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[ CAS No. 623-00-7 ] {[proInfo.proName]}

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Diana M. Soto-Martínez ; Garrett D. Clements ; John E. Díaza, Joy Becher , et al. DOI: PubMed ID:

Abstract: The von Hippel-Lindau (VHL) protein serves as the substrate recognition subunit of the multi-subunit Cullin-2 RING E3 ubiquitin ligase (CRL2VHL), which regulates intracellular concentrations of hypoxia inducible factors (HIFs) through a ubiquitin proteasome system (UPS) cascade. Strategic recruitment of CRL2VHL by bi- or trifunctional targeted protein degraders (e.g., PROTACs®) offers the prospect of promoting aberrant polyubiquitination and ensuing proteasomal degradation of disease-related proteins. Non-peptidic, L-hydroxyproline-bearing VHL ligands such as VH032 (1) and its chiral benzylic amine analog Me-VH032 (2), are functional components of targeted protein degraders commonly employed for this purpose. Herein, we compare two approaches for the preparation of 1 and 2 primarily highlighting performance differences between Pd(OAc)2 and Pd-PEPPSI-IPr for the key C–H arylation of 4-methylthiazole. Results from this comparison prompted the development of a unified, five-step route for the preparation of either VH032 (1) or Me-VH032 (2) in multigram quantities, resulting in yields of 56% and 61% for 1 and 2, respectively. Application of N-Boc-L-4-hydroxyproline rather than N-tert-butoxycarbonyl to shield the benzylic amine during the coupling step enhances step economy. Additionally, we identified previously undisclosed minor byproducts generated during arylation steps along with observations from amine deprotection and amidation reaction steps that may prove helpful not only for the preparation of 1 and 2, but for other VHL recruiting ligands, as well.

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Guo, Sheng ; Wu, Yifan ; Luo, Shao-Xiong Lennon , et al. DOI:

Abstract: Heterogenous catalysts with confined nanoporous catalytic sites are shown to have high activity and size selectivity. A solution-processable nanoporous organic polymer (1-BPy-Pd) catalyst displays high catalytic performance (TON > 200K) in the heterogeneous Suzuki–Miyaura coupling (SMC) reaction and can be used for the preparation of the intermediates in the synthesis of pharmaceutical agents. In comparison to the homogeneous catalyst analogue (2,2′-BPy)PdCl2, the heterogenous system offers size-dependent catalytic activity when bulkier substrates are used. Furthermore, the catalyst can be used to create catalytic impellers that simplify its use and recovery. We found that this system also works for applications in heterogenous Heck and nitroarenes reduction reactions. The metal-binding nanoporous polymer reported here represents a versatile platform for size-selective heterogeneous and recyclable catalysts.

Keywords: nanoporous organic polymer ; heterogeneous catalyst ; Suzuki−Miyaura coupling reaction ; size-selective reaction ; catalyst processing

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Product Details of [ 623-00-7 ]

CAS No. :623-00-7 MDL No. :MFCD00001811
Formula : C7H4BrN Boiling Point : -
Linear Structure Formula :- InChI Key :HQSCPPCMBMFJJN-UHFFFAOYSA-N
M.W : 182.02 Pubchem ID :12162
Synonyms :

Calculated chemistry of [ 623-00-7 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 38.86
TPSA : 23.79 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.61 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.9
Log Po/w (XLOGP3) : 2.53
Log Po/w (WLOGP) : 2.32
Log Po/w (MLOGP) : 2.21
Log Po/w (SILICOS-IT) : 2.5
Consensus Log Po/w : 2.29

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.06
Solubility : 0.16 mg/ml ; 0.00088 mol/l
Class : Soluble
Log S (Ali) : -2.68
Solubility : 0.384 mg/ml ; 0.00211 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.33
Solubility : 0.0842 mg/ml ; 0.000462 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.39

Safety of [ 623-00-7 ]

Signal Word:Danger Class:9
Precautionary Statements:P273-P301+P310+P330 UN#:3077
Hazard Statements:H301-H400 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 623-00-7 ]

* 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 [ 623-00-7 ]
  • Downstream synthetic route of [ 623-00-7 ]

[ 623-00-7 ] Synthesis Path-Upstream   1~101

  • 1
  • [ 623-00-7 ]
  • [ 27149-27-5 ]
Reference: [1] Chemistry - An Asian Journal, 2013, vol. 8, # 7, p. 1408 - 1411
  • 2
  • [ 583-71-1 ]
  • [ 6941-75-9 ]
  • [ 623-00-7 ]
  • [ 67832-11-5 ]
  • [ 70484-01-4 ]
Reference: [1] Russian Journal of General Chemistry, 2010, vol. 80, # 8, p. 1672 - 1676
[2] Russian Journal of General Chemistry, 2014, vol. 84, # 6, p. 1085 - 1090
  • 3
  • [ 67832-11-5 ]
  • [ 6941-75-9 ]
  • [ 124-38-9 ]
  • [ 623-00-7 ]
  • [ 70484-01-4 ]
Reference: [1] Russian Journal of General Chemistry, 2013, vol. 83, # 3, p. 492 - 495[2] Zh. Obshch. Khim., 2013, vol. 83, # 3, p. 439 - 442,4
  • 4
  • [ 583-71-1 ]
  • [ 6941-75-9 ]
  • [ 623-00-7 ]
  • [ 1312479-78-9 ]
  • [ 70484-01-4 ]
Reference: [1] Russian Journal of General Chemistry, 2010, vol. 80, # 9, p. 1779 - 1785
  • 5
  • [ 623-00-7 ]
  • [ 50907-23-8 ]
YieldReaction ConditionsOperation in experiment
98% With sodium azide; ammonium cerium (IV) nitrate In N,N-dimethyl-formamide at 110℃; for 6 h; Inert atmosphere; Green chemistry General procedure: sodiumazide (1.5 mmol) was added to a magnetically stirred solution of nitrile 1a(1 mmol) in anhydrous DMF and the CAN (10 mmol percent) was added. The reactionmixture was constantly stirred for another 6 h at 110 C under nitrogenatmosphere. After the completion of reaction as seen by TLC, the reactionmixture was brought to room temperature and the solvent was evaporatedunder vacuum. The crude thus obtained, was dissolved in ethyl acetate (20 mL)and solution was washed with acidified water (4 M HCl, 15 mL) twice.Separated organic layer was washed with brine solution dried overanhydrous Na2SO4, and solvent was removed under high vacuum to obtaintetrazole 1b as a white crystalline solid in 97percent yield.
98% With bismuth(III) chloride; sodium azide In water; isopropyl alcohol at 160℃; for 4 h; Microwave irradiation General procedure: 2-Furonitrile 1m (186 mg, 2 mmol), NaN3 (260 mg, 4 mmol), BiCl3 (126 mg, 0.4 mmol), and 8 mL of a 3:1 isopropanol/water mixture were added to a 30-mL Pyrex microwave vessel, which was then capped. The microwave vessel was then placed in a Milestone Start Synth microwave reactor. The reaction was magnetically stirred and heated for 1 h at 150°C. The reaction was monitored by thin-layer chromatography (TLC) using an ether/hexane mixture (typically 50/50) for development. The reaction mixture was then diluted with saturated aqueous sodium bicarbonate (20 mL) and was hed with ethyl acetate (2×15 mL). The aqueous sodium bicarbonate layer was cooled with ice and acidified to a pH of 2 or less with concentrated hydrochloric acid, which was added dropwise. The precipitate formed was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried with anhydrous sodium sulfate and decanted into a tared round-bottom flask. The organic layer was concentrated under reduced pressure by rotary evaporation at 40°C and then under high vacuum. The tetrazole product was recrystallized from ethyl acetate and hexane.
98% at 120℃; for 0.5 h; Green chemistry General procedure: To a suspension of the catalyst (0.004 g) in PEG (2 mL), nitrile (1 mmol) and sodium azide (1.2 mmol) were added and the mixture was stirred vigorously at 120 °C for the required time (Table 6). After the reaction was completed (as monitored by TLC), the catalyst was separated with a magnet. HCl (4 N, 10 mL) was then added to the residue, and the tetrazole was extracted with ethyl acetate. The organic extract was washed with distilled water, dried over anhydrous Na2SO4 and then evaporated to give the desired tetrazole.
97.2% at 85℃; for 18 h; at 85 °C, a mixtureof Tetrabutylammonium fluoride trihydrate (TABF3H2O) (1.31 g,5 mmol), 4-bromobenzonitrile (1.82 g, 10 mmol) and trimethylsilylazide (TMSN3) (1.73 g, 15 mmol) was under vigorous stirring conditionsfor 18 h. After completion of the reaction, the mixture was allowedto cool to room temperature, added with ethyl acetate and washedby 3×150 mL hydrochloric acid. The organic layer was isolatedand the remaining aqueous phase was further extracted with ethylacetate. The organic phases were combined and dried using anhydrousMgSO4 to afford 5-(4-bromophenyl)-1H-tetrazole. Yield 97.2percent. Meltingpoint (MP): 260–261 °C. 1H NMR (400 MHz, DMSO‑d6): δ8.19–7.89 (m,2H), 7.83 (d, J=8.6 Hz, 2H). 13C NMR (400 MHz, DMSO‑d6): δ 132.98(s), 129.36 (s), 125.20 (s).
95% With sodium azide; ammonium acetate In N,N-dimethyl-formamide at 70℃; for 3 h; General procedure: The [AMWCNTs-O–Cu(II)–PhTPY] heterogeneous catalyst was subjected to 5 successive reuses under the reaction conditions: For each reaction, nitrile (1.0mmol), NaN3 (1.3mmol) and NH4OAc (1.0mmol) were mixed and stirred in DMF (1mL) in the presence of 4mol-percent of [AMWCNTs-O–Cu(II)–PhTPY] at 70°C in an uncapped vial. After the completion of the reaction, as monitored by TLC using n-hexane/ethyl acetate, the mixture was diluted by H2O (5mL), then the mixture was vacuum-filtered onto a sintered-glass funnel, and the residue was consecutively washed with ethyl acetate (30mL), water (5mL). The heterogeneous catalyst was recharged for another reaction run. The combined supernatant and organic washings were extracted with ethyl acetate (3×10mL), the combined organic layer was dried over anhydrous Na2SO4. Removal of the solvent under vacuum, followed by purification on silica gel using hexane/ethyl acetate as the eluent afforded the pure products.
95% With sodium azide In N,N-dimethyl-formamide at 90℃; for 3.5 h; General procedure: In a double-necked round bottom flask (100 mL) equippedwith a condenser was added a mixture consisting ofnitrile (0.005 mol), NaN3 (0.006 mol), and monodisperse Pt NPsVC in DMF (1.5 mL). The mixture washeated at reflux until TLC monitoring indicated no furtherimprovement in the conversion. The reaction mixture wasthen cooled to room temperature, vacuum-filtered usinga sintered-glass funnel and the residue was washed withethyl acetate (3×10 mL). The filtrate was treated with5 mL HCl (4 mol L−1 to reach pH= 3 and it was allowedto stir for 30 minutes. Subsequently, the organic layer wasseparated, dried over anhydrous Na2SO4 and evaporated.The crude product was purified by recrystallization and/orcolumn chromatography on silica gel eluted with propersolvents to get pure 5-Phenyl 1H-tetrazole.
95% With sodium azide; aminosulfonic acid In N,N-dimethyl-formamide at 120℃; for 5 h; General procedure: A mixture of 4-nitrobenzonitrile (0.296 g, 2 mmol), sodium azide (0.195 g, 3 mmol), and sulfamic acid (0.0097 g, 0.1 mmol) was stirred at 120°C in DMF (5 mL) for the appropriate time (Table 2) until TLC (4:1 n-hexane:ethyl acetate) indicated no further progress in the conversion. After completion of the reaction (as monitored by TLC), the reaction mixture was cooled to room temperature, then 20 mL diethyl ether was added to the mixture and stirred for 10 minutes. The catalyst was separated by simple gravity filtration, washed with diethyl ether (2 £ 10 mL) and dried at 40°C for 30 min. The recovered catalyst wasused for three additional cycles and gave the tetrazole in 95, 85 and 75percent (with 4-nitrobenzonitrile). The filtrate was treated with ethyl acetate (30 mL) and 6 N HCl(20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 5-(4-nitrophenyl) tetrazole (0.363 g), 95percent yield.
94% at 140℃; for 1.33333 h; Green chemistry General procedure: NaN3 (0.975 g, 15 mmol) was dissolved in DES (10 mL) at room temperature by stirring until a clear solution was formed. Then benzonitrile (10 mmol) was added. The reaction mixture was constantly stirred at 140 °C and monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into the cold water (10 mL). The solid was obtained and filtered. The obtained solid is taken into cold water (10 mL). Then it was acidified carefully to pH 5 with 5 M HCl. The organic material was extracted thrice with ethyl acetate; the resultant organic layer was washed with distilled water, dried over anhydrous sodium sulfate, and concentrated to give the crude solid crystalline 5-substituted 1H-tetrazole. The resulting product, although evident as a single compound by TLC, was purified by simple recrystallization from aqueous ethanol giving pure 5-substituted 1H-tetrazoles.
94% With sodium azide; C19H17N3O4(2-)*Cu(2+) In ethylene glycol at 120℃; for 3 h; General procedure: In 25mL round-bottomed flask, sodium azide (0.076g, 1.2mmol) and polymeric copper (II) complex (0.005g) were added to a solution of benzonitrile (0.103g, 1mmol) in ethylene glycol (3mL) with stirring at room temperature. The reaction temperature was raised up to 120°C for 3h. The reaction was monitored by TLC at regular intervals. After completion of the reaction, the reaction mixture was cooled to room temperature and treated with 10mL HCl (2N) and extracted with 10mL ethyl acetate. The resulted organic layers were separated and washed with 2×10mL distilled water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was then purified by column chromatography on silica gel (100–200 mesh) to afford the corresponding products.
92% With sodium azide In N,N-dimethyl-formamide at 110℃; for 3 h; General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol), Cu complex catalyst (0.4 molpercent) and DMF (3 mL) was taken in a round-bottomed flask and stirred at 110 °C temperature. After completion of the reaction the catalyst was separated from the reaction mixture with an external magnet and reaction mixture was treated with ethyl acetate (2 × 20 mL) and 1 N HCl (20 mL). The resultant organic layer was separated and the aqueous layer was again extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with water, concentrated, and the crude material was chromatographed on silica gel (Hexane-EtoAc, 1:1) to afford the pure product.
92% With indium(III) chloride; sodium azide In water; isopropyl alcohol at 160℃; for 4 h; Microwave irradiation General procedure: Synthesis of 4-acetylbenzotetrazole (2c). 4-Acetylbenzonitrile 3c (290 mg, 2 mmol), NaN3 (260 mg, 4 mmol), InCl3(89 mg, 0.4 mmol), and 8 mL of a 3:1 isopropanol/water mixture were added to a 30-mL Pyrex microwave vessel and capped. The microwave vessel was then placed in a Milestone Start Synth microwave reactor. The reaction was magnetically stirred and heated for 1 hour at 160 oC. The pressure in the vessels was not determined. The reaction was monitored by TLC using an ether/hexane mixture (typically50/50) for development. After cooling, the reaction mixture was diluted with saturated aqueous sodium bicarbonate (20mL) and washed with ethyl acetate (2 x 15 mL). The aqueous sodium bicarbonate layer was cooled to 0 oC and acidified to a pH of 2 or less with concentrated hydrochloric acid,which was added drop-wise. The precipitate formed was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and decanted into a tared round bottom flask. The organic layer was concentrated under reduced pressure. The tetrazole product was recrystallized from ethyl acetate and hexane. All reagents mentioned above were used unpurified
90% With sodium azide; copper(II) ferrite In N,N-dimethyl-formamide at 120℃; for 12 h; General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol), catalyst (40 molpercent) and DMF (3 mL) was taken in a round-bottomed flask and stirred at 120 °C temperature for 12 h. After completion of the reaction the catalyst was separated from the reaction mixture with an external magnet and reaction mixture was treated with ethyl acetate (30 mL) and 5 N HCl (20 mL). The resultant organic layer was separated and the aqueous layer was again extracted with ethyl acetate (20 mL). The combined organic layers were washed with water, concentrated, and the crude material was chromatographed on silica gel (Hexane-EtoAc, 1:1) to afford the pure product. refText
90% With sodium azide; copper(l) chloride In N,N-dimethyl-formamide at 120℃; for 12 h; General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol) and copper(I) chloride (4 mole percent) in DMF (2 mL) was stirred at 120 °C for the appropriate time period. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled and treated with 5 mL of HCl (4 mol L−1) and 10 mL of ethyl acetate, successively. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The product thus obtained was recrystallised from acetic acid to afford pure 5-substituted 1H-tetrazoles.
90% at 120℃; for 3 h; General procedure: To a stirred mixture of sodium azide (1.2 mmol) in PEG-400(2 mL), a nitrile compound (1 mmol) and NiNP-PNF (200 mL) were added and heated at 120°C under atmospheric conditions.The reaction progress was monitored by TLC. Upon reaction completion, the mixture was allowed to cool to ambient temperature and then filtered and extracted with ethyl acetate. The organic layer was washed with 1N HCl, dried with anhydrous Na2SO4, and filtered to afford pure 5-substituted tetrazoles.
89% With sodium azide; activated Fuller’s earth In dimethyl sulfoxide at 120℃; for 2 h; Green chemistry General procedure: To a DMSO (3 ml) solution of nitrile (1 mmol), and sodium azide (1.5 mmol), was added catalyst (10 wt percent). The reaction mixture was stirred to 120 0C in an oil bath. The reaction was monitored by TLC. After completion of the reaction, the mixture was filtered to separate the catalyst. The filtrate was quenched with water (30 ml), acidified with 5N HCl (20 ml) to precipitate the product, extracted with ethyl acetate (2 X 20 ml). The combined organic layers were washed with water, dried over sodium sulphate and evaporated under reduced pressure to give the product.
89% at 120℃; for 9 h; General procedure: A mixture of the required nitrile (1 mmol), sodium azide(1 mmol) and the catalyst MNP (0.05 g) was stirred at 120° C in PEG (1 mL) as solvent. After completion of the reaction, as indicated by TLC, the mixture was cooled to room temperature and diluted with 1:1 H2O:Ethyl acetate(10 mL) and then stirred at ambient temperature (10 min). The catalyst was removed by applying a magnetic field, and the decantate was treated with HCl (4 N, 10 mL). The organic layer was separated, washed with water, dried over sodium sulfate and concentrated to precipitate the crude crystalline solid. The pure tetrazoles were characterized bytheir spectroscopic data and melting points.
88% With sodium azide In N,N-dimethyl-formamide at 120℃; for 6.5 h; General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol) and catalyst (0.02 g, contains 0.4 molpercent of Cu(II)) in DMF (3 mL) was taken in a round-bottomed flask and stirred at 120 °C. The progress of the reaction was followed by thin-layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (3×20 mL). The catalyst was removed by using magnetic field or filtration and then the resulting solution was washed with 1N HCl, dried over anhydrous Na2SO4 and then was evaporated. The crude products were obtained in excellent yields. All products were characterized by 1H, 13C NMR, FT-IR, and melting point which were in agreement with literature. We have reported the spectral data of some aromatic and heteroaromatic synthesized compounds
88% at 120℃; for 15 h; Green chemistry General procedure: In a round-bottomed flask, a mixture of nitrile (1 mmol) and sodium azide (1.2 mmol) in the presence of 40 mg of Fe3O4*SBTU*Ni(II) was stirred at 120 °C in PEG for an appropriate time (monitored by TLC). Then, the reaction mixture was cooled down to room temperature. After magnetic separation of catalyst, HCl (4 N, 10 mL) was added to the filtrate and the product extracted with ethyl acetate (2 × 10 mL). The organic layer was washed with water several times, dried with anhydrous Na2SO4 and concentrated to give the crude solid crystalline product.
87% With sodium azide; [Cu(phen)(PPh3)2]NO3 In water; isopropyl alcohol at 65℃; for 0.25 h; Inert atmosphere; Microwave irradiation; Green chemistry General procedure: In a round-bottomed flask, a mixture of organic nitrile 1 (1.0 equiv) and NaN3 (1.5 equiv) was added to 5 ml solution of H2O-IPA (1:1) containing 10 molpercent [Cu(phen)(PPh3)2]NO3 as catalyst under N2 atmosphere. The reaction mixture was irradiated under microwave heating at 245 W for 15–25 min at 65°C. Reaction progress was monitored by thin-layer chromatography (TLC). After reaction completion, the mixture was filtered to remove the catalyst. The filtrate was acidified with 5 N HCl (20 ml) to neutralize the product, extracted with ethyl acetate (2 9 10 ml). The combined organic layer was dried over anhydrous MgSO4. The combined filtrate was subjected to evaporation to obtain the crude compound, which was purified over silica gel column (60–120 mesh) using 50 percent ethyl acetate in hexane as eluent to obtain corresponding 5-substituted 1H-tetrazoles 2 as product.
86% With sodium azide In methanol; N,N-dimethyl-formamide at 20 - 100℃; for 7 h; General procedure: A mixture of benzonitrile (1 mmol), sodium azide (2 mmol), Ln(OTf)3-SiO2 (2008 mg) and DMF/MeOH (4:1, 5 mL) in a pressure vial was initially stirred at room temperature. After 30 min, the temperature of the reaction mixture was raised to 100 °C and stirred for another 7 h. After consumption of 1a (as indicated by TLC), the catalyst was separated by filtration and the filtrate was treated with ethyl acetate (15 mL). The organic layer was washed with 4 N HCl (20 mL). The resultant organic layer was separated and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layer was washed with water (2 × 10 mL), dried over anhydrous sodium sulfate and concentrated to afford white crystalline solid.5-Phenyl-1H-tetrazole(3a)IR (KBr, cm−1): 3331, 2907, 2850, 2611, 1607, 1485, 1433, 1050, 828, 742. 1H NMR (300 MHz, CDCl3): 8.04–8.007 (m, 1H), 7.611–7.574 (m, 2H). 13C NMR (75 MHz, CDCl3): 156.03, 131.19, 129.08, 126.805, 123.924. MS: m/z = 146 [M]+.
82% With trimethylsilylazide; di(n-butyl)tin oxide In 1,4-dioxane at 150℃; for 0.833333 h; Microwave irradiation General procedure: Dibutyltin oxide (0.33 mmol, 82 mg, 0.2 equiv), andtrimethylsilyl azide (3.33 mmol, 383 mg, 2 equiv) were added to a solution of 3-bromobenzonitrile (300mg, 1.67 mmol, 1 equiv) in anhydrous 1,4-dioxane (2 mL/mmol). The reaction mixture was subjectedto microwave irradiation in a tightly sealed microwave vessel for 50 min at 150 0C, then cooled to roomtemperature. The solvent was removed under reduced pressure. The residue was dissolved in diethylether (10 mL and extracted with 2 M aq. NaOH (3 x 10 mL). The aqueous layer was acidified with 4 Maq. HCl to pH 1 and extracted with ethyl acetate (4 x 10 mL). The organic extract was washed withbrine (10 mL), dried over MgSO4, and evaporated under reduced pressure to give the intermediatetetrazole(1.45 mmol, 326 mg, 86percent) as a white solid.
79% With sodium azide; lead(II) chloride In N,N-dimethyl-formamide at 120℃; for 8 h; Inert atmosphere General procedure: Benzonitrile (103 mg, 1 mmol) and sodium azide (97.5 mg, 1.5 mmol) were dissolved in 2 ml of dry DMF in a 25 ml round bottom flask. PbCl2 (27.8 mg, 0.1 mmol, 10 mol percent) was added to the reaction mixture and stirred at 120 °C for 8 h under nitrogen. After completion of the reaction (as monitored by TLC), the reaction mixture was cooled to room temperature and 10 ml of ice water was added followed by addition of 3 N HCl until the reaction mixture became strongly acidic (pH 2-3). The reaction mixture was extracted three times with 20 ml ethyl acetate. The organic layer was washed with brine solution and dried over anhydrous sodium sulfate, and was evaporated under reduced pressure to give a white solid product of 5-phenyl 1H-tetrazole with 81percent yield.
79% With sodium azide In N,N-dimethyl-formamide at 120℃; for 16 h; General procedure: In a round-bottom flask, 0.2 g benzonitrile (2 mmol) and0.4 g sodium azide (6 mmol), were added to 10 mL DMF.To this mixture, 20 mg of functionalized KIT-6 was addedand the reaction mixture was refluxed. The progress ofreaction was monitored by TLC (75:25 ethyl acetate/nhexane).After completion of the reaction, the reactionmixture was cooled and filtered. The solid materials werewashed three times with acetone and then with the water.The catalyst was collected and dried to activation for nextrun. The product was obtained by acidification of solutionwith hydrochloric acid (5 mL, 6 M). The precipitate wasfiltered and recrystallized from a water/ethanol mixture toget pure product as a white powder, yield: 88percent.
78% With sodium azide; silver nitrate In N,N-dimethyl-formamide at 20 - 120℃; for 5 h; General procedure: Sodiumazide (0.378 g, 0.046 mmol) was added to a solution of AgNO3 (5 mg, 10 mmol)in DMF (5 ml) and reaction mixture was stirred for 5 min, to this stirredsolution benzonitrile 1a (0.4 ml, 0.033 mmol) was added dropwise over theperiod of 1 min at room temperature and stirring continued for 10 min at thesame temperature and then heated at 120 C for 5 h. After consumption of 1a,the reaction mixture was cooled to room temperature and chilled by addingcrushed ice into the reaction mixture followed by addition of 2 N HCl tillreaction mixture reached the pH 2. The reaction mixture was then extractedwith ethyl acetate. The organic layer was dried with anhydrous Na2SO4, andconcentrated to obtain tetrazole 2a in 83percent yield as an off white solid (268 mg).
72% With sodium azide; tetra(n-butyl)ammonium hydrogensulfate In water at 85℃; for 9 h; Green chemistry General procedure: General Procedure for Preparation of Tetrazoles in Water(Method II). TBAHS (0.25 mmol) was added to a mixture of nitrile (1 mmol), sodium azide (1.5 mmol), and 2 mL H2O in around-bottomed flask. The reaction mixture was heated to 85 °C. After completion of the reaction (as monitored by TLC), the crude reaction mixture was transferred into a separatory funnel, to which was added 1 N HCl (15 mL) extracted by ethylacetate (EtOAc, 10 mL × 5). The combined organic layers were washed with H2O and dried over anhydrous sodium sulfate, and were evaporated under reduced pressure to give pure 5-substituted-1H-tetrazole.
70% With sodium azide; ammonium chloride In N,N-dimethyl-formamide for 24 h; Reflux General procedure: In a typical procedure, 5-aryl-1H-tetrazoles (1–24) were synthesized by adding aryl nitriles (1 eq.), sodium azide (1.2 eq.), and ammonium chloride (1 eq.) in solvent, the mixture was refluxed for 24 h. Progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, 2.5 mL of 2M NaOH was added and the solution was stirred for half an hour. The reaction mixture was concentrated on reduced pressure, and dissolved in water. 3M HCl was added to the reaction mixture until precipitates formed. The precipitates were filtered and washed with distilled water. The yields of title compounds were found to be moderate to high.
54% With sodium azide; scandium tris(trifluoromethanesulfonate) In water; isopropyl alcohol at 160℃; for 1 h; Microwave irradiation; Sealed tube General procedure: Synthesis of 5-(4-chlorophenyl)-1H-tetrazole (2c) was achieved as follows: 4-chlorobenzonitrile 1c (274 mg, 2 mmol), NaN3 (260 mg, 4 mmol), Sc(OTf)3(197 mg, 0.4 mmol), and 8mL of a 3:1 isopropanol=water mixture were added to a30-mL Pyrex microwave vessel and capped. The microwave vessel was then placedin a Milestone Start Synth microwave reactor. The reaction was magnetically stirredand heated for 1 h at 160 C. The reaction was monitored by thin-layer chromatography(TLC) using an ether=hexane mixture (typically 50=50) for development.The reaction mixture was then diluted with saturated aqueous sodium bicarbonate(20 mL) and washed with ethyl acetate (215mL). The aqueous sodium bicarbonatelayer was cooled with ice and acidified to a pH of 2 or less with concentratedhydrochloric acid, which was added dropwise. The precipitate formed was extractedwith ethyl acetate (315 mL). The combined organic layers were dried with anhydroussodium sulfate and decanted into a tared round-bottom flask. The organiclayer was concentrated under reduced pressure by rotary evaporation at 40 C andthen under high vacuum. The tetrazole product was recrystallized from ethyl acetateand hexane. All reagents mentioned were not unpurified.

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  • 6
  • [ 4648-54-8 ]
  • [ 623-00-7 ]
  • [ 50907-23-8 ]
Reference: [1] RSC Advances, 2017, vol. 7, # 54, p. 34197 - 34207
  • 7
  • [ 108-89-4 ]
  • [ 623-00-7 ]
  • [ 100397-96-4 ]
YieldReaction ConditionsOperation in experiment
72.4%
Stage #1: With n-butyllithium In tetrahydrofuran at -78 - 22℃; for 20.5 h;
I. Preparation Examples PRECURSOR 1: 4-(3-(4-bromophenyl)-1-methyl-1H-pyrazol-4-yl)pyridine 1) (1-(4-bromophenyl)-2-(pyridin-4-yl)ethanone 4-Methylpyridine (10.9 g, 117 mmol) was dissolved in THF (150 ml) and cooled to -78° C. with stirring.
Butyllithium (40 ml, 100 mmol) was added slowly to the solution.
The resulting solution was stirred at -78° C. for 30 min.
A solution of 4-bromobenzonitrile (21.84 g, 120 mmol) in THF (150 ml) was added slowly and the reaction mixture was stirred for 2 h at -78° C.
The resulting solution was allowed to warm and it was stirred at 22° C. for 18 h.
Water was added, and then acidified with 48percent hydrobromic acid.
The solvent was removed on the rotary evaporator and the resulting acidic aqueous solution was refluxed for 2 h.
The cooled aqueous solution was extracted several times with diethyl ether, and upon neutralization of the acidic aqueous layer.
The 4-phenacylpyridine precipitated as a yellow solid (1-(4-bromophenyl)-2-(pyridin-4-yl)ethanone (20 g, 72.4 mmol, 72.4percent yield)). LC-MS (Method B): m/z 278 (M+H), RT: 1.86 min.
Reference: [1] Patent: US2014/148461, 2014, A1, . Location in patent: Paragraph 0334-0335
  • 8
  • [ 623-00-7 ]
  • [ 22090-24-0 ]
Reference: [1] Journal of the American Chemical Society, 1940, vol. 62, p. 2995,3001
  • 9
  • [ 623-00-7 ]
  • [ 30363-03-2 ]
YieldReaction ConditionsOperation in experiment
93.6% at 0 - 20℃; for 12.5 h; Inert atmosphere; Cooling with ice (1)
Synthesis of 2,4,6-tri(4-bromophenyl)-1,3,5-triazine
To a two-neck flask having been substituted with nitrogen, trifluoromethanesulfonic acid (66.6 mmol, 9.99 g) was added, and cooled (0 to 5ºC) over an ice bath. 4-Bromobenzonitrile (19.6 mmol, 3.57 g) was added thereto, and the mixture was stirred for 30 minutes.
Thereafter, the mixture was stirred at room temperature for 12 hours.
Water was added to the mixture, which was then neutralized with NaOH, and then washed with a mixed solvent of chloroform and acetone (50/50), and the organic layer was extracted.
The organic layer was dehydrated over anhydrous magnesium sulfate, and the solvent was distilled off, thereby providing 2,4,6-tri(4-bromophenyl)-1,3,5-triazine as the target product (yield amount: 3.34 g, yield: 93.6percent).
85% With trifluorormethanesulfonic acid In chloroform at 0 - 20℃; for 24.5 h; According to the literature [40], into the flask were quicklyadded dry CHCl3 (20 mL) and trifluoromethanesulfonic acid (6.0 g,40 mmol). The solutionwas cooled down to 0 °C. Then, a solution of4-bromobenzonitrile (3.64 g, 20 mmol) in dry CHCl3 (120 mL) wasdropwise added to the pre-cooled solution. After the solution wasstirred for 0.5 h at 0 °C, the reaction systemwaswarmed up to roomtemperature and stirred for 24 h continuously. Afterwards, into thereaction mixture was added the aqueous ammonia solution (30percent)to neutralize the unreacted trifluoromethanesulfonic acid. After theaddition, the precipitate was formed. The precipitate was filtratedand washed with ethanol, hexane and chloroform to give 2,4,6-tris(4-bromophenyl)-1,3,5-triazine with the yield of 85percent as awhite powder. 1H NMR (300 MHz, CDCl3): d 8.61 (d, J 9 Hz 6H),7.72 (d, J 9 Hz, 6H).
85% With trifluorormethanesulfonic acid In chloroform at 0 - 20℃; for 24.5 h; In a 250 ml three-neck flask, chloroform (20 ml) was added, and trifluoromethanesulfonic acid (6.0 g, 40 mmol) was purged with nitrogen and cooled to0°C. Then, a solution of 4-bromobenzonitrile (3.64 g, 20 mmol) in chloroform was added dropwise thereto. The reaction was carried out at 0°C for half an hour, then the reaction was slowly warmed to room temperature and the reaction was continued for 24 hours. After the reaction was completed, an appropriate amount of aqueous ammonia solution was added thereto to neutralize the remaining trifluoromethanesulfonic acid. After the dropwise addition, a large amount of precipitate was formed. The precipitate was filtered and washed with ethanol, n-hexane and chloroform to obtain Compound 4 in a yield of 85percent.
82.1% at 0 - 20℃; for 18 h; Inert atmosphere A 100-ml four-necked flask was charged with 0.01 mol of p-bromobenzene cyanide, 0.0363 mol of trifluoromethanesulfonic acid under a nitrogen atmosphere, and stirred at 0-5 ° C for 5 hours, then stirred at room temperature for 1 hour, and left at room temperature for 12 hours. ,Add 50 ml of ice water, then add aqueous ammonium hydroxide solution.The pH was adjusted to 8-9, a large amount of precipitate was precipitated, suction filtration, and the cake was rinsed three times with distilled water to give a pale yellow solid.Recrystallization was carried out in a mixture of toluene:ethanol = 3:1, and filtered to obtain white crystals H1.The purity was 98.20percent, and the yield was 82.1percent.
80% With trifluorormethanesulfonic acid In chloroform at 0 - 20℃; for 50 h; Inert atmosphere 4-bromobenzonitrile (4 g, 22 mmol) in dry chloroform (60 mL) was added dropwise into a trifluoromethanesulfonic acid (4 mL, 44 mmol) in dry chloroform (10 mL) containing two necked round bottom flask with stirring at 0 °C under nitrogen gas protection. Heat was given out upon the addition of 4-bromobezonitrile. The reaction mixture was stirred for 2 hours at 0° C and continued to stir for 48 hours under ambient temperature and nitrogen gas protection. It was neutralized by adding small amount of ammonium hydroxide dropwise in water. The organic layer was washed with water for three times and then dried over anhydrous sodium sulphate. Solvent was removed in vacuo. The residual was recrystallized from CH3Cl to obtain a white powder 3.2 g in 80percent yield. 1H NMR (400MHz, CDCl3, δ): 8.55 (d, J = 8.5 Hz, 6H), 7.67 (d, J = 8.5 Hz, 6H). MS(MALDI-TOF, m/z): calcd. for C21H12Br3N3, 545.8634, found 545.8658 [M+H]+.

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Reference: [1] Chemistry - A European Journal, 2015, vol. 21, # 26, p. 9550 - 9555
  • 11
  • [ 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.

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  • 12
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  • [ 623-00-7 ]
  • [ 25699-83-6 ]
YieldReaction ConditionsOperation in experiment
98% at 90℃; for 30 h; sealed tube Following General Procedure A (90 0C, 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with 4-bromobenzonitrile (364 mg, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane / hexanes = 50/50) to provide 330 mg (98 percent isolated yield) of the desired product as a white solid. identificationMp: 89°C. <n="45"/>1H NMR (400 MHz5 CDCI3): δ 7.92-7.93 (d, 1 H1 H7), 7.75-7.78 (m, 2H, H3l5), 7.65-7.70 (m, 3H, H2,B,9), 6.46-6:47 (dd, 1H1 H8).13C NMR (100 MHz, CDCI3): δ 142.95 (C1), 142.50 (C9), 133.68 (C3,5), 126.94 (C7), 118.93 (C2,6), 118.44 (C10), 109.53 (C4), 109.15 (C8). IR (KBr) : v (cm-1) = 3153, 3136, 3066, 2226(CN), 1610, 1528, 1513, 1392, 1342, 1252, 1199, 1176, 1127, 1030, 934, 834, 813, 749, 650, 572, 545. GC/MS: rt = 18.92 min, M/Z = 169. HRMS: 170.0700 (M+H). Theoretical: 170.0718.
82% With copper(I) oxide; caesium carbonate; N-phenyl-2-pyridincarboxamide-1-oxide In acetonitrile for 20 h; Inert atmosphere; Reflux General procedure: In 50 mL round bottom flask, aryl halide (1.0 mmol), pyrazole (1.2 mmol), ligand (0.04 mmol), Cu2O (0.10 mmol), cesium carbonate (2.0 mmol), and dry solvent (20 mL) were placed under nitrogen atmosphere. The reaction mixture was heated in oil bath up to specified temperature under constant stirring for 20 h and then allowed to cool to room temperature. The reaction mixture was filtered through a plug of Celite in a fritted filter funnel and washed with ethyl acetate. If DMSO is used as solvent, it is extracted by washing the filtrate with 25 mL water for three times. The organic phase was dried over anhydrous MgSO4 and was removed under reduced pressure to provide the crude product which was purified by column chromatography on silica gel, using hexane and ethyl acetate in 3:1 ratio, respectively, as an eluent.
78% With copper(l) iodide; tetrabutylammomium bromide; N-(2-aminoethyl)-N'-{2-[(2-aminoethyl)amino]ethyl}ethane-1,2-diamine 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.
Reference: [1] Angewandte Chemie - International Edition, 2007, vol. 46, # 6, p. 934 - 936
[2] Patent: WO2008/4088, 2008, A2, . Location in patent: Page/Page column 43-44
[3] Journal of Organic Chemistry, 2005, vol. 70, # 13, p. 5164 - 5173
[4] New Journal of Chemistry, 2017, vol. 41, # 8, p. 3082 - 3088
[5] European Journal of Organic Chemistry, 2004, # 4, p. 695 - 709
[6] ChemCatChem, 2014, vol. 6, # 8, p. 2373 - 2383
[7] Chemistry - A European Journal, 2014, vol. 20, # 18, p. 5231 - 5236
[8] Tetrahedron Letters, 2016, vol. 57, # 20, p. 2197 - 2200
[9] Tetrahedron, 2013, vol. 69, # 30, p. 6230 - 6233
[10] Organic and Biomolecular Chemistry, 2011, vol. 9, # 12, p. 4671 - 4684
[11] Angewandte Chemie - International Edition, 2009, vol. 48, # 2, p. 333 - 336
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  • [ 623-00-7 ]
  • [ 49584-26-1 ]
Reference: [1] Synthesis, 1986, # 10, p. 852 - 854
[2] Patent: WO2018/30550, 2018, A1,
  • 14
  • [ 110-85-0 ]
  • [ 623-00-7 ]
  • [ 68104-63-2 ]
YieldReaction ConditionsOperation in experiment
3.2 g at 120℃; for 45 h; Inert atmosphere Under a nitrogen atmosphere, a stirred miture of 10.0 grams (0.055 mole) of 4-bromobenzonitrile (available from Aldritch Chemical Company) and 23.7 grams (0.28 mole) of piperazine (available from Aldritch Chemical Company was heated at 120°C for about 45 hours. After this time, the reaction mixture was taken up in 150 ml of aqueous 10percent sodium hydroxide. The resulting solution was extracted with three 50 mL portions of methylene chloride. The combined extracts were washed with one 50 mL portion of an aqueous saturated sodium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 8.6 grams of a green paste. The green paste was purified by column chromatography on silica gel, yielding 3.8 grams of a paste. The paste was taken up in 50 mL of diethyl ether. The resulting solution was warmed on a rotovap and decanted away from the insoluble paste. The decantate was concentrated, yielding 3.2 grams of the title comound. The NMR spectrum was consistent with the proposed structure.
Reference: [1] Journal of Medicinal Chemistry, 2003, vol. 46, # 18, p. 3822 - 3839
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1376 - 1380
[3] Patent: US2002/183342, 2002, A1,
[4] Patent: WO2018/202681, 2018, A1, . Location in patent: Page/Page column 44
  • 15
  • [ 109-01-3 ]
  • [ 623-00-7 ]
  • [ 34334-28-6 ]
YieldReaction ConditionsOperation in experiment
78% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos In toluene at 110℃; for 12 h; Sealed tube 4-Bromobenzonitrile 52a (1.00 mmol) was placed in a reaction tube. Toluene (10 mL), Cs2CO3 (2.50 mmol), Pd2dba3 (0.03 mmol), Xphos (0.12 mmol) and piperazine (2.50 mmol) were added. The tube was sealed and the suspension was warmed to 110 °C and stirred for 12 h. After this time, water was added and the mixture was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated. The residue waxs purified by flash chromatography (hexanes/EtOAc 3:1). White solid. M.p. 186-188 °C. Yield: 78percent. 1H-NMR (δ, ppm): 7.44 (d, 2H, J=8.8 Hz), 6.82 (d, 2H, J=8.8 Hz), 3.31-3.29 (m, 4h), 2,53-2,51 (m, 4H), 2.31 (s, 3H).13C-NMR (δ, ppm): 153.31, 133.40, 120.04, 114.16, 100.02, 54.54, 46.99, 46.03. HRMS (ESI) [M + H]+ calculated for C12H15N3: 201.1266, found: 201.1293.
60% With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 80℃; for 16 h; Inert atmosphere To a solution of 4-bromobenzonitrile 12 (1.5 g, 8.24 mmol) in toluene, N-methylpiperazine (1.4mL, 12.36 mmol), sodium tert-butoxide(1.19 g, 12.36 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.023 g, 0.02mmol), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) (0.036 g, 0.05mmol) were added. The reaction mixture was heated at 80 °C for 16 hours andthen filtered on celite pad. The organic phase was evaporated under reducedpressure. The brown oil was purified by flash chromatography on silica gel(Eluent: CH2Cl2:MeOH 9:1). Compound 13 was obtained as a yellow oil (60percent). 1H NMR (400 MHz,CDCl3): δ(ppm) 2.25(s, 3H); 2.46(t, J=8, 4H); 3.25-3.23(t, J=8, 4H);6.76(d, J=8, 2H); 7.39(d, J=8, 2H). Anal. Calcd. for C12H15N3:C, 71.61; H, 7.51; N, 20.88; found: C, 71.21; H, 7.21; N, 20.78
Reference: [1] European Journal of Medicinal Chemistry, 2018, vol. 150, p. 491 - 505
[2] Tetrahedron Letters, 2013, vol. 54, # 38, p. 5204 - 5206
[3] Patent: WO2009/120826, 2009, A1, . Location in patent: Page/Page column 143; 144
  • 16
  • [ 623-00-7 ]
  • [ 105-36-2 ]
  • [ 26510-95-2 ]
Reference: [1] Green Chemistry, 2017, vol. 19, # 6, p. 1420 - 1424
  • 17
  • [ 109-02-4 ]
  • [ 623-00-7 ]
  • [ 37812-51-4 ]
Reference: [1] Journal of the American Chemical Society, 2014, vol. 136, # 24, p. 8755 - 8765
  • 18
  • [ 623-00-7 ]
  • [ 1906-57-6 ]
  • [ 7153-22-2 ]
YieldReaction ConditionsOperation in experiment
74% With palladium diacetate In 1-methyl-pyrrolidin-2-one at 20 - 140℃; for 24 h; Inert atmosphere General procedure: An oven-dried Schlenk-tube (10 mL) was charged with Pd source (1 mol percent), and ethyl potassium oxalate (0.75 mmol). The tube was evacuated and backfilled with argon (this procedure was repeated three times). After that, iodobenzene (0.5 mmol) and NMP (1.0 mL) were added by syringe under a counter flow of argon at room temperature. The reaction vessel was closed and then placed under stirring in a preheated oil bath. The reaction mixture was stirred for 24 h. Upon completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate, and analyzed by gas chromatography.
Reference: [1] Tetrahedron Letters, 2012, vol. 53, # 43, p. 5796 - 5799
  • 19
  • [ 623-00-7 ]
  • [ 109-94-4 ]
  • [ 7153-22-2 ]
YieldReaction ConditionsOperation in experiment
71%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h;
Stage #2: at -78℃; for 3 h;
Stage #3: With ethanol; iodine; potassium carbonate In tetrahydrofuran; hexane at -78 - 20℃; for 15 h;
General procedure: n-BuLi (1.67 M solution in hexane, 1.32 mL, 2.2 mmol) was added dropwise into a solution of p-bromochlorobenzene (383 mg, 2.0 mmol) in THF (3 mL) at -78 °C for 30 min. Then, ethyl formate (1.6 mL, 20 mmol) was added to the mixture and the obtained mixture was stirred at -78 °C. After 3 h at the same temperature, I2 (1523 mg, 6 mmol), K2CO3 (1382 mg, 10 mmol) and EtOH (3 mL) were added at -78 °C and the mixture was stirred for 14 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (5 mL) and was extracted with CHCl3 (3.x.20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide ethyl 4-chlorobenzoate in 77percent yield. If necessary, the product was purified by short column chromatography (SiO2:hexane:EtOAc=9:1) to give pure ethyl 4-chloro-1-benzoate as a colorless oil.
Reference: [1] Tetrahedron, 2012, vol. 68, # 24, p. 4701 - 4709
  • 20
  • [ 64-17-5 ]
  • [ 201230-82-2 ]
  • [ 623-00-7 ]
  • [ 7153-22-2 ]
Reference: [1] RSC Advances, 2014, vol. 4, # 73, p. 38986 - 38999
  • 21
  • [ 623-00-7 ]
  • [ 7153-22-2 ]
Reference: [1] Chemistry - A European Journal, 2015, vol. 21, # 26, p. 9550 - 9555
  • 22
  • [ 123-75-1 ]
  • [ 623-00-7 ]
  • [ 10282-30-1 ]
Reference: [1] Journal of Organic Chemistry, 2003, vol. 68, # 2, p. 452 - 459
[2] Journal of Organic Chemistry, 2005, vol. 70, # 13, p. 5164 - 5173
[3] Patent: WO2009/120826, 2009, A1, . Location in patent: Page/Page column 153
[4] Patent: WO2009/120849, 2009, A1, . Location in patent: Page/Page column 40
  • 23
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  • [ 536-74-3 ]
  • [ 10282-30-1 ]
  • [ 13041-79-7 ]
  • [ 29822-79-5 ]
  • [ 1552-58-5 ]
Reference: [1] Synlett, 2006, # 18, p. 3005 - 3008
  • 24
  • [ 123-75-1 ]
  • [ 623-00-7 ]
  • [ 536-74-3 ]
  • [ 10282-30-1 ]
  • [ 1591-30-6 ]
  • [ 29822-79-5 ]
Reference: [1] European Journal of Organic Chemistry, 2007, # 4, p. 583 - 587
  • 25
  • [ 1450-14-2 ]
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  • [ 13183-70-5 ]
Reference: [1] Journal of the American Chemical Society, 2008, vol. 130, # 47, p. 15982 - 15989
  • 26
  • [ 1450-14-2 ]
  • [ 623-00-7 ]
  • [ 13183-70-5 ]
  • [ 17921-68-5 ]
Reference: [1] Journal of the American Chemical Society, 2008, vol. 130, # 47, p. 15982 - 15989
  • 27
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  • [ 96-34-4 ]
  • [ 52798-01-3 ]
Reference: [1] Journal of the Chemical Society, Chemical Communications, 1990, # l, p. 48 - 49
[2] Journal of Organic Chemistry, 1996, vol. 61, # 5, p. 1748 - 1755
[3] Tetrahedron, 2007, vol. 63, # 5, p. 1146 - 1153
  • 28
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  • [ 623-00-7 ]
  • [ 876-31-3 ]
Reference: [1] Journal of the American Chemical Society, 2005, vol. 127, # 45, p. 15824 - 15832
  • 29
  • [ 928664-98-6 ]
  • [ 623-00-7 ]
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Reference: [1] Journal of the American Chemical Society, 2011, vol. 133, # 18, p. 6948 - 6951
  • 30
  • [ 623-00-7 ]
  • [ 159259-35-5 ]
  • [ 40817-08-1 ]
Reference: [1] Tetrahedron, 1994, vol. 50, # 28, p. 8301 - 8316
  • 31
  • [ 623-00-7 ]
  • [ 121219-12-3 ]
  • [ 40817-08-1 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 21, p. 10568 - 10580
  • 32
  • [ 623-00-7 ]
  • [ 22265-36-7 ]
YieldReaction ConditionsOperation in experiment
95.4%
Stage #1: With N-acetylcystein In ethanol at 45℃; for 20 h;
Stage #2: With ammonium carbamate In ethanol for 68 h;
In four flask equipped with a mechanical stirrer, thermometer, reflux condenser. takeFor bromoxynil 36.4g (0.2mol) was poured into a beaker, add 100ml of absolute ethanol, stirring to dissolve completely; then weighed 32.4gN- acetylcysteine (0.2mol), into another beaker was then added 150ml of absolute ethanol, stirring the mixture to complete dissolution, then a solution of ethanol will bromoxynil and N- acetylcysteine ethanol solution was poured into four flask, stirred and heated to 45 The reaction 20h . Weigh 8.6g ammonium carbamate (0.11 mol), was slowly added portionwise to a 4-neck flask, 20h, after complete dissolution the reaction, the reactionAfter completion of standing 48h, suction filtered, the filter cake was washed with ethanol, and drying, a white solid product was obtained 38g of bromobenzene formamidine (Compound ), yield 95.4percent, HPLC purity was 99.6percent.
Reference: [1] Patent: CN105669651, 2016, A, . Location in patent: Paragraph 0067; 0068
[2] Proceedings of the Royal Society of London, Series B: Biological Sciences, 1946, vol. 133, p. 20,30
[3] Justus Liebigs Annalen der Chemie, 1975, p. 160 - 194
[4] Patent: WO2010/111483, 2010, A1, . Location in patent: Page/Page column 117
[5] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 7, p. 2369 - 2375
[6] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, p. 3013 - 3032
[7] Patent: EP2862856, 2015, A1,
[8] Tetrahedron Letters, 2018, vol. 59, # 4, p. 361 - 364
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  • [ 22265-36-7 ]
Reference: [1] Journal of the Chemical Society, 1947, p. 390,391
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Reference: [1] Journal of the Chemical Society, 1946, p. 147,149
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  • [ 43038-36-4 ]
Reference: [1] Chemistry - A European Journal, 2015, vol. 21, # 26, p. 9550 - 9555
  • 36
  • [ 623-00-7 ]
  • [ 63139-21-9 ]
  • [ 58743-75-2 ]
YieldReaction ConditionsOperation in experiment
98% With potassium carbonate In water; N,N-dimethyl-formamide at 80℃; for 2.3 h; General procedure: The aryl halide (0.5 mmol), arylboronic acid (0.75 mmol), Cell-NHC-Pd (0.75 molpercent), K2CO3(1 mmol) and DMF:H2O (1:1) (2.5 mL)were successively added into a 25 mL round bottom flask. The mixture was stirred vigorously at 80 °C for the varying specific length of time based on each different substrate. After reaction completion, the solid catalyst was filtered off. The filtrate was extracted with ethyl acetate (3 × 5 mL), washed with water and brine three times, and then dried over anhydrous MgSO4. The MgSO4 was then filtered off. After removal of the solvent, the crude product was purified by preparative TLC (eluent: petroleum ether/ethyl acetate, 20/1) to give the desired product and calculate the yield.
Reference: [1] Carbohydrate Polymers, 2014, vol. 114, p. 476 - 483
[2] Helvetica Chimica Acta, 2015, vol. 98, # 6, p. 805 - 818
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Reference: [1] Patent: US5866568, 1999, A,
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  • [ 623-00-7 ]
  • [ 27466-83-7 ]
Reference: [1] Russian Journal of Organic Chemistry, 1998, vol. 34, # 6, p. 838 - 844
[2] Organic Letters, 2006, vol. 8, # 19, p. 4207 - 4210
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  • [ 67-56-1 ]
  • [ 623-00-7 ]
  • [ 27466-83-7 ]
Reference: [1] Patent: WO2004/31128, 2004, A1, . Location in patent: Page/Page column 10
  • 40
  • [ 623-00-7 ]
  • [ 6148-64-7 ]
  • [ 1528-41-2 ]
YieldReaction ConditionsOperation in experiment
64% With dmap; bis(η3-allyl-μ-chloropalladium(II)); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,3,5-trimethyl-benzene at 140℃; for 20 h; Inert atmosphere General procedure: after standard cycles of evacuation and back-filling with dry and pure nitrogen, an oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with Pd source (see Table 1, Table 2, Table 3 and Table 4), ligand (see Table 1, Table 2, Table 3 and Table 4), N,N-dimethylpyridin-4-amine (DMAP, see Table 1, Table 2, Table 3 and Table 4), and ethyl potassium malonate (see Table 1, Table 2, Table 3 and Table 4). The tube was evacuated and backfilled with argon (this procedure was repeated three times). Under a counter flow of argon, aryl halide (see Table 1, Table 2, Table 3 and Table 4) and solvent (see Table 1, Table 2, Table 3 and Table 4) were added by syringe. The tube was sealed and stirred at room temperature for 10 min. Then the tube was connected to the Schlenk line, which was full of argon, stirred in a preheated oil bath (140-150 °C) for the appointed time (20-25 h). Upon completion of the reaction, the mixture was cooled to room temperature and diluted with diethyl ether, and the yields were determined by gas chromatography using 1,3-dimethoxybenzene as the internal standard.
Reference: [1] Tetrahedron, 2012, vol. 68, # 9, p. 2113 - 2120
  • 41
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  • [ 681-94-7 ]
  • [ 1528-41-2 ]
Reference: [1] Bulletin of the Chemical Society of Japan, 1985, vol. 58, # 11, p. 3383 - 3384
  • 42
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  • [ 141-97-9 ]
  • [ 1528-41-2 ]
  • [ 86369-43-9 ]
Reference: [1] Tetrahedron Letters, 2007, vol. 48, # 18, p. 3289 - 3293
  • 43
  • [ 623-00-7 ]
  • [ 141-97-9 ]
  • [ 1528-41-2 ]
Reference: [1] Tetrahedron, 1982, vol. 38, # 23, p. 3479 - 3483
  • 44
  • [ 623-00-7 ]
  • [ 105-53-3 ]
  • [ 1528-41-2 ]
Reference: [1] Advanced Synthesis and Catalysis, 2011, vol. 353, # 9, p. 1565 - 1574
  • 45
  • [ 623-00-7 ]
  • [ 76590-50-6 ]
  • [ 32446-66-5 ]
YieldReaction ConditionsOperation in experiment
96.3% With pyridine; potassium dihydrogenphosphate; palladium diacetate; copper(II) bis(trifluoromethanesulfonate); [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In N,N-dimethyl acetamide at 120℃; for 12 h; Add N,N-dimethylacetamide (200 mL) to a 500 mL three-necked flask.2-(4-Cyanophenyl)formic acid (II) (35.1 g, 0.2 mol), 4-bromobenzonitrile (III) (72.6 g, 0.4 mol),Potassium phosphate (85.7 g, 0.4 mol), Pd(OAc) 2 (0.45 g, 0.002 mol), CuOTf (12.8 g, 0.06 mol),Pyridine (9.7 g, 0.12 mol) and 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan (2.32 g, 0.004 mol),Stirring, heating to 120 ° C, reaction for 12 hours,The reaction was completely detected by HPLC (2-(4-cyanophenyl)formic acid (II) content was less than 1percent), and the temperature was lowered to room temperature.The solid was slowly added with water, and the solid was dissolved with ethyl acetate and then extracted (50 mL x 3).The resulting organic phase was washed with 5percent aqueous HCl (100 mL) and sat. sodium chloride (100 mL).Dry over anhydrous sodium sulfate, EtOAc (EtOAc m.)The product was obtained as a white solid (44.7 g, yield: 96.3percent).
Reference: [1] Patent: CN108409604, 2018, A, . Location in patent: Paragraph 0055-0060; 0061; 0062; 0063; 0064
  • 46
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  • [ 108-24-7 ]
  • [ 1591-30-6 ]
  • [ 1443-80-7 ]
  • [ 32446-66-5 ]
  • [ 100-47-0 ]
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 3, p. 936 - 942
  • 47
  • [ 623-00-7 ]
  • [ 98-86-2 ]
  • [ 32446-66-5 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 14, p. 6554 - 6562
  • 48
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  • [ 32446-66-5 ]
Reference: [1] Patent: WO2015/189265, 2015, A1,
  • 49
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  • [ 874-89-5 ]
Reference: [1] Journal of Organic Chemistry, 1983, vol. 48, # 12, p. 2120 - 2122
  • 50
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  • [ 74141-07-4 ]
  • [ 874-89-5 ]
Reference: [1] Chemistry Letters, 1985, p. 997 - 998
  • 51
  • [ 64-17-5 ]
  • [ 623-00-7 ]
  • [ 3058-39-7 ]
  • [ 51934-41-9 ]
YieldReaction ConditionsOperation in experiment
80% at 110℃; for 30 h; Schlenk technique; Inert atmosphere; Sealed tube General procedure: A Schlenk tube was charged with Cu2O (7.2 mg, 10 molpercent), l-proline (11.5 mg, 20 molpercent), aryl (or heteroaryl) bromide (1 or 3,0.50 mmol), potassium iodide (KI) (249 mg, 0.75 mmol), and EtOH(1.5 mL) under nitrogen atmosphere. The Schlenk tube was sealedwith a teflon valve, and then the reaction mixture was stirred at110C for a period (the reaction progress was monitored by GCanalysis). After the reaction was completed, GC yield of high volatileproduct was determined using an appropriate internal standard(chlorobenzene or 1-chloro-4-methylbenzene) or the solvent wasremoved under reduced pressure. The residue obtained was puri-fied via silica gel chromatography (eluent: petroleum ether/ethylacetate = 10/1) to afford aryl iodides 2a–2o or heteroaryl iodides4a–4g.
Reference: [1] Catalysis Today, 2016, vol. 274, p. 129 - 132
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  • [ 52364-73-5 ]
Reference: [1] Patent: US6121480, 2000, A,
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  • 54
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  • [ 3032-92-6 ]
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[21] Organic Letters, 2012, vol. 14, # 15, p. 3970 - 3973
[22] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 559 - 576
[23] Chemical Communications, 2014, vol. 50, # 57, p. 7666 - 7669
[24] Organic Letters, 2014, vol. 16, # 24, p. 6302 - 6305
[25] Chemistry Letters, 2014, vol. 43, # 10, p. 1548 - 1550
[26] Chemical Communications, 2015, vol. 51, # 42, p. 8825 - 8828
[27] Chinese Journal of Chemistry, 2015, vol. 33, # 8, p. 967 - 973
[28] Tetrahedron Letters, 2015, vol. 56, # 51, p. 7105 - 7107
[29] Journal of Materials Chemistry C, 2015, vol. 4, # 1, p. 193 - 200
[30] Angewandte Chemie - International Edition, 2016, vol. 55, # 19, p. 5754 - 5759[31] Angew. Chem., 2016, vol. 128, p. 5848 - 5853,6
[32] European Journal of Organic Chemistry, 2016, vol. 2016, # 18, p. 3056 - 3059
[33] Journal of the American Chemical Society, 2017, vol. 139, # 14, p. 5164 - 5174
[34] Inorganic Chemistry, 2018, vol. 57, # 12, p. 7208 - 7221
  • 55
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  • [ 30314-45-5 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1970, p. 3609 - 3616
  • 56
  • [ 3984-22-3 ]
  • [ 623-00-7 ]
  • [ 42287-94-5 ]
Reference: [1] Tetrahedron, 2004, vol. 60, # 50, p. 11533 - 11540
  • 57
  • [ 79-24-3 ]
  • [ 1122-91-4 ]
  • [ 623-00-7 ]
  • [ 25062-46-8 ]
  • [ 131981-75-4 ]
Reference: [1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1991, vol. 40, # 2.2, p. 366 - 372[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1991, # 2, p. 426 - 433
  • 58
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  • [ 6941-75-9 ]
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  • [ 67832-11-5 ]
  • [ 70484-01-4 ]
Reference: [1] Russian Journal of General Chemistry, 2010, vol. 80, # 8, p. 1672 - 1676
[2] Russian Journal of General Chemistry, 2014, vol. 84, # 6, p. 1085 - 1090
  • 59
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  • [ 89642-49-9 ]
YieldReaction ConditionsOperation in experiment
56% at 0 - 20℃; for 3 h; To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) in conc. H2SO4 (10 mL) was added dropwise at 0° C. nitric acid (6 mL).
The reaction mixture was stirred at 0° C. for 30 min, and then at room temperature for 2.5 h.
The resulting solution was poured into ice-water.
The white precipitate was collected via filtration and washed with water until the washings were neutral.
The solid was recrystallized from an ethanol/water mixture (1:1, 20 mL) twice to afford 4-bromo-3-nitrobenzonitrile as a white crystalline solid (2.8 g, 56percent).
1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 150.4, 137.4, 136.6, 129.6, 119.6, 117.0, 112.6; HPLC ret. time 1.96 min, 10-100percent CH3CN, 5 min gradient; ESI-MS 227.1 Ink (MH+).
Reference: [1] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 0673
[2] Recueil des Travaux Chimiques des Pays-Bas, 1922, vol. 41, p. 36
[3] Recueil des Travaux Chimiques des Pays-Bas, 1922, vol. 41, p. 106,107
[4] Chemische Berichte, 1916, vol. 49, p. 2224
[5] Chemische Berichte, 1890, vol. 23, p. 3442
[6] Patent: US2011/98311, 2011, A1,
  • 60
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  • [ 23719-80-4 ]
  • [ 90868-92-1 ]
YieldReaction ConditionsOperation in experiment
72%
Stage #1: for 5.83333 h; Cooling with ice bath
Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol at 20℃;
A solution of 4-bromo-benzonitrile (6.30 g) in tetrahydrofuran (50 ml.) was added over a period of 20 min to a 0.5 M solution of cyclopropylmagnesium bromide in tetrahydrofuran (200 ml.) chilled in an ice bath. After stirring the resulting solution with cooling for 5.5 h, methanol (100 ml_) was added over a period of 20 min. Then sodium borohydride (2.65 g) was added portionwise and the resulting mixture was warmed to room temperature overnight. Aqueous saturated NaHCO3 solution was added and then the pH value of the mixture was adjusted to 8-9 using 1 M hydrochloric acid. The resulting mixture was extracted with dichloromethane and the combined extracts were washed with water and dried (MgSO4). The solvent was evaporated to leave an oil that was dissolved in dichloromethane. The resulting solution was extracted with 1 M hydrochloric acid and the combined aqueous extracts were basified (pH value ca. 8-9) with 4 M aqueous NaOH solution. The aqueous solution was extracted with dichloromethane and the combined organic extracts were washed with water and dried (MgSO4). The solvent was evaporated to afford the title compound as an oil. Yield: 5.56 g (72percent of theory); Mass spectrum (ESI+): m/z = 209/211 (Br) [M+H-NH3]+.
Reference: [1] Patent: WO2010/139673, 2010, A1, . Location in patent: Page/Page column 80; 81
[2] Patent: WO2017/156179, 2017, A1, . Location in patent: Paragraph 00404; 00405; 00406
  • 61
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  • [ 4181-05-9 ]
Reference: [1] Angewandte Chemie (International Edition in English), 2000, vol. 39, # 3, p. X517-521
  • 62
  • [ 2083-91-2 ]
  • [ 623-00-7 ]
  • [ 34403-48-0 ]
Reference: [1] European Journal of Organic Chemistry, 2017, vol. 2017, # 28, p. 4188 - 4193
  • 63
  • [ 1068-69-5 ]
  • [ 623-00-7 ]
  • [ 16116-78-2 ]
Reference: [1] Tetrahedron Letters, 1998, vol. 39, # 26, p. 4745 - 4748
  • 64
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  • [ 22237-13-4 ]
  • [ 58743-78-5 ]
YieldReaction ConditionsOperation in experiment
92% With dichloro bis(acetonitrile) palladium(II); C95H120N20O10(10+)*10F6P(1-); potassium carbonate In ethanol at 50℃; for 1.5 h; General procedure: In a typical run, a mixture of aryl bromide (0.50 mmol),phenylboronic acid (0.55 mmol), K2CO3 (1.5 mmol),0.2 molpercent ligand, 1 molpercent PdCl2(CH3CN)2 in 1.5 mL of ethanol were stirred at 50 C for 1.5 h under air. Solvent ethanol was removed completely under vacuum degree0.09 MPa at 45 C to give a crude product. The pure product was isolated by column chromatography on silica.
Reference: [1] Journal of Materials Chemistry A, 2013, vol. 1, # 41, p. 12909 - 12918
[2] Journal of Inclusion Phenomena and Macrocyclic Chemistry, 2017, vol. 87, # 1-2, p. 29 - 36
  • 65
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  • [ 2199-32-8 ]
Reference: [1] Journal of Organic Chemistry, 1999, vol. 64, # 6, p. 2057 - 2065
  • 66
  • [ 623-00-7 ]
  • [ 56-40-6 ]
  • [ 42288-26-6 ]
Reference: [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 19, p. 4153 - 4161
  • 67
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  • [ 865-47-4 ]
  • [ 71-43-2 ]
  • [ 2920-38-9 ]
  • [ 4210-32-6 ]
  • [ 154532-34-0 ]
Reference: [1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 15, p. 3324 - 3336
  • 68
  • [ 623-00-7 ]
  • [ 154607-01-9 ]
Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 6, p. 2786 - 2791
  • 69
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  • [ 78222-69-2 ]
Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 6, p. 2786 - 2791
  • 70
  • [ 623-00-7 ]
  • [ 320-31-0 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 1, p. 38 - 41
  • 71
  • [ 623-00-7 ]
  • [ 105-07-7 ]
  • [ 134521-16-7 ]
YieldReaction ConditionsOperation in experiment
0.72 g
Stage #1: With TurboGrignard In tetrahydrofuran at -15 - 20℃; for 2.25 h;
Stage #2: at -15 - 0℃; for 1.16667 h;
4-[(4-Cyanophenyl)(hydroxy,)methylJbenzonitrile (lOu, Q1=CN, Q4=CN). To a solution ofiPrMgCl LiCl complex 1.3 M in THF (10.5 ml) at -15°C 4-bromobcnzonitrilc (1.4 g, 7.6 mmol) in THF (4 ml) was added dropwise over 15 mm. The brown solution was stirred for 30 mm at -15 °C and 1.5 h at it The solution was added dropwise to a yellowish solution of 4- formylbenzonitrile (1.0 g, 7.6 mmol) in THF (4 ml) over 10 mm at -15°C. After 1 h stirring at 0°C the light green solution was quenched with aq. sat. NH4C1 (20 ml), TBME (30 ml) andwater (20 ml) were added. After separation of the organic layer the inorganic phase was extracted with TBME (2 x 20 ml). The organic layers were washed with aq. sat. NaC1, combined, dried over Na2SO4 and concentrated at reduced pressure. To the liquid crude product (2 g) EtOAc/hept 1:2 was added. An insoluble pale yellow solid (0.54 g) was filtered off, dissolved in diethylether and precipitated with pentane to afford a pale yellow solid lOu(0.49 g, 27.5percent). The mother liquor was concentrated at reduced pressure and was purified by silica gel flash chromatography (EtOAc/hept 1:2) to afford a pale yellow solid lOu (0.23 g, 13percent).
Reference: [1] Patent: WO2015/189265, 2015, A1, . Location in patent: Page/Page column 121
  • 72
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YieldReaction ConditionsOperation in experiment
99%
Stage #1: at 20℃; for 18 h; Glovebox; Inert atmosphere
Stage #2: With hydrogenchloride In diethyl ether at 20℃; for 1 h; Glovebox; Inert atmosphere
General procedure: In a glove box, a flame-dried GLC vial equipped with a magnetic stir bar is charged with[3a]+[BArF4]– (1.0 molpercent) and Me2PhSiH (2a) (2.1 or 5.0 equiv). The indicated nitrile is added eitherin the glove box (for solid starting materials) or by micro syringe outside the glove box, and theresulting reaction mixture is maintained at room temperature for the indicated time. The reaction isquenched by the addition of a mixture of cyclohexane and tert-butyl methyl ether (90:10) containing4percent Et3N (0.5 mL), and the resulting solution is filtered through a pad of Celite® coated by a smalllayer of silica gel with a solution of cyclohexane and tert-butyl methyl ether (90:10) containing 4percentEt3N (3–4 mL) as eluent. Solvents are removed under reduced pressure, and the residue isdissolved in Et2O (1 mL) followed by addition of HCl (2M in Et2O, 1.0 mL, 2.0 mmol, 10 equiv). Theresulting suspension is stirred for 1 h and filtered, affording the amines as hydrochloride salts aswhite to yellow solids.
98%
Stage #1: With 1,1,3,3-Tetramethyldisiloxane; titanium(IV)isopropoxide In methyl cyclohexane at 60℃; for 24 h; Inert atmosphere
Stage #2: With hydrogenchloride; water In methyl cyclohexane at 20℃; Inert atmosphere
General procedure: To a nitrogen purged screw-caped vial containing 1a (1.0 g, 5.1 mmol, 1.0 equiv) in 6.0 mL of toluene were added TMDS (900 μL, 5.1 mmol, 1.0 equiv) or PMHS (610 μL, 10.2 mmol, 2.0 equiv) and Ti(Oi-Pr)4 (1.5 mL, 5.1 mmol, 1.0 equiv) at rt. The mixture was then heated at 60 °C for 24 h (the colorless solution turned into black and the conversion of the substrate can be followed up by TLC and/or 1H NMR). After cooling to rt, the clear solution was acidified using aqueous 1 M HCl (7.7 mL, 1.5 equiv) and the crude mixture was concentrated under reduced pressure. The resulting solid was filtered, washed with pentane (3*50 mL), and dissolved in ethanol. The filtrate was finally concentrated under reduced pressure affording the amine 2a as a hydrochloride salt.
83%
Stage #1: With iododioxobis(triphenylphosphine)rhenium(V); phenylsilane In toluene for 5 h; Reflux
Stage #2: With hydrogenchloride In diethyl ether; toluene
General procedure: To a solution of ReIO2(PPh3)2 (10 mol percent) in toluene (3 mL) were added the nitrile (1 mmol) and PhSiH3 (300 mol percent). The reaction mixture was stirred at reflux temperature under air atmosphere and the progress of the reaction was monitored by TLC or 1H NMR. Upon completion, the reaction mixture was cooled to ambient temperature, stirred with charcoal during 3 min and then filtered through a plug of alumina/Celite. To the filtrate was added an ethereal solution of HCl (1.5 mol) to induce the precipitation of amine hydrochloride salts. The solids were isolated upon filtration and then washed with n-hexane to afford the pure amine hydrochloride salts, which are all known compounds.
Reference: [1] Synlett, 2017, vol. 28, # 18, p. 2411 - 2414
[2] Tetrahedron, 2014, vol. 70, # 4, p. 975 - 983
[3] Tetrahedron Letters, 2009, vol. 50, # 50, p. 7005 - 7007
[4] Journal of the American Chemical Society, 2016, vol. 138, # 28, p. 8809 - 8814
[5] ACS Catalysis, 2018, vol. 8, # 10, p. 9125 - 9130
[6] Tetrahedron, 2011, vol. 67, # 42, p. 8183 - 8186
[7] Angewandte Chemie - International Edition, 2012, vol. 51, # 43, p. 10808 - 10811[8] Angewandte Chemie, 2012, vol. 124, # 43, p. 10966 - 10969
[9] Journal of Organic Chemistry, 2015, vol. 80, # 14, p. 7281 - 7287
[10] European Journal of Organic Chemistry, 2015, vol. 2015, # 27, p. 5944 - 5948
[11] Organic Letters, 2018, vol. 20, # 22, p. 7212 - 7215
  • 73
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  • [ 3287-99-8 ]
  • [ 26177-44-6 ]
Reference: [1] Journal of the American Chemical Society, 2016, vol. 138, # 28, p. 8781 - 8788
  • 74
  • [ 623-00-7 ]
  • [ 55368-42-8 ]
YieldReaction ConditionsOperation in experiment
97%
Stage #1: With hydrogenchloride In ethanol; chloroform at -65 - 20℃;
Stage #2: With ammonium carbonate In ethanol at 20℃; for 20 h;
Hydrogen chloride gas was passed through a solution of 4-bromobenzonitrile (18.2 g) in chloroform (300 mL) and ethanol (100 mL) at -65 °C for 35 min. Then the solution was warmed up to room temperature, and stirred at room temperature overnight. The solution was evaporated in vacuo, and the resulting residue was dissolved in ethanol (400 mL). To the solution was added ammonium carbonate (48.0 g), and the reaction mixture was stirred at room temperature for 20 h. To the mixture was added water (300 mL), and ethanol was removed by concentration in vacuo. The resulting precipitate was collected by filtration, and washed with water, dried in vacuo to give 6a (22.9 g, 97percent) as a white solid: 1H NMR (DMSO-d6) δ 2.55-4.60 (2H, br), 6.30-8.90 (6H, m); FAB-MS m/z 199, 201 [(M+H)+].
85%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 20℃; for 1 h;
Stage #2: With hydrogenchloride In water
4.2.18
4-Bromobenzimidamide hydrochloride (24)
Beige solid; yield: 85percent. 1H NMR (400 MHz, d6-DMSO): δ 9.58 (br s, 2H), 9.42 (br s, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H).
13C NMR (101 MHz, d6-DMSO): δ 165.4 (C), 132.5 (2CH), 130.7 (2CH), 128.1 (C), 127.7 (C). IR (neat, ν/cm-1): 3322 (br s), 3135 9br s), 1669 (s), 1593 (s), 1480 (m), 1428 (m), 1071 (m), 1009 (m), 841 (m), 776 (m), 695 (s), 623 (s). HRMS (ES-TOF+) calculated for C7H8N2Br 198.9871, found 198.9873.
Reference: [1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 7, p. 2369 - 2375
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 23, p. 6218 - 6223
[3] Magnetic Resonance in Chemistry, 1987, vol. 25, p. 923 - 927
[4] Physical Chemistry Chemical Physics, 2004, vol. 6, # 4, p. 756 - 765
[5] Tetrahedron Letters, 2018, vol. 59, # 4, p. 361 - 364
  • 75
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  • [ 623-00-7 ]
  • [ 55368-42-8 ]
Reference: [1] Molecular Crystals and Liquid Crystals Science and Technology Section A: Molecular Crystals and Liquid Crystals, 1995, vol. 260, # pt 1, p. 139 - 156
  • 76
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  • [ 42823-46-1 ]
Reference: [1] European Journal of Organic Chemistry, 2014, vol. 2014, # 17, p. 3565 - 3569
  • 77
  • [ 583-71-1 ]
  • [ 6941-75-9 ]
  • [ 623-00-7 ]
  • [ 67832-11-5 ]
  • [ 70484-01-4 ]
Reference: [1] Russian Journal of General Chemistry, 2010, vol. 80, # 8, p. 1672 - 1676
[2] Russian Journal of General Chemistry, 2014, vol. 84, # 6, p. 1085 - 1090
  • 78
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  • [ 6941-75-9 ]
  • [ 124-38-9 ]
  • [ 623-00-7 ]
  • [ 70484-01-4 ]
Reference: [1] Russian Journal of General Chemistry, 2013, vol. 83, # 3, p. 492 - 495[2] Zh. Obshch. Khim., 2013, vol. 83, # 3, p. 439 - 442,4
  • 79
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  • [ 6941-75-9 ]
  • [ 623-00-7 ]
  • [ 1312479-78-9 ]
  • [ 70484-01-4 ]
Reference: [1] Russian Journal of General Chemistry, 2010, vol. 80, # 9, p. 1779 - 1785
  • 80
  • [ 201230-82-2 ]
  • [ 623-00-7 ]
  • [ 6638-79-5 ]
  • [ 116332-64-0 ]
Reference: [1] RSC Advances, 2014, vol. 4, # 57, p. 30019 - 30027
  • 81
  • [ 623-00-7 ]
  • [ 126747-14-6 ]
YieldReaction ConditionsOperation in experiment
59.9%
Stage #1: With n-butyllithium; 3 A molecular sieve In tetrahydrofuran; hexanes at -105 - -93℃; for 0.25 h;
Stage #2: With Trimethyl borate In tetrahydrofuran; hexanes at -105 - 20℃; for 2.43333 h;
Stage #3: With hydrogenchloride; water In tetrahydrofuran; hexanes
A solution of 4-bromobenzonitrile (91 g, 0.50 mole) in THF (1.1 L) was dried in the presence of activated 3 molecular sieves at room temp. This solution was filtered and cooled to -100° C. A 1.6 M solution of n-butyllithium in hexanes (355 mL. 0.567 mol) was added to the cold solution over 15 min while maintaining the internal temperature between -105 and -93° C. To the resulting orange reaction mixture was added trimethylborate (81 g, 0.78 mol) over 3 min, briefly increasing the reaction temperature to -72° C. The reaction mixture was recooled to -100° C. over 5 minutes and then was allowed to warm slowly to room temperature over 2.3 h. The reaction mixture was acidified with 4N HCl to pH 2.2, and was diluted with CH2Cl2 (200 mL). The aqueous layer was separated and the organic layer was washed with brine (2.x.200 mL), dried over anhydrous MgSO4, filtered, and the solvent removed under reduced pressure to a pale yellow solid. This solid was additionally purified by dissolution in 1N NaOH and extraction into CH2Cl2/THF (1:1, 2.x.200 mL). The aqueous phase was acidified with 4N HCl to pH 2.2 and was extracted into CH2Cl2/THF (1:1, 500 mL). The combined organic extracts were concentrated to a crude solid (64.6 g) that was triturated with diethyl ether (160 mL) and dried under vacuum to afford the intermediate title compound (44.0 g, 59.9percent) as a white powder. 1H NMR (d6-acetone, 300 MHz): δ 8.03 (d, 2H, J=8.1), 7.75 (d, 2H, J=8.4), 7.54 (s, 2H).
59.9%
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at -105 - -93℃; for 0.25 h;
Stage #2: With Trimethyl borate In tetrahydrofuran; hexanes at -105 - 20℃; for 2.43333 h;
Stage #3: With hydrogenchloride In tetrahydrofuran; hexanes; dichloromethane; water
Preparation of 4-Cyanobenzene Boronic Acid
A solution of 4-bromobenzonitrile (91 g, 0.50 mole) in THF (1.1 L) was dried in the presence of activated 3 Å molecular sieves at room temp.
This solution was filtered and cooled to -100° C. A 1.6 M solution of n-butyllithium in hexanes (355 mL. 0.567 mol) was added to the cold solution over 15 min while maintaining the internal temperature between -105 and -93° C.
To the resulting orange reaction mixture was added trimethylborate (81 g, 0.78 mol) over 3 min, briefly increasing the reaction temperature to -72° C.
The reaction mixture was recooled to -100° C. over 5 minutes and then was allowed to warm slowly to room temperature over 2.3 h.
The reaction mixture was acidified with 4N HCl to pH 2.2, and was diluted with CH2Cl2 (200 mL).
The aqueous layer was separated and the organic layer was washed with brine (2*200 mL), dried over anhydrous MgSO4, filtered, and the solvent removed under reduced pressure to a pale yellow solid.
This solid was additionally purified by dissolution in 1N NaOH and extraction into CH2Cl2/THF (1:1, 2*200 mL).
The aqueous phase was acidified with 4N HCl to pH 2.2 and was extracted into CH2Cl2/THF (1:1, 500 mL).
59.9%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -105 - -93℃; for 0.25 h;
Stage #2: With Trimethyl borate In tetrahydrofuran; hexane at -100 - -72℃; for 0.133333 h;
Preparation of 4-Cyanobenzeneboronic Acid.
Following a modified literature procedure of Perria, G. J.;et al., J. Am. Chem. Soc., 118, 10220-10227 (1996), a solution of 4-bromobenzonitrile (91 g, 0.50 mole) in THF (1.1 L) was dried in the presence of activated 3 Å molecular sieves at room temp.This solution was filtered and cooled to -100° C. Next, 1.6 M solution of n-butyllithium in hexanes (355 ML; 0.567 mol) was added to the cold solution over 15 min while maintaining the internal temperature between -105 and -93° C.
To the resulting orange reaction mixture trimethylborate (81 g, 0.78 mol) was added over 3 min, briefly increasing the reaction temperature to -72° C.
The reaction mixture was re-cooled to -100° C. over 5 min and then was allowed to warm slowly to room temperature over 2.3 h.The reaction mixture was acidified with 4N HCl to PH 2.2 and was diluted with CH2Cl2 (200 ML).The aqueous layer was separated and the organic layer was washed with brine (2-200 ML), dried (MgSO4), filtered, and reduced under pressure to give a pale yellow solid.This solid was additionally purified by dissolution in 1N NaOH and extraction into CH2Cl2/THF (1:1, 2-200 ML).The aqueous phase was acidified with 4N HCl to PH 2.2 and was extracted into CH2Cl2/THF (1:1, 500 ML).The combined organic extracts were concentrated to a crude solid (64.6 g) that was triturated with diethyl ether (160 ML) and dried under vacuum to afford the intermediate title compound (44.0 g, 59.9percent) as a white powder.
1H NMR (d6-acetone, 300 MHz): δ8.03 (d, 2H, J=8.1), 7.75 (d, 2H, J=8.4), 7.54 (s, 2H).
Reference: [1] Organic Letters, 2011, vol. 13, # 17, p. 4479 - 4481
[2] Tetrahedron, 2002, vol. 58, # 29, p. 5779 - 5787
[3] Dyes and Pigments, 2011, vol. 88, # 3, p. 274 - 279
[4] Patent: US2004/6114, 2004, A1, . Location in patent: Page 63
[5] Patent: US7034045, 2006, B1, . Location in patent: Page/Page column 37
[6] Patent: US2003/225266, 2003, A1, . Location in patent: Page 21
[7] European Journal of Organic Chemistry, 2003, # 15, p. 2829 - 2839
[8] Journal of Medicinal Chemistry, 2000, vol. 43, # 23, p. 4354 - 4358
[9] Journal of Organic Chemistry, 2002, vol. 67, # 15, p. 5394 - 5397
[10] Tetrahedron, 2004, vol. 60, # 25, p. 5373 - 5382
[11] Chemical Communications, 2010, vol. 46, # 15, p. 2677 - 2679
[12] Molecular Crystals and Liquid Crystals, 2010, vol. 518, p. 70 - 83
[13] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 8, p. 2743 - 2750
[14] Chemistry - A European Journal, 2013, vol. 19, # 26, p. 8447 - 8456
[15] Journal of Organic Chemistry, 2013, vol. 78, # 13, p. 6427 - 6439
[16] Chemistry Letters, 2002, # 1, p. 60 - 61
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Reference: [1] Patent: US5130318, 1992, A,
[2] Organic Electronics: physics, materials, applications, 2014, vol. 15, # 11, p. 3316 - 3326
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1919 - 1922
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  • [ 126747-14-6 ]
YieldReaction ConditionsOperation in experiment
25% With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane Preparation 42
4-cyanophenylboronic acid
A solution of 10.0 g (54.9 mmol) of 4-bromobenzonitrile in 100 mL of tetrahydrofuran was cooled to -85° C. wherupon 36.0 mL (57.6 mmol) of 1.6 M solution of n-butyllithium in hexane was added.
The mixture was stirred for five minutes and 19.0 mL (82.4 mmol) of triisopropylborate was added.
The mixture was stirred at -85° C. for 30 minutes then warmed to ambient temperature over one hour.
To the mixture was added 35 mL of 5 N hydrochloric acid and stirring was continued for 2.5 hours.
The mixture was diluted with 100 mL of saturated aqueous sodium chloride and extracted three times with 100 mL each of ethyl ether.
The combined organics were dried (MgSO4), filtered and concentrated in vacuo.
The residue was recrystallized from water and filtered to afford 2.0 g (25percent) of the title compound.
25% With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane PREPARATION 42
4-cyanophenylboronic Acid
A solution of 10.0 g (54.9 mmol) of 4-bromobenzonitrile in 100 mL of tetrahydrofuran was cooled to -85° C. whereupon 36.0 mL (57.6 mmol) of 1.6 M solution of n-butyllithium in hexane was added.
The mixture was stirred for five minutes and 19.0 mL (82.4 mmol) of triisopropylborate was added.
The mixture was stirred at -85° C. for 30 minutes then warmed to ambient temperature over one hour.
To the mixture was added 35 mL of 5 N hydrochloric acid and stirring was continued for 2.5 hours.
The mixture was diluted with 100 mL of saturated aqueous sodium chloride and extracted three times with 100 mL each of ethyl ether.
The combined organics were dried (MgSO4), filtered and concentrated in vacuo.
The residue was recrystallized from water and filtered to afford 2.0 g (25percent) of the title compound.
Reference: [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 23, p. 5612 - 5615
[2] Patent: US6303816, 2001, B1,
[3] Patent: US6500865, 2002, B1,
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Reference: [1] Journal of the American Chemical Society, 2016, vol. 138, # 9, p. 2985 - 2988
[2] Organic Process Research and Development, 2017, vol. 21, # 11, p. 1859 - 1863
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  • [ 76-05-1 ]
  • [ 191165-13-6 ]
  • [ 1735-53-1 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 1, p. 38 - 41
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  • [ 925-90-6 ]
  • [ 345965-54-0 ]
YieldReaction ConditionsOperation in experiment
51%
Stage #1: With titanium(IV)isopropoxide In diethyl ether at -70 - 25℃; for 1 h;
Stage #2: With boron trifluoride diethyl etherate In diethyl ether at 25℃; for 2 h;
General procedure: General Procedure G: Cyclopropanation (0459) To a mixture of arylnitrile (1 equivalent) and Ti(Oi-Pr)4 (1.7 equivalents) stirring at −70° C., was added dropwise EtMgBr [3.0 M in ether] (1.1 equivalents). The reaction mixture was allowed to warm to 25° C. and stirred for 1 h. To the above mixture was added BF3.Et2O (3 equivalents) dropwise at 25° C. After the addition, the mixture was stirred for another 2 h, and then quenched with aqueous HCl [2M]. The resulting solution was then basified by adding aqueous NaOH [2M]. The organic material was extracted with ethyl ether. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography (eluting with petroleum ether/EtOAc: 10/1 to 1/1) to give the corresponding 1-aryl-cyclopropanamine. Example 64;quinuclidin-3-yl 1-(biphenyl-4-yl)cyclopropylcarbamate ;Using general procedure G, bromobenzonitrile (3.00 g, 16.5 mmol) was converted to the corresponding 1-(4-bromophenyl)cyclopropanamine (1.80 g, 51percent) as a yellow solid. .
Reference: [1] Patent: US9126993, 2015, B2, . Location in patent: Page/Page column 49; 87
[2] Patent: WO2016/145046, 2016, A1, . Location in patent: Page/Page column 64; 65; 70; 71
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YieldReaction ConditionsOperation in experiment
48%
Stage #1: With titanium(IV) isopropylate In diethyl ether at -78 - 20℃; for 1.16667 h;
Stage #2: for 1 h;
4-bromobenzonitrile (3.00 g, 16.48 mmol) and titanium tetraisopropoxide (5.4 mL, 18.13 mmol) were dissolved in anhydrous ether (40 mL)Cooled to -78 ° C,A solution of ethylmagnesium bromide in diethyl ether (3M, 12 mL, 39.88 mmol) was added dropwise.After dripping,The reaction was continued for 10 minutes at this temperature,And then allowed to react at room temperature for 1 hour.A solution of boron trifluoride in ether (4.2 mL, 36.26 mmol) was added,After stirring for 1 hour,Then add 1N dilute hydrochloric acid and ether.Water phase collection,And basified with 10percent aqueous sodium hydroxide solution,Ethyl acetate extraction.The organic phase is dried,After filtration and concentration,Intermediate 8 (1.7 g) was obtained in 48percent yield.
Reference: [1] Patent: CN106349180, 2017, A, . Location in patent: Paragraph 0097; 0118; 0119; 0120
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Reference: [1] Patent: WO2010/10189, 2010, A1, . Location in patent: Page/Page column 70
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  • [ 557-20-0 ]
  • [ 345965-54-0 ]
Reference: [1] Organic Letters, 2003, vol. 5, # 5, p. 753 - 755
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  • [ 95-92-1 ]
  • [ 302912-31-8 ]
Reference: [1] Chemical Communications, 2013, vol. 49, # 31, p. 3242 - 3244
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  • [ 191165-13-6 ]
  • [ 1735-53-1 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 1, p. 38 - 41
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  • [ 216144-45-5 ]
Reference: [1] Tetrahedron Letters, 2013, vol. 54, # 38, p. 5204 - 5206
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  • [ 330793-38-9 ]
  • [ 1400503-15-2 ]
Reference: [1] Journal of Organic Chemistry, 2012, vol. 77, # 18, p. 8362 - 8366
  • 94
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  • [ 444807-47-0 ]
Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 17, p. 8250 - 8266
  • 95
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Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 17, p. 8250 - 8266
  • 96
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  • [ 107317-58-8 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 1, p. 38 - 41
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  • [ 957207-58-8 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 1, p. 38 - 41
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Reference: [1] Organic Letters, 2015, vol. 17, # 1, p. 38 - 41
  • 99
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  • [ 118863-62-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5323 - 5333
  • 100
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  • [ 885278-75-1 ]
Reference: [1] European Journal of Inorganic Chemistry, 2015, vol. 2015, # 29, p. 4935 - 4945
[2] Medicinal Chemistry Research, 2016, vol. 25, # 10, p. 2399 - 2409
  • 101
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Reference: [1] Patent: US2017/8904, 2017, A1,
[2] Patent: US2017/281784, 2017, A1,
[3] Journal of Medicinal Chemistry, 2018, vol. 61, # 2, p. 583 - 598
[4] Patent: US2018/125821, 2018, A1,
[5] Patent: US2016/45607, 2016, A1,
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