2-prop-2-enylisoindole-1,3-dione

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

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

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

Procedure: N-Allylphthalimide (13.9 g, 74.3 mmol), 1-fluoro-4-iodobenzene (15.0 g, 67.6 mmol) triethylamine (15.0 g, 148 mmol) and Pd(OAc)2 (152 mg) were heated at 104° in a glass bomb with shaking for 18 h under an inert atmosphere. The reaction mixture was dissolved in hot acetonitrile. The catalyst was removed by filtration and the filtrate cooled to 0°. The precipitated white solid product was filtered off and dried under vacuum. This title material (12.55 g) was used without further purification. The catalyst was removed by filtration the filtrate cooled to 0° The precipitated white solid product was filtered off dried under vacuum This title material (12.55 g) was used without further purification

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

Procedure: Following the allylic amide cross metathesis general procedure, 2-allylisoindoline-1,3-dione (5.50 mg, 0.0290 mmol) was treated with 1-hexadecene (63.8 mg, 0.290 mmol), 5.0 mol % of in situ-generated complex 2 (75.0 μL, 0.02 M, 1.50 i&mol; final substrate concentration=0.19 M) and allowed to stir for 1 h. The unpurified product is 85% Z (as determined by 400 MHz 1H NMR analysis). The resulting brown oil was purified by silica gel chromatography (96:2:2 hexanes:EtOAc:CH2Cl2) to afford 19g (9.80 mg, 0.0260 mmol, 87.0% yield, 85% Z isomer) as a white, crystalline solid. M.P. 56-60° C.; IR (neat): 2954(w), 2916 (s), 2849 (m), 1771 (w), 1698 (s), 1614 (w), 1464 (m), 1429 (m), 1400 (m), 1356 (w), 1335 (w), 1294 (w), 1189 (w), 1173 (w), 1155 (w), 1089 (w), 1071 (w), 1052 (w), 1024 (w), 962 (m), 930 (m); 1H NMR (400 MHz, CDCl3): 7.84 (2H, dd, J=5.4, 3.0 Hz), 7.70 (2H, dd, J=5.4, 3.0 Hz), 5.78-5.7 1 (1H, m), 5.54-5.44 (1H, m), 4.23 (2H, dd, J=6.2, 0.8 Hz), [diagnostic E isomer signal: 4.22 (1H, d, J=8 Hz)], 1.99 (2H, dd, J=13.6, 6.8 Hz), 1.43-1.19 (24H, m), 0.88 (3H, t, J=6.8 Hz); 13C NMR (100 MHz, CDCl3): 168.2, 135.6, 134.0, 132.4, 123.4, 123.3, 123.1, 77.4, 39.8, 32.3, 32.1, 29.9, 29.8, 29.8, 29.7, 29.7, 29.6, 29.6,−29.5, 29.3, 29.0,22.8, 14.3; HRMS (ESI+) [M+H]+ calcd for C25H38NO2: 384.2903, found: 384.2905. The resulting brown oil was purified by silica gel chromatography (96:2:2 hexanes:EtOAc:CH2Cl2)

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

Procedure: Following the allylic amide cross metathesis general procedure, 2-allylisoindoline-1,3-dione (5.50 mg, 0.0290 mmol) was treated with 1-hexadecene (63.8 mg, 0.290 mmol), 5.0 mol % of in situ-generated complex 2 (75.0 μL, 0.02 M, 1.50 i&mol; final substrate concentration=0.19 M) and allowed to stir for 1 h. The unpurified product is 85% Z (as determined by 400 MHz 1H NMR analysis). The resulting brown oil was purified by silica gel chromatography (96:2:2 hexanes:EtOAc:CH2Cl2) to afford 19g (9.80 mg, 0.0260 mmol, 87.0% yield, 85% Z isomer) as a white, crystalline solid. M.P. 56-60° C.; IR (neat): 2954(w), 2916 (s), 2849 (m), 1771 (w), 1698 (s), 1614 (w), 1464 (m), 1429 (m), 1400 (m), 1356 (w), 1335 (w), 1294 (w), 1189 (w), 1173 (w), 1155 (w), 1089 (w), 1071 (w), 1052 (w), 1024 (w), 962 (m), 930 (m); 1H NMR (400 MHz, CDCl3): 7.84 (2H, dd, J=5.4, 3.0 Hz), 7.70 (2H, dd, J=5.4, 3.0 Hz), 5.78-5.7 1 (1H, m), 5.54-5.44 (1H, m), 4.23 (2H, dd, J=6.2, 0.8 Hz), [diagnostic E isomer signal: 4.22 (1H, d, J=8 Hz)], 1.99 (2H, dd, J=13.6, 6.8 Hz), 1.43-1.19 (24H, m), 0.88 (3H, t, J=6.8 Hz); 13C NMR (100 MHz, CDCl3): 168.2, 135.6, 134.0, 132.4, 123.4, 123.3, 123.1, 77.4, 39.8, 32.3, 32.1, 29.9, 29.8, 29.8, 29.7, 29.7, 29.6, 29.6,−29.5, 29.3, 29.0,22.8, 14.3; HRMS (ESI+) [M+H]+ calcd for C25H38NO2: 384.2903, found: 384.2905. The resulting brown oil was purified by silica gel chromatography (96:2:2 hexanes:EtOAc:CH2Cl2)

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

Procedure: To a stirred solution of 2-allyl-isoindole-1,3-dione (3-1) (18.9 g, 101 mmol) in degassed TBF (100 mL) at 0° C. was added dropwise a solution of 9-BBN (243 mL of 0.5M in THF, 121 mmol) and the mixture stirred for 18 hours at ambient temperature. K2CO3 (24 g, 172 mmol) and 2,5-dibromopyridine (30 g, 126 mmol) were added, followed by a premixed and aged (70° C. for 30 min) suspension of Pd(OAc)2 (2.6 g, 11.5 mmol) and DPPF (7 g, 12.6 mmol) in degassed DMF (100 mL). The resulting mixture was stirred for 18 hours at 70° C., cooled, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated. To the stirring residue dissolved in TUF (500 mL) were added water (150 mL) and NaHCO3 (33 g) and after 10 minutes, NaBO3•H2O (55 g). After vigorous stirring for 30 minutes, the mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated to an oil. The residue was chromatographed on silica gel (10-20% EtOAc/hexane) to give 13 g of 3-2 as a colorless oil. a premixed The resulting mixture was stirred for 18 hours at 70° C. cooled washed with water and brine dried over MgSO4 concentrated To the stirring residue dissolved in TUF (500 mL) were added water (150 mL) and NaHCO3 (33 g) after 10 minutes After vigorous stirring for 30 minutes the mixture was diluted with ethyl acetate washed with water and brine dried over MgSO4 concentrated to an oil The residue was chromatographed on silica gel (10-20% EtOAc/hexane)

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

Procedure: To a stirred solution of 2-allyl-isoindole-1,3-dione (3-1) (18.9 g, 101 mmol) in degassed TBF (100 mL) at 0° C. was added dropwise a solution of 9-BBN (243 mL of 0.5M in THF, 121 mmol) and the mixture stirred for 18 hours at ambient temperature. K2CO3 (24 g, 172 mmol) and 2,5-dibromopyridine (30 g, 126 mmol) were added, followed by a premixed and aged (70° C. for 30 min) suspension of Pd(OAc)2 (2.6 g, 11.5 mmol) and DPPF (7 g, 12.6 mmol) in degassed DMF (100 mL). The resulting mixture was stirred for 18 hours at 70° C., cooled, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated. To the stirring residue dissolved in TUF (500 mL) were added water (150 mL) and NaHCO3 (33 g) and after 10 minutes, NaBO3•H2O (55 g). After vigorous stirring for 30 minutes, the mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated to an oil. The residue was chromatographed on silica gel (10-20% EtOAc/hexane) to give 13 g of 3-2 as a colorless oil. a premixed The resulting mixture was stirred for 18 hours at 70° C. cooled washed with water and brine dried over MgSO4 concentrated To the stirring residue dissolved in TUF (500 mL) were added water (150 mL) and NaHCO3 (33 g) after 10 minutes After vigorous stirring for 30 minutes the mixture was diluted with ethyl acetate washed with water and brine dried over MgSO4 concentrated to an oil The residue was chromatographed on silica gel (10-20% EtOAc/hexane)

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

Procedure: A mixture of intermediate (1) (0.012 mol), N-allyl-phthalimide (0.012 mol), palladium(II) acetate (0.001 mol) and triethylamine (0.024 mol) was stirred at 100° C. for 12 hours in a bomber, then dissolved in DCM and washed with K2CO3 10%. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 3.2 g of N-[4-[(1E)-3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-propenyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 2; mp. 190° C.). washed with K2CO3 10% The organic layer was separated dried filtered the solvent was evaporated The residue was crystallized from ACN The precipitate was filtered off dried

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

Procedure: A mixture of intermediate (1) (0.012 mol), N-allyl-phthalimide (0.012 mol), palladium(II) acetate (0.001 mol) and triethylamine (0.024 mol) was stirred at 100° C. for 12 hours in a bomber, then dissolved in DCM and washed with K2CO3 10%. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 3.2 g of N-[4-[(1E)-3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-propenyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 2; mp. 190° C.). washed with K2CO3 10% The organic layer was separated dried filtered the solvent was evaporated The residue was crystallized from ACN The precipitate was filtered off dried

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

Procedure: A solution of paraformaldehyde (245 g) was heated to 70° C. in a solution of H2SO4 (360 mL) and H2O (90 mL) using a hot water bath until the mixture became homogenous. Solid N-allylphthalimide (133 g, 0.71 mol) was then added over 10 minutes, keeping the exotherm generated under control. The solution was then stirred at this temperature for an additional 0.5 hour and poured into ice water (1.5 L). The mixture was extracted with ethyl acetate (3×1 L), dried (MgSO4), filtered and concentrated under reduced pressure. The crude solid was then purified through a silica gel plug (1 kg SiO2) from CH2Cl2 as the eluent. This afforded the desired 1,3-dioxane-4-ylmethylphthalimide as a white solid (95 g, 54%). The mixture was extracted with ethyl acetate (3×1 L) dried (MgSO4) filtered concentrated under reduced pressure The crude solid was then purified through a silica gel plug (1 kg SiO2) from CH2Cl2 as the eluent

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

Procedure: To a mixture of potassium phthalimide (310.39 g, 1.68 mol) in DMF (1.0 L) at 0° C. was added allyl bromide (290.4 mL, 3.36 mol) from a dropping funnel over 30 minutes. The reaction was then warmed to room temperature and allowed to stir for 5 days. The mixture was filtered to remove salts while washing the residue with ethyl acetate (1 L), and the filtrate concentrated under reduced pressure. The residue was then partitioned between saturated aqueous NaHCO3 (0.5 L) and CH2Cl2 (0.8 L) and the organic phase separated. The aqueous phase was extracted with CH2Cl2 (2×0.8 L), and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure to give N-allylphthalimide as a white powder (294 g, 94%). 1H NMR (CDCl3) δ 4.30 (d, 2H, J=6.0 Hz), 5.22 (m, 2H), 5.88 (m, 1H), 7.73 (m, 2H), 7.85 (m, 2H). The mixture was filtered to remove salts while washing the residue with ethyl acetate (1 L) the filtrate concentrated under reduced pressure The residue was then partitioned between saturated aqueous NaHCO3 (0.5 L) and CH2Cl2 (0.8 L) the organic phase separated The aqueous phase was extracted with CH2Cl2 (2×0.8 L) the combined organic phases were dried (Na2SO4) filtered concentrated under reduced pressure

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

Procedure: To a mixture of potassium phthalimide (310.39 g, 1.68 mol) in DMF (1.0 L) at 0° C. was added allyl bromide (290.4 mL, 3.36 mol) from a dropping funnel over 30 minutes. The reaction was then warmed to room temperature and allowed to stir for 5 days. The mixture was filtered to remove salts while washing the residue with ethyl acetate (1 L), and the filtrate concentrated under reduced pressure. The residue was then partitioned between saturated aqueous NaHCO3 (0.5 L) and CH2Cl2 (0.8 L) and the organic phase separated. The aqueous phase was extracted with CH2Cl2 (2×0.8 L), and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure to give N-allylphthalimide as a white powder (294 g, 94%). 1H NMR (CDCl3) δ 4.30 (d, 2H, J=6.0 Hz), 5.22 (m, 2H), 5.88 (m, 1H), 7.73 (m, 2H), 7.85 (m, 2H). The mixture was filtered to remove salts while washing the residue with ethyl acetate (1 L) the filtrate concentrated under reduced pressure The residue was then partitioned between saturated aqueous NaHCO3 (0.5 L) and CH2Cl2 (0.8 L) the organic phase separated The aqueous phase was extracted with CH2Cl2 (2×0.8 L) the combined organic phases were dried (Na2SO4) filtered concentrated under reduced pressure