Efficient diphosphane-based catalyst for the palladium-catalyzed suzuki cross-coupling reaction of 3-pyridylboronic acids

Article abstract of DOI:10.1002/ejoc.200900038

A highly active catalyst system derived from PdCl2 and 2,2',6,6'- tetramethoxy-4,4'-bis(diphenylphosphanyl)-3,3'-bi- pyridine (P-Phos) has been developed for the Suzuki cross- coupling reaction of pyridylboronic acid with a variety of aryl halides in good to excellent yields, even in the presence of hindered and functional groups. In addition, P-Phos also exhibited high activity in the palladium-catalyzed Suzuki reaction of 2,6-dimethoxypyridylboronic acid in excellent yields with a fast rate. The steric and electronic effects of the P- Phos-palladium complex to this cross-coupling reaction were also discussed.

Full text of DOI:10.1002/ejoc.200900038

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900038
Efficient Diphosphane-Based Catalyst for the Palladium-Catalyzed Suzuki
Cross-Coupling Reaction of 3-Pyridylboronic Acids
Xing-Li Fu,[a] Lei-Lei Wu,[a] Hai-Yan Fu,[a] Hua Chen,*[a] and Rui-Xiang Li[a]
Keywords: Nitrogen heterocycles / Boron / Cross-coupling / Phosphane ligands / Palladium
A highly active catalyst system derived from PdCl2 and
2,2Ј,6,6Ј-tetramethoxy-4,4Ј-bis(diphenylphosphanyl)-3,3Ј-bi-
pyridine (P-Phos) has been developed for the Suzuki cross-
coupling reaction of pyridylboronic acid with a variety of aryl
halides in good to excellent yields, even in the presence of
hindered and functional groups. In addition, P-Phos also ex-
hibited high activity in the palladium-catalyzed Suzuki reac-
tion of 2,6-dimethoxypyridylboronic acid in excellent yields
with a fast rate. The steric and electronic effects of the P-
Phos–palladium complex to this cross-coupling reaction were
also discussed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
heteroaryl chlorides could be transformed into the desired
products in excellent yields, although these cross-coupling
reactions were proven to be particularly difficult.[8a,8b,8d,9]
The success of this ligand was due to the large and electron-
donating groups connected to the phosphorus atom.[8b,11]
Other ligands such as PCy3,[8c] Tedicyp,[12] and fluorenyl-
phosphanes[13] were also used in this coupling reaction re-
cently.
With the insight gained from the phosphanes mentioned
above we noted that (a) alkylphosphanes exhibited higher
activity than arylphosphanes by reason of the electron-do-
nating properties and bulkiness of the alkyl groups, and at
the same time they were more sensitive to moisture and
air than arylphosphanes, although they could be tuned in
structure (e.g., Buchwald’s ligands) to adapt to the environ-
ment;[11] (b) monophosphanes were proven to be efficient
in the palladium-catalyzed cross-coupling reaction when the
phosphorus atom was connected to an electron-donating
group, but the instability of this unsaturated palladium–
phosphanes complex was also noteworthy. Hence, we ex-
pected to discover an active and stable diphenylphosphane
that could exhibit catalytic activity as high as that of alkyl-
monophosphanes in the Suzuki reaction of pyridine-derived
boronic acids.
The last several decades have seen growing attention
placed on the synthesis of compounds containing heterobi-
aryl moieties, which are found in polymers,[1] ligands,[2]
drugs,[3] and various materials.[4] Among the synthetic path-
ways, the palladium-catalyzed Suzuki–Miyaura cross-coup-
ling reaction between heteroaryl halides and arylboronic
acids provided a general and applicable method for the
preparation of heterobiaryls.[5] In contrast, the reactions
using aryl halides and heteroarylboronic acids[6–8] have
earned less attention, especially those pertaining to pyridyl-
boronic acids.[8]
Pyridine-derived boronic acids do not readily participate
in Suzuki cross-coupling reactions as a result of their insta-
bility and slow rate of transmetalation, which can be attrib-
uted to the electron deficiency of the pyridine ring.[8d,9] In
the past 10 years, several ligands have been developed and
great achievements were obtained in this challenging area.
The group of Bryce reported that Pd(PPh3)4 and Pd-
(PPh3)2Cl2 catalyzed the reaction of substituted pyridylbo-
ronic acid and aryl bromides. This catalyst system could
tolerate amine groups, and the cross-coupling reaction pro-
ceeded smoothly to give the desired products in moderate
to good yields.[10] Afterwards, dialkylbiarylphosphanes
were developed and successfully applied to the Suzuki reac-
tion of several pyridylboronic acids by Buchwald and co-
workers. Both hindered and substituted chlorobenzene and
Results and Discussion
Considering the “pressure to coordinate” viewpoint that
states that the greater the number of phosphanyl atoms the
closer the phosphanes will be to the metal center, which can
increase the stability of the catalyst,[14] we decided to exam-
ine the catalytic activity of several diphosphane ligands in
the palladium-catalyzed Suzuki reaction of 3-pyridylbo-
ronic acid with 4-methoxybromobenzene. According to the
results illustrated in Scheme 1, we discovered that the use
of ligands with either alkyl groups or phenyl groups con-
[a] Key Lab of Green Chemistry and Technology, Ministry of Edu-
cation, The Institute of Homogeneous Catalysis, College of
Chemistry, Sichuan University
No. 29 Wang jiang Road, Chengdu 610064, P. R. China
Fax: +86-28-8541-2904
E-mail: scuhchen@163.com
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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X.-L. Fu, L.-L. Wu, H.-Y. Fu, H. Chen, R.-X. Li
SHORT COMMUNICATION
nected to the diphenylphosphane resulted in the desired
product in low yields. It was observed that the yield was
improved when bulky biphenyl groups were connected to
the phosphanes. It is amazing that the reaction gave a yield
as high as 90% when using the dipyridylphosphane ligand.
2,2Ј,6,6Ј-Tetramethoxy-4,4Ј-bis(diphenylphosphanyl)-
3,3Ј-bipyridine (P-Phos) was developed by the group of
Chan in 2000.[15] As is known, metal complexes of P-Phos
are highly air stable.[16] This advantage is important in in-
dustrial applications and also in tune with our notion to
find a more stable phosphane that can be applied to the
Suzuki reaction. After the selection of phosphanes, we fur-
ther optimized the Suzuki reaction of 3-pyridylboronic acid
with 1-bromo-4-methoxybenzene catalyzed by the P-Phos–
palladium complex. In early optimization studies, we ob-
served that the best ratio of boronic acid/aryl halide was
2:1 and the catalyst exhibited better activity in polar sol-
vents than in nonpolar solvents. Considering that the reac-
tion should be carried out at high temperature, nBuOH was
chosen as solvent to examine the effect of different bases
such as Cs2CO3, K3PO4, Na2CO3, and KOH. Finally,
Scheme 1. Several diphosphanes applied in the Suzuki cross-coup-
ling reaction of 3-pyridylboronic acid with 1-bromo-4-methoxyben-
zene under the reaction conditions: PdCl2 (1 mol-%), phosphane
(2 mol-%), K3PO4 (2 equiv.), nBuOH, 80 °C, 5 h.
Table 1. Suzuki reaction of 3-pyridylboronic acid with different aryl halides.[a]
[a] Reaction conditions: PdCl2 (1 mol-%), P-Phos (2 mol-%), aryl bromide (1.0 equiv.), boronic acid (2.0 equiv.), K3PO4 (2.0 equiv.),
nBuOH (2 mL), nitrogen protection, 100 °C. [b] Yield of isolated product based upon an the average of two runs. [c] Reaction was
conducted with the use of P-Phos (1 mol-%).
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Diphosphane-Based Catalysts for Suzuki Cross-Coupling Reactions
K3PO4 was adopted as the base for good results at Table 2. Suzuki reaction of 2,6-dimethoxy-3-pyridylboronic acid
with different aryl halides.[a]
80 °C.
Under the optimum conditions of PdCl2/P-Phos/K3PO4/
nBuOH, we were pleased to find that the protocol could be
applied to a wide range of different substituted aryl halides.
As illustrated in Table 1, a variety of aryl bromide and chlo-
ride containing electron-donating or electron-withdrawing
groups could be coupled with 3-pyridylboronic acid as ex-
pected.
There are several points to note in Table 1. Some un-
stable groups like NH2 and CHO did not affect the activity
of the catalyst (Table 1, Entries 6, 11, and 22). Furthermore,
we also obtained the desired products in high yields when
the bromides of thiophene, quinoline, and pyridine were
used as reactants (Table 1, Entries 15–17). This revealed
that the introduction of heteroatoms was not detrimental
to the catalyst activity. The protocol could also be applied
to some aryl chlorides with up to 91% yield (Table 1, En-
tries 18–22), although aryl chlorides were challenging sub-
strates in the cross-coupling reaction. It is also notable that
ortho-substituted aryl halides failed to couple with 3-pyr-
idylboronic acid under the initial optimum condition. Con-
sidering that the steric hindrance of ortho-substituted
[a] Reaction conditions: PdCl2 (1 mol-%), P-Phos (2 mol-%), aryl
groups might block the coordination of the P-Phos–palla-
bromide (1.0 equiv.), boronic acid (1.5 equiv.), K3PO4 (2.0 equiv.),
nBuOH (2 mL), nitrogen protection, 100 °C. [b] Yield of isolated
dium complex with the aryl halide, we tried to reduce the
ratio of phosphane to facilitate the oxidative addition. For-
tunately, we achieved success in the coupling of several or-
tho-substituted aryl bromides and chlorides by adjusting
the amount of P-Phos to 1 mol-% (Table 1, Entries 5, 10,
and 21). However, the activity of the catalyst under these
conditions decreased remarkably when aryl halides substi-
tuted in the meta or para positions were used. It can be
envisaged that the stability of the palladium–phosphane
complex decreases with a decrease in the amount of phos-
phane used.
product based upon an the average of two runs.
rus atom,[18] the electron-donating properties of the four
methoxy groups will improve the electron density of the
ring; this factor will provide the two phosphorus atoms with
appropriate complexing ability. Moreover, the weak elec-
tron deficiency of the ligand is beneficial to the reductive
elimination step (Figure 1).
Heterobiaryl-containing pyridine rings are important
building blocks for many biologically active molecules.[17] It
is evident that the Suzuki cross-coupling reaction of substi-
tuted pyridylboronic acid is valuable for the synthesis of
these compounds.[17a] We were delighted that P-Phos could
be effectively applied to the Suzuki reaction of 2,6-dimeth-
oxy-3-pyridylboronic acid to obtain functional heterobiar-
yls. Several aryl halides could be coupled with this more-
hindered pyridylboronic acid in excellent yield (Table 2). We
were amazed that most substrates reacted completely within
2 or 3 h. To the best of our knowledge, this is the fastest
rate that has been described for Suzuki reactions of pyr-
idine-derived boronic acids. The reaction may profit from
the electron-donating properties of the methoxy groups,
which can compensate for the electron deficiency of the pyr-
idine ring.
Figure 1. Structural features of P-Phos and its impact on the effi-
cacy of the catalyst.
Conclusions
In summary, we demonstrated that P-Phos as a highly
The success of P-Phos in the Suzuki reaction was stated stable diphenylphosphane exhibited excellent activity in the
previously. On the basis of these good results, we supposed palladium-catalyzed Suzuki reaction of 3-pyridylboronic
that the bulkiness of the bipyridyl group might favor both acid. The catalyst system could be applied to a wide range
the oxidative addition and the reductive elimination steps of substrates. It is not inhibited in the presence of some
in the generally accepted catalytic cycle. Although the elec- disubstituted groups. In addition, P-Phos also showed high
tron-withdrawing properties of the pyridine ring oppose the catalytic activity in the Suzuki reaction of 2,6-dimethoxy-
complexing ability of the lone electron pair of the phospho- 3-pyridylboronic acid. The structural specialties of P-Phos
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X.-L. Fu, L.-L. Wu, H.-Y. Fu, H. Chen, R.-X. Li
SHORT COMMUNICATION
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[6]
Experimental Section
General Procedure for the Cross-Coupling Reactions of 3-Pyridylbo-
ronic Acid: P-Phos (3.2 mg, 0.005 mmol) and PdCl2 (0.4 mg,
0.0025 mmol) were added to a Schlenk tube equipped with a stir
bar. The flask was evacuated and refilled with nitrogen three times.
Under a nitrogen atmosphere, degassed nBuOH (1 mL) was added
to dissolve the mixture, which was stirred for 5 min at room tem-
perature. The aryl halide (0.25 mmol), pyridylboronic acid
(48.6 mg, 0.5 mmol), and K3PO4 (106 mg, 0.5 mmol) were added
to another Schlenk flask, which was then evacuated and refilled
with nitrogen three times (if the halide was a liquid, it was added
after the next step). The dissolved mixture of PdCl2/P-Phos was
transferred to the Schlenk flask of reactants by syringe. Then,
nBuOH (1 mL) was added. The flask was sealed and heated in an
oil bath at 100 °C for 6–20 h with vigorous stirring. After the reac-
tion was complete, water (3 mL) was added to the mixture. The
organic layer was separated, and the aqueous layer was extracted
with EtOAc (3ϫ). The combined extracts were concentrated. The
residue was then purified by column chromatography on silica gel.
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General Procedure for the Cross-Coupling Reactions of 2,6-Dimeth-
oxy-3-pyridylboronic Acid: As for 3-pyridylboronic acid, but with
the addition of 2,6-dimethoxy-3-pyridylboronic acid (68.1 mg,
0.375 mmol). The reaction mixture was stirred for 2–3 h.
Supporting Information (see footnote on the first page of this arti-
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products illustrated in Tables 1 and 2.
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Acknowledgments
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We thank the Analytical and Testing Center of Sichuan University
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Received: January 15, 2009
Published Online: March 28, 2009
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