CN115181054B - Synthesis method of 3-benzyl indole compound - Google Patents
Synthesis method of 3-benzyl indole compound Download PDFInfo
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- CN115181054B CN115181054B CN202210981101.6A CN202210981101A CN115181054B CN 115181054 B CN115181054 B CN 115181054B CN 202210981101 A CN202210981101 A CN 202210981101A CN 115181054 B CN115181054 B CN 115181054B
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- methylindole
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- trimethylphenol
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- benzyl
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- -1 3-benzyl indole compound Chemical class 0.000 title claims description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 claims abstract description 11
- BPRYUXCVCCNUFE-UHFFFAOYSA-N 2,4,6-trimethylphenol Chemical compound CC1=CC(C)=C(O)C(C)=C1 BPRYUXCVCCNUFE-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000007800 oxidant agent Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 9
- HNUYRDWMYRCVNO-UHFFFAOYSA-N 3-benzyl-1h-indole Chemical class C=1NC2=CC=CC=C2C=1CC1=CC=CC=C1 HNUYRDWMYRCVNO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000654 additive Substances 0.000 claims abstract description 7
- 238000005859 coupling reaction Methods 0.000 claims abstract description 7
- 230000001590 oxidative effect Effects 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 230000000996 additive effect Effects 0.000 claims abstract description 6
- 238000006356 dehydrogenation reaction Methods 0.000 claims abstract description 5
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- DGCBGBZYTNTZJH-UHFFFAOYSA-N 2-bromo-4,5-difluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C=C1Br DGCBGBZYTNTZJH-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 12
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 5
- 150000002475 indoles Chemical class 0.000 description 5
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- 238000005574 benzylation reaction Methods 0.000 description 3
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- FJLGEFLZQAZZCD-MCBHFWOFSA-N (3R,5S)-fluvastatin Chemical compound C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 FJLGEFLZQAZZCD-MCBHFWOFSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- PWVXXGRKLHYWKM-LJQANCHMSA-N eletriptan Chemical compound CN1CCC[C@@H]1CC(C1=C2)=CNC1=CC=C2CCS(=O)(=O)C1=CC=CC=C1 PWVXXGRKLHYWKM-LJQANCHMSA-N 0.000 description 2
- 229960002472 eletriptan Drugs 0.000 description 2
- 229960003765 fluvastatin Drugs 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
- 229960000905 indomethacin Drugs 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 2
- ULFRLSNUDGIQQP-UHFFFAOYSA-N rizatriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1CN1C=NC=N1 ULFRLSNUDGIQQP-UHFFFAOYSA-N 0.000 description 2
- 229960000425 rizatriptan Drugs 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- GZKLJWGUPQBVJQ-UHFFFAOYSA-N sertindole Chemical compound C1=CC(F)=CC=C1N1C2=CC=C(Cl)C=C2C(C2CCN(CCN3C(NCC3)=O)CC2)=C1 GZKLJWGUPQBVJQ-UHFFFAOYSA-N 0.000 description 2
- 229960000652 sertindole Drugs 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- NTUROZDXWLPVHB-UHFFFAOYSA-M sodium;3-diphenylphosphanylbenzenesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C1=CC=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NTUROZDXWLPVHB-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- AMCDZTCOQXPOAZ-UHFFFAOYSA-N 1-hydroxy-2,3-dihydroindol-2-ol Chemical compound C1=CC=C2N(O)C(O)CC2=C1 AMCDZTCOQXPOAZ-UHFFFAOYSA-N 0.000 description 1
- MGUPHQGQNHDGNK-UHFFFAOYSA-N 2,3,6-trifluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC(F)=C1F MGUPHQGQNHDGNK-UHFFFAOYSA-N 0.000 description 1
- SJZATRRXUILGHH-UHFFFAOYSA-N 2,4,6-trifluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=C(F)C=C1F SJZATRRXUILGHH-UHFFFAOYSA-N 0.000 description 1
- VJMYKESYFHYUEQ-UHFFFAOYSA-N 3,4,5-trifluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C(F)=C1 VJMYKESYFHYUEQ-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- CBMIPXHVOVTTTL-UHFFFAOYSA-N gold(3+) Chemical compound [Au+3] CBMIPXHVOVTTTL-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930005303 indole alkaloid Natural products 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- JZQKKSLKJUAGIC-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1C=CN2 JZQKKSLKJUAGIC-UHFFFAOYSA-N 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- VFWRGKJLLYDFBY-UHFFFAOYSA-N silver;hydrate Chemical compound O.[Ag].[Ag] VFWRGKJLLYDFBY-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
Abstract
The invention discloses a synthesis method of 3-benzyl indole compounds, which takes N-methyl indole and 2,4, 6-trimethylphenol as reaction raw materials, heats the raw materials in a solvent in the presence of an oxidant and an additive, and carries out cross dehydrogenation coupling reaction to obtain the target products of the 3-benzyl indole compounds. The invention has the advantages of cheap and easily obtained raw materials, simple operation, good substrate applicability and wide development prospect.
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a method for synthesizing a 3-benzyl indole compound through cross dehydrogenation coupling reaction.
Background
In nature, particularly in living organisms, there are many substances throughout life, a large group of which are compounds containing benzo five-membered heterocycles. Of these compounds, indoles are of the most importance.
Indole and its derivatives are important alkaloids as a class of nitrogen-containing heterocycles. Most of them have unique biological and pharmacological activities, so they are widely used in the pharmaceutical industry. Many drug molecules contain an indole skeleton. Fluvastatin (fluvastatin) is the first fully-chemically synthesized cholesterol-lowering drug, has the advantages of high selectivity, low adverse reaction incidence rate and the like, and is an excellent blood lipid-lowering drug. Rizatriptan (rizatriptan) and eletriptan (eletriptan) are specific drugs for treating migraine, and both bring revolutionary progress to the drug treatment of migraine. Indometacin (indometacin) is useful for the treatment of rheumatic diseases and various arthritis. Indolinediol (pindolol) can be used for treating arrhythmia, angina pectoris and hypertension. Sertindole (sertindole) is a newly developed atypical antipsychotic. In addition, the indole alkaloids such as vincristine, vinblastine and the like have good efficacy on resisting tumors.
In recent years a number of scientific researchers have been working on developing methods for benzylation of the C-3 position of indoles.
The professor Isao Azumaya (J.org.chem.2013, 78,23,12128-12135) developed the coupling reaction of benzyl alcohol and indole for the first time in a water-soluble gold (III)/TPPMS catalytic system, which is one of the most efficient and environmentally friendly benzyl synthesis strategies, and in most cases, a medium yield of the target compound was obtained. Of these, au (III)/TPPMS is an effective catalyst for the benzylation of the strong pi nucleophile 1-methylindole, whereas the common Lewis acids are ineffective.
In 2015, toxotropy et al (Chinese Journal ofCatalysis 2015,36,15-18) developed an efficient method for Pd (0) -catalyzed indole benzylation that has unique regioselectivity. When the reaction is carried out on Pd (PPh 3 ) 4 When carried out in the presence, it provides a route to a wide range of substituted indoles with diarylmethane in their 3-position in 90% -99% yield under mild conditions.
In 2020, amreen K.bains et al (chem. Commun.,2020,56,15442) reported a highly efficient nickel catalyst that could effectively be used for the selective C3-alkylation of 1H-indole with various alcohols. The authors used indole and benzyl alcohol as model substrates, when a mixture of indole (1 mmol), benzyl alcohol (2 mmol), nickel catalyst (5 mol%) and potassium tert-butoxide (0.7 equiv) in toluene (2 mL) was heated at 110deg.C, the target product 3-benzylindole was obtained.
The synthesis of 3-benzylindoles reported to date is essentially all performed using expensive metal catalysts. Therefore, the method has important significance for developing the synthesis of the 3-benzyl indole compound by using only an inexpensive oxidant.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art, and aims to provide a synthesis method of 3-benzyl indole compounds. The 3-benzyl indole compound is synthesized through the cross dehydrogenation coupling reaction, and has the advantages of low cost and easiness in obtaining raw materials, simplicity in operation, wide substrate applicability and the like, and has a wide development prospect.
The invention relates to a synthesis method of 3-benzyl indole compounds, which takes N-methyl indole and 2,4, 6-trimethylphenol as reaction raw materials, heats the raw materials in a solvent in the presence of an oxidant and an additive, and carries out cross dehydrogenation coupling reaction to obtain the target products of the 3-benzyl indole compounds.
The method specifically comprises the following steps:
0.2mmol of N-methylindole, 1.0mmol of 2,4, 6-trimethylphenol and 0.08mmol of additive are respectively added into 1mL of solvent, then oxidant is added, and the reaction is carried out for 48 to 72 hours at the temperature of between 90 and 120 ℃ to obtain the target product.
The structural formula of the 3-benzyl indole compound is shown as the following formula I:
wherein R is a substituent at a different position on the phenyl ring, e.g. methyl (-CH) 3 ) Methoxy (-OCH) 3 ) Various halogen groups (-F, -Cl, -Br, -I) and nitro groups (-NO) 2 ) Cyano (-CN), phenyl (-Ph), and the like.
The structural formula of the N-methylindole is shown as the following formula II:
the structural formula of the 2,4, 6-trimethylphenol is shown as the following formula III:
the reaction scheme is as follows:
wherein R is a substituent at a different position on the phenyl ring, e.g. methyl (-CH) 3 ) Methoxy (-OCH) 3 ) Various halogen groups (-F, -Cl, -Br, -I) and nitro groups (-NO) 2 ) Cyano (-CN), phenyl (-Ph), and the like.
The oxidant comprises di-tert-butyl peroxide (DTBP), tert-butyl hydroperoxide (TBHP), 2, 3-dichloro-5, 6-dicyanobenzoquinone (DDQ), zinc oxide (ZnO), silver oxide (Ag) 2 O), potassium persulfate (K) 2 S 2 O 8 ) Or manganese dioxide (MnO) 2 ). Since different oxidizing agents have great influence on the yield of the reaction, the reaction is carried out by using p-di-tert-butyl peroxide (DTBP), tert-butyl hydroperoxide (TBHP), 2, 3-dichloro-5, 6-dicyanobenzoquinone (DDQ), zinc oxide (ZnO), silver oxide (Ag 2 O), potassium persulfate (K) 2 S 2 O 8 ) Manganese dioxide (MnO) 2 ) The final yields are 0%, 12%, 0%, 18%, 56%, respectively, so that the preferred oxidizing agent in the present invention is manganese dioxide (MnO) 2 )。
Further, by examining the additives 3,4, 5-trifluorobenzoic acid, 2,4, 6-trifluorobenzoic acid, 2,3, 6-trifluorobenzoic acid, 2-bromo-4, 5-difluorobenzoic acid, the final yields were 56%, 37%, 43%, 78%, respectively, so that 2-bromo-4, 5-difluorobenzoic acid is preferred as an additive in the present invention.
Further, since the temperature has a great influence on the reaction yield, the final yields are 39% (90 ℃), 51% (100 ℃), 78% (110 ℃) and 49% (120 ℃) by screening at 90 to 120 ℃, respectively, so that the present invention is preferably at 110℃as the optimal reaction temperature.
Further, by screening for different solvents, for example, 0% yield in Tetrahydrofuran (THF), 33% yield in Dichloromethane (DCM) and 57% yield in acetonitrile (MeCN) and 78% yield in 1, 2-Dichloroethane (DCE) as solvents, the solvent is preferably 1, 2-Dichloroethane (DCE).
Compared with the prior art, the 3-benzyl indole compound is obtained by the coupling reaction of indole derivatives and cheap and easily available 2,4, 6-trimethylphenol. Therefore, the reaction meets the requirements of green chemistry and has wide development prospect.
Detailed Description
The foregoing is further elaborated by the following specific examples, which should not be construed as limiting the protective body of the invention. All technical schemes realized based on the above content of the invention belong to the scope of the invention. The present invention generally and/or specifically describes the materials used in the test as well as the test methods.
Example 1: preparation of Compound Ia
0.2mmol of N-methylindole, 1.0mmol of 2,4, 6-trimethylphenol and 0.08mmol of 2-bromo-4, 5-difluorobenzoic acid were successively introduced into an oven-dried 10mL Schlenk tube, 1mL of 1, 2-dichloroethane solvent was introduced into the Schlenk tube at room temperature using a syringe, and then 2.4mmol of MnO was further introduced 2 The Schlenk tube was sealed and the mixture heated to 110 ℃ for 72 hours; after the reaction is finished, the solvent is evaporated under reduced pressure, and the mixed solution of petroleum ether/ethyl acetate=10/1-30/1 (V/V) is used as a mobile phase for column chromatography separation, so that the product 3-benzyl indole compound is obtained, and the yield is 78%.
1 H NMR(600MHz,CDCl 3 )δ7.58(d,J＝8.0Hz,1H),7.31(dd,J＝8.3,2.4Hz,1H),7.24(ddd,J＝5.0,3.2,1.2Hz,1H),7.13–7.09(m,1H),6.93(s,2H),6.77(s,1H),4.51(s,1H),4.00(s,2H),3.74(s,3H),2.23(s,6H). 13 C NMR(151MHz,CDCl 3 )δ150.29,137.18,133.02,128.79,127.88,127.00,122.81,121.50,119.25,118.70,114.98,109.10,32.59,30.63,15.96.HRMS(ESI)m/z(M+H) + calculated for C 18 H 19 NO:266.1540,observed:266.1542.
Example 2: preparation of Compound Ib
With substrate IIbThe product Ib is prepared in 44% yield by the method of example 1 instead of IIa.
1 H NMR(600MHz,CDCl 3 )δ7.37(s,1H),7.20(dd,J＝8.6,2.4Hz,1H),7.07(ddd,J＝8.3,3.5,1.7Hz,1H),6.93(s,2H),6.71(s,1H),4.51(s,1H),3.97(s,2H),3.71(s,3H),2.48(s,3H),2.24(s,6H). 13 C NMR(151MHz,CDCl 3 )δ150.26,135.61,133.13,128.76,128.08,127.88,127.15,123.12,122.78,118.81,114.33,108.81,32.62,30.54,21.52,15.96.HRMS(ESI)m/z(M+H) + calculated for C 19 H 21 NO:280.1696,observed:280.1692.
Example 3: preparation of Compound ic
With substrate IIcThe product ic was prepared in 78% yield by the method of example 1 instead of IIa.
1 H NMR(600MHz,CDCl 3 )δ7.42(d,J＝8.4Hz,1H),7.27(d,J＝1.9Hz,1H),7.03(dd,J＝8.4,1.8Hz,1H),6.87(s,2H),6.74(s,1H),4.50(s,1H),3.93(s,2H),3.69(s,3H),2.21(s,6H). 13 CNMR(151MHz,CDCl 3 )δ150.36,137.56,132.57,128.68,127.62,127.58,126.40,122.86,120.15,119.36,115.23,109.15,32.67,30.48,15.95.HRMS(ESI)m/z(M+H) + calculated for C 18 H 18 ClNO:300.1150,observed:300.1151.
Example 4: preparation of Compound Id
With substrate IIdThe product Id was prepared in 76% yield by the method of example 1 instead of IIa.
1 H NMR(600MHz,CDCl 3 )δ7.86(s,1H),7.44(dd,J＝8.6,1.6Hz,1H),7.05(d,J＝8.5Hz,1H),6.86(s,2H),6.68(s,1H),4.50(s,1H),3.89(s,2H),3.69(s,3H),2.21(s,6H). 13 C NMR(151MHz,CDCl 3 )δ150.38,132.41,130.36,129.75,128.67,128.00,127.81,126.90,122.88,114.42,111.18,82.29,32.71,30.31,15.95.HRMS(ESI)m/z(M+H) + calculated for C 18 H 18 INO:392.0506,observed:392.0501.
Example 5: preparation of Compound ie
With substrate IIeThe product ie was prepared in 83% yield by the method of example 1 instead of IIa.
1 H NMR(600MHz,CDCl 3 )δ7.45(dd,J＝7.9,1.0Hz,1H),7.32(dd,J＝7.6,1.0Hz,1H),6.89–6.86(m,3H),6.69(s,1H),4.49(s,1H),4.09(s,3H),3.92(s,2H),2.21(s,6H). 13 C NMR(151MHz,CDCl 3 )δ150.37,133.45,132.39,130.96,130.07,128.69,126.51,122.85,119.91,118.60,114.79,103.83,36.51,30.35,15.96.HRMS(ESI)m/z(M+H) + calculated for C 18 H 18 BrNO:344.0645,observed:344.0642.
Example 6: preparation of Compound if
With substrate IIfThe product if was prepared in 89% yield by the method of example 1 instead of IIa.
1 H NMR(600MHz,CDCl 3 )δ7.81(d,J＝7.6Hz,1H),7.76(d,J＝7.8Hz,1H),7.08(td,J＝7.9,1.2Hz,1H),6.87(s,2H),6.83(s,1H),4.61(s,1H),3.96(s,2H),3.79(s,3H),2.22(s,6H). 13 CNMR(151MHz,CDCl 3 )δ150.57,132.91,131.82,131.76,128.66,128.49,128.09,125.40,123.07,119.79,117.93,116.24,37.19,30.15,15.98.HRMS(ESI)m/z(M+H) + calculated for C 18 H 18 N 2 O 3 :311.1390,observed:311.1392.
Example 7: preparation of Compound Ig
With substrate II gThe product Ig was prepared in 42% yield by the method of example 1 instead of IIa.
1 H NMR(600MHz,CDCl 3 )δ7.13–7.09(m,1H),6.93(s,2H),6.88(dd,J＝8.2,1.3Hz,1H),6.49(d,J＝7.2Hz,2H),4.45(s,1H),4.15(s,2H),3.90(s,3H),3.66(s,3H),2.22(s,6H). 13 CNMR(151MHz,CDCl 3 )δ155.09,150.03,138.76,134.22,129.06,126.90,125.69,122.54,122.21,115.92,102.51,99.05,55.10,32.79,32.08,15.97.HRMS(ESI)m/z(M+H) + calculated for C 19 H 21 NO 2 :296.1645,observed:296.1647。
Claims (6)
1. A synthetic method of 3-benzyl indole compounds is characterized in that:
n-methylindole and 2,4, 6-trimethylphenol are used as reaction raw materials, and are heated in a solvent 1, 2-dichloroethane in the presence of an oxidant manganese dioxide and an additive 2-bromo-4, 5-difluorobenzoic acid to carry out cross dehydrogenation coupling reaction, so that a 3-benzylindole compound target product is obtained;
the structural formula of the 3-benzyl indole compound is shown as the following formula I:
the structural formula of the N-methylindole is shown as the following formula II:
the structural formula of the 2,4, 6-trimethylphenol is shown as the following formula III:
wherein R is substituent groups at different positions on the benzene ring, including methyl, methoxy, halogen groups, nitro, cyano and phenyl.
2. The synthesis method according to claim 1, wherein:
the molar amount of the oxidant added is 12 equivalents of the molar amount of N-methylindole.
3. The synthesis method according to claim 1, wherein:
the molar amount of the additive added is 40% of the molar amount of the N-methylindole.
4. The synthesis method according to claim 1, wherein:
the reaction temperature is 90-120 ℃.
5. The method of synthesis according to claim 4, wherein:
the reaction temperature was 110 ℃.
6. The synthesis method according to claim 1, wherein:
the molar ratio of N-methylindole to 2,4, 6-trimethylphenol was 1:5.
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| JP2001270863A (en) * | 2000-03-23 | 2001-10-02 | Mitsui Chemicals Inc | Method for producing 6-substituted indole derivative |
| CN102827061A (en) * | 2012-09-19 | 2012-12-19 | 兰州大学 | 5,6,7- trimethoxy indole derivative, preparation method and use thereof |
| CN111675644A (en) * | 2020-06-08 | 2020-09-18 | 南京医科大学 | Indole diaryl methane compound and preparation method and application thereof |
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|---|---|---|---|---|
| JP2001270863A (en) * | 2000-03-23 | 2001-10-02 | Mitsui Chemicals Inc | Method for producing 6-substituted indole derivative |
| CN102827061A (en) * | 2012-09-19 | 2012-12-19 | 兰州大学 | 5,6,7- trimethoxy indole derivative, preparation method and use thereof |
| CN111675644A (en) * | 2020-06-08 | 2020-09-18 | 南京医科大学 | Indole diaryl methane compound and preparation method and application thereof |
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| Yasushi Imada等.Metal- and Reagent-Free Dehydrogenative Formal Benzyl–Aryl Cross- Coupling by Anodic Activation in 1,1,1,3,3,3-Hexafluoropropan-2-ol.《Angew. Chem. Int. Ed.》.2018,第57卷第12136-12140页. * |
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