Chemistry Reference
In-Depth Information
O
Br
Pd(OAc)
2
, PPh
3
, CO
NHBn
N
Bn
4.51
4.52
Scheme 4.22
Br
O
(Ph
3
P)
2
PdCl
2
, K
2
CO
3
, CO
O
OH
4.53
4.54
Scheme 4.23
MeO
MeO
MeO
MeO
OH
(Ph
3
P)
2
PdCl
2
, K
2
CO
3
, CO
O
I
O
4.55
4.56
Scheme 4.24
4.59
, perhaps the mildest way of forming a carbon-carbon bond (Chapter 2, Section 2.8). The synthesis was
completed by selective reduction of the alkynes and disubstituted alkenes of Sonogashira product
4.61
using
Wilkinson's catalyst, and deprotection.
Under special conditions, double carbonylation can be achieved (Scheme 4.26),
26
although this is rarely
observed. It appears to be favoured by the correct choice of nucleophile and phosphine ligands and, of course,
high CO pressures.
Useful precursors for agrochemicals were obtained by either single or double alkoxycarbonylation of a
dichloropyridine
4.65
(Scheme 4.27).
27
Either product,
4.66
or
4.67
, could be obtained by the choice of the
reaction temperature, on a 120 g scale. For single carbonylation, the expected selectivity (see Chapter 2,
Section 2.1.4) for greater reactivity
to the pyridine nitrogen giving ester
4.67
was found.
In the preparation of a platelet aggregation inhibitor
4.71
on a scale of 123.9 kg, both the bromide
4.69a
and
the iodide
4.69b
could be coupled with the piperidine
4.70
in the presence of carbon monoxide to introduce
the desired amide linkage (Scheme 4.28).
28
While the bromide
4.69a
required somewhat specific conditions
for good yields, the carbonylative coupling of the iodide
4.69b
did not.
Heterocycles may also be carbonylated, to give either ring-expanded heterocycles, or ring-opened
products.
29
These include epoxides (Scheme 4.29), aziridines (Scheme 4.30),
30
oxetanes (Scheme 4.31)
31
and azetidines (Scheme 4.32).
32
The cobalt-catalysed carbonylation of epoxides provides a short route to
-hydroxyesters
4.73
(Scheme 4.29).
33
These useful synthetic building blocks are often obtained in enan-
tiomerically enriched form by the asymmetric reduction of
-ketoesters.
34
As many epoxides are readily
available in very high e.e., the carbonylation chemistry provides a useful alternative route.
Unstrained heterocycles may also be carbonylated, although, owing to the absence of ring strain, which
provides a powerful driving force, more vigorous conditions may be required.
