* 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.
To a stirred solution of 4-phenylbutan-2-one (4) (50 g, 1 mmol) in methanol (350 mL), bromine (19 mL, 1.1mmol) was added at 0°C and the mixture was stirredat 15°C for 4 h. After completion of reaction, the reactionmixture was diluted with water (500 mL) andextracted with dichloromethane (2 x 500 mL). The collectedorganic layer was washed with brine solution and dried over anhydrous Na2SO4 and concentrated underreduced pressure. The residue was dissolved in pet etherand kept in refrigerator for 5 h. The solid was filtered toafford compound 5 as a white solid (72 g, 93.98percent). 1HNMR (300 MHz, CDCl3): δ2.9 (q, 4H), 3.8 (s, 2H), 7.2(m, 3H), 7.3 (m, 2H). 13C NMR (100 MHz, CDCl3):δ29.87, 34.24, 41.38, 126.34 (2C), 128.28 (2C), 128.57,140.29, 201.18.
65%
With bromine; acetic acid In methanol at -5 - 20℃; for 2 h;
4-Phenylbutan-2-one (10 g, 67.5 mmol, 1 eq) as starting material was added to a 100 ml 3-neck flask and 40 ml of MeOH was added. AcOH (4 ml, 67.5 mmol, 1 eq) was slowly added and stirred for 10 min. After cooling to-5 ° C, Br2 (4 ml, 78.3 mmol) was dissolved in 20 ml of MeOH and then slowly added dropwise. After raising the temperature to 15 to 20 , the mixture was stirred for 2 hours. After cooling to 5 , 50 ml of H 2 O was added, and the mixture was stirred for 10 minutes. After layer separation, 20 ml of hexane was added to the organic layer, cooled to 0 and stirred for 30 minutes. The resulting solid was filtered to give a white solid compound (9.9 g, 65percent)
63%
With bromine In methanol; hexane; water
1.1) 1-Bromo-4-phenyl-2-butanone A freshly prepared solution of bromine (258.9 g) in methanol (600 mL) was added dropwise during 1 h 20 min to a stirred solution of benzylacetone (222.3 g) in methanol (600 mL) at 7-10° C. An exothermic reaction took place, and to maintain the necessary temperature (7-10° C.), the flask should be immersed in a ice-water bath. When orange-red color of bromine disappeared, water (1500 mL) was added to the mixture and the obtained mixture was stirred overnight. The organic layer (on the bottom) was separated, water phase was extracted with dichloromethane (2*600 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily residue was dissolved in hexane (2500 mL) and the obtained solution was kept overnight at -10° C. Precipitated fine crystals (needles) were filtered off, washed on filter with cold hexane, dried under reduced pressure at room temperature to give 1-bromo-4-phenyl-2-butanone (213.0 g, 63percent yield), mp 39-40° C. 1H NMR (CDCl3) δ2.95-3.00 (m, 4H); 3.83 (s, 2H); 7.16-7.30 (m, 5H).
34%
Stage #1: With hydrogen bromide; bromine In water; acetic acid at 0 - 20℃; for 4 h; Stage #2: With acetone In water; acetic acid at 20℃; for 14 h;
To a solution of 4-phenylbutan-2-one (20) (3.0 g) in AcOH(7 mL) and 48percent aqueous HBr (3 mL) was added a solution of Br2(6.5 g) in AcOH (5 mL) at 0 C. After stirring the reaction mixtureat room temperature for 4 h, acetone (30 mL) was added to thesolution, and the reaction mixture was further stirred at room temperaturefor 14 h. The mixture was then concentrated in vacuo, dilutedwith brine, and extracted twice with CH2Cl2. The combinedorganic layer was dried over anhydrous MgSO4, and then evaporatedin vacuo. The obtained residue was purified by flash columnchromatography over silica gel with hexane/AcOEt (40:1–10:1) asan eluent to give 21 (1.5 g, 34percent) as a pale brown oil. CI MS m/e (M)+227.
21%
With bromine In methanol at 20℃; for 2 h;
To a solution of ketone 1 (4.52g, 30mmol) 240ml in methanol, a solution of bromine (1.5ml), 30mmol) in 30ml methanol was added in one portion at room temperature. The orange reaction mixture was then stirred at room temperature for 2 h. After the ketone 1 has been consumed, the reaction was quenched by adding a 0.3M sodium thiosulfate solution(18ml) and diluted with EA (450ml). The resulting mixture was washed with 450ml water, then the organic phase was concentrated under reduce pressure to give a residue that was purified by chromatography (PE/EA, 10/1) to give the compound 2 (1.43g, 21percent). 1H-NMR (CDCl3, 400MHz): δ 2.98 (t, 2H) ; 3.02 (t, 2H) ; 3.88(s, 2H); 7.19~7.24(m, 3H); 7.18~7.33(m, 2H). M.W.: 226, 228) ESI-MS: 227, 229 (M+H).
Reference：
[1] Journal of Chemical Sciences, 2015, vol. 127, # 11, p. 2023 - 2028
[2] Patent: KR2017/25682, 2017, A, . Location in patent: Paragraph 0093; 0094-0097
[3] Patent: US2003/149294, 2003, A1,
[4] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 9, p. 3225 - 3234
[5] Synthetic Communications, 2012, vol. 42, # 9, p. 1288 - 1305
[6] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 13, p. 3873 - 3881
[7] Patent: EP3018125, 2016, A1, . Location in patent: Paragraph 0585-0587
[8] Patent: WO2010/109476, 2010, A2, . Location in patent: Page/Page column 12
[9] Chemical Biology and Drug Design, 2010, vol. 75, # 1, p. 68 - 90
[10] Asian Journal of Chemistry, 2017, vol. 29, # 12, p. 2767 - 2770
2
[ 184370-64-7 ]
[ 31984-10-8 ]
Yield
Reaction Conditions
Operation in experiment
87%
With indium(III) triflate; water In acetic acid at 100℃; Sealed tube
General procedure: The reaction mixture of In(OTf)3 (16.8mg, 0.03mmol), 1-haloalkynes (0.3mmol), H2O (0.9mmol), HOAc (0.6mL), in a 5mL sealed tube was stirred at 100°C and monitored periodically by TLC. Upon completion, HOAc was removed under reduced pressure using an aspirator, and then the residue was purified by flash chromatography (PE/EA) on silica gel to afford corresponding carbonyl compounds 2a–2ad.
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 18, p. 9190 - 9195
[2] Chinese Journal of Chemistry, 2016, vol. 34, # 12, p. 1251 - 1254
[3] Tetrahedron, 2016, vol. 72, # 27-28, p. 3818 - 3822
[4] European Journal of Organic Chemistry, 2016, vol. 2016, # 1, p. 116 - 121
3
[ 10290-42-3 ]
[ 31984-10-8 ]
Yield
Reaction Conditions
Operation in experiment
72%
With hydrogen bromide In acetonitrile at 0 - 20℃; for 18 h;
General procedure: Oxalyl chloride (23 mmol) was added dropwise to a solution of the appropriate phenylalkyl acid (1a-f) (10 mmol) in dry CH2Cl2(18.5 mL) cooled at 0 °C. After complete addition, the mixture was stirred at room temperature for 3 h. After this period, the mixture was evaporated to dryness and the obtained phenylalkyl acylchloride was used for the next reaction without further purification. 2N trimethylsilyldiazomethane in dry Et2O (27.3 mL) was added dropwise to a solution of the appropriate phenylalkyl acylchloride (10 mmol) in dry CH3CN (13.5 mL) cooled at 0 °C. After stirring at 0 °C for 2 h, 48percent aqueous HBr (15.3 mL) was added drop wise to the mixture cooled at 0 °C. After complete addition, the mixture was stirred at room temperature overnight, then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and NaHCO3 solution, then dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate/light petroleum (1:2).
Reference：
[1] Journal of Heterocyclic Chemistry, 1980, vol. 17, # 5, p. 1081 - 1085
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 7, p. 2074 - 2083
[3] Patent: US6399640, 2002, B1,
[4] Patent: EP1040102, 2007, B1, . Location in patent: Page/Page column 59
4
[ 645-45-4 ]
[ 18107-18-1 ]
[ 31984-10-8 ]
Yield
Reaction Conditions
Operation in experiment
65%
Stage #1: at 0℃; for 3.1 h; Stage #2: With hydrogen bromide In water; acetic acid at 0℃; for 0.166667 h;
(i) A soln of 3-phenyl-propionyl chloride (2.0 mL; 13.5 mmol) in dry THF (50 mL) was added over 6 min to a 0 °C soln of diazomethyl-trimethyl-silane (2.0 M in hexanes; 15 mL; 30 mmol) in dry THF (50 mL). After 3 h, the rxn was coned to a liquid, (ii) Aq. HBr (48percent; ca. 2.5 eq) was added in one portion to a soln of this crude material in AcOH (30 mL) at 0 °C. After 10 min the rxn was coned. EtOAc (50 mL) was added and the soln washed with water (2 x 15 mL), satd NaHCO3 (3 x 15 mL), water (1 x 15 mL) and satd NaCl (2 x 15 mL). After drying over MgSO4, filtering through a pad of silica with an EtOAc wash and coned to an oil, the crude material was purified by MPLC (SiO2 with a 0 - > 20percent EtOAc in hexanes gradient) yielding bromomethyl ketone as an off-white solid (1.977 g; 65percent). IH NMR (CDC13) δ 7.37 - 7.18 (m, 5H), 3.85 (s, 2H), 3.01 - 2.94 (m, 4H); GC-MS 226/228 ([M]+).
With Oxone; ammonium bromide In methanol for 0.5 h; Reflux
General procedure: Oxone (1.352 g, 2.2 mmol) was added to the well stirred solution of substrate (2 mmol) and NH4Br (0.215 g, 2.2 mmol) in methanol (10 ml) and the reaction mixture was allowed to stir at room temperature (or reflux temperature). After completion of the reaction, as monitored by TLC, the reaction mixture was quenched with aqueous sodium thiosulfate, and extracted with ethyl acetate (3.x.25 ml). Finally, the combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and removal of solvent in vacuo yielded a crude residue, which was further purified by column chromatography over silica gel (finer than 200 mesh) to afford pure products. All the products were identified on the basis of 1H NMR and mass spectral data.
With hydrogen bromide; In acetonitrile; at 0 - 20℃; for 18h;
General procedure: Oxalyl chloride (23 mmol) was added dropwise to a solution of the appropriate phenylalkyl acid (1a-f) (10 mmol) in dry CH2Cl2(18.5 mL) cooled at 0 C. After complete addition, the mixture was stirred at room temperature for 3 h. After this period, the mixture was evaporated to dryness and the obtained phenylalkyl acylchloride was used for the next reaction without further purification. 2N trimethylsilyldiazomethane in dry Et2O (27.3 mL) was added dropwise to a solution of the appropriate phenylalkyl acylchloride (10 mmol) in dry CH3CN (13.5 mL) cooled at 0 C. After stirring at 0 C for 2 h, 48% aqueous HBr (15.3 mL) was added drop wise to the mixture cooled at 0 C. After complete addition, the mixture was stirred at room temperature overnight, then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and NaHCO3 solution, then dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate/light petroleum (1:2).
With hydrogen bromide;
Step B: Preparation of 1-Bromo-4-phenyl-2-butanone. A 0 C. solution of the crude product from Step A (12.89 grams; dry dichloromethane; 150 mL) was treated dropwise with 48% HBr (36.0 mL). When outgassing ceased, the solution was warmed to ambient temperature. After 15 minutes, the reaction was partitioned (isopropyl acetate and water), washed twice with water and dried (magnesium sulfate). Filtration and evaporation furnished the title compound as an oil which crystallized on standing, 1H NMR (400 MHz, CDCl3): delta 7.30-7.16 (mult, 5H), 3.83 (s, 2H), 2.97-2.91 (mult, 4H).
With hydrogen bromide; In dichloromethane; water; at 0 - 20℃;
A 0C solution of the crude product from Step A (12.89 grams; dry dichloromethane; 150 mL) was treated dropwise with 48% HBr (36.0 mL). When outgassing ceased, the solution was warmed to ambient temperature. After 15 minutes, the reaction was partitioned (isopropyl acetate and water), washed twice with water and dried (magnesium sulfate). Filtration and evaporation furnished the title compound as an oil which crystallized on standing, 1H NMR (400MHz, CDCl3): delta 7.30-7.16 (mult, 5H), 3.83 (s, 2H), 2.97-2.91 (mult, 4H).
To a stirred solution of 4-phenylbutan-2-one (4) (50 g, 1 mmol) in methanol (350 mL), bromine (19 mL, 1.1mmol) was added at 0C and the mixture was stirredat 15C for 4 h. After completion of reaction, the reactionmixture was diluted with water (500 mL) andextracted with dichloromethane (2 x 500 mL). The collectedorganic layer was washed with brine solution and dried over anhydrous Na2SO4 and concentrated underreduced pressure. The residue was dissolved in pet etherand kept in refrigerator for 5 h. The solid was filtered toafford compound 5 as a white solid (72 g, 93.98%). 1HNMR (300 MHz, CDCl3): delta2.9 (q, 4H), 3.8 (s, 2H), 7.2(m, 3H), 7.3 (m, 2H). 13C NMR (100 MHz, CDCl3):delta29.87, 34.24, 41.38, 126.34 (2C), 128.28 (2C), 128.57,140.29, 201.18.
65%
With bromine; acetic acid; In methanol; at -5 - 20℃; for 2h;
4-Phenylbutan-2-one (10 g, 67.5 mmol, 1 eq) as starting material was added to a 100 ml 3-neck flask and 40 ml of MeOH was added. AcOH (4 ml, 67.5 mmol, 1 eq) was slowly added and stirred for 10 min. After cooling to-5 C, Br2 (4 ml, 78.3 mmol) was dissolved in 20 ml of MeOH and then slowly added dropwise. After raising the temperature to 15 to 20 , the mixture was stirred for 2 hours. After cooling to 5 , 50 ml of H 2 O was added, and the mixture was stirred for 10 minutes. After layer separation, 20 ml of hexane was added to the organic layer, cooled to 0 and stirred for 30 minutes. The resulting solid was filtered to give a white solid compound (9.9 g, 65%)
63%
With bromine; In methanol; hexane; water;
1.1) 1-Bromo-4-phenyl-2-butanone A freshly prepared solution of bromine (258.9 g) in methanol (600 mL) was added dropwise during 1 h 20 min to a stirred solution of benzylacetone (222.3 g) in methanol (600 mL) at 7-10 C. An exothermic reaction took place, and to maintain the necessary temperature (7-10 C.), the flask should be immersed in a ice-water bath. When orange-red color of bromine disappeared, water (1500 mL) was added to the mixture and the obtained mixture was stirred overnight. The organic layer (on the bottom) was separated, water phase was extracted with dichloromethane (2*600 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily residue was dissolved in hexane (2500 mL) and the obtained solution was kept overnight at -10 C. Precipitated fine crystals (needles) were filtered off, washed on filter with cold hexane, dried under reduced pressure at room temperature to give 1-bromo-4-phenyl-2-butanone (213.0 g, 63% yield), mp 39-40 C. 1H NMR (CDCl3) delta2.95-3.00 (m, 4H); 3.83 (s, 2H); 7.16-7.30 (m, 5H).
34%
To a solution of 4-phenylbutan-2-one (20) (3.0 g) in AcOH(7 mL) and 48% aqueous HBr (3 mL) was added a solution of Br2(6.5 g) in AcOH (5 mL) at 0 C. After stirring the reaction mixtureat room temperature for 4 h, acetone (30 mL) was added to thesolution, and the reaction mixture was further stirred at room temperaturefor 14 h. The mixture was then concentrated in vacuo, dilutedwith brine, and extracted twice with CH2Cl2. The combinedorganic layer was dried over anhydrous MgSO4, and then evaporatedin vacuo. The obtained residue was purified by flash columnchromatography over silica gel with hexane/AcOEt (40:1-10:1) asan eluent to give 21 (1.5 g, 34%) as a pale brown oil. CI MS m/e (M)+227.
21%
With bromine; In methanol; at 20℃; for 2h;
To a solution of ketone 1 (4.52g, 30mmol) 240ml in methanol, a solution of bromine (1.5ml), 30mmol) in 30ml methanol was added in one portion at room temperature. The orange reaction mixture was then stirred at room temperature for 2 h. After the ketone 1 has been consumed, the reaction was quenched by adding a 0.3M sodium thiosulfate solution(18ml) and diluted with EA (450ml). The resulting mixture was washed with 450ml water, then the organic phase was concentrated under reduce pressure to give a residue that was purified by chromatography (PE/EA, 10/1) to give the compound 2 (1.43g, 21%). 1H-NMR (CDCl3, 400MHz): delta 2.98 (t, 2H) ; 3.02 (t, 2H) ; 3.88(s, 2H); 7.19~7.24(m, 3H); 7.18~7.33(m, 2H). M.W.: 226, 228) ESI-MS: 227, 229 (M+H).
With bromine; In methanol; at 7 - 10℃;
A) In a one litre round bottom flask fitted with an overhead stirrer, thermo pocket and dropping funnel was charged methanol (270ml) and benzyl acetone (100g) at 20 to 300C. Bromine solution (118.8 g bromine dissolved in 270 ml methanol) was added during 60 to 90 minutes maintaining internal temperature at 7 to10C. The reaction mass was maintained at same temperature for 2 to 4 hours and checked HPLC for completion of reaction. D. M. water (674 ml) was added at 7 to 100C. The temperature was raised to 20 to 30 C and maintained for 12 hours at the same temperature. The organic layer was separated. The upper aqueous layer was extracted with dichloromethane (270ml) and combined with the organic layer. Dichloromethane was distilled out completely under reduced pressure to obtain viscous residue (140-150 g) which was dissolved in 300 ml toluene.
With bromine; acetic acid; In methanol;Inert atmosphere;
1-Bromo-4-phenylbutan-2-one (6) was prepared by adding bromine(38.2 mL, 1.1 mmol) in acetic acid (1 mL, 0.01 vol) at 0 C toa solution of 4-phenylbutan-2-one (5) (100 g, 1 mmol) in methanol(1000 mL). The mixture was stirred at 15 C for 2 h and reactionmixture was diluted with water (1000 mL) and extracted withdichloromethane (2 × 500 mL) to obtain desired compound 6.The organic fraction was collected, washed with brine solutionand dried over anhydrous Na 2 SO 4 . The crude compound 6 wasresulted as a liquid (160 g) after solvent removal under reducedpressure. The spectroscopic data of compound 6 matches withthe spectral data reported in our previous paper [12].
With sodium iodide; In ethanol; dichloromethane; acetone;
1.2) 1-Iodo-4-phenyl-2-butanone A solution of <strong>[31984-10-8]1-bromo-4-phenyl-2-butanone</strong> (18.9 g) in dry acetone (100 mL) was added dropwise to a stirred solution of sodium iodide (14.0 g) in dry acetone (100 mL) at room temperature. A precipitate of sodium bromide immediately formed. The mixture was stirred overnight at room temperature, filtered and evaporated under reduced pressure. The residue was dissolved in dichloromethane (150 mL). The solution was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The oily residue was dissolved in 95% ethanol (100 mL). The obtained solution was kept at -10 C. overnight. Precipitated pale yellow needles were filtered off, dried under reduced pressure at room temperature to obtain 20.0 g (88% yield) of 1-iodo-4-phenyl-2-butanone, mp 44-45 C. 1H NMR (CDCl3) delta: 2.88-3.07 (m, 4H); 3.75 (s, 2H); 7.16-7.31 (m, 5H).
90 g
With sodium iodide; In acetone; for 12h;
To a degassed stirred solution of 5 (80 g, 1 mmol) in acetone (480 mL), was added sodium iodide(63 g, 1.2 mmol) and stirred at room temperature for 12 h. After completion of the reaction, reaction mixturewas filtered and washed with acetone (200 mL).Then the filtrate was evaporated in vacuo and obtainedcrude product was dissolved in dichloromethane (800mL), washed with water (500 mL) and brine solution(500 mL), dried over anhydrous Na2SO4. The collectedorganic solution was concentrated under reducedpressure to get iodo compound (90 g).
With caesium carbonate; In N,N-dimethyl-formamide;
EXAMPLE 69 5-[3-(4-(3-(2-phenylethyl)-7-propyl-benzofuran-6-yloxy)-1-butoxy)]phenyl-2,4-thiazolidinedione STR84 Step A: Preparation of 1-(3-methoxyphenoxyl)-4-phenyl-2-butanone. A dry, DMF (80 mL) solution of the product of Example 63, Step B (5.519 grams) was exposed to 3-methoxyphenol (3.608 grams) followed by cesium carbonate (9.481 grams). After stirring at ambient temperature for 2 hours the reaction was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried (magnesium sulfate) and filtered. Concentration and silica gel chromatography (5:1 hex/ethyl acetate) completed the isolation of the title compound, a yellow solid. 1 H NMR (400 MHz, CDCl3): delta 7.29-7.14 (mult, 6H), 6.54 (dd, 1H, J=8.3,12.3 Hz), 6.42 (t, 1H, J=2.4 Hz), 6.39 (dd, 1H, J=8.1, 2.5 Hz), 4.49 (s, 2H), 3.76 (s, 3H), 2.93 (s, 2H, overlapping a dt, 1H), 2.70 (dt, 1H, J=7.9, 10.5 Hz).
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
A dry, DMF (80 mL) solution of the product of Example 63, Step B (5.519 grams) was exposed to 3-methoxyphenol (3.608 grams) followed by cesium carbonate (9.481 grams). After stirring at ambient temperature for 2 hours the reaction was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried (magnesium sulfate) and filtered. Concentration and silica gel chromatography (5:1 hex/ethyl acetate) completed the isolation of the title compound, a yellow solid. 1H NMR (400MHz, CDCl3): delta 7.29-7.14 (mult, 6H), 6.54 (dd, 1H, J=8.3, 2.3 Hz), 6.42 (t, 1H, J=2.4 Hz), 6.39 (dd, 1H, J=8.1, 2.5 Hz), 4.49 (s, 2H), 3.76 (s, 3H), 2.93 (s, 2H, overlapping a dt, 1H), 2.70 (dt, 1H, J=7.9, 10.5 Hz).
1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(2-oxo-4-phenylbutoxy)-1H-1,2,3-triazolo[4,5-c][1]benzazepine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With potassium carbonate; In N,N-dimethyl-formamide; acetone;
(a) 7-hydroxy-1-(4-methoxybenzyl)-4(5H),10-dioxo-1H-1,2,3-triazolo[4,5-c][1]benzazepine (200 mg, 0.571 mmole) obtained in Example 25 (e) was dissolved in the mixture of acetone (3 ml) and N,N-dimethylformamide (3 ml), and potassium carbonate (95 mg, 0.687 mmole) and <strong>[31984-10-8]1-bromo-4-phenyl-2-butanone</strong> (156 mg, 0.687 mmole) were added. The mixture was subjected to the reaction and post-treatment in the same way as in Example 73 to give 1-(4-methoxybenzyl)-4(5H),10-dioxo-7-(2-oxo-4-phenylbutoxy)-1H-1,2,3-triazolo[4,5-c][1]benzazepine (267 mg, 94%). 1 H-NMR (DMSO-d6): delta2.80-2.92 (4H, m), 3.71 (3H, s), 4.98 (2H, s), 6.01 (2H, s), 6.85 (1H, dd), 6.90 (2H, d), 6.95 (1H, d), 7.15-7.33 (7H, m), 8.12 (1H, d), 11.18 (1H, s). EIMS: m/z 496 (M+).
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 6h;
A dry, DMF (225 mL) solution of the Step B product (20.212 grams) was exposed to di-isopropylethyl amine (16.22 mL), then to 3-methoxythiophenol (11.424 grams). Stirring at ambient temperature for 6 hours was followed by partition (isopropyl acetate and pH4 pthalate buffer). The organic was washed twice with water, dried (magnesium sulfate) and filtered. Concentration and silica gel chromatography (5:1 hex/CH2Cl2) completed the isolation of the title compound. 1H NMR (400MHz, CDCl3): delta 7.26-7.12 (mult, 6H), 6.83 (dd, 2H, J=4.7, 2.2 Hz), 6.73 (dd, 1H, J=8.3, 2.4 Hz), 3.76 (s, 3H), 3.63 (s, 2H), 2.88 (oct, 4H, J=5.8 Hz).
4-(benzylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
With potassium hydroxide; tetrabutylammomium bromide; In tetrahydrofuran; water;
b. 4-(Benzylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one To a cooled (cold water bath) solution of 4-(benzylthio)azetidin-2-one (5.5 g, 28.5 mmol), tetra-n-butylammonium bromide (0.9 g, 2.85 mmol) and <strong>[31984-10-8]1-bromo-4-phenylbutan-2-one</strong> (7.1 g, 31.3 mmol) in dry THF (100 ml) was added freshly powdered potassium hydroxide (1.8 g, 31.3 mmol), and the mixture stirred vigorously for 2 hr at ambient temperature. Water was added and the product extracted into ethyl acetate, dried (MgSO4) and evaporated to an oil. Treatment with ether gave the product as a white crystalline solid (3.12 g, 32%) mp 79-81 C. 1 H NMR delta (CDCl3), 2.58 (2H, m, CH2 CO), 2.86 (2H, t, J=7.5 Hz, CH2 Ph), 2.96 (1H, dd, J=2.2, 15.2 Hz, H3a,), 3.17, 3.98 (each 1H, d, J=18.5 Hz, NCH2), 3.43 (1H, dd, J=5.1, 15.2 Hz, H3b), 3.70 (2H, s, SCH2), 4.89 (1H, dd, J=2.4, 5.1 Hz, H4), 7.15-7.33 (10 H, m, Ph-H). Found: C, 70.9; H, 6.3; N, 4.3%; C20 H21 NO2 S requires: C, 70.8; H, 6.2; N, 4.1%
trans-3-methyl-4-(benzylthio)azetidin-2-one[ No CAS ]
[ 31984-10-8 ]
trans 3-methyl-4-(benzylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
In tetrahydrofuran;
EXAMPLE 26 trans 3-Methyl-4-(benzylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one A solution of trans-3-methyl-4-(benzylthio)azetidin-2-one (0.73 g, 3.5 mmol) in dry THF (5 ml) was added dropwise over 5 minutes to a suspension of sodium hydride (60% dispersion in oil, 0.15 g, 3.8 mmol) in dry THF (10 ml) under a nitrogen atmosphere at -10 C. The mixture was stirred for 10 minutes at -10 C. and <strong>[31984-10-8]1-bromo-4-phenylbutan-2-one</strong> (0.79 g, 3.5 mmol) in dry THF (10 ml) was added over 5 minutes at -10 C. The mixture was stirred at room temperature for 30 minutes and poured into ice/water. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organics were washed with brine, dried (MgSO4) and evaporated to an oil. This was purified by flash chromatography on silica gel eluding with petroleum ether 40-60 C./ethyl acetate 3:1, 2:1 to give a colourless solid (0.34 g, 27%) mp 69-71 C. 1 H NMR delta (CDCl3) 1.34 (3H, d, J=7 Hz, SCH3), 2.55 (2H, m, CH2 Ph), 2.85 (2H, t, J=8 Hz, COCH2 CH2), 3.11, 3.97 (each 1H, d, J=18 HZ, NCH2), 3.15 (1H, m, H3), 3.70 (2H, m, SCH2), 4.50 (1H, d, J=2 Hz, H4), 7.1-7.4 (10H, m, 2xPh-H).
4-butylthio-1-(4-phenyl-2-oxobutyl)azetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With potassium hydroxide; tetrabutylammomium bromide; In tetrahydrofuran;
B. 4-Butylthio-1-(4-phenyl-2-oxobutyl)azetidin-2-one--A mixture of 4-butylthioazetidin-2-one (3.2 g, 0.02 mol), tetrabutylammonium bromide (0.65 g, 0.002 mol), 1-bromo-4-phenyl-2-oxobutane (5.0 g, 0.022 mol) and powdered potassium hydroxide (1.23 g, 0.022 mol) was stirred in dry tetrahydrofuran (100 ml) for 30 minutes with some cooling from an ice bath. The mixture was partitioned between ethyl acetate-dilute ammonium chloride solution. The aqueous solution was extracted with ether (*2) and the combined extracts were washed with brine, dried and evaporated. Flash chromatography (silica gel, hexane-ethyl acetate) gave the title compound as a yellow oil (3.6 g, 59%). 1 H NMR (CDCl3)delta:
4-(2-hydroxyethylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
NaH; In tetrahydrofuran;
b. 4-(2-hydroxyethylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one Treatment of 4-(2-hydroxyethylthio)azetidin-2-one with <strong>[31984-10-8]1-bromo-4-phenylbutan-2-one</strong> in the presence of NaH in THF gave the title compound as a colourless oil, 1.4 g, 50% yield 1 H NMR delta (CDCl3) 2.64-2.70 (2H, m, Ph-CH2), 2.73-2.80 (2H, m,CO--CH2), 2.90-2.96 (2H, m, O--CH2), 3.00 (1H, dd, J=15.24,2.20 Hz, H3a), 3.50 (1H, dd, J=15.16, 4.95 Hz, H3b), 3.66-3.79 (3H, m, S--CH2, N--CH2), 4.27 (1H, d, J=18.41 Hz, N--CH2), 4.94 (1H, dd, J=5.05, 2.36 Hz, H4), 7.16-7.33 (5H, m, Ph-H).
(i) A soln of 3-phenyl-propionyl chloride (2.0 mL; 13.5 mmol) in dry THF (50 mL) was added over 6 min to a 0 C soln of diazomethyl-trimethyl-silane (2.0 M in hexanes; 15 mL; 30 mmol) in dry THF (50 mL). After 3 h, the rxn was coned to a liquid, (ii) Aq. HBr (48%; ca. 2.5 eq) was added in one portion to a soln of this crude material in AcOH (30 mL) at 0 C. After 10 min the rxn was coned. EtOAc (50 mL) was added and the soln washed with water (2 x 15 mL), satd NaHCO3 (3 x 15 mL), water (1 x 15 mL) and satd NaCl (2 x 15 mL). After drying over MgSO4, filtering through a pad of silica with an EtOAc wash and coned to an oil, the crude material was purified by MPLC (SiO2 with a 0 - > 20% EtOAc in hexanes gradient) yielding bromomethyl ketone as an off-white solid (1.977 g; 65%). IH NMR (CDC13) delta 7.37 - 7.18 (m, 5H), 3.85 (s, 2H), 3.01 - 2.94 (m, 4H); GC-MS 226/228 ([M]+).
ethyl 3-(5-bromo-2-(4-phenethylthiazol-2-ylamino)pyridin-4-yloxy)-4-chlorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With triethylamine; In ethanol; at 70℃; for 6h;
Step E: Preparation of ethyl 3-f5-bromo-2-f4-phenethylthiazol-2- ylamino)pyridin-4-yloxyV4-chlorobenzoate: A flask was charged with ethyl 3- (5-bromo-2-thioureidopyridin-4-yloxy)-4-chlorobenzoate (0.200 g, 0.464 mmol), l-bromo-4-phenylbutan-2-one (0.105 g, 0.464 mmol) and triethylamine (0.0470 g. 0.464 mmol). Ethanol (5 mL) was added and the reaction was heated at 70 0C for 6 hours, and then concentrated to provide ethyl the desired product (0.250 g, 95 yield) as white solid. LC/ MS (apci) M+2H: 560 (100%).
Step F: Preparation of 4-(4-methoxybenzylthioV5-bromo-N-(4- phenethylthiazol-2-vDpyridine-2-amine: l-(4-(4-methoxybenzylthio)-5- bromopyridin-2-yl)thiourea (3.0 g, 7.8 mmol) and l-bromo-4-phenylbutan-2-one (1.77 g, 7.8 mmol) were diluted in EtOH (120 mL). Triethylamine (2.2 ml, 15.6 mmol) was added, and the solution was heated at 75 0C for 3 hours. The solution was cooled and concentrated to half the amount of solvent. The solid was filtered and rinsed with cold EtOH to provide the desired product (2.44 g, 61% yield) as a tan solid.
Step E: Preparation of 4-fbenzyloxy)-5-bromo-N-(4- phenethylthiazol-2-yl)pyridin-2-amine: A flask was charged with l-(4- (benzyloxy)-5-bromopyridin-2-yl)thiourea (2.34 g, 6.92 mmol), l-bromo-4- phenylbutan-2-one (1.65 g, 7.26 mmol), and triethylamine (1.93 ml, 13.8 mmol). Ethanol (100 mL) was added and the reaction was stirred at 75 C for 8 hours. The reaction was cooled and filtered, and the collected solids were washed with water to give the desired product (2.54 g, 77.9% yield) as a white solid.
With N-ethyl-N,N-diisopropylamine; In ethanol; at 70℃; for 2h;
Step G: Preparation of ethyl 2-f5-bromo-2-f4-phenethylthiazol-2-ylammo)p yrdin-4- vDacetate : A flask was charged with ethyl 2-(5-bromo-2- thioureidopyridin-4-yl)acetate (2.200 g, 6.914 mmol), l-bromo-4-phenylbutan-2- pne (1.884 g, 8.297 mmol). DIEA (1.806 mL, 10.37 mmol) and ethanol (100 mL). The mixture was heated stirred at 70 0C for 2 hours, then cooled. The reaction was concentrated, and the residue was partitioned between chloroform and dilute sodium bicarbonate solution. The organic phase was washed with dilute sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The solid residue was recrystallized from hexane/ethyl acetate to give the desired product (1.815 g, 58.81% yield) as a yellow solid.
Example 19 5-Phenethyl-1H-imidazol-2-ylamine To a solution of 1-acetylguanidine (1.34 g, 13.2 mmol) in dimethylformamide (7 ml) a solution of <strong>[31984-10-8]1-bromo-4-phenyl-butan-2-one</strong> (1.5 g, 6.6 mmol) in dimethylformamide (7 ml) was added at 0 C. The mixture was stirred overnight at room temperature and then the solvent was evaporated. Upon addition of ethyl acetate/heptane (1:1) a white solid was formed that was filtered off and washed with ethyl acetate/heptane (1:1). After drying in vacuo the solid was dissolved in a mixture of concentrated hydrochloric acid (2 ml) and methanol (4 ml) and stirred for 2.5 hours at 85 C. The solvent was evaporated and the residue was purified by chromatography (column: Isolute Flash-NH2 from Separtis; eluent: ethyl acetate/methanol=1:1) to yield a light yellow solid (0.063 mg, 5%); MS (EI): 187.2 (M+).
tert-Butyl 4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (IV-1) At 0 C., a solution of tert-butyl 4-carbamothioylpiperidine-1-carboxylate (1.95 g) is added dropwise to a solution of <strong>[31984-10-8]1-bromo-4-phenylbutan-2-one</strong> (2.00 g) in ethanol (20 ml). Under argon, the reaction mixture is stirred at room temperature overnight. Triethylamine (1.7 ml) is added, and the mixture is diluted with ethyl acetate and washed with concentrated sodium chloride solution. The aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure, which gives a mixture of tert-butyl 4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate and tert-butyl 4-[4-hydroxy-4-(2-phenylethyl)-4,5-dihydro-1,3-thiazol-2-yl]piperidine-1-carboxylate. The two compounds are separated chromatographically. This gives tert-butyl 4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (800 mg) and tert-butyl 4-[4-hydroxy-4-(2-phenylethyl)-4,5-dihydro-1,3-thiazol-2-yl]piperidine-1-carboxylate (640 mg). Both compounds can be used for Process 1.2 since the latter compound is, under the reaction conditions, converted into the former. 1H NMR (DMSO-d6): delta 7.28-7.25 (m, 2H), 7.22-7.22 (m, 2H), 7.20-7.18 (m, 1H), 7.13 (s, 1H), 4.00 (bs, 2H), 3.35 (s, 2H), 3.16 (m, 1H), 2.95 (s, 4H), 2.00 (d, 2H), 1.52 (qd, 2H), 1.41 (s, 9H) ppm MS (ESI): 373 ([M+H]+)
B) Toluene (300ml) and triphenyl phosphine (167.5) was charged at 20 to 300C into a 2 litre round bottom flask equipped with an overhead stirrer, thermo pocket and dropping funnel. The toluene solution as obtained in step 1A was added at 20 to 300C. The reaction mass was maintained at the same temperature for about 2 to 4 hours and checked HPLC for completion of reaction. The solid was filtered and washed with toluene (150ml). The wet material obtained was taken in a flask and acetone (500ml) was charged into it and stirred for 2 hours at 20 to 300C. The product was filtered and washed with acetone (100ml). The wet material was dried under vacuum at 40 to 450C for 5 to 8 hours to obtain the title compound (200-220 g).
In toluene; at 20℃; for 12h;
General procedure: alpha-Bromo ketone (12 mmol) was added to the solution of PPh3 (14.4 mmol) in toluene (24 mL) in one portion. Then the mixture was stirred at room temperature for 12h. After filtration, the precipitated phosphonium bromide was mixed with CH2Cl2/EtOAc (20 mL, 1:3) and stirred. To this stirred suspensions, NaOH (2N, aq.) was added slowly until all solids disappeared. Then the reaction mixture was diluted with CH2Cl2 (30 mL), washed with water (3×10 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated and phosphorus ylide reagent was obtained. After that, trifluoromethyl cyclopropyl ketone (10 mol) was mixed with phosphorus ylide reagent (12 mol) in CH2Cl2 (10 mL) under refluxing. The completion of the reaction was monitored by 19F NMR. After completion of the reaction, solvent was evaporated and the residue was purified by column chromatography on silica gel to afford the desired alpha, beta-unsaturatedketone 2 as product. Both E- and Z-type alpha, beta-unsaturated ketones were formed in the reaction.
Neat 3-oxo-3- phenyl-propionic acid ethyl ester (95%; 0.80 mL; 4.4 mmol) was added over 1.5 min to a soln of KO-t-Bu (1.0 M in THF; 4.40 mL; 4.4 mmol) in THF (4.4 mL) at 0 C. After 20 min, the above solid bromomethyl ketone (910 mg; 4.0 mmol) was added in one portion. After an additional 2 h, the rxn was quenched with aq. citric acid. The organic volatiles were removed on a rotary evaporator then the product extracted into EtOAc (25 mL). The soln was washed with water (2 x 8 mL), satd NaCl (1 x 8 mL), dried over MgSO4, filtered through a plug of silica with an EtOAc wash and coned. The product was purified by MPLC (silica; 0 --> 35% EtOAc in hexanes EPO <DP n="43"/>gradient) yielding a clear, colorless liquid (1.199 g; 97%). IH NMR (CDC13) delta 8.02 (m, 2H), 7.60 (m, IH), 7.49 (m, 2H), 7.28 (m, 2H), 7.22 - 7.15 (m, 3H), 4.93 (dd, J = 6.4, 7.6 Hz, IH), 4.13 (q, J = 7.2 Hz, 2H), 3.19 (dd, J = 7.6, 18.4 Hz, IH), 3.12 (dd, J = 6.4, 18.0 Hz, IH), 2.94 - 2.82 (m, 4H), 1.15 (t, J = 7.0 Hz, 3H).
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