* 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.
Sodium hydroxide (0.4 g, 0.01 mol) and phenol (0.94 g, 0.01 mol) were added to anhydrous methanol. After completesolution had occurred, the solution was cooled in an ice bath and 4 (2.67 g, 0.01 mol) was added dropwise by syringe. PhCF3 (0.58 g, 0.004 mol) was added and 19F spectral analysis showed that the solution contained a mixture of CH3OCF2H (46percent) and PhOCF2H= (11percent) [19F NMR (CDCl3) (ppm): δ = -80.9 (d, 2JHF = 75 Hz) [Lit [51]:2JHF = 73.9 Hz]].
Reference：
[1] Journal of Fluorine Chemistry, 2011, vol. 132, # 10, p. 815 - 828
2
[ 65094-22-6 ]
[ 108-95-2 ]
[ 458-92-4 ]
Reference：
[1] Tetrahedron, 2009, vol. 65, # 27, p. 5278 - 5283
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 797 - 804
3
[ 75-61-6 ]
[ 122-52-1 ]
[ 65094-22-6 ]
Yield
Reaction Conditions
Operation in experiment
96%
for 20 h; Heating / reflux
EXAMPLE 4 Synthesis of Diethyl(bromodifluoromethyl)phosphonate Dibromodifluoromethane (209.8 g, 1 mol) is added to a magnetically stirred solution of triethyl phosphite (153.5 g, 0.925 mol) in anhydrous ether (450 ml) under a nitrogen atmosphere. After the addition, the reaction is allowed to warm to room temperature before being refluxed for 20 hours. The volatiles are removed in vacuo, and the product is purified by distillation (b.pt. 50-52° C., 1 mm/Hg) to yield diethyl(bromodifluoromethyl) phosphonate as a colorless liquid (256.3 g, 96percent); 1H NMR (CDCl3): 4.35 (m, 4H), 1.35 (m, 6H). 13C NMR (CDCl3): 122.9, 119.8, 118.6, 115.4, 114.2, 111.1, 66.59, 66.50, 16.56, 16.48.
95%
for 24 h; Inert atmosphere; Reflux
General procedure: A three-neck 1 l flask, fitted with a septum, stir bar, and a water condenser with a nitrogen inlet, was cooled in an ice bath. Dry ether (300 ml) and 99 g (0.6 mol) of triethylphosphite was added to the cooled flask, followed by addition (via syringe) of 134 g (0.64 mol) of dibromodifluoromethane 1. The ice bath was removed and the reaction mixture refluxed for 24 h, followed by removal of the ether, excess 1 and ethyl bromide via rotary evaporation at reduced pressure. The remaining clear liquid was distilled under vacuum through a 6-in. Vigreaux column to give 150 g (95percent) of diethyl bromodifluoromethylphosphonate (bp 99-102 °C/16 mm Hg). 19F NMR(CDCl3) (ppm): δ = -61.9 (d, 2JPF = 92 Hz); 31P NMR (CDCl3) (ppm): δ = -1.2 (t, 2JPF = 93 Hz); 13C NMR (CDCl3) (ppm): δ = 116.8 (td, 1JCF = 330 Hz, 1JCP = 238 Hz), d = 66.3 (2JCP = 7.4 Hz), d = 16.4 (d, 3JCP = 5.88 Hz); 1H NMR (CDCl3)(ppm): δ = 4.41 (qd, 3JHH = 7.0 Hz, 3JHP = 8.5 Hz), d = 1.42 (t, 3JHH = 7.0 Hz). GC-MS, m/z (relative intensity): 268 (0.2), 266 (0.2), 137 (83), 109 (100), 93 (35), 91 (27), 81 (86), 65 (41), 29 (66): IR (P=O) 1285 cm-1: Anal. Calcd. for C5H10O3PCF2Br: C, 22.47percent; H,3.75percent. Found C, 22.34percent; H, 3.80percent.
93%
at 4 - 20℃; Heating / reflux
Diethyl (bromodifluoromethyl)phosphonate (C): A solution of triethyl phosphite (95.50 g, 575 mmol) in 300 mL of anhydrous diethyl ether was cooled, EPO <DP n="66"/>under a nitrogen atmosphere, to 4 0C before addition of dibromodifluoromethane (144.72 g, 690 mmol). The mixture was allowed to warm to room temperature and stirred overnight, then heated to reflux for 24 hours. Ether was removed by rotary evaporation, and the resultant liquid was distilled to afford 142.75 g (93percent) of a clear colorless liquid: bp 144-145 0C (25 mmHg) [ lit. bp 97-98 0C (19 mmHg) (This material is commercially available from Lancaster and Aldrich).
Reference：
[1] Journal of Organometallic Chemistry, 1997, vol. 529, # 1-2, p. 267 - 278
[2] Phosphorus, Sulfur and Silicon and Related Elements, 1997, vol. 122, p. 247 - 259
[3] Patent: US2004/225146, 2004, A1, . Location in patent: Page 4
[4] Journal of Fluorine Chemistry, 2011, vol. 132, # 10, p. 815 - 828
[5] Patent: WO2006/78698, 2006, A1, . Location in patent: Page/Page column 64-65
[6] Journal of Organic Chemistry, 1986, vol. 51, # 25, p. 4768 - 4779
[7] Tetrahedron Letters, 1989, vol. 30, # 50, p. 7013 - 7016
[8] Journal of Fluorine Chemistry, 1989, vol. 44, p. 275 - 284
[9] Journal of Fluorine Chemistry, 2007, vol. 128, # 3, p. 174 - 178
[10] Patent: JP5664635, 2015, B2, . Location in patent: Paragraph 0128; 0129
4
[ 353-59-3 ]
[ 122-52-1 ]
[ 65094-22-6 ]
Yield
Reaction Conditions
Operation in experiment
20%
at 120℃; for 240 h; Autoclave
General procedure: Triethyl phosphite (10.4 g, 0.06 mol) and CFCl3 (10.3 g, 0.075 mol) were placed into a 128 ml Hastelloy C autoclave equipped with a glass liner and magnetic stir bar. The autoclave was sealed and heated to 120 °C for 10 days during which time the pressure in the autoclave remained nearly constant at 59 psig.After cooling, the autoclave was opened and the residue concentrated on a steam bath and distilled under vacuum. After distillation of the unreacted triethyl phosphite, a distillate fraction was obtained (bp = 96-99 °C/8 mm Hg) which contained 15 in approximately 30percent yield. Diethyl ethylphosphonate, diethyl phosphite and triethyl phosphate were also identified as contaminants by NMR spectral data. 19F NMR (CDCl3) (ppm): δ = -73.4 (d, 2JPF = 88 Hz); 31P NMR (CDCl3) (ppm): δ = 2.4 (d, 2JPF = 88 Hz); 13C NMR (CDCl3) (ppm): δ = 113.4 (dd, 1JCF = 316 Hz, 1JCP = 222 Hz), d = 66.6 (d, 2JCP = 7.3 Hz), d = 16.4 (d, 3JCP = 4.4 Hz); 1H NMR (CDCl3) (ppm): δ = 4.40 (apparent pentet, J = 7.0 Hz), d = 1.42 (t, 3JHH = 7.0 Hz),: IR (P=O) 1277 cm-1.
Reference：
[1] Journal of Fluorine Chemistry, 2011, vol. 132, # 10, p. 815 - 828
5
[ 180627-08-1 ]
[ 65094-22-6 ]
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 18, p. 6401 - 6403
6
[ 753-66-2 ]
[ 122-52-1 ]
[ 65094-22-6 ]
[ 80077-69-6 ]
Reference：
[1] Journal of Fluorine Chemistry, 2011, vol. 132, # 10, p. 815 - 828
7
[ 58201-66-4 ]
[ 122-52-1 ]
[ 65094-22-6 ]
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 20, p. 3616 - 3618
8
[ 58201-66-4 ]
[ 122-52-1 ]
[ 65094-22-6 ]
[ 603-35-0 ]
Reference：
[1] Journal of Fluorine Chemistry, 2008, vol. 129, # 7, p. 583 - 589
9
[ 80084-30-6 ]
[ 65094-22-6 ]
Reference：
[1] Journal of Fluorine Chemistry, 1981, vol. 18, p. 197 - 202
10
[ 82845-20-3 ]
[ 65094-22-6 ]
Reference：
[1] Chemistry Letters, 1982, p. 755 - 758
11
[ 58201-66-4 ]
[ 122-52-1 ]
[ 74-96-4 ]
[ 65094-22-6 ]
[ 603-35-0 ]
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 20, p. 3616 - 3618
12
[ 75-44-5 ]
[ 82845-20-3 ]
[ 1478-53-1 ]
[ 65094-22-6 ]
[ 113161-60-7 ]
[ 97480-49-4 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 7, p. 1523 - 1527
With potassium hydroxide In water; acetonitrile at -78 - 20℃; for 0.333333 h;
4-Hydroxybenzaldehyde (1.00 g, 8.20 mmol),KOH (9.20 g, 164 mmol),CH3CN-H2O (50 mL, 1: 1) into a sealed tube,Diethyl bromofluoromethylphosphonate (3 mL, 16.40 mmol) was slowly added dropwise at -78 ° C,Then warmed to room temperature,After 20 min of reaction at room temperature,TLC detection reaction was completed,Saturated NaHCO3 solution was added,Extraction with ethyl acetate,The combined organic phase,Dried over anhydrous Na2SO4,filter,concentrate,Column chromatography (EA: PE = 1: 70),1.01 g of solid are obtained,Yield 72percent.
Reference：
[1] Patent: CN107365248, 2017, A, . Location in patent: Paragraph 0027; 0028
With potassium fluoride In acetonitrile at 20℃; for 12 h; Schlenk technique; Inert atmosphere; Green chemistry
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added Imidazoles/Pyrazoles (0.4 mmol, 1.0 equiv) and KF (46.4 mg, 2.0 equiv) under Ar, followed by MeCN (3 mL) with stirring. 2 (0.40 mmol, 1.0 equiv) were added subsequently. After stirring for 12 h, the reaction mixture was concentrated. The residue was purified with silica gel chromatography to provide pure product.
Stage #1: diethyl (bromodifluoromethyl)phosphonate With zinc In N,N-dimethyl acetamide at 55℃; for 3.5h; Inert atmosphere; Sonication;
Stage #2: With copper(I) bromide In N,N-dimethyl acetamide at 23℃; for 0.5h; Inert atmosphere;
Stage #3: 1,4-bromoiodobenzene In N,N-dimethyl acetamide at 23℃; for 20h; Inert atmosphere;
70%
Stage #1: diethyl (bromodifluoromethyl)phosphonate With cadmium In N,N-dimethyl-formamide at 20℃; for 2h;
Stage #2: 1,4-bromoiodobenzene With copper(l) chloride In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere;
4.1.1 Representative general procedure for the preparation of diethyl α,α-difluoro benzylic phosphonate (7): diethyl α,α-difluoro-4-nitrobenzylphosphonate (7a)
General procedure: A 100-mL flask fitted with a stir bar and a condenser topped with a nitrogen inlet was charged with 2.67g (10.0mmol) of diethyl bromodifluoromethylphosphonate, 1.25g (11mmol) of Cd and 10mL of dry DMF. The mixture was stirred at room temperature for 2h. 19F NMR analysis revealed the formation of (EtO)2P(O)CF2CdX (two doublets at -122.8 and -123.6ppm with J=83Hz, the ration of the two doublets was 1:1) in 91% NMR yield based on starting phosphonate (EtO)2P(O)CF2Br. The unreacted Cd was removed by filtration through a medium frit funnel under a nitrogen atmosphere and the filtrate was treated with 0.69g (7.0mmol) of CuCl and 1.5g (6.0mmol) of 4-nitroiodobenzene at room temperature for 3h. 100mL of ether was added to the reaction mixture and the precipitated solids were removed by filtration and washed with 50mL of ether. The combined ether solutions were washed with NH4Cl(aq) and H2O, dried over Na2SO4, and evaporated to give a residue, which was further purified by silica gel column chromatography. Eluent (CH2Cl2/EtOAc 9:1) gave 1.55g (84%) of 7a, mp 47-48°C.
General procedure: A 100-mL flask fitted with a stir bar and a condenser topped with a nitrogen inlet was charged with 2.67g (10.0mmol) of diethyl bromodifluoromethylphosphonate, 1.25g (11mmol) of Cd and 10mL of dry DMF. The mixture was stirred at room temperature for 2h. 19F NMR analysis revealed the formation of (EtO)2P(O)CF2CdX (two doublets at -122.8 and -123.6ppm with J=83Hz, the ration of the two doublets was 1:1) in 91% NMR yield based on starting phosphonate (EtO)2P(O)CF2Br. The unreacted Cd was removed by filtration through a medium frit funnel under a nitrogen atmosphere and the filtrate was treated with 0.69g (7.0mmol) of CuCl and 1.5g (6.0mmol) of 4-nitroiodobenzene at room temperature for 3h. 100mL of ether was added to the reaction mixture and the precipitated solids were removed by filtration and washed with 50mL of ether. The combined ether solutions were washed with NH4Cl(aq) and H2O, dried over Na2SO4, and evaporated to give a residue, which was further purified by silica gel column chromatography. Eluent (CH2Cl2/EtOAc 9:1) gave 1.55g (84%) of 7a, mp 47-48C.
diethyl (1,1-difluoropenta-2,3-dienyl)phosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
Stage #1: diethyl (bromodifluoromethyl)phosphonate With copper(I) bromide; zinc In N,N-dimethyl-formamide
Stage #2: 1-methylprop-2-ynyl p-toluenesulfonate With copper(I) bromide In N,N-dimethyl-formamide at 20℃; for 12h;
To a solution of diethyl bromodifluoromethylphosphonate (4.8 g) in N,N-dimethylacetamide (9 ml) was added zinc powder (1.17 g) under a nitrogen stream and the reaction mixture was stirred at room temperature for 2 hrs. Insoluble material was filtered off and copper(I) bromide (2.58 g) was added to the filtrate under a nitrogen stream. After stirring the reaction mixture at room temperature for 30 min, tert-butyl 4-iodophenylcarbamate (2.87 g) was added, and the mixture was stirred overnight. Ethyl acetate was added to the reaction mixture and the insoluble material was filtered off. The filtrate was concentrated, introduced into preparative HPLC and purified. Ethyl acetate was added and 4N hydrochloric acid ethyl acetate solution (3 ml) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated and crystals were collected by filtration to give diethyl alpha,alpha-difluoro-4-amino-benzylphosphonate hydrochloride (250 mg, yield 10%).
Stage #1: diethyl (bromodifluoromethyl)phosphonate With zinc In ISOPROPYLAMIDE at 20 - 60℃; for 3h;
Stage #2: With copper(I) bromide In ISOPROPYLAMIDE at 20℃; for 0.5h;
Stage #3: 2-chloro-4-methyl-1-iodobenzene In ISOPROPYLAMIDE at 20℃; for 18h;
41
To a stirred suspension of activated Zn dust (25.3 g, 0.39 mol) in dry DMA (150 mL) was slowly added a solution of diethyl (bromodifluoromethyl)phosphonate (103.6 g, 0.39 mmol) in DMA (75 mL) in a 1-L flask. During the addition, an exothermic reaction occurred. The addition was controlled so that the internal temperature was maintained at 50-60 0C. After the addition was completed, the solution was stirred at room temperature for an additional 3 hours, and then CuBr (55.7 g, 0.39 mol) was added in one portion. The mixture was stirred at the same temperature for 30 minutes to give the organocopper reagent. Methyl 3-chloro-4-iodobenzoate (49 g, 0.194 mol) in DMA (65 mL) was added dropwise at room temperature (exothermic reaction). After being stirred > 18 hours at room temperature, the mixture was portioned between water and ether. The biphasic mixture was passed through Celite and extracted with ether. The extract was washed with brine and dried over MgSO4. The ether was removed by rotary evaporation, and the residue purified by silica chromatography (1:9 ethyl acetate/hexanes Yield 38g, 62%, of clear yellow oil. MS (M+H)+ 313.
[(2-Bromo-4-methyl-phenyl)-difluoro-methyl]-phosphonic acid diethyl ester: A solution of (bromo-difluoro-methyl)-phosphonic acid diethyl ester (25.00 g, 93.6 mmol) in N,N-dimethylacetamide (50 mL) was added drop wise into a suspension of activated zinc (6.12 g, 93.6 mmol) under Argon. The reaction was initiated by heating and kept under 50 C. After the mixture was stirred for 3 h, copper (I) bromide (13.43 g, 93.6 mmol) was added and stirred for 1 h. A solution of 2-bromo-l-iodo-4-methyl-benzene (11.88 g, 40.0 mmol) in N,N-dimethylacetamide (25 mL) was added slowly to the reaction mixture. The resulting suspension was then stirred at room temp for 18 h. Water (100 mL) was added to the reaction mixture and the solution filtered through celite. The filtrate was diluted with EtOAc (250 mL) and organic layer was washed with H20 (50 mL), NaHC03 (5%, 50 mL) and H20 (50 mL). The solvent was removed and the residue was purified by column chromatography on silica gel, eluting with hexanes/EtOAc (4:1) to provide a colorless oil (11.75 g, 82%): .H NMR (300 MHz, CDC13) 8 7.51 (d, 1H), 7.49 (s, 1H), 7.19 (d, 1H), 4.26 (m, 4H), 2.36 (s, 3H), 1.48 (s, 9H), 1.37 (m, 6 H).
63%
To activated Zn (1.2g, 19mmol) in DMA (7mL) was added bromodifluoromethyldiethyl- phosphonate (5.0g, 19mmol) in DMA (7mL). The resulting mixture was stirred at 45C for 3 hours, after which copper(I) bromide (2.7g, 19mmol) was added and stirring was continued for 0.5 hours at room temperature. 3-Bromo-4-iodotoluene (2.8g, 9.4mmol) was then added and the mixture was sonicated at room temperature for 12 hours. The reaction mixture was partitioned between ether and H2O, filtered through Celite, and the organic layer was dried over MgSO4 and concentrated in vacuo to yield 2.1 g (63%) of 27 as a clear, colorless oil;1H NMR (300 MHz, CDCl3) delta 7.51 (d, J = 6 Hz, 1 H), 7.27 (s, 1 H), 7.20 (d, J= 7.5 Hz, 1 H), 4.27 (m, 4 H), 1.36 (t, J = 8.1 Hz)
(1,1-difluorohexa-2,3-dienyl)phosphonic acid diethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
Stage #1: diethyl (bromodifluoromethyl)phosphonate With zinc In N,N-dimethyl-formamide at 20 - 60℃; Inert atmosphere;
Stage #2: With copper(I) bromide In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere;
Stage #3: 1-methylprop-2-ynyl p-toluenesulfonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
3.1. Typical experimental procedure for the synthesis of 1
General procedure: Under N2 atmosphere, to a stirred suspension of Zn dust (1.3 g, 20 mmol) in dry DMF (10 mL) was added slowly a solution of BrCF2PO(OEt)2 (5.34 g, 20 mmol) in DMF (10 mL). The addition was controlled so that the internal temperature was maintained at 50-60 °C. After addition was completed, the solution was stirred at room temperature for an additional 3 h, then CuBr (2.87 g, 20 mmol) was added in one portion. The mixture was stirred at the same temperature for 30 min to give organocopper reagent in DMF. Propargylic acetate or tosylate (12 mmol) in dry DMF (8 mL) was added dropwise at room temperature. After the mixture was stirred at room temperature for 12 h, water was added to quench the reaction. The biphasic mixture was passed through Celite and extracted with Et2O. The extracts were washed with brine, dried over Na2SO4 and evaporated in vacuum. The residue was chromatographed on silica gel using petroleum ether/ethyl acetate as eluent to give the corresponding product 1.
Sodium hydroxide (0.4 g, 0.01 mol) and phenol (0.94 g, 0.01 mol) were added to anhydrous methanol. After completesolution had occurred, the solution was cooled in an ice bath and 4 (2.67 g, 0.01 mol) was added dropwise by syringe. PhCF3 (0.58 g, 0.004 mol) was added and 19F spectral analysis showed that the solution contained a mixture of CH3OCF2H (46%) and PhOCF2H= (11%) [19F NMR (CDCl3) (ppm): delta = -80.9 (d, 2JHF = 75 Hz) [Lit [51]:2JHF = 73.9 Hz]].
Stage #1: diethyl (bromodifluoromethyl)phosphonate With zinc In 1,4-dioxane at 60℃; for 3h; Inert atmosphere;
Stage #2: With copper(l) iodide; 1,10-Phenanthroline In 1,4-dioxane at 20℃; for 0.5h; Inert atmosphere;
Stage #3: methyl 2-iodo-4-(trifluoromethyl)benzoate In 1,4-dioxane at 60℃; for 48h; Inert atmosphere;
With water; potassium hydroxide; In acetonitrile; at 0 - 20℃; for 10h;
To a solution of 4-bromophenol (2.50 g, 14.5 mmol) in acetonitrile (100 mL) were added a solution of KOH (16.2 g, 289 mmol) in H20 (20 mL), and diethyl (bromo-difluoromethyl)phosphonate (10.3 mL, 57.8 mmol), at 0C. The reaction mixture was stirred at room temperature for 10 h, then diluted with H2O (100 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was separated, washed with H2O (3 x 200 mL) and brine (200 mL), then dried over anhydrous Na2S04 and concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 2-5% EtOAc in hexanes) to afford the title compound (2.00 g, 62%) as a colourless oil. 6n (400 MHz, CDCb) 6.46 (t, J12 Hz, 1H), 7.00 (d, 8.3 Hz, 2H), 7.46 (d, 8.8 Hz, 2H).
Example 17 1-(5-(4-(Difluoromethoxy)phenyl)pyrazin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (39) To a stirred solution of 4-bromophenol (5 g, 28.90 mmol) in acetonitrile (350 mL) was added a solution of KOH (32.5 g, 580.35 mmol) in H2O (350 mL) at 0 C., and the mixture was maintained for 5 min. To this mixture, diethyl(bromodifluoromethyl)phosphonate (9.25 mL, 52.02 mmol) was added slowly at same temperature over 15 min (exothermic reaction), and the mixture was allowed to stir at RT. After being stirred for 10 h at RT, the reaction mixture was diluted with EtOAc (100 mL), and the organic layer was separated. The organic layer was washed with H2O (40 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 5-10% EtOAc gradient in hexanes) afforded AM (3.0 g, 13.45 mmol, 46%).
Stage #1: diethyl (bromodifluoromethyl)phosphonate With cadmium In N,N-dimethyl-formamide at 20℃; for 2h;
Stage #2: 2-iodopyridine With copper(l) chloride In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere;
4.1.1 Representative general procedure for the preparation of diethyl α,α-difluoro benzylic phosphonate (7): diethyl α,α-difluoro-4-nitrobenzylphosphonate (7a)
General procedure: A 100-mL flask fitted with a stir bar and a condenser topped with a nitrogen inlet was charged with 2.67g (10.0mmol) of diethyl bromodifluoromethylphosphonate, 1.25g (11mmol) of Cd and 10mL of dry DMF. The mixture was stirred at room temperature for 2h. 19F NMR analysis revealed the formation of (EtO)2P(O)CF2CdX (two doublets at -122.8 and -123.6ppm with J=83Hz, the ration of the two doublets was 1:1) in 91% NMR yield based on starting phosphonate (EtO)2P(O)CF2Br. The unreacted Cd was removed by filtration through a medium frit funnel under a nitrogen atmosphere and the filtrate was treated with 0.69g (7.0mmol) of CuCl and 1.5g (6.0mmol) of 4-nitroiodobenzene at room temperature for 3h. 100mL of ether was added to the reaction mixture and the precipitated solids were removed by filtration and washed with 50mL of ether. The combined ether solutions were washed with NH4Cl(aq) and H2O, dried over Na2SO4, and evaporated to give a residue, which was further purified by silica gel column chromatography. Eluent (CH2Cl2/EtOAc 9:1) gave 1.55g (84%) of 7a, mp 47-48°C.
Stage #1: diethyl (bromodifluoromethyl)phosphonate With cadmium In N,N-dimethyl-formamide at 20℃; for 2h;
Stage #2: 2-iodobiphenyl With copper(l) chloride In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere;
4.1.1 Representative general procedure for the preparation of diethyl α,α-difluoro benzylic phosphonate (7): diethyl α,α-difluoro-4-nitrobenzylphosphonate (7a)
General procedure: A 100-mL flask fitted with a stir bar and a condenser topped with a nitrogen inlet was charged with 2.67g (10.0mmol) of diethyl bromodifluoromethylphosphonate, 1.25g (11mmol) of Cd and 10mL of dry DMF. The mixture was stirred at room temperature for 2h. 19F NMR analysis revealed the formation of (EtO)2P(O)CF2CdX (two doublets at -122.8 and -123.6ppm with J=83Hz, the ration of the two doublets was 1:1) in 91% NMR yield based on starting phosphonate (EtO)2P(O)CF2Br. The unreacted Cd was removed by filtration through a medium frit funnel under a nitrogen atmosphere and the filtrate was treated with 0.69g (7.0mmol) of CuCl and 1.5g (6.0mmol) of 4-nitroiodobenzene at room temperature for 3h. 100mL of ether was added to the reaction mixture and the precipitated solids were removed by filtration and washed with 50mL of ether. The combined ether solutions were washed with NH4Cl(aq) and H2O, dried over Na2SO4, and evaporated to give a residue, which was further purified by silica gel column chromatography. Eluent (CH2Cl2/EtOAc 9:1) gave 1.55g (84%) of 7a, mp 47-48°C.
1-(difluoromethoxy)-2-methyl-3-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7.5 g
With potassium carbonate In acetonitrile at 20℃; for 24h;
7.5 g
With potassium hydroxide In water; acetonitrile at 20℃; for 24h;
16.1 Reference Production Example 16 Step (1)
Reference Production Example 16 Step (1) A mixture of 7.17 g of 2-methyl-3-nitrophenol, 27 g of potassium hydroxide, 25 g of bromodifluoromethyl-diethylphosphonate, 100 mL of water, and 100 mL of acetonitrile was stirred at room temperature for 24 hours. After extraction with ethyl acetate, the organic layer was washed in turn with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 7.50 g of 1-difluoromethoxy-2-methyl-3-nitrobenzene. 1H-NMR (CDCl3) δ(ppm): 7.74 (1H, dd, J = 7.6, 1.8 Hz), 7.40-7.32 (2H, m), 6.56 (1H, t, J = 72.4 Hz), 2.46 (3H, s).
7.50 g
With potassium hydroxide In water; acetonitrile at 20℃; for 24h;
16.1
A mixture of 7.17 g of 2-methyl-3-nitrophenol, 27 g of potassium hydroxide, 25 g of bromodifluoromethyl-diethylphosphonate, 100 mL of water, and 100 mL of acetanilile was stirred at ambient temperature for 24 hr. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, dried by magnesium sulfate anhydride, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 7.50 g of 1-difluoromethoxy-2-methyl-3-nitrobenzene. (0819) 1-difluoromethoxy-2-methyl-3-nitrobenzene 1H-NMR (CDCl3) δ: 7.74 (1H, dd, J = 7.6, 1.8 Hz), 7.40-7.32 (2H, m), 6.56 (1H, t, J = 72.4 Hz), 2.46 (3H, s).
With potassium hydroxide In water; acetonitrile at -20 - 20℃; for 1.15h;
1- [2-(Difluoromethoxy)phenyllethan- 1-one
Potassium hydroxide (105 g, 1872 mmol) was suspended in a mixture of acetonitrile (200 mL) and water (200 mL) and cooled to approximately -20°C. 1-(2-Hydroxyphenyl)ethanone (11.28 mL, 93.7 mmol) was added dropwise, followed by diethyl [bromo(difluoro)methyl]phosphonate (33.27 mL, 187.3 mmol) over 15 minutes. The mixture was then allowed to warm to room temperature over 1 h. The mixture was extracted with ethyl acetate (3 x 200 mL), then the combined organic layers were washedwith brine (50 mL), dried over magnesium sulfate and concentrated under vacuum. The mixture was purified by flash chromatography to afford the title compound (16.0 g, 92%) as a colourless oil. Method B HPLC-MS: MH+ m/z 187, RT 1.77 minutes.
92%
With potassium hydroxide In water; acetonitrile at -20 - 20℃; for 1.25h;
1 1-[2-(Difluoromethoxy)phenyllethan-1-one
Potassium hydroxide (105 g, 1872 mmol) was suspended in a mixture of acetonitrile (200 mL) and water (200 mL) and cooled to approximately -20°C. l-(2- Hydroxyphenyl)ethanone (11.28 mL, 93.7 mmol) was added dropwise, followed by diethyl [bromo(difluoro)methyl]phosphonate (33.27 mL, 187.3 mmol) over 15 minutes. The mixture was then allowed to warm to room temperature over 1 hour. The mixture was extracted with ethyl acetate (3 x 200 mL), then the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated under vacuum. The mixture was purified by flash chromatography to afford the title compound (16.0 g, 92%) as a colourless oil. Method B HPLC-MS: MH+ mlz 187, RT 1.77 minutes
92%
With potassium hydroxide In water; acetonitrile at -20 - 20℃; for 1.25h;
1 INTERMEDIATE 1 1 -[2-(Difluoromethoxy)phenyll ethan- 1-one
INTERMEDIATE 1-[2-(Difluoromethoxy)phenyll ethan- 1-onePotassium hydroxide (105 g, 1872 mmol) was suspended in a mixture ofacetonitrile (200 mL) and water (200 mL) and cooled to approximately -20°C. 1-(2- Hydroxyphenyl)ethanone (11.28 mL, 93.7 mmol) was added dropwise, followed bydiethyl [bromo(difluoro)methyl]phosphonate (33.27 mL, 187.3 mmol) over 15 minutes. The mixture was then allowed to warm to room temperature over 1 h. The mixture was extracted with ethyl acetate (3 x 200 mL), then the combined organic layers were washedwith brine (50 mL), dried over magnesium sulfate and concentrated under vacuum. The mixture was purified by flash chromatography to afford the title compound (16.0 g, 92%) as a colourless oil. Method B HPLC-MS: MH+ m/z 187, RT 1.77 minutes.
92%
With potassium hydroxide In water; acetonitrile at -20 - 20℃; for 1.25h;
Intermediate 1 1-[2-(Difluoromethoxy)phenyl]ethan-1-one
Potassium hydroxide (105 g, 1872 mmol) was suspended in a mixture of acetonitrile (200 mL) and water (200 mL) and cooled to approximately -20° C. 1-(2-Hydroxyphenyl)ethanone (11.28 mL, 93.7 mmol) was added dropwise, followed by diethyl [bromo(difluoro)methyl]phosphonate (33.27 mL, 187.3 mmol) over 15 minutes. The mixture was then allowed to warm to room temperature over 1 hour. The mixture was extracted with ethyl acetate (3×200 mL), then the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated under vacuum. The mixture was purified by flash chromatography to afford the title compound (16.0 g, 92%) as a colourless oil. Method B HPLC-MS: MH+ m/z 187, RT 1.77 minutes.
2-chloro-6-(difluoromethoxy)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With water; potassium hydroxide; In acetonitrile; at 0℃;
To a 250 mL round-bottom flask was added <strong>[18362-30-6]2-chloro-6-hydroxybenzaldehyde</strong> 15a (6 g, 38.32 mmol, 1.0 equiv.) and CH3CN (200 mL), followed by the dropwise addition of potassium hydroxide (21.54 g, 383,89 rnmol, 10.0 equiv.) at 0 C. Water (20 mL) was then added, followed by the dropwise addition of diethyl (bromodifluoromethyl)phosphonate (16.38 g, 61.35 mmol, 1.6 equiv.) and the reaction mixture was stirred 30 min at 0 C. The resulting mixture was quenched with H2O (100 mL) and extracted with ethyl acetate (300 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product (10 mL) was purified by Flash-Prep- HPLC using the following conditions: Column, silica gel; mobile phase, eiuting with PE:EtOAc = 100:0 to 87: 13 over 14 min; Detector, UV 254 nm to provide 2-chloro-6- (difluoromethoxy)benzaldehyde 15b (5.4 g, 68%) as a yellow oil.
53%
To <strong>[18362-30-6]2-chloro-6-hydroxy-benzaldehyde</strong> (20 g, 128.2 mmol) in MeCN (150 mL) was added an aqueous solution of potassium hydroxide (71.7 g, 1282 mmol) in water (50 mL) at 0C and the reaction mixture was stirred at 0C for 10 minutes. Diethyl (bromodifluoromethyl) phosphonate (36.4 mL, 205.1 mmol) was added at 0C. The reaction mixture was stirred at 0C for 30 minutes. After completion of reaction (monitored by TLC), the reaction mixture was poured into water (500 mL). The aqueous layer was extracted with ethyl acetate (1 L X 2). The organic layer was washed with water (500 mL), brine (500 mL) and dried over anhydrous sodium sulphate. The organic layer was evaporated underreduced pressure to yield the crude product which was purified by column chromatography (Si02, 5% EtOAc in hexane) yielding the title compound (13.9g, 53%) as a yellow oil. 1H NMR (400 MHz, CDC13) oe 10.46 (s, 1H), 7.49 (t, J8.2 Hz, 1H), 7.37 (dd, J 8.1, 1.1 Hz, 1H), 7.20 (m, 1H), 6.61 (t, 1H).
53%
To <strong>[18362-30-6]2-chloro-6-hydroxy-benzaldehyde</strong> (20 g, 128.2 mmol) in MeCN (150 mL) was added an aqueous solution of potassium hydroxide (71.7 g, 1282 mmol) in water (50 mL) at 0C and the reaction mixture was stirred at 0C for 10 mi Diethyl (bromodifluoro methyl) phosphonate (36.4 mL, 205.1 mmol) was added at 0C. The reaction mixture was stirred at 0C for 30 mm. After completion of reaction (monitored by TLC), the reaction mixturewas poured into water (500 mL). The aqueous layer was extracted with ethyl acetate (1 L X 2). The organic layer was washed with water (500 mL), brine (500 mL) and dried over anhydrous sodium sulphate. The organic layer was evaporated under reduced pressure to yield the crude product which was purified by column chromatography (Si02, 5% EtOAc in hexane) yielding the title compound (13.9g, 53% yield) as a yellow oil.1H NMR (400 MHz, CDC13) oe 10.46 (s, 1H), 7.49 (t, J 8.2 Hz, 1H), 7.37 (dd, J 8.1, 1.1 Hz, 1H), 7.20 (m, 1H), 6.61 (t, 1H).
53%
With potassium hydroxide; In water; acetonitrile; at 0℃; for 0.666667h;
To <strong>[18362-30-6]2-chloro-6-hydroxybenzaldehyde</strong> (20 g, 128.2 mmol) in acetonitrile (150 mL) was added a solution of potassium hydroxide (71.7 g, 1282 mmol) in water (50 mL) at 0C. The reaction mixture was stirred at 0C for 10 minutes, then diethyl (bromo- - - (0850) difluoromethyl)phosphonate (36.4 mL, 205.1 mmol) was added at 0C. The reaction mixture was stirred at 0C for 30 minutes, then poured into water (500 mL). The aqueous layer was extracted with EtOAc (2 x 1 L). The organic layer was washed with water (500 mL) and brine (500 mL), then dried over anhydrous sodium sulphate and filtered. The organic layers were evaporated under reduced pressure. The resulting crude residue was purified by column chromatography (Si02, 5% EtOAc in hexane) yielding the title compound (13.9 g, 53%) as a yellow oil. deltaEta (400 MHz, CDC13) 10.46 (s, 1H), 7.49 (t, J 8.2 Hz, 1H), 7.37 (dd, J 8.1, 1.1 Hz, 1H), 7.20 (m, 1H), 6.61 (t, 1H).
53%
To <strong>[18362-30-6]2-chloro-6-hydroxybenzaldehyde</strong> (20 g, 128.2 mmol) in acetonitrile (150 mL)was added a solution of potassium hydroxide (71.7 g, 1282 mmol) in water (50 mL) at0C. The reaction mixture was stirred at 0C for 10 minutes, then diethyl (bromodifluoromethyl)phosphonate (36.4 mL, 205.1 mmol) was added at 0C. The reaction mixture was stirred at 0C for 30 minutes, then poured into water (500 mL). The aqueous layer was extracted with EtOAc (2 x 1 L). The organic layer was washed with water (500mL) and brine (500 mL), then dried over anhydrous sodium sulphate and filtered. The organic layers were evaporated under reduced pressure. The resulting crude residue was purified by column chromatography (Si02, 5% EtOAc in hexane) yielding the title compound (13.9 g, 53%) as a yellow oil. oH (400 MHz, CDC13) 10.46 (s, 1H), 7.49 (t, J 8.2 Hz, 1H), 7.37 (dd, J8.1, 1.1 Hz, 1H), 7.20 (m, 1H), 6.61 (t, 1H).
With potassium hydroxide; In water; acetonitrile; at 20℃; for 3h;
Reference Production Example 79 (0849) To a mixture of 50 mL of acetonitrile, 50 mL of water, 10.5 g of potassium hydroxide, and 1.27 g of 3-hydroxyacetophenone, 5.0 g of bromodifluoromethyl diethylphosphonate was added dropwise at -78C. The temperature was raised to room temperature, followed by stirring for 3 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate and the obtained crude product was subjected to silica gel column chromatography to obtain 1-(3-difluoromethylphenyl)ethanone (C79A). 1H-NMR (CDCl3) delta (ppm): 7.80 (1H, dt, J = 7.8, 1.2 Hz), 7.70 (1H, t, J = 1.7 Hz), 7.48 (1H, t, J = 7.9 Hz), 7.34 (1H, dd, J = 8.2, 2.1 Hz), 6.57 (1H, t, J = 73.3 Hz), 2.61 (3H, s).
With potassium hydroxide; In water; acetonitrile; at -78 - 20℃; for 0.333333h;Inert atmosphere;
A MeCN (6.5 mL)/H2O (6.5 mL) mixture of potassium hydroxide (1469 mg, 26.2 mmol) and <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (250 mg, 1.309 mmol) was cooled to -78 C. in an open 50-mL teardrop flask, and bromodifluoromethyl diethylphosphonate (465 mul, 2.62 mmol) was added. The cooling bath was removed, and the white slurry was allowed to warm to rt. After 20 min, the reaction was diluted with EtOAc and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to a colorless oil. Column chromatography (12 g Redisep Gold column, 0-80% EtOAc/hept) afforded 1-bromo-3-(difluoromethoxy)-5-fluorobenzene (189 mg, 0.784 mmol, 59.9% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.15-7.59 (m, 4 H). 19F NMR (376 MHz, DMSO-d6) delta ppm-108.47 (s, 2F)-83.75 (s, 1F).
2-bromo-1-chloro-3-(difluoromethoxy)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With potassium hydroxide; In water; acetonitrile; at -78 - 20℃; for 16.3333h;Inert atmosphere;
To a co?d (-780) souton of 2-bromo-3-choropheno (1.0 g, 4.8 mmo) and potassium hydroxide (5.4 g, 96.4 mmo) nacetonftre (40 mL) and water (40 mL) was added dethy(bromodWuoromethy)phosphonate (1.7 mL, 9.6 mmo) at once. After 20 rnnutes the reacton mixture was warmed to rt and sUrred for 16 h. The mixture was then dHuted w[thwater and extracted with EtOAc (x 3). The combined organic extracts were diled over Na2SO4 and concentrated to obtain the product as an o (1.2 g, 87% yed), which was used drecUy n the next reaction. 1H NMR (500 MHz, CDC3) 5 738 7.33 (m, I H), 730 7.23 (m, IH), 7.13 (rn, J = 8.3, 1,1 Hz, I H), 6.54 (t, J = 73.1 Hz, IH).
With potassium hydroxide; In water; acetonitrile; at -25 - 20℃; for 1.25h;
Step 1: 2-Bromo-6-(difluoromethoxy)benzaldehyde A solution of <strong>[22532-61-2]<strong>[22532-61-2]2-bromo-6-hydroxybenzaldehyd</strong>e</strong> (5.0 g, 25 mmol) in MeCN (120 mL) and a solution of potassium hydroxide (27.9 g, 497 mmol) in H20 (124 mL) was cooled to below -25 C. Diethyl (bromodifiuoromethyi)phosphonate (7.1 mL, 40 mmol) was added dropwise at a rate to maintain the reaction temperature below about -20 C. After about 15 min at or below about -20 , the bath was allowed to warm to rt. After about i h, the reaction was extracted with EtOAc (2 x 100 mL), The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified on silica gel using 10% EtOAc in heptanes to give the title product (3.70 g, 59 %); NMR (400 MHz, CDC13) delta 10.34 (s, 1H), 7.57 (dd, J = 8.1, 1.0 Hz, IH), 7.41 ( J= 8.2 Hz, IH), 7.28 - 7.22. (m, IH), 6.60 (t, J= 73.5 Hz, 1H).
With potassium hydroxide; In water; acetonitrile; at -30 - 20℃; for 0.5h;
3.62. Compound 63: (lR,2R)-N-(6-((5-(difluoromethoxy)-2-ethylphenyl)(methyl)amino)-l-methyl- lH-imidazo[4,5-c]pyridin-4-yl)-2-fluorocyclopropanecarboxamide 3.62.1. Step i): l-Bromo-4-difluoromethoxy-2-nitro-benzene Diethyl(bromodifluoromethyl)phosphonate (2 eq, 1.64mL) is added to a cooled (-30 °C) solution of 4-Bromo-3-nitro-phenol (1 eq, 1.0 g) and KOH (20 eq, 5.17 g) in MeCN/water (46 mL; 1 :1) and the reaction mixture is allowed to warm to room temperature. After 30 min, the mixture is diluted with Et20, the organic phase is separated and the water phase is washed with a further amount of Et20. The combined organics are dried and concentrated. The residue is purified by silica chromatography (5-50 percent EtOAc in petroleum ether) to give the desired product.
4-bromo-2-difluoromethoxy-1-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In water; acetonitrile; at -25 - 20℃; for 2.5h;
1.14.1. Step i): 4-Bromo-2-difluoromethoxy-l-nitrobenzene 5-Bromo-2-nitrophenol (1 eq, 8.0 g) and potassium hydroxide (15 eq, 31.0 g) are dissolved in a 1 :1 solution of H20 and MeCN (240 mL). The reaction is cooled down to -25C, after which diethyl (bromodifluoromethyl) phosphonate (1 eq, 6.5 mL) is carefully added. The cooling bath is removed and the reaction is left stirring for 1 h, while slowly warming up to room temperature. Another 0.6 eq of the phosphonate (4.0 mL) are added at -25C, after which the cooling bath is removed and the reaction mixture is stirred for 90 min at room temperature. After completion of the reaction as shown by LC-MS, the mixture is diluted with Et20 and sat. NaHCOs. Extraction with Et20 (3 x 100 mL) is performed. The combined organics are washed with sat. brine and dried over anhydrous Na2S04. Purification of the crude through column chromatography (silica, cyclohexane/DCM; 100:0 to 90:10) yields the desired product.
5-(difluoromethoxy)-1,3-dimethyl-2-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium hydroxide; In water; acetonitrile; at 0 - 20℃; for 2.0h;
5 - (difluoromethoxy) - 1, 3 - dimethyl - 2 - nitrobenzeneAt room temperature, the 3, 5 - dimethyl -4 - nitro phenol (3.34 g, 20 mmol) with potassium hydroxide (22.4 g, 400 mmol) dissolved in acetonitrile (80 ml) and water (80 ml) in, cooling to 0 C, will bromine fluorine methylphosphonic acid diethyl ester (10.68 g, 40 mmol) is added in the reaction, temperature to room temperature stirring reaction for 2 hours. The reaction solution with ethyl acetate (50 ml × 3) extraction, the combined organic phase with saturated salt water (50 ml) washing, dried with anhydrous sodium sulfate, filtering, evaporating the filtrate, crude product by column chromatography separation and purification (petroleum ether/ethyl acetate (v/v)=20:1 - 10:1) to obtain compound 11 c (3.7 g, yield 90%).
With potassium hydroxide; In water; acetonitrile; at -78 - 20℃; for 0.333333h;
4-Hydroxybenzaldehyde (1.00 g, 8.20 mmol),KOH (9.20 g, 164 mmol),CH3CN-H2O (50 mL, 1: 1) into a sealed tube,Diethyl bromofluoromethylphosphonate (3 mL, 16.40 mmol) was slowly added dropwise at -78 C,Then warmed to room temperature,After 20 min of reaction at room temperature,TLC detection reaction was completed,Saturated NaHCO3 solution was added,Extraction with ethyl acetate,The combined organic phase,Dried over anhydrous Na2SO4,filter,concentrate,Column chromatography (EA: PE = 1: 70),1.01 g of solid are obtained,Yield 72%.
4-(difluoromethoxy)-6-methyl-2H-chromen-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With potassium carbonate In acetonitrile at 20℃; for 48h; Schlenk technique; Inert atmosphere; regioselective reaction;
General procedure for the difluoromethylation of isoflavonoids and flavonoids undermild conditions:
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added 1 (0.4 mmol, 1.0 equiv.) and K2CO3 (2.0 equiv.), after refilled with Ar three times,2 (0.8 mmol, 2.0 equiv.), MeCN (3.0 mL) was added. The Schlenk tube was screw capped.After stirring for 48 h, the reaction mixture was concentrated. The residue was subjected tocolumn chromatography on silica gel to afford the pure product.
60%
With potassium carbonate In acetonitrile at 20℃; for 48h; Inert atmosphere;
10 Embodiment 10
To the 25 ml in the reaction tube, adding 70.4 mg (0.4 mmol, 1 equivalent) compound A - 7,110 mg (2 equivalent) K2CO3, Nitrogen replacement after three times by adding 3 ml acetonitrile (MeCN), injection 142 μl (0.80 mmol) compound B, stirring at room temperature 48 hours, to obtain compound C - 7, and the yield is 60%.
7-(difluoromethoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With potassium carbonate In acetonitrile at 20℃; for 48h; Schlenk technique; Inert atmosphere; regioselective reaction;
General procedure for the difluoromethylation of isoflavonoids and flavonoids undermild conditions:
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added 1 (0.4 mmol, 1.0 equiv.) and K2CO3 (2.0 equiv.), after refilled with Ar three times,2 (0.8 mmol, 2.0 equiv.), MeCN (3.0 mL) was added. The Schlenk tube was screw capped.After stirring for 48 h, the reaction mixture was concentrated. The residue was subjected tocolumn chromatography on silica gel to afford the pure product.
71%
With potassium carbonate In acetonitrile at 20℃; for 48h; Inert atmosphere;
2 Embodiment 2
To the 25 ml in the reaction tube, adding 107 mg (0.4 mmol, 1 equivalent) compound A - 1,110 mg (2 equivalent) K2CO3, Nitrogen replacement after three times by adding 3 ml acetonitrile (MeCN), injection 142 μl (0.80 mmol) compound B,, stirring at room temperature 48 hours, to obtain compound C - 1, and the yield is 71%.
With potassium phosphate; In acetonitrile; at 20℃; for 48h;Schlenk technique; Inert atmosphere;
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added 1 (0.4 mmol, 1.0 equiv.) and K2CO3 (2.0 equiv.), after refilled with Ar three times,2 (0.8 mmol, 2.0 equiv.), MeCN (3.0 mL) was added. The Schlenk tube was screw capped.After stirring for 48 h, the reaction mixture was concentrated. The residue was subjected tocolumn chromatography on silica gel to afford the pure product.
55%
With potassium phosphate; In acetonitrile; at 20℃; for 48h;Inert atmosphere;
To the 25 ml in the reaction tube, adding 108 mg (0.4 mmol, 1 equivalent) compound A - 4,170 mg (2 equivalent) K3PO4, Nitrogen replacement after three times by adding 3 ml acetonitrile (MeCN), injection 142 mul (0.80 mmol) compound B, stirring at room temperature 48 hours, to obtain compound C - 4, and the yield is 55%.
5,7-bis(difluoromethoxy)-3-phenyl-4H-chromen-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With caesium carbonate In acetonitrile at 20℃; for 48h; Schlenk technique; Inert atmosphere; regioselective reaction;
General procedure for the difluoromethylation of isoflavonoids and flavonoids undermild conditions:
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added 1 (0.4 mmol, 1.0 equiv.) and K2CO3 (2.0 equiv.), after refilled with Ar three times,2 (0.8 mmol, 2.0 equiv.), MeCN (3.0 mL) was added. The Schlenk tube was screw capped.After stirring for 48 h, the reaction mixture was concentrated. The residue was subjected tocolumn chromatography on silica gel to afford the pure product.
50%
With caesium carbonate In acetonitrile at 20℃; for 48h; Inert atmosphere;
8 Embodiment 8
To the 25 ml in the reaction tube, adding 101.6 mg (0.4 mmol, 1 equivalent) compound A - 5,522 mg (4 equivalent) Cs2CO3, Nitrogen replacement after three times by adding 3 ml acetonitrile (MeCN), injection 142 μl (0.80 mmol) compound B, stirring at room temperature 48 hours, to obtain compound C - 5 - b, and the yield is 50%.
(R)-7-(difluoromethoxy)-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With potassium carbonate; In acetonitrile; at 20℃; for 48h;Schlenk technique; Inert atmosphere;
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added 1 (0.4 mmol, 1.0 equiv.) and K2CO3 (2.0 equiv.), after refilled with Ar three times,2 (0.8 mmol, 2.0 equiv.), MeCN (3.0 mL) was added. The Schlenk tube was screw capped.After stirring for 48 h, the reaction mixture was concentrated. The residue was subjected tocolumn chromatography on silica gel to afford the pure product.
With caesium carbonate; In acetonitrile; at 20℃; for 48h;Schlenk technique; Inert atmosphere;
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added 1 (0.4 mmol, 1.0 equiv.) and K2CO3 (2.0 equiv.), after refilled with Ar three times,2 (0.8 mmol, 2.0 equiv.), MeCN (3.0 mL) was added. The Schlenk tube was screw capped.After stirring for 48 h, the reaction mixture was concentrated. The residue was subjected tocolumn chromatography on silica gel to afford the pure product.
63%
With caesium carbonate; In acetonitrile; at 20℃; for 48h;Inert atmosphere;
To the 25 ml in the reaction tube, adding 95.2 mg (0.4 mmol, 1 equivalent) compound A - 6,261 mg (2 equivalent) Cs2CO3, Nitrogen replacement after three times by adding 3 ml acetonitrile (MeCN), injection 142 mul (0.80 mmol) compound B, stirring at room temperature 48 hours, to obtain compound C - 6, and the yield is 63%.
3-[(difluoromethyl)thio]-7-methoxy-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: 7-methoxy-1H-indole With water; iodine; thiourea; potassium iodide In 1,4-dioxane at 20℃;
Stage #2: With sodium hydroxide In 1,4-dioxane at 50℃; for 1h;
Stage #3: diethyl (bromodifluoromethyl)phosphonate In 1,4-dioxane at 20℃; for 4h;
7-chloro-3-((difluoromethyl)thio)-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: 7-chloro-1H-indole With water; iodine; thiourea; potassium iodide In 1,4-dioxane at 20℃;
Stage #2: With sodium hydroxide In 1,4-dioxane at 50℃; for 1h;
Stage #3: diethyl (bromodifluoromethyl)phosphonate In 1,4-dioxane at 20℃; for 4h;
3-[(difluoromethyl)sulfanyl]-2,5-dimethyl-1H-pyrrole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: 2,5-Dimethylpyrrole With water; iodine; thiourea; potassium iodide In 1,4-dioxane at 20℃;
Stage #2: With sodium hydroxide In 1,4-dioxane at 50℃; for 1h;
Stage #3: diethyl (bromodifluoromethyl)phosphonate In 1,4-dioxane at 20℃; for 4h;
4-bromo-1-(difluoromethoxy)-2-(trifluoromethyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
To a stirred solution of <strong>[50824-04-9]4-bromo-2-(trifluoromethyl)phenol</strong> (1.0 g, 4.15 mmol) in acetonitrile (25 mL) diethyl (bromodifluoromethyl)phosphonate (2.216 g, 8.30 mmol) was added at OeC. After stirring for 15 min at the same temperature, a solution of potassium hydroxide (2.32 g, 41.5 mmol) in water (25.0 mL) was added dropwise. The resulting mixture was then stirred at 25eC for 16 h. Reaction mixture was then poured onto ice water followed by the addition of ethyl acetate (15 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2/120 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SC>4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel) to afford 0.7 g (58%) of the titled product. 1HNMR (400 MHz, DMSO-d6) U8.04-7.96 (m, 2H), 7.64-7.21 (m, 2H); GC-MS 289.84 (M)+.
2-(difluoromethoxy-d<SUB>1</SUB>)-4-fluoro-1-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
Stage #1: 5-fluoro-2-nitrophenol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere;
Stage #2: With water-d2 In tetrahydrofuran; mineral oil at 0℃; for 0.166667h; Inert atmosphere;
Stage #3: diethyl (bromodifluoromethyl)phosphonate In tetrahydrofuran; mineral oil at 0 - 5℃; for 0.5h; Inert atmosphere;
40 g
Stage #1: 5-fluoro-2-nitrophenol With sodium hydride In tetrahydrofuran; mineral oil at -10 - 0℃; for 1h;
Stage #2: With water-d2 In tetrahydrofuran; mineral oil at 0℃; for 1h;
Stage #3: diethyl (bromodifluoromethyl)phosphonate In tetrahydrofuran; mineral oil at 5℃; for 0.5h;
1.1 (1) Synthesis of C1-2
Compound C1-1 (31.4g, 0.2mol) was dissolved in 600ml of THF (dry),Cool down to 0, add NaH (80g, 2mol, 60% in oil) in batches, react for 1h, then control the temperature at -10, add D2O (200g, 10mol) dropwise, react at 0 for 1h, then control the temperature at -10 At , add BrCF2PO(OEt)2 (106.8g, 0.4mol) dropwise, react for 0.5h at 5, TLC shows that the reaction is complete, dilute with water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, anhydrous Dry over sodium sulfate and concentrate to obtain a crude product, and column chromatography to obtain 40 g of product.
1-(benzyloxy)-2-(difluoromethoxy)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With potassium hydroxide In water; acetonitrile at -78 - 20℃;
B B. 1 -(Benzyloxy)-2-(difluoromethoxy)benzene
To a stirred, cooled (-78 °C) solution of 2-(benzyloxy)phenol (Intermediate 1 16A) (2.50 g, 12.5 mmol) and potassium hydroxide (14.0 g, 250 mmol) in acetonitrile (120 mL) and water (120 mL) was added diethyl (bromodifluoromethyl)phosphonate (4.44 mL, 25.0 mmol). The cooling bath was removed and the mixture was allowed to warm to room temperature. After stirring overnight, the mixture was extracted twice with Et20. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified on silica gel eluting with a 0%-50% EtOAc in hexanes gradient to give the title compound (1 .54 g, 49%). 1H NMR (400 MHz, CD3SOCD3) δ 5.15 (s, 2 H), 6.87-7.00 (m, 2 H), 7.07 (t, J = 76 Hz, 1 H), 7.12-7.49 (m, 7 H); LC-MS (LC-ES) M-H = 249.
To a solution of <strong>[84478-75-1]2-chloro-4-fluoro-5-nitro-phenol</strong> (0.50 g, 2.61 mmol) in CH3CN (10 ml)was added KOH (0.73 g, 13.0 mmol) at ooc and the reaction mixture was stirred at same10 temperature for 30 min. 1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (3.48 g,13.0 mmol) was added dropwise at ooc and the reaction mixture was stirred at roomtemperature for 3h. Progress of the reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was diluted with H20 (20 ml) and extracted with EtOAc(20 ml). The organic layer was separated, dried over anhydrous Na2S04 and15 concentrated under vacuum. The crude obtained was purified by column chromatography(silica, 100-200 mesh, 0 to 6% EtOAc in hexanes) to afford 1-chloro-2-(difluoromethoxy)-5-fluoro-4-nitro-benzene X-12a (0.46 g) as a colourless oil.Yield: 73%1H NMR (400 MHz, DMSO-d6) o 7.41 (t, J=72 Hz, 1H) 8.15 (d, J=6.80 Hz, 1H) 8.21 (d,20 J=6.80 Hz, 1 H).
2-(4-chlorobenzyl)-1-(difluoromethyl)-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium fluoride; In acetonitrile; at 20℃; for 12h;Schlenk technique; Inert atmosphere; Green chemistry;
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added Imidazoles/Pyrazoles (0.4 mmol, 1.0 equiv) and KF (46.4 mg, 2.0 equiv) under Ar, followed by MeCN (3 mL) with stirring. 2 (0.40 mmol, 1.0 equiv) were added subsequently. After stirring for 12 h, the reaction mixture was concentrated. The residue was purified with silica gel chromatography to provide pure product.
2-(chloromethyl)-1-(difluoromethyl)-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With potassium fluoride; In acetonitrile; at 20℃; for 12h;Schlenk technique; Inert atmosphere; Green chemistry;
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added Imidazoles/Pyrazoles (0.4 mmol, 1.0 equiv) and KF (46.4 mg, 2.0 equiv) under Ar, followed by MeCN (3 mL) with stirring. 2 (0.40 mmol, 1.0 equiv) were added subsequently. After stirring for 12 h, the reaction mixture was concentrated. The residue was purified with silica gel chromatography to provide pure product.
1-(difluoromethyl)-2-(methylthio)-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With potassium fluoride; In acetonitrile; at 20℃; for 12h;Schlenk technique; Inert atmosphere; Green chemistry;
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added Imidazoles/Pyrazoles (0.4 mmol, 1.0 equiv) and KF (46.4 mg, 2.0 equiv) under Ar, followed by MeCN (3 mL) with stirring. 2 (0.40 mmol, 1.0 equiv) were added subsequently. After stirring for 12 h, the reaction mixture was concentrated. The residue was purified with silica gel chromatography to provide pure product.
With potassium fluoride; In acetonitrile; at 20℃; for 12h;Schlenk technique; Inert atmosphere; Green chemistry;
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added Imidazoles/Pyrazoles (0.4 mmol, 1.0 equiv) and KF (46.4 mg, 2.0 equiv) under Ar, followed by MeCN (3 mL) with stirring. 2 (0.40 mmol, 1.0 equiv) were added subsequently. After stirring for 12 h, the reaction mixture was concentrated. The residue was purified with silica gel chromatography to provide pure product.
1-(difluoromethyl)-2-phenyl-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With potassium fluoride In acetonitrile at 20℃; for 12h; Schlenk technique; Inert atmosphere; Green chemistry;
General Procedure For the N-Difluoromethylation of Imidazoles and Pyrazoles.
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added Imidazoles/Pyrazoles (0.4 mmol, 1.0 equiv) and KF (46.4 mg, 2.0 equiv) under Ar, followed by MeCN (3 mL) with stirring. 2 (0.40 mmol, 1.0 equiv) were added subsequently. After stirring for 12 h, the reaction mixture was concentrated. The residue was purified with silica gel chromatography to provide pure product.
2-(1-(difluoromethyl)-1H-pyrazol-4-yl)ethan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With potassium fluoride; In acetonitrile; at 20℃; for 12h;Schlenk technique; Inert atmosphere; Green chemistry;
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added Imidazoles/Pyrazoles (0.4 mmol, 1.0 equiv) and KF (46.4 mg, 2.0 equiv) under Ar, followed by MeCN (3 mL) with stirring. 2 (0.40 mmol, 1.0 equiv) were added subsequently. After stirring for 12 h, the reaction mixture was concentrated. The residue was purified with silica gel chromatography to provide pure product.
With potassium fluoride In acetonitrile at 20℃; for 12h; Schlenk technique; Inert atmosphere; Green chemistry;
General Procedure For the N-Difluoromethylation of Imidazoles and Pyrazoles.
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added Imidazoles/Pyrazoles (0.4 mmol, 1.0 equiv) and KF (46.4 mg, 2.0 equiv) under Ar, followed by MeCN (3 mL) with stirring. 2 (0.40 mmol, 1.0 equiv) were added subsequently. After stirring for 12 h, the reaction mixture was concentrated. The residue was purified with silica gel chromatography to provide pure product.
With potassium fluoride; In acetonitrile; at 20.0℃; for 12.0h;Schlenk technique; Inert atmosphere; Green chemistry;
General procedure: To a 25 mL of Schlenk tube equipped with a Teflon septum were added Imidazoles/Pyrazoles (0.4 mmol, 1.0 equiv) and KF (46.4 mg, 2.0 equiv) under Ar, followed by MeCN (3 mL) with stirring. 2 (0.40 mmol, 1.0 equiv) were added subsequently. After stirring for 12 h, the reaction mixture was concentrated. The residue was purified with silica gel chromatography to provide pure product.
6.5 g of compound c25-7 was dissolved in 240 ml of THF, 12 g of NaH was added at 0 C, and stirred for half an hour, and 30 g of heavy water was added dropwise to the reaction at 0 C. After the addition, the reaction was carried out at 0 C for half an hour.16 g of diethyl bromofluoromethylphosphonate was added dropwise to the reaction system at 0 C, and stirred for 2 hours.TLC showed the reaction was completed, extracted with ethyl acetate 300ml was added, the organic phase was dried and concentrated, Column chromatography afforded 6.5g compound c25-8.
To a cooled (0C) solution of <strong>[30478-88-7]3-bromonaphthalen-2-ol</strong> (515 mg, 2.29 mmol) in MeCN (13 mL) and water (13 mL) is added potassium hydroxide (2.56 g, 45.62 mmol). The mixture is stirred at RT for 30 mm, and is then cooled to -78C. Diethyl (bromodifluoromethyl)phosphonate (1.24 g, 4.57 mmol) is added in one portion to the cooled mixture and stirring is then continued at RT overnight. Et20 is added, the layers are separated and the aqueous layer is further extracted with Et20. The combined organic layers are successively washed with 1 M aq. NaOH, water and brine and are then dried over anh. MgSO4, filtered and concentrated under reduced pressure. Purification by FC (from heptane to heptane/EtOAc = 3/7) affords 2-bromo-3- (difluoromethoxy)naphthalene as a pale yellow oil (432 mg, 69%). LC-MS A: tR = 0.95 mm; no ionization.
methyl 4-bromo-3-(difluoromethoxy)thiophene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With potassium hydroxide; In water; acetonitrile; at -10℃; for 1h;
Methyl 4-bromo-3-hydroxythiophene-2-carboxylate (60B) (2.0 g, 8.44 mmol) at rtSoluble in acetonitrile (20mL)Medium, cooling to -10 C, potassium hydroxide (9.5 g, 169 mmol) in water (20 mL)The solution is added to the reaction,Diethyl bromofluoromethylphosphonate(4.5g, 16.9mmol)The mixture was added dropwise to the reaction, and the reaction was stirred at -10 C for 1 hour.The reaction solution was extracted with methyl t-butyl ether (20 mL × 3).The combined organic phases were washed with brine (30 mL).Dry with anhydrous sodium sulfate,Filtered, the filtrate was evaporated to dryness.The crude product was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 20:1 to 10:1)Get a white solid productMethyl 4-bromo-3-(difluoromethoxy)thiophene-2-carboxylate (71A) (1.0 g, yield 41%).
4-(difluoromethoxy)-3-methylbenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33.4%
With potassium hydroxide In water; acetonitrile at -20 - 20℃; for 1.25h;
2 Preparation of 4-(difluoromethoxy)-3-methylbenzaldehyde (9)
Potassium hydroxide (8.176 g, 146.0 mmol, 20.0 eq) was suspended in a mixture of acetonitrile (15 mL) and water (15 mL) and cooled to -20 °C.4-Hydroxy-3-methyl- benzaldehyde (9A) (1.000g, 7.3mmol, 1.0 eq) was dissolved in acetonitrile (10 mL) and was added dropwise, followed by bromodifluoromethyl diethylphosphonate (3.811 g, 14.6 mmol, 2.0 eq) over 15 minutes. Then the mixture was allowed to warm to room temperature over 1h. The mixture was extracted with ethyl acetate (3 × 30 mL). Then it was washed with brine (2 × 30 mL) and finally dried over sodium sulfate. The combined organics were removed under reduced pressure. Resulting residue was dissolved in DCM and loaded to silica gel column (12 g, 0-20% EA/ Hex, TLC 10% EA/Hex). The title compound was obtained as clear oil (9) (0.454 g, 33.4%).1H NMR (300 MHz, CDCl3), d 9.95 (s, 1H), 7.77 - 7.71 (m, 2H), 7.26- 7.19 (m, 1H), 6.62 (t, J = 72.9 Hz, 1H), 2.36 (s, 3H).
2-(difluoromethoxy)-4-methoxy-5-nitropyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In water; acetonitrile; at 20 - 60℃; for 4h;
To a solution of <strong>[607373-82-0]4-methoxy-5-nitropyridin-2-ol</strong> X-18a (0.60 g, 2.73 mmol) in CH3CN (20 mL) and H20 (5 mL) was added KOH (0.77 g, 13.6 mmol) and bromodifluoromethyl diethylphosphonate (3.64 g, 13.6 mmol) slowly at room temperature and the reaction mixture was heated at 60 C for 4h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with H20 (60 mL) and extracted with EtOAc (3 x 40 mL). The organic layer was separated, washed with brine (2 c 50 mL), dried over anhydrous Na2S04 and concentrated under vacuum. The reaction mixture was repeated on 2.70 g and the crude obtained from 2 reactions was clubbed and dissolved in DCM (150 mL) and the crude obtained was purified by column chromatography (silica, 100-200 mesh, 10% EtOAc in hexane) to afford 2-(difluoromethoxy)-4-methoxy-5-nitropyridine X- 18b (1 .55 g, 36%) as a pale yellow liquid. (0954) Yield: 36%. (0955) Basic LCMS Method 2 (ES+): 221 (M+H)+, 82% purity. (0956) 1H NMR (400 MHz, CDCI3) d 4.05 (s, 3H) 6.53 (s, 1 H) 7.52 (t, J=72 Hz, 1 H) 8.76 (s, 1 H).
With potassium hydroxide; In water; acetonitrile; at -78 - 0℃; for 3.25h;
To a solution of tert-butyl 6-hydroxy-1H-indole-1 -carboxylate Xl-2b (2.00 g, 8.57 mmol) in CH3CN (20 mL) and H20 (20 mL) was added KOH (9.62 g, 171 mmol) and (1012) bromodifluoromethyl diethylphosphonate (3.05 mL, 17.1 mmol) slowly at -78 C. After 15 min, the reaction mixture was stirred at 0 C for 3h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with H20 (200 mL) and extracted with EtOAc (2 200 mL). The organic layer was separated, washed with brine (2 30 mL), dried over anhydrous Na2S04 and concentrated under vaccum. The crude obtained was purified by column chromatography (silica, 100-200 mesh, 15% EtOAc in hexane) to afford tert-butyl 6-(difluoromethoxy)-1H-indole-1 - carboxylate Xl-2c (0.68 g) as a yellow oil. (1013) Yield: 21 %. (1014) Basic LCMS Method 2 (ES ): 282 (M-H)-, 74% purity. 1 H NMR (400 MHz, DMSO -cfe) d 1 .63 (s, 9H) 6.73 (d, J=3.91 Hz, 1 H) 7.09 (dd, J=8.80, (1015) 1 .47 Hz, 1 H) 7.23 (t, J=76 Hz, 1 H) 7.66 (d, J=8.31 Hz, 1 H) 7.69 (d, J=3.42 Hz, 1 H) 7.86 (s, 1 H).
With potassium hydroxide; In acetonitrile; at 20℃;Cooling with acetone-dry ice;
A round-bottom flask equipped with a magnetic stir bar was charged with 5- bromo-6-chloro-pyridin-3-ol (1.0 g, 4.8 mmol), and then acetonitrile (20 mL) and water (20 mL) were added. Solid potassium hydroxide (5.4 g, 96 mmol) was added, and the mixture was cooled in a dry ice/acetone bath. When the mixture began to freeze, l-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (2.6 g, 9.6 mmol) was added, and the mixture was allowed to warm to room temperature. The crude mixture was partitioned between water and diethyl ether, and the ether layer was collected, dried, and concentrated to give a colorless oil containing the desired product, which was used without further purification.
4-(difluoromethoxy)-2,6-difluorobenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With potassium hydroxide; In water; acetonitrile; at -20 - 20℃;
a) 4-(Difluoromethoxy)-2,6-difluorobenzonitrile I119 To a suspension of KOH (22.0 g, 392 mmol) in acetonitrile (30 ml.) and water (30 ml.) at -20 C was added <strong>[123843-57-2]2,6-difluoro-4-hydroxybenzonitrile</strong> (3.1 g, 20.0 mmol) portion-wise followed by diethyl (bromodifluoromethyl)phosphonate (10.0 g, 37.4 mmol) and the mixture was stirred at RT overnight. Water was added and the mixture was extracted with EtOAc (50 ml. x 3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (4.0 g, 97%) as a colorless oil. LCMS-C: Rt 2.1 1 min; m/z 205.9 [M+H]+.
1,3-dibromo-5-fluoro-2-difluoromethoxybenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: 2,6-dibromo-4-fluorophenol With potassium hydroxide In water; acetonitrile at 10℃; for 0.25h; Inert atmosphere;
Stage #2: diethyl (bromodifluoromethyl)phosphonate In water; acetonitrile at -20 - 20℃; for 2h; Inert atmosphere;
8 Synthesis of 1,3-bis(trifluorovinyl)-5-fluoro-2-difluoromethoxybenzene [Compound 8]
300 mL four-neck flask equipped with a stirrer was charged with potassium hydroxide (35.78 g, 637.7 mmol) and water (122 mL) under nitrogen atmosphere and the component was dissolved. Then, with stirring at 10° C. or less, a mixed solution of 2,6-dibromo-4-fluorophenol (6.46 g, 23.9 mmol) and acetonitrile (122 mL) was added thereto. After stirring for 15 minutes, the mixture was cooled to -20° C. or less, and diethyl (bromodifluoromethyl)phosphonate (9.80 g, 36.7 mmol) was gradually added dropwise thereto. After completing the dropwise addition, the temperature of the mixture was increased to room temperature and the mixture was stirred for 2 hours. Then the mixture was extracted with methyl t-butyl ether (50 mL×3 times), and the organic layer was washed with a 20% aqueous ammonium chloride solution (50 mL×3 times). The resulting organic layer was dried over anhydrous magnesium sulfate and then the filtrate was concentrated under reduced pressure to give 7.84 g of light yellow solid 1,3-dibromo-5-fluoro-2-difluoromethoxybenzene (purity=97.5 wt %, isolated yield=98%).
1-(difluoromethoxy)-2-iodo-4-nitro-benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With potassium hydroxide; In water; acetonitrile; at 0℃; for 3h;
A solution of <strong>[89487-91-2]2-iodo-4-nitrophenol</strong> 54 (920 mg, 3.5 mmol) and KOH (2.3 g, 42 mmol) in MeCN (30 mL) and H2O (30 mL) was treated with diethyl (bromodifluoromethyl)phosphonate (1.9 mL, 10 mmol) at 0 C for 3 h. The resulting mixture was partitioned between AcOEt (200 mL) and H2O (100 mL), and the organic phase was washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/hexane; 0:100 to 30:70) to afford compound 55 (860 mg, 79%) as a colorless oil. . 1H NMR (CDCl3, 400 MHz) δ: 8.73 (1H, d, J = 3.1 Hz), 8.26 (1H, dd, J = 9.2, 2.4 Hz), 7.28 (1H, d, J = 9.2 Hz), 6.67 (1H, t, J = 71.7 Hz).
4-bromo-1-(difluoromethyl)-1H-1,2,3-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium fluoride In acetonitrile at 20℃; for 15h;
Step A synthesis of compound Int-3
To a mixture of 4-bromo-li/- 1,2, 3-triazole (Int-3a, 1 g, 6.76 mmol), and potassium fluoride (0.785 g, 13.5 mmol) in acetonitrile (15 mL) was added diethyl (bromodifluoromethyl)phosphonate (1.99 g, 7.43 mmol). The resulting reaction was allowed to stir for 15 hours at room temperature. The reaction mixture was then filtered, and concentrated in vacuo. The residue obtained was purified using silica gel chromatography, eluting with a gradient of diethyl ether: petroleum ether- 0:100 to 75:25 to provide compound Int-3. MS: m/z = 198.0, 200.0 [M + H]
With potassium fluoride In acetonitrile at 35℃; for 18h;
1.71.1 Step 1
Diethyl bromo(difluoro)methylphosphonate (5.80 g; 21.9 mmol; 2.0 eq.) was added to a solution containing 5-bromo-1H-indazole (2.20 g; 11.0 mmol; 1.0 eq.) and potassium fluoride (1.27 g; 21.9 mmol; 2.0 eq.) in acetonitrile (37 mL). The reaction was heated to 35°C for 18 hours. The reaction was quenched with water. The aqueous layer was extracted with ethyl acetate. The combined organics were dried with MgSO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column using 25% ethyl acetate in heptanes as the eluting solvents to afford 5-bromo-1-(difluoromethyl)-1H-indazole (2.6 g; 96 %). LCMS (ES) [M+1]+ m/z 248.8.
Stage #1: 1-Adamantanethiol; diethyl (bromodifluoromethyl)phosphonate With potassium hydroxide In water; acetonitrile at 0℃; for 0.25h; Sealed tube;
Stage #2: diethyl (bromodifluoromethyl)phosphonate In water; acetonitrile at 0 - 20℃; for 1.5h; Sealed tube; chemoselective reaction;
4.2. General procedure
General procedure: The starting material (2 mmol) was added to a sealed tube holding 20 mL of a 1:1 mixture of acetonitrile/water and KOH (40 mmol), whichwas cooled using an ice bath. The mixture was vigorously mixed for 15min and then phosphonate 1 (4 mmol) was added to the mixture in oneportion, and mixing and cooling was maintained for an additional 15 -60 min, followed by ~30 min - 2.5 h at r.t. The reaction mixture wasthen diluted with ether (10 mL) and the organic phase separated. Thewater phase was further washed with ether (10 mL). The combinedorganic phase was dried over anhydrous Na2SO4 and the solvent evaporatedto provide a crude product which was purified using columnchromatography on silica gel
Stage #1: 2-mercaptophenylethane With potassium hydroxide In water; acetonitrile at 0℃; for 0.25h; Sealed tube;
Stage #2: diethyl (bromodifluoromethyl)phosphonate In water; acetonitrile at 0 - 20℃; Sealed tube; chemoselective reaction;
4.2. General procedure
General procedure: The starting material (2 mmol) was added to a sealed tube holding 20 mL of a 1:1 mixture of acetonitrile/water and KOH (40 mmol), whichwas cooled using an ice bath. The mixture was vigorously mixed for 15min and then phosphonate 1 (4 mmol) was added to the mixture in oneportion, and mixing and cooling was maintained for an additional 15 -60 min, followed by ~30 min - 2.5 h at r.t. The reaction mixture wasthen diluted with ether (10 mL) and the organic phase separated. Thewater phase was further washed with ether (10 mL). The combinedorganic phase was dried over anhydrous Na2SO4 and the solvent evaporatedto provide a crude product which was purified using columnchromatography on silica gel
General procedure: The starting material (2 mmol) was added to a sealed tube holding 20 mL of a 1:1 mixture of acetonitrile/water and KOH (40 mmol), whichwas cooled using an ice bath. The mixture was vigorously mixed for 15min and then phosphonate 1 (4 mmol) was added to the mixture in oneportion, and mixing and cooling was maintained for an additional 15 -60 min, followed by ~30 min - 2.5 h at r.t. The reaction mixture wasthen diluted with ether (10 mL) and the organic phase separated. Thewater phase was further washed with ether (10 mL). The combinedorganic phase was dried over anhydrous Na2SO4 and the solvent evaporatedto provide a crude product which was purified using columnchromatography on silica gel
Stage #1: decylthiol With potassium hydroxide In water; acetonitrile at 0℃; for 0.25h; Sealed tube;
Stage #2: diethyl (bromodifluoromethyl)phosphonate In water; acetonitrile at 0 - 20℃; Sealed tube; chemoselective reaction;
4.2. General procedure
General procedure: The starting material (2 mmol) was added to a sealed tube holding 20 mL of a 1:1 mixture of acetonitrile/water and KOH (40 mmol), whichwas cooled using an ice bath. The mixture was vigorously mixed for 15min and then phosphonate 1 (4 mmol) was added to the mixture in oneportion, and mixing and cooling was maintained for an additional 15 -60 min, followed by ~30 min - 2.5 h at r.t. The reaction mixture wasthen diluted with ether (10 mL) and the organic phase separated. Thewater phase was further washed with ether (10 mL). The combinedorganic phase was dried over anhydrous Na2SO4 and the solvent evaporatedto provide a crude product which was purified using columnchromatography on silica gel
General procedure: The starting material (2 mmol) was added to a sealed tube holding 20 mL of a 1:1 mixture of acetonitrile/water and KOH (40 mmol), whichwas cooled using an ice bath. The mixture was vigorously mixed for 15min and then phosphonate 1 (4 mmol) was added to the mixture in oneportion, and mixing and cooling was maintained for an additional 15 -60 min, followed by ~30 min - 2.5 h at r.t. The reaction mixture wasthen diluted with ether (10 mL) and the organic phase separated. Thewater phase was further washed with ether (10 mL). The combinedorganic phase was dried over anhydrous Na2SO4 and the solvent evaporatedto provide a crude product which was purified using columnchromatography on silica gel
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