Hydroxide → Diethyl (ethoxymethylene)malonate

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Reaction Steps

As shown in Chart D, commercially available 3-fluoro-4-nitrotoluene (D-0) is brominated to give compound D-1, which is reacted with morpholine to provide compound D-2. Compound D-2 is displaced with an amine (e.g., methylamine) to give compounds of formula D-3. Compounds of formula D-3 are catalytically reduced with hydrogen gas over 5% platinum on carbon and acylated with chloroacetic anhydride in THF to give compounds of formula D-4. Treatment with aqueous hydroxide (e.g., NaOH) in THF converts compounds of formula DA to the free base and affects cyclization to compounds of formula D-5. Reacting compounds of formula D-5 with diethyl ethoxymethylenemalonate affords enamines of formula D-6. Compounds of formula D-6 are cyclized with Eaton's reagent to provide compounds of formula D-7. Aminolysis of the ester of compounds of formula D-7 with a benzylamine (e.g., p-chlorbenzylamine) yields compounds of formula I of the present invention.

Provenance & Evidence