Ancillary Ligand Design in the Development of Palladium Catalysts for Challenging Selective Monoarylation Reactions - New Trends in Cross-Coupling: Theory and Applications - page 230

Pd 0 or Pd II precatalyst / L

L n Pd

A

O

ArNR 2

R 2

Ar X

R 1

Ar

Ar
NR 2

Ar
X

L n Pd L n Pd

B

D

O

R 2

NHR 2

R 1

Ar

Ar

.

Ar
X
NHR 2

HX base

base L n Pd L n Pd

L n Pd

R 2

R 1

O

.

base HX base

R 1

E F O

C

R 2

Figure 5.1 Generalized catalytic cycles for Buchwald-Hartwig amination (left)
and palladium-catalyzed a-arylation reactions (right). L n ¼ ancillary lig-
and(s); Ar-X ¼ (hetero)aryl (pseudo)halide.

predisposed to undergo Ar-X oxidative addition to give B. The steric and
electronic properties of the ligands can serve to discourage unwanted di-
merization within low-coordinate intermediates such as B or D, in addition
to providing selectivity in amine binding (for BHA) or enolate complexation
(for AA) proceeding from B. Both C-N (for BHA) and C-C (for AA) bond re-
ductive elimination involving D and E, respectively, are facilitated by steri-
cally demanding, yet less electron-donating, ligands; from an electronic
perspective, this requirement is orthogonal to the ligand demands associ-
ated with the Ar-X oxidative addition step. Finally, an important and
sometimes overlooked consideration in designing effective catalysts for
BHA, AA and other palladium-catalyzed transformations relates to the e-
cient generation of the requisite L n Pd(0) species (A). Although the direct use
of appropriately ligated Pd(0) species is ideal in this regard, such complexes
are often cumbersome to prepare and/or exhibit air sensitivity, thereby
preventing routine handling under benchtop conditions. Alternative ap-
proaches involve the formation of A in situ through the combination of an
air-stable Pd(II) precursor, a chosen (ideally air-stable) ancillary ligand and a
reductant. Although in some cases phosphines can be employed in excess
both as the ancillary ligand and as the sacrificial reductant in this regard,
the high cost of some structurally complex phosphine ligands renders
such protocols unattractive. Furthermore, such in situ catalyst formation/
reduction strategies, although operationally simple, require the ecient
binding of the added ligand to palladium; when such reactions do not
proceed cleanly, significant decomposition can occur, such that the actual
quantity of A successfully formed and available for catalysis is very low. The
use of preformed, well-characterized L n Pd(II) precatalyst complexes that can
be reduced cleanly to A without consumption of the ancillary ligand offers an