3-chloro-4-(pyrrolidin-1-ylmethyl)phenol

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

Procedure: NaB(OAc)3H (20 g, 0.094 mol) was added in portions for 15 min to a mixture of pyrrolidine (7.78 mL, 0.11 mol) and 3-chloro-4-hydroxybenzaldehyde (12.5 g, 0.079 mol) in CH2Cl2 (100 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 20 h and cooled with an ice bath. Concentrated HCl (18 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with 10 N NaOH to pH 9 (30 mL) and extracted with chloroform (3×100 mL). The combined extracts were dried with Na2SO4, and evaporated. The residue was purified by chromatography (silica gel 63-100μ, 8 mL, CHCl3/5% i-PrOH to give the title compound (8.07 g, 52%) was obtained as white crystals. LCMS-data: 212 and 214 (M+H)+, (calculated for C11H14NOCl 211.6); 1H NMR (400Mz)-data (DMSO-d6, J, Hz): 9.95 (br s, 1H, OH); 7.20 (d, 1H, Ar, J=2 Hz); 7.00 (dd, 1H, Ar, J1=2 Hz, J2=8.1 Hz); 6.89 (d, 1H, Ar, J=8.1); 3.43 (s, 2H, CH2); 2.35-2.40 (m, 4H); 1.63-1.69 (m, 4H). cooling with an ice bath in an atmosphere of argon Ar The mixture was stirred for 20 h cooled with an ice bath The organic layer was separated extracted with chloroform (3×100 mL) The combined extracts were dried with Na2SO4 evaporated The residue was purified by chromatography (silica gel 63-100μ, 8 mL, CHCl3/5% i-PrOH

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

Procedure: Pyrrolidine (22.0 mL, 0.255 mol) was added to a suspension of intermediate 14, 2-chloro-4-hydroxybenzaldehyde (30.8 g, 0.196 mol) in dichloromethane (620 mL). The reaction mixture was cooled with an ice bath. Sodium triacetoxyborohydride (65.8 g, 0.295 mol) was added in portions under stirring. The reaction mixture was stirred for 12 h at room temperature. Water (600 mL) and dichloromethane (600 mL) were added. The reaction mixture was acidified with concentrated HCl to pH˜2. The organic layer was separated. The aqueous one was subjected to extraction with EtOAc (2×500 mL), and the extracts were discarded. The aqueous fraction was alkalized with a saturated solution of potassium carbonate to pH 9-10. The product was extracted with CHCl3 (3×500 mL). The organic layer was dried with anhydrous Na2SO4 (50 g). The solvent was evaporated in vacuo. The obtained oil was refluxed in Et2O (400 mL) for 1 h. Then hexane (200 mL) was added, and the mixture was cooled. The formed residue was separated by filtration and dried. 1H NMR spectrum showed the presence of acetic acid (2.3% w/w). The residue was dissolved in a mixture of Et2O (100 mL) and CH2Cl2 (100 mL), and a solution of NaOH (0.4 g) in water (4 mL) was added. The product was extracted form the organic layer. The extract was dried with anhydrous Na2SO4 (50 g), evaporated, and coevaporated with dioxane. The title compound (23.5 g, 0.11 mol, 56%) was obtained as a pale-yellow powder. LC/MS data: 212.0 and 214.0 (M+H)+ (calculated for C22H14ClNO 211.7). 1H NMR data (DMSO-d6): 9.73 (br.s., 1H, OH); 7.24 (d, 1H, J=8.3 Hz, Ar—H); 6.78 (d, 1H, J=2.4 Hz, Ar—H); 6.70 (d.d., 1H, J1=8.3 Hz, J2=2.4 Hz, Ar—H); 3.54 (s, 2H, CH2Ar); 2.40-2.47 (m, 4H); 1.63-1.70 (m, 4H). The reaction mixture was cooled with an ice bath The reaction mixture was stirred for 12 h at room temperature The organic layer was separated The aqueous one was subjected to extraction with EtOAc (2×500 mL) The product was extracted with CHCl3 (3×500 mL) The organic layer was dried with anhydrous Na2SO4 (50 g) The solvent was evaporated in vacuo The obtained oil was refluxed in Et2O (400 mL) for 1 h Then hexane (200 mL) was added the mixture was cooled The formed residue was separated by filtration dried The residue was dissolved in a mixture of Et2O (100 mL) and CH2Cl2 (100 mL) a solution of NaOH (0.4 g) in water (4 mL) was added The product was extracted form the organic layer The extract was dried with anhydrous Na2SO4 (50 g) evaporated