An efficient class of P,N-type "phMezole-phos" ligands: Applications in palladium-catalyzed Suzuki coupling of aryl chlorides

Article abstract of DOI:10.1002/ejoc.201200355

This study describes an efficient class of hemilabile benzimidazolyl- phosphane ligands that can be easily accessed from commercially available and inexpensive starting materials. The application of this ligand array in the palladium-catalyzed Suzuki-Miyaura coupling reaction of aryl chlorides with arylboronic acids is described. The palladium catalyst generated from this hemilabile phosphane is highly effective in the Suzuki-Miyaura coupling of unactivated aryl chlorides, and catalyst loadings as low as 1 ppm can be achieved. An efficient class of hemilabile benzimidazolyl-phosphane ligands were synthesized. The palladium catalyst generated from this hemilabile phosphane is highly effective in the Suzuki-Miyaura coupling of unactivated aryl chlorides, and catalyst loadings as low as 1 ppm can be achieved.

Full text of DOI:10.1002/ejoc.201200355

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FULL PAPER
DOI: 10.1002/ejoc.201200355
An Efficient Class of P,N-Type “PhMezole-phos” Ligands: Applications in
Palladium-Catalyzed Suzuki Coupling of Aryl Chlorides
Shun Man Wong,[a] Chau Ming So,*[a] Kin Ho Chung,[a] Chak Po Lau,[a] and
Fuk Yee Kwong*[a]
Keywords: Palladium / Ligand design / Cross-coupling / Phosphanes / N,P ligands
This study describes an efficient class of hemilabile benz-
imidazolyl–phosphane ligands that can be easily accessed
from commercially available and inexpensive starting mate-
rials. The application of this ligand array in the palladium-
catalyzed Suzuki–Miyaura coupling reaction of aryl chlorides
with arylboronic acids is described. The palladium catalyst
generated from this hemilabile phosphane is highly effective
in the Suzuki–Miyaura coupling of unactivated aryl chlor-
ides, and catalyst loadings as low as 1 ppm can be achieved.
cies, which can facilitate both oxidative addition and re-
ductive elimination steps. Indeed, monophosphane ligands
Introduction
The palladium-catalyzed Suzuki–Miyaura cross-coupling is may still give stable palladium catalysts. However, mono-
undoubtedly one of the most versatile and useful tools for phosphane ligands have limited coordinative flexibility for
the synthesis of diversified biaryls, which have numerous stabilizing the unstable low-coordinate and low-valent pal-
applications in pharmaceutical, materials, and agricultural ladium complex, which is highly active but easily decom-
chemistry.[1] To deal with the coupling reaction of aryl posed at high temperature or under prolonged heating.
bromides as well as aryl chlorides, many effective support- Consequent decomposition of the active catalysts would
ing ligands have been developed in the past decade. The lead to the formation of inactive palladium black, which
advancement of some notable ligands such as tBu3P,[2] limits the maximum turnover, especially at extremely low
Bellers’s PAP,[3] Buchwald’s biaryl–phosphanes,[4] and Hart- catalyst-loading conditions. Beller and co-workers sug-
wig’s Q-Phos[5] provide excellent catalytic activity in various gested that a several-fold dosage increase of monophos-
cross-coupling reactions with aryl chlorides.[3c] In view of phane ligand is an effective means of preventing decompo-
the characteristics of the ligand structure, they are generally sition of active low-valent palladium complexes, thus en-
electron-rich and sterically hindered monophosphanes. The abling the catalyst loading to be lowered and the TON to
increase of electron-richness can enhance oxidative ad- be maximized.[6,3b] However, the choice between reactivity
dition. Meanwhile, sterically bulky skeletons can assist the and the cost of sacrificing ligand becomes a dilemma and
catalyst complex to generate unsaturated palladium(0) spe- is clearly inefficient. The introduction of hemilabile phos-
Figure 1. Recent developments on P,N-ligands for the Suzuki coupling reaction.
phane ligands that have two basic sites with different donat-
ing ability provided a new way to address this problem. A
hemilabile coordinating group offering both reactivity and
stability towards the palladium center is sensitive to dy-
namic needs of the metal atom at different stages of the
catalytic cycle. For instance, the nitrogen donor atom can
weakly coordinate to soft metal centers (e.g., Pd and Rh)
[a] State Key Laboratory of Chirosciences and Department of
Applied Biology and Chemical Technology, The Hong Kong
Polytechnic University,
Hung Hom, Kowloon, Hong Kong
Fax: +852-2364-9932
E-mail: bccmso@inet.polyu.edu.hk
bcfyk@inet.polyu.edu.hk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200355.
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S. M. Wong, C. M. So, K. H. Chung, C. P. Lau, F. Y. Kwong
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Figure 2. Efficient indolyl–phosphane ligands for coupling reactions.
to stabilize low-valent metal complexes, yet can easily disso-
ciate in solution to provide a vacant site whenever de-
manded.[7] In fact, phosphane ligands that possess potential
hemilabile ability have been studied in the past decade (Fig-
ure 1).[8]
In respect to P,N-type ligands,[9] in 2004, Hor et al. re-
ported active ferrocenyl-derived P,N-type ligands with an
imino group for the Suzuki coupling reaction.[9f] The X-
ray crystal structures showed that the ferrocenyl hemilabile
ligands provided both P- and N-coordination to the palla-
dium center. In 2005, a similar ligand with an aryl scaffold
was also found to be effective in coupling processes.[10] Li-
ang et al. reported an amido–phosphanyl complex as an
effective catalyst for the Suzuki coupling of aryl chlor-
ides.[11] He et al. reported the use of bis(aminophosphane)-
palladium chelated complexes for the Suzuki coupling of
aryl bromides.[9e] Scrivanti et al. reported a P,N-type co-
Figure 3. Strategic design and exploration of a simple and easily
diversified phosphane ligand family.
Results and Discussion
In this study, we used ligands L1–L3 to examine the cata-
ordination
({8-[(di-tert-butylphosphanyl)oxy]quinoline}- lytic activity of this new class of ligands in the Suzuki cou-
PdCl2) complex for low-catalyst-loading Suzuki coupling of pling reaction. To evaluate the effectiveness of the hemilab-
aryl bromides.[12] Palladium complexes supported by these ile ligands, sterically hindered 2-chloro-m-xylene was used
ligands demonstrated excellent catalytic activities towards as the benchmark substrate (Table 1). A range of inorganic
the Suzuki coupling of aryl bromides and/or activated aryl bases were first surveyed in the presence of ligand L2
chlorides at extremely low catalyst loadings (down to (Table 1, Entries 1–7). K3PO4·H2O was found to be the best
1 ppm). However, currently developed hemilabile phos- base in this catalytic system. For commonly used organic
phane ligands, especially, P,N-type phosphane ligands, still solvents [tetrahydrofuran (THF), dioxane, N,N-dimethyl-
have much room for improvement, particularly for the Su- formamide (DMF), toluene, mesitylene and tBuOH], di-
zuki coupling of neutral and deactivated aryl chlorides in oxane was the best single solvent (Table 1, Entries 1 and 8–
systems with extremely low catalyst loadings. This challenge 12).
has still not been met.
Upon investigating the metal/ligand ratio from 1:2 to 1:4,
Our group previously developed a series of indolyl–phos- a ratio of 1:2 provided the highest yield (Table 1, En-
phane ligands that show good to excellent catalytic activity tries 13–15). The use of a metal/ligand ratio of 1:2 was then
in palladium-catalyzed coupling reactions of aryl sulfonates chosen for the further screening trials. Mixing dioxane with
and halides (Figure 2).[13]
mesitylene gave the best result (Table 1, Entry 18). Ligand
To retain the advantage of an effective skeleton and fur- L1 with a diphenylphosphanyl moiety provided only trace
ther introduce beneficial hemilability to the ligand, we were amounts of substrate conversion, whereas the dicyclohex-
inspired to use 2-phenylbenzimidazole as the main ligand ylphosphanyl analogue L2 gave the best catalytic activity.
scaffold. This framework features the same advantages as Ligand L3, bearing
a diisopropylphosphanyl moiety,
the 2-phenylindole scaffold and allows high potential diver- showed a lower catalytic activity in the Suzuki coupling re-
sification from the rapid assembly of two starting compo- action (Table 1, Entries 20).
nents through the application of simple synthetic methods.
A range of aryl chlorides were examined under the pre-
Moreover, the additional nitrogen atom provides a weak liminary optimized reaction conditions (Table 2). It was im-
coordinating site for potential dynamic interaction that mediately clear that the palladium catalyst supported by the
could increase catalyst longevity (Figure 3). Recently, we hemilabile benzimidazolyl–phosphane ligand was highly
have successfully applied this class of benzimidazolyl–phos- active towards the Suzuki coupling reaction.
phane ligands in the Suzuki coupling of aryl mesylates with
The catalyst loading and turnover number for the elec-
arylboronic acids.[14] Herein, we disclose an extension to tron-neutral and deactivated aryl chloride could be reduced
this class of ligands in the Suzuki coupling of aryl chlorides. to 0.001 mol-% Pd (80000 TON) and 0.002 mol-% Pd
2
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“PhMezole-phos” Ligands in Suzuki Coupling of Aryl Chlorides
Table 1. Optimization of the reaction conditions.
catalyst-loading coupling reaction (Table 2, Entries 4 and
5). The result showed that the hemilabile nitrogen coordi-
nating group plays an important role in sustaining the high
catalytic activity of the catalyst.
Generally, heteroaryl chlorides are classified as electron-
deficient aryl chlorides due to the electron-withdrawing
property of the heteroatom. However, under very-low-cata-
lyst-loading conditions, the coordinating property of the
heteroatom to the metal complex becomes significant and
may be problematic for coupling reactions. Indeed, the high
concentration of coordinating substrates may displace the
phosphane ligands to generate inactive complexes and lead
to a reduction in the catalytic activity of the original active
species.
This newly developed system can effectively deal with
pyridyl and the quinolyl substrates when the metal/ligand
ratio is 1:2 at a catalyst loading of 0.01 mol-% Pd. The iso-
lated yield can be as high as 99% (Table 2, Entries 20–23).
Actually, the deleterious coordinating effect becomes seri-
ous when the catalyst loading was reduced to 0.002 mol-%
Pd (Table 2, Entry 24). A slight increase of the metal/ligand
ratio from 1:2 to 1:4 was required to compensate for the
coordinating substrates under the extremely low-catalyst-
loading conditions. The catalyst loading could be further
decreased to 0.001 mol-% Pd, and the isolated yield re-
mained as high as 99% (Table 2, entry 25). This finding
showed that the hemilabile group reduces the dependence
of the reaction on the ligand concentration and can main-
tain the catalyst activity. Our previous X-ray crystallo-
graphic studies confirmed that the benzimidazolyl–phos-
phane ligand L2 is coordinated in a κ2-P,N fashion to the
palladium center.[14]
Conclusions
We have developed a series of efficient hemilabile benz-
imidazolyl–phosphane ligands that can be easily synthe-
sized from inexpensive and commercially available starting
materials. Palladium complexes derived from these ligands
showed excellent catalytic activities for the Suzuki–Miyaura
coupling of aryl chlorides with arylboronic acids, especially
under very-low-catalyst-loading conditions. Benefiting from
the hemilabile benzimidazolyl group, the catalyst loading
for the Suzuki coupling of functionalized aryl chlorides can
be reduced to 1 ppm Pd; the palladium levels in neutral,
deactivated and coordinating aryl chloride systems can be
reduced to 0.001 mol-% Pd. To the best of our knowledge,
this is the lowest catalyst loading achieved by P,N-type
phosphane ligands. In view of the simplicity of the ligand
synthesis as well as the ease with which the ligand skeleton
can be modified, we anticipate that further enhancements
in reactivity and versatility of the ligand series will be at-
tainable.
[a] Reaction conditions: [Pd(OAc)2], M/L = 1:2, 1-chloro-2,6-di-
methylbenzene (1.0 mmol), phenylboronic acid (1.5 mmol), base
(3.0 mmol), solvent (3 mL), 135 °C, N2, 22 h. [b] Calibrated GC
yields are reported (dodecane as internal standard). [c] Ligand =
L1. [d] Ligand = L3.
(37000 TON), respectively (Table 2, Entries 4 and 6). Com-
mon functional groups such as ketone, aldehyde, ester, and
nitrile were compatible with these mild reaction conditions,
and the catalyst loading could generally be reduced to
0.01 mol-% Pd (Table 2, Entries 8–15). The maximum cata-
lytic activity of this new system was also probed (Table 2,
Entries 16–19). When the catalyst loading was reduced to
0.0005 and 0.0002 mol-% Pd, this system was still effectively
able to convert the substrate into the corresponding product
in excellent yields. Although incomplete conversion of sub-
strate was observed when 1 ppm of palladium catalyst was
applied, turnover numbers as high as 720000 (TON) were
achieved.
Experimental Section
We then applied 2-[2-(dicyclohexylphosphanyl)phenyl]-
N-methyl-1H-indole (CM-phos, Figure 2),[13] in which the
General Procedure for Suzuki–Miyaura Couplings of Aryl Chlorides:
nitrogen group is replaced by a C–H group, in the low- [Pd(OAc)2] (2.3 mg, 0.010 mmol) and ligand L2 (Pd/L = 1:2) in
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Table 2. Palladium-catalyzed Suzuki coupling of aryl chlorides.
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“PhMezole-phos” Ligands in Suzuki Coupling of Aryl Chlorides
Table 2. (Continued)
[a] Reaction conditions: [Pd(OAc)2], M/L2 = 1:2, aryl chloride (1.0 mmol), arylboronic acid (1.5 mmol), K3PO4·H2O (3.0 mmol), dioxane
(3 mL), 135 °C, N2. [b] Isolated yield. [c] Dioxane/mesitylene (1:1) as solvent (3 mL). [d] CM-Phos as ligand, calibrated GC yield.
[e] K2CO3 as base. [f] Pd/L = 1:4.
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Wong, C. M. So, F. Y. Kwong, Synlett 2012, 23, 1132.
freshly distilled 1,4-dioxane (10 mL; 0.1 mol-% Pd per 1 mL of
stock solution) was initially prepared with continuous stirring at
room temperature. Arylboronic acid (1.5 mmol), K3PO4·H2O
(3.0 mmol) and a magnetic stirrer bar (3 mmϫ8 mm) were charged
to an array of Schlenk tubes. Each tube was carefully evacuated
and backfilled with nitrogen (3 cycles). Aryl chloride (1.0 mmol)
was then added to the Schlenk tubes. The stock solution was fur-
ther diluted to give different concentrations. The diluted stock solu-
tion was then transferred to Schlenk tubes by using syringes. Fur-
ther solvent was added (final volume 3 mL). This batch of Schlenk
tubes were resealed and magnetically stirred in a preheated 135 °C
oil bath. After completion of the reaction (judged by GC or TLC
analysis), the mixtures were allowed to reach room temperature.
Water (ca. 3 mL) and ethyl acetate (ca. 3ϫ10 mL) were added. The
organic layers were combined and concentrated. The crude prod-
ucts were purified by column chromatography on silica gel (230–
400 mesh).
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Acknowledgments
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We thank the Research Grants Council of Hong Kong (PolyU5010/
11P), the PolyU Internal Competitive Research Grant (A-PG13)
for financial support. We are grateful to Prof. Albert S. C. Chan’s
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Received: March 21, 2012
Published Online: ᭿
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“PhMezole-phos” Ligands in Suzuki Coupling of Aryl Chlorides
N,P-Ligands in Cross-Coupling
S. M. Wong, C. M. So,* K. H. Chung,
C. P. Lau, F. Y. Kwong* .................... 1–7
An Efficient Class of P,N-Type “PhMe-
zole-phos” Ligands: Applications in Pal-
ladium-Catalyzed Suzuki Coupling of Aryl
Chlorides
An efficient class of hemilabile benzimid-
azolyl–phosphane ligands were synthe-
sized. The palladium catalyst generated
from this hemilabile phosphane is highly
effective in the Suzuki–Miyaura coupling
of unactivated aryl chlorides, and catalyst
loadings as low as 1 ppm can be achieved.
Keywords: Palladium / Ligand design /
Cross-coupling / Phosphanes / N,P ligands
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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