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Cite this: Org. Biomol. Chem., 2014, 12, 3887
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Synthesis and properties of chemiluminescent acridinium ester labels with fluorous tags† Anand Natrajan,* David Wen and David Sharpe Acridinium dimethylphenyl esters are highly sensitive chemiluminescent labels that are used in clinical diagnostics. Light emission from these labels is triggered with alkaline peroxide in the presence of the cationic surfactant cetyltrimethylammonium chloride (CTAC). CTAC compresses emission times of these labels to 90% aqueous media using a PR-740 spectroradiometer (camera) on loan from Photo Research Inc. Bandwidth slit: 2 nm; aperture: 2 degrees; exposure time: 5000 ms.
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Org. Biomol. Chem., 2014, 12, 3887–3901 | 3897
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10 → 90% MeCN–water (each with 0.05% TFA). The HPLC fractions were concentrated under reduced pressure. Yield = 84 mg (80%). δH (500 MHz, CD3COOD) 2.69 (s, 6H), 2.86–2.96 (m, 2 H), 2.99–3.13 (m, 2H), 3.63 (m, 2H), 4.80 (t, 2H, J = 6.2 Hz), 6.02 (m, 2H), 7.98 (d, 1H, J = 2.7 Hz), 8.15 (m, 2H), 8.30 (dd, 1H, J = 8.8 Hz, 6.7 Hz), 8.45 (dd, 1H, J = 10.0 Hz, 2.8 Hz), 8.66 (m, 1H), 8.78 (dd, 1H, J = 8.8 Hz, 1.3 Hz), 9.15 (d, 1H, J = 9.4 Hz), 9.22 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.95 (t, 3F, J = 9.8 Hz), −113.88 (m, 2F), −124.93 (m, 2F), −126.57 (m, 2F). MALDI-TOF MS m/z 756.2 (M + H)+; HRMS m/z (M + H)+ 756.1304 (756.1314 calculated). Compounds 3b and 3c were synthesized similarly. Compound 3b. Yield = 38 mg (67%). δH (500 MHz, CD3COOD) 2.67 (s, 6H), 2.80–2.93 (m, 2H), 2.98–3.10 (m, 2H), 3.57–3.64 (m, 2H), 4.78 (t, 2H, J = 6.2 Hz), 6.00 (t, 2H, J = 9.5 Hz), 7.97 (d, 1H, J = 2.8 Hz), 8.13 (s, 2 H), 8.28 (dd, 1H, J = 8.8 Hz, 6.7 Hz), 8.44 (m, 1H), 8.64 (m, 1H), 8.76 (dd, 1H, J = 8.8 Hz, 1.3 Hz), 9.13 (d, 1H, J = 9.4 Hz), 9.21 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.70 (t, 3F, J = 10.1 Hz), −113.60 (m, 2F), −122.33 (m, 2F), −123.37 (m, 2F), −123.92 (m, 2F), −126.70 (m, 2F). MALDI-TOF MS m/z 856.2 (M + H)+; HRMS m/z 856.1249 (M + H)+ (856.1250 calculated). Compound 3c. Yield = 20 mg (36%). δH (500 MHz, CD3COOD) 2.67 (s, 6H), 2.83–2.94 (m, 2H), 2.98–3.13 (m, 2H), 3.60 (m, 2H), 4.78 (t, 2H, J = 6.2 Hz), 6.00 (m, 2H), 7.96 (d, 1H, J = 2.7 Hz), 8.13 (s, 2H), 8.27 (dd, 1H, J = 8.8 Hz, 6.7 Hz), 8.43 (dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.63 (m, 1H), 8.76 (dd, 1H, J = 8.8 Hz, 1.3 Hz), 9.13 (d, 1H, J = 9.4 Hz), 9.20 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.67 (t, 3F, J = 10.0 Hz), −113.57 (m, 2F), −121.11 (m, 2F), −122.36 (m, 4F), −123.22 (m, 2F), −123.85 (m, 2F), −126.68 (m, 2F). MALDI-TOF MS m/z 956.1 (M + H)+; HRMS m/z 956.1197 (M + H)+ (956.1186 calculated). Compound 4a. Compound 3a (60 mg, 0.079 mmol) was suspended in DMF (3 mL) and diisopropylethylamine (0.021 mL, 0.119 mmol) and N,N,N′,N′-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (TSTU, 29 mg, 0.095 mmol) were added. The reaction was stirred at room temperature for 1 hour and was then added drop wise to a stirred solution of iv (170 mg, 0.397 mmol, HBr salt) dissolved in 0.5 M sodium bicarbonate (3 mL) cooled in an ice bath. After 16 hours, the reaction mixture was purified by preparative HPLC as described earlier using a 40 minute gradient 10 → 40% MeCN–water (each with 0.05% TFA). The HPLC fractions containing product 4a were concentrated under reduced pressure. Yield = 60 mg (75%). δH (500 MHz, CD3COOD) 2.28–2.39 (m, 2H), 2.39–2.52 (m, 4H), 2.55 (s, 6H), 2.78–2.86 (m, 2H), 2.96–3.10 (m, 2H), 3.21 (m, 2H), 3.27 (s, 3H), 3.40 (t, 2H, J = 7.2 Hz), 3.56 (m, 2H), 3.59–3.72 (m, 4H), 3.72–3.83 (m, 4H), 4.70 (t, 2H, J = 6.1 Hz), 5.92 (m, 2H), 7.76 (d, 1H, J = 2.7 Hz), 7.91 (s, 2H), 8.23 (dd, 1H, J = 8.8 Hz, 6.7 Hz), 8.39 (dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.59 (m, 2H), 9.09 (d, 1H, J = 9.8 Hz), 9.15 (d, 1H, J = 10.0 Hz); δF (470 MHz, CD3COOD) −81.92 (t, 3F, J = 9.9 Hz), −113.91 (m, 2F), −124.94 (m, 2F), −126.54 (m, 2F). MALDI-TOF MS m/z 1005.4 (M + H)+; HRMS m/z 1005.2835 (M + H)+ (1005.2825 calculated).
3898 | Org. Biomol. Chem., 2014, 12, 3887–3901
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Compounds 4b and 4c were synthesized similarly. Compound 4b. Yield = 23 mg (59%). δH (500 MHz, CD3COOD) 2.32–2.42 (m, 2H), 2.42–2.52 (m, 4H), 2.53 (s, 6H), 2.73–2.88 (m, 2H), 2.97–3.15 (m, 2H), 3.23 (t, 2H, J = 6.6 Hz), 3.29 (s, 3H), 3.42 (t, 2H, J = 7.1 Hz), 3.56 (m, 2H), 3.61–3.74 (m, 4H), 3.74–3.86 (m, 4H), 4.69 (t, 2H, J = 6.0 Hz), 5.92 (m, 2H), 7.71 (m, 1H), 7.91 (s, 2H), 8.23 (m, 1H), 8.41 (dd, 1H, J = 10.0 Hz, 2.6 Hz), 8.52 (d, 1H, J = 8.7 Hz), 8.62 (m, 1H), 9.10 (d, 1H, J = 9.5), 9.16 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.71 (t, 3F, J = 10.1 Hz), −113.78 (m, 2F), −122.36 (m, 2F), −123.39 (m, 2F), −124.02 (m, 2F), −126.75 (m, 2F). MALDI-TOF MS m/z 1105.3 (M + H)+; HRMS m/z 1105.2769 (M + H)+ (1105.2761 calculated). Compound 4c. Yield = 8 mg (52%). δH (500 MHz, CD3COOD) 2.31–2.39 (m, 2H), 2.39–2.53 (m, 4H), 2.63 (s, 6H), 2.78–2.95 (m, 2H), 2.97–3.15 (m, 2H), 3.24 (m, 2H), 3.26 (s, 3H), 3.38 (t, 2H, J = 7.1 Hz), 3.55–3.71 (m, 6H), 3.71–3.85 (m, 4H), 4.75 (t, 2H, J = 6.1 Hz), 5.98 (m, 2H), 7.89 (d, 1H, J = 2.8 Hz), 7.94 (s, 2H), 8.27 (m, 1H), 8.42 (dd, 1H, J = 9.9 Hz, 2.7 Hz), 8.63 (m, 1H), 8.70 (d, 1H, J = 8.7 Hz), 9.12 (d, 1H, J = 9.5 Hz), 9.19 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.67 (t, 3F, J = 10.1 Hz), −113.75 (m, 2F), −122.09 (m, 2F), −122.38 (m, 4F), −123.24 (m, 2F), −123.93 (m, 2F), −126.67 (m, 2F). MALDI-TOF MS m/z 1205.4 (M + H)+; HRMS m/z 1205.2703 (M + H)+ (1205.2697 calculated). Compound 5a. Compound 4a (30 mg, 0.030 mmol) was dissolved in methanol (2 mL) and diisopropylethylamine (DIPEA, 0.026 mL, 0.149 mmol) and glutaric anhydride (17.0 mg, 0.149 mmol) were added. The reaction was stirred at room temperature and monitored by analytical HPLC which showed 98% conversion. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and DIPEA (0.104 mL, 0.597 mmol) and TSTU (180 mg, 0.597 mmol) were added. The reaction was stirred at room temperature and monitored by analytical HPLC which showed complete conversion to the N-hydroxysuccinimide ester. The product 5a was purified by preparative HPLC as described earlier using a 40 minute gradient of 10 → 60% MeCN–water (each with 0.05% TFA). The HPLC fractions containing product 5a were frozen at −80 °C and lyophilized to dryness. Yield = 28 mg (76%). δH (500 MHz, CD3COOD) 2.28–2.36 (m, 2H), 2.36–2.47 (m, 2H), 2.51–2.64 (m, 8H), 2.81 (m, 6H), 2.88–3.12 (m, 8H), 3.17–3.28 (m, 5H), 3.44–3.65 (m, 8H), 3.67–3.77 (m, 4H), 4.72 (t, 2H, J = 6.0 Hz), 5.95 (m, 2H), 7.81 (d, 1H, J = 2.8 Hz), 7.93 (s, 2H), 8.25 (dd, 1H, J = 8.7 Hz, 6.8 Hz), 8.41 (dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.62 (m, 2H), 9.12 (d, 1H, J = 9.6 Hz), 9.18 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.90 (m, 3F), −113.88 (m, 2F), −124.92 (m, 2F), −126.53 (m, 2F). MALDI-TOF MS m/z 1216.4 (M + H)+; HRMS m/z 1216.3448 (M + H)+ (1216.3305 calculated). Compounds 5b and 5c were synthesized similarly. Compound 5b. Yield = 8 mg (45%). δH (500 MHz, CD3COOD) 2.28–2.37 (m, 2H), 2.37–2.47 (m, 2H), 2.47–2.64 (m, 8H), 2.76–2.87 (m, 6H), 2.95–3.12 (m, 8H), 3.15–3.25 (m, 5H), 3.46–3.65 (m, 8H), 3.68–3.78 (m, 4H), 4.71 (t, 2H, J = 6.1 Hz), 5.93 (m, 2H), 7.78 (d, 1H, J = 2.8 Hz), 7.92 (s, 2H), 8.24 (dd, 1H,
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J = 8.8 Hz, 6.7 Hz), 8.41 (dd, 1H, J = 9.9 Hz, 2.7 Hz), 8.55–8.67 (m, 2H), 9.11 (d, 1H, J = 9.5 Hz), 9.17 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.69 (t, 3F, J = 10.0 Hz), −113.69 (m, 2F), −122.30 (m, 2F), −123.36 (m, 2 F), −123.96 (m, 2F), −126.69 (m, 2F). MALDI-TOF MS m/z 1316.8 (M + H)+; HRMS m/z 1316.3292 (M + H)+ (1316.3242 calculated). Compound 5c. Yield = 2 mg (17%). δH (500 MHz, CD3COOD) 2.27–2.36 (m, 2H), 2.36–2.46 (m, 2H), 2.46–2.57 (m, 2H), 2.62 (s, 6H), 2.71–2.90 (m, 6H), 2.93–3.13 (m, 8H), 3.17–3.27 (m, 5H), 3.46–3.66 (m, 8H), 3.67–3.77 (m, 4H), 4.74 (t, 2H, J = 6.1 Hz), 5.96 (m, 2H), 7.86 (d, 1H, J = 2.8 Hz), 7.93 (s, 2H), 8.25 (m, 1 H), 8.41 (dd, 1H, J = 10.0 Hz, 2.7), 8.62 (m, 1H), 8.67 (m, 1H), 9.11 (d, 1H, J = 9.4 Hz), 9.18 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.66 (t, 3F, J = 10.0 Hz), −113.69 (m, 2F), −122.06 (m, 2F), −122.36 (m, 4F), −123.21 (m, 2F), −123.90 (m, 2F), −126.67 (m, 2F). MALDI-TOF MS m/z 1416.5 (M + H)+; HRMS m/z 1416.3582 (M + H)+ (1416.3178 calculated). Compound 7a. Compound 6 (100 mg, 0.206 mmol) was dissolved in acetonitrile (15 mL) and 1H,1H,2H,2H-perfluorohexyl triflate (163 mg, 0.411 mmol) was added. The reaction was stirred at room temperature for 1 hour and monitored by analytical HPLC which showed 89% conversion. The crude mixture was purified by preparative HPLC as described earlier using a 30 minute gradient of 10 → 90% MeCN–water (each with 0.05% TFA). The HPLC fractions containing product 7a were concentrated under reduced pressure. Yield = 163 mg (94%). δH (500 MHz, CD3CN) 2.31 (m, 2H), 2.49 (s, 6H), 2.72–2.86 (m, 2H), 3.11 (s, 6H), 3.55 (m, 2H), 3.65 (m, 2H), 3.90 (s, 3H), 4.26 (t, 2 H, J = 5.6 Hz), 7.63 (m, 2H), 7.76–7.86 (m, 1H), 7.88–7.96 (m, 3H), 8.31 (d, 1H, J = 9.4 Hz), 8.34 (d, 1H, J = 8.7 Hz), 8.45 (d, 1H, J = 8.7 Hz); δF (470 MHz, CD3CN) −81.80 (t, 3F, J = 9.7 Hz), −114.10 (m, 2F), −124.35 (m, 2F), −126.52 (m, 2F). MALDI-TOF MS m/z 733.3 (M)+; HRMS m/z 733.2347 (M)+ (733.2324 calculated). Compounds 7b and 7c were synthesized similarly. Compound 7b. Yield = 25 mg (63%). δH (500 MHz, CD3CN) 2.31 (m, 2H), 2.49 (s, 6H), 2.72–2.86 (m, 2H), 3.11 (s, 6H), 3.55 (m, 2H), 3.65 (m, 2H), 3.90 (s, 3H), 4.26 (t, 2H, J = 5.6 Hz), 7.59–7.64 (m, 2H), 7.79 (m, 1H), 7.90 (m, 1H), 7.92 (s, 2H), 8.28 (m, 1H), 8.31 (m, 1H), 8.45 (m, 1H); δF (470 MHz, CD3CN) −81.54 (t, 3F, J = 9.8 Hz), −113.84 (m, 2 F), −122.31 (m, 2F), −123.37 (m, 4F), −126.62 (m, 2F). MALDI-TOF MS m/z 833.3 (M)+; HRMS m/z 833.2259 (M)+ (833.2260 calculated). Compound 7c. Yield = 81 mg (73%). δH (500 MHz, CD3CN) 2.31 (m, 2H), 2.48 (s, 6H), 2.70–2.86 (m, 2H), 3.11 (s, 6H), 3.55 (m, 2H), 3.65 (m, 2H), 3.90 (s, 3H), 4.25 (t, 2H, J = 5.7 Hz), 7.57–7.63 (m, 2H), 7.77 (m, 1H), 7.88 (m, 1H), 7.92 (m, 2H), 8.25 (m, 1H), 8.28 (m, 1H), 8.44 (m, 1H); δF (470 MHz, CD3CN) −81.52 (m, 3F), −113.86 (m, 2F), −122.12 (m, 2F), −122.32 (m, 4F), −123.15 (m, 2F), −123.38 (m, 2F), −126.58 (m, 2F). MALDI-TOF MS m/z 933.4 (M)+; HRMS m/z 933.2164 (M)+ (933.2196 calculated). Compound 8a. Compound 7a (100 mg, 0.118 mmol), 2,6-ditert-butylpyridine (0.196 mL, 0.886 mmol) and 1,3-propane sultone (216 mg, 1.772 mmol) were added to [BMIM][BF4]
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(1 mL). The reaction was heated at 155 °C in a sealed vial for 16 hours and then cooled to room temperature. The reaction mixture was then transferred into a flask with acetonitrile (5 mL) and 2 N HCl (20 mL) was added. The reaction was refluxed for 16 h and then cooled to room temperature. The crude reaction mixture was purified by preparative HPLC as described earlier using a 40 minute gradient of 10 → 70% MeCN–water (each with 0.05% TFA). The HPLC fractions contain product 8a were concentrated under reduced pressure. Yield = 119 mg (quantitative). δH (500 MHz, CD3COOD) 2.62 (s, 6H), 2.64–2.73 (m, 2H), 2.77–2.88 (m, 2H), 2.99–3.15 (m, 2H), 3.47 (s, 6H), 3.55 (t, 2H, J = 6.2 Hz), 3.88–4.06 (m, 4H), 4.56 (t, 2H, J = 5.6 Hz), 5.93 (m, 2H), 7.84 (d, 1H, J = 2.6 Hz), 8.08 (s, 2H), 8.23 (dd, 1H, J = 8.8 Hz, 6.7 Hz), 8.35 (m, 1H), 8.57 (m, 1H), 8.70 (d, 1H, J = 8.7 Hz), 9.04 (d, 1H, J = 9.4 Hz), 9.13 (d, 1H, J = 9.9 Hz); δF (470 MHz, CD3COOD) −81.95 (t, 3F, J = 9.8 Hz), −114.10 (m, 2F), −124.33 (m, 2F), −126.64 (m, 2F). MALDI-TOF MS m/z 841.4 (M)+; HRMS m/z 841.2216 (M)+ (841.2205 calculated). Compounds 8b and 8c were synthesized similarly. Compound 8b. Yield = 35 mg (63%). δH (500 MHz, CD3COOD) 2.66 (s, 6H), 2.67–2.76 (m, 2H), 2.81–2.92 (m, 2H), 3.00–3.17 (m, 2H), 3.48 (s, 6H), 3.59 (m, 2H), 3.93–4.05 (m, 4H), 4.58 (t, 2H, J = 5.7 Hz), 5.98 (m, 2H), 7.88 (d, 1H, J = 2.7 Hz), 8.12 (s, 2H), 8.26 (dd, 1H, J = 8.8 Hz, 6.8 Hz), 8.38 (dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.61 (m, 1H), 8.75 (dd, 1H, J = 8.7 Hz, 1.3 Hz), 9.08 (d, 1H, J = 9.5 Hz), 9.19 (d, 1H, J = 10.1 Hz); δF (470 MHz, CD3COOD) −81.95 (m, 3F), −113.96 (m, 2F), −122.43 (m, 2F), −123.44 (m, 4F), −126.75 (m, 2F). MALDI-TOF MS m/z 941.4 (M)+; HRMS m/z 941.2151 (M)+ (941.2141 calculated). Compound 8c. Yield = 40 mg (72%). δH (500 MHz, CD3COOD) 2.67 (s, 6H), 2.69–2.78 (m, 2H), 2.80–2.92 (m, 2H), 3.00–3.20 (m, 2H), 3.43–3.70 (m, 8H), 3.92–4.20 (m, 4 H), 4.62 (m, 2H), 5.98 (m, 2H), 7.88 (m, 1H), 8.12 (s, 2H), 8.26 (m, 1H), 8.40 (m, 1H), 8.61 (m, 1H), 8.75 (d, 1H, J = 8.6 Hz), 9.09 (d, 1H, J = 9.3 Hz), 9.19 (m, 1H); δF (470 MHz, CD3COOD) −81.67 (t, 3F, J = 10.1 Hz), −113.79 (m, 2F), −122.12 (m, 2F), −122.36 (m, 4 F), −123.22 (m, 4F), −126.69 (m, 2F). MALDI-TOF MS m/z 1041.2 (M)+; HRMS m/z 1041.2089 (M)+ (1041.2077 calculated). Compound 9a. Compound 8a (54 mg, 0.062 mmol) dissolved in DMF (2 mL) was treated with DIPEA (0.016 mL, 0.092 mmol) and TSTU (20 mg, 0.068 mmol). The reaction was stirred at room temperature for 30 minutes and then this solution was added drop wise to an ice cold, stirred solution of iv (133 mg, 0.31 mmol, HBr salt) dissolved in 0.5 M sodium bicarbonate (2 mL). The reaction was stirred at 0 °C for 2 hours. The crude product was purified by a preparative HPLC as described earlier using a 40 minute gradient of 10 → 60 MeCN–water (each with 0.05% TFA). The HPLC fractions containing product 9a were concentrated under reduced pressure. Yield = 38 mg (55%). δH (500 MHz, CD3COOD) 2.27–2.38 (m, 2H), 2.47 (m, 4H), 2.58 (s, 6H), 2.70 (m, 2H), 2.82 (m, 2H), 2.99–3.24 (m, 4H), 3.26 (s, 3H), 3.38 (m, 2H), 3.48 (s, 6H), 3.52–3.85 (m, 10H), 3.98 (m, 4H), 4.49 (m, 2H), 5.93 (m, 2H), 7.73 (d, 1H, J = 2.7 Hz), 7.88 (s, 2H), 8.25 (m, 1H), 8.33
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(dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.58 (m, 1H), 8.70 (m, 1H), 9.04 (d, 1H, J = 9.4 Hz), 9.14 (d, 1H, J = 10.1 Hz); δF (470 MHz, CD3COOD) −81.93 (m, 3F), −114.06 (m, 2F), −124.31 (m, 2F), −126.61 (m, 2F). MALDI-TOF MS m/z 1090.5 (M)+; HRMS m/z 1090.3828 (M)+ (1090.3716 calculated). Compounds 9b and 9c were synthesized similarly. Compound 9b. Yield = 20 mg (65%). δH (500 MHz, CD3COOD) 2.27–2.38 (m, 2H), 2.49 (m, 4H), 2.63 (s, 6H), 2.73 (m, 2H), 2.85 (m, 2H), 3.04–3.13 (m, 2H), 3.17 (m, 2H), 3.27 (s, 3H), 3.37 (m, 2H), 3.49 (s, 6H), 3.55–3.90 (m, 10H), 3.96–4.05 (m, 4H), 4.52 (m, 2 H), 5.97 (m, 2H), 7.78 (d, 1H, J = 2.7 Hz), 7.92 (s, 2H), 8.28 (dd, 1H, J = 8.7 Hz, 6.7 Hz), 8.35 (dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.61 (m, 1H), 8.78 (d, 1H, J = 8.7 Hz), 9.08 (d, 1H, J = 9.4 Hz), 9.19 (d, 1H, J = 10.1 Hz); δF (470 MHz, CD3COOD) −81.69 (m, 3F), −113.90 (m, 2F), −122.39 (m, 2F), −123.39 (m, 4F), −126.73 (m, 2F). MALDI-TOF MS m/z 1191.5 (M + H)+; HRMS m/z 1190.3691 (M)+ (1190.3652 calculated). Compound 9c. Yield = 4 mg (14%). δH (500 MHz, CD3COOD) 2.27–2.38 (m, 2H), 2.48 (m, 4H), 2.62 (s, 6H), 2.72 (m, 2H), 2.85 (m, 2H), 3.02–3.21 (m, 4H), 3.27 (s, 3H), 3.38 (m, 2H), 3.49 (s, 6H), 3.55–3.92 (m, 10H), 3.96–4.08 (m, 4H), 4.51 (m, 2H), 5.97 (m, 2H), 7.77 (d, 1H, J = 2.7 Hz), 7.91 (s, 2H), 8.28 (m, 1H), 8.35 (m, 1H), 8.61 (m, 1H), 8.77 (d, 1H, J = 8.6 Hz), 9.07 (d, 1H, J = 9.4 Hz), 9.19 (d, 1H, J = 10.1 Hz); δF (470 MHz, CD3COOD) −81.67 (t, 3F, J = 10.1 Hz), −113.83 (m, 2F), −122.13 (m, 2F), −122.35 (m, 4F), −123.25 (m, 4F), −126.68 (m, 2F). MALDI-TOF MS m/z 1290.5 (M)+; HRMS m/z 1290.3627 (M)+ (1290.3588 calculated). Compound 10a. Compound 9a (20 mg, 0.018 mmol) was dissolved in methanol (2 mL) and DIPEA (0.031 mL, 0.178 mmol) and glutaric anhydride (10 mg, 0.089 mmol) were added. The reaction was stirred at room temperature for 1 hour and was then concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and DIPEA (0.062 mL, 0.355 mmol) and TSTU (107 mg, 0.355 mmol) were added. The reaction was stirred at room temperature for 1 hour. The crude reaction mixture was purified by preparative HPLC as described earlier using a 40 minute gradient of 10 → 60% MeCN–water (each with 0.05% TFA). The HPLC fractions containing product 10a were frozen at −80 °C and lyophilized to dryness. Yield = 22 mg (93%). δH (500 MHz, CD3COOD) 2.27–2.38 (m, 2H), 2.42–2.57 (m, 6H), 2.63 (s, 6H), 2.67–2.78 (m, 2H), 2.80 (m, 2H), 2.84 (m, 4H), 2.96–3.12 (m, 10H), 3.17 (m, 2H), 3.23 (s, 3H), 3.50 (s, 6H), 3.51–3.90 (m, 8H), 3.95–4.08 (m, 4H), 4.52 (m, 2H), 5.98 (m, 2H), 7.78 (d, 1H, J = 2.7 Hz), 7.93 (s, 2H), 8.29 (m, 1H), 8.36 (dd, 1H, J = 9.9 Hz, 2.7 Hz), 8.61 (m, 1H), 8.77 (m, 1H), 9.08 (d, 1H, J = 9.4 Hz), 9.19 (d, 1H, J = 10.1 Hz); δF (470 MHz, CD3COOD) −81.92 (t, 3F, J = 9.9 Hz), −114.07 (m, 2F), −124.29 (m, 2F), −126.60 (m, 2F). MALDI-TOF MS m/z 1301.7 (M)+; HRMS m/z 1301.4341 (M)+ (1301.4191 calculated). Compounds 10b and 10c were synthesized similarly. Compound 10b. Yield = 12 mg (68%). δH (500 MHz, CD3COOD) 2.27–2.35 (m, 2H), 2.42–2.57 (m, 6H), 2.60 (s, 6H), 2.67–2.78 (m, 2H), 2.78–2.94 (m, 6H), 2.95–3.12 (m, 10H), 3.17
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Organic & Biomolecular Chemistry
(m, 2H), 3.23 (s, 3H), 3.49 (s, 6H), 3.51–3.90 (m, 8H), 3.95–4.08 (m, 4H), 4.51 (t, 2H, J = 5.6 Hz), 5.97 (m, 2H), 7.77 (d, 1H, J = 2.7 Hz), 7.91 (s, 2H), 8.28 (dd, 1H, J = 8.8 Hz, 6.7 Hz), 8.35 (dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.61 (m, 1H), 8.76 (dd, 1H, J = 8.7 Hz, 1.4 Hz), 9.07 (d, 1H, J = 9.5 Hz), 9.18 (d, 1H, J = 10.1 Hz); δF (470 MHz, CD3COOD) −81.67 (m, 3F), −113.84 (m, 2F), −122.37 (m, 2F), −123.36 (m, 4F), −126.69 (m, 2F). MALDI-TOF MS m/z 1402.9 (M + H)+; HRMS m/z 1401.4303 (M)+ (1401.4133 calculated). Compound 10c. Yield = 3 mg (50%). δH (500 MHz, CD3COOD) 2.26–2.34 (m, 2H), 2.42–2.61 (m, 6H), 2.63 (s, 6H), 2.67–2.74 (m, 2H), 2.78–2.90 (m, 6H), 2.95–3.12 (m, 10 H), 3.19 (m, 2H), 3.22 (s, 3H), 3.50 (s, 6H), 3.51–3.90 (m, 8H), 3.95–4.08 (m, 4H), 4.52 (m, 2H), 5.98 (m, 2H), 7.79 (d, 1H, J = 2.7 Hz), 7.91 (s, 2H), 8.28 (dd, 1H, J = 8.7 Hz, 6.7 Hz), 8.35 (dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.61 (m, 1H), 8.79 (d, 1H, J = 8.5 Hz), 9.07 (d, 1H, J = 9.4 Hz), 9.19 (d, 1H, J = 10.1 Hz); δF (470 MHz, CD3COOD) −81.66 (t, 3F, J = 10.1 Hz), −113.83 (m, 2F), −122.13 (m, 2F), −122.37 (m, 4F), −123.25 (m, 4F), −126.69 (m, 2F). MALDI-TOF MS m/z 1501.9 (M)+; HRMS m/z 1501.4374 (M)+ (1501.4069 calculated).
Acknowledgements We thank Dr Shenliang Wang for assistance in emission spectra measurements.
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Cite this: Org. Biomol. Chem., 2014, 12, 3887
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Synthesis and properties of chemiluminescent acridinium ester labels with fluorous tags† Anand Natrajan,* David Wen and David Sharpe Acridinium dimethylphenyl esters are highly sensitive chemiluminescent labels that are used in clinical diagnostics. Light emission from these labels is triggered with alkaline peroxide in the presence of the cationic surfactant cetyltrimethylammonium chloride (CTAC). CTAC compresses emission times of these labels to 90% aqueous media using a PR-740 spectroradiometer (camera) on loan from Photo Research Inc. Bandwidth slit: 2 nm; aperture: 2 degrees; exposure time: 5000 ms.
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10 → 90% MeCN–water (each with 0.05% TFA). The HPLC fractions were concentrated under reduced pressure. Yield = 84 mg (80%). δH (500 MHz, CD3COOD) 2.69 (s, 6H), 2.86–2.96 (m, 2 H), 2.99–3.13 (m, 2H), 3.63 (m, 2H), 4.80 (t, 2H, J = 6.2 Hz), 6.02 (m, 2H), 7.98 (d, 1H, J = 2.7 Hz), 8.15 (m, 2H), 8.30 (dd, 1H, J = 8.8 Hz, 6.7 Hz), 8.45 (dd, 1H, J = 10.0 Hz, 2.8 Hz), 8.66 (m, 1H), 8.78 (dd, 1H, J = 8.8 Hz, 1.3 Hz), 9.15 (d, 1H, J = 9.4 Hz), 9.22 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.95 (t, 3F, J = 9.8 Hz), −113.88 (m, 2F), −124.93 (m, 2F), −126.57 (m, 2F). MALDI-TOF MS m/z 756.2 (M + H)+; HRMS m/z (M + H)+ 756.1304 (756.1314 calculated). Compounds 3b and 3c were synthesized similarly. Compound 3b. Yield = 38 mg (67%). δH (500 MHz, CD3COOD) 2.67 (s, 6H), 2.80–2.93 (m, 2H), 2.98–3.10 (m, 2H), 3.57–3.64 (m, 2H), 4.78 (t, 2H, J = 6.2 Hz), 6.00 (t, 2H, J = 9.5 Hz), 7.97 (d, 1H, J = 2.8 Hz), 8.13 (s, 2 H), 8.28 (dd, 1H, J = 8.8 Hz, 6.7 Hz), 8.44 (m, 1H), 8.64 (m, 1H), 8.76 (dd, 1H, J = 8.8 Hz, 1.3 Hz), 9.13 (d, 1H, J = 9.4 Hz), 9.21 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.70 (t, 3F, J = 10.1 Hz), −113.60 (m, 2F), −122.33 (m, 2F), −123.37 (m, 2F), −123.92 (m, 2F), −126.70 (m, 2F). MALDI-TOF MS m/z 856.2 (M + H)+; HRMS m/z 856.1249 (M + H)+ (856.1250 calculated). Compound 3c. Yield = 20 mg (36%). δH (500 MHz, CD3COOD) 2.67 (s, 6H), 2.83–2.94 (m, 2H), 2.98–3.13 (m, 2H), 3.60 (m, 2H), 4.78 (t, 2H, J = 6.2 Hz), 6.00 (m, 2H), 7.96 (d, 1H, J = 2.7 Hz), 8.13 (s, 2H), 8.27 (dd, 1H, J = 8.8 Hz, 6.7 Hz), 8.43 (dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.63 (m, 1H), 8.76 (dd, 1H, J = 8.8 Hz, 1.3 Hz), 9.13 (d, 1H, J = 9.4 Hz), 9.20 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.67 (t, 3F, J = 10.0 Hz), −113.57 (m, 2F), −121.11 (m, 2F), −122.36 (m, 4F), −123.22 (m, 2F), −123.85 (m, 2F), −126.68 (m, 2F). MALDI-TOF MS m/z 956.1 (M + H)+; HRMS m/z 956.1197 (M + H)+ (956.1186 calculated). Compound 4a. Compound 3a (60 mg, 0.079 mmol) was suspended in DMF (3 mL) and diisopropylethylamine (0.021 mL, 0.119 mmol) and N,N,N′,N′-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (TSTU, 29 mg, 0.095 mmol) were added. The reaction was stirred at room temperature for 1 hour and was then added drop wise to a stirred solution of iv (170 mg, 0.397 mmol, HBr salt) dissolved in 0.5 M sodium bicarbonate (3 mL) cooled in an ice bath. After 16 hours, the reaction mixture was purified by preparative HPLC as described earlier using a 40 minute gradient 10 → 40% MeCN–water (each with 0.05% TFA). The HPLC fractions containing product 4a were concentrated under reduced pressure. Yield = 60 mg (75%). δH (500 MHz, CD3COOD) 2.28–2.39 (m, 2H), 2.39–2.52 (m, 4H), 2.55 (s, 6H), 2.78–2.86 (m, 2H), 2.96–3.10 (m, 2H), 3.21 (m, 2H), 3.27 (s, 3H), 3.40 (t, 2H, J = 7.2 Hz), 3.56 (m, 2H), 3.59–3.72 (m, 4H), 3.72–3.83 (m, 4H), 4.70 (t, 2H, J = 6.1 Hz), 5.92 (m, 2H), 7.76 (d, 1H, J = 2.7 Hz), 7.91 (s, 2H), 8.23 (dd, 1H, J = 8.8 Hz, 6.7 Hz), 8.39 (dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.59 (m, 2H), 9.09 (d, 1H, J = 9.8 Hz), 9.15 (d, 1H, J = 10.0 Hz); δF (470 MHz, CD3COOD) −81.92 (t, 3F, J = 9.9 Hz), −113.91 (m, 2F), −124.94 (m, 2F), −126.54 (m, 2F). MALDI-TOF MS m/z 1005.4 (M + H)+; HRMS m/z 1005.2835 (M + H)+ (1005.2825 calculated).
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Compounds 4b and 4c were synthesized similarly. Compound 4b. Yield = 23 mg (59%). δH (500 MHz, CD3COOD) 2.32–2.42 (m, 2H), 2.42–2.52 (m, 4H), 2.53 (s, 6H), 2.73–2.88 (m, 2H), 2.97–3.15 (m, 2H), 3.23 (t, 2H, J = 6.6 Hz), 3.29 (s, 3H), 3.42 (t, 2H, J = 7.1 Hz), 3.56 (m, 2H), 3.61–3.74 (m, 4H), 3.74–3.86 (m, 4H), 4.69 (t, 2H, J = 6.0 Hz), 5.92 (m, 2H), 7.71 (m, 1H), 7.91 (s, 2H), 8.23 (m, 1H), 8.41 (dd, 1H, J = 10.0 Hz, 2.6 Hz), 8.52 (d, 1H, J = 8.7 Hz), 8.62 (m, 1H), 9.10 (d, 1H, J = 9.5), 9.16 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.71 (t, 3F, J = 10.1 Hz), −113.78 (m, 2F), −122.36 (m, 2F), −123.39 (m, 2F), −124.02 (m, 2F), −126.75 (m, 2F). MALDI-TOF MS m/z 1105.3 (M + H)+; HRMS m/z 1105.2769 (M + H)+ (1105.2761 calculated). Compound 4c. Yield = 8 mg (52%). δH (500 MHz, CD3COOD) 2.31–2.39 (m, 2H), 2.39–2.53 (m, 4H), 2.63 (s, 6H), 2.78–2.95 (m, 2H), 2.97–3.15 (m, 2H), 3.24 (m, 2H), 3.26 (s, 3H), 3.38 (t, 2H, J = 7.1 Hz), 3.55–3.71 (m, 6H), 3.71–3.85 (m, 4H), 4.75 (t, 2H, J = 6.1 Hz), 5.98 (m, 2H), 7.89 (d, 1H, J = 2.8 Hz), 7.94 (s, 2H), 8.27 (m, 1H), 8.42 (dd, 1H, J = 9.9 Hz, 2.7 Hz), 8.63 (m, 1H), 8.70 (d, 1H, J = 8.7 Hz), 9.12 (d, 1H, J = 9.5 Hz), 9.19 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.67 (t, 3F, J = 10.1 Hz), −113.75 (m, 2F), −122.09 (m, 2F), −122.38 (m, 4F), −123.24 (m, 2F), −123.93 (m, 2F), −126.67 (m, 2F). MALDI-TOF MS m/z 1205.4 (M + H)+; HRMS m/z 1205.2703 (M + H)+ (1205.2697 calculated). Compound 5a. Compound 4a (30 mg, 0.030 mmol) was dissolved in methanol (2 mL) and diisopropylethylamine (DIPEA, 0.026 mL, 0.149 mmol) and glutaric anhydride (17.0 mg, 0.149 mmol) were added. The reaction was stirred at room temperature and monitored by analytical HPLC which showed 98% conversion. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and DIPEA (0.104 mL, 0.597 mmol) and TSTU (180 mg, 0.597 mmol) were added. The reaction was stirred at room temperature and monitored by analytical HPLC which showed complete conversion to the N-hydroxysuccinimide ester. The product 5a was purified by preparative HPLC as described earlier using a 40 minute gradient of 10 → 60% MeCN–water (each with 0.05% TFA). The HPLC fractions containing product 5a were frozen at −80 °C and lyophilized to dryness. Yield = 28 mg (76%). δH (500 MHz, CD3COOD) 2.28–2.36 (m, 2H), 2.36–2.47 (m, 2H), 2.51–2.64 (m, 8H), 2.81 (m, 6H), 2.88–3.12 (m, 8H), 3.17–3.28 (m, 5H), 3.44–3.65 (m, 8H), 3.67–3.77 (m, 4H), 4.72 (t, 2H, J = 6.0 Hz), 5.95 (m, 2H), 7.81 (d, 1H, J = 2.8 Hz), 7.93 (s, 2H), 8.25 (dd, 1H, J = 8.7 Hz, 6.8 Hz), 8.41 (dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.62 (m, 2H), 9.12 (d, 1H, J = 9.6 Hz), 9.18 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.90 (m, 3F), −113.88 (m, 2F), −124.92 (m, 2F), −126.53 (m, 2F). MALDI-TOF MS m/z 1216.4 (M + H)+; HRMS m/z 1216.3448 (M + H)+ (1216.3305 calculated). Compounds 5b and 5c were synthesized similarly. Compound 5b. Yield = 8 mg (45%). δH (500 MHz, CD3COOD) 2.28–2.37 (m, 2H), 2.37–2.47 (m, 2H), 2.47–2.64 (m, 8H), 2.76–2.87 (m, 6H), 2.95–3.12 (m, 8H), 3.15–3.25 (m, 5H), 3.46–3.65 (m, 8H), 3.68–3.78 (m, 4H), 4.71 (t, 2H, J = 6.1 Hz), 5.93 (m, 2H), 7.78 (d, 1H, J = 2.8 Hz), 7.92 (s, 2H), 8.24 (dd, 1H,
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J = 8.8 Hz, 6.7 Hz), 8.41 (dd, 1H, J = 9.9 Hz, 2.7 Hz), 8.55–8.67 (m, 2H), 9.11 (d, 1H, J = 9.5 Hz), 9.17 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.69 (t, 3F, J = 10.0 Hz), −113.69 (m, 2F), −122.30 (m, 2F), −123.36 (m, 2 F), −123.96 (m, 2F), −126.69 (m, 2F). MALDI-TOF MS m/z 1316.8 (M + H)+; HRMS m/z 1316.3292 (M + H)+ (1316.3242 calculated). Compound 5c. Yield = 2 mg (17%). δH (500 MHz, CD3COOD) 2.27–2.36 (m, 2H), 2.36–2.46 (m, 2H), 2.46–2.57 (m, 2H), 2.62 (s, 6H), 2.71–2.90 (m, 6H), 2.93–3.13 (m, 8H), 3.17–3.27 (m, 5H), 3.46–3.66 (m, 8H), 3.67–3.77 (m, 4H), 4.74 (t, 2H, J = 6.1 Hz), 5.96 (m, 2H), 7.86 (d, 1H, J = 2.8 Hz), 7.93 (s, 2H), 8.25 (m, 1 H), 8.41 (dd, 1H, J = 10.0 Hz, 2.7), 8.62 (m, 1H), 8.67 (m, 1H), 9.11 (d, 1H, J = 9.4 Hz), 9.18 (d, 1H, J = 10.1 Hz). δF (470 MHz, CD3COOD) −81.66 (t, 3F, J = 10.0 Hz), −113.69 (m, 2F), −122.06 (m, 2F), −122.36 (m, 4F), −123.21 (m, 2F), −123.90 (m, 2F), −126.67 (m, 2F). MALDI-TOF MS m/z 1416.5 (M + H)+; HRMS m/z 1416.3582 (M + H)+ (1416.3178 calculated). Compound 7a. Compound 6 (100 mg, 0.206 mmol) was dissolved in acetonitrile (15 mL) and 1H,1H,2H,2H-perfluorohexyl triflate (163 mg, 0.411 mmol) was added. The reaction was stirred at room temperature for 1 hour and monitored by analytical HPLC which showed 89% conversion. The crude mixture was purified by preparative HPLC as described earlier using a 30 minute gradient of 10 → 90% MeCN–water (each with 0.05% TFA). The HPLC fractions containing product 7a were concentrated under reduced pressure. Yield = 163 mg (94%). δH (500 MHz, CD3CN) 2.31 (m, 2H), 2.49 (s, 6H), 2.72–2.86 (m, 2H), 3.11 (s, 6H), 3.55 (m, 2H), 3.65 (m, 2H), 3.90 (s, 3H), 4.26 (t, 2 H, J = 5.6 Hz), 7.63 (m, 2H), 7.76–7.86 (m, 1H), 7.88–7.96 (m, 3H), 8.31 (d, 1H, J = 9.4 Hz), 8.34 (d, 1H, J = 8.7 Hz), 8.45 (d, 1H, J = 8.7 Hz); δF (470 MHz, CD3CN) −81.80 (t, 3F, J = 9.7 Hz), −114.10 (m, 2F), −124.35 (m, 2F), −126.52 (m, 2F). MALDI-TOF MS m/z 733.3 (M)+; HRMS m/z 733.2347 (M)+ (733.2324 calculated). Compounds 7b and 7c were synthesized similarly. Compound 7b. Yield = 25 mg (63%). δH (500 MHz, CD3CN) 2.31 (m, 2H), 2.49 (s, 6H), 2.72–2.86 (m, 2H), 3.11 (s, 6H), 3.55 (m, 2H), 3.65 (m, 2H), 3.90 (s, 3H), 4.26 (t, 2H, J = 5.6 Hz), 7.59–7.64 (m, 2H), 7.79 (m, 1H), 7.90 (m, 1H), 7.92 (s, 2H), 8.28 (m, 1H), 8.31 (m, 1H), 8.45 (m, 1H); δF (470 MHz, CD3CN) −81.54 (t, 3F, J = 9.8 Hz), −113.84 (m, 2 F), −122.31 (m, 2F), −123.37 (m, 4F), −126.62 (m, 2F). MALDI-TOF MS m/z 833.3 (M)+; HRMS m/z 833.2259 (M)+ (833.2260 calculated). Compound 7c. Yield = 81 mg (73%). δH (500 MHz, CD3CN) 2.31 (m, 2H), 2.48 (s, 6H), 2.70–2.86 (m, 2H), 3.11 (s, 6H), 3.55 (m, 2H), 3.65 (m, 2H), 3.90 (s, 3H), 4.25 (t, 2H, J = 5.7 Hz), 7.57–7.63 (m, 2H), 7.77 (m, 1H), 7.88 (m, 1H), 7.92 (m, 2H), 8.25 (m, 1H), 8.28 (m, 1H), 8.44 (m, 1H); δF (470 MHz, CD3CN) −81.52 (m, 3F), −113.86 (m, 2F), −122.12 (m, 2F), −122.32 (m, 4F), −123.15 (m, 2F), −123.38 (m, 2F), −126.58 (m, 2F). MALDI-TOF MS m/z 933.4 (M)+; HRMS m/z 933.2164 (M)+ (933.2196 calculated). Compound 8a. Compound 7a (100 mg, 0.118 mmol), 2,6-ditert-butylpyridine (0.196 mL, 0.886 mmol) and 1,3-propane sultone (216 mg, 1.772 mmol) were added to [BMIM][BF4]
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(1 mL). The reaction was heated at 155 °C in a sealed vial for 16 hours and then cooled to room temperature. The reaction mixture was then transferred into a flask with acetonitrile (5 mL) and 2 N HCl (20 mL) was added. The reaction was refluxed for 16 h and then cooled to room temperature. The crude reaction mixture was purified by preparative HPLC as described earlier using a 40 minute gradient of 10 → 70% MeCN–water (each with 0.05% TFA). The HPLC fractions contain product 8a were concentrated under reduced pressure. Yield = 119 mg (quantitative). δH (500 MHz, CD3COOD) 2.62 (s, 6H), 2.64–2.73 (m, 2H), 2.77–2.88 (m, 2H), 2.99–3.15 (m, 2H), 3.47 (s, 6H), 3.55 (t, 2H, J = 6.2 Hz), 3.88–4.06 (m, 4H), 4.56 (t, 2H, J = 5.6 Hz), 5.93 (m, 2H), 7.84 (d, 1H, J = 2.6 Hz), 8.08 (s, 2H), 8.23 (dd, 1H, J = 8.8 Hz, 6.7 Hz), 8.35 (m, 1H), 8.57 (m, 1H), 8.70 (d, 1H, J = 8.7 Hz), 9.04 (d, 1H, J = 9.4 Hz), 9.13 (d, 1H, J = 9.9 Hz); δF (470 MHz, CD3COOD) −81.95 (t, 3F, J = 9.8 Hz), −114.10 (m, 2F), −124.33 (m, 2F), −126.64 (m, 2F). MALDI-TOF MS m/z 841.4 (M)+; HRMS m/z 841.2216 (M)+ (841.2205 calculated). Compounds 8b and 8c were synthesized similarly. Compound 8b. Yield = 35 mg (63%). δH (500 MHz, CD3COOD) 2.66 (s, 6H), 2.67–2.76 (m, 2H), 2.81–2.92 (m, 2H), 3.00–3.17 (m, 2H), 3.48 (s, 6H), 3.59 (m, 2H), 3.93–4.05 (m, 4H), 4.58 (t, 2H, J = 5.7 Hz), 5.98 (m, 2H), 7.88 (d, 1H, J = 2.7 Hz), 8.12 (s, 2H), 8.26 (dd, 1H, J = 8.8 Hz, 6.8 Hz), 8.38 (dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.61 (m, 1H), 8.75 (dd, 1H, J = 8.7 Hz, 1.3 Hz), 9.08 (d, 1H, J = 9.5 Hz), 9.19 (d, 1H, J = 10.1 Hz); δF (470 MHz, CD3COOD) −81.95 (m, 3F), −113.96 (m, 2F), −122.43 (m, 2F), −123.44 (m, 4F), −126.75 (m, 2F). MALDI-TOF MS m/z 941.4 (M)+; HRMS m/z 941.2151 (M)+ (941.2141 calculated). Compound 8c. Yield = 40 mg (72%). δH (500 MHz, CD3COOD) 2.67 (s, 6H), 2.69–2.78 (m, 2H), 2.80–2.92 (m, 2H), 3.00–3.20 (m, 2H), 3.43–3.70 (m, 8H), 3.92–4.20 (m, 4 H), 4.62 (m, 2H), 5.98 (m, 2H), 7.88 (m, 1H), 8.12 (s, 2H), 8.26 (m, 1H), 8.40 (m, 1H), 8.61 (m, 1H), 8.75 (d, 1H, J = 8.6 Hz), 9.09 (d, 1H, J = 9.3 Hz), 9.19 (m, 1H); δF (470 MHz, CD3COOD) −81.67 (t, 3F, J = 10.1 Hz), −113.79 (m, 2F), −122.12 (m, 2F), −122.36 (m, 4 F), −123.22 (m, 4F), −126.69 (m, 2F). MALDI-TOF MS m/z 1041.2 (M)+; HRMS m/z 1041.2089 (M)+ (1041.2077 calculated). Compound 9a. Compound 8a (54 mg, 0.062 mmol) dissolved in DMF (2 mL) was treated with DIPEA (0.016 mL, 0.092 mmol) and TSTU (20 mg, 0.068 mmol). The reaction was stirred at room temperature for 30 minutes and then this solution was added drop wise to an ice cold, stirred solution of iv (133 mg, 0.31 mmol, HBr salt) dissolved in 0.5 M sodium bicarbonate (2 mL). The reaction was stirred at 0 °C for 2 hours. The crude product was purified by a preparative HPLC as described earlier using a 40 minute gradient of 10 → 60 MeCN–water (each with 0.05% TFA). The HPLC fractions containing product 9a were concentrated under reduced pressure. Yield = 38 mg (55%). δH (500 MHz, CD3COOD) 2.27–2.38 (m, 2H), 2.47 (m, 4H), 2.58 (s, 6H), 2.70 (m, 2H), 2.82 (m, 2H), 2.99–3.24 (m, 4H), 3.26 (s, 3H), 3.38 (m, 2H), 3.48 (s, 6H), 3.52–3.85 (m, 10H), 3.98 (m, 4H), 4.49 (m, 2H), 5.93 (m, 2H), 7.73 (d, 1H, J = 2.7 Hz), 7.88 (s, 2H), 8.25 (m, 1H), 8.33
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(dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.58 (m, 1H), 8.70 (m, 1H), 9.04 (d, 1H, J = 9.4 Hz), 9.14 (d, 1H, J = 10.1 Hz); δF (470 MHz, CD3COOD) −81.93 (m, 3F), −114.06 (m, 2F), −124.31 (m, 2F), −126.61 (m, 2F). MALDI-TOF MS m/z 1090.5 (M)+; HRMS m/z 1090.3828 (M)+ (1090.3716 calculated). Compounds 9b and 9c were synthesized similarly. Compound 9b. Yield = 20 mg (65%). δH (500 MHz, CD3COOD) 2.27–2.38 (m, 2H), 2.49 (m, 4H), 2.63 (s, 6H), 2.73 (m, 2H), 2.85 (m, 2H), 3.04–3.13 (m, 2H), 3.17 (m, 2H), 3.27 (s, 3H), 3.37 (m, 2H), 3.49 (s, 6H), 3.55–3.90 (m, 10H), 3.96–4.05 (m, 4H), 4.52 (m, 2 H), 5.97 (m, 2H), 7.78 (d, 1H, J = 2.7 Hz), 7.92 (s, 2H), 8.28 (dd, 1H, J = 8.7 Hz, 6.7 Hz), 8.35 (dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.61 (m, 1H), 8.78 (d, 1H, J = 8.7 Hz), 9.08 (d, 1H, J = 9.4 Hz), 9.19 (d, 1H, J = 10.1 Hz); δF (470 MHz, CD3COOD) −81.69 (m, 3F), −113.90 (m, 2F), −122.39 (m, 2F), −123.39 (m, 4F), −126.73 (m, 2F). MALDI-TOF MS m/z 1191.5 (M + H)+; HRMS m/z 1190.3691 (M)+ (1190.3652 calculated). Compound 9c. Yield = 4 mg (14%). δH (500 MHz, CD3COOD) 2.27–2.38 (m, 2H), 2.48 (m, 4H), 2.62 (s, 6H), 2.72 (m, 2H), 2.85 (m, 2H), 3.02–3.21 (m, 4H), 3.27 (s, 3H), 3.38 (m, 2H), 3.49 (s, 6H), 3.55–3.92 (m, 10H), 3.96–4.08 (m, 4H), 4.51 (m, 2H), 5.97 (m, 2H), 7.77 (d, 1H, J = 2.7 Hz), 7.91 (s, 2H), 8.28 (m, 1H), 8.35 (m, 1H), 8.61 (m, 1H), 8.77 (d, 1H, J = 8.6 Hz), 9.07 (d, 1H, J = 9.4 Hz), 9.19 (d, 1H, J = 10.1 Hz); δF (470 MHz, CD3COOD) −81.67 (t, 3F, J = 10.1 Hz), −113.83 (m, 2F), −122.13 (m, 2F), −122.35 (m, 4F), −123.25 (m, 4F), −126.68 (m, 2F). MALDI-TOF MS m/z 1290.5 (M)+; HRMS m/z 1290.3627 (M)+ (1290.3588 calculated). Compound 10a. Compound 9a (20 mg, 0.018 mmol) was dissolved in methanol (2 mL) and DIPEA (0.031 mL, 0.178 mmol) and glutaric anhydride (10 mg, 0.089 mmol) were added. The reaction was stirred at room temperature for 1 hour and was then concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and DIPEA (0.062 mL, 0.355 mmol) and TSTU (107 mg, 0.355 mmol) were added. The reaction was stirred at room temperature for 1 hour. The crude reaction mixture was purified by preparative HPLC as described earlier using a 40 minute gradient of 10 → 60% MeCN–water (each with 0.05% TFA). The HPLC fractions containing product 10a were frozen at −80 °C and lyophilized to dryness. Yield = 22 mg (93%). δH (500 MHz, CD3COOD) 2.27–2.38 (m, 2H), 2.42–2.57 (m, 6H), 2.63 (s, 6H), 2.67–2.78 (m, 2H), 2.80 (m, 2H), 2.84 (m, 4H), 2.96–3.12 (m, 10H), 3.17 (m, 2H), 3.23 (s, 3H), 3.50 (s, 6H), 3.51–3.90 (m, 8H), 3.95–4.08 (m, 4H), 4.52 (m, 2H), 5.98 (m, 2H), 7.78 (d, 1H, J = 2.7 Hz), 7.93 (s, 2H), 8.29 (m, 1H), 8.36 (dd, 1H, J = 9.9 Hz, 2.7 Hz), 8.61 (m, 1H), 8.77 (m, 1H), 9.08 (d, 1H, J = 9.4 Hz), 9.19 (d, 1H, J = 10.1 Hz); δF (470 MHz, CD3COOD) −81.92 (t, 3F, J = 9.9 Hz), −114.07 (m, 2F), −124.29 (m, 2F), −126.60 (m, 2F). MALDI-TOF MS m/z 1301.7 (M)+; HRMS m/z 1301.4341 (M)+ (1301.4191 calculated). Compounds 10b and 10c were synthesized similarly. Compound 10b. Yield = 12 mg (68%). δH (500 MHz, CD3COOD) 2.27–2.35 (m, 2H), 2.42–2.57 (m, 6H), 2.60 (s, 6H), 2.67–2.78 (m, 2H), 2.78–2.94 (m, 6H), 2.95–3.12 (m, 10H), 3.17
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(m, 2H), 3.23 (s, 3H), 3.49 (s, 6H), 3.51–3.90 (m, 8H), 3.95–4.08 (m, 4H), 4.51 (t, 2H, J = 5.6 Hz), 5.97 (m, 2H), 7.77 (d, 1H, J = 2.7 Hz), 7.91 (s, 2H), 8.28 (dd, 1H, J = 8.8 Hz, 6.7 Hz), 8.35 (dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.61 (m, 1H), 8.76 (dd, 1H, J = 8.7 Hz, 1.4 Hz), 9.07 (d, 1H, J = 9.5 Hz), 9.18 (d, 1H, J = 10.1 Hz); δF (470 MHz, CD3COOD) −81.67 (m, 3F), −113.84 (m, 2F), −122.37 (m, 2F), −123.36 (m, 4F), −126.69 (m, 2F). MALDI-TOF MS m/z 1402.9 (M + H)+; HRMS m/z 1401.4303 (M)+ (1401.4133 calculated). Compound 10c. Yield = 3 mg (50%). δH (500 MHz, CD3COOD) 2.26–2.34 (m, 2H), 2.42–2.61 (m, 6H), 2.63 (s, 6H), 2.67–2.74 (m, 2H), 2.78–2.90 (m, 6H), 2.95–3.12 (m, 10 H), 3.19 (m, 2H), 3.22 (s, 3H), 3.50 (s, 6H), 3.51–3.90 (m, 8H), 3.95–4.08 (m, 4H), 4.52 (m, 2H), 5.98 (m, 2H), 7.79 (d, 1H, J = 2.7 Hz), 7.91 (s, 2H), 8.28 (dd, 1H, J = 8.7 Hz, 6.7 Hz), 8.35 (dd, 1H, J = 10.0 Hz, 2.7 Hz), 8.61 (m, 1H), 8.79 (d, 1H, J = 8.5 Hz), 9.07 (d, 1H, J = 9.4 Hz), 9.19 (d, 1H, J = 10.1 Hz); δF (470 MHz, CD3COOD) −81.66 (t, 3F, J = 10.1 Hz), −113.83 (m, 2F), −122.13 (m, 2F), −122.37 (m, 4F), −123.25 (m, 4F), −126.69 (m, 2F). MALDI-TOF MS m/z 1501.9 (M)+; HRMS m/z 1501.4374 (M)+ (1501.4069 calculated).
Acknowledgements We thank Dr Shenliang Wang for assistance in emission spectra measurements.
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