Importance of the Reducing Agent in Direct Reductive Heck Reactions

Article abstract of DOI:10.1002/cctc.201701206

The role of the reductant in the palladium N-heterocyclic carbene (NHC) catalyzed reductive Heck reaction and its effect on the mechanism of the reaction is reported. For the first time in this type of transformation, the palladium-NHC-catalyzed reductive

Full text of DOI:10.1002/cctc.201701206

Accepted Article
Title: The Importance of the Reducing Agent in Direct Reductive Heck
Reactions
Authors: Saeed Raoufmoghaddam, Subramaniyan Mannathan, Adri
Minnaard, Hans De Vries, Bas De Bruin, and Joost Reek
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10.1002/cctc.201701206
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The Importance of the Reducing Agent in Direct Reductive Heck
Reactions
Saeed Raoufmoghaddam,[a] Subramaniyan Mannathan,[b] Adriaan J. Minnaard,[b] Johannes G. de
Vries,[b, c] Bas de Bruin,[a] Joost N. H. Reek*[a]
Dedication ((optional))
Abstract: The role of reductant in the palladium-NHC catalyzed
reductive Heck reaction and its effect on the mechanism of the
reaction is reported. For the first time in this type of transformation,
the palladium-NHC catalyzed reductive Heck reaction was shown to
proceed in the presence of LiOMe and iPrOH even at 10 °C, very
efficiently producing the products in excellent yields and with
exceptional selectivities. This study shows that the reaction proceeds
through two distinct mechanism depending on the nature of the
reducing agent. In the presence of the protic solvent or acidic media
the reaction undergoes protonation to yield reduced product while in
the absence of proton source, this proceeds through an insertion of
the reductant followed by reductive elimination. The kinetic data
reveal that the oxidative addition is the rate-determining step in the
Scheme 1. Plausible mechanistic pathways; Heck product (via β-hydride
reaction. The reaction profiles show first order kinetics in aryl iodide
elimination) versus reductive Heck product (via protonation or reductive
elimination of [PdII(alkyl)(H)] species).
and palladium, and zero order in LiOMe, benzylideneacetone and
excess amount of NHC ligand. In addition, the reaction progress
kinetic analysis show that neither catalyst decomposition nor product
inhibition occurs during the reaction. DFT calculations of the key steps
confirm that the oxidative addition step is the rate determining step in
the reaction. Deuterium labeling experiments indicate that the product
is formed via protonation of the Pd-Calkyl bond of the intermediate
formed after enone insertion into the Pd-CAr bond. Application of
chiral NHC-ligands in the asymmetric reductive Heck reaction only
result in poor enantioselectivities (ee up to 20%) which is also
substrate specific. DFT calculations suggest that the migration of the
aryl group to the alkene of the substrate is the enantioselectivity
determining step of the reaction. It is further shown that when the
steric bulk at the enone is small (a Me group), the two transition state
barriers from [PdII(L2)(ArI)(enone)] species CRe and CSi, having the Re
and Si face of the enone substrate coordinated to Pd, are very similar
which is in line with the experimental results. With a slightly larger
group (an iso-propyl substituent) a significant difference in energy
barriers is calculated (2.6 kcal mol-1), and indeed in the experiment
this product is formed with modest ee (up to 20%).
Introduction
Despite the massive progress in Heck coupling reactions over the
last decades,1,2 the thorough mechanistic understanding of direct
catalytic reductive Heck reaction remains challenging, possibly
due to couple of rather unexplored catalytic steps of such
reactions. In contrary, the utilization of highly reactive
organometallic reagents has been extensively studied.3,4
Although numerous advances have been made in the palladium-
catalyzed conjugate addition with organometallic reagents
(Grignards, organozincs and boronic acids) in the past decade,5-7
the direct palladium-catalyzed reductive Heck reaction of alkenes
with aryl halides has been hardly investigated.8-12 In general,
replacing the expensive, air and moisture sensitive
organometallic reagents with aryl halides is very tempting for
industrial synthetic transformations. The reductive arylation
product in the palladium-catalyzed reaction was first reported by
Cacchi and it was reasoned that the presence of trialkylamines
and formic acid facilitate the reduction step by acting as the
hydride source thus forming the hydrido-palladium-alkyl
complex.8,9 The reductive Heck product is then produced through
reductive elimination of the complex, whereas β-hydride
elimination of the palladium-alkyl complex forms the Mizoroki–
Heck product (Scheme 1).
[a]
Dr.S. Raoufmoghaddam, Prof. B. de Bruin, Prof. J.N.H. Reek
Van ’t Hoff Institute for Molecular Sciences, University of
Amsterdam, Science Park 904, 1098 XH, Amsterdam, The
Netherlands
E-mail: J.N.H.Reek@uva.nl
It was also proposed that formic acid plays two important roles:
protonation of the Pd-alkyl species and reduction of PdII to Pd0.
Alternatively, we recently reported the reductive Heck reaction
using an N-heterocyclic carbene (NHC) palladium complex,
trialkylamines (i.e. N,N-diisopropylethylamine or DIPEA) and
aprotic solvents (i.e. N-methyl-2-pyrrolidone or NMP).10,12
[b]
[c]
Dr. S. Mannathan, Prof. A. J. Minnaard, Prof. J. G. de Vries
Stratingh Institute for Chemistry, University of Groningen,
Nijenborgh 7, 9747 AG, Groningen, The Netherlands
Prof. J. G. de Vries
Leibniz-Institut für Katalyse e.V. an der Universitat Rostock, Albert-
Einstein-Strasse 29a, 18059 Rostock, Germany
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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It was shown that the nature of the base and solvent have a crucial
role in the reaction, and both affect the catalytic results changing
the regioselectivity of the reaction. Additionally, we found that the
presence of DIPEA as both reductant and base helps the
reductive cleavage step and as a consequence promotes the
formation of the reductive Heck product. Based on our
observations in the previous studies, we proposed that the
reaction does not involve protonation of the Pd-alkyl species to
yield the reductive Heck product. Instead, the role of DIPEA in the
reaction is to act as a reductant through its coordination to
palladium-alkyl species (after iodide dissociation) followed by β-
hydride elimination of the DIPEA to form the hydride species. The
reductive Heck product is formed in the final reductive elimination
step. This role of DIPEA was confirmed by carrying out an
experiment using deuterium labeled trialkylamine (Et3N-d15) which
resulted in the formation of deuterated reductive Heck product.12
This indicates that the hydride source depends on the nature of
solvent (protic or aprotic) and base (reductant or non-reductant)
applied in such a reaction.13-15 In addition, studies on the
asymmetric reductive Heck reaction15,16 have also been reported
by Buchwald, using aryl triflates in an intramolecular fashion to
synthesize chiral 3-substituted indanones with moderate ee
values in the most cases.17 More recently, an enantioselective
palladium-phosphine catalyzed intramolecular reductive Heck
reaction of aryl halides was reported to afford 3-arylindanones
with moderate to high ee values.18 It was proposed that the
addition of trialkylammonium salts in ethylene glycol facilitates the
halide dissociation through its hydrogen bond donor capacity.
Another enantioselective transformation of this class was
reported with the asymmetric arylative dearomatization of indoles
through palladium-phosphine catalyzed reductive Heck reaction
using sodium formate in methanol.19 To date, the asymmetric
reductive Heck reaction is rather limited to intramolecular
reactions, which is particularly interesting for the synthesis of
natural products.17-24 To the best of our knowledge, there are no
examples that describe the direct intermolecular enantioselective
reductive Heck reaction with high ee%, most likely because of the
challenges involved in the asymmetric induction step.
dimethoxybiphenyl (5) (Table 1). We used our previously
optimized reaction conditions,12 but now explored various
solvents in different combinations with various bases. These
experiments revealed that isopropanol as
a
solvent in
combination with K2CO3 as the base gave a good selectivity for
the formation of product 3 with moderate conversion (65%) after
20 h (Table 1, Entries 1-10). Changing the base under the same
conditions showed that LiOMe (1 equiv.) as a base is superior as
it resulted in an excellent yield of 3 (93%) after just 30 min (Entry
12). Moreover, following the product formation over time revealed
that the reaction proceeds to full conversion within just 30 min with
nearly exclusive formation of product 3. The use of other bases
did not further improve the reaction (Entries 20-24) and also
replacing isopropanol with other alcohols lowered the activity and
selectivity (Entries 12-18).
Scheme 2. Deuterium labeling experiment using iPrOD-d1 or iPrOH-d7 in the
reductive Heck coupling reaction. The reaction with iPrOD-d1 only resulted in
the incorporation of one deuterium in the product excluding the possibility of H/D
exchanges between the product and iPrOD-d1 during the reaction.
Notably, upon using 1,1,1,3,3,3-hexafluoroisopropyl alcohol
(HFIPA) instead of iPrOH, the rate of the reaction dropped
substantially, and almost no substrate conversion was observed
after 2 h (Entry 15). This can be explained as it is less prone to be
oxidized compared to iPrOH. The reaction in the absence of base
resulted in complete recovery of the starting materials (Entry 19).
The essential role of iPrOH as solvent/reductant in the reaction
was then probed by two independent labeling experiments using
iPrOD-d1 and iPrOH-d7 (Scheme 2). It was found that the reaction
in iPrOD-d1 results in the formation of the mono-deuterated
product whereas in iPrOH-d7 only the normal product was
detected, suggesting that the product is likely formed by
protonation of the Pd-alkyl intermediate. These results indicate
that the reaction proceeds through protonation of the palladium-
alkyl complex followed by reduction of PdII to Pd0, which is in
contrast to what we found for the reactions carried out with
DIPEA.12
In the current contribution, we report the palladium-NHC
catalyzed direct reductive Heck reaction of para-substituted
benzylideneacetones with 4-iodo-anisole using isopropanol as
both solvent and reductant. The reaction proceeds very efficiently
even at low temperatures (10 oC). Additionally, DFT calculations,
kinetics and other mechanistic studies provided a detailed
mechanistic picture of the reaction. We also probed the direct
intermolecular asymmetric reductive Heck reaction and
elucidated the enantioselectivity determining step by performing
DFT calculations.
Results and Discussion
Initial optimizations. To explore the role of the reductant we
studied the typical reductive Heck reaction between
benzylideneacetone 1 and 4-iodoanisole 2, resulting in the
formation of the expected product (3) with traces of the Heck
product (4; obtained as a mixture of E/Z isomers) and 4,4’-
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Table 1. Palladium-catalyzed reductive arylation[a]
Base
No.
t
Conversion[b]
Yield%[b]
Solvent (v/v)
(equivalent)
h
%
3
4
5
1
0
0
0
0
0
0
0
0
0
1
DIPEA (2)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
4
NMP
100
96
87
75
66
64
63
60
20
65
90
0
8
2
20
20
20
20
20
20
20
20
20
NMP
96
74
43
18
14
10
6
3
NMP/iPrOH (1.5/0.5)
NMP/iPrOH (1/1)
NMP/iPrOH (0.5/1.5)
NMP/iPrOH (0.25/1.75)
NMP/iPrOH (0.1/1.9)
acetone/iPrOH (0.25/1.75)
H2O/iPrOH (0.25/1.75)
iPrOH
13
32
48
50
53
54
12
59
4
5
6
7
8
9
7
10
5
11
12[c]
13
14
15
16
17
18
19
20
Cs2CO3 (1)
LiOMe (1)
LiOMe (1)
LiOMe (1)
LiOMe (1)
LiOMe (1)
LiOMe (1)
LiOMe (1)
-
6
THF/iPrOH (0.25/1.75)
iPrOH
89
99
100
100
5
66
93
93
44
4
4
19
3
0.5
1
3
MeOH/iPrOH (1/1)
EtOH
4
3
0.5
2
4
52
0
HFIPA
1
2
iBuOH
87
100
81
1
73
83
65
-
13
16
3
0
1
PhCH(OH)CH3
Cyclopentanol
iPrOH
0
1
12
-
2
-
Na2CO3 (1)
20
iPrOH
60
55
5
0
21
22
23
24
Cs2CO3 (1)
DIPEA (1)
Et3N (1)
2
iPrOH
iPrOH
iPrOH
iPrOH
99
16
13
44
82
13
9
0
16
0
20
20
20
3
4
0
CsPiv (1)
3
41
0
a) Reaction conditions: 1 (1.65 mmol), 2 (1.10 mmol), Pd(L1)(MA)2 (0.75 mol%) (MA = maleic anhydride; L1 = 1,3-bis(2,4,6-trimethylphenyl)-imidazolium), base (1-2
equiv.), T= 60 °C, solvent (1.5 mL), internal standard = decane, t = 0.5 - 20 h. b) GC Yields and conversions based on 4-iodoanisole. c) ~88% isolated yield.
A reductive pathway, with proton exchange between the alcohol
and the product under the applied reaction conditions, is less
likely as this proton exchange would also lead to incorporation of
two deuterium atoms next to the carbonyl moiety, which is not
observed. We next studied the kinetics of the reaction, monitoring
the product formation in time and processed the data using
reaction progress kinetic analysis25 that provides the typical
graphical rate vs substrate concentration. These kinetic data
revealed first order kinetics in the Pd-NHC catalyst and zero order
in base (LiOMe) and zero order in the excess of the NHC ligand.
Additionally, the reaction progress kinetic analysis showed that
neither catalyst decomposition nor product inhibition plays a
significant role during the reaction under the applied reaction
conditions in the time-span studied.
DFT calculations. To gain additional insight into the mechanism,
we performed DFT-computations investigating various pathways
for the catalytic cycle (Figure 1). The geometry optimizations were
carried out with the TURBOMOLE program package26 using
BP86 functional27,28 together with the def2-TZVP basis set.29 The
given minima comprise no imaginary frequency and the transition
states contain only one imaginary negative frequency (for detailed
data and all minima and optimized geometries see SI).
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Figure 1. Gibbs free energy diagram (∆G0298K in kcal mol-1) of the DFT computed reductive Heck reaction (BP86, def2-TZVP).
Based on the experimental results we considered a pathway
involving oxidative addition of the ArI substrate 2, coordination
and insertion of the enone substrate 1 into the Pd-CAr bond,
followed by protonation of the resulting Pd-Calkyl bond by a
coordinated iPrOH moiety (see Figure 1). The energy of the
various intermediates and transition states indicate that the
oxidative addition is irreversible and the rate-determining step of
the catalytic reaction. This is in agreement with our kinetic
experiments that show first order in [iodo anisole 2] and zero order
in [benzylideneacetone 1] (see SI for detailed information). As we
reported previously,12 the oxidative addition step may proceed
through various species with slightly different activation barriers
([TS2]‡ = [TS1]‡ + 2.9 kcal mol-1), depending on the reaction
conditions. In this respect, the transition state of the oxidative
addition step can be slightly lowered (~3 kcal mol-1) by de-
coordination of the enone 1.
enolate species (D’) can also be formed through isomerization,
but is energetically less favored (~2.7 kcal mol-1 higher in energy;
∆G0298 K (D’)= -11.9 kcal mol-1). Species D and E can be stabilized
by the coordination of iPrOH (~3 kcal mol-1 lower in energy). The
next step considered in the reaction path is palladium-alkyl
protonation to form the product. This is followed by beta-hydrogen
elimination from alkoxide E to form acetone and the palladium-
hydride species F. The computed barrier for this step is low (12
kcal mol-1 from D+IPA) which is in good agreement with the
labeling experiments, described above in Scheme 2, suggesting
protonation as a key step in product formation. Reformation of
the Pd0 species A is proposed to involve base assisted reductive
elimination of HI (LiOMe as a base), which is overall slightly
endergonic.
Mechanism of the reaction. Based on the kinetic data and DFT
calculations, we propose a mechanism as depicted in Scheme 3.
Several species, possibly in equilibrium, may be present for the
oxidative addition step with different energy barriers. We envision
that the catalytic cycle starts with the formation of species A and
A’. Oxidative addition of iodoanisole (2) to Pd0-NHC then takes
place to both species A and A’, thus affording species B or C.
In general, the oxidative addition energy profile indicates that it is
an overall exergonic process to form species B or C. The
formation of species C from species B is an endergonic process.
Species C undergoes migratory insertion to give species D,
proceeding via a low barrier transition state (TS3). Here, a Pd-O-
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According to our kinetic data and DFT calculations, the oxidative
addition is the rate-determining step.
the migratory insertion step from these species are similar. As
observed in the labeling experiment, protonation of the palladium-
alkyl complex in iPrOH occurs to form product 3 and species E. If
species D undergoes β-hydride elimination, the Heck side-
product 4 is formed. Species E converts to species F through β-
hydride elimination resulting in the formation of acetone, which
was also detected experimentally by GC and GC/MS. The final
steps in the mechanism that ultimately leads to reformation of
species A, involve b-hydride elimination from the alcoholate E to
produce acetone (as observed in the reaction mixture), followed
by reductive deprotonation by LiOMe as a base, thereby forming
MeOH and LiI. The abstraction of a proton from a palladium-
hydride species by a base can occur without an activation
barrier.39
Asymmetric reductive Heck reactions. With a clear picture of the
kinetics and mechanism of the reaction in hand, we next
conducted experiments to study the challenging direct
intermolecular asymmetric reductive Heck reaction using chiral
NHC ligands (Table 2). Recently we showed that this reaction
lends itself for an enantioselective intramolecular Heck reaction
using monodentate phosphoramidite ligands.40 The reactions with
the model enone 1 (R=Me) using chiral ligand L4 under different
conditions (in iPrOH at 60 ºC and room temperature or in (S)-(-)-
1-phenylethanol) resulted in <1% ee (entries 2-4). The
mechanism dictates that the insertion of enone 1 into the Pd-CAr
bond of species C is the asymmetric induction step, which should
be controlled by the chiral NHC ligands. It is anticipated that more
sterically hindered enone substrates will be more prone to
induction of enantioselectivity by the ligand. As such, we explored
the reaction by using other enones with bulkier R groups (phenyl,
9-anthracenyl, ethyl, isopropyl, tert-butyl and 1-adamantyl).
Interestingly, moving on from a methyl to an isopropyl group in the
enone substrate increased the ee% value from <1% to 8% (Entry
8). Unfortunately, the experiments with the bulkier 1-adamantyl or
t-butyl substituted enones with greater steric influences gave no
product 3 simply because these substrates are too bulky to
coordinate to the palladium center. As a consequence, the
reaction merely resulted in the formation of homo-coupling
product (Entries 9-10). Additionally, the reaction with the iPr
substituted enone at lower temperatures (room temperature and
even at 10 ºC) gave excellent yields of the product 3 (90-94%)
with slightly higher ee% values of 16% and 19% (Entries 11-12).
Further lowering the temperature to 0 ºC did not result in
conversion as the substrates were recovered unchanged (Entry
13), indicating that 10 ºC is the lowest reaction temperature at
which the reaction still progresses. The reactions with various
chiral NHC ligands were therefore carried out at 10 ºC, however,
this did not further improve the ee values (Entries 14-20).
According to the mechanism supported by our DFT calculations,
the enantioselectivity is determined by aryl migration step. The
DFT calculations show that the energy difference between the
species CRe and CSi, having the enone coordinated to Pd center
with its Re face and Si face, respectively, is very smal. We next
optimized the geometries of species C using enones with different
R groups (methyl and isopropyl) coordinated to the palladium
center.
Scheme 3. Proposed mechanism of the reductive Heck reaction; empty
coordination sites may be occupied by solvent molecules or halides.
As previously reported for similar reactions,31-36 activated alkenes
slow down the oxidative addition step by coordinating to the
palladium zero species, thereby stabilizing the Pd species
through delocalization of the electron density from the electron
rich Pd0. The resulting species C undergoes migratory insertion
into benzylideneacetone to form species D, which is in equilibrium
with the energetically less favored Pd-O-enolate species D’ (~2.7
kcal mol-1 higher in energy). Although this species is less favored
in terms of stability, we cannot rule out that the product is formed
by protonation of this species, which should be with low barrier as
it is after the rate and selectivity determining step. As we were
unable to find the transition state for this step, and it was reported
for reductive elimination reactions to proceeds through the Pd-C
species, 30 the reaction most like goes via D.
Alternatively, species C could form from a halogen-bridged
dimeric species (analogues to B), in particular, when bulky ligands
are involved, possibly leading to the isomeric form of C.37,38 This
alternative Pd species C and its transition states with aryl group
cis-positioned to the NHC ligand were also calulated by DFT-
calculated (see SI, Figure S31) and demonstrated to be similar in
energy (~0.3 kcal lower in energy). Also the energy barriers for
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Table 2. Palladium-catalyzed enantioselective reductive arylation [a]
Entry
1
R
Ligand T(h) T (˚C) Conv.[b] (%) Yield
3
(%)[b] ee%[c]
methyl
methyl
methyl
methyl
phenyl
L1
L4
L4
L4
L4
0.5
1
60
60
60
rt
99
78
80
51
98
-
93
66
63
50
91
-
0
2
<1
<1
<1
<1
-
3[d]
4
4
8
5
1
60
-
6
9-anthracenyl L4
-
7
ethyl
L4
L4
L4
L4
L4
L4
L4
L2
L3
L5
L6
L7
L8
L8
-
-
-
-
-
8
isopropyl
t-butyl
2
60
60
60
rt
99
93
91
96
91
<2
88
89
90
68
<1
14
49
96
0
8
9[e]
10[e]
11
12
13
14
15
16
17
18
19
20
20
20
15
20
20
20
20
20
20
20
20
20
-
1-adamantyl
isopropyl
isopropyl
isopropyl
isopropyl
isopropyl
isopropyl
isopropyl
isopropyl
isopropyl
isopropyl
0
-
94
90
0
16
19
-
10
0
10
10
10
10
60
10
rt
82
83
81
65
0
14
14
19
17
-
13
47
17
15
a) Reaction conditions: 1 (1.65 mmol), 2 (1.10 mmol), Pd(L)(MA)2 (0.75 mol%) (MA = maleic anhydride), LiOMe (1 eq), T= 0 - 60 °C, solvent = iPrOH (2 mL), t = 0.5
- 20 h, Internal standard = decane. b) The conversion and yield determined by GC based on iodo anisole. c) ee% determined by chiral HPLC. d) (S)-(−)-1-Phenylethanol
used as a solvent. e) homo-coupling product (5) as a major product and other by-products formed.
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To further study the asymmetric induction step of the reaction
mechanism, we also probed the migratory insertion step of these
two enones into the Pd center through DFT calculations of the
corresponding transition states (Figure 2). They both undergo
migratory insertion through exergonic processes to give species
D*. However, the energy barrier for the two transition states
starting from the species CRe(Me) and CSi(Me) revealed almost no
differences (0.1 kcal mol-1), whereas the transition states of the
species CRe(iPr) and CSi(iPr) gave larger differences of 2.6 kcal
mol-1, indicating that one pathway is more preferred than the other.
This energy barrier difference observed for the more bulky
substrate is in line with the experiment as for this substrate the
product was produced in 19% ee.
It is also noteworthy to mention that the relative energy barriers at
ambient or elevated temperatures (or due to absence of explicit
solvent effects) may become even closer which rationalizes the
fact that we did not obtain any ee values higher than 20%.
Figure 2. Migratory insertion step and the corresponding transition states of the palladium species (DFT calculations, BP86/def2-TZVP) in the reductive Heck
reaction, ∆G0298 K is in kcal mol-1. Alternative transition states with aryl group cis-positioned to the NHC ligand were also calculated (see the supporting info, Figure
S31) which resulted in 2.1 kcal energy difference between the species CRe(iPr) and CSi(iPr) indicating similar energy barrier (only 0.5 kcal lower compared to the
trans-positioned species) in the migratory insertion step.
~20%) have been obtained. Further optimization of asymmetric
reductive reaction could proceed along these lines.
Conclusions
The effect of reducing agent on palladium-NHC catalyzed direct Experimental Section
reductive Heck reaction of para-substituted benzylideneacetones
General procedure for the reductive arylation reaction.
with 4-iodo anisole has been investigated. Compared to previous
studies, the reaction conditions lead to faster reactions as full
conversion was achieved within 30 min at 60 °C. It was further
shown that the reaction proceeds even at 10 °C. Importantly, the
mechanism of the product forming step can be different and
depends on the nature of the reducing agent. In the presence
iPrOH, the product is formed through protonation of the Pd-alkyl
intermediate, as is clear from deuterium labeling experiments.
This is in contrast to the use of DIPEA, for which was found that
the product is formed by reductive elimination from the alkyl-
hydride species. The kinetic data indicate that under both
conditions the oxidative addition is the rate-determining step,
which is in line with the DFT calculations. Various chiral NHC
ligands were synthesized and evaluated in the asymmetric
reductive Heck reaction, which showed no ee for the bench-mark
substrate. In line with this, the difference in the transition state
barriers of the crucial aryl migration step of the two
[PdII(L2)(ArI)(enone)] species CRe and CSi is negligible. In contrast,
the same transition states for the complexes with a slightly more
bulky substrate (iPr-enone) are 2.6 kcal mol-1 different in energy,
and indeed for this reaction significant, but low ee values (up to
In a flame-dried Schlenk tube, equipped with a stopper and a stirring bar,
1.1 mmol (1 equiv.) of base (LiOMe, 1 M in THF) was added. The solvent
(THF) was then removed under reduced pressure to obtain a white powder.
The Schlenk tube was then charged with Pd0(L)(MA)2 (0.75 mol%), 4-iodo
anisole 2 (1.1 mmol), and benzylideneacetone 1 (1.65 mmol) and
subsequently flushed 3 times with a cycle of vacuum-argon. The solvent
isopropyl alcohol (iPrOH) (2 mL) containing decane as internal standard
was then transferred into the Schlenk tube which was then placed into a
preheated oil bath at 60 ºC. Upon reaction completion (after 30 minutes;
judged by GC), the reaction mixture was cooled down to room temperature
and a sample of 10 µL was taken and diluted to 1 ml with dichloromethane
(DCM) and subsequently subjected to GC/GC-MS analysis (for more
detailed data, see supporting information).
DFT calculation details.
All calculations and geometry optimizations were performed using the
Turbomole program package26, coupled to the PQS Baker optimizer41 via
the BOpt package42 at the spin unrestricted ri-DFT level using the BP86
functional27,28 and the def2-TZVP basis set29 for the geometry
optimizations. All geometries of minima with no imaginary frequencies and
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transition states with one imaginary frequency were characterized by
numerically calculating the Hessian matrix (for detailed information see SI).
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This research has been performed within the framework of the
CatchBio Program. The authors gratefully acknowledge the
support of the Smart Mix Program of the Netherlands Ministry of
Economic Affairs and the Netherlands Ministry of Education,
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Keywords: Reductive Heck; Reductive arylation, Reducing
agent; Pd-catalyed reaction; Asymmetric reductive Heck;
isopropanol
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Saeed Raoufmoghaddam,
Subramaniyan Mannathan, Adriaan J.
Minnaard, Johannes G. de Vries, Bas de
Bruin, Joost N. H. Reek*
Page No. – Page No.
The Importance of the Reducing
Agent in Direct Reductive Heck
Reactions
The role of reductant in the palladium-NHC catalyzed reductive Heck reaction and
its effect on the mechanism of the reaction is reported.
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