Computational insights into the reaction mechanism of the synthesis of quinazoline derivatives via the cyclocondensation reaction between methyl 2-amino-4-(2-diethylaminoethoxy)-5-methoxybenzoate and formamide

Abstract

In this work, the cyclocondensation reaction mechanism between methyl 2-amino-4-(2-diethylaminoethoxy)-5-methoxybenzoate (MAD, 1) and formamide (FME, 2) was theoretically explored at the DFT level using the B3LYP/6-311++G(d,p) computational method. The two paths (a and b) involved in this reaction take place through four steps. CDFT results show the most favourable electrophilic/nucleophilic interaction between the C3 electrophilic center of MAD (1) and the N4 nucleophilic center of FME (2). Activation energy analysis predicts the formation of quinazoline derivative as the main product, in reasonable agreement with experimental results. BET allowed a deeper understanding of the reaction mechanism by revealing the existence of four structural stability domains (SSD) during the processes of CN and OH bond formation. The bond process is as follows: depopulation of V(N) basin with the formation of first CN bond (appearance of V(C,N) basin), cleavage of NH bond with the creation of V(N) and V(H) monosynaptic basins, and finally the appearance of V(H,O) disynaptic basin related to the OH bond. In the case of dehydration, the transition from SSD-I to SSD-II corresponds to the cleavage of the CO bond, whose electron population is transferred to the V(O3) basin. The cleavage of N7-H9 bond with the formation of V(N) and V(H) basins is the first stage, followed by the formation of the OH bond as the second stage.