Configurational and Conformational Proclivity of an α-Cyanoacrylamide Derivative of Ibrutinib

α-Cyanoacrylamide derivatives of ibrutinib are reversible inhibitors of Bruton's tyrosine kinase (BTK), an important target in B-cell-mediated cancers. We prepared the methyl derivative <b>1</b> as part of a larger study and observed interesting complex isomerization behavior that warranted further investigation. Herein, we characterize the solution-state configurational and conformational behavior of <b>1</b> by 1D and 2D temperature-dependent NMR and LC-MS. Synthesis of <b>1</b> by various routes leads to mixtures of <i>E</i> and <i>Z</i> configurational isomers about its alkene centered at C-31 and C-32. Isomers (<i>E</i>)-<b>1</b> and <i>(Z</i>)-<b>1</b> can be separated by reversed-phase HPLC and are stable at room temperature in solution. Interestingly, each configurational isomer undergoes <i>cis</i>/<i>trans</i> conformational isomerization about their respective acrylamide bonds at N-28 with rates dependent on the alkene configuration at C-31. Further, the configurational integrity of the alkene can be compromised at elevated temperatures. Warming pure (<i>E</i>)-<b>1</b> affords a mixture of <i>E</i>- and <i>Z</i>-isomers resulting in the same relative ratio as observed in the initial synthesis of the compound, with each again exhibiting conformational isomerization about their amide bonds. Warming pure (<i>Z</i>)-<b>1</b> affords the same results. Knowledge of the isomerization behavior of α-cyanoacrylamides can inform the synthesis, purification, and utility of this class of molecules.