A general palladium catalyst system for suzuki-miyaura coupling of potassium aryltrifluoroborates and aryl mesylates

Article abstract of DOI:10.1021/jo100846t

(Figure presented) The first general examples of palladium-catalyzed Suzuki-type cross-coupling of aryl and heteroaryl mesylates with potassium aryl and heteroaryltrifluoroborates are presented. In addition to biaryl couplings, the cross-coupling reactions of aryl mesylates with alkyl and vinyltrifluoroborate salts have also been successfully accomplished.

Full text of DOI:10.1021/jo100846t

pubs.acs.org/joc
A General Palladium Catalyst System for Suzuki-Miyaura Coupling of
Potassium Aryltrifluoroborates and Aryl Mesylates§
Wing Kin Chow, Chau Ming So, Chak Po Lau, and Fuk Yee Kwong*
State Key Laboratory of Chiroscience and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
bcfyk@inet.polyu.edu.hk
Received April 29, 2010
The first general examples of palladium-catalyzed Suzuki-type cross-coupling of aryl and heteroaryl
mesylates with potassium aryl and heteroaryltrifluoroborates are presented. In addition to biaryl
couplings, the cross-coupling reactions of aryl mesylates with alkyl and vinyltrifluoroborate salts
have also been successfully accomplished.
Introduction
material, and agricultural chemistry.3 In general, arylboronic
acids are good nucleophilic organoboron reagents in this coupl-
ing reaction.4 However, boronic acids are never ideal because
they exhibit several drawbacks, such as the partial formation of
dimeric and cyclic trimeric boroxines (which depend on storage
water content). This structural ambiguity affects the stoichi-
ometry of boronic acids added to the intended reaction.
Organotrifluoroborate salts are attractive alternatives to aryl-
and heteroarylboronic acids as they are usually sold in high
purity from commercial sources or are readily available from
other organoboron compounds.5,6 Recently, Molander,5,7
Buchwald,8 and others9 made superb efforts to advance the
transition metal-catalyzed Suzuki-Miyaura coupling using
organotrifluoroborate salts as coupling partners.
Using a modular approach for accessing a series of com-
pounds has been one of the most important themes in mo-
dern organic synthesis, since it offers a direct and simple
route to prepare an array of structurally similar, yet diversi-
fied organic molecules.1 Indeed, transition metal-catalyzed
cross-coupling reactions have become innovative protocols
in this area for the construction of either carbon-carbon or
carbon-heteroatom bonds.2
In the field of C(sp2)-C(sp2) cross-coupling reaction, Suzuki-
Miyaura coupling of arylboronic acids with aryl halides repre-
sents a versatile method for the preparation of diversified
biaryls, which have a myriad of applications in pharmaceutical,
§ Dedicated to Prof. Albert S. C. Chan on the occasion of his 60th birthday.
(1) For reviews, see: (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem., Int. Ed. 2005, 44, 4442. (b) Nicolaou, K. C.; Sorensen, E. J. Classic in
Total Synthesis II, More Targets, Strategies and Methods; Wiley-VCH:
Weinheim, Germany, 2003.
(2) (a) de Meijere, A.; Diederich, F., Ed. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2004; Vols. 1-2. (b) Beller,
M.; Bolm, C. Transition Metals for Organic Synthesis, Building Blocks and Fine
Chemicals, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2004; Vols. 1-2. (c) Nigeshi,
E., Ed. Handbook of Organopalladium for Organic Synthesis; Wiley-Interscience:
Weinheim, Germany, 2002; Vols. 1-2. (d) Tsuji, J. Palladium Reagents and
Catalysts, 2nd ed.; Wiley: Chichester, UK, 2004. (e) Yin, L. X.; Liebscher, J. Chem.
Rev. 2007, 107, 133. (f) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651. (g)
Roglans, A.; Pla-Quintana, A.; Moreno-Manas, M. Chem. Rev. 2006, 106, 4622. (h)
Kwong, F. Y.; Chan, A. S. C. Synlett 2008, 1440. (i) Ackermann, L., Modern
Arylation Methods; Wiley-VCH: Weinheim, Germany, 2009.
(3) (a) King, A. O.; Yasuda, N. In Organometallics in Process Chemistry;
Larsen, R. D., Ed.; Springer-Verlag: Berlin, Germany, 2004; pp 205-245. (b)
Miyaura, N. Top. Curr. Chem. 2002, 219, 11. (c) Suzuki, A. In Modern Arene
Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp 53-106.
(d) Suzuki, A. J. Organomet. Chem. 2002, 653, 54.
(4) Hall, D. G., Boronic Acids; Wiley-VCH: Weinheim, Germany, 2006.
(5) For recent reviews on the coupling reactions with R-BF3K salts, see:
(a) Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48, 9240. (b)
Molander, G. A.; Ellis, N. O. Acc. Chem. Res. 2007, 40, 275.
(6) For selected examples, see: (a) Vedejs, E.; Chapman, R. W.; Fields,
S. C.; Lin, S.; Schrimpf, M. R. J. Org. Chem. 1995, 60, 3020–3027. (b)
Molander, G. A.; Cooper, D. J. J. Org. Chem. 2007, 72, 3558. (c) Molander,
G. A.; Ham, J.; Canturk, B. Org. Lett. 2007, 9, 821.
DOI: 10.1021/jo100846t
r
Published on Web 06/30/2010
J. Org. Chem. 2010, 75, 5109–5112 5109
2010 American Chemical Society

Chow et al.
JOCArticle
Results and Discussion
TABLE 1. Initial Optimization of Reaction Parametersa
Aryl sulfonates are important alternatives to aryl halides in
coupling reactions. Moreover, they are good complements to
aryl halides since their phenolic substitution patterns on the
aromatic ring are different from those of halides. Nevertheless,
previous coupling reactions of phenolic electrophiles were
often focused on aryl triflates. In fact, aryl mesylates are attrac-
tive as they are easily accessible from phenols (by reacting with
MsCl under basic medium), relatively low in cost,10 and pro-
vide better hydrolytic stability. However, cross-coupling reac-
tions utilizing aryl mesylates remain limited.11 Perphaps the
high stability of aryl mesylates implies that it is difficult for
these substrates to undergo oxidative addition in coupling
reactions. In fact, aryl mesylates are challenging substrates as
they are even less reactivethan the corresponding aryl tosylates
in cross-coupling reactions.12 Yet, they provide a better atom-
economy than tosylates.13 In 2008, we reported a palladium
catalyst system for the cross-coupling of arylboronic acids with
entry
solvent
base
% yieldb
1
2
3
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
DMF
t-AmOH
MeOH
THF
Cs2CO3
K3PO4 H2O
40
75
3
K3PO4
K2CO3
Et3N
98 (89)c
(87)c
10e
4
5
6d
7
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
82
28
52
79
trace
trace
8
9
10
11
toluene
aReaction conditions: ArOMs (1.0 mmol), Ar0BF3K (2.0 mmol), base
(3.0 mmol), Pd(OAc)2 (1 mol %), CM-phos (4 mol %), solvent (3.0 mL)
with stirring for 18 h at 110 °C under nitrogen. bCalibrated GC yields
were reported with dodecane as the internal standard. cIsolated yields in
parentheses. 4 A molecular sieve (0.1 g, granular) was added. A 65% of
reduction side product, tert-butylbenzene, was formed.
(7) For recent selected examples from Molander’s group, see: (a) Molander,
G. A.; Cavalcanti, L. N.; Canturk, B.; Pan, P. S.; Kennedy, L. E. J. Org. Chem.
2009, 74, 7364. (b) Cho, Y. A.; Kim, D. S.; Ahn, H. R.; Canturk, B.; Molander,
G. A.; Ham, J. Org. Lett. 2009, 11, 4330. (c) Molander, G. A.; Febo-Ayala, W.;
Jean-Gerard, L. Org. Lett. 2009, 11, 3830. (d) Molander, G. A.; Jean-Gerard, L.
J. Org. Chem. 2009, 74, 5446. (e) Dreher, S. D.; Lim, S. E.; Sandrock, D. L.;
Molander, G. A. J. Org. Chem. 2009, 74, 3626. (f ) Molander, G. A.; Jean-
Gerard, L. J. Org. Chem. 2009, 74, 1297. (g) Molander, G. A.; Cooper, D. J.
J. Org. Chem. 2008, 73, 3885. (h) Molander, G. A.; Gormisky, P. E.; Sandrock,
D. L. J. Org. Chem. 2008, 73, 2052. (i) Molander, G. A.; Gormisky, P. E. J. Org.
Chem. 2008, 73, 7481. ( j) Molander, G. A.; Sandrock, D. L. Org. Lett. 2007, 9,
1597. (k) Molander, G. A.; Vargas, F. Org. Lett. 2007, 9, 203.
d
e
˚
aryl mesylates.14,15 This system demonstrated a good func-
tional group tolerance on both electrophilic and nucleophilic
partners. To our best knowledge, there has been no literature
report to date regarding the successful cross-coupling of aryl
mesylates and aryltrifluoroborate salts in general. In view of
the beneficial features of trifluoroborate salts as boronic acid
surrogates, we have investigated the feasibilty of using this
nucleophile in mesylate couplings. Herein, we report the first
general Suzuki-type coupling of aryl mesylates and organo-
trifluoroborates. In particular, the reaction scope can be
extended to heteroarylmesylates, heteroaryl-,16 alkenyl-, and
alkyltrifluoroborate salts.
To explore a high efficacy catalytic system for aryl mesylate
and aryltrifluoroborate salt coupling, 4-tert-butylphenyl me-
sylate and potassium p-tolyltrifluoroborate were chosen as the
benchmark substrates in the model reaction (Table 1). Initial
screening of commonly used inorganic and organic bases
indicated that K3PO4 and K2CO3 were suitable bases for this
coupling reaction (Table 1, entries 3 and 4). In general, a very
small amount of phenolic side product was detected. On the
contrary, when triethylamine was applied as an organic base in
this reaction, a large amount of tert-butylbenzene side product
was observed (Table 1, entry 5). Although adding molecular
sieves could reduce the formation of tert-butylbenzene, it also
suppressed the rate of reaction. Among common solvents
surveyed, t-BuOH gave the best result (Table 1, entries 6-11).
The scope of this reaction was then investigated under the
optimized conditions. A wide range of nonactivated aryl mesy-
lates were examined and the results are listed in Table 2. The
deactivated aryl mesylate containing a p-methoxy-substituted
group was found to be a feasible coupling partner (Table 2,
entry 4). Both ortho-substituted aryl mesylates and aryltri-
fluoroborates were also a good combination for this reaction
(8) Barder, T. E.; Buchwald, S. L. Org. Lett. 2004, 6, 2649.
(9) For recent selected examples, see: (a) Abel, R.; Aggarwal, V. K.
Angew. Chem., Int. Ed. 2009, 48, 6289. (b) Doucet, H. Eur. J. Org. Chem.
2008, 2013. (c) Kabalka, G. W.; Zhou, L.-L.; Naravane, A. Tetrahedron Lett.
2006, 47, 6887. (d) Harker, R. L.; Crouch, R. D. Synthesis 2007, 25. (e) Wu,
J.; Zhang, L.; Luo, Y. Tetrahedron Lett. 2006, 47, 6747. (f ) Wu, J.; Zhang, L.;
Xia, H.-G. Tetrahedron Lett. 2006, 47, 1525. (g) Cella, R.; Cunha, R. L. O.
R.; Reis, A. E. S.; Pimenta, D. C.; Klitzke, C. F.; Stefani, H. A. J. Org. Chem.
2006, 71, 244. (h) Kabalka, G. W.; Al-Masum, M. Tetrahedron Lett. 2005, 46,
6329. (i) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397. ( j) Quach, T. D.;
Batey, R. A. Org. Lett. 2003, 5, 1381. (k) Fang, G.-H.; Yan, Z.-J.; Deng,
M.-Z. Org. Lett. 2004, 6, 357. (l) Darses, S.; Genet, J.-P. Eur. J. Org. Chem.
2003, 4313. (m) Arvela, R. K.; Leadbeater, N. E.; Mack, T. L.; Kormos,
C. M. Tetrahedron Lett. 2006, 47, 217. For a review describing indolyl/
imidazolyl phosphine ligands, see: (n) Zapf, A.; Beller, M. Chem. Commun.
2005, 431. For our recent developments of indolyl phosphine, see: (o) So,
C. M.; Yeung, C. C.; Lau, C. P.; Kwong, F. Y. J. Org. Chem. 2008, 73, 7803.
(10) The prices of the sulfonating agents are as follows (in US dollars):
MsCl, ca. $0.075/g; Tf2O, ca. $5/g, from commercial suppliers in 2005-2006.
(11) For Ni-catalyzed mesylate coupling reactions, see: (a) Percec, V.;
Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org. Chem. 1995, 60, 176. (b) Percec, V.;
Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60, 1060. (c) Percec, V.; Golding,
G. M.; Smidrkal, J.; Weichold, O. J. Org. Chem. 2004, 69, 3447. For Pd-
catalyzed mesylate coupling reactions, see: (d) Fors, B. P.; Watson, D. A.;
Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 13552. (e)
Zhang, L.; Qing, J.; Yang, P.; Wu, J. Org. Lett. 2008, 10, 4971. (f ) So, C. M.;
Zhou, Z.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2008, 47, 6402. (g)
So, C. M.; Lee, H. W.; Lau, C. P.; Kwong, F. Y. Org. Lett. 2009, 11, 317. (h)
Naber, J. R.; Fors, B. P.; Wu, X.; Gunn, J. T.; Buchwald, S. L. Heterocycles
2010, 80, 1215. (i) See refs 14 and 15.
(12) Serjeant, E. P.; Dempsey, B., Eds. Ionization Constants of Organic Acids
in Solution; IUPAC Chemical Data Series No. 23; Pergamon Press: Oxford, UK,
1979 (cf. methanesulfonic acid, pKa = -1.9; p-toluenesulfonic acid, pKa = -2.8;
benzenesulfonic acid, pKa = -6.5; triflic acid, pKa = -14.9 ).
(13) For Ni-catalyzed Suzuki-type coupling with tosylate partners, see:
(a) Zim, D.; Lando, V. R.; Dupont, J.; Monteiro, A. L. Org. Lett. 2001, 3,
3049. (b) Tang, Z. Y.; Hu, Q. S. J. Am. Chem. Soc. 2004, 126, 3058. For Pd-
catalyzed Suzuki-type coupling with tosylate partners, see: (c) Nguyen,
H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818. (d)
Zhang, L.; Meng, T.; Wu, J. J. Org. Chem. 2007, 72, 9346. (e) So, C. M.; Lau,
C. P.; Chan, A. S. C.; Kwong, F. Y. J. Org. Chem. 2008, 73, 7731.
(14) So, C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2008, 47,
8059. One nonactivated ArOMs þ Ar0BF3K was reported.
(15) For an effective system reported by Buchwald and co-workers
focusing on heteroaryl couplings, see: Bhayana, B.; Fors, B. P.; Buchwald,
S. L. Org. Lett. 2009, 11, 3954.
(16) (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles, 2nd ed.;
Wiley-VCH: Weinheim, Germany, 2003. (b) Molander, G. A.; Canturk, B.;
Kennedy, L. E. S. J. Org. Chem. 2009, 74, 973.
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TABLE 2. Pd-Catalyzed Suzuki-Miyaura Coupling of Nonactivated
TABLE 3. Pd-Catalyzed Suzuki-Miyaura Coupling of Functionalized
Aryl Mesylatesa
Aryl Mesylatesa
aReaction conditions: ArOMs (1.0 mmol), Ar0BF3K (2.0 equiv), K3PO4
(3.0 equiv), Pd(OAc)2:ligand = 1:4, t-BuOH (3.0 mL) with stirring for 2 h at
110 °C under nitrogen. bIsolated yields.
aReaction conditions: ArOMs (1.0 mmol), Ar0BF3K (2.0 mmol), K3PO4
(3.0 mmol), Pd(OAc)2:ligand = 1:4 (mol % as indicated, t-BuOH (3.0 mL)
with stirring for 18 h at 110 °C under nitrogen (reaction times were not
optimized for each substrate). bIsolated yields.
achieve these couplings in modest to good yields (Table 4
entries 1, 5, and 6).
Vinyl and alkyltrifluoroborates were also tested as the
coupling partners (Scheme 1). 4-tert-Butylphenyl mesylate
coupled with potassium n-butyltrifluoroborate and potas-
sium trans-styryltrifluoroborate in good yields.
(Table 2, entry 5). The highly sterically hindered potassium
aryltrifluoroborate (Table 2, entry 7) could couple with aryl
mesylate to furnish product in moderate to good yield.
A variety of common functional groups were compatible
under these mild reaction conditions. The functionalized aryl
mesylates containing nitriles, keto, and benzodioxolyl groups
were found to be effective electrophiles (Table 3). Notably, the
couplings of these aryl mesylates were completed within 2 h in
the presence of 2 mol % catalyst loading.
Apart from a variety of aryl mesylates, heteroaryl mesy-
lates and trifluoroborates were also effective coupling part-
ners. Quinolyl and benzothiazolyl substrates showed good
yields of the corresponding coupling products (Table 4,
entries 1 and 6). Thienyl nucleophiles were good nucleophilic
partners that provided moderate to good yield of the pro-
ducts (Table 4, entries 1-6). Particularly noteworthy was the
fact that the thienyl trifluoroborate salt was much superior to
the corresponding thenylboronic acid in this coupling reac-
tion (Table 4, entries 3 vs 4). Heterobiaryl synthesis is mostly
a challenge in cross-coupling reactions. We were also able to
Conclusion
In conclusion, we have reported the first general Suzuki-
Miyaura coupling of unactivated aryl mesylates and aryltri-
fluoroborate salts. The Pd-CM-phos catalyst system is effective
for the coupling of a range of mesylate substrates containing
various common functional groups. In addition to the feasibility
in using heteroaryl mesylates and trifluoroborate salts as elec-
trophiles and nucleophiles, respectively, vinyl and alkyltrifluor-
oborates have also been shown as compatible coupling partners.
Experimental Section
General Procedure for Suzuki-Miyaura Coupling of Aryl
Mesylates. Pd(OAc)2 (2.3 mg, 0.010 mmol) and CM-phos
(Pd:L=1:4) were loaded into a Schlenk tube equipped with a
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TABLE 4. Pd-Catalyzed Suzuki-Miyaura Coupling of Heteroaryl
SCHEME 1. Feasibility of Pd-Catalyzed Suzuki-Miyaura
Mesylates with Potassium Heteroaryltrifluoroborate Saltsa
Coupling of Vinyl- and Alkyltrifluoroborate Saltsa
aReaction conditions: ArOMs (1.0 mmol), nucleophilic partner (2.0
mmol), K3PO4 (3.0 mmol), Pd(OAc)2:L = 1:4, L = CM-phos, t-BuOH
(3.0 mL) with stirring under nitrogen. Isolated yields were reported.
minutes and then placed into a preheated oil bath (110 °C) for the
time period indicated in the table. After completion of reaction as
judged by GC analysis, the reaction tube was allowed to cool to
room temperature and quenched with water and diluted with
EtOAc. The organic layer was separated and the aqueous layer
was washed with EtOAc. The filtrate was concentrated under
reduced pressure. The crude products were purified by flash
column chromatography on silica gel (230-400 mesh) to afford
the desired product. 1H NMR (500 MHz, CDCl3) δ 1.58 (s, 9H),
2.59 (s, 3H), 7.44 (d, J = 8.0 Hz, 2H), 7.66-7.76 (m, 6H); 13C
NMR (100 MHz,CDCl3) δ 21.1, 31.4, 34.4, 125.6, 126.6, 126.8,
129.4, 136.6, 138.2, 138.2, 149.8; MS (EI) m/z (rel intensity) 224
(Mþ, 35), 209 (100), 193 (5), 181 (12), 165 (10).
aReaction conditions: Het- or ArOMs (1.0 mmol), HetAr-BF3K (2.0
mmol), K3PO4 (3.0 mmol), Pd(OAc)2:ligand = 1:4, t-BuOH (3.0 mL)
with stirring under nitrogen for the indicated periods. bIsolated yields.
Acknowledgment. We thank the Research Grants Council
of Hong Kong (CERG: PolyU5005/07P), PolyU Internal
Competitive Research Grant (A-PG13), and the University
Grants Committee Areas of Excellence Scheme (AoE/P-10/
01) for financial support. The authors are grateful to Prof.
Albert S. C. Chan’s research group (PolyU Hong Kong) for
sharing the GC instruments.
Teflon-coated magnetic stir bar. The tube was evacuated and
flushed with nitrogen several times. Precomplexation was ap-
plied by adding freshly distilled dichloromethane (1 mL) and
Et3N (100 μL) into the tube. The solution was stirred and
warmed with a hair dryer for 1 to 2 min until the solvent started
boiling. The solvent was then evaporated under high vacuum.
4-tert-Butylphenyl mesylate (1.0 mmol), potassium p-tolyltri-
fluoroborate (2.0 mmol), and K3PO4 (3.0 mmol) were loaded
into the tube, and the system was further evacuated and flushed
with nitrogen several times. The solvent tert-butanol (3.0 mL) was
then added. The tube was stirred at room temperature for several
Supporting Information Available: Detail experimental pro-
cedures, compound characterization data, and copies of
1H NMR, 13C NMR, MS, and HRMS spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
5112 J. Org. Chem. Vol. 75, No. 15, 2010