Conventional oxidation processes for alkyl aromatics to ketones employ oxidants that tend to generate harmful byproducts and cause severe equipment corrosion, ultimately creating critical environmental problems. Thus, in this study, a practical, efficient, and green method was developed for the synthesis of aromatic ketones by applying a bis(2-butoxyethyl) ether/O2 system under external catalyst-, additive-, and base-free conditions. This O2-mediated oxidation system can tolerate various functional groups and is suitable for large-scale synthesis. Diverse target ketones were prepared under clean conditions in moderate-to-high yields. The late-stage functionalization of drug derivatives with the corresponding ketones and one-pot sequential chemical conversions to ketone downstream products further broaden the application prospects of this approach.