CN117430542B - Synthesis method of trifluoromethyl indole derivative - Google Patents
Synthesis method of trifluoromethyl indole derivative Download PDFInfo
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- CN117430542B CN117430542B CN202311763062.3A CN202311763062A CN117430542B CN 117430542 B CN117430542 B CN 117430542B CN 202311763062 A CN202311763062 A CN 202311763062A CN 117430542 B CN117430542 B CN 117430542B
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- QFHVHZJGQWMBTE-UHFFFAOYSA-N 2-(trifluoromethyl)-1h-indole Chemical class C1=CC=C2NC(C(F)(F)F)=CC2=C1 QFHVHZJGQWMBTE-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000001308 synthesis method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- RJCQBQGAPKAMLL-UHFFFAOYSA-N bromotrifluoromethane Chemical compound FC(F)(F)Br RJCQBQGAPKAMLL-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 19
- 150000002475 indoles Chemical class 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 239000011941 photocatalyst Substances 0.000 claims abstract description 11
- 229940054051 antipsychotic indole derivative Drugs 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- VPCXVCNTHAMRBT-UHFFFAOYSA-N 3,5-difluoro-2,4,6-tris(n-phenylanilino)benzonitrile Chemical compound FC1=C(N(C=2C=CC=CC=2)C=2C=CC=CC=2)C(C#N)=C(N(C=2C=CC=CC=2)C=2C=CC=CC=2)C(F)=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 VPCXVCNTHAMRBT-UHFFFAOYSA-N 0.000 claims description 13
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 claims description 3
- 239000012973 diazabicyclooctane Substances 0.000 claims description 3
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical group C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 3
- -1 9-carbazolyl Chemical group 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229920006391 phthalonitrile polymer Polymers 0.000 claims 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 16
- 238000003786 synthesis reaction Methods 0.000 abstract description 14
- 230000015572 biosynthetic process Effects 0.000 abstract description 13
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 9
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract description 7
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 150000002894 organic compounds Chemical class 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 238000005481 NMR spectroscopy Methods 0.000 description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- 238000001228 spectrum Methods 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- ZFRKQXVRDFCRJG-UHFFFAOYSA-N skatole Chemical compound C1=CC=C2C(C)=CNC2=C1 ZFRKQXVRDFCRJG-UHFFFAOYSA-N 0.000 description 18
- ZQTPBODDVRYHSY-UHFFFAOYSA-N 3-methyl-2-(trifluoromethyl)-1h-indole Chemical compound C1=CC=C2C(C)=C(C(F)(F)F)NC2=C1 ZQTPBODDVRYHSY-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 239000007789 gas Substances 0.000 description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- 239000007795 chemical reaction product Substances 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 229910052731 fluorine Inorganic materials 0.000 description 12
- 239000011737 fluorine Substances 0.000 description 12
- 238000004896 high resolution mass spectrometry Methods 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 11
- 238000010791 quenching Methods 0.000 description 11
- 238000001819 mass spectrum Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- IBMIOOCKERJDCH-UHFFFAOYSA-N 1,3-dimethyl-2-(trifluoromethyl)indole Chemical compound C1=CC=C2C(C)=C(C(F)(F)F)N(C)C2=C1 IBMIOOCKERJDCH-UHFFFAOYSA-N 0.000 description 8
- CLSZROKTPWVQKB-UHFFFAOYSA-N 3-(trifluoromethyl)-1h-indole Chemical compound C1=CC=C2C(C(F)(F)F)=CNC2=C1 CLSZROKTPWVQKB-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- MUFUPZFOJVRDNP-UHFFFAOYSA-N 2-(trifluoromethyl)-1h-indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=C(C(F)(F)F)NC2=C1 MUFUPZFOJVRDNP-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 5
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000006692 trifluoromethylation reaction Methods 0.000 description 3
- NAPPMSNSLWACIV-UHFFFAOYSA-N 1,3-dimethylindole Chemical compound C1=CC=C2C(C)=CN(C)C2=C1 NAPPMSNSLWACIV-UHFFFAOYSA-N 0.000 description 2
- PRWATGACIORDEL-UHFFFAOYSA-N 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile Chemical compound C12=CC=CC=C2C2=CC=CC=C2N1C1=C(C#N)C(N2C3=CC=CC=C3C3=CC=CC=C32)=C(N2C3=CC=CC=C3C3=CC=CC=C32)C(N2C3=CC=CC=C3C3=CC=CC=C32)=C1C#N PRWATGACIORDEL-UHFFFAOYSA-N 0.000 description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- WHOOUMGHGSPMGR-UHFFFAOYSA-N indol-3-ylacetaldehyde Chemical compound C1=CC=C2C(CC=O)=CNC2=C1 WHOOUMGHGSPMGR-UHFFFAOYSA-N 0.000 description 2
- SEOVTRFCIGRIMH-UHFFFAOYSA-N indole-3-acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CNC2=C1 SEOVTRFCIGRIMH-UHFFFAOYSA-N 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000007342 radical addition reaction Methods 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 description 1
- 229960004569 indapamide Drugs 0.000 description 1
- 239000003617 indole-3-acetic acid Substances 0.000 description 1
- IVYPNXXAYMYVSP-UHFFFAOYSA-N indole-3-methanol Chemical compound C1=CC=C2C(CO)=CNC2=C1 IVYPNXXAYMYVSP-UHFFFAOYSA-N 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000003507 refrigerant Substances 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VPAYJEUHKVESSD-UHFFFAOYSA-N trifluoroiodomethane Chemical compound FC(F)(F)I VPAYJEUHKVESSD-UHFFFAOYSA-N 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B61/00—Other general methods
- C07B61/02—Generation of organic free radicals; Organic free radicals per se
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The invention discloses a synthesis method of trifluoromethyl indole derivatives, and relates to the technical field of organic compound synthesis. The synthesis method comprises the following steps: adding indole derivatives, a photocatalyst, alkali and an organic solvent into a reaction vessel, then introducing trifluorobromomethane gas, and reacting at room temperature under normal pressure under irradiation of visible light to obtain the trifluoromethyl indole derivatives. The synthesis method provides a new method for the trifluoromethyl of indole, has the advantages of low cost and availability of raw materials and reagents, low cost, high atom economy, simple and convenient operation, low reaction condition temperature, little environmental pollution and stable product quality, and completely meets the modern industrial production.
Description
Technical Field
The invention relates to the technical field of synthesis of organic compounds, in particular to a synthesis method of trifluoromethyl indole derivatives.
Background
Most of the indole compounds have biological activity and are widely used in medicine, food additives and other fields. For example, indomethacin, an indoleacetic acid drug, is a non-steroidal anti-inflammatory drug with anti-inflammatory, antipyretic and analgesic effects. The cyclomycin and the chlorpheniramine can inhibit appetite and reduce weight, and are good weight-losing medicines. Indapamide is an antihypertensive agent. Indole-3-methanol is an anti-uterine cancer drug. Indole-3-acetaldehyde also has certain anticancer effect. Thus, the synthesis of the indole ring is of great interest.
Trifluoromethyl is introduced into organic molecules due to its unique electronic effect, and can significantly improve the lipophilicity, lipophilicity and metabolic stability of parent compounds, so that trifluoromethyl is widely applied to the fields of medicines, pesticides, materials and the like. Therefore, it is of great importance to study trifluoromethyl indole derivatives having potential physiological activities.
In the existing researches, the synthesis of the trifluoromethyl indole derivative has the defects of high reaction temperature, high raw material cost, complex preparation process, poor atom economy, unstable products and the like. For example:
in 2015, a direct C-H trifluoromethylation of aromatic hydrocarbons mediated with Umemoto's reagent was reported in the cloud-keeping group (chem. Eur. J. 2015, 21, 8355.). The reaction is carried out by forming an electron donor-acceptor (EDA) complex with indole derivatives by Umemoto's reagent, the reaction process is as follows. However, the Umemoto's reagent preparation process is very cumbersome and expensive. On the other hand, the use of Umemoto's reagent discards a relatively large group, resulting in poor atomic economy;
。
in 2019, the Jiang Guofang group of subjects (RSC adv., 2019, 9, 35098) reported a CF under metal-free catalytic conditions 3 SO 2 The Na is used as a trifluoromethyl source to synthesize the trifluoromethyl indole derivative, and the reaction process is shown as follows. According to the method, tert-butyl peroxide is used for oxidizing and selectively introducing trifluoromethyl into the C2 position of indole, and although trifluoromethyl indole derivatives can be successfully obtained, the method is complex in operation steps and needs to be carried out at high temperature;
。
the Zhang Lei group of subjects (Tetrahedron letters, 2023, 118, 154385.) reported that a series of trifluoromethylindoles were obtained rapidly by direct trifluoromethylation in methanol solvent under argon atmosphere using a tagni reagent as the trifluoromethylating reagent at 50 ℃. However, the atom utilization rate of the reagent using togni's is low and the price is relatively high;
。
it can be seen that although various methods for synthesizing trifluoromethyl-containing indole derivatives have been reported, these trifluoromethyl sources generally have the disadvantages of complicated preparation process, high price, difficult industrialization and low atom utilization. Therefore, the research on the synthesis method of the trifluoromethyl indole derivative has the advantages of simple synthesis method, mild reaction conditions, low raw material cost and stable product yield.
Disclosure of Invention
In order to overcome the defects of the existing trifluoromethyl indole derivative synthesis method, the invention provides a trifluoromethyl indole derivative synthesis method, which adopts trifluoromethyl bromide with easy industrial acquisition and high atom economy as a trifluoromethyl source, and the trifluoromethyl indole derivative is obtained through free radical addition reaction with the indole derivative under the catalysis of visible light.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a process for synthesizing trifluoromethyl indole derivative includes such steps as adding indole derivative, photocatalyst, alkali and organic solvent to reactor, introducing trifluorobromomethane gas, and reacting at ordinary temp and pressure under irradiation of visible light.
Preferably, the molar ratio of the indole derivative, the trifluorobromomethane, the photocatalyst and the alkali is (0.5-5): 1-10): 0.005-0.12): 0.5-5.
Preferably, the organic solvent is used in an amount such that the reactants are completely dissolved.
Preferably, the indole derivative has the structural formula:
;
the reaction route of the synthesis method of the trifluoromethyl indole derivative can be expressed by the following reaction formula:
wherein R is 1 Comprising the following steps: h or CH 3 ;R 2 Comprising the following steps: H. CH (CH) 3 Or CHO.
Preferably, the photocatalyst comprises any one of [ Ir (dtbbpy) (ppy) ] PF6, organic dye photocatalyst 2,4, 6-tris (diphenylamino) -3, 5-difluorobenzonitrile (3 DPA2 FBN) and 2,4,5, 6-tetrakis (9-carbazolyl) -isophthalonitrile (4 CzIPN); preferably 3DPA2FBN.
Preferably, the base comprises an inorganic base NaHCO 3 、NaHCO 3 、Na 2 CO 3 、K 2 CO 3 And any one of organic bases DABCO; preferably K 2 CO 3 。
Preferably, the organic solvent comprises CH 2 Cl 2 、DCE、THF、CHCl 3 、CH 3 CN, DMF, meOH, DMSO and 1, 4-dioxane.
Preferably, the light source of visible light includes any one of 3W blue LED, 5W blue LED, 10W blue LED,15W blue LED, 20W blue LED, 30W blue LED, 5W white LED and 5W blue LED.
Preferably, the room temperature is 20-30 ℃.
Preferably, the reaction time is 18h-24h.
Compared with the prior art, the invention selects the trifluorobromomethane as a trifluoromethyl source, and obtains the trifluoromethyl indole derivative through free radical addition under the action of a specific photocatalyst and alkali by visible light catalysis, thereby providing a novel method for the trifluoromethyl of indole. BrCF 3 As a nontoxic and odorless industrial productThe product has the characteristics of low cost and easy obtainment. The trifluoromethyl indole derivative can be synthesized under mild reaction conditions by taking the trifluoromethyl bromide with low cost, easy availability and high atom economy as a trifluoromethyl source, the obtained product has high yield, and the trifluoromethyl indole derivative is easy to separate and purify, does not involve expensive or dangerous (toxic or explosive) reagents, has simple preparation process, and can be safely and efficiently synthesized. Meanwhile, the selection of the raw materials and the synthesis conditions can effectively avoid side reactions, improve the purity of the product, cause little environmental pollution, and the obtained product has stable quality and high economic benefit and can meet the modern industrial production.
In addition, those skilled in the art know that carbon-bromine bonds in the trifluorobromomethane used in the present application are relatively stable, are not easily broken, have a high reaction difficulty, and increase the production of byproducts to some extent, which is why the use of trifluorobromomethane as a trifluoromethyl source is not available in the prior art. The method solves the technical problem of using the trifluorobromomethane as a trifluoromethyl source through the selection of raw materials and the use of a specific photocatalyst and alkali, promotes the synthesis reaction of indole derivatives and the trifluorobromomethane, and ensures that the product reaches stable yield; furthermore, the trifluoromethyl source CF used in the present invention 3 Br is industrially used as a refrigerant and a fire extinguishing agent, so that it is industrially mass, easily available and inexpensive, and therefore the trifluoromethylation process of the present invention has an industrial prospect.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of 2-trifluoromethyl-3-methyl-1H-indole synthesized in example 1 of the present invention;
FIG. 2 is a nuclear magnetic carbon spectrum of 2-trifluoromethyl-3-methyl-1H-indole synthesized in example 1 of the present invention;
FIG. 3 is a nuclear magnetic resonance fluorine spectrum of 2-trifluoromethyl-3-methyl-1H-indole synthesized in example 1 of the present invention;
FIG. 4 is a mass spectrum of 2-trifluoromethyl-3-methyl-1H-indole synthesized in example 1 of the present invention;
FIG. 5 is a nuclear magnetic resonance spectrum of N-methyl-2-trifluoromethyl-3-methylindole synthesized in example 2 of the invention;
FIG. 6 is a nuclear magnetic carbon spectrum of N-methyl-2-trifluoromethyl-3-methylindole synthesized in example 2 of the invention;
FIG. 7 is a nuclear magnetic resonance fluorine spectrum of N-methyl-2-trifluoromethyl-3-methylindole synthesized in example 2 of the present invention;
FIG. 8 is a mass spectrum of N-methyl-2-trifluoromethyl-3-methylindole synthesized in example 2 of the invention;
FIG. 9 is a nuclear magnetic resonance spectrum of 2-trifluoromethyl-1H-indole synthesized in example 3 of the present invention;
FIG. 10 is a nuclear magnetic carbon spectrum of 2-trifluoromethyl-1H-indole synthesized in example 3 of the present invention;
FIG. 11 is a nuclear magnetic resonance fluorine spectrum of 2-trifluoromethyl-1H-indole synthesized in example 3 of the present invention;
FIG. 12 is a nuclear magnetic resonance spectrum of 3-trifluoromethyl-1H-indole synthesized in example 3 of the present invention;
FIG. 13 is a nuclear magnetic carbon spectrum of 3-trifluoromethyl-1H-indole synthesized in example 3 of the present invention;
FIG. 14 is a nuclear magnetic resonance fluorine spectrum of 3-trifluoromethyl-1H-indole synthesized in example 3 of the present invention;
FIG. 15 is a mass spectrum of 2-trifluoromethyl-1H-indole and 3-trifluoromethyl-1H-indole synthesized in example 3 of the present invention;
FIG. 16 is a nuclear magnetic resonance spectrum of 2- (trifluoromethyl) -1H-indole-3-carbaldehyde synthesized in example 4 of this invention;
FIG. 17 is a nuclear magnetic resonance spectrum of 2- (trifluoromethyl) -1H-indole-3-carbaldehyde synthesized in example 4 of this invention;
FIG. 18 is a nuclear magnetic resonance spectrum of 2- (trifluoromethyl) -1H-indole-3-carbaldehyde synthesized in example 4 of this invention;
FIG. 19 is a mass spectrum of 2- (trifluoromethyl) -1H-indole-3-carbaldehyde synthesized in example 4 of this invention.
Detailed Description
The following describes in further detail the embodiments of the present invention with reference to the drawings and examples. The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
Example 1
Synthesis of 2-trifluoromethyl-3-methyl-1H-indole
The synthesis process is shown as the following formula:
,
(1) 3-methyl-1H-indole (0.039 g,0.3mmol,1 equiv.), [ Ir (dtbbpy) (ppy) 2 ]PF 6 (0.0030 g,0.003mmol,0.01 equiv.) and sodium bicarbonate (0.025 g,0.3mmol,1.0 equiv.) were weighed into a reaction flask, 3mL of dimethyl sulfoxide solvent was added, 0.9mmol of trifluorobromomethane gas was charged, and the reaction was allowed to proceed at 25℃under a 20W blue LED lamp for 18 hours, monitored by TLC (PE: EA=5:1), and 5mL of water was added to quench the reaction.
The resulting reaction product, aqueous phase was extracted with ethyl acetate (5 mL extracted 3 times), the organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate=5:1 v/v) to give 0.034g of 2-trifluoromethyl-3-methyl-1H-indole as a yellow solid in 58% yield.
(2) 3-methyl-1H-indole (0.039 g,0.3mmol,1 equiv.), 4CzIPN (0.0024 g,0.003mmol,0.01 equiv.), sodium bicarbonate (0.025 g,0.3mmol,1 equiv.) are weighed into a reaction flask, 3mL of dimethyl sulfoxide solvent is added, 0.9mmol of trifluorobromomethane gas is charged, and the reaction is carried out at 25℃under a 15W blue LED lamp for 12 hours, TLC monitoring reaction (PE: EA=5:1), and 5mL of water is added to quench the reaction.
The resulting reaction product, aqueous phase was extracted with ethyl acetate (5 mL extracted 3 times), the organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate=5:1 v/v) to give 0.037g of 2-trifluoromethyl-3-methyl-1H-indole as a yellow solid in 62% yield.
(3) 3-methyl-1H-indole (0.039 g,0.3mmol,1 equiv.), 2,4, 6-tris (diphenylamino) -3, 5-difluorobenzonitrile (0.0019 g,0.003mmol,0.01equiv. CAS. No. 1403850-00-9), sodium bicarbonate (0.025 g,0.3mmol,1 equiv.) were weighed into a reaction flask, 3mL of dimethyl sulfoxide solvent was added, 0.9mmol of trifluorobromomethane gas was charged, and reacted under a 15W blue LED lamp at 25℃for 24 hours, TLC monitored (PE: EA=5:1), and 5mL of water quench reaction was added.
The resulting reaction product, aqueous phase was extracted with ethyl acetate (5 mL extracted 3 times), the organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate=5:1 v/v) to give 0.042g of 2-trifluoromethyl-3-methyl-1H-indole as a yellow solid in 72% yield.
(4) 3-methyl-1H-indole (0.039 g,0.3mmol,1 equiv.), 2,4, 6-tris (diphenylamino) -3, 5-difluorobenzonitrile (0.0019 g,0.003mmol,0.01 equiv.), potassium bicarbonate (0.030 g,0.3mmol,1.0 equiv.) are weighed into a reaction flask, 3mL of dimethyl sulfoxide solvent, charged with 0.9mmol of trifluorobromomethane gas, reacted at 25℃under a 15W blue LED lamp for 24 hours, TLC monitored reaction (PE: EA=5:1), and 5mL of water quench reaction were added.
The resulting reaction product, aqueous phase was extracted with ethyl acetate (5 mL extracted 3 times), the organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate=5:1 v/v) to give 0.029g of 2-trifluoromethyl-3-methyl-1H-indole as a yellow solid in 49% yield.
(5) 3-methyl-1H-indole (0.039 g,0.3mmol,1 equiv.), 2,4, 6-tris (diphenylamino) -3, 5-difluorobenzonitrile (0.0019 g,0.003mmol,0.01 equiv.), sodium carbonate (0.032 g,0.3mmol,1 equiv.) are weighed into a reaction flask, 3mL of dimethyl sulfoxide solvent, charged with 0.9mmol of trifluorobromomethane gas, reacted at 25℃under a 15W blue LED lamp for 24 hours, TLC monitored reaction (PE: EA=5:1), and 5mL water quench reaction.
The resulting reaction product, aqueous phase was extracted with ethyl acetate (5 mL extracted 3 times), the organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate=5:1 v/v) to give 0.033g of 2-trifluoromethyl-3-methyl-1H-indole as a yellow solid in 55% yield.
(6) 3-methyl-1H-indole (0.039 g,0.3mmol,1 equiv.), 2,4, 6-tris (diphenylamino) -3, 5-difluorobenzonitrile (0.0019 g,0.003mmol,0.01 equiv.), DABCO (0.0447 g,0.3mmol,1 equiv.) were weighed into a reaction flask, 3mL of dimethyl sulfoxide solvent, charged with 0.9mmol of trifluorobromomethane gas, reacted at 25℃under a 15W blue LED lamp for 24 hours, TLC monitored reaction (PE: EA=5:1), and 5mL of water quench reaction were added.
The resulting reaction product, aqueous phase was extracted with ethyl acetate (5 mL extracted 3 times), the organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate=5:1 v/v) to give 0.039g of 2-trifluoromethyl-3-methyl-1H-indole as a yellow solid in 67% yield.
(7) 3-methyl-1H-indole (0.039 g,0.3mmol,1 equiv.), 2,4, 6-tris (diphenylamino) -3, 5-difluorobenzonitrile (0.0019 g,0.003mmol,0.01 equiv.), potassium carbonate (0.025 g,0.3mmol,1.0 equiv.) are weighed into a reaction flask, 3mL of dimethyl sulfoxide solvent, charged with 0.9mmol of trifluorobromomethane gas, reacted at 25℃under a 15W blue LED lamp for 24 hours, and TLC monitoring reaction (PE: EA=5:1) was added to 5mL of water quench reaction.
The resulting reaction product, aqueous phase was extracted with ethyl acetate, the organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate=5:1 v/v) to give 0.045g of 2-trifluoromethyl-3-methyl-1H-indole as a yellow solid in 75% yield.
Comparative example 1
3-methyl-1H-indole (0.039 g,0.3mmol,1 equiv.) fac-Ir (PPy) 3 (0.0020 g,0.003mmol,0.01 equiv.) and sodium bicarbonate (0.025 g,0.3mmol,1 equiv.) are weighed into a reaction flask, 3mL of dimethyl sulfoxide solvent is added, 0.9mmol of trifluorobromomethane gas is charged, and the reaction is carried out at 25℃under a 15W blue LED lamp for 24 hours, TLC monitors the reaction (PE: EA=5:1), and 5mL of water is added to quench the reaction.
The resulting reaction product, the aqueous phase of which was extracted with ethyl acetate (5 mL extracted 3 times), was separated and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate=5:1 v/v) to give 0.015g of 2-trifluoromethyl-3-methyl-1H-indole as a yellow solid in 25% yield.
The products obtained in (1) - (7) of the above example 1 and comparative example 1 were subjected to nuclear magnetic resonance hydrogen spectroscopy 1 H-NMR and nuclear magnetic resonance carbon spectrum 13 C-NMR and nuclear magnetic resonance fluorine spectrum 19 F-NMR) and High Resolution Mass Spectrometry (HRMS) to determine the structural formula. The nuclear magnetic resonance spectrum and the high resolution mass spectrum are shown in figures 1-4, 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (s, 1H), 7.64 (d,J= 8.4 Hz, 1H), 7.38 (d,J= 8.4 Hz, 1H), 7.32 (t,J= 7.2 Hz, 1H), 7.19 (t,J= 8.0 Hz, 1H), 2.44 (q, J = 1.6 Hz, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 135.2, 138.0, 124.7, 122.1 (q,J C-F = 266.8 Hz), 121.5 (q,J C-F = 36.5 Hz), 120.4, 120.1, 114.1 (q,J C-F = 3.0 Hz), 111.5, 8.2; 19 F NMR (376 MHz, CDCl 3 ): δ –58.65; HRMS (ESI) m/z: ([M+H] + ) Calcd for C 10 H 9 NF 3 200.0682, found 200.0682. According to FIGS. 1-4 (FIGS. 1-4 in sequence are 2-trifluoromethyl-3-methyl-)1H-nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum, nuclear magnetic fluorine spectrum and mass spectrum) of indole, it can be confirmed that the products (1) to (7) in example 1 and comparative example 1 are 2-trifluoromethyl-3-methyl-1H-indoles.
Example 2
Synthesis of N-methyl-2-trifluoromethyl-3-methylindole
The synthesis process is shown as the following formula:
n-methyl-3-methylindole (0.3 mmol), 2,4, 6-tris (diphenylamino) -3, 5-difluorobenzonitrile (0.003 mmol) and potassium carbonate (0.3 mmol) were weighed into a reaction flask, 3mL of dimethyl sulfoxide solvent was added, 0.9mmol of trifluorobromomethane gas was charged, and the reaction was carried out at 25℃under a 15W blue LED lamp for 24 hours, and the reaction was monitored by TLC (PE: EA=5:1) and quenched by 5mL of water.
The resulting reaction product, aqueous phase was extracted with ethyl acetate (5 mL extracted 3 times), the organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate=10:1v/v) to give 0.052g of N-methyl-2-trifluoromethyl-3-methylindole as a yellow solid in 82% yield.
Performing nuclear magnetic resonance hydrogen spectrum on the obtained product 1 H-NMR and nuclear magnetic resonance carbon spectrum 13 C-NMR and nuclear magnetic resonance fluorine spectrum 19 F-NMR) and High Resolution Mass Spectrometry (HRMS) to determine the structural formula. The nuclear magnetic resonance spectrum and the high resolution mass spectrum are shown in figures 5-8, 1 H NMR (400 MHz, CDCl 3 ) 7.62 (d,J= 8.0 Hz, 1H), 7.35-7.28 (m, 1H), 7.15 (t,J= 6.8 Hz, 1H), 3.76 (s, 3H), 2.44 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 137.7, 127.0, 124.4, 122.7 (q,J C-F = 268.5 Hz), 122.6 (q,J C-F = 34.5 Hz), 120.2, 119.8, 114.2 (q,J C-F = 3.0 Hz), 109.5, 8.2, 30.8 (q,J C-F = 1.5 Hz), 8.8 (q,J C-F = 1.5 Hz); 19 F NMR (376 MHz, CDCl 3 ): δ –55.92; HRMS (ESI) m/z: ([M+H] + ) Calcd for C 11 H 11 NF 3 214.0838, found 214.0838. According to FIGS. 5-8 (FIGS. 5-8 in sequenceN-nuclear magnetic resonance spectroscopy, and mass spectrometry of the nuclear magnetic resonance spectroscopy of methyl-2-trifluoromethyl-3-methylindole), the obtained product was determined to be N-methyl-2-trifluoromethyl-3-methylindole, and the calculated yield was 82%.
Comparative example 2
N-methyl-3-methylindole (0.3 mmol), 2,4, 6-tris (diphenylamino) -3, 5-difluorobenzonitrile (0.003 mmol) and potassium carbonate (0.3 mmol) were weighed into a reaction flask, 3mL of dimethyl sulfoxide solvent was added, 0.9mmol of trifluoroiodomethane was added, and the reaction was monitored by TLC under a 15W blue LED lamp at 25℃for 24 hours (PE: EA=5:1), and 5mL of water was added to quench the reaction.
The resulting reaction product, aqueous phase was extracted with ethyl acetate (5 mL extracted 3 times), the organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate=10:1v/v) to give 0.018g of N-methyl-2-trifluoromethyl-3-methylindole as a yellow solid in 27% yield.
Example 3
Synthesis of 2-trifluoromethyl-1H-indole and 3-trifluoromethyl-1H-indole
The synthesis process is shown as the following formula:
1H-indole (0.3 mmol), 2,4, 6-tris (diphenylamino) -3, 5-difluorobenzonitrile (0.003 mmol) and potassium carbonate (0.3 mmol) were weighed into a reaction flask, 3mL of dimethyl sulfoxide solvent was added, 0.9mmol of trifluorobromomethane gas was charged, and the reaction was carried out at 25℃under a 15W blue LED lamp for 24 hours, monitored by TLC (PE: EA=5:1), and 5mL of water was added for quenching.
The resulting reaction product, aqueous phase was extracted with ethyl acetate (5 mL extracted 3 times), the organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate=5:1 v/v) to give 0.031g of 2-trifluoromethyl-1H-indole as a yellow solid and 0.015g of 3-trifluoromethyl-1H-indole as a yellow oily liquid in yields of 56% and 27%, respectively.
Performing nuclear magnetic resonance hydrogen spectrum on the obtained compound 1 H-NMR and nuclear magnetic resonance carbon spectrum 13 C-NMR and nuclear magnetic resonance fluorine spectrum 19 F-NMR) and High Resolution Mass Spectrometry (HRMS) to determine the structural formula. Nuclear magnetic resonance spectrum and heightThe resolution mass spectrum is shown in figures 9-15, 2-trifluoromethyl-1H-indole: 1 H NMR (400 MHz, CDCl 3 ) 8.35 (s, 1H), 7.69 (d,J= 8.4 Hz, 1H), 7.43 (d,J= 8.4 Hz, 1H), 7.33 (t,J= 8.0 Hz, 1H), 7.20 (t,J= 8.0 Hz, 1H), 6.93 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ 136.1, 126.0, 125.7 (q,J C-F = 38.9 Hz), 124.8, 122.1, 121.2 (q,J C-F = 266.2 Hz), 121.2, 120.2, 111.7, 104.3 (q,J C-F = 3.5 Hz); 19 F NMR (376 MHz, CDCl 3 ) Delta-60.56, 3-trifluoromethyl-1H-indole: 1 H NMR (400 MHz, CDCl 3 ) 8.35 (s, 1H), 7.77 (d,J= 7.6 Hz, 1H), 7.54 (s, 1H), 7.43 (d,J= 8.0 Hz, 1H), 7.32-7.23 (m, 2H); 13 C NMR (150 MHz, CDCl 3 ) δ 135.8, 125.1, 124.2 (q,J C-F = 6.0 Hz), 123.7 (q,J C-F = 39.0 Hz), 123.5, 123.3, 122.0 (q,J C-F = 249.0 Hz), 121.5, 119.5; 19 F NMR (376 MHz, CDCl 3 ): δ –57.43; HRMS (ESI) m/z: ([M+H] + ) Calcd for C 9 H 7 NF 3 186.0525, found 186.0525. According to FIGS. 9-15 (FIGS. 9-11, in order, 2-trifluoromethyl-1HThe nuclear magnetic hydrogen, nuclear magnetic carbon and nuclear magnetic fluorine spectra of indole are shown in FIGS. 12-14 as 3-trifluoromethyl-1HNuclear magnetic hydrogen, nuclear magnetic carbon and nuclear magnetic fluorine spectra of indole, FIG. 15 is 2-trifluoromethyl-1HMass spectrometry of indole and 3-trifluoromethylindole) to determine that the obtained product is 2-trifluoromethyl-1HIndole and 3-trifluoromethyl-)1HIndole, calculated yields were 56% and 27%, respectively.
Example 4
Synthesis of 2- (trifluoromethyl) -1H-indole-3-carbaldehyde
The synthesis process is shown as the following formula:
1H-indole-3-carbaldehyde (0.3 mmol), 2,4, 6-tris (diphenylamino) -3, 5-difluorobenzonitrile (0.003 mmol) and potassium carbonate (0.3 mmol) were weighed into a reaction flask, 3mL of dimethyl sulfoxide solvent was added, 0.9mmol of trifluorobromomethane gas was charged, and the reaction was allowed to react at 25℃under a 15W blue LED lamp for 24 hours, followed by TLC monitoring (PE: EA=5:1) and 5mL of water was added to quench the reaction.
The resulting reaction product, aqueous phase was extracted with ethyl acetate (5 mL extracted 3 times), the organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate=3:1v/v) to give 0.027g of 2- (trifluoromethyl) -1H-indole-3-carbaldehyde as a yellow solid in 41% yield.
Performing nuclear magnetic resonance hydrogen spectrum on the obtained product 1 H-NMR and nuclear magnetic resonance carbon spectrum 13 C-NMR and nuclear magnetic resonance fluorine spectrum 19 F-NMR) and High Resolution Mass Spectrometry (HRMS) to determine the structural formula. The nuclear magnetic resonance spectrum and the high resolution mass spectrum are shown in figures 16-19, 1 H NMR (400 MHz, CDCl 3 ) 10.10 (s, 1H), 9.25 (s, 1H), 8.53 (d,J= 8.0 Hz, 1H), 7.95 (d,J= 2.8 Hz, 1H), 7.59 (d,J= 7.2 Hz, 1H), 7.40 (t,J= 7.6 Hz, 1H); 13 C NMR (150 MHz, CDCl 3 ) δ 185.1, 136.1, 132.2 (q,J C-F = 1.5 Hz), 126.1, 125.8, 124.5 (q,J C-F = 268.5 Hz), 122.6, 121.8 (q,J C-F = 4.5 Hz), 119.6, 114.0; 19 F NMR (376 MHz, CDCl 3 ): δ –55.52; HRMS (ESI) m/z: ([M+H] + ) Calcd for C 10 H 7 NOF 3 214.0474, found 214.0474. According to FIGS. 16-19 (FIGS. 16-19, in order, 2- (trifluoromethyl) scheme-1H-nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum, nuclear magnetic fluorine spectrum and mass spectrum) of indole-3-carbaldehyde, and can be confirmed that the obtained product is 2- (trifluoromethyl) room-temperature heat-resistant polymer1H-indole-3-carbaldehyde in a calculated yield of 41%.
Comparative example 3
3-methyl-1H-indole (0.039 g,0.3mmol,1 equiv.), ruthenium terpyridyl chloride Ru (bpy) 3 Cl 2 (0.0062 g,0.003mmol,0.01 equiv.), N, N, N ', N' -tetramethyl ethylenediamine TMEDA (0.035 g,0.3mmol,1.0 equiv.) was weighed into a reaction flask, 3mL acetonitrile solvent was added, 0.9mmol of trifluorobromomethane gas was charged, and the reaction was allowed to proceed under a 24W blue LED lamp at 25deg.C for 24 hours, and TLC monitored reaction (PE: EA=5:1) reaction was not allowed to proceed.
Comparative example 4
The same points as comparative example 3 are not repeated, except that the reaction is performed under a 15W blue LED lamp for 24 hours, and the TLC monitoring reaction (PE: ea=5:1) reaction does not occur.
Claims (6)
1. A synthesis method of trifluoromethyl indole derivatives is characterized in that: adding indole derivatives, a photocatalyst, alkali and an organic solvent into a reaction vessel, and then introducing trifluorobromomethane gas to react under visible light to obtain trifluoromethyl indole derivatives;
the indole derivative has the structural formula:
;
wherein R is 1 The method comprises the following steps: h or CH 3 ;R 2 The method comprises the following steps: CH (CH) 3 Or CHO;
the photocatalyst is selected from [ Ir (dtbbpy) (ppy) ] 2 ]PF 6 Any one of organic dye photocatalyst 2,4, 6-tri (diphenyl amino) -3, 5-difluorobenzonitrile and 2,4,5, 6-tetra (9-carbazolyl) -m-phthalonitrile;
the alkali is inorganic alkali or organic alkali; wherein the inorganic base is NaHCO 3 、Na 2 CO 3 、K 2 CO 3 Any one of them; the organic base is DABCO.
2. The method for synthesizing a trifluoromethylindole derivative according to claim 1, wherein: the molar ratio of the indole derivative to the trifluorobromomethane to the photocatalyst to the alkali is (0.5-5)/(1-10)/(0.005-0.12)/(0.5-5).
3. The method for synthesizing a trifluoromethylindole derivative according to claim 1, wherein: the alkali is K 2 CO 3 。
4. The method for synthesizing a trifluoromethylindole derivative according to claim 1, wherein: the light source of the visible light comprises any one of a 3W blue LED, a 5W blue LED, a 10W blue LED, a 15W blue LED, a 20W blue LED, a 30W blue LED, a 5W white LED and a 5W blue LED.
5. The method for synthesizing a trifluoromethylindole derivative according to claim 1, wherein: the temperature of the reaction is 20-30 ℃.
6. The method for synthesizing a trifluoromethylindole derivative according to claim 1, wherein: the reaction time is 18-24 h.
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