CN118063480A - Benzopyran ring-containing spiroindole compound and preparation method thereof - Google Patents
Benzopyran ring-containing spiroindole compound and preparation method thereof Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 93
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical group C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 60
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 57
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 abstract description 28
- XIHUIBHHKFCYOJ-UHFFFAOYSA-N 2-nitro-2h-chromene Chemical compound C1=CC=C2C=CC([N+](=O)[O-])OC2=C1 XIHUIBHHKFCYOJ-UHFFFAOYSA-N 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000000758 substrate Substances 0.000 abstract description 5
- 150000002148 esters Chemical class 0.000 abstract description 2
- -1 spiro indole compound Chemical class 0.000 description 81
- 239000007787 solid Substances 0.000 description 43
- 239000000047 product Substances 0.000 description 42
- 238000002844 melting Methods 0.000 description 38
- 230000008018 melting Effects 0.000 description 38
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 30
- 238000012512 characterization method Methods 0.000 description 30
- 239000011734 sodium Substances 0.000 description 27
- 238000004440 column chromatography Methods 0.000 description 25
- 238000012544 monitoring process Methods 0.000 description 22
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 20
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 9
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 8
- 239000012264 purified product Substances 0.000 description 8
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- QPKYMPPBOCVXOR-UHFFFAOYSA-N 2-(4-methylphenyl)-3-nitro-2h-chromene Chemical compound C1=CC(C)=CC=C1C1C([N+]([O-])=O)=CC2=CC=CC=C2O1 QPKYMPPBOCVXOR-UHFFFAOYSA-N 0.000 description 5
- 229910000144 sodium(I) superoxide Inorganic materials 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- PIAOLBVUVDXHHL-UHFFFAOYSA-N 2-nitroethenylbenzene Chemical compound [O-][N+](=O)C=CC1=CC=CC=C1 PIAOLBVUVDXHHL-UHFFFAOYSA-N 0.000 description 3
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012973 diazabicyclooctane Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical class C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- MRZOEGWSKCWAAB-UHFFFAOYSA-N C1=CC=C2NC=CC2=C1.C1=CC=C2C=CCOC2=C1 Chemical class C1=CC=C2NC=CC2=C1.C1=CC=C2C=CCOC2=C1 MRZOEGWSKCWAAB-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- UUCUQJHYUPXDHN-UHFFFAOYSA-N N-Acetylindole Chemical compound C1=CC=C2N(C(=O)C)C=CC2=C1 UUCUQJHYUPXDHN-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000007934 α,β-unsaturated carboxylic acids Chemical class 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a spiroindole compound containing benzopyran ring and a preparation method thereof. The preparation method comprises the following steps: reacting a compound shown in a formula I with a compound shown in a formula II-1 or a formula II-2 in an organic solvent under the catalysis of alkali to obtain compounds shown in a formula III-1 to a formula III-4: Wherein R 1 is selected from H, cl or Br; r 2 is selected from m-OCH 3、m-Cl、p-CH3 or o-OCH 3;R3 is selected from H, cl, F or Me; r 4 is selected from Bn or n-Bu; r 5 is selected from H, cl, F or Me; r 6 is selected from Bn or n-Bu. According to the preparation method, raw materials used in a reaction system are easy to obtain, the nitrochromene and isatin MBH carbonic ester can be obtained through simple synthesis, the preparation method is efficient, economical and environment-friendly, the substrate expansion range is wide, the reaction condition is mild, the yield is high, and the preparation operation and the post-treatment steps are simple.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a spiroindole compound containing benzopyran rings and a preparation method thereof.
Background
The spiroindole compounds are important spirocyclic compounds, the structures of which are widely existing in the molecular structures of natural products and medicines, and the spiroindole compounds show unique biological activity and pharmacological activity, including antibiosis, antitumor and the like, and have important values in the field of organic chemical synthesis. The benzopyran ring is introduced on the structure of the compound, so that the pharmaceutical activity of the compound can be enhanced, and the compound has anticancer, antiallergic and the like. Many small molecule drugs for the treatment of various diseases also contain a spiroindole skeleton. Therefore, the development of a novel method for efficiently synthesizing the spiro indole compound containing the benzopyran ring is particularly important.
The Yao et al synthesized a series of spirooxindole dihydropyranones (C.S.Yao, X.S.Wang, C.X.Yu.J.Org.Chem.2015,80 (6), 3289-3294) by a [4+2] cyclization reaction of N-hydroxybenzotriazole esters of NHC-catalyzed isatin with gamma-H-containing alpha, beta-unsaturated carboxylic acids. Wu et al report that the asymmetric cyclization tandem reaction of isatin with propenyl pyrazole amide under Takemoto catalyst conditions produced spirooxindole dihydropyranone compounds (X.Y.Wu, F.Sha, Y.Q.Guan.Chem.Commun.2014,50 (74), 10790-10792) in excellent yields. Yu et al report that isatin, phenol, N-acetyl indole, and the like, efficiently synthesize a series of spirocyclic benzopyran indoles (S.M.Yu, X.S.Liu.J.Org.Chem.2020,8 (2), 15-23), and the like, under the catalysis of Lewis acid. Most of the methods for synthesizing the spiroindole compounds containing the benzopyran ring have the problems of expensive catalyst, slow reaction, narrow substrate expansion range and the like.
Therefore, the method for further developing the efficient synthesis of the spiro indole compound containing the benzopyran ring has important application value, and particularly has great significance for developing the efficient, economical and green synthesis method with wide substrate expansion range.
Disclosure of Invention
The invention aims to provide a benzopyran ring-containing spiroindole compound and a preparation method thereof, wherein simple nitrochromene and isatin MBH carbonate are used as raw materials to efficiently prepare the benzopyran ring-containing spiroindole compound, and the prepared nitro-containing spiroindole compound can be reduced into an amine compound and further can be converted into various chemical synthetic drugs or natural products.
In order to achieve the above purpose, the invention adopts the following technical scheme:
In a first aspect, the invention provides a benzopyran ring-containing spiroindole compound, which has a structural general formula shown in formulas III-1 to III-4:
Wherein R 1 is selected from H, cl or Br;
R 2 is selected from m-OCH 3、m-Cl、p-CH3 or o-OCH 3;
r 3 is selected from H, cl, F or Me;
R 4 is selected from Bn or n-Bu;
r 5 is selected from H, cl, F or Me;
r 6 is selected from Bn (benzyl) or n-Bu.
In a second aspect, the present invention provides a process for preparing a spiroindole compound containing a benzopyran ring, comprising:
Reacting a compound shown in a formula I with a compound shown in a formula II-1 or a formula II-2 in an organic solvent under the catalysis of alkali to obtain compounds shown in a formula III-1 to a formula III-4:
Wherein R 1 is selected from H, cl or Br;
R 2 is selected from m-OCH 3、m-Cl、p-CH3 or o-OCH 3;
r 3 is selected from H, cl, F or Me;
R 4 is selected from Bn or n-Bu;
r 5 is selected from H, cl, F or Me;
R 6 is selected from Bn or n-Bu.
In some embodiments, the compound of formula I is a compound of formula II-1 or formula II-2 in a 1:1.5:1 molar ratio of base to feed.
In some embodiments, the base is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, triphenylphosphine, triethylamine, 1, 4-diazabicyclo [2.2.2] octane, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, preferably 4-dimethylaminopyridine.
In some embodiments, the organic solvent for the reaction is selected from one or more of tetrahydrofuran, toluene, ethyl acetate, acetonitrile, 1, 2-dichloroethane, ethanol, dichloromethane, chloroform, preferably acetonitrile.
In some embodiments, the reaction is performed in an air environment after adding the compound of formula I, the compound of formula II-1 or formula II-2, and the organic solvent, followed by adding the base.
In some embodiments, the temperature of the reaction is 20 to 25 ℃ and the time of the reaction is 2 to 6 hours; preferably, the reaction temperature is 25 ℃ (i.e. room temperature) and the reaction time is 4 hours.
In some embodiments, the organic solvent is added in an amount such that the molar concentration of the compound of formula I is between 0.03 and 0.04mol/L, preferably 0.04mol/L.
Wherein, the preparation method of the compound (nitrochromene) shown in the formula I comprises the following steps:
step1, synthesis of nitrostyrene
Adding corresponding aldehyde 1.0equiv into a round bottom flask, adding a certain amount of methanol as a solvent, uniformly mixing, adding nitromethane 1.5equiv, controlling the temperature to be about 0 ℃, stirring, dropwise adding 0.56M sodium hydroxide solution, monitoring the reaction progress by TLC, adding 15% hydrochloric acid solution after the reaction is complete, precipitating a large amount of solid in the system, and performing suction filtration and drying to obtain the required raw material nitrostyrene.
Step2, preparation of nitrochromene
Adding nitrostyrene 1.0equiv and salicylaldehyde 2.0equiv into a round-bottom flask, uniformly mixing at the temperature of about 50 ℃, adding DABCO 0.5equiv, and separating by column chromatography (developing agent: ethyl acetate: petroleum ether=1:30) after the reaction is completed to obtain nitrochromene.
Wherein, the preparation method of the compound (isatoic MBH carbonate of acrylonitrile) shown in the formula II-1 comprises the following steps:
Adding isatin 1.0equiv and acrylonitrile 1.5equiv into a round bottom flask, adding a certain amount of tetrahydrofuran as a solvent, adding 0.15equiv DABCO for catalytic reaction, and separating by column chromatography to obtain white solid. Weighing a proper amount of solid, adding 1.2equiv NaH and a proper amount of dried dichloromethane as solvents, extracting N 2, stirring at low temperature (about 0 ℃) for 10min, adding a mixed solution of di-tert-butyl dicarbonate (1.5 equiv) and dried dichloromethane, stirring at room temperature overnight, monitoring the reaction progress by TLC, and separating by column chromatography to obtain the isatin MBH carbonate of acrylonitrile after the reaction is completed.
Wherein, the preparation method of the compound (isatin MBH carbonate of methyl acrylate) shown in the formula II-2 comprises the following steps:
Adding isatin 1.0equiv and methyl acrylate 5.0equiv into a round bottom flask, adding 0.5equiv DABCO for catalytic reaction without solvent, and separating by column chromatography to obtain white solid. Weighing a proper amount of solid, adding 1.2equiv NaH and a proper amount of dried dichloromethane as solvents, extracting N 2, stirring at low temperature (about 0 ℃) for 10min, adding a mixed solution of di-tert-butyl dicarbonate (1.5 equiv) and dried dichloromethane, stirring at room temperature overnight, monitoring the reaction progress by TLC, and separating by column chromatography to obtain isatin MBH carbonate of methyl acrylate after the reaction is completed.
In some embodiments, the base-catalyzed reaction of nitrochromene and isatin MBH carbonate is used to prepare spiroindole compounds containing benzopyran rings, comprising the steps of:
Step 1, in a round bottom flask, the amount of each reaction raw material added is calculated by mole ratio: nitrochromene-isatin MBH carbonate base=1:1.5:1, the amount of organic solvent added should be such that the molar concentration of nitrochromene is 0.04mol/L, then stirring for 4h in an air environment;
And 2, after the reaction is finished, separating and purifying the product by a column chromatography technology to obtain the spiroindole compound containing the benzopyran ring.
Wherein the reaction temperature in the step (1) is set to room temperature; the base is one of potassium carbonate, sodium carbonate, cesium carbonate, triphenylphosphine, triethylamine, 1, 4-diazabicyclo [2.2.2] octane, 4-dimethylaminopyridine and 1, 8-diazabicyclo [5.4.0] undec-7-ene; the solvent is one of tetrahydrofuran, toluene, ethyl acetate, acetonitrile, 1, 2-dichloroethane, ethanol, dichloromethane and chloroform.
The reaction formula for preparing the benzopyran ring-containing spiroindole compound is as follows:
Compared with the prior art, the invention has the beneficial technical effects that:
The invention prepares the spiroindole derivative containing benzopyran ring by base catalytic reaction of nitrochromene and isatin MBH carbonic ester, and the method realizes the synthesis of the compound through [3+2] cyclization in one pot. In the preparation method disclosed by the invention, raw materials used in a reaction system are easy to obtain, nitrochromene and isatin MBH carbonate can be obtained through simple synthesis, and the existence of nitro in the molecular structure of the benzopyran ring-containing spiroindole compound provides convenience for converting the compound into other functional group compounds. The preparation method is efficient, economical, green, wide in substrate expansion range, mild in reaction condition, high in yield and simple in preparation operation and post-treatment steps.
Detailed Description
The invention is further described below in connection with specific embodiments. The following examples are only for more clearly illustrating the technical aspects of the present invention, and are not intended to limit the scope of the present invention.
Example 1
Preparation of 1 '-butyl-5', 8-dichloro-4- (3-methoxyphenyl) -3 a-nitro-2 '-oxo-3 a,9 b-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (1) and 1 '-butyl-5', 8-dichloro-4- (3-methoxyphenyl) -2 '-oxo-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (2)
Example 1a: in a 50mL round bottom flask, 6-chloro-2- (3-methoxyphenyl) -3-nitro-2H-benzopyran (0.2 mmol,63.4 mg) tert-butyl (1-butyl-5-chloro-3- (1-cyanovinyl) -2-oxoindol-3-yl) carbonate (0.3 mmol,117 mg) was added first, acetonitrile (5 mL) followed by 4-dimethylaminopyridine (0.2 mmol,24.4 mg) and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the product was purified by column chromatography to give 34.2mg of white solid 1 (compound represented by formula 1), melting point 240-242 ℃, yield 29% and 66.2mg of white solid 2 (compound represented by formula 2), melting point 242-244 ℃, yield 61%.
The structural characterization data for the product of formula 1 are as follows:
1H NMR(CDCl3,400MHz)δ7.52(dd,J1＝8.4Hz,J2＝1.2Hz,1H,ArH),7.39～7.35(m,2H,ArH),7.18(dd,J1＝8.8Hz,J2＝2.0Hz,1H,ArH),7.09(s,1H,ArH),7.03(d,J＝8.8Hz,1H,ArH),7.00～6.94(m,3H,ArH),6.90(s,1H,ArH),6.28(d,J＝2.4Hz,1H,CH),6.04(s,1H,CH),4.21(s,1H,CH),3.84(s,3H,OCH3),3.77～3.70(m,1H,CH),3.46～3.39(m,1H,CH),1.55～1.50(m,1H,CH),1.34～1.29(m,1H,CH),1.22～1.09(m,2H,CH2),0.88(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ171.5,160.1,152.5,145.5,141.8,134.2,131.4,130.1,129.8,129.5,128.4,127.2,126.0,124.8,121.5,119.7,118.8,118.5,115.4,111.8,111.7,110.7,96.9,80.6,66.5,55.4,51.1,40.9,29.2,20.1,13.6;
IR(KBr)υ:3420,3108,2960,2934,2873,2232,1716,1607,1542,1485,1431,1345,1257,1228,1191,1126,1036,995,874,852,817,781,731cm-1;
HRMS Calcd(ESI)m/z for C31H25Cl2N3NaO5[M+Na]+:612.1063,found:612.1060.
the structural characterization data for the product of formula 2 are as follows:
1H NMR(CDCl3,400MHz)δ7.69(s,1H,ArH),7.32(d,J＝2.4Hz,1H,ArH),7.22(dd,J1＝8.4Hz,J2＝2.4Hz,1H,ArH),7.05(dd,J1＝8.4Hz,J2＝2.0Hz,1H,ArH),6.96(t,J＝8.0Hz,1H,ArH),6.86(d,J＝8.8Hz,1H,ArH),6.63～6.60(m,1H,ArH),6.57～6.54(m,1H,ArH),6.51～6.50(m,1H,ArH),6.40(d,J＝2.0Hz,1H,CH),5.92(s,1H,CH),3.87～3.80(m,1H,CH),3.67(s,3H,OCH3),3.56～3.49(m,1H,CH),1.70～1.63(m,2H,CH2),1.48～1.38(m,2H,CH2),0.99(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ168.2,159.4,151.8,143.2,141.9,140.8,137.7,136.7,130.7,129.3,129.2,128.3,126.8,124.4,123.3,123.0,120.2,118.9,118.4,118.1,114.4,113.2,112.6,109.9,78.5,69.8,55.1,41.0,29.3,20.0,13.7;
IR(KBr)υ:3399,3067,2964,2935,2211,1708,1599,1485,1417,1369,1340,1247,1226,1205,1181,1036,992,978,897,878,863,821,793,767,714cm-1;
HRMS Calcd(ESI)m/z for C31H24Cl2N2NaO3[M+Na]+:565.1056,found:565.1061.
Example 1b: in a 50mL round bottom flask, 6-chloro-2- (3-methoxyphenyl) -3-nitro-2H-benzopyran (0.1 mmol,31.7 mg) tert-butyl (1-butyl-5-chloro-3- (1-cyanovinyl) -2-oxoindol-3-yl) carbonate (0.15 mmol,58.5 mg) was added first, dichloromethane (3 mL) followed by 4-dimethylaminopyridine (0.1 mmol,12.2 mg) and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the purified product was separated by column chromatography to give 22.4mg of white solid 1 (compound represented by formula 1), melting point 240-242 ℃, yield 38% and 27.6mg of white solid 2 (compound represented by formula 2), melting point 242-244 ℃, yield 51%.
Example 1c: in a 50mL round bottom flask, 6-chloro-2- (3-methoxyphenyl) -3-nitro-2H-benzopyran (0.1 mmol,31.7 mg) tert-butyl (1-butyl-5-chloro-3- (1-cyanovinyl) -2-oxoindol-3-yl) carbonate (0.15 mmol,58.5 mg) was added first, ethyl acetate (3 mL) followed by 4-dimethylaminopyridine (0.1 mmol,12.2 mg) and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the product was purified by column chromatography to give 18.8mg of white solid 1 (compound represented by formula 1), melting point 240-242 ℃, yield 32% and 29.8mg of white solid 2 (compound represented by formula 2), melting point 242-244 ℃, yield 55%.
Example 1d: in a 50mL round bottom flask, 6-chloro-2- (3-methoxyphenyl) -3-nitro-2H-benzopyran (0.1 mmol,31.7 mg) tert-butyl (1-butyl-5-chloro-3- (1-cyanovinyl) -2-oxoindol-3-yl) carbonate (0.15 mmol,58.5 mg) was added first, chloroform (3 mL) followed by 4-dimethylaminopyridine (0.1 mmol,12.2 mg) and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the purified product was separated by column chromatography to give 20.6mg of white solid 1 (compound represented by formula 1), melting point 240-242 ℃, yield 35% and 29.3mg of white solid 2 (compound represented by formula 2), melting point 242-244 ℃, yield 54%.
Example 2
Preparation of 1 '-butyl-8-chloro-4- (3-methoxyphenyl) -5' -methyl-3 a-nitro-2 '-oxo-3 a,7,8,9 b-tetrahydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (3) and 1 '-butyl-8-chloro-4- (3-methoxyphenyl) -5' -methyl-2 '-oxo-7, 8-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (4)
In a 50mL round bottom flask, 6-chloro-2- (3-methoxyphenyl) -3-nitro-2H-benzopyran (0.2 mmol,63.4 mg) tert-butyl (1-butyl-3- (1-cyanovinyl) -5-methyl-2-oxoindol-3-yl) carbonate (0.3 mmol,111 mg) was added first, acetonitrile (5 mL) followed by 4-dimethylaminopyridine (0.2 mmol,24.4 mg) and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the purified product was separated by column chromatography to give 28.4mg of white solid 1 (compound represented by formula 3), melting point 243-245 ℃, yield 25% and 58.5mg of white solid 2 (compound represented by formula 4), melting point 166-168 ℃, yield 56%.
The structural characterization data for the product of formula 3 are as follows:
1H NMR(CDCl3,400MHz)δ7.37(t,J＝7.6Hz,1H,ArH),7.32(d,J＝8.0Hz,1H,ArH),7.18～7.14(m,2H,ArH),7.07～7.05(m,1H,ArH),7.02～6.95(m,3H,ArH),6.92～6.90(m,2H,ArH),6.28(s,1H,CH),6.08(s,1H,CH),4.20(s,1H,CH),3.84(s,3H,CH3),3.75～3.68(m,1H,CH),3.45～3.38(m,1H,CH),2.43(s,3H,CH3),1.54～1.49(m,1H,CH),1.35～1.29(m,2H,CH2),1.23～1.20(m,2H,CH2),0.88(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ171.8,160.0,152.5,144.9,140.8,134.5,134.3,131.7,130.0,129.2,127.1,126.9,126.1,124.8,122.3,119.5,119.3,118.6,115.4,112.1,111.7,109.5,97.1,80.6,66.7,55.4,51.2,40.8,29.3,21.2,20.1,13.7;
IR(KBr)υ:2960,2873,2234,1713,1603,1537,1489,1352,1332,1292,1255,1232,1186,1126,1052,1039,978,939,874,814,776,706cm-1.
HRMS Calcd(ESI)m/z for C32H28ClN3NaO5[M+Na]+:592.1610,found:592.1602.
the structural characterization data for the product of formula 4 are as follows:
1H NMR(CDCl3,400MHz)δ7.67(s,1H,ArH),7.32(d,J＝2.0Hz,1H,ArH),7.19(dd,J1＝8.4Hz,J2＝2.4Hz,1H,ArH),6.91(t,J＝8.0Hz,1H,ArH),6.85(t,J＝8.0Hz,2H,ArH),6.58～6.51(m,3H,ArH),6.45(s,1H,ArH),6.19(s,1H,CH),5.89(s,1H,CH),3.85～3.78(m,1H,CH),3.62(s,3H,OCH3),3.57～3.51(m,1H,CH),2.05(s,3H,CH3),1.72～1.64(m,2H,CH2),1.48～1.41(m,2H,CH2),0.99(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ168.4,159.3,151.8,142.8,141.7,140.9,138.2,136.0,132.5,130.4,129.6,129.0,126.6,124.9,123.2,121.2,120.7,119.0,118.6,118.0,114.1,113.6,112.5,108.8,78.7,70.4,55.0,40.9,29.4,20.7,20.1,13.7;
IR(KBr)υ:3399,3069,2964,2934,2871,2213,1707,1600,1491,1453,1417,1371,1341,1268,1185,1133,1095,1037,992,871,815,795,714cm-1.
HRMS Calcd(ESI)m/z for C32H29ClN2NaO3[M+Na]+:545.1602,found:545.1612.
Example 3
Preparation of 1 '-butyl-8-chloro-5' -fluoro-4- (3-methoxyphenyl) -3 a-nitro-2 '-oxo-3 a,9 b-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (5) and 1 '-butyl-8-chloro-5' -fluoro-4- (3-methoxyphenyl) -2 '-oxo-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (6)
In a 50mL round bottom flask, 6-chloro-2- (3-methoxyphenyl) -3-nitro-2H-benzopyran (0.2 mmol,63.4 mg) tert-butyl (1-butyl-3- (1-cyanovinyl) -5-fluoro-2-oxoindol-3-yl) carbonate (0.3 mmol,112.2 mg) was first added, acetonitrile (5 mL), followed by 4-dimethylaminopyridine (0.2 mmol,24.4 mg) and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the product was purified by column chromatography to give 29.8mg of white solid 1 (compound represented by formula 5), melting point 244-246 ℃, yield 26% and 62.0mg of white solid 2 (compound represented by formula 6), melting point 210-212 ℃, yield 59%. The product structure characterization data are as follows ：1H NMR(CDCl3,400MHz)δ7.37(t,J＝8.0Hz,1H,ArH),7.29～7.26(m,1H,ArH),7.19～7.15(m,2H,ArH),7.09(s,1H,ArH),7.03(d,J＝8.8Hz,1H,ArH),7.01～6.95(m,3H,ArH),6.91～6.90(m,1H,ArH),6.27(d,J＝1.6Hz,1H,CH),6.07(s,1H,CH),4.19(s,1H,CH),3.84(s,3H,CH3),3.78～3.71(m,1H,CH),3.46～3.39(m,1H,CH),1.57～1.49(m,1H,CH),1.34～1.28(m,1H,CH),1.21～1.09(m,2H,CH2),0.88(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ171.6,160.0,159.9(d,J＝243.0Hz),152.5,145.5,139.2,134.3,130.1,129.4,128.2(d,J＝8.0Hz),127.2,126.0,121.6,119.6,118.9,118.5,118.0(d,J＝23.0Hz),115.40,112.5(d,J＝26.0Hz),111.8,111.7,110.6(d,J＝8.0Hz),97.0,80.6,66.8,55.4,51.1,40.9,29.2,20.1,13.7;
IR(KBr)υ:3103,2960,2936,2874,2233,1713,1603,1541,1488,1454,1349,1256,1229,1191,1037,942,867,820,788,700cm-1;
HRMS Calcd(ESI)m/z for C31H25ClFN3NaO5[M+Na]+:596.1359,found:596.1353.
The structural characterization data for the product of formula 6 are as follows:
1H NMR(CDCl3,400MHz)δ7.68(s,1H,ArH),7.32(d,J＝2.4Hz,1H,ArH),7.21(dd,J1＝8.8Hz,J2＝2.4Hz,1H,ArH),6.95(t,J＝8.0Hz,1H,ArH),6.85(d,J＝8.8Hz,1H,ArH),6.79(td,J1＝9.2Hz,J2＝2.8Hz,1H,ArH),6.61～6.53(m,3H,ArH),6.51～6.48(m,1H,ArH),6.20(dd,J1＝7.6Hz,J2＝2.8Hz,1H,CH),5.91(s,1H,CH),3.86～3.79(m,1H,CH),3.64(s,3H,OCH3),3.54～3.47(m,1H,CH),1.70～1.62(m,2H,CH2),1.47～1.38(m,2H,CH2),0.98(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ168.2,159.4,158.9(d,J＝242.0Hz),151.9,143.2,140.9,139.4,137.6,136.9,130.6,129.2,126.8,123.4,123.0(d,J＝9.0Hz),120.3,119.0,118.5,118.1,115.9(d,J＝24.0Hz),114.4,113.3,112.7,109.6(d,J＝7.0Hz),78.5,70.1,55.1,41.1,29.3,20.0,13.7;
IR(KBr)υ:3399,3069,2964,2934,2871,2213,1707,1600,1491,1453,1417,1371,1341,1268,1185,1133,1095,1037,992,871,815,795,714cm-1;
HRMS Calcd(ESI)m/z for C31H24ClFN2NaO3[M+Na]+:549.1352,found:549.1353.
Example 4
Preparation of 1 '-benzyl-8-chloro-4- (3-methoxyphenyl) -3 a-nitro-2' -oxo-3 a,9 b-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3 '-indoline ] -2-carbonitrile (7) and 1' -benzyl-8-chloro-4- (3-methoxyphenyl) -2 '-oxo-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (8)
In a 50mL round bottom flask, 6-chloro-2- (3-methoxyphenyl) -3-nitro-2H-benzopyran (0.2 mmol,63.4 mg), 1-benzyl-3- (1-cyanovinyl) -2-oxoindolin-3-ylcarbonate (0.3 mmol,117 mg), acetonitrile (5 mL) was added first, followed by 4-dimethylaminopyridine (0.2 mmol,24.4 mg) and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the product was purified by column chromatography to give 18.8mg of white solid 1 (compound represented by formula 7), melting point 252-254 ℃, yield 16% and 59.6mg of white solid 2 (compound represented by formula 8), melting point 246-248 ℃, yield 55%.
The structural characterization data for the product of formula 7 are as follows:
1H NMR(CDCl3,400MHz)δ7.44～7.36(m,3H,ArH),7.32～7.26(m,4H,ArH),7.19(d,J＝8.8Hz,1H,ArH),7.11～7.10(m,1H,ArH),7.04(d,J＝7.6Hz,3H,ArH),6.99(t,J＝7.2Hz,2H,ArH),6.93(s,1H,ArH),6.87(d,J＝7.6Hz,1H,ArH),6.27(s,1H,CH),6.19(s,1H,CH),5.00(d,J＝15.6Hz,1H,CH),4.64(d,J＝16.0Hz,1H,CH),4.30(s,1H,CH),3.84(s,3H,OCH3);
13C NMR(CDCl3,100MHz)δ172.3,160.1,152.6,145.0,143.0,134.4,134.2,131.4,130.1,129.5,129.2,127.9,127.3,126.8,126.5,126.2,124.7,124.1,122.4,119.5,118.9,118.6,115.4,112.0,111.7,110.6,96.9,80.6,66.7,55.4,51.0,44.8;
IR(KBr)υ:3064,3031,2940,2840,2235,1720,1609,1548,1486,1465,1359,1339,1296,1257,1166,1125,1035,965,870,856,817,794,780,754,725cm-1;
HRMS Calcd(ESI)m/z for C34H24ClN3NaO5[M+Na]+:612.1297,found:612.1300.
the structural characterization data for the product of formula 8 are as follows:
1H NMR(CDCl3,400MHz)δ7.71(s,1H,ArH),7.37(d,J＝4.4Hz,4H,ArH),7.34(d,J＝2.4Hz,1H,ArH),7.32～7.29(m,1H,ArH),7.20(dd,J1＝8.8Hz,J2＝2.4Hz,1H,ArH),6.97(t,J＝8.8Hz,1H,ArH),6.86～6.80(m,2H,ArH),6.66(t,J＝7.6Hz,1H,ArH),6.52(dd,J1＝8.4Hz,J2＝3.2Hz,2H,ArH),6.46～6.41(m,2H,ArH),6.34～6.32(m,1H,CH),5.90(s,1H,CH),5.07(d,J＝15.6Hz,1H,CH),4.71(d,J＝15.6Hz,1H,CH),3.50(s,3H,OCH3);
13C NMR(CDCl3,100MHz)δ169.0,159.2,151.8,143.2,143.0,141.7,138.0,136.3,134.9,130.5,129.3,129.1,129.0,128.1,127.5,126.7,124.0,123.3,123.2,121.2,120.5,119.0,118.6,118.1,114.7,113.6,112.1,109.9,78.6,70.2,55.0,44.8;
IR(KBr)υ:3430,3061,2937,2214,1709,1609,1549,1488,1466,1455,1417,1345,1260,1230,1173,1039,987,815,792,750,741cm-1;
HRMS Calcd(ESI)m/z for C34H23ClN2NaO3[M+Na]+:565.1289,found:565.1298.
Example 5
Preparation of 1' -benzyl-5 ', 8-dichloro-4- (3-methoxyphenyl) -3 a-nitro-2 ' -oxo-3 a,9 b-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (9) and 1' -benzyl-8-chloro-4- (3-methoxyphenyl) -2' -oxo-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (10)
In a 50mL round bottom flask, 6-chloro-2- (3-methoxyphenyl) -3-nitro-2H-benzopyran (0.2 mmol,63.4 mg), 1-benzyl-5-chloro-3- (1-cyanovinyl) -2-oxoindolin-3-ylcarbonate (0.3 mmol,127.2 mg), acetonitrile (5 mL) and then 4-dimethylaminopyridine (0.2 mmol,24.4 mg) were added and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the purified product was separated by column chromatography to give 22.4mg of white solid 1 (compound represented by formula 9), melting point 248-250 ℃, yield 18% and 62.2mg of white solid 2 (compound represented by formula 10), melting point 260-262 ℃ yield 54%.
The structural characterization data for the product of formula 9 are as follows:
1H NMR(CDCl3,400MHz)δ7.40～7.37(m,3H,ArH),7.34～7.29(m,3H,ArH),7.22(dd,J1＝8.8Hz,J2＝2.4Hz,1H,ArH),7.12(s,1H,ArH),7.06(d,J＝8.8Hz,1H,ArH),7.05～7.02(m,2H,ArH),7.02～6.99(m,1H,ArH),6.97(d,J＝8.0Hz,1H,ArH),6.94～6.91(m,1H,ArH),6.31(d,J＝2.0Hz,1H,CH),6.14(s,1H,CH),4.99(d,J＝15.6Hz,1H,CH),4.63(d,J＝15.6Hz,1H,CH),4.28(s,1H,CH),3.85(s,3H,OCH3);
13C NMR(CDCl3,100MHz)δ171.9,160.1,152.6,145.5,141.5,134.3,133.7,131.5,130.1,129.7,129.3,128.2,128.1,127.4,126.9,126.1,124.6,121.8,119.7,118.6,118.5,115.4,111.8,111.8,111.7,96.9,80.6,66.6,55.4,50.9,45.0;
IR(KBr)υ:3438,3028,2933,2232,1727,1606,1545,1484,1435,1356,1340,1299,1262,1235,1171,1039,970,851,816,785,736cm-1;
HRMS Calcd(ESI)m/z for C34H23Cl2N3NaO5[M+Na]+:646.0907,found:646.0910.
The structural characterization data for the product of formula 10 are as follows:
1H NMR(CDCl3,400MHz)δ7.73(s,1H,ArH),7.41～7.32(m,6H,ArH),7.22(dd,J1＝8.8Hz,J2＝2.4Hz,1H,ArH),6.94(dd,J1＝8.4Hz,J2＝2.0Hz,1H,ArH),6.89～6.85(m,2H,ArH),6.59(dd,J1＝8.4Hz,J2＝2.0Hz,1H,ArH),6.45～6.43(m,2H,ArH),6.40～6.37(m,2H,ArH),5.91(s,1H,CH),5.08(d,J＝15.6Hz,1H,CH),4.71(d,J＝15.6Hz,1H,CH),3.57(s,3H,OCH3);
13C NMR(CDCl3,100MHz)δ168.6,159.4,151.8,143.5,141.5,141.1,138.0,136.5,134.4,130.3,129.3,129.3,129.1,128.6,128.3,127.5,126.7,124.5,123.4,123.0,120.0,118.7,118.2,118.1,114.6,113.4,112.2,110.7,78.5,69.8,55.1,45.0;
IR(KBr)υ:3067,2938,2834,2216,1718,1685,1676,1654,1603,1546,1484,1419,1332,1262,1228,1170,1040,990,871,814,792,747,700cm-1;
HRMS Calcd(ESI)m/z for C34H22Cl2N2NaO3[M+Na]+:599.0900,found:599.0910.
Example 6
Preparation of 1 '-benzyl-8-chloro-5' -fluoro-4- (3-methoxyphenyl) -3 a-nitro-2 '-oxo-3 a,9 b-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (11) and 1 '-benzyl-8-chloro-5' -fluoro-4- (3-methoxyphenyl) -2 '-oxo-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (12)
In a 50mL round bottom flask, 6-chloro-2- (3-methoxyphenyl) -3-nitro-2H-benzopyran (0.2 mmol,63.4 mg), 1-benzyl-3- (1-cyanovinyl) -5-fluoro-2-oxoindolin-3-ylcarbonate (0.3 mmol,122.4 mg), acetonitrile (5 mL) and then 4-dimethylaminopyridine (0.2 mmol,24.4 mg) were added and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the product was purified by column chromatography to give 23.0mg of white solid 1 (compound represented by formula 11), melting point 235-237 ℃, yield 19% and 64.9mg of white solid 2 (compound represented by formula 12), melting point 250-252 ℃, yield 58%.
The structural characterization data for the product of formula 11 are as follows:
1H NMR(CDCl3,400MHz)δ7.39(t,J＝8.0Hz,1H,ArH),7.34～7.29(m,3H,ArH),7.22(dd,J1＝8.8Hz,J2＝2.4Hz,1H,ArH),7.19～7.16(m,1H,ArH),7.14～7.11(m,2H,ArH),7.06(d,J＝9.2Hz,1H,ArH),7.05～7.03(m,2H,ArH),7.02～6.99(m,1H,ArH),6.98(d,J＝8.8Hz,1H,ArH),6.94～6.92(m,1H,ArH),6.81(dd,J1＝8.8Hz,J2＝4.0Hz,1H,ArH),6.30(d,J＝2.4Hz,1H,CH),6.18(s,1H,CH),5.00(d,J＝16.0Hz,1H,CH),4.63(d,J＝16.0Hz,1H,CH),4.27(s,1H,CH),3.85(s,3H,OCH3);
13C NMR(CDCl3,100MHz)δ172.0,160.1,160.0(d,J＝244.0Hz),152.6,145.4,138.9,134.3,133.8,130.1,129.7,129.3,128.1,127.9(d,J＝8.0Hz),127.4,126.8,126.1,121.9,119.7,118.6,118.5,118.0(d,J＝24.0Hz),115.4,112.3(d,J＝25.0Hz),111.8,111.7,111.6(d,J＝8.0Hz),96.9,80.6,66.8,55.4,50.9,45.0;
IR(KBr)υ:3433,2938,2839,2233,1723,1603,1547,1489,1454,1343,1293,1257,1237,1172,1037,941,867,851,812,794,716cm-1;
HRMS Calcd(ESI)m/z for C34H23ClFN3NaO5[M+Na]+:630.1202,found:630.1194.
the structural characterization data for the product of formula 12 are as follows:
1H NMR(CDCl3,400MHz)δ7.73(s,1H,ArH),7.41～7.34(m,6H,ArH),7.22(dd,J1＝8.8Hz,J2＝2.4Hz,1H,ArH),6.89～6.85(m,2H,ArH),6.68(td,J1＝8.8Hz,J2＝2.4Hz,1H,ArH),6.59(dd,J1＝8.4Hz,J2＝2.4Hz,1H,ArH),6.47(d,J＝8.0Hz,1H,ArH),6.44(dd,J1＝8.8Hz,J2＝4.0Hz,1H,ArH),6.40～6.39(m,1H,ArH),6.17(dd,J1＝7.6Hz,J2＝2.8Hz,1H,ArH),5.92(s,1H,CH),5.09(d,J＝15.6Hz,1H,CH),4.69(d,J＝15.6Hz,1H,CH),3.55(s,3H,OCH3);
13C NMR(CDCl3,100MHz)δ168.7,159.4,159.0(d,J＝242.0Hz),151.8,143.5,141.1,139.0,137.9,136.6,134.5,130.7,129.3,129.1,128.9,128.2,127.5,126.8,123.4,123.0(d,J＝8.0Hz),120.1,118.9,118.3,118.1,115.9(d,J＝23.0Hz),114.6,113.4,112.2,110.5(d,J＝9.0Hz),78.5,70.0,55.0,45.0;
IR(KBr)υ:3062,2833,2216,1709,1601,1491,1451,1417,1340,1268,1236,1169,1095,1040,994,872,811,790,761,738cm-1;
HRMS Calcd(ESI)m/z for C34H22ClFN2NaO3[M+Na]+:583.1195,found:583.1203.
example 7
Preparation of 1 '-benzyl-8-chloro-4- (3-methoxyphenyl) -5' -methyl-3 a-nitro-2 '-oxo-3 a,9 b-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (13) and 1 '-benzyl-8-chloro-4- (3-methoxyphenyl) -5' -methyl-2 '-oxo-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (14)
In a 50mL round bottom flask, 6-chloro-2- (3-methoxyphenyl) -3-nitro-2H-benzopyran (0.2 mmol,63.4 mg), 1-benzyl-3- (1-cyanovinyl) -5-methyl-2-oxoindolin-3-ylcarbonate (0.3 mmol,121.2 mg), acetonitrile (5 mL) and then 4-dimethylaminopyridine (0.2 mmol,24.4 mg) were added and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the purified product was separated by column chromatography to give 20.5mg of white solid 1 (compound represented by formula 13), melting point 256-258 ℃, yield 17% and 63.4mg of white solid 2 (compound represented by formula 14), melting point 214-216 ℃, yield 57%.
The structural characterization data for the product of formula 13 are as follows:
1H NMR(CDCl3,400MHz)δ7.37(t,J＝8.0Hz,1H,ArH),7.31～7.26(m,2H,ArH),7.20～7.17(m,3H,ArH),7.08(s,1H,ArH),7.05～7.03(m,3H,ArH),7.00～6.98(m,2H,ArH),6.95～6.92(m,1H,ArH),6.74(d,J＝8.4Hz,1H,ArH),6.31(d,J＝2.0Hz,1H,CH),6.19(s,1H,CH),4.96(d,J＝15.6Hz,1H,CH),4.62(d,J＝15.6Hz,1H,CH),4.28(s,1H,CH),3.83(s,3H,OCH3),2.39(s,3H,CH3);
13C NMR(CDCl3,100MHz)δ172.2,160.0,152.6,144.9,140.5,134.5,134.5,134.3,131.7,130.1,129.4,129.1,127.9,127.3,126.9,126.5,124.7,122.6,119.5,119.1,118.6,115.4,112.1,111.7,110.4,97.0,80.6,66.8,55.4,51.0,44.8,21.2;
IR(KBr)υ:3029,2993,2935,2835,2360,2341,2231,1710,1601,1544,1491,1360,1338,1260,1230,1185,1167,1044,874,815,794cm-1;
HRMS Calcd(ESI)m/z for C35H26ClN3NaO5[M+Na]+:626.1453,found:626.1430.
the product structure characterization data of formula 14 are as follows:
1H NMR(CDCl3,400MHz)δ7.71(s,1H,ArH),7.39～7.35(m,4H,ArH),7.33～7.29(m,2H,ArH),7.21～7.18(m,1H,ArH),6.85～6.81(m,2H,ArH),6.75(d,J＝8.0Hz,1H,ArH),6.53(d,J＝8.0Hz,1H,ArH),6.43(d,J＝8.0Hz,2H,ArH),6.28(s,1H,ArH),6.14(s,1H,CH),5.88(s,1H,CH),5.01(d,J＝15.6Hz,1H,CH),4.79(d,J＝15.2Hz,1H,CH),3.47(s,3H,OCH3),1.99(s,3H,CH3);
13C NMR(CDCl3,100MHz)δ168.9,159.2,151.7,143.1,141.9,140.5,138.5,135.7,135.1,132.8,130.5,129.6,129.0,129.0,128.0,127.6,126.6,124.9,123.3,121.2,120.5,118.8,118.4,118.0,114.4,113.7,112.0,109.5,78.6,70.3,54.8,44.9,20.6;
IR(KBr)υ:3065,2992,2836,2211,1708,1600,1495,1416,1375,1332,1258,1235,1192,1165,1098,1081,1039,984,814,787,703cm-1;
HRMS Calcd(ESI)m/z for C35H25ClN2NaO3[M+Na]+:579.1446,found:579.1416.
Example 8
Preparation of 1 '-butyl-5' -chloro-3 a-nitro-2 '-oxo-4- (p-tolyl) -3a,9 b-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (15) and 1 '-butyl-5' -chloro-2 '-oxo-4- (p-tolyl) -4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (16)
In a 50mL round bottom flask, 3-nitro-2- (p-tolyl) -2H-benzopyran (0.2 mmol,53.4 mg) tert-butyl (1-butyl-5-chloro-3- (1-cyanovinyl) -2-oxoindolin-3-yl) carbonate (0.3 mmol,117 mg), acetonitrile (5 mL) and then 4-dimethylaminopyridine (0.2 mmol,24.4 mg) were added and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the product was purified by column chromatography to give 10.8mg of white solid 1 (compound represented by formula 15), melting point 263-265 ℃, yield 10% and 69.8mg of white solid 2 (compound represented by formula 16), melting point 182-184 ℃, yield 71%.
The structural characterization data for the product of formula 15 are as follows:
1H NMR(CDCl3,400MHz)δ7.48(dd,J1＝8.4Hz,J2＝2.0Hz,1H,ArH),7.38(d,J＝2.0Hz,1H,ArH),7.29～7.26(m,4H,ArH),7.22～7.18(m,1H,ArH),7.07～7.05(m,2H,ArH),6.93(d,J＝8.4Hz,1H,ArH),6.79～6.75(m,1H,ArH),6.34(d,J＝7.6Hz,1H,CH),6.07(s,1H,CH),4.28(s,1H,CH),3.68～3.61(m,1H,CH),3.49～3.41(m,1H,CH),2.41(s,3H,CH3),1.51～1.41(m,1H,CH),1.38～1.29(m,1H,CH),1.23～1.07(m,2H,CH2),0.83(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ171.7,154.1,145.9,141.9,139.8,131.1,130.2,129.7,129.6,129.3,128.9,126.2,124.7,122.2,121.5,118.2,117.2,112.0,110.6,110.0,97.5,80.5,66.7,51.3,40.8,29.2,21.3,20.0,13.6;
IR(KBr)υ:3109,2956,2872,2229,1717,1610,1543,1488,1458,1426,1341,1229,1194,1156,1142,1093,1047,902,879,852,817,765,731cm-1;
HRMS Calcd(ESI)m/z for C31H26ClN3NaO4[M+Na]+:562.1504,found:562.1502.
the product structure characterization data of formula 16 are as follows:
1H NMR(CDCl3,400MHz)δ7.75(s,1H,ArH),7.34(dd,J1＝7.6Hz,J2＝1.6Hz,1H,ArH),7.28～7.26(m,1H,ArH),7.05～7.00(m,2H,ArH),6.90(d,J＝8.0Hz,1H,ArH),6.85～6.79(m,4H,ArH),6.52(d,J＝8.4Hz,1H,ArH),6.31(d,J＝2.0Hz,1H,CH),5.91(s,1H,CH),3.85～3.78(m,1H,CH),3.58～3.51(m,1H,CH),2.20(s,3H,CH3),1.67～1.63(m,2H,CH2),1.48～1.39(m,2H,CH2),0.99(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ168.5,153.4,144.1,141.8,140.4,139.0,137.1,134.2,131.1,128.8,128.7,128.3,126.6,124.8,123.5,123.4,121.7,119.6,117.0,116.7,113.6,109.7,78.3,69.7,41.0,29.3,21.1,20.1,13.7;
IR(KBr)υ:3032,2957,2931,2874,2208,1725,1629,1606,1542,1484,1450,1425,1377,1337,1222,1131,1111,987,957,887,809,762cm-1;
HRMS Calcd(ESI)m/z for C31H25ClN2NaO2[M+Na]+:515.1497,found:515.1497.
example 9
Preparation of 1 '-butyl-5' -methyl-3 a-nitro-2 '-oxo-4- (p-tolyl) -3a,9 b-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (17) and 1 '-butyl-5' -methyl-2 '-oxo-4- (p-tolyl) -4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (18)
In a 50mL round bottom flask, 3-nitro-2- (p-tolyl) -2H-benzopyran (0.2 mmol,53.4 mg) tert-butyl (1-butyl-3- (1-cyanovinyl) -5-methyl-2-oxoindolin-3-yl) carbonate (0.3 mmol,111 mg), acetonitrile (5 mL) and then 4-dimethylaminopyridine (0.2 mmol,24.4 mg) were added and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the product was purified by column chromatography to give 7.2mg of white solid 1 (compound represented by formula 17), melting point 268-270 ℃, yield 7% and 69.8mg of white solid 2 (compound represented by formula 18), melting point 156-158 ℃, yield 74%.
The structural characterization data for the product of formula 17 are as follows:
1H NMR(CDCl3,400MHz)δ7.30～7.25(m,5H,ArH),7.19～7.16(m,2H,ArH),7.06～7.03(m,2H,ArH),6.88(d,J＝8.0Hz,1H,ArH),6.75(t,J＝7.6Hz,1H,ArH),6.34(d,J＝7.6Hz,1H,CH),6.11(s,1H,CH),4.29(s,1H,CH),3.67～3.60(m,1H,CH),3.48～3.41(m,1H,CH),2.42(s,3H,CH3),2.40(s,3H,CH3),1.53～1.42(m,1H,CH),1.36～1.29(m,1H,CH),1.24～1.07(m,2H,CH2),0.83(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ172.1,154.0,145.3,141.0,139.7,134.0,131.3,130.5,129.6,129.1,127.4,126.4,1263,124.9,122.4,122.1,118.0,117.7,112.3,109.3,97.7,80.5,66.9,51.4,40.7,29.3,21.4,21.2,20.1,13.7;
IR(KBr)υ:3110,2954,2930,2870,2231,1709,1603,1543,1498,1458,1351,1320,1230,1183,1122,1045,1020,904,812,762cm-1.
HRMS Calcd(ESI)m/z for C32H29N3NaO4[M+Na]+:542.2050,found:542.2068.
the structural characterization data for the product of formula 18 are as follows:
1H NMR(CDCl3,400MHz)δ7.74(s,1H,ArH),7.35(dd,J1＝7.6Hz,J2＝1.6Hz,1H,ArH),7.26～7.22(m,1H,ArH),7.03～6.99(m,1H,ArH),6.89～6.84(m,2H,ArH),6.80(d,J＝8.0Hz,2H,ArH),6.74(d,J＝8.0Hz,2H,ArH),6.49(d,J＝8.0Hz,1H,ArH),6.13(s,1H,CH),5.89(s,1H,CH),3.83～3.76(m,1H,CH),3.59～3.52(m,1H,CH),2.17(s,3H,CH3),2.02(s,3H,CH3),1.69～1.64(m,2H,CH2),1.48～1.39(m,2H,CH2),0.99(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ168.7,153.3,143.7,141.3,140.9,138.4,136.5,134.6,132.4,130.8,129.1,128.4,126.6,125.2,123.4,121.6,120.1,117.3,116.7,113.9,108.6,78.4,70.3,40.8,29.4,21.0,20.6,20.1,13.7;
IR(KBr)υ:3031,2957,2874,2209,1717,1600,1541,1495,1450,1378,1342,1227,1190,1131,1032,984,887,805,762cm-1;
HRMS Calcd(ESI)m/z for C32H28N2NaO2[M+Na]+:473.2224,found:473.2233.
example 10
Preparation of 1 '-butyl-5' -fluoro-3 a-nitro-2 '-oxo-4- (p-tolyl) -3a,9 b-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (19) and 1 '-butyl-5' -fluoro-2 '-oxo-4- (p-tolyl) -4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (20)
In a 50mL round bottom flask, 3-nitro-2- (p-tolyl) -2H-benzopyran (0.2 mmol,53.4 mg) tert-butyl (1-butyl-3- (1-cyanovinyl) -5-fluoro-2-oxoindolin-3-yl) carbonate (0.3 mmol,112.2 mg) and acetonitrile (5 mL) were added first, followed by 4-dimethylaminopyridine (0.2 mmol,24.4 mg) and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the product was purified by column chromatography to give 11.5mg of white solid 1 (compound represented by formula 19), melting point 270-272 ℃, yield 11% and 63.8mg of white solid 2 (compound represented by formula 20), melting point 144-146 ℃, yield 67%.
The structural characterization data for the product of formula 19 are as follows:
1H NMR(CDCl3,400MHz)δ7.30～7.26(m,4H,ArH),7.25～7.20(m,2H,ArH),7.17～7.15(m,1H,ArH),7.07～7.05(m,1H,ArH),6.94(dd,J1＝8.0Hz,J2＝4.0Hz,1H,ArH),6.79～6.75(m,1H,ArH),6.33(d,J＝7.6Hz,1H,CH),6.10(s,1H,CH),4.27(s,1H,CH),3.68～3.61(m,1H,CH),3.49～3.41(m,1H,CH),2.41(s,3H,CH3),1.51～1.42(m,1H,CH),1.38～1.29(m,1H,CH),1.22～1.06(m,2H,CH2),0.84(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ171.9,159.8(d,J＝243.0Hz),154.1,145.8,139.8,139.4,130.3,129.6,129.3,128.8(d,J＝8.0Hz),126.2,122.2,121.6,118.1,117.6(d,J＝23.0Hz),117.3,112.6,112.3,112.0,110.3(d,J＝8.0Hz),97.6,80.5,66.9,51.3,40.8,29.2,21.3,20.0,13.6;
IR(KBr)υ:3110,2963,2938,2874,2231,1713,1611,1544,1492,1457,1346,1272,1230,1184,1117,1069,1048,906,876,813,766cm-1;
HRMS Calcd(ESI)m/z for C31H26FN3NaO4[M+Na]+:546.1800,found:546.1792.
the structural characterization data for the product of formula 20 are as follows:
1H NMR(CDCl3,400MHz)δ7.75(s,1H,ArH),7.36～7.34(m,1H,ArH),7.28～7.26(m,1H,ArH),7.05～7.01(m,1H,ArH),6.92～6.90(m,1H,ArH),6.87～6.85(m,2H,ArH),6.80～6.76(m,3H,ArH),6.50(dd,J1＝8.8Hz,J2＝4.4Hz,1H,ArH),6.15(dd,J1＝7.6Hz,J2＝2.4Hz,1H,CH),5.93(s,1H,CH),3.85～3.78(m,1H,CH),3.54～3.47(m,1H,CH),2.18(s,3H,CH3),1.70～1.62(m,2H,CH2),1.48～1.39(m,2H,CH2),0.99(t,J＝7.6Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ168.6,159.0(d,J＝241.0Hz),153.5,144.0,140.5,139.3,138.9,137.4,134.0,131.0,128.6,128.4(d,J＝85.0Hz),126.7,123.5,121.8,119.7,117.2,116.8,115.3(d,J＝23.0Hz),113.5,112.3(d,J＝25.0Hz),109.4(d,J＝9.0Hz),78.3,70.0,41.0,29.3,21.0,20.0,13.7;
IR(KBr)υ:3055,2963,2933,2872,2212,1708,1614,1491,1451,1377,1342,1270,1231,1181,1132,987,916,811,767,753cm-1;
HRMS Calcd(ESI)m/z for C31H25FN2NaO2[M+Na]+:499.1792,found:499.1793.
Example 11
Preparation of 1 '-butyl-8-chloro-4- (3-chlorophenyl) -5' -methyl-3 a-nitro-2 '-oxo-3 a,9 b-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (21) and 1 '-butyl-8-chloro-4- (3-chlorophenyl) -5' -methyl-2 '-oxo-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (22)
In a 50mL round bottom flask, 6-chloro-2- (3-chlorophenyl) -3-nitro-2H-benzopyran (0.2 mmol,64.0 mg) tert-butyl (1-butyl-3- (1-cyanovinyl) -5-methyl-2-oxoindol-3-yl) carbonate (0.3 mmol,111 mg) was first added, acetonitrile (5 mL), followed by 4-dimethylaminopyridine (0.2 mmol,24.4 mg) and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the product was purified by column chromatography to give 33.2mg of white solid 1 (compound represented by formula 21), melting point 257-259 ℃ C., yield 29% and 49.4mg of white solid 2 (compound represented by formula 22), melting point 170-172 ℃ C., yield 47%.
The structural characterization data for the product of formula 21 are as follows:
1H NMR(CDCl3,400MHz)δ7.46～7.38(m,3H,ArH),7.33(d,J＝8.0Hz,1H,ArH),7.29～7.26(m,1H,ArH),7.19～7.15(m,2H,ArH),7.04～7.00(m,2H,ArH),6.99(d,J＝7.6Hz,1H,ArH),6.30～6.27(m,1H,CH),6.13(s,1H,CH),4.24(s,1H,CH),3.73～3.68(m,1H,CH),3.46～3.39(m,1H,CH),2.43(s,3H,CH3),1.55～1.49(m,1H,CH),1.35～1.27(m,1H,CH),1.22～1.09(m,2H,CH2),0.87(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ171.8,152.3,144.4,140.8,135.1,134.4,131.8,130.2,130.0,129.3,127.3,126.7,126.5,126.2,124.8,124.5,122.9,119.4,119.2,112.0,109.5,97.1,80.1,66.7,51.2,40.8,29.3,21.2,20.1,13.7;
IR(KBr)υ:2958,2930,2872,2214,1708,1601,1540,1484,1351,1253,1229,1201,1143,1126,1098,1046,975,873,814,783,747cm-1;
HRMS Calcd(ESI)m/z for C31H25Cl2N3NaO4[M+Na]+:596.1114,found:596.1107.
the product structure characterization data of formula 22 are as follows:
1H NMR(CDCl3,400MHz)δ7.68(s,1H,ArH),7.33(d,J＝2.4Hz,1H,ArH),7.21(dd,J1＝8.8Hz,J2＝2.4Hz,1H,ArH),7.02(d,J＝8.0Hz,1H,ArH),6.94(t,J＝7.6Hz,1H,ArH),6.90～6.86(m,3H,ArH),6.84(d,J＝8.8Hz,1H,ArH),6.55(d,J＝8.0Hz,1H,ArH),6.23(s,1H,CH),5.92(s,1H,CH),3.87～3.80(m,1H,CH),3.59～3.52(m,1H,CH),2.10(s,3H,CH3),1.72～1.64(m,2H,CH2),1.48～1.39(m,2H,CH2),0.99(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ168.3,151.6,142.7,140.8,140.7,138.5,136.5,134.1,132.9,130.5,130.1,129.1,128.9,127.1,126.9,124.9,124.7,123.4,121.0,120.9,118.5,118.0,113.5,108.9,78.1,70.4,40.9,29.5,20.8,20.1,13.7;
IR(KBr)υ:3065,2967,2932,2857,2213,1707,1600,1534,1495,1439,1414,1340,1243,1213,1195,1137,1095,972,889,828,786,719,702cm-1;
HRMS Calcd(ESI)m/z for C31H24Cl2N2NaO2[M+Na]+:549.1107,found:549.1116.
example 12
Preparation of 1 '-butyl-5' -chloro-4- (2-methoxyphenyl) -3 a-nitro-2 '-oxo-3 a,9 b-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (23) and 1 '-butyl-5' -chloro-4- (2-methoxyphenyl) -2 '-oxo-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carbonitrile (24)
In a 50mL round bottom flask, first was added tert-butyl 2- (2-methoxyphenyl) -3-nitro-2H-benzopyran (0.2 mmol,56.6 mg), (1-butyl-5-chloro-3- (1-cyanovinyl) -2-oxoindolin-3-yl) carbonate (0.3 mmol,117 mg), acetonitrile (5 mL), followed by 4-dimethylaminopyridine (0.2 mmol,24.4 mg) and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the product was purified by column chromatography to give 21.0mg of white solid 1 (compound represented by formula 23), melting point 216-218 ℃, yield 19% and 64.0mg of white solid 2 (compound represented by formula 24), melting point 158-160 ℃, yield 63%.
The structural characterization data for the product of formula 23 are as follows:
1H NMR(CDCl3,400MHz)δ7.48～7.38(m,4H,ArH),7.20～7.17(m,1H,ArH),7.07～7.03(m,3H,ArH),6.98(d,J＝7.6Hz,1H,ArH),6.91(d,J＝8.0Hz,1H,ArH),6.76(t,J＝7.6HZ,1H,ArH),6.54(s,1H,CH),6.36(d,J＝7.2Hz,1H,CH),4.28(s,1H,CH),3.90(s,3H,CH3),3.72～3.65(m,1H,CH),3.44～3.37(m,1H,CH),1.48～1.40(m,1H,CH),1.33～1.29(m,1H,CH),1.21～1.06(m,2H,CH2),0.83(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ171.6,155.8,154.0,147.2,142.1,130.9,130.5,129.4,129.2,129.2,127.2,126.2,124.7,122.5,122.1,121.4,119.0,118.0,117.4,112.4,110.6,110.4,98.4,74.6,66.4,55.6,51.3,40.7,29.2,20.0,13.6;
IR(KBr)υ:2966,2934,2875,2229,1717,1608,1546,1487,1458,1430,1340,1248,1119,1043,904,816,776,758cm-1;
HRMS Calcd(ESI)m/z for C31H26ClN3NaO5[M+Na]+:578.1453,found:578.1444.
the structural characterization data for the product of formula 24 are as follows:
1H NMR(CDCl3,400MHz)δ7.74(s,1H,ArH),7.31(d,J＝6.8Hz,1H,ArH),7.22(d,J＝7.2Hz,1H,ArH),7.13～6.98(m,5H,ArH),6.84(d,J＝7.6Hz,1H,ArH),6.78～6.70(m,1H,ArH),6.60(d,J＝8.0HZ,1H,ArH),6.45～6.38(m,2H,ArH),6.22(s,1H,CH),3.92～3.85(m,1H,CH),3.58～3.53(m,1H,CH),3.48(s,3H,CH3),1.72～1.65(m,2H,CH2),1.49～1.40(m,2H,CH2),0.99(t,J＝6.8Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ168.6,153.5,144.1,142.2,136.5,130.9,130.3,129.0,128.2,128.0,124.6,123.6,123.3,121.2,120.6,119.2,116.6,116.4,113.6,110.0,109.2,69.7,55.1,46.1,40.9,29.5,20.0,13.7;
IR(KBr)υ:3066,2960,2934,2872,2839,2211,1721,1600,1543,1485,1451,1379,1337,1253,1223,1188,1136,1106,1029,989,881,815,751cm-1;
HRMS Calcd(ESI)m/z for C31H25ClN2NaO3[M+Na]+:531.1446,found:531.1445.
example 13
Preparation of methyl 1 '-butyl-8-chloro-4- (3-methoxyphenyl) -5' -methyl-3 a-nitro-2 '-oxo-3 a,9 b-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carboxylate (25) and methyl 1 '-butyl-8-chloro-4- (3-methoxyphenyl) -5' -methyl-2 '-oxo-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carboxylate (26)
Example 13a: in a 50mL round bottom flask, 6-chloro-2- (3-methoxyphenyl) -3-nitro-2H-benzopyran (0.2 mmol,63.4 mg), methyl 2- (3- ((tert-butoxycarbonyl) oxy) -1-butyl-5-methyl-2-oxoindolin-3-yl) acrylate (0.3 mmol,120.9 mg), acetonitrile (5 mL) and then 4-dimethylaminopyridine (0.2 mmol,24.4 mg) were added and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the purified product was separated by column chromatography to give 21.6mg of white solid 1 (compound represented by formula 25), melting point 250-252℃in 18% yield and 52.2mg of white solid 2 (compound represented by formula 26), melting point 210-212℃in 47% yield.
The structural characterization data for the product of formula 25 are as follows:
1H NMR(CDCl3,400MHz)δ7.35(t,J＝8.0Hz,1H,ArH),7.24(d,J＝7.6Hz,1H,ArH),7.15(s,1H,ArH),7.13(dd,J1＝8.4Hz,J2＝2.4Hz,1H,ArH),7.05(s,1H,ArH),7.00～6.96(m,3H,ArH),6.95～6.93(m,1H,ArH),6.87(d,J＝8.0Hz,1H,ArH),6.27(d,J＝2.0Hz,1H,CH),6.04(s,1H,CH),4.21(s,1H,CH),3.83(s,3H,OCH3),3.72～3.65(m,1H,CH),3.63(s,3H,OCH3),3.46～3.39(m,1H,CH),2.38(s,3H,CH3),1.55～1.50(m,1H,CH),1.35～1.28(m,1H,CH),1.24～1.12(m,2H,CH2),0.88(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ173.8,161.8,159.9,152.5,141.1,140.7,140.4,135.0,133.3,130.3,130.2,129.8,128.8,126.7,126.4,123.8,119.9,119.2,118.8,115.3,111.7,108.7,96.5,80.8,64.8,55.4,52.4,51.7,40.5,29.5,21.2,20.2,13.7;
IR(KBr)υ:2954,2928,2871,1724,1707,1603,1540,1496,1455,1359,1288,1255,1232,1185,1139,1049,883,814,774,758,740cm-1;
HRMS Calcd(ESI)m/z for C33H32ClN2O7[M+H]+:603.1893,found:603.1874.
The structural characterization data for the product of formula 26 are as follows:
1H NMR(CDCl3,400MHz)δ7.86(s,1H,ArH),7.37(s,1H,ArH),7.15(d,J＝7.6Hz,1H,ArH),6.92～6.88(m,1H,ArH),6.80～6.76(m,2H,ArH),6.57(d,J＝8.0Hz,1H,ArH),6.51(d,J＝7.2Hz,1H,ArH),6.47(d,J＝7.6Hz,1H,ArH),6.39(s,1H,ArH),6.12(s,1H,CH),5.87(s,1H,CH),3.85～3.78(m,1H,CH),3.60(s,3H,OCH3),3.57(s,3H,OCH3),3.53～3.49(m,1H,CH),1.99(s,3H,CH3),1.70～1.66(m,2H,CH2),1.48～1.43(m,2H,CH2),0.99(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ170.7,161.9,159.1,151.7,143.1,141.4,140.9,139.6,138.7,135.6,131.5,129.8,128.7,128.6,126.3,124.2,124.0,123.2,119.3,119.2,117.8,114.1,112.4,108.2,78.7,67.9,54.9,51.6,40.6,29.4,20.7,20.2,13.8;
IR(KBr)υ:2956,2871,1713,1601,1496,1465,1435,1415,1343,1233,1197,1137,1095,1040,977,879,810,783,748cm-1;
HRMS Calcd(ESI)m/z for C33H30ClNNaO5[M+Na]+:578.1705,found:578.1687.
Example 13b: in a 50mL round bottom flask, 6-chloro-2- (3-methoxyphenyl) -3-nitro-2H-benzopyran (0.2 mmol,63.4 mg), methyl 2- (3- ((tert-butoxycarbonyl) oxy) -1-butyl-5-methyl-2-oxoindolin-3-yl) acrylate (0.3 mmol,120.9 mg), dichloromethane (5 mL) were added followed by 1, 8-diazabicyclo [5.4.0] undec-7-ene (0.2 mmol,30.4 mg) and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the purified product was separated by column chromatography to give 58.9mg of white solid 1 (compound represented by formula 25), melting point 250-252℃in 49% yield and 19.9mg of white solid 2 (compound represented by formula 26), melting point 210-212℃in 18% yield.
Example 14
Preparation of methyl 1 '-butyl-5' -fluoro-3 a-nitro-2 '-oxo-4- (p-tolyl) -3a,9 b-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carboxylate (27) and methyl 1 '-butyl-5' -fluoro-2 '-oxo-4- (p-tolyl) -4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carboxylate (28)
In a 50mL round bottom flask, 3-nitro-2- (p-tolyl) -2H-benzopyran (0.2 mmol,53.4 mg), methyl 2- (3- ((tert-butoxycarbonyl) oxy) -1-butyl-5-fluoro-2-oxoindol-3-yl) acrylate (0.3 mmol,122.1 mg), acetonitrile (5 mL) followed by 4-dimethylaminopyridine (0.2 mmol,24.4 mg) were added and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the product was purified by column chromatography to give 20.0mg of white solid 1 (compound represented by formula 27), melting point 200-202 ℃, yield 18% and 48.8mg of white solid 2 (compound represented by formula 28), melting point 212-214 ℃, yield 48%.
The product structure characterization data of formula 27 are as follows:
1H NMR(CDCl3,400MHz)δ7.30(d,J＝8.0Hz,2H,ArH),7.25～7.24(m,1H,ArH),7.18～7.10(m,3H,ArH),7.04～7.01(m,2H,ArH),6.88(dd,J1＝8.4Hz,J2＝4.0Hz,1H,ArH),6.76～6.72(m,1H,ArH),6.32(d,J＝7.6Hz,1H,CH),6.06(s,1H,CH),4.26(s,1H,CH),3.63(s,3H,OCH3),3.62～3.57(m,1H,CH),3.48～3.40(m,1H,CH),2.40(s,3H,CH3),1.48～1.42(m,1H,CH),1.36～1.29(m,1H,CH),1.26～1.09(m,2H,CH2),0.84(t,J＝7.6Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ173.9,161.8,159.5(d,J＝241.0Hz),154.1,141.4,140.2,139.8,139.4,132.3(d,J＝8.0Hz),130.9,129.5,128.9,126.5,126.4,121.9,117.9,117.9,116.0(d,J＝23.0Hz),111.5(d,J＝25.0Hz),109.4(d,J＝8.0Hz),96.9,80.7,80.6,65.1,52.4,52.4,51.8,40.6,29.3,21.3,20.2,13.7;
IR(KBr)υ:2957,2872,1712,1614,1545,1492,1456,1336,1260,1227,1185,1135,1049,903,812,756cm-1；
HRMS Calcd(ESI)m/z for C32H30FN2O6[M+H]+:557.2082,found:557.2052.
the structural characterization data for the product of formula 28 are as follows:
1H NMR(CDCl3,400MHz)δ7.92(s,1H,ArH),7.39(dd,J1＝7.6Hz,J2＝1.2Hz,1H,ArH),7.24～7.20(m,1H,ArH),7.01(t,J＝7.2Hz,1H,ArH),6.87(d,J＝8.0Hz,2H,ArH),6.82(d,J＝8.0Hz,2H,ArH),6.77(d,J＝8.0Hz,2H,ArH),6.69(td,J1＝9.2Hz,J2＝2.8Hz,1H,ArH),6.41(dd,J1＝8.8Hz,J2＝4.0Hz,1H,ArH),6.09(dd,J1＝8.0Hz,J2＝2.8Hz,1H,CH),5.91(s,1H,CH),3.85～3.78(m,1H,CH),3.57(s,3H,OCH3),3.47～3.40(m,1H,CH),2.19(s,3H,CH3),1.69～1.62(m,2H,CH2),1.50～1.40(m,2H,CH2),0.99(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ170.9,161.9,158.8(d,J＝240.0Hz),153.4,141.8,140.8,140.1,139.7,138.5,137.1,134.4,130.5,128.4,126.8,123.5,121.5,117.9,116.6,114.0(d,J＝25.0Hz),111.2(d,J＝26.0Hz),108.7(d,J＝8.0Hz),78.4,67.6,51.6,40.7,29.3,21.0,20.2,13.8;
IR(KBr)υ:3161,2956,2872,1719,1684,1604,1493,1455,1355,1270,1244,1154,1106,951,899,820,765cm-1;
HRMS Calcd(ESI)m/z for C32H28FNNaO4[M+H]+:532.1895,found:532.1892.
Example 15
Preparation of methyl 1 '-butyl-5' -methyl-3 a-nitro-2 '-oxo-4- (p-tolyl) -3a,9 b-dihydro-4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carboxylate (29) and methyl 1 '-butyl-5' -methyl-2 '-oxo-4- (p-tolyl) -4H-spiro [ cyclopenta [ c ] benzopyran-1, 3' -indoline ] -2-carboxylate (30)
In a 50mL round bottom flask, 3-nitro-2- (p-tolyl) -2H-benzopyran (0.2 mmol,53.4 mg), methyl 2- (3- ((tert-butoxycarbonyl) oxy) -1-butyl-5-methyl-2-oxoindol-3-yl) acrylate (0.3 mmol,120.9 mg), acetonitrile (5 mL) followed by 4-dimethylaminopyridine (0.2 mmol,24.4 mg) were added and stirred at room temperature for 4H. After completion of the TLC monitoring reaction, the purified product was separated by column chromatography to give 17.6mg of white solid 1 (compound represented by formula 29), melting point 228-230 ℃, yield 16% and 47.5mg of white solid 2 (compound represented by formula 30), melting point 218-220 ℃, yield 47%.
The structural characterization data for the product of formula 29 are as follows:
1H NMR(CDCl3,400MHz)δ7.37(d,J＝8.0Hz,2H,ArH),7.26～7.20(m,3H,ArH),7.17～7.12(m,2H,ArH),7.07(s,1H,ArH),7.02(d,J＝8.0Hz,1H,ArH),6.83(d,J＝7.6Hz,1H,ArH),6.72(t,J＝7.6Hz,1H,ArH),6.33(d,J＝7.6Hz,1H,ArH),6.07(s,1H,CH),4.29(s,1H,CH),3.61(s,3H,OCH3),3.60～3.56(m,1H,CH),3.48～3.41(m,1H,CH),2.40(s,3H,CH3),2.36(s,3H,CH3),1.53～1.43(m,1H,CH),1.41～1.30(m,1H,CH),1.27～1.11(m,2H,CH2),0.84(t,J＝7.2Hz,3H,CH3);
13C NMR(100MHz,CDCl3)δ174.1,162.0,154.0,141.4,140.8,140.7,139.3,133.0,131.0,130.7,129.9,129.4,128.7,126.7,126.5,123.9,121.8,118.2,117.8,108.5,97.1,80.7,65.0,52.3,51.9,40.4,29.4,21.3,21.2,20.2,13.7;
IR(KBr)υ:2956,2872,1730,1701,1604,1541,1496,1457,1437,1353,1332,1261,1231,1135,1049,899,812,755cm-1;
HRMS Calcd(ESI)m/z for C33H32N2NaO6[M+Na]+:575.2153,found:575.2145.
the structural characterization data for the product of formula 30 are as follows:
1H NMR(CDCl3,400MHz)δ7.93(s,1H,ArH),7.39(dd,J1＝7.6Hz,J2＝1.2Hz,1H,ArH),7.19(td,J1＝8.0Hz,J2＝1.2Hz,1H,ArH),6.99(t,J＝7.6Hz,1H,ArH),6.84(d,J＝8.0Hz,1H,ArH),6.77～6.71(m,5H,ArH),6.43(d,J＝8.0Hz,1H,ArH),6.07(s,1H,CH),5.87(s,1H,CH),3.84～3.77(m,1H,CH),3.56(s,3H,OCH3),3.54～3.47(m,1H,CH),2.17(s,3H,CH3),1.96(s,3H,CH3),1.72～1.64(m,2H,CH2),1.50～1.41(m,2H,CH2),1.00(t,J＝7.2Hz,3H,CH3);
13C NMR(CDCl3,100MHz)δ171.0,162.2,153.2,142.7,141.3,140.4,138.0,136.2,135.1,131.5,130.2,128.7,128.2,128.0,126.7,124.6,124.2,123.4,121.4,118.0,116.5,108.1,78.4,67.8,51.6,51.5,40.6,29.5,21.0,20.6,20.2,13.8;
IR(KBr)υ:2956,1948,1927,1850,1813,1752,1734,1718,1710,1685,1604,1576,1483,1437,1388,1343,1332,1230,1136,966,811,756cm-1;
HRMS Calcd(ESI)m/z for C33H31NNaO4[M+Na]+:528.2145,found:528.2121.
the examples provided above show that the preparation method of the spiroindole compound containing benzopyran ring provided by the invention prepares the spiroindole derivative containing benzopyran ring through the base catalytic reaction of nitrochromene and isatin MBH carbonate, and the method is efficient, economical, green, wide in substrate expansion range, mild in reaction condition, high in yield, and simple in preparation operation and post-treatment steps.
The present invention has been disclosed in the preferred embodiments, but the invention is not limited thereto, and the technical solutions obtained by adopting equivalent substitution or equivalent transformation fall within the protection scope of the present invention.
Claims (8)
1. A spiroindole compound containing benzopyran ring is characterized in that the structural general formula is shown in the formula III-1 to III-4:
Wherein R 1 is selected from H, cl or Br;
R 2 is selected from m-OCH 3、m-Cl、p-CH3 or o-OCH 3;
r 3 is selected from H, cl, F or Me;
R 4 is selected from Bn or n-Bu;
r 5 is selected from H, cl, F or Me;
R 6 is selected from Bn or n-Bu.
2. The process for producing a benzopyran ring-containing spiroindole compound according to claim 1, which comprises:
Reacting a compound shown in a formula I with a compound shown in a formula II-1 or a formula II-2 in an organic solvent under the catalysis of alkali to obtain compounds shown in a formula III-1 to a formula III-4:
Wherein R 1 is selected from H, cl or Br;
R 2 is selected from m-OCH 3、m-Cl、p-CH3 or o-OCH 3;
r 3 is selected from H, cl, F or Me;
R 4 is selected from Bn or n-Bu;
r 5 is selected from H, cl, F or Me;
R 6 is selected from Bn or n-Bu.
3. The preparation method of the benzopyran ring-containing spiroindole compound according to claim 2, which is characterized in that the feeding mole ratio of the compound shown in the formula I to the compound shown in the formula II-1 or the compound shown in the formula II-2 to alkali is 1:1.5:1.
4. The method for preparing a benzopyran ring-containing spiroindole compound according to claim 2, wherein the base is one or more selected from potassium carbonate, sodium carbonate, cesium carbonate, triphenylphosphine, triethylamine, 1, 4-diazabicyclo [2.2.2] octane, 4-dimethylaminopyridine, and 1, 8-diazabicyclo [5.4.0] undec-7-ene.
5. The method for preparing a benzopyran ring-containing spiroindole compound according to claim 2, wherein the organic solvent is one or more selected from tetrahydrofuran, toluene, ethyl acetate, acetonitrile, 1, 2-dichloroethane, ethanol, dichloromethane and chloroform.
6. The preparation method of the benzopyran ring-containing spiroindole compound according to claim 2, wherein the reaction is carried out in an air environment after adding the compound shown in formula I, the compound shown in formula II-1 or formula II-2 and the organic solvent, adding the alkali.
7. The process for producing a benzopyran ring-containing spiroindole compound according to claim 2, wherein the reaction temperature is 20 to 25℃and the reaction time is 2 to 6 hours.
8. The process for preparing a benzopyran ring-containing spiroindole compound according to claim 2, wherein the organic solvent is added in an amount such that the molar concentration of the compound of formula I is 0.03 to 0.04mol/L.
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