* 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.
A solution of bromine (155 ml) in dichloromethane (500 ml) was added during 30 min to a solution of 3,4-dihydrocoumarin (450 g, 0.3 mol) in dichloromethane (2000 ml). The mixture was stirred overnight at 15°C, then diluted with dichloromethane (2000 ml), and washed with aqueous sodium bicarbonate (2 x 1000 ml) followed by water (1000 ml). The solution was dried over magnesium sulphate, filtered, and concentrated under reduced pressure. The residue was washed with petroleum ether (2 x 500 ml), and filtrate concentrated. The solid was recrystallised from dichloromethane/petroleum ether to give the bromide (BM1490) as thick white crystals (471 g, 74percent).
46.5%
With bromine In dichloromethane at 20℃; for 7 h;
Reference Example 13 [Step a] To a solution of compound 1 (5.00 g, 33.7 mmol) in dichloromethane (50.0 mL) was added dropwise a solution of bromine (1.80 mL, 35.4 mmol) in dichloromethane (20.0 mL) at room temperature, and the mixture was stirred for 7 hr. To the reaction solution was added water, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The precipitated solid was suspended and washed in diisopropyl ether (10.0 mL), collected by filtration and washed with diisopropyl ether and hexane to give compound 2 (3.56 g, 46.5percent). MS(ESI)m/z: 227, 229(M+1)+.
Reference：
[1] Journal of Organometallic Chemistry, 1990, vol. 387, # 3, p. 381 - 390
[2] Patent: WO2017/49343, 2017, A1, . Location in patent: Paragraph 0066
[3] Patent: EP3135667, 2017, A1, . Location in patent: Paragraph 0425-0426
[4] Justus Liebigs Annalen der Chemie, 1884, vol. 226, p. 359
[5] Journal of Organic Chemistry, 1997, vol. 62, # 24, p. 8522 - 8528
[6] Monatshefte fuer Chemie, 1913, vol. 34, p. 1660
[7] Monatshefte fuer Chemie, 1913, vol. 34, p. 1660
[8] Patent: WO2006/113432, 2006, A2, . Location in patent: Page/Page column 69-70
4
[ 119-84-6 ]
[ 55745-97-6 ]
Reference：
[1] Journal of the Chemical Society, 1956, p. 2455,246
5
[ 119-84-6 ]
[ 13336-31-7 ]
Reference：
[1] Organic Letters, 2007, vol. 9, # 15, p. 2915 - 2918
[2] Journal of Medicinal Chemistry, 1985, vol. 28, # 4, p. 515 - 518
[3] Journal of the Chemical Society, 1954, p. 4299,4301
[4] Patent: WO2014/19344, 2014, A1,
[5] Patent: US2015/79028, 2015, A1,
[6] Patent: WO2014/82380, 2014, A1,
[7] Patent: WO2014/82379, 2014, A1,
[8] Patent: WO2014/131315, 2014, A1,
[9] Patent: US5554620, 1996, A,
[10] Patent: WO2016/44770, 2016, A1,
6
[ 119-84-6 ]
[ 77-78-1 ]
[ 13336-31-7 ]
Reference：
[1] Monatshefte fuer Chemie, 1978, vol. 109, p. 405 - 419
[2] Journal of Organic Chemistry, 1991, vol. 56, # 14, p. 4499 - 4508
7
[ 119-84-6 ]
[ 40731-98-4 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 150 - 200℃; for 1 h;
A mixture of aluminium chloride (90.0 g, 676 mmol) and sodium chloride was stirred at 150 °C until the solid dissolved, and then compound 67-1 (20.0 g. 135 mmol) was added dropwise. At the end of addition, the mixture was stirred at 200 °C for 1 hr. After the reaction was completed, the mixture was cooled to rt and poured slowly into ice-water (500 mL), then filtered to get the crude product. The crude product was purified by beating to give the title compound 67-2 (19 g, 95percent) as a gray solid. The compound was characterized by the following spectroscopic data: MS (ESI. pos.ion) mlr. 149.5 [M+H] +; 'HNMR (400 MHz, CDC13) δ (ppm): 7.41-7.38 (m. 1 H). 7.24-7.19 (m. l H). 6.80-6.79. 6.78-6.77 (d, d, 1H, J = 4.0 Hz), 5.46 (br, 1 H). 3.06-3.03 (m, 2H), 2.69-2.66 (m, 2H).
95%
at 150 - 200℃; for 1 h; Inert atmosphere; Sealed tube
A mixture of aluminium chloride (90.0 g, 676 mmol) and sodium chloride (25 g, 432 mmol) was stirred at 150 °C until the mixture was in molten state, and then compound 1-1 (20.0 g, 135 mmol) was added dropwise. At the end of the addition, the mixture was stirred at 200 °C for 1.0 hr. After the reaction was completed, the mixture was cooled to rt, poured slowly into ice water (500 mL) and filtered to get the crude product. The crude product was triturated with MeOH and filtered to give the title compound as a gray solid (19 g, 95percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 149.5 [M+H]+; and ln NMR (400 MHz, CDC13) δ (ppm): 7.41-7.38 (m, 1H), 7.24-7.19 (m, 1H), 6.80-6.79, 6.78-6.77 (d, d, 1H, J = 4.0 Hz), 5.46 (br, 1H), 3.06-3.03 (m, 2H), 2.69-2.66 (m, 2H).
95%
at 150 - 200℃; for 1 h;
A mixture of aluminium chloride (90.0 g.676 mmol) and sodium chloride (25.0 g.432 mmol) was stirred at 150 °C until the solid was melted, and then compound 1-1 (20.0 g.135 mmol) was added slowly. At the end of the addition, the mixture was stirred at 200 °C for 1.0 hr. After the reaction was completed, the mixture was cooled to rt and poured slowly into ice-water (500 mL). then filtered to get a gray solid which was purified by beating in methanol to give the title compound 1-2 (19.0 g.95percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 149.5 [M+H] and 'HNMR (400 MHz. CDCL)r) (ppm): 7.41-7.38 (m.1H).7.24-7.19 (m.111).6.80-6.79.6.78-6.77 (d, d.1H. ./= 4.0 Hz).5.46 (br.1H), 3.06-3.03 (m, 2H).2.69-2.66 (m, 2H).
95%
at 150 - 200℃;
A mixture of alchlor (90 g, 676 mmol) and sodium chloride (25 g, 432 mmol) was stirred at 150 °C until melted and then compound 3-2 (20 g, 135 mmol) was added dropwise slowly. At the end of the addition, the mixture was stirred at 200 °C for 1 hour. After the reaction was completed, the mixture was cooled to rt and poured into ice water (500 mL). The resulting mixture was filtered. The filter cake was triturated with methanol and filtered to afford the title compound as a gray solid (19 g, 95 percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 149.5 [M+H]+; and *H NMR (400 MHz, CDC13): δ 7.41-7.38 (m, 1H), 7.24-7.19 (m, 1H), 6.80-6.79, 6.78-6.77 (d, d, 1H, J = 4.0 Hz), 5.46 (br, 1H), 3.06-3.03 (m, 2H), 2.69-2.66 (m, 2H) ppm.
95%
at 150 - 200℃; for 1 h;
12391] A mixture of aluminium chloride (90.0 g, 676 mmol) and sodium chloride was stirred at 150° C. until the solid dissolved, and then compound 67-1 (20.0 g, 135 mmol) was added dropwise. At the end of addition, the mixture was stirred at 200° C. for 1 hr. Afier the reaction was completed, the mixture was cooled to rt and poured slowly into ice-water (500 mE), then filtered to get the crude product. The crude product was purified by beating to give the title compound 67-2 (19 g, 95percent) as a gray solid. The compound was characterized by the following spectroscopic data:12392] MS (ESI, pos.ion) mlz: 149.5 [M+H]12393] ‘HNMR (400 MHz, CDC13) ö (ppm): 7.4 1-7.38 (m, 1H), 7.24-7.19 (m, 1H), 6.80-6.79, 6.78-6.77 (d, d, 1H, J=4.0 Hz), 5.46 (br, 1H), 3.06-3.03 (m, 2H), 2.69-2.66 (m, 2H).
81%
at 200 - 210℃; for 1.5 h;
A mixture of 20 g of aluminum chloride, 4 g of sodium chloride and 4 g of dihydrocoumarin was stirred at 200 ° C to 210 ° C for 1.5 hours and cooled to room temperature.Pour the system into an appropriate amount of ice water, add 30 ml of concentrated hydrochloric acid to make the system strong acid, then filter with a triangular funnel to retain the filter cake.The filter cake was washed with 20 ml of ethanol, and finally the filter cake was dried.Thus the title compound (Intermediate II),3.24 grams of brown solid,The yield was 81percent.
Reference：
[1] Patent: WO2014/19344, 2014, A1, . Location in patent: Paragraph 00820
[2] Patent: WO2014/82380, 2014, A1, . Location in patent: Paragraph 00314; 00315
[3] Patent: WO2014/82379, 2014, A1, . Location in patent: Page/Page column 112; 113
[4] Patent: WO2014/131315, 2014, A1, . Location in patent: Page/Page column 112
[5] Patent: US2015/79028, 2015, A1, . Location in patent: Paragraph 2389; 2390; 2391; 2392; 2393
[6] Journal of Organic Chemistry, 2012, vol. 77, # 17, p. 7411 - 7427
[7] Journal of the American Chemical Society, 1988, vol. 110, # 19, p. 6471 - 6480
[8] Patent: CN108997163, 2018, A, . Location in patent: Paragraph 0094; 0095; 0096
[9] Journal of the Chemical Society, 1954, p. 4299,4301
[10] Collection of Czechoslovak Chemical Communications, 1958, vol. 23, p. 663,666, 671
[11] Scientia Pharmaceutica, 1998, vol. 66, # 3, p. 147 - 158
[12] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 12, p. 2801 - 2809
[13] Organic Letters, 2007, vol. 9, # 15, p. 2915 - 2918
[14] Journal of Medicinal Chemistry, 1985, vol. 28, # 4, p. 515 - 518
[15] Patent: US5569655, 1996, A,
[16] Patent: US5554620, 1996, A,
[17] Chemistry of Materials, 2014, vol. 26, # 19, p. 5437 - 5440
[18] Patent: WO2015/95261, 2015, A1, . Location in patent: Page/Page column 72
[19] Patent: WO2015/89842, 2015, A1, . Location in patent: Page/Page column 71-72
[20] Patent: WO2016/44770, 2016, A1, . Location in patent: Page/Page column 895
8
[ 119-84-6 ]
[ 40731-98-4 ]
Reference：
[1] Patent: US4322414, 1982, A,
9
[ 7446-70-0 ]
[ 119-84-6 ]
[ 40731-98-4 ]
Reference：
[1] Journal of the Chemical Society, 1954, p. 4299,4301
10
[ 119-84-6 ]
[ 1641-41-4 ]
Reference：
[1] Patent: CN108997163, 2018, A,
11
[ 119-84-6 ]
[ 33538-83-9 ]
Reference：
[1] Journal of pharmaceutical sciences, 1971, vol. 60, # 8, p. 1188 - 1192
12
[ 119-84-6 ]
[ 128651-99-0 ]
Yield
Reaction Conditions
Operation in experiment
90%
With Iodine monochloride In dichloromethane for 20 h; Inert atmosphere
The synthesis was performed in analogy to Ref. [41]. In aflame dried and argon flushed 250 cm3 two-neck roundbottomflask equipped with dropping funnel and argon-inlet5.00 g dihydrocoumarin (15, 33.8 mmol) was dissolved in35 cm3 DCM. ICl (5.48 g, 33.8 mmol) dissolved in 35 cm3DCM was added through the dropping funnel within15 min. After full conversion (20 h), the reaction mixturewas diluted with 100 cm3 DCM and washed with 0.1 MNa2S2O3-solution (2 9 50 cm3). The combined aqueouslayers were re-extracted with DCM (2 9 50 cm3). Thecombined organic layers were washed with saturated NaClsolution (1 9 200 cm3), dried over MgSO4, filtered, andthe solvent was removed in vacuo. Recrystallization fromDCM/cyclohexane (1/4) afforded 8.28 g (90 percent) 16 ascolorless powder. M.p. 134–136 C (Ref. [37];133–134 C); NMR data were found to agree with thosedescribed in Ref. [41].
Reference：
[1] Monatshefte fur Chemie, 2016, vol. 147, # 3, p. 509 - 521
[2] Journal of Organometallic Chemistry, 1990, vol. 387, # 3, p. 381 - 390
With formic acid In methanol; water Ambient temperature;
100%
With hydrogen In ethyl acetate for 0.833333h; Ambient temperature; Irradiation;
99%
With hydrogen In acetic acid for 12h;
99%
With 2C2H3O2(1-)*Pd(2+)*3Na(1+)*C18H12O9PS3(3-); hydrogen; glycerol at 100℃; for 2h; Schlenk technique;
96%
With hydrogen In ethyl acetate Ambient temperature;
94%
With sodium tetrahydroborate; hydrogen; nickel dichloride In isopropyl alcohol at 40℃; for 6h;
Reduction of oct-1-ene (1).
General procedure: Anhydrous nickel(II) chloride, 1.75 g (14 mmol), was added to a suspension of 1.1 g (30 mmol) of NaBH4 in 20 mL of propan-2-ol to obtain a black colloidal solution. Hydrogen was passed through the solution at a flow rate of 15-20 mL/min, 34 g (0.3 mol) of oct-1-ene (1) was added, and the mixture was stirred for 6 h at 50-60 °C. The mixture was cooled, 1 mL of water was added to accelerate coagulation of the catalyst, the precipitate was filtered off, the solvent was removed from the filtrate by distillation through a column, and the residue was distilled. Yield 28 g (0.246 mol, 82%), bp 124-127°C[20]. Mass spectrum, m/z (Irel, %): 114 (5) [M]+, 85(25), 71 (20), 57 (33), 43 (100).
93%
With methanol; palladium diacetate; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In dichloromethane at 25℃; for 12h; Schlenk technique; Inert atmosphere;
42
Replace the gas environment in the Shrek tube with a nitrogen environment, add coumarin 0.25 mmol, palladium acetate 0.0025 mmol, methylene chloride 0.5 mL, methanol 0.275 mmol, add pinacol borane 0.275 mmol under stirring, and react at room temperature After 12 hours, the reaction solution obtained after the completion of the reaction was subjected to column chromatography, and the target product obtained in 93% yield was a colorless liquid.
93%
With methanol; palladium diacetate; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In dichloromethane at 25℃; for 12h; Sealed tube; Inert atmosphere; chemoselective reaction;
90%
With nickel In tetrahydrofuran at 20℃; for 0.25h;
90%
With hydrogen; acetic acid for 48h;
85%
With Raney nickel (50percent Ni-Al) In sodium hydroxide at 90℃; for 1.5h;
85%
With sodium hydrogen telluride In ethanol for 5h; Heating;
84%
With hydrogen In acetic acid for 3h;
83%
With hydrogen In ethanol at 50℃; for 3h;
81%
With H2SiEt2; C32H43BCeF15Si6 at 25℃; for 0.166667h; Inert atmosphere;
71%
With methanol; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate at 20℃; for 16h; Inert atmosphere; Irradiation; Sealed tube;
60%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; tetrahydroxydiboron; water; triethylamine In tetrahydrofuran at 30℃; for 12h; Schlenk technique; Inert atmosphere;
50%
With baker's yeast; D-glucose In ethanol at 35 - 38℃; for 48h;
18%
With [Ir(COD)((4S)-iPr-Phox)]tetrakis[(3,5-trifluoromethyl)phenyl]borate; hydrogen; N-ethyl-N,N-diisopropylamine In toluene at 20℃; for 8h; Autoclave;
With nickel at 160 - 200℃; Hydrogenation.unter Druck;
With Pd-BaSO4; ethanol Hydrogenation;
With nickel; benzene at 130℃; Hydrogenation;
With nickel; benzene at 85℃; Hydrogenation;
With diethyl ether; nickel at 100℃; Hydrogenation;
With methanol; nickel Hydrogenation;
With ethanol; platinum Hydrogenation;
With palladium; acetic acid Hydrogenation;
With tetralin; palladium; toluene
99 % Chromat.
With sodium hydrogen telluride In ethanol for 4h; Ambient temperature;
With hydrogen In acetic acid
With triethylsilane; silica gel 1.) benzene, room temperature, 16 h, 2.) petroleum ether, ethyl acetate; Yield given. Multistep reaction;
With hydrogen In ethanol for 2h; Ambient temperature;
With sodium hydrogen telluride In ethanol Ambient temperature; Yield given;
With potassium chloride; hydrogen In methanol; water for 0.166667h; catodically pretreated Raney-Ni-powder; other times; hydrogenation in presence of pyridine and coumarine; change of potential during the hydrogenation;
Multi-step reaction with 2 steps
1: water; sodium amalgam
2: Bei der trocknen Destillation
99 %Spectr.
With triethylsilane; indium tribromide; allyl-trimethyl-silane In toluene at 70℃; for 24h;
With hydrogen In glycerol at 100℃; for 3h;
2.2. Pd-catalysed hydrogenation
General procedure: 1 mmol of alkene (146 mg for (E)-4-phenyl-but-3-en-2-one;146 mg for coumarin; 165 mg for 4-nitroacetophenone; 180 mg fortrans-stilbene) was added to a 1 mL of solution of preformed nanoparticlesin glycerol (0.01 mmol Pd, 1.0 mol%). The resulting mixture was stirred at room temperature under argon in a Fisher-Porter bottle. The system was then pressurized with dihydrogen (3 bar) and stirred at100 °C for 3 h. The mixture was then cooled to room temperature. The catalytic mixture was extracted with dichloromethane (3 × 10 mL) and the combined organic phases were dried over anhydrous Na2SO4,filtered and the solvent evaporated under reduced pressure.
With Old Yellow Enzyme 1; NADH In tert-butyl methyl ether; dimethyl sulfoxide at 30℃; for 24h; Enzymatic reaction;
With 5% Pd-BaSO4; hydrogen In tetrahydrofuran at 74.84℃; for 2h; Autoclave;
79 %Chromat.
With hydrogen In glycerol at 80℃; for 2h;
99 %Spectr.
With borane-ammonia complex; 2-H-1,3-di-tert-butyl-2,3-dihydro-1H-1,3,2-diazaphosphole In [D3]acetonitrile at 50℃; for 1h; regioselective reaction;
With hydrogen In methanol at 20℃; for 80h; chemoselective reaction;
With hydrogen In toluene at 100℃; for 15h; Sealed tube;
With aluminum (III) chloride; sodium chloride; at 150 - 200℃; for 1h;
A mixture of aluminium chloride (90.0 g, 676 mmol) and sodium chloride was stirred at 150 C until the solid dissolved, and then compound 67-1 (20.0 g. 135 mmol) was added dropwise. At the end of addition, the mixture was stirred at 200 C for 1 hr. After the reaction was completed, the mixture was cooled to rt and poured slowly into ice-water (500 mL), then filtered to get the crude product. The crude product was purified by beating to give the title compound 67-2 (19 g, 95%) as a gray solid. The compound was characterized by the following spectroscopic data: MS (ESI. pos.ion) mlr. 149.5 [M+H] +; 'HNMR (400 MHz, CDC13) delta (ppm): 7.41-7.38 (m. 1 H). 7.24-7.19 (m. l H). 6.80-6.79. 6.78-6.77 (d, d, 1H, J = 4.0 Hz), 5.46 (br, 1 H). 3.06-3.03 (m, 2H), 2.69-2.66 (m, 2H).
95%
With aluminum (III) chloride; sodium chloride; at 150 - 200℃; for 1h;Inert atmosphere; Sealed tube;
A mixture of aluminium chloride (90.0 g, 676 mmol) and sodium chloride (25 g, 432 mmol) was stirred at 150 C until the mixture was in molten state, and then compound 1-1 (20.0 g, 135 mmol) was added dropwise. At the end of the addition, the mixture was stirred at 200 C for 1.0 hr. After the reaction was completed, the mixture was cooled to rt, poured slowly into ice water (500 mL) and filtered to get the crude product. The crude product was triturated with MeOH and filtered to give the title compound as a gray solid (19 g, 95%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 149.5 [M+H]+; and ln NMR (400 MHz, CDC13) delta (ppm): 7.41-7.38 (m, 1H), 7.24-7.19 (m, 1H), 6.80-6.79, 6.78-6.77 (d, d, 1H, J = 4.0 Hz), 5.46 (br, 1H), 3.06-3.03 (m, 2H), 2.69-2.66 (m, 2H).
95%
With aluminum (III) chloride; sodium chloride; at 150 - 200℃; for 1h;
A mixture of aluminium chloride (90.0 g.676 mmol) and sodium chloride (25.0 g.432 mmol) was stirred at 150 C until the solid was melted, and then compound 1-1 (20.0 g.135 mmol) was added slowly. At the end of the addition, the mixture was stirred at 200 C for 1.0 hr. After the reaction was completed, the mixture was cooled to rt and poured slowly into ice-water (500 mL). then filtered to get a gray solid which was purified by beating in methanol to give the title compound 1-2 (19.0 g.95%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 149.5 [M+H] and 'HNMR (400 MHz. CDCL)r) (ppm): 7.41-7.38 (m.1H).7.24-7.19 (m.111).6.80-6.79.6.78-6.77 (d, d.1H. ./= 4.0 Hz).5.46 (br.1H), 3.06-3.03 (m, 2H).2.69-2.66 (m, 2H).
95%
With aluminum (III) chloride; sodium chloride; at 150 - 200℃;
A mixture of alchlor (90 g, 676 mmol) and sodium chloride (25 g, 432 mmol) was stirred at 150 C until melted and then compound 3-2 (20 g, 135 mmol) was added dropwise slowly. At the end of the addition, the mixture was stirred at 200 C for 1 hour. After the reaction was completed, the mixture was cooled to rt and poured into ice water (500 mL). The resulting mixture was filtered. The filter cake was triturated with methanol and filtered to afford the title compound as a gray solid (19 g, 95 %). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 149.5 [M+H]+; and *H NMR (400 MHz, CDC13): delta 7.41-7.38 (m, 1H), 7.24-7.19 (m, 1H), 6.80-6.79, 6.78-6.77 (d, d, 1H, J = 4.0 Hz), 5.46 (br, 1H), 3.06-3.03 (m, 2H), 2.69-2.66 (m, 2H) ppm.
95%
With aluminum (III) chloride; sodium chloride; at 150 - 200℃; for 1h;
12391] A mixture of aluminium chloride (90.0 g, 676 mmol) and sodium chloride was stirred at 150 C. until the solid dissolved, and then compound 67-1 (20.0 g, 135 mmol) was added dropwise. At the end of addition, the mixture was stirred at 200 C. for 1 hr. Afier the reaction was completed, the mixture was cooled to rt and poured slowly into ice-water (500 mE), then filtered to get the crude product. The crude product was purified by beating to give the title compound 67-2 (19 g, 95%) as a gray solid. The compound was characterized by the following spectroscopic data:12392] MS (ESI, pos.ion) mlz: 149.5 [M+H]12393] ?HNMR (400 MHz, CDC13) oe (ppm): 7.4 1-7.38 (m, 1H), 7.24-7.19 (m, 1H), 6.80-6.79, 6.78-6.77 (d, d, 1H, J=4.0 Hz), 5.46 (br, 1H), 3.06-3.03 (m, 2H), 2.69-2.66 (m, 2H).
81%
With aluminum (III) chloride; sodium chloride; at 200 - 210℃; for 1.5h;
A mixture of 20 g of aluminum chloride, 4 g of sodium chloride and 4 g of dihydrocoumarin was stirred at 200 C to 210 C for 1.5 hours and cooled to room temperature.Pour the system into an appropriate amount of ice water, add 30 ml of concentrated hydrochloric acid to make the system strong acid, then filter with a triangular funnel to retain the filter cake.The filter cake was washed with 20 ml of ethanol, and finally the filter cake was dried.Thus the title compound (Intermediate II),3.24 grams of brown solid,The yield was 81%.
14.5 g (41%)
aluminium trichloride; In methanol; dichloromethane;
(a) Dihydrocoumarin (35 g, 0.236 mol) was added to 62.9 g (0.472 mol) of aluminum chloride and the mixture was heated in an oil-bath at 200 C. for 2.5 h with stirring The reaction mixture was cooled, poured into ice (300 g), 300 ml of methylene chloride added to the mixture, cooled, and 400 ml of methylene chloride was added. The mixture was filtered and the solid residue was dissolved in hot methanol, filtered, and the filtrate was cooled to afford 14.5 g (41%) of 4-hydroxy-indan-1-one.
14.5 g (41%)
aluminium trichloride; In methanol; dichloromethane;
(a) Dihydrocoumarin (35 g, 0.236 mol) was added to 62.9 g (0.472 mol) of aluminum chloride and the mixture was heated in an oil-bath at 200 C. for 2.5 h with stirring. The reaction mixture was cooled, poured into ice (300 g), 300 mL of methylene chloride added to the mixture, cooled, and 400 mL of methylene chloride was added. The mixture was filtered and the solid residue was dissolved in hot methanol, filtered, and the filtrate was cooled to afford 14.5 g (41%) of 4-hydroxy-indan-1-one.
With aluminum (III) chloride; sodium chloride; at 140 - 200℃; for 0.5h;
Step 1: To the molten salt of A1C13 (500 g, 3.75 mol) and NaC1 (100 g, 1.71 mol) was added chroman-2-one (S14-SM, 100 g, 0.68 mol) dropwise at 140 C. After being allowed to stir for 30mins at 180 C - 200 C, the reaction mixture was poured into ice-cooled diluted HC1 (2.5 L,0.5N), and precipitated. The suspension was filtered, and the filter was washed again with diluted aq. HC1 (1 L, 0.5N). The combined precipitate was obtained as 5 14-1.
With aluminum (III) chloride; sodium chloride; at 140 - 200℃; for 0.5h;
Step 1: To the molten salt of A1C13 (500 g, 3.75 mol) and NaCl (100 g, 1.71 mol) was added chroman-2-one (S14-SM, 100 g, 0.68 mol) dropwise at 140 C. After being allowed to stir for 30 mins at 180 C - 200 C, the reaction mixture was poured into ice-cooled diluted HC1 (2.5 L, 0.5N), and precipitated. The suspension was filtered, and the filter was washed again with diluted aq. HC1 (1 L, 0.5N). The combined precipitate was obtained as SI 4-1.
With aluminum (III) chloride; sodium chloride; at 210℃; for 2h;
A mixture of aluminium chloride (27 g, 202 mmol), sodium chloride (5.92 g, 101 mmol)and chroman-2-one (5.0 g, 33.7 mmol) was stirred at 2 10C for 2 hours. The mixture was cooled toroom temperature and poured slowly into ice water. The precipitate was filtered, triturated with methanol and filtered again to give the title compound.
With aluminum (III) chloride; sodium chloride; at 180 - 200℃; for 0.0333333h;
Melted aluminum trichloride (96 g, 720 mmol) at 140 CAnd sodium chloride (32g, 560mmol)Add coumarin (5.92 g, 40 mmol) dropwise, then raise the temperature rapidly to 180 C.And kept between 180 C and 200 C for 2 minutes.This mixture was poured into a mixed solution of ice water and hydrochloric acid.Extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered.Spinning through the column gave compound 49A (3.6 g, 60% yield).
A solution of bromine (155 ml) in dichloromethane (500 ml) was added during 30 min to a solution of 3,4-dihydrocoumarin (450 g, 0.3 mol) in dichloromethane (2000 ml). The mixture was stirred overnight at 15C, then diluted with dichloromethane (2000 ml), and washed with aqueous sodium bicarbonate (2 x 1000 ml) followed by water (1000 ml). The solution was dried over magnesium sulphate, filtered, and concentrated under reduced pressure. The residue was washed with petroleum ether (2 x 500 ml), and filtrate concentrated. The solid was recrystallised from dichloromethane/petroleum ether to give the bromide (BM1490) as thick white crystals (471 g, 74%).
46.5%
With bromine; In dichloromethane; at 20℃; for 7h;
Reference Example 13 [Step a] To a solution of compound 1 (5.00 g, 33.7 mmol) in dichloromethane (50.0 mL) was added dropwise a solution of bromine (1.80 mL, 35.4 mmol) in dichloromethane (20.0 mL) at room temperature, and the mixture was stirred for 7 hr. To the reaction solution was added water, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The precipitated solid was suspended and washed in diisopropyl ether (10.0 mL), collected by filtration and washed with diisopropyl ether and hexane to give compound 2 (3.56 g, 46.5%). MS(ESI)m/z: 227, 229(M+1)+.
With bromine; In chloroform; acetic acid; at 20℃; for 16h;
a) 6-Bromochroman-2-oneTo a solution of 3,4-dihydrocoumarin (3 mL, 24 mmol) in chloroform (15 mL) was added a solution of bromine (1.23 mL, 24 mmol) in acetic acid (5 mL). The resulting dark orange solution was stirred at room temperature for 16 h and turned EPO <DP n="71"/>near colorless. The reaction mixture was diluted with dichloromethane (40 ml_) and washed with saturated sodium hydgrogen carbonate (40 ml_) followed by water (40 ml_). The organic layer was dried over MgSO4, filtered and solvent removed under reduced pressure to give a crude white powder (4 gm) containing the desired mono brominated product and a bis brominated product in a 70:30 ratio. Purification of 1 gm of crude residue by rp-HPLC yielded the desired product as a white powder(470 mg). 1 H NMR (400MHz, D6-DMSO) delta 7.61 (s, 1 H) 7.51 (dd, 1 H) 7.1 (d, J = 8.6Hz, 1 H), 3.1 (t, 2H), 2.7 (t, 2H).
With octadecyltriethoxysilane-treated high-silica Hbeta-20 zeolite; In water; at 130℃; for 24h;
General procedure: The heterogeneous catalysts, stored under ambient conditions,were used for catalytic reactions without any pretreatment. Typically,ester (1 mmol), 1 mL H2O and 10 mg of catalysts and a magneticstarter bar were added to a reaction vessel (Pyrex pressuretube, 13 mL), and the mixture was heated at 130 C under air withstirring at 300 rpm. For the catalytic tests in Table 1 and kineticstudy, conversions and yields were determined by GC-FID usingn-dodecane as an internal standard as follows. After completionof the reaction, acetone (7 mL) was added to the mixture, andthe catalyst was separated by centrifugation. Then, n-dodecane(0.2 mmol) was added to the reaction mixture, and the mixturewas analyzed by GC-FID and GC-MS. The GC-FID sensitivities ofthe products were determined using commercial carboxylic acidsor the isolated products after the reaction. For some of the productsin Tables 2 and 3, we determined isolated yields of the carboxylicacids as follows. After the filtration of the catalyst, followed bywashing the catalyst with acetone (6 mL), and by evaporation,the product was isolated by column chromatography using silicagel 60 (spherical, 63-210 mum, Kanto Chemical Co. Ltd.) with hexane/ethyl acetate (60/40-80/20) as the eluting solvent, followedby analyses by 1H NMR, 13C NMR and GC-MS equipped with thesame column as GC-FID.
With nitric acid; acetic anhydride; acetic acid at 20℃; for 1h;
73%
With nitric acid; acetic anhydride; acetic acid at 18 - 20℃; for 1h;
7.1.1. 6-Nitro-3,4-dihydrocoumarin 14
To a stirred solution of 3,4-dihydrocoumarin 13 (18.00 g,121.5 mmol) in acetic anhydride (90 mL) was added, dropwise, amixture of concentrated nitric acid (15 mL) and glacial acetic acid(30 mL) keeping the temperature between 18 and 20 C. Themixture was stirred (1 h) and then poured into a mixture of iceand water (500 mL). The resulting precipitate was collected,washed well with water and dried in a desiccator under vacuum.The crude product was recrystallized from ethanol (100 mL) givingcompound 14 (17.00 g, 73%) as yellow crystals, mp 128-130 C, lit.mp 130 C.15 LRMS (ES) for C9H7NO4. Calculated mass of molecularion: 216.16 [M+Na]+. Measured mass: 216.15; IR mmax cm1 1778,1514, 1327, 1246, 1089; 1H NMR (400 MHz; d6-DMSO) dH 8.28(1H, d, J = 2.8 Hz, Ar-H), 8.15 (1H, dd, J = 8.7 and 2.8 Hz, Ar-H),7.30 (1H, d, J = 8.7 Hz, Ar-H), 3.15 (2H, t, J = 7.3 Hz, CH2), 2.88(2H, t, J = 7.3 Hz, CH2); 13C NMR (101 MHz; d6-DMSO) dC 167.7(CO), 156.9 (Ar-C), 143.9 (Ar-C), 125.7 (Ar-C), 124.6 (Ar-C),124.3 (Ar-C), 118.0 (Ar-C), 28.2 (CH2), 23.0 (CH2).
With nitric acid
With sulfuric acid; nitric acid In acetic acid for 1.5h; Ambient temperature;
With nitric acid; acetic anhydride In acetic acid at 10 - 20℃; for 1.75h;
3.1.1. Methyl 3-(2-hydroxy-5-nitrophenyl)propanoate (5)
Fuming nitric acid (12.1 mL, 189 mmol) in acetic acid (38.6 mL)was added dropwise during 45 min to chroman-2-one (4)(17.1 mL, 135 mmol) in acetic anhydride (102 mL), keeping thetemperature at 10-20 C. The reaction was stirred for 1 h at roomtemperature and then poured into ice water to give 6-nitrochroman-2-one as a light yellow solid (17 g, 88 mmol, 65%) that wasused without further purification in the next step. 1H NMR(300 MHz, CDCl3): d = 8.13-8.22 (m, 2H), 7.18 (d, J = 8.8 Hz, 1H),3.08-3.19 (m, 2H), 2.83-2.92 (m, 2H). Crude 6-nitrochroman-2-one (17 g, 88 mmol) was dissolved in MeOH (150 mL) and refluxedfor 2 h. The reaction was cooled and poured into water (800 mL). Ayellow precipitation was filtered off and dried in a vacuum oven at60 C for 24 h to give 5 (13.6 g, 60.4 mmol, 68%) as a light yellowpowder.
With diisobutylaluminium hydride In toluene at 20℃; for 0.333333h;
95%
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Inert atmosphere; Reflux;
93%
With methanol; Na/SiO<SUB>2</SUB> In tetrahydrofuran at 0 - 25℃; Inert atmosphere;
92%
With sodium bis(2-methoxyethoxy)aluminium dihydride In toluene for 0.166667h; Heating;
92%
With samarium diiodide; water; triethylamine In tetrahydrofuran at 20℃; for 2h; Inert atmosphere;
92%
With samarium diiodide; water; triethylamine In tetrahydrofuran at 20℃; for 2h; Inert atmosphere;
91%
With lithium aluminium tetrahydride In tetrahydrofuran
91%
With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 0.5h;
90%
With samarium diiodide; water In tetrahydrofuran at 20℃; for 3h;
90%
With isopropyl alcohol In hexane at 20℃; for 0.5h; Inert atmosphere;
87%
With lithium aluminium tetrahydride In diethyl ether at 20℃;
85%
With lithium aluminium tetrahydride
74%
With sodium tetrahydroborate; C36H30F6N10Ni4O10(2+)*2C2F3O2(1-); zinc(II) chloride In tetrahydrofuran at 45℃; for 12h;
66%
With sodium tetrahydroborate In tetrahydrofuran for 2h; Inert atmosphere; Reflux;
31%
With sodium (tert-butylamino)trihydroborate In tetrahydrofuran at 66℃; for 64h;
With lithium aluminium tetrahydride; diethyl ether
With lithium aluminium tetrahydride In diethyl ether Heating;
With lithium aluminium tetrahydride In diethyl ether
With diisobutylaluminium hydride In toluene at 49.9℃;
With lithium aluminium tetrahydride In diethyl ether for 5h; Heating;
99 %Spectr.
With samarium diiodide; water In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere;
With sodium tetrahydroborate In tetrahydrofuran for 2h; Reflux;
1.1
59.2 g of dihydrocoumarin (3,4-dihydro-l-benzpyran-2-one; 0.4 mol) and 22.7 g sodium borohydride (0.6 mol) are refluxed in 350 ml THF for 2 h. After the reaction mixture is cooled to room temperature, 30 ml of saturated aqueous ammonium chloride is added over 10 min. After 4 h the reaction mixture filtered and evaporated at 90 C under high vacuum to yield 51 g of a viscous oil. Proton NMR of this liquid corresponds to 2-(3- hydroxypropyl)-phenol of >98% purity. 1HNMR (CDC13) 6.9 (2H, dd, J=7.8), 7.03 (2H, dd, J=7.8), 3.63 (2H, t, J=6.0), 2.77 (2H,t, J=6.0), 1.89 (2H, p, J=6.0 Hz).
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 5℃; for 1h; Inert atmosphere;
8.40.1 Step-1: Preparation of 2-(3-hydroxypropyl)phenol (73-2):
To a solution of 3,4- dihydro-2H-l-benzopyran-2-one 73-1 (10.0 g, 67.56 mmol) in tetrahydrofuran (25 V) was added LAB (3.84 g, 101 .3 mmol) at 0-5 °C. The reaction mixture was allowed to stir at 0-5 °C over a period of 1 h. The resulting reaction mass was quenched with ammonium chloride solution (400 rnL), extracted with ethyl acetate (2 X 750 mL), organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain compound 73-3 as a colorless liquid 9.2 g (83 %) . The crude compound was taken forward to next step without any purification.
With hydrogenchloride In chloroform at 20℃; for 12h;
88%
With oxygen; benzaldehyde In 1,2-dichloro-ethane at 20℃; for 6.5h;
86%
With 1,2-diphenyl-1,1,2,2-tetrahydroperoxyethane; potassium hydrogencarbonate In acetonitrile at 40℃; for 9h;
Bayer-Villiger reaction (Scheme 2, entry 7) General procedure
General procedure: To a mixture of ketone (1 mmol) in CH3CN (4 mL), THPDPE (1 mmol) and KHCO3 (1 mmol) were added and the solution was stirred at room temperature. After the completion of the reaction, as monitored by TLC, Na2SO3 (3 M, 1mL) and saturated NaCl (5 mL) were added to the mixture and the corresponding products were extracted with CHCl3 (3 × 5 mL). All of the products were characterized on the basis of their melting points, IR, 1H NMR, and 13C NMR spectral analysis and compared with those reported
78%
With trifluorormethanesulfonic acid; 3-chloro-benzenecarboperoxoic acid In dichloromethane for 6h; Ambient temperature;
74%
With trifluoroacetic acid for 15h; Ambient temperature;
73%
With 3-chloro-benzenecarboperoxoic acid; 1-butyl-3-methylimidazolium Tetrafluoroborate at 27℃; for 4.5h;
72%
With 3-chloro-benzenecarboperoxoic acid In 1,2-dichloro-ethane at 40℃; for 31h;
72%
With 3-chloro-benzenecarboperoxoic acid In 1,2-dichloro-ethane at 40℃; for 31h; with/without catalyst;
70%
With Oxone at 40℃; for 20h; Ionic liquid;
65%
With bismuth(lll) trifluoromethanesulfonate In dichloromethane at 20℃; for 22h;
50%
With air; 4-aminoperbenzoic acid In dichloromethane at 20℃; for 14h;
8.a
To a stirred solution of dihydrocoumarin (10 mL, 78.9 mmol) and a catalytic amount of conc. H2SO4 in dry methanol (300 mL) was added and the reaction mixture was then heated at 55° C. for 8 hours. Methanol was evaporated to dryness to give crude product which was subjected to neutralize with K2CO3. The residue was diluted with water and extracted with dichloromethane. Purification of the crude product by column chromatography (20% CH2Cl2:3% EtOAc:77% Hexane as eluent) gave the desired ester as colorless oil (12.80 g, 90%). 1H NMR (400 MHz, CDCl3): 2.71 (3H, t, J=6.4 Hz), 2.89 (2H, t, J=6.4 Hz), 3.67 (3H, s), 6.83-6.87 (2H, m), 7.06-7.12 (2H, m),
Stage #1: ethanol; C6H4(CH2CH2C(O)O) With sulfuric acid at 0℃; for 12h; Inert atmosphere;
Stage #2: With sodium hydrogencarbonate
4
Example 4: Synthesis of 17a and 17b; single diastereomers for monophosphate prodrug synthesis. h- : 1 of Bp)16b (Bp) 16a (Sp)Ethyl 3-(2-hydroxyphenyl)propanoate, 14To a solution of dihydrocoumarin 13 (13 g, 87.74 mmol) in 500 mL of anhydrous ethanol was added catalytic cone. H2SO4 (0.10 mL) at 0 °C under N2 atmosphere. The cooling bath was removed and the reaction was stirred for 12h toward room temperature. The solution was treated with solid NaHC03 at 0 °C to pH = 6.0-6.5 and the resulting suspension was filtered. The filtrate was concentrated under reduced pressure and purified on a silica gel column to give compound 14 (16.2 g, 83.4 mmol) in 95% yield as yellow oil. 1H NMR (400 MHz, CDC13) δ 7.35 (s, 1H), 7.13-7.07 (m, 2H), 6.89-6.84 (m, 2H), 4.14 (q, J = 6.8 Hz, 2H), 2.90 (m, 2H), 2.72 (m, 2H), 1.23 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDC13) δ 175.89, 154.50, 130.74, 128.15, 127.52, 120.93, 117.33, 61.51, 35.39, 24.84, 14.25; MS-ESI+ m/z 195 (M+H+)
Stage #1: C6H4(CH2CH2C(O)O); isopropyl alcohol With sulfuric acid at 20℃; Inert atmosphere; Large scale;
Stage #2: With sodium hydrogencarbonate Large scale;
Isopropyl 3-(2-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(perfluorophenoxy)phosphoryl)oxy)phenyl)propanoate (4)
A dry, N2 flushed, 100 L reactor was charged with dihydrocoumarin (3 kg,20.2 mol) isopropyl alcohol (30.0 L) and H2SO4 (0.09 kg, 0.92 mol). Themixture was stirred at room temperature for 12 hours and then the pH ofthe mixture was adjusted to 6.5~7.0 by addition of NaHCO3 (6.21 kg,73.9 mol). The resulting mixture was filtered through a pad of celite andthe solvent was removed under reduced pressure. To the residue was addeddichloromethane (6 L) and the mixture was dried over anhydrous Na2SO4(3 kg). The mixture was filtered through a pad of silica gel, washed withdichloromethane (18 L) and evaporated under reduced pressure to afford3.8 kg (90.4%) of crude isopropyl ester which was used directly in the nextstep. 1H-NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.09-7.15 (m, 2 H), 6.85-6.90 (m, 2 H), 5.03 (m, 1 H), 2.92 (t, J = 6.8 Hz, 2 H), 2.72 (t, J = 6.8 Hz,2H), 1.23 (d, J = 6.0 Hz, 6 H); LRMS Calcd for C12H17O3 (M + 1)+ 209.12,found 209.20.
73.2 g
With sulfuric acid at 20℃; for 2h;
1 Example 1: Isopropyl 3-(2-hydroxyphenyl)propanoate
Sulfuric acid (0.26 mL) was added to a solution of 3,4-dihydrocoumarin (50.0 g) in isopropyl alcohol (500 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under a reduced pressure, and the resultant residue was diluted with ethyl acetate. The solution was washed with a saturated aqueous sodium bicarbonate solution, water and saturated saline, was then dried over sodium sulfate, and was then concentrated under a reduced pressure. In this manner, the title compound (73.2 g) having the physical property values shown below was produced. 1H-NMR (CDCl3): δ 1.20, 2.66-2.70, 2.87-2.91, 4.95-5.08, 6.86-6.91, 7.06-7.15, 7.35.
With (CH3)5C5*Ir(-OCH2C(C6H5)2NH-) In acetone at 20℃; for 5h;
94%
With [RuCl2(PPh3)2(2-PyCH21,3,5-triaza-7-phosphadamantane)].Br; potassium hydroxide In water for 48h; Schlenk technique; Reflux; Inert atmosphere; Green chemistry;
General Procedure for Lactonization of Diols in Presence ofHydrogen Acceptor
General procedure: An aqueous solution containing 1,4-butanediol (0.5 mmol),cyclohexene (5 mmol, 0.506 mL, 10 equiv), KOH (25 mol%,0.007 g, 0.125 mmol), and 1 or 2 (10 mol%, 0.0506 g or 0.051 g,0.05 mmol) was heated to 100 °C for 48 h in a sealed vessel. Oncompletion of the reaction, the products were extracted withDCM and injected into gas chromatography. γ-Butyrolactonewith 73% and 84% yields was observed with the formation ofcyclohexane with 22% and 24% yields.
Stage #1: C6H4(CH2CH2C(O)O) With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.533333h; Inert atmosphere;
Stage #2: chloro-trimethyl-silane In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; Enzymatic reaction;
With n-butyllithium; diisopropylamine 1.) THF, -78 deg C, 10 min, 2.) 3 h, warm. to RT; Yield given. Multistep reaction;
Stage #1: C6H4(CH2CH2C(O)O) With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃;
Stage #2: chloro-trimethyl-silane In tetrahydrofuran; hexane at 20℃;
With sodium hydroxide In water at 20 - 25℃; for 1h;
6.6.6.a
Dihydrocoumarin (100 g, 0.67 mol) was dissolved in 30% sodium hydroxide solution (180 mL) and was cooled to 20-25 0C. Benzoyl chloride (95 g, 0.67 mol) was added to it slowly over the period of 40 minutes. Reaction mixture was stirred at ambient temperature for 20 minutes. TLC showed that no starting was left. The reaction mixture was cooled to 10- 12 0C and acidified with concentrated hydrochloric acid (57 mL). White solid precipitated out and it was filtered through sintered funnel. The residue was washed with water (2 x 500 mL) and dried under reduced pressure at 80 0C. The crude material was crystallized by toluene to afford 14Og (76%).
With diisobutylaluminium hydride In hexane; toluene at -78℃; for 1h;
95%
With diisobutylaluminium hydride In toluene at -78℃; Inert atmosphere;
95%
With diisobutylaluminium hydride In hexane; toluene at -78℃; for 2.5h;
2.2 4.2.2 (±)-Chroman-2-ol (±)-3a18
To a three-neck round-bottom flask equipped with nitrogen bubbler and dropping funnel were added dihydrocoumarin (5 g, 33.7 mmol) and dry toluene (100 mL). The solution was cooled to -78 °C and DIBAL [1 M solution in hexanes, (37 mL, 37.0 mmol, 1.1 equiv)] was added dropwise over a period of 30 min. The reaction was stirred for 2 h, allowed to warm to room temperature and then quenched with H2O (30 mL). The resulting white suspension was filtered over Celite and washed through with diethyl ether (100 mL). The phases were separated and the aqueous phase was extracted with diethyl ether (200 mL). The combined organic phases were washed with H2O (200 mL) and brine (200 mL). The combined organic layers were dried, filtered and the solvent was removed under vacuum to give the product (4.83 g, 95%) as a colourless oil which was used without further purification. νmax/cm-1 (ATR): 3401 (OH), 3040 (C-H, Ar), 2939 (C-H), 1220 (C-O). 1H NMR (300 MHz, CDCl3): δ 7.14-7.04 (m, 2H, ArH), 6.92-6.80 (m, 2H, ArH), 5.62 (dd, J = 4 Hz, J = 2.6 Hz, 1H, OCHOH), 3.05-2.99 (m, 2H, CH2 and OH), 2.76-2.66 (m, 1H, CH2), 2.11-1.93 (m, 2H, CH2); 13C NMR (75.5 MHz, CDCl3): δ 152.1, 129.4, 127.6, 122.2, 121.0, 117.0 (6 * ArC), 92.3 (OCHOH), 27.2, 20.4 (2 * CH2). HRMS (ES-): found 149.0608. C9H9O2 requires 149.0603.
90%
With lithium tri(t-butoxy)aluminum hydride In tetrahydrofuran at 0℃; for 1.5h;
87%
Stage #1: C6H4(CH2CH2C(O)O) With polymethylhydrosiloxane In toluene at 20℃;
Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran; water for 2h; Heating;
84%
With diisobutylaluminium hydride In toluene at -78℃; for 2h;
79%
With diisobutylaluminium hydride In tetrahydrofuran; hexane at -78℃; for 4.33333h; Inert atmosphere;
65%
With diisobutylaluminium hydride In toluene for 3h;
With Iodine monochloride; In dichloromethane; for 20.0h;Inert atmosphere;
The synthesis was performed in analogy to Ref. [41]. In aflame dried and argon flushed 250 cm3 two-neck roundbottomflask equipped with dropping funnel and argon-inlet5.00 g dihydrocoumarin (15, 33.8 mmol) was dissolved in35 cm3 DCM. ICl (5.48 g, 33.8 mmol) dissolved in 35 cm3DCM was added through the dropping funnel within15 min. After full conversion (20 h), the reaction mixturewas diluted with 100 cm3 DCM and washed with 0.1 MNa2S2O3-solution (2 9 50 cm3). The combined aqueouslayers were re-extracted with DCM (2 9 50 cm3). Thecombined organic layers were washed with saturated NaClsolution (1 9 200 cm3), dried over MgSO4, filtered, andthe solvent was removed in vacuo. Recrystallization fromDCM/cyclohexane (1/4) afforded 8.28 g (90 %) 16 ascolorless powder. M.p. 134-136 C (Ref. [37];133-134 C); NMR data were found to agree with thosedescribed in Ref. [41].
2-(3-Hydroxy-3-methylbutyl)phenol (7)
To a solution of dihydrocoumarin (5.0 g, 33.75 mmol) in anhydrous THF (50 mL) at 0 °C was added dropwise methylmagnesium chloride (101.1 mmol, 33.7 mL, 3.0 M in THF). The reaction mixture was slowly warmed to room temperature and stirred overnight. On completion, the reaction mixture was treated with ice chips containing 25 mL of 1N H2SO4. Extraction of the aqueous phase with Et2O, drying the latter over Na2SO4 and concentration under reduced pressure yielded the diol as a white solid (6.07 g, 100%): mp 110-112 °C; TLC Rf 0.37 (EtOAc : Hex, 1:1); 1H NMR (600 MHz, (CD3)2CO) δ 8.22 (broad s, 1H), 7.06-7.07 (m, 1H), 6.97 (m, 1H), 6.77-6.79 (m, 1H), 6.72 (m, 1H), 3.54 (s, 1H), 2.67-2.70 (m, 2H), 1.71-1.73 (m, 2H), 1.22 (s, 6H); 13C NMR (400 MHz, (CD3)2CO) δ 155.2, 129.9, 129.6, 126.8, 119.6, 115.2, 69.7, 44.1, 29.2, 25.1. Anal. (%) calcd for C11H16O2 C 73.30, H 8.95; found C 73.28, H 8.97.
94%
Stage #1: methylmagnesium chloride; C6H4(CH2CH2C(O)O) In tetrahydrofuran at 0 - 20℃; for 16h;
Stage #2: With water In tetrahydrofuran at 20℃;
Synthesis of 2-(3-Hydroxy-3-methylbutyl)phenol (1)
To a solution of chroman-2-one (300 g, 2.027 mol) in dry THF (500 mL) at 0 °C was added methylmagnesium chloride (2.0 M, 2.3 L solution in THF, and 4.662 mol) drop-wise. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for overnight. The reaction was quenched with water (2 L) and extracted with diethyl ether (2 x 2L). The combined organic layers were dried over Na2SCL, concentrated under reduced pressure to afford 2-(3-hydroxy-3- methylbutyljphenol (1) (290 g, 94%) as a pale yellow solid.
6.25 g
In tetrahydrofuran Ambient temperature;
In tetrahydrofuran; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water
15.A 2,2-Dimethylchroman-8-carboxylic acid
A. Preparation of 2-(3-methyl-3-hydroxybutyl)phenol. To a solution of 200 ml of 3M methyl magnesium chloride in tetrahydrofuran (THF) and 150 ml of THF was added a solution 44.4 g of dihydrocoumarin in THF over a 40 minute period. An additional 150 ml of THF were added and, after cooling the resulting exotherm, the mixture was stirred at room temperature overnight. The solution was cooled and treated with 50 ml of a saturated ammonium chloride solution and 100 ml of water. After stirring one hour, the mixture was added to ice water and extracted with diethyl ether. The organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo to provide 57.5 g of the desired subtitle intermediate, m.p. 113°-115° C.
Stage #1: methylmagnesium chloride; C6H4(CH2CH2C(O)O) In tetrahydrofuran for 18.6667h;
Stage #2: With water In tetrahydrofuran Cooling;
5.A
[0270] Step A: To a solution of methyl magnesium chloride (3M in tetrahydrofuran, 60 mL, 180 mmol) was added a solution of coumarin (11.4 mL, 90 mmol) in tetrahydrofuran (20 mL) drop wise over forty minutes. The reaction was stirred for 18 h. The solution was quenched with ice cold water (20 mL) and extracted with ethyl acetate (2 x 25 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo to obtain the expected compound (13) as a white powder.
2-[2,2-Dimethyl-prop-(E)-ylidene]-chroman[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
Stage #1: neopentyl iodide With titanocene(II) triethylphosphite complex In tetrahydrofuran at -20 - 25℃; for 0.25h;
Stage #2: C6H4(CH2CH2C(O)O) In tetrahydrofuran for 2h; Heating; Further stages.;
Stage #1: 3-(iodomethyl)pentane With titanocene(II) triethylphosphite complex In tetrahydrofuran at -20 - 25℃; for 0.25h;
Stage #2: C6H4(CH2CH2C(O)O) In tetrahydrofuran for 2h; Heating; Further stages.;
26A
A solution of chroman-2-one (444 mg) in THF (1 mL) was treated with dimethylamine (7.5 mL) and stirred at room temperature for 5 hours. The solution was concentrated. The concentrate was filtered through a small pad of silica gel.
Stage #1: C6H4(CH2CH2C(O)O) With potassium hydroxide for 2h; Heating;
Stage #2: allyl bromide In N,N-dimethyl-formamide at 20℃; for 2h;
84%
Stage #1: C6H4(CH2CH2C(O)O) With potassium hydroxide for 2h; Heating;
Stage #2: allyl bromide In N,N-dimethyl-formamide at 20℃; for 20h; Further stages.;
9.1
Step 1 : Preparation of intermediate 3,4-dihydro-2/-/-1 -benzopyran (9a)A suspension of chromanone (1 g, 6.75 mmol) and zinc powder (3.07 g, 47 mmol) in acetic acid (15 mL) was warmed at 100°C for 15 hours. Residue of zinc was then removed by filtration on celite. The filtrate was concentrated under vacuum by co- evaporation with toluene to give the desired product (9a) without further purification (810 mg, 6.03 mmol, 89%).1H NMR (300 MHz, CDCI3) 1 .96-2.07 (m, 2H), 2.80 (t, J = 6.5 Hz, 2H), 4.16-4.22 (m, 2H), 6.78-6.86 (m, 2H), 7.03-7.20 (m, 2H).
Multi-step reaction with 3 steps
1: LiAlH4 / diethyl ether / 5 h / Heating
2: pyridine / 0 °C
3: aq. NaOH / propan-2-ol / 5 h / 70 - 80 °C
Multi-step reaction with 3 steps
1: 99 percent / i-Bu2AlH / toluene / 0.33 h / 20 °C
2: CH2Cl2 / 0.58 h
3: Et3N / CH2Cl2 / 19 h / Heating
Multi-step reaction with 2 steps
1: diisobutylaluminium hydride / toluene / 49.9 °C
2: ZnCl2 / 298 - 463 °C
Multi-step reaction with 2 steps
1: LiAlH4; diethyl ether
2: phosphoric acid / 150 °C
2
Ring opening [Bussolari et al., Tetrahedron Letters 40 (1999) 1241-1244] of dihydrocoumarin (9) with N-ethylbenzylamine (10) in THF at room temperature led to carboxamide 11. Heating 11 with borane-methyl sulfide complex in THF generated tertiary amine 4, which was transformed into its water soluble mesylate salt. Free amine 11 was debenzylated under mild catalytic conditions (Pd-C, dilute HCl, EtOH), yielding amine 2 as its HCl salt (Scheme 2, FIG. 2).
In tetrahydrofuran at 20℃;
2; 2.2
Ring opening [Bussolari et al., Tetrahedron Letters 40 (1999) 1241-1244] of dihydrocoumarin (9) with N-ethylbenzylamine (10) in THF at room temperature led to carboxamide 11. Heating 1 1 with borane-methyl sulfide complex in THF generated tertiary amine 4, which was transformed into its water soluble mesylate salt. Free amine 11 was debenzylated under mild catalytic conditions (Pd-C, dilute HCl, EtOH), yielding amine 2 as its HCl salt (Scheme 2, Fig. 2).
5 Preparation of Chroman-2-ol (Compound 5A)
Preparation of Chroman-2-ol (Compound 5A) Dihydrocoumarin (5 g, 33.74 mmol) was dissolved in 50 mL of toluene and cooled to -78° C. Dibal (1 M solution in toluene, 38 mL, 38 mmol) was added to the reaction flask over a 45 minutes period. The reaction mixture was stirred at this temperature for 2 h. Water (50 mL) was added slowly along with some toluene to ensure a smooth stirring of the reaction mixture. The slurry was warmed to room temperature and stirring was continued overnight. The organic layer was decanted and dried with magnesium sulfate. Solvent was removed via rotatory evaporator to give compound 5A as a clear oil (4.5 g, 89%). MS: 149 (M-1)+
a. 3,4-Dihydro-7-hydroxy-4-(1-naphthyl)coumarin Condensation of resorcinol with 3-(1-naphthyl)acrylic acid in the presence of hydrochloric acid/hydrogen chloride (method of J. D. Simpson and H. Stephen, J. Chem. Soc. (London) 1936, 1382) gave the desired dihydrocoumarin, m.p. 203.5-206.5, in 64% yield.
EXAMPLE 15 3,4-Dihydro-7-hydroxy-4-(1-naphthyl)coumarin A mixture of 3-(1-naphthyl)acrylic acid (50.0g., 0.25 moles) in concentrated hydrochloric acid (1500 ml.) was stirred at reflux while a vigorous stream of hydrogen chloride was passed through the reaction for 6 hours. The solution was allowed to stand overnight at room temperature, then filtered to give a white solid which was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution (3*). The ethyl acetate solution was dried and removal of solvent gave the dihydrocoumarin as a white solid (43.5g., 85% based on consumed starting material) m.p. 193-196 C.
1 EXAMPLE 1
EXAMPLE 1 In a four-necked flask were charged 300 g of methyl 3-(2-oxcyclohexyl)propionate and 2.1 g of 5% palladium-on-activated carbon egg shell catalyst in which 5% of palladium based on the carrier amount was supported on the carrier ('Water-containing 5% Pd-on-carbon Powder E-Type' produced by N.E. Chemcat Co.). The mixture was heated in a nitrogen atmosphere at 250°C for 10 hours with stirring at 240 rpm. The temperature was elevated up to 270°C over a period of 1 hour, and the reaction was continued at that temperature for 15 hours with stirring at 500 rpm. After completion of the reaction, the catalyst was removed by filtration. Gas chromatography analysis of the filtrate revealed that the conversion of methyl 3-(2-oxocyclohexyl)propionate was 100% and the yields of coumarin and 3,4-dihydrocoumarin were 38.4% by mol and 35.2% by mol, respectively, based on the amount of the starting methyl 3(2-oxocyclohexyl)propionate.
With hydrogenchloride; triethylamine In tetrahydrofuran
EXAMPLE 1 2-Chloromethyl-2-hydroxychroman
EXAMPLE 1 2-Chloromethyl-2-hydroxychroman Under a nitrogen gas atmosphere, dihydrocoumarin (15g, 101.2 mmol, manufactured by Wako Pure Chemical Industries, Ltd.), sodium chloroacetate (17.6 g, 151.8 mmol, manufactured by Nacalai Tesque Inc.), and triethylamine (10.2 g, 101.2 mmol) were dissolved in tetrahydrofuran (300 mL) and the resulting solution was cooled to an outside temperature of 0°C. t-Butylmagnesium chloride (1.6 M THF-toluene (2.5:1) solution, 190 mL, 303.7 mmol) was added to the resulting solution over about 1.5 hours at an inside temperature of 2 to 6°C. Subsequently, the mixture was stirred for two hours while maintaining the outside temperature at 0°C. The resulting reaction mixture was added to 2.5 M hydrochloric acid (400 mL), and stirred for two hours at room temperature. The resulting reaction mixture was extracted with ethyl acetate (100 mL * three times). The extract was washed with saturated sodium bicarbonate aqueous solution (80 mL, once) and then with a saturated sodium chloride aqueous solution (80 mL, once), dried over anhydrous sodium sulfate, and filtered. The filtrate was condensed to obtain an yellow oil (18.2 g). The crude product was purified by column chromatography (silica gel, ethyl acetate:hexane = 1:7) to obtain an yellow oil of 2-chloromethyl-2-hydroxychroman (16.2 g, 80%).1H-NMR (400 MHz) δ 2.00-2.08 (2H, m), 2.22-2.28 (2H, m), 2.85-2.91 (1H, m), 3.14-3.26 (1H, m), 3.35 (1H, d, J = 1.96 Hz), 3.87 (2H, dd, J = 11.5, 33.5 Hz), 6.97-7.12 (2H, m), 7.2-7.3 (2H, m). 13C-NMR (100 MHz) δ 21.1, 28.2, 51.3, 94.9, 117.0, 121.2, 121.5, 127.5, 129.1, 161.8
Stage #1: (R)-methyl p-tolyl sulfoxide With lithium diisopropyl amide In tetrahydrofuran; hexane at -40℃; for 1h; Inert atmosphere;
Stage #2: C6H4(CH2CH2C(O)O) In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere;
Stage #1: (4S)-3-(3-phenylpropionyl)-4-(2-propyl)oxazolidin-2-one With lithium chloride; lithium diisopropyl amide In tetrahydrofuran; toluene at -78 - 0℃; for 0.416667h; Inert atmosphere;
Stage #2: C6H4(CH2CH2C(O)O) With lithium diisopropyl amide In tetrahydrofuran; toluene at -78℃; for 0.416667h; Inert atmosphere;
Stage #3: With copper(II) 2-ethylhexanoate In tetrahydrofuran; toluene at -78 - 20℃; for 0.416667h; Inert atmosphere; diastereoselective reaction;
Stage #1: methanol; C6H4(CH2CH2C(O)O) With sodium methylate In methanol at 20℃; for 0.166667h;
Stage #2: dimethyl sulfate With sodium methylate In methanol at 20 - 40℃; for 0.5h;
11 Reference Example 11
78 g of a 28% solution of sodium methoxide in methanol was added to 150 ML of a solution of 50 g of 3,4-dihydrocoumarin in methanol at room temperature, and then this mixture was stirred for 10 minutes at the same temperature.. Then, 96 ML of dimethyl sulfate and 78 g of a 28% solution of sodium methoxide in methanol were successively added to the mixture, which was stirred for another 30 minutes at 20 to 40°C. The reaction mixture was added to a mixture of methylene chloride and water, and adjusted to PH 2 with 6M hydrochloric acid, and then the organic phase was separated therefrom.. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure.. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:1] to yield 61 g of methyl 3-(2-methoxyphenyl) propanoate as colorless oil. NMR(90MHz,CDCl3) δ value: 2.50-2.69(2H,m), 2.86-3.04(2H,m), 3.66(3H,s), 3.82(3H,s), 6.79-6.94(2H,m), 7.11-7.30(2H,m)
With dibutyltin diacetate In tetrahydrofuran at 65℃; for 4h;
General procedure for ring-opening processes
General procedure: An oven-dried reaction flask (20 mL) was charged with amine(1, 4.38 mmol), lactone (2, 2.19 mmol, 1.0 equiv), dibutyltin acetate(20 mol%) and THF (5 mL). The resulting mixture was stirred at65 C for 4 h. The crude products were purified by flash columnchromatography on silica gel to give the desired product.
83%
Stage #1: With gallium; iodobenzene; aluminium at 120℃; for 20h; Inert atmosphere;
Stage #2: benzylamine In toluene at 20℃; for 0.166667h;
Stage #3: C6H4(CH2CH2C(O)O) In touene at 80℃; for 3h;
With diethylzinc In tetrahydrofuran; hexane at 20℃; for 3h; Inert atmosphere;
Typical procedure: To a dry THF solution (10 ml) of the carbonyl compound (1 mmol, 1 equiv) and ethyl dibromofluoroacetate 1 (2 mmol., 2 equiv) was added diethylzinc (1 M in hexane, 2 mmol, 2 equiv) under argon. The reaction mixture was stirred for 3 hours at room temperature. The resulting solution was then quenched with ethanol (15 ml), stirred for 15 min, and concentrated under reduced pressure. The residue was taken up in Et2O (5 ml), filtered over celite and purified by chromatography on silica gel (eluent/cyclohexane-EtOAc), affording the expected product.
With 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine In acetonitrile at 40℃; for 3h;
With dmap In dichloromethane at 70℃; for 8h;
4.2.43. 3-(2-Hydroxyphenyl)-N-phenylpropanamide (A38)
In a round bottom flask, 1 mmol of dihydrocoumarin was dissolved in DCM. To this, 1.1 mmol of aniline was added with .25 mmol of DMAP. The reaction was mixed overnight at room temperature. Following this, the reaction was heated for 8 h at 70 °C. Upon completion of the reaction, the DCM was washed with saturated bicarbonate solution (1×) and with 2 M HCl (1×). The DCM was dried over Na2SO4 and the solvent was removed under reduced pressure. The crude reaction material was carried on to preparative HPLC without further work-up and produced a white solid. 1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.37-7.26 (m, 3H), 7.16-7.07 (m, 3H), 6.95-6.81 (m, 2H), 3.03-2.96 (m, 2H), 2.85-2.77 (m, 2H). LCMS: tR = 10.79 min. m/z = 242.4 (M+H).
With iron(II) acetylacetonate; Selectfluor In acetonitrile at 20℃; for 24h; Inert atmosphere;
47 %Spectr.
With copper(l) iodide; N-hydroxyphthalimide; N,N'-bis(benzyliden)ethylendiamine; Selectfluor; potassium iodide; potassium tetrakis(pentafluorophenyl)borate In acetonitrile at 25℃; for 3h; Inert atmosphere;
With trifluoroacetic acid In toluene at 0 - 20℃; Inert atmosphere;
17.1
Under nitrogen atmosphere, chromanone (768 mg, 5.18 mmol) was added at 0 °C to a solution of trifluoroacetic acid (3.8 μΙ_, 0.05 mmol) and ethylglyoxylate (50% in toluene, 0.2 mL, 1 mmol). The mixture was stirred at 0 °C for 10 minutes then at room temperature overnight. The volatiles were evaporated and the crude material was purified by preparative TLC (cyclohexane/ethyl acetate 70/30) to afford ethyl 2- hydroxy-2-(4-oxo-3,4-dihydro-2H-1 -benzopyran-3-yl)acetate as a colorless oil (17a) (235 mg, 0.94 mmol, 93%, mixture of diastereoisomers).1 H NMR (400 MHz, CDCI3) J1 .24-1 .37 (m, 3H), 3.28-3.53 (m, 1 H), 4.29-4.36 (m, 3H), 4.48-4.98 (m, 3H), 7.01 (d, J = 8.3Hz, 1 H), 7.03-7.10 (m, 1 H), 7.50-7.54 (m, 1 H), 7.90-7.97 (m, 1 H).MS m/z ([M+H]+) 251 .
With 5% active carbon-supported ruthenium; hydrogen; In methanol; at 130℃; under 75007.5 Torr; for 3h;Autoclave;
The hydrogenation of coumarin was carried out in a 25-mL stainless steel autoclave under constant hydrogen pressure. A commercial catalyst TYPE 97 PASTE (surface area 1000 m2/g, moisture content 52.3%, uniform metal location, mean particle size 25 mum) from Johnson Matthey with the composition of 5wt% Ru on active carbon (Ru/C) was used for the hydrogenation. Into the autoclave were inserted 2.8 g of coumarin, 0.14 g of the catalyst in the powder form and 14 mL of solvent. The reaction was carried out at 130 C and from 2-10 MPa of hydrogen pressure.
Stage #1: C6H4(CH2CH2C(O)O) With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h;
Stage #2: N-methoxy-N-methylcyanoformamide In tetrahydrofuran at -78℃; for 0.25h;
Stage #1: C6H4(CH2CH2C(O)O) With lithium diisopropyl amide In tetrahydrofuran at -78 - 0℃; for 1.66667h; Inert atmosphere;
Stage #2: Allyl chloroformate In tetrahydrofuran at -78 - 20℃; for 18h; Inert atmosphere;
3-(2-hydroxyphenyl)-N-(pyridin-4-yl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With potassium <i>tert</i>-butylate In 1,4-dioxane for 2h; Reflux;
1 Synthesis of 3-(2-hydroxyphenyl) -N- (pyridin-4-yl) propanamide
In a 50 mL eggplant type flask,3,4-dihydrocoumarin10.5 g (0.071 mol),4-aminopyridine10.0 g (0.106 mol),1,4-dioxane10 mL was charged,And heated under reflux for 2 hours.After completion of the reaction,The reaction solution was concentrated, and the obtained concentrated solution was purified by silica gel column chromatography to obtain 9.4 g of solid 3- (2-hydroxyphenyl) -N- (pyridin-4-yl) propanamide. The yield was 55%.
Stage #1: C6H4(CH2CH2C(O)O) With lithium diisopropyl amide In tetrahydrofuran at -78℃; Inert atmosphere;
Stage #2: methyl halide With N,N,N,N,N,N-hexamethylphosphoric triamide In tetrahydrofuran at -78 - 0℃; Inert atmosphere;
1.2.1 General procedure for the preparation of 3-substituted tetrahydro-2H-pyran-2-ones 1a-1d,1f1
General procedure: To a solution of diisopropylamine (3.1 mL, 22 mmol) in THF (10 mL) was added BuLi (14 mL, 22.4 mmol, 1.6 M in THF) at -78 °C. After being stirred for 0.5 h, tetrahydro-2H-pyran-2-one (20 mmol in 15 mL THF) was added dropwise. After being stirred for 0.5 h, RX (X=Br or I) (20 mmol) and Hexamethylphosphoric triamide in THF (10 mL) were added to the reaction mixture dropwise. The solution was gradually warmed up to 0 °C. After reaction completion (monitored by TLC), the reaction mixture was quenched by NH4Cl (saturated aq., 10.0 mL) and extracted with ethyl ester (3 × 20 mL). The combined organic layer was washed with NaCl (saturated aq.) and dried (Na2SO4), then the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel) to afford 2-monosubstituted indolin-3-ones 1a-1d, 1f.
With ethyl [2]alcohol; sodium In hexane; mineral oil at 0℃; for 0.0833333h; Inert atmosphere;
15 Example 15
In the 10mL single-mouth bottle,Nitrogen protection,74.1 mg (0.50 mmol) of compound 2a are added,2.5mL hexane,105.9 mg (2.25 mmol) deuterated ethanol (EtOD),129.3 mg (2.25 mmol) of sodium reagent (40 wt%,Dispersions in mineral oils,Particle size 5-10μm),Stir for 5 min at 0°C.Rise to room temperatureThe reaction was quenched with 3.0 M aqueous hydrochloric acid.Add ether and saturated brine to extractThe organic phase is dry,Concentrate, column chromatography,59.4 mg of target compound 5a was obtained.Yield 77%.
77%
With ethyl [2]alcohol; sodium In hexane; mineral oil at 0 - 20℃; for 0.166667h; Inert atmosphere;
3-(2-hydroxyphenyl)-N-methoxy-N-methylpropanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13.3 g
With tris(methyl)aluminum In hexane; dichloromethane at 0℃; for 2.16667h;
With isopropylmagnesium chloride lithium chloride In tetrahydrofuran at -20℃; for 1h; Inert atmosphere;
2 The first step:
General procedure: Weigh compound 6 (13.51 mmol) in 30 mL of dry tetrahydrofuran,Add reagent N,O-dimethylhydroxylamine hydrochloride (27.02mmol), fill with nitrogen, stopper,Put it into a mixed liquid of dry ice and acetone, cool down to -20°C,Grignard reagent isopropylmagnesium chloride (27.02mmol) was added dropwise to react for 1 hour,TLC detected that the reaction of the raw materials was complete, and saturated ammonium chloride solution was added to quench the reaction.Ethyl acetate (15 ml) was extracted three times, and the organic phase was washed with saturated sodium chloride solution.The organic phase was concentrated and subjected to flash column chromatography to obtain the intermediate. Then, the intermediate (11.08 mmol) was weighed into 20 mL of dichloromethane solution, and imidazole (27.70 mmol) was added.After stirring and dissolving, triethyl chlorosilane (16.62 mmol) was added, and the reaction was carried out at room temperature for 1 hour.TLC monitoring the reaction of the reaction raw materials is complete, saturated ammonium chloride solution quenched the reaction,Extracted with ethyl acetate (10 ml) three times, washed once with saturated sodium chloride solution,The recovered organic phase was concentrated in vacuo, and compound 4 was obtained by flash column chromatography.
Stage #1: C6H4(CH2CH2C(O)O) With potassium hydroxide In N,N-dimethyl-formamide for 2h; Reflux;
Stage #2: 1,2-Epoxy-3-bromopropane In N,N-dimethyl-formamide at 30℃; for 2h;
1.1; 2.1 Step 1:
Add dihydrocoumarin (50mmol, 7.41g), potassium hydroxide (55mmol, 3.09g) and DMF (40mL) to a 100mL round bottom flask, and then heat to reflux for 2 h. Then add epibromohydrin (55mmol, 7.53g) to the round bottom flask, and stir the reaction at 30 °C for 2 h. After the reaction, pour saturated brine into the reaction solution, and then extract with ether. The organic phase was dried with anhydrous Na2SO4, spin-dried and passed through silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1). The intermediate was isolated and the yield was 94%.
With aluminum (III) chloride In dichloromethane at 45℃; for 1h;
4 Preparation of Intermediate 3
Add dichloromethane (100ml) and aluminum trichloride (50.8g, 0.381mol) to the reaction flask, add intermediate 2 (theoretical value 0.087mol) in dichloromethane (50ml) solution dropwise with stirring,After the addition, heat to 45°C and react for 1 hour. The reaction is complete, and the temperature is lowered. Pour into ice water (200ml) in batches.The layers were separated, the aqueous layer was extracted with dichloromethane, the organic layers were combined, and concentrated to obtain 7.7 g of pale yellow liquid with a yield of 60%.
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