CN115850111A - Preparation method of nickel-catalyzed aliphatic amine containing gem-difluoroolefin structure - Google Patents
Preparation method of nickel-catalyzed aliphatic amine containing gem-difluoroolefin structure Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 title claims description 7
- 150000001336 alkenes Chemical group 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000000758 substrate Substances 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims abstract description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 17
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims abstract description 16
- 238000005937 allylation reaction Methods 0.000 claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 13
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 13
- VHSVJTYBTJCDFL-UHFFFAOYSA-L 1,2-dimethoxyethane;nickel(2+);dibromide Chemical compound Br[Ni]Br.COCCOC VHSVJTYBTJCDFL-UHFFFAOYSA-L 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- YUYCVXFAYWRXLS-UHFFFAOYSA-N trimethoxysilane Chemical compound CO[SiH](OC)OC YUYCVXFAYWRXLS-UHFFFAOYSA-N 0.000 claims abstract description 9
- STTGYIUESPWXOW-UHFFFAOYSA-N 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline Chemical compound C=12C=CC3=C(C=4C=CC=CC=4)C=C(C)N=C3C2=NC(C)=CC=1C1=CC=CC=C1 STTGYIUESPWXOW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000000926 separation method Methods 0.000 claims abstract description 8
- 239000011775 sodium fluoride Substances 0.000 claims abstract description 8
- 235000013024 sodium fluoride Nutrition 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003446 ligand Substances 0.000 claims abstract description 6
- 239000000463 material Substances 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 229910052759 nickel Inorganic materials 0.000 claims abstract description 3
- 150000001412 amines Chemical class 0.000 claims abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 13
- 239000000047 product Substances 0.000 claims description 11
- ABBZJHFBQXYTLU-UHFFFAOYSA-N but-3-enamide Chemical class NC(=O)CC=C ABBZJHFBQXYTLU-UHFFFAOYSA-N 0.000 claims description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 230000001617 migratory effect Effects 0.000 claims description 7
- 239000003480 eluent Substances 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 5
- 238000010898 silica gel chromatography Methods 0.000 claims description 5
- 229910052786 argon Inorganic materials 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- LYCAIKOWRPUZTN-NMQOAUCRSA-N 1,2-dideuteriooxyethane Chemical compound [2H]OCCO[2H] LYCAIKOWRPUZTN-NMQOAUCRSA-N 0.000 claims description 2
- 238000005303 weighing Methods 0.000 claims description 2
- 238000006115 defluorination reaction Methods 0.000 abstract description 10
- 230000005012 migration Effects 0.000 abstract description 9
- 238000013508 migration Methods 0.000 abstract description 9
- 125000000524 functional group Chemical group 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 5
- 239000012300 argon atmosphere Substances 0.000 abstract 1
- 229910000510 noble metal Inorganic materials 0.000 abstract 1
- 239000000575 pesticide Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- -1 phenylsulfonyl difluorodiazoethane Chemical compound 0.000 description 71
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 4
- 238000006880 cross-coupling reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000002524 organometallic group Chemical group 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- CKBZJTAMRPPVSR-UHFFFAOYSA-N adamantane-1-carboxamide Chemical compound C1C(C2)CC3CC2CC1(C(=O)N)C3 CKBZJTAMRPPVSR-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001345 alkine derivatives Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- KJVRLFWTIGWXFK-UHFFFAOYSA-N n-prop-2-enylbenzamide Chemical group C=CCNC(=O)C1=CC=CC=C1 KJVRLFWTIGWXFK-UHFFFAOYSA-N 0.000 description 2
- 230000001699 photocatalysis Effects 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229910000077 silane Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- GGQQNYXPYWCUHG-RMTFUQJTSA-N (3e,6e)-deca-3,6-diene Chemical compound CCC\C=C\C\C=C\CC GGQQNYXPYWCUHG-RMTFUQJTSA-N 0.000 description 1
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 1
- QCWXDVFBZVHKLV-UHFFFAOYSA-N 1-tert-butyl-4-methylbenzene Chemical compound CC1=CC=C(C(C)(C)C)C=C1 QCWXDVFBZVHKLV-UHFFFAOYSA-N 0.000 description 1
- RQXPGOCXZHCXDG-UHFFFAOYSA-N 3,3,3-trifluoroprop-1-en-2-ylbenzene Chemical compound FC(F)(F)C(=C)C1=CC=CC=C1 RQXPGOCXZHCXDG-UHFFFAOYSA-N 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical compound [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000008430 aromatic amides Chemical class 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 150000004074 biphenyls Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010516 chain-walking reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000005796 dehydrofluorination reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 150000008049 diazo compounds Chemical class 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000003983 fluorenyl group Chemical class C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000004715 keto acids Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 150000004812 organic fluorine compounds Chemical class 0.000 description 1
- 238000007146 photocatalysis Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- KBMBVTRWEAAZEY-UHFFFAOYSA-N trisulfane Chemical compound SSS KBMBVTRWEAAZEY-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of nickel-catalyzed fatty amine containing gem-difluoroolefin structure, which comprises the steps of reacting 18 h at 70 ℃ by using ethylene glycol dimethyl ether nickel bromide as a catalyst, bathocuproine as a ligand, sodium fluoride as a base, trimethoxy silane as a hydrogen source and ethylene glycol dimethyl ether as a solvent under argon atmosphere. The migration defluorination allylation reaction is realized under the mild condition, and the separation yield can reach 93 percent at most. The invention utilizes nickel to catalyze the non-activated olefin and trifluoromethyl substituted olefin as raw materials to carry out the migration defluorination allylation reaction to efficiently synthesize the geminal difluoroolefin compound, and has the remarkable advantages that: the method avoids the use of noble metal catalysts in the traditional method, has high regioselectivity, mild reaction conditions, simple operation, wide substrate universality and functional group compatibility, and high synthesis efficiency. A series of synthesized amine products containing gem-difluoroolefin are widely applied to the fields of pesticide, medicine and material.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a nickel-catalyzed preparation method of a gem-difluoroalkene compound.
Background
The geminal difluoroolefin is a synthesis precursor of various organic fluorine compounds, and has wide application in agricultural chemistry, pharmaceutical chemistry and material science. They are widely used in the research of modern drugs because they have similarities with the space and electron of ketones, aldehydes and esters and are therefore ideal carbonyl bioisosteres, and their metabolic stability is also enhanced. Because of the special properties of geminal difluoroolefins, the development of synthetic geminal difluoroolefins has been a focus of research by chemists. On the one hand, the olefin is abundant in source and easy to prepare, and the development of the reaction using olefin as the starting material is a popular field of research by chemists. On the other hand, the combination of chain walking and cross-coupling reaction is an effective method for realizing remote C-H bond functionalization, and compared with the traditional C-H bond activation of guide group positioning, the method has mild conditions and does not need to install/remove a guide group.
Over the last decades, there has been a wide interest in developing methods for the synthesis of structurally diverse gem-difluoroolefins, such as: in 2015, an example of a nickel-catalyzed dehydrofluorination cyclization reaction to produce a geminal difluoroolefin was reported by the Ichikawa group. In the reaction, alkyne and trifluoromethyl substituted alkene are cyclometalated under the catalysis of nickel, and then the cyclometalated alkyne and trifluoromethyl substituted alkene are eliminated by beta-F to obtain gem-difluoro alkene. See: J. ichikawa.J. Fluorine Chem. [J].2000, 105257-263. The preparation of geminal difluoroolefins is conventionally achieved by geminal difluoroolefination of a carbonyl or diazo compound, such as: in 2019, a Ma Junan subject group at Tianjin university develops a general effective method for constructing chiral and achiral geminal difluoroallylamine through a novel difluoroalkylation reagent, namely phenylsulfonyl difluorodiazoethane, developed by the laboratory. See: J. -l, zeng, y, zhang, m.Org.Lett. [J]2019, 21, 8244-8249. Additionally, S occurs for α -trifluoromethyl-substituted olefins by means of organometallic reagents as nucleophiles N The type 2 addition elimination reaction provides a new way for synthesizing the gem-difluoro olefin compound. For example, the Jiang Huanfeng subject group at the university of southern China, 2020 reported S N Type 2 bis allyl radical of 1,1-bis nucleophile and (trifluoromethyl) olefinDesfluration reactions, see: y. Cai, h. Zeng, c.Org.Chem.Front. [J]. 2020, 71260-1264. The strategy of cross-coupling defluorination of α -trifluoromethyl olefins to construct gem-difluorovinyl groups under mild conditions of photocatalysis or transition metal catalysis has been successfully applied to the synthesis of different gem-difluoroolefins where α -trifluoromethyl olefins can efficiently capture radicals in these reactions and convert trifluoromethyl to gem-difluorovinyl groups by β -fluoro elimination. Such as: in 2016, the group of Zhou Lei subjects of Zhongshan university utilizes a strategy of crossing free radicals and polarities to realize the decarboxylation/defluorination coupling reaction of the first visible light promoted keto acid and trifluoromethyl olefin, and synthesize a series of gamma, gamma-gem-difluoroallyl ketone compounds, see: t, xiao, L, li, L, zhou J, org, chem]2016, 81, 7908-7916. Furthermore, in 2020, southern university Wang Qingmin topic group via triphenylphosphine assisted dehydroxylation of aryl carboxylic acids under photocatalytic conditions gives acyl radicals, which are efficiently synthesized by the strategy of addition with α -trifluoromethylstyrene followed by elimination by reduction of fluorine. See: y. -q. Guo, y. -f. Wu, r. -g. Wang, h. -j. Song, y. -x. Liu, q. -m. Wang.Org.Lett. [J]. 2021, 23, 2353-2358.
The classical cross-coupling reaction refers to a reaction between a nucleophilic reagent (mainly an organometallic reagent) and an electrophilic reagent, wherein the organometallic reagent needs to be prepared in advance, which causes problems of operation and cost, and the organometallic reagent has poor tolerance to a functional group and is sensitive to air and moisture. The above-mentioned methods require expensive metal catalysts, poor regioselectivity of different nucleophiles, and poor functional group tolerance, which severely limit the versatility and potential industrial applications of the methods. In 2020, the Zhu Shaolin subject group at Nanjing university develops a NiH system to realize the preparation of geminal difluoroolefin by the migration defluorination cross-coupling of the high-efficiency selective catalytic inactive olefin and trifluoromethyl substituted olefin, unfortunately, alkyl substituted trifluoromethyl olefin does not react under the condition. See: F. -l. Chen, x. -f. Xu, y. -l. He, g. -p. Huang, s. -l. Zhu.Angew. Chem. Int. Ed. [J]. 2020, 59, 5398-5402.
Prior art relating to gem-difluoroolefin compounds:
[1] huang Shuai, hou Xuelong preparation method of gem-difluoroallyl compounds [ P ]. Chinese patent: CN 114315726A 2022.04.12
[2] Chu Xuejiang, shen Zhiliang, sun Liwen, chen Jiawei. A method for preparing a phosphorylated gem-difluorodiolefin compound in an aqueous phase [ P ]. Chinese patent: CN 115010753. A. 2022.09.06
[3] Chu Xuejiang, shen Zhiliang and Sun Liwen. A method for preparing a geminal difluoroolefin compound [ P ]. Chinese patent: CN 114409515A 2022.04.29
[4] Bi Xi and, zhang Xinyu, li Linxuan, zhang Xiaolong, ning Yongquan. A method for preparing α, α -gem-difluorocarbonyl compounds [ P ]. Chinese patent: CN 114249679A 2022.03.29
The invention can realize the migration defluorination allylation reaction of the allyl amide derivative by reacting 18 h at 70 ℃ under the catalysis of cheap and easily available ethylene glycol dimethyl ether nickel bromide, and is compatible with alkyl or aryl substituted trifluoromethyl olefin substrates. The method has the advantages of mild reaction conditions, simplicity, high efficiency, wide substrate application range, high functional group compatibility and high product yield, can be used for scale-up to gram-scale production and synthesis, and has great significance for the synthesis of fluorine-containing medicaments.
Disclosure of Invention
The invention aims to solve the problem of high regioselectivity of allyl amide derivatives, and provides a method for realizing migration defluorination allylation of allyl amide derivatives under the same reaction condition.
In order to solve the problem of regioselective migration defluorination allylation of an unactivated olefin substrate, the invention can realize the preparation of a geminal difluoroolefin compound at 70 ℃ by screening the types of a catalyst, a ligand and a base, a solvent, temperature, reaction time and the like. The experimental method can be used for synthesizing fluorine-containing medicaments and materials.
In order to achieve the purpose, the invention discloses the following technical scheme
A nickel-catalyzed preparation method of aliphatic amine containing gem-difluoro olefin structure is characterized by comprising the following steps:
(1) Weighing 15 mol% of ethylene glycol dimethyl ether nickel bromide, 15 mol% of bathocuproine (2,9-dimethyl-4,7-biphenyl-1,10-phenanthroline), an unactivated olefin substrate, 3 equiv of trifluoromethyl substituted olefin, 2.5 equiv of sodium fluoride, ethylene glycol dimethyl ether and 2 equiv of trimethoxy silane in a glove box filled with argon, and stirring the reaction system at 70 ℃ to react with 18 h;
(2) After the reaction is finished, concentrating the obtained solution in vacuum, purifying the crude product by silica gel column chromatography, and calculating the separation yield by using a mixture of ethyl acetate and normal hexane as an eluent;
wherein R is 1 Means that:
R 2 means that: me;
R 3 means that: me, n-Pr;
R 4 means that:
the unactivated olefinic substrate is:
the trifluoromethyl substituted alkene is
Wherein the molar ratio of unactivated olefin substrate to trifluoromethyl-substituted olefin is 1:3
The catalyst is ethylene glycol dimethyl ether nickel bromide;
the ligand is bathocuproine;
the base is sodium fluoride;
the hydrogen source is trimethoxy silane;
the solvent is ethylene glycol dimethyl ether;
the time is 18 hours;
the volume ratio of the ethyl acetate to the n-hexane serving as the eluent is 1:10.
the allylamide derivatives of the invention when used as olefinic substrates give migratory defluorinated allylation products.
The invention further discloses the application of the method in the aspect of realizing the gem-difluoro product with high separation rate under mild conditions. The invention also discloses application of the typical compound prepared by the method in the aspects of fluorine-containing medicaments and material synthesis. The experimental results show that: the method has the advantages of high regioselectivity, mild reaction conditions, simple operation, wide substrate universality and functional group compatibility, and high synthesis efficiency. In addition, the geminal difluoroolefin can be used as a platform compound to synthesize a series of functionalized fluorine-containing compounds.
The invention is described in more detail below:
the invention relates to a nickel-catalyzed preparation method of aliphatic amine containing gem-difluoroolefin structure, and develops a preparation method which is cheap, mild in condition, convenient to operate, high in yield and high in regioselectivity in order to meet the requirement of industrialization. Amide is used as a common guide group, has wide source and convenient storage and transportation, so that the scheme of the invention uses the allyl amide derivative as the guide group source to participate in the migration defluorination allylation reaction of trifluoromethyl substituted olefin;
wherein R is 1 Means that:
R 2 means that: me;
R 3 means that: me, n-Pr;
R 4 means that:
the unactivated olefinic substrate is:
the trifluoromethyl substituted alkene is
Wherein the molar ratio of unactivated olefin substrate to trifluoromethyl-substituted olefin is 1:3
The preparation method comprises the following specific steps:
(1) Adding a catalyst, a ligand, alkali, a solvent, silane, an unactivated olefin substrate and trifluoromethyl substituted olefin into a reaction tube, uniformly mixing, and stirring at 70 ℃ to react with 18 h;
(2) After the reaction, the obtained solution was concentrated in vacuo, the crude product was purified by silica gel column chromatography, the migration defluorinated allylation product was separated, and the separation yield was calculated.
Wherein the catalyst is ethylene glycol dimethyl ether nickel bromide; the ligand is bathocuproine (2,9-dimethyl-4,7-biphenyl-1,10-phenanthroline); the alkali is sodium fluoride; one trifluoromethyl substituted olefin is selected; the silane is trimethoxy silane; the solvent in the reaction system is ethylene glycol dimethyl ether.
The invention has the advantages and positive effects that:
1. the pre-installed guide group can regulate and control the regional selectivity, is easy to remove, and is suitable for the allylamide derivatives;
2. the invention can obtain a difluoride product from the allyl amide derivative under the promotion of glycol dimethyl ether nickel bromide;
3. the method can realize that the allylamide derivatives can obtain the migration defluorination allylation products under mild conditions, and has the advantages of mild reaction temperature, rapid reaction, simple preparation process and safe experimental operation process;
4. the substrate has wide application range, a series of alkyl substituted amides and various aromatic amides can be compatible, and alkyl, aromatic hydrocarbon and heterocyclic substituted trifluoromethyl olefin can be suitable.
Detailed Description
The invention is described below by means of specific embodiments. Unless otherwise specified, the technical means used in the present invention are well known to those skilled in the art. In addition, the embodiments should be considered illustrative, and not restrictive, of the scope of the invention, which is defined solely by the claims. It will be apparent to those skilled in the art that various changes or modifications in the components and amounts of the materials used in these embodiments can be made without departing from the spirit and scope of the invention.
Wherein bathocuproine (2,9-dimethyl-4,7-biphenyl-1,10-phenanthroline), ethylene glycol dimethyl ether, trimethoxy silane, ethylene glycol dimethyl ether nickel bromide and the like used in the invention are all sold in the market; the synthesis of non-activated olefinic substrates is described in Triandafillidi, I.A., kokotou, M.G., kokotos.C.G.Org. Lett.2018, 2036-39, and Alhalib, A., kamouka, S., moran. W. J.Org. Lett.2015, 171453-1456. Synthesis of trifluoromethyl substituted alkene substrates is described in the literature: y, lan, F, yang, C, wang,ACS Catal.2018, 89245-9251, and T. Ichatsuka, T. Fujita, J. Ichikawa,ACS Catal.2015, 5, 5947-5950.
example 1
Effect of unactivated olefinic substrate species on migratory defluorinated allylation reactions
A preparation method of nickel-catalyzed geminal difluoroolefin compounds expands the scope of unactivated olefin substrates, wherein the olefin substrates are expanded to contain beta-substituent groups and internal olefins, and the specific steps are as follows:
(1) In a glove box filled with argon, 15 mol% (0.0093 g) of ethylene glycol dimethyl ether nickel bromide, 15 mol% (0.0101 g) bathocuproine (2,9-dimethyl-4,7-biphenyl-1,10-orthophenanthzaphenanthrene) were weighed into a dry reaction tube, 0.2 mmol of unactivated olefinic substrate (see table 1), 0,06 mmol of 2-naphthalene-3,3,3-trifluoropropene, 0.05mmol (0.0210 g) of sodium fluoride, 1 ml,0.04 mmol (51 μ L) of trimethoxysilane were added, and the reaction system was stirred at 70 ℃ for reaction of 18 h;
(2) After the reaction was completed, the resulting solution was concentrated in vacuo, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and n-hexane as an eluent to calculate the separation yield.
TABLE 1 Effect of non-activated olefin species on migratory defluorinated allylation
The structural characterization data of the product obtained in this example are as follows:
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)acetamide (3a)
1 H NMR (400 MHz, CDCl 3 ) δ 7.87–7.78 (m, 4H), 7.52–7.39 (m, 3H), 5.03 (d, J = 8.6 Hz, 1H), 4.06–3.87 (m, 1H), 2.75–2.60 (m, 2H), 1.72 (s, 3H), 1.61–1.52 (m, 1H), 1.42–1.33 (m, 1H), 0.87 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 169.70, 154.56 (t, J = 289.5 Hz), 133.28, 132.51, 130.97, 128.24, 128.00, 127.60, 127.43 (t, J = 3.1 Hz), 126.39, 126.28, 126.04 (t, J = 3.0 Hz), 89.98 (t, J = 18.0 Hz), 49.97, 32.82, 27.18, 23.23, 10.23; 19 F NMR (376 MHz, CDCl 3 ) δ -90.04 (s, 2F). HRMS (ESI) m/z calculated for C 18 H 20 F 2 NO + [M+H] + : 304.1507, found: 304.1513.
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)pivalamide (3b)
δ 7.88–7.77 (m, 4H), 7.53–7.41 (m, 3H), 5.23 (d, J = 8.4 Hz, 1H), 4.01–3.91 (m, 1H), 2.73–2.60 (m, 2H), 1.63–1.53 (m, 1H), 1.47–1.37 (m, 1H), 1.00 (s, 9H), 0.87 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 177.81, 154.57 (dd, J = 291.4, 287.2 Hz), 133.32, 132.59, 131.03 (dd, J = 4.2, 2.9 Hz), 128.36, 127.99, 127.59, 127.48 (t, J = 3.2 Hz), 126.36, 126.26, 126.10 (t, J = 3.0 Hz), 90.06 (dd, J = 21.5, 14.4 Hz), 49.56, 38.56, 33.00, 27.43, 27.35, 10.25; 19 F NMR (376 MHz, Chloroform-d) δ -89.97 (d, J = 41.0 Hz, 1F), -90.33 (d, J = 41.0 Hz, 1F). HRMS (ESI) m/z calculated for C 21 H 26 F 2 NO + [M+H] + : 346.1977, found: 346.1985.
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)tetrahydro-2H-pyran- 4-carboxamide (3c)
1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (dd, J = 16.2, 8.6 Hz, 1H), 7.61–7.33 (m, 1H), 4.99 (d, J = 8.1 Hz, 1H), 3.97 (d, J = 6.2 Hz, 1H), 3.82 (d, J = 10.6 Hz, 1H), 3.16 (t, J = 11.3 Hz, 1H), 2.68 (s, 1H), 1.93 (t, J = 11.4 Hz, 1H), 1.66–1.45 (m, 1H), 1.48–1.34 (m, 1H), 0.87 (t, J = 7.2 Hz, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 173.64, 154.54 (dd, J = 291.5, 287.4 Hz), 133.29, 132.54, 131.14 (dd, J = 4.0, 2.9 Hz), 128.39, 127.93, 127.58, 127.47 (d, J = 3.1 Hz), 126.50, 126.38, 126.04 (t, J = 2.9 Hz), 89.91 (dd, J = 21.5, 14.7 Hz), 67.15 (d, J = 9.9 Hz), 49.80, 42.21, 32.87, 29.06, 27.34, 10.30; 19 F NMR (376 MHz, Chloroform-d) δ -89.82 (d, J = 40.3 Hz, 1F), -90.11 (d, J = 40.4 Hz, 1F). HRMS (ESI) m/z calculated for C 22 H 26 F 2 NO + [M+H] + : 407.1788, found: 407.1787.
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)-2,2- diphenylacetamide (4d)
1 H NMR (400 MHz, CDCl 3 ) δ 7.83–7.76 (m, 3H), 7.70 (s, 1H), 7.51–7.45 (m, 2H), 7.36 (d, J = 8.5 Hz, 1H), 7.28–7.18 (m, 6H), 7.16–7.07 (m, 4H), 5.24 (d, J = 8.6 Hz, 1H), 4.71 (s, 1H), 4.03–3.92 (m, 1H), 2.66–2.54 (m, 2H), 1.57–1.47 (m, 1H), 1.37–1.29 (m, 1H), 0.78 (t, J = 7.4 Hz, 3H); δ 171.42, 154.49 (t, J = 289.6 Hz), 139.43 (d, J = 5.3 Hz), 133.32, 132.61, 130.61, 128.90, 128.83, 128.75 (d, J = 2.4 Hz), 128.33, 128.11, 127.64, 127.46 (t, J= 3.2 Hz), 127.22, 126.35 (d, J = 4.2 Hz), 126.03 (t, J = 3.0 Hz), 89.93 (t, J = 17.8 Hz), 59.41, 49.98, 32.66, 27.27, 10.18; 19 F NMR (376 MHz, Chloroform-d) δ -89.73 (s, 2F). HRMS (ESI) m/z calculated for C 30 H 28 F 2 NO + [M+H] + : 456.2133, found: 456.2142.
(3r,5r,7r)-N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl) adamantane-1-carboxamide (3e)
1 H NMR (400 MHz, CDCl 3 ) δ 7.88–7.78 (m, 4H), 7.51–7.40 (m, 3H), 5.08 (d, J = 8.6 Hz, 1H), 4.04–3.93 (m, 1H), 2.73–2.60 (m, 2H), 1.80 (s, 3H), 1.57 (d, J = 10.7 Hz, 4H), 1.53 (s, 1H), 1.51–1.48 (m, 2H), 1.43 (d, J = 12.2 Hz, 7H), 0.87 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) 13 C NMR (101 MHz, Chloroform-d) δ 177.20, 154.53 (dd, J = 291.3, 287.4 Hz), 133.40, 132.60, 131.37 (dd, J = 4.3, 2.9 Hz), 128.47, 127.96, 127.56, 127.52, 126.43, 126.30, 126.14 (t, J = 2.9 Hz), 89.94 (dd, J = 21.7, 14.5 Hz), 49.47 (t, J = 2.6 Hz), 40.35, 38.88, 36.34, 32.79, 28.00, 27.38, 10.32; 19 F NMR (376 MHz, Chloroform-d) δ -89.64 (d, J = 39.6 Hz, 1F), -89.90 (d, J = 39.8 Hz, 1F). HRMS (ESI) m/z calculated for C 27 H 32 F 2 NO + [M+H] + : 424.2446, found: 424.2451.
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)-2-methylbenzamide (3f)
1 H NMR (400 MHz, CDCl 3 ) δ 7.88–7.80 (m, 4H), 7.52–7.45 (m, 3H), 7.23–7.19 (m, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.90 (t, J = 7.3 Hz, 1H), 6.80 (d, J= 7.1 Hz, 1H), 5.36 (d, J = 9.1 Hz, 1H), 4.20–4.12 (m, 1H), 2.85–2.72 (m, 2H), 2.38 (s, 3H), 1.73–1.66 (m, 1H), 1.54–1.48 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 169.63, 136.54, 135.95, 133.37, 132.65, 130.87, 129.64, 128.45, 128.04, 127.60, 127.57, 127.54, 126.38, 126.28, 126.18, 126.08 (t, J = 2.9 Hz), 125.50, 90.10 (dd, J = 16.6, 12.0 Hz), 50.10, 33.30, 27.59, 19.62, 10.34; 19 F NMR (376 MHz, Chloroform-d) δ -89.78 (d, J = 40.5 Hz, 1F), -89.93 (d, J = 40.6 Hz, 1F). HRMS (ESI) m/z calculated for C 24 H 24 F 2 NO + [M+H] + : 380.1820, found: 380.1828.
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)benzamide (3g)
1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (s, 1H), 7.81–7.76 (m, 3H), 7.49–7.43 (m, 3H), 7.36–7.31 (m, 1H), 7.28–7.25 (m, 2H), 7.14 (t, J = 7.8 Hz, 2H), 5.67 (d, J = 8.7 Hz, 1H), 4.24–4.15 (m, 1H), 2.82–2.80 (dd, J = 5.2, 2.8 Hz, 2H), 1.72–1.63 (m, 1H), 1.58–1.49 (m, 1H), 0.93 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 )δ 166.99, 154.60 (dd, J = 291.3, 287.9 Hz), 134.43, 133.38, 132.59, 131.17, 131.13, 128.56, 128.26, 128.00, 127.60, 127.51 (t, J = 3.1 Hz), 126.52, 126.44, 126.32, 126.03 (t, J = 2.9 Hz), 89.93 (dd, J = 21.1, 15.1 Hz), 50.55, 32.78, 27.37, 10.38.; 19 F NMR (376 MHz, CDCl 3 ) δ -89.75 (d, J= 40.1 Hz, 1F), -89.97 (d, J = 40.1 Hz, 1F). HRMS (ESI) m/z calculated for C 23 H 22 F 2 NO + [M+H] + : 366.1664, found: 366.1670.
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)-4-methoxybenzamide (3h)
1 H NMR (400 MHz, CDCl 3 ) δ 7.83–7.76 (m, 4H), 7.49–7.43 (m, 3H), 7.24–7.17 (m, 2H), 6.65–6.57 (m, 2H), 5.56 (d, J = 8.8 Hz, 1H), 4.23–4.14 (m, 1H), 3.75 (s, 3H), 2.80 (dd, J = 5.4, 2.4 Hz, 2H), 1.70–1.62 (m, 1H), 1.58–1.48 (m, 1H), 0.93 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.45, 161.86, 154.57 (dd, J = 291.5, 287.7 Hz), 133.38, 132.55, 131.27 (dd, J = 3.9, 2.7 Hz), 131.26, 128.56, 128.28, 128.01, 127.59, 127.49 (t, J = 3.1 Hz), 126.65, 126.34 (d, J = 16.1 Hz), 126.03 (t, J = 2.9 Hz), 113.38, 89.94 (dd, J = 21.4, 14.8 Hz), 55.30, 50.46, 32.74, 27.38, 10.41; 19 F NMR (376 MHz, CDCl 3 ) δ -89.79 (d, J = 40.2 Hz, 1F), -90.04 (d, J = 40.2 Hz, 1F). HRMS (ESI) m/z calculated for C 24 H 24 F 2 NO + [M+H] + : 396.1770, found: 396.1778.
4-chloro-N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)benzamide (3i)
1 H NMR (400 MHz, CDCl 3 ) δ 7.81–7.74 (m, 4H), 7.52–7.45 (m, 2H), 7.42 (d, J = 8.5 Hz, 1H), 7.14–7.09 (m, 2H), 7.08–7.00 (m, 2H), 5.56 (d, J = 8.8 Hz, 1H), 4.22–4.14 (m, 1H), 2.88–2.81 (m, 1H), 2.81–2.73 (m, 1H), 1.70–1.66 (m, 1H), 1.59–1.50 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 165.83, 154.57 (dd, J = 291.6, 287.9 Hz), 137.34, 133.32, 132.60, 132.51, 131.25 (dd, J = 4.0, 2.7 Hz), 128.62, 128.39, 127.91, 127.88, 127.59, 127.44 (t, J = 3.0 Hz), 126.57, 126.41, 125.92 (t, J = 2.8 Hz), 89.80 (dd, J = 21.4, 15.0 Hz), 50.86, 32.60, 27.33, 10.43; 19 F NMR (376 MHz, CDCl 3 ) δ -89.63 (d, J= 39.6 Hz, 1F), -89.91 (d, J = 39.7 Hz, 1F). HRMS (ESI) m/z calculated for C 23 H 21 ClF 2 NO + [M+H] + : 400.1274, found: 400.1282.
4-bromo-N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)benzamide (3j)
1 H NMR (400 MHz, CDCl 3 ) δ 7.81–7.74 (m, 4H), 7.52–7.47 (m, 2H), 7.43 (d, J = 8.5 Hz, 1H), 7.25–7.18 (m, 2H), 7.04 (d, J = 8.5 Hz, 2H), 5.50 (d, J= 8.7 Hz, 1H), 4.23–4.15 (m, 1H), 2.89–2.82 (m, 1H), 2.81–2.74 (m, 1H), 1.71–1.65 (m, 1H), 1.57–1.51 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 165.84, 154.59 (dd, J = 291.5, 287.9 Hz), 133.34, 133.09, 132.53, 131.37, 131.26 (dd, J = 3.8, 2.5 Hz), 128.60, 128.01, 127.89, 127.57, 127.43 (t, J = 3.0 Hz), 126.55, 126.39, 125.90 (t, J = 2.9 Hz), 125.79, 89.79 (dd, J= 21.2, 15.2 Hz), 50.88, 32.60, 27.35, 10.37; 19 F NMR (376 MHz, Chloroform-d) δ -89.65 (d, J = 39.7 Hz, 1F), -89.90 (d, J = 39.7 Hz, 1F). HRMS (ESI) m/z calculated for C 23 H 20 F 2 NO + [M+H] + : 444.0769, found: 444.0769
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)-2-naphthamide (3k)
1 H NMR (400 MHz, CDCl 3 ) δ 8.29–8.18 (m, 1H), 7.90 (s, 1H), 7.86–7.76 (m, 5H), 7.54–7.47 (m, 5H), 7.14–7.07 (m, 1H), 6.98 (dd, J = 7.0, 0.9 Hz, 1H), 5.61 (d, J = 9.0 Hz, 1H), 4.34–4.26 (m, 1H), 2.90–2.80 (m, 2H), 1.77–1.70 (m, 1H), 1.60–1.52 (m, 1H), 1.01 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 169.12, 154.67 (dd, J = 291.4, 287.9 Hz), 134.55, 133.62, 133.39, 132.65, 130.98 (dd, J = 3.5, 2.7 Hz), 130.37, 130.06, 128.51, 128.19, 128.05, 127.61, 127.57, 127.03, 126.41, 126.34, 126.30, 126.10 (t, J = 3.0 Hz), 125.38, 124.47, 124.35, 90.11 (dd, J = 20.9, 15.0 Hz), 50.45, 33.24, 27.62, 10.43; 19 F NMR (376 MHz, Chloroform-d) δ -89.58 (d, J = 40.2 Hz, 1F), -89.82 (d, J = 40.2 Hz, 1F). HRMS (ESI) m/z calculated for C 27 H 24 F 2 NO + [M+H] + : 416.1820, found: 416.1827.
N-(6,6-difluoro-5-(naphthalen-2-yl)hex-5-en-3-yl)-4-(trifluoromethyl) benzamide (3l)
1 H NMR (400 MHz, CDCl 3 ) δ 7.80–7.71 (m, 4H), 7.50–7.40 (m, 3H), 7.31 (d, J = 8.3 Hz, 2H), 7.27–7.24 (m, 2H), 5.58 (d, J = 8.7 Hz, 1H), 4.26–4.17 (m, 1H), 2.93–2.84 (m, 1H), 2.82–2.75 (m, 1H), 1.73–1.67 (m, 1H), 1.61–1.53 (m, 1H), 0.96 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 165.53, 154.59 (dd, J = 291.7, 288.1 Hz), 137.38, 133.34, 132.82 (d, J = 32.7 Hz), 132.50, 131.27 (dd, J = 4.0, 2.6 Hz), 128.65, 127.84, 127.56, 127.42 (t, J = 3.0 Hz), 126.85, 126.62, 126.48, 125.86, 125.16 (q, J = 3.7 Hz), 122.21, 89.73 (dd, J= 21.4, 15.1 Hz), 51.08, 32.53, 27.35, 10.43; 19 F NMR (376 MHz, Chloroform-d) δ -63.06(s, 3), -89.58 (d, J = 39.5 Hz, 1F), -89.85 (d, J = 39.5 Hz, 1F). HRMS (ESI) m/z calculated for C 24 H 21 F 5 NO + [M+H] + : 434.1538, found: 434.1544.
N-(5,5-difluoro-2,2-dimethyl-4-(naphthalen-2-yl)pent-4-en-1-yl) benzamide (3m)
1 H NMR (400 MHz, CDCl 3 ) δ 7.82–7.74 (m, 4H), 7.46–7.40 (m, 3H), 7.38–7.32 (m, 3H), 7.24–7.18 (m, 2H), 5.66 (t, J = 5.5 Hz, 1H), 3.13 (d, J = 6.6 Hz, 2H), 2.51–2.42 (m, 2H), 0.85 (s, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.44, 154.73 (dd, J = 291.4, 288.3 Hz), 134.59, 133.31, 132.72 (dd, J = 4.7, 2.5 Hz), 132.52, 131.30, 128.62, 128.48, 127.91, 127.75, 127.44–127.17 (m), 126.67, 126.65, 126.48, 126.29 (t, J = 2.5 Hz), 90.21 (dd, J = 21.9, 13.9 Hz), 48.54, 37.88, 37.40 (t, J = 2.4 Hz), 25.72; 19 F NMR (376 MHz, Chloroform-d) δ -88.39 (d, J = 39.0 Hz, 1F), -90.61 (d, J = 39.0 Hz, 1F). HRMS (ESI) m/z calculated for C 24 H 24 F 2 NO + [M+H] + : 380.1820, found: 380.1819.
N-(1,1-difluoro-2-(naphthalen-2-yl)hept-1-en-4-yl)benzamide (3n)
1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (s, 1H), 7.81–7.77 (m, 3H), 7.49–7.43 (m, 3H), 7.33 (t, J = 7.4 Hz, 1H), 7.25 (dd, J = 6.2, 2.1 Hz, 2H), 7.13 (t, J= 7.8 Hz, 2H), 5.62 (d, J = 8.7 Hz, 1H), 4.31–4.26 (m, 1H), 2.86–2.76 (m, 2H), 1.68–1.55 (m, 2H), 1.41–1.31 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.84, 154.61 (dd, J = 291.3, 287.8 Hz), 134.39, 133.37, 132.57, 131.22 (dd, J = 5.1, 2.6 Hz), 131.16, 128.56, 128.25, 127.99, 127.59, 127.50 (t, J = 3.1 Hz), 126.48, 126.43, 126.30, 126.03 (t, J = 2.9 Hz), 89.92 (dd, J = 21.0, 15.2 Hz), 48.91, 36.66, 33.18, 19.22, 13.94; 19 F NMR (376 MHz, Chloroform-d) δ -89.79 (d, J = 40.1 Hz, 1F), -89.99 (d, J = 40.1 Hz, 1F). HRMS (ESI) m/z calculated for C 24 H 24 F 2 NO + [M+H] + : 380.1820, found: 380.1820.
N-(1,1-difluoro-2-(naphthalen-2-yl)non-1-en-4-yl)benzamide (3o)
1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (s, 1H), 7.81–7.77 (m, 3H), 7.49–7.44 (m, 3H), 7.34 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 3.6 Hz, 2H), 7.14 (t, J = 7.7 Hz, 2H), 5.60 (d, J = 8.8 Hz, 1H), 4.32–4.25 (m, 1H), 2.81 (dd, J = 5.4, 2.1 Hz, 2H), 1.69–1.61 (m, 1H), 1.53–1.45 (m, 1H), 1.37–1.32 (m, 2H), 1.27–1.23 (m, 4H), 0.84 (t, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.78, 159.11–149.27 (m), 134.48, 133.39, 132.59, 131.27–131.15 (m), 131.11, 128.53, 128.23, 127.98, 127.57, 127.51 (t, J = 3.0 Hz), 126.48, 126.40, 126.27, 126.03 (t, J = 2.7 Hz), 89.95 (dd, J = 21.1, 15.3 Hz), 49.14, 34.46, 33.15, 31.64, 25.58, 22.47, 13.92. 19 F NMR (376 MHz, Chloroform-d) δ -89.79 (d, J = 40.1 Hz, 1F), -90.00 (d, J = 40.1 Hz, 1F). HRMS (ESI) m/z calculated for C 26 H 28 F 2 NO + [M+H] + : 408.2133, found: 408.2141
N-(1,1-difluoro-2-(naphthalen-2-yl)non-1-en-4-yl)benzamide (3p)
1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (s, 1H), 7.81–7.77 (m, 3H), 7.49–7.44 (m, 3H), 7.33 (t, J = 7.4 Hz, 1H), 7.26 (d, J = 6.7 Hz, 2H), 7.14 (t, J = 7.7 Hz, 2H), 5.63 (d, J = 8.8 Hz, 1H), 4.31–4.23 (m, 1H), 2.81 (dd, J = 5.2, 2.2 Hz, 2H), 1.65–1.60 (m, 1H), 1.55–1.45 (m, 1H), 1.38–1.31 (m, 2H), 1.28–1.21 (m, 4H), 0.83 (t, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.79, 154.61 (dd, J = 291.4, 288.1 Hz), 134.48, 133.39, 132.59, 131.20 (dd, J = 3.6, 2.3 Hz), 131.12, 128.53, 128.24, 127.98, 127.58, 127.51 (t, J = 3.1 Hz), 126.49, 126.41, 126.27, 126.03 (t, J = 2.9 Hz), 89.96 (dd, J = 21.0, 15.2 Hz), 49.14, 34.46, 33.14, 31.64, 25.59, 22.48, 13.94. 19 F NMR (376 MHz, Chloroform-d) δ -89.79 (d, J = 40.1 Hz, 1F), -90.00 (d, J = 40.1 Hz, 1F). HRMS (ESI) m/z calculated for C 26 H 28 F 2 NO + [M+H] + : 408.2133, found: 408.2138.
from the data in table 1, it follows that under mild conditions, the various types of non-activated olefins described above are suitable for use in the present scheme, most of which can give yields of 80% and above. Analysis of the data in Table 1 leads to the conclusion that the primary, secondary, and tertiary alkyl substituted amides (3 a-3 e) all give the desired product in good yields. 93% of the migratory defluorinated allylation product (3 f) was obtained using N-allylbenzamide as donor; the reaction is applicable to various functionalized aromatic hydrocarbons, and comprises aryl rings with electron-donating, neutral and electron-withdrawing substituents (3 g-3 l). In addition, the β -substituted terminal olefin (3 m) and internal olefin substrate (3 n-3 p), either isomers in the Z or E configuration, are compatible.
Example 2
Effect of trifluoromethyl-substituted olefins on migratory defluorinated allylation
A preparation method of nickel-catalyzed geminal difluoroalkene compound, which expands the scope of trifluoromethyl-substituted alkene substrates. The method comprises the following specific steps:
(1) In a glove box filled with argon, 15 mol% (0.0093 g) of ethylene glycol dimethyl ether nickel bromide, 15 mol% (0.0101 g) bathocuproine (2,9-dimethyl-4,7-biphenyl-1,10-orthophenanthzaphenanthrene), 0.2 mmol (0.0322 g) of N-allylbenzamide, 0.06 mmol of trifluoromethyl substituted olefin (see Table 2), 0.05mmol (0.0210 g) of sodium fluoride, 1 mL ethylene glycol dimethyl ether, 0.04 mmol (51 μ L) of trimethoxysilane were weighed into a dry reaction tube, and the reaction system was stirred at 70 ℃ to react at 18 h;
(2) After the reaction was completed, the resulting solution was concentrated in vacuo, and the crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and n-hexane as an eluent to calculate the separation yield.
TABLE 2 influence of trifluoromethyl substituted alkene substrates on the reaction
N-(6,6-difluoro-5-(4-methoxyphenyl)hex-5-en-3-yl)benzamide (4a)
1 H NMR (400 MHz, CDCl 3 ) δ 7.50 (d, J = 7.4 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.32 (t, J = 7.5 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.90 (d, J = 8.5 Hz, 1H), 4.16–4.06 (m, 1H), 3.74 (s, 3H), 2.68–2.57 (m, 2H), 1.68–1.59 (m, 1H), 1.54–1.45 (m, 1H), 0.91 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.05, 158.94, 154.26 (dd, J = 289.8, 286.7 Hz), 134.68, 131.23, 129.50 (t, J = 3.0 Hz), 128.35, 126.73, 125.61 (dd, J = 3.5, 2.2 Hz), 114.22, 89.36 (dd, J = 20.9, 15.4 Hz), 55.19, 50.32, 32.85, 27.26, 10.32. 19 F NMR (376 MHz, CDCl 3 ) δ -91.30 (d, J = 3.4 Hz, 1F), -91.44 (d, J = 43.8 Hz, 1F). HRMS (ESI) m/z calculated for C 20 H 22 F 2 NO 2 + [M+H] + : 346.1613, found: 346.1619.
N-(6,6-difluoro-5-(4-(trifluoromethoxy)phenyl)hex-5-en-3-yl)benzamide (4b)
1 H NMR (400 MHz, CDCl 3 ) δ 7.54–7.52 (m, 2H), 7.50–7.45 (m, 1H), 7.42–7.35 (m, 4H), 7.18 (d, J = 8.1 Hz, 2H), 5.70 (d, J = 8.7 Hz, 1H), 4.17–4.08 (m, 1H), 2.73–2.63 (m, 2H), 1.71–1.64 (m, 1H), 1.55–1.46 (m, 1H), 0.95 (t, J= 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.17, 154.50 (dd, J = 291.0, 288.6 Hz), 148.45, 134.55, 132.14 (d, J = 1.6 Hz), 131.42, 129.84 (t, J = 3.2 Hz), 128.53, 126.55, 120.42 (q, J = 257.5 Hz), 120.42 (d, J = 257.5 Hz), 89.12 (dd, J = 20.4, 16.3 Hz), 50.20 (t, J = 2.7 Hz), 33.07, 27.45, 10.27; 19 F NMR (376 MHz, CDCl 3 ) δ -57.80 (s, 3F), -89.55 (d, J = 2.2 Hz, 2F). HRMS (ESI) m/z calculated for C 20 H 19 F 2 NO 2 + [M+H] + : 400.1330, found: 400.1335.
N-(6,6-difluoro-5-(4-(methylthio)phenyl)hex-5-en-3-yl)benzamide (4c)
1 H NMR (400 MHz, CDCl 3 ) δ 7.48–7.43 (m, 3H), 7.40–7.33 (m, 2H), 7.30–7.26 (m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 5.67 (d, J = 8.7 Hz, 1H), 4.18–4.08 (m, 1H), 2.75–2.63 (m, 2H), 2.44 (s, 3H), 1.67–1.62 (m, 1H), 1.55–1.45 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.98, 154.35 (dd, J = 290.9, 287.6 Hz), 138.13, 134.56, 131.34, 130.11 (dd, J = 3.4, 2.4 Hz), 128.71 (t, J = 3.2 Hz), 128.46, 126.63, 126.61, 89.36 (dd, J = 21.0, 15.2 Hz), 50.35, 32.64, 27.31, 15.54, 10.35; 19 F NMR (376 MHz, Chloroform-d) δ -90.08 (d, J = 41.2 Hz, 1F), -90.25 (d, J = 41.2 Hz, 1F). HRMS (ESI) m/z calculated for C 20 H 22 F 2 NOS + [M+H] + : 362.1385, found: 362.1390.
N-(6,6-difluoro-5-(3-fluoro-4-methoxyphenyl)hex-5-en-3-yl)benzamide (4d)
1 H NMR (400 MHz, CDCl 3 ) δ 7.57–7.54 (m, 2H), 7.49–7.45 (m, 1H), 7.40–7.36 (dm, 2H), 7.12–7.08 (m, 2H), 6.92–6.86 (m, 1H), 5.72 (d, J = 8.7 Hz, 1H), 4.16–4.07 (m, 1H), 3.84 (s, 3H), 2.66–2.62 (m, 2H), 1.70–1.63 (m, 1H), 1.54–1.45 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.07, 154.42 (dd, J = 291.5, 286.9 Hz), 146.98 (d, J = 10.7 Hz), 134.63, 131.35, 128.46, 126.62, 124.31 (q, J = 3.2 Hz), 116.08 (dt, J = 19.4, 3.4 Hz), 113.59 (d, J = 2.3 Hz), 88.89 (dd, J = 22.3, 14.4 Hz), 56.21, 50.21, 32.84, 27.36, 10.28; 19 F NMR (376 MHz, Chloroform-d) δ -89.94 (d, J = 41.4 Hz, 1F), -90.28 (dt, J = 41.7, 2.4 Hz, 1F), -130.78–-139.64 (m, 1F). HRMS (ESI) m/z calculated for C 20 H 21 F 3 NO 2 + [M+H] + : 364.1519, found: 364.1524.
N-(5-(3,4-dichlorophenyl)-6,6-difluorohex-5-en-3-yl)benzamide (4e)
1 H NMR (400 MHz, CDCl 3 ) δ 7.58–7.52 (m, 2H), 7.50–7.45 (m, 2H), 7.38 (t, J = 8.0 Hz, 3H), 7.27–7.19 (m, 1H), 5.74 (d, J = 8.7 Hz, 1H), 4.24–3.86 (m, 1H), 2.87–2.50 (m, 2H), 1.74–1.60 (m, 1H), 1.50 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.19, 154.53 (dd, J = 293.0, 288.4 Hz), 134.37, 133.60 (dd, J = 4.4, 3.1 Hz), 132.81, 131.67, 131.52, 130.64, 130.15 (t, J = 3.4 Hz), 128.55, 127.76 (t, J = 3.2 Hz), 126.58, 88.69 (dd, J = 22.8, 14.3 Hz), 50.21, 32.90, 27.44, 10.38.; 19 F NMR (376 MHz, Chloroform-d) δ -88.22 (d, J = 37.1 Hz, 1F), -88.50 (d, J = 37.1 Hz, 1F). HRMS (ESI) m/z calculated for C 19 H 18 Cl 2 F 2 NO + [M+H] + : 384.0728, found: 384.0735.
N-(5-(4-bromophenyl)-6,6-difluorohex-5-en-3-yl)benzamide (4f)
1 H NMR (400 MHz, CDCl 3 ) δ 7.52–7.42 (m, 5H), 7.39 (t, J = 7.5 Hz, 2H), 7.24 (t, J = 7.3 Hz, 2H), 5.67 (d, J = 8.6 Hz, 1H), 4.15–4.04 (m, 1H), 2.73–2.61 (m, 2H), 1.68–1.63 (m, 1H), 1.55–1.45 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.08, 154.31 (dd, J = 291.6, 288.1 Hz), 134.49, 132.51 (dd, J = 3.7, 2.3 Hz), 131.92, 131.45, 130.01 (t, J = 3.1 Hz), 128.54, 126.59, 121.62, 89.24 (dd, J = 21.4, 15.2 Hz), 50.23, 32.84, 27.39, 10.34; 19 F NMR (376 MHz, Chloroform-d) δ -89.43 (d, J = 39.5 Hz, 1F), -89.60 (d, J = 39.5 Hz, 1F). HRMS (ESI) m/z calculated for C 19 H 19 BrF 2 NO + [M+H] + : 394.0613, found: 394.0620.
N-(5-([1,1'-biphenyl]-4-yl)-6,6-difluorohex-5-en-3-yl)benzamide (4g)
1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (t, J = 8.3 Hz, 4H), 7.46–7.42 (t, J = 6.4 Hz, 6H), 7.40–7.33 (m, 2H), 7.28 (dd, J = 14.0, 6.5 Hz, 2H), 5.69 (d, J = 8.6 Hz, 1H), 4.25–4.13 (m, 1H), 2.83–2.67 (m, 2H), 1.74–1.64 (m, 1H), 1.59–1.49 (m, 1H), 0.96 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 167.01, 157.34, 154.44 (d, J = 4.2 Hz), 151.58, 140.43, 134.60, 132.61, 131.29, 128.81, 128.72 (t, J = 3.1 Hz), 128.45, 127.48, 127.05, 126.61, 89.56 (dd, J = 18.5, 17.6 Hz); 19 F NMR (376 MHz, CDCl 3 ) δ -89.83 (s, 2F). HRMS (ESI) m/z calculated for C 25 H 24 F 2 NO + [M+H] + : 392.1820, found: 392.1826.
N-(5-(9,9-dimethyl-9H-fluoren-2-yl)-6,6-difluorohex-5-en-3-yl) benzamide (4h)
1 H NMR (400 MHz, CDCl 3 ) δ 7.72–7.68 (m, 2H), 7.41–7.38 (m, 2H), 7.35–7.26 (m, 6H), 7.13 (t, J = 7.7 Hz, 2H), 5.69 (d, J = 8.8 Hz, 1H), 4.26–4.16 (m, 1H), 2.78–2.76 (m, 2H), 1.68–1.63 (m, 1H), 1.59–1.51 (m, 1H), 1.45 (s, 3H), 1.29 (s, 3H), 0.95 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.82, 154.45 (dd, J = 290.7, 287.9 Hz), 138.90, 138.52, 134.49, 132.73 (dd, J = 3.1, 2.1 Hz), 131.20, 128.30, 127.51, 127.23 (t, J = 2.9 Hz), 127.05, 126.56, 122.62, 122.59, 120.32, 120.06, 90.12 (dd, J = 20.6, 15.4 Hz), 50.64, 46.91, 32.77, 27.37, 27.23, 26.74, 10.43; 19 F NMR (376 MHz, CDCl 3 ) δ -90.50 (d, J = 42.7 Hz, 1F), -91.11 (d, J = 42.8 Hz, 1F). HRMS (ESI) m/z calculated for C 28 H 28 F 2 NO + [M+H] + : 432.2133, found: 432.2133.
N-(5-(benzo[d][1,3]dioxol-5-yl)-6,6-difluorohex-5-en-3-yl)benzamide (4i)
1 H NMR (400 MHz, CDCl 3 ) δ 7.57–7.51 (m, 2H), 7.48–7.44 (m, 1H), 7.37 (t, J = 7.5 Hz, 2H), 6.83–6.74 (m, 3H), 5.92 (d, J = 1.4 Hz, 1H), 5.87 (d, J= 1.4 Hz, 1H), 5.74 (d, J = 8.7 Hz, 1H), 4.17–4.08 (m, 1H), 2.66–2.59 (m, 2H), 1.71–1.60 (m, 1H), 1.55–1.46 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.98, 154.32 (dd, J = 290.4, 286.6 Hz), 147.92, 147.00, 134.62, 131.31, 128.43, 127.11 (dd, J = 4.4, 2.8 Hz), 126.66, 121.92 (t, J = 3.0 Hz), 108.90 (t, J = 3.2 Hz), 108.55, 101.18, 89.61 (dd, J = 22.0, 14.9 Hz), 50.24, 33.05, 27.37, 10.34; 19 F NMR (376 MHz, CDCl 3 ) δ -82.25 (d, J = 28.6 Hz, 1F), -87.11 (d, J = 28.6 Hz, 1F). HRMS (ESI) m/z calculated for C 20 H 20 F 2 NO 3 + [M+H] + : 360.1406, found: 360.1412.
methyl 4-(4-benzamido-1,1-difluorohex-1-en-2-yl)benzoate (4j)
1 H NMR (400 MHz, CDCl 3 ) δ 8.01–7.96 (m, 2H), 7.51–7.49 (m, 2H), 7.46–7.42 (m, 3H), 7.37–7.33 (m, 2H), 5.68 (d, J = 8.7 Hz, 1H), 4.16–4.07 (m, 1H), 3.91 (s, 3H), 2.74–2.71 (m, 2H), 1.69–1.65 (m, 1H), 1.54–1.45 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.09, 166.57, 154.58 (dd, J= 292.1, 289.9 Hz), 138.39, 134.51, 131.35, 129.93, 129.19, 128.45, 128.28 (t, J = 3.2 Hz), 126.59, 89.72 (dd, J = 19.9, 16.2 Hz), 52.07, 50.31, 32.74, 27.39, 10.29; 19 F NMR (376 MHz, Chloroform-d) δ -88.30(s, 2F). HRMS (ESI) m/z calculated for C 21 H 22 F 2 NO 3 + [M+H] + : 374.1562, found: 374.1564.
N-(5-(4-cyanophenyl)-6,6-difluorohex-5-en-3-yl)benzamide (4k)
1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 7.3 Hz, 2H), 7.52–7.47 (m, 3H), 7.40 (t, J = 7.6 Hz, 2H), 5.76 (d, J = 8.6 Hz, 1H), 4.12–4.03 (m, 1H), 2.75–2.66 (m, 2H), 1.70–1.64 (m, 1H), 1.55–1.47 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.27, 154.71 (dd, J = 294.3, 289.4 Hz), 138.48 (dd, J = 4.2, 3.4 Hz), 134.31, 132.36, 131.65, 129.03 (t, J = 3.4 Hz), 128.58, 126.58, 118.54, 111.13, 89.52 (dd, J = 22.4, 13.8 Hz), 50.19, 32.81, 27.38, 10.39; 19 F NMR (376 MHz, CDCl 3 ) δ -87.11 (d, J= 34.2 Hz, 1F), -87.33 (d, J = 34.3 Hz, 1F). HRMS (ESI) m/z calculated for C 20 H 19 F 2 N 2 O + [M+H] + : 341.1460, found: 341.1460.
N-(5-(4-(dimethylamino)phenyl)-6,6-difluorohex-5-en-3-yl)benzamide (4l)
1 H NMR (400 MHz, CDCl 3 ) δ 7.38–7.33 (m, 3H), 7.26–7.20 (m, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 8.8 Hz, 2H), 5.69 (d, J = 8.7 Hz, 1H), 4.13–4.03 (m, 1H), 2.86 (s, 6H), 2.66–2.50 (m, 2H), 1.63–1.50 (m, 1H), 1.48–1.40 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.82, 154.18 (dd, J = 288.8, 286.8 Hz), 149.72, 134.67, 131.16, 129.05 (t, J = 3.0 Hz), 128.37 (d, J = 14.2 Hz), 126.76, 120.95, 112.62, 89.25 (dd, J = 20.0, 16.1 Hz), 50.49, 40.41, 32.39, 27.19, 10.39; 19 F NMR (376 MHz, Chloroform-d) δ -91.95 (d, J = 45.7 Hz, 1F), -92.10 (d, J = 45.7 Hz, 1F). HRMS (ESI) m/z calculated for C 21 H 25 F 2 N 2 O + [M+H] + : 359.1929, found: 359.1936.
N-(6,6-difluoro-5-(3-formylphenyl)hex-5-en-3-yl)benzamide (4m)
1 H NMR (400 MHz, CDCl 3 ) δ 9.94 (s, 1H), 7.86 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.58–7.52 (m, 2H), 7.50–7.41 (m, 2H), 7.34 (t, J = 7.6 Hz, 2H), 5.90 (d, J = 8.8 Hz, 1H), 4.26–3.93 (m, 1H), 2.73–2.70 (m, 2H), 1.73–1.60 (m, 1H), 1.57–1.44 (m, 1H), 0.92 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 192.03, 167.28, 154.63 (dd, J = 292.1, 288.6 Hz), 136.67, 134.66 (dd, J = 3.8, 2.3 Hz), 134.42 (t, J = 3.0 Hz), 131.46, 129.54 (t, J = 3.2 Hz), 129.45, 128.66, 128.49, 126.65, 89.37 (dd, J = 21.5, 15.0 Hz), 50.21, 33.03, 27.47, 10.35; 19 F NMR (376 MHz, Chloroform-d) δ -88.92 (d, J = 38.3 Hz, 1F), -89.08 (d, J = 38.4 Hz, 1F). HRMS (ESI) m/z calculated for C 20 H 20 F 2 NO 2 + [M+H] + : 344.1457, found: 344.1463.
N-(6,6-difluoro-5-(4-(trimethylsilyl)phenyl)hex-5-en-3-yl)benzamide (4n)
1 H NMR (400 MHz, CDCl 3 ) δ 7.30–7.21 (m, 5H), 7.16–7.09 (m, 4H), 5.52 (d, J = 8.7 Hz, 1H), 4.00–3.90 (m, 1H), 2.58–2.44 (m, 2H), 1.51–41 (m, 1H), 1.36–1.25 (m, 1H), 0.73 (t, J = 7.4 Hz, 3H), 0.04 (s, 9H); 13 C NMR (101 MHz, CDCl 3 ) δ 168.18, 155.56 (dd, J = 291.0, 288.1 Hz), 141.00, 135.79, 135.05 (dd, J = 2.5, 1.7 Hz), 134.86, 132.39, 129.55, 128.66 (t, J = 3.0 Hz), 127.78, 91.00 (dd, J = 20.0, 15.6 Hz), 51.58, 33.68, 28.46, 11.46, 0.00. 19 F NMR (376 MHz, CDCl 3 ) δ -89.94 (d, J = 40.9 Hz, 1F), -90.10 (d, J = 40.9 Hz, 1F). HRMS (ESI) m/z calculated for C 22 H 28 F 2 NOSi + [M+H] + : 388.1903, found: 388.1912.
N-(5-(benzofuran-2-yl)-6,6-difluorohex-5-en-3-yl)benzamide (4o)
The title compound was isolated as a white solid (78% yield, 93: 7 rr) after chromatography on silica with ethyl acetate/hexane (1:10). 1 H NMR (400 MHz, CDCl 3 ) δ 7.55–7.50 (m, 3H), 7.41 (t, J = 8.2 Hz, 2H), 7.30–7.25 (m, 3H), 7.23–7.20 (m, 1H), 6.85 (s, 1H), 5.99 (d, J = 8.4 Hz, 1H), 4.37–4.29 (m, 1H), 2.82–2.72 (m, 2H), 1.80–1.72 (m, 1H), 1.68–1.60 (m, 1H), 1.02 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 167.37, 155.35 (dd, J = 300.8, 289.1 Hz), 154.27, 149.34 (t, J = 6.5 Hz), 134.55, 131.31, 128.70, 128.45, 126.63, 124.28, 123.11, 120.93, 110.93, 105.09 (dd, J = 8.8, 5.4 Hz), 83.90 (dd, J = 28.2, 12.0 Hz), 50.99, 29.89, 27.52, 10.40; 19 F NMR (376 MHz, Chloroform-d) δ -79.21 (d, J = 23.1 Hz, 1F), -85.71 (d, J = 23.0 Hz, 1F). HRMS (ESI) m/z calculated for C 21 H 20 F 2 NO 2 + [M+H] + : 356.1457, found: 356.1464.
As can be seen from the analysis of the data in Table 2, various substituents on the aromatic ring are well tolerated, including substrates with electron rich (4 a-4 f) or electron withdrawing (4 g-4 m) substituents on the aryl ring. This reaction is compatible with aryl fluoro (4 d), aryl chloro (4 e) and aryl bromide (4 f), which can be used for further derivatization reactions, thereby increasing the complexity of the molecule. Under such mild conditions, it is also applicable to the highly hindered biphenyls (4 g) and fluorenes (4 h), which can tolerate not only the ethers (4 i), esters (4 j) and nitriles (4 k), but also functional groups that are generally easily reduced, such as the aldehyde (4 m). In addition, the first and second substrates are,
heterocyclic furans (4 o), which are common in drug molecules, are also compatible. Fortunately, the alkyl substituted trifluoromethyl alkene (4 p) is compatible under these conditions.
Example 3
The practical synthesis and application potential of the series geminal difluoroolefin compounds synthesized by the invention are as follows:
synthetic application of typical compound in gem-difluoroolefin
TABLE 3 Synthesis of geminal Difluoroalkenes
N-(6,6-difluoro-5-(naphthalen-2-yl)hexan-3-yl)benzamide（5a）
1 H NMR (400 MHz, CDCl 3 ) δ 7.71–7.63 (m, 4H), 7.39–7.30 (m, 3H), 7.25 (t, J = 7.4 Hz, 1H), 7.18 (d, J = 7.5 Hz, 2H), 7.06 (t, J = 7.6 Hz, 2H), 5.89 (td, J = 56.6, 3.2 Hz, 1H), 5.50 (d, J = 8.8 Hz, 1H), 4.17–4.08 (m, 1H), 3.33–3.21 (m, 1H), 2.30–2.20 (m, 1H), 2.11–2.01 (m, 1H), 1.71–1.59 (m, 1H), 1.50–1.41 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H)； 13 C NMR (101 MHz, CDCl 3 ) δ 166.00, 133.45 (dd, J = 4.9, 2.9 Hz), 133.14, 132.41, 131.77, 130.15, 127.67, 127.15, 126.98, 126.72, 126.54, 125.43, 125.28, 125.21, 125.02, 116.57 (t, J = 245.2 Hz), 49.26, 46.84 (t, J = 19.8 Hz), 32.24 (dd, J = 4.3, 3.0 Hz), 27.18, 8.97； 19 F NMR (376 MHz, CDCl 3 ) δ -119.12 (ddd, J = 276.4, 56.6, 15.2 Hz, 1F), -122.94 (ddd, J = 276.4, 56.6, 17.0 Hz, 1F). HRMS (ESI) m/z calculated for C 23 H 24 F 2 NO + [M+H] + : 368.1820, found: 368.1823.
N-(6-((4-(tert-butyl)phenyl)thio)-6,6-difluoro-5-(naphthalen-2-yl) hexan-3-yl)benzamide(5b)
1 H NMR (400 MHz, CDCl 3 ) δ 7.80–7.74 (m, 4H), 7.45–7.39 (m, 5H), 7.36–7.30 (m, 3H), 7.25–7.18 (m, 4H), 5.64 (d, J = 9.3 Hz, 1H), 3.96–3.83 (m, 1H), 3.67–3.48 (m, 1H), 2.40–2.16 (m, 2H), 1.51–1.44 (m, 2H), 1.20 (s, 9H), 0.78 (t, J = 7.4 Hz, 3H)； 13 C NMR (101 MHz, CDCl 3 ) δ 167.03, 153.03, 136.58 (d, J = 6.0 Hz), 136.04, 134.61, 134.08 (d, J = 4.4 Hz), 133.37, 133.15, 131.35, 129.35, 128.62, 128.49, 128.18, 127.72, 126.88, 126.73, 126.30 (d, J = 2.6 Hz), 126.03, 123.15, 51.36 (t, J = 22.3 Hz), 48.94, 35.19, 34.73, 31.20, 28.46, 10.38； 19 F NMR (376 MHz, CDCl 3 ) δ -74.06 (dd, J = 202.7, 11.1 Hz, 1F), -77.53 (dd, J = 202.7, 17.3 Hz, 1F). HRMS (ESI) m/z calculated for C 33 H 36 F 2 NOS + [M+H] + : 532.2480, found: 532.2485.
((5S)-5-ethyl-2-(naphthalen-2-yl)-2-(trifluoromethyl)pyrrolidin-1-yl) (phenyl)methanone(5c)
1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J = 7.6 Hz, 2H), 8.02 (s, 1H), 7.86–7.75 (m, 3H), 7.65 (d, J = 8.7 Hz, 1H), 7.45–7.37 (m, 5H), 3.64–3.57 (m, 1H), 2.83 (dd, J = 14.5, 5.0 Hz, 1H), 1.85–1.77 (m, 1H), 1.56–1.42 (m, 2H), 1.01 (t, J = 7.3 Hz, 3H)； 13 C NMR (101 MHz, CDCl 3 ) δ 150.54, 133.96, 132.33, 132.21, 131.76, 129.74, 127.48, 127.33, 127.24, 126.55, 126.31, 125.86, 125.54, 124.04, 121.66 (d, J = 0.9 Hz), 109.29 (dd, J = 26.5, 19.7 Hz), 77.08 (q, J = 29.3 Hz), 49.39, 31.37, 29.16, 9.23； 19 F NMR (376 MHz, CDCl 3 ) δ -76.33 (s, 3F). HRMS (ESI) m/z calculated for C 24 H 23 F 3 NO + [M+H] + : 398.1726, found: 398.1730.
(E)-N-(6-fluoro-6-(1H-imidazol-1-yl)-5-(naphthalen-2-yl)hex-5-en-3- yl)benzamide(5d)
1 H NMR (400 MHz, CDCl 3 ) δ 7.75–7.64 (m, 4H), 7.48–7.36 (m, 5H), 7.28–7.20 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 6.79 (s, 1H), 5.80 (d, J = 9.1 Hz, 1H), 4.35–4.24 (m, 1H), 3.03–2.92 (m, 2H), 1.77–1.68 (m, 1H), 1.64–1.54 (m, 1H), 0.97 (t, J = 7.4 Hz, 3H), 13 C NMR (101 MHz, CDCl 3 ) δ 167.05, 145.24, 142.66, 137.28, 134.39, 133.29, 132.72, 132.66, 131.35, 129.64, 129.07, 128.42, 128.04, 127.65, 127.36 (d, J = 3.5 Hz), 126.62 (d, J= 3.3 Hz), 126.53, 125.59 (d, J = 2.7 Hz), 118.75 (d, J = 1.8 Hz), 112.39 (d, J = 24.0 Hz), 50.27 (d, J = 2.6 Hz), 36.05, 28.23, 10.48 ; 19 F NMR (376 MHz, CDCl 3 ) δ -91.75 (s, 1F). HRMS (ESI) m/z calculated for C 26 H 25 FN 3 O + [M+H] + : 414.1976, found: 414.1980.
(S)-(2-ethyl-5-fluoro-4-(naphthalen-2-yl)-2,3-dihydro-1H-pyrrol-1-yl) (phenyl)methanone(5e)
1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (t, J = 8.0 Hz, 3H), 7.65 (s, 1H), 7.61–7.55 (m, 3H), 7.50 (d, J = 7.1 Hz, 1H), 7.45 (t, J = 6.1 Hz, 4H), 4.76–4.65 (m, 1H), 3.32–3.19 (m, 1H), 2.76–2.65 (m, 1H), 2.12–2.02 (m, 1H), 1.96–1.86 (m, 1H), 1.07 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 165.59 (d, J = 3.0 Hz), 147.17, 144.34, 135.22 (d, J = 3.4 Hz), 132.41, 130.87 (d, J = 1.3 Hz), 129.64, 129.01 (d, J = 6.4 Hz), 127.04, 126.93, 126.71, 126.60–126.51 (m), 125.35, 124.74, 122.93, 122.86 (d, J = 2.5 Hz), 93.95 (d, J = 6.0 Hz), 56.52, 29.09 (d, J = 4.6 Hz), 25.44, 7.37, -0.49–-5.78 (m); 19 F NMR (376 MHz, CDCl 3 ) δ -110.52 . HRMS (ESI) m/z calculated for C 23 H 21 FNO + [M+H] + : 346.1602, found: 346.1606.
N-(1-(naphthalen-2-yl)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)pentan-3-yl) benzamide(5f)
1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (d, J = 7.7 Hz, 2H), 7.69–7.61 (m, 4H), 7.47 (d, J = 7.8 Hz, 2H), 7.37–7.32 (m, 4H), 7.28 (t, J = 7.7 Hz, 3H), 7.15 (t, J = 7.5 Hz, 2H), 6.16 (d, J = 8.6 Hz, 1H), 4.55–4.48 (m, 1H), 4.21–4.13 (m, 1H), 2.82–2.71 (m, 1H), 2.34–2.24 (m, 1H), 1.73–1.61 (m, 1H), 1.59–1.51 (m, 1H), 0.88 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 166.92, 166.18, 164.13, 135.39, 133.21, 132.40, 131.64, 130.49, 130.23, 127.93, 127.78, 127.37, 127.28, 126.73, 126.58, 125.81, 125.70, 125.58, 125.40, 125.11, 124.28, 122.68, 49.21, 39.75, 37.93, 26.81, 9.36. HRMS (ESI) m/z calculated for C 30 H 28 N 3 O 2 + [M+H] + : 462.2176, found: 462.2180.
The data in table 3 show that geminal difluoroolefin can be used as a platform compound to synthesize a series of functionalized fluorine-containing compounds, and the compound 3f can be successfully converted into 6 useful functional groups. The hydrogenation reaction (5 a) can be realized by using a common Pd/C catalyst; the 3f reacts with p-tert-butyl toluene thiol in ultra-dry DCE for 2 hours to obtain (5 b), the thiol click chemistry is easy to prepare fluoroalkyl sulfide, and the sulfanyl sulfide can efficiently form fluoroalkyl free radical under the action of visible light, as shown in the following: m.o. Zubkov, m.d. Kosobokov, v.v. Levin, v.a. Kokorekin, a.a. Korlyukov, j.hu and a.d. dimman.Chem. Sci.2020, 11737-741. Alpha-CF can be obtained in excellent yields by using a urheen reagent for the reaction 3 A substituted tertiary amine (5 c); nucleophilic vinyl substitution reaction (S) upon treatment of 3f with imidazole N V) has good effect, realizes the bifunctional of geminal difluoroolefin, introduces carbonyl and imidazole functional groups (5 d), and can lead 3f to pass through intramolecular S under the action of strong base NaH N V reacted to convert to (5 e) in 93% yield. In addition, in Cs 2 CO 3 With the aid of (3 f), cyclization reaction of 3f with benzoyl hydrazine gave the asymmetric 2,5-disubstituted 1,3,4-oxadiazole (5 f) in 80% yield. These synthetic transformations of geminal difluoroolefins further demonstrate the utility of the process.
Claims (6)
1. A nickel-catalyzed preparation method of aliphatic amine containing gem-difluoro olefin structure is characterized by comprising the following steps:
(1) Weighing 15 mol% of ethylene glycol dimethyl ether nickel bromide, 15 mol% (2,9-dimethyl-4,7-biphenyl-1,10-phenanthroline), an unactivated olefin substrate, a trifluoromethyl substituted olefin, 2.5 equiv sodium fluoride, ethylene glycol dimethyl ether and 2 equiv trimethoxy silane in a dry reaction tube in a glove box filled with argon, and stirring the reaction system at 70 ℃ to react with 18 h; wherein the molar ratio of unactivated olefin substrate to trifluoromethyl-substituted olefin is 1:3;
(2) After the reaction is finished, concentrating the obtained solution in vacuum, purifying the crude product by silica gel column chromatography, and calculating the separation yield by using a mixture of ethyl acetate and n-hexane as an eluent;
wherein R is 1 Refers to:
R 2 means that: me;
R 3 means that: me, n-Pr;
R 4 means that:
the unactivated olefinic substrate is:
the trifluoromethyl substituted alkene is
The solvent is ethylene glycol dimethyl ether; the volume ratio of the ethyl acetate to the normal hexane serving as the eluent is 1:10.
2. the nickel-catalyzed preparation method of aliphatic amine containing gem-difluoroolefin structure as claimed in claim 1, characterized in that: the reaction temperature is 70 ℃; the catalyst is ethylene glycol dimethyl ether nickel bromide.
3. The method for preparing the fatty amine containing the gem-difluoro olefin structure by nickel catalysis in claim 1 is characterized by comprising the following steps: the ligand is bathocuproine; the alkali is sodium fluoride; the hydrogen source is trimethoxy silane.
4. The nickel-catalyzed preparation method of aliphatic amine containing gem-difluoroolefin structure as claimed in claim 1, characterized in that: allylamide derivatives give migratory defluorinated allylation products when used as olefinic substrates.
5. Use of the process of claim 1 for achieving high separation, high regioselective products under mild conditions.
6. Use of the migratory compounds produced by the process of claim 1 for the synthesis of fluorine-containing drugs and materials.
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| CN110294704A (en) * | 2018-03-24 | 2019-10-01 | 复旦大学 | A method of it prepares containing single fluoroalkyl vinyl hydrocarbon compound |
| CN113527177A (en) * | 2021-08-31 | 2021-10-22 | 南京林业大学 | 2-cyanoindole-substituted gem-difluoroolefin compound and preparation method and application thereof |
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| CN110294704A (en) * | 2018-03-24 | 2019-10-01 | 复旦大学 | A method of it prepares containing single fluoroalkyl vinyl hydrocarbon compound |
| CN113527177A (en) * | 2021-08-31 | 2021-10-22 | 南京林业大学 | 2-cyanoindole-substituted gem-difluoroolefin compound and preparation method and application thereof |
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| Title |
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| WEN-JUN YUE ETAL: "Site-Selective Defluorinative sp3 C−H Alkylation of Secondary Amides", 《J. AM. CHEM. SOC.》, pages 6395 * |
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