CN112375068B - Terminal alkenyl indole derivative and preparation method thereof - Google Patents
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- -1 alkenyl indole derivative Chemical group 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 67
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 44
- 239000001257 hydrogen Substances 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 42
- FWDBOZPQNFPOLF-UHFFFAOYSA-N ethenyl(triethoxy)silane Chemical compound CCO[Si](OCC)(OCC)C=C FWDBOZPQNFPOLF-UHFFFAOYSA-N 0.000 claims abstract description 34
- 125000001424 substituent group Chemical group 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 150000002367 halogens Chemical class 0.000 claims abstract description 19
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 18
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 14
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 12
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 12
- 125000003172 aldehyde group Chemical group 0.000 claims abstract description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 10
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 87
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 40
- 238000000746 purification Methods 0.000 claims description 29
- 239000012043 crude product Substances 0.000 claims description 28
- 238000010898 silica gel chromatography Methods 0.000 claims description 28
- 239000003208 petroleum Substances 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 7
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 5
- 229920002554 vinyl polymer Polymers 0.000 claims description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 2
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical group C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 5
- 229940054051 antipsychotic indole derivative Drugs 0.000 abstract description 4
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 88
- 238000004809 thin layer chromatography Methods 0.000 description 42
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 25
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- 239000000203 mixture Substances 0.000 description 23
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- 238000002844 melting Methods 0.000 description 21
- 230000008018 melting Effects 0.000 description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- 150000002431 hydrogen Chemical class 0.000 description 15
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 150000002475 indoles Chemical class 0.000 description 7
- 238000012986 modification Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 150000001336 alkenes Chemical class 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000001041 indolyl group Chemical group 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- SBNOTUDDIXOFSN-UHFFFAOYSA-N 1h-indole-2-carbaldehyde Chemical compound C1=CC=C2NC(C=O)=CC2=C1 SBNOTUDDIXOFSN-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 229910003074 TiCl4 Inorganic materials 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000609 carbazolyl group Chemical class C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000005686 cross metathesis reaction Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000006772 olefination reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012360 testing method Methods 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
本发明提供了一种末端烯基吲哚衍生物及其制备方法，所述方法包括：将化合物I和乙烯基三乙氧基硅烷在有机溶剂和催化剂条件下反应，获得化合物II所示的末端烯基吲哚衍生物；反应式如下所示，其中，取代基R1选自氢，C1‑C4的烷基，C1‑C4的烷氧基，甲氧基，苄氧基，卤素，硝基，氰基，醚酯基，苯基，醛基，烯丙基，酰氧基和乙烯基；取代基R2选自C1‑C4的烷基，C1‑C4的烷氧基，烯丙基，环己基，环戊基，酰氧基，醛基，醚，酯基，卤素和氰基；取代基R3选自氢，C1‑C4的烷基，苯基和卤素。该烯基吲哚衍生物末端没有取代基，该方法不仅高效简便而且符合步骤经济性要求。
The invention provides a terminal alkenyl indole derivative and a preparation method thereof. The method comprises: reacting compound I and vinyltriethoxysilane under organic solvent and catalyst conditions to obtain the terminal shown in compound II. Alkenyl indole derivatives; the reaction formula is as follows, wherein, the substituent R 1 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, methoxy, benzyloxy, halogen, nitro , cyano group, ether ester group, phenyl group, aldehyde group, allyl group, acyloxy group and vinyl group; Substituent R 2 is selected from C1-C4 alkyl group, C1-C4 alkoxy group, allyl group, Cyclohexyl, cyclopentyl, acyloxy, aldehyde, ether, ester, halogen and cyano; Substituent R 3 is selected from hydrogen, C1-C4 alkyl, phenyl and halogen. The alkenyl indole derivative has no substituent at the end, and the method is not only efficient and convenient, but also meets the requirements of step economy.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a terminal alkenyl indole derivative and a preparation method thereof.
Background
Indole compounds containing an alkenyl structure are an important class of functionalized indole derivatives. They are not only the core building blocks of many drug molecules and pesticide compounds. In addition, the organic molecules also show excellent biological activity due to the alkenyl indole structure. In addition, the alkenyl structure is a very useful functional group to prepare other valuable compounds through various transformations. For example, alkenyl indoles can be converted to carbazole derivatives by olefin cross-metathesis ring-closing reactions; indole derivatives with dihydroxyl functionalization can be prepared by dihydroxylation of olefins; by the epoxidation reaction of an olefin, an epoxidized indole derivative having optical activity can be produced. Accordingly, indoles having an alkenyl structureThe derivatives are star molecules which are of great interest in the fields of medicinal chemistry, biochemistry and the like. Currently, indole compounds having an alkenyl structure can be prepared by the following several methods. (1) The alkynylindoles were subjected to hydrogenation reduction using a palladium on carbon catalyst. (2) Using TiCl4Zn carries out reduction coupling on indole-2-formaldehyde. (2) The witting reaction is carried out using a phosphorus ylide and an indol-2-aldehyde or ketone. These conventional synthesis methods require that functional groups such as alkynyl, halogen or aldehyde groups be placed on the indole ring in advance. The steps of synthesis are increased to a certain extent, and the step economy and atom economy of modern synthetic chemistry are not met. Another useful synthetic method is the direct C-H bond olefination catalyzed by transition metals such as ruthenium, rhodium, palladium, and the like. The method directly activates inert C-H bonds and directly converts the C-H bonds of the indole into alkenyl functional groups. Relatively speaking, the requirements of step economy and atom economy are more satisfied.
However, the prior art is mainly used for the preparation of indole derivatives of non-terminal alkenyl structure, i.e. having various substituents at the terminal of the alkenyl group. Terminal alkene indoles are considered to be a special class of alkenyl indoles, as well as important roles in the terminal alkene structure. Therefore, the development of a synthetic method can directly modify an indole skeleton to obtain an alkenyl indole compound with an end having no substituent, which is of great significance for the preparation of a medicament with an indole structure and the activity research thereof. Therefore, how to prepare an alkenyl indole compound having no substituent at the terminal is a technical problem to be solved urgently.
Disclosure of Invention
The invention aims to provide a terminal alkenyl indole derivative and a preparation method thereof, so that the alkenyl indole derivative without a substituent at the terminal can be successfully prepared, and the method is efficient, simple and convenient and meets the step economy requirement.
In a first aspect of the present invention, there is provided a process for the preparation of a terminal alkenyl indole derivative, the process comprising:
reacting a compound I with vinyltriethoxysilane in the presence of an organic solvent and a catalyst to obtain a terminal alkenyl indole derivative shown in a compound II;
wherein, the substituent R1Selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, methoxy, benzyloxy, halogen, nitro, cyano, ether ester group, phenyl, aldehyde group, allyl, acyloxy and vinyl;
substituent R2Selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, allyl, cyclohexyl, cyclopentyl, acyloxy, aldehyde, ether, ester, halogen and cyano;
substituent R3Selected from hydrogen, C1-C4 alkyl, phenyl and halogen.
Further, the molar weight ratio of the compound I to the vinyltriethoxysilane is 1: (2-4).
Further, the reaction temperature is 80-120 ℃, and the reaction time is 12-24 h.
Further, the catalyst comprises Cu (OAc)2AgF and [ RhCp Cl ]2]2。
Further, the molar weight ratio of the catalyst to the compound I is Cu (OAc)2：AgF：[RhCp*Cl2]2: compound I ═ (2-3): (2-3): (0.01-0.1): 1.
further, the organic solvent is one or more of 1, 2-dichloroethane DCE, dimethylformamide DMF, acetonitrile and DMSO.
Further, the organic solvent is a mixed solvent of 1, 2-dichloroethane DCE and dimethylformamide DMF, and the volume ratio of the 1, 2-dichloroethane DCE to the dimethylformamide DMF is (1-10): 1.
further, after the reaction is completed, separation and purification are carried out, wherein the separation and purification comprises the following steps: and cooling the product obtained by the reaction to room temperature, concentrating to obtain a crude product, and then separating and purifying the crude product by silica gel column chromatography to obtain the pure terminal alkenyl indole derivative.
Further, in the separation and purification by silica gel column chromatography, the organic solvent used is petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (2-10): 1.
in a second aspect of the present invention, there is provided a terminal alkenyl indole derivative, wherein the structural formula of the terminal alkenyl indole derivative is as follows:
wherein, the substituent R1Selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, methoxy, benzyloxy, halogen, nitro, cyano, ether ester group, phenyl, aldehyde group, allyl, acyloxy and vinyl;
substituent R2Selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, allyl, cyclohexyl, cyclopentyl, acyloxy, aldehyde, ether, ester, halogen and cyano;
substituent R3Selected from hydrogen, C1-C4 alkyl, phenyl and halogen;
wherein, the substituent R3When it is hydrogen, R2Is selected from alkoxy of C1-C4, acyloxy, aldehyde group and cyano.
One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:
the present inventors have found that a terminal alkenylindole derivative represented by compound II can be obtained by reacting compound I with vinyltriethoxysilane in an organic solvent under a catalyst condition, and have developed a method for synthesizing an alkenylindole derivative having no substituent at the terminal. The method is not only efficient and simple, but also meets the economic requirement of the steps.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and it is obvious for those skilled in the art to derive other drawings without creative efforts.
FIG. 1 is an H NMR spectrum of a terminal alkenyl indole derivative prepared in example 19 of the present invention;
FIG. 2 is a C NMR spectrum of a terminal alkenyl indole derivative prepared in example 19 of the present invention.
Detailed Description
The present invention will be described in detail below with reference to specific embodiments and examples, and the advantages and various effects of the present invention will be more clearly apparent therefrom. It will be understood by those skilled in the art that these specific embodiments and examples are for the purpose of illustrating the invention and are not to be construed as limiting the invention.
Throughout the specification, unless otherwise specifically noted, terms used herein should be understood as having meanings as commonly used in the art. Accordingly, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is a conflict, the present specification will control.
Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be prepared by existing methods.
In order to solve the technical problems, the embodiment of the invention provides the following general ideas:
according to an exemplary embodiment of the present invention, there is provided a method for preparing a terminal alkenyl indole derivative, the method including:
reacting a compound I with vinyltriethoxysilane in the presence of an organic solvent and a catalyst to obtain a terminal alkenyl indole derivative shown in a compound II;
wherein, the substituent R1Selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, methoxy, benzyloxy, halogen, nitro, cyano, ether ester group, phenyl, aldehyde group, allyl, acyloxy and vinyl;
substituent R2Selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, allyl, cyclohexyl, cyclopentyl, acyloxy, aldehyde, ether, ester, halogen and cyano;
substituent R3Selected from hydrogen, C1-C4 alkyl, phenyl and halogen.
The present applicant has found that a terminal alkenylindole derivative represented by compound II can be obtained by reacting compound I with vinyltriethoxysilane in the presence of an organic solvent and a catalyst, and has developed a method for synthesizing an alkenylindole derivative having no substituent at the terminal by using vinyltriethoxysilane as a alkenylating agent. The method is not only efficient and simple, but also meets the economic requirement of the steps.
As a preferred embodiment, the molar weight ratio of said compound I and said vinyltriethoxysilane is 1: (2-4). Too high or too low of this ratio is detrimental to the reaction;
in a preferred embodiment, the reaction temperature is 80-120 ℃, and the reaction time is 12-24 h. The reaction temperature is too low or too high, which is not favorable for the reaction to be carried out or the reaction to be completed.
As a preferred embodiment, the catalyst comprises Cu (OAc)2AgF and [ RhCp Cl ]2]2。
In a preferred embodiment, the molar weight ratio of the catalyst to the compound I is Cu (OAc)2：AgF：
[RhCp*Cl2]2: compound I ═ (2-3): (2-3): (0.01-0.1): 1. this ratio is either too low or too high to allow complete reaction to the terminal alkenyl indole derivative of compound II.
As a preferred embodiment, the organic solvent is one or more of 1, 2-dichloroethane DCE, dimethylformamide DMF, acetonitrile and DMSO. When the organic solvent is a mixed solvent of 1, 2-dichloroethane DCE and dimethylformamide DMF, the volume ratio of the 1, 2-dichloroethane DCE to the dimethylformamide DMF is (1-10): 1.
as a preferred embodiment, after the reaction is completed, separation and purification are performed, and the separation and purification include: and cooling the product obtained by the reaction to room temperature, concentrating to obtain a crude product, and then separating and purifying the crude product by silica gel column chromatography to obtain the pure terminal alkenyl indole derivative. In the separation and purification by silica gel column chromatography, the organic solvent used is petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (2-10): 1.
according to another exemplary embodiment of the present invention, the terminal alkenyl indole derivative has a structural formula as follows:
wherein, the substituent R1Selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, methoxy, benzyloxy, halogen, nitro, cyano, ether ester group, phenyl, aldehyde group, allyl, acyloxy and vinyl;
substituent R2Selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, allyl, cyclohexyl, cyclopentyl, acyloxy, aldehyde, ether, ester, halogen and cyano;
substituent R3Selected from hydrogen, C1-C4 alkyl, phenyl and halogen;
wherein, the substituent R3When it is hydrogen, R2Is selected from alkoxy of C1-C4, acyloxy, aldehyde group and cyano.
The alkenyl indole derivative with the terminal in the structural general formula of the alkenyl indole derivative has no substituent at the terminal, and has important significance for preparing a medicament with an indole structure and researching the activity of the medicament.
The following will describe in detail a method for preparing a terminal alkenyl indole derivative of the present application with reference to examples and experimental data.
Example 1
In this embodiment: r1Is hydrogen; r2Is methyl; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-1(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: 88 percent.
Compound II-1 was tested:
melting point: 99-100 deg.C
1H NMR(400MHz,CDCl3)δ8.77(d,J＝4.8Hz,2H),8.27(d,J＝7.9Hz,1H),7.57(d,J＝7.2Hz,1H),7.31–7.21(m,2H),7.11–7.02(m,2H),5.50–5.38(m,2H),2.44(s,3H).
13C NMR(100MHz,CDCl3)δ158.18,158.09,136.20,133.90,130.67,128.84,123.89,121.73,118.78,116.76,116.68,115.41,113.66,10.26.
HRMS m/z:calcd forC15H14N3 +[M+H+]236.1182,found 236.1181.
Example 2
In this embodiment: r1Is methyl; r2Is methyl; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-2(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: and 69 percent.
Compound II-2 was tested:
melting point: 64-65 deg.C
1H NMR(400MHz,CDCl3)δ8.75(d,J＝4.8Hz,2H),8.17(d,J＝8.5Hz,1H),7.35(s,1H),7.12–7.00(m,3H),5.49–5.39(m,2H),2.47(s,3H),2.41(s,3H).
13C NMR(100MHz,CDCl3)δ158.25,158.02,134.50,133.99,131.11,130.91,129.07,125.33,118.64,116.48,116.34,115.26,113.55,21.40,10.27.
HRMS m/z:calcd for C16H16N3 +[M+H+]250.1339,found 250.1340.
Example 3
In this embodiment: r1Is bromine; r2Is methyl; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-3(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: 79 percent.
Compound II-3 was tested:
melting point: 98-99 deg.C
1H NMR(400MHz,CDCl3)δ8.77(d,J＝4.8Hz,2H),8.16(d,J＝8.8Hz,1H),7.68(d,J＝1.9Hz,1H),7.34(dd,J＝8.8,2.0Hz,1H),7.14(t,J＝4.8Hz,1H),7.04(dd,J＝17.7,11.5Hz,1H),5.51(dd,J＝11.5,1.5Hz,1H),5.45(dd,J＝17.7,1.5Hz,1H),2.39(s,3H).
13C NMR(100MHz,CDCl3)δ160.84,158.63,157.93,137.26,133.61,131.80,131.46,128.38,126.61,124.33,121.62,121.12,120.77,118.29,111.61,51.67.
HRMS m/z:calcd for C15H13BrN3 +[M+H+]314.0287,found 314.0288.
Example 4
In this embodiment: r1Is chlorine; r2A methyl group; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-4(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: 72 percent.
Compound II-4 was tested:
melting point: 120 ℃ to 121 DEG C
1H NMR(400MHz,CDCl3)δ8.77(d,J＝4.8Hz,2H),8.21(d,J＝8.8Hz,1H),7.52(d,J＝2.0Hz,1H),7.21(dd,J＝8.8,2.1Hz,1H),7.14(t,J＝4.8Hz,1H),7.09–6.99(m,1H),5.51(dd,J＝11.5,1.6Hz,1H),5.45(dd,J＝17.7,1.6Hz,1H),2.39(s,3H).
13C NMR(100MHz,CDCl3)δ158.15,157.93,135.26,134.45,131.93,128.67,127.30,123.85,118.33,117.50,117.03,115.04,114.63,10.19.
HRMS m/z:calcd for C15H13ClN3 +[M+H+]270.0793,found 270.0797.
Example 5
In this embodiment: r1Is methoxy; r2Is methyl; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-5(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: and 63 percent.
Compound II-5 was tested:
melting point: 108 temperature 109 deg.C
1H NMR(400MHz,CDCl3)δ8.74(d,J＝4.8Hz,2H),8.24(d,J＝9.0Hz,1H),7.18–6.97(m,3H),6.91(dd,J＝9.0,2.6Hz,1H),5.54–5.39(m,2H),3.89(s,3H),2.41(s,3H).
13C NMR(100MHz,CDCl3)δ158.16,158.01,155.44,134.62,131.46,131.05,129.14,116.51,116.43,115.23,114.95,112.88,101.05,55.74,10.37.
HRMS m/z:calcd for C16H16N3O+[M+H+]266.1288,found 266.1288
Example 6
In this embodiment: r1Is cyano；R2Is methyl; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-6(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: 66 percent.
Compound II-6 was tested:
melting point: 173 ℃ and 174 DEG C
1H NMR(400MHz,CDCl3)δ8.83(d,J＝4.8Hz,2H),8.29(dd,J＝8.7,0.6Hz,1H),7.90(dd,J＝1.6,0.5Hz,1H),7.50(dd,J＝8.7,1.6Hz,1H),7.24(t,J＝4.8Hz,1H),7.02(dd,J＝17.7,11.6Hz,1H),5.56(dd,J＝11.6,1.5Hz,1H),5.50(dd,J＝17.7,1.5Hz,1H),2.44(s,3H).
13C NMR(100MHz,CDCl3)δ158.4,158.3,157.6,137.8,136.2,130.6,128.0,126.7,123.9,120.4,118.7,117.9,114.8,114.5,104.8,10.1.
HRMS m/z:calcd for C16H13N4 +[M+H+]261.1135,found 261.1138.
Example 7
In this embodiment: r1Is nitro; r2Is methyl; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-7(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), and the mixture was reacted at 90 ℃ C. and checked by TLC (thin layer chromatography) until the reaction was complete. IntoPost-treatment and purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a yellow solid, yield: 56 percent.
Compound II-7 was tested:
melting point: 109 ℃ and 110 DEG C
1H NMR(400MHz,CDCl3)δ8.85(d,J＝4.8Hz,2H),8.50(d,J＝2.2Hz,1H),8.28(d,J＝9.2Hz,1H),8.15(dd,J＝9.2,2.3Hz,1H),7.27(t,J＝4.8Hz,1H),7.02(dd,J＝17.8,11.6Hz,1H),5.58(dd,J＝11.6,1.4Hz,1H),5.53(dd,J＝17.7,1.4Hz,1H),2.48(s,3H).
13C NMR(100MHz,CDCl3)δ158.44,157.81,142.96,139.02,136.99,130.33,127.93,119.02,118.94,118.08,115.85,115.46,113.75,10.17.
HRMS m/z:calcd for C15H13N4O2 +[M+H+]281.1033,found 281.1039.
Example 8
In this embodiment: r1Is methyl; r2Is methyl; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-8(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: 71 percent.
Compound II-8 was tested:
melting point: 145- & ltSUB & gt 146- & lt/SUB & gt
1H NMR(400MHz,CDCl3)δ8.79(d,J＝4.8Hz,2H),8.10–8.01(m,1H),7.45(d,J＝8.0Hz,1H),7.11(t,J＝4.8Hz,1H),7.08–6.97(m,2H),5.46–5.37(m,2H),2.48(s,3H),2.42(s,3H).
13C NMR(101MHz,CDCl3)δ158.11,136.59,133.89,133.27,128.84,128.56,123.30,118.46,116.68,116.08,115.49,113.52,22.06,10.32.
HRMS m/z:calcd for C16H16N3 +[M+H+]250.1339,found 250.1346.
Example 9
In this embodiment: r1Is fluorine; r2Is methyl; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-9(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: 53 percent.
Compound II-9 was tested:
melting point: 126 ℃ and 127 DEG C
1H NMR(400MHz,CDCl3)δ8.77(d,J＝4.8Hz,2H),8.06(dd,J＝11.0,2.4Hz,1H),7.46(dd,J＝8.6,5.5Hz,1H),7.13(t,J＝4.8Hz,1H),7.09–6.95(m,2H),5.46(dd,J＝11.5,1.6Hz,1H),5.41(dd,J＝17.7,1.6Hz,1H),2.41(s,3H).
13C NMR(100MHz,CDCl3)δ162.2,159.8,158.2,158.1,136.4,136.2,134.4,134.4,128.9,127.2,119.4,119.3,117.0,116.54,115.3,110.2,109.9,101.3,101.0,10.3.
HRMS m/z:calcd for C15H13FN3 +[M+H+]254.1088,found 254.1090.
Example 10
In this embodiment: r1Is chlorine; r2Is methyl; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-10(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: and 64 percent.
Compound II-10 was tested:
melting point: 106 ℃ C. & 107 ℃ C. (Perkin Elmer)
1H NMR(400MHz,CDCl3)δ8.78(d,J＝4.8Hz,2H),8.33(d,J＝1.8Hz,1H),7.46(d,J＝8.4Hz,1H),7.20(dd,J＝8.4,1.8Hz,1H),7.14(t,J＝4.8Hz,1H),7.03(dd,J＝17.7,11.5Hz,1H),5.49(dd,J＝11.5,1.5Hz,1H),5.44(dd,J＝17.7,1.4Hz,1H),2.41(s,3H).
13C NMR(101MHz,CDCl3)δ158.18,157.87,136.39,134.59,129.64,129.24,128.66,122.27,119.51,117.11,117.08,115.11,113.99,10.21.
HRMS m/z:calcd for C15H13ClN3 +[M+H+]270.0793,found 270.0794.
Example 11
In this embodiment: r1Is bromine; r2Is methyl;R3is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-11(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: 61 percent.
Compound II-11 was tested:
melting point: 79-80 deg.C
1H NMR(400MHz,CDCl3)δ8.78(d,J＝4.8Hz,2H),8.48(d,J＝1.6Hz,1H),7.41(d,J＝8.3Hz,1H),7.33(dd,J＝8.3,1.7Hz,1H),7.13(t,J＝4.8Hz,1H),7.02(dd,J＝17.7,11.5Hz,1H),5.49(dd,J＝11.5,1.5Hz,1H),5.44(dd,J＝17.7,1.5Hz,1H),2.40(s,3H).
13C NMR(100MHz,CDCl3)δ158.17,157.80,136.68,134.49,129.54,128.61,124.89,119.88,117.45,117.21,117.10,116.82,115.09,10.17.
HRMS m/z:calcd for C15H13BrN3 +[M+H+]314.0287,found 314.0286.
Example 12
In this embodiment: r1Is hydrogen; r2Is ethyl; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-12(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooling the mixture to the room temperature,concentrating under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a yellow solid, yield: 65 percent.
Compound II-12 was tested:
1H NMR(400MHz,CDCl3)δ8.75(d,J＝4.8Hz,2H),8.30–8.22(m,1H),7.64–7.57(m,1H),7.31–7.19(m,2H),7.08(t,J＝4.8Hz,1H),7.04–6.94(m,1H),5.46–5.36(m,2H),2.91(q,J＝7.6Hz,2H),1.33(dd,J＝7.9,7.2Hz,3H).
13C NMR(101MHz,CDCl3)δ158.13,158.06,136.40,133.45,129.76,128.61,123.79,121.89,121.66,118.84,116.78,115.90,113.70,18.02,15.32.
HRMS m/z:calcd for C16H16N3 +[M+H+]250.1339,found 250.1346.
example 13
In this embodiment: r1Is hydrogen; r2Is butyl; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-13(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a yellow solid, yield: 38 percent.
Compound II-13 was tested:
melting point: 86-87 deg.C
1H NMR(400MHz,CDCl3)δ8.77(d,J＝4.8Hz,2H),8.24(d,J＝8.2Hz,1H),7.60(d,J＝7.7Hz,1H),7.24(dt,J＝20.1,7.1Hz,2H),7.11(t,J＝4.8Hz,1H),6.98(dd,J＝17.6,11.7Hz,1H),5.39(dd,J＝14.8,7.9Hz,2H),2.92–2.84(m,2H),1.70(dd,J＝15.5,8.1Hz,2H),1.48(dd,J＝14.9,7.4Hz,2H),0.97(t,J＝7.3Hz,3H).
13C NMR(100MHz,CDCl3)δ158.2,158.2,136.5,133.7,130.2,128.6,123.8,121.7,120.8,119.1,116.9,116.0,113.6,33.1,24.6,23.1,14.1.
HRMS m/z:calcd for C18H20N3 +[M+H+]278.1652,found 278.1659.
Example 14
In this embodiment: r1Is phenyl; r2Is isopropyl; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-14(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: 42 percent.
Compound II-14 was tested:
melting point: 78-79 deg.C
1H NMR(400MHz,CDCl3)δ8.78(d,J＝4.8Hz,2H),8.21(d,J＝8.2Hz,1H),7.80(d,J＝7.9Hz,1H),7.27–7.21(m,1H),7.20–7.16(m,1H),7.13(t,J＝4.8Hz,1H),6.98(dd,J＝17.7,11.4Hz,1H),5.42(dd,J＝11.4,1.7Hz,1H),5.25(dd,J＝17.7,1.7Hz,1H),3.56–3.45(m,1H),1.49(d,J＝7.1Hz,6H).
13C NMR(100MHz,CDCl3)δ158.2,158.1,137.0,133.0,128.7,128.4,125.5,123.4,121.2,120.8,117.5,117.0,113.6,26.1,22.7.
HRMS m/z:calcd for C17H18N3 +[M+H+]264.1495,found 264.1496.
Example 15
In this embodiment: r1Is hydrogen; r2Is allyl; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-15(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: 51 percent.
Compound II-15 was tested:
melting point: 85-86 deg.C
1H NMR(400MHz,CDCl3)δ8.78(d,J＝4.8Hz,2H),8.29(dd,J＝8.3,0.5Hz,1H),7.57(dd,J＝7.7,0.5Hz,1H),7.28(dd,J＝11.4,4.0Hz,1H),7.21(dd,J＝7.6,7.2Hz,1H),7.11(td,J＝4.8,0.6Hz,1H),7.02(dd,J＝17.7,11.5Hz,1H),6.16–6.01(m,1H),5.53–5.38(m,2H),5.15–5.03(m,2H),3.69–3.60(m,2H).
13C NMR(100MHz,CDCl3)δ158.10,136.76,136.27,134.82,130.04,128.51,123.88,121.80,119.13,116.87,116.79,116.68,115.45,113.80,29.29.
HRMS m/z:calcd for C17H16N3 +[M+H+]262.1339,found 262.1346.
Example 16
In this embodiment: r1Is hydrogen; r2Is an ester group; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-16(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: 59 percent.
Compound II-16 was tested:
melting point: 112 ℃ and 113 DEG C
1H NMR(400MHz,CDCl3)δ8.77(d,J＝4.8Hz,2H),8.31(d,J＝8.3Hz,1H),7.63(d,J＝7.8Hz,1H),7.34–7.26(m,6H),7.23(dd,J＝8.1,0.8Hz,1H),7.12(t,J＝4.8Hz,1H),7.04(dd,J＝17.7,11.5Hz,1H),5.64(dd,J＝17.7,1.5Hz,1H),5.48(dd,J＝11.5,1.5Hz,1H),5.15(s,2H),3.94(s,2H).
13C NMR(100MHz,CDCl3)δ171.41,158.08,157.99,136.32,136.02,135.86,129.68,128.45,128.42,128.10,128.09,124.08,122.10,119.18,118.03,117.05,114.02,111.64,66.65,31.57.
HRMS m/z:calcd for C23H20N3O2 +[M+H+]370.1550,found 370.1558.
Example 17
In this embodiment: r1Is hydrogen; r2Is a carboxyl group; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-17(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: 50 percent.
Compound II-17 was tested:
melting point: 102 ℃ to 103 DEG C
1H NMR(400MHz,CDCl3)δ8.77(d,J＝4.8Hz,2H),8.34(d,J＝8.4Hz,1H),7.39(d,J＝7.8Hz,1H),7.31–7.27(m,1H),7.27–7.20(m,1H),7.13(t,J＝4.8Hz,1H),7.04(dd,J＝17.8,11.7Hz,1H),5.70(dd,J＝17.8,1.6Hz,1H),5.46(dd,J＝11.7,1.6Hz,1H),2.41(s,3H).
13C NMR(101MHz,CDCl3)δ168.74,158.17,157.83,133.94,132.09,126.78,126.59,124.58,122.93,122.39,117.40,117.20,116.80,114.42,20.80.
HRMS m/z:calcd for C16H14N3O2 +[M+H+]280.1081,found 280.1088.
Example 18
In this embodiment: r1Is hydrogen, R2Is bromine; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-18(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: and 47 percent.
Compound II-18 was tested:
melting point: 73-74 deg.C
1H NMR(400MHz,CDCl3)δ8.82(d,J＝4.8Hz,2H),8.19–8.14(m,1H),7.65–7.57(m,1H),7.35–7.27(m,2H),7.20(t,J＝4.8Hz,1H),6.95(dd,J＝17.8,11.8Hz,1H),5.97(dd,J＝17.8,1.2Hz,1H),5.57(dd,J＝11.8,1.2Hz,1H).
13C NMR(100MHz,CDCl3)δ158.36,157.62,135.82,133.78,128.88,126.78,124.94,122.71,119.62,119.41,117.76,113.53,97.86.
HRMS m/z:calcd for C14H11BrN3 +[M+H+]300.0131,found 300.0136.
Example 19
In this embodiment: r1Is hydrogen, R2Is an aldehyde group; r3Is hydrogen.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-19(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: 42 percent.
Compound II-19 was tested:
melting point: 81-82 deg.C
1H NMR(400MHz,CDCl3)δ10.18(s,1H),8.87(d,J＝4.8Hz,2H),8.47(dd,J＝7.5,1.7Hz,1H),8.24–8.13(m,1H),7.41–7.34(m,2H),7.31(t,J＝4.9Hz,1H),7.28–7.22(m,1H),5.78(dd,J＝11.3,1.4Hz,1H),5.68(dd,J＝17.4,1.4Hz,1H).
13C NMR(100MHz,CDCl3)δ187.6,158.5,157.2,148.6,136.0,126.4,126.2,125.3,124.8,124.2,122.0,118.7,118.5,113.7.
HRMS m/z:calcd for C15H12N3O+[M+H+]250.0975,found 250.0972.
Example 20
In this embodiment: r1Is hydrogen, R2Is methyl, R3Is phenyl.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-20(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: 72 percent.
Compound II-20 test: r3
Melting point: 95-96 deg.C
1H NMR(400MHz,CDCl3)δ8.99(d,J＝2.4Hz,2H),8.37–8.28(m,1H),7.64–7.57(m,3H),7.56–7.51(m,2H),7.49–7.43(m,1H),7.31(ddd,J＝8.3,7.2,1.4Hz,1H),7.27–7.23(m,1H),7.11(dd,J＝17.7,11.6Hz,1H),5.57–5.42(m,2H),2.46(s,3H).
13C NMR(100MHz,CDCl3)δ157.2,156.0,136.2,134.1,134.0,130.7,129.6,129.4,128.9,128.6,126.6,123.9,121.8,118.8,116.8,115.5,113.8,29.7,10.3.
HRMS m/z:calcd for C21H18N3 +[M+H+]312.1495,found 312.1492.
Example 21
In this embodiment: r1Is hydrogen, R2Is methyl, R3Is bromine.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-21(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%) 1, 2-dichloroethane (2mL), the mixture was reacted at 90 ℃ and TLC (by thin layer chromatography) was checked to completion. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: and 47 percent.
Compound II-21 was tested:
melting point: 70-71 deg.C
1H NMR(400MHz,CDCl3)δ8.77(d,J＝4.8Hz,2H),8.26(dd,J＝8.6,0.6Hz,1H),7.61–7.51(m,1H),7.31–7.20(m,2H),7.05(dd,J＝18.2,12.1Hz,1H),5.50–5.39(m,2H),2.44(s,3H).
13C NMR(100MHz,CDCl3)δ158.2,158.1,136.2,133.9,130.7,128.8,123.9,121.7,118.8,116.8,116.7,115.4,113.7,10.3.
HRMS m/z:calcd for C15H13BrN3 +[M+H+]314.0287,found 314.0274.
Example 22
In this embodiment: r1Is hydrogen, R2Is methyl, R3Is methyl.
The method comprises the following steps: to a 35mL sealed tube with a branch, Compound I-22(0.2mmol), vinyltriethoxysilane (0.6mmol), Cu (OAc)2(0.4mmol)，AgF(0.4mmol)，[RhCp*Cl2]2(2 mol%), 1, 2-dichloroethane (2mL), the mixture was left at 90 deg.CThe reaction was checked by TLC (thin layer chromatography) until the reaction was complete. Carrying out post-treatment purification: cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 5:1, to give the pure product as a white solid, yield: 58 percent.
Compound II-22 was tested:
melting point: 60-61 deg.C
1H NMR(400MHz,CDCl3)δ8.60(s,2H),8.14(d,J＝7.9Hz,1H),7.57(d,J＝7.6Hz,1H),7.29–7.18(m,2H),7.01(dd,J＝17.6,11.6Hz,1H),5.51–5.37(m,2H),2.44(s,3H),2.33(s,3H).
13C NMR(100MHz,CDCl3)δ158.2,156.3,136.3,133.7,130.4,128.5,126.2,123.7,121.4,118.7,116.7,114.8,113.1,15.1,10.2.
HRMS m/z:calcd for C16H16N3 +[M+H+]250.1339,found 250.1345.
Finally, it should also be noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including preferred embodiments and all such alterations and modifications as fall within the scope of the invention.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
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