2-(4-BROMO-PHENYL)-PYRROLIDINE

NaBHExample 145D2-(4-Bromophenyl)pyrrolidine[00814] NaBHNaBH4 (1.52 g, 40 mmol) was added to a solution of 5-(4-bromophenyl)-3, 4-dihydro-2H-pyrrole (4.48 g, 20 mmol) in H2O/MeOH (30 mL, v/v 1:4) at -41 C. After stirred for 4 hrs, the solution was allowed to warm to room temperature. Once the reaction was deemed complete by TLC, the unreacted NaBH4 was quenched by the addition of 2 N HCl. The solution was then diluted with water and ether, and separated two layers. The aqueous layer was washed with an additional portion of ether, basified with 4 M NaOH (pH 12-13) and washed with ethyl acetate. The combined organic extracts were washed with brine, and then dried over Na2SO4. Evaporation of the solvent afforded the title crude product as a yellow oil (3.8 g, yield 84%), which was used directly in the next step. LC-MS (ESI) m/z: 226 (M+1)+.Example 145D2-(4-Bromophenyl)pyrrolidine[00814] NaBH4 (1.52 g, 40 mmol) was added to a solution of 5-(4-bromophenyl)-3, 4-dihydro-2H-pyrrole (4.48 g, 20 mmol) in H20/MeOH (30 mL, v/v 1 :4) at -41 C. After stirred for 4 hrs, the solution was allowed to warm to room temperature. Once the reaction was deemed complete by TLC, the unreacted NaBH4 was quenched by the addition of 2 N HCl. The solution was then diluted with water and ether, and separated two layers. The aqueous layer was washed with an additional portion of ether, basified with 4 M NaOH (pH 12-13) and washed with ethyl acetate. The combined organic extracts were washed with brine, and then dried over Na2SO/t. Evaporation of the solvent afforded the title crude product as a yellow oil (3.8 g, yield 84%), which was used directly in the next step. LC-MS (ESI) m/z: 226 (M+l)+.2-(4-Bromo-phenyl)-pyrrolidine.5-(4-Bromo-phenyl)-3, 4-dihydro-2H-pyrrole (10 mmol) was dissolved in MeOH (w/ 20% HOAc, 5 mL) and cooled to -40 0C. NaBH4 (2 eq, 760 mg) was added and the mixture warmed to room temperature. After 2 hrs the reaction was acidified with HCl (2M, 50 mL) extracted with ether (2x 50 mL), the aqueous layer was basified with NaOH (2M in water, 100 mL) and extracted with EtOAc (2x 50 mL). The organic phase was dried with Na2SO4 and concentrated to an oil. MS: 226 (M+H+).To a mixture of B-IOa (5.50 g, 24.5 mmol) in 20 % acetic acid in MeOH at 0 0C is added sodium boronhydride (1.93 g, 36.8 mmol). The reaction mixture is stirred at 0 0C for 1 h and then 4 h at RT. Then 20 mL IM HCl is added and the reaction mixture is extracted with diethyl ether. The aqueous phase is basified with 10 M aqueous NaOH and extracted with DCM. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. Yield: 3.92 g.Step B: At 0C to a solution of 5-(4-bromophenyl)-3, 4-dihydro-2H-pyrrole (2.0 g, 9.0 mmol) in methanol (20 mL) was slowly added sodium borohydride (684 mg, 18.1 mmol) with stirring. After addition, the reaction mixture was stirred at room temperature for 1 h. TLC (petroleum ether/ethyl acetate=2:1) showed depletion of starting materials. The resultant mixture was diluted with water (30 mL). To the mixture of the above step was added potassium carbonate (1.51 g, 10.9 mmol) and Boc2O (2.3g, 10.5 mmol). The mixture was stirred at 20C for 2 h and thin-layer chromatography plate (developing agent: petroleum ether/ethyl acetate=2/1) showed depletion of starting materials. The mixture was then extracted with ethyl acetate (50 mL*2) and the extract was concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give tert-butyl 2-(4-bromophenyl)pyrrolidine-1-formate (1.5g, yield: 51.1%) as yellow solid.To a stirred solution of 5- (4-bromophenyl) -3, 4-dihydro-2H-pyrrole (2.0 g, 9.0 mmol) at 0 C, Methanol (20 ml) was slowly addedSodium borohydride (684 mg, 18.1 mmol).After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. TLC (petroleum ether / ethyl acetate = 2: 1)Show that the material is completely consumed. The resulting mixture was diluted with water (30 ml).Potassium carbonate (1.51 g, 10.9 mmol) and Boc2O (2.3 g, 10.5 mmol) were added to the mixture in the above step. After the mixture was stirred at 20 C for 2 hours, a thin layer chromatography plate (developing solvent:Petroleum ether / ethyl acetate = 2/1) showed that the starting material was consumed completely. Then ethyl acetate (50 ml x 2)The extract was concentrated under reduced pressure and the residue was purified by chromatography on silica gel2- (4-bromophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester(1.5 g, yield: 51.1%) as a yellow solid.The mixture of 2- (4-bromophenyl) pyrrolidine (452 mg, 2 mmol), 1-iodo-2-methylbenzene (654 mg, 3 mmol), 2, 2'-bis (diphenylphosphanyl) -1, 1'-binaphthalene (249 mg, 0.4 mmol), Tris (dibenzylideneacetone) dipalladium (183 mg, 0.2 mmol), t-BuOK (449 mg, 4 mmol) in toluene (50 mL) was heated to 90 C overnight. The reaction was concentrated in vacuo and purified by chromatography column on silica (eluent: EA/PE = 1/5) to give the product (516 mg, 81.26%) as a colorless oil. 1H NMR (400 MHz, CDCl 3) delta ppm: 7.33 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 4.0 Hz, 1H), 6.94 (t, J = 8.0 Hz, 1H), 6.79 (t, J = 8.0 Hz, 2H), 4.61 (dd, J = 4.0, J=8.0 Hz, 1H), 3.88 (d, J=8.0 Hz, 1H), 2.93 (m, 1H), 2.39 (m, 1H), 2.33 (s, 3H), 2.05-1.76 (m, 3H). MS (ESI, m/e) [M+1] + 258.0.

Molecular Weight:226.11
XLogP3:2.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:225.01531
Monoisotopic Mass:225.01531
Topological Polar Surface Area:12
Heavy Atom Count:12
Complexity:141
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes