Direct access to pyrido/pyrrolo[2,1-b]quinazolin-9(1H)-ones through silver-mediated intramolecular alkyne hydroamination reactions

We report a synthetic methodology for the construction of the fused heterocyclic compounds pyrido[2,1-b]quinazolin-9(1H)-ones and pyrrolo[2,1-b]quinazolin-9(1H)-ones through an AgOTf-catalyzed intramolecular alkyne hydroamination reaction. The methodology is applicable to a wide scope of substrates and produces a series of fused quinazolinone heterocycles in good to excellent yields.

A variety of approaches have been employed to synthesize deoxyvasicione (1) and its derivatives, e.g., the Pd(OAc) 2 -catalyzed carbonyl-insertion reaction [7], the cycloaddition of anthranilic acid iminoketene to a methyl butyrolactam through a sulfinamide anhydride intermediate [9], the intramolecular aza-Wittig reaction with an azide substrate [10], and the cycloaddition of anthranilamide [11]. For the synthesis of vasicinone (5), deoxyvasicinone was subjected to a free-radical bromination using NBS and the subsequent treatment with NaOAc/AcOH as an acetoxylation reagent [12]. However, for most of these synthetic strategies harsh reaction conditions are a necessity, produce unstable sulfonamide anhydride intermediates [2,13], which are dangerous substrates bearing an azide group, and require a high reaction temperature and a long reaction time

Results and Discussion
To establish the overall best experimental conditions for the synthesis of pyrido/pyrrolo[2,1-b]quinazolin-9(1H)-ones, we chose 2-(4-pentynyl)-4(3H)-quinazolinone (6A) as a model substrate to prepare them by an intramolecular hydroamination cyclization. The results of these experiments are summarized in Table 1. Silver trifluoromethanesulfonate (AgOTf) seemed to be the most effective catalyst for this intramolecular hydroamination cyclization ( Table 1, entries 1-6), whereas a product was not afforded in the absence of a catalyst (Table 1, entry 7). We also screened different solvents, and the results demonstrated that non-polar aprotic solvents could promote the reaction. Toluene was the most effective solvent for this cyclization ( Table 1, entry 3 and entries [8][9][10][11][12][13][14][15][16]. The concentration of the substrate in the reaction mixture also affected the product yield. When the concentration was changed from 0.1 M to 1 M, the yield dropped to 82% (Table 1, entry 17). Subsequently, we examined the influence of the reaction temperature, and no better yield could be obtained at a temperature either lower or higher than 80 °C (Table 1, entries 18 and 19). A prolongation of the reaction time to 12 h resulted in a slight decrease of the yield (Table 1, entry 20). Performing the reaction without inert gas (argon) atmosphere also led to a decrease of the yield ( Table 1, entry 21). In summary, the optimum results were obtained when 2-(4-pentynyl)-4(3H)-quinazolinone (6A) in toluene was treated with 5 mol % of AgOTf in a sealed tube under argon protection at 80 °C for 3 h (Table 1, entry 3).
To evaluate the scope of the proposed silver-catalyzed intramolecular hydroamination cyclization reaction, we investigated its AgOTf toluene 71 f a 6A (0.2 mmol) and catalyst (5 mol %) in the specified solvent (2 mL) were heated in a sealed vial under argon protection at 80 °C for 3 h; b the concentration of 6A is 1 M; c the reaction temperature was 60 °C; d the reaction temperature was 100 °C; e the reaction time was 12 h; f the reaction was performed without an argon inert gas atmosphere.
Based on the results of the present studies, we propose a plausible mechanism for the transformation. As depicted in Scheme 2, the intramolecular cyclization is initiated by the activation of the terminal alkyne moiety of the substrate with AgOTf to generate the Ag-alkyne π complex I (or its tautomer II). Subsequently, the Ag-alkyne π complex I or II is converted into complex III through a nucleophilic attack of the nitrogen atom of the amide, and then produces the final product. Products 7A and 9G were recrystallized and their structures were  unambiguously confirmed by X-ray diffraction (XRD) studies (see Supporting Information File 1 for details).

Conclusion
In conclusion, we have developed a chemical methodology for the synthesis of pyrido/pyrrolo[2,1-b]quinazolin-9(1H)-ones through an AgOTf-catalyzed intramolecular alkyne hydroamination cyclization reaction. The methodology is applicable to a wide scope of substrates and generates a series of fused quinazolinone heterocycles in good to excellent yields. It lends itself an alternative method to the construction of innovative molecules with polycyclic architectures. It may be worthwhile to investigate the biological activity of the synthesized structures.

Experimental
Commercially available reagents and solvents were used without further purification. Column chromatography was performed on silica gel. TLC was performed on silica gel GF254 plates. 1 H NMR and 13 C NMR spectra were obtained on Varian 300, Bruker 400 and 500 spectrometers. The chemical shifts for 1 H NMR were recorded in parts per million (ppm) downfield from tetramethylsilane (TMS) with the residual solvent resonance as the internal standard (7.26 ppm for CDCl 3 or 2.50 ppm for DMSO-d 6 ). The chemical shifts for 13 C NMR were recorded in ppm by using the central peak of CDCl 3 (77.23 ppm) or DMSO-d 6 (39.52 ppm) as the internal standard. Coupling constants (J) are reported in Hz and refer to apparent peak multiplications. The abbreviations s, d, t, q, p and m stand for singlet, doublet, triplet, quartet, pentet and multiplet, respectively.
General procedure for the synthesis of substrates 6A-6L and 8A-8L: To a solution of 5-hexynoic acid (3.0 mmol) in dry CH 2 Cl 2 (5 mL) was added EDCI (3.1 mmol) and HOBt (3.1 mmol). The resulting mixture was stirred at rt for 2 h. Then General procedure for the synthesis of the target products 7A-7L and 9A-9L: A vial equipped with a magnetic stir bar was charged with the corresponding substrate 6A-6L or 8A-8L (0.4 mmol) and the catalyst AgOTf (5 mol %) and capped with a septum. The vial was evacuated and backfilled with argon, and this process was repeated three times. Under argon, anhydrous toluene (4 mL) was injected to the vial with a syringe, and the resulting mixture was stirred at rt for 10 min. Afterwards, the vial was kept in a preheated oil bath at 80 °C for the appropriate time. After the reaction was complete, the reaction mixture was cooled to rt and the solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography with petroleum ether/EtOAc 20:1 (v/v) as an eluent to give the desired target compounds 7A-7L and 9A-9L. Compound 7A as an example: 1

Supporting Information
Supporting Information File 1 Detailed experimental procedures for all compounds and precursors, copies of 1 H/ 13 C NMR spectra for all compounds.