4-CYCLOPROPYLBENZALDEHYDE

To a mixture of 4-bromobenzaldehyde (13.5 g, 0.0734 mol), cyclopropylboronic acid (6.3 g, 0.0734 mol), K3P04 .3H20 (33.3 g, 0.147 mol) and PCy3 (20.5 g, 0.0734mol) in toluene/H20 (180 mL, 5:1) was added Pd(OAc )2 (500mg) under N2 . The reaction was heated at 80° C. for 15 hrsunder N2 . The reaction was complete detected by LCMS.Toluene and H20 were removed by vacuum. The crude productwas purified by colunm chromatography on silica gel(eluted with PE:Et0Ac=20: 1) to give the title compound (5.0g, yield: 93.2percent) as a yellow oil. 1 H-NMR ( 400 MHz, CDC13 )oppm 9.94 (s, lH), 7.76 (d, 2H, 1=7.6 Hz), 7.18 (d, 2H, 1=7.6Hz), 2.00-1.94 (m, lH), 1.11-1.07 (m, 2H), 0.82-0.80 (m, 2H).4-Cyclopropylbenzaldehyde was prepared in 80percent yield according to the Example 8, Step A substituting cyclohex-l-en-l-ylboronic acid for cyclopropylboronic acid and 6-(4-bromophenyl)-3-((2-chlorophenyl)thio)-6-(thiophen-3-yl) piperidine -2, 4-dione for 4-bromobenzaldehyde[0721] Synthesis of 4-cyclopropylbe yde: [0722] To a stirred solution of 4-bromobenzaldehyde (500 mg, 2.70 mmol) in toluene (20 mL) under argon atmosphere were added cyclopropyl boronic acid (300 mg, 3.51 mmol), potassium phosphate (1.72 g, 8.10 mmol) and tricyclohexyl phosphine (38 mg, 0.13 mmol) at RT and purged under argon for 30 min. Then palladium acetate (30 mg, 0.13 mmol) was added to the reaction mass; heated to 100 °C and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was diluted with ice cold water (25 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with saturated NaHC0To a solution of 4-bromobenzaldehyde (3.4 g, 0.0 180 mmol) in mixture of toluene:water (40 mL: 3.0 mL) was added tripotassium phosphate (9.5 g, 0.045 mmol), triphenylphosphine (0.719 g, 0.002 mmol) and cyclopropylboronic acid (2.3 g, 0.027 mmol). The reaction mixture was heated at 100°C for 18 h. The reaction mass wasquenched with water and extracted with EtOAc. The organic layer were washed with water and brine, dried over Na2504 and concentrated. The obtained solid was purified by column chromatography to afford 1.70 g of the title product. ‘H NMR (300 IVIHz, DMSO d6): 9.94 (s, 1H), 7.77-7.75 (d, J = 8.4 Hz, 2H), 7.20-7.17 (d, J = 7.8 Hz, 2H), 1.97 (m, 1H), 1.11-1.08 (m, 2H), 0.82-0.80 (m, 2H).Example S53; Preparation of (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine, (4-cyclopropylbenzyl)-[2-(3-trifluoromethoxypheyl)-ethyl]-amine, (4-cyclopropylbenzyl)-[2-(3, 4-dichlorophenyl)-ethyl]-amine, [2-(4-chlorophenyl)-ethyl]-(4-cyclopropylbenzyl)-amine, (4-cyclopropylbenzyl)-[2-(3-trifluoromethylphenyl)-ethyl]-amine, (2, 2-dimethylchroman-6-ylmethyl)-[2-(3-trifluoromethylphenyl)-ethyl]-amine, (2, 2-dimethylchroman-6-ylmethyl)-phenethylamine, (2, 2-difluoro-benzo[1, 3]dioxol-5-ylmethyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine and [2-(3, 4-dichloro-phenyl)-ethyl]-(2, 2-difluoro-benzo [1, 3]dioxol-5-ylmethyl)-amine; Preparation of 4-cyclopropyl benzaldehyde; To a solution of 1-bromo-4-cyclopropylbenzene [synthesized in analogy to a procedure described in J. Org. Chem. 41:2262-2266 (1976)] (1.58 g, 8.04 mmol) in THF at -78° C. was added n-BuLi (5.08 ml, 1.6M solution in hexane, 8.11 mmol) and the reaction mixture was stirred at -78° C. for 10 min. DMF (1.25 ml, 16.08 mmol) was then added and the reaction mixture was stirred at -78° C. for 15 min. The reaction mixture was then warmed to 0° C. slowly (over 2 h) and stirred at 0° C. for 1 h. The reaction was quenched with sat. NHTo a solution of 1-bromo-4-cyclopropylbenzene [synthesised in analogy to a procedure described in J. Org. Chem. 1976, 41, 2262-2266] (1.58 g, 8.04 mmol) in THF at -78° C. was added n-BuLi (5.08 ml, 1.6M solution in hexane, 8.11 mmol) and the reaction mixture was stirred at -78° C. for 10 min. DMF (1.25 ml, 16.08 mmol) was then added and the reaction mixture was stirred at -78° C. for 15 min. General procedure: Method A: A sealed tube equiped with a magnetic stirring bar was charged with the arylhalide (1) or (5) (1.0 equiv), sodium carbonate (2.0 equiv), anhydrous lithium chloride (2.0equiv) and (SIPr)Pd(allyl)Cl (0.05 equiv). Tricyclopropylbismuth (2a) (1.0 equiv), preparedas described above, was dissolved in anhydrous DMF (0.1 M) under argon and was addedinto the sealed tube. Carbon monoxide was bubbled in the reaction mixture for 45 seconds, then the tube was sealed and heated at 40 °C for 16 hours. The reaction mixture was cooledto room temperature, transferred in a separatory funnel containing 20 mL of an aq. sat.NaHCO3 solution and was extracted with EtOAc (3 x 20 mL). The combined organic layerswere washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated underreduced pressure. The residue was purified by flash column chromatography using theindicated solvent system to afford the desired aryl cyclopropyl ketone (3) or (6).Method B: Same as method A except that 1.5 equivalents of tricyclopropylbismuth 2ainstead of 1.0 equivalent and 0.1 equivalents of (SIPr)Pd(allyl)Cl instead of 0.05 equivalentswere used and that the reaction was heated at 80 C instead of 40 C.

Molecular Weight:146.19
XLogP3:2.3
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:2
Exact Mass:146.073164938
Monoisotopic Mass:146.073164938
Topological Polar Surface Area:17.1
Heavy Atom Count:11
Complexity:141
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes