Sulfonic Acid Promoted N-Boc-, N-Cbz-, and N-PMB Cleavage in 1,1,1,3,3,3-Hexafluoro-2-Propanol (HFIP) and Application to Acid Sensitive Substrates.

We report on the mild, sulfonic acid promoted removal of N-Boc, N-Cbz, and N-PMB protecting groups in 1,1,1,3,3,3-hexafluoro-2-propanol (hexafluoroisopropanol; HFIP). According to this method, the typical N-Boc group is removed within 5 min upon treatment with 1.0-1.1 mol equiv of a sulfonic acid, such as methanesulfonic acid in neat HFIP, or within 30 min when HFIP is used as a 10% additive in toluene or dichloromethane. The N-Cbz group is efficiently cleaved with 1.1 mol equiv of methanesulfonic acid in neat HFIP at a slower rate, with near-quantitative removal from typical substrates generally realized within 24 h at room temperature or in shorter durations with mild heating. When conducted accordingly, the acid is essentially consumed by the end of the reaction to afford a near-neutral pH solution. The N-PMB group is cleaved in high yield on treatment with ∼2 mol equiv of methanesulfonic acid in HFIP within a couple of hours at room temperature. The relative reaction rates for these processes allow for selective N-Boc cleavage over N-Cbz groups, affording the chemist orthogonal protection options despite each group being removable under similar acidic conditions.