A Practical Synthesis of Near-Infrared Benzannulated Xanthenoid Dyes

Jin Li and Ruwei Wei contributed equally.

Abstract

Near-infrared dyes are sought after for their potential in biomedical applications. Benzoxanthene dyes with a non-oxygen bridging atom are expected to exhibit longer absorption and emission wavelengths than their oxygen-containing counterparts, yet their synthesis remains unaddressed. Herein, we report the first syntheses of non-oxygen-bridged benzoxanthenes starting from a 7-bromo-2-aminonaphthalene derivative, and discuss their photophysical properties as well as their potential for in vivo imaging.

Key words

fluorescence - near-infrared - benzoxanthene - stability - synthesis

Publication History

Received: 31 March 2023

Accepted after revision: 22 May 2023

Article published online:
07 August 2023

• References and Notes

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• 47 Compound 4 DMF (1.64 mL, 21 mmol, 1.2 equiv.) was mixed with 1,2-dichloroethane (10 mL) and cooled to 0 °C before dropwise addition of POCl₃ (1.98 mL, 21 mmol, 1.2 equiv.) and stirring for 30 min. The resulting mixture was added to a solution of compound 3 (3.5 g, 10 mmol, 1 equiv.) in anhydrous CH₂Cl₂ (10 mL) at 75 °C , and the obtained mixture was stirred for 3 h. The reaction was allowed to cool to the R.T. and quenched by adding saturated Na₂CO₃ solution. The aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL), and the combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The crude extract was purified by column chromatography (EtOAc/PE = 1:50 to 1:25, v/v) to give 4 (2.2 g, 39%) as a yellow solid. Mp 106.9–108.0 °C. ¹H NMR (400 MHz, CDCl₃): δ = 10.35 (s, 1 H), 8.24 (s, 1 H), 7.89 (s, 1 H), 7.66 (d, J = 9.2 Hz, 1 H), 7.11 (d, J = 9.2 Hz, 1 H), 3.69–3.56 (m, 4 H), 3.47–3.35 (m, 2 H), 2.98 (t, J = 6.5 Hz, 2 H), 2.11 (dd, J = 12.6, 5.2 Hz, 4 H). ¹³C NMR (101 MHz, CDCl₃): δ = 191.76, 146.02, 137.14, 132.32, 130.07, 125.98, 125.59, 124.30, 122.17, 115.65, 111.19, 49.59, 49.00, 42.50, 30.09, 23.44, 21.45. HRMS (ESI): m/z [M]⁺ calcd for C₁₇H₁₇BrClNO: 336.0255; found 336.0254.
• 48 Compound 5 Compound 4 (1 g, 2.8 mmol, 1 equiv.) was dissolved in anhydrous THF (20 mL) under an argon atmosphere and cooled to 0 °C before o-tolylmagnesium bromide (5.45 mL, 5.6 mmol, 2 equiv.) was added dropwise. The reaction was quenched after 30 min. Then the reaction was quenched with saturated NH4Cl aqueous solution (50 mL), and extracted with EtOAc (3 × 20 mL). The organic layer was combined, dried over anhydrous Na₂SO₄, filtered and evaporated to a yellow residue. The crude product was purified by column chromatography (PE/CH₂Cl₂ = 6:1, v/v) to yield 5 (1.18 g, 98%) as a white solid. Mp 101.0–102.4 °C. ¹1H NMR (400 MHz, CDCl₃) δ 7.94 (s, 1H), 7.53 (s, 1H), 7.45 (d, J = 9.1 Hz, 1H), 7.31 (d, J = 7.4 Hz, 1H), 7.18 (dd, J = 15.7, 7.4 Hz, 3H), 7.04 (d, J = 9.1 Hz, 1H), 6.32 (s, 1H), 3.61 (t, J = 6.1 Hz, 2H), 3.51 (td, J = 6.8, 3.2 Hz, 2H), 3.31 (dd, J = 6.2, 4.8 Hz, 2H), 2.95 (t, J = 6.5 Hz, 2H), 2.36 (s, 1H), 2.29 (s, 3H), 2.10 – 2.01 (m, 4H). ¹³C NMR (101 MHz, CDCl₃) δ 143.57, 140.40, 136.10, 134.19, 133.95, 130.44, 128.16, 127.66, 127.61, 126.49, 126.05, 125.51, 125.36, 122.38, 115.52, 111.65, 72.17, 49.48, 49.22, 42.82, 30.15, 23.63, 21.75, 19.24. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₆BrClNO: 458.0881; found: 458.0882.
• 49 Compound 7 Compound 5 (2 g, 2.25 mmol, 1 equiv.), 8-bromo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline (6) (0.68 g, 2.7 mmol, 1.2 equiv.) and H₂SO₄ (0.5 mL) (catalytic quantity) were dissolved in AcOH (20 mL) and the resulting mixture was stirred at 70 °C for 8 h. The reaction was allowed to cool to R.T. and quenched by adding saturated NaHCO₃ solution (30 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL), and the combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/CH₂Cl₂ = 8:1, v/v) to give 7 (2 g, 73%) as a white solid. Mp 156–157 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.39 (d, J = 9.1 Hz, 1H), 7.17 – 7.11 (m, 2H), 7.09 – 6.98 (m, 3H), 6.73 (d, J = 7.6 Hz, 1H), 6.22 (s, 1H), 6.16 (s, 1H), 3.63 (t, J = 6.1 Hz, 2H), 3.53 (t, J = 6.9 Hz, 2H), 3.36 – 3.29 (m, 2H), 3.10 (s, 4H), 2.98 (t, J = 6.5 Hz, 2H), 2.80 (t, J = 6.6 Hz, 2H), 2.55 (t, J = 6.1 Hz, 2H), 2.21 (s, 3H), 2.07 (dt, J = 12.8, 6.3 Hz, 4H), 2.04 – 1.90 (m, 4H). ¹³C NMR (101 MHz, CDCl₃): δ = 143.17, 143.15, 141.64, 137.19, 135.52, 133.31, 130.28, 130.19, 129.09, 129.00, 128.91, 127.37, 126.69, 126.30, 125.62, 125.56, 125.49, 125.49, 121.56, 120.17, 115.25, 111.81, 52.95, 50.14, 49.61, 49.54, 49.29, 42.89, 30.23, 29.63, 27.73, 23.74, 22.33, 22.00, 21.89, 19.78. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₆H₃₈Br₂ClN₂: 691.1085; found: 691.1091.
• 50 EC4 Compound 7 (R¹ = H, R² = Me) (0.2 g, 0.29 mmol, 1 equiv.) was dissolved in anhydrous THF (10 mL) under an argon atmosphere and cooled to –78 °C before sec-BuLi (0.49 mL, 1.3 M in hexane, 0.64 mmol, 2.2 equiv.) was added dropwise. After stirring for 30 min, the mixture was added to a solution of methyl 2-phenoxybenzoate (0.13 g, 0.58 mmol, 2 equiv.) in THF (10 mL), and stirring was continued at 0 °C for 30 min. The reaction was quenched by adding saturated NH₄Cl aqueous solution (50 mL), and extracted with EtOAc (3 × 20 mL). The organic layer was combined, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo The crude residue from concentrating the organic extract was dissolved in CH₂Cl₂ (20 mL) containing MeSO₃H (1 mL). After 2 h, chloranil (0.1 g) was added and the mixture was stirred for 4 h. The aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL), and the combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo The residue was purified by column chromatography (CH₂Cl₂/MeOH = 10:1, v/v) to give EC4 (50 mg, 25%) as a green solid. Mp 209.7–209.9 °C. ¹H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.3 Hz, 1H), 7.49 (d, J = 7.4 Hz, 2H), 7.40 (s, 1H), 7.30 (dd, J = 10.5, 6.8 Hz, 5H), 7.23 (s, 1H), 6.92 (d, J = 8.7 Hz, 3H), 6.88 (s, 1H), 6.78 (d, J = 7.2 Hz, 1H), 6.73 (d, J = 7.9 Hz, 1H), 3.87 (s, 2H), 3.62 (s, 2H), 3.55 (t, J = 6.1 Hz, 4H), 3.38 – 3.30 (m, 2H), 2.69 (t, J = 5.6 Hz, 2H), 2.60 (t, J = 6.4 Hz, 2H), 2.21 (s, 3H), 2.14 (dd, J = 15.9, 8.2 Hz, 2H), 2.01 (dd, J = 12.9, 6.5 Hz, 4H), 1.98 – 1.93 (m, 2H), 1.50 (d, J = 4.9 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 161.55, 156.10, 149.55, 148.64, 148.61, 147.38, 147.24, 136.07, 134.98, 134.76, 130.83, 130.67, 129.49, 128.99, 127.69, 127.38, 126.83, 124.83, 124.53, 117.13, 117.04, 115.48, 112.58, 53.89, 52.56, 48.99, 47.54, 42.26, 30.00, 27.45, 25.28, 22.76, 21.18, 20.22, 19.79, 19.54. HRMS (ESI): m/z [M]⁺ calcd for C₄₉H₄₄ClN₂O: 711.3137; found: 711.3132.
• 51 ESi4 Compound 7 (R¹ = H, R² = Me) (0.2 g, 0.29 mmol, 1 equiv.) was dissolved in anhydrous THF (10 mL) under an argon atmosphere and cooled to –78 °C before sec-BuLi (0.49 mL, 1.3 M in hexane, 0.64 mmol, 2.2 equiv.) was added dropwise. After stirring for 30 min, the resulting mixture was added to a solution of dichlorodimethylsilane (0.05 mL, 0.44 mmol, 1.5 equiv.) in THF (10 mL) and the obtained mixture was stirred at 0 °C for 30 min. The reaction was quenched by adding saturated NH₄Cl aqueous solution and extracted with EtOAc (3 × 20 mL). The organic layer was combined, dried over anhydrous Na₂SO₄, filtered and evaporated to a yellow residue. The residue from the organic extract was dissolved in CH₂Cl₂ (20 mL) containing chloranil (0.1 g) and the mixture was stirred for 4 h. The aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL), and the combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (CH₂Cl₂/MeOH = 10:1, v/v) to give ESi4 (100 mg, 58%) as a green solid. Mp 241.5–241.9 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.37 (d, J = 7.7 Hz, 2H), 7.33 (d, J = 9.2 Hz, 2H), 7.12 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 9.2 Hz, 1H), 6.80 (s, 1H), 3.99 (d, J = 17.2 Hz, 4H), 3.71 – 3.58 (m, 4H), 3.53 – 3.47 (m, 2H), 3.11 (dd, J = 13.2, 6.4 Hz, 4H), 2.57 (s, 2H), 2.23 (s, 2H), 2.13 (dd, J = 12.7, 5.9 Hz, 4H), 2.03 (s, 3H), 2.03 – 1.97 (m, 2H), 0.70 (s, 3H), 0.67 (s, 3H). ¹³NMR (151 MHz, CDCl3) δ 165.69, 153.32, 147.51, 143.76, 140.14, 139.17, 138.95, 136.09, 135.66, 134.47, 133.94, 131.70, 130.29, 129.62, 129.54, 128.77, 126.47, 125.96, 125.71, 115.51, 113.32, 53.62, 52.94, 49.84, 49.15, 42.35, 31.44, 29.99, 28.70, 27.43, 23.27, 20.90, 20.44, 19.58, 0.24, 0.21.
• 52 EP4 Compound 7 (R¹/R² = Me) (0.2 g, 0.29 mmol, 1 equiv.) was dissolved in anhydrous THF (10 mL) under an argon atmosphere and cooled to –78 °C before sec-BuLi (0.49 mL, 1.3 M in hexane, 0.64 mmol, 2.2 equiv.) was added dropwise. After stirring for 30 min, the resulting mixture was added to a solution of dichlorophenylphosphine (0.17 g, 0.7 mmol, 2 equiv.) in THF (10 mL) and the obtained mixture was stirred at 0 °C for 30 min. The reaction was quenched by adding saturated NH₄Cl aqueous solution and extracted with EtOAc (3 × 20 mL). The organic layer was combined, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The organic residue was dissolved in CH₂Cl₂ (20 mL) containing chloranil (0.1 g) and the mixture was stirred for 4 h. The aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL), and the combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo The residue was purified by column chromatography (CH₂Cl₂/MeOH = 10:1, v/v) to give EP4 (51 mg, 21%) as a green solid. Mp 248.8–249.5 °C. ¹H NMR (600 MHz, CDCl₃) δ 8.26 (d, J = 16.0 Hz, 1H), 7.72 (dd, J = 12.6, 7.5 Hz, 2H), 7.53 (d, J = 6.9 Hz, 1H), 7.49 (d, J = 5.2 Hz, 2H), 7.43 – 7.37 (m, 2H), 7.25 (d, J = 7.2 Hz, 3H), 7.10 (d, J = 9.3 Hz, 1H), 6.76 (d, J = 5.0 Hz, 1H), 4.30 (d, J = 12.4 Hz, 1H), 4.07 (d, J = 12.9 Hz, 1H), 3.83 (s, 2H), 3.76 (d, J = 15.0 Hz, 1H), 3.67 (d, J = 7.1 Hz, 2H), 3.61 (t, J = 5.8 Hz, 2H), 3.49 (dd, J = 10.6, 5.2 Hz, 2H), 3.09 (dd, J = 19.3, 9.6 Hz, 1H), 2.97 – 2.90 (m, 1H), 2.80 – 2.68 (m, 2H), 2.60 (d, J = 8.6 Hz, 1H), 2.10 (s, 3H), 2.10 – 2.02 (m, 8H), 2.02 (s, 3H). ¹³C NMR (151 MHz, CDCl3) δ 160.64, 154.11, 148.82, 137.30, 137.24, 136.67, 136.43, 136.13, 135.94, 135.78, 134.35, 134.26, 133.87, 133.16, 132.49, 130.05, 129.98, 129.39, 129.31, 128.72, 128.13, 128.00, 127.82, 126.99, 125.80, 116.70, 115.69, 54.16, 52.94, 49.98, 49.22, 42.23, 29.90, 29.70, 27.38, 25.67, 25.62, 23.17, 22.62, 20.91, 19.93. ³¹P NMR (243 MHz, CDCl₃): δ = 8.07. HRMS (ESI): m/z [M]⁺ calcd for C₄₃H₄₃ClN₂OP: 669.2796; found: 669.2797. The exact mass calculated with the ChemDraw for EP4 is 669.2797.
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