* 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] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 12, p. 4309 - 4315
2
[ 66424-92-8 ]
[ 5858-28-6 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With oxalyl dichloride In dichloromethane; dimethyl sulfoxide at -60℃; for 1.08333 h; Stage #2: With triethylamine In dichloromethane; dimethyl sulfoxide at -60 - 20℃;
5.5 ml (63.2 mmol) of oxalyl chloride were added to 50 ml of dichloromethane and cooled to -60° C. After 20 minutes, 9.13 ml (138.6 mmol) of DMSO were added and stirred at -60° C. followed 15 minutes later by the addition of 3.91 g (23.3 mmol) of the 3-hydroxymethyl-p-nitrotoluene obtained in Step 1 at -60° C. and stirring. After 30 minutes, 45 ml of triethylamine were dropped in at -60° C. and then returned to room temperature. After concentrating under reduced pressure, 0.1 M hydrochloric acid was added to the residue followed by extraction with ethyl acetate (150 ml.x.2). The organic phase was then dried with magnesium sulfate and concentrated under reduced pressure to obtain 5.02 g of the target compound (crude yield: 130percent).
84%
With manganese dioxide In dichloromethane
1 3-Methyl-6-nitrobenzaldehyde A mixture of 3-methyl-6-nitrobenzylalcohol (10 g, 59.8 mmol) and manganese dioxide (80 g) in dichloromethane (100 mL) was stirred for 9 h and passed through a celite short column. The eluent was concentrated and the residue was purified by silica gel column chromatography with 8:1 hexane/ethyl acetate to give 8.25 g of the title compound (84percent). 1 H NMR (CDCl3), δ10.44 (s, 1H), 8.05 (d, 1H, J=8.3 Hz), 7.72 (d, 1H, J=1.7 Hz), 7.53 (dd, 1H, J=8.3, 1.7 Hz), 2.53 (s, 3H).
79%
With dipyridinium dichromate In dichloromethane at 20℃; for 6 h; Molecular sieve
PREPARATION 6; 5-Methyl-lH-indole-7-carboxaldehyde a) 5-Methyl-2-nitrobenzaldehyde Dissolve (5-methyl-2-nitrophenyl) methanol (10 g, 59. 88 mmol) in dichloromethane (210 mL). Add 3A molecular sieves (54 g) and pyridinium dichromate (22.53 g, 59. 88 mmol). Stir at room temperature for 6 hours. Pass the crude reaction mixture through a short silica gel column, and remove under reduced pressure. Purification of the residue by flash chromatography (silica gel, 10-20percent ethyl acetate: hexane) gives 7.84 g (79percent) of title compound as colorless oil. 1H NMR (CDC13) 8 10. 41 (m, 1H), 8.02 (m, 1H), 7.69 (s, 1H), 7.53 (d, 1H), 2.51 (s, 3H).
Reference：
[1] Patent: US2004/10004, 2004, A1, . Location in patent: Page 22
[2] Journal of Organic Chemistry, 1980, vol. 45, # 7, p. 1334 - 1336
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2001, vol. 40, # 5, p. 436 - 437
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2001, vol. 40, # 4, p. 329 - 330
[5] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 12, p. 4309 - 4315
[6] Monatshefte fur Chemie, 1999, vol. 130, # 3, p. 481 - 483
[7] Phosphorus, Sulfur and Silicon and the Related Elements, 2003, vol. 178, # 4, p. 707 - 709
[8] Patent: US5719152, 1998, A,
[9] Journal of Chemical Research - Part S, 1998, # 10, p. 656 - 657
[10] Patent: WO2003/76398, 2003, A2, . Location in patent: Page/Page column 19
[11] Monatshefte fur Chemie, 1999, vol. 130, # 4, p. 581 - 583
[12] Chemical Communications, 1999, # 9, p. 833 - 834
[13] Journal of Chemical Research - Part S, 1999, # 5, p. 334 - 335
[14] Patent: US5387684, 1995, A,
3
[ 218623-11-1 ]
[ 5858-28-6 ]
Reference：
[1] Phosphorus, Sulfur and Silicon and the Related Elements, 2002, vol. 177, # 12, p. 2843 - 2846
[2] Journal of Chemical Research, 2005, # 2, p. 105 - 106
[3] Journal of Chemical Research - Part S, 1998, # 11, p. 718 - 719
[4] Monatshefte fur Chemie, 1999, vol. 130, # 5, p. 709 - 712
[5] Tetrahedron Letters, 1999, vol. 40, # 3, p. 561 - 562
[6] Monatshefte fur Chemie, 2001, vol. 132, # 7, p. 871 - 873
[7] Monatshefte fur Chemie, 2001, vol. 132, # 5, p. 651 - 654
[8] Synthetic Communications, 1999, vol. 29, # 5, p. 781 - 784
[9] Synthesis, 1999, # 3, p. 393 - 394
[10] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 1999, vol. 54, # 3, p. 394 - 396
[11] Monatshefte fur Chemie, 1999, vol. 130, # 2, p. 337 - 339
4
[ 79-37-8 ]
[ 66424-92-8 ]
[ 5858-28-6 ]
Yield
Reaction Conditions
Operation in experiment
130%
With hydrogenchloride; triethylamine In dichloromethane; dimethyl sulfoxide
Step 2 Production of 3-formyl-p-nitrotoluene 5.5 ml (63.2 mmol) of oxalyl chloride were added to 50 ml of dichloromethane and cooled to -60°C. After 20 minutes, 9.13 ml (138.6 mmol) of DMSO were added and stirred at -60°C followed 15 minutes later by the addition of 3.91 g (23.3 mmol) of the 3-hydroxymethyl-p-nitrotoluene obtained in Step 1 at -60°C and stirring. After 30 minutes, 45 ml of triethylamine were dropped in at -60°C and then returned to room temperature. After concentrating under reduced pressure, 0.1 M hydrochloric acid was added to the residue followed by extraction with ethyl acetate (150 ml x 2). The organic phase was then dried with magnesium sulfate and concentrated under reduced pressure to obtain 5.02 g of the target compound (crude yield: 130percent).
5.5 ml (63.2 mmol) of oxalyl chloride were added to 50 ml of dichloromethane and cooled to -60 C. After 20 minutes, 9.13 ml (138.6 mmol) of DMSO were added and stirred at -60 C. followed 15 minutes later by the addition of 3.91 g (23.3 mmol) of the 3-hydroxymethyl-p-nitrotoluene obtained in Step 1 at -60 C. and stirring. After 30 minutes, 45 ml of triethylamine were dropped in at -60 C. and then returned to room temperature. After concentrating under reduced pressure, 0.1 M hydrochloric acid was added to the residue followed by extraction with ethyl acetate (150 ml×2). The organic phase was then dried with magnesium sulfate and concentrated under reduced pressure to obtain 5.02 g of the target compound (crude yield: 130%).
84%
With manganese dioxide; In dichloromethane;
1 3-Methyl-6-nitrobenzaldehyde A mixture of 3-methyl-6-nitrobenzylalcohol (10 g, 59.8 mmol) and manganese dioxide (80 g) in dichloromethane (100 mL) was stirred for 9 h and passed through a celite short column. The eluent was concentrated and the residue was purified by silica gel column chromatography with 8:1 hexane/ethyl acetate to give 8.25 g of the title compound (84%). 1 H NMR (CDCl3), delta10.44 (s, 1H), 8.05 (d, 1H, J=8.3 Hz), 7.72 (d, 1H, J=1.7 Hz), 7.53 (dd, 1H, J=8.3, 1.7 Hz), 2.53 (s, 3H).
79%
With dipyridinium dichromate; In dichloromethane; at 20℃; for 6h;Molecular sieve;
PREPARATION 6; 5-Methyl-lH-indole-7-carboxaldehyde a) 5-Methyl-2-nitrobenzaldehyde Dissolve (5-methyl-2-nitrophenyl) methanol (10 g, 59. 88 mmol) in dichloromethane (210 mL). Add 3A molecular sieves (54 g) and pyridinium dichromate (22.53 g, 59. 88 mmol). Stir at room temperature for 6 hours. Pass the crude reaction mixture through a short silica gel column, and remove under reduced pressure. Purification of the residue by flash chromatography (silica gel, 10-20% ethyl acetate: hexane) gives 7.84 g (79%) of title compound as colorless oil. 1H NMR (CDC13) 8 10. 41 (m, 1H), 8.02 (m, 1H), 7.69 (s, 1H), 7.53 (d, 1H), 2.51 (s, 3H).
With pyridinium chlorochromate; In diethyl ether; dichloromethane; ethyl acetate;
Reference Example 1 Synthesis of 5-methyl-2-nitrobenzaldehyde Pyridinium chlorochromate (25.0 g, 116 mmol) was added to methylene chloride (65 ml) while stirring, and then thereto was added 5-methyl-2-nitrobenzyl alcohol (12.9 g, 77.3 mmol). The mixture was stirred at room temperature for 15 hours, and diethyl ether (155 ml) was added. The ether layer was removed by decantation. Diethyl ether (30 ml) was added to the residue, and the ether layer was removed by decantation (3 times). The ether layers were combined, and passed through 15.5 g of silica gel. The obtained solution was concentrated, and subjected to flash chromatography on silica gel using a mixed solvent of hexane/ethyl acetate (8:1), whereby 10.6 g of 5-methyl-2-nitrobenzaldehyde was obtained. NMR (270 MHz, CDCl3) delta 10.44 (s, 1H); 8.04 (d, J=8.4 Hz, 1H); 7.73 (s, 1H); 7.55 (d, J=8.4 Hz, 1H); 2.52 (s, 3H)
With hydrogenchloride; tin(ll) chloride; In water; at 15℃; for 2h;
[0163] The next series of analogs of NBTI were compounds 23 and 24 (Scheme 2). These deaza analogs of the benzoxadiazole substituents were obtained by coupling bromomethyl-2,1-benzisoxazole with 6-mercaptopurine riboside. This bromide was prepared by ring closure of the proper ortho-nitrobenzaldehyde (17-18) in the presence of tin(II)chloride and subsequent bromination with NBS.<ix>
[0138] 5.02 g (63.2 mmol) of the <strong>[5858-28-6]3-formyl-p-nitrotoluene</strong> obtained in Step 2 were dissolved in 50 ml of DMF followed by the addition of 3.06 ml (28.1 mmol) of ethyl mercaptoacetate and 4.85 g (35.1 mmol) of potassium carbonate and stirring at 50 C. After 9.5 hours, the temperature was raised to 80 C. followed by additional heating for 100 minutes. Following completion of the reaction, 250 ml of water were added to the reaction solution followed by extraction with ethyl acetate (100 ml×3) and drying with magnesium sulfate. After concentrating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) followed by additionally purifying by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 2.48 g (11.2 mmol) of the target compound (yield: 48%). [0139] 1H-NMR (400 MHz, CDCl3) (ppm): 7.98 (s, 1H), 7.73 (d, 1H, J=8.28 Hz), 7.65 (s, 1H), 7.27 (d, 1H, J=8.32 Hz), 4.39 (q, 2H), 2.47 (s, 3H), 1.41 (s, 3H)
With toluene-4-sulfonic acid; In toluene; for 3h;reflux with constant water removal (Dean-Stark Trap);
Preparation 9; 9-methyl-6-(tert-butoxycarbonyl)-6, 7-dihydro-6H-[1, 4] diazepino [6,7, 1-hi] indole; 5-Methyl-lH-indole-7-carboxaldehyde; Dissolve <strong>[5858-28-6]5-methyl-2-nitrobenzaldehyde</strong> (7.84 g, 47.52 mmol), 1-butanol (10.55 g, 142.6 mmol) and 4-toluenesulfonic acid monohydrate (0.5 g, 2.6 mmol) in toluene (200 mL). Heat the reaction mixture to reflux with constant water removal (Dean-Stark Trap). Continue to heat the reaction mixture for 3 hours. Add water and extract the aqueous layer with ethyl acetate. Combine the organic layers and dry over sodium sulfate, filter, concentrate under reduced pressure, and purify by flash chromatography (1% v/v triethylamine buffered silica gel, 5% ethyl acetate/hexane) to give the dibutyl acetal derivative as a colorless oil (14 g, 99%).
99%
With toluene-4-sulfonic acid; In toluene; for 3h;Heating / reflux;
b) 2-Dibutoxymethyl-4-methyl-1-nitrobenzene; Dissolve <strong>[5858-28-6]5-methyl-2-nitrobenzaldehyde</strong> (7.84 g, 47.52 mmol), 1-butanol (10.55 g, 142.6 mmol) and toluene-4-sulfonic acid (0.5 g) in toluene (200 mL). Heat to reflux, and remove the water using a Dean-Stark apparatus. Heat for 3 hours. Add water, and extract the aqueous layer with ethyl acetate. Combine the organic layers, dry over sodium sulfate, filter, concentrate under reduced pressure, and purify by flash chromatography (1% v/v triethylamine buffered silica gel, 5% ethyl acetate/hexane) to give 14 g (99%) of the title compound as colorless oil.
(2-Amino-5-methyl-phenyl)-(2-fluoro-phenyl)-methanone (1af) 2-Iodofluorobenzene (2.0 mL, 17 mmol) was dissolved in anhydrous THF (20 mL) under an argon atmosphere and cooled to -20 C. A solution of isopropyl magnesium chloride (8.5 mL, 17.0 mmol) was slowly added, and the solution was stirred for 20 min. <strong>[5858-28-6]2-Nitro-5-methylbenzaldehyde</strong> (2.7 g, 16.5 mmol) in THF (20 mL) was then added, and the mixture was stirred for 20 min at -20 C. and then quenched with saturated aqueous NH4Cl. The mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic portion was collected, dried over MgSO4, filtered and evaporated in vacuo. This material was dissolved in anhydrous CH2Cl2 (80 mL). Silica gel (20.3 g) and pyridinium chlorochromate (5.4 g, 25 mmol) were then added and the suspension was stirred at room temperature for 3 h. The mixture was then filtered through silica gel. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (silica gel, hexanes:EtOAc, 3:2) to provide the 2-nitro-benzophenone (3.7 g, 14 mmol). The benzophenone was dissolved in glacial acetic acid (50 mL), MeOH (50 mL) and deionized H2O (10 mL). Iron powder (<10 micron, 1.0 g) was added with vigorous stirring and the suspension heated to 60 C. After 20 min, additional iron powder (2.0 g) was added and the mixture was stirred at 60 C. for 3 h. After cooling, silica gel (12.5 g) was added and the volatile components were removed in vacuo. The resulting powder was suspended in EtOAc (100 mL) and carefully treated with 1N NaOH until basic to litmus. The suspension was filtered and the organic portion was separated, washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel, hexanes:EtOAc, 1:3) to provide 1af (3.1 g, 94%) MS m/z=230 (M+H).
ethyl N-(5-methyl-2-nitrobenzylidene)anthranilate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In hexane; toluene;
Reference Example 2 Synthesis of ethyl N-(5-methyl-2-nitrobenzylidene)anthranilate To <strong>[5858-28-6]5-methyl-2-nitrobenzaldehyde</strong> (4.26 g, 25.8 mmol) as obtained in Reference Example 1 was added toluene (30 ml), and the mixture was stirred. Thereto was added ethyl anthranilate (4.26 g, 25.8 mmol). After the mixture was refluxed under heating for 10 hours, it was allowed to cool. Then, Molecular Sieves 5A (20.6 g) was added and the mixture was left standing overnight. The mixture was filtered, and the cake was washed 5 times with 20 ml of toluene. The filtrate was concentrated, added with 25 ml of toluene for dissolution, and added with hexane (25 ml) while stirring. The precipitated solid was filtered off, and washed twice with 30 ml of a mixed solvent of toluene/hexane (1:2). The cake was dried in vacuo to give 3.11 g of ethyl N-(5-methyl-2-nitrobenzylidene)anthranilate. NMR (270 MHz, CDCl3) delta 8.79 (s, 1H); 7.03-8.14 (m, 7H); 4.35 (q, J=7.0 Hz, 2H); 2.53 (s, 3H); 1.35 (t, J=7.0 Hz, 3H)
3-chloro-2-(5-methyl-2H-indazol-2-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethyl phosphite; In hexane; toluene;
Reference Example 15 Synthesis of 3-chloro-2-(5-methyl-2H-indazol-2-yl)benzonitrile To 5-methyl-2-nitrobenzaldehyde (10.9 g, 66.0 mmol) as obtained in Reference Example 1 was added toluene (66 ml), and the mixture was stirred. Thereto was added <strong>[6575-11-7]2-amino-6-chlorobenzonitrile</strong> (10.1 g, 66.0 mmol). After refluxing under stirring for one day, molecular seives 5A (66 g) was added thereto and the mixture was left standing overnight. The mixture was filtered, and the cake was washed 6 times with chloroform (70 ml). The washing solution was concentrated and suspended in hexane (70 ml). The resultant solid was filtered off, washed with hexane (70 ml) and hexane (35 ml), and dried in vacuo. Triethyl phosphite (36.5 ml, 212.7 mmol) was added to the residue, and the mixture was refluxed for an hour, followed by cooling. The resultant solid was filtered off, washed 4 times with methanol (30 ml), and dried in vacuo to give 4.87 g of 3-chloro-2-(5-methyl-2H-indazol-2-yl)-benzonitrile. The secondary crystals (0.19 g) were further obtained from the washing solution. NMR (270 MHz, CDCl3) delta 8.5 (s, 1H); 7.2-7.9 (m, 6H); 2.4 (s, 3H)
2-[N-(5-methyl-2-nitrobenzylidene)amino]benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In hexane; toluene;
Reference Example 6 Synthesis of 2-[N-(5-methyl-2-nitrobenzylidene)amino]benzonitrile Toluene (167 ml) and 2-aminobenzonitrile (19.7 g, 167 mmol) were added to <strong>[5858-28-6]5-methyl-2-nitrobenzaldehyde</strong> (27.5 g, 167 mmol) as obtained in Reference Example 1, and the mixture was stirred and refluxed for 14 hours, followed by cooling. The resultant crystals were filtered off, washed with a mixed solvent of hexane/toluene (2:1, 150 ml) and hexane (150 ml) twice to give 27.5 g of 2-[N-(5-methyl-2-nitrobenzylidene)amino]benzonitrile. In addition, the solid precipitated from the filtrate was filtered off and washed with hexane (100 ml and 50 ml) to give 10.0 g of the compound. NMR (270 MHz, CDCl3) delta 9.0 (s, 1H); 8.2 (s, 1H); 7.2-8.1 (m, 6H); 2.5 (s, 3H)
With hydrogenchloride; potassium hexamethylsilazane; In tetrahydrofuran; toluene;
2 3-Methyl-6-nitrostyrene To a suspension of methyltriphenylphosphnium bromide (18.86 g, 52.8 mmol) in THF (120 mL) was added 0.5M potassium hexamethyldisilazide in toluene (106 mL, 53.0 mmol) at -10 C. The mixture was stirred for 40 min at the same temperature and <strong>[5858-28-6]3-methyl-6-nitrobenzaldehyde</strong> (8.0 g, 48 mmol) in THF (60 mL) was added. The mixture was stirred for 1 h at -10 C. and 0.2N hydrochloric acid (400 mL) was added. The mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 15:1 hexane/ethyl acetate to give 5.10 g of the title compound (65%). 1 H NMR (CDCl3), delta7.88 (d, 1H, J=8.3 Hz), 7.39 (d, 1H, J=1.7 Hz), 7.21 (dd, 1H, J=17.2, 11.2 Hz), 7.19 (dd, 1H, J=8.3, 1.7 Hz), 5.71 (dd, 1H, J=17.2, 1.0 Hz), 5.46 (dd, 1H, J=11.2 Hz), 2.46 (s, 3H).
With hydrogenchloride; triethylamine; In dichloromethane; dimethyl sulfoxide;
Step 2 Production of 3-formyl-p-nitrotoluene 5.5 ml (63.2 mmol) of oxalyl chloride were added to 50 ml of dichloromethane and cooled to -60C. After 20 minutes, 9.13 ml (138.6 mmol) of DMSO were added and stirred at -60C followed 15 minutes later by the addition of 3.91 g (23.3 mmol) of the 3-hydroxymethyl-p-nitrotoluene obtained in Step 1 at -60C and stirring. After 30 minutes, 45 ml of triethylamine were dropped in at -60C and then returned to room temperature. After concentrating under reduced pressure, 0.1 M hydrochloric acid was added to the residue followed by extraction with ethyl acetate (150 ml x 2). The organic phase was then dried with magnesium sulfate and concentrated under reduced pressure to obtain 5.02 g of the target compound (crude yield: 130%).
Sodium metal (0.836 g, 0.0363 mol) was dissolved in MeOH (40 mL), and the resulting sodium methoxide solution was cooled to 0 C. To this was added 4-fluorobenzyl cyanide (4.9 g, 0.0363 mol), and the mixture stirred for 30 min. at 0 C. 5-Methyl-2- nitrobenzaldehyde (3.0 g, 0.0181 mol) was added at the same temperature, and the reaction mixture was stirred for a further lh at 0 C. After completion of reaction (monitored by TLC), the precipitated solid was isolated by filtration to give the desired compound as a light yellow colored solid (3.0 g, 58% yield).
Sodium metal (1.9 g, 0.0848 mol) was dissolved in MeOH (180 mL), and the resulting methoxide solution was cooled to 0 C. To this was added 2-(6-methylpyridin-3- yl)acetonitrile (11.19 g, 0.0848 mol), and the reaction mixture was stirred for 30 min. at 0 C. 5-Methyl-2-nitrobenzaldehyde (7.0 g, 0.0424 mol) was added at 0 C, and the mixture was further stirred for lh at 0 C. After completion of reaction (monitored by TLC), the mixture was diluted with water (100 mL), and extracted with EtOAc (3x150 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (20% EtOAc:hexane in silica 100-200 mesh, diameter of column - 5.0 cm, height of silica - approx. 5 inch) to give the desired compound as a yellow colored solid (6.5 g, 59% yield).
In a 50 mL equipped with magnetic stirrerIn a single-necked round bottom flask was added 1.65 g (10 mmol) of <strong>[5858-28-6]5-methyl-2-nitrobenzaldehyde</strong>,Diethyl malonate (1.60 g, lOmmol) and 10 mL of acetic anhydride,The mixture was reacted at 110 C for 6 hours until the starting material disappeared.After cooling to room temperature, dilute with 20 mL of water and extract with dichloromethane. The organic phase was dried and subjected to column chromatography to give a pale yellow oil (2.79 g, yield 90.9%).
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