CN117285453A - Method for synthesizing N-substituted-3-methylindole compound by catalyzing nitrogen heterocyclic carbene oxazoline ring palladium compound - Google Patents
Method for synthesizing N-substituted-3-methylindole compound by catalyzing nitrogen heterocyclic carbene oxazoline ring palladium compound Download PDFInfo
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- CN117285453A CN117285453A CN202311308825.5A CN202311308825A CN117285453A CN 117285453 A CN117285453 A CN 117285453A CN 202311308825 A CN202311308825 A CN 202311308825A CN 117285453 A CN117285453 A CN 117285453A
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- methylindole
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- -1 N-substituted-3-methylindole compound Chemical class 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 title claims description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims abstract description 12
- QBELEDRHMPMKHP-UHFFFAOYSA-N 1-bromo-2-chlorobenzene Chemical class ClC1=CC=CC=C1Br QBELEDRHMPMKHP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000008878 coupling Effects 0.000 claims abstract 2
- 238000010168 coupling process Methods 0.000 claims abstract 2
- 238000005859 coupling reaction Methods 0.000 claims abstract 2
- 238000007363 ring formation reaction Methods 0.000 claims abstract 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 11
- 238000001308 synthesis method Methods 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000003197 catalytic effect Effects 0.000 abstract description 4
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 150000001500 aryl chlorides Chemical class 0.000 abstract 1
- 230000002860 competitive effect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- VUVXYRCGYNRWHP-UHFFFAOYSA-N 3-methyl-1-phenylindole Chemical compound C12=CC=CC=C2C(C)=CN1C1=CC=CC=C1 VUVXYRCGYNRWHP-UHFFFAOYSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 6
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- ZFRKQXVRDFCRJG-UHFFFAOYSA-N skatole Chemical compound C1=CC=C2C(C)=CNC2=C1 ZFRKQXVRDFCRJG-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- HUHQQYKPKMPENB-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3-methylindole Chemical compound C1=CC(OC)=CC=C1N1C2=CC=CC=C2C(C)=C1 HUHQQYKPKMPENB-UHFFFAOYSA-N 0.000 description 3
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- JRTIUDXYIUKIIE-KZUMESAESA-N (1z,5z)-cycloocta-1,5-diene;nickel Chemical compound [Ni].C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 JRTIUDXYIUKIIE-KZUMESAESA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 235000000177 Indigofera tinctoria Nutrition 0.000 description 2
- 229940097275 indigo Drugs 0.000 description 2
- COHYTHOBJLSHDF-UHFFFAOYSA-N indigo powder Natural products N1C2=CC=CC=C2C(=O)C1=C1C(=O)C2=CC=CC=C2N1 COHYTHOBJLSHDF-UHFFFAOYSA-N 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- BPPGPFOTTDXLDS-UHFFFAOYSA-N 1,3-bis[2,6-di(propan-2-yl)phenyl]-2h-imidazole;hydrochloride Chemical compound [Cl-].CC(C)C1=CC=CC(C(C)C)=C1N1C=C[NH+](C=2C(=CC=CC=2C(C)C)C(C)C)C1 BPPGPFOTTDXLDS-UHFFFAOYSA-N 0.000 description 1
- OIRHKGBNGGSCGS-UHFFFAOYSA-N 1-bromo-2-iodobenzene Chemical compound BrC1=CC=CC=C1I OIRHKGBNGGSCGS-UHFFFAOYSA-N 0.000 description 1
- HEDYZFYQYPWWCC-UHFFFAOYSA-N 2-prop-1-en-2-ylaniline Chemical compound CC(=C)C1=CC=CC=C1N HEDYZFYQYPWWCC-UHFFFAOYSA-N 0.000 description 1
- ZUHNGWWGSYPTEC-UHFFFAOYSA-N 3-fluoro-n-prop-2-enylaniline Chemical compound FC1=CC=CC(NCC=C)=C1 ZUHNGWWGSYPTEC-UHFFFAOYSA-N 0.000 description 1
- OISSOJFPFGACLI-UHFFFAOYSA-N 4-methoxy-n-prop-2-enylaniline Chemical compound COC1=CC=C(NCC=C)C=C1 OISSOJFPFGACLI-UHFFFAOYSA-N 0.000 description 1
- IXMWLHYZBJBGNO-UHFFFAOYSA-N CS(=O)(=O)NC(=O)c1ccc(Br)c(Cl)c1 Chemical compound CS(=O)(=O)NC(=O)c1ccc(Br)c(Cl)c1 IXMWLHYZBJBGNO-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- MIVUDWFNUOXEJM-UHFFFAOYSA-N amino(diphenyl)azanium;chloride Chemical compound Cl.C=1C=CC=CC=1N(N)C1=CC=CC=C1 MIVUDWFNUOXEJM-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- UCJGJABZCDBEDK-UHFFFAOYSA-N bazedoxifene Chemical compound C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 UCJGJABZCDBEDK-UHFFFAOYSA-N 0.000 description 1
- 229960000817 bazedoxifene Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical group CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002834 estrogen receptor modulator Substances 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- LQFLWKPCQITJIH-UHFFFAOYSA-N n-allyl-aniline Chemical compound C=CCNC1=CC=CC=C1 LQFLWKPCQITJIH-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- IMACFCSSMIZSPP-UHFFFAOYSA-N phenacyl chloride Chemical compound ClCC(=O)C1=CC=CC=C1 IMACFCSSMIZSPP-UHFFFAOYSA-N 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2265—Carbenes or carbynes, i.e.(image)
- B01J31/2269—Heterocyclic carbenes
- B01J31/2273—Heterocyclic carbenes with only nitrogen as heteroatomic ring members, e.g. 1,3-diarylimidazoline-2-ylidenes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/824—Palladium
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Indole Compounds (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing N-substituted-3-methylindole compounds by catalyzing an azacyclo-carbene oxazoline ring palladium compound. The invention aims to provide a novel synthesis method of N-substituted-3-methylindole compounds, in particular to a method for catalyzing direct coupling ring-closing reaction of o-dichlorobenzene or o-bromochlorobenzene compounds and allylarylamine by using an N-heterocyclic carbene oxazoline ring palladium compound with high catalytic activity as a catalyst to obtain the N-substituted-3-methylindole compounds. The catalyst used in the invention has high catalytic activity, the reaction has good compatibility of products and functional groups, the catalyst is easy to synthesize, and the aryl chloride used in the synthetic route is cheap and easy to obtain. Therefore, the synthetic route provided by the invention has great competitive advantage and industrial production utilization value.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a novel method for efficiently synthesizing N-substituted-3-methylindole compounds by using an azacyclo-carbene oxazoline ring palladium compound as a catalyst.
Background
Indole, english name: the term Indole is made up of the first three letters of the other two words Indigo and oil, since Indole is initially extracted from Indigo oil dye. In the chemical field, indole is taken as an important framework structure, is widely applied to compounds such as drug molecules, natural product molecules and the like, and has good pharmacological activity in a plurality of therapeutic fields such as antihypertensive, antiproliferative, antiviral, antitumor, analgesic, anti-inflammatory and antibacterial. In particular, when a methyl group is present at the 3-position of the indole molecule, the entire indole, i.e., 3-methylindole, exhibits higher biological activity and pharmacokinetic properties than the original molecule. For example, the drug molecule Bazedoxifene is an excellent class of estrogen receptor modulators that are clinically used to prevent post-menstrual osteoporosis. As well as drug molecule 3 (see embodiments) for use in the treatment of diseases caused by sodium channels. Therefore, how to effectively construct the 3-methylindole derivative has important scientific significance and practical application value. The general formula of the N-substituted-3-methylindole compound related to the patent is shown as a structural formula 1:
the current synthesis method of the 3-methylindole compound mainly comprises the following steps:
route one is represented by the route published in the document on pages 851 to 856 of advanced synthesis catalysis, 2006: the method comprises the steps of taking 2-chloroacetophenone as a raw material, firstly preparing and synthesizing 1-chloro-2- (2-chloro-1-methyl vinyl) benzene, and then reacting with aniline under the action of a catalyst and phosphine ligand to obtain 1-phenyl-3-methylindole.
Route one
Route two is represented by the route published in german application chemistry, 2008, 47 volumes 888 to 890: under the action of palladium and phosphine ligand, 1-bromo-2-iodobenzene reacts with allylamine for 15 hours at 140 ℃ to obtain 3-methylindole. Wherein dppf is 1,1' -bis (diphenylphosphine) ferrocene.
Route two
Route three is represented by the route published in the literature on pages 12771 to 12777 of European chemistry, 19, 2013: the method comprises the steps of taking 2-isopropenylaniline and phenylboric acid as initial raw materials, obtaining N-phenyl-2- (2-propenyl) aniline under the catalysis of copper acetate and myristic acid, and then activating the N-phenyl-2- (2-propenyl) aniline through a C-H bond under the action of a catalyst and a ligand to obtain 1-phenyl-3-methylindole.
Route three
Route four is represented by the route published in the literature on pages 12771 to 12777 of European chemistry, 2016, 22: acrolein and N, N-diphenyl hydrazine hydrochloride are taken as initial raw materials, and are subjected to oxidation, addition, reduction and elimination to obtain (1E) -2-propenyl-N, N-diphenyl hydrazone, and then 1-phenyl-3-methylindole is obtained under the reflux conditions of tertiary butyl iodide and acetonitrile.
Route four
Route five is represented by the route published in the document on pages 7704 to 7708 of volume 22, organic flash report 2020: o-dichlorobenzene is used as an initial raw material to react with allylaniline, and 1-phenyl-3-methylindole is obtained under the catalysis of high-activity bis (1, 5-cyclooctadiene) nickel, wherein IPr.HCl is 1, 3-bis (2, 6-diisopropylphenyl) imidazole chloride.
Route five
In summary, these reported synthetic routes have been found to have certain drawbacks:
1) The synthesis route is long, and meanwhile, some dangerous medicines (sodium hydride and acrolein) are used, so that the method has serious production safety hidden trouble and does not meet the requirements of green chemical technology;
2) The metal catalyst unstable to air, such as bis (1, 5-cyclooctadiene) nickel and phosphorus ligand, is required to be used in the synthesis, so that the complexity of experimental operation is increased, and the industrial practical application is not facilitated; and the dosage is higher, thus increasing the reaction cost.
4) The reaction temperature is higher (e.g., the reaction temperature for route two is 140 degrees celsius);
these drawbacks limit to some extent the use of existing synthetic routes in industry. Therefore, a new efficient synthetic route of the N-substituted-3-methylindole compound is provided, and the method has certain urgency and important significance.
Disclosure of Invention
The invention aims to provide a novel synthesis method of N-substituted-3-methylindole compounds, namely an N-substituted-3-methylindole compound synthesized from an o-dichloro aryl compound or an o-bromochlorobenzene compound by using an N-heterocyclic carbene oxazoline ring palladium compound with high catalytic activity as a catalyst.
The catalyst provided by the invention is an azacyclo-carbene oxazoline ring palladium compound with high catalytic activity, and the chemical formula is C 52 H 55 BrN 3 OPd, its specific structural formula is as follows:
the invention provides a new synthetic method route of N-substituted-3-methylindole compounds, which comprises the following specific steps:
the invention provides a novel synthesis method of N-substituted-3-methylindole compounds, which comprises the following specific steps,
to a 25mL schlenk reaction tube under nitrogen was added, in order, sodium t-butoxide (3.5 mmol), an azacarboxazoline ring palladium catalyst Cat.1 (0.5 mol%), 1, 4-dioxane (3 mL), allylarylamine (1.5 mmol), and o-dichlorobenzene or o-bromochlorobenzene (1.0 mmol). The reaction tube was placed in an oil bath and heated to 100 degrees celsius for 24 hours. After the reaction is finished, the solvent is removed under reduced pressure, and the target compound N-substituted-3-methylindole compound is obtained after separation and purification by column chromatography and vacuum drying. The reaction formula of the synthesis method is as follows:
the novel synthesis method of the N-substituted-3-methylindole compound provided by the invention has the advantages that: the chloride is used as a starting material, and is cheap and easy to obtain; the catalyst is stable to air, water and the like, and the catalyst usage amount is low; the reaction process is simple to operate, and has good safety and stability; the compatibility of the substrate functional group is good, and the yield of the product is high.
Drawings
FIG. 1 is a chart showing the hydrogen nuclear magnetic resonance analysis of 1-phenyl-3-methylindole prepared in example 1.
FIG. 2 is a chart showing the hydrogen nuclear magnetic resonance analysis of 1- (4-methoxyphenyl) -3-methylindole prepared in example 2.
FIG. 3 is a chart showing the nuclear magnetic resonance hydrogen spectrum of 1- (3-fluorophenyl) -3-methyl-N-methylsulfonylndole-5-carboxamide (i.e., drug 3) prepared in example 3.
Detailed Description
The present invention is described in further detail by way of examples, which are not intended to limit the scope of the invention.
Example 1: preparation of 1-phenyl-3-methylindole, the reaction formula is as follows:
to a 25mL schlenk reaction tube under nitrogen was added, in order, sodium t-butoxide (3.5 mmol), an azacarboxazoline ring palladium catalyst Cat.1 (0.5 mol%), 1, 4-dioxane (3 mL), N-allylaniline (1.5 mmol), and o-dichlorobenzene (1.0 mmol). The reaction tube was placed in an oil bath and heated to 100 degrees celsius for 24 hours. After the reaction, the solvent was removed under reduced pressure, and separated by column chromatography and dried under vacuum to give a colorless oil, 1-phenyl-3-methylindole. Yield: 0.190g,92%.
Nuclear magnetic analysis: 1 H NMR(CDCl 3 ，600MHz，298K)：δ＝7.65(d，J＝7.7Hz，1H)，7.58(d，J＝8.2Hz，1H)，7.52-7.50(m，4H)，7.35-7.32(m，1H)，7.28-7.19(m，2H)，7.16(d，J＝1.0Hz，1H)，2.41(d，J＝1.1Hz，3H)。
example 2: preparation of 1- (4-methoxyphenyl) -3-methylindole, the reaction formula is as follows:
to a 25mL schlenk reaction tube under nitrogen was added, in order, sodium t-butoxide (3.5 mmol), an azacarboxazoline ring palladium catalyst Cat.1 (2 mol%), 1, 4-dioxane (3 mL), N-allyl-4-methoxyaniline (1.5 mmol), and o-dichlorobenzene (1.0 mmol). The reaction tube was placed in an oil bath and heated to 100 degrees for 24 hours. After the reaction, the solvent was removed under reduced pressure, and the mixture was separated by column chromatography and dried under vacuum to give a white solid, 1- (4-methoxyphenyl) -3-methylindole. Yield: 0.214g,90%.
Nuclear magnetic analysis: 1 H NMR(CDCl 3 ，600MHz，298K)：δ＝7.63(d，J＝7.5Hz，1H)，7.45(d，J＝8.2Hz，1H)，7.40-7.37(m，2H)，7.22-7.15(m，2H)，7.08(d，J＝1.0Hz，1H)，7.03-7.01(m，2H)，3.88(s，3H)，2.39(d，J＝1.1Hz，3H)。
example 3: preparation of 1- (3-fluorophenyl) -3-methyl-N-methylsulfonylndole-5-carboxamide (i.e., drug 3) according to the following reaction scheme:
to a 25mL schlenk reaction tube under nitrogen was added, in order, sodium t-butoxide (3.5 mmol), an azacarboxazoline ring palladium catalyst Cat.1 (2 mol%), 1, 4-dioxane (3 mL), N-allyl-3-fluoroaniline (1.5 mmol), and 4-bromo-3-chloro-N-methylsulfonyl-benzamide (1.0 mmol). The reaction tube was placed in an oil bath and heated to 100 degrees for 24 hours. After the reaction, the solvent was removed under reduced pressure, separated by column chromatography, and dried under vacuum to give a white solid, i.e., 1- (3-fluorophenyl) -3-methyl-N-methylsulfonylndole-5-carboxamide (i.e., drug 3). Yield: 0.229g,66%.
Nuclear magnetic analysis: 1 H NMR(CDCl 3 ，600MHz，298K)：δ＝8.97(s，1H)，8.10(s，1H)，7.67(d，J＝8.3Hz，1H)，7.61(dd，J＝8.3Hz，J＝1.3Hz，1H)，7.51(q，J＝7.5Hz，1H)，7.30-7.28(m，2H)，7.18-7.16(m，1H)，7.11-7.08(m，1H)，3.41(s，3H)，2.39(s，3H)。
Claims (1)
1. a method for synthesizing N-substituted-3-methylindole compounds by catalyzing an azacyclo-carbene oxazoline ring palladium compound is characterized by comprising the following steps:
under the condition of nitrogen, the nitrogen heterocyclic carbene oxazoline ring palladium compound catalyzes o-dichlorobenzene or o-bromochlorobenzene compounds to carry out coupling ring-closing reaction with allylarylamine, and N-substituted-3-methylindole compounds are obtained. The amount of the catalyst added ranges from 0.5mol% to 2mol%. The reaction formula is as follows:
wherein tBuONa is sodium tert-butoxide, cat.1 in the reaction formula is an azacyclo-carbene oxazoline ring palladium compound, and the structural formula is as follows:
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