4.2 PLANIFICACION DE LA FUNDACION ARBOL DE LA ESPERANZA
4.2.1 RESEÑA HISTORICA
4.2.3.5 OBJETIVOS Y ACTIVIDADES POR AREA
4.2.3.5.4 AREA DE TRABAJO SOCIAL
General procedure for the synthesis of 2-hydroxyethyl tosylates 4, 39 and 40:
The compounds were synthesized as published (Bouzide and Sauve 2002).To a stirred solution of ethylene glycol (10 mmol) in methylene chloride (50 mL) were added silver oxide (1.5 eq., 3.48 g, 15 mmol), potassium iodide (0.2 eq., 332 mg, 2 mmol) and toluene sulfonyl chloride (1.1 eq., 2.1 g, 11 mmol). The mixture was stirred at room temperature for 1 hr and then filtered over a celite pad. The filtrate was concentrated and purified by flash chromatography using ethyl acetate/hexane (50/50, v/v).
2-[2-(2-hydroxyethoxy)ethoxy]ethyl tosylate 4:
A colorless oil was obtained (2.4 g, 77 %).
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H-NMR (300 MHz, CDCl3): δ = 7.80 (d, J = 8 Hz, 2H), 7.34 (d, J = 8 Hz, 2H), 4.17 (m, 2H), 3.71 (m,
4H), 3.61 (s, 4H), 3.57 (m, 2H), 2.63 (s, 1H), 2.44 (s, 3H) ppm. 13C-NMR (75 MHz, CDCl3): δ =
145.19, 133.33, 130.17, 128.31, 72.74, 71.14, 70.66, 69.49, 69.07, 62.11, 21.98 ppm. MS (ESI) calc. for [C13H20O6S + H]+.: 305.10; found: 305.31.
TLC (AcOEt/Hexane, 1/1, v/v): Rf = 0.10.
2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy]ethyl tosylate 39:
A colorless oil was obtained (1.9 g, 53 %).
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H-NMR (300 MHz, CDCl3): δ = 7.79 (d, J = 8 Hz, 2H), 7.34 (d, J = 8 Hz, 2H), 4.16 (m, 2H), 3.57 -
3.72 (m, 15H), 2.44 (s, 3H) ppm. 13C-NMR (75 MHz, CDCl3): δ = 145.12, 133.34, 130.14, 128.29,
72.79, 71.07, 70.98, 70.80, 70.66, 69.56, 69.04, 62.06, 21.96 ppm. MS (ESI) calc. for [C15H24O7S + Na]+: 371.11; found: 370.79.
Pentaethylene glycol monotosylate40:
A colorless oil was obtained (2.1 g, 54 %).
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H-NMR (300 MHz, CDCl3): δ = 7.79 (d, J = 8 Hz, 2H), 7.33 (d, J = 8 Hz, 2H), 4.15 (m, 2H), 3.58 -
3.72 (m, 19H), 2.44 (s, 3H) ppm. 13C-NMR (75MHz, CDCl3): δ = 145.10, 135.37, 130.14, 128.30,
72.82, 71.07, 70.93, 70.91, 70.87, 70.84, 70.66, 69.57, 69.01, 62.06, 21.96 ppm. MS (ESI) calc. for [C17H28O8S + Na]+: 415.14; found: 415.63.
TLC (AcOEt): Rf = 0.20.
General procedure for the synthesis of azides 5, 41 and 42:
To a stirred solution of the tosylates 4,39 or 40 (5 mmol) in dimethylformamide (20 mL) sodium azide (2 eq., 10 mmol) was added. The mixture was stirred for 16 hrs at room temperature. Dichloromethane (50 mL) was added and the mixture was washed with brine (4 x 100 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using ethyl acetate/hexane (50/50, v/v).
2-[2-(2-azidoethoxy)ethoxy]ethanol 5:
A colorless oil was obtained (0.73 g, 83 %).
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H-NMR (300 MHz, CDCl3): = 3.46 - 3.78 (m, 11 H), 3.27 - 3.46 (m, 2 H), 2.74 (br. s, 1 H) ppm. 13
C-NMR (75 MHz, CDCl3): = 72.4, 70.5, 70.2, 69.8, 61.5, 50.5 ppm.
MS (ESI) calc. for [C6H13N3O3 + Na]+: 198.09; found: 198.13.
TLC (AcOEt/Hexane, 1/1, v/v): Rf = 0.37.
2-[2-[2-(2-Azidoethoxy)ethoxy]ethoxy]ethanol41:
A colorless oil was obtained (0.69 g, 63 %).
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H-NMR (300 MHz, CDCl3): δ = 3.68 – 3.72 (m, 2H), 3.64 – 3.67 (m, 10H), 3.58 – 3.61 (m, 2H), 3.38
TLC (AcOEt): Rf = 0.25.
14-Azido-3,6,9,12-tetraoxatetradecan-1-ol 42:
A colorless oil was obtained (0.93 g, 71 %).
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H-NMR (300 MHz, CDCl3): δ = 3.67 – 3.75 (br. m, 3H), 3.65 – 3.67 (m, 13H), 3.59 .- 3.62 (m, 2H),
3.38 (t, J = 10 Hz, 2H), 2.61 (br. s, 1H) ppm. 13C-NMR (75 MHz, CDCl3): δ = 72.65, 70.83, 70.78,
70.76, 70.74, 70.71, 70.48, 70.15, 61.89, 50.82 ppm. MS (ESI) calc. for [C10H21N3O5 + Na]+: 286.14; found: 286.18.
TLC (AcOEt): Rf = 0.20.
General procedure for the synthesis of tert-butyl acetates 6, 36, 43 and 44:
To a stirred solution of the azides 5, 41 or 42 (4 mmol) in tert-butanol (30 mL), potassium tert- butoxide (1.5 eq., 6 mmol) was added. The mixture was stirred at 30 °C for 15 min and tert-butyl bromoacetate (2 eq., 8 mmol) was added. The mixture was stirred at 30 °C for 16 hrs and then the solvent was evaporated under reduced pressure. The crude product was dissolved in dichloromethane (30 mL) and washed with brine (3 x 30 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography using ethyl acetate/hexane (50/50, v/v).
Tert-butyl-2-[2-(2-(2-azidoethoxy)ethoxy)ethoxy]acetate 6:
A colorless oil was obtained (0.76 g, 2.6 mmol, 66 %).
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H-NMR (300 MHz, CDCl3): = 4.02 (s, 2 H), 3.62 – 3.72 (m, 10H), 3.38 (t, J = 5 Hz, 2H), 1.47 (s,
9H) ppm. 13C-NMR (75 MHz, CDCl3): = 169.64, 81.55, 70.74, 70.69, 70.66, 70.03, 69.06, 50.70,
28.11 ppm.
MS (ESI) calc. for [C12H23N3O5 + Na]+: 312.15; found: 312.07.
Tert-butyl-2-(2-azidoethoxy)acetate 36:
A colorless oil was obtained (0.40 g, 2.0 mmol, 49 %).
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H-NMR (300 MHz, CDCl3): = 4.02 (s, 2H), 3.72 (t, J = 5 Hz, 2H), 3.44 (t, J = 5 Hz, 2H), 1.48 (s, 9H)
ppm. 13C-NMR (75 MHz, CDCl3): = 169.43, 81.99, 70.29, 69.12, 50.97, 28.24 ppm.
MS (ESI) calc. for [C8H15N3O3 + Na]+: 224.10; found: 224.10.
TLC (AcOEt/Hexane, 1/9, v/v): Rf = 0.25.
Tert-butyl-2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]acetate 43:
A colorless oil was obtained (1.31 g, 3.9 mmol, 98 %).
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H-NMR (300 MHz, CDCl3): = 4.01 (s, 2H), 3.68 – 3.72 (m, 4H), 3.65 – 3.67 (m, 10H), 3.38 (t, J = 5
Hz, 2H), 1.47 (s, 9H) ppm. 13C-NMR (75 MHz, CDCl3): = 169.79, 81.65, 70.87, 70.84, 70.80,
70.79, 70.77, 70.74, 70.17, 69.20, 50.85, 28.26 ppm. MS (ESI) calc. for [C14H27N3O6 + Na]+: 356.18; found: 356.14.
TLC (AcOEt/Hexane, 1/1, v/v): Rf = 0.31.
Tert-butyl-2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate 44:
A colorless oil was obtained (0.64 g, 1.7 mmol, 43 %).
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H-NMR (300 MHz, CDCl3): = 4.01 (s, 2H), 3.65 – 3.71 (m, 17H), 3.38 (t, J = 5 Hz, 2H), 1.47 (s, 9H)
ppm. 13C-NMR (75 MHz, CDCl3): = 169.79, 81.65, 70.87, 70.84, 70.80, 70.79, 70.77, 70.74,
70.17, 69.20, 50.85, 28.26 ppm.
MS (ESI) calc. for [C16H31N3O7 + Na]+: 400.21; found: 400.18.
General procedure for the synthesis of azidoacetic acids 7, 37, 45 and 46:
The tert-butyl acetates 6, 36, 43 or 44 (2.4 mmol) were dissolved in dichloromethane/trifluoroacetic acid (50/50, v/v) and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was dissolved in water (40 mL). The pH was adjusted to pH = 10 by addition of an aqueous sodium hydroxide solution (1 M). The solution was washed with diethylether (3 x 40 mL) and the pH was adjusted to 2 by addition of an aqueous hydrochloric acid solution (3 M). The aqueous layer was extracted with ethyl acetate (5 x 50 mL). The combined extracts were dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The obtained products were used without further purification. Eventually, the crude was purified by flash chromatography using dichloromethane/methanol/acetic acid (90/8/2, v/v/v).
2-[2-(2-(2-azidoethoxy)ethoxy)ethoxy]acetic acid 7:
A yellowish oil was obtained (g, mmol, %).
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H-NMR (300 MHz, CDCl3): δ = 6.33 (br. S, 1H), 4.16 (s, 2H), 3.79-3.74 (m, 2H), 3.73-3.66 (m, 8H),
3.40 (t, J = 4.8 Hz, 2H) ppm. 13C-NMR (75 MHz, CDCl3): δ = 172.35, 71.62, 70.84, 70.58, 70.32,
70.21, 68.96, 50.83 ppm.
MS (ESI) calc. for C8H15N3O5 neg.: 232.21; found: 232.20.
TLC (Dichloromethane/Methanol/Acetic acid, 90/8/2, v/v/v): Rf= 0.25.
2-(2-azidoethoxy)acetic acid 37:
A yellowish oil was obtained (g, mmol, %).
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H-NMR (300 MHz, CDCl3): δ = 9.31 (br. s, 1H), 4.20 (s, 2H), 3.75 (t, J = 5 Hz, 2H), 3.46 (t, J = 5 Hz,
2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]-acetic acid 45:
A yellowish oil was obtained (g, mmol, %).
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H-NMR (400 MHz, CDCl3): δ = 10.08 (br. s, 1H), 4.11 (s, 2H), 3.68 – 3.71 (m, 2H), 3.60 – 3.65 (m,
12H), 3.33 (t, J = 5 Hz, 2H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 173.39, 71.13, 70.58, 70.53,
70.48, 70.41, 70.30, 69.94, 68.51, 50.57 ppm.
MS (ESI) calc. for [C10H19N3O6 + Na]+: 300.12; found: 300.31.
2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-acetic acid 46:
A yellowish oil was obtained (g, mmol, %).
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H-NMR (400 MHz, CDCl3): δ = 8.91 (br. s, 1H), 4.11 (s, 2H), 3.67 – 3.70 (m, 2H), 3.60 – 3.65 (m,
16H), 3.35 (t, J = 5 Hz, 2H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 173.04, 78.89, 70.53, 70.46,
70.44, 70.43, 70.30, 70.26, 70.21, 69.93, 68.66, 50.58 ppm. MS (ESI) calc. for [C12H23N3O7 + Na]+: 344.14; found: 344.34.
Synthesis of 2-azidoacetic acid 34:
The compound was synthesized as published (Parkhouse et al. 2008).
Sodium azide (2 eq., 0.98 g, 15 mmol) was dissolved in water (10 mL) and cooled on an ice bath. Bromoacetic acid (1.04 g, 7.5 mmol) was added to the mixture and was stirred at 5 °C for 2 hrs. The mixture was allowed to warm to room temperature and further stirred for 24 hrs. The mixture was acidified to pH = 5 with an aqueous hydrochloric acid solution (1 M), and extracted with diethylether (3 x 30 mL). The ethereal extract was dried and evaporated to dryness to give 2-azidoacetic acid as pale yellow oil (0.26 g, 32 %).
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Synthesis of 2-azidoethanol 35:
The compound was synthesized as published (Cheng et al. 2005).
2-Chloroethanol (16.1 mL, 200 mmol) was added to a solution of sodium azide (1.23 eq., 16.0 g, 246 mmol) and sodium hydroxide (0.1 eq., 0.8 g, 20 mmol) in water (60 mL). The mixture was stirred at room temperature for 3 days, and sodium sulfate was added (19 g). After 10 min, the mixture was extracted with dichloromethane (3 x 37 mL). The combined organic phases were dried over magnesium sulfate, filtered and evaporated. The residue was distilled to give 2-azidoethanol as colourless oil (16.4 g, 94 %).
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H-NMR (300 MHz, CDCl3): δ = 3.75 (t, J = 10 Hz, 2H), 3.41 (t, J = 10 Hz, 2H), 2.52 (s, 1H) ppm. 13C-
NMR (75 MHz, CDCl3): δ = 61.48, 53.58 ppm.
Synthesis of 2-[2-(2-azidoethoxy)ethoxy]-acetic acid 38:
To a stirred solution of 2-[2-(2-azidoethoxy)ethoxy]ethanol 5 (6 mmol) in acetone (6 mL), cooled to 5 °C, an aqueous solution of chromium oxide (3 eq., 1.8 g, 18 mmol) in hydrochloric acid (10 N, 22.5 mL) was added slowly at such a rate that the internal temperature was maintained between 5 and 15 °C. After the addition was complete, the reaction mixture was stirred at 5 °C for 1.5 hr and then at room temperature for 1 hr. After concentration under reduced pressure, the residue was dissolved in water (10 mL) and extracted with diethylether (6 x 20 mL). The combined extracts were washed with water (3 x 20 mL), dried over magnesium sulfate and concentrated. The crude was purified by flash chromatography using dichloromethane/methanol/acetic acid (90/8/2, v/v/v).
A yellowish oil was obtained (g, mmol, %).
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H-NMR (300 MHz, CDCl3): δ = 10.24 (br. s, 1H), 4.17 (s, 2H), 3.63 – 3.74 (m, 6H), 3.41 (t, J = 5 Hz,
2H) ppm. 13C-NMR (75 MHz, CDCl3): δ = 174.80, 71.03, 70.47, 70.33, 69.99, 68.29, 67.96, 50.57 ppm.
MS (ESI) calc. for [C6H11N3O4 + Na]+: 212.06; found: 212.31.