* 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 selenium(IV) oxide In toluene for 24 h; Inert atmosphere; Reflux
General procedure: A solution of 5.0 g (35 mmol) of 4-methylquinoline (19) and 5.0 g (45 mmol) of SeO2 in toluene under argon was heated to reflux for 24 h. The reaction mixture was diluted with dichloromethane, washed with brine, dried (MgSO4), concentrated, and column chromatographed on silica gel using a mixture of hexanes and ethyl acetate (4:1) as eluant to give 4.0 g (73percent yield) of compound 14A,12 as a solid. 1H NMR δ 10.54 (s, 1 H), 9.22 (d, J = 4.3 Hz, 1 H), 9.04 (d, J = 8.6 Hz, 1 H), 8.24 (d, J = 8.2 Hz, 1 H), 7.84 (t, J = 7.6 Hz, 1 H), 7.81 (d, J = 4.3 Hz, 1 H), 7.76 (t, J = 8.0 Hz, 1 H); 13C NMR δ 193.1, 150.7, 149.5, 137.0, 130.4, 130.3, 129.6, 126.0, 124.7, 124.1. MS (electrospray ionization) m/z 158.0 (100percent) (M+H+), 130.2.
Reference：
[1] Gazzetta Chimica Italiana, 1987, vol. 117, # 2, p. 135 - 136
[2] Chinese Journal of Chemistry, 2016, vol. 34, # 5, p. 519 - 523
[3] Heterocycles, 2003, vol. 60, # 4, p. 953 - 957
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 9, p. 2179 - 2186
[5] Journal of Heterocyclic Chemistry, 1988, vol. 25, p. 819 - 821
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 10, p. 3480 - 3484
[7] Chemical Communications, 2015, vol. 51, # 61, p. 12258 - 12261
[8] Chemistry of Natural Compounds, 2006, vol. 42, # 4, p. 459 - 461
[9] Chemistry Letters, 1991, p. 1271 - 1274
[10] Advanced Synthesis and Catalysis, 2016, vol. 358, # 2, p. 178 - 182
[11] Chemische Berichte, 1953, vol. 86, p. 572
[12] Chemische Berichte, 1954, vol. 87, p. 1179,1183
[13] Chemische Berichte, 1954, vol. 87, p. 1179,1183
[14] Journal of the American Chemical Society, 1937, vol. 59, p. 524
[15] Journal of the American Chemical Society, 1947, vol. 69, p. 1219
[16] Journal of the American Chemical Society, 1941, vol. 63, p. 2654
[17] Liebigs Annalen der Chemie, 1988, p. 455 - 464
[18] Pakistan Journal of Scientific and Industrial Research, 1993, vol. 36, # 9, p. 357 - 359
[19] Gazzetta Chimica Italiana, 1987, vol. 117, # 2, p. 135 - 136
[20] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 14, p. 3771 - 3774
[21] Tetrahedron, 2009, vol. 65, # 12, p. 2512 - 2517
[22] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 3, p. 1201 - 1212
2
[ 5450-80-6 ]
[ 4363-93-3 ]
Reference：
[1] Acta Chimica Academiae Scientiarum Hungaricae, 1981, vol. 107, p. 315 - 320
3
[ 611-35-8 ]
[ 20461-86-3 ]
[ 4363-93-3 ]
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 6, p. 1500 - 1505[2] Angew. Chem., 2017, vol. 129, # 6, p. 1522 - 1527,6
Reference：
[1] Journal of Organic Chemistry, 1986, vol. 51, # 4, p. 536 - 537
[2] Journal of Organic Chemistry, 1986, vol. 51, # 4, p. 536 - 537
12
[ 123-91-1 ]
[ 491-35-0 ]
[ 7446-08-4 ]
[ 7732-18-5 ]
[ 4363-93-3 ]
[ 5428-66-0 ]
Reference：
[1] Journal of the American Chemical Society, 1941, vol. 63, p. 2654
13
[ 491-35-0 ]
[ 7446-08-4 ]
[ 108-88-3 ]
[ 4363-93-3 ]
[ 5428-66-0 ]
Reference：
[1] Chemische Berichte, 1954, vol. 87, p. 1179,1183
14
[ 4363-93-3 ]
[ 2973-27-5 ]
Yield
Reaction Conditions
Operation in experiment
94%
With ammonium acetate; phenyltrimethylammonium tribromide In acetonitrile at 20℃; for 17 h;
General procedure: to a solution of 2-pyridinecarbaldehyde 1 (54 mg, 0.5 mmol) and ammonium acetate (385mg, 5.0 mmol) in MeCN )6ml), was added trimethylphenylammonium tribromide (376 mg, 1.0 mmol) at room temperature. after stirring for 21 h at rt, the reaction mixture was treated with 0.5 M aq Na2S2O3(10 ml), 1.0 M NaHCO3 )15 ml) and extracted with EtOAc (60 mL). The organic layer was washed with 0.5 M Na2S2O3 and successively washed with saturated aq.NaCl, and dried over MgSO4.
50.5%
Stage #1: With sodium bromate; ammonia In water at 90℃; for 2 h; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate
Example 4: Production of 4-quinolinecarbonitrile Into a 15 ml, test tube-shaped reactor equipped with a magnetic stirrer and a reflux condenser were added 0.71 g (4.5 mmol) of 4-quinolinecarboaldehyde, 0.27 g (1.8 mmol) of sodium bromate, 0.6 g (10 mmol) of acetic acid, 0.35 g (5 mmol) of 25percent aqueous ammonia and 1 ml of water, followed by stirring at 90°C for 2 hours. The reaction mixture contained, as a component, 97.4percent (in terms of areal ratio of gas chromatography) of 4-quinolinecarbonitrile. To the reaction mixture were added 30 ml of a saturated aqueous sodium bicarbonate solution and 30 ml of ethyl acetate. The mixture was subjected to phase separation. Then, there were conducted washing with a saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, and distillation under reduced pressure for ethyl acetate removal. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane = 1:1 v/v) to obtain 0.35 g (yield: 50.5percent) of white crystals. Gas mass chromatography was conducted to confirm a molecular ion peak [M+] of 154.
Reference Example 3 4-(Hydroxymethyl)quinoline (Reference Compound No.3-1); A solution of 4-quinolinecarboxylaldehyde (20g, 130mmol) in anhydrous tetrahydrofuran (200mL) was added dropwise for 30 minutes to a suspension of sodium borohydride (5.3g, 140 mmol) in anhydrous tetrahydrofuran (300mL) under ice-cooling, and the mixture was stirred for 1 hour at room temperature. Water (300mL) was added to the mixture, and the whole was then extracted with ethyl acetate (400mL x once, 100mL x three times). The organic layer was washed with brine (200mLx3 times) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was filtered off with diethyl ether and washed to give 14g of the title Reference Compound as an orange-white solid (Yield: 69%) [Show Image] 1H-NMR (500MHz, DMSO-d6) delta 5.04 (dd, J = 5.5, 0.9 Hz, 2H), 5.57 (t, J=5.5 Hz, 1H), 7.57-7.63 (m, 2H), 7.76 (m, 1H), 8.02-8.06 (m, 2H), 8.70 (d, J = 4.3 Hz, 1H)
65%
With sodium tetrahydroborate; ethanol; at 0 - 20℃;
To a solution of 4-quinolinecarboxaldehyde (0.47 g, 3.00 mmol) in a mixture of EtOH:THF=1:1 (40 mL) at 0 C. in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (0.11 g, 3.01 mmol) and the mixture was stirred overnight at RT. The solution was then cooled down to 0 C. before quenching a 6 N aq. HCl solution (2 mL). The reaction mixture was stirred at RT for 15 min then basified with a 2 N aq. NaOH solution (6 mL). EtOH was removed at 40 C. under vacuum and the residue was extracted with CH2Cl2 (2*50 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40 C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) gave, after evaporation and drying, quinolin-4-ylmethanol MDE 32014 as an off-white solid (311 mg, 65% yield). MW: 159.19; Yield: 65%; Off-white solid; Mp ( C.): 109.3 Rf: 0.25 (EtOAc=100%). 1H-NMR (CDCl3, delta): 3.86 (broad s, 1H, OH), 5.23 (s, 2H, OCH2), 7.51-7.56 (m, 2H, 2*ArH), 7.69 (dd, 1H, J=7.6 Hz, ArH), 7.94 (d, 1H, J=8.4 Hz, ArH), 8.09 (d, 1H, J=8.4 Hz, ArH), 8.67-8.77 (m, 1H, ArH). 13C-NMR (CDCl3, delta): 61.3, 118.1, 122.9, 125.8, 126.7, 129.3, 129.7, 146.8, 147.6, 150.2. MS-ESI m/z (% rel. Int.): 160 ([MH]+, 100).
64%
With sodium tetrahydroborate; In water;
Step a) Preparation of 4-Quinolinemethanol A solution of 4-quinolinecarboxaldehyde (55.0 g, 35 mmol) in ether (1 L) was added dropwise over 0.25 hours to a mechanically stirred biphasic solution of NaBH4 (13.24 g, 35 mmol), water (500 mL), and ether (100 mL) at 0 C. After 15 minutes, a second equivalent of NaBH4 (13.24 g, 35 mmol) dissolved in water was added, and the reaction allowed to warm to room temperature over 0.25 hour. The aqueous layer was separated, extracted with CH2 Cl2 (2*1 L), and the combined organic layer washed with water (500 mL), dried (MgSO4), filtered, and evaporated to a solid residue. Crystallization from methylene chloride-ether-hexane afforded 21.7 g (13.6 mmol, 39%) of a white solid. The filtrate was concentrated, and following HPLC separation, crystallization afforded 14.1 g (8.9 mmol, 25%) of a second crop, (35.8 g, 64% total yield), m.p. 95 -97 C. 1 H NMR (CDCl3, 400 MHz) delta: 8.79 (d, J=4.4 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.94 (dd, J=8.4, 0.8 Hz, 1H), 7.70 (td, J=8.3, 1.4 Hz, 1H), 7.55 (td, J=8.5, 1.2 Hz, 1H), 7.54 (d, J=4.7 Hz, 1H), 5.23 (s, 2H), 3.80 (bs, 1H) MS (EI), m/z (rel. intensity)=159 (M+, 58), 130 (100) IR (KBr) v: 3280, 2830, 1585 cm-1 Anal. Calcd. for C10 H9 NO: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.70; H, 5.65; N, 8.84.
With sodium tetrahydroborate; In methanol; at 0℃; for 1h;
Part 1: Quinolin-4-ylmethanol [0216] A solution of quinoline-4-carbaldehyde (0.50 g, 3.24 mmol) dissolved in methanol (5 mL) was cooled to 0 C. Sodium borohydride (0.11 g, 2.91 mmol) was then added portion-wise. After 1 h of stirring at 0 C., 2M HCl (aq) was added drop-wise until pH=5. The methanol was then evaporated in vacuo and the aqueous phase was neutralized by addition of saturated aqueous NaHCO3. The aqueous solution was extracted with CH2Cl2 (3x) and the combined organic extracts were washed with saturated NaHCO3 (aq) and brine. The organic solution was dried over Na2SO4, filtered, and concentrated in vacuo to yield quinolin-4-ylmethanol as a yellow solid. [0217] MS (ES+): 160 [MH+]. 1H NMR (CDCl3, 400 MHz): delta 2.41 (bs, 1H), 5.25 (bs, 2H), 7.55 (ddd, J=4.4, 1.2, 1.2 Hz, 1H), 7.58 (ddd, J=8.4, 7.2, 1.2 Hz, 1H), 7.73 (ddd, J=8.4, 6.8, 1.6 Hz, 1H), 7.97 (ddd, J=8.4, 1.2, 0.4 Hz, 1H), 8.14 (ddd, J=8.0, 1.2, 0.4 Hz, 1H), 8.90 (d, J=4.4 Hz, 1H).
With sodium borohydrid; acetic acid; In methanol; ethanol; dichloromethane; water;
To a stirred solution of 10 g of 4-quinolinecarboxaldehyde in 400 ml of absolute ethanol at room temperature is added 2.4 g of sodium borohydride. After 45 minutes, 20 ml of water is added and the reaction mixture is stirred for an additional 20 minutes. Acetic acid (20 ml) is added slowly. The reaction mixture is evaporated to a small volume and partitioned between water and methylene chloride. The organic layer is washed with saturated potassium carbonate, saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel using methanol/methylene chloride (1:10) as eluent to yield 4-hydroxymethylquinoline; Rf =0.59.
With sodium borohydrid; acetic acid; In methanol; ethanol; dichloromethane; water;
To a stirred solution of 10 g of 4-quinolinecarboxaldehyde in 400 ml of absolute ethanol at room temperature is added 2.4 g of sodium borohydride. After 45 minutes, 20 ml of water is added and the reaction mixture is stirred for an additional 20 minutes. Acetic acid (20 ml) is added slowly. The reaction mixture is evaporated to a small volume and partitioned between water and methylene chloride. The organic layer is washed with saturated potassium carbonate, saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel using methanol/methylene chloride (1: 10) as eluent to yield 4-hydroxymethylquinoline; Rf = 0.59.
With sodium borohydrid; acetic acid; In methanol; ethanol; dichloromethane; water;
To a stirred solution of 10 g of 4-quinolinecarboxaldehyde in 400 ml of absolute ethanol at room temperature is added 2.4 g of sodium borohydride. After 45 minutes, 20 ml of water is added and the reaction mixture is stirred for an additional 20 minutes. Acetic acid (20 ml) is added slowly. The reaction mixture is evaporated to a small volume and partitioned between water and methylene chloride. The organic layer is washed with saturated potassium carbonate, saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel using methanol/methylene chloride (1:10) as eluent to yield 4-hydroxymethylquinoline; Rf =0.59.
NaBH4 (1.26g, 33.4mmol) was added to a solution of 59 (5.0g, 31.8mmol) in MeOH (60 ml) portion-wise at 0 0C over 20 min. The reaction mixture was stirred at room temperature for 1 h before being quenched with H2O followed by extraction with ethyl acetate to give 60.
Stage #1: N,N-diethyl-4-iodobenzamide With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h;
Stage #2: quinoline-4-carboxaldehyde In tetrahydrofuran; hexane for 1h; Further stages.;
Stage #1: quinoline-4-carboxaldehyde; diethyl cyanophosphonate With lithium cyanide In tetrahydrofuran at 20℃;
Stage #2: With samarium diiodide; <i>tert</i>-butyl alcohol In tetrahydrofuran at 20℃;
With hydrogenchloride; sodium borohydrid; In methanol;
Part 1 Quinolin-4-ylmethanol A solution of quinoline-4-carbaldehyde (0.50 g, 3.24 mmol) dissolved in methanol (5 mL) was cooled to 0 C. Sodium borohydride (0.11 g, 2.91 mmol) was then added portion-wise. After 1 h of stirring at 0 C., 2M HCl (aq) was added drop-wise until pH-5. The methanol was then evaporated in vacuo and the aqueous phase was neutralized by addition of saturated aqueous NaHCO3. The aqueous solution was extracted with CH2Cl2 (3*) and the combined organic extracts were washed with saturated NaHCO3 (aq) and brine. The organic solution was dried over Na2SO4, filtered, and concentrated in vacuo to yield quinolin-4-ylmethanol as a yellow solid. MS (ES+): 160 [MH+]. 1H NMR (CDCl3, 400 MHz): delta 2.41 (bs, 1H), 5.25 (bs, 2H), 7.55 (ddd, J=4.4, 1.2, 1.2 Hz, 1H), 7.58 (ddd, J=8.4, 7.2, 1.2 Hz, 1H), 7.73 (ddd, J=8.4, 6.8, 1.6 Hz, 1H), 7.97 (ddd, J=8.4, 1.2, 0.4 Hz, 1H), 8.14 (ddd, J=8.0, 1.2, 0.4 Hz, 1H), 8.90 (d, J=4.4 Hz, 1H).
With caesium carbonate; In tetrahydrofuran; isopropyl alcohol; at 20℃;
General procedure: To a stirredsolution of 7or 15(18.97 mmol) in a mixture of THF (40 mL) and i-PrOH (10 mL), diphenyl(6-methylpyridin-2-yl)(phenylamino)methylphosphonate (18.97 mmol) and Cs2CO3 (24.65 mmol) were added. The mixture wasstirred at room temperature for 4-16 h, and to it, 1 N HCl (75 mL) was added dropwise over a period of 5 min. The reactionmixturewas diluted with MTBE (30 mL) and stirred for1h. The aqueous layer was separated, andthe organic layer was extracted with 1 N HCl (2 × 50 mL). Thecombined aqueous layer was neutralized with 50% aqueous KOH solution (pH 7-8) and extracted with EtOAc (3× 100 mL). The EtOAc solution was dried over anhydrous Na2SO4,filtered, and evaporated to dryness under reduced pressure. The residue waspurified by MPLC on silica gel using EtOAc/Petroleum ether as eluent to give the titled compound 8 or 16as a light yellow solid.
A 2L round-bottom flask was charged with [(6-Methyl-pyridyl-2-yl)- [PHENYLAMINO-METHYL]-PHOSPHONIC] acid diphenyl ester (24.5 g, 57 [MMOL),] quinoline-4- carbaldehyde (11.65 g, 74.1 [MMOL),] 90 mL of tetrahydrofuran, and 180 mL of isopropylalcohol. The reaction mixture was warmed to [25C] and potassium t- butoxide (1. [0M,] 74.1 mL, 74.1 [MMOL)] was added dropwise over 90 minutes. After stirring an additional 30 minutes, hydrochloric acid (2M, 122 mL) was added and the mixture stirred one hour. The solution was heated to [45C] and the pH was adjusted to 5 with [6M] sodium hydroxide, stirred an additional hour, then concentrated in vacuo. The residue was dissolved in chloroform and concentrated onto silica gel. Product was purified by flash chromatography using 0-10% ethylacetate/hexane solvent gradient to afford 10.97 grams of pure material. HPLC [TR] = 5.02 min, LC-MS = 263 (M+1).
Stage #1: quinoline-4-carboxaldehyde; 3-smino-N-(4-(trifluoromethoxy)phenyl)thiophene-2-carboxamide With trifluoroacetic acid In dichloromethane for 2h; Heating / reflux;
Stage #2: With triethylsilane In dichloromethane for 16h; Heating / reflux;
1.2
N-(4-trifluoromethoxyphenyl) 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide: A solution of N-(4-trifluoromethoxyphenyl) 3-aminothiophene-2-carboxamide (1 g, 3.31 mmol) and quinoline-4-carboxaldehyde (347 mg, 2.21 mmol) in trifluoroacetic acid:dichloromethane (1:1, 30 mL) was heated at reflux for 2 h under nitrogen. The reaction was cooled to RT and triethylsilane (0.71 mL, 4.42 mmol) was added. The resulting solution was then stirred at reflux for 16 h under nitrogen. After cooling to RT, the reaction mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (3x100 mL) and saturated sodium bicarbonate solution (50 mL). The organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (20-30% ethyl acetate in hexane) to give EXAMPLE 1 as a light yellow solid, mp: 168-170° C. [0175] 1H-NMR (400 MHz/CDCl3):δ=5.01 (d, J=6.2 Hz, 2H), 6.56 (d, J=5.4 Hz, 1H), 7.12 (s, 1H), 7.22 (d, J=8.7 Hz, 2H), 7.25 (s, 1H), 7.44 (d, J=4.3 Hz, 1H), 7.58 (d, J=9.0 Hz, 2H), 7.62 (t, J=8.2 Hz, 1H), 7.76 (t, J=8.3 Hz, 1H), 8.02 (d, J=7.5 Hz, 2H), 8.17 (d, J=8.3 Hz, 1H), 8.86 (d, J=4.5 Hz, 1H). MS (ES+): 444 [MH+]. [0176] 13C-NMR (400 MHz/CDCl3): δ=45.9, 101.4, 117.9, 118.9, 119.5, 121.9, 122.0, 122.6, 126.5, 127.2, 129.1, 129.7, 130.6, 136.8, 144.5, 145.4, 148.3, 150.7, 155.9, 163.8. Anal. Calcd for C22H16F3N3O2S: C, 59.59; H, 3.64; N, 9.48; F, 12.85; S, 7.23. Found: C, 59.59; H, 3.67; N, 9.46; F, 13.01; S, 7.23.
With triethylsilane In hexane; dichloromethane; ethyl acetate; trifluoroacetic acid
1.2 N-(4-trifluoromethoxyphenyl) 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide
A solution of N-(4-trifluoromethoxyphenyl) 3-aminothiophene-2-carboxamide (1 g, 3.31 mmol) and quinoline-4-carboxaldehyde (347 mg, 2.21 mmol) in trifluoroacetic acid:dichloromethane (1: 1, 30 mL) was heated at reflux for 2 h under nitrogen. The reaction was cooled to RT and triethylsilane (0.71 mL, 4.42 mmol) was added. The resulting solution was then stirred at reflux for 16 h under nitrogen. After cooling to RT, the reaction mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (3*100 mL) and saturated sodium bicarbonate solution (50 mL). The organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (20-30% ethyl acetate in hexane) to give EXAMPLE 1 as a light yellow solid, mp: 168-170° C. 1H-NMR (400 MHz/CDCl3): δ=5.01 (d, J=6.2 Hz, 2 H), 6.56 (d, J=5.4 Hz, 1 H), 7.12 (s, 1 H), 7.22 (d, J=8.7 Hz, 2 H), 7.25 (s, 1 H), 7.44 (d, J=4.3 Hz, 1 H), 7.58 (d, J=9.0 Hz, 2 H), 7.62 (t, J=8.2 Hz, 1 H), 7.76 (t, J=8.3 Hz, 1 H), 8.02 (d, J=7.5 Hz, 2 H), 8.17 (d, J=8.3 Hz, 1 H), 8.86 (d, J=4.5 Hz, 1 H). MS (ES+): 444 [MH+]. 13C-NMR (400 MHz/CDCl3): δ=45.9, 101.4, 117.9, 118.9, 119.5, 121.9, 122.0, 122.6, 126.5, 127.2, 129.1, 129.7, 130.6, 136.8, 144.5, 145.4, 148.3, 150.7, 155.9, 163.8. Anal. Calcd for C22H16F3N3O2S: C, 59.59; H, 3.64; N, 9.48; F, 12.85; S, 7.23. Found: C, 59.59; H, 3.67; N, 9.46; F, 13.01; S, 7.23.
With n-butyllithium; In tetrahydrofuran; hexane; at -78℃; for 0.666667h;
Example 1 5-methyl-3-(4-quinolinyl)-lH-indazole-1-acetic acid a) a- (2-fluoro-5-methylphenyl)-4-quinolinemethanol n-BuLi (2. 5M in hexanes, 5.1 ml) was added dropwise to <strong>[452-62-0]3-bromo-4-fluorotoluene</strong> (2g) in THF (100ml) at-78C. The reaction mixture was stirred for 10 min and then 4- quinolinecarboxaldehyde (1.7g) in THF (10ml) was added dropwise and stirred for 40 min. The reaction mixture was quenched (water) allowed to reach RT and then extracted (EtOAc), dried (MgS04) and concentrated in vacuo. The residue was purified by chromatography (silica, eluting EtOAc: hexane ; 6: 4) to give the subtitle compound as a white solid (1. 15g). MS ESI+ 267 [M+1]
With ammonium acetate; phenyltrimethylammonium tribromide; In acetonitrile; at 20℃; for 17h;
General procedure: to a solution of 2-pyridinecarbaldehyde 1 (54 mg, 0.5 mmol) and ammonium acetate (385mg, 5.0 mmol) in MeCN )6ml), was added trimethylphenylammonium tribromide (376 mg, 1.0 mmol) at room temperature. after stirring for 21 h at rt, the reaction mixture was treated with 0.5 M aq Na2S2O3(10 ml), 1.0 M NaHCO3 )15 ml) and extracted with EtOAc (60 mL). The organic layer was washed with 0.5 M Na2S2O3 and successively washed with saturated aq.NaCl, and dried over MgSO4.
50.5%
Example 4: Production of 4-quinolinecarbonitrile Into a 15 ml, test tube-shaped reactor equipped with a magnetic stirrer and a reflux condenser were added 0.71 g (4.5 mmol) of 4-quinolinecarboaldehyde, 0.27 g (1.8 mmol) of sodium bromate, 0.6 g (10 mmol) of acetic acid, 0.35 g (5 mmol) of 25% aqueous ammonia and 1 ml of water, followed by stirring at 90C for 2 hours. The reaction mixture contained, as a component, 97.4% (in terms of areal ratio of gas chromatography) of 4-quinolinecarbonitrile. To the reaction mixture were added 30 ml of a saturated aqueous sodium bicarbonate solution and 30 ml of ethyl acetate. The mixture was subjected to phase separation. Then, there were conducted washing with a saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, and distillation under reduced pressure for ethyl acetate removal. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane = 1:1 v/v) to obtain 0.35 g (yield: 50.5%) of white crystals. Gas mass chromatography was conducted to confirm a molecular ion peak [M+] of 154.
(Z)-2-pyridin-3-yl-3-quinolin-4-yl-acrylonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With sodium methylate; In methanol; ethanol;
EXAMPLE 2 2-Pyridin-3-yl -3-quinolin-4-yl-acrylonitrile Quinolin-4-carboxaldehyde (4.71 g; 0.03 mol) and <strong>[6443-85-2]3-pyridylacetonitrile</strong> (3.54 g; 0.03 mol) were dissolved in ethanol (100 mL). Sodium methoxide (2 mL of 25% methanol solution) was added. The reaction mixture was heated at reflux for a period of 2.5 hours. The mixture was cooled to ambient temperature. After 18 hours, the precipitated solid was collected, suspended in ethanol and saturated with hydrogen chloride gas. The mixture was cooled and the solid was collected by filtration. The solid was crystallized from methanol to give the title compound (5.8 g; 57% yield) as a dihydrochloride, three quarter hydrate, yellow solid, m.p. 250 C. (dec.). Anal. Calcd for C17 H11 N3 *HCl*3/4 H2 O; C, 59.40; H, 4.25; N, 12.23. Found: C, 59.75; H, 4.10; N, 11.93.
Stage #1: quinoline-4-carboxaldehyde; methyl (4-amino-3-hydroxyphenyl)acetate In ethanol for 22h;
Stage #2: With [bis(acetoxy)iodo]benzene In ethanol for 1h;
5.23.2. [2-(6-Fluoro-1-methyl-3-indolyl)-6-benzoxazolyl]acetic acid (3b)
General procedure: A mixture of 6-fluoro-1-methylindole-3-carbaldehyde (13a) (500 mg, 2.82 mmol) and methyl 4-amino-3-hydroxyphenylacetate (11a) (767 mg, 4.23 mmol) in EtOH (15 ml) was stirred for 22 h, and iodobenzene diacetate (1.09 g, 3.38 mmol) was added portionwise to the mixture. After being stirred for 1 h, the mixture was concentrated, and the residue was purified column chromatography with n-hexane-AcOEt (1:1, v/v) as eluent to give methyl [2-(6-fluoro-1-methyl-3-indolyl)-6-benzoxazolyl]acetate (889 mg, 93%) as a brown solid.
In methanol at 65℃; for 1.5h; Molecular sieve; chemoselective reaction;
4.2.1 Typical experimental procedure for the synthesis of 2-arylbenzimidazoles:
General procedure: o-Phenylenediamine (1, 260mg, 2.4mmol) and 3,4,5-trimethoxybenzaldehyde (2, 392mg, 2mmol) were dissolved in methanol (15mL). To this reaction mixture, 1g molecular sieves 3Å were added and reaction mixture was refluxed for 1.5h. On completion, it was filtered and solvent was evaporated. The residue was purified through column chromatography over silica gel (60-120 mesh) and eluted with hexane-chloroform. Compound 1,2-diarylbenzimidazole (4e) was eluted at 70% chloroform-hexane polarity followed by 2-arylbenzimidazole (3e) at 2% acetone-chloroform.
Intermediate 44: Step a (1-Methyl-1H-imidazol-5-yl)(quinolin-4-yl)methanol Analogous to the general method described in J. Org. Chem. 2004, 69, 8115 and Chem. Pharm. Bull 1997, 1145. To a 2-necked flask containing <strong>[1003-21-0]5-bromo-1-methyl-1H-imidazole</strong> (2.05 g, 12.7 mmol) was added THF (50 mL) and the solution was cooled to 0 C. To this clear homogeneous solution was added isopropyl magnesium chloride-LiCl complex (1.3 M, 10.5 mL, 13.6 mmol) which initially resulted in a white suspension, but became grayish once the addition of the Grignard reagent was complete. The reaction was stirred in an ice bath for 30 min, then a THF solution (20 mL) of quinoline-4-carbaldehyde (1.00 g, 6.36 mmol) was introduced and the reaction mixture became a greenish-grey color, and was subsequently allowed to warm to room temp. After 2 hours, the reaction mixture became brown in color and still remained heterogeneous. The reaction was quenched after 2 hours with saturated NH4Cl solution and the aqueous portion was extracted with EtOAc (4*75 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give an amber oil which solidified to a white solid upon standing. The crude material was triturated with DCM and then MeOH leaving behind the title compound as a white solid. The mother liquors were concentrated and chromatographed on silica gel (30% EtOAc-DCM increasing gradient to 10% MeOH-DCM) to provide more title compound as an off-white solid.
General procedure: In the first synthetic step (step a, Scheme 1), a series of (Z)-substituted diarylacrylonitrile analogues were synthesized by reacting substituted benzyl carbaldehydes with their corresponding substituted phenylacetonitriles in 5% NaOMe in methanol. The reaction mixture was stirred at room temperature for 2-3 h for the reaction to complete and the final product precipitated of the solution. The precipitate was filtered, washed with water and dried to yield the final compound in yields ranging from 70 to 95% (Scheme 1) [16].
20 4.1.1.1. General procedure for synthesis of 2 using Method A5.
General procedure: A mixture of naltrexone hydrochloride (1.HCl, 1.0 equiv), aryl aldehyde(6.0 equiv), and piperidine (2.0 equiv) in methanol (0.1 M) was stirred at 120 °C in a sealed tube. After confirming the consumption of 1 by TLC, the reaction was quenched with saturated aq NaHCO3, and then the reaction mixture was extracted with chloroform, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography or preparative TLC (chloroform/methanol or hexane/ethyl acetate) to afford the corresponding BNTX derivatives 2.
With ammonium hydroxide; potassium hydroxide In ethanol at 80℃;
Synthesis of [4Ql-tpy] ligand: The ligands 4Ql-tpy corresponds to 4-([2,2':6',2''-terpyridin]-4'-yl) quinoline wassynthesized by addition of one equivalent (1.0 g, 6.36 mmol) of quinoline-4-carbaldehyde and two equivalent of 2-acetyl pyridine (1.5 g, 12.64 mmol) in 50 mL ethanol. It was then followed by the addition of KOH (2.5 g, 40 mmol)and 60 mL ammonia solution. The solution was kept refluxing and stirring overnight at 80°C, resulting in the offwhite-colored precipitate. The solution was filtered and washed several times with distilled water until it got freefrom the base and washed with cold ethanol and diethyl ether. The process was depicted in Scheme 2.14. The ligandwas then purified by column chromatography in 2% chloroform and methanol to get pure ligand. The yield of theproduct was found to be 90 % for 2-acetyl pyridine. The formation of ligand was confirmed by proton NMR shownin Figure S4-S5.
78%
Stage #1: 2-acetylpyridine With sodium hydroxide In ethanol; water at 0℃; for 0.5h;
Stage #2: quinoline-4-carboxaldehyde In ethanol; water at 0℃; for 6h;
Stage #3: With ammonium hydroxide In ethanol; water at 20℃;
2.2 Synthesis of 2-quinterpy and 4-quinterpy
General procedure: 2-Quinterpy was synthesised by slight adjustment of a reported procedure [8] adopted from the Kröhnke approach. Sodium hydroxide (0.361g, 9.03mmol) was dissolved in a solution of water (10ml) and ethanol (10ml) then cooled to 0°C. 2-Acetylpyridine, (0.5ml, 4.46mmol) was then added by use of a syringe then stirred at 0°C for 30min. This was followed by the addition of a chilled solution at (0°C) of isoquinolinecarboxaldehyde (0.351g, 2.23mmol) in 20ml ethanol and stirred for 6h while maintaining the temperature at 0°C. The reaction mixture was then allowed to warm up to ambient temperature and thereafter a 25% aqueous ammonia solution (30ml) was added and stirred for a further 18h resulting in the formation of a white precipitate. Water (10ml) was added to the reaction mixture followed by filtration of the precipitate which was rinsed with 50ml of water and then with 20ml of a 1:1 water:ethanol solution. The resulting white solid was dried under vacuum.
61%
With ammonium hydroxide; potassium hydroxide In ethanol; water at 80℃;
48.9%
With ammonium hydroxide; potassium hydroxide In ethanol for 13h;
2.2.1.2. 4'-(4-quinolinyl)-2,2':60 ,200-terpyridine (2-qtpy).
2-acetylpyridine (2.42 g, 20.0 mmol) was added to 20 mL of 4- quinolinylcarboxaldehyde ethanolic solution (1.56 g, 10 mmol). The solution was stirred for 10 min, then KOH (1.12 g, 20 mmol) and NH4OH (29 mL) were added. The mixture was stirred for 13 h. A
(Z)-2-(1H-indol-3-yl)-3-(quinolin-4-yl)acrylonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
General procedure: To an <strong>[771-51-7]indole-3-acetonitrile</strong> derivative (1.0 equiv) dissolved in anhydrous methanol (4mL for 2.31mmol of starting material) in a dried microwave vial, sodium methoxide (1.7 equiv) was added and stirred at room temperature for 15min protected from light. Quinoline/isoquinoline-carboxaldehyde derivative (1.2 equiv) was added and the mixture was subjected to microwave irradiation at 95C for 8.5min. The reaction was cooled to room temperature and then chilled in an ice/salt bath. The resulting precipitate was filtered, washed with methanol, and dried under vacuum to afford a solid as the product.
2-(quinolin-4-yl)-1H-naphthalene[2,3-d]imidazole-4,9-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With sodium metabisulfite In 1,2-dimethoxyethane at 120℃;
42 General procedure for the preparation of compounds T1-T43
General procedure: A solution of 2,3-diamino-1,4-naphthoquinone (1.0 mmol),appropriate aromatic aldehyde (1.0 mmol) with sodium pyrosulfitein DMF was stirred at 120 C overnight. On completion of the reactionmonitored by TLC, the solvent was evaporated and the residuewas purified by silica gel chromatography by DCM/MeOHsystem to afford the final product. If necessary, the crude productcould be recrystallized in methanol or DMSO to afford pure sample.4.1.5.1. 2-(2-Chlorophenyl)-1H-naphtho[2,3-d]imidazole-4,9-dione(T1). Pale yellow solid; yield 80%;
tert-butyl {5-[hydroxy(quinolin-4-yl)methyl]thiazol-2-yl}carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
General procedure: To a stirred solution of 5 (1 equiv.) in THF (~20 mL) was added dropwise a 2.0 M solution of lithium diisopropylamide (LDA) in THF/heptane/ethylbenzene (2.2 equiv.) at -78 C. The reaction mixture was stirred for 30 min at 0 C followed by dropwise addition of aldehyde (1.2equiv.). The solution was stirred for 16 h at room temperature, quenched by a saturated aqueous solution of NH4Cl and extracted with ethyl acetate. The organic phase was dried with MgSO4, evaporated, and the residue was purified by silica gel column chromatography
5,6-dimethoxy-2-((1-(quinolin-4-ylmethyl)piperidin- 4-yl)methyl)-2,3-dihydro-1H-inden-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With sodium tris(acetoxy)borohydride In dichloromethane at 80℃; for 0.333333h; Microwave irradiation;
General procedure: 0.86mmol of the freshly freebased 5,6-dimethoxy-2-(4-piperidinylmethyl)-1-indanone, sodium triacetoxyborohydride (2.58mmol), and corresponding aldehyde (0.86mmol) were dissolved in 20mL of anhydrous dichloromethane. The reaction mixture was subjected to microwave irradiation at 80°C for 20min. The mixture was transferred to a separatory funnel and the organic layer was washed with an aqueous solution of saturated NaHCO3 (20mL). The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (using 2-5% methanol/dichloromethane or 1:1 ethyl acetate/hexane solvent systems) or using a CombiFlash chromatography system.
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