Microwave-promoted Suzuki coupling reactions with organotrifluoroborates in water using ultra-low catalyst loadings

Article abstract of DOI:10.1016/j.tetlet.2005.10.153

The Suzuki reaction in water using parts per million concentrations of palladium is reported using potassium trifluoroborates as alternatives to boronic acids as substrates.

Full text of DOI:10.1016/j.tetlet.2005.10.153

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 217–220
Microwave-promoted Suzuki coupling reactions with
organotrifluoroborates in water using ultra-low catalyst loadings
Riina K. Arvela, Nicholas E. Leadbeater,* Tamera L. Mack and Chad M. Kormos
Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269-3060, USA
Received 12 October 2005; accepted 27 October 2005
Available online 22 November 2005
Abstract—The Suzuki reaction in water using parts per million concentrations of palladium is reported using potassium trifluoro-
borates as alternatives to boronic acids as substrates.
Ó 2005 Elsevier Ltd. All rights reserved.
The Suzuki reaction (palladium-catalyzed cross-cou-
pling of an organoboron compound with an electro-
phile) is one of the most versatile and utilized
reactions for the selective construction of carbon–car-
bon bonds, in particular for the formation of biaryls.1
As the biaryl motif is found in a range of pharmaceuti-
cals, herbicides, and natural products, as well as in con-
ducting polymers and liquid crystalline materials,
development of improved conditions for the Suzuki
reaction has received much recent attention. In general,
it is boronic acids or esters that are used in the reaction.
However, more recently alternative boron reagents have
been developed for use in Suzuki reactions. Of these,
potassium organotrifluoroborate salts have shown par-
ticular potential.2 They are easily prepared and purified
and thus offer ease of handling. Genet and co-workers,3
and Chen and Xia4 have demonstrated the use of aryl-
and heteroaryl-trifluoroborates as substrates in cou-
plings with aryldiazonium and diaryliodonium ions,
respectively, using palladium catalysts. Batey and Quach
reported the synthesis and cross-coupling of tetrabutyl-
ammonium organotrifluoroborate salts with a range of
aryl and alkenyl halides using a mixture of palladium
acetate and dppb as the catalyst and Cs2CO3 as base.5
More recently, Molander and co-workers have pub-
lished a range of procedures for the coupling of potas-
sium organotrifluoroborate salts with a range of
electrophiles and have shown the great scope of these
reagents and simplified the coupling protocols.6–9 The
reactions can be performed in methanol or water, in
the open air, using Pd(OAc)2 as the catalyst and
K2CO3 as base. As well as working with aryl- and alken-
yl-halides and triflates,10 the methodology can be
applied to couplings involving acetates.11 By using a
dialkylphosphanylbiphenyl ligand, aryl chlorides can
be coupled with aryl trifluoroborates.12
We have studied the Suzuki reaction extensively and
found that it is possible to perform couplings of aryl
bromides in neat water using very low catalyst concen-
trations.13,14 Key to the success of the reaction is micro-
wave heating and the use of water as solvent.15
Microwave heating has found a valuable place in the
synthetic chemistÕs toolbox. This is evidenced by the
large number of papers and reviews currently appearing
in the literature.16,17 As well as being energy efficient,
microwave heating can enhance the rate of reactions
and in many cases improve product yields.18 Water is
an excellent solvent for microwave-promoted synthesis.
Although it has a dielectric loss factor, which puts it into
the category of only a medium absorber, even in the
absence of any additives it heats up rapidly upon micro-
wave irradiation. Using a sealed vessel it is possible to
heat water to well above its boiling point. Water also
offers practical advantages over organic solvents. It is
cheap, readily available, and non-flammable. Our reac-
tions were performed using a scientific microwave appa-
ratus, using between 50 ppb and 2.5 ppm palladium, and
are complete in 5 min. This therefore offers an easy, fast,
and efficient route to biaryl-functionalized products.19
Following the recent publication by Kabalka and
Al-Masum on microwave-promoted cross-couplings
involving potassium organotrifluoroborates using
2 mol % PdCl2(dppf),20 we were keen to see if our
*
Corresponding author. Tel.: +1 860 486 5076; fax: +1 860 486
2981; e-mail: nicholas.leadbeater@uconn.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.153

218
R. K. Arvela et al. / Tetrahedron Letters 47 (2006) 217–220
Br
BF3K
µw, Pd
OMe
+
Na2CO3, TBAB, water
MeO
Scheme 1.
Table 1. Coupling of aryl halides with potassium organotrifluoroboratesa
Entry
Aryl halide
Borate
Yield (%)
Entry
Aryl halide
Borate
Yield (%)
75
OMe
BF3K
BF3K
Br
BF3K
1
96
15b
Br
Br
BF3K
2
3
95
95
16
17
0
Br
COMe
OMe
BF3K
BF3K
BF3K
BF3K
BF3K
BF3K
96
Br
Br
Br
MeO
MeO
Br
4
5
6
93
87
90
18
19
20
85
82
85
CN
Br
OMe
BF3K
BF3K
Br
Br
OH
Br
Br
F3C
F3C
BF3K
BF3K
NH2
OMe
BF3K
BF3K
7
8
97
24
21
22
60
87
Br
Br
CF3
CF3
Br
BF3K
OMe
BF3K
BF3K
BF3K
BF3K
BF3K
BF3K
S
Br
9
78
11
98
93
86
4
23
8
12
77
87
77
0
Br
Br
S
S
S
BF3K
10
11
12
13
14
24
N
Br
BF3K
COMe
OMe
COMe
COMe
25
I
Br
BF3K
BF3K
BF3K
26c
27d
28
I
I
Br
Br
COMe
COMe
Cl
Br
a Reactions were run in a sealed tube, using 1 mmol aryl halide, 1.0 mmol potassium organotrifluoroborate, 2.5 ppm Pd, 3.7 mmol of Na2CO3, 1 mL
ethanol, and 1 mL water. An initial microwave irradiation of 300 W was used, the temperature being ramped from rt to 150 °C where it was then
held for 5 min. Temperature was measured with a fiber-optic device inserted into the reaction vessel.
b Mixture of cis and trans products (cis:trans = 10:90).
c Mixture of cis and trans products (cis:trans = 13:87).
d Mixture of cis and trans products (cis:trans = 19:81).

R. K. Arvela et al. / Tetrahedron Letters 47 (2006) 217–220
219
ultra-low metal catalyzed Suzuki coupling protocol
could be extended to use with these versatile substrates
and our initial results are reported here.
entry 8). Although 2-bromothiophene can be used as a
substrate with success (Table 1, entry 9), 2-bromopyri-
dine gives much less promising results (Table 1, entry
10). This mirrors our work on Suzuki couplings in water
using boronic acids where again we find that halopyri-
dines cannot be coupled effectively due to competitive
decomposition of the heterocyclic substrate.14 Represen-
tative aryl iodides and a chloride were screened in the
coupling with potassium phenyltrifluoroborate. Whilst
the iodo-functionalized substrates could be effectively
coupled (Table 1, entries 11–13) 4-chloroacetophenone
could not (Table 1, entry 14). Again, this is not unex-
pected in the light of our work using boronic acids as
coupling partners in ultra-low Pd-catalyzed Suzuki reac-
tions. Looking at other halide substrates, we find that
whilst an alkenyl bromides such as b-bromostyrene
can be coupled efficiently with potassium phenyltrifluo-
roborate (Table 1, entry 15), the sp2–sp3 coupling of this
borate with 1-bromohexane was unsuccessful (Table 1,
entry 16). We have screened representative potassium
organotrifluoroborates. Aryl trifluoroborates couple
effectively with 4-bromoanisole and 4-bromotoluene
under our conditions (Table 1, entries 17–22). Potassium
3-thiophene trifluoroborate couples with aryl bromides
with higher yields being obtained with substrates bear-
ing electron-withdrawing substituents (Table 1, entries
23–25). The vinyl substrate potassium trans-styryltrifluoro-
borate can be used as a coupling partner, a mixture
of cis and trans alkenes being formed in the reaction
with 4-bromoanisole and 4-bromotoluene, the trans-iso-
mer being predominant in both cases (Table 1, entries 26
and 27). This is in contrast to our results obtained using
the boronic acid equivalent of this (trans-2-phen-
ylvinylboronic acid) where the trans-product is formed
exclusively.14 Attempts to use an alkyltrifluoroborate
as a coupling partner were unsuccessful (Table 1, entry
28). This is not surprising given that Molander and
co-workers found that it took 9 mol % PdCl2(dppf) to
couple these substrates.7
In order to gauge the potential of our already estab-
lished Suzuki coupling methodology for use with
organotrifluoroborates, we decided to take the coupling
of 4-bromoanisole and potassium phenyltrifluoroborate
as a test case, working on a 1 mmol scale (Scheme 1).
We first attempted the coupling using sodium carbonate
(3.7 mmol) as a base for the reaction, tetrabutylammo-
nium bromide (TBAB) (1 mmol) as phase-transfer
agent, 2 mL water and 50 ppb palladium as the catalyst.
We obtained a 15% yield of the desired biaryl product.
The reaction mixture was heated to 150 °C where it
was held for 5 min before cooling back to room temper-
ature. We found that if the palladium concentration was
increased to 2.5 ppm, a more respectable 82% product
yield could be obtained.
As a point of note, when working in water, a major
problem can be precipitation of palladium from a stock
solution, particularly when working with a salt such as
palladium acetate. This is avoided by using an acid sta-
bilized stock solution such as that purchased as an ICP
standard for palladium. This can be diluted accord-
ingly to give solutions of the desired concentrations.
For low concentrations, a couple of drops of HCl can
be added to avoid precipitation of palladium from
solution.
When developing our ultra-low palladium concentration
Suzuki couplings using boronic acids as substrates, we
found that a 1:1 (vol) ethanol/water mixture worked just
as with the water/TBAB combination and has the added
advantage of ease of work-up at the end of the reaction.
We therefore screened this in our test reaction with
potassium phenyltrifluoroborate. We found that using
a palladium concentration of 2.5 ppm and keeping all
other conditions the same, ethanol/water solvent mix-
ture gave us a 96% yield of the desired product. Reduc-
tion of the base from 3.7 to 3 equiv has a deleterious
effect on product yield as does decreasing the reaction
temperature from 150 to 135 °C. Thus, our optimal con-
ditions were 1 equiv 4-bromoanisole, 1 equiv potassium
phenyltrifluoroborate, 3.7 equiv Na2CO3, 1:1 water/
ethanol as solvent, 2.5 ppm palladium as catalyst, heat-
ing to 150 °C, and holding at this temperature for 5 min.
With our optimal conditions in hand, we decided to
explore the substrate scope of the reaction by perform-
ing the couplings of ranges of aryl halides and potassium
organotrifluoroborates. Our results are shown in Table
1.21
In summary, we have shown here that by using micro-
wave promotion and water as a solvent, it is possible
to couple a range of potassium organotrifluoroborates
with aryl bromides and iodides efficiently, quickly, and
using low catalyst loadings. The ease of purification of
potassium organotrifluoroborates makes them valuable
starting materials for Suzuki couplings and addition of
this range of substrates to our ultra-low palladium load-
ing methodology increases their versatility.
Acknowledgments
We thank the University of Connecticut for funding and
CEM Microwave Technology for equipment support.
In couplings with potassium phenyltrifluoroborate, a
range of functionalities are tolerated on the aryl
bromide component (Table 1, entries 1–7) although
our results hint at the fact that sterically demanding aryl
bromide substrates could prove problematic (Table 1,
References and notes
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21. Typical procedure for the coupling of aryl halides with
potassium organotrifluoroborates: In a 10 mL glass tube
were placed 4-bromoanisole (187 mg, 0.125 mL,
1.0 mmol), potassium phenyltrifluoroborate (184 mg,
1.0 mmol), Na2CO3 (392 mg, 3.7 mmol), tetrabutylammo-
nium bromide (322 mg, 1.0 mmol), palladium stock solu-
tion (0.5 mL of a 10 ppm solution in water), and water
(1.6 mL) to give a total volume of water of 2 mL and a
total palladium concentration of 2.5 ppm. The vessel was
sealed with a septum and placed into the microwave
cavity. Initial microwave irradiation of 150 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 5 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)
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material extracted and removed. After further extraction
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