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[ CAS No. 288-32-4 ] {[proInfo.proName]}

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Chemical Structure| 288-32-4
Chemical Structure| 288-32-4
Structure of 288-32-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 288-32-4 ]

CAS No. :288-32-4 MDL No. :MFCD00005183
Formula : C3H4N2 Boiling Point : -
Linear Structure Formula :- InChI Key :RAXXELZNTBOGNW-UHFFFAOYSA-N
M.W : 68.08 Pubchem ID :795
Synonyms :
1,3-Diaza-2,4-cyclopentadiene;Glyoxaline

Calculated chemistry of [ 288-32-4 ]

Physicochemical Properties

Num. heavy atoms : 5
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 18.59
TPSA : 28.68 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.67 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 0.06
Log Po/w (WLOGP) : 0.41
Log Po/w (MLOGP) : -0.92
Log Po/w (SILICOS-IT) : 1.36
Consensus Log Po/w : 0.18

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.04
Solubility : 6.21 mg/ml ; 0.0912 mol/l
Class : Very soluble
Log S (Ali) : -0.22
Solubility : 41.4 mg/ml ; 0.608 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.08
Solubility : 5.61 mg/ml ; 0.0824 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.0

Safety of [ 288-32-4 ]

Signal Word:Danger Class:8
Precautionary Statements:P280-P301+P330+P331-P305+P351+P338-P310-P303+P361+P353 UN#:3263
Hazard Statements:H302-H314-H360 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 288-32-4 ]

* 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.

  • Upstream synthesis route of [ 288-32-4 ]
  • Downstream synthetic route of [ 288-32-4 ]

[ 288-32-4 ] Synthesis Path-Upstream   1~200

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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1989, p. 95 - 99
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1989, p. 95 - 99
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Reference: [1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 2-3, p. 499 - 507
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Reference: [1] Oriental Journal of Chemistry, 2015, vol. 31, # 4, p. 2239 - 2245
[2] Oriental Journal of Chemistry, 2015, vol. 31, # 4, p. 2239 - 2245
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Reference: [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 21, p. 4658 - 4666
[2] Synthetic Communications, 2008, vol. 38, # 17, p. 2881 - 2888
[3] Journal of Medicinal Chemistry, 2008, vol. 51, # 10, p. 2944 - 2953
[4] Journal of Organic Chemistry, 2007, vol. 72, # 10, p. 3741 - 3749
[5] Advanced Synthesis and Catalysis, 2013, vol. 355, # 2-3, p. 499 - 507
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YieldReaction ConditionsOperation in experiment
96% at 110℃; for 5 h; General procedure: Imidazole was chosen as the model substrate for theN-arylation reaction in presence of electrospun CuO NFsas catalyst. The reaction flask was packed with 0.1 mM ofCuO NFs, 5 ml of DMF followed by the charging of imidazole(1 mM) and bromobenzene (1 mM) at 110 C withconstant stirring. The progress of the reaction was monitoredby thin layer chromatography (TLC). After completion,the catalyst was separated by centrifuge and washedseveral times with water and ethyl acetate for re-use. Theproduct was isolated by evaporation of solvent in vacuumand purified. The obtained product was characterized withFT-IR for functional group identification and GC-MS for structural confirmation.
Reference: [1] Journal of Nanoscience and Nanotechnology, 2018, vol. 18, # 1, p. 234 - 241
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YieldReaction ConditionsOperation in experiment
88% With sodium hydroxide In water; chlorobenzene Example 16
286.0 g of imidazole were introduced into 1200 g of chlorobenzene in a flask fitted with water separator, and 320 g of 50percent strength aqueous sodium hydroxide solution were added dropwise.
Water was then separated out until the distillate no longer separated into two phases.
After 224 ml of water had been separated out in this way, 100 ml of chlorobenzene were removed by distillation.
202 g of phosgene were subsequently passed in at 80-85° C. over the course of one hour.
When the addition was complete, the mixture was stirred at 90° C. for a further 1 hour while a vigorous stream of nitrogen was passed through the flask, and the precipitate then present was filtered off at 80° C. and rinsed with 200 g of chlorobenzene at 90° C.
The filtrate and the washing liquid were combined and cooled to 0° C.
The precipitate which deposited was filtered off, rinsed with 200 g of dry chlorobenzene, and dried at 60° C. under reduced pressure (50 mbar).
290.6 g of carbonyldiimidazole were thus obtained in the form of colorless crystals having a purity of 97percent.
This corresponded to a yield of 88percent of theory.
Reference: [1] Patent: US2002/111497, 2002, A1,
[2] Patent: WO2005/63718, 2005, A1, . Location in patent: Page/Page column 8-9
[3] Patent: EP1600444, 2005, A1, . Location in patent: Page/Page column 6
[4] Patent: WO2005/63718, 2005, A1, . Location in patent: Page/Page column 8; 9
[5] Patent: EP1600444, 2005, A1, . Location in patent: Page/Page column 6; 7
[6] Patent: EP1600444, 2005, A1, . Location in patent: Page/Page column 6-8
[7] Justus Liebigs Annalen der Chemie, 1957, vol. 609, p. 75,82
[8] Patent: US6353115, 2002, B1, . Location in patent: Page column 5
[9] Patent: US6353115, 2002, B1, . Location in patent: Page column 6
[10] Patent: US6353115, 2002, B1, . Location in patent: Page column 5
[11] Patent: US6353115, 2002, B1, . Location in patent: Page column 5
[12] Journal of Polymer Science, Part A: Polymer Chemistry, 2010, vol. 48, # 2, p. 417 - 424
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Reference: [1] Patent: US2002/111497, 2002, A1,
[2] Patent: US2002/111497, 2002, A1,
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Reference: [1] Patent: US6455702, 2002, B1,
[2] Patent: US6455702, 2002, B1,
[3] Patent: US6455702, 2002, B1,
[4] Patent: US6455702, 2002, B1,
[5] Patent: US6455702, 2002, B1,
[6] Patent: US6455702, 2002, B1,
[7] Patent: US6455702, 2002, B1,
[8] Patent: US6455702, 2002, B1,
[9] Patent: US6455702, 2002, B1,
[10] Patent: US6455702, 2002, B1,
[11] Patent: US2012/53214, 2012, A1, . Location in patent: Page/Page column 9
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Reference: [1] Patent: US6353115, 2002, B1, . Location in patent: Page column 5
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YieldReaction ConditionsOperation in experiment
85% at 20℃; for 2 h; Into a 500 ml flask were added the tetrahydrofuran containing 48.1 g (0.707 mol) of imidazole obtained in Example 2 and 140 g of tetrahydrofuran. After the atmosphere of the system was replaced with nitrogen, 18.5 g (0.094 mol) of diphosgene was added dropwise at room temperature over a period of 2 hours. Thereafter, the same operations as in Example 1 were conducted and white crystals of CDI were taken out. Yield 24.4 g (0.15 mol) (percent yield 85percent). M.p. 111.3 to 116.9°C.
Reference: [1] Patent: EP1731510, 2006, A1, . Location in patent: Page/Page column 5-6
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YieldReaction ConditionsOperation in experiment
70% at 66 - 130℃; for 1.45 h; Example 2; Comparative in Analogy to Example 1 from WO-A-00/14072 In a flask, 68.22 g of imidazole are suspended in 505 g of xylene. The mixture is heated to reflux and dewatered by taking off 5 g of a xylene/water mixture. The temperature is reduced to 66° C. and over the course of 30 minutes 25.2 g of phosgene are metered in with an introduction rate of 50.4 g/h. After about 15 minutes the reaction mixture takes on a consistency like that of chewing gum. When the metering of phosgene is at an end the imidazole hydrochloride by-product is in the form of yellow balls. After a further hour of stirring at this temperature, this temperature is raised to 130° C., and the consistency of the imidazole hydrochloride changes to a brown melt. The melt is drained off at 130° C. It solidifies on cooling to a dark-green, solid mass. The supernatant xylene phase is cooled to 0° C. The precipitated crystals are filtered off and dried at 20 mbar and 50° C. This gives carbonylbisimidazole in the form of white crystals with black fractions (Hazen colour number: 489). The purity is 96.8percent, corresponding to a yield of 70percent of theory.
61.9% at 35 - 55℃; for 3.25 - 3.75 h; Example 3; Inventive; A flask is charged with 375.2 g of dry chloroform and 93.8 g of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 28 g of distillate are taken off under a pressure of 280 mbar and at 30° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 72.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm chloroform at 35° C. 251.1 g of water-clear solution are distilled off from the combined organic phases at 280 mbar and 30° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of chloroform conditioned to a temperature of 0° C. Drying of the crystals at 6 mbar and 30° C. gives 41.5 g of product in the form of white crystals having a Hazen colour number of 44. The purity of the product is 99.5percent, corresponding to a yield of 74.0percent of theory.; Example 4; Inventive; A flask is charged with 358.1 g of dry chloroform and 119.36 g of imidazole and this initial charge is heated to 55° C. At this temperature over the course of 1.75 hours 44.57 g of phosgene are added with an introduction rate of 25.5 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 2 h. In order to ensure a phosgene-free reaction mixture, 5.4 g of distillate are taken off under a pressure of 630 mbar and at 35° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 96.0 g) is removed by filtration at 55° C., the filter cake being washed with twice 100 ml of warm chloroform at 55° C. The combined organic phases are cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of chloroform conditioned to a temperature of 0° C. Drying of the residue at 4 mbar and 46° C. gives 44.3 g of product in crystalline form having a Hazen colour number of 49. The purity of the product is 99.0percent, corresponding to a yield of 61.9percent of theory.
59.9% at 35℃; for 3.25 h; Example 1; Inventive; A flask is charged with 531.5 g of dry dichloromethane and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 36.04 g (0.36 mol) of phosgene are added with an introduction rate of 20.6 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 13.2 g of distillate are taken off under a pressure of 790 to 500 mbar and at 35-25° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 72.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. 250.1 g of water-clear solution are distilled off from the combined organic phases at 790 to 500 mbar and 35-25° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of dichloromethane conditioned to a temperature of 0° C. Drying of the crystals at 4 mbar and 30° C. gives 40.0 g of product in the form of white crystals, Hazen colour number: 69.7. The purity of the product is 99.3percent, corresponding to a yield of 71.2percent of theory.; Example 5 Inventive with Recycling of the Mother Liquor 1st Phosgenation A flask is charged with 531.5 g of dry dichloromethane and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 8.4 g of distillate are taken off under a pressure of 750 to 500 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 80.3 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of dichloromethane conditioned to a temperature of 0° C. After the solid carbonylbisimidazole has been filtered off, 553.0 g of mother liquor M1 are obtained. Drying of the crystals at 5 mbar and 20° C. gives 33.54 g of product in the form of white crystals with a Hazen colour number of 45.1. The purity of the product is 99.6percent. The yield therefore corresponds to 59.9percent of theory. 2nd Phosgenation A flask is charged with 531.5 g of dichloromethane-containing mother liquor M1 from the 1st phosgenation step and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 21.6 g of distillate are taken off under a pressure of 750 to 450 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 86.6 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 100 ml of dichloromethane conditioned to a temperature of 0° C. After the solid carbonylbisimidazole has been filtered off, 553.0 g of mother liquor M2 are obtained. Drying of the crystals at 6 mbar and 30° C. gives 39.4 g of product in the form of white crystals with a Hazen colour number of 33.2. The purity of the product is 98.7percent. The yield therefore corresponds to 70percent of theory. 3rd Phosgenation A flask is charged with 531.5 g of dichloromethane-containing mother liquor M2 from the 2nd phosgenation step and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 9.2 g of distillate are taken off under a pressure of 750 to 500 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 88.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 100 ml of dichloromethane conditioned to a temperature of 0° C. Drying of the crystals at 7 mbar and 20° C. gives 37.3 g of product in the form of white crystals with a Hazen colour number of 41.0. The purity of the product is 98.5percent. The yield therefore corresponds to 65.9percent of theory.
Reference: [1] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 4
[2] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 4
[3] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 3-4; 5
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YieldReaction ConditionsOperation in experiment
90% at 20 - 55℃; for 4 h; To a 1000 ml flask were added 108.3 g (1.59 mol) of imidazole and 630 g of tetrahydrofuran. After the atmosphere of the system was replaced with nitrogen, the imidazole was dissolved under stirring. Thereto was added dropwise 39.3 g (0.2 mol) of diphosgene at room temperature over a period of 2 hours. After completion of the dropwise addition, the stirring was continued at room temperature for 1 hour and then the whole was heated to 55°C, followed by continuous stirring for another 1 hour. Imidazole hydrochloride yielded as a by-product was filtrated with heat and was then washed with 100 g of tetrahydrofuran. The imidazole hydrochloride filtrated off was dried under reduced pressure at 40°C to obtain 83.2 g (0.796 mol) of imidazole hydrochloride (recovery of 100percent). A filtrate containing CDI was concentrated and subjected to toluene-crystallization, and CDI was filtrated off under a nitrogen atmosphere. The CDI filtrated off was dried under reduced pressure at 40°C to obtain 58.0 g (0.358 mol) of CDI as white crystals (yield 90percent). M.p. 111.2 to 118.6°C.
Reference: [1] Patent: EP1731510, 2006, A1, . Location in patent: Page/Page column 5
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Reference: [1] Patent: US6455702, 2002, B1,
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Reference: [1] Patent: US6353115, 2002, B1, . Location in patent: Page column 4
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  • [ 74-86-2 ]
  • [ 1072-63-5 ]
Reference: [1] Russian Journal of Physical Chemistry A, 2007, vol. 81, # 3, p. 335 - 338
[2] J. Appl. Chem. USSR (Engl. Transl.), 1982, vol. 55, # 3, p. 506 - 510[3] Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation), 1982, vol. 55, # 3, p. 555 - 560
[4] J. Appl. Chem. USSR (Engl. Transl.), 1983, vol. 56, # 10, p. 2123 - 2126[5] Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation), 1982, vol. 56, # 10, p. 2289 - 2292
[6] DRP/DRBP Org.Chem.,
[7] Justus Liebigs Annalen der Chemie, 1956, vol. 601, p. 81,104
[8] Patent: US6384216, 2002, B1, . Location in patent: Page column 8
[9] Patent: US2002/38059, 2002, A1,
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  • [ 2768-02-7 ]
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Reference: [1] Tetrahedron Letters, 2007, vol. 48, # 44, p. 7845 - 7848
[2] Mendeleev Communications, 2011, vol. 21, # 6, p. 326 - 328
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Reference: [1] Journal of Heterocyclic Chemistry, 1988, vol. 25, p. 771 - 782
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Reference: [1] Tetrahedron, 2001, vol. 57, # 50, p. 9951 - 9957
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  • [ 107-06-2 ]
  • [ 1072-63-5 ]
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Reference: [1] Organometallics, 2018, vol. 37, # 20, p. 3598 - 3610
[2] Heterocycles, 1992, vol. 34, # 7, p. 1365 - 1373
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Reference: [1] Russian Journal of Organic Chemistry, 2002, vol. 38, # 7, p. 1056 - 1059
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  • [ 16681-56-4 ]
Reference: [1] Tetrahedron Letters, 2009, vol. 50, # 9, p. 1007 - 1009
[2] New Journal of Chemistry, 2018, vol. 42, # 23, p. 18889 - 18893
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430
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Reference: [1] Medicinal Chemistry Research, 2012, vol. 21, # 10, p. 3035 - 3042,8
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Reference: [1] Patent: JP2005/82570, 2005, A, . Location in patent: Page/Page column 4-5
[2] Patent: JP2005/82570, 2005, A, . Location in patent: Page/Page column 5
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YieldReaction ConditionsOperation in experiment
93%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 1 h;
Stage #2: at 20℃; for 16 h;
(Reference Example 18) Synthesis of 1-propyl-1H-imidazole:
Sodium hydride (55percent, 0.966 g, 22.1 mmol) was added to a solution of imidazole (1.37 g, 20.1 mmol) in tetrahydrofuran (50.0 mL) at room temperature.
The reaction liquid was stirred at the same temperature for 1 hour, and then, 1-bromopropane (5.48 mL, 60.3 mmol) was added at room temperature.
The reaction liquid was stirred at the same temperature for 16 hours.
The reaction liquid was filtered through Celite and washed with tetrahydrofuran, and then the filtrate and the washing solution were concentrated under reduced pressure.
The residue was purified by flash column chromatography (silica gel, chloroform/methanol) to obtain 1-propylimidazole (2.07 g, 18.8 mmol, 93percent) as a colorless oil.
1H-NMR (400 MHz, CDCl3) δ: 0.93 (3H, t, J=7.2 Hz), 1.81 (2H, td, J=7.2, 14.4 Hz), 3.90 (2H, t, J=7.2 Hz), 6.91 (1H, s), 7.06 (1H, s), 7.46 (1H, s).
86%
Stage #1: With sodium hydride In tetrahydrofuran; hexane at 20℃;
Stage #2: at 60 - 65℃; Reflux
General procedure: A THF solution of imidazole (1 equivalent) is added to a suspension of NaH (1.1 equivalents) (60 percent in paraffin oil) previously stirred in n-hexane for 15 min. The imidazole solution is added dropwise over a period of 25–30 min at 5–10 °C to avoid vigorous liberation of H2 gas. Once H2 gas evolution ceased, the suspension of imidazole sodium is stirred at RT for 2–3 h to favor complete formation of NaIm salt. To this suspension, corresponding R–Br (0.90 equivalents), was added dropwise over a period of 30 min and further stirred for 3 h or longer to achieve uniform mixing indicated by vertex formation. The thoroughly stirred reaction mixture then was refluxed overnight at 60–65 °C. The reaction mass was then allowed to cool and filtered to remove NaBr salt. THF is removed under a rotary evaporator and DCM is added to the resultant brownish liquid followed by the addition of activated charcoal and anhydrous Na2SO4, stirred for 2–3 h and filtered over Celite. A Celite bed was washed with DCM and DCM removed under vacuum leading to a pale yellowish liquid. The NMR spectra checked in CDCl3 and matches with literature reports [20].
78%
Stage #1: With sodium hydroxide In dimethyl sulfoxide at 20℃; for 1.5 h;
Stage #2: at 20℃;
General procedure: Imidazole (3)/benzimidazole(5) (10 mmol) was dissolved in 10 ml of DMSO and solid NaOH(15 mmol) was then added it. The resulting pale yellow suspensionwas stirred in air at room temperature for 1.5 h, after which, thealkyl bromides or benzyl chlorides (15 mmol) were added andallowed to react until completion (TLC). Water (50 ml) was thenadded and the products were extracted with ethyl acetate. Combinedorganic layers were washed several times with water, thenwith brine, dried over Na2SO4 and subjected to chromatographicpurification over silica (100–200 mesh) using MeOH: EtOAc 5:95(v/v) as the mobile phase. Compounds 4a-f were isolated as yellowoils whereas, the compounds 7a-e were white solid. Spectroscopic data of the N-alkyl imidazoles are in accord with earlier literatureand thus are not shown here [30].
Reference: [1] Dalton Transactions, 2013, vol. 42, # 5, p. 1385 - 1393
[2] Patent: EP3263565, 2018, A1, . Location in patent: Paragraph 0433; 0434
[3] Research on Chemical Intermediates, 2016, vol. 42, # 6, p. 5587 - 5596
[4] New Journal of Chemistry, 2007, vol. 31, # 6, p. 879 - 892
[5] Polyhedron, 2017, vol. 127, p. 68 - 83
[6] Crystal Growth and Design, 2013, vol. 13, # 7, p. 3068 - 3077
[7] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 17, p. 2863 - 2865
[8] New Journal of Chemistry, 2012, vol. 36, # 3, p. 702 - 722
[9] Chemische Berichte, 1882, vol. 15, p. 646[10] Justus Liebigs Annalen der Chemie, 1882, vol. 214, p. 309,320
[11] Bioscience, Biotechnology, and Biochemistry, 1992, vol. 56, # 1, p. 161 - 162
[12] Chemistry Letters, 2005, vol. 34, # 3, p. 442 - 443
[13] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 4, p. 423 - 427
[14] Journal of the Chinese Chemical Society, 2013, vol. 60, # 7, p. 745 - 754
[15] Chemical Biology and Drug Design, 2014, vol. 83, # 3, p. 278 - 288
[16] Molecules, 2014, vol. 19, # 8, p. 11741 - 11759
  • 26
  • [ 288-32-4 ]
  • [ 107-08-4 ]
  • [ 35203-44-2 ]
Reference: [1] Synthetic Communications, 2010, vol. 40, # 15, p. 2291 - 2301
[2] Journal of Materials Chemistry A, 2013, vol. 1, # 22, p. 6572 - 6578
  • 27
  • [ 110-85-0 ]
  • [ 288-32-4 ]
  • [ 290-37-9 ]
  • [ 616-47-7 ]
  • [ 109-08-0 ]
  • [ 13925-00-3 ]
  • [ 693-98-1 ]
Reference: [1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 7.1, p. 1340 - 1345[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 7, p. 1483 - 1488
  • 28
  • [ 288-32-4 ]
  • [ 15813-09-9 ]
YieldReaction ConditionsOperation in experiment
99% With iodine; potassium iodide; sodium hydroxide In water at 20℃; for 3 h; A mixture of KI (29.3 g,176.0 mmol) and I2 (22.4 g, 88.0 mmol) inwater (60 mL) was addedto a solution of 1H-imidazole (3.0 g, 44.1 mmol) in 2 M NaOH(10.6 g, 264.5 mmol). The mixture was stirred at 20 C for 3 h andthen neutralized with 6 M HCl (pH 7). The resulting solid wascollected by filtration, recrystallization from ethanol to give 2 as agrey solid (14.0 g, 99.0percent). Mp 166e168 C. 1H NMR (300 MHz,DMSO-d6) d(ppm) 12.75 (br s, 1H), 7.8 (br s, 1H). MS (EI) m/z 320.8[MH].
99% With iodine; potassium iodide; sodium hydroxide In water at 20℃; for 3 h; 1H-imidazole (3 g, 44.1 mmol) was dissolved in 2M NaOH (10.6 g, 265.0 mmol)KI (29.3 g, 176.0 mmol)And I2 (22.4 g, 88.0 mmol) in 100 mL of water,Reaction at room temperature for 3 hours,Dropping 6M dilute hydrochloric acid to adjust the pH of the reaction solution to neutral,Produce a lot of solid,Suction filtration,Ethanol recrystallization,Obtained as an off-white solid,Yield 99.0percent
85%
Stage #1: With iodine; potassium iodide; sodium hydroxide In water at 20℃; for 48 h;
Stage #2: With hydrogenchloride In water
Step a: 4,5-diiodo-lH-imidazole[0547] A mixture of KI (149.4 g, 0.91 mol) and I2 (151.0 g, 0.59 mol) in water (500 mL) was added to a mixture of lH-imidazole (20.0 g, 0.29 mol) in 2N NaOH (1.0 L). The reaction mixture was stirred at room temperature for 2 d. The mixture was neutralized with 6N HC1 (pH=7) and the resulting solid was collected by filtration, washed with water and dried under vacuum to give 80.0 g of the title compound as a grey solid (85percent> yield).
80% With iodine; potassium iodide; sodium hydroxide In water at 25℃; for 10 h; Inert atmosphere This compound was prepared following a literature procedure.22 To a solution of imidazole 19 (1.11 g, 16 mmol) in NaOH (4 M, 60 mL) wasadded a solution of KI (13.3 g, 80 mmol) and I2 (8.88 g, 35 mmol) inH2O (50 mL) dropwise. The resulting mixture stirred at RT for 10 h.After completion monitored by TLC, the mixture was reduced to pH=8with acetic acid, and the resulting white precipitate was filtered andwashed with cold water. The remaining solid was air dried to afford theproduct 20 as a white creamy solid (4.1 g, 80percent). m.p. 188–190 °C; Rf(hexane/ethyl acetate 1:1): 0.15; 1H NMR (300 MHz, d6-DMSO): δ 7.77(1H, s); 13C NMR (75 MHz, d6-DMSO): δ 141.8, 86.9. The spectroscopicdata matched that reported in the literature.43
54% With iodine; acetic acid In sodium hydroxide; aqueous potassium iodide; ethanol Preparation 70
4,5-Diiodo-1H-imidazole
A solution of iodine (22.5 g, 88 mmol) in 20percent aqueous potassium iodide (150 ml) was added dropwise to a stirred solution of imidazole (3.4 g, 49 mmol) in aqueous sodium hydroxide solution (1M, 300 ml) at room temperature.
After stirring for 16 h, acetic acid was added to neutralise the reaction mixture.
The white precipitate formed was filtered off and washed with water before dissolving in ethanol and concentrating in vacuo to give the title compound (7.7 g, 54percent).
NMR (d6-DMSO, selected data for the free base: 7.8 (br, 1H), 12.75 (br, 1H).
MS (TSP): M/Z (MH+) 320.8; C3H2129I2N2+H requires 320.8.
41% With iodine; potassium iodide; sodium hydroxide In water at 20℃; Inert atmosphere Imidazole (8.4 g, 0.12 mol) and sodium hydroxide (14 g, 0.35 mol) are dissolved in 0.4 Lwater in an 1 L round bottom flask. Potassium iodide (80 g, 0.48 mol) and iodine (55 g, 0.22mol) are dissolved in 0.2 L water. This solution is added dropwise to the imidazole/sodium hydroxide mixture at room temperature. A white solid precipitates and the solution is stirred over night. Acetic acid and sodium thiosulfate are added until the solution is clear and neutral.The white solid is filtered and washed with water. Recrystallization from ethanol leads to finewhite crystals. (16 g, 41 percent).

Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 140, p. 293 - 304
[2] Patent: CN107501272, 2017, A, . Location in patent: Paragraph 0085; 0086; 0087; 0088
[3] Synlett, 2004, # 7, p. 1306 - 1308
[4] Advanced Synthesis and Catalysis, 2013, vol. 355, # 2-3, p. 499 - 507
[5] Advanced Synthesis and Catalysis, 2013, vol. 355, # 16, p. 3231 - 3243
[6] Synthesis, 1994, # 7, p. 681 - 682
[7] Journal of Organic Chemistry, 2005, vol. 70, # 5, p. 1612 - 1619
[8] Tetrahedron Letters, 2001, vol. 42, # 11, p. 2089 - 2092
[9] Chemical Communications, 2006, # 20, p. 2170 - 2172
[10] Tetrahedron Asymmetry, 2004, vol. 15, # 13, p. 2021 - 2028
[11] Tetrahedron, 2008, vol. 64, # 25, p. 5904 - 5914
[12] Patent: WO2012/178015, 2012, A2, . Location in patent: Page/Page column 140
[13] European Journal of Organic Chemistry, 2015, vol. 2015, # 21, p. 4658 - 4666
[14] Angewandte Chemie - International Edition, 2015, vol. 54, # 46, p. 13811 - 13815
[15] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 22, p. 5852 - 5869
[16] Medicinal Chemistry Research, 2011, vol. 20, # 4, p. 401 - 407
[17] European Journal of Organic Chemistry, 2014, vol. 2014, # 26, p. 5681 - 5685
[18] Tetrahedron, 1997, vol. 53, # 42, p. 14481 - 14496
[19] Patent: US6313312, 2001, B1,
[20] Chinese Chemical Letters, 2011, vol. 22, # 12, p. 1427 - 1430
[21] Journal of Organometallic Chemistry, 2012, vol. 697, # 1, p. 33 - 40
[22] Journal of the Chemical Society, 1955, p. 1238
[23] European Journal of Inorganic Chemistry, 2012, # 19, p. 3140 - 3146
[24] Patent: CN106674121, 2017, A, . Location in patent: Paragraph 0030; 0033
  • 29
  • [ 124-68-5 ]
  • [ 530-62-1 ]
  • [ 288-32-4 ]
  • [ 26654-39-7 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 3, p. 481 - 486
  • 30
  • [ 288-32-4 ]
  • [ 22047-25-2 ]
  • [ 20671-53-8 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1982, vol. 18, p. 6 - 10[2] Zhurnal Organicheskoi Khimii, 1982, vol. 18, # 1, p. 9 - 14
  • 31
  • [ 288-32-4 ]
  • [ 107-07-3 ]
  • [ 1615-14-1 ]
Reference: [1] Russian Chemical Bulletin, 2009, vol. 58, # 5, p. 936 - 939
[2] Tetrahedron Letters, 2001, vol. 42, # 35, p. 6097 - 6100
[3] Advanced Synthesis and Catalysis, 2012, vol. 354, # 1, p. 217 - 222
[4] Journal fuer Praktische Chemie (Leipzig), 1957, vol. <4> 4, p. 169,173
[5] Patent: US5965527, 1999, A,
[6] Chemistry - An Asian Journal, 2013, vol. 8, # 8, p. 1910 - 1921
[7] Tetrahedron, 2016, vol. 72, # 10, p. 1285 - 1292
  • 32
  • [ 288-32-4 ]
  • [ 96-49-1 ]
  • [ 1615-14-1 ]
Reference: [1] Patent: US6294532, 2001, B1,
[2] Journal of Medicinal Chemistry, 1993, vol. 36, # 25, p. 4052 - 4060
[3] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 2, p. 215 - 219
  • 33
  • [ 288-32-4 ]
  • [ 86864-60-0 ]
  • [ 1615-14-1 ]
YieldReaction ConditionsOperation in experiment
35% With tetrabutyl ammonium fluoride; potassium carbonate In tetrahydrofuran; ethyl acetate; N,N-dimethyl-formamide Preparatory Example 56
1-(2-Hydroxyethyl)imidazole STR299
3.56 g of 2-bromoethyl t-butyldimethylsilyl ether and 1.97 g of imidazole were dissolved in 70 ml of N,N-dimethylformamide, to which 4 g of potassium carbonate were added, followed by agitation at 90° C. for 2 hours and 40 minutes.
After removal of the solvent by distillation, ethyl acetate was added, followed by washing with water and drying with anhydrous magnesium sulfate.
This was filtered and, after removal of the solvent by distillation, m the resultant residue was dissolved in tetrahydrofuran, to which 12.6 ml of tetrabutylammonium fluoride (1M tetrahydrofuran solution), followed by agitation at room temperature.
After completion of the reaction, the solvent was distilled of and the resultant residue was subjected to silica gel column chromatography (developing solvent: dichloromethane) to obtain 0.59 g of the caption compound (yield 35percent).
1 H-NMR(90 MHz, CDCl3) δ:3.28(bs,1H), 3.6-4.2(m,4H), 6.84(bs,1H), 7.28(bs,1H)
Reference: [1] Patent: US5221671, 1993, A,
  • 34
  • [ 75-21-8 ]
  • [ 288-32-4 ]
  • [ 1615-14-1 ]
Reference: [1] Patent: DE854955, 1951, ,
[2] Medicinal Chemistry Research, 1997, vol. 7, # 2, p. 123 - 136
[3] Journal of Polymer Science, Part A: Polymer Chemistry, 2012, vol. 50, # 18, p. 3728 - 3735
  • 35
  • [ 288-32-4 ]
  • [ 107-07-3 ]
  • [ 1615-14-1 ]
  • [ 118870-95-4 ]
Reference: [1] Russian Chemical Bulletin, 2009, vol. 58, # 5, p. 936 - 939
  • 36
  • [ 50-00-0 ]
  • [ 131543-46-9 ]
  • [ 7664-41-7 ]
  • [ 141-43-5 ]
  • [ 288-32-4 ]
  • [ 1615-14-1 ]
Reference: [1] Patent: JP2005/82551, 2005, A, . Location in patent: Page 4
  • 37
  • [ 50-00-0 ]
  • [ 131543-46-9 ]
  • [ 141-43-5 ]
  • [ 288-32-4 ]
  • [ 1615-14-1 ]
Reference: [1] Patent: JP2005/82551, 2005, A, . Location in patent: Page/Page column 5
  • 38
  • [ 288-32-4 ]
  • [ 75-44-5 ]
  • [ 1193-24-4 ]
  • [ 1193-21-1 ]
Reference: [1] Patent: US5750694, 1998, A,
  • 39
  • [ 288-32-4 ]
  • [ 96-34-4 ]
  • [ 22884-10-2 ]
Reference: [1] Patent: US2010/130746, 2010, A1, . Location in patent: Page/Page column 5
  • 40
  • [ 288-32-4 ]
  • [ 96-34-4 ]
  • [ 22884-10-2 ]
Reference: [1] Patent: WO2005/63717, 2005, A1, . Location in patent: Page/Page column 5
[2] Patent: EP2192126, 2010, A1, . Location in patent: Page/Page column 7
  • 41
  • [ 288-32-4 ]
  • [ 79-08-3 ]
  • [ 22884-10-2 ]
Reference: [1] Patent: US5886177, 1999, A,
  • 42
  • [ 288-32-4 ]
  • [ 2034-22-2 ]
YieldReaction ConditionsOperation in experiment
92% at 40℃; for 3 h; To the three-necked flask was added imidazole (29.24 g, 0.43 mol)Sodium acetate (317.34 g, 3.87 mol)And acetic acid (150 ml),Was dissolved in acetic acid (100 ml) of bromine (65 ml, 1.28 mol)Through the constant pressure separation funnel at room temperature slowly dripping,Control the temperature does not exceed 40 , stirring at room temperature for 3h,The reaction solution was poured into 1.5 L of water, the solid was precipitated,The solid was washed with water,Dried to give compound 5 (120 g, yield 92percent),
Reference: [1] Patent: CN106256830, 2016, A, . Location in patent: Paragraph 0044; 0049; 0050; 0051
[2] Tetrahedron Letters, 2015, vol. 56, # 41, p. 5646 - 5650
[3] Tetrahedron Letters, 1998, vol. 39, # 44, p. 8163 - 8166
[4] Tetrahedron, 1999, vol. 55, # 4, p. 935 - 942
[5] Journal of Organic Chemistry, 1992, vol. 57, # 9, p. 2740 - 2741
[6] Synthetic Communications, 2007, vol. 37, # 6, p. 933 - 939
[7] Chemische Berichte, 1877, vol. 10, p. 1370
[8] Justus Liebigs Annalen der Chemie, 1882, vol. 214, p. 297
[9] Journal of the Chemical Society, 1922, vol. 121, p. 952
[10] Canadian Journal of Chemistry, 1981, vol. 59, p. 339 - 343
[11] Tetrahedron Letters, 2006, vol. 47, # 12, p. 1949 - 1951
[12] Patent: WO2011/150156, 2011, A2, . Location in patent: Page/Page column 103
[13] Journal of the Chinese Chemical Society, 2017, vol. 64, # 1, p. 43 - 54
  • 43
  • [ 288-32-4 ]
  • [ 2302-30-9 ]
  • [ 2034-22-2 ]
  • [ 2302-25-2 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1989, p. 95 - 99
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1989, p. 95 - 99
  • 44
  • [ 288-32-4 ]
  • [ 2034-22-2 ]
  • [ 2302-25-2 ]
Reference: [1] Tetrahedron Letters, 2008, vol. 49, # 1, p. 189 - 194
[2] Tetrahedron Letters, 2015, vol. 56, # 25, p. 3855 - 3857
  • 45
  • [ 288-32-4 ]
  • [ 2302-30-9 ]
  • [ 2034-22-2 ]
Reference: [1] Journal of the Chemical Society, 1922, vol. 121, p. 952
[2] Advanced Synthesis and Catalysis, 2013, vol. 355, # 2-3, p. 499 - 507
  • 46
  • [ 288-32-4 ]
  • [ 67-66-3 ]
  • [ 7726-95-6 ]
  • [ 2302-30-9 ]
  • [ 2034-22-2 ]
Reference: [1] Journal of the Chemical Society, 1922, vol. 121, p. 952
  • 47
  • [ 288-32-4 ]
  • [ 7732-18-5 ]
  • [ 7726-95-6 ]
  • [ 2034-22-2 ]
Reference: [1] Chemische Berichte, 1877, vol. 10, p. 1370
[2] Justus Liebigs Annalen der Chemie, 1882, vol. 214, p. 297
  • 48
  • [ 288-32-4 ]
  • [ 541-41-3 ]
  • [ 19213-72-0 ]
YieldReaction ConditionsOperation in experiment
17% at 0 - 20℃; for 5 h; Imidazole is added to the reactor (3.75g, 55 . 0mmol), thf (50.0 ml), the reaction is cooled to 0 °C, the ethyl chloroformate (2.58 ml, 27 . 0mmol) dropwise wherein the 0 °C stirring 1h rear, moving to the room temperature, reaction 4h. Filtering the reaction liquid, turns on lathe does, its re-dissolved in 100 ml diethyl ether, washed with water, drying by anhydrous magnesium sulphate the organic phase, the turns on lathe does colorless liquid, i.e. compound 3 (1.28g, 17percent yield)
17% at 0 - 20℃; for 5 h; Imidazole is added to the reactor (3.75g, 55 . 0mmol), thf (50.0 ml), the reaction is cooled to 0 °C, the ethyl chloroformate (2.58 ml, 27 . 0mmol) dropwise wherein the 0 °C stirring 1h rear, moving to the room temperature, reaction 4h. Filtering the reaction liquid, turns on lathe does, its re-dissolved in 100 ml diethyl ether, washed with water, drying by anhydrous magnesium sulphate the organic phase, the turns on lathe does colorless liquid, i.e. compound 3 (1.28g, 17percent yield);
Reference: [1] Angewandte Chemie - International Edition, 2012, vol. 51, # 33, p. 8304 - 8308
[2] Organic Letters, 2010, vol. 12, # 20, p. 4572 - 4575
[3] Patent: CN105566347, 2016, A, . Location in patent: Paragraph 0033; 0034; 0035
[4] Patent: CN105503932, 2016, A, . Location in patent: Paragraph 0045; 0046; 0047
[5] Justus Liebigs Annalen der Chemie, 1957, vol. 609, p. 75,82
[6] Tetrahedron Letters, 1982, vol. 23, # 20, p. 2113 - 2116
[7] Journal of Organic Chemistry, 1982, vol. 47, # 21, p. 4040 - 4045
[8] Tetrahedron, 2011, vol. 67, # 46, p. 8851 - 8859
[9] Tetrahedron Letters, 2012, vol. 53, # 9, p. 1060 - 1062
  • 49
  • [ 288-32-4 ]
  • [ 63436-79-3 ]
  • [ 19213-72-0 ]
Reference: [1] Journal of Organic Chemistry, 1980, vol. 45, # 22, p. 4519 - 4522
  • 50
  • [ 288-32-4 ]
  • [ 74877-64-8 ]
  • [ 19213-72-0 ]
Reference: [1] Journal of Organic Chemistry, 1980, vol. 45, # 22, p. 4519 - 4522
  • 51
  • [ 64-17-5 ]
  • [ 530-62-1 ]
  • [ 288-32-4 ]
  • [ 19213-72-0 ]
Reference: [1] Synthetic Communications, 2000, vol. 30, # 1, p. 23 - 30
[2] Russian Journal of Applied Chemistry, 2012, vol. 85, # 3, p. 456 - 459
  • 52
  • [ 288-32-4 ]
  • [ 111-83-1 ]
  • [ 21252-69-7 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With sodium hydroxide In dimethyl sulfoxide at 90℃; for 2 h;
Stage #2: at 20 - 65℃; for 19 h;
A mixture of imidazole (1 .36 g, 20.0 mmol) and sodium hydroxide (0.80 g, 20.0 mmol) in DMSO was heated to 90 °C for 2 h, and then cooled to room temperature. A solution of 1 -bromooctane (3.46 g, 19.0 mmol) in DMSO was added dropwise to the mixture. After stirring at room temperature for 3 h, the mixture was heated up slowly to 65 °C for 16 h with constant stirring. The solution obtained was mixed with water and the product was extracted 4 times with diethyl ether. The diethyl ether phases were combined and dried with sodium sulfate. Diethyl ether was removed under vacuum and the intermediate (9) was obtained as yellow liquid (2.89 g, 89 percent). 1 H NMR (DMSO-d6): δ 7.61 (s, 2H), 7.15 (s, 1 H), 6.87 (s, 1 H), 3.93 (t, 2H), 1 .68 (m, 2H), 1 .25 (m, 10H), 0.85 (t, 3H).
87.7% With sodium hydroxide In dimethyl sulfoxide at 20 - 25℃; Inert atmosphere To a flask equipped with a stirrer, Add the thermometer to the three necked flask 0 · 440 g (11.0 mmol) of NaOH, 0.714 g (10.5 mmol) of imidazole and 10 mL of dimethylsulfoxide (DMSO) were stirred under nitrogen at 20 ° C to 25 ° C to give a clear solution. To this was added dropwise 1.93 g (10.0 mmol)Bromo octane, reaction 4 ~ 6 h, the reaction into 10 mL of water extracted with chloroform 3 X 10 mL, and then washed with water chloroform layer 4 ~ 5 times, and then dried with anhydrous MgS04, filtered to get the filtrate, Removal of chloroform yielded a pale yellow liquid, 1.58 g of N-octylimidazole, in 87.7percent yield.
85% With sodium hydroxide In tetrahydrofuran; waterReflux General procedure: A solution of imidazole 3 (30 mmol) in THF (60 mL) was treated with NaOH (25 mL, 40percent aq) and the alkyl bromide (30 mmol), and the reaction was refluxed overnight. The solvent was evaporated and the crude reaction mixture was extracted with CH2Cl2 against water. The organic layer was washed with water, dried over MgSO4 and concentrated. The final product was distilled under vacuum (~5 mbar) to provide 4 as yellow oily liquid in 80-85percent yield.
82.3%
Stage #1: With potassium hydroxide In dimethyl sulfoxide at 20℃; for 2 h;
Stage #2: for 4 h;
General procedure: A mixture of imidazole (30 mmol, 2.04 g), potassiumhydroxide (30 mmol, 1.68 g) and dimethyl sulfoxide(10 mL) was stirred for 2 h at room temperature. Afterthat, alkyl bromide (25.0 mmol of 1-bromohexane, 1-bromooctane,1-bromodecane, 1-bromododecane, 1-bromotetradecane,1-bromohexadecane, or 1-bromooctadecane)was dropped in slowly and the mixture was stirred for anadditional 4 h. Upon completion, water (30 mL) was addedto the resulting mixture followed by extraction with chloroform(5 x 30 mL). The combined organic layer wasdried over anhydrous magnesium sulfate and the filtratewas concentrated under reduced pressure. The residue wassubjected to flash chromatography with ethyl acetate aseluent to give N-alkyl imidazole. The respective yields ofN-hexyl imidazole, N-octyl imidazole, N-decyl imidazole,N-dodecyl imidazole, N-tetradecyl imidazole, N-hexadecylimidazole and N-octadecyl imidazole are 84.6, 82.3, 81.2,80.5, 80.4, 79.8 and 79.6 percent.
60%
Stage #1: With sodium hydride In tetrahydrofuran for 0.75 h; Inert atmosphere; Cooling with ice
Stage #2: at 20℃; for 24 h; Inert atmosphere
Imidazole (3.41 g, 50 mmol) and NaH (1.34 g, 54 mmol) were dissolved in THF (10 mL) under N2 in an ice bath for 45 min, followed by addition of 1-bromooctane (9.65 g, 50 mmol). The solution was stirred for 24 h at room temperature and then concentrated under reduced pressure after filtration.The residue was purified by flash chromatography (SiO2; petroleum ether/ethyl acetate5 : 1 as eluent) to give 1 as alight yellow oil (5.97 g, 60 percent). δH (CDCl3, 400 MHz) 7.42 (1H, s), 7.01 (1H, s), 6.87 (1H, s), 3.89 (2H, t, J 8.0), 1.76–1.73 (2H, m), 1.31–1.25 (10H, m), 0.87 (3H, t, J 7.2). δC (CDCl3, 100 MHz) 136.2, 128.4, 118.1, 46.4, 31.2, 30.6, 28.6, 28.5,26.0, 22.1, 13.6. m/z (ESI) 181 ([M + H]+). m/z 181.1708. HRMS (ESI) Anal. Calc. for C11H21N2 ([M + H]+) 181.1705.

Reference: [1] Synthetic Communications, 1993, vol. 23, # 13, p. 1783 - 1786
[2] Journal of Physical Chemistry B, 2013, vol. 117, # 48, p. 15014 - 15022
[3] ChemMedChem, 2017, vol. 12, # 11, p. 835 - 840
[4] Patent: WO2018/56902, 2018, A1, . Location in patent: Page/Page column 32
[5] Patent: CN103951702, 2016, B, . Location in patent: Paragraph 0039; 0040
[6] Journal of Materials Chemistry, 2011, vol. 21, # 33, p. 12280 - 12287
[7] Carbohydrate Research, 2015, vol. 412, p. 28 - 33
[8] New Journal of Chemistry, 2007, vol. 31, # 6, p. 879 - 892
[9] Journal of Surfactants and Detergents, 2016, vol. 19, # 4, p. 681 - 691
[10] Journal of Molecular Structure, 2004, vol. 697, # 1-3, p. 131 - 135
[11] Applied Organometallic Chemistry, 2017, vol. 31, # 5,
[12] Applied Organometallic Chemistry, 2018, vol. 32, # 2,
[13] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 17, p. 2863 - 2865
[14] Inorganic Chemistry, 2017, vol. 56, # 13, p. 7558 - 7565
[15] Australian Journal of Chemistry, 2015, vol. 68, # 5, p. 825 - 829
[16] Chemistry - A European Journal, 2018, vol. 24, # 50, p. 13322 - 13335
[17] Macromolecules, 2013, vol. 46, # 12, p. 4799 - 4804
[18] Journal of Organometallic Chemistry, 2000, vol. 598, # 2, p. 409 - 416
[19] Chemistry Letters, 2005, vol. 34, # 3, p. 442 - 443
[20] Journal of Chemical and Engineering Data, 2006, vol. 51, # 4, p. 1274 - 1279
[21] Dyes and Pigments, 2013, vol. 96, # 1, p. 16 - 24,9
[22] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 4, p. 423 - 427
[23] Journal of the Chinese Chemical Society, 2013, vol. 60, # 7, p. 745 - 754
[24] Chemical Biology and Drug Design, 2014, vol. 83, # 3, p. 278 - 288
[25] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 6, p. 1675 - 1680
[26] RSC Advances, 2015, vol. 5, # 4, p. 2869 - 2881
[27] RSC Advances, 2015, vol. 5, # 71, p. 57968 - 57974
[28] Journal of Molecular Catalysis A: Chemical, 2016, vol. 411, p. 34 - 39
[29] RSC Advances, 2015, vol. 5, # 28, p. 21865 - 21876
[30] Patent: US2018/255777, 2018, A1, . Location in patent: Paragraph 0047; 0048; 0065
[31] Dalton Transactions, 2018, vol. 47, # 40, p. 14241 - 14253
  • 53
  • [ 288-32-4 ]
  • [ 629-04-9 ]
  • [ 21252-69-7 ]
YieldReaction ConditionsOperation in experiment
80% With potassium carbonate In acetoneReflux General procedure: Briefly, a mixture of imidazole (100 mmol), alkyl bromide (100 mmol) and K2CO3 (200 mmol) inacetone (200 mL) was refluxed overnight. Upon filtration and solvent removal, the remaining residuewas subjected to flash chromatography with ethyl acetate to produce >90percent yield.
Reference: [1] Molecules, 2018, vol. 23, # 9,
  • 54
  • [ 288-32-4 ]
  • [ 629-27-6 ]
  • [ 21252-69-7 ]
Reference: [1] Russian Journal of Applied Chemistry, 1996, vol. 69, # 12, p. 1841 - 1848
[2] Journal of the American Chemical Society, 2008, vol. 130, # 38, p. 12590 - 12591
[3] Journal of Materials Chemistry A, 2013, vol. 1, # 22, p. 6572 - 6578
[4] RSC Advances, 2018, vol. 8, # 26, p. 14623 - 14632
  • 55
  • [ 288-32-4 ]
  • [ 111-85-3 ]
  • [ 21252-69-7 ]
Reference: [1] European Journal of Medicinal Chemistry, 1990, vol. 25, # 5, p. 449 - 454
  • 56
  • [ 131543-46-9 ]
  • [ 288-32-4 ]
  • [ 492-98-8 ]
Reference: [1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1875, vol. 7, p. 254
[2] Chemische Berichte, 1876, vol. 9, p. 1544[3] Chemische Berichte, 1877, vol. 10, p. 1366
[4] Justus Liebigs Annalen der Chemie, 1858, vol. 107, p. 199
  • 57
  • [ 288-32-4 ]
  • [ 80930-46-7 ]
  • [ 5751-52-0 ]
  • [ 80930-35-4 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1984, vol. 21, p. 311 - 315
  • 58
  • [ 288-32-4 ]
  • [ 570-22-9 ]
Reference: [1] Patent: US4550176, 1985, A,
  • 59
  • [ 288-32-4 ]
  • [ 24067-17-2 ]
  • [ 2301-25-9 ]
YieldReaction ConditionsOperation in experiment
76% With copper(I) sulfide; N,N,N,N,-tetramethylethylenediamine In methanol at 20℃; for 48 h; General procedure: A 10mL round bottom flask was charged with a magnetic stirring bar, benzimidazole 1 (59mg, 0.5mmol), boronic acid 2 (1.0mmol), Cu2S (4mg, 0.025mmol), and MeOH (2mL), followed with the addition of TMEDA (0.075mL, 0.5mmol). The flask was sealed with a septum, through which was inserted 18-gauche needle. This setup allowed air to go into the reaction and avoid contamination of a mixture. The reaction mixture was stirred from 400 to 600rpm for appropriate time and extracted with EtOAc (2×15mL). Combined organic layers were washed with saturated aqueous solution of ethylenediaminetetraacetic acid disodium salt (15mL), and then dried over anhydrous Na2SO4. Volatiles were removed under reduced pressure and the residue was purified by column chromatography (silica gel, hexanes – EtOAc) to yield the title product, which was characterized by 1H NMR, 13C NMR, HRMS, and melting point (if solid).
75% With 2-(4-methoxybenzylidene)-N-phenylhydrazinecarbothioamide; copper(II) acetate monohydrate; potassium carbonate In ethanol at 20℃; for 20 h; General procedure: A mixture of imidazole (1 mmol), phenylboronic acid (2 mmol), K2CO3 (2 mmol), Cu(CH3COO)2H2O (1 mol percent, 1.99 mg) and L1 (1 mol percent, 5.7 mg) in ethanol (5 mL) was stirred at room temperature in a 50 mL oven dried round bottomed flask. After the completion of the reaction (as monitored by TLC), conventional workup of the reaction mixture was done with ethyl acetate (3 × 15 mL) and water (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and the solvent was evaporated in a rotary evaporator under reduced pressure to get the crude product. The crude product was purified by column chromatography on silica gel (DCM: Methanol = 9:1) to afford the pure product.
72% With copper(I) 3-metthylsalicylate; potassium carbonate In methanol at 65℃; for 3 h; General procedure: A dry flask was charged with the nitrogen containing heterocycles (1 mmol), aryl boronic acids (2.2 mmol), potassium carbonate (2 mmol) andCuMeSal (0.015 mmol)then anhydrous methanol (10 ml) was added. The reaction mixture was stirred at 65 oC, open to air, for 3 h (5 h in case of indole and benzimidazole), cooled to room temperature, filtered, and the precipitate was washed with methanol (2 ml), the filtrate was concentrated under vacuum, then stirred with ice water (30 ml) and extracted with ethyl acetate (3 × 50 ml), dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by chromatography or recrystallization as indicated with each compound.
63% With [CuI2(3,2'-pypzpym)]; oxygen In water; acetonitrile at 60℃; for 24 h; Green chemistry General procedure: To a solution of 1 (0.02 mmol) in H2O/MeCN (v/v=2/1, 4 mL) was added 1H-imidazole (1.0 mmol) and arylboronic acid (2 mmol)under O2 atmosphere. The mixture was stirred at 60 °C for 24 h. After cooling to ambient temperature, the mixture was partitioned between water and CH2Cl2. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel.

Reference: [1] ChemCatChem, 2016, vol. 8, # 18, p. 2953 - 2960
[2] Chemistry Letters, 2010, vol. 39, # 7, p. 764 - 765
[3] Tetrahedron, 2018, vol. 74, # 5, p. 606 - 617
[4] Bulletin of the Korean Chemical Society, 2017, vol. 38, # 10, p. 1203 - 1208
[5] Synthetic Communications, 2015, vol. 45, # 2, p. 245 - 252
[6] Tetrahedron, 2016, vol. 72, # 44, p. 7014 - 7020
  • 60
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  • [ 100-00-5 ]
  • [ 2301-25-9 ]
YieldReaction ConditionsOperation in experiment
90% With cerium(IV) oxide; potassium hydroxide In dimethyl sulfoxide at 110℃; for 8 h; Air atmosphere General procedure: In a 25 mL round bottomed flask was taken a mixture of phenol/amine/thiophenol (1.2 mmol, 0.112 g), 4-nitrochlorobenzene (1 mmol, 0.157 g), base KOH (1.2 mmol, 0.08 g) and 1 mL DMSO was added. Further 2.5 mol percent catalyst (4.5 mg) was added to the reaction mixture. The reaction mixture was heated to 110 °C for appropriate time. Reaction is monitored on TLC. After completion of the reaction the catalyst was separated by centrifugation and subsequently washed with dichloromethane. The reaction mixture was diluted with water and the product was extracted by dichoromethane (3 .x. 10 cm3). The organic layer was dried over anhydrous sodium sulfate and was evaporated under reduced pressure to give the product. The product was purified by column chromatography by using pet ether and ethyl acetate solvent system. The purified product was then confirmed by its spectral analysis after analyzing by IR, 1H NMR, and mass spectra.
89% With potassium hydroxide In dimethyl sulfoxide at 100℃; for 4 h; General procedure: A mixture of aryl halide (1.0 mmol), Het-NH (1.2mmol) or amine (4 mmol), KOH (2 mmol), Cu2O/nano-CuFe2O4 magnetic composite (0.010 g) and anhydrous DMSO (2 mL) was stirred at 100 °C. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature and with diluted ethyl acetate and the catalyst was separated by an external magnet from the mixture, washed with acetone, dried in an oven at 80 °C for 3 h and re-used for a consecutive run under the same reaction conditions. The combined ethyl acetate layer was washed with water, dried over anhydrous MgSO4, The residue was purified by recrystallization or short column chromatography on silica gel to afford the target products in excellent yield.
88.3% With copper(II) 29H,31H-tetrabenzo[b,g,l,q]porphine; potassium hydroxide In dimethyl sulfoxide at 90℃; for 24 h; General procedure: In a typical experiment, imidazole (1.2 mmol), aryl halide (1.0 mmol), catalyst, and base (2.0 mmol) were added to a hydrothermal reactor (20 mL). The mixture was heated to the desired temperature with stirring. After the completion of the reaction and cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3 × 15mL). The combined organic extracts were dried with anhydrous Na2SO4 and the obtained product was purified by column chromatography on silica gel using dichloromethane: methanol (100:1, v/v) as the eluent.
84% With potassium hydroxide In dimethyl sulfoxide at 100℃; for 3.5 h; General procedure: A mixture of aryl iodide (1.0 mmol), Het-NH (1.2 mmol), KOH (2 mmol), nanomagnetic Fe3O4-TiO2/Cu2O (0.010 g equal to 1.4 molpercent Cu2O) and anhydrous DMSO (2 mL) was stirred at 100 °C. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature and diluted by ethyl acetate and the catalyst was separated by an external magnet from the mixture, washed with acetone, dried in an oven at 80 °C for 3 h and re-used for a consecutive run under the same reaction conditions. The combined ethyl acetate layer was washed with water and dried over anhydrous MgSO4. The residue was purified by recrystallization or short column chromatography on silica gel to afford the target products in excellent yield.
79% With 2,2'-biimidazole; copper(II) acetate monohydrate; caesium carbonate In dimethyl sulfoxide at 80℃; for 48 h; (1) will p-nitrochlorobenzene 0.158g (1.0mmol), imidazole 0.069g (1.0mmol), Cu (OAc)2·H2O 0.030g (0.15mmol), 2,2- biimidazole 0.022g (0.15mmol), cesium carbonate 0.652g (2mmol), DMSO (2mL) was added the reaction tube with a piston, was heated to 80 deg.] C with stirring for 48 hours reaction.(2) TLC until the reaction was complete the reaction was followed ends.After the reaction was cooled to room temperature, diluted with water, extracted with ethyl acetate 3-4 was added, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product.After the end of (3) to obtain the crude product was purified by column chromatography (petroleum ether / ethyl acetate elution) to give the desired product 17 (79percent yield).
65% With Aliquat (at)366; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 24 h; General procedure: A mixture of p-nitro chlorobenzene 3 (25.0 g, 0.200 mol), appropriatesecondary amine 2a,b,e,f (0.300 mol) and anhydrous potassiumcarbonate (40.0 g) were mixed in DMF (300 mL), and thencatalytic drops of Aliquat 336 reagent were added. The mixturewas heated from 24 to 36 h at 100 C. The reaction mixture wasthen concentrated under vacuum, cooled and poured into ice waterand left aside overnight. The formed solid was filtered, washedwith water and crystallized from ethanol to yield titled compoundsIVa,b,e,f. 1-(4-Nitrophenyl)-1H-imidazole IVa
Yield 65percent as pale yellow solid, mp 203 °C, (as reported) [58,59].

Reference: [1] Synthesis, 2008, # 11, p. 1707 - 1716
[2] Synthetic Communications, 2008, vol. 38, # 4, p. 626 - 636
[3] Journal of Organic Chemistry, 2007, vol. 72, # 8, p. 2737 - 2743
[4] Chinese Journal of Chemistry, 2012, vol. 30, # 10, p. 2394 - 2400
[5] Journal of the American Chemical Society, 2007, vol. 129, # 45, p. 13879 - 13886
[6] Tetrahedron, 2008, vol. 64, # 19, p. 4254 - 4259
[7] RSC Advances, 2015, vol. 5, # 112, p. 92121 - 92127
[8] Chemical Communications, 2004, # 7, p. 778 - 779
[9] Journal of Organic Chemistry, 2007, vol. 72, # 22, p. 8535 - 8538
[10] Journal of Organic Chemistry, 2009, vol. 74, # 20, p. 7951 - 7954
[11] Synthetic Communications, 2012, vol. 42, # 2, p. 279 - 284
[12] Synthetic Communications, 2012, vol. 42, # 1, p. 114 - 121
[13] Synlett, 2006, # 14, p. 2195 - 2198
[14] Tetrahedron, 2008, vol. 64, # 10, p. 2471 - 2479
[15] Synlett, 2008, # 19, p. 3068 - 3072
[16] RSC Advances, 2016, vol. 6, # 93, p. 90154 - 90164
[17] Journal of the American Chemical Society, 2005, vol. 127, # 28, p. 9948 - 9949
[18] Synthesis, 2009, # 15, p. 2517 - 2522
[19] Tetrahedron Letters, 2011, vol. 52, # 41, p. 5220 - 5223
[20] RSC Advances, 2014, vol. 4, # 14, p. 7321 - 7329
[21] New Journal of Chemistry, 2016, vol. 40, # 2, p. 1454 - 1459
[22] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3151 - 3159
[23] Polyhedron, 2012, vol. 34, # 1, p. 143 - 148
[24] Chemistry Letters, 2016, vol. 45, # 2, p. 223 - 225
[25] Advanced Synthesis and Catalysis, 2007, vol. 349, # 11-12, p. 1938 - 1942
[26] Chinese Journal of Catalysis, 2014, vol. 35, # 11, p. 1818 - 1824
[27] Tetrahedron, 2008, vol. 64, # 7, p. 1383 - 1387
[28] Chinese Journal of Chemistry, 2012, vol. 30, # 10, p. 2389 - 2393,5
[29] Research on Chemical Intermediates, 2016, vol. 42, # 10, p. 7611 - 7624
[30] Synthesis, 2010, # 9, p. 1505 - 1511
[31] Journal of Organic Chemistry, 2006, vol. 71, # 21, p. 8324 - 8327
[32] Patent: CN104447557, 2017, B, . Location in patent: Paragraph 0141; 0142; 0143; 0144; 0145; 0146
[33] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
[34] Green Chemistry, 2012, vol. 14, # 5, p. 1268 - 1271
[35] Organic and Biomolecular Chemistry, 2015, vol. 13, # 13, p. 4101 - 4114
[36] Bioorganic Chemistry, 2014, vol. 57, p. 65 - 82
[37] Journal of Organic Chemistry, 2007, vol. 72, # 23, p. 8943 - 8946
[38] Chinese Journal of Chemistry, 2013, vol. 31, # 2, p. 267 - 270
[39] Journal of the Chinese Chemical Society, 2013, vol. 60, # 8, p. 1007 - 1013
[40] Chinese Chemical Letters, 2010, vol. 21, # 1, p. 51 - 54
[41] Monatshefte fur Chemie, 2003, vol. 134, # 1, p. 37 - 43
[42] European Journal of Organic Chemistry, 2011, # 24, p. 4523 - 4527
[43] Patent: US5965743, 1999, A,
[44] Patent: EP1612204, 2006, A1, . Location in patent: Page/Page column 19
[45] RSC Advances, 2014, vol. 4, # 29, p. 15122 - 15130
  • 61
  • [ 288-32-4 ]
  • [ 350-46-9 ]
  • [ 2301-25-9 ]
YieldReaction ConditionsOperation in experiment
80% With potassium carbonate In water; ethyl acetate; N,N-dimethyl-formamide 33.1 1-(4-nitrophenyl)-1H-imidazole:
9 g (64.5 mmoles) of potassium carbonate and 5 g (3.75 ml; 35.2 mmol) of 1-fluoro-4-nitrobenzene are added to a solution of 2 g of imidazole (29.4 mmol) in 14 ml of DMF.
The reaction mixture is agitated for 1.5 hours at 110° C. Ethyl acetate (50 ml) is added to the medium which is washed 3 times with 50 ml of water.
The organic phases are dried over magnesium sulphate and concentrated under vacuum.
4.4 g of product are thus obtained (yield=80percent) in the form of a clear oil and used without further purification in the following stages.
NMR 1H (CDCl3, 100 MHz, δ): 6.92 (t, 1H, Arom. H imidazole), 7.16 (s, 1H, Arom. H imidazole), 7.24-7.32-8.18-8.27 (4s, 4H, Arom. H), 7.59 (s, 1H, Arom. H imidazole).
80% With potassium carbonate In water; ethyl acetate; N,N-dimethyl-formamide 33.1 1-(4-nitrophenyl)-1H-imidazole
9 g (64.5 mmoles) of potassium carbonate and 5 g (3.75 ml; 35.2 mmol) of 1-fluoro-4-nitrobenzene are added to a solution of 2 g of imidazole (29.4 mmol) in 14 ml of DMF.
The reaction mixture is agitated for 1.5 hours at 110° C. Ethyl acetate (50 ml) is added to the medium which is washed 3 times with 50 ml of water.
The organic phases are dried over magnesium sulphate and concentrated under vacuum.
4.4 g of product are thus obtained (yield=80percent) in the form of a clear oil and used without further purification in the following stages.
NMR 1H (CDCl3, 100 MHz, δ): 6.92 (t, 1H, Arom. H imidazole), 7.16 (s, 1H, Arom. H imidazole), 7.24-7.32-8.18-8.27 (4s, 4H, Arom. H), 7.59 (s, 1H, Arom. H imidazole).
95% With NaH In water; ethyl acetate; N,N-dimethyl-formamide; Petroleum ether a
4-(Imidazol-1-yl)nitrobenzene
To a stirred solution of imidazole (34.1 g, 0.50 mol) in DMF (300 ml) under Ar, was added portionwise, over 23 minutes, 60percent NaH in oil (20.02 g, 0.50 mol).
The mixture was then stirred at room temperature for 18 minutes before adding dropwise, over 40 minutes, a solution of 1-fluoro-4-nitrobenzene (70.62 g, 0.50 mol) in DMF (60 ml).
The mixture was then stirred at room temperature overnight.
Water (600 ml) was then added and the solid was filtered off, washed with water, then stirred in boiling ethyl acetate (400 ml), allowed to cool and filtered, washing the solid with more ethyl acetate (50 ml), then petroleum ether (250 ml).
The filtrate, now containing more solid, was refiltered and washed with petroleum ether.
The combined solids were dried in a vacuum desiccator overnight to give 90.14 g (95percent) of the title compound as a yellow solid. δH (360 MHz, DMSO-d6) 7.19 (1H, t, J=1.1 Hz), 7.97-8.03 (3H, m), 8.38 (2H, d, J=9.2 Hz), 8.52 (1H, t).
95% With NaH In water; ethyl acetate; N,N-dimethyl-formamide; Petroleum ether a
4-(Imidazol-1-yl)nitrobenzene
To a stirred solution of imidazole (34.1 g, 0.50 mol) in DMF (300 ml) under Ar, was added portionwise, over 23 minutes, 60percent NaH in oil (20.02 g, 0.50 mol).
The mixture was then stirred at room temperature for 18 minutes before adding dropwise, over 40 minutes, a solution of 1-fluoro-4-nitrobenzene (70.62 g, 0.50 mol) in DMF (60 ml).
The mixture was then stirred at room temperature overnight.
Water (600 ml) was then added and the solid was filtered off, washed with water, then stirred in boiling ethyl acetate (400 ml), allowed to cool and filtered, washing the solid with more ethyl acetate (50 ml), then petroleum ether (250 ml).
The filtrate, now containing more solid, was refiltered and washed with petroleum ether.
The combined solids were dried in a vacuum desiccator overnight to give 90.14 g (95percent) of the title compound as a yellow solid. δH (360 MHz, DMSO-d6) 7.19 (1H, t, J=1.1 Hz), 7.97-8.03 (3H, m), 8.38 (2H, d, J=9.2 Hz), 8.52 (1H, t).
95% With NaH In water; ethyl acetate; N,N-dimethyl-formamide; Petroleum ether 1.
4-(Imidazol-1-yl)nitrobenzene.
To a stirred solution of imidazole (34.1 g, 0.50 mol) in DMF (300 ml) under Ar, was added portionwise, over 23 minutes, 60percent NaH in oil (20.02 g, 0.50 mol).
The mixture was then stirred at room temperature for 18 minutes before adding dropwise, over 40 minutes, a solution of 1-fluoro-4-nitrobenzene (70.62 g, 0.50 mol) in DMF (60 ml).
The mixture was then stirred at room temperature overnight.
Water (600 ml) was then added and the solid was filtered off, washed with water, then stirred in boiling ethyl acetate (400 ml), allowed to cool and filtered, washing the solid with more ethyl acetate (50 ml), then petroleum ether (250 ml).
The filtrate, now containing more solid, was refiltered and washed with petroleum ether.
The combined solids were dried in a vacuum dessicator overnight to give 90.14 g (95percent) of the title compound as a yellow solid. δH (360 MHz, DMSO-d6) 9 (1H, t, J=1.1 Hz), 7.97-8.03 (3H, m), 8.38 (2H, d, J=9.2 Hz), 8.52 (1H, t).
95% With NaH In water; ethyl acetate; N,N-dimethyl-formamide; Petroleum ether Step 4
4-(Imidazol-1-yl)nitrobenzene
To a stirred solution of imidazole (34.1 g, 0.50 mol) in DMF (300 ml) under Ar, was added portionwise, over 23 minutes, 60percent NaH in oil (20.02 g, 0.50 mol).
The mixture was then stirred at room temperature for 18 minutes before adding dropwise, over 40 minutes, a solution of 1-fluoro-4-nitrobenzene (70.62 g, 0.50 mol) in DMF (60 ml).
The mixture was then stirred at room temperature overnight.
Water (600 ml) was then added and the solid was filtered off, washed with water, then stirred in boiling ethyl acetate (400 ml), allowed to cool and filtered, washing the solid with more ethyl acetate (50 ml), then petroleum ether (250 ml).
The filtrate, now containing more solid, was refiltered and washed with petroleum ether.
The combined solids were dried in a vacuum desiccator overnight to give 90.14 g (95percent) of the title compound as a yellow solid. δH (360 MHz, DMSO-d6) 7.59 (1H, t, J=1.1 Hz), 7.97-8.03 (3H, m), 8.38 (2H, d, J=9.2 Hz), 8.52 (1H, t).

Reference: [1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1935 - 1946
[2] Journal of Medicinal Chemistry, 1999, vol. 42, # 24, p. 4981 - 5001
[3] Synthetic Communications, 2008, vol. 38, # 4, p. 626 - 636
[4] Australian Journal of Chemistry, 1993, vol. 46, # 4, p. 417 - 425
[5] Advanced Synthesis and Catalysis, 2007, vol. 349, # 11-12, p. 1938 - 1942
[6] Green Chemistry, 2016, vol. 18, # 20, p. 5580 - 5585
[7] Journal of the American Chemical Society, 2005, vol. 127, # 28, p. 9948 - 9949
[8] Inorganic Chemistry, 2011, vol. 50, # 5, p. 1889 - 1897
[9] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
[10] Patent: US2003/78420, 2003, A1,
[11] Patent: US6809088, 2004, B2,
[12] Patent: US6335445, 2002, B1, . Location in patent: Page column 84
[13] Synthetic Communications, 1993, vol. 23, # 14, p. 1947 - 1952
[14] Tetrahedron, 2007, vol. 63, # 37, p. 9163 - 9171
[15] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 11, p. 1437 - 1444
[16] Monatshefte fur Chemie, 2003, vol. 134, # 1, p. 37 - 43
[17] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1221 - 1227
[18] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 21, p. 5263 - 5267
[19] Patent: EP698024, 1997, B1,
[20] Patent: US5889008, 1999, A,
[21] Patent: US5981529, 1999, A,
[22] Patent: US5854268, 1998, A,
[23] Bulletin of the Chemical Society of Japan, 2011, vol. 84, # 2, p. 205 - 210
[24] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2012, vol. 51, # 5, p. 731 - 738
[25] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5505 - 5512
[26] Patent: US5532236, 1996, A,
[27] Patent: US6150391, 2000, A,
  • 62
  • [ 288-32-4 ]
  • [ 636-98-6 ]
  • [ 2301-25-9 ]
YieldReaction ConditionsOperation in experiment
100% With copper phthalocyanine; sodium hydroxide In dimethyl sulfoxide at 100℃; General procedure: In a 50mL RB, N−H heterocycles (1.0mmol), aryl halide (1mmol), Cu(II)Pc (0.01mmol), NaOH (1.5mmol) and DMSO (2mL) was added. This reaction mixture was stirred to a preheated oil bath at 100°C for 8–12h. After completion of the reaction, it was cooled to room temperature and 20mL ethyl acetate was added. It was filtered; solid catalyst was separated and washed with 2×5mL ethyl acetate. The washing and filtrate were combined and washed with water. Ethyl acetate was removed under reduced pressure and product was purified with column chromatography.
98% With caesium carbonate In dimethyl sulfoxide at 110℃; for 1 h; General procedure: A mixture of CuatCu2O NPs nanocomposite (5 molpercent ofCu), Cs2CO3(1.5 mmol), N-heterocycle (1.0 mmol), aryl halide(1.0 mmol), and DMSO (2 mL) under air was stirred for 1 h at 110 °C.After completion of the reaction as indicated by TLC, the heterogeneous mixture was cooled to room temperature and diluted with ethyl acetate (10 mL). The mixture was filtered through a pad of celite. The filtrate was concentrated and then residue was purified by column chromatography (SiO2, ethyl acetate and n-hexane) to yield pure product. The catalysts were recovered by simple filtration and washed extensively with acetone and deionized water and then drying in the air.
96% With potassium hydroxide In dimethyl sulfoxide at 100℃; for 1.5 h; General procedure: A mixture of aryl halide (1.0 mmol), Het-NH (1.2mmol) or amine (4 mmol), KOH (2 mmol), Cu2O/nano-CuFe2O4 magnetic composite (0.010 g) and anhydrous DMSO (2 mL) was stirred at 100 °C. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature and with diluted ethyl acetate and the catalyst was separated by an external magnet from the mixture, washed with acetone, dried in an oven at 80 °C for 3 h and re-used for a consecutive run under the same reaction conditions. The combined ethyl acetate layer was washed with water, dried over anhydrous MgSO4, The residue was purified by recrystallization or short column chromatography on silica gel to afford the target products in excellent yield.
95% With potassium carbonate In dimethyl sulfoxide at 120℃; for 12 h; Inert atmosphere General procedure: In an oven dried 100 mL round bottom flask, Cu-grafted catalyst(0.05 g), aryl halide (1 mmol), N–H heterocycles (1.2 mmol), K2CO3(2 mmol), and 10 mL DMSO were stirred under nitrogen atmo-sphere, at 100C. The reaction mixtures were collected at differenttime interval and identified by GC–MS and quantified by GC anal-ysis.
95% With potassium carbonate In dimethyl sulfoxide at 120℃; for 12 h; Inert atmosphere General procedure: To a mixture of 0.05 g catalyst and aryl halide (1.0 mmol)in 9.0 cm3 DMSO, Het-NH (1.2 mmol) and K2CO3(2.0 mmol) was added and the mixture was vigorouslystirred at 120 C for the appropriate time under a drynitrogen atmosphere. After completion (as monitored byTLC), the catalyst was filtered, and the filtrate wasextracted with ethyl acetate (3 9 20 cm3) and the combinedorganic layers were dried with anhydrous MgSO4,filtered, and evaporated under reduced pressure. The residuewas purified by column chromatography. The purity ofthe compounds was checked by 1H NMR and yields arebased on aryl bromide. All the products are known and thespectroscopic data (FT-IR and NMR) and melting pointswere consistent with those reported in the literature [36–41].
95% With copper(I) oxide; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 12 h; General procedure: A 10-mL vial was charged with aryl halide (0.5 mmol), Cs2CO3 (1 mmol), Cu2O (0.05 mmol), N-containing heterocycles (0.75 mmol), DMF (1 mL), and a magnetic stir bar. The mixture was stirred at 120 °C (130 °C for entry 19). The reaction mixture was held at this temperature for 12 h (24 h for entry 18, 20, 21, and 25). After allowing the mixture to cool to room temperature, the reaction mixture was extracted with ethyl acetate (3 10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether as the eluent) to provide the target products 3a–3t.
94% With potassium hydroxide In dimethyl sulfoxide at 100℃; for 1.41667 h; General procedure: A mixture of aryl iodide (1.0 mmol), Het-NH (1.2 mmol), KOH (2 mmol), nanomagnetic Fe3O4-TiO2/Cu2O (0.010 g equal to 1.4 molpercent Cu2O) and anhydrous DMSO (2 mL) was stirred at 100 °C. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature and diluted by ethyl acetate and the catalyst was separated by an external magnet from the mixture, washed with acetone, dried in an oven at 80 °C for 3 h and re-used for a consecutive run under the same reaction conditions. The combined ethyl acetate layer was washed with water and dried over anhydrous MgSO4. The residue was purified by recrystallization or short column chromatography on silica gel to afford the target products in excellent yield.
91% With potassium phosphate; copper In dimethyl sulfoxide at 80℃; for 2 h; Inert atmosphere General procedure: An oven dried two-necked round bottom flask was charged with aryl halide (1mmol) and K3PO4 (2mmol), evacuated and backfilled with argon. The azole compound (1mmol) and 2mL of DMSO were added under argon. After that Cu-NP (1.6mmol) was added and the flask was again backfilled with argon. The flask was then immersed in a preheated oil bath at 80°C until the conversion was completed (detected by TLC). The cooled mixture was partitioned between ethyl acetate (10mL) and saturated NH4Cl (10mL). The aqueous layer was extracted with ethyl acetate (2×10mL), the organic layer was washed with brine (20mL), dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography on silica gel using ethyl acetate in hexane (1.5–10percent) as eluent to afford the desired product. All the products have been characterized by 1H NMR, 13C NMR, and mass spectroscopy. For new products, FTIR data were also recorded.
91% With C40H34CuIN6O6; sodium hydroxide In dimethyl sulfoxide at 100℃; for 4 h; Sealed tube General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 °C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
90% With bis(1-dodecylimidazole)cupronium dichlorocuprate; tetrabutylammomium bromide; potassium carbonate In water at 80℃; for 12 h; Green chemistry General procedure: At first [Cu(Im12)2]CuCl2 (0.5 mmol, 0.305 g) was added to a 25 mL round bottom flask containing water (4 mL), indole (0.117 g, 1 mmol) and iodobenzene (0.203 g, 1 mmol).K2CO3 (0.276 g, 2 mmol) and TBAB (0.322 g, 1 mmol) was added and the reaction stirred at 80 °C for 12 h. The reaction progress was monitored by TLC(EtOAc/n-hexane; 1:3 v/v) and after completion, the organic phase was extracted from the ionic liquid with EtOAc (2 8 mL) and concentrated in vacuo. The promoter was used directly for the next run. The product was purified by silica gel column chromatography (EtOAc/n-hexane; 1:3 v/v). The isolated product was dried under vacuum overnight to give a yield of 92percent. All products are known in the literature and were identified by comparison of their FT-IR, 1H, and 13C NMR spectra with the literature data.
87% With potassium phosphate; copper(l) iodide; tetrabutylammomium bromide In water at 120℃; for 8 h; Green chemistry General procedure: A 10 mL of vial was charged with CuI (10 mg, 0.05 mmol), PSP (0.25 mmol, size less than 90 μM), TBAB (40 mg, 0.25 mmol), base (1.0 mmol), aryl halides (0.5 mmol), arylamine (2.0 mmol), H2O (1.0 mL), and a magnetic stir bar. The vessel was sealed with a septum and placed into an oil bath, which was preheated to 70 °C (90 °C for alkyl amine, 120 °C for imidazole). The reaction mixture was stirred for another 16 h (8 h for imidazole). After allowing the mixture to cool to room temperature, the reaction mixture was filtrated, the precipitates were washed with water and ethyl acetate thoroughly. The filtrate was extracted with ethyl acetate (3×25 mL). The combined organic phases was washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatograph on silica gel to afford the desired products.
86% With 2,2'-biimidazole; copper(II) acetate monohydrate; caesium carbonate In dimethyl sulfoxide at 80℃; for 48 h; (1) will nitroiodobenzene 0.248g (1.0mmol), imidazole 0.069g (1.0mmol), Cu (OAc)2·H2O 0.030g (0.15mmol), 2,2- biimidazole 0.022g (0.15mmol), cesium carbonate 0.652g (2mmol), DMSO (2mL) was added the reaction tube with a piston, was heated to 80 deg.] C with stirring for 48 hours reaction.(2) TLC until the reaction was complete the reaction was followed ends.After the reaction was cooled to room temperature, diluted with water, extracted with ethyl acetate 3-4 was added, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product.After the end of (3) to obtain the crude product was purified by column chromatography (petroleum ether / ethyl acetate elution) to give the desired product 13 (yield 86percent).
85% With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 0.5 h; General procedure: The reaction flask, containing 0.02 g Cu(II) nanocatalyst(contains 0.4 molpercent of Cu(II)), imidazole (2.0 mmol),K2CO3 (1.0 mmol), and corresponding aryl halide(1.0 mmol) in 2.5 cm3 DMF, was immersed in a preheated oil bath and the reaction mixture was stirred under air atmosphere at 120 C until no further conversion of the starting aryl halide was observed by thin-layer chromatography(TLC). After completion of the reaction, the resulting mixture was allowed to cool to room temperature,and then the catalyst was separated out by an external permanent magnet, washed with ethyl acetate (EtOAc) anddried. The residue mixture was diluted by H2O and extracted with EtOAc (3 9 10 cm3). The extracted organic phases were dried over anhydrous Na2SO4, filtrated, concentrated and, finally, purified by silica gel chromatography using petroleum ether/ethyl acetate to afford the corresponding pure N-arylimidazole.
82% With copper(l) iodide; 1H-tetrazol-1-ylacetic acid; sodium hydroxide In dimethyl sulfoxide at 90℃; for 6 h; Sealed tube General procedure: CuI (0.05 mmol), L1 (0.1 mmol), aryl halides (1.0 mmol), imidazoles (1.5 mmol), NaOH (2 mmol), and DMSO (2 mL) were added to a 10 mL of sealed tube. The reaction mixture was reacted at 110 °C in a preheated oil bath for 12 h. The reaction mixture was cooled to r.t., diluted with 10 mL H2O, and then the mixture was extracted with ethyl acetate (3× 20 mL). The combined organic phases was washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether, 2:1 to pure ethyl acetate) to afford the target products.#10;
80% With copper(l) chloride; sodium hydroxide; 3-(diphenylphosphino)propionic acid In dimethyl sulfoxide at 120℃; for 14 h; Inert atmosphere; Sealed tube General procedure: NH-containing heterocycle (1.4 mmol) and DMF (2.0 mL) were added to a mixture of CuCl (15.0 molpercent) and ligand 1 (20.0 molpercent) in DMF (2.0 mL), aryl iodide (1.0 mmol), NaOH (2.0 mmol). The mixture was vigorously stirred at 120 °C for 14 h under a dry nitrogen atmosphere. After completion of the reaction (as monitored by TLC), H2O was added and the organic layer was extracted with EtOAc, washed with brine and dried over MgSO4. The solution was filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography. The purity of the compounds was checked by 1H NMR and yields are based on aryl iodide. All the products are known and the spectroscopic data (FT‑IR and NMR) and melting points were consistent with those reported in the literature.
77% With copper(l) chloride; sodium hydroxide; 3-(diphenylphosphino)propionic acid In dimethyl sulfoxide at 100℃; for 12 h; Sealed tube General procedure: CuCl (0.04mmol), L2 (0.08mmol), aryl idione or bromide (0.5mmol), imidazole or 1H-benzo[d]imidazole (0.75mmol), NaOH (1mmol), and DMSO (1mL) was added to a 5mL tube, then sealed. The mixture was stirred at 100°C for certain time. After cooling to room temperature, the mixture was quenched with 10mL H2O and extracted with EtOAc (3×20mL). The combined EtOAc extracts were dried with anhydrous Na2SO4 and filtrated and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel with PE/EtOAc (from 2:1 (v/v) to pure EtOAc) as the eluent to afford the desired products.
73% With potassium carbonate In dimethyl sulfoxide at 120℃; for 12 h; Inert atmosphere General procedure: To a mixture of 0.05 g catalyst and aryl halide (1.0 mmol)in 9.0 cm3 DMSO, Het-NH (1.2 mmol) and K2CO3(2.0 mmol) was added and the mixture was vigorouslystirred at 120 C for the appropriate time under a drynitrogen atmosphere. After completion (as monitored byTLC), the catalyst was filtered, and the filtrate wasextracted with ethyl acetate (3 9 20 cm3) and the combinedorganic layers were dried with anhydrous MgSO4,filtered, and evaporated under reduced pressure. The residuewas purified by column chromatography. The purity ofthe compounds was checked by 1H NMR and yields arebased on aryl bromide. All the products are known and thespectroscopic data (FT-IR and NMR) and melting pointswere consistent with those reported in the literature [36–41].
60% With 2-(2-tert-butylhydrazinecarbonyl)pyridine-1-oxide; tetrabutylammomium bromide; copper; potassium hydroxide In water at 120℃; for 12 h; Sealed tube; Green chemistry Cu (0.05 mmol), L4 (0.1 mmol), aryl halides(0.5 mmol), imidazoles (0.75 mmol), KOH (1 mmol), TBAB (0.15 mol), and H2O(1 mL) were added to a 10 mL sealed tube. The reaction mixture was reacted at120 C in a pre-heated oil bath for 12 h. The reaction mixture was cooled to room temperature, diluted with 10 mL H2O, and then the mixture was extracted with ethyl acetate (3 20 mL). The combined organic phases were washed withwater and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatograph on silica gel (ethyl acetate/petroleum ether, 2:1 to pure ethyl acetate) to afford the target products.
95 %Chromat. With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h; General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.

Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 31, p. 3044 - 3048
[2] Tetrahedron, 2008, vol. 64, # 7, p. 1383 - 1387
[3] Applied Catalysis A: General, 2014, vol. 481, p. 79 - 88
[4] Applied Organometallic Chemistry, 2018, vol. 32, # 1,
[5] RSC Advances, 2016, vol. 6, # 93, p. 90154 - 90164
[6] Chinese Chemical Letters, 2010, vol. 21, # 1, p. 51 - 54
[7] New Journal of Chemistry, 2015, vol. 39, # 4, p. 2901 - 2907
[8] Chemistry Letters, 2016, vol. 45, # 2, p. 223 - 225
[9] European Journal of Inorganic Chemistry, 2017, vol. 2017, # 40, p. 4803 - 4807
[10] Tetrahedron Letters, 2006, vol. 47, # 23, p. 3897 - 3899
[11] Organic Letters, 2009, vol. 11, # 15, p. 3294 - 3297
[12] Synthesis, 2010, # 6, p. 908 - 910
[13] European Journal of Organic Chemistry, 2011, # 18, p. 3353 - 3360
[14] Letters in Organic Chemistry, 2011, vol. 8, # 5, p. 325 - 331
[15] Catalysis Letters, 2011, vol. 141, # 8, p. 1171 - 1181
[16] Journal of the Chinese Chemical Society, 2013, vol. 60, # 8, p. 1007 - 1013
[17] RSC Advances, 2014, vol. 4, # 14, p. 7321 - 7329
[18] Journal of Molecular Catalysis A: Chemical, 2014, vol. 387, p. 7 - 19
[19] Monatshefte fuer Chemie, 2015, vol. 146, # 8, p. 1329 - 1334
[20] Synthetic Communications, 2017, vol. 47, # 19, p. 1797 - 1803
[21] Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 2200 - 2202
[22] Research on Chemical Intermediates, 2016, vol. 42, # 10, p. 7611 - 7624
[23] Applied Organometallic Chemistry, 2018, vol. 32, # 4,
[24] Chemistry - A European Journal, 2009, vol. 15, # 36, p. 8971 - 8974
[25] Monatshefte fur Chemie, 2010, vol. 141, # 9, p. 1009 - 1013
[26] Catalysis Science and Technology, 2013, vol. 3, # 12, p. 3303 - 3316
[27] Transition Metal Chemistry, 2011, vol. 36, # 4, p. 447 - 458
[28] Green Chemistry, 2018, vol. 20, # 23, p. 5346 - 5357
[29] Tetrahedron Letters, 2016, vol. 57, # 29, p. 3140 - 3145
[30] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2018, vol. 57A, # 2, p. 181 - 185
[31] New Journal of Chemistry, 2014, vol. 38, # 9, p. 4267 - 4274
[32] Tetrahedron Letters, 2015, vol. 56, # 46, p. 6360 - 6363
[33] Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 1971 - 1976
[34] Tetrahedron, 2013, vol. 69, # 42, p. 8974 - 8977
[35] Applied Organometallic Chemistry, 2015, vol. 29, # 7, p. 468 - 470
[36] Patent: CN104447557, 2017, B, . Location in patent: Paragraph 0113; 0114; 0115; 0116; 0117; 0118
[37] Monatshefte fur Chemie, 2018, vol. 149, # 6, p. 1101 - 1109
[38] Chinese Chemical Letters, 2013, vol. 24, # 10, p. 893 - 896
[39] Advanced Synthesis and Catalysis, 2017, vol. 359, # 10, p. 1631 - 1636
[40] Synthetic Communications, 2012, vol. 42, # 8, p. 1192 - 1199
[41] Chinese Journal of Chemistry, 2013, vol. 31, # 2, p. 267 - 270
[42] Journal of Chemical Research, 2014, vol. 38, # 2, p. 128 - 129
[43] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 4, p. 1234 - 1239
[44] Chinese Chemical Letters, 2014, vol. 25, # 5, p. 775 - 778
[45] Monatshefte fuer Chemie, 2015, vol. 146, # 8, p. 1329 - 1334
[46] New Journal of Chemistry, 2018, vol. 42, # 19, p. 16013 - 16020
[47] Tetrahedron Letters, 2014, vol. 55, # 21, p. 3249 - 3251
[48] New Journal of Chemistry, 2018, vol. 42, # 12, p. 10421 - 10431
[49] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
[50] Monatshefte fur Chemie, 2003, vol. 134, # 1, p. 37 - 43
[51] ChemPlusChem, 2013, vol. 78, # 12, p. 1491 - 1502
[52] RSC Advances, 2014, vol. 4, # 29, p. 15122 - 15130
[53] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
[54] ChemCatChem, 2015, vol. 7, # 21, p. 3495 - 3502
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  • [ 288-32-4 ]
  • [ 586-78-7 ]
  • [ 2301-25-9 ]
YieldReaction ConditionsOperation in experiment
99% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 12 h; General procedure: A mixture of aryl halide (2.4 mmol) and Cs2CO3(4.0 mmol,0.650 g), nitrogen-containing heterocycle (2.0 mmol), dry DMF(3 mL) solvent and catalyst was stirred at 100C in an oil bath under air. After cooling to room temperature, catalyst was first separated out by centrifugation and the liquid part was extracted with water and diethylether (2 × 15 mL). The organic layers thus collected were combined and washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (mesh 60–120) using an n-hexane/ethylacetate mixture as the eluent to collect the desiredproduct. The product was analyzed by 1H and13C NMR and mass spectroscopy.
98% With copper(I) 3-metthylsalicylate; potassium carbonate In dimethyl sulfoxide at 110℃; for 3 h; General procedure: A dry flask was charged with the nitrogen containing heterocycles (1.5 mmol), aryl halides (1 mmol), potassium carbonate(2 mmol) and CuMeSal (0.01 mmol) then anhydrous DMSO (5 ml) was added. The reaction mixture was stirred at 110°C, open to air, for 3h , cooled to room temperature, filtered, and the precipitate was washed with DMSO (2 ml) then stirred with ice water (30 ml) and extracted with ethyl acetate (3 × 50 ml),dried over sodium sulfate and the solvent was removed under reduced pressure.The residue was purified by chromatography or recrystallization as indicated with each compound.
98% With caesium carbonate In dimethyl sulfoxide at 110℃; for 1 h; General procedure: A mixture of CuatCu2O NPs nanocomposite (5 molpercent ofCu), Cs2CO3(1.5 mmol), N-heterocycle (1.0 mmol), aryl halide(1.0 mmol), and DMSO (2 mL) under air was stirred for 1 h at 110 °C.After completion of the reaction as indicated by TLC, the heterogeneous mixture was cooled to room temperature and diluted with ethyl acetate (10 mL). The mixture was filtered through a pad of celite. The filtrate was concentrated and then residue was purified by column chromatography (SiO2, ethyl acetate and n-hexane) to yield pure product. The catalysts were recovered by simple filtration and washed extensively with acetone and deionized water and then drying in the air.
94% With potassium hydroxide In dimethyl sulfoxide at 100℃; for 2 h; General procedure: A mixture of aryl halide (1.0 mmol), Het-NH (1.2mmol) or amine (4 mmol), KOH (2 mmol), Cu2O/nano-CuFe2O4 magnetic composite (0.010 g) and anhydrous DMSO (2 mL) was stirred at 100 °C. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature and with diluted ethyl acetate and the catalyst was separated by an external magnet from the mixture, washed with acetone, dried in an oven at 80 °C for 3 h and re-used for a consecutive run under the same reaction conditions. The combined ethyl acetate layer was washed with water, dried over anhydrous MgSO4, The residue was purified by recrystallization or short column chromatography on silica gel to afford the target products in excellent yield.
93% With potassium hydroxide In dimethyl sulfoxide at 100℃; for 2.41667 h; General procedure: A mixture of aryl iodide (1.0 mmol), Het-NH (1.2 mmol), KOH (2 mmol), nanomagnetic Fe3O4-TiO2/Cu2O (0.010 g equal to 1.4 molpercent Cu2O) and anhydrous DMSO (2 mL) was stirred at 100 °C. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature and diluted by ethyl acetate and the catalyst was separated by an external magnet from the mixture, washed with acetone, dried in an oven at 80 °C for 3 h and re-used for a consecutive run under the same reaction conditions. The combined ethyl acetate layer was washed with water and dried over anhydrous MgSO4. The residue was purified by recrystallization or short column chromatography on silica gel to afford the target products in excellent yield.
86% With C40H34CuIN6O6; sodium hydroxide In dimethyl sulfoxide at 100℃; for 4 h; Sealed tube General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 °C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
84% With potassium phosphate; copper In dimethyl sulfoxide at 80℃; for 5 h; Inert atmosphere General procedure: An oven dried two-necked round bottom flask was charged with aryl halide (1mmol) and K3PO4 (2mmol), evacuated and backfilled with argon. The azole compound (1mmol) and 2mL of DMSO were added under argon. After that Cu-NP (1.6mmol) was added and the flask was again backfilled with argon. The flask was then immersed in a preheated oil bath at 80°C until the conversion was completed (detected by TLC). The cooled mixture was partitioned between ethyl acetate (10mL) and saturated NH4Cl (10mL). The aqueous layer was extracted with ethyl acetate (2×10mL), the organic layer was washed with brine (20mL), dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography on silica gel using ethyl acetate in hexane (1.5–10percent) as eluent to afford the desired product. All the products have been characterized by 1H NMR, 13C NMR, and mass spectroscopy. For new products, FTIR data were also recorded.
84% With copper(I) oxide; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 12 h; General procedure: A 10-mL vial was charged with aryl halide (0.5 mmol), Cs2CO3 (1 mmol), Cu2O (0.05 mmol), N-containing heterocycles (0.75 mmol), DMF (1 mL), and a magnetic stir bar. The mixture was stirred at 120 °C (130 °C for entry 19). The reaction mixture was held at this temperature for 12 h (24 h for entry 18, 20, 21, and 25). After allowing the mixture to cool to room temperature, the reaction mixture was extracted with ethyl acetate (3 10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether as the eluent) to provide the target products 3a–3t.
84% With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 0.5 h; General procedure: The reaction flask, containing 0.02 g Cu(II) nanocatalyst(contains 0.4 molpercent of Cu(II)), imidazole (2.0 mmol),K2CO3 (1.0 mmol), and corresponding aryl halide(1.0 mmol) in 2.5 cm3 DMF, was immersed in a preheated oil bath and the reaction mixture was stirred under air atmosphere at 120 C until no further conversion of the starting aryl halide was observed by thin-layer chromatography(TLC). After completion of the reaction, the resulting mixture was allowed to cool to room temperature,and then the catalyst was separated out by an external permanent magnet, washed with ethyl acetate (EtOAc) anddried. The residue mixture was diluted by H2O and extracted with EtOAc (3 9 10 cm3). The extracted organic phases were dried over anhydrous Na2SO4, filtrated, concentrated and, finally, purified by silica gel chromatography using petroleum ether/ethyl acetate to afford the corresponding pure N-arylimidazole.
80% With potassium carbonate In dimethyl sulfoxide at 120℃; for 12 h; Inert atmosphere General procedure: In an oven dried 100 mL round bottom flask, Cu-grafted catalyst(0.05 g), aryl halide (1 mmol), N–H heterocycles (1.2 mmol), K2CO3(2 mmol), and 10 mL DMSO were stirred under nitrogen atmo-sphere, at 100C. The reaction mixtures were collected at differenttime interval and identified by GC–MS and quantified by GC anal-ysis.
78% With copper(l) iodide; tetrabutylammomium bromide; triethylentetramine In water at 125℃; for 24 h; General procedure: Iodobenzene (1.0 mmol), imidazole (1.5 mmol), TEPA (2.0 mmol), TBAB (0.3 mmol), CuI (0.1 mmol), and 3 mL H2O were added to a 10 mL flask, which was subsequently capped with a rubber balloon. The mixture was stirred in a preheated oil bath at 125 °C for 12 h. After cooling the mixture to the room temperature, 5 mL water was added and the product was extracted by ethyl acetate (10 mL×3). The combined organic layer was washed by brine (15 mL), dried over anhydrous MgSO4, and evaporated under the reduced pressure. Further purification by silica gel column chromatography (6:1 petroleum ether/ethyl acetate) give the 1-phenyl-1H-imidazole.
76% With potassium <i>tert</i>-butylate In dimethylsulfoxide-d6 at 60℃; General procedure: A mixture of the appropriate N‑nucleophile (2 mmol), 4‑bromonitrobenzene(2 mmol), t‑ButOK or KOH (in the case of 1g, 1h)(2.2 mmol) in dimethyl sulfoxide (2.5 mL) was stirred at 60 °C for 5 h(8 h in the case of 1b). After cooling and addition of water (60 mL),either a solid precipitated which was filtered, washed with water andrecrystallised from an appropriate solvent to give the product, or asuspension was generated which was extracted with ethyl acetate(3 × 30 mL), dried over Na2SO4, concentrated under reduced pressureand recrystallised from an appropriate solvent to give the desiredproduct
90 %Chromat. With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h; General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.

Reference: [1] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3151 - 3159
[2] Applied Catalysis A: General, 2016, vol. 513, p. 53 - 66
[3] Tetrahedron Letters, 2014, vol. 55, # 19, p. 3049 - 3051
[4] Applied Catalysis A: General, 2014, vol. 481, p. 79 - 88
[5] Applied Organometallic Chemistry, 2018, vol. 32, # 1,
[6] Journal of Organic Chemistry, 2006, vol. 71, # 21, p. 8324 - 8327
[7] Tetrahedron, 2008, vol. 64, # 10, p. 2471 - 2479
[8] Bulletin of the Chemical Society of Japan, 2008, vol. 81, # 4, p. 515 - 517
[9] Synthetic Communications, 2012, vol. 42, # 1, p. 114 - 121
[10] Tetrahedron Letters, 2006, vol. 47, # 23, p. 3897 - 3899
[11] RSC Advances, 2014, vol. 4, # 14, p. 7321 - 7329
[12] European Journal of Inorganic Chemistry, 2017, vol. 2017, # 40, p. 4803 - 4807
[13] Journal of the Chinese Chemical Society, 2013, vol. 60, # 8, p. 1007 - 1013
[14] Chemistry Letters, 2016, vol. 45, # 2, p. 223 - 225
[15] RSC Advances, 2016, vol. 6, # 93, p. 90154 - 90164
[16] Research on Chemical Intermediates, 2016, vol. 42, # 10, p. 7611 - 7624
[17] Applied Organometallic Chemistry, 2018, vol. 32, # 4,
[18] Organic Letters, 2009, vol. 11, # 15, p. 3294 - 3297
[19] Chinese Journal of Chemistry, 2012, vol. 30, # 10, p. 2389 - 2393,5
[20] Chinese Chemical Letters, 2010, vol. 21, # 1, p. 51 - 54
[21] Transition Metal Chemistry, 2011, vol. 36, # 4, p. 447 - 458
[22] Journal of Organic Chemistry, 2008, vol. 73, # 22, p. 9121 - 9124
[23] Monatshefte fur Chemie, 2010, vol. 141, # 9, p. 1009 - 1013
[24] European Journal of Organic Chemistry, 2011, # 18, p. 3353 - 3360
[25] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2018, vol. 57A, # 2, p. 181 - 185
[26] Helvetica Chimica Acta, 2008, vol. 91, # 8, p. 1435 - 1442
[27] Green Chemistry, 2010, vol. 12, # 6, p. 1097 - 1105
[28] Catalysis Letters, 2011, vol. 141, # 8, p. 1171 - 1181
[29] Tetrahedron Letters, 2016, vol. 57, # 29, p. 3140 - 3145
[30] Synthetic Communications, 2017, vol. 47, # 19, p. 1797 - 1803
[31] Monatshefte fur Chemie, 2018, vol. 149, # 6, p. 1101 - 1109
[32] Chinese Journal of Chemistry, 2013, vol. 31, # 2, p. 267 - 270
[33] Journal of Molecular Catalysis A: Chemical, 2014, vol. 387, p. 7 - 19
[34] Tetrahedron, 2013, vol. 69, # 30, p. 6230 - 6233
[35] Synthesis, 2012, vol. 44, # 7, p. 1063 - 1068
[36] Journal of Chemical Research, 2015, vol. 39, # 2, p. 73 - 75
[37] Applied Organometallic Chemistry, 2017, vol. 31, # 11,
[38] Tetrahedron, 2008, vol. 64, # 7, p. 1383 - 1387
[39] Tetrahedron Letters, 2008, vol. 49, # 28, p. 4386 - 4389
[40] Tetrahedron, 2006, vol. 62, # 20, p. 4756 - 4761
[41] Tetrahedron Letters, 2009, vol. 50, # 12, p. 1286 - 1289
[42] Monatshefte fur Chemie, 2003, vol. 134, # 1, p. 37 - 43
[43] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
[44] Applied Organometallic Chemistry, 2015, vol. 29, # 7, p. 468 - 470
[45] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 7, p. 1892 - 1895
[46] Chemical Communications, 2007, # 45, p. 4809 - 4811
[47] ChemPlusChem, 2013, vol. 78, # 12, p. 1491 - 1502
[48] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
[49] Inorganic Chemistry, 2016, vol. 55, # 12, p. 6085 - 6094
  • 64
  • [ 288-32-4 ]
  • [ 586-78-7 ]
  • [ 2301-25-9 ]
  • [ 98-95-3 ]
Reference: [1] Catalysis Letters, 2014, vol. 144, # 11, p. 1877 - 1883
  • 65
  • [ 288-32-4 ]
  • [ 100-00-5 ]
  • [ 2301-25-9 ]
  • [ 98-95-3 ]
Reference: [1] Catalysis Letters, 2014, vol. 144, # 11, p. 1877 - 1883
  • 66
  • [ 288-32-4 ]
  • [ 100-19-6 ]
  • [ 2301-25-9 ]
Reference: [1] European Journal of Organic Chemistry, 2011, # 14, p. 2692 - 2696
  • 67
  • [ 288-32-4 ]
  • [ 3383-72-0 ]
  • [ 2301-25-9 ]
  • [ 75912-69-5 ]
Reference: [1] Journal of Medicinal Chemistry, 1985, vol. 28, # 10, p. 1427 - 1432
  • 68
  • [ 288-32-4 ]
  • [ 1215-59-4 ]
  • [ 6953-22-6 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 6, p. 922 - 925
  • 69
  • [ 288-32-4 ]
  • [ 76-83-5 ]
  • [ 15469-97-3 ]
YieldReaction ConditionsOperation in experiment
95.6%
Stage #1: With triethylamine In N,N-dimethyl-formamide at 0℃; for 0.5 h; Large scale
Stage #2: at 0 - 15℃; for 16 h; Large scale
Compound XIII (880g, 12.9mol, 1.0eq.) In the autoclave 50L, 12L DMF were dissolved, cooled To below 0 °C, triethylamine (1308g, 12.9mol, 1.0eq. ) The reaction was kept 30min, 0 ° C solution of the following threePhenyl chloride (3605.0g, 12.9mol, 1.0eq. ) In DMF (16L), drops Bi, 15 ° C overnight with stirring 16 h. Thereaction mixture was poured into water, large amount of solid precipitated, suction filtered, the filter cake washedwith water, drained, dried to obtain compound XIV-1 White The solid 3835.1g, Yield: 95.6percent.
91%
Stage #1: With triethylamine In N,N-dimethyl-formamide at 0℃; for 0.5 h;
Stage #2: at 0 - 20℃;
1-trityl-midazol (Compound 28, Scheme 19) was prepared by adding Et3N (5.1 ml, 36.7 mmol) at 0° C. to a stirred solution of the imidazole Compound 27 (2.5 grams, 36.7 mmol) dissolved in 75 ml DMF. After 30 minutes of stirring, trityl-chloride (10.3 grams, 36.7 mmol) dissolved in DMF (45 ml) was added slowly to the reaction mixture, and the reaction mixture was allowed to reach room temperature while stirred continuously for over night. Thereafter the reaction mixture was quenched with cold water (1 L) to precipitate a solid, which was collected by filtration and recrystallized from hexane/DCM to afford Compound 28 as a white solid (91percent yield).1H NMR (500 MHz, CDCl3)-δ: 7.47 (s, 1H), 7.33-7.30 (m, 9H), 7.16-7.12 (m, 6H), 7.07 (s, 1H), 6.83 (s, 1H).
90% With ammonium chloride; triethylamine In dichloromethane Example 22
Synthesis of 1-tritylimidazole (5)
To a solution of trityl chloride (5.58 g, 20.0 mmol.) in dry methylene chloride (100 ml) cooled down to 0° C. and stirred under Ar, was added dropwise over 1.5 hours a solution of imidazole (1.36 g, 20.0 mmol.) and triethylamine (2.7 mml, 20 mmol.) in 50 ml dry methylene chloride.
At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred under Ar at that temperature overnight.
The reaction mixture was then washed with 20 ml of a 10percent solution of ammonium chloride, then with 20 ml of distilled water.
The organic phase was dried over magnesium sulfate and evaporated in vacuo to yield quantitatively a white solid.
Recrystallization from methylene chloride/hexanes yielded 5.60 g of (5) (yield=90percent after recrystallization).
m.p. 214° C.; 1H NMR (200 MHz, CDCl3) δ7.43 (m, 1H, NCHN), 7.3-7.4 (m, 9H, 3*C6H5), 7.1-7.2 (m, GH, 3*C6H5), 7.0 (m, 1H, Ph3CNCH=CH), 6.81 (m, 1H, Ph3CNCH=CH); 13C NMR (50 MHz, CDCl3) δ142.3, 139.0, 129.6, 128.2, 128.3, 121.6.
90% With ammonium chloride; triethylamine In dichloromethane Example 22
Synthesis of 1-tritylimidazole (5) STR73
To a solution of trityl chloride (5.58 g, 20.0 mmol.) in dry methylene chloride (100 ml) cooled down to 0° C. and stirred under Ar, was added dropwise over 1.5 hours a solution of imidazole (1.36 g, 20.0 mmol.) and triethylamine (2.7 mml, 20 mmol.) in 50 ml dry methylene chloride.
At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred under Ar at that temperature overnight.
The reaction mixture was then washed with 20 ml of a 10percent solution of ammonium chloride, then with 20 ml of distilled water.
The organic phase was dried over magnesium sulfate and evaporated in vacuo to yield quantitatively a white solid.
Recrystallization from methylene chloride/hexanes yielded 5.60 g of (5) (yield=90percent after recrystallization).
m.p. 214° C.; 1 H NMR (200 MHz, CDCl3) δ 7.43 (m, 1H, NCHN), 7.3-7.4 (m, 9H, 3xC6 H5), 7.1-7.2 (m, 6H, 3xC6 H5), 7.0 (m, 1H, Ph3 CNCH=CH), 6.81 (m, 1H, Ph3 CNCH=CH); 13 C NMR (50 MHz, CDCl3) δ 142.3, 139.0, 129.6, 128.2, 128.3, 121.6.
90% With ammonium chloride; triethylamine In dichloromethane Example 22
Synthesis of 1-tritylimidazole (5) STR70
To a solution of trityl chloride (5.58 g, 20.0 mmol.) in dry methylene chloride (100 ml) cooled down to 0° C. and stirred under Ar, was added dropwise over 1.5 hours a solution of imidazole (1.36 g, 20.0 mmol.) and triethylamine (2.7 mml, 20 mmol) in 50 ml dry methylene chloride.
At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred under Ar at that temperature overnight.
The reaction mixture was then washed with 20 ml of a 10percent solution of ammonium chloride, then with 20 ml of distilled water.
The organic phase was dried over magnesium sulfate and evaporated in vacuo to yield quantitatively a white solid.
Recrystallization from methylene chloride/hexanes yielded 5.60 g of (5) (yield=90percent after recrystallization).
m.p. 214° C.; 1 H NMR (200 MHz, CDCl3) δ7.43 (m, 1H, NCHN), 7.3-7.4 (m, 9H, 3*C6 H5), 7.1-7.2 (m, 6H, 3*C6 H5), 7.0 (m, 1H, Ph3 CNCH=CH), 6.81 (m, 1H, Ph3 CNCH=CH); 13 C NMR (50 MHz, CDCl3) δ142.3, 139.0, 129.6, 128.2, 128.3, 121.6.

Reference: [1] Patent: CN104086553, 2016, B, . Location in patent: Paragraph 0065-0068
[2] Patent: US2010/16610, 2010, A1, . Location in patent: Page/Page column 28
[3] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 253 - 256
[4] Tetrahedron, 1999, vol. 55, # 13, p. 4109 - 4122
[5] Patent: US6476216, 2002, B1,
[6] Patent: US6160109, 2000, A,
[7] Patent: US5734041, 1998, A,
[8] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 3, p. 903 - 906
[9] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 1, p. 2 - 6
[10] European Journal of Organic Chemistry, 2011, # 30, p. 6092 - 6099
[11] Heterocycles, 1985, vol. 23, # 11, p. 2895 - 2906
[12] Arzneimittel-Forschung/Drug Research, 1992, vol. 42, # 6, p. 832 - 835
[13] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 857 - 860
[14] Patent: US5039691, 1991, A,
[15] ChemMedChem, 2010, vol. 5, # 6, p. 899 - 910
  • 70
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  • [ 102-10-3 ]
  • [ 15469-97-3 ]
YieldReaction ConditionsOperation in experiment
82.7% With pyridine In acetonitrile EXAMPLE 11
Preparation of 1-triphenylmethylimidazole
A mixture of pyridine (15 ml), diphenyl phosphite (2.34 g, 10 mmole), imidazole (0.68 g, 10 mmole) and triphenylmethanol (2.08 g, 8 mmole) was refluxed for 3 hours.
Pyridine was removed under reduced pressure, and the residue was extracted with dichloromethane.
The extract was washed with a 5percent aqueous hydroxide solution and water in order, dried and evaporated.
Recrystallization of the residue (2.23 g) from acetonitrile gave 2.05 g of 1-triphenylmethylimidazole as colorless needles.
Yield, 82.7percent. M.P., 221°-223° C.
Elementary analysis: Calcd. for C22 H18 N2: C, 85.13percent; H, 5.85percent; N, 9.03percent. Found: C, 85.20percent; H, 6.03percent; N, 9.21percent.
Reference: [1] Patent: US4216333, 1980, A,
  • 71
  • [ 288-32-4 ]
  • [ 87268-78-8 ]
  • [ 15469-97-3 ]
Reference: [1] Russian Journal of Organic Chemistry, 2002, vol. 38, # 9, p. 1360 - 1369
  • 72
  • [ 288-32-4 ]
  • [ 76-84-6 ]
  • [ 15469-97-3 ]
Reference: [1] Patent: US6051573, 2000, A,
  • 73
  • [ 288-32-4 ]
  • [ 95953-45-0 ]
  • [ 15469-97-3 ]
Reference: [1] Journal of the American Chemical Society, 1986, vol. 108, # 22, p. 7023 - 7027
  • 74
  • [ 2232-08-8 ]
  • [ 56-40-6 ]
  • [ 288-32-4 ]
  • [ 1080-44-0 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1988, # 2, p. 356 - 360
  • 75
  • [ 288-32-4 ]
  • [ 389625-48-3 ]
  • [ 18162-48-6 ]
Reference: [1] Patent: US2002/106697, 2002, A1,
  • 76
  • [ 288-32-4 ]
  • [ 7646-93-7 ]
  • [ 18162-48-6 ]
Reference: [1] Patent: US5310897, 1994, A,
  • 77
  • [ 288-32-4 ]
  • [ 192376-55-9 ]
  • [ 98-59-9 ]
  • [ 192376-56-0 ]
  • [ 18162-48-6 ]
Reference: [1] Patent: US5977105, 1999, A,
  • 78
  • [ 288-32-4 ]
  • [ 107-30-2 ]
  • [ 20075-26-7 ]
YieldReaction ConditionsOperation in experiment
58%
Stage #1: With sodium ethanolate In tetrahydrofuran; ethanol at 20℃; for 1 h;
Stage #2: at 20℃;
To a solution of lH-imidazole (40.8 g, 600.00 mmol) in EtOH (1200 niL) under nitrogen was added a solution of sodium ethanolate (40.8 g, 600.00 mmol) in THF (1200 rnL). The resulting solution was stirred for 1 hr at room temperature and concentrated under vacuum. To the residue was added chloro(methoxy) methane (53.4 g, 667.50 mmol) and the resulting solution was stirred for overnight at room temperature. The solids were filtered. The filtrate was concentrated and distilled under reduced pressure, resulted in 40 g (58percent) of l-(methoxym ethyl)- lH-imidazole as white oil.
Reference: [1] European Journal of Organic Chemistry, 2011, # 24, p. 4654 - 4666
[2] Chemical Communications, 2017, vol. 53, # 82, p. 11302 - 11305
[3] Patent: WO2009/139834, 2009, A1, . Location in patent: Page/Page column 142-143
[4] Journal of Organic Chemistry, 1989, vol. 54, # 6, p. 1439 - 1442
[5] Journal of Medicinal Chemistry, 1997, vol. 40, # 2, p. 216 - 225
[6] Patent: US2003/229093, 2003, A1, . Location in patent: Page 20
[7] Patent: WO2004/74283, 2004, A1, . Location in patent: Page 121
  • 79
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  • [ 5467-74-3 ]
  • [ 10040-96-7 ]
YieldReaction ConditionsOperation in experiment
90% With copper(I) sulfide; N,N,N,N,-tetramethylethylenediamine In methanol at 20℃; for 24 h; General procedure: A 10mL round bottom flask was charged with a magnetic stirring bar, benzimidazole 1 (59mg, 0.5mmol), boronic acid 2 (1.0mmol), Cu2S (4mg, 0.025mmol), and MeOH (2mL), followed with the addition of TMEDA (0.075mL, 0.5mmol). The flask was sealed with a septum, through which was inserted 18-gauche needle. This setup allowed air to go into the reaction and avoid contamination of a mixture. The reaction mixture was stirred from 400 to 600rpm for appropriate time and extracted with EtOAc (2×15mL). Combined organic layers were washed with saturated aqueous solution of ethylenediaminetetraacetic acid disodium salt (15mL), and then dried over anhydrous Na2SO4. Volatiles were removed under reduced pressure and the residue was purified by column chromatography (silica gel, hexanes – EtOAc) to yield the title product, which was characterized by 1H NMR, 13C NMR, HRMS, and melting point (if solid).
81% With triethylamine In methanol at 20℃; for 5 h; General procedure: In a typical reaction, arylboronic acid (1 mmol), amino-compound (1 mmol), catalyst (5 wtpercent), Et3N (2 mmol) were mixed in methanol ( 5mL) in a 25mL round bottomed flask. The reaction mixture was subjected under continuous stirring at room temperature for 5 h. Reaction was monitored from time to time using TLC. After completion of the reaction, catalyst was separated with the aid of an external magnet and reaction mixture was taken in ethyl acetate. The organiclayer was washed using brine solution, dried over sodium sulfate. After evaporating the solvent, the crude product was puried by column chromatography using 230–400 silica mesh. The recovered catalyst was washed with methanol and ethyl acetate, dried in oven and kept in desiccator for further use.
74% With [2,2]bipyridinyl; oxygen; copper diacetate In water at 20℃; for 24 h; General procedure: Under an O2 atmosphere, a mixture of 4-methoxyphenylboroic acid (1a, 60.8 mg, 0.40 mmol), imidazole (2a, 13.6 mg, 0.20 mmol), Cu(OAc)2 (3.6 mg, 0.020 mmol), ligand I (3.7 mg, 0.020 mmol), and Brij 30 (21.8 mg, 0.060 mmol) in H2O (4 mL) was stirred at room temperature for 24 h. The mixture was diluted with brine and extracted with AcOEt (30 mL.x.3). The organic layer was washed with H2O (10 mL.x.3) and dried over MgSO4. The solvent was removed under the reduced pressure and the residue was purified by SiO2 column chromatography using AcOEt to give N-(4-methoxyphenyl)imidazole (3aa) (23.7 mg, 68percent).
Reference: [1] Synthesis, 2008, # 5, p. 795 - 799
[2] Tetrahedron, 2018, vol. 74, # 5, p. 606 - 617
[3] Green Chemistry, 2018, vol. 20, # 21, p. 4891 - 4900
[4] Catalysis Communications, 2018, vol. 109, p. 38 - 42
[5] Tetrahedron, 2012, vol. 68, # 38, p. 7794 - 7798
  • 80
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  • [ 106-37-6 ]
  • [ 10040-96-7 ]
YieldReaction ConditionsOperation in experiment
90% With copper(l) iodide; caesium carbonate; dimethylbiguanide In N,N-dimethyl-formamide at 20 - 110℃; for 15.1667 h; General procedure: A 25 mL flask with a magnetic stirring bar was charged with CuI(9.6 mg, 0.05 mmol), metformin (0.1 mmol), Cs2CO3 (652 mg,2.0 mmol), imidazole (1.0 mmol), an aryl halide (1.1 mmol), andDMF (5 mL). The mixture was stirred for 10 min at room temperature,and then heated to 110C for the appropriate amount of time(see Table 2). The progress of the reaction was monitored by TLC.After completion of the reaction, the mixture was extracted with EtOAc (5 1 mL) and the organic phase separated and evaporated. Further purification by column chromatography gave the desired coupled product.
85% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 12 h; General procedure: A mixture of aryl halide (2.4 mmol) and Cs2CO3(4.0 mmol,0.650 g), nitrogen-containing heterocycle (2.0 mmol), dry DMF(3 mL) solvent and catalyst was stirred at 100C in an oil bath under air. After cooling to room temperature, catalyst was first separated out by centrifugation and the liquid part was extracted with water and diethylether (2 × 15 mL). The organic layers thus collected were combined and washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (mesh 60–120) using an n-hexane/ethylacetate mixture as the eluent to collect the desiredproduct. The product was analyzed by 1H and13C NMR and mass spectroscopy.
81% With C40H34CuIN6O6; sodium hydroxide In dimethyl sulfoxide at 100℃; for 4 h; Sealed tube General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 °C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
Reference: [1] Synlett, 2012, vol. 23, # 8, p. 1240 - 1244
[2] Tetrahedron Letters, 2013, vol. 54, # 52, p. 7095 - 7099
[3] Journal of Organic Chemistry, 2007, vol. 72, # 8, p. 2737 - 2743
[4] Applied Catalysis A: General, 2016, vol. 513, p. 53 - 66
[5] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2018, vol. 57A, # 2, p. 181 - 185
[6] Applied Organometallic Chemistry, 2017, vol. 31, # 11,
[7] Tetrahedron, 2017, vol. 73, # 16, p. 2191 - 2195
[8] Synlett, 2008, # 19, p. 3068 - 3072
  • 81
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YieldReaction ConditionsOperation in experiment
94% With C40H34CuIN6O6; sodium hydroxide In dimethyl sulfoxide at 100℃; for 4 h; Sealed tube General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 °C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
92% With copper(l) chloride; sodium hydroxide; 3-(diphenylphosphino)propionic acid In dimethyl sulfoxide at 120℃; for 14 h; Inert atmosphere; Sealed tube General procedure: NH-containing heterocycle (1.4 mmol) and DMF (2.0 mL) were added to a mixture of CuCl (15.0 molpercent) and ligand 1 (20.0 molpercent) in DMF (2.0 mL), aryl iodide (1.0 mmol), NaOH (2.0 mmol). The mixture was vigorously stirred at 120 °C for 14 h under a dry nitrogen atmosphere. After completion of the reaction (as monitored by TLC), H2O was added and the organic layer was extracted with EtOAc, washed with brine and dried over MgSO4. The solution was filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography. The purity of the compounds was checked by 1H NMR and yields are based on aryl iodide. All the products are known and the spectroscopic data (FT‑IR and NMR) and melting points were consistent with those reported in the literature.
82% With Cu/Al2O3; potassium hydroxide In N,N-dimethyl-formamide at 80℃; Green chemistry General procedure: To equimolar amounts (0.1mmol) of the halide and the nitrogenated nucleophile in DMF were added KOH and the 3D heterogeneous Cu/Al2O3 catalytic system. The reaction mixture was heated at 80°C under orbital stirring in a Kimble vial (7mL) for 2–4h. Once the reaction had finished (TLC control), the solvent was separated from the catalyst and this was successively washed with methanol and dichloromethane (5mL). The organic solvents were removed under vacuum and the residue was purified by column chromatography to afford the desired compound (2–4).
82% With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 1 h; General procedure: The reaction flask, containing 0.02 g Cu(II) nanocatalyst(contains 0.4 molpercent of Cu(II)), imidazole (2.0 mmol),K2CO3 (1.0 mmol), and corresponding aryl halide(1.0 mmol) in 2.5 cm3 DMF, was immersed in a preheated oil bath and the reaction mixture was stirred under air atmosphere at 120 C until no further conversion of the starting aryl halide was observed by thin-layer chromatography(TLC). After completion of the reaction, the resulting mixture was allowed to cool to room temperature,and then the catalyst was separated out by an external permanent magnet, washed with ethyl acetate (EtOAc) anddried. The residue mixture was diluted by H2O and extracted with EtOAc (3 9 10 cm3). The extracted organic phases were dried over anhydrous Na2SO4, filtrated, concentrated and, finally, purified by silica gel chromatography using petroleum ether/ethyl acetate to afford the corresponding pure N-arylimidazole.
70% With potassium carbonate In toluene at 110℃; for 14 h; To a solution of N–H heterocycle (1 mmol) and aryl halide (2 mmol) in toluene were added catalyst (0.07 g, 0.016 mmol) and K2CO3 (276 g, 2 mmol) and the mixture stirred at 110 °C for the specified time. The progress of the reaction was monitored by TLC. The reaction mixture allowed cooling to room temperature and ethyl acetate (25 mL) was added and the mixture stirred for 15 min to ensure product removal from catalyst. Then the catalyst was filtered, washed with ethyl acetate (2 9 25 mL). The organic layer was evaporated under vacuum on a rotary evaporator and the crude product was obtained. Further purification was achieved by column chromatography using ethyl acetate/n-hexane gradient. Structural assignments of the products are based on their 1H NMR and melting point.

Reference: [1] Journal of Organic Chemistry, 2009, vol. 74, # 20, p. 7951 - 7954
[2] Tetrahedron Letters, 2007, vol. 48, # 24, p. 4207 - 4210
[3] Journal of the Chinese Chemical Society, 2013, vol. 60, # 8, p. 1007 - 1013
[4] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2018, vol. 57A, # 2, p. 181 - 185
[5] Journal of Chemical Research, 2014, vol. 38, # 2, p. 128 - 129
[6] European Journal of Inorganic Chemistry, 2017, vol. 2017, # 40, p. 4803 - 4807
[7] Synthesis, 2010, # 9, p. 1505 - 1511
[8] Organic Letters, 2009, vol. 11, # 15, p. 3294 - 3297
[9] Chemistry - A European Journal, 2004, vol. 10, # 22, p. 5607 - 5622
[10] Chemistry - A European Journal, 2006, vol. 12, # 13, p. 3636 - 3646
[11] European Journal of Organic Chemistry, 2011, # 18, p. 3353 - 3360
[12] Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 2200 - 2202
[13] Chemistry - A European Journal, 2009, vol. 15, # 36, p. 8971 - 8974
[14] ChemSusChem, 2017, vol. 10, # 24, p. 4855 - 4863
[15] Advanced Synthesis and Catalysis, 2006, vol. 348, # 15, p. 2197 - 2202
[16] Synlett, 2009, # 16, p. 2663 - 2668
[17] Journal of Catalysis, 2016, vol. 334, p. 110 - 115
[18] Monatshefte fur Chemie, 2018, vol. 149, # 6, p. 1101 - 1109
[19] Letters in Organic Chemistry, 2011, vol. 8, # 5, p. 325 - 331
[20] Organic Letters, 2006, vol. 8, # 13, p. 2779 - 2782
[21] Synlett, 2008, # 19, p. 3068 - 3072
[22] Journal of Medicinal Chemistry, 2015, vol. 58, # 24, p. 9680 - 9696
[23] Catalysis Letters, 2016, vol. 146, # 1, p. 193 - 203
[24] Asian Journal of Chemistry, 2013, vol. 25, # 11, p. 6240 - 6242
  • 82
  • [ 288-32-4 ]
  • [ 589-87-7 ]
  • [ 132464-89-2 ]
  • [ 10040-96-7 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 16, p. 6190 - 6199
  • 83
  • [ 288-32-4 ]
  • [ 460-00-4 ]
  • [ 10040-96-7 ]
Reference: [1] Angewandte Chemie - International Edition, 2012, vol. 51, # 32, p. 8012 - 8016
  • 84
  • [ 288-32-4 ]
  • [ 10040-96-7 ]
Reference: [1] Journal of Chemical Research - Part S, 2000, # 8, p. 367 - 369
  • 85
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  • [ 459-57-4 ]
  • [ 10040-98-9 ]
YieldReaction ConditionsOperation in experiment
92% With Aliquat (at)366; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 24 h; General procedure: A mixture of p-fluorobenzaldehyde 1 (25.0 g, 0.200 mol) andappropriate amine 2a–g (0.300 mol) and anhydrous potassium carbonate(40.0 g) were mixed in DMF (300mL), after which catalyticamount of Aliquat 336 reagent was added. The mixture was thenrefluxed for 24 h at 100 C. The mixture was concentrated underlow pressure and left to cool. The mixture was then poured into icewater and left overnight. The formed solid was filtered, washed withwater and crystallized with methanol to yield compounds Ia–g. 4-(1H-imidazol-1-yl) benzaldehyde Ia
Yield 92percent as yellow crystals, mp 152 °C, (as reported) [34,44].
76% With potassium carbonate In N,N-dimethyl-formamide at 110℃; General procedure: A mixture of 4-fluoro acetophenone/4-fluorobenzaldehyde (10 mmol) and imidazole/triazole (10 mmol) were dissolved in dry DMF (20 mL). K2CO3 (12 mmol) was added in small portion within a period of 15 min to the above stirred solution. Mixture was stirred for 10-12 h at 110 °C. Heating discontinued, K2CO3 was filtered off, filtrate extracted with ethyl acetate (3 .x. 15 mL). Organic layer was washed with water (3 .x. 15 mL), dried over anhydrous sodium sulphate and concentrated to given an oil which was purified on silica gel column (60-120 mesh) taking methanol: chloroform (1:99) as an eluent.
1 g With potassium carbonate In N,N-dimethyl-formamide for 6 h; Reflux Intermediate 1 Ethyl 5-(4-(lH-imidazol- l-yl)phenyl)-4H-thieno[3,2-^]pyrrole-2-carboxylate Step- 1 : Preparation of 4-(lH-imidazol-l-yl)benzaldehyde To a solution of 4-fluorobenzaldehyde (1.0 g, 8.06 mmol) in DMF (3 mL) were added 1H- imidazole (2.1 g, 32.2 mmol) and K2C03 (2.2 g, 16.12 mmol). The reaction mass was heated at reflux for 6 h before it was diluted with water and was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 1.0 g of the title product. 1H NMR (300 MHz, DMSO d6) δ 10.03 (s, 1H), 8.47 (s, 1H), 8.07-8.04 (d, = 8.4 Hz, 2H), 7.95-7.93 (m, 3H), 7.17 (s, 1H); MS (m/z): 173 (M+H)+.
Reference: [1] Synthetic Communications, 2008, vol. 38, # 4, p. 626 - 636
[2] New Journal of Chemistry, 2007, vol. 31, # 6, p. 906 - 910
[3] Bioorganic Chemistry, 2014, vol. 57, p. 65 - 82
[4] Journal of Molecular Structure, 2007, vol. 829, # 1-3, p. 202 - 207
[5] Advanced Synthesis and Catalysis, 2007, vol. 349, # 11-12, p. 1938 - 1942
[6] Journal of the American Chemical Society, 2005, vol. 127, # 28, p. 9948 - 9949
[7] European Journal of Medicinal Chemistry, 2009, vol. 44, # 11, p. 4654 - 4660
[8] Medicinal Chemistry Research, 2013, vol. 22, # 11, p. 5248 - 5254
[9] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4302 - 4310
[10] Tetrahedron, 2001, vol. 57, # 22, p. 4781 - 4785
[11] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
[12] Tetrahedron, 2008, vol. 64, # 8, p. 1823 - 1828
[13] Journal of Medicinal Chemistry, 1998, vol. 41, # 13, p. 2390 - 2410
[14] Chemical Communications, 2018, vol. 54, # 69, p. 9603 - 9606
[15] Journal of Medicinal Chemistry, 1987, vol. 30, # 6, p. 1023 - 1029
[16] RSC Advances, 2015, vol. 5, # 92, p. 75425 - 75433
[17] Patent: US7138432, 2006, B1, . Location in patent: Page/Page column 46
[18] Tetrahedron Letters, 2009, vol. 50, # 12, p. 1286 - 1289
[19] Journal of Organic Chemistry, 2013, vol. 78, # 7, p. 3222 - 3234
[20] Medicinal Chemistry Research, 2013, vol. 22, # 4, p. 1756 - 1761
[21] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 7, p. 1695 - 1697
[22] Journal of Chemical Research, 2014, vol. 38, # 8, p. 498 - 501
[23] Patent: WO2016/128905, 2016, A1, . Location in patent: Page/Page column 47
[24] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 12, p. 1107 - 1111
[25] Supramolecular Chemistry, 2017, vol. 29, # 3, p. 193 - 204
[26] Medicinal Chemistry Research, 2017, vol. 26, # 7, p. 1506 - 1515
[27] Molecules, 2017, vol. 22, # 8,
[28] Patent: CN104130192, 2017, B, . Location in patent: Paragraph 0033-0034
[29] Patent: CN107043353, 2017, A, . Location in patent: Paragraph 0034
  • 86
  • [ 288-32-4 ]
  • [ 15164-44-0 ]
  • [ 10040-98-9 ]
YieldReaction ConditionsOperation in experiment
94% With potassium carbonate In dimethyl sulfoxide at 120℃; for 12 h; Inert atmosphere General procedure: To a mixture of 0.05 g catalyst and aryl halide (1.0 mmol)in 9.0 cm3 DMSO, Het-NH (1.2 mmol) and K2CO3(2.0 mmol) was added and the mixture was vigorouslystirred at 120 C for the appropriate time under a drynitrogen atmosphere. After completion (as monitored byTLC), the catalyst was filtered, and the filtrate wasextracted with ethyl acetate (3 9 20 cm3) and the combinedorganic layers were dried with anhydrous MgSO4,filtered, and evaporated under reduced pressure. The residuewas purified by column chromatography. The purity ofthe compounds was checked by 1H NMR and yields arebased on aryl bromide. All the products are known and thespectroscopic data (FT-IR and NMR) and melting pointswere consistent with those reported in the literature [36–41].
93% With copper(l) chloride; sodium hydroxide; 3-(diphenylphosphino)propionic acid In dimethyl sulfoxide at 120℃; for 14 h; Inert atmosphere; Sealed tube General procedure: NH-containing heterocycle (1.4 mmol) and DMF (2.0 mL) were added to a mixture of CuCl (15.0 molpercent) and ligand 1 (20.0 molpercent) in DMF (2.0 mL), aryl iodide (1.0 mmol), NaOH (2.0 mmol). The mixture was vigorously stirred at 120 °C for 14 h under a dry nitrogen atmosphere. After completion of the reaction (as monitored by TLC), H2O was added and the organic layer was extracted with EtOAc, washed with brine and dried over MgSO4. The solution was filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography. The purity of the compounds was checked by 1H NMR and yields are based on aryl iodide. All the products are known and the spectroscopic data (FT‑IR and NMR) and melting points were consistent with those reported in the literature.
90 %Chromat. With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h; General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.
Reference: [1] Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 2200 - 2202
[2] Monatshefte fuer Chemie, 2015, vol. 146, # 8, p. 1329 - 1334
[3] Journal of Chemical Research, 2014, vol. 38, # 2, p. 128 - 129
[4] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
  • 87
  • [ 288-32-4 ]
  • [ 1122-91-4 ]
  • [ 10040-98-9 ]
YieldReaction ConditionsOperation in experiment
67% With potassium carbonate In N,N-dimethyl-formamide at 152℃; for 26 h; General procedure: To a vigorously stirred suspension of the CuNPs/MagSilica catalyst (100 mg) in DMF (6 mL) under air, K2CO3 (276 mg, 2.0 mmol) and imidazole (136 mg, 2.0 mmol) were added. The reaction mixture was stirred for 30 min and then the corresponding aryl halide (1.0 mmol) was added and the reaction flask was immersed in an oil bath at the reflux temperature of DMF (152 °C). The reaction mixture was stirred at this temperature until no further conversion of the starting aryl halide was observed (TLC, GC). The catalyst was immobilized by means of a permanent magnet placed on the outer wall of the reaction flask, and washed twice with Et2O (10 mL each). Finally, the catalyst was dried under vacuum (5 Torr) for its recovery and reuse. The crude reaction mixture was evaporated under vacuum (15 Torr) and the resulting residue was purified by flash column chromatography (silica gel, hexane/AcOEt) to afford the corresponding N-aryl imidazoles (2a-j). All known compounds included in Table 1 were characterized by comparison of their chromatographic and spectroscopic data (1H, 13C NMR, and MS) either with those of the corresponding commercially available pure samples (2g) or with those described in the literature (2a,21 2b,212c,22 2d,21 2e,11a 2f,11a 2h,23 2i,24 2j25).
85 %Chromat. With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h; General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.
Reference: [1] Tetrahedron, 2008, vol. 64, # 19, p. 4254 - 4259
[2] Tetrahedron, 2008, vol. 64, # 10, p. 2471 - 2479
[3] Tetrahedron Letters, 2006, vol. 47, # 23, p. 3897 - 3899
[4] Synthetic Communications, 2012, vol. 42, # 1, p. 114 - 121
[5] Chinese Journal of Chemistry, 2012, vol. 30, # 10, p. 2394 - 2400
[6] RSC Advances, 2015, vol. 5, # 12, p. 8571 - 8578
[7] Synthetic Communications, 2012, vol. 42, # 2, p. 279 - 284
[8] Research on Chemical Intermediates, 2016, vol. 42, # 10, p. 7501 - 7511
[9] Bulletin of the Chemical Society of Japan, 2008, vol. 81, # 4, p. 515 - 517
[10] Tetrahedron, 2014, vol. 70, # 36, p. 6082 - 6087
[11] Applied Organometallic Chemistry, 2017, vol. 31, # 11,
[12] Inorganic Chemistry, 2010, vol. 49, # 1, p. 331 - 338
[13] Tetrahedron, 2008, vol. 64, # 7, p. 1383 - 1387
[14] European Journal of Medicinal Chemistry, 2009, vol. 44, # 11, p. 4654 - 4660
[15] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
  • 88
  • [ 288-32-4 ]
  • [ 104-88-1 ]
  • [ 10040-98-9 ]
Reference: [1] RSC Advances, 2015, vol. 5, # 12, p. 8571 - 8578
[2] Synthetic Communications, 2008, vol. 38, # 4, p. 626 - 636
[3] Journal of Organic Chemistry, 2009, vol. 74, # 20, p. 7951 - 7954
[4] Chemical Communications, 2004, # 7, p. 778 - 779
[5] Advanced Synthesis and Catalysis, 2007, vol. 349, # 11-12, p. 1938 - 1942
[6] Journal of the American Chemical Society, 2005, vol. 127, # 28, p. 9948 - 9949
[7] Tetrahedron, 2008, vol. 64, # 10, p. 2471 - 2479
[8] European Journal of Medicinal Chemistry, 2009, vol. 44, # 11, p. 4654 - 4660
  • 89
  • [ 288-32-4 ]
  • [ 87199-17-5 ]
  • [ 10040-98-9 ]
Reference: [1] ChemCatChem, 2016, vol. 8, # 18, p. 2953 - 2960
  • 90
  • [ 288-32-4 ]
  • [ 24856-58-4 ]
  • [ 12775-96-1 ]
  • [ 10040-98-9 ]
Reference: [1] Patent: US5780498, 1998, A,
  • 91
  • [ 288-32-4 ]
  • [ 104-88-1 ]
  • [ 67-68-5 ]
  • [ 25650-51-5 ]
  • [ 10040-98-9 ]
Reference: [1] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
  • 92
  • [ 288-32-4 ]
  • [ 67-68-5 ]
  • [ 1122-91-4 ]
  • [ 10040-98-9 ]
Reference: [1] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
  • 93
  • [ 288-32-4 ]
  • [ 1194-02-1 ]
  • [ 25372-03-6 ]
YieldReaction ConditionsOperation in experiment
93% With sodium hydride In N,N-dimethyl-formamide at 20 - 100℃; 1500 ml of dry dimethylformamide (DMF) are placed in a 1000 ml four-necked flask while passing nitrogen over it and 72.67 g (0.6 mol) of 4-fluorocyanobenzene and 61.2 g (0.9 mol) of imidazole and finally 21.6 g (0.9 mol) of sodium hydride are added. The reaction mixture is heated to 100° C., stirred at this temperature for 4 hours and subsequently overnight at room temperature. The reaction mixture is then poured into water and the resulting mixture is extracted a number of times with dichloromethane. The organic phase is dried, evaporated on a rotary evaporator and finally dried further at 60° C. under reduced pressure. The yield is 94 g (93percent of theory).1H-NMR (400 MHz, CDCl3): δ=7.27 (s, 1H); 7.35 (s, 1H); 7.54 (d, J=8.8 Hz, 2H); 7.81 (d, J=8.8 Hz, 2H); 7.95 (s, 1H).
Reference: [1] Synthetic Communications, 2008, vol. 38, # 4, p. 626 - 636
[2] Patent: WO2006/56418, 2006, A2, . Location in patent: Page/Page column 57
[3] Patent: US2009/18330, 2009, A1, . Location in patent: Page/Page column 14
[4] Advanced Synthesis and Catalysis, 2007, vol. 349, # 11-12, p. 1938 - 1942
[5] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
[6] Journal of Organic Chemistry, 2011, vol. 76, # 4, p. 1151 - 1154
[7] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 18, p. 3879 - 3887
[8] Tetrahedron Letters, 2009, vol. 50, # 12, p. 1286 - 1289
[9] Journal of Materials Chemistry A, 2017, vol. 5, # 2, p. 535 - 543
  • 94
  • [ 288-32-4 ]
  • [ 623-03-0 ]
  • [ 25372-03-6 ]
YieldReaction ConditionsOperation in experiment
90% With copper(l) iodide; caesium carbonate; dimethylbiguanide In N,N-dimethyl-formamide at 20 - 110℃; for 12.1667 h; General procedure: A 25 mL flask with a magnetic stirring bar was charged with CuI(9.6 mg, 0.05 mmol), metformin (0.1 mmol), Cs2CO3 (652 mg,2.0 mmol), imidazole (1.0 mmol), an aryl halide (1.1 mmol), andDMF (5 mL). The mixture was stirred for 10 min at room temperature,and then heated to 110C for the appropriate amount of time(see Table 2). The progress of the reaction was monitored by TLC.After completion of the reaction, the mixture was extracted with EtOAc (5 1 mL) and the organic phase separated and evaporated. Further purification by column chromatography gave the desired coupled product.
Reference: [1] Journal of the American Chemical Society, 2005, vol. 127, # 28, p. 9948 - 9949
[2] Synthesis, 2009, # 15, p. 2517 - 2522
[3] RSC Advances, 2015, vol. 5, # 112, p. 92121 - 92127
[4] Journal of Organic Chemistry, 2007, vol. 72, # 8, p. 2737 - 2743
[5] Journal of Organic Chemistry, 2007, vol. 72, # 22, p. 8535 - 8538
[6] Synthetic Communications, 2008, vol. 38, # 4, p. 626 - 636
[7] Bulletin of the Chemical Society of Japan, 2008, vol. 81, # 4, p. 515 - 517
[8] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3151 - 3159
[9] Tetrahedron Letters, 2013, vol. 54, # 52, p. 7095 - 7099
[10] Tetrahedron, 2008, vol. 64, # 10, p. 2471 - 2479
[11] Advanced Synthesis and Catalysis, 2007, vol. 349, # 11-12, p. 1938 - 1942
[12] Journal of the American Chemical Society, 2007, vol. 129, # 45, p. 13879 - 13886
[13] Polyhedron, 2012, vol. 34, # 1, p. 143 - 148
[14] Synthesis, 2010, # 9, p. 1505 - 1511
[15] Journal of Organic Chemistry, 2009, vol. 74, # 20, p. 7951 - 7954
[16] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
[17] Synlett, 2006, # 14, p. 2195 - 2198
  • 95
  • [ 288-32-4 ]
  • [ 3058-39-7 ]
  • [ 25372-03-6 ]
YieldReaction ConditionsOperation in experiment
98% With copper(l) iodide; caesium carbonate; dimethylbiguanide In N,N-dimethyl-formamide at 20 - 110℃; for 8.16667 h; General procedure: A 25 mL flask with a magnetic stirring bar was charged with CuI(9.6 mg, 0.05 mmol), metformin (0.1 mmol), Cs2CO3 (652 mg,2.0 mmol), imidazole (1.0 mmol), an aryl halide (1.1 mmol), andDMF (5 mL). The mixture was stirred for 10 min at room temperature,and then heated to 110C for the appropriate amount of time(see Table 2). The progress of the reaction was monitored by TLC.After completion of the reaction, the mixture was extracted with EtOAc (5 1 mL) and the organic phase separated and evaporated. Further purification by column chromatography gave the desired coupled product.
95% With copper(I) oxide; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 12 h; General procedure: A 10-mL vial was charged with aryl halide (0.5 mmol), Cs2CO3 (1 mmol), Cu2O (0.05 mmol), N-containing heterocycles (0.75 mmol), DMF (1 mL), and a magnetic stir bar. The mixture was stirred at 120 °C (130 °C for entry 19). The reaction mixture was held at this temperature for 12 h (24 h for entry 18, 20, 21, and 25). After allowing the mixture to cool to room temperature, the reaction mixture was extracted with ethyl acetate (3 10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether as the eluent) to provide the target products 3a–3t.
93% With C40H34CuIN6O6; sodium hydroxide In dimethyl sulfoxide at 100℃; for 4 h; Sealed tube General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 °C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
91% With copper(l) iodide; 1,10-phenanthroline N-oxide; caesium carbonate In N,N-dimethyl-formamide at 20℃; for 22 h; Inert atmosphere To the three-neck flask, CuI (19 mg, 0.1 mmol, 10 molpercent), 1,10-phenanthroline-N-oxide (39 mg, 0.2 mmol, 20 molpercent), Cs2CO3 (650 mg, 2.0mmol). The reaction flask was evacuated under argon. p-cyanoiodobenzene (229 mg, 1.0 mmol), imidazole (102 mg, 1.5 mmol) and DMF (2 ml) were added under argon atmosphere. The reaction was allowed to proceed at room temperature for 22 hours until the reaction starting material was completely reacted (TLC assay reaction was complete). After completion of the reaction, a brown oil was obtained which was diluted with ethyl acetate. The inorganic salt was removed by filtration and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluant to give 1-(4-carbonitrilephenyl)imidazole as a white solid in 91percent yield.
96%Chromat. With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h; General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.

Reference: [1] Tetrahedron Letters, 2013, vol. 54, # 52, p. 7095 - 7099
[2] Synthetic Communications, 2017, vol. 47, # 19, p. 1797 - 1803
[3] Synlett, 2004, # 1, p. 128 - 130
[4] Journal of Organic Chemistry, 2005, vol. 70, # 13, p. 5164 - 5173
[5] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2018, vol. 57A, # 2, p. 181 - 185
[6] New Journal of Chemistry, 2015, vol. 39, # 4, p. 2901 - 2907
[7] Patent: CN104356131, 2016, B, . Location in patent: Paragraph 0145-0156
[8] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
[9] Catalysis Science and Technology, 2017, vol. 7, # 19, p. 4401 - 4412
  • 96
  • [ 288-32-4 ]
  • [ 126747-14-6 ]
  • [ 25372-03-6 ]
YieldReaction ConditionsOperation in experiment
77% With copper(I) 3-metthylsalicylate; potassium carbonate In methanol at 65℃; for 3 h; General procedure: A dry flask was charged with the nitrogen containing heterocycles (1 mmol), aryl boronic acids (2.2 mmol), potassium carbonate (2 mmol) andCuMeSal (0.015 mmol)then anhydrous methanol (10 ml) was added. The reaction mixture was stirred at 65 oC, open to air, for 3 h (5 h in case of indole and benzimidazole), cooled to room temperature, filtered, and the precipitate was washed with methanol (2 ml), the filtrate was concentrated under vacuum, then stirred with ice water (30 ml) and extracted with ethyl acetate (3 × 50 ml), dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by chromatography or recrystallization as indicated with each compound.
52% With 4,4'-dimethyl-2,2'-bipyridines; oxygen; copper diacetate In water at 20℃; for 24 h; General procedure: Under an O2 atmosphere, a mixture of 4-methoxyphenylboroic acid (1a, 60.8 mg, 0.40 mmol), imidazole (2a, 13.6 mg, 0.20 mmol), Cu(OAc)2 (3.6 mg, 0.020 mmol), ligand I (3.7 mg, 0.020 mmol), and Triton X-100 (38.8 mg, 0.060 mmol) in H2O (4 mL) was stirred at room temperature for 24 h. The mixture was diluted with brine and extracted with AcOEt (30 mL.x.3). The organic layer was washed with H2O (10 mL.x.3) and dried over MgSO4. The solvent was removed under the reduced pressure and the residue was purified by SiO2 column chromatography using AcOEt to give N-(4-methoxyphenyl)imidazole (3aa) (23.0 mg, 66percent).
Reference: [1] ChemCatChem, 2016, vol. 8, # 18, p. 2953 - 2960
[2] Chemistry Letters, 2010, vol. 39, # 7, p. 764 - 765
[3] Synthetic Communications, 2015, vol. 45, # 2, p. 245 - 252
[4] Tetrahedron, 2012, vol. 68, # 38, p. 7794 - 7798
  • 97
  • [ 288-32-4 ]
  • [ 623-00-7 ]
  • [ 25372-03-6 ]
YieldReaction ConditionsOperation in experiment
97% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 12 h; General procedure: A mixture of aryl halide (2.4 mmol) and Cs2CO3(4.0 mmol,0.650 g), nitrogen-containing heterocycle (2.0 mmol), dry DMF(3 mL) solvent and catalyst was stirred at 100C in an oil bath under air. After cooling to room temperature, catalyst was first separated out by centrifugation and the liquid part was extracted with water and diethylether (2 × 15 mL). The organic layers thus collected were combined and washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (mesh 60–120) using an n-hexane/ethylacetate mixture as the eluent to collect the desiredproduct. The product was analyzed by 1H and13C NMR and mass spectroscopy.
88% With copper(l) iodide; 1,10-phenanthroline N-oxide; caesium carbonate In N,N-dimethyl-formamide at 80℃; for 24 h; Inert atmosphere To the three-necked flask, CuI (19 mg, 0.1 mmol, 10 molpercent), 1,10-phenanthroline-N-oxide (39 mg, 0.2 mmol, 20 molpercent), Cs2CO3 (650 mg, 2.0mmol). The reaction flask was evacuated under argon. p-bromobenzonitrile (181 mg, 1.0 mmol), imidazole (102 mg, 1.5 mmol) and DMF (2 mL) were added under argon atmosphere. The reaction was continued for 24 hours at 80 °C until the reaction starting material was completely reacted (TLC assay reaction was complete). After completion of the reaction, a brown oil was obtained which was diluted with ethyl acetate. The inorganic salt was removed by filtration and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluant to give 1-(4-carbonitrilephenyl)imidazole as a pale yellow oil in 88percent yield.
88% With C40H34CuIN6O6; sodium hydroxide In dimethyl sulfoxide at 100℃; for 4 h; Sealed tube General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 °C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
85% With copper(l) iodide; potassium carbonate; <i>L</i>-proline In dimethyl sulfoxide at 85℃; To a mixture of 4-bromobenzonitrile (40 g, 222 mmol) and imidazole (60g, 888 mmol) in DMSO (150 ml) was added L-proline (15.2 g, 132 mmol), CuI (12.6 g, 67 mmol) and K2CO3 (60 g, 444 mmol). The resulting mixture was degassed and heated to 85 °C overnight, then cooled to room temperature and diluted with EA (1 L) and water (300 ml). The aqueous layer was extracted with EA (100 ml x 2). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to afford 19-1 as a white solid (32 g, yield 85percent).
84% With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 0.5 h; General procedure: The reaction flask, containing 0.02 g Cu(II) nanocatalyst(contains 0.4 molpercent of Cu(II)), imidazole (2.0 mmol),K2CO3 (1.0 mmol), and corresponding aryl halide(1.0 mmol) in 2.5 cm3 DMF, was immersed in a preheated oil bath and the reaction mixture was stirred under air atmosphere at 120 C until no further conversion of the starting aryl halide was observed by thin-layer chromatography(TLC). After completion of the reaction, the resulting mixture was allowed to cool to room temperature,and then the catalyst was separated out by an external permanent magnet, washed with ethyl acetate (EtOAc) anddried. The residue mixture was diluted by H2O and extracted with EtOAc (3 9 10 cm3). The extracted organic phases were dried over anhydrous Na2SO4, filtrated, concentrated and, finally, purified by silica gel chromatography using petroleum ether/ethyl acetate to afford the corresponding pure N-arylimidazole.
80% With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 120℃; for 2 h; Inert atmosphere General procedure: A 25-mL Schlenk tube was flame-dried under vacuum and filled with argon after cooling to room temperature. To this tube were added phenol (1.0 mmol), t-BuOK (2.0 mmol). The tube was then evacuated and backfilled with argon (3 cycles). A dry DMSO solution (1.0 mL) of aryl bromides(2.0 mmol) was loaded into a plastic syringe. After the tube was purged with argon, this solutionwas injected into bottom of the tube using a long needle syringe. The mixture was stirred under Ar atmosphere in sealed Schlenk tubes at the corresponding temperature. When the reaction was cooled down to room temperature, the mixture was filtered through a short plug of silica gel and washed with 100 mL dichloromethane and water. The combined organic phase was concentrated under vacuum. The product was purified through flash column chromatography on 200-300 mesh silica gel with petroleum ether/ethyl acetate as eluent with a suitable ratio according to the TLC experiments. The identity and purity of the product were ascertained by GC-MS, HRMS, 1H and 13C NMR spectroscopy.
80% With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 130℃; for 24 h; Inert atmosphere General procedure: To a suspension of 4-bromobenzonitrile (1 equiv), CuI (0.2 equiv) in DMF (10 mL) were added Cs2CO3 (2 equiv) and imidazole (1.4 equiv). The mixture was stirred at 130 °C under N2 for 24 h. After cooling to room temperature, H2O (50 mL) wasadded and the mixture was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (50 mLx3) and dried over Na2SO4. After concentration, the residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the desired products 30 and 31.
74% With copper(I) oxide; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 12 h; General procedure: A 10-mL vial was charged with aryl halide (0.5 mmol), Cs2CO3 (1 mmol), Cu2O (0.05 mmol), N-containing heterocycles (0.75 mmol), DMF (1 mL), and a magnetic stir bar. The mixture was stirred at 120 °C (130 °C for entry 19). The reaction mixture was held at this temperature for 12 h (24 h for entry 18, 20, 21, and 25). After allowing the mixture to cool to room temperature, the reaction mixture was extracted with ethyl acetate (3 10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether as the eluent) to provide the target products 3a–3t.
92 %Chromat. With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h; General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.

Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 22, p. 8535 - 8538
[2] Journal of Organic Chemistry, 2005, vol. 70, # 13, p. 5164 - 5173
[3] Applied Catalysis A: General, 2016, vol. 513, p. 53 - 66
[4] Journal of the Chinese Chemical Society, 2013, vol. 60, # 8, p. 1007 - 1013
[5] Journal of Organic Chemistry, 2007, vol. 72, # 8, p. 2737 - 2743
[6] Journal of the American Chemical Society, 2007, vol. 129, # 45, p. 13879 - 13886
[7] Green Chemistry, 2012, vol. 14, # 5, p. 1268 - 1271
[8] Journal of Organic Chemistry, 2008, vol. 73, # 21, p. 8639 - 8642
[9] Tetrahedron, 2008, vol. 64, # 10, p. 2471 - 2479
[10] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3151 - 3159
[11] Synthesis, 2010, # 9, p. 1505 - 1511
[12] Patent: CN104356131, 2016, B, . Location in patent: Paragraph 0211-0222
[13] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2018, vol. 57A, # 2, p. 181 - 185
[14] European Journal of Organic Chemistry, 2011, # 14, p. 2692 - 2696
[15] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5849 - 5853
[16] Polyhedron, 2012, vol. 34, # 1, p. 143 - 148
[17] Synthesis, 2002, # 11, p. 1597 - 1600
[18] Monatshefte fur Chemie, 2018, vol. 149, # 6, p. 1101 - 1109
[19] Inorganic Chemistry, 2015, vol. 54, # 20, p. 9885 - 9895
[20] Organic Letters, 2009, vol. 11, # 15, p. 3294 - 3297
[21] Chemistry - A European Journal, 2009, vol. 15, # 36, p. 8971 - 8974
[22] Tetrahedron Letters, 2012, vol. 53, # 33, p. 4288 - 4292
[23] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5861 - 5872
[24] Synthesis, 2011, # 23, p. 3915 - 3924
[25] Synthetic Communications, 2017, vol. 47, # 19, p. 1797 - 1803
[26] RSC Advances, 2015, vol. 5, # 12, p. 8571 - 8578
[27] Monatshefte fur Chemie, 2004, vol. 135, # 4, p. 419 - 423
[28] Inorganic Chemistry, 2016, vol. 55, # 12, p. 6085 - 6094
[29] Chemical Communications, 2007, # 45, p. 4809 - 4811
[30] Chemical Communications, 2013, vol. 49, # 31, p. 3230 - 3232
[31] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
  • 98
  • [ 288-32-4 ]
  • [ 1194-02-1 ]
  • [ 584-08-7 ]
  • [ 25372-03-6 ]
Reference: [1] Patent: US5736548, 1998, A,
  • 99
  • [ 288-32-4 ]
  • [ 3433-80-5 ]
  • [ 72459-45-1 ]
Reference: [1] Patent: WO2017/107979, 2017, A1, . Location in patent: Paragraph 294
[2] Synlett, 2006, # 18, p. 3170 - 3172
  • 100
  • [ 288-32-4 ]
  • [ 95-46-5 ]
  • [ 72459-45-1 ]
YieldReaction ConditionsOperation in experiment
20 g
Stage #1: With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 16 h; Inert atmosphere; Reflux
Stage #2: With potassium carbonate In tetrachloromethane for 5 h; Inert atmosphere; Reflux
O-bromotoluene (20g, 117mmol),Bromosuccinimide (22.0 g, 123 mmol),Azobisisobutyronitrile (1 g) was dissolved in dry carbon tetrachloride (200 mL)Heat under reflux for 16 hours under nitrogen.The reaction was cooled to room temperature and filtered,Imidazole (15.9 g, 234 mmol) and potassium carbonate (33 g, 234 mmol) were added to the filtrate,Heat under reflux for 5 hours under nitrogen.LC-MS showed the reaction was complete,The reaction solution was filtered,The filtrate was concentrated,The residue was dissolved in dichloromethane (100 mL)Wash with water (2 × 50 mL).The organic phase is separated,Dried over anhydrous sodium sulfate,filter,concentrate,The residue was purified by flash silica gel column to give 1- (2-bromobenzyl) -1H-imidazole (20 g).
Reference: [1] Patent: CN107312005, 2017, A, . Location in patent: Paragraph 0103; 0104; 0105; 0106
  • 101
  • [ 288-32-4 ]
  • [ 3433-80-5 ]
  • [ 72459-45-1 ]
Reference: [1] European Journal of Organic Chemistry, 2014, vol. 2014, # 25, p. 5469 - 5475
  • 102
  • [ 288-32-4 ]
  • [ 5159-41-1 ]
  • [ 25373-56-2 ]
Reference: [1] Organic Letters, 2006, vol. 8, # 13, p. 2779 - 2782
[2] Journal of Organic Chemistry, 2007, vol. 72, # 16, p. 6190 - 6199
  • 103
  • [ 288-32-4 ]
  • [ 589-15-1 ]
  • [ 72459-46-2 ]
Reference: [1] New Journal of Chemistry, 2004, vol. 28, # 8, p. 1010 - 1018
[2] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 4, p. 1992 - 2010
[3] Journal of the American Chemical Society, 2017, vol. 139, # 24, p. 8267 - 8276
[4] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 2, p. 178 - 182
[5] Journal of Medicinal Chemistry, 2004, vol. 47, # 24, p. 5995 - 6008
[6] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 16, p. 6184 - 6196
[7] Journal of Medicinal Chemistry, 2010, vol. 53, # 4, p. 1712 - 1725
[8] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 15, p. 4011 - 4015
[9] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 18, p. 4752 - 4756
[10] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 684 - 701
[11] ChemistryOpen, 2016, vol. 5, # 6, p. 566 - 573
  • 104
  • [ 288-32-4 ]
  • [ 107-05-1 ]
  • [ 4252-78-2 ]
  • [ 35554-44-0 ]
YieldReaction ConditionsOperation in experiment
64.4%
Stage #1: at 70℃; for 9 h;
Stage #2: at 50 - 100℃; for 5 h;
Stage #3: at 105℃; for 6 h;
This embodiment provides a method for preparing graciousness kang zuo, comprises the steps of: under stirring, sequentially the formic acid 185 g (4.0 µM), 2, 4 - dichloro -2 ' - chloro acetophenone 45.1 g (0.2 µM), triethylamine 10 g (0.1 µM), RuCl2(Pph3)39. 5 G (0.01 µM) into 500 ml three flasks, heating 70 °C insulation reaction 9 h. Reaction finishes cooling to 50 °C, negative pressure steaming to without dripping the liquid, to a room temperature. Adding DMA 175 g (2.0 µM), sodium hydroxide 16 g (0.4 µM), imidazole 22 g (0.32 µM), heating up to 100 °C insulation reaction 5 h, cooled to the room temperature, dropping propyl 24 g (0.32 µM), heating up to 105 °C insulation reaction 6 h. The completion of the reaction to room temperature, add 320 ml water, filtered to obtain [...], crude product by adding 100 ml ethanol, heating reflux 1 h, to room temperature and filtered, to obtain fine graciousness kang zuo 28.7 g, yield 64.4percent, liquid phase analysis purity ≥ 98percent, melting point 50.9 - 52.0 °C.
Reference: [1] Patent: CN108191765, 2018, A, . Location in patent: Paragraph 0023-0034
  • 105
  • [ 288-32-4 ]
  • [ 16265-04-6 ]
Reference: [1] New Journal of Chemistry, 2018, vol. 42, # 23, p. 18889 - 18893
  • 106
  • [ 288-32-4 ]
  • [ 15965-31-8 ]
YieldReaction ConditionsOperation in experiment
52%
Stage #1: With sodium hydroxide In water at 20℃; for 0.25 h;
Stage #2: With sodium hypochlorite solution In water at 10 - 20℃; for 6 h;
Stage #3: With hydrogenchloride In water at 10℃;
Imidazole (10 g, 0.150 mol) and sodium hydroxide (29.4 g, 0.74 mol) were charged to the reaction flask containing water (250 mL) and stirred vigorously for 15 min at ambient temperature.
Cooled the reaction mass to 10 °C and charged sodium hypochlorite (16.7 g, 0.225 mol) to the reaction mixture, during the addition temperature was maintained at 10 °C.
Stirred the reaction mass for 6 h at ambient temperature, the reaction completion was monitored by TLC.
After the completion of the reaction cooled the reaction mass to 10 °C and slowly charged concentrated HCl solution to bring the reaction pH to 6 to 7.
Charged dichloromethane (2 * 200 mL) and stirred for 10 min, separated the organic layer and was washed with saturated brine solution.
The organic layer was dried over sodium sulfate and concentrated the dichloromethane and the crude obtained was purified by column chromatography on a silica gel (230-400 mesh) using ethyl acetate (10-35percent) in petroleum ether as eluant to afford 4-chloroimidazole.
Appearance: Pale yellow solid; Yield = 52percent; M.P. = 118-119 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm = 7.09 (s, 1H, ArH), 7.39 (s, 1H, ArH), 12.42 (s, 1H, NH); 13C NMR (300 MHz, DMSO-d6) δ ppm = 126.7, 128.2, 140.2; LC/MS (ESI-MS) m/z = 103.6 (M + 1).
12% With N-chloro-succinimide In N,N-dimethyl-formamide at 0℃; Step 1.
Synthesis of 4-chloro-1H-imidazole (C33)
To a solution of 1H-imidazole (22.1 g, 324 mmol) in N,N-dimethylformamide at 0° C. was added drop-wise (over 4 hours) a solution of N-chlorosuccinimide (25 g, 190 mmol) in N,N-dimethylformamide (total solvent, 160 mL).
The reaction was stirred at 0° C. for 1 hour, whereupon water (200 mL) was added at 0° C.
The mixture was extracted with ethyl acetate (3*50 mL), and the combined organic layers were concentrated in vacuo.
Purification was carried out using supercritical fluid chromatography (Column: Princeton Cyano, 5 μm; Eluant: 15:85 methanol/carbon dioxide).
The resulting material was purified again, using silica gel chromatography (Mobile phase A: ethyl acetate; Mobile phase B: [20percent (2 M ammonia in methanol) in dichloromethane]; Gradient:
0percent to 10percent B) to afford the title compound as a white solid. Yield: 2.45 g, 23.9 mmol, 12percent. GCMS m/z 102, 104 (M+).
1H NMR (400 MHz, CDCl3) δ 7.00 (d, J=1.2 Hz, 1H), 7.57 (br s, 1H), 11.3 (v br s, 1H).
Reference: [1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5823 - 5828
[2] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 354 - 365
[3] Patent: US2012/252758, 2012, A1, . Location in patent: Page/Page column 30
[4] Patent: US2012/202834, 2012, A1, . Location in patent: Page/Page column 34
  • 107
  • [ 288-32-4 ]
  • [ 15965-31-8 ]
  • [ 15965-30-7 ]
Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 25, p. 9448 - 9454
  • 108
  • [ 288-32-4 ]
  • [ 822-55-9 ]
  • [ 3034-50-2 ]
Reference: [1] Patent: US4977174, 1990, A,
  • 109
  • [ 288-32-4 ]
  • [ 75-26-3 ]
  • [ 4532-96-1 ]
YieldReaction ConditionsOperation in experiment
74%
Stage #1: With sodium hydroxide In dimethyl sulfoxide at 20℃; for 1.5 h;
Stage #2: at 20℃;
General procedure: Imidazole (3)/benzimidazole(5) (10 mmol) was dissolved in 10 ml of DMSO and solid NaOH(15 mmol) was then added it. The resulting pale yellow suspensionwas stirred in air at room temperature for 1.5 h, after which, thealkyl bromides or benzyl chlorides (15 mmol) were added andallowed to react until completion (TLC). Water (50 ml) was thenadded and the products were extracted with ethyl acetate. Combinedorganic layers were washed several times with water, thenwith brine, dried over Na2SO4 and subjected to chromatographicpurification over silica (100–200 mesh) using MeOH: EtOAc 5:95(v/v) as the mobile phase. Compounds 4a-f were isolated as yellowoils whereas, the compounds 7a-e were white solid. Spectroscopic data of the N-alkyl imidazoles are in accord with earlier literatureand thus are not shown here [30].
Reference: [1] Russian Journal of Organic Chemistry, 2003, vol. 39, # 10, p. 1467 - 1470
[2] Polyhedron, 2017, vol. 127, p. 68 - 83
[3] Helvetica Chimica Acta, 2014, vol. 97, # 12, p. 1666 - 1671
  • 110
  • [ 288-32-4 ]
  • [ 75-30-9 ]
  • [ 4532-96-1 ]
Reference: [1] Organometallics, 2011, vol. 30, # 18, p. 4974 - 4982
  • 111
  • [ 288-32-4 ]
  • [ 20671-53-8 ]
  • [ 1122-63-0 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1982, vol. 18, p. 6 - 10[2] Zhurnal Organicheskoi Khimii, 1982, vol. 18, # 1, p. 9 - 14
  • 112
  • [ 288-32-4 ]
  • [ 1072-84-0 ]
Reference: [1] Patent: US4672128, 1987, A,
  • 113
  • [ 288-32-4 ]
  • [ 2314-97-8 ]
  • [ 33468-69-8 ]
  • [ 66675-22-7 ]
Reference: [1] Journal of Organic Chemistry, 1982, vol. 47, # 15, p. 2867 - 2872
  • 114
  • [ 288-32-4 ]
  • [ 2314-97-8 ]
  • [ 81654-07-1 ]
  • [ 33468-69-8 ]
  • [ 66675-22-7 ]
Reference: [1] Journal of Organic Chemistry, 1982, vol. 47, # 15, p. 2867 - 2872
  • 115
  • [ 288-32-4 ]
  • [ 106-40-1 ]
  • [ 2221-00-3 ]
YieldReaction ConditionsOperation in experiment
88% With C40H34CuIN6O6; sodium hydroxide In dimethyl sulfoxide at 100℃; for 4 h; Sealed tube General procedure: For the catalysis reaction, the catalyst C1 (12 mg,0.01 mmol), imidazole (1.0 mmol), aryl halide(1.0 mmol), NaOH (80 mg, 2.0 mmol), and dimethylsulfoxide (DMSO, 5 mL) were taken in a sealed tube. The reaction mixture was stirred at 100 °C for 4 h and then cooled to room temperature. After adding 5 mL of H2O, the solution was extracted with ethyl acetate. The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure.The N-arylated product was finally obtained by columnchromatography on silica gel.
78% With potassium hydroxide In dimethyl sulfoxide at 100℃; for 10 h; General procedure: A mixture of aryl iodide (1.0 mmol), Het-NH (1.2 mmol), KOH (2 mmol), nanomagnetic Fe3O4-TiO2/Cu2O (0.010 g equal to 1.4 molpercent Cu2O) and anhydrous DMSO (2 mL) was stirred at 100 °C. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature and diluted by ethyl acetate and the catalyst was separated by an external magnet from the mixture, washed with acetone, dried in an oven at 80 °C for 3 h and re-used for a consecutive run under the same reaction conditions. The combined ethyl acetate layer was washed with water and dried over anhydrous MgSO4. The residue was purified by recrystallization or short column chromatography on silica gel to afford the target products in excellent yield.
75% With potassium hydroxide In dimethyl sulfoxide at 100℃; for 9 h; General procedure: A mixture of aryl halide (1.0 mmol), Het-NH (1.2mmol) or amine (4 mmol), KOH (2 mmol), Cu2O/nano-CuFe2O4 magnetic composite (0.010 g) and anhydrous DMSO (2 mL) was stirred at 100 °C. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature and with diluted ethyl acetate and the catalyst was separated by an external magnet from the mixture, washed with acetone, dried in an oven at 80 °C for 3 h and re-used for a consecutive run under the same reaction conditions. The combined ethyl acetate layer was washed with water, dried over anhydrous MgSO4, The residue was purified by recrystallization or short column chromatography on silica gel to afford the target products in excellent yield.
75 %Chromat. With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h; General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.

Reference: [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 13, p. 4101 - 4114
[2] Journal of the Chinese Chemical Society, 2013, vol. 60, # 8, p. 1007 - 1013
[3] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2018, vol. 57A, # 2, p. 181 - 185
[4] Journal of the American Chemical Society, 2007, vol. 129, # 45, p. 13879 - 13886
[5] Advanced Synthesis and Catalysis, 2017, vol. 359, # 10, p. 1631 - 1636
[6] Tetrahedron Letters, 2008, vol. 49, # 28, p. 4386 - 4389
[7] Chinese Journal of Chemistry, 2012, vol. 30, # 10, p. 2394 - 2400
[8] Tetrahedron, 2008, vol. 64, # 19, p. 4254 - 4259
[9] Journal of Organic Chemistry, 2007, vol. 72, # 8, p. 2737 - 2743
[10] Synthesis, 2010, # 9, p. 1505 - 1511
[11] Journal of Organic Chemistry, 2007, vol. 72, # 22, p. 8535 - 8538
[12] Chinese Journal of Chemistry, 2013, vol. 31, # 2, p. 267 - 270
[13] Journal of Organic Chemistry, 2008, vol. 73, # 21, p. 8639 - 8642
[14] Green Chemistry, 2012, vol. 14, # 5, p. 1268 - 1271
[15] Research on Chemical Intermediates, 2016, vol. 42, # 10, p. 7611 - 7624
[16] Chemistry Letters, 2016, vol. 45, # 2, p. 223 - 225
[17] Monatshefte fur Chemie, 2010, vol. 141, # 9, p. 1009 - 1013
[18] Chemistry - A European Journal, 2009, vol. 15, # 36, p. 8971 - 8974
[19] Synthetic Communications, 2012, vol. 42, # 2, p. 279 - 284
[20] Organic Letters, 2009, vol. 11, # 15, p. 3294 - 3297
[21] Soft Matter, 2012, vol. 8, # 7, p. 2274 - 2285
[22] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
  • 116
  • [ 288-32-4 ]
  • [ 540-37-4 ]
  • [ 2221-00-3 ]
YieldReaction ConditionsOperation in experiment
75% With copper(l) chloride; sodium hydroxide; 3-(diphenylphosphino)propionic acid In dimethyl sulfoxide at 120℃; for 14 h; Inert atmosphere; Sealed tube General procedure: NH-containing heterocycle (1.4 mmol) and DMF (2.0 mL) were added to a mixture of CuCl (15.0 molpercent) and ligand 1 (20.0 molpercent) in DMF (2.0 mL), aryl iodide (1.0 mmol), NaOH (2.0 mmol). The mixture was vigorously stirred at 120 °C for 14 h under a dry nitrogen atmosphere. After completion of the reaction (as monitored by TLC), H2O was added and the organic layer was extracted with EtOAc, washed with brine and dried over MgSO4. The solution was filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography. The purity of the compounds was checked by 1H NMR and yields are based on aryl iodide. All the products are known and the spectroscopic data (FT‑IR and NMR) and melting points were consistent with those reported in the literature.
80 %Chromat. With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h; General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.
Reference: [1] Green Chemistry, 2013, vol. 15, # 2, p. 336 - 340
[2] Journal of the Chinese Chemical Society, 2013, vol. 60, # 8, p. 1007 - 1013
[3] RSC Advances, 2014, vol. 4, # 14, p. 7321 - 7329
[4] New Journal of Chemistry, 2015, vol. 39, # 4, p. 2901 - 2907
[5] Chemistry - An Asian Journal, 2014, vol. 9, # 12, p. 3418 - 3430
[6] Journal of Chemical Research, 2014, vol. 38, # 2, p. 128 - 129
[7] Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 2200 - 2202
[8] RSC Advances, 2015, vol. 5, # 2, p. 1522 - 1528
[9] Tetrahedron, 2006, vol. 62, # 18, p. 4435 - 4443
[10] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2136 - 2145
[11] RSC Advances, 2014, vol. 4, # 29, p. 15122 - 15130
[12] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
  • 117
  • [ 288-32-4 ]
  • [ 24424-99-5 ]
  • [ 49761-82-2 ]
YieldReaction ConditionsOperation in experiment
100% With guanidine hydrochloride In ethanol at 35 - 40℃; for 0.0166667 h; General procedure: Amine (1 mmol) was added to a magnetically stirred solution of guanidine hydrochloride (15 molpercent) and di-tert-butyl dicarbonate (1.2 mmol) in EtOH (1 mL), at 35-40°C and stirred for appropriate time (Table 1). After completion of the reaction (followed by TLC or GC), EtOH was evaporated under vacuum and the residue either was washed with water to remove the catalyst or was dissolved in CH2Cl2 (or EtOAc) and filtered off to separate out the catalyst. Evaporation of the organic solvent (if used in work up) gives almost a pure product. In the cases of using an excess (Boc)2O the product was washed with petroleum ether or hexane to recover the residual (Boc)2O. If necessary, the product was further purified either by crystallization (hexane and dichloromethane, or diethyl ether and petroleum ether) or silica gel column chromatography using EtOAc-hexane (1: 6) as eluent.
99% With copper In neat (no solvent) at 20℃; for 0.166667 h; General procedure: To a mixture of amine (1.0 mmol) and (Boc)2O (1.2 mmol), copper nano particles (0.1 mmol) was added with vigorous stirring at room temperature or 70 oC for the appropriate time (Scheme 2 and Table 2) until disappearance of the precursor amine was observed in the TLC. After completion, the reaction mixture was diluted with dry ether (5 mL) and catalyst was separated by filtration and the residue was washed with ether. The combined filtrate was evaporated to dryness and dried under vacuum. The N-Boc product is essentially pure on TLC but for getting analytical data the sample was passed through silica-gel (100-200 mesh) column using 10-30percent ethyl acetate in hexane as eluent. The physical data (m.p., FTIR, NMR) of the known compounds were found to be identical with those reported in the literature.
96% With iron(III) trifluoromethanesulfonate In neat (no solvent) at 20℃; for 0.116667 h; Green chemistry General procedure: Fe(OTf)3 (1 molpercent) was added to a magnetically stirred mixture of anamine (1 mmol) and Boc2O (1 mmol) at room temperature. The mixturewas stirred until completion of the reaction (TLC), then diluted withEtOAc and washed with water. The organic layer was dried overanhydrous MgSO4, then the solvent was distillated off under vacuum toyield the highly pure N‑Boc derivatives
95% for 2 h; Inert atmosphere Under nitrogen, imidazole was dissolved in anhydrous tetrahydrofuran (THF), and an appropriate amount of di-tert-butyl dicarbonate was dropped slowly into the solution; then reaction was carried out for about 2 hours accompanied by effervescent and exothermic phenomena. After the reaction was completed, the solvent and tert-butyl alcohol byproduct were removed by vacuum reduced pressure concentration to provide compound 2 as white solid, with yield of about 95percent.
95% for 2 h; Inert atmosphere Under nitrogen system imidazole dissolved in anhydrous tetrahydrofuran (tetrahydrofuran, hereinafter THF) and slowly added dropwise to the appropriate third-butyl dicarbonate (di-tert-butyl dicarbonate), then the reaction exotherm and bubbling, about two hours i.e. the reaction is completed; after completion of the reaction, concentration under reduced pressure, and the solvent was evacuated in vacuo and the third by-product alcohol is removed, to give a white solid of compound 2, producing approximately 95percent.
94% With Amberlyst® A21 In neat (no solvent) at 20℃; for 0.0833333 h; Green chemistry General procedure: Amberlyst® A21 (20 wt percent) was added to a mixture of amine (1 mmole) and (Boc)2O (1 mmole) and the mixture was stirred for the appropriate reaction time as specified in (Table 1). The progress of reaction was monitored by Thin layer chromatography (10-20percent ethyl acetate: hexane) on TLC plates (Merck) precoated with silica. After completion of reaction, the reaction mass was diluted with methanol, filtered off the catalyst which was washed for several times and then dried at 800 °C under reduced pressure for 1 hour and subjected to further recycle study (Table 4). It showed no much more decrease in the product yield indicating high activity of the catalyst. The filtrate was concentrated on rotavacc and the product was purified by column chromatography to afford pure products.
92% With 1,3-disulfonic acid imidazolium hydrogen sulfate In neat (no solvent) at 20℃; for 0.0333333 h; Green chemistry General procedure: Amine (1 mmol) was added to the mixture of (Boc)2O (1 mmol) and DSIMHS (6.5 mg, ~ 0.02 mmol) with constant stirring at room temperature under solvent-free conditions. After completion of the reaction (monitored by TLC),   ethyl acetate (3 × 5 mL) was added to the reaction mixture and the catalyst was decanted and washed with ethyl acetate (2 × 5 mL) and dried. The product was purified by column chromatography, using   ethyl acetate–petroleum ether (2:8) eluent.
90% at 20℃; for 16 h; General procedure: Boc2O (1.0 mmol) was added to a mixture of phenol or amine (1.0 mmol) andMgBr2 · OEt2 (0.1 mmol) in a round-bottom flask, at which point an evolution of gas occurs, and the reaction mixture was stirred magnetically at room temperature (ifnecessary, reactions was heated to∼60 °C). After complete consumption of the phenolor amine (by thin-layer chromatography, TLC; 3–16 h), the reaction mixture wasdiluted with water and extracted with EtOAc (3 × 20mL), and the combined EtOAcextracts were dried with Na2SO4 and concentrated under vacuum rotary evaporation.The residue was isolated by column chromatography through a bed of silicagel and eluted with 5–30percent ethyl acetate in hexane to afford the desired Bocprotectedproduct.
45%
Stage #1: With C12H24KO6(1+)*Br3H(1-) In ethanol at 20℃; for 0.0166667 h;
Stage #2: at 20℃; for 4 h;
For the N-boc protection of amines, to solution of diboc (1 mmol) in ethanol (5 ml) was added {K*18-crown-6]Br3}n (0.001 mmol). The solution was stirred at room temperature for 1 min. The amine (1 mmol) was then added and solution as stirred at room temperature for an appropriate time (table 1). After completion of the reaction, the solvent was removed by water bath distillation. To the residue was added ethyl acetate (5 ml) and the mixture was filtered (the catalyst is insoluble in n-hexane and ethyl acetate). The solid was washed with ethyl acetate ()10 ml*2) amd combined filtrates were reduced to dryness to yield the pure products.

Reference: [1] Tetrahedron Letters, 2008, vol. 49, # 16, p. 2527 - 2532
[2] Tetrahedron Letters, 2011, vol. 52, # 12, p. 1260 - 1264
[3] Monatshefte fur Chemie, 2011, vol. 142, # 10, p. 1035 - 1043
[4] RSC Advances, 2014, vol. 4, # 47, p. 24544 - 24550
[5] Tetrahedron Letters, 2017, vol. 58, # 7, p. 629 - 633
[6] Journal of the Iranian Chemical Society, 2017, vol. 14, # 2, p. 443 - 456
[7] Tetrahedron Letters, 2008, vol. 49, # 21, p. 3527 - 3529
[8] Synthesis, 2008, # 19, p. 3126 - 3130
[9] Comptes Rendus Chimie, 2010, vol. 13, # 5, p. 544 - 547
[10] Letters in Organic Chemistry, 2011, vol. 8, # 1, p. 38 - 42
[11] Journal of Chemical Research, 2013, vol. 37, # 12, p. 757 - 760
[12] Journal of Organic Chemistry, 2006, vol. 71, # 21, p. 8283 - 8286
[13] Patent: US2013/172569, 2013, A1, . Location in patent: Paragraph 0053; 0054
[14] Patent: TWI516478, 2016, B, . Location in patent: Page/Page column 19; 20
[15] Journal of the Chilean Chemical Society, 2013, vol. 58, # 1, p. 1619 - 1623
[16] Tetrahedron Letters, 2004, vol. 45, # 37, p. 6963 - 6965
[17] Synlett, 2007, # 5, p. 806 - 808
[18] Journal of the Iranian Chemical Society, 2012, vol. 9, # 4, p. 495 - 502
[19] Journal of Molecular Liquids, 2013, vol. 177, p. 386 - 393
[20] Journal of the Iranian Chemical Society, 2013, vol. 10, # 2, p. 181 - 188
[21] RSC Advances, 2015, vol. 5, # 26, p. 19790 - 19798
[22] Synthetic Communications, 2015, vol. 45, # 5, p. 653 - 660
[23] Synlett, 2006, # 7, p. 1110 - 1112
[24] Monatshefte fur Chemie, 2012, vol. 143, # 4, p. 631 - 635
[25] Synthetic Communications, 2012, vol. 42, # 1, p. 25 - 32
[26] Tetrahedron Letters, 2007, vol. 48, # 33, p. 5865 - 5868
[27] Chemistry - A European Journal, 2010, vol. 16, # 31, p. 9457 - 9461
[28] Journal of the Chinese Chemical Society, 2011, vol. 58, # 4, p. 538 - 543
[29] Advanced Synthesis and Catalysis, 2005, vol. 347, # 15, p. 1929 - 1932
[30] Chinese Journal of Catalysis, 2013, vol. 34, # 9, p. 1730 - 1733
[31] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 13, p. 1751 - 1756
[32] Patent: US2006/160860, 2006, A1, . Location in patent: Page/Page column 9-10
[33] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 17, p. 4318 - 4321
  • 118
  • [ 288-32-4 ]
  • [ 98015-52-2 ]
  • [ 49761-82-2 ]
Reference: [1] Synthesis, 1986, # 8, p. 627 - 632
[2] Journal of Organic Chemistry, 1985, vol. 50, # 20, p. 3951 - 3953
[3] Patent: US4725680, 1988, A,
  • 119
  • [ 288-32-4 ]
  • [ 98015-51-1 ]
  • [ 49761-82-2 ]
Reference: [1] Synthesis, 1986, # 8, p. 627 - 632
  • 120
  • [ 288-32-4 ]
  • [ 1202657-31-5 ]
  • [ 1312929-42-2 ]
  • [ 49761-82-2 ]
Reference: [1] Synthetic Communications, 2009, vol. 39, # 22, p. 4122 - 4132
  • 121
  • [ 288-32-4 ]
  • [ 75-63-8 ]
  • [ 66675-22-7 ]
  • [ 33468-69-8 ]
Reference: [1] Tetrahedron Letters, 1990, vol. 31, # 9, p. 1279 - 1282
  • 122
  • [ 288-32-4 ]
  • [ 2314-97-8 ]
  • [ 33468-69-8 ]
  • [ 66675-22-7 ]
Reference: [1] Journal of Organic Chemistry, 1982, vol. 47, # 15, p. 2867 - 2872
  • 123
  • [ 288-32-4 ]
  • [ 1184-76-5 ]
  • [ 66675-22-7 ]
  • [ 33468-69-8 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1993, # 6, p. 645 - 648
  • 124
  • [ 288-32-4 ]
  • [ 2314-97-8 ]
  • [ 81654-07-1 ]
  • [ 33468-69-8 ]
  • [ 66675-22-7 ]
Reference: [1] Journal of Organic Chemistry, 1982, vol. 47, # 15, p. 2867 - 2872
  • 125
  • [ 288-32-4 ]
  • [ 112-29-8 ]
  • [ 33529-02-1 ]
YieldReaction ConditionsOperation in experiment
94% at 50℃; Microwave irradiation In a wide-necked Erlenmeyer flask areintroduced 6.8g (0.1 mol) imidazole, 45.5g (0.1 mol)1-bromohexadecan, 2.4g (7.5mmol)tertiobutyllammoniumbromid (TBAB). The mixtureis adsorbed on mixture of potassium carbonate andpotassium hydroxide ratio 1:1 and then irradiatedin an open vessel in a domestic microwave oven300 Watt power for 3 min by period of 20 secondstill it changed to pasty.After dilution in dichloromethane followedby washing with water, the organic phase isseparated and dried over sodium sulfate. Afterfiltration, the solvent is evaporated under vacuum.
88.3% With sodium hydroxide In dimethyl sulfoxide at 20 - 25℃; Inert atmosphere Equipped with a stirrer, a thermometer, a three-necked flask was added 0.440 g (11.0 mmol) NaOH, 0.714 g (10.5 mmol) of imidazole and 10 mL of dimethyl sulfoxide (DMSO), at 20 ° C ~ 25 ° C under nitrogen atmosphere after stirring until a clear solution, to which was added dropwise 2.21 g (10.0 mmol) of bromo decane, the reaction of about 4 ~ 6 h, the reaction was poured into 10 mL of water and extracted with chloroform 3 × 10 mL, washed with water The chloroform layer was 4 to 5 times, and then dried over anhydrous MgSO 4, filtered to obtain a filtrate, the chloroform was removed to give a pale yellow liquid N- decyl-imidazole 1.84 g, yield 88.3percent.
86%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h; Inert atmosphere
Stage #2: at 20℃; Inert atmosphere
General procedure: This compound was synthesized using a variation of the procedure previously reported [32]. Sodium hydride (60percent dispersion in mineral oil, 1.56 g, 39.0 mmol) was suspended in dry THF (50 mL) under Ar at 0 °C. Imidazole (2.16 g, 31.7 mmol) was dissolved in dry THF (20 mL) and added drop-wise. After 30 min, 1-bromodecane (5.41 g, 24.5 mmol) was added. The resulting reaction mixture was then stirred at room temperature overnight. After careful addition of a few drops of water to quench the remaining sodium hydride, the organic solvent was removed in vacuo, and diethyl ether (50 mL) was added. This solution was then washed with water (3 × 50 mL), dried over anhydrous MgSO4, filtered, concentrated, and then purified by flash chromatography (ethyl acetate/hexanes = 10/1 (v/v)) to give the product as a light yellow oil (yield: 4.38 g, 86percent). Spectroscopic and purity data matched those reported for this compound [32].
81.2%
Stage #1: With potassium hydroxide In dimethyl sulfoxide at 20℃; for 2 h;
Stage #2: for 4 h;
General procedure: A mixture of imidazole (30 mmol, 2.04 g), potassiumhydroxide (30 mmol, 1.68 g) and dimethyl sulfoxide(10 mL) was stirred for 2 h at room temperature. Afterthat, alkyl bromide (25.0 mmol of 1-bromohexane, 1-bromooctane,1-bromodecane, 1-bromododecane, 1-bromotetradecane,1-bromohexadecane, or 1-bromooctadecane)was dropped in slowly and the mixture was stirred for anadditional 4 h. Upon completion, water (30 mL) was addedto the resulting mixture followed by extraction with chloroform(5 x 30 mL). The combined organic layer wasdried over anhydrous magnesium sulfate and the filtratewas concentrated under reduced pressure. The residue wassubjected to flash chromatography with ethyl acetate aseluent to give N-alkyl imidazole. The respective yields ofN-hexyl imidazole, N-octyl imidazole, N-decyl imidazole,N-dodecyl imidazole, N-tetradecyl imidazole, N-hexadecylimidazole and N-octadecyl imidazole are 84.6, 82.3, 81.2,80.5, 80.4, 79.8 and 79.6 percent.
76%
Stage #1: With sodium hydroxide In dimethyl sulfoxide at 20℃; for 1.5 h;
Stage #2: at 20℃;
General procedure: Imidazole (3)/benzimidazole(5) (10 mmol) was dissolved in 10 ml of DMSO and solid NaOH(15 mmol) was then added it. The resulting pale yellow suspensionwas stirred in air at room temperature for 1.5 h, after which, thealkyl bromides or benzyl chlorides (15 mmol) were added andallowed to react until completion (TLC). Water (50 ml) was thenadded and the products were extracted with ethyl acetate. Combinedorganic layers were washed several times with water, thenwith brine, dried over Na2SO4 and subjected to chromatographicpurification over silica (100–200 mesh) using MeOH: EtOAc 5:95(v/v) as the mobile phase. Compounds 4a-f were isolated as yellowoils whereas, the compounds 7a-e were white solid. Spectroscopic data of the N-alkyl imidazoles are in accord with earlier literatureand thus are not shown here [30].

Reference: [1] Journal of Materials Chemistry, 2011, vol. 21, # 33, p. 12280 - 12287
[2] Oriental Journal of Chemistry, 2015, vol. 31, # 4, p. 2391 - 2394
[3] Patent: CN103951702, 2016, B, . Location in patent: Paragraph 0049; 0050
[4] Polymer, 2014, vol. 55, # 26, p. 6664 - 6671
[5] New Journal of Chemistry, 2007, vol. 31, # 6, p. 879 - 892
[6] Journal of Surfactants and Detergents, 2016, vol. 19, # 4, p. 681 - 691
[7] European Journal of Inorganic Chemistry, 2015, vol. 2015, # 3, p. 408 - 413
[8] Polyhedron, 2017, vol. 127, p. 68 - 83
[9] Russian Journal of Applied Chemistry, 1996, vol. 69, # 12, p. 1841 - 1848
[10] Organic Letters, 2009, vol. 11, # 8, p. 1757 - 1759
[11] Synthesis, 2009, # 19, p. 3219 - 3226
[12] Organic Letters, 2010, vol. 12, # 21, p. 4988 - 4991
[13] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 17, p. 2863 - 2865
[14] Polish Journal of Chemistry, 1995, vol. 69, # 3, p. 447 - 460
[15] Chemistry Letters, 2005, vol. 34, # 3, p. 442 - 443
[16] Journal of Chemical and Engineering Data, 2006, vol. 51, # 4, p. 1274 - 1279
[17] Electrochimica Acta, 2010, vol. 55, # 20, p. 5652 - 5658
[18] Physical Chemistry Chemical Physics, 2011, vol. 13, # 6, p. 2062 - 2068
[19] Dyes and Pigments, 2013, vol. 96, # 1, p. 16 - 24,9
[20] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 4, p. 423 - 427
[21] Journal of the Chinese Chemical Society, 2013, vol. 60, # 7, p. 745 - 754
[22] Chemical Biology and Drug Design, 2014, vol. 83, # 3, p. 278 - 288
[23] RSC Advances, 2015, vol. 5, # 4, p. 2869 - 2881
[24] RSC Advances, 2015, vol. 5, # 71, p. 57968 - 57974
[25] Langmuir, 2015, vol. 31, # 12, p. 3587 - 3595
[26] RSC Advances, 2015, vol. 5, # 28, p. 21865 - 21876
[27] Molecules, 2018, vol. 23, # 9,
  • 126
  • [ 288-32-4 ]
  • [ 693-58-3 ]
  • [ 33529-02-1 ]
YieldReaction ConditionsOperation in experiment
70% With potassium carbonate In acetoneReflux General procedure: Briefly, a mixture of imidazole (100 mmol), alkyl bromide (100 mmol) and K2CO3 (200 mmol) inacetone (200 mL) was refluxed overnight. Upon filtration and solvent removal, the remaining residuewas subjected to flash chromatography with ethyl acetate to produce >90percent yield.
Reference: [1] Molecules, 2018, vol. 23, # 9,
  • 127
  • [ 288-32-4 ]
  • [ 1002-69-3 ]
  • [ 33529-02-1 ]
Reference: [1] European Journal of Medicinal Chemistry, 1990, vol. 25, # 5, p. 449 - 454
[2] Heterocycles, 1997, vol. 45, # 4, p. 715 - 722
[3] ChemCatChem, 2015, vol. 7, # 4, p. 616 - 624
  • 128
  • [ 288-32-4 ]
  • [ 2050-77-3 ]
  • [ 33529-02-1 ]
Reference: [1] Journal of the American Chemical Society, 2008, vol. 130, # 38, p. 12590 - 12591
[2] Journal of Materials Chemistry A, 2013, vol. 1, # 22, p. 6572 - 6578
  • 129
  • [ 288-32-4 ]
  • [ 459-57-4 ]
  • [ 27996-86-7 ]
Reference: [1] Supramolecular Chemistry, 2017, vol. 29, # 3, p. 193 - 204
  • 130
  • [ 288-32-4 ]
  • [ 463-71-8 ]
  • [ 6160-65-2 ]
Reference: [1] Journal of Organic Chemistry, 1995, vol. 60, # 3, p. 764 - 766
  • 131
  • [ 288-32-4 ]
  • [ 143-15-7 ]
  • [ 4303-67-7 ]
YieldReaction ConditionsOperation in experiment
90% With potassium carbonate In acetone for 7 h; Reflux Imidazole 1 (0.68 g, 10 mmol), bromododecane (2.5 g, 10 mmol)Anhydrous potassium carbonate (2.76 g, 20 mmol) was placed in a 50 mL round-bottomed flask and dissolved in 20 mL of acetone.The combined solution was heated at reflux for 7 h. The acetone solvent was removed by rotary evaporation and subjected to column chromatography(Ethyl acetate as eluent), the ethyl acetate solvent was removed by rotary distillation under reduced pressure, and dried in vacuo,The yield of purified N-dodecylimidazole was 90percent.
88.1% With sodium hydroxide In dimethyl sulfoxide at 20 - 25℃; Inert atmosphere Equipped with a stirrer, a thermometer, a three-necked flask was added 0.440 g (11.0 mmol) NaOH, 0.714 g (10.5 mmol) of imidazole and 10 mL of dimethyl sulfoxide (DMSO), at 20 ° C ~ 25 ° C under nitrogen atmosphere stir until a clear solution, to which was added dropwise 2.49 g (10.0 mmol) of bromo dodecane, reacted for about 4 ~ 6 h, the reaction was poured into 10 mL of water and extracted with chloroform 3 × 10 mL, and then washed with water The chloroform layer was washed 4 to 5 times, and then dried over anhydrous MgSO 4, filtered to obtain a filtrate, the chloroform was removed to give a pale yellow liquid N- dodecyl imidazole 2.08 g, yield 88.1percent.
86%
Stage #1: With sodium hydroxide In tetrahydrofuran; water at 20℃; for 1 h;
Stage #2: at 55℃; for 24 h;
imidazole in an eggplant-shaped flask (2.05g, 30mmol) was dissolved in tetrahydrofuran (15mL), there sodium hydroxide solution (sodium hydroxide 2.47g, 62 mmol, water 5g) was added and stirred for 1 hour at room temperature.Here bromo dodecane (7.48 g, 30 mmol) was added and stirred for 1 day at 55 ° C..After the reaction solution was washed with ethyl acetate, neutralized with hydrochloric acid, it was subjected to three washes with subsequent water.The organic layer was dried over anhydrous magnesium sulfate, filtration using a filter paper and evaporated after removing the magnesium sulfate SiO2and purified by (1, Rf value 0.52 chloroform: methanol = 9) column chromatography .Thereafter, filtered through a syringe filter, an object of the 1-by distilling off the solvent againto obtain a dodecyl imidazole 1 (Yield: 6.10g, 25.8mmol, 86percent yield).
81% With sodium hydroxide In tetrahydrofuran for 72 h; Reflux General procedure: N-Dodecylimidazole was obtained following the procedure ofliterature [45]. To a solution of imidazole (0.7 g, 10 mmol) in NaOH(50percent) solution (1.0 g, 11 mmol), a solution of 1-bromododecane(2.5 g, 10 mmol) in THF (10 mL) was added dropwise. The obtainedmixture was refluxed for three days. After cooling, THF wasremoved by a rotary evaporator. The residue was extracted withdichloromethane three times. The combined organic layer waswashed with water and then dried over anhydrous Na2SO4. The fil-trate was concentrated and purified by a column chromatographyto produce clear yellow oil (2.0 g, 81percent).1H NMR (CDCl3): (ppm) = 0.83 (t, J = 5.1 Hz, 3H, CH3), 1.10–1.21(m, 18H, CH2), 1.69 (br, J = 7.0 Hz, 2H, CH2), 3.84 (t, J = 6.2 Hz, 2H,CH2), 6.89 (s, 1H, ImH), 7.04 (s, 1H, ImH), 7.44 (s, 1H, ImH).13C NMR(CDCl3): (ppm) = 13.7, 22.3, 26.1, 28.7, 28.9, 29.0, 29.2, 20.7, 31.5,46.5, 118.3, 128.2, 136.6
80% With sodium hydroxide In tetrahydrofuran; waterReflux General procedure: A solution of imidazole 3 (30 mmol) in THF (60 mL) was treated with NaOH (25 mL, 40percent aq) and the alkyl bromide (30 mmol), and the reaction was refluxed overnight. The solvent was evaporated and the crude reaction mixture was extracted with CH2Cl2 against water. The organic layer was washed with water, dried over MgSO4 and concentrated. The final product was distilled under vacuum (~5 mbar) to provide 4 as yellow oily liquid in 80-85percent yield.
80.5%
Stage #1: With potassium hydroxide In dimethyl sulfoxide at 20℃; for 2 h;
Stage #2: for 4 h;
General procedure: A mixture of imidazole (30 mmol, 2.04 g), potassiumhydroxide (30 mmol, 1.68 g) and dimethyl sulfoxide(10 mL) was stirred for 2 h at room temperature. Afterthat, alkyl bromide (25.0 mmol of 1-bromohexane, 1-bromooctane,1-bromodecane, 1-bromododecane, 1-bromotetradecane,1-bromohexadecane, or 1-bromooctadecane)was dropped in slowly and the mixture was stirred for anadditional 4 h. Upon completion, water (30 mL) was addedto the resulting mixture followed by extraction with chloroform(5 x 30 mL). The combined organic layer wasdried over anhydrous magnesium sulfate and the filtratewas concentrated under reduced pressure. The residue wassubjected to flash chromatography with ethyl acetate aseluent to give N-alkyl imidazole. The respective yields ofN-hexyl imidazole, N-octyl imidazole, N-decyl imidazole,N-dodecyl imidazole, N-tetradecyl imidazole, N-hexadecylimidazole and N-octadecyl imidazole are 84.6, 82.3, 81.2,80.5, 80.4, 79.8 and 79.6 percent.

Reference: [1] Russian Journal of Organic Chemistry, 2013, vol. 49, # 9, p. 1291 - 1299[2] Zh. Org. Khim., 2013, vol. 49, # 9, p. 1308 - 1316,9
[3] Patent: CN106188014, 2016, A, . Location in patent: Paragraph 0016
[4] Patent: CN103951702, 2016, B, . Location in patent: Paragraph 0059; 0060
[5] Tetrahedron, 2010, vol. 66, # 35, p. 7077 - 7082
[6] Journal of Physical Chemistry B, 2010, vol. 114, # 21, p. 7312 - 7319
[7] Macromolecules, 2012, vol. 45, # 9, p. 3974 - 3985
[8] Tetrahedron, 2016, vol. 72, # 27-28, p. 4117 - 4122
[9] Patent: JP2016/98194, 2016, A, . Location in patent: Paragraph 0035
[10] New Journal of Chemistry, 2007, vol. 31, # 6, p. 879 - 892
[11] Journal of Molecular Catalysis A: Chemical, 2016, vol. 411, p. 34 - 39
[12] Carbohydrate Research, 2015, vol. 412, p. 28 - 33
[13] Journal of Surfactants and Detergents, 2016, vol. 19, # 4, p. 681 - 691
[14] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 17, p. 2863 - 2865
[15] Green Chemistry, 2014, vol. 16, # 6, p. 3117 - 3124
[16] Synthesis, 2009, # 19, p. 3219 - 3226
[17] Helvetica Chimica Acta, 2004, vol. 87, # 11, p. 2742 - 2749
[18] Angewandte Chemie - International Edition, 2013, vol. 52, # 1, p. 455 - 458[19] Angew. Chem., 2013, vol. 125, # 1, p. 473 - 476,4
[20] Polish Journal of Chemistry, 1995, vol. 69, # 3, p. 447 - 460
[21] Journal of Chemical and Engineering Data, 2006, vol. 51, # 4, p. 1274 - 1279
[22] Journal of Materials Chemistry, 2011, vol. 21, # 33, p. 12280 - 12287
[23] Catalysis Communications, 2012, vol. 18, p. 11 - 15
[24] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 4, p. 423 - 427
[25] Journal of the Chinese Chemical Society, 2013, vol. 60, # 7, p. 745 - 754
[26] Chemical Biology and Drug Design, 2014, vol. 83, # 3, p. 278 - 288
[27] Chinese Journal of Catalysis, 2013, vol. 34, # 12, p. 2236 - 2244
[28] Bulletin of the Korean Chemical Society, 2014, vol. 35, # 6, p. 1675 - 1680
[29] RSC Advances, 2015, vol. 5, # 4, p. 2869 - 2881
[30] RSC Advances, 2015, vol. 5, # 71, p. 57968 - 57974
[31] RSC Advances, 2015, vol. 5, # 78, p. 63732 - 63737
[32] Langmuir, 2015, vol. 31, # 12, p. 3587 - 3595
[33] RSC Advances, 2015, vol. 5, # 28, p. 21865 - 21876
[34] RSC Advances, 2016, vol. 6, # 33, p. 27370 - 27377
[35] RSC Advances, 2017, vol. 7, # 75, p. 47335 - 47352
[36] Chinese Chemical Letters, 2016, vol. 27, # 2, p. 226 - 230
[37] Dalton Transactions, 2018, vol. 47, # 40, p. 14241 - 14253
  • 132
  • [ 288-32-4 ]
  • [ 143-15-7 ]
  • [ 71-43-2 ]
  • [ 4303-67-7 ]
Reference: [1] Patent: US4719312, 1988, A,
  • 133
  • [ 288-32-4 ]
  • [ 4292-19-7 ]
  • [ 4303-67-7 ]
Reference: [1] Journal of the American Chemical Society, 2008, vol. 130, # 38, p. 12590 - 12591
[2] Journal of Materials Chemistry A, 2013, vol. 1, # 22, p. 6572 - 6578
  • 134
  • [ 288-32-4 ]
  • [ 51323-71-8 ]
  • [ 4303-67-7 ]
Reference: [1] Green Chemistry, 2009, vol. 11, # 12, p. 1955 - 1960
[2] Catalysis Communications, 2010, vol. 11, # 5, p. 470 - 475
  • 135
  • [ 288-32-4 ]
  • [ 112-52-7 ]
  • [ 4303-67-7 ]
Reference: [1] European Journal of Medicinal Chemistry, 1990, vol. 25, # 5, p. 449 - 454
  • 136
  • [ 288-32-4 ]
  • [ 4303-67-7 ]
Reference: [1] Russian Journal of Applied Chemistry, 1996, vol. 69, # 12, p. 1841 - 1848
  • 137
  • [ 288-32-4 ]
  • [ 7189-69-7 ]
YieldReaction ConditionsOperation in experiment
92% With sulfuryl dichloride In dichloromethane at 0 - 20℃; for 16 h; Inert atmosphere To a solution of imidazole (79.00 g, i.i7 mol, 4.75 eq) in 633 mL of anhydrous dichloromethane wasa solution of sulfuryl chloride (20.0 mL, 0.25 mol, 1.0 eq) in 119 mL of anhydrous dichloromethane via cannulae transfer at 0°C under N2. Reaction warmed totemperature and continued to stir under N2 for 16 hours. The reaction wasand the filtrate condensed under reduced pressure to yield and off white solid.solid was recrystallized in 80 mL of refluxing isopropanol to yield N,N’ —sulfuryldiimidazole as a colorless crystalline solid (44.97g 92percent). 1H NMR (600 MHz,DMSO-d6) ö 8.51 (s, 1H), 7.92 (t, J = 1.5 Hz, 1H), 7.26 — 7.24 (m, iH), 3.33 (s, iH).NMR (i51 MHz, DMSO-d6) ö 138.14, 132.38, 118.93.
64% With sulfuryl dichloride In dichloromethane at 0 - 20℃; C. 1,1'-Bis-imidazole-1-sulfonyl (1-E). To a solution of compound 1-D (20.0 g, 294 mmol) in anhydrous CH2Cl2 (210 mL), cooled to 0° C., was added a solution of sulfuryl chloride (5.0 mL, 61.6 mmol) in CH2Cl2 (28 mL), drop-wise. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. The reaction mixture was filtered, the solvent evaporated under reduced pressure, and the resulting solid crystallized from isopropyl alcohol (100 mL). The white needles were filtered, washed with cold isopropyl alcohol and dried under reduced pressure to afford 7.81 g (64percent) of compound 1-E as a white solid. 1H-NMR (DMSO-d6, 400 MHz): δ 8.50-8.51 (d, 2H), 7.92 (s, 2H), 7.24-7.23 (d, 2H); MS (method 2) m/z 198.9 (M+1).
Reference: [1] Patent: WO2016/172615, 2016, A1, . Location in patent: Page/Page column 8
[2] Chemistry Letters, 2011, vol. 40, # 9, p. 907 - 909
[3] Advanced Synthesis and Catalysis, 2012, vol. 354, # 14-15, p. 2771 - 2776
[4] Advanced Synthesis and Catalysis, 2013, vol. 355, # 1, p. 203 - 208
[5] Organic Letters, 2017, vol. 19, # 19, p. 5244 - 5247
[6] Organic Letters, 2013, vol. 15, # 1, p. 18 - 21
[7] Patent: US2010/160337, 2010, A1, . Location in patent: Page/Page column 17
[8] Tetrahedron, 1991, vol. 47, # 8, p. 1459 - 1472
[9] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 11, p. 4878 - 4888
[10] Patent: WO2013/134518, 2013, A1, . Location in patent: Page/Page column 53
  • 138
  • [ 288-32-4 ]
  • [ 7791-25-5 ]
  • [ 7189-69-7 ]
Reference: [1] European Journal of Organic Chemistry, 2012, # 19, p. 3670 - 3676
  • 139
  • [ 288-32-4 ]
  • [ 98-59-9 ]
  • [ 2232-08-8 ]
YieldReaction ConditionsOperation in experiment
89% at 20℃; for 2 h; (a) In a three-necked round bottomflask equipped with addition funnel, oil trap, magnetic stirringbar and argon atmosphere, imidazole (5.502 g, 0.081 mol) wasdissolved in 25 mL of anhyd. CH2Cl2. The solutionwas cooled to 0 Cand then 6.78 g (0.036 mol) of p-toluenesulfonyl chloride dissolvedin 25 mL of anhydrous methylene chloridewas added dropwise. Theresulting mixture was stirred during 2 h at rt and then filtered oversilica, and the remnant solid was washed with 50 mL of a hexaneeEtOAc(1:1). The filtrate was concentrated in the rotary evaporator,redissolved in 6mL of EtOAc, and induced to precipitate uponaddition of 60 mL of hexane. The resulting white solid was filteredand dried to give 7.12 g of 1-tosyl-1H-imidazol (0.032 mol, 89percentyield).
75% at 20℃; Tosyl chloride (80.27 g; 0.421 mol; 1 eq.) dissolved in 250 ml of dichloromethane is added over 4 hours to imidazole (65.08 g; 0.956 mol; 2.27 eq.) dissolved in 250 ml of dichloromethane, in a 1 litre three-necked flash equipped with a thermometer and under an inert atmosphere.
The reaction medium is left stirring overnight at ambient temperature and then filtered over celite and washed with 500 ml of an ethyl acetate/cyclohexane (1/1) mixture.
The filtrate is concentrated on a rotary evaporator and the solid residue is then taken up in 50 ml of ethyl acetate and precipitated from 500 ml of cyclohexane.
The precipitate formed is filtered off, dried, and taken up in a minimum of dichloromethane.
The organic phase is washed with water and then with a saturated sodium chloride solution.
The aqueous phase is extracted with dichloromethane.
The organic phases are combined, dried over Na2SO4 and concentrated under reduced pressure.
Finally, the residual solid is recrystallized from isopropyl ether.
After filtration and washing with ether, compound 1 is obtained with a 75percent yield.
TLC: Rf=0.6 eluent: CH2Cl2/MeOH 98/2 (v/v)
M.p.: 78° C.
1H NMR CDCl3 δ (ppm): 8 (s, 1H, H3); 7.82 (d, 2H, Hb/b', 3Ja-b=8 Hz); 7.34 (d, 2H, Hc/c', 3Jb-a=8 Hz); 7.28 (dd, 1H, 3J=1.6 Hz, 3J=1.4 Hz, H2); 7.08 (m, 1H, H3); 2.42 (s, 3H, He)
Reference: [1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 7, p. 2209 - 2218
[2] Organic Syntheses, 2000, vol. 77, p. 225 - 225
[3] Tetrahedron, 2016, vol. 72, # 3, p. 379 - 391
[4] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 1855 - 1858
[5] Phosphorus, Sulfur and Silicon and the Related Elements, 2011, vol. 186, # 9, p. 1867 - 1875
[6] Organic Letters, 2018, vol. 20, # 3, p. 736 - 739
[7] Green Chemistry, 2014, vol. 16, # 6, p. 3117 - 3124
[8] Patent: US2007/142324, 2007, A1, . Location in patent: Page/Page column 6
[9] European Journal of Medicinal Chemistry, 1996, vol. 31, # 12, p. 1001 - 1010
[10] Tetrahedron Letters, 2007, vol. 48, # 19, p. 3445 - 3449
[11] Organic Letters, 2010, vol. 12, # 19, p. 4232 - 4235
[12] Biomacromolecules, 2010, vol. 11, # 7, p. 1710 - 1715
[13] Tetrahedron, 2011, vol. 67, # 44, p. 8515 - 8528
[14] Patent: CN105968051, 2016, A, . Location in patent: Paragraph 0017; 0019; 0020
[15] Journal of Chemistry, 2017, vol. 2017,
  • 140
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  • [ 1576-35-8 ]
  • [ 2232-08-8 ]
YieldReaction ConditionsOperation in experiment
98% With tert.-butylhydroperoxide; iodine In water at 20℃; for 0.0166667 h; General procedure: To a mixture of arylsulfonyl hydrazide 1 (0.5 mmol) and amine (0.75 mmol) was added TBHP (0.2 mL, 70percent wt/wt in H2O, 2.0 mmol) followed by molecular iodine (0.025 g, 0.10 mmol, 20 molpercent) at room temperature. The reaction was completed after the addition of iodine within a minute. After completion of the reaction, as indicated by TLC, the reaction mixture was diluted with ethyl acetate, and quenched with saturated sodium thiosulphate solution and extracted twice with ethyl acetate (2 × 10 mL). The organic layer was washed with water and dried over anhyd. sodium sulphate. The solvent was evaporated in vacuo to afford pure sulfonamide derivative (8–12).
Reference: [1] Tetrahedron Letters, 2016, vol. 57, # 11, p. 1232 - 1235
[2] Chinese Journal of Chemistry, 2016, vol. 34, # 4, p. 359 - 362
  • 141
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  • [ 824-79-3 ]
  • [ 2232-08-8 ]
Reference: [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 7, p. 1575 - 1582
  • 142
  • [ 288-32-4 ]
  • [ 536-57-2 ]
  • [ 136918-14-4 ]
  • [ 2232-08-8 ]
Reference: [1] Bulletin of the Chemical Society of Japan, 1980, vol. 53, # 12, p. 3678 - 3682
  • 143
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  • [ 38028-98-7 ]
  • [ 136918-14-4 ]
  • [ 2232-08-8 ]
Reference: [1] Bulletin of the Chemical Society of Japan, 1980, vol. 53, # 12, p. 3678 - 3682
  • 144
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  • [ 136061-86-4 ]
  • [ 2232-08-8 ]
Reference: [1] Journal of Organic Chemistry, 1995, vol. 60, # 7, p. 2003 - 2007
  • 145
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  • [ 75-89-8 ]
  • [ 25370-91-6 ]
  • [ 67696-28-0 ]
  • [ 433-06-7 ]
  • [ 2232-08-8 ]
  • [ 100-51-6 ]
Reference: [1] Journal of the American Chemical Society, 1987, vol. 109, # 7, p. 2062 - 2070
  • 146
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  • [ 1153-45-3 ]
  • [ 2232-08-8 ]
Reference: [1] Russian Journal of Organic Chemistry, 1996, vol. 32, # 10, p. 1495 - 1500
  • 147
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  • [ 136061-86-4 ]
  • [ 2232-08-8 ]
Reference: [1] Journal of Physical Organic Chemistry, 1997, vol. 10, # 3, p. 175 - 181
  • 148
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  • [ 59363-13-2 ]
  • [ 67085-11-4 ]
YieldReaction ConditionsOperation in experiment
99.31% With sodium hydride In N,N-dimethyl-formamide at 58 - 62℃; for 3 h; Cooling with ice (2)Take a concentration of 20percent sodium hydride in DMF, under icecooling,to 2ml / s Was added dropwise with stirring speedof 20percent of the concentration of imidazole in DMF, the reaction was stirred at 60 ° C 60min, after cooling in an ice salt bathmethod, was slowly added to the intermediate product 1, the sodium hydride Of DMF, imidazole in DMF and the weight ratioof the intermediate product as a 7: 7: 5 stirred at 60 ° C in 120min reaction mix, after cooling in an ice salt bath method, areaction solution adding to said reaction mixture 25percent by weight of nhexanewas accounted for the reaction, at a speed of 3rev / sec After stirring for 15min, plus The reaction solution into account the 350percent by weight of the ice, with 3 rev / sec stirreduntil evolution ceased Shen After the precipitate was filtered, the filter cake with accounting for 1/3 times the weight of thefilter cake was washed with water once, in order to speed 2830r / min Conditions centrifugal drying 60min, with the centrifugalaccounted for 2.5 times the weight of the resulting product was dried and 0.05 Times with ethyl acetate and activated carbon,was allowed to stand at 5° C was recrystallized from 13 hours, 50 ° C and By recrystallization of the obtained product wasdried to obtain intermediate 2 detected by HPLC. Intermediate 2 71.5percent yield, wherein the desired product 1(2hydroxy4(4chlorophenyl)butanoic Yl) 1Hydrogen imidazolecontent was 99.31 percent
99.31%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 30℃; for 1 h; Cooling with ice
Stage #2: at 60℃; for 2 h; Cooling with ice
(1) take 7kg concentration of 20percent sodium hydride DMF solution,Under an ice bath condition, 7kg of imidazole DMF solution with a concentration of 20percent was added dropwise with stirring at a speed of 2ml / s and the reaction was stirred at 60 ° C for 60min; after cooling with an ice-salt bath method, 5kg of 1-chloro-4 - (4-chlorophenyl) -2-butanol stirred at 60 ° C for 120min, cooled with ice salt bath to obtain the reaction solution;(2) Take the reaction solution obtained in the step (1), add n-hexane accounting for 25percent of the weight of the reaction solution, stir for 15 min at a speed of 3 rev / sec, add ice water of 350percent Stirring at a speed of 3 revolutions / second to stop the precipitation precipitation, filtering, washing the filter cake with 1/3 times of the weight of the filter cake for 1 time, centrifuging at the speed of 2825r / min for 60 minutes, The obtained product was 2.5 times in weight and 0.05 times in ethyl acetate and activated carbon, and was allowed to stand at -5 ° C for 13 hours for recrystallization. The product obtained after recrystallization was dried at 50 ° C. After testing, the yield of the product of this example was 71.4percent.Using HPLC and standards on the target product and impuritiesThe amount of testing. After testing,The target product1- (2-hydroxy-4- (4-chlorophenyl) butyl) -1-hydro-imidazoleContent of 99.31percent1- (1-Chloro-4- (4-chlorophenyl) butan-2-yl) -1H-imidazoleContent of 0.57percent4- (4- (1-Hydroxyimidazol-1-yl) phenyl) -1-chloro-2-butanolThe content is 0.08percent.
99.31%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 60℃; for 1 h;
Stage #2: at 60℃; for 2 h;
Take 7kg of 20percent sodium hydride in DMF and add dropwise at 2ml/s in ice bath.7kg concentration of 20percent imidazole in DMF, stirred at 60 ° C reaction 60min;After cooling with an ice salt bath, 5 kg of 1-chloro-4-(4-chlorophenyl)-2-butanol was slowly added, and the reaction was stirred at 60° C. for 120 min. After cooling with an ice salt bath, the reaction liquid was obtained; The reaction solution was added with 25percent by weight of n-hexane, stirred at a rate of 3 revolutions per second for 15 minutes, and then added with ice water of 350percent by weight of the reaction solution and stirred at a rate of 3 revolutions per second to stop. Precipitation precipitation, filtration, filter cake weight 1/3 of the water filter cake washed once, at a speed of 2825r/min centrifugal drying 60min, with the weight of the product obtained by the centrifugal drying 2.5 times and 0.05 times the weight of acetic acid The ethyl ester and the activated carbon were recrystallized at -5°C for 13 hours, and the recrystallized product was dried at 50°C to give 1-(2-hydroxy-4-(4-chlorophenyl)butyl). -1 hydrogen-imidazole, purity 99.31percent.
88.2% With sodium hydride In N,N-dimethyl-formamide at 20 - 60℃; for 4.5 h; (2) Synthesis of 1- (4- (4-chlorophenyl) -2-hydroxybutyl) imidazole. The reaction flask was charged with imidazole and dry DMF. The mass ratio of imidazole to DMF was 24: Adding 3-4 portions of sodium hydride in the next portion, stirring at room temperature till no gas was generated, raising the temperature to 60 ° C, mixing 1-chloro-4- (4-chlorophenyl) -2-butanol with DMF to obtain a mixed solution 3, The mass ratio of 1-chloro-4- (4-chlorophenyl) -2-butanol and DMF in the mixed solution 3 of imidazole and sodium hydride was 24: 7.9: 80: 94.8. The mixed solution was added dropwise to the reaction flask , The dropwise addition was completed for 3.5 hours, the reaction temperature was maintained at 60 ° C, the reaction was continued for 1 hour after the dropwise addition was completed, and then cold water was slowly added until all the solids were precipitated and filtered to obtain 1- (4- (4-chlorobenzene Yl) -2-hydroxy-butyl) imidazole;
85% With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride In water; toluene at 0 - 95℃; for 3 h; Example 1. Preparation of (1-f4- (4-chlorophenvl)-2-hydroxy-n-butvll-imidazole) (IV); To a solution of 56.7 g (0.26 mol) of 1-chloro-4-chlorophenyl-2-butanol (J. of Medicinal Chemistry, 1978. Vol. 21. No. 8. p. 842) in 200 ml of toluene 36.2 g (0.9 mol) of sodium hydroxide dissolved in 100 ml of water, 6.4 g (0.028 mol) of benzyltriethyammonium chloride and 35.2 g (0.51 mol) of imidazole (III) are added. The reaction mixture is heated at 93-95 °C for one hour then the temperature is returned to about 60 °C, the phases are separated and to the organic layer water (100 ml) is added. The mixture is first stirred at 22-25 °C for 1 hour then at 0-5 °C for two hours. The crystals are separated by filtration, washed with water (2 x 35 ml) of 0-5 °C to yield 74 g of wet (1- [4- (4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole) which is dried at maximum 50 °C in vacuo to give 61.6 g (95 percent) of the product. Recrystallization from ethyl acetate gives 52.4 g (85 percent) of dry product melting at 104-106 °C.
71.4%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 60℃; for 1 h; Cooling with ice
Stage #2: at 60℃; for 2 h; Cooling with ice
(1) Take 7kg of 20percent sodium hydride in DMF. Under ice bath conditions, At a rate of 2 ml/s, 7 kg of a 20percent imidazole DMF solution was added dropwise while stirring. Stir the reaction at 60 ° C 60min; After cooling with ice salt bath, 5 kg of 1-chloro-4-(4-chlorophenyl)-2-butanol is added slowly, Stirring reaction at 60 ° C 120min, after cooling with ice salt bath, the reaction solution; (2) Take the reaction solution obtained in step (1), Add 25percent by weight of the reaction solution of n-hexane, After 15 min stirring at 3 rpm, Then add ice water, which accounts for 350percent of the weight of the reaction solution, Stir at a speed of 3 revs/second to stop precipitation after filtration. Wash the cake once with 1/3 of the weight of the cake, Drying at a speed of 2825r/min for 60min. With ethyl acetate and activated carbon that weighed 2.5 times and 0.05 times the weight of the centrifugally dried product, respectively. After recrystallization at -5°C for 13 hours, the recrystallized product was dried at 50°C to obtain it. Upon detection, the yield of the product of this example was 71.4percent. The target product and impurity levels were determined using HPLC and standards. After testing, The target product, 1-(2-hydroxy-4-(4-chlorophenyl)butyl)-1H-imidazole, has a content of 99.31percent. The content of 1-(1-chloro-4-(4-chlorophenyl)butan-2-yl)-1-hydro-imidazole is 0.57percent. The content of 4-(4-(1H-hydrogen-imidazol-1-yl)phenyl)-1-chloro-2-butanol was 0.08percent.

Reference: [1] Patent: CN105218455, 2016, A, . Location in patent: Paragraph 0055
[2] Patent: CN105175341, 2017, B, . Location in patent: Paragraph 0048-0052
[3] Patent: CN105175338, 2018, B, . Location in patent: Paragraph 0069-0071
[4] Patent: CN107501190, 2017, A, . Location in patent: Paragraph 0033; 0036; 0043; 0046
[5] Patent: WO2005/70897, 2005, A1, . Location in patent: Page/Page column 7
[6] Patent: CN105198817, 2018, B, . Location in patent: Paragraph 0048-0052; 0055; 0059; 0061-0063; 0065
[7] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 9, p. 3225 - 3234
[8] Patent: CN105198816, 2018, B, . Location in patent: Paragraph 0100-0103
[9] Patent: CN105198814, 2018, B, . Location in patent: Paragraph 0071-0073
[10] Patent: CN105198818, 2018, B, . Location in patent: Paragraph 0107; 0108; 0109
  • 149
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  • [ 24155-42-8 ]
YieldReaction ConditionsOperation in experiment
78.7% With potassium carbonate In water; butanone (b)
An alternative method for the preparation of 1-(2',4'dichlorophenyl)2-(1H-imidazole)-1-ethanol follows.
Four g (17.74 mmol) of (+-)-2-chloro-(2',4'dichlorophenyl)-1-ethanol, prepared by sodium borohydride reduction of 2,2',4'-trichloroacetophenone (purchased from Aldrich Chemical), and 5.00 g (73.44 mmol) of imidazole were dissolved in 15 mL of dry 2-butanone in a 100 mL round bottom flask equipped with a magnetic stirrer bar and reflux condenser.
Four g K2CO3 and a catalytic amount of NaI were added and the solution was refluxed under a nitrogen atmosphere for 36 hours.
After cooling to room temperature, the reaction mixture was filtered.
Ether was added to the filtrate and the resulting solution was washed with 50 mL of water and the layers separated.
The aqueous layer was extracted 3 times with 50 mL portions of ether.
The ether extracts were combined with the previous organic phase and the total dried over anhydrous MgSO4.
After filtration to remove MgSO4, the filtrate was concentrated to give a yellowish oil.
Chromatography of the crude product (CH2Cl2:CH3OH/95:5) provided 3.59 g of purified pale yellow crystals (78.7percent yield).
1-(β-Allyloxy-β-2',4'-dichlorophenylethyl)imidazole (Imazalil):
Reference: [1] Patent: US6207695, 2001, B1,
[2] Patent: US4221803, 1980, A,
  • 150
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  • [ 13692-15-4 ]
  • [ 24155-42-8 ]
YieldReaction ConditionsOperation in experiment
57%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; Inert atmosphere
Stage #2: at 60℃; Inert atmosphere
To a mixture of sodium hydride (0.080 g, 2 mmol) in 5 mL of DMF was added imidazole (0.136 g, 2 mmol) dissolved in 2 mL of DMF.
The solution was stirred for 30 min under nitrogen atmosphere at room temperature before the addition of 2- (2,4-dichlorophenyl) oxirane 2 (0.378 g, 2 mmol) dissolved in 2 mL of DMF.
After, the reaction mixture was stirred at 60 °C for 22 h, TLC indicated the disappearance of the starting material.
Then the solution was brought to room temperature with continuous stirring for 20 min, before DMF was removed with extractions using distilled water and AcOEt.
The resulting solution was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
The crude extract was then purified by flash chromatography on silica eluting with ethyl acetate/hexane 2/8 to afford the white solid 3 (0.293 g, 57percent). Rf: 0.32 (EtOAc/Hex 2/8). m.p. 124e126 C. 1H NMR: (300 MHz,DMSO-D6) d 7.59 (d, J 1.9 Hz, 1H, NeCHeN), 7.52e7.40 (m, 3H),7.05 (s, 1H, CH), 6.84 (s, 1H, CHeN), 6.07 (d, J 4.4 Hz, 1H, OH), 5.08(m, 1H), 4.18 (dd, J 14.2, 3.4 Hz, 1H, NeCH2), 4.04 (dd, J 14.1,7.1 Hz, 1H, NeCH2). 13C NMR: (75.4 MHz, DMSO-D6) d 138.61 (C),137.68 (C),132.69 (CeCl),131.75 (CeCl),129.33 (C),128.36 (C),127.91(C),127.40 (C), 119.96 (C), 68.65 (CHeOH), 51.58 (CH2) ppm.MS [EI]m/z (percent): 257 (M), 239 (2), 221 (56), 175 (58), 147 (13), 113 (8), 108(54), 82 (100), 69 (81), 54 (39), 52 (8).
Reference: [1] Organic Preparations and Procedures International, 1992, vol. 24, # 3, p. 342 - 345
[2] European Journal of Medicinal Chemistry, 2015, vol. 97, p. 275 - 279
  • 151
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  • [ 38083-17-9 ]
YieldReaction ConditionsOperation in experiment
91% With N,N-dimethylbenzamide In toluene at 100 - 110℃; for 4 h; Large scale Step 2: As shown in Figure 1, 300kg of toluene, 300Kg of chloroether ketone, 165Kg of imidazole, and 26Kg of catalyst (N,N dimethyl benzylamide) are fed into the reactor once. During the feeding process, pay attention to the feeding sequence and start. Warming, when the temperature inside the kettle reaches 100-110°C, close the steam valve immediately and start the heat preservation (over-temperature emergency treatment: close the valve, stop the agitation, open the safety valve exhaust, close the valve to the specified temperature, perform heat preservation), and keep warm 4 Hours after the end of the incubation, cooling to 80-90°C, adding 250Kg of water, and washing with water. Then stirring at 50-60°C for 30 minutes, let stand for 30 minutes, divide the water, and then transfer the reaction product into a crystallization kettle for crystallization, cool down for 2 hours, discharge to the centrifuge, and centrifuge to obtain crude GanbuSu with a yield of 91percent. 85percent purity.Step 3: Put 900 kg of toluene and 296 Kg of crude Ganbolin prepared in Step 1 into the reactor, raise the temperature to 80-90°C, and incubate for 2 hours. Add 15Kg of sodium hydroxide and 200Kg of water for caustic washing. Add 200Kg of water after caustic washing. Divide the water, and then press the filter material to the crystallization kettle. Cool down to 35°C with cooling water and feed to the centrifuge. Gan Bao Su (MS showed product mass spectrometry data was 292.76, high-resolution mass spectrometry showed its molecular formula is C15H17ClN2O2), dried vested (yield rate91percent, purity 99percent).
Reference: [1] Patent: CN107739341, 2018, A, . Location in patent: Paragraph 0048; 0061; 0062; 0064; 0067; 0070; 0073
[2] Patent: CN107709341, 2018, A, . Location in patent: Paragraph 0048; 0061; 0064; 0067; 0070; 0073
  • 152
  • [ 288-32-4 ]
  • [ 7598-80-3 ]
  • [ 60628-96-8 ]
Reference: [1] Patent: CN107459486, 2017, A, . Location in patent: Paragraph 0006; 0018-0023
  • 153
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  • [ 60628-96-8 ]
Reference: [1] Tetrahedron, 2004, vol. 60, # 42, p. 9391 - 9396
  • 154
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  • [ 42074-68-0 ]
  • [ 23593-75-1 ]
YieldReaction ConditionsOperation in experiment
92% at 25℃; for 48 h; Green chemistry A clotrimazole synthesis method, the steps are as follows:Take 4mmol of 2-chlorotrityl chloride,8mmol of imidazole and 8mmol of sodium carbonate,Add 20 mL of hexafluoroisopropanol (HFIP),The reaction was allowed to stir at room temperature (25°C) for 48 h. The reaction formula is as follows:After the reaction is completed, the reaction is determined by TLC, andColumn chromatography.The reaction yield was 92percent.
Reference: [1] Patent: CN107629006, 2018, A, . Location in patent: Paragraph 0020; 0021; 0022; 0023; 0024; 0025; 0026-0076
[2] Arzneimittel-Forschung/Drug Research, 1992, vol. 42, # 6, p. 832 - 835
  • 155
  • [ 288-32-4 ]
  • [ 102-10-3 ]
  • [ 66774-02-5 ]
  • [ 108-10-1 ]
  • [ 23593-75-1 ]
Reference: [1] Patent: US4216333, 1980, A,
[2] Patent: US4216333, 1980, A,
  • 156
  • [ 288-32-4 ]
  • [ 102-10-3 ]
  • [ 66774-02-5 ]
  • [ 23593-75-1 ]
Reference: [1] Patent: US4216333, 1980, A,
[2] Patent: US4216333, 1980, A,
  • 157
  • [ 288-32-4 ]
  • [ 20671-53-8 ]
  • [ 50901-46-7 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1982, vol. 18, p. 6 - 10[2] Zhurnal Organicheskoi Khimii, 1982, vol. 18, # 1, p. 9 - 14
  • 158
  • [ 288-32-4 ]
  • [ 74-83-9 ]
  • [ 13750-81-7 ]
Reference: [1] South African Journal of Chemistry, 2012, vol. 65, p. 231 - 238
  • 159
  • [ 288-32-4 ]
  • [ 96-24-2 ]
  • [ 34793-28-7 ]
Reference: [1] Green Chemistry, 2009, vol. 11, # 5, p. 622 - 629
  • 160
  • [ 288-32-4 ]
  • [ 556-52-5 ]
  • [ 34793-28-7 ]
Reference: [1] Patent: US2006/135584, 2006, A1, . Location in patent: Page/Page column 3
  • 161
  • [ 288-32-4 ]
  • [ 67768-61-0 ]
Reference: [1] Tetrahedron, 2004, vol. 60, # 42, p. 9391 - 9396
  • 162
  • [ 288-32-4 ]
  • [ 110-83-8 ]
  • [ 67768-61-0 ]
Reference: [1] Journal of Organic Chemistry, 2008, vol. 73, # 3, p. 1004 - 1007
  • 163
  • [ 288-32-4 ]
  • [ 83682-72-8 ]
  • [ 100-11-8 ]
  • [ 56643-85-7 ]
Reference: [1] Patent: US4632934, 1986, A,
  • 164
  • [ 288-32-4 ]
  • [ 14818-35-0 ]
  • [ 29342-05-0 ]
Reference: [1] Patent: US3972888, 1976, A,
[2] Patent: US3972888, 1976, A,
  • 165
  • [ 288-32-4 ]
  • [ 59190-61-3 ]
  • [ 2466-76-4 ]
  • [ 609-19-8 ]
Reference: [1] Journal of Organic Chemistry, 2000, vol. 65, # 8, p. 2537 - 2543
  • 166
  • [ 288-32-4 ]
  • [ 106-41-2 ]
  • [ 18162-48-6 ]
  • [ 67963-68-2 ]
Reference: [1] Patent: US2011/244481, 2011, A1,
  • 167
  • [ 288-32-4 ]
  • [ 106-41-2 ]
  • [ 144-55-8 ]
  • [ 18162-48-6 ]
  • [ 68-12-2 ]
  • [ 67963-68-2 ]
Reference: [1] Patent: US4831047, 1989, A,
  • 168
  • [ 288-32-4 ]
  • [ 401-78-5 ]
  • [ 60-29-7 ]
  • [ 1801-10-1 ]
Reference: [1] Patent: US6441233, 2002, B1,
  • 169
  • [ 288-32-4 ]
  • [ 15231-91-1 ]
  • [ 18162-48-6 ]
  • [ 17579-79-2 ]
Reference: [1] Patent: US6333435, 2001, B1,
  • 170
  • [ 288-32-4 ]
  • [ 18162-48-6 ]
  • [ 504-63-2 ]
  • [ 73842-99-6 ]
Reference: [1] Patent: US6258360, 2001, B1,
  • 171
  • [ 288-32-4 ]
  • [ 74-96-4 ]
  • [ 111851-98-0 ]
Reference: [1] South African Journal of Chemistry, 2012, vol. 65, p. 231 - 238
  • 172
  • [ 288-32-4 ]
  • [ 33403-97-3 ]
  • [ 18162-48-6 ]
  • [ 2766-43-0 ]
Reference: [1] Patent: US5580872, 1996, A,
  • 173
  • [ 288-32-4 ]
  • [ 403-33-8 ]
  • [ 101184-08-1 ]
YieldReaction ConditionsOperation in experiment
59% With potassium carbonate In dimethyl sulfoxide at 120℃; for 3 h; A mixture of imidazole (132 g, 1.9 mol), methyl 4-fluorobenzoate (170 ml, 1.3 [0385] mol) and potassium carbonate (357 g, 2.6 mol) in DMSO (200 ml)And the mixture was stirred at 120 ° C for 3 hours. After cooling to room temperature, the mixture was added to cold water. The precipitated product was filtered and washed with water. Yield: 59percent.
Reference: [1] Patent: KR101502187, 2015, B1, . Location in patent: Paragraph 0384; 0385
[2] Journal of Medicinal Chemistry, 1990, vol. 33, # 4, p. 1091 - 1097
[3] Patent: US4804662, 1989, A,
  • 174
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  • [ 99768-12-4 ]
  • [ 101184-08-1 ]
YieldReaction ConditionsOperation in experiment
84% With CuI-USY zeolite In methanol at 65℃; for 17 h; General procedure: In a 10-mL round-bottom flask were successively added CuI-USY (ca. 15 mg, 10 molpercent of copper species), the nucleophile (0.75 mmol, 1.5 equiv), the boronic acid (0.5 mmol, 1.0 equiv), and MeOH (3.0 mL). The mixture was refluxed under air for 17 h and analyzed by LCMS. After cooling to r.t., the solvent was removed and the desired compound was isolated by purification on a short pad of silica gel (cyclohexane/EtOAc mixture).
Reference: [1] Synthesis (Germany), 2017, vol. 49, # 6, p. 1223 - 1230
[2] Synthetic Communications, 2012, vol. 42, # 17, p. 2595 - 2605
  • 175
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  • [ 619-42-1 ]
  • [ 101184-08-1 ]
YieldReaction ConditionsOperation in experiment
78% With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 130℃; Inert atmosphere (1) Under N2 protection, 4-bromobenzoic acid methyl ester (4.3g, 20mmol), imidazole (2.04g, 30mmol), cesium carbonate (19.6,60mmol), and cuprous iodide (0.19g, 1mmol) were added to a three-necked flask with 100mL dry DMF. It was heated with stirring to 130°C. After monitoring reaction completion by TLC, 200mL of saturated saline solution was added and extracted with dichloromethane 200mL x 3. The organic phase was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and purified by column chromatography to give a white solid 3.15g, yield 78.00percent.
Reference: [1] Patent: CN105348327, 2016, A, . Location in patent: Paragraph 0055; 0057; 0058
[2] Chemical Communications, 2016, vol. 52, # 69, p. 10505 - 10508
  • 176
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  • [ 619-44-3 ]
  • [ 101184-08-1 ]
YieldReaction ConditionsOperation in experiment
19% With (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; potassium carbonate; copper(I) bromide In N,N-dimethyl-formamide at 100℃; for 48 h; Inert atmosphere; Sealed tube For the synthesis of RK464 (Scheme 2), a round bottom flask with a magnetic stir bar was usedas a reaction vessel. To this vessel, CuBr (7.2 mg, 0.025 mmol), (1R,2R)-N1,N2-dimethyl-cyclohexane-1,2-diamine (16 L, 0.05 mmol), and imidazole (82 mg, 0.6 mmol), were added with DMF (20 mL) as asolvent. The vessel was sealed with a septum and nitrogen gas was passed through it.After reacting the initial mixture of compounds, methyl 4-iodobenzoate (262 mg, 0.5 mmol). K2CO3 (357 mg, 2.6 mmol) were added. Again, nitrogen gas was back-filled and the reaction mixturewas heated in a preheated oil bath for 48 h at constant temperature of 100 °C. Reaction progress wasregularly monitored using TLC. As the reaction progressed, the color of the mixture changed from whiteto yellow. The product was extracted using ethyl acetate and purified using flash chromatography.A pure yellow viscous product (about 40 mg) was obtained and dried under vacuum. Yield: 19percent.1H-NMR (750 MHz, CD3OD) δ: 6.75 (s, 1H, Ar-H), 6.63–6.64 (d, 2H, Ar-H), 6.19-6.20 (d, 2H, Ar-H),6.16 (s, 1H, Ar-H), 2.40 (s, 3H, CH3) (Supplementary Figure S9); HRMS (ESI) calcd C11H10N2O2 for203.0821, found 203.0808 [M+H]+, (Supplementary Figure S14). FT IR νmax cm−1: 1710.61 (carboxyl, for 203.0821, found 203.0808 [M+H]+, (Supplementary Figure S14). FT IR max cm1: 1710.61 (carboxyl,C=O), (Supplementary Figure S20). X-ray crystallography: X-ray crystallography structure for thiscompound is shown in Supplementary Figure S19 with R = 0.2.
Reference: [1] Molecules, 2016, vol. 21, # 7,
  • 177
  • [ 288-32-4 ]
  • [ 7732-18-5 ]
  • [ 877932-98-4 ]
  • [ 110-16-7 ]
  • [ 76095-16-4 ]
Reference: [1] Patent: US5789597, 1998, A,
  • 178
  • [ 288-32-4 ]
  • [ 75-44-5 ]
  • [ 1467-16-9 ]
  • [ 530-62-1 ]
YieldReaction ConditionsOperation in experiment
70% at 66 - 130℃; for 1.45 h; Example 2; Comparative in Analogy to Example 1 from WO-A-00/14072 In a flask, 68.22 g of imidazole are suspended in 505 g of xylene. The mixture is heated to reflux and dewatered by taking off 5 g of a xylene/water mixture. The temperature is reduced to 66° C. and over the course of 30 minutes 25.2 g of phosgene are metered in with an introduction rate of 50.4 g/h. After about 15 minutes the reaction mixture takes on a consistency like that of chewing gum. When the metering of phosgene is at an end the imidazole hydrochloride by-product is in the form of yellow balls. After a further hour of stirring at this temperature, this temperature is raised to 130° C., and the consistency of the imidazole hydrochloride changes to a brown melt. The melt is drained off at 130° C. It solidifies on cooling to a dark-green, solid mass. The supernatant xylene phase is cooled to 0° C. The precipitated crystals are filtered off and dried at 20 mbar and 50° C. This gives carbonylbisimidazole in the form of white crystals with black fractions (Hazen colour number: 489). The purity is 96.8percent, corresponding to a yield of 70percent of theory.
61.9% at 35 - 55℃; for 3.25 - 3.75 h; Example 3; Inventive; A flask is charged with 375.2 g of dry chloroform and 93.8 g of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 28 g of distillate are taken off under a pressure of 280 mbar and at 30° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 72.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm chloroform at 35° C. 251.1 g of water-clear solution are distilled off from the combined organic phases at 280 mbar and 30° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of chloroform conditioned to a temperature of 0° C. Drying of the crystals at 6 mbar and 30° C. gives 41.5 g of product in the form of white crystals having a Hazen colour number of 44. The purity of the product is 99.5percent, corresponding to a yield of 74.0percent of theory.; Example 4; Inventive; A flask is charged with 358.1 g of dry chloroform and 119.36 g of imidazole and this initial charge is heated to 55° C. At this temperature over the course of 1.75 hours 44.57 g of phosgene are added with an introduction rate of 25.5 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 2 h. In order to ensure a phosgene-free reaction mixture, 5.4 g of distillate are taken off under a pressure of 630 mbar and at 35° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 96.0 g) is removed by filtration at 55° C., the filter cake being washed with twice 100 ml of warm chloroform at 55° C. The combined organic phases are cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of chloroform conditioned to a temperature of 0° C. Drying of the residue at 4 mbar and 46° C. gives 44.3 g of product in crystalline form having a Hazen colour number of 49. The purity of the product is 99.0percent, corresponding to a yield of 61.9percent of theory.
59.9% at 35℃; for 3.25 h; Example 1; Inventive; A flask is charged with 531.5 g of dry dichloromethane and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 36.04 g (0.36 mol) of phosgene are added with an introduction rate of 20.6 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 13.2 g of distillate are taken off under a pressure of 790 to 500 mbar and at 35-25° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 72.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. 250.1 g of water-clear solution are distilled off from the combined organic phases at 790 to 500 mbar and 35-25° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of dichloromethane conditioned to a temperature of 0° C. Drying of the crystals at 4 mbar and 30° C. gives 40.0 g of product in the form of white crystals, Hazen colour number: 69.7. The purity of the product is 99.3percent, corresponding to a yield of 71.2percent of theory.; Example 5 Inventive with Recycling of the Mother Liquor 1st Phosgenation A flask is charged with 531.5 g of dry dichloromethane and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 8.4 g of distillate are taken off under a pressure of 750 to 500 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 80.3 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 50 ml of dichloromethane conditioned to a temperature of 0° C. After the solid carbonylbisimidazole has been filtered off, 553.0 g of mother liquor M1 are obtained. Drying of the crystals at 5 mbar and 20° C. gives 33.54 g of product in the form of white crystals with a Hazen colour number of 45.1. The purity of the product is 99.6percent. The yield therefore corresponds to 59.9percent of theory. 2nd Phosgenation A flask is charged with 531.5 g of dichloromethane-containing mother liquor M1 from the 1st phosgenation step and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 21.6 g of distillate are taken off under a pressure of 750 to 450 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 86.6 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 100 ml of dichloromethane conditioned to a temperature of 0° C. After the solid carbonylbisimidazole has been filtered off, 553.0 g of mother liquor M2 are obtained. Drying of the crystals at 6 mbar and 30° C. gives 39.4 g of product in the form of white crystals with a Hazen colour number of 33.2. The purity of the product is 98.7percent. The yield therefore corresponds to 70percent of theory. 3rd Phosgenation A flask is charged with 531.5 g of dichloromethane-containing mother liquor M2 from the 2nd phosgenation step and 93.8 g (1.37 mol) of imidazole and this initial charge is heated to 35° C. At this temperature over the course of 1.75 hours 35.02 g (0.35 mol) of phosgene are added with an introduction rate of 20.0 g/h. The mixture thus obtained is subsequently stirred at the same temperature for 1.5 h. In order to ensure a phosgene-free reaction mixture, 9.2 g of distillate are taken off under a pressure of 750 to 500 mbar and at 35-20° C., an ammonia/water/isopropanol mixture is added to the distillate, and this mixture is discarded. The imidazole hydrochloride by-product (isolated dry weight: 88.1 g) is removed by filtration at 35° C., the filter cake being washed with twice 100 ml of warm dichloromethane at 33° C. The remaining solution is cooled to 0° C., and a suspension forms. The precipitated carbonyl bisimidazole is separated off by filtration and additionally washed with 100 ml of dichloromethane conditioned to a temperature of 0° C. Drying of the crystals at 7 mbar and 20° C. gives 37.3 g of product in the form of white crystals with a Hazen colour number of 41.0. The purity of the product is 98.5percent. The yield therefore corresponds to 65.9percent of theory.
Reference: [1] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 4
[2] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 4
[3] Patent: US2005/272937, 2005, A1, . Location in patent: Page/Page column 3-4; 5
  • 179
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  • [ 503-38-8 ]
  • [ 1467-16-9 ]
  • [ 530-62-1 ]
YieldReaction ConditionsOperation in experiment
90% at 20 - 55℃; for 4 h; To a 1000 ml flask were added 108.3 g (1.59 mol) of imidazole and 630 g of tetrahydrofuran. After the atmosphere of the system was replaced with nitrogen, the imidazole was dissolved under stirring. Thereto was added dropwise 39.3 g (0.2 mol) of diphosgene at room temperature over a period of 2 hours. After completion of the dropwise addition, the stirring was continued at room temperature for 1 hour and then the whole was heated to 55°C, followed by continuous stirring for another 1 hour. Imidazole hydrochloride yielded as a by-product was filtrated with heat and was then washed with 100 g of tetrahydrofuran. The imidazole hydrochloride filtrated off was dried under reduced pressure at 40°C to obtain 83.2 g (0.796 mol) of imidazole hydrochloride (recovery of 100percent). A filtrate containing CDI was concentrated and subjected to toluene-crystallization, and CDI was filtrated off under a nitrogen atmosphere. The CDI filtrated off was dried under reduced pressure at 40°C to obtain 58.0 g (0.358 mol) of CDI as white crystals (yield 90percent). M.p. 111.2 to 118.6°C.
Reference: [1] Patent: EP1731510, 2006, A1, . Location in patent: Page/Page column 5
  • 180
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  • [ 1467-16-9 ]
Reference: [1] Angewandte Chemie - International Edition, 2011, vol. 50, # 29, p. 6661 - 6665
[2] Journal of Fluorine Chemistry, 2011, vol. 132, # 11, p. 925 - 936
  • 181
  • [ 288-32-4 ]
  • [ 1467-16-9 ]
Reference: [1] Angewandte Chemie - International Edition, 2012, vol. 51, # 46, p. 11531 - 11534[2] Angew. Chem., 2012, vol. 124, # 46, p. 11699 - 11702,4
  • 182
  • [ 288-32-4 ]
  • [ 79-44-7 ]
  • [ 1467-16-9 ]
  • [ 69829-55-6 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, # 2, p. 321 - 326[2] Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 2, p. 357 - 362
  • 183
  • [ 288-32-4 ]
  • [ 107-30-2 ]
  • [ 1236784-49-8 ]
  • [ 1467-16-9 ]
Reference: [1] Journal of Organic Chemistry, 2010, vol. 75, # 15, p. 5170 - 5177
  • 184
  • [ 288-32-4 ]
  • [ 624-76-0 ]
  • [ 18162-48-6 ]
  • [ 101166-65-8 ]
Reference: [1] Patent: US2013/59926, 2013, A1, . Location in patent: Page/Page column
  • 185
  • [ 288-32-4 ]
  • [ 443-26-5 ]
  • [ 117296-92-1 ]
Reference: [1] European Journal of Medicinal Chemistry, 1992, vol. 27, # 3, p. 219 - 228
  • 186
  • [ 288-32-4 ]
  • [ 113775-47-6 ]
YieldReaction ConditionsOperation in experiment
84.8% at 75℃; for 0.5 h; 3.2 g (20 mmol) of FeCl3,16.8 g (100 mmol) of 1- (1-chloroethyl) -2,3-dimethylbenzene,7.5 g (110 mmol) of imidazole and 35 ml of ionic liquid ([omim] BF6) were added to the reaction flask,The reaction was stirred at 75 ° C for 0.5 hours,After monitoring the reaction,Pour into the water,Dichloromethane extraction,The organic phase was washed three times,Dry the organic phase over anhydrous sodium sulfate,Concentrated under reduced pressure,The petroleum ether was recrystallized to obtain 17.0 g of 4- [1- (2,3-dimethylphenyl) ethyl] -1H-imidazole,Yield 84.8percent.
Reference: [1] Patent: CN106588778, 2017, A, . Location in patent: Paragraph 0038; 0039; 0040; 0041; 0042; 0043; 0044-0064
  • 187
  • [ 288-32-4 ]
  • [ 113775-47-6 ]
YieldReaction ConditionsOperation in experiment
89.72 % ee at 90℃; for 0.5 h; Inert atmosphere In the presence of nitrogen, 21.2 g (200 mmol) of sodium carbonate,16.8 g (100 mmol) of 1- (1-chloroethyl) -2,3-dimethylbenzene,[1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride 1.4 g (2 mmol),Imidazole 7.5 g (110 mmol) and 50 ml of ionic liquid ([Bmim] BF4)Added to the flask, the reaction was stirred at 90 ° C for 30 minutes, the reaction was monitored,Poured into water, extracted with dichloromethane, the organic phase washed three times,The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure,Petroleum ether obtained by recrystallization16.9 g of 4- [1- (2,3-dimethylphenyl) ethyl] -1H-imidazole,Yield 81.1percent(S) -4- [1- (2,3-Dimethylphenyl) ethyl] -1H-imidazole ee 89.72percent.
Reference: [1] Patent: CN106632051, 2017, A, . Location in patent: Paragraph 0033; 0034; 0035; 0036; 0037; 0038; 0039; 0040-005
[2] Patent: CN106588780, 2017, A, . Location in patent: Paragraph 0022; 0023; 0024; 0025; 0026; 0027; 0028-0050
  • 188
  • [ 288-32-4 ]
  • [ 113775-47-6 ]
Reference: [1] Patent: CN106588779, 2017, A, . Location in patent: Paragraph 0028; 0029; 0030; 0031; 0032; 0033; 0034-0044
  • 189
  • [ 288-32-4 ]
  • [ 3618-04-0 ]
  • [ 18162-48-6 ]
  • [ 676560-15-9 ]
Reference: [1] Patent: US2004/259843, 2004, A1,
[2] Patent: US2005/215784, 2005, A1,
  • 190
  • [ 288-32-4 ]
  • [ 109384-19-2 ]
  • [ 301673-14-3 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: With iodine; triphenylphosphine In acetonitrile at 20℃; for 0.166667 h;
Stage #2: at 20℃; for 0.166667 h;
2)
Synthesis of N-t.butoxycarbonyl-4-iodo-1-piperidine
2.15 g of triphenylphosphine (8.2 mmole) and 2.08 g of iodine (8.2 mmole) are dissolved in 30 ml of acetonitrile.
The reaction medium is left under stirring for 10 minutes at ambient temperature then 918 mg of imidazole (13.5 mmol) is added and stirring is maintained for another 10 minutes at ambient temperature.
Then 1 g (5 mmol) of N-t.butoxycarbonyl-4-hydroxy-1-piperidine is added and stirring is maintained for 24 hours at ambient temperature.
The reaction is treated by adding an aqueous solution of sodium thiosulphate and the acetonitrile is evaporated off under reduced pressure (2 kPa), followed by taking up in ethyl acetate, extracting and washing with an aqueous solution of sodium thiosulphate.
The organic phases are dried over MgSO4, filtered and the ethyl acetate is evaporated off under reduced pressure (2 kPa), followed by chromatography on silica gel eluding with dichloromethane then dichloromethane/methanol 90:10.
1.1 g (Yield=70percent) of colourless oil is recovered.
TLC: Rf=0.8 (silica gel, eluent: CH2Cl2/MeOH 90:10
1H-NMR (CDCl3): δ 1.47 (s, 9H, tBu); 2.03 (m, 4H, -C-CHI-C2-); 3.30 and 3.60 (2m, 4H, -C-N-C-); 4.46 (m, 1H -CI-)
Reference: [1] Patent: US2008/58348, 2008, A1, . Location in patent: Page/Page column 15
  • 191
  • [ 288-32-4 ]
  • [ 162358-05-6 ]
  • [ 162358-07-8 ]
Reference: [1] Patent: US5948820, 1999, A,
  • 192
  • [ 288-32-4 ]
  • [ 506-68-3 ]
  • [ 104619-51-4 ]
YieldReaction ConditionsOperation in experiment
99% for 0.5 h; Inert atmosphere; Reflux Step 1:
To a solution of imidazole (6.8 g, 100 mmol) in CH2Cl2 (500 mL) was added cyanogen bromide (11 mL of 3M in CH2Cl2, 33 mmol) and the resultant mixture was heated under nitrogen at reflux for 30 minutes.
The reaction mixture was cooled to room temperature and filtered.
The filtrate was concentrated to 50 mL and crystallized in the freezer for 2 days.
The solid was collected by filtration, washed with cold CH2Cl2 and dried under vacuum to afford (di-imidazol-1-yl)-methyleneamine (5.3 g, 99percent).
72% for 0.5 h; Reflux To a stirred solution of imidazole (6.80 g, 100 mmol) in anhydrous dichloromethane (500 mL) was added BrCN (3.70 g, 33 mmol) and stirring was continued at reflux for 30 min. The mixture was cooled to room temperature and concentrated to afford di(imidazole-1-yl)methanimine (4.05 g, 72 percent) as a pale yellow solid which was used without further purification.H NMR (DMSO-d6): 10.21 (br s, 1 H, NH), 8.09 (s, 2 H, 2 * CH), 7.57 (s, 2 H, 2 * CH), 7.12 (s, 2 H, 2 * CH).
8% for 0.5 h; Reflux To a solution of 1H-imidazole (42 g, 617 mmol) in dichloromethane (1 L) was added cyanogen bromide (22.5,212 mmol) and the mixture was heated to reflux for 30 minutes,allowed to cool to room temperature and the white solid was filtered off. The filtrate was concentrated to 100 ml andstored in the refrigerator for 3 days. The precipitated solid wasfiltered off to obtain 8 g di(1H-imidazol-l-yl)methanimine(49.6mmol, 8percent).
Reference: [1] Patent: US2012/149718, 2012, A1, . Location in patent: Page/Page column 35
[2] Journal of Organic Chemistry, 2002, vol. 67, # 21, p. 7553 - 7556
[3] Journal of Heterocyclic Chemistry, 2003, vol. 40, # 1, p. 191 - 193
[4] Chemical Communications, 2014, vol. 50, # 91, p. 14257 - 14260
[5] Patent: WO2012/85586, 2012, A1, . Location in patent: Page/Page column 66; 68
[6] Journal of Organic Chemistry, 2008, vol. 73, # 3, p. 1077 - 1087
[7] Journal of Organic Chemistry, 2016, vol. 81, # 11, p. 4516 - 4529
[8] Patent: JP5714745, 2015, B2, . Location in patent: Paragraph 0507; 0508
[9] Patent: WO2007/123936, 2007, A1, . Location in patent: Page/Page column 38
[10] Patent: WO2009/11880, 2009, A2, . Location in patent: Page/Page column 91-92
[11] Patent: WO2010/111483, 2010, A1, . Location in patent: Page/Page column 149
[12] Chemical Communications, 2017, vol. 54, # 5, p. 511 - 514
[13] Patent: WO2018/152405, 2018, A1, . Location in patent: Paragraph 00208
  • 193
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  • [ 590-17-0 ]
  • [ 104619-51-4 ]
Reference: [1] Patent: US2007/105866, 2007, A1, . Location in patent: Page/Page column 65
  • 194
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  • [ 773837-37-9 ]
  • [ 104619-51-4 ]
Reference: [1] Chemical Communications, 2017, vol. 54, # 5, p. 511 - 514
  • 195
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  • [ 36289-36-8 ]
  • [ 104619-51-4 ]
Reference: [1] Chemical Communications, 2017, vol. 54, # 5, p. 511 - 514
  • 196
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  • [ 104619-51-4 ]
Reference: [1] Chemical Communications, 2017, vol. 54, # 5, p. 511 - 514
  • 197
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  • [ 58885-58-8 ]
  • [ 167479-01-8 ]
Reference: [1] Patent: US2005/54640, 2005, A1,
  • 198
  • [ 288-32-4 ]
  • [ 144-55-8 ]
  • [ 161609-84-3 ]
Reference: [1] Patent: EP1308439, 2003, A1,
  • 199
  • [ 288-32-4 ]
  • [ 109-70-6 ]
  • [ 53710-78-4 ]
YieldReaction ConditionsOperation in experiment
73%
Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 1.5 h;
Stage #2: at 20℃;
Anhydrous THF (25 mL) was cooled in an ice bath. After NaH (1.40 g, 35 mmol, 60percent) was added to the THF in one portion, the mixture was stirred at rt for 30 mm and cooled in an ice bath. Then a solution of 1H-imidazole (2.00 g, 30 mmol) in anhydrous THF (6 mL) was added dropwise. The reaction mixture was then warmed to rt and stirred at rt for 1.5 h. To the mixture was added 1 -bromo-3-chloropropane (4.60 g, 30 mmol) dropwise, and stirred at rt overnight. To the resulting mixture was added MeOH (5 mL) in one portion. The resulting mixtue was filtered and the filtrate was concertrated in vacuo. The residue was purified by a silica gel column chromatography (DCM / MeOH (V / V) = 30: 1) to give the title compound as pale yellow oil (3.10 g, 73percent).
73%
Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 1.5 h; Cooling with ice
Stage #2: at 20℃;
Anhydrous THF (25 mL) was cooled in an ice bath.
After NaH (1.40 g, 35 mmol, 60percent) was added to the THF in one portion, the mixture was stirred at rt for 30 min and cooled in an ice bath.
Then a solution of 1H-imidazole (2.00 g, 30 mmol) in anhydrous THF (6 mL) was added dropwise.
The reaction mixture was then warmed to rt and stirred at rt for 1.5 h.
To the mixture was added 1-bromo-3-chloropropane (4.60 g, 30 mmol) dropwise, and stirred at rt overnight.
To the resulting mixture was added MeOH (5 mL) in one portion.
The resulting mixtue was filtered and the filtrate was concertrated in vacuo.
The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=30:1) to give the title compound as pale yellow oil (3.10 g, 73percent).
73%
Stage #1: With sodium hydride In toluene at 20℃; for 1.5 h;
Stage #2: at 20℃;
Under ice-cooling, sodium hydride (60percent, 1.40 g, 35 mmol) was added in one portion to dry tetrahydrofuran (25 mL), and the resulting reaction solution was warmed to room temperature and stirred for 30 minutes.Under ice-cooling, 1H-imidazole (2.00 g, 30 mmol, 6 mL of dry THF solution) was added dropwise, and the resulting reaction solution was warmed to room temperature and stirred for 1.5 h.1-Bromo-3-chloropropane (4.60 g, 30 mmol) was added dropwise and the reaction was allowed to react at room temperature overnight.Methanol (5 mL) was added to the reaction system in one portion, filtered, the solvent was distilled off under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol (V/V) = 30/1).A pale yellow oil (3.10 g, 73percent) was obtained.
Reference: [1] Tetrahedron Letters, 2010, vol. 51, # 28, p. 3666 - 3669
[2] Patent: WO2014/12360, 2014, A1, . Location in patent: Paragraph 00398
[3] Patent: US2015/87639, 2015, A1, . Location in patent: Paragraph 0703
[4] Patent: TWI607995, 2017, B, . Location in patent: Page/Page column 154
[5] European Journal of Organic Chemistry, 2009, # 19, p. 3249 - 3257
[6] Patent: US2004/54186, 2004, A1, . Location in patent: Page 145
[7] European Journal of Medicinal Chemistry, 2016, vol. 109, p. 75 - 88
[8] Patent: CN105439908, 2016, A, . Location in patent: Paragraph 0013; 0014
  • 200
  • [ 288-32-4 ]
  • [ 152537-03-6 ]
  • [ 75-05-8 ]
  • [ 158602-36-9 ]
Reference: [1] Patent: US5281585, 1994, A,
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