Development and Mechanistic Interrogation of Interrupted Chain-Walking in the Enantioselective Relay Heck Reaction

Article abstract of DOI:10.1021/jacs.0c03589

The formation of alkyl-palladium complexes via the nucleopalladation of alkenes is the entry point for a wide range of diverse reactions. One possibility is that the intermediate alkyl-Pd complexes can undergo a "chain-walking"event, to allow for remote functionalization through various termination processes. However, there are few methods to selectively interrupt the chain-walking process at a prescribed location. Herein, we demonstrate that a variety of homoallylic protected amines undergo an interrupted enantioselective relay Heck reaction to give enantioenriched allylic amine products. The selectivity of this process can be diverted to exclusively yield the ene-amide products by virtue of changing the nature of the amine protecting group. To rationalize this observation, we combine experiment and computation to investigate the mechanism of the chain-walking process and termination events. Isotopic labeling experiments and the computed reaction pathways suggest that the system is likely under thermodynamic control, with the selectivity being driven by the relative stability of intermediates encountered during chain-walking. These results illustrate that the chain-walking of alkyl-palladium complexes can be controlled through the alteration of thermodynamic processes and provides a roadmap for exploiting these processes in future reaction development.

Full text of DOI:10.1021/jacs.0c03589

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Article
Development and Mechanistic Interrogation of Interrupted
Chain-Walking in the Enantioselective Relay Heck Reaction
Sean P. Ross, Ajara A. Rahman, and Matthew S Sigman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03589 • Publication Date (Web): 15 May 2020
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Development and Mechanistic Interrogation of Interrupted Chain-
Walking in the Enantioselective Relay Heck Reaction
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Sean P. Ross, Ajara A. Rahman,† and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah, 84112, United States
ABSTRACT: The formation of alkyl–palladium complexes via the nucleopalladation of alkenes is the entry point for a wide
range of diverse reactions. One possibility is that the intermediate alkyl–Pd complexes can undergo a “chain-walking” event,
to allow for remote functionalization through various termination processes. However, there are few methods to selectively
interrupt the chain-walking process at a prescribed location. Herein we demonstrate that a variety of homoallylic protected
amines undergo an interrupted enantioselective relay Heck reaction to give enantioenriched allylic amine products. The
selectivity of this process can be diverted to exclusively yield the ene-amide products by virtue of changing the nature of
the amine protecting group. To rationalize this observation, we combine experiment and computation to investigate the
mechanism of the chain-walking process and termination events. Isotopic labeling experiments and the computed reaction
pathways suggest that the system is likely under thermodynamic control, with the selectivity being driven by the relative
stability of intermediates encountered during chain walking. These results illustrate that the chain-walking of alkyl–
palladium complexes can be controlled through the alteration of thermodynamic processes and provides a roadmap for
exploiting these processes in future reaction development.
Introduction:
ultimate trapping of II with CO2 to yield carboxylic acid D
(Figure 1b).47 Clearly, a significant expansion in the scope
of remote functionalization would be the ability to
intercept the chain walking event at a prescribed position
along the alkyl chain.
Alkene functionalization reactions using π-Lewis acidic
metals, such as Pd(II), are often initiated by the addition of
a nucleophile to the ligated alkene to form a metal-alkyl
intermediate.1 This intermediate can either undergo β-
hydride elimination to reform an alkene (e.g., Heck or
a) remote alcohols terminate the chain-walking process via oxidation
Pd(II)
PyrOx
H
Wacker type reactions), undergo
a
subsequent
H
OH
R3
O
O
R3
[Ox]
-Pd0
R2
Ar
organometallic reaction to ultimately be classified as an
Ar
R2 R1
R3
[Pd]
n
n
R2 R1
n
R1
ArB(OH)2
1-4
alkene difunctionalization reaction,
or the metal can
A
I
B
migrate away from the newly formed bond through
b) Termination of chain-walking by external reagent
iterative β-hydride elimination/migratory insertion
12
processes5-10 (often referred to as “chain-walking”).11,
Ni(II)
Bipy
CO2
H2O
Chain-walking strategies allow for either the regeneration
of the unsaturation remotely, or incorporation of an
R
R
R
H
[Ni]
CO2H
n
n
n
CO2
H2O
II
C
D
external reagent by
a
terminating organometallic
transformation at a site distant from the initial bond
c) homoallylic phthalimides give rise to allylic product
forming event.13-15
O
NPhth
NPhth
Pd(II)
The majority of these termination processes are directed
by the innate nature of the substrate.16-21 As an example, our
group,22-36 as well as others,37-45 have used redox acceptors
to promote the terminating step. In particular, alkenyl
alcohols A have been widely used wherein the alcohol is
ultimately converted into the corresponding carbonyl
product B through a formal oxidation event (I to B, Figure
1a). Contrastingly, Martin,46-48 Marek,49, 50 Mazet,51, 52 Zhu,53-
55 and others,56-63 have used an organometallic step, which
often occurs at the termini of the alkyl chain, to trap the
chain walking process. As a specific example, the remote
functionalization of alkene C is initiated by migratory
insertion into a Ni-H followed by chain-walking and
PyrOx
N
vs
H
Ar
R1
Ar
R1
O
ArB(OH)2
F
R2
R2
G
R2
E
R1
(not formed)
NPhth
Figure 1. a) redox acceptors such as alcohols terminate the
chain-walking process by oxidation, b) termination of the
chain-walking process by external reagent, c) relay Heck
reaction to give allylic products using homoallylic
phthalimide substrates
In this context, we have discovered that a class of alkenyl
substrates, namely homoallylic trisubstituted protected
amines (for example, phthalimide E), undergo an
enantioselective Heck reaction to yield product F (Figure
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1c). Instead of relaying the unsaturation to form ene amide (2aa–2ab), electron donating and withdrawing
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products of type G, akin to the corresponding homoallylic
alcohols that form carbonyls, this chain-walking process is
interrupted to yield allylic phthalimides in a highly
selective manner. This surprising result leads to a range of
synthetic and mechanistic questions including: 1) what is
the synthetic scope of the process? 2) how does the
structure of the protected amine impact product selectivity
(ene amide vs interrupted chain-walking), and 3) what is
the mechanistic origin for the interrupted Heck process; is
it a consequence of thermodynamics or kinetics? Herein,
we investigate these questions in detail revealing that the
reaction has broad scope in terms of the aryl boronic acid,
functional group tolerance, and amine protecting group.
Additionally, through a combination of experimental and
computational techniques, we have explored the basis for
the interruption of the chain-walking process.
substituents at the 3- and 4- positions (2ac–g, 2ba–b, 2be–
f), and multiply substituted aryl boronic acids (2bc–d,
2bg–h). These results reveal several general trends. First, it
was found that the conversion of phthalimide 1b was
higher than 1a (compare 1ag and 1bf) presumably due to
the smaller methyl group. Second, the conversion (and
subsequently the yield) of the transformation is highly
dependent on the electronic nature of the aryl boronic acid
used. For example, electron-deficient boronic acids require
the reaction to be performed at 40 °C in order to achieve
desirable levels of conversion. This is presumably due to
the need to overcome the slower migratory insertion as a
function of using more electron deficient aryl boronic
acids. Fortunately, performing the reaction at elevated
temperatures does not cause an observable decrease in
enantioselectivity. Alternatively, electron-rich aryl boronic
acids were found to add at the newly formed disubstituted
alkene to give the 2:1 adduct 3 in low yield (see SI). The
absolute configuration of products 2a and 2b were
established by comparison of the hydrogenated analogue
of 2bg prepared by this route, and via the redox-relay Heck
reaction of the alcohol analogue of 1b (see SI). It should be
noted that when the standard conditions were applied to
bishomoallylic substate 4 an inseparable mixture of allylic
and homoallylic phthalimides (5a and 5b, respectively)
were formed in a 1.3:1 mixture (Table 1b). Lastly, 1,2-
disubstitued alkenes were found to give mixtures arising
from poor regioselectivity for arylation of the alkene (see
SI).
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Results and Discussion:
The
optimal
conditions
for
the
interrupted
enantioselective Heck arylation of trisubstituted
homoallylic allylic amine derivatives were found to be
similar to those reported for the arylation of homoallylic
trisubstituted alcohols24 with minor modifications (see
supporting information (SI) for details). The product of
this reaction contains a quaternary carbon center with an
appended allylic protected amine. Using these optimized
conditions, the scope of the arylboronic acid was explored
using homoallylic phthalimides 1a and 1b (Table 1a). The
reaction tolerates the use of unfunctionalized aromatics
Table 1. Scope of aryl boronic acid with homoallylic phthalimides 1a and 1b.
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a. For each entry the following notation is used: yield % (conversion %), enantiomeric ratio, reaction temperature. Aryl boronic
acid was added batch-wise in either two (room temperature reactions) or three (40 °C reactions) portions. b. ratio of products
determined by NMR.
Scope of functional group on the alkene. We next
turned our attention to probing the effect of functional
groups attached to the alkene on the reaction outcome
(Table 2). It was found that azides (2c), nitriles (2d),
halides (2h), tosylates (2f), malonates (2g), protected
alcohols (2e, 2j), and protected amines (2i) are all
compatible with the reaction. In general, the yields are
modestly diminished when compared to unfunctionalized
substrates, but the enantioselectivity remains high. The
ability to use electrophiles such as 2e and 2h allows for the
introduction of a wide scope of additional functionality.
Additionally, the use of malonate 2g highlights the
compatibility of this reaction with competing
intramolecular nucleophiles. It should be noted that a
coeluting isomeric product arising from addition of the
aryl group to the internal carbon of the alkene was formed
in low yields (up to 15%, see table 2).
Table 2. Scope of non-participating functional groups.
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Table 3. Scope of compatible functional groups at the
termini.
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For each entry the following notation is used: yield %
(conversion %), enantiomeric ratio, reaction temperature.
Aryl boronic acid was added batch-wise in either two (room
a
temperature reactions) or three (40 °C reactions) portions.
b
isolated in 90% purity, isolated in 95% purity, c isolated in
85% purity.
Scope of “acceptor” groups. Having established the
scope of the reaction in terms of aryl boronic acids (Table
1) and attached functional groups on the alkene (Table 2),
we next explored what other amine derivatives at the
termini were capable of selectively forming the allylic
product (Table 3). We focused our attention on groups that
contained useful N-protecting groups, or desirable
heterocycles. For example, bisprotected amines (2k–m),
monoprotected amines (2o–2r), hydantoins (2n), isatin
(2s), and indolinone (2t) are compatible. This greatly
increases the scope of this transformation to include
protected primary amines with or without orthogonal
protecting groups, as well as protected secondary amines.
Alkylated amines with trifluoroacetamide (2o, 2p) and
sulfonamide protecting groups (2q, 2r) are compatible,
which can be readily removed to give rise to allylic
secondary amines. Additionally, the N–alkyl substituent
tolerates both primary (2o, 2q) and tertiary (2p, 2r)
substituents. Notably, the remote stereocenter in 2p does
not influence the enantioselectivity of the transformation.
Finally, the enantioselectivity of these transformations
remains high regardless of the nature of the group at the
amine.
For each entry the following notation is used: yield %
(conversion %), enantiomeric ratio, reaction temperature.
Aryl boronic acid was added batch-wise in either two (room
temperature reactions) or three (40 °C reactions) portions.
Formation of ene products. In each example reported in
tables 1–3, there was no detectable amount of the isomeric
ene products. However, when N-methyl acetamide 1u was
subjected to the standard reaction conditions, the
bisarylated ene-amide 2u was unexpectedly formed in
moderate yield (44%), with none of the isomeric allyl
product. Doubling the amount of boronic acid to six
equivalents in the reaction resulted in a significantly
improved yield (67%, Table 4a). It was reasoned that the
cause for this switch in selectivity for the formation of the
ene amide type product compared to the structurally
similar trifluoroacetamide could either be due to the
significantly smaller size of the methyl group relative to the
trifluoromethyl group, or due to the more electron rich
carbonyl. To test these hypotheses, the pivaloyl amide 1v
and benzamide 1w were subjected to the reaction
conditions. In both instances, the ene-amides 1v and 2v
were formed exclusively in comparable yields and high
enantioselectivity. These results suggest that the difference
in the electron density of the amide carbonyl is responsible
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for this observed change in selectivity. To further probe the high, then the selective formation of the allylic product
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origin of the addition of two aryl groups, the formation of
2w was investigated at early time points using ex-situ
monitoring (Table 4b). If the initially formed ene-amide H
reacts at a comparable rate with 1w, then at early time
points only a small amount of 2w should be present.
However, at early conversions (<10%) only a trace amount
of a 1:1 adduct presumed to be H was evident, with the
primary product being 2w. This result suggests that the
ene-amide H reacts significantly faster than 1w.
would be under kinetic control. Differentiating between
these two scenarios could allow for insight into how to
design future systems.
Alternatively, the selective formation of the allyl product
could arise from direct involvement of the carbonyl (Figure
3b). For example, the carbonyl could deprotonate the
alkene bound Pd–H intermediate VI, displace the alkene
through ligand exchange (VII), or stabilize the
intermediate Pd–alkyl species (VIII) (Figure 2b). In each
case, the selective formation of the allylic product could
arise from the ability of each of these processes to occur
through a proposed six-membered palladacycle transition
state (VI and VII), or intermediate (VIII).
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Table 4. Scope of amide substrates
a) governed by thermodynamics or kinetics?
Ha He
-He
-Ha
Bu
Bu
Bu
N
Ph
Ph
[Pd]–H
[Pd]–H
Ph [Pd]
III
IV
V
b) is the carbonyl directly involved in the product determining step?
[Pd]
H
H [Pd]
[Pd]
O
O
O
vs
vs
N
N
N
VI
VII
VIII
O
O
O
Figure 2. Mechanistic hypotheses for the interrupted
chain-walking: a) kinetic and/or thermodynamic driven, b)
direct involvement of the carbonyl
Deuterium labeling experiments. On the basis of
previous mechanistic investigations from our group using
deuterium labeling studies to probe the chain-walking
process,64 we investigated the outcome of the reaction
when either of the two methylene subunits of the
homoallylic chain were deuterated (Figure 3). We began
with dideuterosubstrate 1x, which would allow us to probe
whether the reaction proceeds through the intermediacy
of Pd–D intermediate IX (Figure 3a). Subjecting 1x to the
standard reaction conditions resulted in the formation of
2x with no observable deuterium scrambling, as well as a
small amount of the double arylation product (see SI). This
suggests that if Pd–D alkene intermediate IX is formed,
that it exists in equilibrium amounts and no dissociation of
the Pd–D occurs from IX.
For each entry the following notation is used: yield %
(conversion %), enantiomeric ratio, reaction temperature.
Aryl boronic acid was added batch-wise in two portions.
Mechanistic investigations. Above it is demonstrated
that a wide variety of alkenyl amine derivatives selectively
undergo the redox relay Heck reaction to form allylic
products (Tables 1–3), while alkyl and aryl amides
selectively form ene products (Table 4). This observed
disparity led us to explore the mechanism by which the
terminal group imparts selectivity in the chain walking
process.
Importantly,
a
detailed
mechanistic
understanding could guide the future development of site-
selective termination of chain-walking processes.
Therefore, we employed a combination of experimental
and computational approaches to interrogate these
observations.
To confirm the dehydrogenation process occurs from the
allylic carbon, substrates 1y and 1z were subjected to the
reaction conditions (Figure 3b). This resulted in the
formation of monodeuterated products 2y and 2z with no
detection of deuterium scrambling, or dideutero-products.
This result suggests that the reaction is proceeding
through Pd–D alkene complex X, and the final product is
formed via dissociation of the ligated Pd–D or
deprotonation of the Pd–D. The formation of 2y and 2z also
rule out the possibility of an E2-type elimination occurring
from the alkyl-Pd complex IV (Figure 3c). Because the
migratory insertion and -hydride elimination processes
are stereospecific, the alkyl-Pd complex IV-DD would be
formed from 1y or 1z. The exclusive formation of the
monodeuterated alkene III-HD rules out an E2
We reasoned that the selectivity of these processes could
be a result of either the thermodynamics or kinetics of the
chain-walking process (Figure 2a). If the system is under
thermodynamic control, then the alkene ligated Pd–H
species III, alkyl–Pd complex IV, and alkene ligated Pd–H
species V could establish an equilibrium (Figure 2a). If this
were the case, then the selective formation of the allylic
products would be a result of the relative stability of III
compared to V. Alternatively, the selectivity could be
driven by the kinetics of the migratory insertion and -
hydride elimination processes. For example, if the barrier
for migratory insertion of the Pd–H to form IV, or the -
hydride elimination of Pd–He to form V were prohibitively
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elimination via deprotonation of the hydrogen anti to the
Pd to form III-DD.
Figure 3. Deuterium labeling studies: a) deuteration  to
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2
3
4
phthalimide, b) deuteration  to phthalimide, and c)
formation of monodeuterated product rules out an E2
elimination.
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Scheme 1. Computed reaction pathway of homoallylic phthalimides
14.0
14.0
+
+
10.4
9.7
+
+
Et
O
Ph
Pd
CF3
TS2-Phth
N
H
N
6.4
TS3-Phth
N
+
O
O
Ph
O
Et
Me
TS1-Phth
CF3
N
N
Pd
H
Int4-Phth
(ene only)
1.8
Et
O
N
+
0.0
O
+
O
Ph
CF3
N
O
N
N
deprotonation
or
dissociation
Int2-Phth
(allyl only)
Pd
O
O
CF3
deprotonation
N
O
N
N
O
or
Pd
dissociation
Ph
Pd–O 2.26 Å
O
Me Et
O
N
Me
Me
Et
E2 elimination
major product
E2 elimination
E2 elimination
Et
Int3-Phth
(allyl or ene)
N
Int1-Phth
(allyl only)
Ph
O
ruled out by
isotopic labelling
Ph
O
predicted to be cis alkene
(not formed)
DFT studies were performed at the IEFPCM(DMF)-M06/6-31+G(d)//M06/SDD-6-311+G(d,p) level of theory. All energies listed are
reported in kcal/mol. See the supporting information for details
DFT studies. In order to further understand the factors
that differentiate between the formation of the allyl and
ene products, we next turned to DFT calculations. The
reaction pathway was calculated for simplified substrate
analogues of phthalimide (Phth) 1a and N-
methyltrifluoroacetamide (TFA) 1o, both of which showed
high selectivity for formation of the allyl product, and N-
methylacetamide (Acet) 1u, which showed high selectivity
for formation of the ene product. Geometry optimizations
were performed with the SDD effective core potential
(ECP) for Pd and M06 functional and 6-31+G(d) basis set
for all other atoms. Solvent effects were added as energy
correction using the IEFPCM (DMF) implicit solvation
model at the M06/6-311+G(d,p) level (see SI). Since the
selectivity determining step would be determined after the
initial migratory insertion of the aryl-Pd complex, all
stationary points beyond this step were computed. The
results of these calculations are detailed in Schemes 1-5.
Potential energy surface of the relay Heck reaction
with homoallylic phthalimides. We began our
investigation with the homoallylic phthalimide (Scheme 1).
The phthalimide complex Int1-Phth was calculated to be
the most stable intermediate along the pathway. This is in
contrast to previous studies with an alcohol redox acceptor
in which the C–Pd and alkene-Pd–H complexes were found
to be more stable as the Pd migrated towards the redox
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23.7 kcal/mol
acceptor.64 The calculated energy barriers of the following
-hydride elimination and migratory insertion steps (TS1–
+
1
17.5 kcal/mol
2
3
4
5
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7
8
9
3-Phth) are relatively low, which suggests that the system
is under thermodynamic control. Notably, the allyl Pd–H
complex Int2-Phth and the ene Pd–H complex Int4-Phth
are relatively high energy intermediates, with low barriers
leading to either Int1-Phth or Int3-Phth. A possible
mechanism to account for the formation of the allyl
product is an E2 elimination to form Pd(0) from either
Int1-Phth or Int3-Phth. The lowest energy conformer of
Int1-Phth has a favorable anti-periplanar arrangement for
an E2 elimination to occur. However, this geometry would
lead to the formation of the unobserved cis alkene product.
Alternatively, an E2 elimination from Int3-Phth can be
ruled out by the isotopic labelling experiments discussed
in Figure 3c. Therefore, we computationally investigated
the possible mechanisms for loss of Pd–H from Int2-Phth.
+
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DMF-PdH-Phth
DMFH-Pd-Phth
Pd–H 1.52 Å
O–H 2.27 Å
Pd–H 2.07 Å
O–H 1.03 Å
However, a reasonable alternative mechanism is direct
dissociation of the ligated Pd–H by DMF. To test this
hypothesis, the energetics for the displacement of Int2-
Phth and Int4-Phth by DMF were calculated (Figure 4).
Previous reports have shown that the transition state for
similar processes could not be located.65 In line with these,
the dissociation process was found to be endergonic for
both Int2-Phth and Int4-Phth (Figure 4). Importantly,
the process is less endergonic from Int4-Phth. If we
assume that the transition states for these two process
show the same trend, this data suggests that the selectivity
is likely not driven by the relative rates of the dissociation
of the ligated Pd–H from Int2-Phth and Int4-Phth by
DMF.
Scheme 2. Intramolecular deprotonation of Pd–H
20.7
19.9
+
Ph
O
Et
Me
CF3
14.8
N
N
Pd
+
H
Ph
Me
N
O
Et
CF3
O
N
N
Pd
H
O
O
N
Overall, these results suggest that the preferential
formation of the allylic product is likely a result of the
thermodynamics of the system. Additionally, the results
presented in Schemes 2–3 suggest that if the final product
determining step is deprotonation, it is occurring
intermolecularly by DMF or trace water. Alternatively, the
results in Figure 4 show that dissociation of the alkene
from the ligated Pd–H by DMF is also an energetically
viable pathway.
Post-TS4-Phth
Pd–H 1.97 Å
O–H 1.06 Å
TS4-Phth
O
Pd–H 1.64 Å
O–H 1.35 Å
Pre-TS4-Phth
We envisioned that the Pd–H complex Int2-Phth could
undergo either deprotonation of the Pd–H to directly
generate Pd0, ligand exchange of the alkene with the
phthalimide carbonyl, or dissociation of the ligated Pd–H
through an associative mechanism with DMF.64 To
determine the feasibility of intra- or intermolecular
deprotonation of the Pd–H by either the phthalimide
carbonyl (Scheme 2) or DMF (Scheme 3), respectively, the
reaction pathways for these two processes were calculated.
For the phthalimide to deprotonate the Pd–H, Int2-Phth
must first adopt a conformation in which the carbonyl is in
close contact to the hydride (Pre-TS4-Phth). The
intramolecular deprotonation of the Pd–H from this high
energy intermediate occurs with a relatively high barrier of
20.7 kcal/mol. The resulting protonated phthalimide Post-
TS4-Phth would likely undergo rapid deprotonation by
trace water or DMF to yield the corresponding neutral
Pd(0) complex. To investigate whether DMF could serve as
a competent base to deprotonate the Pd–H of Int2-Phth,
the solvate DMF-PdH-Phth and protonated DMF adduct
DMFH-Pd-Phth were calculated (Scheme 3). This process
was found to be thermodynamically favorable, which
suggests that this is a viable pathway for the formation of
the allyl product (see SI for details).
a) dissociation of ligated Pd–H by DMF from Int2-Phth
+
O
CF3
Me
Ph
N
O
N
Et
Pd
H
NPhth
+
Int2-Phth
DMF
+
H
∆G =
Me
9.4 kcal/mol
N
Me
b) dissociation of ligated Pd–H by DMF from Int4-Phth
+
O
CF3
Me
Ph
N
O
N
Et
Pd
H
NPhth
+
Int4-Phth
DMF
+
H
∆G =
Me
4.8 kcal/mol
N
Me
Figure 4. Dissociation of ligated Pd–H by DMF: a)
dissociation from Int2-Phth, b) dissociation from Int4-
Phth
Potential energy surface of the relay Heck reaction
with
homoallylic
acetamides
and
trifluoroacetamides. We next carried out a similar
analysis for the acetamide (Acet) acceptor group (Scheme
4). In contrast to the phthalimide, the carbonyl of the
acetamide shows a significant amount of ligation to the
cationic Pd center throughout the reaction pathway
Scheme 3. Intermolecular deprotonation of Pd–H
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consistent with the amides enhanced Lewis basicity. In DMF be lower than conversion to Int3-TFA. The DMF
1
2
3
4
5
6
7
8
particular, the degree of ligation of the carbonyl to the Pd
center destabilizes TS2-Acet, and stabilizes Int3-Acet and
Int4-Acet. This results in the formation of Int3-Acet being
essentially irreversible. These two factors combined
presumably lead to the preferential formation of the ene-
product.
adduct DMF-PdH-TFA was found to be significantly lower
in energy compared to the phthalimide analogue (15
kcal/mol vs. 24 kcal/mol, Scheme 5) and the deprotonation
of the Pd–H by DMF was found to be energetically
favorable (see SI for details). Additionally, the dissociation
by DMF was found to be more favorable in the case of Int2-
TFA (6 kcal/mol vs. 9 kcal/mol, Scheme 5). Ultimately,
these results suggest that the decomposition of Int2-TFA
to product may preferentially occur via a dissociation or
deprotonation pathway that has a lower barrier than the
formation of Int3-TFA. Importantly, this is consistent with
the experimentally observed allyl selectivity of the
trifluoroacetamide substrates.
Conversely, the potential energy surface of the
trifluoroacetamide (TFA, Scheme 5) is similar to that of the
phthalimide (Phth). One notable difference is Int3-TFA is
the lowest energy species along the pathway. However, the
relative stabilities of Int2-TFA relative to reversion back to
Int1-TFA combined with the relatively high barrier of TS2-
TFA suggests that this system is potentially under kinetic
control. This would require that the barrier for either
deprotonation of Int2-TFA or dissociation of Int2-TFA by
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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31
32
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34
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40
41
42
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44
45
46
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48
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Scheme 4. Computed reaction pathway of N-methylacetamides
+
16.9
15.9
+
+
TS1-Acet
9.5
TS2-Acet
7.9
TS2-Acet
+
7.3
O
CF3
H
Me
N
N
+
TS3-Acet
Ph
Et
Pd
O
N
CF3
O
H
N
Me
Et
Me
Pd–O 2.25 Å
Pd
MeN
Ph
MeN
Int2-Acet
O
(allyl only)
0.0
O
Me Pd–O 2.21 Å
Ph
Et
+
Me
Int4-Acet
(ene only)
CF3
N
N
deprotonation
-3.7
Et
Pd
O
deprotonation
or
or
+
dissociation
Pd–O 2.25 Å
E2 elimination
dissociation
O
Ph
CF3
N
Me
N
N
Me
Pd
O
O
Me
Et
Me
Et
Int1-Acet
(allyl only)
E2 elimination
E2 elimination
Pd–O 2.21 Å
N
Me
N
Me
NMe
Me
O
Ph
Me
(not formed)
Ph
Me
Int3-Acet
(allyl or ene)
DFT studies were performed at the IEFPCM(DMF)-M06/6-31+G(d)//M06/SDD-6-311+G(d,p) level of theory. All energies
listed are reported in kcal/mol. See the supporting information for details
Scheme 5. Computed reaction pathway of N-trifluoromethylacetamides
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Journal of the American Chemical Society
18.7
+
+
1
+
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
TS3-TFA
TS1-TFA
7.3
7.1
TS2-TFA
5.3
4.8*
Et
+
+
O
CF3
H
Me
N
N
Ph
O
CF3
Ph
Et
Pd
N
H
N
Pd
O
F3C
MeN
N
O
0.0
N
Int4-TFA
(ene only)
Me
+
Int2-TFA
(allyl only)
CF3
-1.8
Et
F3C
+
O
O
Deprotonation
CF3
Dissociation
O
deprotonation
or
dissociation
Ph
CF3
N
N
N
17
18
19
20
21
22
23
24
25
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27
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30
31
32
33
34
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36
37
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60
∆G = 6.3 kcal/mol ∆G = -7.7 kcal/mol
N
Pd
Pd
Ph
Pd–O 2.21 Å
Me Et
O
NMe
CF3
O
Me
Et
O
Me
Et
E2 elimination
major product
E2 elimination
E2 elimination
Int1-TFA
(allyl only)
N
CF3
N
CF3
ruled out by
isotopic labelling
Ph
Me
Ph
Me
predicted to be cis alkene
Int3-TFA
(allyl or ene)
(not formed)
DFT studies were performed at the IEFPCM(DMF)-M06/6-31+G(d)//M06/SDD-6-311+G(d,p) level of theory. All energies
listed are reported in kcal/mol. *Minimum using loose convergence criteria. See the supporting information for details
a) deuterium labeling rules out E2 elimination from Int3
Summary of mechanistic studies. The mechanistic
studies presented here have demonstrated that the
-H+
D
H
D
H
-Pd–D
-Pd(0)
Me
Me
Bu
selective formation of the allyl and ene products is driven
primarily by thermodynamics (Figure 5). Additionally,
deuterium labeling studies showed that an E2 elimination
from Int3-D2 does not occur based on the exclusive
formation of 2-HD without any evidence for the formation
of 2-DD (Figure 5a). The computational studies revealed
that the nature of the carbonyl has a direct impact on the
relative stabilities of Int2, Int3, and Int4, with the electron
rich amide carbonyl serving to stabilize Int3 and Int4
(Figure 5b). Importantly, the stabilization of these
intermediates likely results in the preferential formation of
the ene product. Lastly, the computations revealed that the
allyl selective pathways greatly favor the formation of Int1
and Int3 through the intermediacy of Int2 (Figure 5c).
Overall, the results suggest that the selective formation of
the allyl product is a result of deprotonation of the Pd–H
of Int2 or direct dissociation of Pd–H from Int2.
Bu
Bu
R
R
R
�-hydride
elimination
E2
[Pd] D
Ph
Ph
2-DD
not observed
D
Ph
D
elimination
Int3-D2
2-HD
b) carbonyl impacts the thermodyamics of the system via coordination to Pd
+
+
Int4-Acet
Int4-TFA
c) allyl selective substrates establish equilibrium between Int1, Int2, and Int3
[Pd]
H
+PdH Et
-PdH
+PdH
-PdH
Et
Et
N
N
Ph
[Pd]–H
Ph
H
Ph [Pd]
Int1
Int2
Int3
Figure 5. Summary of mechanistic studies: a) Int3 does not
undergo E2 elimination, b) ligation of the carbonyl to the
Pd effects the selectivity, and c) system is under
thermodynamic control
Conclusion
In summary, we have demonstrated that a variety of
homoallylic imides, biscarbamates, sulfonamides, and
trifluoroacetamides are capable of engaging in the relay
Heck reaction to form enantiomerically enriched allylic
amines containing a quaternary center. The scope of this
process is broad with modest to good yields and high
enantioselectivity for all examples. Alternatively, we have
found that homoallylic amides give rise to related ene-
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(3) Liu, Z.; Gao, Y.; Zeng, T.; Engle, K. M., Transition-Metal-
amides products. To explain the observed difference in
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calculations. These studies demonstrated that the
preferential formation of the allylic products is governed
by a combination of the reversible nature of the chain-
walking process and the instability of intermediates that
would lead to ene amide type products. In contrast, the
formation of the ene-amide is governed by the stability
imparted by the general Lewis basicity of the amide
carbonyl. The underlying strategies of using modest
changes to substrate structure to control chain-walking
termination events should impact the discovery and
development of new synthetically attractive remote
functionalization reactions.
Catalyzed 1,2-Carboboration of Alkenes: Strategies, Mechanisms,
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Catalytic Intermolecular Carboamination of Unactivated Alkenes
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
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walking as a strategy in catalytic organic synthesis. Tet. Lett.
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(20) Miura, T.; Nishida, Y.; Morimoto, M.; Murakami, M.,
Enantioselective Synthesis of Anti Homoallylic Alcohols from
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Experimental procedures for all reactions; spectroscopic
characterization data for all new compounds; detailed
1
computational methods; copies of H and 13C NMR spectra;
copies of SFC chromatograms. (PDF)
AUTHOR INFORMATION
Corresponding Author
* Sigman@chem.utah.edu
Present Addresses
†Parvus Therapeutics, 800 Dubuque Avenue, South San
Francisco, CA, 94080
ACKNOWLEDGMENT
M.S.S. thanks the National Institute of Health (NIGMS
R01GM063540), S.P.R thanks the National Institute of Health
for financial support through a F32 Ruth L. Kirschtein NRSA
fellowship (F32 GM128354-01A1). The computational portion
of this work was supported by the National Science
Foundation’s Extreme Science and Engineering Discovery
Environment (XSEDE, CHE190028) and the Center for High
Performance Computing (CHPC) at the University of Utah.
NMR results included in this report were recorded at the
David M. Grant NMR Center, a University of Utah Core
Facility. Funds for construction of the Center and the helium
recovery system were obtained from the University of Utah
and the National Institutes of Health awards 1C06RR017539-
01A1 and 3R01GM063540-17W1 respectively. NMR instruments
were purchased with support of the University of Utah and the
National Institutes of Health award 1S10OD25241-01.
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