Room-Temperature Benzylic Alkylation of Benzylic Carbonates: Improvement of Palladium Catalyst and Mechanistic Study

Article abstract of DOI:10.1021/acs.oprd.9b00210

The palladium catalyst for the nucleophilic substitution of benzyl carbonates was improved by using 1,1′-bis(diisopropylphosphino)ferrocene (DiPrPF) as the ligand. The [Pd(η³-C₃H₅)(cod)]BF₄-DiPrPF catalyst allows the benzylic substitution with soft carbanions to proceed even at 30 °C, affording the desired products in high yields (up to 99% yield). Thermally unstable pyridylmethyl esters are employable as the electrophilic substrates for the benzylic alkylation with the improved catalyst. Furthermore, we investigated the mechanism of the catalytic benzylic alkylation by means of DiPrPF ligand. The palladium(0) complex bearing DiPrPF activates the benzylic C-O bond to form the (benzyl)palladium(II) intermediate at room temperature. The coordination mode of the benzyl ligand would be equilibrium between the η¹- and η³-manner. The nucleophile would preferentially react with the η³-benzyl ligand to give the desired product.

Full text of DOI:10.1021/acs.oprd.9b00210

Article
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Room-Temperature Benzylic Alkylation of Benzylic Carbonates:
Improvement of Palladium Catalyst and Mechanistic Study
Ryoichi Kuwano,*,†,‡ Masashi Yokogi,† Ken Sakai,†,‡,§ Shigeyuki Masaoka,∥ Takashi Miura,†
and Sungyong Won†
†Department of Chemistry, Faculty of Science, Kyushu University, Motooka 744, Nishi-ku, Fukuoka 819-0395, Japan
‡Center for Molecular Systems (CMS), Kyushu University, Motooka 744, Nishi-ku, Fukuoka 819-0395, Japan
§International Institute for Carbon-Neutral Energy Research, Kyushu University, Motooka 744, Nishi-ku, Fukuoka 819-0395, Japan
∥Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: The palladium catalyst for the nucleophilic substitution of benzyl carbonates was improved by using 1,1′-
bis(diisopropylphosphino)ferrocene (DiPrPF) as the ligand. The [Pd(η3-C3H5)(cod)]BF4−DiPrPF catalyst allows the benzylic
substitution with soft carbanions to proceed even at 30 °C, affording the desired products in high yields (up to 99% yield).
Thermally unstable pyridylmethyl esters are employable as the electrophilic substrates for the benzylic alkylation with the
improved catalyst. Furthermore, we investigated the mechanism of the catalytic benzylic alkylation by means of DiPrPF ligand.
The palladium(0) complex bearing DiPrPF activates the benzylic C−O bond to form the (benzyl)palladium(II) intermediate at
room temperature. The coordination mode of the benzyl ligand would be equilibrium between the η1- and η3-manner. The
nucleophile would preferentially react with the η3-benzyl ligand to give the desired product.
KEYWORDS: palladium, benzylic substitution, benzyl carbonate, active methine, (η3-benzyl)metal complex
INTRODUCTION
■
Nucleophilic substitution of benzylic electrophiles is frequently
used in organic synthesis for protecting reactive functional
groups as well as for constructing molecular frameworks.
Benzylic bromides or chlorides are commonly employed as the
electrophilic substrates for the reaction. In the benzylic
electrophiles, their aryl groups lead to an increase in reactivity
of the halide leaving group.1 The enhanced leaving-group
ability often causes significant decomposition of the substrate
and/or undesirable side reactions. Sulfonates are also known as
good leaving groups for the nucleophilic substitution, but their
Figure 1. Allylic vs benzylic substitution.
high reactivities would often cause significant formation of side
products. Therefore, a less reactive functionality, such as
acetate or hydroxide,2 would be often required as the leaving
suggest to us that benzylic carboxylates and carbonates are also
activated with the palladium(0) complex to form (η3-
group for the nucleophilic substitution of such reactive
substrates. Moreover, use of the alkyl halide or sulfonate is
benzyl)palladium C,7 which would be electrophilic (path b).8
disadvantageous for contributing to an environmentally benign
chemical industry. Carboxylates and carbonates would have
less impact on creatures than the halides and sulfonates.
For the nucleophilic substitution of allylic electrophiles,
acetate or a related functionality is often chosen as the leaving
group. Allylic carboxylates react with various nucleophiles in
the presence of a palladium catalyst (Figure 1, path a)3,4 In the
catalytic process, the Tsuji−Trost reaction, palladium(0)
species A activates the allylic CO bond to form an
electrophilic (η3-allyl)palladium(II) intermediate B.5 Coordi-
nation of the palladium to the CC double bond would
facilitate the elimination of the acyloxy group from allylic
carbon. An allylic terminus of B undergoes the attack of
nucleophile to give the alkylation product and regenerate A.6 A
structural analogy between allyl and benzyl groups might
The benzylic esters might function as good substrates for the
nucleophilic substitution in the presence of a palladium
catalyst. However, the η3-coordination of the benzyl ligand is
thermodynamically unfavorable because it involves the
dearomatization of the arene ring. Despite this difficulty,
Fiaud and Legros had successfully developed the benzylic
substitution of naphthylmethyl esters with a palladium catalyst
in 1992.9 The naphthyl group would facilitate generation of the
η3-benzyl intermediate because the fused-arene ring requires
Special Issue: Honoring 25 Years of the Buchwald-Hartwig
Amination
Received: May 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00210
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
a
Table 1. Optimization of Reaction Conditions
b
b
entry
ligand
solvent
base
yield (3aa)
yield (4aa)
1
2
3
4
5
6
7
8
L1
L2
L2
L2
L2
L2
L2
L2
L2
L1
L3
L4
L5
THF
THF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
0
20
49
44
28
0
39
31
0
5
42
0
0
7
0
18
44
24
4
0
11
7
0
2
50
0
0
DMF
dioxane
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DBU
9
10
11
12
13
14
15
16
17
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
c
L6
4
33
0
0
52
L7
L8
L9
L2
29
0
0
43
d
e
e
18
a
Reactions were conducted on a 0.20 mmol scale in a solvent (1.0 mL) at 30 °C for 3 h unless otherwise noted. The ratio of 1a:2a:base:[Pd(η3-
b
C3H5)(cod)]BF4:ligand was 20:30:30:1.0:1.1. Yields were determined by GC analysis and calibrated with an internal standard, tetradecane
(average of two runs). Phosphonium tetrafluoroborate salt of L6 was used as the ligand precursor. The reaction was carried out on a 1.0 mmol
scale with 1.0 mol % catalyst loading for 24 h. Isolated yields.
c
d
e
relatively low energy for its dearomatization. Since then, the
reaction has been studied and expanded by many researchers.10
Enantioselective catalysts, nowadays, have been successfully
developed for the benzylic substitution.11 Meanwhile, the
monocyclic benzyl esters are challenging substrates for
palladium-catalyzed benzylic substitution as compared with
the naphthylmethyl substrates,12 because the benzene ring is
more stabilized with its own aromaticity as compared to
naphthalene.
We previously developed the nucleophilic substitution of the
monocyclic benzyl carbonates13 and acetates.14 The benzylic
esters were converted into the desired products in high yields
with the palladium catalyst, which was generated from a
palladium precursor and appropriate chelating bisphosphine
ligand, e.g., DPPF or DPEphos. With the palladium catalyst,
the reaction required mild heating to afford the desired
benzylation products in high yields. However, the heating
condition sometimes causes the significant decomposition of
benzylic substrates. Herein, we report a highly active palladium
catalyst for the benzylic alkylation of benzyl carbonates with
soft carbanions. The catalyst, 1,1′-bis(diisopropylphosphino)-
ferrocene (DiPrPF)−palladium complex, allows the reaction to
give the desired products in high yields at room temperature.
Under the mild condition, some thermally unstable benzylic
carbonates are transformed into the substitution products in
high yields. Furthermore, we investigated the mechanism of
the catalytic reaction by means of the DiPrPF−palladium
complex.
was sluggish and the rate-determining step in the benzylic
substitution of benzyl carbonates through the DPPF (L1)−
palladium catalysis.13a,b Use of an electron-donating ligand is
known to facilitate oxidative addition to a low-valent metal
complex in general.15 The palladium catalyst might be
improved by using a bidentate ligand bearing alkyl substituents
on its phosphorus atoms. To confirm the working hypothesis,
we attempted the reaction of benzyl methyl carbonate (1a)
with dimethyl malonate (2a) by using DiPrPF16 (L2) in place
of L1. The reaction was conducted in THF at 30 °C in the
presence of Cs2CO3 and 5.0 mol % of the catalyst, which was
prepared in situ from [Pd(η3-C3H5)(cod)]BF4 and L1 or L2
(Table 1, entries 1 and 2). Use of L1 resulted in the formation
of neither the benzylated malonate 3aa nor 4aa, while the L2−
palladium catalyst afforded a mixture of 3aa and 4aa in
moderate combined yield. The rate of the benzylic substitution
was enhanced by using a more polar solvent (entries 2−5).
DMF is the solvent of choice for the present palladium
catalysis (entry 3). The benzyl ester 1a almost disappeared
from the reaction mixture within 3 h to give 3a and 4a in 49%
and 44%, respectively. The efficiency of the palladium catalyst
significantly deteriorated by using bases other than Cs2CO3
(entries 6−8). No benzylation products were detected in the
reaction conducted without any bases, although the methoxide
stemming from 1a might work as a base (entry 9). Choice of
phosphine ligand is crucial for the palladium catalysis (see
Chart 1). The catalysis was remarkably affected by the
substituents on the phosphorus atoms in the ferrocenyl
phosphine ligand. The DPPF−palladium complex could
catalyze the present benzylic substitution in DMF, but
products 3aa and 4aa were obtained in very low yields from
the reaction at 30 °C (entry 10). DCyPF17 (L3) as with L2
functioned as a good spectator ligand for the palladium catalyst
RESULTS AND DISCUSSION
■
Optimization of Catalyst toward the Room-Temper-
ature Benzylic Substitution. We presumed that the
oxidative addition of benzylic C−O bond to palladium(0)
B
DOI: 10.1021/acs.oprd.9b00210
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Chart 1. Structures of Phosphine Ligands
Table 2. Substrate Scope of Benzylic Substitution
to give the benzylation products in high combined yield (entry
11). The catalytic activity disappeared by replacing the
isopropyl or cyclohexyl by a tert-butyl group (entry 12).
Furthermore, the reaction was attempted with a variety of
chelating bis(dicyclohexylphosphino) ligands L5−L9 to
investigate effect of their bridged structure (entries 13−17).
The bridged structure also impacted the catalytic benzylic
substitution. Use of the ligands except L7 resulted in no or
little production of 3aa and 4aa at 3 h. No benzylic
substitution was observed in the reactions using L8 and L9,
although the DPEphos− or xantphos−palladium complex
often works as a good catalyst for the reactions involving the
benzylic C−O bond activation.13a,c−f,18 To our surprise, the
L7−palladium catalyst bearing a biaryl backbone also could
promote the reaction with good efficiency, while the ligand is
inferior to L2 or L3. Under the optimized conditions above,
the benzylic substitution of 1a with 2a was carried out on a 1.0
mmol scale with 1.0 mol % catalyst loading (entry 18). The
benzyl ester 1a was completely consumed within 24 h to give
3aa and 4aa in 43% and 52% isolated yields, respectively.
Substrate Scope. As a result of the optimization of the
reaction conditions, the benzylation of 2a with 1a proceeds
with high efficiency in DMF by using Cs2CO3 as the base and
the [Pd(η3-C3H5)(cod)]BF4−DiPrPF complex as the catalyst.
As with 2a, diethyl phenylmalonate (2b) was benzylated with
1a at 30 °C to give benzylphenylmalonate 3ab in 98% yield
(see Table 2). Both electron-rich and electron-deficient benzyl
esters 1b and 1c also worked as the good electrophilic
substrates for the palladium-catalyzed benzylation to give the
desired products 3bb and 3cb in high yields. The chloro and
alkoxycarbonyl functionalities in the benzylic substrates, 1d
and 1e, were compatible with the palladium catalysis.
Remarkably, the reaction of 1e was completed within 4 h to
form the substitution product 3eb in high yield. However, o-
substituted benzyl ester 1f is much less reactive than other
benzyl esters. The methyl group might hamper the oxidative
addition of the benzylic C−O bond to the palladium(0). The
reaction of 1f with 2b required warming at 50 °C for the
complete conversion to 3fb. A range of α-substituted
malonates also work as the nucleophiles for the catalytic
benzylic substitution. Methyl- and methoxymalonates, 2c and
2d, were alkylated with 1b in high yields under the optimized
condition. (Acetylamino)malonate 2e was converted into the
benzylated product 3be in high yield under a dilute condition
(3.0 mL of DMF) because of the low solubility of 2e. It is
noteworthy that (pyridinyl)methyl carbonates 1g and 1h
reacted with 2b or 2c in high yields through the present
palladium catalysis. The carbonate substrates significantly
decomposed during the catalytic benzylic substitution when
DPPF (L1) was used in place of L2 at 80 °C.13a The thermal
decomposition of 1g and 1h might be avoided by carrying out
the reaction at a lower temperature. With the L2−palladium
complex, no benzylation was observed in the reaction of 1,3-
a
Reactions were conducted on a 1.0 mmol scale in DMF (1.0 mL) at
30 °C unless otherwise noted. The ratio of 1:2:Cs2CO3:[Pd(η3-
C3H5)(cod)]BF4:ligand was 100:110:110:1.0:1.1. At 50 °C. In 3.0
mL of DMF. L3 was used as the ligand in place of L2.
b
c
d
diketone 2f or β-ketoester 2g with 1b at 30 °C. Coordination
of 2f or 2g might obstruct the oxidative addition of 1b to the
palladium(0) species. The successful formations of 3bf and
3bg were achieved by using DCyPF (L3), whose cyclohexyl
substituents might hamper the access of 2f or 2g to the
palladium(0).
Mechanistic Study. A reaction pathway could be
supposed for the present benzylic substitution by analogy to
the Tsuji−Trost reaction as shown in Figure 2.4 The catalytic
cycle starts from the oxidative addition of the benzylic C−O
bond of 1 to palladium(0) species A to form (η3-benzyl)-
palladium(II) intermediate C. The resulting electrophilic
organometallic species undergoes the nucleophilic attack of
Figure 2. Supposed reaction pathway of the palladium-catalyzed
benzylic substitution.
C
DOI: 10.1021/acs.oprd.9b00210
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
the soft carbanion 2′ to afford the benzylated product 3 and
regenerate palladium(0) A.
To confirm the above postulation, the stoichiometric
reaction of the L2−palladium(0) complex and benzyl methyl
carbonate 1a was monitored with NMR measurement (eq 1 in
Scheme 1). The DiPrPF-ligated palladium(0) 5 was prepared
pair of doublets II appeared at 35.1 and 46.5 ppm with 31 Hz
of P−P spin coupling constant. The peaks II would be assigned
to a (benzyl)palladium(II) complex, because the signal of the
benzylic hydrogens was observed at 3.18 ppm in the 1H NMR.
Its H−P coupling disappeared when the spectrum was
observed with 31P decoupling (Figure 4c). The benzyl ligand
would be bound to the palladium atom through η1-
coordination because the signal pattern of its aromatic protons
is similar to those of (η1-benzyl)palladium(II)s in the
literature20 and authentic Pd(η1-benzyl)Cl(L2) (6b) (vide
infra). These observations indicate that the benzylic C−O
bond in 1a is cleaved by the L2−palladium(0) 5 even at room
temperature. As the result of the oxidative addition of the
benzylic C−O bond, 5 would be converted to Pd(η1-
benzyl)(OMe)(L2) (6a) through the decarboxylation of the
leaving group. The undesirable formation of 7 would be caused
by the reductive elimination from 6a.
Scheme 1. Reactions of Palladium(0) 5 with Benzyl Ester 1a
Although no formation of (η3-benzyl)palladium was
detected in the above NMR analyses, (η1-benzyl)palladium
6a might be in equilibrium with the cationic η3-benzyl
complex. To eliminate the methoxide ligand from 6a, silver
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (AgBARF) was
added to in situ generated 6a, which was prepared by the
reaction of L2−palladium(0) 5 with excess 1a in THF (eq 2,
Scheme 1). Yellow precipitate was formed in the reaction
mixture, and the resulting palladium complex was isolated in
70% yield. Its 31P NMR spectrum was observed in CD2Cl2 at
ambient temperature and consisted of a pair of broad peaks IV
at 38.9 and 59.3 ppm (Figure 3c). The structure of the
complex in the solid state was definitely confirmed to be
[Pd(η3-benzyl)(L2)]BARF (8a) by its X-ray crystallographic
structure analysis (vide infra).
To elucidate the structures and dynamic behaviors of the
above (benzyl)palladium species, authentic (η1- and η3-benzyl)
palladium complexes bearing L2 were prepared as shown in
Scheme 2. Pd(η1-benzyl)Cl(L2) (6b) was obtained from the
reaction of Pd(η1-benzyl)Cl(cod)21 (9) with L2 in CH2Cl2 (eq
3, Scheme 2). In the 31P NMR spectrum of 6b, a pair of
doublet peaks appeared at 31.6 and 42.4 ppm with 28 Hz of
P−P coupling constant. The resonances of the aromatic
protons in the benzyl ligand clearly separated into three peaks
at 6.90, 7.01, and 7.76 ppm, which are, respectively, assigned to
in situ by mixing Pd(η3-C3H5)(Cp) and L2 in THF-d8 at
ambient temperature for 10 min.19 The resonance of the
palladium(0) species appeared as a broad peak I at 32.7 ppm in
the 31P NMR spectrum of the resulting mixture (Figure 3a).
An allylcyclopentadiene, which formed through the reductive
elimination from Pd(η3-C3H5)(Cp), may cause the peak to
broaden because of the weak interaction between the triene
and palladium. The palladium(0) 5 gradually reacted with
benzyl carbonate 1a at ambient temperature to give new peaks
II, and then, the signals III of benzyl methyl ether (7)
1
1
gradually emerged in the H NMR spectrum. The 31P and H
NMR spectra of the reaction mixture at 18 h are given in
Figures 3b and 4b, respectively. In the 31P NMR spectrum, a
Figure 3. 31P{1H} NMR spectra (a) of the in situ-generated 5 in THF-d8, (b) of the reaction mixture of 5 and 1a in THF-d8 after 18 h, and (c) of
8a in CD2Cl2 at ambient temperature.
D
DOI: 10.1021/acs.oprd.9b00210
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Figure 4. 1H NMR spectra (a) of the reaction mixture of 5 and 1a in THF-d8 after 5 min, (b) of the reaction mixture after 18 h, (c) of the reaction
mixture after 18 h with 31P decoupling, (d) of authentic 6b, and (e) of authentic 8b.
Scheme 2. Preparation of Authentic (η1- and η3-
Benzyl)palladium(II)s
NMR spectrum turned to sharp doublet peaks below 0 °C,
while the peak at 58.5 ppm shifted to upfield as the
measurement temperature lowered. In the variable-temper-
ature 1H NMR measurements, the coalescent peak of isopropyl
and ferrocene moiety in L2 were clearly resolved to four
double doublets and four singlets, respectively, at −10 °C. On
the NMR time scale, the two benzylic protons are equivalent to
each other and appeared as a triplet at 25 °C or a doublet
below 0 °C. However, the signal started to collapse at −50 °C
and disappeared at −70 °C. These observations suggest that
the η3−η1−η3 isomerization of the benzyl ligand through the
Cα−C1 bond rotation rapidly occurs above −30 °C.22
Although the equilibrium may be slow on the NMR time
scale below −80 °C, we failed to observe the separated signals
for the two benzylic protons in the variable-temperature NMR
analysis.
The molecular structure of [Pd(η3-benzyl)(L2)]BARF (8a)
was determined with the single-crystal X-ray diffractometry. In
the asymmetric unit, one formula unit of 8a could be located
with the (η3-benzyl)palladium cation disordered over two sites,
where the two sites had the occupation factors of 0.74 and
0.26, respectively (see the SI). The major structure of [Pd(η3-
benzyl)(L2)]+ is shown in Figure 5. The crystal structure
obviously indicates that the benzyl ligand is bound to the
palladium atom with its three carbon atoms at benzylic, ipso,
and ortho positions. The ortho C−Pd bond [2.531(6) or
2.37(4) Å] is longer than the benzylic C−Pd bond [2.087(6)
or 2.093(13) Å]. The ligand L2 chelates the palladium atom
with the 106° bite angle, which is close to that reported for
xantphos (L9) rather than that for DPPF (L1).8 Steric
repulsion between the isopropyl groups in L2 is likely to be the
cause of the larger bite angle. The delocalized benzyl anion is
the p-, m-, and o-protons from each splitting pattern and
integral ratio (Figure 4d). The signal at 3.42 ppm was assigned
to the benzylic protons and split into a double doublet because
of the spin coupling with the two nonequivalent phosphorus
atoms. Meanwhile, the authentic (η3-benzyl)palladium(II) was
prepared by treating the solution of in situ generated 6b with
AgOTf (eq 4, Scheme 2).8 As with 8a, the resulting [Pd(η3-
benzyl)(L2)]OTf (8b) exhibited a pair of broad peaks at 39.1
and 58.5 ppm in its 31P NMR spectrum at ambient
1
temperature. In the H NMR spectrum of 8b, the protons in
the benzyl ligand provided relatively sharp peaks at 3.41, 7.03,
7.60, and 7.75 ppm (Figure 4e), while the signals of L2
broadened. Each peak of the benzyl ligand was assigned to its
benzylic, o-, p-, or m-protons, respectively. Furthermore, the
1
31P and H NMR spectra of 8b were observed in THF-d8 at
various temperatures (see the SI). The broad peaks in the 31P
E
DOI: 10.1021/acs.oprd.9b00210
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
than the benzylic C−Pd bond distance. The angle of Pd1−
C23−C24, 78.3(6)° or 76.8(8)°, is comparable to those
reported for the related (η3-allyl)palladium complexes,8,23
indicating that the benzylic carbon is not sp3-hybridized.
To investigate the reactivity of (benzyl)palladium inter-
mediate 6a with a nucleophile, the in situ generated 6a was
treated with dimethyl malonate (2a) in C6D6. The reaction
1
was monitored by 31P and H NMR measurement (Figure 6).
The solution of 6a was prepared by mixing benzyl methyl
carbonate 1a and 0.2 equiv of in situ generated DiPrPF−
palladium(0) 5 in C6D6 for 3 h (Figure 6a,b). The palladium
species 5 and 6a were assigned to the peaks I and II in the 31
P
NMR spectra, respectively. Equimolar 2a was added to the
resulting mixture of 1a and 6a. Its methoxide would act as the
base for generating the malonate carbanion, leading to the
formation of 3aa. Indeed, approximately 65% of 1a was
alkylated with 2a at 5 h in the 1H NMR analysis. Its 31P NMR
spectrum indicates that 6a is the resting state in the catalytic
benzylic substitution (Figure 6c). When the substrates 1a and
2a completely disappeared from the mixture at 24 h, the peaks
II disappeared and I emerged again (Figure 6d). The further
treatment of the resulting 5 with 1a led to the regeneration of
complex 6a (Figure 6e). These observations indicate that the
(η1-benzyl)palladium 6a participates as an intermediate in the
mechanism of the benzylic substitution. However, the benzyl
ligand on the palladium could react with the carbanion of 2a
through the η1−η3 isomerization, because the η3-benzyl might
be more electrophilic than the η1-benzyl ligand in the analogy
with the allyl complex. To evaluate the relative reactivities of
the η1- and η3-benzyl complexes with nucleophiles, 6b and 8b
were treated with excess dibutylamine (10), which worked as a
nucleophile for the palladium-catalyzed benzylic substitution
Figure 5. ORTEP plot of one of the two disordered structures of 8a
at the 30% probability level (0.74 in occupation). The hydrogen
atoms and BARF counteranion have been omitted for clarity. Selected
bond lengths and angles: Pd1A−C23A = 2.087(6) Å; Pd1A−C24A =
2.279(14) Å; Pd1A−C25A = 2.531(6) Å; Pd1A−P1A = 2.384(3) Å;
Pd1A−P2A = 2.287(2) Å; P1A−Pd1A−P2A = 106.48(13)°; Pd1A−
C23A−C24A = 78.3(6)°. Selected bond lengths and angles for the
other structure (0.26 in occupation): Pd1B−C23B = 2.093(13) Å;
Pd1B−C24B = 2.260(13) Å; Pd1B−C25B = 2.37(4) Å; Pd1B−P1B =
2.281(8) Å; Pd1B−P2B = 2.363(6) Å; P1B−Pd1B−P2B = 106.2(4)°;
Pd1B−C23B−C24B = 76.8(8)°.
bound to the palladium atom through its π-orbital, although
the distance between the ortho C and Pd atoms is much longer
Figure 6. Monitoring the benzylic substitution of 1a with 2a through Pd(η3-C3H5)(Cp)−L2 catalyst with the 31P{1H} NMR measurement.
F
DOI: 10.1021/acs.oprd.9b00210
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
even in the absence of base (Scheme 3).13a The (η3-
benzyl)palladium 8b gave the benzylamine 11 in 94% GC
palladium intermediate. Therefore, the present benzylic
alkylation of benzylic esters was facilitated even at room
temperature in DMF.
Scheme 3. Reaction of (η1- or η3-Benzyl)palladium with
Amine 10
CONCLUSIONS
■
We successfully improved the palladium catalyst for the
benzylic alkylation of benzyl carbonates 1 by using 1,1′-
bis(diisopropylphosphino)ferrocene (DiPrPF, L2) in place of
DPPF (L1) as the ligand. The improved catalyst allowed the
alkylation to proceed at room temperature, giving the desired
products with high yields in various combinations of benzyl
esters and active methine compounds. Although the L2−
palladium complex failed to catalyze the reactions using an
ortho-substituted benzyl ester, diketone, or β-keto ester as a
substrate at 30 °C, such substrates are applicable to the
catalytic benzylic substitution by heating at 50 °C.
yield for 3 h, while no formation of 11 was observed at 24 h in
the reaction of 6b. These observations suggest that the
electrophilicity of the benzyl ligand is enhanced through the
η1−η3 isomerization. The nucleophile would preferentially
attack on the η3-benzyl ligand.
On the basis of the above mechanistic studies, a reaction
mechanism of the catalytic benzylic substitution is proposed as
given in Figure 7. The palladium(0) species 5 is generated
1
The reaction mechanism was investigated with H and 31P
NMR analyses by using the L2−palladium catalyst. The NMR
studies suggested that the catalytic benzylic substitution starts
from the oxidative addition of the benzylic C−O bond of 1 to
the palladium(0) species 5 to form (benzyl)palladium(II).
Although the benzyl ligand was mostly bound to the palladium
atom through a σ-bond in the NMR spectra, the η1-benzyl
complex 6 would be in equilibrium in the cationic (η3-
benzyl)palladium 8, which might preferentially undergo the
nucleophilic attack of stabilized carbanion 2 to give 5 and the
benzylated products 3. Indeed, 8b was much more reactive to
the nucleophile attack of amine than 6b. It is noteworthy that
1
all signals of the benzyl ligand were fully assigned in the H
NMR study because L2 has no benzene ring.
In this study, we successfully proved that palladium(0)
species can activate the benzylic C−O bond in benzyl
carbonate to give (benzyl)palladium(II) species. However,
we failed to observe the direct formation of (η3-benzyl)-
palladium from the reaction of 1 with palladium(0) at this
moment. Although we had treated 5 with 1a in DMSO-d6 or
DMF-d7, the reaction resulted in the formation of yellow
precipitations. Furthermore, dynamic behavior of [Pd(η3-
benzyl)(L2)]+ at room temperature would obstruct the
NMR analysis of the reaction in polar solvent.
Figure 7. Proposed mechanism for the catalytic benzylic substitution
of 1.
EXPERIMENTAL SECTION
■
General. [Pd(η3-C3H5)(cod)]BF4,24 Pd(η3-C3H5)(Cp),25
Pd(η1-benzyl)Cl(cod) (9),8 and AgBARF26 were prepared
according to literature procedures. All other reagents were
purchased from commercial suppliers.
from the nucleophilic attack of the stabilized carbanion 2′ on
the cationic (η3-allyl)palladium(II), which is generated in situ
from [Pd(η3-C3H5)(cod)]BF4 and a bidentate bisphosphine.
The catalytic cycle starts from the oxidative addition of benzyl
ester 1 to 5, which would lead to the formation of (η3-
benzyl)palladium intermediate 8 and the methyl carbonate
anion. The leaving group from 1 liberates carbon dioxide to
give methoxide. The mixture of 8 and methoxide is in
equilibrium with (η1-benzyl)palladium 6, which is the resting
state in the catalytic reaction.22 Although the formation of 6 is
thermodynamically favorable in THF, the (η1-benzyl)-
palladium isomerized into 8 to react with the nucleophile 2′,
which is generated through the deprotonation of 2 with
Cs2CO3 or the methoxide. The attack of 2′ on the η3-benzyl
ligand forms the desired product 3 and regenerates the
palladium(0) 5. The formation of 8 from 6 would be
unfavorable in less polar solvent such as THF because it is
accompanied by charge separation. Use of polar solvent would
cause an increase in the concentration of the (η3-benzyl)-
Procedure for the Preparation of Benzyl Methyl
Carbonates. Under a nitrogen atmosphere, a benzyl alcohol
(10 mmol) and pyridine (0.96 mL, 12 mmol, d 0.985 g/mL)
were added to a solution of 4-(dimethylamino)pyridine (122
mg, 1.0 mmol) in dry CH2Cl2 (10 mL) under a N2
atmosphere. Methyl chloroformate (0.92 mL, 12 mmol, d
1.23 g/mL) was carefully added dropwise to the reaction
mixture. The resulting solution was stirred at ambient
temperature. The reaction was quenched with 1 N HCl (20
mL) and extracted three times with CH2Cl2. The combined
organic layer was washed with brine, dried with Na2SO4, and
then evaporated under reduced pressure after filtration. The
residue was purified with flash column chromatography on
silica gel (EtOAc/hexane) to give the desired benzyl methyl
carbonates 1. Spectrum data of 1a,27 1b,27 1d,28 and 1e29 are
accessible in the literature.
G
DOI: 10.1021/acs.oprd.9b00210
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
1
Methyl 4-(Trifluoromethyl)benzyl Carbonate (1c). H
NMR (400 MHz, CDCl3, TMS): δ 3.82 (s, 3H), 5.21 (s, 2H),
7.50 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H). 13C{1H}
NMR (101 MHz, CDCl3): δ 55.1, 68.5, 123.9 (q, J = 272 Hz),
125.6 (q, J = 4 Hz), 128.1, 130.6 (q, J = 33 Hz), 139.2, 155.6.
Anal. Calcd for C10H9F3O3: C, 51.29; H, 3.87. Found: C,
51.26; H, 3.82.
(EtOAc/hexane = 1/10) to give 3ab (316 mg, 98%) as a
colorless oil: 1H NMR (400 MHz, CDCl3, TMS): δ 1.20 (t, J =
7.1 Hz, 6H), 3.61 (s, 2H), 4.19 (q, J = 7.1 Hz, 4H), 6.86−6.91
(m, 2H), 7.10−7.17 (m, 3H), 7.23−7.28 (m, 5H). 13C{1H}
NMR (101 MHz, CDCl3): δ 13.8, 42.9, 61.5, 64.2, 126.7,
127.4, 127.73, 127.76, 128.3, 130.4, 136.0, 137.0, 170.1.
Diethyl 2-(4-Methoxybenzyl)-2-phenylmalonate
(3bb). See ref 13a.The procedure was followed with the use
of 4-methoxybenzyl methyl carbonate (1b) (196 mg, 1.0
mmol) and 2b (260 mg, 1.1 mmol). The reaction was carried
out for 24 h. The crude product was purified with flash column
chromatography (EtOAc/hexane = 1/5) to give 3bb (354 mg,
99%) as a colorless oil: 1H NMR (400 MHz, CDCl3, TMS): δ
1.21 (t, J = 7.2 Hz, 6H), 3.54 (s, 2H), 3.73 (s, 3H), 4.20 (q, J =
7.2 Hz, 4H), 6.67 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H),
7.22−7.28 (m, 5H). 13C{1H} NMR (101 MHz, CDCl3): δ
13.9, 42.1, 55.0, 61.5, 64.3, 113.1, 127.3, 127.7, 127.9, 128.3,
131.4, 137.0, 158.4, 170.1.
1
Methyl 2-Methylbenzyl Carbonate (1f). H NMR (400
MHz, CDCl3, TMS): δ 2.36 (s, 3H), 3.78 (s, 3H), 5.18 (s,
2H), 7.15−7.36 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3):
δ 18.8, 54.7, 67.9, 125.9, 128.7, 129.3, 130.3, 133.2, 137.0,
155.7. Anal. Calcd for C10H12O3: C, 66.65; H, 6.71. Found: C,
66.58; H, 6.71.
1
Methyl Pyridin-3-ylmethyl Carbonate (1g). H NMR
(400 MHz, CDCl3, TMS): δ 3.81 (s, 3H), 5.18 (s, 2H), 7.31
(ddd, J = 0.7, 4.8, 7.8 Hz, 1H), 7.73 (ddd, J = 1.7, 2.0, 7.8 Hz,
1H), 8.60 (dd, J = 1.7, 4.8 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3): δ 55.0, 66.9, 123.4, 130.8,
136.0, 149.7, 149.9, 155.4. Anal. Calcd for C8H9NO3: C, 57.48;
H, 5.43; N, 8.38. Found: C, 57.40; H, 5.42; N, 8.24.
Diethyl 2-[4-(Trifluoromethyl)benzyl]-2-phenylmalo-
nate (3cb). See ref 13a. The procedure was followed with the
use of 4-(trifluoromethyl)benzyl methyl carbonate (1c) (234
mg, 1.0 mmol) and 2b (259 mg, 1.1 mmol). The reaction was
carried out for 24 h. The crude product was purified with flash
column chromatography (EtOAc/hexane = 1/10) to give 3cb
(379 mg, 96%) as a colorless oil. 1H NMR (400 MHz, CDCl3,
TMS): δ 1.20 (t, J = 7.1 Hz, 6H), 3.65 (s, 2H), 4.20 (q, J = 7.1
Hz, 4H), 7.01 (d, J = 8.1 Hz, 2H), 7.23−7.30 (m, 5H), 7.39
(d, J = 8.1 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ
13.8, 42.6, 61.8, 64.1, 124.2 (q, J = 272 Hz), 124.6 (q, J = 4
Hz), 127.7, 128.0, 128.1, 129.0 (q, J = 32 Hz), 130.8, 136.6,
140.4, 169.8.
1
Methyl Pyridin-4-ylmethyl Carbonate (1h). H NMR
(400 MHz, CDCl3, TMS): δ 3.84 (s, 3H), 5.18 (s, 2H), 7.27
(d, J = 6.1 Hz, 2H), 8.62 (d, J = 6.1 Hz, 2H). 13C{1H} NMR
(101 MHz, CDCl3): δ 55.2, 67.4, 121.7, 144.2, 150.1, 155.5.
HRMS (FAB) Calcd for C8H10NO3: 168.0661. Found: m/z =
168.0660 ([M + H]+).
Procedure for Palladium-Catalyzed of Benzylation
with Soft Carbanion. Under a nitrogen atmosphere, a
mixture of 1,1′-bis(diisopropylphosphino)ferrocene (DiPrPF,
L2) (4.6 mg, 11 μmol), [Pd(η3-C3H5)(cod)]BF4 (3.4 mg, 10
μmol), and Cs2CO3 (358 mg, 1.1 mmol) in dry DMF (1.0
mL) was stirred at ambient temperature for 5 min. A benzyl
carbonate 1 (1.0 mmol) and active methylene compound 2
(1.1 mmol) were added to the suspension. The resulting
mixture was stirred at 30 °C. The mixture was diluted with
hexane and water. The aqueous layer was extracted several
times with hexane. The combined organic layer was washed
with brine, dried with MgSO4, and then evaporated under
reduced pressure. The residue was purified with flash column
chromatography on silica gel (EtOAc/hexane) or by
preparative medium-pressure liquid chromatography
(MPLC) after passing through a short column on silica gel
to give the desired product.
Dimethyl 2-Benzylmalonate (3aa) and Dimethyl 2,2-
Dibenzylmalonate (4aa) (Table 1, Entry 18). The
procedure was followed with the use of benzyl methyl
carbonate (1a) (164 mg, 0.99 mmol), dimethyl malonate
(2a) (197 mg, 1.5 mmol), and Cs2CO3 (490 mg, 1.5 mmol).
The reaction was carried out in DMF (3.0 mL) for 24 h. The
crude product was purified with MPLC (EtOAc/hexane = 1/
5) to give 3aa (95.1 mg, 43%) and 4aa (80.0 mg, 52%) as a
colorless oil. 3aa,13a 1H NMR (400 MHz, CDCl3, TMS): δ
3.22 (d, J = 7.8 Hz, 2H), 3.68 (t, J = 7.8 Hz, 1H), 3.69 (s, 6H),
7.16−7.30 (m, 5H). 13C{1H} NMR (101 MHz, CDCl3): δ
34.7, 52.5, 53.5, 126.7, 128.5, 128.7, 137.7, 169.1. 4aa,12d 1H
NMR (400 MHz, CDCl3, TMS): δ 3.23 (s, 4H), 3.64 (s, 6H),
7.09−7.34 (m, 10H). 13C{1H} NMR (101 MHz, CDCl3): δ
39.2, 52.2, 60.4, 127.0, 128.2, 130.0, 136.1, 171.3.
Diethyl 2-(4-Chlorobenzyl)-2-phenylmalonate (3db).
See ref 13a. The procedure was followed with the use of 4-
chlorobenzyl methyl carbonate (1d) (200 mg, 1.0 mmol) and
2b (259 mg, 1.1 mmol). The reaction was carried out for 48 h.
The crude product was purified with flash column chromatog-
raphy (EtOAc/hexane = 1/10) to give 3db (332 mg, 92%) as a
colorless oil. 1H NMR (400 MHz, CDCl3, TMS): δ 1.20 (t, J =
7.1 Hz, 6H), 3.56 (s, 2H), 4.20 (q, J = 7.1 Hz, 4H), 6.81 (d, J =
8.3 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 7.24−7.30 (m, 5H).
13C{1H} NMR (101 MHz, CDCl3): δ 13.9, 42.3, 61.7, 64.1,
127.5, 127.86, 127.91, 128.2, 131.8, 132.7, 134.6, 136.7, 169.9.
Diethyl 2-[4-(Methoxycarbonyl)benzyl]-2-phenylmal-
onate (3eb). See ref 13a. The procedure was followed with
the use of 4-(methoxycarbonyl)benzyl methyl carbonate (1e)
(225 mg, 1.0 mmol) and 2b (259 mg, 1.1 mmol). The reaction
was carried out for 4 h. The crude product was purified with
flash column chromatography (EtOAc/hexane = 1/10) to give
1
3eb (322 mg, 84%) as a colorless oil. H NMR (400 MHz,
CDCl3, TMS): δ 1.21 (t, J = 7.1 Hz, 6H), 3.64 (s, 2H), 3.88 (s,
3H), 4.21 (q, J = 7.1 Hz, 4H), 6.95 (d, J = 8.3 Hz, 2H), 7.20−
7.29 (m, 5H), 7.81 (d, J = 8.3 Hz, 2H). 13C{1H} NMR (101
MHz, CDCl3): δ 13.9, 42.9, 52.0, 61.8, 64.1, 127.6, 128.0,
128.2, 128.6, 129.0, 130.5, 136.6, 141.6, 167.0, 169.9.
Diethyl 2-(2-Methylbenzyl)-2-phenylmalonate (3fb).
See ref 13b. The procedure was followed with the use of 2-
methylbenzyl methyl carbonate (1f) (182 mg, 1.0 mmol) and
2b (259 mg, 1.1 mmol). The reaction was carried out at 50 °C
for 24 h. The crude product was purified with flash column
chromatography (EtOAc/hexane = 1/5) to give 3fb (331 mg,
97%) as a colorless oil. 1H NMR (400 MHz, CDCl3, TMS): δ
1.24 (t, J = 7.1 Hz, 6H), 1.61 (s, 3H), 3.64 (s, 2H), 4.26 (q, J =
7.1 Hz, 4H), 6.96 (d, J = 7.0 Hz, 1H), 7.00−7.10 (m, 5H),
Diethyl 2-Benzyl-2-phenylmalonate (3ab). See ref 13a.
The procedure was followed with the use of 1a (164 mg, 0.99
mmol) and diethyl 2-phenylmalonate (2b) (259 mg, 1.1
mmol). The reaction was carried out for 48 h. The crude
product was purified with flash column chromatography
H
DOI: 10.1021/acs.oprd.9b00210
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
7.16−7.25 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
13.9, 19.0, 38.7, 61.7, 64.2, 125.6, 126.7, 127.4, 127.7, 128.5,
129.6, 130.1, 134.6, 136.2, 138.3, 170.4.
C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C, 69.83; H,
6.49; N, 4.29.
Diethyl 2-Methyl-2-(pyridin-4-ylmethyl)malonate
(3hc). The procedure was followed with the use of 1h (168
mg, 1.0 mmol) and 2c (182 mg, 1.0 mmol). The reaction was
carried out for 24 h. The crude product was purified with flash
column chromatography (EtOAc/hexane = 2/1) to give 3hc
(227 mg, 85%) as a colorless oil. 1H NMR (400 MHz, CDCl3,
TMS): δ 1.22 (t, J = 7.2 Hz, 6H), 1.35 (s, 3H), 3.21 (s, 2H),
4.20 (q, J = 7.2 Hz, 4H), 7.08 (d, J = 5.9 Hz, 2H), 8.50 (d, J =
5.9 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 13.9, 19.7,
40.4, 54.2, 61.5, 125.4, 145.3, 149.5, 171.3. Anal. Calcd for
C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.05; H,
7.29; N, 5.23.
Diethyl 2-(4-Methoxybenzyl)-2-methylmalonate
(3bc). See ref 13b. The procedure was followed with the use
of 1b (197 mg, 1.0 mmol) and diethyl 2-methylmalonate (2c)
(190 mg, 1.1 mmol). The reaction was carried out for 48 h.
The crude product was purified with flash column chromatog-
raphy (EtOAc/hexane = 1/5) to give 3bc (256 mg, 87%) as a
colorless oil. 1H NMR (400 MHz, CDCl3, TMS): δ 1.25 (t, J =
7.1 Hz, 6H), 1.33 (s, 3H), 3.16 (s, 2H), 3.77 (s, 3H), 4.19 (q, J
= 7.1 Hz, 4H), 6.79 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8.6 Hz,
2H). 13C{1H} NMR (101 MHz, CDCl3): δ 14.0, 19.6, 40.2,
54.8, 55.1, 61.2, 113.5, 128.1, 131.1, 158.5, 172.0.
2-Acetyl-2-(4-methoxybenzyl)cyclohexanone (3bf).
See ref 13b. The procedure was followed with the use of 1b
(196 mg, 1.0 mmol), 2-acetylcyclohexanone 2f (140 mg, 1.1
mmol), and DCyPF (L3) (7.1 mg, 12 μmol). The reaction was
carried out at 50 °C for 24 h. The crude product was purified
with flash column chromatography (EtOAc/hexane = 1/5) to
Dimethyl 2-Methoxy-2-(4-methoxybenzyl)malonate
(3bd). See ref 13a. The procedure was followed with the use
of 1b (195 mg, 1.0 mmol) and dimethyl 2-methoxymalonate
(2d) (179 mg, 1.1 mmol). The reaction was carried out for 24
h. The crude product was purified with flash column
chromatography (EtOAc/hexane = 1/2) to give 3bd (252
1
1
give 3bf (234 mg, 90%) as a pale yellow oil. H NMR (400
mg, 90%) as a pale yellow oil. H NMR (400 MHz, CDCl3,
MHz, CDCl3, TMS): δ 1.42 (ddd, J = 4.3, 12.4, 13.8 Hz, 1H),
1.54−1.77 (m, 3H), 1.91−2.01 (m, 1H), 2.09 (s, 3H), 2.24
(ddd, J = 6.0, 12.6, 14.1 Hz, 1H), 2.32−2.39 (m, 1H), 2.46−
2.54 (m, 1H), 3.03 (d, J = 14.2 Hz, 1H), 3.09 (d, J = 14.2 Hz,
1H), 3.77 (s, 3H), 6.67 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7
Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 22.2, 26.8,
27.0, 33.9, 39.1, 42.1, 55.1, 68.8, 113.6, 128.0, 131.2, 158.4,
205.9, 209.6.
Ethyl 1-(4-Methoxybenzyl)-2-oxocyclohexanecarbox-
ylate (3bg). See ref 13b. The procedure was followed with the
use of 1b (196 mg, 1.0 mmol), ethyl 2-oxocyclohexanecarbox-
ylate 2g (188 mg, 1.1 mmol), and L3 (6.6 mg, 11 μmol). The
reaction was carried out at 50 °C for 120 h. The crude product
was purified with flash column chromatography (EtOAc/
hexane = 1/5) to give 3bg (221 mg, 76%) as a colorless solid.
1H NMR (400 MHz, CDCl3, TMS): δ 1.19 (t, J = 7.12 Hz,
3H), 1.44 (ddd, J = 5.0, 11.7, 13.6 Hz, 1H), 1.54−1.78 (m,
3H), 1.95−2.05 (m, 1H), 2.36−2.51 (m, 3H), 2.83 (d, J = 13.9
Hz, 1H), 3.23 (d, J = 13.9 Hz, 1H), 3.77 (s, 3H), 4.08 (dq, J =
10.8, 7.1 Hz, 1H), 4.13 (dq, J = 10.8, 7.1 Hz, 1H), 6.77 (d, J =
8.7 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H). 13C{1H} NMR (101
MHz, CDCl3): δ 14.0, 22.5, 27.6, 35.8, 39.5, 41.3, 55.2, 61.2,
62.2, 113.4, 128.5, 131.3, 158.3, 171.1, 207.5.
TMS): δ 3.29 (s, 2H), 3.45 (s, 3H), 3.73 (s, 6H), 3.74 (s, 3H),
6.78 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H). 13C{1H}
NMR (101 MHz, CDCl3): δ 38.1, 53.0, 53.8, 54.8, 85.6, 113.4,
126.2, 130.8, 158.4, 168.4.
Diethyl 2-(Acetylamino)-2-(4-methoxybenzyl)-
malonate (3be). See ref 13a. The procedure was followed
with the use of 1b (193 mg, 0.98 mmol) and diethyl 2-
(acetylamino)malonate (2e) (243 mg, 1.1 mmol). The
reaction was carried out in DMF (3.0 mL) for 72 h. The
crude product was purified with flash column chromatography
(EtOAc/hexane = 1/1) to give 3be (312 mg, 95%) as a
colorless solid. 1H NMR (400 MHz, CDCl3, TMS): δ 1.29 (t, J
= 7.1 Hz, 6H), 2.03 (s, 3H), 3.59 (s, 2H), 3.77 (s, 3H), 4.25
(dq, J = 10.7, 7.1 Hz, 2H), 4.28 (dq, J = 10.7, 7.1 Hz, 2H),
6.53 (br s, 1H), 6.79 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz,
2H). 13C{1H} NMR (101 MHz, CDCl3): δ 14.0, 23.0, 36.9,
55.1, 62.5, 67.3, 113.7, 127.1, 130.8, 158.7, 167.6, 169.0.
Diethyl 2-Phenyl-2-(pyridin-3-ylmethyl)malonate
(3gb). The procedure was followed with the use of methyl
pyridin-3-ylmethyl carbonate (1g) (166 mg, 0.99 mmol) and
2b (260 mg, 1.1 mmol). The reaction was carried out for 48 h.
The crude product was purified with flash column chromatog-
raphy (EtOAc/hexane = 1/1) to give 3gb (303 mg, 94%) as a
pale yellow oil. 1H NMR (400 MHz, CDCl3, TMS): δ 1.21 (t,
J = 7.0 Hz, 6H), 3.58 (s, 2H), 4.21 (q, J = 7.0 Hz, 4H), 7.06
(dd, J = 4.8, 7.8 Hz, 1H), 7.18−7.31 (m, 6H), 8.14 (d, J = 1.8
Hz, 1H), 8.40 (d, J = 4.8 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3): δ 13.9, 40.2, 61.8, 64.1, 122.6, 127.7, 128.1, 131.8,
136.6, 137.8, 148.1, 151.6, 169.8. Anal. Calcd for C19H21NO4:
C, 69.71; H, 6.47; N, 4.28. Found: C, 69.81; H, 6.41; N, 4.28.
Diethyl 2-Phenyl-2-(pyridin-4-ylmethyl)malonate
(3hb). The procedure was followed with the use of methyl
pyridin-4-ylmethyl carbonate (1h) (164 mg, 0.98 mmol) and
2b (260 mg, 1.1 mmol). The reaction was carried out for 24 h.
The crude product was purified with flash column chromatog-
raphy (EtOAc/hexane = 1/1) to give 3hb (303 mg, 94%) as a
pale yellow oil. 1H NMR (400 MHz, CDCl3, TMS): δ 1.20 (t,
J = 7.1 Hz, 6H), 3.59 (s, 2H), 4.21 (q, J = 7.1 Hz, 4H), 6.84 (d,
J = 5.9 Hz, 2H), 7.22−7.31 (m, 5H), 8.37 (d, J = 5.9 Hz, 2H).
13C{1H} NMR (101 MHz, CDCl3): δ 13.8, 42.0, 61.9, 63.6,
125.6, 127.7, 128.1, 136.4, 145.3, 149.2, 169.7. Anal. Calcd for
Reaction of L2−Palladium(0) 5 with 1a (Scheme 1,
Equation 1). In a nitrogen-filled dry-box, Pd(η3-C3H5)(Cp)
(3.1 mg, 15 μmol) and L2 (6.5 mg, 16 μmol) were dissolved in
THF-d8 (0.7 mL) in a vial. The resulting solution was
transferred into a screw-capped NMR tube. The tube was
sealed with a cap containing a septum and then removed from
the dry-box. The solution was analyzed with NMR measure-
ments. Benzyl ester 1a (3.2 mg, 19 μmol) was added to the
1
solution which was then mixed well with shaking. Its H,
1H{31P}, and 31P{1H} NMR spectra were observed after 5 min
and 1, 2, 3, 6, and 18 h.
Reaction of 5, 1a, and Silver Tetrakis[3,5-bis-
(trifluoromethyl)phenyl]borate (AgBARF) (Scheme 1,
Equation 2). Under a nitrogen atmosphere, a solution of
Pd(η3-C3H5)(Cp) (4.3 mg, 20 μmol) and L2 (8.8 mg, 21
μmol) in dry THF (0.5 mL) was stirred for 10 min. Benzyl
ester 1a (16.7 mg, 0.10 mmol) was added to the solution. After
2 h, AgBARF (21.3 mg, 22 μmol) was added to the mixture.
After 15 min, the solvent was removed in vacuo. The residue
I
DOI: 10.1021/acs.oprd.9b00210
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
1
was dissolved in dry CH2Cl2. The resulting suspension was
filtered through a Cerite pad. The filtrate was condensed to ca.
0.5 mL under reduced pressure, and layered with dry Et2O.
The Et2O was allowed to diffuse into the CH2Cl2 solution at
−30 °C. The yellow−orange crystals of [Pd(η3-benzyl)-
(DiPrPF)]BARF (8a) (20.3 mg, 70%) were collected with
solution was analyzed with H and 31P{1H} NMR measure-
ments. Then, malonate 2a (14.8 mg, 0.11 mmol) was added to
the mixture. The NMR spectra of the mixture were observed
after 5 and 24 h. The mixture was treated with 1a (14.1 mg, 87
μmol) again and analyzed with NMR measurements after 2 h.
Reaction of 6b or 8b with Dibutylamine (10) (Scheme
3). Under a nitrogen atmosphere, dibutylamine (10) (6.3 mg,
49 μmol) was added to a solution of 6b (3.3 mg, 5.1 μmol) or
8b (3.8 mg, 5.0 μmol) and tetradecane (7.5 mg) in dry THF
(0.5 mL) at ambient temperature. The mixture was stirred at
60 °C and analyzed with GC. The GC yields of benzyldibutyl-
amine (11) were calibrated with tetradecane as the internal
standard.
1
filtration and used for the X-ray diffraction study. H NMR
(400 MHz, CD2Cl2): δ 0.6−1.5 (br, 24 H), 1.8−2.2 (br, 2H),
2.2−2.7 (br, 2H), 3.11 (t, J = 3.8 Hz, 2H), 4.2−4.6 (br, 4H),
4.53 (br s, 4H), 6.77 (d, J = 7.0 Hz, 2H), 7.55−7.62 (m, 5H),
7.66 (t, J = 7.4 Hz, 2H), 7.73 (s, 8H). 31P{1H} NMR (162
MHz, CD2Cl2, 85% H3PO4 aq.): δ 38.9 (br, 1P), 59.3 (br, 1P).
Anal. Calcd for C61H55BF24FeP2Pd: C, 49.54; H, 3.75. Found:
C, 49.61; H, 3.73.
Pd(η1-benzyl)Cl(DiPrPF) (6b) (Scheme 2, Equation 3).
Under a nitrogen atmosphere, dry CH2Cl2 (1.0 mL) was added
to a mixture of Pd(η1-benzyl)Cl(cod)8,21 (34.2 mg, 0.10
mmol) and L2 (41.8 mg, 0.10 mmol). The solution was stirred
at ambient temperature for 15 min. The mixture was filtered
through a Cerite pad. The filtrate was condensed to ca. 0.2 mL
under reduced pressure and layered with dry hexane. The
hexane was allowed to diffuse into the CH2Cl2 solution at −30
°C. The yellow−orange crystals of 6b (51.3 mg, 79%) were
collected with filtration. 1H NMR (400 MHz, THF-d8): δ 1.02
(dd, J = 7.1, 16.0 Hz, 6H), 1.14 (dd, J = 7.0, 13.0 Hz, 6H),
1.19 (dd, J = 6.8, 14.4 Hz, 6H), 1.48 (dd, J = 7.2, 15.6 Hz,
6H), 2.57 (octet, J = 7.1 Hz, 2H), 2.77 (octet, J = 7.4 Hz, 2H),
3.42 (dd, J = 5.1, 9.1 Hz, 2H), 4.35−4.46 (m, 8H), 6.90 (t, J =
7.4 Hz, 1H), 7.01 (t, J = 7.6 Hz, 2H), 7.76 (d, J = 7.7 Hz, 2H).
31P{1H} NMR (162 MHz, THF-d8, 85% H3PO4 aq.): δ 31.6
(d, J = 28 Hz, 1P), 42.4 (d, J = 28 Hz, 1P).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.9b00210.
■
S
ORTEP plots of 8a and a copy of 1H, 13C, and 31P NMR
spectra for new compounds and the benzylic sub-
stitution products (PDF)
X-ray data for 8a (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rkuwano@chem.kyuhshu-univ.jp.
ORCID
Ryoichi Kuwano: 0000-0001-9994-6979
Shigeyuki Masaoka: 0000-0003-2678-2269
Notes
[Pd(η1-benzyl)(DiPrPF)]OTf (8b) (Scheme 2, Equation
4). Under a nitrogen atmosphere, dry CH2Cl2 (1.0 mL) was
added to a mixture of Pd(η1-benzyl)Cl(cod)8,21 (34.0 mg, 0.10
mmol) and L2 (42.0 mg, 0.10 mmol). After the solution was
stirred at ambient temperature for 5 min, silver triflate (27.3
mg, 0.11 mmol) was added to the mixture. After 10 min, the
resulting mixture was filtered through a Cerite pad. The filtrate
was condensed to ca. 0.2 mL under reduced pressure and
layered with dry Et2O. The Et2O was allowed to diffuse into
the CH2Cl2 solution at −30 °C. The yellow−orange crystals of
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partly supported by the JSPS KAKENHI Grants
JP16H04149 and JP15KT0066. We thank the Cooperative
Research Program of “Network Joint Research for Material
Devices” for HRMS measurements.
REFERENCES
■
(1) (a) Slator, A. The chemical dynamics of the reactions between
sodium thiosulphate and organic halogen compounds. Part I. Alkyl
haloids. J. Chem. Soc., Trans. 1904, 85, 1286−1304. (b) Slator, A. The
chemical dynamics of the reactions between sodium thiosulphate and
organic halogen compounds. Part II. Halogen-substituted acetates. J.
Chem. Soc., Trans. 1905, 87, 481−494. (c) Slator, A.; Twiss, D. F. The
chemical dynamics of the reactions between sodium thiosulphate and
organic halogen compounds. Part. III. J. Chem. Soc., Trans. 1909, 95,
93−103. (d) Conant, J. B.; Kirner, W. R. The relation between the
structure of organic halides and the speed of their reaction with
inorganic iodides. I. The problem of alternating polarity in chain
compounds. J. Am. Chem. Soc. 1924, 46, 232−252. (e) Conant, J. B.;
Hussey, R. E. The relation between the structure of organic halides
and the speeds of their reaction with inorganic iodides. II. A study of
the alkyl chlorides. J. Am. Chem. Soc. 1925, 47, 476−488. (f) Conant,
J. B.; Kirner, W. R.; Hussey, R. E. The relation between the structure
of organic halides and the speeds of their reaction with inorganic
iodides. III. The influence of unsaturated groups. J. Am. Chem. Soc.
1925, 47, 488−501. (g) King, J. F.; Tsang, G. T. Y.; Abdelmalik, M.
M.; Payne, N. C. Nucleophilic-substitution factors. 1. Coplanar vs
orthogonal bimolecular substitution at a benzylic carbon. X-ray
structure of 2-isobutyl-1,3-dihydrobenzo[c]thiophenium perchlorate.
J. Am. Chem. Soc. 1985, 107, 3224−3232.
1
8b (75.8 mg, 99%) were collected with filtration. H NMR
(400 MHz, THF-d8, at −10 °C): δ 0.91 (dd, J = 7.1, 17.1 Hz,
6H), 1.13 (dd, J = 6.6, 14.6 Hz, 6H), 1.18 (dd, J = 6.6, 16.1
Hz, 6H), 1.40 (dd, J = 7.1, 17.5 Hz, 6H), 2.12 (octet, J = 7.1
Hz, 2H), 2.61−2.75 (m, 2H), 3.44 (d, J = 7.8 Hz, 2H), 4.47 (s,
2H), 4.56 (s, 2H), 4.61 (s, 2H), 4.68 (s, 2H), 7.02 (dd, J = 4.2,
7.0 Hz, 2H), 7.56−7.62 (m, 1H), 7.76 (t, J = 7.5 Hz, 2H).
31P{1H} NMR (162 MHz, THF-d8, 85% H3PO4): δ 39.1 (br,
1P), 58.5 (br, 1P). 31P{1H} NMR (162 MHz, THF-d8, 85%
H3PO4, at −10 °C): δ 36.6 (d, J = 33 Hz, 1P), 55.6 (d, J = 33
Hz, 1P). Anal. Calcd for C30H43F3FeO3P2PdS: C, 47.11; H,
5.67. Found: C, 46.86; H, 5.65.
Monitoring the Catalytic Benzylic Substitution of 1a
with 2a with NMR Measurement (Figure 6). In a nitrogen-
filled dry-box, Pd(η3-C3H5)(Cp) (4.4 mg, 21 μmol) and L2
(9.2 mg, 22 μmol) were dissolved in dry C6D6 (0.7 mL) in a
vial. The resulting solution was transferred into a screw-capped
NMR tube. The tube was sealed with a cap containing a
septum and then removed from the dry-box. The in situ
generated 5 was analyzed with 31P{1H} NMR measurement.
Benzyl ester 1a (17.2 mg, 0.10 mmol) was added to the
solution of 5 and mixed well with shaking. After 3 h, the
(2) (a) Yasuda, M.; Somyo, T.; Baba, A. Direct carbon-carbon bond
formation from alcohols and active methylenes, alkoxyketones, or
J
DOI: 10.1021/acs.oprd.9b00210
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
indoles catalyzed by indium trichloride. Angew. Chem., Int. Ed. 2006,
45, 793−796. (b) Huang, W.; Wang, J. L.; Shen, Q. S.; Zhou, X. G.
An efficient Yb(OTf)3 catalyzed alkylation of 1,3-dicarbonyl
compounds using alcohols as substrates. Tetrahedron Lett. 2007, 48,
3969−3973. (c) Hikawa, H.; Yokoyama, Y. Palladium-catalyzed
benzylation of unprotected anthranilic acids with benzyl alcohols in
water. Org. Lett. 2011, 13, 6512−6515.
(3) (a) Atkins, K. E.; Walker, W. E.; Manyik, R. M. Palladium
catalyzed transfer of allylic groups. Tetrahedron Lett. 1970, 11, 3821−
3824. (b) Hata, G.; Takahashi, K.; Miyake, A. Palladium-catalysed
exchange of allylic groups of ethers and esters with active-hydrogen
compounds. J. Chem. Soc. D 1970, 1392−1393. (c) Takahashi, K.;
Miyake, A.; Hata, G. Palladium-catalyzed exchange of allylic groups of
ethers and esters with active hydrogen compounds. II. Bull. Chem. Soc.
Jpn. 1972, 45, 230−236.
(4) (a) Trost, B. M. Organopalladium intermediates in organic
synthesis. Tetrahedron 1977, 33, 2615−2649. (b) Tsuji, J. New
general synthetic methods involving π-allylpalladium complexes as
intermediates and neutral reaction conditions. Tetrahedron 1986, 42,
4361−4401.
(5) Tsuji, J.; Kiji, J.; Imamura, S.; Morikawa, M. Organic syntheses
by means of noble metal compounds. VIII. Catalytic carbonylation of
allylic compounds with palladium chloride. J. Am. Chem. Soc. 1964,
86, 4350−4353.
(6) Tsuji, J.; Takahashi, H.; Morikawa, M. Organic syntheses by
means of noble metal compounds XVII. Reaction of π-allylpalladium
chloride with nucleophiles. Tetrahedron Lett. 1965, 6, 4387−4388.
(7) (a) Liegault, B.; Renaud, J. L.; Bruneau, C. Activation and
functionalization of benzylic derivatives by palladium catalysts. Chem.
Soc. Rev. 2008, 37, 290−299. (b) Kuwano, R. Catalytic trans-
formations of benzylic carboxylates and carbonates. Synthesis 2009,
2009, 1049−1061. (c) Trost, B. M.; Czabaniuk, L. C. Structure and
reactivity of late transition metal η3-benzyl complexes. Angew. Chem.,
Int. Ed. 2014, 53, 2826−2851. (d) Le Bras, J.; Muzart, J. Production
of Csp3-Csp3 bonds through palladium-catalyzed Tsuji-Trost-type
reactions of (hetero)benzylic substrates. Eur. J. Org. Chem. 2016,
2016, 2565−2593.
(8) Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig, J. F. A
highly active palladium catalyst for intermolecular hydroamination.
Factors that control reactivity and additions of functionalized anilines
to dienes and vinylarenes. J. Am. Chem. Soc. 2006, 128, 1828−1839.
(9) (a) Legros, J.-Y.; Fiaud, J.-C. Palladium-catalyzed nucleophilic
substitution of naphthylmethyl and 1-naphthylethyl esters. Tetrahe-
dron Lett. 1992, 33, 2509−2510. (b) Legros, J.-Y.; Toffano, M.; Fiaud,
J.-C. Palladium-catalyzed substitution of esters of naphthylmethanols,
1-naphthylethanols, and analogues by sodium dimethyl malonate.
Stereoselective synthesis from enantiomerically pure substrates.
Tetrahedron 1995, 51, 3235−3246.
benzylation of 3-aryl oxindoles. J. Am. Chem. Soc. 2010, 132, 15534−
15536.
(12) (a) Recio, A., III; Heinzman, J. D.; Tunge, J. A. Decarboxylative
benzylation and arylation of nitriles. Chem. Commun. 2012, 48, 142−
144. (b) Zhu, Y.; Rawal, V. H. Palladium-catalyzed C3-benzylation of
indoles. J. Am. Chem. Soc. 2012, 134, 111−114. (c) Maji, T.;
Ramakumar, K.; Tunge, J. A. Retro-Claisen benzylation: direct use of
benzyl alcohols in Pd-catalyzed couplings with nitriles. Chem.
Commun. 2014, 50, 14045−14048. (d) Cao, X. Q.; Zhang, Y. G.
Palladium catalyzed direct benzylation/allylation of malonates with
alcohols in situ C-O bond activation. Green Chem. 2016, 18, 2638−
2641. (e) Punna, N.; Das, P.; Gouverneur, V.; Shibata, N. Highly
diastereoselective synthesis of trifluoromethyl indolines by inter-
ceptive benzylic decarboxylative cycloaddition of nonvinyl, trifluor-
omethyl benzoxazinanones with sulfur ylides under palladium
catalysis. Org. Lett. 2018, 20, 1526−1529. (f) Torregrosa, R. R. P.;
Mendis, S. N.; Davies, A.; Tunge, J. A. Palladium-catalyzed
decarboxylative benzylation of acetylides and enolates. Synthesis
2018, 50, 3205−3216.
(13) (a) Kuwano, R.; Kondo, Y.; Matsuyama, Y. Palladium-catalyzed
nucleophilic benzylic substitutions of benzylic esters. J. Am. Chem. Soc.
2003, 125, 12104−12105. (b) Kuwano, R.; Kondo, Y. Palladium-
catalyzed benzylation of active methine compounds without addi-
tional base: remarkable effect of 1,5-cyclooctadiene. Org. Lett. 2004, 6,
3545−3547. (c) Kuwano, R.; Kondo, Y.; Shirahama, T. Trans-
formation of carbonates into sulfones at the benzylic position via
palladium-catalyzed benzylic substitution. Org. Lett. 2005, 7, 2973−
2975. (d) Kuwano, R.; Kusano, H. Palladium-catalyzed nucleophilic
substitution of diarylmethyl carbonates with malonate carbanions.
Chem. Lett. 2007, 36, 528−529. (e) Kuwano, R.; Kusano, H. Benzyl
protection of phenols under neutral conditions: palladium-catalyzed
benzylations of phenols. Org. Lett. 2008, 10, 1979−1982. (f) Makida,
Y.; Usui, K.; Ueno, S.; Kuwano, R. Palladium-catalyzed benzylic
substitution of benzyl carbonates with phosphorus nucleophiles.
Chem. Lett. 2017, 46, 1814−1817.
(14) Yokogi, M.; Kuwano, R. Use of acetate as a leaving group in
palladium-catalyzed nucleophilic substitution of benzylic esters.
Tetrahedron Lett. 2007, 48, 6109−6112.
(15) Thompson, W. H.; Sears, C. T. Kinetics of oxidative addition to
iridium(I) complexes. Inorg. Chem. 1977, 16, 769−774.
(16) Butler, I. R.; Cullens, W. R.; Kim, T.-J. Synthesis of some
isopropylphosphinoferrocenes. Synth. React. Inorg. Met.-Org. Chem.
1985, 15, 109−116.
(17) Kim, T.-J.; Kim, Y.-H.; Kim, H.-S.; Shim, S.-C.; Kwak, Y.-W.;
Cha, J.-S.; Lee, H. S.; Uhm, J.-K.; Byun, S.-I. Functionalized
organometallic ligand (1) synthesis of some ferrocene derivatives of
cyclohexyl- and cyclopentadienyl-phosphines. Bull. Korean Chem. Soc.
1992, 13, 588−592.
(10) (a) Torregrosa, R. R. P.; Ariyarathna, Y.; Chattopadhyay, K.;
Tunge, J. A. Decarboxylative benzylations of alkynes and ketones. J.
Am. Chem. Soc. 2010, 132, 9280−9282. (b) Tabuchi, S.; Hirano, K.;
Miura, M. Palladium-catalyzed asymmetric benzylic alkylation of
active methylene compounds with α-naphthylbenzyl carbonates and
pivalates. Angew. Chem., Int. Ed. 2016, 55, 6973−6977. (c) Najib, A.;
Hirano, K.; Miura, M. Palladium-catalyzed asymmetric benzylic
substitution of secondary benzyl carbonates with nitrogen and oxygen
nucleophiles. Org. Lett. 2017, 19, 2438−2441. (d) Li, T. R.;
Maliszewski, M. L.; Xiao, W. J.; Tunge, J. A. Stereospecific
decarboxylative benzylation of enolates: development and mechanistic
insight. Org. Lett. 2018, 20, 1730−1734.
(18) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. New diphosphine
ligands based on heterocyclic aromatics inducing very high
regioselectivity in rhodium-catalyzed hydroformylation: effect of the
bite angle. Organometallics 1995, 14, 3081−3089.
(19) Otsuka, S.; Yoshida, T.; Matsumoto, M.; Nakatsu, K.
Bis(tertiary phosphine)palladium(0) and -platinum(0) complexes:
preparations and crystal and molecular structures. J. Am. Chem. Soc.
1976, 98, 5850−5858.
(20) (a) Fryzuk, M. D.; Clentsmith, G. K. B.; Rettig, S. J. Reactivity
of electrophilic palladium alkyl cations stabilized by electron-rich
chelating diphosphine ligands. Evidence for dinuclear intermediates
and the formation of a dinuclear mixed-valence methyl cation. J.
Chem. Soc., Dalton Trans. 1998, 2007−2016. (b) Lin, Y.-S.;
Yamamoto, A. Direct carbonylation of benzyl alcohol and its analogs
catalyzed by palladium and HI in aqueous systems and mechanistic
studies. Bull. Chem. Soc. Jpn. 1998, 71, 723−734.
(11) (a) Assie, M.; Legros, J. Y.; Fiaud, J. C. Asymmetric palladium-
catalyzed benzylic nucleophilic substitution: high enantioselectivity
with the DUPHOS family ligands. Tetrahedron: Asymmetry 2005, 16,
́
1183−1187. (b) Assie, M.; Meddour, A.; Fiaud, J.-C.; Legros, J.-Y.
Enantiodivergence in alkylation of 1-(6-methoxynaphth-2-yl)ethyl
acetate by potassium dimethyl malonate catalyzed by chiral palladium-
DUPHOS complex. Tetrahedron: Asymmetry 2010, 21, 1701−1708.
(c) Trost, B. M.; Czabaniuk, L. C. Palladium-catalyzed asymmetric
(21) Stockland, R. A., Jr; Anderson, G. K.; Rath, N. P.; Braddock-
Wilking, J.; Ellegood, J. C. Synthesis of the complexes [PdCIR(cod)]
(R = benzyl, ethyl; cod = 1,5-cyclooctadiene). β-Elimination from
K
DOI: 10.1021/acs.oprd.9b00210
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
[PdCIEt(cod)] to give the η1, η2 and η3 isomers of [Pd2(μ-
Cl)2(C8H13)2]. Can. J. Chem. 1996, 74, 1990−1997.
(22) Becker, Y.; Stille, J. K. The dynamic (1- and -3-benzylbis-
(triethylphosphine)palladium(II) cations. Mechanisms of intercon-
version. J. Am. Chem. Soc. 1978, 100, 845−850.
(23) van Haaren, R. J.; Goubitz, K.; Fraanje, J.; van Strijdonck, G. P.
F.; Oevering, H.; Coussens, B.; Reek, J. N. H.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. An X-ray study of the effect of the bite angle of
chelating ligands on the geometry of palladium(allyl) complex-
es:implications for the regioselectivity in the allylic alkylation. Inorg.
Chem. 2001, 40, 3363−3372.
(24) White, D. A. Cationic diene complexes of palladium(II) and
platinum(II). Inorg. Synth. 1972, 13, 55−65.
(25) Tatsuno, Y.; Yoshida, T.; Otsuka, S. (η3-Allyl)palladium(II)
complexes. Inorg. Synth. 1979, 19, 220−223.
(26) Hayashi, Y.; Rohde, J. J.; Corey, E. J. A novel chiral super-Lewis
acidic catalyst for enantioselective synthesis. J. Am. Chem. Soc. 1996,
118, 5502−5503.
(27) Mukai, T.; Hirano, K.; Satoh, T.; Miura, M. Palladium-
catalyzed direct benzylation of azoles with benzyl carbonates. Org.
Lett. 2010, 12, 1360−1363.
(28) Kumar, S.; Jain, S. L. Non-symmetrical dialkyl carbonate
synthesis promoted by 1-(3-trimethoxysilylpropyl)-3-methylimidazo-
lium chloride. New J. Chem. 2013, 37, 3057−3061.
(29) Ohkoshi, M.; Michinishi, J.-y.; Hara, S.; Senboku, H.
Electrochemical carboxylation of benzylic carbonates: alternative
method for efficient synthesis of arylacetic acids. Tetrahedron 2010,
66, 7732−7737.
L
DOI: 10.1021/acs.oprd.9b00210
Org. Process Res. Dev. XXXX, XXX, XXX−XXX