* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] European Journal of Organic Chemistry, 2013, # 12, p. 2445 - 2452
[2] ChemCatChem, 2014, vol. 6, # 1, p. 109 - 112
[3] Tetrahedron, 2014, vol. 70, # 13, p. 2286 - 2293
2
[ 86-90-8 ]
[ 64169-34-2 ]
[ 19477-73-7 ]
Yield
Reaction Conditions
Operation in experiment
38%
With sodium tetrahydroborate In 1,2-dimethoxyethane at 20 - 30℃; for 4 h;
The feed solution for the reaction was prepared by dissolving 227 g of 4-bromophthalic anhydride in 300 g of ethylene glycol dimethyl ether at 20° C. This solution was then added to the reducing agent, which was prepared as a slurry of 22.7 g of sodium BOROHDYRIDE in 200 g ethylene glycol dimethyl ether at 20°C. As the starting material was added to the reducing agent slurry, an increase in temperature from 20°C to 30°C was noted. After approximately 3.0 hours, all of the 4-bromophthalic anhydride had been added to the sodium borohydride slurry, and the reaction was allowed to continue, with stirring, for a further one hour at 26° C. Neutralisation of the excess sodium borohydride was performed by the careful addition of 200 g water and 70 g hydrochloric acid (as a 32percent aqueous solution). The pH of the neutralized reaction mixture dropped to pH 1-2, and the temperature rose from 26° C to 31° C. Phase separation was achieved by heating the mixture to 50° C, at which point two clearly distinguishable phases were observed: a heavy aqueous phase and a clear organic phase. The lower, aqueous, phase (223 g) was carefully removed, following which the organic phase was washed with aqueous NaCl solution (200 g, 15percent w/w) to remove the residues of H3BO3 formed during the work-up, then the aqueous ethylene glycol dimethyl ether (262 g) was partially distilled off from the organic phase over a temperature range of 74 to 91° C in a reboiler. Crude 5-bromophthalide was then crystallized from the organic phase residue by controlled cooling of said residue from 91°C to 25° C over a period of one hour, following which the temperature was held constant at 25° C for a further one hour. The crystallized material was filtered and washed with aqueous 50percent ethylene glycol dimethyl ether. The filtration residue thus formed was found to contain approximately 80percent 5-bromophthalide and 20percent 6-bromophthalide. In order to further purify the desired product, a slurry of 240 g of the wet, crude 5-bromophthalide was prepared in 240 g of aqueous 90percent ethylene glycol dimethyl ether at 25° C. This slurry was then heated to 85° C to obtain a solution, and re-crystallisation of the 5-bromophthalide was achieved by lowering the temperature from 85° C to 25°C over a period of one hour, and then holding at the lower temperature for a further one hour. The crystallized product was then filtered and washed with 90 g of aqueous 90percent ethylene glycol dimethyl ether, following which 97 g of wet residue was dried at 80° C for a period of 2 hours. The dried product thus formed (83 g) was subjected to HPLC analysis, and was found to contain >99percent 5-bromophthalide. The direct yield was approximately 38percent.
33%
With sodium tetrahydroborate In tetrahydrofuran at 5 - 25℃; for 3.5 h;
The feed solution for the reaction was prepared by dissolving 197 g of 4-bromophthalic anhydride in 250 g of THF at 25° C. This solution (density = 1.15 g/ml) was then added to the reducing agent, which was prepared as a slurry of 18.5 g of sodium borohydride in 150 g THF pre-cooled to 5° C prior to the addition of said solution. As the starting material was added to the reducing agent slurry, an increase in temperature from 5°C to 15°C was noted. After approximately 2.5 hours, all of the 4-bromophthalic anhydride had been added to the sodium borohydride slurry, and the reaction was allowed to continue, with stirring, for a further one hour at 25° C. Neutralisation of the excess sodium borohydride was performed by the careful addition of 120 g water and 60g hydrochloric acid (as a 32percent aqueous solution). The pH of the neutralized reaction mixture dropped to pH 1-2, and the temperature rose from 25° C to 30° C. Phase separation was achieved by heating the mixture to 58° C, at which point two clearly distinguishable phases were observed: a heavy aqueous phase having a density of 1.15 G/ML, and a clear organic phase having a density of 1.03 g/ml. The lower, aqueous, phase (159 g) was carefully removed, following which the organic phase was washed with aqueous NaCl solution (140 g, 10percent w/w) to remove the residues of H3BO3 formed during the work-up, then the THF (267 g) was partially distilled off from the organic phase over a temperature range of 70 to 75° C in a reboiler. Crude 5-bromophthalide was then crystallized from the organic phase residue (317 g) by adding 30 g water and controlled cooling of said residue from 75° C to 30° C over a period of one hour, following which the temperature was held constant at 30° C for a further one hour. The crystallized material was filtered and washed with 100g THF. The filtration residue thus formed (113 g, LOD-25percent) was found to contain approximately 90percent 5-bromophthalide and 10percent 6-bromophthalide. In order to further purify the desired product, a slurry of 100 g of the wet, crude 5-bromophthalide was prepared in 140 g of THF containing 6percent water at 25° C. This slurry was then heated to 60° C, and held at that temperature for one hour. Re-crystallization of the 5-bromophthalide was achieved by lowering the temperature from 60° C to 25°C over a period of one hour, and then holding at the lower temperature for a further one hour. The crystallized product was then filtered and washed with 40 g of THF, following which 65 g of wet residue was dried at 80° C for a period of 2 hours. The dried product thus formed (53 g) was subjected to HPLC and NMR analysis, and was found to contain >98percent 5-bromophthalide. The direct yield was approximately 33percent. The filtrate contained approximately 21 g of a recoverable mixture of 5-bromophthalide (70percent) and 6- bromophthalide (30percent). The overall yield of this process (after recycling the mother liquor) was between 37 and 40percent.
With hydrogen bromide; copper(I) bromide; sodium nitrite In water at 0℃; for 0.333333 h;
Step c: 6-Bromoisobenzofuran-1(3H)-one A solution of NaNO2 (2.2 g, 0.040 mol) in H2O (22 mL) was added to a mixture of 6-aminoisobenzofuran-1(3H)-one (5.0 g, 0.030 mol) in HBr (70 mL, 48percent) over 5 min at 0° C. The mixture was stirred for 20 minutes before it was pipetted into an ice cold solution of CuBr (22 g, 0.21 mol) in HBr (48percent, 23 mL). The resulting dark brown mixture was stirred for 20 min and was then diluted with H2O (200 mL) to produce an orange precipitate. The precipitate was filtered off, treated with sat. NaHCO3 solution, and extracted with EtOAc (20 mL*3). The organics were dried over Na2SO4 and evaporated in vacuo to give 6-bromoisobenzofuran-1(3H)-one (5.4 g, 84percent). 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=1.8, 1H), 7.80 (dd, J=8.1, 1.8, 1H), 7.39 (d, J=8.1, 1H), 5.28 (s, 2H).
84%
With hydrogen bromide; copper(I) bromide; sodium nitrite In water at 0 - 80℃; for 0.333333 h;
6-Amino-1(3H)-isobenzofuranone (3.0 g, 20 mmol) obtained from Example 26-(1) was dissolved in a mixture of 47percent aqueous hydrobromic acid solution (15 ml) and water (15 ml), then the mixture was cooled to 0°C, and a solution of sodium nitrite (1.45 g, 21 mmol) in water (7 ml) was slowly added thereto. Further, a solution of copper (I) bromide (3.6 g, 25 mmol) dissolved in 47percent aqueous hydrobromic acid solution (10 ml) was added to the reaction mixture, and the resulting mixture was stirred at 80°C for 20 minutes. After cooling the mixture, the liberated product was collected by filtration and then washed with water. The obtained pale brown solid was dissolved in ethyl acetate, then the insoluble material was removed by filtration, and the filtrate was washed successively with a 1N aqueous solution of hydrochloric acid, an aqueous solution of sodium hydrogen carbonate, and an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to afford the title compound (3.57 g, 84percent yield) as a crystalline solid. NMR spectrum (400 MHz, CDCl3) δ ppm: 5.289 (2H, s), 7.391 (1H, d, J=8 Hz), 7.808 (1H, dd, J=8, 2 Hz), 8.068 (1H, d, J=2 Hz) IR spectrum ν max KBr cm-1: 1778, 1458, 1359, 1191, 1046, 998, 768 Mass spectrum m/z (EI): 214, 212 (M+), 185, 183, 157, 155.
84%
Stage #1: With hydrogen bromide; sodium nitrite In water at 0℃; for 0.333333 h; Stage #2: With copper(I) bromide In water for 0.333333 h; Cooling with ice
A solution of NaNO2 (2.2 g, 0.040 mol) in H2O (22 mL) was added to a mixture of 6-aminoisobenzofuran-1(3H)-one (5.0 g, 0.030 mol) in HBr (70 mL, 48percent) over 5 min at 0° C. The mixture was stirred for 20 minutes before it was pipetted into an ice cold solution of CuBr (22 g, 0.21 mol) in HBr (48percent, 23 mL). The resulting dark brown mixture was stirred for 20 min and was then diluted with H2O (200 mL) to produce an orange precipitate. The precipitate was filtered off, treated with sat. NaHCO3 solution, and extracted with EtOAc (20 mL*3). The organics were dried over Na2SO4 and evaporated in vacuo to give 6-bromoisobenzofuran-1(3H)-one (5.4 g, 84percent). 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=1.8, 1H), 7.80 (dd, J=8.1, 1.8, 1H), 7.39 (d, J=8.1, 1H), 5.28 (s, 2H).
Reference：
[1] Patent: US2008/9524, 2008, A1, . Location in patent: Page/Page column 410
[2] Patent: EP1362856, 2003, A1, . Location in patent: Page/Page column 159
[3] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 1265
[4] Chemistry of Heterocyclic Compounds, 2010, vol. 46, # 2, p. 140 - 145
[5] Journal of Medicinal Chemistry, 2015, vol. 58, # 9, p. 3997 - 4015
[6] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 5, p. 1195 - 1204
[7] European Journal of Medicinal Chemistry, 2010, vol. 45, # 5, p. 1941 - 1946
[8] Patent: US2011/98311, 2011, A1,
5
[ 87-41-2 ]
[ 19477-73-7 ]
Yield
Reaction Conditions
Operation in experiment
66%
at 20℃; for 69 h;
NBS (53.4 g, 300 mmol, 1.5 eq) was added portion wise to a solution of phthalide (Sl-I) (26.83 g, 200 mmol. 1 O eq) in a mixture of TFA (100 mL) and sulfuric acid (45 mL) at rt over 9 h. The reaction mixture (an orange solution) was stirred at rt for about 60 h. (Crude NMR showed the reaction is complete.) Then the reaction mixture was poured onto ice, extracted with methylene chloride (3 x 300 mL). The combined organic phase was dried over MgSO4, filtered and concentrated to afford a yellow solid. The residue was purified by flash-column chromatography (5-10percent ethyl acetate-hexanes) to afford the desired product Sl-2 (white solid, 28.17g, 66percent) and the other regioisomer S3-1 (white solid, 12.7g, 30percent). 1H NMR (400 MHz, CDCl3) 8 8.04 (d, J= 1.8 Hz, 1 H), 7.78 (dd, J= 1.8, 7.9 Hz, 1 H), 7.37 (d, J= 7.9 Hz, 1 H), 5.26 (s, 2 H).
57%
With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid In ethyl acetate for 95 h;
6-Bromoisobenzofuran-1(3H)-one (20a) In a 100 mL round bottom flask was dissolved isobenzofuran-1(3H)-one (4.01 g, 29.9 mmol) in trifluoroacetic acid (14 mL, 182 mmol) and sulfuric acid (6.5 mL, 122 mmol). N-Bromosuccinimide (7.95 g, 1.49 mmol) was added portionwise over 8 hours and the solution was stirred at room temperature for an additional 87 hours. The solution was diluted with water (40 mL) and ethyl acetate (40 mL). The pH of the aqueous layer was neutralized with 1M aq. NaOH and sat. aq. NaHCO3. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3*50 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, and concentrated on to silica. The crude product was then purified by flash column chromatography using 10-20percent ethyl acetate in hexanes to yield 20a as white solid in 57percent yield. 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J=1.5 Hz, 1H), 7.77 (dd, J=8.3, 1.5 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 5.27 (s, 2H). LCMS found 212.9 [M+H]+.
Reference：
[1] Patent: WO2010/132670, 2010, A2, . Location in patent: Page/Page column 50-51
[2] Journal of the American Chemical Society, 2016, vol. 138, # 29, p. 9085 - 9088
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
[4] Patent: US2015/259331, 2015, A1, . Location in patent: Paragraph 0195
[5] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 5, p. 1195 - 1204
[6] Chemistry of Heterocyclic Compounds, 2010, vol. 46, # 2, p. 140 - 145
[7] Patent: US2011/98311, 2011, A1,
[8] Organic Letters, 2012, vol. 14, # 14, p. 3748 - 3751
[9] Tetrahedron, 2013, vol. 69, # 15, p. 3287 - 3292
[10] Journal of Medicinal Chemistry, 2015, vol. 58, # 9, p. 3997 - 4015
[11] Patent: US2015/231142, 2015, A1,
[12] Patent: CN105153013, 2017, B,
6
[ 171011-37-3 ]
[ 64169-34-2 ]
[ 19477-73-7 ]
Reference：
[1] European Journal of Organic Chemistry, 2013, # 12, p. 2445 - 2452
[2] ChemCatChem, 2014, vol. 6, # 1, p. 109 - 112
[3] Tetrahedron, 2014, vol. 70, # 13, p. 2286 - 2293
7
[ 86-90-8 ]
[ 64169-34-2 ]
[ 19477-73-7 ]
Yield
Reaction Conditions
Operation in experiment
38%
With sodium tetrahydroborate In 1,2-dimethoxyethane at 20 - 30℃; for 4 h;
The feed solution for the reaction was prepared by dissolving 227 g of 4-bromophthalic anhydride in 300 g of ethylene glycol dimethyl ether at 20° C. This solution was then added to the reducing agent, which was prepared as a slurry of 22.7 g of sodium BOROHDYRIDE in 200 g ethylene glycol dimethyl ether at 20°C. As the starting material was added to the reducing agent slurry, an increase in temperature from 20°C to 30°C was noted. After approximately 3.0 hours, all of the 4-bromophthalic anhydride had been added to the sodium borohydride slurry, and the reaction was allowed to continue, with stirring, for a further one hour at 26° C. Neutralisation of the excess sodium borohydride was performed by the careful addition of 200 g water and 70 g hydrochloric acid (as a 32percent aqueous solution). The pH of the neutralized reaction mixture dropped to pH 1-2, and the temperature rose from 26° C to 31° C. Phase separation was achieved by heating the mixture to 50° C, at which point two clearly distinguishable phases were observed: a heavy aqueous phase and a clear organic phase. The lower, aqueous, phase (223 g) was carefully removed, following which the organic phase was washed with aqueous NaCl solution (200 g, 15percent w/w) to remove the residues of H3BO3 formed during the work-up, then the aqueous ethylene glycol dimethyl ether (262 g) was partially distilled off from the organic phase over a temperature range of 74 to 91° C in a reboiler. Crude 5-bromophthalide was then crystallized from the organic phase residue by controlled cooling of said residue from 91°C to 25° C over a period of one hour, following which the temperature was held constant at 25° C for a further one hour. The crystallized material was filtered and washed with aqueous 50percent ethylene glycol dimethyl ether. The filtration residue thus formed was found to contain approximately 80percent 5-bromophthalide and 20percent 6-bromophthalide. In order to further purify the desired product, a slurry of 240 g of the wet, crude 5-bromophthalide was prepared in 240 g of aqueous 90percent ethylene glycol dimethyl ether at 25° C. This slurry was then heated to 85° C to obtain a solution, and re-crystallisation of the 5-bromophthalide was achieved by lowering the temperature from 85° C to 25°C over a period of one hour, and then holding at the lower temperature for a further one hour. The crystallized product was then filtered and washed with 90 g of aqueous 90percent ethylene glycol dimethyl ether, following which 97 g of wet residue was dried at 80° C for a period of 2 hours. The dried product thus formed (83 g) was subjected to HPLC analysis, and was found to contain >99percent 5-bromophthalide. The direct yield was approximately 38percent.
33%
With sodium tetrahydroborate In tetrahydrofuran at 5 - 25℃; for 3.5 h;
The feed solution for the reaction was prepared by dissolving 197 g of 4-bromophthalic anhydride in 250 g of THF at 25° C. This solution (density = 1.15 g/ml) was then added to the reducing agent, which was prepared as a slurry of 18.5 g of sodium borohydride in 150 g THF pre-cooled to 5° C prior to the addition of said solution. As the starting material was added to the reducing agent slurry, an increase in temperature from 5°C to 15°C was noted. After approximately 2.5 hours, all of the 4-bromophthalic anhydride had been added to the sodium borohydride slurry, and the reaction was allowed to continue, with stirring, for a further one hour at 25° C. Neutralisation of the excess sodium borohydride was performed by the careful addition of 120 g water and 60g hydrochloric acid (as a 32percent aqueous solution). The pH of the neutralized reaction mixture dropped to pH 1-2, and the temperature rose from 25° C to 30° C. Phase separation was achieved by heating the mixture to 58° C, at which point two clearly distinguishable phases were observed: a heavy aqueous phase having a density of 1.15 G/ML, and a clear organic phase having a density of 1.03 g/ml. The lower, aqueous, phase (159 g) was carefully removed, following which the organic phase was washed with aqueous NaCl solution (140 g, 10percent w/w) to remove the residues of H3BO3 formed during the work-up, then the THF (267 g) was partially distilled off from the organic phase over a temperature range of 70 to 75° C in a reboiler. Crude 5-bromophthalide was then crystallized from the organic phase residue (317 g) by adding 30 g water and controlled cooling of said residue from 75° C to 30° C over a period of one hour, following which the temperature was held constant at 30° C for a further one hour. The crystallized material was filtered and washed with 100g THF. The filtration residue thus formed (113 g, LOD-25percent) was found to contain approximately 90percent 5-bromophthalide and 10percent 6-bromophthalide. In order to further purify the desired product, a slurry of 100 g of the wet, crude 5-bromophthalide was prepared in 140 g of THF containing 6percent water at 25° C. This slurry was then heated to 60° C, and held at that temperature for one hour. Re-crystallization of the 5-bromophthalide was achieved by lowering the temperature from 60° C to 25°C over a period of one hour, and then holding at the lower temperature for a further one hour. The crystallized product was then filtered and washed with 40 g of THF, following which 65 g of wet residue was dried at 80° C for a period of 2 hours. The dried product thus formed (53 g) was subjected to HPLC and NMR analysis, and was found to contain >98percent 5-bromophthalide. The direct yield was approximately 33percent. The filtrate contained approximately 21 g of a recoverable mixture of 5-bromophthalide (70percent) and 6- bromophthalide (30percent). The overall yield of this process (after recycling the mother liquor) was between 37 and 40percent.
Reference：
[1] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 5, p. 1195 - 1204
[2] Chemistry of Heterocyclic Compounds, 2010, vol. 46, # 2, p. 140 - 145
[3] Patent: US2011/98311, 2011, A1,
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 9, p. 3997 - 4015
[5] Patent: US2015/231142, 2015, A1,
12
[ 19477-73-7 ]
[ 670256-21-0 ]
Yield
Reaction Conditions
Operation in experiment
91%
With lithium hydroxide In tetrahydrofuran; methanol; water at 20℃; for 16 h;
6-Bromo-3H-isobenzofuran-1-one (5.0 g, 23.47 mmol) was weighed and added to a three-neck bottle.Measure tetrahydrofuran: methanol: water (2:1:1, 80 mL), add to a three-neck bottle, stir for 10 minutes.After dissolution, lithium hydroxide (3.45 g, 70.42 mmol) was added and stirred at room temperature for 16 hours.After the reaction of the raw materials was monitored by thin layer chromatography, the reaction mixture was concentrated, and water (100 mL) was added.The pH was adjusted to 3 with 2N hydrochloric acid and extracted three times with 100 mL of ethyl acetate.The organic phase is then washed with water and the organic phase is washed with saturated sodium chloride.Dried over anhydrous sodium sulfate, filtered and concentrated.This gave 3.3 g (91percent) of a white solid.
Reference：
[1] Patent: CN108250058, 2018, A, . Location in patent: Paragraph 0261; 0264-0267
13
[ 19477-73-7 ]
[ 594-27-4 ]
[ 72985-23-0 ]
Yield
Reaction Conditions
Operation in experiment
88%
With tris-(o-tolyl)phosphine In N,N,N,N,N,N-hexamethylphosphoric triamide at 50℃; for 2 h;
Tris(dibenzylideneacetone)dipalladium (0) (30 mg, 0.033 mmol), tri-o-tolylphosphine (40 mg, 0.13 mmol), and tetramethyltin (600 mg, 3.35 mmol) were dissolved in hexamethylphosphoramide (0.6 ml), and 6-bromo-1(3H)-isobenzofuranone (144 mg, 0.676 mmol) obtained from Example 26-(2) was added thereto, then the mixture was heated at 50°C for 2 hours. After cooling the reaction mixture, the mixture was diluted with ethyl acetate, and washed successively twice with water and twice with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to chromatography on a silica gel (5 g) column (eluent; hexane : ethyl acetate = 3 : 1). The fractions containing the target compound were concentrated, and the obtained solid was recrystallized to afford the title compound (88.3 mg, 88percent yield) as a crystalline solid. NMR spectrum (400 MHz, CDCl3) δ ppm: 2.472 (3H, s), 5.284 (2H, s), 7.376 (1H, d, J=8 Hz), 7.497 (1H, d, J=8 Hz), 7.721 (1H, s).
With methanol; lithium hydroxide; water; In tetrahydrofuran; at 20℃;
Example 65; N-{(lS, 2R)-1-(3, 5-difluorobenzyl)-2-hydroxy-3-[(6- neopentyl-3, 4-dihydro-lH-isochromen-4-yl) amino] propyl} acetamide; Step One; 5-Bromo-2-carboxymethoxymethyl-benzoic acid; Lithium hydroxide monohydrate (11.80 g, 281.6 mmol) was added at room temperature over several minutes to a solution of 5- bromophthalide (20.0 g, 93.88 mmol) in a 2: 1: 1 solution of tetrahydrofuran/methanol/water (570 mL) and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and azeotropically dried with benzene to give 5-Bromo-2-hydroxymethyl-benzoic acid as a white solid. The material was used without further purification : 1H NMR (300 MHz, CDC13 + CD30D) 8 7. 89 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8. 3,1. 9 Hz, 1H), 3.99 (s, 2H); ESI MS (negative mode) m/z 229 [C8H7BrO3-H]-. Sodium hyride (15.0 g, 375 mmol, 60% dispersion in mineral oil) was added in small portions over the course of 0.5 h at room temperature to a solution of 5- Bromo-2-hydroxymethyl-benzoic acid in tetrahydrofuran (235 mL) containing bromoacetic acid (14.35 g, 103.2 mmol) and sodium iodide (1.41 g, 9.4 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and poured into water and then extracted with diethyl ether. The aqueous phase was acidified with 10% hydrochloric acid to pH 3-4 and extracted several times with ethyl acetate. The combined ethyl acetate phases were washed with water and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated to yield-Bromo- 2-carboxymethoxymethyl-benzoic acid as a white solid. The material was used without further purification
With methanol; lithium hydroxide; water; In tetrahydrofuran; at 20℃;
Lithium hydroxide monohydrate (11.80 g, 281.6 mmol) was added at room temperature over several minutes to a solution of 5-bromophthalide (20.0 g, 93.88 mmol) in a 2: 1: 1 solution of tetrahydrofuran/methanol/water (570 mL) and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and azeotropically dried with benzene to give 5-bromo-2-hydroxymethyl-benzoic acid as a white solid. The material was used without further purification :'H NMR (300 MHz, CDC13 + CD30D) 8 7.89 (d, J = 8.3 Hz, 1 H), 7.67 (d, J = 1.9 Hz, 1 H), 7.50 (dd, J= 8.3, 1.9 Hz, 1H), 3.99 (s, 2H); MS (ESI-) m/z229 [C8H7BrO3-H]-. Sodium hydride (15.0 g, 375 mmol, 60% dispersion in mineral oil) was added in small portions over the course of 0.5 h at room temperature to a solution of 5- bromo-2-hydroxymethyl-benzoic acid in tetrahydrofuran (235 mL) containing bromoacetic acid (14.35 g, 103.2 mmol) and sodium iodide (1.41 g, 9.4 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and poured into water and then extracted with diethyl ether. The aqueous phase was acidified with 10% hydrochloric acid to pH 3-4 and extracted several times with ethyl acetate. The combined ethyl acetate phases were washed with water and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated to yield 5- bromo-2-carboxymethoxymethyl-benzoic acid as a white solid. The material was used without further purification :'H NMR (300 MHz, CD30D) b 7.93-7. 86 (m, 2H), 7.55-7. 50 (m, 1H), 4.98 (s, 2H), 4.23 (s, 2H); MS (ESI-) m/z287 [C10HgBrO5 H]-.
With diisobutylaluminium hydride; In hexane; dichloromethane; at -78℃; for 1.5h;
Step 1: at -78 , dichloromethane (20.0mL) of 6- Buromofutarido ( 144,550Mg, solution DIBAL-H (2.7mL of 2.58 mmol), was added slowly 1.0 M) in hexane, the mixture was stirred for 1.5 hours at -78 C..The resulting mixture of saturated Na2SO4was quenched with, warmed to room temperature.To the mixture Na anhydrous2SO4was added and after the mixture was stirred for 12 hours, filtered, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography 6-bromo-1,3-dihydro-isobenzofuran-1-ol (145,530mg, 96%) as a yellow oil.
With hydrogen bromide; copper(I) bromide; sodium nitrite; In water; at 0℃; for 0.333333h;
Step c: 6-Bromoisobenzofuran-1(3H)-one A solution of NaNO2 (2.2 g, 0.040 mol) in H2O (22 mL) was added to a mixture of 6-aminoisobenzofuran-1(3H)-one (5.0 g, 0.030 mol) in HBr (70 mL, 48%) over 5 min at 0 C. The mixture was stirred for 20 minutes before it was pipetted into an ice cold solution of CuBr (22 g, 0.21 mol) in HBr (48%, 23 mL). The resulting dark brown mixture was stirred for 20 min and was then diluted with H2O (200 mL) to produce an orange precipitate. The precipitate was filtered off, treated with sat. NaHCO3 solution, and extracted with EtOAc (20 mL*3). The organics were dried over Na2SO4 and evaporated in vacuo to give 6-bromoisobenzofuran-1(3H)-one (5.4 g, 84%). 1H NMR (300 MHz, CDCl3) delta 8.05 (d, J=1.8, 1H), 7.80 (dd, J=8.1, 1.8, 1H), 7.39 (d, J=8.1, 1H), 5.28 (s, 2H).
84%
With hydrogen bromide; copper(I) bromide; sodium nitrite; In water; at 0 - 80℃; for 0.333333h;
6-Amino-1(3H)-isobenzofuranone (3.0 g, 20 mmol) obtained from Example 26-(1) was dissolved in a mixture of 47% aqueous hydrobromic acid solution (15 ml) and water (15 ml), then the mixture was cooled to 0C, and a solution of sodium nitrite (1.45 g, 21 mmol) in water (7 ml) was slowly added thereto. Further, a solution of copper (I) bromide (3.6 g, 25 mmol) dissolved in 47% aqueous hydrobromic acid solution (10 ml) was added to the reaction mixture, and the resulting mixture was stirred at 80C for 20 minutes. After cooling the mixture, the liberated product was collected by filtration and then washed with water. The obtained pale brown solid was dissolved in ethyl acetate, then the insoluble material was removed by filtration, and the filtrate was washed successively with a 1N aqueous solution of hydrochloric acid, an aqueous solution of sodium hydrogen carbonate, and an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to afford the title compound (3.57 g, 84% yield) as a crystalline solid. NMR spectrum (400 MHz, CDCl3) delta ppm: 5.289 (2H, s), 7.391 (1H, d, J=8 Hz), 7.808 (1H, dd, J=8, 2 Hz), 8.068 (1H, d, J=2 Hz) IR spectrum nu max KBr cm-1: 1778, 1458, 1359, 1191, 1046, 998, 768 Mass spectrum m/z (EI): 214, 212 (M+), 185, 183, 157, 155.
84%
A solution of NaNO2 (2.2 g, 0.040 mol) in H2O (22 mL) was added to a mixture of 6-aminoisobenzofuran-1(3H)-one (5.0 g, 0.030 mol) in HBr (70 mL, 48%) over 5 min at 0 C. The mixture was stirred for 20 minutes before it was pipetted into an ice cold solution of CuBr (22 g, 0.21 mol) in HBr (48%, 23 mL). The resulting dark brown mixture was stirred for 20 min and was then diluted with H2O (200 mL) to produce an orange precipitate. The precipitate was filtered off, treated with sat. NaHCO3 solution, and extracted with EtOAc (20 mL*3). The organics were dried over Na2SO4 and evaporated in vacuo to give 6-bromoisobenzofuran-1(3H)-one (5.4 g, 84%). 1H NMR (300 MHz, CDCl3) delta 8.05 (d, J=1.8, 1H), 7.80 (dd, J=8.1, 1.8, 1H), 7.39 (d, J=8.1, 1H), 5.28 (s, 2H).
copper(I) bromide; In water; hydrogen bromide;
Step c: 6-Bromoisobenzofuran-1(3H)-one A solution of NaNO2 (2.2 g, 0.040 mol) in H2O (22 mL) was added to a mixture of 6-aminoisobenzofuran-1(3H)-one (5.0 g, 0.030 mol) in HBr (70 mL, 48%) over 5 min at 0 C. The mixture was stirred for 20 minutes before it was pipetted into an ice cold solution of CuBr (22 g, 0.21 mol) in HBr (48%, 23 mL). The resulting dark brown mixture was stirred for 20 min and was then diluted with H2O (200 mL) to produce an orange precipitate. The precipitate was filtered off, treated with sat. NaHCO3 solution, and extracted with EtOAc (20 mL*3). The organics were dried over Na2SO4 and evaporated in vacuo to give 6-bromoisobenzofuran-1(3H)-one (5.4 g, 84%). 1H NMR (300 MHz, CDCl3) delta 8.05 (d, J=1.8, 1H), 7.80 (dd, J=8.1, 1.8, 1H), 7.39 (d, J=8.1, 1H), 5.28 (s, 2H).
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; at 60℃; for 2.5h;
To a stirred solution of 6-bromoisobenzofuran- 1 (3H)-one (2.00 g, 9.40 mmol, 1.0 eq) in chloroform (20 ml) was added N-Bromosuccinimide (NBS, 1.92 g, 10.8 mmol, 1.15 eq) and 2,2'-Azobis(2-methylpropionitrile) (AIBN, 154 mg, 0.94 mmol, 0.1 eq), and the resultant mixture was heated to 60 C for 2.5 hours. The reaction mixture was washed with saturated NaHCC followed by brine, dried over MgS04, and was concentrated to dryness. The residue was purified by column chromatography (PE/Et O Ac= 10/1) to afford 3,6-dibromoisobenzofuran- l (3H)-one (2.00 g, 73% yield) as a white solid.
61%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In chloroform; for 2.5h;Reflux;
10196] 3,6-Dibromoisobenzofuran-1(3H)-one (21a) In a SOmE round bottom flask was added 6-bromoisobenzothran- 1(3H)-one (1.00 g, 4.69 mmol), N-bromosuccinimide (958 mg, 5.38 mmol), 2,2?-azobis(2-methylpropionitrile) (75 mg, 0.46 mmol), and chloroform (23 mE). The mixture was refluxed for 2.5 hours, then cooled to room temperature and quenched with sat. aq. NaHCO3 (25 mE). The organic layer was removed, washed with water (20 mE), washed with brine (15 mE), and concentrated on to silica. The crude product was purified by flash column chromatography using a gradient of 5-10% ethyl acetate in hexanes to yield 21 a as a white solid in61% yield. ?H NMR (500 MHz, CDC13) oe 8.06 (d, J=1 .5 Hz, 1H), 7.90 (dd, J=8.1, 1.7 Hz, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.37 (s, 1H). ECMS does not ionize.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In 1,2-dichloro-ethane; for 2h;Reflux;
6-Bromo-phthalide (2.30g, 10.9mmol) was added to a solution of N-bromosuccinimide (2.1g, 11.8mmol), azobisisobutyronitrile (0.1g, 0.06mmol) in 1,2-dichloroethane (60mL). The mixture was heated to reflux for 2hrs, cooled to room temperature, and concentrated under reduced pressure. The residue was washed with water (10mL*3) to give compound 50-f. The product was used directly for the next step without further purification.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 2h;Reflux;
Starting material 6 (2.0 g, 9.39 mmol) and NBS (N-bromosuccinimide) (1.84 g, 1.5 mmol),AIBN (azobisisobutyronitrile) (154 mg, 0.94 mmol) was added to carbon tetrachloride (30 mL).The reaction mixture was refluxed for 2 h, cooled to rt and filtered. The solvent was evaporated to give the compound 7.Add water (10 mL) and reflux for 1 h.Cooled and extracted with EtOAc (200 mL).The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered.The solvent was evaporated to give Compound 8 (2.05 g, 95%).
With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; at 20℃; for 69h;
NBS (53.4 g, 300 mmol, 1.5 eq) was added portion wise to a solution of phthalide (Sl-I) (26.83 g, 200 mmol. 1 O eq) in a mixture of TFA (100 mL) and sulfuric acid (45 mL) at rt over 9 h. The reaction mixture (an orange solution) was stirred at rt for about 60 h. (Crude NMR showed the reaction is complete.) Then the reaction mixture was poured onto ice, extracted with methylene chloride (3 x 300 mL). The combined organic phase was dried over MgSO4, filtered and concentrated to afford a yellow solid. The residue was purified by flash-column chromatography (5-10% ethyl acetate-hexanes) to afford the desired product Sl-2 (white solid, 28.17g, 66%) and the other regioisomer S3-1 (white solid, 12.7g, 30%). 1H NMR (400 MHz, CDCl3) 8 8.04 (d, J= 1.8 Hz, 1 H), 7.78 (dd, J= 1.8, 7.9 Hz, 1 H), 7.37 (d, J= 7.9 Hz, 1 H), 5.26 (s, 2 H).
57%
With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; In ethyl acetate; for 95h;
6-Bromoisobenzofuran-1(3H)-one (20a) In a 100 mL round bottom flask was dissolved isobenzofuran-1(3H)-one (4.01 g, 29.9 mmol) in trifluoroacetic acid (14 mL, 182 mmol) and sulfuric acid (6.5 mL, 122 mmol). N-Bromosuccinimide (7.95 g, 1.49 mmol) was added portionwise over 8 hours and the solution was stirred at room temperature for an additional 87 hours. The solution was diluted with water (40 mL) and ethyl acetate (40 mL). The pH of the aqueous layer was neutralized with 1M aq. NaOH and sat. aq. NaHCO3. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3*50 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, and concentrated on to silica. The crude product was then purified by flash column chromatography using 10-20% ethyl acetate in hexanes to yield 20a as white solid in 57% yield. 1H NMR (500 MHz, CDCl3) delta 7.98 (d, J=1.5 Hz, 1H), 7.77 (dd, J=8.3, 1.5 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 5.27 (s, 2H). LCMS found 212.9 [M+H]+.
1,2-Dichloroethane (25mL)was added to a mixture of 6-methoxyphthalide (670 mg, 4.5 mmol), N-bromosuccinimide (890 mg, 5 mmol), azobisisobutyronitrile (41 mg, 0.2 mmol), and refluxed for 1 h. The reaction mixture was kept in an ice bath for 2 h then filtered. The solvent was removed under reduced pressure. Water (10 mL) was then added and the resulting mixture refluxed for 1 h. The reaction mixture was then cooled to room temperature and extracted with EtOAc. The combined organic phases were dried and concentrated under reduced pressure. 2.2.2.1 Methyl 5-bromo-2-formylbenzoate (7b) 6-Bromophthalide was prepared by portion wise addition of phthalide (1 g, 7.45 mmol) to a mixture of trifluoroacetic acid (TFA) (3.7 mL) and sulfuric acid (1.7 mL) at room temperature for 9 h. The reaction mixture was stirred at room temperature for 60 h, then poured onto ice and extracted with ethyl acetate. The combined organic phases were subsequently washed with a saturated solution of sodium bicarbonate and brine. After evaporation of the solvents in vacuum, the crude product was purified by column chromatography on silica gel (n-hexane/EtOAc: 9/1) to yield the desired product. 1H NMR (300 MHz, CDCl3): delta=8.01 (d, J=1.8 Hz, 1H), 7.80 (dd, J=8.4, 1.8 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 5.29 (s, 2H). 13C NMR (75 MHz, CDCl3): delta=169.5, 145.2, 137.2, 128.7, 127.9, 123.9, 123.1, 69.6. The representative procedures B and A outlined above were followed to prepare 7b, which was isolated as a light yellow solid. Mp=114-116 C. 1H NMR (300 MHz, CDCl3): delta=10.57 (s, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.80 (s, 1H), 7.79 (d, J=1.8 Hz, 1H), 3.99 (s, 3H). 13C NMR (75 MHz, CDCl3): delta=191.0, 165.4, 135.7, 133.5, 133.4, 130.0, 128.1, 53.2. HRMS (EI): m/z calcd for C9H7BrO3 (M+): 241.9579; found: 241.9577.
With sulfuric acid; trifluoroacetic acid; In 1,2-dichloro-ethane; at 20℃; for 69h;Reflux;
6-Bromophthalide was prepared by portion wise addition of phthalide (1 g, 7.45 mmol) to a mixture of trifluoroacetic acid (TFA) (3.7 mL) and sulfuric acid (1.7 mL) at room temperature for 9 h. The reaction mixturewas stirred at room temperature for 60 h, then poured onto ice and extracted with ethyl acetate. The combined organic phases were subsequently washed with a saturated solution of sodium bicarbonate and brine. After evaporation of the solvents in vacuum, the crude product was purified by column chromatography on silica gel (n-hexane/EtOAc: 9/1) to yield the desired product
To a stirring room temperature solution of 4-bromophthalic anhydride (3.00 g, 13.22 mmol) in ethanol (10 mL) and tetrahydrofuran (50 mL), under a blanket of nitrogen, add sodium borohydride (1.96 g, 52.86 mmol), in portions. Stir this mixture at ambient temperature for 8 hours and then quench with 2N HC1 (12 mL) and then excess water. Extract the resulting aqueous mixture with diethyl ether then ethyl acetate. Wash the combined extracts with water and brine; dry (sodium sulfate) and concentrate them in vacuo to give a mixture of 5-bromo-3H-isobenzofuran-l-one and 6-bromo-3H- isobenzofuran-1-one, 2.78 g (98%). Use as is without purification. Place the mixture of 5-bromo-3H-isobenzofuran-l-one and 6-bromo-3H- isobenzofuran-1-one (1.50 g, 7.04 mmol), bis (pinacolato) diboron (2.06 g, 8.10 mmol), PdCl2 (dppf) 2'CH2Cl2 (180 mg, 0.246 mmol), potassium acetate (2.07 g, 21.13 mmol) and anhydrous dimethyl sulfoxide (22 mL) in a round bottom flask. Put the reaction in an oil bath and stir it at 85C for 8 hours. Cool the dark brown colored reaction to ambient temperature, quench with ample water and extract the resulting aqueous mixture with dichloromethane. Wash the combined extracts with water and brine; then dry (sodium sulfate) and evaporate them in vacuo. Purify the resulting dark solid on a flash column (silica gel; 0%-20% gradient of THF in CH2C12 then 5% MeOH/20% THF/CH2C12) to provide the product as a mixture of the two title components, 785 mg (43%).
With tris-(o-tolyl)phosphine;tris-(dibenzylideneacetone)dipalladium(0); In N,N,N,N,N,N-hexamethylphosphoric triamide; at 50℃; for 2h;
Tris(dibenzylideneacetone)dipalladium (0) (30 mg, 0.033 mmol), tri-o-tolylphosphine (40 mg, 0.13 mmol), and tetramethyltin (600 mg, 3.35 mmol) were dissolved in hexamethylphosphoramide (0.6 ml), and <strong>[19477-73-7]6-bromo-1(3H)-isobenzofuranone</strong> (144 mg, 0.676 mmol) obtained from Example 26-(2) was added thereto, then the mixture was heated at 50C for 2 hours. After cooling the reaction mixture, the mixture was diluted with ethyl acetate, and washed successively twice with water and twice with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to chromatography on a silica gel (5 g) column (eluent; hexane : ethyl acetate = 3 : 1). The fractions containing the target compound were concentrated, and the obtained solid was recrystallized to afford the title compound (88.3 mg, 88% yield) as a crystalline solid. NMR spectrum (400 MHz, CDCl3) delta ppm: 2.472 (3H, s), 5.284 (2H, s), 7.376 (1H, d, J=8 Hz), 7.497 (1H, d, J=8 Hz), 7.721 (1H, s).
b. 3,6-Dibromo-Phthalide 6-Bromophthalide (5.85 gms; 0.0275 mole), N-bromosuccinimide (4.89 gm; 0.0275 mole) and azobisbutyronitrile (0.1 gm) were gently refluxed in dry carbon tetrachloride (200 ml.) for 2 hours. On cooling, the succinimide was filtered off and the solvent removed in vacuo to give an oil, which was used immediately.
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; In ethanol; at 150℃; for 0.0694444h;Microwave;
In a 10 mL glass tube was placed (4-([(2- methoxyphenyl)sulfonyl]amino}methyl)phenyl)boronic acid (0.321 g, 1.00 mmol), 5- bromophthalide (0.213 g, 1.00 mmol), bis(triphenylphosphine)palladium (II) chloride (0.035 g, 0.05 mmol), Et3N (0.42 mL, 3.00 mmol), ethanol (4.2 mL) and a magnetic stir bar. The vessel was sealed with a septum and placed into the microwace cavity. Microwace irradiation was used, and the reaction mixture was keep at 1500C for 350 seconds. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the contents were filter through the Celite. The filtrate was concentrated under vacuum. The crude residue was purified by flash chromatography (ethyl acetate/hexanes, 100% hexanes to 1 :1) to yield 0.324 g (79%) of 6-[4-([(2- methoxyphenyl)sulfonyl]amino}methyl)phenyl]-3-hydroisobenzofuran-l-one as yellow solid. MS (M+H)+ 410; (M-H)" 408
A solution of «-butyllithium in hexanes (2.50 M, 48.4 mL, 121.1 mmol, 1.2 eq) was added to a solution of diisopropylamine (16.97 mL, 121.1 mmol, 1.2 eq) in tetrahydrofuran (400 mL) at -78 C. The resulting mixture was stirred vigorously at -78 C for 30 min, warmed up to 0 C for 5 min, and cooled back to -78 C. A solution of the bromophthalide Sl-2 (21.5 g, 100.9 mmol, 1.0 eq) in tetrahydrofuran (200 mL) was added slowly via a cannula. The resulting dark solution was allowed to warm slowly to -50 C over 3 h. Methyl crotonate (1 1.77 mL, 1 1 1.02 mmol, 1.1 eq) was added slowly and the resulting mixture was allowed to warm up to rt without removing the cooling bath. The reaction mixture was poured into 1 N HCl solution (600 mL) and extracted with ethyl acetate (3 x 200 mL). The organic extracts were combined and dried over anhydrous MgSO4. The dried solution was filtered and the filtrate was concentrated, dried under high vacuum, providing an orange foamy solid (27.5 g), which was used for the next reaction without purification.; The above crude product was dissolved in methylene chloride (250 mL). BF3-Et2O (2.53 mL, 20.18 mmol, 0.2 eq) was added drop- wise at rt. The resulting brownish mixture was stirred at rt for 1 h (Monitored by TLC. Desired product is less polar) and poured into 0.5 N HCl solution (600 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (2 x 200 mL). The organic extracts were combined and dried over anhydrous MgSO4. The dried solution was filtered and the filtrate was concentrated, providing a thick brownish oil. The product Sl-3 was purified by flash-column chromatography (5- 10% ethyl acetate-hexanes) to afford compound Sl-3 as an off-white solid (6.32 g, 22%, two steps). 1H NMR (500 MHz, CDCl3) delta 12.68 (s, 1 H), 8.52 (s, 1 H), 7.63- 7.61 (d, J= 8.5 Hz, 1 H), 7.52-7.50 (d, J- 8.5 Hz, 1 H), 7.07 (s, 1 H), 4.01 (s, 3 H), 2.63 (s, 3 H).
With potassium phosphate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 100℃; for 1.5h;
Intermediate 18: 6-Ethyl-3H-isobenzofuran-l-one[0508] A mixture of 6-bromo-3H-isobenzofuran-l-one (Intermediate 72, 0.7g) and potassium phosphate (1.9g) in THF (7.3ml) and water (3.7ml) was degassed and palladium chloride dppf adduct with DCM (0.134g) and triethyl borane (1M solution in THF, 4.3ml) were added. The resultant mixture was stirred and heated at 100C for 1.5 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water and brine then dried (Na2S04) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give 6-ethyl-3H-isobenzofuran-l-one (0.435g) as a colourless oil.[0509] LCMS (method F) r/t 3.58 (M+H) 163.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In toluene; for 5h;
2.2.2.4 Methyl 4-formyl-[1,1'-biphenyl]-3-carboxylate (7e) For preparation of the intermediate 6-phenylphthalide, toluene (2.3 mL) was added to a mixture of <strong>[19477-73-7]6-bromophthalide</strong> (280 mg, 1.3 mmol), phenylboronic acid (319.4 mg, 2.6 mmol), tetrakis(triphenylphosphine) palladium (pd(pph3)4) (75.7 mg, 0.065 mmol), and sodium carbonate solution (1.9 mL, 2 M). The reaction mixture was refluxed for 5 h followed by adding water (2 mL) and extraction with ethyl acetate (10 mL, three times).
With 1,4-diaza-bicyclo[2.2.2]octane; copper(l) iodide; at 130℃; for 24h;Sealed tube; Inert atmosphere;
General procedure: An oven dried pressure tube was chargedwith aryl bromide (1 mmol), CuI (1 mmol), DABCO (2 mmol) and dry DMSO (5 mL).Then the tube was sealed with a teflon cap and heated with stirring at 130 Cin N2 atmosphere for 12 - 36 h. The completions of reactions weremonitored by TLC. The reaction mixture was then cooled to room temperature. Themass was passed through celite bed, packed in a sinter funnel. Then thefiltered reaction mixture was extracted with ethyl acetate (3 X 20) washed withwater (3 X 20) and brine solution (3 X 10). Ethyl acetate part were collectedand dried over Na2SO4, and then evaporated under reducedpressure. The crude products were purified by column chromatography on silicagel to obtain pure product.
6-((methyl-d<SUP>3</SUP>)thio)isobenzofuran-1(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With 1,4-diaza-bicyclo[2.2.2]octane; copper(l) iodide; at 130℃; for 12h;Sealed tube; Inert atmosphere;
An oven dried pressure tube charged with 5a (210mg, 1 mmol), CuI (190mg, 1 mmol), DABCO (224mg, 2 mmol) and d6-DMSO (5 mL) in presence of N2atmosphere, is heated at 130 oC for 12 h. The reaction mixture was then cooled to roomtemperature and filtered through celite bed. It was then extracted with EtOAc(3 x 60 mL), water (3 x 20 mL) and brine (20 mL) andthen evaporated under reduced pressure. The crude products were purified by columnchromatography on silica gel to obtain the corresponding white solid in 71%yield. NMR analysis of the product shows the formation of 6-((methyl-d3)thio)isobenzofuran-1(3H)-one(7n): 1HNMR (600 MHz, CDCl3): delta 7.64 (d, 1H, J = 1.8 Hz), 7.52 (dd, 1H, J= 1.8 Hz, 8.4 Hz), 7.37 (d, 1H, J =8.4 Hz), 5.27 (s, 2H).
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