Enantioselective Aza-Michael Reactions of Pyrazoles: Synthesis of INCB0184124

Significance

The synthesis of janus kinase inhibitor INCB018424 was accomplished using an ­organocatalytic aza-Michael reaction as key step. The Hayashi-Jørgensen type catalysts 1 and 2 were found to promote the conjugate addition of different pyrazoles to (E)-3-cyclopentylacrylaldehyde in good yields and enantioselectivities. The use of acidic additives had a beneficial effect on the reaction rate, but the enantioselectivity decreased when too strong acids were used. Under optimized conditions three different pyrazoles were employed for the Michael reaction and the obtained products were further converted into the target molecule.