Oxidative and Reductive Cross-Coupling Reactions Catalyzed by an Anionic "ligandless" Palladium Complex

Article abstract of DOI:10.1021/acs.oprd.8b00274

The anionic complex [NBu₄][Pd(DMSO)Cl₃], which can be synthesized on a gram scale in a single step starting from commercially available starting materials, has been shown to be an active catalyst in the Mizoroki-Heck reaction of aryl halides. We present two new catalytic applications of this complex: the base-free oxidative Heck reaction and the reductive homodimerization of aryl halides. This complex outperformed other palladium salts. In the latter reaction, the catalyst loading could be reduced to 0.01 mol %. The scope of the reactions has been explored, demonstrating the potential of the anionic palladium complex in these catalytic transformations.

Full text of DOI:10.1021/acs.oprd.8b00274

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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Oxidative and Reductive Cross-Coupling Reactions Catalyzed by an
Anionic “Ligandless” Palladium Complex
Felix Schroeter, Swantje Lerch, and Thomas Strassner*
Physikalische Organische Chemie, TU Dresden, Bergstr. 66, 01062 Dresden, Germany
S
* Supporting Information
ABSTRACT: The anionic complex [NBu4][Pd(DMSO)Cl3], which can be synthesized on a gram scale in a single step starting
from commercially available starting materials, has been shown to be an active catalyst in the Mizoroki−Heck reaction of aryl
halides. We present two new catalytic applications of this complex: the base-free oxidative Heck reaction and the reductive
homodimerization of aryl halides. This complex outperformed other palladium salts. In the latter reaction, the catalyst loading
could be reduced to 0.01 mol %. The scope of the reactions has been explored, demonstrating the potential of the anionic
palladium complex in these catalytic transformations.
KEYWORDS: palladium, anionic complex, oxidative Heck reaction, reductive dimerization
a surrogate for the aryl halide) and an alkene for the synthesis
of stilbenes (Scheme 1a).33−57 A viable alternative for the
synthesis of symmetric biphenyls is the reductive homodime-
rization58 of aryl halides (Scheme 1b).59−80 These reactions
are of interest for applications on an industrial scale.81−84
We recently presented the anionic palladium complex 1a
(Scheme 1c) as an active catalyst in the Mizoroki−Heck
reaction of activated aryl chlorides.85 We performed an in-
depth analysis of the reasons for the high catalytic activity,86
which explained the higher activity of 1a compared with 1b
and 1c and suggested that complex 1a might also be suitable
for other cross-coupling reactions. Earlier results by Dyson87,88
and Trzeciak,89−92 among others,93−98 on related anionic
palladium complexes support this suggestion (Scheme 1d).
Therefore, we investigated the performance of complex 1a in
the oxidative Heck reaction and the reductive homodimeriza-
tion in comparison with various commercially available
palladium precatalysts. We explored the scope of these
reactions and found that 1a is indeed a suitable precatalyst
for these transformations.
INTRODUCTION
■
The formation of C−C bonds is the basis for every organic
synthesis.1 Among the most straightforward and well-
established methods are palladium-catalyzed cross-coupling
reactions.2−5 While the Mizoroki−Heck reaction allows access
to stilbenes (Scheme 1a),6−14 the Suzuki−Miyaura reaction,
Scheme 1. Investigated Reactions and Representative
Catalyst Systems
RESULTS AND DISCUSSION
■
Oxidative Heck Reaction. As a model system for the
oxidative Heck reaction, we chose the reaction of phenyl-
boronic acid and styrene. To avoid excess amounts of the more
expensive boronic acid, we used an excess of styrene in the
reaction. We began the optimization using oxygen as the
oxidizing agent (Table 1, entry 1). However, the yield was only
13%.
With copper acetate monohydrate as a co-oxidant, the yield
increased to 35%, but to some extent, undesired biphenyl
formed by homocoupling of the boronic acid (Table 1, entry
among others, yields biphenyls (Scheme 1b).15−23 However,
most of these cross-coupling reactions suffer from low atom
economy and the necessity to use toxic, air-sensitive organo-
metallic reagents.24−26 Among the required aryl halides, aryl
chlorides are the reaction partners of choice since they are less
expensive, but on the other side, they are also less reactive.
One approach to attenuate these drawbacks is the develop-
ment of the oxidative Heck reaction27−32 of a boronic acid (as
Special Issue: Work from the Organic Reactions Catalysis Society
Meeting 2018
Received: August 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.8b00274
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
acetonitrile complex also led to good yields of 88% and 86%,
respectively (Table 2, entries 7 and 8).
Table 1. Optimization of the Reaction Conditions for the
Oxidative Heck Reaction
a
Next, we explored the scope of the reaction (Scheme 2).
The reaction tolerates different methyl-substituted boronic
a
Scheme 2. Substrate Scope of the Oxidative Heck Reaction
catalyst
(mol %)
T
yield
(%)
entry
oxidant (equiv)
solvent (°C)
1
2
1a (1)
1a (1)
air
DMF
100
100
13
35
Cu(OAc)2·H2O (0.2)/ DMF
air
3
4
5
6
7
8
9
1a (1)
1a (1)
1a (1)
1a (1)
1a (0.5)
1a (1)
1a (1)
BQ (0.2)/air
BQ (1.1)
K2S2O8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
100
100
100
100
100
80
48
100
4
b
CuSO4
2
BQ (1.1)
BQ (1.1)
BQ (1.1)
25
24
53
120
a
Reaction conditions: 1 mmol of PhB(OH)2, 1.5 mmol of styrene, 2
mL solvent. Abbreviations: DMF = dimethylformamide, BQ =
b
benzoquinone. 2.2 equiv instead of 1.1 equiv.
2). Benzoquinone (BQ) was more efficient as a co-oxidant
(Table 1, entry 3). A quantitative yield of stilbene was achieved
when BQ was used as a stoichiometric oxidant (Table 1, entry
4). Other oxidants were less efficient (Table 1, entries 5 and
6). Lowering the catalyst loading or altering the reaction
temperature had a detrimental effect on the catalytic activity
(Table 1, entries 7−9). While dioxane, acetonitrile, and
dimethylacetamide also performed well (Table S1, entries 1−
3), the other tested solvents were inefficient (Table S1, entries
4−7). We chose dimethylformamide (DMF) for further
optimization because of its lower volatility. Using equimolar
amounts of styrene and phenylboronic acid is less efficient in
the reaction (Table S1, entry 8); however, an excess of
phenylboronic acid is as efficient as an excess of styrene (Table
S1, entry 9). No base was required for this reaction, which
further improved the atom economy of the process.
a
Reaction conditions: (A) 1 mmol of arylboronic acid, 1.5 mmol of
styrene; (B) 1.5 mmol of arylboronic acid, 1 mmol of styrene. Isolated
yields are shown.
acids. For example, 4-methylstilbene (2b) was isolated in 73%
yield. The yield of 2-methylstilbene (2c) was lower, indicating
that the catalyst is sensitive to steric demand, but to a lesser
extent than in the Mizoroki−Heck reaction.85 Different alkenes
can be employed in the reaction. For example, butyl acrylate
and phenylboronic acid yield butyl cinnamate (2e) in 77%
yield. We noticed that certain substrates only gave low yields
using procedure A. Under the reaction conditions, decom-
position of the boronic acid is possible. In these cases, using
excess boronic acid instead of excess styrene led to improved
results (Scheme 2, conditions B). With these adapted
conditions, both electron-withdrawing and electron-donating
substituents are tolerated well.
Under the optimized reaction conditions, we compared
different palladium precursors (Table 2). Analogously to
Table 2. Comparison of Different Precatalysts in the
a
Oxidative Heck Reaction
The reaction is also applicable on gram scale (Scheme 3)
without the need for flame-dried glassware. To obtain excellent
a
entry
catalyst
1a
1b
yield (%) entry
catalyst
yield (%)
Scheme 3. Gram-Scale Oxidative Heck Reaction
1
2
3
4
100
79
5
6
7
8
Pd(OAc)2
Pd(DMSO)2Cl2
PdCl2
52
58
88
86
1c
66
Na2PdCl4
50
Pd(MeCN)2Cl2
a
Reaction conditions: 1 mmol of PhB(OH)2, 1.5 mmol of styrene.
a
The isolated yield is shown.
earlier results,85 complex 1a performed best (Table 2, entry 1).
The presence of bromide ions in 1b lowers the catalytic activity
(Table 2, entry 2) because bromide binds more strongly to the
palladium center and thus slows substrate binding.9,86,96,99−101
Using the sodium salt of the palladate anion (1c) is also less
efficient, presumably because of the observed lower solubility
(Table 2, entry 3). Other palladium salts were less efficient
(Table 2, entries 4−6), although palladium chloride and its
yields of the stilbene coupling product, styrene must be added
dropwise to a stirred mixture of the remaining reagents in
DMF at 50 °C. Then the reaction mixture is heated to 100 °C
and stirred for 3 days. If styrene is added in one portion, the
yield is significantly lower (14%). Under the optimized
reaction conditions, 1.4 g (78% yield) of stilbene 2a was
isolated.
B
DOI: 10.1021/acs.oprd.8b00274
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Organic Process Research & Development
Article
Reductive Homodimerization of Aryl Bromides. The
dimerization of 4-bromoacetophenone takes place under
reductive reaction conditions. We began the optimization
with a search for a suitable reductant (Table 3). Earlier
at that temperature but dropped to 94% when the temperature
was lowered to 100 °C (Table 3, entries 15 and 16).
Under the optimized reaction conditions, we compared the
different precatalysts (Table 4). Again, complex 1a out-
Table 3. Optimization of the Reaction Conditions for the
Reductive Homodimerization
Table 4. Precatalyst Comparison in the Reductive
Homodimerization
a
a
loading of 1a
T
conv.
(%)
yield
(%)
entry
catalyst
1a
1b
yield (%) entry
catalyst
yield (%)
entry
(mol %)
reductant
TBACl
ascorbic
acid
HQ
HCO2Na
Zn
base
(°C)
1
2
3
4
100
70
5
6
7
8
Pd(DMSO)2Cl2
PdCl2
Pd(MeCN)2Cl2
Na2PdCl4
23
31
36
38
1
2
0.1
0.1
NaOAc
NaOAc
140
140
41
6
0
3
1c
30
Pd(OAc)2
21
3
4
5
6
7
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.03
0.01
0.01
0.001
0.1
NaOAc
NaOAc
NaOAc
NaOAc
Cs2CO3
K2CO3
NaOH
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
140
140
140
140
140
140
140
140
140
140
140
140
120
100
58
75
96
40
4
1
a
Reaction conditions: 1 mmol of 4-bromoacetophenone.
performed all of the other palladium sources (Table 4, entry
1). In this reaction, the reactivities of the other precatalysts
were considerably lower (Table 4, entries 4−8). For example,
palladium chloride led to a yield of only 31% (Table 4, entry
6). At these low catalyst loadings, decomposition of the
catalyst has a more pronounced detrimental effect on the
catalytic activity, which is reflected by the low yield obtained
with palladium acetate (Table 4, entry 4).
Mg
100
100
100
100
100
100
86
3
HQ
HQ
HQ
HQ
HQ
HQ
HQ
HQ
HQ
HQ
93
98
48
100
100
86
8
9
10
11
12
13
14
15
16
b
b
100
100
c
c
Next, we explored the scope of this reaction (Table 5). The
model substrate was efficiently coupled in 95% isolated yield at
49
45
100
94
100
94
0.1
a
Table 5. Best Results upon Screening the Substrate Scope of
Reaction conditions: 1 mmol of 4-bromoacetophenone, 3 h.
Abbreviations: TBACl = tetrabutylammonium chloride; HQ =
the Reductive Homodimerization with Electron-Deficient
a
b
c
Substrates
hydroquinone. The reaction time was 6 h instead of 3 h. The
reaction time was 24 h instead of 3 h.
observations suggested that tetrabutylammonium chloride
(TBACl) would be suitable for this transformation (Table 3,
entry 1).86 However, the desired product was not formed.
Instead, debromination to give acetophenone occurred, which
accounted for the conversion of 41%. Ascorbic acid
decomposed under the reaction conditions and led to only
trace amounts of product (Table 3, entry 2), while a 40% yield
was obtained with hydroquinone (HQ) (Table 3, entry 3).
Stronger reductants, such as sodium formate, zinc, and
magnesium, led to nearly quantitative debromination (Table
3, entries 4−6).
The use of a stronger base was required for a high yield of
the desired product (Table 3, entries 7−10). Among the tested
bases, potassium phosphate gave the dimerization product in
quantitative yield (Table 3, entry 10). Under these reaction
conditions, the catalyst loading could be reduced to 0.03 mol
% and even to 0.01 mol % with a slight decrease in yield (Table
3, entries 11 and 12). At this stage, a quantitative yield of the
product was obtained when the reaction time was slightly
prolonged (Table 3, entry 13). However, when the catalyst
loading was further reduced, the reaction remained incomplete
even after 24 h of reaction time (Table 3, entry 14).
Alternatively, the reaction can be performed at 120 °C with
a catalyst loading of 0.1 mol %. The yield of 100% was retained
b
yields (%)
entry
Ar
conditions
3
4
5
1
2
3
4
5
6
4-Ac-Ph (a)
4-Ac-Ph (a)
4-NC-Ph (b)
4-OHC-Ph (c)
4-NO2-Ph (d)
3,5-(CF3)2-Ph (e)
A
95
89
73
72
(3)
17
0
0
C, 6 h
B
C, 72 h
C, 6 h
A
0
(3)
(8)
65
0
(2)
(3)
0
0
29
a
Reaction conditions: (A) 0.03 mol % 1a, 140 °C, 3 h; (B) 0.1 mol %
1a, 140 °C, 3 h; (C) 0.1 mol % 1a, 100 °C, until conversion was
b
complete (see the indicated times). Isolated yields, except for values
in parentheses, which were determined by GC.
a catalyst loading of 0.03 mol % (Table 5, entry 1, conditions
A). However, for other electron-deficient aryl bromides,
noncatalyzed nucleophilic aromatic substitution of the bromide
by HQ becomes a major side reaction. Another important side
reaction is protodebromination, which accounts for the high
conversion of the substrates (Table S2). On the basis of the
results of the optimization, two alternatives were tested: (1)
the catalyst loading was increased, since it might accelerate the
C
DOI: 10.1021/acs.oprd.8b00274
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Organic Process Research & Development
Article
a
catalyzed reaction relative to the noncatalyzed side reaction
(Table 5, conditions B); (2) the reaction temperature was
lowered to 100 °C to minimize side reactions, and
subsequently, the reaction time was increased until conversion
of the substrates was complete (Table 5, conditions C). These
approaches are summarized in Table S2. We found that the
optimum reaction conditions vary from substrate to substrate.
For example, 4,4-dicyanobiphenyl (3b) was accessible in a
good yield of 73% with conditions B (Table 5, entry 3). In
contrast, 4,4-diformylbiphenyl (3c) can be obtained in 72%
using conditions C (Table 5, entry 4). Nevertheless, neither of
these approaches was successful in the syntheses of 3d and 3e,
where only small amounts of the desired product were formed
(Table 5, entries 5 and 6).
Since the reaction conditions have to be separately
optimized for each compound to reach maximum efficiency,
we preoptimized the reaction conditions in the reaction of
electron-rich aryl bromides (Table S3). While these substrates
do not allow nucleophilic aromatic substitution, we found that
hydrodebromination was still an issue. A slightly increased
catalyst loading offered an optimum between the desired
reaction and the side reaction. Then we compared the yields
under two different sets of reaction conditions (Table 6).
Scheme 4. Gram-Scale Reductive Aryl Halide Dimerization
a
The isolated yield is shown.
available on a gram scale, in the oxidative Heck reaction and
the reductive dimerization of aryl halides. In both reactions,
the complex outperformed other conventional and commer-
cially available palladium salts. In the oxidative Heck reaction,
the reaction conditions can be adapted to yield various
substituted stilbenes. In the reductive dimerization, the
reactivity of the complex depends on balancing the reaction
conditions to minimize side reactions, such as nucleophilic
aromatic substitution and hydrodebromination. Excellent
isolated yields were also obtained upon 10-fold scale-up of
the reactions with only slight adaptions to the reaction
protocol. These results show that complex 1a is also suitable
for cross-coupling reactions on a larger scale.
Table 6. Reaction Scope of the Reductive
Homodimerization with Electron-Rich Substrates
a
EXPERIMENTAL SECTION
■
General Considerations. All of the reactions were
performed under an argon atmosphere unless stated otherwise.
Solvents of at least 99.0% purity were used in all of the
reactions in this study. Toluene and DMF were distilled from
calcium hydride and stored over molecular sieves (4 Å). The
following compounds were synthesized according to literature
procedures: 1a−c,85 Pd(DMSO)2Cl2,108 and Pd-
(MeCN)2Cl2.109 All of the other chemicals were obtained
from common suppliers and used without further purification.
1H and 13C spectra were acquired on Bruker NMR Avance 300
entry
Ar
conditions
yield (%)
1
2
3
4
5
6
Ph
A
35 (3f)
43 (3f)
35 (3g)
57 (3g)
35 (3h)
46 (3h)
B, 48 h
A
B, 48 h
A
4-Me-Ph
and Bruker DRX 500 spectrometers. H and 13C spectra were
1
4-MeO-Ph
referenced internally using the solvent resonances (1H at 7.26
ppm and 13C at 77.0 ppm for CDCl3). Chemical shifts (δ) are
given in parts per million and coupling constants (J) in Hertz.
Elemental analyses were performed by the microanalytical
laboratory of our institute on a Hekatech EA 3000 Euro Vector
elemental analyzer. GC−MS measurements were carried out
on an Agilent 7890A gas chromatograph with an Agilent 5975
series mass-selective detector.
B, 72 h
a
Reaction conditions: (A) 0.25 mol % 1a, 140 °C, 6 h; (B) 0.25 mol
% 1a, 100 °C, until conversion was complete (see the indicated
times). Isolated yields are shown.
Again, at 140 °C, the yields were low, while the substrate was
completely consumed (Table 6, conditions A). Performing the
reaction at a lower temperature until the substrate was
completely consumed led to improved yields (Table 6,
conditions B). The best yield of 57% was obtained for 3g
(Table 6, entry 4). Aryl chlorides were unreactive under the
employed conditions. The occurrence of debromination of the
substrates indicates that the catalyst might also be used in
hydrodehalogenation reactions,102−104 which are frequently
discussed for the treatment of organic-halide-containing
wastewater.105−107
Excellent yields on a larger scale could also be achieved upon
increasing the catalyst load and prolonging the reaction time
(Scheme 4). Again, it was observed that the order of addition
of the reagents was important for obtaining a high yield and
that no flame-dried glassware was necessary to perform the
reaction.
Small-Scale General Catalytic Procedure. All of the
solid reagents were placed in a 10 mL crimp vial, which was
capped with a butyl rubber septum. The vial was evacuated and
subsequently filled with argon three times, and then the solvent
and afterward all of the liquid reagents were added via syringe.
The vials were placed in a preheated aluminum block and
stirred for the indicated time. For determination of the GC
yield, the mixture was diluted with DCM (2 mL). Dodecane
(175 mg) was added as an internal standard, and 50 μL
aliquots of the reaction mixture were dissolved in DCM (2
mL). Then 1 mL of this solution was placed onto a plug of
silica and rinsed with DCM (2 mL). The obtained solution was
analyzed by GC−MS. The yield was determined using a
calibration curve. All yields given are averages of two separate
runs.
CONCLUSION
We investigated the catalytic activity of the anionic “ligandless”
palladium complex [NBu4][Pd(DMSO)Cl3] (1a), which is
For determination of the isolated yields, the reaction mixture
was filtered over Celite and poured into water (10 mL), and
the aqueous phase was extracted with DCM (2 × 10 mL). The
■
D
DOI: 10.1021/acs.oprd.8b00274
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Organic Process Research & Development
Article
(2) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Palladium-catalyzed
cross-coupling reactions in total synthesis. Angew. Chem., Int. Ed.
2005, 44, 4442−4489.
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combined organic phases were washed with water (3 × 20 mL)
and dried over sodium sulfate. The solvent was evaporated
under reduced pressure, and the raw product was adsorbed
onto silica and purified by column chromatography on silica
gel. Product characterization data are given in the Supporting
Information.
Gram-Scale Procedure for the Oxidative Heck
Reaction. In an argon-purged Schlenk tube containing a
magnetic stirring bar, phenylboronic acid (1.22 g, 10 mmol),
benzoquinone (1.31 g, 1.1 equiv), and catalyst 1a (53 mg, 1
mol %) were dissolved in 20 mL of dry DMF. The mixture was
heated to 50 °C under stirring, and styrene (1.56 g, 1.5 equiv)
was added dropwise during a period of 30 min. The mixture
was heated to 100 °C for 72 h under stirring, cooled to room
temperature, and filtered over Celite. Then water (50 mL) was
added to the reaction mixture, and the aqueous phase was
extracted with DCM (3 × 50 mL). The combined organic
phases were washed with water (3 × 30 mL) and dried over
MgSO4. The crude product was adsorbed onto silica and
purified by column chromatography using silica gel (column
diameter, 60 mm; eluent, hexanes). The product was dried
under reduced pressure at 50 °C and obtained as a colorless
solid (1.407 g, 78% yield).
Gram-Scale Procedure for the Reductive Aryl Halide
Dimerization. In an argon-purged Schlenk tube containing a
magnetic stirring bar, 4-bromoacetophenone (1.99 g, 10
mmol) and hydroquinone (1.21 g, 1.1 equiv) were dissolved
in 20 mL of dry DMF. The mixture was heated to 50 °C under
stirring, and catalyst 1a (2.6 mg, 0.05 mol %, via stock
solution) and potassium phosphate (2.56 g, 1.1 equiv) were
added successively. The mixture was heated to 140 °C for 24 h,
cooled to room temperature, and filtered over Celite. Then
water (50 mL) was added to the reaction mixture, and the
aqueous phase was extracted with DCM (3 × 50 mL). The
combined organic phases were washed with water (3 × 30 mL)
and dried over MgSO4. The crude product was adsorbed onto
silica and purified by column chromatography using silica gel
(column diameter, 60 mm; eluent, 2:1 hexanes/ethyl acetate).
The product was dried under reduced pressure at 50 °C and
obtained as gray solid (1.038 g, 87% yield).
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.8b00274.
Supplemental tables and characterization data for the
products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: thomas.strassner@chemie.tu-dresden.de.
ORCID
Thomas Strassner: 0000-0002-7648-457X
Notes
The authors declare no competing financial interest.
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