cyclopropanol

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: Alcohol 14 (2.30 g; 19.8 mmol) was dissolved in dry DMF (96 ml) and pyridinium dichromate (PDC) (3.5 eq., 26 g) was added in one portion. The reaction mixture was stirred overnight at room temperature and then poured into 300 ml of water and extracted with (4×80 ml) of ether. The organic layers were combined, washed with brine and concentrated under reduced pressure. The residue was then dissolved in chloroform (30 ml) and the solution was extracted two times with 25 ml of a 10% aqueous solution of NaOH. Combined aqueous phases were then extracted with chloroform (2×25 ml) and acidified with 10% aqueous HCl followed by an extraction with ether (4×50 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to give the desired product (+,−)-cis-2-ethylcyclopropylacetic acid (15) as a colorless oil (1.7 g, 66%) Characterization: Nmr (1H, 13C), ir, ms extracted with (4×80 ml) of ether washed with brine concentrated under reduced pressure The residue was then dissolved in chloroform (30 ml) the solution was extracted two times with 25 ml of a 10% aqueous solution of NaOH Combined aqueous phases were then extracted with chloroform (2×25 ml) followed by an extraction with ether (4×50 ml) The combined organic phases were dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: The above unsaturated alcohol 8 (930 mg, 4.55 mmol) was converted to the cyclopropyl alcohol as described in Example 1 to give 900 mg of [1-(3,4-diethyl benzene)-cyclopropyl]-ethanol (9) as a pale yellow oil in 91% yield. The above cyclopropyl alcohol (900 mg, 4.12 mmol) was oxidized as described in Example 1 to give 520 mg of 1-(3,4-diethyl benzene) cyclopropaneacetaldehyde (10) as a clear oil in 58% yield. 1H NMR (400 MHz, CDCl3) δ9.77 (t, J=2.5 Hz, 1H, aldehyde), 7.08 (m, 3H, aromatic), 2.62 (m, 4H, aliphatic 2CH2), 2.59 (d, J=2.8 Hz, 2H, aliphatic CH2), 1.20 (m, 6H, aliphatic, 2CH3), 1.02 (dd, J=6.3, 4.9 Hz, 2H, aliphatic CH2), 0.87 (dd, J=6.0, 4.4 Hz, 2H, aliphatic CH2).

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

Procedure: The above unsaturated alcohol 8 (70 mg, 0.34 mmol) was converted to the cyclopropyl alcohol as described in Example 1 to give 29 mg of [1-(3,5-di-t-butyl phenyl)-cyclopropyl]-ethanol (9) as a pale yellow oil in 40% yield. 1H NMR (400 MHz, CDCl3) δ7.25 (d, J=1.8 Hz, 1H, aromatic), 7.15 (d, J=1.8 Hz, 2H, aromatic), 3.65 (q, J=12.5, 6.7 Hz, 2H, aliphatic CH2), 1.83 (t, J=6.9 Hz, 2H, aliphatic CH2), 1.31 (s, 18H, aliphatic 6CH2), 1.18 (t, J=5.6 Hz, 1H, alcohol), 0.84 (dd, J=9.9, 4.5 Hz, 2H, aliphatic CH2), 0.71 (dd, J=10.0, 3.9 Hz, 2H, aliphatic CH2). The above cyclopropyl alcohol (29 mg, 0.13 mmol) was oxidized as described in Example 1 to give 29 mg of 1-(3,5-di-t-butyl phenyl)-cyclopropaneacetaldehyde (10) as a clear oil in 100% yield. 1H NMR (400 MHz, CDCl3) δ9.79 (t, J=2.6 Hz, 1H, aldehyde), 7.25 (s, 1H, aromatic), 7.12 (d, J=1.3 Hz, 2H, aromatic), 2.59 (d, J=2.5 Hz, 2H, aliphatic CH2), 1.31 (s, 18H, aliphatic 6CH2), 1.04 (dd, J=10.7, 5.2 Hz, 2H, aliphatic CH2), 0.88 (dd, J=10.6, 5.5 Hz, 2H, aliphatic CH2).

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

Procedure: The above unsaturated alcohol 8 (70 mg, 0.34 mmol) was converted to the cyclopropyl alcohol as described in Example 1 to give 29 mg of [1-(3,5-di-t-butyl phenyl)-cyclopropyl]-ethanol (9) as a pale yellow oil in 40% yield. 1H NMR (400 MHz, CDCl3) δ7.25 (d, J=1.8 Hz, 1H, aromatic), 7.15 (d, J=1.8 Hz, 2H, aromatic), 3.65 (q, J=12.5, 6.7 Hz, 2H, aliphatic CH2), 1.83 (t, J=6.9 Hz, 2H, aliphatic CH2), 1.31 (s, 18H, aliphatic 6CH2), 1.18 (t, J=5.6 Hz, 1H, alcohol), 0.84 (dd, J=9.9, 4.5 Hz, 2H, aliphatic CH2), 0.71 (dd, J=10.0, 3.9 Hz, 2H, aliphatic CH2). The above cyclopropyl alcohol (29 mg, 0.13 mmol) was oxidized as described in Example 1 to give 29 mg of 1-(3,5-di-t-butyl phenyl)-cyclopropaneacetaldehyde (10) as a clear oil in 100% yield. 1H NMR (400 MHz, CDCl3) δ9.79 (t, J=2.6 Hz, 1H, aldehyde), 7.25 (s, 1H, aromatic), 7.12 (d, J=1.3 Hz, 2H, aromatic), 2.59 (d, J=2.5 Hz, 2H, aliphatic CH2), 1.31 (s, 18H, aliphatic 6CH2), 1.04 (dd, J=10.7, 5.2 Hz, 2H, aliphatic CH2), 0.88 (dd, J=10.6, 5.5 Hz, 2H, aliphatic CH2).

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

Procedure: In a 15 mL round-bottom flask (oven dried and under argon) was added anhydrous dichloroethane (6 mL) and diethyl zinc (0.34 mL, 3.3 mmol). The mixture was cooled to 0° C. and chloroiodomethane (0.43 mL, 6.0 mmol) was slowly added via syringe. The reaction mixture was stirred at 0° C. for 5 min. and a solution of the above homoallylic alcohol (2: R2 =H; 0.41 g, 1.57 mmol) in dichloroethane (2 mL) was slowly added. The mixture was allowed to warm to room temperature and stirred for one hour. The reaction mixture was then quenched with saturated NH4Cl and the aqueous phase was extracted with EtOAc (2×15 mL). The organic solution was washed with saturated NaCl, dried (Na2SO4) and concentrated in vacuo. Crude [1-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)-cyclopropyl]ethanol (3: R2 =H) was recovered in 63% yield (0.27 g) and carried directly on to the next step. To a solution of the above cyclopropyl alcohol (3: R2 =H; 0.25 g, 0.92 mmol) in 5 mL CH2Cl2 at room temperature was added PCC (0.4 g, 1.84 mmol). The reaction mixture was stirred for 3 hours and then filtered and rinsed with 15% EtOAc/hexane through a pad of celite/silica gel. Solvent was removed in vacuo to provide 230 mg of 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-cyclopropaneacetaldehyde (4: R2 =H) as a white solid in 93% yield. 1H NMR (400 MHz, CDCl3) δ9.78 (t, J=2.5 Hz, 1H, aldehyde), 7.20 (d, J=8.1 Hz, 1H, aromatic), 7.18 (d, J=2.0 Hz, 1H, aromatic), 6.99 (dd, J=8.1 and 2.1 Hz, 1H, aromatic), 2.57 (d, J=2.6 Hz, 2H, CH2), 1.66 (s, 4H, 2CH2), 1.26 (s, 6H, 2CH3), 1.25 (s, 6H, 2CH3), 1.02 (dd, J=6.4, 4.7 Hz, 2H, CH2), 0.87 (dd, J=6.1,4.6 Hz, 2H, CH2). In a 15 mL round-bottom flask (oven dried and under argon) to warm to room temperature stirred for one hour The reaction mixture was then quenched with saturated NH4Cl the aqueous phase was extracted with EtOAc (2×15 mL) The organic solution was washed with saturated NaCl dried (Na2SO4) concentrated in vacuo Crude [1-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)-cyclopropyl]ethanol (3: R2 =H) was recovered in 63% yield (0.27 g) The reaction mixture was stirred for 3 hours filtered rinsed with 15% EtOAc/hexane through a pad of celite/silica gel Solvent was removed in vacuo

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

Procedure: To a 2-neck 15-mL flask equipped with a temperature probe, N2 inlet, and septum was added 1 g of 4 (7.28 mmol, 1.0 equiv) and 3.0 mL THF. The solution was cooled to an internal temperature of 0° C. with an ice bath. To this solution was added 2.95 mL of 33 wt % n-Hexyllithium (7.28 mmol, 1.0 equiv) slowly via syringe pump over 1 hour. Internal temperature rose to 6.8° C. and solution became yellow. In a separate 3-neck 100-mL flask equipped with a temperature probe, N2 inlet, and septum 0.82 g of lithium acetylide-ethylenediamine complex (8.01 mmol, 1.1 equiv) was slurried in 5.0 mL of DMPU at room temperature. To this room temperature slurry, the cold solution of the deprotonated cyclopropanol was transferred via cannula over 5 min. After the addition, the brown mixture was heated to an internal temperature of 52° C. with a heating mantle for 3 hours or until greater than 98% conversion was observed by GC. The brown mixture was cooled with an ice bath to 3° C. and then the ice bath was removed to prevent freezing. To this was slowly added 17.5 mL of 0.5 N HCl and an ice bath was applied to maintain an internal temperature below 21° C. The mixture was then diluted with 10 mL MTBE and 5 mL of water before transfer to a separatory funnel and removal of the aqueous layer. The aqueous layer was extracted once with 15 mL MTBE and then the combined organic layers were washed with 20 mL water followed by 20 mL brine. The organic layer was then concentrated in vacuo to afford 1.27 g of rac-5 as a yellow oil (72 wt %). 1H NMR (400 MHz, CDCl3) δ 3.24 (dt, 1H, J=2.6, 5.3 Hz), 2.25 (dt, 2H, J=2.6, 7.6 Hz), 1.96 (t, 1H, J=2.6 Hz), 1.92 (s, 1H, OH), 1.64 (pent, 2H, J=7.3 Hz), 1.38 (sext, 1H, J=6.9 Hz), 1.24 (sext, 1H, J=6.9 Hz), 0.93 (m, 1H), 0.72 (m, 1H), 0.35 (q, 1H, J=6.0 Hz); 13C NMR (100 MHz, CDCl3) δ 84.49, 68.37, 52.45, 30.50, 27.74, 20.17, 18.01, 14.25; GC: HP1 (30 m×0.32 mm; 0.25 μm), 25 psi, 200° C. front inlet. 5 min @ 50° C., ramp 25° C./min to 250° C. then hold for 4 min, tr(4)=7.15 min, tr(rac-5)=6.72 min. rose to 6.8° C. After the addition the brown mixture was heated to an internal temperature of 52° C. with a heating mantle for 3 hours or until greater than 98% conversion The brown mixture was cooled with an ice bath to 3° C. the ice bath was removed to maintain an internal temperature below 21° C The mixture was then diluted with 10 mL MTBE and 5 mL of water before transfer to a separatory funnel removal of the aqueous layer The aqueous layer was extracted once with 15 mL MTBE the combined organic layers were washed with 20 mL water The organic layer was then concentrated in vacuo to afford 1.27 g of rac-5 as a yellow oil (72 wt %) HP1 (30 m×0.32 mm; 0.25 μm), 25 psi, 200° C. front inlet 5 min @ 50° C. tr(4)=7.15 min, tr(rac-5)=6.72 min.

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

Procedure: To a 2-neck 15-mL flask equipped with a temperature probe, N2 inlet, and septum was added 1 g of 4 (7.28 mmol, 1.0 equiv) and 3.0 mL THF. The solution was cooled to an internal temperature of 0° C. with an ice bath. To this solution was added 2.95 mL of 33 wt % n-Hexyllithium (7.28 mmol, 1.0 equiv) slowly via syringe pump over 1 hour. Internal temperature rose to 6.8° C. and solution became yellow. In a separate 3-neck 100-mL flask equipped with a temperature probe, N2 inlet, and septum 0.82 g of lithium acetylide-ethylenediamine complex (8.01 mmol, 1.1 equiv) was slurried in 5.0 mL of DMPU at room temperature. To this room temperature slurry, the cold solution of the deprotonated cyclopropanol was transferred via cannula over 5 min. After the addition, the brown mixture was heated to an internal temperature of 52° C. with a heating mantle for 3 hours or until greater than 98% conversion was observed by GC. The brown mixture was cooled with an ice bath to 3° C. and then the ice bath was removed to prevent freezing. To this was slowly added 17.5 mL of 0.5 N HCl and an ice bath was applied to maintain an internal temperature below 21° C. The mixture was then diluted with 10 mL MTBE and 5 mL of water before transfer to a separatory funnel and removal of the aqueous layer. The aqueous layer was extracted once with 15 mL MTBE and then the combined organic layers were washed with 20 mL water followed by 20 mL brine. The organic layer was then concentrated in vacuo to afford 1.27 g of rac-5 as a yellow oil (72 wt %). 1H NMR (400 MHz, CDCl3) δ 3.24 (dt, 1H, J=2.6, 5.3 Hz), 2.25 (dt, 2H, J=2.6, 7.6 Hz), 1.96 (t, 1H, J=2.6 Hz), 1.92 (s, 1H, OH), 1.64 (pent, 2H, J=7.3 Hz), 1.38 (sext, 1H, J=6.9 Hz), 1.24 (sext, 1H, J=6.9 Hz), 0.93 (m, 1H), 0.72 (m, 1H), 0.35 (q, 1H, J=6.0 Hz); 13C NMR (100 MHz, CDCl3) δ 84.49, 68.37, 52.45, 30.50, 27.74, 20.17, 18.01, 14.25; GC: HP1 (30 m×0.32 mm; 0.25 μm), 25 psi, 200° C. front inlet. 5 min @ 50° C., ramp 25° C./min to 250° C. then hold for 4 min, tr(4)=7.15 min, tr(rac-5)=6.72 min. rose to 6.8° C. After the addition the brown mixture was heated to an internal temperature of 52° C. with a heating mantle for 3 hours or until greater than 98% conversion The brown mixture was cooled with an ice bath to 3° C. the ice bath was removed to maintain an internal temperature below 21° C The mixture was then diluted with 10 mL MTBE and 5 mL of water before transfer to a separatory funnel removal of the aqueous layer The aqueous layer was extracted once with 15 mL MTBE the combined organic layers were washed with 20 mL water The organic layer was then concentrated in vacuo to afford 1.27 g of rac-5 as a yellow oil (72 wt %) HP1 (30 m×0.32 mm; 0.25 μm), 25 psi, 200° C. front inlet 5 min @ 50° C. tr(4)=7.15 min, tr(rac-5)=6.72 min.

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

Procedure: Cyclopropanol (542 μL, 8.69 mmol) is added to a suspension of methyl 5-chloropyrazine-2-carboxylate (1.0 g, 5.79 mmol) and potassium carbonate (1.60 g, 11.59 mmol) in dimethylformamide (11.6 mL). The reaction mixture is stirred for 15 hours at room temperature then for 24 hours at 50° C. The reaction is cooled to ambient temperature, diluted with water, and extracted with ethyl acetate (3 times). The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. The crude product is purified by silica gel flash chromatography, eluting with ethyl acetate/hexane (0:100) to ethyl acetate/hexane (35:65) to give the title compound (610 mg, 54%). ES/MS (m/e): 195.0 (M+1). for 24 hours at 50° C The reaction is cooled to ambient temperature extracted with ethyl acetate (3 times) dried over sodium sulfate filtered concentrated under reduced pressure to give a brown oil The crude product is purified by silica gel flash chromatography eluting with ethyl acetate/hexane (0:100) to ethyl acetate/hexane (35:65)

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

Procedure: Cyclopropanol (542 μL, 8.69 mmol) is added to a suspension of methyl 5-chloropyrazine-2-carboxylate (1.0 g, 5.79 mmol) and potassium carbonate (1.60 g, 11.59 mmol) in dimethylformamide (11.6 mL). The reaction mixture is stirred for 15 hours at room temperature then for 24 hours at 50° C. The reaction is cooled to ambient temperature, diluted with water, and extracted with ethyl acetate (3 times). The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. The crude product is purified by silica gel flash chromatography, eluting with ethyl acetate/hexane (0:100) to ethyl acetate/hexane (35:65) to give the title compound (610 mg, 54%). ES/MS (m/e): 195.0 (M+1). for 24 hours at 50° C The reaction is cooled to ambient temperature extracted with ethyl acetate (3 times) dried over sodium sulfate filtered concentrated under reduced pressure to give a brown oil The crude product is purified by silica gel flash chromatography eluting with ethyl acetate/hexane (0:100) to ethyl acetate/hexane (35:65)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-(2,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), cyclopropanol (2 equiv), sodium tert-butoxide (2 equiv), 1,4-dioxane (0.03 M) were combined and stirred at 25° C. The reaction mixture was loaded directly onto a silica gel column and purified using flash chromatography (0-50% ethyl acetate in hexane) column, to give the title compound (80% yield) as clear oil. MS (ESI) m/z 471.5 [M+1]+. purified