Boron Reagent Activation in Suzuki–Miyaura Coupling - New Trends in Cross-Coupling: Theory and Applications - page 334

BF 3 K BF 2 (OH)K BF(OH) 2 K B(OH) 3 K

R R R R

BF 2 BF(OH) B(OH) 2

R R R

Scheme 8.11 Hydrolysis of organotrifluoroborates to boronic acids via mixed li-
gated species.

under aqueous conditions if it is not rapidly quenched by base or an alter-
native sacrificial fluorophile.
Initial mechanistic investigations into the origin of the high performance
of the organotrifluoroborate salts in SM coupling, particularly when com-
pared with the corresponding boronic acid, 62 indicated that the organotri-
fluoroborate salt itself was not the active transmetallation species. 14,63 It was
shown by NMR spectroscopy that hydrolysis occurred via mixed fluoro-
hydroxy borate intermediates (Scheme 8.11). Base titrations of the tri-
fluoroborate and observations of the mixed ligated species by electrospray
ionization mass spectrometry provided evidence in support of

this

proposal. 38,64
However, it was later shown that the mixed fluoro-hydroxy borates usually
have a very low population and computational analysis (DFT) of the trans-
metallation of the various intermediates indicated that the pathway became
more favourable as all of the fluoride ligands on boron were sequentially
replaced by hydroxide. 65 This is consistent with a reduction in the nucleo-
philicity of the organic fragment, when ligated by the highly electronegative
fluoride, and also a reduction in the ability of the ligand to bridge the metal
species. In other words, the mixed fluoro-hydroxy borates are solely
intermediates en route to the boronic acid, with transmetallation primarily
occurring through the latter. 63,65
This conclusion was reinforced by a kinetic analysis of [ 2 H 4 ]-3 and [ 2 H 0 ]-4
under conditions where they compete for limiting 5, confirming the boronic
acid as the most reactive species. 63,65 Indeed, even when the proportion of
[ 2 H 4 ]-3 was only 10% in the presence of 90% of unlabelled [ 2 H 0 ]-4, after just
10% conversion the cross-coupled product 6 contained 60% of the labelled
ring, i.e. that coming from [ 2 H 4 ]-3, before its isotopic enrichment was diluted
to 10% at 100% conversion (Scheme 8.12).
Overall, it could therefore be concluded that the high performance
of trifluoroborates in SM coupling was not due to the liberation of a more
ecient mixed fluoro-hydroxy borate species for transmetallation, but
instead due to a reduction in the amount of side products generated. 65 These
side reactions stem predominantly from the boronic acid reagent (Scheme 8.13),
with the use of organotrifluoroborate salts strongly suppressing them.
The palladium(II) precatalyst activation by boronic acid generates homo-
coupled product through a two-stage double transmetallation-reductive
elimination sequence. Fluoride has been shown to effect a hydrolytic re-
duction of palladium(II) that yielded a monophosphine complex 66,67 and