Suzuki-Miyaura coupling of aryl tosylates catalyzed by an array of indolyl phosphine-palladium catalysts

Full text of DOI:10.1021/jo8014819

Suzuki-Miyaura Coupling of Aryl Tosylates Catalyzed by an Array
of Indolyl Phosphine-Palladium Catalysts
Chau Ming So, Chak Po Lau, Albert S. C. Chan, 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, Hung Hom, Kowloon, Hong Kong
bcfyk@inet.polyu.edu.hk
ReceiVed July 10, 2008
A family of indolyl phosphine ligands was applied to Suzuki-Miyaura cross-coupling of aryl tosylates.
Catalyst loading can be reduced to 0.2 mol % for coupling of nonactivated aryl tosylate. A challenging
example for room temperature coupling is realized. The scope of this highly active Pd/L2 system can be
extended to other boron nucleophiles, including trifluoroborate salts and boronate esters. The ligand
structural comparisons toward the reactivity in tosylate couplings are also described.
Introduction
stability translates into an inferior reactivity in palladium-
catalyzed coupling processes.5 However, nickel-catalyzed aryl
tosylate couplings have been reported.6
The Suzuki-Miyaura reaction employing organoboron nu-
cleophiles represents one of the most effective methods for the
construction of C(sp2)-C(sp2) linkages,1 and constitutes numer-
ous applications in pharmaceutical and material chemistry.2 Aryl
iodides, bromides, triflates, nonaflates, and more recently
chlorides3 are commonly used for the synthesis of substituted
arenes. In fact, aryl tosylates are less expensive than the
corresponding triflates and nonaflates and are therefore desirable
alternatives.4 Moreover, aryl tosylates are more convenient to
use because they are more stable toward hydrolysis than
corresponding triflates and usually have high crystallinity.
Although they have several beneficial features, their superior
Considerable efforts have been undertaken by researchers in
both academia and industry over the past decade to expand the
feasibility on difficult aryl/alkenyl tosylate couplings.7,8 To our
knowledge, there are only two publications to date on the Pd-
catalyzed Suzuki-Miyaura coupling of aryl tosylates.7a,b On
the contrary to aryl chloride coupling reactions,9 we speculate
that tosylate coupling reactions are particularly sensitive to the
nature and skeleton of the supporting phosphine ligands. For
example, Josiphos-type ligands10 were reported by Hartwig and
co-workers to be effective for Kumada coupling of aryl
tosylates,7c but they were ineffective in the corresponding
(1) (a) de Meijere, A.; Diederich, F., Eds. 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: Chichester, UK, 2002; Vols. 1-2. (d) Hassan, J.; Se´vignon,
M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359. (e) Tsuji,
J. Palladium Reagents and Catalysts, 2nd ed.; Wiley: Chichester, UK, 2004. (f)
Yin, L.; Liebscher, J. Chem. ReV. 2007, 107, 133. (g) Corbet, J.-P.; Mignani, G.
Chem. ReV. 2006, 106, 2651. (h) Roglans, A.; Pla-Quintana, A.; Moreno-Manas,
M. Chem. ReV. 2006, 106, 4622.
(2) (a) King, A. O.; Yasuda, N. In Organometallics in Process Chemistry;
Larsen, R. D., Ed.; Springer-Verlag: Berlin Heidelberg, 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) The prices of the sulfonating agent are as follows: TsCl, approximately
0.05 USD/g; Tf2O, approximately 5 USD/g, from commercial suppliers in 2005-
2006. Note: TsCl is a solid form and is sold in an ordinary reagent bottle, while
Tf2O is a moisture-sensitive liquid and is usually sold in an ampule.
(5) For mechanistic studies on oxidative addition of aryl tosylates by Pd-
complexes, see: Roy, A. H.; Hartwig, J. F Organometallics 2004, 23, 194.
(6) For Ni-catalyzed Suzuki cross-coupling of aryl tosylates, 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.
(3) For a pertinent review on aryl chloride couplings, see: Littke, A. F.; Fu,
G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
10.1021/jo8014819 CCC: $40.75
Published on Web 09/11/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7731–7734 7731

So et al.
TABLE 1. Investigations on the Effectiveness of the Indolyl
Phosphine Ligands L1-L8 in Suzuki-Miyaura Coupling of
Nonactivated ArOTsa
entry
ligand
base
% yieldb
1
2
3
L1 (R′′ ) Ph)
K3PO4 ·H2O
K3PO4 ·H2O
K3PO4 ·H2O
K3PO4 ·H2O
K3PO4 ·H2O
Cs2CO3
<1
93
86
0
99
85
<1
14
<1
<1
2
L2 (R′′ ) Cy)
FIGURE 1. Ligand diversification from the 2-arylindole template.
L3 (R′′ ) i-Pr)
no ligand
4
5c
6
L2 (R′′ ) Cy)
Suzuki-Miyaura reactions as reported by the Buchwald group.7a
In addition to aryl tosylates, aryl mesylates are attractive but
difficult substrates. We recently disclosed the first general
amination of aryl mesylates11 using the indolyl phosphine L2
(CM-phos) as the supporting ligand.12 In fact, it is desirable to
develop a series of ligands that can be easily fine-tuned in
dealing with the narrow window for these challenging substrates.
Herein, we report our efforts on the application of a series
indolyl phosphine ligands in tackling the tosylate substrates in
Suzuki-Miyaura coupling. These ligands displayed excellent
catalytic activity in coupling of aryl/alkenyl tosylates with
different organoboron nucleophiles.
L2 (R′′ ) Cy)
7
8
9
10
11
12
13
14d
L2 (R′′ ) Cy)
Na2CO3
KOt-Bu
L2 (R′′ ) Cy)
L4 (R′ ) H, R′′ ) Ph)
L5 (R′ ) H, R′′ ) Cy)
L6 (R′ ) OMe, R′′ ) Cy)
L7 (R′ ) Me, R′′ ) Cy)
L8 (R′ ) H, R′′ ) i-Pr)
L6 (R′ ) OMe, R′′ ) Cy)
K3PO4 ·H2O
K3PO4 ·H2O
K3PO4 ·H2O
K3PO4 ·H2O
K3PO4 ·H2O
K3PO4 ·H2O
<1
<1
2
a Reaction conditions: ArOTs (1.0 mmol), PhB(OH)2 (2.0 mmol),
base (3.0 mmol), Pd(OAc)2 (0.01 mmol, 1.0 mol%), L1-L3 (0.04
mmol), t-BuOH (3.0 mL), at 110 °C under N2 for 2 h (see the
Supporting Information for experimental details). b Calibrated GC yields
were reported with dodecane as the internal standard. c DMF solvent
was used. d Toluene solvent was used.
Results and Discussion
We recently reported a series of N-P bound amino-phosphine
ligands which can be easily accessed by Fischer indolization13
from commercially available starting materials (Figure 1).14
They showed the highest activity achieved so far for the
Suzuki-Miyaura coupling of aryl chlorides employing amino-
phosphine ligands. On the basis of the attractive feature of this
ligand synthesis that the ligand framwork can be easily tuned
by a cross matching of two starting materials, we developed
another series of C-P bound phosphine ligands for our further
investigations,15 especially in the area of aryl arenesulfonate
couplings (Figure 1). These ligands can be simply purified by
single crystallization (without tedious chromatographic purifica-
tion throughout the whole synthetic process) and showed
exceptionally high air-stability in both solid and solution states.16
The efficacy of both N-P bound and C-P bound indolyl
phosphine ligands on Suzuki-Miyaura coupling of tosylate
substrate was investigated. We used the nonactivated 4-tert-
butylphenyl tosylate and phenylboronic acid as the model
substrates for our trial runs (Table 1). We initially applied 1
mol % of Pd(OAc)2 with 4 equiv of ligands for the prototypical
reactions. It is obvious that ligand L1 with a diphenylphosphino
moiety did not provide any substrate conversion. In contrast,
the more electron-rich dicyclohexylphosphino L2 (CM-phos)
and diisopropylphosphino L3 analogues showed good to excel-
lent catalytic activity (entries 1-3). Control experiment revealed
that the supporting ligand was necessary for the successful
transformation (entries 2 vs 4). The use of t-BuOH and DMF
as the reaction solvent gave comparable results (entries 2 and
5),17 while dioxane and THF provided moderate product yields.
Upon screening of commonly used inorganic bases, we found
(7) For ArOTs substrates, 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) Roy, A. H.; Hartwig, J. F. J. Am.
Chem. Soc. 2003, 125, 8704. (d) Limmert, M. E.; Roy, A. H.; Hartwig, J. F. J.
Org. Chem. 2005, 70, 9364. (e) Ackermann, L.; Althammer, A. Org. Lett. 2006,
8, 3457. (f) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653. (g) Hamann, B. C.; Hartwig,
J. F. J. Am. Chem. Soc. 1998, 120, 7369. (h) Gelman, D.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2003, 42, 5993. (i) Ferna´ndez-Rodr´ıguez, M. A.; Shen, Q.;
Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 2180. (j) Munday, R. H.; Martinelli,
J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 2754.
(8) For alkenyl-OTs substrates, Suzuki coupling, see: (a) Steinhuebel, D.;
Baxter, J. M.; Palucki, M.; Davies, I. W. J. Org. Chem. 2005, 70, 10124. (b)
Klapars, A.; Campos, K. R.; Chen, C.-y.; Volante, R. P. Org. Lett. 2005, 7,
1185. (c) Hansen, A. L.; Skrydstrup, T. Org. Lett. 2005, 7, 5585. (d) Hansen,
A. L.; Ebran, J.-P.; Ahlquist, M.; Norrby, P.-O.; Skrydstrup, T. Angew. Chem.,
Int. Ed. 2006, 45, 3349.
(9) For a recent review on the development and application of bulky electron-
rich phosphines for Pd-catalyzed cross-coupling reaction of aryl halides and
sulfonates, notably through the work of Beller, Buchwald, Fu, and Hartwig
groups, see: Zapf, A.; Beller, M. Chem. Commun. 2005, 431.
(10) For Josiphos-type ligands, see:Togni, A.; Breutel, C.; Schnyder, A.;
Spindler, F.; Landert, H.; Tigani, A. J. Am. Chem. Soc. 1994, 116, 4062.
(11) So, C. M.; Zhou, Z.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed.
2008, 47, 6402.
(15) For the first Pd-catalyzed Suzuki-Miyaura coupling of aryl mesylates,
see: So, C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2008, doi:
10.1002/anie.200803193.
(12) CM-phos: CM represents the initial of the inventor. Particularly in this
case, CM-phos has the meaning of the nature of the phosphine ligand, i.e.,
Carbene-Metal-phosphine.
(16) There were no detectable phosphine oxide signals of L2 from 31P NMR,
when the solid-form ligand was allowed to stand either under air for 1 week or
in solution-form for at least 3 days. In contrast, Pt-Bu3 has been shown to be
destroyed in air within 2 h, see: (a) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin,
J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158. (b) Barder, T. E.; Buchwald,
S. L. J. Am. Chem. Soc. 2007, 129, 5096.
(13) For general indole syntheses, see: (a) Robinson, B. The Fischer Indole
Synthesis; Wiley: Chichester, UK, 1982. For an alternative 2-arylindole synthesis,
see:(b) Denmark, S.; Baird, J. D. Org. Lett. 2004, 6, 3649.
(14) So, C. M.; Lau, C. P.; Kwong, F. Y. Org. Lett. 2007, 9, 2795.
7732 J. Org. Chem. Vol. 73, No. 19, 2008

Suzuki-Miyaura Coupling of Aryl Tosylates
TABLE 2. Pd-Catalyzed Suzuki-Miyaura Coupling of Aryl
TABLE 3. Pd-Catalyzed Suzuki-Miyaura Coupling of Heteroaryl
Tosylates with Arylboronic Acidsa
or Vinyl Tosylates with Arylboronic Acidsa
a Reaction conditions: Het-OTs or VinylOTs (1.0 mmol), Ar′B(OH)2
(2.0 mmol), K3PO4 ·H2O (3.0 mmol), Pd(OAc)2 (mol % as indicated),
Pd:L ) 1:4, t-BuOH (3.0 mL), at 110 °C under N2. b Isolated yields.
c DMF solvent was used.
SCHEME 1. Suzuki-Miyaura Coupling of Aryl Tosylates
with Other Organoboron Nucleophiles
a Reaction conditions: ArOTs (1.0 mmol), Ar′B(OH)2 (2.0 mmol),
K3PO4 ·H2O (3.0 mmol), Pd(OAc)2 (mol % as indicated), Pd:L ) 1:4,
t-BuOH (3.0 mL), at 110 °C under N2 for the indicated period of time
(see the Supporting Information). b Isolated yields.
-products were not observed from GC-MS analyses. Notably,
the catalyst loading for the coupling of nonactivated aryl tosylate
can be down to 0.2 mol % of Pd for the first time (entry 2). A
variety of functional groups were compatible under these mild
reaction conditions, including keto, nitrile, aldehyde, and ester
(entries 4-9). For the first time, the electron-rich (deactivated)
p-anisyl tosylate was demonstrated to be a feasible coupling
partner (entry 10).
that K3PO4 monohydrate and Cs2CO3 were suitable bases for
this aryl tosylate coupling reaction (entries 6-8). In addition
to phosphines L1-L3, an array of amino-phosphines L4-L8
were examined. However, it seems amino-phosphines are not
effective under these alcoholic reaction conditions (entries
9-13). We observed ligand decomposition (from hydrolysis of
the N-P bond) during the course of the reactions. To eliminate
the hydrolytic cleavage problem of amino-phosphines, we
further investigated the applicability of these ligands using
toluene as the reaction medium (entry 14). Although we did
not observe any ligand decomposition, no significant conversion
of the substrate was observed. Thus, the N-P bound amino-
phosphines are generally inferior in tosylate coupling reactions.
To test the effectiveness of the C-P bound indolyl phos-
phines, a range of aryl tosylates were examined, using the
optimized reaction conditions (Table 2). In general, essentially
complete conversions were observed within 2-4 h when 0.5-1
mol % of Pd was used. Homocoupled and reduction side
Apart from functionalized aryl tosylates, heteroaryl and vinyl
tosylates were effective substrates in the Pd/L2 catalytic system
(Table 3). Sterically congested arylboronic acids were efficiently
coupled with quinolyl tosylates in excellent yields (entries 1
and 2). It is noteworthy that the extremely hindered 2,4-di-tert-
butyl-6-methoxyphenylboronic acid was found to be a capable
coupling partner in this reaction (entry 3). The scope of tosylate
coupling reactions can also be extended to vinyl tosylate (entry
4). Remarkably, an example of aryl tosylate coupling at room
temperature reaction was realized (entry 5). These results
indicate the palladium catalyst derived from CM-phos is highly
active for tosylate coupling reactions.
Although boronic acids are widely used as the coupling
nucleophiles, the exploration of other boronic acid surrogates
(17) Although DMF provided slightly better product yield, t-BuOH was
chosen for further study due to its relatively less toxicity.
J. Org. Chem. Vol. 73, No. 19, 2008 7733

So et al.
Experimental Section
General Procedure for Suzuki-Miyaura Coupling of Aryl
Tosylates. Pd(OAc)2 (2.3 mg, 0.010 mmol) and ligand (0.040
mmol) were loaded into an oven-dried Schlenk tube equipped with
a Teflon-coated magnetic stir bar. The tube was evacuated and
flushed with nitrogen several times. Precomplexation was applied
by adding freshly distilled dichloromethane and Et3N into the tube.
The solution was stirred and warmed with a hair dryer for about 1
to 2 min until the solvent started boiling. The solvent was then
evaporated under high vacuum. Aryl tosylate (1.0 mmol), arylbo-
ronic acid (2.0 mmol), and K3PO4 ·H2O (3.0 mmol) were loaded
into the tube, and the system was further evacuated and flushed
with nitrogen three times. The solvent tert-butanol (3.0 mL) was
then added. The tube was stirred at room temperature for several
minutes and then placed into a preheated oil bath (110 °C) for the
time period as indicated in the tables. 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. 4-tert-
Butylbiphenyl20 (example from Table 2, entry 1): hexane, Rf 0.55;
1H NMR (400 MHz, CDCl3) δ 1.72 (s, 9H), 7.64 (t, J ) 7.4 Hz,
1H), 7.72-7.82 (m, 4H), 7.89-7.96 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 31.3, 34.4, 125.6, 126.7, 126.9, 128.6, 138.2, 140.9, 150.0;
MS (EI) m/z (rel intensity) 210 (M+, 35), 195 (100), 178 (20), 167
(30). 6-(2,4-Di-tert-butyl-6-methoxyphenyl)quinoline (example from
Table 3, entry 3): EtOAc:hexane ) 1:9, Rf 0.15; white solid, mp
136.4-138.1 °C; 1H NMR (400 MHz, CDCl3) δ 1.19 (s, 9H), 1.42
(s, 9H), 3.56 (s, 3H), 6.92 (s, 1H), 7.24-7.31 (m, 4H), 8.02 (d, J
) 7.9 Hz, 1H), 8.14 (d, J ) 8.5 Hz, 1H), 8.87 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 31.1, 32.5, 34.8, 36.6, 55.5, 105.7, 116.0,
120.5, 127.0, 127.2, 127.5, 129.2, 133.9, 135.5, 138.3, 147.0, 148.4,
149.6, 150.6, 157.3; MS (EI) m/z (rel intensity) 347 (M+, 100),
332 (75), 317 (5), 302 (3), 290 (5), 276(75), 261(30); HRMS calcd
for C24H29N: 347.2244, found 347.2253. (See the Supporting
Information for experimental details.)
FIGURE 2. An investigation on an interplay of the phosphino group
on the ligand scaffold toward the reactivity in tosylate couplings.
in this catalytic system is still needed.18 An aryl trifluoroborate
salt and a pinacol boronate ester were successfully coupled with
aryl tosylates under our catalytic system (Scheme 1).
To study the importance of the phosphino group position on
the indolyl ligand toward the efficiency of tosylate coupling
reactions, we independently prepared a similar new phosphine
ligand L9 (Figure 2). However, we did not observe any
reactivity of the catalyst when L9 was subjected to the coupling
of 4-tert-butylphenyl tosylate with phenylboronic acid. We were
surprised that dramatic differences on reactivity were obtained
when the position of the phosphino group was interchanged (but
the ligand scaffold remained the same). Presumably the phos-
phino group on the aryl ring (instead of on the heterocyclic
ring) provides better geometry of chelation to the palladium
center and facilitates the oxidative addition of the Ar-OTs bond.
Thus, tosylate couplings are likely sensitive to the structure of
the ligand. Therefore, high ligand diversity is crucial to achieve
problematic coupling reactions.
Conclusion
In conclusion, we reported our study on a series of simple
indolyl phosphines to the Suzuki-type coupling of substituted
arenesulfonates. A variety of aryl, heteroaryl, and vinyl tosylates
were efficiently coupled with different organoboron nucleo-
philes. These easily accessible indolyl-type phosphine ligands
in combination with Pd-complex precursor showed good activity
(0.2 to 3.0 mol % Pd) in nonactivated tosylate coupling
reactions. Particularly noteworthy is that the first example for
room temperature Pd-catalyzed Suzuki-Miyaura cross-coupling
of aryl tosylate was also successfully realized. This Pd/CM-
phos catalyst provides a useful alternative system to the
Buchwald-type biaryl phosphines,19 which constitute effective
Suzuki-Miyaura coupling of aryl tosylates.
Acknowledgment. We thank the Research Grants Council
of Hong Kong (Project No. CERG: PolyU 5005/07P) and
University Grants Committee Areas of Excellence Scheme
(Project No. AoE/P-10/01) for financial support.
Supporting Information Available: Detailed experimental
1
procedures, characterization data, and copies of H, 13C, 31P
NMR, MS, HRMS, and IR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) For a review describing organotrifluoroborate salts in coupling reactions,
see: Molander, G A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(19) To our best knowledge, there are only two publications to date on the
effective Suzuki-Miyaura coupling of aryl tosylates. The ligand structures are
the Buchwald-type phosphines. See refs 7a and 7b for 2-dicyclohexylphosphino-
2′,4′,6′-triisopropylbiphenyl and 2-dicyclohexylphosphino-2′,4′,6′-trimethoxyl-
biphenyl, respectively.
JO8014819
(20) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 9550.
7734 J. Org. Chem. Vol. 73, No. 19, 2008