CN113979918A - C-3-position five-membered spiro indolone derivative containing all-carbon tetra-substituted olefin structure and preparation and application thereof - Google Patents
C-3-position five-membered spiro indolone derivative containing all-carbon tetra-substituted olefin structure and preparation and application thereof Download PDFInfo
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Abstract
The invention discloses a C-3 position pentanary spiro indolone derivative containing an all-carbon tetra-substituted olefin structure, a preparation method and application thereof, belonging to the technical field of organic chemical synthesis and comprising the following steps: adding 2-iodoaryl acrylamide compound with eneyne, phenylboronic acid compound, organic ligand and alkali into an organic solvent, and reacting under the action of a catalyst to obtain the C-3-bit five-membered spiro indolone derivative containing an all-carbon four-substituted olefin structure. The invention adopts one-pot synthesis, has the advantages of high product yield, high purity, high atom economy and the like, has good scientific research value and application prospect, provides a brand new route for preparing C-3 position pentabasic spiro indolone derivatives containing all-carbon tetra-substituted olefin structures, can play an important role in the fields of pharmaceutical intermediates, pesticide intermediates and the like, reduces the production cost, and has good application value and potential in industry and scientific research.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a C-3 position pentanary spiro indolone derivative containing an all-carbon tetrasubstituted olefin structure, and a preparation method and application thereof.
Background
The C-3 position pentanary spiro indolone refers to indole derivatives with pentanary spiro structure at C-3 position of 2-indolone. The structure widely exists in natural alkaloids and drug molecules with biological activity, and has the functions of resisting tumor, bacteria, HIV, malaria, virus, fever, sodium channel blocker and the like (chem.Commun.2018, 54, 6607; bioorg.Med.chem.Lett, 2011, 21, 5916). Meanwhile, the all-carbon four-substituted olefin structure is often found in natural products and drug molecules, and because of the structural particularity, the all-carbon four-substituted alkenyl is widely applied in the fields of biology, materials, physics and the like (chem. Rev.2007, 107, 4698-4745). The existing method for synthesizing C-3 five-membered spiro indolone derivatives mainly comprises intramolecular and intermolecular cycloaddition reactions, transition metal catalytic reactions, oxidation reactions and the like. However, no report has been made on the preparation of C-3 spiro indolone derivatives having an all-carbon tetrasubstituted olefin structure. In order to better expand the utilization rate of the spiro indolone, the development of a novel preparation method of C-3 five-membered spiro indolone is necessary, and the method has the advantages of easily obtained raw materials, simple conditions and high atom economy.
Disclosure of Invention
Aiming at the technical problems, the invention provides a C-3 position pentabasic spiro indolone derivative containing an all-carbon tetra-substituted olefin structure, a preparation method and application thereof.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
a C-3 position pentanary spiro indolone derivative containing an all-carbon tetra-substituted olefin structure is disclosed, wherein the structural formula of the C-3 position pentanary spiro indolone derivative containing the all-carbon tetra-substituted olefin structure is shown in a formula (I):
wherein R is1、R2、R3、R4Independently selected from H, cyano, nitro, hydroxy, phenyl, substituted phenyl, methylenedioxy, C1-C6Alkyl radical, C2-C6Alkenyl radical, C1-C6Alkoxy, halogen, halogeno C1-C6Alkyl and halo C1-C6Any one of alkoxy groups.
A preparation method of C-3 position five-membered spiro indolone derivatives containing all-carbon four-substituted olefin structures comprises the following steps: adding a 2-iodoaryl acrylamide compound with eneyne shown in a formula (II), a phenylboronic acid compound shown in a formula (III), an organic ligand and alkali into an organic solvent, and reacting under the action of a catalyst to obtain a C-3 spiro indolone derivative containing an all-carbon tetra-substituted olefin structure;
wherein R is1、R2、R3、R4Independently selected from H, cyano, nitro, hydroxy, phenyl, substituted phenyl, methylenedioxy, C1-C6Alkyl radical, C2-C6Alkenyl radical, C1-C6Alkoxy, halogen, halogeno C1-C6Alkyl and halo C1-C6Any one of alkoxy groups.
Said C is1-C6Alkyl means a straight or branched chain alkyl group having 1 to 6 carbon atoms, including C1Alkyl radical, C2Alkyl radical, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group; and may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and the like.
C1-C6Alkoxy means C1-C6Radicals of alkyl radicals bound to oxygen atomsAnd (4) clustering.
Halogen means halogen elements and can be F, Cl, Br and I.
Halogen substituted C1-C6Alkyl means C substituted by halogen1-C6The alkyl group may be trifluoromethyl, pentafluoroethyl, difluoromethyl, chloromethyl, or the like.
In the preparation method, the 2-iodoaryl acrylamide compound with eneyne shown in the formula (II) and the phenylboronic acid compound shown in the formula (III) can be mixed together for reaction, in the reaction process, firstly, the 2-iodoaryl acrylamide compound with eneyne (II) is subjected to oxidation addition, then intramolecular Heck reaction, intramolecular carbon metallization reaction to generate an alkenyl palladium complex, then the phenylboronic acid compound (III) and the alkenyl palladium complex are subjected to metal transfer, and finally, the C-3-position spiro indolone derivative (I) containing an all-carbon tetra-substituted olefin structure is generated through reduction elimination.
The reaction mechanism of the present invention is as follows:
first, Pd0Firstly, the compound is oxidized and added with C-I bond of 2-iodoaryl acrylamide compound (II) with eneyne to generate intermediate A, and the intermediate A is further subjected to intramolecular Heck reaction to form
An alkyl Pd (II) species B, then an intramolecular carbon metallization reaction of B occurs due to the proper distance between palladium and an acetylene bond to generate an alkenyl palladium complex C, then a phenylboronic acid compound (III) and C undergo a metal transfer to generate an intermediate D, and finally the D is reduced and eliminated to generate a C-3 position five-membered spiro indolone derivative (I) containing an all-carbon tetra-substituted olefin structure and Pd0And (4) regenerating.
Further, the organic solvent includes any one of methanol, ethanol, acetonitrile, tetrahydrofuran, N-dimethylformamide, 1, 4-dioxane, dimethyl sulfoxide, toluene, xylene, and N-methylpyrrolidone.
Further, the organic ligand includes any one of triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tris (2-methoxyphenyl) phosphine, tris (4-fluorophenyl) phosphine, 1' -bis (diphenylphosphine) ferrocene, and 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl.
Further, the base includes any one of potassium carbonate, sodium bicarbonate, potassium phosphate, cesium carbonate, triethylamine, and tributylene diamine.
Further, the catalyst is a palladium compound; the palladium compound includes any one of palladium acetate, palladium chloride, palladium bromide, palladium iodide, tetratriphenylphosphine palladium, palladium trifluoroacetate, tris (dibenzylideneacetone) dipalladium and bis (dibenzylideneacetone) palladium.
Further, the mol ratio of the 2-iodoaryl acrylamide compound with eneyne to the phenylboronic acid compound is 1: 1-3; the molar ratio of the 2-iodoaryl acrylamide compound with eneyne to the catalyst is 1: 0.05-0.4; the molar ratio of the 2-iodoaryl acrylamide compound with eneyne to the organic ligand is 1: 0.1 to 2; the molar ratio of the 2-iodoaryl acrylamide compound with eneyne to the base is 1: 1-5; the dosage ratio of the 2-iodoaryl acrylamide compound with eneyne to the organic solvent is 1 mmol: 5-15 mL; for example, 1 mmol: 5mL, 1 mmol: 8mL, 1 mmol: 10mL, 1 mmol: 12mL and 1 mmol: 15 mL.
Further, the reaction temperature is 25-140 ℃ and the reaction time is 1-24 h.
Further, the preparation method also comprises a post-treatment purification step.
Still further, the post-treatment purification step comprises: after the reaction is finished, cooling to room temperature, oscillating for extraction, collecting an organic layer, drying, and performing rotary evaporation and concentration to obtain a crude product; and then crystallizing, recrystallizing, carrying out chromatography, and eluting to obtain the final product with high purity and high yield.
Specifically, water and ethyl acetate are used as extracting agents for extraction for 1-3 times, wherein the volume ratio of the water to the ethyl acetate is 2-5: 1, collecting upper liquid; with anhydrous Na2SO4Drying, dryingAfter drying, ethyl acetate is evaporated by a rotary evaporator, and the residue (crude product) is crystallized and recrystallized and then is subjected to chromatography by a 200-mesh 400-mesh silica gel column; using ethyl acetate and petroleum ether as eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1: 1-10.
Further, the mixture of ethyl acetate and saturated saline solution in the same volume ratio was used as an extractant for extraction.
An application of C-3 position five-membered spiro indolone derivative containing all-carbon four-substituted olefin structure in a drug intermediate.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, a palladium compound is used as a catalyst, a phosphine compound is used as a ligand, and a 2-iodoaryl acrylamide compound with eneyne in a formula (II) and a phenylboronic acid compound in a formula (III) react in an organic solvent to obtain a C-3-position pentanary spiro indolone derivative containing an all-carbon tetra-substituted olefin structure in one step. The invention adopts a one-pot method to prepare a target product, has the advantages of single product selectivity, high yield, high purity, high atom economy and the like by optimizing conditions, provides a brand new route and a new idea for the C-3 position pentabasic spiro indolone derivative containing the all-carbon tetra-substituted olefin structure, can play an important role in the fields of pharmaceutical intermediates, pesticide intermediates and the like, and has good application value and potential in industry and scientific research.
Drawings
FIG. 1 is the nuclear magnetic spectrum of the product obtained in example 1;
FIG. 2 is the nuclear magnetic spectrum of the product obtained in example 2;
FIG. 3 is the nuclear magnetic spectrum of the product obtained in example 3;
FIG. 4 is the NMR spectrum of the product obtained in example 4;
FIG. 5 is the NMR spectrum of the product obtained in example 5;
FIG. 6 is the nuclear magnetic spectrum of the product obtained in example 6;
FIG. 7 is a nuclear magnetic spectrum of the product obtained in example 7;
FIG. 8 is the NMR spectrum of the product obtained in example 8.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that each intervening value, between the upper and lower limit of that range, is also specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification. The specification and examples are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are open-ended terms that mean including, but not limited to.
Example 1
To toluene was added N- (2-iodophenyl) -N-methyl-2- (2- (phenylethynyl) phenyl) acrylamide of the above formula (II), (III) phenylboronic acid, palladium acetate (Pd (OAc)2) Triphenylphosphine (PPh)3) And cesium carbonate (Cs)2CO3) Then, the reaction was stirred and sealed at room temperature for 24 hours.
Wherein the compound of formula (II) is reacted with palladium acetate (Pd (OAc)2) In a molar ratio of 1: 0.05; a compound of formula (II) with triphenylphosphine (PPh)3) In a molar ratio of 1: 0.1; a compound of formula (II) with cesium carbonate (Cs)2CO3) In a molar ratio of 1: 3; the molar ratio of compound of formula (II) to compound of formula (III) is 1: 1.2; and the ratio of the compound of formula (II) to toluene, in millimoles (mmol) and milliliters (mL), is 1: 5.
after the reaction is finished, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline solution in an equal volume ratio, performing oscillation extraction for 3 times, collecting an organic layer, drying, performing rotary evaporation concentration to obtain a crude product, performing crystallization and recrystallization on the crude product, performing 300-mesh silica gel column chromatography, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1: 5, obtaining a target product of a compound (C) with a formula (I) and a white solid appearance30H23NO)。
For product C obtained in this example30H23The result of nuclear magnetic resonance analysis of NO is:1HNMR (500MHz, deuterated chloroform CDCl)3)δ：7.41-7.34(m，5H)，7.27-7.23(m，5H)，7.18-7.15(m，1H)，7.11(d，J＝7.0Hz，1H)，7.02-6.99(m，2H)，6.91(t，J＝7.5Hz，1H)，6.86(d，J＝7.5Hz，1H)，6.72(d，J＝7.5Hz，1H)，6.54(d，J＝8.0Hz，1H)，3.57(d，J＝15.5Hz，1H)，3.25(s，3H)，3.17(d，J＝15.0Hz，1H)。
13CNMR (125MHz, deuterated chloroform CDCl)3)δ：178.9，147.3，143.1，142.9，142.1，141.7，137.2，136.5，134.2，129.9，129.2，128.8，128.2(double)，128.0，127.4，127.3，126.9，125.4，123.3，123.1，123.0，108.0，58.1，46.5，26.4。
Through measurement and calculation: product C30H23NO yield 96%, purity 98.9% (HPLC), melting point: 179 ℃ and 180 ℃.
Example 2
To toluene was added N- (2-iodo-4-methoxyphenyl) -N-methyl-2- (2- (phenylethynyl) phenyl) acrylamide of the above formula (II), (III) phenylboronic acid, palladium acetate (Pd (OAc)2) Triphenylphosphine (PPh)3) And cesium carbonate (Cs)2CO3) The reaction was then stirred at room temperature and sealed for 24 h.
Wherein the compound of formula (II) is reacted with palladium acetate (Pd (OAc)2) In a molar ratio of 1: 0.05; a compound of formula (II) with triphenylphosphine (PPh)3) In a molar ratio of 1: 0.1; a compound of formula (II) with cesium carbonate (Cs)2CO3) In a molar ratio of 1: 3; the molar ratio of compound of formula (II) to compound of formula (III) is 1: 1.2; and the ratio of the compound of formula (II) to toluene, in millimoles (mmol) and milliliters (mL), is 1: 10.
after the reaction is finished, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline solution in an equal volume ratio, performing oscillation extraction for 3 times, collecting an organic layer, drying, performing rotary evaporation concentration to obtain a crude product, performing crystallization and recrystallization on the crude product, performing 300-mesh silica gel column chromatography, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1: 3, obtaining a target product of a compound (C) with a formula (I) and a white solid appearance31H25NO2)。
For product C obtained in this example31H25NO2The nuclear magnetic resonance analysis was carried out, and the results were:1HNMR (500MHz, deuterated chloroform CDCl)3)δ：7.39-7.33(m，5H)，7.28-7.22(m，4H)，7.16(t，J＝6.5Hz，1H)，7.00(t，J＝7.5Hz，1H)，6.91(t，J＝7.5Hz，1H)，6.79-6.73(m，4H)，6.54(d，J＝8.0Hz，1H)，3.72(s，3H)，3.58(d，J＝15.5Hz，1H)，3.23(s，3H)，3.17(d，J＝15.5Hz，1H)。
13CNMR (125MHz, deuterated chloroform CDCl)3)δ：178.5，156.2，147.3，142.8，142.1，141.6，137.1，136.6，136.4，135.4，129.9，129.2，128.8，128.2，127.9，127.4，127.3，126.8，125.4，123.3，112.1，110.6，108.3，58.4，55.6，46.5，26.5。
Through measurement and calculation: product C31H25NO2Yield 91%, purity 98.1% (HPLC), melting point: 238 ℃ and 239 ℃.
Example 3
To toluene was added 2- (5-fluoro-2- (phenylethynyl) phenyl) -N- (2-iodophenyl) -N-methacrylamide of formula (II) above, (III) phenylboronic acid, palladium acetate (Pd (OAc)2) Triphenylphosphine (PPh)3) And cesium carbonate (Cs)2CO3) The reaction was then stirred at room temperature and sealed for 24 h.
Wherein the compound of formula (II) is reacted with palladium acetate (Pd (OAc)2) In a molar ratio of 1: 0.05; a compound of formula (II) with triphenylphosphine (PPh)3) In a molar ratio of 1: 0.1; a compound of formula (II) with cesium carbonate (Cs)2CO3) In a molar ratio of 1: 3; the molar ratio of compound of formula (II) to compound of formula (III) is 1: 1.2; and the ratio of the compound of formula (II) to toluene, in millimoles (mmol) and milliliters (mL), is 1: 10.
after the reaction is finished, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline solution in an equal volume ratio, performing oscillation extraction for 3 times, collecting an organic layer, drying, performing rotary evaporation concentration to obtain a crude product, performing crystallization and recrystallization on the crude product, performing 300-mesh silica gel column chromatography, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1: 5, obtaining a target product of a compound (C) with a formula (I) and a white solid appearance30H22FNO)。
The product obtained in this exampleSubstance C30H22The result of nuclear magnetic resonance analysis by FNO is as follows:1HNMR (500MHz, deuterated chloroform CDCl)3)δ：7.42-7.36(m，5H)，7.29-7.23(m，5H)，7.17-7.16(m，1H)，7.12(d，J＝7.0Hz，1H)，7.03(t，J＝7.5Hz，1H)，6.87(d，J＝8.0Hz，1H)，6.63-6.60(m，1H)，6.48-6.45(m，1H)，6.42-6.40(m，1H)，3.60(d，J＝15.5Hz，1H)，3.26(s，3H)，3.20(d，J＝15.5Hz，1H)。
13CNMR (125MHz, deuterated chloroform CDCl)3)δ：178.3，163.4，161.4，149.3，149.2，143.1，142.7，141.9，137.9，136.0，135.9，133.4，129.9，129.1，128.9，128.5，128.0，127.4，126.9，126.8，126.7，123.1，115.0，114.8，110.4，110.2，108.2，57.9，46.7，26.5。
Through measurement and calculation: product C30H22FNO yield 96%, purity 98.7% (HPLC), melting point: 170 ℃ and 171 ℃.
Example 4
To toluene was added N- (2-iodophenyl) -2- (5-methoxy-2- (phenylethynyl) phenyl) -N-methacrylamide of formula (II) above, (III) phenylboronic acid, palladium acetate (Pd (OAc)2) Triphenylphosphine (PPh)3) And cesium carbonate (Cs)2CO3) The reaction was then stirred at room temperature and sealed for 24 h.
Wherein the compound of formula (II) is reacted with palladium acetate (Pd (OAc)2) In a molar ratio of 1: 0.05; a compound of formula (II) with triphenylphosphine (PPh)3) In a molar ratio of 1: 0.1; a compound of formula (II) with cesium carbonate (Cs)2CO3) In a molar ratio of 1: 3; the molar ratio of compound of formula (II) to compound of formula (III) is 1: 1.2; and the ratio of the compound of formula (II) to toluene, in millimoles (mmol) and milliliters (mL), is 1: 10.
after the reaction is finished, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline solution in an equal volume ratio, oscillating and extracting for 3 times, and collectingAnd (3) carrying out mechanical layer drying, rotary evaporation and concentration to obtain a crude product, carrying out crystallization and recrystallization on the crude product, and then carrying out 300-mesh silica gel column chromatography, wherein a mixed solution of ethyl acetate and petroleum ether is used as an eluent, and the volume ratio of ethyl acetate to petroleum ether is 1: 3, obtaining a target product of a compound (C) with a formula (I) and a white solid appearance31H25NO2)。
For product C obtained in this example31H25NO2The nuclear magnetic resonance analysis was carried out, and the results were:1HNMR (500MHz, deuterated chloroform CDCl)3)δ：7.44-7.41(m，4H)，7.37-7.32(m，1H)，7.29-7.23(m，5H)，7.16(t，J＝7.0Hz，1H)，7.10(d，J＝7.0Hz，1H)，7.01(t，J＝7.0Hz，1H)，6.85(d，J＝7.5Hz，1H)，6.61-6.57(m，2H)，6.02(d，J＝1.0Hz，1H)，3.58(d，J＝15.5Hz，1H)，3.36(s，3H)，3.24(s，3H)，3.19(d，J＝15.5Hz，1H)。
13CNMR (125MHz, deuterated chloroform CDCl)3)δ：179.1，158.9，143.1(double)，142.7，142.1，139.6，137.3，136.4，134.3，130.1，129.2，128.8，128.1，128.0，127.3，126.9，123.9，123.1，122.9，116.3，109.0，108.0，57.4，54.7，47.0，26.4。
Through measurement and calculation: product C31H25NO2Yield 96%, purity 98.0% (HPLC), melting point: 170 ℃ and 171 ℃.
Example 5
To toluene was added N- (2-iodophenyl) -N-methyl-2- (2- (p-tolylethynyl) phenyl) acrylamide of the above formula (II), (III) phenylboronic acid, palladium acetate (Pd (OAc)2) Triphenylphosphine (PPh)3) And cesium carbonate (Cs)2CO3) The reaction was then stirred at room temperature and sealed for 24 h.
Wherein the compound of formula (II) is reacted with palladium acetate (Pd (OAc)2) In a molar ratio of 1: 0.05; a compound of formula (II) with triphenylphosphine (PPh)3) In a molar ratio of 1: 0.1; formula (I)I) Compound with cesium carbonate (Cs)2CO3) In a molar ratio of 1: 3; the molar ratio of compound of formula (II) to compound of formula (III) is 1: 1.2; and the ratio of the compound of formula (II) to toluene, in millimoles (mmol) and milliliters (mL), is 1: 10.
after the reaction is finished, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline solution in an equal volume ratio, performing oscillation extraction for 3 times, collecting an organic layer, drying, performing rotary evaporation concentration to obtain a crude product, performing crystallization and recrystallization on the crude product, performing 300-mesh silica gel column chromatography, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1: 5, obtaining a target product of a compound (C) with a formula (I) and a white solid appearance31H25NO)。
For product C obtained in this example31H25The result of nuclear magnetic resonance analysis of NO is:1HNMR (500MHz, deuterated chloroform CDCl)3)δ：7.27-7.24(m，7H)，7.20-7.19(m，2H)，7.16(d，J＝6.5Hz，1H)，7.11(d，J＝7.0Hz，1H)，7.00(t，J＝7.5Hz，2H)，6.93(t，J＝7.5Hz，1H)，6.86(d，J＝7.5Hz，1H)，6.72(d，J＝7.5Hz，1H)，6.62(d，J＝8.0Hz，1H)，3.56(d，J＝15.0Hz，1H)，3.26(s，3H)，3.15(d，J＝15.0Hz，1H)，2.41(s，3H)。
13CNMR (125MHz, deuterated chloroform CDCl)3)δ：179.0，147.3，143.2(double)，141.9，139.2，137.1，136.9，136.6，134.3，130.0，129.6，129.3，128.2(double)，128.0，127.4，126.9，125.5，123.4，123.2，123.1，108.1，58.2，46.7，26.6，21.4。
Through measurement and calculation: product C31H25NO yield 96%, purity 98.7% (HPLC), melting point: 223 ℃ and 224 ℃.
Example 6
To toluene was added 2- (2- ((4-chlorophenyl) ethynyl) phenyl) -N-, (II) above2-iodophenyl) -N-methylacrylamide, (III) phenylboronic acid, palladium acetate (Pd (OAc)2) Triphenylphosphine (PPh)3) And cesium carbonate (Cs)2CO3) The reaction was then stirred at room temperature and sealed for 24 h.
Wherein the compound of formula (II) is reacted with palladium acetate (Pd (OAc)2) In a molar ratio of 1: 0.05; a compound of formula (II) with triphenylphosphine (PPh)3) In a molar ratio of 1: 0.1; a compound of formula (II) with cesium carbonate (Cs)2CO3) In a molar ratio of 1: 3; the molar ratio of compound of formula (II) to compound of formula (III) is 1: 1.2; and the ratio of the compound of formula (II) to toluene, in millimoles (mmol) and milliliters (mL), is 1: 10.
after the reaction is finished, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline solution in an equal volume ratio, performing oscillation extraction for 3 times, collecting an organic layer, drying, performing rotary evaporation concentration to obtain a crude product, performing crystallization and recrystallization on the crude product, performing 300-mesh silica gel column chromatography, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1: 5, obtaining a target product of a compound (C) with a formula (I) and a white solid appearance30H22ClNO)。
For product C obtained in this example30H22The result of nuclear magnetic resonance analysis of ClNO is:1HNMR (500MHz, deuterated chloroform CDCl)3)δ：7.38-7.32(m，4H)，7.30-7.22(m，5H)，7.18(t，J＝7.0Hz，1H)，7.12-7.09(m，1H)，7.05-7.01(m，2H)，6.97(t，J＝7.5Hz，1H)，6.88(d，J＝7.5Hz，1H)，6.72(d，J＝7.5Hz，1H)，6.63(d，J＝8.0Hz，1H)，3.51(d，J＝15.5Hz，1H)，3.25(s，3H)，3.19(d，J＝15.5Hz，1H)。
13CNMR (125MHz, deuterated chloroform CDCl)3)δ：178.7，147.4，143.3，142.5，141.5，140.6，137.9，135.0，133.9，133.2，131.5，129.2，129.1，128.4，128.3，128.1，127.5，127.1，125.3，123.5，123.1，123.0，108.1，58.0，46.8，26.5。
Through measurement and calculation: product C30H22The yield of ClNO was 88% and the purity 98.5% (HPLC),melting point: 206- & lt207 & gt.
Example 7
To toluene was added N- (2-iodophenyl) -N-methyl-2- (2- (phenylethynyl) phenyl) acrylamide of the above formula (II), (III) 3-methoxyphenylboronic acid, palladium acetate (Pd (OAc))2) Triphenylphosphine (PPh)3) And cesium carbonate (Cs)2CO3) The reaction was then stirred at room temperature and sealed for 24 h.
Wherein the compound of formula (II) is reacted with palladium acetate (Pd (OAc)2) In a molar ratio of 1: 0.05; a compound of formula (II) with triphenylphosphine (PPh)3) In a molar ratio of 1: 0.1; a compound of formula (II) with cesium carbonate (Cs)2CO3) In a molar ratio of 1: 3; the molar ratio of compound of formula (II) to compound of formula (III) is 1: 1.2; and the ratio of the compound of formula (II) to toluene, in millimoles (mmol) and milliliters (mL), is 1: 10.
after the reaction is finished, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline solution in an equal volume ratio, performing oscillation extraction for 3 times, collecting an organic layer, drying, performing rotary evaporation concentration to obtain a crude product, performing crystallization and recrystallization on the crude product, performing 300-mesh silica gel column chromatography, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1: 5, obtaining a target product of a compound (C) with a formula (I) and a white solid appearance31H25NO2)。
For product C obtained in this example31H25NO2The nuclear magnetic resonance analysis was carried out, and the results were:1HNMR (500MHz, deuterated chloroform CDCl)3)δ：7.39-7.32(m，5H)，7.25(t，J＝15.5Hz，1H)，7.17(t，J＝8.0Hz，1H)，7.11(d，J＝7.0Hz，1H)，7.02-6.98(m，2H)，6.90(t，J＝7.5Hz，1H)，6.86(d，J＝7.5Hz，2H)，6.82-6.81(m，1H)，6.72(d，J＝7.5Hz，2H)，6.54(d，J＝7.5Hz，1H)，3.71(s，3H)，3.58(d，J＝15.5Hz，1H)，3.25(s，3H)，3.18(d，J＝15.0Hz，1H)。
13CNMR (125MHz, deuterated chloroform CDCl)3)δ：178.8，159.2，147.3，144.3，143.1，141.9，141.6，137.3，136.3，134.1，129.8，128.9，128.8，128.2(double)，127.3(double)，125.4，123.3，123.1，122.9，121.8，115.0，112.1，108.0，58.0，55.1，46.5，26.4。
Through measurement and calculation: product C31H25NO2Yield 90%, purity 98.8% (HPLC), melting point: 243 and 244 ℃.
Example 8
To toluene was added N- (2-iodophenyl) -N-methyl-2- (2- (phenylethynyl) phenyl) acrylamide of the above formula (II), (III) 3-bromobenzeneboronic acid, palladium acetate (Pd (OAc)2) Triphenylphosphine (PPh)3) And cesium carbonate (Cs)2CO3) The reaction was then stirred at room temperature and sealed for 24 h.
Wherein the compound of formula (II) is reacted with palladium acetate (Pd (OAc)2) In a molar ratio of 1: 0.05; a compound of formula (II) with triphenylphosphine (PPh)3) In a molar ratio of 1: 0.1; a compound of formula (II) with cesium carbonate (Cs)2CO3) In a molar ratio of 1: 3; the molar ratio of compound of formula (II) to compound of formula (III) is 1: 1.2; and the ratio of the compound of formula (II) to toluene, in millimoles (mmol) and milliliters (mL), is 1: 10.
after the reaction is finished, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline solution in an equal volume ratio, performing oscillation extraction for 3 times, collecting an organic layer, drying, performing rotary evaporation concentration to obtain a crude product, performing crystallization and recrystallization on the crude product, performing 300-mesh silica gel column chromatography, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1: 5, obtaining a target product of a compound (C) with a formula (I) and a white solid appearance30H22BrNO)。
For product C obtained in this example30H22BrNO was analyzed by nmr and the results were:1HNMR (500MHz, deuterated chloroform CDCl)3)δ：7.42-7.36(m，6H)，7.31-7.27(m，2H)，7.20(d，J＝8.0Hz，1H)，7.12(t，J＝8.0Hz，2H)，7.05-7.01(m，2H)，6.93-6.88(m，2H)，6.72(d，J＝8.0Hz，1H)，6.51(d，J＝8.0Hz，1H)，3.54(d，J＝15.5Hz，1H)，3.27(s，3H)，3.16(d，J＝15.5Hz，1H)。
13CNMR (125MHz, deuterated chloroform CDCl)3)δ：178.7，147.4，145.0，143.2，141.4(double)，138.4，134.9，133.9，131.9，129.9，129.6，129.0，128.5，128.3，127.9，127.6，127.4，125.5，123.4，123.1，123.0，122.2，108.1，58.0，46.4，26.5。
Through measurement and calculation: product C30H22BrNO yield 86%, purity 98.6% (HPLC), melting point: 155 ℃ and 156 ℃.
Examples 9 to 16
According to the correspondence shown in Table 1, taking example 1 as an example, a catalyst of palladium acetate (Pd (OAc))2The same procedure was followed except that the palladium compound was replaced with another palladium compound in the same molar amount, and the product yields obtained were as shown in table 1.
TABLE 1 product yields on different catalysts
Therefore, under the catalysis of different palladium compounds, the corresponding products can be obtained, the overall zero-valent palladium compound has better reaction effect than divalent palladium compound, and the Pd (OAc)2The best catalytic effect.
Examples 17 to 22
The ligand triphenylphosphine (PPh) in example 1 was added to the reaction mixture of example 1 according to the correspondence shown in Table 2, taking example 1 as an example3) The other ligands with the same molar amount were replaced with the other ligands with the same molar amount, and the other operations were the same, and the product yields obtained are shown in table 2.
TABLE 2 product yields for different ligands
It can be seen that of all the ligands, triphenylphosphine (PPh)3) Has proper coordination, and the yield of other ligands is obviously reduced.
Examples 24 to 28
According to the correspondence shown in table 3, taking example 1 as an example, the alkali cesium carbonate of example 1 was replaced with the other alkali of the same volume, and the other operations were the same, and the obtained product yields are shown in table 3.
TABLE 3 product yields in different solvents
It follows that the base also has some influence on the end result, with cesium carbonate having the best effect and potassium phosphate, and other solvents, all with a considerable reduction in yield.
Examples 29 to 33
According to the correspondence shown in table 4, taking example 1 as an example, the solvent toluene of example 1 was replaced with the other solvent of the same volume, and the other operations were the same, and the product yields obtained are shown in table 4.
TABLE 4 product yields in different solvents
It can be seen that the solvent also has some effect on the end result, with toluene having the best effect, 1, 4-dioxane, and other solvents having a greatly reduced yield.
From the above, it is clear from all the examples that when the method of the present invention is used, the compounds of formula (II) and (III) can be smoothly reacted to obtain the desired product, and the yield is good, the post-treatment is simple, and the effects are obtained depending on the combined synergistic effect of a plurality of factors such as the catalyst, the ligand, the base and the solvent.
Comparative examples 1 and 2
The same as example 1, except that the volume ratio of ethyl acetate to petroleum ether was 1: 3.
the detection shows that the purity of the products obtained in comparative example 1 and comparative example 2 is reduced compared with that of the product obtained in example 1. The reason for this analysis is that since the separation effect is different for different eluents, the purity of the product is reduced by either too high or too low polarity of the eluent.
Comparative example 3
The difference from example 1 is that the reaction temperature is 110 ℃.
Comparative example 4
The difference from example 1 is that the reaction temperature is 130 ℃.
The detection proves that the purity of the product obtained in the comparative example 3 is similar to that of the product obtained in the example 1, the product has no difference basically, the yield of the product obtained in the comparative example 4 is slightly reduced compared with that of the product obtained in the example 1, and the analysis reason is that partial reaction is reduced and eliminated when the alkenyl palladium is generated due to overhigh temperature, and the phenylboronic acid does not participate in the reaction fully.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. The C-3 position pentanary spiro indolone derivative containing the all-carbon tetra-substituted olefin structure is characterized in that the structural formula of the C-3 position pentanary spiro indolone derivative containing the all-carbon tetra-substituted olefin structure is shown as the formula (I):
wherein R is1、R2、R3、R4Independently selected from H, cyano, nitro, hydroxy, phenyl, substituted phenyl, phenyleneMethylenedioxy, C1-C6Alkyl radical, C2-C6Alkenyl radical, C1-C6Alkoxy, halogen, halogeno C1-C6Alkyl and halo C1-C6Any one of alkoxy groups.
2. The method for preparing C-3 five-membered spirocyclic indolone derivatives containing all-carbon tetrasubstituted olefin structure according to claim 1, comprising the steps of: adding a 2-iodoaryl acrylamide compound with eneyne shown in a formula (II), a phenylboronic acid compound shown in a formula (III), an organic ligand and alkali into an organic solvent, and reacting under the action of a catalyst to obtain a C-3 spiro indolone derivative containing an all-carbon tetra-substituted olefin structure;
wherein R is1、R2、R3、R4Independently selected from H, cyano, nitro, hydroxy, phenyl, substituted phenyl, methylenedioxy, C1-C6Alkyl radical, C2-C6Alkenyl radical, C1-C6Alkoxy, halogen, halogeno C1-C6Alkyl and halo C1-C6Any one of alkoxy groups.
3. The method for preparing C-3 position pentabasic spirocyclic indolone derivatives containing all-carbon tetrasubstituted olefin structure according to claim 2, wherein said organic solvent comprises any one of methanol, ethanol, acetonitrile, tetrahydrofuran, N-dimethylformamide, 1, 4-dioxane, dimethyl sulfoxide, toluene, xylene and N-methylpyrrolidone.
4. The method for preparing the C-3 position pentabasic spirocyclic indolone derivative containing an all-carbon tetrasubstituted olefin structure according to claim 2, wherein the organic ligand comprises any one of triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tris (2-methoxyphenyl) phosphine, tris (4-fluorophenyl) phosphine, 1' -bis (diphenylphosphine) ferrocene and 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl.
5. The method for preparing the C-3 position pentabasic spirocyclic indolone derivative containing an all-carbon tetrasubstituted olefin structure according to claim 2, wherein the base comprises any one of potassium carbonate, sodium bicarbonate, potassium phosphate, cesium carbonate, triethylamine and tributylenediamine.
6. The method for preparing the C-3 position pentabasic spiro indolone derivative containing the all-carbon tetrasubstituted olefin structure according to claim 2, wherein the catalyst is a palladium compound; the palladium compound includes any one of palladium acetate, palladium chloride, palladium bromide, palladium iodide, tetratriphenylphosphine palladium, palladium trifluoroacetate, tris (dibenzylideneacetone) dipalladium and bis (dibenzylideneacetone) palladium.
7. The method for preparing C-3 five-membered spirocyclic indolone derivative containing all-carbon four-substituted olefin structure according to claim 2, wherein the molar ratio of the 2-iodoaryl acrylamide compound having enyne to the phenylboronic acid compound is 1: 1-3; the molar ratio of the 2-iodoaryl acrylamide compound with eneyne to the catalyst is 1: 0.05-0.4; the molar ratio of the 2-iodoaryl acrylamide compound with eneyne to the organic ligand is 1: 0.1 to 2; the molar ratio of the 2-iodoaryl acrylamide compound with eneyne to the base is 1: 1-5; the dosage ratio of the 2-iodoaryl acrylamide compound with eneyne to the organic solvent is 1 mmol: 5-15 mL.
8. The preparation method of the C-3 position pentabasic spiro indolone derivative containing the all-carbon tetra-substituted olefin structure as claimed in claim 2, wherein the reaction temperature is 25-140 ℃ and the reaction time is 1-24 h.
9. The method for preparing C-3 five-membered spirocyclic indolone derivatives containing all-carbon four-substituted olefin structure according to claim 2, wherein the method further comprises a post-treatment purification step.
10. The use of a C-3 five-membered spirocyclic indolone derivative containing an all-carbon tetrasubstituted olefin structure according to claim 1 in pharmaceutical intermediates.
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| MINGHAO ZHANG等: "A palladium-catalyzed Heck/[4 + 1] decarboxylative cyclization cascade to access diverse heteropolycycles by using α-bromoacrylic acids as C1 insertion units", 《ORG. CHEM. FRONT.》 * |
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