A Palladium NNC-Pincer Complex as an Efficient Catalyst Precursor for the Mizoroki?Heck Reaction

Article abstract of DOI:10.1002/adsc.201800099

The Mizoroki?Heck reaction of aryl halides (iodides, bromides, or chlorides) with activated alkenes in the presence of a palladium NNC-pincer complex at ppb to ppm loadings gave the corresponding internal alkenes in excellent yields. The total turnover number and turnover frequency reached up to 8.70×10⁸ and 1.21×10⁷ h^?1 (3.36×10³ s^?1), respectively. The catalyst was applied in a ten-gram-scale synthesis of the UV-B sunscreen agent octinoxate (2-ethylhexyl 4-methoxycinnamate). Reaction-rate analyses, transmission electron microscopic examination of the reaction mixture, and poisoning tests suggested that a monomeric palladium species is the catalytically active species in the catalytic cycle. (Figure presented.).

Full text of DOI:10.1002/adsc.201800099

Title: A Palladium NNC-Pincer Complex as an Extremely Efficient
Catalyst Precursor for the Mizoroki–Heck Reaction
Authors: Go Hamasaka, Shun Ichii, and Yasuhiro Uozumi
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10.1002/adsc.201800099
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Palladium NNC-Pincer Complex as an Efficient Catalyst
Precursor for the Mizoroki–Heck Reaction
Go Hamasaka,a,b Shun Ichii,a,b and Yasuhiro Uozumia,b,c,d,
*
a
Institute for Molecular Science (IMS), Myodaiji, Okazaki 444-8787, Japan
FAX: +81-564-59-5574; Phone: +81-564-59-5571; E-mail: uo@ims.ac.jp
b
SOKENDAI (The Graduate University for Advanced Studies), Myodaiji, Okazaki 444-8787, Japan
Green Nanocatalysis Research Team, RIKEN Center for Sustainable Resource Sciences, Hirosawa, Wako 351-0198,
Japan
c
d
JST-ACCEL, Myodaiji, Okazaki 444-8787, Japan
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The Mizoroki–Heck reaction of aryl halides (2-ethylhexyl
4-methoxycinnamate).
Reaction-rate
(iodides, bromides, or chlorides) with activated alkenes in analyses, transmission electron microscopic examination of
the presence of a palladium NNC-pincer complex at ppb to the reaction mixture, and poisoning tests suggested that a
ppm loadings gave the corresponding internal alkenes in monomeric palladium species is the catalytically active
excellent yields. The total turnover number and turnover species in the catalytic cycle.
frequency reached up to 8.70 × 108 and 1.21 × 107 h–1 (3.36
× 103 s–1), respectively. The catalyst was applied in a ten-
Keywords: Mizoroki-Heck reaction; palladium catalysis;
gram-scale synthesis of the UV-B sunscreen agent
octinoxate
pincer complex; aryl halides; alkenes
that operate at ppm loadings is highly desirable.[10,11]
Palladium pincer complexes are attracting
considerable attention from organic chemists because
such catalysts display the required high level of
activity in a variety of catalytic reactions.[12] In
particular, several palladium pincer complexes have
been used in the Mizoroki–Heck reaction at ppb to
ppm loadings.[13,14] However, the substrate scopes of
these catalytic systems are generally too narrow.
We recently reported that at loadings of 1 mol ppb
to 1 mol ppm of the palladium NNC-pincer complex
1[15] catalyzed the allylic arylation of allyl acetates
with sodium tetraarylborates to give the
corresponding products in high yields.[16] Inspired by
these results, we conjectured that the palladium
NNC-pincer complex 1 might also show a high
catalytic activity in the Mizoroki–Heck reaction. Here,
we report successful Mizoriki–Heck reactions in the
presence of ppb-to-ppm loadings of complex 1. The
reactions of a wide variety of aryl iodides or
bromides with terminal alkenes proceeded smoothly
with quite low loadings (1 mol ppb to 10 mol ppm) of
complex 1. The reaction of an activated aryl chloride
also proceeded in the presence of complex 1 at a 100
mol ppm loading. To demonstrate the utility of this
catalytic system, we conducted a ten-gram-scale
synthesis of the UV-B sunscreen agent octinoxate (2-
ethylhexyl 4-methoxycinnamate) in the presence of 1
mol ppm of complex 1. Several experiments were
Introduction
Palladium-catalyzed carbon–carbon bond-forming
reactions are important and are widely used in
syntheses of pharmaceuticals, agrochemicals, and
organic materials on both laboratory and industrial
scales.[1] In particular, Mizoroki–Heck,[2] Suzuki–
Miyaura,[3]
Negishi,[4]
Migita–Kosugi–Stille,[5]
Hiyama,[6] and Sonogashira[7] reactions are
recognized as indispensable reactions in organic
chemistry.[8] However, a percent (parts-per-hundred)-
level loading of a palladium catalyst is usually
required in these reactions to obtain the desired
products in reasonable yields within acceptable
reaction times. When these reactions are used in
preparations of valuable products such as
pharmaceuticals, agrochemicals, or organic materials,
toxic palladium metal contaminants have to be
removed from the final products; for example, the
permissible level of Pd contaminants in oral drugs is
10 ppm or less.[9] Consequently, the removal of
palladium contamination from commercial products
involves considerable effort and cost. In addition, the
depletion of palladium resources has been recognized
as a problem awaiting a solution. Decreasing the
loading of the palladium catalyst is one promising
route toward a solution of these difficulties. In this
context, the development of highly active catalysts
1
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10.1002/adsc.201800099
Advanced Synthesis & Catalysis
performed to identify the catalytically active species.
Reaction-rate analyses, transmission electron
microscopic analysis of the reaction mixture, and
poisoning tests (mercury-amalgamation and Crabtree
tests) showed that a ligandless monomeric palladium
species is the catalytically active species in this
reaction system.
We also examined the catalytic activity of various
other palladium catalysts in this reaction (Scheme 1).
The cationic palladium NNC-pincer complex 5
showed a lower catalytic activity than complex 1.
Nonsubstituted, dimethyl, or monophenyl 1,10-
phenanthroline palladium complexes 6–8 gave
cinnamate 4aa in 35–62% yield. A low yield (<10%)
of 4aa was obtained when the bipyridine-based
complexes 9 and 10 were used as catalysts. The 1,10-
phenanthroline framework is therefore effective in
Results and Discussion
this
reaction.
The
reaction
dichloride
with
or
bis(acetonitrile)palladium
(11)
First, we screened the reaction conditions for the
reaction of iodobenzene (2a) with butyl acrylate (3a)
in the presence of a 1 mol ppm loading of complex 1
at 140 °C (Table 1). When we tested various bases in
N-methylpyrrolidin-2-one (NMP), no reaction took
place in the presence of potassium carbonate or
sodium bicarbonate (Table 1, entries 1 and 2). When
sodium acetate or potassium phosphate was used as
the base, moderate yields of butyl cinnamate [4aa;
butyl (2E)-3-phenylacrylate] were obtained (entries 3
and 4). The reaction in the presence of N,N-
diisopropylethylamine gave cinnamate 4aa in 23%
yield (entry 5). A quantitative yield of 4aa was
obtained in the presence of tributylamine as the base
(entry 6). We also screened various solvents [N,N-
dimethylformamide (DMF), N,N-dimethylacetamide
(DMA), hexan-1-ol, m-xylene, benzonitrile, and
diethylene glycol diethyl ether] (entries 7–12), and
we found that NMP was the optimal solvent for this
reaction.
palladium(II) acetate (12) afforded 4aa in 64 and
70% yield, respectively. The catalytic activities of
bis(triphenylphosphine)palladium(II) chloride (13)
and palladium(II) chloride (14) were lower than those
of 11 and 12. Phosphine ligand did not enhance the
catalytic activity. We also examined the reaction with
Nájera’s catalyst 15,[17] which is known to be an
effective catalyst for the Mizoroki–Heck reaction,
and we obtained 4aa in 58% yield. During the
screening of the catalysts, complex 1 therefore
showed the highest catalytic activity.
Table 1. Screening of Bases and Solvents in the Mizoroki–
Heck Reaction of Iodobenzene (2a) with Butyl Acrylate
(3a) in the Presence of 1 mol ppm Complex 1[a]
Entry Base
Solvent
NMP
Yield, %[b]
1
K2CO3
0
2
NaHCO3 NMP
0
3
4
5
6
7
8
9
NaOAc
K3PO4
iPr2NEt
nBu3N
nBu3N
nBu3N
nBu3N
nBu3N
nBu3N
nBu3N
NMP
NMP
NMP
NMP
DMF
DMA
Hexan-1-ol
m-xylene
PhCN
45
52
23
100 (99)[c]
24
28
24
4
58
16
Scheme 1. Screening of Palladium Catalysts in the
Mizoroki–Heck Reaction of Iodobenzene (2a) with Butyl
Acrylate (3a). Reaction conditions: catalyst (1 mol ppm,
10
11
12
n
1.0 × 10–6 mmol), 2a (1.0 mmol), 3a (1.2 mmol), Bu3N
EtO[(CH2)2O]2Et
[a] Reaction conditions: 1 (1 mol ppm, 1.0 × 10–6 mmol), 2a
(1.0 mmol), 3a (1.2 mmol), base (1.2 mmol), solvent (1.0
(1.2 mmol), NMP (1.0 mL), 140 °C, 15 h. The yield was
determined by GC analysis with mesitylene as an internal
standard.
[b]
mL), 140 °C, 15 h. Determined by GC analysis with an
internal standard (mesitylene). [c] Isolated yield.
2
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10.1002/adsc.201800099
Advanced Synthesis & Catalysis
To demonstrate that our catalytic system works at a
the yield of 4aa was 13%, we added DCT to the
reaction mixture. A suppression of the reaction was
then observed (Figure 1, red line), and the desired
product 4aa was obtained in 37% GC yield after an
additional 8 h [Scheme 3(c)]. It has been reported that
DCT coordinates to monomeric palladium species[20]
to give a stable and catalytically inactive DCT–Pd
complex [Figure 3(a)], whereas DCT cannot
coordinate to palladium clusters because of its
structural rigidity [Figure 3(b)]. Consequently, the
result of the Crabtree test suggests that a monomeric
palladium species is involved in this catalytic cycle.
If palladium clusters were essential to promote the
catalytic process, the Mizoroki–Heck reaction should
proceed efficiently in the presence of DCT. Although
palladium nanoparticles were observed by the TEM
analysis, the Crabtree test suggested that monomeric
palladium species are generated under the reaction
conditions. From these experimental results, the
catalytic cycle shown in Scheme 4 is proposed.
Palladium complex 1 is reduced under the thermal
conditions to form the monomeric palladium(0)
species A and/or palladium(0) clusters E. An
equilibrium between A and E should exist under the
reaction conditions. The monomeric Pd(0) species A
promotes the Mizoroki–Heck reaction, and a
monomeric palladium(II) species B is generated
through the reaction of A with the haloarene. The
usual Mizoroki–Heck process then takes place, giving
desired product along with regeneration of A.
Therefore, complex 1 acts as a good precursor for the
catalytically highly active palladium(0) species A.
ppb loading, we examined the Mizoroki–Heck
reaction of iodobenzene (2a) with butyl acrylate (3a)
in the presence of a 1 mol ppb loading of complex 1
(Scheme 2) under solvent-free conditions at 160 °C
for 72 h, and we obtained cinnamate 4aa in 87%
yield. In this case, the total turnover number was 8.70
× 108 and the turnover frequency was 1.21 × 107 h–1
(3.36 × 103 s–1).
Scheme 2. The Mizoroki–Heck Reaction of Iodobenzene
(2a) with Butyl Acrylate (3a) in the Presence of 1 mol ppb
of Complex 1.
We performed several experiments to identify the
catalytically active species in our reaction. Initially,
we checked the time course of the yield of cinnamate
4aa in the reaction of iodobenzene (2a) with butyl
acrylate (3a) in the presence of 1 mol ppm of
complex 1 [Figure 1 (black line) and Scheme 3(a)].
An induction period was observed in the initial stages
of this reaction (up to 1 h), suggesting that the
catalytic active species is generated in situ. We next
performed a transmission electron microscopy (TEM)
analysis of the reaction mixture after the reaction.
Palladium nanoparticles were observed in the
reaction mixture (Figure 2). The average size of these
nanoparticles was estimated to be 2.2 ± 0.7 nm.
These experimental results showed that complex 1 is
a precursor of the actual catalytically active species in
this reaction. To obtain more information on the
catalytic active species, we performed a mercury-
amalgamation test.[18] Under the standard reaction
conditions (Table 1 entry 6), the addition of one drop
of mercury to the reaction mixture at two hours, when
the GC yield of 4aa was 15%, significantly retarded
the reaction, which finally gave 4aa in 19% GC yield
after an additional eight hours [Figure 1 (blue line)
and Scheme 3(b)]. If a ligandless palladium metal
species (i.e., a ligandless monomeric palladium
species and/or palladium cluster) is generated in situ,
the reaction should be inhibited by the amalgamation
of this species with Hg. This experimental result
indicates that a ligandless palladium species is indeed
the catalytically active species in this reaction.
Although the TEM observations and the mercury-
amalgamation test suggested that the complex 1 is a
precursor of the catalytically active species, it was
unclear at this stage whether the catalytically active
species consists of palladium clusters or monomeric
palladium species. We therefore performed a
Crabtree test [the addition of dibenzo[a,e]cyclooctene
(DCT)].[19] After starting the reaction under the
standard conditions (Table 1 entry 6) for 2 h, when
Figure 1. Time Course of the Yield of the Reaction of
Iodobenzene (2a) with Butyl Acrylate (3a) in the Presence
of 1 mol ppm Complex 1. Standard Conditions (black
line); Mercury-Amalgamation Test (blue line); Crabtree
Test (red line).
3
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10.1002/adsc.201800099
Advanced Synthesis & Catalysis
Scheme 4. Proposed Catalytic Cycle.
Scheme 3. (a) Standard Reaction Conditions; (b) Mercury-
Amalgamation Test; (c) Crabtree Test.
Complex 1 was used in the Mizoroki–Heck
reactions of a variety of aryl iodides with alkenes
(Scheme 5). The reaction of p-, m-, and o-
iodotoluenes (2b–d) with butyl acrylate (3a) in the
presence of a 1 mol ppm loading of complex 1 gave
the corresponding tolylacrylates 4ba, 4ca, and 4da in
high yields. The position of the methyl group on the
aromatic ring did not affect the efficiency of the
reaction. A variety of iodobenzenes substituted with
electron-donating groups (2e–g) or electron-
withdrawing groups (2h–n) gave the corresponding
internal alkenes 4ea–na in high yields. This reaction
system tolerated catalyst-poisoning functionalities
such as methylsulfanyl (4fa) or dimethylamino (4ga)
groups. The reactions of 1-fluoro-4-iodobenzene (2o),
4-iodobiphenyl (2p), and 1-iodonaphthalene (2q)
with acrylate 3a gave the corresponding alkenes 4oa,
4pa, and 4qa in 99, 86, and 72% yield, respectively.
In this catalytic system, iodohetarenes also underwent
the reaction. Complex 1 catalyzed the reaction of 5-
iodoindole (2r) with 3a to give 4ra in 91% yield. The
reaction of 2-iodothiophene (2s), carried out in the
presence of 10 mol ppm of complex 1 and NaOAc
instead of Bu3N, gave the desired alkene 4sa in 92%
yield.
Figure 2. TEM Image of the Reaction Mixture (Table 1,
entry 6). Average diameter of nanoparticles: 2.2 ± 0.7 nm.
Next, we examined the reaction with other terminal
alkenes
3b–e.
Styrene
(3b)
and
N,N-
dimethylacrylamide (3c) gave the desired products
4ab and 4ac, respectively, in good yields. The
reaction of iodobenzene (2a) with phenyl vinyl
sulfone (3d) or 1-phenylprop-2-en-1-ol (3e) also
proceeded in the presence of 10 mol ppm of complex
1 to afford 4ad and 4ae in 86 and 69% yield,
respectively.
Figure 3. Schematic Structures of DCT (a) with
Monomeric Pd Species, (b) with Pd Clusters.
4
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10.1002/adsc.201800099
Advanced Synthesis & Catalysis
efficiency increased dramatically. A lower catalyst
loading (1 mol ppm) and a shorter reaction time (24
h) could be achieved in the reactions of
bromobenzene (16a) and 4-bromoacetophenone
(16h) with styrene (2b), giving the stilbenes 4ab and
4hb in 99 and 95% yield, respectively. Whereas the
reactions of 16e and 16x with 3a did not proceed
efficiently, these compounds reacted efficiently with
styrene (2b) to give 4eb and 4xb, respectively, in
good yields.
Scheme 6. Substrate Scope of the Mizoriki–Heck Reaction
of Aryl Bromides 16 with Alkenes 3 in the Presence of
Complex 1. Reaction conditions: 1 (10 mol ppm, 1.0 × 10–5
mmol), 16 (1.0 mmol), 3 (1.2 mmol), NaOAc (1.5 mmol),
NMP (1.0 mL), 140 °C, 48 h. The yields refer to isolated
Scheme 5. Substrate Scope of the Mizoriki–Heck Reaction
of Aryl Iodides 2 with Alkenes 3 in the Presence of
Complex 1. Reaction conditions: 1 (1 mol ppm, 1.0 × 10–6
n
[c]
products. [a] 160 °C. [b] 1 (1 mol ppm, 1.0 × 10–6 mmol).
mmol), 2 (1.0 mmol), 3 (1.2 mmol), Bu3N (1.2 mmol),
24 h. [d] The ratio of regioisomers ( arylation/ arylation)
NMP (1.0 mL), 140 °C, 15 h. The yields refer to isolated
[a]
[b]
products. 1 (10 mol ppm, 1.0 × 10–5 mmol). NaOAc
was determined by 1H NMR.
n
[c]
(1.5 mmol) was used instead of Bu3N. Containing 9%
of the -arylated product.
We also applied our catalytic system to the
reaction of a less-reactive aryl chloride. Thus, the
reaction of 4-chloroacetophenone (17) with styrene
(3b) proceeded in the presence of 100 ppm loading of
1 in NMP at 160 °C for 48 hours to give alkene 4hb
in 25% yield (Scheme 7).
A ppm loading of complex 1 also catalyzed the
Mizoroki–Heck reaction of aryl bromides (Scheme 6).
The reaction of bromobenzene (16a) with butyl
acrylate (3a) in the presence of a 10 mol ppm loading
of complex 1 in NMP at 140 °C for 48 hours gave
alkene 4aa in 99% isolated yield.[21,22] 2-
Bromonaphthalene (16b) and 1-bromopyrene (16c)
also underwent the reaction to afford the
corresponding alkenes 4ta and 4ua in 94 and 84%
yield, respectively. The reaction of bromobenzenes
16h, 16v, and 16w, containing electron-withdrawing
groups, proceeded smoothly to give the
corresponding acrylates 4ha, 4va, and 4wa in good
yields. On the other hand, bromobenzenes 16b and
16e, containing electron-donating substituents, gave
moderate yields of the corresponding products 4ba
and 4ea. The reaction of 3-bromopyridine (16x) with
3a also failed to proceed efficiently. When styrene
(2b) was used as the coupling partner, the reaction
Scheme 7. The Mizoroki–Heck Reaction of 4-
Chloroacetophenone (17) with Styrene (3b).
To demonstrate the utility of our catalytic system,
we used complex 1 in a ten-gram-scale synthesis of
the UV-B sunscreen agent octinoxate (4ef; 2-
5
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10.1002/adsc.201800099
Advanced Synthesis & Catalysis
ethylhexyl 4-methoxycinnamate)[23] (Scheme 8). The
reaction of 1-iodo-4-methoxybenzene (2e; 9.36 g,
40.0 mmol) with acrylate 3f (9.93 mL, 48.0 mmol) in
the presence of 1 mol ppm complex 1 (20 g) and
tributylamine in NMP at 140 °C for 15 h gave 10.86
g (94%) of octinoxate (4ef). The resulting product 4ef
was tested for metal contamination by ICP-AES
analysis to detect palladium. This result indicated
that the content of palladium in the product was
below 1 weight ppm (<1 g Pd/g 4ef).
product that was purified by chromatography [silica gel,
hexane–EtOAc (20:1)] to give butyl (2E)-3-phenylacrylate
(4aa) as a colorless oil; yield: 201 mg (0.99 mmol, 99%).
Butyl (2E)-3-Phenylacrylate (4aa) [CAS: 52392-64-0]:
1
Colorless oil. H NMR (396 MHz, CDCl3, δ): 7.69 (d, J =
16.0 Hz, 1H), 7.55–7.51 (m, 2H), 7.40–7.37 (m, 3H), 6.45
(d, J = 16.0 Hz, 1H), 4.21 (t, J = 6.8 Hz, 2H), 1.73–1.66 (m,
2H), 1.49–1.40 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3, δ): 167.20, 144.63, 134.52, 130.28,
128.93, 128.12, 118.33, 64.51, 30.83, 19.28, 13.84. EI-MS:
m/z 204 (M+).
The Mizoroki–Heck Reaction of Iodobenzene (2a) with
Butyl Acrylate (3a) in the Presence of a 1 mol ppb
Loading of the Complex 1 (Scheme 2): A Schlenk tube
and a stirrer bar were treated with piranha solution (3:1
concd H2SO4–30% aq H2O2) for 30 min, then rinsed with
pure water and treated with aqua regia (1:3 concd aq HCl–
concd. aq HNO3) for 30 min. The treated Schlenk tube and
stirrer bar were rinsed vigorously with pure water to
remove acid components then dried with heating. This
reaction vessel was charged with dry Et2O (5 mL), Et3N (1
mL), and TMSCl (0.5 mL) under N2 to cap any surface
silanols on the glassware. After stirring at room
temperature for 30 min, the mixture was removed by
decantation and the vessel was washed with acetone and
pure water, then dried with heating.
Scheme 8. Ten-Gram-Scale Synthesis of the UV-B
Sunscreen Agent Octinoxate (4ef) in the Presence of 1 mol
ppm Complex 1.
The palladium complex 1 (0.47 mg, 0.001 mmol) was
dissolved in NMP (10 mL). The catalyst solution (10 L;
1.0 × 10–6 mmol) was further diluted with NMP (10 mL).
The resulting solution (10 L, 1.0 × 10–9 mmol) was added
to a mixture of PhI (2a; 203 mg, 1.0 mmol), butyl acrylate
(3a; 0.17 mL, 1.2 mmol), and Bu3N (0.28 mL, 1.2 mmol),
and the resulting mixture was degassed by three freeze–
pump–thaw cycles. The mixture was then stirred
vigorously at 160 °C for 72 h under N2. The mixture was
cooled to 25 °C, and purified by direct chromatography
[silica gel, hexane–EtOAc (20:1)] to give butyl (2E)-3-
phenylacrylate (4aa); yield: 177 mg (0.87 mmol, 87%).
Conclusion
In summary, we have found that complex 1 is a
good catalyst precursor for the Mizoroki–Heck
reaction. The reaction of aryl halides with activated
terminal alkenes in the presence of quite low loadings
of complex 1 gave the desired coupling products in
excellent yields. In the reaction of iodobenzene with
butyl acrylate, the total turnover number and turnover
frequency reached 8.70 × 108 and 1.21 × 107 h–1 (3.36
× 103 s−1), respectively. Reaction-rate analysis,
poisoning tests (mercury-amalgamation and Crabtree
tests), and TEM analyses of the reaction mixture
suggested that a monomeric Pd(0) species is involved
in the catalytic cycle. The catalyst was successfully
applied to a ten-gram-scale synthesis of the UV-B
sunscreen agent octinoxate. Further catalytic
Ten-Gram-Scale Synthesis of the UV-B Sunscreen
Agent Octinoxate (4ef) (Scheme 8). A Schlenk tube and a
stirrer bar were cleaned with aqua regia (1:3 concd aq
HCl–concd aq HNO3) for 30 min, washed with
sequentially with pure water and acetone, and dried with
heating. The palladium complex 1 (0.47 mg, 0.001 mmol)
was dissolved in NMP (10 mL). The catalyst solution (400
µL, 20 µg, 4.0 × 10–5 mmol) was added to a mixture of 4-
iodoanisole (2e; 9.36 g, 40.0 mmol), 2-ethylhexyl acrylate
(3f; 9.93 mL, 48.0 mmol), and Bu3N (11.2 mL, 48.0
mmol) in NMP (40 mL). The resulting solution was
degassed by three freeze–pump–thaw cycles, and then
stirred vigorously at 140 °C for 15 h under N2. The mixture
was then cooled to 25 °C, diluted with t-BuOMe (40 mL),
and washed with 0.5 M aq HCl (60 mL). The aqueous
layer was extracted with t-BuOMe (3 × 20 mL) and the
extracts were combined, washed with brine (50 mL), and
dried over Na2SO4. The resulting solution was
concentrated under reduced pressure to give a crude
product was that was purified by chromatography [silica
gel, hexane–EtOAc (20:1)] to give 2-ethylhexyl (2E)-3-(4-
methoxyphenyl)acrylate (4ef) as a colorless oil; yield:
10.86 g (37.6 mmol, 94%).
applications of complex
investigation in our laboratory.
1
are now under
Experimental Section
Typical Procedure for the Mizoroki–Heck Reaction of
Aryl Halides with Alkenes (Table 1, entry 6): A Schlenk
tube and a stirrer bar were treated with aqua regia (1:3
concd aq HCl– concd aq HNO3) for 30 min, washed
sequentially with pure water and acetone, and dried with
heating. The palladium complex 1 (0.47 mg, 0.001 mmol)
was dissolved in NMP (10 mL), and the catalyst solution
(10 L, 1 × 10–6 mmol) was added to a mixture of PhI (2a;
203 mg, 1.0 mmol), butyl acrylate (3a; 0.17 mL, 1.2
mmol), and Bu3N (0.28 mL, 1.2 mmol) in NMP (1.0 mL).
The resulting solution was degassed by means of three
freeze–pump–thaw cycles, and then stirred vigorously at
140 °C for 15 h under N2. The mixture was then cooled to
25 °C, diluted with t-BuOMe (15 mL), transferred to a
separatory funnel, and washed with 0.5 M aq HCl (20 mL).
The aqueous layer was extracted with t-BuOMe (3 × 10
mL), and the extracts were combined, washed with brine
(20 mL), and dried over Na2SO4. The resulting solution
was concentrated under reduced pressure to give a crude
2-Ethylhexyl (2E)-3-(4-Methoxyphenyl)acrylate (4ef)
1
[CAS: 83834-59-7]: Colorless oil. H NMR (396 MHz,
CDCl3, δ): 7.63 (d, J = 16.0 Hz, 1H), 7.49 (d, J = 8.8 Hz,
2H), 6.91 (d, J = 9.2 Hz, 2H), 6.32 (d, J = 16.0 Hz, 1H),
4.12–4.10 (m, 2H), 3.84 (s, 1H), 1.68–1.62 (m, 1H), 1.46–
1.24 (m, 9H), 0.94–0.89 (m, 7H). 13C NMR (100 MHz,
CDCl3, δ): 167.65, 161.37, 144.22, 129.77, 127.28, 115.88,
114.35, 66.88, 55.43, 38.95, 30.54, 29.04, 23.91, 23.08,
14.16, 11.11. EI-MS: m/z 290 (M+).
TEM Analysis: A sample for TEM analysis was prepared
as follows. After the Heck reaction of iodobenzene (2a)
6
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10.1002/adsc.201800099
Advanced Synthesis & Catalysis
with butyl acrylate (3a), the reaction mixture was dropped
onto a copper grid covered with a carbon membrane. The
sample was rinsed with water and ethanol then dried under
air. The resulting sample was then examined by TEM.
[8] C. C. C. Johansson Seechurn, M. O. Kitching, T. J.
Colacot, V. Snieckus, Angew. Chem. Int. Ed. 2012, 51,
5062–5085; Angew. Chem. 2012, 124, 5150–5174.
[9] In the preparation of oral drugs, the permitted level of
contamination of the products by palladium is than 10
ppm. The ICH Q3D guidelines can be downloaded
here:
Poisoning Tests: The palladium complex 1 (0.47 mg,
0.001 mmol) was dissolved in NMP (10 mL). The resulting
catalyst solution (10 µL, 1 mol ppm Pd) was added to a
mixture of PhI (2a) (203 mg, 1.0 mmol), butyl acrylate
(3a) (0.17 mL, 1.2 mmol), and Bu3N (0.28 mL, 1.2 mmol)
in NMP (1.0 mL). The resulting solution was degassed by
three freeze–pump–thaw cycles, and then stirred
vigorously at 140 °C for 2 h under N2. Then one drop of
Hg(0) or a 2 mol ppm solution of DCT in NMP was added
under flowing N2. The mixture was further stirred at
140 °C. Yields were determined by GC, with mesitylene as
an internal standard.
http://www.ich.org/products/guidelines/quality/article/q
uality-guidelines.html (accessed Jan 5, 2018).
[10] a) V. Farina, Adv. Synth. Catal. 2004, 346, 1553–
1582; b) C. Deraedt, D. Astruc, Acc. Chem. Res. 2014,
47, 494–503; c) D. Roy. Y. Uozumi, Adv. Synth. Catal.
2018, 360, 602–625.
[11] For recent examples on the C-C bond forming
reaction with palladium catalysts at ppm loadings, see:
a) T. Baran, N. Baran, A. Mentes, Appl. Organomet.
Chem. 2018, 32, e4076; b) T. Baran, I. Sargin, M. Kaya,
P. Mulercikas, S. Kazlauskaite, A. Mentes, Chem. Eng.
J. 2018, 331, 102–113; c) P. A. Mane, S. Dey, K. V.
Vivekananda, Tetrahedron Lett. 2017, 58, 25–29; d) F.
Puls, N. Richter, O. Kataeva, H. J. Knolker, Chem. Eur.
J. 2017, 23, 17576–17583; e) V. Ramakrishna, N. D.
Reddy, Dalton Trans. 2017, 46, 8598–8610; f) S. J.
Sabounchei, M. Hosseinzadeh, M. Zarepour-jevinani, B.
Ghanbari, New J. Chem. 2017, 41, 9701–9709.
Acknowledgements
This research project was supported by JST-ACCEL program
(JPMJAC1401). We appreciate funding from the JSPS (Grant-in-
Aid for Young Scientists (B) No. 17K14524 and Grant-in-Aid for
JSPS Research Fellow No. 17J05446).
References
[1] a) C. Torborg, M. Beller, Adv. Synth. Catal. 2009, 351,
3027–3043; b) J. Magano, J. R. Dunetz, Chem. Rev.
2011, 111, 2177–2250; c) A. F. P. Biajoli, C. S.
Schwalm, J. Limberger, T. S. Claudino, A. L. Monteiro,
J. Braz. Chem. Soc. 2014, 25, 2186–2214; d) S. Xu, E.
H. Kim, A. Wei, E.-i. Negishi, Sci. Technol. Adv.
Mater. 2014, 15, 044201 (23 pp).
[12] a) M. Albrecht, G. van Koten, Angew. Chem. Int. Ed.
2001, 40, 3750–3781; Angew. Chem. 2001, 113, 3886–
3898; b) M. E. van der Boom, D. Milstein, Chem. Rev.
2003, 103, 1759–1792; c) J. T. Singleton, Tetrahedron,
2003, 59, 1837–1857; d) K. J. Szabó, Synlett, 2006,
811–824; e) D. Benito-Garagorri, K. Kirchner, Acc.
Chem. Res. 2008, 41, 201–213; f) N. Selander, K. J.
Szabó, Dalton Trans. 2009, 6267–6279; g) N. Selander,
K. J. Szabó, Chem. Rev. 2011, 111, 2048–2076; h)
Organometallic Pincer Chemistry, Topics in
Organometallic Chemistry; Vol. 40; Springer, (Eds.: G.
van Koten, D. Milstein), Heidelberg, 2013.
[2] a) T. Mizoroki, K. Mori, A. Ozaki Bull. Chem. Soc.
Jpn. 1971, 44, 581; b) R. F. Heck, J. P. Nolley, Jr., J.
Org. Chem. 1972, 37, 2320–2322; c) I. P. Beletskaya,
A. V. Cheprakov, Chem. Rev. 2000, 100, 3009–3066.
[3] a) N. Miyaura, K. Yamada, A. Suzuki, Tetrahedron
Lett. 1979, 20, 3437–3440; b) N. Miyaura, T. Yanagi,
A. Suzuki, Synth. Commun. 1981, 11, 513–519; c) N.
Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–2483
[13] For reports on the Mizoroki–Heck reaction with
palladium pincer complexes at ppm loadings, see: a) M.
Ohff, A Ohff, M. E. van der Boom, D. Milstein, J. Am.
Chem. Soc. 1997, 119, 11687–11688; b) F. Miyazaki,
K. Yamaguchi, M. Shibasaki, Tetrahedron Lett. 1999,
40, 7379–7383; c) D. Morales-Morales, C. Grause, K.
Kasaoka, R. Redón, R. E. Cramer, C. M. Jensen, Inorg.
Chim. Acta, 2000, 300–302, 958–963; d) S. Sjövall, O.
F. Wendt, C. Andersson, J. Chem. Soc., Dalton Trans.
2002, 1396–1400; e) I. G. Jung, S. U. Son, K. H. Park,
K.-C. Chung, J. W. Lee, Y. K. Chung, Organometallics
2003, 22, 4715–4720; f) M.-H. Huang, L.-C. Liang,
Organometallics 2004, 23, 2813–2816; g) C. S.
Consorti, G. Ebeling, F. R. Flores, F. Rominger, J.
Dupont, Adv. Synth. Catal. 2004, 346, 617–624; h) K.
Takenaka, M. Minakawa, Y. Uozumi, J. Am. Chem.
Soc. 2005, 127, 12273–12281; i) J. L. Bolliger, O.
Blacque, C. M. Frech, Chem. Eur. J. 2008, 14, 7969–
7977; j) Q.-L. Luo, J.-P. Tan, Z.-F. Li, Y. Qin, L. Ma,
D.-R. Xiao Dalton Trans. 2011, 40, 3601–3609.
[4] a) E. Negishi, A. O. King, N. Okukado, J. Org. Chem.
1977, 42, 1821–1823; b) E. Negishi, Acc. Chem. Res.
1982, 15, 340–348; c) P. Knochel, R. D. Singer, Chem.
Rev. 1993, 93, 2117–2188.
[5] a) M. Kosugi, K. Sasazawa, Y. Shimizu, T. Migita,
Chem. Lett. 1977, 6, 301–302; b) D. Milstein, J. K.
Stille, J. Am. Chem. Soc. 1978, 100, 3636–3638; c) J. K.
Stille, Angew. Chem. Int. Ed. Engl. 1986, 25, 508–524;
Angew. Chem. 1986, 98, 504–519.
[6] a) Y. Hatanaka, T. Hiyama, J. Org. Chem. 1988, 53,
918–920; b) S. E. Denmark, J. H.-C. Liu, Angew. Chem.
Int. Ed. 2010, 49, 2978–2986; Angew. Chem. 2010, 122,
3040–3049; c) Y. Nakao, T. Hiyama, Chem. Soc. Rev.
2011, 40, 4893–4901; d) T. Komiyama, Y. Minami, T.
Hiyama, ACS Catal. 2017, 7, 631–651.
[7] a) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron
Lett. 1975, 16, 4467–4470; b) K. Sonogashira, J.
Organomet. Chem. 2002, 653, 46–49.
[14] For reports on the Mizoroki–Heck reaction with
palladium pincer-complexes at ppb loadings, see: a) K.
7
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10.1002/adsc.201800099
Advanced Synthesis & Catalysis
Takenaka, Y. Uozumi, Adv. Synth. Catal. 2004, 346,
1693–1696; b) M. S. Yoo, D. Ryu, J. Kim, K. H. Ahn,
Organometallics 2006, 25, 2409–2411.
[20] In ref. 19, it was reported that DCT coordinates to
homogeneous platinum metal to form stable and
catalytically inactive complexes. To discuss the
mechanism of our catalytic system briefly, we consider
homogeneous palladium as a monomeric palladium
species.
[15] M. Kuritani, S. Tashiro, M. Shionoya, Chem. Asian J.
2013, 8, 1368–1371.
[16] G. Hamasaka, F. Sakurai, Y. Uozumi, Chem.
Commun. 2015, 51, 3886–3888.
[21] No reaction of 16a with 3a took place in the presence
of Bu3N.
[17] D. A. Alonso, C. Nájera, C. Pacheco, Adv. Synth.
Catal. 2002, 344, 172–183.
[22] When Pd(OAc)2 was used as the catalyst, the reaction
of 16a with 3a proceeded to give 4aa in 51% yield. The
catalytic activity of complex 1 was superior to that of
Pd(OAc)2 in this reaction.
[18] G. M. Whitesides, M. Hackett, R. L. Brainard, J.-P. P.
M. Lavalleye, A. F. Sowinski, A. M. Izumi, S. S.
Moore, D. W. Brown, E. M. Staudt, Organometallics
1985, 4, 1819–1830.
[23] For
information
on
octinoxate,
see:
http://www.smartskincare.com/skinprotection/sunblock
s/sunblock_octinoxate.html (accessed Jan 5, 2018)
[19] a) D. R. Anton, R. H. Crabtree, Organometallics
1983, 2, 855–859; b) C. S. Consorti, F. R. Flores, J.
Dupont, J. Am. Chem. Soc. 2005, 127, 12054–12065.
8
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Advanced Synthesis & Catalysis
FULL PAPER
A Palladium NNC-Pincer Complex as an
Extremely Efficient Catalyst Precursor for the
Mizoroki–Heck Reaction
Adv. Synth. Catal. Year, Volume, Page – Page
Go Hamasaka, Shun Ichii, Yasuhiro Uozumi*
9
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