5-bromo-2,3-dihydro-1H-inden-1-amine

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

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

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

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

Procedure: To a vigorously stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-amine (8.54 g, 40.3 mmol) and potassium carbonate (11.1 g, 80 mmol) in water (100 mL) and ethyl acetate (100 mL) was added benzyl chloroformate (7.56 g, 44.3 mmol). The reaction was stirred at rt overnight before being diluted with water (200 mL) and dichloromethane (200 mL). The organic phase was collected and the aqueous phase was extracted once more with dichloromethane (100 mL). The clear colourless organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a white solid. The material was co-evaporated once with diethyl ether and the residue was triturated with diethyl ether. The white solid was collected by filtration and dried on air to afford the title compound as a white solid (11.5 g, 82%). MS (ESI): m/z [M+H]+ 347.0 The organic phase was collected the aqueous phase was extracted once more with dichloromethane (100 mL) The clear colourless organic layers were dried over sodium sulfate filtered concentrated under reduced pressure to afford a white solid the residue was triturated with diethyl ether The white solid was collected by filtration dried on air

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

Procedure: At 0° C. and under protective atmosphere, a solution of 2-Propanesulfonyl chloride (11.87 mL, 121 mmol) in DCM (121 mL) was added gradually to a solution of 5-bromo-2,3-dihydro-1H-inden-1-amine (12.8 g, 60.4 mmol) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (4.83 mL, 32.1 mmol) in Dichloromethane (300 mL). The reaction was stirred at rt overnight. The reaction mixture was washed with 1N KHSO4 (1×) and sat NaHCO3 (2×) before being dried on Na2SO4 and solvent evaporated in vacuo to afford a green oil. Purification by column chromatography (25% EtOAc in heptane) afforded the title compound as a white solid. The reaction mixture was washed with 1N KHSO4 (1×) before being dried on Na2SO4 and solvent evaporated in vacuo to afford a green oil Purification by column chromatography (25% EtOAc in heptane)

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

Procedure: Zinc dust (28.0 g, 428 mmol) was added to a suspension of (E)-5-bromo-2,3-dihydro-1H-inden-1-one oxime (19.4 g, 86 mmol) in acetic acid (30 mL). The suspension was stirred at rt for 48 h. The reaction was filtered over Kiezelguhr gel. The residue was rinsed with ethyl acetate (2×100 mL). The combined filtrates were concentrated under reduced pressure to obtain a yellow oil. The yellow oil was partitioned between ethyl acetate (200 mL) and 2 N aq. HCl (200 mL). The acidic layer was separated before being basified using aq. 4 N NaOH and a white suspension was formed. Ethyl acetate (200 mL) was added and the milky mixture was filtered over Kiezelguhr gel. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a clear light yellow oil (10.8 g, 59%). MS (ESI): m/z [M−NH2]+ 198.0 The reaction was filtered over Kiezelguhr gel The residue was rinsed with ethyl acetate (2×100 mL) The combined filtrates were concentrated under reduced pressure to obtain a yellow oil The yellow oil was partitioned between ethyl acetate (200 mL) and 2 N aq. HCl (200 mL) The acidic layer was separated a white suspension was formed the milky mixture was filtered over Kiezelguhr gel The organic phase was separated dried over sodium sulfate filtered concentrated under reduced pressure

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

Procedure: Zinc dust (28.0 g, 428 mmol) was added to a suspension of (E)-5-bromo-2,3-dihydro-1H-inden-1-one oxime (19.4 g, 86 mmol) in acetic acid (30 mL). The suspension was stirred at rt for 48 h. The reaction was filtered over Kiezelguhr gel. The residue was rinsed with ethyl acetate (2×100 mL). The combined filtrates were concentrated under reduced pressure to obtain a yellow oil. The yellow oil was partitioned between ethyl acetate (200 mL) and 2 N aq. HCl (200 mL). The acidic layer was separated before being basified using aq. 4 N NaOH and a white suspension was formed. Ethyl acetate (200 mL) was added and the milky mixture was filtered over Kiezelguhr gel. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a clear light yellow oil (10.8 g, 59%). MS (ESI): m/z [M−NH2]+ 198.0 The reaction was filtered over Kiezelguhr gel The residue was rinsed with ethyl acetate (2×100 mL) The combined filtrates were concentrated under reduced pressure to obtain a yellow oil The yellow oil was partitioned between ethyl acetate (200 mL) and 2 N aq. HCl (200 mL) The acidic layer was separated a white suspension was formed the milky mixture was filtered over Kiezelguhr gel The organic phase was separated dried over sodium sulfate filtered concentrated under reduced pressure

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

Procedure: prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-5-bromo-indane

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

Procedure: At 0° C. and under protective atmosphere, a solution of 2-propanesulfonyl chloride (11.87 mL, 121 mmol) in DCM (121 mL) was added gradually to a solution of 5-bromo-2,3-dihydro-1H-inden-1-amine (12.8 g, 60.4 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.83 mL, 32.1 mmol) in dichloromethane (300 mL). The reaction was stirred at rt overnight. The reaction mixture was washed with 1N KHSO4 (1×) and sat NaHCO3 (2×) before being dried on Na2SO4 and solvent evaporated in vacuo to afford a green oil. Purification by column chromatography (25% EtOAc in hept) afforded the title compound as a white solid (6.0 g, 18.9 mmol, 31%). MS (ESI): m/z [M−H]− 317.0. The reaction mixture was washed with 1N KHSO4 (1×) before being dried on Na2SO4 and solvent evaporated in vacuo to afford a green oil Purification by column chromatography (25% EtOAc in hept)

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

Procedure: To a solution of 5-bromo-2,3-dihydro-1H-inden-1-amine (23.57 mmol, 5 g) in ethyl acetate (40 mL) was added potassium carbonate (47.1 mmol, 6.52 g) as a solution in water (40.0 mL). The whole was stirred vigorously before benzyl chloroformate (25.9 mmol, 3.65 mL, 4.42 g) was added and stirring continued overnight. The reaction was quenched with more water and was extracted with DCM (2×). The organic layers were separated and dried using a hydrophobic frit, and were concentrated in vacuo to give desired product as a brown solid (5.5 g, 15.9 mmol, 67.4%). 1H NMR (400 MHz, CDCl3) δ 1.82 (m, 1H) 2.60 (m, 1H) 2.85 (m, 1H) 2.90 (m, 1H), 4.95 (d, 1H) 5.18 (m, 3H) 7.18 (d, 1H) 7.34 (m, 7H). was added The reaction was quenched with more water was extracted with DCM (2×) The organic layers were separated dried were concentrated in vacuo

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

Procedure: The title compound was prepared from 2-chlorobenzimidazole and racemic 1-amino-5-bromoindane (prepared by Procedure B from 5-bromo-1-indanone) by Procedure A (30 min at 170° C.). The product was isolated by preparative LCMS to give the title compound as the free base and as a mixture of enantiomers (white solid, mp 242-243° C.). MS(ES+) m/z 328 ([M+1]+, 100). 1NMR (DMSO-d6) δ 1.92 (m, 1H), 2.50 (m, 1H), 2.83 (m, 1H), 2.95 (m, 1H), 5.35 (m, 1H), 6.82-7.02 (m, 3H), 7.12-7.35 (m, 4H), 7.46 (s, 1H), 10.7 (s, 1H). The product was isolated by preparative LCMS

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