Prominent Ligand Types in Modern Cross-Coupling Reactions - New Trends in Cross-Coupling: Theory and Applications - page 42

R 3

Pd(OAc) 2 (5 mol %)
dtbpf (10 mol %)
K 2 CO 3

X

R 3

R 1 R 2 R 1

H

R 2

NMP
110 - 130 °C

NH 2

60 −− 97 %
up to 99:1 regioselectivity

Figure 2.23 Regioselective Pd-catalyzed indolization.

( t -Bu) 2 P

Me

Pd(OAc) 2 / PPF t Bu
NaO t -Bu

Cl N(H) n -Bu

PPh 2

n -BuNH 2

Fe

85 °C, 2h

Me Me

89 %, 130:1 mono:diarylation

PPF t Bu

Figure 2.24 Aryl amination using Josiphos PPFtBu.

Hartwig later revisited this class of ligands with the aim of identifying a
catalyst that is both highly active and selective for arylation of primary
amines and thiols, including the use of heteroaryl halides. 89 The air stability
and chelating ability of CyPFtBu, which contains a dicyclohexylphosphino
group in addition to a di-tert-butylphosphino group, was attractive for this
purpose as it has two electron-donating PR 2 groups with considerable steric
bulk, although the ligand synthesis is not straightforward. 90 Furthermore, it
was surmised that the chelating ability (six-membered chelate) of this ligand
should give rise to a more stable catalyst that is robust towards ligand dis-
placement by amines or heterocycles. 91 Studies on amination reactions
demonstrated this to be true. In the chloropyridine series, the CyPFtBu/
Pd catalyst system was shown to be effective for the coupling of octylamine
with yields ranging from 83 to 93% and selectivity for monoarylation
with exceptionally low catalyst loadings (0.001-0.01% Pd), as shown in
Figure 2.25. 92 The high selectivity for monoarylation, however, makes the
arylation of secondary amines challenging with this ligand class. 92b
This system was also successfully applied to a variety of nitrogen-
containing heterocyclic aryl chloride derivatives and chloroarenes utilizing
primary alkylamines, benzophenone imine and benzophenone hydrazone as
nucleophiles. Aryl bromides underwent effective amination with primary
alkylamines with catalyst loadings as low as 0.0005% (5 ppm) Pd. More
interestingly, the Pd/CyPFtBu system was found to be an ecient catalyst for
the amination of aryl/heteroaryl iodides, substrates which are typically more
challenging in aryl amination reactions. 93 A variety of aryl and heteroaryl
iodides underwent amination with primary amines, although high catalyst
loadings (up to 0.5 mol% Pd) were required in comparison with the analo-
gous reactions involving aryl bromides and chlorides. Shen and Hartwig also
utilized the CyPFtBu-based catalyst to develop the first aryl amination