Chemistry Reference
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commonly used transition metal in large-scale couplings, followed by
copper (C-N and C-O bond formation) and nickel (Kumada cross-coupling).
Some of the reasons for this are: (a) the very thorough understanding of
reaction mechanisms with Pd; (b) the very large number of commercially
available Pd precatalysts;
3
and (c) the extensive list of ligands (mostly
phosphines) that have been developed to perform in combination with this
metal. The Nobel Prize in Chemistry awarded in 2010 to Professors Heck,
Negishi and Suzuki for their contributions to ''palladium-catalyzed cross-
couplings in organic synthesis'' has also contributed to the increasing
popularity of these chemistries.
4
Medicinal chemists have enthusiastically embraced these technologies
as a way of accessing new molecules that would previously have been very
dicult to prepare. At the same time, successful project progression in
pharmaceutical companies requires the involvement of process groups to
satisfy the increasing demand for active pharmaceutical ingredients (APIs)
destined for pharmaceutical development and clinical trials. And it is at
this stage of development in these groups where chemistries are pushed to
the limit in terms of robustness and eciency. As a result, process
chemists are understandably conservative regarding the incorporation of
new transformations into their synthetic arsenal due to the need for pro-
cesses that are reliable, predictable and mechanistically well understood.
However, since the late 1990s, the adoption of transition metal-catalyzed
coupling reactions in process chemistry has shown an impressive growth,
as demonstrated by the statistics in Table 15.1,
5
and we can arguably say
that this trend can only continue to increase in the future. An excellent
example of this is ring-closing metathesis, a technology that has been
around for decades but that only very recently has received particular
Table 15.1
Statistics on the number of transition metal-catalyzed large-scale
couplings (4100 mmol) published in mainstream literature by date.
5
Number of large-scale couplings (4100 mmol) by date
Before 2000
Type of coupling
2001-2010
2011-December 2013
Suzuki-Miyaura
5
53
16
Heck
10
20
2
Sonogashira
4
17
5
Kumada-Corriu
3
3
3
Negishi
0
10
1
Stille
1
1
0
Hayashi-Miyaura
0
3
0
Tsuji-Trost
1
3
3
Carbonylation
5
8
1
Cyanation
1
14
0
Nozaki-Hiyama-Kishi
0
1
1
Ring-closing metathesis
0
6
3
C-N bond formation
0
13
9
Migita
0
2
3
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