Efficient Synthesis of Novel Pyranoquinoline Derivatives from Simple Acetanilide Derivatives: Experimental and Theoretical Study of their Physicochemical Properties using DFT Calculations

Uma reação conveniente para sintetizar piranoquinolinas úteis a partir de derivados de 2-cloroquinolina-3-carbaldeído e dimedona na presença de KF-Al2O3 é descrita. Rendimentos razoáveis (41-50%), matérias-primas facilmente encontradas e catalisador eficiente pouco caro são os destaques deste método. Foi proposto um mecanismo de reação. A atribuição dos deslocamentos químicos foi feita com ajuda de cálculos de teoria do funcional da densidade (DFT). Os deslocamentos químicos de ressonância magnética nuclear (NMR) calculados têm boa concordância com dados experimentais. Valores de deslocamento químico independente de núcleo (NICS) foram usados como medida quantitativa do caráter aromático relativo de piranoquinolinas. Os valores calculados de NICS do grupo fenila de compostos piranoquinolínicos são menores que aqueles do benzeno.


Introduction
The quinoline nucleus comprises a class of heterocycles, which has been exploited more immensely than any other nucleus for the development of potent drugs. A range of pharmacological properties, such as antibacterial, antitumor, anti-inflammatory, antimalarial, antioxidant, antimicrobial and antifungal activities of this important class of heterocycles are found in the literature ( Figure 1). 1 Additionally, quinoline derivatives find use in the synthesis of fungicides, biocides, alkaloids, rubber chemicals, flavoring agents and as antifoaming agent in refineries. 2 On the other hand, pyran derivatives possess a wide-range spectrum of biological activities including antiviral, antitumor, and mutagenicity activities. 3 However, an extensive literature survey reveals that sufficient efforts have not been made to combine these heterocycles, pyranoquinolines, in the same molecular scaffold. 4 Pyranoquinolines possess a wide range of interesting biological activities, such as anti-allergic, anti-inflammatory, psychotropic, and estrogenic activities. 5 Thus, the development of an efficient method for their synthesis still attracts much interest.
KF-Al 2 O 3 was introduced by Clark as a solid base and has been applied as catalyst to a wide variety of organic synthesis. Several recent articles have reviewed this field. 6 The strongly basic nature of KF-Al 2 O 3 allows it to replace organic bases in a number of reactions. In the context of our general interest in the synthesis of heterocycles, 7 herein, we Efficient Synthesis of Novel Pyranoquinoline Derivatives from Simple Acetanilide Derivatives J. Braz. Chem. Soc. 1254 propose a facile synthesis of pyranoquinoline derivatives 5 using KF-Al 2 O 3 as an efficient, commercially available and non-toxic catalyst (Scheme 1). Good yield and low cost of the reagents are the salient features of this method. The reaction starts from easily accessible starting material, which makes it an interesting process for the preparation of pyranoquinolines 5. 2-Chloroquinoline-3-carbaldehyde derivatives are very useful starting material for synthesis of a wide variety of heterocycles 8 and can be easily synthesized from acetanilide derivatives with Vilsmeyer-Haack reaction. 9 Additionally, a combination of experimental and density functional theory (DFT) calculations was also used to investigate their physicochemical properties, such as nuclear magnetic resonance (NMR) data, and aromaticity. It was shown that DFT methods perform NMR spectra calculations very well and give accurate results. 10 On the other hand, aromaticity is a vital property of conjugated cyclic molecules in the determination of their structure, reactivity, and stability. Aromaticity is not a directly measurable or computable quantity. 11 Among the magnetic criteria, nucleus-independent chemical shift (NICS) continues to gain popularity as an easily computed, generally applicable criterion to characterize aromaticity and antiaromaticity of different compounds. 12 NICS is computed as the negative magnetic shielding at selected points at the ring center, above or below the ring. Negative NICS values indicate aromaticity, whereas positive values indicate antiaromaticity, and small values represent non-aromaticity. It is recommended that the NICS(1) (at points 1 Å above the ring center) to be the best measure of the π-electron delocalization in a cyclic molecule. 13 In this paper we use NICS as quantitative measures for aromatic character in pyranoquinolines 5. The 1 H NMR and 13 C NMR chemical shifts of pyranoquinolines (5a) were also determined by DFT calculations with the help of full spectral analysis.

General information
All chemicals required for the synthesis of pyranoquinolines 5 were purchased from Fluka (Neu-Ulm, Germany), Sigma-Aldrich (St. Louis, MO, USA), and Merck (Darmstadt, Germany) and were used as received. The KF-Al 2 O 3 support was prepared according to previously reported procedure. 6 The synthesized compounds 5 all gave satisfactory spectroscopic data. A Bruker (DRX-400 Avance) NMR was used to record the 1 H NMR and 13 C NMR spectra. All NMR spectra were determined in CDCl 3 at ambient temperature. Gas chromatography-mass spectrometry (GC-MS) (Agilent HP 6890, electron ionization (EI), 70 eV, HP-5 column (30 m × 0.25 mm × 0.2 µm), HP 5793 mass selective detector) was used to record the mass spectra.

Computational methods
All geometry optimizations and frequency calculations of all species were carried out using the Gaussian 03 program. 14 Density functional theory with the Becke three parameters hybrid functional (DFT-B3LYP) calculations were performed with a 6-31+G(d,p) basis set. Vibrational frequencies were calculated at the same level to ensure that each stationary point is a real minimum. Harmonic oscillator approximation was also used for the thermodynamic partition functions. After geometry optimization and frequency calculations, zero-point energies (ZPEs) and thermal corrections were obtained at 298 K. The NMR computations were performed using the gauge-independent atomic orbital (GIAO) and continuous set of gauge transformations (CSGT) methods. 15 NICS values are calculated at 1 Å above the plane of the optimized compounds, NICS(1), using the GIAO method at B3LYP/6-31+G(d, p).
General procedure for synthesis of acetanilide 2 To a solution of 60 mL water and 8 mL aniline (0.08 mol) were added 10 mL acetic anhydride (0.1 mol). The reaction mixture was stirred at 40-50 °C for 30 min. After completion of the reaction, the mixture was poured into ice-cold water and stirred for 10 min, which resulted in precipitation of acetanilide 2. The solid precipitate was filtered, washed with 30 mL of cold water, and then dried.
General procedure for synthesis of 2-chloroquinoline-3carbaldehydes 3 To stirred DMF (3.6 mL, 46 mmol), 12.5 mL POCl 3 (134 mmol) were added dropwise at 0-5 °C. The mixture was allowed to stir for 30 min. Acetanilide 2 (18.5 mmol) was then added and the resulting solution heated for 12 h at 80-90 °C. The mixture was poured into ice-cold water and stirred for 10 min, which resulted in yellow precipitation of the desired 2-chloroquinoline-3-carbaldehydes 3. The precipitate was filtered and washed with water and then dried. The compounds were purified by recrystallization from ethyl acetate.
General procedure for synthesis of pyranoquinolines 5 To a stirred suspension of 100 mg KF-Al 2 O 3 in acetonitrile (5 mL) were added 2-chloroquinoline-3carbaldehyde 3 (1 mmol) and dimedone (140 mg, 1 mmol). The reaction mixture was stirred at 80-90 °C for 10 h. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the solvent was removed under reduced pressure, and the residue was separated by preparative TLC (eluent: petroleum ether/ethyl acetate 5:1) to afford the desired compound 5.
To find the optimal conditions for the synthesis of pyranoquinolines 5, reaction of 2-chloroquinoline-3carbaldehyde 3a and dimedone 4 in the presence of a base was chosen as a model reaction. A mixture of 3a (1 mmol), dimedone 4 (1 mmol), and solvent (5 mL) was stirred under various reaction conditions. Our first experiment showed that the presence of a base such as K 2 CO 3 or KF-Al 2 O 3 is required to achieve the synthesis of 5a. K 2 CO 3 was less effective compared to KF-Al 2 O 3 . We then continued to optimize the model reaction by considering the efficiency of polar and nonpolar solvents. A polar solvent such as CH 3 CN was much better than a nonpolar solvent. The effect of temperature was also studied by carrying out the model reaction at room temperature and 80-90 °C. It was observed that the yield was increased as the reaction temperature was raised to 80 °C. The structures of the products were confirmed by EI-MS, 1 H NMR, and 13 C NMR analysis (see Supplementary Information). The 1 H NMR and 13 C NMR spectra of the product clearly indicated the formation of 5a. The characteristic signals for 5a in the 1 H NMR spectra were a singlet for the protons of methyl groups at 1.22 ppm, a singlet for CH 2  To generalize this method, we used a series of 2-chloroquinoline-3-carbaldehyde derivatives to obtain their corresponding pyranoquinolines 5 ( Table 2). As shown in Table 2, all the substrates consistently underwent reaction to the desired pyranoquinolines 5 in moderate yields.
A plausible mechanism for the present reaction to produce pyranoquinolines 5 is proposed in Scheme 3. In the first step, dimedone can undergo a Knoevenagel condensation with 2-chloroquinoline-3-carbaldehyde 4 in refluxing CH 3 CN to afford the intermediate I with the release of H 2 O. Subsequently, the ring closures proceed through an addition-elimination reaction to give the desired pyranoquinolines 5 under reaction conditions.

NMR calculations
Atom numbering in accordance with molecular structure of pyranoquinoline 5a is given in Figure 2. A main important goal of this part is to properly assign the experimental NMR data to the computed data of 5a. At first, the geometry of the molecule was optimized. After that, 1 H NMR and 13 C NMR chemical shifts calculations were performed using B3LYP/6-31+G(d,p). Chemical shifts were reported in parts per million relative to tetramethylsilane (TMS) for 1 H NMR and 13 C NMR spectra. Relative chemical shifts were calculated by using the corresponding TMS shielding calculated at the same theoretical level as the reference. The relations between the   experimental 1 H and 13 C chemical shifts (d exp ) and magnetic isotropic shielding constants (d calc ) are usually linear and described by the following equation: d exp = a + b d calc .
The slope and intercept of the least-square correlation are utilized to predict chemical shifts. The relative 1 H and 13 C chemical shifts were calculated by two methods: Gauge-Independent Atomic Orbital (GIAO) and Continuous Set of Gauge Transformations (CSGT) ( Table 3). According to the comparison between experimental and calculated data, the calculated 1 H chemical shifts are in acceptable agreement with the experimental results obtained by the GIAO method. The determination coefficient for proton chemical shifts in GIAO method is determined to be 0.9976 as shown in Figure 3.

Aromaticity calculations
This study also includes benzene molecule calculations for comparison and study of the addition effect of the ring on the aromaticity properties (NICS) of benzene. The results show that NICS for the phenyl group of pyranoquinoline compounds 5 are less than that for benzene, as expected (Table 4). An account for the decrease of the aromaticity in such systems is lower resonance energies per π electron than benzene. Their values are close to the ideal aromaticity index (NICS(1) = −10.2 ppm) stated by the NICS model for benzene.
Interestingly, the aromaticity of the phenyl group of pyranoquinoline systems 5 was deeply affected by substitution. Generally, substitution decreases the aromaticity of the phenyl group of pyranoquinolines 5 compared to benzene. NICS values predict decreasing and increasing effects for the electron donating group (such as OCH 3 , with NICS(1) = −8.9147 ppm, Table 4, entry 4) and electron withdrawing groups (such as Br with NICS(1) = −9.4087 ppm, Table 4, entry 3), respectively.
It should be mentioned that the NICS index does not allow the aromaticity of a polycyclic conjugated system like pyranoquinoline systems 5 to be estimated directly. On the other hand, it is not easy to know how to use NICS values for different ring systems to handle a global property like aromaticity. , introduced the summation of the NICS values as a global aromaticity index. 16 As a result, the summation of NICS values for a given polycyclic system produces a single quantity called the "total NICS". Therefore, in this study the sum of the NICS calculated at 1 Å above the rings, ∑ NICS(1), is also used to evaluate the aromaticity of each molecule as a whole ( Table 4). As shown in Table 4, substitution decreases the aromaticity of pyranoquinoline systems 5 and the unsubstituted pyranoquinoline 5a is proposed as the most aromatic compound among 4 species. On the other hand, methoxide as an electron donating moiety decreases the aromaticity of pyranoquinoline 5d.

Conclusions
In summary, we have described a simple and efficient protocol for the synthesis of novel pyranoquinoline derivatives in moderate yields. The synthesis is based on the Knoevenagel condensation of dimedone to various 2-chloroquinoline-3-carbaldehydes, followed by an   addition-elimination reaction. Additionally, NICS as quantitative measure for aromatic character and 1 H NMR and 13 C NMR chemical shifts of pyranoquinolines were also determined by DFT calculations with the help of full spectral analysis. The results show that NICS for the phenyl group of pyranoquinoline molecules 5 are less than that for benzene.

Supplementary Information
Supplementary information (copies of 1 H NMR, 13 C NMR and EI-MS of synthesized compounds (3a-3d and 5a-5d) and DFT calculation information) is available free of charge at http://jbcs.sbq.org.br as PDF file.