(Chroman-2-yl)methanamine

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:

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

Procedure: A mixture of 2-chlorocarbonyl-3,4-dihydro-2H-1-benzopyran (0.47 mol) in N,N-dimethylacetamide (100 ml), a solution of thiophene (4%) (3 ml) and 2,2'-oxybispropane (400 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue, potassium acetate (20 g) and benzenemethanamine (50 g) in N,N-dimethylacetamide (2 ml) and methanol (300 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue in methanol (500 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in 1,1'-oxybisethane and washed with a NaOH-solution. The organic layer was dried (MgSO4), filtered off and evaporated. The residue (70 g) was distilled at 70° C. (0.1 mm Hg), yielding 48.7 g (63.5%) of (±)-3,4-dihydro-2H-1-benzopyran-2-methanamine (interm. 15-c). the filtrate was evaporated the filtrate was evaporated the filtrate was evaporated washed with a NaOH-solution The organic layer was dried (MgSO4) filtered off evaporated The residue (70 g) was distilled at 70° C. (0.1 mm Hg)

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

Procedure: LAH pellets (3.2 g, 84.3 mmole) were added slowly to a stirred solution of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (15 g, 84.3 mmole) in THF (150 ml). After the vigorous reaction subsided, the mixture was refluxed for 1 hr and then cooled. To the hot mixture were added sequentially, H2O (3.2 ml), 15% NaOH (3.2 ml), and then H2O (12.8 ml). The mixture was filtered and the filter cake washed with THF. The THF filtrate was concentrated in vacuo, and Kugelrohr distilled to a clear oil (13.85 g, 100%). This alcohol intermediate was stirred in SOCl2 for 18 hr. The excess SOCl2 was removed in vacuo and the resulting dark oil was Kugelrohr distilled to a clear oil (8.65 g, 56.2%). This alkyl chloride intermediate was heated to 100° in DMF with NaN3 (4.32 g, 66 mmole) and KI (0.2 g) for 72 hr. The mixture was diluted with H2O (250 ml) and extracted with CH2Cl2 three times. The CH2Cl2 extracts were concentrated in vacuo. The residue was hydrogenated at 60 psi over 10% Pd/C (1 g) in ethanol and 37% HCl (10 ml) for 3 hr. H2O (20 ml) was added and the mixture was filtered. The ethanol was removed in vacuo and the aqueous residue was made basic with 10 N NaOH. The mixture was extracted three times with ethyl acetate (50 ml portions). The extracts were concentrated in vacuo and the tan oil was Kugelrohr distilled to a dear oil (6.35 g, 82.2%). The product was used without further purification. After the vigorous reaction the mixture was refluxed for 1 hr cooled To the hot mixture were added sequentially The mixture was filtered the filter cake washed with THF The THF filtrate was concentrated in vacuo, and Kugelrohr distilled to a clear oil (13.85 g, 100%) The excess SOCl2 was removed in vacuo distilled to a clear oil (8.65 g, 56.2%) extracted with CH2Cl2 three times The CH2Cl2 extracts were concentrated in vacuo The residue was hydrogenated at 60 psi over 10% Pd/C (1 g) in ethanol and 37% HCl (10 ml) for 3 hr H2O (20 ml) was added the mixture was filtered The ethanol was removed in vacuo The mixture was extracted three times with ethyl acetate (50 ml portions) The extracts were concentrated in vacuo distilled to a dear oil (6.35 g, 82.2%) The product was used without further purification

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

Procedure: LAH pellets (3.2 g, 84.3 mmole) were added slowly to a stirred solution of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (15 g, 84.3 mmole) in THF (150 ml). After the vigorous reaction subsided, the mixture was refluxed for 1 hr and then cooled. To the hot mixture were added sequentially, H2O (3.2 ml), 15% NaOH (3.2 ml), and then H2O (12.8 ml). The mixture was filtered and the filter cake washed with THF. The THF filtrate was concentrated in vacuo, and Kugelrohr distilled to a clear oil (13.85 g, 100%). This alcohol intermediate was stirred in SOCl2 for 18 hr. The excess SOCl2 was removed in vacuo and the resulting dark oil was Kugelrohr distilled to a clear oil (8.65 g, 56.2%). This alkyl chloride intermediate was heated to 100° in DMF with NaN3 (4.32 g, 66 mmole) and KI (0.2 g) for 72 hr. The mixture was diluted with H2O (250 ml) and extracted with CH2Cl2 three times. The CH2Cl2 extracts were concentrated in vacuo. The residue was hydrogenated at 60 psi over 10% Pd/C (1 g) in ethanol and 37% HCl (10 ml) for 3 hr. H2O (20 ml) was added and the mixture was filtered. The ethanol was removed in vacuo and the aqueous residue was made basic with 10 N NaOH. The mixture was extracted three times with ethyl acetate (50 ml portions). The extracts were concentrated in vacuo and the tan oil was Kugelrohr distilled to a dear oil (6.35 g, 82.2%). The product was used without further purification. After the vigorous reaction the mixture was refluxed for 1 hr cooled To the hot mixture were added sequentially The mixture was filtered the filter cake washed with THF The THF filtrate was concentrated in vacuo, and Kugelrohr distilled to a clear oil (13.85 g, 100%) The excess SOCl2 was removed in vacuo distilled to a clear oil (8.65 g, 56.2%) extracted with CH2Cl2 three times The CH2Cl2 extracts were concentrated in vacuo The residue was hydrogenated at 60 psi over 10% Pd/C (1 g) in ethanol and 37% HCl (10 ml) for 3 hr H2O (20 ml) was added the mixture was filtered The ethanol was removed in vacuo The mixture was extracted three times with ethyl acetate (50 ml portions) The extracts were concentrated in vacuo distilled to a dear oil (6.35 g, 82.2%) The product was used without further purification

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

Procedure: The mixture of 5.4 g (0.033 mol) (-)-2-aminomethylchroman (example 92f; αD =-122.8), 6.1 g (0.06 mol) triethylamine, 9.5 g (0.03 mol) N-(4-bromobutyl) saccharin and 80 ml anhydrous dimethyl formamide was heated to 60° C. for 4 h. The solvent was evaporated at 0.01 torr. The residue (13.5 g) was dissolved in toluene/ethyl acetate (5:1) and chromatographed on silica (300 g). The fraction (5.8 g) obtained by elution with toluene/ethyl acetate 1:1 was rechromatographed on 150 g of silica, providing 3.7 g of chemically pure 2-(N-[4-(1,1-Dioxido-3-oxo-2,3-di-hydro-benzisothiazol-2-yl)butyl]aminomethyl}chroman. The solvent was evaporated at 0.01 torr The residue (13.5 g) was dissolved in toluene/ethyl acetate (5:1) chromatographed on silica (300 g) The fraction (5.8 g) obtained by elution with toluene/ethyl acetate 1:1 was rechromatographed on 150 g of silica

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

Procedure: The mixture of 5.4 g (0.033 mol) (-)-2-aminomethylchroman (example 92f; αD =-122.8), 6.1 g (0.06 mol) triethylamine, 9.5 g (0.03 mol) N-(4-bromobutyl) saccharin and 80 ml anhydrous dimethyl formamide was heated to 60° C. for 4 h. The solvent was evaporated at 0.01 torr. The residue (13.5 g) was dissolved in toluene/ethyl acetate (5:1) and chromatographed on silica (300 g). The fraction (5.8 g) obtained by elution with toluene/ethyl acetate 1:1 was rechromatographed on 150 g of silica, providing 3.7 g of chemically pure 2-(N-[4-(1,1-Dioxido-3-oxo-2,3-di-hydro-benzisothiazol-2-yl)butyl]aminomethyl}chroman. The solvent was evaporated at 0.01 torr The residue (13.5 g) was dissolved in toluene/ethyl acetate (5:1) chromatographed on silica (300 g) The fraction (5.8 g) obtained by elution with toluene/ethyl acetate 1:1 was rechromatographed on 150 g of silica

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

Procedure: The compound is prepared from 2-aminomethyl-3,4-dihydro-2H-chromene and 2-(4-bromobutyl)-2H-naphth[1,8-cd]isothiazole 1,1-dioxide (available from 2H-naphth [1,8-cd]isothiazole 1,1-dioxide and 1,4-dibromobutane using a base) according to the working directions of

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

Procedure: The compound is prepared from 2-aminomethyl-3,4-dihydro-2H-chromene and 2-(4-bromobutyl)-2H-naphth[1,8-cd]isothiazole 1,1-dioxide (available from 2H-naphth [1,8-cd]isothiazole 1,1-dioxide and 1,4-dibromobutane using a base) according to the working directions of

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

Procedure: The oily amine (1.63 g, 10 mmol) and sulfamide (1.92 g, 20 mmol) were combined in dioxane (50 mL) and brought to reflux for 2 h. The solution was cooled and evaporated in vacuo to yield an oil, which was purified via column chromatography (DCM:Methanol 10:1) to yield a white solid. The solid was recrystallized from ethyl acetate/hexane to yield chroman-2-ylmethylsulfamide as a white solid. to reflux for 2 h The solution was cooled evaporated in vacuo to yield an oil, which was purified via column chromatography (DCM:Methanol 10:1) to yield a white solid The solid was recrystallized from ethyl acetate/hexane