Published on Web 11/24/2004
Highly Active Palladium Catalysts Supported by Bulky
Proazaphosphatrane Ligands for Stille Cross-Coupling:
Coupling of Aryl and Vinyl Chlorides, Room Temperature
Coupling of Aryl Bromides, Coupling of Aryl Triflates, and
Synthesis of Sterically Hindered Biaryls
Weiping Su, Sameer Urgaonkar, Patrick A. McLaughlin, and John G. Verkade*
Contribution from the Department of Chemistry, Gilman Hall, Iowa State UniVersity,
Ames, Iowa 50011
Received August 18, 2004; E-mail: jverkade@iastate.edu
Abstract: A family of proazaphosphatrane ligands [P(RNCH2CH2)2N(R′NCH2CH2): R ) R′ ) i-Bu, 1; R )
Bz, R′ ) i-Bu, 3; R ) R′ ) Bz, 4] for palladium-catalyzed Stille reactions of aryl chlorides is described.
Catalysts derived from ligands 1 and 4 efficiently catalyze the coupling of electronically diverse aryl chlorides
with an array of organotin reagents. The catalyst system based on the ligand 3 is active for the synthesis
of sterically hindered biaryls (di-, tri-, and tetra-ortho substituted). The use of ligand 4 allows room-
temperature coupling of aryl bromides and it also permits aryl triflates and vinyl chlorides to participate in
Stille coupling.
Introduction
handicapped by the need to use aryl bromides or iodides as the
reaction partner. Surprisingly, unlike the case with other Pd-
The coupling of two sp2-centered carbons remains an
important goal as well as a challenge for synthetic organic
chemists. Among various strategies, transition-metal-catalyzed
processes, especially those catalyzed by palladium, have made
significant contributions to this field.1 The palladium-catalyzed
Stille cross-coupling2 of aryl halides (or halide equivalents) with
organotin reagents is an important C-C bond forming reaction
that has found wide application in natural product synthesis,3
carbohydrate chemistry,4 and biological research,5 which in part
stems from the ready availability of organotin reagents, their
air- and moisture-stability and the excellent functional group
tolerance of this approach. Until recently, this method was
catalyzed processes (e.g., Suzuki,6 Heck,7 and Buchwald-
Hartwig amination8 reactions), wherein a myriad of catalyst
systems allow coupling of economically attractive but notori-
ously unreactive aryl chlorides, the same is not true for the Stille
coupling of aryl chlorides.9 Here, the low reactivity of aryl
chlorides has generally been attributed to its reluctance to
participate in oxidative addition, the first step of the catalytic
cycle. However, significant progress has been achieved recently.
For example, Fu,10 in his pioneering studies, disclosed a
palladium-catalyst, based on sterically demanding electron-rich
P(t-Bu)3 as the supporting ligand, for the Stille cross-coupling
(6) For leading references to Suzuki couplings of aryl chlorides, see (a) Old,
D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722;
(b) Littke, A. F.; Fu, G. C. Angew Chem., Int. Ed. Engl. 1998, 37, 3387.
(c) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
(d) Bedford, R. B.; Cazin, C. S. J. Chem. Commun. 2001, 1540. (e) Li, G.
Y. Angew. Chem., Int. Ed. 2001, 40, 1513. (f) Herrmann, W. A.; Reisinger,
C.-P.; Spiegler, M. J. Organomet. Chem. 1998, 557, 93. (g) Zhang, C.;
Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem. 1999, 64, 3804. (h)
Urgaonkar, S. Nagarajan, M. Verkade, J. G. Tetrahedron Lett. 2002, 43,
8921.
(7) For leading references to Heck reactions of aryl chlorides, see (a) Littke,
A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989. (b) Selvakumar, K.;
Zapf, A.; Beller, M. Org. Lett. 2002, 4, 3031. (c) Schnyder, A.; Aemmer,
T.; Indolese, A. F.; Pittelkow, U.; Studer, M. AdV. Synth. Catal. 2002, 344,
495. (d) Proeckl, S. S.; Kleist, W.; Gruber, M. A.; Koehler, K. Angew.
Chem., Int. Ed. 2004, 43, 1881.
(1) (a) Heck, R. F. Palladium Reagents in Organic Synthesis; Academic
Press: New York, 1985. (b) Tsuji, J. Palladium Reagents and Catalysts:
InnoVations in Organic Synthesis; Wiley & Sons: New York, 1995. (c)
Mitchell, T. N. In Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998, Chapter 4.
(2) For reviews of the Stille reaction, see: (a) Stille, J. K. Pure Appl. Chem.
1985, 57, 1771. (b) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25,
508. (c) Pereyre, M.; Quintard, J. P.; Rahm, A. Tin in Organic Synthesis;
Butterwoth: London, 1987. (d) Farina, V.; Krishnamurthy, V.; Scott, W.
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Angew. Chem., Int. Ed. 2002, 41, 4176.
(3) For recent applications of the Stille reaction in natural product synthesis,
see (a) Nicolaou, K. C.; Li, Y.; Sugita, K.; Monenschein, H.; Guntupali,
P.; Mitchell, H. J.; Fylaktakidou, K. C.; Vourloumis, D.; Giannakakou, P.;
O’Brate, A. J. Am. Chem. Soc. 2003, 125, 15443. (b) Kadota, I.; Takamura,
H.; Sato, K.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc.
2003, 125, 46. (c) Lin, S.-Y.; Chen, C.-L.; Lee, Y.-J. J. Org. Chem. 2003,
68, 2968. (d) Boger, D. L.; Ichikawa, S.; Jing, H. J. Am. Chem. Soc. 2000,
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M.; Chung, J. Y. L.; Yasuda, N.; Hughes, D. L.; Reider, P. J. Org. Lett.
2000, 2, 1081.
(8) For leading references to Buchwald-Hartwig amination reactions of aryl
chlorides, see: (a) Wolfe, J. P.; Tomori, J.; Sadighi, J. P.; Yin, J.; Buchwald,
S. L. J. Org. Chem. 2000, 65, 1158. (b) Hartwig, J. F.; Kawatsura, M.;
Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem.
1999, 64, 5575. (c) Huang, J.; Grasa, G. A.; Nolan, S. P. Org. Lett. 1999,
1, 1307. (d) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett.
1998, 39, 2367. (e) Bei, X.; Uno, T.; Norris, J.; Turner, H. W.; Weinberg,
W. H.; Guram, A. S.; Petersen, J. L. Organometallics 1999, 18, 1840. (f)
Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369. (g)
Reddy, N. P.; Tanaka, M.; Tetrahedron Lett. 1997, 38, 4807. (h) Urgaonkar,
S.; Nagarajan, M.; Verkade, J. G. Org. Lett. 2003, 5, 815.
(4) Kuribayashi, T.; Gohya, S.; Mizuno, Y.; Satoh, S. J. Carbohyd. Chem.
1999, 18, 383.
(5) Nicolaou, K. C.; King, N. P.; Finlay, M. R. V.; He, Y.; Roschangar, F.;
Vourloumis, D.; Vallberg, H.; Sarabia, F.; Ninkovic, S.; Hepworth, D.
Bioorg. Med. Chem. 1999, 7, 665.
(9) For Pd-catalyzed Stille reactions of activated aryl chlorides, see, Kosugi,
M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Chem. Lett. 1977, 301
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10.1021/ja0450096 CCC: $27.50 © 2004 American Chemical Society
J. AM. CHEM. SOC. 2004, 126, 16433-16439
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