Synthesis, Characterization, and Tautomerism of 1,3-Dimethyl Pyrimidine-2,4,6-Trione s-Triazinyl Hydrazine/Hydrazone Derivatives

Sharma, Anamika; Jad, Yahya; Siddiqui, Mohammed R. H.; Torre, Beatriz G. de la; Albericio, Fernando; El-Faham, Ayman

doi:https://doi.org/10.1155/2017/5702962

Journal of Chemistry

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Abstract Introduction Results and Discussion Conclusion Additional Points Conflicts of Interest Acknowledgments Supplementary Materials References Copyright Related Articles

Research Article | Open Access

Volume 2017 | Article ID 5702962 | https://doi.org/10.1155/2017/5702962

Synthesis, Characterization, and Tautomerism of 1,3-Dimethyl Pyrimidine-2,4,6-Trione s-Triazinyl Hydrazine/Hydrazone Derivatives

Anamika Sharma,¹Yahya Jad,¹Mohammed R. H. Siddiqui,²Beatriz G. de la Torre,^3,4Fernando Albericio ,^2,4,5,6and Ayman El-Faham^2,7

Academic Editor: José M. G. Martinho

Received23 Jan 2017

Revised31 Mar 2017

Accepted12 Apr 2017

Published24 May 2017

Abstract

1,3,5-Triazines and pyrimidine-2,4,6-triones belong to that class of compounds which are well known in literature for possessing wide range of biological activities. Here, we report a new family of compounds that encompasses these two structures. The union of both heterocycles was carried out through a hydrazone moiety incorporated into an acetyl group at the position 5 of 1,3-dimethyl pyrimidine derivative. The synthetic strategy adopted allowed the preparation of the target compounds with excellent yields and good purities. The synthesized compounds were well characterized by NMR (¹H and ¹³C), HRMS, and elemental analysis. Furthermore, the tautomerism of enhydrazine versus hydrazone has also been studied.

1. Introduction

1,3,5-Triazines and their analogues have gained considerable attention because they are found in numerous natural and synthetic biologically and pharmacologically active targets. 1,3,5-Triazine or s-triazine belongs to the group of heterocyclic compounds having significant applications within pharmaceuticals, textile, rubber, and plastics industries, and as polymer photostabilizers, herbicides, dyestuffs, optical bleaches, explosives, and surface active agents [1, 2]. Several derivatives of s-triazine have exhibited antimicrobial [3], antibacterial [4], antifungal [3], anti-HIV [5], anticancer [6, 7], and a wide range of other biological activities [8–10]. Recently some of 1,3,5-triazine-Schiff base exhibited some activity against Mycobacterium tuberculosis H37Rv [11] and moderate to excellent antiproliferative activity with high selectivity against the human lung cancer cell line H460 [12, 13]. Triazine derivatives are widely employed in many biomedical research fields: cancer chemotherapeutic agents [14], multidrug resistance modulators [15], and trifunctional scaffolds in bundle protein preparation [16].

Pyrimidine-2,4,6-triones (barbiturates) are another group of synthetic compounds known to possess biological activity. Their most remarkable action is on the central nervous system. They are extensively used for producing effects ranging from mild sedation to anaesthesia [17–21] as anticonvulsants, anxiolytics, sedative, and antiepileptic agents, as well as antitumoral agents [22–26]. They have found a prominent place in pharmaceutical industry because of their biochemical effects on calcium, acetylcholine, biogenic amines, glutamate, aspartate, and gamma-aminobutyric acid [27]. Other members of this family have found applications as antimicrobial and antifungal agents [28, 29]. Recently Neumann et al. reported a number of pyrimidine-2,4,6-trione derivatives, including phenylhydrazones of 5-acylpyrimidine-2,4,6-trione exhibiting potent growth inhibition with very low cell toxicity [30].

Prompted by such facts it is worthy to envisage that combination of such bioactive moieties (Figure 1) may form new biologically active agents. Herein, we report the synthesis of novel class of s-triazine-pyrimidinetrione hydrazone derivatives and their tautomeric behavior as well.

2. Experimental Section

2.1. Materials

All solvents were used without further purification. The ¹H NMR and ¹³C NMR spectra (Supporting Information Figures S1–S23 in Supplementary Material available online at https://doi.org/10.1155/2017/5702962) were recorded on a JEOL 400 MHz spectrometer at room temperature in CDCl₃ and/or DMSO-d₆ using internal standard δ = 0 ppm. Elemental analysis were performed on Perkin-Elmer 2400 elemental analyzer. Melting points were determined on a Mel-Temp apparatus and are uncorrected. Fourier transform infrared spectroscopy (FTIR) spectra were recorded on Nicolet 6700 spectrometer from KBr discs. Ultrasonic bath was purchased from Selecta (Barcelona, Spain). High-resolution mass spectrometric data were obtained using a Bruker microTOF-Q II instrument operating at room temperature and a sample concentration of approximately 1 ppm. All compounds were named by using ChemBioDraw Ultra version 14.0, Cambridge Soft Corporation (Cambridge, MA, USA).

2.2. Synthesis of 2-Chloro-4,6-disubstituted-s-triazine Derivatives 2a–h

The target chloroderivatives were prepared following the reported method with slight modification [31].

2.2.1. N-Benzyl-4-chloro-6-(piperidine-1-yl)-1,3,5-triazine-2-amine (2c, Supporting Information Figure S1 in Supplementary Material)

White solid in yield 85%; mp = 151-152°C; ¹H NMR (400 MHz, CDCl₃) δ = 1.54–1.64 (m, 6H, 3CH₂), 3.72 (brs, 4H, 2 NCH₂), 4.58 (t, 2H, J = 4.4 Hz, CH₂-Ph) 7.25–7.29 (m, 5H, C₆H₅); ¹³C NMR (100 MHz, CDCl₃) δ = 24.6, 25.6, 25.8, 44.6, 44.8, 127.3, 127.4, 128.5, 164.0, 165.6, 169.5. Anal. Cacl. for C₁₅H₁₈ClN₅ (303.79): C, 59.30; H, 5.97; N, 23.05; Found: C, 59.15; H, 6.09; N, 23.21.

2.2.2. N-Benzyl-4-chloro-6-morpholino-1,3,5-triazine-2-amine (2d, Supporting Information Figure S2 in Supplementary Material)

White solid in yield 81%; mp = 158-159°C; ¹H NMR (400 MHz, CDCl₃) δ = 3.67 (brs, 4H, 2 NCH₂), 3.77 (brs, 4H, 2 OCH₂), 4.58 (d, 2H, J = 6.0 Hz, CH₂-Ph), 7.26–7.32 (m, 5H, C₆H₅); ¹³C NMR (100 MHz, CDCl₃) δ = 44.4, 44.9, 66.2, 127.4, 128.7, 164.5, 165.6, 169.5. Anal. Cacl. for C₁₄H₁₆ClN₅O (305.77): C, 54.99; H, 5.27; N, 22.90; Found: C, 55.15; H, 5.12; N, 23.13.

2.2.3. 4-(4-Chloro-6-(piperidin-1-yl)-1,3,5-triazine-2-yl)morpholine (2e, Supporting Information Figure S3 in Supplementary Material)

White solid in yield 89%; mp = 125-126°C; ¹H NMR (400 MHz, CDCl₃) δ = 1.52–1.64 (m, 6H, 3CH₂), 3.68–3.76 (m, 12H, 2 OCH₂, and 4 NCH₂); ¹³C NMR (100 MHz, CDCl₃) δ = 24.6, 25.8, 43.8, 44.1, 163.9, 164.5, 169.5. Anal. Cacl. for C₁₂H₁₈ClN₅O (283.76): C, 50.79; H, 6.39; N, 24.68; Found: C, 50.65; H, 6.41; N, 24.81.

2.2.4. 4-Chloro-N,N-diethyl-6-morpholino-1,3,5-triazine-2-amine (2f, Supporting Information Figure S4 in Supplementary Material)

White crystals in 87% yield; mp = 87–89°C; ¹H NMR (400 MHz, CDCl₃) δ = 1.11 (t, 6H, J = 7.2 Hz, 2CH₃), 3.46–3.53 (m, 4H, 2CH₂), 3.67 (brs, 4H, 2NCH₂), 3.75 (brs, 4H, 2OCH₂) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 12.5, 13.2, 41.2, 41.6, 41.4, 43.7, 163.9, 164.4, 169.2 ppm. Anal. Cacl. for C₁₁H₁₈ClN₅O (271.75): C, 48.62; H, 6.68; N, 25.77; Found: C, 48.87; H, 6.56; N, 25.99.

2.2.5. 4-Chloro-N,N-diethyl-6-(piperidin-1-yl)-1,3,5-triazine-2-amine (2g, Supporting Information Figure S5 in Supplementary Material)

White crystals in 89% yield; mp = 54°C (Lit [31]; mp 56°C, yield 89%). ¹H NMR (400 MHz, CDCl₃) δ = 1.09 (t, 6H, Hz, 2CH₃), 1.49–1.59 (m, 6H, 3CH₂), 3.43–3.52 (q, 4H, 2CH₂), 3.66 (t, 4H, Hz, 2CH₂) ppm; ¹³CNMR (100 MHz, CDCl₃) δ = 12.5, 13.2, 24.5, 25.6, 41.2, 41.5, 44.3, 163.9, 169.1 ppm.

2.2.6. 4-(4-Chloro-6-methoxy-1,3,5-triazine-2-yl)morpholine (2h, Supporting Information Figure S6 in Supplementary Material)

White crystals in 85% yield; mp = 96-97°C; ¹H NMR (400 MHz, CDCl₃) δ = 3.66 (t, 4H, HMz, 2NCH₂), 3.78 (t, 4H, , 2OCH₂), 3.90 (s, 3H, OCH₃) ppm; ¹³C NMR (100 MHz, CDCl₃) δ = 43.8, 54.4, 66.4, 166.6, 172.1 ppm. Anal. Cacl. for C₈H₁₁ClN₄O₂ (230.65): C, 41.66; H, 4.81; N, 24.29; Found: C, 41.82; H, 4.96; N, 24.02.

2.3. General Method for the Synthesis of 2-Hydrazino-4,6-disubstituted-1,3,5-triazine (3a–h)

The hydrazine derivatives were prepared according to the reported method with slight modification [12, 32]. Hydrazine hydrate (10 mL, 80%) was added in portion to a solution of 2-chloro-4,6-disubstituted-1,3,5-triazine 2a–h (20 mmol) in 50 mL acetonitrile at room temperature and then the reaction mixture was sonicated for 60 min at 60°C. Acetonitrile and excess hydrazine were removed under vacuum and then excess diethylether was added to afford the product as a white solid in yield >90% and used directly without further purification for the condensation reaction with 4.

2.4. Synthesis of 1,3-Dimethyl-5-acetyl Barbituric Acid (4)

Compound 4 was prepared following the reported method with slight modification [30, 33]: 1,3-dimethyl barbituric acid (50 mmol) was suspended in very small amount of water (5–10 mL) and a concentrated water solution of sodium bicarbonate (NaHCO₃, 50 mmol) was added. Acetic anhydride was added after the gas evolution ceased. The white precipitate was formed after about 5 minutes and the mixture was stirred overnight at room temperature. The white precipitate was filtered and dissolved in 15–20% ammonium hydroxide (NH₄OH). To neutralise, hydrochloric acid (HCl) was added under cold conditions (as the reaction is exothermic) until pH was below 1. The increase in temperature was witnessed followed by formation of precipitate which was filtered and allowed to dry at room temperature. The product obtained as white solid from ethanol in yield 83%; mp 94–96°C; ¹H NMR (400 MHz, CDCl₃) δ = 2.70 (s, 3H, CH₃), 3.32 (s, 3H, CH₃), 3.35 (s, 3H, CH₃), 17.21 (s, 1H, enolic OH); ¹³C NMR (100 MHz, CDCl₃) δ = 24.8, 27.9, 28.1, 95.9, 150.5, 161.2, 169.5, 196.2 (Supporting Information Figure S7 in Supplementary Material).

2.5. General Method for the Synthesis of Pyrimidine-2,4,6-trione s-1,3,5-Triazine Hydrazine Derivatives (5a–h)

To a solution of 4 (10 mmol) in ethanol (30 mL) containing 2-3 drops of acetic acid, 2-hydrazino-4,6-disubstituted-1,3,5-triazine 3a–h (10 mmol) was added and the reaction mixture was stirred under reflux for 3 h. The solvent was reduced under vacuum and the precipitated product was filtered off and dried at room temperature. The products were collected and recrystallized from ethylacetate.

2.5.1. 5-(1-(2-(4,6-Dimorpholino-1,3,5-triazin-2-yl)hydrazinyl)ethylidene)-1,3-dimethyl Pyrimidine-2,4,6(1H,3H,5H)-trione (5a, Supporting Information Figure S8 in Supplementary Material)

White solid, 82% yield, mp = 142–144°C, IR (KBr, cm⁻¹) 3244 (NH), 1695, 1651 (C=O), 1593 (C=N, C=C); ¹H NMR (400 MHz, CDCl₃) δ = 2.75 (s, 3H, CH₃), 3.30 (s, 6H, 2CH₃), 3.69–3.74 (m, 16H, 8CH₂), 14.21 (s, 1H, NH), ¹³C NMR (100 MHz, CDCl₃) δ = 16.8, 27.7, 27.9, 43.8, 61.6, 89.4, 151.3, 162.7, 163.7, 165.9, 171.3. HRMS (ESI+, Supporting Information Figure S9 in Supplementary Material) m/z calcd for C₁₉H₂₇N₉O₅ [M+H]⁺ = 462.2208; found: 462.2215; Anal. Calc. for C₁₉H₂₇N₉O₅ (461.48): C, 49.45; H, 5.90; N, 27.32; Found: C, 49.66; H, 5.98; N, 27.45.

2.5.2. (Z)-5-(1-(2-(4,6-Di(piperidin-1-yl)-1,3,5-triazin-2-yl)hydrazono)ethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5b, Supporting Information Figure S10 in Supplementary Material)

White solid, 87% yield, mp = 224–226°C, IR (KBr, cm⁻¹) 3213 (NH), 1701, 1651 (C=O), 1593 (C=N, C=C); ¹H NMR (400 MHz, CDCl₃) δ = 1.54–1.63 (m, 12H, 6CH₂), 2.74 (s, 3H, CH₃), 3.30 (s, 6H, 2CH₃), 3.68–3.71 (m, 8H, 4CH₂), 14.35 (s, 1H, NH), ¹³C NMR (100 MHz, CDCl₃) δ = 16.8, 24.7, 25.7, 27.7, 44.4, 89.0, 151.5, 163.0, 163.4, 169.7, HRMS (ESI+, Supporting Information Figure S11 in Supplementary Material) m/z calcd for C₂₁H₃₁N₉O₃ [M+H]⁺ = 458.2623; found: 458.2651. Anal. Calc. for C₂₁H₃₁N₉O₃ (457.54): C, 55.13; H, 6.83; N, 27.55; Found: C, 55.29; H, 6.90; N, 27.74.

2.5.3. (Z)-5-(1-(2-(4-(Benzylamino)-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)hydrazono)ethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5c, Supporting Information Figure S12 in Supplementary Material)

White solid, 83% yield, mp = 193-194°C, IR (KBr, cm⁻¹) 3336, 3250 (NH), 1678, 1622 (C=O), 1577 (C=N, C=C); ¹H NMR (400 MHz, CDCl₃) δ = 1.54–1.64 (m, 6H, 3CH₂), 2.69 (s, 3H, CH₃), 3.28 (s, 6H, 2CH₃), 3.72 (s, 4H, 2CH₂), 4.52 (d, 2H, J = 6 Hz, CH₂), 5.90 (s, 1H, NH), 7.23–7.27 (m, 5H, CH aromatic), 14.8 (s, 1H, NH), ¹³C NMR (100 MHz, CDCl₃) δ = 12.3, 17.1, 18.4, 24.6, 25.7, 43.1, 44.8, 58.4, 91.2, 167.4, 177.3, HRMS (ESI+, Supporting Information Figure S13 in Supplementary Material) m/z calcd for C₂₃H₂₉N₉O₃ [M+H]⁺ = 480.2466; found: 480.2468. Anal. Calc. for C₂₃H₂₉N₉O₃ (479.55): C, 57.61; H, 6.10; N, 26.29; Found: C, 57.87; H, 6.22; N, 26.53.

2.5.4. (Z)-5-(1-(2-(4-(Benzylamino)-6-morpholino-1,3,5-triazin-2-yl)hydrazono)ethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5d, Supporting Information Figure S14 in Supplementary Material)

White solid, 83% yield, mp = 233–235°C, IR (KBr, cm⁻¹) 3336, 3292 (NH), 1681, 1612 (C=O), 1583 (C=N, C=C); ¹H NMR (400 MHz, DMSO-d₆) δ = 2.66 (s, 3H, CH₃), 3.13 (s, 6H, 2CH₃), 3.59–3.68 (m, 8H, 4CH₂), 4.46 (s, 2H, CH₂), 7.22–7.20 (m, 6H, 5 Ar-H, NH), 14.2 (s, 1H, NH) ¹³C NMR (100 MHz, DMSO-d₆) δ = 16.4, 27.3, 43.5, 65.9, 91.3, 126.8, 127.4, 128.2, 150.8, 167.4, 177.3 (s, 1H, CH) HRMS (ESI+, Supporting Information Figure S15 in Supplementary Material) m/z calcd for C₂₂H₂₇N₉O₄ [M+H]⁺ = 482.2259; found: 482.2242. Anal. Calc. for C₂₂H₂₇N₉O₄ (481.52): C, 54.88; H, 5.65; N, 26.18; Found: C, 54.63; H, 5.54; N, 26.00.

2.5.5. (Z)-1,3-Dimethyl-5-(1-(2-(4-morpholino-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)hydrazono)ethyl) pyrimidine-2,4,6(1H,3H,5H)-trione (5e, Supporting Information Figure S16 in Supplementary Material)

Yellow solid, 80% yield, mp = 198-199°C, IR (KBr, cm⁻¹) 3246 (NH), 1688, 1651 (C=O), 1585 (C=N, C=C); ¹H NMR (400 MHz, CDCl₃) δ = 1.57–1.66 (m, 6H, 3CH₂), 2.77 (s, 3H, CH₃), 3.30 (s, 6H, 2CH₃), 3.69–3.79 (m, 12H, 6CH₂), 14.35 (s, 1H, NH), ¹³C NMR (100 MHz, CDCl₃) δ = 16.8, 18.4, 24.5, 25.8, 43.7, 44.0, 44.9, 58.4, 66.6, 89.4, 151.4, 162.4, 170.7, HRMS (ESI+, Supporting Information Figure S17 in Supplementary Material) m/z calcd for C₂₀H₂₉N₉O₄ [M+H]⁺ = 460.2415; found: 460.2398. Anal. Calc. for C₂₀H₂₉N₉O₄ (459.51): C, 52.28; H, 6.36; N, 27.43; Found: C, 52.51; H, 6.54; N, 27.70.

2.5.6. (Z)-5-(1-(2-(4-(Diethylamino)-6-morpholino-1,3,5-triazin-2-yl)hydrazono)ethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5f, Supporting Information Figure S18 in Supplementary Material)

Orange solid, 91% yield, mp = 165–167°C, IR (KBr, cm⁻¹) 3285 (NH), 1677, 1645 (C=O), 1595 (C=N, C=C); ¹H NMR (400 MHz, CDCl₃) δ = 1.11 (t, 6H, J = 6.4 Hz, 2CH₃), 2.75 (s, 3H, CH₃), 3.27–3.29 (m, 6H, 2CH₃), 3.51 (q, 4H, J = 6.4 Hz, 2CH₂), 3.66–3.75 (m, 8H, 4CH₂), 14.25 (s, 1H, CH), ¹³C NMR (100 MHz, CDCl₃) δ = 13.2, 16.0, 16.8, 27.7, 27.9, 41.0, 41.6, 43.6, 43.8, 66.7, 66.9, 89.2, 151.4, HRMS (ESI+, Supporting Information Figure S19 in Supplementary Material) m/z calcd for C₁₉H₂₉N₉O₄ [M+H]⁺ = 448.2415; found: 448.2400. Anal. Calc. for C₁₉H₂₉N₉O₄ (447.50): C, 51.00; H, 6.53; N, 28.17; Found: C, 51.24; H, 6.69; N, 28.41.

2.5.7. (Z)-5-(1-(2-(4-(Diethylamino)-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)hydrazono)ethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5g, Supporting Information Figure S20 in Supplementary Material)

White solid, 90% yield, mp = 135–137°C, IR (KBr, cm⁻¹) 3285 (NH), 1677, 1645 (C=O), 1595 (C=N, C=C); ¹H NMR (400 MHz, CDCl₃) δ = 1.11 (t, 6H, J = 6.8 Hz, 2CH₃), 1.54–1.62 (m, 6H, 3CH₂), 2.75 (s, 3H, CH₃), 3.30 (m, 6H, 2CH₃), 3.51 (q, 4H, J = 6.8 Hz, 2CH₂), 3.68–3.71 (m, 4H, 2CH₂), 14.35 (s, 1H, CH), ¹³C NMR (100 MHz, CDCl₃) δ = 13.1, 16.8, 24.7, 25.7, 27.7, 41.6, 44.5, 89.0, 151.5, 162.5, 162.7, 169.7, HRMS (ESI+, Supporting Information Figure S21 in Supplementary Material) m/z calcd for C₂₀H₃₁N₉O₃ [M+H]⁺ = 446.2623; found: 446.2609. Anal. Calc. for C₂₀H₃₁N₉O₃ (445.53): C, 53.92; H, 7.01; N, 28.30; Found: C, 54.09; H, 7.20; N, 28.54.

2.5.8. (Z)-5-(1-(2-(4-Methoxy-6-morpholino-1,3,5-triazin-2-yl)hydrazono)ethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5h, Supporting Information Figure S22 in Supplementary Material)

White solid, 87% yield, mp = 260–262°C, IR (KBr, cm⁻¹) 3321 (NH), 1686, 1651 (C=O), 1588 (C=N, C=C); ¹H NMR (400 MHz, CDCl₃) δ = 2.76 (s, 3H, CH₃), 3.30 (s, 6H, 2CH₃), 3.78–3.97 (m, 8H, 4CH₂), 4.07 (s, 3H, CH₃), 14.65 (s, 1H, NH), ¹³C NMR (100 MHz, CDCl₃) δ = 16.9, 45.1, 45.3, 56.4, 66.3, 66.4, 90.0, 151.2, 156.6, 161.0, 161.4, 162.0, 162.5, 170.9, HRMS (ESI+, Supporting Information Figure S23 in Supplementary Material) m/z calcd for C₁₆H₂₂N₈O₅ [M+H]⁺ = 407.1786; found: 407.1771. Anal. Calc. for C₁₆H₂₂N₈O₅ (406.40): C, 47.29; H, 5.46; N, 27.57; Found: C, 47.54; H, 5.53; N, 27.82.

3. Results and Discussion

The general method for the preparation of triazine derivatives is nucleophilic displacement of chlorine present in the inexpensive commercially available cyanuric chloride (1, 2,4,6-trichloro-1,3,5-triazine) because of the reactivity of its chlorine atoms toward nucleophiles in presence of hydrochloride acceptor like sodium carbonate, bicarbonate, hydroxide, or tertiary amines [34–36]. Here, we report synthesis of 2-chloro-4,6-disubstituted-s-triazine derivatives using 1. Secondary amines like morpholine, diethylamine, and piperidine were chosen due to their known pharmacological properties [1, 37]. Taking advantage of the different reactivity in front of the nucleophiles of the tri-, di-, and monochloroderivatives of s-triazine, products 2a–i (Scheme 1) were obtained through one pot reaction [12]. Thus, 1 was reacted at 0°C for 2 h with the first amine (1 equiv.) in acetone-water media or methanol in the presence of NaHCO₃ (1 equiv.) as hydrogen chloride scavengers. The second amine was added dropwise followed by addition of NaHCO₃ (1 equiv.) and the reaction temperature was raised gradually to room temperature and kept under stirring for 12 h (Scheme 1) to afford the target product. In case of the methoxy derivative 2h, the reported method [33] was used for its preparation and then reacted with the amine as mentioned in Scheme 1. Finally, the hydrazine derivatives 3a–h were obtained by treatment of 2a–h with hydrazine hydrate (80%) in acetonitrile and sonicated for 1 h [12] to afford the products in excellent yields and purities above 90%. (Scheme 1) which was used directly with 5-acetyl-1,3-dimethylbarbituric acid 4 without further purification.

The products 5a–h were obtained by reaction of the 2-hydrazino-4,6-disubstituted-s-triazine derivatives 3a–h with 1,3 dimethyl-5-acetylpyrimidine-2,4,6-trione 4, which was obtained as previously described [33] in ethanol in the presence of drops of glacial acetic acid (Scheme 1) to afford the target products in excellent yields and purities as observed from their spectral data.

Compound 4 may exist in three tautomeric forms 4A, 4B, and 4C as shown in Figure 2. In solution, the NMR spectra in CDCl₃ showed that it exists in the enol form 4C which agreed with our previous reported data [35], rather than keto form 4A (Figure 2). The ¹H NMR spectra for compound 4 showed a singlet at δ 17.24; this peak is related to the OH group of the enol form 4C and it appears at low field due to the strong hydrogen bond between the OH and the carbonyl carbon of the acetyl group. On the other hand, the expected peak at δ 4.3 related to the CH flanked between the two carbonyl groups (-CO-CH-CO-) in the keto form 4A was not observed. The ¹H NMR showed that two singlet peaks at δ 3.29 and 3.34 related to the two N-CH₃ which agreed with structure 4C rather than 4B. The ¹³C NMR for compound 4 also confirmed the enol form 4C rather than the keto form or the enol form 4B, where ¹³C NMR showed peaks at δ 24.8 (CH₃), two peaks at 27.9 and 28.1 for the 2 N-CH₃, 95.9 (C4=C-OH), 150.5 (C1), 161.0 (C5), 169.5 (acetyl C=O), and 196.2 (C=C3-OH) (Supporting Information Figure S7 in Supplementary Material). This observation is in agreement with the reported data by Sharma et al. [38] and Giziroglu et al. [39].

Once it is established that 4 exists only in an enol form, the structure of 5a–h was studied, in particular respect to the enhydrazine-hydrazone tautomerism. In this case, the hydrazine moiety incorporates two NH. Thus in addition to the NH (in green, Figure 3), which can stabilizes the molecule (enhydrazine form) through a six-member ring as happens in the case of the enol form 4B or 4C (Figure 2), which is not the case for the hydrazone form 5b-A. The NMR data supported the structure 5b-B more than the others.

Taking as example compound 5b, it may exist in three tautomeric structures 5b-A, 5b-B, and 5b-C as indicated in Figure 3. ¹H NMR in DMSO-d₆ showed multiple peaks at δ 1.54–1.63 for the three methylene groups (-CH₂-)₃ of the piperidine moiety, singlet at δ 2.74 for the methyl group (N=C-CH₃), singlet at δ 3.29 for the two methyl group (N-CH₃), triplet for the two methylene groups (-CH₂N)₂ of piperidine ring, and a singlet peak at δ 14.4 for NH related to the hydrazine moiety. The ¹³C NMR of 5b showed peaks at δ 17.1 (C_e), 24.86, 25.8 (CH₂, piperidine), 27.4 (2 N-CH₃), 44.4 (2N-CH₂, piperidine), 89.2 (C_c), 151.5, 163.1, 163.6, and 169.8 (C_a, C_b, , and C=N of triazine). These data are in good agreement with the structure 5b-B more than 5b-C. The HRMS showed the exact mass 480.2451 as calculated for C₂₃H₃₅N₉O₂S [M+H]⁺ = 480.2466 (Supporting Information Figure S11 in Supplementary Material).

The NMR data for all the target products showed that 5a–h exist in the enhydrazine form B rather than the hydrazone form A or C as shown in Figure 3, where the two peaks in range of δ 90.0 and 198.0 ppm are related to the two carbon similar to those of the enhydrazine form (C=C-NH-NH-). In addition, the hydrogen bond in the enhydrazine form stabilizes the structure 5b-B more than the hydrazone isomer 5b-A as shown in Figure 3. This is also in agreement with the reported data for aroylhydrazine derivatives reported by Giziroglu et al. [39].

To expand the scope of this work, compound 5b was modelled using molecular mechanics MM2 calculations. Quantum mechanical calculations were carried out using Gaussian98 suite of programs. Geometry optimization was done by DFT method using B3LYP/6-31 basis set to assess the relative stability of the diastereomeric species (Figure 4). The calculated relative energy of hydrazone (5b-A) is −963917.8 kcal/mole while that of enhydrazine (5b-B) is −963940.7 kcal/mole, while the calculated relative energy of 5b-C geometry was optimized and found to be −963939.1561 kcal/mol, which shows higher energy level when compared with 5b-A and 5b-B. Hence on comparison 5b-C is found to be least stable amongst all the three diastereomers. From the energy values it can be seen that theoretically 5b-B is more favorable compared to 5b-A and 5b-C. From the energy values it can be found that the difference in energy level is 22.9 kcal/mol. Hence, explaining the stability of the enhydrazine (5b-B) form over hydrazone form (5b-A).

The antibacterial screening for all the products against gram positive [S. aureus (29213) and B. subtilis (6051) and gram negative E. coli (25822) and P. aeruginosa (27583)] showed no activity; this might be due to the poor solubility and precipitation during the dilution process.

4. Conclusion

Reaction of 2-hydrazino-2,6-disubstituted-1,3,5-triazine with 5-acetyl-1,3-dimethyl barbituric acid in ethanol affords the hydrazine derivatives in the enhydrazine form as a pure isomer rather than the hydrazone form as observed from the spectral data. The geometry optimization was done by DFT method using B3LYP/6-31 to calculate the relative energy of the three structures 5b-A, 5b-B, and 5b-C and indicated that the enhydrazine 5b-B is the most stable structure while 5b-A and 5b-C are less stable which agrees with the NMR spectral data. Although no significant activity of the first family of these compounds has been found as antibacterial, more derivatives are being prepared for overcoming the solubility problems, which are believed to be the cause of the poor biological activity.

Additional Points

Supporting Information. ¹H NMR, ¹³C NMR spectra, and HRMS for the prepared compounds will be available online in Supplementary Material.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

The authors thank the International Scientific Partnership Program ISPP at King Saud University (ISPP# 0061) (Saudi Arabia). The research at South Africa was funded by National Research Foundation (NRF) and the University of KwaZulu-Natal.

Supplementary Materials

Figure S1: ¹H NMR and ¹³C NMR for 2c.

Figure S2: ¹H NMR and ¹³C NMR for 2d.

Figure S3: ¹H NMR and ¹³C NMR for 2e.

Figure S4: ¹H NMR and ¹³C NMR for 2c.

Figure S5: ¹H NMR and ¹³C NMR for 2g.

Figure S6: ¹H NMR and ¹³C NMR for 2h.

Figure S7: ¹H NMR and ¹³C NMR for 4.

Figure S8: ¹H NMR and ¹³C NMR for 5a.

Figure S9: HRMS forcompound 5a.

Figure S10: ¹H NMR and ¹³C NMR for 5b.

Figure S11: HRMS for compound 5b.

Figure S12: ¹H NMR and ¹³C NMR for 5c.

Figure S13: HRMS for compound 5c.

Figure S14: ¹H NMR and ¹³C NMR for 5d.

Figure S15: HRMS for compound 5d.

Figure S16: ¹H NMR and ¹³C NMR for 5e.

Figure S17: HRMS for compound 5e.

Figure S18: ¹H NMR and ¹³C NMR for 5f.

Figure S19: HRMS of compound 5f.

Figure S20: ¹H NMR and ¹³C NMR for 5g.

Figure S21: HRMS for compound 5g.

Figure S22: ¹H NMR and ¹³C NMR for 5h.

Figure S23: HRMS for compound 5h.

Supplementary Material

References

D. R. Shah, R. P. Modh, and K. H. Chikhalia, “Privileged s-triazines: structure and pharmacological applications,” Future Medicinal Chemistry, vol. 6, no. 4, pp. 463–477, 2014.
View at: Publisher Site | Google Scholar
R. Kumar, A. D. Singh, J. Singh, H. Singh, R. K. Roy, and A. Chaudhary, “1,2,3-triazine scaffold as a potent biologically active moiety: a mini review,” Mini-Reviews in Medicinal Chemistry, vol. 14, no. 1, pp. 72–83, 2014.
View at: Publisher Site | Google Scholar
J. P. Raval, A. R. Rai, N. H. Patel, H. V. Patel, and P. S. Patel, “Synthesis and in vitro antimicrobial activity of N'-(4-(arylamino)-6-(pyridin-2-ylamino)-1,3,5-triazin-2-yl)benzohydrazide,” International Journal of ChemTech Research, vol. 3, no. 1, pp. 616–620, 2009.
View at: Google Scholar
S. Nishigaki, F. Yoneda, H. Matsumoto, and K. Morinaga, “Synthetic antibacterials. I. Nitrofurylvinyl-s-triazine derivatives,” Journal of Medicinal Chemistry, vol. 12, no. 1, pp. 39–42, 1969.
View at: Google Scholar
D. H. Mahajan, C. Pannecouque, E. De Clercq, and K. H. Chikhalia, “Synthesis and studies of new 2-(coumarin-4-yloxy)-4,6-(substituted)-S-triazine derivatives as potential anti-HIV agents,” Archiv der Pharmazie, vol. 342, no. 5, pp. 281–290, 2009.
View at: Publisher Site | Google Scholar
Z. Nie, C. Perretta, P. Erickson et al., “Structure-based design, synthesis, and study of pyrazolo[1,5-a][1,3,5]triazine derivatives as potent inhibitors of protein kinase CK2,” Bioorganic and Medicinal Chemistry Letters, vol. 17, no. 15, pp. 4191–4195, 2007.
View at: Publisher Site | Google Scholar
Z. Nie, C. Perretta, P. Erickson et al., “Structure-based design and synthesis of novel macrocyclic pyrazolo[1,5-a] [1,3,5]triazine compounds as potent inhibitors of protein kinase CK2 and their anticancer activities,” Bioorganic and Medicinal Chemistry Letters, vol. 18, no. 2, pp. 619–623, 2008.
View at: Publisher Site | Google Scholar
V. K. Pandey, S. Tusi, Z. Tusi, M. Joshi, and S. Bajpai, “Synthesis and biological activity of substituted 2,4,6-s-triazines,” Acta Pharmaceutica, vol. 54, no. 1, pp. 1–12, 2004.
View at: Google Scholar
A. Agarwal, K. Srivastava, S. K. Puri, and P. M. S. Chauhan, “Synthesis of substituted indole derivatives as a new class of antimalarial agents,” Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 12, pp. 3133–3136, 2005.
View at: Publisher Site | Google Scholar
W. Zhu, Y. Liu, Y. Zhao et al., “Synthesis and biological evaluation of novel 6-hydrazinyl-2,4-bismorpholino pyrimidine and 1,3,5-triazine derivatives as potential antitumor agents,” Archiv der Pharmazie, vol. 345, no. 10, pp. 812–821, 2012.
View at: Publisher Site | Google Scholar
V. R. Avupati, R. P. Yejella, V. R. Parala et al., “Synthesis, characterization and in vitro biological evaluation of some novel 1,3,5-triazine-Schiff base conjugates as potential antimycobacterial agents,” Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 21, pp. 5968–5970, 2013.
View at: Publisher Site | Google Scholar
H. H. Al-Rasheed, M. Al Alshaikh, J. M. Khaled, N. S. Alharbi, and A. El-Faham, “Ultrasonic irradiation: synthesis, characterization, and preliminary antimicrobial activity of novel series of 4,6-disubstituted-1,3,5-triazine containing hydrazone derivatives,” Journal of Chemistry, vol. 2016, Article ID 3464758, 9 pages, 2016.
View at: Publisher Site | Google Scholar
H. Singh, L. D. S. Yadav, K. N. Shukla, and R. Dwivedi, “Synthesis of new 1,3,4-oxadiazolo [3, 2-a]-s-triazine-5,7-dithiones and the dithionone analogues as potential antifungal agents,” Indian Journal of Pharmaceutical Sciences, vol. 54, no. 1, pp. 33–37, 1992.
View at: Google Scholar
M. Jarman, H. M. Coley, I. R. Judson et al., “Synthesis and cytotoxicity of potential tumor-inhibitory analogues of trimelamol (2,4,6-Tris[(hydroxymethyl)methylamino]-1,3,5-triazine) having electron-withdrawing groups in place of methyl,” Journal of Medicinal Chemistry, vol. 36, no. 26, pp. 4195–4200, 1993.
View at: Publisher Site | Google Scholar
A. Dhainaut, G. Régnier, G. Atassi et al., “New triazine derivatives as potent modulators of multidrug resistance,” Journal of Medicinal Chemistry, vol. 35, no. 13, pp. 2481–2496, 1992.
View at: Publisher Site | Google Scholar
D. C. Tahmassebi and T. Sasaki, “Synthesis of a three-helix bundle protein by reductive amination,” Journal of Organic Chemistry, vol. 63, no. 3, pp. 728–731, 1998.
View at: Publisher Site | Google Scholar
J. Y. Lee, M. E. Brune, R. B. Warner et al., “Antihypertensive activity of ABBOTT-81282, a nonpeptide angiotensin II antagonist, in the renal hypertensive rat,” Pharmacology, vol. 47, no. 3, pp. 176–187, 1993.
View at: Publisher Site | Google Scholar
L. Brunton, J. Lazo, and K. G. Parker, Gilman's The Pharmacological Basis of Therapeutics, Mc Graw-Hill, New York, NY, USA, 11th edition, 2005.
M. W. Johns, “Sleep and hypnotic drugs,” Drugs, vol. 9, no. 6, pp. 448–478, 1975.
View at: Publisher Site | Google Scholar
S. R. Whittle and A. J. Turner, “Differential effects of sedative and anticonvulsant barbiturates on specific [3H]GABA binding to membrane preparations from rat brain cortex,” Biochemical Pharmacology, vol. 31, no. 18, pp. 2891–2895, 1982.
View at: Publisher Site | Google Scholar
H. Brunner, K.-P. Ittner, D. Lunz, S. Schmatloch, T. Schmidt, and M. Zabel, “Highly enriched mixtures of methohexital stereoisomers by palladium-catalyzed allylation and their anaesthetic activity,” European Journal of Organic Chemistry, vol. 2003, no. 5, pp. 855–862, 2003.
View at: Publisher Site | Google Scholar
K. E. Lyons and R. Pahwa, “Pharmacotherapy of essential tremor: an overview of existing and upcoming agents,” CNS Drugs, vol. 22, no. 12, pp. 1037–1045, 2008.
View at: Publisher Site | Google Scholar
C. Uhlmann and W. Fröscher, “Low risk of development of substance dependence for barbiturates and clobazam prescribed as antiepileptic drugs: results from a questionnaire study,” CNS Neuroscience and Therapeutics, vol. 15, no. 1, pp. 24–31, 2009.
View at: Publisher Site | Google Scholar
E. Maquoi, N. E. Sounni, L. Devy et al., “Anti-invasive, antitumoral, and antiangiogenic efficacy of a pyrimidine-2,4,6-trione derivative, an orally active and selective matrix metalloproteinases inhibitor,” Clinical Cancer Research, vol. 10, no. 12 I, pp. 4038–4047, 2004.
View at: Publisher Site | Google Scholar
H.-J. Breyholz, S. Wagner, A. Faust et al., “Radiofluorinated pyrimidine-2,4,6-triones as molecular probes for noninvasive MMP-targeted imaging,” ChemMedChem, vol. 5, no. 5, pp. 777–789, 2010.
View at: Publisher Site | Google Scholar
P. Bartsch, D. Cataldo, R. Endele et al., “Pharmaceutical compositions of pyrimidine-2, 4, 6-triones,” Google Patents, 2011.
View at: Google Scholar
J. A. Richter and J. R. Holtman Jr., “Barbiturates: their in vivo effects and potential biochemical mechanisms,” Progress in Neurobiology, vol. 18, no. 4, pp. 275–319, 1982.
View at: Publisher Site | Google Scholar
A. Padmaja, G. S. Reddy, A. Venkata Nagendra Mohan, and V. Padmavathi, “Michael adducts—Source for biologically potent heterocycles,” Chemical and Pharmaceutical Bulletin, vol. 56, no. 5, pp. 647–653, 2008.
View at: Publisher Site | Google Scholar
V. Padmavathi, G. D. Reddy, B. C. Venkatesh, and A. Padmaja, “One-pot synthesis of 5-{[Bis(azolylmethylthio)]methylene}pyrimidine-2,4,6- (1H,3H,5H)-triones,” Archiv der Pharmazie, vol. 344, no. 3, pp. 165–169, 2011.
View at: Publisher Site | Google Scholar
D. M. Neumann, A. Cammarata, G. Backes, G. E. Palmer, and B. S. Jursic, “Synthesis and antifungal activity of substituted 2,4,6-pyrimidinetrione carbaldehyde hydrazones,” Bioorganic & Medicinal Chemistry, vol. 22, no. 2, pp. 813–826, 2014.
View at: Publisher Site | Google Scholar
H. A. Ghabbour and A. El-Faham, “Crystal structure of 4-chloro-N,N-diethyl-6-(piperidin-1-yl)-1,3,5-triazin-2-amine, C12H20ClN5,” Zeitschrift fur Kristallographie—New Crystal Structures, vol. 231, no. 1, pp. 243–245, 2016.
View at: Publisher Site | Google Scholar
S. T. Asundaria, S. A. Patel, K. M. Mehta, and K. C. Patel, “Synthesis, characterization and antimicrobial studies of some novel 1,3,4-thiadiazolium-2-thiolate derivatives,” South African Journal of Chemistry, vol. 63, pp. 141–144, 2010.
View at: Google Scholar
B. S. Jursic and D. M. Neumann, “Preparation of 5-formyl- and 5-acetylbarbituric acids, including the corresponding Schiff bases and phenylhydrazones,” Tetrahedron Letters, vol. 42, no. 48, pp. 8435–8439, 2001.
View at: Publisher Site | Google Scholar
T. J. Mooibroek and P. Gamez, “The s-triazine ring, a remarkable unit to generate supramolecular interactions,” Inorganica Chimica Acta, vol. 360, no. 1, pp. 381–404, 2007.
View at: Publisher Site | Google Scholar
A. Solankee and R. Tailor, “Synthesis, characterisation and biological screening of s-triazine based chalcones and its derivatization into phenyl pyrazolines, isoxazoles,” International Letters of Chemistry, Physics and Astronomy, vol. 47, pp. 109–119, 2015.
View at: Publisher Site | Google Scholar
S. D. Desai, K. R. Desai, K. H. Chikhalia, C. Pannecouque, and E. De Clercq, “Synthesis of a novel class of some 1, 3, 5-triazine derivatives and their anti-HIV activity,” International Journal of Drug Design and Discovery, vol. 2, pp. 361–368, 2011.
View at: Google Scholar
B. Liu, T. Sun, Z. Zhou, and L. Du, “A systematic review on antitumor agents with 1, 3, 5-triazines,” Medicinal Chemistry, vol. 5, pp. 131–148, 2015.
View at: Publisher Site | Google Scholar
A. Sharma, Y. Jad, H. Ghabbour et al., “Synthesis, crystal structure and DFT studies of 1,3-Dimethyl-5-propionylpyrimidine-2,4,6(1H,3H,5H)-trione,” Crystals, vol. 7, no. 1, p. 31, 2017.
View at: Publisher Site | Google Scholar
E. Giziroglu, M. Aygün, C. Sarikurkcu et al., “Synthesis, characterization and antioxidant activity of new dibasic tridentate ligands: X-ray crystal structures of DMSO adducts of 1,3-dimethyl-5-acetyl-barbituric acid o-hydroxybenzoyl hydrazone copper(II) complex,” Inorganic Chemistry Communications, vol. 36, pp. 199–205, 2013.
View at: Publisher Site | Google Scholar

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Copyright © 2017 Anamika Sharma et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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