COUPLING IN THE ABSENCE OF TERTIARY-AMINES .5. REMOVAL OF THE 2-NITROBENZENESULFENYL (NPS) GROUP WITH 1-HYDROXYBENZOTRIAZOLE IN THE PRESENCE OF ANILINE OR N-METHYLANILINE

In a search for conditions of acidolytic removal of amine protecting g roups leading to salts of the deblocked amine that can be acylated wit hout addition of a tertiary amine, cleavage of the 2-nitrobenzenesulfe nyl (Nps) group with hydroxybenzotriazole (HOBt) in 2,2,2-trifluoroeth anol was attempted. The Nps group was smoothly removed, but the result ing salt of the amine component could not be acylated unless deprotona ted with a tertiary base. A rationale is now proposed for this unsatis factory outcome of the cleavage reaction and for the concomitant surpr ising reduction of HOBt to benzotriazole. Based on the proposed mechan ism, a new approach was designed for the removal of the Nps group. It was cleaved with HOBt in the presence of weakly basic nucleophiles suc h as aniline, N-methylaniline or 8-aminoquinoline. The protecting grou p was transferred smoothly to the amino group of the nucleophilic acce ptor leaving the deblocked amine component in the form of its HOBt sal t. This was then readily acylated without addition of a tertiary amine . (C) Munksgaard 1995.