Takuya Yokosaka, Tetsuhiro Nemoto and Yasumasa Hamada Chem. Comm.
The Hamada group in Chiba report a rather unexpected and unusual acid-mediated skeletal rearrangement in specific polyfunctional compounds. The complex cascade rearrangement itself is remarkable; however, I was struck by the indole Boc group present in the substrate and product. The conditions for the rearrangement reported require 8 equivalents of TFA in DCM at zero degrees for 3 hours. These conditions are, of course, standard conditions for cleavage of a Boc group (though ambient temperature is usual).
A quick look at the literature indicates that an indole Boc group can be cleaved with TFA in DCM at ambient temperature in under an hour. I don’t see anything in this molecule, other than the pathway of reactivity reported, that would prevent deprotection. This issue is only addressed in passing in a footnote saying that the substrate doesn’t deprotect under these conditions. Nothing is said about the product, which isn’t potected from cleavage by an alternative path of reactivity.
The group point out improved yield under dilute conditions, but that isn’t due to the stability of the product as the experimental indicates the reaction mixture is concentrated immediately after reaction is complete (presumably at, at least, ambient temperature).
The torturous proposed mechanism involves elimination of the hydroxy group followed by a dearomatising Fridel-Crafts addition to the electron rich aromatic ring. Rearomatisation reveals an iminium species that can undergo Pictet-Spengler reaction at the 2- position of the indole.
So why do they not observe deprotection? Why isn’t this addressed in the paper? How essential is the Boc group to reactivity (no other protecting groups were tried)? Would this work with Cbz? Fmoc? Why attempt to use a protecting group under conditions that the group would be expected to cleave in the first place? What am I missing?