A highly efficient microwave-assisted Suzuki coupling reaction of aryl perfluorooctylsulfonates with boronic acids

Article abstract of DOI:10.1021/ol0496428

A new strategy to improve the efficiency of Suzuki coupling reactions is introduced by combining fast microwave reaction with easy fluorous separation. Aryl perfluorooctylsulfonates derived from the corresponding phenols are coupled with aryl boronic acid

Full text of DOI:10.1021/ol0496428

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1473-1476
A Highly Efficient Microwave-Assisted
Suzuki Coupling Reaction of Aryl
Perfluorooctylsulfonates with Boronic
Acids
Wei Zhang,* Christine Hiu-Tung Chen, Yimin Lu, and Tadamichi Nagashima
Fluorous Technologies, Inc., UniVersity of Pittsburgh Applied Research Center,
970 William Pitt Way, Pittsburgh, PennsylVania 15238
w.zhang@fluorous.com
Received February 27, 2004
ABSTRACT
A new strategy to improve the efficiency of Suzuki coupling reactions is introduced by combining fast microwave reaction with easy fluorous
separation. Aryl perfluorooctylsulfonates derived from the corresponding phenols are coupled with aryl boronic acids to form biaryls under
general microwave conditions. Both intermediates and products are purified by solid-phase extraction over FluoroFlash silica gel. Application
of this tagging strategy to multistep synthesis of biaryl-substituted hydantoin is also described.
The palladium-catalyzed cross-coupling of aryl halides with
aryl boronic acids (Suzuki coupling) is a powerful reaction
for the construction of biaryls.1 Its scope has been extended
through the use of aryl triflates (ArOSO2CF3) or aryl
nonaflates (ArOSO2(CF2)3CF3) as halide equivalents.2 Aryl
perfluoroalkylsulfonates prepared from a wide range of
commercially available phenols have shown high reactivity,
good stability for room-temperature storage and chromatog-
raphy, and resistance towards hydrolysis.3
Applications of Suzuki coupling reactions for parallel and
combinatorial syntheses have been explored by conducting
the reaction under microwave irradiation4 or on solid support5
with a linker such as perfluoroalkylsulfonyl.6 However, the
microwave reaction does not directly address the separation
issue, which is usually the bottleneck of high-throughput
synthesis. Microwave-assisted solid-phase reactions have
limitations on solvent selection due to resin swelling and
thermostability issues.7 We report here a new strategy that
(4) (a) Olofsson, K.; Hallberg, A.; Larhed, M. In MicrowaVes in Organic
Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, 2002; pp 379-403.
(b) Hayes, B. L. MicrowaVe Synthesis: Chemistry at the Speed of Light;
CEM Publishing: Matthews, NC, 2002. (c) Larhed, M.; Moberg, C.;
Hallberg, A. Acc. Chem. Res. 2002, 35, 717.
(5) Selected papers: (a) Li, W.; Burgess, K. Tetrahedron Lett. 1999,
40, 6527 (b) Brase, S.; Schroen, M. Angew. Chem., Int. Ed. 1999, 38, 1071.
(c) Vanier, Y.; Lorge, F.; Wagner, A.; Mioskowski, C. Angew. Chem., Int.
Ed. 2000, 39, 1679. (d) Pourbaix, C.; Carreaux, F.; Carboni, B. Org. Lett.
2001, 3, 803. (e) Yamada, Y. M. A.; Takeda, K.; Takahashi, H.; Ikegami
Org. Lett. 2002, 4, 3371. (f) Lan, P.; Berta, D.; Porco, J. A.; South, M. S.;
Parlow, J. J. J. Org. Chem. 2003, 68, 9678. (g) Organ, M. G.; Mayer, S. J.
Comb. Chem. 2003, 5, 118. (h) Wade, J. V.; Krueger, C. A. J. Comb. Chem.
2003, 5, 267. (i) Zhu, S.; Shi, S.; Gerritz, S. W.; Sofia, M. J. J. Comb.
Chem. 2003, 5, 205. (j) Byun, J.-W.; Lee, Y. S. Tetrahedron Lett. 2004,
45, 1837. See also general reviews: (k) Negishi, E., Ed. Hankbook of
Palladium Chemistry; Wiley: New York, 2002. (l) Lorsbury, B. A.; Kurt,
M. J. Chem. ReV. 1999, 99, 1549. (m) Brase, S.; Kirchhoff, J. H.;
Kobberling, J. Tetrahedron 2003, 59, 885.
(1) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Suzuki,
A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 2. (c) Stanforth,
S. P. Tetrahedron 1998, 54, 263. (d) Suzuki, A. J. Organomet. Chem. 1999,
576, 147.
(2) (a) Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85.
(b) Scott, W. J.; McMurry, J. E. Acc. Chem. Res. 1988, 21, 47. (c) Ritter,
K. Synthesis 1993, 735. (d) Baraznenok, I. L.; Nenajdenko, V. G.;
Balenkova, E. S. Tetrahedron 2000, 56, 3077.
(3) Zhu, J.; Bigot, A.; Tran Huu Dau, M. E. Tetrahedron Lett. 1997, 38,
1181. (b) Neuville, L.; Bigot, A.; Tran Huu Dau, M. E.; Zhu, J. J. Org.
Chem. 1999, 64, 7638. (c) Grushin, V. V. Organomettallics 2000, 19, 1888.
(d) Zhang, X.; Sui, Z. Tetrahedron Lett. 2003, 44, 3071.
(6) (a) Pan, Y.; Ruhland, B.; Holmes, C. P. Angew. Chem., Int. Ed. 2001,
40, 2288. (b) Pan, Y.; Holmes, C. P. Org. Lett. 2001, 3, 2769.
(7) (a) Larhed, M.; Lindeberg, G.; Hallberg, A. Tetrahedron Lett. 1996,
37, 8219. (b) Kappe, O. C.; Stadler, A. In MicrowaVes in Organic Synthesis;
Loupy A., Ed.; Wiley-VCH: Weinheim, 2002; pp 405-433.
10.1021/ol0496428 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/27/2004

Scheme 1. Fluorous Synthesis of Biaryls
significantly improves the efficiency of Suzuki coupling
reactions by combining fast microwave reaction with easy
fluorous separation.
Figure 1. 1H NMR (CDCl3) of 1a after F-SPE.
Fluorous synthesis unites the attractive features of solution-
phase chemistry with the convenient workup of solid-phase
chemistry.8 Molecules attached with a perfluoroalkyl “phase
tag” can be easily isolated from the reaction mixture by
fluorous separation techniques such as fluorous solid-phase
extraction (F-SPE).9 The fluorous Suzuki coupling reaction
employs aryl perfluorooctylsulfonates (ArOSO2(CF2)7CF3)
as precursors. The perfluorooctylsulfonyl group has enough
fluorines (17) to serve as a fluorous tag for F-SPE. Recently,
we reported the use of aryl perfluorooctylsulfonate tag in
palladium-mediated cross-coupling reactions for the forma-
tion of a C-S bond.10,11 We now extend the application of
this fluorous tag to the synthesis of the C-C bond of biaryls.
A variety of phenols were converted to the corresponding
aryl perfluorooctylsulfonates by reacting them with com-
mercially available perfluorooctylsulfonylfluoride under mild
conditions, using K2CO3 as a base in dimethylformamide
(DMF) at 70 °C for 5 h (Scheme 1).12 The crude aryl
perfluorooctylsulfonate 1 has greater than 90% purity and
is used directly for the next step reaction. If further
purification is needed, this can be accomplished by crystal-
lization from MeOH or by F-SPE purification on FluoroFlash
cartridges.13 Two F-SPE fractions need to be collected; the
first elution with 80:20 MeOH/H2O contains unreacted
phenol and other nonfluorous compounds; the second elution
with MeOH contains the desired aryl perfluorooctylsulfonate
1. After F-SPE, the purity is greater than 95% (Figure 1).14
Suzuki coupling is a substrate-dependent reaction, which
is reflected by numerous publications on the optimization
of catalyst, base, solvent, and other reaction conditions.1,5
The lack of a general procedure suitable for a broad range
of substrates limits the application of Suzuki reactions in
high-throughput synthesis. As a powerful and easily control-
lable heating source, microwave irradiation can generate
more consistent results than the conventional heating source.4
In our development of fluorous Suzuki coupling reactions,
a literature procedure15 for the coupling of triflates was
adapted for the reaction of aryl perfluorooctylsulfonates.16
Thus, we used [Pd(dppf)Cl2] (dppf ) 1,1′-bis(diphenylphos-
phino)ferrocene) as a catalyst, K2CO3 as a base, and 4:4:1
toluene/acetone/H2O as a cosolvent. The reactions were
conducted in a sealed-tube under single-mode microwave
irradiation at 100-130 °C for 10 min. This general condition
is compatible with a range of functionalized aryl perfluo-
rooctylsulfonates with methoxy, aldehyde, ketone, and
heterocyclic groups. It is also compatible with a broad range
of boronic acids, including sterically hindered ortho-isopro-
poxy-substituted boronic acid and electron-deficient 3,4-
dichlorophenylboronic acid (Table 1).17 The purification of
the final product is straightforward; the organic layer of the
(8) Recent reviews: (a) Curran, D. P. Angew. Chem., Int. Ed. 1998, 37,
1175. (b) Curran, D. P. In Stimulating Concepts in Chemistry; Stoddard,
F., Reinhoudt, D., Shibasaki, M., Eds.; Wiley-VCH: New York, 2000; pp
25-37. (c) Curran, D. P.; Hadida, S.; Studer, A.; He, M.; Kim, S.-Y.; Luo,
Z.; Larhed, M.; Hallberg, A.; Linclau, B. In Combinatorial Chemistry: A
Practical Approach; Fenniri, H., Ed.; Oxford University Press: Oxford,
2000; Vol. 2, pp 327-352. (d) Dobbs, A. P.; Kimberley, M. R. J. Fluorine
Chem. 2002, 118, 3. (e) Zhang, W. Tetrahedron 2003, 59, 4475.
(9) (a) Curran, D. P. Synlett 2001, 1488. (b) Yoshida, J.; Itami, K. Chem.
ReV. 2002, 102, 3693. (c) Tzschucke, C. C.; Markert, C.; Bannwarth, W.;
Roller, S.; Hebel, A.; Haag, R. Angew. Chem., Int. Ed. 2002, 41, 3964.
(10) Zhang, W.; Lu, Y.; Chen, C. H-T. Mol. DiVersity 2003, 7, 199.
(11) For early work on microwave-assisted cross-coupling reactions and
fluorous liquid-liquid separations, see: (a) Larhed, M.; Hoshino, M.;
Hadida, S.; Curran, D. P.; Hallberg, A. J. Org. Chem. 1997, 62, 5583. (b)
Olofsson, K.; Kim, S. Y.; Larhed, M.; Curran, D. P.; Hallberg, A. J. Org.
Chem. 1999, 64, 4539.
(12) Representative Procedure for the Preparation of Aryl Perfluo-
rooctylsulfonates. To a mixture of 5-hydroxy-1-tetralone (3.24 g, 20.0
mmol) and K2CO3 (2.90 g, 21.0 mmol) in 15 mL of DMF was added
perfluorooctylsulfonic fluoride (8.37 g, 16.7 mmol) dropwise through an
addition funnel. After heating at 70 °C for 5 h, the mixture was poured
onto 100 mL of water and extracted with EtOAc. The organic portion was
dried over MgSO4, and the solvent was evaporated under vacuum to give
perfluorooctylsulfonate 1a (9.79 g, 91% yield). The crude product was used
for the next step. It can be further purified by recrystallization with MeOH
or by F-SPE.
(13) FluoroFlash silica gel charged in the SPE cartridges contains a Si-
(Me)2C8F17 stationary phase. For more information about F-SPE, please
log on to http://www.fluorous.com/download/fspe.pdf.
1
(14) Purities were assessed by H NMR.
(15) Pridgen, L. N.; Huang, G. K. Tetrahedron Lett. 1998, 39, 8421.
(16) Representative Procedure for the Suzuki Cross-Coupling
Reaction. A septum-sealed microwave tube charged with aryl perfluorooc-
tylsulfonate 1a (84.0 mg, 0.13 mmol), 4-methoxyboronic acid (18.9 mg,
0.12 mmol), Pd(pddf)Cl2 (10.6 mg, 0.013 mmol), and K2CO3 (36.0 mg,
0.26 mmol) in 0.8 mL of a 4:4:1 acetone/toluene/H2O cosolvent was
irradiated in a monomode microwave cavity (150W, 130 °C, 10 min). The
reaction mixture was washed with 1 mL of H2O. The organic layer was
loaded onto a 5 g FluoroFlash cartridge preconditioned with 80:20 MeOH/
H2O. The cartridge was eluted with 10 mL of 80:20 MeOH/H2O. The
fraction was concentrated to give biaryl 2a (27.6 mg, 91% yield). The
fluorous species were washed from the cartridge with 20 mL of MeOH.
1474
Org. Lett., Vol. 6, No. 9, 2004

Table 1. Structures and Yields of Biaryls
reaction mixture was directly loaded onto a FluoroFlash SPE
cartridge. The biaryl product was collected in the fraction
of 80:20 MeOH/H2O, while the cleaved fluorous tag
remained on the cartridge until the wash with MeOH was
done. To avoid the coelution of the other organic component
in the MeOH/H2O fraction, boronic acid was used as the
limiting agent (∼0.95 equiv). After F-SPE, biaryl compounds
were isolated in 75-95% yields with purity greater than
90%.14 No detectable amount of dppf ligand was observed
(17) Pd-catalyzed microwave reactions were conducted under a license
from Personal Chemistry.
1
by H NMR analysis.18
Org. Lett., Vol. 6, No. 9, 2004
1475

Scheme 2. Fluorous Synthesis of Biaryl-Substituted Hydantoin 7
We also demonstrated the use of the fluorous sulfonyl tag
of protecting the hydroxyl group in the early steps and
activating the phenol for cross-coupling at the last step. The
high solubility of aryl perfluorooctylsulfonates in common
organic solvents and the high thermostability of the perfluo-
rosulfonyl tag render the fluorous molecules good substrates
for solution-phase microwave reactions. Other than formation
of C-C and C-S bonds, the perfluorooctylsulfonate moiety
is amenable to other kinds of cross-coupling reactions to form
C-H, C-N, C-O, C-P, and C-CN bonds. We believe
this readily available, highly efficient, and synthetically
versatile fluorous tag will have broad applications in solution-
phase parallel and combinatorial syntheses.
in a multistep synthesis of a biaryl-substituted hydantoin 7
(Scheme 2). The hydroxyl group of 4-hydroxybenzaldehyde
was protected by converting it to a fluorous sulfonate. The
tagged benzaldehyde 3 underwent a reductive amination
reaction. The resulting amine 4 was treated with an isocy-
anate to form urea 5, which spontaneously cyclized to form
hydantoin 6. In the last step, the fluorous sulfonyl group was
detagged by the Suzuki coupling reaction to form the C-C
bond of biaryl 7. The efficiency of this multistep synthesis
is facilitated by easy F-SPE purification of the reaction
intermediates 4 and 6. The perfluorosulfonyl tag has been
demonstrated to be tolerant to reductive amination and
isocyanate reactions. The tagged intermediates were also
found to be stable during F-SPE separations.
In this fluorous multistep synthesis, the tagging is ac-
complished at the phenol derivatization and the detagging
is conducted at the Suzuki cross-coupling step. No synthetic
steps are added just for the sake of putting in and taking off
the fluorous tag. In addition to simplifying the intermediate
purification, the perfluorosulfonyl group has the functions
Acknowledgment. We thank the National Institutes of
General Medical Sciences for the SBIR funding (1R43GM-
66415-01 and 2R44GM062717-02).
1
Supporting Information Available: H NMR spectra for
aryl perfluorooctylsulfonates 1a-d, biaryls 2a-k, com-
pounds 4 and 6, and biaryl-substituted hydantoin 7. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) No further quantitative analysis has been attempted to detect the
residue of catalyst and ligand in final products.
OL0496428
1476
Org. Lett., Vol. 6, No. 9, 2004