Journal of Chemistry
Volume 2017 (2017), Article ID 5610707, 6 pages
https://doi.org/10.1155/2017/5610707

Research Article

Enaminonitrile as Building Block in Heterocyclic Synthesis: Synthesis of Novel 4H-Furo[2,3-d][1,3]oxazin-4-one and Furo[2,3-d]pyrimidin-4(3H)-one Derivatives

Manal M. El-Shahawi and Ahmed K. El-Ziaty

Chemistry Department, Faculty of Science, Ain Shams University, Abbasia, Cairo 11566, Egypt

Correspondence should be addressed to Manal M. El-Shahawi; elshahawi31@yahoo.com

Received 24 January 2017; Accepted 28 March 2017; Published 20 April 2017

Academic Editor: Xinyong Liu

Copyright © 2017 Manal M. El-Shahawi and Ahmed K. El-Ziaty. 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.

Abstract.

2-Amino-4,5-diphenylfuran-3-carbonitrile 1 was utilized as building block for the construction of new furo[2,3-d]pyrimidin-4(3H)-one derivative 2 and 4H-furo2,3-d 1,3oxazin-4-one derivative 3 via treatment with acetic anhydride and benzoyl chloride, respectively. The 4H-furo2,3-d 1,3oxazin-4-one derivative 3 was transformed into novel furo[2,3-d]pyrimidin-4(3H)-ones 4–8, tetrazolylfuran derivative 10, and furo[3,2-d]imadazolone derivative 11 via reaction with various nitrogen nucleophiles. The structure features of the synthesized compounds were established from their spectral and elemental analyses.

1. Introduction

Substituted and fused furans are one of the most important scaffolds in medicinal chemistry due to owning various biological activities including antimicrobial, antitumor, antiviral, antidepressant, and antihistaminic effects [1]. On the other hand, pyrimidines and fused pyrimidines represent an important class of heterocyclic compounds due to their biological activities [2–7]. Among the fused pyrimidines, the furopyrimidines attract the attention of the chemists due to possessing broad scope of pharmaceutical activities such as anticancer [8, 9], antiviral [10, 11], and antimicrobial [12] activities. There are great numbers of synthetic strategies for the preparation of furo2,3-d pyrimidines [10, 13–20]. Substituted 2-aminofuran-3-carbonitriles are known as easily obtainable starting material for synthesis of furo2,3-d pyrimidines using different reagents [13–16]. In the context of our sustained efforts to construct fused oxazine systems [21–23] and other heterocycles with potent antimicrobial activities [24–27], herein we reported the utility of 2-amino-4,5-diphenylfuran-3-carbonitrile [28] in synthesis of furo2,3-d 1,3oxazin-4-one and its transformation into different furo2,3-d pyrimidines and other heterocyclic systems via reactions with different nitrogen nucleophiles.

2. Experimental

Melting points were recorded on a Gallenkamp melting point apparatus. The FTIR spectra were run on a Pye Unicam SP 3-300 spectrometer. ¹H-NMR spectra were recorded on a JEOL ECA-500 (300 MHz) spectrometer; chemical shifts were expressed in part per million (ppm) against TMS as an internal standard. ¹³C-NMR spectra were run at 75.46 MHz. The MS spectra were measured on Agilent 5977A/MSD mass spectrometers (Agilent Technologies, USA) at 70 eV. Elemental analysis was performed by Vario EL-III elemental analysis.

2.1. 2,5,6-Triphenylfuro[2,3-d]pyrimidin-4(3H)-one 2

A mixture of amino carbonitrile 1 (3 g, 10 mmol) and benzoyl chloride (30 mL) was refluxed for 24 hrs. The excess solvent was distilled off and the remaining solid was crystallized from benzene to give 2 as brown crystals, m.p. 122–124°C, yield 49%. Anal. Calcd. for C₂₄H₁₆N₂O₂ (364.388): C, 79.11; H, 4.42; N, 7.69. Found: C, 79.07; H, 4.45; N, 7.65. IR (KBr, ν cm⁻¹): 3169 (NH), 1687 (CO). ¹H-NMR (DMSO-d₆) (ppm): 12.93 (s, 1H NH, exchangeable by D₂O), 7.92–7.44 (m, 15H, Ar-H); ¹³C-NMR (DMSO-d₆) δ (ppm): 167.87, 133.50, 130.99, 129.78, 129.12. MS m/z (%): 364 (M+∙, 100), 345 (10), 204 (9), 128 (15), 122 (18), 105 (42), 77 (40).

2.2. 2-Methyl-5,6-diphenyl-4H-furo[2,3-d][1,3]oxazin-4-one 3

A solution of amino carbonitrile 1 (3 g, 10 mmol) and freshly distilled acetic anhydride (30 mL) was heated under reflux for 24 hrs. The excess of acetic anhydride was removed and the remaining solid was crystallized from benzene to give 3 as gray crystals, m.p. 196–198°C, yield 55%. Anal. Calcd. for C₁₉H₁₃NO₃ (303.303): C, 75.24; H, 4.32; N, 4.62. Found: C, 75.20; H, 4.30; N, 4.65. IR (KBr, ν cm⁻¹): 1773 (CO). ¹H-NMR (DMSO-d₆) δ (ppm): 7.70–7.00 (m, 10H, Ar-H), 2.4 (s, 3H, CH₃); ¹³C- NMR (DMSO-d₆) δ (ppm): 167.68, 163.56, 156.18, 146.88, 145.68, 130.27, 129.44, 129.26, 129.16, 129.03, 128.83, 126.82, 21.90. MS m/z (%): 303 (M+∙, 100), 261 (96), 204 (18), 178 (14), 128 (28), 105 (31), 77 (33).

2.3. 3-Amino-2-methyl-5,6-diphenylfuro[2,3-d]pyrimidin-4-one 4

A mixture of furo2,3-d 1,3oxazinone 3 (1.5 g, 5 mmol) and hydrazine hydrate (0.25 mL, 5 mmol) was stirred at room temperature in absolute ethanol (30 mL) for 30 min. The solid produced was filtered off, dried, and then crystallized from dioxane to afford 4 as pale yellow crystals, m.p. 212–214°C, yield 87%. Anal. Calcd. for C₁₉H₁₅N₃O₂ (317.330): C, 71.92; H, 4.76; N, 13.24. Found: C, 71.95; H, 4.80; N, 13.27. IR (KBr, ν cm⁻¹): 3308, 3256 (NH₂), 1691 (CO). ¹H-NMR (DMSO-d₆) δ (ppm): 7.75–7.30 (m, 10H, Ar-H), 5.79 (s, 2H, NH₂, exchangeable by D₂O), 2.4 (s, 3H, CH₃). ¹³C-NMR (DMSO-d₆) δ (ppm): 161.76, 157.64, 157.48, 146.27, 131.10, 130.50, 129.50, 129.31, 128.92, 128.66, 126.72, 104.95, 22.45. MS m/z (%): 317 (M+∙, 100), 260 (9), 184 (15), 178 (4), 128 (4), 105 (13), 77 (12).

2.4. 2-Methyl-5,6-diphenylfuro[2,3-d]pyrimidin-4-one 5

A mixture of furo2,3-d 1,3oxazinone 3 (1.5 g, 5 mmol) in formamide (15 mL) was refluxed for 3 hrs. The reaction mixture, after cooling, was poured into ice/cold water and the separated solid was filtered off, dried, and crystallized from benzene to give 5, as pale yellow crystals, m.p. 225-226°C, yield 75%. Anal. Calcd. for C₁₉H₁₄N₂O₂ (302.317): C, 75.53; H, 4.67; N, 9.27. Found: C, 75.51; H, 4.64; N, 9.30. IR (KBr, ν cm⁻¹): 3474, (NH), 1676 (CO). ¹H-NMR (DMSO-d₆) δ (ppm): 12.63 (s, 1H, NH, exchangeable by D₂O), 7.50–7.29 (m, 10H, Ar-H), 2.4 (s, 3H, CH₃); ¹³C-NMR (DMSO-d₆) (ppm): 161.40, 151.96, 148.31, 129.95, 129.43, 129.25, 128.86, 74.51, 22.45. MS m/z (%): 302 (M+∙, 3), 288 (9), 271 (100), 256 (14), 216 (9), 189 (13), 105 (3), 77 (6).

2.5. 3-Hydroxy-2-methyl-5,6-diphenylfuro[2,3-d]pyrimidin-4-one 6

A solution of furo2,3-d 1,3oxazin-4-one 3 (1.5 g, 5 mmol) and hydroxylamine hydrochloride (0.34 g, 5 mmol) in pyridine (10 mL) was heated under reflux for 3 hrs. The reaction mixture was allowed to cool and then poured into ice/HCl. The obtained solid was filtered off, dried, and crystallized from benzene to give 6 as pale yellow crystals, m.p. 70–72°C, yield 77%. Anal. Calcd. for C₁₉H₁₄N₂O₃ (318.316): C, 71.69; H, 4.43; N, 8.80. Found: C, 71.65; H, 4.40; N, 8.83. IR (KBr, ν cm⁻¹): 3412, (br, OH), 1670 (CO). ¹H-NMR (DMSO-d₆) δ (ppm): 8.02–7.20 (m, 10H, Ar-H), 7.36 (s, 1H, OH, exchangeable by D₂O), 2.46 (s, 3H, CH₃); ¹³C-NMR (DMSO-d₆) δ (ppm): 167.19, 137.99, 134.21, 129.74, 129.40, 129.25, 128.54, 128.27, 49.91, 22.40. MS m/z (%): 318 (M+∙, 3), 317 (13), 286 (19), 271 (21), 236 (38), 231 (20), 189 (11), 105 (100), 77 (51).

2.6. 1-(2-Methyl-4-oxo-5,6-diphenylfuro[2,3-d]pyrimidin-3(4H)-yl)thiourea 7

A mixture of furo2,3-d 1,3oxazinone 3 (1.5 g, 5 mmol), thiosemicarbazide (0.45 g, 5 mmol), and acetic acid (15 mL) was heated under reflux for 4 hrs. The reaction mixture was concentrated and poured into ice/cold water. The formed solid was filtered off, washed with water, dried, and then crystallized from toluene to give 7 as violet crystals, m.p. 168–170°C, yield 50%. Anal. Calcd. for C₂₀H₁₆N₄O₂S (376.420): C, 63.82; H, 4.28; N, 14.88; S, 8.52. Found: C, 63.78; H, 4.32; N, 14.85; S, 8.55. IR (KBr, ν cm⁻¹): 3377, 3360, 3290 (NH, NH₂), 1672 (CO), 1179 (C=S). ¹H-NMR (DMSO-d₆) δ (ppm): 10.63 (s, 1H, NH, exchangeable by D₂O), 9.50 (s, 2H, NH₂, exchangeable by D₂O), 7.60–7.29 (m, 10H, Ar-H), 2.25 (s, 3H, CH₃). MS m/z (%): 376 (M+∙, 1), 304 (22), 303 (100), 261 (94), 204 (16), 178 (14), 128 (27), 105 (44), 77 (39).

2.7. 2-Methyl-5,6-diphenyl-3-p-tolylfuro[2,3-d]pyrimidin-4(3H)-one 8

A mixture of furo2,3-d 1,3oxazinone 3 (1.5 g, 5 mmol), p-toluidine (0.53 g, 10 mmol), and n-butanol (15 mL) was heated under reflux for 3 hrs. The reaction mixture was concentrated and the solid formed after cooling was filtered off, dried, and then crystallized from ethanol to afford 8 as brown crystals, m.p. 160–162°C, yield 50%. Anal. Calcd. for C₂₆H₂₀N₂O₂ (392.436): C, 79.58; H, 5.13; N, 7.14. Found: C, 79.53; H, 5.16; N, 7.14. IR (KBr, ν cm⁻¹): 1698 (CO). ¹H-NMR (DMSO-d₆) δ (ppm): 7.67–7.04 (m, 14H, Ar-H), 2.46 (s, 3H, CH₃). MS m/z (%): 392 (M+∙, 8), 373 (12), 368 (22), 337 (21), 302 (100), 261 (30), 206 (14), 178 (15), 128, (27), 105 (71), 77 (47).

2.8. 2-Acetamido-N-(4-aminophenyl)-4,5-diphenylfuran-3-carboxamide 9

A mixture of furo2,3-d 1,3oxazinone 3 (1.5 g, 5 mmol), p-phenylenediamine (0.54 g, 5 mmol), and dioxane (15 mL) was heated under reflux for 3 hrs. The reaction mixture was concentrated and the solid formed after cooling was filtered off, dried, and then crystallized from ethanol to afford 9 as yellow crystals, m.p. 200–202°C, yield 60%. Anal. Calcd. for C₂₅H₂₁N₃O₃ (411.437): C, 72.98; H, 5.14; N, 10.21. Found: C, 73.02; H, 5.16; N, 10.17. IR (KBr, ν cm⁻¹): 3401, 3324 (2NH), 1699 (br, CO). ¹H-NMR (DMSO-d₆) δ (ppm): 12.07 (s, 1H, NH, exchangeable by D₂O), 9.77 (s, 1H, NH, exchangeable by D₂O), 7.33–7.14 (m, 14H, Ar-H), 5.09 (s, 2H, NH₂ exchangeable by D₂O), 2.46 (s, 3H, CH₃). ¹³C-NMR (DMSO-d₆) δ (ppm): 163.55, 159.53, 146.92, 141.72, 133.84, 130.60, 130.46, 128.97, 128.66, 127.89, 127.32, 125.10, 124.65, 123.23, 114.36, 101.78, 66.89, 21.28. MS m/z (%): 411 (M+∙, 2), 337 (14), 302 (100), 261 (10), 189 (13), 178 (10), 128, (21), 105 (74), 77 (42).

2.9. Procedure for Preparation of 10 and 11

A mixture of furo2,3-d 1,3oxazinone 3 (1.5 g, 5 mmol) and sodium azide (0.65 g, 5 mmol) in glacial acetic acid (15 mL) was heated under reflux for 3 hrs. The reaction mixture was allowed to cool and then poured onto ice/cold water and the separated solid was filtered, washed with water, and dried. Fractional crystallization from ethanol gave tetrazole derivative 10 and the insoluble fraction was crystallized from dioxane to yield the imidazolone derivative 11.

2.9.1. 2-(5-Methyl-1H-tetrazol-1-yl)-4,5-diphenylfuran-3-carboxylic acid 10

White crystals; m.p. > 300°C, yield 35%. Anal. Calcd. for C₁₉H₁₄N₄O₃ (346.328): C, 65.89; H, 4.07; N, 16.18. Found: C, 65.92; H, 4.05; N, 16.14. IR (KBr, ν cm⁻¹): 3431 (br, OH, acid), 1669 (CO, acid). ¹H NMR (DMSO-d₆) δ (ppm): 11.25 (s, 1H, COOH, exchangeable by D₂O), 8.20–7.35 (m, 10H, Ar-H), 2.14 (s, 3H, CH₃). MS m/z (%): 346 (M+∙, 30), 301 (100), 273 (25), 128 (13), 105 (65), 77 (50).

2.9.2. 3-Acetyl-5,6-diphenyl-1H-furo[3,2-d]imidazol-2(3H)-one 11

Pale yellow crystals; m.p. > 300°C, yield 65%. Anal. Calcd. for C₁₉H₁₄N₂O₃ (318.316): C, 71.69; H, 4.43; N, 8.80. Found: C, 71.66; H, 4.46; N, 8.84. IR (KBr, ν cm⁻¹): 3262 (NH), 1746, 1668 (2CO). ¹H NMR (DMSO-d₆) δ (ppm): 11.98 (s, 1H, NH, exchangeable by D₂O), 7.95–7.06 (m, 10H, Ar-H), 2.45 (s, 3H, CH₃). MS m/z (%): 318 (M+∙, 26), 303 (70), 275 (100), 128 (30), 105 (78), 77 (45).

3. Results and Discussion

2-Amino-4,5-diphenylfuran-3-carbonitrile 1 [28] was used as precursor for the preparation of the target heterocyclic compounds. Thus, benzoylation of 1 using benzoyl chloride afforded 2,5,6-triphenylfuro2,3-d pyrimidin-4(3H)-one 2 as a sole product. The IR spectrum of 2 showed strong absorption bands at 3169 and 1687 cm⁻¹ corresponding to NH and CO groups, respectively. Moreover, the ¹H-NMR spectrum of 2 exhibited a singlet (exchangeable by D₂O) at δ 12.93 attributed to NH group. ¹³C-NMR spectrum of 2 displayed signals at δ of 167.87 ppm corresponding to CO of pyrimidinone ring. Formation of furo2,3-d pyrimidinone 2 is believed to proceed via benzoylation of the amino group and conversion of cyano group to the amide group, followed by 1,6-exo-trig cyclization of the amino group to the carbonyl group as formulated in Scheme 1. On the other hand, by treatment of 2-amino-4,5-diphenylfuran-3-carbonitrile 1 with freshly distilled acetic anhydride for 24 hours, the desired furo2,3-d 1,3oxazin-4-one 3 was formed via acetylation of the amino group and complete hydrolysis of cyano group to the acid group, followed by 1,6-exo-trig cyclization of enolated carbonyl group to acid group (Scheme 1). IR spectrum of 3 displayed absorption band at 1773 cm⁻¹ characteristic for CO group of oxazine ring; additionally, ¹³C-NMR spectrum of 3 showed signals at δ 167.68 and 21.90 ppm corresponding to CO of oxazine ring and CH₃, respectively.

Scheme 1

Oxazinone ring is very reactive semiacid anhydride ring and can be transformed into pyrimidinone ring via reaction with various nitrogen nucleophiles. Thus, stirring furo2,3-d 1,3oxazin-4-one 3 with hydrazine hydrate in ethanol yielded 3-amino-2-methyl-5,6-diphenylfuro2,3-d pyrimidin-4-one 4 (Scheme 2). IR spectrum of 4 exhibited absorption bands at 3308, 3256, and 1691 cm⁻¹ due to NH₂ and CO groups and ¹H-NMR (DMSO-d₆) showed signal at δ 5.79 ppm which disappeared by D₂O, confirming the presence of NH₂ group; also ¹³C-NMR spectrum of 4 revealed signal at δ 161.76 ppm due to CO of pyrimidinone ring. On the other hand, boiling furo2,3-d 1,3oxazin-4-one 3 with formamide afforded furo2,3-d pyrimidin-4-one derivative 5 (Scheme 2). Furthermore, furo2,3-d pyrimidin-4-one derivative 6 was obtained on reacting hydroxylamine hydrochloride and furo2,3-d 1,3oxazin-4-one 3 (Scheme 2). Spectral data supported the proposed structure 6 as IR spectrum exhibited bands at 3412 cm⁻¹ (br, OH) and 1670 cm⁻¹ (CO); also ¹H-NMR (DMSO-d₆) showed the appearance of band at δ 7.36 ppm which disappeared by D₂O, indicating the presence of OH group. Additionally, ¹³C-NMR spectrum of 6 exhibited signal at δ 167.19 ppm due to CO of pyrimidinone ring. Refluxing compound 3 with thiosemicarbazide in acetic acid for 4 hours yielded the thiourea derivative 7 (Scheme 2).

Scheme 2

On the other hand, when furo2,3-d 1,3oxazin-4-one 3 was allowed to react with p-toluidine in refluxing n-butanol the corresponding furo2,3-d pyrimidin-4-one derivative 8 was produced (Scheme 3). On the contrary, the reaction of 3 with p-phenylenediamine in boiling dioxane yielded the furancarboxamide derivative 9, whose structure was deduced from spectral and analytical data (Scheme 3). ¹H-NMR spectrum revealed signals at δ 12.07 (s, 1H, NH, exchangeable by D₂O), 9.77 (s, 1H, NH, exchangeable by D₂O), 7.33–7.14 (m, 14H, Ar-H), 5.09 (s, 2H, NH₂ exchangeable by D₂O), and 2.46 (s, 3H, CH₃). Moreover, ¹³C-NMR spectrum of 9 exhibited two signals at δ 163.55 and 159.53 ppm representing C=O of CH₃CONH and C=O of CONHAr, respectively.

Scheme 3

Reaction of furo2,3-d 1,3oxazinone 3 with sodium azide in boiling acetic acid furnished two products separated by fractional crystallization: tetrazolylfuran derivative 10 which was crystallized from ethanol and furo3,2-d imidazolone derivative 11 which was crystallized from dioxane (Scheme 3). Anomalous heteroring opening of oxazinone by azide was supposed to occur via nucleophilic attack of azide either at C-2 of oxazinone ring followed by ring opening and addition of azido group on cyano group to yield tetrazolylfuran derivative 10 or at C-4 of oxazinone followed by Curtius’s rearrangement to isocyanate intermediate and then cyclization to give furo3,2-d imidazolone derivative 11 as summarized at Scheme 4.

Scheme 4

4. Conclusion

A new series of furo2,3-d pyrimidin-4(3H)-one derivatives, 4H-furo2,3-d 1,3oxazin-4-one and heterosubstituted furan, has been synthesized and their chemical structures were confirmed by different spectral and elemental analyses. Similar to related compounds, the synthesized compounds are expected to have anticipated pharmaceutical and biological potentiality.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

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