Different strategies for the synthesis of 2′-hydroxy-4′-methylsulfonylacetophenone are reported in the present paper. This compound is considered as a key synthon for the synthesis of new flavonoid derivatives designed as potential cyclooxygenase-2 inhibitors. The retrosynthetic approach via 3′-methylsulfonylacetophenone, which included three synthetic pathways, did not allow us to obtain the expected compound. However, a synthesis from 3-mercaptophenol led to the desired acetophenone in three steps: thiophenol methylation, Friedel–Crafts acetylation and oxidation of the sulphide to the corresponding sulfone. The desired compound, 2′-hydroxy-4′-methylsulfonylacetophenone, will be used as a synthon for the preparation of novel flavonoid derivatives, such as 2′-hydroxychalcones, flavanones, flavones, and flavonols.