Chemistry Reference
In-Depth Information
PdL
n
or Ni, R'-X
Kumada
PdL
n,
base, R'-X
R
MgBr
R
Heck
PdL
n,
base, Cu, R'-X
R
H
Sonogashira
PdL
n
or Ni, R'-X
ZnX
R-R'
R
PdL
n,
F
-
, R'-X
Hiyama
PdL
n,
base, R'-X
Suzuki
Negishi
SiX
3
R
Sn(R'')
3
PdL
n
, R'-X
Stille
B(OH)
2
R
R
Scheme 8.1 A selection of Pd-catalysed cross-coupling reactions.
F
O
N
N
S
H
2
N
N
NH
2
O
N
N
N
CO
2
H
Lamictal
GSK
$1843 m (51
st
)
Cl
Crestor
AstraZeneca
$2049 m (42
nd
)
OH
OH
Cl
Cl
N
N
n
-Bu
N
N
N
N
NK
N
N
HO
N
N
N
N
HN
N
N
O
N
Avapro
Bristol Myers Squibb
$2372 m (35
th
)
Cozaar
Merck & Co. Inc.
$3163 m (19
th
)
Gleevec
Novartis
$2554 m (30
th
)
HN
N
O
Figure 8.1 Examples of ''blockbuster'' drugs with biaryl moieties. Figures in paren-
theses are overall rank based on stated revenue in 2006.
Of the palladium-catalysed cross-coupling reactions available (Scheme 8.1),
Suzuki-Miyaura (SM) coupling has emerged as the one that has enjoyed the
most widespread application,
9
with numerous relatively non-toxic and stable
reagents now commercially available. A vast array of developments have been
reported,
9
from expansion of the substrate scope to include unactivated aryl
chlorides
10
and sterically demanding substrates,
11
to reducing the catalyst
loadings to very low levels,
12
e.g.
o
0.05 mol%,
13
and lower reaction tempe-
ratures.
14,15
Indeed, SM coupling has become the ''gold standard'' for biaryl
construction, arguably resulting in the ubiquity of this moiety in modern
medicinal chemistry,
16
with biaryls present in many ''blockbuster'' drug
molecules (Figure 8.1).
8.1.2 Boron Reagents
The key to the success of the SM coupling reaction stems from the ex-
ceptional functional group tolerance of the catalyst system and the mild
Search WWH ::
Custom Search