N-(4-BROMOPHENYL)MORPHOLINE

General procedure: In a round-bottomed flask, the substrate (1 mmol) and aqueous HBr(48percent) (1 mL) were mixed in DMSO (1 mL). The mixture was stirredat corresponding temperature for 1–4 h. After cooling to roomtemperature, the reaction was adjusted to pH 7–8 with aqueous NaOHsolution (4 M). Then the mixture was washed twice with EtOAc, andthe combined organic extracts were dried, filtered and concentratedunder reduced pressure to give bromination products.General procedure: 1, 4-Dioxane (5 mL) was added to a mixture of substrate (1.5 mmol) and NaBr (3.09 g, 30 mmol). Catalyst 4a, 2.5 mol percent (25 mg, 0.0375 mmol) was dissolved in 15 mL of a pH 4.2 phosphate solution (NaHTo a mixture of 4-phenylmorpholine (816mg, 5mmol) and DMSO (429mg, 5.5mmol) in ethyl acetate (20mL) was added 84 hydrobromic acid (48percent, 1.85g, 5.5mmol) at 60°C under air. The mixture was stirred at 60°C, then potassium carbonate (1g) was added to the solution and the mixture were stirred for another 0.5h. After cooling down to room temperature and evaporation of the solvent under vacuum, the residue was purified by column chromatography on silica gel with a mixture of hexane and ethyl acetate (10:1) as eluent to give 4-(4-bromophenyl)morpholine as a white solid (1.03g, 85percent yield). Reference Example 2c Bromine (10.8 g, 67.4 mmol) was added to a solution of 4-(4-morpholinyl)benzene (10.0 g, 61.3 mmol) in ethanol (100 mL) at 0° C., and the mixture was stirred for 1 hour at room temperature. Zu einer Loesung von 20 g (122.5 mmol) [N-PHENYHNORPHOLIN] in 170 mL Essigsaeure wird bei Raumtemperatur eine Loesung von 6.94 [ML] (134.8 mmol) Brom in 25 mL Essigsaeure ueber einen Zeitraum von [40] min. langsam zugetropft. Nach 30 min. Ruehren bei Raumtemperatur wird das Reaktionsgemisch in 750 mL Wasser ein- geruehrt und mit 45percent-iger Natronlauge auf pH 11 eingestellt. Der entstehende Nieder- schlag wird abgesaugt, mit Wasser gewaschen und im Hochvakuum getrocknet. Nach Umkristallisation aus Ethanol erhaelt man 18.6 g (62.9 percent d. [TH.) DER] Titelverbindung. [LH-NMR] (200 MHz, DMSO-d6) : 8 = 7.37 [(M, 2H), ] 6.89 (m, 2H), 3. 73 (m, 4H), 3.08 (m, 4H). HPLC (Methode [1)] : [RT =] 3.9 min. MS (ESIpos) : m/z = 242 (M+H) +.To a solution of 4-phenyl-morpholine (18g, 110.4 [MMOL)] in ethanol [(400MOL)] cooled in an iced bath, was added dropwise bromine (5. [95ML, ] 116 [MMOL).] The mixture was stirred at room temperature for 2 h and then poured into water. The solution was basified with [NAOH] 1 N. The resulting precipitate was filtered and dried. After crystallisation from diisopropyl ether, the title compound was obtained as white crystals (15g, 56.13percent) ; m. p. [126-128°C.]To an ice-cooled solution of 4-phenyl-morpholine (18g, 110.4 [MMOL)] in ethanol (400ml), was added dropwise bromine (5.95 ml, 115.9 [MMOL).] After addition the mixture was warmed to room temperature and stirred for 2 hours. The mixture was poured into water and the solution was basified with 1 N sodium hydroxide solution. The resulting precipitate was filtered, washed with water and dried. Recrystallisation from diisopropyl ether gave the title compound as white crystals (15g, 56.13percent) ; m. p. [ 126-128°C.]To a solution of [4-PHENYLMORPHOLINE (18G, ] 110.4 [MMOL)] in ethanol (400ml) cooled in an iced bath, was added dropwise bromine (5.95 ml, 115.9 [MMOL)] and the mixture was stirred at room temperature for 2 hours. The mixture was poured into water and the solution was made basic by addition of a solution of sodium hydroxide [(1N).] The resulting precipitate was filtered, washed with water and dried. Crystallisation from diisopropyl ether gave the title compound as white crystals [(15G, ] 56.13percent) ; m. p. 126- [128°C.]To a 50 mL sealed tube were added R-(+)-2, 2'-bis(diphenylphosphino)-1, 1'-binaphthyl (0.20 g, 0.31 mmol), tris(dibenzylideneacetone)dipalladium (0.095 g, 0.10 mmol), sodium tert-butoxide (0.49 g, 5.0 mmol), p-dibromobenzene (1.00 g, 4.15 mmol) and morpholine (0.37 mL, 4.2 mmol), then anhydrous toluene (8 mL) was added under nitrogen protection. A solution of tris(dibenzylideneacetone)dipalladium(0) (0.093 g, 0.1 mmol) and (±)-BINAP (0.13 g, 0.21 mmol) in toluene (7 mL) was degassed with argon for 10 min and then heated at 110 °C for 15 min. The reaction mixture was allowed to cool to room temperature before potassiumtert-butoxide (0.53 g, 4.73 mmol), 1, 4-dibromobenzene (80) (0.6 g, 2.54 mmol) and morpholine (332 µL, 3.82 mmol) were added. The resulting mixture was heated at reflux for 16 h, cooled to room temperature and filtered through a pad of Celite®, the pad was further washed with toluene (30 mL) and the combined filtrates evaporated under reduced pressure to give the crude product. Purification by flash chromatography on silica eluting with hexane-ethyl acetate (6:1) gave the desired amine81(0.19 g, 47percent) as a colourless solid; mp 110–111 °C;νmax/cmTo a stirred solution of morpholine (2.0 g, 23.0 mmol), 1, 4-dibromo benzene (19.4 g, 82.2 mmol) and 1, 4-dioxane (10.0 mL) in sealed tube, 0s2003 (22.4 g, 68.7 mmol)was added and degasified with argon. To the above solution Pd2(dba)3 (0.2 g, 0.22mmol) and 2-(di-tert-butylphosphino)biphenyl (0.6 g, 2.0 mmol) was added andheated at 100 00 for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate, the organic layer was washed with water, brine solution and dried. Finally, concentrated under vacuo and purified by the column chromatography to yield the desired product (1 .5 g, 26.96percent) as a yellow solid. LCMS: (M+2) =244.0; 1HNMR: (ODd3, 300MHz) 6 7.34-7.37 (d, 2H), 6.76-6.79 (d, 2H), 3.84-3.87 (t, 4H), 3.10-3.13 (t, 4H).A solution of 1-bromo-4-iodobenzene (5.0 g, 18 mmol), morpholine (1.85 mL, 21 mmol), sodium tert-butoxide (2.4 g, 25 mmol), 18-crown-6 (6.6 g, 25 mmol) in THF (150 mL)was purged with Ar for 20 min, then BINAP (0.11 g, 0.18 mmol) and Pd