Pd(PhCN)2Cl2/P(t-Bu)3: A versatile catalyst for Sonogashira reactions of aryl bromides at room temperature

Article abstract of DOI:10.1021/ol0058947

(matrix presented) Pd(PhCN)₂Cl₂/P(t-Bu)₃ serves as an efficient and a versatile catalyst for room-temperature Sonogashira reactions of aryl bromides.

Full text of DOI:10.1021/ol0058947

ORGANIC
LETTERS
2000
Vol. 2, No. 12
1729-1731
Pd(PhCN)2Cl2/P(t-Bu)3: A Versatile
Catalyst for Sonogashira Reactions of
Aryl Bromides at Room Temperature
Thomas Hundertmark, Adam F. Littke, Stephen L. Buchwald,* and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139
sbuchwal@mit.edu; gcf@mit.edu
Received April 5, 2000
ABSTRACT
Pd(PhCN)2Cl2/P(t-Bu)3 serves as an efficient and a versatile catalyst for room-temperature Sonogashira reactions of aryl bromides.
The Sonogashira coupling reaction of terminal acetylenes
with aryl and vinyl halides provides a powerful method for
synthesizing conjugated alkynes, an important class of
molecules that have found application in diverse areas
ranging from natural product chemistry to materials sci-
ence.1,2 With respect to the organic halide, the following order
of reactivity has been observed: vinyl iodide ≈ vinyl
bromide > aryl iodide > vinyl chloride . aryl bromide.2
For aryl bromides, the least reactive of the commonly
employed organic halides, efficient Sonogashira coupling
typically requires heating to ∼80 °C.2 Obviously, reactions
that proceed at room temperature have significant practical
advantages relative to those that require elevated tempera-
tures. To the best of our knowledge, however, the only
descriptions of room-temperature Sonogashira couplings of
unactivated aryl bromides are the reports of Sinou (three
examples)3 and Villemin (two examples).4
We and others have recently demonstrated that palladium
catalysts that incorporate bulky, electron-rich phosphines can
display unusually high reactivity in a wide range of coupling
processes.5-8 To date, however, there have been no reports
of applications of these ligands to the Sonogashira reaction.
In this Letter, we establish that one such ligand, P(t-Bu)3,
does indeed furnish a highly active catalyst for Sonogashira
couplings, providing a mild, efficient, and general method
for effecting reactions of aryl bromides at room temperature
(Scheme 1).
Scheme 1
(1) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470. (b) Cassar, L. J. Organomet. Chem. 1975, 93, 253-257. (c)
Dieck, H. A.; Heck, R. F. J. Organomet. Chem. 1975, 93, 259-263.
(2) (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; Chapter
5. (b) Brandsma, L.; Vasilevsky, S. F.; Verkruijsse, H. D. Application of
Transition Metal Catalysts in Organic Synthesis; Springer-Verlag: Berlin,
1998; Chapter 10. (c) Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proced.
Int. 1995, 27, 127-160. (d) Sonogashira, K. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon: New York, 1991; Vol. 3, Chapter
2.4.
For our optimization studies, we chose to focus on the
Sonogashira coupling of 4-bromoanisole, an electron-rich and
(3) Nguefack, J.-F.; Bolitt, V.; Sinou, D. Tetrahedron Lett. 1996, 31,
5527-5530.
(4) Villemin, D.; Goussu, D. Heterocycles 1989, 29, 1255-1261.
10.1021/ol0058947 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/18/2000

therefore relatively unreactive aryl bromide, as our test
substrate. As shown in Scheme 2, we have found that, among
Table 1. Room-Temperature Sonogashira Couplings Catalyzed
by Pd(PhCN)2Cl2/P(t-Bu)3
Scheme 2
9
the five ligands that are illustrated, P(t-Bu)3 is uniquely
effective in accomplishing the palladium-catalyzed Sono-
gashira reaction at room temperaturestriarylphosphines, as
well as sterically demanding and electron-rich PCy3, furnish
essentially none of the desired coupling product.10 Additional
optimization experiments have revealed that replacement of
Pd(MeCN)2Cl2/NEt3 with Pd(PhCN)2Cl2/HN(i-Pr)2 leads to
a modest enhancement in reactivity.11
By use of these conditions, we can catalyze the Sono-
gashira coupling of a wide variety of aryl bromides and
(5) For pioneering studies, see the following references. (a) Carbonyla-
tion: Huser, M.; Youinou, M.-T.; Osborn, J. A. Angew. Chem., Int. Ed.
Engl. 1989, 28, 1386-1388. Ben-David, Y.; Portnoy, M.; Milstein, D. J.
Am. Chem. Soc. 1989, 111, 8742-8744. (b) Dechlorination: Ben-David,
Y.; Gozin, M.; Portnoy, M.; Milstein, D. J. Mol. Catal. 1992, 73, 173-
180.
(6) (a) Coupling of vinyl- or arylsilanes: Gouda, K.-i.; Hagiwara, E.;
Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1996, 61, 7232-7233. (b) Amine
arylation: Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38, 4807-
4810. Nishiyama, M.;Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39,
617-620. Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120,
7369-7370. Bei, X.; Guram, A. S.; Turner, H. W.; Weinberg, W. H.
Tetrahedron Lett. 1999, 40, 1237-1240. (c) Suzuki reaction: Shen, W.
Tetrahedron Lett. 1997, 38, 5575-5578. Firooznia, F.; Gude, C.; Chan,
K.; Satoh, Y. Tetrahedron Lett. 1998, 39, 3985-3988. Bei, X.; Crevier,
T.; Guram, A. S.; Jandeleit, B.; Powers, T. S.; Turner, H. W.; Uno, T.;
Weinberg, W. H. Tetrahedron Lett. 1999, 40, 3855-3858. (d) Heck
reaction: Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc.
1999, 121, 2123-2132. (e) Ketone arylation: Kawatsura, M.; Hartwig, J.
F. J. Am. Chem. Soc. 1999, 121, 1473-1478. (f) Alkoxide arylation: Mann,
G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999,
121, 3224-3225. Watanabe, M.; Nishiyama, M.; Koie, Y. Tetrahedron Lett.
1999, 40, 8837-8840. (g) Amidocarbonylation: Kim, J. S.; Sen, A. J. Mol.
Catal. A 1999, 143, 197-201.
(7) (a) Suzuki reaction and amine arylation: Old, D. W.; Wolfe, J. P.;
Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722-9723. (b) Alkoxide
arylation: Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J.
P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369-4378. (c) Ketone
arylation: Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360-1370.
(8) (a) Suzuki reaction: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
1998, 37, 3387-3388. (b) Heck reaction: Littke, A. F.; Fu, G. C. J. Org.
Chem. 1999, 64, 10-11. (c) Stille reaction: Littke, A. F.; Fu, G. C. Angew.
Chem. Int. Ed. 1999, 38, 2411-2413.
(9) For a pioneering study of the use of P(t-Bu)3 in palladium-catalyzed
coupling reactions, see: Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetra-
hedron Lett. 1998, 39, 617-620.
(10) Notes: (a) For the triarylphosphines and for PCy3, essentially no
reaction is observed even after 24 h at room temperature (e 5% yield). (b)
Preliminary experiments with recently reported biaryl dialkyl phosphines
indicate that catalysts derived from these ligands, while useful at ∼50 °C,
are inefficient at room temperature. The origins of these differences in
reactivity are being investigated in our laboratories.
(11) Notes: (a) Pd2(dba)3 provides a slightly less active catalyst. (b)
Toluene and THF may be used in place of dioxane. (c) Couplings proceed
extremely slowly in the absence of CuI.
terminal acetylenes at room temperature (Table 1).12 Thus,
bromobenzene reacts with an array of alkynes in good to
excellent yields (entries 1-3). As illustrated in entries 4-7,
less reactive 4-bromoanisole also couples with high ef-
(12) General procedure: Pd(PhCN)2Cl2 (11.5 mg, 0.030 mmol) and CuI
(3.8 mg, 0.020 mmol; stored under argon or nitrogen) are added to a dry,
4-mL septum-capped vial, which is then sparged with argon and charged
with dioxane (1.0 mL; Aldrich Sure/Seal anhydrous/99.8%). P(t-Bu)3 (250
µL of a 0.25 M solution in dioxane; 0.062 mmol; P(t-Bu)3 is sold by Strem
Chemicals in a Sure/Seal bottle as a 10 wt % solution in hexane), HN(i-
Pr)2 (170 µL, 1.20 mol; Aldrich Sure/Seal 99.5%), the aryl bromide (1.00
mmol), and the alkyne (1.20 mmol) are added via syringe to the stirred
reaction mixture. During the reaction, which is followed by TLC or by
GC, precipitation of [H2N(i-Pr)2]Br is observed. After the aryl bromide has
been consumed, the reaction mixture is diluted with EtOAc (5 mL), filtered
through a small pad of silica gel (with EtOAc rinsings), concentrated, and
purified by flash chromatography.
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Org. Lett., Vol. 2, No. 12, 2000

ficiency. Even very electron-rich 4-bromo-N,N-dimethyla-
niline reacts cleanly at room temperature (entry 8). The
coupling of 4′-bromoacetophenone that is depicted in entry
9 establishes that ketones are compatible with the reaction
conditions. Finally, Pd(PhCN)2Cl2/P(t-Bu)3 can even effect
Sonogashira couplings of hindered aryl bromides at room
temperature (entries 10-12).
Sonogashira reactions of aryl bromides, accomplishing a
wide range of couplings at room temperature. We believe
that this system compares favorably with other catalyst
systems that have been reported for this process. This study
provides further evidence of the usefulness of bulky, electron-
rich phosphines in palladium-catalyzed coupling reactions.
Acknowledgment. For support, T.H. thanks the Deutsche
Forschungsgemeinschaft (research fellowship), A.F.L. thanks
the Natural Sciences and Engineering Research Council of
Canada (predoctoral fellowship), S.L.B. thanks the National
Institutes of Health (GM34917), Pfizer, and Merck, and
G.C.F. thanks Bristol-Myers Squibb, Merck, Novartis, Pfizer,
and Pharmacia & Upjohn.
Because the goal of this study has been to establish a truly
general protocol for room-temperature Sonogashira couplings
of aryl bromides, we have applied an identical experimental
procedure to all of the reactions that are illustrated in Table
112si.e., the reactions have not been individually optimized
(e.g., with respect to catalyst loading). We have briefly
addressed the issue of whether a lower catalyst loading may
be employed, and we have found that it maysthus, 4-bromo-
anisole cleanly couples with phenylacetylene in the presence
of just 0.5% Pd(PhCN)2Cl2/1.0% P(t-Bu)3 (reaction time: 22
h; 99% isolated yield w ∼200 turnovers).
Supporting Information Available: An experimental
procedure, as well as 1H NMR data and literature references
for the products illustrated in Table 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
In summary, we have determined that Pd(PhCN)2Cl2/P(t-
Bu)3 serves as an efficient and a versatile catalyst for
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