at room temperature in this aqueous medium using as low
as 0.1% PTS (entries 9 and 11). More lipophilic aryl
chlorides, such as the pentenyl ester of indomethacin, may
require gentle heating en route to biaryl 28 (Scheme 2).
ing alternative 6 readily catalyzed the cross-coupling of the
triflate in good isolated yield (Table 5, entries 5 and 6).
In summary, dilute aqueous solutions of nonionic am-
phiphiles have been shown to serve well in water-based
media for Suzuki-Miyaura reactions at ambient tempera-
tures. Of the various amphiphiles studied, on the basis of
the data obtained to date, commercially available18 PTS
appears to offer the best opportunities for success in such
cross-couplings, although other surfactants can, on occasion,
be equally as effective. Reaction scope includes lipophilic
aryl fluorosulfonates, aryl iodides, and aryl bromides cata-
lyzed by the commercially available dppf analogue 5. In the
presence of 6, likewise a commercially available catalyst,
sterically hindered aryl chlorides and aryl fluorosulfonates
are suitable reaction partners. Product isolation uses standard
(extractive) workup procedures (see below19 and the Sup-
porting Information). We are currently investigating applica-
tion of this technology to the synthesis of heteroaromatic
biaryls; results will soon be reported.
Scheme 2. Coupling of the Pentenyl Ester of Indomethacin
The option to use pseudohalides as substrates in Suzuki-
Miyaura reactions has also been evaluated under these
aqueous conditions. The triflate of â-naphthol was found to
react readily under the same conditions (2% PTS/water, 2%
catalyst 5) used with halides (cf. Tables 1-4) to afford the
corresponding biaryl product in good yield (Table 5, entry
Acknowledgment. We warmly thank Zymes, LLC both
for financial support and for providing PTS and Eastman
for supplying TPGS. Catalysts were generously supplied by
Dr. Tom Colacot (Johnson Matthey; Pd(dtbpf)Cl2, CAS no.
95408-45-0) and Ms. Astrid Metzger (Umicore AG & Co.
KG; Neolyst CX31, CAS no. 884879-23-6). We acknowl-
edge technical assistance from Mr. John B. Unger (UCSB).
T.B.P. thanks the Danish Chemical Society, Boehringer-
Ingelheim, and the UCSB Affiliates for additional funds.
Table 5. Suzuki-Miyaura Reactions of Aryl Fluorosulfonatesa
Supporting Information Available: Detailed experi-
mental procedures and full characterization of new com-
pounds. This material is available free of charge via the
OL702714Y
(15) To the best of our knowledge, the only publication describing the
use of aryl perfluorooctylsulfonates in Suzuki-Miyaura cross-couplings:
Zhang, W.; Chen, C. H.-T.; Lu, Y.; Nagashima, T. Org. Lett. 2004, 6, 1473-
1476.
(16) Based on the reactivity differences observed between triflates and
nonaflates; see: Ho¨germeier, J.; Reissig, H.-U. Chem. Eur. J. 2007, 13,
2410-2420 and references cited therein.
(17) n-C8F17SO2F is available for $165/mol (100 g). On that scale, (CF3-
SO2)2O sells for $237/mol and n-C4F9SO2F costs $256/mol. When purchas-
ing 1 kg, the price drops to $127/mol and $145/mol, respectively, for the
latter two. However, SciFinder gives no price quote for n-C8F17SO2F on
that scale.
(18) Sigma-Aldrich catalog #698717; available in May, 2008.
(19) (a) Standard procedure for Suzuki-Miyaura in PTS/water.
4-Methoxy-2′-methylbiphenyl (23; Table 4, entry 4). To a 5 mL round-
bottom flask was added a 15 mm long prolate spheroid magnetic stir bag.
5 (6 mg, 0.009 mmol), and 4-methoxyphenylboronic acid (114 mg, 0.75
mmol). Under a positive flow of argon while stirring were added each via
syringe Et3N (0.21 mL, 1.5 mmol), aqueous PTS (1% w/w, 2 mL), and
2-chlorotoluene (60 µL, 0.51 mmol). The reaction was stirred at rt and
conversion was monitored by GC. After 24 h the contents of the flask were
diluted with brine and extracted three times with ethyl acetate. The solution
obtained was dried over anhydrous MgSO4, filtered, and concentrated by
rotary evaporation. The solid residue was purified by flash chromatography
eluting with a gradient from 1/99 to 5/95 diethyl ether/petroleum ether to
afford the product biaryl (86 mg, 85%) as a white solid; 1H NMR (400
MHz, CDCl3) matches previously reported spectral data. (b) Tang, Z.-Y.;
Hu, Q.-S. J. Am. Chem. Soc. 2004, 126, 3058-3059.
a General conditions: aryl fluorosulfonate (0.50 mmol), arylboronic acid
(0.75 mmol), Pd cat. (0.01 mmol), Et3N (1.50 mmol), aqueous PTS solution
(2% w/w, 1 mL). b Isolated. c 2 mL of aqueous PTS solution.
1). Promising alternatives to triflates are the longer chain
fluorosulfonates, such as nonaflates and perfluorooctylsul-
fonates. The latter, which have not commonly been used in
this context,15 are particularly appealing. Not only are they
expected to show somewhat higher reactivity relative to aryl
nonaflates,16 but their precursor, perfluorooctylsulfonyl fluo-
ride, is attractively priced.17 The coupling of â-naphthyl
perfluorooctylsulfonate proceeds smoothly at room temper-
ature to afford 29 in excellent yield. Both fluorosulfonates
derived from estrone, however, are totally unreactive in the
presence of catalyst 5 in this aqueous medium, even at
elevated temperatures. Again, switching to the NHC-contain-
1336
Org. Lett., Vol. 10, No. 7, 2008