CN113563147A - Method for selective deuteration of carbon-hydrogen bond at benzyl position of aromatic ring - Google Patents
Method for selective deuteration of carbon-hydrogen bond at benzyl position of aromatic ring Download PDFInfo
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- CN113563147A CN113563147A CN202110863225.XA CN202110863225A CN113563147A CN 113563147 A CN113563147 A CN 113563147A CN 202110863225 A CN202110863225 A CN 202110863225A CN 113563147 A CN113563147 A CN 113563147A
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- Prior art keywords
- carbon
- mol
- deuterated
- added
- chloroform
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 125000003118 aryl group Chemical group 0.000 title claims abstract description 66
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title claims abstract description 57
- 238000000034 method Methods 0.000 title claims abstract description 28
- 229910052739 hydrogen Inorganic materials 0.000 title abstract description 56
- 239000001257 hydrogen Substances 0.000 title abstract description 56
- 125000001743 benzylic group Chemical group 0.000 claims abstract description 106
- 239000003054 catalyst Substances 0.000 claims abstract description 60
- 239000010948 rhodium Substances 0.000 claims abstract description 23
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 19
- 229910052751 metal Inorganic materials 0.000 claims abstract description 18
- 239000002184 metal Substances 0.000 claims abstract description 18
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims abstract description 4
- 238000004440 column chromatography Methods 0.000 claims description 35
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 35
- 239000002994 raw material Substances 0.000 claims description 33
- 229910001386 lithium phosphate Inorganic materials 0.000 claims description 23
- 239000007858 starting material Substances 0.000 claims description 23
- TWQULNDIKKJZPH-UHFFFAOYSA-K trilithium;phosphate Chemical compound [Li+].[Li+].[Li+].[O-]P([O-])([O-])=O TWQULNDIKKJZPH-UHFFFAOYSA-K 0.000 claims description 23
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical group [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 claims description 12
- 239000011903 deuterated solvents Substances 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-WFGJKAKNSA-N deuterated acetone Substances [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- HSYLTRBDKXZSGS-UHFFFAOYSA-N silver;bis(trifluoromethylsulfonyl)azanide Chemical group [Ag+].FC(F)(F)S(=O)(=O)[N-]S(=O)(=O)C(F)(F)F HSYLTRBDKXZSGS-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 4
- QVLTVILSYOWFRM-UHFFFAOYSA-L CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C Chemical group CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C QVLTVILSYOWFRM-UHFFFAOYSA-L 0.000 claims description 3
- FOIXSVOLVBLSDH-UHFFFAOYSA-N Silver ion Chemical compound [Ag+] FOIXSVOLVBLSDH-UHFFFAOYSA-N 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- MCVFFRWZNYZUIJ-UHFFFAOYSA-M lithium;trifluoromethanesulfonate Chemical compound [Li+].[O-]S(=O)(=O)C(F)(F)F MCVFFRWZNYZUIJ-UHFFFAOYSA-M 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 229910000161 silver phosphate Inorganic materials 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- 229910017744 AgPF6 Inorganic materials 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001492 aromatic hydrocarbon derivatives Chemical class 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 229910001544 silver hexafluoroantimonate(V) Inorganic materials 0.000 claims description 2
- FJOLTQXXWSRAIX-UHFFFAOYSA-K silver phosphate Chemical compound [Ag+].[Ag+].[Ag+].[O-]P([O-])([O-])=O FJOLTQXXWSRAIX-UHFFFAOYSA-K 0.000 claims description 2
- 229940019931 silver phosphate Drugs 0.000 claims description 2
- 229910001494 silver tetrafluoroborate Inorganic materials 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 229910052805 deuterium Inorganic materials 0.000 abstract description 7
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 230000004913 activation Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 description 168
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 165
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 97
- 238000006243 chemical reaction Methods 0.000 description 88
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 44
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 41
- 238000005160 1H NMR spectroscopy Methods 0.000 description 41
- 238000001228 spectrum Methods 0.000 description 34
- CSCPPACGZOOCGX-MICDWDOJSA-N 1-deuteriopropan-2-one Chemical compound [2H]CC(C)=O CSCPPACGZOOCGX-MICDWDOJSA-N 0.000 description 22
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 16
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 238000004611 spectroscopical analysis Methods 0.000 description 7
- 239000000758 substrate Substances 0.000 description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- VNWKTOKETHGBQD-MICDWDOJSA-N deuteriomethane Chemical compound [2H]C VNWKTOKETHGBQD-MICDWDOJSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001465 metallisation Methods 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- 230000035502 ADME Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001721 carbon Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- 230000005445 isotope effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical group 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- -1 silver ions Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
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- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
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- C07D311/78—Ring systems having three or more relevant rings
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- 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)]
- C07F9/32—Esters thereof
- C07F9/3258—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
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- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a selective deuteration method for carbon-hydrogen bonds at the benzyl position of an aromatic ring. The method utilizes a metal rhodium catalyst to carry out eta on aromatic ring6Coordinate activation, enabling it to selectively undergo hydrogen deuterium exchange with the deuterated reagent at the benzylic position. The method disclosed by the invention does not need to add strong acid or strong base, uses a cheap and easily-obtained deuteration reagent as a deuterium source, has good universality on various aromatic hydrocarbons with different functional groups, can be applied to later-stage selective deuteration of complex drug molecules, and has high application value.
Description
Technical Field
The invention relates to the technical field of hydrogen and deuterium exchange, in particular to a method for selectively deuterating a benzyl carbon-hydrogen bond from common aromatic hydrocarbon.
Background
The C-D bond is more stable than the C-H bond in the organism due to the kinetic isotope effect of the deuterium atom. In drug development, introduction of deuterium atoms into specific sites of a target molecule, such as the benzyl position of an aryl group, can significantly alter its pharmacokinetic properties (ADME). In addition, deuterated compounds have wide application in the research of reaction mechanisms.
At present, the following methods are mainly used for synthesizing the benzyl carbon-hydrogen bond deuterated compounds:
(1) obtained by multi-step synthesis starting from a commercially available deuterated raw material. This process is generally a cumbersome procedure and the overall yield is not high.
(2) Starting from raw materials which are not marked by deuterium, the synthesis is carried out by directly exchanging hydrogen and deuterium at the benzyl position, and the steps are simple and direct. However, currently, few reports of implementing deuteration of the benzylic carbon-hydrogen bond by using the method are available, and a great limitation exists. It is composed ofOne such method involves hydrogen capture at the benzyl position of the substrate molecule by a strong base (e.g., potassium tert-butoxide/DMSO) followed by hydrogen deuterium exchange with a deuterating reagent (Hu, Y.; Liang, L.; Wei, W.; Sun, X.; Zhang, X.; Yan, M.tetrahedron 2015,71, 1425; Tie, L.; Shan, X. -H.; Qu J. -P.; Kang, Y. -B.org.Chem.Front.2021, DOI:10.1039/d1qo002 00265 a). The method has poor compatibility of substrate functional groups and is only suitable for simpler molecules. Another type of process is carried out using transition metal catalysts, such as Pd/C, Ru, Ni, Co, Rh, Ir, etc. (Sajiki, H.; Aoki, F.; Esaki, H.; Maegawa, T.; Hirota, K.Org.Lett.2004,6,1485; Neubert, L.; Michalik, D.; Bahn, S.; S.Neumann, H.; Atzrodt, J.; Derdau, V.; Holla, W.; Belr, M.J.Am.Chem.Soc.2012,134, 12239; Heys, J.R.J.Label. Radiogrm 2010,53716; Palmer, W.N.; Chirik, P.J.ACS.2017, 7,5674; Rhinert, L.Harry, Buel. D.R.J.R.P.R.C.D.R.D.J., C.D.J., R.D.D.J., C.D.D. J., C.D.J., R.D.J., C. J., R.D. J., R.D.J., C. J., W.R.R.R.J., W., H., W.R. J., H., W.R.J., H., W., H., P.J., H., P.R.R.J., H., H., W., H., A. metallization, A metallization, a metallization. However, the use of transition metal catalyzed benzylic deuteration often suffers from selectivity problems due to the influence of other carbon-hydrogen bonds in the molecule, e.g., sp on the aromatic ring2The carbon-hydrogen bond is also deuterated.
In conclusion, selective deuteration of carbon-hydrogen bonds at the benzylic position of the aromatic ring has important significance in organic chemistry and pharmaceutical chemistry, but the existing methods have the problems of narrow substrate applicability, poor deuteration selectivity and the like, and limit the application of the methods in late selective deuteration of complex molecules.
Disclosure of Invention
Aiming at the defects of narrow applicability, poor deuteration selectivity and the like of the existing substrate, the invention provides a method for selectively deuterating carbon-hydrogen bonds at the benzyl position of an aromatic ring. The method passing η6The coordination activation is realized by the following specific mechanism: aromatic ring and metal rhodium ([ Rh ] s)]) Occurrence of eta6After coordination, the acidity of the C-H bond at the benzyl position is greatly enhanced. This makes the benzylic C-H bond easier to H/D exchange than other C-H bonds, providing the basis for selective deuteration at the benzylic position.
The purpose of the invention is realized by the following technical scheme:
a method for selectively deuterating benzyl position of aromatic ring comprises reacting S with nitrogen1And a metal rhodium catalyst ([ Rh ]]) Silver salt ([ Ag ]]) Mixing uniformly, adding a deuterated solvent (solvent), stirring at 80-140 ℃ to completely react, cooling to room temperature, concentrating, and performing column chromatography separation to obtain a compound S1-d, the benzylic deuteration, is specifically represented by the following formula:
wherein, the raw material S1Is an aromatic hydrocarbon or an aromatic hydrocarbon derivative;
the metal rhodium catalyst is a derivative of pentamethylcyclopentadienyl rhodium dichloride dimer;
the silver salt is a silver salt with a weakly coordinating counter silver ion;
the deuterated solvent is deuterated methanol or deuterated acetone, and when the deuterated solvent is deuterated acetone, phosphate is required to be added as inorganic Base (Base); at this time, the raw material S1The ratio of the metal rhodium catalyst to the silver salt to the inorganic base to the deuterated acetone is 1: (5-10 mol%): (10-40 mol%): (10-100 mol%): (0.5-4 mol/L);
when the deuterated solvent is deuterated methanol, the raw material S is prepared1The ratio of the metal rhodium catalyst to the silver salt to the deuterated solvent is 1: (5-10 mol%): (10-40 mol%): (0.5-4 mol/L);
the silver salt and the metal rhodium catalyst satisfy a molar ratio of [ Ag ]/[ Rh ] ═ 2: 1.
preferably, the feedstock S1Wherein the R group is a hydrogen atom, an alkyl group, an aryl group or a hetero atom, but is not limited to these groups.
Preferably, the metal rhodium catalyst is a derivative of pentamethylcyclopentadienyl rhodium dichloride dimer, which is shown as follows:
of these, catalyst 10(cat.10) works best.
Preferably, the silver salt is AgNTf2、AgOTf、AgSbF6、AgBF4、AgPF6Any one or combination of several of them according to any proportion, wherein AgNTf2The effect is optimal.
Preferably, the inorganic base is selected from phosphates, such as any one or a combination of several of lithium phosphate, sodium phosphate and silver phosphate according to any ratio, wherein lithium phosphate is most preferable.
Preferably, inorganic salts with weakly coordinating counter silver ions are also added as additives to the reaction.
Preferably, the additive is LiNTf2、NaNTf2、KNTf2Any one or a combination of a plurality of materials in any proportion of LiOTf, NaOTf and KOTf, wherein NaNTf2The effect is optimal.
Preferably, the starting material S1The ratio of the metal rhodium catalyst to the silver salt to the inorganic base to the deuterated acetone is as follows: 1: 2.5 mol%: 10 mol%: 10 mol%: 1 mol/L.
Preferably, the starting material S1The ratio of the metal rhodium catalyst to the silver salt to the deuterated methanol is as follows: 1: 2.5 mol%: 10 mol%: 1 mol/L.
The invention has the following beneficial effects:
(1) most of the raw materials used in the invention are commercially available, the operation and treatment are convenient, and special purification treatment is not needed.
(2) The method is simple and convenient to operate, and the target compound can be obtained with high yield, high deuteration rate and high selectivity by only mixing and heating all reactants.
(3) The substrate has wide functional group compatibility, and can be applied to the late deuteration reaction of complex bioactive molecules and drug molecules.
Detailed Description
The present invention will be described in detail below based on preferred embodiments, and objects and effects of the present invention will become more apparent, and it should be understood that the specific embodiments described herein are merely illustrative of the present invention and are not intended to limit the present invention.
The following examples are provided to select different substrates, to specify the specific operation of the reaction, the specific conditions of the reaction, and to better illustrate the present invention from a range of different structures. The product was identified by nuclear magnetism and the chiral product was detected by supercritical liquid chromatography (SFC).
Example 1
Under nitrogen atmosphere, the raw materials 1(0.2mmol,30.0mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in this order2(0.02mmol,7.8mg)，Li3PO4(0.02mmol, 2.3mg) and finally acetone-d was added6(0.2 mL). After the reaction was stirred at 120 ℃ for 24 hours, it was cooled to room temperature, and internal standards 1,1, 2, 2-tetrachloroethane (0.2mmol,33.6mg) and deuterated chloroform (0.5mL) were added, and the benzyl deuteration of the target product was 86% and the nuclear magnetic yield was 99% as determined by nuclear magnetic hydrogen spectroscopy.1H NMR(500MHz,Chloroform-d)δ7.16(d,J＝8.7Hz,2H),6.85(d,J＝8.7Hz,2H),3.80(s,3H),2.92–2.80(m,0.14H,86％D),1.28–1.16(m,6H).13C NMR(126MHz,Chloroform-d)δ157.6,127.2,141.0,113.7,55.2,33.2(benzylic carbon of remaining 1),32.8(t,J＝19.5Hz,benzylic carbon of deuterated 1),24.19–24.08(m,–CH3carbon).
Example 2
To a reaction flask were added, in order, under nitrogen atmosphere, raw material 2(0.2mmol,24.0mg), catalyst 1(0.005mmol,3.1mg), AgOTf (0.02mmol,5.1mg), NaOTf (0.2mmol, 34.4mg), and finally, methanol-d was added4(0.2 mL). After the reaction was stirred at 120 ℃ for 24 hours, it was cooled to room temperature, and internal standards 1,1, 2, 2-tetrachloroethane (0.2mmol,33.6mg) and deuterated chloroform (0.5mL) were added, and the benzyl deuteration of the target product was determined to be 50% by nuclear magnetic hydrogen spectroscopy, with a nuclear magnetic yield of 99%.1H NMR(500MHz,Chloroform-d)δ7.30–7.26(m,2H),7.23–7.21(m,2H),7.19–7.15(m,1H),2.95–2.86(m,0.50H,50％D),1.26–1.21(m,6H).13C NMR(126MHz,Chloroform-d)δ148.74–148.71(m,aromatic carbon adjacent to benzylic carbon),128.2,126.3,125.6,34.0(benzylic carbon of remaining 2),33.53(t,J＝19.5Hz,benzylic carbon of deuterated 2),23.81–23.70(m,–CH3 carbon).
Example 3
To a reaction flask, raw material 3(0.2mmol,29.7mg), catalyst 11(0.005mmol,3.7mg), AgNTf were added in this order under nitrogen atmosphere2(0.02mmol,7.8mg)，NaNTf2(0.2mmol, 60.6mg), and finally, methanol-d was added4(0.2 mL). After the reaction was stirred at 120 ℃ for 24 hours, it was cooled to room temperature, and an internal standard 1,1, 2, 2-tetrachloroethane (0.2mmol,33.6mg) and deuterated chloroform (0.5mL) were added, and the benzyl deuteration of the target product was 83% and the nuclear magnetic yield was 99% as determined by nuclear magnetic hydrogen spectroscopy.1H NMR(500MHz,Chloroform-d)δ7.31(d,J＝8.3Hz,2H),7.14(d,J＝8.3Hz,2H),2.38–2.31(m,0.51H,83％D),1.34(s,6H).13C NMR(126MHz,Chloroform-d)δ148.2,134.8–134.7(m,aromatic carbon adjacent to benzylic methyl carbon),128.7,125.1,34.3,31.4,20.8–19.4(m,benzylic methyl carbon).
Example 4
Under nitrogen atmosphere, the raw material 4(0.2mmol,26.8mg) and the catalyst 12(0.01 mm) were added to a reaction flask in this orderol,7.4mg)，AgNTf2(0.04mmol,15.6mg)，NaNTf2(0.2mmol, 60.6mg), and finally, methanol-d was added4(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 85%. The benzyl deuteration rate of the target product is determined to be 72 percent through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.28–7.27(m,2H),7.18–7.13(m,3H),2.48–2.44(m,0.56H,72％D),1.90–1.81(m,1H),0.90(d,J＝6.5Hz,6H).13C NMR(126MHz,Chloroform-d)δ141.7–141.6(m,aromatic carbon adjacent to benzylic carbon),129.1,128.0,125.6,45.5(benzylic carbon of remaining 4),45.2–44.3(m,benzylic carbon of deuterated 4),30.28–29.99(m,–CH carbon),22.38–22.24(m,–CH3 carbon).
Example 5
Under nitrogen atmosphere, the raw materials 5(0.2mmol,33.6mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in this order2(0.02mmol,7.8mg)，NaNTf2(0.2mmol, 60.6mg), and finally, methanol-d was added4(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product with the yield of 81%. The benzyl deuteration rate of the target product is determined to be 88 percent through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.33–7.30(m,4H),7.24–7.22(m,6H),4.02–4.00(m,0.23H,88％D).13C NMR(126MHz,Chloroform-d)δ141.07–141.04(m,aromatic carbon adjacent to benzylic carbon),128.9,128.4,126.1,41.9–40.9(m,benzylic carbon).
Example 6
Under nitrogen atmosphere, the raw material 6(0.2mmol,36.4mg), catalyst 26(0.01mmol,8.6mg), AgNTf were added to the reaction flask in this order2(0.02mmol,7.8mg)，NaNTf2(0.2mmol, 60.6mg), and finally, methanol-d was added4(0.2 mL). The reaction is stirred for 48 hours at 140 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 92%. The benzyl deuteration rate of the target product is determined to be 90% through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.28–7.25(m,4H),7.22–7.20(m,4H),7.18–7.16(m,2H),4.16–4.12(m,0.10H,90％D),1.64–1.62(m,3H).13C NMR(126MHz,Chloroform-d)δ146.34–146.30(m,aromatic carbon adjacent to benzylic carbon),128.3,127.6,126.0,44.7(benzylic carbon of remaining 6),44.3(t,J＝19.5Hz,benzylic carbon of deuterated 6),21.83–21.71(m,–CH3 carbon).
Example 7
The starting materials 7(0.2mmol,39.3mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in this order under nitrogen atmosphere2(0.02mmol,7.8mg)，NaNTf2(0.4mmol, 121.2mg), and finally, methanol-d was added4(0.2 mL). The reaction is stirred for 48 hours at 140 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 92%. The benzyl deuteration rate of the target product is determined to be 87% by nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.62–7.61(m,2H),7.57–7.55(m,2H),7.47–7.44(m,2H),7.37–7.32(m,3H),3.03–2.95(m,0.13H,87％D),1.33–1.32(m,6H).13C NMR(126MHz,Chloroform-d)δ147.98–147.96(m,aromatic carbon adjacent to benzylic carbon),141.2,138.7,128.7,127.1,127.0,126.9,126.8,33.8(benzylic carbon of remaining 7),33.4(t,J＝19.5Hz,benzylic carbon of deuterated 7),24.00–23.90(m,–CH3 carbon).
Example 8
In a nitrogen atmosphereThe reaction flask was charged with the starting materials 8(0.2mmol,26.8mg), catalyst 10(0.005mmol,3.5mg), AgNTf in that order2(0.02mmol,7.8mg)，NaNTf2(0.2mmol, 60.6mg), and finally, methanol-d was added4(0.4 mL). After the reaction was stirred at 120 ℃ for 24 hours, it was cooled to room temperature, and an internal standard 1,1, 2, 2-tetrachloroethane (0.2mmol,33.6mg) and deuterated chloroform (0.5mL) were added, and the benzyl deuteration of the target product was 80% and the nuclear magnetic yield was 99% as determined by nuclear magnetic hydrogen spectroscopy.1H NMR(500MHz,Chloroform-d)δ7.32–7.27(m,2H),7.19–7.16(m,3H),2.62–2.56(m,0.2H,80％D),1.61–1.57(m,2H),1.25–1.23(m,3H),0.82(t,J＝7.4Hz,3H).13C NMR(126MHz,Chloroform-d)δ147.54–147.52(m,aromatic carbon adjacent to benzylic carbon),128.1,126.9,125.6,41.5(benzylic carbon of remaining 8),41.0(t,J＝19.5Hz,benzylic carbon of deuterated 8),31.00–30.89(m,–CH2 carbon),21.62–21.51(m,–CH3 carbon),12.00–11.98(m,–CH3 carbon).
Example 9
The starting materials 9(0.2mmol,32.5mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in this order under nitrogen atmosphere2(0.02mmol,7.8mg)，NaNTf2(0.4mmol, 121.2mg), and finally, methanol-d was added4(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 87%. The benzyl deuteration rate of the target product is determined to be 66% through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.33–7.30(m,2H),7.24–7.23(m,2H),7.21–7.18(m,1H),2.55–2.49(m,0.34H,68％D),1.91–1.85(m,4H),1.79–1.76(m,1H),1.50–1.38(m,4H),1.33–1.24(m,1H).13C NMR(126MHz,Chloroform-d)δ148.09–148.07(m,aromatic carbon adjacent to benzylic carbon),128.3,126.82–126.80(m),125.8,44.6(benzylic carbon of remaining 9),44.1(t,J＝19.3Hz,benzylic carbon of deuterated 9),34.47–34.37(m,–CH2 carbon),26.93–26.92(m,–CH2 carbon),26.2.
Example 10
The starting materials 10(0.2mmol,26.4mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in this order under nitrogen atmosphere2(0.02mmol,7.8mg)，NaNTf2(0.2mmol, 60.6mg), and finally, methanol-d was added4(0.2 mL). After the reaction was stirred at 120 ℃ for 24 hours, it was cooled to room temperature, and internal standards 1,1, 2, 2-tetrachloroethane (0.2mmol,33.6mg) and deuterated chloroform (0.5mL) were added, and the benzyl deuteration ratios of the target products were 87% and 48% and the nuclear magnetic yield was 99% as determined by nuclear magnetic hydrogen spectroscopy.1H NMR(500MHz,Chloroform-d)δ7.22–7.12(m,4H),3.21–3.116(m,0.13H,87％D),2.94–2.80(m,1.04H,48％D),2.32–2.27(m,1H),1.63–1.57(m,1H),1.30–1.28(m,3H).13C NMR(126MHz,Chloroform-d)δ148.51–148.43(m,aromatic carbon adjacent to benzylic carbon),143.65–143.54(m,aromatic carbon adjacent to benzylic carbon),125.8,124.08–124.05(m),122.9,39.14–38.55(m,benzylic–CH carbon),34.33–34.12(m,benzylic–CH2 carbon),31.11–30.60(m,–CH2 carbon),19.49–19.40(m,–CH3 carbon).
Example 11
Under nitrogen atmosphere, raw material 11(0.2mmol,26.4mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to a reaction flask in this order2(0.02mmol,7.8mg)，NaNTf2(0.2mmol, 60.6mg), and finally, methanol-d was added4(0.1 mL). The reaction is stirred for 24 hours at 120 ℃, cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 72%. The benzyl deuteration rate of the target product is determined to be 81 percent through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.09–7.04(m,4H),2.77–2.72(m,0.76H,81％D),1.79–1.77(m,4H).13C NMR(126MHz,Chloroform-d)δ137.11–137.06(m,aromatic carbon adjacent to benzylic carbon),129.1,125.4,29.36–28.29(m,benzylic carbon),23.15–22.94(m,–CH2carbon).
Example 12
The starting materials 12(0.2mmol,33.2mg), catalyst 21(0.005mmol,4.4mg), AgSbF were added to the reaction flask in this order under nitrogen atmosphere6(0.02mmol,6.9mg)，KNTf2(0.4mmol, 127.7mg) and finally methane-d was added4(0.2 mL). The reaction is stirred for 48 hours at 80 ℃, cooled to room temperature, and subjected to direct column chromatography to obtain a target product with the yield of 86%. The benzyl deuteration rate of the target product is determined to be 88 percent through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.78–7.76(m,2H),7.53–7.51(m,2H),7.38–7.34(m,2H),7.30–7.27(m,2H),3.88–3.85(m,0.24H,88％D).13C NMR(126MHz,Chloroform-d)δ143.14–143.11(m),141.75–141.71(m),126.71,126.66,125.02–125.00(m),119.8,36.89–35.96(m,benzylic carbon).
Example 13
To a reaction flask were added, in order, raw material 13(0.2mmol,36.1mg), catalyst 23(0.005mmol,4.5mg), AgOTf (0.02mmol,5.1mg), LiNTF under nitrogen atmosphere2(0.2mmol, 57.4mg) and finally methane-d was added4(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 83%. The benzyl deuteration rate of the target product is determined to be 92 percent through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.75–7.74(m,2H),7.50–7.48(m,2H),7.36–7.29(m,4H),3.95–3.91(m,0.08H,92％D),1.50–1.48(m,3H).13C NMR(126MHz,Chloroform-d)δ148.96–148.94(m),140.55–140.49(m),126.9,124.0,119.8,42.4(benzylic carbon of remaining 14),42.0(t,J＝19.8Hz,benzylic carbon of deuterated 14),18.1.
Example 14
The raw materials 14(0.2mmol,36.1mg), catalyst 10(0.01mmol,7.0mg), AgPF were added to the reaction flask in this order under nitrogen atmosphere6(0.04mmol,10.1mg), KOTf (0.2mmol, 37.6mg), and finally, methanol-d was added4(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 83%. The benzyl deuteration rate of the target product is determined to be 76% through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.75(d,J＝7.7Hz,2H),7.32–7.28(m,2H),7.24–7.22(m,4H),2.87–2.84(m,0.96H,76％D).13C NMR(126MHz,Chloroform-d)δ137.37–137.27(m,aromatic carbon adjacent to benzylic carbon),134.5,128.1,127.4,126.9,123.7,28.93–28.31(m,benzylic carbon).
Example 15
The starting materials 15(0.2mmol,30.4mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in succession under nitrogen2(0.02mmol,7.8mg)，Li3PO4(0.02mmol, 2.3mg) and finally acetone-d was added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 87%. The benzyl deuteration rate of the target product is determined to be 64 percent through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.22–7.20(m,1H),7.18–7.14(m,1H),6.94–6.91(m,1H),6.86–6.84(m,1H),3.83(s,3H),3.36–3.28(m,0.36H,64％D),1.22–1.20(m,6H).13C NMR(126MHz,Chloroform-d)δ156.74–156.72(m),136.99–136.96(m,aromatic carbon adjacent to benzylic carbon),126.5,125.98–125.96(m),120.5,110.3,55.3,26.6(s,benzylic carbon of remaining 17),26.2(t,J＝19.8Hz,benzylic carbon of deuterated 17),22.66–22.57(m,–CH3 carbon).
Example 16
Under nitrogen atmosphere, the raw materials 16(0.2mmol,27.2mg), catalyst 10(0.01mmol,7.0mg), AgNTf were added to the reaction flask in this order2(0.04mmol,15.6mg)，Li3PO4(0.2mmol, 23mg) and finally acetone-d was added6(0.2 mL). After the reaction was stirred at 120 ℃ for 24 hours, it was cooled to room temperature, and an internal standard 1,1, 2, 2-tetrachloroethane (0.2mmol,33.6mg) and deuterated chloroform (0.5mL) were added, and the benzyl deuteration of the target product was 70% and the nuclear magnetic yield was 99% as determined by nuclear magnetic hydrogen spectroscopy.1H NMR(500MHz,Chloroform-d)δ7.12–7.10(m,2H),6.85–6.82(m,2H),3.79(s,3H),2.62–2.57(m,0.60H,70％D),1.21–1.19(m,3H).13C NMR(126MHz,Chloroform-d)δ157.1,135.65–135.60(m,aromatic carbon adjacent to benzylic carbon),128.1,113.1,54.5,27.34–26.33(m,benzylic carbon),15.28–15.11(m,–CH3 carbon).
Example 17
The starting materials 17(0.2mmol,26.8mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in this order under nitrogen atmosphere2(0.02mmol,7.8mg)，Li3PO4(0.02mmol, 2.3mg) and finally acetone-d was added6(0.2 mL). After the reaction was stirred at 120 ℃ for 24 hours, it was cooled to room temperature, and internal standards 1,1, 2, 2-tetrachloroethane (0.2mmol,33.6mg) and deuterated chloroform (0.5mL) were added, and the benzyl deuteration of the target product was 74% and the nuclear magnetic yield was 99% as determined by nuclear magnetic hydrogen spectroscopy.1H NMR(500MHz,Chloroform-d)δ7.09–7.06(m,1H),7.04–7.02(m,1H),6.84–6.81(m,1H),6.79–6.78(m,1H),4.20–4.16(t,J＝5.0Hz,2H),2.80–2.75(m,0.53H,74％D),2.03–1.98(m,2H).13C NMR(126MHz,Chloroform-d)δ154.91–154.87(m),129.8,127.2,122.19–122.08(m,aromatic carbon adjacent to benzylic carbon),120.1,116.7,66.4,24.85–23.98(m,benzylic carbon),22.35–22.15(m,–CH2 carbon).
Example 18
The starting materials 18(0.2mmol,36.4mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in succession under nitrogen2(0.02mmol,7.8mg)，Li3PO4(0.02mmol, 2.3mg) and finally acetone-d was added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 97%. The benzyl deuteration rate of the target product is determined to be 63 percent through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.21–7.13(m,4H),7.04–6.99(m,4H),4.03–4.00(m,0.75H,63％D).13C NMR(126MHz,Chloroform-d)δ151.94–151.91(m),128.9,127.6,122.9,120.53–120.41(m,aromatic carbon adjacent to benzylic carbon),116.4,27.83–26.96(m,benzylic carbon).
Example 19
The starting materials 19(0.2mmol,32.6mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in succession under nitrogen2(0.02mmol,7.8mg)，Na3PO4(0.02mmol，3.3mg)，NaNTf2(0.2mmol, 60.6mg), and finally acetone-d was added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 55%. The benzyl deuteration rate of the target product is determined to be 52 percent through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.11–7.06(m,2H),6.71(d,J＝9.1Hz,0.13H,93％D),2.91(s,6H),2.85–2.80(m,0.48H,52％D),1.23–1.21(m,3H).13C NMR(126MHz,Chloroform-d)δ148.95–148.90(m),137.21–137.17(m,aromatic carbon adjacent to benzylic carbon),126.79–126.78(m),112.99–112.52(m,aromatic carbon at ortho position of NMe2),40.9,33.0(s,benzylic carbon of remaining 22),32.7(t,J＝19.2Hz,benzylic carbon of deuterated 22),24.21–24.10(m,–CH3 carbon).
Example 20
The starting material 23(0.2mmol,40.5mg), catalyst 11(0.005mmol,3.7mg), AgNTf were added to the reaction flask in this order under nitrogen atmosphere2(0.02mmol,7.8mg)，Li3PO4(0.02mmol，2.3mg)，NaNTf2(0.2mmol, 60.6mg), and finally acetone-d was added6(0.2 mL). The reaction was stirred at 120 ℃ for 24 hours, then cooled to room temperature and subjected to direct column chromatography to obtain the target product with a yield of 77%. The benzyl deuteration rate of the target product is determined to be 76% through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.28(t,J＝7.4Hz,2H),7.23(t,J＝7.7Hz,2H),7.19(d,J＝7.3Hz,1H),7.15(d,J＝7.4Hz,2H),7.10(d,J＝8.3Hz,2H),3.93–3.91(m,0.48H,76％D).13C NMR(126MHz,Chloroform-d)δ140.53–140.46(m,aromatic carbon adjacent to benzylic carbon),139.56–139.49(m,aromatic carbon adjacent to benzylic carbon),131.9,130.2,128.8,128.55,128.54,126.3,41.22–40.38(m,benzylic carbon).
Example 21
Under nitrogen atmosphere, the raw materials 21(0.2mmol,49.0mg), catalyst 10(0.005mmol,3.5mg), AgBF were added to the reaction flask in this order4(0.02mmol,3.8mg), LiOTf (0.2mmol, 31.2mg), and finally methane-d was added4(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 98%. The benzyl deuteration rate of the target product is determined to be 87% by nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.71(d,J＝7.5Hz,1H),7.63(d,J＝1.9Hz,1H),7.58(d,J＝8.1Hz,1H),7.50–7.45(m,2H),7.37–7.34(m,1H),7.31–7.28(m,1H),3.83–3.80(m,0.26H,87％D).13C NMR(126MHz,Chloroform-d)δ145.11–145.08(m),142.76–142.72(m,aromatic carbon adjacent to benzylic carbon),140.72–140.67(m,aromatic carbon adjacent to benzylic carbon),129.8,128.22–128.20(m),127.1,126.9,125.0,121.0,120.4,119.9,36.69–35.93(m,benzylic carbon).
Example 22
Under nitrogen atmosphere, the raw materials 22(0.2mmol,48.5mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in this order2(0.02mmol,7.8mg)，NaNTf2(0.2mmol, 60.6mg), and finally, methanol-d was added4(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 90%. The benzyl deuteration rate of the target product is determined to be 83 percent and 59 percent through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.71(d,J＝7.5Hz,1H),7.63(d,J＝1.9Hz,1H),7.58(d,J＝8.1Hz,1H),7.50–7.45(m,2H),7.37–7.34(m,1H),7.31–7.28(m,1H),3.83–3.80(m,0.26H,87％D).13C NMR(126MHz,Chloroform-d)δ145.11–145.08(m),142.76–142.72(m,aromatic carbon adjacent to benzylic carbon),140.72–140.67(m,aromatic carbon adjacent to benzylic carbon),129.8,128.22–128.20(m),127.1,126.9,125.0,121.0,120.4,119.9,36.69–35.93(m,benzylic carbon).
Example 23
Under nitrogen atmosphere, the raw materials 23(0.2mmol,30.0mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in this order2(0.02mmol,7.8mg)，NaNTf2(0.2mmol, 60.6mg), and finally, methanol-d was added4(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product with the yield of 59%. The benzyl deuteration rate of the target product is determined to be 64 percent through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.30–7.27(m,2H),7.20–7.175(m,3H),3.39(t,J＝6.4Hz,2H),3.35(s,3H),2.70–2.65(m,0.72H,64％D),1.91–1.86(m,2H).13C NMR(126MHz,Chloroform-d)δ141.97–141.90(m,aromatic carbon adjacent to benzylic carbon),128.5,128.3,125.8,71.93–71.90(m),58.6,32.31–31.43(m,benzylic carbon),31.26–31.10(m).
Example 24
Under nitrogen atmosphere, the raw materials 24(0.2mmol,40.5mg), catalyst 10(0.01mmol,7.0mg), AgNTf were added to the reaction flask in this order2(0.04mmol,15.6mg)，Ag3PO4(0.02mmol，8.4mg)，NaNTf2(0.2mmol, 60.6mg), and finally acetone-d was added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 99%. The benzyl deuteration rate of the target product is determined to be 70% through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.82–7.78(m,4H),7.50–7.48(m,2H),7.44–7.41(m,4H),7.25–7.24(m,2H),7.17–7.13(m,3H),4.06–4.02(m,2H),2.74–2.69(m,0.60H,70％D),2.04–2.00(m,2H).13C NMR(126MHz,Chloroform-d)δ140.95–140.88(m,aromatic carbon adjacent to benzylic carbon),132.1(d,J＝2.9Hz),131.9,131.5(d,J＝10.2Hz),130.8,128.4(d,J＝13.2Hz),128.3,125.9,64.1(d,J＝6.0Hz),32.01–30.90(m,benzylic carbon).
Example 25
The starting materials 25(0.2mmol,44.0mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in succession under nitrogen atmosphere2(0.02mmol,7.8mg)，Li3PO4(0.02mmol, 2.3mg) and finally acetone-d was added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 95%. The benzyl deuteration rates of the target products are determined to be 77 percent and 85 percent through nuclear magnetic hydrogen spectra.1H NMR(500MHz,Chloroform-d)δ7.19(d,J＝7.9Hz,2H),7.09(d,J＝8.0Hz,2H),3.72–3.67(m,0.15H,85％D),3.65(s,3H),2.45–2.41(m,0.47H,77％D),1.87–1.79(m,1H),1.49–1.48(m,3H),0.89(d,J＝6.7Hz,6H).13C NMR(126MHz,Chloroform-d)δ175.2,140.49–140.42(m,aromatic carbon adjacent to benzylic carbon),137.71–137.65(m,aromatic carbon adjacent to benzylic carbon),129.3,127.1,51.9,44.99–44.04(m,containing two benzylic carbons),30.12–29.96(m),22.32–22.29(m),18.57–18.46(m).
Example 26
The starting materials 26(0.2mmol,38.8mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in succession under nitrogen atmosphere2(0.02mmol,7.8mg)，Li3PO4(0.02mmol，2.3mg)，NaNTf2(0.2mmol, 60.6mg), and finally acetone-d was added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 91%. The benzyl deuteration rate of the target product is determined to be 85 percent through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.21–7.17(m,1H),7.15–7.13(m,1H),6.89–6.83(m,2H),3.81(s,3H),3.66(s,3H),2.95–2.90(m,0.31H,85％D),2.61–2.60(m,2H).13C NMR(126MHz,Chloroform-d)δ173.8,157.4,129.9,128.74–128.67(m,aromatic carbon adjacent to benzylic carbon),127.6,120.4,110.1,55.1,51.4,33.95–33.82(m),26.07–25.14(m,benzylic carbon).
Example 27
The starting materials 27(0.2mmol,44.0mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in this order under nitrogen atmosphere2(0.02mmol,7.8mg)，NaNTf2(0.2mmol, 60.6mg), and finally, methanol-d was added4(0.2 mL). The reaction was stirred at 120 ℃ for 24 hours, then cooled to room temperature and subjected to direct column chromatography to obtain the target product with a yield of 93%. The benzyl deuteration rate of the target product is determined to be 76% through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.28–7.25(m,2H),7.20–7.15(m,3H),5.73(s,1H),3.05(t,J＝7.0Hz,2H),2.66–2.60(m,0.48H,76％D),2.17(t,J＝7.6Hz,2H),1.97–1.93(m,2H),1.80–1.69(m,1H),0.89(d,J＝6.8Hz,6H).13C NMR(126MHz,Chloroform-d)δ172.8,141.43–141.37(m,aromatic carbon adjacent to benzylic carbon),128.4,128.3,125.9,46.7,35.90–35.85(m),35.12–34.39(m,benzylic carbon),28.4,27.19–27.03(m),20.00.
Example 28
The starting materials 28(0.2mmol,35.0mg), catalyst 10(0.01mmol,7.0mg), AgNTf were added to the reaction flask in this order under nitrogen atmosphere2(0.04mmol,15.6mg)，Li3PO4(0.02mmol，2.3mg)，NaNTf2(0.2mmol, 60.6mg), and finally acetone-d was added6(0.2 mL). The reaction was stirred at 120 ℃ for 24 hours, then cooled to room temperature and subjected to direct column chromatography to obtain the target product with a yield of 77%. The benzyl deuteration rate of the target product is 91 percent through nuclear magnetic hydrogen spectrum determination.1H NMR(500MHz,Chloroform-d)δ7.35–7.32(m,2H),7.27–7.25(m,1H),7.25–7.21(m,2H),3.74(d,J＝9.7Hz,1H),3.62–3.52(m,0.09H,91％D),3.40(d,J＝9.7Hz,1H),2.90(s,3H),2.80(d,J＝16.8Hz,1H),2.54(d,J＝16.8Hz,1H).13C NMR(126MHz,Chloroform-d)δ173.9,142.42–142.38(m,aromatic carbon adjacent to benzylic carbon),128.8,127.0,126.6,56.62–56.56(m),38.73–38.66(m),37.0(s,benzylic carbon of remaining 33),36.7(t,J＝20.3Hz,benzylic carbon of deuterated 33),29.5.
Example 29
The raw materials 29(0.2mmol,55.1mg), catalyst 10(0.01mmol,7.0mg), AgNTf were added to the reaction flask in this order under nitrogen atmosphere2(0.04mmol,15.6mg)，Li3PO4(0.02mmol，2.3mg)，NaNTf2(0.2mmol, 60.6mg), and finally acetone-d was added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 79%. The benzyl deuteration rate of the target product is determined to be 60% through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.69(d,J＝8.2Hz,2H),7.28–7.24(m,4H),7.21–7.18(m,1H),7.08–7.07(m,2H),4.66(t,J＝6.1Hz,1H),3.20–3.17(m,2H),2.76–2.72(m,0.81H,60％D),2.41(s,3H).13C NMR(126MHz,Chloroform-d)δ143.3,137.67–137.60(m,aromatic carbon adjacent to benzylic carbon),136.8,129.6,128.7,128.6,127.0,126.7,44.17–44.06(m),35.72–34.88(m,benzylic carbon),21.5.
Example 30
Under nitrogen atmosphere, the raw materials 30(0.2mmol,50.2mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in this order2(0.02mmol,7.8mg)，Li3PO4(0.02mmol，2.3mg)，NaNTf2(0.2mmol, 60.6mg), and finally acetone-d was added6(0.2 mL). Stirring the reaction solution at 120 ℃ for 24 hours, cooling the reaction solution to room temperature, and directly carrying out column chromatography to obtain the targetThe yield of the title product was 94%. The benzyl deuteration rate of the target product is determined to be 72 percent through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.83–7.80(m,2H),7.71–7.68(m,2H),7.29–7.24(m,4H),7.22–7.19(m,1H),3.92–3.91(m,2H),3.00–2.95(m,0.56H,72％D).13C NMR(126MHz,Chloroform-d)δ168.1,137.93–137.85(m,aromatic carbon adjacent to benzylic carbon),133.8,132.0,128.8,128.5,126.6,123.1,39.20–39.07(m),34.53–33.54(m,benzylic carbon).
Example 31
The raw materials 31(0.2mmol,29.8mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in this order under nitrogen atmosphere2(0.02mmol,7.8mg)，NaNTf2(0.2mmol, 60.6mg), HOTf (0.24mmol, 36.0mg), and finally, methanol-d was added4(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 85%. The benzyl deuteration rate of the target product is determined to be 68 percent through nuclear magnetic hydrogen spectrum.1H NMR(600MHz,Chloroform-d)δ7.28–7.25(m,2H),7.21–7.18(m,1H),7.15–7.13(m,2H),5.96(s,3H),3.37–3.31(m,1H),2.66–2.59(m,0.65H,68％D),2.02–1.97(m,1H),1.85–1.80(m,1H),1.31(d,J＝6.6Hz,3H).13C NMR(126MHz,Chloroform-d)δ139.58–139.42(m,aromatic carbon adjacent to benzylic carbon),128.7,128.1,126.5,119.4(q,J＝320.4Hz),49.3,35.92–35.77(m),31.37–30.53(m,benzylic carbon),18.1.
Example 32
The starting materials 32(0.2mmol,54.6mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in succession under nitrogen atmosphere2(0.02mmol,7.8mg)，Li3PO4(0.02mmol，2.3mg)，NaNTf2(0.2mmol，60.6mg) and finally acetone-d is added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 83%. The benzyl deuteration rate of the target product is determined to be 78% by nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.68–7.63(m,3H),7.22–7.17(m,3H),7.07(d,J＝6.2Hz,1H),6.96(t,J＝7.4Hz,1H),3.91–3.89(m,2H),2.89–2.84(m,0.45H,78％D),2.36(s,3H).13C NMR(126MHz,Chloroform-d)δ144.0,142.00–141.94(m,aromatic carbon adjacent to benzylic carbon),134.0,131.71–131.58(m),129.6,127.7,127.3,125.09–125.07(m),123.6,114.9,49.88–49.73(m),27.81–27.03(m,benzylic carbon),21.5.
Example 33
Under nitrogen atmosphere, the raw materials 33(0.2mmol,50.5mg), catalyst 10(0.01mmol,7.0mg), AgNTf were added to the reaction flask in this order2(0.04mmol,15.6mg)，NaNTf2(0.2mmol, 60.6mg), and finally, methanol-d was added4(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 82%. The benzyl deuteration rate of the target product is determined to be 72 percent through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.54(d,J＝8.0Hz,2H),7.32–7.27(m,4H),7.24–7.21(m,1H),7.18–7.16(m,2H),3.00–2.98(m,2H),2.96–2.91(m,0.57H,72％D).Quantitative 13C NMR(151MHz,Chloroform-d)δ145.7(s,1C),141.02–140.95(m,1C),128.8(s,2C),128.4(s,5C),126.1(s,1C),125.26–125.18(m,2C),124.4(m,J＝271.8Hz,1C,–CF3 carbon),37.63–37.49(m,1C,benzylic carbon adjacent to 4-CF3C6H4–group),37.25–36.49(m,benzylic carbon adjacent to phenyl group,containing 0.07undeuterated C,0.47mono-deuterated C,0.46di-deuterated C,70％D).19F NMR(471MHz,Chloroform-d)δ-62.3.
Example 34
To a reaction flask, raw material 34(0.2mmol,32.8mg,>99/1 e.r.)，catalyst 10(0.005mmol,3.5mg)，AgNTf2(0.02mmol,7.8mg)，Li3PO4(0.02mmol, 2.3mg) and finally acetone-d was added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 90%. The benzyl deuteration rate of the target product is determined to be 62% through nuclear magnetic hydrogen spectrum. Product e.r. value determined by SFC was 97/3, SFC conditions were: OD-3 column, MeOH/CO2＝5:95,1.5mL/min,210nm,tmajor＝0.914min,tminor＝1.103min；1H NMR(500MHz,Chloroform-d)δ7.31–7.28(m,2H),7.24–7.19(m,3H),3.30–3.23(m,0.38H,62％D),2.69–2.64(m,1H),2.60–2.55(m,1H),1.34–1.28(m,3H).13C NMR(126MHz,Chloroform-d)δ178.4,145.44–145.40(m,aromatic carbon adjacent to benzylic carbon),128.5,126.69–126.67(m),126.5,42.57–42.48(m),36.13–35.58(m,benzylic carbon),21.83–21.72(m).
Example 35
To a reaction flask, raw material 35(0.2mmol,32.8mg,>99/1 e.r.)，catalyst 10(0.005mmol,3.5mg)，AgNTf2(0.02mmol,7.8mg)，Li3PO4(0.02mmol, 2.3mg) and finally acetone-d was added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 90%. The benzyl deuteration rate of the target product is determined to be 70% through nuclear magnetic hydrogen spectrum. The product e.r. value was determined by SFC to be 98.6/1.4, SFC conditions were: OD-3 column, MeOH/CO2＝1:99 to 5:95,1.0mL/min,215nm,tmajor＝1.686min,tminor＝2.442min；1H NMR(500MHz,Chloroform-d)δ7.31–7.28(m,2H),7.20–7.17(m,3H),3.28(s,3H),3.31–3.20(m,2H),2.90–2.83(m,0.30H,70％D),1.88–1.80(m,2H),1.27–1.26(m,3H).13C NMR(126MHz,Chloroform-d)δ146.95–146.91(m,aromatic carbon adjacent to benzylic carbon),128.3,126.96–126.94(m),125.9,70.8,58.5,37.95–37.85(m),36.4(s,benzylic carbon of remaining 41),35.97(t,J＝19.5Hz,benzylic carbon of deuterated 41),22.25–22.13(m).
Example 36
Under nitrogen atmosphere, the raw material 36(0.2mmol,50.2mg,97.5/2.5 e.r.), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in this order2(0.02mmol,7.8mg)，Li3PO4(0.02mmol，2.3mg)，NaNTf2(0.2mmol, 60.6mg), and finally acetone-d was added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 92%. The benzyl deuteration rate of the target product is determined to be 70% through nuclear magnetic hydrogen spectrum. Product e.r. value determined by SFC was 95/5, SFC conditions were: OD-3 column, MeOH/CO2＝3:97,1.5mL/min,210nm,tminor＝1.690min,tmajor＝1.903min；1H NMR(500MHz,Chloroform-d)δ7.80–7.78(m,2H),7.68–7.66(m,2H),7.52–7.50(m,2H),7.34–7.31(m,2H),7.27–7.25(m,1H),5.59–5.55(m,0.25H,75％D),1.94–1.92(m,3H).13C NMR(126MHz,Chloroform-d)δ168.1,140.24–140.18(m,aromatic carbon adjacent to benzylic carbon),133.8,131.9,128.4,127.62–127.60(m),127.40–127.38(m),123.1,49.6(s,benzylic carbon of remaining 42),49.3(t,J＝21.3Hz,benzylic carbon of deuterated 42),17.46–17.36(m).
Example 37
In nitrogen atmosphere, the reaction is carried out in sequenceThe flask was charged with starting material 37(0.2mmol,44.2mg), catalyst 10(0.02mmol,14.0mg), AgNTf2(0.08mmol,31.2mg)，Li3PO4(0.02mmol, 2.3mg) and finally acetone-d was added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 90%. The benzyl deuteration rate of the target product is 57 percent through nuclear magnetic hydrogen spectrum determination.1H NMR(500MHz,Chloroform-d)δ6.60(s,0.11H,89％D),6.49(s,2H,89％D),6.16(s,1H),4.95–4.86(m,1H),4.06–3.97(m,2H),3.68(t,J＝9.0Hz,1H),3.49(t,J＝8.4Hz,1H),2.26–2.19(m,2.60H,57％D).13C NMR(126MHz,Chloroform-d)δ160.5,157.98–157.94(m),139.30–139.11(m),123.36–122.86(m),112.30–111.80(m),74.9,67.8,42.5,21.20–20.28(m).
Example 38
The starting materials 38(0.2mmol,86.7mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in succession under nitrogen2(0.02mmol,7.8mg)，Li3PO4(0.02mmol，2.3mg)，NaNTf2(0.2mmol, 60.6mg), and finally acetone-d was added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 50%. The benzyl deuteration rate of the target product is 79 percent determined by nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.09(s,4H),5.67(s,1H),4.35(s,4H),2.60–2.52(m,0.86H,79％D),2.19–2.17(m,2H),2.08(s,6H),1.94(s,3H),1.56(t,J＝7.0Hz,1H),1.31–1.26(m,10H),0.88(t,J＝6.9Hz,3H).13C NMR(126MHz,Chloroform-d)δ170.8,170.1,140.72–140.69(m,aromatic carbon adjacent to benzylic carbon),138.30–138.26(m,aromatic carbon adjacent to benzylic carbon),128.5,128.2,64.6,58.2,35.50–34.98(m,benzylic carbon),33.68–33.54(m),31.9,31.55–31.39(m),29.5,29.29–29.22(m),29.02–28.39(m,benzylic carbon),24.1,22.6,20.8,14.1.
Example 39
The starting materials 39(0.2mmol,65.5mg), catalyst 10(0.01mmol,7.0mg), AgNTf were added to the reaction flask in this order under nitrogen atmosphere2(0.04mmol,15.6mg)，Li3PO4(0.02mmol，2.3mg)，NaNTf2(0.2mmol, 60.6mg), and finally acetone-d was added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product with the yield of 88%. The benzyl deuteration rate of the target product is determined to be 52 percent through nuclear magnetic hydrogen spectrum.1H NMR(500MHz,Chloroform-d)δ7.17(d,J＝8.2Hz,1H),7.00(d,J＝8.1Hz,1H),6.90(s,1H),5.44(s,0.5H,50％D),3.25–3.21(m,1H),3.11–3.07(m,1H),2.93–2.80(m,1H),2.29(d,J＝13.0Hz,1H),1.96(s,3H),1.89–1.64(m,4H),1.42–1.35(m,4H),1.23–1.21(m,9H),0.93(s,3H).13C NMR(126MHz,Chloroform-d)δ170.06–169.98(m),147.19–147.13(m,aromatic carbon adjacent to benzylic carbon),145.66–145.62(m,aromatic carbon adjacent to benzylic carbon),134.76–134.67(m,aromatic carbon adjacent to benzylic carbon),126.93–126.91(m),124.12–123.84(m),123.8,49.76–49.65(m),45.11–45.08(m),38.3,37.4,37.2,36.1,33.39–32.80(m,benzylic–CH carbon),30.13–29.29(m,benzylic–CH2 carbon),25.24–25.22(m),23.96–23.81(m),23.55–23.50(m),18.9,18.78–18.68(m),18.6.
Example 40
Under nitrogen atmosphere, the raw materials 40(0.2mmol,56.8mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in this order2(0.02mmol,7.8mg)，Li3PO4(0.02mmol，2.3mg)，NaNTf2(0.2mmol, 60.6mg), and finally acetone-d was added6(0.2 mL). The reaction was stirred at 120 ℃ for 24 hours, cooled to room temperature and directly columnedChromatography gave the desired product in 93% yield. The benzyl deuteration rates of the target products are determined to be 66 percent and 53 percent through nuclear magnetic hydrogen spectra.1H NMR(500MHz,Chloroform-d)δ7.20(d,J＝8.6Hz,1H),6.71(d,J＝8.5Hz,0.90H,10％D),6.64–6.61(m,0.82H,18％D),3.77(s,3H),2.90–2.86(m,0.94H,53％D),2.50–2.47(m,1H),2.39–2.37(m,1H),2.27–2.22(m,0.34H,66％D),2.17–2.10(m,0.89H,11％D),2.06–1.93(m,3H),1.62–1.41(m,6H),0.90(s,3H).13C NMR(126MHz,Chloroform-d)δ220.82–220.78(m),157.51–157.47(m),137.69–137.59(m,aromatic carbon adjacent to benzylic carbon),131.97–131.86(m,aromatic carbon adjacent to benzylic carbon),127.33–126.15(m),113.8,111.91–111.47(m),55.10–55.04(m),50.3,47.90–47.80(m),43.87–43.20(m,benzylic–CH carbon),38.27–38.18(m),35.77–35.24(m,-deuterated carbon of carbonyl group),31.5,29.58–29.08(m,benzylic–CH2carbon),26.46–26.25(m),25.84–25.73(m),21.67–21.39(m),13.76–13.31(m).
EXAMPLE 41
The starting materials 41(0.2mmol,115.4mg), catalyst 10(0.005mmol,3.5mg), AgNTf were added to the reaction flask in this order under nitrogen atmosphere2(0.02mmol,7.8mg)，Li3PO4(0.02mmol，2.3mg)，NaNTf2(0.2mmol, 60.6mg), and finally acetone-d was added6(0.2 mL). The reaction is stirred for 24 hours at 120 ℃, then cooled to room temperature, and subjected to direct column chromatography to obtain a target product, wherein the yield is 90%. The benzyl deuteration rate of the target product is determined to be 70% through nuclear magnetic hydrogen spectrum.1H NMR(600MHz,Chloroform-d)δ7.35(d,J＝8.2Hz,1H),7.18(dd,J＝8.3,2.2Hz,1H),7.07–7.05(m,3H),6.82–6.81(m,2H),5.28(t,J＝9.4Hz,1H),5.20(t,J＝9.7Hz,1H),5.05(t,J＝9.6Hz,1H),4.32–4.25(m,2H),4.14(dd,J＝12.4,2.3Hz,1H),4.03–3.96(m,2.60H,70％D),3.81–3.78(m,1H),2.07(s,3H),2.05(s,3H),1.99(s,3H),1.70(s,3H),1.39(t,J＝7.0Hz,3H).13C NMR(126MHz,Chloroform-d)δ170.7,170.3,169.4,168.7,157.5,139.02–138.95(m,aromatic carbon adjacent to benzylic carbon),135.1,134.5,130.98–130.92(m,aromatic carbon adjacent to benzylic carbon),129.8,125.9,114.5,79.4,76.1,74.1,72.5,68.4,63.3,62.2,38.20–37.24(m,benzylic carbon),20.7,20.59,20.58,20.2,14.8.
Claims (9)
1. The method for selectively deuterating benzyl position of aromatic ring is characterized in that raw material S is put in nitrogen atmosphere1Uniformly mixing a metal rhodium catalyst and a silver salt, adding a deuterated solvent, stirring at 80-140 ℃ to enable the mixture to react completely, cooling to room temperature, concentrating, and performing column chromatography separation to obtain a compound S1-d, the benzylic deuteration, is specifically represented by the following formula:
wherein, the raw material S1Is an aromatic hydrocarbon or an aromatic hydrocarbon derivative;
the metal rhodium catalyst is a derivative of pentamethylcyclopentadienyl rhodium dichloride dimer;
the silver salt is a silver salt with a weakly coordinating counter silver ion;
the deuterated solvent is deuterated methanol or deuterated acetone, and when the deuterated solvent is deuterated acetone, phosphate is required to be added as inorganic base; at this time, the raw material S1The ratio of the metal rhodium catalyst to the silver salt to the inorganic base to the deuterated acetone is 1: (5-10 mol%): (10-40 mol%): (10-100 mol%): (0.5-4 mol/L);
when the deuterated solvent is deuterated methanol, the raw material S is prepared1The ratio of the metal rhodium catalyst to the silver salt to the deuterated solvent is 1: (5-10 mol%): (10-40 mol%): (0.5-4 mol/L);
the silver salt and the metal rhodium catalyst satisfy a molar ratio of [ Ag ]/[ Rh ] ═ 2: 1.
2. the method of claim 1, wherein the aryl ring is benzylically selective deuteratedIn that the raw material S1Wherein the R group is a hydrogen atom, an alkyl group, an aryl group or a heteroatom.
3. The method of claim 1, wherein the metal rhodium catalyst is selected from the group consisting of
4. The method of selective deuteration at benzyl position on aromatic ring according to claim 1, wherein the silver salt is AgNTf2、AgOTf、AgSbF6、AgBF4、AgPF6Any one or combination of a plurality of the components according to any proportion.
5. The method for selective deuteration at benzyl position in aromatic ring according to claim 1, wherein the phosphate is any one or a combination of several of lithium phosphate, sodium phosphate and silver phosphate according to any ratio.
6. The method of selective deuteration at benzylic position of aromatic ring according to claim 1, wherein inorganic salt with weakly coordinating counter silver ion is added as additive.
7. The method of claim 6, wherein the additive is LiNTf2、NaNTf2、KNTf2Any one or a combination of a plurality of materials of LiOTf, NaOTf and KOTf according to any proportion.
8. The method of selective deuteration at benzyl position on aromatic ring as claimed in claim 1, wherein said starting material S is1The ratio of the metal rhodium catalyst to the silver salt to the inorganic base to the deuterated acetone is as follows: 1: 2.5 mol%: 10 mol%: 10 mol%: 1 mol/L.
9. The method of selective deuteration at benzyl position on aromatic ring as claimed in claim 1, wherein said starting material S is1The ratio of the metal rhodium catalyst to the silver salt to the deuterated methanol is as follows: 1: 2.5 mol%: 10 mol%: 1 mol/L.
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| WO2015129813A1 (en) * | 2014-02-26 | 2015-09-03 | 国立大学法人 長崎大学 | Deuteration method and deuteration catalyst |
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| US20150203440A1 (en) * | 2012-08-02 | 2015-07-23 | Bayer Cropscience Ag | Process for preparing substituted biphenyls by c-h activation |
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