## 3 Results and Discussion  
### Chalcones and Flavonones Synthesis  
The compounds obtained in this work were synthesized by aldol condensation between 4\({}^{\prime}\)- and/or 6\({}^{\prime}\)-substituted 2\({}^{\prime}\)-hydroxyacetophenones and either 4-hydroxy or 4-methoxybenzaldehyde, using NaH and LiHMDS (Scheme 1). **Scheme 1. ** General procedure for the synthesis of chalcones and flavanones. Compounds **1** and **3** were synthesized, as far as we could confirm, using for the first time in the aldol condensation the strong non-nucleophilic base NaH, which was used with success in similar condensations [43; 44]. The experimental results in the synthesis of chalcones **1-3**, with very good yields (\(\sim\)80%) and relatively low reaction times (3 to 4 h), proves that NaH is an effective and efficient base in the aldol condensation when it is desired to obtain non-hydroxylated chalcones, other than at the C-2\({}^{\prime}\) position. As referred above (Introduction), the hydroxyl groups present in the reagents require protection before the aldol condensation because in the strong basic conditions used, the phenoxide ions can undergo transformation into quinones and consequently prevent the formation of the desired chalcones. So, in order to obtain the desired compounds (the ones bearing hydroxyl and/or methoxyl groups), chalcones **2** and **3** need to be treated with acid to cleave the benzyl groups. The mixture used (HCl/AcOH) is one of the less harsh conditions and, in fact, removed the benzyl groups, but the obtained products were, in fact, flavanones **4** and **5** (Scheme 1). This can be explained by the acidic conditions used and the fact that those conditions favor the chalcones' isomerization into flavanones [45]. On the other hand, these extra steps, the protection and deprotection of hydroxyl groups, contribute to decrease the overall yield. For example, if we consider the synthesis of flavanones **4** and **5**, their precursors' chalcones **2** and **3** have excellent yields (80%), and the deprotection step, which produces the flavanones, is less efficient. This demonstrates that, due to this step, the flavanones' overall yield will be below 50%. At the same time, the yields (Scheme 1) allowed the assumption that the deprotection of the ring A hydroxyl groups is easier. Since our purpose was the synthesis of chalcones bearing hydroxyl and methoxyl groups, taking into consideration that these substituents might improve the activity, and that the synthesis of flavanones **4** and **5** involves three steps, namely, (i) protection of the reagent's hydroxyl groups, (ii) aldol condensation and (iii) cleavage of the protecting groups, we envisaged the synthesis of the desired chalcones using another base. Knowing that LiHMDS was used in the synthesis of hydroxylated flavones without the protection step and with good results [46; 47], we tested its use in the synthesis of chalcone **6** (Scheme 1). The experimental results showed that, using LiHMDS as the base, it is possible to synthesize polyhydroxylated chalcones in a one-pot process. However, although the desired chalcone was obtained, the yield was very low and its isomeric form, flavanone **7**, was also obtained. It should be highlighted that this reaction was accomplished at room temperature, controlled by TLC and finished after 5 days, when no more conversion was detected and 80% of the starting acetophenone was recovered. These data suggest that the conversion rate is high and that the reaction does not occur due to a lack of energy. We may suggest that using other sources of energy, such as a microwave, could originate higher yields. The synthesized compounds' structures were confirmed by detailed analysis of their 1D and 2D NMR spectra, MS spectra (e.g., in Figures S1-S9, supplementary material) and available literature data; moreover, their purity was confirmed by UHPLC. Herein, chalcones' and flavanones' characterization is briefly discussed.