Vinylogous Winstein Rearrangement: Unexpected Isomerization of an Azide-Substituted Cyclohexadiene-Fe(CO)3 Complex

In the course of our research into enzyme-triggered CO-releasing molecules (ET-CORMs), we were interested in using 2-acetoxy-5-azido-1,3-cyclohexadiene-Fe(CO)3 (rac-2) as a building block for further structural modification by means of Cu -catalyzed azide-alkyne cycloaddition (CuAAC click chemistry). Treatment of [2-acetoxy-cyclohexadienyl-Fe(CO)3]+[PF6]- with Zn(N3)2, TMS-N3, or NaN3 surprisingly afforded 2-acetoxy-1-azido-2,4-cyclohexadiene-Fe(CO)3 (rac-9) as the main product. We could show that rac-2 is primarily formed under kinetic control but undergoes a rapid isomerization to rac-9 (as the thermodynamic product) in a formal vinylogous Winstein rearrangement under concomitant migration of the Fe(CO)3 moiety. This unprecedented reaction displays a 1st order kinetics and appears to proceed via an ionic (rather than a concerted intramolecular) mechanism as supported by crossover experiments using deuterated compounds. The CuAAC reaction of rac-9 with propargylic alcohol afforded triazole rac-13, which was demonstrated (by headspace-gas chromatography (GC)) to act as an ET-CORM in the presence of porcine liver esterase.

Automated summary

In this research, we investigated the use of enzyme-triggered CO-releasing molecules (ET-CORMs). We were interested in modifying 2-acetoxy-5-azido-1,3-cyclohexadiene-Fe(CO)3 (rac-2) using Cu-catalyzed azide-alkyne cycloaddition (CuAAC click chemistry). Surprisingly, the treatment of [2-acetoxy-cyclohexadienyl-Fe(CO)3]+[PF6]- with certain azide compounds resulted in the formation of 2-acetoxy-1-azido-2,4-cyclohexadiene-Fe(CO)3 (rac-9) as the main product. We discovered that rac-2 is primarily formed under kinetic control and undergoes a rapid isomerization to rac-9, a thermodynamic product, through a vinylogous Winstein rearrangement mechanism. We also found that rac-9 can act as an enzyme-triggered CO-releasing molecule (ET-CORM) in the presence of porcine liver esterase.