ethyl 2-(4-bromo-2-formylphenoxy)acetate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-formylphenoxyacetic acid ethyl ester (2.47 g, 8.7 mmol), 2,4-thiazolidinedione (1.13 g (90%), 8.7 mmol), and ammonium acetate (671 mg, 8.7 mmol) was mixed with toluene (9 mL) in a sealed vial and heated by microwaves to 120° C. for 600 s. After cooling to room temperature and scratching the inside of the glass, the product precipitated out. The precipitate was filtered and washed with toluene to give the title compound as a yellow solid (2.38 g, 71%). After cooling to room temperature the product precipitated out The precipitate was filtered washed with toluene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-formylphenoxyacetic acid ethyl ester (1.44 g, 5 mmol) was dissolved in dichloromethane (50 mL) and glycine ethyl ester hydrochloride (1.39 g, 10 mmol) as well as Et3N (1.4 mL, 10 mmol) was added. The mixture was stirred at room temperature for 4 h. Water and dichloromethane was added and the organic phase was passed through a phase separation filter and then evaporated to give {4-bromo-2-[(E)-ethoxycarbonylmethyliminomethyl]phenoxy}acetic acid ethyl ester, which was redissolved in dichloromethane (50 mL) and treated with NaBH(OAc)3 (2.11 g, 10 mmol) and AcOH (1 mL), and then stirred at room temperature for 5 h. Saturated Na2CO3, water and dichloromethane was added, and the organic phase was passed through a phase separation filter and evaporated to give the title compound (1.56 g, 84% overall yield). the organic phase was passed through a phase separation filter evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-formylphenoxyacetic acid ethyl ester (1.44 g, 5 mmol) was dissolved in dichloromethane (50 mL) and glycine ethyl ester hydrochloride (1.39 g, 10 mmol) as well as Et3N (1.4 mL, 10 mmol) was added. The mixture was stirred at room temperature for 4 h. Water and dichloromethane was added and the organic phase was passed through a phase separation filter and then evaporated to give {4-bromo-2-[(E)-ethoxycarbonylmethyliminomethyl]phenoxy}acetic acid ethyl ester, which was redissolved in dichloromethane (50 mL) and treated with NaBH(OAc)3 (2.11 g, 10 mmol) and AcOH (1 mL), and then stirred at room temperature for 5 h. Saturated Na2CO3, water and dichloromethane was added, and the organic phase was passed through a phase separation filter and evaporated to give the title compound (1.56 g, 84% overall yield). the organic phase was passed through a phase separation filter evaporated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (−78° C.) solution of (trimethylsilyl)acetylene (3.93 g, 40.0 mmol) in dry THF (40 mL) was slowly added a 2.5 M solution of butyllithium in hexanes (14.54 mL, 36.36 mmol). After stirring for 30 minutes at −78° C., the mixture was transferred to a cooled (−78° C.) solution of (4-bromo-2-formylphenoxy)acetic acid ethyl ester (10.44 g, 36.36 mmol) in dry THF (120 mL). Upon completion, the reaction mixture was stirred at −78° C. for 45 minutes. Saturated aq. NH4Cl (40 mL) was slowly added to the reaction mixture followed by Et2O (40 mL). The quenched reaction mixture was allowed to warm up to room temperature. The phases were separated and the aqueous phase was extracted with Et2O (2×). The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude oil was purified by column chromatography (SiO2), then was stirred for 90 min with polystyrene-supported trisamine (PS-Trisamine, 4.17 mmol/g, 8 g) in CH2Cl2 (160 mL). The resin was filtered off and the filtrate was concentrated in vacuo to give the title compound as pale yellow oil (7.6 g, 19.7 mmol, 54%). LC/MS (an10p8) Rt 4.30 min, m/z 408 [M+Na]+; 1H NMR (CDCl3): δ 0.24 (s, 9H), 1.31 (t, 3H), 4.27 (q, 2H), 4.71 (s, 2H), 5.79 (s, 1H), 6.74 (d, 1H), 7.39 (dd, 1H), 7.79 (d, 1H). Upon completion, the reaction mixture was stirred at −78° C. for 45 minutes The quenched reaction mixture to warm up to room temperature The phases were separated the aqueous phase was extracted with Et2O (2×) The combined organic phases were washed with brine dried (MgSO4) concentrated in vacuo The crude oil was purified by column chromatography (SiO2) was stirred for 90 min with polystyrene- The resin was filtered off the filtrate was concentrated in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (−78° C.) solution of (trimethylsilyl)acetylene (3.93 g, 40.0 mmol) in dry THF (40 mL) was slowly added a 2.5 M solution of butyllithium in hexanes (14.54 mL, 36.36 mmol). After stirring for 30 minutes at −78° C., the mixture was transferred to a cooled (−78° C.) solution of (4-bromo-2-formylphenoxy)acetic acid ethyl ester (10.44 g, 36.36 mmol) in dry THF (120 mL). Upon completion, the reaction mixture was stirred at −78° C. for 45 minutes. Saturated aq. NH4Cl (40 mL) was slowly added to the reaction mixture followed by Et2O (40 mL). The quenched reaction mixture was allowed to warm up to room temperature. The phases were separated and the aqueous phase was extracted with Et2O (2×). The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude oil was purified by column chromatography (SiO2), then was stirred for 90 min with polystyrene-supported trisamine (PS-Trisamine, 4.17 mmol/g, 8 g) in CH2Cl2 (160 mL). The resin was filtered off and the filtrate was concentrated in vacuo to give the title compound as pale yellow oil (7.6 g, 19.7 mmol, 54%). LC/MS (an10p8) Rt 4.30 min, m/z 408 [M+Na]+; 1H NMR (CDCl3): δ 0.24 (s, 9H), 1.31 (t, 3H), 4.27 (q, 2H), 4.71 (s, 2H), 5.79 (s, 1H), 6.74 (d, 1H), 7.39 (dd, 1H), 7.79 (d, 1H). Upon completion, the reaction mixture was stirred at −78° C. for 45 minutes The quenched reaction mixture to warm up to room temperature The phases were separated the aqueous phase was extracted with Et2O (2×) The combined organic phases were washed with brine dried (MgSO4) concentrated in vacuo The crude oil was purified by column chromatography (SiO2) was stirred for 90 min with polystyrene- The resin was filtered off the filtrate was concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl (4-bromo-2-formylphenoxy)acetate (Example 1, 6.00 g, 21.0 mmol) in 200 mL abs EtOH was stirred under Ar and the mixture was cooled to 0° C. To this mixture was added NaBH4 (199 mg, 5.24 mmol) in portions. The reaction was stirred for 1 hour where TLC (25% EtOAc/hexanes) revealed complete reaction. At this point, 1 N HCl was added dropwise until slightly acidic and the EtOH was removed under reduced pressure. Water (100 mL) was added and the reaction transferred to a separatory funnel where it was extracted 3×100 mL with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and removed in vacuo to provide the product (5.41 g, 89%) as a pure white solid. 1H-NMR (acetone-d6, δ): 1.24 (t, 3H), 4.21 (q, 2H), 4.76 (s, 2H), 4.85 (s, 2H), 6.98 (d, 1H), 7.46 (dd, 1H); 7.61 (d, 1H); LRMS (GC/MS/EI) 308 [M]+. reaction was removed under reduced pressure Water (100 mL) was added the reaction transferred to a separatory funnel where it was extracted 3×100 mL with EtOAc The combined organic layers were dried over Na2SO4 filtered removed in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound was prepared according to a literature procedure. (Yoo et al., Bioorg. Med. Chem. 5:445, 1997). To ethyl (4-bromo-2-formylphenoxy)acetate (Example 1, 14.3 g, 49.7 mmol) was added, under Ar, 115 mL absolute EtOH. To this mixture was added 5.28 g (77.7 mmol) sodium ethoxide and the reaction allowed to reflux overnight. Sulfuric acid (conc., 2 mL) was then added, and the reaction allowed to reflux an additional 2 hours. The mixture was then cooled to rt, 50 mL was added and the pH adjusted to neutrality with 1 N NaOH. The mixture was then extracted with 150 mL EtOAc, and the combined organic phase was washed with brine (2×150 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo. Purification by Biotage® separation using 5% EtOAc/hexanes provided 3.62 g (27%) of the desired compound. 1H-NMR (CDCl3, 67 ): 1.43 (t, 3H), 4.45 (q, 2H), 7.46-7.57 (m, 3H), 7.82 (s, 1H); LRMS (GC/MS/EI) 268 [M]+. The compound was prepared to reflux overnight to reflux an additional 2 hours 50 mL was added The mixture was then extracted with 150 mL EtOAc the combined organic phase was washed with brine (2×150 mL) dried over Na2SO4 filtered The solvent was removed in vacuo Purification by Biotage® separation

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This compound was prepared according to a literature procedure (Yoo et al., Bioorg. Med. Chem. 5:445, 1997). 5-Bromo-2-hydroxybenzaldehyde (10.0 g, 49.7 mmol) was dissolved in 90 mL anhyd. DMF and the mixture was cooled to 0° C. NaH (60% dispersion in mineral oil, 2.38 g, 59.6 mmol) was added in portions and the reaction was stirred at 0° C. for 1 hour. Ethyl bromoacetate (9.95 g, 59.6 mmol) was then added dropwise over 10 minutes and the reaction was stirred at rt overnight (18 hours). After this time, 30 mL of 1 N HCl was added to adjust the pH to acidity, and the reaction mixture was transferred to a separatory funnel and extracted with EtOAc (3×60 mL). The combined organics rinsed with water (2×40 mL), dried over MgSO4, filtered, and concentrated in vacuo to provide a thick oil. Purification by flash chromatography (10% EtOAc/hexanes) provided the product as a clear oil (14.0 g, 98%). 1H-NMR (CD2Cl2, δ): 1.29 (t, 3H), 4.26 (q, 2H), 4.78 (s, 2H), 6.83 (d, 1H), 7.65 (dd, 1H), 7.94 (s, 1H), 10.47 (s, 1H); LRMS (GC/MS/EI) 286 [M]+. This compound was prepared the reaction was stirred at rt overnight (18 hours) the reaction mixture was transferred to a separatory funnel extracted with EtOAc (3×60 mL) The combined organics rinsed with water (2×40 mL) dried over MgSO4 filtered concentrated in vacuo to provide a thick oil Purification by flash chromatography (10% EtOAc/hexanes)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-formylphenoxyacetic acid ethyl ester (2.47 g, 8.7 mmol), 2,4-thiazolidinedione (1.13 g (90%), 8.7 mmol), and ammonium acetate (671 mg, 8.7 mmol) was mixed with toluene (9 mL) in a sealed vial and heated by microwaves to 120° C. for 600 s. After cooling to room temperature and scratching the inside of the glass, the product precipitated out. The precipitate was filtered and washed with toluene to give the title compound as a yellow solid (2.38 g, 71%). After cooling to room temperature the product precipitated out The precipitate was filtered washed with toluene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2-formylphenoxyacetic acid ethyl ester (1.44 g, 5 mmol) was dissolved in dichloromethane (50 mL) and glycine ethyl ester hydrochloride (1.39 g, 10 mmol) as well as Et3N (1.4 mL, 10 mmol) was added. The mixture was stirred at room temperature for 4 h. Water and dichloromethane was added and the organic phase was passed through a phase separation filter and then evaporated to give {4-bromo-2-[(E)-ethoxycarbonylmethyliminomethyl]phenoxy}acetic acid ethyl ester, which was redissolved in dichloromethane (50 mL) and treated with NaBH(OAc)3 (2.11 g, 10 mmol) and AcOH (1 mL), and then stirred at room temperature for 5 h. Saturated Na2CO3, water and dichloromethane was added, and the organic phase was passed through a phase separation filter and evaporated to give the title compound (1.56 g, 84% overall yield). the organic phase was passed through a phase separation filter evaporated