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Limited Quantity
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Structure of 696-59-3 * 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 Organic Chemistry, 1990, vol. 55, # 24, p. 6024 - 6027
3
[ 696-59-3 ]
[ 29709-35-1 ]
Yield
Reaction Conditions
Operation in experiment
58%
With acetic acid; ethylenediamine In 1,4-dioxane
PREPARATION 6 1-(2-aminoethyl)pyrrole (The compound of formula (G)) A mixture of 2,5-dimethoxytetrahydrofuran (90 g, 680 mmol), ethylenediamine (36 g, 600 mmol), acetic acid (600 ml), and dioxane (800 mL) was heated under reflux for 4 hours, and then stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was made basic with a 50percent solution of potassum hydroxide (400 mL) and refluxed for 5 hours. The cooled aqueous solution was then extracted with chloroform (3*300 mL). The combined extracts were evaporated and separated via an acid/base extraction (1M, HCl solution, 400 mL) to give 38.3 g of the title compound, 1-(2-aminoethyl)pyrrole (58percent), as a dark brown oil.
Reference：
[1] Patent: US5041442, 1991, A,
4
[ 696-59-3 ]
[ 591-19-5 ]
[ 107302-22-7 ]
Yield
Reaction Conditions
Operation in experiment
86%
at 90℃; for 1.33333 h; Green chemistry
General procedure: Amine (1 mmol), 2,5-dimethoxytetrahydrofuran (1.1 mmol)and L-(+)-tartaric acid–choline chloride based DES (1.5 g) were added to a 50 mL round bottom flask and the reaction mixturewas stirred at 90 °C. The progress of the reaction was monitoredby TLC. After completion of the reaction, the mixture was cooled to room temperature and the product was extracted with ethyl acetate.After the evaporation of the solvent, the residue was purified by columnchromatography on silica gel to afford the pure product. The DES wasdried under vacuumand reused for the next cycle.
85%
With ionic liquid immobilized on γ-Fe2O3(at)SiO2 nanoparticles In water at 100℃; for 1.5 h;
General procedure: To a solution of amine (1 mmol) in water (2 ml) was added tetrahydro-2,5-dimethoxyfuran (1.1 mmol) and γ-Fe2O3(at)SiO2–Sb-IL (0.08 g). The reaction mixture was stirred at 100 °C for a certain period of time as required to complete the reaction. During that time, the reaction was monitored constantly by TLC. After completion of the reaction, the catalyst was removed by using a magnet and washed with ethyl acetate. The aqueous solution was extracted by ethyl acetate (3 × 5 ml). The combined organic phase was dehydrated with anhydrous sodium sulfate. After the evaporation of the solvent, the residue was purified by silica gel flash chromatography using petroleum ether/ethyl acetate as the eluent to afford the pure product.
Reference：
[1] Asian Journal of Chemistry, 2013, vol. 25, # 1, p. 501 - 504
[2] Journal of Molecular Liquids, 2014, vol. 198, p. 259 - 262,4
[3] Applied Catalysis A: General, 2013, vol. 457, p. 34 - 41
[4] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 9, p. 1039 - 1043
[5] Journal of Heterocyclic Chemistry, 2000, vol. 37, # 1, p. 15 - 24
[6] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 2, p. 492 - 495
[7] Tetrahedron, 2016, vol. 72, # 35, p. 5444 - 5455
5
[ 696-59-3 ]
[ 591-19-5 ]
[ 107302-22-7 ]
[ 219928-13-9 ]
Reference：
[1] Synthesis, 1999, # 1, p. 74 - 79
[2] Synthesis, 1999, # 1, p. 74 - 79
6
[ 696-59-3 ]
[ 106-50-3 ]
[ 52768-17-9 ]
Yield
Reaction Conditions
Operation in experiment
94%
With ionic liquid immobilized on γ-Fe2O3(at)SiO2 nanoparticles In water at 100℃; for 1.66667 h;
General procedure: To a solution of amine (1 mmol) in water (2 ml) was added tetrahydro-2,5-dimethoxyfuran (1.1 mmol) and γ-Fe2O3(at)SiO2–Sb-IL (0.08 g). The reaction mixture was stirred at 100 °C for a certain period of time as required to complete the reaction. During that time, the reaction was monitored constantly by TLC. After completion of the reaction, the catalyst was removed by using a magnet and washed with ethyl acetate. The aqueous solution was extracted by ethyl acetate (3 × 5 ml). The combined organic phase was dehydrated with anhydrous sodium sulfate. After the evaporation of the solvent, the residue was purified by silica gel flash chromatography using petroleum ether/ethyl acetate as the eluent to afford the pure product.
93%
at 90℃; for 1.66667 h; Green chemistry
General procedure: Amine (1 mmol), 2,5-dimethoxytetrahydrofuran (1.1 mmol)and L-(+)-tartaric acid–choline chloride based DES (1.5 g) were added to a 50 mL round bottom flask and the reaction mixturewas stirred at 90 °C. The progress of the reaction was monitoredby TLC. After completion of the reaction, the mixture was cooled to room temperature and the product was extracted with ethyl acetate.After the evaporation of the solvent, the residue was purified by columnchromatography on silica gel to afford the pure product. The DES wasdried under vacuumand reused for the next cycle.
65%
With magnesium iodide etherate In acetonitrile at 80℃; for 10 h;
General procedure: A Schlenk reaction tube was charged with primary aromatic amine (5.0 mmol), 2,5-dimethoxytetrahydrofuran (6.0 mmol), MgI2 etherate (10percent mmol), and acetonitrile (10 mL). The reaction mixture was stirred at 80 °C for several hours and then concentrated in vacuo. The residue was purified by flash column chromatography on a silica gel to give the desired product.
Reference：
[1] Applied Catalysis A: General, 2013, vol. 457, p. 34 - 41
[2] Journal of Molecular Liquids, 2014, vol. 198, p. 259 - 262,4
[3] Tetrahedron, 2011, vol. 67, # 5, p. 898 - 903
7
[ 696-59-3 ]
[ 542-05-2 ]
[ 100-46-9 ]
[ 28957-72-4 ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: at 70℃; for 1 h; Stage #2: With hydrogenchloride; sodium acetate In water at 0 - 20℃;
Preparation of 8-Benzyl-8-aza-bicyclo[3.2.1]octan-3-one; A solution of 2,5-dimethoxy tetrahydro furan (15 g, 113 mmol) in 1N HCI (250 mL) was heated to 700C and maintained for 1 h. The reaction mixture was cooled to O0C, acetone di carboxylic acid (18.2 g, 125 mmol), conc.HCI (11 mL), sodium acetate (18.5 g, 136 mmol) and benzyl amine (14 mL, 125 mmol) were added sequentially, then the reaction <n="103"/>mixture was allowed to rt slowly and maintained over night. The reaction mass was filtered through celite bed, aqueous layer of the filtrate was basified with NaOH solution and extracted with EtOAc (2 x 400 ml_). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product as brown colored liquid (21.5 g, 88percent). 1HNMR(CDCI3): δ 7.25-7.5(m, 5H), 3.8(s, 2H), 3.54(s, 2H), 2.66-2.8(m, 2H), 2.02-2.3(m, 4H), 1.6-1.7(m, 2H). Mass: (M+1) 216 calculated for C14H17NO.
72%
Stage #1: With hydrogenchloride In water at 80℃; for 2 h; Stage #2: With hydrogenchloride; sodium acetate In water at 0 - 55℃; for 14 h; Stage #3: With sodium hydroxide In water at 20℃;
A solution of 2,5-dimethoxytetrahydrofuran (19.8 g, 149.8 mmol) in 0.1M hydrochloric acid (180 ml, 18.0 mmol) was stirred at 80°C for 2 hours. The reaction solution was cooled to 0°C, acetonedicarboxylic acid (19.8 g, 149.8 mmol), concentrated hydrochloric acid (13.8 ml, 164.8 mmol), sodium acetate (14.8 g, 179.8 mmol), and benzylamine (17.7 g, 164.8 mmol) were added to the reaction solution, and the mixture was stirred at the same temperature for 12 hours and at 55°C for 2 hours. The reaction solution was cooled to room temperature, and an aqueous solution of 4M sodium hydroxide (70 ml) was added, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and then concentrated under a reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to give a title compound (23.3 g, 108 mmol, 72percent) as a light yellow oil product. 1H-NMR (400 MHz, CDCl3) δ:1.61-1.66 (2H, m), 2.10-2.13 (2H, m), 2.19-2.23 (2H, m), 2.67-2.72 (2H, m), 3.50 (2H, m), 3.75 (2H, s), 7.26-7.43 (5H, m). ESI-MS: m/z = 216 (M+H+).
61%
Stage #1: for 1 h; Reflux Stage #2: With sodium acetate In water at 0 - 50℃; for 6 h; Stage #3: With sodium hydroxide In water
Step 1: 8-benzyl-8-azabicyclo[3.2.1]octan-3-one A solution of 2,5-dimethoxytetrahydrofuran (2.2 mL) in hydrochloric acid (0.1N, 20 mL) was stirred under refluxing for 1 hour and then cooled to 0° C. 1,3-acetone-dicarboxylic acid (2.5 g), benzylamine (2.25 mL) and 10percent sodium acetate solution (10 mL) were added therein. The reaction mixture was stirred for 1 hour at room temperature, and additionally stirred for 5 hours at 50° C., and then cooled under ice bath. The reaction mixture was alkalized to pH 12 using a 2N sodium hydroxide solution. After layer-separated, the aqueous phase is diluted with ethyl acetate. The combined organic phase was washed with water, dried with anhydrous sodium sulfate, filtered and vaporized under reduced pressure. The concentrate was separated through column chromatography (petroleum ether/ethyl acetate=4/1, v/v) to obtain the product as brown oil (2239 mg, yield: 61percent). 1HNMR (CDCl3, 300 MHz) δ: 7.43-7.24 (m, 5H), 3.75 (s, 2H), 3.49-3.48 (m, 2H), 2.72-2.66 (m, 2H), 2.23 (s, 1H), 2.18-2.16 (m, 1H), 2.14-2.09 (m, 2H), 1.66-1.59 (m, 2H).
60%
Stage #1: With hydrogenchloride In water for 0.333333 h; Stage #2: With disodium hydrogenphosphate; sodium hydroxide In water at 0 - 20℃; Stage #3: With hydrogenchloride In water at 85℃; for 2 h;
Intermediate I-25 (8-benzyl-8-azabicyclo[3.2.1]octan-3-one)Concentrated hydrochloric acid (3 mL) was added to a stirred suspension of intermediate I-24 (8.2 g, 62 mmol, 1 eq) in water (17 mL), the reaction mixture was stirred for additional 20 minutes and diluted with water (25 mL). In a separate flask cooled to 0° C. on an ice bath, concentrated hydrochloric acid (9 mL) was added slowly to a solution of benzyl amine (10 g, 93 mmol, 1.5 eq) in water (35 mL), and this solution was added to the above solution of I-24. A solution of 1,3-acetonedicarboxylic acid (10 g, 68 mmol, 1.1 eq) in water (40 mL) was added followed by a solution of sodium hydrogen phosphate (4.4 g, 31 mmol, 5.0 eq) in water (20 mL). The acidity was adjusted from pH 1 to pH 4.5 using a solution of NaOH (40percent in water). The resulting cloudy and pale- yellow solution was stirred overnight at room temperature. The reaction mixture was acidified to pH 3 from pH 7.5 using aqueous HCl solution (50percent in water) and stirred at 85° C. for 2 hours. The crude reaction mixture was cooled to room temperature, basified to pH 12 using a solution of NaOH (40percent in water) and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, the solids were removed by filtration and the filtrate was concentrated. The crude reaction product was purified by silica gel chromatography to give I-25 as a yellow oil (8.0 g, 60percent). 1H-NMR (CDCl3) δ : 7.59 (d, J=7.2 Hz, 2H), 7.31-7.40 (m, 3H), 4.04 (s, 2H), 3.75 (s, 2H), 3.13 (d, J=12.0 Hz, 2H), 2.22-2.30 (m, 4H), 1.75-1.80 (m, 2H). MS (ESI): ink 216 (M+H+).
Stage #1: With hydrogenchloride In water at 0℃; Stage #2: With sodium acetate In water at 0 - 50℃; for 3.66667 h; Stage #3: With sodium hydroxide In water at 0℃;
To a solution of 0.025 M aqueous hydrochloric acid (100 ml) at [0°C] was added 2, [5-DIMETHOXY-TETRAHYDROFURAN] (30 ml 231 [MMOL).] The reaction was stirred at [0°C] overnight. The reaction was then diluted with water (200 ml) and benzyl amine hydrochloride (40 grams, 278 [MMOL),] 3-oxo-pentanedioic acid (33.7 grams, 231 [MMOL),] and sodium acetate (10.7 grams, 130 [MMOL)] were added. The reaction was stirred for 5 minutes at [0°C,] warmed to ambient temperature and stirred for 90 minutes, then heated to [50°C] for two hours, cooled to [0°C] and basified to pH = 10 with 50 [percent] aqueous sodium hydroxide (14 [ML).] The reaction mixture was extracted with ethyl acetate (3 times) and the organic layers were combined and washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo to give a brown oil. Silica gel chromatography gave the title compound (33.46 grams, 67 percent yield
Reference：
[1] Tetrahedron Letters, 1986, vol. 27, # 19, p. 2131 - 2134
[2] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 913 - 916
13
[ 696-59-3 ]
[ 100-01-6 ]
[ 4533-42-0 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 90℃; for 1.66667 h; Green chemistry
General procedure: Amine (1 mmol), 2,5-dimethoxytetrahydrofuran (1.1 mmol)and L-(+)-tartaric acid–choline chloride based DES (1.5 g) were added to a 50 mL round bottom flask and the reaction mixturewas stirred at 90 °C. The progress of the reaction was monitoredby TLC. After completion of the reaction, the mixture was cooled to room temperature and the product was extracted with ethyl acetate.After the evaporation of the solvent, the residue was purified by columnchromatography on silica gel to afford the pure product. The DES wasdried under vacuumand reused for the next cycle.
85%
With ionic liquid immobilized on γ-Fe2O3(at)SiO2 nanoparticles In water at 100℃; for 1 h;
General procedure: To a solution of amine (1 mmol) in water (2 ml) was added tetrahydro-2,5-dimethoxyfuran (1.1 mmol) and γ-Fe2O3(at)SiO2–Sb-IL (0.08 g). The reaction mixture was stirred at 100 °C for a certain period of time as required to complete the reaction. During that time, the reaction was monitored constantly by TLC. After completion of the reaction, the catalyst was removed by using a magnet and washed with ethyl acetate. The aqueous solution was extracted by ethyl acetate (3 × 5 ml). The combined organic phase was dehydrated with anhydrous sodium sulfate. After the evaporation of the solvent, the residue was purified by silica gel flash chromatography using petroleum ether/ethyl acetate as the eluent to afford the pure product.
62%
With magnesium iodide etherate In acetonitrile at 80℃; for 12 h;
General procedure: A Schlenk reaction tube was charged with primary aromatic amine (5.0 mmol), 2,5-dimethoxytetrahydrofuran (6.0 mmol), MgI2 etherate (10percent mmol), and acetonitrile (10 mL). The reaction mixture was stirred at 80 °C for several hours and then concentrated in vacuo. The residue was purified by flash column chromatography on a silica gel to give the desired product.
Reference：
[1] Journal of the Iranian Chemical Society, 2011, vol. 8, # 3, p. 851 - 856
[2] Synlett, 2009, # 14, p. 2245 - 2248
[3] ChemCatChem, 2013, vol. 5, # 12, p. 3743 - 3749
[4] Journal of Molecular Liquids, 2014, vol. 198, p. 259 - 262,4
[5] Asian Journal of Chemistry, 2013, vol. 25, # 1, p. 501 - 504
[6] Synthetic Communications, 2012, vol. 42, # 16, p. 2471 - 2477
[7] Monatshefte fur Chemie, 2013, vol. 144, # 3, p. 405 - 409
[8] Applied Catalysis A: General, 2013, vol. 457, p. 34 - 41
[9] Journal of Chemical Research, 2009, # 1, p. 14 - 16
[10] RSC Advances, 2015, vol. 5, # 93, p. 76221 - 76228
[11] Tetrahedron, 2011, vol. 67, # 5, p. 898 - 903
[12] Journal of Heterocyclic Chemistry, 2000, vol. 37, # 1, p. 15 - 24
[13] Chemical Physics Letters, 2003, vol. 367, # 1-2, p. 62 - 71
[14] Patent: EP1202724, 2003, B1,
[15] Synthetic Communications, 2012, vol. 42, # 4, p. 548 - 553
[16] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 6, p. 1778 - 1786
[17] Patent: CN106565682, 2017, A, . Location in patent: Paragraph 0117; 0119; 0120; 0121
14
[ 696-59-3 ]
[ 100-01-6 ]
[ 4533-42-0 ]
[ 10220-22-1 ]
Reference：
[1] Synthesis, 1999, # 1, p. 74 - 79
[2] Synthesis, 1999, # 1, p. 74 - 79
15
[ 696-59-3 ]
[ 5469-69-2 ]
[ 5096-76-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1981, vol. 24, # 1, p. 59 - 63
16
[ 696-59-3 ]
[ 106-40-1 ]
[ 5044-39-3 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 90℃; for 1.33333 h; Green chemistry
General procedure: Amine (1 mmol), 2,5-dimethoxytetrahydrofuran (1.1 mmol)and L-(+)-tartaric acid–choline chloride based DES (1.5 g) were added to a 50 mL round bottom flask and the reaction mixturewas stirred at 90 °C. The progress of the reaction was monitoredby TLC. After completion of the reaction, the mixture was cooled to room temperature and the product was extracted with ethyl acetate.After the evaporation of the solvent, the residue was purified by columnchromatography on silica gel to afford the pure product. The DES wasdried under vacuumand reused for the next cycle.
88%
With ionic liquid immobilized on γ-Fe2O3(at)SiO2 nanoparticles In water at 100℃; for 1 h;
General procedure: To a solution of amine (1 mmol) in water (2 ml) was added tetrahydro-2,5-dimethoxyfuran (1.1 mmol) and γ-Fe2O3(at)SiO2–Sb-IL (0.08 g). The reaction mixture was stirred at 100 °C for a certain period of time as required to complete the reaction. During that time, the reaction was monitored constantly by TLC. After completion of the reaction, the catalyst was removed by using a magnet and washed with ethyl acetate. The aqueous solution was extracted by ethyl acetate (3 × 5 ml). The combined organic phase was dehydrated with anhydrous sodium sulfate. After the evaporation of the solvent, the residue was purified by silica gel flash chromatography using petroleum ether/ethyl acetate as the eluent to afford the pure product.
66%
With magnesium iodide etherate In acetonitrile at 80℃; for 6 h;
General procedure: A Schlenk reaction tube was charged with primary aromatic amine (5.0 mmol), 2,5-dimethoxytetrahydrofuran (6.0 mmol), MgI2 etherate (10percent mmol), and acetonitrile (10 mL). The reaction mixture was stirred at 80 °C for several hours and then concentrated in vacuo. The residue was purified by flash column chromatography on a silica gel to give the desired product.
Reference：
[1] Synlett, 2009, # 14, p. 2245 - 2248
[2] Chemistry of Heterocyclic Compounds, 2014, vol. 49, # 12, p. 1732 - 1739
[3] Journal of Organic Chemistry, 2006, vol. 71, # 25, p. 9341 - 9347
[4] Tetrahedron, 2012, vol. 68, # 39, p. 8147 - 8155
[5] Synthetic Communications, 2012, vol. 42, # 16, p. 2471 - 2477
[6] Monatshefte fur Chemie, 2013, vol. 144, # 3, p. 405 - 409
[7] Journal of Molecular Liquids, 2014, vol. 198, p. 259 - 262,4
[8] Applied Catalysis A: General, 2013, vol. 457, p. 34 - 41
[9] RSC Advances, 2015, vol. 5, # 93, p. 76221 - 76228
[10] Journal of Materials Chemistry, 2003, vol. 13, # 5, p. 1011 - 1022
[11] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 9, p. 1039 - 1043
[12] Tetrahedron, 2011, vol. 67, # 5, p. 898 - 903
[13] Journal of Heterocyclic Chemistry, 2000, vol. 37, # 1, p. 15 - 24
[14] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 15, p. 4325 - 4327
[15] Chemistry - A European Journal, 2009, vol. 15, # 38, p. 9664 - 9668
[16] Electrochimica Acta, 2011, vol. 56, # 12, p. 4645 - 4649
[17] Crystal Growth and Design, 2010, vol. 10, # 5, p. 2342 - 2349
[18] Synthetic Communications, 2012, vol. 42, # 4, p. 548 - 553
[19] Tetrahedron, 2016, vol. 72, # 35, p. 5444 - 5455
A mixture of p-toluenesulfonamide (20 g, 116.8 mmol) and 2,5-dimethoxytetrahydrofuran (20 mL, 154 mmole) in acetic acid (100 mL) was heated at reflux for 2 hours. The mixturewas allowed to cool to room temperature, then poured into water (1 L). The mixture was allowed to stand for 1 hour, then the precipitate was isolated by filtration and recrystallised form ethanol to give N-tosylpyrrole (19.72 g, 76percent) as colourless crystals.
Reference：
[1] Synthetic Communications, 1995, vol. 25, # 12, p. 1857 - 1861
[2] Journal of Chemical Research, 2009, # 1, p. 14 - 16
[3] Tetrahedron Letters, 2007, vol. 48, # 23, p. 4047 - 4050
[4] Organic Preparations and Procedures International, 2006, vol. 38, # 5, p. 495 - 500
[5] Tetrahedron Letters, 2009, vol. 50, # 34, p. 4807 - 4809
[6] Synlett, 2009, # 14, p. 2245 - 2248
[7] Synthesis (Germany), 2017, vol. 49, # 20, p. 4711 - 4716
20
[ 696-59-3 ]
[ 556-18-3 ]
[ 23351-05-5 ]
Reference：
[1] Synthesis, 2009, # 6, p. 980 - 984
21
[ 696-59-3 ]
[ 16133-49-6 ]
[ 59194-26-2 ]
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 7, p. 3491 - 3499
[2] Organic and Biomolecular Chemistry, 2017, vol. 15, # 34, p. 7157 - 7164
With magnesium iodide etherate; In acetonitrile; at 80℃; for 2h;
General procedure: A Schlenk reaction tube was charged with primary aromatic amine (5.0 mmol), 2,5-dimethoxytetrahydrofuran (6.0 mmol), MgI2 etherate (10percent mmol), and acetonitrile (10 mL). The reaction mixture was stirred at 80 °C for several hours and then concentrated in vacuo. The residue was purified by flash column chromatography on a silica gel to give the desired product.
96%
With ionic liquid immobilized on gamma-Fe2O3(at)SiO2 nanoparticles; In water; at 100℃; for 0.5h;
General procedure: To a solution of amine (1 mmol) in water (2 ml) was added tetrahydro-2,5-dimethoxyfuran (1.1 mmol) and gamma-Fe2O3(at)SiO2?Sb-IL (0.08 g). The reaction mixture was stirred at 100 °C for a certain period of time as required to complete the reaction. During that time, the reaction was monitored constantly by TLC. After completion of the reaction, the catalyst was removed by using a magnet and washed with ethyl acetate. The aqueous solution was extracted by ethyl acetate (3 × 5 ml). The combined organic phase was dehydrated with anhydrous sodium sulfate. After the evaporation of the solvent, the residue was purified by silica gel flash chromatography using petroleum ether/ethyl acetate as the eluent to afford the pure product.
95%
With bismuth (III) nitrate pentahydrate; at 20℃; for 0.0833333h;Sonication; Neat (no solvent);
General procedure: Amine 2 (1.0 mmol), 2,5-dimethoxytetrahydrofuran (1, 1.2 mmol) and bismuth nitrate pentahydrate (24 mg, 5 molpercent) was irradiated in a B5510-DTH (Branson ultrasonic cleaner; Model-5510, frequency 42 kHz with an output power 135 Watts), as specified in Table 2. After completion of the reaction (monitored by TLC) diethyl ether (10 mL) was added to the reaction mixture and filtered. Pure product was isolated from the reaction mixture after evaporation of ether.
95%
With L-(+)-tartaric acid-choline chloride based deep eutectic solvent; at 90℃; for 0.5h;Green chemistry;
General procedure: Amine (1 mmol), 2,5-dimethoxytetrahydrofuran (1.1 mmol)and L-(+)-tartaric acid?choline chloride based DES (1.5 g) were added to a 50 mL round bottom flask and the reaction mixturewas stirred at 90 °C. The progress of the reaction was monitoredby TLC. After completion of the reaction, the mixture was cooled to room temperature and the product was extracted with ethyl acetate.After the evaporation of the solvent, the residue was purified by columnchromatography on silica gel to afford the pure product. The DES wasdried under vacuumand reused for the next cycle.
93%
With bismuth (III) nitrate pentahydrate; at 90℃; for 0.166667h;Microwave irradiation;
A mixture of 4-methoxyaniline (2.50 g, 20 mmol), 2,5-dimethoxytetrahydrofuran(3.20 g, 24 mmol) and bismuth(III) nitrate pentahydrate (0.6 g ) was placed in a three-necked flask in a microwave oven equipped with a temperature sensor and a reflux condenser. Then the mixture was irradiated for 10 min (300W) at 90 oC. After completion of the reaction, the mixture was cooled and extracted with diethyl ether (3 × 50 mL). The combined organic layers were driedwith anhydrous magnesium sulfate. The solvent was removed and the crude product was purified by column chromatography on silica gelusing petroleum ether and acetone (10:1, v/v) as the eluent to give the pure product 1-(4-methoxyphenyl)pyrrole (3.20 g, 93percent yield): m.p.108?112°C (lit.37 104?108 °C).
76%
With Oxone; In acetonitrile; at 110℃; for 0.3h;Microwave irradiation;
General procedure: Oxone (0.09 g, 0.30 mmol) was added to a solution of the aromatic primary amines (2.5 mmol) and 2,5-dimethoxytetrahydrofuron (3.0 mmol) in a solvent (5 mL) was further added (Scheme1). The reaction mixture was heated under microwave irradiation for 10 min at 110 ± 10 °C. The reaction mixture was irradiated until total consumption of the amine was verified by TLC. Water was added and the products were extracted with EtOAc (3x20 mL). The organic phasewas dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The product was purified on a silica gel column chromatography eluted with mixture of ethylacetate/hexane (1:4) to afford the product.
74%
With silica sulfuric acid; In neat (no solvent, solid phase);Milling; Green chemistry;
General procedure: To the mixture of SSA catalyst (125 mg) with silica gel (875 mg), 2,5-dimethoxy-tetrahydrofuran (DMTHF) (2 mmol) and a primary amine (2 mmol) (for compound 10, 5 : 1 mmol) were added. The mixture was grinded in a glass mortar with a pestle for 5-15 min. Progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was dissolved in diethyl ether, then filtrated. The filtrate solvent was evaporated under vacuum. Thus obtained the corresponding crude product was purified by column chromatography on silica gel with n-hexane and ethyl acetate as eluents.
With L-(+)-tartaric acid-choline chloride based deep eutectic solvent; at 90℃; for 1.33333h;Green chemistry;
General procedure: Amine (1 mmol), 2,5-dimethoxytetrahydrofuran (1.1 mmol)and L-(+)-tartaric acid-choline chloride based DES (1.5 g) were added to a 50 mL round bottom flask and the reaction mixturewas stirred at 90 C. The progress of the reaction was monitoredby TLC. After completion of the reaction, the mixture was cooled to room temperature and the product was extracted with ethyl acetate.After the evaporation of the solvent, the residue was purified by columnchromatography on silica gel to afford the pure product. The DES wasdried under vacuumand reused for the next cycle.
88%
With ionic liquid immobilized on gamma-Fe2O3(at)SiO2 nanoparticles; In water; at 100℃; for 1h;
General procedure: To a solution of amine (1 mmol) in water (2 ml) was added tetrahydro-2,5-dimethoxyfuran (1.1 mmol) and gamma-Fe2O3(at)SiO2-Sb-IL (0.08 g). The reaction mixture was stirred at 100 C for a certain period of time as required to complete the reaction. During that time, the reaction was monitored constantly by TLC. After completion of the reaction, the catalyst was removed by using a magnet and washed with ethyl acetate. The aqueous solution was extracted by ethyl acetate (3 × 5 ml). The combined organic phase was dehydrated with anhydrous sodium sulfate. After the evaporation of the solvent, the residue was purified by silica gel flash chromatography using petroleum ether/ethyl acetate as the eluent to afford the pure product.
70%
With Oxone; In acetonitrile; at 110℃; for 0.3h;Microwave irradiation;
General procedure: Oxone (0.09 g, 0.30 mmol) was added to a solution of the aromatic primary amines (2.5 mmol) and 2,5-dimethoxytetrahydrofuron (3.0 mmol) in a solvent (5 mL) was further added (Scheme1). The reaction mixture was heated under microwave irradiation for 10 min at 110 ± 10 C. The reaction mixture was irradiated until total consumption of the amine was verified by TLC. Water was added and the products were extracted with EtOAc (3x20 mL). The organic phasewas dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The product was purified on a silica gel column chromatography eluted with mixture of ethylacetate/hexane (1:4) to afford the product.
66%
With magnesium iodide etherate; In acetonitrile; at 80℃; for 6h;
General procedure: A Schlenk reaction tube was charged with primary aromatic amine (5.0 mmol), 2,5-dimethoxytetrahydrofuran (6.0 mmol), MgI2 etherate (10% mmol), and acetonitrile (10 mL). The reaction mixture was stirred at 80 C for several hours and then concentrated in vacuo. The residue was purified by flash column chromatography on a silica gel to give the desired product.
According to Scheme 20, <strong>[1005-38-5]4-amino-6-chloro-2-methylthiopyrimidine</strong> 151 was reacted with 1 equivalent of 2,5-dimethoxytetrahydrofuran in refluxing acetic acid to provide 6-chloro-2-methylthio-4-(1-pyrrolyl)pyrimidine 152: 1H NMR (CDCl3) delta2.75 (s,3H), 6.55 (d,2H), 7.05 (s,1H), 7.65 (d,2H).
2.0 g of <strong>[46004-37-9]methyl 4-amino-2-chlorobenzoate</strong> were dissolved in 10 ml of acetic acid, 2.0 ml of 2,5-dimethoxytetrahydrofuran were added thereto, and the mixture was heated under reflux for 15 minutes.. After cooling the reaction solution, the solvent was evaporated.. The obtained residue was mixed with EtOAc and saturated NaHCO3 aq. and extracted.. The organic layer was washed with brine, and dried over sodium sulfate anhydride.. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc (4:1)) to obtain 2.1 g of methyl 2-chloro-4-(1H-pyrrol-1-yl)benzoate.
2,3-bis-(2-(N-methylpiperazine)benzylidene)succinaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With potassium acetate; acetic acid; In water; at 110℃; for 12h;Heating / reflux;
4.5 g of 2-(N-methylpiperazine)benzaldehyde (30 mmol) prepared in the above step was added to the 250 ml round-bottomed flask. Thereafter, 2 ml of 2,5-dimethoxytetrahydrofuran(15 mmol), 2 g of potassium acetate (20 mmol), 1 ml of acetic acid(16 mmol) and 1 ml of water were added to the flask. The reaction mixture was refluxed at 110° C. for 12 hours. After the reaction was terminated, the reaction mixture was cooled to the room temperature. Thereafter, water was added to the reaction mixture. The reaction mixture was extracted with 100 ml of chloroform for three times. The chloroform layers were collected, washed with water for three times and dried with anhydrous magnesium sulfate. The chloroform was removed under reduced pressure. The resulting residue was purified with column chromatography, to give the title compound as a yellow crystal (4.5 g, yield: 65percent) [0145] mp:218220° C. Rf: 0.3 (CHCl3:MeOH=8:2). 1H-NMR(CDCl3/TMS) (ppm): delta2.25(s, 6H, OCH3), 2.402.85(BRD, 16H, N-CH2-CH2-N), 6.94(dt, 2H, J=1.2, 7.5 Hz), 7.04(dd, 2H, 2H, J=1.2, 7.5 Hz), 7.22(dd, 2H, J=1.2, 7.8 Hz), 7.32(dt, 2H, J=1.2, 7.5 Hz), 7.92(s, 2H, CHC-), 9.70(s, 2H, CHO).
(1) To a solution of <strong>[33786-89-9]5-chloro-1,3-phenylenediamine</strong> (2.00 g) in acetic acid (20 mL) was added 2,5-dimethoxytetrahydrofuran (1.8 mL). After 4 hours at reflux, the reaction mixture was concentrated. The residue was suspended in satd. NaHCO3 and EtOAc. The reaction mixture was filtered and the organic layer was collected, washed with satd. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by chromatography (silica gel: EtOAc/hexane: 1/4) afforded 0.54 g of 3-chloro-5-(1-pyrrolyl)aniline. MS (m/z) 193 (MH+).
Intermediate 4b and 2,5-dimethoxytetrahydrofuran (525mul) are added to acetic acid (17mL) and heated to 110°C for 3 hours. The mixture is then cooled to room temperature, diluted with water and the pH is adjusted to 10 using 2M NaOH. The reaction mixture is extracted using ethyl acetate (4 times). The organic phase is washed with water and saturated brine solution and dried over Na2SO4. The solvent is removed under reduced pressure. The residue is dissolved again in ethyl acetate and the resulting solid particles are removed by filtration. The solvent is again removed under reduced pressure to yield the desired intermediate 4c (790mg).
3-(4-nitrophenyl)-2-pyrrolopropionic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium acetate; acetic acid; In water;
(b) 3-(4-nitrophenyl)-2-pyrrolopropionic acid methyl ester (98) A mixture of <strong>[1991-83-9]4-nitrophenylalanine</strong> (2.03 g, 9.66 mmol), 2,5-dimethoxytetrahydrofuran (2.15 mL, 16.6 mmol), and sodium acetate (1.603 g, 19.5 mmol) in 10 mL of water and 10 mL acetic acid was heated to 100 0 C. for 20 minutes. The black solid was partitioned between EtOAc and H2O. The organic layer was dried and the solvent was removed. 0.6 g of pure compound (3-(4-nitrophenyl)-2-pyrrolopropionic acid) was obtained by column chromatography (5% MeOH/CH2Cl2). The product was treated with TMSCHN2 to provide the methyl ester (98).
1) A mixture of <strong>[46004-37-9]4-amino-2-chlorobenzoic acid methyl ester</strong> (0.46 g) and 2,5-dimethoxytetrahydrofuran (0.33 mL) in AcOH (16 mL) was heated under reflux for 2 h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The extract was washed with satd. NaHCO3 and brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane/EtOAc 5/1) to yield 0.48 g of 2-chloro-4-1-pyrrolyl)benzoic acid methyl ester. ESMS: m/z 236 (MH-). 2)The product obtained above was hydrolyzed with LiOH to give the title compound. ESMS: m/z 220 (M-H)-.
REFERENTIAL EXAMPLE 43 Production of 6-methyl-3-(1-pyrrolyl)benzyl alcohol 158 mg of <strong>[18595-12-5]methyl 3-amino-6-methylbenzoate</strong> was dissolved in 3 ml of acetic acid, and 139 mg of 2,5-dimethoxytetrahydrofuran was added. The mixture was heated under reflux for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography Wakogel C-200, 10 g; eluding solvent: hexane/ethyl acetate=10/1) to give 185 mg (yield 87%) of methyl 3-(1-pyrrolyl)-6-methylbenzoate, m.p. 56-57 C.
PREPARATION 53 A solution of ethyl 4-aminocinnamate (1 g) and 2,5-dimethoxytetrahydrofuran (0.677 ml) in toluene (3 ml) and acetic acid (3 ml) was refluxed for 5 hours with removing methanol. After cooling, the mixture was washed with water twice and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified with column chromatography eluding with n-hexane -ethyl acetate to give ethyl 4-(1-pyrrolyl)cinnamate (740 mg) as colorless crystals. mp: 86-87° C. NMR (CDCl3, delta): 1.37 (3H, t, J=7 Hz), 4.29 (2H, q, J=7 Hz), 6.32-6.49 (2H), 7.12 (2H, t, J=1 Hz), 7.41 (2H, d, J=9 Hz), 7.60 (2H, d, J=9 Hz), 7.69 (1H, d, J=16 Hz)
Stage B: 6-methoxy-3-nitro-2-(1-pyrrolyl)pyridine 10.45 g (0.0791 mol; 1.2 eq) of 2,5-dimethoxy-tetrahydrofuran and 12.00 g (0.0791 mol; 1.2 eq) of 4chloropyridine hydrochloride are stirred for 10 minutes in 300 cm3 of dioxane. 11.15 g (0.0659 mol) of 2-amino-6methoxy-3-nitropyridine are added and the solution is brought to reflux for 4 h. The dioxane is evaporated under reduced pressure. The residue is taken up in 250 cm3 of water and then extracted with 500 cm3 of ethyl ether. The ether phase is washed with water, separated by settling, dried over MgSO4, decolored with animal charcoal and concentrated on a rotary evaporator. 11.12 g (0.0507 mol) of an orange powder are obtained. Yield: 76.9% Melting point: 70 C.
With sodium acetate; acetic acid; In water; 1,2-dichloro-ethane; at 76℃; for 4h;Product distribution / selectivity;
2,5-Dimethoxytetrahydrofuran (DMT, 0.29 mL, 2.23 mmol) was added to around bottom flask (50 mL) containing the following biphasic mixture of L-Cystine dimethyl ester dihydrochloride 98% purity (Aldrich, 0.343 g, 1.0 mmol), sodium acetate (0.1674 g, 2.0 mmol), acetic acid (0.55 mL), 1,2-dichloroethane (1.66 mL) and distilled water (1.1 mL). The medium is refluxed during 4 hours at 76 C. under a nitrogen atmosphere. After cooling to room temperature, dichlormethane (198 mL) is added to the reaction mixture. The separated organic layer is then extracted with water (5×290 mL), dried over anhydrous MgSO4, filtrated (5 micrometer Buchner filter) and evaporated under vacuum. The crude orange oil is purified by two successive column chromatographies on silica gel Si-60 (Merck) 43-60 mm, using the following solvent mixtures: 1) first column, 25 g: SiO2, diethyl ether 400 ml, Rf=0.67 (analytical TLC onto Si-F254 Merck, UV-revelation). 2) second column, 25 g SiO2, CH2Cl2/EtOH 9/1 450 ml. The purified dipyrrole ester is obtained as a yellow oil which is stored at 4 C. away from light (yield 25%). Structural Analyses 1H: NMR (CDCl3, 300 MHz): d (ppm): 6.80 (t, 2.1 Hz, 2H), 6.30 (t, 2.1 Hz, 2H), 5.10-4.90 (m, 1H), 3.78-3.63 (dd, 3H), 3.40 (m, 1H), 3.20 (dd, 3.9 Hz, 1.2 Hz, 13C:NMR (CDCl3, 75 MHz): d (ppm): 169.80 (CO), 169.70 (CO), 120.33 (CH), 109.74 (CH), 109.66 (CH), 109.60 (CH), 109.35 (CH), 60.95 (CH), 60.58 (CH), 53.27 (CH), 53.20 (CH), 33.96 (CH2), 33.33 (CH2); High-resolution MS (CI, i-Butane): m/z 369.093109 (16.94%, MH+), (calculated mass: 369.094276: 3.2 ppm difference).
With 4-chlorpyridine hydrochloride; In 1,4-dioxane; for 1h;Heating / reflux;
Referential Example 5; 5-Chloro-3-iodo-2-(1H-pyrrol-1-yl)pyridine; [Show Image] [Show Image] <strong>[211308-81-5]5-Chloro-3-iodo-2-amino-pyridine</strong> (3.50 g) was dissolved in 1,4-dioxane (70 mL). To the resulting solution were added 2,5-dimethoxytetrahydrofuran (2.31 g) and 4-chloropyridine hydrochloride (2.89 g). The resulting mixture was heated under reflux for 1 hour. After the reaction mixture was cooled to room temperature, it was concentrated. The concentrate was diluted with water and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The filtrate was then concentrated. The residue thus obtained was purified by silica gel column (ethyl acetate:hexane=1:10) to give the title compound (4.14 g). 1H-NMR(CDCl3)delta:6.34(2H,t,J=2.1Hz)7.18(2H,t,J=2.1Hz)8.26(1H,d ,J=2.4Hz),8.39(1H,d,J=2.4Hz).
Intermediate 42: 2-Bromo-5-(lH-pyrrol-l-yl)benzoic acid; Dimethoxytetrahydrofuran (3.0 mL, 23.1 mmol) was added to a stirred solution of <strong>[2840-02-0]5-amino-2-bromobenzoic acid</strong> (5.0 g, 23.1 mmol) in AcOH (20 mL) and the reaction mixture was heated at 120 0C for 30 minutes. The reaction mixture was cooled, concentrated in vacuo and the residue was diluted with MeOH/DCM (20:80) and filtered through silica gel, then the filtrate was concentrated in vacuo to give the title compound as an off-white solid (4.20 g, 68%) that was used crude in the next reaction: 1H NMR 56.28 (2H, t), 7.43 (2H, t), 7.63 - 7.67 (IH, m), 7.75 (IH, d), 7.87 (IH, d), 13.57 (IH, s); MS 267.
With magnesium iodide etherate; In acetonitrile; at 80℃; for 6h;
General procedure: A Schlenk reaction tube was charged with primary aromatic amide (5.0 mmol), 2,5-dimethoxytetrahydrofuran (6.0 mmol), MgI2 etherate (10% mmol), and acetonitrile (10 mL). The reaction mixture was stirred at 80 C for several hours and then concentrated in vacuo. The residue was purified by flash column chromatography on a silica gel to give the desired product.
With magnesium iodide etherate; In acetonitrile; at 80℃;
General procedure: A Schlenk reaction tube was charged with each amine (5.0 mmol), 2,5-dimethoxytetrahydrofuran (6.0 mmol), MgI2 etherate (10% mmol), and acetonitrile (10 mL). The reaction mixture was stirred at 80 C for several hours and then concentrated in vacuo. Flash column chromatography afforded the desired products. The ratio of each product was determined by column chromatography isolation or GC analysis.
With magnesium iodide etherate; In acetonitrile; at 80℃;
General procedure: A Schlenk reaction tube was charged with each amine (5.0 mmol), 2,5-dimethoxytetrahydrofuran (6.0 mmol), MgI2 etherate (10percent mmol), and acetonitrile (10 mL). The reaction mixture was stirred at 80 °C for several hours and then concentrated in vacuo. Flash column chromatography afforded the desired products. The ratio of each product was determined by column chromatography isolation or GC analysis.
With magnesium iodide etherate; In acetonitrile; at 80℃;
General procedure: A Schlenk reaction tube was charged with each amine (5.0 mmol), 2,5-dimethoxytetrahydrofuran (6.0 mmol), MgI2 etherate (10% mmol), and acetonitrile (10 mL). The reaction mixture was stirred at 80 C for several hours and then concentrated in vacuo. Flash column chromatography afforded the desired products. The ratio of each product was determined by column chromatography isolation or GC analysis.
With ionic liquid immobilized on gamma-Fe2O3(at)SiO2 nanoparticles; In water; at 100℃; for 1.66667h;
General procedure: To a solution of amine (1 mmol) in water (2 ml) was added tetrahydro-2,5-dimethoxyfuran (1.1 mmol) and gamma-Fe2O3(at)SiO2-Sb-IL (0.08 g). The reaction mixture was stirred at 100 C for a certain period of time as required to complete the reaction. During that time, the reaction was monitored constantly by TLC. After completion of the reaction, the catalyst was removed by using a magnet and washed with ethyl acetate. The aqueous solution was extracted by ethyl acetate (3 × 5 ml). The combined organic phase was dehydrated with anhydrous sodium sulfate. After the evaporation of the solvent, the residue was purified by silica gel flash chromatography using petroleum ether/ethyl acetate as the eluent to afford the pure product.
93%
With L-(+)-tartaric acid-choline chloride based deep eutectic solvent; at 90℃; for 1.66667h;Green chemistry;
General procedure: Amine (1 mmol), 2,5-dimethoxytetrahydrofuran (1.1 mmol)and L-(+)-tartaric acid-choline chloride based DES (1.5 g) were added to a 50 mL round bottom flask and the reaction mixturewas stirred at 90 C. The progress of the reaction was monitoredby TLC. After completion of the reaction, the mixture was cooled to room temperature and the product was extracted with ethyl acetate.After the evaporation of the solvent, the residue was purified by columnchromatography on silica gel to afford the pure product. The DES wasdried under vacuumand reused for the next cycle.
65%
With magnesium iodide etherate; In acetonitrile; at 80℃; for 10h;
General procedure: A Schlenk reaction tube was charged with primary aromatic amine (5.0 mmol), 2,5-dimethoxytetrahydrofuran (6.0 mmol), MgI2 etherate (10% mmol), and acetonitrile (10 mL). The reaction mixture was stirred at 80 C for several hours and then concentrated in vacuo. The residue was purified by flash column chromatography on a silica gel to give the desired product.
With pyridinium p-toluenesulfonate; In 1,4-dioxane; at 50℃; for 1h;Reflux;
To a stirred solution of 2,5-dimethoxytetrahydrofuran (b) (1.6 mL, 12.4 mmol, 1.3 equiv) and PPTS (3.2 g, 12.4 mmol, 1.3 equiv) in 1,4-dioxane (20 mL) at 50 C, a solution of aminopyrrole (a) (1.47g, 9.55 mmol, 1.0 eq.) in 1,4-dioxane (6 mL) was added slowly. The resulting mixture was brought to reflux and stirred for 1 h. The reaction mixture was then concentrated, dissolved in EtOAc (50 mL) and dried over anhydrous MgS04. The crude product was purified by flash column chromatography (10% EtOAc in Hexane) to give (c) as a yellow solid (1.036 g, 53% yield). 1H NMR (400 MHz, CDC13) delta 8.99 (s, 1H), 7.04 - 7.01 (m, 2H), 6.89 (t, J= 3.1 Hz, 1H), 6.29 (t, J = 2.9 Hz, 1H), 6.27 - 6.24 (m, 2H), 4.28 (q, J= 7.1 Hz, 2H), 1.29 (t, J= 7.1 Hz, 3H).
43%
With pyridinium p-toluenesulfonate; In 1,4-dioxane; for 0.5h;Reflux; Inert atmosphere;
To a stirred solution of 2,5-dimethoxytetrahydrofuran (0.681 g, 5.15 mmol, 1.4 equiv) and PPTS (1.29 g, 5.15 mmol, 1.4 equiv) in 1,4-dioxane (18 mL) at 50 C, aminopyrrole 3 (0.567 g, 3.68 mmol, 1.0 equiv) in 1,4-dioxane (4 mL) was added slowly and the reaction was brought to reflux and stirred for 30 min. The reaction mixture was then concentrated, dissolved in EtOAc (20 mL) and filtered through a pad of silica gel. Flash column chromatography (silica gel, hexanes:EtOAc 9:1) yielded bispyrrole 5 (0.323 g, 1.58 mmol, 43% yield) as a brown solid.
With pyridinium p-toluenesulfonate; In 1,4-dioxane; at 50℃; for 0.5h;
Marinopyrrole A was synthesized by a previously described method (Nicolaou. K.C., etai, Tetrahedron Letters, 2011, 52, 2041-2043) with minor modifications (Scheme 1). Briefly, a solution of aminopyrrole 1, 2, 5-dimethoxytetrahydrofuran and PPTS in 1,4-dioxane was stirred at 50 C for 30 minutes. The mixture was concentrated, dissolved in ethyl acetate, and filtered through a pad of silica gel. The residue was chromatographed on silica gel (10% ethyl acetate- hexane) to give 3 as a brown solid. To a solution of 2-iodoanisole in THF, BuLi was added at - 78 C and the solution was stirred for 20 minutes. The compound 3 was dissolved in THF and slowly added to the lithiated anisole solution and stirred for 1 hour at -78 C. The reaction was quenched by the addition of NH4C1 solution, diluted with EtOAc, washed with water, concentrated and purified by silica gel column chromatography using 10% EtOAc in hexane to yield 4. O-anisic acid in benzene was refluxed with SOCl2 to convert into acid chloride. The solution was then concentrated and the acid chloride was dissolved in CH2C12 and added to a slurry of A1C13 in CH2C12 at 0 C and then a solution of 4 in CH2C12 was added slowly. The resulting solution was allowed to warm to 25 C and stirred overnight. A saturated aqueous solution of NaHC03 and CH2C12 was then added and the resulting mixture was stirred for 1 hour and then filtered through Celite. The biphasic mixture was extracted with CH2C12, and the combined organic layers were dried, filtered, and concentrated. The residue was purified by flash column chromatography (hexanes: EtOAc 2:3) to afford 5. To a solution of 5 in CH2C12 at 0 C, S02C12 was added dropwise, and the solution was allowed to stir at 0 C for 1 h. Saturated aqueous NaHC03 solution was added and the resulting biphasic mixture was extracted with CH2C12. The combined organics concentrated and the residue was purified by flash column chromatography (hexanes: EtOAc 4: 1) to afford (±)-6 as an off- white solid. To a solution of (±)-6 in CH2C12 at 0 C, 1 M solution of BBr3 in CH2C12 was added drop wise and the mixture was allowed to stir at 0 C for 1 h. Saturated aqueous NaHC03 was then added, and the biphasic mixture was extracted with CH2C12. The combined organics were concentrated and the residue was purified by flash column chromatography (hexanes :EtO Ac 9: 1) to afford 7 as a bright yellow solid. To synthesize KA01, Ac20, Et3N and DMAP were added to a solution of 7 in CH2C12, and the resulting solution was stirred at 25 C for 12 hours. The reaction mixture was diluted with EtOAc and washed sequentially with aqueous 1 M HC1, H20, and brine. The organic layer was then dried (MgS04), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 4:1) to provide 8 (KA01). The purity of KAOl was confirmed by HPLC and structure was confirmed by NMR and mass spectroscopic methods
A mixture of <strong>[6575-11-7]2-amino-6-chlorobenzonitrile</strong> (17.72 g, 0.116 mol) and tetrahydro-2,5- dimethoxyfuran (0.116 mol) in HO Ac (100 ml) was stirred and refluxed for 30 min. Subsequently, the mixture was cooled and evaporated. The residue was purified over silica gel on a glass filter (eluent: DCM). The product fractions were collected and the solvent was evaporated. The residue was crystallized from EtOH. Yield: 18.83 g of intermediate 1 (80 % yield).
80%
With acetic acid; for 0.5h;Reflux;
A mixture of <strong>[6575-11-7]2-amino-6-chlorobenzonitrile</strong> (17.72 g, 0.116 mol) and tetrahydro-2,5- dimethoxyfuran (0.116 mol) in HO Ac (100 ml) was stirred and re fluxed for 30 min. Subsequently, the mixture was cooled and evaporated. The residue was purified over silica gel on a glass filter (eluent: DCM). The product fractions were collected and the solvent was evaporated. The residue was crystallized from EtOH. Yield: 18.83 g of intermediate 3 (80 % yield).
80%
With acetic acid; for 0.5h;Reflux;
A mixture of <strong>[6575-11-7]2-amino-6-chlorobenzonitrile</strong> (17.72 g, 0.116 mol) and tetrahydro-2,5-dimethoxyfuran (0.116 mol) in HOAc (100 ml) was stirred and refluxed for 30 mm. Subsequently, the mixture was cooled and evaporated. The residue was purified over silica gel on a glass filter (eluent:DCM). The product fractions were collected and the solvent was evaporated. The residue was crystallized from EtOH. Yield: 18.83 g of intermediate 3 (80% yield).
General procedure: A mixture of <strong>[103273-01-4]2-bromo-4-tert-butylaniline</strong> (2.28 g, 10 mmol), 2,5-dimethoxytetrahydrofuran (4.2 g, 30 mmol) and glacial acetic acid (150 mL) in a 250 mL three-necked RB flask was refluxed under nitrogen for 17 h. Then it was cooled, poured into aq. HCl (200 mL) and extracted with CH2Cl2, then combined organic phase was washed with water and dried over MgSO4. After workup, the crude product was purified by column chromatography (PE) to afford 3ac as a white powder (1.97 g, 52 %); Rf = 0.28 (PE); m. p. 138 -140 C; 1H-NMR (CDCl3, 300 MHz) delta: 8.18 (d, J = 7.5 Hz, 2H), 7.85 (d, J = 11.4 Hz, 1H), 7.55 (d, J = 10.8 Hz, 1H), 7.42 (m, 3H), 7.29 (m, 2H), 7.12 (d, J = 7.8 Hz, 2H), 1.45 (s, 9H); 13C-NMR (CDCl3, 100 MHz) delta: 153.85, 141.01, 133.88, 131.20, 130.45, 126.03, 125.89, 123.42, 123.20, 120.35, 119.89, 110.18, 36.06, 31.32.
A solution of 2-amino-6-methyl enzonitrile (25.0 g, 0.189 mol) and tetrahydro-2,5- dimethoxyfuran (25.0 g, 0.189 mol) in HOAc (200 ml) was refluxed for 4 h. After reaction, the solvent was evaporated and the product was dried in vacuo and directly used as such in the next reaction step. Yield: 33.0 g of intermediate 1.
33 g
With acetic acid; for 4h;Reflux;
A solution of <strong>[56043-01-7]2-amino-6-methylbenzonitrile</strong> (25.0 g, 0.189 mol) and tetrahydro-2,5-dimethoxythran (25.0 g, 0.189 mol) in HOAc (200 ml) was refluxed for 4 h. After reaction, the solvent was evaporated and the product was dried in vacuo and directly used as such in the next reaction step. Yield: 33.0 g of intermediate 1.
Step 1: 1 -(5-Chloro-2-ethylphenyl)-1 H-pyrrole 5-Chloro-2-ethylaniline (10.8 g, 69.44 mmoA) and 25-dimethoxy-tetrahydrofuran (9.87 mL, 76.38 mmoA) was refluxed for 3 h n AcOH (20 mL), The reacton mixture was evaporated and the residue was dUuted n EtOAc, washed wfth water, NaHCO3 saturated solution, brine, and then dred over Na2SO4, The sovent was evaporated and the crude was purified by Biotage SP1 Flash Chromatography (gradient euton from 0% to 15% of EtOAc in hexane) to afford the title compound (12.52 g, 88%).1H NMR (600 MHz, DMSO-d6) 7.36 - 7.47 (m, 2H), 7.31 (d, J = 1.3 Hz, 1 H), 6.93 (t, J = 2.1 Hz, 2H), 6.23 (t, J = 2.1Hz, 2H), 2.46 (q, J = 7.5 Hz, 2H), 0.99 (t, J = 7.5 Hz, 3H).
General procedure: A 100-mL round-bottomed single-neck flask equipped with a condenser and a magnetic stir bar was charged with appropriated 4-substituted-2-nitroaniline (25.0mmol), 2,5-dimethoxytetrahydofurane (25.0mmol) and 40mL of glacial acetic acid. The flask was refluxed until disappearance of starting material (ca. 2 h). After the reaction mixture was cooled to rt, removal of the volatiles under reduced pressure gave the crude product which was purified by column-chromatography (Petroleum Ether/EtOAc=9:1 then 7:3) to give the desired 1-(4-substituted-2-nitrophenyl)-1H-pyrrole.
4-methoxy-2-(1H-pyrrol-1-yl)benzo[d]thiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With 4-chlorpyridine hydrochloride; In 1,4-dioxane; for 3h;Inert atmosphere; Reflux;
General procedure: To a solution of the appropriate arylamine (29.4 mmol)in dioxane (210 ml), 2,5-dimethoxytetrahydrofuran (5.36 g,40.6 mmol) and 4-cloropyridinium hydrochloride (6.79 g,45.3 mmol) were added. The mixture was refluxed under anitrogen atmosphere for 3 h. After removal of the solventunder reduced pressure, the residue was treated with 50 mlof CH2Cl2 and filtered. The filtrate was concentrated invacuo and the residue was purified with flash column chromatography,using various solvent mixtures as eluent. In thecase of 1, after removal of the solvent under reduced pressure,the residue was treated with 50 ml of EtOAc and filtered.EtOAc was removed under reduced pressure from thefiltrate and the residue was treated with 10% NaHCO3 (20ml) and extracted with EtOAc (2 x 50 ml). The aqueousphase was cooled (ice bath) and acidified with 10% HCl, andextracted with EtOAc (2 x 50 ml). The combined organicextracts were washed with a saturated NaCl solution, driedover anhydrous Na2SO4 and concentrated under reducedpressure.
methyl 2-chloro-5-(pyrrolidin-1-yl)isonicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1 g
With sodium tetrahydroborate; sulfuric acid; In tetrahydrofuran; methanol; at 0 - 20℃; for 48.5h;
Preparation of methyl 2-chloro-5-(pyrrolidin-l-yl) isonicotinate: to a solution of <strong>[1073182-59-8]methyl 5-amino-2-chloroisonicotinate</strong> (2 g, 10.6 mmol, 1 eq) in MeOH: THF (1 : 1) (80 mL), 4N H2S04 (20 mL) was added 2,5-dimethoxytetrahydrofuran (4.19 g, 31.8 mmol, 3 eq) and NaBH4 (1.2 g, 31.8 mmol, 3 eq) at 0 C over a period of 30 min and stirred at RT for 48 h. After completion, the reaction mixture was poured into water (50 mL), neutralized with NaHC03 and extracted with EtOAc (3 x 25 mL). The combined extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2S04, filtered and evaporated. The crude residue was purified by column chromatography (100 -200 mesh silica EtOAc: Hexane (10: 90)), to afford to 2-chloro-5-(pyrrolidin-l- yl) isonicotinate (1 g) as off white solid.
5-bromo-3-nitro-2-(1H-pyrrol-1-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With acetic acid; for 4h;Reflux;
<strong>[6945-68-2]5-bromo-3-nitropyridine-2-amine</strong> 25g (114.67mmol) and then 2,5-dimethoxytetrahydrofuran 16.34mL (126.13mmol) is dissolved into acetic acid (150mL) it was stirred under reflux for 4 hours. When the reaction was complete and extracted with NaHCO3 solution into a supersaturated after EA and the organic layer was dried over MgSO4. In EA / Hex eluant separated by column chromatography to obtain the target compound 83-1 , 15.37g (50%).
General procedure: A mixture of 4-chloro-2-nitroaniline SI-1 (8.6 g, 50 mmol) and 2,5-dimethoxytetrahydrofuran SI-2 (7.3 g, 55 mmol) in acetic acid (140 mL) was refluxed with vigourous stirring. After the reaction finished as indicted by TLC, the reaction mixture was cooled to room temperature, and then poured into water. The mixture was then extracted three times with diethyl ether. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude residue was treated with silica gel chromatography to give as a light-yellow product SI-3 (8.7 g, 78%)
1-(1H-pyrrol-1-yl)cyclopropane-1-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.8 g
In the 2, 5 - dimethoxy tetrahydrofuran (3 . 16 g, 24 mmol) and 20 ml water is added in the mixed solution of 1 ml of concentrated hydrochloric acid and stir at room temperature for 1 hour; then adding sodium acetate solid (3 . 28 g, 40 mmol) and 1 - amino-cyclopropane -1 - carboxylic acid (2 . 02 g, 20 mmol). The mixed liquid stir at room temperature overnight; then diluted with water, adding 1 M hydrochloric acid in about pH4; then ethyl acetate extraction; separating the ethyl acetate, then dilute sodium chloride aqueous solution for washing twice; anhydrous sodium sulfate solid dry ethyl acetate phase; filtering to remove the drying agent, the filtrate on the rotary evaporimeter turns on lathe does; residue by column chromatography to obtain the 1.8 g product1 A.
Step i. DMF (30 mL) and ethyl-5-bromovalerate (S4) (1.5 mL, 9.48 mmol) were added to NaN3 (1.880 g, 28.92 mmol) maintained under N2. The ensuing mixture was magnetically stirred for 18 then H2O (30 mL) was added. The aqueous phase was extracted with Et2O (4x 30 mL) and the organic extracts were combined and successively washed with H2O (3x 20 mL) and brine (2x 30 mL). The organic extracts were then dried (MgSO4), filtered, and concentrated under reduced pressure to provide a pale-yellow crude residue containing compound S5 (1.90 g). Compound S5 was not purified, but immediately subject to the reaction outlined below. Step ii. HCl (1.6 mL of a 10 M aqueous solution) and 5% Pd/C (250 mg, 0.12 mmol, 1.2%) were added toa solution of compound S5 in EtOH (60 mL). The ensuing mixture was reacted under H2 in a Parr shaker hydrogenator (33 psi). After 1 h, the mixture was filtered through as plug of Celite then concentrated under reduced pressure to provide a compound S6 (2.63 g) as a colourless solid. Compound S6 was not purified, but immediately subject to the reaction outlined below. Step iii. Glacial acetic acid (380 muL, 6.66 mmol) was added to a magnetically stirred solution of 2,5-dimethoxytetrahydrofuran (1.70 mL, 13.1 mmol) in H2O (30 mL) and ensuing solution was heated at reflux under N2. After 2.5 h, the magnetically stirred solution was cooled to r.t. and CH2Cl2 (35 mL) and NaOAc (1.37 g, 16.6 mmol) and compound S6 (as a 15 mL aqueous solution) were added; the flask waswrapped in foil to exclude light. After 18 h, the pH of the aqueous phase was adjusted to ~9 with Na2CO3 (saturated aqueous solution) and the phases separated. The aqueous phase was further extracted with CH2Cl2 (4x 30 mL), the organic extracts were combined, dried (MgSO4) and passed through a plug ofsilica gel (CH2Cl2 elution) to provide pyrrole S7 (1.41 g, 7.20 mmol, 76% yield over 3 steps) as a colourless oil.
With iron(III) chloride; In water; at 100℃; for 4h;
Add the raw materials <strong>[369-35-7]2-fluoro-4-nitroaniline</strong> (3.9g, 0.025mol), 2,5-dimethoxytetrahydrofuran (3.96g, 0.30mol) and FeCl3 (0.1g, 0.38mmol) to water (50mL) The reaction was carried out at 100 C for 4 hours, and the reaction solution was cooled to room temperature and suction filtered to obtain 4.26 g of a solid with a yield of 83.7%.
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