and
the “pyridine-dissociated” intermediate 18M can both un-
dergo β-hydride elimination, and the energy profiles origi-
nating from these species are shown in Figure 11. In both
pathways, the energy barriers of vinyl pyrrolidine product
dissociation (via structures 22 and 31; red pathway) are large
relative to the barriers associated with isomerization between
primary and secondary palladium-alkyl intermediates (blue
pathway). Therefore, both pathways are consistent with the
experimentally observed intramolecular deuterium scram-
bling into the β-vinyl position (eq 6). The overall barriers
evident on these profiles, however, suggest the “pyridine-
ligated” pathway (Figure 11A) is unlikely. The barrier for
product dissociation via 22 is calculated to be higher in
energy than the barrier calculated for turnover-limiting
aminopalladation (Figure 9). Turnover-limiting product
dissociation is not consistent with the Hammett correlation
observed with the different sulfonamide nucleophiles (Figure 6),
and the pyridine-dissociated pathway (Figure 11B) pro-
vides an energetically viable alternative for the β-hydride
elimination and product dissociation steps.
idine-ligated pathway or a pyridine-dissociated pathway.
The former pathway features direct insertion of the alkene
into the palladium-amidate bond (Scheme 7, 9 f 10),
followed by dissociation of the pyridine from PdII (10 f
18). The latter pathway features dissociation of pyridine
prior to the insertion of alkene into the palladium-amidate
bond (Scheme 7, 9 f 16 f 18). The two proposed path-
ways feature different turnover limiting steps, alkene
insertion (9 f 10) vs pyridine disscociation (9 f 16), both
of which are consistent with the experimental data, in-
cluding (a) the rate law, (b) the Hammett plot (pyridine
dissociation should proceed more rapidly with more-
electron-rich trans amidate ligands), and (c) reversible
β-hydride elimination after the turnover-limiting step of
the mechanism.
The pyridine-dissociated pathway for β-hydride elimina-
tion (Scheme 7, 18 f 29) is favored over the originally
proposed pyridine-ligated pathway (Scheme 5, 10 f 11) based
on computational analysis. The regeneration of palladium(II)
catalyst from palladium-hydride intermediate 29 proceeds via
irreversible reductive elimination of AcOH. Facile reox-
idation of palladium(0) complex 37 takes place in compe-
tition with catalyst decomposition.
Modified Proposed Catalytic Mechanism. The collection of
experimental and computational data presented above pro-
vides the basis for a slightly revised catalytic cycle for the
Pd(OAc)2/pyridine-catalyzed aerobic oxidative intramolecu-
lar amination of alkenes (Scheme 7). This mechanism reflects
the two possible aminopalladation pathways, in which the
PdII-amidate-alkene intermediate 9 can react via a pyr-
Conclusion
The mechanistic study presented in this paper provides a
thorough analysis of palladium-catalyzed Wacker-type aerobic
oxidative amination reactions. Experimental and compu-
tational data suggest a catalytic mechanism that consists
of (1) steady-state formation of a PdII-amidate-alkene inter-
mediate, (2) alkene insertion into a Pd-N bond, (3)
reversible β-hydride elimination, (4) irreversible AcOH
reductive elimination, and (5) aerobic oxidation of palladium(0)
to regenerate the active catalyst trans-Pd(OAc)2(py)2. Two
energetically viable pathways, including a pyridine-ligated
(31) Although pathways involving direct reaction of a Pd-H species with
molecular oxygen have been proposed to initiate catalyst regeneration, recent
computational work provides compelling evidence that this catalytic system
must proceed through Pd0; see: (a) Popp, B. V.; Stahl, S. S. Chem.;Eur.
J. 2009, 15, 2915–2922. (b) Keith, J. M.; Goddard, W. A. J. Am. Chem. Soc.
2009, 131, 1416–1425.
(32) For a thorough description of β-hydride elimination and HOAc-
reductive elimination pathways, see the Supporting Information.
1040 J. Org. Chem. Vol. 76, No. 4, 2011

Ye et al.
JOCFeatured Article
and a pyridine-dissociated pathway, have been identified
for the key C-N bond-forming step. The difference between
these two nearly isoenergetic pathways lies in the coordi-
nation environment at Pd when the alkene inserts into the
palladium-amidate bond. Analysis of natural charges
and bond lengths of the alkene-insertion transition state
reveal that this formal migratory insertion process can be
described as an intramolecular attack of the nitrogen
nucleophile onto the coordinated alkene. The possible involve-
ment of ligand-dissociated pathways for nucleopalladation of
alkenes has important practical implications for the de-
velopment of enantioselective reactions. Dissociation of
a chiral ligand from PdII will result in formation of an
achiral catalyst. Depending on the relative energies of the
other steps in the mechanism, this process could account
for some of the historical difficulty in developing enantio-
selective Wacker-type oxidative cyclization reactions.
cis-4-hexen-1-ol (27 g, 90% yield). The identity and purity of cis-
4-hexen-1-ol was confirmed by comparison of the 1H NMR
spectrum to that reported in the literature.33
(Z)-4-Hexenyltoluenesulfonamide 1 was prepared via se-
quential formation of the mesylate from cis-4-hexen-1-ol and
SN2 substitition of the mesylate by tosylamide according to
literature procedures.17
(Z)-4-Hexenyltoluenesulfonamide-d3 (6-d3-1).
The procedure for preparation of CD3-labeled (Z)-4-hexe-
nyltoluenesulfonamide 6-d3-1 was the same as that of
(Z)-4-hexenyltoluenesulfonamide, with the exception that
CD3MgI (1.0
M in diethyl ether) was used instead
of CH3MgBr.33 (Z)-4-Hexenylbenzenesulfonamide-d3: 1H
NMR (CDCl3) δ 7.74 (dt, J = 8.4, 1.8 Hz, 2H), 7.31 (dt,
J = 8.4, 1.8 Hz, 2H), 5.44 (dt, J = 10.8, 0.9 Hz, 1H), 5.27 (dt,
J = 7.2, 10.8 Hz, 1H), 4.50 (t, J = 6.0 Hz, 1H), 2.95 (dt, J =
6.9, 6.3 Hz, 2H), 2.43 (s, 3H), 2.03 (dq, J = 7.2, 1.2 Hz, 2H),
1.54 (m, 2H); 2H NMR (CHCl3) δ 1.52 (s, 3D); 13C NMR
(CDCl3) δ 143.5, 137.2, 129.9, 129.2, 127.3, 125.2, 43.1, 29.5,
24.1, 21.7, 12.1 (heptad, J = 19.2 Hz); HRMS (ESI) calcd for
Experimental Section
Representative Procedure for Gas-Uptake Kinetics. A typical
reaction was conducted as follows. A 25 mL round-bottom flask
with a stirbar was attached to an apparatus with a calibrated
volume and a pressure transducer designed to measure the gas
pressure within the sealed reaction vessel. The apparatus was
evacuated to 10 Torr and filled with oxygen to 800 Torr, and this
cycle was repeated 10 times. The pressure was established at 675
Torr. When the pressure stabilized in the apparatus, stock
solutions of Pd(OAc)2 (2.5 mM, in 3.2 mL toluene) and pyridine
(1.2M, in 0.4 mL toluene) were added via syringe through a
septum. The flask was heated to 80 °C. When the temperature
stabilized, stock solution of substrate (1.0 M, in 0.4 mL toluene) was
added via syringe through a septum. Data was acquired using
custom software written within LabVIEW. Correlations between
oxygen uptake and conversion were made by analysis by 1H NMR
spectroscopy with 1,3,5-trimethoxybenzene as an internal standard.
Representative Procedure for Reactions with Isotopically La-
beled Substrates. Pd(OAc)2 (0.4 mg, 2 μmol) was added to 13 ꢀ
100 mm disposable culture tubes. The reaction tubes were placed
into a custom 48-well parallel reactor mounted on a large
capacity mixer, and the headspace was purged with molecular
oxygen for ca. 15 min. Solutions of pyridine (8 μmol in 0.5 mL
of toluene) and substrate (0.1 mmol in 0.5 mL of toluene) were
added to the tubes. The reactions were carried out for 24 h
under an oxygen atmosphere (1 atm) at 80 °C. Following
removal of the solvent under vacuum, the crude oxidative amination
product was purified via column chromatography with ethyl acet-
ate/hexanes and analyzed by 1H NMR spectroscopy.
C
13H16D3NO2SNa 279.1223, found 279.1211.
CH2D-labeled (Z)-4-hexenyltosylamide 2.
40. Alkyne 39 was synthesized according to literature
procedures.34 To a solution of 39 (4 g, 20 mmol) in MeOH
(50 mL) were added Lindlar’s catalyst (100 mg) and quinoline
(1 mL, 8.5 mmol). The mixture was agitated under an H2
atmosphere (8 psig) at room temperature for 2 h. The catalyst
was filtered, and the solvent was removed under vacuum. The
residue was purified by silica gel chromatography (hexane/ethyl
1
acetate) to afford 40 (3.23 g, 79% yield over three steps): H
NMR (CDCl3) δ 5.66 (m, 1H), 5.50 (m, 1H), 4.53 (dd, J = 4.2,
2.7 Hz, 1H), 4.24 (ddd, J = 12.6, 7.2, 1.2 Hz, 1H), 4.10 (ddd, J =
12.6, 7.2, 1.2 Hz, 1H), 3.86 (m, 1H), 3.74 (dt, J = 9.6, 6.6 Hz,
1H), 3.48 (M, 1H), 3.39 (dt, J = 9.6, 6.6 Hz, 1H), 3.12 (br, 1H),
2.20 (m, 2H), 1.81-1.50 (m, 8H).
Substrate Syntheses. (Z)-4-Hexenylbenzenesulfonamide 1.
41. To a solution of allylic alcohol 40 (3 g, 15 mmol) in
i
methylene dichloride (50 mL) were added Pr2NEt (2.6 g,
cis-4-Hexen-1-ol 38 was prepared by a modification of the
literature procedure.33 A 3.0 M ethereal solution of MeMgBr
(100 mL, 0.3 mmol) was added to a stirring suspension of
(dppp)NiCl2 (610 mg, 1.1 mmol) in 200 mL of dry toluene under
an N2 atmosphere. The stirring was continued at room tem-
perature for 20 min. 4,5-Dihydropyran (25 g, 0.3 mol) was
added, and the solution was heated to 90 °C and stirred over-
night. The cooled reaction mixture was poured into a saturated
ammonium chloride solution and extracted with ether. The
extract was dried with MgSO4, and the solvent was removed
under vacuum. The residue was purified by distillation to afford
20 mmol) and MsCl (1.8 g, 16 mmol) at 0 °C via syringe. The
reaction was monitored by TLC. After the reaction was
complete, water (40 mL) was added. The mixture was ex-
tracted with diethyl ether. The extract was dried with
MgSO4, and the solvent was removed under vacuum. The
residue was purified by silica gel chromatography (hexane/
ethyl acetate) to afford 41 (1.9 g, 59% yield): 1H NMR
(CDCl3) δ 5.66 (m, 2H), 4.57 (dd, J = 4.2, 2.7 Hz, 1H),
4.16 (d, J = 5.1 Hz, 2H), 3.88 (m, 1H), 3.75 (dt, J = 9.6, 6.6
Hz, 1H), 3.50 (m, 1H), 3.39 (dt, J = 9.6, 6.6 Hz, 1H), 2.23
(m, 2H), 1.71-1.50 (m, 8H).
(33) Wenkert, E.; Michelotti, E. L.; Swindell, C. S.; Tingoli, M. J. Org.
Chem. 1984, 49, 4894–4899.
(34) Heitz, M. P.; Wagner, A.; Mioskowski, C.; Noel, J. P.; Beaucourt,
J. P. J. Org. Chem. 1989, 54, 500–503.
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Ye et al.
JOCFeatured Article
6-d1-42. Under an N2 atmosphere, LiAlD4 (150 mg, 4 mmol)
was suspended in dry diethyl ether (20 mL). Compound 41 (600
mg, 2.8 mmol) was added slowly via a syringe to this solution.
The resulting suspension was refluxed for 2 h. Excess LiAlD4
was quenched with water and then with an aqueous solution of
NaOH (40%, 10 mL). The mixture was stirred for 1 h. The white
solid was filtered, and the solvent was removed under vacuum to
afford crude 6-d1-42 (471 mg, 91%): 1H NMR (CDCl3) δ 5.44
(m, 2H), 4.58 (dd, J = 4.2, 2.7 Hz, 1H), 3.87 (m, 1H), 3.75 (dt,
J = 9.6, 6.6 Hz, 1H), 3.50 (M, 1H), 3.39 (dt, J = 9.6, 6.6 Hz, 1H),
2.12 (m, 2H), 1.71-1.50 (m, 10H).
(CDCl3) 5.70 (d, J = 10.8 Hz, 1H), 5.50 (ddd, J = 10.8, 8.4, 6.6
Hz, 1H), 4.52 (dd, J = 4.2, 2.7 Hz, 1H), 3.86 (m, 1H), 3.75 (dt,
J = 9.6, 6.6 Hz, 1H), 3.49 (m, 1H), 3.41 (dt, J = 9.6, 6.6 Hz, 1H),
2.30 (m, 2H), 2.19 (s, 1H), 1.79-1.51 (m, 8H).
6-d2-41. This compound was prepared according to the
procedure used for 41 (see above) (62% yield): 1H NMR
(CDCl3) δ 5.41 (m, 2H), 4.58 (dd, J = 4.2, 2.7 Hz, 1H), 3.88
(m, 1H), 3.75 (dt, J = 9.6, 6.6 Hz, 1H), 3.50 (m, 1H), 3.39 (dt,
J = 9.6, 6.6 Hz, 1H), 2.13 (m, 2H), 1.71-1.50 (m, 8H).
6-d2-42. Under an N2 atmosphere, LiAlH4 (500 mg, 13 mmol)
was suspended in dry diethyl ether (40 mL). Then 6-d2-41 (1.5 g,
6.8 mmol) was added via a syringe. The mixture solution was
refluxed for 2 h. The excess LiAlH4 was quenched by water, and
then an aqueous solution of NaOH (40%, 10 mL) was added.
The mixture was stirred for 1 h. The white solid was filtred, and
the solvent was removed under vacuum to afford crude 6-d2-42
(1.18 g, 94%): 1H NMR (CDCl3) δ 5.65 (m, 2H), 4.57 (dd, J =
4.2, 2.7 Hz, 1H), 3.86 (m, 1H), 3.76 (dt, J = 9.6, 6.6 Hz, 1H), 3.52
(m, 1H), 3.39 (dt, J = 9.6, 6.6 Hz, 1H), 2.23 (m, 2H), 1.71-1.50
(m, 9H).
6-d2-43. This compound was synthesized according to the
procedure used for 6-d1-43 (see above) (75% yield over two
steps): 1H NMR (CDCl3) δ 5.57 (m, 1H), 5.39 (m, 1H), 4.27 (t,
J = 6.6 Hz, 2H), 3.06 (s, 3H), 2.21 (q, J = 7.2 Hz, 2H), 1.86 (m,
2H), 1.63 (m, 1H); 13C NMR (CDCl3) δ 128.5, 125.9, 69.7, 37.6,
29.1, 22.9, 12.4 (p, J = 19.6 Hz).
3. Compound 3 was prepared according to the literature
procedure used for 117 (60% yield, colorless oil): 1H NMR
(CDCl3) δ 7.76 (dt, J = 8.4, 1.8 Hz, 2H), 7.30 (dt, J = 8.4,
1.8 Hz, 2H), 5.45 (dd, J = 10.8, 6.6 Hz, 1H), 5.27 (m, 1H), 4.52
(t, J = 1.8 Hz, 1H), 2.96 (dt, J = 6.9, 6.6 Hz, 2H), 2.43 (s, 3H),
2.03 (q, J = 7.2 Hz, 2H), 1.54 (m, 3H); 2H NMR (CDCl3) δ 1.51
(s, 2D); 13C NMR (CDCl3) δ 143.6, 137.3, 129.9, 129.1, 127.3,
125.3, 43.1, 29.6, 24.2, 21.7, 12.4 (t, J = 19.6 Hz); HRMS (ESI)
calcd for C13H17D2NO2S 255.1262, found 255.1259.
6-d1-43. To a solution of crude 6-d1-42 (471 mg, ∼2.6 mmol)
in MeOH (5 mL) was added TsOH H2O (10 mg, 0.05 mmol).
3
The mixture was stirred for 1 h. Then Na2CO3 (50 mg, 0.5 mmol)
was added, and the mixture was stirred for 30 min. The solid was
filtered, and the solvent was removed under low vacuum. The
crude oil was dissolved in CH2Cl2 (20 mL), and Et3N (1 mL) and
MsCl (400 mg, 3.5 mmol) were then added slowly via syringe.
The mixture was stirred overnight at room temperature. After
the reaction was complete (by TLC), water (20 mL) was added.
The mixture was extracted with diethyl ether. The extract was
dried with MgSO4, and the solvent was removed under vacuum.
The residue was purified by silica gel chromatography (hexane/
ethyl acetate) to afford 6-d1-43 (214 mg, 78% yield): 1H NMR
(CDCl3) δ 5.52 (m, 1H), 5.37 (m, 1H), 4.23 (t, J = 6.6 Hz, 2H),
3.01 (s, 3H), 2.18 (q, J = 7.2 Hz, 2H), 1.83 (m, 2H), 1.60 (m, 2H);
13C NMR (CDCl3) δ 128.4, 125.9, 69.7, 37.5, 29.1, 22.8, 12.7 (t,
J = 19.6 Hz).
2. This compound was prepared according to the literature
procedure used for 117 (60% yield, colorless oil): 1H NMR
(CDCl3) δ 7.76 (dt, J = 8.4, 1.8 Hz, 2H), 7.31 (dt, J = 8.4, 1.8
Hz, 2H), 5.45 (m, 1H), 5.28 (m, 1H), 4.42 (t, J = 1.8 Hz, 1H),
2.95 (dt, J = 6.9, 6.3 Hz, 2H), 2.43 (s, 3H), 2.03 (q, J = 7.2 Hz,
2H), 1.54 (m, 4H); 2H NMR (CHCl3) δ 1.53 (s, 1D); 13C NMR
(CDCl3) δ 143.6, 137.3, 129.9, 129.1, 127.4, 125.4, 43.1, 29.6,
24.2, 21.7, 12.9 (t, J = 19.8 Hz); HRMS (ESI) calcd for
C13H18DNO2S, 254.1199, found 254.1192.
Diene 5.
CHD2-Labeled (Z)-4-Hexenyltosylamide 3.
46. The compound was prepared by a modification of the
literature procedure.36 A 1.0 M ethereal solution of CD3MgI
(35 mL, 35 mmol) was added to a stirring suspension of (dppe)NiCl2
(526 mg, 1 mmol) in 40 mL of dry benzene under N2, and stirring
was continued at room temperature for 20 min. 4,5-Dihy-
dropyran (2.8 g, 40 mmol) was added, and the solution was
refluxed for 2 h. The cooled reaction mixture was poured into
a solution of saturated ammonium chloride and extracted
with ether. The extract was dried with MgSO4, and the
solvent was removed under reduced pressure. The crude
product was dissolved in toluene, and Et3N (6 mL) and MsCl
(0.44 mL, 4.5 mmol) were added slowly via syringe to the
toluene solution. The mixture was stirred overnight at room
temperature. After the reaction was completed, water (20 mL) was
added. The mixture was extracted with diethyl ether. The
extract was dried with MgSO4 followed by the removal of
solvent under reduced pressure. The residue was purified by
silica gel chromatography (hexane/ethyl acetate) to afford 46
45. The compound 44 was synthesized from 4-pentyn-1-ol
according to literature procedures.35 Compound 44 was hydro-
genated according to the procedure used for compound 40 to
afford 45 (95%, colorless oil): 1H NMR (CDCl3) δ 6.28 (dt, J =
11.7, 7.5 Hz, 1H), 5.79 (dt, J = 11.7, 1.8 Hz, 1H), 4.58 (dd, J =
4.2, 2.7 Hz, 1H), 3.88 (m, 1H), 3.75 (dt, J = 9.6, 6.6 Hz, 1H), 3.70
(s, 3H), 3.50 (m, 1H), 3.41 (dt, J = 9.6, 6.6 Hz, 1H), 2.75 (m, 2H),
1.81-1.45 (m, 8H).
6-d2-40. Under an N2 atmosphere, LiAlD4 (1.1 g, 27 mmol)
was suspended in dry diethyl ether (40 mL). Compound 45 (3.4 g,
15 mmol) was added to this suspension at -20 °C via syringe.
The mixture was warmed to 0 °C and stirred for 2 h. The excess
LiAlD4 was quenched with water, and then an aqueous solution
of NaOH (40%, 10 mL) was added. The mixture was stirred for
1 h. The white solid was filtered, and the solvent was removed
1
(5.4 g, 92% yield over two steps): H NMR (CDCl3) δ 5.64
1
under vacuum to afford crude 6-d2-40 (2.8 g, 93%): H NMR
(35) Kita, Y.; Okunaka, R.; Honda, T.; Shindo, M.; Taniguchi, M.;
Kondo, M.; Sasho, M. J. Org. Chem. 1991, 56, 119–125.
(36) Wadman, S.; Whitby, R.; Yeates, C.; Kocienski, P.; Cooper, K.
J. Chem. Soc., Chem. Commun. 1987, 241–243.
1042 J. Org. Chem. Vol. 76, No. 4, 2011

Ye et al.
JOCFeatured Article
(d, J = 10.8 Hz, 1H), 5.38 (dt, J = 10.8, 7.2 Hz, 1H), 4.22 (t,
J = 6.9 Hz, 2H), 3.00 (s, 3H), 2.51 (dq, J = 6.9, 1.5 Hz, 2H).
47. To a solution of 46 (5.4 g, 3.2 mmol) in DMSO (20 mL),
NaCN (1.6 g, 3.2 mmol), and NaI (480 mg, 3.2 mmol) were
added under an N2 atmosphere. The mixture was stirred at 55 °C
for 12 h. After the reaction was complete, water (50 mL) was
added. The mixture was extracted with diethyl ether. The extract
was dried with MgSO4, and the solvent was removed under
vacuum. The residue was purified by distillation to give 47 (2.8 g,
89% yield, colorless liquid): 1H NMR (CDCl3) δ 5.64 (d, J =
10.8 Hz, 1H), 5.41 (m, 1H), 2.40 (m, 4H).
48. The compound was prepared by a modification of the
literature procedure.37 To a solution of 47 (1.1 g, 11 mmol) in a
2:1 (volume ratio) mixture of THF and HMPA was slowly
added via syringe a solution of LDA (6.1 mL 1.8 M in THF, 11
mmol) at -78 °C under an N2 atmosphere. After the solution
was stirred for 30 min at -78 °C, 1-bromo-2-butyne (1.6 g, 15
mmol) was added.38 The mixture was stirred for 3 h at -78 °C
and then was warmed to room temperature. After the reaction
was complete, water (40 mL) was added. The mixture was
extracted with diethyl ether. The extract was dried with MgSO4,
and the solvent was removed under vacuum. The residue was
purified by silica gel chromatography (hexane/ethyl acetate) to
give 48 (750 mg, 45% yield over two steps): 1H NMR (CDCl3)
δ 5.69 (m, 2H), 5.44 (m, 2H), 2.58 (p, J = 7.2 Hz, 1H), 2.39 (m,
4H), 1.66 (dp, J = 6.9, 0.9 Hz, 3H); 13C NMR (CDCl3) δ 128.4,
128.2, 125.1, 125.0, 122.1, 32.0, 29.13, 29.11, 13.2; HRMS (ESI)
calcd for C10H12D3NNa 175.1290, found 175.1295.
5. Under an N2 atmosphere, 48 (350 mg, 2.3 mmol) was added
to a suspension of LiAlH4 (150 mg, 4 mmol) in dry THF (10 mL)
at 0 °C, and the mixture was stirred overnight at room tem-
perature. After the reaction was complete, water (0.5 mL) was
added. To the crude reaction mixture Et3N (1 mL) and TsCl
(570 mg, 3 mmol) were added via a syringe. The mixture was
stirred for 12 h. After the reaction was complete, water (20 mL)
was added. The mixture was extracted with diethyl ether. The
extract was dried with MgSO4, and the solvent was removed
under vacuum. The residue was purified by silica gel chroma-
tography (ethyl acetate/hexanes) to afford 5 (550 mg, 77% yield,
colorless oil): 1H NMR (CDCl3) δ 7.74 (dt, J = 8.4, 1.8 Hz, 2H),
7.31 (dt, J = 8.4, 1.8 Hz, 2H), 5.51 (m, 2H), 5.29 (m, 2H), 4.54 (t,
J = 1.8 Hz, 1H), 2.87 (t, J = 6.6 Hz, 2H), 2.43 (s, 3H), 2.01 (t,
J = 6.9 Hz, 4H), 1.60 (m, 1H), 1.55 (dt, J = 6.9, 0.9 Hz, 3H); 2H
NMR (CHCl3) δ 1.49 (s, 3D); 13C NMR (CDCl3) δ 143.5, 137.2,
129.9, 127.9, 127.8, 127.3, 126.3, 126.2, 46.9, 39.1, 29.43, 29.41,
21.7, 13.1; HRMS (ESI) calcd for C17H22D3NO2SNa 333.1692,
found 333.1705.
theory (RDFT)40 calculations were performed with the hybrid
density-functional, B3LYP.41,42 A combination of the Stuttgart
RSC 1997 ECP43 for Pd and the all-electron 6-31þG(d) basis
sets (Basis I)44 for all other atoms were used for gas-phase
geometry optimization and normal-mode analyses. Full geome-
try optimizations were carried out in internal coordinates using
the Berny algorithm.45 Frequency calculations were performed
at optimized geometries and transition states, confirming that
each optimized minimum has zero imaginary frequencies and
each optimized transition state has exactly one imaginary
frequency. When visual inspection of the single negative eigen-
value defining a saddle point did not clearly confirm the reaction
trajectory, IRC calculations were performed to verify that the
identified transition state corresponded to the appropriate
reactant/product potential energy surface.46 Zero-point energy
and additional thermochemical corrections were calculated at
80 °C using the identified normal modes. Charge analyses were
carried out on converged spin-restricted density matrices using
the natural population analysis (NPA) method47 as implemen-
ted within NBO 3.1 in G03.
At the calculated stationary points, solvation-corrected sin-
gle-point total energy calculations were carried out with the Pd
basis detailed above and the 6-311þG(d,p) basis (Basis II) on all
other atoms with electrostatic and nonelectrostatic solvation
effects evaluated using the integral-equation-formalism polariz-
able-continuum model (IEF-PCM).48 These calculations were
used to predict the solvation free energy under typical catalytic
conditions (i.e., toluene solvent at 80 °C (353 K)). The solvation
cavity was generated using UFF radii, explicitly treating hydro-
gen atoms, and the radii were scaled by a factor of 1.2. The PCM
input was modified with the following parameters to define the
physical characteristics of the solvent (ε = 2.24, F = 0.810 g cm-1
,
3
˚
r = 2.82 A). The dielectric constant (ε) used here was determined
with eq 9.49 The temperature range over which eq 9 is
reported is 207-316 K; however, we find that eq 9 repro-
duces, with necessary accuracy, dielectric constants at the
higher temperature examined here.50 The density (F) of toluene at
353 K was determined using a 24-parameter empirical model
(40) Koch, W., Holthausen, M. C. A Chemist’s Guide to Density Func-
tional Theory; Wiley-VCH: Weinheim, 2000.
(41) Becke, A. D. J. Chem. Phys. 1993, 98, 1372–1377.
(42) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.
(43) (a) The Stuttgart RSC 1997 ECP basis set for Pd was obtained from
the Extensible Computational Chemistry Environment Basis Set Database,
version 02/25/04, as developed and distributed by the Molecular Science
Computing Facility, Environmental and Molecular Sciences Laboratory,
which is part of the Pacific Northwest Laboratory, P.O. Box 999, Richland,
WA 99352, and funded by the U.S. Department of Energy. The Pacific
Northwest Laboratory is a multiprogram laboratory operated by Battelle
Memorial Institute for the U.S. Department of Energy under contract DE-
Computational Studies. All computations were performed
with the Gaussian 03 (G03) program39 using resources provided
by NSF TeraGrid partners. Spin-restricted density functional
€
AC06-76RLO 1830. (b) Andrae, D.; Haussermann, U.; Dolg, M.; Stoll, H.;
Preuss, H. Theor. Chim. Acta 1990, 77, 123–141.
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Molecular Orbital Theory; Wiley: New York, 1986.
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Chem. 1996, 17, 49–56. (b) Peng, C. Y.; Schlegel, H. B. Isr. J. Chem. 1993, 33,
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(48) For an overview of solvation models and reviews on PCM methods,
see: (a) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105, 2999–
3093. (b) Cramer, C. J.; Truhlar, D. G. Chem. Rev. 1999, 99, 2161–2200. For
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H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.,
Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.;
Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda,
R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
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ꢁ
references on our current approach, see: (c) Cances, E.; Mennucci, B.;
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J. Org. Chem. Vol. 76, No. 4, 2011 1043

Ye et al.
JOCFeatured Article
that is valid for T = 223-423 K and P = 1-30 atm.51
εðTÞ ¼ 3:26 - 0:00344T þ 1:59 ꢀ 10- 6T2
where n = the number of rotational and translational modes
G353K ¼ H353K - TðS353K þ Scorr
Þ
ð12Þ
ð13Þ
ð9Þ
(ΔG353K
Scorr ¼ RTðQ°=QÞ ¼ 2:36 kcal mol- 1
We report Gibbs free energies at 353
K
)
3
(eqs 10-13). Since the reported free energies are corrected for
a solvated environment, an additional energy correction (Scorr
to the translation entropy component of the gas-phase entropy
was included. This correction (eq 13) is necessary to account for
the standard state change from gas (1 atm) to solution (1 M).52
where R = 0.001987 kcal mol-1 K-1 and T = 353.15 K and
)
3
3
Q°/Q = 28. 977.
Acknowledgment. We are grateful to the NIH for finan-
cial support of this work (R01 GM67163) and the NSF for
partial support of the computational studies through Teragrid
resources provided by NCSA and the Pittsburgh Super-
computing Center (TG-CHE070040N).
Esolv ¼ Etot þ Gsol
ð10Þ
X
X
1
2
hvi
n
H353K ¼ Esol
þ
hvi þ
þ
kbT
ð11Þ
ehv =k T - 1
2
i
b
i
i
Supporting Information Available: Experimental details,
characterization for all new compounds, and computational
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
(51) McLinden, M. O.; Splett, J. D. J. Res. Natl. Inst. Stand. Technol.
2008, 113, 29–67.
(52) Cramer, C. J. Essentials of Computational Chemistry: Theories and
Models; Wiley: New York, 2002; pp 341-342.
1044 J. Org. Chem. Vol. 76, No. 4, 2011