CN115974795A - Disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N heterocycle and synthetic method thereof - Google Patents
Disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N heterocycle and synthetic method thereof Download PDFInfo
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- 125000005010 perfluoroalkyl group Chemical group 0.000 title claims abstract description 22
- MKCBRYIXFFGIKN-UHFFFAOYSA-N bicyclo[1.1.1]pentane Chemical class C1C2CC1C2 MKCBRYIXFFGIKN-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 10
- 238000010189 synthetic method Methods 0.000 title description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 144
- 238000006243 chemical reaction Methods 0.000 claims abstract description 78
- 239000012043 crude product Substances 0.000 claims abstract description 30
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 25
- 239000012044 organic layer Substances 0.000 claims abstract description 22
- 238000010791 quenching Methods 0.000 claims abstract description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 230000001699 photocatalysis Effects 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 239000007788 liquid Substances 0.000 claims abstract description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 238000007146 photocatalysis Methods 0.000 claims abstract description 4
- 239000000047 product Substances 0.000 claims abstract description 4
- 238000001308 synthesis method Methods 0.000 claims abstract description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 42
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 23
- 239000003208 petroleum Substances 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- -1 perfluoro Chemical group 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 150000003153 propellanes Chemical class 0.000 claims description 4
- ZTXSPLGEGCABFL-UHFFFAOYSA-N 1.1.1-propellane Chemical compound C1C23CC31C2 ZTXSPLGEGCABFL-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000010410 layer Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 16
- PGRFXXCKHGIFSV-UHFFFAOYSA-N 1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I PGRFXXCKHGIFSV-UHFFFAOYSA-N 0.000 description 15
- 238000000926 separation method Methods 0.000 description 10
- 239000012267 brine Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 6
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000005286 illumination Methods 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- IWVPWPYTOHQPMH-UHFFFAOYSA-N 1-methyl-5,6-diphenylpyrazin-2-one Chemical compound C=1C=CC=CC=1C=1N=CC(=O)N(C)C=1C1=CC=CC=C1 IWVPWPYTOHQPMH-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 3
- 239000001294 propane Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- BULLJMKUVKYZDJ-UHFFFAOYSA-N 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluoro-6-iodohexane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I BULLJMKUVKYZDJ-UHFFFAOYSA-N 0.000 description 1
- BBZVTTKMXRPMHZ-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoro-2-iodopropane Chemical compound FC(F)(F)C(F)(I)C(F)(F)F BBZVTTKMXRPMHZ-UHFFFAOYSA-N 0.000 description 1
- CHPVQLYVDDOWNT-UHFFFAOYSA-N 1-methylquinoxalin-2-one Chemical compound C1=CC=C2N=CC(=O)N(C)C2=C1 CHPVQLYVDDOWNT-UHFFFAOYSA-N 0.000 description 1
- OHXPGWPVLFPUSM-KLRNGDHRSA-N 3,7,12-trioxo-5beta-cholanic acid Chemical class C1CC(=O)C[C@H]2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC(O)=O)C)[C@@]4(C)C(=O)C[C@@H]3[C@]21C OHXPGWPVLFPUSM-KLRNGDHRSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229940125373 Gamma-Secretase Inhibitor Drugs 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical class CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- HGWXXIZVRRTDKT-UHFFFAOYSA-N ethyl 2,2-difluoro-2-iodoacetate Chemical compound CCOC(=O)C(F)(F)I HGWXXIZVRRTDKT-UHFFFAOYSA-N 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical class FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 239000003540 gamma secretase inhibitor Substances 0.000 description 1
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical class CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical class O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- UXPOJVLZTPGWFX-UHFFFAOYSA-N pentafluoroethyl iodide Chemical compound FC(F)(F)C(F)(F)I UXPOJVLZTPGWFX-UHFFFAOYSA-N 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- FFRYUAVNPBUEIC-UHFFFAOYSA-N quinoxalin-2-ol Chemical compound C1=CC=CC2=NC(O)=CN=C21 FFRYUAVNPBUEIC-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N heterocycle and a synthesis method thereof. Firstly, nitrogen-containing heterocycle, [1.1.1] propeller alkane, perfluoro-iodoalkane and alkali catalyst are added into an organic solvent, and stirred and reacted for 6 to 24 hours at normal temperature under the photocatalysis condition; after the reaction is finished, adding saturated saline solution to quench the reaction, adding an organic solvent ethyl acetate to extract and layer, taking an organic layer, drying, filtering and concentrating to obtain a dark brown liquid crude product, and purifying the crude product by silica gel column chromatography to obtain a target product, namely the disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N heterocycle. The method disclosed by the invention is mild in reaction condition, green and environment-friendly, simple in experimental operation, good in reaction selectivity and high in product yield.
Description
Technical Field
The invention belongs to the technical field of chemical industry, in particular to the technical field of synthesis of pharmaceutical and chemical intermediates, and particularly relates to disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N heterocycle and a synthesis method thereof.
Background
The three-dimensional small ring stent is very important in modern drug discovery, can expand chemical space of similar drugs and optimize the waiting timeAnd (4) selecting the medicines. Wherein, bicyclo [1.1.1]Pentanes (BCPs) are rigid, linear, sp-rich 3 The motif of (A) can be used as a biological allelic substituent of an aromatic ring, alkyne and a t-Bu group, and the bioactive molecule introduced into the structure can effectively improve lipid solubility, cell membrane penetrability and drug metabolic stability, so that the motif of (A) is widely applied to the development of new drugs. Furthermore, bicyclic [1.1.1] 1]The pentane unit can realize 180-degree space separation of key pharmacophores, so that the pentane unit can be used as a non-classical bioisostere to replace an aromatic ring.
The compounds (V) (VI) (VII) are some biologically active disubstituted BCP derivatives, e.g. the compound (V) is a gamma-secretase inhibitor. These all represent the value of application of BCP structures in the field of drug research. Therefore, there is a great interest in developing a new method for the simple, economical and green synthesis of disubstituted BCP and derivatives thereof. The photocatalytic organic synthesis has the advantages of mild reaction conditions, renewable energy sources, high reaction efficiency and the like.
Disclosure of Invention
The invention aims to solve the problems in the prior art and provides a method for synthesizing disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N heterocycle.
The method of the invention specifically comprises the following steps:
adding a nitrogen-containing heterocycle, 1.1.1] propellane, perfluoro-iodoalkane and a base catalyst into an organic solvent, and stirring and reacting for 6-24 hours at normal temperature under a photocatalytic condition, wherein the reaction formula is as follows:
the molar ratio of the added nitrogen-containing heterocycle, the [1.1.1] propeller alkane and the perfluoro iodoalkane is 1-3.
The structural formula of the nitrogen-containing heterocycle is shown as
Wherein R is 1 Is hydrogen, alkyl, benzyl, substituted benzyl, or an ester group; r is 2 Is a substituted or unsubstituted phenyl group;
said [1.1.1]The propellane has the structural formula
The structural formula of the perfluoro iodoalkane is I-R f (ii) a Wherein is C 2 F 5 、 i C 3 F 7 、C 4 F 9 、C 6 F 13 、C 8 F 17 Or CF 2 COOEt。
The alkali catalyst is one of potassium phosphate, triethylene diamine, triethylamine, N-diisopropylethylamine, cesium carbonate, tetrabutylammonium iodide and 1, 8-diazabicycloundecen-7-ene, and the molar ratio of the added alkali catalyst to the nitrogen-containing heterocycle is 1-5, preferably 3.
The organic solvent is one of ethyl acetate, dichloromethane, acetonitrile, acetone, 1, 4-dioxane, N-dimethylformamide, dimethyl carbonate and N-methylpyrrolidone, and the mass ratio of the organic solvent to the nitrogen-containing heterocycle is 10-100, preferably 15-50.
The reaction time is preferably 12 to 18 hours.
The wavelength of light used for photocatalysis is 365-455 nm, preferably 400-420 nm.
After the reaction in the step (2) is finished, adding saturated saline solution to quench the reaction, and adding an organic solvent ethyl acetate to extract and stratify; drying the organic layer with anhydrous magnesium sulfate or anhydrous sodium sulfate, filtering, concentrating to obtain a dark brown liquid crude product, and purifying the crude product by silica gel column chromatography to obtain a light yellow solid target product containing perfluoroalkyl and N-heterocyclic disubstituted bicyclo [1.1.1] pentane; the solvent used for silica gel column chromatography is 1:3 ethyl acetate and petroleum ether.
Another object of the present invention is to provide a disubstituted bicyclic ring containing perfluoroalkyl and N-heterocycle synthesized by the above method
[1.1.1]Pentane with the structural formula
Wherein R is 1 Is hydrogen, alkyl, benzyl, substituted benzyl, or an ester group; r is 2 Is a substituted or unsubstituted phenyl group; r f Is C 2 F 5 、 i C 3 F 7 、C 4 F 9 、C 6 F 13 、C 8 F 17 Or CF 2 COOEt。
The invention takes nitrogen-containing heterocycle, [1.1.1] propellane and perfluoro-iodoalkane as raw materials, and obtains N heterocycle substituted BCP containing perfluoro-alkane and derivatives thereof with high selectivity and high yield under the condition of photoreaction through base catalysis under mild condition. The prepared disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N heterocycle is a novel disubstituted BCP structure, can realize 180-degree key pharmacodynamic group space separation, and is a non-classical biological electron isostere of para-disubstituted benzene ring. Meanwhile, the perfluoroalkyl group exists in the molecular structure, so that the molecule has potential high lipid solubility, cell membrane penetrability and drug metabolic stability, and has good research and application values.
Detailed Description
The invention is further described with reference to the following specific examples, but the scope of protection of the invention is not limited thereto: example 1.
1-methyl-5, 6-diphenyl-pyrazinone (262mg, 1mmol), [1.1.1]Propylalane (66mg, 1mmol), perfluoroiodobutane (346mg, 1mmol), 1, 8-diazabicycloundec-7-ene (456mg, 3mmol) were added to a reaction flask, dissolved by adding N-methylpyrrolidone (5 g), and the reaction was stirred under illumination at 410nm for 16 hours. After the reaction, adding a saline solution (20 g) to quench the reaction, adding ethyl acetate (20 g), fully stirring, standing for layering, and removing an organic layerAfter drying over magnesium sulfate, filtration and concentration, a dark brown crude product is obtained, which is purified by silica gel column chromatography (ethyl acetate: petroleum ether =1 3) to yield 360mg of a light yellow solid with a yield of 66% and a melting point of 146 ℃. 1 H NMR(400MHz，CDCl 3 )δ7.40(dd，J＝4.8，2.3Hz，3H)，7.20(dd，J＝7.3，2.1Hz，2H)，7.13(s，5H)，3.30(s，3H)，2.55(s，6H)； 13 C NMR(101MHz，CDCl 3 )δ155.3，151.6，138.0，137.6，132.7，132.5，130.0，129.6，129.3，129.2，127.8，127.1，51.0，41.8，37.9(t，J＝37.8Hz)，33.7， 13 C NMR for C 4 F 9 could not be assigned； 19 F NMR(471MHz，CDCl 3 )δ-81.03–-81.09(m)，-115.64–-117.48(m)，-121.42–-122.98(m)，-125.32–-126.91(m)；HRMS(ESI+)：Calculated for C 26 H 19 F 9 N2O：[M+H]+
547.1426，Found 547.1427。
Example 2.
1-methyl-5, 6-diphenyl-pyrazinone (262mg, 1mmol), [1.1.1] propeller alkane (165 mg,
2.5 mmol), pentafluoroiodoethane (492mg, 3mmol) and potassium phosphate (636mg, 3mmol) were charged into a reaction flask, dissolved in acetonitrile (4.1 g), and the reaction mixture was stirred under 365nm light for 18 hours. After the reaction, a brine solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was fully stirred and then allowed to stand for layering, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a dark brown crude product, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1). 1 H NMR(500MHz，CDCl 3 )δ7.40(t，J＝5.8Hz，3H)，7.19(dd，J＝7.5，1.8Hz，2H)，7.13(s，5H)，3.30(s，3H)，2.51(s，6H)； 13 C NMR(126MHz，CDCl 3 )δ155.3，151.6，138.0，137.6，132.7，132.5，130.0，129.6，129.3，129.2，127.7，127.1，50.6，41.5，37.0(t，J＝30.2Hz)，33.7， 13 C NMR for C 2 F 5 could not be assigned； 19 F NMR(471MHz，CDCl 3 )δ-82.65，-120.86；
HRMS(ESI+)：Calculated for C 24 H 19 F 5 N2O：[M+H]+447.149，Found 447.1493。
Example 3.
1-methyl-5, 6-diphenyl-pyrazinone (262mg, 1mmol), [1.1.1]Propylalane (132mg, 2mmol), heptafluoro-2-iodopropane (888mg, 3mmol) and 1, 8-diazabicycloundec-7-ene (532mg, 3.5 mmol) were charged into a reaction flask, dissolved in acetonitrile (4.1 g), and reacted under stirring at 410nm for 12 hours. After the reaction was completed, a saline solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was sufficiently stirred and then allowed to stand for layering, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a dark brown crude product, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1). 1 H NMR(500MHz，CDCl 3 )δ7.40(d，J＝6.8Hz，3H)，7.19(dd，J＝7.5，1.8Hz，2H)，
7.12(s，5H)，3.30(s，3H)，2.57(s，6H)； 13 C NMR(126MHz，CDCl 3 )δ155.3，151.4，138.0，137.6，132.7，132.5，130.0，130.0，129.3，129.2，127.7，127.1，52.0，41.7，36.5(d，J＝26.5Hz)，33.7， 13 C NMR for i C 3 F 7 could not be assigned； 19 F NMR(471MHz，CDCl 3 )δ-74.62(d，J＝8.8Hz)，-183.26–-183.29(m)；HRMS(ESI+)：Calculated for C 25 H 19 F 7 N2O：[M+H]+497.1458，Found 497.1456。
Example 4.
1-methyl-5, 6-diphenyl-pyrazinone (262mg, 1mmol), [1.1.1] propeller alkyl (99 mg,
1.5 mmol), perfluoroiodohexane (892mg, 2mmol) and 1, 8-diazabicycloundecen-7-ene (380mg, 2.5 mmol) were charged into a reaction flask, dissolved in methylene chloride (4.3 g), and reacted under stirring at 395nm for 24 hours. After the reaction, a saline solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was sufficiently stirred and then allowed to stand for layering, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a dark brown crude product, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1). 1 H NMR(400MHz，CDCl 3 )δ7.41(dt，J＝5.6，2.9Hz，3H)，7.20(dd，J＝7.3，2.1Hz，2H)，7.13(s，5H)，3.30(s，3H)，2.55(s，6H)； 13 C NMR(101MHz，CDCl 3 )δ155.3，151.6，138.0，137.6，132.7，132.5，130.0，129.6，129.3，129.2，127.8，127.1，51.0，41.8，38.0(t，J＝31.5Hz)，33.7， 13 C NMR for C 6 F 13 could not be assigned； 19 F NMR(471MHz，CDCl 3 )δ-80.78–-80.83(m)，-116.30–-116.37(m)，-121.30–-121.36(m)，-121.87–-121.93(m)，-122.92(s)，-126.08–-126.16(m)；
HRMS(ESI+)：Calculated for C 28 H 19 F 13 N 2 O：[M+H]+647.1363，Found 647.1363。
Example 5.
1-methyl-5, 6-diphenyl-pyrazinone (262mg, 1mmol), [1.1.1] propeller-ane (165 mg,
2.5 mmol), perfluorooctyliodoalkane (1092mg, 2mmol), 1, 8-diazabicycloundecen-7-ene (456mg, 3mmol) were charged into a reaction flask, dissolved with dichloromethane (5 g), and reacted under stirring at 410nm for 6 hours. After the reaction is finished, salt is addedThe reaction was quenched with aqueous solution (20 g), ethyl acetate (20 g) was added, stirring well and then left to layer, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give a dark brown crude product, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1) to give 463mg of a pale yellow solid, yield 62%, melting point 159 ℃. 1 H NMR(500MHz，CDCl 3 )δ7.40(d，J＝6.7Hz，3H)，7.20(dd，J＝7.5，1.7Hz，2H)，
7.13(s，5H)，3.30(s，3H)，2.55(s，6H)； 13 C NMR(126MHz，CDCl 3 )δ155.3，151.6，138.0，137.6，132.7，132.5，130.0，129.6，129.3，129.2，127.7，127.1，51.0，41.8，38.0(t，J＝31.5Hz)，33.7， 13 C NMR for C 8 F 17 could not be assigned； 19 F NMR(471MHz，CDCl 3 )δ-80.74–-80.78(m)，-116.29–-116.36(m)，-121.24–-121.28(m)，-121.64–-121.68(m)，-121.89–-121.92(m)，-122.68–-122，73(m)，-126.07–-126.11(m)；HRMS(ESI+)：Calculated for C 30 H 19 F 17 N 2 O：[M+H]+747.1299，Found 747.1299。
Example 6.
1-methyl-2 (1H) -quinoxalinone (160mg, 1mmol), [1.1.1] properalane (198mg, 3mmol), ethyl difluoroiodoacetate (1250mg, 5mmol), tetrabutyl ammonium iodide (1.1g, 3mmol) were charged into a reaction flask, and N-methylpyrrolidone (2.4 g) was added to dissolve, and the reaction was stirred under illumination at 420nm for 10 hours. After the reaction, a brine solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was stirred sufficiently and allowed to stand for separation, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a dark brown crude product, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether =1:
3) Purification gave 226mg of a pale yellow liquid in a yield of 65%. 1 H NMR(500MHz，CDCl 3 )δ7.84(d，
J＝8.0Hz，1H)，7.54(t，J＝7.8Hz，1H)，7.34(t，J＝7.6Hz，1H)，7.29(d，J＝8.4Hz，1H)，4.36(q，J＝7.1Hz，2H)，3.66(s，3H)，2.43(s，6H)，1.37(t，J＝7.1Hz，3H)； 13 C NMR(126MHz，CDCl 3 )δ163.3(t，J＝34.0Hz)，155.3，154.5，133.4，132.8，130.4，130.2，123.7，113.6，112.2(t，J＝250.7Hz)，62.8，50.5(t，J＝3.8Hz)，41.5，
39.2(t，J＝31.5Hz)，28.6，14.2； 19 F NMR(471MHz，CDCl 3 )δ-111.55；HRMS(ESI+)：Calculated for C 18 H 18 F 2 N 2 O 3 ：[M+H]+349.1358，Found 349.1359。
Example 7.
O-vanillin derivatives (338mg, 1mmol), [1.1.1]Propylalane (132mg, 2mmol), perfluoroiodobutane (1384mg, 4mmol) and cesium carbonate (977mg, 3mmol) were put in a reaction flask, dissolved in N-methylpyrrolidone (5 g), and reacted under stirring at 410nm for 16 hours. After the reaction was completed, a saline solution (20 g) was added to quench the reaction, ethyl acetate (16.9 g) was added, the mixture was sufficiently stirred and then allowed to stand for separation, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a dark brown crude product, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1. 1 H NMR(500MHz，CDCl 3 )δ10.46(s，1H)，7.87(d，J＝7.8Hz，1H)，7.56(t，J＝7.5Hz，1H)，7.48(d，J＝8.3Hz，1H)，7.45–7.42(m，1H)，7.35(t，J＝7.5Hz，1H)，7.17(d，J＝4.4Hz，2H)，4.57–4.50(m，2H)，4.28(t，J＝5.7Hz，2H)，3.88(s，3H)，2.56(s，6H)，2.26(td，J＝11.6，5.8Hz，2H)； 13 C NMR(126MHz，CDCl 3 )δ189.9，154.7，154.3，152.9，151.2，133.0，132.6，130.7，130.4，129.9，124.4，123.7，119.7，118.0，113.7，72.2，56.0，51.3，42.0，39.6，37.9(t，J＝30.2Hz)，28.0， 13 C NMR for C 4 F 9 could not be assigned； 19 F NMR(471MHz，CDCl 3 )δ-81.06(t，J＝9.9Hz)，-116.57–-116.66(m)，-122.11–-122.35(m)，-125.48–-126.07(m)；HRMS(ESI+)：Calculated for C 28 H 23 F 9 N 2 O 4 ：
[M+H]+623.1587，Found 623.1586。
Example 8.
Ibuprofen derivatives (378mg, 1mmol) and [1.1.1]Propane (132mg, 2mmol), perfluoroiodobutane (692mg, 2mmol) and N, N-diisopropylethylamine (228mg, 1.5 mmol) were charged into a reaction flask, dissolved by adding acetone (7.56 g), and reacted under stirring at 455nm for 8 hours. After the reaction was completed, a saline solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was sufficiently stirred and then allowed to stand for layering, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a dark brown crude product, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1) to obtain 470mg of a pale yellow solid, yield 71%, melting point 80 ℃. 1 H NMR(500MHz，CDCl 3 )δ7.85(dd，J＝7.9，0.9Hz，1H)，7.51–7.45(m，1H)，7.38–7.31(m，2H)，7.09(d，J＝8.1Hz，2H)，7.05(d，J＝8.1Hz，2H)，4.53–4.47(m，1H)，4.46–4.36(m，3H)，3.59(q，J＝7.1Hz，1H)，2.55(s，6H)，2.44(d，J＝7.2Hz，2H)，1.84(dt，J＝13.5，6.8Hz，1H)，1.42(d，J＝7.2Hz，3H)，0.90(d，J＝6.6Hz，6H)； 13 C NMR(126MHz，CDCl 3 )δ174.7，154.6，154.3，140.7，137.2，133.0，132.9，130.5，130.4，129.4，127.1，123.8，113.8，61.0，51.2，45.1，45.0，41.9，40.6，37.9(t，J＝30.2Hz)，30.2，22.4，18.3， 13 C NMR for C 4 F 9 could not be assigned； 19 F NMR(471MHz，CDCl 3 )δ-81.08(t，J＝9.9Hz)，-115.53–-116.68(m)，-121.39–-122.89(m)，-125.25–-126.08(m)；
HRMS(ESI+)：Calculated for C 32 H 31 F 9 N2O 3 ：[M+H]+663.2264，Found 663.2265。
Example 9.
Loxoprofen derivatives (418mg, 1mmol) and [1.1.1]Propylalane (165mg, 2.5 mmol), perfluoroiodobutane (692mg, 2mmol) and 1, 8-diazabicycloundece-7-ene (456 mg, 3mmol) were charged into a reaction flask, dissolved in acetone (12.54 g), and reacted under stirring at 410nm for 16 hours. After the reaction was completed, a saline solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was sufficiently stirred and then allowed to stand for separation, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a dark brown crude product, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1). 1 H NMR(500MHz，CDCl 3 )δ7.85(dd，J＝7.9，1.1Hz，1H)，7.51–7.44(m，1H)，7.34(dd，J＝15.6，7.8Hz，2H)，7.08(q，J＝8.3Hz，4H)，4.52–4.34(m，4H)，3.59(q，J＝7.1Hz，1H)，3.11(dd，J＝13.9，
2.6Hz，1H)，2.54(s，6H)，2.48(dd，J＝11.8，4.8Hz，1H)，2.38–2.29(m，2H)，2.13–2.05(m，2H)，1.96(d，J＝6.5Hz，1H)，1.78–1.70(m，1H)，1.58–1.50(m，1H)，1.41(d，J＝7.2Hz，3H)； 13 C NMR(126MHz，CDCl 3 )δ220.09，174.5，154.6，154.3，139.1，137.8，132.9，132.9，130.5，130.4，129.2，127.4，123.8，113.7，61.0，51.2，50.9，45.0，41.9，40.5，38.1，37.9(t，J＝30.2Hz)，35.2，29.3，20.5，18.3， 13 C NMR for C 4 F 9 could not be assigned； 19 F NMR(471MHz，CDCl 3 )δ-80.51–-81.75(m)，-115.67–-117.56(m)，-121.36–-123.00(m)，-125.38–-126.96(m)；HRMS(ESI+)：Calculated for C 34 H 31 F 9 N2O 4 ：[M+H]+703.2213，Found 703.2214。
Example 10.
Flurbiprofen derivatives (416mg, 1mmol) [1.1.1]]Propylalane (198mg, 3mmol), perfluoroiodobutane (692mg, 2mmol) and 1, 8-diazabicycloundec-7-ene (760mg, 5mmol) were charged into a reaction flask, dissolved by adding acetone (16.64 g), and reacted under stirring at 410nm for 15 hours. After the reaction, a brine solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was sufficiently stirred and then allowed to stand for separation, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a dark brown crude product, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1). 1 H NMR(500MHz，CDCl 3 )δ7.84(dd，J＝8.0，1.3Hz，1H)，7.56–7.52(m，2H)，7.47(ddd，J＝17.2，11.8，4.6Hz，3H)，7.41–
7.29(m，4H)，7.07–6.92(m，2H)，4.59–4.39(m，4H)，3.65(q，J＝7.1Hz，1H)，2.56(s，6H)，1.47(d，J＝7.2Hz，3H)； 13 C NMR(126MHz，CDCl 3 )δ173.9，159.6(d，J＝249.5Hz)，154.6，154.3，141.2(d，J＝7.6Hz)，135.3，132.9(d，J＝10.1Hz)，130.8(d，J＝3.8Hz)，130.5，130.4，128.9(d，J＝2.5Hz)，128.5，128.0，127.9，127.8，123.8，123.4(d，J＝3.8Hz)，115.2(d，J＝23.9Hz)，113.7，61.3，51.2，44.9，41.9，40.6，37.9(t，J＝30.2Hz)，18.2， 13 C NMR for C 4 F 9 could not be assigned； 19 F NMR(471MHz，CDCl 3 )δ-80.70–-81.49(m)，-116.25–-116.93(m)，-117.24(s)，-121.90–-122.80(m)，-125.56–-126.42(m)；HRMS(ESI+)：Calculated for C 34 H 26 F 10 N 2 O 3 ：[M+H]+701.1857，Found 701.1855。
Example 11.
Mixing indomethacin derivative (391mg, 1mmol) and [1.1.1]Propylalane (132mg, 2mmol), perfluoroiodobutane (1730mg, 5mmol) and triethylamine (303mg, 3mmol) were put in a reaction flask, and dimethyl carbonate (5 g) was added thereto to dissolve them, followed by stirring at 410nm for 20 hours. After the reaction was completed, a saline solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was sufficiently stirred and then allowed to stand for layering, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a dark brown crude product, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1) to obtain 365mg of a yellow liquid with a yield of 54%. 1 H NMR(500MHz，CDCl 3 )δ7.83(dd，J＝7.9，1.3Hz，1H)，7.78(s，1H)，7.39(ddd，J＝8.4，7.1，1.4Hz，1H)，7.34–7.27(m，2H)，7.12(d，J＝8.7Hz，1H)，6.90(d，J＝2.3Hz，1H)，6.77(dd，J＝8.7，2.4Hz，1H)，4.44(t，J＝4.0Hz，4H)，3.82(s，3H)，3.59(s，2H)，2.56(s，6H)，2.26(s，3H)； 13 C NMR(126MHz，CDCl 3 )δ171.9，154.6，154.3，154.2，133.6，132.9，132.8，130.5，130.4，130.1，128.8，123.8，113.6，111.0，110.9，103.7，100.4，60.9，55.9，51.3，41.9，40.7，37.9(t，J＝30.2Hz)，30.3，11.7， 13 C NMR for C 4 F 9 could not be assigned； 19 F NMR(471MHz，CDCl 3 )δ-80.38–-81.77(m)，-115.60–-117.58(m)，-121.32–-123.02(m)，-125.32–-127.25(m)；HRMS(ESI+)：Calculated for C 31 H 26 F 9 N 3 O 4 ：[M+H]+676.1852，Found 676.1857。
Example 12.
Mixing the solid-reducing alcohol acid derivative (386mg, 1mmol) and [1.1.1]Propane (165mg, 2.5 mmol), perfluoroiodobutane (692mg, 2mmol), triethylenediamine (336mg, 3mmol) were charged in a reaction flask, anddimethyl carbonate (24 g) was added and dissolved, and the reaction was stirred under 400nm light for 18 hours. After the reaction, a brine solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was sufficiently stirred and then allowed to stand for separation, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a dark brown crude product, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1). 1 H NMR(500MHz，CDCl 3 )δ7.82(d，J＝7.3Hz，1H)，7.49(t，J＝7.3Hz，1H)，7.33(dd，J＝12.5，5.3Hz，2H)，7.06(d，J＝8.9Hz，2H)，
6.59(d，J＝8.8Hz，2H)，4.49(s，4H)，2.54(s，6H)，1.48(s，6H)； 13 C NMR(126MHz，
CDCl 3 )δ173.9，154.5，154.2，153.7，132.8，132.7，130.5，130.4，129.0，127.3，123.9，120.1，113.7，79.3，61.9，51.2，41.9，40.4，37.9(t，J＝30.2Hz)，25.2， 13 C NMR for C 4 F 9 could not be assigned； 19 F NMR(471MHz，CDCl 3 )δ-81.08–-81.22(m)，-116.65–-116.79(m)，-122.32–-122.36(m)，-126.05–-126.11(m)；
HRMS(ESI+)：Calculated for C 29 H 24 ClF 9 N 2 O 4 ：[M+H]+671.1354，Found 671.1355。
Example 13.
Isoxemic acid derivatives (440mg, 1mmol) and [1.1.1]Propylalane (198mg, 3 mmol), perfluoroiodobutane (692mg, 2mmol), 1, 8-diazabicycloundec-7-ene (456mg, 3 mmol) were added to the reaction flask, dissolved by adding 1, 4-dioxane (4.4 g), and reacted under stirring at 410nm for 16 hours. After the reaction, adding a saline solution (20 g) to quench the reaction, adding ethyl acetate (20 g), fully stirring, standing for layering, drying an organic layer with anhydrous magnesium sulfate, filtering, concentrating to obtain a dark brown crude product, and performing silica gel column chromatography (ethyl acetate: petroleum) on the crude productEther =1: 3) Purification gave 471mg of a yellow liquid in 65% yield. 1 H NMR(500MHz，CDCl 3 )δ8.03(d，J＝2.1Hz，1H)，7.89(d，J＝7.6Hz，1H)，7.83(dd，J＝8.0，1.0Hz，1H)，7.56(dd，J＝10.7，4.2Hz，1H)，7.53–7.46(m，2H)，7.38(t，J＝8.0Hz，2H)，7.31(dd，J＝11.2，4.6Hz，2H)，6.98(d，J＝8.4Hz，1H)，5.18(s，2H)，4.48(dd，J＝8.8，4.3Hz，4H)，3.56(s，2H)，2.55(s，6H)； 13 C NMR(126MHz，CDCl 3 )δ190.7，171.4，160.6，154.6，154.3，140.4，136.2，135.5，133.0，132.9，132.8，132.5，130.6，130.5，129.5，129.3，127.9，127.1，125.2，123.9，121.2，113.6，73.6，61.2，51.3，41.9，40.6，40.0，37.9(t，J＝30.2Hz)， 13 C NMR for C 4 F 9 could not be assigned； 19 F NMR(471MHz，CDCl 3 )δ-80.41–-81.73(m)，-116.55–-116.65(m)，-122.26–-122.32(m)，-125.95–-126.07(m)；HRMS(ESI+)：Calculated for C 35 H 25 F 9 N 2 O 5 ：
[M+H]+725.1693，Found 725.1692。
Example 14.
Dehydrocholic acid derivatives (588mg, 1mmol) and [1.1.1]Propylalane (165mg, 2.5 mmol), perfluoroiodobutane (692mg, 2mmol) and 1, 8-diazabicycloundece-7-ene (684mg, 4.5 mmol) were charged into a reaction flask, dissolved in N, N-dimethylformamide (6 g), and the reaction was stirred under illumination at 410nm for 16 hours. After the reaction was completed, a saline solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was sufficiently stirred and then allowed to stand for layering, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a dark brown crude product, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1). 1 H NMR(500MHz，CDCl 3 )δ7.84(dd，J＝8.0，1.2Hz，1H)，7.58–7.51(m，1H)，7.43(d，J＝8.3Hz，1H)，7.34(t，J＝7.6Hz，1H)，4.48(t，J＝5.4Hz，2H)，4.41(t，J＝5.7Hz，2H)，2.88(dd，J＝31.5，18.4Hz，3H)，2.54(s，6H)，2.30(dd，J＝22.9，11.7Hz，5H)，2.24(d，J＝11.8Hz，2H)，2.15(dd，J＝26.3，14.5Hz，4H)，2.02(d，J＝9.9Hz，1H)，1.98–
1.90(m，3H)，1.82(t，J＝11.1Hz，1H)，1.75–1.70(m，1H)，1.59(dd，J＝19.1，
9.5Hz，1H)，1.39(s，3H)，1.33–1.23(m，5H)，1.03(s，3H)，0.78(d，J＝6.6Hz，3H)； 13 C NMR(126MHz，CDCl 3 )δ211.9，209.0，208.7，173.9，154.6，154.3，133.0，132.9，130.5，130.5，123.8，113.7，60.5，56.8，51.7，51.2，51.1，49.0，46.8，45.5，45.5，45.0，42.8，41.9，40.7，38.6，37.9(t，J＝30.2Hz)，36.5，36.0，35.4，35.3，31.2，30.2，27.6，25.1，21.9，18.6，11.8， 13 C NMR for C 4 F 9 could not be assigned； 19 F NMR(471MHz，CDCl 3 )δ-80.26–-81.80(m)，-115.52–-117.63(m)，-121.26–-123.02(m)，-125.24–-127.00(m)；HRMS(ESI+)：Calculated for C 44 H 49 F 9 N2O 6 ：[M+H]+873.352，Found 873.352。
Example 15.
1-benzyl-5, 6-diphenyl-pyrazinone (338mg, 1mmol), [1.1.1] propeller alkane (165 mg,
2.5 mmol), perfluoroiodobutane (692mg, 3mmol), 1, 8-diazabicycloundecen-7-ene (456mg, 3mmol) were charged into a reaction flask, dissolved with dichloromethane (24 g), and the reaction was stirred under 410nm illumination for 16 hours. After the reaction, a brine solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was stirred sufficiently and then allowed to stand for layering, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a dark brown crude product, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether =1:3) Purification gave 343mg of a pale yellow solid in 55% yield, melting point 89 ℃. 1 H NMR(500MHz,CDCl 3 )δ7.34(t,J＝7.5Hz,1H),7.24(d,J＝8.7Hz,5H),7.11(d,J＝1.9Hz,5H),6.99(d,J＝7.3Hz,2H),6.85(dd,J＝6.3,2.7Hz,2H),5.11(s,2H),2.58(s,6H)； 13 C NMR(126MHz,CDCl 3 )δ155.0,152.5,137.9,137.5,136.0,132.9,131.9,130.5,129.5,129.3,128.6,128.5,127.7,127.5,127.2,127.1,51.1,48.7,41.9,37.9(t,J＝31.5Hz), 13 C NMR for C 4 F 9
could not be assigned； 19 F NMR(471MHz,CDCl 3 )δ-81.03–-81.07(m),-116.50–-116.59(m),-122.29–-122.31(m),-126.00–-126.04(m)；HRMS(ESI+):Calculated for C 32 H 23 F 9 N2O:[M+H]+623.1739,Found 623.174。
Example 16.
Mixing 1- (4-methylbenzyl) -5, 6-diphenyl-pyrazinone (352mg, 1mmol) and [1.1.1] propellane
(165mg, 2.5 mmol), perfluoroiodobutane (692mg, 2mmol) and 1, 8-diazabicycloundece-7-ene (608mg, 4 mmol) were charged into a reaction flask, dissolved in 1, 4-dioxane (10 g), and reacted with stirring under illumination at 410nm for 24 hours. After the reaction, a brine solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was sufficiently stirred and then allowed to stand for separation, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a dark brown crude product, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1). 1 H NMR(500MHz,CDCl 3 )δ7.35(t,J＝7.5Hz,1H),7.25(t,J＝7.7Hz,2H),7.10(d,J＝1.4Hz,5H),7.01(dd,J＝7.3,4.0Hz,4H),6.75(d,J＝8.0Hz,2H),5.06(s,2H),2.57(s,6H),2.28(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ155.0,152.4,138.0,137.6,137.3,133.0,132.9,132.0,130.5,129.5,129.3,129.2,128.6,127.7,127.2,127.0,51.1,48.5,41.9,37.9(t,J＝31.5Hz),21.1, 13 C NMR for C 4 F 9 could not be assigned； 19 F NMR(471MHz,CDCl 3 )δ-81.03–-81.07(m),-116.52–-116.56(m),-122.28–-122.31(m),-125.97–-126.03(m)；
HRMS(ESI+):Calculated for C 33 H 25 F 9 N2O:[M+H]+637.1896,Found 637.1888。
Example 17.
1- (4-chlorobenzyl) -5, 6-diphenyl-pyrazinone (372mg, 1mmol), [1.1.1]Propane (165mg, 2.5 mmol), perfluoroiodobutane (692mg, 2mmol) and 1, 8-diazabicycloundec-7-ene (456 mg, 3mmol) were charged into a reaction flask, dissolved by addition of N-methylpyrrolidone (5 g), and the reaction was stirred under illumination at 400nm for 18 hours. After the reaction, a brine solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was sufficiently stirred and then allowed to stand for separation, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a dark brown crude product, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1). 1 H NMR(500MHz,CDCl 3 )δ7.36(t,J＝7.5Hz,1H),7.28–7.24(m,2H),7.19–7.14(m,2H),7.14–7.06(m,5H),6.99(d,J＝7.2Hz,2H),6.79(d,J＝8.4Hz,2H),5.06(s,2H),2.57(s,6H)； 13 C NMR(126MHz,CDCl 3 )δ155.0,152.6,137.6,137.4,134.5,133.5,133.1,131.8,130.5,129.7,129.3,128.8,128.8,128.7,127.7,127.1,51.1,48.1,41.9,37.9(t,J＝31.5Hz), 13 C NMR for C 4 F 9 could not be assigned； 19 F NMR(471MHz,CDCl 3 )δ-81.03–81.07(m),-116.51–-116.57(m),-122.27–-122.31(m),-125.96–-126.03(m)；HRMS(ESI+):Calculated for C 32 H 22 ClF 9 N 2 O:[M+H]+657.135,Found 657.1346。
Example 18.
Quinoxaline-2 (1H) -one (146mg, 1mmol), [1.1.1]Propylalane (165mg, 2.5 mmol), perfluoroiodobutane (692mg, 2mmol) and 1, 8-diazabicycloundece-7-ene (304mg, 2mmol) were charged into a reaction flask, dissolved in ethyl acetate (14.6 g), and reacted under stirring at 420nm for 16 hours. After the reaction was completed, a saline solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was sufficiently stirred and then allowed to stand for separation, an organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a dark brown crude product, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1). 1 H NMR(500MHz,Acetone)δ11.22(s,1H),7.77(d,J＝7.9Hz,1H),7.53(t,J＝7.3Hz,1H),7.39(d,J＝8.0Hz,1H),7.32(t,J＝7.6Hz,1H),2.55(s,6H)； 13 C NMR(126MHz,Acetone)δ155.9,154.3,132.5,132.2,130.2,128.9,123.3,115.2,50.8,41.7,37.5(t,J＝31.5Hz), 13 C NMR for C 4 F 9 could not be assigned； 19 F NMR(471MHz,Acetone)δ-81.95(t,J＝10.1Hz),-116.90–-116.97(m),-122.78–-122.85(m),-126.65–-126.71(m)；HRMS(ESI+):Calculated for C 17 H 11 F 9 N2O:
[M+H]+431.08,Found 431.0808。
Example 19.
1-methyl-5, 6-di-p-tolyl-pyrazinone (290mg, 1mmol), [1.1.1]Propylalane (165mg, 2.5 mmol), perfluoroiodobutane (692mg, 3mmol) and 1, 8-diazabicycloundec-7-ene (152mg, 1mmol) were charged into a reaction flask, dissolved in methylene chloride (2.9 g) and reacted under stirring at 410nm for 12 hours. After the reaction, adding a saline solution (20 g) to quench the reaction, adding ethyl acetate (20 g), fully stirring, standing for layering, drying an organic layer with anhydrous magnesium sulfate, filtering, concentrating to obtain a dark brown crude product, and performing silica gel column chromatography (ethyl acetate: petroleum ether =) on the crude product1: 3) Purification gave 344mg of a pale yellow solid in 60% yield, melting point 168 ℃. 1 H NMR(500MHz,CDCl 3 )δ7.20(d,J＝7.8Hz,2H),7.05(dd,J＝17.1,8.0Hz,4H),6.94(d,J＝8.0Hz,2H),3.28(s,3H),2.54(s,6H),2.38(s,3H),2.25(s,3H)； 13 C NMR(126MHz,CDCl 3 )δ155.4,151.2,139.6,137.8,136.7,134.9,132.7,129.8,129.8,129.7,129.1,128.5,51.0,41.8,37.9(t,J＝31.5Hz),33.6,21.4,21.1, 13 C NMR for C 4 F 9 could not be assigned； 19 F NMR(471MHz,CDCl 3 )δ-80.03–-81.08(m),-116.49–-116.56(m),-122.29–-122.31(m),-125.99–-126.05(m)；HRMS(ESI+):Calculated for C 28 H 23 F 9 N 2 O:[M+H]+575.1739,Found 575.1734。
Example 20.
5, 6-bis (4-bromophenyl) -1-methyl-pyrazinone (418mg, 1mmol), [1.1.1]Propylalane (165mg, 2.5 mmol), perfluoroiodobutane (692mg, 2mmol) and 1, 8-diazabicycloundece-7-ene (456 mg, 3mmol) were charged into a reaction flask, and 1, 4-dioxane (5 g) was added thereto and dissolved, followed by stirring under 410nm light for 16 hours. After the reaction was completed, a saline solution (20 g) was added to quench the reaction, ethyl acetate (20 g) was added, the mixture was sufficiently stirred and then allowed to stand for layering, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a dark brown crude product, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1) to obtain 316mg of a pale yellow solid, a yield of 45%, and a melting point of 134 ℃. 1 H NMR(500MHz,CDCl3)δ7.57(d,J＝8.4Hz,2H),7.31–7.28(m,2H),7.07(d,J＝8.4Hz,2H),7.00–6.97(m,2H),3.28(s,3H),2.53(s,6H)； 13 C NMR(126MHz,CDCl3)δ155.1,152.3,136.9,136.3,132.7,131.5,131.5,131.1,131.0,130.9,124.4,121.6,51.0,41.7,37.9(t,J＝31.5Hz),33.7, 13 C NMR for C4F 9 could not be assigned； 19 F NMR(471MHz,CDCl 3 )δ-81.03–-81.09(m),-116.55–-116.61(m),-122.27–-122.33(m),-125.99–-126.06(m)；HRMS(ESI+):Calculated for C26H 17 Br 2 F 9 N 2 O:[M+H]+702.9637,Found 702.9597。
The obtained novel disubstituted bicyclo [1.1.1] pentane derivative containing perfluoroalkyl and N heterocycle has potential application prospect in the fields of pharmaceutical chemicals, materials, dyes and the like.
Claims (10)
1. The synthesis method of disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N heterocycle is characterized in that:
adding a nitrogen-containing heterocycle, 1.1.1] propellane, perfluoro-iodoalkane and a base catalyst into an organic solvent, and stirring and reacting for 6-24 hours at normal temperature under a photocatalytic condition, wherein the reaction formula is as follows:
the molar ratio of the added nitrogen-containing heterocycle, the [1.1.1] propeller alkane and the perfluoro iodoalkane is 1-3; the molar ratio of the added base catalyst to the nitrogen-containing heterocycle is 1-5; the feeding mass ratio of the organic solvent to the nitrogen-containing heterocycle is 10-100; the wavelength of light used for photocatalysis is 365-455 nm;
the structural formula of the nitrogen-containing heterocycle is shown as
Wherein R is 1 Is hydrogen, alkyl, benzyl, substituted benzyl, or an ester group; r 2 Is substituted or unsubstituted phenyl;
said [1.1.1]The structural formula of the propellane is as follows
The structural formula of the perfluoro iodoalkane is I-R f (ii) a Wherein is C 2 F 5 、 i C 3 F 7 、C 4 F 9 、C 6 F 13 、C 8 F 17 Or CF 2 COOEt；
After the reaction in the step (2) is finished, adding saturated saline solution to quench the reaction, and adding an organic solvent ethyl acetate to extract and stratify; and (3) drying the organic layer by using anhydrous magnesium sulfate or anhydrous sodium sulfate, filtering and concentrating to obtain a dark brown liquid crude product, and purifying the crude product by using a silica gel column chromatography to obtain a light yellow solid target product containing perfluoroalkyl and N heterocyclic disubstituted bicyclo [1.1.1] pentane.
2. The method for synthesizing disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N-heterocycle according to claim 1, wherein: the alkali catalyst is one of potassium phosphate, triethylene diamine, triethylamine, N-diisopropylethylamine, cesium carbonate, tetrabutylammonium iodide and 1, 8-diazabicycloundecen-7-ene.
3. The method for synthesizing disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N-heterocycle according to claim 1, wherein: the organic solvent is one of ethyl acetate, dichloromethane, acetonitrile, acetone, 1, 4-dioxane, N-dimethylformamide, dimethyl carbonate and N-methylpyrrolidone.
4. The method for synthesizing disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N-heterocycle according to claim 1, wherein: the molar ratio of the nitrogen-containing heterocycle, the [1.1.1] propellane and the perfluoroalkyl iodide added in the step (1) is 1.
5. The method for synthesizing disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N-heterocycle according to claim 1, wherein: the molar ratio of the base catalyst to the nitrogen-containing heterocycle added in the step (1) is 3.
6. The method for synthesizing disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N-heterocycle according to claim 1, wherein: in the step (1), the feeding mass ratio of the organic solvent to the nitrogen-containing heterocycle is 15-50.
7. The method for synthesizing disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N-heterocycle according to claim 1, wherein: the reaction time in the step (1) is 12 to 18 hours.
8. The method for synthesizing disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N-heterocycle according to claim 1, wherein: the wavelength of light used for photocatalysis in the step (1) is 400-420 nm.
9. The method for synthesizing disubstituted bicyclo [1.1.1] pentane containing perfluoroalkyl and N-heterocycle according to claim 1, wherein: the solvent used in the silica gel column chromatography is a solvent with the volume ratio of 1:3 ethyl acetate and petroleum ether.
10. Disubstituted bicyclo [1.1.1] containing perfluoroalkyl and N-heterocycle obtained by the synthesis method according to any one of claims 1-9]Pentane of the formula
Wherein R is 1 Is hydrogen, alkyl, benzyl, substituted benzyl, or an ester group; r 2 Is a substituted or unsubstituted phenyl group; r is f Is C 2 F 5 、 i C 3 F 7 、C 4 F 9 、C 6 F 13 、C 8 F 17 Or CF 2 COOEt。/>
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| US20180186781A1 (en) * | 2016-12-08 | 2018-07-05 | Board Of Regents, The University Of Texas System | Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (dlk) kinase for the treatment of disease |
| CN109071409A (en) * | 2016-03-14 | 2018-12-21 | 斯帕罗化学股份公司 | The method for preparing bicyclic [the 11 1] pentane replaced |
| WO2022178559A1 (en) * | 2021-02-22 | 2022-08-25 | The Trustees Of Princeton University | 2-substituted bicyclo[1.1.1]pentanes |
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| CN109071409A (en) * | 2016-03-14 | 2018-12-21 | 斯帕罗化学股份公司 | The method for preparing bicyclic [the 11 1] pentane replaced |
| US20180186781A1 (en) * | 2016-12-08 | 2018-07-05 | Board Of Regents, The University Of Texas System | Bicyclo[1.1.1]pentane inhibitors of dual leucine zipper (dlk) kinase for the treatment of disease |
| WO2022178559A1 (en) * | 2021-02-22 | 2022-08-25 | The Trustees Of Princeton University | 2-substituted bicyclo[1.1.1]pentanes |
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