* 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] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1989, vol. 28, # 1-11, p. 687 - 689
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1989, vol. 28, # 1-11, p. 687 - 689
[3] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1988, vol. 27, # 1-12, p. 916 - 919
2
[ 614-99-3 ]
[ 16867-03-1 ]
Reference：
[1] Patent: US4061644, 1977, A,
3
[ 614-99-3 ]
[ 3326-71-4 ]
Reference：
[1] Inorganic and Nano-Metal Chemistry, 2017, vol. 47, # 2, p. 288 - 293
[2] Heterocycles, 2014, vol. 88, # 1, p. 387 - 401
[3] Bulletin de la Societe Chimique de France, 1897, vol. <3> 17, p. 423
[4] Yakugaku Zasshi, 1955, vol. 75, p. 1066,1068[5] Chem.Abstr., 1956, p. 5616
[6] Phosphorus, Sulfur and Silicon and the Related Elements, 2006, vol. 181, # 9, p. 2079 - 2087
[7] Patent: US2006/178532, 2006, A1, . Location in patent: Page/Page column 8
[8] Patent: US2006/258740, 2006, A1, . Location in patent: Page/Page column 8-9
[9] Phosphorus, Sulfur and Silicon and the Related Elements, 2008, vol. 183, # 1, p. 136 - 143
[10] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 16, p. 7565 - 7572
[11] European Journal of Medicinal Chemistry, 2009, vol. 44, # 8, p. 3340 - 3344
[12] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2010, vol. 49, # 4, p. 526 - 531
[13] Journal of Medicinal Chemistry, 2010, vol. 53, # 20, p. 7392 - 7404
[14] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 22, p. 7836 - 7841
[15] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 2, p. 332 - 335
[16] Chinese Journal of Chemistry, 2011, vol. 29, # 10, p. 2153 - 2156
[17] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 5, p. 1505 - 1508
[18] Journal of Medicinal Chemistry, 2013, vol. 56, # 2, p. 437 - 450
[19] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 8, p. 2286 - 2297
[20] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 4, p. 945 - 948
[21] Medicinal Chemistry Research, 2014, vol. 23, # 4, p. 2080 - 2092
[22] Archives of Pharmacal Research, 2014, vol. 37, # 7, p. 852 - 861
[23] Journal of Fluorescence, 2016, vol. 26, # 1, p. 345 - 353
[24] Bioorganic Chemistry, 2016, vol. 65, p. 126 - 136
[25] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 19, p. 4661 - 4665
[26] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2017, vol. 174, p. 214 - 222
[27] Chinese Journal of Chemistry, 2017, vol. 35, # 9, p. 1437 - 144
[28] Chinese Chemical Letters, 2018, vol. 29, # 3, p. 441 - 446
[29] Patent: CN104892639, 2018, B, . Location in patent: Paragraph 0074
4
[ 614-99-3 ]
[ 16874-34-3 ]
Yield
Reaction Conditions
Operation in experiment
96.9%
With 5%-palladium/activated carbon; hydrogen In ethanol at 30 - 150℃; Large scale
10359] 3010 g (21.5 mol) of thran-2-carboxylic acid ethyl ester, 500 ml of ethanol (1percent MEK) and 20 g of catalyst, palladium on A-carbon dry, 5percent Pd, type K-0227T) are initially introduced together and heated under a hydrogen pressure of 20 bat The reaction starts at 30-40°C. and is relatively strongly exothermic. After 1-1.5 hat 60-70° C., the hydrogen absorption is as good as finished. The mixture is slowly heated to 140-150° C. and then stirred for a further 2-3 hat this temperature. GC control: starting material no longer present.10360] Filter off from the catalyst and concentrate the filtrate on a rotary evaporator (water bath: 60-70° C., 200-20 mbar). The crude yield is 3055 g.10361] The evaporated crude product is distilled with the addition of 0.1percent by weight of Na2CO3 over a short column (b.p.: 9 1-93° C./40 mbar).10362] Yield: 2999 g (96.9percent of theory)10363] ‘H NMR (400 MHz, chioroform-d) ö 4.44 (dd, J=8.4, 5.2 Hz, 1H), 4.20 (qd, J=7.1, 1.7 Hz, 2H), 4.05-3.98 (m, 1H), 3.95-3.88 (m, 1H), 2.30-2.19 (m, 1H), 2.06-1.85 (m, 3H), 1.29 (t, J=7.1 Hz, 3H)10364] ‘3C NMR (101 MHz, CDC13) ö 173.38, 76.80,69.33, 60.87, 30.20, 25.27, 14.24
Reference：
[1] Patent: US2015/376546, 2015, A1, . Location in patent: Paragraph 0359; 0360; 0361; 0362; 0363; 0364
[2] Journal of the American Chemical Society, 1923, vol. 45, p. 3041
[3] Journal of the American Chemical Society, 1949, vol. 71, p. 3622,3623
[4] Journal of the American Chemical Society, 1935, vol. 57, p. 2556,2557
[5] Bulletin de la Societe Chimique de France, 1941, vol. <5>8, p. 373,920[6] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1939, vol. 208, p. 587
[7] Annales de Chimie (Cachan, France), 1957, vol. <13>2, p. 682,700
5
[ 614-99-3 ]
[ 618-30-4 ]
Reference：
[1] American Chemical Journal, 1890, vol. 12, p. 38
6
[ 614-99-3 ]
[ 585-70-6 ]
[ 32460-04-1 ]
Reference：
[1] Gazzetta Chimica Italiana, 1884, vol. 14, p. 174
[2] Chemische Berichte, 1878, vol. 11, p. 842,1840[3] Gazzetta Chimica Italiana, 1878, vol. 8, p. 297
7
[ 50-00-0 ]
[ 614-99-3 ]
[ 2528-00-9 ]
Yield
Reaction Conditions
Operation in experiment
98%
With hydrogenchloride; zinc(II) chloride In dichloromethane at 35℃;
Example 1; Ethyl 5-chloromethylfuran-2-carboxylate; To a solution of 100 g (0.71 M) of ethyl 2-furoate in 250 ml of 5 dichloromethane are added 30.6 g (1.02 M) of paraformaldehyde and 25.4 g(0.19 M) of zinc chloride. Gaseous hydrogen chloride is passed into the reaction medium. An exothermic reaction is observed, and the temperature reaches350C. The evolution of gas is maintained up to the end of the reaction, which is monitored by thin-layer chromatography (TLC). The product obtained is then o purified by chromatography on silica using dichloromethane as eluent, to give134.6 g of ethyl 5-chloromethylfuran-2-carboxylate in the form of a colourless oil. EPO <DP n="28"/>Yield: 98percent.1H NMR (200 MHz/DMSO-d6) δ (ppm): 1.28 (t, 3H); 4.27 (d, 2H); 4.51 (s, 2H);6.39 (d, 1 H); 7.02 (d, 1 H).
Reference：
[1] Patent: WO2007/14619, 2007, A1, . Location in patent: Page/Page column 26-27
[2] Synlett, 2009, # 20, p. 3349 - 3351
[3] Journal of Organic Chemistry USSR (English Translation), 1988, vol. 24, p. 1681 - 1685[4] Zhurnal Organicheskoi Khimii, 1988, vol. 24, # 9, p. 1864 - 1869
[5] Journal of Medicinal Chemistry, 1986, vol. 29, # 11, p. 2154 - 2163
8
[ 614-99-3 ]
[ 2528-00-9 ]
Reference：
[1] Annali di Chimica (Rome, Italy), 1950, vol. 40, p. 30,32
[2] Technology Reports of the Osaka University, 1958, vol. 8, p. 475,476
[3] Doklady Akademii Nauk Armyanskoi SSR, 1953, vol. 17, p. 97,101, 103
[4] Justus Liebigs Annalen der Chemie, 1953, vol. 580, p. 169,187
[5] DRP/DRBP Org.Chem.,
[6] Patent: DE830050, 1951, ,
General procedure: A mixture of acid (0.2 mmol), alcohol (0.6 mmol) and GO (50 wt%, calculated with the mass of acid) in ethyl alcohol or DCE (1 mL) was placed in a test tube equipped with a magnetic stirring bar. The mixture was stirred at 100 C for 24 h. After the reaction was finished, filtered the GO, solvent was removed, and the residue was separated by column chromatography to give the pure sample.
88%
toluene-4-sulfonic acid; In toluene; at 20℃; for 5h;Reflux;
Toluene (100 ml), ethanol (12.33 g, 267.67 mmol) and 2-furancarboxylic acid (25 g, 223.05 mmol) were added into a 200-ml flask in this order at room temperature and then p-toluenesulfonic acid monohydrate (6.65 g, 34.96 mmol) was charged thereto. The solution was gently heated and subjected to reflux dehydration for 3 to 5 hours. After reflux dehydration, the solution was cooled to around room temperature, added with triethylamine (5.64 g, 55.76 mmol) at room temperature, stirred and then added with silica gel. After stirring for a while, the silica gel was filtered off. After the solvent of the filtrate was removed in vacuum distillation, ethyl 2-furancarboxylate (27.60 g, 88%) was isolated in distillation.
80%
With sulfuric acid;Reflux;
Furan-2-carboxylic acid (5 g, 44.6 mmol) was dissolved in ethanol (100 mL), c.H2S04 (1.0 mL) was added and the solution heated to reflux overnight. The reaction mixture was concentrated in vacuo then partitioned between ethyl acetate (100 mL) and saturated NaHC03 (100 mL). The organic phase was washed using water then brine, dried (MgS04) and concentrated in vacuo to give ethyl furan-2-carboxylate (4.5 g, 80%). 1H NMR (400 MHz, CDCI3): delta = 7.57 (d, J = 1 .2 Hz, 1 H), 7.18 (d, J = 3.5 Hz, 1 H), 6.51 (dd, J = 3.5, 1 .2 Hz, 1 H), 4.37 (q, J = 7.1 Hz, 2H), 1 .38 (t, J = 7.1 Hz, 3H).
With thionyl chloride; for 2h;Reflux;
General procedure: To a stirred solution of carboxylic acid (1.0 eq.) in ethanol (2 M) was added thionyl chloride (2.0 eq.) dropwise at room temperature, and then refluxed for 2 hours. After it was cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give crude product, which was chromatographed on silica gel column using 1:30 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product esters in 80% - 95% yields. Esters (1.0 eq.) were added dropwise to a stirred solution of acetonitrile (2.0 eq.) and NaH (3.0 eq.) in THF (2 M) at room temperature, and then refluxed for 1h . After it was cooled to room temperature, Water was added dropwise to the reaction mixture under ice bath until no gas bubbles generated, and employing dilute hydrochloric acid neutralization to neutral, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:4 to 1:2 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product beta-ketonitriles, white or light yellow solid compounds in 50% - 85% yields. Finally, stirred in concentrated sulfuric acid (3 M) at room temperature for 5 to 10 hours. The reaction mixture was neutralized to neutral by ammonia water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:1 to 2:1 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product beta-ketoamides 1a-p, white solid compounds in 45% - 85% yields.
420 mg
With sulfuric acid; at 100℃; for 48h;
To a stirred solution of furan-2- carboxylic acid (500 mg) in Ethanol (30 ml) was added Cone H SO (1 ml) drop wise and refluxed for 2 days AT 100 degree Celsius. Reaction was monitored by NMR. The reaction mixture was concentrated under vacuum to obtain crude was diluted with Saturated Sodium Bicarbonate Solution and Extracted with DCM (3 X 150 ml), organic layer dried over anahydrous sodium sulphate, Concentrated under reduced pressure to obtain ethyl pyrazine- 2-carboxylate (420 mg). XH NMR (400 MHz, DMSO-ri6) d 7.88 - 8.04 (m, 1H), 7.29 (d, J = 3.42 Hz, 1H), 6.63 - 6.72 (m, 1H), 4.27 (q, J= 7.17 Hz, 2H), 1.28 (t, J= 7.09 Hz, 3H).
With sodium hydride; In tetrahydrofuran; mineral oil; at 80℃; for 1h;
Step 1: Preparation of 3-(2-furyl)-3-oxo-propanenitrile To a stirred solution of acetonitrile (7.51 mL, 1423 mmol) and sodium hydride (8.56 g, 214 mmol, 60% in mineral oil) in tetrahydrofuran (100 mL) at 20 C. was added ethyl furan-2-carboxylate (10.0 g, 71.4 mmol) dropwise. The reaction mixture was heated to 80 C. for 1 h. The mixture was cooled to 0 C. and water (40 mL) was added until no bubbles were being generated and then neutralized to pH=7 with aqueous 4 M hydrogen chloride. The aqueous layer was extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO, 40 g silica, 0-30% ethyl acetate in petroleum ether, gradient over 20 min) to give 3-(2-furyl)-3-oxo-propanenitrile (7.5 g, 55.5 mmol, 78%) as a yellow solid. 1H NMR (400 MHz, Chloroform-d) delta 7.68 (d, J=1.1 Hz, 1H), 7.40 (d, J=3.5 Hz, 1H), 6.66 (dd, J=1.7, 3.7 Hz, 1H), 3.99 (s, 2H).
With sodium hydride; In tetrahydrofuran; for 1h;Reflux;
General procedure: To a stirred solution of carboxylic acid (1.0 eq.) in ethanol (2 M) was added thionyl chloride (2.0 eq.) dropwise at room temperature, and then refluxed for 2 hours. After it was cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give crude product, which was chromatographed on silica gel column using 1:30 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product esters in 80% - 95% yields. Esters (1.0 eq.) were added dropwise to a stirred solution of acetonitrile (2.0 eq.) and NaH (3.0 eq.) in THF (2 M) at room temperature, and then refluxed for 1h . After it was cooled to room temperature, Water was added dropwise to the reaction mixture under ice bath until no gas bubbles generated, and employing dilute hydrochloric acid neutralization to neutral, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:4 to 1:2 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product beta-ketonitriles, white or light yellow solid compounds in 50% - 85% yields. Finally, stirred in concentrated sulfuric acid (3 M) at room temperature for 5 to 10 hours. The reaction mixture was neutralized to neutral by ammonia water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:1 to 2:1 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product beta-ketoamides 1a-p, white solid compounds in 45% - 85% yields.
With ammonia In ethylene glycol at 48 - 49℃; for 12h;
9
2-Furancarboxamide Starting Materials Ethyl-2-Furancarboxylate 0.5 mol Ammonia (gas) Excess, bubbled through system Ethylene glycol 150 g. Operating Conditions Pressure Atmospheric Temperature/time regime 48-49° C./12 h. Work-up One liter of water was added, pH was adjusted to 6.5-7.0 with 10% aqueous HCl, the aqueous solution was extracted with chloroform (5 × 100 mL), the organic phase was separated and the chloroform eliminated by distillation at atmospheric pressure leaving 15 g. of a cream-colored residue, m.p. 141.8-142.7° C. The aqueous mother liquor was concentrated to 600 mL by evaporation, saturated with sodium chloride, extracted with chloroform (5 × 100 mL) and the extract treated as above, yielding another crop of cream-colored crystals. (15 g, m.p. 141.7-142.8° C.) Yield 51%
45%
With ammonia; calcium chloride In methanol at 80℃; for 24h; Inert atmosphere;
With 5%-palladium/activated carbon; hydrogen; In ethanol; at 30 - 150℃; under 15001.5 Torr;Large scale;
10359] 3010 g (21.5 mol) of thran-2-carboxylic acid ethyl ester, 500 ml of ethanol (1% MEK) and 20 g of catalyst, palladium on A-carbon dry, 5% Pd, type K-0227T) are initially introduced together and heated under a hydrogen pressure of 20 bat The reaction starts at 30-40C. and is relatively strongly exothermic. After 1-1.5 hat 60-70 C., the hydrogen absorption is as good as finished. The mixture is slowly heated to 140-150 C. and then stirred for a further 2-3 hat this temperature. GC control: starting material no longer present.10360] Filter off from the catalyst and concentrate the filtrate on a rotary evaporator (water bath: 60-70 C., 200-20 mbar). The crude yield is 3055 g.10361] The evaporated crude product is distilled with the addition of 0.1% by weight of Na2CO3 over a short column (b.p.: 9 1-93 C./40 mbar).10362] Yield: 2999 g (96.9% of theory)10363] ?H NMR (400 MHz, chioroform-d) oe 4.44 (dd, J=8.4, 5.2 Hz, 1H), 4.20 (qd, J=7.1, 1.7 Hz, 2H), 4.05-3.98 (m, 1H), 3.95-3.88 (m, 1H), 2.30-2.19 (m, 1H), 2.06-1.85 (m, 3H), 1.29 (t, J=7.1 Hz, 3H)10364] ?3C NMR (101 MHz, CDC13) oe 173.38, 76.80,69.33, 60.87, 30.20, 25.27, 14.24
With hydrogenchloride; zinc(II) chloride; In dichloromethane; at 35℃;
Example 1; Ethyl 5-chloromethylfuran-2-carboxylate; To a solution of 100 g (0.71 M) of ethyl 2-furoate in 250 ml of 5 dichloromethane are added 30.6 g (1.02 M) of paraformaldehyde and 25.4 g(0.19 M) of zinc chloride. Gaseous hydrogen chloride is passed into the reaction medium. An exothermic reaction is observed, and the temperature reaches350C. The evolution of gas is maintained up to the end of the reaction, which is monitored by thin-layer chromatography (TLC). The product obtained is then o purified by chromatography on silica using dichloromethane as eluent, to give134.6 g of ethyl 5-chloromethylfuran-2-carboxylate in the form of a colourless oil. EPO <DP n="28"/>Yield: 98%.1H NMR (200 MHz/DMSO-d6) delta (ppm): 1.28 (t, 3H); 4.27 (d, 2H); 4.51 (s, 2H);6.39 (d, 1 H); 7.02 (d, 1 H).
With C30H34Cl2N2P2Ru; potassium methanolate; hydrogen; In tetrahydrofuran; at 100℃; under 38002.6 - 76005.1 Torr; for 5h;Glovebox; Autoclave;
General procedure: In a glove box, add a ruthenium complex Ia (0.3 to 0.7 mg, 0.0002 to 0.001 mmol) to a 300 mL autoclave,Potassium methoxide (35-700 mg, 0.5-10 mmol), tetrahydrofuran (4-60 mL), and ester compounds (10-200 mmol).After sealing the autoclave, take it out of the glove box and fill it with 50 100atm of hydrogen.The reaction kettle was heated and stirred in an oil bath at 100 C for 10 to 336 hours.After the reaction kettle was cooled in an ice-water bath for 1.5 hours, the excess hydrogen was slowly released.The solvent was removed from the reaction solution under reduced pressure, and the residue was purified with a short silica gel column to obtain an alcohol compound. The results are shown in Table 5.
With manganese(IV) oxide; caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; 1-butyl-3-methylimidazolium Tetrafluoroborate; at 20℃; for 24h;Inert atmosphere;
General procedure: In a typical procedure, a capped vessel was charged with ionic liquid BmimBF4 (0.5 mL) and put under positive pressure of nitrogen. DBU (0.5 mmol) and Cs2CO3 (1.5 mmol) were added followed by the aldehyde (0.5 mmol) and MnO2 (1.5 mmol). The reaction mixture was stirred for a few minutes and alcohol (1.5 mmol) was added. The reaction mixture was stirred at ambient temperature for 24 h. The mixture was then filtered through a thin pad of silica, which was washed with ethyl acetate (30 mL). The filtrate was analyzed by TLC and 1H NMR and then concentrated under vacuum. The resulting residue was purified by flash chromatography on silica gel where needed.
41.8%Chromat.
With oxone||potassium monopersulfate triple salt; at 20℃; for 20h;Green chemistry;
1.44 mmol of furfural, 100 mmol of ethanol and 0.30 g of Oxone were placed in a 50 mL round bottom flask, and the reaction was stirred at room temperature for 20 h. After the completion of the reaction, water was added to the reaction system to dissolve the oxidizing agent Oxone, followed by liquid-liquid separation, and a liquid phase product containing ethyl furoate was taken for detection. After gas chromatography analysis, the yield of ethyl furoate was 41.8%.
With lithium hexamethyldisilazane; In tetrahydrofuran; at 0℃; for 3h;
To a solution of 4-picoline (4.6 g, 49.4 mmol) and <strong>[614-99-3]ethyl 2-furancarboxylate</strong> (7.7 g, 54.9 mmol) in tetrahydrofuran (40 ml) was dropwise added lithium bis(trimethylsilyl)amide (100 ml, 100 mmol) over 1 hour at 0C under an atmosphere of nitrogen gas, followed by stirring as it was for 2 hours. Hexane (140 ml) was added to the reaction mixture, and the resulting crystals were collected by filtration. The resulting crystals were dissolved in ethyl acetate and a saturated aqueous ammonium chloride solution. The organic layer was washed with a saturated aqueous ammonium chloride solution twice and brine, dried over anhydrous sodium sulfate and concentrated. Hexane was added to the residue, and the resulting precipitates were collected by filtration and washed with hexane, to give the title compound (6.5 g, 70 %) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) delta ppm; 4.26 (2H, s), 6.77 (1H, dd, J = 2.0, 3.6 Hz), 7.31 (2H, dd, J = 1.6, 4.4 Hz), 7.65 (1H, dd, J = 0.8, 3.6 Hz), 8.05 (1H, dd, J = 0.8, 2.0 Hz), 8.51 (2H, dd, J = 1.6, 4.4 Hz).
70%
With lithium hexamethyldisilazane; In tetrahydrofuran; hexane; ethyl acetate;
Reference Example 2 1-(2-Furyl)-2-(4-pyridyl)-1-ethanone Lithium bis(trimethylsilyl)amide (100 mL, 100 mmol) was added dropwise over 1 hour to a solution of 4-picoline (4.6 g, 49.4 mmol) and <strong>[614-99-3]ethyl 2-furancarboxylate</strong> (7.7 g, 54.9 mmol) in tetrahydrofuran (40 mL) at 0 C. in a nitrogen atmosphere, followed by stirring as such for 2 hours. Hexane (140 mL) was added to the reaction solution, and the resulting crystals were collected by filtration. The resulting crystals were dissolved in ethyl acetate and an aqueous saturated ammonium chloride solution. The organic layer was washed with an aqueous saturated ammonium chloride solution (*2) and brine, dried over anhydrous sodium sulfate, and concentrated. Hexane was added to the residue, and the resulting precipitates were collected by filtration and washed with hexane, to give the title compound (6.5 g, 70%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) delta ppm; 4.26 (2H, s), 6.77 (1H, dd, J=2.0, 3.6 Hz), 7.31 (2H, dd, J=1.6, 4.4 Hz), 7.65 (1H, dd, J=0.8, 3.6 Hz), 8.05 (1H, dd, J=0.8, 2.0 Hz), 8.51 (2H, dd, J=1.6, 4.4 Hz).
70%
With ammonium chloride; lithium hexamethyldisilazane; In tetrahydrofuran; hexane; ethyl acetate;
Reference Example 1 1-(2-Furyl)-2-(4-pyridyl)-1-ethanone In a nitrogen atmosphere, lithium bis(trimethylsilyl)amide (100 mL, 100 mmol) was added dropwise into a solution of 4-picoline (4.6 g, 49.4 mmol) and <strong>[614-99-3]ethyl 2-furancarboxylate</strong> (7.7 g, 54.9 mmol) in tetrahydrofuran (40 mL) at 0C over 1 hour, followed by stirring as it was for 2 hours. Hexane (140 mL) was added to the reaction solution, and the resulting crystals were collected by filtration. The resulting crystals were dissolved in ethyl acetate and an aqueous saturated solution of ammonium chloride. The organic layer was washed with an aqueous saturated solution of ammonium chloride (*2) and brine, dried over anhydrous sodium sulfate,and concentrated. Hexane was added to the residue, and the resulting precipitates were collected by filtration and washed with hexane, to give the title compound (6.5 g, 70%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) delta ppm; 4. 26 (2H, s), 6. 77 (1H, dd, J= 2. 0, 3. 6 Hz), 7. 31 (2H, dd, J= 1. 6, 4. 4 Hz), 7. 65 (1H, dd, J= 0. 8, 3. 6 Hz), 8. 05 (1H, dd, J= 0. 8, 2. 0 Hz), 8. 51 (2H, dd, J= 1. 6, 4. 4 Hz).
70%
With lithium hexamethyldisilazane; In tetrahydrofuran; at 0℃; for 3h;
Reference Example 1 1-(2-Furyl)-2-(4-pyridyl)-1-ethanone In a nitrogen atmosphere, lithium bis (trimethylsilyl) amide (100 mL, 100 mmol) was added dropwise into a solution of 4-picoline (4.6 g, 49.4 mmol) and <strong>[614-99-3]ethyl 2-furancarboxylate</strong> (7.7 g, 54.9 mmol) in tetrahydrofuran (40 mL) at 0 C. over 1 hour, followed by stirring as it was for 2 hours. Hexane (140 mL) was added to the reaction solution, and the resulting crystals were collected by filtration. The resulting crystals were dissolved in ethyl acetate and an aqueous saturated solution of ammonium chloride. The organic layer was washed with an aqueous saturated solution of ammonium chloride (*2) and brine, dried over anhydrous sodium sulfate, and concentrated. Hexane was added to the residue, and the resulting precipitates were collected by filtration and washed with hexane, to give the title compound (6.5 g, 70%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) delta ppm; 4.26 (2H, s), 6.77 (1H, dd, J=2.0, 3.6 Hz), 7.31 (2H, dd, J=1.6, 4.4 Hz), 7.65 (1H, dd, J=0.8, 3.6 Hz), 8.05 (1H, dd, J=0.8, 2.0 Hz), 8.51 (2H, dd, J=1.6, 4.4 Hz).
With lithium hexamethyldisilazane; In tetrahydrofuran; hexane; at 20℃; for 3h;
Lithium bis (trimethylsilyl)amide M in hexanes, 50 mL) was added dropwise over 60 minutes to a solution of 4-methylpyrimidine (2.33 g, 24.8 mmol) and ethyl 2-furoate (3.85 g, 27.4 mmol) in tetrahydrofuran (20 mL) under an atmosphere of nitrogen. The mixture was stirred at ambient temperature for two hours then hexane (200 mL) was added and the precipitate was filtered. The solid was treated with saturated aqueous ammonium chloride solution, filtered and washed with water and dried in vacuo to give the title compound (8.62 g, 93%) as a yellow solid. # 1H NMR (DMSO) showed a mixture of enol and keto tautomers : Keto tautomer: 4.39 (s, 2H), 6.75 (dd, 1 H), 7.08 (m, 1 H), 7.53 (dd, 1 H), 7.61 (d, 1H), 8.04 (dd, 1 H), 9.08 (d, 1H). Enol. tautomer: 5.99 (s, 1H), 6.64 (dd, 1H), 7.04. (d, 1H), 7.85 (dd, 1H), 8.15 (d, 1 H), 8.61 (s, 1 H), 8.74 (d, 1 H). ESI/MS (m/e, %) : 189 [(M+1) +, 100].
85%
With lithium hexamethyldisilazane; In tetrahydrofuran; hexanes; at 0 - 20℃; for 3h;
To a solution of 4-methylpyrimidine (0.93 g, 9.9 mmol) and ethyl 2-furoate (1.54 g, 11 mmol) in anhydrous THF (8 mL) at 0C, under Ar, was added dropwise via syringe pump (1 hour) a solution of lithium bis (trimethylsilyl) amide (1 M solution in hexanes, 20 mL). The resulting mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with a saturated aqueous solution of ammonium chloride and water, then dried under vacuum to yield the title compound as a yellow solid (1.59g, 85%). ESI/MS m/e: 189 ( [M+H] +, ClOH8N202)
With Na(1+)*C12H27AlNO5(1-); In tetrahydrofuran; toluene; at 0 - 20℃; for 0.5h;
General procedure: The following experimental procedure for the partial reduction of ethyl benzoate to benzaldehyde is representative. A dry and argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with ethyl benzoate (0.07 mL, 0.5 mmol) and THF (5 mL). After cooling to 0 C, cis-2,6-dimethylmorpholine-modified Red-Al (2.5 mL, 0.4 M 1.0 mmol) was added dropwise and the mixture was stirred for 30 min at the room temperature. The reaction was stopped aqueous 1 N HCl (5 mL) and the product was extracted with diethyl ether (10 mL). The ether layer was dried over anhydrous magnesium sulfate. GC analysis showed a 98% yield of benzaldehyde. All products in Table 1 were confirmed through comparison with GC data of authentic sample.
With lithium hexamethyldisilazane; In tetrahydrofuran; hexane; at 20℃;
Lithium bis (trimethylsilyl)amide M in hexanes, 100 mL, 100 mmol) was added dropwise over 60 minutes to a solution of 4-methyl-2- (methylthio)pyrimidine g, 50.0 mmol) and ethyl 2-furoate (7.70 g, 55.0 mmol) in tetrahydrofuran (22 mL) under an atmosphere of nitrogen. The mixture was stirred at ambient temperature overnight then hexane (200 mL) was added and the precipitate was filtered. The solid was treated with saturated aqueous ammonium chloride solution, filtered and washed with water and dried. Purification by flash chromatography (8: 2 ethyl acetate/hexanes to 5: 1 ethyl acetate/hexanes) gave the title compound (10.32 g, 88%) as a yellow solid. # 1H NMR (DMSO) showed a mixture of enol and keto tautomers: Keto tautomer: 2.42 (s, 3H), 4.35 (s, 2H), 6.75 (dd, 1 H), 7.22 (d, 1 H), 7.60 (dd, 1 H), 8.05 (d, 1 H), 8.60 (d, 1 H). Enol tautomer: 2.42 (s, 3H), 6.18 (s, 1 H), 6.70 (dd, 1 H), 7.05 (m, 2H), 7.90 (d, 1 H), 8.45 (d, 1H). ESI/MS (m/e, %) : 235 [(M+1) +, 100].
2.50 g (17.66 mmol) furan-2-carbocylic ethylester and 0.52 ml (1.77 mmol) titanium tetra-isopropyloxide are placed in 56 ml diethyl ether, 12.48 ml (37.44 mmol) ethylmagnesium bromide (Grignard reagent in tetrahydrofuran) in 28 ml diethyl ether are added dropwise within 1 hour, while the temperature should not rise above 20 C. The reaction mixture is stirred for 1.5 hours, then hydrolyzed with 180 ml 10% sulphuric acid. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried and evaporated to dryness. The residue is purified by chromatography. Yield: 0.650 g (30% of theoretical)
5,6-Dichloro-3-(2-furoyl)-4-azaoxindole-1-N-t-butyl carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.98 g (88%)
With sodium; In ethanol;
EXAMPLE 51 5,6-Dichloro-3-(2-furoyl)-4-azaoxindole-1-N-t-butyl carboxamide 5,6-Dichloro-3-(2-furoyl)-4-azaoxindole was first prepared according to the procedure of Example 1B, using <strong>[136888-26-1]5,6-dichloro-4-azaoxindole</strong> (763 mg, 3.76 mmol), sodium (0.43 g, 18.8 mmol), ethyl-2-furoate (1.05 g, 7.5 mmol) and ethanol (25 mL). Yield: 0.98 g (88%). The title compound was prepared from 5,6-dichloro-3-(2-furoyl)-4-azaoxindole according to the procedure of Example 1C, using 5,6-dichloro-3-(2-furoyl)-4-azaoxindole (721 mg, 2.43 mmol), triethylamine (1.8 mL, 15.4 mmol), t-butyl isocyanate (1.4 mL, 12.3 mmol) and DMSO (20 mL). The reaction time was 22 hours. The crude product was triturated with methanol and recrystallized from hexane. Yield: 218 mg (23%). Analysis calc'd for C17 H15 Cl2 N3 O4: C 51.53, H 3.82, N 10.60. Found: C 51.70, H 3.81, N 10.57. M.p. 205-206 C. 1 H NMR (DMSO-d6) delta9.37 (br s, 1H), 8.32 (s, 1H), 7.91 (s, 1H), 7.85 (d, J=3.7 Hz, 1H), 6.69 (d, J=3.7 Hz, 1H), 1.38 (s, 9H). IR (KBr disc) 1730, 1620, 1605, 1590, 1555, 1535 cm-1. MS m/e (relative percent) 397(0.5), 395(2), 298(21), 296(33), 230(62), 228(100), 95(40).
0.98 g (88%)
With sodium; In ethanol;
Example 51 5,6-Dichloro-3-(2-furoyl)-4-azaoxindole-1-N-t-butyl carboxamide 5,6-Dichloro-3-(2-furoyl)-4-azaoxindole was first prepared according to the procedure of Example 1B, using <strong>[136888-26-1]5,6-dichloro-4-azaoxindole</strong> (763 mg, 3.76 mmol), sodium (0.43 g, 18.8 mmol), ethyl-2-furoate (1.05 g, 7.5 mmol) and ethanol (25 mL). Yield: 0.98 g (88%). The title compound was prepared from 5,6-dichloro-3-(2-furoyl)-4-azaoxindole according to the procedure of Example 1C, using 5,6-dichloro-3-(2-furoyl)-4-azaoxindole (721 mg, 2.41 mmol), triethylamine (1.8 mL, 15.4 mmol), t-butyl isocyanate (1.4 mL, 12.3 mmol) and DMSO (20 mL). The reaction time was 22 hours. The crude product was triturated with methanol and recrystallized from hexane. Yield: 218 mg (23%). Analysis calc'd for C17H15Cl2N3O4: C 51.53, H 3.82, N 10.60. Found: C 51.70, H 3.81, N 10.57. M.p. 205 - 206C. 1H NMR (DMSO-d6) delta 9.37 (br s, 1H), 8.32 (s, 1H), 7.91 (s, 1H), 7.85 (d, J = 3.7 Hz, 1H), 6.69 (d, J = 3.7 Hz, 1H), 1.38 (s, 9H). IR (KBr disc) 1730, 1620, 1605, 1590, 1555, 1535 cmmin1. MS m/e (relative percent) 397(0.5), 395(2), 298(21), 296(33), 230(62), 228(100), 95(40).
To an ice cold suspension of 0.92 g (23 mmol) of sodium hydride (NaH 60% dispersion in mineral oil) (previously washed with hexane and dried under vacuum) in 25 mL of 1,2- dimethoxyethane (DME) was added 0.9 g (5.76 mmol) of [METHYL CYCLOHEXYLACETATE,] and the resulting mixture was stirred at [0 C] for 20 min. Then 1.2 g (8.56 mmol) [OF ETHYL 2-FUROATE] was added, and the reaction mixture was heated at reflux overnight. The mixture was then cooled to [0C,] quenched by the addition of 1 M [HC1] solution to pH=3, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to give a brown oil which was chromatographed on silica gel [(BIOTAGE ;] 10% hexane in dichloromethane) to afford 1.1 g (76% yield) of desired 2-cyclohexyl-3-furan-2-yl-3- [OXO-PROPIONIC ACID METHYL ESTER] as indicated by 1H NMR. A mixture of 1.1 g (4.4 mmol) [OF 2-CYCLOHEXYL-3-FURAN-2-YL-3-OXO-P7 OPIONIC ACID] [METHYL ESTER,] 0.592 g (4.2 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester, 76 mg (0.4 mmol, 10 mol%) of p-toluenesulfonic acid monohydrate (PTSA), and 50 mL of chlorobenzene was heated at 120 [C] overnight. The reaction mixture was then concentrated to a residue which was chromatographed on silica gel (7% methanol in dichloromethane) to afford 0.46 g (32% yield) of desired 6-cyclohexyl-5-furan-2-yl-7-oxo-4,7-dihydro- pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as indicated [BY IH] NMR; LC-MS- calcd for [C18HL9N304] [[M++H] +] : 342.14, found: 342.3. Conversion of 6-cyclohexyl-5-furan-2-yl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine- 2-carboxylic acid methyl ester to 6-cyclohexyl-5-furan-2-yl-7-oxo-4,7-dihydro-pyrazolo[1,5- [AJPYYIMIDINE-2-CARBOXYLIC ACID] (595) was accomplished via the well known LiOH saponification protocol where the yield was 77%. [LC-MS-CALCD] for [CI7HI7N304] [M++H]+: 328.13, found : 328. 1. 1H NMR [(DMSO-D6)] [8] 8.06-8. 05 (d, J= 2 Hz, 1H), 6.99-6. 98 (d, J= 3.6 Hz, 1H), 6.80-6. 78 (d [OF D,] J= 3.6 Hz, J= 2 Hz, [1H),] 6.39 (s, [1H),] 2.79-2. 71 [(M,] 1H), 2.25-2. 16 [(M,] 2H), 1.77-1. 75 [(M,] [2H),] 1.66-1. 65 [(M,] 1H), 1.59-1. 55 [(M,] 2H), 1.25-1. 20 [(M,] 3H). Note that the same synthetic scheme was carried out for [3-FLUORO-BENZOIC ACID METHYL] ester as depicted above to afford [6-CYCLOHEXYL-5-(3-FLUORO-PHENYL)-7-OXO-4, 7-DISLYDRO-] pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (598); the cyclization yield was slightly improved (54%).
General procedure: To a solution of ethyl benzoate (0.14 g, 1.0 mmol) in THF (10 mL) was slowly added LDBBA (2.4 mL, 0.5 M in THF-hexane, 1.2 mmol) and the mixture was stirring for 3 h at 0 C. To this was slowly added n-butylmagnesium chloride (0.94 mL, 1.6 M in Et2O, 1.5 mmol). After being stirred for 30 min at room temperature, the reaction mixture was quenched with aqueous 1 N HCl (10 mL) and extracted with diethyl ether (2 × 10 mL). The combined organic layers were dried over MgSO4 and filtered. After the removal of solvents in vacuo, purification of the residue by column chromatography on silica gel gave 1-phenylpentan-1-ol (108 mg, 66%). All products in this Letter were confirmed by comparison with data reported in the literatures.5
General procedure: Under Ar atmosphere in a dry Schlenk tube, a mixture of NaH (6.0 mmol) and trifluoroacetate (6.0 mmol) was stirred in THF (5 mL) at room temperature for 10 min. To this mixture enolizable ketones (5.0 mmol) in THF (5 mL) was added dropwise at 0 C under Ar atmosphere. After stirring for 2-6 h at reaction temperature, the reaction solution was cooled to 0 C again and quenched with 6 mL of 1 mol/L HCl. After stirring for additional 15 min, the mixture was neutralized with saturated NaHCO3 solution. After usual workup, the residue was purified by chromatography on silica gel to afford the trifluoromethyl alkyl ketone products.
General procedure: Under Ar atmosphere in a dry Schlenk tube, a mixture of NaH (6.0 mmol) and trifluoroacetate (6.0 mmol) was stirred in THF (5 mL) at room temperature for 10 min. To this mixture enolizable ketones (5.0 mmol) in THF (5 mL) was added dropwise at 0 C under Ar atmosphere. After stirring for 2-6 h at reaction temperature, the reaction solution was cooled to 0 C again and quenched with 6 mL of 1 mol/L HCl. After stirring for additional 15 min, the mixture was neutralized with saturated NaHCO3 solution. After usual workup, the residue was purified by chromatography on silica gel to afford the trifluoromethyl alkyl ketone products.
General procedure: The following experimental procedure for the synthesis of morpholino(phenyl)-methanone is representative. A dry and argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with morpholine (0.18 mL, 2.1 mmol) and 10 mL THF. After cooling to 0 C, DIBALH (2.0 mL, 1.0 M in hexane, 2.0 mmol) was added dropwise and stirred for 3 h at same temperature. To a reaction mixture was slowly added ethyl benzoate (0.14 g, 1.0 mmol) and stirred for 10 min. The reaction was stopped by the aqueous 1 N HCl (10 mL) and extracted with diethyl ether (2*10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel yielded morpholino(phenyl)methanone (184 mg, 96%).
General procedure: The following experimental procedure for the synthesis of 1-phenylpentanone is representative. A dry and argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with morpholine (0.18mL, 2.1mmol) and 10mL THF. After cooling to 0C, DIBALH (2.0mL, 1.0M in hexane, 2.0mmol) was added dropwise and stirred for 3h at same temperature. To a reaction mixture was slowly added ethyl benzoate (0.14g, 1.0mmol) and stirred for 10min. Then, n-BuLi (1.25mL, 1.6M in hexane, 2.0mmol) was added and the mixture was stirred for 10min again. The reaction was stopped by the aqueous 1N HCl (10mL) and extracted with diethyl ether (2×10mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel yielded 1-phenylpentanone (150mg, 92%).
With hydrogenchloride; zinc(II) chloride; In chloroform; at 25 - 30℃; for 5h;
3.9 g of zinc chloride was added to a solution of 16.0 mL of paraldehyde and 16.9 g of ethyl 2-furoate in 36 mL of chloroform. Hydrogen chloride was passed through the mixture during 5 h at 25-30C under vigorous stirring. Then, 50 mL of chloroform was added; the reaction mixture was washed with water (2 30 mL) and dried over calcium chloride. Solvent was removed under reduced pressure, and the residue was distilled in vacuum to give 10.0 g (41%) of the target product with bp 91C (1 mmHg). 1 NMR spectrum (CDCl3), delta, ppm: 1.33 t (3, 3-ethyl, JHH 7.0 Hz), 1.18 d (3, 3-chloroethyl, JHH 7.2 Hz), 4.32 q (2, 2, JHH 7.0 Hz), 5.09 q (1, l, JHH 7.2 Hz), 6.41 d (1, 4-furan, JHH 3.6 Hz), 7.07 d (1, 3-furan, JHH 3.6 Hz).
With sodium cyanide; In N,N-dimethyl-formamide; at 50℃; for 24h;Molecular sieve;
General procedure: Aldehyde 1 (1.0 mmol; 1.0 equiv.) and 4 A molecular sieves (300 mg) were added to a mixture of DMF (3.0 mL) and an appropriate alcohol (or a thiol) (3.0 mL). To the above solution was added sodium cyanide (1.5 mmol; 1.5 equiv). The reaction mixture was stirred in an open flask at 50 C and monitored by TLC. After the complete consumption of 1, the mixture was poured into water (25 mL) and extracted with diethyl ether (5 × 10 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude mixture was further purified by column chromatography on silica gel using ethyl acetate/hexane as the eluent to furnish the desired ester compound 3. The aqueous layer was acidified with HCl, extracted with ether, and concentrated to yield the corresponding carboxylic acid 6, which was sufficiently pure needing no further purification.
With oxygen; potassium carbonate; at 140℃; under 2250.23 Torr; for 4h;Autoclave;
General procedure: Catalytic experiments were carried out in a 120ml autoclave equipped with a magnetic agitator and automatic temperature control. A typical procedure for the reaction of FUR with ethanol is described as follow: 15ml ethanol, 0.2g FUR, 0.05g Au/Al2O3 and 0.05g K2CO3 are charged into the autoclave. The autoclaved is sealed and purged. Oxygen is introduced at room temperature till P=0.3MPa, then heated to 140C and kept for 4h. After the reaction, the autoclave was cooled, purged and the products were analyzed by GC and GC-MS
With oxygen; potassium carbonate; at 140℃; under 2250.23 Torr; for 4h;Autoclave; Sealed tube;
General procedure: Catalytic experiments were carried out in a 120 mL autoclaveequipped with a magnetic stirrer and automatic temperature control.After the FUR, Au catalyst, K2CO3 and the alcohol were added,the reactor was sealed, and purged with pure O2 for three times toremove the air. Then, the pressure of oxygen was charged to 0.3MPa and the reaction mixture was heated to 140 C and kept for4 h. When the reaction was finished, the solution was diluted withacetonitrile after the reactor was cooled to room temperature. Theproducts were qualitatively detected by an Agilent 7890A/5975Cgas chromatography-mass spectrometry (GC-MS). The conversionof FUR and selectivity of the product were quantitatively obtainedby GC instrument with the FID detector.
(Z)-1-(furan-2-yl)-3-hydroxy-1-(pyridin-2-yl)but-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
General procedure: To a suspension of sodium (15.21 mmol) in 20 mL of toluene, the appropriate heterocyclic carboxylate (12.01 mmol) in 25 mL of toluene was slowly added; then acetone or aryl methyl ketones (12.01 mmol) in 10 mL of toluene was added at 0 C. The resulting mixture was stirred at room temperature for two days. The precipitate formed was filtered, washed with toluene, dissolved in water, and neutralized with acetic acid to pH 5. After extraction with CH2Cl2, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was filtered through silica using CH2Cl2/MeOH as eluant to give the desired products 1-10 as a white solid in 35%-48% yield. beta-keto-enol forms were recrystallized from methanol (95%) to obtain target compounds 1-10 which were confirmed by FT-IR, 1H-NMR, 13C-NMR, elemental analysis, and mass spectroscopy.
(Z)-1-(furan-2-yl)-3-hydroxy-3-phenylprop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
General procedure: To a suspension of sodium (15.21 mmol) in 20 mL of toluene, the appropriate heterocyclic carboxylate (12.01 mmol) in 25 mL of toluene was slowly added; then acetone or aryl methyl ketones (12.01 mmol) in 10 mL of toluene was added at 0 C. The resulting mixture was stirred at room temperature for two days. The precipitate formed was filtered, washed with toluene, dissolved in water, and neutralized with acetic acid to pH 5. After extraction with CH2Cl2, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was filtered through silica using CH2Cl2/MeOH as eluant to give the desired products 1-10 as a white solid in 35%-48% yield. beta-keto-enol forms were recrystallized from methanol (95%) to obtain target compounds 1-10 which were confirmed by FT-IR, 1H-NMR, 13C-NMR, elemental analysis, and mass spectroscopy.
With C25H38O2P2Ru; at 120℃; for 20h;Inert atmosphere; Sealed tube;
Under an argon atmosphere, the metal complex (0.05mol%), the reaction substrate (1.0mol), and borane (1.0mol) were added to a 10mL sealed tube, and placed in an oil bath at 120C and stirred for 12 hours. After the reaction was completed, the heterocyclic borate product was separated by column chromatography in an air environment. The yield was 85%.
(±)-(p-tolylsulfinyl)methyl 2-furyl ketone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
General procedure: A freshly prepared solution of LDA (6.46 mmol, 2 eq.) in THF fromdiisopropylamine (7.11 mmol, 2.2 eq.) in THF (10 mL) at -78 C and 2 M de nBuLi solution in hexane (3.23 mL, 6.46 mmol, 2 eq.), is added over the corresponding methyl sulfoxide (3.23 mmol, 1 eq.) in THF (10 mL), at -78C, under argon. After stirring for 30 min. the formed carbanion solution is added over a THF solution (10 mL) of the corresponding ethyl carboxylate (3.23 mmol, 1 eq.), at -78C, under argon. After stirring for 30 min., the reaction mixture was quenched with saturated NH4Cl, aqueous solution and 1M H2SO4 was added until pH 3-4. The aqueous phase was then extracted with EtOAc (5 x 50 mL), washed with saturated NaHCO3 aqueous solution and saturated NaCl aqueous solution, and dried over Na2SO4. After removing the solvent at vacuo, the residue was purified by flash chromatography, to give the corresponding -ketosulfoxide.
With 2,2,6,6-tetramethylpiperidinylmagnesium chloride; Br(1-)*C9H18N(1-)*Mg(2+); In tetrahydrofuran; 2-methyltetrahydrofuran; at -40 - -20℃; for 2h;Large scale;
To a 5000 L cryogenic reactor, ethyl 2-furoate (1) (150 kg, 1071 mol 1.0 eq) was charged, followed by THF (600 kg) and triisopropyl borate (304 kg, 1617 mol, 1.51 eq). The mixture was cooled to -45±5 C. A solution of TMPMgCl-TMPMgBr in THF/2-Me-THF (1860 kg, 0.92 M, 1711.2 mol, 1.51 eq) was charged over two hours while keeping the internal temperature below -50 C. The resulting mixture was stirred at between -40 and -50 C for two hours, and the reaction was deemed complete. The reaction was quenched with 154 kg of MeOH, keeping the internal temperature below 20 C. The mixture was transferred to another reactor containing 3N HCl (3000 kg). The resulting mixture was distilled under vacuum to remove organic solvents. After distillation, additional 3N HCl (900 kg) was charged. The mixture was filtered. The wet crude product (358.0 kg) was slurried with 775 kg of 3N HCl for two hours and filtered to give 275 kg boronic acid 2 (HPLC assay 69.2%, 190.3 kg after correction for assay, 96.5% yield). HPLC Purity: 99.2 % by area at 264 nm absorption. 1H NMR (400 MHz, d-DMSO): delta 8.52 (s, 2H), 7.92 (d, J= 1.1 Hz, 1H), 6.77 (d, J= 1.1 Hz, 1H), 4.33 (q, J= 7.0 Hz, 2H), 1.30 (q, J= 7.0 Hz, 3H); 13C NMR (400 MHz, d-DMSO): delta 160.70, 146.70, 146.47, 126.85, 116.91, 61.54, 13.96; MS (ESI) m/z 185.1 (Calcd for M+H: 185.1). (0193) Example 3: Comparison of amidomagnesium halides
With oxygen; potassium carbonate; at 140℃; under 2250.23 Torr; for 4h;Autoclave; Sealed tube;
General procedure: Catalytic experiments were carried out in a 120 mL autoclaveequipped with a magnetic stirrer and automatic temperature control.After the FUR, Au catalyst, K2CO3 and the alcohol were added,the reactor was sealed, and purged with pure O2 for three times toremove the air. Then, the pressure of oxygen was charged to 0.3MPa and the reaction mixture was heated to 140 C and kept for4 h. When the reaction was finished, the solution was diluted withacetonitrile after the reactor was cooled to room temperature. Theproducts were qualitatively detected by an Agilent 7890A/5975Cgas chromatography-mass spectrometry (GC-MS). The conversionof FUR and selectivity of the product were quantitatively obtainedby GC instrument with the FID detector.
With oxygen; potassium carbonate; calcium oxide; at 140℃; under 2250.23 Torr; for 4h;Autoclave; Sealed tube;
General procedure: Catalytic experiments were carried out in a 120 mL autoclaveequipped with a magnetic stirrer and automatic temperature control.After the FUR, Au catalyst, K2CO3 and the alcohol were added,the reactor was sealed, and purged with pure O2 for three times toremove the air. Then, the pressure of oxygen was charged to 0.3MPa and the reaction mixture was heated to 140 C and kept for4 h. When the reaction was finished, the solution was diluted withacetonitrile after the reactor was cooled to room temperature. Theproducts were qualitatively detected by an Agilent 7890A/5975Cgas chromatography-mass spectrometry (GC-MS). The conversionof FUR and selectivity of the product were quantitatively obtainedby GC instrument with the FID detector.
With tert-Butyl peroxybenzoate; copper diacetate; at 110℃; for 12h;
15 mmol of chloroform was added to a 100 mL one-necked flask, and then 50 mmol of ethanol and 1 mmol of the initiator t-butyl peroxybenzoate 4 mmol and the catalyst Cu(OAc) 20.4 mmol were refluxed at 110 C for 12 hours.Cooling to room temperature, adding saturated NaHCO3 solution, extracting, removing the solvent under reduced pressure to obtain a crude product, and then using flash column chromatographyThe product was isolated in 150.5 mg (yield: 71%).
ethyl 5-(7-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)furan-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
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%;
With tris(2-phenylpyridinato-N,C2′)iridium(III) In dimethyl sulfoxide Irradiation;
General Procedure for the Syntheses of Alkylated Heteroarenes (1-39).
General procedure: In a 4 mL oven-driedvial, redox-active ester (0.2 mmol, 1.0 equiv.), photocatalyst Ir(ppy)3(0.5 mol%), heteroarene (2.0mmol, 10.0 equiv.) were added to degassed DMSO (2 mL). The mixture was stirred overnight (12-24 h) at room temperature under two 25W white LED irradiation. The reaction process wasmonitored by thin layer chromatography (TLC). After redox-active ester was consumed, themixture was quenched with water, extracted three times with ethyl acetate, and concentrated invacuo. Purification of the crude products by silica gel column chromatography (eluent: PE/EA orPE/DCM) gave the desired products.
With tris(2-phenylpyridinato-N,C2′)iridium(III) In dimethyl sulfoxide Irradiation;
General Procedure for the Syntheses of Alkylated Heteroarenes (1-39).
General procedure: In a 4 mL oven-driedvial, redox-active ester (0.2 mmol, 1.0 equiv.), photocatalyst Ir(ppy)3(0.5 mol%), heteroarene (2.0mmol, 10.0 equiv.) were added to degassed DMSO (2 mL). The mixture was stirred overnight (12-24 h) at room temperature under two 25W white LED irradiation. The reaction process wasmonitored by thin layer chromatography (TLC). After redox-active ester was consumed, themixture was quenched with water, extracted three times with ethyl acetate, and concentrated invacuo. Purification of the crude products by silica gel column chromatography (eluent: PE/EA orPE/DCM) gave the desired products.
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