A surprisingly mild and versatile method for palladium-catalyzed Suzuki cross-couplings of aryl chlorides in the presence of a triarylphosphine

Article abstract of DOI:10.1039/b107888g

In the presence of new air-stable triarylphosphine 2, palladium-catalyzed Suzuki reactions of a wide array of aryl chlorides can be accomplished in uniformly good yield, including couplings of very sterically demanding and electronically deactivated subst

Full text of DOI:10.1039/b107888g

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A surprisingly mild and versatile method for palladium-catalyzed
Suzuki cross-couplings of aryl chlorides in the presence of a
triarylphosphine†
Shih-Yuan Liu, Michael J. Choi and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 USA.
E-mail: gcf@mit.edu
Received (in Corvallis, OR, USA) 30th August 2001, Accepted 21st September 2001
First published as an Advance Article on the web 8th November 2001
In the presence of new air-stable triarylphosphine 2,
palladium-catalyzed Suzuki reactions of a wide array of aryl
chlorides can be accomplished in uniformly good yield,
including couplings of very sterically demanding and
electronically deactivated substrates; activated aryl chlo-
rides can be coupled at room temperature. In terms of scope
and mildness, Pd–2 compares well with other catalyst
systems that have been described for Suzuki reactions of aryl
chlorides, thereby establishing that triarylphosphines should
the unusual reactivity of 2, as demonstrated by the slow
be regarded as fertile ground for future ligand-design efforts
for palladium-catalyzed couplings of aryl chlorides.
coupling that we observe when we employ the corresponding
non-silylated ligand (3; entry 3). Entry 4 establishes that PPh3 is
not useful under these conditions.
The palladium-catalyzed cross-coupling of organic halides/
triflates with organoboron reagents [Suzuki reaction; e.g., eqn.
(1)] is a powerful and widely used method for carbon–carbon
New triarylphosphine 2, which is air- and moisture-stable
both in the solid state and in solution, serves as a remarkably
versatile ligand for Suzuki cross-couplings of aryl chlorides. As
shown in Table 2, a variety of chlorides, including hindered
(entries 2–5) and electronically deactivated (entry 6) ones, react
with a range of boronic acids in very good yield. The sterically
demanding coupling that is illustrated in entry 5, which
furnishes a tri-ortho-substituted biaryl in 93% yield, is espe-
cially worthy of note.11,12
We have determined that, in the presence of triarylphosphine
2, Suzuki cross-couplings of activated aryl chlorides can be
accomplished at rt. To date, only a few other ligands have
achieved this objective.13 For room-temperature couplings, use
of Pd(OAc)2 as the palladium source and an ~ 1+1 ratio of
Pd+ligand provide the highest reactivity among the conditions
that we have examined. With these conditions, we can effect
Suzuki cross-couplings of a range of activated aryl chlorides,
including heteroaryl (entry 2) and ortho-substituted (entry 3)
substrates, with arylboronic acids in excellent yield (Table 3).
In summary, we have prepared a new, air-stable triaryl-
phosphine (2), and we have established that it serves as an
(1)
bond formation.1 Until recently, aryl chlorides, an attractive
class of substrates due to their low cost and ready availability,2
were generally not suitable coupling partners in palladium-
catalyzed Suzuki reactions.3 However, during the past few years
this deficiency has been remedied through the use of ligands
such as electron-rich, sterically hindered phosphines4 and
carbenes.5,6
The low reactivity of aryl chlorides in palladium-catalyzed
coupling reactions is often ascribed to their reluctance to
oxidatively add to palladium, and the unusual effectiveness of
strongly electron-donating ligands in achieving Suzuki cross-
couplings of aryl chlorides is consistent with this hypothesis.
Thus, at the time that we initiated our studies, there were no
examples of Suzuki reactions of unactivated aryl chlorides by
palladium catalysts that bear triarylphosphines,7,8 which are
generally significantly less electron-rich than trialkylphos-
phines.
In this communication, we describe our discovery that a wide
array of palladium-catalyzed Suzuki reactions of aryl chlorides
can be achieved through the use of a new ferrocene-derived
triarylphosphine (2). In the presence of this air-stable, sterically
demanding ligand, we can effect the Suzuki cross-coupling of
activated aryl chlorides at rt, and we can accomplish reactions of
unactivated aryl chlorides, including sterically hindered and
electron-rich substrates, at 70 °C.
Table 1 Suzuki reaction of an unactivated aryl chloride: triarylphosphines
as ligands
Phosphine 1, previously reported by Price and Simpkins,9
serves as a moderately efficient ligand for the palladium-
catalyzed coupling of p-chlorotoluene with o-tolylboronic acid
(37% yield by GC after 24 h at 70 °C; Table 1, entry 1). An
increase in the steric demand of the bottom ring of the ligand
(Cp ? Cp*; 2) leads to a substantial increase in reactivity (entry
2 vs. entry 1).10 The TMS group is an important contributor to
Entry
Ligand
% Yield by GC after 24 ha
1
2
3
4
1
37
87
8
2
3
† Electronic supplementary information (ESI) available: experimental
procedures and compound characterization data. See http://www.rsc.org/
suppdata/cc/b1/b107888g/
PPh3
< 2
a Average of two runs.
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Chem. Commun., 2001, 2408–2409
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b107888g

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Table 2 Scope of the Suzuki reaction of unactivated aryl chlorides catalyzed
by Pd–triarylphosphine 2
including hindered, heteroaryl, and electronically deactivated
chlorides, react in uniformly good yield. The ability of this
system to achieve cross-couplings of activated aryl chlorides at
rt is particularly noteworthy. Because 2 is a triarylphosphine,
the high reactivity of Pd–2 (in terms of scope and mildness,
comparable to sterically demanding trialkylphosphines and
greater than carbene ligands) is unexpected. In view of the ease
with which the structure of 2 can be modified, we anticipate that
further enhancements in reactivity will be possible, as well as
the design of effective ligands for asymmetric catalysis.
Support has been provided by Bristol-Myers Squibb, Merck,
the National Institutes of Health (National Institute of General
Medical Sciences, R01-GM62871), Novartis, and Pfizer. We
thank Frontier Scientific for donating arylboronic acids.
Isolated
Entry
1
Aryl chloride
Arylboronic acid
yielda
90%
Notes and references
1 For reviews, see: N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95,
2457; A. Suzuki, J. Organomet. Chem., 1999, 576, 147; N. Miyaura, in
Advances in Metal-Organic Chemistry, ed. L. S. Liebeskind, JAI,
London, 1998, Vol. 6, pp. 187–243; A. Suzuki, in Metal-Catalyzed
Cross-Coupling Reactions, ed. F. Diederich, P. J. Stang, Wiley-VCH,
New York, 1998, Chapter 2.
2 For a general discussion, see: V. V. Grushin and H. Alper, Chem. Rev.,
1994, 94, 1047; R. Stürmer, Angew. Chem., Int. Ed., 1999, 38, 3307.
3 For an overview, see: A. F. Littke, C. Dai and G. C. Fu, J. Am. Chem.
Soc., 2000, 122, 4020.
4 For early work, see: (a) D. W. Old, J. P. Wolfe and S. L. Buchwald, J.
Am. Chem. Soc., 1998, 120, 9722; J. P. Wolfe, R. A. Singer, B. H. Yang
and S. L. Buchwald, J. Am. Chem. Soc., 1999, 121, 9550; (b) A. F.
Littke and G. C. Fu, Angew. Chem., Int. Ed., 1998, 37, 3387, ref. 3; (c)
X. Bei, H. W. Turner, W. H. Weinberg, A. S. Guram and J. L. Petersen,
J. Org. Chem., 1999, 64, 6797.
5 For early work, see: W. A. Herrmann, C.-P. Reisinger and M. Spiegler,
J. Organomet. Chem., 1998, 557, 93; T. Weskamp, V. P. W. Bohm and
W. A. Herrmann, J. Organomet. Chem., 1999, 585, 348; C. Zhang, J.
Huang, M. L. Trudell and S. P. Nolan, J. Org. Chem., 1999, 64,
3804.
2
3
4
86%
82%
95%
5
6
93%
88%
6 For other early work, see: F. Firooznia, C. Gude, K. Chan and Y. Satoh,
Tetrahedron Lett., 1998, 39, 3985. See also: G. Y. Li, Angew. Chem.,
Int. Ed., 2001, 40, 1513.
a Average of two runs.
7 For a single example of a Suzuki coupling of an activated aryl chloride
by a Pd–triarylphosphine catalyst, see: P. Kocovsky, S. Vyskocil, I.
Cisarova, J. Sejbal, I. Tislerova, M. Smrcina, G. C. Lloyd-Jones, S. C.
Stephen, C. P. Butts, M. Murray and V. Langer, J. Am. Chem. Soc.,
1999, 121, 7714.
Table 3 Suzuki reaction of activated aryl chlorides at room temperature
8 As our investigation was nearing completion, Richards described one
Suzuki coupling of an unactivated aryl chloride (p-chlorotoluene) and
one reaction of an activated aryl chloride (p-chloronitrobenzene) that
proceed in good yield by GC at 60 °C, using a Pd–tris(2-methylferroce-
nyl)phosphine catalyst: T. E. Pickett and C. J. Richards, Tetrahedron
Lett., 2001, 42, 3767. This catalyst furnishes modest yields in couplings
of deactivated and ortho-substituted aryl chlorides ( < 50% by GC).
9 D. Price and N. S. Simpkins, Tetrahedron Lett., 1995, 36, 6135.
10 For a related observation of a change in reactivity upon conversion of a
remote Cp group to a C5Ph5 group, see: Q. Shelby, N. Kataoka, G. Mann
and J. Hartwig, J. Am. Chem. Soc., 2000, 122, 10 718.
Isolated
Entry
1
Aryl chloride
Arylboronic acid
yielda
11 Suzuki cross-couplings that efficiently generate tri-ortho-substituted
biaryls are very uncommon, especially with aryl chlorides as substrates.
For a discussion, see ref. 3.
89%
12 This catalyst system is also very active for Suzuki reactions of aryl
bromides. For example, in the presence of 0.25% Pd2dba3–0.5% 2, the
cross-coupling of 2-bromo-m-xylene with o-tolylboronic acid proceeds
in 99% isolated yield after 24 h at rt. To the best of our knowledge, only
P(t-Bu)3 has been shown to effect a room-temperature Suzuki reaction
of an unactivated aryl bromide to generate a tri-ortho-substituted biaryl
(ref. 3).
13 Only Buchwald's aryldialkylphosphines are effective for room-tem-
perature couplings of unactivated aryl chlorides: ref. 4a. See also: ref. 4b
(six examples); D. Zim, A. L. Monteiro and J. Dupont, Tetrahedron
Lett., 2000, 41, 819 (two examples); P. Kocovsky, S. Vyskocil, I.
Cisarova, J. Sejbal, I. Tislerova, M. Smrcina, G. C. Lloyd-Jones, S. C.
Stephen, C. P. Butts, M. Murray and V. Langer, J. Am. Chem. Soc.,
1999, 121, 7714 (one example).
2
3
93%
95%
a Average of two runs.
effective ligand in palladium-catalyzed Suzuki couplings of aryl
chlorides. In the presence of Pd–2, a diverse array of substrates,
Chem. Commun., 2001, 2408–2409
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