1-cyclopentylprop-2-en-1-ol

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A nitrogen-purged, 2-L, 3-neck flask containing 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile (114.14 g, 0.4715 mol) was sequentially charged (while stirring) with LiCl (39.62 g, 0.9347 mol), LiOAc (15.41 g, 0.2334 mol), DMAc (283 mL), and H2O (28.3 mL). The solution was then purged (subsurface) with N2 for 1 h. The flask was then charged with 1-cyclopentyl-prop-2-en-1-ol (73.70 g, 0.5808 mol), Et3N (6.5 mL, 0.0466 mol, 10% of the total to be added), and Pd(OAc)2 (5.2487 g, 0.0234 mol) followed by a careful purge of the headspace. The reaction was heated towards 75° C. Once the internal temperature reached 60° C. the reaction may exotherm. It took a total of 20 minutes to heat the reaction to 75° C. Fifteen minutes after the internal temp had reached 60° C., an aliquot was removed and analyzed by HPLC, showing a 3:1 ratio of starting material to product. At this point, a second addition of NEt3 (13.0 mL, 0.0933 mol, 20% of the total to be added) was added to the reaction. Each addition of TEA causes additional exotherms. Twenty minutes after the second NEt3 addition, an aliquot was removed and analyzed by HPLC, showing a 2:1 ratio of starting material to product. Ten minutes later, the third portion of NEt3 (46.0 mL, 0.3300 mol, 70% of the total to be added) was added to the reaction. Thirty-five minutes after the final NEt3 addition, an aliquot was removed and analyzed by HPLC, showing >70:1 ratio of product to starting material. The reaction was heated for 30 min more, then cooled to <30° C. over 15 min. The flask was charged with H2O (500 mL), MTBE (500 mL), DARCO (28.5 g), and celite (28.5 g). The solution stirred well for 2 hours then filtered over a cake of celite (28.5 g packed in a 4″ buchner funnel). This filtration of the bilayer through celite was slow, and the vacuum caused a significant portion of the organic solvent to boil away. The cake was washed with MTBE (250 mL followed by 125 mL). The filtrate was added to a separatory funnel with an additional portion of MTBE (200 mL), the phases mixed well, and the lower aqueous layer removed. The organic phase was extracted with H2O (200 mL) and the phases mixed well. The lower aqueous layer was removed. The organic layer was extracted with a 5% NaCl/H2O solution (200 mL). The phases were separated and the organic layer was added to a 1 L, 3-neck flask. The solution was concentrated by atmospheric distillation until the internal volume was ˜2 volumes. After cooling below reflux, an aliquot was removed and analyzed by K-F titration, showing 0.35% H2O. An additional portion of MTBE (150 mL) was added and distillation continued until the internal volume was again ˜2 volumes. After cooling below reflux, an aliquot was removed and analyzed by K—F titration, showing 0.14% H2O. The solution was cooled under nitrogen and held overnight at rt. The solution was used directly in the next reaction without further processing. 1H NMR (300 MHz, CDCl3): 1.52–1.72 (m, 9), 1.77 (s, 6), 2.73–2.92 (m, 4), 6.90–7.00 (m, 1), 7.33–7.39 (m, 1) A nitrogen-purged was sequentially charged The solution was then purged (subsurface) with N2 for 1 h a careful purge of the headspace reached 60° C. the reaction a total of 20 minutes to heat the reaction to 75° C Fifteen minutes had reached 60° C. an aliquot was removed At this point, a second addition of NEt3 (13.0 mL, 0.0933 mol, 20% of the total to be added) was added to the reaction Each addition of TEA Twenty minutes after the second NEt3 addition an aliquot was removed Ten minutes later, the third portion of NEt3 (46.0 mL, 0.3300 mol, 70% of the total to be added) was added to the reaction Thirty-five minutes after the final NEt3 addition an aliquot was removed The reaction was heated for 30 min more cooled to <30° C. over 15 min The flask was charged with H2O (500 mL), MTBE (500 mL), DARCO (28.5 g), and celite (28.5 g) then filtered over a cake of celite (28.5 g This filtration of the bilayer through celite The cake was washed with MTBE (250 mL followed by 125 mL) The filtrate was added to a separatory funnel with an additional portion of MTBE (200 mL) the phases mixed well the lower aqueous layer removed The organic phase was extracted with H2O (200 mL) the phases mixed well The lower aqueous layer was removed The organic layer was extracted with a 5% NaCl/H2O solution (200 mL) The phases were separated the organic layer was added to a 1 L, 3-neck flask The solution was concentrated by atmospheric distillation until the internal volume After cooling below reflux an aliquot was removed An additional portion of MTBE (150 mL) was added distillation After cooling below reflux an aliquot was removed The solution was cooled under nitrogen held overnight at rt The solution was used directly in the next reaction without further processing

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-chloro-5-ethoxy-4-iodo-pyridine (1.5 g, 5.3 mmol), 1-cyclopentyl-2-propen-1-ol (0.83 g, 6.61 mmol), sodium acetate (0.54 g, 6.6 mmol), palladium (II) acetate (24 mg, 0.11 mmol) in DMAC (10 mL) was heated to 90° C. under N2 for 16 hours. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated. Purification by silica gel chromatography (0% to 60% EtOAc in hexanes) gave the desired product (1.2 g, 58%). 1H NMR (300 MHz, CDCl3): δ 1.44 (t, J=7.0 Hz, 3 H), 1.55–1.87 (m, 8 H), 2.75 (m, 2 H), 2.86 (m, 3 H), 4.11 (q, J=7.0 Hz, 2 H), 7.09 (s, 1 H), 7.89 (s, 1 H). The reaction mixture was partitioned between 1N HCl and EtOAc The organic layers were washed with saturated NaHCO3, brine dried over MgSO4 concentrated Purification by silica gel chromatography (0% to 60% EtOAc in hexanes)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-chloro-5-ethoxy-4-iodo-pyridine (1.5 g, 5.3 mmol), 1-cyclopentyl-2-propen-1-ol (0.83 g, 6.61 mmol), sodium acetate (0.54 g, 6.6 mmol), palladium (II) acetate (24 mg, 0.11 mmol) in DMAC (10 mL) was heated to 90° C. under N2 for 16 hours. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated. Purification by silica gel chromatography (0% to 60% EtOAc in hexanes) gave the desired product (1.2 g, 58%). 1H NMR (300 MHz, CDCl3): δ 1.44 (t, J=7.0 Hz, 3 H), 1.55–1.87 (m, 8 H), 2.75 (m, 2 H), 2.86 (m, 3 H), 4.11 (q, J=7.0 Hz, 2 H), 7.09 (s, 1 H), 7.89 (s, 1 H). The reaction mixture was partitioned between 1N HCl and EtOAc The organic layers were washed with saturated NaHCO3, brine dried over MgSO4 concentrated Purification by silica gel chromatography (0% to 60% EtOAc in hexanes)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-2-chloro-1-methanesulfonyl-benzene (1.5 g, 5.6 mmol), 1-cyclopentyl-2-propen-1-ol (0.88 g, 6.96 mmol) and sodium acetate (0.57 g, 6.9 mmol) in DMAC (20 mL) was purged with N2 for 30 mins. Palladium (II) acetate (25 mg, 0.11 mmol) was added and the mixture was heated to 90° C. under N2 for 16 hours. The reaction mixture was partitioned between 1 N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a brown oil. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the desired product (1.2 g, 69%). 1H NMR (300 MHz, CDCl3): δ 1.56–1.85 (br m, 8 H), 2.83 (m, 3 H), 2.96 (t, J=7.5 Hz, 2 H), 3.25 (s, 3 H), 7.29 (dd, J=8.1, 1.5 Hz, 1 H), 7.39 (d, J=1.5 Hz, 1 H), 8.04 (d, J=8.1 Hz, 1 H). was purged with N2 for 30 mins The reaction mixture was partitioned between 1 N HCl and EtOAc The organic layers were washed with saturated NaHCO3, brine dried over Na2SO4 concentrated to a brown oil Purification by flash column chromatography (0% to 20% EtOAc in hexanes)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-2-chloro-1-methanesulfonyl-benzene (1.5 g, 5.6 mmol), 1-cyclopentyl-2-propen-1-ol (0.88 g, 6.96 mmol) and sodium acetate (0.57 g, 6.9 mmol) in DMAC (20 mL) was purged with N2 for 30 mins. Palladium (II) acetate (25 mg, 0.11 mmol) was added and the mixture was heated to 90° C. under N2 for 16 hours. The reaction mixture was partitioned between 1 N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a brown oil. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the desired product (1.2 g, 69%). 1H NMR (300 MHz, CDCl3): δ 1.56–1.85 (br m, 8 H), 2.83 (m, 3 H), 2.96 (t, J=7.5 Hz, 2 H), 3.25 (s, 3 H), 7.29 (dd, J=8.1, 1.5 Hz, 1 H), 7.39 (d, J=1.5 Hz, 1 H), 8.04 (d, J=8.1 Hz, 1 H). was purged with N2 for 30 mins The reaction mixture was partitioned between 1 N HCl and EtOAc The organic layers were washed with saturated NaHCO3, brine dried over Na2SO4 concentrated to a brown oil Purification by flash column chromatography (0% to 20% EtOAc in hexanes)

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of (4-bromo-2-fluorophenoxy)acetonitrile (2.5 g, 10.8 mmol), 1-Cyclopentyl-2-propen-1-ol (2.0 g, 16.2 mmol), dichlorobis (triphenylphosphine) palladium (II) (151 mg, 0.22 mmol), and sodium bicarbonate (1.08 g, 12.9 mmol) in N-methylpyrrolidinone (20 mL) was heated to 140° C. under N2 for 5 hours. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a black oil. The oil was purified by flash column chromatography (Hexanes to 10% EtOAc in hexanes) to give the desired product (2.7 g, 93%). 1H NMR (CDCl3): δ 1.52–1.83 (m, 8H), 2.75 (m, 2H), 2.85 (m, 3H), 4.80 (s, 2H), 6.92–7.06 (m, 3H). The reaction mixture was partitioned between 1N HCl and EtOAc The organic layer was washed with saturated NaHCO3, brine dried over Na2SO4 concentrated to a black oil The oil was purified by flash column chromatography (Hexanes to 10% EtOAc in hexanes)

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of (4-bromo-2-fluorophenoxy)acetonitrile (2.5 g, 10.8 mmol), 1-Cyclopentyl-2-propen-1-ol (2.0 g, 16.2 mmol), dichlorobis (triphenylphosphine) palladium (II) (151 mg, 0.22 mmol), and sodium bicarbonate (1.08 g, 12.9 mmol) in N-methylpyrrolidinone (20 mL) was heated to 140° C. under N2 for 5 hours. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a black oil. The oil was purified by flash column chromatography (Hexanes to 10% EtOAc in hexanes) to give the desired product (2.7 g, 93%). 1H NMR (CDCl3): δ 1.52–1.83 (m, 8H), 2.75 (m, 2H), 2.85 (m, 3H), 4.80 (s, 2H), 6.92–7.06 (m, 3H). The reaction mixture was partitioned between 1N HCl and EtOAc The organic layer was washed with saturated NaHCO3, brine dried over Na2SO4 concentrated to a black oil The oil was purified by flash column chromatography (Hexanes to 10% EtOAc in hexanes)

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 5-bromo-1-chloro-3-ethyl-2-methoxy-benzene (2 g, 8 mmol), 1-Cyclopentyl-2-propen-1-ol (1.3 g, 10.4 mmol), dichlorobis (triphenylphosphine) palladium (II) (110 mg, 0.16 mmol), and sodium bicarbonate (0.81 g, 9.6 mmol) in N-methylpyrrolidinone (15 mL) was heated to 140° C. under N2 for 5 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to black oil. The oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the desired product (1.9 g, 82%). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.6 Hz, 3 H), 1.53–1.81 (m, 8 H), 2.65 (q, J=7.6 Hz, 2 H), 2.74 (m, 2 H), 2.79–2.87 (m, 3 H), 3.81 (s, 3 H), 6.90 (s, 1 H), 7.03 (m, 1 H). The reaction mixture was partitioned between 1N HCl and EtOAc The organic layer was washed with saturated NaHCO3, brine dried over Na2SO4 concentrated to black oil The oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes)

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1-cyclopentyl-2-propen-1-ol (34 g, 0.266 mol), 2-fluoro-4-bromo-difluoromethyl benzene, (40 g, 0.177 mol, 1.5 equiv), and NaHCO3 (17.8 g, 0.212 mol, 1.2 equiv) in anhydrous NMP (200 mL) was heated to 140° C. for 1 h, resulting in complete conversion by TLC. The reaction mixture was poured into water and extracted with CH2Cl2. The organic layer was separated, washed with brine and dried over anhydrous Na2SO4. After the removal of the solvent, the residue was purified by column chromatography using hexanes/ethyl acetate, and the product-containing fractions combined and concentrated. The residue was fractionally distilled through a Vigreux column to give 16 g (33%) of the desired product (bp 100° C./0.2 Torr). resulting in complete conversion by TLC extracted with CH2Cl2 The organic layer was separated washed with brine dried over anhydrous Na2SO4 After the removal of the solvent the residue was purified by column chromatography concentrated The residue was fractionally distilled through a Vigreux column

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-(4-bromo-2-fluorophenyl)propan-2-ol (5.8 g, 25.0 mmol) in anhydrous NMP (63 mL) was added 1-Cyclopentyl-2-propen-1-ol (3.15 g, 25.0 mmol), NaHCO3 (4.2 g, 50 mmol) and PdCl2(PPh3)2 (350 mg, 2 mol %). The mixture was heated to 140° C. for 4 hours before it was cooled down to room temperature. The reaction was diluted with aqueous NH4Cl, extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried with Na2SO4 and evaporated to dryness. The mixture was purified by flash column chromatography (10–50% EtOAc in hexanes) to give the product (2.5 g, 36% yield). 1H NMR (300 MHz, CDCl3) δ: 1.56–1.82 (m, 8 H), 1.62 (s, 6 H), 2.74–2.78 (m, 2 H), 2.82–2.89 (m, 2 H), 6.84–6.88 (m, 1 H), 6.93–6.95 (m, 1 H), 7.40–7.44 (m, 1 H). was cooled down to room temperature extracted with EtOAc (3×50 mL) The combined organic extracts were washed with brine dried with Na2SO4 evaporated to dryness The mixture was purified by flash column chromatography (10–50% EtOAc in hexanes)

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of bromide (1.3 g, 6.02 mmol, from step 1), 1-Cyclopentyl-2-propen-1-ol (1.14 g, 9.07 mmol), dichlorobis (triphenylphosphine) palladium (II) (85 mg, 0.12 mmol), sodium bicarbonate (0.61 g, 7.25 mmol) in N-methylpyrrolidinone (12 mL) was heated to 140° C. under N2 for 5 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a brown oil. The oil was purifed by silica gel chromatography to give the title compound as a yellow oil (0.74 g, 47%). The reaction mixture was partitioned between 1N HCl and EtOAc The organic layer was washed with saturated NaHCO3, brine dried over Na2SO4 concentrated to a brown oil

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A nitrogen-purged, 2-L, 3-neck flask containing 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile (114.14 g, 0.4715 mol) was sequentially charged (while stirring) with LiCl (39.62 g, 0.9347 mol), LiOAc (15.41 g, 0.2334 mol), DMAc (283 mL), and H2O (28.3 mL). The solution was then purged (subsurface) with N2 for 1 h. The flask was then charged with 1-cyclopentyl-prop-2-en-1-ol (73.70 g, 0.5808 mol), Et3N (6.5 mL, 0.0466 mol, 10% of the total to be added), and Pd(OAc)2 (5.2487 g, 0.0234 mol) followed by a careful purge of the headspace. The reaction was heated towards 75° C. Once the internal temperature reached 60° C. the reaction may exotherm. It took a total of 20 minutes to heat the reaction to 75° C. Fifteen minutes after the internal temp had reached 60° C., an aliquot was removed and analyzed by HPLC, showing a 3:1 ratio of starting material to product. At this point, a second addition of NEt3 (13.0 mL, 0.0933 mol, 20% of the total to be added) was added to the reaction. Each addition of TEA causes additional exotherms. Twenty minutes after the second NEt3 addition, an aliquot was removed and analyzed by HPLC, showing a 2:1 ratio of starting material to product. Ten minutes later, the third portion of NEt3 (46.0 mL, 0.3300 mol, 70% of the total to be added) was added to the reaction. Thirty-five minutes after the final NEt3 addition, an aliquot was removed and analyzed by HPLC, showing >70:1 ratio of product to starting material. The reaction was heated for 30 min more, then cooled to <30° C. over 15 min. The flask was charged with H2O (500 mL), MTBE (500 mL), DARCO (28.5 g), and celite (28.5 g). The solution stirred well for 2 hours then filtered over a cake of celite (28.5 g packed in a 4″ buchner funnel). This filtration of the bilayer through celite was slow, and the vacuum caused a significant portion of the organic solvent to boil away. The cake was washed with MTBE (250 mL followed by 125 mL). The filtrate was added to a separatory funnel with an additional portion of MTBE (200 mL), the phases mixed well, and the lower aqueous layer removed. The organic phase was extracted with H2O (200 mL) and the phases mixed well. The lower aqueous layer was removed. The organic layer was extracted with a 5% NaCl/H2O solution (200 mL). The phases were separated and the organic layer was added to a 1 L, 3-neck flask. The solution was concentrated by atmospheric distillation until the internal volume was ˜2 volumes. After cooling below reflux, an aliquot was removed and analyzed by K-F titration, showing 0.35% H2O. An additional portion of MTBE (150 mL) was added and distillation continued until the internal volume was again ˜2 volumes. After cooling below reflux, an aliquot was removed and analyzed by K-F titration, showing 0.14% H2O. The solution was cooled under nitrogen and held overnight at rt. The solution was used directly in the next reaction without further processing. 1H NMR (300 MHz, CDCl3): 1.52-1.72 (m, 9), 1.77 (s, 6), 2.73-2.92 (m, 4), 6.90-7.00 (m, 1), 7.33-7.39 (m, 1) A nitrogen-purged was sequentially charged The solution was then purged (subsurface) with N2 for 1 h a careful purge of the headspace reached 60° C. the reaction a total of 20 minutes to heat the reaction to 75° C Fifteen minutes had reached 60° C. an aliquot was removed At this point, a second addition of NEt3 (13.0 mL, 0.0933 mol, 20% of the total to be added) was added to the reaction Each addition of TEA Twenty minutes after the second NEt3 addition an aliquot was removed Ten minutes later, the third portion of NEt3 (46.0 mL, 0.3300 mol, 70% of the total to be added) was added to the reaction Thirty-five minutes after the final NEt3 addition an aliquot was removed The reaction was heated for 30 min more cooled to <30° C. over 15 min The flask was charged with H2O (500 mL), MTBE (500 mL), DARCO (28.5 g), and celite (28.5 g) then filtered over a cake of celite (28.5 g This filtration of the bilayer through celite The cake was washed with MTBE (250 mL followed by 125 mL) The filtrate was added to a separatory funnel with an additional portion of MTBE (200 mL) the phases mixed well the lower aqueous layer removed The organic phase was extracted with H2O (200 mL) the phases mixed well The lower aqueous layer was removed The organic layer was extracted with a 5% NaCl/H2O solution (200 mL) The phases were separated the organic layer was added to a 1 L, 3-neck flask The solution was concentrated by atmospheric distillation until the internal volume After cooling below reflux an aliquot was removed An additional portion of MTBE (150 mL) was added distillation After cooling below reflux an aliquot was removed The solution was cooled under nitrogen held overnight at rt The solution was used directly in the next reaction without further processing