# Environmentally Friendly Green \(O\)-Alkylation Reaction for Ethenzamide Synthesis
## 3 Results
### Synthesis of Ethenzamide in the Presence of Microwave Radiation, Ultrasound and Mechanochemically  
An important advantage of reactions conducted under PTC conditions is the possibility of carrying out the process both in the case of classical methods and in the presence of microwave radiation, ultrasound, or in mechanochemical reactions. The research was continued using microwave radiation (MW) first, because significant literature data and our previous experience in synthesis show that in the case of these reactions the reaction time can be shortened several times by minimizing the share of organic solvents or replacing them with a more ecological alternative such as glycerin or water. Interestingly, in MW processes, it is beneficial to use small amounts of dimethylformamide, which, in addition to the ability to transfer microwave energy, also acts as a catalyst. As shown in Table 2, microwave-assisted reactions were conducted to synthesize ethenzamide (**6**) with various catalysts, solvents, and reaction conditions. The TBAB-catalyzed reaction (with K\({}_{2}\)CO\({}_{3}\)) under solvent-free conditions achieved the highest yield (92%) in just 90 s, indicating the very high yield using direct microwave-assisted reaction. Using DMF as a solvent, the reaction yield was slightly dropped to 85%; the glycerin-DIPEA system had a lower reaction yield (69%). Water as a solvent with TBAB and K\({}_{2}\)CO\({}_{3}\) produces a substantial yield (80%). Furthermore, BTBAC- and TEAC-catalyzed reactions also have high yields (~90%). Under PTC-free conditions in water, the yield dropped to 78%. Without base catalysts, no reaction occurred. We continued our research into the possibility of using ultrasound as a source of energy for the reaction system. Under ultrasound (US)-assisted PTC of ethenzamide (with K\({}_{2}\)CO\({}_{3}\)), TBAB in water could result in a reaction yield of 84% in 10 min. No reaction occurs in the absence of K\({}_{2}\)CO\({}_{3}\). BTBAC and TEBA could result in higher yields (88% and 89%, respectively) compared to that of TBAB. TEAC performs less effectively (74%). In the absence of PTC, the reaction yield drops significantly to 30%. These results showed that US-assisted PTC synthesis of ethenzamide could achieve high efficiency and yields within short period (Table 3). To further investigate the PTCs under solvent-free conditions, mechanochemical synthesis of ethenzamide were conducted under TBAB, TEAC, BTBAB, and TEBA. Compared to the above MW and US conditions, the mechanochemical synthesis exhibits low efficiency due to the lack of solvents to disperse the reactants and PTCs, which reduced the catalytic efficacy of the PTCs and was not able to lower the activation energy (E\({}_{\text{a}}\)) for efficient \(O\)-alkylation. With the grinding time increased from 20 min to 60 min for TEBA-catalyzed reaction, the yield was improved from 52% to 60%. The relatively low yields may be further improved by optimizing the reaction conditions (Table 4). \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**No** & **Catalyst PTC** & **Solvent** & **Conditions** & **Time [min]** & **Yield [\%]** \\ \hline
1 & TBAB & - & K\({}_{2}\)CO\({}_{3}\) & 20 & 23 \\
2 & TEAC & - & K\({}_{2}\)CO\({}_{3}\) & 20 & 17 \\ \hline \hline \end{tabular}
\end{table} 
Table 4: Mechanochemical synthesis of ethenzamide.