* 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.
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 ]
Yield
Reaction Conditions
Operation 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
3
[ 496-16-2 ]
[ 55745-70-5 ]
Yield
Reaction Conditions
Operation 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.
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,
12
[ 496-16-2 ]
[ 124-38-9 ]
[ 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
13
[ 496-16-2 ]
[ 110-18-9 ]
[ 124-38-9 ]
[ 35700-40-4 ]
Reference：
[1] Patent: US5519034, 1996, A,
14
[ 496-16-2 ]
[ 110-18-9 ]
[ 35700-40-4 ]
Reference：
[1] Patent: US6207678, 2001, B1,
15
[ 496-16-2 ]
[ 76429-69-1 ]
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 14, p. 7529 - 7537
[2] Synlett, 2005, # 18, p. 2837 - 2842
[3] Patent: WO2007/27917, 2007, A2, . Location in patent: Page/Page column 26
16
[ 496-16-2 ]
[ 17403-47-3 ]
Yield
Reaction Conditions
Operation 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
17
[ 496-16-2 ]
[ 69999-15-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1980, vol. 23, # 4, p. 405 - 412
18
[ 496-16-2 ]
[ 4885-02-3 ]
[ 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
19
[ 496-16-2 ]
[ 20485-44-3 ]
[ 196799-45-8 ]
Yield
Reaction Conditions
Operation 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] Chemistry - A European Journal, 2017, vol. 23, # 3, p. 563 - 567
26
[ 496-16-2 ]
[ 13414-56-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 24, p. 5567 - 5573
27
[ 496-16-2 ]
[ 189035-22-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 22, p. 4790 - 4798
28
[ 496-16-2 ]
[ 115010-11-2 ]
Yield
Reaction Conditions
Operation 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,
29
[ 496-16-2 ]
[ 107-06-2 ]
[ 115010-11-2 ]
Yield
Reaction Conditions
Operation 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 Example 1 2,3-Dihydrobenzofuran-5-carbaldehyde Titanium chloride (28 ml) was dropwise added to a dichloromethane (100 ml) solution containing 2,3-dihydrobenzofuran (10.0 g, 83.2 mmols) and dichloromethyl methyl ether (11.3 ml, 0.125 mmols), while cooling with ice. The mixture was stirred for 1 hour, while still cooling with ice, and then water was added thereto. Dichloromethane was removed under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated saline solution, then dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified through silica-gel chromatography (hexane/ethyl acetate=1/1) to obtain 11.4 g (yield: 92%) of the target compound. This was oily. NMR (CDCl3) delta: 3.28 (2H, t, J=8.8 Hz), 4.70 (2H, t, J=8.8 Hz), 6.88 (1H, d, J=8.4 Hz), 7.67 (1H, dd, J=1.0 Hz, 8.4 Hz), 7.75 (1H, d, J=1.0 Hz), 9.83 (1H, s)
60%
tin(IV) chloride; In dichloromethane;
EXAMPLE 52A 2,3-Dihydrobenzofuran-5-carboxaldehyde To a stirred solution of alpha,alpha-dichloromethyl methyl ether (2.15 g, 19 mmol, 1.35 eq) in methylene chloride (30 mL) at -40 C. was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH2 Cl2 (5 mL) maintaining the temperature at or below -35 C. The mixture was warmed to 0 C., stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was diluted with ether, and the phases separated. The organic phase was concentrated in vacuo, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid. b.p. 119-121 C. at 0.3 mm Hg.
60%
tin(IV) chloride; In dichloromethane;
EXAMPLE 52A 2,3-Dihydrobenzofuran-5-carboxaldehyde To a stirred solution of alpha,alpha-dichloromethyl methyl ether (2.15 g, 19 mmol, 1.35 eq) in methylene chloride (30 mL) at -40 C. was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH2 Cl2 (5 mL) maintaining the temperature at or below -35 C. The mixture was warmed to 0 C., stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was diluted with ether, and the phases separated. The organic phase was concentrated in vacuo, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid. b.p. 119-121 C. at 0.3 mm Hg.
With bromine; In dichloromethane; at 20℃; for 2.75h;
Dissolve 2,3-dihydrobenzofuran (1,5 g, 41.6 mmol) in dichloromethane (35 mL),Br2 (6.65 g, 41.6 mmol) was weighed and dissolved in dichloromethane (15 mL). The mixture was added dropwise to the above mixture within 45 minutes at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, a saturated NaHSO3 solution (25 mL) was added to quench, and extracted with dichloromethane (15 mL × 3). The separated organic layer was washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the target compound as a white solid 7.5 g, yield: 91%. This white solid was 5-bromo-2,3-dihydrobenzofuran (the compound 2).
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 70.3%). 1H-NMR (300 MHz, CDCl3, delta): 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%
With bromine; acetic acid; at 10℃; for 1.16667h;
To a chilled (10C) 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 (28%) of the title compound as a white solid, m. p. 45C- 48C. The filtrate was concentrated to afford 5.1 g of 5-bromo-2, 3-dihydrobenzofuran which was 70% pure.
With bromine; sodium carbonate; In hexane; water;
Reference Example 69 To a mixture of 2,3-dihydrobenzofuran (11.06 g) and sodium carbonate (14.8 g) in hexane (100 ml) was added dropwise at 0 C. a solution of bromine (4.8 ml) in hexane (20 ml) for 1.5 hours, and the mixture was stirred at room temperature for 1 hour. To the mixture was added water, and the mixture was extracted with hexane. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give gray crystals of 5-bromo-2,3-dihydrobenzofuran (17.64 g). 1H-NMR (200 MHz, CDCl3) delta 3.20 (2H, t, J=8.8 Hz), 4.57 (2H, t, J=8.8 Hz), 6.66 (1H, d, J=8.4 Hz), 7.17-7.30 (2H, m).
With N-Bromosuccinimide;zirconium(IV) chloride; In dichloromethane; at 20℃; for 1h;Conversion of starting material;
Bromination using NBS has been found to be applicable for use with a wide range of aromatic starting materials or substrates, as is EPO <DP n="25"/>summarized in Table 1 . For example, anisole can be brominated by use of 1 equivalent of NBS in the presence of 5 mol % of ZrCI4 at -78 0C to afford p- bromoanisole in 98% yield as sole product (Table 1 , Entry 1 ). However, in the absence of ZrCI4 the halogenation does not proceed, even at room temperature (Table 1 , Entry 1 ).[00111] All of the substrates shown in Table 1 were brominated to give the corresponding monobromo products in excellent yield and regioselectivity. In most cases, the reaction can proceed at very low temperature and no further purification is necessary. In addition. Table 1 reveals that the halogenation of the present invention is compatible with a variety of substituents.Table 1 ZrCI4 Catalyzed Bromination of Aromatic Compounds EPO <DP n="26"/>(5 mol %), CH2CI2 (4d See spectroscopic data for characterization.
With N-Bromosuccinimide; In acetonitrile; at 20℃; for 3h;
[188.2] Dihydrobenzofuran (9.34 g) was dissolved in 130 ml of acetonitrile, 13.9 g of N-bromosuccinimide was added thereto and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated, then the residue was dissolved in ethyl acetate and successively washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed, to give 15. 94 g of the title compound.1H-NMR(CDCl3) delta: 3.02 (t, J=8.8Hz, 2H) 4.57 (t, J=8.8Hz, 2H) 6.66 (d, J=8.0Hz, 1H) 7.12-7.21 (m, 1H) 7.28-7.29 (m, 1H)
With sodium methylate; carbonic acid dimethyl ester; In methanol; at 85℃; for 5h;Product distribution / selectivity;
Example 5 Mixtures of diols, dimethyl carbonate and the selected base were refluxed in an oil bath under nitrogen atmosphere as reported in Tables 3 and 4. Cooled samples of the reaction mixtures were filtered on silica pads and the recovered clear solutions were analysed by gas chromatography.
100%Chromat.
With potassium tert-butylate; carbonic acid dimethyl ester; at 90℃; for 0.5h;Product distribution / selectivity;
Example 5 Mixtures of diols, dimethyl carbonate and the selected base were refluxed in an oil bath under nitrogen atmosphere as reported in Tables 3 and 4. Cooled samples of the reaction mixtures were filtered on silica pads and the recovered clear solutions were analysed by gas chromatography.
92%Chromat.
With sodium methylate; carbonic acid dimethyl ester; at 90℃; for 2h;Product distribution / selectivity;
Example 5 Mixtures of diols, dimethyl carbonate and the selected base were refluxed in an oil bath under nitrogen atmosphere as reported in Tables 3 and 4. Cooled samples of the reaction mixtures were filtered on silica pads and the recovered clear solutions were analysed by gas chromatography.
5.8 g
With toluene-4-sulfonic acid; In benzene; at 80℃; for 2h;
(2) 9.2 g of 2-hydroxyphenylethanol, the acidic catalyst p-toluenesulfonic acid 10.2g was sequentially added to the organic solvent benzene. The reaction was carried out for 2 h at a heating temperature of 80 C. After the reaction is completed, the reaction solution is cooled to 18 C. Add water to the cooled reaction solution, mix well and mix well. After standing, liquid separation, drying the organic phase with anhydrous sodium sulfate, Filtration and distillation under reduced pressure to obtain phenazone new intermediate 2,3-dihydrobenzofuran 5.8 g.
To a stirred solution of 2,3-dihydrobenzo[b]furan (9.4 mL, 83.4 mmol) in dichloromethane (250 mL) under Ar at -5 C. was added dropwise titanium(IV) chloride (18 mL, 167.0 mmol) over 15 min, maintaining the temperature below 0 C. After addition was complete, the red-brown reaction mixture was allowed to stir for a further 10 min before alpha,alpha-dichloromethyl methyl ether (8.3 mL, 91.6 mmol) was added dropwise [CAUTION-exotherm] maintaining the temperature below 0 C. Upon complete addition, the vivid crimson reaction mixture was allowed to warm to ambient temperature over 2 h, and was then cautiously poured onto a saturated aqueous solution of sodium bicarbonate (700 mL). The mixture was filtered through a pad of Kieselguhr, which was washed through with dichloromethane. The phases were separated and the aqueous phase was extracted with dichloromethane (2×400 mL). The combined organic fractions were washed with brine (300 mL), dried (magnesium sulfate) and concentrated in vacuo to afford a mixture [5-CHO:7-CHO (4:1)] of aldehyde products (11.48 g, 93%) as a green-black liquid which as used without further purification.
With N-chloro-succinimide;zirconium(IV) chloride; In dichloromethane; at 20℃; for 12.0h;Conversion of starting material;
Chlorination using NCS has been found to be applicable for use with a wide range of aromatic starting materials or substrates, as is shown in Table 2. All the substrates treated with 1 equivalent of NCS and 5 mole % of ZrCU afforded the corresponding chlorinated compounds. The reaction at room temperature afforded a high yield of chlorinated product with high regioselectivity. In some cases, a small amount of regioisomers (Entry 3) or dichlorinated products (Entries 4 and 5) were observed.Table 2 ZrCIj Catalyzed Chlorination of Aromatic Compounds by NCS2-CI : 4-CI (13: 87)b EPO <DP n="27"/>1 -CI : 1 ,4-di-CI(83: 17)ba Reaction conditions. Substrate (0.5 mmol), NCS (0.5 mmol), ZrCI4 (5 mol %), CH2CI2 (4 mL). b Determined by 1H NMR. c See spectroscopic data for characterization.
2.28 g
With N-chloro-succinimide; acetic acid; In acetonitrile; at 10 - 35℃; for 48.0h;
a) 5-chloro-2,3-dihydrobenzofuran A mixture of 2,3-dihydrobenzofuran (2.00 g), NCS (2.70 g), acetic acid (2.0 mL) and acetonitrile (20 mL) was stirred at room temperature for 2 days. The reaction mixture was diluted with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.28 g). 1H NMR (300 MHz, DMSO-d6) delta 3.18 (2H, t, J=8.8 Hz), 4.54 (2H, t, J=8.7 Hz), 6.76 (1H, dd, J=8.5, 0.3 Hz), 7.10 (1H, ddt, J=8.4, 2.3, 0.8 Hz), 7.27 (1H, dt, J=2.1, 1.1 Hz).
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 80ØC over 2 hours. The mixture was heated to an inner temperature of 80 to 90ØC, 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: 100%)
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: 100%)
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: 94%) of the title compound.
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 (100%) of 2,3-dihydrobenzofuran-5-sulfonyl chloride as a tan oil. (TLC Rf chloroform/hexanes=1/1)
100%
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 (100%) of 2,3-dihydrobenzofuran-5-sulfonyl chloride as a tan oil. (TLC Rf chloroform/hexanes=1/1)
94%
In 1,2-dichloro-ethane;
Example 9 Preparation of 5-chlorosulfonyl-2,3-dihydrobenzo[b]furan (11) 2,3-Dihydrobenzo[b]furan (Aldrich, 5.6 mL, 50 mmol) was added to a suspension of sulfur trioxide-dimethylformamide complex (Aldrich, 9.2 g, 60 mmol) in 1,2-dichloroethane (Aldrich, 20 mL). After being heated at 80 C. for 1 hour, the reaction mixture was cooled to room temperature, and thionyl chloride (Aldrich, 4.5 mL, 57 mmol) was introduced. The reaction mixture was then heated at 70 C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into ice water (100 mL) and extracted with ether (3*30 mL). Combined organic layers were washed with brine, then dried (MgSO4). Removal of solvent under vacuum yielded a light yellow solid (10.2 g, 94%). TLC Rf 0.45 (9:1 of hexane-ethyl acetate); MS (electrospray) 219 (M+1); 1H NMR (CDCl3) delta 3.35 (t, 2H, J=7.2 Hz), 4.78 (t, 2H, J=7.2 Hz), 6.92 (d, 1H, J=3.1 Hz), 7.82 (s, 1H), 7.83 (d, 1H, J=3.1 Hz).
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 (91.7% 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 %).'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 %). 1H NMR 270 MHz (Chloroform-d) delta 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).
With sulfuryl dichloride; In N,N-dimethyl-formamide;
Part A Preparation of 5-(2,3-dihydrobenzofuranyl) sulfonyl chloride To a solution of 3.35 g of anhydrous N,N-dimethylformamide at 0 C. under nitrogen was added 6.18 g of sulfuryl chloride, whereupon a solid formed. After stirring for 15 minutes, 4.69 g of 2,3-dihydrobenzofuran was added, and the mixture heated at 100 C. for 2 hours. The reaction was cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated the crude material. This was recrystallized from ethyl acetate to afford 2.45 g of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride.
With sulfuryl dichloride; In N,N-dimethyl-formamide;
Part A Preparation of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride To a solution of 3,35 g of anhydrous N,N-dimethylformamide at 0 C. under nitrogen was added 6.18 g of sulfuryl chloride, whereupon a solid formed. After stirring for 15 minutes, 4.69 g of 2,3-dihydrobenzofuran was added, and the mixture heated at 100 C. for 2 hours. The reaction was cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated the crude material. This was recrystallized from ethyl acetate to afford 2.45 g of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride.
With sulfuryl dichloride; In N,N-dimethyl-formamide;
Part B Preparation of 5-(2,3-dihydrobenzofuranyl) sulfonyl chloride To a solution of 3.35 g of anhydrous N,N-dimethylformamide at 0 C. under nitrogen was added 6.18 g of sulfuryl chloride, whereupon a solid formed. After stirring for 15 minutes, 4.69 g of 2,3-dihydrobenzofuran was added, and the mixture heated at 100 C. for 2 hours. The reaction was cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated the crude material. This was recrystallized from ethyl acetate to afford 2.45 g of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride.
With sulfuryl dichloride; In N,N-dimethyl-formamide;
Part A Preparation of 5-(2,3-dihydrobenzofuranyl)sulfonyl Chloride To a solution of 3.35 g of anhydrous N,N-dimethylformamide at 0 C. under nitrogen was added 6.18 g of sulfuryl chloride, whereupon a solid formed. After stirring for 15 minutes, 4.69 g of 2,3-dihydrobenzofuran was added, and the mixture heated at 100 C. for 2 hours. The reaction was cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated the crude material. This was recrystallized from ethyl acetate to afford 2.45 g of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride.
With sulfuryl dichloride; In N,N-dimethyl-formamide;
Part A Preparation of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride To a solution of 3.35 g of anhydrous N,N-dimethylformamide at 0 C. under nitrogen was added 6.18 g of sulfuryl chloride, whereupon a solid formed. After stirring for 15 minutes, 4.69 g of 2,3-dihydrobenzofuran was added, and the mixture heated at 100 C. for 2 hours. The reaction was cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated the crude material. This was recrystallized from ethyl acetate to afford 2.45 g of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride.
With chlorosulfonic acid; In water;
2,3-dihydrobenzofuran (6.0 g, 49.94 mmol) is added over 20 minutes to chlorosulfonic acid (29.09 g, 249.69 mmol) at -20 C. The reaction mixture is quenched by addition of ice followed by water (20 mL). The mixture is then extracted with ethyl acetate. The combined organic estracts are washed with brine, dried (Na2 SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (30% ethyl acetate/hexane) to give 2,3-dihydrobenzofuran-5-sulfonyl chloride (3.3 g).
With chlorosulfonic acid; In water;
2,3-dihydrobenzofuran (6.0 g, 49.94 mmol) is added over 20 minutes to chlorosulfonic acid (29.09 g, 249.69 mmol) at -20 C. The reaction mixture is quenched by addition of ice followed by water (20 mL). The mixture is then extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2 SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (30% ethyl acetate/hexane) to give 2,3-dihydrobenzofuran-5-sulfonyl chloride (3.3 g).
With sulfuryl dichloride; In N,N-dimethyl-formamide;
Part A Preparation of 5-(2,3-dihydrobenzofuranyl) sulfonyl chloride To a solution of 3.35 g of anhydrous N,N-dimethylformamide at 0 C. under nitrogen was added 6.18 g of sulfuryl chloride, whereupon a solid formed. After stirring for 15 minutes, 4.69 g of 2,3-dihydrobenzofuran was added, and the mixture heated at 100 C. for 2 hours. The reaction was cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated the crude material. This was recrystallized from ethyl acetate to afford 2.45 g of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride.
With sulfuryl dichloride; In N,N-dimethyl-formamide;
Part A Preparation of 5-(2,3-dihydrobenzofuranyl) sulfonyl chloride To a solution of 3.35 g of anhydrous N,N-dimethylformamide at 0 C. under nitrogen was added 6.18 g of sulfuryl chloride, whereupon a solid formed. After stirring for 15 minutes, 4.69 g of 2,3-dihydrobenzofuran was added, and the mixture heated at 100 C. for 2 hours. The reaction was cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated the crude material. This was recrystallized from ethyl acetate to afford 2.45 g of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride.
With sulfuryl dichloride; In N,N-dimethyl-formamide;
Part B Preparation of 5-(2,3-dihydrobenzofuranyl) sulfonyl chloride To a solution of 3.35 g of anhydrous N,N-dimethylformamide at 0 C. under nitrogen was added 6.18 g of sulfuryl chloride, whereupon a solid formed. After stirring for 15 minutes, 4.69 g of 2,3-dihydrobenzofuran was added, and the mixture heated at 100 C. for 2 hours. The reaction was cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated the crude material. This was recrystallized from ethyl acetate to afford 2.45 g of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride.
With sulfuryl dichloride; In N,N-dimethyl-formamide;
Part A Preparation of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride To a solution of 3.35 g of anhydrous N,N-dimethylformamide at 0 C. under nitrogen was added 6.18 g of sulfuryl chloride, whereupon a solid formed. After stirring for 15 minutes, 4.69 g of 2,3-dihydrobenzofuran was added, and the mixture heated at 100 C. for 2 hours. The reaction was cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated the crude material. This was recrystallized from ethyl acetate to afford 2.45 g of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride.
With chlorosulfonic acid;
EXAMPLE 1; N-[7-(4-piperidinyl)oxy-1-benzofuran-5-yl]-2-methoxy-5-methylbenzenesulfonamide; Example 1 was prepared as follows: 7-iodo-N-(2-methoxy-5-methylphenyl)-1-benzofuran-5-sulfonamide is produced starting from 2,3-dihydrobensofuran. Treatment with chlorosulfonic acid gives the corresponding sulfonyl chloride, which is iodinated using iodine monochloride. Aromatization is done using NBS, resulting in 7-iodo-N-(2-methoxy-5-methylphenyl)-1-benzofuran-5-sulfonamide after treatment with cresidine. Hydrolysis of 7-iodo-N-(2-methoxy-5-methylphenyl)-1-benzofuran-5-sulfonamide in alkaline solution using copper as catalyst results in 7-hydroxy-N-(2-methoxy-5-methylphenyl)-1-benzofuran-5-sulfonamide. Reaction with a methyl carbamate protected mesylate of 4-hydroxypiperidine, results in methyl 4-[(5-[(2-methoxy-5-methylphenyl)amino]sulfonyl}-1-benzofuran-7-yl)oxy]piperidine-1-carboxylate, which is hydrolysed in alkaline solution giving the title compound.
With sulfuryl dichloride; N,N-dimethyl-formamide; at 0 - 100℃; for 2.25h;
Part A Preparation of 5-(2,3-dihydrobenzofuranyl) sulfonyl chloride To a solution of 3.35 g of anhydrous N,N-dimethylformamide at 0 C. under nitrogen was added 6.18 g of sulfuryl chloride, whereupon a solid formed.. After stirring for 15 minutes, 4.69 g of 2,3-dihydrobenzofuran was added, and the mixture heated at 100 C. for 2 hours.. The reaction was cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated the crude material.. This was recrystallized from ethyl acetate to afford 2.45 g of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride.
With sulfuryl dichloride; In N-methyl-acetamide; ethyl acetate;
A. 2,3-Dihydrobenzofuran-5-sulfonyl Chloride To. 3.35 g of dimethylformamide, at 0 C. under an atmosphere of nitrogen, added 6.18 g of sulfuryl chloride. The mixture was stirred 15 min and treated with 4.69 g of 2,3-dihydrobenzofuran. The mixture was then heated at 100 C. for 1.5 h, cooled to about 40 C., poured onto ice, extracted with CH2 Cl2, dried over MgSO4, filtered, and concentrated in vacuo. The residue was taken up in ethyl acetate, cooled to 5 C. for 16 h, and the resultant pink crystals collected by vacuum filtration to provide 6.12 g of the title product. TLC: Rf=0.41, 10% ethyl acetate in hexane. (1 H)-NMR (CDCl3) consistent with structure.
With sulfuryl dichloride; In N-methyl-acetamide; ethyl acetate;
A. 2,3-Dihydrobenzofuran-5-sulfonyl chloride To 3.35 g of dimethylformamide, at 0 C. under an atmosphere of nitrogen, added 6.18 g of sulfuryl chloride. The mixture was stirred 15 min and treated with 4.69 g of 2,3-dihydrobenzofuran. The mixture was then heated at 100 C. for 1.5 h, cooled to about 40 C., poured onto ice, extracted with CH2 Cl2, dried over MgSO4, filtered, and concentrated in vacuo. The residue was taken up in ethyl acetate, cooled to 5 C. for 16 h, and the resultant pink crystals collected by vacuum filtration to provide 6.12 g of the title product. TLC: Rf=0.41, 10% ethyl acetate in hexane. (1 H)-NMR (CDCl3) consistent with structure.
With n-butyllithium; In tetrahydrofuran; hexane; at -78 - 0℃;Cooling with ethanol-dry ice;
INTERMEDIATE 77 7-Bromo-2, 3-dihydrobenzofuran* A solution of 2- (2, 6-dibromphenoxy) ethyl bromide (1.08 g, 3 mmol; Intermediate 76) in a mixture of THF (12 mL) and hexane (3 mL) was cooled in a ethanol/dry ice bath for 30 min. n-BuLi in hexane (2 mL of 1.5 M solution) was added dropwise over 15 min. The reaction mixture was stirred at-78 C for another 30 min after which time the bath was allowed to slowly warm to 0 C. The mixture was poured onto water and extracted with diethyl ether (2x100 mL). The combined extract was dried and concentrated to give a pale brown oil (0.5 g) containing the product contaminated with approximately 25 % 2,3- dihydrobenzofuran. This material was used as such for further synthesis but could if necessary be purified by flash chromatography [eluent : hexane- EtOAc/hexane (5: 95) ]. 'H NMR (400 MHz, CDC13) 8 3.30 (t, 2 H), 4.65 (t, 2 H), 6.71 (t, 1 H), 7.11 (dd, 1 H), 7.25 (dd, 1 H). *Previously reported in Tetrahedron Lett. 1998,39, 2219-2222.
With n-butyllithium; In N-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: 5% ethyl acetate in petroleum ether). 9.85 g (Yield: 35%) of 7-formyl-2,3-dihydrobenzofuran are obtained--M.p.: 55 C.
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 (>99% 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.
EXAMPLE 82 N,N,N',N'-Tetramethylethylenediamine (231.4 g) was added at ambient temperature to a solution of n-butyl lithium (2.5M, 800 ml) in hexane (2.5 l) followed by a solution of 2,3-dihydrobenzo[b]furan (102 g) in hexane (25 ml). The mixture was stirred under nitrogen at ambient temperature for 5 hours. The resulting suspension was added slowly to dry ice (300 g) and hexane (500 ml) under nitrogen. After stirring at ambient temperature for 16 hours, the mixture was diluted with water (2 l), and the layers separated. The aqueous layer was washed with hexane, acidified to pH 1 with concentrated hydrochloric acid, cooled and the precipitate collected by filtration. This was washed with water and dichloromethane and dried at 80 C. in vacuo to give 2,3-dihydrobenzo[b]furan-7-carboxylic acid (39.6 g), m.p. 164-165 C. The hexane layer was filtered, dried over sodium sulphate and concentrated. On cooling, further product was obtained (32.7 g), m.p. 170 C.
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, 54.7%) 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, 54.7%) as a white solid, mp 167-169.5C.
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 10% 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, 18%). 1 H NMR (CDCl3) delta 7.35(1H,d), 7.11(1H,d), 6.59(1H,t), 4.37(2H,t), 2.99(2H,t).
PREPARATION 32 2,3-Dihydrobenzo[b]furan-7-oic acid N,N,N',N'-Tetramethylethylenediamine (38 ml) was dissolved in hexane (300 ml), cooled in an ice-bath and n-butyllithium (100 ml of a 2.5M solution in hexane) added. The mixture was stirred at 0 C. for 15 minutes before adding 2,3-dihydrobenzo[b]furan (30 g) dropwise over 30 minutes. The mixture was allowed to warm to room temperature over 30 minutes, stirred at room temperature for a further 4 hours, poured onto an excess of solid carbon dioxide and left to stand for 3 days by which time the solvent had evaporated off. The residue was partitioned between ethyl acetate (1L) and 4N aqueous hydrochloric acid solution (240 ml), the layers separated and the aqueous layer extracted with ethyl acetate (500 ml). The organic extracts were combined, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The residue was then triturated with diethyl ether to give 2,3-dihydrobenzo[b]furan-7-oic acid as a white solid (21 g) 1H-NMR (CDCl3): delta=7.75 (1H d), 7.31 (1H, d), 6.88 (1H, t), 4.69 (2H, t), 3.20 (2H, t) ppm.
With silver nitrate; acetyl chloride; In water; acetonitrile; at 0 - 20℃; for 5.0h;
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 0C. 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 0-5C and for 4 h at room temperature. 20 mL of water was added to the reaction flask at 0C 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 (54%) as a yellow solid.
44.4%
With nitric acid; acetic acid; at 65 - 75℃; for 0.5h;Product distribution / selectivity;
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 65C, 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 65-75C. 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, 44.4%).
35%
With silver nitrate; acetyl chloride; In acetonitrile; at 0℃; for 1.0h;
General procedure: A solution of 29 (1.0mmol) in CH3CN was cooled to 0C and was added with silver nitrate (1.0mmol) and acetyl chloride (1.0mmol). The reaction mixture was stirred at 0C for 1h. After completion, the reaction mixture was diluted with water and extracted with EtOAc several times. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the desire product.
29%
With nitric acid; acetic acid; In water; at 70℃; for 0.5h;
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 70% aqueous nitric acid dropwise. The reaction was monitored by TLC (EtOAc-hexanes (15: 85) ). The mixture was warmed to 70C where the reaction began. The remainder of the nitric acid was then added while maintaining the reaction at 70C. 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 (29%) of 5-nitro-2, 3-dihydrobenzofuran as a tan solid.
17%
With nitric acid; acetic acid; at 0 - 20℃; for 2.0h;
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 20% EtOAc/hexane to provide 21 (6.4 g, 17%) as a pale brown powder; 1H NMR (CDCl3) delta: 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.
sec-BuLi (20.00 ml, 1.4 M in cyclohexane, 28.00 mmol) was added to a solution of 2,3-dihydro-benzofuran (2.40 mL, 21.30 mmol) and tetramethylethylenediamine (TMEDA, 10.00 mL) in THF at -20 C. The resulting mixture was stirred for 1 hour, then DMF (3.00 mL, 38.75 mmol) was added and stirring was continued for another 30 minutes. The reaction mixture was quenched with water and diluted with ether. The resulting solution was washed with brine, dried over MgSO4 and concentrated to afford the desired title aldehyde.
In dichloromethane; at 0 - 20℃; for 0.5h;Cooling with ice;
Take compound IX-1 (564 muL, 5 mmol) in dichloromethane (6.024 mL, 0.83 M),Add chlorosulfonic acid (731 muL, 11 mmol) dropwise under ice bath conditions,The reaction solution was then slowly warmed to room temperature.After 30 minutes,TLC monitors the end of the reaction.Quench with water (15 mL) in an ice bath.Dichloromethane (5mL x 3) extraction,Combined organic phases,Wash with saturated saline (5mL x 2),Dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,Compound IX-2 was obtained (yellow-white solid, 765 mg, yield 70%).
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