Boron Reagent Activation in Suzuki–Miyaura Coupling - New Trends in Cross-Coupling: Theory and Applications - page 332

In a somewhat complementary study, employing phosphine-free con-
ditions, Schmidt et al. used UV spectroscopy to measure the rates of reaction
between phenylboronic acid and an equilibrium mixture of [Pd II (OAc) 2 ] and
base (NaOAc) versus the reaction of [Pd II (OAc) 2 ] with an equilibrium mixture
of phenylboronic acid and base (Scheme 8.9). 48 Under the former con-
ditions, where neutral boronic acid was added to the premixed solution of
catalyst and base, thus analogous to the oxo-palladium pathway, biphenyl
generation occurred around 1.3-2 times more rapidly.
Aqueous base is often employed in SM coupling; indeed, a survey of
around 40 000 such couplings revealed that more than half were predicted to
have an aqueous biphase present. 49 Aqueous-organic biphases can readily
form upon addition of an inorganic base 47 to solvent mixtures such as
THF-water. 49 Analyses of reagent speciation in such biphasic mixtures
indicate that boronic acid is present in the bulk organic phase, 49 with small
proportions of trihydroxyborate present in the aqueous phase. Since
hydroxide can readily undergo phase transfer to the bulk medium in order to
form the key catalytic intermediate, [Pd(OH)ArL n ], a biphase can be
particularly effective for the oxo-palladium pathway because it limits
sequestration of boron reagent, in the form of the trihydroxyborate, in the
bulk phase. Single-phase systems are likely more primed for the boronate
pathway.
Further studies on the transmetallation event by Jutand and co-workers 50
have demonstrated that the counter-cation, which is inevitably added with
an anionic base, has a decelerating effect on the overall rate. This was
proposed to be due to a deactivating coordination to Ar-Pd-OH; whereby the
least coordinating anion led to the greatest rate: NBu 4 + 4K + 4Cs + 4Na + .
Additives are commonly employed to assist transmetallation of the
boronic acid. This could be envisaged as proceeding via an assisted trans-
metallation or more effectively as proceeding via generation of a discrete
reagent. Stoichiometric amounts of silver oxide have been shown to be
highly effective in assisting polyfluorophenyl 51-54 and n-alkyl 55 couplings.
Attempts to deduce the nature of the enhancing effect were made whereby
oxidative addition intermediates were isolated and reacted stoichiome-
trically with the silver oxide and boronic acid in a toluene-water biphase. 54
It was proposed that silver oxide effects an ecient replacement of the iodo
ligand on palladium with a hydroxide group, thus priming the complex

i ) NaOAc, DMF/H 2 O (4:1)
ii ) 2 Ph-B(OH) 2

k rel = 1.3 - 2

[Pd(OAc) 2 ] Ph-Ph

i ) NaOAc, DMF/H 2 O (4:1)
ii ) [Pd(OAc) 2 ]

k rel = 1

2 Ph-B(OH) 2 Ph-Ph

Scheme 8.9 Relative rates of stoichiometric transmetallation in the homocoupling
of phenylboronic acid, where the base is pre-equilibrated with either
the boronic acid or palladium(II) catalyst.