Microwave-promoted Suzuki reactions of aryl chlorides in aqueous media

Article abstract of DOI:10.1021/jo047975c

(Chemical Equation Presented) The microwave-promoted Suzuki coupling reaction of aryl chlorides with boronic acids performed in an aqueous media was studied using the air- and moisture-stable catalyst POPd2 (dihydrogen di-μ-chlorodichlorobis(di-test-butylphosphinito-κP)dipalladate (2-)). This catalyst system under microwave conditions (150°C, 15 min) provided coupled products with yields ranging from 64% to 99%. This method tolerated a variety of substituents and sterically hindered substrates.

Full text of DOI:10.1021/jo047975c

SCHEME 1a
Microwave-Promoted Suzuki Reactions of
Aryl Chlorides in Aqueous Media
Guobin Miao, Ping Ye, Libing Yu,* and
Carmen M. Baldino
a
Optimal conditions: 1 equiv of aryl chloride, 1.5 equiv of
ArQule Inc., 19 Presidential Way,
Woburn, Massachusetts 01801
phenylboronic acid, 3 mol % of POPd2, 4 equiv of Cs2CO3, 12 mol
of TBAI, DMF/H2O, microwave, 150 °C, 15 min.
%
lyu@arqule.com
apply this catalyst system to parallel synthesis, we found
that the reaction usually gave 10-30% yield of desired
product with a major side product identified as the
homocoupling of the boronic acids.
Received November 15, 2004
The microwave-promoted Suzuki coupling reaction of aryl
chlorides with boronic acids performed in an aqueous media
was studied using the air- and moisture-stable catalyst
POPd2 (dihydrogen di-µ-chlorodichlorobis(di-tert-butylphos-
phinito-κP)dipalladate (2-)). This catalyst system under
microwave conditions (150 °C, 15 min) provided coupled
products with yields ranging from 64% to 99%. This method
tolerated a variety of substituents and sterically hindered
substrates.
To improve the reaction yields, we turned to microwave
conditions as part of our ongoing efforts to apply micro-
wave chemistry to parallel synthesis.5 Microwave ir-
radiation has been reported to promote metal-mediated
6
reactions such as the Suzuki cross coupling. Recently,
Leadbeater and co-workers reported the microwave-
promoted Suzuki cross-coupling reaction in aqueous
7
media without ligands. However, the yields related to
The palladium-catalyzed cross-coupling reaction of aryl
halides and triflates has been shown to be a powerful
and frequently employed method for the formation of
carbon-carbon bonds.1 The use of aryl chlorides in this
reaction is now of great interest to synthetic chemists
due to the availability of a broad range of inexpensive
materials in this class.2 A number of authors have
published on the cross coupling of aryl chlorides with
boronic acids using various palladium catalyst systems,
which have provided chemists access to several versatile
chlorides were poor to moderate compared to those of
bromides.
We chose an aqueous solvent system (DMF/H O, 5:1)
2
,2
to start our experiments based on Leadbeater’s work, the
documented advantages of employing a polar and ioni-
8
cally conducting solvent for microwave heating, and the
ability to dissolve cesium carbonate, the base of choice
for this chemistry. In fact, this solvent system gave better
results than other neat solvents such as DMF, THF, or
dioxane. We also found that the use of tert-butylammo-
nium iodide (TBAI) as an additive was beneficial in this
mixed solvent system, similar to previous reports em-
ploying neat water as the solvent.9
Based on these results, we undertook the optimization
of the initial reaction conditions by varying temperature,
ratio of reactants, and percentage of catalysts using 4-Cl-
acetophenone and phenyl boronic acid as a model reaction
3
methods across a variety of aryl chlorides. However,
these methods all require inert conditions, which repre-
sent obstacles for the utility of this chemistry in parallel
synthesis.
Recently, Li reported an air-stable palladium complex
POPd2 1 (dihydrogen di-µ-chlorodichlorobis(di-tert-but-
ylphosphinito-κP) dipalladate that could be used as an
efficient catalyst in the cross-coupling reaction of aryl
(
Scheme 1). The reactions were evaluated by monitoring
4
chlorides with boronic acids. In our initial attempt to
the consumption of the starting materials and the ap-
pearance of either the desired product or the homocou-
pling side product by HPLC. First, temperature variation
was tested, which appeared to be crucial to the reaction.
Below 120 °C, the homocoupling side product was ob-
(1) (a) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J.
Am. Chem. Soc. 1999, 121, 9550-9561. (b) Littke, A. F.; Dai, C.; Fu,
G. C. J. Am. Chem. Soc. 2000, 122, 4020-4028. (c) Netherton, M. R.;
Fu, G. C. Org. Lett. 2001, 3, 4295-4298. (d) Review: Littke, A. F.; Fu,
G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.
(2) (a) Bei, X.; Turner, H. W.; Weinberg, H.; Guram, A. S. J. Org.
Chem. 1999, 64, 6797-6803. (b) Leadbeater, N. E.; Marco, M. Org.
Lett. 2002, 4 (17), 2973-2976. (c) Alonso, D. A.; Najera, C.; Pacheco,
M. C. J. Org. Chem. 2002, 67 (16), 5588-5594. (d) Molander, G. A.;
Biolatto, B. J. J. Org. Chem. 2003, 68, 4302-4314 and reference herein.
(5) Evans, M. D.; Ring, J.; Schoen, A.; Bell, A.; Edwards, P.;
Berthelot, D.; Nicewonger, R.; Baldino, C. M. Tetrahedron Lett. 2003,
44, 9337-9341.
(6) (a) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002,
35, 717-727. (b) Villemin, D.; G o´ mez-Escalonilla, M. H.; Saint-Clair,
J. Tetrahedron Lett. 2001, 42, 635-637. (c) Blettner, C. G.; K o¨ nig, W.
A.; Stenzel, W.; Schotten, T. J. Org. Chem. 1999, 64, 3885-3890.
(7) Leadbeater, N. E.; Marco, M. Org. Lett. 2002, 4, 2973-2976.
(8) Review: Lidstr o¨ m, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225-9283.
(
3) (a) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org.
Chem. 1999, 64, 3804-3805. (b) Zapf, A.; Ehrentraut, A.; Beller, M.
Angew. Chem., Int. Ed. 2000, 39, 4153-4155.
2
(4) (a) POPd catalyst is commercially available exclusively from
CombiPhos Catalysts, Inc. Website: www.combiphos.com. (b) Li, G.
Y. Angew. Chem., Int. Ed. 2001, 40, 1513-1516. (c) Li, G. Y.; Zheng,
G.; Noonan, A. F. J. Org. Chem. 2001, 66 (25), 8677-8688. (d) Li, G.
Y. J. Org. Chem. 2002, 67 (11), 3643-3650.
(9) Leadbeater, N. E.; Marco, M. Angew. Chem., Int. Ed. 2003, 42,
1407-1409.
10.1021/jo047975c CCC: $30.25 © 2005 American Chemical Society
2332
J. Org. Chem. 2005, 70, 2332-2334
Published on Web 02/17/2005

TABLE 1. Suzuki Cross-Coupling Reactions Using
Various Pd Catalysts with Microwave and Conventional
TABLE 2. Suzuki Cross-Coupling of Aryl Chlorides
with Aryl Boronic Acidsa
a
Heating
a
Reaction conditions: 1 equiv of aryl chloride, 1.5 equiv of
phenylboronic acid, 3 mol % of POPd2, 4 equiv of Cs2CO3, 12 mol
b
%
of TBAI, microwave, 150 °C, 15 min in DMF/H2O (5/1). Yields
determined by UV quantification based on authentic samples.
excess of the boronic acid based on chloride provided the
best yield of the cross-coupled product. With a ratio of
boronic acid to chloride greater than 1.5, we started to
observe formation of homocoupling side products, which
complicated the purification of the desired product.
Finally, the effect of catalyst loading was examined. A
range of 1-5 mol % of the catalyst was evaluated, and it
was found that 3 mol % gave the most consistent results.
It is noteworthy that in all cases a reaction time of 15
min was sufficient for complete consumption of the
starting aryl chloride.
To optimize the catalyst system further and the
microwave conditions for this reaction, we performed the
chemistry in the presence of various catalysts, with both
microwave irradiation and conventional heating (Table
1). It was found that microwave heating did not improve
a
Reaction conditions: 1 equiv of aryl chloride, 1.5 equiv of
phenylboronic acid, 3 mol % of Pd catalyst, 4 equiv of Cs2CO3, 12
mol % of TBAI, in DMF/H2O (5/1), either microwave heating (150
°
C, 15 min) or thermal heating (150 °C, 2 h). b Yields determined
by UV quantification based on authentic samples, and the yields
for thermal heating experiments are in parentheses.
served as the major component. Temperatures ranging
from 180 to 200 °C favored decomposition products
derived from the boronic acids. Ultimately, the optimal
temperature was determined to be 150 °C on the basis
of a number of experiments, and this was then used as a
standard for the optimization of other parameters. Sec-
ond, the ratio of boronic acid to aryl chloride was
optimized. An excess of boronic acid is generally required
for chloride coupling due to competitive protodeborona-
3 4
the yields when Pd(PPh ) was employed as the catalyst
and, in fact, in most cases actually reduced the yield of
the desired product. However, the microwave conditions
did provide consistent improvement in the chemistry with
2 2
both Pd(OAc) and POPd . Palladium acetate resulted in
moderate yields with microwave irradiation as expected
from Leadbeater’s report.7 On the other hand, the
9
tion reactions. In our study, it was found that a 50%
catalyst POPd
2
clearly outperformed the other catalysts
J. Org. Chem, Vol. 70, No. 6, 2005 2333

TABLE 3. Suzuki Cross-Coupling of Aryl Chlorides
with 5-Indolyl Boronic Acida
To further understand the scope of this chemistry, we
tested a variety of boronic acids and aryl chlorides under
the optimized conditions. From Table 2, it is clear that
this is a general method that tolerates both electron-rich
and electron-deficient substituents. This trend held true
for both the boronic acids and the aryl chlorides. In
addition, even an ortho-substituted boronic acid provided
a very good yield of the corresponding biphenyl product
(
entry 8). On the basis of these results, the chemistry
was now well suited for utilization in the parallel
synthesis of diverse screening libraries.
Finally, we chose to apply this method to the synthesis
of 5-arylindoles, a biologically relevant class of hetero-
cycles. 5-Arylindoles have been reported to be agonists
of the CNS neurotransmitter serotonin,10 and Yang first
reported the preparation of this class of compounds via
the Suzuki cross-coupling of 5-indolylboronic acid with
aryl bromides.11 Our synthesis was initiated by preparing
solutions of eight aryl chlorides, the catalyst POPd
CO , and 5-indolylboronic acid in the appropriate solvents
Table 3). These reagent solutions were added to 2-dram
2 2
, Cs -
3
(
vials mixed well and then transferred to microwave vials
using a liquid handler (Tecan). The reaction mixtures
were then subjected to microwave irradiation, which
provided the 5-substituted indoles in good isolated yields,
shown in Table 3.
In summary, we have developed a novel, general, and
effective method for the Suzuki cross-coupling reaction
of aryl chlorides by utilizing microwave irradiation and
the POPd2 catalyst system in aqueous media. This
method provides a convenient and versatile approach
relative to existing methods that frequently require more
rigorous conditions due to the air-sensitive nature of
other catalysts. Hence, our synthetic strategy is quite
adaptable to the automated parallel synthesis of small
molecule libraries as illustrated in this report.
Supporting Information Available: Experimental pro-
1
13
cedures and H and C NMR spectra for compounds listed in
Table 3. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO047975C
a
Reaction conditions: 1 equiv of aryl chloride, 1.5 equiv of
phenylboronic acid, 3 mol % of POPd2, 4 equiv of Cs2CO3, 12 mol
b
(10) Agarwal, A.; Pearson, P. P.; Taylor, E. W.; Li, H. B.; Dahlgren,
T.; Hersl o¨ f, M.; Yang, Y.; Lambert, G.; Nelson, D. L.; Regan, J. W.;
Martin, A. R. J. Med. Chem. 1993, 36, 4006-4014.
%
of TBAI, microwave, 150 °C, 15 min in DMF/H2O (5/1). Isolated
yield.
(
11) (a) Yang Y.; Martin, A. R. Heterocycles 1992, 34, 1395-1398.
under the microwave conditions affording improved
yields in all cases.
(
b) Yang, Y.; Martin, A. R.; Nelson, D. L.; Regan, J. Heterocycles 1992,
34, 1169-1175.
2334 J. Org. Chem., Vol. 70, No. 6, 2005