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Cl
OMe
F
Br
(Ph
3
P)
4
Pd
+
Cl
Cl
OMe
DME/H
2
O
NaOH, 80°C
Cl
B(OH)
2
F
NH
2
20 kg scale
O
Cl
Cl
5-HT
2C
receptor antagonist
F
Scheme 3.4 Wyeth's synthesis of a 5-HT
2C
receptor antagonist using a chemoselec-
tive Suzuki-Miyaura coupling.
I
N
(Ph
3
P)
4
Pd
THF, rt
+
NN
N
l
N
N
Cl
Cl
Scheme 3.5 Chemoselective Negishi coupling of an aryl iodide.
compared with the use of more advanced Pd precatalysts with higher
reactivities.
Gontcharov et al. at Wyeth Research disclosed a process to make a 5-HT
2C
receptor antagonist in which the first step consisted of a (Ph
3
P)
4
Pd-catalyzed
Suzuki-Miyaura coupling reaction carried out on a 20 kg scale
(Scheme 3.4).
30
In this case, the chemoselective coupling of a chloride-
containing aryl bromide was achieved. This may have proved to be chal-
lenging in terms of selectivity while using a more active precatalyst.
In 2007, a Negishi cross-coupling between the in situ-prepared 2-pyr-
idylzinc chloride and 5-iodo-2-chloropyrimidine catalyzed by (Ph
3
P)
4
Pd af-
forded the product in a single step on a kilogram scale (Scheme 3.5).
31
This
chemoselective coupling of a chloride-containing aryl iodide is particularly
noteworthy, as the chloride is in the inherently most reactive position for a
standard S
N
Ar reaction.
3.5 L
2
Pd(0) Complexes
The use of triarylphosphines such as Ph
3
P as ligands limits the scope of the
aryl halide substrate to aryl iodides or activated aryl bromides. Since aryl
chlorides would be desirable substrates from a cost point of view as they are
industrial feedstocks, substantial research efforts have been focused on
overcoming this limitation. The use of trialkyl- and dialkyl-based phosphine
ligands came as a breakthrough in this area (see Chapter 2 for details), al-
though some of these ligands are air sensitive or even pyrophoric in nature,
posing safety concerns especially during scale-up. Such risks are avoided
by using preformed Pd catalysts of these ligands, where the complexes
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