Ancillary Ligand Design in the Development of Palladium Catalysts for Challenging Selective Monoarylation Reactions - New Trends in Cross-Coupling: Theory and Applications - page 238

also proved effective with regard to the cross-coupling of six-membered
heteroaryl bromides and chlorides with ammonia, although in some par-
ticularly challenging cases diminished monoarylation selectivity was ob-
served. A diverse array of aminopyridines, aminoquinolines and related
NH 2 -functionalized heterocycles, including benzothiophene, indole, benzo-
thiazole, benzoxazole, pyrazine, quinoxaline, pyrimidine, pyridazine and
carbazole rings, were prepared (24 examples; 36-99%; Figure 5.6). Although
base-sensitive functionalities such as cyano and carbonyl groups, and also
heterocyclic addenda, were reasonably well tolerated in this chemistry, room
temperature reactions were limited to a relatively small number of examples
featuring primarily aryl bromides and electronically activated (hetero)aryl
chlorides at higher catalyst loadings (typically 5 mol%). 39
Interest in the development of new and effective cross-coupling chemistry
involving five-membered heteroaryl halide reaction partners arises from the
potential utility of such reactions in the synthesis of biologically active
compounds. In the pursuit of a catalyst system capable of allowing the
hitherto unknown BHA of five-membered heteroaryl halides with ammonia,
Buchwald and co-workers conducted further ligand screenings. 39 Whereas
catalysts based on Me 3 (OMe)XPhos (L6) performed poorly in the cross-
coupling of ammonia with 4-bromo-1-(4-fluorophenyl)pyrazole (9% mono-
arylation), the di(1-adamantyl)phosphino-functionalized BrettPhos ligand
variant L5 afforded a high yield (78%) of the desired ammonia monoaryla-
tion product. The use of P1/L5 catalyst mixtures (2 mol% each) was exploited
in the monoarylation of ammonia using a range of five-membered heteroaryl
bromides and chlorides including benzothiazoles, indazoles, imidazoles and
pyrazoles (8 examples; 50-96%; Figure 5.6). The cross-coupling of the rather
hindered 4-bromo-1,3,5-trimethylpyrazole with ammonia proved chal-
lenging when using the P1/L5 catalyst system (40%); for this and another
trisubstituted pyrazole substrate, the use of P3/L7 afforded the desired
monoarylation product in good yield (78 and 82%). 39
Beller's group has also contributed to the development of effective pal-
ladium catalysts for the monoarylation of ammonia. In two publications, 42,43
they detailed that appropriately constructed imidazole-derived monophos-
phine ligands including L8 are capable of supporting active complexes
for the monoarylation of ammonia. However, high reaction temperatures
(Z120 1C), pressures of inert gases (10 bar N 2 ) and catalyst loadings
(1-4 mol% Pd, 4-16 mol% ligand) are commonly required when using such
catalysts in order to obtain satisfactory catalytic performance, and the
demonstrated scope of the reaction in the aryl electrophile is limited.
5.2.4 Heterobidentate j 2 -P,N Ligands: Chemoselectivity and
Room Temperature Reactions
Given the successful application of sterically demanding monophosphine
and bisphosphine ligands in both BHA and AA chemistry, it is surprising
that electronically intermediate heterobidentate ligands featuring pairings