* 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.
Reference：
[1] European Journal of Organic Chemistry, 2015, vol. 2015, # 22, p. 4922 - 4930
7
[ 67832-11-5 ]
[ 68837-59-2 ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium hydroxide In waterReflux
4-bromo-2-methylbenzonitrile (1 mmol) was suspended in water (49 mL) and potassium hydroxide was added (50 mmol); the reaction mixture was stirred at reflux overnight. After cooling, the basic solution was washed with ethyl acetate (3 x 15 mL), acidified with hydrochloric acid (6M) and extracted with ethyl acetate (3 x 15 mL). The organic phase deriving from the acidic extraction was dried over anhydrous sodium sulfate and concentrated in vacuo, yielding the desired product as a white solid. Yield: 60percent. TLC (dichloromethane – methanol 9:1): Rf = 0.46. Mp: 182°C. 1H-NMR (300 MHz, CD3OD) δ (ppm) 7.80 (d, J = 8.4 Hz, 1H, H6), 7.48 (s, 1H, H3), 7.42 (d, J = 8.4 Hz, 1H, H5), 2.56 (s, 3H, CH3).
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 754 - 763
[2] Chemische Berichte, 1887, vol. 20, p. 1017
[3] Journal fuer Praktische Chemie (Leipzig), 1889, vol. <2> 39, p. 486
[4] Chemische Berichte, 1887, vol. 20, p. 1017
[5] Journal fuer Praktische Chemie (Leipzig), 1889, vol. <2> 39, p. 486
[6] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 21, p. 5936 - 5940
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78 - 20℃; Stage #3: With hydrogenchloride In water
To a solution of 4-bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF (100 ml) at -78°C under a nitrogen atmosphere was added dropwise a 2.5 M solution of n-butyl lithium (4.48 ml, 11.2 mmol). The mixture was stirred at -78°C for 1h and then poured onto solid carbon dioxide (5 g) in THF (50 ml). The mixture was allowed to warm to room temperature. Water was added (200 ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid identified as 4-cyano-3-methylbenzoic acid (1.2 g, 73percent).
73%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Stage #2: at 20℃;
Example B 4-Cyano-3-methylbenzoic acid To a solution of 4-bromo-2-methylbenzonitrile (2.0g, 10.2mmol) in THF (100ml) at -78°C under a nitrogen atmosphere was added dropwise a 2.5M solution of n-butyl lithium (4.48ml, 11.2mmol). The mixture was stirred at -78°C for 1h and then poured onto solid carbon dioxide (5g) in THF (50ml). The mixture was allowed to warm to room temperature. Water was added (200ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid identified as 4-cyano-3-methylbenzoic acid (1.2g, 73percent).
73%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Stage #2: at 20℃;
To a solution of 4-bromo-2-methylbenzonitrile (2.0g, 10.2mmol) in THF (100ml) at -78°C under a nitrogen atmosphere was added dropwise a 2.5M solution of n-butyl lithium (4.48ml, 11.2mmol). The mixture was stirred at -78°C for lh and then poured onto solid carbon dioxide (5g) in THF (50ml). The mixture was allowed to warm to room temperature. Water was added (200ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HC1 and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgS04, and concentrated in vacuo to give a white solid; yielding (73percent).
73%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78 - 20℃; Stage #3: With water In tetrahydrofuran; water
To a solution of 4-bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF (100 ml) at -78° C. under a nitrogen atmosphere was added dropwise a 2.5M solution of n-butyl lithium (4.48 ml, 11.2 mmol).. The mixture was stirred at -78° C. for 1 h and then poured onto solid carbon dioxide (5 g) in THF (50 ml).. The mixture was allowed to warm to room temperature.. water was added (200 ml) and the mixture was extracted with diethyl ether (3 times).. The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times).. The combined chloroform extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 1.2 g (73percent).
64%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Stage #2: at 20℃;
Asolution of nBuLi in THF (2.5 M, 4.49 mL, 11.2 mmol) was added dropwise to astirred solution of 4-bromo-2-methylbenzonitrile (2.0 g,10.2 mmol) in dry THF (100 mL) at −78° C. and the solution stirred at −78° C.for 1 h. A stream of dry CO2 was bubbled through the solution for 10 min andthe mixture warmed to 20° C. The mixture was diluted with water (100 ml) andwashed with Et2O (3×20 mL). The aqueous phase was acidified to pH 2 with cHCland extracted with CHCl3 (3×50 mL) and the organic fraction was dried and thesolvent evaporated to give crude acid 171 (1.05 g, 64percent)
60.8%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Inert atmosphere Stage #2: at -78 - 20℃; for 1 h; Inert atmosphere Stage #3: With hydrogenchloride In water; ethyl acetate
A solution of 2.5 M n-butyllithium in hexanes(6.7 mL, 16.8 mmol) was added to anhydrous THF (15 mL) at −78 °C. A solution of 4-bromo-2-methylbenzonitrile 21 (3.0 g, 15.3 mmol) in THF (15 mL) was then added dropwise and allowed to stir for 30 min. Dry ice (solid CO2) was added and the solution was allowed to stir 1 h while warming to room temperature. The reaction was then concentrated in vacuo and the resulting residue was triturated in ether and filtered. The solid was dissolved in EtOAc and washed with 2 M HCl and brine. The organic layer was isolated, dried over MgSO4, concentrated in vacuo, then triturated in ether/ hexane and dried under high vacuum. Obtained 4-cyano-3-methylbenzoic acid 22 (1.5 g, 60.8percent yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.18 (s, 1H), 8.02–8.09 (m, 1H), 7.75–7.81 (m, 1H), 2.61 (s, 3H).
34%
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at -78℃; Inert atmosphere Stage #2: at 20℃; Stage #3: With hydrogenchloride In water
To a -780C cooled solution of 4-bromo-2-methylbenzonitrile (4.00 g, 20.40 mmol) in THF (200 mL) under nitrogen atmosphere, 2.5M solution of n-BuLi in hexanes (10 ml_, 25 mmol) was slowly added and the resulting solution left to stir at -780C for 1 hour. This solution was slowly poured into a mixture of solid CO2 (10 g) in THF (100 mL) and it was stirred at room temperature overnight. The solvent was concentrated in vaccuo, water was added, it was extracted with diethyl ether (x 3) and the aqueous phase was acidified with 5N hydrochloric acid. The solid was filtered and dried to yield 1.11 g (34percent yield) of the title compound.LRMS: m/z 160(M-I )-Retention time: 4.82min (method B)
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 17, p. 4585 - 4589
[2] Patent: EP1449844, 2004, A1, . Location in patent: Page 21
[3] Patent: EP1512687, 2005, A1, . Location in patent: Page/Page column 7
[4] Patent: WO2006/18443, 2006, A1, . Location in patent: Page/Page column 21
[5] Patent: US6664249, 2003, B1, . Location in patent: Page column 11
[6] Patent: JP5789603, 2015, B2, . Location in patent: Paragraph 0346
[7] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 7, p. 1880 - 1897
[8] Patent: WO2014/127350, 2014, A1, . Location in patent: Page/Page column 146
[9] Patent: WO2010/43377, 2010, A1, . Location in patent: Page/Page column 89
[10] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 8124 - 8134
17
[ 67832-11-5 ]
[ 73831-13-7 ]
Yield
Reaction Conditions
Operation in experiment
73%
With hydrogenchloride; n-butyllithium In tetrahydrofuran; water
EXAMPLE B 4-Cyano-3-methylbenzoic acid To a solution of 4-bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF (100 ml) at -78° C. under a nitrogen atmosphere was added dropwise a 2.5M solution of n-butyl lithium (4.48 ml, 11.2 mmol). The mixture was stirred at -78° C. for 1 h and then poured onto solid carbon dioxide (5 g) in THF (50 ml). The mixture was allowed to warm to room temperature. Water was added (200 ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 1.2 g (73percent).
73%
With hydrogenchloride; n-butyllithium In tetrahydrofuran; water
Example C 4Cyano-3methylbenzoic acid To a solution of 4bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF (100 ml) at -78° C. under a nitrogen atmosphere was added dropwise a 2.5M solution of n-butyl lithium (4.48 ml, 11.2 mmol). The mixture was stirred at -78° C. for 1 h and then poured onto solid carbon dioxide (5 g) in THF (50 ml). The mixture was allowed to warm to room temperature. Water was added (200 ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 1.2 g (73percent).
Reference：
[1] Russian Journal of General Chemistry, 2010, vol. 80, # 8, p. 1672 - 1676
[2] Russian Journal of General Chemistry, 2014, vol. 84, # 6, p. 1085 - 1090
20
[ 67832-11-5 ]
[ 6941-75-9 ]
[ 124-38-9 ]
[ 623-00-7 ]
[ 70484-01-4 ]
Reference：
[1] Russian Journal of General Chemistry, 2013, vol. 83, # 3, p. 492 - 495[2] Zh. Obshch. Khim., 2013, vol. 83, # 3, p. 439 - 442,4
21
[ 67832-11-5 ]
[ 376646-62-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With borane In tetrahydrofuran at 0 - 80℃; Inert atmosphere Stage #2: With hydrogenchloride In 1,4-dioxane; ethyl acetate for 0.0833333 h;
[0617j To a solution of 4-bromo-2-methylbenzonitrile (3.0 g, 15 mmol) in anhydrous THF (20 mL) under nitrogen at 0 °C was added 1.0 M solution of borane in THF (46 mL). The reaction mixture was stirred at 0 °C for 1 h, and heated at 80 °C overnight. The reaction mixture was cooled to 0 °C and slowly quenched with MeOH, concentrated in vacuo. The crude product was treated with EtOAc (20 mL) and 4 M of HC1 in 1,4-dioxane (8.0 mL, 32 mmol) for 5 mm. The solid was filtered, rinsed with diethyl ether, dried to give the title compound as a white powder (3.24 g, yield: 100percent). LCMS: RT 0.75 mm.; MH+ 200.0. ‘H NMR (300 MHz, DMSOd6) 5: 8.28 (br. s., 2H), 7.42 - 7.54 (m, 2H), 7.34 (d, J = 7.93 Hz, 1H), 3.99 (d, J = 4.15 Hz, 2H), 2.35 (s, 3H).
90%
With THF·BF3 In tetrahydrofuran at 0 - 80℃; for 17 h;
[0114] To a solution of 4-bromo-2-methylbenzonitrile (3 g, 15 mmol) in THF (20 mL), BH3 THF (45 mL, 45 mmol) was added. The solution was stirred at 0 °C for 1 h and heated to 80 °C for 16 h. Then the mixture was quenched with MeOH. After concentrated, the residue was stirred with saturated HCl/EtOAc solution and filtered. The filter cake was rinsed with ether (20 mL x3) and dried under vacuum to afford (4-bromo-2-methylphenyl)methanamine (3.2 g, yield: 90percent) as white solid. ESI-MS (M+H)+: 200.1 Preparation of tert-butyl 4-bromo-2-methylbenzylcarbamate
69%
With borane-THF In tetrahydrofuran at 0 - 80℃; for 3 h;
To a solution of 4-bromo-2-methylbenzonitrile (3 g, 15 mmol) in THF (20 mL) was added BH3·THF (45 mL, 45 mmol) at 0 °C. The solution was stirred for 1 h and heated to 80 °C for 2 h. The mixture was quenched with H2O and extracted with EtOAc (50 mL x 3). The organic layer was concentrated in vacuo to afford a residue which was suspended in saturated HCl/EtOAc and filtered. The filter cake was washed with diethyl ether (20 mL x 3) and dried under vacuum to afford the desired product (2.1 g, yield 69percent) as white solid. ESI-MS (M+H)+: 200.1.
Stage #1: With borane-THF In tetrahydrofuran at 0 - 80℃; for 17 h; Stage #2: With hydrogenchloride In ethyl acetate
To a solution of 4-bromo-2-methylbenzonitrile (3 g, 15 mmol) in THF (20 mL),BH3THF (45 mL, 45 mmol) was added. The solution was stirred at 0 °C for 1 h and heated to 80°C for 16 h. Then the mixture was quenched with MeOH. After concentrated, the residue wasstirred with saturated HC1/EtOAc solution and filtered. The filter cake was rinsed with ether (20mL x3) and dried under vacuum to afford (4-bromo-2-methylphenyl)methanamine (3.2 g, yield:90percent) as white solid. ESI-MS (M+H) : 200.1
Stage #1: methyl magnesium iodide; 4-bromo-2-methylbenzonitrile In tetrahydrofuran at 20 - 70℃; for 74h;
Stage #2: With hydrogenchloride; water at 0 - 20℃; for 18h;
19.1 1. Synthesis of 1-(4-bromo-2-methylphenyl)ethan-1-one
a solution of 4-bromo-2-methyl-benzonitrile (4.0 g, 20.4 mmol) in THF (20 mL) was added dropwise iodo(methyl)magnesium (3 M, 10.2 mL) at rt. The reaction mixture was heated to reflux (~70 °C) for 2 h and then was cooled to rt and stirred for 72 h. The reaction mixture was placed in an ice-water cooling bath and saturated aqueous NH4Cl solution (100 mL) was added, followed by EtOAc (100 mL). The layers were separated and the aqueous phase was extracted with EtOAc (100 mL). The combined organic extracts were concentrated in vacuo and the resulting residue was treated with an HCl solution (4 N, 20 mL) at 0 °C. The mixture was then stirred at rt for 18 h. The reaction mixture was extracted with EtOAc (50 mL) and the organic layer was washed with H2O (50 mL), dried (Na2SO4), and filtered. The filtrate was concentrated in vacuo to give 1-(4-bromo-2-methylphenyl)ethan-1-one as a pale orange oil (3.04 g, yield: 70%). ESI-MS (M+H)+: 213.0.1H NMR (500 MHz, CDCl3) d: 7.57 (d, J = 7.9 Hz, 1H), 7.43- 7.40 (m, 2H), 2.56 (s, 3H), 2.52 (s, 3H).
70%
In tetrahydrofuran at 20℃; for 74h; Reflux;
57.1 1. Synthesis of 1-(4-bromo-2-methylphenyl)ethan-1-one
Methylmagnesium iodide (3M, 10.2 mL) was added dropwise to a solution of 4-bromo-2- methyl-benzonitrile (4.0 g, 20 mmol) in THF (20 mL) at RT. The reaction mixture was heated under reflux for 2 h, cooled to RT, and stirred for a further 72 h. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH4Cl solution (100 mL) and extracted into EtOAc (2 x 100 mL). The combined organics were concentrated in vacuo and the residue treated with aqueous HCl solution (4 N, 20 mL) at 0 °C and the mixture was then stirred at RT for 18 h. The reaction mixture was extracted with EtOAc (50 mL), washed with H2O (50 mL), dried (Na2SO4), and concentrated in vacuo to give the title compound as a pale orange oil (3.0 g, 70%). LCMS m/z = 213.0 [M+H]+
70%
Stage #1: methyl magnesium iodide; 4-bromo-2-methylbenzonitrile In tetrahydrofuran at 70℃; for 74h;
Stage #2: With hydrogenchloride; water at 0 - 20℃; for 18h;
86.1 1. Synthesis of 1-(4-bromo-2-methylphenyl)ethan-1-one
To a solution of 4-bromo-2-methyl-benzonitrile (4.0 g, 20.4 mmol) in THF (20 mL) was added dropwise iodo(methyl)magnesium (3 M, 10.2 mL) at rt. The reaction mixture was heated to reflux (~70 °C) for 2 h and then was cooled to rt and stirred for 72 h. The reaction mixture was placed in an ice-water cooling bath and saturated aqueous NH4Cl solution (100 mL) was added, followed by EtOAc (100 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (100 mL). The combined organic extracts were concentrated in vacuo and the resulting residue was treated with an HCl solution (4 N, 20 mL) at 0 °C. The mixture was then stirred at rt for 18 h. The reaction mixture was extracted with EtOAc (50 mL) and the organic layer was washed with H2O (50 mL), dried (Na2SO4), and filtered. The filtrate was concentrated in vacuo to give 1-(4-bromo-2-methylphenyl)ethan-1-one as a pale orange oil (3.04 g, yield: 70%). ESI-MS (M+H)+: 213.0.1H NMR (500 MHz, CDCl3) δ: 7.57 (d, J = 7.9 Hz, 1H), 7.43- 7.40 (m, 2H), 2.56 (s, 3H), 2.52 (s, 3H).
70%
Stage #1: methyl magnesium iodide; 4-bromo-2-methylbenzonitrile In tetrahydrofuran at 70℃; for 74h;
Stage #2: With hydrogenchloride; water at 0 - 20℃; for 18h;
86.1 1. Synthesis of 1-(4-bromo-2-methylphenyl)ethan-1-one
To a solution of 4-bromo-2-methyl-benzonitrile (4.0 g, 20.4 mmol) in THF (20 mL) was added dropwise iodo(methyl)magnesium (3 M, 10.2 mL) at rt. The reaction mixture was heated to reflux (~70 °C) for 2 h and then was cooled to rt and stirred for 72 h. The reaction mixture was placed in an ice-water cooling bath and saturated aqueous NH4Cl solution (100 mL) was added, followed by EtOAc (100 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (100 mL). The combined organic extracts were concentrated in vacuo and the resulting residue was treated with an HCl solution (4 N, 20 mL) at 0 °C. The mixture was then stirred at rt for 18 h. The reaction mixture was extracted with EtOAc (50 mL) and the organic layer was washed with H2O (50 mL), dried (Na2SO4), and filtered. The filtrate was concentrated in vacuo to give 1-(4-bromo-2-methylphenyl)ethan-1-one as a pale orange oil (3.04 g, yield: 70%). ESI-MS (M+H)+: 213.0.1H NMR (500 MHz, CDCl3) δ: 7.57 (d, J = 7.9 Hz, 1H), 7.43- 7.40 (m, 2H), 2.56 (s, 3H), 2.52 (s, 3H).
With diethyl ether Erhitzen des vom Aether befreiten Reaktionsgemisches und anschliessend Erwaermen mit wss. Essigsaeure;
<strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (1 mmol) was suspended in water (49 mL) and potassium hydroxide was added (50 mmol); the reaction mixture was stirred at reflux overnight. After cooling, the basic solution was washed with ethyl acetate (3 x 15 mL), acidified with hydrochloric acid (6M) and extracted with ethyl acetate (3 x 15 mL). The organic phase deriving from the acidic extraction was dried over anhydrous sodium sulfate and concentrated in vacuo, yielding the desired product as a white solid. Yield: 60%. TLC (dichloromethane - methanol 9:1): Rf = 0.46. Mp: 182C. 1H-NMR (300 MHz, CD3OD) delta (ppm) 7.80 (d, J = 8.4 Hz, 1H, H6), 7.48 (s, 1H, H3), 7.42 (d, J = 8.4 Hz, 1H, H5), 2.56 (s, 3H, CH3).
With sulfuric acid; trifluoroacetic acid; In water; at 65℃; for 18h;
A. 4-Bromo-2-methylbenzamide. A solution of 4-bromo-2- methylbenzonitrile (1.0 g, 5.1 mmol), trifluoroacetic acid (4.0 mL) and sulfuric acid (1.0 mL) were combined and heated to 65 C for 18 h. The reaction was poured into ice water and the product precipitated and was collected by filtration. The resulting material was dried under vacuum overnight to afford the title compound as a white solid (0.96 g, 88%). MS (ESI) m/z 420.5 [M+ 1]+.
75%
With water; potassium hydroxide; In ethanol; at 80℃; for 16h;
Preparation 15: 2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzamide; Step 1 : 4-bromo-2-methylbenzamide; To a solution of <strong>[67832-11-5]4-Bromo-2-methylbenzonitrile</strong> (3.00 g, 15.3 mmol) in ethanol (9 mL) was added 10% aqueous potassium hydroxide (8.60 mL, 15.3 mmol). The reaction was heated to 8O0C for 16 h. The reaction was cooled to 40C and the precipitated solid was filtered and washed with water to give the title compound as a white solid (2.45 g, 75%). 1H NMR (500 MHz, DMSO-d6) delta ppm 7.71 (bs, 1 H), 7.40 (m, 3H), 7.26 (d, 1 H), 2.31 (s, 3H).
With potassium hydroxide; water; In ethanol; for 6h;Heating / reflux;
4-Bromo-2-methylcyanobenzene (1Og, 51 mmol) was added to EtOH/water (4:1, 180 ml), to this was added KOH (6.3g, 112 mmol) and the reaction was heated at reflux for 6 hours. The reaction was allowed to cool (solid precipitated). The EtOH was removed in vacuo until 25% of the original volume remained. The solid was filtered and dried. NMR (299.955 MHz) 7.71 (s, IH), 7.45 (s, IH), 7.40 - 7.38 (m, 2H), 7.28 (d, IH), 2.34 (s, 3H); m/z 215.
To a solution of 4-bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF (100 ml) at -78C under a nitrogen atmosphere was added dropwise a 2.5 M solution of n-butyl lithium (4.48 ml, 11.2 mmol). The mixture was stirred at -78C for 1h and then poured onto solid carbon dioxide (5 g) in THF (50 ml). The mixture was allowed to warm to room temperature. Water was added (200 ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid identified as 4-cyano-3-methylbenzoic acid (1.2 g, 73%).
73%
Example B 4-Cyano-3-methylbenzoic acid To a solution of 4-bromo-2-methylbenzonitrile (2.0g, 10.2mmol) in THF (100ml) at -78C under a nitrogen atmosphere was added dropwise a 2.5M solution of n-butyl lithium (4.48ml, 11.2mmol). The mixture was stirred at -78C for 1h and then poured onto solid carbon dioxide (5g) in THF (50ml). The mixture was allowed to warm to room temperature. Water was added (200ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid identified as 4-cyano-3-methylbenzoic acid (1.2g, 73%).
73%
To a solution of 4-bromo-2-methylbenzonitrile (2.0g, 10.2mmol) in THF (100ml) at -78C under a nitrogen atmosphere was added dropwise a 2.5M solution of n-butyl lithium (4.48ml, 11.2mmol). The mixture was stirred at -78C for lh and then poured onto solid carbon dioxide (5g) in THF (50ml). The mixture was allowed to warm to room temperature. Water was added (200ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HC1 and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgS04, and concentrated in vacuo to give a white solid; yielding (73%).
73%
To a solution of 4-bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF (100 ml) at -78 C. under a nitrogen atmosphere was added dropwise a 2.5M solution of n-butyl lithium (4.48 ml, 11.2 mmol).. The mixture was stirred at -78 C. for 1 h and then poured onto solid carbon dioxide (5 g) in THF (50 ml).. The mixture was allowed to warm to room temperature.. water was added (200 ml) and the mixture was extracted with diethyl ether (3 times).. The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times).. The combined chloroform extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 1.2 g (73%).
64%
Asolution of nBuLi in THF (2.5 M, 4.49 mL, 11.2 mmol) was added dropwise to astirred solution of 4-bromo-2-methylbenzonitrile (2.0 g,10.2 mmol) in dry THF (100 mL) at -78 C. and the solution stirred at -78 C.for 1 h. A stream of dry CO2 was bubbled through the solution for 10 min andthe mixture warmed to 20 C. The mixture was diluted with water (100 ml) andwashed with Et2O (3×20 mL). The aqueous phase was acidified to pH 2 with cHCland extracted with CHCl3 (3×50 mL) and the organic fraction was dried and thesolvent evaporated to give crude acid 171 (1.05 g, 64%)
60.8%
A solution of 2.5 M n-butyllithium in hexanes(6.7 mL, 16.8 mmol) was added to anhydrous THF (15 mL) at -78 C. A solution of 4-bromo-2-methylbenzonitrile 21 (3.0 g, 15.3 mmol) in THF (15 mL) was then added dropwise and allowed to stir for 30 min. Dry ice (solid CO2) was added and the solution was allowed to stir 1 h while warming to room temperature. The reaction was then concentrated in vacuo and the resulting residue was triturated in ether and filtered. The solid was dissolved in EtOAc and washed with 2 M HCl and brine. The organic layer was isolated, dried over MgSO4, concentrated in vacuo, then triturated in ether/ hexane and dried under high vacuum. Obtained 4-cyano-3-methylbenzoic acid 22 (1.5 g, 60.8% yield) as a white solid. 1H NMR (400 MHz, CDCl3) delta (ppm) 8.18 (s, 1H), 8.02-8.09 (m, 1H), 7.75-7.81 (m, 1H), 2.61 (s, 3H).
34%
To a -780C cooled solution of 4-bromo-2-methylbenzonitrile (4.00 g, 20.40 mmol) in THF (200 mL) under nitrogen atmosphere, 2.5M solution of n-BuLi in hexanes (10 ml_, 25 mmol) was slowly added and the resulting solution left to stir at -780C for 1 hour. This solution was slowly poured into a mixture of solid CO2 (10 g) in THF (100 mL) and it was stirred at room temperature overnight. The solvent was concentrated in vaccuo, water was added, it was extracted with diethyl ether (x 3) and the aqueous phase was acidified with 5N hydrochloric acid. The solid was filtered and dried to yield 1.11 g (34% yield) of the title compound.LRMS: m/z 160(M-I )-Retention time: 4.82min (method B)
With sodium carbonate In 1,2-dimethoxyethane; water for 3.5h; Heating;
Stage #1: 4-bromo-2-methylbenzonitrile; 3-fluoro-4-methoxy-phenylboronic acid With potassium carbonate In water at 20℃; for 0.25h;
Stage #2: With palladium dichloride In water
4.3. General procedure for the preparation of compounds 3a-r
General procedure: A reaction mixture of 2a-e (5.0 mmol, 1.0 equiv.), differentsubstituted 4-bromobenzonitrile (6.0 mmol, 1.2 equiv.) and potassiumcarbonate (12.5 mmol, 2.5 equiv.) in PEG400/H20 (10 mL/10 mL) was stirred at room temperature for 15 min, and PdCl2(0.05 mmol, 0.01 equiv.) was subsequently added. Stirring wascontinued for an additional 15 h until complete consumption ofstarting material as judged by TLC. Then the reaction mixture waspoured into water (80 mL) and extracted with ethyl acetate(30 mL*3). The organic layers were washed with brine, dried overanhydrous Na2SO4, filtered and condensed under reduced pressure.The residuewas then purified via column chromatography on silicagel, eluting with EtOAc/petroleum ether to 3a-r as white solid.
With potassium carbonate; palladium dichloride In water at 20℃; for 15h;
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In monoethylene glycol diethyl ether; water;Heating / reflux;
Method B. A mixture of 4-bromo-2-methylbenzonitrile (1.8 g, 9. 18 mmol), 4-tert- butyl-dimethylsilyoxyphenylboronic acid (3.0 g, 11.9 mmol), sodium carbonate (13.8 mL of 2 M aqueous solution, 27.5 MMOL), tetrakis (triphenylphosphine) palladium (0.53 g, 0.46 mmol), and ethylene glycol dimethyl ether (70 mL) were heated to reflux overnight. The mixture was cooled to room temperature and poured into water, then extracted with ethyl acetate (3x), washed with brine, dried over sodium sulfate, filtered, and the solvent evaporated. Purification by silica chromatography (15 %-25 % ethyl acetate-hexane) to yield 1. 81 g (94 %) of the title compound as a yellowish solid: MP 177-178 C ; H NMR (DMSO-d6): 6 2.52 (3H, s), 6.88 (2H, d, J= 8.50 Hz), 7.60 (3H, d, J= 8. 49 Hz), 7.71 (1H, s), 7.77 (2H, d, J= 8. 12 Hz), 9.79 (1H, s); IR 2220 CM-1 ; MS (ESI) M/Z 208 (M-H)-. Anal. for CL4HNNO : Calc'd: C: 80.36, H: 5.30, N: 6.69 Found : C: 79. 91, H: 5.27, N: 6.57.
With sodium carbonate;Pd(PPh3)4; In ethanol; hexane; dichloromethane; benzene;
Example 106A 4'-methoxy-3-methyl-1,1'-biphenyl-4-carbonitrile <strong>[67832-11-5]4-Bromo-2-methylbenzonitrile</strong> (4.9 g, 25.0 mmol), Pd(PPh3)4 (578 mg) in benzene (50 mL) and 2.0 M aqueous solution of Na2CO3 (25 mL, 50.0 mmol) was treated with 4-methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) and heated at 75 C. for 17 hours. The mixture was allowed to cool to room temperature and the phases were separated. The aqueous phase was extracted with diethyl ether (3*40 mL). The original benzene layer and the diethyl ether extracts were combined, filtered over celite, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography over silica using a mixture of hexane/CH2Cl2 (3:1) to provide the title compound as a white powder (5.73 g, 85% yield). 1H-NMR (300 MHz, CDCl3) delta 2.35 (3H), 3.70 (s, 3H), 6.80-7.50 (m, 7H); MS (DCI) m/z 224 (M+H)+.
85%
With sodium carbonate;Pd(PPh3)4; In ethanol; hexane; dichloromethane; benzene;
EXAMPLE 164A 4'-methoxy-3-methyl-1,1'-biphenyl-4-carbonitrile <strong>[67832-11-5]4-Bromo-2-methylbenzonitrile</strong> (4.9 g, 25.0 mmol), Pd(PPh3)4 (578 mg) in benzene (50 mL) and 2.0 M aqueous solution of Na2CO3 (25 mL, 50.0 mmol) was treated with 4-methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) and heated at 75 C. for 17 hours. The mixture was allowed to cool to room temperature and the phases were separated. The aqueous phase was extracted with diethyl ether (3*40 mL). The original benzene layer and the diethyl ether extracts were combined, filtered over celite, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography over silica using a mixture of hexane/CH2Cl2 (3:1) to provide the title compound as a white powder (5.73 g, 85 % yield). 1H-NMR (300 MHz, CDCl3) delta 2.35 (3H), 3.70 (s, 3H), 6.80-7.50 (m, 7H); MS (DCI) m/z 224 (M+H)+.
85%
With sodium carbonate;Pd(PPh3)4; In ethanol; hexane; dichloromethane; benzene;
EXAMPLE 164A 4'-methoxy-3-methyl-1,1'-biphenyl-4-carbonitrile <strong>[67832-11-5]4-Bromo-2-methylbenzonitrile</strong> (4.9 g, 25.0 mmol), Pd(PPh3)4 (578 mg) in benzene (50 mL) and 2.0 M aqueous solution of Na2CO3 (25 mL, 50.0 mmol) was treated with 4-methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) and heated at 75 C. for 17 hours. The mixture was allowed to cool to room temperature and the phases were separated. The aqueous phase was extracted with diethyl ether (3*40 mL). The original benzene layer and the diethyl ether extracts were combined, filtered over celite, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography over silica using a mixture of hexane/CH2Cl2 (3:1) to provide the title compound as a white powder (5.73 g, 85% yield). 1H-NMR (300 MHz, CDCl3) delta2.35 (3H), 3.70 (s, 3H), 6.80-7.50 (m, 7H); MS (DCI) m/z 224 (M+H)+.
General procedure: A reaction mixture of 2a-e (5.0 mmol, 1.0 equiv.), differentsubstituted 4-bromobenzonitrile (6.0 mmol, 1.2 equiv.) and potassiumcarbonate (12.5 mmol, 2.5 equiv.) in PEG400/H20 (10 mL/10 mL) was stirred at room temperature for 15 min, and PdCl2(0.05 mmol, 0.01 equiv.) was subsequently added. Stirring wascontinued for an additional 15 h until complete consumption ofstarting material as judged by TLC. Then the reaction mixture waspoured into water (80 mL) and extracted with ethyl acetate(30 mL*3). The organic layers were washed with brine, dried overanhydrous Na2SO4, filtered and condensed under reduced pressure.The residuewas then purified via column chromatography on silicagel, eluting with EtOAc/petroleum ether to 3a-r as white solid.
Step 1: tert-butyl 3-(4-cyano-3-methylphenyl)acrylateA mixture of 4-bromo-2-methyl benzonitirle (5 g, 0.025 mol), tert-butylacrylate (15 ml_, 0.102 mol), and triethylamine (10.6 ml_, 0.076 mol) in dry acetonitrile (50 ml_) was purged with nitrogen for 10 min. Palladium acetate (0.286 g, 0.0012 mol) and triphenyl phosphine (0.334 g, 0.0012 mol) were added to the reaction mixture and refluxed at 9O C for 48hrs. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography using silica gel (60-120mesh) and pet ether/ethyl acetate as an elutent to afford the title compound as a white solid (5.3 g, 85%). 1H-NMR (DMSO d6, 400MHz) delta 7.84 (1 H,s), 7.79-7.81 (1 H, d), 7.69-7.71 (1 H, d), 7.53-7.57(1 H, d), 6.67-6.71 (1 H, d), 2.49 (3H, s), 1.49 (9H, s).
With N-Methyldicyclohexylamine;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; johnphos; In 1,4-dioxane; at 70℃; for 16h;
N-HYDROXYAMIDINE 1; N-Hydroxy 3-methyl-4-(2-(tert-butoxecarbonyl) ethyl) benzamidine; Step A: tert-Butyl 3- (3-methyl-4-cyanophenyl) acrylate; A solution of 10.0 g (51. 0 mmol) of 4-bromo-2-methylbenzonitile in 80 mL of 1,4-dioxane was treated with 7.19 g (56.1 mmol) of tert-butyl acrylate, 10.96 g (56.1 mol) of N- methyldicyclohexylamine, 228 mg (0.76 mol) of 2- (di-tert-butylphosphino) biphenyl, and 396 mg (0.38 mol) of tris (dibenzylideneacetone) dipalladium (0)-chloroform adduct. The resulting mixture was heated at 70 C for 16 h and cooled to rt. The reaction mixture was filtered though a filter paper, and the filtrate was concentrated. The crude product was partitioned into four portions. Chomatography on four Biotage 40M cartridges using 19: 1 v/v hexanes/EtOAc as the eluant followed by pooling of product fractions afforded 10.0 g of the title compound :'H NMR (500 MHz, CDCl3) o 1.55 (s, 9H), 2.58 (s, 3H), 6.44 (d, J = 16.0, 1H), 7.41 (d, J = 8.0, 1H), 7.45 (s, 1H), 7.53 (d, J = 16.0, 1H), 7.61 (d, J = 8.0, 1H).
Description 91; 4-Bromo-2-methylbenzaldehyde (D91); To 4-bromo-2-methylbenzonitrile (2 g, 10.2 mmol) in toluene (60 mL) cooled to 5 C under argon was added Dibal-H (11.2 mL, 1M solution in toluene, 11.2 mmol) dropwise. The reaction was stirred at 50C for 30 minutes then MeOH (3 mL) and 2 M H2SO4 (10 mL) were added dropwise. The mixture was stirred for ~19h then concentrated in vacuo. The residue was re-dissolved in water/EtOAc. The organic layer was dried and concentrated to give the crude title compound as a brown oil <n="88"/>(1.81 g) which was used in the next step without further purification. 6H (CDCI3, 400MHz) 10.20 (1 H, s), 7.65 (1H, d), 7.50 (1 H1 dd), 7.43 (1 H, m), 2.64 (3H, s).
With diisobutylaluminium hydride; In hexane; at -78 - 20℃; for 1.5h;
To a solution of 4-bromo-3-methylbenzonitrile (0.975 g; 5.00 mmol) in anhyd CH2Cl2(7.5 mL) at -40 C. was added DIBAL-H (7.5 mL of a 1M solution in hexanes; 7.5 mmol), dropwise over 5 min. The mixture was stirred 30 min at -40 C., removed from the cooling bath and stirred 1 h at rt. The mixture was cooled in an ice bath, and excess hydride was quenched by dropwise addition of MeOH. After stirring 20 min, Rochelle's salt (satd aq. solution) was added, the mixture was stirred at rt overnight, and the layers were separated. The aqueous layer was extracted with CH2Cl2(×2), combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless solid (Note 1). Note 1 The title compound was oxidized rapidly on standing in air to a mixture of benzaldehyde and benzoic acid. The title compound was prepared from 4-bromo-2-methylbenzonitrile according to the procedure described for Example I-IX-1 with exceptions as follows: the reaction temperature was -78 C. (instead of -40 C.); the reaction was quenched with MeOH at -78 C. (instead of ice bath temp), followed by addition of 6M HCl at -78 C. (instead of satd Rochelle's salt); after quenching the reaction mixture was stirred 30 min at room temperature (instead of overnight). Colorless oil;
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 79℃; for 6h;
4-Bromo-2-bromomethylbenzonitrile (TJA01043) C8H5Br2N MW 274.94. <strong>[67832-11-5]4-Bromo-2-methylbenzonitrile</strong> (5.00 g, 25.5 mmol), N-bromosuccinimide (4.99 g, 28.1 mmol), benzyl peroxide (0.198 g, 0.816 mmol) and carbon tetrachloride (100 mL) were loaded to a r.b. flask and set to reflux (79 C) for 6 h. Once cooled the succinimide was filtered off and carbon tetrachloride removed via a dry ice-acetone cooled rotary evaporator. The residues were dissolved in dichloromethane (100 mL) and washed with distilled H2O (50 mL x 3) and brine (50 mL x 2). Dried over Na2SO4 and solvent removed in vacuo to leave yellow residues. Column chromatography (hexane/dichloromethane 60:40) eluted the title compound as a yellow solid. Recrystallisation (cyclohexane) gave a white crystalline solid (5.07 g, 73 %), mp 61.7-77.2 0C; <n="87"/>i?/ 0.30 (hexane/dichloromethane 60:40), c.f. 0.36 (dibromobenzylbromide), 0.36 (4- bromo-2-methylbenzonitrile) ;HPLC (60 % CH3CN in H2O) R, 3.130 (50.62 %), 2.701 (42.38 %, dibromobenzylbromide) ; MS (EI), m/z 274.0 (M- - H, 34 %).
56%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 18h;Reflux; Inert atmosphere;
Step 1: 4-Bromo-2-(bromomethy])benzonitrile A mixture of 4-bromo-2-tnethylbenzonitrile (2.0 g, 10 mmol), l-bromopyrrolidine-2,5-dione (1.82 g, 10,2 mmol) and benzoic peroxyanhydride (0.124 g, 0.510 mmol) in CCU (10 mL) was heated at reflux under nitrogen for about 18 h. The reaction was cooled to rt, diluted with DCM (25 mL) and washed with sat. aq. NaIiC03 (20 mL) and water (20 mL). The organic layer was dried over Na2S04 and filtered. The residue was dried onto silica gel and purified on silica gel using a gradient of 0-20% EtOAc in heptane. The product fractions were combined and concentrated to yield the title compound (1.57g, 56%); NMR (400 M i l/. CDC13) delta 7.73 (d, J ------ 1.8 Hz, 1 1 1 ). 7.57 (dd, J = 8.3, 1.8 Hz, IH), 7.52 i d . J = 8.3 Hz, 1H), 4.57 (s, 2H).
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 16h;
[0455j To a solution of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (2 g, 10.2 mmol) in 15 mL CC14were added NBS (1.8 g, 10.2 mmol) and AIBN (340 mg, 2.08 mmol). The mixture was stirred at 80 C for 16 h. After diluted with water (30 mL), the mixture was extracted with DCM (50 mL x2). The combined organic layer was washed with H20 (30 mL x 2), dried (Na2SO4), filtered and concentrated. The crude product was used in the next step without further purification.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 6h;
A mixture of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (15.00 g, 74.2 mmol), NBS (13.87 g, 77.9mmol) and benzoyl peroxide (0.63 g, 2.60 mmol) in CC14 (250 ml) was heated at 80 C for 6 hr.The suspension was filtered and concentrated. The residue was purified by flash chromatography(EtOAc in petroleum ether: 0 to 10%) to afford the title compound.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 6h;
A mixture of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (15.00 g, 74.2 mmol), NBS (13.87 g, 77.9mmol) and benzoyl peroxide (0.63 g, 2.60 mmol) in CC14 (250 ml) was heated at 80 C for 6 hr.The suspension was filtered and concentrated. The residue was purified by flash chromatography(EtOAc in petroleum ether: 0 to 10%) to afford the title compound.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 6h;
Step A: 4-bromo-2-(bromomethyl)benzonitrileA mixture of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (15.00 g, 74.2 mmol), NBS (13.87 g, 77.9 mmol) and benzoyl peroxide (0.63 g, 2.60 mmol) in Cd4 (250 ml) was stirred at 80 C for 6 h. The suspension was filtered and concentrated. The residue was purified via a BIOTAGE columnusing 0-10% EtOAc/petroleum ether as eluting solvents to afford the title compound.
With N-Bromosuccinimide; benzyl peroxide; In tetrachloromethane; for 6h;Reflux;
<strong>[67832-11-5]4-Bromo-2-methylbenzonitrile</strong> 1 (80 g, 408.16 mmol), N-bromosuccinimide (72.24 g,408.16 mmol), benzyl peroxide (197.74 g, 816.32 mmol) and carbon tetrachloride were loaded in a flask and set to reflux for 6 hours. Once cooled, the succinimide precipitate was filtered off and carbon tetrachloride was removed via a dry ice-acetone cooled rotary evaporator. The residue was dissolved in dichloromethane (300 mL), washed with distilled water (200 mLx3) and brine (200 mLx2), dried over sodium sulfate, filtered and concentrated to leave a residue. The residue was purified by silica gel column chromatography to give the title compound.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 6h;
A mixture of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (15.00 g, 74.2 mmol), NBS (13.87 g, 77.9 mmol) and benzoyl peroxide (0.63 g, 2.60 mmol) in CCl4 (250 ml) was heated at 80 C. for 6 hr. The suspension was filtered and concentrated. The residue was purified by flash chromatography (EtOAc in petroleum ether: 0 to 10%) to afford the title compound
Intermediate T2-Methyl-4-methylsulfanyl-benzonitrile To a solution of 4-bromo-2-methylbenzonitrile (2 g, 10.20 mmol) in DMF (50 ml) is added NaSMe (1.260 g, 17.98 mmol) and the reaction left stirring at RT overnight. After this time the contents are diluted with water before extracting into EtOAc. The organic moiety is separated and washed with H2O, NaHCO3, Brine, dried (MgSO4) and evaporated down to give a pale yellow solid; MS m/z=164.0 [M+H]+; H NMR 400.13 MHz (CDCl3) -7.50 (1H, d), 7.12 (1H, s), 7.09 (1H, d), 2.51 (6H, s).
In N,N-dimethyl-formamide at 20℃; for 15h; Inert atmosphere;
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 79℃; for 6h;
4-Bromo-2-bromomethylbenzonitrile (TJA01043); CgH5Br2N MW 274.94 4-Bromo-2-methylbenzonitrile (5.00 g, 25.5 mmol), N-bromosuccinimide (4.99 g, 28.1 mmol), benzyl peroxide (0.198 g, 0.816 mmol) and carbon tetrachloride (100 mL) were loaded to a r. b. flask and set to reflux (79 °C) for 6 h. Once cooled the succinimide was filtered off and carbon tetrachloride removed via a dry ice-acetone cooled rotary evaporator. The residues were dissolved in dichloromethane (100 mL) and washed with distilled H20 (50 mL x 3) and brine (50 mL x 2). Dried over Na2S04 and solvent removed in vacuo to leave yellow residues. Column chromatography (hexane/dichloromethane 60: 40) eluted the title compound as a yellow solid. Recrystallisation (cyclohexane) gave a white crystalline solid (5.07 g, 73 %), mp 61.7- 77.2 °C which was then used without further purification; Rf 0.30 (hexane/dichloromethane 60: 40), c. f. 0.36 (dibromobenzylbromide), 0.36 (4-bromo-2- methylbenzonitrile). HPLC (60 % CH3CN in H20) Rt 3.130 (50.62 %), 2.701 (42.38 %, dibromobenzylbromide); MS (EI), m/z 274.0 (M+, 34 %).
dibenzoyl peroxide; In chloroform; at 85℃; for 48h;
To a stirred mixture of 4-Bromo-2-methyl-benzonitrile (5.00 g, 25.5 mmol) in CCl4 (40 mL) under argon was added N-bromosuccinamide (5.00 g, 28.1 mmol) and a catalytic amount of benzoyl peroxide. This mixture was heated at 85 C. for 2 days and cooled to room temperature. The precipitate was filtered off and the cake was rinsed with CCl4 (2×10 mL). The filtrate was concentrated in vacuo to give 7.2 g crude 4-Bromo-2-bromomethyl-benzonitrile (quantitative yield) which was used without further purification.
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; water;
EXAMPLE B 4-Cyano-3-methylbenzoic acid To a solution of 4-bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF (100 ml) at -78 C. under a nitrogen atmosphere was added dropwise a 2.5M solution of n-butyl lithium (4.48 ml, 11.2 mmol). The mixture was stirred at -78 C. for 1 h and then poured onto solid carbon dioxide (5 g) in THF (50 ml). The mixture was allowed to warm to room temperature. Water was added (200 ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 1.2 g (73%).
1.2 g (73%)
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; water;
Example C 4Cyano-3methylbenzoic acid To a solution of 4bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF (100 ml) at -78 C. under a nitrogen atmosphere was added dropwise a 2.5M solution of n-butyl lithium (4.48 ml, 11.2 mmol). The mixture was stirred at -78 C. for 1 h and then poured onto solid carbon dioxide (5 g) in THF (50 ml). The mixture was allowed to warm to room temperature. Water was added (200 ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 1.2 g (73%).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 20 - 90℃; for 25h;
A mixture of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (14, 22 g, 112 mmol), benzoyl peroxide (2.7 g, 11 mmol) in 400 mL carbon tetrachloride was treated with n-bromosuccimide (21 mL, 247 mmol) at room temperature, then warmed up to 90 C. and stirred for 15 h. After 15 h of reaction, another 20 g of NBS was added and the reaction was stirred at 90 C. for another 10 h. Thin layer chromatography (TLC) revealed that all the starting material had been consumed. The reaction was cooled down to room temperature, filtered, and washed with hexane (100 mL). The filtrate was concentrated in vacou, and the crude product was purified via flash chromatography (silica gel) eluting with a gradient of 4/1 hexanes/EtOAc to 2/1 hexanes/EtOAc, to give as a white solid, 4-bromo-2-(dibromomethyl)benzonitrile 15, 29.6 g. Found MS (ES+): 354 (M+H)+.
With N-Bromosuccinimide; Perbenzoic acid; In tetrachloromethane; at 20 - 90℃; for 25h;
Synthesis of 6-bromo-l -chlorophthalazine (18) Step A: A mixture of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (14, 22 g, 112 mraol), benzoyl peroxide (2.7 g, 11 mmol) in 400 mL carbon tetrachloride was treated with n- bromosuccimide (21 mL, 247 mmol) at RT, then warmed up to 90 0C and stirred for 15 h. After 15 h of reaction, another 20 g of NBS was added and the reaction was stirred at 90 0C for another 1O h. Thin layer chromatography (TLC) revealed that all the starting material had been consumed. The reaction was cooled down to RT, filtered, and washed with hexane (100 mL). The filtrate was concentrated in vacuo, and the crude product was purified via flash chromatography (silica gel) eluting with a gradient of 4/1 hexanes/EtOAc to 2/1 hexanes/EtOAc, to give as a white solid, 4-bromo-2- (dibromomethyl)benzonitrile IS, 29.6g. Found MS (ES+): 354 (M+H)+.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 85℃; for 10h;
Compound BB-2H-1 (11.50 g, 58.66 mmol) was dissolved in carbon tetrachloride (150 mL) at room temperature, followed by addition of N-bromobutanimide (31.32 g, 175.98 mmol) and benzoyl peroxide (1.42 g, 5.87 mmol). After completion of the addition, the reaction mixture was heated to 85 C and stirred for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, followed by filtration. The filter cake was wash with ethyl acetate (50 mL). The filtrate was combined and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (50 mL), washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the title compound BB-2H-2 (pale-yellow solid, 20.00 g). The crude product was used directly in the next step without purification. 1H NMR (400MHz,CDCl3) delta: 8.18 (d, J = 1.8 Hz, 1H), 7.60 (dd, J = 1.8, 8.3 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 6.92 (s, 1H).
10.21 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 3.00 g of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> in 50 ml of dry tetrahydrofuran at -78C. After stirring at this temperature for 30 minutes, 4.22 ml of triisopropyl borate are added, and then the mixture is stirred at -78C for a further 45 minutes. 30 ml of 1 N HCl are added to the reaction mixture. The phases are separated and the aqueous phase is extracted three more times with 100 ml of diethyl ether/tetrahydrofuran (1:1) each time. The combined organic phases are dried with sodium sulphate, filtered and concentrated to 4 ml in vacuo. The remaining oil is mixed with 100 ml of pentane, and the precipitate which has separated out is filtered off with suction and washed twice with pentane. Drying under high vacuum results in 1.82 g of the title compound as a white solid. Rt = 2.93.
10.21 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 3.00 g of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> in 50 ml of dry tetrahydrofuran at -78 C. after stirring at this temperature for 30 minutes, 4.22 ml of triisopropyl borate are added, and then the mixture is stirred at -78 C. for a further 45 minutes. 30 ml of 1N are added to the reaction mixture. The phases are separated and the aqueeous phase is extracted three more times with 100 ml of diethyl ether/tetrahydrofuran (1,1) each time. The combined organic phases are dried with sodium sulphate, filtered and concentrated to 4 ml in vacuo. The remaining oil is mixed with 100 ml of pentane, and the precipitate which has separated out is filtered off with suction and washed twice with penteane. Drying under high vacuum results in 1.82 g of the title compound as a white solid. Rt. 2.93.
Reference Example 5-46 4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-2-methylbenzonitrile A solution of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (1.0 g) in tetrahydrofuran (16 mL) was cooled to an external temperature of -78 C. in a nitrogen atmosphere, and a solution of n-butyllithium in hexane (1.57 M, 3.5 mL) was added dropwise. After stirring at -78 C. for 40 minutes, triisopropyl borate (1.5 mL) was added dropwise and the mixture was stirred at room temperature for 1.5 hours. 1 M hydrochloric acid (10 mL) was added to the reaction solution, followed by extraction with diethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was dissolved in toluene (4 mL) and tetrahydrofuran (3 mL), and 2,2-dimethyl-1,3-propanediol (531 mg) and anhydrous magnesium sulfate (catalytic amount) were added, after which the mixture was stirred at room temperature for five minutes. The insoluble matter in the reaction solution was filtered off, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1?20:1) to give the title compound as a colorless solid (778 mg, 67%). 1H NMR (300 MHz, CDCl3) delta ppm 1.02 (s, 6H), 2.54 (s, 3H), 3.78 (s, 4H), 7.56 (d, J=7.7 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 7.73 (s, 1H).
10.21 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 3.00 g of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> in 50 ml of dry tetrahydrofuran at -78C. After stirring at this temperature for 30 minutes, 4.22 ml of triiso propyl borate are added, and then the mixture is stirred at -78C for a further 45 minutes. 30 ml of 1 N HCI are added to the reaction mixture. The phases are separated and the aqueous phase is extracted three more times with 100 ml of diethyl ether/tetrahydrofuran (1 :1) each time. The combined organic phases are dried with sodium sulphate, filtered and concentrated to 4 ml in vacuo. The remaining oil is mixed with 100 ml of pentane, and the precipitate which has separated out is filtered off with suction and washed twice with pentane. Drying under high vacuum results in 1.82 g of the title compound as a white solid. Rt = 2.93.
47.1
PREPARATION 47;4-Bromo-2-(2-oxoethyl)benzonitrile.Step 1 : 4-Bromo-2-methylbenzonitrile (5.00 g, 25.50 mmol) and t- butoxybis(dimethylamino)methane were heated to 1400C with vigorous stirring. After ~ 2hrs, the bubbling of the distilling t-butanol ceased and the reaction was cooled, slurried with hexanes (30 mL) and filtered to obtain 4.6 g, (72%) of 4-bromo-2-(2- dimethylaminovinyl)benzonitrile as an orange solid: NMR (CDCI3) 7.46 (d, J = 1.7 Hz, 1 H), 7.27 (d, J = 9.1 Hz, 1 H), 7.02-6.97 (m,2H), 7.28 (d, J = 13.3 Hz, 1H), 2.92 (s, 6H).
With hydrogenchloride; carbon dioxide; In tetrahydrofuran; hexane;
(a) 4-Cyano-3-methylbenzoic acid n-Butyl lithium (1.38M in hexane, 5.54 ml, 7.65 mmol) was added dropwise to a solution of 2-methyl-4-bromobenzonitrile (1.5 g, 7.65 mmol) in THF (40 ml) at -100 C. The resulting dark red solution was stirred for 5 min., quenched by the cautious addition of solid carbon dioxide and warmed to room temperature. The solution was diluted with 10% aqueous sodium hydroxide and extracted with ethyl acetate. The aqueous layer was acidified with ice-old 4N aqueous HCl, extracted with dichloromethane and the extracts dried over sodium sulphate and evaporated to furnish a white solid (880 mg), MS (+EI) 233 ([M+TMS]+), 1H NMR (d6 -DMSO) 13.50 (1H, br. s), 8.00 (1H, s), 7.92-7.86 (2H, m), 2.55 (3H, s).
With triethylamine;palladium diacetate; tris-(o-tolyl)phosphine; In acetonitrile; at 200℃; for 2h;microwave irradiation;
9.0 g <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong>, 2.76 g tri-o-tolylphosphine, 3.11 ml acrylic acid and 25.1 ml triethylamine are dissolved in 80 ml acetonitrile. The reaction mixture is degassed , then 2.0 g palladium (ll)acetate were added and the mixture stirred two hours under microwave irradiation at 2000C. The cooled reaction mixture was diluted by addition of 50 ml ethylacetate. Thereby (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid precipitated as a white solid. The precipitate was filtered off and dried in vacuo to obtain 2.5g (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid. The filtrate was washed with 1 N HCI, thereby (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid precipitated again as a white solid. The precipitate was filtered off and dried in vacuo to obtain 2.Og (E)-3-(4- EPO <DP n="67"/>Cyano-3-methyl-phenyl)-acrylic acid. The filtrate was reduced in vacuo to one third of its volume, 150 ml diethylether were added, thereby (E)-3-(4-Cyano-3-methyl-phenyl)- acrylic acid precipitated again as a white solid. The precipitate was filtered off and dried in vacuo to obtain 840 mg (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid. C11 H9NO2 (187.20), MS(ESI): 188.1 (M+H+), Rf(ethyl acetate : methanol = 9:1) = 0.16.
Stage #1: 4-bromo-2-methylbenzonitrile With n-butyllithium In tetrahydrofuran; hexane at -95℃; for 0.166667h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -95℃; for 0.5h;
74
Reference Example 74 4-formyl-2-methylbenzonitrile n-Butyl lithium hexane solution (33.6 mL, manufactured by Kanto Chemical Co., Inc) was dripped to a tetrahydrofuran/hexane solution (246 mL/66 mL) of 4-bromo-2-methylbenzonitrile (9.45 g, manufactured by Lancaster) over 20 minutes at -95° C. or less at a nitrogen ambience. After the dripping was ended, the resultant mixture was stirred for 10 minutes at -95° C., and a tetrahydrofuran solution (52 mL) of N,N-dimethylformamide (4.48 mL, manufactured by Kanto Chemical Co., Inc) was dripped there into over 20 minutes at -95° C. or less. The resultant blend was further stirred for 10 minutes, and the temperature of the blend was increased to room temperature. A saturated ammonium chloride aqueous solution was added to the reaction solution, and extraction was performed by using ethyl acetate. An organic layer was washed with a saturated sodium bicarbonate solution and a saturated saline solution, dried by using sodium sulfate, and concentrated under a reduced pressure, so that 7.11 g of the titled compound was obtained. The obtained residue was directly used for the next reaction. 1H-NMR (CDCl3) 10.1 (1H, s), 7.83 (1H, s), 7.79 (2H, s), 2.65 (3H, s)
Stage #1: 4-bromo-2-methylbenzonitrile With n-butyllithium In tetrahydrofuran at -78℃; for 0.0833333h; Inert atmosphere;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -78℃; for 0.333333h; Inert atmosphere;
24.A 4-Formyl-2-methylbenzonitrile
To a stirred solution of 4-bromo-2-methylbenzonitrile (4.0 g, 20 mmol) in 100 mL of anhydrous THF was added BuLi (1.6 M, 12.8 mL) dropwise at -78 °C under nitrogen atmosphere. After the addition, the pale red solution was stirred for 5 min at -78 °C and dry DMF (2.2 mL) then added dropwise. After 20 min, the reaction mixture was poured onto a saturated solution of sodium chloride (100 mL). The organic phase was separated, extracted with diethyl ether (100 mL), dried over Na2SO4 and distilled off the solvent to afford 4-formyl-2-methylbenzonitrile. MS m/z: 146 (M+1)+.
(Ss)-ethylidene-N-tert-butyl-sulphinamide[ No CAS ]
[ 67832-11-5 ]
[ 1065064-94-9 ]
Yield
Reaction Conditions
Operation in experiment
24%
(a) (Ss,R)-2-methyl-propane-2-sulphinic acid-[2-(5-bromo-2-cyano-phenyl)-1 - methyl-ethyl]-amide; <n="24"/>6.0 ml (42.8 mmol) diisopropylamine are dissolved in 80 ml THF, slowly combined with 26.7 ml (42.8 mmol) butyllithium solution (1.6 M in n-hexane) at 00C, stirred for 30 min. Then this solution is cooled to -78C and a solution of 4.0 g (20.4 mmol) 4-bromo-2-methyl-benzonithle in 15 ml THF is slowly added dropwise. This mixture is stirred for 70 minutes at -78C and then a solution of 1.5 g (10.2 mmol) (Ss)-ethylidene-N-tert.-butyl-sulphinamide (prepared analogously to J. Ellman et al. J. Org. Chem. 2001 , 66, 8772 from acetaldehyde and (Ss)-tert.-butylsulphinamide) in 15 ml THF is added dropwise. The mixture is stirred for 2.5 hours at -70 to -65C. The reaction mixture is combined with 5 ml sat. Ammonium chloride solution and after thawing it is combined with water and ethyl acetate. The aqueous phase is extracted three times with ethyl acetate, the combined organic phases are dried on sodium sulphate and evaporated to dryness in vacuo. The residue is purified by column chromatography on silica gel (eluant DCM/MeOH 100:3) Yield: 830 mg (24%) Rt value: 1.45 min (Method B) Mass spectrum: (M+H)+ = 343/345 (bromine isotope)
(a) (S.q,R)-2-methyl-propane-2-sulphinic acid-r2-(5-bromo-2-cvano-phenyl)-1- methyl-ethyli-amide; 6.0 ml (42.8 mmol) diisopropylamine are dissolved in 80 ml THF, slowly combined with 26.7 ml (42.8 mmol) butyllithium solution (1.6 M in n-hexane) at 00C, stirred for 30 min. Then this solution is cooled to -78C and a solution of 4.0 g (20.4 mmol) 4-bromo-2-methyl-benzonithle in 15 ml THF is slowly added dropwise. The mixture is stirred for 70 minutes at -78C and then a solution of 1.5 g (10.2 mmol) (Ss)-ethylidene-N-tert.-butyl-sulphinamide (prepared analogously to J. Ellman et al. J. Org. Chem. 2001 , 66, 8772 from acetaldehyde and (Ss)-tert.-butylsulphinamide) in 15 ml THF is added dropwise thereto. The mixture is stirred for 2.5 hours at -70 to -65C. The reaction mixture is combined with 5 ml sat. ammonium chloride solution and after thawing it is mixed with water and ethyl acetate. The aqueous phase is extracted three times with ethyl acetate, the combined organic phases are dried on sodium sulphate and <n="65"/>evaporated to dryness i. vac. The residue is purified by column chromatography on silica gel (eluant DCM/MeOH 100:3) Rt value: 1.45 min (Method B) Mass spectrum: (M+H)+ = 343/345 (bromine isotopes)
Stage #1: methyllithium With cerium(III) chloride In tetrahydrofuran; diethyl ether at -65 - 20℃; for 24.5h;
Stage #2: 4-bromo-2-methylbenzonitrile In tetrahydrofuran; diethyl ether at -65 - -40℃; for 4h;
48
In a dried apparatus, Cerium (III) trichloride ultradry (5g, 20.28 mmol) is introduced under Ar and anhydrous THF is added (40 ml). The resultant suspension gives a milky solution after 24h stirring at RT. The mixture is then cooled to -650C and a solution of MeLi (1.6 M in Et2O, 12.67 ml_, 20.28 mmol) is added dropwise and the canary yellow suspension is stirred for 30 min. A solution of 4-bromo-2-methylbenzonitrile (1.365 g, 6.76 mmol) in THF (5 ml) is added and the reaction is further stirred at -650C for 4h before allowing to warm to -4O0C. The brown suspension is quenched by addition of 20 ml of 25% ammoniaque solution and then allow to warm to RT. The resulting solids are removed by filtration on a pad of Celite and washed three times with EtOAc. The combined filtrates are washed with brine, dried over Na2SO4 and concentrated in vacuo to give the desired compound as a colorless liquid. Rt = 0.735 min (Acquity UPLC BEH C18, 2.1x50mm, 1.7 micron, detection 215nM, 0.1 min 2% CH3CN in H2O , 2% to 100% CH3CN in H2O in 1.5min, 0.4 min 100% CH3CN + 0.1% TFA, flow rate 1.0ml/min); MS: 211 (M-NH3+1 , 79Br)+ .
With tetraphosphorus decasulfide In ethanol at 70℃; for 10h; Inert atmosphere;
With sodium hydrogensulfide; magnesium chloride In N,N-dimethyl-formamide at 20℃; for 1.5h;
3.1
To a slurry solution of sodium hydrosulphide (2.80 g, 50 mmol) and magnesium chloride hexahydrate (5.05 g, 25 mmol) in dimethylformamide (50 ml) is added 4-bromo-2-methyl benzonitrile (4.90 g, 50 mmol) in one portion and the resulting green slurry is stirred at room temp for 90 minutes. The reaction mixture is poured onto water (200 ml) and the resultant precipitate filtered and washed with water. This yellow solid is then suspended in 2N HCI (200 ml) and stirred for 1 hour, then filtered, washed with water and hexane and dried in vacuuo to give 4- bromo-2-methyl-thiobenzamide (820 mg).
With hydroxylamine hydrochloride; water; sodium hydroxide In ethanol at 80℃; for 12h;
A.24.a Step a) 4-Bromo-N-hydroxy-2-methyl-benzamidine
A solution of 4-bromo-2-methylbenzonitrile (1.0 g, 5.1 mmol), hydroxylaminehydrochloride (0.71 g, 10.2 mmol) and NaOH (408 mg, 10.2 mmol) in ethanol (10 mL)and water (1 mL) was stirred at 80 °C for 12 h. The reaction mixture was concentratedunder reduced pressure to give a crude product and water (10 mL) was added dropwiseinto the reaction mixture. The reaction mixture was filtered and the filter cake was washed with 10 mL water and dried under vacuum to give the title compound (900 mg, 77.0%) as a white solid. MS (ESI): m/z = 229.1 [M+Hj
With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol Reflux;
11
In a 500 mL round-bottom flask, 4-bromo-2-methylbenzonitrile (5 g, 25 mmol) was dissolved in 200 mL of methanol. To the mixture was added hydroxylammonium chloride (1.72 g, 25 mmol) followed by DIEA (diisopropylethylamine) (8.7 mL, 50 mmol). The mixture was heated at reflux for overnight. The solvents were removed. The residue was dissolved in 200 mL of CHCl3. To the mixture was added 2-furoyl chloride (3.97 ml, 25 mmol) followed by DIEA (8.7 mL, 50 mmol). After reaction completion, the mixture was extracted with chloroform and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was dissolved in 200 mL of dioxanes. To the mixture was added 1 eq of DIC (N,N'-diisopropylcarbodiimide) followed by 1 eq of DIEA. The mixture was then heated at reflux overnight. After reaction completion, the mixture was cooled down. The solvents were removed in vacuo. The residue was then extracted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography on silica gel in a 0-20% ethyl acetate/hexanes gradient to afford 2.23 g of the desired compound 3-(4-Bromo-2-methyl-phenyl)-5-furan-2-yl-[1,2,4]-oxadiazole as a white powder in an overall yield of 36%.Chemical Formula: C13H9BrN2O2; MW: 305.13; HPLC Purity>99.0%; (254 nm) ESMS: tR=7.81 min; m/z 305.1 (M+1);1H-NMR (250 MHz, D6-DMSO): 8.18-8.19 (m, 1 H), 7.92 (d, J=8.3, 1H), 7.58-7.70 (m, 3H), 6.86-6.90 (m, 1H), 2.59 (s, 3H)
With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol Reflux;
1 Formula IVa Example: 3-(4-l3romo-2-methyl-phe- nyl)-5-furan-2-yl-[ 1,2,4] -oxadiazole
In a 500 mE round-bottom flask, 4-bromo-2-meth- ylbenzonitrile (5 g, 25 mmol) was dissolved in 200 mE of methanol. To the mixture was added hydroxylammonium chloride (1.72 g, 25 mmol) followed by DIEA (diisopropylethylamine) (8.7 mE, 50 mmol). The mixture was heated at reflux for overnight. The solvents were removed. The residue was dissolved in 200 mE of CHC13. To the mixture was added 2-throyl chloride (3.97 ml, 25 mmol) followed by DIEA (8.7 mE, 50 mmol). After reaction completion, the mixture was extracted with chloroform and watet The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was dissolved in 200 mE of dioxanes. To the mixture was added 1 eq of DId (N, N’-diisopropylcarbodiimide) followed by 1 eq of DIEA. The mixture was then heated at reflux overnight. Afier reaction completion, the mixture was cooled down. The solvents were removed in vacuo. The residue was then extracted with ethyl acetate and watet The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography on silica gel in a 0-20% ethyl acetate hexanes gradient to afford 2.23 g of the desired compound 3-(4-l3romo-2-methyl-phenyl)-5-thran-2-yl-[1 ,2,4]-oxadi- azole as a white powder in an overall yield of 36%.
Preparation 89 4-Aminomethyl-3-methyl-benzoic acid methyl ester Add the palladium acetate (1.5 g, 6.5 mmol), 1,1'-bis(diphenylphosphino)ferrocene (4.4 g, 7.9 mmol), <strong>[67832-11-5]4-bromo-2-methyl-benzonitrile</strong> (12.5 g, 64 mmol), methanol (159 ml), acetonitrile (240 ml), triethylamine (46 ml) to the Parr autoclave. Seal the autoclave, purge with N2 (6*), purge with carbon monoxide (6*), and pressurize with carbon monoxide (862 KPa). Heat the reaction at 100 C. for 24 hrs. Allow the reaction mixture to cool to room temperature and filter. Concentrate the filtrate. Re-dissolve the residue (41 g) in methanol (1 L). Add 7N ammonia in methanol (428 mL) and Raney nickel (8 ml). Purge with nitrogen gas (3*), purge with hydrogen gas (3*), and pressurize with hydrogen gas to 419 KPa. Heat it at 40 C. for 18 hrs. Allow to cool to room temperature and filter the reaction mixture. Concentrate the filtrate to provide the crude title compound (16.8 g).
Stage #1: 4-bromo-2-methylbenzonitrile With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃;
Stage #2: (RS)-N-ethylidene-tert-butanesulfinamide In tetrahydrofuran; hexane at -78 - -65℃;
26.a
6.0 ml (42.8 mmol) diisopropylamine are dissolved in 80 ml THF, slowly mixed with 26.7 ml (42.8 mmol) butyllithium solution (1.6 M in n-hexane) at 0° C. and stirred for 30 min. Then this solution is cooled to -78° C. and a solution of 4.0 g (20.4 mmol) 4-bromo-2-methyl-benzonitrile in 15 ml THF is slowly added dropwise. This mixture is stirred for 70 minutes at -78° C. and then a solution of 1.5 g (10.2 mmol) (Ss)-ethylidene-N-tert.-butyl-sulphinamide (prepared analogously to J. Ellman et al. J. Org. Chem. 2001, 66, 8772 from acetaldehyde and (Ss)-tert.-butylsulphinamide) in 15 ml THF is added dropwise. The mixture is stirred for 2.5 hours at -70 to -65° C. The reaction mixture is combined with 5 ml of sat. ammonium chloride solution and after thawing water and ethyl acetate are added. The aqueous phase is extracted three times with ethyl acetate, the combined organic phases are dried through sodium sulphate and evaporated to dryness i. vac. The residue is purified by column chromatography on silica gel (eluant DCM/MeOH 100:3)Rt value: 1.45 min (Method B)C14H19BrN2OS (343.28)Mass spectrum: (M+H)+=343/345 (bromine isotopes)
With tetraethylammonium chloride;palladium diacetate; In N,N-dimethyl acetamide; at 100℃; for 15h;Inert atmosphere;
Example 10; 3-(4-(5-(8-Bromo-6-(trifluor omethyl)imidazo [ 1 ,2-a] pyridin-2-yl)- 1 ,2,4-oxadiazol-3-yl)-3- methylphenyl) butanoic acid[00364] tert-Butyl 3-(4-cyano-3-methylphenyl) but-2-enoate (52).; To a stirred solution of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (5.O g, 26 mmol) in dimethylacetamide (50 mL) was added tert-butyi crotonate (4.35 g, 30.6 mmol) and the reaction mixture was degassed with argon. To this solution, Pd(OAc)2 (0.114 g, 0.510 mmol) was added followed by tetraethylammonium chloride (4.22 g, 25.5 mmol) and the reaction was stirred at 1000C for 15 h. After completion, the reaction mixture was quenched with ice cold water and extracted with ether. The combined organic layers were washed with water, saturated NaCl solution, dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by column chromatography to afford the title intermediate 52 as a yellow solid (5.2 g, yield 80%).
Stage #1: 4-bromo-2-methylbenzonitrile With N-Bromosuccinimide; 1,1'-azobis(1-cyanocyclohexanenitrile) In tetrachloromethane for 24h; Heating / reflux;
Stage #2: sodium methylate In methanol at 20℃; for 2h;
10
Intermediate 10: 4-bromo-2-(methoxymethyl)benzoic acidThe nitrile, 4-bromo-2-methylbenzonitrile (750mg, 3.83 mmol), N-bromosuccinimide (2.0g, 26.0 mmol) and l,l'azobis(cyclohexanecarbonitrile) (lOOmg, 0.410 mmol) dissolved in 30.0 ml of carbon tetrachloride was refluxed 24 hours, the resulting reaction mixture filtered and concentrated. The resulting residue was then dissolved in a 25% sodium methoxide solution in methanol (10 mL) stirred 2 hours at room temperature. This mixture was then concentrated, partitioned between water and ethyl acetate. The organic layer was separated then concentrated under reduced pressure. The resulting residue was purify on silicagel (heptane/ ethyl acetate 9:1) to yield (320 mg) of the intermediate 4-bromo-2- (methoxymethyl)benzonitrile. This residue was dissolved in isobutanol (4.0 mL) heated to reflux. Distilled water (0.5 mL) and sodium hydroxide (400mg, 10 mmol) were added. The reaction mixture was stirred at this temperature for 48 hours. The solvents were then evaporated , the resulting residue dissolved in distilled water (5.0 mL). This solution was acidified with aqueous IN HCl, a pale red solid formed which was filtered and dried (200 mg, 27%). Trituration with ethyl acetate gave a pale solid (34 mg, 4%). IH NMR (600 MHz, EPO DMSO-D6) δ ppm 3.38 (s, 3 H) 4.75 (s, 2 H) 7.60 (dd, J=8.32, 1.66 Hz, 1 H) 7.74 (s, 1 H) 7.80 (d, J=8.45 Hz, 1 H).
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 80℃; for 5h;Inert atmosphere;
Preparation 14: 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzonitrile; A mixture of dichloro[1 ,1 ,'-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct (2.12 g, 2.55 mmol), potassium acetate (7.66 g, 76.5 mmol), and bis(pinacolato) diboron (7.12 g, 28.1 mmol) was flushed with nitrogen. 1 ,2- dimethoxyethane (130 ml_) and <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (5.00 g, 25.5 mmol) were added. The reaction was stirred at 80C for 5 h. The reaction was cooled to room temperature and filtered through celite. The filtrate was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. Silica gel was added and the mixture was concentrated. The crude material was purified by silica column chromatography eluting with a gradient of 0%- 45% ethyl acetate / heptane to give the title compound (5.07 g, 82%) as a white solid. 1H NMR (500 MHz, DMSO-d6) delta ppm 7.70 (m, 2H), 7.57 (d, 1 H), 2.45 (s, 3H), 1.26 (s, 12H).
69%
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 5h;
Example 1: Synthesis of 4-{4-{1-hydroxyethyl)pyridin-3-yl)-2-methylbenzonitrileStep 1: 2-methyl-4-(4,4,5l5-tetramethyl-1 ,3 2-dioxaborolan-2-yl)benzonitrile (1a)A mixture of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (1 g, 5.10 mmol), bis(pinacolato)diboron (1.554 g, 6.12 mmol), potassium acetate (1.001 g, 10.20 mmol) and PdCI2(dppf).CH2CI2 adduct (0.208 g, 0.255 mmol) in 1 ,4-Dioxane (12.75 ml) was heated to 80 C for 5 hr. The mixture was concentrated, and the residue was purified via Biotage (0-10% EtOAc/heptane; SNAP50 column) giving compound 1 as white solid (860 mg, 69%). 1H NMR (400 MHz, CDCI3) delta ppm 1.28 (s, 12 H) 2.38 - 2.52 (m, 3 H) 7.51 (d, J=7.64 Hz, 1 H) 7.55 - 7.64 (m, 1 H) 7.67 (s, 1 H).
69%
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 5h;
A mixture of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (1 g, 5.10 mmol), bis(pinaco.ato)diboron (1.554 g. 6.12 mmol), potassium acetate (1.001 g, 10.20 mmol) and PdCI2(dppf).CH2CI? adduct (0.208 g, 0.255 mmol) in 1 ,4-dioxane (12.75 ml) was heated to 800C for 5 h. The mixture was concentrated, and the residue was purified via Biotage (0*10% EtOAc/heptane; SNAP50 column) giving compound 2-methyl-4-(4,4,5,5-tetramethyl- 113<;2-dioxaborolan-2-yl)benzonit?le as a white solid (860 mg, 69%). 1H NMR (400 MHz, chloroform-d) d ppm 1.28 (s, 12 H) 2.38 - 2.52 (m, 3 H) 7.51 (d, J«7.64 Hz, 1 H) 7.557.64 (m, 1 H) 7.67 (s, 1 H).
1.55 g
With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; tricyclohexylphosphine; In 1,4-dioxane; at 100℃; for 1h;Microwave irradiation; Inert atmosphere;
Preparation 76 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile [0289] In a microwave tube, combined Pd2(dba)3 (0.070 g, 0.077 mmol) and tricyclohexylphosphine (0.103 g, 0.367 mmol). Dioxane (15.32 ml) was added and the resulting mixture was stirred for 30 minutes at room temperature. Bis(pinacolato)diboron (1.425 g, 5.61 mmol), potassium acetate (0.751 g, 7.65 mmol) and 4-bromo-2- methylbenzonitrile (1 g, 5.10 mmol) were added successively. The tube was flushed with nitrogen. Then the reaction mixture was stirred in microwave at 100C for 1 hour. The mixture was treated with water (26 mL), and extracted with ether. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give the title compound (1.55 g) which was used in next step without further purification.
With sodium carbonate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In water; acetonitrile; at 85℃; for 18h;Inert atmosphere of nitrogen;
(S)-tert-Butyl 4-( 1 -amino- 1 -oxo-3-(4-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2- yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 180 mg) and <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (72 mg) in acetonitrile (8 mL) were treated with an aqueous solution of sodium carbonate (2M, 0.348 mL) and nitrogen was bubbled through the mixture. 1,1 delta(Di-fert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85C for 18 h. The mixture was concentrated and purified by chromatography on silica eluting with 50 to 100% ethyl acetate / ohexane to afford the subtitled compound (127 mg). m/e (APCI-) 505 [M-H]"
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 15h;Inert atmosphere;
General procedure for coupling reaction: An oven-dried resealable Schlenk tube were charged with Pd(OAc)2 (6.7 mg, 0.03 mmol), Xantphos (34.7 mg, 0.06 mmol), 2-methylpropane-2-sulfinamide (145 mg, 1.2 mmol) and Cs2CO3 (650 mg, 2.0 mmol). The Schlenk tube was evacuated and back-filled with argon. <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (196 mg, 1.0 mmol) and dioxane (3 ml) were added and the Schlenk tube was then sealed with a Teflon screw cap and placed in a preheated oil bath at 100oC for 15 h. After cooling of the reaction mixture to room temperature, water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The product was purified by flash chromatography. Yield: 228 mg, 97 % [table-1, entry-5].
With potassium phosphate; copper(l) iodide; trans-N,N,N?,N'-tetramethylcyclohexane-1,2-diamine; In toluene; at 110℃;Inert atmosphere;
General procedure: In a Schlenk tube are added 6-azaindole (0.846 mmol), potassium phosphate (1.78 mmol) and CuI(0.042 mmol). The tube is twice evacuated and back-filled with Ar. Toluene (1 ml), 2-chloro-5-iodotoluene (0.846 mmol) and (trans)-N,N'-dimethyl-1,2-cyclohexanediamine (0.085 mmol) are added. The tube is sealed and the reaction mixture is stirred for 22 h at 110 C. The reaction mixture is diluted with dichloromethane and dry loaded on silica gel to be purified by flash chromatography (hexane/EtOAc 10% to 30%) to give 1-(4-chloro-3-methylphenyl)-1H-pyrrolo[2,3-c]pyridine as a white solid (184 mg).
With sodium t-butanolate In toluene for 16h; Inert atmosphere; Reflux;
S.1.3
A solution of 3-(3-chloro-5-methyl-phenyl)-3-trifluoromethyl-pyrrolidine (8.50 g, 29.9 mmol), 4-bromo-2-methoxybenzonitrile (7.04 g, 35.9 mmol), tris(dibenzylideneacetone) dipalladium (1 .096 g, 1.20 mmol), NaOtBu (4.255 g, 44.28 mmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthen (xanthphos CAS [161265-03-8], 1 .30 g, 2.21 mmol) in degassed toluene (120 ml.) was heated at reflux under argon for 16 h. After cooling, water was added and the mixture was filtered. The aqueous phase was extracted with ethyl acetate, dried over Na2S04 and concentrated in vacuum. The residue was purified by flash chromatography on silica gel to obtain the title compound (3.7 g, 31 %). Characterization by HPLC-MS: 4.559 min, M = 399.00Characterization by 1H-NMR (400 MHz, CDCI3):δ = 2.48 (s, 3H), 2.56 (m, 1 H), 2.87 (m, 1 H), 3.50 (m, 1 H), 3.60 (m, 1 H), 3.79 (d, 1 H), 4.10 (d, 1 ), 6.41 (m, 2H), 7.27 (m, 2H), 7.39 (s, 1 H) 7.45 (d, 1 H) ppm.
With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 150℃; for 0.25h;Microwave irradiation; Inert atmosphere; Sealed tube;
Example 1174'-(3- [(3S)- 1 -(cyclopropylcarbonyl)-3 -pyrrolidinyljmethyl} -5-oxo- 1 ,5-dihydro-4H- l,2,4-triazol-4-yl)-3'-fluoro-3-methyl-4-biphenylcarbonitrilea) A solution of 5-[(3S)-l-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[2-fluoro-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-l,2,4-triazol-3-one (0.245 mmol) in dioxane (1.5 mL) was treated with <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (0.245 mmol), dichloro[ 1 , 1 '-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10 mg), and 2M aq potassium carbonate (0.736 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in a microwave (Biotage Initiator) at 150 C for 15 min. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH ~4 using IN aq HC1 and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, treated with Si-Thiol (Silicycle, 20 mg), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (20-50%) acetonitrile/water + 0.1%> NH4OH) to afford the title compound as an amorphous off-white solid (57%). MS(ES)+ m/e 446.2 [M+H]+.
Stage #1: 4-bromo-2-methylbenzonitrile With n-butyllithium In tetrahydrofuran at -78℃; for 1h;
Stage #2: (+)-(1R,6S)-2,2,6-trimethyl-1-cyclohexanecarbaldehyde In tetrahydrofuran at -78℃; for 1h;
51
To a solution of 4-bromo-2-methylbenzonitrile (494.4 mg, 2.52mmol) in tetrahydrofuran (6 mL) at -78 °C was added n-butyl lithium (1 .6 mL, 2.52 mmol) and the mixture was stirred for 1 hour. Then the product of Example 1 b (300 mg, 1 .94 mmol) in tetrahydrofuran (2 mL ) was added and the mixture was stirred at -78 °C for 1 hour. Aqueous saturated ammonium chloride (20 mL) was added to quench the reaction and then it was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 50:1 ) to afford 150 mg of a white solid which was further purified by prep-HPLC to afford the title compound as a white solid (32 mg, Yield: 6%). Mp = 1 1 1 -1 13 °C; Rf = 0.4 (30:1 ) petroleum ether/: ethyl acetate); 1H NMR (400 MHz, CDCI3) δ 7.53 (d, J = 8.0 Hz, 1 H), 7.36 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 5.08 (s, 1 H), 2.55 (s, 3 H), 1 .86-1 .77 (m, 1 H), 1 .68-1 .57 (m, 2 H), 1 .52-1 .47 (m, 3 H), 1 .39 (d, J = 10.8 Hz, 1 H), 1 .31 -1 .25 (m, 1 H), 1 .15 (s, 3 H), 1 .06 (s, 3 H), 0.96-0.93 (m, 1 H), 0.54 (d, J =6.4 Hz, 3 H) ppm; Mass spectrum (ESI +ve) m/z 272 (M+H+); [a]D26 2 = +3.20° (c = 0.25, dichloromethane).
Multi-step reaction with 3 steps
1.1: diisopropylamine; n-butyllithium / tetrahydrofuran / 1.5 h / -40 °C
1.2: 0.25 h / -40 °C
2.1: methanol; sodium tetrahydroborate / tetrahydrofuran / -40 - 20 °C
3.1: sulfuric acid / ethanol / 24 h / Reflux
Multi-step reaction with 2 steps
1.1: diisopropylamine; n-butyllithium / tetrahydrofuran / -40 °C / Inert atmosphere
1.2: 0.25 h / -40 °C
2.1: sodium tetrahydroborate; methanol / tetrahydrofuran / 20 °C
2.2: 24 h / Reflux
Stage #1: 4-bromo-2-methylbenzonitrile With n-butyllithium; diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at -40 - 0℃; for 1.75h;
Stage #2: With sodium tetrahydroborate In tetrahydrofuran; N,N-dimethyl-formamide at 20℃;
Stage #3: With sulfuric acid In tetrahydrofuran; N,N-dimethyl-formamide for 24h; Reflux;
6-bromo-3 ,4-dihydro- 1 H-isochromen- 1-one
Method A: A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogeninlet needle, and thermocouple was charged with diisopropylamine (3.10 g, 30.6 mmol) and 30mL of THE. The reaction mixture was cooled at -20 °C while n-BuLi (2.5 M, 12.2 mL, 30.6 mmol) was added dropwise via syringe keeping the internal temperature below 0 °C. The resulting reaction mixture was stirred at 0 °C for 15 mm. The reaction mixture was then cooled at -40 °C while 4-bromo-2-methylbenzonitrile (4.00 g, 20.4 mmol) in 10 mL of THF was addeddropwise via syringe over 1 h. An internal temperature of ca. -40 °C was maintained during the addition. The resulting reaction mixture was stirred at -40 °C for 30 mm and then charged with DMF (2.98 g, 40.8 mmol, ca. 50 ppm water) in one portion. The reaction mixture was stirred at - 40 °C for 15 mm. The reaction mixture was quenched with MeOH (5 vol., 20 mL) and then charged with NaBH4 (0.770 g, 20.4 mmol) in one portion and allowed to warm to roomtemperature. After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HC1 (with cooling) to adjust the pH to 2-3. The reaction mixture was extracted with EtOAc and then solvent-switched to EtOH (40 mL). H2S04 (98%, 20.0 g, 204 mmol) was added in one portion and the resulting reaction mixture was stirred at reflux for 24 h. After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature and then solvent-switched to EtOAc. The resulting organic layer was washed with water, brine, and solvent-switched to MTBE. Precipitation from 1:1 MTBE:heptane afforded 6-bromo-3 ,4-dihydro- 1H-isochromen- 1 -one
Stage #1: 4-bromo-2-methylbenzonitrile With n-butyllithium; diisopropylamine In tetrahydrofuran at -40℃; for 1.5h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -40℃; for 0.25h;
30.1 INTERMEDIATE 30 (Method 1)
A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle, and thermocouple was charged with diisopropylamine (4.36 mL, 30.6 mmol) and 30 mL of THF. The reaction mixture was cooled at -20 °C while «-BuLi (2.5 M, 12.2 mL, 30.6 mmol) was added dropwise via syringe keeping the internal temperature below 0 °C. The resulting reaction mixture was stirred at 0 °C for 15 minutes. The reaction was then cooled at -40 °C while 4-bromo-2-methylbenzonitrile (4.00 g, 20.4 mmol) in 10 mL of THF was added dropwise via syringe over 1 hour. An internal temperature of ca. -40 °C was maintained during the addition. The resulting reaction mixture was stirred at -40 °C for 30 minutes and then charged with DMF (ca. 50 ppm water) in one portion. The reaction mixture was stirred at -40 °C for 15 minutes. The reaction mixture was quenched with MeOH (5 vol., 20 mL) and then charged with NaB¾ (0.77 g, 20.4 mmol) in one portion and allowed to warm to room temperature. After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HC1 (with cooling) to adjust the pH to 2-3. The reaction mixture was extracted with EtOAc and then solvent-switched to EtOH. H2S04 (98%, 10.9 mL, 204 mmol) was added in one portion and the resulting reaction mixture was stirred at reflux for 24 hours. After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature and then solvent-switched to EtOAc. The resulting organic layer was washed with water, washed with brine, and solvent-switched to MTBE. Crystallization from 1 : 1 MTBE:heptane afforded 6-bromo-3,4-dihydro-l H-isochromen- 1 -one.
Stage #1: 4-bromo-2-methylbenzonitrile With n-butyllithium; diisopropylamine In tetrahydrofuran at -40℃; Inert atmosphere;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -40℃; for 0.25h;
A INTERMEDIATE 5 6-bromo-3 ,4-dihydro- lH-isochromen- 1 -one Method A:
A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle, and thermocouple was charged with diisopropylamine (3.10 g, 30.6 mmol) and 30 mL of THF. The reaction mixture was cooled at -20 °C while n-BuLi (2.5 M, 12.2 mL, 30.6 mmol) was added dropwise via syringe keeping the internal temperature below 0 °C. The resulting reaction mixture was stirred at 0 °C for 15 min. The reaction mixture was then cooled at -40 °C while 4-bromo-2-methylbenzonitrile (4.00 g, 20.4 mmol) in 10 mL of THF was added dropwise via syringe over 1 h. An internal temperature of ca. -40 °C was maintained during the addition. The resulting reaction mixture was stirred at -40 °C for 30 min and then charged with DMF (2.98 g, 40.8 mmol, ca. 50 ppm water) in one portion. The reaction mixture was stirred at -40 °C for 15 min. The reaction mixture was quenched with MeOH (5 vol., 20 mL) and then charged with NaBH4 (0.770 g, 20.4 mmol) in one portion and allowed to warm to room temperature. After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HC1 (with cooling) to adjust the pH to 2- 3. The reaction mixture was extracted with EtOAc and then solvent-switched to EtOH (40 mL). H2S04 (98%o, 20.0 g, 204 mmol) was added in one portion and the resulting reaction mixture was stirred at reflux for 24 h. After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature and then solvent-switched to EtOAc. The resulting organic layer was washed with water, brine, and solvent-switched to MTBE. Precipitation from 1 :1 MTBE:heptane afforded 6-bromo-3,4-dihydro-lH-isochromen-l-one.
Step l:4-(2-Hydroxyethoxy)-2-methylbenzonitrile (3_46_2) [00389] Sodium hydride (60 %, 0.62 g, 40.8 mmol) was added slowly to ethylene glycol (40 mL) and the resulting mixture was stirred at room temperature for 0.5 hour. <strong>[67832-11-5]4-Bromo-2-methylbenzonitrile</strong> 3_46_1 (2.0 g, 10.2 mmol) was then added followed by copper(I) bromide (0.44 g, 3.06 mmol) and the reaction mixture was heated at 120C for 2 hours, cooled to room temperature, poured into water (300 mL), and extracted with ethyl acetate (3 x 100 mL). The combined ethyl acetate layers were washed with water (2 x 200 mL) and brine (1 x 200 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 3_46_2 (1.6 g, 88 % yield) as a pale yellow solid. [00390] NMR (400 MHz, CDC13): delta = 2.51 (s, 3H), 3.94-4.04 (m, 2H), 4.07- 4.15 (m, 2H), 6.74-6.87 (m, 2H), 7.53 (d, J = 8.6 Hz, 1H).
ethyl 1-amino-6-bromo-3,3-dimethyl-3,4-dihydronaphthalene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
Anhydrous diglyme (18mL) was added to a dry round-bottomed flask and cooled to -78C. Diisopropylamine (1.45mL, 10.2 mmol) and n-butyllithium (2.5M in hexanes, 4.1 mL, 10.2 mmol) were added. The reaction was allowed to briefly warm up to 0C with stirring before recooling to -78C. A solution of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (1.0 g, 5.1 mmol) in diglyme (3 mL) was added slowly dropwise, causing the reaction to evolve a dark red color, and was allowed to stir for 20 minutes. Ethyl-3, 3 -dimethyl acrylate (1.06 mL, 7.65 mmol) was then added dropwise. Concurrently, to a separate dry round bottomed flask was added diglyme (6 mL) and zinc dust (834 mg, 12.75 mmol). The reaction was cooled to -78C, then iodine (2.59 g, 10.2 mmol) was added slowly portionwise. The mixture was removed from the -78C bath and gently warmed with a heat gun until all traces of iodine were removed. The mixture was re- cooled to -78C and then added to the first reaction vessel. The reaction was allowed to warm to room temperature over the course of 2 hours, then was quenched by the addition of saturated aqueous NH4CI. The aqueous solution was extracted 5x with ether, then the combined organic extracts were washed 5x with water and lx with brine. The organic layer was isolated, driedover MgSO/t, filtered, and concentrated in vacuo. Further purification via flash chromatography (2% - 15% EtOAc:hex) furnished 890 mg of the desired product as a yellow solid, 54% yield.
50%
Toa dry flask containing anhydrous diglyme (18 mL) was added diisopropylamine (1.45mL, 10.2 mmol). The solution was cooledto -78C in a dry ice bath, then n-butyllithium(2.5 M in hexane, 4.1 mL, 10.2 mmol) was added slowly. A solution of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (5, 1.00 g, 5.1 mmol) in anhydrousdiglyme (~3 mL) was added slowly dropwise, then the solution allowed to stirfor 45 minutes before the dropwise addition of ethyl-3,3-dimethylacrylate (1.06 mL, 7.65 mmol) was added dropwise. The solution was allowedto stir for 1 hour at -78C before addition of a freshly prepared solution ofzinc iodide (3.26 g, 10.2 mmol) in anhydrous diglyme (6 mL). The suspension was allowed slowly warm toroom temperature and stir an additional 2 hours. Reaction was quenched with sat. aq. NH4Cl,then extracted 3x with diethyl ether.Organic layer was washed 3x with H2O, 1x with brine, thenisolated, dried, filtered, and concentrated.Purification by flash chromatography (100% hex to 5% EtOAc:hex) isolatedthe desired product as a yellow oil, (867 mg, 50% yield). 1H NMR(500 MHz, CDCl3) delta 7.41 (dd, J = 8.3, 2.1 Hz, 1H), 7.33 (d, J= 2.1 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 6.23 (s, 2H), 4.25 (q, J= 7.1 Hz, 2H), 2.62 (s, 2H), 1.34 (t, J = 7.1 Hz, 3H), 1.19 (s, 6H).
Stage #1: N,N-dimethyl-formamide With n-butyllithium; diisopropylamine In tetrahydrofuran; mineral oil at -20 - 0℃; for 0.25h; Inert atmosphere;
Stage #2: 4-bromo-2-methylbenzonitrile In tetrahydrofuran; N,N-dimethyl-formamide at -40℃; for 1.5h;
Stage #3: With sodium tetrahydroborate In tetrahydrofuran; N,N-dimethyl-formamide at 20℃;
5 INTERMEDIATE 5 6-bromo-3,4-dihydro-1H-isochromen-1-one
6-bromo-3,4-dihydro-1H-isochromen-1-one; Method A: A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogeninlet needle, and thermocouple was charged with diisopropylamine (3.10 g, 30.6 mmol) and 30mL ofTHF. The reaction mixture was cooled at -20 oc while n-BuLi (2.5 M, 12.2 mL, 30.6mmol) was added dropwise via syringe keeping the internal temperature below 0 °C. Theresulting reaction mixture was stirred at 0 °C for 15 min. The reaction mixture was then cooled at -40 °C while 4-bromo-2-methylbenzonitrile ( 4.00 g, 20.4 mmol) in 10 mL of THF was added dropwise via syringe over 1 h. An internal temperature of ca. -40 oc was maintained during theaddition. The resulting reaction mixture was stirred at -40 °C for 30 min and then charged withDMF (2.98 g, 40.8 mmol, ca. 50 ppm water) in one portion. The reaction mixture was stirred at-40 °C for 15 min. The reaction mixture was quenched with MeOH (5 vol., 20 mL) and then charged with NaBH4 (0.770 g, 20.4 mmol) in one portion and allowed to warm to roomtemperature. After complete reduction of intermediate aldehyde (as judged by HPLC analysis),the reaction mixture was carefully quenched with 5 M HCl (with cooling) to adjust the pH to 2-3.The reaction mixture was extracted with EtOAc and then solvent-switched to EtOH (40 mL).H2S04 (98%, 20.0 g, 204 mmol) was added in one portion and the resulting reaction mixture was stirred at reflux for 24 h. After complete cyclization (monitored by HPLC analysis), the reactionmixture was cooled to room temperature and then solvent-switched to EtOAc. The resultingorganic layer was washed with water, brine, and solvent-switched to MTBE. Precipitation from1:1 MTBE:heptane afforded 6-bromo-3,4-dihydro-1H-isochromen-1-one.
Stage #1: 4-bromo-2-methylbenzonitrile With n-butyllithium; diisopropylamine In tetrahydrofuran at -40℃; for 0.5h; Inert atmosphere;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -40℃; for 0.5h; Further stages;
A 6-bromo-3,4-dihydro-1H isochromen-1-one
General procedure: A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle, and ther-mocouple was charged with diisopropylamine (3.10 g, 30.6 mmol) and 30 mL of THF. The reaction mixture wascooled at -20 °C while n-BuLi (2.5 M, 12.2 mL, 30.6 mmol) was added dropwise via syringe keeping the internaltemperature below 0 °C. The resulting reaction mixture was stirred at 0 °C for 15 min. The reaction mixture wasthen cooled at -40 °C while 4-bromo-2-methylbenzonitrile (4.00 g, 20.4 mmol) in 10 mL of THF was added dropwisevia syringe over 1 h. An internal temperature of ca. -40 °C was maintained during the addition. The resulting reactionmixture was stirred at -40 °C for 30 min and then charged with DMF (2.98 g, 40.8 mmol, ca. 50 ppm water) in oneportion. The reaction mixture was stirred at-40 °C for 15 min. The reaction mixture was quenched with MeOH (5vol., 20 mL) and then charged with NaBH4 (0.770 g, 20.4 mmol) in one portion and allowed to warm to roomtemperature. After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixturewas carefully quenched with 5 M HCl (with cooling) to adjust the pH to 2-3. The reaction mixture was extracted withEtOAc and then solvent-switched to EtOH (40 mL). H2SO4 (98%, 20.0 g, 204 mmol) was added in one portion andthe resulting reaction mixture was stirred at reflux for 24 h. After complete cyclization (monitored by HPLC analysis),the reaction mixture was cooled to room temperature and then solvent-switched to EtOAc. The resulting organiclayer was washed with water, brine, and solvent-switched to MTBE. Precipitation from 1:1 MTBE:heptane afforded6-bromo-3,4-dihydro-1H-isochromen-1-one.
With sodium tetrahydroborate; nickel dichloride; In methanol; at 0℃; for 1h;
<strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (2.0g, 0.01 mol) was taken in methanol along with NiCl2 (2.41g,0.01 mol). ln the same pot acetic anhydride was taken (2.0g, 0.020mol). The reaction was cooled to 0 OC. NaBH4 (2.7g, 0.07mol) was added slowly to the reaction while stirring at the same temperature for 1 hr. The reaction mixture was concentrated under reduced pressure and was extracted with ethyl acetate. The organic layer was separated, dried using sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to yield N-(4-bromo-2-methylbenzyl)acetamide( 1.1 g). LC-MS (methanol, ESI): m/z = 242 (M+H). 1H-NMR (400 MHz, CDCl3): 7.71 (1H, m), 7.47 (1H, m), 7.38 (1H, m), 5.98(1H, s), 3.75 (1H, m), 3.43 (1H, d), 2.31 (3H, s), 2.04 (3H, s).
1.1 g
With methanol; sodium tetrahydroborate; nickel dichloride; at 0 - 20℃; for 1h;
<strong>[67832-11-5]4-bromo-2-methyl benzonitrile</strong> (2.0 g, 0.01 mol) was taken in methanol along with NuiCl2 (2.41 g, 0.01 mol). In the same pot acetic anhydride was taken (2.0 g, 0.020 mol). The reaction was cooled to 0C. NaBH4 (2.7 g, 0.07 mol) was added slowly to the reaction while stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and was extracted with ethylacetate. The organic layer was separated, dried using sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to yield N-(4-bromo-2-methyl-benzyl)acetamide.(1.1 g). LC-MS (methanol, ESI): m/z = 242 (M+H). 1H-NMR (400 MHz, CDCl3): 7.71 (1H, m), 7.47 (1H, m), 7.38 (1H, m), 5.98(1H, s), 3.75 (1H, m), 3.43 (1H, d), 2.31 (3H, s),2.04 (3H, s).
1.1 g
With methanol; sodium tetrahydroborate; nickel dichloride; at 0 - 20℃; for 1h;
<strong>[67832-11-5]4-bromo-2-methyl benzonitrile</strong> (2.0 g, 0.01 mol) was taken in methanol along with NuiCl2 (2.41 g, 0.01 mol). In the same pot acetic anhydride was taken (2.0 g, 0.020 mol). The reaction was cooled to 0C. NaBH4 (2.7 g, 0.07 mol) was added slowly to the reaction while stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and was extracted with ethylacetate. The organic layer was separated, dried using sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to yield N-(4-bromo-2-methyl-benzyl)acetamide.(1.1 g). LC-MS (methanol, ESI): m/z = 242 (M+H). 1H-NMR (400 MHz, CDCl3): 7.71 (1H, m), 7.47 (1H, m), 7.38 (1H, m), 5.98(1H, s), 3.75 (1H, m), 3.43 (1H, d), 2.31 (3H, s),2.04 (3H, s).
1.1 g
With sodium tetrahydroborate; nickel dichloride; In methanol; at 0℃; for 1h;
Step 3: Preparation of N-(4-bromo-2-methyl-benzyl)acetamide;: <strong>[67832-11-5]4-bromo-2-methyl benzonitrile</strong> (2.0 g, 0.01 mol) was taken in methanol along with NiC12 (2.41 g, 0.01 mol). In the same pot acetic anhydride was taken (2.0 g, 0.020 mol). The reaction was cooled to 0C.NaBH (2.7 g, 0.07 mol) was added slowly to the reaction while stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and was extracted with ethylacetate. The organic layer was separated, dried using sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to yield N-(4-bromo-2-methyl- benzyl)acetamide.(1 .1 g).LC-MS (methanol, ESI): mlz = 242 (M+H).1H-NMR (400 MHz, CDC13): 7.71 (1H, m), 7.47 (1H, m), 7.38 (1H, m), 5.98(1H, s), 3.75 (1H, m), 3.43 (1H, d), 2.31 (3H, s),2.04 (3H, s)
1.1 g
With sodium tetrahydroborate; nickel dichloride; In methanol; at 0℃; for 1h;
Step 3: Preparation of N-(4-bromo-2-methyl-benzyl)acetamide;: <strong>[67832-11-5]4-bromo-2-methyl benzonitrile</strong> (2.0 g, 0.01 mol) was taken in methanol along with NiC12 (2.41 g, 0.01 mol). In the same pot acetic anhydride was taken (2.0 g, 0.020 mol). The reaction was cooled to 0C.NaBH (2.7 g, 0.07 mol) was added slowly to the reaction while stirring at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and was extracted with ethylacetate. The organic layer was separated, dried using sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography to yield N-(4-bromo-2-methyl- benzyl)acetamide.(1 .1 g).LC-MS (methanol, ESI): mlz = 242 (M+H).1H-NMR (400 MHz, CDC13): 7.71 (1H, m), 7.47 (1H, m), 7.38 (1H, m), 5.98(1H, s), 3.75 (1H, m), 3.43 (1H, d), 2.31 (3H, s),2.04 (3H, s)
Methyl magnesium bromide (3 M in tetrahydrofuran) was added at rt drop wise to a solution of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (4 g) in dry THF (15 mL) and was then heated to reflux for 2 h and then stirred at rt for 3 d. The mixture was chilled in an ice bath, saturated aqueous ammonium chloride solution (100 mL) was added and the mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and the remaining residue was treated with 4 N HCl at 0 C. and was stirred at rt for 18 h. The mixture was extracted with EtOAc and the organic layer was washed with water, dried and the solvent was removed under reduced pressure to yield the desired product (88% yield).
88%
In tetrahydrofuran; for 2h;Reflux;
Intermediate 24a) Methyl magnesium bromide (3 M in tetrahydrofuran) was added at rt drop wise to a solution of 4-bromo-2- methylbenzonitrile (4 g) in dry THF (15 mL) and was then heated to reflux for 2 h and then stirred at rt for 3 d. The mixture was chilled in an ice bath, saturated aqueous ammonium chloride solution (100 mL) was added and the mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and the remaining residue was treated with 4 N HCI at 0 C and was stirred at rt for 18 h. The mixture was extracted with EtOAc and the organic layer was washed with water, dried and the solvent was removed under reduced pressure to yield the desired product (88% yield).
(2S,3R,4R)-ethyl 1-acetyl-4-amino-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroqinoline-6-carboxylate[ No CAS ]
(2S,3R,4R)-ethyl 1-acetyl-4-((4-cyano-3-methylphenyl)amino)-2-cyclopropyl-3-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With tris-(dibenzylideneacetone)dipalladium(0); monophosphine 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene; caesium carbonate; In toluene; at 80℃; for 3h;Inert atmosphere;
(2S,3R,4R)-ethyl I -acetyl-4-amino-2-cyclopropyl-3-methyl- I ,2,3,4-tetrahydroqu inoline-6-carboxylate(for a preparation see Intermediate 225, 162 mg, 0.512 mmol), <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (181mg, 0.922 mmol), Pd2(dba)3 (47 mg, 0.051 mmol), Q-Phos (38 mg, 0.053 mmol) and Cs2CO3 (334mg, 1.024 mmol) were combined in dry toluene (3 mL). The reaction mixture was de-gassed and then heated at 80 C under nitrogen for 3 h. The reaction stopped and cooled to rt and partitioned between ethyl acetate and water. The organic layer was separated and aqueous layer further extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and conc. to give-403 mg of crude orange residue. This was purified by chromatography on SiC2 (25 g) eluting with0-50% ethyl acetate/cyclohexane over 330 mL to give the product (208 mg, 0.482 mmol, 94%) as anoil. LCMS (2 mm Formic): Rt = 1.16 mi [MH] = 432.
With C35H20F34NO3(1-)*Pd(2+)*Cl(1-); N-ethyl-N,N-diisopropylamine; tri tert-butylphosphoniumtetrafluoroborate; In water; at 120℃; for 0.333333h;Microwave irradiation;
General procedure: A mixture of the aryl halide (0.5 mmol), amine (5.0 equiv), Mo(CO)6 (0.5 equiv), DIPEA (3.0 equiv), palladacycle 1 (1 mol % Pd), [(t-Bu)3PH]BF4 (2 mol %, for aryl bromides only) and water (1.0 mL) was heated in a pressure tube at 110 C (for aryl iodides) or 120 C (for aryl bromides) under microwave irradiation. The reaction was monitored by TLC. When the reaction has completed, the reaction mixture was cooled to room temperature.
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In water; toluene; at 100℃; for 2h;Inert atmosphere;
General procedure: 4.1.1 4-Cyclopropyl-2-fluoro-6-methylbenzonitrile (2a) A solution of cyclopropylboronic acid (9.07 g, 105 mmol) and 4-bromo-2-fluoro-6-methylbenzonitrile (17 g, 80 mmol) in toluene (120 mL) was degassed with nitrogen for 10 min, followed by addition of K3PO4 (34 g, 160 mmol), H2O (6 mL), Pd2(dba)3 (3.66 g, 8 mmol), X-Phos (7.62 g, 16 mmol) under continuous flow of nitrogen. The reaction mixture was stirred at 100 C for 2 h. After addition of water (100 mL) and extraction with EtOAc (300 mL), the organic phases were washed with saturated brine. The combined organic layer was dried over Na2SO4, and the solvent was removed in vacuo. The crude product was purified on a silica gel column using hexane/EtOAc (95:5, v/v) as eluent to afford 2a (10.5 g, 75.0%) as a white solid. 4.1.7 4-Cyclopropyl-2-methylbenzonitrile (2b) Using a method similar to that of 2a, compound 2b was synthesized as a white solid (1.6 g, 85.0%). MS (ESI) m/z 158.1 [M+H]+; 1H NMR (400 MHz, CDCl3): delta 7.46 (d, J = 8.00 Hz, 1H), 6.97 (s, 1H), 6.91 (d, J = 8.00 Hz, 1H), 2.49 (s, 3H), 1.93-1.82 (m, 1H), 1.13-1.02 (m, 2H), 0.79-0.70 (m, 2H).
With trimethylaluminum; ammonium chloride In toluene at 60℃; for 16h; Inert atmosphere;
29.A Step A: 4-bromo-2-methylbenzimidamide.
To a solution ofNH4Cl (l 0 mmol) in dry toluene (10)was added AlMe3 (5 mL, 10 mmol) dropwise under Ar at 0°C, and the solution was stirred at rtfor 2 h. This was followed by the addition of 4-bromo-2-methylbenzonitrile (5 mmol) and themixture was stin·ed at 60°C 16 h. After cooling to 0°C, MeOH (10 rnl) was added and the15 mixture was stin·ed at rt for 1 hour. The mixture was filtered, and the solid was washed withMeOH (50 ml). The filtrate was concentrated and the solid residue was washed with ether to givethe title compound which was used for the next step without purification.
4-(dibromofluoromethyl)-2-methylbenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
Stage #1: 4-bromo-2-methylbenzonitrile With isopropylmagnesium bromide; lithium bromide In tetrahydrofuran at -40 - 20℃; for 3.16667h; Inert atmosphere;
Stage #2: dibromodifluoromethane In tetrahydrofuran at 20 - 35℃; for 1.01667h; Inert atmosphere;
4.2 General procedure for the dibromofluoromethylation of aryl Grignard reagent 2, prepared from aryl halide (Ar-X,1) and i-PrMgBr, with CF2Br2 in the presence of LiBr
General procedure: To a stirred mixture of Ar-X (1, 1.0 mmol) and lithium bromide (208 mg, 2.4 mmol) in THF (3.5mL) was added dropwise a solution of i-PrMgBr in THF (2.0 M, 0.53 mL, 1.06 mmol) at -40°C under Ar and the resulting mixture was stirred at -40°C for 10 min and at room temperature for 3 h. To a stirred solution of dibromodifluoromethane (CF2Br2) in THF (4.90 M, 0.49 mL and 2.4 mmol) was added dropwise the prepared solution of ArMgBr 2 in THF via cannula at between room temperature and 35°C over 1 min. and the resulting solution was stirred for 1 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (10 mL×3). The combined extracts were dried over Na2SO4. Concentration of the solvent in vacuo afforded a residue, which was purified by silica gel column chromatography (hexane/EtOAc=10/1) and recycle GPC to give α,α-dibromo-α-fluorotoluene derivative 8.
To a solution of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (4.00 g, 20.4 mmol) in THF (40 mL) was added dropwise lithium diisopropylamide (2 Mm THF, 16 mL, 32 mmol) in THF (10 mL) over a period of 20 mm at -78 C under nitrogen atmosphere. After stirring 2 hr at the sametemperature, iodomethane (3.48 g, 24.5 mmol) was added dropwise over a period of 20 mm. The mixture was warmed to room temperature, stirred for 3 h, re-cooled to 0 C and acidified with 1 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-10% ethyl acetate inpetroleum ether) to afford the title compound. LCMS [M+H] = 210.
To a solution of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (4.00 g, 20.4 mmol) in THF (40 mL) was added dropwise lithium diisopropylamide (2 Mm THF, 16 mL, 32 mmol) in THF (10 mL) overperiod of 20 mm at -78 C under nitrogen atmosphere. After stirring 2 hr at the sametemperature, iodomethane (3.48 g, 24.5 mmol) was added dropwise over a period of 20 mm. The mixture was warmed to room temperature, stirred for 3 h, re-cooled to 0 C and acidified with 1 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-10% ethyl acetate inpetroleum ether) to afford the title compound. LCMS [M+H] = 210.
0.34 g
[0402] To a solution of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (0.4 g, 2.0 mmol) in dry THF (10 mL) was slowly added LDA (1.3mL, 1.8 M in THF) at -78 C and stirred at this temperature for additional 30 min. Methyl iodide (0.15 mL, 2.4 mmol) wasadded) at -78 C to the above dark purple solution and the mixture was warmed to room temperature over 3 h. Thereaction was quenched with water, extracted with ether, which was then was washed with brine, dried and concentrated.4-Bromo-2-ethylbenzonitrile (0.34 g) was purified by Combiflash.
30Step A: 4-bromo-2-ethylbenzonitrile<BOLD> </BOLD>A solution of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (4.00 g, 20.4 mmol) in THF (40 mL) was addeddropwise to a solution of lithium diisopropylamide (2.0 M in THF, 16 mL, 32.0 mmol) in THF(10 mL) over a period of 20 mm at -78 C under nitrogen atmosphere. After 2 h, iodomethane(3.48 g, 24.5 mmol) was added dropwise over a period of 20 mm at the same temperature. Thereaction mixture was allowed to warm to room temperature and stirred for 3 h. The mixture wasre-cooled to 0 C and acidified with 1 M hydrochloric acid to pHi. The aqueous layer was extracted with ethyl acetate several times. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was then purified by flash chromatography on a silica gel column using 0-10% ethyl acetate/petroleum ether as theeluting solvents to give the title compound. ?H NIVIR (400 MHz, CDC13) 7.46 (s, 1H), 7.44-7.35 (m, 2H), 2.81 (q, J 7.7 Hz, 2H), 1.26 (t, J= 7.6 Hz, 3H).
To a solution of <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (4.00 g, 20.4 mmol) in THF (40 mL) was added dropwise lithium diisopropylamide (2 M in THF, 16 mL, 32 mmol) in THF (10 mL) over a period of 20 min at -78 C. under nitrogen atmosphere. After stirring 2 hr at the same temperature, iodomethane (3.48 g, 24.5 mmol) was added dropwise over a period of 20 min. The mixture was warmed to room temperature, stirred for 3 h, re-cooled to 0 C. and acidified with 1 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (0-10% ethyl acetate in petroleum ether) to afford the title compound. LCMS [M+H]+=210.
[0617j To a solution of 4-bromo-2-methylbenzonitrile (3.0 g, 15 mmol) in anhydrous THF (20 mL) under nitrogen at 0 °C was added 1.0 M solution of borane in THF (46 mL). The reaction mixture was stirred at 0 °C for 1 h, and heated at 80 °C overnight. The reaction mixture was cooled to 0 °C and slowly quenched with MeOH, concentrated in vacuo. The crude product was treated with EtOAc (20 mL) and 4 M of HC1 in 1,4-dioxane (8.0 mL, 32 mmol) for 5 mm. The solid was filtered, rinsed with diethyl ether, dried to give the title compound as a white powder (3.24 g, yield: 100percent). LCMS: RT 0.75 mm.; MH+ 200.0. ?H NMR (300 MHz, DMSOd6) 5: 8.28 (br. s., 2H), 7.42 - 7.54 (m, 2H), 7.34 (d, J = 7.93 Hz, 1H), 3.99 (d, J = 4.15 Hz, 2H), 2.35 (s, 3H).
90%
With boron trifluoride-tetrahydrofuran complex; In tetrahydrofuran; at 0 - 80℃; for 17h;
[0114] To a solution of 4-bromo-2-methylbenzonitrile (3 g, 15 mmol) in THF (20 mL), BH3 THF (45 mL, 45 mmol) was added. The solution was stirred at 0 °C for 1 h and heated to 80 °C for 16 h. Then the mixture was quenched with MeOH. After concentrated, the residue was stirred with saturated HCl/EtOAc solution and filtered. The filter cake was rinsed with ether (20 mL x3) and dried under vacuum to afford (4-bromo-2-methylphenyl)methanamine (3.2 g, yield: 90percent) as white solid. ESI-MS (M+H)+: 200.1 Preparation of tert-butyl 4-bromo-2-methylbenzylcarbamate
69%
With borane-THF; In tetrahydrofuran; at 0 - 80℃; for 3h;
To a solution of 4-bromo-2-methylbenzonitrile (3 g, 15 mmol) in THF (20 mL) was added BH3·THF (45 mL, 45 mmol) at 0 °C. The solution was stirred for 1 h and heated to 80 °C for 2 h. The mixture was quenched with H2O and extracted with EtOAc (50 mL x 3). The organic layer was concentrated in vacuo to afford a residue which was suspended in saturated HCl/EtOAc and filtered. The filter cake was washed with diethyl ether (20 mL x 3) and dried under vacuum to afford the desired product (2.1 g, yield 69percent) as white solid. ESI-MS (M+H)+: 200.1.
2-methyl-4-(1H-pyrazol-1-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With copper(l) iodide; 8-quinolinol; potassium carbonate In dimethyl sulfoxide at 100℃;
12a Example 1 2A: 2-Methyl-4-( 1 H-pyrazol- 1 -yl)benzonitrile
[00188] 4-Bromo-2-methylbenzonitrile (300 mg, 1.5 mmol), 1H-pyrazole (830 mg, 12 mmol), Cul (440 mg, 2.3 mmol), K2C03 (630 mg, 4.6 mmol), quinolin-8-ol (330 mg, 2.3mmol) and DMSO (2 mL) were added to a 5 mL vial. The vial was quickly purged with argon and sealed, and the contents were stirred at 100 °C overnight. The reaction mixture was diluted with DCM (5 mL) and loaded onto a 40 g silica column. The column was eluted with EtOAc/Hexanes (0-100%). The fractions of interest were pooled and concentrated to obtain Example 12A (100 mg, 0.56 mmol, 36 % yield) as a white solid.‘H NMR (400 MHz, CDC13) ö 8.05 - 7.95 (m, 1H), 7.82 - 7.66 (m, 3H), 7.64 - 7.52 (m,1H), 6.52 (dd,J=2.6, 1.8 Hz, 1H), 2.62 (s, 3H).
Stage #1: 4-bromo-2-methylbenzonitrile With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol Reflux;
Stage #2: 2-furancarbonyl chloride With N-ethyl-N,N-diisopropylamine In chloroform
Stage #3: With N-ethyl-N,N-diisopropylamine; diisopropyl-carbodiimide Reflux;
11 Formula IVa Example: 3-(4-Bromo-2-methyl-phenyl)-5-furan-2-yl- jl,2,4j -oxadiazole:
In a 500 mL round-bottom flask, 4-bromo-2-methylbenzonitrile (5 g, 25 mmol) was dissolved in 200 mL of methanol. To the mixture was added hydroxylammonium chloride (1.72 g, 25 mmol) followed by DIEA (diisopropylethylamine) (8.7 mL, 50 mmol). The mixture was heated at reflux for overnight. The solvents were removed. The residue was dissolved in 200 ml. of CHC13. To the mixture was added 2-furoyl chloride (3.97 ml, 25 mmol) followed by DIEA (8.7 mL, 50 mmol). After reaction completion, the mixture was extracted with chloroform and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was dissolved in 200 mL of dioxanes. To the mixture was added 1 eq of DIC (N, N’-diisopropylcarbodiimide) followed by 1 eq of DIEA. The mixture was then heated at reflux overnight. After reaction completion, the mixture was cooled down. The solvents were removed in vacuo. The residue was then extracted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The cmde was purified by flash chromatography on silica gel in a 0-20% ethyl acetate/ hexanes gradient to afford 2.23 g of the desired compound 3-(4-Bromo-2-methyl- phenyl)-5-furan-2-yl-[1,2,41-oxadiazole as a white powder in an overall yield of 36%. Chemical Formula: C13H9BrN2O2 MW: 305.13; HPLC Purity > 99.0%; (254 nm) ESMS: tR= 7.81 mm; m/z 305.1 (M+1); ‘H-NMR (250 MI-Tz, D6-DMSO): 8.18-8.19 (m, 1 H), 7.92 (d, J= 8.3, 1H), 7.58- 7.70 (m, 3H), 6.86- 6.90 (m, 1H), 2.59 (s, 3H)
4-(2,3-dihydro-1H-inden-1-yl)-2-methylbenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With pyridine; nickel(II) iodide; 4,4'-dimethyl-2,2'-bipyridines; magnesium chloride; zinc; In N,N-dimethyl acetamide; at 25℃; for 16h;Inert atmosphere; Glovebox; Schlenk technique;
General procedure: To a flame-dried Schlenk tube equipped with a stir bar was loaded aryl bromide (0.3 mmol, 100 mol%) and benzyl chloride (0.6 mmol, 200 mol%), followed by addition of ligand 1b (0.03 mmol, 10 mol%), zinc powder (39 mg, 0.6 mmol, 300 mol%), and MgCl2 (28.6 mg, 0.3 mmol, 100 mol%). The tube was moved into an anhydrous glove box, then NiI2 (9.4 mg, 0.03 mmol, 10 mol%) was added. The tube was capped with a rubber septum and moved out of the glove box. N,N-Dimethylacetamide (1 mL) and pyridine (24 muL, 0.3 mmol, 100 mol%) were added by using a syringe. The mixture was stirred for 16 h under N2 atmosphere at 25 C, then directly loaded onto a silica column without work-up. The residue in the reaction vessel was rinsed with small amount of petroleum ether. Flash column chromatography provided the product as a solid or oil.
2-methyl-4-(1-(m-tolyl)ethyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With pyridine; nickel(II) iodide; 4,4'-dimethyl-2,2'-bipyridines; magnesium chloride; zinc; In N,N-dimethyl acetamide; at 25℃; for 16h;Inert atmosphere; Glovebox; Schlenk technique;
General procedure: To a flame-dried Schlenk tube equipped with a stir bar was loaded aryl bromide (0.3 mmol, 100 mol%) and benzyl chloride (0.6 mmol, 200 mol%), followed by addition of ligand 1b (0.03 mmol, 10 mol%), zinc powder (39 mg, 0.6 mmol, 300 mol%), and MgCl2 (28.6 mg, 0.3 mmol, 100 mol%). The tube was moved into an anhydrous glove box, then NiI2 (9.4 mg, 0.03 mmol, 10 mol%) was added. The tube was capped with a rubber septum and moved out of the glove box. N,N-Dimethylacetamide (1 mL) and pyridine (24 muL, 0.3 mmol, 100 mol%) were added by using a syringe. The mixture was stirred for 16 h under N2 atmosphere at 25 C, then directly loaded onto a silica column without work-up. The residue in the reaction vessel was rinsed with small amount of petroleum ether. Flash column chromatography provided the product as a solid or oil.
With pyridine; nickel(II) iodide; 4,4'-dimethyl-2,2'-bipyridines; magnesium chloride; zinc; In N,N-dimethyl acetamide; at 25℃; for 16h;Inert atmosphere; Glovebox; Schlenk technique;
General procedure: To a flame-dried Schlenk tube equipped with a stir bar was loaded aryl bromide (0.3 mmol, 100 mol%) and benzyl chloride (0.6 mmol, 200 mol%), followed by addition of ligand 1b (0.03 mmol, 10 mol%), zinc powder (39 mg, 0.6 mmol, 300 mol%), and MgCl2 (28.6 mg, 0.3 mmol, 100 mol%). The tube was moved into an anhydrous glove box, then NiI2 (9.4 mg, 0.03 mmol, 10 mol%) was added. The tube was capped with a rubber septum and moved out of the glove box. N,N-Dimethylacetamide (1 mL) and pyridine (24 muL, 0.3 mmol, 100 mol%) were added by using a syringe. The mixture was stirred for 16 h under N2 atmosphere at 25 C, then directly loaded onto a silica column without work-up. The residue in the reaction vessel was rinsed with small amount of petroleum ether. Flash column chromatography provided the product as a solid or oil.
5,9-diiodo-7,7-dimethyl-7H-benzo[C]fluorene[ No CAS ]
[ 62-53-3 ]
C57H40N4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: 5,9-diiodo-7,7-dimethyl-7H-benzo[C]fluorene; aniline With (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate at 60℃; for 1h; Inert atmosphere;
Stage #2: 4-bromo-2-methylbenzonitrile at 150℃; for 2h; Inert atmosphere;
Synthesis examples of the compound represented by formula (1-60)
Under an argon atmosphere, 5,9-diiodo-7,7-diphenyl -7H- benzo [C] fluorene 4.7g of aniline 1.6g were dissolved in 1,2,4-trimethylbenzene 30 ml, palladium bis (dibenzylidene ) 0.045g, in addition sodium t- butoxide 1.8g, and the (4- (dimethyl amino) phenyl) di-t- butylphosphine 0.060g, was heated for 1 hour at 60 . Further added 4-bromo-2-methyl benzonitrile 4.5g in there,It was heated for 2 hours at 150 . After cooling to room temperature, after which water was added 30 ml, using a separatory funnel, the organic layer was washed with water. After removing the aqueous layer, the combined organic layer, by a rotary evaporator to yield the crude product was concentrated. The crude product column purification on silica gel: after (solvent ethyl acetate / toluene = 0.05 / 1 (volume ratio)), then subjected to sublimation purification, the desired compound of Formula (1-60) was obtained 4.8g (81% yield).
5,9-diiodo-7,7-dimethyl-7H-benzo[C]fluorene[ No CAS ]
[ 95-64-7 ]
C51H44N4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
Stage #1: 5,9-diiodo-7,7-dimethyl-7H-benzo[C]fluorene; 4-amino-o-xylene With (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In 5,5-dimethyl-1,3-cyclohexadiene at 70℃; for 1h; Inert atmosphere;
Stage #2: 4-bromo-2-methylbenzonitrile In 5,5-dimethyl-1,3-cyclohexadiene at 145℃; for 5h; Inert atmosphere;
Synthesis examples of the compound represented by formula (1-73)
Under an argon atmosphere, 5,9-diiodo-7,7-dimethyl -7H- benzo [C] fluorene 5.1g and 3,4-dimethyl aniline 2.8g dissolved in dehydrated xylene 200ml, palladium bis (dibenzylidene) 0.1 g, sodium t- butoxide 3.4 g, and the addition of (4- (dimethylamino) phenyl) di t- butylphosphine 0.16 g, and heated for 1 hour at 70 ° C.. It was further added 4-bromo-2-methylbenzonitrile 4.5g thereto, and heated for 5 hours at 145 ° C.. After cooling to room temperature, after which water was added 100 ml, using a separatory funnel, the organic layer was washed with water. After removing the aqueous layer, the combined organic layer, by a rotary evaporator to yield the crude product was concentrated. The crude product column purification on silica gel: after (solvent ethyl acetate / heptane / toluene = 0.01 / 3/1 (volume ratio)), then subjected to sublimation purification, represented by formula (1-73) the purpose of the compound was obtained 1.8g (26% yield)
5,9-diiodo-7,7-dimethyl-7H-benzo[C]fluorene[ No CAS ]
C57H30(2)H10N4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
Stage #1: aniline-d5; 5,9-diiodo-7,7-dimethyl-7H-benzo[C]fluorene With (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In 5,5-dimethyl-1,3-cyclohexadiene at 70℃; for 2h; Inert atmosphere;
Stage #2: 4-bromo-2-methylbenzonitrile In 5,5-dimethyl-1,3-cyclohexadiene at 145℃; for 4h; Inert atmosphere;
Synthesis examples of the compound represented by formula (1-74)
Under an argon atmosphere, to dissolve the 5,9-dibromo-7,7-diphenyl--7H- benzo [C] fluorene 6.3g and aniline -d5 2.5g of dehydrated xylene 150ml, palladium bis (dibenzylidene) 0.35g , sodium t- butoxide 12 g, and the addition of (4- (dimethylamino) phenyl) di t- butylphosphine 0.48 g,. 7It was heated for 2 hours at 0 . Further added 4-bromo-2-methyl benzonitrile 5.1g in there, was heated for 4 hours at 145 . After cooling to room temperature, after which water was added 30 ml, using a separatory funnel, the organic layer was washed with water. After removing the aqueous layer, the combined organic layer, by a rotary evaporator to yield the crude product was concentrated. The crude product column purification on silica gel: after (solvent ethyl acetate / heptane / toluene = 0.01 / 2/1 (volume ratio)), and subjected to sublimation purification, is represented by formula (1-74) that the purpose of the compound was obtained 3.8g (41% yield).
To a solution of 4-bromo-2-methylbenzonitrile (3 g, 15 mmol) in THF (20 mL),BH3THF (45 mL, 45 mmol) was added. The solution was stirred at 0 C for 1 h and heated to 80C for 16 h. Then the mixture was quenched with MeOH. After concentrated, the residue wasstirred with saturated HC1/EtOAc solution and filtered. The filter cake was rinsed with ether (20mL x3) and dried under vacuum to afford (4-bromo-2-methylphenyl)methanamine (3.2 g, yield:90%) as white solid. ESI-MS (M+H) : 200.1
N-t-butoxycarbonyl-3-iodo-D-alanine methyl ester[ No CAS ]
methyl N-(tert-butoxycarbonyl)-4-cyano-3-methyl-D-phenylalaninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
To a stirred suspension of zinc dust, 179 mg (2.73 mmol, 3 eq.) in dry N,Ndimethylformamide (1 mL) were added successively iodine, 35 mg (0.137 mmol, 15 mol%), (5)-methyl 2-((tert-butoxyc arbonyl)amino) -3 -iodopropanoate, 300 mg (0.911 mmol) and iodine, 35 mg (0.137 mmol, 15 mol%) and the resulting mixture was stirred at r.t, for 1 h (light exotherm observed). Tris-(dibenzylideneacetone)dipalladium, 42mg (46 imol, 5 mol%), dicyclohexyl(2?,6?-dimethoxybiphenyl-2-yl)phosphine, 37 mg(91 ttmol, 10 mol%) followed by 4-bromo-2-niethylbenzonitrile, 232 mg (1.18 mmol,1,3 eq.) were added and the mixture was stirred at 50 C for 18 h. The solvent wasremoved under reduced pressure and the residue was purified by flash columnchromatography on silica gel (eluent: eye lohexane/ethyl acetate, 9:1) to give theproduct, 184 mg (63%) as an orange oil.LC-MS (Method 1): R = 3.39 nun; MS (ES+): m/z = 319 (M+H), 263 ([M-tBu]+H), 219 ([M-Boc]+H).?H-NMR (500 MHz, CDC13) d [ppm] = 1,41 (s, 9H), 2,52 (s, 3H), 3.02 (dd, 1H), 3,16 (dd, 1H), 3.73 (s, 3H), 4,58 (q, 1H), 5.00 (d, 1H), 7.04 (d, 1H), 7.10 (s, 1H), 7.52 (d,1H).
N-[(4-bromo-2-methyl-phenyl)methyl]-2-methoxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.49 mmol
Stage #1: 4-bromo-2-methylbenzonitrile With borane-THF In tetrahydrofuran at 0 - 20℃; for 18h;
Stage #2: 2-Methoxybenzoyl chloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; for 16h;
62 N-[(4-bromo-2-methyl-phenyl)methyl]-2-methoxy-benzamide
General procedure: To a solution of 4-bromo-2-methyl-benzonitrile (5.10 mmol) dissolved in THF (30 mL) was added, at 0 °C, a borane tetrahydrofuran complex solution (1 M in THF, 15.30 mmol).The solution was stirred at 0 °C for 30 mm before being warmed upto RT and stirred for 18 h. The reaction was quenched dropwise with MeOH. Volatiles were concentrated under reduced pressure and the residue was partitioned with an aqueous solution of NaOH (1 M) and EtOAc. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give crude 4-bromo-2-methyl-phenyl)methanamine, which was then dissolved in THF (20 mL) and N,N-diisopropylethylamine (15.29 mmol) was added. The solution was cooled to 0 0C before 2-methoxybenzoyl chloride (5.61 mmol) was added. It was then stirred at 0 °C for 20 mm before the reaction was warmed up to RT and stirred for 16 h. The reaction was quenched with a saturated aqueous solution of NH4CI, worked-up, and purified (column chromatography, 0-30 % EtOAc in heptane) to give the titled compound (2.49 mmol). UPLC-MS (ES, Short acidic): 1.85 mi mlz 336.1 [M+2]
tert-butyl 2-(4-cyano-3-methylphenyl)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;Inert atmosphere;
General procedure: To a round bottom flask was added compound 3 (0.5 g,1.97 mmol), K3PO4 (1.25 g, 5.9 mmol), Pd2(dba)3 (0.018 g,0.02 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene(0.023 g, 0.039 mmol), corresponding bromophenyl substituents(2.36 mmol) and 10 mL dioxane. The reaction mixture was thoroughly degassed with nitrogen, and heated at 100 C overnight. After cooling to room temperature, the reaction mixture was partitioned between H2O and ethyl acetate. The organic layers were combined and concentrated. The resulting crude material was purified via silica gel chromatography by eluting with a gradient of 1:3-2:1ethyl acetate/petroleum ether to give the title compounds 4a-e.
General procedure: A reaction mixture of 2a-e (5.0 mmol, 1.0 equiv.), differentsubstituted 4-bromobenzonitrile (6.0 mmol, 1.2 equiv.) and potassiumcarbonate (12.5 mmol, 2.5 equiv.) in PEG400/H20 (10 mL/10 mL) was stirred at room temperature for 15 min, and PdCl2(0.05 mmol, 0.01 equiv.) was subsequently added. Stirring wascontinued for an additional 15 h until complete consumption ofstarting material as judged by TLC. Then the reaction mixture waspoured into water (80 mL) and extracted with ethyl acetate(30 mL*3). The organic layers were washed with brine, dried overanhydrous Na2SO4, filtered and condensed under reduced pressure.The residuewas then purified via column chromatography on silicagel, eluting with EtOAc/petroleum ether to 3a-r as white solid.
Stage #1: 4-bromo-2-methylbenzonitrile; 4-methoxy-2-methylphenyl boronic acid With potassium carbonate In water at 20℃; for 0.25h;
Stage #2: With palladium dichloride In water
4.3. General procedure for the preparation of compounds 3a-r
General procedure: A reaction mixture of 2a-e (5.0 mmol, 1.0 equiv.), differentsubstituted 4-bromobenzonitrile (6.0 mmol, 1.2 equiv.) and potassiumcarbonate (12.5 mmol, 2.5 equiv.) in PEG400/H20 (10 mL/10 mL) was stirred at room temperature for 15 min, and PdCl2(0.05 mmol, 0.01 equiv.) was subsequently added. Stirring wascontinued for an additional 15 h until complete consumption ofstarting material as judged by TLC. Then the reaction mixture waspoured into water (80 mL) and extracted with ethyl acetate(30 mL*3). The organic layers were washed with brine, dried overanhydrous Na2SO4, filtered and condensed under reduced pressure.The residuewas then purified via column chromatography on silicagel, eluting with EtOAc/petroleum ether to 3a-r as white solid.
2-methyl-4-(4-methylpiperazin-1-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 110℃; for 2h;Inert atmosphere;
Add palladium acetate (57.3mg, 0.255mmol) to <strong>[67832-11-5]4-bromo-2-methylbenzonitrile</strong> (1g, 5.1mmol), N-methylpiperazine (510mg, 5.1mmol), BINAP (238mg, 0.51 mmol) and cesium carbonate (2.5 g, 7.65 mmol) in 1,4-dioxane (20 mL), replaced with nitrogen 3 times, warmed to 110 C. and stirred for two hours.The reaction system was cooled to room temperature and filtered, and the solution was concentrated. The residue was purified by flash column chromatography (ethyl acetate) to obtain 2-methyl-4- (4-methylpiperazin-1-yl) benzonitrile (1.17 g, Yield: 87%) as a brown solid.
With bis(1,5-cyclooctadiene)nickel (0); iridium(lll) bis[2-(2,4-difluorophenyl)-5-methylpyridine-N,C20]-4,40-di-tert-butyl-2,20-bipyridine hexafluorophosphate; sodium carbonate; 4,4'-di-tert-butyl-2,2'-bipyridine In 1,4-dioxane at 20℃; for 12h; Irradiation;
1,3,5-tris(4-bromo-2-methylphenyl)triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With trifluorormethanesulfonic acid at 20℃; for 12h; Inert atmosphere; Sealed tube;
1,3,5-tris(4-bromo-2-methylphenyl)triazine (8a).
Methods for synthesis were based upon an adaption of previously reported methods.[4] 4-bromo-2-methylbenzonitrile (5.0 g, 25.5 mmol) was added to a 250 mL round bottom flask. The flask was purged with argon and triflic acid (5 mL, 65.6 mmol) was added to the vessel. The vessel was sealed and allowed to stir for 12 h at room temperature. Then, the flask was unsealed and the reaction quenched using a mixture of NH4OH and ice water until the mixture turned white. The material was decanted and lightly ground in a mortar and pestle to disperse the insoluble material. Dispersed crude product was reintroduced to the NH4OH/ water-ice mixture to ensure complete quenching of the reaction product. The resulting product was filtered over a glass frit and allowed to dry. The dried crude product was washed with CH2Cl2 and yielded to title compound. Yield: 15.64 g, 78%. 1H NMR (CDCl3): d 8.11 [3H, d, J(H-H) ¼ 8.0 Hz, aryl CH], 7.53 (4 H, m, aryl CH), 7.49 (2 H, m, aryl CH), 2.75 (9H, s, CH3). 13C NMR (CDCl3): d 173.1 (aryl C-N), 141.2 (aryl C-CH3), 134.7 (aryl CH), 134.6 (aryl C-C), 132.8 (aryl CH), 129.3 (aryl CH), 125.8 (aryl C-Br), 22.2 (CH3).
4-[4-[2-[3-[(2S,6R)-2,6-dimethylmorpholine-4-carbonyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-1-yl]acetyl]piperazin-1-ium-1-yl]-3-methylbenzonitrile 2,2,2-trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 4-bromo-2-methylbenzonitrile; (x)C2HF3O2*C19H29N5O3 With caesium carbonate; ruphos In 1,4-dioxane at 100℃; Inert atmosphere;
Stage #2: trifluoroacetic acid In N,N-dimethyl-formamide; acetonitrile
26.6 Step 6: 4-[4-[2-[3-[(2S,6R)-2,6-dimethylmorpholine-4-carbonyl]-5,6-dihydro-4H- cyclopenta[c]pyrazol-1-yl]acetyl]piperazin-1-ium-1-yl]-3-methyl-benzonitrile;2,2,2- trifluoroacetate
Under N2 atomsphare, a solution of 2-(3-((2R,6S)-2,6-dimethylmorpholine-4- carbonyl)-5,6-dihydro-cyclopenta[c]pyrazol-1(4H)-yl)-1-(piperazin-1-yl)ethanone (30 mg, 0.080 mmol) in 0.8 ml of dioxane charged in a 10 ml of microwave vial were added RuPhos (6.21 mg, 7.99 µmol), and 4-bromo-2-methylbenzonitrile (31.4 mg, 0.160 mmol), followed by the addition of Cs2CO3 (78 mg, 0,240 mmol). The vial was capped and the reaction was stirred at 100 C overnight. The mixture was then filtered and the filtrate was concentrated. The residue was dissolved in 1.5 ml of DMF and purified by a preparative HPLC (50 g C-18 column), eluting with 10-100% water in ACN + 0.05% TFA, to give the title compound. [M+H]+ 491.3.
With potassium phosphate; 1-(2,2-diphenyl-2λ4,3λ4-[1,3,2]diazaborolo[4,5,1-ij]quinolin-1(2H)-yl)-3-phenylpropan-1-one; 4,4'-di-tert-butyl-2,2'-bipyridine; nickel dibromide In dimethyl sulfoxide at 25℃; for 22h; Irradiation;
N<SUP>4</SUP>-((1S,4S)-4-N-tert-butoxycarbonylaminocyclohexyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine[ No CAS ]
4-((4-(((1s,4s)-4-aminocyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 4-bromo-2-methylbenzonitrile; N<SUP>4</SUP>-((1S,4S)-4-N-tert-butoxycarbonylaminocyclohexyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; Inert atmosphere;
Stage #2: With sulfuric acid; water at 90℃; for 1h; Cooling with ice;
6.1; 6.1.1 Step 4. Synthesis of compounds 1-7
General procedure: Under the protection of nitrogen, to compound 1-3 (113mg, 0.3mmol), one of the intermediates (0.36mmol) among 1-5 to 1-11,Tris(dibenzylideneacetone)dipalladium (14mg, 0.015mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (22mg, 0.0375mmol), cesium carbonate (195mg, 0.6 Anhydrous dioxane (3 mL) was added to the mixture of mmol), and the mixture was refluxed and stirred overnight.Suction filtration, solvent recovery under reduced pressure to obtain a residue.Purified by silica gel column chromatography, using CH2Cl2:EtOH (25:1) as the eluent to obtain the intermediate, and then dissolve it with 2mL CH2Cl2. Under ice bath conditions, add 1mL CF3COOH, and react at room temperature for 40min.The solvent was recovered under reduced pressure to obtain a residue, which was dissolved in anhydrous methanol (2 mL), and adjusted to pH>8 with 1N NaOH aqueous solution.The solvent was recovered under reduced pressure to obtain the residue, which was purified by silica gel column chromatography with CH2Cl2:MeOH:TEA (30:1:1-20:1:1) as the eluent to obtain a white solid. Yield: 35-55%.
With C41H40O16; N-ethyl-N,N-diisopropylamine In acetone at 20℃; for 40h; Schlenk technique; Inert atmosphere; Irradiation;
2.4. Typical experimental procedure for the photoreduction of arylhalides catalyzed by HARCP
General procedure: In a 10 mL schlenk tube with a magnetic stirring bar, aryl halide1 (0.1 mmol), HARCP (10 mol%), DIPEA (8 equiv) were dissolved inacetone (1 mL). The reaction mixtures were then irradiated with23 W CFL (at approximately 2 cm away from the light source)under nitrogen atmosphere. When the reaction finished, the solventin the reaction was removed with rotary evaporation andyields of photoreduction products 2 were calculated by 1H NMRwith hexamethyldisiloxane as the internal standard.
With chloro-trimethyl-silane; NiCl2 * 4 pyridine; zinc; [C(CH3)=N-(2-(t-Bu)C6H4)]2 In N,N-dimethyl acetamide at 30℃; for 24h; Inert atmosphere; Sealed tube; Glovebox; regioselective reaction;
2.1 General procedure of arylalkylation reaction
General procedure: An oven-dried 10 mL reaction tube equipped with a magneticstir bar was introduced to an argon-filled glove box. NiCl2·Py4 (11.3 mg, 0.025 mmol, 5 mol%), L1 (8.8 mg,0.025 mmol, 5 mol%), zinc (97.5 mg, 1.5 mmol, 3.0 equiv.)and anhydrous N,N-dimethylaniline (DMA) (2 mL) wereadded in this order. Then acrylate (0.5 mmol, 1.0 equiv.), aryliodide (0.75 mmol, 1.5 equiv.), acetal (0.5 mmol, 1.0 equiv.)and chlorotrimethylsilane (TMSCl) (190 μL, 1.5 mmol, 3.0equiv.) were added to the resulting mixture. The tube wassealed with a rubber stopper, and stirred at 30 °C for 24 h.After the reaction was complete, water (10 mL) was added,and then extracted with ethyl acetate (10 mL×3). The combinedorganic layers were dried over Na2SO4 and concentratedunder reduced pressure. The residue was purifiedby column chromatography using petroleum ether and ethylacetate as eluent, to afford the desired product.
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