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"-tri substituted guanidines is described. The sequence involves as key intermedi ate a bis-electrophilic chlorothioformamidine that is stable, easy to prepa re and also easy to handle. Supported chlorothioformamidine, prepared in tw o steps from Merrifield resin undergoes smooth nucleophilic addition of a p rimary amine to afford the corresponding supported isothiourea. The guanidi ne is obtained in satisfactory yield and good purity through a functionaliz ing-release process by heating the supported isothiourea in the presence of a primary amine in toluene at 100 degreesC. Compatibility of this sequence with several functional groups is demonstrated.