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[ CAS No. 402-45-9 ] {[proInfo.proName]}

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Product Citations

Product Citations      Expand+

Anushree Mondal ; Pronay Roy ; Jaclyn Carrannatto , et al. DOI: PubMed ID:

Abstract: The prenylated-flavin mononucleotide-dependent decarboxylases (also known as UbiD-like enzymes) are the most recently discovered family of decarboxylases. The modified flavin facilitates the decarboxylation of unsaturated carboxylic acids through a novel mechanism involving 1,3-dipolar cyclo-addition chemistry. UbiD-like enzymes have attracted considerable interest for biocatalysis applications due to their ability to catalyse (de)carboxylation reactions on a broad range of aromatic substrates at otherwise unreactive carbon centres. There are now ∼35[thin space (1/6-em)]000 protein sequences annotated as hypothetical UbiD-like enzymes. Sequence similarity network analyses of the UbiD protein family suggests that there are likely dozens of distinct decarboxylase enzymes represented within this family. Furthermore, many of the enzymes so far characterized can decarboxylate a broad range of substrates. Here we describe a strategy to identify potential substrates of UbiD-like enzymes based on detecting enzyme-catalysed solvent deuterium exchange into potential substrates. Using ferulic acid decarboxylase (FDC) as a model system, we tested a diverse range of aromatic and heterocyclic molecules for their ability to undergo enzyme-catalysed H/D exchange in deuterated buffer. We found that FDC catalyses H/D exchange, albeit at generally very low levels, into a wide range of small, aromatic molecules that have little resemblance to its physiological substrate. In contrast, the sub-set of aromatic carboxylic acids that are substrates for FDC-catalysed decarboxylation is much smaller. We discuss the implications of these findings for screening uncharacterized UbiD-like enzymes for novel (de)carboxylase activity.

Purchased from AmBeed: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;

Canale, Vittorio ; Czekajewska, Joanna ; Klesiewicz, Karolina , et al. DOI: PubMed ID:

Abstract: The alarming increase in the resistance of bacteria to the currently available antibiotics necessitates the development of new effective antimicrobial agents that are active against bacterial pathogens causing major public health problems. For this purpose, our inhouse libraries were screened against a wide panel of clin. relevant Gram-pos. and Gram-neg. bacteria, based on which compound I was selected for further optimization. Synthetic efforts in a group of arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines, followed with an in vitro evaluation of the activity against multidrug-resistant strains identified compound 44 (1-(3-chlorophenyl)-3-(1-{3-phenyl-3-[3-(trifluoromethyl)phenoxy] propyl}piperidin-4-yl)urea). Compound 44 showed antibacterial activity against Gram-pos. bacteria including fatal drug-resistant strains i.e., Staphylococcus aureus (methicillin-resistant, MRSA; vancomycin-intermediate, VISA) and Enterococcus faecium (vancomycin-resistant, VREfm) at low concentrations (0.78-3.125 μg/mL) comparable to last resort antibiotics (i.e., vancomycin and linezolid). It is also potent against biofilm-forming S. aureus and Staphylococcus epidermidis (including linezolid-resistant, LRSE) strains, but with no activity against Gram-neg. bacteria (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa). Compound 44 showed strong bactericidal properties against susceptible and drug-resistant Gram-pos. bacteria. Depolarization of the bacterial cytoplasmic membrane induced by compound 44 suggests a dissipation of the bacterial membrane potential as its mechanism of antibacterial action. The high antimicrobial activity of compound 44, along with its selectivity over mammalian cells (lung MCR-5 and skin BJ fibroblast cell lines) and no hemolytic properties toward horse erythrocytes, proposes arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines for development of novel antibacterial agents.

Keywords: Arylurea derivatives ; Antibacterial properties ; Anti-MRSA activity ; Anti-VRE activity ; Anti-LRSE activity ; Depolarization of bacterial cell membrane

Purchased from AmBeed: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;

Product Details of [ 402-45-9 ]

CAS No. :402-45-9 MDL No. :MFCD00002363
Formula : C7H5F3O Boiling Point : -
Linear Structure Formula :- InChI Key :BAYGVMXZJBFEMB-UHFFFAOYSA-N
M.W : 162.11 Pubchem ID :67874
Synonyms :

Calculated chemistry of [ 402-45-9 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 1
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 33.47
TPSA : 20.23 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.29 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.51
Log Po/w (XLOGP3) : 2.82
Log Po/w (WLOGP) : 3.56
Log Po/w (MLOGP) : 2.57
Log Po/w (SILICOS-IT) : 2.35
Consensus Log Po/w : 2.56

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.96
Solubility : 0.178 mg/ml ; 0.0011 mol/l
Class : Soluble
Log S (Ali) : -2.9
Solubility : 0.203 mg/ml ; 0.00125 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.7
Solubility : 0.325 mg/ml ; 0.002 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 402-45-9 ]

Signal Word:Danger Class:4.1,6.1
Precautionary Statements:P210-P240-P241-P261-P264-P270-P271-P280-P301+P310+P330-P302+P352-P304+P340+P312-P305+P351+P338+P310-P332+P313-P370+P378-P403+P233-P405-P501 UN#:2926
Hazard Statements:H228-H301-H315-H318-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 402-45-9 ]

* 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 [ 402-45-9 ]
  • Downstream synthetic route of [ 402-45-9 ]

[ 402-45-9 ] Synthesis Path-Upstream   1~28

  • 1
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  • [ 98-17-9 ]
Reference: [1] Chemistry - A European Journal, 2015, vol. 21, # 7, p. 2855 - 2861
[2] Catalysis Letters, 2015, vol. 145, # 4, p. 1014 - 1021
  • 2
  • [ 75-63-8 ]
  • [ 108-95-2 ]
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  • [ 444-30-4 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 8, p. 2293 - 2299
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 8, p. 2293 - 2299
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  • [ 80783-62-6 ]
  • [ 108-95-2 ]
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  • [ 444-30-4 ]
  • [ 98-17-9 ]
Reference: [1] Tetrahedron Letters, 1982, vol. 23, # 38, p. 3929 - 3930
  • 4
  • [ 129922-37-8 ]
  • [ 108-95-2 ]
  • [ 402-45-9 ]
  • [ 444-30-4 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 18, p. 6905 - 6917
  • 5
  • [ 98-08-8 ]
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  • [ 444-30-4 ]
  • [ 98-17-9 ]
  • [ 95-48-7 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1990, # 6, p. 937 - 942
  • 6
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  • [ 35852-58-5 ]
YieldReaction ConditionsOperation in experiment
88% With N-chloro-succinimide; zirconium(IV) chloride In dichloromethane at -78 - 20℃; for 6 h; In a round bottom flask was added 4-(trifluoromethyl)benzaldehyde (1.54 g, 6.75 mmol, 1.0 equiv), and CH2Cl2 (20 mL) followed by mCPBA (1.52 g, 6.78 mmol, 1.0 equiv) at room temperature Stir for 2 hours,After the reaction is complete, add 15 ml of saturated NaHSO3 aqueous solution to the system and transfer to a separatory funnel for extraction. Collect and combine the organic phases, add anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain 4-(trifluoromethyl)phenol. The yield was 71percent.In a round bottom flask, add NCS (25.0 mmol, 3.4 g) and CH2Cl2 (20.0 mL) and cool to -78 °C.ZrCl4 (0.5 mmol, 300 mg) was added followed by 4-(trifluoromethyl)phenol (25.0 mmol) and the reaction stirred at room temperature for 6 hours.After the reaction was completed, the mixture was extracted with saturated aqueous NaHCO 3 . The organic phase was collected and combined. After the solvent was removed, 2-chloro-4-trifluoromethylphenol was obtained with a yield of 88percent.
88% With N-chloro-succinimide; zirconium(IV) chloride In dichloromethane at -78 - 20℃; for 6 h; Inert atmosphere Add 4-(trifluoromethyl)benzaldehyde (6.75 mmol, 1.0 equiv) to a round bottom flask.CH2Cl2 (20 mL),Then add mCPBA (6.78 mmol, 1.0 equiv),Stir at room temperature for 2 h,After the reaction, 15 ml of a saturated aqueous solution of NaHSO 3 was added to the system.Transfer to a separatory funnel for extraction, collect and combine the organic phase, add anhydrous sodium sulfate and dry to obtain a solution of 4-(trifluoromethyl)phenol.The monitored yield was 85percent.Add NCS (5.74 mmol) to a round bottom flask under inert gas conditionsAnd CH2Cl2 (20.0 mL),Cool to -78 °C and add ZrCl4 (0.115 mmol).Then adding a solution of 4-(trifluoromethyl)phenol,The reaction was stirred at room temperature for 6 hours.After the reaction, extraction is carried out with a saturated aqueous solution of NaHCO 3 , and the organic phase is collected and combined.After removing the solvent, 2-chloro-4-trifluoromethylphenol was obtained in a yield of 88percent.
71% With chlorine In 1,2-dichloro-ethane Ia. 2-Chloro-α,α,α-trifluoro-p-cresol
Chlorine gas is passed through a flow meter into a solution of α,α,α-trifluoro-p-cresol (4.05 g. 0.025 mole) in ethylene dichloride (200 ml.) at 0° C. until the theoretical volume has been absorbed.
The solvent is stripped off and the residue distilled to give 2-chloro-α,α,α-trifluoro-p- cresol (3.5 g. 71percent) b.p. 80°-82° C. at 33 mm.
71% With chlorine In 1,2-dichloro-ethane Ia. 2-Chloro-α,α,α-trifluoro-p-cresol
Chlorine gas is passed through a flow meter into a solution of α,α,α-trifluoro-p-cresol (4.05 g. 0.025 mole) in ethylene dichloride (200 ml.) at 0° C. until the theoretical volume has been absorbed.
The solvent is stripped off and the residue distilled to give 2-chloro-α,α,α-trifluoro-p-cresol (3.5 g. 71percent) b.p. 80°-82° C. at 33 mm.

Reference: [1] Patent: US4607128, 1986, A,
[2] Journal of the American Chemical Society, 2009, vol. 131, p. 4031 - 4041
[3] Patent: CN107915584, 2018, A, . Location in patent: Paragraph 0025; 0026; 0027; 0028
[4] Patent: CN108276254, 2018, A, . Location in patent: Paragraph 0012; 0013; 0014; 0015
[5] Patent: US4076741, 1978, A,
[6] Patent: US30361, 1980, E1,
[7] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 14, p. 3347 - 3351
[8] Organic Letters, 2013, vol. 15, # 9, p. 2128 - 2131
[9] Chem.Abstr., 1974, vol. 80, # 3253,
  • 7
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  • [ 35852-58-5 ]
  • [ 113281-23-5 ]
  • [ 113281-24-6 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 1861 - 1864
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 1861 - 1864
  • 8
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  • [ 110230-36-9 ]
  • [ 35852-58-5 ]
  • [ 113281-23-5 ]
  • [ 113281-24-6 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 1861 - 1864
  • 9
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  • [ 454-81-9 ]
Reference: [1] European Journal of Medicinal Chemistry, 2012, vol. 56, p. 108 - 119
  • 10
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  • [ 201230-82-2 ]
  • [ 1891-90-3 ]
Reference: [1] Chemistry - A European Journal, 2012, vol. 18, # 2, p. 419 - 422
  • 11
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  • [ 400-99-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 22, p. 6842 - 6851
[2] European Journal of Medicinal Chemistry, 2012, vol. 56, p. 108 - 119
  • 12
  • [ 402-45-9 ]
  • [ 107-21-1 ]
  • [ 2968-93-6 ]
Reference: [1] Patent: JP2005/289857, 2005, A, . Location in patent: Page/Page column 38
  • 13
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  • [ 328-90-5 ]
Reference: [1] European Journal of Organic Chemistry, 2001, # 15, p. 2911 - 2915
  • 14
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  • [ 57478-19-0 ]
Reference: [1] MedChemComm, 2015, vol. 6, # 4, p. 671 - 676
[2] RSC Advances, 2016, vol. 6, # 108, p. 106778 - 106789
[3] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 11, p. 3046 - 3059
  • 15
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  • [ 4864-01-1 ]
Reference: [1] Patent: WO2011/25982, 2011, A2,
  • 16
  • [ 402-45-9 ]
  • [ 402-10-8 ]
Reference: [1] Tetrahedron, 2007, vol. 63, # 41, p. 10127 - 10132
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 2, p. 727 - 739
[3] Organometallics, 2018, vol. 37, # 19, p. 3243 - 3247
  • 17
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  • [ 146539-83-5 ]
Reference: [1] Journal of Organic Chemistry, 1993, vol. 58, # 6, p. 1385 - 1392
  • 18
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  • [ 67589-15-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 21, p. 6414 - 6416
[2] Angewandte Chemie - International Edition, 2014, vol. 53, # 34, p. 9026 - 9029[3] Angew. Chem., 2014, vol. 126, # 34, p. 9172 - 9175,4
  • 19
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  • [ 78950-29-5 ]
  • [ 67589-15-5 ]
Reference: [1] Journal of the Chemical Society, Chemical Communications, 1995, # 19, p. 2009 - 2010
  • 20
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  • [ 81107-97-3 ]
YieldReaction ConditionsOperation in experiment
90% With bromine In dichloromethane at 20℃; Example 13: tert-butyl 2-(2-bromo-4-(trifluoromethyl)phenoxy)acetate (15)a) 4.8 ml of Bromine (92.6 mmol, 1 eq.) in 50ml of DCM was added dropwise to a solution of 15g of 4-(trifluoromethyl)phenol (92.6 mmol, leq.) in 200 ml of DCM at rt. Tthe mixture was stirred overnightand then washed with aqueousNa2SCh and brine, dried, and evaporated in vacuo to give 20 g (90percent) 2-bromo- 4-(trifluoromethyl)phenol (14) exhibiting 90percent purity by HPLC.
40 g With bromine In dichloromethane at 20℃; for 12 h; Cooling 32 g of p-trifluoromethylphenol was dissolved in 200 ml of dichloromethane,Under cooling, equimolar bromine was added dropwise,About 2h drops finished,Then stirred at room temperature for 12 h,The system was washed with saturated sodium bicarbonate to neutral,dry,The solvent was distilled off to obtain 40 g of a thick liquid.The resulting thickened liquid is 2-bromo-4-trifluoromethylphenol,
Reference: [1] Tetrahedron, 2003, vol. 59, # 34, p. 6545 - 6558
[2] Patent: WO2009/89192, 2009, A1, . Location in patent: Page/Page column 30-31
[3] Chemistry - A European Journal, 2012, vol. 18, # 11, p. 3286 - 3291
[4] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 4, p. 734 - 745
[5] Tetrahedron Letters, 2001, vol. 42, # 45, p. 8093 - 8096
[6] Tetrahedron, 2004, vol. 60, # 28, p. 5919 - 5930
[7] Patent: CN106336380, 2017, A, . Location in patent: Paragraph 0102; 0103
[8] Patent: US2018/110824, 2018, A1, . Location in patent: Paragraph 0465
  • 21
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Reference: [1] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 4, p. 734 - 745
  • 22
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  • [ 79427-88-6 ]
Reference: [1] Synthesis, 2001, # 15, p. 2259 - 2262
[2] European Journal of Organic Chemistry, 2001, # 15, p. 2911 - 2915
[3] Patent: WO2014/165816, 2014, A1,
  • 23
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  • [ 459-57-4 ]
  • [ 90035-20-4 ]
YieldReaction ConditionsOperation in experiment
73% With caesium carbonate In N,N-dimethyl-formamide at 20 - 85℃; Intermediate 52: 4-[4-(Trifluoromethyl)phenyl]oxy}benzaldehyde; To a solution of the commercially available of 4-(trifluoromethyl)phenol (9.1 g, 56 mmol, 1.2 equiv.) in DMF (100 mL) was added successively cesium carbonate (22.8 g, 70 mmol, 1.5 equiv.) and 4-fluorobenzaldehyde (5 mL, 46.6 mmol) at room temperature. The reaction mixture was then stirred at 85°C for 16h before being cooled and filtered. The resulting filtrate was concentrated to dryness and the crude oil was purified by flash chromatography (SiO2, cyclohexane/ethyl acetate 70/30) to give the title compound (9.0 g, 73percent yield) as a colorless oil. 1H NMR (CDCI3) δ 9.97 (s, 1 H), 7.91 (m, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.20-7.11 (m, 4H). LCMS: (M+H)+ = 267, Rt= 3.53 min.
70% With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 4 h; Inert atmosphere To a homogeneous mixture of 4-(trifluoromethyl)phenol (1.2 g, 7.5 mmol) and 4-fluorobenzaldehyde (0.8 mL, 7.5 mmol) in anhydrous DMF (15 mL), under an argon atmosphere, was added potassium carbonate (1.04 g, 7.5 mmol). The mixture was heated at 150 °C for 4 h before being poured over ice. The resultant precipitate was isolated by vacuum filtration, washed thoroughly with water, dried under vacuum to afford the desired compound (1.4 g, 70percent) as a cream colored solid, which was used without further purification. MS (ESI): 267.1 (M + H)+.
Reference: [1] Patent: WO2010/15652, 2010, A2, . Location in patent: Page/Page column 52-53
[2] Patent: WO2009/152082, 2009, A1, . Location in patent: Page/Page column 59; 180
[3] Bioorganic and Medicinal Chemistry, 1998, vol. 6, # 1, p. 15 - 30
[4] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 10, p. 1801 - 1804
[5] Journal of Medicinal Chemistry, 2015, vol. 58, # 7, p. 3036 - 3059
[6] Patent: US9266841, 2016, B2, . Location in patent: Page/Page column 18
  • 24
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  • [ 90035-20-4 ]
YieldReaction ConditionsOperation in experiment
69% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 5 h; Inert atmosphere; Schlenk technique; Green chemistry General procedure: Under an argon atmosphere, a Schlenk tube was charged with MCM-41-2N-Cu(OAc)2(46 mg, 0.025 mmol), nitroarene 1 (0.5 mmol), phenol 2 (1.0 mmol), Cs2CO3 (1.0 mmol) and DMF (3 mL). The reaction mixture was stirred at 100 °C for 5 h under Ar. After being cooled to room temperature, the mixture was diluted with ethyl acetate (20 mL) and filtered. The MCM-41-2N-Cu(OAc)2 catalyst was washed with distilled water (2 × 5 mL), DMF (2 × 5 mL) and EtOH (2 × 5 mL) and could be reused in the next run. The filtrate was washed with water (2 × 10 mL) and dried over anhydrous MgSO4. After removal of the solvent under reduced pressure, the residue was purified by column chromatography (EtOAc/hexane) on silica gel to afford the desired product 3.
62% With copper(II) acetate monohydrate; caesium carbonate In N,N-dimethyl-formamide at 100℃; for 4 h; Inert atmosphere; Schlenk technique General procedure: Under N2 atmosphere, a Schlenk tube was charged with nitroarenes 1 (0.5 mmol), phenols 2 (1.0 mmol), Cu(OAc)2·H2O (5 mol percent), and Cs2CO3 (1.0 mmol) in DMF (3 mL) at room temperature. After that, the mixture was stirred constantly at 100 °C (oil bath temperature) for 4 h. After the completion of the reaction, as monitored by TLC and GC–MS analysis, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtrated. The filtrate was concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford the desired arylated product 3.
Reference: [1] Journal of Chemical Research, 2017, vol. 41, # 12, p. 725 - 729
[2] Tetrahedron, 2012, vol. 68, # 43, p. 8905 - 8907
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YieldReaction ConditionsOperation in experiment
75% With iodine; sodium hydrogencarbonate; thiourea In tetrahydrofuran; water Step A:
a,a a-Trifluoro-o-iodo-p-cresol.
A mixture of iodine (91.6 mmol, 23.2 g) and sodium bicarbonate (91.6 mmol, 7.7 g) was added to a solution of α,α,α-trifluoro-p-cresol (83.3 mmol, 13.5 g) in THF (90 mL) and H2O (90 mL) and the reaction mixture was allowed to stand at room temperature overnight.
Sufficient thiourea (5percent solution) was added to remove the excess iodine as indicated by the color change of the reaction from deep violet to brown.
The reaction mixture was extracted with ether (3*100 mL), the extract was dried, filtered and the filtrate was concentrated to obtain a brown oil.
This oil was distilled (bp 105° C. at 44 mm Hg) to obtain α,α,α-trifluoro-o-iodo-p-cresol (4.1 g, 75percent pure, admixed with the starting α,α,α-trifluoro-p-cresol).
63% With iodine; sodium carbonate In tetrahydrofuran; water at 25℃; for 24 h; S3. Under stirring, to 4- (trifluoromethyl) phenol (6) (241mmol, 39g) in tetrahydrofuran (200mL) and water (200 mL)Were sequentially added iodine (265mmol, 67g) and sodium carbonate (265mmol, 28g),The reaction was stirred for 25 After 24h, TLC monitoring starting 4- (trifluoromethyl) phenol (6) completion of the reaction;Post-treatment: adding 5percent thiourea solution to remove excess iodine, extracted with ether three times, collecting organic phase, drying, concentrated crude product. The crude product was isolated by column chromatography under the following conditions: petroleum ether: dichloromethane = 10: 1 to 6: 1 (by volume) to give the compound 2-iodo-4- (trifluoromethyl) phenol (7) , 42.7 g), the yield was 63percent
63% With iodine; sodium carbonate In tetrahydrofuran; water at 25℃; for 24 h; Under stirring conditions,To a solution of 4- (trifluoromethyl) phenol (6)(241 mmol, 39 g) in tetrahydrofuran (200 mL)And water (200 mL)The solution was added with iodine in this order(265 mmol, 67 g)And sodium carbonate (265 mmol, 28 g),After stirring at 25 for 24 h,TLC monitoring of starting materials 4- (trifluoromethyl) phenol (6)The reaction is complete;Post-processing:Adding the appropriate amount of 5percent thiourea solution to remove excess iodine,Extracted three times with ether,The organic phase was collected, dried,Concentrated after the crude product.The crude product was separated by column chromatography,The condition is:Petroleum ether: dichloromethane = 10: 1 to 6: 1 (volume ratio),To give the compound 2-iodo-4- (trifluoromethyl) phenol (7)(Yellow solid, 42.7 g),The yield was 63percent,
Reference: [1] Patent: US2002/143017, 2002, A1,
[2] Patent: CN106397425, 2017, A, . Location in patent: Paragraph 0019; 0040; 0041
[3] Patent: CN106397426, 2017, A, . Location in patent: Paragraph 0044; 0045; 0058; 0062
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 16, p. 7029 - 7042
[5] Journal of Medicinal Chemistry, 2005, vol. 48, # 20, p. 6326 - 6339
[6] Synlett, 2007, # 14, p. 2227 - 2231
[7] Patent: WO2006/21759, 2006, A1, . Location in patent: Page/Page column 27
[8] Patent: WO2004/89885, 2004, A1, . Location in patent: Page 32
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YieldReaction ConditionsOperation in experiment
50% With hydrogenchloride; chloroamine-T; sodium iodide In ethyl acetate; N,N-dimethyl-formamide EXAMPLE 1
Synthesis of 2-Iodo-4-Trifluoromethylphenol (Scheme 1: 8)
4-Trifluoromethylphenol (25 g, 154 mmol; Compound 7 in the above Scheme 1) was taken in DMF (100 mL) and to the resulting suspension was added NaI (30 g, 200 mmol) and stirred for 15 min. Chloramine-T (38.5 g, 169 mmol) was added to the reaction mixture and it was stirred for 6 h at room temperature.
The reaction mixture was acidified by the addition of 1N HCl and was poured into ice-water mixture (4 L).
The resulting suspension was stirred for some time, the light brown solid was filtered and purified on a flash column (25percent ethyl acetate in hexanes), to give 22.2 g (50percent) of the title compound (Compound 8).
Reference: [1] Patent: US2003/55084, 2003, A1,
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YieldReaction ConditionsOperation in experiment
12% With tin(IV) chloride; paraformaldehyde In toluene EXAMPLE XXIX
p-Trifluoromethylsalicylaldehyde
To a solution of p-trifluoromethylphenol (7.1 g, 44 mmol) and 2,6-lutidine (1.9 g, 17.6 mmol) in toluene (80 mL) was slowly added SnCl4 (1.2 g, 4.4 mmol).
The solution was stirred at room temperature for 20 minutes.
Paraformaldehyde was added (3.2 g, 106 mmol) and the reaction was stirred at 110° C. for 12 hours.
After cooling to room temperature, the reaction mixture was poured into water (250 mL), and adjusted to pH 1 with concentrated HCl.
The mixture was extracted with diethyl ether (500 mL), and the organic layer was washed twice with saturated brine and dried over Na2SO4.
The solvent was removed by rotary evaporation to leave a yellow oil.
The oil was loaded onto a silica gel column and eluted with 6:1 hexane:ethyl acetate.
The yield of product was 1.0 g (12percent).
1H NMR (CDCl3): δ 7.21-7.91 (m, 12H), 9.91 (s, 1H), 11.32 (s, 1H).
Reference: [1] Patent: US6576779, 2003, B1,
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 14, p. 3855 - 3859
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