CN104844651A - Method for preparing six fluorine phosphonic acid ester base fe organism derivatives - Google Patents
Method for preparing six fluorine phosphonic acid ester base fe organism derivatives Download PDFInfo
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Abstract
The invention relates to a soft and effective method for preparing six fluorine phosphonic acid ester base fe organism derivatives. 2 - aryl aromatic nitrile and br two fluorine methyl phosphonic acid diethyl ester are applied as raw materials. A series of six fluorine phosphonic acid ester base fe organism derivatives is prepared under the function of photo-catalyst. The using of free radical reagent of high toxicity is not used in the method, and thus the method is environment friendly and economic. The exposure of visible light is used and the reaction under high temperature is avoided, and the reaction condition is mild. The invention has the advantages taht the separation and purification is convenient, the waste is little, special demand to the bottom reaction materials is not necessary, the application is wide, and the application value is high.
Description
Technical field
The present invention relates to organic chemical industry and field of fine chemical, specifically a kind of synthetic method of 6-difluoro methylphosphonic acid diethyl-ester group phenanthridine derivatives.
Background technology
Because fluorine atom volume is little, electronegativity is large, cloud density is high, be introduced into the materialization and biological property that parent compound in organic molecule, can be changed, therefore fluorochemicals has the specificity in many application, as fluoro-containing macromolecule material has high chemical resistant properties and thermostability, and the introducing of fluorine atom or fluoro-containing group, the simulation of organifying compound, perviousness, electronic effect, barriering effect significantly strengthens, thus make fluorochemical at medicine, the aspects such as agricultural chemicals often have the incomparable advantage of other medicines, therefore organic fluorine chemistry has penetrated into each field of organic chemistry now, the research of fluorochemicals in recent years enjoys the favor of chemist, scientific research personnel makes every effort to introduce fluorine element in organic compound, to obtain the organic medicinal and the Pesticidal products that there are sp act, along with scientific-technical progress, fluorochemicals is used widely in numerous field of fine chemical such as agricultural chemicals, medicine, coating, dyestuff, tensio-active agent, high performance materials.
Organic two fluoro phosphonate ester compounds are the important pharmaceutical intermediate of a class and organic synthesis reagent, are widely used in the fields such as plant growth regulating, antiviral and animal antitumor drug.The method of wherein synthesizing two fluoro phosphonate ester compound one classes important is: transition metal-catalyzed two fluoro phosphonic acid esters.Its kind of pressing metal catalyst is different, can divide following two classes: the two fluoro phosphonate reaction of (1) copper catalysis; (2) two fluoro phosphonate reaction of palladium chtalyst.But due to the phosphorus part of the use costliness in these route of synthesis, reaction is carried out at a higher temperature, thus limits the application of these class methods.Another kind of method utilizes two fluoro phosphonic acid ester free radicals to react, under radical initiator AIBN effect, the two fluoro phosphonic acid esters that phenylseleno replaces produce two fluoro phosphonic acid ester free radicals, but these class methods use radical initiator AIBN that is poisonous and instability.Utilization is cleaned, and effective implemention difluoro phosphine esterification, remains the target that organic synthesis worker seek assiduously.
Summary of the invention
Synthetic method for above-mentioned existing two fluoro phosphonate ester compounds needs to use expensive phosphorus part, reaction is carried out at a higher temperature, the defects such as the poisonous radical initiator AIBN with instability need be used, the invention provides a kind of method of gentleness, efficiently preparation 6 difluoridate (DF) ester group phenanthridine derivatives.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
A kind of synthetic method of 6-difluoro methylphosphonic acid diethyl-ester group phenanthridine derivatives, with 2-aryl virtue isonitrile and bromine difluoro methyl diethyl phosphonate for raw material, under visible ray illumination, add photocatalyst, alkali and organic solvent, stirring reaction, Reactive Synthesis 6-difluoro methylphosphonic acid diethyl-ester group phenanthridines compounds, reaction conditions is: protection of inert gas, under room temperature condition, the reaction times is 36-48 hour; Its reaction formula is as follows:
；
Substituent R in described reaction formula on two aromatic rings
1for H, 4-F, 4-Me, 4-CF
3, 4,6-dimethyl or 4,6-dichloro; R
2for H, 4-Me, 4-Et, 4-n-Pr, 4-OMe, 4-F, 4-Cl, 4-Ph or 2-Me;
Described light source is 20 watts of LED, 40 watts of LED or 5 light blue look LED;
Described photocatalyst is that three (2-phenylpyridines) close iridium, [4,4'-di-t-butyl-2,2'-dipyridyl] two [2-2-phenylpyridines] close iridium hexafluorophosphate, dichloro three (2,2'-bis-pyridine) closes ruthenium (II) hexahydrate, eosin W or W S or rhodamine B;
Described photocatalyst consumption is 0.01-0.05 times of 2-aryl virtue isonitrile mole number;
The mol ratio of described raw material is 2-aryl virtue isonitrile: bromine difluoro methyl diethyl phosphonate is 1:2 ~ 6;
Described alkali is salt of wormwood, sodium carbonate, sodium bicarbonate, potassium primary phosphate, potassiumphosphate, sodium-acetate, Potassium ethanoate, triethylamine or diisopropylethylamine;
Described alkali consumption is 2-4 times of 2-aryl virtue isonitrile mole number;
Described solvent is fluorobenzene, chlorobenzene, acetonitrile, ethylene dichloride, methylene dichloride, dimethyl sulfoxide (DMSO), DMF or tetrahydrofuran (THF), and solvent load is 10mL/mmol 2-aryl virtue isonitrile.
Beneficial effect of the present invention:
The present invention adopts 2-aryl virtue isonitrile and bromine difluoro methyl diethyl phosphonate to be raw material, under photocatalyst effect, prepare a series of 6-difluoro methylphosphonic acid diethyl-ester group phenanthridines analog derivative, present method does not relate to and employs the use that highly toxic free radical causes reagent, more green, economical; With under radiation of visible light, avoid the reaction under high temperature, reaction conditions is gentle, and separating-purifying is convenient, and waste discharge is few, and to the substrate of reaction without particular requirement, the plurality of advantages such as applied widely, has very high using value; Compared with traditional difluoridate (DF) ester free radical reaction, owing to utilizing visible light catalyst to transmit electronics and energy, whole catalytic cycle process is made to keep redox-neutral, therefore without the need to the oxygenant of the amount of substances such as interpolation, it also avoid the use that highly toxic free radical causes reagent, be a kind of method of gentleness, efficiently preparation 6 difluoridate (DF) ester group phenanthridine derivatives simultaneously.
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated.
A kind of synthetic method of 6-difluoro methylphosphonic acid diethyl-ester group phenanthridine derivatives, with 2-aryl virtue isonitrile and bromine difluoro methyl diethyl phosphonate for raw material, under visible ray illumination, add photocatalyst, alkali and organic solvent, stirring reaction, Reactive Synthesis 6-difluoro methylphosphonic acid diethyl-ester group phenanthridines compounds, reaction conditions is: protection of inert gas, under room temperature condition, the reaction times is 36-48 hour; Its reaction formula is as follows:
; Substituent R in described reaction formula on two aromatic rings
1for H, 4-F, 4-Me, 4-CF
3, 4,6-dimethyl or 4,6-dichloro; R
2for H, 4-Me, 4-Et, 4-n-Pr, 4-OMe, 4-F, 4-Cl, 4-Ph or 2-Me; Described light source is 20 watts of LED, 40 watts of LED or 5 light blue look LED; Described photocatalyst is that three (2-phenylpyridines) close iridium, [4,4'-di-t-butyl-2,2'-dipyridyl] two [2-2-phenylpyridines] close iridium hexafluorophosphate, dichloro three (2,2'-bis-pyridine) closes ruthenium (II) hexahydrate, eosin W or W S or rhodamine B; Described photocatalyst consumption is 0.01-0.05 times of 2-aryl virtue isonitrile mole number; The mol ratio of described raw material is 2-aryl virtue isonitrile: bromine difluoro methyl diethyl phosphonate is 1:2 ~ 6; Described alkali is salt of wormwood, sodium carbonate, sodium bicarbonate, potassium primary phosphate, potassiumphosphate, sodium-acetate, Potassium ethanoate, triethylamine or diisopropylethylamine; Described alkali consumption is 2-4 times of 2-aryl virtue isonitrile mole number; Described solvent is fluorobenzene, chlorobenzene, acetonitrile, ethylene dichloride, methylene dichloride, dimethyl sulfoxide (DMSO), DMF or tetrahydrofuran (THF), and solvent load is 10mL/mmol 2-aryl virtue isonitrile.
Reaction process of the present invention and to obtain the structure of product as follows:
Embodiment 1
The synthesis of diethyl difluoro (phenanthridin-6-yl) methylphosphonate (2a)
Take 2-phenyl benzene isonitrile 1a(1mmol), bromine difluoridate (DF) ethyl ester (4.0mmol), three (2-phenylpyridines) close iridium (0.05mmol) and sodium bicarbonate (2.0mmol), and join in the Schlenk reaction flask of 25mL successively, then, add acetonitrile (10.0mL), and react 40h under being placed in 20 watts of LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, the yield obtaining product diethyl difluoro (phenanthridin-6-yl) methylphosphonate is 78%.
1H NMR (400 MHz, CDCl
3): δ = 8.66 (d,
J = 7.6 Hz, 1H), 8.59 (d,
J = 7.6 Hz, 2H), 8.23 (d,
J = 7.2 Hz, 1H), 7.87 (t,
J = 7.2 Hz, 1H), 7.69-7.79 (m, 3H), 4.45-4.62 (m, 4H),1.42 (t,
J = 7.2 Hz, 6H)；
13C NMR (125 MHz, CDCl
3): δ = 150.5 (td,
J 1= 25.4,
J 2= 13.3 Hz), 141.7, 133.9, 131.1, 130.5, 129.0, 128.9, 127.7, 126.8, 125.5, 124.8, 122.4 122.1, 119.9 (td,
J 1= 260.8,
J 2= 213.8 Hz), 64.93, 64.88, 16.57, 16.52。
Embodiment 2
The synthesis of diethyl difluoro (8-methylphenanthridin-6-yl) methylphosphonate (2b)
Take 2-p-methylphenyl benzene isonitrile 1b(0.5mmol), bromine difluoridate (DF) ethyl ester (1.0mmol), three (2-phenylpyridines) close iridium (0.02mmol) and sodium carbonate (1.0mmol), and join in the Schlenk reaction flask of 25mL successively, then, add methylene dichloride (5.0mL), and react 48h under being placed in 5 light blue LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, the yield obtaining product diethyl difluoro (8-methylphenanthridin-6-yl) methylphosphonate is 76%.
1H NMR (400 MHz, CDCl
3): δ = 8.54 (d,
J = 8.0 Hz, 2H), 8.20 (d,
J = 8.0 Hz, 1H), 8.36(s, 1H), 7.68-7.76 (m, 3H), 4.51-4.59 (m, 4H),2.61 (s, 3H), 1.42 (t,
J = 7.2 Hz, 6H)；
13C NMR (125MHz, CDCl
3): δ = 150.2 (td,
J 1= 26.0,
J 2= 14.2 Hz), 141.4, 137.8, 132.9, 131.8, 130.4, 128.8, 128.5, 127.4, 126.0, 124.9, 122.3, 121.9, 119.8 (td,
J 1= 260.9,
J 2= 213.5 Hz), 64.84, 64.80. 21.9, 16.56, 16.52。
Embodiment 3
The synthesis of diethyl (8-ethylphenanthridin-6-yl) difluoromethylphosphonate (2c)
Take 2-to ethylphenyl benzene isonitrile 1c(0.5mmol), bromine difluoridate (DF) ethyl ester (2.0mmol), [4, 4'-di-t-butyl-2, 2'-dipyridyl] two [2-2-phenylpyridines] close iridium hexafluorophosphate (0.01mmol) and triethylamine (2.0mmol), and join in the Schlenk reaction flask of 25mL successively, then, add tetrahydrofuran (THF) (5.0mL), and react 36h under being placed in 40 watts of LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, the yield obtaining product diethyl (8-ethylphenanthridin-6-yl) difluoromethylphosphonate is 72%.
1H NMR (400 MHz, CDCl
3): δ = 8.51-8.59 (m, 2H), 8.39 (s, 1H), 8.21(d,
J = 8.0 Hz, 1H), 7.67-7.78 (m, 3H), 4.50-4.59 (m, 4H),2.91 (q,
J= 7.6 Hz, 2H), 1.42 (t,
J = 7.2 Hz, 6H), 1.37 (t,
J= 7.6 Hz, 3H)；
13C NMR (125MHz, CDCl
3): δ = 150.3 (td,
J 1= 26.0,
J 2= 14.9 Hz), 144.0, 141.5, 132.0, 131.9, 130.4, 128.8, 128.5, 126.4,125.7, 124.9, 122.4, 121.9, 120.0 (td,
J 1= 260.9,
J 2= 213.8 Hz), 64.83, 64.78, 29.2, 16.56, 16.51, 15.5。
Embodiment 4
The synthesis of diethyl difluoro (8-propylphenanthridin-6-yl) methylphosphonate (2d)
Take 2-to propyl group phenyl benzene isonitrile 1d(0.5mmol), bromine difluoridate (DF) ethyl ester (1.0mmol), dichloro three (2, 2'-bis-pyridine) close ruthenium (II) hexahydrate (0.02mmol) and potassiumphosphate (1.0mmol), and join in the Schlenk reaction flask of 25mL successively, then, add ethylene dichloride (5.0mL), and react 42h under being placed in 20 watts of LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, the yield obtaining product diethyl difluoro (8-propylphenanthridin-6-yl) methylphosphonate is 71%.
1H NMR (400 MHz, CDCl
3): δ = 8.50-8.57 (m, 2H), 8.36 (s, 1H), 8.19 (d,
J = 8.0 Hz, 1H), 7.67-7.75 (m, 3H), 4.48-4.57 (m, 4H),2.83 (t,
J = 7.2Hz, 2H), 1.71-1.79 (m, 2H), 1.42 (t,
J = 7.2 Hz, 6H), 0.99 (t,
J = 7.2Hz, 3H)；
13C NMR (125MHz, CDCl
3): δ = 150.2 (td,
J 1= 26.0,
J 2= 14.9 Hz), 142.5, 141.4, 132.3, 132.0, 130.4, 128.8, 128.5, 125.6, 124.9, 124.0, 122.3, 121.9, 119.9 (td,
J 1= 260.8,
J 2= 213.8 Hz), 64.84, 64.79, 38.2, 24.5, 16.58, 16.53, 13.8。
Embodiment 5
The synthesis of Diethyl difluoro (8-methoxyphenanthridin-6-yl) methylphosphonate (2e)
Take 2-p-methoxyphenyl benzene isonitrile 1e(1.0mmol), bromine difluoridate (DF) ethyl ester (3.0mmol), rhodamine B (0.02mmol, ) and Potassium ethanoate (4.0 mmol), and join in the Schlenk reaction flask of 25mL successively, then, add fluorobenzene (10.0mL), and react 46h under being placed in 40 watts of LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, obtaining product diethyl difluoro (8-methoxyphenanthridin-6-yl) methylphosphonate yield is 78%.
1H NMR (400 MHz, CDCl
3): δ = 8.59 (d,
J = 8.0 Hz, 1H), 8.42 (d,
J = 8.0 Hz, 1H), 8.18 (d,
J = 8.0 Hz, 1H), 7.63-7.70 (m, 2H), 7.46-7.50(m, 2H), 4.48-4.57 (m, 4H), 3.97 (s, 3H), 1.42 (t,
J = 7.2 Hz, 6H)；
13C NMR (125MHz, CDCl
3): δ = 159.0, 150.1 (td,
J 1= 26.0,
J 2= 14.7 Hz), 141.9, 131.2, 128.1, 127.9, 127.6, 127.0, 125.4, 122.1, 121.5, 119.8 (td,
J 1= 260.6,
J 2= 213.6 Hz), 107.1, 64.85, 64.80, 55.6, 16.60, 16.54。
Embodiment 6
The synthesis of diethyl difluoro (8-fluorophenanthridin-6-yl) methylphosphonate (2f)
Take 2-to fluorophenyl benzene isonitrile 1f(1.0mmol), bromine difluoridate (DF) ethyl ester (4.0mmol), eosin W or W S (0.02mmol) and diisopropylethylamine (4.0 mmol), and join in the Schlenk reaction flask of 25mL successively, then, add chlorobenzene (10.0mL), and react 48h under being placed in 20 watts of LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, the yield obtaining product diethyl difluoro (8-fluorophenanthridin-6-yl) methylphosphonate is 60%.
1H NMR (400 MHz, CDCl
3): δ = 8.70 (d,
J = 8.0 Hz, 1H), 8.56 (d,
J = 8.0 Hz, 1H), 8.26 (s, 1H), 8.23 (d,
J = 8.0 Hz, 1H), 7.77-7.79 (m, 2H), 7.64-7.69 (m, 1H), 4.47-4.58 (m, 4H),1.42 (t,
J = 7.2 Hz, 6H)；
13C NMR (125MHz, CDCl
3): δ = 161.3 (d,
J = 247.5 Hz), 150.2 (td,
J 1= 25.6,
J 2= 14.4 Hz), 141.5, 130.7, 129.3, 128.9, 127.6, 126.5 (d,
J = 4.2 Hz), 124.9 (d,
J = 8.4 Hz), 124.5, 121.9, 120.6 (d,
J = 23.8 Hz), 119.9 (td,
J 1= 260.8,
J 2= 213.4 Hz), 111.7 (d,
J = 23.3 Hz), 65.0, 64.95, 16.54, 16.49。
Embodiment 7
The synthesis of diethyl (8-chlorophenanthridin-6-yl) difluoromethylphosphonate (2g)
Take 2-rubigan benzene isonitrile 1g(1.0mmol), bromine difluoridate (DF) ethyl ester (2.0mmol), three (2-phenylpyridines) close iridium (0.03mmol) and salt of wormwood (4.0 mmol), and join in the Schlenk reaction flask of 25mL successively, then ethylene dichloride (10.0mL) is added, and react 45h under being placed in 20 watts of LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, the yield obtaining product diethyl (8-chlorophenanthridin-6-yl) difluoromethylphosphonate is 63%.
1H NMR (400 MHz, CDCl
3): δ = 8.62 (d,
J = 8.0 Hz, 1H), 8.51-8.58 (m, 2H), 8.24 (s, 1H), 7.85 (d,
J = 8.0 Hz, 1H), 7.75-7.81 (m, 2H), 4.48-4.56 (m, 4H), 1.43 (t,
J = 7.2 Hz, 6H)；
13C NMR (125MHz, CDCl
3): δ = 150.2 (td,
J 1= 25.6,
J 2= 14.5 Hz), 141.7, 133.9, 132.3, 131.8, 130.7, 129.4, 129.3, 126.2, 125.5, 124.3, 124.1, 122.0, 119.9 (td,
J 1= 260.8,
J 2= 213.6 Hz), 65.0, 64.95, 16.56, 16.50；
19F NMR (470 MHz, CDCl
3) δ = -105.1 (d,
J = 110.1 Hz, 2F)。
Embodiment 8
The synthesis of diethyl difluoro (8-(trifluoromethyl) phenanthridin-6-yl) methylphosphonate (2h)
Take 2-to trifluorophenyl benzene isonitrile 1h(1.0mmol), bromine difluoridate (DF) ethyl ester (3.0mmol), three (2-phenylpyridines) close iridium (0.05mmol) and sodium-acetate (3.0 mmol), and join in the Schlenk reaction flask of 25mL successively, then methylene dichloride (10.0mL) is added, and react 40h under being placed in 5 light blue LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, the yield obtaining product diethyl difluoro (8-(trifluoromethyl) phenanthridin-6-yl) methylphosphonate is 50%.
1H NMR (400 MHz, CDCl
3): δ = 8.89 (s, 1H), 8.81 (d,
J = 8.4 Hz, 1H), 8.64 (d,
J = 8.4 Hz, 1H), 8.29 (d,
J = 8.4 Hz, 1H), 8.10 (d,
J = 8.4 Hz, 1H), 7.81-7.89 (m, 2H), 4.46-4.55 (m, 4H),1.43 (t,
J = 7.2 Hz, 6H)；
13C NMR (125 MHz, CDCl
3): δ = 150.5(m), 142.4, 136.0, 130.9, 130.3, 129.6 (q,
J = 34.0Hz), 129.4, 127.1, 126.6, 124.5, 123.9, 123.6, 123.1(q,
J = 270.8 Hz), 122.5, 120.0 (td,
J 1= 260.6,
J 2= 213.8 Hz), 65.05, 65.0, 16.53, 16.48。
Embodiment 9
The synthesis of diethyl difluoro (8-phenylphenanthridin-6-yl) methylphosphonate (2i)
Take 2-xenyl benzene isonitrile 1i(1.0mmol), bromine difluoridate (DF) ethyl ester (4.0mmol), [4, 4'-di-t-butyl-2, 2'-dipyridyl] two [2-2-phenylpyridines] close iridium hexafluorophosphate (0.02mmol) and Potassium ethanoate (3.0 mmol), and join in the Schlenk reaction flask of 25mL successively, then, add dimethyl sulfoxide (DMSO) (10.0mL), and react 40h under being placed in 40 watts of LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, the yield obtaining product diethyl difluoro (8-phenylphenanthridin-6-yl) methylphosphonate (2i) is 56%.
White solid, mp 118-120℃；
1H NMR (400 MHz, CDCl
3): δ = 8.81 (s, 1H), 8.75 (d,
J = 8.4Hz, 1H), 8.63 (d,
J = 8.4 Hz, 1H), 8.24 (d,
J = 8.0 Hz, 1H), 8.15 (d,
J = 8.0 Hz, 1H), 7.70-7.8 (m, 4H), 7.50-7.55 (m, 2H), 4.50-4.58 (m, 4H),1.42 (t,
J = 7.2 Hz, 6H)；
13C NMR (125MHz, CDCl
3): δ = 150.4 (td,
J 1= 26.0,
J 2= 14.8 Hz), 141.8, 140.5, 140.0, 132.9, 130.6, 129.1, 129.0, 128.0, 127.6, 127.5, 126.2, 124.8, 124.7, 123.0, 122.2, 119.8 (td,
J 1= 260.8,
J 2= 213.4 Hz), 64.92, 64.87, 16.56, 16.52。
Embodiment 10
The synthesis of diethyl difluoro (10-methylphenanthridin-6-yl) methylphosphonate (2j)
Take 2-o-tolyl benzene isonitrile 1j(1.0mmol), bromine difluoridate (DF) ethyl ester (2.0mmol), dichloro three (2, 2'-bis-pyridine) close ruthenium (II) hexahydrate (0.03mmol) and triethylamine (4.0 mmol), and join in the Schlenk reaction flask of 25mL successively, then N is added, dinethylformamide (10.0mL), and react 42h under being placed in 5 light blue LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, the yield obtaining product diethyl difluoro (10-methylphenanthridin-6-yl) methylphosphonate (2j) is 68%.
White solid, mp 75-76℃；
1H NMR (400 MHz, CDCl
3): δ = 8.85 (d,
J = 8.0 Hz, 1H), 8.54 (d,
J = 8.0 Hz, 1H), 8.28 (d,
J = 8.0 Hz, 1H), 7.69-7.79 (m, 3H), 7.63 (d,
J = 8.0 Hz, 1H), 4.50-4.59 (m, 4H), 3.15 (s, 3H), 1.42 (t,
J = 7.2 Hz, 6H)；
13C NMR (125MHz, CDCl
3): δ = 150.4 (td,
J 1= 24.8,
J 2= 13.5 Hz), 142.8, 135.6, 135.4, 133.5, 130.8, 128.3, 128.0, 127.1, 126.7, 126.2, 125., 123.9, 119.9 (td,
J 1= 260.0,
J 2= 213.2 Hz), 64.86, 64.81, 27.1, 16.59, 16.54。
Embodiment 11
The synthesis of diethyl difluoro (2-fluorophenanthridin-6-yl) methylphosphonate (2k)
Take 4-fluorine 2-phenyl benzene isonitrile 1k(1.0mmol), bromine difluoridate (DF) ethyl ester (3.5mmol), eosin W or W S (0.04mmol) and diisopropylethylamine (2.0mmol), and join in the Schlenk reaction flask of 25mL successively, then fluorobenzene (10.0mL) is added, and react 36h under being placed in 20 watts of LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, the yield obtaining product diethyl difluoro (2-fluorophenanthridin-6-yl) methylphosphonate (2k) is 65%.
White solid, mp 111-113℃；
1H NMR (400 MHz, CDCl
3): δ = 8.60 (d,
J= 7.6 Hz, 1H), 8.53 (d,
J = 7.6 Hz, 1H), 8.17-8.22 (m, 2H), 7.88 (t,
J = 7.6 Hz, 1H), 7.77 (t,
J = 7.6 Hz, 1H), 7.46-7.52 (m, 1H), 4.46-4.56 (m, 4H),1.42 (t,
J = 7.2 Hz, 6H)；
13C NMR (125 MHz, CDCl
3): δ = 162.5 (d,
J= 247.6 Hz), 150.3(td,
J 1= 26.0,
J 2= 14.2 Hz), 138.6, 133.3 (d,
J= 3.3 Hz), 132.9 (d,
J = 8.9 Hz), 131.2, 128.4, 126.9, 126.5, 125.4, 122.6, 119.9 (td,
J 1= 260.2,
J 2= 213.6 Hz), 118.1 (d,
J= 24.0 Hz), 107.2 (d,
J = 23.3 Hz), 64.90, 64.85, 16.53, 16.49。
Embodiment 12
The synthesis of diethyl difluoro (2-methylphenanthridin-6-yl) methylphosphonate (2l)
Take 4-methyl 2-phenyl benzene isonitrile 1l(1.0mmol), bromine difluoridate (DF) ethyl ester (4mmol), rhodamine B (0.01mmol) and salt of wormwood (3.0 mmol), and join in the Schlenk reaction flask of 25mL successively, then, add chlorobenzene (10.0mL), and react 39h under being placed in 40 watts of LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, the yield obtaining product diethyl diethyl difluoro (2-methylphenanthridin-6-yl) methylphosphonate (2l) is 59%.
White solid, mp 102-104℃；
1H NMR (400 MHz, CDCl
3): δ = 8.68 (d,
J= 7.6 Hz, 1H), 8.59 (d,
J = 8.0 Hz, 1H), 8.39 (s, 1H), 8.12 (d,
J= 8.0 Hz, 1H), 7.89 (t,
J = 7.6 Hz, 1H), 7.73 (t,
J = 7.6 Hz, 1H), 7.60 (d,
J = 7.6 Hz, 1H), 4.48-4.56 (m, 4H),2.66 (s, 3H), 1.41 (t,
J = 7.2 Hz, 6H)；
13C NMR (100 MHz, CDCl
3): δ = 150.0 (td,
J 1= 25.6,
J 2= 14.8 Hz), 140.1, 139.1, 133.6, 130.9, 130.8, 130.3, 127.6, 126.8, 124.7, 123.9, 122.4, 121.7, 119.8 (td,
J 1= 260.2,
J 2= 213.5 Hz), 64.88, 64.83, 22.0, 16.55, 16.50。
Embodiment 13
The synthesis of diethyl difluoro (3-(trifluoromethyl) phenanthridin-6-yl) methylphosphonate (2m)
Take 5-trifluoromethyl-2-phenyl benzene isonitrile 1m(1.0mmol), bromine difluoridate (DF) ethyl ester (5mmol), three (2-phenylpyridines) close iridium (0.02mmol) and sodium carbonate (4.0 mmol), and join in the Schlenk reaction flask of 25mL successively, then, add acetonitrile (10.0mL), and react 43h under being placed in 5 light blue LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, the yield obtaining product diethyl difluoro (3-(trifluoromethyl) phenanthridin-6-yl) methylphosphonate (2m) is 63%.
White solid, mp 115-116℃；
1H NMR (400 MHz, CDCl
3): δ = 8.62-8.67 (m, 2H), 8.51 (s, 1H), 8.27 (d,
J = 8.4 Hz, 1H), 7.99 (t,
J = 7.6 Hz, 1H), 7.80-7.87 (m, 2H), 4.47-4.56 (m, 4H),1.42 (t,
J = 7.2 Hz, 6H)；
13C NMR (125 MHz, CDCl
3): δ = 150.8(m), 143.5, 133.1, 131.9, 131.0, 129.5, 128.2, 126.8, 126.3, 126.0, 123.4 (q,
J= 271.8 Hz), 123.1, 123.0, 122.9, 119.9 (td,
J 1= 260.6,
J 2= 213.3 Hz), 64.55, 64.49, 16.46, 16.41。
Embodiment 14
The synthesis of diethyl difluoro (2,4-dimethylphenanthridin-6-yl) methylphosphonate (2n)
Take 4, 6-dimethyl-2-phenyl benzene isonitrile 1n(1.0mmol), bromine difluoridate (DF) ethyl ester (2mmol), [4, 4'-di-t-butyl-2, 2'-dipyridyl] two [2-2-phenylpyridines] close iridium hexafluorophosphate (0.03mmol) and sodium bicarbonate (2.0 mmol), and join in the Schlenk reaction flask of 25mL successively, then, add ethylene dichloride (10.0mL), and react 45h under being placed in 20 watts of LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, obtain product diethyl difluoro (2, 4-dimethylphenanthridin-6-yl) yield of methylphosphonate (2n) is 69%.
White solid, mp 102-104℃；
1H NMR (400 MHz, CDCl
3): δ = 8.63 (d,
J = 7.2 Hz, 1H), 8.55 (d,
J = 7.2 Hz,1H), 8.18 (s, 1H), 7.71 (t,
J = 7.2 Hz, 1H), 7.68 (t,
J = 7.2 Hz, 1H), 7.45 (s, 1H), 4.38-4.47 (m, 4H), 2.89 (s, 3H), 2.57 (s, 3H), 1.39 (t,
J = 7.2 Hz, 6H)；
13C NMR (125 MHz, CDCl
3): δ = 147.8 (td,
J 1= 25.2,
J 2= 14.5 Hz), 139.0, 138.9, 138.7, 133.9, 131.5, 130.5, 127.3, 126.4, 124.7, 123.6, 122.6, 119.8 (td,
J 1= 260.8,
J 2= 213.6 Hz), 119.3, 64.49, 64.44, 22.1, 18.1, 16.53, 16.48。
Embodiment 15
The synthesis of diethyl (2,4-dichlorophenanthridin-6-yl) difluoromethylphosphonate (2o)
Take 4, 6-bis-chloro-2-phenyl benzene isonitrile 1o(1.0mmol), bromine difluoridate (DF) ethyl ester (3mmol), [dichloro three (2, 2'-bis-pyridine) close ruthenium (II) hexahydrate (0.04mmol) and potassium primary phosphate (3.0 mmol), and join in the Schlenk reaction flask of 25mL successively, then, add methylene dichloride (10.0mL), and react 46h under being placed in 40 watts of LED, after reaction terminates, removal of solvent under reduced pressure, use petrol ether/ethyl acetate as eluent, silicagel column is separated, obtain product diethyl (2, 4-dichlorophenanthridin-6-yl) yield of difluoromethylphosphonate (2o) is 55%.
White solid, mp 118-120℃；
1H NMR (500 MHz, CDCl
3): δ = 9.02 (d,
J = 7.6 Hz, 1H), 8.65-8.75 (m, 2H), 8.60 (s, 1H), 7.93-798 (m, 2H), 7.83-7.88 (m, 1H), 4.38-4.46 (m, 4H), 1.46 (t,
J = 7.2 Hz, 6H)；
13C NMR (125 MHz, CDCl
3): δ = 152.0 (td,
J 1= 25.8,
J 2= 14.2 Hz), 142.4, 131.9, 131.7, 129.1, 128.8, 128.7, 126.9, 126.7, 126.4, 124.6, 123.3, 122.6, 120.1 (td,
J 1= 260.4,
J 2= 213.5 Hz), 63.85, 63.79, 16.49, 16.44。
Isonitrile compounds, particularly in generation nitrogen-containing hetero compounds, has critical role.The present invention adopts 2-aryl virtue isonitrile and bromine difluoro methyl diethyl phosphonate to be raw material, under photocatalyst effect, prepares a series of 6-difluoro methylphosphonic acid diethyl-ester group phenanthridines analog derivative.Present method, without the need to the oxygenant of the amount of substances such as interpolation, it also avoid the use of the use of highly toxic radical initiator simultaneously, more green, economical; With under radiation of visible light, avoid the reaction under high temperature, reaction conditions is gentle, and separating-purifying is convenient, and waste discharge is few, and to the substrate of reaction without particular requirement, the plurality of advantages such as applied widely, has very high using value; Described post-reaction treatment is easy, only needs to add water, extracts, pillar layer separation method, with the mixed solvent of sherwood oil and ethyl acetate for eluent just can obtain 6-difluoro methylphosphonic acid diethyl-ester group phenanthridine derivatives.
The present invention is raw materials used is 2-aryl virtue isonitrile and bromine difluoro methyl diethyl phosphonate, under the catalytic condition of visible ray, add photocatalyst, alkali and organic solvent, there is free radical cyclization in room temperature environment and obtain a series of 6-difluoro methylphosphonic acid diethyl-ester group phenanthridine derivatives, the present invention utilizes visible ray as energy derive, room temperature can be carried out, compared with traditional free radical isocyanide insertion reaction, electronics and energy is transmitted owing to utilizing photocatalyst, whole catalytic cycle process is made to keep redox-neutral, therefore without the need to the oxygenant of the amount of substances such as interpolation, it also avoid the use of highly toxic organotin reagent simultaneously, a kind of gentle, the method of efficient preparation 6 difluoridate (DF) ester group phenanthridine derivatives.
Claims (9)
1. the synthetic method of a 6-difluoro methylphosphonic acid diethyl-ester group phenanthridine derivatives, it is characterized in that: the method with 2-aryl virtue isonitrile and bromine difluoro methyl diethyl phosphonate for raw material, under visible ray illumination, add photocatalyst, alkali and organic solvent, stirring reaction, Reactive Synthesis 6-difluoro methylphosphonic acid diethyl-ester group phenanthridines compounds, reaction conditions is: protection of inert gas, under room temperature condition, the reaction times is 36-48 hour; Its reaction formula is as follows:
。
2. the synthetic method of 6-difluoro methylphosphonic acid diethyl-ester group phenanthridine derivatives as claimed in claim 1, is characterized in that: the substituent R in described reaction formula on two aromatic rings
1for H, 4-F, 4-Me, 4-CF
3, 4,6-dimethyl or 4,6-dichloro; R
2for H, 4-Me, 4-Et, 4-n-Pr, 4-OMe, 4-F, 4-Cl, 4-Ph or 2-Me.
3. the synthetic method of 6-difluoro methylphosphonic acid diethyl-ester group phenanthridine derivatives as claimed in claim 1, is characterized in that: described light source is 20 watts of LED, 40 watts of LED or 5 light blue look LED.
4. the synthetic method of 6-difluoro methylphosphonic acid diethyl-ester group phenanthridine derivatives as claimed in claim 1, it is characterized in that: described photocatalyst is that three (2-phenylpyridines) close iridium, [4,4'-di-t-butyl-2,2'-dipyridyl] two [2-2-phenylpyridines] close iridium hexafluorophosphate, dichloro three (2,2'-bis-pyridine) closes ruthenium (II) hexahydrate, eosin W or W S or rhodamine B.
5. the synthetic method of 6-difluoro methylphosphonic acid diethyl-ester group phenanthridine derivatives as claimed in claim 1, is characterized in that: described photocatalyst consumption is 0.01-0.05 times of 2-aryl virtue isonitrile mole number.
6. the synthetic method of 6-difluoro methylphosphonic acid diethyl-ester group phenanthridine derivatives as claimed in claim 1, is characterized in that: the mol ratio of described raw material is 2-aryl virtue isonitrile: bromine difluoro methyl diethyl phosphonate is 1:2 ~ 6.
7. the synthetic method of 6-difluoro methylphosphonic acid diethyl-ester group phenanthridine derivatives as claimed in claim 1, it is characterized in that: described alkali is salt of wormwood, sodium carbonate, sodium bicarbonate, potassium primary phosphate, potassiumphosphate, sodium-acetate, Potassium ethanoate, triethylamine or diisopropylethylamine.
8. the synthetic method of 6-difluoro methylphosphonic acid diethyl-ester group phenanthridine derivatives as claimed in claim 1, is characterized in that: described alkali consumption is 2-4 times of 2-aryl virtue isonitrile mole number.
9. the synthetic method of 6-difluoro methylphosphonic acid diethyl-ester group phenanthridine derivatives as claimed in claim 1, it is characterized in that: described solvent is fluorobenzene, chlorobenzene, acetonitrile, ethylene dichloride, methylene dichloride, dimethyl sulfoxide (DMSO), N, dinethylformamide or tetrahydrofuran (THF), solvent load is 10mL/mmol 2-aryl virtue isonitrile.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105153032A (en) * | 2015-10-13 | 2015-12-16 | 遵义医学院 | Preparation method of 6-H-phenanthridine compounds by one-pot process |
| CN105218581A (en) * | 2015-11-06 | 2016-01-06 | 洛阳师范学院 | A kind of synthetic method of 3-difluoro methylphosphonic acid diethyl-ester group oxoindole derivative |
| CN105820166A (en) * | 2016-04-21 | 2016-08-03 | 华东理工大学 | New method for photocatalytic green synthesis of dihydrocarboline and derivative thereof |
| CN112441875A (en) * | 2019-08-27 | 2021-03-05 | 浙江工业大学 | Method for copper photocatalytic synthesis of 9-trifluoromethyl-9, 10-dihydrophenanthrene compound |
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| TIEBO XIAO, ET AL.: "Synthesis of 6-substituted phenanthridines by metal-free, visible-light induced aerobic oxidative cyclization of 2-isocyanobiphenyls with hydrazines", 《GREEN CHEMISTRY》 * |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105153032A (en) * | 2015-10-13 | 2015-12-16 | 遵义医学院 | Preparation method of 6-H-phenanthridine compounds by one-pot process |
| CN105218581A (en) * | 2015-11-06 | 2016-01-06 | 洛阳师范学院 | A kind of synthetic method of 3-difluoro methylphosphonic acid diethyl-ester group oxoindole derivative |
| CN105820166A (en) * | 2016-04-21 | 2016-08-03 | 华东理工大学 | New method for photocatalytic green synthesis of dihydrocarboline and derivative thereof |
| CN112441875A (en) * | 2019-08-27 | 2021-03-05 | 浙江工业大学 | Method for copper photocatalytic synthesis of 9-trifluoromethyl-9, 10-dihydrophenanthrene compound |
| CN112441875B (en) * | 2019-08-27 | 2022-03-18 | 浙江工业大学 | Method for copper photocatalytic synthesis of 9-trifluoromethyl-9, 10-dihydrophenanthrene compound |
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