Conspectus
This Account
presents an overview
of a promising
collection of
phosphine ligands simply made from the modular Fischer indolization
process and their applications in modern arylation processes. Using
one easily accessible 2-arylindole scaffold, three major phosphino-moiety-positioned
ligand series can be readily generated. We have attempted to explore
challenging electrophilic and nucleophilic partners for the coupling
reaction using the modular ligand tool. For the electrophilic partner
study, CM-phos-type ligands, where the phosphino group
is located at the 2-arene position of 2-arylindole, allow the successful
cross-coupling of aryl mesylates. The CM-phos ligand
forms a palladacycle before entering the cross-coupling catalytic
cycle. For the nucleophilic partner investigation, the indole C3-positioned
phosphines show the first accomplishment of Pd-catalyzed organotitanium
nucleophile arylation. Indeed, the aryl-titanium nucleophile undergoes
cross-coupling more efficiently than does the organoboron coupling
partner in particular cases. Moreover, in the indole C3-positioned
phosphine series, the −PPh2-containing ligands perform
better in the highly sterically hindered cross-coupling of aryl chlorides
than do ligands containing the −PCy2 moiety. The
catalyst loading can even be reduced to 0.2 mol % Pd for tetra-ortho-substituted biaryl synthesis. This finding offers
a new perspective on the next-generation design of phosphine ligands
in which the sterically bulky and electron-rich −PR2 group (R = alkyl) may not be necessary for the cross-coupling of
aryl chlorides. In general, we hypothesize that a good balance of
steric and electronic properties for entertaining the oxidative addition
and reductive elimination steps is crucial to the success of the reaction.
For the steric factor, the highly sterically congested −PR2 group normally favors the reductive elimination, yet we conjecture
that this sterically bulky group would serve as an obstacle for the
incoming aryl halides. For the electronic factor, the electron rich
−PR2 group is believed to support the oxidative
cleavage of the C(Ar)–Cl bond by donating more electron density
to the corresponding σ* orbital. Nevertheless, the high electron
richness of the −PR2 group may disfavor the reductive
elimination electronically. Overall, an appropriate balance of both
electron density and steric bulkiness is suggested to allow the sterically
hindered cross-coupling to proceed smoothly. We have found that the
−PPh2-containing ligand is a good starting point
for this investigation. The formation of aromatic carbon–carbon
(C–C) and carbon–heteroatom (C–X) bonds from
aryl chlorides was successfully realized using our proprietary phosphines.
In addition to the indole-core-bearing ligand skeleton, we also
explored the relevant imidazolyl and carbazolyl phosphines for their
unique applications. Interestingly, the carbazolyl ligand, having
more flexible C–N axial chirality, displays particular interchangeable
Pd–N and Pd–arene coordination, which facilitates both
oxid...
