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13.4.5 Kumada-Corriu Cross-Coupling in Flow
The Kumada-Corriu cross-coupling reaction utilizes Grignard reagents as
nucleophilic reagents in the transmetallation step. This transformation has
been of historical importance since it was the first useful cross-coupling
reaction. Its application in continuous flow has been limited; an example of
this cross-coupling strategy in flow involved the use of a silicon-supported
salen-nickel catalyst (Figure 13.19).
49
The catalyst was loaded in a micro
packed-bed reactor and applied in the reaction between 4-bromoanisole and
phenylmagnesium chloride. The coupled product was obtained in 62% yield.
However, significant amounts of by-products were also observed (25% of
reduced product and 7% of homocoupling). The yield decreased signifi-
cantly after a few hours owing to deposition of magnesium salts on the
catalyst support.
13.4.6 Murahashi Cross-Coupling in Flow
Similarly to Kumada-Corriu cross-coupling, the Murahashi cross-coupling
reaction utilizes strong nucleophiles, in this case organolithium species, as
coupling partners, which limits its practicality and functional group toler-
ability. An example of this methodology in flow is shown in Figure 13.20.
50
Aryllithium species are prepared via a halogen-lithium exchange in flow by
treating aryl bromides with n-butyllithium. Owing to the excellent mixing
and heat transfer capacities of microreactor technology, this reaction could
be carried out at 0 1C and could thus be completed in a few seconds. Next,
the aryllithium reagent was fed to a second reactor and merged with a
stream of an aryl bromide and a PEPPSI-SIPr catalyst. The use of a homo-
geneous and very reactive catalyst was crucial
to avoid side product
formation.
Ph
Br
immobilized Ni catalyst
MeO
MeO
25%
MeO
+
62%
+
RT
OMe
PhMgCl
Kumada-Cor riu Coupling
MeO
7%
Me
N
N
Si
Ni
O
O
Me
O
immobilized Ni catalyst
Figure 13.19 Kumada-Corriu coupling in flow using a packed-bed reactor filled
with immobilized Ni catalyst.
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