N-methoxy-N,2-dimethylpropanamide

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-(t-Boc)-4-Methoxy-2-methylaniline (1.00 g, 4.2 mmol) was dissolved in anhydrous THF (15 mL) under an atmosphere of Argon (g). The solution was cooled to −40° C. and sec-butyllithium (1.4 M in cyclohexane, 6.61 mL, 0.59 g) was added slowly as to maintain an internal temperature of <−25° C. After reaching 1 equivalent of sec-butyllithium (˜3.3 mL) the reaction mixture turned bright yellow signifying the deprotonation of the amide nitrogen. Upon completion of the addition of sec-butyllithium, the reaction mixture was then cooled to −50° C. over 10 minutes and a solution of N-Methoxy-N-methylisobutanamide (0.67 g, 4.63 mmol) in THF (3 mL) was added. The reaction mixture was allowed to warm to −10° C. over 30 minutes while stirring. Upon completion, the mixture was partitioned between Et2O (50 mL) and 0.5 N HCl (50 mL). The aqueous layer was extracted once more with Et2O (25 mL). The combined ether layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo providing a yellowish-brown oil. The above reaction was performed a second time immediately after the first reaction was complete. Therefore, the total amount of starting material (N-(t-Boc)-4-methoxy-2-methylaniline, 2.0 g, 8.4 mmol) was doubled. The crude reaction mixture (from 2.0 g) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (3 mL) was added to the solution and stirred at room temperature for 48 hours. When the reaction reached completion, DCM (50 mL) was added and the reaction mixture was transferred to a separatory funnel and washed with saturated NaHCO3 (50 mL) followed by brine (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo giving a deep yellow oil which was purified by column chromatography (0-20% ethyl acetate/hexanes) to yield an amber oil (1.21 g, 71%): TLC Rf 0.53 in 20% EtOAc/hexanes. 1H NMR (600 MHz, CDCl3) δ 7.73 (s, 1H), 7.18-7.17 (d, 1H, J=8.7 Hz), 7.01 (d, 1H, J=2.4 Hz), 6.78-6.76 (dd, 1H J1=8.7 Hz, J2=2.4 Hz), 6.16 (s, 1H), 3.84 (s, 3H), 2.60-2.58 (d, 2H, J=7.14 Hz), 1.97-1.95 (m, 1H), 0.97-0.96 (d, 6H, J=6.6 Hz). 13C NMR (150 MHz, CDCl3) δ 154.1, 139.8, 130.9, 129.3, 110.88, 110.72, 101.9, 100.4, 55.9, 37.8, 29.0, 22.5. Elemental analysis calculated for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 77.07; H, 8.50; N, 6.81. to maintain an internal temperature of <−25° C the reaction mixture was then cooled to −50° C. over 10 minutes to warm to −10° C. over 30 minutes Upon completion, the mixture was partitioned between Et2O (50 mL) and 0.5 N HCl (50 mL) The aqueous layer was extracted once more with Et2O (25 mL) The combined ether layers were washed with brine (50 mL) dried over anhydrous Na2SO4 concentrated in vacuo providing a yellowish-brown oil The above reaction immediately after the first reaction The crude reaction mixture (from 2.0 g) stirred at room temperature for 48 hours was added the reaction mixture was transferred to a separatory funnel washed with saturated NaHCO3 (50 mL) The organic layer was dried over Na2SO4 concentrated in vacuo giving a deep yellow oil which was purified by column chromatography (0-20% ethyl acetate/hexanes)

反応条件: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following the procedure described by R. D. Clark et al. in Synthesis, 871 (1991), (4-chloro-2-methyl-phenyl)-carbamic acid tert-butyl ester (2.18 g, 9 mmole) was dissolved in anhydrous THF (30 ml) and cooled to −40° C. and s-BuLi (14.56 ml 1.3N in cyclohexane) was added slowly at such a rate to maintain the temperature below −25° C. The bright yellow solution was cooled to −50° C. and a solution of N-methoxy-N-methyl-isobutyramide (1.24 g, 9.5 mmole) in THF (5 ml) was added. The mixture was allowed to warm up to −10° C. over a 20 m period during which time the solution turned nearly colorless. Ether (50 ml) was added and the solution was poured into 1% aqueous HCl (50 ml). The aqueous layer was extracted a second time with ether (30 ml) and the combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and evaporated to dryness to afford the crude product which was purified by column chromatography (silica gel) eluting with ethyl acetate:hexane (4:1) to afford pure [4-chloro-2-(3-methyl-2-oxo-butyl)-phenyl]-carbamic acid tert-butyl ester. to maintain the temperature below −25° C The bright yellow solution was cooled to −50° C. to warm up to −10° C. over a 20 m period during which time the solution The aqueous layer was extracted a second time with ether (30 ml) the combined organic extracts were washed with water and brine dried over sodium sulfate filtered evaporated to dryness to afford the crude product which was purified by column chromatography (silica gel) eluting with ethyl acetate:hexane (4:1)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following the procedure described by R. D. Clark et al. in Synthesis, 871 (1991), (4-chloro-2-methyl-phenyl)-carbamic acid tert-butyl ester (2.18 g, 9 mmole) was dissolved in anhydrous THF (30 ml) and cooled to −40° C. and s-BuLi (14.56 ml 1.3N in cyclohexane) was added slowly at such a rate to maintain the temperature below −25° C. The bright yellow solution was cooled to −50° C. and a solution of N-methoxy-N-methyl-isobutyramide (1.24 g, 9.5 mmole) in THF (5 ml) was added. The mixture was allowed to warm up to −10° C. over a 20 m period during which time the solution turned nearly colorless. Ether (50 ml) was added and the solution was poured into 1% aqueous HCl (50 ml). The aqueous layer was extracted a second time with ether (30 ml) and the combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and evaporated to dryness to afford the crude product which was purified by column chromatography (silica gel) eluting with ethyl acetate:hexane (4:1) to afford pure [4-chloro-2-(3-methyl-2-oxo-butyl)-phenyl]-carbamic acid tert-butyl ester. to maintain the temperature below −25° C The bright yellow solution was cooled to −50° C. to warm up to −10° C. over a 20 m period during which time the solution The aqueous layer was extracted a second time with ether (30 ml) the combined organic extracts were washed with water and brine dried over sodium sulfate filtered evaporated to dryness to afford the crude product which was purified by column chromatography (silica gel) eluting with ethyl acetate:hexane (4:1)

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

実験手順: A solution of N-(pyridin-2-yl)pivalamide (3.20 g, 18.0 mmol), n-BuLi (15.00 mL, 2.1 eq.) and N-methoxy-N-methylisobutyramide (2.60 g, 1.1 eq) were reacted as outlined in Scheme 1 to give 3.10 g (69%) of N-(3-isobutyrylpyridin-2-yl)pivalamide. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.21 (d, J=7.03 Hz, 6 H) 1.35 (s, 9 H) 3.55 (dt, J=13.70, 6.78 Hz, 1 H) 7.08 (dd, J=7.91, 4.69 Hz, 1 H) 8.19 (dd, J=8.20, 2.05 Hz, 1 H) 8.63 (dd, J=4.83, 1.90 Hz, 1 H) 11.51 (br. s., 1 H).

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

実験手順: A solution of N-(pyridin-2-yl)pivalamide (3.20 g, 18.0 mmol), n-BuLi (15.00 mL, 2.1 eq.) and N-methoxy-N-methylisobutyramide (2.60 g, 1.1 eq) were reacted as outlined in Scheme 1 to give 3.10 g (69%) of N-(3-isobutyrylpyridin-2-yl)pivalamide. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.21 (d, J=7.03 Hz, 6 H) 1.35 (s, 9 H) 3.55 (dt, J=13.70, 6.78 Hz, 1 H) 7.08 (dd, J=7.91, 4.69 Hz, 1 H) 8.19 (dd, J=8.20, 2.05 Hz, 1 H) 8.63 (dd, J=4.83, 1.90 Hz, 1 H) 11.51 (br. s., 1 H).

反応条件: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-(t-Boc)-4-Methoxy-2-methylaniline (1.00 g, 4.2 mmol) was dissolved in anhydrous THF (15 mL) under an atmosphere of Argon (g). The solution was cooled to −40° C. and sec-butyllithium (1.4 M in cyclohexane, 6.61 mL, 0.59 g) was added slowly as to maintain an internal temperature of <−25° C. After reaching 1 equivalent of sec-butyllithium (˜3.3 mL) the reaction mixture turned bright yellow signifying the deprotonation of the amide nitrogen. Upon completion of the addition of sec-butyllithium, the reaction mixture was then cooled to −50° C. over 10 minutes and a solution of N-Methoxy-N-methylisobutanamide (0.67 g, 4.63 mmol) in THF (3 mL) was added. The reaction mixture was allowed to warm to −10° C. over 30 minutes while stirring. Upon completion, the mixture was partitioned between Et2O (50 mL) and 0.5 N HCl (50 mL). The aqueous layer was extracted once more with Et2O (25 mL). The combined ether layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo providing a yellowish-brown oil. The above reaction was performed a second time immediately after the first reaction was complete. Therefore, the total amount of starting material (N-(t-Boc)-4-methoxy-2-methylaniline, 2.0 g, 8.4 mmol) was doubled. The crude reaction mixture (from 2.0 g) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (3 mL) was added to the solution and stirred at room temperature for 48 hours. When the reaction reached completion, DCM (50 mL) was added and the reaction mixture was transferred to a separatory funnel and washed with saturated NaHCO3 (50 mL) followed by brine (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo giving a deep yellow oil which was purified by column chromatography (0-20% ethyl acetate/hexanes) to yield an amber oil (1.21 g, 71%): TLC Rf 0.53 in 20% EtOAc/hexanes. 1H NMR (600 MHz, CDCl3) δ 7.73 (s, 1H), 7.18-7.17 (d, 1H, J=8.7 Hz), 7.01 (d, 1H, J=2.4 Hz), 6.78-6.76 (dd, 1H J1=8.7 Hz, J2=2.4 Hz), 6.16 (s, 1H), 3.84 (s, 3H), 2.60-2.58 (d, 2H, J=7.14 Hz), 1.97-1.95 (m, 1H), 0.97-0.96 (d, 6H, J=6.6 Hz). 13C NMR (150 MHz, CDCl3) δ 154.1, 139.8, 130.9, 129.3, 110.88, 110.72, 101.9, 100.4, 55.9, 37.8, 29.0, 22.5. Elemental analysis calculated for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 77.07; H, 8.50; N, 6.81. to maintain an internal temperature of <−25° C the reaction mixture was then cooled to −50° C. over 10 minutes to warm to −10° C. over 30 minutes Upon completion, the mixture was partitioned between Et2O (50 mL) and 0.5 N HCl (50 mL) The aqueous layer was extracted once more with Et2O (25 mL) The combined ether layers were washed with brine (50 mL) dried over anhydrous Na2SO4 concentrated in vacuo providing a yellowish-brown oil The above reaction immediately after the first reaction The crude reaction mixture (from 2.0 g) stirred at room temperature for 48 hours was added the reaction mixture was transferred to a separatory funnel washed with saturated NaHCO3 (50 mL) The organic layer was dried over Na2SO4 concentrated in vacuo giving a deep yellow oil which was purified by column chromatography (0-20% ethyl acetate/hexanes)

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

実験手順: A solution of N-(pyridin-2-yl)pivalamide (3.20 g, 18.0 mmol), n-BuLi (15.00 mL, 2.1 eq.) and N-methoxy-N-methylisobutyramide (2.60 g, 1.1 eq) were reacted as outlined in Scheme 1 to give 3.10 g (69%) of N-(3-isobutyrylpyridin-2-yl)pivalamide. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.21 (d, J=7.03 Hz, 6 H) 1.35 (s, 9 H) 3.55 (dt, J=13.70, 6.78 Hz, 1 H) 7.08 (dd, J=7.91, 4.69 Hz, 1 H) 8.19 (dd, J=8.20, 2.05 Hz, 1 H) 8.63 (dd, J=4.83, 1.90 Hz, 1 H) 11.51 (br. s., 1 H).

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

実験手順: To a solution of thiophene-3-carboxylic acid (26.65 g) in THF (300 ml) was added 2M lithium diisopropylamide (229 ml) dropwise at 0–5° C. with stirring under nitrogen, and the resulting mixture stirred for 15 min. A solution of N-methoxy-N,2-dimethylpropanamide (30 g) in THF (150 ml) was added dropwise over a period of 1 hr. When the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 hr. It was poured onto water, the layers separated and the aqueous washed with ether. The aqueous was acidified with conc. hydrochloric acid and extracted with ethyl acetate, the organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give the sub-title compound as a solid (38.91 g). the resulting mixture stirred for 15 min When the addition stirred for 2 hr It was poured onto water the layers separated the aqueous washed with ether extracted with ethyl acetate the organic extracts were dried over anhydrous magnesium sulfate filtered evaporated under reduced pressure