Reaction of Ph₃P(SCN)₂ with Further Orthohydroxy Carboxylic Acid Systems, Including Substituted β-Keto Acids: Synthesis of Novel 2-Thio-1,3-oxazines and Their Subsequent Transformation with Amines

Abstract

We now report the first reaction of Ph₃P(SCN)₂ with 4,6-dihydroxy-5-methylisophthalic acid to give 10-methyl-2,8-dithio-1,3-oxazino-1,3-benzoxazine-4,6-dione. Also, the enol tautomer has been utilized in the reaction of β-keto acids with Ph₃P(SCN)₂ to give novel 2-thio-1,3-oxazines. Subsequent reaction of the 2-thio-1,3-oxazines with benzylamine resulted in opening of the oxazine ring and gave novel dibenzylamino-enamides, which could be cyclized to thiouracils. The reaction of 2-thio-1,3-oxazines with morpholine at low temperature led to the production of unstable 2-Mercapto-2-morpholino-1,3-oxazines. 2-Mercapto-2-morpholin-4-yl-2,3,5,6,7,8-hexahydro-4H-1,3-benzoxazin-4-one was observed to lose H₂S at room temperature to give 2-morpholin-4-yl-5,6,7,8-tetrahydro-4H-1,3-benzoxazin-4-one, which was subsequently tested and found to exhibit some antiplatelet activity.

Keywords:

• Dicarboxylic acid
• β-keto acids
• 2-morpholino-1,3-oxazines
• 2-thio-1,3-oxazines
• thiouracils

ACKNOWLEDGMENTS

The authors gratefully acknowledge the financial support of the Australian Research Council (Australian Postgraduate Award) and La Trobe University. They also acknowledge the preliminary work carried out by Jacob Nankervis.