The Suzuki coupling of aryl chlorides under microwave heating

Article abstract of DOI:10.1002/adsc.200404144

Simple, inexpensive catalysts formed in situ from tricyclohexylphosphine and palladium acetate or a phosphite-based palladacycle show unprecedented activity in the Suzuki coupling of deactivated, non-activated and activated aryl chloride substrates under microwave heating.

Full text of DOI:10.1002/adsc.200404144

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The Suzuki Coupling of Aryl Chlorides under Microwave
Heating
Robin B. Bedford,a,* Craig P. Buttsa,* Timothy E. Hurst,a Pelle Lidstrçmb
a
Department of Chemistry, University of Exeter, Exeter EX4 4QD, UK
Fax: (þ44)-1392-263-434, e-mail: r.bedford@ex.ac.uk, C. P.Butts@ex.ac.uk
b
Personal Chemistry AB, Kungsgatan 76, SE-753 18 Uppsala, Sweden
E-mail: Pelle.lidstrom@personalchemistry.com
Received: May 21, 2004; Accepted: September 13, 2004
Abstract: Simple, inexpensive catalysts formed in situ
from tricyclohexylphosphine and palladium acetate
or a phosphite-based palladacycle show unprece-
dented activity in the Suzuki coupling of deactivated,
non-activated and activated aryl chloride substrates
under microwave heating.
used in such reactions under ꢀclassicalꢁ heating condi-
tions do not prove to have particularly high thermal sta-
bility. We have recently reported that the pre-catalyst 1,
typically formed in situ from 2 and PCy3 not only shows
extremely high activity in the Suzuki coupling of aryl
chlorides, but also is very long-lived.[8]
À
Keywords: aryl chlorides; C C bond formation; met-
allacycles; microwaves; palladium; Suzuki coupling
The use of microwave heating has led to the facilitation
of a great number of reactions[1] and, with recent
changes in microwave design, can now be applied to par-
allel screening programmes. The Suzuki reaction
(Scheme 1) is a powerful technique for the formation
of biaryl species.[2]
We wondered whether the high longevity of 2 would
enable it to be used effectively in the coupling of aryl
chloride substrates under microwave heating. This in-
deed proved to be the case, but surprisingly we found
that even simpler systems based on PCy3 and palladium
acetate are equally effective. The preliminary findings of
this study are presented below.
Scheme 1. The Suzuki biaryl coupling reaction.
Rather than perform extensive base optimisation, we
focussed on the use of K3PO4 as this is both inexpensive
Many recent studies on this process have focussed on and tolerant of a wide range of substrate functionality.
the development of catalyst systems that are able to ac- While some activity is observed in toluene, far better re-
tivate electronically challenging aryl chloride sub- sults are obtained in 1,4-dioxane and this solvent was
strates.[3] It would therefore be highly desirable if a cat- used for the rest of the study.
alyst system couldbe designed for the Suzuki coupling of
Initial studies were performed on the coupling of phe-
aryl chloride substrates under microwave heating.[4,5] As nylboronic acid with 4-chloroanisole since this aryl
yet, to the best of our knowledge, the only catalyst that chloride is electronically deactivated and thus provides
shows reasonable activity in the coupling of deactivated a challenging and useful indication of catalyst perform-
aryl chlorides under microwave heating is one formed in ance. Representative results are summarised in Table 1.
situ from palladium acetate and tetrabutylammonium
We were pleased to find that the coupling proceeds
bromide (TBAB) in the presence of water.[6] The active with high conversion at 1808C within 10 min (entry 1)
catalyst in this case is presumably colloidal palladium with a catalyst formed in situ from 2 and one equivalent
supported by the TBAB.[7]
of PCy3 per Pd. Increasing the time to 20 min leads to a
The lack of homogeneous catalysts for the coupling of slight increase in conversion but also to an increased
aryl chlorides under microwave heating may be due to amount of biphenyl impurity due to homo-coupling of
the fact that many of the alkylphosphine-based catalysts the boronic acid, which is used in excess (entry 2).
Adv. Synth. Catal. 2004, 346, 1627–1630
DOI: 10.1002/adsc.200404144
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Robin B. Bedford et al.
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Table 1. Suzuki coupling of 4-chloroanisole with phenylboronic acid.[a]
Entry
Catalyst [mol % Pd]
Temperature [8C]
Time [min]
Conversion [%][b]
Biphenyl [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2þPCy3 (1.0)
180
180
150
150
150
150
150
150
150
150
150
150
150
150
150
10
20
30
20
10
20
20
10
20
20
30
20
20
20
20
89
93
92
79
<1
2
<1
2
2
2
1
4
1
2
2þPCy3 (1.0)
2þPCy3 (1.0)
2þPCy3 (1.0)
2þPCy3 (1.0)
48
2þPCy3 (1.0)
73[c]
78[d, e]
16
2þPCy3 (1.0)
2þP(t-Bu)3 (1.0)
Pd(OAc)2 (1.0)
0
4
Pd(OAc)2 þPCy3 (1.0)
Pd(OAc)2 þ2 PCy3 (1.0)
Pd(OAc)2 þ2 PCy3 (1.0)
Pd(OAc)2 þ2 PCy3 (1.0)
Pd(OAc)2 þ2 PCy3 (0.05)
[Pd(dba)2]
98
2
90[c]
7[d]
61
<1[e]
3
1
14
50
[a]
Conditions: 4-chloroanisole (1.0 mmol), phenylboronic acid (1.5 mmol), K3PO4 (2.0 mmol), 1,4-dioxone (4 mL).
Conversion to coupled product determined by GC (hexadecane standard).
Water (0.5 mL) added (total solvent volume¼4 mL).
[b]
[c]
[d]
[e]
Under air.
GC analysis shows the presence of an unidentified side product.
Good activity is also seen when the temperature is re- as a precursor for a catalyst that can be used under mi-
duced to 1508C (entries 3–5), although slightly longer crowave heating (entry 15) it is somewhat less active
reaction times (20–30 min) are required for optimal than either 2 or palladium acetate and leads to a far high-
conversions. Comparing entries 4, 6 and 7 it can be er contamination of the product with biphenyl.
seen that the catalyst system is remarkably stable with
Having established that a palladium acetate/PCy3
respect to both air and water with essentially no change mixture is an excellent catalyst for the coupling of an
in activity observed. As we have previously observed electronically deactivated aryl chloride we next under-
with classical heating, P(t-Bu)3 is not as effective a ligand took a brief investigation of its performance with a range
as PCy3 for the Suzuki coupling of aryl chlorides when of aryl chlorides and both aryl- and alkylboronic acids,
used in conjunction with a palladacyclic precursor (en- the results of which are outlined in Table 2.
try 8).[8,9] In addition, a larger amount of biphenyl impur-
The high temperature and short reaction time (1808C,
ity is observed. For these reasons we focussed on cata- 10 min) used in this study gave very satisfactory results
lysts containing PCy3 for the rest of the study. in most cases although the increased temperature often
We were surprised to find that while both palladium led to the formation of side products. Thus, all of the re-
acetate and catalysts formed in situ from palladium ace- actions with phenylboronic acid show the presence of
tate and one equivalent of PCy3 are inactive (entries 9 some biphenyl, as does the coupling of chlorobenzene
and 10), increasing the P:Pd ratio to 2:1 gives an ex- with 2-tolylboronic acid (entry 5). In this case the bi-
tremely active catalyst system (entry 11). As with the phenyl results from an Ullmann coupling of the chloride.
catalyst formed from 2 and PCy3, this system is also tol- As with 4-chloroanisole, it should be possible to circum-
erant to added water (entry 12). However, it is not stable vent this by using less forcing conditions.
with respect to air, with very low activity observed when
Steric hindrance in the 2-position of either the aryl
the reaction is performed under aerobic conditions (en- chloride or the boronic acid is tolerated, but the intro-
try 13). Reasonable conversion is seen at catalyst load- duction of three ortho-functions into the biaryl product
ings as low as 0.05 mol % Pd (entry 14). By contrast, is difficult and only low yields of product are formed (en-
when the experiment outlined in entry 11 was repeated try 6).[11] In this case substantial amounts of meta-xylene
under thermal conditions in a sealed tube, conversions are observed as a result of hydrodeboration of the xylyl-
were somewhat lower at 45% at 30 min and 64% after boronic acid. Methylboronic acid can also be used as a
18 hours. We have previously shown that dibenzylidene- substrate, albeit with somewhat limited success.
acetone-containing palladium complexes do not make
In summary, catalysts formed in situ from the inexpen-
particularly useful precursors for aryl chloride Suzuki sive, readily available and comparatively easily handled
catalysts formed in situ from PCy3,[9] possibly as a result phosphine, tricyclohexylphosphine, and either the palla-
of the often non-innocent nature of the tenacious dba li- dacyclic precursor 2 or palladium acetate show very
gand.[10] Here we find that whilst [Pd(dba)2] can be used good activity in the Suzuki coupling of aryl chloride sub-
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Adv. Synth. Catal. 2004, 346, 1627–1630

Suzuki Coupling of Aryl Chlorides under Microwave Heating
COMMUNICATIONS
[a]
Table 2. Suzuki coupling of aryl chlorides with aryl and alkyl boronic acids catalysed by Pd(OAc)2/PCy3.
Entry
Aryl chloride
Boronic acid
Product
Conversion [%][b]
87[c]
1
2
3
81[c, d]
94[c]
4
5
85[c]
94[c]
6
31[e]
33
7
MeB(OH)2
[a]
Conditions: aryl chloride (1.0 mmol), boronic acid (1.5 mmol), K3PO4 (2.0 mmol), 1,4-dioxane (3.5 mL), H2O (0.5 mL).
Conversion to coupled product determined by GC (hexadecane standard).
Contains 3–10% biphenyl.
Contains an unidentified side-product.
Contains 28% meta-xylene.
[b]
[c]
[d]
[e]
modes. After cooling, water (10 mL) was added and the prod-
strates under microwave heating. While palladium ace-
tate is obviously a highly useful palladium precursor and
appropriate for most applications, the greater air toler-
ance of the catalyst formed from 2 may sometimes prove
advantageous, for instance, in high throughput screen-
ing programmes.
uct mixture was extracted with CH2Cl2 (3ꢀ40 mL), dried
(MgSO4), concentrated under vacuum, hexadecane (internal
standard, 0.068 M in dioxane, 1 mL) added and conversion to
product determined by GC.
Acknowledgements
We thank the University of Exeter for financial support (TEH),
Personal Chemistry for the loan of an EmrysTM Liberator and
Johnson Matthey for the loan of palladium salts.
Experimental Section
General Method for the Suzuki Coupling of Aryl
Chlorides
References and Notes
Stock solutions of the appropriate palladium precursor and
phosphine, made up under nitrogen, each in 1,4-dioxane
(1 mL) were added to a 5-mL microwave reaction vial, the
aryl chloride (1.0 mmol), boronic acid (1.5 mmol) and K3PO4
(2.0 mmol) were added and then the total solvent volume
was corrected to 4 mL with 1,4-dioxane or dioxane and water.
The mixture was heated in a Personal Chemistry EmrysTM Lib-
erator at the appropriate temperature, under ꢀfixed hold timeꢁ
conditions for the appropriate time in either ꢀnormal absorp-
tionꢁ (neat dioxane) or ꢀhigh absorptionꢁ (water/dioxane mix)
[1] For a recent review, see: P. Lidstrçm, J. Tierney, B. Wa-
they, J. Westman, Tetrahedron 2001, 57, 10229.
[2] For recent reviews, see: a) N. Miyaura, A. Suzuki, Chem.
Rev. 1995, 95, 2457; b) S. P. Stanforth, Tetrahedron 1998,
54, 263; c) A. Suzuki, J. Organomet. Chem. 1999, 576,
147.
[3] A. F. Littke, G. C. Fu, Angew. Chem. Int. Ed. 2002, 41,
4176.
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Robin B. Bedford et al.
COMMUNICATIONS
[4] For the use of microwaves in coupling reactions, see: M.
Larhed, C. Moberg, A. Hallberg, Acc. Chem. Res., 2002,
35, 717.
[5] For a recent report on the microwave-assisted Kumada
and Negishi couplings of aryl chlorides see: P. Walla,
O. C. Kappa, Chem. Commun. 2004, 564.
c) R. B. Bedford, S. L. Hazelwood, M. E. Limmert,
D. A. Albisson, S. M. Draper, P. N. Scully, S. J. Coles,
M. B. Hursthouse, Chem. Eur. J. 2003, 9, 3216.
[9] R. B. Bedford, C. S. J. Cazin, S. J. Coles, T. Gelbrich, P. N.
Horton, M. B. Hursthouse, M. E. Light, Organometallics
2003, 22, 987.
[6] N. E. Leadbeater, M. Marco, Org. Lett. 2002, 4, 2973.
[7] R. B. Bedford, M. E. Blake, C. P. Butts, D. Holder,
Chem. Commun. 2003, 466.
[8] a) R. B. Bedford, C. S. J. Cazin, S. L. Hazelwood, Angew.
Chem. Int. Ed. 2002, 41, 4120; b) R. B. Bedford, S. L. Ha-
zelwood, M. E. Limmert, Chem. Commun. 2002, 2610;
[10] For leading references see: C. Amatore, A. Jutand, A.
Thuilliez, J. Organomet. Chem. 2002, 643–644, 416.
[11] The introduction of three ortho-substituents can be par-
ticularly problematic, for a discussion see: J. P. Wolfe,
R. A. Singer, B. H. Yang, S. L. Buchwald, J. Am. Chem.
Soc. 1999, 121, 9550.
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