Pd/P(t-Bu)3: A mild and general catalyst for stille reactions of aryl chlorides and aryl bromides

Article abstract of DOI:10.1021/ja020012f

Pd/P(t-Bu)₃ serves as an unusually reactive catalyst for Stille reactions of aryl chlorides and bromides, providing solutions to a number of long-standing challenges. An unprecedented array of aryl chlorides can be cross-coupled with a range of organotin reagents, including SnBu₄. Very hindered biaryls (e.g., tetra-ortho-substituted) can be synthesized, and aryl chlorides can be coupled in the presence of aryl triflates. The method is user-friendly, since a commercially available complex, Pd(P(t-Bu)₃)₂, is effective. Pd/P(t-Bu)₃ also functions as an active catalyst for Stille reactions of aryl bromides, furnishing the first general method for room-temperature cross-couplings.

Full text of DOI:10.1021/ja020012f

Published on Web 05/11/2002
Pd/P(t-Bu)3: A Mild and General Catalyst for Stille Reactions
of Aryl Chlorides and Aryl Bromides
Adam F. Littke, Lothar Schwarz, and Gregory C. Fu*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
Received January 2, 2002
Abstract: Pd/P(t-Bu)3 serves as an unusually reactive catalyst for Stille reactions of aryl chlorides and
bromides, providing solutions to a number of long-standing challenges. An unprecedented array of aryl
chlorides can be cross-coupled with a range of organotin reagents, including SnBu4. Very hindered biaryls
(e.g., tetra-ortho-substituted) can be synthesized, and aryl chlorides can be coupled in the presence of
aryl triflates. The method is user-friendly, since a commercially available complex, Pd(P(t-Bu)3)2, is effective.
Pd/P(t-Bu)3 also functions as an active catalyst for Stille reactions of aryl bromides, furnishing the first
general method for room-temperature cross-couplings.
Introduction
available compounds, aryl chlorides are generally more desirable
substrates than are bromides or iodides.7 However, aryl chlorides
have proved to be reluctant coupling partners, perhaps due in
part to the strength of the C-Cl bond.8,9
In recent years, tremendous progress has been reported in
the development of powerful new methods for carbon-carbon
bond formation. Cross-coupling reactions, particularly pal-
ladium-catalyzed processes, have been an important component
of this progress.1
Stille cross-couplings2,3 have proved to be an especially
popular tool for synthetic organic chemists, due in part to the
air and moisture stability of organotin reagents, as well as the
excellent functional group compatibility of the process.4 Nev-
ertheless, significant room for improvement remains. For
example, increasing the scope of the reaction and developing
more versatile catalysts that operate under milder conditions
would represent important advances.
The development of more versatile catalysts represents a
second potential opportunity for enhancing the utility of the
Stille reaction. Regarding existing catalysts, Mitchell has noted
in a recent review: “A look at the catalyst (or to be exact,
precatalyst) and cocatalyst combinations, together with solvent
variations, which have been used in the papers cited above will
make it clear that there is in fact no ‘ideal’ system, but that
each reaction will basically require optimization. If readers are
slightly bewildered by this plethora of possibilities, they are
not alone: the author of these lines is, too!”10,11 The general
need for an elevated reaction temperature, which is undesirable
from the standpoints of substrate stability and functional group
compatibility, is another drawback of previously reported
catalysts for Stille cross-couplings.
With regard to scope, one of the most apparent limitations
in the palladium-catalyzed Stille reaction has been the inability
to couple unactivated aryl chlorides.5,6 From a practical view-
point, because of their lower cost and the wider diversity of
During the past few years, we have been exploring the
application of electron-rich, sterically demanding P(t-Bu)3 in a
variety of palladium-catalyzed processes, including Suzuki,12
* Corresponding author. E-mail: gcf@mit.edu.
(1) (a) Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J.,
Eds.; Wiley-VCH: New York, 1998. (b) Tsuji, J. Palladium Reagents and
Catalysts, InnoVations in Organic Synthesis; Wiley: New York, 1995.
(2) (a) Kosugi, M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Chem. Lett. 1977,
301-302. (b) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636-
3638.
(6) Shirakawa and Hiyama have described a nickel catalyst that cross-couples
aryl chlorides with organotin compounds. The yields for electron-rich aryl
chlorides are moderate (up to 66%). Shirakawa, E.; Yamasaki, K.; Hiyama,
T. J. Chem. Soc., Perkin Trans. 1 1997, 2449-2450. Shirakawa, E.;
Yamasaki, K.; Hiyama, T. Synthesis 1998, 1544-1549.
(7) (a) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047-1062. (b) Grushin,
V. V.; Alper, H. In ActiVation of UnreactiVe Bonds and Organic Synthesis;
Murai, S., Ed.; Springer-Verlag: Berlin, Germany, 1999; pp 193-226.
(8) Bond dissociation energies for Ph-X: Cl (96 kcal/mol); Br (81 kcal/mol);
I (65 kcal/mol). See ref 7a.
(9) For overviews on coupling reactions of aryl chlorides, see: (a) Stu¨rmer,
R. Angew. Chem., Int. Ed. 1999, 38, 3307-3308. (b) Reference 7.
(10) Mitchell, T. N. Metal-catalyzed Cross-coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: New York, 1998; p 178. Farina and Roth
have observed: “...the Stille reaction has been carried out in a variety of
solvents using many different catalytic systems, and no general consensus
has emerged from the literature as to the rationale for selecting a particular
set of conditions...” [Farina, V.; Roth, G. P. In AdVances in Metal-Organic
Chemistry; Liebeskind, L. S., Ed.; JAI: London, UK, 1996; Vol. 5, p 45].
(11) For applications of the Stille reaction in automated parallel synthesis, the
need for a truly versatile catalyst system is particularly acute.
(3) For reviews of the Stille reaction, see: (a) Farina, V.; Krishnamurthy, V.;
Scott, W. J. Org. React. 1997, 50, 1-652. (b) Mitchell, T. N. In Metal-
catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-
VCH: New York, 1998; Chapter 4.
(4) (a) For a discussion of applications of the Stille reaction in natural products
synthesis (e.g., lepicidin aglycon and rapamycin), see: Nicolaou, K. C.;
Sorensen, E. J. Classics in Total Synthesis; VCH: New York, 1996; Chapter
31. (b) For some very recent examples, see: Williams, D. R.; Meyer, K.
G. J. Am. Chem. Soc. 2001, 123, 765-766. White, J. D.; Carter, R. G.;
Sundermann, K. F.; Wartmann, M. J. Am. Chem. Soc. 2001, 123, 5407-
5413. Liras, S.; Lynch, C. L.; Fryer, A. M.; Vu, B. T.; Martin, S. F. J. Am.
Chem. Soc. 2001, 123, 5918-5924. Hannessian, S.; Ma, J.; Wang, W. J.
Am. Chem. Soc. 2001, 123, 10200-10206. Smith, A. B., III; Minbiole, K.
P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942-
10953.
(5) Only activated aryl chlorides have proved to be suitable substrates. See:
(a) Reference 3a, pp 12-16. (b) Reference 3b. (c) Li, J. J.; Gribble, G. W.
Palladium in Heterocyclic Chemistry; Pergamon: New York, 2000.
9
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J. AM. CHEM. SOC. 2002, 124, 6343-6348
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A R T I C L E S
Littke et al.
Heck,13 Negishi,14 and Sonogashira15 couplings.16,17 In this
report, we demonstrate that Pd/P(t-Bu)3 also serves as a versatile
catalyst for Stille reactions, providing the first general method
for couplings of aryl chlorides (eq 1) and for room-temperature
couplings of aryl bromides (eq 2).18
Figure 1. Outline of the catalytic cycle for the Stille cross-coupling reaction.
Table 1. Effect of Additives on the Rate of Pd/P(t-Bu)3-Catalyzed
Stille Cross-Coupling of 4-Chlorotoluene with Vinyltributyltin
Results and Discussion
entry
additive (1.1 equiv)
% yield after 8 h (GC)a
Aryl and Vinyl Chlorides. To the best of our knowledge,
at the time that we began our investigation, there were no
examples of palladium-catalyzed Stille reactions in which an
unactivated aryl chloride served as a coupling partner.5,19 Based
on our earlier success in accomplishing Suzuki and Heck
reactions of a wide array of aryl chlorides using Pd2(dba)3/P(t-
Bu)3 as a catalyst,12a,13a in initial studies we attempted to apply
this system to the cross-coupling of 4-chlorotoluene and
vinyltributyltin; unfortunately, we obtained only a small amount
of 4-vinyltoluene after 8 h at 100 °C (eq 3).
1
2
3
4
5
6
7
8
none
NEt3
Cs2CO3
NaOH
TBAF‚3H2O
KF
CsF
CsF (2.2 equiv)
12
16
40
42
24
28
50
59
a Average of two runs.
possibility that enhancing the reactivity of the organotin reagent
would facilitate the Stille cross-coupling process.
The use of nucleophiles to increase the reactivity of organotin
species, via hypercoordinate intermediates, is a well-established
strategy in organic chemistry.21 In fact, nucleophilic activation
of organotin reagents has been exploited by others in palladium-
catalyzed Stille cross-couplings. For example, Martinez has
reported that tetrabutylammonium difluorotriphenylstannate is
a very reactive phenylating agent for couplings of vinyl
triflates,22 and several groups have demonstrated that organotin
reagents can be activated through intramolecular coordination
by a Lewis base (e.g., an amine).23
In view of the capacity of Pd2(dba)3/P(t-Bu)3 to catalyze
Suzuki and Heck reactions of aryl chlorides, we hypothesized
that oxidative addition is probably occurring at an acceptable
rate under these conditions (eq 3) and that a sluggish subsequent
step, perhaps transmetalation,20 might be impeding effective
catalysis (Figure 1). We therefore decided to explore the
We therefore surveyed an array of potential activators of the
organotin species (Table 1). Although NEt3 furnishes only a
small rate enhancement (entry 1 vs entry 2), Cs2CO3 and
NaOH24,25 provide significant acceleration (entries 3 and 4). In
view of the well-established fluorophilicity of tin, we felt that
fluoride additives might serve as particularly effective activa-
tors.22,26,27 We discovered that fluoride sources can indeed
facilitate Stille cross-couplings, with CsF being the most efficient
(12) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 1998, 37, 3387-
3388. (b) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020-4028.
(13) (a) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10-11. (b) Littke, A.
F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989-7000.
(14) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719-2724.
(15) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000,
2, 1729-1731.
(16) For pioneering studies by Koie of Pd/P(t-Bu)3-catalyzed reactions, see:
Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617-
620. (b) Yamamoto, T.; Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1998,
39, 2367-2370. (c) Watanabe, M.; Nishiyama, M.; Koie, Y. Tetrahedron
Lett. 1999, 40, 8837-8840.
(17) For early studies by others of Pd/P(t-Bu)3-catalyzed reactions, see: (a)
Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-
Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580. (b) Mann, G.; Incarvito,
C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 3224-
3225. (c) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121,
1473-1478. (d) Kim, J. S.; Sen, A. J. Mol. Catal. A 1999, 143, 197-201.
(18) Part of our work on Stille reactions of aryl chlorides has been the subject
of a preliminary communication: Littke, A. F.; Fu, G. C. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 2411-2413.
(21) Chemistry of Tin; Smith, P. J., Ed.; Blackie: New York, 1998.
(22) Martinez, A. G.; Barcina, J. O.; Cerezo, A. de F.; Subramanian, L. R. Synlett
1994, 1047-1048. See also: Fouquet, E.; Pereyre, M.; Rodriguez, A. L.
J. Org. Chem. 1997, 62, 5242-5243. Fouquet, E.; Rodriguez, A. L. Synlett
1998, 1323-1324.
(23) For early examples, see: (a) Vedejs, E.; Haight, A. R.; Moss, W. O. J.
Am. Chem. Soc. 1992, 114, 6556-6558. (b) Brown, J. M.; Pearson, M.;
Jastrzebski, J. T. B. H.; van Koten, G. J. Chem. Soc., Chem. Commun.
1992, 1440-1441. (c) Farina, V. Pure Appl. Chem. 1996, 68, 73-78. (d)
Fouquet, E.; Pereyre, M.; Rodriguez, A. L. J. Org. Chem. 1997, 62, 5242-
5243.
(24) For Stille cross-couplings of aryl bromides and aryl iodides in the presence
of hydroxide, see: Roshchin, A. I.; Bumagin, N. A.; Beletskaya, I. P.
Tetrahedron Lett. 1995, 36, 125-128.
(25) For Hiyama cross-couplings in the presence of hydroxide, see: Hagiwara,
E.; Gouda, K.-i.; Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1997, 38,
439-442. See also: Mateo, C.; Fernandez-Rivas, C.; Cardenas, D. J.;
Echavarren, A. M. Organometallics 1998, 117, 3661-3669.
(19) After our initial report (ref 18), Nolan described a Pd(OAc)2/imidazolium
salt/TBAF system that effects Stille reactions of unactivated aryl chlorides
in modest yield (15-64%): Grasa, G. A.; Nolan, S. P. Org. Lett. 2001, 3,
119-122.
(20) For mechanistic studies of the Stille reaction, as well as leading references,
see: (a) Reference 3. (b) Casado, A. L.; Espinet, P.; Gallego, A. M.;
Martinez-Ilarduya, J. M. Chem. Commun. 2001, 339-340. (c) Cotter, W.
D.; Barbour, L.; McNamara, K. L.; Hechter, R.; Lachicotte, R. J. J. Am.
Chem. Soc. 1998, 120, 11016-11017.
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Pd/P(t-Bu)3 as a Catalyst for Stille Reactions
A R T I C L E S
Table 4. Stille Cross-Couplings of Aryl Chlorides Catalyzed by
Table 2. Pd/P(t-Bu)3-Catalyzed Stille Cross-Couplings of an Array
of Aryl Chlorides with a Vinyltin Reagent
Pd(P(t-Bu)3)2
entry
aryl chloride
yield (%)a
1
2
3
4
5
4-acetyl
4-n-Bu
4-OMe
4-NH2
87b
80
82 (90)
61
71 (84)
2,5-Me2
a All yields are isolated yields (average of two runs). Values in
parentheses are yields measured by GC for reaction products that are volatile.
b Reaction temperature: 80 °C.
Table 3. Pd/P(t-Bu)3-Catalyzed Stille Cross-Couplings of an Array
of Organotin Reagents with a Deactivated Aryl Chloride
a All yields are isolated yields (average of two runs). b Reaction run at
60 °C.
excellent yield (entries 1-3). Interestingly, Pd/P(t-Bu)3 even
effects transfer of simple alkyl groups, which are typically rather
reluctant participants in Stille reactions (entry 4).29,30
a All yields are isolated yields (average of two runs).
Although the reactivity and the versatility of Pd2(dba)3/P(t-
Bu)3 in palladium-catalyzed coupling processes compare very
favorably to catalysts based on other ligands, the air sensitivity
of P(t-Bu)3 is a drawback. To address this issue, we have
demonstrated that, for Negishi and Heck couplings of aryl
chlorides, use of Pd(P(t-Bu)3)2, a more air-stable, crystalline
complex,31 circumvents the need to handle P(t-Bu)3 itself.13b,14
Now that Pd(P(t-Bu)3)2 is commercially available,32 the at-
tractiveness of this approach is even greater.
Clearly, extending this strategy to Pd/P(t-Bu)3-catalyzed Stille
couplings of aryl chlorides would enhance the utility of our
method. We have recently established that Pd(P(t-Bu)3)2 can
indeed be employed as a catalyst for such reactions. In this
investigation, we focused our attention on couplings that are
particularly challenging, and we were pleased to observe that
this easy-to-handle catalyst is remarkably effective (Table 4).
Because the efficiency of other catalysts for Stille reactions
is very sensitive to steric effects,33 we were interested in
determining whether Pd(P(t-Bu)3)2 might prove to be useful for
among those that we have examined (entries 5-7). An increase
in the quantity of CsF produces a further enhancement in the
reaction rate (1.1f2.2 equiv; entry 7 vs entry 8).
Under this set of conditions, vinyltributyltin can be cross-
coupled with a broad spectrum of aryl chlorides (Table 2).28
Thus, electron-poor 4′-chloroacetophenone and electron-neutral
4-(n-butyl)chlorobenzene furnish the desired styrene derivatives
in good yield (entries 1 and 2). Even deactivated, very electron-
rich aryl chlorides can be cross-coupled (entries 3 and 4),
although the reaction of p-chloroaniline proceeds in more
moderate yield. Hindered aryl chlorides also undergo Stille
coupling under these conditions (entry 5).
This catalyst system is versatile with respect to not only the
aryl chloride but also the organotin reagent (Table 3). With the
same experimental procedure, phenyl-, 1-ethoxyvinyl-, and
allyltributyltin cross-couple with deactivated p-chloroanisole in
(26) For early examples of the use of fluoride to accelerate other (non-Stille)
cross-coupling reactions, see: (a) Electron-poor aryl chlorides with
organosilicon compounds: Gouda, K.-i.; Hagiwara, E.; Hatanaka, Y.;
Hiyama, T. J. Org. Chem. 1996, 61, 7232-7233. (b) Aryl bromides and
triflates with organoboron compounds: Wright, S. W.; Hageman, D. L.;
McClure, L. D. J. Org. Chem. 1994, 59, 6095-6097.
(29) For the Stille cross-couplings of the other organotin reagents illustrated in
Table 3, essentially no butyl transfer is observed (<2%).
(30) From a practical point of view, it is worth noting that many Stille reactions
are plagued by difficulties in separating the desired product from the
organotin residue (ref 3a). This is not an issue under our conditions,
presumably due to efficient in situ generation of insoluble Bu3SnF.
(31) (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. (c) Yoshida, T.; Otsuka, S. Inorg. Synth. 1990, 28,
113-119. This report states that Pd(P(t-Bu)3)2 is “stable in air in the solid
state”. Although we have encountered no difficulties handling Pd(P(t-Bu)3)2
in air, we recommend that it be stored under nitrogen.
(27) It is worth noting that Kosugi has reported that Pd(dba)2/PPh3/TBAF does
not effect Stille couplings of aryl chlorides. Fugami, K.; Ohnuma, S.-y.;
Kameyama, M.; Saotome, T.; Kosugi, M. Synlett 1999, 63-64.
(28) Notes: (a) These cross-coupling reactions do not appear to be highly air
or moisture sensitive. For example, they can be conducted in reagent-grade
dioxane that has simply been sparged with argon. (b) In the absence of
Pd2(dba)3 or of P(t-Bu)3, no reaction (<2% conversion) is observed. (c)
Cross-coupling is also observed, albeit more slowly, when PCy3 is used
instead of P(t-Bu)3. (d) Stille reactions in THF proceed with comparable
efficiency as in dioxane; couplings in toluene are somewhat slower. (e)
Pd2(dba)3 provides better results than Pd(OAc)2. (f) The reactions proceed
to completion with only 1.1 equiv of CsF and with only 3.6% P(t-Bu)3,
but more slowly than under the conditions described in Table 2.
(32) Strem Chemicals (Newburyport, MA), catalog no. 46-0252.
(33) For example, see: (a) Saa, J. M.; Martorell, G.; Garcia-Raso, A. J. Org.
Chem. 1992, 57, 678-685. (b) Farina, V.; Krishnan, B.; Marshall, D. R.;
Roth, G. P. J. Org. Chem. 1993, 58, 5434-5444. (c) Hoye, T. R.; Chen,
M. J. Org. Chem. 1996, 61, 7940-7942. (d) Anderson, J. C.; Namli, H.;
Roberts, C. A. Tetrahedron 1997, 53, 15123-15134.
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A R T I C L E S
Littke et al.
the synthesis of highly hindered biaryls. Gratifyingly, we
discovered that sterically demanding 2-chloro-m-xylene couples
with phenyltributyltin and even o-tolyltributyltin to furnish di-
and tri-ortho-substituted biaryls in excellent yield (Table 4,
entries 1 and 2).
Equation 5 illustrates that Pd/P(t-Bu)3 activates the C-Cl bond
of 4-chlorophenyl triflate, in preference to the C-OTf bond,
with excellent selectivity.40,41
Most remarkable is the nearly quantitative synthesis of a tetra-
ortho-substituted biaryl from two di-ortho-substituted precursors
(entry 3). The generation of tetra-ortho-substituted biaryls,
particularly unsymmetrical ones, is a challenging task, and there
are few examples of successful syntheses of this class of
compounds via cross-coupling.34,35 To the best of our knowl-
edge, the process illustrated in entry 3 represents the first
effective synthesis of a tetra-ortho-substituted biaryl through a
Stille reaction;36 typically, products arising from butyl transfer
or from homocoupling of the halide or the organotin reagent
are observed.
Cross-couplings that involve heteroaromatic substrates are an
important family of processes, providing compounds of high
value.5c We have determined that Pd(P(t-Bu)3)2 catalyzes the
coupling of 3-chloropyridine with phenyltributyltin to furnish
the desired biaryl in good yield (entry 4). However, Stille
reactions of heterocycles are not uniformly efficient: as
illustrated in entry 5, a moderate yield of product is obtained
in the cross-coupling of a 2-stannylpyridine.37
To establish the generality of this unprecedented selectivity
in a Stille cross-coupling for a chloride over a triflate, we
performed the intermolecular competition experiment depicted
in eq 6. When we allow 4-n-butylchlorobenzene and 4-methyl-
phenyl triflate to compete for phenyltributyltin, we obtain almost
exclusively the product that arises from coupling of the aryl
chloride (85% yield) and only a trace of the biaryl that originates
from reaction of the triflate (2% yield).
As far as we are aware, there have been no reports of Stille
cross-couplings of aryl chlorides that proceed at room temper-
ature.38 We have discovered that, for activated aryl chlorides,
Pd/P(t-Bu)3 can serve as an effective catalyst for this process.
For example, 4′-chloroacetophenone undergoes coupling with
1-ethoxyvinyltributyltin at room temperature (eq 4).39
Because our goal has been to provide a general procedure
that will couple even very challenging substrate pairs, until this
point we have employed a standard palladium loading of 3%
in the Stille cross-couplings of aryl chlorides that we have
described (Tables 2-4). Particularly for pharmaceutical/
industrial applications, it is desirable to be able to employ low
catalyst loadings. For most reactions, this should be straight-
forward. For example, in the case of the Stille cross-coupling
that is illustrated in eq 7, the catalyst loading can simply be
decreased to 0.1% Pd(P(t-Bu)3)2, without otherwise modifying
the reaction conditions, and the desired biaryl can still be isolated
in 92% yield. The turnover number of 920 for this process is
the highest that has been observed for a Stille coupling of an
aryl chloride.
For non-P(t-Bu)3-based palladium catalysts, triflates are much
more reactive cross-coupling substrates than are chlorides.1
(34) For examples of difficulties in synthesizing tetra-ortho-substituted biaryls
via cross-coupling methodology, see: (a) Watanabe, T.; Miyaura, N.;
Suzuki, A. Synlett 1992, 207-210. (b) Johnson, M. G.; Foglesong, R. J.
Tetrahedron Lett. 1997, 38, 7001-7002. (c) Yamada, I.; Yamazaki, N.;
Yamaguchi, M.; Yamagishi, T. J. Mol. Catal. A 1997, 120, L13-L15. (d)
Huang, J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889-9890. (e) Bohm,
V. P. W.; Weskamp, T.; Gsto¨ttmayr, C. W. K.; Herrmann, W. A. Angew.
Chem., Int. Ed. 2000, 39, 1602-1604. (f) Chaumeil, H.; Signorella, S.; Le
Drian, C. Tetrahedron 2000, 56, 9655-9662. (g) Feuerstein, M.; Doucet,
H.; Santelli, M. Tetrahedron Lett. 2001, 42, 6667-6670.
(35) For examples of successful syntheses of tetra-ortho-substituted biaryls via
cross-coupling, see: (a) Suzuki: Cammidge, A. N.; Crepy, K. V. L. Chem.
Commun. 2000, 1723-1724. (b) Negishi: Reference 14. (c) Yin, J.; Rainka,
M. P.; Zhang, X.-X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1162-
1163.
(36) Saa has reported the synthesis of tetra-ortho-substituted biaryls from aryl
triflates and aryltin reagents in very modest yield (<26%): Saa, J. M.;
Martorell, G. J. Org. Chem. 1993, 58, 1963-1966.
(37) Side reactions, such as hydrodehalogenation and homocoupling of the aryl
chloride, are also observed.
Not only aryl halides but also vinyl halides are an important
family of substrates for cross-coupling reactions. As far as we
are aware, there are no examples of Stille couplings of
unactivated vinyl chlorides.42 We have established that Pd/P(t-
Bu)3 serves as an effective catalyst for this process (eq 8). For
palladium-catalyzed couplings that employ ligands other than
P(t-Bu)3, vinyl halides are generally more reactive than aryl
halides. However, as we have previously observed for Pd/P(t-
Bu)3-catalyzed Suzuki12b and Heck13b reactions, for Pd/P(t-Bu)3-
(38) For an example of a coupling of a Cr(CO)3-complexed aryl chloride, see:
Prim, D.; Tranchier, J.-P.; Rose-Munch, F.; Rose, E.; Vaissermann, J. Eur.
J. Inorg. Chem. 2000, 901-905.
(39) Notes: (a) As with other processes catalyzed by Pd/P(t-Bu)3 that are
conducted at room temperature (refs 12b and 13b), use of a Pd:phosphine
ratio of 1:1, rather than 1:2, leads to a faster reaction. (b) Use of 0.75%
Pd2(dba)3/1.5% Pd(P(t-Bu)3)2 (same amounts of Pd and P(t-Bu)3 as in eq
4; both Pd2(dba)3 and Pd(P(t-Bu)3)2 are easy-to-handle solids) provides a
similar result. (c) Pd/P(t-Bu)3 can also catalyze room-temperature Stille
reactions of electron-neutral aryl chlorides, but the processes are very slow;
for example, after 14 days, 4-chlorotoluene cross-couples with phenyl-
tributyltin to furnish 4-methylbiphenyl in 78% isolated yield (0.75%
Pd2(dba)3/1.5% Pd(P(t-Bu)3)2).
(40) For analogous results with Pd/P(t-Bu)3-catalyzed Suzuki reactions, see
Reference 12b.
(41) Use of 0.75% Pd2(dba)3/1.5% Pd(P(t-Bu)3)2 furnishes a convenient alterna-
tive to 1.5% Pd2(dba)3/3.0% P(t-Bu)3, since Pd2(dba)3 and Pd(P(t-Bu)3)2
are easy-to-handle solids.
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Pd/P(t-Bu)3 as a Catalyst for Stille Reactions
A R T I C L E S
Table 5. Room-Temperature Stille Cross-Couplings of an Array of
Aryl Bromides with a Vinyltin Reagent
Table 6. Room-Temperature Stille Cross-Couplings of an Array of
Aryl Bromides with an Alkynyltin Reagent
a All yields are isolated yields (average of two runs).
Table 7. Room-Temperature Stille Cross-Couplings of Aryl
Bromides
a All yields are isolated yields (average of two runs). b Solvent: Et2O.
catalyzed Stille processes, aryl chlorides couple in preference
to vinyl chlorides (eq 9).
a All yields are isolated yields (average of two runs). b Solvent: Et2O.
noted in the Introduction, previously reported catalyst systems
are not entirely general, and they require elevated temperatures.43
We have determined that Pd/P(t-Bu)3 effects the room-
temperature cross-coupling of a wide variety of aryl bromides
with a broad range of organotin reagents. As illustrated in Table
5, in the presence of 1% Pd, Stille couplings of vinyltin reagents
proceed in very good yield.44 Activated (entry 1), electron-
Aryl Bromides. Although the palladium-catalyzed Stille
reaction of aryl bromides is a well-established process,3 there
nevertheless remains room for improvement. For example, as
(42) For some examples of Stille couplings of activated vinyl chlorides, see:
(a) Peet, W. G.; Tam, W. J. Chem. Soc., Chem. Commun. 1983, 853-854.
(b) Kobayashi, Y.; Kato, N.; Shimazaki, T.; Sato, F. Tetrahedron Lett. 1988,
29, 6297-6300. (c) Liebeskind, L. S.; Wang, J. Tetrahedron Lett. 1990,
31, 4293-4296. (d) Rubin, Y.; Knobler, C. B.; Diederich, F. J. Am. Chem.
Soc. 1990, 112, 1607-1617. (e) Farina, V.; Hauck, S. I. J. Org. Chem.
1991, 56, 4317-4319. (f) Liebeskind, L. S.; Yu, M. S.; Yu, R. H.; Wang,
J.; Hagen, K. S. J. Am. Chem. Soc. 1993, 115, 9048-9055. (g) May, P.
D.; Larsen, S. D. Synlett 1997, 895-896.
(43) For examples of room-temperature Stille reactions of activated aryl
bromides, see: (a) Bumagin, N. A.; Gulevich, Yu. V.; Beletskaya, I. P.
Bull. Acad. Sci. USSR., DiV. Chem. Sci. 1984, 1044-1049. (b) Barchin,
B. M.; Valenciano, J.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J. J.
Org. Lett. 1999, 1, 545-547.
(44) Stille reactions in Et2O proceed with comparable efficiency as in toluene;
couplings in dioxane are somewhat slower.
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J. AM. CHEM. SOC. VOL. 124, NO. 22, 2002 6347

A R T I C L E S
Littke et al.
neutral (entry 2), and deactivated (entries 3 and 4) aryl bromides
react cleanly under these conditions. Ortho substituents are well-
tolerated (entries 5-7), even for a very electron-rich aryl
bromide (entry 8), although with an extremely challenging di-
ortho-substituted aryl bromide, a somewhat lower yield is
obtained (entry 9).
Under the same conditions, Pd/P(t-Bu)3 also catalyzes room-
temperature cross-couplings of aryl bromides with alkynyltin
reagents (Table 6). Thus, reactions of activated (entry 1), ortho-
substituted (entry 2), ortho-substituted and deactivated (entry
3), and di-ortho-substituted (entry 4) bromides furnish aryl-
acetylenes in excellent yield.
For certain organotin reagents, Pd/P(t-Bu)3-catalyzed Stille
cross-couplings under the conditions described in Tables 5 and
6 are not efficient. For these substrates, a fluoride-activation
strategy has proved to be effective (CsF; Table 7). Thus,
1-ethoxyvinyl-, phenyl-, 2-thienyl-, and allyltributyltin couple
with bulky 2-bromotoluene (entries 1-4), as well as hindered
and deactivated 1-bromo-2,4-dimethoxybenzene (entries 5-8),
in very good yield at room temperature.
examples to date of effective Stille couplings of unactivated
aryl and vinyl chlorides. We have demonstrated the transfer of
a wide array of groups (including alkyl) from the organotin
reagent, the synthesis of very hindered biaryls (e.g., tetra-ortho-
substituted), the unprecedented reaction of an aryl chloride in
preference to an aryl triflate, and coupling with a low catalyst
loading. The method is user-friendly, since a commercially
available complex, Pd(P(t-Bu)3)2, can serve as the catalyst.
(b) The development of a general method for Stille
reactions of aryl bromides at room temperature. We have
reported very versatile procedures for cross-coupling a broad
spectrum of aryl bromides with a diverse range of organotin
reagents, all at room temperature. These are the first examples
of room-temperature Stille couplings of unactivated aryl bro-
mides.
Thus, relative to previously reported catalysts for Stille cross-
coupling reactions, Pd/P(t-Bu)3 exhibits unique reactivity. We
anticipate that this catalyst system will find use in an extensive
array of applications.45
Acknowledgment. Support has been provided by the Alex-
ander von Humboldt-Stiftung (postdoctoral fellowship to L.S.),
Boehringer-Ingelheim, Bristol-Myers Squibb, the National
Institutes of Health (National Institute of General Medical
Sciences, R01-GM62871), the Natural Sciences and Engineering
Research Council of Canada (predoctoral fellowship to A.F.L.),
Novartis, and Pharmacia. We thank Michael J. Smith for the
preparation of o-tolyltributylstannane. Funding for the MIT
Department of Chemistry Instrumentation Facility has been
provided in part by NSF CHE-9808061 and NSF DBI-9729592.
Finally, we have briefly examined the applicability of Pd/
P(t-Bu)3 to the Stille cross-coupling of vinyl bromides. Equation
10 illustrates that this catalyst system can couple even very
sterically demanding substrates in good yield at room temper-
ature.
Supporting Information Available: Experimental procedures
and compound characterization data (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Conclusions
We have established that Pd/P(t-Bu)3 serves as an unusually
versatile catalyst for Stille reactions of aryl chlorides and
bromides, providing solutions to a number of long-standing
challenges. Noteworthy aspects of this study include the
following:
JA020012F
(45) Since our original report (ref 18), several groups have already described
applications of our method for Stille cross-coupling: (a) Kraxner, J.; Arlt,
M.; Gmeiner, P. Synlett 2000, 125-127. (b) Zhu, J.; Price, B. A.; Zhao, S.
X.; Skonezny, P. M. Tetrahedron Lett. 2000, 41, 4011-4014. (c) Zhang,
N.; Thomas, L.; Wu, B. J. Org. Chem. 2001, 66, 1500-1502. (d) Pereira,
R.; Iglesias, B.; de Lera, A. R. Tetrahedron 2001, 57, 7871-7881.
(a) The development of a general method for Stille
reactions of aryl chlorides. We have described the only
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6348 J. AM. CHEM. SOC. VOL. 124, NO. 22, 2002