Ancillary Ligand Design in the Development of Palladium Catalysts for Challenging Selective Monoarylation Reactions - New Trends in Cross-Coupling: Theory and Applications - page 229

C sp 2 -C sp 3 bond-forming methods that enjoy widespread use in both
academic and industrial settings. Such synthetic protocols are of particular
utility in the construction of biologically active compounds, given the
ubiquitous nature of both substituted aniline and a-arylated carbonyl
sub-structures within such sought-after target molecules.
Prior to the development of BHA chemistry, the construction of C sp 2 -N
bonds was limited primarily to classical arene nitration-reduction reaction
sequences, and also nucleophilic aromatic substitutions employing selected
amine nucleophiles in combination with electron-poor, and thus highly
activated, aryl halide electrophiles. Similarly, before the establishment of
palladium-catalyzed methods, the AA of carbonyl compounds required the
use of electron-poor aryl halide reaction partners and in many cases the use
of preformed enolate nucleophiles. While these more conventional synthetic
methods can be employed successfully in the construction of C sp 2 -N and
C sp 2 -C sp 3 bonds, they suffer from a number of important limitations, in-
cluding: low substrate scope owing to the aforementioned need for activated
reactants, poor functional group tolerance given the rather harsh reaction
conditions/reagents employed and the required use of air-sensitive and/or
toxic reagents based on tin and other metals. The development of palladium-
catalyzed BHA and AA methodologies served to circumvent these synthetic
limitations, enabling reactions to be conducted eciently and under mild,
user-friendly conditions employing amines and carbonyl compounds directly
in combination with structurally diverse (hetero)aryl (pseudo)halides.
5.1.1 Mechanistic Overview
The evolution of palladium-catalyzed BHA and AA chemistry has been de-
scribed in a number of comprehensive reviews, 9-14 and the mechanisms 15-19
of these transformations have been elucidated. Although the precise nature
of the elementary transformations, catalytic intermediates and turnover-
limiting step of such catalytic cycles can vary with substrate, base and
catalyst composition, the mechanistic pathways of these reactions
commonly proceed as outlined in Figure 5.1. Oxidative addition of the
(hetero)aryl (pseudo)halide (i.e., Ar-X) to an L n Pd(0) species (A) affords the
Pd(II) intermediate B. In the case of BHA, amine binding to B to give C
followed by base-induced hydrodehalogenation generates the amido inter-
mediate, D; subsequent C-N bond reductive elimination affords the aniline
derivative with concomitant regeneration of A. For palladium-catalyzed AA,
the intermediate B is transformed into the enolate complex E (which can
exist in equilibrium with the Pd-O species F) in the presence of an appro-
priate carbonyl compound and base, with C-C bond reductive elimination
affording the a-arylated carbonyl compound with re-formation of A. Notably,
the ancillary ligand(s) (i.e.,L n ) employed, typically phosphines or N-hetero-
cyclic carbenes, have a direct influence on the course of the elementary
transformations. 20-22 Electron-rich and sterically demanding ligands
promote the formation of low-coordinate compounds of type A that are