tert-butyl 1-(hydroxymethyl)cyclopropane-1-carboxylate

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

Procedure: Under ice cooling, to a tetrahydrofuran solution (20 ml) of 1-(tert-butoxycarbonyl)cyclopropanecarboxylic acid (1.79 g) and triethylamine (1.48 ml) was added dropwise isobutyl chlorocarbonate (1.37 ml), followed by stirring for 1 hour. Under ice cooling, the supernatant was added dropwise to a mixed solvent solution of sodium borohydride (1.09 g) in tetrahydrofuran (20 ml) and water (5 ml), and stirred for 30 minutes. A 10% aqueous citric acid solution was added, and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford tert-butyl 1-(hydroxymethyl)cyclopropanecarboxylate (1.28 g). stirred for 30 minutes extracted with ethyl acetate The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution dried over anhydrous sodium sulfate concentrated under reduced pressure

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

Procedure: Under ice cooling, to a tetrahydrofuran solution (20 ml) of 1-(tert-butoxycarbonyl)cyclopropanecarboxylic acid (1.79 g) and triethylamine (1.48 ml) was added dropwise isobutyl chlorocarbonate (1.37 ml), followed by stirring for 1 hour. Under ice cooling, the supernatant was added dropwise to a mixed solvent solution of sodium borohydride (1.09 g) in tetrahydrofuran (20 ml) and water (5 ml), and stirred for 30 minutes. A 10% aqueous citric acid solution was added, and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford tert-butyl 1-(hydroxymethyl)cyclopropanecarboxylate (1.28 g). stirred for 30 minutes extracted with ethyl acetate The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution dried over anhydrous sodium sulfate concentrated under reduced pressure

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

Procedure: Step 3 To a stirred suspension of tert-butyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (0.16 g, 0.929 mmol) and sodium hydrogen carbonate (0.312 g, 3.72 mmol) in DCM (5.57 mL) at room temperature was added Dess-Martin periodinane (0.788 g, 1.86 mmol). The mixture was stirred at room temperature for 1 hour before it was quenched by the addition of a 1:1 mixture of saturated NaHCO3 solution and saturated Na2S2O3 solution. After stirring for an additional 1 hour the phases were separated and the aqueous phase was extracted into DCM (×2). Combined organic extracts were dried (Na2SO4), filtered and concentrated giving tert-butyl 1-formylcyclopropane-1-carboxylate which was used without further purification, 0.141 g. was quenched by the addition of a 1:1 mixture of saturated NaHCO3 solution and saturated Na2S2O3 solution After stirring for an additional 1 hour the phases were separated the aqueous phase was extracted into DCM (×2) Combined organic extracts were dried (Na2SO4) filtered concentrated

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

Procedure: Step 3 To a stirred suspension of tert-butyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (0.16 g, 0.929 mmol) and sodium hydrogen carbonate (0.312 g, 3.72 mmol) in DCM (5.57 mL) at room temperature was added Dess-Martin periodinane (0.788 g, 1.86 mmol). The mixture was stirred at room temperature for 1 hour before it was quenched by the addition of a 1:1 mixture of saturated NaHCO3 solution and saturated Na2S2O3 solution. After stirring for an additional 1 hour the phases were separated and the aqueous phase was extracted into DCM (×2). Combined organic extracts were dried (Na2SO4), filtered and concentrated giving tert-butyl 1-formylcyclopropane-1-carboxylate which was used without further purification, 0.141 g. was quenched by the addition of a 1:1 mixture of saturated NaHCO3 solution and saturated Na2S2O3 solution After stirring for an additional 1 hour the phases were separated the aqueous phase was extracted into DCM (×2) Combined organic extracts were dried (Na2SO4) filtered concentrated

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

Procedure: Step 2 To a stirred solution of 1-tert-butyl 1-ethyl cyclopropane-1,1-dicarboxylate (0.5 g, 2.33 mmol) in THF (11.7 mL) at −78° C. was added lithium tri-tert-butoxyaluminum hydride solution (11.7 mL, 11.7 mmol) dropwise. The mixture was warmed to room temperature and stirred overnight before it was quenched at 0° C. by the addition of a saturated solution of potassium sodium tartrate. EtOAc was added the phases were separated and the aqueous phase was extracted into EtOAc (×2). Combined organic extracts were dried (Na2SO4), filtered and concentrated providing tert-butyl 1-(hydroxymethyl)-cyclopropane-1-carboxylate which was used without further purification, 0.438 g. was quenched at 0° C. by the addition of a saturated solution of potassium sodium tartrate EtOAc was added the phases were separated the aqueous phase was extracted into EtOAc (×2) Combined organic extracts were dried (Na2SO4) filtered concentrated

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

Procedure: Under ice cooling, to a tetrahydrofuran solution (20 ml) of 1-(tert-butoxycarbonyl)cyclopropanecarboxylic acid (1.79 g) and triethylamine (1.48 ml) was added dropwise isobutyl chlorocarbonate (1.37 ml), followed by stirring for 1 hour. Under ice cooling, the supernatant was added dropwise to a mixed solvent solution of sodium borohydride (1.09 g) in tetrahydrofuran (20 ml) and water (5 ml), and stirred for 30 minutes. A 10% aqueous citric acid solution was added, and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford tert-butyl 1-(hydroxymethyl)cyclopropanecarboxylate (1.28 g). stirred for 30 minutes extracted with ethyl acetate The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution dried over anhydrous sodium sulfate concentrated under reduced pressure