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XPhosPdcycle (5 mol%),
Cu(OAc)
2
(50 mol%),
Ar-Cl, K
3
PO
4
, DEA
MeN
O
O
B
O
Ar
49-96%
R
R
N
N
DMF, 100 °C, 24 hr
Scheme 8.18
SM coupling of 2-pyridyl MIDA boronate with aryl chlorides.
Cu(OAc)
2
Ar
K
3
PO
4
DEA
N
Cu(DEA)
2
L
m
Pd
MeN
(
A
)
(
C
)
O
O
B
O
B(X)
n
Cu
KOAc
y
N
N
(
D
)
N
(
B
)
Ar-Cl
Scheme 8.19 Coupling of the 2-pyridyl moiety employing four strategies in concert
to minimize degradation of
the intermediate boronic acid and
derivatives.
cross-coupled product to that when the MIDA boronate was employed,
Scheme 8.17. The total synthesis of (+)-dictyosphaeric acid A provided
excellent validation of the approach, in which a vinylic MIDA boronate,
whose boronic acid can be unstable towards polymerization at high
concentrations, was cross-coupled with an alkenyl iodide with an isolated
yield of 82%.
85
This work has also been extended to include the 2-pyridyl moiety, which
was successfully (49-96%) cross-coupled with unactivated aryl chlorides
(Scheme 8.18), arguably one of the most dicult aryl cross-couplings.
86
Side reactions in SM coupling are not exclusively, but predominantly,
centred around the boron reagent and a number of strategies for their at-
tenuation have been developed.
68
The 2-pyridyl moiety is notoriously dif-
ficult to cross-couple (as the nucleophilic component) and the MIDA system
applies four strategies in concert for effective coupling (Scheme 8.19):
A. Catalyst activation - Employing a rapidly activated precatalyst liberates
an XPhos-ligated palladium(0) complex under the reaction con-
ditions.
87
These electron-rich Buchwald catalyst systems shift the
turnover-limiting step from oxidative addition towards transmetalla-
tion, thereby making the resting state Pd(II) rather than Pd(0), and
accelerating transmetallation. Faster turnover then decreases the net
reaction time, thus minimizing the extent of exposure of the boronic
acid to the reaction medium.
B. Boron reagent activation - Silver
51-53
and copper
88
salts have been
shown to increase the rate of transmetallation to palladium. Silver may
effect more rapid halogen-hydroxide exchange on palladium to gen-
erate the key oxo-palladium intermediate, whereas copper appears to
effect a more ecient transmetallation with boron. In the 2-pyridyl
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