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
Augusto Rivera, Álvaro Castillo, Jaime Ríos-Motta, Diego Quiroga
Organics · pp. 12–12 · Published 3 Mar 2026
10.3390/org7010012Abstract
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.
References (24)
- 1 Asif, 2014, Chemical Characteristics, Synthetic Methods, and Biological Potential of Quinazoline and Quinazolinone Derivatives
- 2 Deharkar, 2021, Review on Synthesis Route of Quinazoline-Based Hybrid Derivatives [DOI]
- 3 Meyer, 1943, The Niementowski Reaction. The Use of Methyl Anthranilate or Isatoic Anhydride with Substituted Amides or Amidines in the Formation of 3-substituted-4-keto-3,4-dihydroquinazolines. the course of the reaction [DOI]
- 4 Grimmel, 1946, A New Synthesis of 4-Quinazolones [DOI]
- 5 Zentmyer, 1949, The So-called Acylanthranils (3,1,4-Benzoxazones). I. Preparation; Reactions with Water, Ammonia, And Aniline; Structure 1 [DOI]
- 6 Grytsak, 2024, [1,2,4]Triazino[2,3-c]Quinazoline Hybrids with Azole and Azine Heterocycles: Design, Synthesis, Antibacterial and Antiradical Activity
- 7 Mohamed, 2024, Design, Synthesis, and Antiproliferative Activity of New 1,2,3-Triazole/Quinazoline-4-One Hybrids as Dual EGFR/BRAF V600E Inhibitors [DOI]
- 8 Donka, 2025, Design, Synthesis, and Antimicrobial Evaluation of Novel Quinazoline Piperazine Phosphorodiamidate Hybrids as Potent DNA Gyrase Inhibitors [DOI]
- 9 Wang, 2025, Design, Synthesis and Biological Evaluation of Novel Platelet-Derived Growth Factor Receptor-α (PDGFR-α) Inhibitors Based on 4-Anilinoquinoline and 4-Anilinoquinazoline Scaffolds [DOI]
- 10 Bhat, 2025, Hexokinase 2 Inhibition Study of Lonidamine-Tacrine/Quinazoline Hybrids: Design, Synthesis, Molecular Docking, and Dynamics Simulations [DOI]
- 11 Narmada, 2025, Design and Synthesis of New Quinazoline Hybrid Molecules as EGFR Targeting Anti-Breast Cancer Agents and Computational Studies [DOI]
- 12 Albay, 2025, Synthesis and Evaluation of Aldose Reductase Inhibition of New Thiazolidine-Quinazoline Hybrids through in Vitro and in Silico Approaches [DOI]
- 13 Hassan, 2025, Design, Synthesis, and Anticancer Evaluation of New Quinazoline Hybrids: DNA Intercalation, Topoisomerase IIα Inhibition, and in Silico Studies [DOI]
- 14 Saleh, 2025, 6,7-Dimethoxy-2-Methyl-4-Substituted Quinazolines: Design, Synthesis, EGFR Inhibitory Activity, in Vitro Cytotoxicity, and in Silico Studies [DOI]
- 15 Chorell, 2025, Design, Synthesis, and Biophysical Characterization of Pyridine Bis-Quinazoline Derivatives as Selective G-Quadruplex DNA Stabilizers [DOI]
- 16 Murthy, 2016, A Simple Approach for the Synthesis of Fused Quinazoline-Based Tetracyclic Compounds via a Multicomponent Reaction Strategy [DOI]
- 17 Liu, 2012, Copper-Catalyzed Domino Synthesis of Isoquinolino[2,3-a]Quinazolinones [DOI]
- 18 Wu, 2020, A Cascade Synthesis of 11 BH-Imidazo[1,2-c]Isoquinolino[2,1-a]Quinazoline Derivatives Catalyzed by AgOTf [DOI]
- 19 Rivera, 2013, Solvent-Free Mannich-Type Reaction of Tetraazatricyclododecane (TATD) with Phenols [DOI]
- 20 Rivera, 2012, 1,3-Dinitrosoimidazolidine
- 21 Rivera, 2012, 1,1′-[Imidazolidine-1,3-Diylbis(Methylene)]Bis-(1H-Benzotriazole) [DOI]
- 22 Rivera, 1993, A Novel Manich Type Reaction Using Aminals in Alkaline Medium [DOI]
- 23 Rivera, 2012, 2,2′-[Imidazolidine-1,3-Diylbis(Methylene)]Diphenol [DOI]
- 24 Rivera, 2010, Synthesis of a New Series of N,N′-Dimethyltetrahydrosalen (H2 [H2Me]Salen) Ligands by the Reductive Ring-Opening of 3,3′-Ethylene-Bis(3,4-Dihydro-6-Substituted-2H-1,3-Benzoxazines) [DOI]
Cited by 0
No indexed citations yet.
Related research
- A Novel Catalytic Synthesis of Flavones under Autoclave Conditions and Comparative Study of Anti-cancer Activity — shares topic coverage
- Thermostability and in-vitro Antibacterial Activity of Aqueous Extracts of Tetrapleura tetraptera Pods on Multidrug Resistant Clinical Isolates — shares topic coverage
- Acute Toxicity, Phytochemistry and Anti-diarrheal Effects of Celtis integrifolia Lam. Aqueous Leaf Extract in Wistar Albino Rats — shares topic coverage
- Understanding the Reactivity of Trimethylsilyldiazoalkanes Participating in [3+2] Cycloaddition Reactions towards Diethylfumarate with a Molecular Electron Density Theory Perspective — shares topic coverage
- Understanding the Origin of the Regioselectivity in Non-Polar [3+2] Cycloaddition Reactions through the Molecular Electron Density Theory — shares topic coverage
Article metrics
Real usage data collected on this platform.
0
Page views
0
PDF downloads
0
Outbound clicks
0
Citations
Views by country
Approximate, from request IP at view time — not citizenship or institution. Countries with fewer than 5 views are grouped as "Other".
No views recorded yet.
Traffic sources
Referring site, by host.
No traffic recorded yet.
Views and downloads exclude known bots/crawlers. Citations combines this platform's own DOI-resolved index with each external source's own reported total — see Cited by above for individually listed citing works. Last refreshed 0 seconds ago.