* 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.
A mixture of compound 1 (250.0 g, 1.16 mol), Zn(CN)2 (135.0 g, 1.16 mol) and Pd(PPh3)4 (25 g, 0.02 mol) in dry DMF (1500 mL) was stirred at 80 °C for 24 hours under N2. TLC (petroleum ether: ethyl acetate = 10:1) showed the reaction was complete, then the mixture was poured into toluene (1500 mL) and washed with 2 N NH3 H2O (800 mLx2). The aqueous layer was extracted with toluene (800 mLx2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product, which was purified by column chromatography (first petroleum ether, then petroleum ether: ethyl acetate 10:1) to afford compound 2 (25.5 g, yield: 42percent) as a grey solid and recover compound 1 (170 g) as yellow solid.1H NMR (300 MHz, CDCI3): δ 8.46-8.47 (d, J = 3.0 Hz, 1 H), 8.31-8.34 (dd, J = 9.0 Hz, 1 H), 7.53-7.56 (d, J = 9.0 Hz, 1 H), 2.68 (s, 3H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 23, p. 6273 - 6278
[2] Patent: WO2006/117669, 2006, A1, . Location in patent: Page/Page column 41; 113
Reference：
[1] Organic Letters, 2003, vol. 5, # 7, p. 1131 - 1134
[2] Journal of Materials Chemistry, 2011, vol. 21, # 26, p. 9523 - 9531
[3] Chemische Berichte, 1898, vol. 31, p. 2884
[4] Chemische Berichte, 1898, vol. 31, p. 2884
[5] Chemische Berichte, 1918, vol. 51, p. 561
[6] Helvetica Chimica Acta, 1922, vol. 5, p. 58
[7] Journal of the American Chemical Society, 1961, vol. 83, p. 4564 - 4571
[8] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1973, p. 2940 - 2948
4
[ 529-19-1 ]
[ 939-83-3 ]
[ 71516-35-3 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 16, p. 2753 - 2758
[2] Organic and Biomolecular Chemistry, 2003, vol. 1, # 13, p. 2326 - 2335
5
[ 939-83-3 ]
[ 16634-91-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 12, p. 2203 - 2211
6
[ 939-83-3 ]
[ 1975-52-6 ]
Reference：
[1] Journal of the Indian Chemical Society, 1937, vol. 14, p. 144,150
[2] Patent: WO2006/117669, 2006, A1,
7
[ 67-56-1 ]
[ 939-83-3 ]
[ 77324-87-9 ]
Yield
Reaction Conditions
Operation in experiment
82%
With hydrogenchloride In dichloromethane; water for 96 h; Heating / reflux
To a solution of compound 2 (64.0 g, 0.39 mol) in MeOH (1500 mL), H2O (50 mL) and CH2CI2 (500 mL) was purged with HCI gas till the solution was saturated. The mixture was left standing for 48 hours, then refluxed for 48 hours. TLC (petroleum ether: ethyl acetate = 10:1) showed the reaction was complete, then the mixture was concentrated in vacuo to give crude product, which was purified by column chromatography (first petroleum ether, then petroleum ether: ethyl acetate 1 :1) to afford compound 3 (33 g, yield: 82percent) as a yellow solid and recover compound 2 (42 g) as a grey solid. 1H NMR (400 MHz, CDCI3): 1H NMR δ 8.76 (S, 1 H), 8.22- 8.24 (dd, J = 8.0 Hz, 1 H), 7.42-7.44 (d, J = 8.0 Hz, 1 H), 3.95 (s, 3H), 2.71 (s, 3H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 23, p. 6273 - 6278
[2] Patent: WO2006/117669, 2006, A1, . Location in patent: Page/Page column 41; 114
8
[ 939-83-3 ]
[ 90326-54-8 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1941, vol. 546, p. 277,291
9
[ 939-83-3 ]
[ 103440-54-6 ]
Reference：
[1] Patent: WO2006/117669, 2006, A1,
10
[ 939-83-3 ]
[ 79669-49-1 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1941, vol. 546, p. 277,291
11
[ 939-83-3 ]
[ 54811-38-0 ]
Reference：
[1] Patent: WO2006/117669, 2006, A1,
12
[ 939-83-3 ]
[ 2840-04-2 ]
Reference：
[1] Patent: WO2006/117669, 2006, A1,
13
[ 939-83-3 ]
[ 50670-64-9 ]
Yield
Reaction Conditions
Operation in experiment
96%
With hydrogen In ethanol; ethyl acetate
Step 2: 5-Amino-2-methylbenzonitrile: A mixture of 2-methyl-5-nitrobenzonitrile (25.0 g, 154 mmol), 10percent palladium on charcoal (2.5 g) ethyl acetate (150 mL) and ethanol (150 mL) is stirred under an atmosphere of hydrogen. The catalyst is removed by filtration through a pad of celite and the filtrate is concentrated to give 5-amino-2-methylbenzonitrile (also see, Scholz, D. et al. J. Med Chem., 41,1050-1059 (1998)) (19.6 g, 96percent) as a tan solid. MS: m/e = 133 (M + H).
Reference：
[1] Patent: WO2005/97750, 2005, A1, . Location in patent: Page/Page column 69
[2] Organic Letters, 2017, vol. 19, # 18, p. 4746 - 4749
[3] Organic Letters, 2003, vol. 5, # 7, p. 1131 - 1134
[4] Journal of Materials Chemistry, 2011, vol. 21, # 26, p. 9523 - 9531
[5] Patent: US5596006, 1997, A,
[6] Acad. Romine Bulet. stiint., 1949, vol. <A> 1, p. 253,257[7] Chem.Abstr., 1952, p. 937
[8] Chemische Berichte, 1898, vol. 31, p. 2884
[9] Justus Liebigs Annalen der Chemie, 1941, vol. 546, p. 277,291
[10] Patent: US2009/54395, 2009, A1, . Location in patent: Page/Page column 45
14
[ 939-83-3 ]
[ 50670-64-9 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1938, vol. <5> 5, p. 1350,1356
15
[ 939-83-3 ]
[ 156001-51-3 ]
Reference：
[1] Organic Letters, 2003, vol. 5, # 7, p. 1131 - 1134
[2] Justus Liebigs Annalen der Chemie, 1941, vol. 546, p. 277,291
[3] Journal of Materials Chemistry, 2011, vol. 21, # 26, p. 9523 - 9531
16
[ 939-83-3 ]
[ 523977-64-2 ]
Reference：
[1] Organic Letters, 2003, vol. 5, # 7, p. 1131 - 1134
[2] Journal of Materials Chemistry, 2011, vol. 21, # 26, p. 9523 - 9531
17
[ 939-83-3 ]
[ 156001-53-5 ]
Reference：
[1] Organic Letters, 2003, vol. 5, # 7, p. 1131 - 1134
[2] Journal of Materials Chemistry, 2011, vol. 21, # 26, p. 9523 - 9531
With hydrogen;palladium 10% on activated carbon; In ethanol; ethyl acetate;
Step 2: 5-Amino-2-methylbenzonitrile: A mixture of <strong>[939-83-3]2-methyl-5-nitrobenzonitrile</strong> (25.0 g, 154 mmol), 10% palladium on charcoal (2.5 g) ethyl acetate (150 mL) and ethanol (150 mL) is stirred under an atmosphere of hydrogen. The catalyst is removed by filtration through a pad of celite and the filtrate is concentrated to give 5-amino-2-methylbenzonitrile (also see, Scholz, D. et al. J. Med Chem., 41,1050-1059 (1998)) (19.6 g, 96%) as a tan solid. MS: m/e = 133 (M + H).
59.6%
palladium; In ethanol; ethyl acetate;
EXAMPLE XV 3-Amino-6-methylbenzonitrile STR25 A suspension of 8.11 g (50 mmol) of 6-methyl-3-nitrobenzonitrile and 0.81 g of 10% of palladium-on-charcoal in 50 ml of ethanol and 50 ml of ethyl acetate is hydrogenated under 2.9 bar for 1 hour. The catalyst is filtered off, the filtrate is concentrated and the residue is crystallized from ether/petroleum ether. Yield: 59.6% of theory Melting point: 88 C.
With iron; ammonium chloride; In 1,4-dioxane; ethanol; water; at 25 - 80℃; for 16.0h;
Step 1. Preparation of 5-amino-2-methyl-benzonitrile (B18-1): A stirred suspension of <strong>[939-83-3]2-methyl-5-nitro benzonitrile</strong> (20 g, 123.45 mmol) in a mixture of dioxane (640 mL), ethanol (480 mL) and water (160 mL) at 25 C. was treated with NH4Cl (26.4 g, 493.8 mmol) followed by treatment with iron powder (34.4 g, 617.2 mmol). The mixture was then heated at 80 C. for 16 hours. The mixture was filtered through a Celite bed and concentrated. The resultant residue was diluted with EtOAc (600 mL), washed with water (150 mL) and brine (100 mL), and dried over anhydrous sodium sulfate. The organic solution was then concentrated to provide B18-1 as an orange solid. Yield: 18.2 g. 1H NMR (CDCl3): delta 7.08 (d, 1H), 6.84-6.9 (m, 1H), 6.75-6.82 (m, 1H), 3.65-3.82 (m, 2H) and 2.4 (s, 3H). Mass: (M+1) 133 calculated for C8H8N2. The product was used below to prepare B18-2 without further purification.
With potassium carbonate; In methanol; for 0.166667h;Heating / reflux;
A mixture of <strong>[939-83-3]2-cyano-4-nitrotoluene</strong> (10 g, 6.17 mmol), benzaldehyde (6.51 g, 6.17 mmol) and potassium carbonate (20 g) in MeOH (200 mL) was heated at reflux for 10 min. The mixture was cooled to ambient temperature over 30 min, whereupon precipitation of the product was complete. The product was isolated by filtration and washed successively with 1N HCl, water and MeOH then air dried. There was obtained 13.0 g of the benzamide (mp 269.8 C.) as evident from the lack of a nitrile adsorption in the IR and the appearance of peaks at 3357.1, 3193.6 (-NH2) and 1648.7 cm-1 (H2NC(O)-); LRMS (M-NO)+ m/z=238.
With potassium carbonate; In methanol; for 0.166667h;Heating / reflux;
A mixture of <strong>[939-83-3]2-cyano-4-nitrotoluene</strong> (10 g, 6.17 mmol) benzaldehyde (6.51 g, 6.17 mmol) and potassium carbonate (20 g) in MeOH (200 mL) was heated at reflux for 10 min. The mixture was cooled to ambient temperature over 30 min, whereupon precipitation of the product was complete. The product was isolated by filtration and washed successively with 1N HCl, water and MeOH then air dried. There was obtained 13.0 g of the benzamide (mp 269.8 C) as evident from the lack of a nitrile adsorption in the IR and the appearance of peaks at 3357.1, 3193.6 (-NH2) and 1648.7 cm-1 (H2NC(=O)-); LRMS (M-NO)+ m/z = 238.
tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 80℃; for 24.0h;
A mixture of compound 1 (250.0 g, 1.16 mol), Zn(CN)2 (135.0 g, 1.16 mol) and Pd(PPh3)4 (25 g, 0.02 mol) in dry DMF (1500 mL) was stirred at 80 C for 24 hours under N2. TLC (petroleum ether: ethyl acetate = 10:1) showed the reaction was complete, then the mixture was poured into toluene (1500 mL) and washed with 2 N NH3 H2O (800 mLx2). The aqueous layer was extracted with toluene (800 mLx2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product, which was purified by column chromatography (first petroleum ether, then petroleum ether: ethyl acetate 10:1) to afford compound 2 (25.5 g, yield: 42%) as a grey solid and recover compound 1 (170 g) as yellow solid.1H NMR (300 MHz, CDCI3): delta 8.46-8.47 (d, J = 3.0 Hz, 1 H), 8.31-8.34 (dd, J = 9.0 Hz, 1 H), 7.53-7.56 (d, J = 9.0 Hz, 1 H), 2.68 (s, 3H).
With hydrogenchloride; In dichloromethane; water; for 96.0h;Heating / reflux;
To a solution of compound 2 (64.0 g, 0.39 mol) in MeOH (1500 mL), H2O (50 mL) and CH2CI2 (500 mL) was purged with HCI gas till the solution was saturated. The mixture was left standing for 48 hours, then refluxed for 48 hours. TLC (petroleum ether: ethyl acetate = 10:1) showed the reaction was complete, then the mixture was concentrated in vacuo to give crude product, which was purified by column chromatography (first petroleum ether, then petroleum ether: ethyl acetate 1 :1) to afford compound 3 (33 g, yield: 82%) as a yellow solid and recover compound 2 (42 g) as a grey solid. 1H NMR (400 MHz, CDCI3): 1H NMR delta 8.76 (S, 1 H), 8.22- 8.24 (dd, J = 8.0 Hz, 1 H), 7.42-7.44 (d, J = 8.0 Hz, 1 H), 3.95 (s, 3H), 2.71 (s, 3H).
1-ethyl-2-(β-anilinovinyl)-quinolinium iodide[ No CAS ]
2-[3-(2-cyano-4-nitrophenyl)allylidene]-1-ethyl-1,2-dihydroquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With acetic anhydride; triethylamine; In N-methyl-acetamide;
EXAMPLE 5 Preparation of 2-[3-(2-cyano-4-nitrophenyl)allylidene]-1-ethyl-1,2-dihydroquinoline, FIG. 14. The condensation of 4.02 g. (0.01 mole) of 2-(2-anilinovinyl)-1-ethylquinolinium iodide (prepared as described in British Pat. No. 344,409 m.p. 263-5 C. (dec.)) with <strong>[939-83-3]2-cyano-4-nitrotoluene</strong> (1.67 g., 0.01 mole) was effected in 15 ml. of dimethylformamide containing 2 ml. of acetic anhydride by heating the reaction mixture to reflux, adding 1.01 g. (0.01 mole) of triethylamine, heating at reflux for 1 to 2 minutes and cooling rapidly. The precipitate was collected, washed successively with dimethylformamide, water and ether and then dried to yield 47% of theory of blue dye base m.p. 250-252 C. Calcd. for C21 H17 N3 O2: %C, 73.4; %H, 4.98; %N, 12.23; Found: %C, 72.4; %H, 4.9; %N, 12.2.
With sodium azide; In N,N-dimethyl-formamide; at 110℃; for 4.0h;Green chemistry;
General procedure: A mixtureof benzonitrile and sodium azide was added to 0.5g of 30mol% CAN supportedHY-zeolite in DMF. Then the reaction mixture was stirred at 110 C forspecified time. The progress of the reaction was monitored by TLC. Aftercompletion of the reaction the catalyst was removed by simple filtration andthe filtrate was treated with 1N HCl solution followed by extraction with ethylacetate twice. The combined organic layer was finally washed with water anddried over anhydrous sodium sulfate and was evaporated under reduced pressure.The crude product was recrystallized from hot ethanol to obtain pure 5-phenyl-1H-tetrazole. The same procedure has beenfollowed for other tetrazole derivatives. All the synthesized compounds except 10& 11 (Table 4) are known compounds and their spectral dataand physical properties are identical with those reported in literature.
(E)-2-(2-(dimethylamino)vinyl)-5-nitrobenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
In N,N-dimethyl-formamide; at 70℃; for 2.0h;
A mixture of <strong>[939-83-3]2-methyl-5-nitrobenzonitrile</strong> (235a) (5 g, 30.8 nunol) and 1-ten- butoxy-N,N,N?,N?-tetramethylmethanediamine (Bredereck?s reagent) (10.19 mL, 49.3 mmol) in dry DMF (lO mL) was heated at 70 C for 2 Ii. The reaction was cooled to room temperature and concentrated in vacuum; the crude product was triturated with 120 mL ofhexanes/ethyl acetate (5:1), and stirred for JO mm. The solid obtained was collected by filtration washed with hexanes (2 x 75 mL), dried under vacuum to afford (E)-2-(2- (dimethylamino)vinyl)-5-nitrobenzonirrile (235b) (6.07 g, 91 % yield) as a light brown solid; ?H NMR: ?H NMR (300 IvIHz, DMSO-d6) oe 8.35 (d, .1= 2.5 Hz, 1 H), 8.06 (ddd, .1 = 9.2, 2.6, 0.7 Hz, I H), 7.93 (d, J= 13.0 Hz, I H), 7.70 (d, J 9.4 Hz, 1 H), 5.29 (d, J = 12.9Hz, IH), 3.04 (s, 6H); MS (ES-) 252.1 (M+Cl).
potassiumhexacyanoferrate(II) trihydrate[ No CAS ]
[ 7745-92-8 ]
[ 939-83-3 ]
Yield
Reaction Conditions
Operation in experiment
69%
With sodium carbonate; In water; N,N-dimethyl-formamide; at 120℃; for 18.0h;
A round-bottomed flask (10 mL) was charged with 2-Iodo-4-nitrotoluene (1.5 mmol, 0.394 g), Na2CO3 (1.8 mmol, 0.190 g), the catalyst (0.0075 g, 1.7 mol%) and 1:1 (V/V) DMF/H2O (5 mL). The reaction mixture was heated to 120 C and K4[Fe(CN)6].3H2O (0.60 mmol, 0.253 g) was then added. The final mixture was stirred for 18 h. at 120 C. After allowing the mixture to cool to room temperature, the catalyst was filtrated.Then H2O (15 mL) was added to the mixture and the product was extracted with ethyl acetate (3 10 mL). The organic extracts were collective and dried over anhydrous Na2SO4. Evaporation of the solvent afforded the crude desired product, which was purified by column chromatography using hexane/EtOAc 20:6 (v/v) as the eluents, to afford the title compound. Yield: 69%. Yellow solid.M.p. 101-104 oC.1H-NMR (250 MHz, CDCl3/TMS) delta (ppm): 2.00 (s, 3H, CH3), 7.96 (d, J = 1.7 Hz, 1H), 8.05 (dd, J = 10.0, J = 1.5 Hz 1H), 8.42-8.47 (m, 1H). IR (KBr, cm-1): 2954, 2924, 2853, 2720, 2517, 2114, 1614, 1516, 1343, 1100, 954, 903, 851, 821, 808, 774, 732, 600, 461. Anal.Calcd.for C8H6N2O2 (162.26): C, 59.26; H, 3.73; N, 17.28. Found: C, 59.18; H, 3.66; N, 17.91.
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