Ancillary Ligand Design in the Development of Palladium Catalysts for Challenging Selective Monoarylation Reactions - New Trends in Cross-Coupling: Theory and Applications - page 233

the catalyst resulting from the formation of Werner-type ammine adducts;
aggregation of amido intermediates of type D (Figure 5.1, where R ¼ H)
leading to inactive bridged polynuclear species; the slow rate of reductive
elimination from sterically unencumbered intermediates of type D; 30 and, as
alluded to in Section 5.1, uncontrolled polyarylation arising due to the
competitive nature of the product (hetero)arylamines relative to ammonia
when using most commonly employed BHA catalysts. 27-29 Although the
use of copper-based catalysts does allow for the direct cross-coupling of
(hetero)aryl bromides and iodides with ammonia, 29,31 such catalysts are not
able to accommodate analogous chloride or sulfonate reagents in a useful
manner, thereby restricting significantly the utility of such methods. Not-
withstanding these notable challenges, the development of useful BHA
protocols that allow the selective monoarylation of ammonia with a broad
range of (hetero)aryl (pseudo)halides has been achieved in recent years,
resulting from the design and/or application of new classes of sterically
demanding ancillary ligands.

5.2.1 Development of Palladium-Catalyzed Ammonia
Monoarylation
The ecient, selective monoarylation of ammonia by use of BHA protocols
was first disclosed by Shen and Hartwig in 2006. 32 They successfully
employed the palladium(II) precatalyst (CyPF-tBu)PdCl 2 featuring the
commercially available JosiPhos ligand, CyPF-tBu (L1), which had been
developed previously at Solvias for use in the asymmetric hydrogenation of
alkenes. 33 Although the use of the chiral (non-racemic) ligand L1 repre-
sented an unusual choice in this cross-coupling application given the lack
of stereocenters in the cross-coupling products, it is worthy of note that the
use of alternative monodentate phosphine [P(tBu) 3 , XPhos, QPhos] or
N-heterocyclic carbene (IPr) ligands or bisphosphines (DPPF, BINAP) re-
sulted in negligible reaction under the forcing reaction conditions employed
(80 psi ammonia, 90 1C). 32 These observations support the idea that the
rigid, sterically demanding and electron-rich nature of L1 discourages un-
wanted polyarylation, in addition to possibly increasing the catalyst lifetime.
In a subsequent publication 3 years later, Vo and Hartwig 34 described sig-
nificant improvements to this palladium-catalyzed ammonia monoarylation
chemistry through the use of Pd[P(o-tol) 3 ] 2 /L1 as the precatalyst mixture.
This catalyst system allowed for the ecient monoarylation of ammonia
using aryl bromides, chlorides, iodides and tosylates, including substrates
featuring base-sensitive groups, without the routine need for high ammonia
pressures (Figure 5.3). Notwithstanding the significance of this report 34 in
terms of advancing the state-of-the-art with regard to the selective mono-
arylation of ammonia under BHA conditions, the need for relatively high
reaction temperatures and the small demonstrated scope in the heteroaryl
(pseudo)halide reaction partner left room for improvement. Klinkenberg
and Hartwig 30

subsequently reported on the stoichiometric reactivity and