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than ''phosphine-free'' reactions, which makes the term ''ligand-acceler-
ated'' somewhat ambiguous in this context. TON and turnover frequency
(TOF) records are always never obtained in reactions involving phosphine
complexes of palladium. Nevertheless, synthetic chemists often choose
phosphine-assisted catalysis for their syntheses. For example, in the review
by Torborg and Beller of industrial applications of Pd-catalysed reactions,
145
most of the cited processes use (o-tol)
3
P-based catalytic systems for multi-
kilogram syntheses, the few remaining being ''phosphine-free'' reactions.
Apparently, from the viewpoint of technology, the reliability and reprodu-
cibility of the process outweigh the expense of the ligand and generous
precatalyst loading and such merits are inherent in ligand-accelerated Heck
chemistry. The same is true in complex organic syntheses. A recent example
of the use of the classical Heck protocol for selectively linking two complex
natural compounds, each abundant in functionality and with chiral centres
and a second double bond, is illustrated in Scheme 9.31.
146
Simple phosphine complexes can sometimes solve challenging tasks. For
example, although sp
3
substrates remain in general an unresolved target, in
specific cases, e.g. involving electron-deficient arylsulfonyldifluoromethyl
bromide, a Mizoroki-Heck reaction at the sp
3
centre was realized by Reu-
trakul and co-workers through the use of the Pd(PPh
3
)
4
complex at a high
initial loading.
147
The first classical ligand-accelerated protocols using basic triarylphos-
phine ligands exhibited low reactivity with deactivated aryl bromides and
zero reactivity with aryl chlorides. The search for more reactive catalytic
systems was intensive and advanced in parallel with similar studies in the
cross-coupling chemistry. The latter brought forward multiple effective
protocols serviced by many advanced ligands of the phosphine and carbene
families optimized for solving specific tasks for different combinations of
substrates, and gave exceptionally mild room-temperature methods for
processing the least reactive electron-rich and sterically hindered chloro
I
H
O
Pd(OAc)
2
(6 mol%)
4(o-tol)
3
P, E t
3
N
DMF, 120°C, 15 h
O
+
COOR
H
H
NHAc
H
O
O
H
H
ROOC
AcHN
Scheme 9.31 Classical Heck protocol for the synthesis of a hybrid of two natural
molecules, isoalantolactone and lappaconitine (R is the diterpene part
of this alkaloid).
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