A novel ionic liquid (IL) supported, green synthetic protocol has been developed toward the synthesis of oxo and thio hydantoin analogues tethered with tetrahydro-β-carboline by the use of focused microwave irradiation. IL-bound tryptophan underwent a Pictet−Spengler reaction with various carbonyl compounds to generate the IL- immobilized tetrahydro-β-carbolines in aqueous isopropanol media. Subsequent reaction of substituted tetrahydro-β-carboline derivatives with various isocyanates and isothiocyanate provided a three-dimensional combinatorial library in a traceless fashion