Continuous-flow synthesis of biaryls enabled by multistep solid-handling in a lithiation/borylation/Suzuki-Miyaura cross-coupling sequence

Article abstract of DOI:10.1002/anie.201105223

Let it flow: An efficient and modular synthesis of biaryls under continuous-flow conditions has been realized by a lithiation/borylation/Suzuki- Miyaura cross-coupling sequence under ambient conditions. Aryl bromides and heteroaromatic precursors can be t

Full text of DOI:10.1002/anie.201105223

DOI: 10.1002/anie.201105223
Flow Chemistry
Continuous-Flow Synthesis of Biaryls Enabled by Multistep Solid-
Handling in a Lithiation/Borylation/Suzuki–Miyaura Cross-Coupling
Sequence**
Wei Shu, Laurent Pellegatti, Matthias A. Oberli, and Stephen L. Buchwald*
Continuous-flow methods have gained considerable interest
over the last decade since they offer several advantages over
traditional batch manufacturing processes.[1,2] Recently, the
scope of continuous-flow processes has expanded to include
multistep synthetic transformations, which are attractive in
that they can result in less waste due to fewer purification
steps and less manipulation of compounds. Yet, the develop-
ment of multistep continuous-flow syntheses remains a
particularly difficult challenge due to increased complexity
as compared to single step processes. Flow-rate synergy,
solvent compatibility, and the effect of by-products and
impurities must be considered and optimized in downstream
reactions.[3] In addition, a major challenge for the develop-
ment of multistep syntheses in continuous flow is the handling
of the solids, which usually leads to irreversible clogging.
Although ultrasonication has been used to address this
problem in one-step continuous-flow methodologies,[4] to
the best of our knowledge, no examples of multistep
continuous-flow methods including a solid-forming reaction
have been disclosed.
tions with the aid of acoustic irradiation (Scheme 1). After the
completion of our work, the one-pot preparation of magne-
sium di(hetero)aryl- and magnesium dialkenylboronates for
Suzuki–Miyaura coupling reactions was reported by Knochel
et al.[13]
Scheme 1. Biaryl synthesis in continuous flow by a lithiation/boryla-
tion/Suzuki–Miyaura cross-coupling sequence.
We started our investigation by examining the lithiation of
4-bromoanisole by n-butyllithium (2.5m in hexanes) in THF
at room temperature under flow conditions (Figure 1), which
we found to be completed in only two seconds. Unfortunately,
À
Palladium-catalyzed C C bond-forming reactions serve
as useful methods in the synthesis of functionalized materials
and biologically active compounds.[5] The Suzuki–Miyaura
coupling reaction (SMC) can be regarded as one of the most
important reactions for these bond-forming processes.[6,7] In
general, organoboron reagents are prepared via lithium[8] or
magnesium organometallic compounds in a two-step pro-
cess.[9,10] Given the significance of biaryls in the pharmaceut-
ical industry, we anticipated that the preparation of a
boronate reagent,[11] immediately followed by a Suzuki–
Miyaura cross-coupling reaction in one single streamlined
process would be of great interest for the chemical commun-
ity.[12] Herein, we report the three-step synthesis of biaryls
from the lithiation of aryl halides/heteroarenes, followed by
borylation and Suzuki–Miyaura coupling under continuous-
flow conditions. Notably, this process was made possible
through efficient handling of solids under multistep condi-
Figure 1. Continuous-flow setup for the room-temperature lithiation/
borylation of 4-bromoanisole.
when the lithiation reaction was quenched by a stream of
B(OiPr)3 (0.33m in THF, 200 mLminÀ1), lithium triiso-
propyl(4-methoxyphenyl)borate (2a) precipitated from the
solution, blocking the reactor tubing. We isolated 2a and
tested its solubility in various solvents including THF, 1,4-
dioxane, NMP, acetone, DMF, DMSO, and water; little
solubility of 2a was seen in any case. However, we found
that when the stream exiting from the first reactor was
quenched with a more dilute B(OiPr)3 solution (0.05m, flow
rate = 1 mLminÀ1) with acoustic irradiation, the lithiation/
borylation reaction could proceed smoothly.
[*] Dr. W. Shu, Dr. L. Pellegatti, Dr. M. A. Oberli, Prof. Dr. S. L. Buchwald
Department of Chemistry, Massachusetts Institute of Technology
77 Massachusetts Avenue, Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
[**] W.S., L.P., and S.L.B. thank Novartis International AG for funding.
M.A.O. acknowledges funding from the Novartis foundation. The
Varian NMR instrument used was supported by the NSF (Grant
Nos. CHE 9808061 and DBI 9729592).
We next focused on the coupling reaction of aryl halides
with 2a, generated in flow as above. We examined the
reaction of 2a with 4-bromo-3-fluorobenzonitrile (3a) in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105223.
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batch employing our recently developed second-generation
palladium precatalysts 6 (Figure 2).[14] When this reaction was
carried out in THF at 608C for 4 min, it was found that only
precatalysts bearing SPhos or XPhos as ligand could facilitate
full conversion of the aryl halide, affording the desired
product 4a in 72% and 98% GC yield, respectively
(Figure 2).
Figure 3. Continuous-flow setup for the lithiation/borylation/Suzuki–
Miyaura cross-coupling sequence of two aryl halides.
ensure a good mixing of the three-phase SMC reaction
stream, the second and third reactors were placed in a
sonication bath. Finally, the product stream was collected
upon exiting the third reactor.
Next, we set out to explore the scope of this three-step
triphasic flow system using various aryl halides (Scheme 2).
Using the setup as shown in Figure 3, various aryl bromides
could be lithiated at room temperature. The reaction
sequence could be successfully carried out with para-, meta-,
ortho-, and multi-substituted aryl bromides. In the third step,
a broad range of aryl bromides and chlorides could be applied
to this process. Aryl halides with both electron-withdrawing
and electron-donating substituents were well tolerated under
Figure 2. Precatalysts 6 with different biaryl phosphine ligands.
With good conditions in hand, a microfluidic system was
assembled as shown in Figure 3. Solutions of aryl bromides in
tetrahydrofuran and n-butyllithium in hexanes (1.6m or 2.5m)
were loaded into syringes and introduced into a reactor made
of a PFA (perfluoroalkoxyalkane) tubing (0.04’’ inner diam-
eter) at room temperature. Upon exiting the first reactor, the
stream was mixed with a B(OiPr)3 solution at a T mixer, and
the combined streams were subsequently introduced into
another PFA-tubing reactor (0.04’’ inner diameter). After
exiting the second reactor, the reaction stream was combined
with, respectively, an aqueous KOH solution (0.87m) and a
solution of aryl halide and precatalyst 6e in THF. This
solution was introduced into a third PFA-tubing reactor
(0.04’’ inner diameter). In order to avoid reactor clogging and
Scheme 2. Substrate scope of the lithiation/borylation/Suzuki–Miyaura
cross-coupling sequence of two organic halides (yield of isolated
product based on 3). For details, see Supporting Information. [a] The
Suzuki–Miyaura cross-coupling reaction was finished in 4 min.
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the optimal reaction conditions; notably, various heteroaro-
matic halides, such as quinoline, isoquinoline, pyrimidine, and
benzothiophene, could also be employed in this lithiation/
borylation/Suzuki–Miyaura cross-coupling reaction, affording
the corresponding biaryls in good to excellent yields.
We next applied this protocol to the lithiation/borylation/
Suzuki–Miyaura cross-coupling of heteroarenes with aryl
halides. It is known that five-membered 2-heteroaromatic
boronic acids are unstable at room temperature and are
especially challenging coupling partners for Suzuki–Miyaura
reactions due to quick decomposition under basic aqueous
conditions.[15] The realization of
a lithiation/borylation/
Suzuki–Miyaura cross-coupling of heteroarenes with func-
tionalized aryl or heteroaryl halides would be of great interest
for the synthesis of pharmaceuticals and agrochemicals. Thus,
we chose thiophene and 3-bromoisoquinoline as coupling
partners to investigate this process. It was found that
thiophene could be deprotonated at room temperature with
n-butyllithium (1.6m) in four minutes. Keeping the instability
of 2-heteroaromatic boron reagents and the insolubility of
lithium triisopropyl(thiophen-2-yl)borate in mind, we modi-
fied our standard setup by quenching the lithiation reaction at
room temperature and reducing the residence time in the
second reactor to 6 seconds (Figure 4).
Scheme 3. Lithiation/borylation/Suzuki–Miyaura cross-coupling of
heteroarenes with aryl halides (yield of isolated product based on 3).
[a] 0.44m NaF aqueous solution was used instead of KOH. [b] 0.87m
KF aqueous solution was used instead of KOH.
Scheme 4. Synthesis of 4b in continuous flow.
In summary, we have demonstrated an efficient and
modular synthesis of biaryls from aryl halide substrates by a
lithiation/borylation/Suzuki–Miyuara
cross-coupling
sequence in continuous flow. In the case of heteroarenes,
direct lithium–proton exchange allows the use of heteroar-
enes in this three-step flow strategy. Significantly, this
protocol represents the first example of a three-phase flow
process with an efficient solid handling in multistep syntheses
under acoustic irradiation, which features easy operation,
ambient conditions, and inexpensive starting materials. Of
importance is that the lithiation is conducted at room
temperature using commercially available n-butyllithium
solutions, which greatly enhances the synthetic utility of this
process.
Figure 4. Continuous-flow setup for the lithiation/borylation/Suzuki–
Miyaura cross-coupling sequence of heteroarenes with aryl halides.
Next, we evaluated the scope of lithiation/borylation/
Suzuki–Miyaura cross-coupling reactions of heteroarenes
with aryl halides. Thiophenes and furans could be deproton-
ated smoothly at room temperature and followed by a
borylation and a Suzuki–Miyaura cross-coupling reaction
with ortho-substituted aryl or heteroaromatic halides, yielding
the desired products in good yields (Scheme 3). It is note-
worthy that by using this protocol, low-cost heteroarenes can
be implemented directly, without using unstable 2-heteroar-
omatic boronic acids or more expensive 2-heteroaromatic
bromides.
To further demonstrate the potential applications of this
flow system, we synthesized 4b by lithiation/borylation of 4-
bromanisole, followed by Suzuki–Miyaura coupling with 1-
bromo-2,4-difluorobenzene using the setup in Figure 3. 4b is a
key intermediate for the synthesis of Diflunisal,[16] a non-
steroidal anti-inflammatory drug with analgesic and anti-
pyretic effects[17] (Scheme 4).
Experimental Section
General procedure: ATHF solution of aryl bromides or heteroarenes
was loaded into a plastic syringe, and n-butyllithium solution (1.6m or
2.5m in hexanes) was loaded into a second plastic syringe. These two
solutions were mixed at a T mixer and delivered to the first
microreactor made of PFA tubing (0.04’’ inner diameter) using a
Harvard Apparatus syringe pump. A second syringe pump was used
to pump B(OiPr)3 (0.05m in THF) and mix it with the stream exiting
the first reactor at a scecond T mixer. The mixed stream was
introduced into the second microreactor (PFA tubing, 0.04’’ inner
diameter). The base solution was loaded into a fourth plastic syringe
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Communications
and pumped into the system using a third Harvard Apparatus syringe
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6e in THF was loaded into the fifth plastic syringe, which was merged
with the combined stream of base solution and the mixture from the
second reactor using a fourth Harvard Apparatus syringe pump. The
combined mixture was introduced into the third microreactor (PFA
tubing, 0.04’’ inner diameter). Upon exiting the reactor, the mixture
was collected. Further details on the flow setup and workup
procedures can be found in the Supporting Information.
Received: July 25, 2011
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Revised: September 5, 2011
Published online: September 20, 2011
Keywords: cross-coupling · flow chemistry · palladium ·
.
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