CN114835580A - Method for introducing gamma-deuteration into carbonyl compound - Google Patents
Method for introducing gamma-deuteration into carbonyl compound Download PDFInfo
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- CN114835580A CN114835580A CN202210540934.9A CN202210540934A CN114835580A CN 114835580 A CN114835580 A CN 114835580A CN 202210540934 A CN202210540934 A CN 202210540934A CN 114835580 A CN114835580 A CN 114835580A
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- 238000000034 method Methods 0.000 title claims abstract description 39
- 150000001728 carbonyl compounds Chemical class 0.000 title claims abstract description 15
- 229910052805 deuterium Inorganic materials 0.000 claims abstract description 46
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 41
- 239000012046 mixed solvent Substances 0.000 claims abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 18
- -1 olefin compound Chemical class 0.000 claims abstract description 15
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000000758 substrate Substances 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 239000011259 mixed solution Substances 0.000 claims abstract description 9
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 9
- 239000003999 initiator Substances 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 150000003254 radicals Chemical class 0.000 claims abstract description 4
- 238000005286 illumination Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 81
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- HDMHBHNRWDNNCD-UHFFFAOYSA-N 1-[(2-hydroxyethoxy)methyl]-6-(phenylsulfanyl)thymine Chemical compound OCCOCN1C(=O)NC(=O)C(C)=C1SC1=CC=CC=C1 HDMHBHNRWDNNCD-UHFFFAOYSA-N 0.000 claims description 2
- XMNIXWIUMCBBBL-UHFFFAOYSA-N 2-(2-phenylpropan-2-ylperoxy)propan-2-ylbenzene Chemical compound C=1C=CC=CC=1C(C)(C)OOC(C)(C)C1=CC=CC=C1 XMNIXWIUMCBBBL-UHFFFAOYSA-N 0.000 claims description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 41
- 125000000524 functional group Chemical group 0.000 abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 26
- 239000012969 di-tertiary-butyl peroxide Substances 0.000 description 26
- 239000007788 liquid Substances 0.000 description 26
- 238000000746 purification Methods 0.000 description 26
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 22
- XTCXSNIRIUQZLY-UHFFFAOYSA-N benzyl 2-sulfanylacetate Chemical compound SCC(=O)OCC1=CC=CC=C1 XTCXSNIRIUQZLY-UHFFFAOYSA-N 0.000 description 21
- 230000003595 spectral effect Effects 0.000 description 18
- 238000006467 substitution reaction Methods 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- CORMBJOFDGICKF-UHFFFAOYSA-N 1,3,5-trimethoxy 2-vinyl benzene Natural products COC1=CC(OC)=C(C=C)C(OC)=C1 CORMBJOFDGICKF-UHFFFAOYSA-N 0.000 description 2
- UAJRSHJHFRVGMG-UHFFFAOYSA-N 1-ethenyl-4-methoxybenzene Chemical compound COC1=CC=C(C=C)C=C1 UAJRSHJHFRVGMG-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- PDELBHCVXBSVPJ-UHFFFAOYSA-N 2-ethenyl-1,3,5-trimethylbenzene Chemical compound CC1=CC(C)=C(C=C)C(C)=C1 PDELBHCVXBSVPJ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000005619 boric acid group Chemical group 0.000 description 2
- MKUWVMRNQOOSAT-UHFFFAOYSA-N but-3-en-2-ol Chemical compound CC(O)C=C MKUWVMRNQOOSAT-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 150000001975 deuterium Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 239000001082 (3R)-3-sulfanylpentan-2-one Substances 0.000 description 1
- QWMJEUJXWVZSAG-UHFFFAOYSA-N (4-ethenylphenyl)boronic acid Chemical compound OB(O)C1=CC=C(C=C)C=C1 QWMJEUJXWVZSAG-UHFFFAOYSA-N 0.000 description 1
- SKYXLDSRLNRAPS-UHFFFAOYSA-N 1,2,4-trifluoro-5-methoxybenzene Chemical compound COC1=CC(F)=C(F)C=C1F SKYXLDSRLNRAPS-UHFFFAOYSA-N 0.000 description 1
- BOVQCIDBZXNFEJ-UHFFFAOYSA-N 1-chloro-3-ethenylbenzene Chemical compound ClC1=CC=CC(C=C)=C1 BOVQCIDBZXNFEJ-UHFFFAOYSA-N 0.000 description 1
- CEWDRCQPGANDRS-UHFFFAOYSA-N 1-ethenyl-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(C=C)C=C1 CEWDRCQPGANDRS-UHFFFAOYSA-N 0.000 description 1
- SZECUQRKLXRGSJ-UHFFFAOYSA-N 3-Mercapto-2-pentanone Chemical compound CCC(S)C(C)=O SZECUQRKLXRGSJ-UHFFFAOYSA-N 0.000 description 1
- ABAPGTZHOYRXAH-UHFFFAOYSA-N CC(C(C1=CC=C(C)C=C1)=O)S Chemical compound CC(C(C1=CC=C(C)C=C1)=O)S ABAPGTZHOYRXAH-UHFFFAOYSA-N 0.000 description 1
- LXXNWCFBZHKFPT-UHFFFAOYSA-N Ethyl 2-mercaptopropionate Chemical compound CCOC(=O)C(C)S LXXNWCFBZHKFPT-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- NSJNRJYQQPRCLF-UHFFFAOYSA-N N-methyl-2-sulfanylacetamide Chemical compound CNC(=O)CS NSJNRJYQQPRCLF-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- FNDXFUBHPXBGMD-UHFFFAOYSA-N OP(O)O.OP(O)(O)=O Chemical group OP(O)O.OP(O)(O)=O FNDXFUBHPXBGMD-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- PBGVMIDTGGTBFS-UHFFFAOYSA-N but-3-enylbenzene Chemical compound C=CCCC1=CC=CC=C1 PBGVMIDTGGTBFS-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical group [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 description 1
- 229960002373 loxoprofen Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229930015698 phenylpropene Natural products 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- HJWLCRVIBGQPNF-UHFFFAOYSA-N prop-2-enylbenzene Chemical compound C=CCC1=CC=CC=C1 HJWLCRVIBGQPNF-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- AWARHXCROCWEAK-UHFFFAOYSA-N tert-butyl n-prop-2-enylcarbamate Chemical compound CC(C)(C)OC(=O)NCC=C AWARHXCROCWEAK-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- KOZCZZVUFDCZGG-UHFFFAOYSA-N vinyl benzoate Chemical compound C=COC(=O)C1=CC=CC=C1 KOZCZZVUFDCZGG-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—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
- 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
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for introducing gamma-deuteration into carbonyl compounds, which comprises the following steps: dissolving an olefin compound and an alpha-carbonyl mercaptan compound in a mixed solvent of an organic solvent and deuterium water to obtain a mixed solution; and adding a phosphine reagent and a free radical initiator into the mixed solution, and reacting under the illumination condition to convert the substrate into a corresponding gamma-deuterated carbonyl compound. The method for introducing deuteration has the characteristics of higher deuteration efficiency, good selectivity, good functional group tolerance, high yield, mild reaction conditions, no need of metal to participate in reaction and wide substrate range, and is particularly suitable for selectively introducing deuteration at a specific position of a carbon chain.
Description
Technical Field
The invention relates to the technical field of molecular marking, in particular to a method for introducing gamma-deuteration into a carbonyl compound.
Background
The deuteration is an important marking means and has important application in drug metabolism, new reaction mechanism research, nuclear magnetism, mass spectrum and other researches. Introduction of deuteration at a suitable position in a drug molecule can greatly alter the metabolism and pharmacokinetic properties of the drug. In 2017, the first deuterated drug, deuterobenzazine, was approved by the FDA, and research on deuterated drugs and development of deuterated methods were greatly facilitated.
Conventional synthesis of deuterium substituted compounds often uses a hydrogen isotope exchange strategy to introduce deuterium isotopes into the compound in a single step without the need for re-synthesis, with advantages in atom and step economics, with more fully developed H/D exchange processes typically catalyzed by acids/bases or transition metals. However, acid/base catalyzed hydrogen isotope exchange processes, while selectively allowing deuterium to replace acidic or basic C-H bonds in a molecule, typically require higher reaction temperatures, likely destroying or affecting other sensitive functional groups in the reaction substrate; the major disadvantages of transition metal catalysis are poor regioselectivity of deuterium substitution and unstable deuterium substitution rate of different substrates, which limits their wide application in organic synthetic chemistry, and selective introduction of deuterium substitution at specific positions of the carbon chain remains challenging and practical. In view of the above, there is a need in the art for a method capable of selectively introducing deuteration at a specific position of a carbon chain with high efficiency.
Disclosure of Invention
In view of the drawbacks of the prior art, it is an object of the present invention to provide a method for introducing γ -deuteration in carbonyl compounds. The key point of the present invention is to utilize the active radical intermediate with single carbon atom center existing in the chemical reaction process to make deuterium atom capable of combining with the active center specifically to generate C-D bond, and further generate deuterium substituted compound with single site selectivity, thereby eliminating the possibility of generating multi-site deuterium substituted compound from the source. Meanwhile, the whole process is driven by a normal-temperature neutral photoreaction system without metal mediation or catalysis, the functional group tolerance of a reaction substrate and the operability of the synthesis process are effectively improved, no waste with high pollution or toxicity is generated, and the economic cost of synthesis and post-treatment is effectively controlled. In the implementation result, the method has the advantages of high efficiency of introduction of deuterons, wide applicable substrate range and the like, and is particularly suitable for introducing deuterium atom substitution on the gamma-carbon of the carbonyl compound. The purpose of the invention is realized by the following scheme:
the first aspect of the present invention provides a method for introducing γ -deuteration into a carbonyl compound, characterized in that the method is as follows:
dissolving an olefin compound and an alpha-carbonyl mercaptan compound in a mixed solvent of an organic solvent and deuterium water to obtain a mixed solution;
and step two, adding a phosphine reagent and a free radical initiator into the mixed solution, and reacting under the illumination condition to convert the substrate into a corresponding gamma-deuterated carbonyl compound.
Preferably, the olefin compound in the first step has a structural formula:
wherein R is 1 Is one of aliphatic hydrocarbon group, aromatic group, ester group, amide group and ether bond, R 2 Is one of hydrogen, aliphatic hydrocarbon group and aromatic group.
Preferably, the olefin compound in the first step has a structural formula:
wherein R is 1 Is composed of
One of (1), R 2 Is H,
R and R' can be hydrogen, aliphatic hydrocarbon group, (hetero) aromatic group, trifluoromethyl, boric acid group, phosphine, (phosphite) phosphoric acid group, or phosphite) One or more of sulfonyl, halogen, ester, amide, carboxyl, hydroxyl, (thio) ether bond, acyl, aldehyde, amine, imine, (iso) cyano, (nitrite) nitro.
Preferably, the α -carbonylthiol compound in the first step has a structural formula:
wherein R is 3 Is one of aliphatic alkyl, aryl, alkoxy and amido, R 4 Is one of hydrogen, aliphatic hydrocarbon group and aromatic group.
Preferably, the α -carbonylthiol compound in the first step has a structural formula:
wherein R is 3 Is composed of
One of (1), R 4 Is H,
Wherein R and R' are one or more of hydrogen, aliphatic hydrocarbon group, (hetero) aromatic group, trifluoromethyl group, boric acid group, phosphine, (phosphorous) group, (sulfuryl) group, halogen, ester group, amide group, carboxyl group, hydroxyl group, (thio) ether bond, acyl group, aldehyde group, amine, imine, (iso) cyano group and (nitryl) group.
Preferably, the equivalent ratio of the olefin compound to the alpha-carbonylthiol compound in the first step is 1: 1-5.
Preferably, the organic solvent in the step one is one selected from dichloromethane, acetonitrile, ethyl acetate, chloroform, acetone, DMF, deuterated methanol, diethyl ether, tetrahydrofuran and toluene, and the volume ratio of the organic solvent to deuterium oxide is 0.5-5: 1.
Preferably, the organic solvent is ethyl acetate, and the volume ratio of the organic solvent to the deuterium oxide is preferably 2: 1.
Preferably, the phosphine reagent in the second step is one of Ph2POEt, PPh3, HEPT and PCy3, the equivalent weight of the phosphine reagent is 1.0-5.0 equivalent weight relative to the olefin compound, and PPh3 is preferred.
Preferably, the initiator in the second step is one of di-tert-butyl peroxide, dicumyl peroxide and dibenzoyl peroxide, the initiator is used in an equivalent of 2.0 to 5.0 equivalents relative to the olefin compound, and the initiator is preferably di-tert-butyl peroxide.
The preferred route of the invention is as follows:
preferably, the lighting conditions in the second step are that the mixed solution is placed between two 65W household Compact Fluorescent Lamps (CFLs), and the distance between the mixed solution and the CFLs is 1-10 cm, which causes the temperature of the solution to rise and affects the experimental results.
Preferably, the reaction time in the second step is 6-24 hours, and the preferred reaction time is 15 hours.
Compared with the prior art, the invention has the following beneficial effects:
(1) the method for introducing gamma-deuterium substitution into a carbonyl compound has the advantages of high deuterium substitution efficiency and high yield, all products are subjected to deuterium substitution at a single site, no multi-site deuterium substitution substance is generated, the single-site deuterium substitution rate of the products obtained by the implementation of the preferred conditions exceeds 80 percent and can reach 96 percent at most, wherein the majority of the products can obtain the yield which is higher than good, and the half of the products can obtain the excellent yield, and the highest yield in each embodiment can reach 98 percent;
(2) the method for introducing the gamma-deuterium substitution into the carbonyl compound has simple reaction conditions, does not need metal mediation or catalysis, has no obvious danger or toxicity on the required raw materials and the generated substances, and can carry out the reaction at normal temperature;
(3) the method for introducing gamma-deuterium substitution into the carbonyl compound has the advantages of good functional group tolerance, wide substrate selection range and capability of smoothly reacting substrates with various functional group substitutions or molecular structures to generate expected products.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that it would be obvious to those skilled in the art that various changes and modifications can be made without departing from the spirit of the invention. All falling within the scope of the present invention.
General procedure for the experiment: a50 mL dry flask was charged with 4.0 equivalents of PPh 3 And dissolved in anhydrous ethyl acetate, followed by addition of D 2 O (V: V ═ 2:1), olefin substrate (1.0 eq) and thiol substrate (3.0 eq) and stirred for several minutes. After adding DTBP (4.5 equivalents) to the system, the flask was exposed to 65W household compact fluorescent lamps on both sides (4 cm apart to keep the system in the flask at room temperature) for 15 hours to allow reaction to occur. After the reaction is finished, the reaction solution is washed by water and then extracted by ethyl acetate, organic layers are combined and washed by saturated NaCl solution, Na 2 SO 4 Drying, filtering, concentrating, and purifying by silica gel column chromatography to obtain the target product.
Example 1
According to the general operating scheme, 0.5mmol of styrene, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 115mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 90%, and the deuteration rate is 85%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ7.43-7.29(m,5H),7.29-7.21(m, 2H),7.21-7.08(m,3H),5.10(s,2H),2.70-2.56(m,1H),2.37(t,J＝7.5 Hz,2H),2.03-1.90(m,2H). 13 C NMR(101MHz,CDCl 3 )δ173.3,141.3,136.1, 128.6,128.5,128.4,128.2,126.0,66.2,34.7(t,J＝19.4Hz),33.6,26.4.HRMS (ESI)([M+H] + )Calcd.for C 17 H 17 DO 2 :256.1442；found:256.1444。
example 2
According to the general operating scheme, 0.5mmol of styrene, 1.5mmol of benzyl thioglycolate and PPh 3 (3.0equiv.), DTBP (4.0equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 93mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 73%, and the deuteration rate is 86%. The nuclear magnetic data are consistent with example 1.
Example 3
According to the general operating scheme, 0.5mmol of styrene, 1.0mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 79mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 62%, and the deuteration rate is 88%. The nuclear magnetic data are consistent with example 1.
Example 4
According to the general operating scheme, 0.5mmol of styrene, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), and the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (5mL, V: 4: 1). After the reaction is finished, 117mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 92%, and the deuteration rate is 58%. Nuclear magnetic data and examples1 are identical.
Example 5
According to the general procedure, 0.5mmol of 2,4, 6-trimethylstyrene, 1.5mmol of benzyl thioglycolate and PPh are used 3 (4.0equiv.), DTBP (4.5equiv.), and the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 140mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 94%, and the deuteration rate is 86%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ7.43-7.26(m,5H),6.81 (s,2H),5.13(s,2H),2.64-2.53(m,1H),2.46(t,J＝7.2Hz,2H),2.25(s, 6H),2.23(s,3H),1.84-1.74(m,2H). 13 C NMR(101MHz,CDCl 3 )δ173.3,136.0, 135.3,135.2,135.2,128.9,128.6,128.4,128.3,66.3,34.5,28.5(t,J＝19.3 Hz),24.3,20.8,19.7.HRMS(ESI)([M+H] + )Calcd.for C 20 H 23 DO 2 :298.1912；found: 298.1912。
example 6
According to the general operating scheme, 0.5mmol of p-methoxystyrene, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 117mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 82%, and the deuteration rate is 86%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ7.44-7.24(m,5H),7.05(d,J＝8.5 Hz,2H),6.80(d,J＝8.6Hz,2H),5.10(s,2H),3.75(s,3H),2.61-2.51(m, 1H),2.35(t,J＝7.5Hz,2H),1.98-1.85(m,2H). 13 C NMR(101MHz,CDCl 3 )δ 173.4,157.9,136.1,133.4,129.4,128.6,128.2,128.2,113.8,66.1,55.2,33.8 (t,J＝19.4Hz),33.5,26.7.HRMS(ESI)([M+H] + )Calcd.for C 18 H 19 DO 3 :286.1548； found:286.1550。
example 7
According to the general operating scheme, 0.5mmol of 4-vinylphenylboronic acid, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), and the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 121mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 81%, and the deuteration rate is 86%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CD 3 OD)δ7.66(d,J＝7.6Hz,1H),7.51(d, J＝7.2Hz,1H),7.40-7.22(m,5H),7.20-7.02(m,2H),5.08(s,2H),2.65 -2.52(m,1H),2.33(t,J＝7.3Hz,2H),1.96-1.84(m,2H). 13 C NMR(101MHz, CD 3 OD)δ175.0,145.0,137.7,135.1,134.8,129.5,129.3,129.2,128.8,67.2, 35.7(t,J＝19.5Hz),34.4,27.6.HRMS(ESI)([M+Na] + )Calcd.for C 17 H 18 DBO 4 : 322.1331；found:322.1332。
example 8
According to the general operating scheme, 0.5mmol of m-chlorostyrene, 1.5mmol of benzyl thioglycolate and PPh are used 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 109mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 75%, and the deuteration rate is 84%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ7.44-7.28(m,5H),7.24-7.08(m, 3H),7.07-6.97(m,1H),5.12(s,2H),2.66-2.55(m,1H),2.37(t,J＝7.4 Hz,2H),2.01-1.89(m,2H). 13 C NMR(101MHz,CDCl 3 )δ173.1,143.4,136.0, 134.2,129.7,128.6,128.3,126.7,126.3,66.3,34.4(t,J＝19.5Hz),33.5, 26.2.HRMS(ESI)([M+Na] + )Calcd.for C 17 H 16 DClO 2 :312.0872；found:312.0878。
example 9
According to the general operating scheme, 0.5mmol of indene, 1.5mmol of benzyl thioglycolate and PPh are used 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 119mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 89%, and the deuteration rate is 86%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ7.43-7.27(m,5H),7.22-7.15(m,2H),7.15 -7.07(m,2H),5.14(s,2H),3.12(dd,J＝15.6,7.8Hz,1.5H),2.99-2.80 (m,1H),2.64(dd,J＝15.5,7.2Hz,1.5H),2.54(dd,J＝7.5,1.7Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ172.8,142.7,136.0,128.6,128.2,128.2,126.3,124.5, 66.2,40.0,39.0,38.7(t,J＝20.3Hz),36.1.HRMS(ESI)([M+Na] + )Calcd.for C 18 H 17 DO 2 :290.1262；found:290.1265。
example 10
According to the general procedure, 0.5mmol of N-vinylpyrrolidone, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 127mg of colorless liquid is obtained through treatment and purification, namely the product, wherein the yield is 97%, and the deuteration rate is 93%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ7.46-7.28(m,5H),5.12(s,2H), 3.37(t,J＝7.0Hz,2H),3.34-3.24(m,1H),2.44-2.31(m,4H),2.06-1.95 (m,2H),1.92-1.83(m,2H). 13 C NMR(101MHz,CDCl 3 )δ175.2,172.9,135.9, 128.6,128.3,128.3,66.4,47.1,41.6(t,J＝21.1Hz),31.5,31.0,22.5,17.9. HRMS(ESI)([M+H] + )Calcd.for C 15 H 18 DNO 3 :263.1500；found:263.1506。
example 11
According to the general operating scheme, 0.5mmol of cyclohexyl vinyl ether, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 136mg of colorless liquid is obtained through treatment and purification, namely the product, wherein the yield is 98 percent, and the deuteration rate is 96 percent. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ7.46-7.28(m,5H),5.11(s,2H), 3.50-3.39(m,1H),3.24-3.10(m,1H),2.46(t,J＝7.4Hz,2H),1.94-1.86 (m,2H),1.87-1.78(m,2H),1.76-1.63(m,2H),1.57-1.46(m,1H),1.32 -1.09(m,5H). 13 C NMR(101MHz,CDCl 3 )δ173.5,136.1,128.5,128.2,128.2, 77.4,66.1(t,J＝21.5Hz),66.1,32.2,31.2,25.8,25.4,24.1.HRMS(ESI)([M+H] + ) Calcd.for C 17 H 23 DO 3 :278.1861；found:278.1863。
example 12
According to the general operating scheme, 0.5mmol of vinyl benzoate, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 112mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 75%, and the deuteration rate is 93%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ8.03(dd,J＝8.3,1.2Hz,2H),7.55 (tt,J＝7.4,1.2Hz,1H),7.43(dd,J＝10.8,4.5Hz,2H),7.39-7.27(m,5H), 5.11(s,2H),4.43-4.27(m,1H),2.55(t,J＝7.4Hz,2H),2.19-2.08(m, 2H). 13 C NMR(101MHz,CDCl 3 )δ172.7,166.5,135.8,133.0,130.2,129.6,128.6, 128.4,128.3,128.3,66.4,63.6(t,J＝22.8Hz),31.0,24.1.HRMS(ESI)([M+Na] + ) Calcd.for C 18 H 17 DO 4 :322.1160；found:322.1163。
example 13
According to the general procedure 0.5mmol of 1-buten-3-ol, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), and the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 61mg of colorless liquid is obtained through treatment and purification, namely the product, wherein the yield is 55%, and the deuteration rate is 86%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CD 3 OD)δ7.44-7.24(m,5H),5.11(s,2H), 3.76-3.63(m,1H),2.38(t,J＝7.4Hz,2H),1.82-1.68(m,1H),1.68-1.55 (m,1H),1.48-1.34(m,1H),1.13(d,J＝6.2Hz,3H). 13 C NMR(101MHz,CD 3 OD) δ175.2,137.7,129.6,129.2,129.2,68.1,67.2,39.0(t,J＝19.2Hz),35.0, 23.5,22.3.HRMS(ESI)([M+Na] + )Calcd.for C 13 H 17 DO 3 :246.1211；found:246.1212。
example 14
According to the general procedure, 0.5mmol of tert-butyl N-allylcarbamate, 1.5mmol of benzyl mercaptoacetate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 61mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 80%, and the deuteration rate is 83%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ7.45-7.29(m,5H),5.11 (s,2H),4.57(br s,1H),3.11(t,J＝6.0Hz,2H),2.38(t,J＝7.4Hz,2H), 1.71-1.62(m,2H),1.55-1.38(m,1H),1.44(s,9H). 13 C NMR(101MHz,CDCl 3 ) δ173.3,156.0,136.0,128.6,128.2,128.2,79.2,66.2,40.1,33.8,29.1(t, J＝19.3Hz),28.4,22.0.HRMS(ESI)([M+Na] + )Calcd.for C 17 H 24 DNO 4 :331.1739； found:331.1740。
example 15
According to the general procedure, 0.5mmol of allylbenzene, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 89mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 66%, and the deuteration rate is 84%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ7.41-7.29(m,5H),7.29-7.22(m, 2H),7.21-7.09(m,3H),5.11(s,2H),2.70-2.56(m,2H),2.38(t,J＝7.3 Hz,2H),1.76-1.60(m,3H). 13 C NMR(101MHz,CDCl 3 )δ173.5,142.1,136.1, 128.6,128.4,128.3,128.2,125.8,66.2,35.5,34.2,30.5(t,J＝19.5Hz),24.5. HRMS(ESI)([M+Na] + )Calcd.for C 18 H 19 DO 2 :292.1418；found:292.1419。
example 16
According to the general procedure, 0.5mmol of 4-phenyl-1-butene, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 113mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 80%, and the deuteration rate is 84%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ7.42-7.30(m,5H),7.30-7.22(m, 2H),7.20-7.10(m,3H),5.10(s,2H),2.59(t,J＝7.8Hz,2H),2.35(t,J ＝7.5Hz,2H),1.73-1.57(m,4H),1.40-1.30(m,1H). 13 C NMR(101MHz,CDCl 3 ) δ173.6,142.5,136.1,128.6,128.4,128.3,128.2,125.7,66.1,35.7,34.2, 31.0,28.4(t,J＝19.2Hz),24.7.HRMS(ESI)([M+Na] + )Calcd.for C 19 H 21 DO 2 : 306.1575；found:306.1574。
example 17
According to the general procedure, 0.5mmol of 2,4, 6-trimethylstyrene, 1.5mmol of ethyl 2-mercaptopropionate, PPh 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 113mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 91%, and the deuteration rate is 87%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ6.82(s,2H),4.17(q,J＝7.1 Hz,2H),2.63-2.45(m,2H),2.27(s,6H),2.24(s,3H),1.84-1.70(m,1H), 1.61-1.50(m,1H),1.28(t,J＝7.1Hz,3H),1.23(d,J＝7.0Hz,3H). 13 C NMR (101MHz,CDCl 3 )δ176.5,135.9,135.5,135.1,128.9,60.3,40.1,33.0,26.7 (t,J＝19.5Hz),20.8,19.5,17.1,14.3.HRMS(ESI)([M+H] + )Calcd.for C 16 H 23 DO 2 : 250.1912；found:250.1912。
example 18
According to the general procedure 0.5mmol of styrene, 1.5mmol of 2-mercapto-1- (p-tolyl) propan-1-one, PPh 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 86mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 68%, and the deuteration rate is 87%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ7.77(d,J＝8.1Hz,2H), 7.31-7.17(m,5H),7.15(d,J＝7.2Hz,2H),3.50-3.36(m,1H),2.71-2.54 (m,1H),2.41(s,3H),2.21-2.08(m,1H),1.80-1.68(m,1H),1.22(d,J＝ 6.9Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ203.8,143.7,141.9,134.1,129.3,128.5, 128.5,128.4,125.9,39.6,35.2,33.2(t,J＝19.6Hz),21.6,17.4.HRMS(ESI) ([M+H] + )Calcd.for C 18 H 19 DO:254.1650；found:254.1650。
example 19
According to the general procedure, 0.5mmol of styrene, 1.5mmol of 3-mercapto-2-pentanone, PPh 3 (4.0equiv.), DTBP (4.5equiv.), and the reaction solvent is a mixed solvent of dichloromethane and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 60mg of colorless liquid is obtained through treatment and purification, namely the product, wherein the yield is 63 percent, and the deuteration rate is 85 percent. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ7.32-7.26(m,2H),7.22-7.11(m, 3H),2.59-2.48(m,1H),2.43(tt,J＝8.0,5.6Hz,1H),2.12(s,3H),1.98 -1.88(m,1H),1.77-1.68(m,1H),1.68-1.59(m,1H),1.59-1.47(m,1H), 0.87(t,J＝7.5Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ212.5,141.8,128.4,128.4, 126.0,54.0,33.3(t,J＝19.4Hz),32.6,28.9,24.6,11.6.HRMS(ESI)([M+H] + ) Calcd.for C 13 H 17 DO:192.1493；found:192.1492。
example 20
According to the general procedure 0.5mmol of styrene, 1.5mmol of 2-mercapto-N-methylacetamide, PPh 3 (4.0equiv.), DTBP (4.5equiv.), and the reaction solvent is a mixed solvent of dichloromethane and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 61mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 69%, and the deuteration rate is 88%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ7.33-7.26(m,2H),7.24-7.13(m, 3H),5.39(br s,1H),2.80(d,J＝4.8Hz,3H),2.70-2.58(m,1H),2.17(t, J＝7.5Hz,2H),2.04-1.90(m,2H). 13 C NMR(101MHz,CDCl 3 )δ173.4,141.5, 128.5,128.4,126.0,35.8,34.9(t,J＝19.4Hz),27.0,26.3.HRMS(ESI)([M+H] + ) Calcd.for C 11 H 14 DNO:179.1289；found:179.1290。
example 21
According to the general operating scheme, 0.5mmol of styrene, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of deuterated methanol and deuterated water (6mL, V: V ═ 2: 1). After the reaction is finished, 70mg of colorless liquid is obtained through treatment and purification, namely the product, wherein the yield is 55 percent, and the deuteration rate is 93 percent. The nuclear magnetic data are consistent with example 1.
Example 22
According to the general operating scheme, 0.5mmol of p-trifluoromethylstyrene, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), and the reaction solvent is a mixed solvent of dichloromethane and deuterium water (6mL, V: V ═ 2: 1). After the reaction is finished, 123mg of colorless liquid is obtained through treatment and purification, namely the product, wherein the yield is 76%, and the deuteration rate is 89%. Nuclear magnetic and mass spectral data: 1 H NMR(400MHz,CDCl 3 )δ7.52(d,J＝8.1Hz,2H),7.43-7.29 (m,5H),7.26(d,J＝8.0Hz,2H),5.12(s,2H),2.78-2.61(m,1H),2.38(t, J＝7.4Hz,2H),2.03-1.94(m,2H). 13 C NMR(101MHz,CDCl 3 )δ173.1,145.4, 136.0,128.8,128.6,128.3,128.3,125.4(q,J＝3.7Hz),66.3,34.5(t,J＝19.3Hz),33.5,26.1. 19 F NMR(377MHz,CDCl 3 )δ-62.34.HRMS(ESI)([M+Na] + ) Calcd.for C 18 H 16 DF 3 O 2 :346.1136；found:346.1136。
example 23
According to the general operating scheme, 0.5mmol of styrene, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), and the reaction solvent is a mixed solvent of acetonitrile and deuterium oxide (6mL, V: V ═ 2: 1). After the reaction is finished, 82mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 64 percent, and the deuteration rate is 82 percent. The nuclear magnetic data are consistent with example 1.
Comparative example 1
According to the literature, 0.5mmol of loxoprofen and 10 mol% of B (C) are used 6 F 5 ) 3 The reaction was carried out in an oil bath at 100 ℃ for 12 hours in chloroform (1.0mL) and deuterium water (50 equiv.). After the reaction is finished, 116mg of white solid is obtained through treatment and purification, namely the product, the yield is 94%, and the deuteration rates of two sites are 87% and 73% respectively. Nuclear magnetic data: 1 H NMR(400MHz,CDCl 3 )δ7.23(d,J＝7.7Hz,2H),7.12(d,J＝7.7Hz,2H), 3.70(q,J＝7.2Hz,1H),3.11(d,J＝13.9Hz,1H),2.50(d,J＝14.0Hz,1H), 2.37–2.28(m,0.27H),2.13–2.04(m,1.13H),2.00–1.90(m,1H),1.77 –1.67(m,1H),1.58–1.51(m,1H),1.49(d,J＝7.2Hz,3H). 13 C NMR(101 MHz,CDCl 3 )δ220.6,180.3,139.1,137.6,129.1,127.6,51.0,50.5,50.3,44.9, 37.6,35.1,35.1,29.0,20.4,20.4,20.3,18.1。
comparative example 2
According to literature reports, 0.5mmol of quinoline, 1 mol% of a graphic iron catalyst, D 2 (4atm), tetrahydrofuran (2mL) as a reaction solvent, and reacted in an oil bath at 45 ℃ for 24 hours. After the reaction is finished, 50mg of colorless liquid is obtained through treatment, namely the product, the yield is 76%, and the deuteration rates of two sites are 91% and 34% respectively. Nuclear magnetic data: 1 H NMR(400MHz, CDCl 3 )δ8.77(m,0.09H),8.01(d,J＝8.5Hz,1H),7.91–7.89(m,1H),7.59 (d,J＝8Hz,1H),7.54(ddd,J＝8.5,6.9,1.5Hz,1H),7.34(ddd,J＝8.5, 6.9,1.5Hz,1H),7.15(d,J＝8.4Hz,0.66H). 13 C NMR(101MHz,CDCl 3 )δ150.1, 148.0,135.7,129.2,129.1,128.0,127.5,126.2,120.7。
comparative example 3
According to the general operating scheme, 0.5mmol of styrene, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (14mL, V: V ═ 0.4: 1). After the reaction is finished, 66mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 52%, and the deuteration rate is 95%. The nuclear magnetic data are consistent with example 1.
Comparative example 4
According to the general operating scheme, 0.5mmol of styrene, 1.5mmol of benzyl thioglycolate and PPh 3 (4.0equiv.), DTBP (4.5equiv.), the reaction solvent is a mixed solvent of ethyl acetate and deuterium water (4.5mL, V: 8: 1). After the reaction is finished, 116mg of colorless liquid is obtained through treatment and purification, namely the product, the yield is 91%, and the deuteration rate is 35%. The nuclear magnetic data are consistent with example 1.
TABLE 1 product yields and deuterations for examples 1-23 and comparative examples 1-4
Examples 1-23 show that the present invention has a wide selection range of substrates, and table 1 shows that the yield and deuteration ratio of the product are excellent when the preferred organic solvent is ethyl acetate, and the experimental conditions are simple as compared with comparative examples 1-2. Comparative example 1 and comparative example 2 are conventional deuterium substituted compound synthesis techniques, and it has been found that a heated oil bath is required, the reaction conditions are strict, and the rate of deuterium substitution is unstable. From the comparison in table 1, the volume ratio of the mixed solvent of the ethyl acetate and the deuterium oxide water in comparative examples 3 and 4 is out of the range of 0.5-5: 1, it can be seen that the yield of comparative example 3 is significantly reduced and the deuteration rate of comparative example 4 is significantly reduced.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes or modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention. The embodiments and features of the embodiments of the present application may be combined with each other arbitrarily without conflict.
Claims (9)
1. A method for introducing gamma-deuteration in carbonyl compounds, comprising:
dissolving an olefin compound and an alpha-carbonyl mercaptan compound in a mixed solvent of an organic solvent and deuterium water to obtain a mixed solution;
and step two, adding a phosphine reagent and a free radical initiator into the mixed solution, and reacting under the illumination condition to convert the substrate into a corresponding gamma-deuterated carbonyl compound.
2. The method as claimed in claim 1, wherein the olefin compound in the first step has a structural formula:
wherein R is 1 Is one of aliphatic hydrocarbon group, aromatic group, ester group, amide and ether, R 2 Is one of hydrogen, aliphatic hydrocarbon group and aromatic group.
3. According to the claimsThe method for introducing γ -deuteration in carbonyl compound according to claim 1, wherein the α -carbonylthiol compound in the first step has a structural formula:
wherein R is 3 Is one of aliphatic alkyl, aryl, alkoxy and amido, R 4 Is one of hydrogen, aliphatic hydrocarbon group and aromatic group.
4. The method as claimed in claim 1, wherein the equivalent ratio of the olefin compound to the α -carbonylthiol compound in the step one is 1: 1-5.
5. The method as claimed in claim 1, wherein the organic solvent in the first step is one selected from dichloromethane, acetonitrile, ethyl acetate, chloroform, acetone, DMF, deuterated methanol, diethyl ether, tetrahydrofuran, and toluene, and the volume ratio of the organic solvent to deuterated water is 0.5-5: 1.
6. the method of claim 1, wherein the phosphine reagent used in step two is one of Ph2POEt, PPh3, HEPT, and PCy3, and the amount of the phosphine reagent used is 1.0 to 5.0 equivalents relative to the olefin compound.
7. The method of claim 1, wherein the initiator used in the second step is one of di-tert-butyl peroxide, dicumyl peroxide and dibenzoyl peroxide, and the equivalent of the initiator is 2.0 to 5.0 equivalents relative to the olefin compound.
8. The method of claim 1, wherein the light irradiation in step two is performed by placing the mixed solution between two 65W household Compact Fluorescent Lamps (CFLs) at a distance of 1-10 cm.
9. The method as claimed in claim 1, wherein the reaction time in step two is 6-24 h.
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