An efficient palladium-benzimidazolyl phosphine complex for the Suzuki-Miyaura coupling of aryl mesylates: Facile ligand synthesis and metal complex characterization

Article abstract of DOI:10.1039/c2cc15972d

A new class of easily accessible hemilabile benzimidazolyl phosphine ligands has been developed. The ligand skeleton is prepared from commercially available and inexpensive o-phenylenediamine and 2-bromobenzoic acid. With catalyst loading down to 0.5 mol% palladium, excellent catalytic activity towards the Suzuki-Miyaura coupling of aryl mesylates is still observed. This represents the lowest catalyst loading achieved so far for this reaction in general. X-Ray crystallography shows that new ligand L2 is coordinated with Pd in a κ²-P,N fashion.

Full text of DOI:10.1039/c2cc15972d

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COMMUNICATION
An efficient palladium–benzimidazolyl phosphine complex for the
Suzuki–Miyaura coupling of aryl mesylates: facile ligand synthesis
and metal complex characterizationw
Kin Ho Chung, Chau Ming So,* Shun Man Wong, Chi Him Luk, Zhongyuan Zhou,
Chak Po Lau and Fuk Yee Kwong*
Received 26th September 2011, Accepted 23rd November 2011
DOI: 10.1039/c2cc15972d
A new class of easily accessible hemilabile benzimidazolyl
phosphine ligands has been developed. The ligand skeleton is
prepared from commercially available and inexpensive o-phenylene-
diamine and 2-bromobenzoic acid. With catalyst loading down
to 0.5 mol% palladium, excellent catalytic activity towards the
Suzuki–Miyaura coupling of aryl mesylates is still observed.
This represents the lowest catalyst loading achieved so far for
this reaction in general. X-Ray crystallography shows that new
ligand L2 is coordinated with Pd in a j2-P,N fashion.
Fig. 1 Selected ligand examples for efficient Suzuki coupling of aryl
halides, tosylates and mesylates.
Palladium-catalyzed Suzuki–Miyaura coupling of aryl halides
and arylboronic acids is one of the most versatile tools for the
synthesis of diversified biaryls which have numerous applications
in pharmaceutical, natural product, advanced material and
agricultural chemistry.1,2 Huge efforts have been undertaken by
researchers aiming to activate and utilize aryl halides, especially
chlorides, as electrophiles for a variety of cross-coupling
reactions.1,3 In fact, aryl sulfonates are important alternatives
and/or complements to aryl halides in cross-coupling reactions
since their availability and substitution pattern on the aromatic
ring may have differences when compared to aryl halides.4
However, previous coupling reactions were mainly focused on
more reactive aryl triflates due to lack of effective catalysts for
activating aryl tosylates and mesylates. Indeed, aryl tosylates and
mesylates are ideal phenolic electrophiles as they are also easily
accessible from phenols, yet in relatively low cost.5 They have a
better hydrolytic stability when compared to the corresponding
aryl triflates. Moreover, aryl mesylates offer a more attractive
atom-economy than aryl tosylates.6 Although beneficial features
are noted, aryl mesylates are challenging substrates as they are
even less reactive than the corresponding aryl tosylates in cross-
coupling reactions.7
(to enhance oxidative addition) and sterically bulky (to facilitate
reductive elimination) components. However, well-known efficient
ligands such as P(t-Bu)3, PCy3, and JohnPhos in palladium-
catalyzed cross-coupling of aryl halides are obscurely ineffective
ligands in the case of aryl sulfonates (Fig. 1).8
Recently, we reported a palladium catalyst system (Pd–
CM-phos) for the cross-coupling of aryl mesylates and aryl-
boronic acids.9 Buchwald’s BrettPhos also displayed excellent
reactivity in palladium-catalyzed Suzuki–Miyaura coupling of
both aryl tosylates and mesylates.10
With respect to the established catalytic systems for promoting
Suzuki coupling of aryl halides, catalysts developed for Suzuki
coupling of challenging sulfonates, such as aryl tosylates11 and
mesylates,12 are still limited. In fact, there is no literature report
concerning the successful application of P,N-type ligands for this
reaction. Thus, versatile catalysts for widespread applications of
aryl sulfonate coupling reactions are needed. Certainly, it would
be further attractive if structurally diversified ligand skeletons
can be assembled from multiple components via a simple ‘‘cross-
matching’’ synthetic strategy.
Phosphine ligands containing potential hemilabile coordinating
groups for cross-coupling reactions have been studied in the past
decade (Fig. 2).13 Hor and co-workers described the dynamic
interaction between the hemilabile group (e.g. nitrogen donor) and
the palladium center that could increase the catalyst longevity.13b
Inspired by the unique feature of P,N-type hemilabile
ligands in cross coupling of aryl halides and the effectiveness
of monophosphines (e.g. Brettphos and CM-phos) for the
coupling of aryl mesylates, we are interested in designing a
new family of hemilabile P,N-type ligands for promoting aryl
Pioneering establishments in designing effective phosphines for
Pd-catalyzed coupling of aryl halides generally contain electron-rich
State Key Laboratory of Chirosciences, Department of Applied
Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hung Hom, Kowloon, Hong Kong.
E-mail: bccmso@inet.polyu.edu.hk, bcfyk@inet.polyu.edu.hk;
Fax: +852-2364-9932
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc15972d
c
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Fig. 2 Interactions and examples of hemilabile P,N ligands for
Scheme 1 Synthetic pathway of the benzimidazolyl phosphine ligands.
Suzuki coupling of aryl halides.
The hemilabile group possibly reduces the need for ligand
concentration to maintain the catalyst activity. Thus Pd(OAc)2
and metal/ligand ratio 1 : 2 were then chosen for further
screening. For the palladium sources, Pd2(dba)3, PdCl2,
Pd(TFA)2, gave similar yields while Pd(OAc)2 provided the
best result. Several bases were tested in the presence of ligand
L2. Although K3PO4 was the most efficient base among
several bases investigated, some phenolic side products (from
hydrolysis of sulfonate) were found after prolonged heating.
K2CO3 and Na2CO3 showed a lower reactivity for the aryl
mesylate coupling reaction. Yet, no phenolic side product was
observed after 24 h heating.
Fig. 3 Features of new P,N-type phosphine ligand family.
mesylate coupling that can have a better catalyst longevity (Fig. 2).
To the best of our knowledge, there has been no successful
example reported to date for P,N ligands in C–C bond coupling
using aryl mesylates. Herein, we report our efforts on developing a
new class of hemilabile benzimidazolyl phosphines for the
Suzuki coupling of aryl mesylates. This new series of ligands
embodies a highly tunable, yet easily accessible, main skeleton
with a hemilabile coordinating site (Fig. 3). The ligand backbone
could be obtained by a direct assembly of commercially available
and inexpensive o-phenylenediamine and 2-bromobenzoic acid in
the presence of polyphosphoric acid (Scheme 1).14
The scope of this reaction was then investigated under the
preliminary optimized conditions. A range of aryl mesylates
were examined and the results are listed in Table 1. In general,
0.5 mol% of Pd was effective to handle a wide range of aryl
mesylates and complete conversions were observed within
24 hours. The deactivated aryl mesylate containing an ortho-
methoxy substituted group was found to be a feasible coupling
partner. Either ortho-substituted aryl mesylates or arylboronic
acids were also good substrates for this reaction. The function-
alized aryl mesylates containing keto, ester, aldehyde and
nitrile groups were found to be feasible electrophiles under
the reaction conditions. Phenolic side products were minimized
by using Na2CO3 as base for some substrates, isolated yields of
desired products could be as high as 99%. Apart from
common aryl mesylates, heteroaryl mesylates were also examined.
Benzothiazolyl and pyridyl substrates could couple with aryl-
boronic acids to furnish products in moderate to excellent
yields. It is worthy of note that heteroaryl boronic acid was
found to be a capable coupling partner in this reaction.
To further gain the insight into the metal–ligand inter-
actions, we attempted to complex the PdCl2(CH3CN)2 with
one equivalent of L2 in dichloromethane at room temperature
(Scheme 2). The X-ray crystallographic data confirmed that
the benzimidazolyl ligand L2 is coordinated in a k2-P,N
fashion (see ESIw for details).
In summary, a new series of P,N hemilabile ligands has been
developed. This family of ligands embodies a benzimidazolyl
backbone and is easily accessible from commercially available
and inexpensive diamine and benzoic acid.14 The degree of
potential structural variation is high, since this protocol can
generate multiple entities of skeletons from two main compo-
nents. Particularly noteworthy is that all ligand synthetic steps
require no chromatographic purification which potentially
gives a feature of scale up synthesis. To the best of our
knowledge, we have succeeded in showing the first examples
of P,N ligands that can effectively deal with aryl mesylate
coupling. Moreover, we have also achieved the lowest catalyst
This synthetic protocol could generate multiple entities of
ligand structures via a ‘‘cross-matching’’ approach from two
components. Particularly noteworthy is that the ligand scaffold,
2-(2-bromophenyl)-1H-benzoimidazole (1), could be synthesized
in a 100 mmol scale with good yield without difficulties in both
synthetic and purification processes. With the methylated ligand
precursor 2, the benzimidazolyl phosphines L1–L3 could be
afforded in good yields by lithiation and subsequently trapping
with ClPR2 (Scheme 1). This family of ligands exhibits excellent
air stability in both solid and solution states. It should be noted
that no chromatographic purification is needed in all synthetic
steps which offers additional advantage to this new ligand series.
To test the effectiveness of the new ligands, electronically
neutral 4-tert-butylphenyl mesylate and 4-tolylboronic acid
were used as the model substrates in our benchmark reaction
(see ESIw, Table S1). A catalyst loading of 0.5 mol% Pd was
initially applied for evaluating the new ligand efficacy. Ligand
L1 with a diphenylphosphino moiety provided trace substrate
conversion while the dicyclohexylphosphino analogue, L2,
gave the best catalytic activity. Ligand L3 bearing a diisopropyl-
phosphino moiety showed a lower catalytic activity towards
the Suzuki coupling reaction. Interestingly, the P,N ligand L2
displayed a significantly better activity than CM-phos in cross-
coupling of aryl mesylates. Upon investigating the metal/ligand
ratio from 1 : 1 to 1 : 4, the ratio of 1 : 2 provided the highest
yield, which differs from the Pd–CM-phos system in which the
metal/ligand ratio was at least 1 : 4 for giving the best result.9b
c
1968 Chem. Commun., 2012, 48, 1967–1969
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Table 1 Palladium-catalyzed Suzuki coupling of aryl mesylatesa
Organic Synthesis, ed. E.-i. Negishi, Wiley-Interscience, 2002,
vol. 1–2; (d) J. Hassan, M. Sevignon, C. Gozzi, E. Schulz and
´
M. Lemaire, Chem. Rev., 2002, 102, 1359; (e) J. Tsuji, Palladium
Reagents and Catalysts, Wiley, Chichester, 2nd edn, 2004;
(f) J.-P. Corbet and G. Mignani, Chem. Rev., 2006, 106, 2651;
(g) L. Ackermann, Modern Arylation Methods, Wiley-VCH,
Weinheim, 2009; (h) X. F. Wu, P. Anberasan, H. Neumann and
M. Beller, Angew. Chem., Int. Ed., 2010, 49, 9047–9050.
2 (a) A. O. King and N. Yasuda, in Organometallics in Process
Chemistry, ed. R. D. Larsen, Springer, Berlin, 2004, pp. 205–246
and references therein; (b) N. Miyaura, Top. Curr. Chem., 2002,
219, 11; (c) A. Suzuki, in Modern Arene Chemistry, ed. D. Astruc,
Wiley-VCH, Weinheim, 2002, pp. 53–106.
3 A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 2002, 41, 4176.
4 For recent reviews, see: (a) B.-J. Li, D.-G. Yu, G.-L. Sun and
Z.-J. Shi, Chem.–Eur. J., 2011, 17, 1728; (b) C. M. So and
F. Y. Kwong, Chem. Soc. Rev., 2011, 40, 4963.
5 The prices of the sulfonating agents are: MsCl, approx. USD$10
per mol; Tf2O, approx. USD$418 per mol, from Aldrich catalog
(2009–2010).
6 B. M. Trost, Angew. Chem., Int. Ed. Engl., 1995, 34, 259.
7 Ionization Constants of Organic Acids in Solution, ed. E. P. Serjeant
and B. Dempsey, Pergamon Press, Oxford, UK, 1979. (cf. methane-
sulfonic acid, pKa = À1.9; p-toluenesulfonic acid, pKa = À2.8;
benzenesulfonic acid, pKa = À6.5; triflic acid, pKa = À14.9).
8 Ligand screening for Suzuki coupling of aryl tosylates, see:
(a) H. N. Nguyen, X. Huang and S. L. Buchwald, J. Am. Chem.
Soc., 2003, 125, 11818; (b) L. Zhang, T. Meng and J. Wu, J. Org.
Chem., 2007, 72, 9346.
9 (a) C. M. So, C. P. Lau and F. Y. Kwong, Angew. Chem., Int. Ed.,
2008, 47, 8059; (b) Note: Pd/CM-phos catalyst system requires at
least Pd : L ratio of 1 : 4 for a better catalytic activity.
10 B. Bhayana, B. P. Fors and S. L. Buchwald, Org. Lett., 2009, 11, 3954.
11 For Pd-catalyzed Suzuki-type coupling using tosylate partners, see:
(a) H. N. Nguyen, X. Huang and S. L. Buchwald, J. Am. Chem.
Soc., 2003, 125, 11818; (b) L. Zhang, T. Meng and J. Wu, J. Org.
Chem., 2007, 72, 9346; (c) C. M. So, C. P. Lau, A. S. C. Chan and
F. Y. Kwong, J. Org. Chem., 2008, 73, 7731. For Ni-catalyzed
Suzuki-type coupling using tosylate partners, see: (d) D. Zim,
V. R. Lando, J. Dupont and A. L. Monteiro, Org. Lett., 2001,
3, 3049; (e) Z. Y. Tang and Q. S. Hu, J. Am. Chem. Soc., 2004,
126, 3058; (f) T. Tu, H. Mao, C. Herbert, M. Xu and K. H. Dotz,
¨
Chem. Commun., 2010, 46, 7796; (g) H. Gao, Y. Li, Y. G. Zhou,
F. S. Han and Y. J. Lin, Adv. Synth. Catal., 2011, 353, 309.
12 For Pd-catalyzed mesylate coupling reactions, see: (a) B. P. Fors,
D. A. Watson, M. R. Biscoe and S. L. Buchwald, J. Am. Chem. Soc.,
2008, 130, 13552; (b) L. Zhang, J. Qing, P. Yang and J. Wu, Org.
Lett., 2008, 10, 4971; (c) C. M. So, Z. Zhou, C. P. Lau and
F. Y. Kwong, Angew. Chem., Int. Ed., 2008, 47, 6402;
(d) C. M. So, H. W. Lee, C. P. Lau and F. Y. Kwong, Org. Lett.,
2009, 11, 317; (e) J. R. Naber, B. P. Fors, X. Wu, J. T. Gunn and
S. L. Buchwald, Heterocycles, 2010, 80, 1215; (f) W. K. Chow,
C. M. So, C. P. Lau and F. Y. Kwong, J. Org. Chem., 2010,
75, 5109; (g) G. A. Molander and F. Beaumard, Org. Lett., 2011,
13, 1242; (h) W. K. Chow, C. M. So, C. P. Lau and F. Y. Kwong,
Chem.–Eur. J., 2011, 17, 6913; (i) P. Y. Yeung, C. M. So, C. P. Lau
and F. Y. Kwong, Angew. Chem., Int. Ed., 2010, 49, 8918;
(j) C. M. So, C. P. Lau and F. Y. Kwong, Chem.–Eur. J., 2011,
17, 761; see ref. 9 and 10. For Ni-catalyzed mesylate coupling
reactions, see: (k) V. Percec, J. Y. Bae and D. H. Hill, J. Org.
Chem., 1995, 60, 1060; (l) V. Percec, G. M. Golding, J. Smidrkal and
O. Weichold, J. Org. Chem., 2004, 69, 3447; (m) see ref. 11f and g.
13 For reviews, see: (a) F. Y. Kwong and A. S. C. Chan, Synlett, 2008,
1440; (b) Z. Weng, S. Teo and T. S. A. Hor, Acc. Chem. Res., 2007,
40, 676. For the recent developments of P,N-type hemilabile
phosphine ligands for Suzuki coupling of aryl halides, see:
(c) Z. Weng, S. Teo, L. L. Koh and T. S. A. Hor, Organometallics,
2004, 23, 4342; (d) A. Scrivanti, V. Beghetto, U. Matteoli,
S. Antonaroli, A. Marini and B. Crociani, Tetrahedron, 2005,
61, 9752; (e) L. C. Liang, P. S. Chien and M. H. Huang, Organo-
metallics, 2005, 24, 353; (f) M. Guo, F. Jian and R. He, Tetra-
hedron Lett., 2006, 47, 2033; (g) A. Caiazzo, S. Dalili and
A. K. Yudin, Org. Lett., 2002, 4, 2597.
a
Reaction conditions: Pd(OAc)2 (0.5 mol%), Pd : L2
= 1 : 2,
ArOMs (1.0 mmol), arylboronic acid (2.0 mmol), K3PO4 (3.0 mmol),
t-BuOH (3 mL), at 120 1C under N2 for 24 h. Isolated yields were
reported. 1 mol% of Pd(OAc)2. K2CO3 as base. Na2CO3 as base,
b
c
d
at 120 1C under N2 for 18 h.
Scheme 2 Complexation of P,N ligand L2 with PdCl2(MeCN)2.
loading reported so far for Suzuki coupling of aryl mesylates
in general. This catalyst longevity finding possibly provides
relevance for a direction of future ligand design for conducting
other difficult aryl mesylate couplings.
We thank the Research Grants Council of Hong Kong (PolyU
5014/10P) and SKL of Chirosciences for financial support.
Notes and references
1 (a) Metal-Catalyzed Cross-Coupling Reactions, ed. A. de Meijere
and F. Diederich, Wiley-VCH, Weinheim, 2nd edn, 2004, vol. 1–2;
(b) M. Beller and C. Bolm, Transition Metals for Organic Synthesis,
Building Blocks and Fine Chemicals, Wiley-VCH, Weinheim,
2nd edn, 2004, vol. 1–2; (c) Handbook of Organopalladium for
14 According to the Aldrich catalog (2009–2010), o-phenylenediamine
costs 0.18 USD/G and 2-bromobenzoic acid costs 0.88 USD/G.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1967–1969 1969