Modern Heck Reactions - New Trends in Cross-Coupling: Theory and Applications - page 381

other well-known reactions leading to phosphine depletion (catalysed oxi-
dation, aryl scrambling, etc.). The cycle is supported for some time because 2
mol of phosphine are usually loaded, so the monophosphine complex would
be partially recovered, but the concentration of such species would be low.
Hartwig and co-workers experimentally demonstrated a very important
feature of ligand-accelerated processes. 149 Such processes readily and
spontaneously switch to ''phosphine-free'' processes if (a) more reactive aryl
halides are used and (b) the reactions are run at higher temperatures, per-
mitting ''phosphine-free'' oxidative addition even of less reactive substrates.
Phosphine-free and ligand-accelerated processes can run competitively.
Therefore, even the phosphine complexes of palladium can serve as pre-
catalysts for ''phosphine-free'' catalytic processes.
Murray et al., by screening a large set of Mizoroki-Heck reactions of aryl
bromides with a wide range of electronic and steric demands with terminal
and internal olefins under widely varied conditions and a large set of both
phosphine-free precatalysts and palladium-phosphine complexes, identified
a general protocol suitable for the majority of substrate combinations
(Scheme 9.33). 150 Not surprisingly, the protocol thus identified is very close
to the Littke-Fu protocol with some variations of solvent/additive. In add-
ition to tris(tert-butyl)phosphine, taken as preformed Pd 0 (PdL 2 )orPd I
([Pd(L)Br] 2 ) complexes, a bulky electron-rich analogue of dppf was found
to be an equally effective ligand delivering somewhat more uniform results
across the series.
A few recent examples are presented to show the possibilities of the Littke-
Fu protocol, with particular attention to a few instances of the use of other
ligands. Thus, the arylation of amidoacrylates by highly electron-rich sub-
stituted p-bromoanilines using the Littke-Fu protocol at room temperature
gives amidocinnamates, further used in enantioselective hydrogenation to
give optically active amino acids with high yields and enantioselectivities 151
(Scheme 9.34).
Very interesting phenomena throwing light on the detailed operation of
the ligand-accelerated Heck reaction and ligand control over selectivity were
established by Skrydstrup and co-workers in a series of papers devoted to the
use of alkenyl tosylates and phosphonates. 152-154 It should be noted that the
application of such leaving groups in Heck chemistry is practically unknown,
although due to the development of new-generation phosphine ligands they
are fairly well accommodated in cross-coupling chemistry. Skrydstrup and

R 2

PBu t 2

Br

R 1

Z

Pd (DB PF) Cl 2 (2 mol% )
Cy 2 NMe, Bu 4 NCl
DM A, 80°C , 24 h

Fe

+

R 1

PBu t 2

R 2 Z

R R

53-99%

DBPF

Scheme 9.33 Generic ligand-accelerated protocol suitable for a broad range of aryl
bromides and olefins.