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In-Depth Information
PR
2
PR
2
2
R
2
R
2
R
2
R
2
R
2
PPh
3
Ph
3
P
P
P
P
P
P
P
Pd
Pd
Pd
Pd
4PPh
3
P
Ph
3
P
PPh
3
P
P
P
R
2
R
2
R
2
R
2
R
2
IV
14-electron
species
I
II
18-electron
species
III
16-electron
species
ArSAr'
product
reductive elimination
ArBr
oxidative addition
R
2
R
2
Ar
P
Ar
P
Pd
Pd
Ar'S
P
Br
P
R
2
R
2
VI
Hartwig
intermediate
V
ci s
Fitton Rick
intermediate
Br
Ar'S
substitution
Scheme 15.39 Proposed catalytic cycle for Migita coupling employing bidentate
ligands.
bromide ligand with thiolate would generate Hartwig complex VI, which can
then reductively eliminate desired product ArSAr
0
and IV, which restarts the
catalytic cycle.
15.4 Conclusion
As the examples throughout this chapter have shown, process chemists can
now leverage a wide range of transition metal-catalyzed couplings for C-C
and C-heteroatom bond formation. The eciency of these technologies has
reached a point where cost is not a deterring factor for their application on
scale due to low catalyst loadings in many cases.
Residual metal removal must be addressed if the coupling is positioned
near the end of the synthetic route and many possibilities for this exist.
171
Activated carbon is the preferred choice owing to cost and availability as
prepacked cartridges, but early process groups can resort to more sophisti-
cated metal scavengers such as functionalized silicas to remove a variety of
metals.
In addition to Pd, the preferred metal in most couplings, the application
of first-row metals such as Fe, Ni and Cu in coupling chemistry represents an
attractive and promising alternative to precious metals. Copper has been the
most widely employed non-precious metal on the process scale with recent
advances in C-N bond formation. Nickel follows as the preferred metal for
Kumada couplings. Iron has seen much more limited use and only one ex-
ample was found applied to Kumada coupling on a large scale. We expect to
see more of this chemistry in the future. With the increasing cost of Pd, the
investigation of non-precious metals such as Fe, Ni and Cu should result in
new technologies that may replace Pd and provide more sustainable
processes.
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