Rational Structural Diversification and Application of DalPhos Ligands for use in Challenging C-N Cross-Coupling Reactions
Date
2013-05-01
Authors
Maclean, Mark
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Abstract
Transition-metal catalyzed transformations have revolutionized modern chemical
synthesis; the 2001, 2005, and 2010 Nobel prizes in Chemistry attest to their broad
applicability in academia and industry. To this end, advances in transition metal
catalysis are rooted in the development of ancillary ligands that are capable of
supporting electronically and coordinatively unsaturated metal centers. The Pdcatalyzed
cross-coupling of amines and (hetero)aryl (pseudo)halides (Buchwald-
Hartwig amination), to afford synthetically useful arylamines, has benefitted greatly in
this regard.
The use of highly efficient P,N-phenylene (‘DalPhos’) ligands in challenging CN
cross-coupling reactions (e.g. hydrazine and ammonia monoarylation), has recently
been disclosed by the Stradiotto group. Herein, a Pd/Mor-DalPhos catalyst system has
been exploited for the preparation of a diverse range of (hetero)aryl hydrazines, useful
synthons for the synthesis of myriad heterocyclic scaffolds, including N-aryl
pyrazolones. These compounds have been identified as a potent class of anti-aggregants
that may prevent the formation of toxic A? oligomer species, serving as candidates for
the treatment of Alzheimer’s Disease. Employing a tandem monoarylation/condensation
protocol, 25 examples of structurally diverse Edaravone derivatives were afforded in
good yield. Biological testing allowed for the identification of several compounds highly
active toward inhibition of A?-40 and biotin-A?42 formation; their IC50 values were
also determined.
Given the literature precedent for improved catalyst activity arising from subtle
changes to the ancillary ligand framework, rational structural diversification of Mor-
DalPhos has been achieved in an effort to improve efficiency. Eight new DalPhos
variants prepared in good to excellent yield, featuring substitution of the phenylenebackbone
with electron-withdrawing and donating groups, thiomorpholino substitution,
and two structural isomers where the phenylene-backbone has been replaced with
pyridine. New variants were combined with [Pd(cinnamyl)Cl]2 to yield coordination
complexes which may allow for a greater understanding of the catalytic cycle for BHA.
Finally, new ligands were screened in a series of challenging C-X (X = N, C, O) cross-coupling
reactions; a pyridine-bridged ligand variant displays unparalled activity in
acetone arylation.