康 · 学术 | Reaction of the Day No. 1734

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 AcidSensitive Substrates

Eddie X. Yang, Amanda Pecora, Ethan L. Fisher, Christopher W. am Ende, and John M. Humphrey*

Medicine Design, Pfizer Inc., Groton, Connecticut 06340, United States

—J. Org. Chem. 2026, 91, 7126-7133.

Recommended by Bingbing Chang_MC5 and Yuting Gao_ MC3

KEY WORDS: deprotection (反应类型), N-H (成键类型), N?Boc?amine, N?Cbz?amine, N?PMB-amine (原料), free amines (产物), MsOH, sulfonic acid, HFIP (其他).

ABSTRACT: John M. Humphrey et al. from Pfizer 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.

Acid promoted N-Boc cleavage of acid sensitive substrates in HFIP

N-Boc cleavage of acid labile silyl ethers with MsOH in HFIP

N-Boc cleavage of additional acid labile substrates with MsOH in HFIP

N-Cbz cleavage with MsOH in HFIP

Substrate Examples and Yields for N-Cbz Cleavage via MsOH in HFIP

Single-vessel N-Cbz to N-Boc conversion mediated by MsOH/HFIP

N-PMB cleavage and resistance of ethyl carbamates

Example of the effectiveness of Humphrey’s Magic Purple vs. other common stains

Summary and Comments

John M. Humphrey et al. from Pfizer report a method using stoichiometric sulfonic acid in HFIP for high-yield deprotection of N-Boc, N-Cbz, and N-PMB carbamates. HFIP’s high dielectric constant stabilizes carbocation intermediates, enabling selective N-Boc removal even with acid-sensitive groups like epoxides and silyl ethers. For scales >1 mmol, use 10% HFIP in toluene (preferred over DCM for safety and easier solvent removal) to control off-gassing; reactions complete in 30-60 min at rt. N-Cbz cleavage requires harsher conditions (more HFIP, longer time, or heat), while N-PMB deprotection takes hours in HFIP with 2 eq acid but shows no reaction in DCM. Substrate concentration is flexible (0.1–1.0 M). The method uses only stoichiometric acid (1.0-1.1 eq, or ～ 2.1 eq for basic substrates), which is consumed by the amine product, reducing acid waste; products are often isolated as crystalline salts by filtration, and N-Cbz/N-PMB substrates benefit from aqueous acid/base workup to remove byproducts. They also provide a new TLC stain for visualizing carbamates.