DeVasher et al.
cles42 provides catalysts capable of promoting coupling
reactions of aryl bromides at room temperature and
reactions of aryl chlorides under mild conditions.43
Since Casalnuovo’s44 initial report of cross-coupling
reactions catalyzed by Pd(TPPMS)3, several examples of
Pd-catalyzed cross-coupling reactions have been demon-
strated in aqueous solvents.11,15,45,46 TPPTS and related
water-soluble phosphines give synthetically useful yields,
but typically require aryl iodide or activated aryl bromide
substrates and high temperatures. Although water-
soluble phosphines have been developed with a variety
of water-solubilizing groups, nearly all of these ligands
are based on the triphenylphosphine core. We are inter-
ested in applying water-soluble, sterically demanding
alkyl- or arylphosphines to aqueous phase cross-coupling
reactions in an effort to achieve similar levels of activity
with aryl bromides and chlorides that have been achieved
in organic solvents.47,48 We and others have shown that
bulky alkylphosphine/Pd catalysts47,49,50 or palladacyclic
catalysts51,52 efficiently couple aryl bromides under mild
conditions and achieve modest activities with aryl chlo-
rides in water. Herein we report that t-Bu-Amphos
(Figure 1) provides active catalysts for the Suzuki,
Sonogashira, and Heck couplings of aryl bromides under
mild conditions in aqueous solvents.
FIGURE 1. Water-soluble phosphine ligands.
Palladium-catalyzed cross-coupling reactions have be-
come a powerful method for the formation of C-C and
C-heteroatom bonds. In particular, the Heck,16,17 Sono-
gashira,18 Suzuki,19-21 and Hartwig-Buchwald22-25 reac-
tions are widely used synthetic methodologies. Modest
catalytic activity and difficulty separating homogeneous
palladium catalysts from organic products can present
hurdles to large-scale implementation, however. Phos-
phine ligands are generally required to achieve reason-
able levels of activity with unactivated aryl bromide
substrates at temperatures below 100 °C. Triphenylphos-
phine is the most commonly used ligand, but catalysts
derived from triarylphosphines typically show little
reactivity toward the less reactive aryl chlorides, except
at very high temperatures. Recently it has been shown
that replacing triarylphosphines with sterically demand-
ing trialkylphosphines,26-35 sterically demanding N-het-
erocyclic carbenes,36-41 or ligands that form palladacy-
Results
Suzuki Coupling. In our initial communication47 we
reported that the sterically demanding, water-soluble
phosphines t-Bu-Amphos and t-Bu-Pip-phos (Figure 1)
gave highly active catalysts for the Suzuki coupling of
aryl bromides in water/acetonitrile solvent mixtures at
room temperature. Cyclohexyl-substituted ligands, such
as Cy-Pip-phos and DCPES, gave less active catalysts.
A 1:1 L:Pd ratio gave the most active catalysts for each
of the alkylphosphine ligands, while catalyst activity was
significantly diminished at higher L:Pd ratios. Excellent
yields were obtained with aryl bromides with a range of
steric and electronic properties, using both t-Bu-Amphos
and t-Bu-Pip-phos as ligands (Table 1). Both hydrophilic
and hydrophobic aryl bromides gave excellent yields in
this system. Highly functionalized substrates, such as a
protected amino acid (1f, entry 6), were efficiently coupled
to give a biphenylalanine derivative (3f). Modest activity
toward an activated aryl chloride (1g) was observed with
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