2,3-Dihydro-1-benzofuran-5-carbaldehyde [C9H8O2]

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13 reactions in Reaxys

2017-10-28 13h:13m:57s (EST)

O

1. Query

O

Search as: As drawn

1/8

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O

N

O

Rx-ID: 9180608 View in Reaxys 1/13 Yield 100%

Conditions & References 1 :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). With trichlorophosphate, Time= 9.5h, T= 70 - 90 °C Patent; Takeda Pharmaceutical Company Limited; EP1792899; (2007); (A1) English View in Reaxys

98 %

1 :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. Stage 1: With trichlorophosphate, T= 30 - 70 °C Stage 2: With water in N,N-dimethyl-formamide, Time= 1h, T= 20 °C Patent; USV LIMITED; SATHE, Dhananjay, Govind; BHISE, Nandu, Baban; GATNE, Parag, Sukumar; PATNEKAR, Subodh, Shashikant; DEORE, Raviraj, Bhatu; MAHAJAN, Anil, Dinkar; WO2010/41271; (2010); (A2) English View in Reaxys

93 %

With trichlorophosphate, Time= 12h, T= 75 °C , Vilsmeier-Haack Formylation Chen, Wen; Yang, Li-Juan; Li, Yan; Wang, Xue-Quan; Wang, Shao-Jie; Wan, Wei-Chao; Zhang, Hong-Bin; Yang, Xiao-Dong; Letters in Drug Design and Discovery; vol. 10; nb. 7; (2013); p. 561 - 571 View in Reaxys

93 %

1.1 : Preparation of 5 - Aldehyde Dihydrobenzofuran (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. , Time= 12h, T= 85 °C , Cooling with ice Patent; Yunnan University; Yang Xiaodong; Zhang Hongbin; Chen Wen; Wang Xuequan; Yang Lijuan; Li Liang; (38 pag.); CN102766135; (2017); (B) Chinese View in Reaxys

86 %

With trichlorophosphate, Time= 12h, T= 80 - 85 °C Uchikawa, Osamu; Fukatsu, Kohji; Tokunoh, Ryosuke; Kawada, Mitsuru; Matsumoto, Kiyoharu; Imai, Yumi; Hinuma, Shuji; Kato, Koki; Nishikawa, Hisao; Hirai, Keisuke; Miyamoto, Masaomi; Ohkawa, Shigenori; Journal of Medicinal Chemistry; vol. 45; nb. 19; (2002); p. 4222 - 4239 View in Reaxys

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85 - 90 %

1 :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 With trichlorophosphate, Time= 4 - 5h, T= 80 - 85 °C Patent; TEVA PHARMACEUTICAL INDUSTRIES LTD.; TEVA PHARMACEUTICALS USA, INC.; WO2008/151170; (2008); (A2) English View in Reaxys 1 :EXAMPLE 1 : Preparation of 2, 3- DIHYDROBENZOFURAN -5- CARBALDEHYDE (FORMULA XII, wherein i1^ represents a single bond); 400 g of 2,3-dihydro benzofuran of Formula XIII (wherein =* represents a single bond) and 566 ml of dimethyl formamide (DMF) were charged into a clean and dry 4 neck round bottom flask followed by stirring for about 5 minutes. 544 ml of phosphorous oxy chloride was slowly added through a dropper for 65 minutes at 3O0C. The reaction solution was heated to 95-98°C followed by stirring for 4 hours for the completion of the reaction. The reaction mass was then cooled to 100C and quenched into ice slowly followed by stirring for 20-30 minutes. 1300 ml of caustic lye was added to the solution at 25 - 350C to adjust the pH of the reaction mass to neutral. The reaction mass was extracted with dichloromethane (3X1000 ml) and separated the organic layer and aqueous layer. The combined organic layer was washed with brine solution (2000 ml). The resultant organic layer was distilled completely below 6O0C to afford 497 g of the title compound. With trichlorophosphate, Time= 5.16667h, T= 30 - 98 °C Patent; DR. REDDY'S LABORATORIES LTD.; DR. REDDY'S LABORATORIES, INC.; WO2008/150953; (2008); (A1) English View in Reaxys

14.5 g

4 : example 3 Take a 1001 ^ three mouth reaction bottle,2,3-dihydrobenzofuran (128, 0.1111) was dissolved in nitrogen,Nitrogendimethylformamide (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. With phosphorus pentachloride, Time= 10h, T= 70 - 80 °C Patent; Hangzhou Duyi Technology Co., Ltd.; Bian Gaofeng; Wang Jian; Zheng Zengying; Li Zhenye; (7 pag.); CN106554345; (2017); (A) Chinese View in Reaxys

O HO

O O

O

Rx-ID: 46204100 View in Reaxys 2/13 Yield 80 %

Conditions & References With dipotassium hydrogenphosphate, fac-tris(2-phenylpyridinato-N,C2')iridium(III), tris-(trimethylsilyl)silane, dimethyl dicarbonate in acetonitrile, Time= 6h, T= 20 °C , Schlenk technique, Inert atmosphere, Sealed tube, Irradiation Zhang, Muliang; Li, Nan; Tao, Xingyu; Ruzi, Rehanguli; Yu, Shouyun; Zhu, Chengjian; Chemical Communications; vol. 53; nb. 73; (2017); p. 10228 - 10231 View in Reaxys

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O

O Cl

Rx-ID: 43109628 View in Reaxys 3/13 Yield

Conditions & References

65 %

With (4,4-dimethyl-2,6-dioxo-cyclohexyl)-phenyl-iodonium betaine, trimethylsilyl trifluoromethanesulfonate in dichloromethane, T= 20 °C , Kinetics Chelli, Saloua; Troshin, Konstantin; Mayer, Peter; Lakhdar, Sami; Ofial, Armin R.; Mayr, Herbert; Journal of the American Chemical Society; vol. 138; nb. 32; (2016); p. 10304 - 10313 View in Reaxys O

Cl

O

Cl

Rx-ID: 4607417 View in Reaxys 4/13 Yield

Conditions & References With tin(IV) chloride in dichloromethane, Title compound not separated from byproducts Tasker, Andrew S.; Sorensen, Bryan K.; Jae, Hwan-Soo; Winn, Martin; Von Geldern, Thomas W.; Dixon, Douglas B.; Chiou, William J.; Dayton, Brian D.; Calzadila, Samuel; Hernandez, Lisa; Marsh, Kennan C.; WuWong, J. Ruth; Opgenorth, Terry J.; Journal of Medicinal Chemistry; vol. 40; nb. 3; (1997); p. 322 - 330 View in Reaxys 3 :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 α,αdichloromethyl 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.x.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, 93percent) as a green-black liquid which as used without further purification. Stage 1: With titanium tetrachloride in dichloromethane, Time= 0.416667h, T= -5 - 0 °C Stage 2: in dichloromethane, Time= 2h, T= 0 - 20 °C Stage 3: With sodium hydrogencarbonate in dichloromethane, water Patent; VERNALIS RESEARCH LIMITED; US2005/187282; (2005); (A1) English View in Reaxys

O

N

O

Br

O

Rx-ID: 9769668 View in Reaxys 5/13 Yield 98 %

Conditions & References With n-butyllithium in tetrahydrofuran, hexane, T= -78 - 20 °C Matsunaga, Nobuyuki; Kaku, Tomohiro; Ojida, Akio; Tanaka, Toshimasa; Hara, Takahito; Yamaoka, Masuo; Kusaka, Masami; Tasaka, Akihiro; Bioorganic and Medicinal Chemistry; vol. 12; nb. 16; (2004); p. 4313 - 4336 View in Reaxys

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O

Rx-ID: 13289317 View in Reaxys 6/13 Yield 100%

Conditions & References R.1 : Reference Example 1: 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) With trichlorophosphate in water, N,N-dimethyl-formamide Patent; Takeda Chemical Industries, Ltd.; EP1334732; (2003); (A1) English View in Reaxys

100%

R.1 : Synthesis of 2,3-Dihydrobenzofuran-5-carbaldehyde 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) With trichlorophosphate in water, N,N-dimethyl-formamide Patent; Ishida, Hajime; Fukuta, Makoto; US2004/18239; (2004); (A1) English View in Reaxys

94%

R.1 : 2,3-Dihydrobenzofuran-5-carbaldehyde 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 sodium hydrogencarbonate, trichlorophosphate in N,N-dimethyl-formamide Patent; Takeda Chemical Industries, Ltd.; US6348485; (2002); (B1) English View in Reaxys Reaction Steps: 2 1: 100 percent / Br2 2: 98 percent / n-BuLi / tetrahydrofuran; hexane / -78 - 20 °C With n-butyllithium, bromine in tetrahydrofuran, hexane Matsunaga, Nobuyuki; Kaku, Tomohiro; Ojida, Akio; Tanaka, Toshimasa; Hara, Takahito; Yamaoka, Masuo; Kusaka, Masami; Tasaka, Akihiro; Bioorganic and Medicinal Chemistry; vol. 12; nb. 16; (2004); p. 4313 - 4336

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View in Reaxys

O

Li

O

Br

Rx-ID: 24199131 View in Reaxys 7/13 Yield

Conditions & References 19.i : (i) (i) Production of Ethyl 2,3-Dihydronaphtho[2,3-b]furan-6-carboxylate 5-Bromo-2,3-dihydrobenzofuran (38.86 g), which was prepared according to the literature (Alabaster, Ramon J. et al., Synthesis, 1988, vol. 12, pp950.), was dissolved in THF (300 mL) and cooled to -78° C. n-Butyl-lithium in hexane (1.6M; 160 mL) was added to the solution and stirred for 30 min. DMF (40 mL) was added to the mixture and was allowed to warm to room temperature. Water was added to the mixture and the solvent was evaporated. The residue was diluted with ethyl acetate, washed with water and brine, dried and concentrated to give crude product of 5-formyl-2,3-dihydrobenzofuran (28.47 g) as an oil. in tetrahydrofuran, hexane, water, N,N-dimethyl-formamide Patent; Takeda Chemical Industries, Ltd.; US6649643; (2003); (B1) English View in Reaxys

O

Cl

O Cl

O O

Rx-ID: 1638389 View in Reaxys 8/13 Yield 92 %

Conditions & References With titanium tetrachloride in dichloromethane, Time= 1h, Vilsmeier-Haack reaction Uchikawa, Osamu; Fukatsu, Kohji; Tokunoh, Ryosuke; Kawada, Mitsuru; Matsumoto, Kiyoharu; Imai, Yumi; Hinuma, Shuji; Kato, Koki; Nishikawa, Hisao; Hirai, Keisuke; Miyamoto, Masaomi; Ohkawa, Shigenori; Journal of Medicinal Chemistry; vol. 45; nb. 19; (2002); p. 4222 - 4239 View in Reaxys

92%

R.1 : 2,3-Dihydrobenzofuran-5-carbaldehyde 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: 92percent) of the target compound. This was oily. NMR (CDCl3) δ: 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) With titanium chloride in dichloromethane, water Patent; Takeda Chemical Industries, Ltd.; US6034239; (2000); (A1) English View in Reaxys

92 %

With titanium tetrachloride in dichloromethane, Time= 1h Patent; Takeda Chemical Industries, Ltd.; EP1199304; (2002); (A1) English View in Reaxys

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90 %

With tin(IV) chloride in dichloromethane, Time= 0.333333h, T= 0 °C Monte, Aaron P.; Marona-Lewicka, Danuta; Cozzi, Nicholas V.; Nichols, David E.; Journal of Medicinal Chemistry; vol. 36; nb. 23; (1993); p. 3700 - 3706 View in Reaxys

60%

52.A : 2,3-Dihydrobenzofuran-5-carboxaldehyde EXAMPLE 52A 2,3-Dihydrobenzofuran-5-carboxaldehyde To a stirred solution of α,α-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 2,3dihydrobenzofuran (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, 60percent) as a colorless liquid. b.p. 119-121° C. at 0.3 mm Hg. With tin(IV) chloride in dichloromethane Patent; Abbott Laboratories; US6162927; (2000); (A1) English View in Reaxys

60%

52.A : 2,3-Dihydrobenzofuran-5-carboxaldehyde EXAMPLE 52A 2,3-Dihydrobenzofuran-5-carboxaldehyde To a stirred solution of α,α-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 2,3dihydrobenzofuran (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, 60percent) as a colorless liquid. b.p. 119°-121° C. at 0.3 mm Hg. With tin(IV) chloride in dichloromethane Patent; Abbott Laboratories; US5767144; (1998); (A1) English View in Reaxys Patent; Abbott Laboratories; US5622971; (1997); (A1) English View in Reaxys

Br

N

O

Cl

O O

O Br

Rx-ID: 8573403 View in Reaxys 9/13 Yield 75 %

Conditions & References Stage 1: With n-butyllithium in tetrahydrofuran, T= -40 °C , Metallation Stage 2: in tetrahydrofuran, T= -40 - 20 °C , Formylation, Parham cyclization Plotkin, Michael; Chen, Sanyou; Spoors, P. Grant; Tetrahedron Letters; vol. 41; nb. 14; (2000); p. 2269 - 2273 View in Reaxys

HO

O

Br

O Br

Rx-ID: 15914396 View in Reaxys 10/13 Yield

Conditions & References Reaction Steps: 2 1.1: K2CO3 / dimethylformamide 2.1: n-BiLu / tetrahydrofuran / -40 °C

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2.2: 75 percent / tetrahydrofuran / -40 - 20 °C With n-butyllithium, potassium carbonate in tetrahydrofuran, N,N-dimethyl-formamide, 1.1: Alkylation / 2.1: Metallation / 2.2: Formylation Plotkin, Michael; Chen, Sanyou; Spoors, P. Grant; Tetrahedron Letters; vol. 41; nb. 14; (2000); p. 2269 - 2273 View in Reaxys

O O

Rx-ID: 24454242 View in Reaxys 11/13 Yield

Conditions & References

58%

4-[E,Z-2-(2,3-Dihydrobenzo[b]furan-5-yl)ethenyl]benzo[b]thiophene-2-carboxamidine hydrochloride The bromide (117.9 mg, 0.59 mmol) was treated with 2 equiv. of n-BuLi in THF at -78° C. under N2 followed by DMF to yield 2,3-dihydrobenzofuran-5-carboxaldehyde (51.3 mg, 58percent) after workup and chromatography (12percent EtOAc/hexanes) as a pale yellow syrup. Patent; Eisai Co., Ltd.; US5340833; (1994); (A1) English View in Reaxys

O

Cl

O

Cl

Rx-ID: 1638388 View in Reaxys 12/13 Yield

Conditions & References

55 %

With titanium tetrachloride Kelly, David P.; Jenkins, Margot J.; Journal of Organic Chemistry; vol. 49; nb. 3; (1984); p. 409 - 413 View in Reaxys

O

O N

O

Rx-ID: 73047 View in Reaxys 13/13 Yield

Conditions & References With hydrogenchloride, aluminium trichloride, benzene Baddeley et al.; Journal of the Chemical Society; (1956); p. 2455,246 View in Reaxys

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