Organic Process Research & Development 2006, 10, 833−837
Open-Vessel Microwave-Promoted Suzuki Reactions Using Low Levels of
Palladium Catalyst: Optimization and Scale-Up
Nicholas E. Leadbeater,*,† Victoria A. Williams,† Thomas M. Barnard,‡ and Michael J. Collins, Jr.‡
Department of Chemistry, UniVersity of Connecticut, Unit 3060, 55 North EagleVille Road,
Storrs, Connecticut 06269-3060, U.S.A., and CEM MicrowaVe Technology, 3100 Smith Farm Road,
Matthews, North Carolina 28104, U.S.A.
Abstract:
ous flow cell could end up being time-consuming, reopti-
mization of reaction conditions often being required. The
other option is to use a batch-type process. This could either
involve using one large vessel12-14 or parallel batch reac-
tors.15,16 A drawback with performing large-scale reactions
in batch mode can be the penetration of microwave irradia-
tion into the reaction mixture as the vessel size is increased.
Continuously stirring the reaction mixture offsets this
problem to some degree.
Representative Suzuki couplings in water using low catalyst
concentrations in conjunction with microwave heating have
been transferred from sealed-vessel to open-vessel reaction
conditions. They have then been scaled-up to the mole scale
using a dedicated multimode microwave apparatus. The reac-
tions are complete within 20 min of heating at reflux.
Our research in the area of microwave-promoted chem-
istry recently led to the discovery that it is possible to perform
Suzuki couplings in water using ultralow quantities of
palladium catalyst.17-20 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 rapidly
Introduction
Microwave-promoted synthesis is an area of increasing
interest in both academic and industrial laboratories.1-3 As
well as being energy efficient,4 microwave heating can also
enhance the rate of reactions and in many cases improve
product yields. An area of increasing research interest is the
scale-up of microwave-promoted chemistries. While many
reactions have been performed on the small scale using
microwave heating, few have been further developed into
larger-scale syntheses. This clearly needs to be addressed if
the technology is going to impact process chemistry.5,6 There
are two possible scale-up options. The first is to use a
continuous flow microwave cell, this technology being used
successfully for a number of different reactions.7-11 The
drawback of a continuous flow microwave apparatus is that
it can be difficult to process solids, highly viscous liquids,
or heterogeneous reaction mixtures. Also, adaptation of
conditions from simple small-scale reactions to the continu-
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* To
whom
correspondence
should
be
addressed.
E-mail:
† University of Connecticut.
‡ CEM Microwave Technology.
(1) A number of books on microwave-promoted synthesis have been published
recently: (a) Kappe, C. O.; Stadler, A. MicrowaVes in Organic and
Medicinal Chemistry; Wiley-VCH: Weinhiem, 2005. (b) Lidstro¨m, P.,
Tierney, J. P., Eds. MicrowaVe-Assisted Organic Synthesis; Blackwell:
Oxford, 2005. (c) Loupy, A., Ed. MicrowaVes in Organic Synthesis; Wiley-
VCH: Weinheim, 2002. (d) Hayes, B. L. MicrowaVe Synthesis: Chemistry
at the Speed of Light; CEM Publishing: Matthews, NC, 2002.
(2) For a recent review see: Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43,
6250.
(3) For other reviews on the general area of microwave-promoted organic
synthesis see: (a) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res.
2002, 35, 717. (d) Lew, A.; Krutzik, P. O.; Hart, M. E. Chamberlain, A.
R. J. Comb. Chem. 2002, 4, 95. (e) Lidstro¨m, P.; Tierney, J. P.; Wathey,
B.; Westman, J. Tetrahedron 2001, 57, 9225.
(4) Gronnow, M. J.; White, R. J.; Clark, J. H.; Macquarrie, D. J. Org. Process
Res. DeV. 2005, 9, 516-518.
(5) For a discussion of scale-up of microwave-assisted organic synthesis see:
Roberts, B. A.; Strauss, C. R. In MicrowaVe-Assisted Organic Synthesis;
Lidstro¨m, P., Tierney, J. P., Eds.; Blackwell: Oxford, 2005.
(6) For a review see: Roberts B. A.; Strauss, C. R. Acc. Chem. Res. 2005, 38,
653.
(19) (a) Arvela, R. K.; Leadbeater, N. E.; Mack, T. M.; Kormos, C. M.
Tetrahedron Lett. 2006, 47, 217. (b) Arvela, R. K.; Leadbeater, N. E. Org.
Lett. 2005, 7, 2101.
(20) Arvela, R. K.; Leadbeater, N. E.; Collins, M. J. Tetrahedron 2005, 61,
9349.
10.1021/op0600613 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/23/2006
Vol. 10, No. 4, 2006 / Organic Process Research & Development
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