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generally low to moderate even when freshly-prepared boronic acids are
employed in Suzuki-Miyaura cross-couplings, employing the corresponding
MIDA boronate results in excellent yields of the desired cross-coupled
products (Table 1).
Entry
1
2
3
4
R B
H3C
R B(OH)2 or
N
O
O
O
O
1 eq 1 eq
A B
R
O
Boc
N
% remaining after benchtop
storage under air
A (15 days) B (>60 days)
7 >95
95
5 >95 a
Ot-Bu
Cl 1 mmol
Pd(OAc)2, SPhos
K3PO4, dioxane:H2O (5:1)
60 °C, 6 h
Boc
N
SO2Ph SO2Ph
N
95
N
a cross coupling conducted at 100 °C
O
C
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
R
C
Ot-Bu
Cross Coupling
Isolated Yield (%)
with A with B
68 94
61 90
79 98
14 93
Table 1: Stability and slow-release cross-coupling studies of MIDA boronates vs.
boronic acids.
MIDA Boronates for Classically Challenging
Suzuki-Miyaura Cross-Couplings
The power of this slow-release concept has been further illustrated by
utilizing various MIDA boronates of which the corresponding boronic
acids have historically exhibited challenges with respect to either storage
or use, including 2-heterocyclic, vinyl and cyclopropyl boronic acids.
Because these organoboron species readily decompose through a variety
of pathways, the effi ciency with which their corresponding MIDA boronates
may be coupled is particularily noteworthy (Table 2).
R B
H3C N
O
O
O
O
Cl R'
Pd(OAc)2, SPhos, K3PO4
dioxane/H2O (5:1), 60 °C, 6 h
R R'
Entry R MIDA R' Cl
Product Isolated Yield (%)
H3C
N
N
N
1
S B O
O
H3C
O
O Cl N
S
N
97
2
Boc
N
N
B O
O
O
O
Cl
O
N
CH3
Boc
N
O
N
CH3
98
H3C 3
N
B O
O
O
O Cl
N NH2
N NH2
76
H3C
N
H3C CH3 H3C CH3
4
B O
O
O
O Cl
CH3
CH3
79
Table 2: Slow-release cross-coupling of MIDA boronates with historically challenging
substrates.
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Organometallics
2-Pyridinylboronic Acid MIDA Ester as a Stable
2-Pyridinyl Boron Anion Equivalent
The development of a viable air-stable surrogate for the notoriously
unstable 2-pyridinylboronic acid has been a long-standing challenge
in the fi eld of cross-coupling. This motif is ubiquitous in drug-like small
molecules, and therefore of particular importance to the synthetic community.
While 2-pyridinylboronic acid surrogates exist, their use is often
complicated by air- and moisture-sensitivity as well as their somewhat
variable and impure compositions. In contrast, Burke and coworkers
found that 2-pyridinyl MIDA boronate is isolable, benchtop and chromatography
stable, and under slow-release conditions can be successfully
coupled with a variety of aryl and heteroaryl chlorides (Table 3).
H3C N
N
B O
O
O
O
Cl R
Pd2(dba)3, XPhos, K3PO4
Cu(OAc) 2, K2CO3
DMF/IPA (4:1), 100 °C, 4 h
N R
Entry Cl R Product Isolated Yield (%)
1
2
3
Cl
Cl
Cl
719390
N
N
O
C CH3
CN
N
N
N
N
N
O
C CH3
Table 3: Slow-release cross-coupling of 2-pyridinylboronic acid MIDA ester.
References: (1) Gillis, E. P.; Burke, M. D. Aldrichimica Acta 2009, 131, 17. (2) Knapp, D. M.;
Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961.
Pyridinyl MIDA Boronates from Aldrich
Cl
N
N
H3C
N
B
O
O
O O
719390
H3C
N
700908
H3C
N
B O O
O O
N OCH3
701084
B O O
O O
Br
H3CO
N
N
H3C
N
723959
N
B
O
O
O O
H3C
N
702269
H3C
N
723053
B O O
O O
B
O
O
O O
CN
Br
H3CO
For a complete list of MIDA boronates available from
Aldrich Chemistry, visit Aldrich.com/mida
H3C
N
N
72
60
79
H3C
N
B O O
O O
N
704563
H3C
N
703370
H3C
N
699845
B O O
O O
B O O
O O
15