1,4-dioxaspiro[4.5]decan-8-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: Dissolve 1,4-dioxaspiro[4.5]decan-8-amine (785 mg, 0.005 mol; see Liebigs (1990) Ann. Chem. 8:781-7) in CH2Cl2 and then add H2O (20 mL) followed by saturated NaHCO3 solution (50 mL). Add a toluene solution of phosgene (20% solution, 5 mL) to the reaction mixture and stir at room temperature for 1 hour. Dry the CH2Cl2 layer (Na2SO4) and concentrate under reduced pressure. Dissolve the resulting oil in dry toluene to produce a stock solution (˜0.2 M) of (1,4-dioxa-spiro[4.5]dec-8-yl)-carbamoyl chloride. Dry the CH2Cl2 layer (Na2SO4) concentrate under reduced pressure Dissolve the resulting oil in dry toluene

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

Procedure: To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.4 g) in tetrahydrofuran (30 mL) was added 1,4-dioxaspiro[4.5]decan-8-amine (1.0 g) and diisopropylethylamine (5 mL). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (300 mL) and washed with water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound. washed with water, brine dried over Na2SO4 Filtration and evaporation of the solvent

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

Procedure: To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.4 g) in tetrahydrofuran (30 mL) was added 1,4-dioxaspiro[4.5]decan-8-amine (1.0 g) and diisopropylethylamine (5 mL). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (300 mL) and washed with water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound. washed with water, brine dried over Na2SO4 Filtration and evaporation of the solvent

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1,4-dioxaspiro[4.5]decan-8-amine (from J&W PharmLab, 0.40 g, 2.5 mmol), 7-chloro-6-nitrothieno[3,2-b]pyridine (0.29 g, 1.4 mmol) and triethylamine (0.38 mL, 2.7 mmol) in isopropyl alcohol (4.4 mL) was stirred at 90° C. for 2 h. The mixture was concentrated to give the desired product to be used in the next step directly. LCMS calculated for C15H18N3O4S (M+H)+: m/z=336.1. Found: 336.0. The mixture was concentrated

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

Procedure: To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.4 g) in tetrahydrofuran (30 mL) was added 1,4-dioxaspiro[4.5]decan-8-amine (1.0 g) and diisopropylethylamine (5 mL). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (300 mL) and washed with water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound. washed with water, brine dried over Na2SO4 Filtration and evaporation of the solvent

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-(3,3-dimethyl-but-1-ynyl)-3-iodo-thiophene-2-carboxylic acid methyl ester (0.5 g, 1.5 mmol), palladium acetate (0.033 g, 0.15 mmol), BINAP (0.093 g, 0.15 mmol), cesium carbonate (0.733 g, 2.25 mmol) and 1,4-Dioxa-spiro[4.5]dec-8-ylamine (0.706 g, 4.5 mmol) in toluene (8 mL) was degassed with N2 then heated to 110° C. for 8 h. The reaction was diluted with ethyl acetate filtered through a Celite pad and purified by silica gel chromatography (0-40% hexane/ethylacetate) to give the title compound in 50% yield. MS (m/z): 378.1 [M+H]; HPLC retention time: 5.12 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid). was degassed with N2 The reaction was diluted with ethyl acetate filtered through a Celite pad purified by silica gel chromatography (0-40% hexane/ethylacetate)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-(3,3-dimethyl-but-1-ynyl)-3-iodo-thiophene-2-carboxylic acid methyl ester (0.5 g, 1.5 mmol), palladium acetate (0.033 g, 0.15 mmol), BINAP (0.093 g, 0.15 mmol), cesium carbonate (0.733 g, 2.25 mmol) and 1,4-Dioxa-spiro[4.5]dec-8-ylamine (0.706 g, 4.5 mmol) in toluene (8 mL) was degassed with N2 then heated to 110° C. for 8 h. The reaction was diluted with ethyl acetate filtered through a Celite pad and purified by silica gel chromatography (0-40% hexane/ethylacetate) to give the title compound in 50% yield. MS (m/z): 378.1 [M+H]; HPLC retention time: 5.12 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid). was degassed with N2 The reaction was diluted with ethyl acetate filtered through a Celite pad purified by silica gel chromatography (0-40% hexane/ethylacetate)

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

Procedure: To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.4 g) in tetrahydrofuran (30 mL) was added 1,4-dioxaspiro[4.5]decan-8-amine (1.0 g) and diisopropylethylamine (5 mL). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (300 mL) and washed with water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound. washed with water, brine dried over Na2SO4 Filtration and evaporation of the solvent

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ammonia gas was bubbled into a solution of 1,4-dioxaspiro[4.5]decan-8-one (31.2 g, 199.77 mmol, 1.00 equiv) in methanol (300 mL). The resulting solution was stirred for 8 hrs at 0-10° C. This was followed by the addition of sodium borohydride (11.4 g, 301.35 mmol, 1.51 equiv) in several batches at 0-10° C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 4×300 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 20 g (64%) of 1,4-dioxaspiro[4.5]decan-8-amine as colorless oil. The resulting solution was stirred for 1 h at room temperature The resulting solution was extracted with 4×300 mL of dichloromethane The resulting mixture was washed with 2×100 mL of brine The mixture was dried over anhydrous sodium sulfate concentrated under vacuum