CN113666862A - Method for preparing chiral 3-nitroindole compound by nickel-catalyzed asymmetric nitration reaction - Google Patents
Method for preparing chiral 3-nitroindole compound by nickel-catalyzed asymmetric nitration reaction Download PDFInfo
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- CN113666862A CN113666862A CN202110947604.7A CN202110947604A CN113666862A CN 113666862 A CN113666862 A CN 113666862A CN 202110947604 A CN202110947604 A CN 202110947604A CN 113666862 A CN113666862 A CN 113666862A
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- 238000006396 nitration reaction Methods 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 35
- -1 3-nitroindole compound Chemical class 0.000 title claims description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- LSMXNZJFLGIPMS-UHFFFAOYSA-N 3-nitro-1h-indole Chemical class C1=CC=C2C([N+](=O)[O-])=CNC2=C1 LSMXNZJFLGIPMS-UHFFFAOYSA-N 0.000 claims abstract description 52
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000003446 ligand Substances 0.000 claims abstract description 23
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000012414 tert-butyl nitrite Substances 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 239000000654 additive Substances 0.000 claims abstract description 8
- 230000000996 additive effect Effects 0.000 claims abstract description 8
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical group CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 239000003208 petroleum Substances 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 239000002808 molecular sieve Substances 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 239000012043 crude product Substances 0.000 claims description 10
- 239000003480 eluent Substances 0.000 claims description 10
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical class C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 claims description 10
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 125000005587 carbonate group Chemical group 0.000 claims description 2
- OCMNCWNTDDVHFK-UHFFFAOYSA-L dichloronickel;1,2-dimethoxyethane Chemical group Cl[Ni]Cl.COCCOC OCMNCWNTDDVHFK-UHFFFAOYSA-L 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- APNSGVMLAYLYCT-UHFFFAOYSA-N isobutyl nitrite Chemical compound CC(C)CON=O APNSGVMLAYLYCT-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 14
- 239000000758 substrate Substances 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- 239000000047 product Substances 0.000 description 20
- 239000007858 starting material Substances 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000012512 characterization method Methods 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 229910052759 nickel Inorganic materials 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- HHZRZWWHCXRUNV-UHFFFAOYSA-N 3-nitro-1,3-dihydroindol-2-one Chemical class [N+](=O)([O-])C1C(NC2=CC=CC=C12)=O HHZRZWWHCXRUNV-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- QPIHJLWIYLBARQ-UHFFFAOYSA-N 3-nitroindol-2-one Chemical class C1=CC=CC2=NC(=O)C([N+](=O)[O-])=C21 QPIHJLWIYLBARQ-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 238000010523 cascade reaction Methods 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 150000005623 oxindoles Chemical class 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- OHZZVRGJXKCOLS-DJKKODMXSA-N 2-[[2-[[2-[(3e)-6-fluoro-2-methyl-3-[(4-methylsulfinylphenyl)methylidene]inden-1-yl]acetyl]amino]acetyl]amino]acetic acid Chemical compound CC1=C(CC(=O)NCC(=O)NCC(O)=O)C2=CC(F)=CC=C2\C1=C\C1=CC=C(S(C)=O)C=C1 OHZZVRGJXKCOLS-DJKKODMXSA-N 0.000 description 1
- 238000010485 C−C bond formation reaction Methods 0.000 description 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical compound [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 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
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- 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
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- 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
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
- B01J2231/4283—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using N nucleophiles, e.g. Buchwald-Hartwig amination
-
- 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
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
- B01J2531/0241—Rigid ligands, e.g. extended sp2-carbon frameworks or geminal di- or trisubstitution
- B01J2531/0244—Pincer-type complexes, i.e. consisting of a tridentate skeleton bound to a metal, e.g. by one to three metal-carbon sigma-bonds
-
- 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
- B01J2531/84—Metals of the iron group
- B01J2531/847—Nickel
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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- Indole Compounds (AREA)
Abstract
The invention provides a method for preparing chiral 3-nitroindole compounds by nickel-catalyzed asymmetric nitration, which comprises the following steps: in a solvent, under the action of an additive, a nickel catalyst and a ligand, an asymmetric nitration reaction is carried out on an indole-2-ketone compound I and tert-butyl nitrite II to obtain a chiral 3-nitroindole compound III. The invention constructs chiral 3-nitroindole by nickel-catalyzed asymmetric nitration, and has the advantages of low catalyst cost, convenient operation, wide substrate application range, cheap and easily obtained reaction raw materials and the like.
Description
Technical Field
The invention relates to a method for preparing a chiral 3-nitroindole compound by nickel-catalyzed asymmetric nitration, belonging to the technical field of organic synthesis.
Background
Nitro is considered to be a functional group with wide and unique application in medicinal chemistry, and plays different roles in various medicaments due to the characteristics of being capable of serving as a hydrogen bond acceptor, having very high electron withdrawing capacity and reduced potential and the like (K.Nepali, H.Y.Lee, J.P.Liou, J.Med.Chem.2019,62, 2851-2893.). On the other hand, nitro groups are also of great significance in organic synthesis as precursors which can undergo various functional group transformations. The traditional nitration reaction has the limitations of harsh reaction conditions, low regioselectivity, difficult post-treatment and the like. Therefore, how to introduce nitro group gently and efficiently becomes a hot point for organic chemists to study.
In 2009, the Savinov group reported a mild, selective nitration of phenol (d.koley, o.c. col, loson, s.n.savinov, org.lett.2009,11, 4172-. In recent years, tert-butyl nitrite has been widely used in nitration reactions due to its advantages such as mild reaction conditions and high activity. In 2014, Jiao team developed a method for synthesizing oxidized indole containing nitro group by carbon-nitrogen cascade reaction and carbon-carbon bond formation (t.shen, y.yuan, n.jiao, chem.commun. (Camb.) -2014, 50, 554-556.). In 2015, the Liu team achieved C (sp3) -H nitration by palladium catalysis (W.Zhang, S.ren, J.Zhang, Y.Liu, J.Org.chem.2015,80, 5973-. In 2017, Wei et al constructed nitro-containing quaternary carbon centers using oxindole substituted at the 3-position as a substrate (Wei, Wen-Ting, Zhu, Wen-Ming, Ying, Wei-Wei, Wang, Yi-Ning, Bao, Wen-Hui, adv.Synth.Catal.2017.). Although there are many reports of nitration reactions, there are few reports of the construction of quaternary carbon centers with nitro groups. However, according to the knowledge of the people, the method for directly and asymmetrically constructing the quaternary carbon center containing the nitro group by only one-step reaction is not available, so that the method still has great development space in the field.
3, 3-disubstituted oxindole is a special heterocyclic skeleton in the field of medicinal chemistry, and exists in various natural products and bioactive molecules. Traditionally such frameworks have been formed by condensation of aniline and carbonyl compounds, and more recently have been obtained by domino cyclization and cascade reactions, as well as coupling of oxidised indoles with nucleophiles or free radical reagents (H.F. Klare, A.F. Goldberg, D.C. Duquette, B.M. Stoltz, Org.Lett.2017,19, 988-. The substituent and absolute configuration of C3 position in the 3, 3-disubstituted oxoindole compound have important influence on the biological activity thereof, and the chiral 3-nitro-2-oxoindole compound is an important compound, so that the development of an efficient method for synthesizing the compound has important significance.
The synthesis of 3-nitro-2-oxindole compounds is also reported in the patent literature. For example: chinese patent document CN107200705A discloses a method for synthesizing 3-nitro-2-oxindole, which uses 2-indolone derivatives as raw materials, 1, 4-dioxane as solvent, and tert-butyl nitrite to react at 25 ℃, but only obtains racemic product, which is not in accordance with atom economy, and the reaction route is as follows:
chinese patent document CN110590639A discloses a method for synthesizing 3-nitro-2-oxindole compounds with copper nitrate, but 1.5 times equivalent of copper nitrate is used in the reaction, and only a racemic product is obtained, which is not economical and environmentally friendly, and the reaction route is as follows:
at present, the existing methods can not obtain a product with a single configuration. Therefore, the construction of chiral 3-nitroindoles having asymmetric quaternary carbon centers via transition metals and chiral ligands is of great interest in view of economic cost and increasing demand for chiral compounds. The invention is therefore proposed.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a method for preparing a chiral 3-nitroindole compound by nickel-catalyzed asymmetric nitration, which solves the defects of unstable nitration reagent, low reaction selectivity, uncontrollable reaction system, low reaction efficiency, complex reaction post-treatment and incapability of obtaining a single-configuration product in the existing nitration reaction.
The technical scheme of the invention is as follows:
a method for preparing chiral 3-nitroindole compounds by nickel-catalyzed asymmetric nitration comprises the following steps:
in a solvent, under the action of an additive, a nickel catalyst and a ligand, carrying out asymmetric nitration reaction on an indole-2-ketone compound I and tert-butyl nitrite II to obtain a chiral 3-nitroindole compound III;
wherein in the compound of formula I, R1Is 1 or more substituents on the phenyl ring to which it is attached, each R1Each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, phenyl or C5-C14 aryl; r2Is hydrogen, C1-C6 alkyl, C5-C14 aryl or C5-C14 heteroaryl, the heteroatom of which is O, N or S; r3Is an alkyl, aryl or carbonate protecting group;
in the formula of the compound of formula III, the substituent R1And the substitution position and R in the compound of formula I1Same, substituent R2、R3Are respectively reacted with R in the compound of formula I2、R3The same is true.
According to the invention, preferably, R is1Is hydrogen, halogen, C1-C6 alkoxy or phenyl; r2Is C1-C6 alkyl, phenyl, p-methylphenyl, benzyl, biphenyl, 2-thienylmethyl or
R3Is tert-butyloxycarbonyl or adamantyloxycarbonyl.
Preferably, according to the invention, the solvent is dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, 1, 4-dioxane, acetone, acetonitrile, toluene or p-xylene; the ratio of the volume of the solvent to the mole number of the indole-2-ketone compound I is 2-10 mL:1 mmol.
According to the invention, the additive is preferably tert-butyl alcohol, and the molar ratio of the additive to the indole-2-ketone compound I is 0.8-1.2: 1.
According to the invention, the nickel catalyst is preferably a divalent nickel catalyst; further preferably, said ligandIs nickel chloride dimethoxyethane (NiCl)2DME); the molar ratio of the nickel catalyst to the indole-2-ketone compound I is 0.05-0.1: 1.
Preferably according to the invention, the ligand is a Ph-PyBox ligand, the structure of which is shown in formula IV below, commercially available or synthesized according to the literature (Synlett,2005,15, 2321-2324); further preferably, the ligand is (S) -4-Cl-Ph-PyBox; the molar ratio of the ligand to the nickel catalyst is 1-1.2: 1.
According to the invention, the mol ratio of the indole-2-ketone compound I to the tert-butyl nitrite II is preferably 1: 1.2-2, and more preferably 1: 1.5.
According to the invention, preferably, the reaction system for asymmetric nitration reaction of the indole-2-ketone compound I and tert-butyl nitrite II is also added
Molecular sieves of
The ratio of the mass of the molecular sieve to the mole number of the indole-2-ketone compound I is 0.5-1g:1 mmol.
According to the invention, the preferable temperature of the nitration reaction is-20 to 0 ℃.
According to the invention, the atmosphere of the nitration reaction is preferably air or oxygen; further preferably oxygen.
According to the invention, the time of the nitration reaction is preferably 7-12 hours.
According to the invention, after the asymmetric nitration reaction of the indole-2-ketone compound I and the tert-butyl nitrite II, the product can be separated and characterized according to a conventional separation and purification method. Preferably, the post-treatment steps of the reaction liquid obtained after asymmetric nitration of the indole-2-ketone compound I and the tert-butyl nitrite II are as follows: removing the solvent from the obtained reaction liquid, and separating and purifying the obtained crude product by silica gel column chromatography to obtain a chiral 3-nitroindole compound III, wherein the eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether in the mixed solvent is 0.02-0.05: 1.
The reaction route of the invention is shown as the following formula:
in the formula, R1、R2、R3As described above.
The invention has the following technical characteristics and beneficial effects:
the invention takes indole-2-ketone compounds and tert-butyl nitrite as raw materials, and constructs chiral 3-nitrooxoindole compounds through nickel catalytic asymmetric nitration reaction. Compared with the existing synthesis method of 3-nitrooxoindole, the invention successfully obtains a product with a high single configuration through the catalysis of transition metal and chiral ligand, and has high reaction stereoselectivity.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and starting materials, unless otherwise specified, are commercially available or may be prepared according to known methods.
The Box ligand used in the examples was (S) -4-Cl-Ph-PyBox, which has the formula V below:
example 1
A method for preparing chiral 3-nitroindole compounds (IIIa) by nickel-catalyzed asymmetric nitration reaction comprises the following reaction route:
the preparation method comprises the following specific steps: a5 mL round bottom flask was charged with indol-2-one (i.e., starting material Ia, 62mg, 0.2mmol), tert-butyl nitrite (i.e., starting material II, 31mg, 0.3mmol), nickel catalyst (NiCl)2DME, 3.3mg, 0.015mmol), Box ligand (7mg, 0.016mmol), tert-butanol (15mg, 0.2mmol),
Molecular sieve 100mg and dichloromethane 1mL, then in the oxygen atmosphere, 0 ℃ stirring reaction, by TLC detection reaction progress until starting material Ia disappeared (reaction time 12 h). After the reaction, the solvent was removed from the obtained reaction solution, and the obtained crude product was separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether: 1: 50-1: 20, v/v) to obtain the target product 34mg, yield 48%, 80% ee.
The characterization data of the 3-nitroindoles (IIIa) are as follows:
1H NMR(400MHz,CDCl3)δ8.06(d,J＝8.2Hz,1H),7.63-7.53(m,2H),7.52-7.39(m,5H),7.34(td,J＝7.7,1.1Hz,1H),1.63(s,9H)；
13C NMR(100MHz,CDCl3)δ165.7,148.6,141.2,132.5,131.8,130.5,128.9,128.7,126.1,125.4,122.4,116.2,94.9,85.7,28.1；
HRMS(ESI)calcd(m/z)for C19H18N2O5:[M+Na]+377.1108,found 377.1105。
example 2
A method for preparing chiral 3-nitroindole compounds (IIIb) by nickel-catalyzed asymmetric nitration reaction comprises the following reaction route:
the preparation method comprises the following specific steps: a5 mL round bottom flask was charged with indol-2-one (i.e., starting material Ib, 65mg, 0.2mmol), tert-butyl nitrite (i.e., starting material II, 31mg, 0.3mmol), nickel catalyst (NiCl)2DME, 3.3mg, 0.015mmol), Box ligand (7mg, 0.016mmol), tert-butanol (15mg, 0.2mmol),
Molecular sieve 100mg and dichloromethane 1mL, then in the oxygen atmosphere, 0 ℃ stirring reaction, by TLC detection reaction progress until the raw material disappeared (reaction time 12 h). After the reaction was completed, the solvent was removed from the obtained reaction solution, and the obtained crude product was separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether: 1:50 to 1:20, v/v) to obtain 39mg of the objective product, with a yield of 54%, 81% ee.
The characterization data of the 3-nitroindoles (IIIb) are as follows:
1H NMR(400MHz,CDCl3)δ8.04(d,J＝8.2Hz,1H),7.64-7.49(m,2H),7.31(m,3H),7.23(d,J＝8.1Hz,2H),2.37(s,3H),1.62(s,9H)；
13C NMR(100MHz,CDCl3)δ165.9,148.6,141.1,140.9,132.4,129.6,128.8,128.6,126.0,125.3,122.6,116.2,94.8,85.6,28.1,21.3；
HRMS(ESI)calcd(m/z)forC20H20N2O5:[M+Na]+391.1264,found 391.1262。
example 3
A method for preparing chiral 3-nitroindole compounds (IIIc) by nickel-catalyzed asymmetric nitration reaction comprises the following reaction route:
the preparation method comprises the following specific steps: a5 mL round bottom flask was charged with indol-2-one (i.e., starting material IC, 84mg, 0.2mmol), tert-butyl nitrite (i.e., starting material II, 31mg, 0.3mmol), nickel catalyst (NiCl)2DME, 3.3mg, 0.015mmol), Box ligand (7mg, 0.016mmol), tert-butanol (15mg, 0.2mmol),
Molecular sieve 100mg and dichloromethane 1mL, then in the oxygen atmosphere, 0 ℃ stirring reaction, by TLC detection reaction progress until the raw material disappeared (reaction time 12 h). After the reaction was completed, the solvent was removed from the obtained reaction solution, and the obtained crude product was separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether: 1: 50-1: 20, v/v) to obtain 65mg of the target product, with a yield of 73%, 94% ee.
The characterization data of the 3-nitroindoles (IIIc) are as follows:
1H NMR(400MHz,CDCl3)δ7.70(dd,J＝9.0,4.4Hz,1H),7.24-7.06(m,5H),7.00-6.89(m,2H),4.01-3.75(m,2H),2.39-2.20(m,9H),1.70(m,6H)；
13C NMR(100MHz,CDCl3)δ166.0,159.7(d,C-F,1JC-F＝246.5Hz),147.3,136.9(d,C-F,4JC-F＝2.7Hz),130.6,130.3,128.6,128.1,123.9(d,C-F,3JC-F＝8.4Hz),118.6(d,C-F,2JC-F＝22.8Hz),117.4(d,C-F,3JC-F＝7.8Hz),111.8(d,C-F,2JC-F＝25.2Hz),92.8(d,J＝1.9Hz),85.7,41.3,40.9,36.0,31.1；
HRMS(ESI)calcd(m/z)for C26H25FN2O5:[M+Na]+487.1640,found 487.1644。
example 4
A method for preparing chiral 3-nitroindole compounds (IIId) by nickel-catalyzed asymmetric nitration reaction comprises the following reaction route:
the preparation method comprises the following specific steps: to a 5mL round bottom flask was added indol-2-one (i.e., raw material id, 99mg, 0.2mmol), tert-butyl nitrite (i.e., raw material II)31mg, 0.3mmol), nickel catalyst (NiCl)2DME, 3.3mg, 0.015mmol), Box ligand (7mg, 0.016mmol), tert-butanol (15mg, 0.2mmol),
Molecular sieve 100mg and dichloromethane 1mL, then in the oxygen atmosphere, 0 ℃ stirring reaction, by TLC detection reaction progress until the raw material disappeared (reaction time 12 h). After the reaction was completed, the solvent was removed from the obtained reaction solution, and the obtained crude product was separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether: 1: 50-1: 20, v/v) to obtain 74mg of the objective product, with a yield of 68%, 94% ee.
The characterization data of the 3-nitroindoles (IIId) are as follows:
1H NMR(400MHz,CDCl3)δ7.71(dd,J＝9.0,4.4Hz,1H),7.51-7.46(m,2H),7.42-7.35(m,4H),7.34-7.29(m,1H),7.17(dd,J＝7.1,2.7Hz,1H),7.10(td,J＝8.9,2.8Hz,1H),6.99(d,J＝8.2Hz,2H),3.97-3.83(m,2H),2.25-2.16(m,9H),1.66(m,6H)；
13C NMR(100MHz,CDCl3)δ166.0,159.7(d,C-F,1JC-F＝246.6Hz),147.3,140.8,140.1,137.0(d,C-F,4JC-F＝2.3Hz),130.8,129.5,128.9,127.6,127.2,127.0,123.9(d,C-F,3JC-F＝8.3Hz),118.7(d,C-F,2JC-F＝22.7Hz),117.5(d,C-F,3JC-F＝7.8Hz),111.8(d,C-F,2JC-F＝25.4Hz),92.7(d,C-F,4JC-F＝1.5Hz),85.8,41.3,40.5,36.0,31.1；
HRMS(ESI)calcd(m/z)for C32H29FN2O5:[M+Na]+563.1949,found 563.1942。
example 5
A method for preparing chiral 3-nitroindole compounds (IIIe) by nickel-catalyzed asymmetric nitration reaction comprises the following reaction route:
the preparation method comprises the following specific steps: a5 mL round bottom flask was charged with indol-2-one (i.e., raw material ie, 85mg, 0.2mmol), tert-butyl nitrite (i.e., raw material II, 31mg, 0.3mmol), nickel catalyst (NiCl)2DME, 3.3mg, 0.015mmol), Box ligand (7mg, 0.016mmol), tert-butanol (15mg, 0.2mmol),
Molecular sieve 100mg and dichloromethane 1mL, then in the oxygen atmosphere, 0 ℃ stirring reaction, by TLC detection reaction progress until the raw material disappeared (reaction time 12 h). After the reaction was completed, the solvent was removed from the obtained reaction solution, and the obtained crude product was separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether: 1: 50-1: 20, v/v) to obtain 75mg of the objective product, yield 80%, 93% ee.
The characterization data of 3-nitroindole (IIIe) are as follows:
1H NMR(400MHz,CDCl3)δ7.80(dd,J＝9.1,4.4Hz,1H),7.19-7.03(m,3H),6.82(dd,J＝5.1,3.5Hz,1H),6.73(d,J＝3.5Hz,1H),4.08(m,2H),2.24(m,9H),1.70(m,6H)；
13C NMR(100MHz,CDCl3)δ165.7,159.8(d,C-F,1JC-F＝246.8Hz),147.4,137.3(d,C-F,4JC-F＝2.7Hz),131.7,129.1,127.1,126.4,123.8(d,C-F,3JC-F＝8.5Hz),118.9(d,C-F,2JC-F＝22.8Hz),117.5(d,C-F,3JC-F＝7.9Hz),111.8(d,C-F,2JC-F＝25.3Hz),92.0(d,C-F,4JC-F＝1.8Hz),85.9,41.3,36.0,35.0,31.1；
HRMS(ESI)calcd(m/z)for C24H23FN2O5S:[M+Na]+493.1204,found 493.1201。
example 6
A method for preparing chiral 3-nitroindole compounds (IIIf) by nickel-catalyzed asymmetric nitration reaction comprises the following reaction route:
the preparation method comprises the following specific steps: a5 mL round bottom flask was charged with indol-2-one (i.e., starting material if, 96mg, 0.2mmol), tert-butyl nitrite (i.e., starting material II, 31mg, 0.3mmol), nickel catalyst (NiCl)2DME, 3.3mg, 0.015mmol), Box ligand (7mg, 0.016mmol), tert-butanol (15mg, 0.2mmol),
Molecular sieve 100mg and dichloromethane 1mL, then in the oxygen atmosphere, 0 ℃ stirring reaction, by TLC detection reaction progress until the raw material disappeared (reaction time 12 h). After the reaction was completed, the solvent was removed from the obtained reaction solution, and the obtained crude product was separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether: 1: 50-1: 20, v/v) to obtain 58mg of the objective product, with a yield of 55%, and 90% ee.
The characterization data of the 3-nitroindoles (IIIf) are as follows:
1H NMR(400MHz,CDCl3)δ7.92-7.80(m,2H),7.45(d,J＝7.5Hz,1H),7.30-7.15(m,2H),7.08(td,J＝8.8,2.8Hz,1H),6.95(dd,J＝7.4,2.8Hz,1H),6.55(s,1H),4.80(d,J＝15.3Hz,1H),4.40(d,J＝15.3Hz,1H),1.60(s,9H),1.59(s,9H)；
13C NMR(100MHz,CDCl3)δ166.0,159.5(d,C-F,1JC-F＝246.0Hz),150.6,148.2,137.0(d,C-F,4JC-F＝2.7Hz),136.2,131.6,128.5,124.5 124.3(d,C-F,3JC-F＝8.7Hz),123.0,120.6,118.4(d,C-F,2JC-F＝22.8Hz),117.2(d,C-F,3JC-F＝7.7Hz),115.9,112.1(d,C-F,2JC-F＝25.6Hz),112.0,92.1(d,C-F,4JC-F＝1.8Hz),85.5,84.7,33.5,28.1,28.0；
HRMS(ESI)calcd(m/z)for C27H28FN3O7:[M+NH4]+543.2250,found 543.2253。
example 7
A method for preparing chiral 3-nitroindole compounds (III g) by nickel-catalyzed asymmetric nitration reaction comprises the following reaction route:
the preparation method comprises the following specific steps: a5 mL round bottom flask was charged with indol-2-one (i.e., starting material I g, 86mg, 0.2mmol), tert-butyl nitrite (i.e., starting material II, 31mg, 0.3mmol), nickel catalyst (NiCl)2DME, 3.3mg, 0.015mmol), Box ligand (7mg, 0.016mmol), tert-butanol (15mg, 0.2mmol),
Molecular sieve 100mg and dichloromethane 1mL, then in the oxygen atmosphere, 0 ℃ stirring reaction, by TLC detection reaction progress until the raw material disappeared (reaction time 12 h). After the reaction was completed, the solvent was removed from the obtained reaction solution, and the obtained crude product was separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether: 1:50 to 1:20, v/v) to obtain 51mg of the objective product, with a yield of 54%, 91% ee.
The characterization data of the 3-nitroindoles (IIIg) are as follows:
1H NMR(400MHz,CDCl3)δ7.31(d,J＝2.4Hz,1H),7.29(d,J＝8.5Hz,1H),7.19-7.07(m,3H),6.97-6.88(m,2H),6.73(dd,J＝8.5,2.4Hz,1H),3.83(m,5H),2.26-2.19(m,9H),1.70(m,6H)；
13C NMR(100MHz,CDCl3)δ166.9,162.4,147.4,142.3,131.3,130.5,128.4,127.7,125.2,114.3,110.8,102.2,93.1,85.4,55.7,41.3,40.5,36.0,31.1；
HRMS(ESI)calcd(m/z)for C27H28N2O6:[M+H]+477.2638,found 477.2644。
example 8
A method for preparing chiral 3-nitroindole compounds (IIIh) by nickel-catalyzed asymmetric nitration reaction comprises the following reaction route:
the preparation method comprises the following specific steps: a5 mL round bottom flask was charged with indol-2-one (i.e., starting material I g, 95mg, 0.2mmol), tert-butyl nitrite (i.e., starting material II, 31mg, 0.3mmol), nickel catalyst (NiCl)2DME, 3.3mg, 0.015mmol), Box ligand (7mg, 0.016mmol), tert-butanol (15mg, 0.2mmol),
Molecular sieve 100mg and dichloromethane 1mL, then in the oxygen atmosphere, 0 ℃ stirring reaction, by TLC detection reaction progress until the raw material disappeared (reaction time 12 h). After the reaction was completed, the solvent was removed from the obtained reaction solution, and the obtained crude product was separated and purified by column chromatography (eluent: ethyl acetate: petroleum ether: 1: 50-1: 20, v/v) to obtain 71mg of the objective product, yield 67%, 93% ee.
The characterization data of the 3-nitroindoles (IIIg) are as follows:
1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.56(d,J＝7.2Hz,2H),7.49-7.33(m,5H),7.18-7.08(m,3H),7.00-6.90(m,2H),4.02-3.79(m,2H),2.23(m,9H),1.70(m,6H)；
13C NMR(100MHz,CDCl3)δ166.6,147.5,145.2,141.5,140.0,131.0,130.5,129.0,128.5,128.3,127.9,127.3,124.5,123.8,121.4,114.7,93.1,85.5,41.3,40.8,36.0,31.1；
HRMS(ESI)calcd(m/z)for C32H30N2O5:[M+NH4]+540.2493,found 540.2489。
comparative example 1
A process for the preparation of chiral 3-nitroindoles (iiia) by nickel catalysed asymmetric nitration is as in example 1, except that: the target product ee value is 75 percent and is lower than that of the example 1 of the invention under the same conditions as the example 1 without adding tert-butyl alcohol, which shows that the addition of the additive can improve the stereoselectivity of the reaction.
Comparative example 2
A process for the preparation of chiral 3-nitroindoles (iiia) by nickel catalysed asymmetric nitration is as in example 1, except that: the yield of the target product is 10% and is far lower than that of the target product obtained in the example 1 of the invention under the same conditions as the example 1 without adding the nickel catalyst.
Comparative example 3
A process for the preparation of chiral 3-nitroindoles (iiia) by nickel catalysed asymmetric nitration is as in example 1, except that: the target product ee value is 0% without adding chiral ligand and with the same conditions as example 1.
In the comparative example, no chiral ligand is added, and the obtained product is a racemic product, which is not in line with economy and environmental protection.
The above embodiments are only some examples of the present invention, and the present invention is not limited thereto in any way, and any simple modification, equivalent change and modification to the above embodiments according to the technical spirit of the present invention are within the technical scope of the present invention.
Claims (10)
1. A method for preparing chiral 3-nitroindole compounds by nickel-catalyzed asymmetric nitration comprises the following steps:
in a solvent, under the action of an additive, a nickel catalyst and a ligand, carrying out asymmetric nitration reaction on an indole-2-ketone compound I and tert-butyl nitrite II to obtain a chiral 3-nitroindole compound III;
wherein in the compound of formula I, R1Is 1 or more substituents on the phenyl ring to which it is attached, each R1Each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, phenyl or C5-C14 aryl; r2Is hydrogen, C1-C6 alkyl, C5-C14 aryl or C5-C14 heteroaryl, the heteroatom of which is O, N or S; r3Is an alkyl, aryl or carbonate protecting group;
in the formula of the compound of formula III, the substituent R1And the substitution position and R in the compound of formula I1Same, substituent R2、R3Are respectively reacted with R in the compound of formula I2、R3The same is true.
2. The method for preparing chiral 3-nitroindoles as claimed in claim 1, wherein R is1Is hydrogen, halogen, C1-C6 alkoxy or phenyl; r2Is C1-C6 alkyl, phenyl, p-methylphenyl, benzyl, biphenyl, 2-thienylmethyl or
R3Is tert-butyloxycarbonyl or adamantyloxycarbonyl.
3. The method of claim 1, wherein the solvent is dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, 1, 4-dioxane, acetone, acetonitrile, toluene, or p-xylene; the ratio of the volume of the solvent to the mole number of the indole-2-ketone compound I is 2-10 mL:1 mmol.
4. The method for preparing chiral 3-nitroindole compounds according to claim 1, wherein the additive is tert-butanol, and the molar ratio of the additive to indole-2-one compounds I is 0.8-1.2: 1.
5. The method for preparing chiral 3-nitroindoles as claimed in claim 1, wherein the nickel catalyst is a divalent nickel catalyst; preferably, the nickel catalyst is nickel chloride dimethoxyethane (NiCl)2DME); the molar ratio of the nickel catalyst to the indole-2-ketone compound I is 0.05-0.1: 1.
6. The process for preparing chiral 3-nitroindoles according to claim 1 wherein the ligand is a Ph-PyBox ligand, preferably (S) -4-Cl-Ph-PyBox; the molar ratio of the ligand to the nickel catalyst is 1-1.2: 1.
7. The method for preparing chiral 3-nitroindole compounds according to claim 1, wherein the molar ratio of indole-2-one compound I to tert-butyl nitrite II is 1: 1.2-2, preferably 1: 1.5.
8. The method for preparing chiral 3-nitroindole compounds according to claim 1, wherein the reaction system in which the indole-2-one compound I and tert-butyl nitrite II are subjected to asymmetric nitration reaction is further added
Molecular sieves of
The ratio of the mass of the molecular sieve to the mole number of the indole-2-ketone compound I is 0.5-1g:1 mmol.
9. The method for preparing chiral 3-nitroindole compounds according to claim 1, wherein the nitration reaction temperature is-20 to 0 ℃; the atmosphere of the nitration reaction is air or oxygen, preferably oxygen; the nitration reaction time is 7-12 hours.
10. The method for preparing chiral 3-nitroindole compounds according to claim 1, wherein the post-treatment step of the reaction liquid obtained after asymmetric nitration of indole-2-one compounds I and tert-butyl nitrite II is as follows: removing the solvent from the obtained reaction liquid, and separating and purifying the obtained crude product by silica gel column chromatography to obtain a chiral 3-nitroindole compound III, wherein the eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether in the mixed solvent of the ethyl acetate and the petroleum ether is 0.02-0.05: 1.
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| CN114437103A (en) * | 2022-01-25 | 2022-05-06 | 山东大学 | Method for synthesizing chiral tetrahydrobenzoxepin compound through gold-catalyzed asymmetric cycloaddition reaction |
| CN114437103B (en) * | 2022-01-25 | 2023-01-06 | 山东大学 | Method for synthesizing chiral tetrahydrobenzoxepin compound through gold-catalyzed asymmetric cycloaddition reaction |
| CN114874127A (en) * | 2022-05-23 | 2022-08-09 | 中国药科大学 | Preparation method of difluorocarbonylation indolone compound |
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