1,4-bis(bromomethyl)benzene

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

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

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

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

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

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

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4,8,11-Tris(diethoxyphosphoryl)-1,4,8,11-tetraazacyclotetradecane (see Bridger et. al. J Med. Chem. 1995, 38, 366-378) (6.1 g, 0.01 mol) and K2CO3 (1.89 g, 0.013 mol) in CH3CN (150 ml) was added α,α'-dibromo-p-xylene (13.2 g, 0.05 mol) and the reaction mixture stirred at 70° C. for 1 hour. The solution was cooled to room temperature and the solvent removed under reduced pressure. The residue was partitioned between brine (50 ml) and CH2Cl2 (100 ml). The organic phase was separated, dried (Na2SO4) and concentrated to a minimum volume. The solid was filtered off and the solvent evaporated under reduced pressure to give the crude product as a pale yellow oil. Purification by column chromatography in silica gel (CH2Cl2CH3OH, 25:1) gave 1-[1-methylene-4-(bromo-methylene)phenylene]-4,8,11-tris(diethoxyphosphoryl-1,4,8,11-tetraazacyclotetra-decane (4.7 g, 59%) as a pale yellow oil. 1H NMR (CDCl3) δ 1.21-1.37 (m, 18 H), 1.66-1.74 (m, 2 H), 1.82-1.91 (m, 2 H), 2.30-2.35 (m, 2 H), 2.58-2.63 (m, 2 H), 2.99-3.16 (m, 12 H), 3.48 (s, 2 H), 3.95-4.07 (m, 12 H), 4.48 (s, 2 H), 7.21-7.35 (4 H). The solution was cooled to room temperature the solvent removed under reduced pressure The residue was partitioned between brine (50 ml) and CH2Cl2 (100 ml) The organic phase was separated dried (Na2SO4) concentrated to a minimum volume The solid was filtered off the solvent evaporated under reduced pressure to give the crude product as a pale yellow oil Purification by column chromatography in silica gel (CH2Cl2CH3OH, 25:1)

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

Procedure: To a solution ethyl (3S)-3-(4-hydroxyphenyl)hex-4-ynoate (0.1 g, 0.43 mmol) and 1,4-bis(bromomethyl)benzene (0.227 g, 0.861 mmol) in DMF (5 mL) is added Cs2CO3 (0.28 g, 0.861 mmol) at 0° C. The reaction mixture is allowed to warm to room temperature over 2 h. The reaction mixture is diluted with water (25 mL) and extracted with EtOAc (3×10 mL). The combined organic layer is washed with water (10 mL×3) and saturated brine solution (10 mL), dried, filtered, and evaporated to dryness. The crude product is purified by silica gel chromatography, eluting with hexane:ethyl acetate (9.0:1.0) to give the title compound (0.1 g, 55.9%). ESI/MS m/z (M+H)+ 415.4. extracted with EtOAc (3×10 mL) The combined organic layer is washed with water (10 mL×3) and saturated brine solution (10 mL) dried filtered evaporated to dryness The crude product is purified by silica gel chromatography eluting with hexane:ethyl acetate (9.0:1.0)

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

Procedure: To a mixture of α,α'-dibromo-p-xylene (7.0 g, 26.5 mmol) in toluene (200 m L) was added tri-n-butylamine (3.4 3 g, 18.6 mmol) under argon gas. The reaction mixture was stirred for several days at room temperature under argon at which time the tri-n-butylammonium salt had crystallized out of solution. The crystals were filtered and washed with toluene (3×50 mL) and hexanes (3×50 mL) and dried: 1H NMR (CDCl3) δ0.97 (t, 9H), 1.39 (m, 6H), 1.76 (m, 6H), 3.32 (m, 6H), 4.4 7 (s, 2H), 4.96 (s, 2H), 7.4 2-7.59 (dd, 4H). had crystallized out of solution The crystals were filtered washed with toluene (3×50 mL) and hexanes (3×50 mL) dried

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

Procedure: A mixture of tri-n-butylphosphine (5.7 g, 28.4 mmol) in toluene (50 mL) was added dropwise to a mixture of α,α'-dibromo-p-xylene (15 g, 56.8 mmol, 2 eq.) in 200 mL of toluene under argon gas. The reaction mixture was allowed to stir for several days at room temperature under argon, after which time the tri-n-butylphosphonium bromide salt had crystallized out of solution. The crystals were filtered and washed three times each with 50 mL portions toluene and hexanes, then air dried: 1H NMR (CDCl3) δ0.93 (t, 9H), 1.45 (m, 12H), 2.40 (m, 6H), 4.33-4.37 (d, 2H), 4.47 (s, 2H), 7.37-7.40 (d, 2H), 7.46-7.49 (dd, 2H). after which time the tri-n-butylphosphonium bromide salt had crystallized out of solution The crystals were filtered washed three times each with 50 mL portions toluene and hexanes air dried

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

Procedure: 1-(4-Fluorophenyl)-3-[3-hydroxy-3-(4-hydroxyphenyl)-propyl]-4-(4-methoxyphenyl)-azetidin-2-one was reacted with 1,4-bisbromomethylbenzene and potassium carbonate analogously to Example IV, giving a colorless solid (29) of molecular weight 604.52 (C33H31BrFNO4); MS (ESI): 605.2 (MH+).

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

Procedure: 3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-azetidin-2-one was reacted with 1,4-bisbromomethylbenzene and potassium carbonate analogously to Example IV, giving a colorless solid (25) of molecular weight 604.52 (C33H31BrFNO4); MS (ESI): 605.2 (MH+).