2. Synthesis of 1-alkyl-3-oxo-carbo-and heterocycles

Another aspect of our work was the synthesis of heterocyclic substituted malonates, cyanoacetates or acetoacetates, which can be used as synthons for further cyclization reactions.

To study a general entry in this class of compounds, we started from 1-hydroxy-3-oxo compounds 1, which were converted to 1-chloro-3-oxo carbo- and heterocycles 2. By reaction with active methylene compounds such as malonates or acetoacetates the formation of 1-alkyl-3-oxo-carbo-and heterocycles 3 should be achieved. However, the yields of 3 depend strongly on the nature of the substituent A in position 2 of the former 1,3-dicarbonyl compound. We found that only electron withdrawing groups such as nitro- or cyano groups (and in a few cases halogen substituents) facilitated the alkylation to give in good yields the 1-alkyl-3-oxo-carbo-and heterocycles 3.

By this method we were able to synthesize a great variety of compounds by variation of the basic ring system and the active methylene compound (a small seelction is shown in the formula scheme below, e.g. 2-quinolones and cyanoacetates in 3a, 2-pyridones and acetylacetone in 3b, coumarins and acetoacetates in 3c, phenalenones and malonates in 3d or benzoquinolizinones and dimedone in 3e.).

A mixture of 4-chloro-3-substituted-2-quinolone (10 mmol), diethyl malonate (20 mmol) and anhydrous potassium carbonate was stirred at ambient temperature for 2-6 hours in dimethyl formamide. After dilution with ice/water the solution was slowly acidified with conc. hydrochloric acid to pH=1 to precipitate the product. After standing for some hours the precipitate was filtered and washed with water. Yield: 80-95%.

References