* 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 sodium tetrahydroborate In methanol; diethyl ether; water
Synthesis of (1-Methyl-1H-imidazol-2-yl)methanol (BB6) To a solution of compound (BB5) (40.5 g, 368 mmol) in MeOH (300 mL) at 0° C. was added NaBH4 (20.89 g, 551 mmol) portion wise. The reaction mixture was slowly warmed to room temperature and stirred for 5 h. The reaction mixture was cooled to 0° C., H2O (150 mL) was added and the mixture was stirred for 30 min at room temperature then concentrated in vacuo. The crude residue was dissolved in H2O (150 mL) and extracted with CHCl3 (4*200 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was stirred with Et2O (150 mL) and filtered to afford (BB6) (36 g, 87percent) as a white solid. Rf: 0.4 (15percent MeOH/CHCl3). 1H NMR (400 MHz, CDCl3): δ 6.89 (1H, app d), 6.83 (1H, app d), 4.66 (2H, s), 3.72 (31-1, s); m/z 113 (MH)+.
42%
Stage #1: With sodium tetrahydroborate In ethanol at 20℃; for 2 h; Stage #2: With methanol In ethanol
Sodium borohydride (380 mg, 10 mmol) was added to a solution of 1-methyl-1H-imidazole-2-carbaldehyde (1.1 g, 10 mmol) in ethanol (25 .ml). The mixture was stirred atroom temperature for 2 hours. The reaction was quenched by addition of methanol (20ml). The mixture was partitioned between water and dichloromethane. The combinedorganic extracts were dried over magnesium sulfate and concentrated to give the productas a white solid (480 mg, 42percent yield). ]H-NMR (400 MHz, CDC13): 3.73 (3H, s, Me),4.32 (1H, bs, OH), 4.67 (2H, s, CH2), 6.84 (1H, s, CH), 6.90 (1H, s, CH).
Reference：
[1] Tetrahedron, 2000, vol. 56, # 4, p. 645 - 657
[2] Patent: US2012/322722, 2012, A1,
[3] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 2, p. 363 - 386
[4] Tetrahedron, 1996, vol. 52, # 48, p. 15171 - 15188
[5] South African Journal of Chemistry, 2012, vol. 65, p. 231 - 238
[6] Patent: WO2006/24820, 2006, A1, . Location in patent: Page/Page column 127
[7] Patent: WO2007/42545, 2007, A1, . Location in patent: Page/Page column 18
[8] Patent: US2008/125467, 2008, A1, . Location in patent: Page/Page column 19-20
[9] Patent: EP1422228, 2004, A1, . Location in patent: Page 222
[10] Patent: WO2006/34277, 2006, A1, . Location in patent: Page/Page column 60
[11] Patent: US2007/185136, 2007, A1, . Location in patent: Page/Page column 67
2
[ 13750-81-7 ]
[ 20485-43-2 ]
Yield
Reaction Conditions
Operation in experiment
100%
With dihydrogen peroxide In water at 20℃; for 72 h;
First, 1-methylimidazole-2-carboxaldehyde was prepared according to the literature procedure[23]. The synthesis procedure then followed that of Im2COOH (1b) above and the yield was also quantitative after the removal of water under high vacuum (no washing with diethylether/water was necessary). Note: heating causes decarboxylation. Yield: 100percent. Mp=99–101°C. δH (400MHz, D2O): 7.42, 7.39 (2H, s, Im-H) and 4.08ppm (3H, s, NCH3); δC (400MHz, D2O): 158.67, 139.68, 125.83, 118.46, 36.73ppm. IR ν (KBr): 3347(m) 3119(m), 2663(w), 1641(s), 1683(m), 1507(s), 1449(m), 1388(s), 1338(s), 1285(s), 1173(m), 1123(s), 961(m) 910(m), 776(s), 685(s) cm−1. Anal. Calc. for C5H8N2O3 (144.12); C, 41.67; H, 5.59; N, 19.44percent. Found: C, 41.28; H, 5.23; N, 19.12percent.
Reference：
[1] South African Journal of Chemistry, 2010, vol. 63, p. 95 - 104
[2] Journal of Inorganic Biochemistry, 2015, vol. 145, p. 11 - 18
[3] South African Journal of Chemistry, 2012, vol. 65, p. 231 - 238
3
[ 616-47-7 ]
[ 67-56-1 ]
[ 68-12-2 ]
[ 62366-53-4 ]
[ 13750-81-7 ]
Yield
Reaction Conditions
Operation in experiment
79%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at -78 - 20℃; for 2 h;
General procedure: n-BuLi (1.67 M solution in hexane, 1.3 mL, 2.2 mmol) was added dropwise into a solution of p-bromoanisole (383 mg, 2.0 mmol) in THF (3 mL) at -78 °C for 30 min. Then, DMF (0.22 mL, 2.2 mmol) was added to the mixture and the obtained mixture was stirred at rt. After 2 h at the same temperature, THF was removed. Then, MeOH (3 mL) was added to the residue and the mixture was stirred at room temperature. After 30 min, I2 (1523 mg, 6 mmol) and K2CO3 (829 mg, 6 mmol) were added at 0 °C and the obtained mixture was stirred for 22 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (5 mL) and was extracted with CHCl3 (3.x.20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide methyl 4-methoxy-1-benzoate in 82percent yield. If necessary, the product was purified by short column chromatography (SiO2:hexane:EtOAc=9:1) to give pure methyl 4-methoxybenzoate as a colorless oil.
Stage #1: With n-butyllithium In tetrahydrofuran at -70℃; for 0.5 h; Stage #2: at -70 - 0℃; for 2 h;
To a solution of 1- methylimidazole (8.2 g, 100 mmol) in dry THF (100 mL) cooled to -70 0C, was added dropwise a solution of nBuLi in THF. After stirring for 30 min at the same temperature, the solution was treated with freshly distilled DMF (7.3 g, 100 mmol). The resultant yellow suspension was stirred at 0 0C for 2 h, and quenched with ice- water. The mixture was extracted with EtOAc, and the organic extracts dried (Na2SO4) before evaporation to afford an oily residue, which was distilled under reduced pressure to afford the title product (68percent yield). 1H-NMR (CDCl3) 69.76 (s, EPO <DP n="82"/>IH, CHO), 7.22 (s, IH, Im-CH), 7.07 (s, IH, Im-CH), 3.96 (s, 3H, CH3). EI-HRMS: m/z calcd for C5H6N2O 110.0480, found 110.0481 (100percent), 82.0493 (60percent).
Reference：
[1] Inorganica Chimica Acta, 2011, vol. 375, # 1, p. 213 - 219
[2] Dalton Transactions, 2015, vol. 44, # 17, p. 8013 - 8020
[3] Chemistry - A European Journal, 2015, vol. 21, # 36, p. 12735 - 12740
[4] Dalton Transactions, 2011, vol. 40, # 40, p. 10416 - 10433
[5] Tetrahedron, 2000, vol. 56, # 4, p. 645 - 657
[6] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 8, p. 2379 - 2386
[7] Monatshefte fur Chemie, 2016, vol. 147, # 12, p. 2209 - 2220
[8] New Journal of Chemistry, 2018, vol. 42, # 13, p. 10467 - 10471
[9] Patent: WO2007/45096, 2007, A1, . Location in patent: Page/Page column 41; 79-80
[10] Organic and Biomolecular Chemistry, 2009, vol. 7, # 8, p. 1633 - 1641
[11] European Journal of Organic Chemistry, 2011, # 30, p. 6092 - 6099
[12] Journal of Organometallic Chemistry, 1990, vol. 385, # 3, p. 417 - 427
[13] Journal of Medicinal Chemistry, 1991, vol. 34, # 4, p. 1363 - 1368
[14] Journal of Medicinal Chemistry, 1984, vol. 27, # 11, p. 1431 - 1438
[15] Tetrahedron, 1996, vol. 52, # 48, p. 15171 - 15188
[16] European Journal of Inorganic Chemistry, 2005, # 17, p. 3513 - 3523
[17] CrystEngComm, 2013, vol. 15, # 47, p. 10157 - 10160
[18] Croatica Chemica Acta, 2014, vol. 87, # 2, p. 153 - 160
5
[ 10111-08-7 ]
[ 74-88-4 ]
[ 13750-81-7 ]
Yield
Reaction Conditions
Operation in experiment
59%
With potassium carbonate In ethanol; N,N-dimethyl-formamide at 50℃; for 5 h;
Stir at room temperature To a solution of 1H-imidazole-2-carbaldehyde (250 mg, 2.6 mmol) and K2CO3 (431 mg, 3.12 mmol) in DMF (2.5 mL) was added methyl iodide (442 mg, 3.12 mmol). The mixture was stirred at 50° C. for 5 h and allowed to cool to remove solids. Water was added to the filtrate and extracted three times with ethyl acetate. The combined extracts were washed with saturated saline and dried over anhydrous sodium sulfate. The mixture was concentrated by suction and filtered to give 1-methyl-1H-imidazole-2-carboxaldehyde as a pale yellow oil (168 mg, yield 59percent).
Reference：
[1] Patent: CN103570683, 2018, B, . Location in patent: Paragraph 0711; 0715-0717
[2] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 2, p. 363 - 386
[3] Chemico-Biological Interactions, 2016, vol. 259, p. 85 - 92
6
[ 616-47-7 ]
[ 67-56-1 ]
[ 68-12-2 ]
[ 62366-53-4 ]
[ 13750-81-7 ]
Yield
Reaction Conditions
Operation in experiment
79%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at -78 - 20℃; for 2 h;
General procedure: n-BuLi (1.67 M solution in hexane, 1.3 mL, 2.2 mmol) was added dropwise into a solution of p-bromoanisole (383 mg, 2.0 mmol) in THF (3 mL) at -78 °C for 30 min. Then, DMF (0.22 mL, 2.2 mmol) was added to the mixture and the obtained mixture was stirred at rt. After 2 h at the same temperature, THF was removed. Then, MeOH (3 mL) was added to the residue and the mixture was stirred at room temperature. After 30 min, I2 (1523 mg, 6 mmol) and K2CO3 (829 mg, 6 mmol) were added at 0 °C and the obtained mixture was stirred for 22 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (5 mL) and was extracted with CHCl3 (3.x.20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide methyl 4-methoxy-1-benzoate in 82percent yield. If necessary, the product was purified by short column chromatography (SiO2:hexane:EtOAc=9:1) to give pure methyl 4-methoxybenzoate as a colorless oil.
With sodium dihydrogenphosphate; diisopropylamine In tetrahydrofuran; water; ethyl acetate; N,N-dimethyl-formamide
Synthesis of 1-Methyl-1H-imidazole-2-carbaldehyde (BB5) To a solution of 1-methyl imidazole (57 g, 0.7 mmol) in THF (250 mL) was added LDA (2 M solution in THF, 348 mL) at -60° C. and the stirred for 3 h. The reaction mixture was cooled -78° C., DMF (75 mL) was added rapidly, and the reaction mixture was slowly allowed to room temperature and stirred at ambient temperature overnight. The reaction mixture was cooled to 0° C., a solution of NaH2PO4 (100 g in 350 mL H2O) was added and the resulting mixture was stirred for 30 min. The mixture was filtered to remove insoluble material and the filtrate was extracted with DCM (4*400 mL). The combined organic extracts were concentrated in vacuo and the crude residue was purified by column chromatography (silica gel, 100-200 mesh, 30percent EtOAc/pet. ether) to provide (BB5) (41 g, 53percent) as a yellow solid. Rf: 0.3 (15percent MeOH/CHCl3). 1H NMR (400 MHz, CDCl3): δ 9.82 (1H, s), 7.28 (1H, app d), 7.13 (1H, app d), 4.04 (3H, s); m/z 111 (MH)+.
Reference：
[1] Patent: US2012/322722, 2012, A1,
[2] Liebigs Annalen der Chemie, 1980, # 4, p. 542 - 556
Reference：
[1] South African Journal of Chemistry, 2012, vol. 65, p. 231 - 238
13
[ 616-47-7 ]
[ 107-31-3 ]
[ 13750-81-7 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 11, p. 2691 - 2698
14
[ 616-47-7 ]
[ 109-94-4 ]
[ 13750-81-7 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 11, p. 2691 - 2698
15
[ 616-47-7 ]
[ 50-00-0 ]
[ 13750-81-7 ]
Reference：
[1] Archives of Toxicology, 1998, vol. 72, # 5, p. 289 - 295
16
[ 13750-81-7 ]
[ 124312-73-8 ]
Reference：
[1] Tetrahedron Letters, 2004, vol. 45, # 29, p. 5581 - 5583
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 8, p. 2379 - 2386
17
[ 13750-81-7 ]
[ 74-88-4 ]
[ 111851-98-0 ]
Yield
Reaction Conditions
Operation in experiment
84%
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 5 h;
Example 76A1 -Ethyl- lH-imidazole-2- carbaldehyde[00631] To a suspension of lH-imidazole-2- carbaldehyde (480 mg, 5 mmol) and potassium carbonate (936 mg, 6 mmol) in N, N-dimethylformamide (7 mL) was added iodoethane (829 mg, 6mmol) and the mixture was heated at 50 °C for 5 hrs. Solvent was removed under reduced pressure. The residue was partitioned between water (30 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 1 -ethyl- lH-imidazole-2- carbaldehyde as light yellow oil (520 mg, yield 84percent). 1H MR (400 MHz, CDC13) δ (ppm): 1.42- 1.46 (t, J= 7.2 Hz, 3H), 4.42-4.47 (q, 2H), 7.19 (s, IH), 7.29 (s, IH), 9.82 (s, IH). LC-MS (ESI) m/z: 125 (M+l)+.
Stage #1: 1-methyl-1H-imidazole With n-butyllithium In tetrahydrofuran; hexane at -78 - -73℃; for 0.0833333h; Inert atmosphere;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -78 - -73℃; for 0.0833333h; Inert atmosphere;
Stage #3: With hydrogenchloride In water at 20℃; for 1h;
97%
Stage #1: 1-methyl-1H-imidazole With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.0833333h; Inert atmosphere;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -78℃; for 1h;
Stage #3: With hydrogenchloride In tetrahydrofuran; hexane at 20℃; for 1h;
94%
With n-butyllithium In tetrahydrofuran at -78 - 20℃; Inert atmosphere;
83%
Stage #1: 1-methyl-1H-imidazole With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -78 - 20℃;
80%
Stage #1: 1-methyl-1H-imidazole With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h;
Stage #2: N,N-dimethyl-formamide at 20℃; for 2h;
73%
Stage #1: 1-methyl-1H-imidazole With n-butyllithium In tetrahydrofuran at 0℃; Inert atmosphere;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at 0℃; Inert atmosphere;
72%
Stage #1: 1-methyl-1H-imidazole With n-butyllithium In tetrahydrofuran at -15℃;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -15℃;
Stage #3: In water at 20℃;
70%
Stage #1: 1-methyl-1H-imidazole With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.33333h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -78 - 20℃; for 20h;
68%
Stage #1: 1-methyl-1H-imidazole With n-butyllithium In tetrahydrofuran at -70℃; for 0.5h;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -70 - 0℃; for 2h;
To a solution of 1- methylimidazole (8.2 g, 100 mmol) in dry THF (100 mL) cooled to -70 0C, was added dropwise a solution of nBuLi in THF. After stirring for 30 min at the same temperature, the solution was treated with freshly distilled DMF (7.3 g, 100 mmol). The resultant yellow suspension was stirred at 0 0C for 2 h, and quenched with ice- water. The mixture was extracted with EtOAc, and the organic extracts dried (Na2SO4) before evaporation to afford an oily residue, which was distilled under reduced pressure to afford the title product (68% yield). 1H-NMR (CDCl3) 69.76 (s, EPO IH, CHO), 7.22 (s, IH, Im-CH), 7.07 (s, IH, Im-CH), 3.96 (s, 3H, CH3). EI-HRMS: m/z calcd for C5H6N2O 110.0480, found 110.0481 (100%), 82.0493 (60%).
56%
Stage #1: 1-methyl-1H-imidazole With n-butyllithium In tetrahydrofuran; hexane at -78℃; Inert atmosphere;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere;
52%
Stage #1: 1-methyl-1H-imidazole With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -78 - 20℃; for 1h;
Stage #3: With ammonium chloride In tetrahydrofuran; hexane; water
52%
Stage #1: 1-methyl-1H-imidazole With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Darkness;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane for 0.333333h; Inert atmosphere; Darkness;
24.8%
Stage #1: 1-methyl-1H-imidazole With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;
Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at 25℃; for 16h;
216 l-methyl-lH-imidazole-2-carbaldehyde
To a solution of l-methylimidazole (3 g, 36.54 mmol, 2.91 mL, 1 eq) in THF (30 mL) was added n-BuLi (2.5 M, 21.92 mL, 1.5 eq) dropwise at -78 °C under N2 atmosphere. After stirring lhr, DMF (8.01 g, 109.62 mmol, 8.43 mL, 3 eq) was added dropwise and the mixture was stirred for another 16 hr at 25 °C. The reaction mixture was diluted with H20 (10 mL). The mixture was extracted with DCM (20 mL * 3). The combined organic phase was washed with brine (10 mL * 3), dried with anhydrous Na2S04, filtered and concentrated in vacuum. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 1/0 to 1 : 1). Compound l-methylimidazole-2-carbaldehyde (1 g, 9.08 mmol, 24.8% yield) was obtained as yellow oil.
With n-butyllithium 1.) diethyl ether, from -80 deg C to 0 deg C, 2.) RT, 6 h; Yield given. Multistep reaction;
With lithium diisopropyl amide 1.) hexane, THF, from -60 deg C to -50 deg C, 3 h, 2.) RT, overnight; Yield given. Multistep reaction;
With sodium tetrahydroborate; In methanol; diethyl ether; water;
Synthesis of (1-Methyl-1H-imidazol-2-yl)methanol (BB6) To a solution of compound (BB5) (40.5 g, 368 mmol) in MeOH (300 mL) at 0 C. was added NaBH4 (20.89 g, 551 mmol) portion wise. The reaction mixture was slowly warmed to room temperature and stirred for 5 h. The reaction mixture was cooled to 0 C., H2O (150 mL) was added and the mixture was stirred for 30 min at room temperature then concentrated in vacuo. The crude residue was dissolved in H2O (150 mL) and extracted with CHCl3 (4*200 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was stirred with Et2O (150 mL) and filtered to afford (BB6) (36 g, 87%) as a white solid. Rf: 0.4 (15% MeOH/CHCl3). 1H NMR (400 MHz, CDCl3): delta 6.89 (1H, app d), 6.83 (1H, app d), 4.66 (2H, s), 3.72 (31-1, s); m/z 113 (MH)+.
42%
Sodium borohydride (380 mg, 10 mmol) was added to a solution of 1-methyl-1H-imidazole-2-carbaldehyde (1.1 g, 10 mmol) in ethanol (25 .ml). The mixture was stirred atroom temperature for 2 hours. The reaction was quenched by addition of methanol (20ml). The mixture was partitioned between water and dichloromethane. The combinedorganic extracts were dried over magnesium sulfate and concentrated to give the productas a white solid (480 mg, 42% yield). ]H-NMR (400 MHz, CDC13): 3.73 (3H, s, Me),4.32 (1H, bs, OH), 4.67 (2H, s, CH2), 6.84 (1H, s, CH), 6.90 (1H, s, CH).
[(1-Methyl-1 H-imidazol-2-yl)-methanol] (13) To a solution of 1-methyl-2-imidazole carbaldehyde (12) (500 mg, 4.5 mmol) in methanol (5 ml_) at O0C was added sodium borohydride (85 mg, 2.2 mmol) portion wise and stirred for 30 min. Reaction was followed by TLC and was quenched by adding acetone at O0C. The reaction mixture was diluted with water and ethylacetate. The compound 13 (510 mg) was isolated as white solid along with inorganic impurity after concentration of aqueous layer.
Example 1.3Methylimidizolyl Methanol, Thiazole Methanol, Methyl Thiodiazolyl Methanol; Aldehyde (100 mg, 0.91 mmol) in diethyl ether at 0 C. was added lithium aluminium hydride (51.7 mg, 1.36 mmol), then the resulting mixture was warmed to r.t. After 1 h, the reaction was quenched with Na2SO4.10H2O and stirred for a couple of hours. The organic solution was filtrated. The residue was purified with flash chromatography to give the corresponding alcohol as a white solid. 1H-NMR: (300 MHz, CDCl3), delta: 6.86 (m, 2H); 4.57 (s, 2H); 3.88 (br, 1H); 3.65 (s, 3H).Same as the above procedure to prepare the thiazolyl methanol, a light yellow oil. 1H-NMR: (300 MHz, CDCl3), delta: 6.86 (m, 2H); 4.57 (s, 2H); 3.88 (br, 1H); 3.65 (s, 3H).Methyl thiodiazolyl methanol, a light yellow oil. 1H-NMR: (300 MHz, CDCl3), delta: 5.05 (s, 2H); 2.68 (s, 3H).Thiazolyl methanol, a light yellow oil. 1H-NMR: (300 MHz, CDCl3), delta: 7.77 (d, 1H); 7.35 (d, 1H); 4.99 (s, 2H).
To a suspension of aluminum lithium hydride (758 mg) in THF (10 ml), a solution of 1-methylimidazole-2-carboxyaldehyde (2.00 g) in THF (20 ml) was added dropwise at 0C under nitrogen atmosphere. After finishing the dropping, water (0.8 ml), 15% aqueous solution of sodium hydroxide (0.8 ml) and water (2.4 ml) were sequentially added to the mixture at 0C, and the mixture was stirred for 2.5 hours at room temperature. The mixture was dried over magnesium sulfate, and the insolubles were filtered off. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane-ethyl acetate, to give 2-hydroxymethyl-1-methylimidazole (1.82 g) as colorless crystals. 1H-NMR (200 MHz, CDCl3) delta 3.73 (3H, s), 4.63 (2H, s), 6.81 (1H, d, J = 1.2 Hz), 6.86 (1H, d, J = 1.2 Hz). Elemental Analysis C5H8N2O·0.05H2O Calcd. C, 53.13; H, 7.22; N, 24.78; Found. C, 53.42; H, 7.45; N, 24.57.
With lithium aluminium tetrahydride; In diethyl ether; at 0 - 20℃; for 1h;
Example 1.3: Methylimidizolyl Methanol, Thiazole Methanol, Methyl Thiodiazolyl Methanol [0281] Aldehyde (100 mg, 0.91 mmol) in diethyl ether at 0 0C was added lithium aluminium hydride (51.7 mg, 1.36 mmol), then the resulting mixture was warmed to r.t. After 1 h, the reaction was quenched with Na2SO4-IOH2O and stirred for a couple of hours. The organic solution was filtrated. The residue was purified with flash chromatography to give the corresponding alcohol as a white solid. 1H-NMR: (300 MHz, CDCl3), delta: 6.86 (m, 2 H); 4.57 (s, 2 H); 3.88 (br, 1 H); 3.65 (s,3 H).
With sodium tetrahydroborate; In methanol; at 20℃; for 48h;
To 10 g of 1-methyl-2-imidazolecarboxaldehyde dissolved in 200 ml of methanol are added 5.2 g of sodium borohydride, and the mixture is left for 48 hours at room temperature. The solvents are evaporated off and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 6.5 g of the expected product. 1H NMR delta in ppm (DMSO d6): 3.67 (s, 3H); 4.49 (d, 2H); 5.36 (t, 1H); 6.78 (d, 1H); 7.08 (d, 1H). m.p.=108.2C
(ii) To a solution of 4.96 g (43.9 mmole) 2-hydroxymethyl-1-methylimidazole in 50 ml dioxane was added 4.90 g (44.1 mmole) selenium dioxide and the mixture stirred at 85-90 C. for five hours, at room temperature for 36 hours, at 85 C. for eight hours and finally at room temperature for 15 hours. The reaction mixture was filtered, the solvent evaporated in vacuo to yield 4.81 g of crude aldehyde which was distilled to give 2.11 g of product as colorless crystals, b.p. 65 C. at 2.8 mm Hg.
With selenium(IV) oxide; In 1,4-dioxane;
(ii) To a solution of 4.96 g (43.9 mmole) 2-hydroxymethyl-1-methylimidazole in 50 ml dioxane was added 4.90 g (44.1 mmole) selenium dioxide and the mixture stirred at 85-90 C. for five hours, at room temperature for 36 hours, at 85 C. for eight hours and finally at room temperature for 15 hours. The reaction mixture was filtered, the solvent evaporated in vacuo to yield 4.81 g of crude aldehyde which was distilled to give 2.11 g of product as colorless crystals, b.p. 65 C. at 2.8 mm Hg.
Stage #1: ethyl [(pyridin-2-ylmethyl)amino]acetate; N-methyl-2-imidazolcarboxaldehyde With hydrogen In methanol at 20℃; for 48h;
Stage #2: With potassium carbonate In ethanol; water at 20℃; for 48h;
With potassium carbonate; In ethanol; N,N-dimethyl-formamide; at 50℃; for 5h;
Stir at room temperature To a solution of 1H-imidazole-2-carbaldehyde (250 mg, 2.6 mmol) and K2CO3 (431 mg, 3.12 mmol) in DMF (2.5 mL) was added methyl iodide (442 mg, 3.12 mmol). The mixture was stirred at 50 C. for 5 h and allowed to cool to remove solids. Water was added to the filtrate and extracted three times with ethyl acetate. The combined extracts were washed with saturated saline and dried over anhydrous sodium sulfate. The mixture was concentrated by suction and filtered to give 1-methyl-1H-imidazole-2-carboxaldehyde as a pale yellow oil (168 mg, yield 59%).
[4-(6-[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1H-benzimidazol-2-yl)-butyl]-dipropyl-amine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The compound (39.8 mg) obtained in Example 114-4 was dissolved in methanol (1.0 ml) and then added with 2-imidazole carboxaldehyde (13.3 mg) and trimethyl orthoformate (0.030 ml), followed by stirring at room temperature for 30 minutes. The solution was gradually added with sodium borohydride (10.5 mg), followed by stirring at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. After having been washed with water, the solution was extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Subsequently, the residue was dissolved in methanol (1.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (63.2 mg), acetic acid (0.023 ml), trimethyl orthoformate (0.030 ml), and sodium cyanoborohydride (23.2 mg), followed by stirring at room temperature for 30 minutes. The solution was added with acetic acid (0.045 ml) and stirred at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. After having been washed with a 1 mol/l sodium hydroxide aqueous solution, the solution was extracted with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (27.6 mg) of the subject compound as a white solid. MS(FAB,Pos.):m/z=477[M+H]+1H-NMR(500MHz,DMSO-d6):delta=0.89(3H,t,J=7.3Hz),1.63-1.69(4H,m),1.70-1.81(2H,m),1.94-2.01(2H,m),2.84-3.00(4H,m),3.03-3.09(2H,m),3.19-3.23(2H,m),3.72(3H,s),3.90(2H,s),4.13(2H,s),4.21(2H,s),4.41( 2H,t,J=7.3Hz),7.49(1H,s),7.53(1H,s),7.59(1H,d,J=8.4Hz),7.64-7.66(3H,m),7.81(1H,s),10.50(1H,s).
[3-(6-[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-quinolin-2-yl)-propyl]-dipropylamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The compound (62.6 mg) obtained in Example 119-9 was dissolved in methanol (1.2 ml). Then, a 4 mol/l hydrogen chloride/dioxane solution (1.2 ml) was added to the solution, and the whole was stirred at room temperature for 2 hours. After the solution had been subjected to an anion-exchange resin (Amberlite IRA-410), the solvent was distilled off under reduced pressure. The residue was dissolved in anhydrous methanol (1.0 ml) and added with 2-imidazole carboxaldehyde (25.0 mg) and trimethyl orthoformate (0.056 ml), followed by stirring at room temperature for 16 hours. Then, sodium borohydride (19.3 mg) was added to the solution, and the whole was stirred at room temperature for 6 hours. After the reaction, the solvent was distilled off under reduced pressure and the residue was added with water, followed by extraction with chloroform. Subsequently, the extract was then dried with magnesium sulfate, followed by distilling the solvent off. The residue was dissolved in anhydrous methanol (2.3 ml) and then added with 1-methyl-2-imidazole carboxaldehyde (28.6 mg) and sodium cyanoborohydride (32.0 mg). Then, the solution was adjusted to about pH 5 with acetic acid, followed by stirring at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Then, the residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution. The solution was dried with magnesium sulfate and the solvent was then distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (19.6 mg) of the subject compound as a pale-yellow solid. MS(FAB,Pos.):m/z=474[M+H]+1H-NMR(500MHz,DMSO-d6+D2O):delta=0.92(6H,t,J=7.3Hz),1.63-1.71(4H,m),2.19-2.22(2H,m),3.02-3.06(4H,m),3.13-3.19(4H,m),3.72(3H,s),3.95(2H,s),4.13(2H,s),4.20(2H,s),7.46( 2H,s),7.60(2H,s),7.75(1H,d,J=8.8Hz),7.94(1H,d,J=8.1Hz),8.04( 1H,d,J=9.0Hz),8.10(1H,br),8.62(1H,d,J=8.8Hz).
2-[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-6-(3-dipropylaminopropyl)-naphtalene hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The compound (280 mg) obtained in Example 121-11 was dissolved in anhydrous methanol (5.0 ml) and added with trimethyl orthoformate (0.154 ml) and 2-imidazole carboxaldehyde (90.1 mg), followed by stirring at room temperature for 2 hours under a nitrogen atmosphere. Subsequently, the solution was added with sodium borohydride (53.3 mg) in an ice bath and stirred at room temperature for 30 minutes. After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the solution, and the whole was stirred. The solution was subjected to extraction with chloroform. The extract was washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. Then, the organic layer was dried with anhydrous sodium sulfate. The residue obtained was dissolved in anhydrous methanol (10ml) and added with sodium cyanoborohydride (93.6 mg), acetic acid (3.00 ml), and 1-methyl-2-imidazole carboxaldehyde (120 mg), followed by stirring at room temperature for 2 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform. The solution was added with a saturated aqueous sodium bicarbonate solution and stirred. The solution was subjected to extraction with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and then the solvent was distilled off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (318 mg) of the subject compound as a white solid. MS(FAB,Pos.):m/z=473[M+H]+1H-NMR(500MHz,DMSO-d6+D2O):delta=0.89(6H,t,J=7.3Hz),1.62(4H,sext.,J=7.3Hz),2.03(2H,q uint.,J=7.9Hz),2.79(2H,t,J=7.8Hz),2.99-3.02(4H,m),3.09(2H,t,J=8.1Hz),3.85(2H,s),4.10(2H,s),4.18(2H, s),7.43(1H,d,J=1.8Hz),7.44(1H,s),7.45(1H,d,J=1.8Hz),7.50(1H, d,J=8.4Hz),7.59(2H,d,J=1.4Hz),7.71(1H,s),7.77(1H,d,J=8.5Hz), 7.83(1H,s),7.83(1H,d,J=8.4Hz).
[5-(6-[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-quinolin-2-yl)-pentyl]-dipropylamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The compound (52.6 mg) obtained in Example 123-4 was dissolved in methanol (1.6 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (1.6 ml), followed by stirring at room temperature for 1.5 hours. After the reaction, the solvent was distilled off under reduced pressure. The residue was neutralized with an anion-exchange resin (Amberlite IRA-410) and the solvent was then distilled off. The residue was dissolved in anhydrous methanol (1.0 ml) and added with 2-imidazole carboxaldehyde (17.3 mg). The mixture was stirred at room temperature for 2 hours and then added with sodium borohydride (13.6 mg), followed by stirring at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform, followed by washing with water. The organic layer was dried with magnesium sulfate and the solvent was then distilled off. The residue was dissolved in anhydrous methanol (1.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (19.8 mg) and sodium cyanoborohydride (22.6 mg). The resulting solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 14 hours. After completion of the reaction, chloroform was added to the solution, followed by washing with a 1 mol/l sodium hydroxide aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was then distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid. Consequently, hydrochloride (45.4 mg) of the subject compound was obtained as a white solid. MS(FAB,Pos.):m/z=502[M+H]+1H-NMR(500MHz,DMSO-d6+D2O):delta=0.91(6H,t,J=7.3Hz),1.39(2H,t,J=7.8Hz),1.60-1.73(6H,m),1.82-1.88(2H,m),2.97-3.09(6H,m),3.16(2H,t,J=8.1Hz),3.73(3H,s),3.97(2H,s),4.13(2H, s),4.20(2H,s),7.46(2H,dd,J=2.0,4.9Hz),7.59(2H,s),7.85(1H,d,J =8.5Hz),8.01(1H,d,J=9.0Hz),8.13(1H,d,J=8.5Hz),8.18(1H,s),8.7 8(1H,d,J=7.3Hz).
[4-(5-[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1-propyl-1H-benzimidazol-2-yl)-butyl]-dipropyl-amine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Lithium aluminum hydride (40.6 mg) was suspended in THF (3.0 ml) and cooled to 0C. A solution (2.0 ml) of the compound (97.1 mg) obtained in Example 128-4 in THF was dropped in this suspension. Then, the suspension was stirred at 0C for 1 hour. Furthermore, lithium aluminum hydride (41.0 mg) was added to the suspension, and the whole was stirred for 2 days. After completion of the reaction, sodium sulfate decahydrate was added to the suspension until bubbling was stopped. Subsequently, a 1 mol/l sodium hydroxide aqueous solution was added to the suspension until a white precipitate was generated. Solid matter was separated through filtration and the solvent was then distilled off from the filtrate under reduced pressure. The residue was dried under vacuum, dissolved in methanol (2.0 ml), and added with trimethyl orthoformate (0.11 ml) and 2-imidazole carboxaldehyde (31.0 mg). Then, the solution was stirred for 1 hour and then cooled to 0C. The solution was added with sodium borohydride (19.7 mg) and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in 1 mol/l hydrochloric acid and the aqueous layer was then washed with chloroform. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate, followed by distilling the solvent off. The residue was dissolved in methanol (2.0 ml) and added with acetic acid (0.10 ml) and 1-methyl-2-imidazole carboxaldehyde (35.1 mg), followed by cooling to 0C. The solution was added with sodium cyanoborohydride (31.7 mg) and stirred at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with saturate saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (89.4 mg) of the subject compound as a white solid. MS(FAB,Pos.):m/z=519[M+H]+1H-NMR(500MHz,DMSO-d6):delta=0.89-0.95(9H,m),1.67-1.94(10H,m),2.96-3.00(4H,m),3.12-3.13(2H,m),3.26(2H,t,J=7.3Hz),3.72(3H,s),3.91(2H,s),4.13(2H, s),4.21(2H,s),4.41(2H,t,J=7.3Hz),7.49(1H,s),7.52(1H,s),7.64( 2H,s),7.72(1H,d,J=8.5Hz),7.82(1H,s),7.90(1H,d,J=8.5Hz),10.61 (1H,s).
With sodium sulfate; In dichloromethane; at 0 - 20℃;Product distribution / selectivity;
To a stirred mixture of 1-methyl-1H-imidazole-2-carbaldehyde (2.5 g, 23 mmol) and anhydrous sodium sulfate (26.9 g, 190 mmol) in anhydrous dichloromethane (500 mL) was added <strong>[59434-19-4]4-aminoisobenzofuran-1(3H)-one</strong> (2.8 g, 19 mmol) at 0 C. After the addition, the mixture was stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with dichloromethane (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether to give (E)-4-((1-methyl-1H-imidazol-2-yl)methyleneamino)benzofuran-1(3H)-one (5 g, yield 98%) as a white solid. LC-MS (ESI) m/z: 242 (M+1)+
98%
With sodium sulfate; In dichloromethane; at 0 - 20℃; for 144h;Reflux;Product distribution / selectivity;
Example 72A(£)-4-(( 1 -Methyl- lH-imidazol-2-yl)methyleneamino)benzofuran- 1 (3H)-one[00622] To a stirred mixture of 1 -methyl- lH-imidazole-2-carbaldehyde (2.5 g, 23 mmol) and anhydrous sodium sulfate (26.9 g, 190 mmol) in anhydrous dichloromethane (500 mL) was added 4- aminoisobenzofuran- l(3H)-one (2.8 g, 19 mmol) at 0 C. After the addition, the mixture was stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with dichloromethane (50 mL*3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether to give (£)-4-((l -methyl- lH-imidazol-2-yl)methyleneamino)benzofuran-l(3H)-one (5 g, yield 98%) as a white solid. LC-MS (ESI) m/z: 242 (M+l)+.
With magnesium sulfate In acetonitrile for 48h; Reflux;
139A
A solution of 1-methyl-1H-imidazole-2-carbaldehyde (659 mg, 6.0 mmol), 4-amino-6-fluoroisobenzofuran-1(3H)-one (1.0 g, 6.0 mmol), and anhydrous magnesium sulfate (7.2 g, 60.0 mmol) in acetonitrile (100 mL) was heated to reflux for 2 days. The solution was filtered and the solvents were removed in vacuum. The crude product was re-crystallized from isopropanol to afford the title compound (1.068 g, yield 68%) LC-MS (ESI) m/z: 260 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.04 (s, 3H), 5.49 (s, 2H), 7.24 (s, 1H), 7.54-7.58 (m, 2H), 7.73-7.76 (m, 1H), 8.70 (s, 1H).
A mixture of <strong>[59434-19-4]4-aminoisobenzofuran-1(3H)-one</strong> (298 mg, 2 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (440 mg, 4 mmol) in ethyl propionate (20 mL) was cooled to 0 C. Then a solution of sodium ethoxide in ethanol [sodium (184 mg, 8 mmol) in ethanol (10 mL)] was added drop-wise. After the addition, the mixture was stirred at room temperature for 3 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=5:1 to 1, ethyl acetate: methanol=50:1 to 25:1, ammonia hydrate 1 mL) to give ethyl 2,3-bis(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg, yield 16%). LC-MS (ESI) m/z: 380 (M+1)+
[3-(6-[(1H-imidazol-2-ylmethyl)-(1-methyl-1H-imidazol-2-ylmethyl)-amino]-methyl}-1-methyl-1H-benzimidazol-2-yl)-benzyl]-dipropyl-amine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The compound (31.2 mg) obtained in Example 18-6 was dissolved in methanol (1.0 ml) and added with acetic acid (30 mul) and 1-methyl-2-aminomethylimidazole (15.4 mg), and the whole was stirred at room temperature for 2 hours. Sodium cyanoborohydride (22.7 mg) was added thereto and the whole was stirred at room temperature for 15 hours. Furthermore, 2-imidazole carboxaldehyde (18.0 mg) was added thereto and the whole was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (25.6mg) of the subj ect compound as a white solid. MS(FAB,Pos.):m/z=525[M+H]+ 1H-NMR(500MHz,DMSO-d6):delta=0.88(6H,t,J=7.3Hz),1.70-1.83(4H,m),2.97-3.07(4H,br),3.75(3H,s),3.93(2H,s),4.15(2H,s),4.17(3H,s),4.23(2H,s),4.47(2H,d,J=4.9Hz),7.54-7.55(2H,m),7.57(1H,d,J=8.3Hz),7.65(2H,s),7.74(1H,d,J=8.3Hz),7.81(1H,t,J=8.1Hz),7.99(1H,d,J=8.1Hz),8.03(1H,d,J=7.8Hz),8.32(1H,s),8.40(1H,s).
With dihydrogen peroxide; In water; at 20℃; for 72h;
First, 1-methylimidazole-2-carboxaldehyde was prepared according to the literature procedure[23]. The synthesis procedure then followed that of Im2COOH (1b) above and the yield was also quantitative after the removal of water under high vacuum (no washing with diethylether/water was necessary). Note: heating causes decarboxylation. Yield: 100%. Mp=99-101C. deltaH (400MHz, D2O): 7.42, 7.39 (2H, s, Im-H) and 4.08ppm (3H, s, NCH3); deltaC (400MHz, D2O): 158.67, 139.68, 125.83, 118.46, 36.73ppm. IR nu (KBr): 3347(m) 3119(m), 2663(w), 1641(s), 1683(m), 1507(s), 1449(m), 1388(s), 1338(s), 1285(s), 1173(m), 1123(s), 961(m) 910(m), 776(s), 685(s) cm-1. Anal. Calc. for C5H8N2O3 (144.12); C, 41.67; H, 5.59; N, 19.44%. Found: C, 41.28; H, 5.23; N, 19.12%.
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 5h;
Example 76A1 -Ethyl- lH-imidazole-2- carbaldehyde[00631] To a suspension of lH-imidazole-2- carbaldehyde (480 mg, 5 mmol) and potassium carbonate (936 mg, 6 mmol) in N, N-dimethylformamide (7 mL) was added iodoethane (829 mg, 6mmol) and the mixture was heated at 50 °C for 5 hrs. Solvent was removed under reduced pressure. The residue was partitioned between water (30 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (20 mLx3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 1 -ethyl- lH-imidazole-2- carbaldehyde as light yellow oil (520 mg, yield 84percent). 1H MR (400 MHz, CDC13) delta (ppm): 1.42- 1.46 (t, J= 7.2 Hz, 3H), 4.42-4.47 (q, 2H), 7.19 (s, IH), 7.29 (s, IH), 9.82 (s, IH). LC-MS (ESI) m/z: 125 (M+l)+.
Example 74AEthyl 2,3 -bis(l -methyl- lH-imidazol-2-yl)-4-oxo- 1 ,2,3,4-tetrahydroquinoline-5-carboxylate[00627] A mixture of 4-aminoisobenzofuran- l(3H)-one (298 mg, 2 mmol) and 1 -methyl- lH-imidazole- 2- carbaldehyde (440 mg, 4 mmol) in ethyl propionate (20 mL) was cooled to 0 C. Then a solution of sodium ethoxide in ethanol [sodium (184 mg, 8 mmol) in ethanol (10 mL)] was added drop-wise. After the addition, the mixture was stirred at room temperature for 3 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL><4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified bychromatography (silica gel, petroleum ether/ethyl acetate = 5: 1 to 1, ethyl acetate: methanol=50: l to 25: 1, ammonia hydrate 1 mL) to give ethyl 2,3-bis(l -methyl- lH-imidazol-2-yl)-4-oxo- 1,2,3,4- tetrahydroquinoline-5-carboxylate (120 mg, yield 16%). LC-MS (ESI) m/z: 380 (M+l)+.
With magnesium sulfate; In acetonitrile; for 48h;Reflux;Product distribution / selectivity;
Example 139A(£)-6-Fluoro-4-((l -methyl- lH-imidazol-2-yl)methyleneamino)isobenzofuran- 1 (3H)-one[00798] A solution of 1 -methyl- lH-imidazole-2-carbaldehyde (659 mg, 6.0 mmol), 4-amino-6- fluoroisobenzofuran- 1 (3H)-one (1.0 g, 6.0 mmol), and anhydrous magnesium sulfate (7.2 g, 60.0 mmol) in acetonitrile (100 mL) was heated to reflux for 2 days. The solution was filtered and the solvents were removed in vacuum. The crude product was re-crystallized from isopropanol to afford the title compound (1.068 g, yield 68%) LC-MS (ESI) m/z: 260 (M+l)+. ¾-NMR (400 MHz, DMSO-d6) delta (ppm): 4.04 (s, 3H), 5.49 (s, 2H), 7.24 (s, 1H), 7.54-7.58 (m, 2H), 7.73-7.76 (m, 1H), 8.70 (s, 1H).
General procedure: n-BuLi (1.67 M solution in hexane, 1.3 mL, 2.2 mmol) was added dropwise into a solution of p-bromoanisole (383 mg, 2.0 mmol) in THF (3 mL) at -78 C for 30 min. Then, DMF (0.22 mL, 2.2 mmol) was added to the mixture and the obtained mixture was stirred at rt. After 2 h at the same temperature, THF was removed. Then, MeOH (3 mL) was added to the residue and the mixture was stirred at room temperature. After 30 min, I2 (1523 mg, 6 mmol) and K2CO3 (829 mg, 6 mmol) were added at 0 C and the obtained mixture was stirred for 22 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (5 mL) and was extracted with CHCl3 (3×20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide methyl 4-methoxy-1-benzoate in 82% yield. If necessary, the product was purified by short column chromatography (SiO2:hexane:EtOAc=9:1) to give pure methyl 4-methoxybenzoate as a colorless oil.
The general procedure to synthesize (E)-4-(1-alkyl-1H-imidazol-2-yl)but-3-en-2-one.
General procedure: To a flask equipped with a stir bar and a condenser was added carboxaldehyde (4 mmol, 1.0 equiv), 1- triphenylphosphoranylidene)-2-propanone (4.2 mmol, 1.05 equiv), and toluene (8 mL). The reaction mixture was stirred at 70 C for 5 h. After completion, the reaction mixture was acidified to PH 3 with 1M HCl, and extracted with DCM (15 mL × 3). The aqueous layer was basified to PH 9 with sodium bicarbonate, and the resulting mixture was extracted with DCM (15 mL × 3). The DCM extracts from basic aqueous layer were combined, dried over anhydrous magnesium sulfate, and concentrated to give the corresponding (E)-4-(1-alkyl-1H-imidazol-2-yl)but-3-en-2-one.
With potassium carbonate; In methanol; at 0 - 20℃;Inert atmosphere;
General procedure: To a solution of N-Methyl-1H-imidazole-2-carbaldehyde (2) (0.400 g, 3.47 mmol) in anhydrous CH3OH (40 mL), K2CO3 (0.483 g, 3.5 mmol) was added at 0 C. A solution of amine (3.5 mmol) was added dropwise. The temperature was maintained at 0 C for 20 min, then wormed to room temperature and stirred overnight. The mixture was filtered and the product was obtained as yellow oil.
(4Z)-2-thioxo-4-[(1-methyl-1H-imidazol-2-yl)methylene]-1-allylimidazol-5(4H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With hydrogenchloride
1 Experimental
2.1 (4Z)-2-Thioxo-4-[(1-methyl-1H-imidazol-2-yl)methylene]-1-allyl-imidazol-5(4H)-one (3) 1-Methyl-2-imidazolecarbaldehyde (0.155 g, 1.4 mmol) was added to a solution of thiohydantoin 1 (0.22 g, 1.4 mmol) in 3 ml of 2% KOH solution in EtOH, and this mixture was stirred at room temperature for 3 h. The precipitate that formed was filtered off and then suspended in 5 ml of water. Concentrated HCl solution was added under stirring to bring the pH to 7. The yellow-orange precipitate was filtered off, washed with diethyl ether and dried in air to obtain compound 3 (0.358 g, 96%). M.p. 125-127 °C. 1H NMR (DMSO-d6), 3.82 (s, 3H, CH3), 4.41 (d, 2H, CH2, J = 5.09 Hz), 5.10 (d, 1H, CH2, J = 18 Hz), 5.16 (d, 1H, CH2, J = 10.5 Hz), 5.86 (ddd., 1H, =CH, J1 = 5.20 Hz, J2 = 10.5 Hz, J3 = 18 Hz), 6.71 (s, 1H, =CH), 7.29 (s, 1H, Im), 7.43 (s, 1H, =CH, Im). IR, ν/cm-1: 3239, 1741, 1720, 1650. UV-Vis, nm (ε, M-1 cm-1): 309 (2585), 389 (8250), 412 (9916). Anal. Calc. for С11Н12N4OS (3): С, 49.61; Н, 5.30; N, 21.04. Found: C, 49.47; Н, 4.62; N 21.06%.
(4Z)-2-thioxo-4-[(1-methyl-1H-imidazol-2-yl)methylene]-1-(n-propyl)imidazol-5(4H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With hydrogenchloride
2 (4Z)-2-Thioxo-4-[(1-methyl-1H-imidazol-2-yl)methylene]-1-allyl-imidazol-5(4H)-one (3)
2.2 (4Z)-2-Thioxo-4-[(1-methyl-1H-imidazol-2-yl)methylene]-1-(n-propyl)-imidazol-5(4H)-one (4) 1-Methyl-2-imidazolecarbaldehyde (0.25 g, 2.5 mmol) was added to a solution of thiohydantoin 2 (0.4 g, 2.5 mmol) in 5 ml of 2% KOH solution in EtOH, and this mixture was stirred at room temperature for 3 h. The precipitate that formed was filtered off and then suspended in 5 ml of water. Concentrated HCl solution was added under stirring to bring the pH to 7. The light-yellow precipitate was filtered off, washed with diethyl ether and dried in air to obtain compound 4 (0.61 g, 89%). M.p. 150-152 °C. 1H NMR (DMSO-d6), 0.86 (t, 3 H, CH3 J = 7.43 Hz); 1.63 (m, 2H, CH2), 3.73 (т, 2H, CH2, J = 7.04 Hz) 3.82 (s, 3H, CH3), 6.55 (s, 1H, =CH), 7.22 (s, 1H, Im), 7.36 (s, 1H, =CH, Im). IR, ν/cm-1: 2940, 1730, 1680. UV-Vis, nm (ε, M-1 cm-1): 311 (1700), 383 (5100), 410 (6200). Anal. Calc. for С11Н14N4OS (4): С, 52.78; Н, 5.64; N, 22.38. Found: C, 52.61; Н, 5.68; N 22.34%.
ethyl 2-(1-methyl-1H-imidazol-2-yl)-1H-benzimidazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With air; In N,N-dimethyl-formamide; at 120℃; for 17h;
The mixture of <strong>[37466-90-3]ethyl 3,4-diaminobenzoate</strong> (2.0 g, 11.1 mmol) and 1-methyl-1H-imidazole-2- carboxyaldehyde (1.17 g, 10.4 mmol) in dry N,N-dimethylformamide (50 mL) was heated at80 C for 1 hour. Then the reaction vessel was filled with oxygen and the whole was heated under oxygen atmosphere at 120 C for 16 hours. The mixture was concentrated, added with 100 mL of water and extracted with chloroform (4 x 30 mL). Extracts were dried over magnesium sulphate, filtered through celite and concentrated. The raw product was purified by chromatography on silicagel (eluent: heptane/ethyl acetate, gradient 0-90%). 1.69 g of the title product were obtained as a solid (yield 60%). MS-ESI: (mlz) calculated for C14H13N402[M-H]: 269.1, found 269.1.
In tetrahydrofuran; diethyl ether; at 0℃; for 3.0h;
To a solution of i-methyl-i H-imidazole-2-carbaldehyde (10.0 g) in THF (100 mL)was added Mel (1.0 M in diethyl ether, 182 mL) at 0C. The mixture was stirred at 0C for 3 hours,and then quenched with NH4CI solution (250 mL). The resulting mixture was extracted with EA (5x400 mL). The combined organic phases were dried and concentrated to afford i-(i-methyl1 H-imidazol-2-yl)ethanol (ii .0 g).
N-[2-(1H-imidazol-4-yl)ethyl]-N-[(E)-(1-methyl-1Himidazol-2-yl)methylidene]amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
In ethanol for 4h; Reflux;
2.3. General procedure for synthesis of the Schiff base (HSB1)
General procedure: Schiff base (HBS1) was synthesised according to a previouslydescribed [28] procedure (Scheme 1): To a solution of histamine(5.4 mmol) in dry methanol: benzene (40 cm3, 3:1) was addedimidazole-2-carboxaldehyde (5.4 mmol). The resulting yellow solutionwas refluxed for 4 h and the reaction was monitored by TLC(MeOH: hexane, 1:5). Molecular sieve (4 Å) was added and thereaction stirred overnight at room temperature. The molecularsieve was filtered off and the solvent removed under reducedpressure to yield a yellow solid. The solidwaswashed with cold, dryethanol and air-dried. The purity and chemical structures of thecompound was proved by FT-IR, 1H and 13C NMR and CHNOelemental analyses.
With formic acid In methanol at 80℃; Inert atmosphere;
1 Synthesis of imidazole imide ligand compound b
Add to 25 mL of two-necked flask 2,4,6-triphenylaniline(963.6 mg, 3 mmol, 1.2 eq.),Replace with Ar three times,Then 10 mL of a methanol solution containing 1-methyl-imidazole-2-carbaldehyde (275.3 mg, 2.5 mmol, 1 eq.) Was added,Formic acid (0.1 mL), refluxed at 80 ° C,TLC followed by detection until 1-methyl-imidazole-2-carboxaldehyde disappeared.The solvent was spun dry, recrystallized with 40 mL of n-hexane 5 times,413.2 mg of a yellow solid was obtained with a yield of 40%.
40%
With formic acid In methanol at 80℃; Inert atmosphere;
1.2 (2) Synthesis of imidazole imine ligand compound b
To a 25 mL two-neck flask was added 2,4,6-triphenyl aniline (963.6 mg, 3 mmol, 1.2 eq.), which was replaced with Ar three times, and then 1-methyl-imidazole-2-carbaldehyde (275.3 mg) was added. , 2.5mmol, 1eq.) methanol solution 10mL,Formic acid (0.1 mL), refluxed at 80°C,TLC followed the detection until the 1-methyl-imidazole-2-carbaldehyde starting material disappeared. The solvent was derotated and recrystallized five times with 40 mL of n-hexane to give a yellow solid, 413.2 mg, yield 40%.
With formic acid In methanol Reflux; Schlenk technique; Inert atmosphere;
Multi-step reaction with 2 steps
1.1: dichloromethane / 16 h / 20 °C
2.1: palladium 10% on activated carbon; hydrogen / ethanol / 20 °C
2.2: 2 h / 0 - 20 °C
(S)-3-((R)-2-chloro-3-hydroxy-3- (1-methyl-1H-imidazol-2-yl)propanoyl)-4-benzyloxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
Stage #1: (4S)-(+)-3-(chloroacetyl)-4-(phenylmethyl)-2-oxazolidinone With titanium tetrachloride In dichloromethane at 0℃; for 0.333333h;
Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 1h;
Stage #3: N-methyl-2-imidazolcarboxaldehyde In dichloromethane at 0℃; for 4h;
10 (Example 10)(S) -3 - ((R) -2-chloro-3-hydroxy-3- (1 -methyl- 1 H-imidazol-2-yl) propanoyl) -4-Benzyloxazolidin-2-oneSynthesis of
To a solution of (S) -3- (2-chloroacetyl) -4-benzyloxazolidin-2-one (1.00 g, 3.95 mmol) in dichloromethane (10 mL)Titanium tetrachloride (0.869 mL, 7.90 mmol)Was added at 0 ° C., and the mixture was stirred at 0 ° C. for 20 minutes. Diisopropylethylamine (1.38 mL, 7.90 mmol) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour.1-Methyl-1H-imidazole-2-carbaldehyde (487 mg, 4.35 mmol) was added to the resulting reaction solution at 0 ° C. and the mixture was stirred at 0 ° C. for 4 hours. A saturated aqueous solution of ammonium chloride (3 mL) was added to the reaction solution, and then a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added thereto,to prepare an aqueous solution having a pH of 7. The resulting aqueous solution was extracted three times with ethyl acetate, and the organic layer was concentrated under reduced pressure. Ethyl acetate (8 mL) was added to the residue. Saturated aqueous sodium bisulfite solution (8 mL) was added and the mixture was stirred for 2 hours. The organic layer was separated,The aqueous layer was extracted three times with ethyl acetate. The collected organic layer was washed with saturated aqueous sodium chloride solution,Dried over anhydrous sodium sulfate, filtered,The filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, n-hexane / ethyl acetate)(S) -3 - ((R) -2-Chloro-3-hydroxy-3- (1 -methyl- 1 H-imidazol-2-yl) propanoyl) -4-benzyloxazolidin-2-one(719 mg, 2.07 mmol, 52%, 99% de)As a white powder.
2-(diphenylphosphino)-N-((1-methyl-1H-imidazol-2-yl)methyl)ethylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
210 mg
Under argon protection and room temperature, add a solution of imidazolaldehyde (110mg, 1.0mmol) in tetrahydrofuran (6mL) to a Shrek flask, and then dropwise add a solution of diphenylphosphineethylamine (290mg, 1.0mmol) in tetrahydrofuran (6mL). ), React for 1 h at room temperature; then use an oil pump to dry tetrahydrofuran through a Shrek line connected to the cold trap, add 6 mL of toluene, and add a toluene solution of diisobutylaluminum hydride (DIBAL) (1.5 mol / L, 1.2mL, diisobutylaluminum hydride (1.8mmol), react at room temperature for 2h, then add 10mL of water to quench the reaction, separate the organic phase, extract the aqueous phase with ether (3 × 20mL), combine the obtained organic phases, After drying with sodium sulfate, it was spin-dried and separated by column chromatography (the eluent used was a mixture of dichloromethane and methanol, and the volume ratio of dichloromethane and methanol was 20: 1) to obtain a light yellow oily liquid, namely Target product (210 mg yield, 65% yield).
(1E)-(1-methyl-1H-imidazol-2-yl)-N-(4-(4-(((E)-(1-methyl-1H-imidazol-2-yl)methylidene)amino)benzyl)phenyl)methanimine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
In methanol at 20℃; for 5h;
2.2. Synthesis of compounds L1-L3
General procedure: For L1, pyridine-2-carbaldehyde (2 mmol), 4,4'-methylenedianiline (1 mmol) and Ac (2 mmol) were stirred in MeOH (10 mL) at room temperature for 5 h. The white solid (L1) was collected by vacuum filtration, recrystallized from methanol and dried in a desiccator under reduced pressure. Compounds L2 and L3 were prepared analogically with 6-methylpyridine-2- carbaldehyde (for L2) and 1-methyl-1 H -imidazole-2-carbaldehyde (for L3) used instead of pyridine-2-carbaldehyde.
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