4-(4-Bromobenzyl)morpholine

Morpholine (13, 1.4 mL, 1.39 g, 16 mmol) was added to a solution of 4-bromobenzyl bromide (12, 1.0 g, 4 mmol) in acetonitrile (50 mL) and the mixture was heated to reflux for 4 h. Then water was added and the mixture was extracted with CHTo a stirred suspension of morpholine (8.37 g, 96 mmol) and 1-bromo-4- (bromomethyl)benzene (20.00 g, 80 mmol) in acetonitrile and potassium carbonate (27.65 g, 200 mmol) was added at room temperature and the mixture was stirred at 60°C overnight. After allowing to reach room temperature, the suspension was filtered and the filtrate was absorbed on silica gel. The crude filtrate was purified by column chromatography using a 120 g silica gel cartridge. Solvent A: Hexane. Solvent B: Ethyl Acetate (EtOAc). Gradient: 2 min hold 100percent A followed by a 27 min ramp to 40percent B and then 3 min hold 40percent B. The desired fractions were pooled together and concentrated under reduced pressure to obtain 1 as a white solid (19.5 g, 76 mmol, Yield 89percent). 1H NMR (500 MHz; CDCl3) 5 2.43-2.45 (m, 4H), 3.46 (s, 2H), 3.71-3.73 (m, 4H), 7.22- 7.24 (m, 2H), 7.44-7.47 (m, 2H) ppm. Purity by LCMS (UV Chromatogram, 190-450nm) 94percent, rt = 5.0 min, m/z 256 (M+H)Preparation 1 Synthesis of 4-(4-bromo-benzyl)-morpholine (1). To a solution of morpholine (2.61 ml, 30 mmol) in DMSO (25 ml) was added 4-bromobenzylbromide (2.5 g, 10 mmol). Reaction mixture was stirred at ambient temperature for 30 min. Solvents were evaporated in vacuum. Residue was dissolved in EtOAc (150 ml) and extracted with 5percent aq. NaHCOTo a solution of 4-bromobenzyl bromide (15 g, 60 mmol) in EtOH (200 mL) was added morpholine (6 mL, 66 mmol) and K2C03 (33 g, 238 mmol) and the mixture was stirred at ref lux for 5 hours. The mixture was filtered and the solvent was evaporated under reduced pressure.The crude material was treated with Et20 and the mixture was filtered. The solvent was evaporated under reduced pressure to afford the title compound (13 g). LCMS method: Method 1, RT: 1.20 mi Ml: 256/258 [M+l]General procedure: In a Biotage microwave vial (which serves as a general borosilicate glass vessel) equipped with a magnetic stir bar, the benzylic fluoride (1 equiv) was weighted and then freshly ground 1, 1, 1-tris(hydroxymethyl)propane (2) (1.1 equiv) was added. The amine (2 equiv) was added through a syringe and finally, the vial was capped and purged with argon. The reaction was placed in an oil bath and stirred at 100 °C for 24 hours. At the end of the heating period, an aqueous Na2CO3 (1 M) solution was added (on the typical scale, 1 mL was used) and the reaction mixture was stirred to loosen up its pasty form. This mixture was then extracted with 3 × Et2O and the combined organic extracts were washed with brine, dried on anhydrous MgSO4, filtered and evaporated in vacuo. At this point, conversion was measured by 1H NMR. Silica gel column chromatography followed when necessary.A solution of To a stirred suspension of Preparation 2 4-[[4-(4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl]methyl]morpholine To a stirred suspension of General procedure: To a stirred solution of 10 (1.00g, 4.00mmol) and K2CO3 (1.66g, 12.00mmol) in acetonitrile (20mL) was added dropwise diethylamine solution (1.20g, 16.00mmol) at room temperature for 2h. The solvent was evaporated in vacuo and the residue was then dissolved in EtOAc (50mL) and washed with water (20mL×3), the organic layers were washed with brine, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to provide the 11a (0.83g, 84.7% yield) as an off-white liquid. (0041) Then, a mixture of 11a (0.83g, 3.43mmol), bis(pinacolato)diboron (0.96g, 3.77mmol), PdCl2(dppf)-CH2Cl2 (0.084g, 0.103mmol) and potassium acetate (0.67g, 6.86mmol) in anhydrous 1, 4-dioxane (15mL) was purged with argon and heated at 100C for 2.5h. The reaction was then treated with 6 (1.20g, 3.60mmol), 2.0M aqueous Na2CO3 (5mL) and another portion of PdCl2(dppf)-CH2Cl2 (0.084g, 0.103mmol), then heated at 110C for 12h under argon. The reaction mixture was cooled to room temperature, filtered, and concentrated. The final compound was purified by MPLC (ISCO CombiFlash purification system) (MeOH/DCM, eluted from 0% to 10%), The fractions were collected, concentrated to afford 12a (0.72g, 57.2% yield).STR139 Part A. 4-[(4-Bromophenyl)methyl]morpholine. STR140 Following the procedure of Example 34, Part A, the benzyl morpholine was obtained as an oil in 100% yield. IR (KBr) 2803, 1487, 1111 cm-1; 1 H NMR (CDCl3) delta 2.43 (t, J=4.5 Hz, 4H), 3.45 (s, 2H), 3.71 (t, J=4.5 Hz, 4H), 7.22 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H); FDMS m/e 255 (M+, 79 Br) and 257 (M+, 81 Br); Anal. Calcd for C11 H14 BrNO: C, 51.58; H, 5.51; N, 5.47. Found: C, 51.77; H, 5.66; N, 5.68.REFERENCE EXAMPLE 46 4-(4-Bromobenzyl) morpholine Using an analogous procedure to that described for Reference Example 31, 5.0 g (27.0 mmol) of 3-bromobenzaldehyde, 2.35 g (27.0 mmol) of morpholine, 1.95 g (32.4 mmol) of acetic acid and 2.21 g (35.1 mmol) of sodium cyanoborohydride in 100 mL of ethanol were reacted at room temperature. Workup provided 4.5 g of 4-(4-bromobenzyl) morpholine as a white solid, mp 68-71 C.; 1H NMR (DMSO-d6) delta 7.51 (d, J=8 Hz, 2H), 7.27 (d, J=8 Hz, 2H), 3.56 (t, J=5 Hz, 4H), 3.43 (s, 2H), 2.33 (t, J=5 Hz, 4H). MS (ES) mlz 256.1, 258.1 (M+1). Analysis for C11H14BrNO: Calcd: C, 51.58;H, 5.51; N, 5.47 Found: C, 51.76;H, 5.50; N, 5.35.General procedure: To a solution of compound 6r (401.3 mg, 1 mmol), Pd(OAc)2 (22.5 mg, 0.1 mmol), P(O-Tolyl)3 (60.9 mg, 0.2 mmol), Et3N (303.6 mg, 417 muL, 3 mmol) in ACN (10 mL) was added a solution of R2X (heteroaryl or aryl halides, X=Br, I; 1.5 mmol) in ACN (5 mL) dropwise under an argon atmosphere in a sealed tube. The mixture was stirred under an argon atmosphere at 40 C for 16-48 h. The reaction mixture was then cooled, concentrated under vacuum and re-dissolved in CH2Cl2. After filtering, the filtrate was washed with saturated NaCl aqueous solution, dried with MgSO4 and concentrated under vacuum. The crude material was purified by column chromatography (PE/EA) on silica gel to afford compound 6ra-rt.This reaction showed high stereo- and regioselectivity.

Molecular Weight:256.14
XLogP3:2.3
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:255.02588
Monoisotopic Mass:255.02588
Topological Polar Surface Area:12.5
Heavy Atom Count:14
Complexity:163
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes