Cross-Coupling Chemistry in Continuous Flow - New Trends in Cross-Coupling: Theory and Applications - page 620

21% yield was obtained for the Mizoroki Heck reaction between phenyl
iodide and n-butyl cinnamate within a 3 min residence time (the catalyst
loading was below 0.001 mol%).
13.4 Carbon-Carbon Bond Formation
in Continuous Flow
13.4.1 Suzuki-Miyaura Cross-Coupling in Flow
Suzuki-Miyaura cross-coupling (SMC) is one of the most utilized catalytic
reactions in the pharmaceutical industry. It permits the reliable formation of
carbon-carbon bonds by utilizing organoboron nucleophiles, which are
stable and commercially available coupling partners. Owing to its broad
utility in a variety of specialty applications, this reaction is one of the most
studied cross-coupling examples in continuous flow microreactors. 3
Typically, reaction times in continuous flow are much shorter than in the
corresponding batch experiments. This is often due to the elevated amounts
of catalyst available when utilizing immobilized palladium sources, 29 or
to the rapid heat transfer and the elevated reaction temperatures that can
be safely reached in microreactors. Ecient heat transfer allows for rapid
activation of the molecules, which permits fast reactions. Microreactors
are typically heated via conductive heating (e.g. hot-plates, oil-baths, GC
ovens), 22 via resistive heating (e.g. cartridge heaters), via inductive heating 14
or via microwave irradiation. 30
The ability to combine several reaction steps in one continuous and
interrupted flow process constitutes a time- and cost-ecient alternative to
the typical elaborate multistep procedures in synthetic organic chemistry. 31
However, utilizing a continuous flow strategy for multistep syntheses is not
straightforward. First, reagents, solvents and impurities from the first re-
action steps need to be compatible with the downstream reactions or need to
be eciently removed. Second, subsequent addition of dissolved reagents
results in a diluted downstream reaction, which can make the reaction less
ecient.
In the ideal situation, all reagents are compatible with the subsequent
transformations and no intermediate purification is required. This consti-
tutes an easily implemented flow strategy and resembles the one-pot batch
strategies. An example involves a subsequent lithiation, borylation and SMC
reaction sequence (Figure 13.8). 32 In a first PFA capillary microreactor,
a lithium-halogen exchange was performed at room temperature. The
reaction stream was subsequently merged with B(O i Pr) 3 to produce the
corresponding boronate coupling partner. Next, aryl halide, XPhos precat
and aqueous KOH solution were added to enable the SMC reaction to pro-
ceed. Owing to the partial insolubility of the boronate, acoustic irradiation
was required to prevent microreactor clogging. The method was further ex-
tended to the direct deprotonation of five-membered heterocycles. A similar
protocol was developed to lithiate aryl halides with electrophilic functional