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HazMat fee for 500 gram (Estimated)
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USD 80+
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Structure of 927-74-2 * 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 hydrogenchloride In water at 5 - 50℃; for 3 h;
A mixture of 4-dihydro-2H-pyridine (293.2 g 3.5 mol) and concentrated HCl (1. 1 mL) was cooled to 5 °C. While continuing to cool externally, 3-BUTYN-1-OL (231.5 g, 3.3 mol) was added over a period of 30 min allowing the temperature to reach 50 °C. Reaction was held with mixing at room temperature for 2.5 hr before it was diluted with MTBE (1.0 L). The resulting mixture was washed with saturated sodium bicarbonate (2X150 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to afford 500 g (98percent crude yield) of product; GC areapercent of 96percent.
86%
With pyridinium p-toluenesulfonate In dichloromethane
2-But-3-ynyloxy-tetrahydro-pyran (2)A solution of 3-butyn-l-ol 1 (1.0Og, 14.3 mmol) and PPTS (0.72g, 2.9 mmol) in CH2Cl2 (20 niL) was treated dropwise with dihydopyran (1.7 mL, 19 mmol) and the resulting mixture was stirred for overnight. The reaction mixture was diluted with CH2Cl2 (80 mL) and washed with 0.02 N NaOH (50 mL) and brine (100 mL). The organic layer was dried over MgSC>4 and concentrated and the residue was purified with 3~5percent EtOAc in hexane on silica gel to give 1.9Og of compound 2 (12.3 mmol, 86percent yield): 1H NMR (CDCl3) δ 4.63 (t, J= 3.4 Hz, IH)5 3.92-3.77 (m, 2H), 3.59-3.45 (m, 2H), 2.47 (td, J = 7.1, 2.8 Hz, 2H), 1.96 (t, J= 2.5 Hz, IH), 1.90-1.44 (m, 6H).
84%
With pyridinium p-toluenesulfonate In dichloromethane at 0 - 20℃; for 3.5 h; Inert atmosphere
Pyridinium p-toluene sulfonate (10.43 g, 41.5 mmol) was added to a solution of 3-butyn-1-ol (30.0 mL, 396 mmol) and 3,4-dihydro-2H-pyran (37.9 mL, 415 mmol) in CH2Cl2 (150 mL), and the whole was stirred at 0 C for 2 h and then at room temperature for a further 1.5 h. The reaction was quenched with saturated aqueous NaHCO3 solution (150 mL) and the aqueous layer extracted with CH2Cl2 (150 mL). The combined organic extracts were dried (MgSO4), and the solvent removed in vacuo. The residue was purified by distillation (bp 70–102C,24 mm Hg; 96–104 C, 24 mm Hg) to yield the title compound as a pale yellow oil (51.26 g, 84percent); Rf 0.42 [petroleum ether (40–60C)–EtOAc, 5:1]. IR (neat, max, cm-1): 3291, 2941, 2870. 1H NMR (400 MHz, CDCl3, , ppm, J/Hz): 4.54 (1H, t, J = 3.5,H-2), 3.78 (1H, ddd, J = 11.7, 8.4, 3.1, H-6), 3.72 (1H, td, J = 9.7, 7.0, H-6), 3.46 (1H, td, J = 9.7, 7.0, H-1), 3.43–3.38 (1H,m, H-1), 2.38 (2H, td, J = 7.0, 2.6, H-2), 1.89 (1H, t, J = 2.6, H-4), 1.78–1.69 (1H, m, H-3), 1.62 (1H, dt, J = 11.6, 3.5, H-3),1.54–1.38 (4H, m, H-4, 5). 13C NMR (100 MHz, CDCl3, , ppm): 98.6 (CH), 81.3 (C), 69.2 (CH), 65.4 (CH2), 62.0 (CH2),30.4 (CH2), 25.3 (CH2), 19.8 (CH2), 19.3 (CH2). LC-MS (ES+) m/z 155 [M + H]+, [M]+ C9H14O2. Spectral data were consistent with literature values [18].
82%
With toluene-4-sulfonic acid In dichloromethane at 25℃; for 24 h;
A solution of 3-butyn-1-ol (50 g, 1 equiv, 713 mmol), p-toluenesulfonic acid monohydrate (1.36 g, 0.01 equiv, 7.13 mmol), and dihydropyran (71.7 mL, 1.10 equiv, 785 mmol) in dichloromethane (500 mL) is stirred at 25° C. for 24 hours. Saturated sodium bicarbonate solution (500 mL) is then slowly added, and the mixture is extracted with dichloromethane (500 mL). The organic extract is dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product, which is purified by vacuum distillation to afford the title compound (90 g, 82percent): b.p.: 65° C., 1 mm Hg.
68%
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 16 h;
To but-3-yn-1-ol (40.0 g, 570.0 mmol) and 3,4-dihydro-2H-pyran (48.0 g, 570.0 mmol) in anhydrous dichloromethane (350 mL) was added pyridium p-toluenesulfonate (0.45 g, 1.80 mmol). The mixture was stirred at room temperature for 16 hours. Solvent was evaporated, and the residue was purified by vacuum distillation to give 2-but-3-ynyloxy-tetrahydro-pyran as a light yellow liquid. Yield: 60.0 g (68percent)
68%
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 16 h;
To but-3-yn-1-ol (40.0 g, 570.0 mmol) and 3,4-dihydro-2H-pyran (48.0 g, 570.0 mmol) in anhydrous dichloromethane (350 mL) was added pyridium p-toluenesulfonate (0.45 g, 1.80 mmol). The mixture was stirred at room temperature for 16 hours. Solvent was evaporated, and the residue was purified by vacuum distillation to give 2-but-3-ynyloxy-tetrahydro-pyran as a light yellow liquid. Yield: 60.0 g (68percent).
21.8 g
With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 6 h; Cooling with ice
10.0 g (0.14 mol) of a compound represented by the formula (I-9a) and 1.79 g (7.1 mmol) of pyridinium p-toluenesulfonate were added to a flask and dissolved in 50 mL of dichloromethane. While ice-cooling, a dichloromethane solution of 15.6 g (0.19 mol) of 3,4-dihydro-2H-pyran was added dropwise. After stirring at room temperature for 6 hours, it was washed with saturated aqueous sodium bicarbonate solution and brine. By distilling off the solvent, the compound represented by the formula (I-9b) 21.8 g (0.14 mol) was obtained.
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2
[ 142-68-7 ]
[ 927-74-2 ]
[ 40365-61-5 ]
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[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 15, p. 4638 - 4641
3
[ 110-87-2 ]
[ 927-74-2 ]
[ 40365-61-5 ]
Reference：
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4
[ 927-74-2 ]
[ 40365-61-5 ]
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5
[ 49624-41-1 ]
[ 927-74-2 ]
[ 40365-61-5 ]
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6
[ 40365-61-5 ]
[ 927-74-2 ]
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13
[ 75-21-8 ]
[ 1066-26-8 ]
[ 927-74-2 ]
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[4] Patent: US2125384, , ,
14
[ 22273-77-4 ]
[ 65-85-0 ]
[ 927-74-2 ]
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15
[ 75-21-8 ]
[ 74-86-2 ]
[ 927-74-2 ]
[ 540-51-2 ]
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16
[ 2134-29-4 ]
[ 90965-06-3 ]
[ 927-74-2 ]
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17
[ 75-21-8 ]
[ 74-86-2 ]
[ 927-74-2 ]
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23
[ 927-74-2 ]
[ 2345-51-9 ]
Yield
Reaction Conditions
Operation in experiment
76%
With sodium periodate; sodium dichromate; nitric acid In waterCooling with ice
Preparation 1: Synthesis of 3-butynoic acidOH03-butynoic acid was prepared from the oxidation of 3-butyn-1-oI and following the reported procedure (Schmieder-van de Vondervoort, L. et a., P. L. SynIett2002, 2002, 0243). Water (45 mL) was added to a 150 mL single neck RBF fitted with a magnetic. stirrer bar. 65percent HNO3 (0.17 mL, 5 molpercent, 2.5 mmol), Na2Cr2O7 (0.15 g, I molpercent, 0.5 mmol) and NaIO4 (23.53 g, 2.2 eq., 110 mmol) were subsequently added to the RBF and the mixture was stirredvigorously on an ice bath for 15 mm. 3.78 mL of 3-butyn-1-ol (1 eq., 50 mmol) dissolved in45 mL of chilled water was added to this mixture slowly and the reaction mixture was left for18 — 24 hrs (ice bath was not removed to let the ice melt and temperature of reaction mixturerise slowly to rt). After this time, the product was extracted in diethyl ether (80 mL X 6). All ofthe fractions were combined and dried over anhydrous magnesium sulphate. The solventwas removed usinga rotary evaporator to give an orange/yellowish viscous liquid.Subsequent addition of dichloromethane and removal of solvent on a rotary evaporator (under vacuum) 4-5 times gave 3.20 g of an off white/yellowish solid (38 mmol, yield 76percent).1H NMR (400 MHz, CDCI3) 6 3.38 (d, 2H, J 2.7 Hz), 2,25 (t, IH, J = 2.7 Hz); 13C NMR(400 MHz, CDCI3) 6 173.8, 74.8, 72.4, 25.6
Reference：
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24
[ 98-59-9 ]
[ 927-74-2 ]
[ 23418-85-1 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - 0℃; for 0.583333 h; Inert atmosphere Stage #2: at 0℃; for 0.5 h; Inert atmosphere
A solution of n-BuLi (2.80 mL, 2.60 M, 7.27 mmol) in hexanes was added dropwise to a solution of 6 (0.50 mL, 6.61 mmol) in THF (7.5 mL) at -78 °C. After 5 min at -78 °C, stirring was continued for 30 min at 0 °C. p-TsCl (1.51 g, 7.93 mmol) in THF (8 mL) was added, and the reaction was stirred for 30 min at 0 °C. H2O (2 mL) was added, and the mixture was extracted with Et2O (3.x.10 mL). The combined organic phases were dried (Na2SO4), and the solvent was removed under reduced pressure to give 1.41 g (95percent) of 12 as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 4.08 (t, J=7.1 Hz, 2H), 2.53 (dt, J=7.1, 2.6 Hz, 2H), 2.43 (s, 3H), 1.95 (t, J=2.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 145.0, 132.7, 129.9, 127.9, 78.3, 70.7, 67.4, 21.6, 19.4; IR (neat) 3290, 2962, 2919, 1598, 1359, 1190, 1176, 980, 904, 815 cm-1; mass spectrum (ESI) m/z 247.0399 [C11H12O3S (M+23) requires 247.0400], 471 (base), 247, 225.
95%
With dmap; triethylamine In dichloromethane at 0℃; for 4 h;
To a stirred solution of 3-butynol (1.47 g, 21.05 mmol), triethylamine (3.5 mL, 25.26 mmol) and 4-dimethylaminopyridine (25 mg, 0.210 mmol) in CH2Cl2 (20 mL) was added p-toluenesulfonyl chloride (4.0 g, 21.05 mmol) at 0 oC. After 4 h, the reaction mixture was quenched with H2O and extracted with CH2Cl2 (2.x.10 mL) and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography on silica gel (PE/EtOAc, 15:1) gave the product 23 (4.48 g, 95percent) as a pale yellow oil. 1H NMR (300 MHz, CDCl3, d): 7.78 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 4.08 (t, J = 7.2 Hz, 2H), 2.53 (td, J = 6.9, 2.1 Hz, 2H), 2.43 (s, 3H), 1.96 (d, J = 2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3, d): 145.1, 132.8, 129.9, 128.0, 78.4, 70.8, 67.5, 21.7, 19.4; IR (neat): 3292, 3055, 2962, 2125, 1599, 1359 cm-1; HRMS (ESI) (M + Na)+ calcd for C11H12O3SNa+, 247.0405; found 247.0408.
91%
With triethylamine In dichloromethane at 10 - 20℃; Large scale
Add 1 (1400g, 19.97mol) and 7L DCM to a 20L four-neck flask; TEA (11038 ml, 27.6 mol) was added at 10° C.,and TsCl (7254 g, 38.04 mol) was added in portions, and the mixture was stirred at room temperature overnight. The NMR showed that 2.33 L of water was added without raw materials, and the aqueous phase was back-extracted once with DCM (1.17 L). The organic phase was combined, washed twice (2*2.73 L), dried over anhydrous magnesium sulfate for 10 minutes, filtered, and spin-dried at 50°C. to obtain a brown-yellow oily liquid 2 of 4081 g in a yield of 91percent.
90%
With lithium hydroxide monohydrate In tetrahydrofuran at 20 - 30℃; for 16 h;
To a solution of but-3-yn-l-ol (100 g, 1.42 mol) in THF (500 mL) was added L1OH.H2O (89.5 g, 2.13mol) in four portions, followed by the portionwise addition of 4- methylbenzene- 1 -sulfonyl chloride (270 g, 1.42 mol) while maintaining a temperature between 20-30 °C. The resulting mixture was stirred at RT for 16 h, diluted with water (300 mL) and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with brine (100 ml), dried ( a2S04), filtered and concentrated under reduced pressure to give the title compound as an oil (286 g, 90percent).
88%
With dmap; triethylamine In dichloromethane at 0 - 20℃; for 16 h; Inert atmosphere
p-TsCl (598 mg, 3.14 mmol was added with stirring to 3-butyn-1-ol (0.22 mL, 2.85 mmol), NEt3 (0.5mL, 3.70 mmol) and 4-(dimethylamino)pyridine (34 mg, 0.28 mmol) in CH2Cl2 (11.5 mL) at 0 °C. After16 h at room temperature, aqueous NaOH (1.0 M; 10 mL) was added and the mixture stirred for a further15 min. The phases were separated and the organic layer diluted with CH2Cl2 (20 mL), washedsequentially with brine (20 mL) and H2O (20 mL), and dried (MgSO4), rotary evaporated andchromatographed (30percent EtOAc in hexanes) to yield sulfonate 39 as a clear colorless oil (564 mg, 88percent).
85%
at 15 - 20℃; for 20.3333 h;
Butynyl-1-tosylate (24). Method I: A mixture of p-toluenesulfonyl chloride (62.21 g, 0.323 mol) and pyridine (31 mL, 0.383 mol) was warmed to get a colorless solution, and then cooled to get small crystals. 3-Butyn-1-ol (23) (23 mL, 0.29 mol) was added dropwise by syringe during about 20 min with stirring at 15° C. The resulting mixture was stirred below 20° C. under nitrogen atmosphere for 20 h. Water was added with cooling. The mixture was extracted with ethyl acetate (4.x.120 mL). The organic solution was washed with 5percent aqueous sulfuric acid (3.x.120 mL), water (100 mL), 10percent aqueous sodium hydrogen carbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash column chromatography on silica gel (800 g), eluting with ethyl acetate-hexanes (0-10percent) to afford the tosylate 24 (56.13 g) as colorless oil in 85percent yield.11 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 4.08 (t, J=6.9-7.2 Hz, 2H), 2.54 (dt, J=2.7 Hz, J=6.9-7.2 Hz, 2H), 2.43 (s, 3H), 1.94 (t, J=2.7 Hz, 1H).
81%
With triethylamine In dichloromethane at 0 - 20℃; for 12 h;
Step-1: Synthesis of but-3-yn-1-yl 4-methylbenzenesulfonate To a stirred solution of but-3-yn-1-ol (5 g, 0.0714 mmol) in dichloromethane (50 mL) at 0° C. was added triethylamine (10.82 g, 0.107 mmol) and tosyl chloride (13.61 g, 0.0714 mmol). The reaction mixture was stirred at room temperature for 12 h, after completion of reaction (monitored by TLC), reaction mixture was diluted with dichloromethane. The organic layer was washed with water, brine and dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford but-3-yn-1-yl 4-methylbenzenesulfonate (13 g, 81percent).
77%
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 50.5 h;
Method II: A solution of sodium hydroxide (22.53 g, 0.563 mol) in water (200 mL) was added to a mixture of 3-butyn-1-ol (23) (26.76 g, 0.370 mol) and p-toluenesulfonyl chloride (86.3 g, 0.448 mol) in THF (500 mL). The resulting mixture was stirred at room temperature for 50.5 h and concentrated to remove the organic solvent. The residue was extracted with ethyl acetate (3.x.100 mL). The combined organic solution was washed with brine, dried over Na2SO4 and concentrated to afford a residue. The residue was purified by column chromatography on silica gel (200 g), eluting with 0-10percent EtOAc in hexanes, to afford the tosylate 24 (68.70 g) as an oil in 77percent yield.
62%
With pyridine In dichloromethane for 12 h;
To compound 206A (2.16mL. 28.5mmol) was added CH2Cl2 (95mL), pyridine (3.5mL, 42.8mmol) and TsCl (8.2g, 42.8mmol) and the solution was stirred for 12 hours. Purified solution by flash column chromatography using (30percentEtOAc/hexanes) to yield compound 206B (3.9g, 62percent).
16%
With pyridine In dichloromethane at 20℃; for 16 h;
Example 78A but-3-ynyl 4-methylbenzenesulfonate To a mixture of 3-butyn-1-ol (0.5 g, 8.3 mmol) in CH2Cl2 (20 mL) and pyridine (1.7 mL, 33.2 mmol) was added p-toluenesulfonyl chloride (1.7 g, 8.7 mmol). This mixture was stirred at ambient temperature for 16 h then diluted with CH2Cl2 (20 mL) and quenched with aqueous 1percent HCl (5 mL). The layers were separated and the organic layer was washed with aqueous 1percent HCl (5 mL) and brine (5 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via column chromatography (4:1 hexanes:EtOAc) to provide the title compound (0.30 g, 1.3 mmol, 16percent yield). MS (DCI/NH3) m/z 242 (M+NH4)+.
13.52 g
With triethylamine In dichloromethane at 0 - 20℃;
To 500 ml of dichloromethane, 10.00 g of 3-butyn-1-ol and triethylamine (40 ml) was added and the resulting solution was cooled to 0° C. To the cooled solution, 30.00 g of p-toluenesulfonyl chloride was slowly added and following stifling overnight at room temperature, water was added to the reaction mixture, which was extracted twice with 200 ml of dichloromethane. The organic layer was washed twice with 200 ml of water and dried over magnesium sulfate. After filtering the magnesium sulfate, the organic layer was concentrated and the residue was purified by column chromatography (Wakogel C-200; hexane:ethyl acetate=6:1) to give 13.52 g of an O-tosyl compound.
Reference：
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25
[ 121-44-8 ]
[ 98-59-9 ]
[ 927-74-2 ]
[ 23418-85-1 ]
[ 554-68-7 ]
Yield
Reaction Conditions
Operation in experiment
97%
at 0 - 20℃; for 21 h;
3-Butyn-1-ol (1.8 g, 25 mmol) was dissolved in methylene chloride (CH2CL2) (40 mL) and triethylamine (ET3N) (4.18 mL, 30 mmol). The solution was stirred at 0°C followed by addition of p-toluenesulfonyl chloride (5.05 g, 26.25 mmol). The reaction was allowed to warm to room temperature over a period of 1 hour and stirring was continued overnight. Thin layer chromatography (TLC) analysis (hexanes/ethyl acetate (EtOAc) 6: 1) after 20 hours of reaction showed a complete consumption OF 3-BUTYN-1-OL. The precipitated triethylamine HYDROCHLORIDC was filtered off and the filtrate washed with water (H20) (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate (NA2S04) and the solvent evaporated away to give 155 as a light-yellow oil (5.45 g, 97percent). The crude oil was used without further purification; however, it could be purified on a silica gel column, first eluting with 8percent EtOAc in hexanes followed by 40percent EtOAc in hexanes.
Reference：
[1] Synthesis, 1992, # 1-2, p. 146 - 150
29
[ 5029-67-4 ]
[ 927-74-2 ]
[ 395652-44-5 ]
Yield
Reaction Conditions
Operation in experiment
67%
With potassium phosphate In water; isopropyl alcohol at 80℃; for 20 h; Sealed tube
General procedure: In a sealed tube, aryl iodide (1 mmol, 1 equiv.), K3PO4(2 mmol,2 equiv.), catalyst (2 molpercent Pd) were suspended in i-PrOH (3 mL)and H2O (3 mL). The acetylene derivative (1.2 mmol, 1.2 equiv.)was added and the resulting mixture was stirred at 80C for 20 h.After cooling to room temperature, EtOAc (20 mL) and H2O (20 mL)were added and the mixture was filtered over a pad of Celite®.The aqueous layer was extracted twice with EtOAc (2 × 20 mL). Thecollected organics extracts were washed by brine (60 mL), driedon MgSO4, filtered and concentrated under reduced pressure. Thecrude product was purified by flash chromatography.
Reference：
[1] Applied Catalysis A: General, 2014, vol. 482, p. 157 - 162
30
[ 109-04-6 ]
[ 927-74-2 ]
[ 395652-44-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In 1,4-dioxane at 20℃; Inert atmosphere
Under nitrogen atmosphere, and at r.t., CuT (0.06 g, 0.31 mmol), dry Et3N (1.32 mL, 9.49 mmol) and bis-(triphenylphosphine)-palladium chloride (0.13 g, 0.18 mmol) were sequentially added to a solution of 2-bromopyridine (0.60 mL, 6.33 mmol) in 1,4-dioxane (10 mL). Then, but-3-yn-1-ol (0.57 mL, 7.59 mmol) was added dropwise at the same temperature.The resulting reaction mixture was left stirred overnight, then concentrated under reduced pressure, dissolved in EtOAc (80 mL) and washed with H20 (3 x 10 mL). The organic layer was dried over Na2504 and concentrated to dryness to give an oily crude (1.1 g). Purification by typical silica gel flash chromatography using a Teledyne ISCO apparatus (Cy/EtOAc from 90:10 to 30:70) afforded the pure title compound (0.84 g, 90percent), as a white solid. R= 1.25 mm. MS(ESI) m/z: 148 EM-H], 170 EM-Na], 186 EM-K]. ‘H NMR (DMSO-d6): ö 8.55—8.49 (m, 1H),7.76 (td, 1H, J= 7.8, 1.8 Hz), 7.44 (d, 1H, J= 7.8 Hz), 7.33 (ddd, 1H, J= 7.8, 4.9, 1.8 Hz), 4.92 (t, 1H, J= 5.2 Hz), 3.62-3.58 (m, 2H), 2.58 (t, 2H, J= 6.8 Hz).
77%
at 0 - 70℃;
Example 199 ;3 -Methoxy- N -methyl- N -( 4-(pyridin- 2-yl)but - 3 -ynyl)benzamide; 199(A) 4-(Pyridin-2-yl)but-3-yn-1-01; To a suspension of CuI (301 mg, 1.58 mmol) in TEA (40 mL) were added 2- bromopyridine (5 g, 31.6 mmol), followed by Pd2Cl2(PPh3)2 (1.11 g, 1.58 mmol) to give a yellow orange suspension. After cooling down to 0°C under N2, 3-butyn-l-ol (2.28 g, 31.6 mmol) was added. The resulting reaction mixture turned black and it was stirred overnight at 70°C. The reaction mixture was quenched at 0°C with water, TEA was removed under low pressure, and the organic layer was extracted 3x using DCM, washed with Ammonia, water, brine, dried over MgS04, filtered and concentrated. The crude residue was purified over silicagel chromatography (prepacked 250 g silicagel column, DCM/MeOH : from 99/1 to 95/5 as eluent) to afford 3.60 g of 4- (pyridin-2-yl)but-3-yn-1-ol as a brown oil (Yield : 77percent). LCMS (RT) : 1.58min; MS (ES+) gave m/z : 148 Rf (DCM/MeOH : 95/5) =0.23
Reference：
[1] Tetrahedron Letters, 2005, vol. 46, # 10, p. 1717 - 1720
[2] Journal of Organic Chemistry, 2003, vol. 68, # 3, p. 762 - 769
[3] Patent: WO2014/144836, 2014, A2, . Location in patent: Paragraph 0526; 0527
[4] European Journal of Organic Chemistry, 2011, # 2, p. 271 - 279
[5] Patent: WO2005/123703, 2005, A2, . Location in patent: Page/Page column 207
[6] Molecules, 2010, vol. 15, # 12, p. 9157 - 9173
[7] Journal of Organic Chemistry, 2003, vol. 68, # 8, p. 3327 - 3329
[8] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 8, p. 1077 - 1080
31
[ 927-74-2 ]
[ 395652-44-5 ]
Yield
Reaction Conditions
Operation in experiment
74%
Stage #1: at 20℃; Stage #2: at 20 - 80℃; for 20.5 h;
Example 32; 2-(4-(5-PhgpEl-2H-tetrazol-2-yl)but-1-3TY1)pyLidine; 32(A) 4-(Pyridin-2- )but-3-yn-1-ol; In a dry reaction tube containing in suspension iodide copper (38 mg, 0.2 mmol) and triethylamine (11 mL, 80 mmol), were added 2-bromopyridine (632 mg, 4 mmol) and Pd (PPh3)2Cl2 (140 mg, 0.2 mmol). A yellow suspension is obtained and after a few minutes of stirring at room temperature, was added a solution of but-3-yn-1-ol (280 mg, 4 mmol) in triethylamine (2.2 mL). Immediatly the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 80°C for 20h. Triethylamine was concentrated under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH4CI, water and brine, dried (MgS04) and concentrated. The product was purified by flash chromatography (prepacked 15 g silicagel column, from DCM 100percent to DCM/MeOH : 98/2 as eluent) to afford 440 mg of 4-(pyridin-2-yl)but-3-yn-l-ol (Yield : 74percent) as brown oil. Rf:(DCM/MeOH : 95/5) = 0.5 LCMS (RT) : 0.60min; MS (ES+) gave m/z : 148.1
With diisopropylamine;copper(l) iodide; palladium diacetate; triphenylphosphine; In Isopropyl acetate; at 15 - 40℃; for 10.5h;
The product from Example 1A (3.1 kg, 9.68 mol) in isopropyl acetate (49.2 kg) was purged with N2 for about 10 minutes and then cooled to about 15 C. The mixture was treated with palladium(II) acetate (22 g, 0.10 mol), triphenylphosphine, (51 g, 0.19 mol), copper(I) iodide (38 g, 0.19 mol), and 3-butyn-1-ol (0.91 kg, 12.59 moles) while continuing to purge with N2.The mixture was then treated with diisopropylamine (1.97 kg, 19.37 mol), by addition over about 30 minutes.After 2 hours, the suspension was heated to about 40 C. After about 8 hours, the reaction mixture was cooled to room temperature and filtered through a pad of Celite.The pad was washed with isopropyl acetate (12 kg) and the filtrate was washed with 5% NaHCO3 solution and then washed with water.The organic layer was then distilled to dryness.The residue (2.03 kg, 80% assayed yield) was carried onto the tosylation step.A small sample was purified by silica gel chromatography. 1H NMR (CDCl3 at 400 MHz) delta1.81 (t, 1H), 3.07 (t, 2H), 4.01 (q, 2H), 6.56 (s, 1H) 7.41-7.50 (m, 2H), 7.67 (m, 5H); 13C NMR (CDCl3 at 100 MHz) delta32.3, 60.6, 103.6, 110.1, 111.2, 118.8, 119.0, 122.8, 127.6, 129.3, 132.2, 133.8, 145.8, 154.6, 157.0 with 2 peaks overlapping.
With diisopropylamine;copper(l) iodide; palladium diacetate; triphenylphosphine; In Isopropyl acetate; at 22 - 60℃; for 8.5h;
The product from Example 3A (14.95 g, 50 mmol), palladium(II) acetate (0.11 g, 0.5 mmol), triphenylphosphine (0.26 g, 1.0 mmol), and copper(l) iodide (0.19 g, 1.0 mmol) were combined in isopropyl acetate (100 ML).nitrogen gas was bubbled through the reaction mixture for about 15 minutes.The mixture was treated with 3-butyn-1-ol (5.6 ML, 75.0 mmol) stirred briefly and then treated with diisopropylamine (42 ML, 300 mmol) slowly over about 10 minutes.After stirring for 2 hours at about 22 C., the mixture was heated at about 60 C. for about 6 hours and then cooled to about 22 C. The reaction mixture was filtered through a pad of Celite (~5 g) and the Celite was washed with isopropyl acetate (~30 ML).The filtrate was washed with saturated NaHCO3 solution (100 ML, 2*), 10% Na2S2O3 solution (100 ML, 2*), brine (50 ML), dried over Na2SO4, and distilled to dryness.The residue was purified by silica gel column chromatography to provide the title compound (8.7 g, 72% yield). MS DCl (M+NH4)+ m/z at 258, 260; 1H NMR (CDCl3 at 400 MHz) delta3.03 (m, 2H), 3.98 (m, 2H), 6.45 (m, 1 H), 7.25-7.32 (m, 2H), 7.60 (d, 1H); 13C NMR CDCl3 at 100 MHz) delta32.2, 60.6, 103.0, 112.1, 115.4, 122.8, 126.1, 130.4, 153.1, 157.0.
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; at 18 - 25℃; for 18h;
A mixture of 1 ,1-dimethylethyl 4-iodobenzoate (1.1 g, 3.62 mmol, e.g. which can be preparable e.g. according to E.C.Taylor, J. Org. Chem., 1995, 60(24), 7947), 3-butyn-1- ol (0.36 ml, 4.70 mmol, 1.3 equivalents), bis(triphenylphosphine)palladium(ll)dichloride [(PPh3)2PdCI2] (0.13 g ,018 mmol, 5 mol%) and copper(l)iodide (0.014 g, 0.07 mmol, 2 mol%) in triethylamine (5 ml) was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). The organic phase was collected by passing through a hydrophobic frit and evaporated to give a dark brown oil (1.3 g). This was purified by flash chromatography on silica gel (100 g silica cartridge, FlashMaster II), eluting with a gradient of 0 to 100% ethyl acetate in <n="200"/>cyclohexane over 20 minutes. Fractions containing product (obtained from 4:1 cyclohexane : ethyl acetate eluant) were pooled and evaporated to dryness to give the title compound as a brown gummy oil (0.9 g). 1 H NMR (400 MHz, chloroform-d) delta (delta) ppm 1.60 (9H, s), 1.85 (1H, t, J=6.27Hz ), 2.73 (2H, t, J=6.27Hz), 3.85 (2H, q, J=6.27Hz), 7.45 (2H1 d, J=8.53Hz), 7.92 (2H, d, J=8.53Hz).
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 24.3333h;
6-(4-Hydroxy-but-1-ynyl)-2,3-dihydro-isoindolin-1-oneTo a mixture of 6-Bromo-2, 3-dihydro-isoindolin-1-one (3Og, 0.14mole), bis (triphenylphosphine) palladium dichloride (5 g, 0.007 mole), CuI (2.6 g, 0.01 mole), dry Et3N (700 mL) in dry DMF (700 mL) was added 3-butyn-1-ol (21.3 mL, 0.28 mole) slowly drop- wise. The reaction mixture was bubbled with argon for 20 min and heated at 100 C for 24 h. The solvent was evaporated and the crude residue was washed with DCM (100 mL), filtered and dried to 6-(4-Hydroxy-but-1-ynyl)-2,3-dihydro-isoindolin-1-one as a pale grey solid (24 g, <n="40"/>85%). 1H-NMR (DMSO-d6, 300 MHz): delta 8.6 (1H1 s), 7.5-7.6 (2H, d), 7.5 (1H,s), 4.9 (1H, t), 4.3 (2H1 s), 3.6-3.7 (2H, t), 2.4-2.6 (2H, t); MS: M+1: 202 (201)
1. 5 g (10. 56 mmol) of <strong>[450-93-1]4-fluoro-2-methoxyphenol</strong> are introduced into 120 ml of dichloromethane and there are then added, with stirring, 4.5 g and 9.0 g (37.56 mmol) of polymer-bound triphenylphosphine (polymer-C6H4P (C6H5) 2, on copolymer of 98 % styrene and 2 % divinylbenzene) in 2 portions and then 1.4718 g (21 mmol) of 3-butyn- l-ol dissolved in a small amount of dichloromethane. Then 7.267 g (31.56 mmol) of azodicarboxylic acid diethyl ester (DEAD) are added in portions and the brown reaction mixture is stirred overnight at 25 C. GC analysis shows a conversion of more than 66 %. For working up, 60 ml of trifluoroacetic acid are added to the reaction mixture and the mixture is stirred at 25C for 1.5 hours. The reaction mixture is poured into 300 ml of ammonium chloride solution, stirred well and extracted three times with diethyl ether. The combined organic phases are washed with 2 portions each of ammonium chloride solution, water and brine and concentrated by evaporation under reduced pressure. The desired title compound is obtained in the form of a viscous oil in a crude yield of 810 mg (40 % of theory).
bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In diethylamine; at 80℃; for 16h;Heating / reflux;
Intermediate 34 4- (2, 6-Dichlorophenvl) butan-1-ol i) 4-(2, 6-Dichlorophenvl) but-3-yn-1-ol A solution of 1, 3-dichloro-2-iodobenzene (3.8g) in diethylamine (100mL) was treated with dichlorobis (triphenylphosphine) palladium (lI) (364mg) and copper iodide (199mg) and was heated at reflux. 3-Butyn-1-ol (962mg) was added and the reaction mixture was stirred at 80C for 16 h. The reaction mixture was then concentrated in vacuo. The residue was purified by chromatography (SPE, gradient from cyclohexane to dichloromethane) to give the title compound (2.2g) LCMS RT = 3.06 min
bis(triphenylphosphine)palladium(II) dichloride[ No CAS ]
[ 927-74-2 ]
[ 460746-47-8 ]
[ 460746-48-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
With copper(I) iodide; triethylamine; In N-methyl-acetamide; dichloromethane;
EXAMPLE 1B 4-[2-(2-hydroxyethyl)-1-benzofuran-5-yl]benzonitrile To a solution of Example 1A (5.19 g, 16.2 mmol), triethylamine (5.60 mL, 40.4 mmol) and 3-butyn-1-ol (1.90 g, 27.2 mmol) in dimethylformamide (13 mL) at 20 C. was added cuprous iodide (0.46 g, 2.4 mmol) and bis-triphenylphosphine palladium dichloride (0.56 g, 0.80 mmol). The mixture was stirred at 65 C. for 12 hours then cooled to ambient temperature and diluted with dichloromethane (20 mL) and hexane (100 mL). Celite (5 g) was added with stirring and the solids were removed by filtration. The filtrate was washed with water (600 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (3*100 mL). The combined organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure to give a tan solid. The solid was chromatographed on silica with 3% methanol in dichloromethane to give the titled compound (4.02 g, 95%). MS (DCI) m/z 263 [M+H]+.
95%
With copper(I) iodide; triethylamine; In N-methyl-acetamide; dichloromethane;
Example 1B 4-[2-(2-hydroxyethyl)-1-benzofuran-5-yl]benzonitrile To a solution of Example 1A (5.19 g, 16.2 mmol), triethylamine (5.60 ML, 40.4 mmol) and 3-butyn-1-ol (1.90 g, 27.2 mmol) in dimethylformamide (13 mL) at 20 C. was added cuprous iodide (0.46 g, 2.4 mmol) and bis-triphenylphosphine palladium dichloride (0.56 g, 0.80 mmol). The mixture was stirred at 65 C. for 12 hours then cooled to ambient temperature and diluted with dichloromethane (20 mL) and hexane (100 mL). Celite (5 g) was added with stirring and the solids were removed by filtration. The filtrate was washed with water (600 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (3*100 mL). The combined organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure to give a tan solid. The solid was chromatographed on silica with 3% methanol in dichloromethane to give the titled compound (4.02 g, 95%). MS (DCI) m/z 263 (M+H)+;
95%
With copper(I) iodide; triethylamine; In N-methyl-acetamide; dichloromethane;
Example 1B 4-[2-(2-hydroxyethyl)-1-benzofuran-5-yl]benzonitrile To a solution of Example 1A (5.19 g, 16.2 mmol), triethylamine (5.60 mL, 40.4 mmol) and 3-butyn-1-ol (1.90 g, 27.2 mmol) in dimethylformamide (13 mL) at 20 C. was added cuprous iodide (0.46 g, 2.4 mmol) and bis-triphenylphosphine palladium dichloride (0.56 g, 0.80 mmol). The mixture was stirred at 65 C. for 12 hours then cooled to ambient temperature and diluted with dichloromethane (20 mL) and hexane (100 mL). Celite (5 g) was added with stirring and the solids were removed by filtration. The filtrate was washed with water (600 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (3*100 mL). The combined organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure to give a tan solid. The solid was chromatographed on silica with 3% methanol in dichloromethane to give the titled compound (4.02 g, 95%). MS (DCI) m/z 263 [M+H]+;
With potassium carbonate; aniline; benzenesulfonyl chloride; In dichloromethane; butanone;
EXAMPLE 13 N-[5'-(3-butynyloxy)-4'-chloro-2'-fluorophenyl]-3-(trifluoromethyl)glutaramic acid (Compound 94) Potassium carbonate (7.8 g, 56 mmol) was added to a solution of <strong>[84478-72-8]5-amino-2-chloro-4-fluorophenol</strong> (3.23 g, 19.9 mmol) in 50 ml methyl ethyl ketone and the reaction mixture was stirred at room temperature for 1 hour. Then 4.2 g (19.9 mmol) 4-phenylsulfonyloxy-1-butyne (prepared from benzenesulfonyl chloride and 3-butyn-1-ol according to known procedure) was added and the reaction mixture was refluxed for 24 hours. The reaction was poured into 50 ml water and the layers were separated. The aqueous layer was extracted with EtOAc (1*50 ml) and the combined organics were washed with H2 O (3*50 ml), dried over MgSO4, and concentrated. The residue was dissolved in 110 ml CH2 Cl2 and filtered through a short pad of silica gel which was repeatedly rinsed with CH2 Cl2 (4*100 ml). The combined organics were concentrated in vacuo to yield 0.95 g (22% yield) of the desired product as a brown oil. The aniline was reacted with 3-(trifluoromethyl)glutaric anhydride as described in Example 2 to yield the desired product, m.p. 136-137 C.
With potassium carbonate; aniline; benzenesulfonyl chloride; In CH2 -Cl2; butanone;
EXAMPLE 19 N-[5'-(3-butynyloxy)-4'-chloro-2'-fluorophenyl]-3-(trifluoromethyl)glutarimide (Compound 140). Potassium carbonate (7.8 g, 56 mmol) was added to a solution of <strong>[84478-72-8]5-amino-2-chloro-4-fluorophenol</strong> (3.23 g, 19.9 mmol) in 50 ml methyl ethyl ketone and the reaction mixture was stirred at room temperature for 1 hour. Then 4.2 g (19.9 mmol) 4-phenylsulfonyloxy-1-butyne (prepared from benzenesulfonyl chloride and 3-butyn-1-ol according to known procedure) was added and the reaction mixture was refluxed for 24 hours. The reaction was poured into 50 ml water and the layers were separated. The aqueous layer was extracted with EtOAc (1*50 ml) and the combined organics were washed with H2 O (3*50 ml), dried over MgSO4, and concentrated. The residue was dissolved in 110 ml CH2 -Cl2 and filtered through a short pad of silica gel which was repeatedly rinsed with CH2 -Cl2 (4*100 ml). The combined organics were concentrated in vacuo to yield 0.95 g (22% yield) of the desired product as a brown oil. The aniline was reacted with 3-(trifluoromethyl)glutaric anhydride as described in Examples 1 and 2 to yield the desired product, m.p. 89-91 C.
With piperidine;tetrakis(triphenylphosphine) palladium(0); at 80℃; for 3h;
(Reference example 9) 4-(4-Cyclopropylphenyl)butyric acid Bromine (12.5 mL, 244 mmol) was dropwise added to a solution of cyclopropylbenzene (25.0 g, 212 mmol) in chloroform (430 mL) with stirring at -78C and the mixture was stirred for 45 minutes. A 10% aqueous sodium sulfite solution and water were added to the reaction mixture at -78C and chloroform was added thereto to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane) to obtain <strong>[1124-14-7]1-bromo-4-cyclopropylbenzene</strong> (35.5 g, yield: 85%). Tetrakis-(triphenylphosphine)palladium (5.33 g, 4.61 mmol) and 3-butyn-1-ol (31.5 g, 450 mmol) were added to a solution of the obtained <strong>[1124-14-7]1-bromo-4-cyclopropylbenzene</strong> (35.5 g, 180 mol) in piperidine (345 mL) and the mixture was stirred at 80C under nitrogen atmosphere for 3 hours. The reaction mixture was evaporated under reduced pressure and ethyl acetate and a 1N aqueous hydrochloric acid solution were added to the residue to separate it. The thus obtained organic phase was separated, washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 4:1-3:1) to obtain 4-(4-cyclopropylphenyl)but-3-yn-1-ol (30.2 g, yield: 90%). A 6N aqueous sulfuric acid solution (250 mL) was added to a solution of the obtained 4-(4-cyclopropylphenyl)but-3-yn-1-ol (27.8 g, 149 mmol) in methanol (300 mL) and the mixture was heated under reflux for 6 hours. After it was left to stand, methanol of the reaction mixture was evaporated under reduced pressure and ethyl acetate was added thereto to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The thus obtained residue was purified by silica gel chromatography (hexane:ethyl acetate, 4:1-2:1) to obtain 1-(4-cyclopropylphenyl)-4-hydroxybutan-1-one (18.7 g, yield: 61%). Hydrazine monohydrate (10.4 mL) and potassium hydroxide (14.4 g) were added to a solution of the obtained 1-(4-cyclopropylphenyl)-4-hydroxybutan-1-one (17.5 g, 85.8 mmol) in ethylene glycol (90 mL) and the mixture was heated under reflux at 180C for 6 hours. Water was added to the reaction mixture to dilute it and ethyl acetate was added thereto to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate, 5:1-3:1) to obtain 4-(4-cyclopropylphenyl)butan-1-ol (15.8 g, yield: 97%). TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl free radical) (905 mg, 5.79 mmol) and a sodium hydrogenphosphate buffer solution (300 mL, 0.67M, pH 6.7) were added to a solution of the obtained 4-(4-cyclopropylphenyl)butan-1-ol (15.7 g, 83.0 mmol) in acetonitrile (300 mL) and the mixture was stirred at 35C for 10 minutes. After an aqueous sodium chlorite solution (16.4 g, water 80 mL) was added to the reaction mixture, a 2% aqueous hypochlorous acid solution (42.3 mL) was further added dropwise thereto and the mixture was stirred at 35C for 2 hours. A 1N aqueous sodium hydroxide solution (250 mL) was added to the reaction mixture and the mixture was poured into ice-water (300 mL) added with sodium sulfite (30 g), followed by stirring of the mixture for 5 minutes. Ether was added thereto to separate it. An aqueous phase was taken, concentrated hydrochloric acid was added thereto to acidify it and ether was added thereto to separate it. The thus obtained organic phase was separated and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 4-(4-cyclopropylphenyl)butyric acid (15.8 g, yield: 88%) as a white solid.
With copper(l) iodide;bis-triphenylphosphine-palladium(II) chloride; In triethylamine; at 0 - 20℃; for 4.0h;
A Mixture of 13.85 g of <strong>[79055-52-0]2,4-dibromo-6-methyl-pyridine</strong> [79055-52-0], 1.80 g of bis(triphenylphosphine) palladium(II)chloride and 0.50 g of copper(I)iodide in 330 ml of triethylamine is treated with 4.30 ml of 3-butin-1-ol [927-74-2] under Ar atmosphere at 0C. The reaction mixture is stirred for 4 hours at room temperature, diluted with water and extracted with tert-butyl methyl ether (2x). The combined organic phases are dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation. From the residue, the title compound is obtained as beige solid by re-crystallization from hot ethyl acetate-heptane 3:2. Rf = 0.15 (EtOAc-heptane 2:1); Rt = 2.51 (gradient I). Radicals NR1R2:
4-(4-bromo-6-methyl-pyridin-2-yl)-but-3-en-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide;bis-triphenylphosphine-palladium(II) chloride; In triethylamine; at 0 - 20℃; for 4.0h;
A Mixture of 13.85 g of <strong>[79055-52-0]2,4-dibromo-6-methyl-pyridine</strong> [79055-52-0], 1.80 g of bis(triphenylphosphine) palladium(II)chloride and 0.50 g of copper(I)iodide in 330 ml of triethylamine is treated with 4.30 ml of 3-butin-1-ol [927-74-2] under Ar atmosphere at 0C. The reaction mixture is stirred for 4 hours at room temperature, diluted with water and extracted with tert-butyl methyl ether (2x). The combined organic phases are dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation. From the residue, the title compound is obtained as beige solid by re-crystallization from hot ethyl acetate-heptane 3:2. Rf = 0.15 (EtOAc-heptane 2:1); Rt = 2.51 (gradient I).
With pyrrolidine;copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); at 80℃; for 6h;
Preparation of 4-(4-Chloro-2-methoxy-phenyl)-butyric acid (IXa)-Prepared as described in Scheme 2; 4-(4-Chloro-2-methoxy-phenyl)-but-3-yn-1-ol; To a stirred solution of <strong>[174913-09-8]<strong>[174913-09-8]2-bromo-5-chloroanisol</strong>e</strong> (2 g, 9 mmol), Pd(PPh3)4 (520 mg, 0.45 mmol), and CuI (400 mg) in pyrrolidine (20 mL) was added a solution of 3-butyn-1-ol (1.26 g, 18 mmol) in pyrrolidine (30 mL). The reaction mixture was stirred at 80 C. for 6 h, and then concentrated in vacuo. The resulting residue was extracted with ethyl acetate and the organic phase was washed with 1N hydrochloric acid, followed by water, then brine, and dried over sodium sulfate. Upon removal of the solvent under reduced pressure, the crude product was subjected to column chromatography on silica gel (gradient elution with 0%-40% EtOAc/hexane) to give 4-(4-chloro-2-methoxy-phenyl)-but-3-yn-1-ol as a colorless oil (1.46 g, 76.7%). 1H NMR (300 MHz, CDCl3) delta ppm 7.29 (d, J=8.2 Hz, 1H), 6.88 (dd, J=8.2, 1.6 Hz, 1H), 6.85 (d, J=1.6 Hz, 1H), 3.87 (s, 3H), 3.82 (t, J=6.2 Hz, 2H), 2.73 (t, J=6.2 Hz, 2H), 1.92 (br. s, 1H).
bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; at 20 - 65℃; for 20h;
Intermediate 25; 4-(2,3-Difluorophenyl)-3-butyn-1-ol; To a solution of <strong>[38573-88-5]1-<strong>[38573-88-5]bromo-2,3-difluorobenzene</strong></strong> (10.0 g, 51.82 mmol, Aldrich) in dimethylamine (200 ml) under nitrogen were added Bis(tripheylphenylphosphine)palladium(II) dichloride (0.73 g, 1.037 mmol), copper(I) iodide (0.1 g, 0.525 mmol) and 3-butyn-1-ol (11.76 ml). The temperature was raised from ambient to 65° C. and held there with stirring for 20 h, after which the mixture was cooled and all volatiles removed by rotary evaporation. The residue was partitioned between a mixture of 2N HCl (400 ml), brine (100 ml) and dichloromethane (400 ml). A second 100 ml dichloromethane extract and the layers were separated and aqueous was washed with DCM (100 ml). Extracts were combined and the mixture passed through a hydrophobic frit and evaporated under reduced pressure to give a dark brown oil. This oil was purified using a CombiFlash.(R). Companion.(R). 330 g Redisep.(R). silica column eluting with a gradient of cyclohexane:ether (0 to 100percent) affording the title compound as a light orange oil (9.149).H.p.l.c. Rt=2.76 min.1H nmr (CDCl3) delta: 1.88 (1H, t), 2.75 (2H, t), 3.86 (2H, q), 7.01 (1H, m), 7.10 (1H, m), 7.17 (1H, m).
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; at 90℃; for 5h;Inert atmosphere;
To a solution of 2-Bromo-l-chloro-4-iodo-benzene (1 1.8 g, 37.2 mmol) and but-3-yn-l-ol (2.9 g, 40.9 mmol) in dried triethylamine (50 mL) was added copper (I) iodide (1.4 g, 7.4 mmol) and then bis(triphentlphosphine)palladium (II) dichloride (3.0 g, 3.7 mmol). The mixture was degassed by nitrogen for 3 times and then kept stirred at 90 C for 5 h. The resulting mixture was diluted with EtOAc and then filtered. The filtrate was concentrated under reduced pressure and purified via flash-chromatography on silica gel (10 % EtOAc in petroleum ether) to give 4-(3-Bromo-4-chloro-phenyl)-but-3-yn-l-ol (7.4 g, yield 77 %) as white solid. MS ESI calc'd. For Ci0H8BrClO [M + H]+ 261, found 261.
3-(4-hydroxybut-1-yn-1-yl)-1-tosyl-1H-indole-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; triethylamine; triphenylphosphine; palladium dichloride; In N,N-dimethyl-formamide; at 20 - 30℃;Inert atmosphere;
Example 3 Synthesis of 3-(4-hydroxybut-1-inyl)-1-tosyl-1H-indole-5-carbonitrile (IV) <strong>[676273-39-5]3-iodo-1-tosyl-1H-indole-5-carbonitrile</strong> (V) (12.5 g, 28.3 mmol), PdCl2 (150 mg, 0.85 mmol), PPh3 (668 mg, 2.55 mmol) and CuI (162 mg, 0.85 mmol) are suspended in a mixture of triethylamine (65 mL) and DMF (60 mL) under inert atmosphere. The mixture is heated to the temperature of 30 C., then treated with a solution (10 mL) obtained by dissolving 3-butyn-1-ol (2.7 mL, 30.0 mmol) in DMF added by slow dripping. At the end of the addition the reaction mixture is left to stand at ambient temperature and maintained under stirring overnight. The mixture is then diluted with ethyl acetate (200 mL) and treated with a solution of 1M HCl until markedly acid. The phases are separated and the organic phase is washed sequentially with a saturated solution of NaHCO3 with the addition of a 33% solution of NH4OH, an 0.1M solution of Na2S2O3 and a saturated solution of NaCl. The organic phase is dried on Na2SO4, filtered, and concentrated at low pressure. Crude product (IV) is obtained as a solid (11 g), which is not purified but used "as is" in the subsequent reaction.A portion of the crude product is purified by flash chromatography (petroleum ether/AcOEt 50/50) to obtain chemically pure product ( IV) as a white solid. [0065] 1H-NMR (400 MHz, CDCl3), delta: 7.97 (1H, d, J=8.4 Hz); 7.89 (1H, s); 7.71-7.68 (3H, m); 7.50 (1H, d, J=8.8 Hz); 7.20 (1H, d, J=8.4 Hz); 3.78 (2H, m); 3.65 (1H, bs); 2.67 (2H, t, J=6.4 Hz); 2.29 (3H, s).
tert-butyl 6-(4-hydroxybut-1-ynyl)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
<strong>[115309-57-4]ter<strong>[115309-57-4]t-butyl 6-chloronicotinate</strong></strong> (2.0 g, 9.39 mmol) is dissolved in dimethoxyethane (50 ml) and added in succession with water (30 mE), potassium carbonate (5.18 g, 37.6 mmol), copper(I) iodide (0.1 g, 0.5 mmol), triphenylphosphine (0.26 g, 1 mmol) and 10 percent (w/w) palladium on carbon (0.3 g). The reaction mixture is stirred for 30 minutes at room temperature, then added with 2-methyl-3-butyn-2-ol (5 ml, 50 mmol), heated at 80 C. for 5 hours, then cooled, filtered through Celite, diluted with water (150 mE) and extracted with ethyl acetate (100 mEx2). The organic phase is washed with water, dried over sodium sulfate, filtered and concentrated evaporated in vacuo. The resulting reaction crude is purified by column and flash chromatography on silica gel to give tert-butyl 6-(4-hydroxybut-1-ynyl)nicoti- nate (1.7 g, 73%) as colorless oil.
tert-butyl 4-(2-(but-3-yn-1-yloxy)ethyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
182 mg
But-3-yn-i-ol (72 mg, i.03 mmol) was dissolved in THF (3.5 ml). Sodium hydride (6i.6 mg,1.54 mmol) was added to the reaction and this was stirred for 30 mins. tert-Butyl 4-(2- bromoethyl)piperidine-i-carboxylate (300 mg, 1.03 mmol) was added and stirred at room temperature for i8 hours. The reaction mixture was quenched with methanol and water, then concentrated under reduced pressure. The aqueous solution remaining was extracted withDCM (2 x 20 ml) and the combined organics dried (Mg504) and concentrated to give the titlecompound (i82 mg);LC-MS: Rt 1.12 mins, mlz 560.6 [M+H] Method 2minLowpHvo3
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. 4.1.12.1 4-(6-Bromoquinolin-4-yl)but-3-yn-1-ol (14a) This compound was prepared from <strong>[927801-23-8]6-bromo-4-iodoquinoline</strong> (12) (100 mg, 0.30 mmol) and commercially available but-3-yn-1-ol (13a) (21 mg, 0.30 mmol) according to the general synthesis procedure E to afford the title compound (58 mg, 0.21 mmol, 70% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) delta 8.88 (d, J = 4.5 Hz, 1H, Ar-H), 8.38 (d, J = 2.0 Hz, 1H, Ar-H), 7.98 (d, J = 9.0 Hz, 1H, Ar-H), 7.93 (dd, J = 9.0, 2.0 Hz, 1H, Ar-H), 7.61 (d, J = 4.5 Hz, 1H, Ar-H), 5.05 (t, J = 5.5 Hz, 1H, OH), 3.69 (q, J = 6.5 Hz, 2H, CH2), 2.77 (t, J = 6.5 Hz, 2H, CH2). ESI-MS: m/z = 276 [M+H]+.
4-(5-chloro-2-methoxyphenyl)but-3-yn-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With pyrrolidine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); at 80℃; for 18h;Inert atmosphere;
A solution of <strong>[60633-25-2]2-bromo-4-chloro-1-methoxybenzene</strong> (15 g, 67.7 mmol), copper(I)iodide (1.290 g, 6.77 mmol) and Pd(PPh3)4 (3.91 g, 3.39 mmol) in pyrrolidine (35 mL) was degassed with nitrogen. But-3-yn-l-ol (9.49 g, 135 mmol) was added via cannula and thereaction mixture was heated at 80 C for 18 hours. The reaction mixture was cooled to roomtemperature and partitioned between saturated aqueous ammonium chloride and ethyl acetate(3 x 300 mL). The organic layers were combined, washed with water, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated. Purification by flash chromatography (silica gel, 0-40 % ethyl acetate in heptanes) afforded the title compound (12.5 g, 88 %).
at 100℃; for 1h;Sealed tube; Microwave irradiation;
General procedure: The 4-substituted methyl (phenylsulfonyl)carbamate was dissolved in the chosen alcohol (2 mL) in a microwave vial, which was closed using an aluminum open-top seal with PTFE-faced septum. The reaction mixture was heated under microwave irradiation at 100-120 oC for 20-60 min. The crude reaction mixture was concentrated under reduced pressure and the residue was purified using silica gel column chromatography to yield the desired (aryl)carbamate.
4-(2-bromo-5-(trifluoromethyl)phenyl)but-3-yn-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; at 20℃; for 0.25h;Inert atmosphere;
To the N2 purged solution of TEA (10 ml) and DMF (10 ml) was added but-3-yn-1-ol (0.75 g, 10.69 mmol), <strong>[640280-28-0]1-bromo-2-iodo-4-(trifluoromethyl)benzene</strong> (2.5g, 7.12 mmol), copper(I) iodide (0.27g, 1.425 mmol), bis(triphenylphosphine)palladium(II) chloride (0. 50g, 0.712 mmol) at room temperature and stirred further for 15 mm. After completionof reaction as indicated by TLC, reaction mass was poured in to water and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, conc under reduced pressure and purified by column chromatography to obtain title compound (1 .4g, 67%). LCMS (ESI): m/z 292.96(M+H)t
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 20.0℃; for 16h;
To a stirred solution of <strong>[143250-10-6]2-bromo-5-methoxypyrazine</strong> (10 g, 53.47 mmol) in DMF (100 mL), but-3-yn-1-ol (2.6 g,37.38 mmo), TEA {427 mmol), Cui (1 g, 5.3 mmo) and Pd(PPh3)2Cb (6 g, 5.3 mmol) were added at rt for 16 h.The reaction mixture was diluted with cold water, extracted with EtOAc and washed with water and brinesolution. The separated organic layers were dried over anhydrous Na2S04, filtered and the filtrated wasconcentrated to get a cruede residue that was purified by flash column chromatography using 20% EtOAc inpet ether as an eluent to obtain 5 g (53 %) of the title compound as a gummy solid. LC-MS (method 21): Rt = 1.68 min; m/z = 179.28 (M+H+).
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; diisopropylamine; In tetrahydrofuran; at -30 - 20℃; for 19h;
Into a glass reaction vessel equipped with a stirrer and a capacity of 200 mL,3.51 g of 4-bromo-2-iodo-1- (trifluoromethyl) benzene(10.0 mmol), 67 mL of dehydrated tetrahydrofuran,8.4 mL (60.0 mmol) of diisopropylamine,701.9 mg (1.0 mmol) of dichlorobis (triphenylphosphine) palladium (II), 190.5 mg (1.0 mmol) of copper (I) iodide) Was added, and while keeping the internal temperature at -30 C., 832 muL of 3-butyn-1-ol(11.0 mmol) were added, followed by reaction at room temperature for 19 hours.The solvent was distilled off under reduced pressure, and a saturated aqueous solution of ammonium chloride was added to the resulting reaction crude productThe mixture was extracted with diethyl ether, dried over magnesium sulfate and the solvent was distilled off under reduced pressure,Silica gel column chromatography (hexane: ethyl acetate = 8: 2)To obtain 2.5 g of compound (C14-e) as a pale yellow solid.
4-(2-(methylmercapto)pyrimidin-5-yl)-3-butyn-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.6%
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; triphenylphosphine; In toluene; at 50℃; for 16h;Inert atmosphere;
Compound 1 (103 g, 0.5022 mol, 1.0 eq), Compound A (70.4 g, 1.045 mol, 2.0 eq), triethylamine (152.5 g, 1.5067 mol, 3.0 eq), CuI (4.8 g, 0.0251 mol, 0.05 eq) And 500 mL of toluene was added to the reaction flask, and the nitrogen was replaced twice, then Pd(PPh3)4 (8.7 g, 0.0075 mol, 0.015 eq), PPh3 (4.0 g, 0.0151 mol, 0.03 eq) was added, and the temperature was raised under nitrogen protection. The reaction was carried out for 50 hours at 50 degrees, and the reaction was detected by TLC (PE/EA = 2/1), and the starting of the reaction was completed. Heating was stopped, cooled, filtered through celite pad, and the filtrate was concentrated to give a pale yellow solid compound 2 (73.7g, 0.3794mol), 75.6% yield
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