# The Synthesis and Biological Evaluation of 2-(1H-Indol-3-yl)quinazolin-4(3H)-One Derivatives
## 2 Results and Discussion  
### Chemistry  
The starting point of our research was the search for the optimal conditions of the model reaction of commercially available \(1H\)-indole-3-carboxaldehyde (**1a**) with anthranilamide (**2a**). Initially, we screened the reaction conditions using various Bransted acids. The best result was achieved when the reaction mixture was stirred at reflux for 4 h in acetonitrile in the presence of \(p\)-TSA (\(p\)-toluenesulfic acid). In this case, the yield of desired quinazoline **3a** was 33% (Scheme 1a). A thorough analysis and separation of the reaction mixture revealed the formation of indole (**4a**) and unsubstituted quinazoline **5a**. In other acidic conditions (amberlyst-15, CH\({}_{3}\)CN or toluene; NH\({}_{4}\)Cl or AcOH, EtOH; citric acid, toluene, etc. ), various side processes were observed, which significantly decreased the yield of the desired product. Next, we found that changing the reaction initiator to Al\({}_{2}\)O\({}_{3}\) led to the formation of 2-(\(1H\)-indol-3-yl)-2,3-dihydroquinazolin-4(\(1H\))-one (**6a**) as a major product (Scheme 1b). In addition to dihydroquinazoline **6a**, some indole (**4a**) was isolated from the reaction mixture. The obtained results (Scheme 1a,b) indicate that the key intermediate quinazoline **6a** is unstable under used reaction conditions and can be oxidized to form the desired quinazoline **3a** or undergo degradation affording 3-unsubstituted indole (**4a**). Control experiments showed that the dihydroquinazoline **6a** in the EtOAc, CH\({}_{2}\)Cl\({}_{2}\), and ethanol solutions was oxidized to key quinazoline **3a** upon standing in air. Moreover, the deformylation reaction and its related cleavage processes are well known and widely used as a key step for the preparation of natural and synthetic compounds [42; 43; 44; 45]. Finally, the desired product **3a** was obtained in a quantitative yield when the reaction was performed in \(N\),\(N\)-dimethylacetamide (DMAC) in the presence of Na\({}_{2}\)S\({}_{2}\)O\({}_{5}\) at 150 \({}^{\circ}\)C (Scheme 1c). Presumably, the true initiator of the cyclocondensation was NaHSO\({}_{3}\), which was in situ generated via the hydrolysis of the starting Na\({}_{2}\)S\({}_{2}\)O\({}_{5}\)[46]. With the optimized conditions in hand, we examined the substrate scope of this reaction. Initially, we performed the reaction at a 3 mmol scale and found that the yield of the desired product **3a** was 86% (Scheme 2). Next, we found that anthranilamide (**2a**) reacted smoothly with various \(N\)-substituted 3-formylindoles **1** to form the corresponding products **3b-g** in good to excellent yields. When indole-3-carboxaldehydes **1** containing easily removal groups at the nitrogen atom were used, we isolated the indolyluiazolinone **3a** instead of the expected \(N\)-substituted indolyluquinazolinones **3h-j**. The products **3m**, **n**, containing an aromatic substituent at the C(2) position of the indole core, were detected only in trace amounts, while quinazolininone **5a** was isolated in 59 and 37% yields, respectively. The formation of quinazoline **5a** in these cases could be associated with the better leaving nature of the 2-aryindoles in the intermediate dihydroquinazolinones. The halogen atoms in the starting indole **1** or anthranilamide **2** did not have a significant influence on the yields of the desired products **3k**, **1**, **o**, and 3p. A reduced yield of indolyluinzolinone **3q** was associated with the partial thioamidation of the \(1H\)-indole-3-carboxaldehyde (**1a**) by elemental sulfur upon the prolonged heating of the reaction mixture [47]; among the major indolyluquinazolinone **3q**, we isolated \(N\),\(N\)-dimethyl-1\(H\)-indole-3-carbothioamide (**7a**) in a 21% yield (for details see Supplementary Materials). We also performed the reaction of indole-2-carboxaldehyde (**1o**) with anthranilamide (**2a**) and isolated the corresponding product **3r** in a high yield. **Scheme 2. ** The synthesis of substituted indolylquinazolinones 3.