tert-butyl cyclopropanecarboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an Ar atmosphere at 0° C., BuLi (2.5M in hexanes, 80 mL, 0.20 mol) was added dropwise to a solution of iPr2NH (27.2 mL, 194 mmol, distilled from NaOH) in dry THF (200 mL) in 30 min. The reaction mixture was stirred for 30 min, cooled to −70° C. and then, t-butyl cyclopropanecarboxylate (25.0 g, 176 mmol) was added dropwise in 30 min. The resultant mixture was allowed to warm up to −35° C., cooled again to −70° C. and then 1-bromo-5-chloropentane (36 mL, 50.7 g, 273 mmol) was added dropwise in 15 min. The reaction mixture was allowed to reach −5° C., stirred for 3 h, poured into a mixture of ice (100 mL), H2O (100 mL), brine (200 mL) and aqueous HCl (2 M, 200 mL) and extracted with Et2O (2×300 mL). The combined organic layers were washed with a mixture of brine and saturated aqueous NaHCO3 (10:1, 300 mL) and dried. The remaining oil was purified by fractional distillation under reduced pressure to give 104c (31.5 g, 73%) as a colorless liquid. bp: T=67-74° C. (p=0.001 mbar). 1H NMR: 3.52 (t, J=6.6 Hz, 2H), 1.77 (quintet, J=6.8 Hz, 2H), 1.48-1.38 (m, 6H), 1.42 (s, 9H), 1.10 (dd, J=6.5 Hz, 3.8 Hz, 2H), 0.59 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR: δ 174.1, 79.9, 45.2, 34.2, 32.7, 28.2 (3×), 27.20, 27.17, 24.3, 15.4 (2×). HRMS calcd for C13H24ClO2 (MH+): 247.1465, found: 247.1465. to warm up to −35° C. cooled again to −70° C. to reach −5° C. stirred for 3 h extracted with Et2O (2×300 mL) The combined organic layers were washed with a mixture of brine and saturated aqueous NaHCO3 (10:1, 300 mL) dried The remaining oil was purified by fractional distillation under reduced pressure

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

Procedure: Compound 104a was prepared, likewise the procedure described for 103b, starting from t-butyl cyclopropanecarboxylate (Kohlrausch, K. W. F. et al. Z Elektrochem. Angew. Phys. Chem, 1937, 43, 282-285) (12.5 g, 88 mmol), 1-bromo-4-chlorobutane (13.7 mL, 117 mmol) and LDA (prepared from BuLi (2.5M in hexanes, 37 mL, 92.5 mmol) and iPr2NH (12.3 mL, 88 mmol, distilled from NaOH)) to give, after purification by fractional distillation under reduced pressure, 104a (10.73 g 52%) as a colorless oil. bp: T=57-61° C. (p=0.001 mbar). 1H NMR: δ 3.52 (t, J=6.6 Hz, 2H), 1.76 (quintet, J=6.8 Hz, 2H), 1.64-1.54 (m, 2H), 1.51-1.46 (m, 2H), 1.42 (s, 9H), 1.12 (dd, J=6.6, 3.9 Hz, 2H), 0.60 (dd, J=6.6, 3.9 Hz, 2H). 13C NMR: δ 173.9, 80.0, 45.1, 33.6, 32.9, 28.2 (3×), 25.3, 24.2, 15.4 (2×). HRMS calcd for C12H22ClO2 (MH+): 233.1308, found: 233.1308. to give after purification by fractional distillation under reduced pressure, 104a (10.73 g 52%) as a colorless oil T=57-61° C. (p=0.001 mbar)

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

Procedure: Under a N2 atmosphere at −60° C., a solution of t-butyl cyclopropanecarboxylate (80.05 g, 0.507 mol) and 1,4-dibromobutane (2193 g, 1.01 mol) in dry THF (800 mL) was added dropwise to a solution of LDA (2 M in THF/heptane/ethylbenzene, 380 mL, 0.76 mol) in 1.5 h. Stirring was continued for 5 h, during which the reaction mixture was allowed to slowly reach rt. After that, the reaction mixture was poured into saturated aqueous NH4Cl (1 L). The organic layer was separated and concentrated in vacuo to a smaller volume. The aqueous layer was extracted with Et2O (3×200 mL). The combined organic layers were washed with saturated aqueous NH4Cl (2×400 mL) and brine (400 mL) and dried. The remaining residue was purified by fractional distillation under reduced pressure to give 103b (51.4 g, 94% pure by GC, 34%) as a slightly yellow oil. bp: T=93-96° C. (p=0.075-0.087 Torr). 1H NMR: δ 3.40 (t, J=6.8 Hz, 2H), 1.85 (quintet, J=7.1 Hz, 2H), 1.65-1.46 (m, 4H), 1.43 (s, 9H), 1.12 (q, J=3.5 Hz, 2H), 0.60 (q, J=3.5 Hz, 2H). 13C NMR: δ 174.0, 79.8, 33.6, 33.2, 32.8, 27.9 (3×), 26.3, 23.9, 15.1 (2×). HRMS calcd for C12H21BrO2 (MH+): 277.0803, found: 277.0807. was allowed to slowly reach rt The organic layer was separated concentrated in vacuo to a smaller volume The aqueous layer was extracted with Et2O (3×200 mL) The combined organic layers were washed with saturated aqueous NH4Cl (2×400 mL) and brine (400 mL) dried The remaining residue was purified by fractional distillation under reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9.9 ml (70.32 mmol) of diisopropylamine were initially charged in 35 ml of THF, 28.1 ml (70.32 mmol) of a 2.5 M solution of n-butyllithium in n-hexane were added at −40° C. and the mixture was stirred for 30 min. The reaction mixture was then cooled to −78° C., and a solution of 10 g (70.32 mmol) of tert-butyl cyclopropanecarboxylate in 5 ml of THF was added dropwise. The mixture was stirred at −78° C. for 4 h, and a solution of 5.8 ml (66.81 mmol) of allyl bromide in 5 ml of THF was then added dropwise. The reaction mixture was slowly warmed to RT overnight, and aqueous ammonium chloride solution was then added carefully. The mixture was extracted three times with methyl tert-butyl ether. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. This gave 10.7 g (83.5% of theory) of the target compound. The mixture was stirred at −78° C. for 4 h The reaction mixture was slowly warmed to RT overnight The mixture was extracted three times with methyl tert-butyl ether The combined organic phases were dried over sodium sulfate concentrated under reduced pressure

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

Procedure: 21.2 ml (52.7 mmol) of a 2.5 M solution of n-butyllithium in n-hexane were added dropwise to a solution, cooled to −78° C., of 7.4 ml (52.7 mmol) of diisopropylamine in 20 ml of abs. THF. During the addition, the reaction temperature was kept below −60° C. After 30 min of stirring at −60° C. to −70° C., this solution was added dropwise to a solution, cooled to −78° C., of 5.0 g (35.2 mmol) of tert-butyl cyclopropanecarboxylate and 15.2 g (70.3 mmol) of 1,4-dibromobutane in 20 ml of abs. THF. After the end of the addition, cooling was removed and the mixture was slowly warmed to RT with stirring. After a further 5 h of stirring at RT, the reaction mixture was added to saturated aqueous ammonium chloride solution. The mixture was extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 50:1). This gave 4.62 g (44.6% of theory) of the target compound. During the addition was kept below −60° C this solution was added dropwise to a solution After the end of the addition cooling was removed with stirring After a further 5 h of stirring at RT the reaction mixture was added to saturated aqueous ammonium chloride solution The mixture was extracted three times with dichloromethane The combined organic phases were dried over magnesium sulfate concentrated under reduced pressure The product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 50:1)

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

Procedure: 50.99 g (454.4 mmol) of potassium tert-butoxide were dissolved in 454 ml of abs. THF and cooled to 0° C. The solution was stirred vigorously, and 50 g (478.3 mmol) of cyclopropanecarbonyl chloride were added dropwise such that the reaction temperature did not exceed 50° C. (cooling required). After the addition has ended, the resultant suspension was stirred for another 30 min. After cooling, the reaction mixture was, under reduced pressure, concentrated to about one third of the original volume and then added to 2 liters of saturated aqueous ammonium chloride solution. The pH was adjusted to 8 by addition of saturated sodium bicarbonate solution and the mixture was then extracted three times with diethyl ether. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure without heating (cold water bath). The residue was distilled at a bath temperature of about 85° C. and 42 mbar. This gave 43.1 g (63.2% of theory) of the target compound as a clear liquid. did not exceed 50° C. (cooling required) After the addition After cooling concentrated to about one third of the original volume added to 2 liters of saturated aqueous ammonium chloride solution The pH was adjusted to 8 by addition of saturated sodium bicarbonate solution the mixture was then extracted three times with diethyl ether The combined organic phases were dried over magnesium sulfate concentrated under reduced pressure without heating (cold water bath) The residue was distilled at a bath temperature of about 85° C. and 42 mbar

Conditions: temp:-75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 15.9 ml (1.15 eq.) diisopropylamine were dissolved in 65 ml THF and cooled to ca −10° C. 65 ml (1.08 eq.) 1.6 M BuLi solution in hexane were added over 25 min, maintaining the temperature between −10° C. and 0° C. After 50 min at ca. −5° C., the reaction mixture was cooled to −75° C. A solution of 15 g (96.7 mmol, 1 eq., 92% w/w purity) cyclopropanecarboxylic acid tert-butyl ester in 20 ml THF was added over 15 min keeping the temperature between −75° C. and −70° C. The reaction mixture was stirred 5 h at −75° C. (milky reaction mixture obtained after 2.5 h). A solution of 12.87 g (1.10 eq.) allyl bromide was added over 20 min keeping the temperature between −75° C. and −60° C. The reaction mixture was stirred at −78° C. for 1 h, warmed to RT and stirred overnight. The reaction mixture was cooled to 0° C. 100 ml sat. aq. ammonium chloride solution were added followed by 30 ml water providing a clear biphasic mixture. The mixture was extracted 3 times with 50 ml TBME. The organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure (40° C./20 mbar) to afford 16.44 g of crude product. The crude product was distilled (2 mbar; ca 40° C. distillation head temperature) to provide the title compound in ca 65% yield. cooled to ca −10° C maintaining the temperature between −10° C. and 0° C the temperature between −75° C. and −70° C (milky reaction mixture obtained after 2.5 h) the temperature between −75° C. and −60° C The reaction mixture was stirred at −78° C. for 1 h warmed to RT stirred overnight The reaction mixture was cooled to 0° C The mixture was extracted 3 times with 50 ml TBME dried over sodium sulfate filtered concentrated under reduced pressure (40° C./20 mbar) to afford 16.44 g of crude product The crude product was distilled (2 mbar; ca 40° C. distillation head temperature)