# Environmentally Friendly Green \(O\)-Alkylation Reaction for Ethenzamide Synthesis
## 5 Discussion  
This study was aimed at determining the optimal conditions for the \(O\)-alkylation reaction, based on the example of the synthesis of ethenzamide (**6**) by the reaction of salicamide (**5**) with ethyl iodide. The synthesis was carried out under conventional conditions in the presence of organic solvents such as ethanol or dimethylformamide as well as in solvent-free conditions. The reactions were supported by phase transfer and other catalysts such as DABCO and crown ether. The results were very interesting because they proved that after just 15 minutes, the expected product can be obtained in solvent-free conditions with a yield of 69-86%. Then, we continued our research in a microwave reactor, which brought amazing results because it was observed that after just 2 minutes, an efficiency of up to 90% could be achieved. Interestingly, in MW-assisted reactions, even in the absence of a catalyst, an efficiency of 78% is achieved. It is worth noting, however, that the lack of potassium carbonate in the reaction medium makes it impossible to obtain ethenzamide (**6**). We observed similar dependencies in the reactions in the presence of ultrasound, i.e., the non-catalytic process occurred but with lower efficiency, while the lack of potassium carbonate was a critical parameter for obtaining the product. In US-assisted reactions, yields of 74-89% were achieved within 10 minutes, which is a very satisfactory result considering that the process took place in very mild conditions (atmospheric pressure, temperature 40 \({}^{\circ}\)C). The last stage of the research included attempts to carry out the process in mechanochemical conditions, which allowed us to obtain the expected ethenzamide (**6**) within 20 min with yields even above 50% in the non-catalytic process. Despite lower yields than in other methods, this one is certainly equally interesting but undoubtedly requires optimization. Undoubtedly, the stage of product isolation from the post-reaction mixture should also be refined, e.g., by adding zeolites or sand, which we have already tested in our previous studies in the synthesis of aripiprazole [33]. Based on the latest literature data and patent databases regarding the synthesis of organic compounds, a trend of searching for new environmentally friendly technologies is clearly observed. This phenomenon is also present in the pharmaceutical industry, where at the stage of searching for new drugs, and especially in the area of synthesis, methodsfrom the area of green chemistry are promoted. Undoubtedly, an important aspect in the case of environmentally friendly processes is the use of catalysts that are non-toxic and significantly affect the selectivity and efficiency of the process. All these aspects are met when the process is carried out under phase transfer catalysis (PTC) conditions. Bearing the above in mind, the \(O\)-alkylation methods we have developed are consistent with current trends in organic synthesis. The conditions used allowed us to minimize toxic conditions and significantly improve the product isolation process, which was based only on adding water and filtering the product. This means that not only the synthesis process itself but also the product isolation is more ecological than in the case of other conventional synthesis methods, where not only the reaction but also the product isolation is carried out using organic solvents. Our latest research proves that the developed synthesis methods are universal. We are currently conducting research on the application of the developed method of ethenzamide synthesis in the presence of microwave radiation and ultrasound for the synthesis of new \(O\)-derivatives of salicimide with anticancer properties that can be used in the treatment of breast cancer and for the synthesis of new acetylcholinesterase inhibitors.