1-bromo-2-ethylbenzene

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

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of the N-(2-ethylphenyl)acetamide (7.35 g, 45.03 mmol), anhydrous K2CO3 (6.22 g, 45.03 mmol), copper(I) bromide (452.2 mg, 3.15 mmol) in 1-bromo-2-ethylbenzene was stirred and heated to 200° C. under argon for 48 h. After cooling the reaction mixture was poured into ice-H2O and extracted with ethyl acetate (2×500 mL), the combined organics were washed with brine, dried over anhydrous (K2CO3), filtered and concentrated to dryness. The crude product was purified using an ISCO machine using a ethyl acetate-hexane gradient to afford the product, N,N-bis(2-ethylphenyl)acetamide (8.1 g, 67%). After cooling the reaction mixture extracted with ethyl acetate (2×500 mL) the combined organics were washed with brine dried over anhydrous (K2CO3) filtered concentrated to dryness The crude product was purified

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 8.53 g (350 mmol) of magnesium in 270 mL of dry THF was added 50 g (270 mmol) of 1-bromo-2-ethyl benzene. The temperature was maintained at 50° C. during addition, then was heated under reflux. After 1 h, the solution was cooled to -78° C. under N2, and 54.42 g (324 mmol) of allyl iodide was added dropwise. The mixture was allowed to warm to room temperature, stirred for an additional 2 h, then cooled to 0° C. The reaction was quenched by addition of 2M HCl and 500 mL of ether and the layers were separated. The organic layer was washed with 30 mL of saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The oily residue was filtered through silica gel with 20% ethyl acetate-hexane and the eluate was concentrated to afford the crude 1-allyl-2-ethylbenzene as a colorless oil. was heated under reflux the solution was cooled to -78° C. under N2 to warm to room temperature cooled to 0° C The reaction was quenched by addition of 2M HCl and 500 mL of ether the layers were separated The organic layer was washed with 30 mL of saturated NaHCO3 solution and brine dried over MgSO4 filtered concentrated The oily residue was filtered through silica gel with 20% ethyl acetate-hexane the eluate was concentrated

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

Procedure: Into a 250-mL round-bottom flask protected by N2 was placed tetrahydrofuran (100 mL), Mg (1.0 g, 41.67 mmol, 2.14 equiv) and I2 (0.010 g). Then a solution of 1-bromo-2-ethylbenzene (3.6 g, 19.45 mmol, 1.00 equiv) in THF (15 mL) was added dropwise. The resulting mixture was heated to reflux for 1 h. Then it was cooled to 0° C. and oxirane (50 mL) was added. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of 20 mL of NH4Cl (aq.). The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). Purification afforded 1.83 g (63%) of 2-(2-ethylphenyl)ethan-1-ol as a colorless oil. The resulting mixture was heated to reflux for 1 h The reaction was then quenched by the addition of 20 mL of NH4Cl (aq.) The resulting solution was extracted with 3×50 mL of ethyl acetate concentrated under vacuum Purification

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

Procedure: Into a 250-mL round-bottom flask protected by N2 was placed tetrahydrofuran (100 mL), Mg (1.0 g, 41.67 mmol, 2.14 equiv) and I2 (0.010 g). Then a solution of 1-bromo-2-ethylbenzene (3.6 g, 19.45 mmol, 1.00 equiv) in THF (15 mL) was added dropwise. The resulting mixture was heated to reflux for 1 h. Then it was cooled to 0° C. and oxirane (50 mL) was added. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of 20 mL of NH4Cl (aq.). The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). Purification afforded 1.83 g (63%) of 2-(2-ethylphenyl)ethan-1-ol as a colorless oil. The resulting mixture was heated to reflux for 1 h The reaction was then quenched by the addition of 20 mL of NH4Cl (aq.) The resulting solution was extracted with 3×50 mL of ethyl acetate concentrated under vacuum Purification

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (1.0 g, 2.39 mmol), 1-bromo-2-ethylbenzene (572.0 mg, 3.11 mmol, Aldrich), Pd2(dba)3 (218 mg, 0.23 mmol, GLR), Xantphos (276 mg, 0.46 mmol, GLR) and sodium-tert-butoxide (458 mg, 4.784 mmol) in toluene (20 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was heated at 100° C. for 1 h under microwave irradiation. After completion, reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-20% ethyl acetate in hexane) to obtain 4-(2-ethylphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (400 mg, 33%) as a brown solid. MS (ESI, positive ion) m/z; 522.1 (M+1) was degassed with nitrogen for 10 minutes After completion, reaction mixture extracted with ethyl acetate (3×50 mL) The combined organic layer was dried over sodium sulfate concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-20% ethyl acetate in hexane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (1.0 g, 2.39 mmol), 1-bromo-2-ethylbenzene (572.0 mg, 3.11 mmol, Aldrich), Pd2(dba)3 (218 mg, 0.23 mmol, GLR), Xantphos (276 mg, 0.46 mmol, GLR) and sodium-tert-butoxide (458 mg, 4.784 mmol) in toluene (20 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was heated at 100° C. for 1 h under microwave irradiation. After completion, reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-20% ethyl acetate in hexane) to obtain 4-(2-ethylphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (400 mg, 33%) as a brown solid. MS (ESI, positive ion) m/z; 522.1 (M+1) was degassed with nitrogen for 10 minutes After completion, reaction mixture extracted with ethyl acetate (3×50 mL) The combined organic layer was dried over sodium sulfate concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-20% ethyl acetate in hexane)

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of the N-(2-ethylphenyl)acetamide (7.35 g, 45.03 mmol), anhydrous K2CO3 (6.22 g, 45.03 mmol), copper(I) bromide (452.2 mg, 3.15 mmol) in 1-bromo-2-ethylbenzene was stirred and heated to 200° C. under argon for 48 h. After cooling the reaction mixture was poured into ice-H2O and extracted with ethyl acetate (2×500 mL), the combined organics were washed with brine, dried over anhydrous (K2CO3), filtered and concentrated to dryness. The crude product was purified using an ISCO machine using a ethyl acetate-hexane gradient to afford the product, N,N-bis(2-ethylphenyl)acetamide (8.1 g, 67%). After cooling the reaction mixture extracted with ethyl acetate (2×500 mL) the combined organics were washed with brine dried over anhydrous (K2CO3) filtered concentrated to dryness The crude product was purified

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

Conditions: temp:-105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-bromo-2-ethylbenzene (3.70 g, 20 mmol) in 100 mL of anhydrous THF was cooled to −78° C. (liquid nitrogen/EtOH) under nitrogen. Then 1.4M solution of sec-BuLi in cyclohexane (15 mL, 21 mmol) was added dropwise at −78° C. The mixture was stirred for 10 min, then a solution of R-(+)-propylene oxide (1.51 g, 1.8 mL, 26 mmol) in 15 mL of THF was added dropwise at −100° C. to −90° C., then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then 20 mL of water was added and mixture was extracted with EtOAc (2×60 mL), the extract was dried over Na2SO4 and evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.55 in EtOAc/hexane 3:7) to give (2R)-1-(2-ethylphenyl)propan-2-ol (877 mg, 26%) as pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.19 (m, 4H), 4.02 (m, 1H), 2.80 (m, 2H), 2.68 (q, J=7.53 Hz, 2H), 1.51 (s, 1H), 1.28 (d, J=6.21 Hz, 3H), 1.22 (t, J=7.53 Hz, 3H). The mixture was stirred at −100° C. to −90° C. for 2 h the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C The mixture was stirred warmed to 0° C. overnight Then 20 mL of water was added mixture was extracted with EtOAc (2×60 mL) the extract was dried over Na2SO4 evaporated to give crude oil, which was purified by column (silica gel, EtOAc/hexane 1:9, Rf=0.55 in EtOAc/hexane 3:7)

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

Procedure: Under an atmosphere of dry nitrogen a magnetically stirred suspension of anhydrous tetrahydrofuran (Aldrich, 300 mL) and magnesium turnings (Aldrich, 1.2 g, 49 mmol) was treated dropwise at room temperature with 1-bromo-2-ethylbenzene (Aldrich, 6.1 mL, 44 mmol). After 10 minutes the reaction mixture began to reflux mildly. After the addition was complete the reaction mixture was heated to reflux overnight (18 h). A separate flask was flushed with dry nitrogen and then charged with anhydrous tetrahydrofuran (Aldrich, 100 mL) and 3,3-dimethylbutyl-trimethoxysilane (Huls, 11.4 mL, 49 mmol). The Grignard solution was cooled to room temperature and then added to the silane solution at room temperature via stainless steel cannula. The reaction mixture stirred at room temperature overnight (18 h). Ethyl alcohol (Aldrich, 5 mL) was added to quench any remaining Grignard. The reaction mixture was concentrated on a rotary evaporator and distilled in vacuum to give 3.7 g (30%) of the title compound as a colorless oil (b.p. 107-108° C. at 0.5 mm Hg, 99% GC-purity): C16H28O2Si (Mw=280). to reflux mildly After the addition was heated to reflux overnight (18 h) A separate flask was flushed with dry nitrogen to quench any remaining Grignard The reaction mixture was concentrated on a rotary evaporator distilled in vacuum

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

Procedure: A 1000 mL round bottomed flask was charged with magnesium turnings (1.97 g, 81.0 mmol, Aldrich) and ether (500 mL, Aldrich). Bromo-2-ethylbenzene (14.0 mL, 101 mmol, Aldrich) was added over 30 minutes. The reaction stirred for three hours at room temperature and became dark brown in color. The contents were refluxed for one hour. The contents were cooled to 0° C. and isoamyl-trimethoxysilane (15.9 g, 82.8 mmol, previously prepared by reaction between isoamyl magnesiumbromide and tetramethylortho-silicate) was added over 25 minutes. The reaction was stirred at room temperature overnight (18 hours) during which time a white precipitate formed. The contents were poured into water (500 mnL), the layers separated and the product extracted into ether (3×150 mL). The combined organic portions were dried (MgSO4), filtered and the solvent removed via rotary evaporation providing 29.6 g crude material. Distillation under reduced pressure (b.p. 109° C., 1.1 mm Hg) produced (2-ethylphenyl)-3-methylbutyl-dimethoxysilane (7.68 g, 28.8 mmol, 35.6% yield); C15H26SiO2 (Mw=266.45); 1H NMR (CDCl3) δ7.7 (m, 1H), 7.3 (m, 1H), 7.2 (m, 2H), 3.5 (s, 6H), 2.8 (q, 2H), 1.4 (m, 1H), 1.2(m, 5H), 0.8(m, 8H); 13C NMR (CDCl3) δ150.5, 135.9, 131.2, 130.3, 128.0, 124.9, 50.3, 31.5, 30.7, 28.6, 21.9, 16.1, 10.9; IR (capillary film) ν3054, 2974, 1590, 1467, 1370, 1200, 1118, 1023, 936, 874 803, MS m/z (relative abundance) 266 (0.02), 195 (100), 163 (59.1), 160 (28.8), 133 (25.5), 105 (11.2), 91 (12.3), 59 (18.4). The contents were refluxed for one hour The contents were cooled to 0° C. was added over 25 minutes The reaction was stirred at room temperature overnight (18 hours) during which time a white precipitate formed the layers separated the product extracted into ether (3×150 mL) The combined organic portions were dried (MgSO4) filtered the solvent removed via rotary evaporation providing 29.6 g crude material Distillation under reduced pressure (b.p. 109° C., 1.1 mm Hg)