* 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.
The synthesis of an exemplary "bottom fragment" 15 for making dictyostatin and analogs is shown in Figure 1.1,3-Propanediol 3 was elaborated via Evans chiral auxiliary-based methods to the known, bis-TBS-protected Homer-Wadsworth-Emmons product 10 in nine steps. See, Phukan, P. ; Sasmal, S. ; Maier, M. E. Eur. J. Org. Chem. 2003, 1733, and Andrus, M. B. ; Argade, A. B. Tetrahedron Lett. 1996, 37, 5049.
99%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil for 0.916667 h; Inert atmosphere Stage #2: at 20℃; for 0.833333 h; Inert atmosphere
To a dried 250 mL RBF under an atmosphere of argon at room temperature was added 1 00 mL of distilled THF and 2.1 g of sodium hydride (60percent dispersion in mineral oil; Aldrich). The mixture was stirred vigorously and 1 ,3-propanediol (4.0 g, 50 mmol; Aldrich) was added over 1 0 minutes via syringe. The reaction was allowed to stir for 45 minutes before tert-butyldimethylsilyl chloride (7.9 g, 52.7 mmol; Aldrich) was added portion wise over 5 minutes. The reaction was then allowed to stir for a further 45 minutes at room temperature before being quenched slowly with 20 mL of 10percent aqueous sodium carbonate solution. This mixture was then transferred to a separatory funnel. After being vigorously shaken, the biphasic mixture was separated and the aqueous phase was further extracted with two 50 mL portions of ether. The combined organic phases are then dried with sodium sulfate and filtered through a plug of 1 inch of Celite and 1 inch of flash silica (silica gel 60, EMD) via a 100 mL sinter funnel under vacuum into a 500 mL RBF, with the sodium sulfate residue washed with a further 50 mL of ether. The collected solution was then reduced under vacuum on a Buchi rotary evaporator to give compound L, as a light yellow oil in 99percent yield and >95percent purity
99%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.916667 h; Inert atmosphere Stage #2: at 20℃; for 0.833333 h; Inert atmosphere
Synthesis of Intermediate L Compound L was prepared according to the procedure of McDougal, P. G.; Rico, J. G.; Oh, Y.-L; Condon, B. J. Org. Chem., 1986, 51, 3388-3390. To a dried 250 mL RBF under an atmosphere of argon at room temperature was added 100 mL of distilled THF and 2.1 g of sodium hydride (60percent dispersion in mineral oil; Aldrich). The mixture was stirred vigorously and 1,3-propanediol (4.0 g, 50 mmol; Aldrich) was added over 10 minutes via syringe. The reaction was allowed to stir for 45 minutes before tert-butyldimethylsilyl chloride (7.9 g, 52.7 mmol; Aldrich) was added portion wise over 5 minutes. The reaction was then allowed to stir for a further 45 minutes at room temperature before being quenched slowly with 20 mL of 10percent aqueous sodium carbonate solution. This mixture was then transferred to a separatory funnel. After being vigorously shaken, the biphasic mixture was separated and the aqueous phase was further extracted with two 50 mL portions of ether. The combined organic phases are then dried with sodium sulfate and filtered through a plug of 1 inch of Celite and 1 inch of flash silica (silica gel 60, EMD) via a 100 mL sinter funnel under vacuum into a 500 mL RBF, with the sodium sulfate residue washed with a further 50 mL of ether. The collected solution was then reduced under vacuum on a Buchi rotary evaporator to give compound L, as a light yellow oil in 99percent yield and >95percent purity. The 1H NMR spectrum in CDCI3 agreed with the previously reported data. (See, McDougal, P. G.; Rico, J. G.; Oh, Y.-L; Condon, B. J. Org. Chem., 1986, 51, 3388-3390.)
98%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 2 h; Inert atmosphere Stage #2: at 20℃;
To a solution of 60 sodium hydride (2.1g, 60percent disp. in 61 mineral oil, 52.6mmol) in dry 48 THF (60mL), a solution of 62 propane-1,3-diol (3.9mL, 52.6mmol) in dry THF (20mL) was added under argon at 0°C. The reaction mixture was stirred for 120min at the same temperature, and then a solution of 63 tert-butyldimethylsilyl chloride (7.9g, 52.6mmol) in dry THF (20ml) was added dropwise. After stirring overnight, the reaction was quenched with satd aq NaHCO3 (50ml). The aqueous layer was washed with Et2O (3×20mL). The combined organic layers were washed with brine (30ml), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give 9.81g (98percent) of alcohol 49 9 as a yellow oil, which was pure enough to be used for Mitsunobu reaction. 1H NMR (300MHz, CDCl3) δ 3.84–3.76 (m, 4H), 2.60 (s, 1H), 1.82–1.73 (m, 2H), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR (75MHz, CDCl3) δ 63.4, 62.8, 34.9, 26.5, 18.8, −4.9
90%
Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 2.5 h; Inert atmosphere Stage #2: at 20℃; Inert atmosphere Stage #3: With methanol; sodium hydrogencarbonate In tetrahydrofuran at 20℃; Inert atmosphere
To a solution of 1,3-propanediol (3 mL, 40 mmol) in THF (60 mL) was added NaH (1.2 g, 60percent, 20 mmol) at rt. After stirring for 2.5 h, TBSCl (630 mg, 4.3 mmol) was added and the mixture was stirred overnight before the addition of NaHCO3 solution in MeOH. The solution was then extracted with DCM, washed with water and brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography (30percent EtOAc in hexanes) to afford 2-((tert-butyldimethylsilyl)oxy)ethanol ether (800 mg, 90percent based on TBSCl) as a colorless oil. To a solution of this TBS ether (590 mg, 3.11 mmol) in DCM (29 mL) was added NaHCO3 and Dess-Martin periodinane at rt. After stirring for 30 min, the solution was concentrated, diluted with hexane to participate byproduct, filtered and concentrated carefully to give crude 2-((tert-butyldimethylsilyl)oxy)acetaldehyde. A solution of this crude aldehyde in t-BuOH (13 mL) and 2-methyl-2-butene (1.5 mL) was treated with a solution of NaClO2 (500 mg, 5.5 mmol) and NaH2PO4 (1.85 g, 15.4 mmol) in water (12 mL) dropwise. After stirring for 1 h, the reaction was partitioned between brine and DCM. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography (30percent EtOAc in hexanes) to afford acid 11 (431 mg, 68percent over 2 steps) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 3.91 (2H, t, J = 6.1 Hz), 2.58 (2H, t, J = 6.1 Hz), 0.89 (9H, s), 0.09 (6H, s).
90%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.75 h; Inert atmosphere Stage #2: at 0 - 20℃; for 12 h; Inert atmosphere
To a stirred solution of 1,3-propane diol 17 (3.0 g, 39.42 mmol) in dry THF (40 mL) at 0 °C was added oil free NaH (0.95 g, 39.42 mmol, 1.0 equiv) in portions over 15 min. The reaction mixture was stirred at room temperature for 30 min, then cooled to 0 °C after which TBDMSCl (5.94 g, 39.42 mmol, 1.0 equiv) was added. The reaction mixture was stirred at room temperature for 12 h. It was then quenched with ice cold water (10 mL) and the solution extracted with EtOAc (3 .x. 30 mL). The combined organic layers were washed with water, brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography using petroleum ether/EtOAc (9:1 to 4:1) as eluent to give 18 (6.75 g, 90percent) as a colorless oil. IR (CHCl3) ν = 3368, 2931, 2859, 1473, 1257, 1065, 985, 838, 774 cm-1. 1H NMR (400 MHz, CDCl3/TMS): δ = 0.033 (s, 6H), 0.86 (s, 9H), 1.71-1.74 (m, 2H), 2.93 (br s, 1H), 3.73 (t, J = 5.5 Hz, 2H), 3.78 (t, J = 5.5 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ = -5.4 (2C), 18.1, 25.7 (3C), 34.1, 62.4, 62.8.
71%
With 1H-imidazole; dmap In dichloromethane at 25℃; for 18 h; Inert atmosphere
General procedure: A mixture of (S)-3 (2.38 g, 13.52 mmol), imidazole (1.11 g, 16.38 mmol), TBSCl (2.26 g, 15.0 mmol) and DMAP (catalytic) in CH2Cl2 (30 mL) was magnetically stirred for 18 h. The mixture was poured into water (20 mL), and extracted with Et2O (3 * 10 mL). The ether layer was washed with water (2 * 10 mL) and brine (1 * 5 mL), and dried. Removal of the solvent followed by chromatography of the residue (silica gel, 0-10percent Et2O/hexane) afforded pure 5. Yield: 3.60 g (92percent).
63%
Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 1 h; Inert atmosphere Stage #2: at 0 - 20℃; for 12 h; Inert atmosphere
To a suspension of NaH (1.1 g, 27.3 mmol) in THF (40 mL) at RT was added 1,3-propanediol (2.28 g, 30 mmol) in THF (8 mL). The suspension was stirred for 1 h before being cooled to 0 °C. TBSCl (4.11 g, 27.3 mmol) in THF (10 mL) was added dropwise. The reaction mixture was allowed to warm to RT and was stirred for 12 h. The reaction was quenched by the addition of 10percent (w/w) aqueous K2CO3 (10 mL). The aqueous solution was concentrated in vacuo to remove the THF component and then was extracted with Et2O (100 mL). The combined organic extracts were washed with H2O (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by FC on silica gel (hexanes/EtOAc = 100:1-5:1) to afford the TBS ether 21 (3.27 g, 63percent) as a colorless oil
51%
With triethylamine In hexane; acetonitrile at 20℃; for 24 h; Inert atmosphere
General procedure: In a flame-dried100 mL round-bottom flask equipped with a teflon magnetic stir bar,diol(5.0 mmol) was added to acetonitrile (12.5 mL) and hexanes (37.5 mL).Triethylamine (Et3N, 0.84 mL, 6.00 mmol, 1.2 equiv) and tertbutyldimethylsilylchloride (TBSCl, 0.53 g, 5.0 mmol, 1.0 equiv) were addedto the solution and the resulting biphasic mixture was stirred vigorously atroom temperature for 24 h under a N2 atmosphere. The reaction was quenchedwith saturated aqueous ammonium chloride (NH4Cl, 50 mL), and extractedwith ethyl acetate (EtOAc, 3 50 mL). The combined organic phase waswashed with brine (3 50 mL) and dried over anhydrous sodium sulfate(Na2SO4). The crude product was purified by silica gel column chromatography(10–15percent EtOAc/hexanes).
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[ 203738-77-6 ]
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With dichlorosulfoxide; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃;
100%
Stage #1: 3-[(tert-butyldimethylsilyl)oxy]propan-1-ol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane for 0.5h;
Stage #2: With triethylamine In dichloromethane at -78 - 0℃; Further stages.;
100%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃;
100%
With Dess-Martin periodane In dichloromethane at 20℃; for 0.5h;
99%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; for 2h;
99%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78℃; for 3h;
98%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; for 1h;
98%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78℃; Inert atmosphere;
98%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78℃; Inert atmosphere;
98%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; iodosylbenzene; ytterbium(III) tris(trifluoromethanesulfonate) In dichloromethane at 0℃; for 2h;
98%
With sulphur trioxide pyridine complex; dimethyl sulfoxide; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1.5h;
98%
With sulphur trioxide pyridine complex; dimethyl sulfoxide; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 23℃; for 1.5h; Schlenk technique;
97%
Stage #1: 3-[(tert-butyldimethylsilyl)oxy]propan-1-ol With oxalyl dichloride; dimethyl sulfoxide In tetrahydrofuran at -78℃; Inert atmosphere;
Stage #2: With triethylamine In tetrahydrofuran at -78 - 20℃; for 0.25h; Inert atmosphere;
96%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 23℃; for 1h;
95%
With pyridine-SO3 complex; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 0℃;
95%
Stage #1: 3-[(tert-butyldimethylsilyl)oxy]propan-1-ol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 1h;
Stage #2: With triethylamine In dichloromethane at -78 - 20℃;
4.2. 3-((tert-Butyldimethylsilyl)oxy)propanal (6)
DMSO (2.13 mL, 30 mmol, 1.5 equiv) was added to a solution of oxalyl chloride (2.25 mL, 26 mmol, 1.3 equiv) in CH2Cl2 (90 mL) at -78 °C, the mixture was stirred for 15 min and then a solution of alcohol 5 (3807 mg, 20 mmol, 1 equiv) in CH2Cl2 (10 mL) was added to the reaction at -78 °C and the mixture was stirred for 1 h. Triethylamine (13 mL) was added to the reaction at -78 °C and the cooling bath was removed. After the mixture reach room temperature, it was diluted with Et2O (50 mL) and the organic phase was washed with water (50 mL), brine (50 mL), dried (MgSO4), and concentrated. The product was purified by flash chromatography (hexanes/EtOAc 95:5) to furnish the aldehyde (3570 mg, 19 mmol, 95 % yield) as a colorless oil. Rf 0.50 (hexanes/EtOAc 90:10). 1H NMR (250MHz, CDCl3) δ 0.03 (s, 6H), 0.85 (s, 9H), 2.56 (td, J=5.8, 1.9Hz, 2H), 3.95 (t, J=6.0Hz, 2H), 9.77 (d, J=1.6Hz, 1H). 13C NMR (62.9MHz, CDCl3) δ -5.5 (2CH3), 18.1 (C), 25.7 (3CH3), 46.5 (CH2), 57.3 (CH2), 201.8 (CH)
94%
Stage #1: 3-[(tert-butyldimethylsilyl)oxy]propan-1-ol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 1h; Inert atmosphere;
Stage #2: With triethylamine In dichloromethane at -78 - 20℃; for 0.5h;
92%
With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃;
92%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 0℃;
92%
With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃;
91%
With 2,2,6,6-tetramethyl-1-piperidinyloxy free radical; sodium chlorine monoxide; Sodium hydrogenocarbonate In dichloromethane
91%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane
91%
Stage #1: 3-[(tert-butyldimethylsilyl)oxy]propan-1-ol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -60℃; for 0.5h; Inert atmosphere;
Stage #2: With triethylamine In dichloromethane at -60 - 0℃; Inert atmosphere;
90%
With Dess-Martin periodane In dichloromethane at 20℃; for 4h;
90%
With sulphur trioxide pyridine complex; dimethyl sulfoxide; triethylamine Inert atmosphere;
90%
Stage #1: 3-[(tert-butyldimethylsilyl)oxy]propan-1-ol With oxalyl dichloride In dichloromethane; dimethyl sulfoxide at -78℃; for 1h;
Stage #2: With triethylamine In dichloromethane; dimethyl sulfoxide at -78℃;
90%
With 1-methyl-1H-imidazole; [2,2]bipyridinyl; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper(II) bromide In acetonitrile
89%
With pyridinium chlorochromate In dichloromethane at 0 - 20℃;
89%
With sulphur trioxide pyridine complex; dimethyl sulfoxide; triethylamine In dichloromethane at 0 - 20℃; for 168h;
28 Preparation of Intermediate 1g: 3-((tert-butyldimethylsilyl)oxy)propanal
Preparation of Intermediate 1g: 3-((tert-butyldimethylsilyl)oxy)propanal. [0405] In a 1 L round-bottom flask equipped with a stir bar, Tertbutyldimethylsilyloxypropanol (20 g, 105 mmol) was dissolved in DCM (500 mL). Et3N (43.9 mL, 315 mmol) was added. In a second 500 mL flask equipped with a stir bar, S03.Py (25.08 g, 158 mmol) was dissolved in DMSO (100 mL, 1409 mmol). The resulting solution was added dropwise to the alcohol solution at 0°C (in an ice-water bath). The reaction was stirred while warming to room temperature over the weekend. Water and DCM were added to the mixture in a separatory funnel. The organics were then washed with water, extracted in DCM, dried over MgS04, filtered and concentrated (cold) under reduced pressure to give crude product mixture. Purification by silica gel column chromatography (330 g column, 100% DCM) provided the title compound (17.7 g, 89%). [0406] 1H NMR (400 MHz, CDCI3) = 9.81 (t, J = 2.1 Hz, 1 H), 3.99 (t, J = 6.0 Hz, 2H), 2.61 (td, J = 6.0, 2.3 Hz, 2H), 0.88 (s, 9H), 0.07 (s, 6H).
89%
With sulphur trioxide pyridine complex; dimethyl sulfoxide; triethylamine In dichloromethane at 0 - 20℃;
1.1g Intermediate 1g: 3-((tert-butyldimethylsilyl)oxy)propanal
Intermediate 1g: 3-((tert-butyldimethylsilyl)oxy)propanal In a 1 L round-bottom flask equipped with a stir bar, Tertbutyldimethylsilyloxypropanol (20 g, 105 mmol) was dissolved in DCM (500 ml_). Et3N (43.9 ml_, 315 mmol) was added. In a second 500 ml_ flask equipped with a stirbar, S03.Py (25.08 g, 158 mmol) was dissolved in DMSO (100 ml_, 1409 mmol). The resulting solution was added dropwise to the alcohol solution at 0 C (in an ice-water bath). The reaction was stirred while warming to rt over the weekend. Water and DCM were added to the mixture in a separatory funnel. The organics were then washed with water, extracted in DCM, dried over MgS04, filtered and concentrated (cold) under reduced pressure to give crude product mixture. Purification by silica gel column chromatography (330 g column, 100% DCM) provided the title compound (17.7 g, 89%). 1H NMR (400 MHz, CDCI3) = 9.81 (t, J = 2.1 Hz, 1 H), 3.99 (t, J = 6.0 Hz, 2H), 2.61 (td, J = 6.0, 2.3 Hz, 2H), 0.88 (s, 9H), 0.07 (s, 6H).
89%
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In dimethyl sulfoxide at 20℃; for 4h;
88%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In tetrahydrofuran 1.) 1.25 h; 2.) from -78 deg C to rt., 2h;
88%
Stage #1: 3-[(tert-butyldimethylsilyl)oxy]propan-1-ol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 1h; Inert atmosphere;
Stage #2: With triethylamine In dichloromethane at -78 - 20℃; for 1.25h; Inert atmosphere;
3-((tert-Butyldimethylsilyl)oxy)propanal 22
To a solution of oxalyl chloride (1.2 mL, 14.3 mmol) in CH2Cl2 (50 mL) at -78 °C was added DMSO (2.0 mL, 28.6 mmol) in CH2Cl2 (10 mL). The solution was stirred for 30 min before primary alcohol 21 (2.47 g, 13 mmol) in CH2Cl2 (10 mL) was added. The solution was stirred at -78 °C for 1h. Et3N (9.0 mL, 65 mmol) was added and the solution was held at -78 °C for 15 min before being warmed to RT over 1 h. The reaction was quenched by the addition of H2O (12 mL). The layers were separated and the aqueous fraction was extracted with CH2Cl2 (100 mL). The combined organic fractions were washed with H2O (30 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title aldehyde 22 (2.15 g, 88%) as a colorless oil
88%
With sulphur trioxide pyridine complex; triethylamine In dichloromethane; dimethyl sulfoxide at 20℃; for 4h;
88%
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In ethyl acetate at 80℃; for 11h;
87%
With aluminum(III) oxide; pyridinium chlorochromate In dichloromethane at 20℃; for 1h;
86%
With pyridine-SO3 complex; dimethyl sulfoxide; triethylamine In dichloromethane at 0 - 20℃; for 3h;
86%
With sodium chlorine monoxide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium bromide In dichloromethane at 0℃;
86%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -60 - 20℃; for 1h; Green chemistry;
85%
With anhydrous Sodium acetate; pyridinium chlorochromate In dichloromethane for 2.5h; Ambient temperature;
85%
Stage #1: 3-[(tert-butyldimethylsilyl)oxy]propan-1-ol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 1h;
Stage #2: With triethylamine In dichloromethane at -78℃; for 0.166667h;
84%
With anhydrous Sodium acetate; pyridinium chlorochromate In dichloromethane at 0 - 25℃; for 3h; Inert atmosphere;
4.11 3-tert-Butyldimethylsilyloxypropanal 10
To a cooled (0 °C) and stirred suspension of PCC (10.6 g, 49.0 mmol) and NaOAc (0.1 equiv) in CH2Cl2 (60 mL) was added alcohol 9 (6.2 g, 32.63 mmol) in one portion. After stirring for 3 h, the reaction mixture was diluted with Et2O (60 mL) and the supernatant passed through a pad of silica gel (2″ × 1″). Removal of the solvent in vacuo followed by column chromatography of the residue (silica gel, 0-10% EtOAc/hexane) furnished pure 10. Yield: 5.15 g (84%); IR: 2712, 1726 cm-1; 1H NMR: δ 0.05 (s, 6H), 0.91 (s, 9H), 2.44-2.48 (m, 2H), 3.68 (t, J = 6.2 Hz, 2H), 9.71 (t, J = 1.4 Hz, 1H). 13C NMR: δ -6.1, -3.6, 19.2, 32.6, 64.5, 203.0. Anal. Calcd for C9H20O2Si: C, 57.39; H, 10.70. Found: C, 57.51; H, 10.94.
83%
82%
With Dess-Martin periodane In dichloromethane at 20℃; for 4h; Cooling with ice;
1.2 Step 2: Synthesis of 3-(tert-butyldimethylsilyloxy)propanal, the reaction formula is as follows:
3-(tert-Butyldimethylsilyloxy)propanol (1.90 g, 10 mmol) was dissolved in dichloromethane (20 mL)Add Dess Martin reagent (6.36g, 15mmol) under ice bath.After stirring at room temperature for 4 hours,Quenched by the addition of saturated aqueous sodium bicarbonate,Dilute with dichloromethane (100 mL),Wash twice with saturated aqueous sodium bicarbonate and once with brine.The organic layer was dried with sodium sulfate, filtered and evaporatedPurification by silica gel column chromatography to obtain 1.55 g of colorless oil, yield 82%;
78%
With aluminum(III) oxide; pyridinium chlorochromate In dichloromethane at 20℃; for 5h; Inert atmosphere;
77%
With sulphur trioxide pyridine complex; triethylamine In dimethyl sulfoxide for 0.166667h; Ambient temperature;
77%
With pyridine-SO3 complex; triethylamine In dimethyl sulfoxide at 20℃; for 0.166667h;
76%
With anhydrous Sodium acetate; pyridinium chlorochromate In dichloromethane at 20℃; for 2h;
76%
With pyridinium chlorochromate In dichloromethane at 20℃; for 3h;
76%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; Inert atmosphere;
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0℃; for 0.5h;
96%
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane for 15h; Ambient temperature;
96%
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane
87%
With 1H-imidazole; iodine; triphenylphosphine In diethyl ether; acetonitrile at 0 - 25℃; for 1.16667h; Inert atmosphere;
85%
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane for 2.5h; Inert atmosphere;
84%
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 20℃; for 2.5h; Darkness; Inert atmosphere;
82%
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; Darkness;
80%
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 20℃; for 12h; Inert atmosphere;
Synthesis of Intermediate M
To a dried 100 mL RBF under an atmosphere of argon at room temperature was added 25 mL of HPLC grade DCM, 0.81 g (5 mmol) of Compound L, 0.37 g (5.5 mmol) of imidazole (Aldrich), 1 .45 g (5.5 mmol) of triphenylphosphine (Aldrich) and 1 .4 g (5.5 mmol) of iodine (Fisher Chemicals). The reaction mixture was then stirred at room temperature for 12 hours, after which time it was diluted with hexane (100 mL) and filtered through a plug of 1 inch of Celite and 2 inches of flash silica (silica gel 60, EMD) via a 100 mL sinter funnel under vacuum into a 500 mL RBF. The collected solution was then reduced under vacuum on a Buchi rotary evaporator to give compound M, as a light clear oil in 80% yield and >95% purity. Residual triphenylphosphine may be removed by re-dissolving the product in hexane and filtering through another Celite/silica plug as described above
80%
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 20℃; for 12h; Inert atmosphere;
M Synthesis of Intermediate M
Synthesis of Intermediate M Compound M was prepared according to the procedure of Jakobsche, C. E.; Peris, G.; Miller, S. J. Angew. Chemie., Int. Ed., 2008, 47, 6707. To a dried 100 mL RBF under an atmosphere of argon at room temperature was added 25 mL of HPLC grade DCM, 0.81 g (5 mmol) of Compound L, 0.37 g (5.5 mmol) of imidazole (Aldrich), 1.45 g (5.5 mmol) of triphenylphosphine (Aldrich) and 1.4 g (5.5 mmol) of iodine (Fisher Chemicals). The reaction mixture was then stirred at room temperature for 12 hours, after which time it was diluted with hexane (100 mL) and filtered through a plug of 1 inch of Celite and 2 inches of flash silica (silica gel 60, EMD) via a 100 mL sinter funnel under vacuum into a 500 mL RBF. The collected solution was then reduced under vacuum on a Buchi rotary evaporator to give compound M, as a light clear oil in 80% yield and >95% purity. Residual triphenylphosphine may be removed by re-dissolving the product in hexane and filtering through another Celite/silica plug as described above. The 1H NMR spectrum in CDCI3agreed with the previously reported data. (See, Jakobsche, C. E.; Peris, G.; Miller, S. J. Angew. Chemie., Int. Ed., 2008, 47, 6707.)
75%
With 1H-imidazole; iodine; triphenylphosphine In acetonitrile at 0 - 20℃; for 2h; Darkness;
70%
With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 3h; Sealed tube; Inert atmosphere;
41%
With 1H-imidazole; iodine; triphenylphosphine In diethyl ether; acetonitrile at 0 - 20℃;
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0 - 20℃; for 2h;
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0 - 20℃; for 15h; Darkness;
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane for 4h; Inert atmosphere; Darkness;
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0 - 20℃; Inert atmosphere;
13.2 g
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 20℃; for 1.83333h; Inert atmosphere;
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0 - 25℃; for 16h;
1.1B [0352] STEP 1B: tert-butyl(3-iodopropoxy)dimethylsilane
Imidazole (1.50 eq) and iodine (1.35 eq) were added to a solution of PPh3 (1.20 eq) in DCM.3- ((tert-butyldimethylsilyl)oxy)propan-1-ol (1.00 eq) in DCM was added dropwise to the mixture, which was stirred at 25°C for 16 h. TLC (Petroleum ether/Ethyl acetate = 5/1, compound 3B: Rf = 0.89) indicated tert-butyl(3-iodopropoxy)dimethylsilane was consumed completely. The reaction mixture was concentrated under reduced pressure and the resulting residue purified by column chromatography (SiO2, PMA Petroleum ether/Ethyl acetate = 1/0 to 100/1).
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃;
A mixture <strong>[504-07-4]5,6-<strong>[504-07-4]dihydrouracil</strong></strong> (4.45g, [39. 028MMOL), 3-{ [TERT-] butyl (dimethyl) silyl] [OXY} PROPAN-L-OL] (3 mL, 13.01 mmol) and [CS2CO3] (16.95g, 52.04 mmol) in dry DMF (120 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. Combined organic extracts were washed with water and brine, dried over [NA2S04] and the solvent evaporated [IN VACUO.] Purified by chromatography on silica gel using ethyl acetate and hexane (60: 40) to give the title compound. Selected Signals: 1H NMR [(CDC13)] 8 5.48 (s, [1H),] 3.86 (t, 2H, J=7.5Hz, 7.45Hz), 3.68 (t, 2H, J=6.4Hz, 6.4Hz), 3.4 (m, 2H), 2.72 (t, 2H, J=6.7Hz, 6.8Hz), 1.81 (m, 2H), 0.91 (s, 9H), 0.06 (s, 6H).
With 4-methylmorpholine N-oxide In dichloromethane; acetonitrile
1.1 Step 1
Step 1 Tetrapropylammonium perruthenate (0.18 g, 5.3 mmol) was added to a mixture of methylene chloride (20 mL) and acetonitrile (2 mL) containing 3-(tert-butyldimethylsilyloxy)-propanol (2 g, 0.01 mmol), N-methylmorpholine N-oxide (1.76 g) and 4 Å molecular sieves. The reaction mixture was stirred at RT overnight and then filtered through a pad of silica gel. The filtrate was concentrated under vacuo to afford 3-(tert-butyldimethylsilyloxy)-propionaldehyde (1.3 g, 66%).
66%
With 4-methylmorpholine N-oxide In dichloromethane; acetonitrile
12.1 Step 1
Step 1 Tetrapropylammonium perruthenate (0.18 g, 5.3 mmol) was added to a mixture of methylene chloride (20 mL) and acetonitrile (2 mL) containing 3-(tert-butyldimethylsilyloxy)-propanol (2 g, 0.01 mmol), N-methylmorpholine N-oxide (1.76 g) and 4 Å molecular sieves. The reaction mixture was stirred at RT overnight and then filtered through a pad of silica gel. The filtrate was concentrated under vacuo to afford 3-(tert-butyldimethylsilyloxy)-propionaldehyde (1.3 g, 66%).
Stage #1: 3-tert-butyldimethylsilyloxy-1-propanol With sodium acetate; pyridinium chlorochromate In dichloromethane at 0 - 20℃; for 4h;
Stage #2: ethyl (triphenylphosphoranylidene)acetate In dichloromethane at 0 - 20℃; for 24h;
5.2.2. Synthesis of (E)-Ethyl 5-(tert-butyldimethylsilyloxy) pent-2-enoate (16)
To a mixture of PCC (5.1 g, 23.64 mmol, 1.5 equiv.) and NaOAc (1.94 g, 23.64 mmol, 1.5 equiv.) in dry CH2Cl2 (60 mL) was added a solution of alcohol (18) (3.0 g, 5.76 mmol) in CH2Cl2 (15 mL) at 0 °C. The reaction mixture was stirred for 4 h at rt and then diluted with petroleum ether/EtOAc (7: 3, 80 mL). The slurry was stirred and filtered through a pad of silica gel and Celite. The residue was washed 3 to 4 times with petroleum ether/EtOAc (7: 3) and filtered. The filtrate was concentrated to give virtually pure aldehyde, which was used directly in the next reaction. To a stirred solution of aldehyde (4.05 g, 18.07 mmol) in dry DCM (60 mL) at 0 °C was added C2-Wittig (6.04 g, 1.1 equivalents ylide). The mixture was stirred at room temperature for 24 h at rt, solvent was removed under vacuum and crude residue was purified by silica gel column chromatography using petroleum ether/EtOAc (9: 1) as eluent to afford 16 (3.34 g, 82% overall two stages). Colorless oil.; IR (CHCl3, cm-1): 3054, 2930, 2897, 2856, 1724, 1655, 1472, 1464, 1448, 1388, 1367, 1313, 1257, 1176, 1097, 1043, 980, 867, 837, 776, 668.; 1H NMR (400 MHz, CDCl3): δ 0.04 (s, 6H), 0.89 (s, 9H), 1.26 (t, J 7.3 Hz, 3H), 2.38-2.43 (m, 2H), 3.70 (t, J = 6.8 Hz, 2H), 4.15 (q, J = 7.3 Hz, 2H), 5.85 (dt, J = 15.6 & 1.5 Hz, 1H), 6.91 (dt, J = 15.6 & 1.5 Hz, 1H).; 13C NMR (100 MHz, CDCl3): δ 5.35, 14.23, 25.63, 25.85, 35.67, 60.14, 61.55, 122.93, 145.83, 166.48.; HRMS (ESI): Calcd. for C13H26O3Si H: 259.1729 found: 259.1721.
Stage #1: 3-tert-butyldimethylsilyloxy-1-propanol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.416667h;
Stage #2: ethyl (triphenylphosphoranylidene)acetate With triethylamine In dichloromethane at -78 - 20℃;
54
Methyl sulphoxide (1. 9MOI, 26. 8MMOL) was added to a cooled (-78°C) solution of oxalyl chloride (2. 16MOI, 24. 7MMOL) in dichloromethane (100MOI), and after 10 minutes, a solution of 3-(TERT-BUTYL-DIMETHYL-SILANYLOXY)-PROPAN-1-OL (3g, 15. 8mmol) in DICHLOROMETHANE (25ML) was added dropwise. Once addition was complete, the solution was stirred for a further 15 minutes. Triethylamine (8ml, 57. 5MMOL) was added, followed by dropwise addition of a solution of (ETHOXYCARBONYLMETHYLENE) TRIPHENYLPHOSPHORANE (10g, 29. 9MMOL) in DICHLOROMETHANE (50ml), and the reaction mixture allowed to warm to room temperature. The mixture was washed with water (4x), dried (MGS04) and concentrated under reduced pressure. The residue was pre-adsorbed onto silica gel and purified by column chromatography using diethyl ether: pentane (2.5 : 97.5) as eluant to afford the title compound, 1.3g ;'H NMR (CDCI3, 400MHZ) 8 : 0.02 (s, 6H), 0.87 (s, 9H), 1.26 (t, 3H), 2.40 (m, 2H), 3.74 (t, 2H), 4.18 (q, 2H), 5.84 (d, 1H), 6.95 (m, 1H).
6-(3-((tert-butyldimethylsilyl)oxy)propoxy)pyridazine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.2 g
With sodium hydride; In tetrahydrofuran; at 20℃; for 18h;
3-((tert-butyldimethylsilyl)oxy)propan-1-ol (2.5 g) was dissolved in tetrahydrofuran (30 mL). At 0 C., sodium hydride (0.58 g) was added to the solution, and then <strong>[35857-89-7]6-chloro-pyridazine-3-carbonitrile</strong> (1.7 g) was added thereto. The mixture was stirred for 18 hours at room temperature, and then saturated aqueous ammonium chloride solution was added thereto. The resultant was subjected to extraction with ethyl acetate, and the resultant organic layer was concentrated. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2.2 g). 1HNMR (CDCl3): 0.037 (s, 6H), 0.87 (s, 9H), 2.04 (m, 2H), 3.79 (t, 2H), 4.71 (t, 2H), 7.04 (d, 1H), 7.65 (d, 1H).
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