Photoredox Catalysis in a
Complex Pharmaceutical Setting:
Toward the Preparation of JAK2 Inhibitor LY2784544
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Abstract
We
report a detailed investigation into the application of visible
light-mediated photocatalysis to a challenging bond construction in
a complex pharmaceutical target. The optimized reaction allowed the
direct coupling of <i>N</i>-methylmorpholine with an unfunctionalized
pyridazine in good yield and selectivity, and with high purity of
the product isolated via crystallization. The reaction also facilitated
the expedient synthesis of a range of analogues via the use of other
commercially available <i>N</i>-methyl substituted tertiary
amines, and therefore it represents an attractive tool for medicinal
chemistry. Furthermore, a number of other interesting photoredox reactions
were discovered during the course of this investigation, such as a
formal methylation reaction via C–N bond cleavage, functionalization
of C–H bonds alpha to amides, and a visible light-mediated
iminium ion reduction