Efficient Synthesis of Amino-1,3-Oxazines from Thi...

Org. Process Res. Dev. 2020, 24, 2853−2863.

DOI: 10.1021/acs.oprd.0c00369

◆In the medicinal chemistry synthesis of 1, trifluoromethane sulfonic anhydride was used to cyclize thiourea 2, affording a 1:9 mixture of amino-1,3-oxazine3 and amino-1,3-thiazine 4, respectively

◆During attempts to find optimal conditions for the conversion of thiourea 2 into aminothiazine 23, it was found that using conditions using TMSCl, DMSO which was expected to spontaneously cyclize to form the corresponding aminothiazine (23), instead gave rise solely to the amino-1,3-oxazine (24)

◆Armed with this finding, it was found that the desired amino-1,3-oxazine (3) was formed cleanly and rapidly with no trace of the corresponding amino-1,3-thiazine (4)

◆Monitoring this reaction by 13C NMR demonstrates consumption of the 44 formation of a species bearing a quaternary carbon atom that has a chemical shift, in agreement with the expected value for a carbodiimide intermediate

◆Given that the reaction can be performed in the presence of either TMSCl or HCl, it is proposed that both can serve to activate DMSO to form sulfonium salts, which are capable of activation of the thiourea, enabling the elimination of dimethylsulfide and sulfur to form the carbodiimide intermediate, which spontaneously cyclizes for form amino-1,3-oxazine.