Chemistry Reference
In-Depth Information
PhMe-DMSO (2.5:1)
Dean-Stark
reflux, 3 hr
MeN
O
B(OH)
2
O
B
O
O
94%
HO
O
O
HO
N
HO
OH
MeN
i) B(OR)
3
, THF
ii) MIDA, DMSO,
Δ
O
O
R-M
RB
O
O
R = 2-pyridyl, ethynyl
MeN
i) BBr
3
, DCM
O
O
86%
O
O
TMS
B
O
O
ii) MeCN,
N
NaO
ONa
Scheme 8.15 Preparation of MIDA boronates for different substrate classes.
The quaternization at boron from nitrogen ligation usually renders the
MIDA boronates free-flowing, crystalline solids that are stable to air, mois-
ture and silica gel chromatography and can be stored without precaution
''on the bench top,''
74
including the notorious 2-heterocyclic surrogates. The
use of MIDA boronates in SM coupling was originally designed by Burke and
co-workers for their use in iterative coupling processes, for which stability
towards cross-coupling, yet ready liberation of the active species when re-
quired, is pivotal for success.
78
It has been proposed that the future of
automated synthesis lies in iterative synthesis,
79
where bifunctional building
blocks, with all the functionality and stereochemistry set, are coupled
together using only one type of reaction. This is followed by a deprotection of
latent functionality, activating the material towards further coupling and
subsequent repetition. Much development is still required before iterative
cross-coupling (ICC) becomes reality, but MIDA boronates have exhibited
strong potential in this regard.
78,80
This is because they are stable to many
reaction conditions but upon treatment with mild aqueous base the boronic
acid is released for cross-coupling. The utility of MIDA boronates has been
amply demonstrated in a number of natural product syntheses.
78,81,82
Owing to the effective removal of the vacant p-orbital required for trans-
metallation (via either pathway), under anhydrous SM coupling conditions
MIDA boronates are inert.
80
Dynamic
1
H NMR experiments have been em-
ployed to compare the stability of MIDA boronates with N-methyldiethano-
lamine boronates, which do undergo cross-coupling under anhydrous SM
coupling conditions. No fluxionality was detected with the MIDA boronates,
but significant broadening and shifting of the peaks was observed when the
N-methyldiethanolamine boronates were heated, indicative that MIDA bor-
onates are conformationally rigid whereas N-methyldiethanolamine bor-
onates undergo conformational flipping (Scheme 8.16).
83
MIDA boronates are remarkably resistant to a variety of reaction conditions
and reagents, meaning that they can be carried through synthetic sequences
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