Development and application of allyl, 2-sulfonylethyl and 2-thioethyl carbamate linkers for solid phase N-acyliminium ion chemistry

We have evaluated the allyl, 2-sulfonylethyl (SEC) and 2-thioethyl (TEC) carbamate linker systems for their application in solid supported N-acyliminium ion chemistry. As model reactions the syntheses of both homoallylic amines (via a three component protocol starting from an immobilised primary carbamate) and 2-substituted pyrrolidines (via carbamate bound 4,4-diethoxy-2-phenylbutylamine) were conducted. The required precursor p-nitrophenyl carbonate resins were prepared in high yields from cheap starting materials. All linkers proved to be stable under the required cationic reaction conditions. A serious drawback of the allyl carbamate linker is the tedious work up procedure which is required for the removal of the remains of the cleavage cocktail. The SEC linker is excellently stable to both Lewis and protic acidic conditions combined with a moderate base stability thus allowing the use of amines as reactants or bases in subsequent reactions. Cleavage of SEC linker bound amines was easily effected by treatment of the resins with a cocktail of 1 M NaOMe in THF-MeOH (2:1). The widest synthetic scope was found with the TEC linker which combined a sufficient stability against the cationic conditions required for N-acyliminium ion chemistry with complete stability under basic conditions. Cleavage of TEC linker bound amines could be effected by treatment with strong acid or by oxidation of the sulfide to the sulfone (to give the SEC linker) followed by addition of the basic cleavage cocktail.