An efficient synthesis of 3-alkyl-2-diversity-substituted benzofuro[3,2- d ]pyrimidin-4(3 H )-one derivatives

Abstract

Benzofuro[3,2-d]pyrimidine derivatives are prepared using aza-Wittig reactions of iminophosphoranes with n-butyl isocyanate at 40–50 °C to give carbodiimide intermediates, which are reacted with nitrogen-oxygen-containing nucleophiles to give 3-alkyl-2-amino (aryloxy/alkoxy)-benzofuro[3,2-d]pyrimidin-4(3H)-ones in satisfactory yields in the presence of a catalytic amount of sodium ethoxide or K₂CO₃. The iminophosphorane also reacts directly with excess carbon disulfide, followed by n-propylamine; further reaction with alkyl halides or halogenated aliphatic esters in the presence of anhydrous K₂CO₃ produces the corresponding 2-alkylthio-3-n-propyl-benzofuro[3,2-d]pyrimidin-4(3H)-ones in good yields. Their structures of the products are confirmed by ¹H NMR, ¹³C NMR, mass spectrometry, infrared and elemental analysis.

Introduction

Heterocyclic compounds containing nitrogen are an integral part of the chemical and life sciences and have attracted the attention of many researchers in order to explore their potential. Derivatives of benzofuro[3,2-d]pyrimidine, which are important heterocyclic moieties, have been considered as templates for drug discovery for many years and demonstrate a broad spectrum of biological activities including anti-inflammatory, antiviral, analgesic, antiproliferative and antimicrobial.^1–3 On the contrary, benzofuro[3,2-d]pyrimidine derivatives as bioisosters of quinazoline derivatives, such as the existing anticancer medicines gefitinib, erlotinib and tandutinib, have promoted a significant current interest in facile and general routes to these molecules in synthetically useful yields. Although some derivatives of benzofuropyrimidines have shown good analgesic, anti-inflammatory, antimicrobial, anticoccidial and blood sugar–lowering activities,^4–6 there are only a few reports on the synthesis of 3-alkyl-2-diversity-substituted benzofuro[3,2-d]pyrimidin-4(3H)-ones, which are of considerable interest as potential biologically active compounds or pharmaceuticals. The methods described for the preparation of some representative derivatives of this ring system involve the reaction of 3-amino-2-(ethoxycarbonyl)benzofurans with orthoformate and an amine, the rearrangement of benzofuro[3,2-d]oxazines by treatment with an amine or the cyclization of 3-amino-2-(aminocarbonyl)benzofuran with acyl chlorides.^7,8 However, 3-alkyl-2-diversity-substituted benzofuro[3,2-d]pyrimidin-4(3H)-ones are not easily accessible by currently existing routes.

An important application of the aza-Wittig reaction is for the synthesis of a plethora of heterocyclic compounds. In recent years, we have been interested in the preparation of derivatives of nitrogen heterocyclic compounds via aza-Wittig reactions under mild conditions. In continuation of our research, we herein report our efforts towards the design and synthesis of 3-alkyl-2-diversity-substituted benzofuro[3,2-d]pyrimidin-4(3H)-ones via aza-Wittig reactions.^9–13

Results and discussion

As described in detail previously, ¹⁴ the synthesis of the key intermediate 4 has been reported earlier. It was easily obtained by the reaction of compound 3 with Ph₃P and Et₃N in C₂Cl₆ under basic conditions (Scheme 1). The iminophosphorane 4 was subsequently reacted with n-butyl isocyanate at 40–50 °C to give carbodiimide 5, which was used directly without further purification.

Scheme 1.

Preparation of iminophosphorane 4 and carbodiimide 5.

The synthetic route used to synthesize the benzofuro[3,2-d]pyrimidin-4(3H)-one products is outlined in Scheme 2. The 3-n-butyl-2-morpholino(or piperidin-1-yl)-benzofuro[3,2-d]pyrimidin-4(3H)-ones 6a and 6b were obtained from carbodiimide 5 by reaction with morpholine and piperidine, respectively, followed by treatment with a catalytic amount of sodium ethoxide to give the desired products in satisfactory yields at room temperature. The 2-aryloxy-3-n-butyl-benzofuro[3,2-d]pyrimidin-4(3H)-ones 7a and 7b were obtained in good yields at 50–60 °C by treating carbodiimide 5 with different phenols in the presence of a catalytic amount of anhydrous K₂CO₃. The carbodiimide 5 was also allowed to react with aliphatic alcohols (R ³ OH) to give 2-alkoxy-3-n-butyl-benzofuro[3,2-d]pyrimidin-4(3H)-ones 8a and 8b in satisfactory yields in the presence of catalytic amounts of R ³ ONa.

Scheme 2.

Preparation of compounds 6a, 6b, 7a, 7b, 8a, and 8b.

In addition, we have found that the iminophosphorane 4 reacted directly with excess carbon disulfide over 24 h at 40–50 °C, which was followed by reaction with n-propylamine. Further treatment with alkyl halides or halogenated aliphatic esters in the presence of anhydrous K₂CO₃ produced 2-alkylthio-3-n-propyl-benzofuro[3,2-d]pyrimidin-4(3H)-ones 9a-d in good yield (Scheme 3).

Scheme 3.

Preparation of compounds 9a-d.

The structures of the products were established based on their ¹H NMR, ¹³C NMR, mass spectrometry (MS), infrared (IR) and elemental analysis. For example, the ¹H NMR spectral data of 8a show signals for the –OCH₂ and NCH₂CH₂CH₂ groups at 4.64–4.59 and 4.18–1.37 ppm as multiplets, and the CH₃ at 1.49 and 0.97 ppm as triplets. The phenyl signals appeared at 7.97–7.36 ppm. In the IR spectrum of compound 8a, a strong stretching vibration due to the C=O appeared at 1703 cm⁻¹. The MS spectrum of 8a shows a molecular ion peak (M⁺) at m/z 286 with 50% abundance.

Conclusion

In conclusion, we have developed an efficient synthesis of 3-alkyl-2-diversity-substituted benzofuro[3,2-d]pyrimidin-4(3H)-ones in good yields via aza-Wittig reaction of iminophosphorane 4. Due to the easily accessible and versatile starting materials, mild reaction conditions, good yields and wide range of substituents, this method is expected to serve as a new tool for preparing many biologically and pharmaceutically active 3-alkyl-2-diversity-substituted benzofuro[3,2-d]-pyrimidin-4(3H)-ones.

Experimental

General

Melting points were recorded using an uncorrected X-4 digital melting point apparatus. MS were measured by using a Finnigan Trace MS spectrometer. IR were recorded on a PE-983 infrared spectrometer as KBr pellets with absorptions in cm⁻¹. ¹H NMR and ¹³C NMR were recorded in CDCl₃ (or DMSO-d₆) using a Varian Mercury 400 spectrometer with resonances relative to tetramethylsilane (TMS) as an internal standard. Elemental analyses were recorded on a PerkinElmer CHN 2400 instrument.

Preparation of ethyl 3-((butylimino)methyleneamino)benzofuran-2-carboxylate (5)

A mixture of compound 4 (0.93 g, 2 mmol) and n-butyl isocyanate (2.2 mmol) was stirred for 20–24 h at 40–50 °C under N₂. The solvent was removed under reduced pressure to give carbodiimide 5, which was used directly without further purification.

Preparation of compounds 6a and 6b

To a solution of 5 prepared above in CH₂Cl₂ (5 mL), morpholine or piperidine was added (2 mmol). After stirring for 0.5–1 h, the solution was condensed and anhyd. EtOH (8 mL) with EtONa (0.3 mmol, 10% equivalents) in EtOH were added. The mixture was stirred for 6–8 h at room temperature. The solution was evaporated and the residue was recrystallized from EtOH to give 6a or 6b.

3-butyl-2-morpholino-benzofuro[3,2-d]pyrimidin-4(3H)-one (6a)

White crystals (86% yield), m.p.: 168–170 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.02–8.00 (m, 1H, ArH), 7.64–7.56 (m, 2H, ArH), 7.42–7.40 (m, 1H, ArH), 4.25–4.21 (m, 2H, NCH₂), 3.90–3.88 (m, 4H, 2 × CH₂), 3.24–3.22 (m, 4H, 2 × CH₂), 1.78–1.74 (m, 2H, CH₂), 1.36–1.32 (m, 2H, CH₂), 0.96 (t, J = 7.2 Hz, 3H, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 157.2, 157.1, 154.8, 142.0, 136.8, 129.4, 123.7, 122.8, 121.5, 112.9, 66.5, 51.4, 44.8, 30.7, 20.1, 13.8. IR (KBr) 1702 (C=O) cm⁻¹. MS m/z (%) = 327 (M⁺, 50), 285 (100), 243 (41), 186 (65), 130 (28). Anal. calcd for C₁₈H₂₁N₃O₃ (327.4): C, 66.04; H, 6.47; N, 12.84; found: C, 66.00; H, 6.50; N, 12.87.

3-butyl-2-(piperidin-1-yl)-benzofuro[3,2-d]pyrimidin-4(3H)-one (6b)

White crystals (82% yield), m.p.: 176–178 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.01–7.99 (m, 1H, ArH), 7.65–7.42 (m, 3H, ArH), 4.24–4.20 (m, 2H, NCH₂), 3.15–3.12 (m, 4H, 2 × CH₂N), 1.78–1.75 (m, 2H, CH₂), 1.45–1.22 (m, 8H, 4 × CH₂), 0.98 (t, J = 7.2 Hz, 3H, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 157.2, 157.1, 154.8, 142.0, 136.8, 129.4, 123.7, 122.8, 121.5, 112.9, 66.5, 46.2, 32.5, 30.7, 25.3, 20.1, 13.8. IR (KBr) 1701 (C=O) cm⁻¹. MS m/z (%) = 325 (M⁺, 68), 285 (100), 186 (54), 130 (43). Anal. calcd for C₁₉H₂₃N₃O₂ (325.4): C, 70.13; H, 7.12; N, 12.91; found: C, 70.09; H, 7.15; N, 12.88.

Preparation of compounds 7a and 7b

To a solution of 5 (2 mmol) in CH₃CN (5 mL), K₂CO₃ (0.3 g, 2 mmol) and ArOH (2.1 mmol) in anhydrous CH₃CN (10 mL) were added. The mixture was stirred for 6–8 h at 50–60 °C. The solution was concentrated under reduced pressure and the residue was recrystallized from C₂H₅OH/CH₂Cl₂ (1:2, v/v) to 7a or 7b.

2-(p-tolyloxy)-3-butyl-benzofuro[3,2-d]pyrimidin-4(3H)-one (7a)

White crystals (75% yield), m.p.: 185–187 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 7.83–7.82 (m, 1H, ArH), 7.61–7.59 (m, 1H, ArH), 7.53–7.49 (m, H, ArH), 7.32–7.28 (m, 3H, ArH), 7.17–7.14 (m, 2H, ArH), 4.36–4.32 (m, 2H, NCH₂), 2.43 (s, 3H, Ar-CH₃), 1.88–1.82 (m, 2H, CH₂), 1.53–1.44 (m, 2H, CH₂), 1.00 (t, J = 7.2 Hz, 3H, CH₃). ¹³C NMR (100 MHz, DMSO-d₆): δ = 157.2, 154.0, 153.6, 141.5, 135.8, 135.7, 130.2, 139.4, 123.4, 122.6, 121.8, 121.2, 112.8, 42.5, 30.7, 21.0, 20.1, 13.8. IR (KBr) 1701 (C=O) cm⁻¹. MS (70 eV) m/z (%) = 348 (M⁺, 58), 265 (100), 185 (28), 121(38). Anal. calcd for C₂₁H₂₀N₂O₃ (348.4): C, 72.40; H, 5.79; N, 8.04; found: C, 72.36; H, 5.83; N, 8.00.

2-(4-methoxyphenoxy)-3-butyl-benzofuro[3,2-d]pyrimidin-4(3H)-one (7b)

White crystals (78% yield), m.p.: 179–181 °C. ¹H NMR (400 MHz, DMSO-d₆): δ = 7.84–7.82 (m, 1H, ArH), 7.61–7.50 (m, 2H, ArH), 7.32–7.28 (m, 1H, ArH), 7.21–7.17 (m, 2H, ArH), 7.01–6.97 (m, 2H, ArH), 4.36–4.32 (m, 2H, NCH₂), 3.87 (s, 3H, CH₃), 1.88–1.80 (m, 2H, CH₂), 1.52–1.47 (m, 2H, CH₂), 1.00 (t, J = 7.2, 3H, CH₃). ¹³C NMR (100 MHz, DMSO-d₆): δ = 157.4, 157.2, 154.2, 153.6, 145.5, 141.5, 135.7, 129.4, 123.5, 122.6, 122.4, 121.8, 114.6, 112.8, 55.7, 42.5, 30.7, 20.1, 13.8. IR (KBr) 1705 (C=O) cm⁻¹. MS (70 eV) m/z (%) = 364 (M⁺, 22), 250 (100), 185 (56), 130 (60). Anal. calcd for C₂₁H₂₀N₂O₄ (364.4): C, 69.22; H, 5.53; N, 7.69; found: C, 69.16; H, 5.50; N, 7.63.

Preparation of compounds 8a and 8b

To a solution of 5 (ca. 2 mmol) prepared above in anhydrous ROH (8 mL), RONa (0.2 mmol, 10% equivalents) in ROH was added. The mixture was stirred for 8–10 h at room temperature. The solvent was evaporated under reduced pressure and the residue was recrystallized to give 8a or 8b.

3-butyl-2-ethoxy-benzofuro[3,2-d]pyrimidin-4(3H)-one (8a)

White crystals (80% yield), m.p.: 113–114 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.97–7.95 (m, 1H, ArH), 7.62–7.52 (m, 2H, ArH), 7.39–7.36 (m, 1H, ArH), 4.64–4.59 (m, 2H, NCH₂), 4.18–4.14 (m, 2H, CH₂), 1.74–1.70 (m, 2H, CH₂), 1.49 (t, J = 7.2 Hz, 3H, CH₃), 1.46-1.37 (m, 2H, CH₃), 0.97 (t, J = 7.2 Hz, 3H, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 157.2, 154.2, 153.8, 141.7, 135.3, 129.2, 123.4, 122.9, 121.4, 112.9, 65.2, 41.8, 30.4, 20.1, 14.3, 13.8. IR (KBr) 1703 (C=O) cm⁻¹. MS m/z (%) = 286 (M⁺, 50), 269 (100), 215 (81), 186 (98), 159 (69). Anal. calcd for C₁₆H₁₈N₂O₃ (286.3): C, 67.12; H, 6.34; N, 9.78; found: C, 67.08; H, 6.30; N, 9.75.

2-butoxy-3-butyl-benzofuro[3,2-d]pyrimidin-4(3H)-one (8b)

White crystals (68% yield), m.p.: 96–98 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.98–7.96 (m, 1H, ArH), 7.63–7.60 (m, 2H, ArH), 7.58–7.52 (m, 1H, ArH), 4.57–4.54 (m, 2H, NCH₂), 4.18–4.14 (m, 2H, CH₂), 1.88–1.81 (m, 2H, CH₂), 1.74–1.76 (m, 2H, CH₂), 1.57–1.39 (m, 4H, 2 × CH₂), 1.03 (t, J = 7.2 Hz, 3H, CH₃), 0.97 (t, J = 7.2 Hz, 3H, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 157.2, 154.4, 153.8, 141.7, 135.3, 129.2, 123.4, 122.9, 121.4, 112.9, 69.0, 41.8, 30.7, 30.4, 20.1, 19.3, 13.8, 13.7. IR (KBr) 1707 (C=O) cm⁻¹. MS m/z (%) = 314 (M⁺, 1), 264 (100), 185 (85), 130 (69). Anal. calcd for C₁₈H₂₂N₂O₃ (314.4): C, 68.77; H, 7.05; N, 8.91; found: C, 68.76; H, 7.10; N, 8.93.

Preparation of compounds of 9a-d

To a solution of iminophosphorane 4 (9.30 g, 20 mmol) in dry CH₂Cl₂ and CH₃CN (20 mL, v/v = 1:1), excess carbon disulfide (15 mL) was added. After the reaction mixture was refluxed for 24–28 h, the solvent was condensed under reduced pressure and ether (10 mL) was added to precipitate triphenylphosphine sulphide. The precipitate was removed by filtration, and the filtrate was followed by reaction with n-propylamine (20 mmol) directly without further purification. The mixture was stirred for 2 h at room temperature and the obtained white precipitate was filtered to give 3-propyl-2-thioxo-2,3-dihydrobenzofuro[3,2-d]pyrimidin-4(1H)-one, which was used directly without further purification.

To a solution of 3-propyl-2-thioxo-2,3-dihydrobenzofuro[3,2-d]pyrimidin-4(1H)-one (2 mmol) in dry DMF (5 mL), alkyl halide (2 mmol) and solid potassium carbonate (0.28 g, 2 mmol) were added. The mixture was stirred for 5–6 h at 50–60 °C. The solution was cooled and diluted with water (20 mL). The solid product obtained was filtered and recrystallized from CH₂Cl₂/petroleum ether to give 2-alkylthio-benzofuro[3,2-d]pyrimidin-4(3H)-ones 9a-d in good yield. ¹⁵