New Approaches Towards Inhibitors of Folate-Dependent Enzymes: Rapid Synthesis of 5-Deazapterins From Uracil Derivatives
Interest in 5-deazapterins (or pyrido[2,3-d]pyrimidine derivatives as they are more commonly known) has increased dramatically in recent years, based upon a diverse range of biological properties and the discovery that folate antagonists elicit highly species-specific responses (1). To continue our interest in the synthesis of simple nitrogen-containing heterocycles, we set out to develop a new method for the synthesis of highly-functionalised 5-deazapterins, based upon a modification of the Bohlmann-Rahtz pyridine synthesis (2), that would be appropriate for the rapid assembly of a targeted library of folate antagonists. Central to our approach was the need to develop a novel method, using readily available starting materials and simple experimental procedures, for the synthesis of structurally diverse heterocycles with complete control of regiochemistry. In the Bohlmann-Rahtz heteroannulation reaction, Michael addition-cyclodehydration of ethyl β-aminocrotonate 1 and ethynyl ketone 2 proceeds via aminopentadienone intermediate 3 (Scheme 1) that is heated (2) to 160 °C or spontaneously cyclodehydrates in the presence of acetic acid or amberlyst 15 ion exchange resin.
KeywordsExcellent Yield Michael Addition Pyrimidine Derivative Methanol Acetic Acid Michael Acceptor
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