Pd–Phosphine Precatalysts for Modern Cross-Coupling Reactions - New Trends in Cross-Coupling: Theory and Applications - page 111

Ph Ph

P

P

Cl

Fe Pd

99.1°

Pd

Cl

P

Ph Ph

P

Figure 3.14 Bite angle of the dppf ligand in precatalyst dppfPdCl 2 .

PdCl 2 (CH 3 CN) 2 +dppf dppfPdCl 2

Scheme 3.18 Preparation of dppfPdCl 2 .

NBoc

N

N

Br

O NBoc

Cl

B

O

N N Cl

O

N

N

O

NH 2

Cl

NH 2

1) dppfPdCl 2 ·CH 2 Cl 2
Cs 2 CO 3 ,Bu 4 NBr
2) HCl, EtOH/EtOAc

Cl

F

F

Scheme 3.19 Suzuki-Miyaura coupling as part of the synthesis of crizotinib.

This can help improve reactions that are otherwise problematic, such as
Kumada coupling of secondary alkylmagnesium chlorides, where the re-
ductive elimination occurs faster than the b-hydride elimination. 70,71 Nu-
merous examples of the use of the precatalyst dppfPdCl 2 in catalysis can be
found in the literature. 72 The orange, air-stable catalyst was prepared ori-
ginally by reacting a suitable Pd precursor with dppf ligand (Scheme 3.18). 70
As in the previous examples, the catalytically active species is proposed to
be the dppfPd(0) species, although its isolation is very challenging.
This catalyst is commercially available in three forms: dppfPdCl 2 CH 2 Cl 2 ,
dppfPdCl 2 Me 2 CO and solvent-free dppfPdCl 2 . 73 Johnson Matthey was the
first company to commercialize both the ligand and catalyst for bulk
applications.
Recently, a large-scale Suzuki-Miyaura coupling of ArBr with a boronic
ester was reported for the six-step synthesis of crizotinib using dppfPdCl 2
catalyst (Scheme 3.19). 74
In 2010, an ecient synthesis of multi-kilogram quantities of BMS-764459
was reported, which features an ecient palladium-catalyzed cyanation of a
5-chloropyrazinone, as shown in Scheme 3.20. 75
In general, the dppfPdCl 2 precatalyst is particularly useful for borylation of
Ar-Br 76 and carbonylation. 77
Just as in the case of the activity variation of (Ph 3 P) 4 Pd versus (t-Bu 3 P) 2 Pd,
exchanging the Ph of dppf with a bulkier more electron-rich t-Bu group
dramatically enhanced the reactivity of the precatalyst to allow the coupling
of less reactive aryl halides (Figure 3.15).