We report a metal catalyst-free, HF-free and open-flask green protocol for the electrophilic hydrazination of enoxy silanes at an energy-efficient room temperature, taking advantage of the eco-safe EtOH–H2O solvent.
In
contrast to the conventional 1,4-addition process, regioselective
1,2-addition of silyl enol ethers to quinones can now be achieved via a palladium(II) enolate pathway that provides access
to 4-hydroxy-4-(2-oxo-2-arylethyl)cyclohexa-2,5-dien-1-one derivatives.
This quinone alkylation protocol proceeds under mild reaction conditions
at ambient temperature under open air and does not require either
an external ligand for the palladium or the use of a base. Additionally,
the cyclohexadienone products have been exploited as synthetic precursors
for the construction of fused heteroaryl systems.
IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compounds such as 12 with improved potency and selectivity. Additionally 12 demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective 21, which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis.
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