An original traceless linker strategy for solid-phase synthesis of N,N',N''-substituted guanidines.

An original sequence for solution- and solid-phase synthesis of N,N',N"-trisubstituted guanidines is described. The sequence involves as key intermediate a bis-electrophilic chlorothioformamidine that is stable, easy to prepare and also easy to handle. Supported chlorothioformamidine, prepared in two steps from Merrifield resin, undergoes smooth nucleophilic addition of a primary amine to afford the corresponding supported isothiourea. The guanidine is obtained in satisfactory yield and good purity through a functionalizing-release process by heating the supported isothiourea in the presence of a primary amine in toluene at 100 degrees C. Compatibility of this sequence with several functional groups is demonstrated.