In the first step of the synthesis of a potential enzyme inhibitor, an unknown side product was observed in the 1H-NMR spectra. The quinazolinone major product is formed by nucleophilic addition (NA) of 2-aminobenzamide and a substituted benzaldehyde in the presence of base and an oxidant. Using K2CO3 and I2 in DMF forms the major and side product, while using NaHSO3 in DMAC only forms the major product. The amount of side product is correlated to the presence of electron withdrawing groups on the benzaldehyde, with the highest yield observed with 4-NO2 and lowest with unsubstituted and 4-MeO. Using GC-MS, side products showed m/z 126 mass units greater than the major products due to the replacement of a hydrogen by an iodine (127 m/z). The structure of the iodo derivative was confirmed by H-H COSY and independent synthesis. Furthermore, it was observed that the starting material 2-aminobenzamide readily iodinates in the presence of K2CO3 and I2 while the major product does not. Therefore, the side product cannot be explained by iodination of the major product; rather the kinetics of the competing reaction with the benzaldehyde are consistent with the observed results. To confirm this hypothesis, competition experiments were run between the substituted and unsubstituted benzaldehydes and the product mixture was analyzed by GC-MS. A Hammett plot indicated that electron withdrawing groups react at a slower rate toward NA, while electron donating groups react faster. More side product is formed by 4-NO2 because it reacts more slowly in NA, allowing more 2-aminobenzamide to iodinate, forming more side product. Conversely, 4-MeO reacts faster toward NA, not allowing 2-aminobenzamide to iodinate, and forming less side product. The formation and yield of the side product is due to the iodination of 2-aminobenzamide limited by the kinetics of the NA of substituted benzaldehydes.

Identification of novel quinazolinone side products and proposed mechanism involving substituent effect kinetics determined by Hammett plot analysis

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