Mechanistic Insight into Palladium-Catalyzed Cycloisomerization: A Combined Experimental and Theoretical Study

Article abstract of DOI:10.1021/jacs.7b05436

The cycloisomerization of enynes catalyzed by Pd(OAc)₂ and bis-benzylidene ethylenediamine (bbeda) is a landmark methodology in transition-metal-catalyzed cycloisomerization. However, the mechanistic pathway by which this reaction proceeds has remained unclear for several decades. Here we describe mechanistic investigations into this reaction using enynamides, which deliver azacycles with high regio- and stereocontrol. Extensive ¹H NMR spectroscopic studies and isotope effects support a palladium(II) hydride-mediated pathway and reveal crucial roles of bbeda, water, and the precise nature of the Pd(OAc)₂ pre-catalyst. Computational studies support these mechanistic findings and lead to a clear picture of the origins of the high stereocontrol that can be achieved in this transformation, as well as suggesting a novel mechanism by which hydrometalation proceeds.

Full text of DOI:10.1021/jacs.7b05436

Article
pubs.acs.org/JACS
Mechanistic Insight into Palladium-Catalyzed Cycloisomerization: A
Combined Experimental and Theoretical Study
Aroonroj Mekareeya,† P. Ross Walker,† Almudena Couce-Rios,‡ Craig D. Campbell,† Alan Steven,§
Robert S. Paton,*,† and Edward A. Anderson*,†
†Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, U.K.
‡Departament de Química, Universitat Auton
̀ ̀
oma de Barcelona, 08193 Cerdanyola del Valles, Spain
§AstraZeneca Pharmaceutical Techology and Development, Charter Way, Macclesfield, Cheshire SK10 2NA, U.K.
S
* Supporting Information
ABSTRACT: The cycloisomerization of enynes catalyzed by
Pd(OAc)2 and bis-benzylidene ethylenediamine (bbeda) is a
landmark methodology in transition-metal-catalyzed cyclo-
isomerization. However, the mechanistic pathway by which this
reaction proceeds has remained unclear for several decades. Here
we describe mechanistic investigations into this reaction using
enynamides, which deliver azacycles with high regio- and
stereocontrol. Extensive 1H NMR spectroscopic studies and
isotope effects support a palladium(II) hydride-mediated pathway and reveal crucial roles of bbeda, water, and the precise
nature of the Pd(OAc)2 pre-catalyst. Computational studies support these mechanistic findings and lead to a clear picture of the
origins of the high stereocontrol that can be achieved in this transformation, as well as suggesting a novel mechanism by which
hydrometalation proceeds.
phosphine ligand or bbeda).6 Since these pioneering studies,
INTRODUCTION
■
palladium-catalyzed cycloisomerization has been widely ex-
Transition-metal-catalyzed cycloisomerizations are among the
ploited in methodology3 and synthesis contexts.4b,5b,7 Our
most atom-efficient methods to access organic ring systems.1
group has shown that Pd(OAc)2/bbeda is particularly effective
The appeal of these skeletal reorganizations lies in both the
in catalyzing the cycloisomerization of enynamides to
importance of ring synthesis in organic chemistry and the
pyrrolidine and piperidine enamides (Scheme 1, eq 2),8 useful
diversity of products that can arise from a single substrate,
depending on the mechanistic pathway taken.1a,b,2 Among the
heterocycles that can undergo a variety of further ring-forming
transformations.9
many transition metals that have been used for enyne
cycloisomerization, palladium catalysts have seen widespread
Despite this rich history, the mechanism by which the
Pd(OAc)2/bbeda catalyst system operates is far from clear.
use, with extensive work from Trost and co-workers
Under Pd2dba3 catalysis, it is widely accepted that reaction of
demonstrating the versatility of this metal in three particularly
robust catalyst systems (Scheme 1, eq 1):3 Pd(OAc)2/
Pd(0) with acetic acid generates a palladium(II) hydride species
triarylphosphine,4 Pd(OAc)2/bis-benzylidene ethylenediamine
(Scheme 2, Path A), which effects cycloisomerization by alkyne
(bbeda),4d,e,5 and Pd2dba3·CHCl3/AcOH (with or without
hydropalladation (1 → 2), alkene carbopalladation (3), and β-
hydride elimination. This latter process, which regenerates
palladium(II) hydride, can give rise to three isomeric products:
Scheme 1. Palladium-Catalyzed Cycloisomerization of
a 1,3-diene and (E)- or (Z)-1,4-dienes (4−6, respectively),
depending on the hydrogen atom involved. In contrast, it is not
apparent that this mechanism also operates for Pd(OAc)2/
bbeda, not least as there is no obvious pathway for the
generation of palladium(II) hydride from these components.
This in part likely contributed to early proposals4d,e,5 that this
catalyst instead effects cycloisomerization by a Pd(II) →
Pd(IV) oxidative coupling to form an intermediate palladacy-
clopentene 7 (Path B),4d,5c,10 followed by β-hydride elimination
(8) and then reductive eliminationa route believed to
Enynes and Enynamides
Received: May 26, 2017
© XXXX American Chemical Society
A
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Scheme 2. Mechanistic Dichotomy for Pd-Catalyzed Enyne
Cycloisomerization
Scheme 3. Regio- and Stereoselectivity in the Cyclization of
Mono- and 1,2-Disubstituted Enynamides
useful reference point of a reaction widely recognized to
proceed through a metallacycle intermediate.1g,6f
operate for other transition metals such as ruthenium and
rhodium.1g,6f However, despite the proposal of Pd(IV)
palladacycles in other palladium-catalyzed processes,11 no
direct evidence for palladacyclopentenes has been reported.
Other support for this pathway includes high selectivity for β-
hydride elimination “away” from the newly formed ring
(leading to a 1,4-diene), which would be favored on geometric
grounds as the C−Pd and bridgehead C−H bonds cannot
easily adopt a syn-coplanar orientation in palladacycle 7, and
also through the observation of different product distributions
between the various palladium catalyst systems.3a,6e In light of
this continuing uncertainty, both mechanistic explanations have
been routinely adopted.12
Under the Pd(OAc)2/bbeda catalytic manifold, we found
that the cycloisomerization of 1,2-disubstituted alkenes occurs
with high stereo- and regioselectivity: enynamides (E)-1b/c
gave predominantly the (E)-1,4-dienes 5b and 5c, with minor
amounts of 1,3-diene and only traces of (Z)-1,4-diene, while
reaction of enynamides (Z)-1b/c also afforded 5b and 5c as the
major products, but now with minor amounts of (Z)-1,4-diene
and only traces of 1,3-diene.15 The equivalent cyclization of
(Z)-1c under ruthenium catalysis led to a contrasting product
ratio, with (Z)-1,4-diene 6c being the major product. As this
latter cyclization likely proceeds through a ruthenacycle
intermediate,16 this differing selectivity already seemed
suggestive of distinct mechanistic pathways.
On the basis of our own experimental observations,8 we
questioned whether enynamide cyclizations could offer new
insight into this mechanistic puzzle, and a deeper under-
standing of the high stereoselectivity that can be achieved in the
cyclizations. We report here studies that offer compelling
evidence for palladium(II) hydride intermediacy in enynamide
cycloisomerization under Pd(OAc)2/bbeda catalysis, including
the discovery of significant kinetic isotope effects, the influence
of water and the nature of the precatalyst on the reaction
pathway, and three distinct processes that depend on bbeda.
Alongside this, theoretical analysis of the reaction mechanism
rationalizes reaction stereoselectivity, and leads to the proposal
of a new mechanism for hydropalladation.
We also observed very high levels of substrate stereocontrol
in cycloisomerizations that generate new stereocenters (Table
1). Entry 1 shows the influence of a substituent adjacent to the
ynamide nitrogen atom, which gave a single regio- and
stereoisomer of pyrrolidine enamide 5d. The formation of
trisubstituted piperidine enamide 5e (Entry 2) proceeded with
equivalent stereoselectivity, but reduced regioselectivity, with
small amounts of 1,3- and 1,5-diene produced alongside the
(E)-1,4-diene 5e. The formation of a 1,5-diene may reflect a
reversible β-hydride elimination in the final step of the catalytic
pathway, as is often seen in Heck reactions. A disubstituted
enynamide tether also led to exceptional stereocontrol in the
formation of tetrasubstituted pyrrolidine 5f (Entry 3).17 Entries
4 and 5 depict cyclizations that generate quaternary stereo-
centers with remarkable stereocontrol, with pyrrolidines 5g and
5h formed as single isomers. The exquisite stereoselectivity
imparted in these cyclizations can be rationalized by a
theoretical analysis of the reaction pathway (see below), in
which the irreversible cyclization step operates with very high
levels of stereocontrol.
RESULTS AND DISCUSSION
■
Reaction Optimization and Regio-/Stereoselectivity
Observations. A screen of palladium-catalyzed enyne cyclo-
isomerization conditions4−6 had revealed that cyclization of
enynamide 1a to amidodiene 4a (Scheme 3a) could best be
effected using Pd(II) precatalysts, with Pd(OAc)2/bbeda
offering superior reactivity.8,13 Pd2dba3·CHCl3/AcOH systems
gave poor conversion unless employed in combination with
bbeda, which effected rapid conversion of 1a to 4a, albeit at
higher temperature. Cyclization of enynamide 1a under Ru
catalysis (5 mol% Cp*Ru(cod)Cl in MeCN)14 provided a
Deuterium Crossover Experiments/1H NMR Spectro-
scopic Reaction Profiling. Deuterium crossover experiments
could offer insight as to whether an inter- or intramolecular
hydride transfer takes place; the former would suggest
involvement of a discrete palladium hydride species, while the
B
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Table 1. Diastereoselective Cycloisomerizations of
a
Enynamides with Substituted Tethers
Figure 1. 1H NMR spectroscopic profiles of reaction of enynamide 1a,
and deuterated enynamide D-1a. Graphs a−c show the conversion of
1a (blue) to 4a (red); reaction conditions are indicated. Graph d
shows the conversion of D-1a (blue) to 4a (red) and D-4a (green);
total product formation is shown in gray.21
a
Reaction conditions: 5 mol% Pd(OAc)2, 5 mol% bbeda, toluene
b
(0.167 M), 60 °C, 30 min; entry 2 reaction time = 90 min. Isolated
c
yield. Ratio of 1,3-:1,4-:1,5-dienes as determined by 1H NMR
spectroscopic analysis of the crude reaction mixture.
latter would be more consistent with a metallacycle pathway.
To explore this, deuterated toluenesulfonyl enynamide D-1a
(>98% D)18 and non-deuterated p-nitrobenzenesulfonyl enyn-
amide 1i were reacted in a 1:1 ratio using each of the catalyst
systems (Scheme 4). With Pd2dba3·CHCl3/AcOH/bbeda,
species, formed through oxidative addition of Pd(0) with acetic
acid;3b,6,20 whereas the ruthenium-catalyzed reaction likely only
requires ligand exchange of cyclooctadiene and the substrate in
the Cp*Ru(I)(L)2 complex. A marked difference in reaction
profile was observed with Pd(OAc)2/bbeda (graph c): despite
this being a superior catalyst system (compared to the other
catalysts) in terms of conversion and scope, this reaction
exhibited a distinct induction period that presumably relates to
the generation of an active catalyst species from Pd(OAc)2. The
conversion of D-1a to the deuterated product D-4a was also
monitored (graph d): this reaction required a much extended
reaction time to reach full conversion compared with non-
deuterated1a, revealing significant deuterium isotope effects
(vide infra). Of greater intrigue was the observation that the
extent of product deuteration changed during the reaction. At
early stages, only protiated product was produced (red curve),
whereas at later stages, the deuterated product was formed
almost exclusively (green curve)in this case leading to a drop
of deuterium incorporation from 100% D in the starting
material D-1a, to ∼70% in the product D-4a.
This result led us to speculate that water has a crucial impact
on reaction progress and product formation, with deuterium
loss arising from an exchange process with water present in the
NMR reaction solvent. We therefore set about comparing the
reaction profiles of 1a and D-1a using d8-toluene containing
varying concentrations of water (determined by Karl Fischer
titration); the results of these collected experiments are
illustrated in Figure 2. Non-deuterated 1a was first tested
using pre-dried d8-toluene as solvent (dried for several days
over 4 Å molecular sieves, 3 ppm H2O).22 We found that a
somewhat extended reaction time was required to reach
completion (Figure 2, graph HA) compared to the reaction
using “bottle” d8-toluene (82 ppm of H2O, graph HB),
indicating a beneficial effect of water on reaction rate. This
trend extended to water-saturated d8-toluene (480 ppm, graph
Scheme 4. Deuterium Crossover Experiments
complete crossover of the deuterium label was observed. In
contrast, under ruthenium catalysis, no crossover occurred and
D-4a was isolated with 83% D incorporation (supporting an
intramolecular hydride transfer pathway). Finally, products 4a
and 4i arising from the equivalent Pd(OAc)2/bbeda experiment
also featured nearly equivalent amounts of deuterium
incorporation (43 and 44% respectively), thus supporting
intermolecular transfer of hydride via a discrete Pd−H/D
intermediate under both palladium-catalyzed reaction con-
ditions.
To compare the three reaction manifolds in more detail, we
next monitored the cyclizations of 1a using 1H NMR
spectroscopy. Under Pd2dba3·CHCl3/AcOH/bbeda or Cp*Ru-
(cod)Cl catalysis (Figure 1, graphs a and b), immediate
conversion of starting material to product was observed,
sugggesting that a catalytically competent species is present, or
rapidly formed, at the start of the reaction.19 In the case of
Pd2dba3·CHCl3, this is presumably a palladium(II) hydride
C
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1
Figure 2. (a) H NMR spectroscopic reaction profiles of 1a (graphs HA−HD) and D-1a (graphs DA−DD) using dry, bottle, and H2O- or D2O-
saturated d8-toluene as reaction solvent. Graphs HA−HD show the conversion of 1a (blue) to 4a (red) and D-4a (green). Graphs DA−DD shows
the conversion of D-1a (blue) to 4a (red) and D-4a (green); total product formation is shown in gray. (b) Comparison of increasing water content
on reaction of enynamide 1a.21 All reactions run at 35 °C, 0.167 M in substrate, using 5 mol% Pd(OAc)2/bbeda.
HC), where a further acceleration was observed; a summary of
this effect is illustrated in Figure 2b. Interestingly, running the
reaction in d8-toluene saturated with D2O led to the
incorporation of a small amount of deuterium into the product
(graph HD), thus confirming that adventitious water can
indeed serve as a source of “hydride”. The equivalent reactions
of the deuterated substrate D-1a (graphs DA-DD) showed that
as the water (H2O) content of the reaction solvent increases, so
does the proportion of protiated product 4a (red curves in
graphs DA-DC), which is consistently and exclusively produced
at the start of all reactions. Notably, around 15% of protiated
product was produced in both reactions DA and DD, despite
the use of 100% deuterated substrate and a reaction medium
devoid of H2O. This observation was later to be rationalized
through discovery of the pathway for reaction initiation.23
The Role of Water. We hypothesized that water could
accelerate the reaction through involvement in the initiation
process. Bedford et al.24 recently characterized the influence of
water on Pd(OAc)2, which in organic solutions exists as a
trimeric complex [Pd3(OAc)6], a structure with D3h symmetry
featuring bridging acetate ligands.25 In the presence of water,
this trimer is in equilibrium with the [Pd3(OAc)5OH] (Figure
3a), in which one of the bridging acetate ligands has been
replaced by a bridging hydroxide ion.24 In increasingly water-
rich environments, a greater proportion of this complex is
formed, and we questioned whether this could act as a more
reactive pre-catalyst. To test this, [Pd3(OAc)5OH] was
prepared as reported by Bedford.24 Reaction of 1a with
[Pd3(OAc)5OH]/bbeda in pre-dried d8-toluene indeed showed
a reduced induction period (Figure 3a, red curve), compared to
[Pd3(OAc)6]/bbeda in H2O-saturated d8-toluene (blue curve),
suggesting that hydrolysis of [Pd3(OAc)6] is an important
process in reaction initiation. Interestingly, the post-initiation
rate of these reactions was similar, which may imply that a
common catalytic species forms from both pre-catalysts.
The Role of bbeda. Although Pd(OAc)2-catalyzed cyclo-
isomerizations can operate in the absence of bbeda, reactions in
1
which it is present reach completion more rapidly. H NMR
spectroscopic reaction profiles for the cycloisomerization of 1a
showed that bbeda-free reactions fail to reach completion after
>3 h (Figure 4, red curve), compared to ∼15 min in its
presence (blue curve). The appearance of these reactions also
differs markedly: in the absence of bbeda, black particulates
develop over time, as opposed to a consistent yellow color (and
Figure 3. Effects of water on the cycloisomerization of 1a to 4a
(product formation shown). (a) Structure of [Pd3(OAc)5OH].25b (b)
[Pd3(OAc)5OH]/bbeda in dried d8-toluene (red) and [Pd3(OAc)6]/
bbeda in H2O-saturated d8-toluene (blue). Reactions carried out with
5 mol% [Pd]/bbeda at room temperature.
Figure 4. Influence of bbeda on the cycloisomerization of 1a. (a)
Reaction profile in the presence (blue) and absence (red) of bbeda;
and a delayed bbeda addition (green). (b) Visual comparison of
bbeda-promoted and bbeda-free reactions.
D
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little or no particulate formation) in reactions containing the
imine. Possible roles of bbeda include that of a ligand which
accelerates the catalytic cycle,7f or a stabilizing component for
off-cycle palladium species. Interestingly, addition of bbeda
after 20 min reaction time to a bbeda-free reaction did not lead
to a marked acceleration (Figure 4, green curve) but did result
in a somewhat higher rate of reaction being sustained compared
to the bbeda-free reaction. Although these two reactions may
well operate by different pathways, this could indicate that
bbeda inhibits catalyst aggregation.
D-1a (graphs DA and DD, Figure 2). The reactions of a
number of other substrates deuterated at various positions did
not lead to any deuteration of the enamide alkene, suggesting
the substrate is not the origin of hydride. This left bbeda
itselfand a key observation of the production of small
amounts of benzaldehyde at early stages of our NMR
experiments.26 This aldehyde could arise from Lewis acid
(i.e., Pd(II)) promoted hydrolysis of bbeda by water in the
reaction solvent, a process that would release a primary amine
(9, Figure 6a), which could then undergo β-hydride elimination
From these experiments, it also seemed possible that bbeda
might also be involved in precatalyst deaggregation and/or
reaction initiation. To explore this, we titrated solutions of
[Pd3(OAc)5(OH)] and [Pd3(OAc)6] in anhydrous d8-toluene
with bbeda (Figure 5). A dramatic effect was seen on addition
Figure 5. Effect of bbeda on (a) [Pd3(OAc)5OH] and (b)
[Pd3(OAc)6]. Titrations performed in dry d8-toluene at room
temperature.
of even 0.25 equiv of bbeda to [Pd3(OAc)5(OH)] (titration a):
the 1H NMR signals corresponding to this complex at δH 1.70,
1.60, and 1.55 ppm shifted downfield (dashed arrows), and a
significant new signal appeared at 1.69 ppm (*). The
proportion of [Pd3(OAc)6] (+, 1.67 ppm) appeared to
increase; with addition of further bbeda, this peak was
consumed. Under these conditions, it thus seems that these
two complexes are in facile equilibrium, and that
[Pd3(OAc)5(OH)] is converted by bbeda to an unidentified
species, which we suggest to be a deaggregated complex. In
contrast, a solution of pure [Pd3(OAc)6] was barely affected by
bbeda until 1.0−1.5 equiv of ligand was added (titration b).
The greater susceptibility of [Pd3(OAc)5(OH)] to the action of
bbeda may explain the decreased induction period observed
when using this complex, or [Pd3(OAc)6] in water-rich
reactions (see Figure 3); however, the dramatically enhanced
rate of reactions run in the presence of bbeda (Figure 4) yet
remained unexplained.
Figure 6. Bbeda as a source of hydride. (a) Proposed mechanism for
the formation of Pd(II)−H from bbeda. (b) Use of d4-bbeda leads to
complete deuteration of D-4a from D-1a. (c) Use of d4-bbeda leads to
partial deuteration of 4a from 1a.21 (d) Use of d4-bbeda with enyne 12
also leads to partial deuteration of 13.
to generate palladium(II) hydride. Tautomerization of the
resulting imine 10 to the corresponding enamine could then
release further hydrogen atoms. For water-free reactions (where
only traces of benzaldehyde were observed), nucleophilic
activation via addition of acetate to Pd(II)-complexed bbeda
could lead to an aminal (11) that could also be susceptible to β-
hydride elimination.
To test this, d4-bbeda was prepared by reaction of d4-
ethylenediamine with benzaldehyde.18 To our delight, cyclo-
isomerization of D-1a in dry toluene using d4-bbeda afforded
D-4a with >98% deuteration (Figure 6b), thus supporting the
proposal that bbeda itself is the source of hydride in the initiation
pathway, and explaining the formation of protiated product in
experiments using D-4a and h4-bbeda. Furthermore, reaction of
the protiated substrate 1a in dry toluene with d4-bbeda (5 mol
%) led to a low level of product deuteration (15%),27
Initiation Pathway. Although we had now identified a
number of different factors that influenced the rate of initiation,
the source of the putative palladium(II) hydride remained a
mystery, particularly given the consistent low levels of protiated
product observed under anhydrous/protium-free reactions of
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reinforcing this hypothesis (Figure 6c). Equally importantly, we
also observed deuterium incorporation (15%) using enyne 12
(87% yield), thus supporting this process as a general
mechanism for initiation of enyne cycloisomerization using
Pd(OAc)2/bbeda (Figure 6d).
Batch Dependency. During these investigations, we also
uncovered a critical dependence of the stereochemical outcome
of the reaction on the batch of Pd(OAc)2 employed as catalyst.
This discovery was made through the chance purchase of
Pd(OAc)2 from a different supplier, which led to an unexpected
ratio of enamide alkene geometries ((Z):(E)-4a = 80:20),
rather than the typical ratio of ∼97:3. Screening of further
samples of Pd(OAc)2 gave variable results, the most extreme
being a reversal of stereoselectivity to 40:60 in favor of the (E)-
isomer. This batch-dependency was soon explained upon
Figure 8. 1H NMR spectroscopic reaction profile for conversion of 1a
to (Z)-4a and (E)-4a catalyzed by [Pd3(OAc)5)(NO2)]/bbeda, in pre-
dried d8-toluene at 35 °C, and X-ray crystal structure of
Pd3(OAc)5NO2.25a
1
acquisition of H NMR spectra of the various catalysts: while
our original bottle of Pd(OAc)2 exhibited a 1H NMR spectrum
(in CDCl3) characteristic of pure Pd(OAc)2 (Figure 7, batch 1,
catalyst did not result in alkene isomerization, suggesting that
the two isomers arise during the cycloisomerization as a
consequence of a divergent reaction mechanism, rather than
through product isomerization. While the mechanistic origin of
this isomer mixture remains unknown, recent studies on alkyne
semireduction using Pd(PEt3)4 and formic acid suggest that
isomerization of alkenylpalladium complexes formed through
hydropalladation can be facile.30
Computational Analysis of the Reaction Pathway.
With significant experiemental evidence for the intermediacy of
palladium(II) hydride species in hand, we set out to explore the
reaction pathway from a theoretical perspective to establish
whether a hydropalladation reaction mechanism would prove
energetically feasible. In addition, we hoped to rationalize the
stereoselectivity of the reaction, and to gain insight into the
observed kinetic isotope effects.31 Density functional theory
(DFT) and local coupled cluster calculations were performed
with Gaussian09 rev D.01 and with Orca v4.32 The meta-
generalized gradient approximation (meta-GGA) TPSS ex-
change-correlation functional33 was used for all geometry
optimizations34 with density fitting for Coulomb integrals (RI-
J), a fine integration grid and the Karlsruhe def2-TZVP basis set
for all elements.35 A quasi-harmonic approximation36 was used
in which the treatment of vibrational entropies switches from a
rigid-rotor harmonic oscillator to a free rotor at frequencies
below 100 cm−1, implemented in Python.37 Dispersion effects
were included by a Becke−Johnson damped D3-correction38
and solvation effects by an SMD description of toluene.39
Single point energy calculations were also performed with
hybrid meta-GGA functionals (M06 and PW6B95-D3), and
with the DLPNO-CCSD(T) local coupled cluster method for
comparison.40 The energy profile is qualitatively consistent
across the different methods, and the RMSD between between
TPSS-D3 and DLPNO-CCSD(T) energies over the entire
catalytic cycle is only 2.9 kcal/mol. Computed diastereo-
selectivities are consistent within 1 kcal mol−1 across different
levels (see the Supporting Information (SI) for full details).
The putative catalytic cycle, involving hydropalladation,
migratory insertion and β-hydride elimination steps, was
obtained with a monomeric Pd-catalyst41 with a single acetate
ligand, using model system 1j (Figure 9), which closely
resembles substrate 1a with the alkyne substituent (n-Hex in
1a) represented by a methyl group.
1
Figure 7. H NMR spectra (CDCl3) of batches of Pd(OAc)2, and
batch-dependent product ratios for cycloisomerization of 1a.
a singlet corresponding to the D3h-symmetric [Pd3(OAc)6]
trimer, minor peaks arise from [Pd3(OAc)5OH]),25a other
samples showed increasing amounts of an impurity (batches 2
and 3), with the worst product ratio arising from samples devoid
of [Pd3(OAc)6]. This latter batch in fact consisted solely of
[Pd3(OAc)5(NO2)], an impurity common in Pd(OAc)2 that
arises from its method of production, as previously
characterized by Cotton and Murillo.25a,28 The ability of this
“impurity” to mediate palladium-catalyzed reactions has been
documented, albeit in many cases its presence does not affect
the reaction outcome;29 the observation of such a significant
overturning of product selection is, to our knowledge,
unprecedented. The synthesis of pure Pd(OAc)2 from
Pd(NO3)2 and NaOAc as reported by Stolyarov and co-
workers28 offers a convenient solution to this problem, and
delivers palladium(II) acetate of purity equivalent to the
1
original supply; H NMR spectroscopic analysis of subsequent
commercial batches of Pd(OAc)2 gave reassurance that these
would behave as expected. Interestingly, monitoring of the
reaction of 1a with [Pd3(OAc)5(NO2)]/bbeda (Figure 8)
revealed that reactions with this catalyst proceeded at a
somewhat lower rate than pure Pd(OAc)2/bbeda, and that the
isomeric ratio of enamide products remained consistent
throughout the reaction. Submission of pure (Z)-4a to this
Hydropalladation occurs from the Pd(0) acetic acid complex
A. The expected palladium(II) hydride complex was found to
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Figure 9. SMD-TPSS-D3/def2-TZVP//TPSS/def2-TZVP energy profile for the catalytic cycle of the cycloisomerization.
Figure 10. DFT calculations rationalize the stereochemical outcome of the anti-diastereoselective cycloisomerization of enynamide 1k.
be significantly less stable at all levels of theory, by 21.4−33.1
kcal mol−1.42 As hydropalladation takes place to give B, transfer
of the hydrogen atom to the β-carbon of the ynamide is
facilitated by an agostic interaction with the metal (TS_AB,
ΔG⧧ = 7.4 kcal mol−1), suggesting that a discrete palladium(II)
hydride is not formed, or is not located as an energy minimum
on the potential energy surface; in effect, oxidative addition to
Pd(0) by acetic acid, and hydropalladation, take place as a
single concerted process from the favored substrate-bound
Pd(0)(HOAc) complex. As well as representing a new pathway
for alkyne hydrometalation, complex A also accounts for the
facile exchange of H/D with water in the reaction solvent (and
with hydrolyzed bbeda) which can thus be mediated by acetic
acid rather than requiring a specific isotope exchange process at
the metal. It also accounts for the difficulty in detecting elusive
palladium(II) hydride species by 1H NMR spectroscopy, and is
consistent with the notion that oxidative addition of Pd(0) into
acetic acid is rapid and reversible.20b Subsequent to this
irreversible hydrometalation to give B, the metal then effects
carbopalladation of the alkene (TS_BC, ΔG⧧ = 16.9 kcal
G
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mol−1), leading to an alkylpalladium species C that remains
complexed to the enamide alkene. Carbopalladation is also
irreversible at all levels of theory considered, and is followed by
rate-limiting β-hydride elimination (TS_C′D, ΔG⧧ = 20.4 kcal
mol−1), a process that first requires endothermic enamide
decomplexation and C−C bond rotation in order to position
the C−Pd bond syn-coplanar with the C−H bond (C → C′).
The degree of reversibility of β-hydride elimination is
challenging to assess, as it depends on the kinetics of product
dissociation from the resultant (alkene)Pd(H)(OAc) complex
(D or E), and complexation with the next molecule of
substrate. This is in part likely to be product dependent, as only
in certain cases is alkene isomerization observed in the product.
Formation of product-bound Pd(0)(HOAc) complex E from D
is facile, with a barrier of 2.1 kcal/mol. This is true across all
levels of theory, where the barrier for this step ranges from 1.7−
4.2 kcal/mol. In TS_DE the κ2-acetate rotates out of the plane
to adopt a κ1-coordination mode bound cis to the hydride (see
the SI for full details).
The calculated energy profile of 1j is consistent with room
temperature reactivity:43 the energetic span of the computed
catalytic cycle (20.4 kcal mol−1) is commensurate with a t1/2 of
3 min. To compute the KIEs we applied the Bigeleisen−Mayer
equation with a parabolic tunneling correction based on scaled
TPSS/def2-TZVP harmonic frequencies at 35 °C.44 Our
calculations predict a primary KIE for β-hydride elimination
of 2.225,45 an inverse secondary KIE of 0.916 for
carbopalladation, and a primary KIE for alkyne hydro-
palladation of 4.689 (12.671 with a parabolic tunneling
correction). The latter value may reflect the trifurcated nature
of bonding to the hydrogen atom in the hydropalladation
transition state TS_AB.46
The stereoselectivity of the cyclization of enynamide 1e (see
Table 1, entry 1) was next modeled using substrate 1k (Figure
10). The carbopalladation substrate derived from 1k exists in
two energetically similar conformations: 14-anti and 14-syn,
the diastereomeric transition states from which (TS-15-anti
and TS-15-syn) lead to products anti-16 (the observed
outcome) and syn-16 respectively. A free energy difference
between these transition states of ΔΔG⧧ = 3.4 kcal mol−1
corresponds to a calculated diastereoselectivity of >180:1,47
which is consistent with the observed reaction outcome. The
energy difference between these transition states (consistent
with M06 and DLPNO-CCSD(T), as discussed in the SI) can
be rationalized by changes in torsional strain upon
carbopalladation of the alkene by the alkenylpalladium
complex: in the case of transition state TS-15-anti, this strain
is relieved as carbopalladation proceeds (from the eclipsed C−
H bonds to red and green hydrogens in 14-anti). For the
alternative transition state TS-15-syn, eclipsing interactions
increase during this step (from the staggered C−H bonds to
red and green hydrogens in 14-syn).48
Scheme 5. Primary KIE for β-Hydride Elimination
generate 1,3-diene products. The ratio of 1,3:1,4-dienes (4b: D-
5b/D-6b, as determined by integration of appropriate peaks in
the 1H NMR spectrum)50 was found to be 8.09, compared to a
ratio of 3.54 for (E)-1b, which gives an experimental KIE for β-
hydride elimination of 2.29. This value is consistent with other
reports on β-hydride elimination from alkylpalladium com-
plexes, and with the computed value (2.07 at 60 °C; 2.23 at 35
°C for model substrate 1j).45,49,51
While the isotope effect associated with β-hydride elimi-
nation is consistent with computation and with literature
values, the overall difference in reaction rate between substrates
1a and D-1a at typical catalyst loadings of 5 mol% is not
explained by β-hydride elimination alone. Although negligible
KIEs would be expected from the hydropalladation and
carbopalladation steps, it seemed possible that off-cycle
equilibrium processes might be affected by the difference in
activation energies between hydro- and deuteriopalladation.
The path from product decomplexation to substrate association
(and subsequent irreversible hydropalladation) could involve
complexation of palladium by bbeda, or its hydrolysis product,
or catalyst re-aggregation (to dimeric or trimeric complexes).
These processes would be expected to depend on catalyst
concentration,52 with hydropalladation perturbing the equilibria
by effectively sequestering monomeric “active” Pd(0)(AcOH).
This indeed turned out to be the case. The relative rates of
reaction of substrates 1a and D-1a were compared at various
catalyst concentrations (by observation of the post-induction
regions of reactions such as HA and DA, see Figure 2, once the
production of protiated product has plateaued in reactions
involving D-1a). The rates of cyclization of each substrate were
measured at five different catalyst loadings (0.5, 1, 2.5, 5, and 10
mol%, Figure 11a), with each experiment run in triplicate. The
rate constants for both substrates, and their associated errors
(one standard deviation) are shown in the table in Figure 11.
Plateau effects were observed for both substrates at higher
catalyst concentrations:52 for 1a, this occurs at or above 5 mol
%, while for D-1a, at or above 2.5 mol%. We speculate this may
be related to the difference in energy barriers for hydro- vs
deuteriopalladation, which in the latter case could increase the
extent of off-cycle catalyst sequestration, compared to substrate
complexation and entry to the catalytic cycle. The dominance
of hydropalladation at early reaction stages using D-1a adds
support to the influence of this step on entry to the catalytic
cycle. In addition, this data allowed us to determine the order of
Experimental Observations on Isotope Effects.49 The
data collected in the time course experiments indicate the
influence of several isotope effects, resulting in marked
differences in reaction rate and isotope incorporation as the
reaction proceeds. We now turned to correlation of our
computational work with these experimental observations, in
particular the KIE for the rate-determining β-hydride
elimination. This was achieved by comparison of the product
distribution from disubstituted alkene (E)-1b with that of its
deuterated equivalent (E)-D-1b (Scheme 5, >98% D, E:Z >
20:1), where β-deuteride elimination is required for the latter to
reaction with respect to the metal catalyst. A plot of ln(kobs
)
against ln([Pd(OAc)2]) showed a linear relationship (Figure
11b), supporting the proposal of a monomeric palladium
species as the active catalyst.53
Alongside this, we were intrigued to observe that the rate of
cycloisomerization of (Z)-D-1b exceeded that of (Z)-1b
H
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Scheme 6. Pd-Catalyzed Cycloisomerization: Overview
Figure 11. Dependence of reaction rate on catalyst concentration. kH
and kD are given in units of 103 mol dm−3 s−1. Errors of one standard
deviation are shown. (a) kH(obs) and kD(obs) at different catalyst
concentrations; table shows values and ratios of observed rate
constants. (b) Plot of ln(kH(obs)) against ln[Pd(OAc)2] shows first-
order dependence with respect to the catalyst. See the SI for further
details.
(Figure 12); comparison of the steady-state regions of these
reactions (6−11 min) gave a gradient ratio of 0.87 ( 0.01).
liberates benzaldehyde and amine complex 17, which under-
goes β-hydride elimination to form Pd(II)−H complex 18a
(this process could also be promoted by addition of acetate, see
Scheme 6a). Throughout the reaction, additional bbeda (or the
derived amine ligand) could stabilize off cycle Pd(II) species
(19), thereby prolonging catalyst lifetime. The resultant
L2Pd(II)H(OAc) complex 18a is in equilibrium with L2Pd(0)-
(κ2-HOAc) 18b, with the latter form predicted computationally
to be favored on binding the enynamide substrate (A), and
required for hydropalladation.54 Notably, acetic acid complex
18b also explains the facile exchange of H/D with water. The
substrate-complexed Pd(0) catalyst (A) then effects an
irreversible “oxidative hydropalladation” of the alkyne compo-
nent (to give B), followed by irreversible carbopalladation with
a pseudo-axially oriented alkene group. The resulting
alkylpalladium(II) species (C) offers a possible resting state
of the catalyst; further reaction requires an endergonic
decomplexation of the enamide from the metal, C−C bond
rotation, and agostic coordination of the bridgehead hydrogen
atom (C′). β-Hydride elimination then proceeds rapidly and
potentially reversibly, delivering a Pd(II)H(OAc)(alkene)
complex (D) that is in equilibrium with Pd(0)(AcOH) (E).
Finally, we note that although original proposals for different
reaction pathways using Pd(II) or Pd(0) precatalysts were
based on observed differences in reaction outcomes or product
distributions, we suggest that these may relate more to the
influence of the specific ligand environment around the metal
center, rather than the cycloisomerization pathway itself.
Figure 12. Isotope effect from alkene deuteration.21
The reason for this secondary KIE is not clear: with the
theoretical pathway indicating carbopalladation to be non-rate-
determining, we suggest that this effect could relate to
differences between the two isotopes in agostic interactions,
or hyperconjugation effects during the enamide decomplex-
ation/β-hydride elimination steps, or during product decom-
plexation.
DISCUSSION
■
The above experimental and theoretical studies provide strong
support for a hydropalladation mechanism for Pd(OAc)2/
bbeda-catalyzed enynamide cycloisomerization. A full outline of
the proposed reaction pathway is illustrated in Scheme 6.
Reaction initiation entails a number of processes, commencing
with a water-promoted Pd3(OAc)6 equilibrium with
[Pd3(OAc)5(OH)], the latter of which undergoes bbeda-
assisted deaggregation, presumably to give a monomeric
[(bbeda)Pd(OAc)2] complex. Partial hydrolysis of this complex
I
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(3) (a) Trost, B. M. Acc. Chem. Res. 1990, 23, 34−42. (b) Trost, B.
M. Chem. - Eur. J. 1998, 4, 2405−2412.
CONCLUSION
■
Palladium-catalyzed enyne cycloisomerization is a fundamen-
tally important reaction manifold in this field of ring synthesis.
Despite the utility of the Pd(OAc)2/bbeda catalyst system,
mechanistic understanding has remained elusive. Through
extensive NMR studies with deuterated substrates, we have
uncovered the crucial influences of water, the precatalyst, and
the ligand itself in this reaction. Our demonstration that bbeda
itself serves as a source of Pd(II)−H, combined with theoretical
analysis of the reaction pathway correlated with experimental
isotope effects, offers a new level of understanding of this classic
cyclization process, and offers enhanced understanding for the
design of applications of this chemistry in stereoselective
synthesis.
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(13) See the SI for full details of reaction optimization.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b05436.
■
S
Experimental details of NMR time course experiments,
characterization of novel compounds, H and 13C NMR
1
spectra, and additional experimental details (PDF)
AUTHOR INFORMATION
Corresponding Authors
*robert.paton@chem.ox.ac.uk
*edward.anderson@chem.ox.ac.uk
ORCID
Alan Steven: 0000-0002-0134-0918
Robert S. Paton: 0000-0002-0104-4166
Edward A. Anderson: 0000-0002-4149-0494
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to Prof. Barry Trost on the occasion of
his 75th birthday. E.A.A. thanks the EPSRC (EP/K005391/1,
EP/H025839/1) for support. R.S.P. thanks the Chemical
Structure Association Trust. We acknowledge the use of the
EPSRC UK National Service for Computational Chemistry
Software (CHEM773) in carrying out this work. A.M. thanks
the Royal Thai Government and the DPST project for a
studentship. A.C.-R. is grateful to the Spanish MINECO for an
FPI fellowship. We also thank Dr. John M. Brown for valuable
discussions on isotope effects.
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DOI: 10.1021/jacs.7b05436
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