Versatile catalysts for the Suzuki cross-coupling of arylboronic acids with aryl and vinyl halides and triflates under mild conditions

Article abstract of DOI:10.1021/ja0002058

Through the use of Pd₂(dba)₃/P(t-Bu)₃ as a catalyst, a wide range of aryl and vinyl halides, including chlorides, undergo Suzuki cross-coupling with arylboronic acids in very good yield, typically at room temperature; through use of Pd(OAc)₂/PCy₃, a diverse array of aryl and vinyl triflates react cleanly at room temperature. Together, these two catalyst systems cover a broad spectrum of commonly encountered substrates for Suzuki couplings. Furthermore, they display novel reactivity patterns, such as the selective cross-coupling by Pd₂(dba)₃/P(t-Bu)₃ of an aryl chloride in preference to an aryl triflate, and they can be used at low loading, even for reactions of aryl chlorides. Preliminary mechanistic work indicates that a palladium monophosphine complex is the active catalyst in the cross-coupling of aryl halides.

Full text of DOI:10.1021/ja0002058

4020
J. Am. Chem. Soc. 2000, 122, 4020-4028
Versatile Catalysts for the Suzuki Cross-Coupling of Arylboronic
Acids with Aryl and Vinyl Halides and Triflates under Mild
Conditions
Adam F. Littke, Chaoyang Dai, and Gregory C. Fu*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
ReceiVed January 19, 2000
Abstract: Through the use of Pd2(dba)3/P(t-Bu)3 as a catalyst, a wide range of aryl and vinyl halides, including
chlorides, undergo Suzuki cross-coupling with arylboronic acids in very good yield, typically at room
temperature; through use of Pd(OAc)2/PCy3, a diverse array of aryl and vinyl triflates react cleanly at room
temperature. Together, these two catalyst systems cover a broad spectrum of commonly encountered substrates
for Suzuki couplings. Furthermore, they display novel reactivity patterns, such as the selective cross-coupling
by Pd2(dba)3/P(t-Bu)3 of an aryl chloride in preference to an aryl triflate, and they can be used at low loading,
even for reactions of aryl chlorides. Preliminary mechanistic work indicates that a palladium monophosphine
complex is the active catalyst in the cross-coupling of aryl halides.
Introduction
a general protocol that could reliably effect cross-coupling,
independent of the structure of the reactants, would be worth-
while.
In 1998, we discovered that Pd2(dba)3/P(t-Bu)3 catalyzes the
Suzuki cross-coupling of a wide array of aryl chlorides and
arylboronic acids (eq 1).6 The high reactivity of this system
The palladium-catalyzed Suzuki cross-coupling of aryl halides
and aryl triflates with arylboronic acids to form biaryls has
emerged as an extremely powerful tool in organic synthesis.1
Compounds that contain a biaryl linkage have a diverse spectrum
of applications, ranging from materials science2 to pharmaceu-
ticals. For example, with respect to pharmaceuticals, the biaryl
group is a key feature in the sartan family of drugs for high
blood pressure3,4 and in important natural products, such as the
vancomycin antibiotics.5 Although the Suzuki cross-coupling
is most commonly used to synthesize biaryls, reactions of vinyl
halides/triflates with arylboronic acids, to generate styrene
derivatives, are an important component of the broad utility of
the process. The innocuous nature of boronic acids, which are
generally nontoxic and thermally, air-, and moisture-stable, is
a practical advantage of the Suzuki reaction, relative to many
other cross-coupling processes.
toward typically unreactive aryl chlorides suggested to us that
it might serve as a very versatile catalyst, under mild conditions,7
for Suzuki cross-couplings of other substrates. In this report,
we describe significant progress toward substantiating that
possibility.
There are a large number of parameters in a Suzuki reaction s
palladium source, ligand, additive, solvent, temperature, etc. s
and there are, correspondingly, a large number of protocols for
accomplishing the transformation, the choice of which depends
on the structure of the reactants.1 Clearly, the development of
Results and Discussion
Suzuki Cross-Coupling of Aryl Chlorides. By way of
background, at the time that we initiated our studies of palladium
chemistry, one of the most important limitations of the Suzuki
cross-coupling reaction was the poor reactivity of aryl chlorides,
which are perhaps the most attractive family of aryl halide
substrates due to their low cost and their ready availability.8,9
In fact, prior to 1998, reports of efficient palladium-catalyzed
Suzuki couplings of aryl chlorides were limited to reactions of
(1) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457-2483. (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168. (c)
Miyaura, N. In AdVances in Metal-Organic Chemistry; Liebeskind, L. S.,
Ed.; JAI: London, 1998; Vol. 6, pp 187-243. (d) Suzuki, A. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998; Chapter 2. (e) Stanforth, S. P. Tetrahedron
1998, 54, 263-303.
(2) For example, see: Step Growth Polymers for High-Performance
Materials; Hedrick, J. L., Labadie, J. W., Eds.; ACS Symp. Ser. 624;
American Chemical Society: Washington, DC, 1996.
(6) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387-
3388.
(7) “There are few examples of ambient temperature Suzuki-type biaryl
couplings”: ref 1b.
(8) The low reactivity of aryl chlorides in cross-coupling reactions is
generally ascribed to their reluctance to oxidatively add to Pd(0). Aryl
halides that bear an electron-withdrawing group oxidatively add to Pd(0)
more readily than do the corresponding unsubstituted aryl halides. For
discussions, see: Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047-
1062.
(3) The key step in the synthesis of Losartan is a Suzuki cross-coupling
reaction: Smith, G. B.; Dezeny, G. C.; Hughes, D. L.; King, A. O.;
Verhoeven, T. R. J. Org. Chem. 1994, 59, 8151-8156.
(4) For reviews on sartans and Losartan, see: (a) Birkenhager, W. H.;
de Leeuw, P. W. J. Hypertens. 1999, 17, 873-881. (b) Goa, K. L.; Wagstaff,
A. J. Drugs 1996, 51, 820-845.
(5) For a review, see: Nicolaou, K. C.; Boddy, C. N. C.; Brase, S.;
Winssinger, N. Angew. Chem., Int. Ed. 1999, 38, 2096-2152.
(9) Stu¨rmer, R. Angew. Chem., Int. Ed. 1999, 38, 3307-3308.
10.1021/ja0002058 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/15/2000

Versatile Catalysts for Suzuki Cross-Coupling
J. Am. Chem. Soc., Vol. 122, No. 17, 2000 4021
Table 1. Suzuki Cross-Couplings of Activated Aryl Chlorides at
Room Temperature
activated substrates (i.e., heteroaryl chlorides and aryl chlorides
that bear an electron-withdrawing group), which generally only
proceeded at high temperature (75-130 °C).10,11 Since 1998,
several research groups have described electron-rich ligands for
palladium that overcome this limitation, specifically, aryldialkyl-
phosphines (Buchwald;12 Bei and Guram13), P(t-Bu)3 (Fu6,14),
and N-heterocyclic carbenes (Nolan;15 Herrmann16).17,18 With
respect to Suzuki couplings of aryl chlorides that proceed at
room temperature, the only successful catalyst systems reported
to date are those of Buchwald (very general) and of Kocovsky
(one example).18
In our initial communication, we reported a general method
for the Suzuki cross-coupling of aryl chlorides and arylboronic
acids in the presence of a Pd2(dba)3/P(t-Bu)3 catalyst system,
with Cs2CO3 as the base (80-90 °C in dioxane; eq 1);6,19 toward
the end of that study, we discovered that CsF is also a highly
effective base.20,21 We have since investigated the replacement
of CsF by less expensive KF,12b,c and we have found that Suzuki
reactions are even more rapid in the presence of KF. The
P(t-Bu)3:Pd is an important parameter: whereas use of a 1:1
ratio furnishes a very active catalyst, use of a 2:1 ratio leads to
a Isolated yield, average of two runs. b 1.5% Pd2(dba)3 and 3%
P(t-Bu)3 were used.
(10) (a) Gronowitz, S.; Ho¨rnfeldt, A.-B.; Kristjansson, V.; Musil, T.
Chem. Scr. 1986, 26, 305-309. (b) Thompson, W. J.; Jones, J. H.; Lyle, P.
A.; Thies, J. E. J. Org. Chem. 1988, 53, 2052-2055. (c) Mitchell, M. B.;
Wallbank, P. J. Tetrahedron Lett. 1991, 32, 2273-2276. (d) Alcock, N.
W.; Brown, J. M.; Hulmes, D. I. Tetrahedron: Asymmetry 1993, 4, 743-
746. (e) Janietz, D.; Bauer, M. Synthesis 1993, 33-34. (f) Uemura, M.;
Nishimura, H.; Kamikawa, K.; Nakayama, K.; Hayashi, Y. Tetrahedron
Lett. 1994, 35, 1909-1912. (g) Beller, M.; Fischer, H.; Herrmann, W. A.;
Ofele, K.; Brossmer, C. Angew. Chem., Int. Ed. Engl. 1995, 34, 1848-
1849. (h) Zhang, H.; Chan, K. S. Tetrahedron Lett. 1996, 37, 1043-1044.
(i) Saito, S.; Sakai, M.; Miyaura, N. Tetrahedron Lett. 1996, 37, 2993-
2996. (j) Shen, W. Tetrahedron Lett. 1997, 38, 5575-5578.
(11) For pioneering work on nickel-catalyzed cross-couplings of aryl
chlorides and arylboronic acids, see: (a) Saito, S.; Oh-tani, S.; Miyaura,
N. J. Org. Chem. 1997, 62, 8024-8030. (b) Indolese, A. F. Tetrahedron
Lett. 1997, 38, 3513-3516.
(12) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9722-9723. (b) Wolfe, J. P.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 1999, 38, 2413-2416. (c) Wolfe, J. P.; Singer, R. A.; Yang, B. H.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550-9561.
(13) (a) 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. (b) Bei, X.; Turner, H. W.; Weinberg, W. H.; Guram, A. S.; Petersen,
J. L. J. Org. Chem. 1999, 64, 6797-6803.
an extremely slow reaction.22 Among palladium sources,
Pd2(dba)3 is superior to Pd(OAc)2.23
With this improved method, we can cleanly effect Suzuki
cross-couplings of activated aryl chlorides under significantly
milder conditions (room temperature) and with lower catalyst
loadings (0.5% Pd2(dba)3 and 1% P(t-Bu)3) than we had
previously reported (Table 1; cf. eq 1).24-26 Thus, 4′-chloro-
acetophenone cross-couples efficiently with sterically hindered,
with electron-rich, and with electron-poor arylboronic acids
(entries 1-3, Table 1).27 Chloro-substituted pyridines and
thiophenes, which have the potential to bind to palladium
through nitrogen or sulfur, are also suitable substrates for room-
temperature Suzuki reactions (entries 4-6, Table 1).
More vigorous conditions are typically required to effect
Suzuki cross-couplings of electron-rich aryl chlorides (70-100
°C; Table 2). The use of a slightly higher P(t-Bu)3:Pd ratio
(1.5:1) at higher reaction temperatures appears to stabilize the
catalyst and to decrease the precipitation of palladium metal.28
Under these conditions, electron-rich aryl chlorides, including
4-chloroaniline, couple efficiently with both aryl- and alkyl-
boronic acids (entries 1-3, Table 2).29
(14) For other applications of P(t-Bu)3 in palladium-catalyzed couplings
of aryl chlorides, see: (a) Amination: Nishiyama, M.; Yamamoto, T.; Koie,
Y.; Tetrahedron Lett. 1998, 39, 617-620. Hartwig, J. F.; Kawatsura, M.;
Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem.
1999, 64, 5575-5580. (b) Heck reaction: Littke, A. F.; Fu, G. C. J. Org.
Chem. 1999, 64, 10-11. Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J.
Am. Chem. Soc. 1999, 121, 2123-2132. (c) Reaction of ketone enolates:
Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473-1478.
(d) Reaction of alkoxides: 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. (e)
Amidocarbonylation: Kim, J. S.; Sen, A. J. Mol. Catal. A 1999, 143, 197-
201. (f) Stille reaction: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
1999, 38, 2411-2413.
Room-Temperature Suzuki Cross-Coupling of Aryl Bro-
mides. There are relatively few examples of Suzuki cross-
couplings of aryl bromides that proceed at room temperature.30
(22) For an explanation of this observation, see the section that describes
mechanistic work on Suzuki cross-couplings of aryl chlorides and aryl
bromides (vide infra).
(15) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem.
1999, 64, 3804-3805.
(23) For our original optimization work, see ref 6.
(16) (a) Herrmann, W. A.; Reisinger, C.-P.; Spiegler, M. J. Organomet.
Chem. 1998, 557, 93-96. (b) Weskamp, T.; Bohm, V. P. W.; Herrmann,
W. A. J. Organomet. Chem. 1999, 585, 348-352.
(24) In the absence of P(t-Bu)3, no coupling between 4′-chloroacetophe-
none and o-tolylboronic acid is observed at room temperature (cf. Table 1,
entry 1).
(25) Under these nonaqueous conditions, hydrolytic cleavage of the B-C
bond is not a concern. For discussions of this issue, see ref 1.
(26) Dioxane is also a suitable solvent.
(17) See also: Firooznia, F.; Gude, C.; Chan, K.; Satoh, Y. Tetrahedron
Lett. 1998, 39, 3985-3988.
(18) See also: Kocovsky, P.; Vyskocil, S.; Cisarova, I.; Sejbal, J.;
Tislerova, I.; Smrcina, M.; Lloyd-Jones, G. C.; Stephen, S. C.; Butts, C.
P.; Murray, M.; Langer, V. J. Am. Chem. Soc. 1999, 121, 7714-7715.
(19) For an application of this method, see: Firooznia, F.; Gude, C.;
Chan, K.; Marcopulos, N.; Satoh, Y. Tetrahedron Lett. 1999, 40, 213-216.
(20) See footnote 9 of ref 6.
(27) Cross-coupling can also be effected at 0 °C, although the reaction
is slower.
(28) However, as we have observed for Suzuki cross-couplings of
electron-poor aryl chlorides, reactions of electron-rich aryl chlorides proceed
very slowly when a 2:1 ratio of P(t-Bu)3:Pd is employed.
(29) The need for a higher temperature for the reaction of cyclopentyl-
boronic acid may be due to the slower rate of transmetalation by alkylboron
compounds, relative to arylboron compounds. For example, see ref 21b.
(21) (a) Ichikawa, J.; Moriya, T.; Sonoda, T.; Kobayashi, H. Chem. Lett.
1991, 961-964. (b) Wright, S. W.; Hageman, D. L.; McClure, L. D. J.
Org. Chem. 1994, 59, 6095-6097.

4022 J. Am. Chem. Soc., Vol. 122, No. 17, 2000
Littke et al.
Table 4. Suzuki Cross-Couplings of Aryl Iodides at Room
Table 2. Suzuki Cross-Couplings of Unactivated Aryl Chlorides
Temperature
a Isolated yield, average of two runs.
Table 3. Suzuki Cross-Couplings of Aryl Bromides at Room
Temperature
a Isolated yield, average of two runs. b 2.4% P(t-Bu)3 was used. c 1.1
equiv of AgBF4 was added.
with sterically hindered o-tolylboronic acid (entries 1-3, Table
3). Particularly noteworthy are the reactions of very electron-
rich 4-bromo-N,N-dimethylaniline (entries 3-4, Table 3) and
4-bromophenol (entry 5, Table 3), which proceed to completion
in 0.3-5 h.
The Pd2(dba)3/P(t-Bu)3 catalyst system is also tolerant of
electronic variation in the arylboronic acid component. For
example, 2-bromotoluene reacts cleanly at room temperature
with electron-poor, electron-neutral, and electron-rich boronic
acids (entries 6-8, Table 3).32
Room-Temperature Suzuki Cross-Coupling of Aryl Io-
dides. Aryl iodides are usually the most reactive aryl halides
in palladium-catalyzed cross-coupling reactions.33 We have
established that, under the conditions that we have developed,
a wide array of Suzuki reactions of aryl iodides with arylboronic
acids proceed in excellent yield at room temperature (Table 4;
94-98%). Thus, electronically diverse aryl iodides react
uniformly cleanly with sterically hindered o-tolylboronic acid
(entries 1-3, Table 4), and electronically diverse arylboronic
acids couple efficiently with 2-iodotoluene (entries 4-6, Table
4).34 Di-ortho-substituted biaryls are also readily accessible
(entry 7, Table 4).
a Isolated yield, average of two runs.
As a consequence, Buchwald’s recent report of a general method
for accomplishing this process represents a notable advance.12
We have determined that we can effect room-temperature
Suzuki cross-couplings of a broad spectrum of aryl bromides
and arylboronic acids using the Pd2(dba)3/P(t-Bu)3 catalyst
system that we have described for the coupling of aryl
chlorides.31 As illustrated in Table 3, this catalyst furnishes the
desired biaryls in excellent yields (92-99%). Thus, aryl
bromides that are electron-poor or electron-rich couple cleanly
Surprisingly, under these conditions, cross-couplings of aryl
iodides are slower than the corresponding reactions of aryl
bromides. This observation suggests that, in the case of aryl
(30) (a) Campi, E. M.; Jackson, W. R.; Marcuccio, S. M.; Naeslund, C.
G. M. J. Chem. Soc., Chem. Commun. 1994, 2395. (b) Anderson, J. C.;
Namli, H.; Roberts, C. A. Tetrahedron 1997, 53, 15123-15134. (c) Johnson,
C. R.; Johns, B. A. Synlett 1997, 1406-1408. (d) Bumagin, N. A.; Bykov,
V. V. Tetrahedron 1997, 53, 14437-14450. (e) Albisson, D. A.; Bedford,
R. B.; Lawrence, S. E.; Scully, P. N. Chem. Commun. 1998, 2095-2096.
(f) Uozumi, Y.; Danjo, H.; Hayashi, T. J. Org. Chem. 1999, 64, 3384-
3388. (g) Kamatani, A.; Overman, L. E. J. Org. Chem. 1999, 64, 8743-
8744. (h) Bussolari, J. C.; Rehborn, D. C. Org. Lett. 1999, 1, 965-967.
(31) Room temperature Suzuki cross-couplings of aryl bromides can also
be accomplished with Pd(OAc)2 as the palladium source and PCy3 as the
phosphine.
(32) Because these reaction mixtures are heterogeneous, the relative times
that are necessary for the cross-couplings to proceed to completion may
not reflect the relative intrinsic reactivities of the substrates.
(33) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: New York, 1998. (b) Tsuji, J. Palladium Reagents
and Catalysis; Wiley: New York, 1995. (c) Farina, V. In ComprehensiVe
Organometallic Chemistry 2; Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Eds.; Pergamon: New York, 1995; Vol. 12, Chapter 3.4. (d) Reference 1.
(34) For the Suzuki reaction illustrated in entry 4, cross-coupling was
slow in the absence of AgBF4. Use of (n-Bu)4NCl or (n-Bu)4NF as an
additive was also effective.

Versatile Catalysts for Suzuki Cross-Coupling
J. Am. Chem. Soc., Vol. 122, No. 17, 2000 4023
Table 5. Suzuki Cross-Couplings of Aryl Triflates at Room
Temperature
iodides, oxidative addition may not be the turnover-limiting step
of the catalytic cycle.35
Room-Temperature Suzuki Cross-Coupling of Aryl Tri-
flates. Because they are easily synthesized from readily available
phenols, aryl triflates are an important family of substrates for
cross-coupling reactions.36 In the case of Suzuki reactions, aryl
triflates are known to be less reactive than the corresponding
iodides and bromides,37 and elevated reaction temperatures have
been employed in essentially all of the reactions of aryl triflates
that have been reported to date.38
In our initial studies, we attempted to apply the Pd2(dba)3/
P(t-Bu)3 catalyst system to the coupling of 4-methoxyphenyl
triflate and o-tolylboronic acid. Surprisingly, we observed no
appreciable reaction at room temperature or even after 8 h at
60 °C. The addition of KBr37 or the use of Pd(OAc)2 did not
significantly improve the coupling process. We decided to
explore other trialkylphosphines as ligands, based on speculation
that the larger steric demand of a triflate relative to a halide
might require the use of a less bulky, but nevertheless electron-
rich, phosphine. We were pleased to discover that when we
employ a Pd(OAc)2/PCy3 catalyst system, the Suzuki reaction
of 4-methoxyphenyl triflate and o-tolylboronic acid proceeds
to completion within 6 h at room temperature (1% Pd(OAc)2,
1.2% PCy3, 3.3 equiv of KF).39,40
a Isolated yield, average of two runs. b 5% Pd(OAc)2/6% PCy3 was
used.
Under these conditions, we can efficiently cross-couple a
broad spectrum of aryl triflates and arylboronic acids in quite
good yield (Table 5). Variation in the electronic nature of the
aryl triflate and of the arylboronic acid is well-tolerated (entries
1-6, Table 5), as is the presence of ortho substituents (entry 7,
Table 5; 5% Pd(OAc)2).41
Table 6. Suzuki Cross-Couplings To Form Sterically Hindered
Biaryls
Suzuki Cross-Coupling of Sterically Hindered Substrates.
Although there have been a number of reports of Suzuki
reactions of aryl halides that form hindered biaryls (i.e., two or
more ortho substituents), couplings of this type can be difficult,
requiring vigorous conditions and furnishing modest yields.1 In
particular, Suzuki cross-couplings that efficiently generate
biaryls with three ortho substituents are not commonplace,
especially with aryl chlorides as substrates.12c,42
We have established that we can synthesize sterically hindered
biaryls from a variety of precursors in good yield (Table 6, 89-
(35) For further discussion, see the section that describes mechanistic
work on Suzuki cross-couplings of aryl iodides (vide infra).
(36) For reviews of the chemistry of vinyl and aryl triflates, see: (a)
Ritter, K. Synthesis 1993, 735-762. (b) Stang, P. J.; Hanack, M.;
Subrmanian, L. R. Synthesis 1982, 85-126.
(37) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201-
2208.
(38) (a) For a report of a room-temperature cross-coupling of phenyl
triflate with 9-octyl-9-BBN, see ref 37. (b) For a report of a room-
temperature cross-coupling of a vinylboronic acid with an actiVated aryl
triflate (bearing a 4-(ethoxycarbonyl) group), see: Torrado, A.; Lopez, S.;
Alvarez, R.; de Lera, A. R. Synthesis 1995, 285-293.
a Standard conditions: 1.0 equiv of aryl halide. 1.1 equiv of boronic
acid, 3.3 equiv of KF, THF. b Isolated yield, average of two runs.
c Product contained 4% 2.2′-dimethylbiphenyl. d 1.5 equiv of boronic
acid, 2.0 equiv of K3PO4, and toluene as solvent; the product from one
run contained 5% mesitylene.
(39) Cone angle of PCy3: 170°. Cone angle of P(t-Bu)3: 182°. For an
extensive compilation of phosphine cone angles, see: Rahman, M. M.; Liu,
H.-Y.; Eriks, K.; Prock, A.; Giering, W. P. Organometallics 1989, 8, 1-7.
(40) Notes: (1) Use of Pd2(dba)3/PCy3 leads to a slower cross-coupling
reaction. (2) It is likely that o-tolylboronic acid is reducing Pd(II) to
catalytically active Pd(0); consistent with this hypothesis, we observe the
formation of ∼1% of the homocoupled product, 2,2′-dimethylbiphenyl. For
a mechanistic study and leading references, see: Moreno-Manas, M.; Perez,
M.; Pleixats, R. J. Org. Chem. 1996, 61, 2346-2352. (3) No cross-coupling
is observed in the absence of PCy3. (4) Use of 1% Pd(OAc)2/2.4% PCy3,
instead of 1% Pd(OAc)2/1.2% PCy3, leads to a slower reaction. (5) Pd-
(OAc)2(PCy3)2 and Pd(PCy3)2 are also effective cross-coupling catalysts.
(41) Under other, more vigorous conditions for Suzuki reactions,
hydrolysis of the triflate is sometimes observed. For example, see: (a)
Coudret, C.; Mazenc, V. Tetrahedron Lett. 1997, 38, 5293-5296. (b) Fu,
J.-m.; Snieckus, V. Tetrahedron Lett. 1990, 31, 1665-1668.
98%) using the palladium sources (Pd2(dba)3 or Pd(OAc)2) and
the phosphines (P(t-Bu)3, PCy3) that we have described above.
For example, aryl chlorides serve as excellent substrates for
Suzuki cross-couplings that generate disubstituted (entry 1, Table
6) and trisubstituted biaryls (entries 2 and 3, Table 6). The
reaction tolerates substrates that bear two substituents ortho to
either the chlorine (entry 2, Table 6) or the boronic acid (entry
3, Table 6), and it proceeds under relatively mild conditions
and with moderate catalyst loadings. While our standard system
for Suzuki reactions of aryl chlorides (Pd2(dba)3/P(t-Bu)3) can
(42) (a) For the cross-coupling of a heteroaryl chloride, see refs 10d and
10h. (b) For a nickel-catalyzed cross-coupling, see: Galland, J.-C.; Savignac,
M.; Genet, J.-P. Tetrahedron Lett. 1999, 40, 2323-2326.

4024 J. Am. Chem. Soc., Vol. 122, No. 17, 2000
Table 7. Chemoselective Suzuki Cross-Couplings
Littke et al.
Table 8. Suzuki Cross-Couplings with Low Catalyst Loadings
a Standard conditions: 1.0 equiv of aryl halide, 1.1 equiv of boronic
acid, 3.3 equiv of KF, dioxane or THF. b Isolated yield, average of
two runs.
a Standard conditions: 1.0 equiv of aryl halide, 1.0 equiv of boronic
acid, 3.0 equiv of KF, THF, room temperature. b Isolated yield.
an aryl triflate. As illustrated in entry 4 of Table 7, Pd2(dba)3/
P(t-Bu)3 does indeed react with the chloride of 4-chlorophen-
yltriflate in preference to the triflate, with excellent selectiVity.
In contrast, Pd(OAc)2/PCy3 exhibits the conventional pattern
of reactivity (entry 5, Table 7).47 Thus, simply through ap-
propriate choice of catalyst, one can selectively cross-couple
an aryl chloride in the presence of an aryl triflate, or vice versa.
The competition experiment illustrated in eq 2 provides
further evidence for the remarkable selectivity of Pd2(dba)3/
P(t-Bu)3 for chlorides over triflates. These data indicate that
also be employed for the synthesis of trisubstituted biaryls
(entries 2 and 3, Table 6), we have found the use of less
sterically hindered PCy3 to be advantageous for this particular
application.
Suzuki cross-couplings of aryl bromides also furnish disub-
stituted (entry 4, Table 6) and trisubstituted (entries 5 and 6,
Table 6) biaryls in excellent yield. These reactions proceed
cleanly at room temperature in the presence of 0.5% Pd2(dba)3/
1.2% P(t-Bu)3. To the best of our knowledge, there are only
two examples of room-temperature couplings of unactivated aryl
bromides to produce di-ortho-substituted biaryls,12c,30b and there
is no precedent for room-temperature coupling of an unactivated
aryl bromide to produce a tri-ortho-substituted biaryl.43
Relative Reactivity of Aryl Chlorides, Bromides, Iodides,
and Triflates: Chemoselective Suzuki Cross-Coupling. For
substrates that bear more than one halide/triflate, the ability to
effect selective monofunctionalization through Suzuki cross-
coupling can be a powerful tool.44 For previously described
palladium catalysts, the general order of reactivity is the
following: I > Br J OTf . Cl.1
We have established that with the Pd2(dba)3/P(t-Bu)3 catalyst
system it is possible to carry out highly selective monofunc-
tionalizations of difunctionalized arenes (Table 7). Not surpris-
ingly, an iodo and a bromo group react in preference to a chloro
group, providing the chlorinated biaryl in excellent yield (entries
1 and 2, Table 7). In the case of 4-bromophenyltriflate, we
observe very selective reaction of the bromide in the presence
of the triflate (entry 3, Table 7).45,46
k
Ar-Cl/kAr-OTf exceeds 20 for this reaction.48,49
Suzuki Cross-Coupling with Low Catalyst Loadings. We
developed the Suzuki cross-coupling methods reported above
(Tables 1-5) with the goal of providing general and reliable
procedures that should work on the first try for a large majority
of the substrates that one might encounter; we therefore did
not attempt to optimize reaction conditions for each substrate
pair. Of course, in an industrial setting, cost considerations
provide a strong impetus for optimizing a particular process,
especially with respect to minimizing the amount of catalyst
that is used. To provide a sense for the turnover numbers that
are achievable with Pd2(dba)3/P(t-Bu)3, we have examined
Suzuki cross-couplings of several substrates with low catalyst
loadings (Table 8).
We chose to explore the Suzuki reaction of 2-chlorobenzoni-
trile with p-tolylboronic acid, due to the fact that the product,
2-cyano-4′-methylbiphenyl, is a key intermediate in the synthesis
of angiotensin II receptor antagonists that are used for the
treatment of hypertension.50 At room temperature this cross-
coupling proceeds in 99% yield with a 0.1% loading of
palladium (0.05% Pd2(dba)3), corresponding to ∼1000 turnovers
(entry 1, Table 8). An even higher turnover number can be
In view of the low reactivity of aryl triflates toward the Pd2-
(dba)3/P(t-Bu)3 catalyst system, we speculated that it might even
be possible to effect a selective Suzuki coupling of a chloride
in the presence of a triflate. To the best of our knowledge, there
is no precedent in any palladium-catalyzed cross-coupling
process for greater reactivity toward an aryl chloride than toward
(43) Thus far, our attempts to efficiently produce biaryls that bear four
ortho substituents have been unsuccessful.
(44) For example, see: (a) Kawada, K.; Arimura, A.; Tsuri, T.; Fuji,
M.; Komurasaki, T.; Yonezawa, S.; Kugimiya, A.; Haga, N.; Mitsumori,
S.; Inagaki, M.; Nakatani, T.; Tamura, Y.; Takechi, S.; Taishi, T.; Kishino,
J.; Ohtani, M. Angew. Chem., Int. Ed. 1998, 37, 973-975. (b) Hird, M.;
Gray, G. W.; Toyne, K. J. Mol. Cryst. Liq. Cryst. 1991, 206, 187-204.
(45) The Pd(OAc)2/PCy3 catalyst system also reacts with the bromide
of 4-bromophenyltriflate with very high selectivity. For conditions under
which Pd(PPh3)4 furnishes high selectivity, see ref 37 (in contrast with ref
41b).
(46) A competition experiment between 4-ethylbromobenzene (1 equiv)
and 4-methylphenyltriflate (1 equiv) for reaction with phenylboronic acid
(1 equiv) using Pd(OAc)2/PCy3 as the catalyst resulted in exclusive coupling
with the aryl bromide; in contrast, only modest selectivity for the bromide
was reported for a Suzuki reaction catalyzed by Pd(PPh3)4 (ref 37).
(47) In the presence of 3.0% Pd(OAc)2/3.6% PCy3, low selectivity is
observed.
(48) The phosphine, not the palladium source, controls chloride/triflate
selectivity. A competition experiment conducted with Pd(OAc)2/P(t-Bu)3
yielded results similar to the experiment conducted with Pd2(dba)3/P(t-Bu)3.
(49) Use of 1% Pd(OAc)2/1.2% PCy3 leads to predominant Suzuki cross-
coupling of the aryl triflate, rather than the aryl chloride.
(50) For leading references, see: Goubet, D.; Meric, P.; Dormoy, J.-R.;
Moreau, P. J. Org. Chem. 1999, 64, 4516-4518.

Versatile Catalysts for Suzuki Cross-Coupling
J. Am. Chem. Soc., Vol. 122, No. 17, 2000 4025
Table 9. Suzuki Cross-Couplings of Vinyl Halides and Vinyl
Triflates
achieved at higher temperature; thus, at 90 °C, the Suzuki
reaction goes to completion with just 0.01% Pd, corresponding
to nearly 10,000 turnovers (entry 2, Table 8; 97% yield). This
is the highest turnover number that we are aware of for a Suzuki
cross-coupling of an aryl chloride.51,52
We can also achieve high turnover with other substrates. For
example, we observe a turnover number of ∼900 at 100 °C for
the Suzuki reaction of chlorobenzene and p-tolylboronic acid
(entry 3, Table 8). With respect to aryl bromides, we can cross-
couple electron-rich, deactivated p-bromoanisole with o-tolyl-
boronic acid at room temperature in 98% yield with 0.01% Pd,
corresponding to a turnover number of ∼10,000 (entry 4,
Table 8).53
Suzuki Cross-Coupling of Vinyl Halides and Vinyl Trif-
lates. Vinyl halides/triflates are another important family of
cross-coupling partners in the Suzuki reaction;1 couplings of
this class of compounds have played a key role in the synthesis
of a diverse array of natural products, including palytoxin,54
rutamycin,55 and epothilone.56 In light of our success in
developing general and mild catalyst systems for coupling aryl
halides/triflates, we decided to pursue the application of these
methods to Suzuki reactions of the corresponding vinyl com-
pounds. As shown in Table 9, we have found that it is indeed
possible to efficiently cross-couple vinyl halides/triflates with
boronic acids, under conditions very similar to those employed
for the corresponding aryl compounds.
For vinyl chlorides, Pd2(dba)3/P(t-Bu)3 has proved to be an
excellent catalyst, furnishing the desired coupling products in
good yield at 50-60 °C. Thus, as illustrated in entries 1 and 2
of Table 9, olefins that bear a substituent geminal to the chloro
group react cleanly under these conditions. The cross-coupling
of 1-chloro-2-methylbutene establishes that the reaction also
tolerates a substituent cis to the chloride (entry 3). To the best
of our knowledge, these data represent the first examples of
Suzuki couplings of unactivated vinyl chlorides: previous
reports have been limited to activated substrates wherein the
vinyl chloride is conjugated to an electron-withdrawing group.57
In other palladium-catalyzed cross-coupling processes, vinyl
chlorides have proved to be significantly more reactive than
aryl chlorides.33 To investigate the relative reactivity of aryl
and vinyl chlorides in Suzuki reactions catalyzed by Pd2(dba)3/
P(t-Bu)3, we conducted a competition experiment between
chlorobenzene and 1-chlorocyclopentene for o-tolylboronic acid
a Standard conditions: 1.0 equiv of vinyl halide/triflate, 1.1 equiv
of boronic acid, 3.3 equiv of KF, THF. b Isolated yield, average of two
runs.
(eq 3). Interestingly, we observed that Pd2(dba)3/P(t-Bu)3 reacts
preferentially with chlorobenzene. As far as we know, this is
the first palladium-based cross-coupling catalyst that reacts more
readily with an aryl chloride than with a vinyl chloride.
Just as Pd2(dba)3/P(t-Bu)3 can couple aryl bromides or iodides
in very good yield at room temperature (Tables 3 and 4), under
identical conditions it can also couple vinyl bromides or iodides,
including sterically hindered 2-bromo-3-methylbutene (entries
4-6, Table 9). It is important to note that there have been several
other examples of room-temperature Suzuki reactions of unac-
tivated (albeit less bulky) vinyl bromides.58
We have conducted competition experiments between aryl
bromides/iodides and their vinyl counterparts. As with chlorides
(eq 3), we have found that aryl bromides/iodides react more
rapidly than do vinyl bromides/iodides (eq 4), by a small margin.
To the best of our knowledge, this reactivity pattern is unique
to the Pd2(dba)3/P(t-Bu)3 catalyst system.1
(51) (a) Beller, M.; Fischer, H.; Herrmann, W. A.; Ofele, K.; Brossmer,
C. Angew. Chem., Int. Ed. Engl. 1995, 34, 1848-1849. (b) References 12b
and 12c.
(52) This corresponds to producing 5.7 g of 2-cyano-4′-methylbiphenyl
with 1.4 mg of Pd2(dba)3.
(53) To the best of our knowledge, 950 is the highest turnover number
that has been reported for a room-temperature Suzuki coupling of an aryl
bromide (with an activated aryl bromide, 4-bromoacetophenone; ref 30e).
(54) Armstrong, R. W.; Beau, J.-M.; Cheon, S. H.; Christ, W. J.; Fujioka,
H.; Ham, W.-H.; Hawkins L. D.; Jin, H.; Kang, S. H.; Kishi, Y.; Martinelli,
M. J.; McWhorter, W. W.; Mizuno, M.; Nakata, M.; Stutz, A. E.; Talamas,
F. X.; Taniguchi, M.; Tino, J. A.; Ueda, K.; Uenishi, J.-i.; White, J. B.;
Yonaga, M. J. Am. Chem. Soc. 1989, 111, 7525-7530.
(55) Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc. 1993,
115, 11446-11459.
Vinyl triflates are a particularly useful class of cross-coupling
substrates because of their ready synthesis from carbonyl
compounds.1,36 Due to the potential lability of vinyl triflates,
the availability of mild reaction conditions can be critical for
efficient coupling of sensitive substrates. We have established
(56) Su, K.-S.; Meng, D.; Bertinato, P.; Balog, A.; Sorensen, E. J.;
Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. Angew.
Chem., Int. Ed. Engl. 1997, 36, 757-759.
(57) (a) Satoh, N.; Ishiyama, T.; Miyaura, N.; Suzuki, A. Bull. Chem.
Soc. Jpn. 1987, 60, 3471-3473. (b) Boland, G. M.; Donnelly, D. M. X.;
Finet, J.-P.; Rea, M. D. J. Chem. Soc., Perkin Trans. 1 1996, 2591-2597.

4026 J. Am. Chem. Soc., Vol. 122, No. 17, 2000
Littke et al.
containing species that is present (31P: δ 85.6; THF-d8).64
Furthermore, in the presence of excess phosphine (P(t-Bu)3:Pd
) 2-4:1), only Pd(P(t-Bu)3)2 and free P(t-Bu)3 are detected.
Thus, the bisphosphine adduct is favored over the monophos-
phine and the trisphosphine across a wide range of P(t-Bu)3:Pd
ratios.65
When we monitor the Suzuki cross-coupling of 3-chloro-
pyridine and o-tolylboronic acid by 31P NMR (2.5% Pd2(dba)3/
5% P(t-Bu)3; THF-d8), essentially the only species that we
observe during the course of the reaction is Pd(P(t-Bu)3)2.66
Since the overall P(t-Bu)3:Pd ratio is 1:1, this suggests that one-
half of the palladium is in the form of Pd(P(t-Bu)3)2 and the
other half of the palladium is in the form of a phosphine-free
complex.
Pd(P(t-Bu)3)2 does not appear to be the active catalyst in our
Suzuki cross-coupling process. Thus, the reaction of 3-chloro-
pyridine with o-tolylboronic acid in the presence of 3% Pd-
(P(t-Bu)3)2 proceeds sluggishly at room temperature (eq 6).67
However, the addition of phosphine-free Pd2(dba)3 to the
Pd(P(t-Bu)3)2 produces a marked increase in the rate of cross-
coupling (eq 6).68,69
Figure 1. Outline of the catalytic cycle for the Suzuki cross-coupling
reaction.
that, as with aryl triflates, the combination of Pd(OAc)2 and
PCy3 furnishes good yields for room-temperature Suzuki
reactions of vinyl triflates (entries 7-9, Table 9).59 Even
extremely hindered substrates cross-couple under these condi-
tions,60 although the reaction requires a higher catalyst loading
and proceeds in somewhat lower yield if the boronic acid is
also bulky (entries 8 and 9, Table 9). As far as we know, there
are only scattered examples of Suzuki couplings of vinyl triflates
that occur at room temperature.61
In a Pd(OAc)2/PCy3-catalyzed competition experiment be-
tween an aryl triflate and a vinyl triflate for reaction with
o-tolylboronic acid, we observe the “typical” pattern of aryl vs
vinyl reactivity: greater reactivity of the vinyl compound (eq
5; >100:1 selectivity).62 This result further highlights the
unusual reactivity of Pd2(dba)3/P(t-Bu)3 toward aryl halides.
These observations suggest that a palladium monophosphine
adduct may be the active catalyst in these Suzuki couplings70,71
and that phosphine-free palladium complexes that are present
in the reaction mixture may serve an important role by increasing
the concentration of the active catalyst. The unusual cross-
coupling activity furnished by P(t-Bu)3 may therefore be
attributable both to its size and to its electron-richness: the steric
demand favors dissociation (relative to less bulky phosphines)
to a monophosphine complex that, due to the donating ability
of P(t-Bu)3, readily undergoes oxidative addition.
For Suzuki reactions of aryl bromides, we observe behavior
similar to that of aryl chlorides. Thus, when the cross-coupling
of 1-bromo-4-ethylbenzene with phenylboronic acid is moni-
tored by 31P NMR (0.5% Pd2(dba)3/1.2% P(t-Bu)3, 3.3 equiv
of KF), Pd(P(t-Bu)3)2 is the only species that we detect. In a
Mechanistic Study of the Suzuki Cross-Coupling of Aryl
Chlorides and Aryl Bromides. An outline of the commonly
accepted mechanism for the Suzuki cross-coupling reaction is
illustrated in Figure 1.1 To gain some insight into the Pd2(dba)3/
P(t-Bu)3 catalyst system, we have pursued a series of NMR and
reactivity studies.
In our initial investigation, we focused on determining what
forms upon mixing P(t-Bu)3 with Pd2(dba)3. We found through
1
31P and H NMR studies that, for P(t-Bu)3:Pd ratios between
0.5 and 1.5:1, Pd(P(t-Bu)3)263 is the only identifiable phosphine-
(58) (a) Roush, W. R.; Moriarty, K. J.; Brown, B. B. Tetrahedron Lett.
1990, 31, 6509-6512. Roush, W. R.; Koyama, K.; Curtin, M. L.; Moriarty,
K. J. J. Am. Chem. Soc. 1996, 118, 7502-7512. (b) Baldwin, J. E.;
Chesworth, R.; Parker, J. S.; Russell, A. T. Tetrahedron Lett. 1995, 36,
9551-9554. (c) Johnson, C. R.; Johns, B. A. Tetrahedron Lett. 1997, 38,
7977-7980. Johns, B. A.; Pan, Y. T.; Elbein, A. D.; Johnson, C. R. J. Am.
Chem. Soc. 1997, 119, 4856-4865. (d) Koch, F.; Heitz, W. Macromol.
Chem. Phys. 1997, 198, 1531-1544. (e) Uenishi, J.; Kawahama, R.;
Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1998, 63, 8965-8975.
(59) Pd2(dba)3 and P(t-Bu)3 are less effective catalyst components.
(60) The vinyl triflate in entries 8 and 9 has proved to be a challenging
substrate in other cross-coupling processes. For example, see: Busacca, C.
A.; Eriksson, M. C.; Fiaschi, R. Tetrahedron Lett. 1999, 40, 3101-3104.
(61) (a) Unactivated vinyl triflates: Sasaki, M.; Fuwa, H.; Inoue, M.;
Tachibana, K. Tetrahedron Lett. 1998, 39, 9027-9030. Brosius, A. D.;
Overman, L. E.; Schwink, L. J. Am. Chem. Soc. 1999, 121, 700-709.
Reference 30g. (b) Activated vinyl triflates: Yasuda, N.; Xavier, L.; Rieger,
D. L.; Li, Y.; DeCamp, A. E.; Dolling, U.-H. Tetrahedron Lett. 1993, 34,
3211-3214. Fu, J.-m.; Chen, Y.; Catelhano, A. L. Synlett 1998, 1408-
1410.
(64) (a) In the 1H NMR spectrum, there is a small doublet at δ 1.27,
which we have not been able to identify. (b) Through 31P and 1H NMR
experiments, we have established that dba is not coordinated to Pd(P(t-
Bu)3)2.
(65) (a) For a closely related study, see: Paul, F.; Patt, J.; Hartwig, J. F.
Organometallics 1995, 14, 3030-3039. (b) The behavior of P(t-Bu)3 stands
in contrast to that of PPh3: Amatore, C.; Jutand, A.; Khalil, F.; M’Barki,
M. A.; Mottier, L. Organometallics 1993, 12, 3168-3178.
(66) A very small singlet at δ 90.7 is observed at the beginning of the
reaction, but it disappears as the reaction progresses.
(67) This is consistent with our observation that the cross-coupling of
aryl chlorides is very slow when a P(t-Bu)3:Pd ratio of 2:1 is employed.
(68) In the absence of P(t-Bu)3, Pd2(dba)3 is not an effective catalyst for
the cross-coupling of aryl chlorides.
(69) For those concerned about the oxygen sensitivity of P(t-Bu)3, the
0.5% Pd(P(t-Bu)3)2/0.25% Pd2(dba)3 catalyst system provides a practical
alternative to 0.5% Pd2(dba)3/1% P(t-Bu)3, since Pd(P(t-Bu)3)2 and Pd2-
(dba)3 are both air-stable solids. Also, P(t-Bu)3 is available as a solution in
a Sure-Seal bottle from Strem Chemicals.
(70) (a) For a related conclusion regarding a different catalyst for the
Suzuki cross-coupling of aryl chlorides, see ref 13b. (b) In contrast, for
Suzuki reactions with PPh3-based catalysts, a palladium bisphosphine adduct
is usually invoked (ref 1).
(71) For a study of palladium complexes that contain one P(t-Bu)3 ligand,
see: Krause, J.; Cestaric, G.; Haack, K.-J.; Seevogel, K.; Storm, W.;
Po¨rschke, K.-R. J. Am. Chem. Soc. 1999, 121, 9807-9823.
(62) Farina has shown that vinyl triflates oxidatively add to Pd(PPh3)4
more rapidly than do aryl triflates: Farina, V.; Krishnan, B.; Marshall, D.
R.; Roth, G. P. J. Org. Chem. 1993, 58, 5434-5444.
(63) (a) Otsuka, S.; Yoshida, T.; Matsumoto, M.; Nakatsu, K. J. Am.
Chem. Soc. 1976, 98, 5850-5858. (b) Yoshida, T.; Otsuka, S. J. Am. Chem.
Soc. 1977, 99, 2134-2140.

Versatile Catalysts for Suzuki Cross-Coupling
J. Am. Chem. Soc., Vol. 122, No. 17, 2000 4027
Table 10. Suzuki Cross-Couplings Using a Low Loading of
P(t-Bu)3
separate experiment, we have established that Pd(P(t-Bu)3)2 is
a relatively ineffective catalyst for the cross-coupling of aryl
bromides.72
Mechanistic Study of the Suzuki Cross-Coupling of Aryl
Iodides. For Pd2(dba)3/P(t-Bu)3-catalyzed Suzuki reactions of
aryl iodides, Pd(P(t-Bu)3)2 is not the resting-state palladium-
phosphine complex, in contrast to aryl chlorides and aryl
bromides. During the cross-coupling of 4-iodotoluene with
phenylboronic acid (0.5% Pd2(dba)3/1.2% P(t-Bu)3, 3.3 equiv
of KF), we observe two resonances by 31P NMR, one at δ 63.4
(free P(t-Bu)3) and one at δ 58.5;73 we have tentatively assigned
the resonance at δ 58.5 to an oxidative addition adduct.74 If
this assignment is correct, then it appears that, with this catalyst
system, the turnover-limiting step for the coupling of aryl iodides
occurs after oxidative addition.
a Standard conditions: 1.0 equiv of aryl chloride, 1.0-1.1 equiv of
boronic acid, 3.0-3.3 equiv of KF, THF. b Isolated yield.
Interestingly, as noted in the section on Suzuki reactions of
aryl iodides, we have found that cross-couplings of aryl
bromides catalyzed by Pd2(dba)3/P(t-Bu)3 proceed more rapidly
than do the corresponding reactions of aryl iodides. However,
when we conduct a competition experiment between 1-bromo-
4-ethylbenzene and 4-iodotoluene for phenylboronic acid (1
equiv of each of the three components) using 0.5% Pd2(dba)3/
1.2% P(t-Bu)3 as the catalyst, we find that essentially only the
aryl iodide is coupled. A possible explanation for these
observations is that aryl iodides undergo oxidative addition more
rapidly than do aryl bromides (and irreversibly), but that rate-
limiting transmetalation of the resulting Pd(P(t-Bu)3)(Ar)(I) is
less rapid than is transmetalation of Pd(P(t-Bu)3)(Ar)(Br).75
Mechanistic Study of the Role of KF. In Suzuki cross-
coupling reactions, it is generally believed that Lewis-base
additives facilitate the process by binding to the organoboron
reagent, forming a more reactive four-coordinate “ate” complex
that transfers the organic group to palladium (Figure 1).1 In the
Wright report that describes the usefulness of fluoride salts in
Suzuki reactions, it was suggested that treatment of arylboronic
acids with excess fluoride might produce [Ar-BF3]-, and that
this might be the species that transfers the aryl group to
palladium.21b
Suzuki Cross-Couplings with a Low Loading of P(t-Bu)3.
The mechanistic studies described above suggest that a pal-
ladium monophosphine complex is the active species in the Pd2-
(dba)3/P(t-Bu)3-catalyzed Suzuki cross-coupling of aryl chlorides
and aryl bromides. Unfortunately, during the course of the
reaction, nearly all of the palladium is in the form of Pd(P(t-
Bu)3)2 and phosphine-free palladium, rather than the catalytically
active monophosphine complex. One way to obtain a larger
proportion of this complex, relative to Pd(P(t-Bu)3)2, is to use
a lower ratio of phosphine to palladium.
We have found that use of a ratio of phosphine to palladium
lower than 1:1 can indeed lead to an active catalyst system
for Suzuki reactions of aryl chlorides (Table 10). Thus, in
the presence of 1.5% P(t-Bu)3/1.5% Pd2(dba)3 (w 1.5:3.0
P(t-Bu)3:Pd), 4-chlorophenyltriflate cross-couples with phenyl-
boronic acid in 24 h at room temperature (entry 1, Table 10;
97%). This result is comparable to that obtained under otherwise
identical conditions with twice the amount of P(t-Bu)3. We have
discovered that it is even possible to cleanly effect cross-
coupling with a 1:5 ratio of phosphine to palladium (entries 2
and 3, Table 10).78
It is important to note that low-phosphine conditions cannot
be applied universally: for example, less activated aryl chlorides
such as 4-chloroanisole couple in lower yield (entry 4, Table
10; 75%) than under the general reaction conditions (entry 1,
Table 2; 88%).79 On the basis of first-try dependability, we
therefore recommend use of the general protocol, although for
large-scale applications it may be worthwhile to explore low-
phosphine conditions.
However, when we treat 4-bromo-N,N-dimethyaniline with
K[o-tolyl-BF3]76 and Pd2(dba)3/P(t-Bu)3, we observe no biaryl
product after 12 h at room temperature (eq 7), a period of time
Conclusions
during which the cross-coupling of 4-bromo-N,N-dimethyaniline
and o-tolylboronic acid proceeds to completion in the presence
of 3.3 equiv of KF. It therefore seems unlikely in our catalyst
system that K[o-tolyl-BF3] is responsible for transferring the
aryl group to palladium.77
We have developed general and high-yielding methods for
accomplishing Suzuki coupling reactions of arylboronic acids
with aryl and vinyl halides (Pd2(dba)3/P(t-Bu)3) and triflates
(Pd(OAc)2/PCy3) (eqs 8 and 9). With these versatile catalyst
systems, electronically and sterically diverse reactants can be
efficiently cross-coupled, without the need for substrate-specific
optimization of reaction conditions. Noteworthy capabilities of
these catalysts include the following: cross-coupling of typically
unreactive aryl chlorides, including electron-rich aryl chlorides
such as 4-chloroaniline; room-temperature cross-coupling of aryl
bromides, iodides, and triflates; synthesis of hindered di- and
tri-ortho-substituted biaryls; for Pd2(dba)3/P(t-Bu)3, very high
(72) As with aryl chlorides (ref 69), Pd(P(t-Bu)3)2/Pd2(dba)3 is an
effective catalyst and may be used in place of Pd2(dba)3/P(t-Bu)3.
(73) We also detect the resonance at δ 58.5 when we treat 4-iodotoluene
with Pd2(dba)3 and P(t-Bu)3 in the absence of phenylboronic acid and KF.
(74) The resonance disappears at the end of the reaction, at which time
a resonance for Pd(P(t-Bu)3)2 appears at δ 85.6.
(75) For related conclusions regarding Suzuki reactions catalyzed by
PPh3-based palladium complexes, see: Smith, G. B.; Dezeny, G. C.; Hughes,
D. L.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1994, 59, 8151-8156.
(76) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M.
R. J. Org. Chem. 1995, 60, 3020-3027.
(77) KArBF3 has been shown to serve as an arylating agent in palladium-
catalyzed cross-couplings with arenediazonium salts: Darses, S.; Genet,
J.-P.; Brayer, J.-L.; Demoute, J.-P. Tetrahedron Lett. 1997, 38, 4393-4396.
Darses, S.; Michaud, G.; Genet, J.-P. Eur. J. Org. Chem. 1999, 1875-
1883.
(78) Hartwig has noted that an effective catalyst for palladium-catalyzed
C-O bond formation can be formed from a 1:2 mixture of phosphine and
palladium: Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J.
Am. Chem. Soc. 1999, 121, 3224-3225.
(79) Under low-phosphine conditions above room temperature, there
appears to be a greater tendency to form insoluble Pd(0).

4028 J. Am. Chem. Soc., Vol. 122, No. 17, 2000
Littke et al.
complex may be the active catalyst, and it is likely that the
steric bulk and the electron-richness of the phosphine are the
key to the activity of these systems. Ongoing studies are directed
at additional mechanistic investigations and at the development
of other applications of P(t-Bu)3 in palladium-catalyzed cross-
coupling processes.
Acknowledgment. Support has been provided by Bristol-
Myers Squibb, Merck, the National Science Foundation, the
Natural Sciences and Engineering Research Council of Canada
(predoctoral fellowship to A.F.L. and postdoctoral fellowship
to C.D.), Novartis, the Petroleum Research Fund, Pfizer,
Pharmacia & Upjohn, Procter & Gamble, and Union Carbide.
selectivity for the following order of reactivity, I > Br > Cl,
with chlorides being much more reactive than triflates; cross-
coupling at low catalyst loading (e.g., 9700 turnovers for the
reaction of an aryl chloride); cross-coupling of normally
unreactive vinyl chlorides; and room-temperature cross-coupling
of vinyl bromides, iodides, and triflates.
In terms of both scope and mildness of conditions, these
catalysts for the Suzuki reaction fare well when compared with
other catalysts that have been described, and in a number of
instances they display reactivity that has no precedent. Prelimi-
nary mechanistic work suggests that a palladium monophosphine
Supporting Information Available: Experimental proce-
dures and compound characterization data (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA0002058