Modern Heck Reactions - New Trends in Cross-Coupling: Theory and Applications - page 380

derivatives. Comparison with the current status of cross-coupling excellently
highlights the difference between it and Heck chemistry, in which the course
of development was closely similar, but the results were much more modest.
In fact, there is just a single well-established new-generation protocol, dis-
covered by Hartwig and co-workers by high-throughput ligand screening, 148
and thoroughly investigated by Littke and Fu 126 to rely on a single ligand -
tris(tert-butyl)phosphine. None of the other state-of-the-art ligands that gave
a powerful push to C-C and C-heteroatom cross-coupling chemistry turned
out to be effective and generally useful in Heck chemistry.
However, even with the advent of the new-generation phosphine-acceler-
ated Heck chemistry there are still no peer protocols for

(a) room-temperature reactions of chloro derivatives;
(b) processing of sterically hindered substrates, e.g. aryls with a 2,6-dis-
ubstitution pattern;
(c) protocols for less reactive aryl tosylates, mesylates and similar sub-
strates (alkenyl tosylates are reactive; see below). Chloroarenes have so
far failed to achieve a decent place in Heck chemistry, whereas in
cross-coupling reactions the availability of good mild protocols has
made chloroarenes common substrates, no less useful than bromides
and triflates.

Ligand-accelerated protocols use rather high loadings of Pd precatalysts,
rarely less than 1 mol% and often higher. This could be regarded as a
paradox - indeed, if such ancillaries accelerate the rate-limiting oxidative
addition stage, then why are such systems capable of running no more than
100 catalytic cycles? As a matter of common sense, the reason for such a low
eciency of ''well-defined'' Pd catalysts should be associated with the co-
ordination chemistry of palladium. Active species most likely contain a
single phosphine ligand. Hartwig and co-workers 149 established that
monophosphine species easily lose the phosphine ligand after oxidative
addition to afford an anionic phosphine-free species, existing in solution as
a dimer. The anionic complex is more reactive towards olefins than phos-
phine complex (Scheme 9.32).
Thus, in the ligand-accelerated catalytic cycles monophosphine complexes
are unstable due to displacement of phosphine from the shell, and also

ArX

L X

Ar X X

X -

LPd Pd Pd

Ar P d X Ar P d X

X X A r

lig and-accelerated
cy c le

"phosphine-fr ee"
cycle

Scheme 9.32 Switching from a ligand-accelerated to a phosphine-free catalytic

cycle.