Prominent Ligand Types in Modern Cross-Coupling Reactions - New Trends in Cross-Coupling: Theory and Applications - page 54

PCy 2 P( t -Bu) 2

Br

Ph Ph

Ph

Mg, then CuCl, ClP( t -Bu) 2

n -BuLi, then ClPCy 2

67 %

71 %

CyJohnPhos JohnPhos

Figure 2.40 Synthesis of CyJohnPhos (left) and JohnPhos (right).

In related studies on ketone enolate a-arylation, it was found that analogs
of DavePhos with alkyl substituents in the 2 0 -position on the biaryl backbone
(R ¼ Me, i-Pr) were particularly effective (Figure 2.41). 151 These ligands
showed similar or better activities than DavePhos. Similar earlier findings
with JohnPhos derivatives in other reactions 144-148 prompted the authors to
suggest that binding of the dimethylamino group in DavePhos is not im-
portant for catalysis.
In fact, Ko ˇ ovsk´ and co-workers had earlier reported a Pd-C interaction
in closely related Pd complexes of MAP 152 and MOP 153 through NMR and
X-ray crystallographic studies (Figure 2.42). 154 The MAP complex was highly
active in amination and Suzuki-Miyaura reactions, suggesting that the Pd-C
interaction should be considered in catalysis.
It became apparent that subtle changes to the ligand backbone can lead to
dramatic differences in reactivity. In some instances (e.g., Suzuki-Miyaura
reaction of hindered substrates, 146,147 ketone a-arylation 151 ), the substituted
biarylphosphine ligands cannot be replaced with the more easily prepared
JohnPhos ligands. However, as mentioned above, the syntheses of the sub-
stituted biarylphosphine ligands required multiple steps and only modest
yields were obtained. Accordingly, a serious effort was undertaken to
streamline the syntheses of the ligands and provide a means of practical
modification of the ligand scaffold. An improved route was developed in
which aryl Grignard reagents were added to benzyne (generated in situ from
1-bromo-2-chlorobenzene), generating functionalized o-metallated biaryls
which were then reacted directly with ClPCy 2 or ClP(t-Bu) 2 in the presence of
CuCl (Figure 2.43). 155 Using this convenient one-pot procedure, functiona-
lized biarylphosphines were synthesized in modest to moderate yields (18-
53%) on several gram scales from readily available starting materials without
chromatography.
This modular synthesis 156 allowed the facile modification and steady
improvement/fine tuning of this ligand class over the next several years,
leading to an entire library of ligands, many of which are now commercially
available in multi-kilogram quantities. 48 The ability to tailor specific ligand
attributes towards different applications has made this ligand class
exceptionally powerful in many cross-coupling processes, especially C-N, 157
C-C 158 and C-O 159 bond-forming reactions. The high reactivity and select-
ivity of biarylphosphines can be traced to specific structural elements that
they contain (Figure 2.44). It has been shown that oxidative addition is faster