4-Morpholinobenzaldehyde

General procedure: A mixture of p-fluorobenzaldehyde 1 (25.0 g, 0.200 mol) andappropriate amine 2a–g (0.300 mol) and anhydrous potassium carbonate(40.0 g) were mixed in DMF (300mL), after which catalyticamount of Aliquat 336 reagent was added. The mixture was thenrefluxed for 24 h at 100 C. The mixture was concentrated underlow pressure and left to cool. The mixture was then poured into icewater and left overnight. The formed solid was filtered, washed withwater and crystallized with methanol to yield compounds Ia–g. 4-Morpholinobenzaldehyde Id General procedure: 4-Fluoro benzaldehyde (2.036mL, 0.019mol), pyrrolidine or morpholine (0.019mol), and potassium carbonate (Kp-Fluorobenzaldehyde (1.07 mL, 10 mmol) was dissolved in dimethylformamide (30 mL) where potassium carbonate (2.52 g, 20 mol) and morpholine (814 mL, 10 mmol) were added, and this was stirred at room temperature for 14 hours. 4-Fluorobenzaldehyde 15 (1.8 mL, 17.24 mmol), 1-acetylpiperazine (1 mL, 11.49 mmol) and Na2CO3 (1.83 g, 17.24 mmol) weredissolved in H2O (40 mL) and the stirred at 100°C overnight. After extraction with DCM, thecombined organic layers were concentrated under reduced pressure and silica gel columnchromatography (20percent EtOAc/PE) yielded 17b (2.36 g, 55percent). 1H NMR (400 MHz, DMSO-d6)δ 9.97 (s, 1H), 9.73 (s, 1H), 8.11-7.89 (m, 2H), 7.72 (d, J = 8.9 Hz, 2H), 7.43 (q, J = 8.4 Hz, 2H), 7.03 (d, J = 8.9 Hz, 2H), 3.72 (m, 4H), 3.32 (m, 4H); 13C NMR (101 MHz, DMSO-d6) δ 191.0, 154.9, 131.7, 126.7, 118.3, 65.8, 46.6; HRMS (ESI-MS): Calculated for C11H14NO2 [M+H]+:192.10191; found: 192.10186.A solution of 4-iodobenzaldehyde (1 g, 4.31 mmol) in MeOH (50 mL) was mixed with trimethyl orthoformate (4 mL, 36.10 mmol) and p-toluenesulfonic acid (5 mg). The reaction was stirred at room temperature for 3 h and then quenched by adding excess of sodium bicarbonate solid and stirred for 1 h. The solid was removed by filtration and the filtrate was concentrated to yield 1-dimethoxymethyl-4-iodo-benzene (1.2 g, 100percent). A mixture of 1-dimethoxymethyl-4-ido-benzene (1.2 g, 4.31 mmol), cesium carbonate (1.4 g, 4.31 mmol), morpholine (0.375 g, 4.31 mmol), and palladium tetrakis(triphenyl)phosphine (0.25 g, 0.216 mmol) in toluene (60 mL) and tert-butanol (10 mL) was thoroughly degassed and stirred at 110° C. for 28 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3.x.100 mL), concentrated to afford a solid residue. Purification by column chromatography left 4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 60percent). A solution of 4-(4-dimethoxyrnethyl-phenyl)-morpholine (0.61 g, 2.58 mmol) in THF (20 mL) was mixed with HCl in ether (10 mL, 10 mmol) and stirred at room temperature for 2 h. The reaction mixture was then neutralized with 1 N sodium bicarbonate aqueous to pH 9 and extracted with DCM (3.x.100 mL), to afford 4-morpholin-4-yl-benzaldehyde (0.37 g, 75percent).A mixture of 2-amino-4, 6-dimethoxybenzamide (0.15 g, 0.765 mmol), 4-morpholin-4-yl-benzaldehyde (0.15 g, 0.765 mmol), sodium hydrogensulfite (0.136 g, 0.765 mmol) and p-toluenesulfonic acid (10 mg) in N, N-dimethyl acetamide (10 mL) was stirred at 155° C. for 14 h. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The solid was collected by filtration, washed with water and MeOH to yield 5, 7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one (0.109 g, 39percent).A solution of 5, 7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one (0.109 g, 0.297 mmol) in DCM (5 mL) and MeOH (5 mL) was mixed with HCl in ether (3 mL, 3 mmol), stirred for 1.5 h, concentrated. The solid formed was rinsed with Hexanes, collected by filtration and washed with hexanes and DCM to yield the hydrochloride (0.115 g, 95percent) as a brown solid. Selected data: MS (m/z): 368.13; MP 217.5-219.4° C. (hydrochloride).A solution of 4-iodobenzaldehyde (1 g, 4.31 mmol) in MeOH (50 mL) was mixed with trimethyl orthoformate (4 mL, 36.10 mmol) and p-toluenesulfonic acid (5 mg). The reaction was stirred at room temperature for 3 h and then quenched by adding excess of sodium bicarbonate solid and stirred for 1 h. The solid was removed by filtration and the filtrate was concentrated to yield 1-dimethoxymethyl-4-iodo-benzene (1.2 g, 100percent). A mixture of 1-dimethoxymethyl-4-iodo-benzene (1.2 g, 4.31 mmol), cesium carbonate (1.4 g, 4.31 mmol), morpholine (0.375 g, 4.31 mmol), and palladium tetrakis(triphenyl)phosphine (0.25 g, 0.216 mmol) in toluene (60 mL) and tert-butanol (10 mL) was thoroughly degassed and stirred at 110° C. for 28 h. The reaction was quenched by adding water (50 mL), extracted with DCM (3×100 mL), concentrated to afford a solid residue. Purification by column chromatography left 4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 60percent). A solution of 4-(4-dimethoxymethyl-phenyl)-morpholine (0.61 g, 2.58 mmol) in THF (20 mL) was mixed with HCl in ether (10 mL, 10 mmol) and stirred at room temperature for 2 h. The reaction mixture was then neutralized with 1 N sodium bicarbonate aqueous to pH 9 and extracted with DCM (3×100 mL), to afford 4-morpholin-4-yl-benzaldehyde (0.37 g, 75percent).A mixture of 4-(4-[1, 3]dioxolan-2-yl-phenyl)-morpholine (690 mg, 2.933 mmol) in methanol (5 mL) was treated with 10 drops concentrated aqueous hydrochloric acid. The mixture was stirred at room temperature for 1 hour. To this solution was added 5 drops of water and stirring was continued for 2 hours at ambient temperature. The solution was then poured into ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (2.x.50 mL) and extracted with ethyl acetate (2.x.50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give 4-morpholin-4-yl-benzaldehyde as a tan waxy solid (550 mg, 98percent).General procedure: A round bottomedflask was charged with bromobenzene (4 mmol), aniline (4 mmol), TBAB (3 mmol), and K2CO3 (4 mmol) under a dry nitrogen atmosphere. A solution of (Ph2P)2py (0.05 mol percent in 2 mL of DMAc) and a solution of palladiumacetate (0.025 mol percent in 2 mL of DMAc) was added through a rubber septum, and the resulting mixture was heated at 135 C for the appropriate time. Uponcompletion of the reaction, the mixture was cooled to room temperature and quenched with H2O. After extraction with CH2Cl2 (3 20 mL), the combinedorganic layer was dried over MgSO4. The solvent was evaporated and the cruderesidue was purified by silica gel chromatography, using n-hexane/EtOAc aseluent to provide the desired product. The products were characterized byNMR spectroscopyGeneral procedure: In a typical run, an oven-dried 10 ml round bottom flask was charged with a known mole percent of catalyst, NaOtBu (1.3 mmol), amine (1.2 mmol) and aryl halide (1 mmol) with the appropriate solvent(s) (4 ml). The flask was placed in a preheated oil bath at required temp. After the specified time the flask was removed from the oil bath, water (20 ml) was added, and extraction with ether (4×10 ml) was done. The combined organic layers were washed with water (3×10 ml), dried over anhydrous Na2SO4, and filtered. Solvent was removed under vacuum. The residue was dissolved in acetonitrile and analyzed by GC–MS.

Molecular Weight:191.23
XLogP3:0.8
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:191.094628657
Monoisotopic Mass:191.094628657
Topological Polar Surface Area:29.5
Heavy Atom Count:14
Complexity:182
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes