Suzuki-miyaura cross-coupling reactions in flow: Multistep synthesis enabled by a microfluidic extraction

Article abstract of DOI:10.1002/anie.201101480

Continuous success: A continuous-flow Suzuki-Miyaura cross-coupling reaction starting from phenols was made possible through use of an efficient microfluidic extraction operation and a packed-bed reactor. Various biaryls were obtained in excellent yield (

Full text of DOI:10.1002/anie.201101480

DOI: 10.1002/anie.201101480
Flow Chemistry
Suzuki–Miyaura Cross-Coupling Reactions in Flow: Multistep
Synthesis Enabled by a Microfluidic Extraction**
Timothy Noꢀl, Simon Kuhn, Andrew J. Musacchio, Klavs F. Jensen,* and Stephen L. Buchwald*
The synthesis of complex organic molecules typically involves
multiple reaction steps and requires the isolation and
purification of reaction intermediates. As a result, synthetic
chemistry is a very labor-intensive and time-consuming
undertaking. Several strategies have been developed in
order to increase the efficiency of multistep syntheses, such
as, protecting group free syntheses,[1] one-pot syntheses,[2]
cascade reactions,[3] and multicomponent reactions.[4]
Although this method has allowed the construction of
complex molecules without the need for purification and
isolation of intermediates, swelling of certain polymer sup-
ports, deposition of products and by-products, catalyst leach-
ing,[9] and the necessity to periodically replace the cartridges
limit the practicality of these systems. Lastly, several unit
operations have been developed in order to achieve separa-
tions and purifications in a continuous fashion, such as, a
single-step liquid–liquid microextraction[10] and a microfluidic
distillation.[11] These unit operations have successfully been
implemented in continuous-flow syntheses.[12,13]
Cross-coupling reactions serve as powerful methods to
construct carbon–carbon and carbon–heteroatom bonds in a
variety of biologically active molecules.[14,15] The Suzuki–
Miyaura cross-coupling reaction (SMC) can be regarded as
one of the most important of these bond-forming process-
es.[16,17] This method allows for the coupling of aryl halides/
pseudo halides with aryl boronic acids or aryl boronates.
Notably, aryl triflates have been shown to be one of the most
efficient coupling partners. However, the lack of commer-
cially available triflates and their instability requires their
preparation prior to their use in the SMC reaction and makes
them less attractive for SMC reactions. These are central
reasons why synthetic chemists try to circumvent the use of
aryl triflates and employ the commercially available aryl
halides. Nevertheless, the use of phenols would be of high
interest because of their availibility and low cost. Here, we
describe a microfluidic system that is suitable to transform
phenols into their corresponding aryl triflates, which are,
subsequently, transformed into biaryls by means of a SMC
reaction (Scheme 1). This process posseses a unique chemical
In the last decade, the use of continuous-flow reactors for
multistep syntheses has gained a considerable amount of
interest because they allow for integration of the individual
reaction steps and subsequent separations in one single
streamlined process. These microreactors provide several
advantages compared to traditional batch reactors, for
example, enhanced heat- and mass-transfer, safety of oper-
ation, precise control over residence (reaction) time, isolation
of sensitive reactions from air and moisture, and the ease of
scale-up or operating several devices in parallel (numbering
up).[5,6] Several approaches have been developed in order to
combine multiple reaction steps in one single continuous
operation. One strategy involves the use of telescoping
reactions in which reagents are added consecutively in order
to achieve further transformations of a given starting product
without the use of intermediate purifications. This technique
has proven very effective for multistep flow chemisty because
it simplifies the microfluidic setup dramatically.[7] However,
excess reagents and by-products formed during the reaction
can negatively affect the downstream reactions which signifi-
cantly limits the generality of this method. Another approach
has been the use of immobilized reagents, catalysts and
scavengers in order to achieve multistep syntheses in flow.[8]
[*] Dr. T. Noꢀl, A. J. Musacchio, Prof. Dr. S. L. Buchwald
Department of Chemistry
Massachusetts Institute of Technology
77 Massachusetts Avenue, Cambridge, MA 02139 (USA)
Fax: (+1)617-253-3297
E-mail: sbuchwal@mit.edu
Homepage: http://mit.edu/chemistry/buchwald/
Scheme 1. Synthesis of biaryls starting from substituted phenols.
challenge because by-products formed in the first reaction can
negatively affect the downstream reaction. Moreover, since
catalytic reactions are very sensitive to small amounts of
impurities an effective strategy to remove these by-products
needs to be utilized.
A microfluidic system was assembled as shown in
Figure 1. The first reaction, the formation of aryl triflate,
was carried out in a 100 mL reactor made of PFA (perfluoro-
alkoxyalkane) tubing (0.02’’ inner diameter, 50 cm length) at
room temperature. Solutions of triflic anhydride (Tf2O), as
well as phenol and triethylamine in toluene were loaded into
syringes and introduced into the microfluidic system through
syringe pumps. The triflic anhydride and reagent streams
Dr. S. Kuhn, Prof. Dr. K. F. Jensen
Department of Chemical Engineering
Massachusetts Institute of Technology
77 Massachusetts Avenue, Cambridge, MA 02139 (USA)
E-mail: kfjensen@mit.edu
[**] T.N., S.K., A.J.M., K.F.J., and S.L.B. thank the Novartis International
AG for funding. T.N. is a Fulbright Postdoctoral Fellow. S.K.
acknowledges funding from the Swiss National Science Foundation
(SNF). A.J.M. is an Undergraduate Research Opportunities Pro-
gram (U.R.O.P.) student at Massachusetts Institute of Technology.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101480.
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5943

Communications
(Scheme 2) and the correspond-
ing boronic acid, tetrabutylam-
monium bromide (TBAB) as a
phase transfer catalyst, and
aqueous K3PO4. This biphasic
mixture was next introduced
into a 400 mL packed-bed reac-
tor filled with stainless steel
spheres (60–125 mm packing)
reactor which was placed in a
908C oil bath. These dramati-
cally enhance the mixing in
biphasic mixtures by improving
the contact between the two
phases.[15b]
Stainless
steel
Figure 1. Microreactor setup for the continuous-flow synthesis of palladium-catalyzed Suzuki–Miyaura
cross-coupling reactions starting from substituted phenols.
spheres are an inert and com-
were combined in a T-mixer. This T-mixer was cooled in a
NaCl/ice bath in order to effectively dissipate the heat
generated by the exothermic triflate formation. Although
quantitative yields were obtained for the intermediate triflate,
without cooling, poor and irreproducible overall yields for the
SMC-coupled product were obtained. We hypothesize that a
side product is formed which cannot be efficiently extracted
out of the organic stream and inhibits the catalyst in the SMC
reaction. Upon exiting the first reactor, the reaction was
quenched with 2m hydrochloric acid (HCl) establishing a
slug-flow regime. This enabled the extraction of triethylamine
and other salts through convective mass transfer between the
two phases. Next, the two phases were separated in a phase
separation device by using a thin porous fluoropolymer
membrane that selectively wets the organic phase (Figure 2).
This selective wetting of the membrane by the organic phase
facilitates the separation process based on the capillary
Scheme 2. XPhos ligand 1 and second-generation XPhos precatalyst 2
used in the palladium-catalyzed Suzuki–Miyaura cross-coupling reac-
tions.
mercially available material, which exhibits an excellent
chemostability, a high tolerance towards basic solutions, and
a good thermal conductivity,[18] which makes these beads an
ideal choice for use as a packing material. Finally, the product
stream was merged with a quench of water and ethyl acetate
(EtOAc).
Our initial investigation focused on finding a solvent that
was compatible with both steps of the process. Ethereal
solvents proved to be ideal for the SMC reaction,[19] however,
these were not compatible with triflic anhydride. Moreover,
the by-products formed during the triflate formation reaction
completely shut down the SMC reaction even in the presence
of a continuous liquid–liquid extraction step. Toluene was
found to be the optimal solvent for both steps. The by-
products formed in the first reaction could be efficiently
removed by continuous extraction and allowed the SMC
reaction to proceed. We observed that complete conversion of
phenol and quantitative yields for the corresponding triflate
could be obtained in a matter of seconds using 1.2 equivalents
of triflic anhydride (see the Supporting Information). After
exiting the separation device, the organic phase was combined
with boronic acid and 2 mol% XPhos precatalyst 2 dissolved
in 1-methyl-2-pyrrolidinone (NMP), aqueous TBAB, and
aqueous K3PO4. It is worth mentioning that this second-
generation XPhos precatalyst 2 is easily obtained in a one-pot
procedure starting from commercially available chemicals
and generates the catalytically active L1Pd0 species quickly
and efficiently.[19,20] These advantages make this class of
precatalysts ideally suited for continuous-flow reactions
Figure 2. Sketch of the phase separation device.
pressure difference.[10a] To successfully operate the separation
device the combined fluidic resistance from the separated
organic stream needs to be less than the separated aqueous
stream. In addition, the pressure difference between the
organic and the aqueous side across the membrane needs to
be less than the capillary pressure difference. Since the second
reaction step involves the use of a packed-bed reactor with an
associated increase in pressure drop, the aforementioned two
criteria were met by adding backpressure to the aqueous side
of the separator. The organic phase was combined with
solutions of second-generation XPhos precatalyst
2
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Angew. Chem. Int. Ed. 2011, 50, 5943 –5946

where scalability and fast initiation of the catalyst are
required.
our two-step protocol (Table 1, examples 3b and 3c). Both
electron-rich and electron-deficient boronic acids appeared to
be efficient coupling partners (Table 1). Heteroaromatic
boronic acids underwent the SMC reaction to form the
desired products in excellent overall yields (Table 1, sub-
strates 3h–l). For most heteroaromatic boronic acids, longer
reaction times were required to obtain a full conversion of the
aryl triflate (residence time reactor 1 = 203 s; residence time
reactor 2 = 320 s) (Table 1, substrates 3h, 3i, 3j, and 3l). For
substrate 3l, 3 mol% of precatalyst 2 was required in order to
obtain complete conversion.
This process could be applied to the cross-coupling of
various phenols with a wide range of arylboronic acids
(Table 1). Under optimized conditions, most reactions could
be finished with residence times of 152 s in the first reactor
and 240 s in the packed-bed reactor. Typically, isolated yields
of more than 95% yield were obtained. Both electron-rich
and electron-deficient phenols could be used. Also phenols
bearing ortho substituents could be efficiently employed in
Table 1: Suzuki–Miyaura cross-coupling of ArOH and Ar’B(OH)2 using
The use of a continuous liquid–liquid extraction device, a
packed-bed reactor and the ease with which our microfluidic
setup could be stabilized were key requisites for the successful
the microfluidic setup.[a]
À
formation of C C coupled products starting from phenols. To
further demonstrate the robustness of our system, we were
able to run experiments for more then 4 h without any
interruption to collect in total 5 mmol of product (Table 1,
substrates 3m and 3n). This result demonstrates one of the
major advantages of flow chemistry, which is the ease to scale-
up reactions and, more specifically, biphasic reactions. In
batch, biphasic conditions require advanced and expensive
mixers, using baffles or special designs in agitator blades.
In conclusion, we have developed a continuous-flow
microfluidic system that can efficiently transform phenols
into their corresponding aryl triflates and, subsequently,
convert the intermediate triflates into biaryls by means of a
Suzuki–Miyaura cross-coupling reaction. Key for the success
in this multistep synthesis was the use of a microfluidic
extraction operation to remove impurities generated in the
first reaction and a packed-bed reactor to increase the mixing
efficiency of the biphasic Suzuki–Miyaura cross-coupling
reaction. It is noteworthy that the start-up and steady-state
of this microfluidic system was easily achieved and, as a result,
the cross-coupling of various phenols with a wide range of
arylboronic acids was possible (14 examples). Excellent
results were obtained in all cases.
Experimental Section
A toluene solution of the phenol substrate (1.0m) and triethylamine
(1.5m) was loaded into a SGE glass syringe (5 mL) and a toluene
solution of triflic anhydride (1.2m) was loaded into a second glass
SGE syringe (5 mL). These two solutions were delivered to the first
microreactor (100 mL volume) using a single Harvard Apparatus
syringe pump (20 mLminÀ1). A second syringe pump was used to
pump 2m HCl (80 mLminÀ1) and mix it with the triflate stream
exciting the first reactor. This stream was delivered to a continuous
liquid–liquid extraction device. An NMP solution of boronic acid
(1.5m) and XPhos precatalyst 2 (0.02m) was loaded in a fourth syringe
(5 mL Normject plastic syringe), an aq. TBAB solution (0.1m) was
loaded in a fifth syringe (5 mL Normject plastic syringe) and aq.
K3PO4 (4m) was loaded in a sixth syringe (5 mL Normject plastic
syringe). These three solutions were merged with the organic phase
coming from the extraction device and delivered to a packed-bed
reactor (400 mL, packed with 60–125 mm stainless steel spheres) at
908C using two additional syringe pumps (20 mLminÀ1). Upon exiting
[a] 1) ArOH (1.0 equiv), Tf2O (1.2 equiv), Et3N (1.5 equiv), toluene, room
temperature. 2) 2m HCl. 3) Ar’B(OH)2 (1.5 equiv), XPhos precatalyst 2
(2 mol%), NMP, TBAB (10 mol%) in H2O, aq. K3PO4. [b] Residence time
reactor 1=152 s; residence time reactor 2=240 s. [c] Residence time
reactor 1=203 s; residence time reactor 2=320 s. [d] Yield of isolated
product on a 1 mmol scale. [e] 3 mol% of 2 was used. [f] Yield of isolated
product on a 5 mmol scale.
the reactor, the reaction was quenched with EtOAc (200 mLminÀ1
)
and H2O (200 mLminÀ1). The flow rates and pressures were allowed to
stabilize to a steady state. Next, a sample was collected in order to
obtain exactly 1 mmol of product. Further details on the equipment
Angew. Chem. Int. Ed. 2011, 50, 5943 –5946
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5945

Communications
setup and workup procedures can be found in the Supporting
Information.
Sample analysis: GC analysis was used to determine the
conversions. NMR spectroscopy and IR spectroscopy were used to
identify the products.
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Received: February 28, 2011
Revised: April 6, 2011
Published online: May 17, 2011
Keywords: flow chemistry · microreactors · palladium · Suzuki–
.
Miyaura cross-coupling · synthetic methods
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