The application of organic bases in microwave-promoted Suzuki coupling reactions in water

Article abstract of DOI:10.1016/j.tetlet.2006.01.092

Traditionally, mineral bases are used in Suzuki coupling protocols. The use of DBU or DABCO as alternative bases for the reaction is reported and the application discussed.

Full text of DOI:10.1016/j.tetlet.2006.01.092

Tetrahedron Letters 47 (2006) 1909–1912
The application of organic bases in microwave-promoted
Suzuki coupling reactions in water
Florine Chanthavong and Nicholas E. Leadbeater*
Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269-3060, USA
Received 19 October 2005; revised 17 January 2006; accepted 18 January 2006
Abstract—Traditionally, mineral bases are used in Suzuki coupling protocols. The use of DBU or DABCO as alternative bases for
the reaction is reported and the application discussed.
Ó 2006 Elsevier Ltd. All rights reserved.
The Suzuki reaction (palladium-catalyzed cross-coup-
ling of aryl halides with boronic acids) is one of the
most versatile and utilized reactions for the selective
construction of carbon–carbon bonds, in particular for
the formation of biaryls.1 As the biaryl motif is found
in a range of pharmaceuticals, herbicides, and natural
products, as well as in conducting polymers and liquid
crystalline materials, development of improved condi-
tions for the Suzuki reaction has received much recent
attention. Indeed, in the last 10 years, there have been
over 1000 publications on the area of aryl–aryl bond
formation. We have studied the Suzuki reaction exten-
sively and found that it is possible to perform couplings
of aryl bromides in neat water using low concentration
of ‘ligandless’ palladium as a catalyst.2,3 Key to the suc-
cess of the reaction is microwave heating and the use of
water as solvent.4,5 As well as being energy efficient,
microwaves can also enhance the rate of reactions, and
in many cases improve product yields. Water proves to
be an excellent solvent for microwave-promoted synthe-
sis.6 Using a sealed vessel it is possible to heat water to
well above its boiling point. Water also offers practical
advantages over organic solvents.
scales, translation of methodologies to larger scale
apparatus can be problematic. There are two possible
scale-up options: the first is to use a continuous flow
microwave cell,7 a technology found to be successful
for a number of different reactions8–10 including Suzuki
couplings.11–14 The other option is to use a batch-type
process. This could either involve using one large vessel
or parallel batch reactors. For a microwave operating at
the typical frequency of 2.45 GHz, microwave penetra-
tion is generally in the order of centimeter, depending
on the dielectric properties of the reaction medium. This
therefore limits the size of a large batch reactor. Success
has been found using one large batch reactor,15–17 and
also using the parallel approach.18,19 In our attempts
to scale up our Suzuki coupling chemistry, we have
focused our attention thus far on a microwave system
that combines the advantages of a batch reactor with
those of a continuous flow reactor.20,21 It is a single-mode
apparatus with one 80 mL vessel in the microwave cav-
ity. The reaction mixture is passed into and out of the
vessel by use of a peristaltic pump, which functions, as
well as reaction’s conditions are controlled through a
computer. This gives a high degree of automation to
the process. The reaction mixture can be introduced into
the microwave vessel from two separate feed lines. After
the reaction is complete, the reaction vessel can be
vented to release excess pressure, and then the contents
of the reactor can be pumped into a collection vessel.
Since only one reaction vessel is used, the time taken
to cool the reaction mixture down to room temperature
at the end of the run is significantly shorter than that
reported for the parallel batch reactors using multimode
apparatus. If necessary, the reactor can then be cleaned
with solvent before the next run.
Scale-up of microwave-promoted reactions has been an
issue of considerable interest over the last few years.
Although chemists are discovering that microwave
chemistry has the advantage of greatly reducing reaction
times and improving product yields when run on small
*
Corresponding author. Tel.: +1 860 486 5076; fax: +1 860 486
2981; e-mail: nicholas.leadbeater@uconn.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.092

1910
F. Chanthavong, N. E. Leadbeater / Tetrahedron Letters 47 (2006) 1909–1912
When performing Suzuki reactions in water using either
a flow-through set-up or the hybrid stop-flow apparatus,
the solubility of the organic reagents can be problematic.
This can be alleviated by using a 1:1 ethanol/water mix-
ture as the solvent. However, this in turn leads to solu-
bility issues pertaining to the mineral base used in the
reaction. To overcome this problem, we were keen to
determine whether liquid organic bases could be used
in aqueous-phase Suzuki reactions thus giving us a
wholly homogeneous reaction mixture. Our results are
presented here.
dropped (Table 1, entry 9), this being attributed to com-
petitive decomposition of starting materials. Reduction
of the palladium loading below 0.4 mol % resulted in a
significant decrease in product yield; hence our ultra-
low catalyst loading methodology was not amenable to
the change from mineral to organic base. When screen-
ing other solvents in the coupling protocol, good results
were only acquired when aqueous media were utilized
(Table 1, entries 10–12). Expectantly, we also found that
lower yield of product was obtained when using conven-
tional heating compared to microwave heating (Table 1,
entry 13). Thus, our optimal conditions were 1 equiv
aryl halide, 1 equiv phenylboronic acid, 1 equiv DBU,
1:1 water/ethanol as solvent, 0.4 mol % Pd(OAc)2, heat-
ing to 150 °C and holding at this temperature for 10 min
using microwave heating.
Traditionally, the Suzuki reaction is performed using a
mineral base such as an alkali-metal carbonate. Over
the last year there have been a number of reports of
the use of amines as ligands in conjunction with simple
palladium salts such as Pd(OAc)2 in Suzuki reactions,
but these still require the use of an additional mineral
base.22 To probe these reported conditions more thor-
oughly, and to also solve our problem of solubility, we
screened three simple amines as bases for the Suzuki
coupling of 4-bromoanisole and phenylboronic acid in
the absence of an additional mineral base (Table 1).
Working on a 1 mmol scale, using a 1:1 water/ethanol
mixture as solvent and 0.4 mol % Pd(OAc)2 as catalyst
precursor, we screened DBU, DABCO, and 1,1,3,3-tetra-
methylguanidine (TMG), running the reactions for
10 min at 150 °C using microwave heating. Both DBU
and TMG worked well as bases for the reaction (Table
1, entries 1 and 2) but DABCO gave a significantly low-
er yield (Table 1, entry 3). Working with DBU, a screen
of base concentration showed that a 1:1 ratio of base to
aryl halide was optimal, and that a considerable de-
crease in yield was obtained if less base was used (Table
1, entries 4 and 5). A screen of reaction temperature
showed that below 100 °C, little product was obtained
(Table 1, entries 6–8) and above 150 °C product yields
With our optimal conditions in hand, we decided to
explore the substrate scope of the reaction by performing
the couplings of a range of aryl halides with phenyl-
boronic acid. Our results are shown in Table 1.23 Good
yields were obtained with most of the substrates
screened. However, the use of sterically hindered aryl
halides was not satisfactory as low yields were acquired
(Table 2, entries 8 and 9). In the case of 4-bromophenol,
significant decomposition was observed, which showed
some level of functional group intolerance when DBU
was used as a base in the reaction.24 Aryl bromide and
iodide substrates gave comparable product yields while
the corresponding chlorides gave appreciably lower
yields.
Having shown the applicability of the amine base meth-
odology to small scale couplings, we next performed the
reaction using the hybrid stop-flow apparatus, working
on a 20 mmol scale per batch. Using the same reaction
conditions, we were able to scale up the reaction as
Table 1. Study of reaction parameters for the microwave-promoted Suzuki coupling of 4-bromoanisole and phenylboronic acid in water using
a
Pd(OAc)2
Br
B(OH)2
µw, Pd(OAc)2
OMe
+
water
MeO
Entry
Reaction conditionsb,c
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13d
0.4 mol % Pd(OAc)2, 1 mmol DBU, H2O/EtOH, 150 °C
0.4 mol % Pd(OAc)2, 1 mmol TMG, H2O/EtOH, 150 °C
0.4 mol % Pd(OAc)2, 1 mmol DABCO, H2O/EtOH, 150 °C
0.4 mol % Pd(OAc)2, 0.5 mmol DBU, H2O/EtOH, 150 °C
0.4 mol % Pd(OAc)2, 0.1 mmol DBU, H2O/EtOH, 150 °C
0.4 mol % Pd(OAc)2, 1 mmol DBU, H2O/EtOH, 50 °C
0.4 mol % Pd(OAc)2, 1 mmol DBU, H2O/EtOH, 80 °C
0.4 mol % Pd(OAc)2, 1 mmol DBU, H2O/EtOH, 100 °C
0.4 mol % Pd(OAc)2, 1 mmol DBU, H2O/EtOH, 180 °C
0.4 mol % Pd(OAc)2, 1 mmol DBU, acetone, 150 °C
0.4 mol % Pd(OAc)2, 1 mmol DBU, DMF, 150 °C
0.4 mol % Pd(OAc)2, 1 mmol DBU, EtOAc, 150 °C
99
97
59
45
13
1
20
74
56
0
0
0
79
0.4 mol % Pd(OAc)2, 1 mmol DBU, H2O/EtOH, 150 °C conventional heating
a 1 mmol of 4-bromoanisole, 1 mmol of PhB(OH)2, 2 mL solvent. Microwave irradiation: initial power of 50 W, temperature ramped to that stated
and held there for 10 min.
b Conditions changed from entry 1 are highlighted in bold.
c Using 1:1 ratio of water/ethanol in entries 1–9.
dReaction mixture placed into a pre-heated oil-bath and held there for 13 min.

F. Chanthavong, N. E. Leadbeater / Tetrahedron Letters 47 (2006) 1909–1912
1911
Table 2. Coupling of aryl halides with phenylboronic acida
simple for application to flow-through or stop-flow
scale-up using microwave heating.
Entry
Aryl halide
Yield (%)
OMe
1
99
Acknowledgements
Br
Br
The NSF REU program is thanked for funding (CHE-
0354012).
2
3
81
94
COMe
References and notes
Br
Br
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Br
OMe
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Br
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10
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a Reactions were run in a sealed tube, using 1.0 mmol aryl halide,
1.0 mmol phenylboronic acid, 0.4 mol % Pd(OAc)2, 1.0 mmol DBU,
1.0 mL ethanol, and 1.0 mL water. An initial microwave irradiation
of 50 W was used, the temperature being ramped from rt to 150 °C
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´
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as a base. As well as adding to the literature in an area
of current interest, this new protocol is operationally
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23. Typical procedure for the coupling of aryl halides with
phenylboronic acid: In a 10 mL glass tube was placed
4-bromoanisole (187 mg, 0.125 mL, 1.0 mmol), phenyl-
boronic acid (122 mg, 1.0 mmol), DBU (152 mg, 0.149 mL,
1.0 mmol), and Pd(OAc)2 (1 mg, 0.4 mol %). After adding
water (1 mL) and ethanol (1 mL), the vessel was sealed
with a septum and placed into the microwave cavity (CEM
Discover). Initial microwave irradiation of 50 W was used,
the temperature being ramped from rt to the desired
temperature of 150 °C. Once this was reached, the reaction
mixture was held at this temperature for 10 min. The
reaction mixture was stirred continuously during the
reaction. After allowing the mixture to cool to room
temperature, the reaction vessel was opened and the
contents poured into a separating funnel. Water (30 mL)
and ethyl acetate (30 mL) were added, and the organic
material extracted and removed. After further extraction
of the aqueous layer with ethyl acetate, combining the
organic washings, and drying them over MgSO4, the ethyl
acetate was removed in vacuo leaving the crude product.
That product was then isolated and characterized by
comparison of NMR data with that in the literature.
24. Interestingly, no reference is made to the reactivity of
phenolic substrates in the literature reports of Pd(OAc)2/
amine catalyst systems used in conjunction with mineral
bases.
´
19. Alcazar, J.; Diels, G.; Schoentjes, B. QSAR Comb. Sci.
2004, 23, 906.
20. Arvela, R. K.; Leadbeater, N. E.; Collins, M. J. Tetra-
hedron 2005, 61, 9349.
21. The apparatus is commercially available from CEM
Microwave Technology and is called ‘Voyager’.