Ancillary Ligand Design in the Development of Palladium Catalysts for Challenging Selective Monoarylation Reactions - New Trends in Cross-Coupling: Theory and Applications - page 234

[Pd(P( o -Tol) 3 ) 2 ] / L1
(0.1-2.0 mol% each)

X

NH 2

R

R

NaO t Bu
1,4-dioxane
50-100 °C

P( t Bu) 2

E

E

n = 5 equiv
(or 200 psi)

X = I, Br,
Cl, OTs
E = N, CH

>35 examples
44-99%

PCy 2

Fe

n NH 3

L1

R'

[Pd(cinnamyl)Cl] 2 (1.25 mol%)
L1

n = 3 equiv

(2.5 mol%)

R'

R

R

KO t Bu (3 equiv.)
1,4-dioxane
90 °C

H

Br

16 examples
31-89%

Figure 5.3 Selective palladium-catalyzed ammonia monoarylation employing the

JosiPhos ligand CyPF-tBu (L1).

kinetics of ammonia cross-coupling reactions employing Pd/L1, whereby the
catalyst resting state was found to be an (L1)Pd(aryl)(NH 2 ) complex of type D
(Figure 5.1).

5.2.2 Palladium-Catalyzed Ammonia Monoarylation in
Heterocycle Synthesis
Encouraged by the seminal work of Vo and Hartwig in applying L1 in
palladium-catalyzed ammonia monoarylation, Stradiotto and co-workers
demonstrated subsequently that [Pd(cinnamyl)Cl] 2 /L1 precatalyst mixtures
could be applied successfully in analogous reactions employing functiona-
lized 2-bromoarylacetylenes, 35 whereby KOtBu-catalyzed hydroamination of
the putative 2-aminoarylacetylene intermediates affords NH-indoles by way
of a one-pot process (Figure 5.3). The establishment of this protocol is sig-
nificant in that it represented the first reported synthesis of the biologically
important indole framework directly from ammonia employing metal-cata-
lyzed cross-coupling. Nonetheless, the lack of success in this chemistry when
using 2-chloroarylacetylenes, heteroaryl halides or 2-bromoarylacetylenes
featuring sp 3 substituents at the alkynyl terminus brings to light important
limitations of this [Pd(cinnamyl)Cl] 2 /L1-catalyzed protocol.
In 2013, Stradiotto and co-workers reported on the successful application
of BippyPhos (L2) in a remarkably broad spectrum of BHA applications; 36
notably, [Pd(cinnamyl)Cl] 2 /L2 mixtures were shown to accommodate the
largest diversity of NH-containing substrates reported for a single Pd-ligand
catalyst system. Included in the reaction scope were a number of sterically/
electronically varied and challenging NH-containing substrates including
ammonia, hydrazine and NH-indoles. The unique ability of the [Pd(cinna-
myl)Cl] 2 /L2 catalyst system to accommodate such divergent nucleophilic
partners was exploited in the development of a novel one-pot synthesis of
N-arylindoles and related heterocyclic derivatives involving three sequential
and selective C-N bond-forming steps,

the first of which was the