Chemistry Reference
In-Depth Information
P
hC
N
(Ph
3
P)
2
PdCl
2
PdCl
2
+2Ph
3
P
Scheme 3.15 Preparation of (Ph
3
P)
2
PdCl
2
.
i)
SiMe
3
O
O
O
SiMe
3
i) aq. NaOH
I
HN
HN
0.5 mol% (Ph
3
P)
2
PdCl
2
0.5 mol% CuI
Et
3
N, EtOAc
ii) THF/MeOH, charcoal
HN
ii) AcOH
O
N
H
O
N
H
O
N
H
eniluracil
60 kg scale
Scheme 3.16 Large-scale Sonogashira coupling catalyzed by (Ph
3
P)
2
PdCl
2
.
O
O
1mol%(Ph
3
P)
2
PdCl
2
1mol%CuI
I
OH
O
O
O
O
O
O
+
N
OH
Et
3
N,EtOH,rtto57°C
84 %
N
0.5 kg scale
N
N
HO
OH
HO
OH
O
O
O
O
O
O
O
O
O
O
O
O
O
OH
N
Scheme 3.17
(Ph
3
P)
2
PdCl
2
catalyzed Sonogashira coupling.
loading in a Sonogashira reaction could be reduced to 0.5 mol%
(Ph
3
P)
2
PdCl
2
with 0.5 mol% CuI co-catalyst. The final product was isolated
with Pd and Cu levels below 2 and 1 ppm, respectively.
The in situ formation of the catalyst by mixing PdCl
2
and Ph
3
P was very
inecient (as judged by the almost complete insolubility of PdCl
2
in EtOAc)
in comparison with the use of preformed (Ph
3
P)
2
PdCl
2.
68
This highlights one
of the advantages of using a preformed catalyst over the in situ-formed
catalyst.
ˆ
timac et al. at GlaxoSmithKline in 2010 developed a process to a lead
antibacterial compound (Scheme 3.17). One of the initial steps consisted of a
(Ph
3
P)
2
PdCl
2
-catalyzed Sonogashira coupling,
69
as in the previous example.
As discussed in Chapter 2, the properties of bidentate ligands also may
have a profound influence on a specific cross-coupling reaction. It was early
identified that the larger bite angle (99.11) of a dppf ligand was very im-
portant in facilitating the reductive elimination step in the catalytic cycle
(Figure 3.14).
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