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
Angew. Chem. Int. Ed. 2011, 50, 10665 –10669
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10665