{'fraction_non_alphanumeric': 0.03937791601866252, 'fraction_numerical': 0.03073094867807154, 'mean_word_length': 4.890802491755221, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 1, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Facile One-Pot Synthesis of Functionalized Quinoline-Fused Fluorescent Dihydro/Spiro-quinazolinone Derivatives

A facile and efficient method has been developed for the synthesis of quinoline-fused fluorescent dihydro/spiro-quinazolinones. A plausible mechanism involving an acid-mediated enaminone intermediate is provided. The reaction proceeded using p-toluene sulfonic acid as a green promoter. The methodology was successful in synthesizing various quinoline-appended spiro-quinazolinones 4a–o. The synthetic utility of compounds 4a–o was demonstrated by synthesizing compounds 6a–d via Suzuki coupling as a key reaction. Significantly, the π–π* electronic transition of compounds 4c and 4k showed a blue shift. The molar extinction coefficient (ε), Stoke’s shift (Δu̅), and quantum yield (Φf)c were calculated for these derivatives (4c and 4k).


■ INTRODUCTION
The chemistry of quinoline scaffolds is well documented. Owing to their biological properties, it leads to great interest among medicinal chemists in the development of drug candidates. Various classical methods such as Skraup, Doebner-von Miller, Friedlander, Pfitzinger, Conrad-Limpach, and Combes synthesis are known for a quinoline ring system. 1 Later, due to the importance of the quinoline backbone, a number of new methods have been developed by employing both transition metals and metal-free conditions such as CuCN, LiCl 3 , RuCl 3 , 2 Yb(OTf) 3 , 3 tungsten vinylidene complex, 4 BF 3 OEt 2 , 5,6 benzotriazoleiminium salts, etc. 7 Notably, cabozantinib, and bosutinib are a few FDA-approved marketed anticancer drugs containing a quinoline moiety 8 and a quinazolinone skeleton present in many drugs and natural products such as bouchardatine, rutaecarpine, etc. (Figure 1). 9 Owing to the diverse range of pharmacological activities, various methods have been developed using copper, 10,11 iridium, 12 manganese, 13 silver, 14 vanadium, 15 cyanuric chloride, 16 cationic Amberlyst-15 resin, 17 clays, 18 p-TSA, 19 starch sulfate, 20 and TFA 21 for the synthesis of quinazolinone derivatives. Indeed, the nitrogen-containing heterocyclic compounds play a significant role in biological activities such as chorismate mutase inhibitors, IRAP inhibitors, etc. ( Figure  1). 22 Recently, molecular hybridization has been developed as a tool in the development of hybrid analogues with enhanced potency by combining two or more pharmacophores of bioactive scaffolds. The molecular hybridization of various biologically active pharmacophores resulted in lead compounds with multifaceted biological activity wherein specific as well as multiple targets were involved. 23 Thus, we were interested to develop molecular hybridization having quinoline and quinazolinone cores. A few reports are available for the synthesis of quinoline-fused quinazolines. One such example is Luotonin A (Figure 1), a pyrroloquinazolinoquinoline alkaloid extracted from the Chinese medicinal plant Peganum nigellastrum. Nevertheless, although the mechanism is unknown, Luotonin A is cytotoxic toward the murine leukemia P-388 cell line (IC 50 1.8 μg/mL). 24 To minimize waste and reaction time, "step-economic" and "pot-economic" syntheses have emerged as efficient and sustainable reaction protocols. Since the beginning, one-pot reactions have grown in two directions, namely, multiple orthogonal, irreversible steps are combined, while in the second case, multiple reversible steps are coupled to one irreversible step using an enzymatic catalyst. 25 To the best of our knowledge, the synthesis of quinoline-appended quinazolinone in a one-pot manner is reported via thermal electrocyclization of aldimine 26 (Scheme 1, equation 1) and the synthesis of 2-hetero-substituted 2,3-dihydroquinazolin-4(3H)ones is carried out using Mont. K10 clay as a catalyst 27 (Scheme 1, equation 2). Thus, we have developed a novel onepot protocol for the synthesis of quinoline-appended quinazolinones from a reaction of 2-aminoacetophenone, 1,3cyclohexanedione, and anthranilamide utilizing p-TSA as a reagent, and the products thus formed have been evaluated for photophysical properties (Scheme 1, equation 3). It should be noted that both the quinoline and the quinazolinone rings in the products have been formed simultaneously in the one-pot reaction.

■ RESULTS AND DISCUSSION
At first, 1.0 equiv of each of 2-aminoacetophenone 1a, 1,3cyclohexanedione 2a, and anthranilamide 3a were treated with 2.0 equiv of p-TSA in a sealed tube at 100°C under a neat condition over 12 h, affording 9-methyl-3,4-dihydro-1'H,2Hspiro[acridine-1,2′-quinazolin]-4′(3′H)-one 4a in a 17% yield along with an inseparable mixture. Compound 4a was thoroughly characterized by spectroscopic methods. To prevent the formation of undesired byproducts, the reaction was performed in a periodic addition of the reagents. Thus, initially, a mixture of 1.0 equiv of 1a, and 1.0 equiv of 2a was treated with 2.0 equiv of p-TSA in a sealed tube and heated at 100°C for 3 min. Following this, 1.0 equiv of 3a was added and stirred for 12 h at 100°C. The reaction yielded 4a in a 17% yield and a new compound 9-methyl-3,4-dihydroacridin-1(2H)-one 5a in a 74% yield as the major product (Table 1,  entry 1).
To improve the yield of 4a, parameters such as temperature, reagents, the mole ratio of reactants, and solvents were considered. Thus, a reaction with a 1:1 ratio of compounds 1a and 2a in the presence of 2 equiv of p-TSA at 100°C for 3 min   . Also, various equivalents of substrates were taken in the presence of 2 equiv of p-TSA at 100°C for 3 min, followed by the addition of 3a, and the temperature of the reaction system was increased to 115°C. We observed that no significant improvement in the yield was noticed. However, in all of the cases, a trace of 5a was observed ( Table 1, entries 18−20). Furthermore, to remove the intermittent addition of anthranilamide 3 into the reaction, we performed a reaction by adding all of the reactants (1, 2, and 3), p-TSA, and DMSO together and heating at 100°C for 3 min, followed by heating at 115°C over 12 h. We observed no change in the yield percentage of the expected products 4a and 5a.
Based on the structure of product 4, a plausible mechanism is proposed in Scheme 2. Thus, 2-aminoacetophenone 1a undergoes Friedlander condensation with 1,3-cyclohexanedione 2a in the presence of p-TSA to form an isolable acridinone intermediate 5. The structure of the representative compound 4b was confirmed by spectroscopic data analysis (see SI), and the relative stereochemistry was assigned based on single-crystal Xray analysis ( Figure 5). 28 Encouraged by the preliminary results, we investigated the scope of the reaction with several 2-aminoacetophenones, 2aminoamides, and 1,3-cyclohexanedione (Figures 3−5 and  Table 2). Under optimized conditions, (Table 1, entry 7) all of the reactions went smoothly to produce the respective quinoline-appended quinazolinones 4 as the major product and acridinone as the minor product 5. It was observed that the unsubstituted 2-aminobenzamide 3a gave a higher yield compared to those with bromine-substituted aminobenzamides 3b and 3c. This might be due to the interaction of the bulky Br group with the quinoline methyl in the imine intermediate. The bulky methyl substitutions on the aliphatic ring of the compound did not affect the yield of the reaction. The reaction gave only acridinone 5 as the sole product when the reaction was performed with 3-aminofuran-2-carboxamide and 2aminobenzene sulfonamide.
The bromine substitutions on the derivatives facilitated further synthetic transformations of the molecules. The effectiveness of this methodology was further scrutinized by a gram-scale synthesis of 4a under optimized reaction conditions giving a yield of 81%.
To demonstrate the synthetic utility of compounds synthesized, several biphenyl tethered quinoline-appended spiro-quinazolinones were synthesized via the Suzuki coupling reaction, as shown in Scheme 3. Thus, compounds 4c, 4d, and 4n were treated with various aryl boronic acids in the presence  of Pd(OAc) 2 as a catalyst and K 2 CO 3 as a base to afford respective arylated products 6a−d in an 89−95% yield.
Photophysical Studies. The structural uniqueness of quinoline-appended dihydro/spiro-quinazolinones encouraged us to explore their photophysical properties. Thus, compounds 4c and 4k were chosen for the investigation. Initially, to establish solvatochromic property, UV−visible spectra of 4c and 4k were recorded using solvents such as acetonitrile, methanol, tetrahydrofuran, 1,4-dioxane, and toluene. Two absorption bands were observed in all of the solvents, as shown in Figures 6 and 7. A higher energy band in the range 228 to 287 nm begins with π−π* electronic transition [intramolecular charge transfer (ICT)] and other bands with lower energy n−π* electronic transition in the region 345−365 nm were observed. While increasing the solvent polarity from toluene to acetonitrile, a blue shift was observed for both compounds.
The wavelength shifted from 287 nm in toluene to 228 nm in acetonitrile to give a shift of 59 nm for compound 4c. For compound 4k, a similar shift of 57 nm was observed in the respective solvent. The hypsochromic (blue) shift observed can be associated due to the decrease in the dipole moment in the excited state as compared to the ground state, stabilizing the ground-state energy in polar solvents. 29 Furthermore, the molar extinction coefficient (ε) was calculated using Lambert− Beer's law (A = εcl). The molar extinction coefficient value of both the derivatives decreased with the decrease in solvent polarity. As the solvent polarity decreased, the value of the molar extinction coefficient of 4c decreased from 5.1295 × 10 4 to 0.5664 × 10 4 M −1 cm −1 (Table 3). In the case of 4k, the value of the molar extinction coefficient decreases from 10.3089 × 10 4 to 1.1268 × 10 4 M −1 cm −1 (Table 4).  Tables 3 and 4.
Both the compounds 4c and 4k exhibited a large Stoke's shift in the ranges from 20 542 to 12 390 and 21 320 to 10 212 cm −1 , which is associated with highly polarizable π-conjugated systems due to ICT. It has also been noted that a large red shift was observed in the excited state when methanol was used as a solvent, as shown in Figures 6 and 7 1b, 2b. This might be due to the stronger electron-withdrawing nature of the quinoline ring and the presence of a strong electron-donating amino group in the molecule. Protonation of the compound by the solvent also facilitates the red shift. 30 The extended π conjugation induced by the aryl system encouraged us to further investigate the photophysical properties of the Suzuki coupled products 6a−d. Thus, UV− visible and fluorescence spectra of compounds 6a−d were measured in methanol and the spectra are displayed in Figure 8 a,b. The absorption spectra of compounds 6 a−d showed two bands in the region of 240−380 nm. The first absorption band is related to higher energy with a lower wavelength π−π* transition that appeared in the range of 250−280 nm and another medium energy belonging to the n−π* transition of the compounds appeared as a shoulder in the region of 330− 380 nm for compounds 6a−d. Also, in fluorescence spectra, the medium energy exhibits emission at 367 nm (6a), 371 nm (6b), 380 nm (6c), and 380 nm (6d).
Furthermore, Stoke's shift and the molar extinction coefficient for the π−π* transition were calculated for 6a−d.   higher Stoke's shift than the biarylated derivatives 6c−d. The complete photophysical data along with fluorescence quantum yield (Φ f ) for the synthesized biaryls are summarized in Table  5. It was observed that much increase in the quantum yield was not observed when the phenyl ring was tethered to quinolineappended quinazolinones. It was observed that the quantum yield and Stoke's shift values obtained for the quinoline-appended quinazolinones were higher compared to other spiro-and cyclic-quinazolinone heterocyclic derivatives. 31 This class of quinoline-based compounds with a high quantum yield and Stoke's shift values is very useful as labels in biochemical and technical applications. 32 In conclusion, an efficient one-pot synthesis of quinolineappended quinazolinone derivatives has been accomplished via Friedlander condensation. A plausible reaction mechanism is provided, and a representative structure of product 4b was confirmed by XRD. The synthetic utility of the products is demonstrated by the Suzuki coupling reaction. Further, photophysical properties of compounds 4c and 4k were evaluated and synthesized biphenyl tethered quinolineappended quinazolinones were found to be promising blueemissive fluorescent molecules.

■ EXPERIMENTAL SECTION
General Remarks. All of the reactions were carried out in oven-dried glassware. Progress of reactions was monitored by thin-layer chromatography (TLC), while purification of crude compounds was done by column chromatography using silica gel (Mesh size 100−200). The NMR spectra were recorded on a Bruker 400 MHz NMR spectrometer (400 MHz for 1 H NMR and 100 MHz for 13 C NMR) with CDCl 3 or (CD 3 ) 2 SO as a solvent and TMS as an internal reference. Integrals are in accordance with assignments; coupling constants were reported in Hertz (Hz). All 13 C spectra are proton-decoupled. Multiplicity is indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), and br s (broad singlet). FTIR spectra were recorded on a Perkin-Elmer RX-I FTIR, and absorbance is reported in cm −1 . HRMS analyses were recorded using a Q-Tof Micro mass spectrometer (different mass analyses based on the availability of instruments). Yields refer to quantities obtained after chromatography. Absorption spectra were recorded using a JASCO V-670 spectrophotometer. Steady-state fluorescence spectra were recorded on a Hitachi F-7000 FL Spectro fluorophotometer by excitation at the respective absorption maxima.
Quantum yields of compounds were estimated by comparison with the known quantum yields of anthracene in ethanol (Φ = 0.27) at an excitation wavelength of 246 nm using the following equation: where Φ is the quantum yield, I is the integrated intensity, OD is the optical density, and n is the refractive index. The subscript R refers to anthracene. The molar extinction coefficient (ε) was calculated using Lambert−Beer's law The Stoke's Shift was calculated using the following equation: General Procedure for the Synthesis of 2-Amino-5bromoacetophenone (1b). To a stirred solution of 1-(2aminophenyl)ethanone (0.5 g, 3.7 mmol) in 5 mL of CH 3 CN at 0°C, N-bromosuccinimide (0.66 g, 3.7 mmol) was added dropwise and dissolved in 5 mL of CH 3 CN. The mixture was General Procedure for the Synthesis of 2-Amino-5bromobenzamide (3b). In a screw-capped reaction tube, 2aminobenzamide (0.5 mmol) was dissolved in acetonitrile (2 mL) and N-bromosuccinamide (0.6 mmol) dissolved in CH 3 CN was added, and the reaction mixture was heated at 60°C for 10 min. Then, the mixture was diluted with EtOAc and washed with saturated brine. The organic layer separated was dried over anhyd. Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified through a column of silica gel (petroleum ether), affording 1-(2-amino-5-bromophenyl) ethanone.
General Procedure for the Synthesis of Quinoline-Appended Quinazolinone 4a−o. A sealed tube containing 2-aminoacetophenone (1 mmol), 1,3-cyclohexanedione (1.0 mmol), anthranilamide (1.0 mmol), and p-toluenesulfoniconic acid (TSA) (2.0 mmol) was heated initially at 100°C for 5 min. Next, DMSO (300 μL) was added and then the reaction temperature was increased to 115°C continuously for 12 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water, EtOAc, and washed using a 10% NaOH solution. The combined organic layer was dried over anhyd. Na 2 SO 4 and the solvent was evaporated under reduced pressure. The crude mixture was purified by silica gel column chromatography to obtain pure compounds 4a−o.   13 13