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Structure of 1192-62-7 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 5, p. 3116 - 3124
5
[ 1192-62-7 ]
[ 3199-50-6 ]
Yield
Reaction Conditions
Operation in experiment
61%
With N-Bromosuccinimide In DMF (N,N-dimethyl-formamide)
To a solution of 2-acetylfuran (20 mmol) in DMF (20 mL) was added portionwise N-bromosuccinimide (22 mmol) with stirring. The reaction mixture was stirred overnight, then poured onto cold water. The product was extracted with ether (200 mL, 3* times). Yield 61percent, mp 92-93° C. (hexanes/ether, Lit. mp 94-95° C.; see Gilman H., et al., J. Am. Chem. Soc., 53, 4192-4196 (1931). 1H NMR (CDCl3); δ 2.45 (s, 3H), 6.49 (d, J=3.9 Hz, 1H), 7.12 (d, J=3.6 Hz, 1H). 13C NMR; δ 8185.4, 154.4, 128.2, 118.9,114.3, 25.7.
50.4%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 24 h;
To a solution of 1 (10 g, 90 mmol) in DMF 40 mL, NBS (19g, 108 mmol) was added by keeping the temperature at 0 °C. Thereaction mixture was stirred overnight at room temperature. Upon completion,the reaction mixture was poured into ice-cold water. The mixture was dilutedwith EtOAc, and the insoluble material was filtered off through Celite. Theorganic layer of the filtrate was washed with brine, dried anhydrous magnesiumsulfate, and concentrated. The residue was chromatographed (SiO2,EtOAc/n-hexane, 1/19, v/v) to afford compound 2 (8.7 g, 45.4mmol, 50.4percent). 1H NMR (500 MHz, CDCl3,δ, ppm): 2.46 (3H. s),6.49 (1H, d, J = 3.4 Hz), 7.12 (1H,d, J = 3.4 Hz). MS m/z 188 (M + H)+.
44.5%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 0.5 h;
Synthesis of 2-acetyl-5-bromofuran (29) 2-Acetylfuran (2.2 g, 20 mmol) was dissolved in DMF (20 mL), followed by addition of N-bromosuccinimide (3.91 g, 22 mmol). The mixture was reacted at room temperature for 30 min and then added into distilled water (50 mL), and the layers were separated with ethyl acetate (50 mL x 2). The ethyl acetate layer was dried with anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the residue was subjected to medium-pressure preparative chromatography using ethyl acetate/hexane (1/15) as an elution solvent to obtain Compound 29. Yield 1.68 g (yield rate 44.5percent).
44.5%
With N-Bromosuccinimide In hexane; water; ethyl acetate; N,N-dimethyl-formamide
Synthesis of 2-acetyl-5-bromofuran (29) 2-Acetylfuran (2.2 g, 20 mmol) was dissolved in DMF (20 mL), followed by addition of N-bromosuccinimide (3.91 g, 22 mmol). The mixture was reacted at room temperature for 30 min and then added into distilled water (50 mL), and the layers were separated with ethyl acetate (50 mL*2). The ethyl acetate layer was dried with anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the residue was subjected to medium-pressure preparative chromatography using ethyl acetate/hexane (1/15) as an elution solvent to obtain Compound 29. Yield 1.68 g (yield rate 44.5percent).
28%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃;
To a stirred solution of compound 4 (5.0 g, 45.45 mmol) and DMF (50 mL), NBS (8.8 g, 50 mmol) was added portion-wise at room temperature under stirring. The reaction mixture was allowed to stir at room temperature overnight. 50percent starting material remained by TLC and LCMS. Reaction mixture was poured into cold water and the compound was extracted with diethyl ether (150 mL X 3). Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure. Crude compound was purified by column chromatography using 5percent ethyl acetate in n-hexane as an eluent to afford compound 43 (2.4 g, 28percent) as a white solid.
Reference：
[1] Journal of Natural Products, 2017, vol. 80, # 9, p. 2561 - 2565
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 14, p. 3658 - 3664
[3] Patent: US2005/282853, 2005, A1, . Location in patent: Page/Page column 15; 19
[4] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 7, p. 1784 - 1788
[5] Organic Letters, 2017, vol. 19, # 21, p. 5976 - 5979
[6] Patent: EP2030635, 2009, A1, . Location in patent: Page/Page column 26; 50
[7] Patent: US2010/278733, 2010, A1,
[8] Patent: WO2013/130892, 2013, A1, . Location in patent: Paragraph 00287
[9] Patent: US2010/29745, 2010, A1, . Location in patent: Page/Page column 14
6
[ 1192-62-7 ]
[ 383-63-1 ]
[ 326-90-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; Stage #2: With hydrogenchloride In water; ethyl acetate
Into a 500 mL flask was weighed 20.0 g (181.6 mmol) of 2-acetylfuran, 50 mL of THF, and 24 mL of ethyl trifluoroacetate. The resulting solution was cooled to 0-3 °C in an ice bath and 1.0 M LiHMDS was added (200 mL). The reaction was allowed to warm to room temperature where it remained overnight. The reaction was then concentrated in vacuo to remove THF and the residue was washed into a separatory funnel with ethyl acetate and 1.0 M HCl. The ethyl acetate was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The resulting 4,4,4-trifluoro-1-furan-2-yl-butane-1,3-dione was recovered as a brown semisolid, yield: 32.5 g (100+percent).
82.6%
With sodium In ethanol at 20℃;
General procedure: Ethyl trifluoroacetate 9 (0.047 mol) and 2-acetyl furan (0.047 mol) were added dropwise to a solution of ethanol (55 mL) containing thinly sliced sodium (0.047 mol), and stirred over night at room temperature. Then,the solution was poured in ice-water containing concentrated sulfuric acid. The solution was extracted with dichloromethane, dried, concentrated and purified on a column of silica using a 10percent gradient of ethyl acetate in hexanes to afford 10 (82.6percenty). 10(0.020 mmol) was added drop wise into a solution of hydrazinobenzene(0.020 mmol), ethanol(50ml)and acetic acid(0.5 ml), then refluxed.The cooled mixture was concentrated under vacumm and the pyrazole11(66.7percenty) was obtained after purification by silicagel(a5percentgradient of ethyl acetate in hexanes). Pyrazole 11(0.043mol) was dissolved in acetone (120 ml) and KMnO4(0. 071mmol) was added. This mixture was heated at 60°C for 3 h and cooled to room temperature.Then isopropyl alcohol was added and stirred at room temperature overnight. The reaction mixture was filtered and concentrated. The residue was dissolved in 1N NaOH, washed and acidified with 2N HCl solution to obtain 12(46.3 percent y).The amide derivatives 13-14 were prepared through acyl chlorides derived from 12. A solution of 12 (0.004mol) in thionyl chloride(10mL) was refluxed for 5 hand then concentrated under vacuum. The crude acylchloride was added dropwise to a cooled solution(0°C) of substituted aniline(0.004mol) and TEA (0.008mol) in dichloromethane (10mL). The mixture was stirred over night at room temperature, and then purified on a column of silica using a gradient of e thyl acetate in hexanes to afford the pure products.
Reference：
[1] Patent: WO2008/73825, 2008, A1, . Location in patent: Page/Page column 134
[2] Chinese Chemical Letters, 2016, vol. 27, # 4, p. 566 - 570
[3] Synthesis, 1997, # 11, p. 1321 - 1324
[4] Journal of the American Chemical Society, 1950, vol. 72, p. 2948,2949
[5] Journal of Fluorine Chemistry, 2002, vol. 118, # 1-2, p. 135 - 147
[6] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 2, p. 343 - 346
[7] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 15, p. 5370 - 5383
[8] Journal of Fluorine Chemistry, 2006, vol. 127, # 6, p. 780 - 786
[9] Russian Journal of General Chemistry, 2007, vol. 77, # 10, p. 1732 - 1741
[10] Chemistry of Heterocyclic Compounds, 2008, vol. 44, # 5, p. 606 - 614[11] Khim. Geterotsikl. Soedin., 2008, # 5, p. 765 - 775,11
[12] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 6, p. 1581 - 1588
[13] Advanced Synthesis and Catalysis, 2015, vol. 357, # 14-15, p. 3076 - 3080
[14] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 545 - 551
[15] Chinese Chemical Letters, 2018, vol. 29, # 6, p. 911 - 914
7
[ 1192-62-7 ]
[ 326-90-9 ]
Yield
Reaction Conditions
Operation in experiment
39%
Stage #1: With potassium <i>tert</i>-butylate In benzene Stage #2: at 5 - 20℃; for 16.3333 h; Stage #3: With sulfuric acid In waterCooling with ice
[00141] Scheme 6: Synthesis of the diketone intermediate 4,4,4-trifluoro- 1 -(furan-2- vDbutane- 1 ,3-dione 19 6 1; [00142] The diketone 19 was synthesized from acetylfuran and trifluoracetate to obtain the 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione 19 product as follows. 2- Acetylfuran 18 (11.0 g, 210 mmol) was dissolved in benzene (210 mL). At room temperature was added KOtBu (23.6 g, 210 mol). The resulting red solution was cooled to 5° C. Ethyl trifluoracetate 6 (25 mL, 29.8 g, 210 mmol) was added dropwise in approximately 20 minutes keeping the temperature below 15 °C. Then the mixture was stirred for 16 hours at room temperature. The mixture was poured in ice- water (300 mL) containing concentrated sulfuric acid (5 g). The aqueous mixture was extracted with tBME (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4) and concentrated to give a dark brown oil (20.8 g). The crude product was purified by kugelrohr distillation to give compound 19 (17.0 g, 39percent) as a yellowish oil.
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1986, vol. 22, # 12, p. 2341 - 2345[2] Zhurnal Organicheskoi Khimii, 1986, vol. 22, # 12, p. 2610 - 2614
14
[ 1192-62-7 ]
[ 4637-24-5 ]
[ 17168-45-5 ]
Yield
Reaction Conditions
Operation in experiment
97%
at 100℃; for 9 h;
A mixture of 2-acetylfuran (25.0 g, 0.227 mmol) and N,N-dimethylformamide dimethylacetal (40 ml) was stirred at 100°C for 9 hours. After cooling as it was, the reaction mixture was concentrated. To the residue were added diethyl ether and hexane. The resulting solid was collected by filtration and washed with hexane, to give the title compound (36.5 g, 97percent) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ ppm; 2.88 (3H, br s), 3.14 (3H, br s), 5.65 (1H, d, J= 12.6 Hz), 6.60 (1H, dd, J=2.0, 3.4 Hz), 7.10 (1H, dd, J = 0.8, 3.4 Hz), 7.68 (1H, d, J = 12.6 Hz), 7.79 (1H, dd, J = 0.8, 2.0 Hz).
97%
at 100℃; for 9 h;
Reference Example 5 3-(Dimethylamino)-1-(2-furyl)-2-propen-1-one A mixture of 2-acetylfuran (25.0 g, 0.227 mmol) and N,N-dimethylformamide dimethylacetal (40 ml) was stirred at 100° C. for 9 hours. After cooling as it was, the reaction solution was concentrated. Diethyl ether and hexane were added to the residue, and the resulting solid was collected by filtration and washed with hexane, to give the title compound (36.5 g, 97percent) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm; 2.88 (3H, br s), 3.14 (3H, br s), 5.65 (1H, d, J=12.6 Hz), 6.60 (1H, dd, J=2.0, 3.4 Hz), 7.10 (1H, dd, J=0.8, 3.4 Hz), 7.68 (1H, d, J=12.6 Hz), 7.79 (1H, dd, J=0.8, 2.0 Hz).
Reference：
[1] Patent: EP1439175, 2004, A1, . Location in patent: Page 45-46
[2] Patent: US2004/6082, 2004, A1, . Location in patent: Page/Page column 22
[3] Journal of Heterocyclic Chemistry, 1996, vol. 33, # 6, p. 1707 - 1710
[4] Organic Process Research and Development, 2008, vol. 12, # 3, p. 490 - 495
[5] Journal of the Korean Chemical Society, 2011, vol. 55, # 2, p. 243 - 250
[6] Asian Journal of Chemistry, 2012, vol. 24, # 4, p. 1837 - 1843
[7] Journal of the Chinese Chemical Society, 2003, vol. 50, # 2, p. 283 - 296
[8] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 21, p. 6282 - 6285
[9] Synthetic Communications, 2012, vol. 42, # 10, p. 1521 - 1531
[10] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 6, p. 1581 - 1588
[11] Journal of Heterocyclic Chemistry, 2014, vol. 51, # SUPPL. 1, p. E384-E388
[12] Research on Chemical Intermediates, 2015, vol. 41, # 6, p. 3759 - 3765
[13] Chemical Biology and Drug Design, 2017, vol. 90, # 5, p. 936 - 942
[14] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 545 - 551
[15] Bioorganic Chemistry, 2019, vol. 83, p. 549 - 558
15
[ 1192-62-7 ]
[ 17168-45-5 ]
Yield
Reaction Conditions
Operation in experiment
168 g
at 110℃; for 3 h;
2-acetyl-furan (121 g, 1.1 mol) and N, N- dimethylformamide dimethyl acetal (155 g, 1.3 mol) was dissolved in 500 ml of anhydrous dimethyl formamide, in 110 was refluxed for 3 hours. After the spin-dry solvent, ether was added and the product was precipitated crystals were separated and dried to give 168 g of yellow crystals.
Reference：
[1] Patent: CN105237518, 2016, A, . Location in patent: Paragraph 0048
16
[ 1192-62-7 ]
[ 403-42-9 ]
[ 154258-82-9 ]
Reference：
[1] Journal of the Chemical Society - Dalton Transactions, 1997, # 21, p. 4025 - 4035
17
[ 1192-62-7 ]
[ 206564-00-3 ]
Reference：
[1] Heterocycles, 1998, vol. 47, # 2, p. 689 - 702
[2] Organic Process Research and Development, 2008, vol. 12, # 3, p. 490 - 495
Stage #1: 1-(2-furyl)-1-ethanone; ethyl trifluoroacetate, With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃;
Stage #2: With hydrogenchloride In water; ethyl acetate
1.a
Into a 500 mL flask was weighed 20.0 g (181.6 mmol) of 2-acetylfuran, 50 mL of THF, and 24 mL of ethyl trifluoroacetate. The resulting solution was cooled to 0-3 °C in an ice bath and 1.0 M LiHMDS was added (200 mL). The reaction was allowed to warm to room temperature where it remained overnight. The reaction was then concentrated in vacuo to remove THF and the residue was washed into a separatory funnel with ethyl acetate and 1.0 M HCl. The ethyl acetate was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The resulting 4,4,4-trifluoro-1-furan-2-yl-butane-1,3-dione was recovered as a brown semisolid, yield: 32.5 g (100+%).
100%
With sodium ethanolate In ethanol for 2h; Reflux;
4.4.1 General procedure for the synthesis of β-diketones
General procedure: To a solution of freshly prepared NaOEt from Na (1.67 equiv.) and absolute EtOH (15mL), aryl/alkyl methylketone (1.0 equiv.) was added. After 5min, ethyl trifluoroacetate (1.07 equiv.) was added, and the reaction mixture was then stirred for 2h under reflux. When possible, the product was isolated by precipitation of the reaction mixture, which was poured onto a solution of 1M HCl (25mL) in ice (25g), with the crude product collected by filtration and further used without purification. If a precipitate was not formed, extraction with EtOAc (3×15mL) from the water phase was performed. The combined organic phases were washed with brine (30mL) and dried over anhydrous Na2SO4 before the final evaporation of solvents under reduced pressure. 4,4,4-trifluoro-1-(furan-2-yl)-3-hydroxybut-2-en-1-one (13a): Yield quantitative; brown transparent oil; 1H NMR (400MHz, CDCl3): δ (ppm)=6.50 (s, 1H,=CH), 6.64 (dd, J1=1.7Hz, J2=3.6Hz, 1H, furanyl-H4), 7.35 (dd, J1=0.8Hz, J2=3.6Hz, 1H, furanyl-H3), 7.69 (dd, J1=0.8Hz, J2=1.7Hz, 1H, furanyl-H5), 1H from OH is exchanged; MS (ESI-) m/z calc. for C8H4F3O3 [M-H]- 205.0, found 204.9; Rf=0.51 (EtOAc/n-Hex, 2:1, v/v).
82.6%
With sodium In ethanol at 20℃;
General procedure for synthesis of compounds 13-14
General procedure: Ethyl trifluoroacetate 9 (0.047 mol) and 2-acetyl furan (0.047 mol) were added dropwise to a solution of ethanol (55 mL) containing thinly sliced sodium (0.047 mol), and stirred over night at room temperature. Then,the solution was poured in ice-water containing concentrated sulfuric acid. The solution was extracted with dichloromethane, dried, concentrated and purified on a column of silica using a 10% gradient of ethyl acetate in hexanes to afford 10 (82.6%y). 10(0.020 mmol) was added drop wise into a solution of hydrazinobenzene(0.020 mmol), ethanol(50ml)and acetic acid(0.5 ml), then refluxed.The cooled mixture was concentrated under vacumm and the pyrazole11(66.7%y) was obtained after purification by silicagel(a5%gradient of ethyl acetate in hexanes). Pyrazole 11(0.043mol) was dissolved in acetone (120 ml) and KMnO4(0. 071mmol) was added. This mixture was heated at 60°C for 3 h and cooled to room temperature.Then isopropyl alcohol was added and stirred at room temperature overnight. The reaction mixture was filtered and concentrated. The residue was dissolved in 1N NaOH, washed and acidified with 2N HCl solution to obtain 12(46.3 % y).The amide derivatives 13-14 were prepared through acyl chlorides derived from 12. A solution of 12 (0.004mol) in thionyl chloride(10mL) was refluxed for 5 hand then concentrated under vacuum. The crude acylchloride was added dropwise to a cooled solution(0°C) of substituted aniline(0.004mol) and TEA (0.008mol) in dichloromethane (10mL). The mixture was stirred over night at room temperature, and then purified on a column of silica using a gradient of e thyl acetate in hexanes to afford the pure products.
54%
With potassium <i>tert</i>-butylate In benzene for 15h; Ambient temperature;
With diethyl ether; sodium ethanolate
Stage #1: ethyl trifluoroacetate, With sodium methylate In diethyl ether for 0.0833333h;
Stage #2: 1-(2-furyl)-1-ethanone In diethyl ether at 20℃;
Stage #1: 1-(2-furyl)-1-ethanone With sodium methylate In methanol at 20℃; for 1h;
Stage #2: ethyl trifluoroacetate, In methanol for 24h; Heating;
Stage #1: ethyl trifluoroacetate, With sodium methylate In diethyl ether for 0.0833333h;
Stage #2: 1-(2-furyl)-1-ethanone In diethyl ether at 20℃; Further stages.;
With sodium hydride
With sodium hydride
With sodium methylate In tetrahydrofuran; methanol at 0 - 20℃;
Step a
General procedure: To a freshly prepared sodium methylate solution in methanol and THF ethyl trifluoroacetate (1.2 equiv) was added under stirring at 0° followed by addition of ketone 2 (1.0 equiv). The reaction mixture was allowed to stir for additional 3-24 h until the starting materials were consumed, as determined by thin-layer chromatography (TLC). Then the solvent was removed under reduced pressure and the residue was acidified with hydrochloric acid (1 N), followed by extracted with acetic ether. The combined organic layers were dried (MgSO4), Fitered and the filtrate was concentrated under reduced pressure. The crude product was puried by column chromatography. Yield: 40-90%. For some cases, the crude products can be straight used for step c without the column chromatography procedure.
With sodium hydride In tetrahydrofuran Reflux;
With sodium ethanolate In benzene
With sodium In ethanol at 20℃; Inert atmosphere;
General procedure for synthesis of compounds A10-A11
General procedure: Ethyl trifluoro acetate 18 (0.048 mol) and 2-acetyl furan(0.048 mol) were added dropwise to a solution of ethanol (55 mL) containing thinly sliced sodium (0.048 mol), and stirredovernight at room temperature. Then, the solution was poured in ice-water containing concentrated sulfuric acid. The solutionwas extracted with dichloromethane, dried, concentrated and purified on a column of silica using a 10% gradient of ethyl acetatein hexanes to afford 19. 19 (0.020 mmol) was added dropwise into a solution of substituted-hydrazine (0.020 mmol), ethanol (50mL) and acetic acid (0.5 mL), then refluxed. The cooled mixture was concentrated under vacumm and the pyrazole 20 wasobtained after purification by silica gel (a 5% gradient of ethyl acetate in hexanes). Pyrazole 20 (0.043 mol) was dissolved inacetone (120 mL) and KMnO4 (0. 071 mmol) was added. This mixture was heated at 60 oC for 3 h and cooled to roomtemperature. Then isopropyl alcohol was added and stirred at room temperature overnight. The reaction mixture was filtered andconcentrated. The residue was dissolved in 1 mol/L NaOH, washed and acidified with 2 mol/L HCl solution to obtain 21. Theamide derivatives 22 were prepared through the acyl chlorides derived from 21. A solution of 21 (0.004 mol) in thionyl chloride(10 mL) was refluxed for 5 h and then concentrated under vacuum. The crude acylchloride was added dropwise to a cooledsolution (0 oC) of 2-aminoethanol (0.004 mol) and TEA (0.008 mol) in dichloromethane (10 mL). The mixture was stirred atroom temperature for 0.5h to afford 22, The compound 6 was added dropwise to a cooled solution (0 oC) of compound 22 (0.004mol) and TEA (0.008 mol) in dichloromethane (10 mL). The mixture was stirred overnight at room temperature, and thenpurified on a column of silica using a gradient of ethyl acetate in hexanes to afford the pure products.
Stage #1: ethyl trifluoroacetate, With sodium methylate In tetrahydrofuran; methanol at 0℃; for 0.5h;
Stage #2: 1-(2-furyl)-1-ethanone In tetrahydrofuran; methanol at 20℃;
Synthesis of 1,3-diones 6a-6c
General procedure: To a freshly prepared sodium methylate solution (1.5 equiv) in methanol and THF, ethyl trifluoroacetate (1.2 equiv) was added under stirring at 0 °C. The mixture was stirred for 30 min followed by addition of ketone 5a-5c (1.0 equiv). The reaction mixture was stirred for another 12-24 h until the starting materials were consumed. Then the mixture was concentrated under reduced pressure and the resulted residue was acidified with hydrochloric acid (1 N) and extracted with acetic ether. The combined organic layers were dried (MgSO4), filtered and concentrated to dryness. The product was purified by column chromatography. Yield: 72-84 %
With sodium hydroxide In methanol; water at 15 - 20℃; for 15h;
87%
With ethanol; sodium hydroxide at 20℃; for 3h;
86%
With sodium hydroxide In ethanol at 20℃; for 7h;
(E)-1-(Furan-2-yl)-3-(4-methoxyphenyl)prop-2-en-1-one (15d)
To a stirred of solution 2-acetylfuran (2.43 g, 22.03 mmol) and 4-methoxybenzaldehyde(3.00 g, 22.03 mol) in EtOH (20 mL) was added aq1 M NaOH (50 mL). The mixture was stirred at r.t. for 7 h and quenched with aq 1 M HCl. The mixture was extracted with CH2Cl2,dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure.The crude product was purified by silica gel flash column chromatographyto give 15d (4.30 g, 18.85 mol) in 86% yield as a yellowsolid; mp 86-87 °C; Rf = 0.26 (hexane/EtOAc 4:1).1H NMR (400 MHz, CDCl3): = 7.83 (d, J = 15.6 Hz, 1 H), 7.62 (dd, J =1.6, 0.8 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 15.6 Hz, 1 H),7.28-7.33 (m, 1 H), 6.91 (d, J = 8.4 Hz, 2 H), 6.56 (dd, J = 3.6, 1.6 Hz, 1H), 3.81 (s, 3 H).13C NMR (100 MHz, CDCl3): = 177.9, 161.6, 153.7, 146.2, 143.5,130.1, 127.3, 118.7, 117.0, 114.2, 112.3, 55.2.
75%
With potassium hydroxide In water at 20℃; for 12h;
63%
With sodium hydroxide In methanol
61%
With potassium hydroxide In methanol at 20℃; Cooling with ice;
52%
With sodium hydroxide In ethanol; water for 4h; Cooling with ice;
Preparation of the Chalcones
General procedure: An Illustrative Procedure with (E)-1-Aryl-3-(2-pyrrolyl)-2-propenones (3k). 2-Pyrrolecarbaldehyde (12 mmol), acetophenone (13 mmol), and 24 mmol of NaOH in ethanol (20 mL) and water (10 mL) were mixed in an ice-bath and stirred for 4 h in the bath. The mixture was neutralized with 1 M-HCl aqueous solution to pH 8-9. The resulting precipitate was collected and recrystallized from ethanol.
39%
With sodium hydroxide In ethanol Ambient temperature;
With sodium hydroxide; ethanol
With potassium hydroxide In ethanol; water at 0 - 20℃;
With sodium hydride; In tetrahydrofuran; at 70℃; for 1h;
Part B. Preparation of ethyl 3-(2-furyl)-3-oxopropanoate. To a suspension of hexane-washed sodium hydride (3.5 g of 60% dispersion in mineral oil, 90.8 mmol) in 200 mL of tetrahydrofuran was added diethyl carbonate (10.7 g, 90.8 mmol) and 2-acetylfuran (5.0 g, 45.4 mmol). The resulting mixture was stirred at 70 C for 1h and then was cooled to room temperature and quenched by the slow addition of 10% aq HCl. The tetrahydrofuran was removed in vacuo and the aqueous was extracted with ethyl acetate. The organics were washed with water and brine, dried (MgSO4) and concentrated in vacuo to yield 6.9 g (83%) of the title compound which was sufficiently pure to be used without purification. 1H-NMR(CDCl3)delta: 7.61 (t, 1H), 7.27 (dd, 1H), 6.57 (dd, 1H), 4.20 (q, 2H), 3.84 (s, 2H), 1.25 (t, 3H)ppm.
71%
With sodium hydride; at 20 - 90℃; for 3h;
To a solution of 60% sodium hydride (95.4 mmol) in diethyl carbonate (90 mi) was slowly added 2-acetylfurane (5.50 g, 45.4 mmol). The resulting solution was stirred at room temperature for 1 hour and at 90C for 2 hours. The reaction mixture was poured into ice/water and acetic acid (5 mL) was added. The mixture was extracted with ethyl acetate (2x75 mL). The organic layer was washed with water (2x50 mL), brine (50 mL), dried (Na2SO4), and the solvent removed under reduced pressure. Purification by flash chromatography with silica gel and ethyl acetate/n-hexane (4: 1) as eluent gave the title compound (5.90 g, 71%) as a red oil. 8 (200 MHz, CDCl3) : 1.26 (t, J=7.2 Hz, 3H); 3.86 (s, 2H); 4.21 (q, J=7.2 Hz, 2H); 6.58 (dd, J1=3. 4 Hz, J2=1.7 Hz, 1H) ; 7.28 (d, J=3. 4 Hz, 1H) ; 7.62 (d, J=1. 7 Hz, 1H).
In tetrahydrofuran; ethanol;
REFERENCE EXAMPLE 3 Ethyl 2-furoylacetate Sodium hydride (4.4 grams) and 10.7 grams of diethyl carbonate are suspended in 60 ml of tetrahydrofuran and 10 grams of 2-acetylfuran is gradually added thereto by keeping the inner temperature at 40to 50 C. A small amount of ethanol is added thereto, heated to reflux for three hours, and the reaction is made stopped by addition of 20 ml of ethanol. The mixture is poured into ice water, extracted with ether, the ether extracts are combined, washed with water, dried with anhydrous magnesium sulfate, and ether is evaporated therefrom. The resulting oil is purified by distilling in vacuo to give 10 grams of pale yellow oily product, b.p. 90 C./3 mmHg.
With sodium hydride; In tetrahydrofuran;Reflux;
To a solution of 2-acetylfuran 1 (1 eq) in THF (0.5M), was added NaH (2 eq). The solution was brought to reflux. The reaction was monitored by NMR. Upon consumption of the starting material, the reaction mixture was diluted with diethyl ether. The mixture was then washed with 1M HCl, water, and saturated brine. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
With C28H35ClCoN5(1+)*Cl(1-); potassium tert-butylate; hydrogen; In tetrahydrofuran; at 20℃; under 37503.8 Torr; for 16h;Autoclave;
General procedure: In an argon filled glove box, the cobalt catalyst (LNHC/CoCl2 or Co-2a) and the base wereweighted into a 4mL vial equipped with a magnetic stir bar, followed by addition of the solvent.After shaking of the vial for 30 seconds, the carbonyl substrate was then added. The vial wasplaced into a Parr Instruments autoclave, which was then sealed, removed from the glove boxand purged with hydrogen gas. The autoclave was heated to certain temperature. After reactionfor 16 hours, the autoclave was cooled down to 0 oC before releasing the hydrogen gas. Forquantitative GC analysis, biphenyl (1.0 mmol) as internal standard was added. The organiclayer was then filtrated and diluted for GC analysis. The stereo-selectivity of the hydrogenatedproducts of cyclohexanones were determined by NMR with mesitylene as the internal standard.The desired hydrogenation product was further isolated by flash column chromatography.
93.8%
With C40H37ClN2PRuS(1+)*C24H20B(1-); isopropyl alcohol; potassium hydroxide; at 82℃; for 2h;Catalytic behavior;
General procedure: The mixture of a ketone (0.2 mmol) and base (0.08 mmol)containingthe catalyst (0.1 mol%) in 2-propanol (6 ml) was stirred at82 C. After the reactionwas complete, diethyl ether could be addedto the mixture and extract the ruthenium complexes followed byfiltration and neutralized with 1N HCl, washed with water anddried over anhydrous Na2SO4. Conversion obtained is related to theresidual unreacted ketone. Percentage of conversionwas calculatedby using GC method of the crude mixture and compared with theauthentic samples. Acetone was identified as only by-product in allthe cases. As the catalyst is stable in all organic solvents and it canbe recovered and the work up process is also very simple for thiscatalytic system.
With [RhCl2(p-cymene)]2; dimethylamine borane; In tetrahydrofuran; at 70℃; for 24h;Inert atmosphere; Sealed ampoule;
General procedure: To an oven dried, argon purged, ampoule containing [Ru(p-cymene)Cl2]2 (15.3 mg, 0.05 mmol, 2.5 mol%), substrate (1 mmol) and dry thf (to make a total of 3 mL), a solution of dimethylamine borane in thf was added. The ampoule was sealed and heated at 70 C for 24 hours then cooled to room temperature; Method A - The reaction mixture was diluted with CH2Cl2 (30 mL) and passed through a short pad of silica followed by diethyl ether (100 mL). The solvents were concentrated in vacuo to afford the crude product.
With C55H41ClN2O3P2Ru; isopropyl alcohol; potassium hydroxide; In m-xylene; at 20 - 82℃; for 4h;Inert atmosphere;
General procedure: In an oven-dried round bottom flask, were placed ketone (2.4 mmol), catalyst (3 mol), base (12 mol), internal standard (m-xylene, 30 L, 0.24 mmol) and i-PrOH (5 mL) at room temperature. The reaction mixture was heated at 82 C for the required reaction time under an atmosphere of nitrogen. Aliquots (0.2 mL) were taken at fixed time and the catalyst removed as precipitate from the reaction mixture by the addition of diethyl ether. The organic layer was neutralized with 1 N HCl, washed with water and dried over anhydrous Na2SO4. The combined organic layer passed through a short path of silica gel and then subjected to GCMS analysis. The conversions obtained are related to the residual unreacted ketone and are averages of two runs in the case of all catalytic reactions.
With C52H42BrClN2O2P2Ru; isopropyl alcohol; potassium hydroxide; at 82℃; for 5h;
General procedure: The mixture of a catalyst (0.1 mol %), ketone (2.1 mmol), base (0.005 mmol) and isopropanol (6 mL) were refluxed at 82 C in an open atmosphere for the required reaction time. After completion of the reaction, the reaction mixture was cooled to room temperature and then added diethyl ether for extract the catalyst. Then it was neutralized with 1N HCl, washed with water and dried over anhydrous Na2SO4. The percentage of conversion was calculated by using GC-MS analysis of the crude products. For 1H NMRanalysis, the crude product was chromatographed on a silica gel column with n-hexane - ethyl acetate (10:1) as an eluting solvent to give the corresponding alcohol and then characterized by 1H NMR spectroscopy.
With iron(III) chloride; C6H13BN2; In dichloromethane; at 20℃;
General procedure: To a solution of ketone (0.25 mmol) in DCM (1 mL) was added NHC-BH3 4 (24-27 mg, 0.2-0.25 mmol) and anhydrous FeCl3 (0.125-0.25 mmol) at room temperature, the mixture was stirred for 30 min-1 h. The residue was dried in vacuo and purified by flash column chromatography (silica gel) to give the corresponding alcohols 9a-r.
1-6 Example 2
5.5 g of 2-acetylfuran,Dissolved in 30ml of water,85.0 g of iodine and 200 ml of water were added dropwise at 30 ° C.Then, an aqueous NaOH solution (concentration: 2 mol/L) was added dropwise to adjust the pH to 7,Filter to remove the precipitate,The pH of the reaction solution was adjusted to 1 with hydrochloric acid (concentration: 0.5 mol/L).Filter the precipitated solid and dry it.Obtained 2.32 g of 2-furancarboxylic acid,The yield was 95%.
80%
With hydroxylamine hydrochloride; iodine In dimethyl sulfoxide at 100℃; for 5h;
67%
With Oxone; trifluoroacetic acid In 1,4-dioxane for 10h; Reflux; Green chemistry;
Benzoic Acid (3a); Typical Procedure from Acetophenone or Phenylacetylene
General procedure: To a mixture of acetophenone (100 mg, 1 equiv) or phenylacetylene (1 equiv) in dioxane (5 mL), Oxone (2 equiv) and TFA (2 equiv) were added. The mixture was then heated to reflux for 10 h and then cooled to r.t. H2O (10 mL) was added and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were treated with sat. NaHCO3 solution and the aqueous layer was poured onto crushed ice and treated with 2 M HCl; a colorless solid precipitated out. The precipitate was filtered off and dried in vacuo to give benzoic acid (3a) after column chromatography (silica gel; EtOAc-hexane, 1:9) as a white crystalline solid; yield: 0.096 g (95%) from 1a; mp 122-123 °C.
66%
Stage #1: 1-(2-furyl)-1-ethanone With iodine; dimethyl sulfoxide In chlorobenzene at 110℃; for 3h;
Stage #2: With tert.-butylhydroperoxide In chlorobenzene at 20 - 110℃; for 10h;
34 Example 34: Preparation of furan-2-carboxylic acid (formula (2-20))
Add 1 mmol of 2-acetylfuran (formula (1-20)), 6 mmol of DMSO, 0.1 mmol of I2, 2 mL of chlorobenzene solvent to a 10 mL two-neck round bottom flask equipped with a magnetic stirrer.Then the reaction flask was placed in an oil bath preheated to 110 ° C, and the magnetic stirrer was turned on for 3 h.The reaction flask was taken out, cooled to room temperature, 2 mmol of TBHP was added, and the reaction was continued at a temperature of 110 ° C for 10 h.The reaction solution was quenched by the addition of water, and then the pH was adjusted to about 11 with a sodium hydroxide solution having a concentration of 0.1 mol/L, and the aqueous phase was taken and washed three times with diethyl ether.Then, the pH was adjusted to about 2 with a hydrochloric acid solution having a concentration of 0.1 mol/L, and then extracted three times with diethyl ether. The three ether extracts were combined, and the ether was evaporated under reduced pressure.The column chromatography was further carried out, and the eluate containing the target compound was collected by using a mixture of ethyl acetate/petroleum ether volume ratio of 1:25 as an eluent.The solvent was distilled off to give the product thiophene-2-carboxylic acid in an isolated yield of 66%.
58%
With Iron(III) nitrate nonahydrate; iodine; oxygen; dimethyl sulfoxide at 110℃; for 12h; Sealed tube; Green chemistry;
Typical Procedure for the Synthesis of carboxylic acid (2a) from acetophenone (1a)
General procedure: To a 20-mL tube equipped with a magnetic stirring bar was added acetophenone 1a (120 mg, 1 mmol), 2 mL of DMSO, iodine (25 mg, 0.1 mmol) and Fe(NO3)3·9H2O (40 mg, 0.1 mmol). Then the tube was sealed after being charged with oxygen to replace the air in it. The tube was placed into a preheated oil bath (130°C), and the reaction solution was stirred for 12h. Then the reaction was quenched with water, and the pH of the aqueous phase was adjusted to 11 with 0.1 mol/L NaOH. After being washed with ethyl acetate (3 x 3 mL), the pH of the aqueous phase was adjusted to 2 with 0.1mol/L HCl and extracted with ether (3 x 6 mL). The combined ether phase was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography on silica gel using ethyl acetate/petroleum ether as eluent to afford 2a as a white solid (104 mg, 85% yield). 1H NMR(600 MHz, DMSO-d6) δ 12.88 (s, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.62-7.59 (m, 1H), 7.50-7.48 (m, 2H); 13C NMR (125MHz, DMSO-d6) δ 167.3, 132.7, 130.8, 129.2, 128.5.
58%
With Iron(III) nitrate nonahydrate; iodine; oxygen In dimethyl sulfoxide at 10℃; for 12h; Sealed tube;
34 Example 34: Preparation of furan-2-carboxylic acid (formula (2-20))
1 mmol of 2-acetylfuran (formula (1-20)), 0.1 mmol of I was added to a 25 mL glass tube equipped with a magnetic stir bar.2, 0.1 mmol of Fe (NO3)3·9H2O, 2mL of DMSO, replace the air in the glass tube with oxygen, seal the glass tube, then put the sealed glass tube into the oil bath preheated to 110 ° C, and turn on the magnetic stirrer, after 12h reaction, remove the sealing glass Tube, wait until it is cooled to room temperature, add water to the reaction solution to quench the reaction, then adjust the pH to about 11 with sodium hydroxide solution at a concentration of 0.1 mol / L, wash three times with ethyl acetate, the concentration of the aqueous phase is 0.1 mol /L hydrochloric acid solution to adjust the pH to about 2, and then extracted three times with diethyl ether, the three ether extracts were combined, the ether was evaporated under reduced pressure, and then separated by column chromatography to ethyl acetate / petroleum ether volume ratio 1 The mixture of 25 was used as an eluent, and the eluate containing the target compound was collected, and the solvent was evaporated to give the product furan-2-carboxylic acid. The isolated yield was 58%.
48%
With 18-crown-6 ether; potassium <i>tert</i>-butylate; oxygen In 1,2-dimethoxyethane at 60℃; for 15h;
9%
With sodium chloride; sodium nitrite In water
1 EXAMPLE 1
EXAMPLE 1 Concentrated hydrochloric (B.P., (B. 196 ml), was added to a stirred mixture of 2-acetylfuran (44 g) in water (600 ml) at 65° C and then a solution of sodium nitrite (168 g) in water (800 ml) added steadily below the surface over 13/4 hours. A further amount of sodium nitrite (28 g) in water (150 ml) was added over 20 minutes raising the pH to 3.4. After 1 hour at 65° more sodium nitrite (12 g) in water (60 ml) was added raising the pH to 4.4. After 40 minutes the solution was cooled to room temperature, filtered and sodium chloride (320 g) added and the solution extracted with methylene chloride (3 * 200 ml). Evaporation of the methylene chloride left a residue of 2-acetylfuran (11.0 g; 25%). The aqueous layer was adjusted to pH 2.8 (hydrochloric acid) and extracted with ethyl acetate (4 * 200 ml). Evaporation of the extracts gave furoic acid (3.8 g; 9%). The aqueous layer was adjusted to pH 0.2 with hydrochloric acid and extracted with ethyl acetate (5 * 200 ml), the organic extracts being washed sequentially with saturated sodium chloride solution.
Multi-step reaction with 2 steps
1: iodine; dimethyl sulfoxide / chlorobenzene / 120 °C
2: tert.-butylhydroperoxide / 13 h
With hydrogenchloride; phosphoric acid; sodium nitrite In water at 40℃;
1.S1; 2.S1; 3.S1; 4-6; 1.S1; 2.S1; 3.S1; 4.S1 Step S1: Preparation of furanoic acid
Add water, hydrochloric acid, 2-acetylfuran and catalyst in the oxidation kettle in proportion. After the oxidation kettle is heated to 40°C,Then, phosphoric acid and sodium nitrite solution were slowly added dropwise to it to obtain the oxidation product furanonic acid;
The procedure was the same as in Examples 1 to 9, the catalyst used being diethylzinc (1 mol %, based on the substrate) and N,N'-bis-(1-(R)-phenylethyl)-1,2-ethylene-(1 mol %), but the acetophenone was replaced by one of the prochiral ketones or dietones shown in Table V. In all cases, a greater proportion of the (S) enantiomer was obtained, with the ee between 65 and 80%.
95%
With (1S,2S)-(+)-N-tosyl-1,2-diphenylethane-1,2-diamine[eta6-1-isopropyl-4-methylbenzene]-ruthenium(II); formic acid; triethylamine; In dichloromethane; ethyl acetate; at 50℃; for 18h;Inert atmosphere;
To a solution of 1-(furan-2-yl)ethanone (5) (5.0g, 45.5mmol) in dry EtOAc (50mL) under argon was added a formic acid-triethylamine azeotropic mixture (5:2, 10mL) followed by the addition of Ru-catalyst S,S (24.0mg, 0.1mol%), which was pre-dissolved in DCM (5mL). The resulting reaction mixture was slowly warmed to 50C and allowed to stir until completion (18h), as indicated by TLC analysis. The reaction mixture was diluted with water (50mL) and extracted with EtOAc (3×40mL). The combined organic layers were washed with an aqueous saturated solution of NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography eluting with 10% EtOAc:hexanes to furnish the desired alcohol 4 (4.8g, 95% yield) as colorless oil; Rf 0.20 (hexanes/EtOAc, 9:1); [alpha]D24 -24.2 (c 0.48 in ethanol); [lit. [alpha]D23 -24.3 (c 6.0 in ethanol)]; 1H NMR (300MHz, CDCl3): delta 7.37 (1H, d, J=0.9Hz, ArH), 6.32 (1H, dd, J=3.2, 1.8Hz, ArH), 6.22 (1H, d, J=3.2Hz, ArH), 4.87 (1H, q, J=6.6Hz, C2HOH), 2.15 (1H, s, OH), 1.54 (3H, d, J=6.6Hz, CC1H3); 13C NMR (125MHz, CDCl3): delta 157.5, 141.8, 110.0, 105.0, 63.5, 21.2; IR (neat, cm-1): 3462, 2985, 2935, 1668, 1149, 877, 731.
92%
With formic acid; (R)-RuCl(eta6-mesitylene)-(S,S)-TsDPEN; triethylamine; In dichloromethane; at 20℃; for 24h;
To a solution of acylfuran 7 (15 g, 136.4 mmol) in CH2Cl2 (20 mL) was added a prepared solution of formic acid/triethylamine (40 mL, 2:1 (mol/mol)) and Noyori asymmetric transfer hydrogenation catalyst (R)-Ru(eta6-mesitylene)-(S,S)-TsDPEN (0.2 g, 0.25 mol%). The resulting solution was stirred at room temperature for 24 h. Then it was diluted with water (90 mL) and extracted with Et2O (200 mL x 3). The combined organic layer was washed with saturated aqueous NaHCO3 (50 mL) saturated brine (50 mL), dried over Na2SO4 and then concentrated under reduced pressure to give a residue. Flash chromatography on silica gel eluting with hexane/Et2O (1:1, v/v) gave furfuryl alcohol 9 (14 g, 92%) as colorless oil
85%
With recombinant alcohol dehydrogenase evo-1.1.030; NADH; In aq. phosphate buffer; isopropyl alcohol; at 35℃; for 44h;pH 7.0;Enzymatic reaction;
General procedure: Acetylfuran (5, 550 mg, 5.0 mmol) was dissolved in isopropanol (25 mL) and added to a solution of NADH (0.5 mmol) and alcohol dehydrogenase (evo-1.1.200, 250 U) in phosphate buffer (pH 7.0, 100 mM, 225 mL). The reaction mixture was incubated at 35 C (125 rpm) for 12 h until TLC indicated full conversion. The solution was saturated with NaCl and afterwards extracted with diethyl ether/pentane (2:1, 4×50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield the analytically pure alcohol (R)-6 (528 mg, 4.72 mmol, 94%, 99% ee) as pale yellow liquid.
65%
Daucas carota root; extract of; In water; at 37 - 40℃; for 50h;pH 7.0;Enzymatic reaction; Aqueous phosphate buffer;Conversion of starting material;
The General Methodology for the Reduction of the Substituted Acetophenones; 100 mg of each of the compounds in Table 1 entry No. 1-10 and other similarly related compounds were added to a crude extract of 2 gm Daucas carota (protein 1 gm/ml) in 50 ml of 0.1 M sodium phosphate buffer pH 6.5 to 7.5. The reactions were incubated in a shaking incubator for 30 to 50 hours. The product formed was isolated and purified by flash chromatography and the product obtained was confirmed by standard spectral data.
With (1S,2S)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine-ruthenium(mesitylene); sodium formate; cetyltrimethylammonim bromide; sodium hydrogencarbonate; In dichloromethane; water; at 20℃; for 24h;
To a 500 mL Erlenmeyer flask of HCO2Na (37 g, 0.545 mol) in deionized H2O (272 mL) was added furan ketone 10 (15 g, 0.136 mol) and CH2Cl2 (2 mL). After degassing (3x) and addition of small quantity of NaHCO3 to adjust the basicity, surfactant cetyltrimethylammonium bromide (5 g, 10 mol%) was added and stirred for 5 minutes. Noyori asymmetric catalyst (R)-Ru("6-mesitylene)-(S,S)-TsDPEN (85 mg, 0.1 mol%) was added and the resulting solution was stirred at room temperature for 24 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with saturated NaHCO3, dried over Na2SO4, and concentrated under reduced pressure. The resulting crude furan alcohol was further dissolved in 228 mL of THF/H2O (3:1) and cooled to 0 ºC. Solid NaHCO3 (23 g, 0.273 mol), NaOAc?3H2O (18.6 g, 0.136 mol), and NBS (24.2 g, 0.136 mol) were added to the solution and the mixture was stirred for 1 h at 0 ºC. The reaction was quenched with saturated NaHCO3 (200 mL), extracted (3 x 300 mL) with Et2O, dried over Na2SO4, and concentrated under reduced pressure. The crude mixture of allylic alcohols was further dissolved in CH2Cl2 (200 mL) and the solution was cooled to -78 ºC. Catalytic amount of DMAP (1.22 g 7 mol%) was added to the reaction mixture, followed by addition of (Boc)2O (59.5 g, 0.273 mol) in CH2Cl2 (70 ml). The resulting solution was allowed to stir for 12 h at -78 ºC to -30 ºC. The reaction was quenched with saturated NaHCO3, extracted with Et2O (3x), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography with elution of 6% Et2O in hexane to give Boc-protected pyranone (.-L)-9 (15g, 66 mmol, 48%,alpha:beta = 4:1).
With sodium formate; In water; at 40℃;
General procedure: For asymmetric transfer hydrogenation of ketones, the catalyst 5 (15.0 mg, 4.0 mumol of Ru based on the ICP analysis), HCO2Na (0.27 g, 10.0 mmol), ketone (0.40 mmol), and 2.0 mL of water were added in a 10 mL round bottom flask in turn. The mixture was allowed to react at 40 C for 3.0-9.0 h. [For asymmetric transfer hydrogenation of quinolines, the catalyst 5 (15.0 mg, 4.0 mumol of Ru based on the ICP analysis), HCO2Na (0.27 g, 10.0 mmol), quinolines (0.40 mmol), and 2.0 mL (2.0 M HCOOH/HCOONa buffer solution, pH = 5.0) were added in a 10 mL round bottom flask in turn. The mixture was allowed to react at 40 C for 10.0-24 h.] During that time, the reaction was monitored constantly by TLC. After completion of the reaction, the catalyst was separated via centrifuge (10,000 r/min) for the recycle experiment. The aqueous solution was extracted by Et2O (3 × 3.0 mL). The combined Et2O was washed with brine twice and dehydrated with Na2SO4. After the evaporation of Et2O, the residue was purified by silica gel flash column chromatography to afford the desired product. The conversion could be determined by an external standard method, and the ee value could be determined by chiral GC using a Supelco beta-Dex 120 chiral column (30 m × 0.25 mm (i.d.), 0.25 mum film) or a HPLC analysis with a UV-Vis detector using a Daicel OJ-H/OD-H/OB-H chiralcel column (Phi 0.46 × 25 cm).
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; C26H29N4O3S(1+)*Cl(1-); sodium formate; In water; at 20℃; for 7h;Catalytic behavior;
General procedure: To a solution of ligand 5d (2.1 mg, 0.004 mmol) in water (1 mL) was added [Cp*RhCl2]2 (1.2 mg, 0.002 mmol), HCO2Na (41 mg, 3.0 mmol), and ketone (2.0 mmol). The reaction mixture was stirred at room temperature for the time as indicated in Tables 1 and 2 . The reaction mixture was extracted by ethyl ether. The conversion was determined by 1H NMR analysis of the crude product. After concentration, the crude product was purified by chromatography on silica gel to give the pure product.
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; C49H67FeN2O2PS; hydrogen; lithium tert-butoxide; In isopropyl alcohol; at 20℃; under 15201.0 Torr; for 12h;Inert atmosphere; Autoclave;
In a high-purity argon atmosphere, [Ir(COD)Cl]2 (3.4 mg, 0.005 mmol)The chiral ligand L6 (9.2 mg, 0.011 mmol) was dissolved in isopropanol (1 mL).Stirring for 3 hours at room temperature gives an orange clear solution. 20 muL (0.001 mol%) of this orange solution was taken with a microinjector and added to 2-furylacetophenone (2 mmol),In a mixed system of isopropanol (2 mL) and lithium tert-butoxide (1 mol%). Place the reaction system in an autoclaveStir for 12 hours at room temperature under H2 (20 atm) conditions. Remove the solvent under reduced pressureColumn chromatography (silica gel, eluent: ethyl acetate) gave pure 1-(2-furyl) phenylethanol,The product was analyzed by HPLC and found to have an ee value of 92%.
With formaldehyd; RuCl2(eta6-benzene)(R)-2-(3-(furan-2-carbonyl)thioureido)propanoic acid; triethylamine; In water; at 60℃; for 15h;Catalytic behavior;
General procedure: HCOOH-Et3N (molar ratio 1.0:5.1) mixture was added to the Ru(II)-benzene complex (0.005 mmol) in water (0.5 mL).Subsequently ketone (1 mmol) was introduced into the mixture and stirred at 60C for 15 h. Then, the reaction mixture was cooled to room temperature, quenched with ice and extracted with dichloromethane. The extracts were dried over Na2SO4, filtered, then passed through a silica gel short column with N-hexane-ethyl acetate (1:1) eluent to remove the Ru catalyst.
With Fe(CO)Cl((C6H5)2PCH2CHNCHC6H5CHC6H5NHCH2CH2P(C6H5)2)(1+)*B(C6H5)4(1-)=FeC43H40ClN2OP2B(C6H5)4; potassium tert-butylate; isopropyl alcohol; at 28℃; for 0.00277778h;Catalytic behavior;
General procedure: The procedures for the transfer hydrogenation using complexes (S,S)-1 and (S,S)-1tol as catalyst precursors were similar to those that are described in previous examples. Stock solution 1 (SS1) was prepared by measuring a certain quantity of the complex into a small vial and then dissolving it in 3.04 g of dichloromethane (DCM). The stock solution 2 (SS2) was prepared by dissolving KOtBu in iPrOH. These solutions were used only after all the solids were completely dissolved and were stored for less than two days. The pre-calculated mass of stock solution 1 was measured into a vial and the DCM was evaporated to obtain a yellow solid. The required mass of the substrate was then added to a measured mass of isopropanol to get mixture 1 (M1). A required mass of SS2 was added to a second vial containing iPrOH to give mixture 2 (M2). To initiate the reaction, M1 and M2 were efficiently mixed by transferring the solutions from vial to vial. The final concentrations of the reagents were adjusted to be as follows: : [Cat. (S,S)-1] = 6.73 x 10-5 M, [KOtBu] = 5.45 x 10-4 M, [substrate] = 0.412 M, [iPrOHj = 12.4 M, 28 C. The samples were taken by injecting small portions of the reaction mixture into septa-sealed GC vials containing aerated iPrOH for efficient quenching of the reaction. Samples were analyzed using a Perkin-Elmer Autosystem XL chromatograph with a chiral column (CP chirasil-Dex CB 25 m x 2.5 mm). Hydrogen gas was used as a mobile phase at a column pressure of 5 psi. The injector temperature was 250 C, and the FID temperature was 275 C. The amount of reduced alcohol in the sample was determined relative to the amount of the substrate.
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; (RC,SFc)-1-[bis(3,5-di-tert-butylphenyl)phosphino]-2-[1-N-(6-methylpyridin-2-ylmethyl)aminoethyl] ferrocene; potassium tert-butylate; hydrogen; In ethanol; at 25 - 30℃; under 15201.0 Torr; for 12h;Autoclave;
General procedure: To a 20 mL hydrogenation vessel were added the catalyst precursor [{Ir(cod)Cl}2] (1.7 mg, 2.53 mumol), ligand 2f (4.5 mg, 6.06 mumol), and anhydrous EtOH (3 mL) under a nitrogen atmosphere. The mixture was stirred for 1.0 h at 25-30 C to give a clear yellow solution. After placing the vessel in an autoclave, the ketone (10 mmol) and t-BuOK (28 mg, 0.253 mmol) were added. The autoclave was replaced with H2 three times, and the reaction mixture was stirred at room temperature until no obvious hydrogen pressure drop was observed. After releasing the hydrogen pressure, the reaction mixture was filtered through a short silica gel column. The solvent in the filtrate was removed to determine the yield and the product obtained was analyzed by HPLC to determine the enantiomeric excess.
With hydrogen; lithium hydroxide; 9-amino-9-deoxyepicinchonine; In methanol; at 25℃; under 45004.5 Torr; for 3h;Autoclave;
General procedure: Definite quantities of catalyst, chiral diamine, base, solvent, and heteroaromatic methyl ketones were placed into a 60mL stainless steel autoclave equipped with a magnetic stirrer bar. The autoclave was purged with hydrogen three times and the hydrogen pressure was increased to the desired level. The mixture was then stirred at room temperature for a suitable time. At the end of the reaction, the reactor was decompressed. Finally, the products were separated by centrifugation and analyzed by a GC instrument with an FID detector and beta-DEX120 capillary column. The ee value was calculated from the equation: ee (%)=100×(S-R)/(S+R).
With silver tetrafluoroborate; diethoxymethylane; C26H29N3O2*Cl(1-)*Ir(1+)*C8H12; at 20℃; for 20h;
General procedure: A flask was charged with azolium salt L12 (0.02 mmol, 9.1 mg),Ag2O (0.01 mmol, 2.4 mg) and CH2Cl2(1 mL). After stirring the resulting mixture at room temperature for 2 h in the dark, CH2Cl2 was removed in vacuo. Then, a THF (1 mL) solution of [IrCl(cod)]2(0.01 mmol, 6.9 mg) was added to the reaction vessel. The resulting mixture was stirred at room temperature for an additional 4 h in the dark, filtered through a membrane filter, and evaporated to dry-ness in vacuo. Subsequently, to the resulting flask containing yellow solid of the unpurified IrCl(cod)(NHC) complex, a solution of AgBF4(0.025 mmol, 4.9 mg) in CPME (2 mL) was added, and then stirred at room temperature for 1 h. Finally, propiophenone (0.5 mmol,66 mg) and (EtO)2MeSiH (2.25 mmol, 294 mg) were added to the resulting CPME solution (see Appendix A. Supplementary data fordetails). After stirring at room temperature for 20 h under open-air conditions, K2CO3(2 mg) and MeOH (2 mL) were added. Then, the resulting mixture was stirred at room temperature for 2 h. Afterevaporation of the solvents, the residue obtained was purified bycolumn chromatography on silica gel (Et2O/n-hexane = 3:7) to give(S)-1-phenyl-1-propanol (61 mg, 91% isolated yield). The ee was measured by chiral GLC.
With C50H47Cl2N3P2Ru; C50H47Cl2N3P2Ru; sodium isopropylate; isopropyl alcohol; at 20℃; for 1h;Inert atmosphere;
General procedure: Ruthenium complex (3.7 mg, 0.004 mmol), ketone (2 mmol) andNaOiPr (0.4 mL, 0.1 M) were dissolved in degassed iPrOH (10 mL) and the mixture was stirred under nitrogen atmosphere at appropriate temperature. A small volume of sample was taken from reaction mixture and diluted with diethyl ether (1:1), and rapidly filtered using a short silica pad. The conversion and enantiomeric excess were determined by GC using Agilent HP-Chiral 20B column(30 m, 0.25 mm, 0.25 mm) and by HPLC using Supelco AD-H, OD-Hchiral columns.
With C43H47ClFeIrN2P; potassium tert-butylate; hydrogen; In ethanol; at 20℃; under 15201.0 Torr; for 12h;Autoclave;
General procedure: (RC, SFe)-1-[2-(bis(3,5-dimethylphenyl)phosphino)ferrocenyl]N-(6-pyridyl-2-methyl)ethylamine (12.6 mg, 0.022 mmol), [Ir(COD)Cl2 (7.32 mg, 1 mmol)Was added to a 25 mL Schlenk reaction tube,Vacuum / nitrogen three times, 2 mL of anhydrous ethanol was purged with nitrogen, and the mixture was stirred at room temperature for 1 hour. Acetophenone (4.8 g, 40 mmol) was added to a 100 mL autoclave, Add 30 mLThe nitrogen-substituted absolute ethanol, Then, the reaction liquid is added into the reaction kettle,After replacing the hydrogen three times, the pressure was increased to 20 atm,The mixture was stirred at room temperature for 24 hours, TLC showed that the reaction was complete and the product was obtained as a pale yellow liquid (R)-1-phenylethanol 2.2 g in 90.9% yield and 78% ee.
With C19H33MnNO3P2(1+)*Br(1-); hydrogen; sodium t-butanolate; In ethanol; at 50℃; under 22502.3 Torr; for 3h;Autoclave;
General procedure: General Procedure: All catalytic hydrogenation experiments using molecular hydrogen were carried out in a Parr Instruments autoclave (300 mL) advanced with an internal alloy plate include up to 8 uniform reaction vials (4 mL) equipped with a cap and needle penetrating the septum. Representative experiment: Under an argon atmosphere, a vial was charged with Manganese Complex of example 2.1 and base which were dissolved in 2 mL of dried solvent. The resulting red solution was stirred briefly before the ketone or ketoester (0.5 or 1 mmol) was added. The vial was placed in the alloy plate which was then placed into the autoclave. Once sealed, the autoclave was purged 5 times with hydrogen, then pressurized to 30 bar and heated to desired temperature. Afterwards, the autoclave was cooled to RT, depressurized, and the reaction mixture was analyzed by GC-FID or HPLC as well as GC-MS. Product isolation was performed via column chromatography using silica gel as stationary phase and w-pentane / ethylacetate or w-pentane / acetone mixture as eluent. Individual reaction conditions: [a] 2 mol cat., 5 mol NaOiBu, 0.5 mmol substrate, 30 bar, 3h, 50 C, EtOH (1,5 mL) [b] 2 mol cat., 5 mol NaOiBu, 0.5 mmol substrate, 30 bar, 3h, 70 C, EtOH (1,5 mL) [c] 2 mol% cat., 5 mol% NaOiBu, 0.5 mmol substrate, 30 bar, 3h, 50 C, toluene (1,5 mL) [d] 2 mol% cat., 5 mol% NaOiBu, 0.5 mmol substrate, 30 bar, 3h, 50 C, z'PrOH (1,5 mL) [e] 2 mol% cat., 5 mol% NaOiBu, 0.5 mmol substrate, 30 bar, 3h, 50 C, /PrOH (1,5 mL) [f] 1 mol% cat., 5 mol% KOiBu, 0.5 mmol substrate, 30 bar, 4-5h, 40 C, tert-amyl alcohol (1,5 mL) [g] 1 mol% cat., 5 mol% KOiBu, 0.5 mmol substrate, 30 bar, 16h, 50 C, toluene (1,5 mL) [h] 2 mol% cat., 5 mol% KOiBu, 0.5 mmol substrate, 30 bar, 8h, 100 C, dioxan (1,5 mL) [i] 1 mol% cat., 5 mol% KOiBu, 1 mmol substrate, 30 bar, 4h, 30 C, 1,4-dioxane (2 mL) [j] 1 mol% cat., 5 mol% KOiBu, 1 mmol substrate, 30 bar, 4h, 40 C, tert-amyl alcohol (2 mL) [k] 1 mol% cat., 5 mol% KOiBu, 1 mmol substrate, 30 bar, 4h, 80 C, tert-amyl alcohol (2 mL) [1] 2 mol% cat., 5 mol% KOiBu, 1 mmol substrate, 30 bar, 4h, 50 C, toluene (2 mL) [m] 2 mol% cat., 5 mol% KOiBu, 1 mmol substrate, 30 bar, 4h, 80 C, tert-amyl alcohol(2 mL) [n] 2 mol% cat., 5 mol% NaOiBu, 0.5 mmol substrate, 30 bar, 3h, 70 C, PrOH (1,5 mL) [o] 2 mol% cat., 5 mol% NaOiBu, 0.5 mmol substrate, 30 bar, lh, 50 C, /PrOH (1 mL) SP = side product (Hydrogenation of double bond) Table 1:
With formaldehyd; RuCl2(eta6-benzene)(S)-2-(3-benzoylthioureido)propanoic acid; triethylamine; In water; at 60℃; for 15h;Catalytic behavior;
General procedure: HCOOH-Et3N (molar ratio 1.0:5.1) mixture was added to the Ru(II)-benzene complex (0.005 mmol) in water (0.5 mL).Subsequently ketone (1 mmol) was introduced into the mixture and stirred at 60C for 15 h. Then, the reaction mixture was cooled to room temperature, quenched with ice and extracted with dichloromethane. The extracts were dried over Na2SO4, filtered, then passed through a silica gel short column with N-hexane-ethyl acetate (1:1) eluent to remove the Ru catalyst.
With formaldehyd; RuCl2(eta6-benzene)(R)-2-(3-(thiophene-2-carbonyl)thioureido)propanoic acid; triethylamine; In water; at 60℃; for 15h;Catalytic behavior;
General procedure: HCOOH-Et3N (molar ratio 1.0:5.1) mixture was added to the Ru(II)-benzene complex (0.005 mmol) in water (0.5 mL).Subsequently ketone (1 mmol) was introduced into the mixture and stirred at 60C for 15 h. Then, the reaction mixture was cooled to room temperature, quenched with ice and extracted with dichloromethane. The extracts were dried over Na2SO4, filtered, then passed through a silica gel short column with N-hexane-ethyl acetate (1:1) eluent to remove the Ru catalyst.
With bromopentacarbonylmanganese(I); potassium tert-butylate; isopropyl alcohol; (R,R)-N,N-bis(2-hydroxy-1-phenylethyl)ethanediamide; at 80℃; for 20h;Inert atmosphere; Schlenk technique;
General procedure: Mn(CO)5Br (16.2 mg; 6 mol%) and ligand L4a (6.6 mg; 2 mol%) were added under a flow of argon to a flame dried 25 mL Schlenk flask containing a PTFE coated stirring bar. After three vacuum/argon cycles 2 mL of isopropyl alcohol were added to the Schlenk flask. The yellowish suspension was stirred for 10 min at room temperature and another 2 mL of isopropyl alcohol, containing potassium tert-butoxide (22.4 mg; 20 mol%), were added via syringe to the continuously stirred solution. After 10 min the Substrate (1 mmol) was added to clear yellow reaction solution and the glas wall of the Schlenk flask was rinsed with 2 mL of isopropyl alcohol. The Schlenk flask was placed in a heating block, heated to 80 C and kept at this temperature for 20 hours. After this time the Schlenk flask was removed from heating block and was allowed to cool to room temperature. The reaction solution was filtered through a small pipette plug of silica and the silica was washed with additional isopropyl alcohol. The conversion and yield of the reaction were determined by GC using hexadecane as internal standard. The ee value of the reaction was measured either by GC or HPLC.
With potassium tert-butylate; (Rc,Sp)-N-5,6,7,8-tetrahydroquinolinyl-1-(2-diphenylphosphino)ferrocenylethylamine manganese; isopropyl alcohol; at 20℃; for 2h;Inert atmosphere;
General procedure: a) Add 1-acetylnaphthalene (0.17g, 1mmol), potassium tert-butoxide (22mg, 0.2mmol) and catalyst (7mg, 0.01mmol) to a 50ml round-bottomed flask, and then add them to the round-bottomed flask. 30 ml of isopropanol was replaced with nitrogen for 10 times, and the reaction was stirred. The reaction temperature was 20 C. The reaction was stopped after 2 hours of reaction. The reaction was detected by GC, and the conversion was determined to be 94%. The ee value measured by LC was 93%.
A mixture of 2-acetylfuran (25.0 g, 0.227 mmol) and N,N-dimethylformamide dimethylacetal (40 ml) was stirred at 100C for 9 hours. After cooling as it was, the reaction mixture was concentrated. To the residue were added diethyl ether and hexane. The resulting solid was collected by filtration and washed with hexane, to give the title compound (36.5 g, 97%) as a brown solid.1H NMR (400 MHz, DMSO-d6) delta ppm; 2.88 (3H, br s), 3.14 (3H, br s), 5.65 (1H, d, J= 12.6 Hz), 6.60 (1H, dd, J=2.0, 3.4 Hz), 7.10 (1H, dd, J = 0.8, 3.4 Hz), 7.68 (1H, d, J = 12.6 Hz), 7.79 (1H, dd, J = 0.8, 2.0 Hz).
97%
at 100℃; for 9h;
Reference Example 5 3-(Dimethylamino)-1-(2-furyl)-2-propen-1-one A mixture of 2-acetylfuran (25.0 g, 0.227 mmol) and N,N-dimethylformamide dimethylacetal (40 ml) was stirred at 100 C. for 9 hours. After cooling as it was, the reaction solution was concentrated. Diethyl ether and hexane were added to the residue, and the resulting solid was collected by filtration and washed with hexane, to give the title compound (36.5 g, 97%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) delta ppm; 2.88 (3H, br s), 3.14 (3H, br s), 5.65 (1H, d, J=12.6 Hz), 6.60 (1H, dd, J=2.0, 3.4 Hz), 7.10 (1H, dd, J=0.8, 3.4 Hz), 7.68 (1H, d, J=12.6 Hz), 7.79 (1H, dd, J=0.8, 2.0 Hz).
88%
at 100℃; for 16h;
A mixture of DMF*DMA (21.9 g, 297.17 mmol, 3.6 eq) and 1-(furan-2-yl)ethanone (10.0 g, 90.81 mmol, 1.0 eq,) was heated at 100 C. for 16 h. The reaction mixture was then cooled to RT and diluted with cold water. The yellow precipitates were filtered under vacuum and washed with excess water followed by hexane. The yellow solid (13.4 g, 88%) was used as such for next step without further purification. LCMS: 166 [M+1]+
60%
In ethanol; for 12h;Reflux;
N,N-Dimethylformamide dimethyl acetal (3.60mL; 0.027mol) was added dropwise into a solution of 2-furyl methyl ketone (3g; 0.027mol) in warm ethanol. The mixture was refluxed overnight for 12h. After that time, the solvent was removed under reduced pressure and the brown solid was crystalized in hexane giving yellow crystals whose NMR spectrum matches the literature (yield 60%) [30]. (0008) 1H NMR (400MHz, CDCl3) delta ppm: 7.79 (d, J=12.5Hz, 1H); 7.48 (s, 1H); 7.06 (d, J=3.4Hz, 1H); 6.47 (dd, J=3.4, 1.7Hz, 1H); 5.67 (d, J=12.5Hz, 1H); 3.13 (s, 3H); 2.92 (s, 3H).
Reflux;
General procedure: Aryl ketone 2 (1.0 equiv) and N,N-dimethylformamide dimethyl acetal (5.0-10.0 equiv) were refluxed until the starting materials were consumed, as determined by TLC. Then the solvent was evaporated under reduced pressure until DMF-DMA was fully removed. The crude products can be straight used for step c. Yield: 100%
Reflux;
General procedure: General procedure: A mixture of appropriately substituted arylmethyl ketone (4 mmol) and DMF-DMA (20 mmol)was refluxed for8-12 h and monitored by TLC. After complete consumption ofsubstituted methyl ketone, the mixture was subjected to rotaryevaporation under reduced pressure to remove the excess of DMFDMAand the liberated methanol. After that DMSO (6-8 mL) and 4-azidobenzenesulfonamide (4 mmol) were added to reactionmixture. After addition, reaction mixture was allowed to stir at 90C for 8-10 h in silicon oil bath. After completion, reaction mixturewas poured into water to afford required product (7a-7j). Crudeproduct thus obtained was recrystalized with ethanol.
In toluene; for 4h;Reflux;
General procedure: The N, N-Dimethylformamide dimethyl acetal (1.0 equiv) and different aromatic ethanones (1a-1c, 1.0 equiv) in dry toluene and the reaction mixture was heated to reflux for 4 h. The solvent was removed under reduced pressure to give the residue (2a-2c). Then, a solution of guanidine hydrochloride (1.0 equiv) and sodium ethoxide (1.0 equiv) in ethanol was added to the residue, stirred at room temperature overnight. The solvent was removed by distillation, and the residue was subjected to column chromatography which was eluted by ethyl acetate in petroleum ether to obtain compounds 3a-3c as solid.
In 5,5-dimethyl-1,3-cyclohexadiene;Reflux;
General procedure: To a solution of aryl ethenone 4a-j (20mmol) in xylene (50mL), dimethylformamide-dimethylacetal (5) (2.38g, 20mmol), was added and then the reaction was refluxed for 7h. The xylene was distilled off and the product was triturated with diethyl ether (5mL). The resulting solid was filtered and washed with cold petroleum ether to afford the pure compounds 6a-j, respectively. The physical properties of 6a-j were identical to those reported [19-22].
With sodium hydride; In toluene; mineral oil; for 5h;Reflux;
General procedure: To a solution of ketone (20 mmol) in toluene (80 mL) was added dimethyl carbonate (60 mmol) and NaH (40 mmol, 60%). The reaction mixture was refluxed for 5 h until TLC indicated the total consumption of the ketone. After cooling, the reaction mixture was poured into ice-water (100 mL), acidified with 3 M HCl to pH 2-3 and extracted with EtOAc (100 mL x3). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether /EtOAc = 10/1) to afford the desired compound.
With oxygen; sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 6h;
General procedure: A round-bottom flask that was flame-dried and cooled under dry air or oxygen atmosphere was charged with alcohol 6 or 33 (0.5 mmol) and THF (2.5 mL). After stirring at 0 C for 5 min, NaH powder (1 mmol, 2 equiv) was added in one portion, and the mixture was allowed to warm to room temperature. The reaction was quenched by addition of saturated NH4Cl (2 mL) after the indicated time, extracted with EtOAc (10 mL×2), and washed by brine (15 mL). The combined organic phase was dried over MgSO4, the solvent was removed under vacuum, and the residue was purified by flash chromatography on silica gel to give the desired ketone product 7 and 34. For isolations of acids 8 and 35/36: the combined aqueous phase was acidified with 2 M HCl, and then extracted with EtOAc (10 mL×2) and washed by brine (15 mL). The combined organic phase was dried over Na2SO4, the solvent was removed under vacuum to give acid product that can be further purified by flash chromatography on silica gel.
97%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium tert-butylate; copper(I) triflate; 5-[(2S)-pyrrolidine-2-yl]-1H-tetrazole; In N,N-dimethyl-formamide; at 25℃; for 0.5h;Catalytic behavior;
General procedure: A round-bottom flask was charged with alcohol (2 mmol), CuOTf (0.1 mmol, 0.05 equiv) (S)-5-(pyrrolidin-2-yl)-1H-tetrazole (0.1 mmol, 0.05 equiv), TEMPO (0.1 mmol, 0.05 equiv), t-BuOK (2 mmol, 1 equiv) and DMF (5 ml). The reaction mixture was stirred at 25 C open to air until the completion of the reaction, as monitored by TLC. The mixture was then diluted with CH2Cl2 (20 ml), washed with water, dried over Na2SO4, and evaporated under vacuum to give the crude product, which was purified by column chromatography to give the pure product.
> 95%
With potassium osmate(VI) dihydrate; tetrabutyl-ammonium chloride; oxygen; In aq. phosphate buffer; tert-butyl alcohol; at 50℃; for 12h;pH 10;Sealed tube;
Add 0.2 mg of K2Os042H20 (0.0005 mmol) to a 15 ml pressure reaction tube, and add 1.5 ml of potassium phosphate buffer solution (pH 10).Add 1.0 ml of tert-butanol and 0.3 mg of tetrabutylammonium chloride,Stir well and replace with oxygen, then add 0.03 ml (0.3 mmol) of 1- (2-furyl) -1-methyl methanolThe reaction tube was sealed and heated and stirred in a water bath at 50 C for 12 hours. After the reaction, the reaction mixture was deflated. 10 mg of sodium hydrogen sulfate and 0.20 ml of acetic acid were added to the reaction solution. After stirring for 10 minutes, the upper organic phase was distilled under reduced pressure ( -0.099 MPa), and 2-acylfuran was separated. The gas chromatographic analysis showed that the conversion of 1- (2-furyl) -1-methylmethanol was 100%, and the yield of 2-acetylfuran was more than 95%.
76%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium acetate; (S)-3-phenyl-2-(phenylamino)propionic acid; copper(ll) bromide; In water; for 12h;Reflux; Schlenk technique;
General procedure: A mixture of 1-phenethyl alcohol (1.0 mmol), N-(phenyl)phenylalanine(0.0241 g, 0.1 mmol), CuBr2 (0.0223 g, 0.1 mmol),NaOAc (0.1640 g, 2.0 mmol), TEMPO (0.0156 g, 0.1 mmol), andH2O (3.0 mL) were placed into a 100 mL Schlenk tube, whichwas vigorously stirred in air under reflux for 12 h. After thereaction, the product was extracted with CH2Cl2 (3 × 2.0 mL).The combined organic phase was washed with H2O (3.0 mL) anddried over anhydrous MgSO4. After concentration undervacuum, the residue was purified by column chromatography toafford acetophenone.Isolated yield: 0.1080 g (90%).
Example 10 Example 2 was repeated, except that 2 mmol of <strong>[4208-64-4]1-(2-furyl)ethanol</strong> were reacted over 24 hours. Yield of 2-furyl methyl ketone: 85% (selectivity 91%)
62%Chromat.
With air; multiwall carbon nanotube supported on r-ruthenium dioxide nanoparticle; In toluene; at 110℃; for 20h;
General procedure: Five milligram of r-RuO2/MWCNT (0.68 mol%) was stirred with3 mL of toluene taken in a round-bottomed flask equipped with a condenser and a magnetic stirrer. The substrate (1 mmol) was added to the stirring solution and then the mixture was refluxed at 110C under atmospheric pressure of air. The completion of the reaction was checked by GC. After the reaction, the r-RuO2/MWCNTwas separated out from the reaction mixture by simple centrifugation and the products and unconverted reactants were analyzed by GC without any purification. Selectivity of the product for each reaction was also calculated.
With N-Bromosuccinimide; In DMF (N,N-dimethyl-formamide);
To a solution of 2-acetylfuran (20 mmol) in DMF (20 mL) was added portionwise N-bromosuccinimide (22 mmol) with stirring. The reaction mixture was stirred overnight, then poured onto cold water. The product was extracted with ether (200 mL, 3* times). Yield 61%, mp 92-93 C. (hexanes/ether, Lit. mp 94-95 C.; see Gilman H., et al., J. Am. Chem. Soc., 53, 4192-4196 (1931). 1H NMR (CDCl3); delta 2.45 (s, 3H), 6.49 (d, J=3.9 Hz, 1H), 7.12 (d, J=3.6 Hz, 1H). 13C NMR; delta 8185.4, 154.4, 128.2, 118.9,114.3, 25.7.
50.4%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 24h;
To a solution of 1 (10 g, 90 mmol) in DMF 40 mL, NBS (19g, 108 mmol) was added by keeping the temperature at 0 C. Thereaction mixture was stirred overnight at room temperature. Upon completion,the reaction mixture was poured into ice-cold water. The mixture was dilutedwith EtOAc, and the insoluble material was filtered off through Celite. Theorganic layer of the filtrate was washed with brine, dried anhydrous magnesiumsulfate, and concentrated. The residue was chromatographed (SiO2,EtOAc/n-hexane, 1/19, v/v) to afford compound 2 (8.7 g, 45.4mmol, 50.4%). 1H NMR (500 MHz, CDCl3,delta, ppm): 2.46 (3H. s),6.49 (1H, d, J = 3.4 Hz), 7.12 (1H,d, J = 3.4 Hz). MS m/z 188 (M + H)+.
44.5%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 0.5h;
Synthesis of 2-acetyl-5-bromofuran (29) 2-Acetylfuran (2.2 g, 20 mmol) was dissolved in DMF (20 mL), followed by addition of N-bromosuccinimide (3.91 g, 22 mmol). The mixture was reacted at room temperature for 30 min and then added into distilled water (50 mL), and the layers were separated with ethyl acetate (50 mL x 2). The ethyl acetate layer was dried with anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the residue was subjected to medium-pressure preparative chromatography using ethyl acetate/hexane (1/15) as an elution solvent to obtain Compound 29. Yield 1.68 g (yield rate 44.5%).
44.5%
With N-Bromosuccinimide; In hexane; water; ethyl acetate; N,N-dimethyl-formamide;
Synthesis of 2-acetyl-5-bromofuran (29) 2-Acetylfuran (2.2 g, 20 mmol) was dissolved in DMF (20 mL), followed by addition of N-bromosuccinimide (3.91 g, 22 mmol). The mixture was reacted at room temperature for 30 min and then added into distilled water (50 mL), and the layers were separated with ethyl acetate (50 mL*2). The ethyl acetate layer was dried with anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the residue was subjected to medium-pressure preparative chromatography using ethyl acetate/hexane (1/15) as an elution solvent to obtain Compound 29. Yield 1.68 g (yield rate 44.5%).
28%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃;
To a stirred solution of compound 4 (5.0 g, 45.45 mmol) and DMF (50 mL), NBS (8.8 g, 50 mmol) was added portion-wise at room temperature under stirring. The reaction mixture was allowed to stir at room temperature overnight. 50% starting material remained by TLC and LCMS. Reaction mixture was poured into cold water and the compound was extracted with diethyl ether (150 mL X 3). Combined organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure. Crude compound was purified by column chromatography using 5% ethyl acetate in n-hexane as an eluent to afford compound 43 (2.4 g, 28%) as a white solid.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 5h;
2-Acetylfuran is dissolved in N,N-dimethylformamide (5 g, 1.1 mol/L), and N-bromosuccinimide (1 eq.) is added.After stirring for 5 hours at room temperature, the reaction mixture is poured into ice water and the precipitate formed is drained.1H NMR (300 MHz, CDCl3, delta in ppm): 2.47 (s, 3H); 6.49 (d, 1H, J=3.6 Hz); 7.12 (d, 1H, J=3.6 Hz).
With N-Bromosuccinimide;
90 mmol of 2-acetylfuran was dissolved in 40 mL of dimethylformamide (DMF), then 108 mmol of N-bromosuccinimide (NBS) was added at 0 C. The mixture was stirred overnight at room temperature. The mixture contained 1-(5 -bromo-2-furyl)ethanone after reaction. The reaction mixture described in Step 1 was diluted with ethyl acetate and filtered. The organic phase in the filtrate was washed with saturated salt solution and dried over anhydrous sodium sulfate, concentrated, and separated by chromatography to yield 1-(5-bromo-2-furyl)ethanone. 1H NMR (500 MHz, CDCl3, ?, ppm): 2.46 (3H. s), 6.49 (1H, d, J=3.4 Hz), 7.12 (1H, d, J=3.4 Hz). MS m/z 188 (M+H)+.
1-(furan-2-yl)-2-(isochroman-1-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With carbon tetrabromide In neat (no solvent) at 100℃; for 48h;
69%
With 2,3-dicyano-5,6-dichloro-p-benzoquinone at 100℃; for 2h;
65%
With indium(III) chloride; N-hydroxyphthalimide; oxygen; copper(II) bis(trifluoromethanesulfonate) at 75℃;
50%
With manganese(IV) oxide; methanesulfonic acid In diethyl ether at 20℃;
45%
With sodium persulfate; copper(ll) bromide at 80℃; for 24h;
6 4.1.6 1-(Furan-2-yl)-2-(isochroman-1-yl)ethanone 3f
General procedure: 4.1. General procedure for the CDC reaction of benzylic ethers with carbonyl compounds To a solution of 1 or 4 (0.25mmol, 1equiv), 2 (1.25 mmol, 5 equiv) and CuBr2 (0.05 mmol, 0.2 equiv) was added Na2S2O8 (0.75 mmol, 3 equiv). Then the mixture was stirred at 80°C until the starting material disappeared monitored by TLC. After that, the above mixture was directly purified by flash chromatography (ethyl acetate/petroleum ether as eluent) to give the desired product 3 or 5.
With N-iodo-succinimide; oxygen In toluene at 45℃; for 4h;
1-4 Example 3:
Add 150 g of acetylfuran and 600 g of toluene to the reaction kettle and stir well.Then add 0.45 g of a cuprous oxide and copper complex, 0.75 g of iodosuccinimide,Oxygen was introduced into the system to a pressure of 0.9 MPa, and the reaction was stirred at 45 ° C for 4 h.After the oxidation is completed, it is filtered and the solvent is recovered to obtain 183.2 g of 2-furylglyoxylic acid (yield: 96.03%, purity: 99.32%).
86%
With hydrogenchloride; n-Butyl nitrite; sulfuric acid; γ-Al2O3/Pd(II); water at 40 - 55℃; for 1h;
1.2; 3.2; 5.2; 6.2; 1 (2) Preparation of furanone acid
20 g of 2-acetylfuran was dissolved in 150 mL of 10% dilute hydrochloric acid solution,Add 2g of concentrated sulfuric acid,0.1g catalyst γ-Al2O3/Pd(II),Control the temperature to 40-55 ° C, add 20.6 g of n-butyl nitrite, use 1 h,After the addition was completed, the reaction was stirred for 1 h.After the reaction, pH 2.8 was adjusted, and the catalyst was recovered by filtration.The filtrate was extracted with 100 mL of dichloromethane to extract n-butanol and unreacted acetylfuran from the reaction.The aqueous phase is an aqueous solution of furanoic acid. Adding 50 g of industrial salt to the aqueous furfurone acid solution,Adjust the pH of hydrochloric acid to less than 0.5, and extract it 3 times with 120 mL of butyl acetate each time.The organic phases were combined, and the organic solvent was evaporated under reduced pressure to give 21.9 g of furonic acid.The yield was 86%.The conversion of acetylfuran by high performance liquid chromatography was 96%.The purity of the obtained furanosonic acid was 99.1%.
41%
With pyridine; selenium(IV) oxide at 110℃; for 12h; Inert atmosphere;
22%
With pyridine; selenium(IV) oxide at 90 - 110℃;
16.2%
Stage #1: 1-(2-furyl)-1-ethanone With hydrogenchloride; sodium nitrite In water at 65℃; for 3.66h;
Stage #2: With hydrogenchloride In water
Preparation of 2-(furan-2-yl)-2-oxoacetic acidTo a suspension of 1 -(furan-2-yl)ethanone (5g, 45.5mmol) in water (68ml) was added concentrated HC1 (22.3ml ) and heated at 65 °C, then the aqueous sodium nitrite (22g, 318.5mmol , dissolved in water 107ml) was added dropwisely over 2h with the resulted PH at 3.0-3.5. After the mixture was heated at 65°C for lh, another batch of aqueous sodium nitrite (1.4g, 20mmol, dissolved in water 7ml) was added dropwisely and heated at 65 °C for another 40 min; the reaction was stopped and cooled to room temperature. 300ml of DCM was added, and the aqueous phase was extracted with DCM (100ml x3), the aqueous phase was adjusted PH to 0.5 by cond. HC1, and extracted by ethyl acetate (100ml x3), the combined organic phase was washed by brine, dried over sodium sulphate, and concentrated to dryness, the residue was dissolved by small amount of ethyl acetate and petroleum ether, and kept at room temperature, the solid was precipitated out, washed by petroleum ether and dried to give the desired product (1 ,03g, 16.2%) as brown solid.m/z [M-l]" 139.0
16.2%
With hydrogenchloride; water; sodium nitrite at 65℃;
Preparation of 2-(furan-2-yl)-2-oxoacetic acid
Preparation of 2-(furan-2-yl)-2-oxoacetic acid To a suspension of 1-(furan-2-yl)ethanone (5 g, 45.5 mmol) in water (68 ml) was added concentrated HCl (22.3 ml) and heated at 65, then the aqueous sodium nitrite (22 g, 318.5 mmol, dissolved in water 107 ml) was added dropwisely over 2 h with the resulted PH at 3.0-3.5. After the mixture was heated at 65 for 1 h, another batch of aqueous sodium nitrite (1.4 g, 20 mmol, dissolved in water 7 ml) was added dropwisely and heated at 65 for another 40 min; the reaction was stopped and cooled to room temperature. 300 ml of DCM was added, and the aqueous phase was extracted with DCM (100 mlx3), the aqueous phase was adjusted PH to 0.5 by cond. HCl, and extracted by ethyl acetate (100 mlx3), the combined organic phase was washed by brine, dried over sodium sulphate, and concentrated to dryness, the residue was dissolved by small amount of ethyl acetate and petroleum ether, and kept at room temperature, the solid was precipitated out, washed by petroleum ether and dried to give the desired product (1.03 g, 16.2%) as brown solid. m/z [M-1]- 139.0
18 g (64.3%)
6 EXAMPLE 6
The solution was next adjusted to pH 3.5 and extracted with methylene chloride (2 * 100 ml) to remove unreacted 2-acetylfuran (1.8 g; 8%), then adjusted to pH 2.8 and extracted with ethyl acetate (4 * 100 ml) to remove furoic acid and phthalic acid (8.6 g) and finally adjusted to pH 0.2 and extracted with ethyl acetate (5 * 100 ml). Evaporation of the ethyl acetate gave 18 g (64.3%) of fur-2-ylglyoxylic acid m.p. 81°-91° C.
With selenium(IV) oxide Inert atmosphere;
With selenium(IV) oxide
With pyridine; selenium(IV) oxide at 90 - 110℃; Inert atmosphere;
With pyridine; selenium(IV) oxide at 110℃; for 4h; Inert atmosphere;
With pyridine; selenium(IV) oxide
With hydrogenchloride; phosphoric acid; sulfuric acid; sodium nitrite In water at 61 - 65℃;
2 Specific preparation method of furanone acid aqueous solution:
In the reaction apparatus, 80 g of acetylfuran, 450 g of water, 210 ml of hydrochloric acid and 15 ml of sulfuric acid and 60 g of phosphoric acid were added, the reaction temperature was controlled at 61-65 ° C, 39% sodium nitrite solution was added, and subjected to deuteration, rearrangement, and hydrolysis to form an aqueous solution of furanone acid for later use.
With pyridine; selenium(IV) oxide at 90 - 110℃; for 5h;
With pyridine; selenium(IV) oxide for 3.5h; Reflux;
With pyridine; selenium(IV) oxide at 120℃; Inert atmosphere;
With selenium(IV) oxide
With nitric acid; toluene-4-sulfonic acid; sodium nitrite In water at 5 - 60℃;
1-6 Example 3
27.5 g of 2-acetylfuran was dissolved in 150 mL of 68% nitric acid to prepare reaction solution 1.51.9g of sodium nitrite and then 0.43g p-toluenesulfonic acid (1% mol) was dissolved in 150mL of water,The reaction solution 2 is configured such that the molar ratio of 2,2-acetylfuran and sodium nitrite is 1: 3, and the reaction solution 1 is poured into the cooling tower A.The reaction liquid 2 is poured into the cooling tower B, and the temperature of the cooling tower is set to 5 °C; After the pre-cooling is completed, use different metering pumps to pump the reaction solution 1, reaction solution 2 into the inlet of the continuous flow microchannel reactor, and set the flow rate of the metering pump to 5mL / min.The temperature of the microchannel reactor is set to 60 ° C and the pressure is about 1.7Mpa. After all the reaction solution passes through the microchannel reactor,The product solution collected at the discharge port is pumped into an extraction tower, and the extractant is 600 mL of ethyl acetate.After extraction, the organic phase was dehydrated with anhydrous sodium sulfate, and filtered after removing the water.35.8g of crude 2-oxo-2-furylacetic acid was weighed, the crude product was poured into a recrystallization column, and 50mL was added to obtain trichloromethaneRecrystallization was performed to obtain 31.72 g of a solid with a yield of 90.5% and tested by HPLC (external standard method),The purity of the product is 99.5%
With pyridine; selenium(IV) oxide at 90 - 110℃; for 1h;
With selenium(IV) oxide
With pyridine; selenium(IV) oxide at 90 - 110℃; for 5h;
With selenium(IV) oxide
With pyridine; selenium(IV) oxide at 90 - 110℃; for 5h; Inert atmosphere;
With selenium(IV) oxide In pyridine at 90 - 110℃; for 5h;
With pyridine; selenium(IV) oxide at 90 - 110℃; for 5h;
4 4- (2-Furyl)-2-(4-methoxyphenyl)thiazole (TZ24-6)
Example 4 4- (2-Furyl)-2-(4-methoxyphenyl)thiazole (TZ24-6) A suspension of 2-acetylfuran (0.661 g, 6.00 mmol) and hydroxy(tosyloxy)iodo-benzene (Koser's Reagent, 2.35 g, 6.00 mmol) in dry dichloromethane (12 mL) was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo. To the residues were added 4-methoxythiobenzamide (1.00 g, 6.00 mmol) and dry ethanol (24 mL), and the mixture was heated at reflux for 4 hours. The solvent was evaporated in vacuo, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed with water and brine, and was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (toluene) to give crude crystals, which were recrystallized from isopropyl ether - hexane giving TZ24-6 as pale brown crystals (668 mg, 43.4 %). mp. 77 - 78 °C.
(b) 3-(5-Acetyl-furan-2-yl)-benzenesulfonamide3-aminobenzenesulfonamide (750mg, 4.36 mmol) was suspended in 6.8 mL of water. Concentrated hydrochloric acid (2.16 mL) was then added followed by dropwise addition of an aqueous solution of sodium nitrite (391mg, 5.67 mmol in 2.1 mL) at O0C. The reaction was stirred at O0C for 15 minutes. Acetyl furan (437 muL, 4.36 mmol) in 3 mL of acetone was added followed by copper chloride hydrate (238 mg, 1.4 mmol) in 2 mL of water. The reaction was then slowly allowed to warm to room temperature and stirred for 72 hours by which time a brown solid had formed. The volatile solvents were evaporated and a mixture of dichloromethane and ethyl acetate was added to the remaining aqueous solution. The mixture was triturated. Solvents were removed and more ethyl acetate was added. The solid was then isolated by filtration. When the purity of the compound is low, it can be recrystallised at this stage using a mixture petroleum ether/ethyl acetate. 1H NMR (d6-DMSO, ppm): 8.22 (s, IH), 8.05 (d, J = 7.88 Hz, IH), 7.81 (d, J = 7.86 Hz, IH), 7.67 (t, J= 7.82 Hz, IH), 7.57 (d, J= 3.72 Hz, IH), 7.47 (s, 2H), 7.29 (d, J= 3.74 Hz, IH), 2.45 (s, 3H). MS (+ESI): 266.1 (M+H+).
With sodium hydroxide In methanol; water at 20 - 25℃; for 6h;
5.1. Typical experimental procedure for the synthesis of 1,3-diarylpropenones (6)
General procedure: An aqueous solution of sodium hydroxide (20%, 10 mL) was added slowly to the stirring solution of the appropriate aryl aldehyde (1 mmol) and appropriate acetophenone (1 mmol) in methanol (20 mL) in 100 mL conical flask. The stirring was continued for 6 h, keeping the temperature of reaction mixture between 20 and 25 °C. The reaction mixture was then poured into ice cold water (100 mL). It was then neutralized with hydrochloric acid (5%). A yellow solid was obtained after filtration which was recrystallized from ethanol and was used further for the next step.
With sodium hydroxide In methanol; water at 20℃; for 15h;
With sodium hydroxide In methanol; water at 20℃; for 15h;
77%
With sodium hydroxide In ethanol; water at 20℃;
62%
With sodium hydroxide In ethanol Reflux;
With sodium hydroxide In methanol; water at 20 - 25℃; for 6h;
5.1. Typical experimental procedure for the synthesis of 1,3-diarylpropenones (6)
General procedure: An aqueous solution of sodium hydroxide (20%, 10 mL) was added slowly to the stirring solution of the appropriate aryl aldehyde (1 mmol) and appropriate acetophenone (1 mmol) in methanol (20 mL) in 100 mL conical flask. The stirring was continued for 6 h, keeping the temperature of reaction mixture between 20 and 25 °C. The reaction mixture was then poured into ice cold water (100 mL). It was then neutralized with hydrochloric acid (5%). A yellow solid was obtained after filtration which was recrystallized from ethanol and was used further for the next step.
With sodium hydroxide In methanol; water at 20℃; for 15h;
With hydrogenchloride; In water; isopropyl alcohol; at 90 - 95℃; for 0.5h;pH 4;
General procedure: To a stirred mixture of 1-(furan-2-yl)ethanone (1a) or 1-(thiophen-2-yl)ethanone (1b) (10 mmol), <strong>[25150-61-2]pyrrolidine hydrochloride</strong> (10 mmol) and 1/5th of paraformaldehyde (10 mmol) in isopropanol (10 mL) was added conc. HCl dropwise to adjust the pH of the solution to 4. The reaction mixture was then heated in an oil bath at 90-95 C for 30 min with stirring. Other four portion of the paraformaldehyde were added at 15 min interval. The reaction mixture was further refluxed for 6-8 h. The solvent was distilled off. The residue obtained was washed with hexane (2 × 5 mL). The Mannich base of pyrrolidine obtained as a HCl salt were used further without purification.A mixture of above Mannich salt (10 mmol) and imidazole/1H-1,2,4-triazole (12 mmol) in 10 mL ethanol : water (3:2) was heated for 5-9 h at 90 C. The organic solvent was distilled off and the compound was extracted with dichloromethane (2 × 5 mL). The combined organic layer was dried over sodium sulphate and concentrated to give the crude product which was purified by column chromatography using methanol: chloroform (1: 99) as an eluant to provide the required compounds (2a-2d).
With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; 2-(2-(diphenylphosphanyl)phenyl)benzo[d]oxazole; potassium hydroxide In toluene at 110℃; for 24h; Schlenk technique; Inert atmosphere;
4.3. General procedure for alkylation reactions
General procedure: [Cp*IrCl2]2 (1 mol %, 0.01 mmol, 8.0 mg), 4a (2 mol %, 0.02 mmol,7.6 mg), KOH (10 mol %, 0.1 mmol, 5.6 mg), and toluene (5 mL) wereadded to a 25mL Schlenk tube with stirring under N2 at roomtemperature. Then ketones/secondary alcohols/amines (1 mmol),primary alcohols (1.1 mmol) were added by syringe. The reactionmixture was heated to 110 °C under reflux in an oil bath for 24 h. Itwas cooled to ambient temperature. Then it was concentrated invacuo, and purified by flash column chromatography with petroleumether/ethyl acetate to afford the corresponding alkylatedproduct.
77%
With (1,4-dimethyl-5,7-diphenyl-1,2,3,4-tetrahydro-6H-cyclopenta[b]pyrazin-6-one)(triphenylphosphine)(dicarbonyl)iron; caesium carbonate In toluene at 90℃; for 16h; Schlenk technique; Inert atmosphere;
58%
With [Mn(HN(C2H4PiPr2)2)(CO)2Br]; caesium carbonate In tert-Amyl alcohol at 140℃; for 22h; Inert atmosphere;
41%
With lithium tert-butoxide In toluene at 110℃; for 12h; Inert atmosphere;
41%
With dimanganese decacarbonyl; sodium hydroxide In toluene at 110℃; for 2h; Inert atmosphere; Glovebox; Sealed tube;
With di-tert-butyl peroxide; tetra-(n-butyl)ammonium iodide In ethyl acetate; <i>tert</i>-butyl alcohol at 120℃; for 3h;
6 Example 6:
In a 50-ml round-bottomed flask, 0.1103 g (1.0 mmol) of 2-acetylfuran was added, and 0.2015 g (1.1 mmol)Molar) saccharin, 0.0739 g (0.2 mmol) of tetrabutylammonium iodide, 0.1802 g (2.0 mmol) of tert-butyl peroxy peroxide, 6.0 mmolLit ethyl acetate (EtOAc), heated at 120 ° C, and reacted for 3 hours to complete 2-acetylfuran reaction (thin layer chromatography TLC monitoring).The reaction mixture was poured into 20 ml of water and extracted with ethyl acetate (10 ml x 3). Combine the organic phases with anhydrous sodium sulfatedry. After the solvent was distilled off, the residue was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 6/1) to obtain a white solid.It was 0.2794 g with a yield of 96%.
89%
With tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide In nitromethane at 120℃; for 6h;
76%
With tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide In decane; ethyl acetate at 130℃; for 3h; Sealed tube;
With palladium(II) trifluoroacetate; triphenylphosphine; silver carbonate In 1,2-dimethoxyethane; dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere; Glovebox;
6-chloro-4-(2-fluorophenyl)-2-(furan-2-yl)quinoline[ No CAS ]
(5E, 11E)-2,8-dichloro-6,12-bis(2-fluorophenyl)dibenzo[b,f][1,5]diazocine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.3%; 10.3%
With diphenyl hydrogen phosphate; for 0.05h;Microwave irradiation;
General procedure: 2-Aminobenzophenone 1 (1 mmol), heteroaromatic ketone 2 (1 mmol), and diphenylphosphate (DPP) (0.5 mmol) were mixed without any organic solvent and the reaction mixture was irradiated in the microwave oven(RE-555 TCW, Samsung, Busan, Korea) for 3 min. Resulting reaction mixture was diluted with 50 mL of ethyl acetate, neutralized with aqueous 10% NaOH and extracted with ethylacetate three times, washed with water, and dried using MgSO4. Products were purified by column chromatography (ethyl acetate/n-hexane = 1/20-1/40 v/v) to give the corresponding quinoline compounds 3-7. (Analytical data provided in Supporting Information).
2-acetyl-furan (121 g, 1.1 mol) and N, N- dimethylformamide dimethyl acetal (155 g, 1.3 mol) was dissolved in 500 ml of anhydrous dimethyl formamide, in 110 was refluxed for 3 hours. After the spin-dry solvent, ether was added and the product was precipitated crystals were separated and dried to give 168 g of yellow crystals.
With N-(tert-butyloxycarbonyl)-L-isoleucine; palladium diacetate; potassium carbonate; p-benzoquinone; In N,N-dimethyl acetamide; water; at 80℃; for 20h;
To a dried Schlenk reaction flask was added palladium acetate (6.7mg, 0.03mmol), Boc-L-Ile-OH (13.9mg, 0.06mmol), or Boc-D-Ile-OH (13.9mg, 0.06mmol), potassium carbonate (62.2mg, 0.45mmol), BQ (3.2mg, 0.03mmol), water (21.6mg, 1.2mmol) and DMA (1.5mL).Adding the corresponding ferrocene substrate 1 (0.3mmol) and heterocyclic aromatic 2 (0.6mmol).The reaction was heated to 80 deg.] C in an air atmosphere.After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate, extracted with ethyl acetate.The combined organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate and filtered.The solvent was removed under reduced pressure to obtain the target product residue I (ethyl acetate / petroleum ether = 1 / 15-1 / 2, v / v, 2% Et by column chromatography3N)20 hours.Red oil (66.3mg, 63% yield, 99% ee)
In acetic acid; at 120℃; for 0.666667h;Microwave irradiation;
General procedure: A ketone compound, paraformaldehyde and suitable amine were taken in 1:1.2:1 mol ratios and heated in 10 mL of glacial acetic acid at 120 C at 70 Watt for series A and B for several times. The reactions were monitored by TLC using CHCl3: MeOH (9:1 or 8:2) as a solvent system. The compounds were purified by crystallisation. Chemical structures of the compounds were confirmed by 1H NMR (data were not present) and their reported melting points. Amine part was morpholine in Series A (1-9) and <strong>[6091-44-7]piperidine</strong> in Series B (10-18). Physical data of the compounds obtained by microwave irradiation method are reported in Table 2 (See Supplementary File).
With lithium hexamethyldisilazane; In tetrahydrofuran; at 0℃; for 1h;Inert atmosphere;
Compounds 1 and 2 were dissolved in THF. Subsequently, LiHMDS was added dropwise. The reaction was carried out under Argon atmosphere at 0C for about 1 h after LiHMDS had been added. The solvent was evaporated and the reaction mixture was purified by adding a 1 :1 mixture of EtOAc/6M aq.HCI, separating the aqueous phase, and subsequent washes of the organic phase 1 :1 with H2O and brine. Final traces of H2O were removed with Na2SO4 and finally the organic solvent was removed by evaporation.
3-(2,4-dichlorothiazol-5-yl)-1-(furan-2-yl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With sulfuric acid; acetic acid at 20℃;
Synthesis of 3-(2,4-dichloro-1,3-thiazol-5yl)-1-(furan/thiophen-2-yl)prop-2-en-1-one derivatives (4ah): General Procedure
General procedure: 2,4-Dichlorothiazole-5-carbaldehyde (2) (0.01 mole) and 2-acetylthiophen/2-acetylfuran derivatives (3a) (0.01 mole) were dissolved in glacial acetic acid (30 ml). After heating gently, catalytic amount of concentrated H2SO4 (1 ml) was added. The reaction mixture was then kept at room temperature for 48-96 hours. The separated solid was collected by filtration, washed with cold ethanol and dried to give pure product. The spectral data of some selected representative compounds prepared according to this procedure are given below: 4a) 3-(2,4-Dichlorothiazol-5-yl)-1-(furan-2-yl)prop-2-en-1-one. IR (KBr , cm-1): 1651 (C=O stretch), 1589 and 1460 (C=C 1stretch). 1H-NMR(400 MHz, CDCl3 ): δ 6.61-6.63 (m, 1H, C4-H of furan), 7.12 (d, J = 15.64 Hz, 1H, =CHα); 7.34 (d, J =3.64 Hz, 1H, C3 -H of furan),7.67 (d, J = 1.04 Hz, 1H, C5-H of furan),7.88 (d, J = 15.56 Hz, 1H, =CHβ ).LC-MS (m/z): 273.97 (M++1).
1-(2-(furan-2-yl)-2-oxoethyl)-1H-pyrrole-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetonitrile; at 20℃; for 12h;
To a cold solution of hydroxylamine hydrochloride (0.38 g, 5.5 mmol, 1.1 equiv.) in anhydrous acetonitrile (50 mL), triethylamine (0.77 mL, 5.5 mmol, 1.1 equiv.) and 1H-pyrrole-2-carboxaldehyde (5.0 mmol, 1.0 equiv.) were added and stirred for around 30 mins. Then phthalic anhydride (0.75 g, 5.05 mmol, 1.01 equiv.) was slowly added under nitrogen protection. The resulting mixture was stirred at 80 C for about 8 h. After concentration, the resulting residue was added cold CH2Cl2 (30 ml × 3) and stirred. The combined filtrates were washed with 5% ammonia water to remove phthalic acid completely. The separated organic layer was dried over anhydrous Na2SO4, and then concentrated under reduced pressure. Finally the residue was purified by passing it through a short silica gel column using CHCl3 as eluent to give pure <strong>[4513-94-4]1H-<strong>[4513-94-4]pyrrole-2-carbonitrile</strong></strong> as yellow oil (80%).3 A mixture of <strong>[4513-94-4]1H-<strong>[4513-94-4]pyrrole-2-carbonitrile</strong></strong> (3.0 mmol, 1.0 equiv.), substituted methyl bromide (3.3 mmol, 1.1 equiv.) and K2CO3 (3.6 mmol, 1.2 equiv.) was stirred in CH3CN (20 mL) at room temperature. After being stirred for 12 h, the reaction mixture was concentrated under reduced pressure, diluted with EtOAc (30 mL), and washed with H2O (30 mL). The water layer was extracted with EtOAc (30 mL) one more time. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane: EtOAc = 10:1) to afford 1b as white solid.
With tert.-butylhydroperoxide; phosphomolybdic acid; copper diacetate; In water; acetonitrile; at 90℃;
The synthetic steps of 2-acetylfuran are:0.096 g of <strong>[3208-16-0]2-<strong>[3208-16-0]ethylfuran</strong></strong> (1 mmol)Add to 1.5mL of a mixed solvent of water and acetonitrile (volume ratio 2: 1),To this was added 710 muL (5 mmol) of a 70% aqueous solution of tert-peroxide,After stirring well, add 6 mg (3 mol%) of copper acetate and 18 mg (1 mol%) of phosphomolybdic acid,The reaction was performed at 90 C, and the reaction was monitored by TLC until the raw material reaction <strong>[3208-16-0]2-<strong>[3208-16-0]ethylfuran</strong></strong> was completed.Extracted with ethyl acetate (3 times * 10 mL), combined organic phases were washed once with saturated brine,Dry over anhydrous sodium sulfate and remove the solvent by evaporation in vacuo.Purification by column chromatography gave the target product 2-acetylfuran with a yield of 66%.
General procedure: Complexes 4, 6, 8 and 10-12 were prepared by the following method. SacH (0.5mmol, 91.6mg) in water (5mL) was added to a solution of Pd(OAc)2 (0.25mmol, 56.1mg) in MeCN (10mL) and the solution was stirred for 30min at rt. Then, the corresponding phosphine (0.5mmol) in MeOH (10mL) was added to this solution and the resulting solutions were refluxed over a day. Complexes 2, 5 and 9 were synthesized using the same procedure, but the SacH/phosphine ratio was 2:1. In the case of 9, DMSO (10mL) was added to the reaction medium to dissolve the solid particles. The powders of these complexes were obtained after removal of the solvents using a rotary evaporator.
(1) Slowly add 80 ml of deionized water to 40 g of concentrated sulfuric acid to make a dilute sulfuric acid solution, weigh 80 g of sodium nitrite and add it to 120 mL of deionized water to make a sodium nitrite solution; (2) Into a 500 mL reaction flask (three-necked flask) equipped with a stirring, thermometer, and double constant-pressure dropping funnel, add 100 mL of deionized water, 25 g of acetylfuran, 0.5g of copper sulfate and 0.5g of tetrabutylammonium chloride, start stirring, and when the temperature rises to 60 C, start to add 10mL of the dilute sulfuric acid solution prepared in step 1), After 10 minutes, 160 ml of the sodium nitrite solution prepared in step 1) were added dropwise simultaneously to control the dropping rate. The two solutions were dropped at the same time (4h), and the reaction was held at 55 to 65 C for 1 hour; (3) After the reaction is completed, it is cooled to 30 C, and the reaction solution (pH value 3.0-7.0) is extracted twice with ethyl acetate (50 mL) to obtain the aqueous phase (2-furanethylketone sodium salt) and ethyl acetate phase (unreacted raw materials and impurities); (4) The ethyl acetate phase was subjected to vacuum distillation (30 min, pressure -0.095 MPa) to recover 2 g of unreacted 2-acetylfuran; The aqueous phase was adjusted to pH 1 with a 30% dilute sulfuric acid solution, and then extracted 4 times with ethyl acetate (50 mL). The organic phases (ethyl acetate phase) were combined, 10 g of anhydrous sodium sulfate was added to the organic phase for drying, and concentrated to obtain crude 2-furanacetone acid. To the crude 2-furanacetone acid was added dichloromethane with twice the crude mass of 2-furanacetone acid and recrystallized to obtain 25g of 2-furanacetone acid in a yield of 78%; (5) Step (4) Extract the remaining water phase and adjust the pH value to 6-7 with 20% sodium hydroxide solution. A total of 430 g of solution was obtained, and then stored in a refrigerator at -10 C for 24 h, and a large number of white crystals precipitated. Low temperature (-10 ) suction filtration to obtain 120 g of solid sodium sulfate and 310 g of low saline with 3% salt content. The low brine was continuously distilled under reduced pressure for 60 minutes (pressure -0.095 MPa), 80 g of recycled water and about 200 g of recycled low brine were obtained, and the salt content of the recycled low brine was 5%. It is the same as Example 1, except that dilute sulfuric acid is configured using recovered water, sodium nitrite is configured using recovered low brine, and the reaction is performed under the same other conditions to obtain 26 g of 2-furanacetone acid with a yield of 82%; Crystallize to obtain 130 g of solid sodium sulphate and 320 g of low brine, 4% salt content of low brine, and low pressure distilled (60 min, pressure -0.095 MPa), 80 g of recycled water and about 305 g of recycled low brine were used, and the salt content of the recycled low brine was 6%.
(3,4-dimethoxyphenyl)acetic acid 4-furan-2-yl-6,7-dimethoxynaphthalen-2-yl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
Stage #1: (3,4-Dimethoxyphenyl)acetic acid With phosphoric acid; trifluoroacetic anhydride In acetonitrile at 25℃; for 0.5h;
Stage #2: 1-(2-furyl)-1-ethanone In acetonitrile at 25 - 80℃; for 20h;
Synthesis of 3a′, 3a-x and 3aa-ag; General Procedure
General procedure: Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoricacid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of oxygenatedarylacetic acids 1a-d (1.0 mmol) in MeCN (15 mL) at 25 °C. The reactionmixture was stirred at 25 °C for 30 min. Ketone 2a-x or 2aa-ad(0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at25 °C, and the reaction mixture was stirred at reflux (80 °C) for 20 h.The solvent of reaction mixture was concentrated, the residue was dilutedwith water (10 mL) and the mixture was extracted with CH2Cl2(3 × 20 mL). The combined organic layers were washed with brine,dried, filtered and evaporated to afford the crude product under reducedpressure. Purification on silica gel (hexanes/EtOAc = 10:1 to1:1) afforded compounds 3a′, 3a-x and 3aa-ag.
4-furan-2-yl-6,7-dimethoxynaphthalen-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: (3,4-Dimethoxyphenyl)acetic acid With phosphoric acid; trifluoroacetic anhydride In acetonitrile at 25℃; for 0.5h;
Stage #2: 1-(2-furyl)-1-ethanone In acetonitrile at 25 - 80℃;
Synthesis of 3h-1, 3k-1, 3o-1, 3v-1 and 3w-1; General Procedure
General procedure: Trifluoroacetic anhydride (TFAA, 230 mg, 1.1 mmol) and phosphoricacid (H3PO4, 110 mg, 1.1 mmol) were added to a solution of homoveratricacid (1a, 98 mg, 0.5 mmol) in MeCN (15 mL) at 25 °C. The reactionmixture was stirred at 25 °C for 30 min. Ketone 2h, 2k, 2o, 2v or2w (0.5 mmol) in MeCN (5 mL) was added to the reaction mixture at25 °C and the reaction mixture was stirred at reflux (80 °C) for 20 h.The solvent of reaction mixture was concentrated, the residue was dilutedwith water (10 mL) and the mixture was extracted with CH2Cl2(3 × 20 mL). The combined organic layers were washed with brine,dried, filtered and evaporated to afford crude product under reducedpressure. Purification on silica gel (hexanes/EtOAc = 10:1 to 1:1) affordedcompounds 3h-1, 3k-1, 3o-1, 3v-1 and 3w-1.
(E)-3-(1,3-diphenyl-1H-pyrazol-4-yl)-1-(furan-2-yl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With sodium hydroxide In ethanol; water at 20℃;
General procedure for the synthesis of(E)-3-[1-phenyl-3-(4-R-phenyl)-1H-pyrazol-4-yl]-1-[thio phen(or furan)-2-yl]prop-2-en-1-ones 6a-6d.
General procedure: Equimolar amounts of compound 4a or 4b and 2-acetylthiophene (5a) or 2-acetylfuran (5b) were added toa solution of sodium hydroxide (5 mol %) in a water-ethanol mixture (1:2, 30 mL). The mixture was stirredat room temperature for 1-2 h, and the solid productwas filtered off, and recrystallized from methanol.
1-(5-(7-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)furan-2-yl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With pyridine; palladium diacetate; silver carbonate In 1,4-dioxane at 100℃; Schlenk technique; regioselective reaction;
1-(5-(2-Phenylimidazo[1,2-a]pyridin-3-yl)thiophen-2-yl)ethan-1-one (S1a); Typical Procedure
General procedure: A 25 mL, dried Schlenk tube was charged with 2-phenylimidazo[1,2-a]pyridine (S1) (77.70 mg, 0.4 mmol), 1-(thiophen-2-yl)ethan-1-one(2a) (151.4 mg, 1.2 mmol, 3 equiv), Pd(OAc) 2 (8.980 mg, 0.04 mmol,10 mol%), Ag 2 CO 3 (165.5 mg, 0.6 mmol, 1.5 equiv), pyridine (31.64mg, 0.4 mmol, 1 equiv) and dioxane (1 mL). Then, the mixture wasstirred at 100 °C under air until the reaction was complete (monitoredby TLC). EtOAc (20 mL) and saturated aqueous NaCl (20 mL) were add-ed to the cooled reaction mixture, which was then filtered through asintered funnel. The aqueous layer was extracted with EtOAc (3 × 20mL). The combined organic layers were dried with Na 2 SO 4 and evaporated under vacuum to afford a residue. The residue was purified bycolumn chromatography (silica gel, petroleum ether/EtOAc) to obtainpure product S1a as a yellow solid; yield: 73%;
(2Z,4E)‑2‑cyano‑3,5‑bis(methylsulfanyl)‑5‑(2‑furyl)penta‑2,4‑dienoic acid amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With sodium hydroxide; In dimethyl sulfoxide; at 20℃;
General procedure: To a solution of 3,3-bis(methylsulfanyl)methylenemalononitrile 1 (1.70 g, 10 mmol) in 20 mL of DMSO, keton 2a - j (10 mmol) and powdered sodium hydroxide (0.8 20 mmol) were added, and the mixture was magnetically stirred for 4 - 5 h at room temperature. After addition of 300 mL of water to the mixture, the solution was stirred for 12 h at room temperature. The formed precipitate was collected by filtra- tion and washed several times with water. After drying under air, the formed product was recrystallized using methanol or ethanol to obtain the pure products.
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