The synthesis of 2-amino-4(3H)-quinazolinones and related heterocycles via a mild electrocyclization of aryl guanidines

Consecutive Utilization of Mechanochemical and Microwave Methods for the Synthesis of Boc‐2‐amino‐quinazolin‐4(3H)‐ones and DFT Study of Mechanism 6π‐Diazaelectrocyclization Process

“…There are notable advantages of consecutive BM/MW reaction route described in this account in comparison to published synthetic procedures (Scheme 1). [3,4,6] Firstly, our procedure is simpler, as the number of reaction steps from aryl amine is reduced from three to two, both employing ecofriendly methodologies. Guanylation does not require any precautions from moisture or air, and no reagent is needed in cyclization step.…”

“…to rearomatization by [1,5]H shift into the most stable product 17. Relative Gibbs free energies for saddle points on the reaction path from reactant 4 to product 17 are 51.9, 31.9 and 58.2 kcal mol À 1 (TS2, TS3 and TS4, respectively) indicating that the activation energies for the first step (t-butanol elimination) and for the third step ( [1,4]H shift) are unrealistically high (forbidding). This result is not supported experimentally, since the heterocycle product was obtained and none of the intermediates between TS2 and TS4 was detected in the reaction mixture.…”

“…Tentative reaction mechanism for conversion of aryl guanidines to Boc-2-amino-quinazolin-4(3H)-one products was proposed on the basis of earlier accounts (Scheme 6). [4,6,7] Reaction is triggered by elimination of t-butanol and formation of intermediate isocyanate. Isocyanate undergoes 6π-diazaelectrocyclization process, which is followed by the final reaction step, the [1,5]-H migration.…”

“…[23] Similarly, the Suzuki-Miyaura reaction of aryl bromides with phenylboronic acid was carried out by ball milling and subsequent MW irradiation. [24] Mechanism of the formation of quinazoline moiety by electrocyclization of the isocyanate intermediate formed by thermal elimination of alcohol was proposed earlier, [4,6,7] but the details of the mechanism was not investigated either experimentally or computationally. The formation of the isocyanate intermediate was claimed in accordance to the results of thermolysis of arylcarbamates.…”

Synthesis, Antiproliferative, and Antioxidant Evaluation of 2-Pentylquinazolin-4(3H)-one(thione) Derivatives with DFT Study

“…Quinazolinones have been synthesized by different methodologies [28,30,31,32,33,34,35,36,37], in the present study, the conventional methodology to construct novel qunizolinone compounds has been adopted, followed by the study of the antiproliferative activity, antioxidant activity, and DFT calculations for the synthesized compounds.…”