Air- And moisture-stable Xantphos-ligated palladium dialkyl complex as a precatalyst for cross-coupling reactions

Article abstract of DOI:10.1039/c9cc06946a

Although xantphos has been employed in a variety of palladium-catalyzed cross-coupling reactions, there has been little progress in developing Xantphos-ligated precatalysts. In this report, we describe a Xantphos-ligated palladium dialkyl complex that acts as a powerful precatalyst for C-N, C-S, and C-C cross-coupling reactions. This precatalyst is air- and moisture stable but can be thermally activated in the absence of external reagents. Additionally, potential catalyst inhibitors are not generated during the precatalyst activation. This complex thus represents a convenient alternative to previously reported classes of Xantphos-ligated precatalysts.

Full text of DOI:10.1039/c9cc06946a

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Air- and moisture-stable Xantphos-ligated
palladium dialkyl complex as a precatalyst for
cross-coupling reactions†
Cite this: Chem. Commun., 2020,
6, 407
5
Received 6th September 2019,
Accepted 2nd December 2019
a
ab
ab
Rina Takahashi,
Koji Kubota
*
and Hajime Ito
*
DOI: 10.1039/c9cc06946a
rsc.li/chemcomm
Although xantphos has been employed in a variety of palladium- during such reactions, which significantly decreases the reaction
catalyzed cross-coupling reactions, there has been little progress in rate due to the very high binding constant for the ligand in the
4
developing Xantphos-ligated precatalysts. In this report, we describe bis-ligated species. Thus, the development of a Xantphos-ligated
a Xantphos-ligated palladium dialkyl complex that acts as a powerful precatalyst that does not form bis-ligated palladium species
precatalyst for C–N, C–S, and C–C cross-coupling reactions. This should be highly desirable.
precatalyst is air- and moisture stable but can be thermally activated
Buchwald and co-workers have developed a series of highly
in the absence of external reagents. Additionally, potential catalyst active palladacyclic precatalysts that bear a variety of phosphine
5
inhibitors are not generated during the precatalyst activation. This ligands. These complexes are commonly referred to as Buchwald
complex thus represents a convenient alternative to previously precatalysts and have become a valuable tool for cross-coupling
reported classes of Xantphos-ligated precatalysts.
reactions. Moreover, such Xantphos-ligated palladacyclic precatalysts
are now commercially available as Xantphos Pd G2 (Aldrich, product
Palladium-catalyzed cross-coupling reactions have become one no. 763047), Xantphos Pd G3 (Aldrich, product no. 763039) and
of the most powerful and versatile methods for the formation of Xantphos Pd G4 (Aldrich, product no. 900329) (Fig. 1a). However,
1
C–C and C–X bonds in academic and industrial settings. The these precatalysts form carbazole-based byproducts upon catalyst
development of specialized phosphine- and N-heterocyclic- activation, which could potentially lead to subsequent catalyst
carbene-(NHC)-based ligands, which promote fundamental inhibition and complicate the purification step.
steps in the catalytic cycle such as oxidative addition, trans-
In this report, we describe the synthesis of air- and moisture-
metallation, and reductive elimination, has led to significant stable palladium dialkyl complex bearing Xantphos ligand and
1
advances in this field. Furthermore, recent studies have revealed its application as a precatalyst for cross-coupling reactions
6
,7
that the generation of catalytically active and coordinatively (Fig. 1b). This precatalyst can be activated thermally via a
unsaturated monoligated Pd(0) species is crucial for the success
1
,2
of cross-coupling reactions. In this context, the development
of readily available and bench-stable palladium precatalysts
that form monoligated Pd(0) species has attracted considerable
1
interest in the synthetic-chemistry community.
Xantphos, a diphosphine ligand with a large bite angle, has
been employed in a variety of palladium-catalyzed C–C- and
3
C–heteroatom-bond-forming reactions. However, Buchwald
and co-workers have reported that the catalytically inactive
bis-ligated palladium species Pd(Xantphos) is readily formed
2
a
Division of Applied Chemistry and Frontier Chemistry Center,
Faculty of Engineering, Hokkaido University, Sapporo, Hokkaido, Japan.
E-mail: kbt@eng.hokudai.ac.jp, hajito@eng.hokudai.ac.jp
b
Institute for Chemical Reaction Design and Discovery (WPI-ICReDD),
Hokkaido University, Sapporo, Hokkaido, Japan
†
Electronic supplementary information (ESI) available. CCDC 1938978. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9cc06946a
Fig. 1 Xantphos-ligated palladium(II) precatalysts for cross-coupling
reactions.
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reductive elimination under concomitant formation of a
catalytically active, coordinatively unsaturated L Pd(0) species. The
n
sole byproduct of this activation is 1,2-bis(trimethylsilyl)ethane,
which does not interfere with the catalyst. Notably, this newly
developed precatalyst is easy to handle and exhibit a long shelf-
life, i.e., strict exclusion of air and water is not necessary.
Our initial effort focused on the synthesis of a Xantphos-
ligated palladium dialkyl complex through a ligand-exchange
2 2
reaction between (COD)Pd(CH TMS) (1) (COD = 1,5-cyclo-
8
octadiene; TMS = trimethylsilyl) and Xantphos (2) (Table 1).
Unfortunately, when the reaction was carried out in tetra-
hydrofuran (THF) at room temperature, the desired product,
(
Xantphos)Pd(CH TMS) (3), was not obtained. Instead, an insoluble
2 2
compound, which was identified as the bis-ligated palladium
4,9
species, Pd(Xantphos)
2
(4), was obtained (entry 1). Reactions in
simple alkane solvents also failed to generate 3 (entries 2 and 3). Fig. 2 Monitoring the temperature-dependent reductive elimination of
1
,2-bis(trimethylsilyl)ethane (5) from 3.
Pleasingly, the reaction in acetonitrile (MeCN) provided 3 in
moderate yield (entry 4), and 3 was obtained in high yield when
the reaction time was shortened to 20 minutes (entry 5). These
results indicate that shorter reaction times may suppress the
undesired reductive elimination from 3 that decreases the yield
of 3. We also found that lowering the reaction temperature
avoided the formation of 4 in favour of 3 in THF or diethyl ether
of the reductive elimination reaction was monitored at different
reaction temperatures using H NMR spectroscopy (Fig. 2). The
reductive elimination of 3 proceeded rapidly at 80 1C and 60 1C
to form 1,2-bis(trimethylsilyl)ethane (5) quantitatively within
6
4
a precatalyst for a number of cross-coupling reactions, as
palladium-catalyzed cross-coupling reactions are typically carried
out at 60 1C or higher.
To evaluate the performance of 3 as a precatalyst, we examined
its efficacy in promoting C–N cross-coupling reactions between
aryl halides and amides (Fig. 3). 1-Bromo-2-methylbenzene (6a)
reacted with benzamide (7a) in the presence of 3 to afford the
desired product (8a) in high yield. For comparison, we also tested
the Buchwald palladacycle precatalyst G3 (Xantphos Pd G3)
instead of 3 for this coupling reaction, which provided the almost
same product yield. These results show that the catalytic activity
1
0 minutes. In contrast, the reductive elimination was slow at
0 1C. These results indicate that 3 could potentially be used as
(entries 6 and 7). Complex 3 was obtained as an air- and moisture-
stable solid that can be handled at room temperature. For the
long-term storage, low temperatures (À30 1C) are required in
order to avoid decomposition (see the ESI† for details).
The molecular structure of 3 was determined by a single-
crystal X-ray diffraction analysis (Fig. S2, ESI†), which revealed a
square-planar cis geometry around the Pd center.
10
To determine the conditions required for the thermal activa-
tion of 3 to generate the catalytically active species, the progress
a
Table 1 Preparation of the Xantphos-ligated palladium dialkyl complex 3a
1c
of 3 is comparable to that of the Buchwald precatalyst G3.
b
Entry
Solvent
Temperature (1C)
Time
Yield (%) of 3
1
2
3
4
5
6
7
THF
Cyclohexane
Pentane
rt
rt
rt
rt
rt
0
16 h
16 h
16 h
16 h
20 min
16 h
20 min
—
—
—
52
84
43
89
CH
CH
3
CN
CN
3
THF
Et
2
O
0
a
Conditions: 1 (0.10 mmol) and 2 (0.10 mmol) in the specified solvent
b
(
0.1 M) were stirred under an atmosphere of nitrogen. Isolated yields based Fig. 3 Comparison of the catalytic performance of 3 with those of other
on the initial amount of 2.
catalyst precursors.
408 | Chem. Commun., 2020, 56, 407--410
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a,b,c,d
Moreover, 3 showed significantly higher catalytic activity than Table 2 Evaluation of the catalytic activity of 3
2
traditional catalyst precursors such as Pd(OAc) /Xantphos or
Pd(dba) /Xantphos in these C–N coupling reactions.
2
Next, we investigated the catalytic performance of 3 in C–N
coupling reactions using various amine nucleophiles (Table 2a
1
0,11
and b).
A variety of aryl halides reacted efficiently with
benzamide to give the desired products (8a–8c) in good to
excellent yield (Table 2a). The reaction using 2-pyrrolidone also
proceeded efficiently to form 8d in good yield (Table 2a).
4-Methoxy-substituted aniline (9) reacted with aryl halides that
bear electron-donating and -withdrawing groups to afford the
desired products (10a–10c) in good to high yield (Table 2b).
The performance of 3 was further evaluated in C–S coupling
1
2
reactions with thiol nucleophiles (Table 2c). The reaction of
-methoxybenzyl thiol proceeded to afford the desired products
12a–12c) in high yield, and the reaction with thiophenol
4
(
provided the corresponding diaryl sulfide (12d) in high yield.
We also confirmed that the developed precatalyst 3 was
applicable to Suzuki–Miyaura cross-coupling reactions with a
variety of arylboronic acids (13) (Table 2d). Notably, the use of
0.1 mol% of the catalyst provided excellent yield of 14a. The reaction
of base-sensitive 2-furylboronic acid (13j) proceeded smoothly
to give the desired coupling product (14j) in good yield.
We speculated that 3 might also be a suitable precatalyst for
base-free Suzuki–Miyaura cross-coupling reactions, as 3 can be
activated thermally. To this end, we investigated the coupling
reactions between aryl halide (6k) and triol borate (15) in the
1
3
presence of 3 as a precatalyst (Scheme 1). The targeted
coupling product (16) was obtained in high yield.
Recently, mechanochemical organic synthesis using ball
milling has attracted considerable interests due to the attrac-
tive advantages, which include the avoidance of potentially
1
4
harmful organic solvents and simple operational handling.
In this context, we applied mechanochemical ball milling to the
solvent-free gram-scale synthesis of 3. The reaction between 1
(3.0 mmol) and 2 was carried out in a stainless-steel ball-milling
jar (25 mL) with two stainless-steel balls (diameter: 10 mm),
which furnished 3 in 97% yield (2.5 g) (Scheme 2). This result
demonstrates the synthetic utility of mechanochemical ball
milling for the preparation of 3, which does not require organic
solvents and temperature control.
In conclusion, we have demonstrated that a Xantphos-ligated
palladium dialkyl complex can serve as a high-performance
precatalyst for various cross-coupling reactions, thus providing
a convenient alternative to previously reported classes of pre-
catalysts. Notably, this complex can be easily prepared, stored for
several months and easily activated under thermal conditions
without the generation of any potential catalyst inhibitors. We bromides (6; 0.5 mmol), amides (7; 0.6 mmol), and Cs CO (0.7 mmol)
expect that the design of this precatalyst will find wide-spread
applications in cross-coupling chemistry.
This work was financially supported by the Japan Society coupling with thiols: 3 (5.0 mol%), aryl bromides (6; 0.5 mmol), thiols
for the Promotion of Science (JSPS) via KAKENHI grants
JP18H03907, JP17H06370, and JP19K15547; by the Institute
for Chemical Reaction Design and Discovery (ICReDD), which in THF/H O (3 : 1, 0.38 M).
a
Conditions for the C–N coupling with amides: 3 (4.0 mol%), aryl
2
3
b
in dioxane (0.5 M). Conditions for the C–N coupling with aryl amines:
(0.5 mol%), aryl bromides (6; 1.0 mmol), amine (9; 1.2 mmol) and
3
c
Na(O-t-Bu) (1.4 mmol) in toluene (0.5 M). Conditions for the C–S
d
(
11; 0.5 mmol), and DIPEA (1.0 mmol) in dioxane (0.5 M). Conditions
for the C–C coupling with boronic acids: 3 (0.25 mol%), aryl bromides
6; 0.5 mmol), arylboronic acids (13; 0.6 mmol), and K PO (1.0 mmol)
(
3
4
2
was established by the World Premier International Research
Initiative (WPI) of MEXT (Japan); and by MEXT (Japan) through
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