* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With IrCl3·3H3O; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,3,5-trimethyl-benzene at 165℃; for 18 h;
General procedure: To a vial was added aniline (1.0 mmol), IrCl3·3H3O (5.0 molpercent based on 1,3-propanediol),rac-BINAP (7.5 molpercent) under air. To the vial was added mesitylene (0.5 mL) then1,3-propanediol (1.3 mmol) was added and stirred at 165 °C for 18 h. After the reaction, the resulting mixture was diluted with hexane. Then, the mixture was filtrated by filter paper, and was concentrated in vacuo. The resulting residue was purified by flash column chromatography on SiO2 (tBuOMe:Hexane=1:15) to yield 2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine.
With IrCl3·3H3O; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,3,5-trimethyl-benzene at 165℃; for 18 h;
To a vial was added 3-(phenylamino)propan-1-ol (8: 1.0 mmol, 151.3 mg), IrCl3·3H3O (5.0molpercent, 17.6 mg), rac-BINAP (7.5 molpercent, 46.7 mg) under air. To the vial was added mesitylene (1.0 mL) and stirred at 165 °C for 18 h. After the reaction, the resulting residue was purified by flash column chromatography on SiO2 (tBuOMe:Hexane=1:15) to yield 5a(45.3 mg) in 26percent yield (based on starting material) and 4a (18.0 mg) in 19percent yield.
With IrCl3·3H3O; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,3,5-trimethyl-benzene at 165℃; for 18 h;
Eq. 1 : To a vial was added 3-(phenylamino)propan-1-ol (8: 1.0 mmol, 151.3 mg), p-toluidine(4b: 1.0 mmol), IrCl3·3H3O (5.0 molpercent, 17.6 mg), rac-BINAP (7.5 molpercent, 46.7 mg) under air.To the vial was added mesitylene (1.0 mL) and stirred at 165 °C for 18 h. After the reaction, theresulting residue was purified by flash column chromatography on SiO2(tBuOMe:Hexane=1:15) to yield 5a and 5b as a mixture. Then PTLC (Wako Silicagel 70 PF254Plate-Wako, tBuOMe:Hexane=1:15) was used for purification to give 5a (15.1 mg) in 9percent yieldand 5b (48.7 mg) in 26percent yield, respectively (based on starting material).
With IrCl3·3H3O; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,3,5-trimethyl-benzene at 165℃; for 18 h;
Eq. 2 : To a vial was added 8 (1.0 mmol, 151.3 mg), 3a (1.0 mmol, 107.3 mg), IrCl3·3H3O(5.0 molpercent, 17.6 mg), rac-BINAP (7.5 molpercent, 46.7 mg) under air. To the vial was addedmesitylene (1.0 mL) and stirred at 165 °C for 18 h. After the reaction, the resulting residue waspurified by flash column chromatography on SiO2 (tBuOMe:Hexane=1:15) to yield 5a and 3a asa mixture and 4a (19.7 mg) in 21percent yield. Then PTLC (Wako Silicagel 70 PF254 Plate-Wako,tBuOMe:Hexane=1:15) was used for purification to give 5a (20.3 mg) in 12percent yield (based onstarting material) and 3a (76.8 mg) in 52percent yield, respectively.
Reference：
[1] Journal of the American Chemical Society, 1920, vol. 42, p. 1723
9
[ 62-53-3 ]
[ 479-59-4 ]
Reference：
[1] Journal of the American Chemical Society, 1920, vol. 42, p. 1723
10
[ 76859-24-0 ]
[ 479-59-4 ]
[ 76859-15-9 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1980, # 21, p. 1009 - 1011
[2] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 5, p. 1770 - 1779
11
[ 80574-26-1 ]
[ 80574-24-9 ]
[ 479-59-4 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 9, p. 2465 - 2477
[2] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 9, p. 2465 - 2477
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 9, p. 3117 - 3126
14
[ 76859-18-2 ]
[ 479-59-4 ]
[ 76859-19-3 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 5, p. 1770 - 1779
[2] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 5, p. 1770 - 1779
15
[ 109-70-6 ]
[ 62-53-3 ]
[ 479-59-4 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 925 - 926
[2] Chemische Berichte, 1892, vol. 25, p. 2802
[3] Chemische Berichte, 1892, vol. 25, p. 2802
16
[ 101359-27-7 ]
[ 479-59-4 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1985, vol. 50, # 5, p. 1048 - 1056
17
[ 635-46-1 ]
[ 479-59-4 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1985, vol. 50, # 5, p. 1048 - 1056
18
[ 635-46-1 ]
[ 109-70-6 ]
[ 479-59-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2011, # 30, p. 6100 - 6109
[2] Chemische Berichte, 1892, vol. 25, p. 2802
19
[ 76859-14-8 ]
[ 479-59-4 ]
[ 76859-15-9 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 5, p. 1770 - 1779
[2] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 5, p. 1770 - 1779
20
[ 109-70-6 ]
[ 767-92-0 ]
[ 479-59-4 ]
Reference：
[1] Chemische Berichte, 1892, vol. 25, p. 2802
[2] Chemische Berichte, 1918, vol. 51, p. 1219
21
[ 109-70-6 ]
[ 100-61-8 ]
[ 479-59-4 ]
Reference：
[1] Chemische Berichte, 1892, vol. 25, p. 2802
22
[ 109-70-6 ]
[ 103-70-8 ]
[ 479-59-4 ]
Reference：
[1] Chemische Berichte, 1892, vol. 25, p. 2802
23
[ 31379-14-3 ]
[ 479-59-4 ]
Reference：
[1] Chemische Berichte, 1892, vol. 25, p. 2802
24
[ 479-59-4 ]
[ 70173-54-5 ]
Yield
Reaction Conditions
Operation in experiment
80%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 5 h;
A 10mL DMF solution of julolidine (675 mg, 3.90 mmol) and NBS(832 mg, 4.68 mmol) was stirred for 5 h at room temperature. Thecrude product was purified by silica column chromatography(hexane/methylene chloride3/1) to obtain JeBr (786 mg, 80percent) as ared oil. 1H NMR (500 MHz, CDCl3): d/ppm: 6.87 (s, 2H), 3.10 (t, 4H,J5.50 Hz), 2.70 (t, 4H, J6.35 Hz),1.94 (m, 4H). 13CNMR(500 MHz,CDCl3): d/ppm: 142.0, 129.3, 123.7, 107.3, 50.0, 27.6, 21.9. IR (KBr,cm1): 3045, 2935, 2836,1581,1506,1462,1446,1310. TOFMS-EI (m/z): calcd. for (M) C12H14NBr: 251.0310, found: 251.0309.
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1984, vol. 32, # 5, p. 1770 - 1779
[2] Canadian Journal of Chemistry, 2009, vol. 87, # 2, p. 440 - 447
[3] Journal of Organic Chemistry, 2011, vol. 76, # 22, p. 9391 - 9408
[4] Dyes and Pigments, 2013, vol. 99, # 3, p. 653 - 660
[5] European Journal of Organic Chemistry, 2011, # 30, p. 6100 - 6109
[6] Tetrahedron, 2007, vol. 63, # 1, p. 103 - 114
[7] Journal of Organic Chemistry, 1952, vol. 17, p. 1281,1288
[8] Chemical Communications, 2010, vol. 46, # 36, p. 6666 - 6668
[9] Patent: KR2016/99254, 2016, A, . Location in patent: Paragraph 0081; 0082; 0084; 0085
25
[ 479-59-4 ]
[ 68-12-2 ]
[ 33985-71-6 ]
Yield
Reaction Conditions
Operation in experiment
92%
With trichlorophosphate In dichloromethane at 20℃; for 4 h; Inert atmosphere
Julolidine (0.5 g, 2.89 mmol), DMF (0.255 g, 3.49 mmol)and POCl3 (0.535 g, 3.49 mmol) were dissolved in DCM(15 mL) and the mixture was stirred at room temperaturefor 4 h under an inert argon atmosphere. The solution’scolor turned green and the degree of advancement was followedby TLC. The solution was treated with aq. NaOH(2 M) and the crude product then was extracted withEt2O. After two aqueous washings, the organic phase wasdried on MgSO4, filtered and concentrated under vacuum.The product was then purified on column chromatographyusing 40percent–50percent Et2O: Hexane was used as the eluentto give 0.48 g (83.08percent) (the reaction yield was upto 92percent when 1.5 g julolidine was used as starting material)of a light yellow solid product.1H NMR (300 MHz,CDCl3: = 9597 (s, 1 H), 7.29 (s, 1 H), 3.308 (t, J =57 Hz, 4 H), 2.787 (t, J = 62, 4 H), 2.002–1.92 (m, J =63, 4 H).
80%
Stage #1: at 0℃; Inert atmosphere Stage #2: at 0 - 20℃; Inert atmosphere
2,3,6,7-Tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline-9-carbaldehyde was synthesized according to the described method [Kauffman, Joel M.; Imbesi, Steven J.; Aziz, Mohammed Abdul - Organic Preparations and Procedures International, 2001, vol. 33, 6, p. 603 - 613] with some modifications: to a magnetically stirred solution of POCl3 (2.2 ml, 23 mmol) in DMF (2 ml) julolidine (2) (2 g, 11.6 mmol) and DMF (2 mL) under argon was added dropwise at 0 °C. Then the mixture was allowed to stir for 3 h at rt (TLC). Ammonium hydroxide was added for neutralization and the solution was deluted with ethyl acetate and washed with water several times. The residue was purified by column chromatography (silica gel, 10percent ethyl acetate/hexane). Yield 1.8 g (80percent). 1H NMR (300 MHz, CDCl3): δ 9.63 (s, 1H), 7.28 (s, 2H), 3.31 (t, J=5.8 Hz, 4H), 2.81 (t, J= 6.2 Hz, 4H), 1.97–2.06 (m, 4H).
71%
With trichlorophosphate In N,N-dimethyl-formamide at 90℃; for 4.5 h;
The synthesis of 9-formyljulolidinewas carried outmodifying a reported procedure [45,46]. In brief,phosphorous oxychloride (1.1 mL, 11.55 mmol) was added dropwise to N,N-dimethyl-formamide(2 mL, 25.85 mmol) at 0 °C. A solution of julolidine (2.0015 g, 11.55 mmol) in DMF (3.5 mL, 45.24 mmol)was then added and the mixture was stirred at 90 °C for 4.5 h. The solution was allowed to coolat room temperature (rt) and neutralized to pH 6–8 by the addition of a saturated sodium acetatesolution (~30 mL). After stirring overnight at rt, a greenish-yellow solid precipitate was recoveredvia filtration, washed with water (30 mL) and dried under high vacuum. The crude product waspurified through column chromatography on silica gel using ethyl acetate/CHCl3 (70/30 v/v) aseluent mixture. 1.65 g of FJUL were recovered (71percent yield). FT-IR (KBr, cm-1): 2758, 1651, 1594,1527, 1321. 1H-NMR (CDCl3): δ (ppm) = 9.6 (s, 1H, CHO), 7.3 (s, 2H, aromatic), 3.3 (t, J = 5.8 Hz,4H, NCH2), 2.7 (t, J = 6.3 Hz, 4H, NCH2CH2CH2), 1.9 (m, 4H, NCH2CH2). 13C-NMR (CDCl3): δ (ppm) = 190.1 (-CHO), 147.9 (-N-C(-C-)=C-), 129.5 (-C(=C)-CH=C(-C)-CH=), 124.0 (-CH-(CH=)C-CHO),120.33 (-CH2-C(=C-)-CH(=C)), 50.0 (-N(-CH2)-), 27.7 (-N(-CH2-CH2-CH2-)-), 21.3 (-N(-CH2-CH2-CH2-)-).EI-MS m/z (percent): 201 (100, M+).
60%
With trichlorophosphate In dichloromethane at 25℃; for 8 h;
In brief, phosphorous oxychloride (0.29 mL, 3.17 mmol) was added dropwise to a solution of julolidine(0.5 g, 2.88 mmol) and N,N-dimethylformamide (0.27 mL,3.45 mmol) in anhydrous dichloromethane (5 mL) and the mixture was stirred for 8 h at 25 C. The reaction was treated with an aqueous solution of sodium hydroxide (2 M) and the mixture was stirred at 0 C for 4 h. The organic layer was extracted with diethyl ether, dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography on silica gel (230400 mesh) using diethyl ether/n-hexane (3/7 v/v) as eluent mixture (Rf 0.37) (60percent yield). FT-IR (KBr, cm1): 2950, 2895, 1662, 1600, 1320, 900, 720.1H NMR (CDCl3) (ppm): 9.6 (s, 1H, CHO), 7.3 (s, 2H, aromatic), 3.3(t, 4H NCH2), 2.7 (t, 4H NCH2CH2CH2), 1.9 (m, 4H NCH2CH2).13C NMR (CDCl3) (ppm): 191.3 (CHO), 149.1 (CeN aromatic),128.5 to 122.0 (aromatic), 49.3 (NCH2), 28.1 to 20.4 (NCH2CH2CH2). EI-MS m/z (percent): 201 (100, M).
42.7%
at 80 - 100℃; for 2 h; Inert atmosphere; Cooling with ice
Dry N,N-dimethylformamide (DMF) (3.4 mL, 43.9 mmol) was charged into around bottom flask fitted with a magnetic stirrer and pressure-equalizing dropping funnel. The flask was purged withdry nitrogen and cooled in an ice bath. Phosphorus oxychloride (0.79 mL, 8.5 mmol) was then added slowly to the DMF. A solution of 2,3,6,7-tetrahydro-1H,5H-benzo-quinolizine(julolidine) (1.47 g, 8.5 mmol) in DMF (1.36 mL) was then added with vigorous stirring to the mixture and the resulting mixture was heated at 80-100 °C for 2 h. The solution was allowed to cool to room temperature and was poured into ice water. The solution was neutralized to pH 6-8 by addition of saturated sodium acetate. The desired aldehyde precipitated out of solution as a greenish-yellow solid. The solid was filtered, washed with water and hexane, and dried to obtain pure aldehyde 1 (0.731 g). Yield: 42.7percent. 1H NMR (500 MHz, CDCl3) δ 1.37 (p, 2x2H), 2.8 (t, 2x2H),3.3 (2x2H, t), 7.29 (2x1H, s), 9.6 (s, 1H, CHO).
Reference：
[1] Tetrahedron, 2007, vol. 63, # 1, p. 103 - 114
[2] Organic Preparations and Procedures International, 2001, vol. 33, # 6, p. 603 - 613
[3] Journal of Nanoscience and Nanotechnology, 2015, vol. 15, # 11, p. 8813 - 8819
[4] Chemistry - A European Journal, 2010, vol. 16, # 30, p. 9257 - 9263
[5] Chemical Communications, 2014, vol. 50, # 78, p. 11507 - 11510
[6] Journal of Materials Chemistry, 2006, vol. 16, # 34, p. 3512 - 3520
[7] Tetrahedron Letters, 2018, vol. 59, # 29, p. 2788 - 2792
[8] Angewandte Chemie, 1993, vol. 105, # 6, p. 913 - 915
[9] Molecules, 2017, vol. 22, # 8,
[10] Tetrahedron, 2010, vol. 66, # 6, p. 1254 - 1260
[11] Dyes and Pigments, 2015, vol. 113, p. 47 - 54
[12] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 8, p. 2453 - 2459
[13] Journal of the American Chemical Society, 1993, vol. 115, # 16, p. 7192 - 7198
[14] Dyes and Pigments, 2015, vol. 123, p. 341 - 348
[15] Journal of Molecular Structure, 2016, vol. 1112, p. 97 - 109
26
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[ 33985-71-6 ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: at 0℃; for 1.25 h; Stage #2: for 1.16667 h;
N,N-Dimethylformamide (21.4 g) was placed in a flask and stirred with cooling on an ice bath, and phosphorus oxychloride (13.3 g) was dropwise added over 15 minutes. The mixture was stirred at the same temperature for 1 hour, and a solution of julolidine (5.1 g) represented by the following (F-1) in N,N-dimethylformamide (10 ml) was dropwise added over 10 minutes. After 1 hour, a reaction mixture was poured into a diluted sodium hydroxide aqueous solution (200 ml), and an organic component was extracted with toluene. The solvent was distilled off, and a residue was purified by silica gel column chromatography, to give the following compound (F-2). 5.3 g. Yield 91 percent.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 5h;
A 10mL DMF solution of julolidine (675 mg, 3.90 mmol) and NBS(832 mg, 4.68 mmol) was stirred for 5 h at room temperature. Thecrude product was purified by silica column chromatography(hexane/methylene chloride3/1) to obtain JeBr (786 mg, 80%) as ared oil. 1H NMR (500 MHz, CDCl3): d/ppm: 6.87 (s, 2H), 3.10 (t, 4H,J5.50 Hz), 2.70 (t, 4H, J6.35 Hz),1.94 (m, 4H). 13CNMR(500 MHz,CDCl3): d/ppm: 142.0, 129.3, 123.7, 107.3, 50.0, 27.6, 21.9. IR (KBr,cm1): 3045, 2935, 2836,1581,1506,1462,1446,1310. TOFMS-EI (m/z): calcd. for (M) C12H14NBr: 251.0310, found: 251.0309.
With N-Bromosuccinimide; In tetrahydrofuran; for 5h;Reflux;
Add Julolidine (3g, 17.3mmol) into a 250ml round-bottomed flask, add THF (50.0mL) and stir well. Nbromosuccimide (3.4g, 19mmol) is added and refluxed for 5 hours. When the reaction is complete, the mixture is extracted with chloroform and water and then extracted with aqueous solution. After removal of the solvent, red solid Sub1-1 was obtained after purification by column chromatography with hexane.
With trichlorophosphate; In dichloromethane; at 20℃; for 4h;Inert atmosphere;
Julolidine (0.5 g, 2.89 mmol), DMF (0.255 g, 3.49 mmol)and POCl3 (0.535 g, 3.49 mmol) were dissolved in DCM(15 mL) and the mixture was stirred at room temperaturefor 4 h under an inert argon atmosphere. The solution?scolor turned green and the degree of advancement was followedby TLC. The solution was treated with aq. NaOH(2 M) and the crude product then was extracted withEt2O. After two aqueous washings, the organic phase wasdried on MgSO4, filtered and concentrated under vacuum.The product was then purified on column chromatographyusing 40%-50% Et2O: Hexane was used as the eluentto give 0.48 g (83.08%) (the reaction yield was upto 92% when 1.5 g julolidine was used as starting material)of a light yellow solid product.1H NMR (300 MHz,CDCl3: = 9597 (s, 1 H), 7.29 (s, 1 H), 3.308 (t, J =57 Hz, 4 H), 2.787 (t, J = 62, 4 H), 2.002-1.92 (m, J =63, 4 H).
80%
2,3,6,7-Tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline-9-carbaldehyde was synthesized according to the described method [Kauffman, Joel M.; Imbesi, Steven J.; Aziz, Mohammed Abdul - Organic Preparations and Procedures International, 2001, vol. 33, 6, p. 603 - 613] with some modifications: to a magnetically stirred solution of POCl3 (2.2 ml, 23 mmol) in DMF (2 ml) julolidine (2) (2 g, 11.6 mmol) and DMF (2 mL) under argon was added dropwise at 0 C. Then the mixture was allowed to stir for 3 h at rt (TLC). Ammonium hydroxide was added for neutralization and the solution was deluted with ethyl acetate and washed with water several times. The residue was purified by column chromatography (silica gel, 10% ethyl acetate/hexane). Yield 1.8 g (80%). 1H NMR (300 MHz, CDCl3): delta 9.63 (s, 1H), 7.28 (s, 2H), 3.31 (t, J=5.8 Hz, 4H), 2.81 (t, J= 6.2 Hz, 4H), 1.97-2.06 (m, 4H).
71%
With trichlorophosphate; In N,N-dimethyl-formamide; at 90℃; for 4.5h;
The synthesis of 9-formyljulolidinewas carried outmodifying a reported procedure [45,46]. In brief,phosphorous oxychloride (1.1 mL, 11.55 mmol) was added dropwise to N,N-dimethyl-formamide(2 mL, 25.85 mmol) at 0 C. A solution of julolidine (2.0015 g, 11.55 mmol) in DMF (3.5 mL, 45.24 mmol)was then added and the mixture was stirred at 90 C for 4.5 h. The solution was allowed to coolat room temperature (rt) and neutralized to pH 6-8 by the addition of a saturated sodium acetatesolution (~30 mL). After stirring overnight at rt, a greenish-yellow solid precipitate was recoveredvia filtration, washed with water (30 mL) and dried under high vacuum. The crude product waspurified through column chromatography on silica gel using ethyl acetate/CHCl3 (70/30 v/v) aseluent mixture. 1.65 g of FJUL were recovered (71% yield). FT-IR (KBr, cm-1): 2758, 1651, 1594,1527, 1321. 1H-NMR (CDCl3): delta (ppm) = 9.6 (s, 1H, CHO), 7.3 (s, 2H, aromatic), 3.3 (t, J = 5.8 Hz,4H, NCH2), 2.7 (t, J = 6.3 Hz, 4H, NCH2CH2CH2), 1.9 (m, 4H, NCH2CH2). 13C-NMR (CDCl3): delta (ppm) = 190.1 (-CHO), 147.9 (-N-C(-C-)=C-), 129.5 (-C(=C)-CH=C(-C)-CH=), 124.0 (-CH-(CH=)C-CHO),120.33 (-CH2-C(=C-)-CH(=C)), 50.0 (-N(-CH2)-), 27.7 (-N(-CH2-CH2-CH2-)-), 21.3 (-N(-CH2-CH2-CH2-)-).EI-MS m/z (%): 201 (100, M+).
60%
With trichlorophosphate; In dichloromethane; at 25℃; for 8h;
In brief, phosphorous oxychloride (0.29 mL, 3.17 mmol) was added dropwise to a solution of julolidine(0.5 g, 2.88 mmol) and N,N-dimethylformamide (0.27 mL,3.45 mmol) in anhydrous dichloromethane (5 mL) and the mixture was stirred for 8 h at 25 C. The reaction was treated with an aqueous solution of sodium hydroxide (2 M) and the mixture was stirred at 0 C for 4 h. The organic layer was extracted with diethyl ether, dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography on silica gel (230400 mesh) using diethyl ether/n-hexane (3/7 v/v) as eluent mixture (Rf 0.37) (60% yield). FT-IR (KBr, cm1): 2950, 2895, 1662, 1600, 1320, 900, 720.1H NMR (CDCl3) (ppm): 9.6 (s, 1H, CHO), 7.3 (s, 2H, aromatic), 3.3(t, 4H NCH2), 2.7 (t, 4H NCH2CH2CH2), 1.9 (m, 4H NCH2CH2).13C NMR (CDCl3) (ppm): 191.3 (CHO), 149.1 (CeN aromatic),128.5 to 122.0 (aromatic), 49.3 (NCH2), 28.1 to 20.4 (NCH2CH2CH2). EI-MS m/z (%): 201 (100, M).
42.7%
With trichlorophosphate; at 80 - 100℃; for 2h;Inert atmosphere; Cooling with ice;
Dry N,N-dimethylformamide (DMF) (3.4 mL, 43.9 mmol) was charged into around bottom flask fitted with a magnetic stirrer and pressure-equalizing dropping funnel. The flask was purged withdry nitrogen and cooled in an ice bath. Phosphorus oxychloride (0.79 mL, 8.5 mmol) was then added slowly to the DMF. A solution of 2,3,6,7-tetrahydro-1H,5H-benzo-quinolizine(julolidine) (1.47 g, 8.5 mmol) in DMF (1.36 mL) was then added with vigorous stirring to the mixture and the resulting mixture was heated at 80-100 C for 2 h. The solution was allowed to cool to room temperature and was poured into ice water. The solution was neutralized to pH 6-8 by addition of saturated sodium acetate. The desired aldehyde precipitated out of solution as a greenish-yellow solid. The solid was filtered, washed with water and hexane, and dried to obtain pure aldehyde 1 (0.731 g). Yield: 42.7%. 1H NMR (500 MHz, CDCl3) delta 1.37 (p, 2x2H), 2.8 (t, 2x2H),3.3 (2x2H, t), 7.29 (2x1H, s), 9.6 (s, 1H, CHO).
1.1 1: Phosphorus oxychloride (1.17 g, 7.62 mmol) was slowly added dropwise to a round bottom flask containing DMF (1.67 g, 22.87 mmol) in an ice salt bath. After the addition was completed, the ice bath was removed. Vilsmeier-Haack reagent was prepared by stirring at room temperature for half an hour under nitrogen.Then, a DMF solution in which julolidine (1.2 g, 6.93 mmol) was dissolved was slowly added dropwise thereto, and after completion of the dropwise addition, it was refluxed at 90 C for 4 hours. Pour the reacted material into ice water to make it reverseShould stop, continue to stir for at least 2h, a yellow solid precipitated,Finally, suction filtration gave a pale yellow solid.
Stage #1: 2-(4-amino-phenylazo)-1,3-dimethyl-3H-imidazol-1-ium chloride With hydrogenchloride; acetic acid; sodium nitrite In water at 5℃; for 0.5h;
Stage #2: julolidine With sodium hydrogencarbonate In ethanol; water at 5 - 20℃; for 1h;
Dye 6; Ci-Synthetic scheme; A mixture consisting of monoazo dye (2.5 g), of concentrated hydrochloric acid (2.5 mL) , of acetic acid(2 mL) and of water (38 mL) is cooled to 50C and a solution of sodium nitrite (0.8 g) dissolved in water(2 mL) is then added dropwise, while maintaining the reaction medium at a temperature below 50C. After reaction for 30 minutes, urea (0.1 g) is added. The diazonium salt solution obtained previously is poured dropwise into a solution consisting of julolidine(1.73 g) dissolved in water (25 mL) and ethanol (10 mL) in the presence of sodium hydrogencarbonate (2 g) , while taking care to maintain the reaction medium at a temperature below 50C. After stirring for one hour, the pH is brought to 7 with aqueous NaHCO3 solution and the temperature is allowed to return to room temperature. The solution is evaporated under vacuum. The residue obtained is purified by chromatography on silica-60 gel, using the dichloromethane/methanol binary mixture as eluent. After evaporation under vacuum, 450 mg of blue powder are thus obtained. The analyses indicate that the expected product has indeed been obtained (NMR, HPLC, MS) .
N,N-Dimethylformamide (21.4 g) was placed in a flask and stirred with cooling on an ice bath, and phosphorus oxychloride (13.3 g) was dropwise added over 15 minutes. The mixture was stirred at the same temperature for 1 hour, and a solution of julolidine (5.1 g) represented by the following (F-1) in N,N-dimethylformamide (10 ml) was dropwise added over 10 minutes. After 1 hour, a reaction mixture was poured into a diluted sodium hydroxide aqueous solution (200 ml), and an organic component was extracted with toluene. The solvent was distilled off, and a residue was purified by silica gel column chromatography, to give the following compound (F-2). 5.3 g. Yield 91 %.
Stage #1: 3-cyano-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene With sulfuric acid In N,N-dimethyl-formamide at 0 - 5℃;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 0 - 5℃;
Stage #3: julolidine
10
The 2-aminothiophene derivative 10a (5.0 g, 0.028 mol) was dissolved in a minimum amount of dimethylformamide (10 ml), and sulfuric acid (8 ml, 54% V/V) was added. The mixture was cooled to 0-5° C. with stirring for half an hour. Sodium nitrite (1.93 g, 0.028 mol) was dissolved in water (10 ml) and cooled to 0-5° C. to form dilute nitrous acid. This solution was slowly added to the 2-aminothiophene derivative solution, with the temperature being kept in the range of 0-5° C. Stirring was continued for one hour, after which the diazonium salt 10b was formed.Julolidine (4.85 g, 0.028 mol) was dissolved in a solution prepared from water (10 ml) and hydrochloric acid (5 ml, 10 M), and the solution was cooled to a temperature between 0-5° C. The diazonium solution 10b was added to the Julolidine coupling component solution slowly over a period of one hour to keep the temperature below 5° C. The reaction mixture was stirred for 2 hours, during which the temperature was raised to room temperature. The pH of the solution was raised by adding sodium hydroxide solution (5-10%) to obtain a pH in the range between 5.5 and 7. The precipitated dye 10 was filtered and washed with plenty of water to get rid of the excess sodium hydroxide, then recrystallized from an ethyl acetate/petroleum ether (40-60) mixture (8:2), m.p. 116-122° C., (50% yield).
Stage #1: diethyl 5-amino-3-methyl-2,4-thiophenedicarboxylate With sulfuric acid In N,N-dimethyl-formamide at 0 - 5℃;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 0 - 5℃;
Stage #3: julolidine
5
The 2-aminothiophene derivative 5a (5.56 gm, 0.0216 mmol) was dissolved in minimum amounts of dimethylformamide (10 ml), and sulfuric acid (8ml, 54% V/V) was added. The dissolved solid was cooled to 0-5° C. with stirring for half an hour. Sodium nitrite (1.49 g, 0.0216 mmol), dissolved in water (10 ml), was added, and the mixture was cooled to 0-5° C. This solution was slowly added slowly to the 2-aminothiophene derivative solution with temperature being kept in the range of 0-5°C. Stirring was continued for one hour, after which the diazonium salt 5b was formed.Julolidine (3.74 g, 0.0216 mmol) was dissolved in a solution prepared from water (10 ml) and hydrochloric acid (5 ml, 10M), and the solution was cooled to a temperature between 0-5° C. The diazonium solution 5b was added to the Julolidine coupling component solution slowly over a period of one hour to keep the temperature below 5° C. The reaction mixture was stirred for 2 hours, during which the temperature was raised to room temperature. The pH of the solution was raised by adding sodium hydroxide solution (5-10%) to obtain a pH in the range between 5.5 and 7. The precipitated dye 5 was filtered and washed with plenty of water to get rid of the excess sodium hydroxide, then recrystallized from an ethyl acetate/petroleum ether (40-60) mixture (8:2), m.p. 117-119° C., (33% yield).
The 2-aminothiophene derivative 11a (2.96.0 g, 0.014 mol) was dissolved in a minimum amount of dimethylformamide (10 ml), and sulfuric acid (8 ml, 54% V/V) was added. The mixture was cooled to 0-5 C. with stirring for half an hour. Sodium nitrite (0.97 g, 0.014 mol) was dissolved in water (10 ml) and cooled to 0-5 C. to form dilute nitrous acid. This solution was slowly added to the 2-aminothiophene derivative solution, with the temperature being kept in the range of 0-5 C. Stirring was continued for one hour, after which the diazonium salt 11b was formed.Julolidine (2.50 gm, 0.014 mol) was dissolved in a solution prepared from water (10 ml) and hydrochloric acid (5 ml, 10M), and the solution was cooled to a temperature between 0-5 C. The diazonium solution 11b was added to the julolidine coupling component solution slowly over a period of one hour to keep the temperature below 5 C. The reaction mixture was stirred for 2 hours, during which the temperature was raised to room temperature. The pH of the solution was raised by adding sodium hydroxide solution (5-10%) to obtain a pH in the range between 5.5 and 7. The precipitated dye 11 was filtered and washed with plenty of water to get rid of the excess sodium hydroxide, then recrystallized from an ethyl acetate/petroleum ether (40-60) mixture (8:2), m.p. 98-103 C., (68% yield).
Stage #1: ethyl 2-amino-5-phenylthiophene-3-carboxylate With sulfuric acid In N,N-dimethyl-formamide at 0 - 5℃;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 0 - 5℃;
Stage #3: julolidine
1
The substituted 2-aminothiophene 1a (1.5 gm, 6.0 mmol) was dissolved in minimum amounts of dimethylformamide (5 ml), and sulfuric acid (4 ml, 54% V/V) was added. The dissolved solid was cooled to 0-5° C. with stirring for half an hour. Sodium nitrite (0.5 g, 6.0 mmol) was dissolved in water (5 ml) and cooled to 0-5° C. to form dilute nitrous acid. This solution was slowly added to the 2-aminothiophene derivative solution with the temperature kept in the range of 0-5° C. Stirring was continued for one hour, after which the diazonium salt 1b was formed. Julolidine (1.04 g, 6.0 mmol) was dissolved in a solution prepared from water (10 ml) and hydrochloric acid (2 ml, 10M), and the solution was cooled to a temperature between 0-5° C. The diazonium solution 1b was added to the Julolidine coupling component solution slowly over a period of one hour to keep the temperature below 5° C. Stirring was continued for 2 hours, during which the temperature was raised to room temperature. The pH of the solution was raised by adding sodium hydroxide solution (5-10%) to maintain the pH in the range between 5.5 and 7. The precipitated dye 1 was then filtered and washed with plenty of water to get rid of the excess sodium hydroxide, and then recrystallized from ethyl acetate/petroleum ether (40-60) mixture (8:2). m.p. 183-186, (81% yield).The ultraviolet-visible spectra of azo dye 1 in various solvents are shown in FIG. 1.
Stage #1: 2-amino-5-phenylthiophene-3-carboxylic acid methyl ester With sulfuric acid In N,N-dimethyl-formamide at 0 - 5℃;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 0 - 5℃;
Stage #3: julolidine
2
The substituted 2-aminothiophene 2a (2.5 g, 10.7 mmol) was dissolved in minimum amounts of dimethylformamide (5 ml), and sulfuric acid (6 ml, 54% V/V) was added. The dissolved solid was cooled to 0-5° C. with stirring for half an hour. Sodium nitrite (0.74 g, 10.7 mmol) dissolved in water (10 ml) and cooled to 0-5° C. to form dilute nitrous acid. This solution was slowly added to the 2-aminothiophene derivative solution with the temperature being kept in the range of 0-5° C., and stirring was continued for one hour, after which the diazonium salt 2b was formed.Julolidine (1.85 g, 10.7 mmol) was dissolved in a solution prepared from water (10 ml) and hydrochloric acid (3 ml, 10M), and the solution was cooled to a temperature between 0-5° C. The diazonium solution 2b was added to the Julolidine coupling component solution slowly over a period of one hour to keep the temperature below 5° C. Stirring was continued for 2 hours, during which the temperature was raised to room temperature. The pH of the solution was raised by adding sodium hydroxide solution (5-10%) to obtain a pH in the range between 5.5 and 7. The precipitated dye 2 was filtered and washed with plenty of water to get rid of the excess sodium hydroxide, then recrystallized from ethyl acetate/petroleum ether (40-60) mixture (8:2), m.p. 194-197, (79% yield).
Stage #1: 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbonitrile With sulfuric acid In N,N-dimethyl-formamide at 0 - 5℃;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 0 - 5℃;
Stage #3: julolidine
12
The 2-aminothiophene derivative 12a (5.0 g, 0.026 mol) was dissolved in a minimum amount of dimethylformamide (10 ml), and sulfuric acid (8 ml, 54% V/V) was added. The mixture was cooled to 0-5° C. with stirring for half an hour. Sodium nitrite (1.79 g, 0.026 mol) was dissolved in water (10 ml) and cooled to 0-5° C. to form dilute nitrous acid. This solution was slowly added to the 2-aminothiophene derivative solution, with the temperature being kept in the range of 0-5° C. Stirring was continued for one hour, after which the diazonium salt 12b was formed.Julolidine (4.63 g, 0.026 mol) was dissolved in a solution prepared from water (10 ml) and hydrochloric acid (5 ml, 10M), and the solution was cooled to a the temperature between 0-5° C. The diazonium solution 12b was added to the julolidine coupling component solution slowly over a period of one hour to keep the temperature below 5° C. The reaction mixture was stirred for 2 hours, during which the temperature was raised to room temperature. The pH of the solution was raised by adding sodium hydroxide solution (5-10%) to obtain a pH in the range between 5.5 and 7. The precipitated dye 12 was filtered and washed with plenty of water to get rid of the excess sodium hydroxide, then recrystallized from an ethyl acetate/petroleum ether (40-60) mixture (8:2), m.p. 184-186° C., (76% yield).
Stage #1: ethyl 2-amino-3-cyano-4-methylthiophene-5-carboxylate With sulfuric acid In N,N-dimethyl-formamide at 0 - 5℃;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 0 - 5℃;
Stage #3: julolidine
3
The substituted 2-aminothiophene 3a (5.36 gm, 0.0256 mol) was dissolved in minimum amounts of dimethylformamide (10 ml), and sulfuric acid (8 ml, 54% V/V) was added. The dissolved solid was cooled to 0-5° C. with stirring for half an hour. Sodium nitrite (1.76 g, 0.0256 mmol) was dissolved in water (10 ml) and cooled to 0-5° C. to form dilute nitrous acid. This solution was slowly added to the 2-aminothiophene derivative solution with the temperature being kept in the range of 0-5° C. Stirring was continued for one hour, after which the diazonium salt 3b was formed.Julolidine (4.42 g, 0.0255 mmol) was dissolved in a solution prepared from water (10 ml) and hydrochloric acid (5 ml, 10M), and the solution was cooled to a temperature between 0-5° C. The diazonium solution 3b was added to the Julolidine coupling component solution slowly over a period of one hour to keep the temperature below 5° C. Stirring was continued for two hours, during which the temperature was raised to room temperature. The pH of the solution was raised by adding sodium hydroxide solution (5-10%) to obtain a pH in the range between 5.5-7. The precipitated dye 3 was filtered and washed with plenty of water to get rid of the excess sodium hydroxide, then recrystallized from ethyl acetate/petroleum ether (40-60) mixture (8:2), m.p. 196-198° C., (80% yield).
Stage #1: methyl 2‐amino‐4H,5H,6H‐cyclopenta[b]thiophene‐3‐carboxylate With sulfuric acid In N,N-dimethyl-formamide at 0 - 5℃;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 0 - 5℃;
Stage #3: julolidine
9
The 2-aminothiophene derivative 9a (5.0 g, 0.025 mol) was dissolved in a minimum amount of dimethylformamide (10 ml), and sulfuric acid (8 ml, 54% V/V) was added. The mixture was cooled to 0-5° C. with stirring for half an hour. Sodium nitrite (1.73 g, 0.025 mol) was dissolved in water (10 ml) and cooled to 0-5° C. to form dilute nitrous acid. This solution was slowly added to the 2-aminothiophene derivative solution, with the temperature being kept in the range of 0-5° C. Stirring was continued for one hour, after which the diazonium salt 9b was formed.Julolidine (4.33 g, 0.025 mol) was dissolved in a solution prepared from water (10 ml) and hydrochloric acid (5 ml, 10M), and the solution was cooled to a temperature between 0-5° C. The diazonium solution 9a was added to the julolidine coupling component solution slowly over a period of one hour to keep the temperature below 5° C. The reaction mixture was stirred for 2 hours, during which the temperature was raised to room temperature. The pH of the solution was raised by adding sodium hydroxide solution (5-10%) to obtain a pH in the range between 5.5 and 7. The precipitated dye 9 was filtered and washed with plenty of water to get rid of the excess sodium hydroxide, then recrystallized from ethyl acetate/petroleum ether (40-60) mixture (8:2), m.p. 176-179° C., (67% yield).
Stage #1: 2-ethyl 4-methyl 5-amino-3-methyl-2,4-thiophenedicarboxylate With sulfuric acid In N,N-dimethyl-formamide at 0 - 5℃;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 0 - 5℃;
Stage #3: julolidine
4
The 2-aminothiophene derivative 4a ( 4.94 gm, 0.0203 mol) was dissolved in minimum amounts of dimethylformamide (10 ml), and sulfuric acid (8 ml, 54% V/V) was added. The dissolved solid was cooled to 0-5° C. with stirring for half an hour. Sodium nitrite (1.40 g, 0.0203 mol) was dissolved in water (10 ml) and cooled to 0-5° C. to form dilute nitrous acid. This solution was slowly added to the 2-aminothiophene derivative solution, with the temperature being kept in the range of 0-5° C. Stirring was continued for one hour, after which the diazonium salt 4b was formed.Julolidine (3.52 g, 0.0203 mmol) was dissolved in a solution prepared from water (10 ml) and hydrochloric acid (5 ml, 10M), and the solution was cooled to a the temperature between 0-5° C. The diazonium solution 4b was added to the julolidine coupling component solution slowly over a period of one hour to keep the temperature below 5° C. The reaction mixture was stirred for 2 hours, during which the temperature was raised to room temperature. The pH of the solution was raised by adding sodium hydroxide solution (5-10%) to obtain a pH in the range between 5.5-7. The precipitated dye 4 was filtered and washed with plenty of water to get rid of the excess sodium hydroxide, then recrystallized from ethyl acetate/petroleum ether (40-60) mixture (8:2) m.p. 127-129° C., (30% yield).
Stage #1: 5-acetyl-2-amino-4-methylthiophene-3-carbonitrile With sulfuric acid In N,N-dimethyl-formamide at 0 - 5℃;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 0 - 5℃;
Stage #3: julolidine
6
The 2-aminothiophene derivative 6a (5.42 g, 0.0301 mmol) was dissolved in minimum amounts of dimethylformamide (10 ml), and sulfuric acid (8 ml, 54% V/V) was added. The mixture was cooled to 0-5° C. with stirring for half an hour. Sodium nitrite (2.08 g, 0.0301 mmol ) was dissolved in water ( 10 ml ) and cooled to 0-5° C. to form dilute nitrous acid. This solution was slowly added to the 2-aminothiophene derivative solution, with the temperature being kept in the range of 0-5° C. Stirring was continued for one hour, after which the diazonium salt 6b was formed.Julolidine (5.22 g, 0.0301 mmol) was dissolved in a solution prepared from water (10 ml) and hydrochloric acid (5 ml, 10 M), and the solution was cooled to the temperature between 0-5° C. The diazonium solution 6b was added to the julolidine coupling component solution slowly over a period of one hour to keep the temperature below 5° C. The reaction mixture was stirred for 2 hours, during which the temperature was raised to room temperature. The pH of the solution was raised by adding sodium hydroxide solution (5-10%) to obtain a pH in the range between 5.5 and 7. The precipitated dye 6 was filtered and washed with plenty of water to get rid of the excess sodium hydroxide, then recrystallized from an ethyl acetate/petroleum ether (40-60) mixture (8:2), m.p. 175-177° C. (72% yield).
Stage #1: 5-acetyl-2-amino-4-methyl-thiophene-3-carboxylic acid methyl ester With sulfuric acid In N,N-dimethyl-formamide at 0 - 5℃;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 0 - 5℃;
Stage #3: julolidine
7
The 2-aminothiophene derivative 7a (5.40 g, 0.0253 mmol) was dissolved in minimum amounts of dimethylformamide (10 ml), and sulfuric acid (8 ml, 54% V/V) was added. The mixture was cooled to 0-5° C. with stirring for half an hour. Sodium nitrite (1.75 g, 0.0253 mmol ) was dissolved in water (10 ml) and cooled to 0-5° C. to form dilute nitrous acid. This solution was slowly added to the 2-aminothiophene derivative solution with the temperature being kept in the range of 0-5° C. Stirring was continued for one hour, after which the diazonium salt 7b was formed.Julolidine (4.38 g, 0.0253 mol) was dissolved in a solution prepared from water (10ml) and hydrochloric acid (5 ml, 10M), and the solution was cooled to a temperature between 0-5° C. The diazonium solution 7b was added to the Julolidine coupling component solution slowly over a period of one hour to keep the temperature below 5° C. The reaction mixture was stirred for 2 hours, during which the temperature was raised to room temperature. The pH of the solution was raised by adding sodium hydroxide solution (5-10%) to obtain a pH in the range between 5.5 and 7. The precipitated dye 7 was filtered and washed with plenty of water to get rid of the excess sodium hydroxide, then recrystallized from an ethyl acetate/petroleum ether (40-60) mixture (8:2), m.p. 111-113° C., (49% yield).
Stage #1: 5-Acetyl-2-amino-4-methyl-thiophen-3-carbonsaeureethylester With sulfuric acid In N,N-dimethyl-formamide at 0 - 5℃;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 0 - 5℃;
Stage #3: julolidine
8
The 2-aminothiophene derivative 8a (5.45 g, 0.024 mol) was dissolved in a minimum amount of dimethylformamide (10 ml), and sulfuric acid (8ml, 54% V/V) was added. The mixture was cooled to 0-5° C. with stirring for half an hour. Sodium nitrite (1.66 g, 0.024 mol) was dissolved in water (10 ml) and cooled to 0-5° C. to form dilute nitrous acid. This solution was slowly added to the 2-aminothiophene derivative solution, with the temperature being kept in the range of 0-5° C. Stirring was continued for one hour, after which the diazonium salt 8b was formed.Julolidine (4.16 g, 0.024 mol) was dissolved in a solution prepared from water (10 ml) and hydrochloric acid (5 ml, 10M), and the solution was cooled to a temperature between 0-5° C. The diazonium solution 8b was added to the julolidine coupling component solution slowly over a period of one hour to keep the temperature below 5° C. The reaction mixture was stirred for 2 hours, during which the temperature was raised to room temperature. The pH of the solution was raised by adding sodium hydroxide solution (5-10%) to obtain a pH in the range between 5.5 and 7. The precipitated dye 8 was filtered and washed with plenty of water to get rid of the excess sodium hydroxide, then recrystallized from ethyl acetate/petroleum ether (40-60) mixture (8:2), m.p. 125-127° C., (21% yield).
Stage #1: 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid methyl ester With sulfuric acid In N,N-dimethyl-formamide at 0 - 5℃;
Stage #2: With sodium nitrite In water; N,N-dimethyl-formamide at 0 - 5℃;
Stage #3: julolidine
13
The 2-aminothiophene derivative 13a (2.93 g, 0.013 mol) was dissolved in a minimum amount of dimethylformamide (10 ml), and sulfuric acid (8 ml, 54% V/V) was added. The mixture was cooled to 0-5° C. with stirring for half an hour. Sodium nitrite (0.90 g, 0.013 mol) was dissolved in water (10 ml) and cooled to 0-5° C. to form dilute nitrous acid. This solution was slowly added to the 2-aminothiophene derivative solution, with the temperature being kept in the range of 0-5° C. Stirring was continued for one hour, after which the diazonium salt 13b was formed.Julolidine (2.25 g, 0.013 mol) was dissolved in a solution prepared from water (10 ml) and hydrochloric acid (5 ml, 10M), and the solution was cooled to the temperature between 0-5° C. The diazonium solution 13b was added to the julolidine coupling component solution slowly over a period of one hour to keep the temperature below 5° C. The reaction mixture was stirred for 2 hours, during which the temperature was raised to room temperature. The pH of the solution was raised by adding sodium hydroxide solution (5-10%) to obtain a pH in the range between 5.5 and 7. The precipitated dye 13 was filtered and washed with plenty of water to get rid of the excess sodium hydroxide, then recrystallized from an ethyl acetate/petroleum ether (40-60) mixture (8:2), m.p. 149-153° C., (25% yield).
Stage #1: 4-aminopyridine With nitrosylsulfuric acid; sulfuric acid In acetic acid; propionic acid at 5℃;
Stage #2: julolidine In methanol; acetic acid; propionic acid at 5 - 10℃; for 16h;
Stage #3: With sodium carbonate In methanol; water; acetic acid; propionic acid
1
100 mL of anhydrous acetic acid and 500 mL of anhydrous propionic acid were added to 200 g of solution at 40% w/v of nitrosylsulphuric acid in sulphuric acid, the mixture was then cooled to below 5° C., and 50 g of 4-aminopyridine was added gradually. The mixture thus obtained was diluted by adding 200 mL of propionic acid and 40 mL of acetic acid, then a solution of 50 g of julolidine in 200 mL of methanol was added dropwise, keeping the temperature below 10° C. The reaction mixture was neutralized after 16 h of reaction at a temperature below 5° C. by introduction of 500 mL of water, 300 g of ice then 500 mL of 30% soda. The product (A) was extracted with ethyl acetate, and purified by chromatography on silica gel. 5 mL of dimethylsulphate was added to 5 g of pure product (A), diluted in 50 mL of dichloromethane, then the reaction mixture was stirred for 2 h. The mixture was concentrated by distillation of the solvents under vacuum, then the residue obtained was purified by dissolution in methyl ethyl ketone followed by precipitation with heptane. 7.12 g of a blue powder was obtained. Analyses indicated that it corresponded to the expected compound [i].
Stage #1: pyridin-3-ylamine With hydrogenchloride; sodium nitrite In water at 0℃; for 0.333333h;
Stage #2: With urea In water
Stage #3: julolidine With hydrogenchloride; ammonia more than 3 stages;
3
6.3 g of 3-aminopyridine, 17 mL of 35% hydrochloric acid and 65 g of ice were mixed in a 500-mL three-necked flask. A solution of 5.08 g of sodium nitrite in 20 mL of water was added dropwise, keeping the temperature of the mixture at 0° C. On completion of addition, the mixture was stirred for 20 min at 0° C. then a solution of 400 mg of urea in 10 mL of water was added. A solution of 11.6 g of julolidine in a mixture of ethanol (25 mL), 35% hydrochloric acid (16 mL) and ice (22 g) was added dropwise, keeping the temperature below 10° C. After 3 h at 5° C., the reaction mixture was neutralized by adding ammonia, until the pH was 9.5. The paste thus obtained was extracted with ethyl acetate with addition of water. The organic phase was dried and concentrated under vacuum; the product thus obtained was purified by chromatography (silica gel, eluent heptane/ethyl acetate) and a pure fraction of a powder of a deep red color was collected (4.3 g), corresponding to the expected compound (product (C)). The product obtained in the above stage (127 mg) was dissolved in toluene (5 mL), 86 μL of dimethylsulphate was added and the reaction mixture was stirred for 72 h. The toluene was removed under vacuum, the product obtained was treated with water for 4 h at room temperature then dried under vacuum, obtaining a deep violet solid (170 mg). Analyses indicated that it corresponded to the expected compound [iii].
Stage #1: 2-Amino-1-methylbenzimidazole With nitrosylsulfuric acid; phosphoric acid; sulfuric acid; acetic acid at 2 - 5℃; for 0.75h;
Stage #2: With aminosulfonic acid for 0.25h;
Stage #3: julolidine With sodium hydrogencarbonate; sodium carbonate; acetic acid more than 3 stages;
4
10 g of 2-amino-1-methyl benzimidazole was dissolved in a hot mixture of 60 ml of orthophosphoric acid and 20 ml of acetic acid. 26 g of nitrosylsulphuric acid (at 40% in sulphuric acid) was diluted in 25 mL of 98% phosphoric acid at 10° C. in a 250-mL three-necked flask equipped with a thermometer and an argon supply. The first solution was poured dropwise into the second, maintaining the temperature between 2 and 5° C., in 30 min. The mixture was stirred for 15 min. 3.3 g of sulphamic acid was added and the mixture was stirred for 15 min. 13 g of julolidine, previously melted, was dissolved in 25 mL of DMF and 9 g of acetic acid. The diazonium salt obtained in the preceding operation was poured dropwise into this solution, keeping the temperature below 10° C. The reaction mixture was diluted with 50 mL of water then kept at 0° C. for 18 h. 500 g of ice was added, then 100 mL of 30% soda; once more 500 g of ice and 150 mL of 30% soda. The mixture thus obtained was further diluted with 2 L of water then adjusted to pH 7 by adding sodium hydrogencarbonate (190 g). The precipitate obtained was filtered (9.6 g) and dried. 1 g was purified by chromatography (silica, eluent dichloromethane/methanol). 100 mg of a red powder was obtained. Analyses indicated that it corresponded to the expected compound (D). 100 mg of D was dissolved in 20 mL of dichloromethane, and 500 μl of dimethyl sulphate was added dropwise to this mixture at room temperature. The solution was stirred for 5 min, then poured into 250 mL of ethyl ether. The precipitate was filtered and washed with 4×50 mL of ethyl ether. After drying, 50 mg of a black paste was recovered. Analyses indicated that it corresponded to the expected compound [iv].
30 mL of 35% hydrochloric acid was added to 13.21 g of suspension of aminoimidazole in 100 mL of water, the mixture was cooled to -5 C. then a solution of 7 g of sodium nitrite in 10 mL of water was added dropwise, keeping the temperature below 0 C. Then 5 g of sulphanilic acid was added, the mixture was poured into an acid solution of julolidine obtained beforehand by mixing 8.75 g of julolidine, 175 mL of water and 225 mL of acetic acid and 40 g of sodium acetate, maintained at 0 C. After 2 h at 5 C., the reaction mixture was diluted, and adjusted to pH 8 with soda. The precipitated product (B) was filtered and washed with water. 5 g of (B) was dissolved in 50 mL of dichloromethane, and 5 mL of dimethylsulphate and 1.53 g of sodium acetate were added successively. After stirring for 2 h, the mixture was concentrated under vacuum, taken up in 100 mL of methyl ethyl ketone and then 100 mL of heptane was added. The precipitate obtained was washed with heptane, and 4.5 g of violet-black powder was obtained. After treatment with ion-exchange resin, the expected product [ii] was obtained in the form of hydrochloride (2.56 g). Analyses indicated that it corresponded to the expected compound [ii].
Stage #1: 2-aminopyridine N-oxide With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5h;
Stage #2: julolidine With hydrogenchloride In water at 10 - 20℃; for 2h;
Stage #3: With sodium acetate In water
5
11.8 g of julolidine was dissolved at 40° C. in 100 mL of water to which 5.7 mL of 35% hydrochloric acid had been added. 10 g of pyridine-2-amine 1-oxide (prepared according to the methods described in Synth. Commun. 1977, 509-514) was dissolved in 100 mL of water to which 17.4 mL of 35% hydrochloric acid had been added. A solution of 4.7 g of sodium nitrite dissolved in 10 mL of water was added, maintaining the temperature of the mixture at 0° C. The mixture was stirred for 30 min at 0° C. It was then poured into the acidic solution of julolidine, keeping the temperature below 10° C. The mixture was returned to room temperature in two hours. Addition of 70 g of sodium acetate brought the pH of the mixture to 4.2. After extraction with dichloromethane, rinsing with water, drying over sodium sulphate, filtration, concentration under vacuum, trituration in ether, filtration of the powder obtained and drying under vacuum, 10 g of dark violet powder was collected. Analyses showed that it corresponded to the expected product (E), with minor impurities. 5 g of (E) was dissolved in 20 mL of N-methylpyrrolidinone (NMP) and the solution was heated to 60° C. 4.05 g of dimethylsulphate was added to the mixture. After 2 h 30 min the solution was cooled to room temperature. 50 mL of 20% ammonia solution was added. After 15 h at room temperature, the mixture was extracted with dichloromethane (2×100 mL), washed with water, dried and concentrated under vacuum. The dark blue oil obtained was washed twice with isopropyl ether, then triturated in a third fraction. After filtration, rinsing with ether and drying under vacuum, 2 g of brown powder was collected. Analyses showed that it corresponded to the expected product [v].
With water-d2; Orthoboric acid at 70℃; for 6h; Ionic liquid;
General Procedures for the Preparation of 2-methoxynaphthalene-1-d
General procedure: To a stirring solution of 2-methoxynaphthalene (47.4 mg, 0.3 mmol) in [bmim]PF6 (0.2 mL) was added D2O (120 mg, 6 mmol) and boric acid (18.6 mg, 0.3 mmol) at room temperature. The solution was warmed to 70°C and stirred for 12h under air. The reaction was then purified by a flash column chromatography on silica gel using petroleum ether as eluent to obtain the product as white solid (44.8 mg, 94%yield)
85%
With tris(pentafluorophenyl)borate; water-d2 In chloroform-d1 at 80℃; for 24h; Sealed tube; regioselective reaction;
With IrCl3·3H3O; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,3,5-trimethyl-benzene; at 165℃; for 18h;
Eq. 2 : To a vial was added 8 (1.0 mmol, 151.3 mg), 3a (1.0 mmol, 107.3 mg), IrCl3·3H3O(5.0 mol%, 17.6 mg), rac-BINAP (7.5 mol%, 46.7 mg) under air. To the vial was addedmesitylene (1.0 mL) and stirred at 165 C for 18 h. After the reaction, the resulting residue waspurified by flash column chromatography on SiO2 (tBuOMe:Hexane=1:15) to yield 5a and 3a asa mixture and 4a (19.7 mg) in 21% yield. Then PTLC (Wako Silicagel 70 PF254 Plate-Wako,tBuOMe:Hexane=1:15) was used for purification to give 5a (20.3 mg) in 12% yield (based onstarting material) and 3a (76.8 mg) in 52% yield, respectively.
With IrCl3·3H3O; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,3,5-trimethyl-benzene at 165℃; for 18h;
General procedure for the direct N-alkylation of aniline with 1,3-propanediols:
General procedure: To a vial was added aniline (1.0 mmol), IrCl3·3H3O (5.0 mol% based on 1,3-propanediol),rac-BINAP (7.5 mol%) under air. To the vial was added mesitylene (0.5 mL) then1,3-propanediol (1.3 mmol) was added and stirred at 165 °C for 18 h. After the reaction, the resulting mixture was diluted with hexane. Then, the mixture was filtrated by filter paper, and was concentrated in vacuo. The resulting residue was purified by flash column chromatography on SiO2 (tBuOMe:Hexane=1:15) to yield 2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine.
With IrCl3·3H3O; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,3,5-trimethyl-benzene at 165℃; for 18h;
Eq. 1 : To a vial was added 3-(phenylamino)propan-1-ol (8: 1.0 mmol, 151.3 mg), p-toluidine(4b: 1.0 mmol), IrCl3·3H3O (5.0 mol%, 17.6 mg), rac-BINAP (7.5 mol%, 46.7 mg) under air.To the vial was added mesitylene (1.0 mL) and stirred at 165 °C for 18 h. After the reaction, theresulting residue was purified by flash column chromatography on SiO2(tBuOMe:Hexane=1:15) to yield 5a and 5b as a mixture. Then PTLC (Wako Silicagel 70 PF254Plate-Wako, tBuOMe:Hexane=1:15) was used for purification to give 5a (15.1 mg) in 9% yieldand 5b (48.7 mg) in 26% yield, respectively (based on starting material).
With IrCl3·3H3O; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,3,5-trimethyl-benzene at 165℃; for 18h;
To a vial was added 3-(phenylamino)propan-1-ol (8: 1.0 mmol, 151.3 mg), IrCl3·3H3O (5.0mol%, 17.6 mg), rac-BINAP (7.5 mol%, 46.7 mg) under air. To the vial was added mesitylene (1.0 mL) and stirred at 165 °C for 18 h. After the reaction, the resulting residue was purified by flash column chromatography on SiO2 (tBuOMe:Hexane=1:15) to yield 5a(45.3 mg) in 26% yield (based on starting material) and 4a (18.0 mg) in 19% yield.
Stage #1: 3,4-Dichlorocyclobut-3-ene-1,2-dione; julolidine In toluene at 110℃; for 3h;
Stage #2: With hydrogenchloride; acetic acid In water; toluene at 110℃; for 2h;
1 Example 1
260 mL of toluene was added to Compound 1 (2.29 mL, 2.30 g, 13.3 mmol) and Compound 2 (2 g)And refluxed at 110 ° C. for 3 hours. After cooling to 50 ° C or lower,And concentrated under reduced pressure. To the obtained crude product, 40 mL of acetic acid,40 mL of water and 2 mL of 12 N concentrated hydrochloric acid were added, and at 110 ° C.,And heated for 2 hours with vigorous stirring.After cooling to room temperature, it was allowed to stand overnight,After washing the obtained precipitate with chloroform,And dried under reduced pressure to obtain 1.7 g of compound 3
1.7 g
Stage #1: 3,4-Dichlorocyclobut-3-ene-1,2-dione; julolidine In toluene at 110℃; for 3h;
Stage #2: With hydrogenchloride; water; acetic acid at 110℃; for 2h;
1 Synthesis Example 1
260 mL of toluene was added to Compound 1 (2.29 mL, 2.30 g, 13.3 mmol) and Compound 2 (2 g)And refluxed at 110 ° C. for 3 hours. After cooling to 50 ° C or lower,And concentrated under reduced pressure. To the obtained crude product, 40 mL of acetic acid,40 mL of water and 2 mL of 12 N concentrated hydrochloric acid were added, and at 110 ° C.,And heated for 2 hours with vigorous stirring.After cooling to room temperature, it was allowed to stand overnight,After washing the obtained precipitate with chloroform,Dried under reduced pressure,1.7 g of compound 3 was obtained.
1.7 g
Stage #1: 3,4-Dichlorocyclobut-3-ene-1,2-dione; julolidine In toluene at 110℃; for 3h;
Stage #2: With hydrogenchloride; water; acetic acid at 110℃; for 2h;
1 (Synthesis Example 1) Synthesis of squarylium compound 1
260 mL of toluene was added to Compound 1 (2.29 mL, 2.30 g, 13.3 mmol) and Compound 2 (2 g),Refluxed at 110 ° C. for 3 hours.After cooling to below 50 ° C,Concentrated under reduced pressure.In the obtained crude product,Acetic acid 40 mL,40 mL water,Add 2mL of 12N concentrated hydrochloric acid and stir vigorously at 110 ° C.Heated for 2 hours.After cooling to room temperatureLeave it overnight,After washing the resulting precipitate with chloroform,Vacuum drying,1.7 g of compound 3 was obtained.
Stage #1: ethyl 2-aminobenzothiazole-6-carboxylate With nitrosylsulfuric acid In acetic acid; propionic acid at 0 - 20℃; for 0.25h;
Stage #2: julolidine With aminosulfonic acid In methanol; water; acetic acid; propionic acid at 0 - 4℃; for 1.08333h;
1 Ethyl 2-[(E)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-9-yldiazenyl]-1,3-benzothiazole-6-carboxylate (42)
A solution of ethyl 2-amino-l,3-benzothiazole-6-carboxylate (2.22 g, 10 mmol) in a 1:1 mixture of acetic and propionic acids (50 mL) was cooled to 0-4°C and then treated with 3.1 mL of 40% nitrosylsulfuric acid over the course of 5 min. The resulting suspension was stirred at 0-4°C for 5 min and then at room tem perature for another 5 min to give a clear solution and then cooled back to 0-4°C before being used in the next step. A solution of julolidine (2.1 g, 12 mmol) in MeOH (15 mL) was combined with a solution of sulfamic acid (0.3 g) in water (100 mL) and then cooled to 0-4°C. To this mixture was added the previously prepared diazonium salt over the course of 5 min. The reaction was stirred for 1 h and then diluted with water (400 mL) and neutralized with 90 mL of thiethylamine. The precipitated solid was extracted with ethyl acetate, washed with saturated NaHC03, dried over Na2SC>4 and concentrated under reduced pressure. The obtained residue was triturated with warm 1:1 hexane-ethyl acetate (30 mL) and the resultant solid collected by filtration. Drying under reduced pressure afforded 0.8 g (48%) of sufficiently pure dye 42 as a dark purple solid. *H N MR (CDCI3) δ 8.51 (d, J=1.5 Hz, 1H), 8.11 (skewed dd, Ji=8.7 Hz, J2=1.5 Hz, 1H), 8.01 (skewed d, J=8.7 Hz, 1H), 7.61 (s, 2H), 4.42 (q, J=7.2 Hz, 2H), 3.39 (t, J=6 Hz, 4H), 2.80 (t, J=6 Hz, 4H), 2.00 (m, 4H), 1.43 (t, J=7.2 Hz, 3H).
With dipotassium peroxodisulfate; potassium iodide at 60℃; for 12h;
7
Adding the compound of formula (4c), the compound of formula (2a), potassium persulfate, potassium iodide,The molar ratio is 1: 1.5: 2: 0.2, where the compound of formula (4c) is 2 mmol.The reaction was stirred at 60 ° C for 12 hours.After the reaction is completed, cool, add an appropriate amount of dichloromethane, extract with water, dry the organic phase and suction filter.The filtrate was spin-evaporated to remove the solvent, and the residue was subjected to silica gel column chromatography and eluted with petroleum ether.TLC detection, the effluent containing the product was combined, the solvent was distilled off on a rotary evaporator,Vacuum drying to give the target product as a brown solid,Yield was 34% and purity was 99.5% (HPLC).
34%
With dipotassium peroxodisulfate; potassium iodide In water; N,N-dimethyl-formamide at 60℃; for 12h; Green chemistry;
Stage #1: julolidine; ethyl 4-(4-formylphenoxy)butyrate With toluene-4-sulfonic acid In toluene at 120℃; for 10h;
Stage #2: With chloranil In toluene at 15 - 20℃; for 1h;
1 The preparation of malachite green dye (R1=R2=R4=R5=H, R3=OCH2CH2CH2COOCH2CH3, X=Cl-), the basic synthesis process is as follows:
Dissolve 347 mg of julonidine, 236 mg of para-modified benzaldehyde, and 190 mg of p-toluenesulfonic acid monohydrate in 5 mL of toluene, reflux at 120°C for 10 hours and then cool to room temperature.Add 246 mg of tetrachlorobenzoquinone and react at 15°C for 1 hour, spin-dry the solvent to purify by silica gel column chromatography to obtain 190 mg of the target compound.The hydrogen NMR spectrum of the synthetic dye is shown in Figure 1; the NMR carbon spectrum is shown in Figure 2. The specific data are as follows
Stage #1: julolidine; 2-formylterephthalic acid With copper(I) bromide In toluene at 150℃; for 24h;
Stage #2: In toluene at 20 - 30℃; for 5h;
3 The preparation of malachite green dye (R1=COO-, R2=R3=R5=H, R4=COOH), the basic synthesis process is as follows
Dissolve 347 mg of julonidine, 95 mg of 2-aldehyde-4-carboxybenzoic acid, and 11 mg of copper bromide in 15 mL of toluene, reflux at 150°C for 24 hours and then reduce to room temperature.Add 454mg of dichlorodicyanobenzoquinone to react at 30°C for 5 hours, spin off the solvent and purify by silica gel column chromatography to obtain 48mg of target molecule. The proton nuclear magnetic spectrum of the synthetic dye is shown in Figure 3. The specific data are as follows
With trichlorophosphate In chloroform at -10 - 60℃;
Method B [25]
General procedure: Anhydrous chloroform (20 mL), an appropriate aromatic amine (65 mmol) and 3-dimethylaminoacrolein (55 mmol) were placed in a flask equipped with a thermometerand a dropping funnel. The mixture was cooled to -10 °C, and a solution of 55 mmol ofPOCl3 in 8 mL of chloroform was added, keeping the temperature below 0 °C. Then, themixture was allowed to warm up to room temperature and stirred overnight. It was nextheated to 60 °C and kept at this temperature for 2 h. Chloroform was distilled off underreduced pressure, and 25 mL of methanol was added with stirring and cooling. The reactionmixture was poured onto 50 g of crushed ice and neutralized with 20% NaOH. Thecrude product was filtered and recrystallized from ethanol. As before, the aldehydes 1h, 1i and 1j were purified by flash chromatography on silica gel (pore size 60 Å, 230-400mesh particle size) using chloroform as the mobile phase.
With air In water; dimethyl sulfoxide at 100℃; for 12h; Green chemistry; regioselective reaction;
84%
In water; dimethyl sulfoxide at 100℃; for 12h;
8 Example 8:
Add 1-methyl-2(1H)-quinoxalinone (0.48g, 3mmol) and julonidine (1.038g, 6mmol) into the reaction flask, and add the solvent (water: dimethyl sulfoxide = 1: 2) Dissolve (15g), stir and react at 100°C for 12 hours.After the reaction, the reaction solution was cooled to room temperature and diluted with cold water. Ethyl acetate (30g) was added, stirred and separated into layers. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a dark yellow crude product. Purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:3) to obtain 0.834 g of yellow liquid, with a yield of 84%
Stage #1: 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline With bromine In dichloromethane at 0 - 20℃; for 72h; Schlenk technique; Sealed tube;
Stage #2: With sodium hydroxide In dichloromethane; water monomer; ethyl acetate at 20℃; for 1h; Schlenk technique; Sealed tube;
Stage #3: With hydrogenchloride
With glacial acetic acid In lithium hydroxide monohydrate for 12h;
4.1 Synthesis of the first intermediate D1
Julolidine (1.0 mmol), aqueous formaldehyde solution (0.6 mmol) in acetic acid (25 mL) were mixed and stirred for 12 hours, 100 mL of water was then added. The aqueous solution was extracted with dichloromethane (30 mL x 3). The organic extract was washed with brine and used Na2SO4 dried. After the solvent was distilled off under reduced pressure, it was purified by 200-300 mesh silica gel column chromatography. with petroleum ether/ethyl acetate (20:1) Elution gave the first intermediate as a pale yellow solid in 45% yield.
With potassium carbonate In 2,2,2-trifluoroethanol at 90℃;
30
Take 15mL pressure-resistant tube, add 2,3,6,7-tetrahydro-1H,5H-pyridine[3,2,1-ij]quinoline 34.6mg (0.20mmol), 2,2-difluorovinyl 4-(trifluoromethyl)benzenesulfonic acid 115.2mg (0.40mmol), anhydrous potassium carbonate 13.8mg (0.1mmol), trifluoroethanol 1mL, at 90 °C,N2 Reaction under protective conditions for 16 hours. After the end of the reaction, 10mL of water was added to quench the reaction, and then 10mL of ethyl acetate and 5mL of saturated saline were added to wash, the organic phase was collected in layers, and the aqueous phase was extracted with ethyl acetate twice , each time the amount of ethyl acetate was 5mL, the organic phase was combined, anhydrous sodium sulfate was added to dry, vacuum distillation was added to remove the solvent, and then the product was obtained by column chromatography with a yield of 66%.
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