A simple and efficient protocol for the chemoselective mono-N-Boc protection of various structurally diverse amines with di-tert-butyl dicarbonate using 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as solvent and catalyst is described. The catalyst can be readily separated from the reaction products and recovered for direct reuse. No competitive side reactions such as formation of isocyanate, urea, and N,N-di-Boc were observed. a-Amino alcohols afforded the N-Boc derivatives without oxazolidinone formation.Due to the great stability in the course of various base-catalyzed nucleophilic substitutions and catalytic hydrogenation reactions, 1 the tert-butoxycarbonyl (Boc) group is perhaps one of the most important protecting groups, especially for amines and amine derivatives. The removal of the Boc protecting group can be easily carried out in a bench scale with CF 3 CO 2 H at room temperature, and 10% H 2 SO 4 in 1,4-dioxane, or in large-scale operations with hot formic acid. In addition, owing to the resistance of the N-Boc functionality to racemization during peptide synthesis, it has become a fundamental tool of the Merrifield strategy for solid-phase peptide synthesis. 2 This utility is clearly due to the ease of introducing and removing the Boc group and to the fact that it can be perfectly orthogonally associated with many other protecting groups. Due to its high reactivity and reasonable stability, in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) 3 or inorganic bases, the common practice for N-tertbutoxycarbonylation is the treatment of an amine with ditert-butyl dicarbonate [(Boc) 2 O]. 4 However, these methodologies have various drawbacks such as long reaction times, and the high toxicity of DMAP. Furthermore, the base-catalyzed reactions are often associated with the formation of isocyanate, 5 urea, 3 and N,N-di-Boc derivatives. 6 These disadvantages can be avoided by electrophilic activation of (Boc) 2 O in the presence of acids. There are examples of the Brønsted and Lewis acid catalyzed N-tertbutoxycarbonylation of amines with for example, H 3 PW 12 O 40 , 7 H 2 NSO 3 H, 8 Zn(ClO 4 ) 2 ·6H 2 O, 9 ZrCl 4 , 10 LiClO 4 , 11 Cu(BF 4 ) 2 , 12 Montmorillonite K10, 13 sulfonic acid functionalized silica, 14 I 2 , 15 and indium (III) halides. 16 These procedures, although effective, have certain drawbacks: the reactions require highly reactive or environmentally harmful catalysts and anhydrous conditions, use of solvents, and extractive workup to isolate the product from the catalyst. Moreover, the use of acid-catalyzed Boc protection of amines is limited because of the strong affinity of acids for amino groups, which do not allow regeneration of the acids in reaction. Furthermore, they are decomposed or deactivated by the amines and their derivatives when more than the stoichiometric amounts are used. 17 Despite the improvement in performing the N-tertbutoxycarbonylation, new and milder conditions are still required.Over the last years, the utilization of fluorinated alcohols in organic reactions has been ...