* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With trifluorormethanesulfonic acid In dichloromethane at 80℃; for 1 h; High pressure; Inert atmosphere; Green chemistry
General procedure: Trifluoromethane sulfonic acid (3 eq.) was gently added to a cooled (0 °C) solution of a 3-Phenylpropionic acid (0.5 mmol) in dry CH2Cl2 (1.0 mL) in a 12 mL Q-tube™ pressure tube, furnished by QLabtech. The temperature was raised to room temperature. A Teflon septum was placed on the top of the tube and the appropriate cap and pressure adapter were used. The mixture was heated in an oil bath at 80 °C. The reaction was monitored by TLC and GC/MS until the reactant disappeared. The mixture was poured into ice and extracted three times with CH2Cl2. The organic phase collected was dried on Na2SO4, filtered and concentrated under vacuum. The desired pure product was separated from the crude by flash chromatography.
98%
at 20℃;
Briefly, into a 250-mL round-bottom flask, was placed a solution of 2- methylbenzaldehyde (8 g, 66.58 mmol, 1.00 equiv) in ethanol (80 mL), malonic acid (7.6 g, 73.03 mmol, 1.10 equiv), Pyridine (5 mL). The resulting solution was heated to reflux for 48 hr and allowed to cool to room temperature. The crystalline mass which formed was collect by filtration and washed with ethanol. This resulted in 6 g (55percent) of (E -3-o- tolylacrylic acid as a white solid. Next, into a 250-mL round-bottom flask was placed a solution of (is)-3-o-tolylacrylic acid (12 g, 73.99 mmol, 1.00 equiv) in methanol (80 mL), Palladium carbon (2 g, 10percent). Hydrogen was bubbled into the solution and the resulting solution was stirred overnight at room temperature. The solids were filtered out and the residue was concentrated under vacuum. This resulted in 12 g (98percent) of 3-o-tolylpropanoic acid as colorless oil. Next, a solution of 3-o-tolylpropanoic acid (12 g, 73.08 mmol, 1.00 equiv) in TfOH (70 mL) was placed into a 250-mL round-bottom flask. The resulting solution was stirred overnight at room temperature. Then, ice-water was added and extracted with DCM. The combined organic phases were dried over anhydrous Na2S04. After filtration and concentration, the residue was applied onto a silica gel column with EA/PE=1/100 to 1/50. This resulted in 10.6 g (98percent) of 4-methyl-2,3-dihydroinden-l-one as a white solid. Next, a solution of l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole (270 mg, 1.36 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) was placed into a 100-mL 3- necked round-bottom flask. This was followed by the addition of n-BuLi (0.55 mL, 2.5M) with dropwise under N2 and stirred for 1 h at -70°C. To this was added 4-methyl-2,3- dihydroinden-l-one (200 mg, 1.37 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) dropwise. The reaction mixture was warmed to room temperature over a period of 1 h and the mixture was continued to stir overnight at rt. Then water was added and extracted with EA. The combined organic phases were dried over anhydrous a2S04. After filtration and concentration, the residue was purified by MPLC. This resulted in 250 mg (53percent) of 4- methyl- 1 -(1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-imidazol-2-yl)-2,3 -dihydro- 1 H-inden- l-ol as colorless oil. Finally, a solution of 4-methyl-l-(l-((2- (trimethylsilyl)ethoxy)methyl)- 1 H-imidazol-2-yl)-2,3 -dihydro- 1 H-inden- 1 -ol ( 100 mg, 0.29 mmol, 1.00 equiv) in HCOOH (10 mL), Palladium carbon (10 mg) was placed into a 100 mL round bottom flask. The resulting solution was heated to reflux for one overnight. The pH value of the solution was adjusted to 8 with aqueous sodium bicarbonate solution and extracted with EA. The combined organic phases were dried over anhydrous Na2S04. After filtration and concentration, the residue was purified by MPLC. This resulted in 40 mg (67percent) of 2-(4-methyl-2,3-dihydro-lH-inden-l-yl)-lH-imidazole as a white solid. LCMS(m/e) 199 (M+H); XH NMR (300 MHz, CDC13) δ ppm 6.96-7.18 (m, 3H), 6.93 (s, 2H), 4.59 (t, J=8.1 Hz, 1H), 2.80-3.00 (m, 2H), 2.50-2.62 (m, 1H), 2.29 (s, 3H), 2.45-2.29 (s, 1H).
98%
at 20℃;
Briefly, into a 250-mL round-bottom flask, was placed a solution of 2-methylbenzaldehyde (8 g, 66.58 mmol, 1.00 equiv) in ethanol (80 mL), malonic acid (7.6 g, 73.03 mmol, 1.10 equiv), Pyridine (5 mL). The resulting solution was heated to reflux for 48 hr and allowed to cool to room temperature. The crystalline mass which formed was collect by filtration and washed with ethanol. This resulted in 6 g (55percent) of (E)-3-o-tolylacrylic acid as a white solid. Next, into a 250-mL round-bottom flask was placed a solution of (E)-3-o-tolylacrylic acid (12 g, 73.99 mmol, 1.00 equiv) in methanol (80 mL), Palladium carbon (2 g, 10percent). Hydrogen was bubbled into the solution and the resulting solution was stirred overnight at room temperature. The solids were filtered out and the residue was concentrated under vacuum. This resulted in 12 g (98percent) of 3-o-tolylpropanoic acid as colorless oil. Next, a solution of 3-o-tolylpropanoic acid (12 g, 73.08 mmol, 1.00 equiv) in TfOH (70 mL) was placed into a 250-mL round-bottom flask. The resulting solution was stirred overnight at room temperature. Then, ice-water was added and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4. After filtration and concentration, the residue was applied onto a silica gel column with EA/PE=1/100 to 1/50. This resulted in 10.6 g (98percent) of 4-methyl-2,3-dihydroinden-1-one as a white solid. Next, a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (270 mg, 1.36 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) was placed into a 100-mL 3-necked round-bottom flask. This was followed by the addition of n-BuLi (0.55 mL, 2.5M) with dropwise under N2 and stirred for 1 h at −70° C. To this was added 4-methyl-2,3-dihydroinden-1-one (200 mg, 1.37 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) dropwise. The reaction mixture was warmed to room temperature over a period of 1 h and the mixture was continued to stir overnight at rt. Then water was added and extracted with EA. The combined organic phases were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by MPLC. This resulted in 250 mg (53percent) of 4-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2,3-dihydro-1H-inden-1-ol as colorless oil. Finally, a solution of 4-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2,3-dihydro-1H-inden-1-ol (100 mg, 0.29 mmol, 1.00 equiv) in HCOOH (10 mL), Palladium carbon (10 mg) was placed into a 100 mL round bottom flask. The resulting solution was heated to reflux for one overnight. The pH value of the solution was adjusted to 8 with aqueous sodium bicarbonate solution and extracted with EA. The combined organic phases were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by MPLC. This resulted in 40 mg (67percent) of 2-(4-methyl-2,3-dihydro-1H-inden-1-yl)-1H-imidazole as a white solid. LCMS (m/e) 199 (M+H); 1H NMR (300 MHz, CDC3) δ ppm 6.96-7.18 (m, 3H), 6.93 (s, 2H), 4.59 (t, J=8.1 Hz, 1H), 2.80-3.00 (m, 2H), 2.50-2.62 (m, 1H), 2.29 (s, 3H), 2.45-2.29 (s, 1H).
Reference：
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With trifluorormethanesulfonic acid; In dichloromethane; at 80℃; for 1h;High pressure; Inert atmosphere; Green chemistry;
General procedure: Trifluoromethane sulfonic acid (3 eq.) was gently added to a cooled (0 C) solution of a 3-Phenylpropionic acid (0.5 mmol) in dry CH2Cl2 (1.0 mL) in a 12 mL Q-tube pressure tube, furnished by QLabtech. The temperature was raised to room temperature. A Teflon septum was placed on the top of the tube and the appropriate cap and pressure adapter were used. The mixture was heated in an oil bath at 80 C. The reaction was monitored by TLC and GC/MS until the reactant disappeared. The mixture was poured into ice and extracted three times with CH2Cl2. The organic phase collected was dried on Na2SO4, filtered and concentrated under vacuum. The desired pure product was separated from the crude by flash chromatography.
98%
With trifluorormethanesulfonic acid; at 20℃;
Briefly, into a 250-mL round-bottom flask, was placed a solution of 2- methylbenzaldehyde (8 g, 66.58 mmol, 1.00 equiv) in ethanol (80 mL), malonic acid (7.6 g, 73.03 mmol, 1.10 equiv), Pyridine (5 mL). The resulting solution was heated to reflux for 48 hr and allowed to cool to room temperature. The crystalline mass which formed was collect by filtration and washed with ethanol. This resulted in 6 g (55%) of (E -3-o- tolylacrylic acid as a white solid. Next, into a 250-mL round-bottom flask was placed a solution of (is)-3-o-tolylacrylic acid (12 g, 73.99 mmol, 1.00 equiv) in methanol (80 mL), Palladium carbon (2 g, 10%). Hydrogen was bubbled into the solution and the resulting solution was stirred overnight at room temperature. The solids were filtered out and the residue was concentrated under vacuum. This resulted in 12 g (98%) of 3-o-tolylpropanoic acid as colorless oil. Next, a solution of 3-o-tolylpropanoic acid (12 g, 73.08 mmol, 1.00 equiv) in TfOH (70 mL) was placed into a 250-mL round-bottom flask. The resulting solution was stirred overnight at room temperature. Then, ice-water was added and extracted with DCM. The combined organic phases were dried over anhydrous Na2S04. After filtration and concentration, the residue was applied onto a silica gel column with EA/PE=1/100 to 1/50. This resulted in 10.6 g (98%) of 4-methyl-2,3-dihydroinden-l-one as a white solid. Next, a solution of l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole (270 mg, 1.36 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) was placed into a 100-mL 3- necked round-bottom flask. This was followed by the addition of n-BuLi (0.55 mL, 2.5M) with dropwise under N2 and stirred for 1 h at -70C. To this was added 4-methyl-2,3- dihydroinden-l-one (200 mg, 1.37 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) dropwise. The reaction mixture was warmed to room temperature over a period of 1 h and the mixture was continued to stir overnight at rt. Then water was added and extracted with EA. The combined organic phases were dried over anhydrous a2S04. After filtration and concentration, the residue was purified by MPLC. This resulted in 250 mg (53%) of 4- methyl- 1 -(1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-imidazol-2-yl)-2,3 -dihydro- 1 H-inden- l-ol as colorless oil. Finally, a solution of 4-methyl-l-(l-((2- (trimethylsilyl)ethoxy)methyl)- 1 H-imidazol-2-yl)-2,3 -dihydro- 1 H-inden- 1 -ol ( 100 mg, 0.29 mmol, 1.00 equiv) in HCOOH (10 mL), Palladium carbon (10 mg) was placed into a 100 mL round bottom flask. The resulting solution was heated to reflux for one overnight. The pH value of the solution was adjusted to 8 with aqueous sodium bicarbonate solution and extracted with EA. The combined organic phases were dried over anhydrous Na2S04. After filtration and concentration, the residue was purified by MPLC. This resulted in 40 mg (67%) of 2-(4-methyl-2,3-dihydro-lH-inden-l-yl)-lH-imidazole as a white solid. LCMS(m/e) 199 (M+H); XH NMR (300 MHz, CDC13) delta ppm 6.96-7.18 (m, 3H), 6.93 (s, 2H), 4.59 (t, J=8.1 Hz, 1H), 2.80-3.00 (m, 2H), 2.50-2.62 (m, 1H), 2.29 (s, 3H), 2.45-2.29 (s, 1H).
98%
With trifluorormethanesulfonic acid; at 20℃;
Briefly, into a 250-mL round-bottom flask, was placed a solution of 2-methylbenzaldehyde (8 g, 66.58 mmol, 1.00 equiv) in ethanol (80 mL), malonic acid (7.6 g, 73.03 mmol, 1.10 equiv), Pyridine (5 mL). The resulting solution was heated to reflux for 48 hr and allowed to cool to room temperature. The crystalline mass which formed was collect by filtration and washed with ethanol. This resulted in 6 g (55%) of (E)-3-o-tolylacrylic acid as a white solid. Next, into a 250-mL round-bottom flask was placed a solution of (E)-3-o-tolylacrylic acid (12 g, 73.99 mmol, 1.00 equiv) in methanol (80 mL), Palladium carbon (2 g, 10%). Hydrogen was bubbled into the solution and the resulting solution was stirred overnight at room temperature. The solids were filtered out and the residue was concentrated under vacuum. This resulted in 12 g (98%) of 3-o-tolylpropanoic acid as colorless oil. Next, a solution of 3-o-tolylpropanoic acid (12 g, 73.08 mmol, 1.00 equiv) in TfOH (70 mL) was placed into a 250-mL round-bottom flask. The resulting solution was stirred overnight at room temperature. Then, ice-water was added and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4. After filtration and concentration, the residue was applied onto a silica gel column with EA/PE=1/100 to 1/50. This resulted in 10.6 g (98%) of 4-methyl-2,3-dihydroinden-1-one as a white solid. Next, a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (270 mg, 1.36 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) was placed into a 100-mL 3-necked round-bottom flask. This was followed by the addition of n-BuLi (0.55 mL, 2.5M) with dropwise under N2 and stirred for 1 h at -70 C. To this was added 4-methyl-2,3-dihydroinden-1-one (200 mg, 1.37 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) dropwise. The reaction mixture was warmed to room temperature over a period of 1 h and the mixture was continued to stir overnight at rt. Then water was added and extracted with EA. The combined organic phases were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by MPLC. This resulted in 250 mg (53%) of 4-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2,3-dihydro-1H-inden-1-ol as colorless oil. Finally, a solution of 4-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2,3-dihydro-1H-inden-1-ol (100 mg, 0.29 mmol, 1.00 equiv) in HCOOH (10 mL), Palladium carbon (10 mg) was placed into a 100 mL round bottom flask. The resulting solution was heated to reflux for one overnight. The pH value of the solution was adjusted to 8 with aqueous sodium bicarbonate solution and extracted with EA. The combined organic phases were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by MPLC. This resulted in 40 mg (67%) of 2-(4-methyl-2,3-dihydro-1H-inden-1-yl)-1H-imidazole as a white solid. LCMS (m/e) 199 (M+H); 1H NMR (300 MHz, CDC3) delta ppm 6.96-7.18 (m, 3H), 6.93 (s, 2H), 4.59 (t, J=8.1 Hz, 1H), 2.80-3.00 (m, 2H), 2.50-2.62 (m, 1H), 2.29 (s, 3H), 2.45-2.29 (s, 1H).
With PPA; In dichloromethane;
2,3-Dihydro-4-methyl-1H-inden-1-one See K. T. Potts and R. Robinson, J. Chem. Soc., 2466 (1955). A solution of 12.0 g (73.2 mmol) of 2-methylbenzenepropanoic acid in 125 ml of methylene chloride was added portion-wise to 500 g of polyphosphoric acid. The mixture was heated for six hours on the steam bath and the resulting orange solution was diluted with 1.5 l of ice. The solid was collected, washed with water, and air dried to give 7.2 g crude material. Recrystallization from ethanol/water gave 5.8 g of the desired product; mp 94-97. Extraction of the original diluted reaction mixture with methylene chloride gave an additional lot. Total recovery was 7.7 g (72%).
With hydrogen; potassium hydroxide; In water; at 20℃; under 760.051 Torr; for 1h;Green chemistry;
General procedure: 1.0 mmol, 0.148 g), catalyst BPPd(0)Si (5 mol%, 0.0836 g), andKOH (1.0 equiv., 5 mL 0.2 M solution) were added to the reactionflask under hydrogen gas (1 atm). The reaction mixture was stirredat room temperature for 30 min followed by catalyst filtration andwashing with 10 mL of water and ethyl acetate. The pH was adjusted to 2e3 using 1 N HCl. The organic phase was collectedafter solvent extraction from ethyl acetate and dried over MgSO4and in vacuo. The product was purified by silica-gel column chromatographyand analyzed by 1H NMR spectroscopy.
98%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;
Briefly, into a 250-mL round-bottom flask, was placed a solution of 2- methylbenzaldehyde (8 g, 66.58 mmol, 1.00 equiv) in ethanol (80 mL), malonic acid (7.6 g, 73.03 mmol, 1.10 equiv), Pyridine (5 mL). The resulting solution was heated to reflux for 48 hr and allowed to cool to room temperature. The crystalline mass which formed was collect by filtration and washed with ethanol. This resulted in 6 g (55%) of (E -3-o- tolylacrylic acid as a white solid. Next, into a 250-mL round-bottom flask was placed a solution of (is)-3-o-tolylacrylic acid (12 g, 73.99 mmol, 1.00 equiv) in methanol (80 mL), Palladium carbon (2 g, 10%). Hydrogen was bubbled into the solution and the resulting solution was stirred overnight at room temperature. The solids were filtered out and the residue was concentrated under vacuum. This resulted in 12 g (98%) of 3-o-tolylpropanoic acid as colorless oil. Next, a solution of 3-o-tolylpropanoic acid (12 g, 73.08 mmol, 1.00 equiv) in TfOH (70 mL) was placed into a 250-mL round-bottom flask. The resulting solution was stirred overnight at room temperature. Then, ice-water was added and extracted with DCM. The combined organic phases were dried over anhydrous Na2S04. After filtration and concentration, the residue was applied onto a silica gel column with EA/PE=1/100 to 1/50. This resulted in 10.6 g (98%) of 4-methyl-2,3-dihydroinden-l-one as a white solid. Next, a solution of l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole (270 mg, 1.36 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) was placed into a 100-mL 3- necked round-bottom flask. This was followed by the addition of n-BuLi (0.55 mL, 2.5M) with dropwise under N2 and stirred for 1 h at -70C. To this was added 4-methyl-2,3- dihydroinden-l-one (200 mg, 1.37 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) dropwise. The reaction mixture was warmed to room temperature over a period of 1 h and the mixture was continued to stir overnight at rt. Then water was added and extracted with EA. The combined organic phases were dried over anhydrous a2S04. After filtration and concentration, the residue was purified by MPLC. This resulted in 250 mg (53%) of 4- methyl- 1 -(1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-imidazol-2-yl)-2,3 -dihydro- 1 H-inden- l-ol as colorless oil. Finally, a solution of 4-methyl-l-(l-((2- (trimethylsilyl)ethoxy)methyl)- 1 H-imidazol-2-yl)-2,3 -dihydro- 1 H-inden- 1 -ol ( 100 mg, 0.29 mmol, 1.00 equiv) in HCOOH (10 mL), Palladium carbon (10 mg) was placed into a 100 mL round bottom flask. The resulting solution was heated to reflux for one overnight. The pH value of the solution was adjusted to 8 with aqueous sodium bicarbonate solution and extracted with EA. The combined organic phases were dried over anhydrous Na2S04. After filtration and concentration, the residue was purified by MPLC. This resulted in 40 mg (67%) of 2-(4-methyl-2,3-dihydro-lH-inden-l-yl)-lH-imidazole as a white solid. LCMS(m/e) 199 (M+H); XH NMR (300 MHz, CDC13) delta ppm 6.96-7.18 (m, 3H), 6.93 (s, 2H), 4.59 (t, J=8.1 Hz, 1H), 2.80-3.00 (m, 2H), 2.50-2.62 (m, 1H), 2.29 (s, 3H), 2.45-2.29 (s, 1H).
98%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;
Briefly, into a 250-mL round-bottom flask, was placed a solution of 2-methylbenzaldehyde (8 g, 66.58 mmol, 1.00 equiv) in ethanol (80 mL), malonic acid (7.6 g, 73.03 mmol, 1.10 equiv), Pyridine (5 mL). The resulting solution was heated to reflux for 48 hr and allowed to cool to room temperature. The crystalline mass which formed was collect by filtration and washed with ethanol. This resulted in 6 g (55%) of (E)-3-o-tolylacrylic acid as a white solid. Next, into a 250-mL round-bottom flask was placed a solution of (E)-3-o-tolylacrylic acid (12 g, 73.99 mmol, 1.00 equiv) in methanol (80 mL), Palladium carbon (2 g, 10%). Hydrogen was bubbled into the solution and the resulting solution was stirred overnight at room temperature. The solids were filtered out and the residue was concentrated under vacuum. This resulted in 12 g (98%) of 3-o-tolylpropanoic acid as colorless oil. Next, a solution of 3-o-tolylpropanoic acid (12 g, 73.08 mmol, 1.00 equiv) in TfOH (70 mL) was placed into a 250-mL round-bottom flask. The resulting solution was stirred overnight at room temperature. Then, ice-water was added and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4. After filtration and concentration, the residue was applied onto a silica gel column with EA/PE=1/100 to 1/50. This resulted in 10.6 g (98%) of 4-methyl-2,3-dihydroinden-1-one as a white solid. Next, a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (270 mg, 1.36 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) was placed into a 100-mL 3-necked round-bottom flask. This was followed by the addition of n-BuLi (0.55 mL, 2.5M) with dropwise under N2 and stirred for 1 h at -70 C. To this was added 4-methyl-2,3-dihydroinden-1-one (200 mg, 1.37 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) dropwise. The reaction mixture was warmed to room temperature over a period of 1 h and the mixture was continued to stir overnight at rt. Then water was added and extracted with EA. The combined organic phases were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by MPLC. This resulted in 250 mg (53%) of 4-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2,3-dihydro-1H-inden-1-ol as colorless oil. Finally, a solution of 4-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-2,3-dihydro-1H-inden-1-ol (100 mg, 0.29 mmol, 1.00 equiv) in HCOOH (10 mL), Palladium carbon (10 mg) was placed into a 100 mL round bottom flask. The resulting solution was heated to reflux for one overnight. The pH value of the solution was adjusted to 8 with aqueous sodium bicarbonate solution and extracted with EA. The combined organic phases were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by MPLC. This resulted in 40 mg (67%) of 2-(4-methyl-2,3-dihydro-1H-inden-1-yl)-1H-imidazole as a white solid. LCMS (m/e) 199 (M+H); 1H NMR (300 MHz, CDC3) delta ppm 6.96-7.18 (m, 3H), 6.93 (s, 2H), 4.59 (t, J=8.1 Hz, 1H), 2.80-3.00 (m, 2H), 2.50-2.62 (m, 1H), 2.29 (s, 3H), 2.45-2.29 (s, 1H).
Pd-C; In tetrahydrofuran;
Methyl-benzenepropanoic acid See W. E. Backmann and E. K. Raunio, J. Amer. Chem. Soc., 72:2530 (1950). A mixture of 14.5 g (8.95 mmol) of trans-2-methylcinnamic acid in 200 ml of THF and 1.0 g 5% Pd-C was hydrogenated at room temperature (three atmospheres). The mixture was filtered and the pale yellow filtrate was evaporated to give 14.5 g of a tan solid suitable for use in the next step. An analytical sample was obtained by recrystallization from n-hexane; mp 101-103.
With hydrogen;Rh/Al2O3; In tetrahydrofuran; under 2585.81 Torr; for 6h;
3-o-Tolyl-acrylic acid (10.00 g, 62.00 mmol) in THF was mixed with Rh/Al2O3 (800 mg) and hydrogenated at 50 psi for 6 hours. The resulting mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was dissolved in THF and cooled to 0 C. LAH (62.00 mL, 1.0 M in THF, 62.00 mmol) was added and the reaction mixture was stirred for 14 hours. The resulting mixture was quenched with NaOH and extracted with Et2O (3×250 mL). The combined organic extracts were washed with H2O (3×150 mL), brine (1×150 mL), dried over MgSO4 and concentrated to give the title alcohol.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 18.33h;
Add 2-methylhydrociimamic acid (18.4 mmol) to anhydrous tetrahydrofuran (100 mL) and cool to 0 C. Slowly add lithium aluminum hydride (2.20 g, 58. 0 mmol) and remove the ice bath after 20 minutes. Stir at room temperature under nitrogen for 18 H. Cool the reaction to 0 C and quench the reaction by slowly adding water (2.2 mL), 15% sodium hydroxide (2.2 mL), and water (6.6 mL). Filter off the aluminum salts. Add brine (100 mL) and 5 N sodium hydroxide (30 mL) to the filtrate and extract with ethyl acetate (3 X 100 mL). Dry the ethyl acetate extracts with magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 2.65 g (96%) OF 3-O-TOLYL-PROPAN-1-OL : LH NMR (CDC13) : 7.18-7. 10 (m, 4H), 3.72 (t, 2H), 2.72-2. 69 (m, 2H), 2.33 (s, 3H), 1.90- 1.83 (m, 2H), 1.60 (BR S, 1H).
70%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 25℃; for 3h;
General procedure: To a suspension of LiAlH4 (39 mg, 1.03 mmol) in dry THF (3.0 mL) cooled at 0 C, a solution of 2-(adamantan-1-yl)acetic acid (200 mg, 1.03 mmol) in dry THF (3.0 mL) was added. The reactionmixture was stirred for 3 hours at 25 C then water was added dropwise at 0 C and the resultingmixture was extracted with diethyl ether (2 x 10 mL). The organic layers were extracted and driedover anhydrous Na2SO4, filtered and evaporated to afford the title compound 14j as an amorphouswhite solid (42% yield). 1H NMR (300 MHz, CDCl3): delta 3.75 (t, 2H, J = 6.0 Hz), 1.98 (s, 2H), 1.82 - 1.56(m, 12H), 1.38 (t, 2H, J = 6.4 Hz).
69.3%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 1h;
3-(o-Tolyl)propan-1-olTo a solution of 3-(o-tolyl)propanoic acid (2 g, 12.18 mmol) in THF (20 mL) dropwise added a 1 M LAH in THF (14.62 mL, 14.62 mmol) solution at 0 C and stirred for 1 h at 0 C. The reaction mixture was quenched with saturated Na2S04solution (15 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine solution (15 mL), dried over anhydrous Na2S04and concentrated to afford 3-(o- tolyl)propan-1-ol (1.3 g, 8.45 mmol, 69.3 % yield) LC-MS m/z 150.98 (M+H)+, 1.95 min (ret. time).
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 14h;
3-o-Tolyl-acrylic acid (10.00 g, 62.00 mmol) in THF was mixed with Rh/Al2O3 (800 mg) and hydrogenated at 50 psi for 6 hours. The resulting mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was dissolved in THF and cooled to 0 C. LAH (62.00 mL, 1.0 M in THF, 62.00 mmol) was added and the reaction mixture was stirred for 14 hours. The resulting mixture was quenched with NaOH and extracted with Et2O (3×250 mL). The combined organic extracts were washed with H2O (3×150 mL), brine (1×150 mL), dried over MgSO4 and concentrated to give the title alcohol.
(2S,4R)-1-[(2R,3S)-2-Hydroxy-4-phenyl-3-(3-o-tolyl-propionylamino)-butyl]-4-(pyridin-4-ylmethoxy)-piperidine-2-carboxylic acid tert-butylamide[ No CAS ]
(3aR,4R,5R,6aS)-5-(Tetrahydro-pyran-2-yloxy)-4-[(E)-(S)-3-(tetrahydro-pyran-2-yloxy)-5-o-tolyl-pent-1-enyl]-hexahydro-cyclopenta[b]furan-2-one[ No CAS ]
{(1R,2R,3R,5S)-5-Hydroxy-3-(tetrahydro-pyran-2-yloxy)-2-[(E)-(S)-3-(tetrahydro-pyran-2-yloxy)-5-o-tolyl-pent-1-enyl]-cyclopentyl}-acetaldehyde[ No CAS ]
(Z)-7-{(1R,2R,3R,5S)-5-Hydroxy-3-(tetrahydro-pyran-2-yloxy)-2-[(E)-(S)-3-(tetrahydro-pyran-2-yloxy)-5-o-tolyl-pent-1-enyl]-cyclopentyl}-hept-5-enoic acid[ No CAS ]
EXAMPLE 15 Preparation of Fmoc-(D,L)-5-methyl-2-aminotetraline-2-carboxylic acid (Fmoc-(D,L) 5-MeAtc-OH) A mixture of 2-methylhydrocinnamic acid (3.0 g, 18.3 mmole), oxalyl chloride (3.19 ml, 36.6 mmole) and methylene chloride (30 ml) was cooled in an ice bath and N,N-dimethylformamide (0.14 ml, 1.81 mmole) was added dropwise. The mixture was stirred at room temperature overnight. Concentration in vacuo gave 3-(2-methylphenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step as a crude.
In dichloromethane; N,N-dimethyl-formamide;
Step 1 A mixture of 2-methylhydrocinnamic acid (3.0 g, 18.3 mmole), oxalyl chloride (3.19 ml, 36.6 mmole) and methylene chloride (30 ml) was cooled in an ice bath and N,N-dimethylformamide (0.14 ml, 1.81 mmole) was added dropwise. The mixture was stirred at room temperature overnight. Concentration in vacuo gave 3-(2-methylphenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step as a crude.
[Example 1] Synthesis of 3-chloro-4-methylbenzo[b]thiophene-2-carboxylic acid To a heated stirring mixture of 2-methylhydrocinnamic acid (20.00 g, 122 mmol), pyridine (1.0 mL, 12.2 mmol) and thionyl chloride (11.0 mL, 152 mmol) at 150C there was slowly added dropwise thionyl chloride (32.0 mL, 396 mmol) at 150C over a period of 2.5 hours, and stirring was continued for 3 hours. After 3 hours, the mixture was returned to room temperature, water (120 mL), 35% hydrochloric acid (12 mL) and tetrahydrofuran (200 mL) were added and the mixture was stirred at 60C for 30 minutes. After 30 minutes, the tetrahydrofuran was distilled off under reduced pressure and the precipitated crystals were filtered out and dissolved in ethanol (100 mL) and water (300 mL) and stirred at 90C for 1 hour, after which the solution was returned to room temperature and stirred overnight. The crystals that further precipitated were filtered out and recrystallized with a mixture of toluene (500 mL) and hexane (500 mL) to obtain 3-chloro-4-methylbenzo[b]thiophene-2-carboxylic acid (17.85 g, 78.7 mmol) (yield: 65%). 1H-NMR (400 MHz, CDCl3) delta(ppm): 7.64(1H,d), 7.34(1H,t), 7.16(1H,d), 3.80(1H,br), 2.92(3H,s).
To a heated stirring mixture of 2-methylhydrocinnamic acid (36.00 g, 219 mmol), pyridine (1.9 mL, 23.5 mmol) and thionyl chloride (24.0 mL, 333 mmol) at 150C there was slowly added dropwise thionyl chloride (55.0 mL, 763 mmol) at 150C over a period of 2.5 hours, and stirring was continued for 3 hours. After 3 hours, the mixture was returned to room temperature, water (220 mL) and tetrahydrofuran (360 mL) were added and the mixture was stirred for 40 minutes. After 40 minutes, the tetrahydrofuran was distilled off under reduced pressure and extraction was performed with ethyl acetate (extraction with 360 mL followed by extraction with 180 mL), after which the extract was washed with water (180 mL, 3 times), sodium hydroxide (17.5 g, 438 mmol) dissolved in water (70 mL) was added and the precipitate crystals were filtered out and dried to obtain sodium 3-chloro-4-methylbenzo[b]thiophene-2-carboxylate (47.50 g) as a crude solid. The product was used without purification for the following reaction
Method B: To a solution of 2-methylhydrocinnamic acid (12 mg, 0.08 mmol, 1 .5 eq.) in DMF (1 mL), DIPEA (34 mu, 0.20 mmol, 4.0 eq.), and TBTU (24 mg, 0.08 mmol, 1 .5 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 min. Then (+/-)-[4-chloro- 2-(1 ,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester (17 mg, 0.05 mmol, 1 .0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. 1 M aq. NaOH (0.50 mL) was added. The mixture was stirred at r.t. for 2 hours. The solution was neutralized with formic acid (0.50 mL), filtered, and then purified by prep. HPLC (column: Atlantis, 30x75 mm, 10 um, UV/MS, acidic conditions) to give the desired acid as a white solid.
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