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14
MIDA Boronates for Suzuki–Miyaura
Cross-Couplings
Aldrich.com
Organometallics
Aaron Thornton, Ph.D.
Product Manager
aaron.thornton@sial.com
Professor Martin Burke and coworkers recently prepared retinal using
key MIDA building block BB1 in iterative Suzuki-Miyaura cross coupling
reactions (Scheme 1). The MIDA unit of BB1 is unreactive under these
conditions, allowing for the selective cross-coupling of BB1 with triene
(1). Subsequent hydrolysis of the MIDA unit of (2) followed by a second
Suzuki-Miyaura reaction provided all-trans-retinal.
H3C
CH3
CH3
B(OH)2
H3C N
BB1
O
B O
Br O O
703478
Pd(OAc)2, SPhos, K3PO4
H3C CH3
CH3
H3C
N
B O
O
O
O
CH3 1 toluene
23 °C, 78%
CH3 2
1. aq. NaOH, THF, 23 °C
CH3 H
2.
Br O
Pd(OAc)2, SPhos, K3PO4, THF
23 °C, 66%
CH3 CH3 H3C
H
CH3
O
CH3
all-trans-retinal
Scheme 1: Iterative Suzuki-Miyaura cross-couplings in the synthesis of
all-trans-retinal.
Reference: Lee, S. J. et al. J. Am. Chem. Soc. 2008, 130, 466.
The many advantages of the MIDA boronate platform include air and
moisture stability, stability under anhydrous cross-coupling conditions,
compatibility with a range of common and harsh reagents, solubility
in various organic solvents, silica gel compatibility, and the ability to
undergo slow release cross-couplings.
MIDA Boronates from Aldrich:
H3C
N
B O O
O O
697311
H3C
H3C
N
B O
O
CH2 O
O
707252
TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis.
H2C
H2C
H3C
N
B O O
O O
N
B
O
O
O O
H3C
698709 700231
N
B
O
O
O O
H3C
704415
HC
S
N
B
O
O
O O
H3C
708828
For complete list of MIDA boronates available from
Aldrich Chemistry, visit Aldrich.com/mida
Slow-Release of Unstable Boronic Acids from
MIDA Boronates
In addition to attenuated reactivity towards anhydrous cross-coupling
conditions, MIDA boronates also possess the capacity for in situ slowrelease
of boronic acids under aqueous basic conditions (Scheme 2).
Harnessing this phenomenon, boronic acids that are notoriously unstable
can be eff ectively utilized in cross-coupling when employed as MIDA
boronates. While aqueous solutions of NaOH promote the fast hydrolysis
of MIDA boronates to their corresponding boronic acids, the use of aqueous
K3PO4 allows for the slow-release of relatively unstable boronic acids,
preventing decomposition of the organometallic species and improving
overall yields for many Suzuki-Miyaura reactions.
Slow Release of Unstable Boronic Acids
R B
H3C
Pd-catalyst
N
O
O
O
O
mild aqueous base (e.g. K3PO4)
Cl R'
R B(OH)2
Scheme 2: Slow-release of unstable boronic acids from MIDA boronates.
Burke and coworkers examined this slow-release concept by comparing
various freshly prepared boronic acids with their corresponding MIDA
boronates. The study revealed that many boronic acids decompose
signifi cantly via various pathways, including protodeborylation, oxidation,
and polymerization, after just 15 days of benchtop storage under air. On
the other hand, the corresponding MIDA boronates were remarkably
stable, with >95% of each MIDA remaining after ≥60 days of benchtop
storage under air. In addition to complications related to storage, the
overall effi ciency of cross-coupling for these reagents is also impacted
by the nature of the boron unit. For example, while isolated yields are
R R'