Computational and Experimental Study on Molecular Structure of Benzo[g]pyrimido[4,5-b]quinoline Derivatives: Preference of Linear over the Angular Isomer

Abstract

A series of 5-aryl-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione was synthesized through an environmental friendly multicomponent methodology and characterized with FT-IR (Fourier Transform infrared spectroscopy), ¹H NMR (Nuclear Magnetic Resonance ), ¹³C NMR and GC-MS (gas chromatography-mass spectrometry). The 5-(4-methoxyphenyl)-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione 4c compound was characterized by X-ray single crystal diffraction. The geometry of 4c has been fully optimized using DFT (Density functional theory), B3LYP functional and 6-31G(d,p) basis set, thus establishing the ground state energy and thermodynamic features for the mentioned compound, which are in accordance with the experimental data and the crystal structure. The experimental results reveal a strong preference for the regioselective formation of 4c linear four fused rings over the angular four fused and suggest a possible kinetic control in product formation.

1. Introduction

The use of environmental friendly procedures is nowadays a standard tool in synthetic applications because of their benefits both in chemistry and environmental point of views. In this sense, reactions assisted by microwave (MW) radiation are well known because of their advantages over conventional methods, becoming an important and almost regular methodology for the synthesis of organic compounds [1,2,3,4,5,6,7,8]. On the other hand, multicomponent reaction (MCR), most running with atom economy, offer convenient procedures for the introduction of structural diversity of heterocyclic compounds which are prepared by a straightforward manner, in a single synthetic step [9,10,11,12,13,14,15,16,17]. Combining the advantages of MCR with those of microwave assisted organic synthesis under solvent-free conditions provides fast and efficient methods for the synthesis of heterocyclic systems, which are among the most common scaffolds in compounds with diverse applications.

Quinoline derivatives are synthetic targets because they exhibit a wide range of biological and pharmacological activities [18,19,20,21,22,23]. Compared with other derivatives that exhibit high fluorescence, quinolone derivatives are among the best candidates in the design of electroluminescent materials [24,25]. Its fusion with other interesting heterocyclic nucleus such as pyrimidine have afforded systems with high usefulness, such the pyrimido[4,5-b]quinoline, which have been synthesized by diverse procedures, involving condensation and cyclocondensation reactions [26,27,28,29,30,31,32,33,34].

Our research group has made great efforts to develop synthetic strategies to obtain highly functionalized heterocycles [13,14,23,27,28,29,35,36]. In this sense, we have recently reported about simple and environmental friendly MCR one-pot procedures for the synthesis of heterofused-quinolines such as: pyrazolo[3,4-b]quinolindiones [23], prepared by MW assisted synthesis under solvent-free/catalyst-free conditions, or pyrimido[4,5-b]quinolindiones [36] by heating in ethanol. In these reactions, also reported by other researches, the dihydroderivatives are obtained as final products (Scheme 1) [37,38].

Continuing with our studies for the synthesis of aza-heterocycles, we have decided to investigate the MCR of 6-aminopyrimidin-4-ones 1, naphthalene-1,2,4(3H)-trione 2 and aromatic aldehydes 3 under MW irradiation and solvent-free/catalyst free conditions in order to obtain benzopyrimidoquinolines, and so providing results for a comparative analysis with previous reported experiments [39] and the better knowledge of the reaction type involved in the formation of carbon–carbon bonds [40,41].

2. Materials and Methods

2.1. Materials and Methods

All reagents used in this work were purchased commercially without further purification. Identifications of compounds and measurements of properties were carried out by general procedures employing the following equipment: Microwave irradiation was carried out with microwave oven CEM Discover (CEM Corporation, Matthews, NC, USA) with controlled power and temperature. Melting points were determined in a Büchi Melting Point Apparatus (BUCHI Latinoamérica, Valinhos, SP, Brasil) and are reported without any corrections. The ¹H and ¹³C NMR (Nuclear Magnetic Resonance) spectra were measured at RT (Room Temperature) on a Bruker Avance 400 spectrometer (Bruker, Rheinstetten, Germany) operating at 400 and 100 MHz, respectively, and using.

Dimethyl Sulfoxide deuterated (DMSO-d₆) as solvent and tetramethylsilane (TMS) as internal standard. The mass-spectra were scanned on a Hewlett Packard HP Engine-5989 spectrometer (Hewlett Packard, Palo Alto, CA, USA), equipped with a direct inlet probe which was operating at 70 eV. Elemental analyses were obtained using a LECO CHNS-900 elemental analyzer (LECO Corporation, Saint Joseph, MI, USA).

2.2. Synthesis

General Procedure for the MCR of Compounds 4a–q

The mixture of 6-aminopyrimidin-4-one 1 (1 mmol), naphthalene-1,2,4(3H)-trione 2 (1 mmol) and aldehyde 3 (1 mmol), were irradiated for 5–9 min and 200 °C under solvent-free conditions. Upon completion, monitored by thin-layer chromatography (TLC), the reaction mixture was cooled to room temperature. The solid was further purified by recrystallization from EtOH (95%).

2-methylthio-5-phenyl-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4a). 80%. m.p. > 300 °C. IR (KBr, υ cm⁻¹), 3398 (N-H st), 2689 (CH₃ st), 1652, 1630 (C=O st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.55 (s, 3H, SCH₃), 5.25 (s, 1H, CH), 7.11 (t, J = 6.78 Hz, 1H, Hp), 7.21 (t, J = 7.28 Hz, 2H, Hm), 7.30 (d, J = 7.78 Hz, 2H, Ho), 7.76–7.84 (m, 2H, H8, H9), 7.90 (d, J = 7.28 Hz, 1H, H7), 8.03 (d, J = 7.03 Hz, 1H, H10), 9.60 (s, 1H, NH), 12.49 (s, 1H, NH). ¹³C NMR δ (ppm): 12.7 (SCH₃), 54.3 (C5), 117.4 (C4a), 124.5 (Cp), 125.3 (Co), 125.6 (C10), 127.3 (Cm), 127.9 (C7), 130.3, 131.8 (C10a), 133.2 (C8), 134.6 (C9), 139.3 (C5a), 145.0 (Ci), 179.1 (C=O), 181.6 (C=O). MS: (70 eV) m/z = 401 (16, M⁺), 325 (19), 324 (100), 276 (13). Anal. Calcd. for C₂₂H₁₅N₃O₃S C, 65.82; H, 3.77; N, 10.47; found C, 65.85; H, 3.80; N, 10.45.

2-methylthio-5-(4-methylphenyl)-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4b). 80%. m.p. > 300 °C (dec). IR (KBr, υ cm⁻¹), 3395 (N-H st), 2929 (CH₃ st), 1651 (C=O st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.18 (s, 3H, CH₃), 2.55 (s, 3H, SCH₃), 5.21 (s, 1H, CH), 7.00 (d, J = 8.03 Hz, 2H, Hm), 7.16 (d, J = 8.03 Hz, 2H, Ho), 7.77–7.84 (m, 2H, H8, H9), 7.90 (d, J = 7.53 Hz, 1H, H7), 8.02 (d, J = 7.03 Hz, 1H, H10), 9.58 (s, 1H, NH), 12.51 (s, 1H, NH). ¹³C NMR δ (ppm): 12.7 (p-CH₃), 20.5 (SCH₃), 34.1 (C5), 117.7 (C4a), 125.6 (C10), 125.9 (C7), 127.7 (Co), 128.7 (Cm), 130.3 (C6a), 131.9 (C10a), 133.3 (C8), 134.8 (C9), 135.6 (C2), 139.2 (C5a), 142.2 (Ci), 179.2 (C=O), 181.7 (C=O). MS: (70 eV) m/z (%) = 415 (30, M⁺), 324 (100), 276 (14). Anal. Calcd. for C₂₃H₁₇N₃O₃S C, 66.49; H, 4.12; N, 10.11; found C, 66.48; H, 4.13; N, 10.14.

5-(4-methoxyphenyl)-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4c). Yellow crystalline solid, 80%. m.p. > 300 °C (dec). IR (KBr, υ cm⁻¹), 3272 (N-H st), 2841 (CH₃ st), 1674, 1650 (C=O st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.55 (s, 3H, SCH₃), 3.65 (s, 3H, OCH₃), 5.18 (s, 1H, H5), 6.76 (d, J = 8.79 Hz, 2H, Ho), 7.18 (d, J = 8.79 Hz, 2H, Hm), 7.77–7.85 (m, 2H, H8, H9), 7.90 (d, J = 7.53 Hz,1H, H7), 8.02 (d, J =7.03 Hz, 1H, H10), 9.60 (s, 1H, H12), 12.52 (s, 1H, H3). ¹³C NMR δ (ppm): 12.7 (SCH₃), 34.0 (OCH₃), 55.0 (C5), 114.0 (Co), 129.0 (Cp), 158.0 (C=O). MS: (70 eV) m/z = 431 (61, M⁺), 325 (19), 324 (100), 276 (18), 248 (12). Anal. Calcd. for C₂₃H₁₇N₃O₄S C, 64.03; H, 3.97; N, 9.74; found C, 64.02; H, 4.01; N, 9.78.

2-methylthio-5-(3,4,5-trimethoxyphenyl)-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4d). 80%. m.p. 265 °C. IR (KBr, υ cm⁻¹), 3264 (N-H st), 2933 (CH₃ st), 1656 (C=O st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.55 (s, 3H, SCH₃), 3.58 (s, 3H, OCH₃), 3.67 (s, 6H, OCH₃), 5.22 (s, 1H, CH), 6.57 (s, 2H), 7.77–7.85 (m, 2H, H9, H8), 7.93 (d, J = 8.53 Hz, 1H, H7), 8.03 (d, J = 8.78 Hz, 1H, H10), 9.49 (s, 1H, NH), 12.48 (s, 1H, NH). ¹³C NMR δ (ppm): 12.5 (SCH₃), 34.5 (C5), 55.7 (OCH₃), 59.6 (OCH₃), 105.2 (Co), 125.4 (C7), 125.7 (C10), 133.0 (C8), 134.5 (C9), 135.6, 136.3 (C5a), 139.2, 140.3 (Ci), 152.4 (C11a), 178.9 (C=O), 181.5 (C=O). MS: (70 eV) m/z (%) = 491 (48, M⁺), 460 (17), 325 (19), 324 (100), 276 (18). Anal. Calcd. for C₂₅H₂₁N₃O₆S C, 61.09; H, 4.31; N, 8.55; found C, 61.12; H, 4.30; N, 8.58.

2-methylthio-5-(2-thienyl)-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4e). 70%. m.p. > 300 °C. IR (KBr, υ cm⁻¹), 3384 (N-H st), 2969 (CH₃ st), 1655 (C=O st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.55 (s, 3H, SCH₃), 5.53 (s, 1H, CH), 6.81–6.85 (m, 2H, Hetaryl), 7.25 (d, J = 6.28 Hz, 1H, Hetaryl) 7.77–7.86 (m, 2H, H9, H8), 7.97 (d, J = 8.53 Hz, 1H, H7), 8.04 (d, J = 8.53 Hz, 1H, H10), 9.86 (s, 1H, NH), 12.64 (s, 1H, NH). ¹³C NMR δ (ppm): 12.7 (SCH₃), 29.1 (CH), 116.6 (C4a), 124.3 (CH, Hetaryl), 124.5 (CH, Hetaryl), 125.7 (C10), 126.0 (CH, Hetaryl), 126.7 (C7), 130.3 (C6a), 131.7 (C10a), 133.3 (C8), 134.8 (C9), 138.9 (C5a), 148.0 (C2), 179.1 (C=O), 181.5 (C=O). MS: (70 eV) m/z (%) = 407 (100, M⁺), 392 (11), 346 (18), 324 (59), 276 (18). Anal. Calcd. for C₂₀H₁₃N₃O₃S₂ C, 58.95; H, 3.22; N, 10.31; found C, 58.99; H, 3.25; N, 10.34.

5-(4-fluorophenyl)-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4f). 70%. m.p. > 300 °C. IR (KBr, υ cm⁻¹), 3337 (NH st), 1656 (C=O st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.56 (s, 3H, SCH₃), 5.25 (s, 1H, H5), 7.03 (t, J = 8.79 Hz, 2H, Ho), 7.34 (d, J = 7.03 Hz, 2H, Hm), 7.79–7.83 (m, 2H, H8, H9), 7.90 (d, J = 6.78 Hz, 1H, H7), 8.03 (d, J = 7.28 Hz, 1H, H10), 9.64 (s, 1H, NH), 12.53 (s, 1H, NH). ¹³C NMR δ (ppm): 12.8 (SCH₃), 35.7 (C5), 114.8 (C4a), 124.8 (C10), 128.6 (C7), 129.4 (Co), 129.5 (Cm), 131.1 (C8), 134.6 (C9), 141.2 (Ci), 145.5, 162.3, 178.6 (C=O). MS: (70 eV) m/z (%) = 419 (84, M⁺), 417, (25), 474 (50), 324 (100). Anal. Calcd. for C₂₂H₁₄FN₃O₃S C, 63.00; H, 3.36; N, 10.02; found C, 63.04; H, 3.34; N, 10.05.

5-(4-chlorophenyl)-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4g). 80%. m.p. > 300 °C. IR (KBr, υ cm⁻¹), 3367 (NH st), 2684 (CH₃ st), 1652, 1626 (C=O st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.55 (s, 3H, SCH₃), 5.23 (s, 1H, H5), 7.26 (d, J = 8.54 Hz, 2H, Ho), 7.32 (d, J = 8.54 Hz, 2H, Hm), 7.79–7.82 (m, 2H, H8, H9), 7.90 (d, J = 7.03 Hz, 1H, H7), 8.03 (d, J = 7.03 Hz, 1H, H10), 9.66 (s, 1H, NH), 12.53 (s, 1H, NH). ¹³C NMR δ (ppm): 12.7 (SCH₃), 34.3 (C5), 125.6 (C10), 125.9 (C7), 128.1 (Co), 129.7 (Cm), 130.4 (C6a), 131.8 (C10a), 133.3, 134.7 (C9), 139.4 (C5a), 143.9 (Ci), 178.5 (C4), 179.2 (C=O), 181.6 (C=O). MS: (70 eV) m/z (%) = 437 (6, M⁺²), 436 (5.7, M⁺¹), 435 (15, M⁺), 326 (6), 325 (18), 324 (100), 276 (13). Anal. Calcd. for C₂₂H₁₄ClN₃O₃S C, 60.62; H, 3.24; N, 9.64; found C, 60.64; H, 3.22; N, 9.68.

5-(4-bromophenyl)-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4h). 80%. m.p. > 300 °C. IR (KBr, υ cm⁻¹), 3369 (NH st), 1658 (C=O st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.56 (s, 3H, SCH₃), 5.33 (s, 1H, H5), 7.54 (d, J = 8.28 Hz, 2H, Ho), 7.58 (d, J = 8.28 Hz, 2H, Hm), 7.77–7.82 (m, 2H, H8, H9), 7.89 (d, 1H, J = 7.27 Hz, H7), 8.03 (d, 1H, J = 7.03 Hz, H10), 9.72 (s, 1H, NH), 12.55 (s, 1H, NH). ¹³C NMR δ (ppm): 12.7 (SCH₃), 35.0 (C5), 116.5 (C5a), 125.0, 125.6 (C10), 125.9 (C7), 127.8 (Co), 129.5 (Cm), 131.7 (C10a), 133.2 (C8), 134.7 (C9), 139.7 (Ci), 149.3 (C2), 162.2, 178.9 (C4), 179.0 (C=O), 181.5 (C=O). MS: (70 eV) m/z (%) = 469 (17), 467 (8), 325 (19), 324 (100), 276 (14). Anal. Calcd. for C₂₂H₁₄BrN₃O₃S C, 55.01; H, 2.94; N, 8.75; found C, 55.04; H, 2.98 N, 8.72.

3-methyl-2-(methylthio)-5-phenyl-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4i). Red solid. 81%. m.p. 277 °C. IR (KBr, υ cm⁻¹), 3227 (N-H st), 1647 (C=O, st), 1522 (C=C, st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.62 (s, 3H, SCH₃), 3.31 (s, 3H, NCH₃), 5.24 (s, 1H. CH) 7.10 (t, J = 7.03 Hz, 1H, Hp), 7.20 (t, J = 7.53 Hz, 2H, Hm), 7.29 (d, J = 7.28 Hz, 2H, Ho), 7.70–7.81 (m, 2H, H9, H8), 7.87 (d, J = 7.53 Hz, 1H, H7), 8.01 (d, J = 7.28 Hz, 1H, H10), 9.68 (s, 1H, NH). ¹³C NMR δ (ppm): 14.4 (SCH₃), 30.0 (NCH₃), 35.3 (C5), 117.4 (C4a), 125.6 (C10), 125.8 (C7), 126.4 (Cp), 128.0 (Co), 128.6 (Cm), 130.3 (C6a), 131.8 (C10a), 133.2 (C8), 134.7 (C9), 139.2 (C5a), 145.0 (Ci), 149.7 (C2), 160.2 (C4, C=O), 161.6 (C12a), 179.1 (C=O), 181.5 (C=O). MS: (70 eV) m/z (%) = 414 (11, M⁺), 337 (100). Anal. Calcd. for C₂₃H₁₇N₃O₃S C, 66.49; H, 4.12; N, 10.11; found C, 66.47; H, 4.15; N, 10.12.

3-methyl-2-(methylthio)-5-(4-methylphenyl)-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4j). Red solid. 75 %. m.p. 280 °C. IR (KBr, υ cm⁻¹), 3234 (NH st), 1650 (C=0 st), (1521 C=C st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.18 (s, 3H, p-CH₃), 2.63 (s, 3H, SCH₃), 2.75 (s, 3H, NCH₃), 5.22 (s, 1H, H5), 7.02 (d, J = 8.03 Hz, 2H, Hm), 7.17 (d, J = 8.03, 2H, Ho), 7.79–7.83 (m, 2H, H8, H9), 7.90 (d, J = 7.28 Hz, 1H, H7), 8.03 (d, J = 7.28 Hz, 1H, H-10), 9.72 (s, 1H, NH). ¹³C NMR δ (ppm): 14.4 (p-CH₃), 20.5 (SCH₃), 29.8 (NCH₃), 34.9 (C5), 117.6 (C4a), 125.6 (C10), 125.8 (C7), 127.8 (Co), 128.6 (Cm), 130.3 (C6a), 131.8 (C10a), 133.2 (C8), 134.7 (C9), 135.5 (C11a), 139.1 (C5a), 142.1 (Ci), 149.7 (C2), 160.2 (C=O), 161.4 (C12a), 179.2 (C=O), 181.6 (C=O). MS: (70 eV) m/z (%) = 429 (22, M⁺), 337 (100). Anal. Calcd. for C₂₄H₁₉N₃O₃S C, 67.12; H, 4.46; N, 9.78; found C, 67.15; H, 4.45; N, 9.76.

3-methyl-5-(4-methoxyphenyl)-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4k). Red solid. 70%. m.p. 282 °C. IR (KBr, υ cm⁻¹), 3222 (NH st), 1647 (C=O st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.63 (s, 3H, SCH₃), 3.32 (s, 3H, NCH₃), 3.84 (s, 3H, OCH₃), 5.21 (s, 1H, H5), 6.77 (d, J = 8.79 Hz, 2H, Ho), 7.21 (d, J = 8.53 Hz, 2H, Hm), 7.78–7.82 (m, 2H, H8, H9), 7.89 (d, J = 8.54 Hz, 1H, H7), 8.03 (d, J = 8.53 Hz, 1H, H10), 9.66 (s, 1H, NH). ¹³C NMR δ (ppm): 14.4 (SCH₃), 29.9 (NCH₃), 34.4 (C5), 54.9 (OCH₃), 113.5 (Co), 117.7 (C4a), 125.6 (C10), 128.8 (Cm), 130.3 (C6a), 131.8 (Ci), 133.1 (C7), 134.7 (C9), 137.3 (C10a), 138.9 (C5a), 149.6 (C2), 157.8 (C2), 160.2 (C=O), 161.4 (C12a). MS: (70 eV) m/z (%) = 445 (45, M⁺), 337 (100). Anal. Calcd. for C₂₄H₁₉N₃O₄S C, 64.71; H, 4.30; N, 9.43; found C, 64.75; H, 4.27; N, 9.45.

3-methyl-2-(methylthio)-5-(3,4,5-trimethoxyphenyl)-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4l). Brown solid. 80%. m.p. 263 °C. IR (KBr, υ cm⁻¹), 3243 (NH st), 1648 (C=O st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.62 (s, 3H, SCH₃), 3.33 (s, 3H, NCH₃), 3.56 (s, 3H, OCH₃), 3.67 (s, 6H, OCH₃), 5.21 (s, 1H, H5), 6.57 (s, 2H, Ho) 7.78–7.82 (m, 2H, H8, H9), 7.91 (d, J = 7.28 Hz, 1H, H7), 8.03 (d, J = 7.28 Hz, 1H, H10), 9.60 (s, 1H, NH). ¹³C NMR δ (ppm): 14.4 (SCH₃), 29.9 (NCH₃), 35.6 (C5), 55.8 (OCH₃), 59.7 (OCH₃), 105.6 (Co), 117.1 (C4a), 125.6 (C7), 125.8 (C10), 130.4 (C6a), 131.8 (C10a), 133.1 (C8), 134.6 (C9), 136.5 (C5a), 140.6 (Ci), 149.7 (C2), 152.5 (C11a), 161.5 (C12a), 179.1 (C=O), 181.6 (C=O). MS: (70 eV) m/z (%) = 505 (76, M⁺), 474 (15), 337 (100). Anal. Calcd. for C₂₆H₂₃N₃O₆S C, 61.77; H, 4.59; N, 8.31; found C, 61.79; H, 4.62; N, 8.34.

3-methyl-2-(methylthio)-5-(4-trifluoromethylphenyl)-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4m). Red solid. 75%. m.p. >300 °C. IR (KBr, υ cm⁻¹), 3447 (NH st), 1687 (C=O st), 1519 (C=C st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.74 (s, 3H, SCH₃), 2.88 (s, 3H, NCH₃), 5.33 (s, 1H, H5), 7.39 (d, J = 7.03 Hz, 1H, H7), 7.56 (d, J = 7.06 Hz, 2H, Ho), 7.72–7.74 (d, J = 7.03 Hz, 2H, Hm), 7.80 (t, 1H, H8), 7.89 (t, 1H, H9), 8.03 (d, J = 7.03 Hz, 1H, H10), 9.88 (s, 1H, NH). ¹³C NMR δ (ppm): 14.5 (SCH₃), 29.9 (NCH₃), 35.7 (C5), 99.5 (C4a), 111.6 (C5a), 127.0 (C10), 127.3 (Co), 128.0 (C7), 128.9 (Cm), 133.2 (C8), 135.4 (C9), 139.7 (Ci), 149.8 (C2), 157.3, 159.2 (C6a), 160.2 (C=O), 166.1 (C12a), 178.3 (C=O), 198.50 (C6). MS: (70 eV) m/z (%) = 480 (18, M⁺), 337 (100), 437 (40). Anal. Calcd. for C₂₄H₁₆F₃N₃O₃S C, 59.62; H, 3.34; N, 8.69; found C, 59.65; H, 3.30; N, 8.73.

5-(benzo[d][1,3]dioxol-6-yl)-3-methyl-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4n). Red solid. 75%. m.p. 254 °C. IR (KBr, υ cm⁻¹), 3225 (NH st), 1647 (C=O st), 1519 (C=C st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.63 (s, 3H, SCH₃), 3.34 (s, 3H, NCH₃), 5.19 (s, 1H, H5), 5.91 (s, 2H, CH₂), 6.74 (d, J = 6.79 Hz, 2H, aryl), 6.86 (s, 1H, aryl), 7.78–7.84 (m, 2H, H8, H9), 7.91 (d, J = 7.89 Hz, 1H, H7), 8.03 (d, J = 8.02 Hz, 1H, H10), 9.72 (s, 1H, NH). ¹³C NMR δ (ppm): 14.45 (SCH₃), 29.9 (NCH₃), 35.0 (C5), 100.7 (CH₂), 107.8, 108.6 (C2′-C6′), 117.3 (C4a), 121.0 (C5′), 125.6 (C10), 125.9 (C7), 130.4 (C6a), 131.8 (C10a), 133.2 (C8), 134.7 (C9), 139.1 (C5a), 145.8 (Ci), 146.9 (C11a), 149.6 (C2), 160.3 (C=O), 161.6 (C12a), 179.2 (C=O), 181.6 (C6). MS: (70 eV) m/z (%) = 458 (38, M⁺), 337 (100). Anal. Calcd for C₂₄H₁₇N₃O₅S C, 62.74; H, 3.73; N, 9.15; found C, 62.71; H, 3.71; N, 9.18.

5-(4-fluorophenyl)-3-methyl-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4o). Red solid. 74%. m.p. 276 °C. IR (KBr, υ cm⁻¹), 3237 (NH st), 1646 (C=O st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.61 (s, 3H, SCH₃), 3.30 (s, 3H, NCH₃), 5.22 (s, 1H, H5), 7.01 (d, J = 7.30 Hz, 2H, Ho), 7.32 (t, J = 7.30 Hz, 2H, Hm), 7.77–7.82 (m, 2H, H8, H9), 7.87 (d, J = 7.98 Hz, 1H, H7), 8.01 (d, J = 7.03 Hz, 1H, H10), 9.73 (s, 1H, NH). ¹³C NMR δ (ppm): 14.4 (SCH₃), 29.9 (NCH₃), 34.8 (C5), 114.6 (C4a), 114.8 (C6a), 117.1 (C10a), 125.6 (C10), 125.9 (C7), 129.8 (Co), 130.3 (Cm), 131.7 (C11a), 133.2 (C8), 134.7 (C9), 139.3 (Ci), 149.8 (C2), 179.1 (C=O), 181.5 (C=O). MS: (70 eV) m/z (%) = 441 (7, M⁺), 432 (22), 430 (42), 387 (75), 337 (100). Anal. Calcd. for C₂₃H₁₆FN₃O₃S C, 63.73; H, 3.72; N, 9.69; found C, 63.77; H, 3.76; N, 9.70.

5-(4-chlorophenyl)-3-methyl-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4p). Red solid. 71%. m.p. 283 °C. IR (KBr, υ cm⁻¹), 3233 (NH st), 1648 (C=O st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.62 (s, 3H, SCH₃), 3.31 (s, 3H, NCH₃), 5.24 (s, 1H, H5), 7.24 (d, J =8.28 Hz, 2H, Ho), 7.32 (d, J = 8.28 Hz, 2H, Hm), 7.78–7.82 (m, 2H, H8, H9), 7.88 (d, J = 7.28 Hz, 1H, H7), 8.02 (d, J = 7.28 Hz, 1H, H10), 9.75 (s, 1H, NH). ¹³C NMR δ (ppm): 14.4 (SCH₃), 29.8 (NCH₃), 35.1 (C5), 116.8 (C4a), 125.6 (C10), 125.9 (C7) 127.9 (Co), 129.8 (Cm), 133.2 (C8), 134.7 (C9), 139.5 (C5a), 143.9 (Ci), 149.7 (C2), 160.2 (C4), 161.8 (C12a), 179.1 (C=O), 181.5 (C=O). MS: (70 eV) m/z (%) 448 (12, M⁺), 337 (100). Anal. Calcd. for C₂₃H₁₆ClN₃O₃S C, 61.40; H, 3.58; N, 9.34; found C, 61.37; H, 3.57; N, 9.33.

5-(4-bromophenyl)-3-methyl-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione (4q). Red solid. 76%. m.p. 264 °C. IR (KBr, υ cm⁻¹), 3228 (NH st), 1650 (C=O st). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 2.62 (s, 3H, SCH₃), 3.30 (s, 3H, NCH₃), 5.20 (s, 1H, H5), 7.25 (d, J = 8.29 Hz, 2H, Ho), 7.37 (d, J = 8.53 Hz, 2H, Hm), 7.77–7.81 (m, 2H, H8, H9), 7.88 (d, J = 7.27 Hz, 1H, H7), 8.01 (d, J = 8.03 Hz, 1H, H10), 9.73 (s, 1H, NH). ¹³C NMR δ (ppm): 14.4 (SCH₃), 29.8 (NCH₃), 35.2 (C5), 99.4 (C4a), 116.7 (C5a), 119.5 (Cp) 125.5 (C10), 125.8 (C7), 130.2 (Co), 130.3 (C6a), 130.9 (Cm), 131.7 (C10a), 133.2 (C8), 134.7 (C9), 139.4 (Ci), 144.3 (C11a), 149.7 (C2), 160.1 (C4), 161.8 (C12a), 179.0 (C=O), 181.5 (C=O). MS: (70 eV) m/z (%) = 492 (9, M⁺), 337 (100). Anal. Calcd. for C₂₃H₁₆BrN₃O₃S C, 55.88; H, 3.26; N, 8.50; found C, 55.91; H, 3.29; N, 8.49.

¹H NMR spectra and spectroscopic data for all compounds are included in the supplementary materials.

2.3. Computational Details

DFT (Density functional theory) and B3LYP/6-31G(d,p) Analysis

The 5-(4-methoxyphenyl)-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione 4c compound was optimized based on the crystal structure. The geometry has been fully optimized using DFT with the Becke three-parameter hybrid exchange and the Lee–Yang–Parr correlation density functional (B3LYP) and the Pople’s split-valence 6-31G(d,p) extended basis set. The optimum structures obtained were further certified as true minima by constructing and diagonalizing the corresponding Cartesian Hessian matrix, this procedure providing also the harmonic vibrational frequencies which, after properly scaled by the recommended scaling factor 0.964, allow reliable calculations of the thermal corrections to the molecular energy. The conformational studies, natural bond orbital (NBO) and nonlinear optical (NLO) analysis on the title compound were performed; the NBO analyses were done on B3LYP/6-31+G(d,p) wave functions obtained with the B3LYP/6-31G(d,p) optimum geometries. All calculations were performed by using Gaussian 09W program package (Version A.02, Gaussian, Inc., Wallingford, CT, USA, 2009) [42].

3. Results and Discussion

3.1. Chemistry

For the preparation of benzo[g]pyrimido[4,5-b]quinolines, three-component reactions assisted by MW irradiation were carried out using as reagents 6-amino-2-(methylthio)pyri,idin-4(3H)-one 1, naphthalene-1,2,4(3H)-trione 2 and benzaldehyde 3a, in equimolar amounts. Taking as a model reaction the synthesis of 4a, we have tested several reaction conditions, combining diverse solvents (ethanol, acetic acid and ethylenglycol), temperatures and power of the microwave source in order to find the optimal conditions (

Table 1. Evaluation of the parameters of the multicomponent reaction (MCR) of compound 4a. *

Entry	Reaction Conditions	Time (min)	Yield ** (%)
1	MW (microwave, 150 °C) solvent/catalysis-free	10	50
2	MW (200 °C) solvent/catalysis-free	5	80
3	MW (150 °C) AcOH/Ethanol (3:1)	10	50
4	MW (200 °C) AcOH/Ethanol (3:1)	5	65
5	MW (150 °C) AcOH/Ethylenglycol (3:1)	10	50
6	MW (200 °C) AcOH/Ethylenglycol (3:1)	5	70
7	Reflux, Ethanol	120	30
8	Reflux, AcOH	90	50
9	Reflux, AcOH/Ethylenglycol (3:1)	60	45
10	Reflux, AcOH/Ethylenglycol (1:3)	60	45

* Equimolar amounts of reactants (1.0 mmol). Ratio (v/v) for the solvent mixture; ** Isolated yield.

). It was found that the product 4a is formed with higher yield under solvent/catalyst-free conditions, (Table 1, entry 2). The synthesis of 4a was carried out at reflux (using ethanol, acetic acid, ethylenglycol or a mixture of both) obtaining low yields and longer reaction times in contrast to MW method. When ethanol was used as the solvent by conventional heating, the desired product 4a was obtained after 2 h in low yield (30%, Table 1, entry 7). In the case of using AcOH or AcOH/Ethylenglycol mixtures moderate similar yields were obtained (45–50%, entry 8–10).

The extension of reaction times, keeping the same reaction conditions, did not lead to the formation of aromatized derivative. On the contrary, a decrease was observed in the reaction yield and double recrystallization of the crude reaction is required, first using a N,N-Dimethylformamide (DMF)-Ethanol mixture (ratio 1–9 v/v) and the isolated solid is then recrystallized from ethanol.

Considering the optimal conditions, that is, solvent/catalysis-free conditions, and in order to show the generality and scope of this protocol, we tried various aromatic aldehydes, 6-amino-2-(methylthio)pyrimidin-4(3H)-one and 6-amino-3-methyl-2-(methylthio)pyrimidin-4(3H)-one, to prepare a series of compounds 4a–q (Scheme 2).

In all cases, the starting materials were completely consumed, in times ranged between 5 to 9 min, to afford the 5-aryl-2-methyltio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione derivatives 4a–q with high yields (70–81%) after easy work-up (

Table 2. Results of microwave (MW)-assisted synthesis of 4a–q compounds, in solvent/catalyst-free conditions.

Compound 4	R	Ar	Time (min)	Yield * (%)	mp (°C)
a	H	C6H5	5	80	>300
ba		p-CH3-C6H4	5	80	>300 a
ca		p-OCH3-C6H4	5	80	>300 a
d		3,4,5-tri-OCH3-C6H2	5	80	265
e		2-Thienyl	5	70	>300
f		p-F-C6H4	5	70	>300
g		p-Cl-C6H4	5	80	>300
h		p-Br-C6H4	5	80	>300
i	CH3	C6H5	6	81	277
j		p-CH3-C6H4	8	75	280
k		p-OCH3-C6H4	9	70	282
l		3,4,5-tri-OCH3-C6H2	6	80	263
m		p-CF3-C6H4	6	75	>300
n		3,4-(OCH2O)-C6H3	8	75	254
o		4-F-C6H4	9	74	276
p		4-Cl-C6H4	6	71	283
q		4-Br-C6H4	6	76	264

^a Compounds which showed decomposition. * Isolated yield.

).

This reaction permits the use of aromatic aldehydes with electron withdrawing group (EWG) or electron releasing group (ERG), but also to 2- or/and 3-substitutedpyrimidin-4-ones with good yields. As shown in Table 2, the difference between the yields of the compounds obtained are not significant, results suggest that the electronic nature of the substituent on aromatic aldehydes and the pyrimidin-4-ones have no significant effect on rate, yields and the course to lead to aromatization of pyridinic ring.

This protocol is a like a Mannich-type reaction, which compared with conventional methods, does not require long reaction times, and the use of flammable solvents, or expensive and toxic catalysts (ionic liquids, superacid, Brønsted acids), to obtain regioselectivelly the reaction products [40,41,43,44].

The structures of 5-aryl-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione 4a–q derivatives were elucidated from the standart spectroscopic and analytical methods (¹H, ¹³C NMR, IR, mass spectra and Elemental Analysis (EA). The naphtoquinone system formed by the two non-equivalent nucleophilic center of 6-aminopyrimidinone 1 (-NH₂ group and C-5), is evidenced from ¹H NMR spectra. All derivatives 4a–q showed a singlet between 5.17–5.53 ppm assigned to methine proton (stereogenic centre) and other single between 9.21–9.89 ppm corresponding to NH of the pyridine ring. All protons exhibit chemical shift signals in their respective expected region. In this reaction, two possible regioisomer could be formed depending on the carbonyl group of naphthalene-1,2,4(3H)-trione 2 involved in the cyclocondensation with the amino group (Figure 1).

NOESY (Nuclear Overhauser Effect Spectroscopy) experiments show no correlation between the NH from dihydropyridine (DHP) ring and aromatic protons of the naphtoquinone system as expected for the non-linear derivatives 5. It is clear that the lack of correlation is not sufficient to rule out a structure, but this is confirmed with the rest of spectroscopic analysis. In similar work, we have changed the amino-heterocyclic component (5-amino-1-NH-pyrazole by 6-amino-pyrimidinone), both bearing two non-equivalent nucleophilic center (-NH₂ group and C-4 in pyrazole or C-5 in pyrimidinone). In order to obtain pyrazolo[3,4-b]quinolindiones derivatives, the reaction with (1-NH)-5-aminopyrazole, which has an additional nucleophilic center lead regioselectivelly to the formation of non-linear tetracyclic dihydrocompounds. The difference between the works is the change of process regioselectivity, ortho-quinone derivatives (angular) are obtained with aminopyrazoles [23] and para-quinone derivatives (lineal) are obtained with aminopyrimidinones [37]. Now, as compared to similar work previously reported [39], the absolute configuration of the products 4 was determined by both the NMR and the X-ray analysis, showing that the linear isomer is isolated [45] including a computational study of the molecular structure of 4 compounds.

3.2. Theoretical Calculations

To unambiguously define the structures of 4, we attempted to obtain a crystal of suitable for X-ray analysis (Figure 2). Crystal of 5-(4-methoxyphenyl)-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione 4c was grown in ethanol (95%) using the slow evaporation method at room temperature (RT) [45].

In accordance with the X-ray structural analysis of 5-(4-methoxyphenyl)-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione 4c, the computational studies indicate that the dihydropyridine ring in these compounds has a boat conformation due to the presence of a sp³ hybridized C5-atom in which the aryl ring occupies the pseudo-axial position. The orientation of the additional substituent on the C5-aryl ring (CH₃O) located on the para-positions with respect to the heterocyclic ring may be syn-orientated to the C5-H bond (synperiplanar, C5-H sp), or may lie above the heterocyclic ring and anti-orientated to the C5-H bond (antiperiplanar, C5-H ap) (Figure 3).

The optimized structures of the compound considered in the present study are illustrated in Figure 3, in which the CH₃O group has the more stable planar conformation. Structural and bonding analysis of these compounds is started by comparison of the selected bond lengths, and bond dihedral angles. Orientation of the CH₃S group with respect to the heterocyclic ring pyrimidine is denoted by a dihedral angleτ1 (N₁-C₂-S₁₉-C₂₀), inter-ring dihedral angles defining orientations of the aryl ring towards the heterocyclic ring are indicated as τ2 (C₁₄-C₅-C₂₄-C₂₉), and the inner dihedral angles of the dihydropyridine ring are denoted by τ3 (N₁₂-C₁₃-C₁₄-C₅) and τ4 (N₁₂-C₁₈-C₁₅-C₅), and dihedral angle τ5 (C₂₈-C₂₇-O₄₄-C₄₅) the 4-metoxi group the 5-aryl, which are extracted from the optimized structures of compound 4c (Figure 3) and listed in

Table 3. X-ray experimental analysis data and lengths, angles and dihedral angles bonds of 4c calculated by Density functional theory (DFT) method.

Parameter			Parameter
Bond Length (Å)	Experimental X-ray	6-31G(d,p)	Bond Length (Å)	Experimental X-ray	6-31G(d,p)
N1-C2	1.31 (4)	1.33	C11-C17	1.50 (4)	1.49
N1-C13	1.37 (4)	1.40	C11-C18	1.50 (4)	1.51
C2-N3	1.36 (4)	1.38	C11-O23	1.22 (4)	1.21
C2-S19	1.75 (3)	1.76	N12-C13	1.38 (4)	1.40
N3-C4	1.39 (4)	1.47	N12-C18	1.37 (4)	1.41
C4-C14	1.43 (4)	1.44	C13-C14	1.37 (4)	1.39
C4-O21	1.24 (4)	1.21	C15-C18	1.34 (4)	1.36
C5-C14	1.52 (4)	1.51	C16-C17	1.39 (4)	1.41
C5-C15	1.52 (4)	1.52	S19-C20	1.79 (3)	1.80
C5-C24	1.54 (5)	1.52	C24-C25	1.39 (4)	1.41
C6-C15	1.47 (4)	1.49	C24-C29	1.38 (5)	1.40
C6-C16	1.50 (4)	1.50	C25-C26	1.38 (5)	1.39
C6-O22	1.22 (4)	1.21	C26-C27	1.38 (5)	1.41
C7-C8	1.38 (4)	1.4	C27-C28	1.40 (5)	1.40
C7-C16	1.39 (4)	1.40	C27-O44	1.37 (4)	1.38
C8-C9	1.39 (5)	1.39	C28-C29	1.37 (5)	1.40
C9-C10	1.38 (5)	1.40	O44-C45	1.44 (4)	1.45
C10-C17	1.40 (4)	1.40
Bond Angles (°)	Experimental X-ray	6-31G(d,p)	Bond Angles (°)	Experimental X-ray	6-31G(d,p)
C2-N1-C13	115.2 (3)	116.7	C5-C14-C13	124.0 (3)	121.5
N1-C2-N3	123.4 (3)	124.3	C5-C15-C6	117.4 (3)	116.6
N1-C2-S19	122.6 (2)	119.5	C5-C15-C18	122.1 (3)	122.0
N3-C2-S19	114.0 (2)	116.2	C6-C15-C18	120.4 (3)	121.4
C2-N3-C4	123.1 (2)	121.1	C6-C16-C7	119.0 (3)	118.9
N3-C4-C14	114.8 (3)	113.8	C6-C16-C17	121.5 (3)	121.4
N3-C4-O21	120.0 (3)	114.7	C7-C16-C17	119.4 (3)	119.8
C14-C4-O21	125.2 (3)	131.5	C10-C17-C11	119.8 (3)	118.9
C14-C5-C15	109.0 (3)	110.7	C10-C17-C16	120.4 (3)	120.0
C15-C5-C24	110.7 (3)	108.4	C11-C17-C16	119.8 (3)	121.0
C15-C6-C16	117.7 (3)	116.5	C11-C18-N12	113.4 (3)	114.8
C15-C6-O22	120.9 (3)	122.5	C11-C18-C15	123.3 (3)	123.1
C16-C6-O22	121.3 (3)	120.9	N12-C18-C15	123.2 (3)	122.1
C8-C7-C16	119.9 (3)	120.1	C2-S19-C20	101.5 (15)	104.5
C7-C8-C9	120.7 (3)	120.1	C5-C24-C25	121.9 (3)	118.8
C8-C9-C10	120.1 (3)	120.0	C5-C24-C29	120.2 (3)	121.6
C9-C10-C17	119.5 (3)	120.0	C25-C24-C29	117.8 (3)	119.6
C17-C11-C18	117.0 (3)	115.8	C24-C25-C26	121.4 (3)	120.7
C17-C11-O23	123.9 (3)	123.9	C25-C26-C27	119.9 (3)	118.6
C18-C11-O23	119.1 (3)	120.2	C26-C27-C28	119.1 (3)	121.8
C13-N12-C18	120.6 (3)	118.9	C27-C28-C29	119.9 (3)	118.4
N1-C13-N12	114.2 (3)	115.0	C24-C29-C28	121.9 (3)	121.0
N1-C13-C14	126.1 (3)	123.6	C27-O44-C45	117.9 (3)	117.8
N12-C13-C14	119.7 (3)	121.4	O44-C27-C26	124.5 (3)	123.2
C4-C14-C5	118.8 (3)	118.0	O44-C27-C28	116.4 (3)	116.0
C4-C14-C13	117.2 (3)	120.4
Dihedral Angles (°)	Experimental X-ray	6-31G(d,p)	Dihedral Angles (°)	Experimental X-ray	6-31G(d,p)
N1-C2-N3-C4	−0.7 (5)	1.3	C16-C17-C11-C18	−0.9 (5)	4.3
C13-N1-C2-N3	1.5 (5)	−1.3	C10-C17-C11-C18	177.8 (3)	−175.5
C13-N1-C2-S19	−178.9 (2)	179.2	C6-C15-C18-N12	179.5 (3)	174.5
S19-C2-N3-C4	179.7 (2)	−179.2	C5-C15-C18-N12	2.7 (5)	−6.1
C2-N3-C4-O21	176.3 (3)	−178.1	C6-C15-C18-C11	2.2 (5)	−5.2
C2-N3-C4-C14	−2.4 (5)	1.2	C5-C15-C18-C11	−174.6 (3)	174.2
O21-C4-C14-C13	−174.1 (3)	175.6	O24-C11-C18-15	178.7 (3)	178.5
N3-C4-C14-C13	4.6 (5)	−3.6	C17-C11-C18-15	1.1 (5)	−2.1
O21-C4-C14-C5	6.7 (5)	−5.8	O24-C11-C18-N12	1.2 (5)	−1.2
N3-C4-C14-C5	−174.7 (3)	175	C17-C11-C18-N12	−176.4 (3)	178.1
C13-C14-C5-C15	12.7 (5)	−18.2	C15-C18-N12-C13	5.7 (5)	−8.5
C4-C14-C5-C15	−168.1 (3)	163.1	C11-C18-N12-C13	−176.8 (3)	171.2
C13-C14-C5-C24	−109.7 (4)	102.8	C2-N1-C13-C14	1.1 (5)	−1.3
C4-C14-C5-C24	69.5 (4)	−75.9	C2-N1-C13-N12	−177.8 (3)	178.1
C14-C5-C15-C18	−10.8 (5)	18.4	C4-C14-C13-N1	−4.2 (5)	3.9
C24-C5-C15-C18	111.8 (4)	−104.7	C5-C14-C13-N1	174.9 (3)	−174.6
C14-C5-C15-C6	172.3 (3)	−162.1	C4-C14-C13-N12	174.7 (3)	−175.5
C24-C5-C15-C6	−65.1 (4)	74.8	C5-C14-C13-N12	−6.2 (5)	5.9
C18-C15-C6-O22	174.9 (3)	−168.9	C18-N12-C13-N1	175.1 (3)	−170.9
C5-C15-C6-O22	−8.1 (5)	11.6	C18-N12-C13-C14	−3.9 (5)	8.5
C18-C15-C6-C16	−5.5 (5)	10.1	N1-C2-S19-C20	−8.6 (3)	0.1
C5-C15-C6-C16	171.4 (3)	−169.4	N3-C2-S19-C20	171.1 (3)	−179.4
O22-C6-C16-C7	6.3 (5)	−8.4	C14-C5-C24-C29	71.1 (3)	−39.3
C15-C6-C16-C7	−173.2 (3)	172.6	C14-C5-C24-C29	−50.3 (4)	83.1
O22-C6-C16-C17	−174.7 (3)	171.1	C14-C5-C24-C25	−110.0 (3)	141.4
C15-C6-C16-C17	5.7 (5)	−7.9	C15-C5-C24-C25	128.7 (3)	−96.2
C17-C16-C7-C8	1.0 (5)	0.1	C25-C24-C29-C28	−0.1 (5)	−0.5
C6-C16-C7-C8	180.0 (3)	179.6	C5-C24-C29-C28	178.9 (3)	−179.8
C16-C3-C3-C9	0.4 (6)	−0.2	C24-C29-C28-C27	−0.5 (5)	0.1
C7-C8-C9-C10	−0.5 (6)	0.1	C29-C28-C27-O44	−178.6 (3)	179.9
C8-C9-C10-C17	−0.7 (5)	0.1	C29-C28-C27-C26	0.5 (5)	0.3
C7-C16-C17-C10	−2.2 (5)	0.2	O44-C27-C26-C25	179.1 (3)	180
C6-C16-C17-C10	178.8 (3)	−179.4	C35-C27-C26-C25	0.0 (4)	−0.4
C7-C16-C17-C11	176.5 (3)	−179.7	C27-C26-C25-C24	−0.6 (5)	0
C6-C16-C17-C11	−2.5 (5)	0.8	C29-C24-C25-C26	0.7 (4)	0.4
C9-C10-C17-C16	2.1 (5)	−0.3	C35-C24-C25-C26	−178.3 (3)	179.8
C9-C10-C17-C11	−176.6 (3)	179.6	C26-C27-O44-C45	9.9 (4)	−0.1
C16-C17-C11-O24	−178.4 (3)	−176.4	C28-C27-O44-C45	−171.0 (3)	179.9
C10-C17-C11-O24	0.3 (5)	3.8

. These orientations may influence the molecular energy content and the changes of some characteristic bond lengths, bond angles and bond dihedral angles.

To study the vibrational characteristics and structural parameters of 5-(4-methoxyphenyl)-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione 4c, we performed a theoretical study at DFT level, which allows us to set the geometric and energetic parameters of the title compound. The optimized structure with B3LYP/6-31G(d,p) level is shown in Figure 2 [46,47,48,49,50]. The calculated geometric parameter (bond lengths, bond angles and dihedral angles) at same levels of calculation for title compound was compared with the experimental parameters, see Table 3, showing very good correlation.

The minimum point structures located on the potential surface scan (PES) for 5-(4-methoxyphenyl)-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione 4c was submitted for optimization using the B3LYP/6-31G(d,p) computational levels and theoretical approximations were performed in the gas phase. From the rotation of different groups, the minimum energy conformation and valuable structural information about compound are obtained. In order to reveal all possible conformational of the title compound, a detailed potential energy curve for τ1 (N₁-C₂-S₁₉-C₂₀), τ2 (C₁₄-C₅-C₂₄-C₂₉), and τ4 (C₂₈-C₂₇-O₄₄-C₄₅) dihedral angles was performed in steps of 10° from 0° to 360° and are described in Figure 4.

Structure of highest and lowest energy conformers for τ1, τ2 and τ4 dihedral angles and the computed values of these dihedral angles are given in Figure 4. The PES graphs are plotted using the conformation energies (kJ/mol) in Figure 5. The minimum energy curves for τ1 (N₁-C₂-S₁₉-C₂₀) dihedral angle were obtained at −0.78758° (−17.9 Kcal/mol), τ2 (C₁₄-C₅-C₂₄-C₂₉) −90.71251° (−18.0 Kcal/mol), and τ4 (C₁₅-C₅-C₂₄-C₂₉) at 178.04179° (−17.9 Kcal/mol) for B3LYP level.

Vibrational spectral assignments (

Table 4. Fourier Transform infrared spectroscopy (FT-IR) Experimental and computed vibrational bands for compound 4c and their assignments at B3LYP/6-31G(d,p) level.

υ	Experimental	Calculate		Assignment
		Un-Scaled	Scaled
1	3272	3459	3334	N12-H stretching
		3450	3325	N3-H stretching
2	2841	3141	3027	O-CH3 bending symmetric
		3127	3014	O-CH3 stretching asymmetric
		3108	2996	S-CH3 stretching asymmetric
		3039	2929	O-CH3 stretching symmetric
		3018	2909	S-CH3 stretching symmetric
3	1674	1851	1784	C4=O21 stretching
4	1650	1822	1756	C11=O23 stretching
5	1620	1811	1745	C6=O22 stretching
6	1496	1495	1436	C=N stretching
7	1450	1467	1409	C=N stretching
8	1390	1350	1297	C-N stretching
9	1332	1185	1138	C-N stretching
10	1247	1126	1082	C-N stretching

) were performed on the recorded FT-IR spectra, based on the theoretically predicted wavenumbers by DFT methods, using 6-31G(d,p) basis set [50]. The observed spectra are in good agreement with the simulated spectra.

The assignment of experimental vibrational bands to normal vibration modes is based on the comparison with related molecules and with results of the calculations obtained. We consider the B3LYP/6-31G(d,p) calculations because the scale factors used are well defined for this base set and also because the compared molecule was optimized at the same calculation level (0.961 ± 0.045) [51].

N-H vibrations

The bands at 3459 cm⁻¹ and 3450 cm⁻¹ are assigned to the symmetrical stretches of the N-H groups, N₁₂ and N₃, respectively. These bands appear overlapping in the experimental spectrum at 3272 cm⁻¹.

C=O groups vibrations

The C=O stretches are observed as medium intensity bands at 1674 cm⁻¹, 1650 cm⁻¹ and 1620 cm⁻¹. The DFT calculation gives the stretch wave number at 1784 cm⁻¹ for stretching the C₄=O₂₁ group, 1756 cm⁻¹ for C₁₁=O₂₃ and 1745 cm⁻¹ for C₆=O₂₂ after scaling. The difference between the calculated and experimental wave numbers can be attributed to the conjugation of C=O bonds to the phenyl ring, which is expected to decrease the wave numbers of the stretches.

C=N vibrations

Stretch bands C=N expected in the range of 1672–1566 cm⁻¹. For compound 4c, the stretching mode C=N is assigned to 1496 cm⁻¹ and 1450 cm⁻¹ in FT-IR spectrum and theoretically at 1495 (1436) and 1467 (1409) cm⁻¹.

C-N vibrations

The C-N stretching vibrations are moderately to strongly in the 1275 ± 55 cm⁻¹ region. According to reports in the literature, assign stretches of C-N are reported at 1184, 1367, and 1373 cm⁻¹ for different compounds [52,53,54]. For compound 4c the bands at 1390 and 1332 cm⁻¹ are assigned to the C-N stretching modes and theoretically (DFT) at 1126 (1082), 1185 (1138) and 1350 (1297) cm⁻¹.

Two factors may be responsible for the discrepancies between the experimental and computed wavenumbers of the compound. The first is caused by the environment (gas and solid phase) and the second is because the experimental values are inharmonic wavenumbers while the calculated values are harmonic ones. Therefore, the calculated values are very close to experimental measures.

Natural bond orbital (NBO) analysis allows a detailed description of the electronic structure of compound 4c, in terms of occupancy and composition of the group of NBOs Lewis (see

Table 5. Occupation of natural orbitals and hybrids for 4c calculated by the DFT/B-3LYP/6-31G(d,p) method for the representative atoms.

Donor Lewis NBOs (Natural Bond Orbital)	Type	Electronic Density	Hybridization	Contribution of Natural Atomic Orbitals (%)
					s	p	d
C4-O21	σ	1.99441	0.5952(sp2.01)C + 0.8036(sp1.43)O	C	33.23	66.68	0.09
				O	41.00	58.65	0.34
C4-O21	π	1.98431	0.5492 (sp1.00)C + 0.835 (sp1.00)O	C	0.01	99.81	0.18
				O	0.01	99.69	0.31
C6-O22	σ	1.99483	0.5895 (sp2.31)C + 0.8078 (sp1.38)O	C	30.22	69.68	0.11
				O	41.88	57.80	0.01
C6-O22	π	1.94776	0.5813 (sp99.99)C + 0.8137 (sp99.99)O	C	0.01	99.84	0.14
				O	0.02	99.67	0.31
C11-O23	σ	1.99525	0.5885 (sp2.30)C + 0.8085 (sp1.38)O	C	30.26	69.63	0.11
				O	41.89	57.79	0.32
C11-O23	π	1.95767	0.5756 (sp1.00)C + 0.8177 (sp1.00)O	C	0.00	99.85	0.15
				O	0.00	99.69	0.31
C15-C18	σ	1.97340	0.7021 (sp1.83)C + 0.7121 (sp1.51)C	C	35.30	64.66	0.04
				C	39.87	60.10	0.03
C15-C18	π	1.77932	0.7191 (sp1.00)C + 0.6949 (sp1.00)C	C	0.00	99.94	0.06
				C	0.00	99.95	0.05
C2-S19	σ	1.97646	0.7439 (sp2.38)C + 0.6683 (sp5.04)S	C	29.51	70.38	0.10
				S	16.44	82.84	0.73
C27-O44	σ	1.99168	0.5705 (sp3.02)C + 0.8213 (sp2.01)O	C	24.82	74.97	0.21
				O	33.17	66.76	0.07
N12-H31	σ	1.98356	0.8596 (sp2.52)N + 0.5110 (s99.89)H	N	28.02	71.96	0.02
				H	99.89	0.11
N3-H30	σ	1.98394	0.8551 (sp2.61)N + 0.5184 (s99.90)H	N	27.68	72.29	0.02
				H	99.90	0.10
N1	LP a (1)	1.89271	sp2.45	N	28.94	70.90	0.16
N3	LP a (1)	1.61063	p1.00	N	0.00	98.99	0.01
N12	LP a (1)	1.73427	sp90.58	N	1.09	98.89	0.01
O21	LP a (1)	1.97642	p1.00	O	58.92	41.03	0.04
O21	LP a (2)	1.84939	p99.99	O	0.03	99.73	0.24
O22	LP a (1)	1.97885	Sp0.72	O	58.07	41.88	0.04
O22	LP a (2)	1.88965	p1.00	O	0.00	99.80	0.20
O23	LP a (1)	1.97850	Sp0.72	O	58.02	41.93	0.05
O23	LP a (2)	1.88503	p1.00	O	0.05	99.74	0.20
O44	LP a (1)	1.96389	sp1.59	O	38.53	61.41	0.06
O44	LP a (2)	1.84157	p1.00	O	0.00	99.91	0.09
S19	LP a (1)	1.98246	Sp0.48	N	67.55	32.43	0.02
S19	LP a (2)	1.82875	p1.00	N	0.00	99.94	0.05

^a Lone pair on natural Lewis structure.

) and not Lewis (see

Table 6. Occupation of natural bond orbitals (NBO) no Lewis and hybrids for 4c calculated by the DFT/B-3LYP/6-31G(d,p) method for the representative atoms.

Acceptor not Lewis	Type	Electronic Density	Hybridization	Contribution of Natural Atomic Orbitals (%)
					s	p	d
C4-O21	σ *	0.00892	0.8036 (sp2.01)C − 0.5952 (sp1.43)O	C	33.23	66.68	0.09
				O	41.00	58.65	0.34
C4-O21	π *	0.35268	0.8357 (p1.00)C − 0.5492 (p1.00)O	C	0.01	99.81	0.18
				O	0.01	99.69	0.31
C6-O22	σ *	0.00782	0.8078 (sp2.31)C − 0.5895 (sp1.38)O	C	30.22	69.68	0.11
				O	41.88	57.80	0.01
C6-O22	π *	0.20945	0.8137 (p99.99)C − 0.5813 (p99.99)O	C	0.01	99.84	0.14
				O	0.02	99.67	0.31
C11-O23	σ *	0.00754	0.8085 (sp2.30)C − 0.5885 (sp1.38)O	C	30.26	69.63	0.11
				O	41.89	57.79	0.32
C11-O23	π *	0.19366	0.8177 (p1.00)C − 0.5756 (p1.00)O	C	0.00	99.85	0.15
				O	0.00	99.69	0.310
C15-C18	σ *	0.02406	0.7121 (sp1.83)C − 0.7021 (sp1.51)C	C	35.30	64.66	0.04
				C	39.87	60.10	0.03
C15-C18	π *	0.24133	0.6949 (p1.00)C − 0.7191 (p1.00)C	C	0.00	99.94	0.06
				C	0.00	99.95	0.05
C2-S19	σ *	0.05230	0.6683 (sp2.38)C − 0.7439 (sp5.04)S	C	29.51	70.38	0.10
				S	16.44	82.84	0.73
C27-O44	σ	0.02955	0.8213 (sp3.02)C − 0.5705 (sp2.01)O	C	24.82	74.97	0.21
				O	33.17	66.76	0.07
N12-H31	σ *	0.02603	0.5110 (sp2.52)N − 0.8596 (s99.89)H	N	28.02	71.96	0.02
				H	99.89	0.11
N3-H30	σ	0.01822	0.5184 (sp2.61)N + 0.8551 (s99.90)H	N	27.68	72.29	0.02
				H	99.90	0.10

). 224 NBOs were calculated for this compound, representative NBOs are highlighted by finding three carbonyl-like bonds (C₄=O₂₁, C₆=O₂₂, C₁₁=O₂₃), a non-aromatic double bond (C₁₅=C₁₈), four heteroatom bonds (C₂-S₁₉, C₂₇-O₄₄, N₁₂-H₃₁ and N₃-H₃₀) and solitary pairs of N and O (N₁, N₃, N₁₂, S₁₉, O₂₁, O₂₂, O₂₃ and O₄₄) of the expected Lewis structure. For each of the molecular orbitals, the corresponding percentage of s, p, d character is included.

In Lewis type orbitals, as seen in Table 5, the σ bond (C₄-O₂₁) is formed from the sp^2.01 hybrid on carbon, mixture of s (33.23%) p (66.68%) d (0.09%); on the other hand, the π bond (C₄-O₂₁) is formed from the sp^1.00 hybrid on carbon and oxygen, mixture of s (0.01%) p (99.81%) d (0.18%); the electronic densities or maximum occupations calculated for σ (C₄-O₂₁), π (C₄-C₂₁), σ (C₆-C₂₂) and π (C₆-N₂₂) are 1.99441, 1.98431, 1.99483 and 1.94776, respectively. Therefore, these results allow to infer that these bonds are controlled by the character p of the hybrid orbitals.

The energy values E₂ for the interaction between the filled orbital i (donors) and the vacant orbital j (acceptors) or other molecular subsystem, calculated according to the theory of the second order perturbation, Equation (1), predicts the occurrence of delocalization or hyperconjugation [55,56]. The higher the value of E₂, the more intense the interaction between electron donors and the greater the degree of conjugation of the whole system [57].

$$E_2=∆E_{ij}=q_i\frac{F{\left(i,j\right)}^2}{{\epsilon }_j-{\epsilon }_i}$$

(1)

q_i = Occupation or electronic density of the donor orbital.

E_i and E_j are the diagonal elements and F(i, j) is the element of the Fock NBO diagonal matrix.

Therefore, we calculated the hyperconjugative interaction and density transfer of lone pair electron (LP) of the N₃ and N₁₂ atoms to neighboring π antibonding orbitals. Similarly, the conjugation of carbonyl groups to neighboring atoms via π* → π*, see

Table 7. Analysis perturbation theory second order in Fock matrix in NBO by level calculation B3LYP/6-31G (d,p) for compound 4c.

Donor NBO (i)	Acceptor NBO (j)	E2	Ej-Ei	F(i,j)
		Kcal/mol	a.u	a.u
LP N3	π* N1-C2	65.72	0.26	0.116
LP N3	π* C4-O21	44.57	0.30	0.104
LP N12	π* C13-C14	41.73	0.30	0.101
LP N12	π* C15-C18	39.97	0.30	0.101
π* C4-O21	π* C13-C14	256.96	0.01	0.080
π* C6-O22	π* C15-C18	94.72	0.02	0.076
π* C11-O23	π* C15-C18	41.82	0.04	0.075
π* C11-O23	π* C16-C17	76.69	0.03	0.075

.

In Table 7, the important contribution of LP N → π* interactions to the overall stability of the system is observed. Stability explained by the intramolecular electron transfer that occurs with these interactions. As evidence of this orbital phenomenon, it is the lowest electronic density on N3 and N12 compared to N1 (Table 6). The energy involved in the hyperconjugative interactions of the bonds between carbon and oxygen atoms of the carbonyl groups of molecule 4c, give the most intense interactions and correspond to the highest degree of conjugation occurring in the α,β-unsaturated intramolecular system of aromatic ketones. π* (C₄-O₂₁) → π* (C₁₃-C₁₄), 257 kcal/mol; π* (C₆-O₂₂) → π* (C₁₅-C₁₈), 94.7 kcal/mol; π* (C₁₁-O₂₃) → π* (C₁₅-C₁₈), 41.8 kcal/mol; π* (C₁₁-O₂₃) → π* (C₁₆-C₁₇), 76.7 kcal/mol.

In the analysis of the nonlinear optical properties (NLO) for 4c, the polarization of the molecule, induced by an external radiation field, it often resembles the generation of a dipole moment induced by an external electric field. Under the weak polarization condition, a Taylor serial development in the electric field components can be used to demonstrate the dipole interaction with the electric field of external radiation.

The first static hyperpolarizability (β₀) and its related properties (β, α₀ and Δα) were calculated using the B3LYP/6-31G(d,p) level based on the finite field approach. The total static dipole moment μ, average polarizability α₀, anisotropy polarizability Δα and hyperpolarizability of first average β₀, using the components x, y and z is defined as:

$$\mu ={({\mu }_x^2+ {\mu }_y^2+ {\mu }_z^2)}^{1/2}$$

(2)

$${\alpha }_0=\frac{1}{3}\left({\alpha }_{xx}+{\alpha }_{yy}+{\alpha }_{zz}\right)$$

(3)

$$\mathsf{\Delta }\alpha =2^{-1/2}{\left[{\left({\alpha }_{xx}-{\alpha }_{yy}\right)}^2+{\left({\alpha }_{yy}-{\alpha }_{zz}\right)}^2+{\left({\alpha }_{zz}-{\alpha }_{xx}\right)}^2+6{\alpha }_{xz}^2\right]}^{1/2}$$

(4)

First order hyperpolarizability is

$$\beta ={\left({\beta }_x^2+{\beta }_y^2+{\beta }_z^2\right)}^{1/2}$$

(5)

where

$${\beta }_y=\left({\beta }_{yyy}+{\beta }_{yzz}+{\beta }_{yxx}\right)$$

(6)

$${\beta }_z=\left({\beta }_{zzz}+{\beta }_{zxx}+{\beta }_{zyy}\right)$$

(7)

$${\beta }_x=\left({\beta }_{xxx}+{\beta }_{xyy}+{\beta }_{xzz}\right)$$

(8)

$$\beta ={\left[{\left({\beta }_{xxx}+{\beta }_{xyy}+{\beta }_{xzz}\right)}^2+{\left({\beta }_{yyy}+{\beta }_{yzz}+{\beta }_{yxx}\right)}^2+{\left({\beta }_{zzz}+{\beta }_{zxx}+{\beta }_{zyy}+\right)}^2\right]}^{1/2}$$

(9)

The polarizability and hyperpolarizability data are reported in atomic units (a.u), by Gaussian 09, reason why were converted into electrostatic units (esu) (α: 1 au = 0.1482 × 10⁻²⁴ esu; β: 1 au = 8.639 × 10⁻³³ esu). The mean polarization α₀ and total polarizability Δα for 4c are 45.46 × 10⁻²⁴ esu and 30.66 × 10⁻²⁴ esu, respectively. The total molecular dipole momentum and first order hyperpolarizability are 1.88 Debye and 3768.07 × 10⁻³³ esu, respectively, see

Table 8. Electrical dipole moment, polarizability and first order hyperpolarizability of 4c at the level DFT/B3LYP/6-31G(d,p).

Dipole Moment		Polarizability			First Order Hyperpolarizability
Parameter	D	Parameter	a.u	esu (10−24)	Parameter	a.u	esu (10−33)
μx	−0.28	αxx	373.29	55.26	βxxx	1497.24	12941.0
μy	−1.34	αxy	7.513	1.11	βxxy	−165.57	−1431.10
μz	−1.28	αyy	336.29	49.78	βxyy	665.94	5755.80
μ0	1.88	αxz	12.913	1.91	βyyy	−3426.60	−29,616.0
		αyz	55.10	8.15	βxxz	420.33	3633.0
		αzz	211.86	31.36	βxyz	72.03	622.60
		α0	307.15	45.46	βyyz	438.54	3790.30
		Δα	207.15	30.66	βxzz	20.44	176.73
					βyzz	−87.92	−759.93
					βzzz	−25.13	−217.26
					β0 3768.07 × 10−33

.

These analysis frequently, are compared with the family of urea, as a reference for characterizing organic NLO materials [58,59]. The total dipole moment of the molecule is about 2.22 times lower than urea, and hyperpolarizability first order is 5.89 times higher than urea (μ and β for urea are 4.1775 Debye and 638.906 × 10⁻³³ esu at the same calculation level). This result indicates the good non-linearity of the molecule.

The intramolecular charge transfer process, is determined by the separation E between the HOMO (highest energy occupied molecular orbital) and LUMO (lowest energy unoccupied molecular orbital) levels. Energy susceptible to adjust to λ in the range of visible light or tunable laser, by controllable variations due to the nature donor-acceptor of the groups. As an indirect method for determining potential NLO properties, the basal and excited state of a molecule is calculated and these results are used in the qualitative estimation of the efficiency of the intramolecular charge transfer process [60,61]. Which is related to the intramolecular electronic transfer in 5-arylaryl-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione derivatives, the carbonyl groups being the acceptors of this charge transfer.

Finally, we compare the ground state energies of the optimized structures for 5-(4-methoxyphenyl)-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione 4c (obtained) and 5c (Isomer angular uninsulated), with the aim to understand thermodynamic approach for the regiochemistry of the reaction shown

Table 9. Ground state energies (enthalpy, Gibbs free energy and entropy) calculated for 4c and 5c compounds.

Thermodynamic Parameters	4c	5c
Enthalpy (H/a.u)	−549.949	−1181.96
Gibbs free energy (G/a.u)	−549.994	−1182.04
Entropy (S/cal mol−1 K−1)	93.941	172.531
ZEP (Zero-point energy) vibrational energy (Kcal/mol)	226.975	226.194
ZEP + electronic energy	−1749.749	−1749.758

. The calculated values show that 5c is thermodynamically more stable, however, is not formed. This suggests a kinetic control of the reaction.

4. Conclusions

To sum up, we can say this is an environmental friendly and straightforward methodology, to obtain by one-pot, three-component reactions the highly functionalized 5-aryl-2-methylthio-5,12-dihydrobenzo[g]pyrimido[4,5-b]quinoline-4,6,11(3H)-trione derivatives, with minimal waste formation, avoiding the use of toxic and/or hazardous solvents and reagents. The experimental results reveal a strong preference for the regioselective formation of linear four fused rings over the angular four fused rings. We have provided a theoretical/experimental comparative study to explain the regioselectivity that suggest a possible kinetic control in product formation.

The results of NBO analysis for compound 4c, indicate that N12 is the bridge connecting the adjacent π systems, through orbital overlap p (LP N) and π* (C–C). Consequently, there is an intramolecular charge transfer originated by the movement of electronic clouds, from the donor to the acceptor (C=O groups), which is related to the nonlinear optical properties.