* 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.
Stage #1: With sodium iodide In N,N-dimethyl-formamide at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 20℃; for 1 h; Inert atmosphere
General procedure: Bromoisoindolin-1-one (2.0 g, 9.43 mmol) was dissolved with warming in DMF (150 mL),then cooled to 0°C. NaH (415 mg, 10.4 mmol) was added and the mixture stirred under N2 at 0°C for 0.5 h. Methyl iodide (0.65 mL, 10.4 mmol) was added dropwise and the reaction allowed to warm to room temperature and stir for another I h. A small quantity of water was added to quench the reaction then the DMF removed under reduced pressure to give an oily yellow residue which was dissolved in EtOAc (150 mL). This solution waswashed with water (3x100 mL), brine (100 mL) and dried (Na2SO4)., Removal of the solvent under reduced pressure gave a solid which was purified by filtration through a plug of silica gel (10percent acetone/CH2C12 as eluant). The title compound was isolated as a very pale yellow crystalline solid (1.64 g, 80percent). ‘ H NMR [400 MHz, (CD3)2S0] ö 7.85 (dd, J= 1.5, 0.6 Hz, 1 H), 7.66 (dd, J= 8.0, 1.7 Hz, 1 H), 7.59 (d, J— 8.0 Hz, I H), 4.46 (s,2 H), 3.05 (s, 3 H). LRMS (APCI) calcd for C9H8BrNO 226, 228 (MH), found 226, 228.
Reference：
[1] Patent: WO2014/28968, 2014, A1, . Location in patent: Page/Page column 64; 107
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9542 - 9555
[3] E-Journal of Chemistry, 2011, vol. 8, # 3, p. 1108 - 1113
2
[ 79670-17-0 ]
[ 74-89-5 ]
[ 1254319-51-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 50℃; for 4 h;
35.1: 6-Bromo-2-methylisoindolin-1-one To a solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1.00 g, 3.25 mmol) in THF (6.5 mL) was a solution of methylamine in THF (2M, 8.12 mL, 16.24 mmol). The reaction mixture was heated at 50°C for 4 hours and then concentrated under vacuum. The residue was taken up in EtOAc and the organic layer was then washed with an aqueous 1M HCl solution, brine, dried (Na2SO4), filtered, concentrated under vacuum to give the title compound (0.73 g, 100percent) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 3.19 (m, 3H), 4.32 (s, 2H), 7.31 (d, 1H), 7.63 (dd, 1H), 7.96 (d, 1H).
100%
at 50℃; for 4 h;
35.1: 6-Bromo-2-methylisoindolin-1-one To a solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1.00 g, 3.25 mmol) in THF (6.5 mL) was a solution of methylamine in THF (2M, 8.12 mL, 16.24 mmol). The reaction mixture was heated at 50° C. for 4 hours and then concentrated under vacuum. The residue was taken up in EtOAc and the organic layer was then washed with an aqueous 1M HCl solution, brine, dried (Na2SO4), filtered, concentrated under vacuum to give the title compound (0.73 g, 100percent) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 3.19 (m, 3H), 4.32 (s, 2H), 7.31 (d, 1H), 7.63 (dd, 1H), 7.96 (d, 1H).
100%
at 50℃; for 4 h;
35.1 : 6-Bromo-2-methylisoindolin-1 -oneTo a solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1.00 g, 3.25 mmol) in THF (6.5 ml_) was a solution of methylamine in THF (2M, 8.12 ml_, 16.24 mmol). The reaction mixture was heated at 50°C for 4 hours and then concentrated under vacuum. The residue was taken up in EtOAc and the organic layer was then washed with an aqueous 1 M HCI solution, brine, dried (Na2SO4), filtered, concentrated under vacuum to give the title compound (0.73 g, 100percent) as a yellow solid.1 H NMR (400 MHz, CDCI3): 5 3.19 (m, 3H), 4.32 (s, 2H), 7.31 (d, 1 H), 7.63 (dd, 1 H), 7.96 (d, 1 H).
Reference：
[1] E-Journal of Chemistry, 2011, vol. 8, # 3, p. 1108 - 1113
17
[ 79670-17-0 ]
[ 1254319-51-1 ]
Reference：
[1] E-Journal of Chemistry, 2011, vol. 8, # 3, p. 1108 - 1113
18
[ 79669-50-4 ]
[ 1254319-51-1 ]
Reference：
[1] E-Journal of Chemistry, 2011, vol. 8, # 3, p. 1108 - 1113
19
[ 79669-49-1 ]
[ 1254319-51-1 ]
Reference：
[1] E-Journal of Chemistry, 2011, vol. 8, # 3, p. 1108 - 1113
20
[ 1254319-51-1 ]
[ 73183-34-3 ]
[ 1313399-38-0 ]
Yield
Reaction Conditions
Operation in experiment
28%
With potassium acetate In dimethyl sulfoxide at 90℃; for 5 h; Inert atmosphere
6-Bromo-2-raethylisoindolin-l-one (723 mg, 3.41 mmol), bis(pinacolato)diboron (1.04 g, 4.09 mmol), potassium acetate (1.00 g, 10.2 mmol) and PdCl2(dppf) catalyst (139 mg, 0.17 mmol) were weighed into a flask which was sealed under N2. DMSO (15 mL) was added, and the entire mixture stirred at 90°C for 5 h. Upon cooling, the reaction mixture was diluted with water (250 mL) and extracted with CH2C12 (5x50 mL). The combined CH2C12 fractions were in turn washed with water (2x100 mL), brine (100 mL), dried (Na2S04), filtered and the solvent removed under reduced pressure to yield the crude product. Purification was carried out by flash column chromatography on silica gel (20percent THF/CH2C12 as eluant) to give the title compound as a crystalline beige solid (262 mg, 28percent). NMR [400 MHz, (CD3)2SO] δ 7.91 (br s, 1 H), 7.85 (dd, J = 7.6, 1.0 Hz, 1 H), 7.59 (dd, J = 7.5, 0.6 Hz, 1 H), 4.49 (s, 2 H), 3.07 (s, 3 H), 1.32 (s, 12 H). LRMS (APCI+) calcd for Ci5H2iBN03 274 (MH+), found 274.
Reference：
[1] Patent: WO2011/75784, 2011, A1, . Location in patent: Page/Page column 113-114
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9542 - 9555
[3] Patent: WO2017/107089, 2017, A1, . Location in patent: Page/Page column 37; 38
Methyl 5-bromo-2-methylbenzoate (3 g) in ethyl acetate (100 mL) was treated with N- chlorosuccinimide (1.749 g). The mixture was stirred and heated under reflux whilst being irradiated with a halogen lamp for 5 h. The reaction mixture was cooled and washed with 10% aqueous sodium metabisufite (100 niL) and water. The organic phase was dried over magnesium sulfate and concentrated to an oil. The crude product was treated with 8M methylamine in ethanol (20 mL) and the resulting mixture heated under reflux for 30 min. After cooling, the solution was concentrated to an oil, and the mixture purified on silica gel eluting with ethyl acetate to afford the sub-titled compound (0.300 g).1U NMR (399.824 MHz, CDCl3) delta 7.94 (d, IH), 7.61 (dd, IH), 7.28 (d, IH), 4.30 (s, 2H), 3.17 (s, 3H).
With potassium acetate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In water; acetonitrile; at 90℃; for 4h;Inert atmosphere of nitrogen;
(S)-tert-Butyl 4-( 1 -amino- 1 -oxo-3-(4-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2- yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 300 mg), 6-bromo-2-methylisoindolin-l-one (Example 30, step (i), 131 mg) and potassium acetate (171 mg) in a mixture of acetonitrile (15 mL) and water (5 mL) was stirred under nitrogen at 900C with 1,1 delta(di-fert-butylphosphino)ferrocene palladium dichloride (378 mg). After 4 h the reaction mixture was cooled to room temperature and diluted with water (50 mL). The products were extracted with ethyl acetate (3 x 50 mL) and the combined extracts dried over magnesium sulfate and concentrated to afford the sub-titled compound (200 mg).m/e (MultiMode+) 436 [M+2Eta-BOC]+
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 90℃; for 5h;Inert atmosphere;
6-Bromo-2-raethylisoindolin-l-one (723 mg, 3.41 mmol), bis(pinacolato)diboron (1.04 g, 4.09 mmol), potassium acetate (1.00 g, 10.2 mmol) and PdCl2(dppf) catalyst (139 mg, 0.17 mmol) were weighed into a flask which was sealed under N2. DMSO (15 mL) was added, and the entire mixture stirred at 90C for 5 h. Upon cooling, the reaction mixture was diluted with water (250 mL) and extracted with CH2C12 (5x50 mL). The combined CH2C12 fractions were in turn washed with water (2x100 mL), brine (100 mL), dried (Na2S04), filtered and the solvent removed under reduced pressure to yield the crude product. Purification was carried out by flash column chromatography on silica gel (20% THF/CH2C12 as eluant) to give the title compound as a crystalline beige solid (262 mg, 28%). NMR [400 MHz, (CD3)2SO] delta 7.91 (br s, 1 H), 7.85 (dd, J = 7.6, 1.0 Hz, 1 H), 7.59 (dd, J = 7.5, 0.6 Hz, 1 H), 4.49 (s, 2 H), 3.07 (s, 3 H), 1.32 (s, 12 H). LRMS (APCI+) calcd for Ci5H2iBN03 274 (MH+), found 274.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 10h;Inert atmosphere;
To a solution of <strong>[1254319-51-1]6-bromo-2-methylisoindolin-1-one</strong> (5 g,22.1 mmol) in dmf (30 mL) was added bis(pinacolato)diboron (6.18 g,24.3 mmol) and potassium acetate (6.51 g,66.4 mmol). The reaction mixture was degassed and backfilled with N2 gas,and 1,1 ?-bis(diphenylphosphino)fenocene palladium(II)dichloride dichloromethane (0.903 g,1.106 mmol) was added.The reaction mixture was stined at 80 C for 10 hours. After diluting with EtOAc and water, The organic layer was concentrated and purified on silica column (100% EtOAc) to get the product as a mixture of the title compound as a boronic ester and boronic acid,which was not further purified.MS: 274 (m+1)?H NMR (500 MHz,CDCl3): oe 8.33 (s,1H),7.98 (d,7.5 Hz,1H),7.46 (d,7.5 Hz,1H),4.41 (s,2H),3.22 (s,3H),1.38 (s,12H). The following intermediates in table c were preparedaccording to scheme c using the procedure outlined in the synthesis intermediate cl using 1,1?-bis(di-tert-butylphosphino)fenocene palladium dichloride or 1,1 ?-bis(diphenylphosphino)ferrocene palladium(II)dichloride dichloromethane complex as the palladium catalyst with toluene or dmf as the reaction solvent. The starting material bromide was either commercially available,known in the literature,or prepared using the protocol in scheme B.
General procedure: Bromoisoindolin-1-one (2.0 g, 9.43 mmol) was dissolved with warming in DMF (150 mL),then cooled to 0C. NaH (415 mg, 10.4 mmol) was added and the mixture stirred under N2 at 0C for 0.5 h. Methyl iodide (0.65 mL, 10.4 mmol) was added dropwise and the reaction allowed to warm to room temperature and stir for another I h. A small quantity of water was added to quench the reaction then the DMF removed under reduced pressure to give an oily yellow residue which was dissolved in EtOAc (150 mL). This solution waswashed with water (3x100 mL), brine (100 mL) and dried (Na2SO4)., Removal of the solvent under reduced pressure gave a solid which was purified by filtration through a plug of silica gel (10% acetone/CH2C12 as eluant). The title compound was isolated as a very pale yellow crystalline solid (1.64 g, 80%). ? H NMR [400 MHz, (CD3)2S0] oe 7.85 (dd, J= 1.5, 0.6 Hz, 1 H), 7.66 (dd, J= 8.0, 1.7 Hz, 1 H), 7.59 (d, J- 8.0 Hz, I H), 4.46 (s,2 H), 3.05 (s, 3 H). LRMS (APCI) calcd for C9H8BrNO 226, 228 (MH), found 226, 228.
35.1: 6-Bromo-2-methylisoindolin-1-one To a solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1.00 g, 3.25 mmol) in THF (6.5 mL) was a solution of methylamine in THF (2M, 8.12 mL, 16.24 mmol). The reaction mixture was heated at 50C for 4 hours and then concentrated under vacuum. The residue was taken up in EtOAc and the organic layer was then washed with an aqueous 1M HCl solution, brine, dried (Na2SO4), filtered, concentrated under vacuum to give the title compound (0.73 g, 100%) as a yellow solid. 1H NMR (400 MHz, CDCl3): delta 3.19 (m, 3H), 4.32 (s, 2H), 7.31 (d, 1H), 7.63 (dd, 1H), 7.96 (d, 1H).
100%
In tetrahydrofuran; ethyl acetate; at 50℃; for 4h;
35.1: 6-Bromo-2-methylisoindolin-1-one To a solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1.00 g, 3.25 mmol) in THF (6.5 mL) was a solution of methylamine in THF (2M, 8.12 mL, 16.24 mmol). The reaction mixture was heated at 50 C. for 4 hours and then concentrated under vacuum. The residue was taken up in EtOAc and the organic layer was then washed with an aqueous 1M HCl solution, brine, dried (Na2SO4), filtered, concentrated under vacuum to give the title compound (0.73 g, 100%) as a yellow solid. 1H NMR (400 MHz, CDCl3): delta 3.19 (m, 3H), 4.32 (s, 2H), 7.31 (d, 1H), 7.63 (dd, 1H), 7.96 (d, 1H).
100%
In tetrahydrofuran; at 50℃; for 4h;
35.1 : 6-Bromo-2-methylisoindolin-1 -oneTo a solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1.00 g, 3.25 mmol) in THF (6.5 ml_) was a solution of methylamine in THF (2M, 8.12 ml_, 16.24 mmol). The reaction mixture was heated at 50C for 4 hours and then concentrated under vacuum. The residue was taken up in EtOAc and the organic layer was then washed with an aqueous 1 M HCI solution, brine, dried (Na2SO4), filtered, concentrated under vacuum to give the title compound (0.73 g, 100%) as a yellow solid.1 H NMR (400 MHz, CDCI3): 5 3.19 (m, 3H), 4.32 (s, 2H), 7.31 (d, 1 H), 7.63 (dd, 1 H), 7.96 (d, 1 H).
for 5h;Reflux;
Methyl 5-bromo-2-(bromomethyl)benzoate (23 g) was added to methylamine (300 mL, 30% alcoholic solution). The mixture was heated to reflux with stirring for 5 hours. The reaction mixture was cooled to RT and the solvent was removed in vacuo. The residuewas purified by column chromatography on silica gel eluting with ENPE = 1:1 to provide the subtitle compound. MS ESI: mlz = 226 [M+H].
In methanol; ethanol;Reflux;
To a solution of compound 2a (15 g, 50 mmol) in methanol (150 ml) was added methylamine (25 ml, 33% inethanol), and the reaction was refluxed overnight. After the organic solvent was drained off, the mixture was separatedby silica gel column chromatography (PE/EA= 3:1) to provide compound 2b as a yellow oily. MS(ESI) m/z:225.9(M+H)+.
methyl 2-(5-bromo-2-methylisoindolin-1-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of <strong>[1254319-51-1]6-bromo-2-methylisoindolin-1-one</strong> (10.1 g) in THE (250 mL) was addedLDA (33.5 mL, 2 M in THE) at -20C. The mixture was stirred at 0C for 30 minutes andthen methyl 2-bromoacetate (10.3 g) was added at 0C. The mixture was allowed towarm to RT and stirred for 20 hours. The mixture was poured into water (300 mL) and then extracted with EA (200 mL x 3). The combined organic phases were washed with brine (50 mL) and dried over Na2504. After filtration and evaporation of the solvent, the obtained residue was purified by column chromatography on silica gel eluting with ENPE = 1:3 to provide the title compound. MS ESI: mlz = 298 [M+H].
With trifluorormethanesulfonic acid; In dichloromethane; at 0 - 20℃;Inert atmosphere;
General procedure: To a solution of methyl 2-((benzylcarbamoyl)oxy)benzoate (282 mg, 0.988 mmol) in drydichloromethane (4.94 mL, 0.2 M), trifluoromethanesulfonic acid (0.88 mL, 10 eq) was added at 0 C.The mixture was stirred at 20 C under argon atmosphere for 1 hr. Then the mixture was quenched with20 mL of ice water and the whole was extracted with dichloromethane (50 mL x 2). The organic layerwas dried over sodium sulfate and the solvent was evaporated to give a crude oil mixture. The crudeproduct was purified by column chromatography (eluent: ethyl acetate: chloroform = 1 : 2) to affordisoindolin-1-one (74.1 mg, 0.557 mmol, 56% yield) as colorless oil.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; toluene;Inert atmosphere; Reflux;
General procedure: 5-Bromo-2-methylisoindolin-1-one (520 mg, 2.30 mmol) and thiophene-2-boronic acid (442mg, 3.45 mmol) were dissolved in a mixure of toluene (12 mL) and EtOH (6 mL). A solutionof 2 M Na2CO3 (3 mL) and Pd(dppf)Cl2 (94 mg, 0.12 mmol) were added and the entiremixture heated at reflux under N2 for 2 h. Additional thiophene-2-boronic acid (294 mg, 2.30mmol) was added and reflux continued under N2 overnight. Upon cooling, the mixture wasdiluted with water (100 mL) and extracted with CH2Cl2 (6x50 mL). The combined organicfractions were dried (Na2SO4), filtered, and the solvent removed under reduced pressure togive a crude solid which was purified by flash column chromatography on silica gel (EtOAcas eluant). The title compound was isolated as a light-brown solid (510 mg, 97%).
2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine[ No CAS ]
6-(2,6-bis(benzyloxy)pyridin-3-yl)-2-methyl-2,3-dihydroisoindol-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; for 10h;Sealed tube; Inert atmosphere; Heating;
A stirred solution of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine 25-1 (2.19 g, 5.25 mmol) and <strong>[1254319-51-1]6-bromo-2-methylisoindolin-1-one</strong> (31-1) (474 mg, 2.10 mmol) in dioxane/water (30 mL), in a sealed tube, was degassed for 10 minutes under an argon atmosphere. PdCl2(dppf)-DCM (153 mg, 210 mumol) was added and the reaction was heated to 80 C for 10 h. TLC was checked in 30% ethyl acetate/hexane, which showed the complete consumption of starting material and formation of the desired spot at rf 0.4 in 30% ethylacetate- hexane. The reaction mixture was diluted with ethyl acetate, washed with water. The layers were separated and the organic layer was concentrated under reduced pressure. The crude residue was purified using combiflash (50% ethyl acetate/hexane) and concentrated to afford 6-(2,6-Bis- benzyloxy-pyridin-3-yl)-2-methyl-2,3-dihydro-isoindol-1-one (31-1) (725 mg, 1.66 mmol, 79% yield). LC MS: ES+ 437.2.
To a mixed solution of compound 2b (5 g, 22 mmol), bisboronic acid pinacol (8.5 g, 33 mmol) and KOAc (3.2g, 33 mmol) in 1,4 dioxane (50 ml) was added Pd(dppf)2Cl2 (1g), and flushed with nitrogen. The reaction flask wassealed and the reaction was stirred overnight at 85C. After cooling to room temperature, an aqueous Na2CO3 solution(2.5M, 10ml), Pd(dppf)2Cl2 (1g) and 2,5-dibromo-3-nitropyridine (9 g, 33 mmol) were added. After flushed with nitrogenfor 10 minutes, the reaction flask was sealed and the mixture was stirred overnight at 85C. The reaction was pouredinto water and extracted with ethyl acetate. The organic phase mixture was dried over Na2SO4, dried by suction andpurified by silica gel column chromatography (PE:EA=10:1 to 1:1) to provide compound 2c as a yellow solid.HNMR(DMSO),9.1(s,1H),8.8(s,1H),7.7-7.8(m,3H),4.5(s,2H),3.1(s,3H).MS(ESI)m/z:347.9(M +H)+.
(2-methyl-3-oxoisoindolin-5-yl)boronic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 10h;Inert atmosphere;
To a solution of 6-bromo-2-methylisoindolin-l-one (5 g, 22.1 mmol) in DMF (30 mL) was added bis(pinacolato)diboron (6.18 g, 24.3 mmol) and potassium acetate (6.51 g, 66.4 mmol). The reaction mixture was degassed and backfilled with N2 gas, and l, l'-bis(diphenyl-phosphino)ferrocene palladium(II)dichloride dichloromethane (0.903 g, 1.106 mmol) was added. The reaction mixture was stirred at 80 C for 10 hours. After diluting with EtOAc and water, the organic layer was concentrated and purified on silica column (100% EtOAc) to get the product as a mixture of the title compound as a boronic ester and boronic acid, which was not further purified. MS: 274 (M+1). 1H MR (500 MHz, CDC13): delta 8.33 (s, 1 H), 7.98 (d, 7.5 Hz, 1 H), 7.46 (d, 7.5 Hz, 1 H), 4.41 (s, 2 H), 3.22 (s, 3 H), 1.38 (s, 12 H).
2-chloro-3-(1-((1-fluorocyclopentyl)methyl)-1H-pyrazol-4-yl)-6-methylpyridine[ No CAS ]
6-(3-(1-((1-fluorocyclopentyl)methyl)-1H-pyrazol-4-yl)-6-methylpyridin-2-yl)-2-methylisoindolin-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Potassium acetate (294 mg, 3.00 mmol), bis(pinacolato)diboron (305 mg, 1.200 mmol), 6-bromo-2- methylisoindolin-l-one (271 mg, 1.200 mmol) and 2nd Generation XPHOS precatalyst (59.0 mg, 0.075 mmol) were added to a 8 mL reaction vial equipped with a stir bar. The vial was evacuated and charged 3x with nitrogen. 1,4-Dioxane (8 mL) was added, the vial was again evacuated and charged (3x) with nitrogen, and the borylation reaction was heated to 100C. Monitored by LCMS; once borylation was complete the reaction was cooled to room temperature and 2-chloro-3 -(-(( 1- fluorocyclopentyl)methyl)-lH-pyrazol-4-yl)-6-methylpyridine (INTERMEDIATE F7; 294 mg, 1.0 mmol) and l, -bis(di-tert-butylphosphino)ferrocene palladium dichloride (48.9 mg, 0.075 mmol) were added to the reaction. The vial was evacuated and charged 3x with nitrogen, then added 3M aqueous K2C03 (1.0 mL, 3.00 mmol). The reaction was then heated to 70C overnight. LCMS shows reaction is substantially complete. Cooled to room temperature, then partitioned between water and ethyl acetate. The organic was filtered over a bed of sodium sulfate. The aqueous was extracted twice more with ethyl acetate, and the organic from those extractions was used to wash the sodium sulfate as well. The combined filtrate was evaporated and taken up again in DCM, then purified by silica gel chromatography, eluting with 20-100% 3 : 1 EtOAc:EtOH in hexanes. The major peak was isolated and the volatiles were evaporated. The solid was scraped to a small particle size and treated with diethyl ether. The suspension was filtered and the solid was collected as the title compound. MS: 405 (M+l). 1H NMR (500 MHz, CDC13): delta 7.89 (s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.21 (s, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.04(s, 1H), 4.39 (s, 2H), 4.23 (d, J=21.6 Hz, 2H), 3.20 (s, 3H), 2.62 (s, 3H), 1-77-1.58 (m, 8H).
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