1-(4-BROMOBENZYL)PYRROLIDINE

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of 4-bromobenzyl-pyrrolidine (1 equiv, 120 mg), Pd2(dba)3 (2.0% equiv, 9.15 mg), t-Bu3P (1.6% equiv, 1.6 mg), benzylamine (1 equiv, 53.6 mg) and NaOtBu3 (1.5 equiv, 72 mg) in toluene (5 mL) was heated at 70° C. for 8 h.

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 1-(4-bromo-benzyl)-pyrrolidine (1.6 g, 6.5 mmol) in THF (20 mL) at −78° C. (acetone/dry ice bath) was added slowly down the side of the flask a solution of nBuLi (2.6 mL, 6.5 mmol, 2.5 M THF). After 15 minutes a solution of Intermediate 7, 3-(morpholin-4-ylcarbonyl)cyclobutanone (1.0 g, 5.4 mmol, in 7 mL of THF) precooled to −78° C. was added slowly. After 30 minutes the reaction was quenched cold with 1N HCl (20 mL). This mixture was diluted with EtOAc and then the layers were separated and the organic layer was discarded. The aqueous layer was basified with 1N NaOH and extracted with CHCl3/iPrOH (3:1). The organic layer was dried over MgSO4, filtered and concentrated to give a yellow oil. This material was purified by flash column chromatography using a 40 g ISCO™ column, eluting with a gradient of 3%, 5%, 10%, 20%, 30%/0 MeOH/CHCl3 with 0.1% NH4OH. The product containing fraction were collected and concentrated under reduced pressure to give the title compound (379 mg, 20% yield): Rf=0.3 (30% MeOH/CH2Cl2); LRMS m/z Calcd for C20H28N2O3, 344.4, found, 345 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.42 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 4.58 (brs, 1H), 3.62-3.55 (m, 8H), 3.34-3.32 (m, 2H), 2.87 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 2.77-2.71 (m, 2H), 2.64-2.59 (m, 2H), 2.48-2.45 (m, 4H), 1.75-1.70 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 173.8, 144.4, 137.8, 129.3, 125.3, 72.9, 67.0, 66.9, 60.3, 54.2, 46.0, 42.6, 40.9, 28.1, 23.5. was added slowly After 30 minutes the reaction was quenched cold with 1N HCl (20 mL) This mixture was diluted with EtOAc the layers were separated extracted with CHCl3/iPrOH (3:1) The organic layer was dried over MgSO4 filtered concentrated to give a yellow oil This material was purified by flash column chromatography eluting with a gradient of 3%, 5%, 10%, 20%, 30%/0 MeOH/CHCl3 with 0.1% NH4OH The product containing fraction were collected concentrated under reduced pressure

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4.8 g (20.0 mmol) 1-(4-bromo-benzyl)-pyrrolidine, 1.75 mL (30.0 mmol) propargylalcohol, 2.31 g (2.0 mmol) tetrakis-triphenylphosphane-palladium, 381 mg (2.0 mmol) CuI and 7.07 mL diisopropylamine in 100 mL acetonitrile is heated for 14 h at 60° C. under an argon atmosphere. The solvent is distilled off i.vac., the residue is taken up in water, exhaustively extracted with EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5). The solvent is distilled off i.vac exhaustively extracted with EtOAc the organic phase is dried over Na2SO4 is purified on silica gel (EtOAc/MeOH/NH3 95:5:0.5)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 12.5 g (50 mmol) 4-bromobenzylbromide is slowly added dropwise to a solution of 4.52 mL (55 mmol) pyrrolidine and 10.3 mL (60 mmol) ethyldiisopropylamine in 100 mL THF and stirred overnight at RT. The precipitate is filtered off and the solvent is eliminated i.vac. The product is obtained as a light-brown liquid which is further reacted without purification. The precipitate is filtered off The product is obtained as a light-brown liquid which is further reacted without purification

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 1-(4-bromo-benzyl-pyrrolidine (1.6 g, 6.5 mmol) in THF (20 mL) at −78° C. (acetone/dry ice bath) was added slowly down the side of the flask a solution of nBuLi (2.6 mL, 6.5 mmol, 2.5 M THF). After 15 minutes a solution of Intermediate 7, 3-(morpholin-4-ylcarbonyl)cyclobutanone (1.0 g, 5.4 mmol, in 7 mL of THF) precooled to −78° C. was added slowly. After 30 minutes the reaction was quenched cold with 1N HCl (20 mL). This mixture was diluted with EtOAc and then the layers were separated and the organic layer was discarded. The aqueous layer was basified with 1 N NaOH and extracted with CHCl3/iPrOH (3:1). The organic layer was dried over MgSO4, filtered and concentrated to give a yellow oil. This material was purified by flash column chromatography using a 40 g ISCO™ column, eluting with a gradient of 3%, 5%, 10%, 20%, 30% MeOH/CHCl3 with 0.1% NH4OH. The product containing fraction were collected and concentrated under reduced pressure to give the title compound (379 mg, 20% yield): Rf=0.3 (30% MeOH/CH2Cl2); LRMS m/z Calcd for C20H28N2O3, 344.4, found, 345 (M+1) APCI: 400 MHz 1H NMR (CDCl3) δ 7.42 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 4.58 (brs, 1H), 3.62-3.55 (m, 8H), 3.34-3.32 (m, 2H), 2.87 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 2.77-2.71 (m, 2H), 2.64-2.59 (m, 2H), 2.48-2.45 (m, 4H), 1.75-1.70 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 173.8, 144.4, 137.8, 129.3, 125.3, 72.9, 67.0, 66.9, 60.3, 54.2, 46.0, 42.6, 40.9, 28.1, 23.5. was added slowly After 30 minutes the reaction was quenched cold with 1N HCl (20 mL) This mixture was diluted with EtOAc the layers were separated extracted with CHCl3/iPrOH (3:1) The organic layer was dried over MgSO4 filtered concentrated to give a yellow oil This material was purified by flash column chromatography eluting with a gradient of 3%, 5%, 10%, 20%, 30% MeOH/CHCl3 with 0.1% NH4OH The product containing fraction were collected concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Pyrrolidine (20.0 mL, 0.240 mole) was added to a stirred solution of 4-bromobenzyl bromide (10.0 g, 40.0 mmol) in anhydrous CH2Cl2 (20 mL) at 0° C. under nitrogen. The resultant solution was allowed to stir at room temperature for 1 h. The reaction mixture was diluted with EtOAc (150 mL) before it was washed with half-saturated aqueous NaHCO3 (50 mL). After drying over MgSO4, filtration, and concentration, the oily residue was chromatographed on silica [20% EtOAc in hexanes, then 10% EtOH/Et3N (2/1) in THF/hexanes (1/1)] to provide 9.02 g of the benzyl pyrrolidine (94%) as an oil. was washed with half-saturated aqueous NaHCO3 (50 mL) After drying over MgSO4, filtration, and concentration the oily residue was chromatographed on silica [20% EtOAc in hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 1-(4-Bromo-benzyl)-pyrrolidine (Lednicer, Daniel; Lyster, Stanley C.; Duncan, Gordon W. Mammalian antifertility agents. IV. Basic 3,4-dihydronaphthalenes and 1,2,3,4-tetrahydro-1-naphthols. Journal of Medicinal Chemistry (1967), 10(1), 78–84, J. Org. Chem; EN; 46; 17; 1981; 3571–3574) (0.71 g, 2.96 mmol) in THF (13 mL) at −78° C. (isopropanol/CO2) was added a solution of n-butyl lithium (1.6 mL, 3.93 mmol, 2.5 M hexanes). After 15 minutes a pre-cooled (−78 □C) solution of 3-pyrrolidin-1-ylmethyl-cyclobutanone (Intermediate 6, General procedure B Step C) (0.2 g, 1.3 mmol, in 3 mL THF) was added down the side of the flask. After TLC analysis indicated complete consumption of starting material the reaction was quenched cold by the addition of a saturated solution of NH4Cl. The reaction was then warmed to room temperature and diluted with CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were discarded. The aqueous layer was then extracted with 3:1 (CHCl3:isopropyl alcohol) and the combined organic layers were dried over magnesium sulfate, filtered through a fritted funnel, and concentrated under reduced pressure. The material was purified by trituration using ether:hexanes to yield the title compound (0.24 mg, 58% yield) as a colorless solid and a mixture of cis:trans isomers. was added down the side of the flask consumption of starting material the reaction was quenched cold by the addition of a saturated solution of NH4Cl diluted with CH2Cl2 The layers were separated the aqueous layer was extracted with CH2Cl2 The aqueous layer was then extracted with 3:1 (CHCl3:isopropyl alcohol) the combined organic layers were dried over magnesium sulfate filtered through a fritted funnel concentrated under reduced pressure The material was purified by trituration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 1-(4-bromo-benzyl)-pyrrolidine (1.9 g, 7.9 mmol) in 13 mL of tetrahydrofuran at −78 C (iPrOH/dry ice) was added slowly down the side of the flask a solution of n-butyl lithium (3.2 mL, 7.9 mmol, 2.5 M in THF). After 30 minutes a precooled −78 C (iPrOH/CO2 ice) solution of 3-benzyloxymethyl-cyclobutanone (1.0 g, 5.3 mmol, in 1 mL of THF) was added via cannula down the side of the flask (wash 1 mL). The resulting solution was stirred at −78 C for 30 minutes, then quenched with a saturated solution of aqueous NH4OH and diluted with EtOAc. The layers were separated and the organic layer was dried over magnesium sulfate, filtered through a fritted funnel and then concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a Biotage column, eluting with a gradient of 2% MeOH/CH2Cl2 w/0.1% NH4OH through 30% MeOH/CH2Cl2 w/0.1% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to yield the title compound (1.3 g, 71% yield) as a colorless oil and a 3:1 mixture of cis:trans isomers. quenched with a saturated solution of aqueous NH4OH diluted with EtOAc The layers were separated the organic layer was dried over magnesium sulfate filtered through a fritted funnel concentrated under reduced pressure Purification of this material eluting with a gradient of 2% MeOH/CH2Cl2 The product containing fractions were collected concentrated under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of 4-bromobenzyl-pyrrolidine (1 equiv, 120 mg), Pd2(dba)3 (2.0% equiv, 9.15 mg), t-Bu3P (1.6% equiv, 1.6 mg), benzylamine (1 equiv, 53.6 mg) and NaOtBu3 (1.5 equiv, 72 mg) in toluene (5 mL) was heated at 70° C. for 8 h.