Ancillary Ligand Design in the Development of Palladium Catalysts for Challenging Selective Monoarylation Reactions - New Trends in Cross-Coupling: Theory and Applications - page 239

of soft and hard donor atoms have received little attention in these appli-
cations; this is especially true in the light of the proven utility of k 2 -P,N
ligands in alternative late metal-catalyzed chemical transformations (e.g.,
PHOX 44 in alkene hydrogenation, allylic substitution). Sterically demanding
k 2 -P,N ligands represent conceptually appealing targets of inquiry in BHA
and AA chemistry, given their potential to discourage unwanted dimerization
of catalytic intermediates (e.g., B, D and E in Figure 5.1) - processes that
inhibit the performance of monophosphine-based palladium catalysts.
Moreover, while challenging (hetero)aryl (pseudo)halide oxidative addition
reactions can be enabled via incorporation of an electron-rich dialkylphos-
phino ligand donor fragment, a k 2 -P,N ligand of this type should also render
the palladium centers in key catalytic intermediates of type D and E
(Figure 5.1) less electron rich than their bisphosphine-ligated counterparts,
thereby providing an electronic means of promoting challenging reductive
eliminations in addition to sterically promoted processes. Finally, bulky k 2 -
P,N ligands may offer an effective means of achieving selectivity in challenging
palladium-catalyzed BHA and AA monoarylation reactions, by favoring the
binding of small, unhindered substrates, rather than their more hindered
monoarylated derivatives, proceeding from catalytic intermediates of type B.
The successful application of sterically demanding k 2 -P,N ligands in the
palladium-catalyzed selective monoarylation of ammonia was first disclosed
in 2010 by Stradiotto and co-workers. 45,46 In an initial report, 45 Me-DalPhos
(L9) was shown to be effective in BHA chemistry involving a wide range of
(hetero)aryl chlorides and NH-containing substrates, including ammonia.
However, whereas L9 was observed to afford high conversions and good
monoarylation selectivities in the cross-coupling of ammonia with ortho-
substituted aryl chlorides, the use of alternative aryl chlorides lacking steric
bias resulted in diminished monoarylation selectivity. 45 Subsequent ligand
optimization gave rise to the Mor-DalPhos ligand (L10), which was shown to
be highly effective for the palladium-catalyzed cross-coupling of ammonia
with aryl chlorides and tosylates, including those lacking ortho substitution;
included in this report are the first examples of room temperature BHA
chemistry involving ammonia. 46 Reactions employing [Pd(cinnamyl)Cl] 2 /L10
catalyst mixtures proceeded with high monoarylation selectivity, generally at
low catalyst loadings and under mild reaction conditions without the need
for high pressures of ammonia (Figure 5.7). Aryl chlorides bearing electron-
donating groups at the para or meta positions that have proven to be par-
ticularly challenging in ammonia monoarylation chemistry were effectively
cross-coupled, as were substrates containing N, O, F or S heteroatoms.
Sterically biased ortho-substituted aryl chlorides were also found to be
suitable reaction partners, as were some heteroaryl chlorides. Whereas the
use of [Pd(cinnamyl)Cl] 2 /L10 catalyst mixtures in the monoarylation of am-
monia with (hetero)aryl chlorides required heating (Z50 1C), analogous re-
actions involving aryl tosylates were found to proceed at room temperature
with good yields (69-83%) being obtained for both unhindered and ortho-
substituted substrates.