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Br
R
+
PEPPSI-SIPr (5 mol%)
n-
BuLi
MeOH
Br
R
R
R
0°C
2.6 s
50 °C
94 s
Lithium-halogen
exchange
Murahashi
coupling
OMe
N
N
S
S
F
3
C
MeO
90%
82%
64%
87%
80%
i
-Pr
i
-Pr
N
N
Cl
Pd
Cl
i
-Pr
i
-Pr
N
Cl
PEPPSI-SIPr
Figure 13.20 Microreactor
assembly
for
the
lithiation-Murahashi
coupling
sequence.
13.4.7 Hiyama Cross-Coupling in Flow
Hiyama coupling is a mild cross-coupling method that utilizes organosilicon
nucleophiles. These coupling partners are inexpensive, easy to prepare and
non-toxic. Despite these apparent advantages, only a single example can be
found in which Hiyama coupling has been performed under continuous flow
conditions (Figure 13.21).
51
Pd was immobilized on a diphenylphosphine-
bonded silica gel, which was loaded in a micro packed-bed reactor. Several
aryl bromides were coupled with trimethoxysilylbenzene in the presence of
2 equiv. of tetra-n-butylammonium fluoride, which activated silicon for
transmetallation.
13.4.8 Negishi Cross-Coupling in Flow
Negishi cross-coupling utilizes organozinc coupling partners. Despite its
popularity in batch, only a single example details its application in
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