3-methoxycyclohexan-1-amine

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

Procedure: To a stirred solution of 3-methoxycyclohexanamine (0.200 g, 1.5 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.144 mL, 1.9 mmol). The reaction mixture was stirred at room temperature for 16 hrs and then concentrated. The mixture was diluted with ethyl acetate and washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a brown oil (0.140 g, 44%). The material was used without further purification. concentrated The mixture was diluted with ethyl acetate washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride dried (anhydrous sodium sulfate) filtered concentrated

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

Procedure: A mixture of 3-methoxycyclohexanecarboxylic acid, mixture of cis and trans 97% (1.50 g, 9.5 mmol), diphenylphosphoryl azide (2.043 mL, 9.5 mmol), and triethylamine (1.582 mL, 11.4 mmol) in anhydrous toluene (65 mL) was heated at reflux for 3 hrs. The mixture was cooled to 0° C., sodium trimethylsilanolate (18.964 mL of a 1 M solution in tetrahydrofuran, 19.0 mmol) was added, and the mixture stirred for 30 mins at room temperature. The reaction was quenched with 5% aqueous citric acid (100 mL), stirred, concentrated to approximately half volume under reduced pressure, washed with diethyl ether (2×), adjusted to basic pH with sodium hydroxide, and extracted with methylene chloride (3×). The combined organic layers were washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (5-12% methanol/methylene chloride) to give partially purified material. The residue was dissolved in methylene chloride and extracted with 1 N aqueous hydrochloric acid (3×). The combined aqueous layers were adjusted to basic pH with 15% aqueous sodium hydroxide and extracted with methylene chloride (3×). The combined organic fractions were dried (anhydrous sodium sulfate), filtered, concentrated, suspended in hexanes/methylene chloride, and filtered. Concentration of the organics gave a yellow liquid (0.272 g). 1H NMR (300 MHz, CDCl3) (mixture of diastereomers) δ 3.52 (m, 1H), 3.28 (s, 3H), 2.99 (m, 1H), 1.95-1.00 (m, 10H). was heated at reflux for 3 hrs The reaction was quenched with 5% aqueous citric acid (100 mL) stirred concentrated to approximately half volume under reduced pressure washed with diethyl ether (2×) extracted with methylene chloride (3×) The combined organic layers were washed with saturated aqueous sodium chloride dried (anhydrous sodium sulfate) filtered concentrated in vacuo The crude material was purified by silica gel chromatography (5-12% methanol/methylene chloride) to give partially purified material extracted with 1 N aqueous hydrochloric acid (3×) extracted with methylene chloride (3×) The combined organic fractions were dried (anhydrous sodium sulfate) filtered concentrated filtered