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Reference：
[1] Archiv der Pharmazie, 1998, vol. 331, # 12, p. 405 - 411
2
[ 872-31-1 ]
[ 40032-73-3 ]
Yield
Reaction Conditions
Operation in experiment
87%
With N-chloro-succinimide In acetic acid
Step A: Preparation of 2-chloro-3-bromothiophene To a round bottomed flask were added glacial acetic acid (115.0 mL) along with 3-bromothiophene (25.0 g, 153.3 mmole). The reaction mixture was heated to reflux and N-chlorosuccinimide (20.58 g, 154.0 mmole) was added portion-wise (Note: reaction vigorous upon each[addition]). After the addition was complete the reaction mixture was refluxed for three additional hours. The reaction mixture was cooled, poured onto ice/water and extracted (ethyl acetate). The combined extracts were washed with water, dilute HCl, and brine. Solvent removal yielded 27.91 g (87percent) of a dark liquid. The sample was distilled before further use.
n-Butyl lithium (2.5 M in hexanes, 105 [ML)] is slowly added to a solution of diisopropylamine (36.8 [ML)] in [THF] (600 [ML)] at 0 [C.] After 15 min, the mixture is cooled [TO-70 C.] A solution [OF 3-BROMO-2-CHLOROTHIOPHENE] (49.4 g) in THF (20 [ML)] is added maintaining the internal temperature [BELOW-65 C.] After 15 min, [DMF] [(25.] 2 mL) is added. The mixture is stirred at-70 C for 15 min and then allowed to warm to room temperature. The reaction mixture is quenched with saturated aq. NH4C1 solution (200 [ML)] and concentrated in vacuo to one-half volume. The residue is diluted with EtOAc (500 mL) and the aqueous layer is separated. The aqueous layer is extracted with EtOAc (2 x 100 [ML).] The combined organic layers are washed with brine (100 [ML),] dried [(MGSO4),] and concentrated to afford an oil. The oil is purified by column chromatography (heptane; [HEPTANE/ETOAC,] 20/1; 10/1). After concentration the resulting solid is suspended in heptane (75 [ML)] and filtered to afford [30.] 3 g of the title compound [AS A] light yellow solid. Physical characteristics. M. p. [61-] [62 C ; H] NMR [(300 MHZ, DMSO-D6) 6] 9.82, 8.14 ; 13C NMR (100 MHz, CDCl3) 8 181.6, 140.9, [138.] 5, [138. 1,] 112.8. Anal. Found: C, 26.68 ; [H,] 0. [91] ; Br, [35.] 11; [CL,] 15.78 ; S, 14.17.
Preparation 10. 4-Bromo-5-chloro-2-thiophenecarbaldehyde n-Butyl lithium (2.5 M in hexanes, 105 mL) is slowly added to a solution of diisopropylamine (36.8 mL) in THF (600 mL) at 0 C. After 15 min, the mixture is cooled to -70 C. A solution of <strong>[40032-73-3]3-bromo-2-chlorothiophene</strong> (49.4 g) in THF (20 mL) is added maintaining the internal temperature below -65 C. After 15 min, DMF (25.2 mL) is added. The mixture is stirred at -70 C. for 15 min and then allowed to warm to room temperature. The reaction mixture is quenched with saturated aq. NH4Cl solution (200 mL) and concentrated in vacuo to one-half volume. The residue is diluted with EtOAc (500 mL) and the aqueous layer is separated. The aqueous layer is extracted with EtOAc (2*100 mL). The combined organic layers are washed with brine (100 mL), dried (MgSO4), and concentrated to afford an oil. The oil is purified by column chromatography (heptane; heptane/EtOAc, 20/1; 10/1). After concentration the resulting solid is suspended in heptane (75 mL) and filtered to afford 30.3 g of the title compound as a light yellow solid. Physical characteristics. M.p.61-62 C.; 1H NMR (300 MHz, DMSO-d6) delta 89.82, 8.14; 13C NMR (100 MHz, CDCl3) delta 181.6, 140.9, 138.5, 138.1, 112.8. Anal. Found: C, 26.68; H, 0.91; Br, 35.11; Cl, 15.78; S, 14.17. aa0-5aa
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃;
Step A: <strong>[40032-73-3]3-bromo-2-chlorothiophene</strong> (1.00 mL), 3-aminophenylboronic acid (2.2266 g) and palladium tetrakistriphenylphosphine (544.8 mg) were combined in a mixture of 40 mL of dimethoxyethane and 15 mL of 2.0 M aqueous potassium carbonate under an atmosphere of dry N2. The reaction mixture was heated at 90 C. overnight. The reaction mixture was then cooled to room temperature and partitioned between EtOAc and water. The EtOAc layer was then dried over MgSO4, filtered and concentrated under vacuum. The resulting residue was purified using silica gel chromatography eluding with a 1:1 solution of DCM/Hexanes, followed by a 4:3 solution of DCM/Hexanes and finally a 2:1 solution of DCM/Hexanes, to give 1.80 g of 3-(2-chlorothiophen-3-yl)benzenamine.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃;
<strong>[40032-73-3]3-bromo-2-chlorothiophene</strong> (1.00 mL), 3-aminophenylboronic acid(2.2266 g) and palladium tetrakistriphenylphosphine (544.8 mg) were combined in a mixture of 40 mL of dimethoxyethane and 15 mL of 2.0 M aqueous potassium carbonate under an <n="67"/>atmosphere of dry N2. The reaction mixture was heated at 90 0C overnight. The reaction mixture was then cooled to room temperature and partitioned between EtOAc and water. The EtOAc layer was then dried over MgSO4, filtered and concentrated under vacuum. The resulting residue was purified using silica gel chromatography eluting with a 1:1 solution of DCM/Hexanes, followed by a 4:3 solution of DCM/Hexanes and finally a 2:1 solution of DCM/Hexanes, to give 1.80 g of 3-(2-chlorothiophen-3-yl)benzenamine.
With n-butyllithium; diisopropylamine; In tetrahydrofuran; n-heptane; N,N-dimethyl-formamide;
Preparation 61 4-Bromo-5-chloro-2-thiophenecarbaldehyde [BQ.2] n-BuLi (2.5 M in hexanes, 105 mL) is slowly added to a solution of diisopropylamine (36.8 mL) in THF (600 mL) at 0 C. After 15 min, the mixture is cooled to -70 C. A solution of <strong>[40032-73-3]3-bromo-2-chlorothiophene</strong> (49.4 g) in THF (20 mL) is added maintaining the internal temperature <-65 C. After 15 min, DMF (25.2 mL) is added. The mixture is stirred at -70 C. for 15 min and then allowed to warm to room temperature. The reaction mixture is quenched with saturated aq. NH4Cl solution (200 mL) and concentrated in vacuo to one-half volume. The residue is diluted with EtOAc (500 mL) and the aqueous layer is separated. The aqueous layer is extracted with EtOAc (2*100 mL). The combined organic layers are washed with brine (100 mL), dried (MgSO4), and concentrated to afford an oil. The oil is purified by column chromatography (heptane; heptane/EtOAc, 20/1; 10/1) and the resulting solid is suspended in heptane (75 mL) and filtered to afford 30.3 g (54%) of the title compound as a light yellow solid. Physical characteristics: M.p. 61-62 C.; 1H NMR (300 MHz, DMSO-d6) delta 9.82, 8.14; 13C NMR (100 MHz, CDCl3) delta 181.6, 140.9, 138.5, 138.1, 112.8.
Step A: Preparation of 2-chloro-3-bromothiophene To a round bottomed flask were added glacial acetic acid (115.0 mL) along with 3-bromothiophene (25.0 g, 153.3 mmole). The reaction mixture was heated to reflux and N-chlorosuccinimide (20.58 g, 154.0 mmole) was added portion-wise (Note: reaction vigorous upon each[addition]). After the addition was complete the reaction mixture was refluxed for three additional hours. The reaction mixture was cooled, poured onto ice/water and extracted (ethyl acetate). The combined extracts were washed with water, dilute HCl, and brine. Solvent removal yielded 27.91 g (87%) of a dark liquid. The sample was distilled before further use.
(a) 4-Bromo-5-chlorothiophene-2-carboxylic acid-(2'-hydroxyphenyl)-ester At room temperature, 55 g of 2,2-dichloro-1,3-benzodioxol is added to 50 g of <strong>[40032-73-3]4-bromo-5-chlorothiophene</strong> in 200 ml of methylene chloride. While cooling with ice, 67.5 g of aluminum trichloride is added in portions. The whole is then stirred for 5 minutes at room temperature and refluxed for a further 5 minutes. Finally, it is poured into ice water, stirred and suction filtered. Working up in the usual manner gives 84 g of a crude crystalline product of melting point 145-147 C. and which is used in the next stage.
5-(2-chloro-3-thienyl)-2,4,6(1H,3H,5H)pyrimidinetrione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With n-butyllithium; In tetrahydrofuran;
EXAMPLE 20 5-(2-Chloro-3-thienyl)-2,4,6(1H,3H,5H)pyrimidinetrione Following the method of Gronowitz et al. [Chemica Scripta 15, p. 2 (1980)], <strong>[40032-73-3]2-chloro-3-bromothiophene</strong> is reacted with n-butyl lithium in ether at -70 C. After 15 minutes, the organolithium reagent is poured into a solution of alloxan in tetrahydrofuran at -70 C. The reaction mixture is allowed to warm to room temperature for 2 hours, and 5-(2-chloro-3-thienyl)-2,4,6(1H,3H,5H)-pyrimidinetrione isolated according to Example 5. The same procedure is employed with 4-bromo-2-chlorothiophene to produce 5-(5-chloro-3-thienyl)-2,4,6(1H,3H,5H)pyrimidinetrione.
2-phenyl-4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine[ No CAS ]
4-[4-(2-chloro-thiophen-3-yl)-benzyl]-2-phenyl-morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 120℃; for 0.0833333h;Microwave irradiation;
Example 16: 4-[4-(2-Chloro-thiophen-3-yl)-benzyl]-2-phenyl-morpholine; 91mg of 4-(4-Bromo-ben2yl)-2-phenyl-morpholine was combined with 77mg of bis(pinacolato)diboron, 81mg of potassium acetate, 16mg tetrakis(triphenylphosphine)palladium(0), and 1.9mL DMF. The mixture was heated in a microwave reactor at 120C for 7 minutes and cooled. 0.7mL of 2M aqueous sodium carbonate was added along with 81mg of 2-Chloro-3-bromothiophene in 0.12mL DMF. The mixture was heated in the microwave reactor for an additional 5 minutes at 12O0C. The reaction was cooled and filtered through Celite, washing with methylene chloride. The residue was diluted with 4mL DCM and 130mg of MP-TsOH resin (4.2mmol/g loading) was added and the mixture agitated at room temperature overnight. The solution is filtered and the resin is then washed with 2M NH3 in methanol to liberate product. The resin is washed several times with methylene chloride, concentrated in vacuo and purified by reverse phase HPLC. 10.9mg of product is obtained as oil, 10% yield. ES MS m/z 398 The above compound was made in the same manner as Example 24 but with the appropriate aryl bromide. 5% yield, ES MS m/z 370
With N-ethyl-N,N-diisopropylamine;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 48h;
A solution of <strong>[40032-73-3]3-bromo-2-chlorothiophene</strong> (2.43 g, 12.3 mmol), 2,5-difluorophenylboronic acid (2.91 g, 18.4 mmol), diisopropylethylamine (4.8 g, 37 mmol) and [Iota, - bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (300 mg, 0.37 mmol) was stirred in dioxane (100 mL) and water (10 mL) at 80 C for two days. Toluene (100 mL) was added. The organic phase was washed with 1 M NaOH (aq.), 1 M HC1 (aq.) and brine, dried and concentrated to a brown oil. The brown oil was purified by distillation (twice) in a Kugelrohr apparatus at 120 C and -10 mbar resulting in 0.73 g (26%) of the intermediate 2-chloro-3-(2,5-difluorophenyl)thiophene. 1H MR (500 MHz, CDC13) delta ppm 7.01 - 7.23 (m, 5 H).
26%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; water; at 80℃; for 48h;
A solution of <strong>[40032-73-3]3-bromo-2-chlorothiophene</strong> (2.43 g, 12.3 mmol), 2,5-difluorophenylboronic acid (2.91 g, 18.4 mmol), DIPEA (4.8 g, 37 mmol) and Pd(dppf)Cl2.CH2Cl2 (300 mg, 0.37 mmol) was stirred in dioxane (100 mL) and water (10 mL) at 80 C. for two days. Toluene (100 mL) was added. The organic phase was washed with 1 M NaOH, 1 M HCl and brine, dried and concentrated to a brown oil. The brown oil was purified by distillation (twice) in a Kugelrohr apparatus at 120 C. and 10 mbar resulting in 0.73 g (26%) of the intermediate 2-chloro-3-(2,5-difluorophenyl)thiophene. 1H NMR (500 MHz, CDCl3) delta ppm 7.01-7.23 (m, 5H).
the three 100mL flask with a nitrogen apparatus, 40 ml of DMF was added, followed by adding 2.18g (0.02mol) of p-aminophenol and 1.92g (0.02mol) of sodium tert-butoxide (that is, the STB), at room temperature, the reaction was stirred about 1h, then add 0.02mol2- chloro-3-bromothiophene and 2.76g (0.02mol) K2CO3, And stirring was continued at room temperature, the progress of the reaction by TLC, After completion of the reaction, the solvent DMF was distilled off under reduced pressure, dissolved with 50ml of chloroform, and extracted with distilled water, The chloroform layer was dried over anhydrous sodium sulfate, and allowed to stand overnight, and dried to obtain the product, namely 4- (3-bromo-2-thienyl group) aniline.
3,6-di(2-chlorothienyl-3-yl)thieno[3,2-b]thiophene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
Under a nitrogen atmosphere, 1.97 g (10.0 mmol) of <strong>[40032-73-3]3-bromo-2-chlorothiophene</strong> (Wako Pure Chemical Industries) and 12 ml of THF (dehydrated grade) were added to a 100 ml Schlenk reaction vessel. The solution was cooled to 0 C., and 5.5 ml (11 mmol) of a THF solution of isopropylmagnesium chloride (Sigma-Aldrich, 2.0 M) was added dropwise. The mixture was aged at 0 C. for 1 hour and at 25 C. for 2 hours. Meanwhile, 1.50 g (11.0 mmol) of zinc chloride (Wako Pure Chemical Industries, Ltd.) and 15 ml of THF (dehydrated grade) were added to another 100 ml Schlenk reaction vessel under a nitrogen atmosphere, and the mixture was cooled to 0 C. To the obtained white fine slurry solution, the Grignard reagent of <strong>[40032-73-3]3-bromo-2-chlorothiophene</strong> previously prepared was added dropwise using Teflon cannula and 3 ml of THF (dehydration grade) was added to 100 ml Schlenk reaction vessel And Teflon cannula were added while washing. The resulting mixture was stirred at 0 C. for 30 minutes and further at room temperature for 15 minutes.992 mg (3.33 mmol) of 3,6-dibromothieno [3,2-b] thiophene (Wako Pure Chemical Industries, Ltd.) as a white fine slurry liquid of the produced 2-chlorothienyl-3-zinc derivative and tetrakis Phosphine) palladium (Tokyo Chemical Industry) 69.7 mg (0.0600 mmol, 1.80 mol% based on 3,6-dibromothieno [3,2-b] thiophene) was added. After conducting the reaction at 50 C. for 5 hours, the reaction vessel was cooled with water and 20 ml of 1 M hydrochloric acid was added to terminate the reaction. The mixture was extracted with toluene, and the organic phase was washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: toluene). The mixture was concentrated under reduced pressure, and the obtained residue was washed with 15 ml of hexane. The resulting residue was purified by recrystallization from hexane / toluene = 3/2 to obtain 708 mg of a pale yellow solid of 3,6-di (2-chlorothienyl-3-) thieno [3,2-b] thiophene ( Yield 57%).
1,4-di(2-chlorothien-3-yl)-2,3-difluorobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
Under a nitrogen atmosphere, 7.08 g (35.9 mmol) of <strong>[40032-73-3]3-bromo-2-chlorothiophene</strong> (Tokyo Chemical Industry Co., Ltd.) and 70 ml of THF (dehydrated grade) were added to a 300 ml Schlenk reaction vessel. The solution was cooled to 0 C., and 18.5 ml (37.0 mmol) of a THF solution of isopropylmagnesium chloride (Sigma-Aldrich, 2.0 M) was added dropwise. The mixture was aged at 0 C. for 1 hour (preparation of Grignard reagent). Meanwhile, in a nitrogen atmosphere, 5.90 g (43.2 mmol) of zinc chloride (Wako Pure Chemical Industries, Ltd.) and 60 ml of THF (dehydration grade) were added to another 500 ml Schlenk reaction vessel and cooled to 0 C. To the obtained white fine slurry solution, the Grignard reagent of <strong>[40032-73-3]3-bromo-2-chlorothiophene</strong> previously prepared was dropped using Teflon cannula, and further 5 ml of THF (dehydration grade) was charged into a 300 ml Schlenk reaction vessel And Teflon cannula were added while washing. The resulting mixture was stirred at 0 C. for 30 minutes and further at room temperature for 90 minutes. 3.26 g (12.0 mmol) of 1,4-dibromo-2,3-difluorobenzene (Tokyo Chemical Industry Co., Ltd.) as a white fine slurry solution of the produced 2-chlorothienyl-3-zinc derivative and tetrakis Phosphine) palladium (Tokyo Chemical Industry Co., Ltd.) (0.181 mmol, 1.51 mol% based on 1,4-dibromo-2,3-difluorobenzene) was added. After conducting the reaction at 45 C. for 4 hours, the reaction vessel was cooled with water and the reaction was stopped by adding 150 ml of 1N hydrochloric acid. The mixture was extracted with toluene, and the organic phase was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (developing solvent: toluene / hexane = 1: 1). The mixture was concentrated under reduced pressure, and the obtained residue was washed with 20 ml of hexane. The obtained residue was purified by recrystallization from heptane / toluene = 2/1 to obtain 1.88 g of 1,4-di (2-chlorothienyl-3 -) - 2,3-difluorobenzene as a colorless solid(Yield 45%).
Under a nitrogen atmosphere, a 100 ml Schlenk reaction vessel was charged with 2,3-dibromothiophene (Tokyo Chemical Industry) 2.18 g (9.00 mmol) and THF (dehydration grade) 40 ml were added. This solution was cooled to 0 C., and 4.60 ml (9.20 mmol) of a THF solution of ethyl magnesium chloride (Sigma-Aldrich, 2.0 M) was added dropwise. The mixture was aged at 0 C. for 1 hour (preparation of Grignard reagent). Meanwhile, 1.36 g (10.0 mmol) of zinc chloride (Wako Pure Chemical Industries, Ltd.) and 20 ml of THF (dehydrated grade) were added to another 200 ml Schlenk reaction vessel under a nitrogen atmosphere and cooled to 0 C. To the obtained white fine slurry solution, the Grignard reagent of 2,3-dibromothiophene prepared previously was dropped using Teflon cannula, and further using 5 ml of THF (dehydration grade), 100 ml Schlenk reaction vessel and Teflon I threw in the cannula while washing it. The resulting mixture was stirred at 0 C. for 30 minutes and further at room temperature for 1 hour. 3-bromothienyl-2-zinc derivative of a white fine slurry solution,1,8-dichloro-2,7-bis(trifluoromethanesulfonyloxy) naphthalene obtained in Synthesis Example 21.48 g (3.00 mmol) of tetrakis (triphenylphosphine) palladium (Tokyo Chemical Industry Co., Ltd.) as a catalyst, 52.0 mg (0.0448 mmol,1.50 mol% based on 1,8-dichloro-2,7-bis(trifluoromethanesulfonyloxy)naphthalene) was added. After conducting the reaction at 50 C. for 20 hours, the reaction vessel was cooled with water and 100 ml of 1N hydrochloric acid was added to terminate the reaction. The mixture was extracted with toluene, and the organic phase was washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: toluene). The mixture was concentrated under reduced pressure, and the obtained residue was washed with 20 ml of hexane. The obtained residue was purified by recrystallization from heptane / toluene = 2/1 to obtain 638 mg of 2,7-di(3-bromothienyl-2-yl)-1,8-dichloronaphthalene (yield 41%).
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