8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile

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

Procedure: To a stirred suspension of lithium aluminium hydride (1M solution in ether; 94.9 ml; 94.9 mmol) at −78° C. was added a solution of 8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (14 g; 63.264 mmol) in ether (40 ml) over 30 minutes and the mixture stirred cold for 1 hour, then allowed to warm to ambient temperature and stirred for 3 hours. The resultant mixture was cooled in an ice bath and to the mixture was added in turn water (2 ml), 15% NaOH solution (2 ml) and water (2 ml). The resultant white granular solid was collected on a filter and rinsed twice with diethyl ether. The filtrate was evaporated to give the crude product as a colourless oil (12 g). 1H NMR δ (ppm) (CDCl3): 3.93 (4H, s), 2.68 (2H, s), 1.63-1.57 (4H, m), 1.54-1.48 (4H, m), 1.25 (2H, d, J=6.6 Hz), 0.65-0.50 (1H, m), 0.46-0.40 (2H, m), 0.02 (2H, q, J=4.9 Hz). MS (m/e)=226. stirred for 3 hours The resultant white granular solid was collected on a filter rinsed twice with diethyl ether The filtrate was evaporated

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

Procedure: To a stirred suspension of lithium aluminium hydride (1M solution in ether; 94.9 ml; 94.9 mmol) at −78° C. was added a solution of 8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (14 g; 63.264 mmol) in ether (40 ml) over 30 minutes and the mixture stirred cold for 1 hour, then allowed to warm to ambient temperature and stirred for 3 hours. The resultant mixture was cooled in an ice bath and to the mixture was added in turn water (2 ml), 15% NaOH solution (2 ml) and water (2 ml). The resultant white granular solid was collected on a filter and rinsed twice with diethyl ether. The filtrate was evaporated to give the crude product as a colourless oil (12 g). 1H NMR δ (ppm) (CDCl3): 3.93 (4H, s), 2.68 (2H, s), 1.63-1.57 (4H, m), 1.54-1.48 (4H, m), 1.25 (2H, d, J=6.6 Hz), 0.65-0.50 (1H, m), 0.46-0.40 (2H, m), 0.02 (2H, q, J=4.9 Hz). MS (m/e)=226. stirred for 3 hours The resultant white granular solid was collected on a filter rinsed twice with diethyl ether The filtrate was evaporated

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

Procedure: To a stirred solution of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (20 g; 119.6136 mmol) and (bromomethyl)cyclopropane (17.76 g 12.6 ml; 131.57 mmol) in THF (100 ml) at −10° C. was added KHMDS (0.5M solution in toluene; 263.15 ml; 131.57 mmol) dropwise and the solution allowed to warm to ambient temperature with stirring for 18 hours. The reaction was cooled in an ice bath and quenched with sat. ammonium chloride solution and the solvent evaporated. The residue was partitioned between EtOAc (300 ml) and water (100 ml adjusted to pH 4 with 1 N HCl). The organic phase was separated, dried over MgSO4, filtered and evaporated to give an orange oil. (21.0 g) 1H NMR δ (ppm) (CDCl3): 3.99-3.89 (4H, m), 2.08 (2H, d, J=13.5 Hz), 1.96-1.72 (9H, m), 0.96-0.82 (1H, m), 0.59-0.53 (2H, m), 0.17 (2H, q, J=5.1 Hz). The reaction was cooled in an ice bath quenched with sat. ammonium chloride solution the solvent evaporated The residue was partitioned between EtOAc (300 ml) and water (100 ml adjusted to pH 4 with 1 N HCl) The organic phase was separated dried over MgSO4 filtered evaporated to give an orange oil

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

Procedure: To a stirred solution of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (20 g; 119.6136 mmol) and (bromomethyl)cyclopropane (17.76 g 12.6 ml; 131.57 mmol) in THF (100 ml) at −10° C. was added KHMDS (0.5M solution in toluene; 263.15 ml; 131.57 mmol) dropwise and the solution allowed to warm to ambient temperature with stirring for 18 hours. The reaction was cooled in an ice bath and quenched with sat. ammonium chloride solution and the solvent evaporated. The residue was partitioned between EtOAc (300 ml) and water (100 ml adjusted to pH 4 with 1 N HCl). The organic phase was separated, dried over MgSO4, filtered and evaporated to give an orange oil. (21.0 g) 1H NMR δ (ppm) (CDCl3): 3.99-3.89 (4H, m), 2.08 (2H, d, J=13.5 Hz), 1.96-1.72 (9H, m), 0.96-0.82 (1H, m), 0.59-0.53 (2H, m), 0.17 (2H, q, J=5.1 Hz). The reaction was cooled in an ice bath quenched with sat. ammonium chloride solution the solvent evaporated The residue was partitioned between EtOAc (300 ml) and water (100 ml adjusted to pH 4 with 1 N HCl) The organic phase was separated dried over MgSO4 filtered evaporated to give an orange oil

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

Procedure: To a stirred solution of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (20 g; 119.6136 mmol) and (bromomethyl)cyclopropane (17.76 g 12.6 ml; 131.57 mmol) in THF (100 ml) at −10° C. was added KHMDS (0.5M solution in toluene; 263.15 ml; 131.57 mmol) dropwise and the solution allowed to warm to ambient temperature with stirring for 18 hours. The reaction was cooled in an ice bath and quenched with sat. ammonium chloride solution and the solvent evaporated. The residue was partitioned between EtOAc (300 ml) and water (100 ml adjusted to pH 4 with 1 N HCl). The organic phase was separated, dried over MgSO4, filtered and evaporated to give an orange oil. (21.0 g) 1H NMR δ (ppm) (CDCl3): 3.99-3.89 (4H, m), 2.08 (2H, d, J=13.5 Hz), 1.96-1.72 (9H, m), 0.96-0.82 (1H, m), 0.59-0.53 (2H, m), 0.17 (2H, q, J=5.1 Hz). The reaction was cooled in an ice bath quenched with sat. ammonium chloride solution the solvent evaporated The residue was partitioned between EtOAc (300 ml) and water (100 ml adjusted to pH 4 with 1 N HCl) The organic phase was separated dried over MgSO4 filtered evaporated to give an orange oil

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8-cyclopropylmethyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile, prepared from 1,4-dioxa-spiro[4.5]decane-8-carbonitrile and cyclopropylmethyl bromide in a similar fashion as described for 5, (3.00 g, 13.6 mmol) in tetrahydrofuran (40 mL) at −78° C. was added a 1M solution of diisobutylaluminium hydride in toluene (20.3 mL, 20.3 mmol, 1.5 eq.) and the reaction was allowed to warmed to 0° C. over a period of 3 h. The mixture was recooled to −78° C., neutralized by dropwise addition of a 10% aqueous citric acid solution and warmed to room temperature. The mixture was partitioned between methyl-tert.butyl ether and water, the aqueous phase extracted twice with methyl-tert.butyl ether and the combined organics were dried over magnesium sulphate, filtered and evaporated to give 8-cyclopropylmethyl-1,4-dioxa-spiro[4.5]decane-8-carbaldehyde. was recooled to −78° C. warmed to room temperature The mixture was partitioned between methyl-tert.butyl ether and water the aqueous phase extracted twice with methyl-tert.butyl ether the combined organics were dried over magnesium sulphate filtered evaporated

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

Procedure: To a stirred suspension of lithium aluminium hydride (1M solution in ether; 94.9 ml; 94.9 mmol) at −78° C. was added a solution of 8-(cyclopropylmethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (14 g;63.264 mmol) in ether (40 ml) over 30 minutes and the mixture stirred cold for 1 hour, then allowed to warm to ambient temperature and stirred for 3 hours. The resultant mixture was cooled in an ice bath and to the mixture was added in turn water (2 ml), 15% NaOH solution (2 ml) and water (2 ml). The resultant white granular solid was collected on a filter and rinsed twice with diethyl ether. The filtrate was evaporated to give the crude product as a colourless oil (12 g). 1H NMR δ (ppm)(CDCl3): 3.93 (4H, s), 2.68 (2H, s), 1.63-1.57 (4H, m), 1.54-1.48 (4H, m), 1.25 (2H, d, J=6.6 Hz), 0.65-0.50 (1H, m), 0.46-0.40 (2H, m), 0.02 (2H, q, J=4.9 Hz). MS (m/e)=226. stirred for 3 hours The resultant white granular solid was collected on a filter rinsed twice with diethyl ether The filtrate was evaporated

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

Procedure: To a stirred solution of 1,4-dioxaspiro[4.5]decane-8-carbonitrile (20 g; 119.6136 mmol) and (bromomethyl)cyclopropane (17.76 g 12.6 ml; 131.57 mmol) in THF (100 ml) at −10° C. was added KHMDS (0.5M solution in toluene; 263.15 ml ; 131.57 mmol) dropwise and the solution allowed to warm to ambient temperature with stirring for 18 hours. The reaction was cooled in an ice bath and quenched with sat. ammonium chloride solution and the solvent evaporated. The residue was partitioned between EtOAc (300 ml) and water (100 ml adjusted to pH 4 with 1 N HCl). The organic phase was separated, dried over MgSO4, filtered and evaporated to give an orange oil. (21.0 g) 1H NMR δ (ppm)(CDCl3): 3.99-3.89 (4H, m), 2.08 (2H, d, J=13.5 Hz), 1.96-1.72 (9H, m), 0.96-0.82 (1H, m), 0.59-0.53 (2H, m), 0.17 (2H, q, J=5.1 Hz). The reaction was cooled in an ice bath quenched with sat. ammonium chloride solution the solvent evaporated The residue was partitioned between EtOAc (300 ml) and water (100 ml adjusted to pH 4 with 1 N HCl) The organic phase was separated dried over MgSO4 filtered evaporated to give an orange oil