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Structure of 3973-18-0 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium hydroxide In toluene at 0 - 45℃; for 3 h; Inert atmosphere
4.2.2. 2-(Prop-2-ynyloxy)ethanol (2). A solution of propargylbromide(2.5mL, 80percent in toluene, 22.5mmol) and ethylene glycol (2.5mL) wasflushedwith argon and cooled to 0 C in an ice bath. Powdered NaOH(1.08 g, 45.0 mmol) was added and the reaction mixture was stirredat 45 C for 3 h. The precipitate was filtered, washed with DCM(23 mL), and the filtrate was extracted with DCM (310 mL). Afterevaporation of the solvent the crude productwas purified using silicagel column chromatography (Hexane:EtOAc/2:1) to yield 1.34 g (60percent)of 2 as a pale yellow oil. Rf0.25 (Hexane:EtOAc/2:1). IR: n(neat)1106; 1246; 1729; 2115; 2868; 2935; 3287; 3400 cm1. 1H NMR(CDCl3, 250 MHz): d2.42 (1H, t, J2.2 Hz), 2.99 (1H, s), 3.55 (2H, t,J4.4 Hz), 3.66 (2H, t, J4.4 Hz), 4.12 (2H, d, J2.2 Hz). 13C NMR(CDCl3, 62.5 MHz): d58.1, 61.2, 71.0, 74.6, 79.3. HRMS (ESI): [MH]calcd for C5H9O2: 101.0603, found: 101.0602.
46.9%
With sodium hydride In toluene; mineral oil at 45℃; for 3 h;
Step 12-(prop-2-ynyloxy)ethanol (JS206) Ethylene glycol (5 ml, 0.089 mol) was cooled on ice and NaH (60percent in mineral oil; 0.894 g, 0.022 mol) was added slowly to form a viscous white paste. Propargyl bromide (80percent solution in toluene; 2.49 ml, 0.022 mol) was added drop wise and the reaction mixture was stirred at 45 °C for 3h. The reaction was carefully quenched with H20 and extracted with CHCI3 (3x) and CH2CI2 (5x). The combined organic extracts were dried (MgS04), filtered and concentrated in vacuo. Flash chromatography (Pet Ether; 10percent to 50percent EtOAc/Pet Ether) afforded the title compound as a light yellow oil (1.0316 g, 0.0103 mmol, 46.9percent). Rf = 0.39 (1 :1 Pet Ether/EtOAc); IR (vmax/cm"1, thin film): 3390 (O-H stretch), 3286, 2936, 2668 (C-H stretch), 1354, 1 105, 1065, 1027; 1 H NMR (600 MHz, CDCIs): δΗ = 2.06 (bs, 1 H, 1 -H), 2.46 (J = 2.4 Hz, 1 H, 7-H), 2.65 (ap.t, J = 4.7 Hz, 2H, 3-H), 3.77 (ap.t, J = 4.3 Hz, 2H, 2-H), 4.20 (d, J = 2.3 Hz, 2H, 5-H); 13C NMR (150 MHz, CDCI3): 5c = 58.5 (C-5), 61 .8 (C-2), 71 .3 (C-3), 74.9 (C-7), 79.6 (C-6); LRMS m/z (Cl+): 101 [M+H]+; HRMS m/z (Cl+): Found 101 .06094; C5H902 requires 101 .06025;
43.2%
With sodium hydride In toluene; mineral oil at 45℃; for 7.5 h; Inert atmosphere
To a stirred solution of ethylene glycol (16.70g, 269.1mmol) under nitrogen was slowly added, portionwise, sodium hydride (2.69g, 67.3mmol, 60percent in mineral oil). Once effervescence stopped, propargyl bromide (10.0g, 67.3mmol, 80percent (w/w) in toluene) was added to the white suspension, heated to 45°C and stirred at this temperature for 7.5h. After cooling to rt, water (10cm3) was added and the mixture was extracted with chloroform (3×10cm3). The organic layers were combined, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using gradient elution from 30/70 v/v diethyl ether/ petroleum ether to 100percent diethyl ether to give the product (2.91g, 29.1mmol, 43.2percent) as pale yellow oil; (found (EI): M++Na, 123.0416. C5H8NaO2 requires M 123.0417); νmax/cm−1 (thin film) 3398 (OH), 3281 (≡CH), 2934 and 2870 (CH2), 2116 (C≡C), 1354, 1104 (C–O–C), 1065, 1027, 888; δH (300MHz, CDCl3) 4.22 (2 H, d, J 2.4, ≡CCH2), 3.80–3.75 (2H, m, CH2O), 3.67–3.65 (2H, m, CH2O), 2.48 (1 H, t, J 2.4, ≡CH), 2.33 (1H, t, J 6.0, OH); δC (100MHz, CDCl3) 79.42 (≡CH), 74.67 (C≡CH), 71.16 (CH2), 61.63 (CH2), 58.36 (CH2); ESI-MS m/z (CI) 123 (M++Na).
28%
Stage #1: Inert atmosphere Stage #2: at 20 - 45℃; for 12 h;
This compound was prepared according to a literature procedure.™ Ethylene glycol (24.83 g, 0.40 mol) was slowly added into the NaH (2.4 g, 0.1 mol) under nitrogen atmosphere. The mixture was stirred until the bubble cease. Propargyl bromide (11.9 g, 0.10 mmol) was added in slowly and the reaction was allowed to stir at 45 °C for 3 h then at room temoerature for 12 h. The reaction mixture was extracted with CH2CI2, washed with water and dried over MgS04. The crude mixture was filtered, concentrated and purified by reduced pressure distillation to give the product as a colorless liquid (2.81 g, 28percent). XH NMR (500 MHz, CDC13) δ 4.21 (d, J = 2.3, 2H, CH2C≡C), 3.82 - 3.75 (m, 2Η, CH20), 3.69 - 3.64 (m, 2Η, CH2OH), 2.46 (t, J = 2.3, 1H, C≡CH), 2.11 (s, 1H, OH). 13C MR (126 MHz, CDCI3) δ 79.6 (CH2C≡CH), 74.8 (CH2C≡CH), 71.3 (CH20), 61.9 (CH2OH), 58.6
Reference：
[1] European Journal of Organic Chemistry, 2017, vol. 2017, # 28, p. 4091 - 4103
[2] Angewandte Chemie - International Edition, 2014, vol. 53, # 15, p. 3854 - 3858[3] Angew. Chem., 2014, vol. 126, # 15, p. 3934 - 3939,5
[4] Journal of the American Chemical Society, 2012, vol. 134, # 14, p. 6491 - 6497
[5] Tetrahedron, 2014, vol. 70, # 35, p. 5961 - 5965
[6] Synthesis, 1992, # 11, p. 1164 - 1169
[7] Journal of the American Chemical Society, 2013, vol. 135, # 32, p. 12004 - 12012
[8] Journal of Organic Chemistry, 2008, vol. 73, # 1, p. 249 - 258
[9] Patent: WO2012/168733, 2012, A1, . Location in patent: Page/Page column 105-106
[10] Tetrahedron Asymmetry, 2013, vol. 24, # 13-14, p. 844 - 852
[11] Chemistry - A European Journal, 2011, vol. 17, # 9, p. 2724 - 2733
[12] Journal of Organic Chemistry, 2013, vol. 78, # 19, p. 9647 - 9658
[13] Organic and Biomolecular Chemistry, 2018, vol. 16, # 29, p. 5254 - 5274
[14] European Journal of Organic Chemistry, 2007, # 28, p. 4711 - 4720
[15] Journal of the American Chemical Society, 2013, vol. 135, # 24, p. 9055 - 9077
[16] Patent: WO2014/190024, 2014, A1, . Location in patent: Paragraph 00137
[17] Organic Letters, 2008, vol. 10, # 6, p. 1047 - 1050
[18] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 10, p. 3039 - 3042
[19] Patent: US2011/28450, 2011, A1, . Location in patent: Page/Page column 34; 36
[20] Patent: WO2011/12600, 2011, A1, . Location in patent: Page/Page column 73-74
[21] Patent: WO2016/40806, 2016, A1, . Location in patent: Paragraph 0310-0311
[22] Cell Chemical Biology, 2018, vol. 25, # 9, p. 1086 - 7,1094
[23] Chemistry - A European Journal, 2018, vol. 24, # 55, p. 14613 - 14616
23 mL of ethylene glycol (compound 33) was dissolved in 100 mL of dry tetrahydrofuran, cooled to 0 C, and 5.5 g of sodium hydride was added in small batches. After the addition was completed, the reaction was continued at this temperature for 2 hours.Weigh 10g of 3-bromopropyne in 30mL of dry tetrahydrofuran, and slowly add it to the above reaction. After completion, react at room temperature overnight. 20 mL of water was added to the reaction system, tetrahydrofuran was concentrated, and extracted with ethyl acetate (40 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5.5 g of compound 34 by column chromatography. The yield was 64.9%.
60%
With sodium hydroxide; In toluene; at 0 - 45℃; for 3h;Inert atmosphere;
4.2.2. 2-(Prop-2-ynyloxy)ethanol (2). A solution of propargylbromide(2.5mL, 80% in toluene, 22.5mmol) and ethylene glycol (2.5mL) wasflushedwith argon and cooled to 0 C in an ice bath. Powdered NaOH(1.08 g, 45.0 mmol) was added and the reaction mixture was stirredat 45 C for 3 h. The precipitate was filtered, washed with DCM(23 mL), and the filtrate was extracted with DCM (310 mL). Afterevaporation of the solvent the crude productwas purified using silicagel column chromatography (Hexane:EtOAc/2:1) to yield 1.34 g (60%)of 2 as a pale yellow oil. Rf0.25 (Hexane:EtOAc/2:1). IR: n(neat)1106; 1246; 1729; 2115; 2868; 2935; 3287; 3400 cm1. 1H NMR(CDCl3, 250 MHz): d2.42 (1H, t, J2.2 Hz), 2.99 (1H, s), 3.55 (2H, t,J4.4 Hz), 3.66 (2H, t, J4.4 Hz), 4.12 (2H, d, J2.2 Hz). 13C NMR(CDCl3, 62.5 MHz): d58.1, 61.2, 71.0, 74.6, 79.3. HRMS (ESI): [MH]calcd for C5H9O2: 101.0603, found: 101.0602.
46.9%
With sodium hydride; In toluene; mineral oil; at 45℃; for 3h;
Step 12-(prop-2-ynyloxy)ethanol (JS206) Ethylene glycol (5 ml, 0.089 mol) was cooled on ice and NaH (60% in mineral oil; 0.894 g, 0.022 mol) was added slowly to form a viscous white paste. Propargyl bromide (80% solution in toluene; 2.49 ml, 0.022 mol) was added drop wise and the reaction mixture was stirred at 45 C for 3h. The reaction was carefully quenched with H20 and extracted with CHCI3 (3x) and CH2CI2 (5x). The combined organic extracts were dried (MgS04), filtered and concentrated in vacuo. Flash chromatography (Pet Ether; 10% to 50% EtOAc/Pet Ether) afforded the title compound as a light yellow oil (1.0316 g, 0.0103 mmol, 46.9%). Rf = 0.39 (1 :1 Pet Ether/EtOAc); IR (vmax/cm"1, thin film): 3390 (O-H stretch), 3286, 2936, 2668 (C-H stretch), 1354, 1 105, 1065, 1027; 1 H NMR (600 MHz, CDCIs): deltaEta = 2.06 (bs, 1 H, 1 -H), 2.46 (J = 2.4 Hz, 1 H, 7-H), 2.65 (ap.t, J = 4.7 Hz, 2H, 3-H), 3.77 (ap.t, J = 4.3 Hz, 2H, 2-H), 4.20 (d, J = 2.3 Hz, 2H, 5-H); 13C NMR (150 MHz, CDCI3): 5c = 58.5 (C-5), 61 .8 (C-2), 71 .3 (C-3), 74.9 (C-7), 79.6 (C-6); LRMS m/z (Cl+): 101 [M+H]+; HRMS m/z (Cl+): Found 101 .06094; C5H902 requires 101 .06025;
43.2%
With sodium hydride; In toluene; mineral oil; at 45℃; for 7.5h;Inert atmosphere;
To a stirred solution of ethylene glycol (16.70g, 269.1mmol) under nitrogen was slowly added, portionwise, sodium hydride (2.69g, 67.3mmol, 60% in mineral oil). Once effervescence stopped, propargyl bromide (10.0g, 67.3mmol, 80% (w/w) in toluene) was added to the white suspension, heated to 45C and stirred at this temperature for 7.5h. After cooling to rt, water (10cm3) was added and the mixture was extracted with chloroform (3×10cm3). The organic layers were combined, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using gradient elution from 30/70 v/v diethyl ether/ petroleum ether to 100% diethyl ether to give the product (2.91g, 29.1mmol, 43.2%) as pale yellow oil; (found (EI): M++Na, 123.0416. C5H8NaO2 requires M 123.0417); numax/cm-1 (thin film) 3398 (OH), 3281 (?CH), 2934 and 2870 (CH2), 2116 (C?C), 1354, 1104 (C-O-C), 1065, 1027, 888; deltaH (300MHz, CDCl3) 4.22 (2 H, d, J 2.4, ?CCH2), 3.80-3.75 (2H, m, CH2O), 3.67-3.65 (2H, m, CH2O), 2.48 (1 H, t, J 2.4, ?CH), 2.33 (1H, t, J 6.0, OH); deltaC (100MHz, CDCl3) 79.42 (?CH), 74.67 (C?CH), 71.16 (CH2), 61.63 (CH2), 58.36 (CH2); ESI-MS m/z (CI) 123 (M++Na).
28%
This compound was prepared according to a literature procedure. Ethylene glycol (24.83 g, 0.40 mol) was slowly added into the NaH (2.4 g, 0.1 mol) under nitrogen atmosphere. The mixture was stirred until the bubble cease. Propargyl bromide (11.9 g, 0.10 mmol) was added in slowly and the reaction was allowed to stir at 45 C for 3 h then at room temoerature for 12 h. The reaction mixture was extracted with CH2CI2, washed with water and dried over MgS04. The crude mixture was filtered, concentrated and purified by reduced pressure distillation to give the product as a colorless liquid (2.81 g, 28%). XH NMR (500 MHz, CDC13) delta 4.21 (d, J = 2.3, 2H, CH2C?C), 3.82 - 3.75 (m, 2Eta, CH20), 3.69 - 3.64 (m, 2Eta, CH2OH), 2.46 (t, J = 2.3, 1H, C?CH), 2.11 (s, 1H, OH). 13C MR (126 MHz, CDCI3) delta 79.6 (CH2C?CH), 74.8 (CH2C?CH), 71.3 (CH20), 61.9 (CH2OH), 58.6
With potassium hydroxide; at 0 - 35℃;
Example 11 2-(prop-2-ynyloxy)ethanol (11b) To a mixture of 5 ml of ethylene glycol, 11a and 3.4 ml of propargyl bromide (7a) was added at 0 C. with vigorous stirring 3g of powdered KOH in portions over 5 min. A vigorous reaction ensued after a few minutes which was controlled by external cooling to keep the temperature below 35 C. After stirring for 1 hr at ambient temperature the reaction mixture was diluted with 50 ml of water and the product was extracted 5 times with ethyl acetate. The combined organic layers were once washed with sat. aq. NaCl, dried and concentrated. The product was purified by chromatography over silica, using a gradient of heptane-ethyl acetate as eluent, to provide 1.7 g of 11b as colorless oil; Rf 0.30 (heptane/ethyl acetate 1/1). NMR (CDCl3) delta 2.48 (t, 1, acetylene-H), 2.00 (t, 1, CH2O), 3.65 (t, 2, CH2), 3.77 (m, 2, CH2), 4.22 (d, 2, CH2).
With potassium hydroxide; at 0 - 35℃;
To a mixture of 5 ml of ethylene glycol, 11a and 3.4 ml of propargyl bromide (7a) was added at O0C with vigorous stirring 3 g of powdered KOH in portions over 5 min. A vigorous reaction ensued after a few minutes which was controlled by external cooling to keep the temperature below 350C. After stirring for 1 hr at ambient temperature the reaction mixture was diluted with 50 ml of water and the product was extracted 5 times with ethyl acetate. The combined organic layers were once washed with sat. aq. NaCl, dried and concentrated. The product was purified by chromatography over silica, using a gradient of heptane-ethyl acetate as eluent, to provide 1.7g of lib as colorless oil; Rf 0.30 (heptane/ethyl acetate 1/1). NMR (CDCl3) delta 2.48 (t, 1, acetylene-H), 2.00 (t, 1, CH2OH), 3.65 (t, 2, CH2), 3.77 (m, 2, CH2), 4.22 (d, 2, CH2).
Preparation of 2-(prop-2-yn-l-yloxy)ethanol 3. To a cooled ethane- 1,2-diol (1) (150 mL) was slowly added NaH oil dispersion (43.2 g) over 1 h at -30 C. The mixture was stirred at ambient temperature for additional 1 h. To the reaction mixture was slowly added 9.2 M propargyl bromide (2) solution in toluene (45.47 g) over 30 min under cooling bath (-10 C). The mixture was stirred at 50 C for 60 h. It was then partitioned between EtOAc (400 mL) and water (200 mL). The aqueous layer was separated and extracted with EtOAc (200 mL). The organic layers were combined, washed with brine (100 mL) and dried over anhydrous MgS04. The insoluble was filtered and the filtrate was evaporated in vacuo. The crude material was purified by silica gel column chromatography (silica gel: 800 g, solvent: hexanes (2 L) followed by 50% EtOAc in hexanes (4L)). The desired fractions were combined and evaporated in vacuo to give the titled compound (9.63 g, 31%) as a yellow oil. This material was used for the next reaction without further purification. [0311] LH NMR (400 MHz, CDC13) delta 4.19-4.22 (2H, m), 3.73-3.79 (2H, m), 3.63-3.67 (2H, m), 2.45 (1H, t, J= 2.4 Hz), 1.96 (1H, t, J= 6.0 Hz).
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
4-Methylbenzene-1-sulfonyl chloride (4.2 g, 0.022 mol)was added to a solution of <strong>[3973-18-0]2-(prop-2-ynyloxy)ethanol</strong> (2 g, 0.02mol), triethylamine (4.04 g, 0.04 mol) in dichloromethane (30 mL) at 0 C. Themixture was stirred at room temperature for 2 hours. Water (100 mL) was added,and the mixture was extracted with dichloromethane (3x50 mL). The combinedlayers were washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified by flashchromatography (on 24 g silica gel, eluting with ethyl acetate/ petroleum etherfrom 0% to 30%) to afford 2-(prop-2-ynyloxy)ethyl 4-methylbenzenesulfonate(3.58 g, yield: 70%) as a yellow oil. . 1HNMR (400 MHz, CDCl3) delta 2.42 (s, 1H), 2.45 (m, 3H), 3.70-3.75 (m,2H), 4.12 (s, 2H), 4.16-4.20 (m, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.81 (d, J=12.0Hz, 2H).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 6h;
Silylether 331 (0.86 g, 4 mmol) was dissolved in acetonitrile (20 mL) in a plastic culture tube and cooled to 0C. Aqueous HF (48% w/w, 1 mL) was then added and the solution stirred at 0C for 3 hours. The reaction mixture was poured slowly into 100 mL saturated aqueous NAHC03 and extracted with ether (3 x 50 mL). The combined organic extracts were washed with brine, dried (K2C03), filtered, and concentrated to afford a colorless oil (0. 5G). This oil was dissolved in anhydrous CH2CL2 (5 mL), cooled to 0C, and then Hunig's base was added (2 mL) followed by tosyl chloride (0.76 g, 4.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The solution was diluted with CHUCK (50 mL) and washed with saturated aqueous NAHC03 and brine. The aqueous washes were back-extracted with CH2C12 (50 mL). The combined organic extracts were dried on MGS04, filtered, and concentrated to give 332 as a colorless oil (0. 81G, 80% yield). Data for 332 : HNMR (3 00 MHz, CDC13) : 6 7.74 (m, 2H), 7.27 (m, 2H), 4.12 (t, J= 5 Hz, 2H), 4.05 (d, , J= 2 Hz, 2H), 3.66 (t, J = 5 Hz, 2H), 2.38 (s, 3H), 2.34 (t, J= 2 Hz, 1H) ; 13C NMR (75 MHz, CDC13) : 8 144.8, 133.0, 129.8, 128.0, 78.9, 75.0, 68.8, 67.1, 58.4, 21.6.
500 mg
With pyridine; at 0 - 4℃; for 24h;Inert atmosphere;
General procedure: 4-hydroxy-2-butanone (20, 1.00 g, 11.35 mmol) was pipetted into a dry flask and cooled to 0C under nitrogen atmosphere. 7N methanolic ammonia (11.2 mL, 79 mmol) was added via syringe, and the solution was allowed to stir at 0C for 3 hours. A solution of hydroxylamine-O-sulfonic acid (1.476 g, 13.05 mmol) in methanol (9.7 mL) was added dropwise, then was allowed to stir for an additional 16 hours while slowly warming to room temperature. The reaction was filtered through a sintered glass funnel, then transferred to a reaction vessel and re-cooled to 0C. Triethylamine (1.58 mL,11.35 mmol) was added, then molecular iodine (2.88 g, 11.35 mmol) was added slowly in 10 equal portions until the purple/brown color of iodine persisted in the reaction vessel. The solvent was removed under reduced pressure, and purification of the crude isolate via Kugelrohr distillation (60C, 1-3 torr) delivered the 2,2-diazirinyl intermediate as a clear oil (304 mg, 27% yield). A portion of this intermediate (300 mg, 3.00 mmol) was dissolved in dry pyridine (6 mL) and cooled to 0C in an ice bath. To this solution was added p-toluenesulfonyl chloride (628 mg, 3.30 mmol). The reaction mixture was allowed to stir for 24 hours at 0-4C, then was poured into a mixture of 37%w/v HCl (15 mL) and ice (80 mL). The resulting suspension was extracted 3x with ether, then the pooled organic layers were washed with 1N HCl solution, 1N NaOH solution, water, and brine. The organic extract was dried over MgSO4, vacuum filtered, and concentrated to a clear oil (428 mg, 15% yield over 3 steps) used without further purification. TLC Rf (2:1 hex:EtOAc) = 0.6. 1HNMR (500 MHz, CDCl3) delta 7.82 (d, J = 7.9 Hz, 2H), 7.37 (d, J= 7.9 Hz, 2H), 3.96 (t, J = 6.4 Hz, 2H), 2.46 (s, 3H), 1.68 (t, J= 6.4 Hz, 2H), 1.01 (s, 2H).
With hydrogen fluoride; In water; acetonitrile; at 0℃; for 3h;
Silylether 331 (0.86 g, 4 mmol) was dissolved in acetonitrile (20 mL) in a plastic culture tube and cooled to 0C. Aqueous HF (48% w/w, 1 mL) was then added and the solution stirred at 0C for 3 hours. The reaction mixture was poured slowly into 100 mL saturated aqueous NAHC03 and extracted with ether (3 x 50 mL). The combined organic extracts were washed with brine, dried (K2C03), filtered, and concentrated to afford a colorless oil (0. 5G). This oil was dissolved in anhydrous CH2CL2 (5 mL), cooled to 0C, and then Hunig's base was added (2 mL) followed by tosyl chloride (0.76 g, 4.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The solution was diluted with CHUCK (50 mL) and washed with saturated aqueous NAHC03 and brine. The aqueous washes were back-extracted with CH2C12 (50 mL). The combined organic extracts were dried on MGS04, filtered, and concentrated to give 332 as a colorless oil (0. 81G, 80% yield). Data for 332 : HNMR (3 00 MHz, CDC13) : 6 7.74 (m, 2H), 7.27 (m, 2H), 4.12 (t, J= 5 Hz, 2H), 4.05 (d, , J= 2 Hz, 2H), 3.66 (t, J = 5 Hz, 2H), 2.38 (s, 3H), 2.34 (t, J= 2 Hz, 1H) ; 13C NMR (75 MHz, CDC13) : 8 144.8, 133.0, 129.8, 128.0, 78.9, 75.0, 68.8, 67.1, 58.4, 21.6.
2-(prop-2-ynyloxy)ethyl-1H,1H,2H,2H-perfluorodecane-1-sulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With triethylamine; In dichloromethane; at 0℃;Inert atmosphere;
2-(Prop-2-ynyloxy)ethyl-lflr,l^,27/,2^-perfluorodecane-l-sulfonate (20); In a 25 mL round bottomed flask, distilled triethylamine (0.24 mL, 1.7 mmol) followed by lH,lH,2H,2H-perfluorodecane sulfonyl chloride (273 mg, 0.5 mmol) were added to a solution of <strong>[3973-18-0]2-(prop-2-ynyloxy)ethanol</strong> (140 mg, 1.4 mmol) in DCM (3.0 mL) at 0C under a nitrogen atmosphere. The mixture was allowed to stir for 3 hours before being quenched with NaHCO3, extracted with DCM, and the organic phases dried over MgSO4. The solvent was removed under reduced pressure to give a crude solid product. Purification by column chromatography on silica gel (15% Et2O in hexane) afforded the target product as a white solid (71 mg, 0.12 mmol, 23% yield).
2‐(prop‐2‐yn‐1‐yloxy)ethyl methanesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;
To a stirred solution of 2-(prop-2-yn-1-yloxy)ethanol (7.90 g, 78.9 mmol) in DCM (80.0 mL) was added TEA (15.9 g, 158 mmol) followed by the addition of a solution of methanesulfonyl chloride (13.6 g, 119 mmol) at 0 C under nitrogen atmosphere. The resulting solution was stirred for additional 2 h at room temperature. Upon completion, the reaction was quenched with water (100 mL) at 0 C. The mixture was extracted with EtOAc (2 x 100 mL). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford 2-(prop-2-yn-1-yloxy)ethyl methanesulfonate (14.0 g, 99 %) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) d 4.37-4.28 (m, 2H), 4.21 (d, J = 2.4 Hz, 2H), 3.76-3.63 (m, 2H), 3.53-3.42 (m, 1H), 3.19 (s, 3H).
With triethylamine; In diethyl ether; at 0℃;
2-(prop-2-ynyloxy)ethyl methanesulfonate (11c) A solution of 1.7 g of 11b and 3 ml of triethyl amine in 20 ml of diethyl ether was treated at 0 C. with 1.5 ml of methanesulfonyl chloride. The mixture was stirred for an additional 30 min and then diluted with 35 ml of water and extracted with ethyl acetate. The combined organic layers were washed with 1M aq. K2CO3 solution and water, dried and concentrated, to provide 2.45 of 11c as a colorless oil; Rf 0.45 (heptane/ethyl acetate 1/1). NMR (CDCl3) delta 2.48 (t, 1, acetylene-H), 3.08 (s, 3, CH3SO2), 3.82 (m, 2, CH2), 4.03 (d, 2, CH2), 4.41 (m, 2, CH2).
With triethylamine; In diethyl ether; at 0℃;
A solution of 1.7 g of lib and 3 ml of triethyl amine in 20 ml of diethyl ether was treated at O0C with 1.5 ml of methanesulfonyl chloride. The mixture was stirred for an additional 30 min and then diluted with 35 ml of water and extracted with ethyl acetate. The combined organic layers were washed with IM aq. K2CO3 solution and water, dried and concentrated, to provide 2.45 of lie as a colorless oil; Rf 0.45 (heptane/ethyl acetate 1/1).NMR (CDCl3) delta 2.48 (t, 1, acetylene-H), 3.08 (s, 3, CH3SO2), 3,82 (m, 2, CH2), 4.03( d, 2, CH2), 4.41 (m, 2, CH2).
With zinc(II) iodide; zinc;1,2-bis-(diphenylphosphino)ethane; cobalt(II) bromide; In tetrahydrofuran; at 35℃; for 1h;Inert atmosphere;
<Example 36>Production of 2-((4-methylcyclohexa-l,4-dienyl)methoxy)ethanol and2-((5-methylcyclohexa- 1 ,4-dienyl)methoxy)ethanol[Chem. 23]7.74 g (0.019 mol) of l,2-bis(diphenylphosphino)ethane, 4.05 g (0.019 mol) of cobalt bromide, 11.82 g (0.037 mol) of zinc iodide, and 2.42 g (0.037 mol) of zinc were added to 460 ml of THF, and the solution was stirred for 15 minutes at 70C. The solution was cooled to room temperature, and 74.89 g (1.10 mol) of isoprene was added thereto. Subsequently, 92.70 g (0.93 mol) of alkynyl alcohol was slowly added dropwise to the mixture in a water bath. The resulting mixture was stirred for one hour at 35C, and then the solvent was distilled off under a reduced pressure. To the residue thus obtained, 460 ml of toluene and 460 ml of water were added (stirred for 10 minutes, and left to stand for 10 minutes). The mixture was filtered through Celite in a nitrogen atmosphere, and then the organic layer of solution thus obtained was separated. The solvent was distilled off under reduced pressure, and the crude product thus obtained was purified by Claisen distillation (101C-113C, at 3 torr). Thus, 106.6 g of diene alcohol was obtained as a colorless oil. Yield 68.5% (l,4-type/l,5-type = 91/9). 'H-NMRiCDC , 300MuEtazeta)delta:1.68 (s, 3H) , 2.31 (brs, 1H), 2.64 (brs, 4H), 3.48 - 3.52 (m, 2H), 3.70 - 3.75 (m, 2H), 3.93 (s, 2H), 5.43 - 5.45 (m, 1H), 5.70 - 5.71 (m, 1H);HRMS (ESI):As CioHi602 Calculated value: [M+H]+ 167.1430Found value: 167.1432
With 1,2-bis-(diphenylphosphino)ethane; cobalt(II) bromide; zinc(II) iodide; zinc; In tetrahydrofuran; at 35℃; for 1h;
[Synthesis 6]Production of 2-((4-methylcyclohexa-l,4-dienyl)methoxy)ethanol and 2-((5-methylcyclohexa- l,4-dienyl)methoxy)ethanol(1,4type)In 460 ml of THF, 7.74 g (0.019 mol) of l,2-bis(diphenylphosphino)ethane, 4.05 g (0.019 mol) of cobalt bromide, 11.82 g (0.037 mol) of zinc iodide, and 2.42 g (0.037 mol) of zinc were dissolved, and the mixture was stirred at 70C for 15 minutes. After cooling to room temperature, 74.89 g (1.10 mol) of isoprene was added thereto, and then 92.70 g (0.93 mol) of an alkyne alcohol was added dropwise slowly, with cooling in a water bath. After stirring at 35C for 1 hour, the solvent was removed by distillation under reduced pressure. To the obtained residue, 460 ml of toluene and 460 ml of water were added (stirring: 10 minutes, allowing to stand: 10 minutes). Under nitrogen atmosphere, filtration was conducted through Celite, and then the obtained solution was phase separated. The solvent was removed by distillation under reduced pressure. The obtained crude product was purified by Claisen distillation (101 to 113C/3 torr). Thus, 106.6 g of the diene alcohols were obtained as a colorless oily substance. Yield: 68.5% (l,4-type/l,5-type=91/9).?-NIvIR (CDCI3, 300 MHz) ?:1.68 (s, 3H), 2.31 (brs, 1H), 2.64 (brs, 4H), 3.48-3.52 (m, 2H), 3.70-3.75 (m, 2H), 3.93 (s, 2H), 5.43-5.45 (m, 1H), 5.70-5.71 (m, 1H);HRMS(ESI):[M+H]+ calcd for CioHi602: 167.1430; found: 167.1432
With 1,2-bis-(diphenylphosphino)ethane; cobalt(II) bromide; zinc(II) iodide; zinc; In tetrahydrofuran; at 35℃; for 1h;
In 460 ml of THF, 1,2-bis(diphenylphosphino)ethane (7.74 g, 0.019 mol), cobalt bromide (4.05 g, 0.019 mol), zinc iodide (11.82 g, 0.037 mol), and zinc (2.42 g, 0.037 mol) were dissolved, followed by stirring at 70 C. for 15 minutes. After cooling to room temperature, isoprene (74.89 g, 1.10 mol) was added. Then, an alkyne alcohol (92.70 g, 0.93 mol) was slowly added dropwise with cooling in a water bath. After stirring at 35 C. for 1 hour, the solvent was evaporated under reduced pressure, and the obtained crude product was purified by Claisen distillation (101 to 113 C./3 torr). Thus, 106.6 g of the title compounds, diene alcohols, were obtained as a colorless oily substance. [0113] Yield: 68.5% (1, 4 type/1, 5 type=91/9). Note that the following NMR spectrum data are those of the major product (1,4 type). [0114] 1H NMR (CDCl3, 300 MHz): delta 5.71-5.70 (m, 1H), 5.45-5.43 (m, 1H), 3.93 (s, 2H), 3.75-3.70 (m, 2H), 3.52-3.48 (m, 2H), 2.64 (brs, 4H), 2.31 (brs, 1H), 1.68 (s, 3H); [0115] HRMS (ESI): calcd for C10H17O [M+H]+167.1430, found 167.1432
<Example 37>Production of 2-((4-methylcyclohexa-l,4-dienyl)methoxy)ethyl 4-methylbenzenesulfonate and 2-((5 -methylcyclohexa- 1 ,4-dienyl)methoxy)ethyl 4-methylbenzenesulfonate[Chem. 24] 100.00 g (0.59 mol) of the diene alcohol obtained in Example 36, 90.29 g (0.89 mol) of Iriethylamine, and 73.20 g (0.89 mol) of 1-methylimidazole were dissolved in 400 ml of toluene. In an ice bath, a toluene solution (400 ml) of 130.33 g (0.68 mol) of p-toluenesulfonyl chloride was slowly added dropwise to the solution, and then the resulting mixture was stirred for one hour at room temperature. Water was added thereto, and the organic layer was separated. The obtained organic layer was washed sequentially with 15% sulfuric acid, water, and a saturated aqueous sodium hydrogen carbonate. The solvent was distilled off under reduced pressure, and thus 188.01 g of the desired tosylate was obtained as a colorless oil. Yield 98.1% (l,4-type/l,5-type = 91/9).1.67 (s, 3H), 2.44 (s, 3H), 2.58 (brs, 4H), 3.58 - 3.55 (m, 2H), 3.84 (s, 2H), 4.18 - 4.14 (m, 2H), 5.41 - 5.40 (m, 1H), 5.64 - 5.63 (m, 1H), 7.33 (d, J = 8.3 Hz, lH), 7.80 (d, J = 8.3 Hz, 1H);HRMS (ESI):Calculated value: [M+H]+ 323.1312Found value: 323.1325
[Synthesis 7]Production of 2-((4-methylcyclohexa- l,4-dienyl)methoxy)ethyl4-methylbenzenesulfonate and 2-((5-methylcyclohexa- l,4-dienyl)methoxy)ethyl 4-methylbenzenesulfonate (1,4type) (1,4type)+ +In 400 ml of toluene, 100.00 g (0.59 mol) of the diene alcohols obtained in Synthesis 6, 90.29 g (0.89 mol) of triethylamine, 73.20 g (0.89 mol) of 1-methylimidazole were dissolved. To this solution cooled in an ice bath, a toluene solution (400 ml) of 130.33 g (0.68 mol) of p-toluenesulfonyl chloride was added dropwise slowly, followed by stirring at room temperature for 1 hour. Water was added thereto, and phase separation was conducted. The obtained organic layer was washed with 15% sulfuric acid, water, and saturated aqueous sodium hydrogen carbonate in this order. The solvent was removed by distillation under reduced pressure. Thus, 188.01 g of the target tosylates were obtained as a colorless oily substance. Yield: 98.1% (l,4-type/l,5-type=91/9). ?-NMR (CDC13, 300 MHz) ?:1.67 (s, 3H), 2.44 (s, 3H), 2.58 (brs, 4H), 3.58-3.55 (m, 2H), 3.84 (s, 2H), 4.18-4.14 (m, 2H), 5.41-5.40 (m, 1H), 5.64-5.63 (m, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H);HRMS (ESI):[M+H]+ calcd for C17H22O4S: 323.1312; found: 323.1325
The diene alcohols (100.00 g, 0.59 mol) obtained in Example 16, triethylamine (90.29 g, 0.89 mol), and 1-methylimidazole (73.20 g, 0.89 mol) were dissolved in 400 ml of toluene. With cooling in an ice-bath, a toluene solution (400 ml) of p-toluenesulfonyl chloride (130.33 g, 0.68 mol) was slowly added dropwise, followed by stirring at room temperature for 1 hour. Water was added thereto, and the resultant layers were separated from each other. The obtained organic layer was washed with 15% sulfuric acid, water, and saturated aqueous sodium hydrogen carbonate in this order. The solvent was evaporated under reduced pressure. Thus, 188.01 g of the target title compounds, tosylates, were obtained as a colorless oily substance. Yield: 98.1%. Note that the following NMR spectrum data are those of the major product (1,4 type). [0118] 1H NMR (CDCl3, 300 MHz): delta 7.80 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.3 Hz, 2H), 5.64-5.63 (m, 1H), 5.41-5.40 (m, 1H), 4.18-4.14 (m, 2H), 3.84 (s, 2H), 3.58-3.55 (m, 2H), 2.58 (brs, 4H), 2.44 (s, 3H), 1.67 (s, 3H); [0119] HRMS (ESI): calcd for C17H23O4S [M+H]+323.1312, found 323.1325
4-methyl-N-((1R,2R)-2-(2-((4-methylcyclohexa-1,4-dienyl)methoxy)ethylamino)-1,2-diphenylethyl)benzenesulfonamide hydrochloride[ No CAS ]
4-methyl-N-((1R,2R)-2-(2-((5-methylcyclohexa-1,4-dienyl)methoxy)ethylamino)-1,2-diphenylethyl)benzenesulfonamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
<Example 38>Production of4-methyl-N-(( 1 R,2R)-2-(2-((4-methylcyclohexa- 1 ,4-dienyl)methoxy)ethylamino)- 1 ,2-diphenylethyl)ben zenesulfonamide hydrochloride and4-methyl-N-(( 1 R,2R)-2-(2-((5-methylcyclohexa- 1 ,4-dienyl)methoxy)ethylamino)- 1 ,2-diphenylethyl)ben zenesulfonamide hydrochloride[Chem. 25]2.2 g (6.9 mmol) of the tosylate obtained in Example 37 was dissolved in 10 ml of toluene, and 0.90 g (6.9 mmol) of DEPEA and 2.53 g (6.9 mmol) of (R,R)-TsDPEN were added to the solution. The resulting mixture was stirred for 27 hours at 135C. Water was added thereto, and the organic layer was separated. The obtained organic layer was washed with water, then 20% hydrochloric acid was added thereto. The resulting mixture was stirred for one hour at room temperature, and then was precipitated under ice cooling. Crystals precipitated therefrom were collected by filtration, and thus 3.14 g of the desired diamine hydrochloride was obtained as a white solid. Yield 82.3%.'H-NMRiCDCla, 300MHz)5:1.43-1.80(m, 6H), 2.32(s, 3H), 2.42-2.70(m, 2H), 3.40-3.55(m, 2H), 3.70-3.85(m, 2H) ,3.77(d, lH), 4.30(m, lH), 4.45 (d, lH), 6.93-7.38(m, 14H);HRMS (ESI):As C3iH37N203SCalculated value: [M-C1]+ 517.2519Found value: 517.2523
<Example 39>Production of RuCl((R,R)-0-HT-Tsdpen)[Chem. 26]25.15 g (45.20 mmol) of the diamine hydrochloride produced in Example 38 was dissolved in 375 ml of 3-methoxypropanol and 75 ml of water. 10.74 g (41.09 mmol) of ruthenium trichloride trihydrate and 3.45 g (41.09 mmol) of sodium hydrogen carbonate were added to the solution, and the resulting mixture was stirred for 45 minutes at 120C. 3-methoxypropanol was recovered, and then 425 ml of MIBK and 16.63 g (164.4 mmol) of triethylamine were added to the reaction liquid, and the mixture was stirred for one hour at 60C. Heptane was added to the residue which washed by 0.3 M hydrochloric acid, and the residue was subjected to crystallization. And thus 22.26 g of the desired Ru complex was obtained. Yield 83.3%.'H-NMRiCDCls, 500MuEtazeta)delta:2.26 (s, 3H), 2.52 (s, 3H), 3.14 - 3.10 (m, 1H), 3.60 - 3.56 (m, lH), 3.98 - 3.91 (m, 4H), 4.58 - 4.45 (m, 2H), 4.96 - 4.92 (m, lH), 5.46 (brd, J = 3.6 Hz, 1H), 5.62 (d, J = 6.3 Hz, 1H), 5.75 (d, J = 6.3 Hz, 1H), 6.05 (brd, J = 3.6 Hz, 1H), 6.60 (d, J = 7.3 Hz, 2H), 6.75 - 6.69 (m, 4H),7.21 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 7.3 Hz, 1H), 6.88 (d, J = 8.0 Hz, 2H), 7.17 - 7.08 (m, 4H);HRMS (ESI): Calculated value: [M+H]+ 651.1057Found value: 651.1008
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
General procedure: Method A To a solution of compound 3 (150 mg, o.27 mmol), alcohol (0.81 mmol), and EDCI (576 mg, 3.0 mmol) in CH2Cl2 (30 mL) was added DMAP (122 mg, 1.0 mmol), and the mixture was stirred at room temperature for 12 h. Ethyl acetate (60 mL) was added, and the organic phase was washed three times with water, once with brine, dried, and finally concentrated. There is no need to further purify the residue.
N-((1R,2R)-2-amino-1,2-diphenylethyl)-2,4,6-triisopropylbenzenesulfonamide[ No CAS ]
[ 3973-18-0 ]
[ 98-59-9 ]
[ 78-79-5 ]
[ 1433838-11-9 ]
Yield
Reaction Conditions
Operation in experiment
10.53 g
[Synthesis 8]Production of 2,4,6-triisopropyl-N-((lR,2R)-2-(2-((4-methylcyclohexa-l,4-dienyl)methoxy)etheyl amino)- l,2-diphenylethy)benzenesulfonamide In 25 ml of toluene, 6.03 g (18.82 mmol) of the above-described tosylates obtained in Synthesis 7 were dissolved. To this solution, 2.43 g (18.82 mmol) of DIPEA and 9.00 g (18.80 mmol) of (R,R)-TIPPsDPEN were added, foUowed by stirring at 135C for 13 hours. After that, the solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene/ethyl acetate=20/l>15/l). Thus, 10.53 g of the title compound was obtained as a colorless oily substance. Yield: 89.0%. ?-NMR (CDCI3, 300 MHz) 5:1.06 (d, J=6.9 Hz, 3H), 1.21 (d, J=6.9 Hz, 3H), 1.87 (brs, 1H), 1.68 (s, 3H), 2.60 (brs, 4H), 2.71-2.48 (m, 2H), 3.52-3.34 (m, 2H), 3.55 (d, J=8.9 Hz, 1H), 3.77 (s, 2H), 3.95 (septet, J=6.7 Hz, 3H), 4.40 (d, J=8.9 Hz, 1H), 5.44 (m, 1H), 5.64 (m, 1H),6.52 (brs, 1H), 6.74-7.28 (m, 12H);HRMS(ESI):[M+H]+ calcd for C39H53N2O3S: 629.3771; found: 629.3771
[Synthesis 10]Production of N-((lR,2R)-2-(2-((4-methylcyclohexa-l,4-dienyl)methoxy)ethylamino)-l,2-diphen ylethyl)-2-(trifluoromethyl)benzenesulfonamide hydrochlorideIn 31.6 ml of toluene, 8.07 g (26.1 mmol) of the above-described tosylates obtained in Synthesis 7 were dissolved. To this solution, 3.38 g (26.2 mmol) of DIPEA, 10.00 g (23.8 mmol) of (R,R)-0-TFTsDPEN and 4.34 g (26.2 mmol) of potassium iodide were added, followed by stirring at 135C for 6 hours. The reaction solution was concentrated and purified with a silica gel column chromatography to obtain 10.1 g of diamine (Yield: 74.5 %). Then, 110 ml of dichloromethane and 65.3 ml of HCl in methanol solution (IN) were added to 10.1 g (17.7 mmol) of the diamine, followed by stirring for 0.5 hours, and the solvent was removed to obtain 11.1 g of the target diamine hydrochloride. Yield: 93.9%?- MRCDMSO, 300MHz) 8:1.62(m, 3H), 2.60(s, 3H), 2.78-3.12(m, 2H), 3.52-3.70(m, 2H), 3.86(s, 2H) ,4.75(m,1H), 4.92(m, 1H), 5.40(m, 1H), 5.68(m, 1H), 6.75-7.35(m, 10H), 7.40(t, 1H), 7.50(t, 1H), 7.60(d, 1H), 7.75(d, 1H), 8.90(m, 1H), 8.98(brd, 1H), 9.92(brd, 1H);-57.16;HRMS (ESI):[M-C1]+ calcd for - HCl: 571.2237; found: 571.2244
N-((1R,2R)-2-amino-1,2-diphenylethyl)-2,4,6-trimethylbenzenesulfonamide[ No CAS ]
[ 3973-18-0 ]
[ 98-59-9 ]
[ 78-79-5 ]
[ 1360897-80-8 ]
Yield
Reaction Conditions
Operation in experiment
0.71 g
[Synthesis 12]Production of 2,4,6-trimethyl-N-((lR,2R)-2-(2-((4-methyl cyclohexa-l,4-dienyl)methoxy)ethylamino)-l,2-diphenylethyl)benzenesulfonamid eIn 5 ml of toluene, 1.0 g (3.0 mmol) of the above-described tosylates obtained in Synthesis 7 was dissolved. To this solution, 0.39 g (3.0 mmol) ofDIPEA and 1.3 g (3.3 mmol) of (R,R)-MESsDPEN were added, followed by stirring at 120C for 8 hours. After that, the solvent was removed by distillation under reduced pressure. The obtained residue was purified with a silica gel column chromatography (toluene/ethyl acetate=4/l). Thus, 0.71 g of the title compound was obtained as a colorless oily substance. Yield: 44.7 %.
[Synthesis 14]Production of 4-methyl-N-((lR,2R)-2-(2-((4-methyl cyclohexa-l,4-dienyl)methoxy)ethylamino)cyclohexyl)benzenesulfonamide hydrochlorideIn 26 ml of toluene, 5.06 g (16.4 mmol) of the above-described tosylates obtained in Synthesis 7 were dissolved. To this solution, 2.12 g (16.4 mmol) of DIPEA, 4.00 g (14.9 mmol) of (R,R)-TsCYDN and 2.72 g (16.4 mmol) of potassium iodide were added, followed by stirring at 135C for 20 hours. The reaction solution was concentrated and purified with a silica gel column to obtain 2.9 g of diamine (Yield: 46.9 %). Then, 42 ml of dichloromethane and 24.6 ml of HCI in methanol solution (IN) were added to 2.8 g (6.69 mmol) of the diamine, followed by stirring for 0.5 hours, and the solvent was removed to obtain 2.9 g of the target diamine hydrochloride. Yield: 94.7 %.H-NMRiDMSO, 300MHz) 5:0.95-1.30(m, 4H), 1.50(m, 2H), 1.63(s, 3H), 2.10(m, 2H), 2.40(s, 3H), 2.60(m, 2H), 2.95(brd, IH), 3.18(m, 2H), 3.60(m, 2H), 3.90(s, 2H), 5.40(m, IH), 5.70(m, IH), 7.40(d, IH), 7.75(d, IH), 8.15(d, IH), 8.23(brd, IH), 9.10(brd, IH)HRMS(ESI): [M-C1]+ calcd for C23H34N2O3S: 419.2363; found: 419.2365
With copper diacetate; sodium L-ascorbate; In water; N,N-dimethyl-formamide; at 70℃;
General procedure: To a mixture of azide component example 1.3 (0.80 g; 1.70 mmol) and the alkyne component 11.1 (0.564 ml; 2.37 mmol) in DMF (20 ml) is added a mixture of copper(ll) acetate (46 mg; 0.254 mmol) and sodium L-ascorbate (101 mg; 0.51 mmol) in water (2.0 ml). The mixture is stirred at 70C overnight and then exaporated to dryness. The residue is purified by silica gel column chromatography (gradient: DCM / (methanol / ammonia 9:1) 95:5 70:30. The crude product is further purified by RP-HPLC (modifier: TFA) to yield the title compound as a TFA salt. Yield: 0.401 g (36% of theory). C29H41ClN12O4 x 2 TFA ESI Mass spectrum: m/z = 657 [M+H]+; m/z = 655 [M-H]-. RP-HPLC: Rt = 0.77 min (HPLC Method 4).
2-(prop-2-yn-1-yloxy)ethyl trifluoromethanesulfonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 2,6-dimethylpyridine; In dichloromethane; at 0 - 22℃; for 2.25h;Inert atmosphere;
To a stirred solution of 2-(2-propynyloxy)ethanol (0.25g, 2.5mmol) and 2,6-lutidine (0.35g, 3.3mmol) in dichloromethane (5cm3) was added dropwise trifluoromethanesulfonic anhydride (0.70g, 2.5mmol) at 0-5C. The solution was then stirred at 5-10C for 45min, heated to 22C and stirred at this temperature for 1.5h. In a separate round-bottomed flask, triethylamine (0.37g, 3.7mmol) was added to a solution of (R,R)-TsDPEN (0.57g, 1.6mmol) in dichloromethane (3cm3) at 5C. The triflate solution was then added dropwise to this TsDPEN solution whilst maintaining the temperature between 0-5C. The reaction mixture was warmed to rt and left to stir overnight. The solution was then diluted with saturated NaHCO3 (20cm3) and extracted with dichloromethane (10cm3). The organic layer was washed further with saturated NaHCO3 (2×20cm3), water (20cm3), saturated NaCl (20cm3), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (20/80v/v EtOAc/petroleum ether) to give 6 (0.45g, 1.0mmol, yield 64.3%) as a colourless oil.
With 2,6-dimethylpyridine; In dichloromethane; at -50 - -10℃; for 2h;Inert atmosphere;
Preparation of 2-(prop-2-yn-l-yloxy)ethyl trifluoromethanesulfonate 4. To a solution of 2-(prop-2-yn-l-yloxy)ethanol (3) (1.50 g, 15.0 mmol) in (( (20 mL) was added 2,6-lutidine (2.44 mL, 21.0 mmol) followed by trifluoromethanesulfonic anhydride (3.15 mL, 18.7 mmol) at -50 C under argon atmosphere. The mixture was stirred at -10 C for 2 h. It was then partitioned between 50% EtOAc in hexanes (150 mL) and brine (15 mL). The organic layer was separated, washed with brine (15 mL) and dried over anhydrous MgS04. The insoluble was filtered and the filtrate was evaporated in vacuo. The crude material was purified by silica gel column chromatography (silica gel: 50 g, solvent 10% EtOAc in hexanes (500 mL)). The desired fractions were combined and evaporated in vacuo to give the titled compound (2.49 g, 72%) as a dark brown oil. This material was used for the next reaction without further purification. [0313] ln NMR (400 MHz, CDC13) delta 4.64-4.66 (2H, m), 4.22^1.25 (2H, m), 3.85-3.88 (2H, m), 2.48-2.49 (1H, m).
The diamine hydrochlorides (25.15 g, 45.20 mmol) of Example 18 were dissolved in a mixture solvent of 375 ml of 3-methoxypropanol and 75 ml of water. Ruthenium trichloride.trihydrate (10.74 g, 41.09 mmol) and sodium hydrogen carbonate (3.45 g, 41.09 mmol) were added thereto, followed by stirring at 120 C. for 45 minutes. After 3-methoxypropanol was recovered, 425 ml of MIBK and triethylamine (16.63 g, 164.4 mmol) were added, followed by stirring at 60 C. for 1 hour. After washing with 0.3 M hydrochloric acid, crystallization was performed by adding heptane. The precipitated crystals were collected by filtration. Thus, 22.26 g of the title compounds, ruthenium monomers, were obtained. Yield: 83.3%. Note that the following NMR spectrum data are those of the major product (1,4 type). [0126] 1H NMR (CD2Cl2, 500 MHz): delta 7.21 (d, J=8.0 Hz, 2H), 7.17-7.08 (m, 4H), 6.88 (d, J=8.0 Hz, 2H), 6.84 (d, J=7.3 Hz, 1H), 6.75-6.69 (m, 4H), 6.60 (d, J=7.3 Hz, 2H), 6.05 (brd, J=3.6 Hz, 1H), 5.75 (d, J=6.3 Hz, 1H), 5.62 (d, J=6.3 Hz, 1H), 5.46 (brd, J=3.6 Hz, 1H), 4.96-4.92 (m, 1H), 4.58-4.45 (m, 2H), 3.98-3.91 (m, 4H), 3.60-3.56 (m, 1H), 3.14-3.10 (m, 1H), 2.52 (s, 3H), 2.26 (s, 3H); [0127] HRMS (ESI): calcd for C31H34ClN2O3RuS [M+H]+651.1017, found 651.1008
The tosylates (2.2 g, 6.9 mmol) obtained in Example 17 were dissolved in 10 ml of toluene, and DIPEA (0.90 g, 6.9 mmol) and (R,R)-TsDPEN (2.53 g, 6.9 mmol) were added thereto, followed by stirring at 135 C. for 27 hours. Water was added thereto, and the resultant layers were separated from each other. The obtained organic layer was washed with water, and then 20% hydrochloric acid was added thereto. After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration under ice-cooling. Thus, 3.14 g of the target title compounds, diamine hydrochlorides, were obtained as a white solid. Yield: 82.3%. Note that the following NMR spectrum data are those of the major product (1,4 type). [0122] 1H-NMR (d6-DMSO, 300 MHz) delta: 9.76 (brs, 1H), 8.98-8.80 (m, 2H), 7.30-6.72 (m, 14H), 5.68 (m, 1H), 5.42 (m, 1H), 4.84 (m, 1H), 4.62 (m, 1H), 3.85 (s, 2H), 3.61 (m, 2H), 3.06-2.80 (m, 2H), 2.57 (brs, 4H), 2.21 (s, 3H), 1.64 (s, 3H); [0123] HRMS (ESI): calcd for C31H37N2O3S [M-Cl]+517.2519, found 517.2523
With tetrabutylammonium borohydride; 1,2-bis-(diphenylphosphino)ethane; cobalt(II) bromide; zinc(II) iodide; zinc; In dichloromethane; toluene; at 45℃; for 1h;
In 175 mL of dichloromethane, 1,2-bis(diphenylphosphino)ethane (1.73 g, 4.40 mmol), cobalt bromide (0.865 g, 4.00 mmol), and zinc iodide (4.2 g, 13.15 mmol) were dissolved, followed by stirring at 30 C. for 30 minutes. Then, 2-(propynyloxy)ethanol (8.94 g, 91.0 mmol) and butadiene (20% by weight toluene solution) (36.8 ml, 136.5 mmol) were added thereto, and then Bu4NBH4 (1.1 g, 4.3 mmol) was added. After stirring at 45 C. for 1 hour, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1). Thus, 11.7 g of the title compound, an alcohol, was obtained as a colorless oily substance. Yield: 85.0%. [0149] 1H NMR (CDCl3, 300 MHz): delta 5.80-5.60 (m, 3H), 3.92 (s, 1H), 3.72 (t, 2H), 3.48 (t, 2H), 2.75-2.60 (m, 4H), 2.22 (brs, 1H)
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0℃; for 3h;Inert atmosphere;
General procedure: Bis-boc-adenine1,2 (302 mg, 0.90 mmol) and triphenylphosphine (467 mg, 1.78 mmol) were dissolved in THF (10 mL), and the mixture was stirred at C. 2-(Prop-2-yn-1-yloxy)ethanol3 (134 mg, 1.34 mmol) and a 40% solutionof DEAD in toluene (0.82 mL, 1.79 mmol) were added. The reaction mixture was stirred for 3hours at C and then concentrated under reduced pressure. The residue was purified by flash column chromatography (0-4% CH3OH in CH2Cl2) to give the crude intermediate S1. This was dissolved in CH3OH (3.5 mL) and 3 M HCl (3.5 mL) was added. The reaction mixture was stirred at 45 C for 16 h and then neutralised by the addition of a 0.2 M aqueous solution of Na2CO3. The mixture was concentrated under reduced pressure and then dissolved in DMF followed by filtration and concentration under reduced pressure. The residue was purified by flash column chromatography (0-20% CH3OH in CH2Cl2) to give the product S2 as a white powder (51 mg, 26% over two steps).
2-(3-(6-bromoquinolin-4-yl)prop-2-ynyloxy)ethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; for 5h;Inert atmosphere;
General procedure: 6-Bromo-4-iodoquinoline (12) (1.0 equiv), Pd(PPh3)2Cl2 (0.1 equiv), CuI (0.15 equiv) and triethylamine were charged in a three neck round bottom flask. The flaskwas fitted with a N2 inlet adapterand purged with N2 for 10 min. The solution of alkyne (1.0 equiv)was then added via syringe and purged with N2 for another 10 min. The reaction mixture was stirred at 50 C for 5 h. After thecompletion of reaction, the mixture was concentrated underreduced pressure and the residue was dissolved in EtOAc, washedwith 1 N NaOH and water, then the organic phase was dried over magnesium sulfate. The crude product was purified by silica gel column chromatography yielded the desired compound. 4.1.12.6 2-(3-(6-Bromoquinolin-4-yl)prop-2-ynyloxy)ethanol (14f) This compound was prepared from <strong>[927801-23-8]6-bromo-4-iodoquinoline</strong> (12) (100 mg, 0.30 mmol) and commercially available 2-(prop-2-ynyloxy)ethanol (13f) (30 mg, 0.30 mmol) according to the general synthesis procedure E to afford the title compound (55 mg, 0.18 mmol, 60% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) delta 8.92 (d, J = 4.5 Hz, 1H, Ar-H), 8.32 (d, J = 2.0 Hz, 1H, Ar-H), 8.01 (d, J = 9.0 Hz, 1H, Ar-H), 7.95 (dd, J = 9.0, 2.0 Hz, 1H, Ar-H), 7.69 (d, J = 4.5 Hz, 1H, Ar-H), 4.73 (t, J = 5.5 Hz, 1H, OH), 4.61 (s, 2H, CH2), 3.64-3.61 (m, 2H, CH2), 3.60-3.56 (m, 2H, CH2). ESI-MS: m/z = 306 [M+H]+.
With copper(II) sulfate; sodium L-ascorbate; In tetrahydrofuran; at 20℃;Inert atmosphere;
To a solution of compound 4 (79.7 mg, 0.1 mmol) and <strong>[3973-18-0]monopropargyl ethylene glycol</strong>(15.0 mg, 0.15 mmol) under argon,Intetrahydrofuran (3 mL) was rapidly added 0.38 mL of CuSO4 (1.0Maq) and 0.75 mLof sodium ascorbate (1.0 M aq), and the reaction was allowed to proceed at roomtemperature overnight. The organic phase was dried, filtered, and subjected tocolumn chromatography to give Compound 5t (81.7 mg, yield 91%), which waspurified by chromatography on silica gel eluting with water. %).
General procedure: An oven-dried vial was charged with Cu(OTf)2 (5 mg, 0.015 mmol), LN5 (6 mg, 0.03 mmol),t-BuONa (2 mg, 0.03 mmol) and bis(pinacolato)diboron (0.9144 g, 0.36 mmol). After being sealed with a septum, the vial was connected to an argon-vacuum line and was evacuated and back filled with argon (x 3). CH3CN (2 mL) and methanol (0.9 mmol) were added and the mixture was stirred for 30 min. Then alkyne 1 (0.3 mmol) was added, the mixture usually turned to a dark brown color after addition. The mixture was stirred at 50 oC for 3h. After 3h, water were added and the aqueous phase was extracted with ethyl acetate (3 x 3 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography. Note: The carbon bearing the boron can?t be detected for all hydroboration products2in 13C NMR spectra.
With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 4 - 55℃; for 24h;Inert atmosphere;
General procedure: Alkynes 16 or 11a-11d (6mmol) were added to a solution of salinomycin azido derivative 15 (10mmol), Na ascorbate (1mmol), and copper sulphate (3mmol) in tert-butanol (5mL) at 4C, followed by adding water (5mmol), and stirring continuously for 24hat 55C. Then, the reaction was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The product was purified by flash chromatography to give 1,2,3-triazole derivatives 3a-3g and 4a-4d.
(S)-methyl 5-amino-4-(4-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate[ No CAS ]
(S)-methyl 5-amino-4-(4-(3-(2-hydroxyethoxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
A solution of (S)-methyl 5-amino-4-(4-bromo-l-oxoisoindolin-2-yl)-5-oxopentanoate (6.93 g) in DMF (40 mL) was treated with Et3N (40 mL). Nitrogen was bubbled through the mixture for 25 minutes and the mixture was split equally into 4 giving (S)-methyl 5-amino-4-(4- bromo-l-oxoisoindolin-2-yl)-5-oxopentanoate (1.732 g, 4.88 mmol) in DMF (10 mL) and triethylamine (10 mL) per vial. To each was added 2-(prop-2-yn-l-yloxy)ethanol (from for example Matrix, 0.93 mL, 9.75 mmol) and copper(l) iodide (0.074 g, 0.389 mmol). Nitrogen was again bubbled through for 2 minutes. To each reaction was then addedbis(triphenylphosphine)palladium(ll) dichloride (0.265 g, 0.378 mmol) and the sealed mixtures heated at 80C overnight. Additional 2-(prop-2-yn-l-yloxy)ethanol (0.93 mL, 9.75 mmol) was added and heating continued for a further day. The reaction mixtures were concentrated under reduced pressure and absorbed onto silica gel. Purification via chromatography (ISCO Combiflash, 80 g column, 60 ml/min, 0-93.5% (3:1 EtOAc / EtOH) / hexanes over 33 minutes) yielded the title compound (0.549 g, 1.47 mmol, 30% yield) as an orange oil. LC/MS: RT= 0.56 min, m/z = 375.1.
(2S,3S,4R)-2-azidomethylpyrrolidine-3,4-diol[ No CAS ]
C10H18N4O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 24h;
General procedure: To a 0.30mL of a solution of azide 14 (23mM in tBuOH-H2O (2: 1)) in an eppendorf, 0.10mL of a solution of the corresponding alkyne (a-s) (83mM in tBuOH) was added followed by 25muL of an aqueous solution of sodium ascorbate (30mM) and 25muL of an aqueous solution of CuSO4 (9.4mM). The final concentration of the azide 14 in each eppendorf was 15mM. The resulting mixtures were shaken at room temperature for 24h and monitored for completion by TLC and ESI-MS (see Supplementary data for mass spectra analysis). Then, the reactions were diluted with water to the desired concentration and placed in a 96-well microtiter plate in order to perform the enzymatic assays. In the preliminary screening of the resulting crude (pyrrolidin-2-yl)triazoles 14a-s, % of inhibition towards beta-glucosidase from almonds was determined at 10muM of the pyrrolidine-triazole on each well (assuming quantitative conversion in the click reaction).
(2R,3S,4R)-2-azidomethyl-pyrrolidine-3,4-diol[ No CAS ]
C10H18N4O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 24h;
General procedure: To a 0.30mL of a solution of azide 14 (23mM in tBuOH-H2O (2: 1)) in an eppendorf, 0.10mL of a solution of the corresponding alkyne (a-s) (83mM in tBuOH) was added followed by 25muL of an aqueous solution of sodium ascorbate (30mM) and 25muL of an aqueous solution of CuSO4 (9.4mM). The final concentration of the azide 14 in each eppendorf was 15mM. The resulting mixtures were shaken at room temperature for 24h and monitored for completion by TLC and ESI-MS (see Supplementary data for mass spectra analysis). Then, the reactions were diluted with water to the desired concentration and placed in a 96-well microtiter plate in order to perform the enzymatic assays. In the preliminary screening of the resulting crude (pyrrolidin-2-yl)triazoles 14a-s, % of inhibition towards beta-glucosidase from almonds was determined at 10muM of the pyrrolidine-triazole on each well (assuming quantitative conversion in the click reaction).
Step 1: 2-(prop-2-yn-1-yloxy)ethan-1-ol To a stirred mixture of sodium hydride (60% in mineral oil, 115 mg, 2.8 mmol) in anhydrous N,N-dimethylformamide (20 ml) at 0 C. was added ethane-1,2-diol (3.9 g, 63 mmol) and stirred at 0 C. for 0.5 hour. To the resulting mixture was added 3-bromoprop-1-yne (5.0 g, 42 mmol) at 0 C. and stirred at 50 C. overnight. TLC showed the reaction was complete. The reaction mixture was quenched with ice water (20 ml) and partitioned between ethyl acetate (80 ml) and water (100 ml). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (50 ml*2). The combined organic layers were washed with brine (80 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 0-20% ethyl acetate in hexane) to afford 2-(prop-2-yn-1-yloxy)ethanol (3.4 g, yield 80%) as colorless oil.
With pyridinium p-toluenesulfonate; In dichloromethane; at 0℃;
A solution of 2-(prop-2-yn-l-yloxy) ethan-l-ol (2.20 g, 21.9 mmol), 3,4- dihydro-2H-pyran (2.70 g, 32.9 mmol) and PPTS (1.10 g, 4.39 mmol) in DCM (30mL) was stirred at room temperature overnight. Solvent was evaporated under vacuum and the crude was purified by flash chromatography on silica gel eluting with ethyl acetate /petroleum ether (0%- 50%) to yield 1.80 g (44% yield) of the title compound as a colorless oil. NMR (300 MHz, DMSO-c) delta 4.60 - 4.51 (m, 1H), 4.14 (d, J = 2.4 Hz, 2H), 3.78 - 3.65 (m, 2H), 3.60 - 3.35 (m, 5H), 1.73 - 1.58 (m, 2H), 1.50 - 1.40 (m, 4H).
General procedure: General synthetic procedure of alkyne derivatives 6. A solution ofCX-4945 (350.0 mg, 1.0 mmol) and TBTU (385.0 mg, 1.2 mmol) in20 mL of acetone was stirred at room temperature. After 15 min, excessTEA was added and the reaction mixture was stirred for another 15 min.Alkynol 5 (1.2 mmol) was then added and the reaction mixture waskept stirring under reflux for 24 h. The solvent was then removed byevaporation under reduced pressure, and DCM was added. The organiclayer was washed with saturated NaHCO3 solution twice and wateronce, and dried over sodium sulfate. The filtrate was concentrated under reduced pressure to give crude compounds 6a-d as yellow oil.Yields: 6a: 82.3%, 6b: 91.2%, 6c: 83.7%, 6d: 87.2%. The crude productswere used directly for the subsequent reaction without further purification.
Weigh 1g of compound 34 in 50mL of dichloromethane, add 2g of triethylamine and 3g of p-nitrophenyl chloroformate, stir overnight at room temperature, and concentrate by column chromatography to obtain 1g of compound 35.Yield: 37.7%
4-((2-azidoethyl)amino)-N-(3-chlorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
N-(3-chlorophenyl)-N'-hydroxy-4-((2-(4-((2-hydroxyethoxy)methyl)-1H-1,2,3-triazole-1-yl)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16.4%
With copper(l) iodide; In water; acetonitrile; at 20℃; for 8.5h;Cooling with ice;
4-((2-azidoethyl)amino)-N-(3-chlorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine (III-2, 0.5g, 1.55mmol) into a 50mL eggplant-shaped bottle,Add 2mL of water and 12mL of acetonitrile solution respectively.Under an ice bath, add ethoxylated propynol (181 muL, 1.86 mmol) and cuprous iodide (59 mg, 0.31 mmol), and keep stirring for 0.5 h.Then transfer to room temperature and continue to stir the reaction for about 8h,TLC monitored the reaction until the reaction was complete (developing agent: dichloromethane: methanol = 15:1 v/v); the solvent was distilled off under reduced pressure, methanol (20 mL) was added and stirred for 30 min, filtered with suction, and the solvent was distilled off under reduced pressure to obtain a light brown solid , Column chromatography purification (eluent: petroleum ether: ethyl acetate = 2:1 ~ 1:4v/v), to obtain 100mg white solid I-4, the yield was 16.4%,
4-((2-azidoethyl)amino)-N-(2-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
N-(2-fluorophenyl)-N'-hydroxy-4-((2-(4-((2-hydroxyethoxy)methyl)-1H-1,2,3-triazole-1-yl)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27.6%
With copper(l) iodide; In water; acetonitrile; at 20℃; for 8.5h;Cooling with ice;
4-((2-azidoethyl)amino)-N-(2-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine (III-3, 0.75g, 2.45mmol) into a 50mL eggplant-shaped bottle,Add 2mL of water and 12mL of acetonitrile solution respectively. Under ice bath, add ethoxylated propynol (290 muL, 2.94 mmol) and cuprous iodide (93 mg, 0.49 mmol), and keep stirring for 0.5 h.Then transfer to room temperature and continue to stir the reaction for about 8h,TLC monitored the reaction until the reaction was complete (developing agent: dichloromethane: methanol = 15:1 v/v); the solvent was distilled off under reduced pressure, methanol (20 mL) was added and stirred for 30 min, filtered with suction, and the solvent was distilled off under reduced pressure to obtain a light brown solid , Column chromatography purification (eluent: petroleum ether: ethyl acetate = 2:1 ~ 1:4v/v), to obtain 275mg white solid I-6, the yield was 27.6%,
4-((2-azidoethyl)amino)-N-(4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
N-(4-fluorophenyl)-N'-hydroxy-4-((2-(4-((2-hydroxyethoxy)methyl)-1H-1,2,3-triazole-1-yl)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17.3%
With copper(l) iodide; In water; acetonitrile; at 20℃; for 8.5h;Cooling with ice;
4-((2-azidoethyl)amino)-N-(4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine (III-4, 0.75g, 2.45mmol) into a 50mL eggplant-shaped bottle,Add 3mL of water and 18mL of acetonitrile solution respectively. Under ice bath, add ethoxylated propynol (290 muL, 2.94 mmol) and cuprous iodide (93 mg, 0.49 mmol),Keep warm and stir for 0.5h, then transfer to room temperature and continue stirring for about 8h.TLC monitored the reaction until the reaction was complete (developing agent: dichloromethane: methanol = 15:1 v/v); the solvent was distilled off under reduced pressure, methanol (20 mL) was added and stirred for 30 min, filtered with suction, and the solvent was distilled off under reduced pressure to obtain a light brown solid , Column chromatography purification (eluent: petroleum ether: ethyl acetate = 2:1 ~ 1:4v/v), to obtain 165mg white solid I-8, the yield was 17.3%,
4-((2-azidoethyl)amino)-N'-hydroxy-N-(o-tolyl)-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
N-(2-methylphenyl)-N'-hydroxy-4-((2-(4-((2-hydroxyethoxy)methyl)-1H-1,2,3-triazole-1-yl)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20.6%
With copper(l) iodide; In water; acetonitrile; at 20℃; for 8.5h;Cooling with ice;
4-((2-azidoethyl)amino)-N'-hydroxy-N-(o-tolyl)-1,2,5-oxadiazole-3-carboxamidine (III-5,0.75g , 2.45mmol) into a 50mL eggplant-shaped bottle,Add 3mL of water and 18mL of acetonitrile solution respectively.Under ice bath, add ethoxylated propynol (290 muL, 2.94 mmol) and cuprous iodide (93 mg, 0.49 mmol), and keep stirring for 0.5 h.Then transfer to room temperature and continue to stir the reaction for about 8h,TLC monitored the reaction until the reaction was complete (developing agent: dichloromethane: methanol = 15:1 v/v); the solvent was distilled off under reduced pressure, methanol (20 mL) was added and stirred for 30 min, filtered with suction, and the solvent was distilled off under reduced pressure to obtain a light brown solid , Column chromatography purification (eluent: petroleum ether: ethyl acetate = 2:1 ~ 1:4v/v),200 mg of white solid I-8 was obtained with a yield of 20.6%,
4-((2-azidoethyl)amino)-N'-hydroxy-N-(m-tolyl)-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
C17H22N8O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24.7%
With copper(l) iodide; In water; acetonitrile; at 20℃; for 8.5h;Cooling with ice;
4-((2-azidoethyl)amino)-N'-hydroxy-N-(m-tolyl)-1,2,5-oxadiazole-3-carboxamidine (III-6,0.60g , 1.98mmol) into a 50mL eggplant-shaped bottle,Add 2mL of water and 12mL of acetonitrile solution respectively.Under an ice bath, add ethoxylated propynol (230 muL, 2.37 mmol) and cuprous iodide (74 mg, 0.39 mmol), and keep stirring for 0.5 h.Then transfer to room temperature and continue to stir the reaction for about 8h,TLC monitors the reaction until the reaction is complete (developing agent: dichloromethane: methanol = 15:1 v/v);The solvent was distilled off under reduced pressure, methanol (20 mL) was added, stirred for 30 min, and filtered with suction.The solvent was distilled off under reduced pressure to obtain a light brown solid,Column chromatography purification (eluent: petroleum ether: ethyl acetate = 2:1 ~ 1:4v/v), to obtain 197mg white solid I-2, the yield was 24.7%,
4-((2-azidoethyl)amino)-N'-hydroxy-N-(p-methylphenyl)-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
N-(4-methylphenyl)-N'-hydroxy-4-((2-(4-((2-hydroxyethoxy)methyl)-1H-1,2,3-triazole-1-yl)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27.2%
With copper(l) iodide; In water; acetonitrile; at 20℃; for 8.5h;Cooling with ice;
4-((2-azidoethyl)amino)-N'-hydroxy-N-(p-methylphenyl)-1,2,5-oxadiazole-3-carboxamidine (III-7, 0.80g, 2.64mmol) into a 50mL eggplant-shaped bottle,Add 2mL of water and 12mL of acetonitrile solution respectively. Under an ice bath, add ethoxylated propynol (315 muL, 3.17 mmol) and cuprous iodide (101 mg, 0.53 mmol), and keep stirring for 0.5 h.Then transfer to room temperature and continue to stir the reaction for about 8h. TLC monitors the reaction until the reaction is complete (developing agent: dichloromethane: methanol = 15:1 v/v);The solvent was distilled off under reduced pressure, methanol (20 mL) was added and stirred for 30 min, filtered with suction, and the solvent was distilled off under reduced pressure to obtain a light brown solid, which was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 2: 1 to 1: 4v/v), to obtain 290mg white solid I-14, the yield is 27.2%,
4-((2-azidoethyl)amino)-N'-hydroxy-N-(2-bromophenyl)-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
N-(2-bromophenyl)-N'-hydroxy-4-((2-(4-((2-hydroxyethoxy)methyl)-1H-1,2,3-triazole-1-yl)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16.8%
With copper(l) iodide; In water; acetonitrile; at 20℃; for 8.5h;Cooling with ice;
4-((2-azidoethyl)amino)-N'-hydroxy-N-(2-bromophenyl)-1,2,5-oxadiazole-3-carboxamidine (III-8, 0.5g, 1.36mmol) into a 50mL eggplant-shaped bottle,Add 2mL of water and 12mL of acetonitrile solution respectively.Under an ice bath, add ethoxylated propynol (160 muL, 1.63 mmol) and cuprous iodide (52 mg, 0.27 mmol), and keep stirring for 0.5 h.Then transfer to room temperature and continue to stir the reaction for about 8h,TLC monitored the reaction until the reaction was complete (developing agent: dichloromethane: methanol = 15:1 v/v); the solvent was distilled off under reduced pressure, methanol (20 mL) was added and stirred for 30 min, filtered with suction, and the solvent was distilled off under reduced pressure to obtain a light brown solid , Column chromatography purification (eluent: petroleum ether: ethyl acetate = 2:1 ~ 1:4v/v), to obtain 100mg white solid I-16, the yield was 16.8%,
4-((2-azidoethyl)amino)-N'-hydroxy-N-(3-chloro-4-fluorophenyl)-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
N-(4-fluoro-3-chlorophenyl)-N'-hydroxy-4-((2-(4-((2-hydroxyethoxy)methyl)-1H-1,2,3-triazol-1-yl)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27.5%
With copper(l) iodide; In water; acetonitrile; at 20℃; for 8.5h;Cooling with ice;
4-((2-azidoethyl)amino)-N'-hydroxy-4-(3-chloro-4-fluorophenyl)-1,2,5-oxadiazole-3-carboxamidine ( III-9, 0.80g, 2.35mmol) into a 50mL eggplant-shaped bottle,Add 3mL of water and 18mL of acetonitrile solution respectively. Under ice bath, add ethoxylated propynol (280muL, 2.82mmol) and cuprous iodide (90mg, 0.47mmol), keep warm and stir for 0.5h, then transfer to room temperature and continue stirring for about 8h. TLC monitors the reaction Until the reaction is complete (developing agent: dichloromethane: methanol = 15:1 v/v); the solvent is distilled off under reduced pressure, methanol (20 mL) is added and stirred for 30 min, filtered with suction, and the solvent is distilled off under reduced pressure to obtain a light brown solid with a column layer Analysis and purification (eluent: petroleum ether: ethyl acetate = 2:1 ~ 1:4v/v), to obtain 285mg white solid I-18, the yield was 27.5%,
4-((2-azidoethyl)amino)-N-(4-chlorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
N-(4-chlorophenyl)-N'-hydroxy-4-((2-(4-((2-hydroxyethoxy)methyl)-1H-1,2,3-triazole-1-yl)ethyl)amino)-1,2,5-oxadiazole-3-carboxamidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16%
With copper(l) iodide; In water; acetonitrile; at 20℃; for 8.5h;Cooling with ice;
4-((2-azidoethyl)amino)-N-(4-chlorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboxamidine (III-1, 1.50g, 4.65mmol) into a 50mL eggplant-shaped bottle,Add 3mL of water and 18mL of acetonitrile solution respectively.Under ice bath, add ethoxylated propynol (544 muL, 5.58 mmol) and cuprous iodide (177 mg, 0.93 mmol), and keep stirring for 0.5 h.Then transfer to room temperature and continue to stir the reaction for about 8h. TLC monitors the reaction until the reaction is complete (developing agent: dichloromethane: methanol = 15:1 v/v);The solvent was distilled off under reduced pressure, methanol (20 mL) was added and stirred for 30 min, filtered with suction, and the solvent was distilled off under reduced pressure to obtain a light brown solid, which was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 2: 1 to 1: 4v/v), to obtain 290mg white solid I-2, the yield is 16.0%,
4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione[ No CAS ]
2-(2,6-dioxopiperidin-3-yl)-4-(3-(2-hydroxyethoxy)prop-1-yn-1-yl)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With copper(l) iodide; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 16h;
To a degassed solution of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (10.0 g, 29.66 mmol) in dry N,N-dimethylformamide (160 mL) were added [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane adduct (3.1 g, 4.44 mmol), copper(I) iodide (1.4 g, 7.36 mmol), N-ethyl-N-isopropylpropan-2-amine (100 mL) and 2-(prop-2-yn-l-yloxy)ethan-l-ol (4.4 g, 44.34 mmol). The resulting mixture was stirred at 80 C for 16 h under nitrogen. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography with 0-100% ethyl acetate in petroleum ether to afford 2-(2,6-dioxopiperi din-3 -yl)-4-(3 -(2-hydroxyethoxy)prop- 1 -yn- 1 -yl)isoindoline- 1,3- dione (3.0 g, 28%) as a gray solid. MS (ESI) calc?d for (C18H16N2O6) [M+H]+, 357.1; found, 357.0.
With phosphomolybdic acid; toluene-4-sulfonic acid In 5,5-dimethyl-1,3-cyclohexadiene at 140 - 145℃; for 8h;
5; 6 Example 5:
Add 73 grams (0.5mol) of 2,3,3,3-tetrafluoropropionic acid, 1L reaction vessel equipped with a thermometer, reflux condenser, water separator and agitator.150 grams (1.5mol) propargyloxy glycol,5 grams of p-toluenesulfonic acid, 5 grams of phosphomolybdic acid and400 grams of xylene,React at 140-145°C for 8 hours until no water is released.After the completion of the reaction, the solvent and excess propargyloxyglycol were recovered by distillation, and 112.9 g of 2,3,3,3-tetrafluoropropionic propargyloxyglycol was obtained by distillation under reduced pressure, with a yield of 99.0%.
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; copper (I) iodide; triethylamine In N,N-dimethyl-formamide at 70℃; for 5h; Inert atmosphere;
1 Step 1:
[0406] Compound C193-1 (or C192-1) (100 mg, 0.31mmol), compound C193-2 (78 mg, 0.78mmol), cuprous iodide (12 mg, 0.06mmol), Pd(dppf)Cl2 (87 mg, 0.12mmol) and triethylamine (94 mg, 0.93mmol) were dissolved in 4 mL of anhydrous DMF. The mixture was reacted with stirring at 70°C under nitrogen protection for 5h. The solvent was removed under reduced pressure, and the crude product was purified by thin layer chromatography to afford off-white solid compound C193-3 (70 mg, yield: 66.0%). LCMS: [M + H]+ = 343.
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