[ CAS No. 1885-46-7 ] {[proInfo.proName]}

Name: 1885-46-7|Difluoromethyl trifluoromethanesulfonate|98%
Brand: Ambeed
SKU: A831633
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Quality Control of [ 1885-46-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1885-46-7 ]

SDS Specification

Alternatived Products of [ 1885-46-7 ]

Product Details of [ 1885-46-7 ]

CAS No. :	1885-46-7	MDL No. :	MFCD28054469
Formula :	C₂HF₅O₃S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DAANAKGWBDWGBQ-UHFFFAOYSA-N
M.W :	200.08	Pubchem ID :	542802
Synonyms :

Calculated chemistry of [ 1885-46-7 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	3
Num. H-bond acceptors :	8.0
Num. H-bond donors :	0.0
Molar Refractivity :	22.07
TPSA :	51.75 Å²

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) :	-6.24 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.07
Log Po/w (XLOGP3) :	1.81
Log Po/w (WLOGP) :	4.26
Log Po/w (MLOGP) :	0.52
Log Po/w (SILICOS-IT) :	1.93
Consensus Log Po/w :	1.92

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.02
Solubility :	1.9 mg/ml ; 0.00949 mol/l
Class :	Soluble
Log S (Ali) :	-2.52
Solubility :	0.61 mg/ml ; 0.00305 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.04
Solubility :	18.1 mg/ml ; 0.0904 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.71

Safety of [ 1885-46-7 ]

Signal Word:	Danger	Class:	8,3
Precautionary Statements:	P210-P233-P240-P241-P242-P243-P264-P270-P280-P301+P312+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P370+P378-P403+P235-P405-P501	UN#:	2920
Hazard Statements:	H225-H302-H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 1885-46-7 ]

* 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 [ 1885-46-7 ]
Downstream synthetic route of [ 1885-46-7 ]

[ 1885-46-7 ] Synthesis Path-Upstream 1~8

1
[ 1885-46-7 ]
[ 767-00-0 ]
[ 332-25-2 ]

Reference： [1] ChemMedChem, 2015, vol. 10, # 4, p. 715 - 726

2
[ 1885-46-7 ]
[ 104-88-1 ]
[ 73960-07-3 ]

Yield	Reaction Conditions	Operation in experiment
49%	Stage #1: With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; potassium hydroxide; tert-butyl XPhos In 1,4-dioxane; water at 100℃; Inert atmosphere Stage #2: With potassium hydroxide In 1,4-dioxane; water; acetonitrile at 20℃; for 0.0333333 h;	General procedure: [a] Reactions were performed on a 0.5 mmol scale to determine yields by ¹⁹F NMR spectroscopy with PI1CF₃ as an internal standard added after the reaction.; Note: The hydroxylation reaction was set-up under an inert atmosphere according to the literature procedure. [Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 10694.] To an oven-dried 4 mL vial was added Pd₂(dba)₃ (9.2 mg, .010 mmol, 4.0 mol percent Pd), 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (^lBu- XPhos, 17.0 mg, .040 mmol, 8.0 mol percent), KOH (1.0-3.0 equiv), degassed H₂0 (150-300 μ) and dioxane (250-500 μΚ). The aryl halide (0.5 mmol, 1.0 equiv) was added (solid aryl halides were weighed into the vial prior to adding solvent, and liquid aryl bromides were added neat by syringe after the addition of solvent). The vial was sealed with a Teflon-lined cap and heated at 100 °C for 1-18 h. The solution was allowed to cool, and the reaction was diluted with acetonitrile (500-750 μ, such that the total volume of dioxane and acetonitrile is 1.0 mL) and 6M KOH (700-850 μ, such that the final aqueous solvent volume is 1.0 mL). The resulting mixture was stirred rapidly at room temperature, and HCF₂0Tf (210 μ, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with ]0 (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgS04, concentrated, and purified by silica gel chromatography.

Reference： [1] Patent: WO2014/107380, 2014, A1, . Location in patent: Paragraph 00166-00167

3
[ 1885-46-7 ]
[ 2142-63-4 ]
[ 101975-23-9 ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; potassium hydroxide; tert-butyl XPhos In 1,4-dioxane; water at 100℃; Inert atmosphere Stage #2: With potassium hydroxide In 1,4-dioxane; water; acetonitrile at 20℃; for 0.0333333 h;	General procedure: [a] Reactions were performed on a 0.5 mmol scale to determine yields by ¹⁹F NMR spectroscopy with PI1CF₃ as an internal standard added after the reaction.; Note: The hydroxylation reaction was set-up under an inert atmosphere according to the literature procedure. [Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 10694.] To an oven-dried 4 mL vial was added Pd₂(dba)₃ (9.2 mg, .010 mmol, 4.0 mol percent Pd), 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (^lBu- XPhos, 17.0 mg, .040 mmol, 8.0 mol percent), KOH (1.0-3.0 equiv), degassed H₂0 (150-300 μ) and dioxane (250-500 μΚ). The aryl halide (0.5 mmol, 1.0 equiv) was added (solid aryl halides were weighed into the vial prior to adding solvent, and liquid aryl bromides were added neat by syringe after the addition of solvent). The vial was sealed with a Teflon-lined cap and heated at 100 °C for 1-18 h. The solution was allowed to cool, and the reaction was diluted with acetonitrile (500-750 μ, such that the total volume of dioxane and acetonitrile is 1.0 mL) and 6M KOH (700-850 μ, such that the final aqueous solvent volume is 1.0 mL). The resulting mixture was stirred rapidly at room temperature, and HCF₂0Tf (210 μ, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with ]0 (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgS04, concentrated, and purified by silica gel chromatography.

Reference： [1] Patent: WO2014/107380, 2014, A1, . Location in patent: Paragraph 00166-00167

4
[ 1885-46-7 ]
[ 101975-23-9 ]

Yield	Reaction Conditions	Operation in experiment
46%	Stage #1: With dihydrogen peroxide In water; acetonitrile at 20℃; for 0.25 h; Stage #2: With potassium hydroxide In water; acetonitrile at 20℃; for 0.0333333 h;	General procedure: [a] Reactions were performed on a 0.1 mmol scale to determine yields by F NMR spectroscopy with PhCF₃ as an internal standard added after the reaction. Isolated yields are shown in parenthesis for reactions performed on a 0.5 mmol scale.; To a 20 mL vial was added the aryl boronic acid (0.5 mmol, 1.0 equiv), acetonitrile (1.0 mL) and 30percent aqueous hydrogen peroxide (500 μ). The reaction was stirred at room temperature for 15 minutes. After this time, 12M KOH (500 μΚ) was added carefully. Note: the addition of KOH causes rapid decomposition of the unreacted hydrogen peroxide. This reaction is exothermic, and gas is evolved. The resulting mixture was stirred rapidly at room temperature, and HCF₂OTf (210 μ_^, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with 0 (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgSC , concentrated, and purified by silica gel chromatography.

Reference： [1] Patent: WO2014/107380, 2014, A1, . Location in patent: Paragraph 00157-00162

5
[ 6602-32-0 ]
[ 1885-46-7 ]
[ 947249-27-6 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium hydroxide In water; acetonitrile at 20℃; for 0.5 h;	General procedure: To a vigorously stirred solution of 2-chloro-6-hydroxypyridine(0.13 g, 1.0 mmol) in acetonitrile (2 mL) at room temperature was added a 6 M aqueous solution of potassium hydroxide (2 mL). Difluoromethyltriflate (0.38 mL, 3.0 mmol, 3 equiv.) was added dropwiseto the reaction mixture which was maintained at room temperature by means of a water bath (the reaction is exothermic), and the medium was stirred for 30 min. The mixture was diluted with water(20 mL) and extracted with diethyl ether (2 ×10 mL) and ethyl acetate(3 ×10 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel with pentane/diethylether (100:0 to 70:30) as eluent to afford the pure title compound

Reference： [1] Journal of Fluorine Chemistry, 2017, vol. 203, p. 155 - 165

6
[ 1885-46-7 ]
[ 695-96-5 ]
[ 1214348-81-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium hydroxide In water; acetonitrile for 0.0833333 h; Cooling with ice	[1555] 36 ml of aqueous potassium hydroxide solution(6M) were added to a solution of 3.5 g (16.9 mmol) of2-bromo-4-chlorophenol in 36 ml of acetonitrile, the mixturewas cooled in an ice bath and 6.5 ml (26.9 mmol, 1.6 eq.) ofdifluoromethyl trifluormethanesulphonate [Angew. Chern.Int. Ed. 2013, 52, 1-5; Journal of Fluorine Chemistry 2009,130, 667-670] were added dropwise with vigorous stirring.The reaction mixture was stirred for 5 min and diluted with200 ml of water. The aqueous phase was extracted twice within each case 150 ml of diethyl ether. The combined organicphases were dried (sodium sulphate), filtered, concentratedunder reduced pressure and dried. The aqueous phase wasonce more extracted with diethyl ether. The organic phasewas dried (sodium sulphate), filtered, concentrated underreduced pressure and dried. Yield of the two combined residues:3.4 g (80percent of theory)[1556] LC/MS [Method 9]: R,=3.51 min; MS (ESipos):m/z=256 (M+Ht[1557] 1H-NMR (400 MHz, DMSO-d6): o [ppm]=7.91 (d,lH), 7.55 (dd, lH), 7.37 (d, lH), 7.30 (t, lH).
80%	With potassium hydroxide In water; acetonitrile for 0.0833333 h; Cooling with ice	36 ml of aqueous potassium hydroxide solution (6M) were added to a solution of 3.5 g (16.9 mmol) of 2-bromo-4-chlorophenol in 36 ml of acetonitrile, the mixture was cooled in an ice bath and 6.5 ml (26.9 mmol, 1.6 eq.) of difluoromethyl trifluormethanesulphonate [Angew. Chem. mt. Ed. 2013, 52, 1-5; Journal of Fluorine Chemistry 2009, 130, 667-670] were added dropwise with vigorous stirring. The reaction mixture was stirred for 5 mm and diluted with 200 ml of watet The aqueous phase was extracted twice with in each case 150 ml of diethyl ethet The combined organic phases were dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. The aqueous phase was once more extracted with diethyl ethet The organic phase was dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. Yield of the two combined residues: 3.4 g (80percent of theory)10654] LC/MS [Method 9]: R=3.51 mm; MS (ESIpos):mlz=256 (M+H), 10655] ‘H-NMR (400 MHz, DMSO-d5): ö [ppm]=7.91 (d, 1H), 7.55 (dd, 1H), 7.37 (d, 1H), 7.30 (t, 1H).
3.4 g	With potassium hydroxide In water; acetonitrile for 0.0833333 h; Cooling with ice	36 ml of aqueous potassiumhydroxide solution (6M) were added to a solution of 3.5 g (16.9 mmol) of2-bromo-4-chlorophenol in 36 ml of acetonitrile, the mixture was cooled in anice bath and 6.5 ml (26.9 mmol, 1.6 eq.) of difluoromethyl trifluormethanesulphonate were added dropwise with vigorous stirring. The reaction mixture was stirredfor 5 min and diluted with 200 ml of water. The aqueous phase was extractedtwice with in each case 150 ml of diethyl ether. The combined organic phaseswere dried (sodium sulphate), filtered, concentrated under reduced pressure anddried. The aqueous phase was once more extracted with diethyl ether. Theorganic phase was dried (sodium sulphate), filtered, concentrated under reducedpressure and dried. Yield of the two combined residues: 3.4 g (80percent of theory)

Reference： [1] Patent: US2016/52884, 2016, A1, . Location in patent: Paragraph 1554-1557
[2] Patent: US2016/272637, 2016, A1, . Location in patent: Paragraph 0652; 0653; 0654; 0655
[3] Patent: KR2015/137095, 2015, A, . Location in patent: Paragraph 2270-2273

7
[ 16879-02-0 ]
[ 1885-46-7 ]
[ 1214377-45-3 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium hydroxide In water; acetonitrile at 20℃; for 0.5 h;	To a vigorously stirred solution of 2-chloro-6-hydroxypyridine(0.13 g, 1.0 mmol) in acetonitrile (2 mL) at room temperature was added a 6 M aqueous solution of potassium hydroxide (2 mL). Difluoromethyltriflate (0.38 mL, 3.0 mmol, 3 equiv.) was added dropwiseto the reaction mixture which was maintained at room temperature by means of a water bath (the reaction is exothermic), and the medium was stirred for 30 min. The mixture was diluted with water(20 mL) and extracted with diethyl ether (2 ×10 mL) and ethyl acetate(3 ×10 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel with pentane/diethylether (100:0 to 70:30) as eluent to afford the pure title compound(129 mg, 72percent yield); 1H NMR (400 MHz, CDCl3): δ 7.62 (t, 1H,J = 7.9 Hz), 7.37 (t, 1H, J = 72.2 Hz), 7.07 (d, 1H, J = 7.9 Hz), 6.76(d, 1H, J = 8.0 Hz) ppm. 13C NMR (101 MHz, CDCl3): δ 158.3, 148.5,142.1, 120.1, 113.8 (t, J= 259 Hz), 109.6 ppm 19F NMR (376 MHz,CDCl3): δ −89.3 (d, 2F, J = 71.4 Hz) ppm. HRMS (ESI) calcd forC6H5ClF2NO [M + H]+: 180.002. Found: 180.000.

Reference： [1] Journal of Fluorine Chemistry, 2017, vol. 203, p. 155 - 165

8
[ 41288-96-4 ]
[ 1885-46-7 ]
[ 1206980-28-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium hydroxide In water; acetonitrile at 20℃; for 0.5 h;	General procedure: To a vigorously stirred solution of 2-chloro-6-hydroxypyridine(0.13 g, 1.0 mmol) in acetonitrile (2 mL) at room temperature was added a 6 M aqueous solution of potassium hydroxide (2 mL). Difluoromethyltriflate (0.38 mL, 3.0 mmol, 3 equiv.) was added dropwiseto the reaction mixture which was maintained at room temperature by means of a water bath (the reaction is exothermic), and the medium was stirred for 30 min. The mixture was diluted with water(20 mL) and extracted with diethyl ether (2 ×10 mL) and ethyl acetate(3 ×10 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel with pentane/diethylether (100:0 to 70:30) as eluent to afford the pure title compound

Reference： [1] Journal of Fluorine Chemistry, 2017, vol. 203, p. 155 - 165

[ 1885-46-7 ] Synthesis Path-Downstream 1~81

1
[ 1493-13-6 ]
[ 693-85-6 ]
[ 1885-46-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,1965,vol. 2,p. 152 - 156

2
[ 1717-59-5 ]
[ 2926-30-9 ]
[ 75-46-7 ]
[ 1885-46-7 ]

Reference： [1]Journal of Organic Chemistry,1989,vol. 54,p. 3023 - 3027

3
[ 942128-13-4 ]
[ 358-23-6 ]
S-(difluoromethyl)-phenyl-2-bromophenylsulfonium trifluoromethanesulfonate [ No CAS ]
[ 1493-13-6 ]
[ 1885-46-7 ]

Reference： [1]Organic Letters,2007,vol. 9,p. 1863 - 1866

4
[ 942128-14-5 ]
[ 358-23-6 ]
[ 132-65-0 ]
[ 1885-46-7 ]

Reference： [1]Organic Letters,2007,vol. 9,p. 1863 - 1866

5
[ 1493-13-6 ]
[ 81290-20-2 ]
[ 420-56-4 ]
[ 1885-46-7 ]

Reference： [1]Journal of Fluorine Chemistry,2009,vol. 130,p. 667 - 670

6
[ 1493-13-6 ]
[ 81290-20-2 ]
[ 1885-46-7 ]

Yield	Reaction Conditions	Operation in experiment
74%		Triflic acid (1.2 eq., 8.45g, 5mL, 56.3mmol) was introduced into a Schlenk's vessel using a gas-tight syringe and was then carefully treated with TiCl4 (1.17%, 0.104g, 0.06mL, 0.547mmol) under an inert atmosphere and vigorous stirring. After 5min, the homogeneous solution was evacuated at 13mbar over 10min until gas evolution ceased. The mixture was cooled to-20C and Ruppert's reagent (6.65g, 7mL, 46.8mmol) was very carefully added via syringe, the mixture was stirred for 5minat-20C, and then very slowly rose to room temperature by placing a water bath. The mixture was stirred 1h more. Volatile materials were distilled off in vacuo (130mbar) and trapped in N2 trap. The volatile material was recovered from the N2 trap after slow temperature rise under argon, to afford 9.82g of colourless liquid difluoromethyl trifluoromethanesulfonate (6.97g, 34.8mmol, 74%). 1H NMR (CDCl3, 400MHz): δ=6.64 (t, JH-F=60Hz, 1H, -CHF2) ppm.
		TiC4 (0.512 mL, 4.64 mmol) was added dropwise to trifluoromethanesulfonic acid (49.5 mL, 557 mmol) under vigorous stirring at 25 C, and the mixture was kept at 25 C for 5 mm. Then the reaction mixture was evacuated at 10-15 Torr until gas evolution ceased (ca. 5-10 mm). The mixture was cooled to -20 C,and trimethyl(trifluoromethyl)silane (66.0 g, 464 mmol) was added. The mixture was kept at-20 C for 2 mm, then the cooling bath was replaced with an ice/water bath for 2 mi andthen with a water bath with 25 C. The reaction mixture was stirred at 25 C for 2 h, andthen distilled under a reduced pressure (6 kPa) at 25 C to give the title compound. ‘H NMR(400 MHz, CDC13): ö = 6.86 (t, J 68.1 Hz, 1H).

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 143,p. 473 - 490
[2]Chemical Communications,2014,vol. 50,p. 6056 - 6059
[3]Patent: WO2018/118670,2018,A1 .Location in patent: Page/Page column 89

7
[ 533-31-3 ]
[ 1885-46-7 ]
[ 1226157-22-7 ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium hydroxide; In water; acetonitrile; at 20℃; for 0.0333333h;	General procedure: Into a 20 mL vial was placed the phenol or thiophenols (0.5 mmol, 1.0 equiv), acetonitrile (1.0 mL) and 6M aqueous KOH (1.0 mL). The mixture was stirred rapidly at room temperature and HCF2OTf (210 μ, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with FLO (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgSC , concentrated, and purified by silica gel chromatography.; The reaction was performed according to the general procedure for the difluoromethylation of phenols on a 0.5 mmol scale. The product was purified by silica gel chromatography to give 2c as a clear oil (49 mg, 52% yield). XH NMR (600 MHz, CDC13) δ 6.75 (d, J= 8.4 Hz, 1H), 6.67 (s, 1H), 6.59 (d, J= 8.4 Hz, 1H), 6.40 (t, J= 74.1 Hz, 1H), 5.99 (s, 2H). 13C NMR (151 MHz, CDC13) δ 148.27 (s), 145.47 (t, J= 3.1 Hz), 145.32 (s), 1 16.19 (t, J= 260.0 Hz), 1 12.72 (s), 108.07 (s), 102.80 (s), 101.78 (s). 19F NMR (376 MHz, CDC13) δ -82.74 (d, J = 74.1 Hz).

Reference： [1]Patent: WO2014/107380,2014,A1 .Location in patent: Paragraph 0078-0082; 0087-0090

8
[ 1885-46-7 ]
[ 540-38-5 ]
[ 128140-82-9 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium hydroxide; In water; acetonitrile; at 20℃; for 0.0333333h;	General procedure: Into a 20 mL vial was placed the phenol or thiophenols (0.5 mmol, 1.0 equiv), acetonitrile (1.0 mL) and 6M aqueous KOH (1.0 mL). The mixture was stirred rapidly at room temperature and HCF2OTf (210 mu, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with FLO (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgSC , concentrated, and purified by silica gel chromatography.; The reaction was performed according to the general procedure for the difluoromethylation of phenols on a 0.5 mmol scale. The product was purified by silica gel chromatography to give 2e as a clear oil (98 mg, 72% yield). XH NMR (400 MHz, CDC13) delta 7.67 (d, J= 8.9 Hz, 2H), 6.89 (d, J= 8.8 Hz, 2H), 6.48 (t, J= 73.4 Hz, 1H). 13C NMR (151 MHz, CDC13) delta 150.89 (t, J= 2.9 Hz), 138.82 (s), 121.80 (s), 1 15.54 (t, J = 261.2 Hz), 89.08 (s). 19F NMR (376 MHz, CDC13) delta -83.62 (d, J= 73.4 Hz).

Reference： [1]Patent: WO2014/107380,2014,A1 .Location in patent: Paragraph 0078-0082; 0095-0098

9
[ 97-53-0 ]
[ 1885-46-7 ]
[ 199854-32-5 ]

Yield	Reaction Conditions	Operation in experiment
51%	With potassium hydroxide; In water; acetonitrile; at 20℃; for 0.0333333h;	General procedure: Into a 20 mL vial was placed the phenol or thiophenols (0.5 mmol, 1.0 equiv), acetonitrile (1.0 mL) and 6M aqueous KOH (1.0 mL). The mixture was stirred rapidly at room temperature and HCF2OTf (210 μ, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with FLO (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgSC , concentrated, and purified by silica gel chromatography.

Reference： [1]Patent: WO2014/107380,2014,A1 .Location in patent: Paragraph 0076-0078

10
[ 1885-46-7 ]
[ 53-16-7 ]
[ 1454765-39-9 ]

Yield	Reaction Conditions	Operation in experiment
50%	With potassium hydroxide; In water; acetonitrile; at 20℃; for 0.0333333h;	General procedure: Into a 20 mL vial was placed the phenol or thiophenols (0.5 mmol, 1.0 equiv), acetonitrile (1.0 mL) and 6M aqueous KOH (1.0 mL). The mixture was stirred rapidly at room temperature and HCF2OTf (210 μ, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with FLO (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgSC , concentrated, and purified by silica gel chromatography.; The reaction was performed according to the general procedure for the difluoromethylation of phenols on a 0.5 mmol scale. The product was purified by silica gel chromatography to give 2x (81 mg, 50% yield). NMR (600 MHz, CDC13) δ 7.27 (d, J= 8.4 Hz, 1H), 6.91 (d, J= 8.6 Hz, 1H), 6.86 (s, 1H), 6.47 (t, J= 74.3 Hz, 1H), 2.91 (dd, J = 8.7, 3.6 Hz, 2H), 2.51 (dd, J= 19.1, 8.8 Hz, 1H), 2.43 - 2.38 (m, 1H), 2.27 (t, J= 10.8 Hz, 1H), 2.05 (ddd, J= 23.9, 13.4, 5.9 Hz, 2H), 1.97 (d, J= 10.5 Hz, 1H), 1.69 - 1.40 (m, 7H), 0.91 (s, 3H). 13C NMR (151 MHz, CDC13) δ 220.57 (s), 149.20 (t, J= 2.6 Hz), 138.46 (s), 137.01 (s), 126.71 (s), 119.68 (s), 116.86 (s), 1 16.07 (t, J= 259.1 Hz), 50.42 (s), 47.91 (s), 44.05 (s), 38.06 (s), 35.82 (s), 31.54 (s), 29.43 (s), 26.29 (s), 25.79 (s), 21.57 (s), 13.81 (s). 19F NMR (376 MHz, CDC13) δ -82.49 (d, J= 74.3 Hz).

Reference： [1]Patent: WO2014/107380,2014,A1 .Location in patent: Paragraph 0076-0078; 00154-00157

11
[ 1885-46-7 ]
3-acetylphenylboronic acid [ No CAS ]
[ 101975-23-9 ]

Yield	Reaction Conditions	Operation in experiment
46%		General procedure: [a] Reactions were performed on a 0.1 mmol scale to determine yields by F NMR spectroscopy with PhCF3 as an internal standard added after the reaction. Isolated yields are shown in parenthesis for reactions performed on a 0.5 mmol scale.; To a 20 mL vial was added the aryl boronic acid (0.5 mmol, 1.0 equiv), acetonitrile (1.0 mL) and 30% aqueous hydrogen peroxide (500 mu). The reaction was stirred at room temperature for 15 minutes. After this time, 12M KOH (500 muKappa) was added carefully. Note: the addition of KOH causes rapid decomposition of the unreacted hydrogen peroxide. This reaction is exothermic, and gas is evolved. The resulting mixture was stirred rapidly at room temperature, and HCF2OTf (210 mu^, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with 0 (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgSC , concentrated, and purified by silica gel chromatography.

Reference： [1]Patent: WO2014/107380,2014,A1 .Location in patent: Paragraph 00157-00162

12
[ 1885-46-7 ]
[ 41492-05-1 ]
[ 1454765-32-2 ]

Yield	Reaction Conditions	Operation in experiment
62%		General procedure: [a] Reactions were performed on a 0.5 mmol scale to determine yields by 19F NMR spectroscopy with PI1CF3 as an internal standard added after the reaction.; Note: The hydroxylation reaction was set-up under an inert atmosphere according to the literature procedure. [Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 10694.] To an oven-dried 4 mL vial was added Pd2(dba)3 (9.2 mg, .010 mmol, 4.0 mol % Pd), 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (lBu- XPhos, 17.0 mg, .040 mmol, 8.0 mol %), KOH (1.0-3.0 equiv), degassed H20 (150-300 mu) and dioxane (250-500 muKappa). The aryl halide (0.5 mmol, 1.0 equiv) was added (solid aryl halides were weighed into the vial prior to adding solvent, and liquid aryl bromides were added neat by syringe after the addition of solvent). The vial was sealed with a Teflon-lined cap and heated at 100 C for 1-18 h. The solution was allowed to cool, and the reaction was diluted with acetonitrile (500-750 mu, such that the total volume of dioxane and acetonitrile is 1.0 mL) and 6M KOH (700-850 mu, such that the final aqueous solvent volume is 1.0 mL). The resulting mixture was stirred rapidly at room temperature, and HCF20Tf (210 mu, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with ]0 (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgS04, concentrated, and purified by silica gel chromatography.

Reference： [1]Patent: WO2014/107380,2014,A1 .Location in patent: Paragraph 00166-00167

13
[ 1885-46-7 ]
[ 1638-22-8 ]
[ 1454765-32-2 ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium hydroxide; In water; acetonitrile; at 20℃; for 0.0333333h;	General procedure: Into a 20 mL vial was placed the phenol or thiophenols (0.5 mmol, 1.0 equiv), acetonitrile (1.0 mL) and 6M aqueous KOH (1.0 mL). The mixture was stirred rapidly at room temperature and HCF2OTf (210 μ, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with FLO (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgSC , concentrated, and purified by silica gel chromatography.; The reaction was performed according to the general procedure for the difluoromethylation of phenols on a 0.5 mmol scale. The product was purified by silica gel chromatography to give 2b as a clear oil (68 mg, 68% yield). XH NMR (600 MHz, CDC13) δ 7.16 (d, J= 8.2 Hz, 2H), 7.03 (d, J= 8.0 Hz, 2H), 6.47 (t, J= 4.3 Hz, 1H), 2.59 (t, J= 7.7 Hz, 2H), 1.62 - 1.54 (m, 2H), 1.35 (dd, J= 14.8, 7.4 Hz, 2H), 0.93 (t, J= 7.3 Hz, 3H). 13C MR (151 MHz, CDC13) δ 149.19 (t, J= 2.8 Hz), 140.17 (s), 129.61 (s), 1 19.45 (s), 1 16.15 (t, J= 258.9 Hz), 34.89 (s), 33.61 (s), 22.25 (s), 13.89 (s). 19F NMR (376 MHz, CDC13) δ -82.61 (d, J= 74.3 Hz).

Reference： [1]Patent: WO2014/107380,2014,A1 .Location in patent: Paragraph 0078-0082; 0083-0086

14
[ 1885-46-7 ]
[ 1638-22-8 ]
[ 1215100-19-8 ]
[ 1454765-32-2 ]

Yield	Reaction Conditions	Operation in experiment
12%; 75%	With potassium hydroxide; In water; acetonitrile; at 20℃; for 0.0333333h;	General procedure: Into a 20 mL vial was placed the phenol or thiophenols (0.5 mmol, 1.0 equiv), acetonitrile (1.0 mL) and 6M aqueous KOH (1.0 mL). The mixture was stirred rapidly at room temperature and HCF2OTf (210 μ, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with FLO (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgSC , concentrated, and purified by silica gel chromatography.

Reference： [1]Patent: WO2014/107380,2014,A1 .Location in patent: Paragraph 0076; 0078

15
[ 1885-46-7 ]
[ 2142-63-4 ]
[ 101975-23-9 ]

Yield	Reaction Conditions	Operation in experiment
71%		General procedure: [a] Reactions were performed on a 0.5 mmol scale to determine yields by 19F NMR spectroscopy with PI1CF3 as an internal standard added after the reaction.; Note: The hydroxylation reaction was set-up under an inert atmosphere according to the literature procedure. [Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 10694.] To an oven-dried 4 mL vial was added Pd2(dba)3 (9.2 mg, .010 mmol, 4.0 mol % Pd), 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (lBu- XPhos, 17.0 mg, .040 mmol, 8.0 mol %), KOH (1.0-3.0 equiv), degassed H20 (150-300 mu) and dioxane (250-500 muKappa). The aryl halide (0.5 mmol, 1.0 equiv) was added (solid aryl halides were weighed into the vial prior to adding solvent, and liquid aryl bromides were added neat by syringe after the addition of solvent). The vial was sealed with a Teflon-lined cap and heated at 100 C for 1-18 h. The solution was allowed to cool, and the reaction was diluted with acetonitrile (500-750 mu, such that the total volume of dioxane and acetonitrile is 1.0 mL) and 6M KOH (700-850 mu, such that the final aqueous solvent volume is 1.0 mL). The resulting mixture was stirred rapidly at room temperature, and HCF20Tf (210 mu, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with ]0 (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgS04, concentrated, and purified by silica gel chromatography.

Reference： [1]Patent: WO2014/107380,2014,A1 .Location in patent: Paragraph 00166-00167

16
[ 1885-46-7 ]
[ 104-88-1 ]
[ 73960-07-3 ]

Yield	Reaction Conditions	Operation in experiment
49%		General procedure: [a] Reactions were performed on a 0.5 mmol scale to determine yields by 19F NMR spectroscopy with PI1CF3 as an internal standard added after the reaction.; Note: The hydroxylation reaction was set-up under an inert atmosphere according to the literature procedure. [Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 10694.] To an oven-dried 4 mL vial was added Pd2(dba)3 (9.2 mg, .010 mmol, 4.0 mol % Pd), 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (lBu- XPhos, 17.0 mg, .040 mmol, 8.0 mol %), KOH (1.0-3.0 equiv), degassed H20 (150-300 mu) and dioxane (250-500 muKappa). The aryl halide (0.5 mmol, 1.0 equiv) was added (solid aryl halides were weighed into the vial prior to adding solvent, and liquid aryl bromides were added neat by syringe after the addition of solvent). The vial was sealed with a Teflon-lined cap and heated at 100 C for 1-18 h. The solution was allowed to cool, and the reaction was diluted with acetonitrile (500-750 mu, such that the total volume of dioxane and acetonitrile is 1.0 mL) and 6M KOH (700-850 mu, such that the final aqueous solvent volume is 1.0 mL). The resulting mixture was stirred rapidly at room temperature, and HCF20Tf (210 mu, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with ]0 (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgS04, concentrated, and purified by silica gel chromatography.

Reference： [1]Patent: WO2014/107380,2014,A1 .Location in patent: Paragraph 00166-00167

17
[ 1885-46-7 ]
[ 134-62-3 ]
[ 1454765-40-2 ]

Yield	Reaction Conditions	Operation in experiment
50%		General procedure: [a] Reactions were performed on a 0.1 mmol scale to determine yields by 19F NMR spectroscopy with PI1CF3 as an internal standard added after the reaction. Isolated yields are shown in parenthesis for reactions performed on a 0.5 mmol scale. ; Note: The borylation reaction was set-up under an inert atmosphere. To an oven- dried 20 mL vial was added arene (0.5 mmol, 1.0 equiv), and 1.0 mL of a stock solution containing 0.5 mol % [Ir(COD)OMe]2, 1.0 mol % 4,4'-di-tert-butyl bipyridine (dtbpy), and 0.75 equiv of Beta2Rho. The vial was sealed with a Teflon-lined cap and heated at 80 C for 18 h. The solution was allowed to cool, and the volatile components were removed in vacuo. To the crude ArBPin was added acetonitrile (1.0 mL) and 30% aqueous hydrogen peroxide (500 muKappa). The reaction was stirred at room temperature for 15 minutes. After this time, 12M KOH (500 muKappa) was added carefully. Note: the addition of KOH causes rapid decomposition of the unreacted hydrogen peroxide. This reaction is exothermic, and gas is evolved. The resulting mixture was stirred rapidly at room temperature, and HCF2OTf (210 mu^, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with 0 (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgS04, concentrated, and purified by silica gel chromatography.; The reaction was performed according to the general procedure for the difluoromethoxylation of arenes on a 0.5 mmol scale. The product was purified by silica gel chromatography to give 8a as a white solid (64 mg, 50% yield). NMR (600 MHz, CDC13) delta 7.01 (s, 1H), 6.94 (s, 1H), 6.91 (s, 1H), 6.49 (t, J = 73.8 Hz, 1H), 3.52 (d, J= 5.6 Hz, 2H), 3.22 (d, J= 5.5 Hz, 2H), 2.36 (s, 3H), 1.23 (s, 3H), 1.10 (s, 3H). 13C NMR (151 MHz, CDC13) delta 169.99 (s), 150.94 (t, J= 2.7 Hz), 140.63 (s), 138.78 (s), 123.92 (s), 120.74 (s), 115.77 (t, J = 260.0 Hz), 114.34 (s), 43.23 (s), 39.25 (s), 21.27 (s), 14.10 (s), 12.79 (s). 19F NMR (376 MHz, CDC13) delta -83.16 (d, J = 73.8 Hz).

Reference： [1]Patent: WO2014/107380,2014,A1 .Location in patent: Paragraph 00167-00172

18
[ 120-47-8 ]
[ 1885-46-7 ]
[ 773134-78-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium hydroxide; In water; acetonitrile; at 20℃; for 0.0333333h;	General procedure: Into a 20 mL vial was placed the phenol or thiophenols (0.5 mmol, 1.0 equiv), acetonitrile (1.0 mL) and 6M aqueous KOH (1.0 mL). The mixture was stirred rapidly at room temperature and HCF2OTf (210 μ, 1.5 mmol, 3.0 equiv) was added at once. Note: the reactions are exothermic. The mixture was stirred vigorously for 2 minutes. The reaction was diluted with FLO (8 mL) and extracted with ether (2 x 8 mL). The combined organic layers were dried over MgSC , concentrated, and purified by silica gel chromatography.; The reaction was performed according to the general procedure for the difluoromethylation of phenols on a 0.5 mmol scale. The product was purified by silica gel chromatography to give 2a as a clear oil (98 mg, 90% yield). XH NMR (500 MHz, CDC13) δ 8.06 (d, J= 8.7 Hz, 2H), 7.15 (d, J= 8.5 Hz, 2H), 6.59 (t, J= 73.2 Hz, 1H), 4.37 (q, J= 7.1 Hz, 2H), 1.39 (t, J= 7.1 Hz, 3H). ljC NMR (151 MHz, CDC13) δ 165.66 (s), 154.61 (t, J (s), 1 18.59 (s), 115.40 (t, J= 261.0 Hz), 61.13 (s), 14.29 (s). 19F NMR (376 MHz, CDC13) δ -84.25 (d, J= 73.2 Hz).

Reference： [1]Patent: WO2014/107380,2014,A1 .Location in patent: Paragraph 0078-0082

19
[ 1885-46-7 ]
[ 767-00-0 ]
[ 332-25-2 ]

Reference： [1]ChemMedChem,2015,vol. 10,p. 715 - 726

20
[ 1885-46-7 ]
(4-acetylphenyl)(mesityl)iodonium trifluoromethanesulfonate trifluoromethanesulfonate [ No CAS ]
[ 709-63-7 ]