CN116462706A - Synthesis method of organic phosphonyl fluoride compound - Google Patents
Synthesis method of organic phosphonyl fluoride compound Download PDFInfo
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- CN116462706A CN116462706A CN202211546278.XA CN202211546278A CN116462706A CN 116462706 A CN116462706 A CN 116462706A CN 202211546278 A CN202211546278 A CN 202211546278A CN 116462706 A CN116462706 A CN 116462706A
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- -1 phosphonyl fluoride compound Chemical class 0.000 title claims abstract description 82
- 238000001308 synthesis method Methods 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 238000003682 fluorination reaction Methods 0.000 claims abstract description 30
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- 239000012025 fluorinating agent Substances 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 11
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 claims description 8
- 235000019743 Choline chloride Nutrition 0.000 claims description 8
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 claims description 8
- 229960003178 choline chloride Drugs 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000012298 atmosphere Substances 0.000 claims description 5
- 239000012429 reaction media Substances 0.000 claims description 5
- 229910001495 sodium tetrafluoroborate Inorganic materials 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 claims description 3
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 3
- 229940035437 1,3-propanediol Drugs 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 9
- 239000010949 copper Substances 0.000 abstract description 9
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052802 copper Inorganic materials 0.000 abstract description 5
- 238000004334 fluoridation Methods 0.000 abstract description 5
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 230000035484 reaction time Effects 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 230000009286 beneficial effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- FBHHZEPZBVNZRM-UHFFFAOYSA-N [fluoro(phenyl)phosphoryl]benzene Chemical compound C=1C=CC=CC=1P(=O)(F)C1=CC=CC=C1 FBHHZEPZBVNZRM-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 150000002222 fluorine compounds Chemical class 0.000 description 3
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical class [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000010702 perfluoropolyether Substances 0.000 description 2
- FFUQCRZBKUBHQT-UHFFFAOYSA-N phosphoryl fluoride Chemical compound FP(F)(F)=O FFUQCRZBKUBHQT-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- CCBDFSFCAHWFJF-UHFFFAOYSA-N 1-methoxy-3-(3-methoxyphenyl)phosphonoylbenzene Chemical compound COC1=CC=CC(P(=O)C=2C=C(OC)C=CC=2)=C1 CCBDFSFCAHWFJF-UHFFFAOYSA-N 0.000 description 1
- WILMTQKUPOOLFE-UHFFFAOYSA-N 1-methoxy-4-(4-methoxyphenyl)phosphonoylbenzene Chemical compound C1=CC(OC)=CC=C1P(=O)C1=CC=C(OC)C=C1 WILMTQKUPOOLFE-UHFFFAOYSA-N 0.000 description 1
- GGIQQYHOHRKDNO-UHFFFAOYSA-N 1-methyl-3-(3-methylphenyl)phosphonoylbenzene Chemical compound CC1=CC=CC(P(=O)C=2C=C(C)C=CC=2)=C1 GGIQQYHOHRKDNO-UHFFFAOYSA-N 0.000 description 1
- GCUWBTGMXUIKOB-UHFFFAOYSA-N 1-methyl-4-(4-methylphenyl)phosphonoylbenzene Chemical compound C1=CC(C)=CC=C1P(=O)C1=CC=C(C)C=C1 GCUWBTGMXUIKOB-UHFFFAOYSA-N 0.000 description 1
- RMZNXRYIFGTWPF-UHFFFAOYSA-N 2-nitrosoacetic acid Chemical compound OC(=O)CN=O RMZNXRYIFGTWPF-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 229910020808 NaBF Inorganic materials 0.000 description 1
- VWBYXJRDIQCSLW-UHFFFAOYSA-N O=[P](c1ccccc1)c1ccccc1 Chemical compound O=[P](c1ccccc1)c1ccccc1 VWBYXJRDIQCSLW-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- ACLBAKCXXIZYJV-UHFFFAOYSA-N chembl1463773 Chemical compound C=1C=CC=CC=1CP(=O)CC1=CC=CC=C1 ACLBAKCXXIZYJV-UHFFFAOYSA-N 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- HJPHBJYOODQSLK-UHFFFAOYSA-N dicyclohexyl(oxo)phosphanium Chemical compound C1CCCCC1[P+](=O)C1CCCCC1 HJPHBJYOODQSLK-UHFFFAOYSA-N 0.000 description 1
- IWQIEVOJUWFMSB-UHFFFAOYSA-N dihexylphosphane Chemical compound CCCCCCPCCCCCC IWQIEVOJUWFMSB-UHFFFAOYSA-N 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000012803 optimization experiment Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 150000002927 oxygen compounds Chemical class 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- XMAXUBOLEVIRGX-UHFFFAOYSA-N phosphanium;fluoride Chemical class [F-].[PH4+] XMAXUBOLEVIRGX-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- MDDUHVRJJAFRAU-YZNNVMRBSA-N tert-butyl-[(1r,3s,5z)-3-[tert-butyl(dimethyl)silyl]oxy-5-(2-diphenylphosphorylethylidene)-4-methylidenecyclohexyl]oxy-dimethylsilane Chemical compound C1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C(=C)\C1=C/CP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 MDDUHVRJJAFRAU-YZNNVMRBSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/34—Halides thereof
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of an organic phosphono fluoride compound, which is characterized in that the organic phosphono fluoride compound is subjected to fluorination reaction under the action of a fluorination reagent such as copper tetrafluoro-acetonitrile or copper tetrafluoro-acetonitrile to obtain the organic phosphono fluoride compound. The fluoridation reagent used in the synthesis method is cheap and easy to obtain, has good stability, and can avoid using expensive and unstable fluoridation reagent; meanwhile, the high-efficiency and high-selectivity conversion of the organic phosphine oxide compound into the organic phosphonofluoride compound can be realized under the mild condition, and the tolerance range of the functional group is wide.
Description
Technical Field
The invention relates to a method for synthesizing an organic phosphono fluoride compound, in particular to a method for synthesizing the organic phosphono fluoride compound by taking an organic phosphono oxide compound as a raw material under the action of fluoridation reagents such as copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, sodium tetrafluoroborate, ammonium hexafluorophosphate or potassium hexafluorophosphate and the like, belonging to the field of organic synthesis.
Background
The organic phosphonyl fluoride compound contains phosphoryl fluoride bond (O=P-F) in the molecule, is a compound with biological activity and is often used as a probe or an effective inhibitor in enzyme reaction. Since the last century, the preparation, nature and use of organophosphonic acid fluoride compounds have been of great interest and research.
The reaction of phosphine-containing organic compounds with specific fluorinating agents is an important route for preparing the building up of phosphoryl fluoride bonds, however, these reactions have the disadvantages of harsh reaction conditions, long reaction times, the need to use expensive, unstable and moisture sensitive reagents, etc.
In recent years, chemists have developed nucleophilic fluorination reactions of organic phosphine oxide compounds containing P (O) -H bonds with fluoride ions to effectively synthesize organic phosphine fluoride compounds under milder reaction conditions. Because of the weak nucleophilic properties of fluoride ions, these reactions often require the addition of copper catalyst chlorides or other oxidants to convert P (O) -H to other intermediates such as P (O) -Cl, and then produce the organophosphonic fluoride compounds by nucleophilic reaction with fluoride ions (j. Org. Chem.2016,81,10043-10048, chem. Commun.,2014,50,10879-10882,Tetrahedron Letters 59 (2018) 2965-2969).
Recently, chinese patent (CN 112174761 a) disclosed that phosphine oxide compounds are obtained under the action of perfluoro polyether chain carboxylate fluorinating agent to obtain phosphoryl fluoride products, but its selectivity of directly fluorinating phosphine oxide compounds with perfluoro polyether chain carboxylate is relatively low, and the obtained intermediate needs further water to promote conversion into phosphoryl fluoride products.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide a method for synthesizing an organic phosphonofluoride compound by directly fluorinating an organic phosphonooxide with high yield and high selectivity.
In order to achieve the technical aim, the invention provides a synthesis method of an organic phosphonyl fluoride compound, which comprises the steps that the organic phosphonyl fluoride compound is subjected to fluorination reaction under the action of a fluorination reagent to obtain the organic phosphonyl fluoride compound;
the organophosphinoxy compound has the following structural formula:
the organic phosphonic acid fluoride compound has the following structural formula:
wherein R is 1 And R is 2 Independently selected from C 1 ～C 10 Saturated aliphatic hydrocarbon radicals, phenyl radicals, naphthyl radicals, benzyl radicals or substituted phenyl radicals; the substituent contained in the substituted phenyl is C 1 ～C 10 Alkyl or C of (2) 1 ～C 10 An alkoxy group;
the fluorinating agent comprises at least one of copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, sodium tetrafluoroborate, ammonium hexafluorophosphate and potassium hexafluorophosphate.
R in the organic phosphonyl fluoride compound of the invention 1 And R is 2 Is a substituent group introduced by an organophosphinoxy compound, generally R 1 And R is 2 Are stable substituent groups and can not be fluorinated by the fluorinating agents such as copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate and the like. R is R 1 And R is 2 The substituents may be the same or different, and are generally the same. R is R 1 And R is 2 Independently selected from C 1 ～C 10 Saturated aliphatic hydrocarbon radicals, phenyl radicals, naphthyl radicals, benzyl radicals or substituted phenyl radicals; the substituted phenyl contains C 1 ～C 10 Saturated aliphatic hydrocarbon radicals or C 1 ～C 10 An alkoxy group. C (C) 1 ～C 10 The saturated aliphatic hydrocarbon group of (a) may be a straight-chain alkyl group such as n-butyl group, n-octyl group, etc., and when the number of carbon atoms is 3 or more, it may further contain a cycloalkyl group or a branched alkyl group such as cyclohexyl group, isopentyl group, etc. The substituted phenyl groups are groups derived from phenyl groups and contain common substituents, e.g. C, on the phenyl ring 1 ～C 10 Alkyl or C of (2) 1 ～C 10 Alkoxy group or the like, C 1 ～C 10 Alkyl groups such as methyl, ethyl, hexyl, octyl and the like, and when the number of carbon atoms is 3 or more, branched alkyl groups such as isopropyl isopentyl and the like; c (C) 1 ～C 10 Alkoxy groups such as methoxy, propoxy, isobutoxy, and the like.
The organophosphinoxy compounds of the present invention are typically as follows: diphenylphosphine oxide, bis (p-methylphenyl) phosphine oxide, bis (p-methoxyphenyl) phosphine oxide, bis (m-methylphenyl) phosphine oxide, bis (m-methoxyphenyl) phosphine oxide, dibenzylphosphine oxide, dihexylphosphine oxide, 1' -dinaphthyl phosphine oxide, dicyclohexylphosphine oxide.
As a preferred embodiment, the molar ratio of the fluorinating agent to the organophosphinoxide compound is 0.2 to 1.2:1. The preferred fluorinating agent contains 4 or 6 fluorine substituents which are fluorinated and the molar ratio of the fluorinating agent is controlled within a preferred range to facilitate efficient fluorination of the organophosphinoxide compound.
As a preferred embodiment, the fluorinating agent comprises copper tetraacetonitrile hexafluorophosphate and/or copper tetraacetonitrile tetrafluoroborate. The fluoridation of the organic phosphine oxide compound can be smoothly carried out by adopting fluorinating agents such as sodium tetrafluoroborate, ammonium hexafluorophosphate, potassium hexafluorophosphate and the like, but the yield of target products is relatively low, and the copper tetrafluoro-phosphate tetraacetonitrile and the copper tetrafluoro-borate tetraacetonitrile have more beneficial fluoridation effect on the organic phosphine oxide compound.
As a preferred embodiment, the fluorination reaction uses THF, CH as the reaction medium 3 CN, 1, 4-dioxane, CH 2 Cl 2 At least one of toluene, DMF, DMSO, ethanol, methanol, choline chloride/urea, choline chloride/1, 3-propanediol, choline chloride/glycerol. The different reaction mediums have a certain influence on the fluorination reaction of the organic phosphine oxide compound, and the most preferable reaction medium is THF and/or CH through screening of a large amount of reaction mediums 3 CN。
As a preferred embodiment, the fluorination reaction conditions are: under the protection atmosphere, the reaction is carried out for more than 2 hours at the temperature of higher than 40 ℃. As a more preferable embodiment, the fluorination reaction conditions are: and reacting for 4-8 hours at 50-100 ℃ under the protection atmosphere. Along with the extension of the reaction temperature and the reaction time, the fluorination reaction efficiency of the organic phosphine oxide compound is increased, and the yield of the target product is relatively improved, but when the reaction temperature is about 60 ℃ and the reaction time is 6 hours, the yield of the target product reaches the peak value, and the temperature is further increased or the reaction time is prolonged, so that side reactions possibly exist, and the yield of the target product is reduced. The most preferred reaction temperature is 60 to 70℃and the most preferred reaction time is 5 to 7 hours. A protective atmosphere such as nitrogen, or an inert gas such as argon, etc.
After the fluorination reaction of the invention is completed, dichloromethane, chloroform, diethyl ether, ethyl acetate or toluene is used as an extractant to separate the organic phosphonofluoride compound.
The reaction mechanism of converting the organic phosphine oxide compound into the organic phosphono compound through the fluorination reaction is as follows, under the condition of proper temperature, the organic phosphine oxide compound is isomerized into an intermediate A, and nucleophilic substitution reaction is carried out on the intermediate A and the hexafluorophosphate group in the copper tetraacetonitrile hexafluorophosphate to obtain intermediates B and F - ，F - And carrying out nucleophilic substitution reaction with the intermediate B to obtain an intermediate C, wherein the intermediate C loses hydrogen ions to obtain a target product.
Compared with the prior art, the technical scheme of the invention has the beneficial technical effects that:
1) The fluorinating agent adopted by the invention is common commercial fluorine-containing compound, is cheap and easy to obtain, is beneficial to reducing the cost, has good stability, and can avoid using expensive and unstable fluorinating agent.
2) Cu (MeCN) used in the present invention 4 PF 6 、Cu(MeCN) 4 BF 4 、NaBF 4 、NH 4 PF 6 Or KPF 6 And the like, the organic phosphine oxide compound can be fluorinated under milder reaction conditions to synthesize the organic phosphine fluoride compound with high yield and high selectivity, and the tolerance range of the functional group is wide.
Detailed Description
The following detailed description of the present invention will provide further clarity and understanding of the above-described features, advantages and objects of the present invention. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. The invention may be embodied in many other forms than described herein and similarly modified by those skilled in the art without departing from the spirit or scope of the invention, which is therefore not limited to the specific embodiments disclosed below.
Preferable examples of conditions:
the following examples are examples of the optimum reaction conditions obtained by condition optimization experiments with diphenylphosphine oxide as the reaction substrate: into a 25mL two-necked flask, 0.5mmol of diphenylphosphine oxide and 0.5mmol of Cu (MeCN) were charged at room temperature under nitrogen atmosphere 4 PF 6 (and 5mL THF), then the flask was placed in an oil bath reactor with magnetic stirring, and the reaction was carried out at 60℃for 6 hours, after the completion of the reaction, 10mL of water and 10mL of ethyl acetate were added for extraction and separation, and the product diphenylphosphoryl fluoride was obtained by column chromatography in 92% yield.
It is worth noting that the addition of water in the examples is only to promote phase separation, which is advantageous for extraction separation, and the addition of water does not affect selectivity and yield of diphenylphosphoryl fluoride.
Diphenyl phosphoryl fluoride is a yellow oily liquid.
1 H NMR(500MHz,CDCl 3 ):δ7.45-7.52(m,4H),7.58-7.64(m,2H),7.78-7.86(m,4H)；
13 C NMR(100MHz,CDCl 3 ):δ128.7(dd,J＝140.2,22.3Hz),128.9(d,J＝14.6Hz),131.3(dd,J＝11.5,1.7Hz),133.6(d,J＝2.5Hz)；
31 P NMR(162MHz,CDCl 3 ):δ40.87(d,J＝1019.9Hz)；
19 F NMR(376MHz,CDCl3):δ-74.98(d,J＝1019.7Hz)；
The following experimental groups 1 to 20, the above examples being referred to, carry out a comparative illustration of the conversion of diphenylphosphino oxygen to diphenylphosphoryl fluoride under different conditions:
the influence of different fluorinating agents on the fluorination reaction of the organic phosphine oxide compound is examined in the experimental groups 1 to 5 in the table, and the experiment shows that: the fluorination reaction of the organic phosphine oxide compound can be smoothly carried out by adopting copper tetrafluoroacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, sodium tetrafluoroborate, ammonium hexafluorophosphate, potassium hexafluorophosphate and the like as the fluorination reagent, but when the copper tetrafluoroacetonitrile hexafluorophosphate or copper tetraacetonitrile tetrafluoroborate is adopted as the fluorination reagent, the yield of a target product can reach about 90 percent, and the effect is obviously better than other fluorination reagents.
The influence of the use amount of different fluorinating agents on the fluorination reaction of the organic phosphine oxide compound is examined in the experimental groups 1 and 6 to 7 in the table, and the experiment shows that: the increase of the amount of the fluorinating agent is beneficial to improving the yield of the target product, but the increase of the amount of the fluorinating agent to a certain time has no obvious influence on the yield of the target product.
The influence of different reaction temperatures and times on the fluorination reaction of the organic phosphine oxide compound is examined in the above table in experimental groups 1 and 8 to 15, and the experiment shows that: the reaction temperature and the reaction time are prolonged within a certain range, so that the fluorination reaction of the organic phosphine oxide compound is beneficial, the yield of the target product can be increased, but when the reaction temperature is about 60 ℃, and the reaction time is 6 hours, the yield of the target product reaches a peak value, the temperature is further increased or the reaction time is prolonged, side reactions possibly exist, the yield of the target product is reduced, and the reaction temperature is too low or the reaction time is too short, and the yield of the target product is obviously reduced, therefore, the most preferred reaction temperature is 60-70 ℃, and the most preferred reaction time is 5-7 hours.
The influence of different reaction mediums on the fluorination reaction of the organic phosphine oxide compound is shown by experiments in the experimental groups 1 and 16-20 in the table, wherein the experimental groups show that: the reaction medium is preferably tetrahydrofuran or acetonitrile, which can obviously promote the fluorination reaction and is favorable for the fluorination reaction to reach the optimal state, and although organic solvents such as methanol, ethanol, DMSO and the like and deep eutectic solvents such as choline chloride/Urea (ChCl/1, 3-propanediol), choline chloride/glycerol (ChCl/glycone) and the like can lead the reaction to be smoothly carried out, the effect is far worse than that of tetrahydrofuran.
Examples 1 to 8 below are under most preferred reaction conditions to examine the effect of the conversion of different organophosphinoxycompounds to organophosphinoid fluoride compounds. The method comprises the following steps:
into a 25mL two-necked flask, 0.5mmol of the organophosphorous oxygen compound and 0.5mmol of Cu (MeCN) were charged at room temperature under nitrogen protection 4 PF 6 And 5mL of THF, then the flask was placed in an oil bath reactor with magnetic stirring, and the reaction was carried out at 60℃for 6 hours. After the reaction is finished, 10mL of water and 10mL of ethyl acetate are added for extraction and separation, and the target product is obtained through column chromatography.
Example 1
The structural formula of the target product is as follows:
the desired product was a yellow liquid in 89% yield.
1 H NMR(500MHz,CDCl 3 ):δ2.38(s,6H),7.26-7.30(m,4H),7.66-7.74(m,4H)；
13 C NMR(100MHz,CDCl 3 ):δ21.5,125.6(dd,J＝143.6,22.1Hz),129.4(d,J＝14.3Hz),131.1(dd,J＝11.6,1.9Hz),144.2(d,J＝2.5Hz)；
31 P NMR(162MHz,CDCl 3 ):δ41.98(d,J＝1016.2Hz)；
19 F NMR(376MHz,CDCl 3 ):δ-75.26(d,J＝1016.9Hz)。
Example 2
The structural formula of the target product is as follows:
the desired product was a colorless liquid in 87% yield.
1 H NMR(500MHz,CDCl 3 ):δ3.87(s,6H),6.90(m,4H),7.6(m,4H)；
13 C NMR(100MHz,CDCl 3 ):δ55.31,114.23(d,J＝15.0Hz),120.14(d,J＝149.0,23.9Hz),133.26(d,J＝11.0,2.0Hz),163.32(d,J＝3.0Hz)；
31 P NMR(162MHz,CDCl 3 ):δ42.38(d,J＝1010.7Hz)；
19 F NMR(376MHz,CDCl 3 ):δ72.72(d,J＝1010.4Hz)。
Example 3
The structural formula of the target product is as follows:
the desired product was a colorless oily liquid in 89% yield.
1 H NMR(500MHz,CDCl 3 ):δ2.46(s,6H),7.35-7.42(m,4H),7.56-7.70(m,4H)；
13 C NMR(100MHz,CDCl 3 ):δ22.0,127.8(dd,J＝11.5,2.3Hz),129.1(d,J＝15.0Hz),129.6(dd,J＝139.8,21.6Hz),132.3(dd,J＝11.6,2.4Hz),133.7(d,J＝2.3Hz),139.2(d,J＝13.6Hz)；
31 P NMR(162MHz,CDCl 3 ):δ41.66(d,J＝1020.2Hz)；
19 F NMR(376MHz,CDCl 3 ):δ-75.51(d,J＝1020.5Hz)。
Example 4
The structural formula of the target product is as follows:
the desired product was a white solid in 82% yield.
1 H NMR(300MHz,CDCl 3 ):δ3.76(s,6H),7.10-7.16(m,2H),7.29-7.42(m,6H)；
13 C NMR(100MHz,CDCl 3 ):δ54.7,115.6(dd,J＝12.2,2.4Hz),120.1(d,J＝2.6Hz),124.1(dd,J＝11.4,2.1Hz),129.1(dd,J＝140.2,22.5Hz),130.7(d,J＝17.2Hz),160.1(d,J＝17.2Hz)；
31 P NMR(162MHz,CDCl 3 ):δ40.7(d,J＝1019.8Hz)；
19 F NMR(376MHz,CDCl 3 ):δ-74.9(d,J＝1019.8Hz).
Example 5
The structural formula of the target product is as follows:
the desired product was a colorless liquid in 86% yield.
1 H NMR(500MHz,CDCl 3 ):3.16(dd,J＝16.0,J＝8.7Hz,4H),7.19-7.23(m,4H),7.31-7.40(m,6H)；
13 C NMR(100MHz,CDCl 3 ):δ35.0(dd,J＝86.3,14.8Hz),127.3(d,J＝3.8Hz),128.6(d,J＝2.9Hz),129.7(d,J＝7.7Hz),130.2(d,J＝5.9Hz)；
31 P NMR(162MHz,CDCl 3 ):δ58.16(d,J＝1039.8Hz)；
19 F NMR(376MHz,CDCl 3 ):δ-77.22(d,J＝1039.8Hz).
Example 6
The structural formula of the target product is as follows:
the desired product was a yellow liquid in 79% yield.
1 H NMR(500MHz,CDCl 3 ):1.09–1.29(m,6H),1.35–1.55(m,4H),1.72(d,J＝1.7Hz,2H),1.75–1.90(m,8H),1.90–1.98(m,2H)；
13 C NMR(400MHz,CDCl 3 ):δ24.53(dd,J＝4.5,90.3Hz),25.82(dd,J＝3.0,11.2Hz),34.39(d,J＝13.8Hz),35.21(d,J＝12.8Hz)；
31 P NMR(162MHz,CDCl 3 ):δ70.65(d,J＝1033.8Hz)；
19 F NMR(376MHz,CDCl 3 ):δ-95.06(d,J＝1033.8Hz).
Example 7
The structural formula of the target product is as follows:
the desired product was a white solid in 87% yield.
1 H NMR(500MHz,CDCl 3 ):δ7.50-7.63(m,6H),7.88-7.94(m,2H),7.99(dd,J＝16.7,7.6Hz,2H),8.13(d,J＝7.9Hz,2H),8.53-8.62(m,2H)；
13 C NMR(100MHz,CDCl 3 ):δ124.8(d,J＝15.8Hz),125.5(dd,J＝136.7,18.6Hz),126.6(d,J＝5.8Hz),127.3,128.4,129.7(d,J＝1.8Hz),133.3(d,J＝11.2Hz),133.8(d,J＝11.6Hz),134.5(dd,J＝11.8,4.2Hz),134.9(d,J＝2.9Hz)；
31 P NMR(162MHz,CDCl 3 ):δ44.56(d,J＝1020.7Hz)；
19 F NMR(376MHz,CDCl 3 ):δ-68.07(d,J＝1020.7Hz)。
Example 8
The structural formula of the target product is as follows:
the desired product was a colorless liquid in 68% yield.
1 H NMR(500MHz,CDCl 3 ):δ0.82(t,J＝6.6Hz,6H),1.24-1.36(m,8H),1.38-1.47(m,4H),1.56-1.70(m,4H),1.79-1.91(m,4H)；
13 C NMR(100MHz,CDCl 3 ):δ14.3,21.5(d,J＝4.8Hz),22.5,28.1(dd,J＝88.3,14.1Hz),30.5(d,J＝14.2Hz),31.6；
31 P NMR(162MHz,CDCl 3 ):δ70.53(d,J＝1017.7Hz)；
19 F NMR(376MHz,CDCl 3 ):δ-78.67(d,J＝1017.7Hz)。
Claims (7)
1. A method for synthesizing an organic phosphonyl fluoride compound is characterized in that: carrying out fluorination reaction on the organic phosphine oxide compound under the action of a fluorination reagent to obtain an organic phosphonofluoride compound;
the organophosphinoxy compound has the following structural formula:
the organic phosphonic acid fluoride compound has the following structural formula:
wherein R is 1 And R is 2 Independently selected from C 1 ～C 10 Saturated aliphatic hydrocarbon radicals, phenyl radicals, naphthyl radicals, benzyl radicals or substituted phenyl radicals; the substituent contained in the substituted phenyl is C 1 ～C 10 Alkyl or C of (2) 1 ～C 10 An alkoxy group;
the fluorinating agent comprises at least one of copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, sodium tetrafluoroborate, ammonium hexafluorophosphate and potassium hexafluorophosphate.
2. The method for synthesizing an organic phosphonic acid fluoride compound according to claim 1, characterized in that: the molar ratio of the fluorinating agent to the organic phosphine oxide compound is 0.2-1.2:1.
3. The method for synthesizing an organic phosphonic acid fluoride compound according to claim 1 or 2, characterized in that: the fluorinating agent comprises copper tetraacetonitrile hexafluorophosphate and/or copper tetraacetonitrile tetrafluoroborate.
4. The method for synthesizing an organic phosphonic acid fluoride compound according to claim 1, characterized in that: the fluorination reaction adoptsThe reaction medium of (C) is THF, CH 3 CN, 1, 4-dioxane, CH 2 Cl 2 At least one of toluene, DMF, DMSO, ethanol, methanol, choline chloride/urea, choline chloride/1, 3-propanediol, choline chloride/glycerol.
5. The method for synthesizing an organic phosphonic acid fluoride compound according to claim 4, characterized in that: the reaction medium adopted in the fluorination reaction is THF and/or CH 3 CN。
6. The method for synthesizing an organic phosphonic acid fluoride compound according to claim 1, 2, 4 or 5, characterized in that: the conditions of the fluorination reaction are as follows: under the protection atmosphere, the reaction is carried out for more than 2 hours at the temperature of higher than 40 ℃.
7. The method for synthesizing an organic phosphonic acid fluoride compound according to claim 6, characterized in that: the conditions of the fluorination reaction are as follows: and reacting for 4-8 hours at 50-100 ℃ under the protection atmosphere.
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