Solvent-Free Mechanochemical Deprotection of <i>N</i>-Boc Group

Abstract

Boc protection group could be readily removed in a very mild mechanochemical conditions. In a short reaction time, ball milling of Boc-protected amines with p-toluenesulfonic acid in solvent-free conditions affords corresponding amine p-TsOH salts.

Peptide synthesis: ball-milling, in solution, or on solid support, what is the best strategy?

“…Alternatively, removal of the Boc group under mechanochemical conditions was realized. While ball-milling Boc-IA-OBn with 37% aqueous HCl furnished HCl·H-IA-OBn contaminated with products arising from hydrolysis of the benzyl ester group, pure TFA·H-IA-OBn was obtained in quantitative yield by ballmilling Boc-IA-OBn with TFA (5.0 equiv) [24]. Overall, the Boc-VVIA-OBn peptide was obtained in 5 steps with 59% yield and 88% purity (Scheme 1).…”

Solvent-free N-Boc deprotection by ex situ generation of hydrogen chloride gas

“…To our delight, methyl and benzyl esters and ethers remained under these conditions (13,14,15,18). Furthermore, due to the anhydrous and neat conditions, the presence of an acetal group is well tolerated and 21 was quantitatively obtained with perfect chemoselectivity.…”

“…14 Efforts have been made to improve on sustainability, but in reality, even the solvent-recycling and solvent-free N-Boc deprotections still require post-synthesis manipulations and purification steps, inviting further improvement. 12,15,16 To solve these current problems, we confided in our previous experience with gas chemistry. Herein, we present an N-Boc deprotection method with high functional group tolerance and expanded orthogonality while also being a green alternative to standard methods.…”

Recent Advances in Mechanochemical Organic Synthesis

“…Mechanochemical nitration reactions of aromatics are extended to various reagents: NaNO 3 in conjunction with MoO 3 as an additive [43], BiNO 3 with MgSO 4 [44], as well as BiNO 3 alone was applied for nitration of fullerene C 60 [45]. Amine guanylation with N,N′-Di-Boc-1H-pyrazole-1-carboxamidine [46] and facile Boc deprotection was achieved with TsOH [47]. Another mechanochemical nitrogen deprotection (N-demethylation) by modified Polonovski reaction of various alkaloid N-oxide hydrochlorides (of biologically interesting molecules, dextromethorphan, atropine, noscapine, and benzoyltropine) was carried out using iron dust and LAG (Figure 9) [48].…”