Linear Stepwise Synthesis of 2-(Naphthalen-1-yl)-2,3,5,6-tetrahydro-1H-isoquinolino[8,1,2-hij]quinazoline: A Novel Fused Heteroaromatic Framework

In the present work, we describe the synthesis of a new heterocyclic derivative, 2-(naphthalen-1-yl)-2,3,5,6-tetrahydro-1H-isoquinolino[8,1,2-hij]quinazoline 1, using the reaction between the aminal 1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane 2 (TATD) and 1-naphthylamine 3 as the first scaffold of a four-step linear synthetic route. In the first step, a condensation catalyzed by acetic acid in 96% ethanol was carried out, leading to the formation of the intermediate 3-(naphthalen-1-yl)-1,2,3,4-tetrahydrobenzo[h]quinazoline 4. Subsequently, this intermediate was acylated with 2-chloroacetyl chloride in the presence of triethylamine and under an inert atmosphere, obtaining the compound 2-chloro-1-(3-(naphthalen-1-yl)-3,4-dihydrobenzo[h]quinazolin-1(2H)-yl)ethan-1-one 5. In the third step, an intramolecular Friedel–Crafts cyclization was carried out using aluminum trichloride as a catalyst, yielding 2-(naphthalen-1-yl)-1,2,3,6-tetrahydro-5H-isoquinolino[8,1,2-hij]quinazolin-5-one 6. Finally, the reduction of this lactam with phosphorus pentachloride and sodium borohydride under anhydrous conditions led to the further closure of the polycyclic system, yielding the final product 1. The proposed route demonstrates the feasibility of using TATD 2 as a versatile precursor for constructing condensed heterocyclic systems of structural interest and potential relevance in advanced organic synthesis.