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allowing the construction of a wide range of bonds: sp
3
-sp
3
,sp
3
-sp
2
,sp
2
-sp
3
and sp
2
-sp
2
. The use of the well-defined system in comparison with the
older in situ-generated system
74
was found to increase substantially the
scope and the reliability of the cross-coupling. Most notably, 15 was active at
lower catalyst loadings (1 versus 2mol%).
In 2009, Organ and co-workers began to study the mechanism of the alkyl-
alkyl Negishi reaction.
76
Using DFT investigations, it was shown that
transmetallation was the rate-limiting step and not oxidative addition.
Moreover, a Pd-Zn interaction was identified in the mechanism. The latter
was postulated to facilitate reductive elimination, in combination with the
ligand. This was thought to be possible by the generation of a sterically
crowded environment in the coordination sphere of the Pd atom.
Organ's group also investigated the role of additives in Negishi coupling.
77
Bromide salts were found to promote the reaction whereas the counter-
cation was observed to have a minor effect. Titration studies also showed
that the coupling remained dormant until a minimum ratio of 1:1 between
LiBr and nBuZnBr was achieved. This suggested that higher-order zincates of
formula Li
m
Zn(nBu)Br
3
(2-m)
were likely to be the active transmetallating
agents (Scheme 4.15).
To corroborate the postulate that higher-order zincates were involved in
the Negishi reaction, Organ and co-workers studied in more detail the
addition of lithium bromide to the reaction medium. Mass spectrometry
78
was used to identify the negatively charged species resulting from mixtures
of LiBr and nBuZnBr in various solvents. DMI and NMP were found to be
essential to form and stabilize higher-order zincates such as nBuZnBr
2
and
nBuZnBr
3
2
. This was also confirmed by NMR studies. Finally, studies in-
volving directly isolated and pure crystalline RZnBr
3
2
zincates
79
definitely
proved the involvement of these species in the reaction. Reaction occurred in
2 h in THF to yield the desired compounds in excellent yields (Scheme 4.16).
In 2010, Organ and co-workers reported the use of a new complex in the
reaction, [Pd(IPent)(PEPPSI)] (4).
80
This complex proved to be much more
active than the previously reported [Pd(IPr)(PEPPSI)] (15), especially for the
preparation of highly functionalized tetra-ortho-substituted biaryls
(Scheme 4.17). As reported previously for Suzuki-Miyaura cross-coupling,
the flexible steric bulk
23
of the IPent ligand was postulated as the key to
success in the more challenging reactions.
[Pd(IPent)(PEPPSI)] (4) was also found to be an excellent precatalyst for the
coupling of secondary alkylzinc halides with aryl/heteroaryl halides.
81
Most
2
Br
Br
LiBr
ZnBr
2
LiZnBr
3
LiBr
ZnBr
2
LiZnBr
3
n
Bu
Zn
Br
Li
n
Bu
Zn
2xLi
n
Bu
Zn
Br
Br
Br
Postulated
transmetallating agent
Scheme 4.15 Postulated transmetallating agents in Negishi coupling.
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