Efficient synthesis of unsymmetrical trisubstituted 1,3,5-triazines catalyzed by hemoglobin

Abstract

• Protein-catalyzed synthesis of 1,3,5-triazines is reported for the first time. • Hemoglobin exhibits excellent activity and high yields are obtained in 10 min. • This work extends the application of hemoglobin in organic synthesis. 1,3,5-triazines are important bioactive compounds that have been extensively studied in organic chemistry. In this work, a green and efficient process for the synthesis of unsymmetrical trisubstituted 1,3,5-triazines from isothiocyanate ( 1 ) with amidines ( 2 ) and 1,1,3,3-tetramethylguanidine (TMG, 3) was developed. Under optimal conditions (isothiocyanate (0.1 mmol), amidines (0.1 mmol), 1,1,3,3-tetramethylguanidine (0.1 mmol), DMSO (1 mL), hemeprotein (heme concentration: 0.05 mol%), TBHP (3 equiv), room temperature, 10 min), high yields of 1,3,5-triazines (81%–96%) could be obtained when HbRb (Hemoglobin from rabbit blood) was used as the catalyst. This enzymatic method demonstrates the great potential for the synthesis of unsymmetrical trisubstituted 1,3,5-triazines and extends the application of enzyme catalytic promiscuity in organic synthesis.