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[ CAS No. 496-16-2 ]

{[proInfo.proName]} (Synonyms:2,3-Dihydrobenzofuran) ,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 496-16-2
Chemical Structure| 496-16-2
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Product Details of [ 496-16-2 ]

CAS No. :496-16-2 MDL No. :MFCD00005855
Formula : C8H8O Boiling Point : 188-189°C at 760 mmHg
Linear Structure Formula :- InChI Key :-
M.W :120.15 g/mol Pubchem ID :10329
Synonyms :

Safety of [ 496-16-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 496-16-2 ]

  • Upstream synthesis route of [ 496-16-2 ]
  • Downstream synthetic route of [ 496-16-2 ]

[ 496-16-2 ] Synthesis Path-Upstream   1~30

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  • [ 66826-78-6 ]
YieldReaction ConditionsOperation in experiment
70.3% With bromine In 1,4-dioxane; ethyl acetate Preparation 94
To an ice-cooled dioxane (30 ml) was slowly added liquid bromine (2.66 g) and this mixture was stirred for 30 minutes at said temperature.
To the mixture was added dropwise 2,3-dihydrobenzofuran (2 g), and the resulting mixture was stirred for 3 hours at room temperature.
The solvent was removed under reduced pressure.
The residue was dissolved in AcOEt (50 ml) and the solution was washed with saturated aqueous NaHCO3 solution and brine, and dried over MgSO4.
The solvent was evaporated to give an orange oil as a crude product.
The crude product was purified on an SiO2 column (hexane-AcOEt 20:1) to give 2.33 g of 5-bromo-2,3 dihydrobenzofuran as white crystals (yield 70.3percent).
1H-NMR (300 MHz, CDCl3, δ): 3.11(2H, t, J=11 Hz), 4.57(2H, t, J=11 Hz), 6.66(1H, d, J=8 Hz), 7.20(1H, d, J=8 Hz), 7.30(1H, s)
28% at 10℃; for 1.16667 h; To a chilled (10°C) solution of 10 g (83 mmol) of 2, 3-dihydrobenzofuran in 50 mL of acetic acid, 4 mL (78 mmol) of bromine in 6 mL of acetic acid was added dropwise over a 10 minute period. After 1 hour, the mixture was made basic by cautiously pouring the reaction mixture into saturated/solid aqueous sodium bicarbonate and stirring overnight. The mixture was then extracted with three 100 mL portions of EtOAc. The combined organic layers were washed with two 50 mL portions of saturated aqueous sodium bicarbonate, three 50 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated to afford a yellow oil. The oil was diluted with hexane and passed through a pad (600 mL funnel) of silica gel eluting with hexane to afford a white solid which was diluted with cold (dry ice-acetone) hexane and collected by filtration to afford 4.7 g (28percent) of the title compound as a white solid, m. p. 45°C- 48°C. The filtrate was concentrated to afford 5.1 g of 5-bromo-2, 3-dihydrobenzofuran which was 70percent pure.
Reference: [1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 16, p. 4313 - 4336
[2] Chemistry - A European Journal, 2017, vol. 23, # 5, p. 1044 - 1047
[3] Synthesis, 1988, # 12, p. 950 - 952
[4] Patent: US6333324, 2001, B1,
[5] Patent: WO2003/82787, 2003, A1, . Location in patent: Page/Page column 137-138
[6] Synlett, 2005, # 18, p. 2837 - 2842
[7] Patent: US6235771, 2001, B1,
[8] Patent: WO2007/27917, 2007, A2, . Location in patent: Page/Page column 23-25
[9] Patent: EP1394147, 2004, A1, . Location in patent: Page 92
  • 2
  • [ 496-16-2 ]
  • [ 68-12-2 ]
  • [ 55745-70-5 ]
YieldReaction ConditionsOperation in experiment
100% at 70 - 90℃; for 9.5 h; 2,3-Dihydrobenzofuran (100 g, 832 mmol) and N,N-dimethylformamide (134 g, 1830 mmol) were mixed and heated, and phosphorus oxychloride (255 g, 1643 mmol) were added thereto at an inner temperature of 70 to 80°C over 2 hrs.
The reaction mixture was heated at an inner temperature of 80 to 90°C and stirred for 7.5 hrs.
Then, the resulting mixture was added dropwise to water (1000 g) under cooling, and stirred at room temperature for 5 hrs.
The resulting mixture was extracted with toluene, and the extract was washed sequentially with water, saturated sodium bicarbonate aqueous solution and water, and the organic layer was concentrated under vacuum to give a toluene solution of the title compound (amount 340 g, apparent yield 100percent).
98%
Stage #1: at 30 - 70℃;
Stage #2: With water In N,N-dimethyl-formamide at 20℃; for 1 h;
To a solution of 2,3-dihydrobenzofuran (600.0 g, 4.99 moles) in N,N-dimethylformamide(804 g, 10.98 moles) was added drop-wise phosphorous oxychloride (1530 g, 9.96 moles) over a period of 45 min maintaining the temperature of reaction mixture between 30- 35°C. The mixture was slowly heated to 7O0C and stirred for 8 hr. The mixture was cooled to room temperature and poured into 8 lit of ice-cold water and stirred for 1 hr. The reaction mixture was saturated with sodium chloride and then the product was extracted with ethyl acetate (6L). The extract was washed with saturated aqueous solution of sodium bicarbonate (1.5 L) and concentrated under reduced pressure to obtain (725 g, 98percent) of the title compound.
93% at 85℃; for 12 h; Cooling with ice (31.4 ml, 0.333πο1) was slowly added dropwise to N, N-dimethylformamide (28.4 ml, 0.366 mol). After 10 minutes of reaction, the mixture was slowly added dropwise , 3-dihydrobenzofuran (1,20.0g, 0.166πο1), remove the ice bath, heating at 85 ° C stirring reaction for 12 hours, the reaction system into the ice water, add sodium hydroxide solution, adjust the PH value The organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh), petroleum ether-ethyl acetate ( 5: 1) as eluant, to give 5-aldehyde dihydrobenzofuran (2,22.8 g) in a yield of 93percent.
85% at 80 - 85℃; for 4 - 5 h; Example 1; Synthesis of 2,3-dihydrobenzofuran-5-carboxaldehdye:Phosphorous oxychloride (255.58 g, 1.666 mol) was slowly added to a solution of DMF (355.0 ml) and 2, 3-dihydrobenzofuran (100 g, 0.833 mol) maintaining the temperature 80-850C. The reaction mixture was stirred for 4-5 hr and the reaction progress monitored by HPLC. The reaction mixture was then poured into ice water and extracted with toluene (2000 ml). The organic layer was washed with 5percent sodium bicarbonate solution (500 ml) and then 10percent brine solution (500 ml). The organic layer was distilled off under vacuum at 50-600C. A liquid product was isolated. Yield: 85- 90percent, Purity: 90-92 percent
14.5 g at 70 - 80℃; for 10 h; Take a 1001 ^ three mouth reaction bottle,2,3-dihydrobenzofuran (128, 0.1111) was dissolved in nitrogen,Nitrogen-dimethylformamide (120 g, 1.64 mil) was placed in a reaction flask,Heated to 70 ° C to 80 ° C in 2 hours with mechanical agitation, In part by adding phosphorus pentachloride / nitrogen,Nitrogen-dimethylformamide mixed formylating reagent (25 g, 0.2 mol).The reaction mixture was incubated for 8 hours.After the reaction,The reaction mixture was added dropwise to ice water (l0 g) and stirred at room temperature for 5 hours.Toluene 50mL extraction,Organic layer followed by water,Saturated aqueous sodium bicarbonate solution and washed with water,Dried over anhydrous sodium sulfate,filter,The organic layer was concentrated to give product 2, 3-dihydrobenzofuran-5-carbaldehyde (14. 5 g, 0.08 mil).This product can be used for the production of lamivudine.

Reference: [1] Patent: EP1792899, 2007, A1, . Location in patent: Page/Page column 11
[2] Patent: WO2010/41271, 2010, A2, . Location in patent: Page/Page column 28
[3] Letters in Drug Design and Discovery, 2013, vol. 10, # 7, p. 561 - 571
[4] Patent: CN102766135, 2017, B, . Location in patent: Paragraph 0035-0036
[5] Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4222 - 4239
[6] Patent: WO2008/151170, 2008, A2, . Location in patent: Page/Page column 45
[7] Patent: CN106554345, 2017, A, . Location in patent: Paragraph 0032-0033
[8] Patent: WO2008/150953, 2008, A1, . Location in patent: Page/Page column 29
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YieldReaction ConditionsOperation in experiment
100% With trichlorophosphate In water; N,N-dimethyl-formamide Reference Example 1:
Synthesis of 2,3-dihydrobenzofuran-5-carbaldehyde
2,3-Dihydrobenzofuran (100.0 g, 832.3 mmol) and N,N-dimethylformamide (133.8 g, 1830.6 mmol) were mixed and heated, and phosphorus oxychloride (255.2 g, 1643.0 mmol) was added dropwise thereto at an inner temperature of 70 to 80OEC over 2 hours.
The mixture was heated to an inner temperature of 80 to 90OEC, stirred for 7.5 hours, cooled and then added dropwise to 1000 g of water, followed by stirring at room temperature for 5 hours.
After extracting with toluene and washing in turn with water, saturated sodium bicarbonate water and water, the organic layer was concentrated under reduced pressure to obtain a toluene solution of the title compound (yield: 340 g, apparent yield: 100percent)
100% With trichlorophosphate In water; N,N-dimethyl-formamide REFERENCE EXAMPLE 1
Synthesis of 2,3-Dihydrobenzofuran-5-carbaldehyde
2,3-Dihydrobenzofuran (100.0 g, 832.3 mmol) and N,N-dimethylformamide (133.8 g, 1830.6 mmol) were mixed and heated, and phosphorus oxychloride (255.2 g, 1643.0 mmol) was added dropwise thereto at an inner temperature of 70 to 80° C. over 2 hours.
The mixture was heated to an inner temperature of 80 to 90° C., stirred for 7.5 hours, cooled and then added dropwise to 1000 g of water, followed by stirring at room temperature for 5 hours.
After extracting with toluene and washing in turn with water, saturated sodium bicarbonate water and water, the organic layer was concentrated under reduced pressure to obtain a toluene solution of the title compound (yield: 340 g, apparent yield: 100percent)
94% With sodium hydrogencarbonate; trichlorophosphate In N,N-dimethyl-formamide Reference Example 1
2,3-Dihydrobenzofuran-5-carbaldehyde
To a solution of 2,3-dihydrobenzofuran (100.0 g, 832 mmols) in N,N-dimethylformamide (134.0 g, 1.83 mols) was added dropwise phosphorus oxychloride (255.1 g, 1.66 mols), then the mixture was stirred at 80-90° C. for 7.5 hours.
The mixture was cooled to room temperature, poured into water (1 L) and stirred for 15 hours.
The product was extracted with toluene (1.5 L).
The extract was washed with water (500 mL) followed by a saturated aqueous solution of sodium bicarbonate (500 mL) and concentrated under reduced pressure to obtain 115.9 g (yield: 94percent) of the title compound.
Reference: [1] Patent: EP1334732, 2003, A1,
[2] Patent: US2004/18239, 2004, A1,
[3] Patent: US10098866, 2018, B2,
[4] Patent: US6348485, 2002, B1,
[5] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 16, p. 4313 - 4336
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  • [ 4885-02-3 ]
  • [ 55745-70-5 ]
Reference: [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4222 - 4239
[2] Patent: US6034239, 2000, A,
[3] Patent: EP1199304, 2002, A1, . Location in patent: Referential example 1
[4] Journal of Medicinal Chemistry, 1993, vol. 36, # 23, p. 3700 - 3706
[5] Patent: US6162927, 2000, A,
[6] Patent: US5767144, 1998, A,
[7] Patent: US5622971, 1997, A,
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  • [ 55745-70-5 ]
  • [ 196799-45-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 3, p. 322 - 330
[2] Patent: US2005/187282, 2005, A1, . Location in patent: Page/Page column 8
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  • [ 542-88-1 ]
  • [ 55745-70-5 ]
Reference: [1] Journal of Organic Chemistry, 1984, vol. 49, # 3, p. 409 - 413
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Reference: [1] Journal of the Chemical Society, 1956, p. 2455,246
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  • [ 40492-52-2 ]
Reference: [1] Synthesis, 1988, # 12, p. 950 - 952
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  • [ 13196-10-6 ]
  • [ 152560-12-8 ]
  • [ 152560-17-3 ]
Reference: [1] Tetrahedron: Asymmetry, 1993, vol. 4, # 6, p. 1307 - 1324
[2] Tetrahedron: Asymmetry, 1993, vol. 4, # 6, p. 1307 - 1324
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  • [ 13196-10-6 ]
Reference: [1] Tetrahedron: Asymmetry, 1993, vol. 4, # 6, p. 1307 - 1324
[2] Tetrahedron: Asymmetry, 1993, vol. 4, # 6, p. 1307 - 1324
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  • [ 35700-40-4 ]
YieldReaction ConditionsOperation in experiment
54.7% With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In hexane a.
Preparation of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a)
To a solution of n-BuLi (1.7 M, 123 ml, 0.21 mol) in 400 ml of hexane at room temperature was added 24.3 g (0.21 mol) of N,N,N',N'-tetramethylethylenediamine (TMEDA), followed by a hexane (40 ml) solution of 2,3-dihydrobenzo[b]furan (14) (12.56 g, 0.11 mol).
The mixture was stirred under argon at room temperature for 4 hours, and then poured into dry ice (pre-washing with anhydrous ether).
After stirring at ambient temperature overnight, the mixture was diluted with water (300 ml), and the layers separated.
The aqueous layer was acidified with conc. HCl to pH 1, cooled and the precipitate collected on a filter.
This was recrystallized from CH2 Cl2 to give 15a (9.43 g, 54.7percent) as a white solid, mp 167°-169.5° C.
54.7% With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In hexane a.
Preparation of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a)
To a solution of n-BuLi (1.7 M, 123 ml, 0.21 mol) in 400 ml of hexane at room temperature was added 24.3 g (0.21 mol) of N,N,N',N'-tetramethylethylenediamine (TMEDA), followed by a hexane (40 ml) solution of 2,3-dihydrobenzo[b]furan (14) (12.56 g, 0.11 mol).
The mixture was stirred under argon at room temperature for 4 hours, and then poured into dry ice (pre-washing with anhydrous ether).
After stirring at ambient temperature overnight, the mixture was diluted with water (300 ml), and the layers separated.
The aqueous layer was acidified with conc. HCl to pH 1, cooled and the precipitate collected on a filter.
This was recrystallized from CH2Cl2 to give 15a (9.43 g, 54.7percent) as a white solid, mp 167-169.5°C.
18% With n-butyllithium; N,N,N,N,-tetramethylethylenediamine; carbon dioxide In tetrahydrofuran; sodium hydroxide EXAMPLE 21
7-Carboxy-2,3-dihydrobenzofuran(22)
To a stirred solution of 2,3-dihydrobenzofuran (1 g, 0.0083 mol) and dry TMEDA (1 eq.) in dry tetrahydrofuran (30 mL) at -10° C. under argon, was added n-BuLi (1.6 M hexane solution) (5 mL, 0.008 mol).
The reaction mixture was maintained at this temperature for 20 min and then carbon dioxide was bubbled through the reaction mixture as it warmed to room temperature.
The reaction mixture was concentrated in vacuo to afford a yellow oil.
The oil was dissolved in 10percent sodium hydroxide (100 mL), washed with methylene chloride (2*25 mL), and acidified with HCl.
The white solid product was filtered, washed with water and air-dried to afford the carboxylic acid (22) (0.22 g, 18percent).
1 H NMR (CDCl3) δ 7.35(1H,d), 7.11(1H,d), 6.59(1H,t), 4.37(2H,t), 2.99(2H,t).
Reference: [1] Patent: US4888353, 1989, A,
[2] Patent: EP234872, 1991, B1,
[3] Patent: US5122361, 1992, A,
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  • [ 35700-40-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 24, p. 5567 - 5573
[2] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 1999, vol. 54, # 11, p. 1469 - 1473
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5579 - 5601
[4] Journal of Medicinal Chemistry, 1990, vol. 33, # 1, p. 171 - 178
[5] Monatshefte fuer Chemie, 1990, vol. 121, # 11, p. 883 - 891
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  • [ 110-18-9 ]
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  • [ 35700-40-4 ]
Reference: [1] Patent: US5519034, 1996, A,
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  • [ 110-18-9 ]
  • [ 35700-40-4 ]
Reference: [1] Patent: US6207678, 2001, B1,
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  • [ 17403-47-3 ]
YieldReaction ConditionsOperation in experiment
54% With silver nitrate; acetyl chloride In water; acetonitrile at 0 - 20℃; for 5 h; Silver nitrate (1.41 g, 8.32 mmol) and coumaran 3 (0.59 mL, 8.32 mmol) were dissolved in acetonitrile (10 mL) and placed in a 100 mL three-necked flask equipped with a dropping funnel, condenser and drying tube, and thermometer. 0.59 mL (8.32 mmol) of acetyl chloride was added to the reaction mixture at 0°C. As the quantity of silver chloride increased, further dilution with acetonitrile and more vigorous stirring were used to help maintain reactant contact for 1 h at 0–5°C and for 4 h at room temperature. 20 mL of water was added to the reaction flask at 0°C and then an additional 10 mL of water was added when the mixture was at room temperature. Exhaustive treatments of solid and liquid materials with ethyl acetate were used to extract the products. The organic layer was concentrated, dried over MgSO4, and then purified by column chromatography(EA/n-hexane) to give 740 mg of 5 (54percent) as a yellow solid.
44.4% at 65 - 75℃; for 0.5 h; Example 14: Preparation of (R)-2-[[[4-(3-methoxylpropoxy)-3-methyl-2-pyridyl]methyl]-sulfinyl]-6,7-dihydro-3H-benzofuro[5,6-d]imidazole sodium (sodium salt of Compound 30) Step 1: Preparation of 5-nitro-2,3-dihydrobenzofuran [Show Image] 2,3-Dihydrobenzofuran (36 g, 0.3 mol) was added to glacial acetic acid (100 mL), heated to 65°C, then concentrated nitric acid (25 mL, 0.36 mol) was added dropwise into the reaction solution, the temperature of the reaction solution was controlled at 65-75°C. After the end of dropwise addition, the agitation was kept for 0.5 h. It was then cooled to room temperature, filtered, washed with water, and dried to obtain a product (22 g, 44.4percent).
29% With nitric acid; acetic acid In water at 70℃; for 0.5 h; To a solution of 25.5 g (0.212 mol) of 2, 3-dihydrobenzofuran in 175 mL of acetic acid was added about one quarter of 4.5 mL (0.227 mol) of 70percent aqueous nitric acid dropwise. The reaction was monitored by TLC (EtOAc-hexanes (15: 85) ). The mixture was warmed to 70°C where the reaction began. The remainder of the nitric acid was then added while maintaining the reaction at 70°C. After 30 minutes, the reaction was cooled and poured into 1.5 L of ice water. The black solid was collected by filtration washing with water. The solid was partitioned between 500 mL of saturated aqueous sodium bicarbonate and 150 mL of EtOAc. The aqueous layer was separated and extracted with three 150 mL portions of EtOAc. The combined organic layers were washed with three 100 mL portions of saturated aqueous sodium bicarbonate, 100 mL of saturated aqueous ammonium chloride, 100 mL of brine, dried over magnesium sulfate, filtered, and concentrated to afford a red oil/solid. The mixture was dissolved in dichloromethane and passed through a pad of silica gel eluting with dichloromethane and concentrated. The resulting red mixture was triturated with ether-hexanes (1: 1) and filtered to afford 10.5 g (29percent) of 5-nitro-2, 3-dihydrobenzofuran as a tan solid.
17% at 0 - 20℃; for 2 h; To a solution of 20 (27.1 g, 226 mmol) in acetic acid (100 mL) was slowly added nitric acid (11.2 mL, 249 mmol) at 0 °C. After stirring at room temperature for 2 h, the reaction mixture was poured into a mixture of ice and 12 N NaOH (100 mL). The mixture was extracted with EtOAc. The extract was washed with aqueous NH4Cl and brine, dried and concentrated. The residue was purified by flash chromatography on SiO2 with an eluent of 20percent EtOAc/hexane to provide 21 (6.4 g, 17percent) as a pale brown powder; 1H NMR (CDCl3) δ: 3.30 (2H, t, J = 8.7 Hz), 4.74 (2H, t, J = 8.7 Hz), 6.81 (1H, d, J = 9.6 Hz), 8.07-8.12 (2H, m); Anal. Calcd for C8H7NO: C, 58.18; H, 4.27; N, 8.48. Found: C, 57.93; H, 4.19; N, 8.27.

Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5579 - 5601
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 13, p. 3821 - 3830
[3] Patent: EP2532665, 2012, A1, . Location in patent: Page/Page column 41
[4] Patent: WO2003/82787, 2003, A1, . Location in patent: Page/Page column 138-139
[5] Journal of Medicinal Chemistry, 2010, vol. 53, # 18, p. 6681 - 6698
[6] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 21, p. 6430 - 6446
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Reference: [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 3, p. 322 - 330
[2] Patent: US2005/187282, 2005, A1, . Location in patent: Page/Page column 8
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YieldReaction ConditionsOperation in experiment
35% With n-butyllithium In <i>N</i>-methyl-acetamide; hexane; water; ethyl acetate; Petroleum ether (1)
7-Formyl-2,3-dihydrobenzofuran
108 ml of an n-butyllithium solution (2.1M) in hexane and 26.7 g (230 mmol) of tetramethylethylenediamine (TMEDA) are introduced into a 1 liter round-bottomed flask.
The mixture is stirred at room temperature for 15 minutes and 23 g (190 mmol) of 2,3-dihydrobenzofuran are added.
The mixture is stirred for 4 hours at 35° C., cooled to -78° C. and 13.9 g (190 mmol) of dimethylformamide are added.
The temperature is allowed to return to 20° C., 500 ml of water are added and extraction is carried out with ethyl acetate (3*200 ml).
The organic phases are combined, dried and concentrated under vacuum.
The residue is purified by silica flash chromatography (elution: 5percent ethyl acetate in petroleum ether).
9.85 g (Yield: 35percent) of 7-formyl-2,3-dihydrobenzofuran are obtained--M.p.: 55° C.
Reference: [1] Patent: US6063810, 2000, A,
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  • [ 196799-45-8 ]
Reference: [1] Patent: US2008/194650, 2008, A1, . Location in patent: Page/Page column 26
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Reference: [1] Patent: US2008/255230, 2008, A1,
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  • [ 42933-43-7 ]
Reference: [1] ACS Catalysis, 2016, vol. 6, # 12, p. 8162 - 8165
[2] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 21, p. 6430 - 6446
[3] Patent: EP2532665, 2012, A1,
[4] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 13, p. 3821 - 3830
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5579 - 5601
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  • [ 13414-56-7 ]
Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 3, p. 563 - 567
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  • [ 206347-30-0 ]
Reference: [1] Patent: WO2005/58858, 2005, A1, . Location in patent: Page/Page column 168-169
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  • [ 42933-43-7 ]
  • [ 13414-56-7 ]
Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 3, p. 563 - 567
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  • [ 13414-56-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 24, p. 5567 - 5573
  • 25
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  • [ 189035-22-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2003, vol. 46, # 22, p. 4790 - 4798
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  • [ 115010-11-2 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With sulfur trioxide-N,N-dimethylformamide complex In 1,2-dichloro-ethane at 85℃; for 1 h;
Stage #2: With thionyl chloride In 1,2-dichloro-ethane at 20 - 75℃; for 1 h;
3.56 g (29.6 mmol) 2,3-dihydrobenzofuran was added to a slurry of 5.44 g (35.5 mmol) sulfur trioxide-N,N-dimethylformamide complex in 12 mL 1,2-dichloroethane under argon. The reaction was heated to 85° C. for 1 hour and then cooled to room temperature. Thionyl chloride (2.6 mL, 35.5 mmol, 1.2 eq) was added dropwise and the reaction was slowly heated over the course of one hour, by which time it had reached 75° C. The mixture was allowed to cool to room temperature and 100 mL of methylene chloride and 100 mL water were added. The organic extract was separated, dried over magnesium sulfate, filtered and evaporated to afford 6.56 g (100percent) of 2,3-dihydrobenzofuran-5-sulfonyl chloride as a tan oil. (TLC Rf chloroform/hexanes=1/1)
100%
Stage #1: With sulfur trioxide-N,N-dimethylformamide complex In 1,2-dichloro-ethane at 85℃; for 1 h;
Stage #2: With thionyl chloride In 1,2-dichloro-ethane at 20 - 75℃; for 1 h;
2,3-Dihydrobenzofuran-5-sulfonyl chloride; Prepared from commercially available 2,3-dihydrobenzofuran as described in the patent EP 0583960A2.3.56 g (29.6 mmol) 2,3-dihydrobenzofuran was added to a slurry of 5.44 g (35.5 mmol) sulfur trioxide-N,N-dimethylformamide complex in 12 mL 1,2-dichloroethane under argon. The reaction was heated to 85° C. for 1 hour and then cooled to room temperature. Thionyl chloride (2.6 mL, 35.5 mmol, 1.2 eq) was added dropwise and the reaction was slowly heated over the course of one hour, by which time it had reached 75° C. The mixture was allowed to cool to room temperature and 100 mL of methylene chloride and 100 mL water were added. The organic extract was separated, dried over magnesium sulfate filtered and evaporated to afford 6.56 g (100percent) of 2,3-dihydrobenzofuran-5-sulfonyl chloride as a tan oil. (TLC Rf chloroform/hexanes=1/1)
91.7% With thionyl chloride In water; N,N-dimethyl-formamide; toluene EXAMPLE 4
Preparation of 2,3-dihydrobenzofuran-5-sulfonyl chloride
Sulfur trioxide-N,N-dimethylformamide complex (9.2 g, 60 mmoles) and N,N-dimethylformamide (20 ml) were added to a 250 ml, 3-necked flask under nitrogen purge.
The solution was stirred at room temperature and 2,3-dihydrobenzofuran (6.0 g, 50 mmoles) was added dropwise.
The solution was slowly heated to 85°-90° C. over the course of one hour.
The light brown solution was allowed to come to room temperature and thionyl chloride (7.2 g, 60 mmoles) was added dropwise.
The mixture was allowed to stir one hour at room temperature.
The solution was slowly heated to 85° C. and was maintained at that temperature for 1 hour.
The solution was allowed to cool to 40° C. Toluene (25 ml) was added to the solution, which was then poured into a mixture of ice and water (50 ml).
Another 25 ml aliquot of toluene was added.
The mixture was stirred for 10 minutes to dissolve any solids and the layers were separated.
The aqueous layer was extracted with toluene (3*25 ml).
The combined toluene layers were washed with water and dried over magnesium sulfate.
The magnesium sulfate was removed and washed with toluene.
The toluene was removed under vacuum, leaving 10.0 g of the title product (91.7percent yield).
Nuclear magnetic resonance assays confirmed the identity of the title compound. FDMS (MeOH) m/e 218 (M+).
Analysis for C8 H7 ClO3 S: Theory: C, 43.94; H, 3.23. Found: C, 44.14; H, 3.24.
23% With chlorosulfonic acid In dichloromethane at 5 - 20℃; INTERMEDIATE 54 2, 3-Dihydro-benzofuran-5-sulfonyl chloride Chlorosulphonic acid (43.4 g, 0.366 mol) in DCM (10 mL) was added to a cold solution (5 °C) of 2, 3-dihydrobenzofuran (20 g, 0.166 mol) in DCM (200 mL). After the addition the reaction was left with stirring at room temperature overnight. The reaction mixture was quenched with water (150 mL) keeping the temperature below 10 °C. The organic phase was separated and washed with an aqueous solution of NaHCO3 (13,9 g dissolved in 150 mL of water). The organic solvents were evaporated to yield the title compound as a solid residue 3.3 g (23 percent).'H NMR 270 MHz (CDC13) 8 ppm 3.32 (t, J=8. 91 Hz, 2 H) 4.75 (t, J=8. 91 Hz, 2 H) 6.90 (d, J=9. 15 Hz, 1 H) 7.78-7. 90 (m, 2 H)
23% With chlorosulfonic acid In dichloromethane at 5 - 20℃; Intermediate 1; 2,3-Dihydro-benzofuran-5-sulfonyl chlorideChlorosulphonic acid (43.4 g, 0.366 mol) in DCM (10 mL) was added to a cold solution (5 °C) of 2,3-dihydrobenzofuran (20 g, 0.166 mol) in DCM (200 mL). After the addition the reaction was left at room temperature over night. The reaction mixture was quenched with water (150 mL) keeping the temperature below 10 °C. The organic phase was separated and washed with aqueous solution OfNaHCO3 (13, 9 g in 150 mL of water). The organic solvents were evaporated giving a solid residue 3.3 g (23 percent). 1H NMR 270 MHz (Chloroform-d) δ ppm 3.32 (t, J=8.91 Hz, 2 H) 4.75 (t, J=8.91 Hz, 2 H) 6.90 (d, J=9.15 Hz, 1 H) 7.78 - 7.90 (m, 2 H).

Reference: [1] Patent: US2005/267074, 2005, A1, . Location in patent: Page/Page column 25; 44
[2] Patent: US2008/227744, 2008, A1, . Location in patent: Page/Page column 12-13
[3] Patent: US6506754, 2003, B1,
[4] Patent: US5387681, 1995, A,
[5] Patent: WO2005/58858, 2005, A1, . Location in patent: Page/Page column 129
[6] Patent: WO2006/62481, 2006, A1, . Location in patent: Page/Page column 27
[7] Patent: US5968942, 1999, A,
[8] Patent: US6046190, 2000, A,
[9] Patent: US6140505, 2000, A,
[10] Patent: US6150556, 2000, A,
[11] Patent: US6143747, 2000, A,
[12] Patent: US5455258, 1995, A,
[13] Patent: US5552419, 1996, A,
[14] Patent: US5506242, 1996, A,
[15] Patent: US5753660, 1998, A,
[16] Patent: US5705500, 1998, A,
[17] Patent: US5776971, 1998, A,
[18] Patent: US6143788, 2000, A,
[19] Patent: US5756533, 1998, A,
[20] Patent: US5968970, 1999, A,
[21] Patent: US6172101, 2001, B2,
[22] Patent: US5985870, 1999, A,
[23] Patent: US2006/293361, 2006, A1, . Location in patent: Page/Page column 3
[24] Patent: US6388132, 2002, B1, . Location in patent: Page column 48
[25] Patent: US6372778, 2002, B1, . Location in patent: Example 180
[26] Patent: US5585397, 1996, A,
[27] Patent: US5783701, 1998, A,
  • 27
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  • [ 115010-11-2 ]
YieldReaction ConditionsOperation in experiment
99% With thionyl chloride In water EXAMPLE 1
Preparation of 2,3-dihydrobenzofuran-5-sulfonyl chloride
To a 250 ml, 3-neck flask under nitrogen purge was added 9.2 grams (60 mmoles) of sulfur trioxide-N,N-dimethylformamide complex and 20 ml of 1,2-dichloroethane.
The slurry was stirred at room temperature and 2,3-dihydrobenzofuran (6.0 g, 50 mmoles) was added dropwise at room temperature.
The slurry was slowly heated to 85° C. and aliquots were monitored for the progress of the reaction.
After one hour the reaction was complete.
The reaction slurry was allowed to come to room temperature, at which time thionyl chloride (7.2 g, 60 mmoles) was added dropwise.
The reaction mixture was slowly heated over the course of one hour, by which time it had reached 75° C.
The mixture was allowed to cool to room temperature.
Water (100 ml) was then added to the slurry.
The aqueous layer was extracted with 1,2-dichloroethane (3*25 ml).
The 1,2-dichloroethane layers were combined and washed with water (25 ml) and dried over magnesium sulfate.
The magnesium sulfate was filtered and washed with 1,2-dichloroethane.
The 1,2-dichloroethane was removed under vacuum to give 11 grams of the title compound (>99percent yield).
Nuclear magnetic resonance assays confirmed the identity of the title compound. FDMS (MeOH) m/e 218 (M+).
Analysis for C8 H7 ClO3 S: Theory: C, 43.94; H, 3.23. Found: C, 44.13; H, 3.34.
Reference: [1] Patent: US5387681, 1995, A,
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  • [ 196597-78-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4222 - 4239
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4222 - 4239
[3] Patent: WO2008/150953, 2008, A1,
[4] Patent: WO2008/150953, 2008, A1,
[5] Patent: WO2008/151170, 2008, A2,
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Reference: [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4222 - 4239
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 19, p. 4222 - 4239
[3] Letters in Drug Design and Discovery, 2013, vol. 10, # 7, p. 561 - 571
[4] Patent: CN102766135, 2017, B,
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Reference: [1] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1591 - 1597
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