Palladium-indolylphosphine-catalyzed hiyama cross-coupling of aryl mesylates

Article abstract of DOI:10.1021/ol802493z

(Chemical Equation Presented) Aryl mesylates are found to be applicable as electrophiles in organosilicon-mediated coupling reactions. The catalyst system comprising 2 mol % of Pd(OAc)₂ and CM-phos supporting ligand is highly effective in catalyzing Hiyama cross-coupling of various aryl and heteroaryl mesylates. Interesting acid additive effects show that the presence of 0.25-0.50 equiv of acetic acid efficiently suppresses the mesylate decomposition and generally promotes the coupling product yields.

Full text of DOI:10.1021/ol802493z

ORGANIC
LETTERS
2009
Vol. 11, No. 2
317-320
Palladium-Indolylphosphine-Catalyzed
Hiyama Cross-Coupling of Aryl
Mesylates
Chau Ming So, Hang Wai Lee, Chak Po Lau, and Fuk Yee Kwong*
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for
Drug DiscoVery and Synthesis and Department of Applied Biology and Chemical
Technology, The Hong Kong Polytechnic UniVersity, Kowloon, Hong Kong
bcfyk@inet.polyu.edu.hk
Received October 28, 2008
ABSTRACT
Aryl mesylates are found to be applicable as electrophiles in organosilicon-mediated coupling reactions. The catalyst system comprising 2
mol % of Pd(OAc)2 and CM-phos supporting ligand is highly effective in catalyzing Hiyama cross-coupling of various aryl and heteroaryl
mesylates. Interesting acid additive effects show that the presence of 0.25-0.50 equiv of acetic acid efficiently suppresses the mesylate
decomposition and generally promotes the coupling product yields.
The exploration and development of new and general
catalytic methods for organic synthesis remains at the center
of modern day organic chemistry since they empower
scientists working in areas as diverse as the total synthesis
of natural products1 to the preparation of analogues of lead
compounds for drug discovery.2 In fact, transition-metal-
catalyzed cross-coupling represents a versatile protocol in
organic synthesis for the connection of two different frag-
ments together via the formation of carbon-carbon and/or
carbon-heteroatom bonds.3 Aryl halides, of course, are the
most commonly used electrophiles in these reactions.4
However, aryl sulfonates such as tosylates and mesylates
are less effective than triflates in the application of this class
of catalysis, mainly due to their relative inertness toward
oxidative addition by palladium complexes.5,6 Appropriate
ligand choice in these processes is recognized to have a
significant impact on the outcome of such reactions.7
Recently, synthetic chemists have been remarkably adept at
(3) (a) de Meijere, A., Diederich, F., Ed. Metal-Catalyzed Cross-
Coupling Reactions; 2nd ed.; Wiley-VCH: Weinheim, 2004; Vols. 1 and
2. (b) Beller, M.; Bolm, C., Transition Metals for Organic Synthesis,
Building Blocks and Fine Chemicals, 2nd ed.; Wiley-VCH: Weinheim, 2004;
Vols. 1 and 2. (c) Nigeshi, E., Ed. Handbook of Organopalladium for
Organic Synthesis; Wiley-Interscience: New York, 2002; Vols. 1 and 2.
(d) Tsuji, J. Palladium Reagents and Catalysts, 2nd ed.; Wiley: Chichester,
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)
Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275. (i) Kwong, F. Y.;
Chan, A. S. C. Synlett. 2008, 1440. (j) Surry, D. S.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2008, 47, 6338. (k) Martin, R.; Buchwald, S. L. Acc. Chem.
Res. 2008, 41, 1461. (l) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
(4) For a pertinent review focused on aryl chloride couplings, see: Littke,
A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(1) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis. Targets,
Strategies, and Methods; VCH: Weinheim, 1996.
(2) For selected examples, see: (a) Goodson, F. E.; Hauck, S. I.; Hartwig,
J. F. J. Am. Chem. Soc. 1999, 121, 7527. (b) Suzuki, T.; Tanaka, S.; Yamada,
I.; Koashi, Y.; Yamada, K.; Chida, N. Org. Lett. 2000, 2, 1137. (c) Zhang,
X. X.; Sadighi, J. P.; Mackewitz, T. W.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 7606. (d) Harwood, E. A.; Hopkins, P. B.; Sigurdsson,
S. T. J. Org. Chem. 2000, 65, 2959. (e) Tanoury, G. J.; Senanayake, C. H.;
Hett, R.; Kuhn, A. M.; Kessler, D. W.; Wald, S. A. Tetrahedron Lett. 1998,
39, 6845. (f) Morita, S.; Kitano, K.; Matsubara, J.; Ohtani, T.; Kawano,
Y.; Otsubo, K.; Uchida, M. Tetrahedron 1998, 54, 4811. For a recent book
chapter, see: (g) King, A. O.; Yasuda, N. In Organometallics in Process
Chemistry; Larsen, R. D., Ed.; Springer-Verlag: Berlin, Heidelberg, 2004;
pp 205-245.
10.1021/ol802493z CCC: $40.75
Published on Web 12/19/2008
2009 American Chemical Society

devising effective ligands for specific bond constructions
under palladium catalysis (Figure 1), and the extension of
these reactions to aryl tosylates8 and mesylates9 couplings
is highly noteworthy.10
mesylates.13 Additionally, a beneficial additive effect on this
coupling process will also be described.
Table 1. Initial Screening on the Feasibility of Hiyama
Cross-Coupling of Aryl Mesylatea
entry
promotor/base
solvent
toluene
THF
DMF
THF/t-BuOH (1:1)
t-BuOH
toluene/t-BuOH (1:1)
t-BuOH
% yieldb
1
2
3
4
5
6
7
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
CsF
23
14
4
58
81
83
0
Figure 1. Effective ligand examples for Pd-catalyzed cross-coupling
of aryl benzensulfonates, tosylates, and mesylates.
As part of our continuing interest in the use of easily
accessible indolylphosphine ligands for mediating C-C
bond-forming reactions,9c,11 we herein report our efforts at
expanding the scope of the Hiyama cross-coupling12 to aryl
8
9
10
11
12c
KF
t-BuOH
t-BuOH
t-BuOH
t-BuOH
trace
0
K2CO3
K3PO4
Cs2CO3
TBAF
0
0
8
(5) For mechanistic studies on Pd-mediated oxidative addition of aryl
tosylates, see: Roy, A. H.; Hartwig, J. F. Organometallics 2004, 23, 194,
and references therein.
t-BuOH
a Reaction conditions: ArOMs (0.5 mmol), ArOMs/PhSi(OMe)3/TBAF
) 1:2:2; Pd(OAc)2/CM-phos ) 1:4; 90 °C for 16 h in the specified solvent
(1.0 mL, total solvent volume) under N2. b Calibrated GC yields were
reported using tetradecane as the internal standard. c 4 mol % of Pd(OAc)2
was used at 60 °C.
(6) Ni-catalyzed cross-coupling of aryl tosylates/mesylates are prece-
dented; 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. (c) Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold, O. J.
Org. Chem. 2004, 69, 3447. (d) Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org.
Chem. 1995, 60, 1060. (e) Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem.
1995, 60, 1066. (f) Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995,
60, 6895. (g) Ueda, M.; Saitoh, A.; Oh-tani, S.; Miyaura, N. Tetrahedron
1998, 54, 13079. (h) Kobayashi, Y.; Mizojiri, R. Tetrahedron Lett. 1996,
37, 8531. (i) Tang, Z.-Y.; Spinella, S.; Hu, Q.-S. Tetrahedron Lett. 2006,
47, 2427. (j) Lipshutz, B. H.; Butler, T.; Swift, E. Org. Lett. 2008, 10, 697.
(k) Wilson, D. A.; Wilson, C. J.; Rosen, B. M.; Percec, V. Org. Lett. 2008,
10, 4879. (l) Gao, C.-Y.; Yang, L.-M J. Org. Chem. 2008, 73, 1624. For a
related reference on homocoupling of aryl mesylates, see: (m) Percec, V.;
Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org. Chem. 1995, 60, 176.
(7) For a review, see: Zapf, A.; Beller, M. Chem. Commun. 2005, 431,
and references therein.
In order to probe the feasibility of a Hiyama cross-coupling
of an aryl mesylate, a series of screening experiments were
carried out (Table 1). 4-tert-Butylphenyl mesylate and
PhSi(OMe)3 were used as the model substrates, and 2 mol
% of Pd(OAc)2 with CM-phos ligand were used as the initial
catalytic system for our prototypical reaction. Since the
transmetalation of organosilanes proceeds smoothly after the
activation by fluoride anion,14 we initially applied TBAF as
the promoter. Among the commonly used organic solvents
we examined, t-BuOH and toluene/t-BuOH mixtures gave
(8) For ArOTs substrates and Suzuki coupling, see: (a) Nguyen, H. N.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818. (b) Zhang,
L.; Meng, T.; Wu, J. J. Org. Chem. 2007, 72, 9346. (c) So, C. M.; Lau,
C. P.; Chan, A. S. C.; Kwong, F. Y. J. Org. Chem. 2008, 73, 7731. For
Kumada coupling, see: (d) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 8704. (e) Limmert, M. E.; Roy, A. H.; Hartwig, J. F. J. Org.
Chem. 2005, 70, 9364. (f) Ackermann, L.; Althammer, A. Org. Lett. 2006,
8, 3457. For Buchwald-Hartwig C-N bond coupling, see: (g) Huang, X.;
Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 6653. (h) Hamann, B. C.; Hartwig, J. F. J. Am.
Chem. Soc. 1998, 120, 7369. (i) Ogata, T.; Hartwig, J. F. J. Am. Chem.
Soc. 2008, 130, 13848. For Sonogashira coupling using activated ArOTs,
see: (j) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42,
5993. For Hiyama coupling, see: (k) Zhang, L.; Wu, J. J. Am. Chem. Soc.
2008, 130, 12250. For C-S bond formation (one example), see: (l)
Ferna´ndez-Rodrı´guez, M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 2180. For carbonylation, see: (m) Munday, R. H.; Martinelli,
J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 2754. For alkenyl-
OTs substrates and Suzuki coupling, see: (n) Steinhuebel, D.; Baxter, J. M.;
Palucki, M.; Davies, I. W. J. Org. Chem. 2005, 70, 10124. For
Buchwald-Hartwig amidation, see: (o) Klapars, A.; Campos, K. R.; Chen,
C.-y.; Volante, R. P. Org. Lett. 2005, 7, 1185. For Heck coupling, see: (p)
Hansen, A. L.; Skrydstrup, T. Org. Lett. 2005, 7, 5585. (q) Hansen, A. L.;
Ebran, J.-P.; Ahlquist, M.; Norrby, P.-O.; Skrydstrup, T. Angew. Chem.,
Int. Ed. 2006, 45, 3349.
(10) Ar-OMs is more inert than Ar-OTs. For reference, usually the lower
the pKa of the conjugate acid, the better the leaving group (cf. methane-
sulfonic acid, pKa ) -1.9; p-toluenesulfonic acid, pKa ) -2.8; benzene-
sulfonic acid, pKa ) -6.5; triflic acid, pKa ) -14.9). Serjeant, E. P.,
Dempsey, B., Eds. Ionization Constants of Organic Acids in Solution;
IUPAC Chemical Data Series No. 23; Pergamon Press: Oxford, UK, 1979
.
(11) (a) So, C. M.; Lau, C. P.; Kwong, F. Y. Org. Lett. 2007, 9, 2795.
(b) So, C. M.; Yeung, C. C.; Lau, C. P.; Kwong, F. Y. J. Org. Chem. 2008,
73, 7803. (c) Reference 8c.
(12) For reviews and examples of the Hiyama couplings, see: (a)
Hiyama, T. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: New York, 1998; Chapter 10. (b) Hiyama,
T. J. Organomet. Chem. 2002, 653, 58. (c) Denmark, S. E.; Sweis, R. F.
Acc. Chem. Res. 2002, 35, 835. (d) Denmark, S. E.; Sweis, R. F. In Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A., Diederich,
F., Eds.; Wiley-VCH: Weinheim, 2004; Chapter 4. (e) Denmark, S. E.;
Baird, J. D. Chem.sEur. J. 2006, 12, 4954. (f) Strotman, N. A.; Sommer,
S.; Fu, G. C. Angew. Chem., Int. Ed. 2007, 46, 3556. (g) Denmark, S. E.;
Butler, C. R. Org. Lett. 2006, 8, 63.
(13) Hiyama coupling of ArOMs remains sporadically studied, and there
is only one publication to date. During the completion of our experimental
work, a closely related paper on Hiyama coupling appeared. Zhang, L.;
Qing, J.; Yang, P.; Wu, J. Org. Lett. 2008, 10, 4971. The authors used 4
mol % of Pd(OAc)2 with Xphos ligand at 90 °C as the optimized catalytic
system.
(9) For ArOMs substrates and C-N bond formation, see: (a) So, C. M.;
Zhou, Z.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2008, 47, 6402.
(b) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 13552. For ArOMs Suzuki coupling, see: (c) So,
C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2008, 47, 8059.
(d) For carbonylation, see ref 8m.
(14) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918.
318
Org. Lett., Vol. 11, No. 2, 2009

the best results (entries 1-6). We next tested other fluoride
salts. However, neither CsF nor KF provided the desired
product (entries 7 and 8). General inorganic bases such as
K2CO3, K3PO4, and Cs2CO3 were found to be inferior in the
reaction (entries 9-11). Lowering the reaction temperature
to 60 °C significantly retarded the rate of reaction (entry 12).
In fact, we routinely observed ∼10-15% of problematical
Table 3. Pd-Catalyzed Hiyama Cross-Coupling of ArOMsa
Scheme 1. Silyl Ether Cleavage by TBAF
phenolic side products being formed during the course of
the initial screenings as judged by GC-MS analyses. We
wondered whether the formation of this phenolic side product
might be triggered by the alkaline hydrolysis of the aryl
mesylate in the presence of the methoxide, which was
generated by the nucleophilic cleavage of silyl ether using
TBAF (Scheme 1).15 In order to reduce side product
formation, as well as to further increase the desired product
yield, we introduced an acid additive to the reaction mixture
(Table 2).
Our rationale for adding acetic acid to the reaction mixtures
Table 2. Acid Additive Effect in Hiyama Coupling of ArOMsa
entry
acid additiveb
% yieldc
1
2
no AcOH added
0.25 equiv AcOH
0.50 equiv AcOH
1.00 equiv AcOH
2.00 equiv AcOH
75
88 (94)d
85
3
4e
5e
(65)d
(27)d
a Reaction conditions: as in Table 1. b Equivalence with respected to
TBAF. c Isolated yields. d Calibrated GC yield in parentheses. e 4 mol %
of Pd(OAc)2 was used, at 90 °C for 8 h.
was to neutralize the methoxide anion, and thus to reduce
the possibility of alkaline hydrolysis of the aryl mesylate.
Gratifyingly, when 0.25 equiv of acetic acid was introduced,
the desired product yield was enhanced (Table 2, entry 1 vs
2). In general, the addition of 0.25-0.50 equiv of acetic acid
is sufficient to suppress the phenolic side product formation
(15) For references on nucleophilic attack of fluoride anion to cleave
silyl ether in generating alkoxide, see: Thomas, S. E. Organic Synthesis -
The Roles of Boron and Silicon; Oxford University Press: Oxford, 1991.
a Reaction conditions: see Tables 1 and 2. b Isolated yields.
Org. Lett., Vol. 11, No. 2, 2009
319

(Table 2, entries 2 and 3). However, excess acetic acid added
reduced the rate of reaction (Table 2, entries 4 and 5).
To evaluate the effectiveness of our new catalytic system,
a range of aryl mesylates was examined using the preliminary
optimized reaction conditions (Table 3). Complete conver-
sions of aryl mesylates were normally observed between
6-16 h at 90 °C.16 Beneficial effects of the acid additive
were generally found (Table 3, e.g., entries 1 vs 2, 10 vs 11,
17 vs 18). Both PhSi(OMe)3 and PhSi(OEt)3 provided similar
yields of the desired product (entries 1 and 3). Electron-
deficient nucleophiles furnished the coupling product in good
yield (entry 4). Essentially no electronic effect on both
electrophilic and nucleophilic partners was observed in this
coupling process, which is in contrast to Wu’s recent report.13
Sterically hindered substrates also coupled smoothly to give
the desired product (entry 17).17 Deactivated 4-methoxyphe-
nyl mesylate was found to be a feasible substrate in this
reaction (entry 19). Functional groups such as ester and
ketone were compatible under these reaction conditions
(entries 20-23). For instance, we also further examined the
relative activity between the chloro and mesylate group (not
shown in Table 3). 4-Chlorophenyl mesylate was used as
the model substrate for this investigation. Almost complete
selectivity (>99%) on the coupling of the chloro group was
observed (i.e., no 4-chlorobiphenyl was formed as monitored
by GC-MS analysis).
Table 4. Pd-Catalyzed Hiyama Coupling of Heteroaryl
Mesylatesa
a Reaction conditions: see Tables 1 and 2. b Isolated yields.
mol % of Pd is generally sufficient to catalyze this coupling
process. Particularly noteworthy is that we have also
demonstrated the beneficial effect of acid additives which
very effectively suppress phenolic side product formation.
These findings may prove of relevance for improving Si-
based cross-couplings of aryl sulfonates (e.g., mesylate/
tosylate/triflate) and open up the possibility of expanding
the scope to other related types of catalysis.
Apart from a variety of aryl mesylates, heteroaryl mesy-
lates were effective substrates for Hiyama coupling (Table
4). Quinolyl and benzothiazolyl substrates provided moderate
to good yields of the corresponding coupling products (Table
4, entries 1-3). However, when the heterocyclic substrate
was used as the nucleophilic partner, only 29% of the desired
product was obtained (entry 4).
In summary, we have succeeded in devising an effective
system for performing Hiyama cross-couplings on aryl and
heteroaryl mesylates. In the presence of CM-phos ligand, 2
Acknowledgment. We thank the Research Grants Council
of Hong Kong (CERG: PolyU5005/07P), PolyU Internal
Competitive Research Grant (A-PH51), and the University
Grants Committee Areas of Excellence Scheme (AoE/P-10/
01) and for financial support. Special thanks to Prof. Albert
S. C. Chan’s research group (PolyU Hong Kong) for sharing
of GC-FID and GC-MS instruments.
Supporting Information Available: General consider-
ations, detailed experimental procedures, references of known
compounds, product characterization data, and copies of 1H
NMR, 13C NMR, and MS spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) The reaction time for each substrate has not been optimized. In
general, 16 h is sufficient for complete conversion of all aryl mesylates.
(17) In ref 13, Wu and co-workers reported that ∼5% yield of the
coupled product was observed when ortho-substituted aryl mesylate was
used.
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