CN112375086A - Preparation method of chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound - Google Patents
Preparation method of chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound Download PDFInfo
- Publication number
- CN112375086A CN112375086A CN202011438913.3A CN202011438913A CN112375086A CN 112375086 A CN112375086 A CN 112375086A CN 202011438913 A CN202011438913 A CN 202011438913A CN 112375086 A CN112375086 A CN 112375086A
- Authority
- CN
- China
- Prior art keywords
- indolenine
- furan
- chiral spiro
- beta
- palladium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of chiral spiro [ furan-3, 3 '-indolenine ] -2-ketone compounds, which synthesizes the chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compounds through palladium-catalyzed intramolecular asymmetric arylation of beta, beta-disubstituted enamine, and specifically comprises the following steps: palladium salt is used as a catalyst, and the corresponding chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound is generated by the combined action of a ligand and an alkaline compound in an organic solvent at the temperature of 40-100 ℃. The invention takes easily prepared beta, beta-disubstituted enamine derivatives as raw materials, and realizes the rapid construction of chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compounds by one-step construction of a ring and two chemical bonds. The method has the advantages of mild reaction conditions, simple and convenient operation, easily obtained reaction raw materials, wide substrate applicability, easy separation of target products and the like.
Description
Technical Field
The invention belongs to the technical field of catalytic synthesis, and relates to a preparation method of chiral spiro [ furan-3, 3 '-indolenine ] -2-ketone compounds, in particular to a method for synthesizing chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compounds by palladium-catalyzed intramolecular asymmetric arylation of beta, beta-disubstituted enamine.
Background
Chiral 3,3' -indolenine derivatives are widely distributed in natural products and have wide application, such as several compounds shown in formula A, wherein the first compound is spiro-cyclopentenone separated from 24-hour broth culture of Clostridium KMC 003; the second compound was a polyhalogenated indole-imidazole alkaloid isolated from the marine bryozoan, chartellapapyr, acea, in denmark in the 80 th 20 th century. Many indole alkaloids have good physiological activity, such as antiinflammatory, antitumor, anti-infection, diuresis, blood sugar lowering, blood pressure lowering, etc. Although chartelline does not have significant biological activity, it is of interest to many synthetic chemists due to the uniqueness and complexity of its structure. The third compound, Strictamine alstonine, is a natural product with important biological activity, and is mainly present in apocynaceae plants. In the minority nationality areas such as Shuangguang and Yunnan, the leaf of the nerium apetalum (also called as the 'lamp stand leaf') of apocynaceae is used as a national medicine for treating diseases such as chronic tracheitis and pertussis. Modern pharmacological studies show that the alstonia alkaloid has the biological activities of resisting cancer, resisting bacteria, resisting inflammation, relieving cough and the like. The alkaloid has a complex structure and outstanding biological activity, so that the alkaloid is widely concerned by synthetic chemists. Therefore, many researchers now synthesize these compounds by various methods, and the synthesis of such compounds by asymmetric synthesis methods is of great research interest. The synthesis of chiral 3H-indole derivatives by transition metal catalysis is widely studied at present, but is mainly realized by an asymmetric dearomatization reaction strategy for aromatic ring internal enamine structures, aromatic amines and the like. Among them, most of the strategies reported in the literature are transition metal catalyzed asymmetric dearomatization reaction of 1H-indole derivatives, and a small part of them is constructed chiral 3H-indole derivatives by intramolecular dearomatization reaction of arylamine compounds. The above dearomatization reaction strategy requires the prior preparation of 1H-indole or arylamine as a substrate, and the synthesis of such substrates is complicated, so the above method has great limitations. The beta, beta-disubstituted enamine derivative is easy to prepare and can be synthesized in one step only by the dehydration condensation reaction of cheap ketone and amine. By taking beta, beta-disubstituted enamine derivatives as raw materials, the chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound with a unique structure can be rapidly synthesized by asymmetric arylation reaction in palladium catalytic molecules, can be applied to the establishment of a potential bioactive molecule library, and has a great application value.
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a method for preparing chiral spiro [ furan-3, 3 '-indolenine ] -2-one compounds, which utilizes easily prepared reaction raw materials to synthesize the chiral spiro [ furan-3, 3' -indolenine ] -2-one compounds in one step with high efficiency by a palladium-catalyzed intramolecular cyclization reaction of beta, beta-disubstituted enamine derivatives.
The preparation method of the chiral spiro [ furan-3, 3 '-indolenine ] -2-ketone compound is characterized in that a beta, beta-disubstituted enamine derivative shown in a formula (1) is used as a raw material, the reaction is carried out in an organic solvent at the temperature of 40-140 ℃ under the combined action of a palladium catalyst, a ligand and an alkaline compound, and after the reaction is finished, the chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound shown in the formula (2) is obtained through post-treatment, wherein the reaction general formula is as follows:
in the formula: r1One selected from alkyl, alkoxy, trifluoromethyl or halogen; r2Is alkyl or phenyl.
The chiral spiro [ furan-3, 3' -indolenine]Process for the preparation of (E) -2-keto compounds, characterized in that R is1The alkyl in (A) is selected from C1-C10 straight chain or branched chain alkane, R1The alkoxy in (1) is selected from C1-C10 straight chain or branched chain alkoxy, R1The halogen in (A) is selected from one of fluorine, chlorine or bromine; r2The alkyl in (1) is selected from C1-C10 straight chain or branched chain alkane. To, have no application
The preparation method of the chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound is characterized in that the organic solvent is any one of dichloromethane, dichloroethane, toluene, m-xylene, methanol, ethanol, methyl tert-butyl ether, diethyl ether, tetrahydrofuran or 1, 4-dioxane, the volume ratio of the organic solvent to the beta, beta-disubstituted enamine derivative is 1-6: 1, the volume unit is milliliter, and the amount unit of the substance is millimole.
The preparation method of the chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound is characterized in that a palladium catalyst is any one of palladium tetratriphenylphosphine, palladium bis (tri-tert-butylphosphino), palladium tris (dibenzylideneacetone) dipalladium, palladium bis (dibenzylideneacetone), palladium acetate, diacetonitrile palladium dichloride and allyl palladium chloride dimer. 1, 1-bis (diphenylphosphino) -ferrocene
The chiral spiro [ furan-3, 3' -indolenine]A process for preparing (E) -2-ketone compounds, characterized in that the ligand is selected from (S) -Bn-Phox, (S) -onetBu-Phox、(S)-iPr-Phox、(S)-Ph-Phox、(S,Sp)-Bn-Phosferrox、(S,Sp)-tBu-Phosferrox、(S,Sp)-iPr-Phosferrox、 (S,Sp) -any one of Ph-Phosferrox, the chinese translations of the above ligands in the order: (S) -4-benzyl-2- (2- (diphenylphosphino) phenyl) -4, 5-dihydrooxazole, (S) -4-tert-butyl-2- (2- (diphenylphosphino) phenyl) -4, 5-dihydrooxazole, (S) -4-isopropyl-2- (2- (diphenylphosphino) phenyl) -4, 5-dihydrooxazole, (S) -4-phenyl-2- (2- (diphenylphosphino) phenyl) -4, 5-dihydrooxazole, (S) -1- (diphenylphosphino) -2- [ (S) -4-benzyloxazolin-2-yl]Ferrocene, (S) -1- (diphenylphosphino) -2- [ (S) -4-tert-butyl-oxazoline-2-yl]Ferrocene, (S) -1- (diphenylphosphino) -2- [ (S) -4-isopropyloxazoline-2-yl]Ferrocene, (S) -1- (diphenylphosphino) -2- [ (S) -4-phenyloxazoline-2-yl]Ferrocene any one of
The preparation method of the chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound is characterized in that the alkaline compound is any one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium acetate, potassium phosphate, disodium hydrogen phosphate, sodium carbonate, potassium carbonate or cesium carbonate.
The preparation method of the chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound is characterized in that the molar ratio of the beta, beta-disubstituted enamine derivative, the palladium catalyst, the ligand and the alkaline compound is 1: 0.1-0.4: 0.1-0.8: 1-5.
The preparation method of the chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound is characterized in that the reaction temperature is 60-100 ℃, and the reaction time is 20-72 h.
The preparation method of the chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound is characterized by comprising the following post-treatment steps: after the reaction is finished, removing the organic solvent by rotary evaporation, and then carrying out column chromatography separation to obtain a target product; the mobile phase of the column chromatography is a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-10: 1.
By adopting the technology, compared with the prior art, the invention has the following beneficial effects:
the invention takes the beta, beta-disubstituted enamine derivative as the raw material, and the chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound is efficiently synthesized in one step by the intramolecular cyclization reaction under the combined action of a palladium catalyst, a ligand, an alkaline compound and the like.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto;
example 1
To a dried Schlenk tube were added β, β -disubstituted enamine derivative 1a (56.4mg,0.2mmol), palladium acetate (4.5mg, 0.02mmol), (S) -4-phenyl-2- (2- (diphenylphosphino) phenyl) -4, 5-dihydrooxazole (9.7mg, 0.024mmol), and potassium tert-butoxide (33.7mg,0.3mmol) in this order under a nitrogen atmosphere. Tetrahydrofuran (2.0mL,0.1M) was then added via syringe and the reaction mixture reacted at 85 ℃ for 36h, after completion of the reaction the solution was concentrated under reduced pressure and the residue was purified by chromatography on silica eluting with ethyl acetate/petroleum ether 1:3(v/v) to give product 2a in 58% yield with an er value of 94/6 by HPLC. [ Daicel Chiralpak OD-H column (25 cm. times.0.46 cm ID),nhexane/iPrOH＝80/20,0.7 mL/min,254nm；tminor＝15.8min,tmajor＝19.5min].1H NMR(500MHz, CDCl3)δ7.59(d,J＝7.7Hz,1H),7.40(t,J＝7.7Hz,1H),7.37(d,J＝ 7.3Hz,1H),7.24(t,J＝7.5Hz,1H),4.78-4.64(m,2H),2.84(dt,J＝ 13.4,8.2Hz,1H),2.65-2.49(m,1H),2.40(s,3H)；13C NMR(125MHz, CDCl3)δ177.7,173.4,155.4,139.1,129.5,126.3,121.5,120.8,66.4, 63.9,31.5,16.6.HRMS m/z(ESI+):Calculated for C12H11NNaO2 ([M+Na]+):224.0682,Found:224.0688.
example 2
To a dried Schlenk tube were added β, β -disubstituted enamine derivative 2a (59.2mg,0.2mmol), palladium acetate (4.5mg, 0.02mmol), (S) -4-tert-butyl-2- (2- (diphenylphosphino) phenyl) -4, 5-dihydrooxazole (9.3mg, 0.024mmol), sodium tert-butoxide (19.2mg,0.2mmol) in this order under a nitrogen atmosphere. Dichloromethane (2.0mL,0.1M) was then added via syringe and the reaction mixture reacted at 60 ℃ for 72h, then the solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether 1:3(v/v) to give product 2b in 45% yield with an er value of 93/7 as determined by HPLC. [ Daicel Chiralpak C2 column (25 cm. times.0.46 cm ID),nhexane/iPrOH＝80/20,0.7mL/min,254 nm；tminor＝19.7min,tmajor＝22.8min].1H NMR(500MHz,CDCl3)δ 7.46(d,J＝7.8Hz,1H),7.22-7.08(m,2H),4.81-4.50(m,2H),2.82(dt,J ＝13.4,8.2Hz,1H),2.64-2.47(m,1H),2.38(s,6H)；13C NMR(125MHz, CDCl3)δ176.7,173.5,152.8,139.2,136.3,130.0,122.2,120.2,66.4, 63.6,31.5,21.3,16.5.HRMS m/z(ESI+):Calculated for C13H13NNaO2 ([M+Na]+):238.0838,Found:238.0844.
example 3:
to a dry Schlenk tube were added, in order, β -disubstituted enamine derivative 3a (64.8mg,0.2mmol), palladium acetate (4.5mg, 0.02mmol), (S) -4-isopropyl-2- (2- (diphenylphosphino) phenyl) -4, 5-dihydrooxazole (8.9mg, 0.024mmol), and potassium acetate (29.4mg,0.3 mmol) under a nitrogen atmospherel). Dichloroethane (2.0mL,0.1M) was then added via syringe and the reaction mixture reacted at 100 ℃ for 20h, then the solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with ethyl acetate/petroleum ether 1:3(v/v), to give the product 3b in 52% yield, with an er value of 93/7 as determined by HPLC. [ Daicel Chiralpak C2 column (25 cm. times.0.46 cm ID),nhexane/iPrOH＝80/20,0.7mL/min, 254nm；tminor＝12.4min,tmajor＝14.0min].1H NMR(500MHz,CDCl3) δ7.49(d,J＝8.0Hz,1H),7.27(s,1H),7.21(s,1H),4.80-4.64(m,2H), 2.94(dt,J＝13.8,6.9Hz,1H),2.83(dt,J＝13.4,8.2Hz,1H),2.62-2.53 (m,1H),2.38(s,3H),1.25(d,J＝6.9Hz,6H)；13C NMR(125MHz, CDCl3)δ176.7,173.6,153.5,147.5,139.3,127.5,120.4,119.6,66.4, 63.7,34.2,31.6,24.2,16.5.HRMS m/z(ESI+):Calculated for C15H17NNaO2([M+Na]+):266.1151,Found:266.1155.
example 4
To a dried Schlenk tube were added β, β -disubstituted enamine derivative 4a (60.0mg,0.2mmol), bis (cyanophenyl) palladium dichloride (7.7mg, 0.02mmol), (S) -4-tert-butyl-2- (2- (diphenylphosphino) phenyl) -4, 5-dihydrooxazole (9.3mg, 0.024mmol), and sodium acetate (82.3mg,1.0mmol) in this order under a nitrogen atmosphere. Toluene (100mL,0.002M) was then added via syringe and the reaction mixture reacted at 85 ℃ for 36h, then the solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with ethyl acetate/petroleum ether 1:3(v/v), to give product 4b in 49% yield, which was determined to have an er value of 96/4 by HPLC. [ Daicel Chiralpak C2 column (25 cm. times.0.46 cm ID),nhexane/iPrOH＝80/20,0.7 mL/min,254nm；tminor＝18.2min,tmajor＝19.9min].1H NMR(500MHz, CDCl3)δ7.53(dd,J＝8.2,4.7Hz,1H),7.14-7.06(m,2H),4.71(dd,J＝ 7.8,6.5Hz,2H),2.85(dt,J＝13.5,8.0Hz,1H),2.67-2.55(m,1H),2.39 (s,3H)；13C NMR(125MHz,CDCl3)δ177.3,172.7,161.4(d,J＝245.0 Hz),151.7,140.6(d,J＝9.0Hz)121.6(d,J＝8.8Hz),116.2(d,J＝23.4 Hz),109.6(d,J＝25.5Hz),66.3,64.3,31.4,16.6.HRMS m/z(ESI+): Calculated for C12H10FNNaO2([M+Na]+):242.0588,Found:242.0592.
example 5
To a dried Schlenk tube were added β, β -disubstituted enamine derivative 5a (56.4mg,0.2mmol), palladium acetate (4.5mg, 0.02mmol), (S) -4-tert-butyl-2- (2- (diphenylphosphino) phenyl) -4, 5-dihydrooxazole (9.3mg, 0.024mmol), and potassium carbonate (41.4mg,0.3mmol) in this order under a nitrogen atmosphere. Methanol (12.0mL, 0.03M) was then added via syringe and the reaction mixture reacted at 85 ℃ for 36h, then the solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether 1:3(v/v) to give the product 5b in 54% yield, with an er value of 93/7 as determined by HPLC. [ Daicel Chiralpak C2 column (25 cm. times.0.46 cm ID),nhexane/iPrOH＝80/20,0.7mL/min,254 nm；tminor＝18.3min,tmajor＝24.0min].1H NMR(500MHz,CDCl3)δ 7.39(s,1H),7.24(d,J＝7.6Hz,1H),7.05(d,J＝7.6Hz,1H),4.77-4.61 (m,2H),2.81(dt,J＝13.3,8.2Hz,1H),2.61-2.49(m,1H),2.41(s,3H), 2.38(s,3H)；13C NMR(125MHz,CDCl3)δ177.7,173.5,155.7,139.7, 136.2,126.8,121.5,121.0,66.3,63.5,31.5,21.5,16.5.HRMS m/z (ESI+):Calculated for C13H13NNaO2([M+Na]+):238.0838,Found: 238.0841.
example 6
To a dried Schlenk tube were added β, β -disubstituted enamine derivative 6a (56.4mg,0.2mmol), palladium acetate (4.5mg, 0.02mmol), (S) -4-tert-butyl-2- (2- (diphenylphosphino) phenyl) -4, 5-dihydrooxazole (9.3mg, 0.024mmol), and cesium carbonate (97.7mg,0.3mmol) in this order under a nitrogen atmosphere. Ethanol (2.0mL,0.1M) was then added via syringe and the reaction mixture reacted at 85 ℃ for 40h, then the solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether 1:3(v/v) to give the product 6b in 87% yield with an er value of 87/13 as determined by HPLC. [ Daicel Chiralpak C2 column (25 cm. times.0.46 cm ID),nhexane/iPrOH＝80/20,0.7mL/min,254nm； tmajor＝15.7min,tminor＝17.2min].1H NMR(500MHz,CDCl3)δ7.19(t, J＝7.8Hz,2H),7.12(t,J＝7.5Hz,1H),4.76-4.61(m,2H),2.88-2.74(m, 1H),2.57(s,3H),2.63-2.49(m,1H),2.39(s,3H)；13C NMR(125MHz, CDCl3)δ176.4,173.5,153.8,138.9,130.8,130.5,126.1,118.8,66.3, 64.0,31.5,16.9,16.5.HRMS m/z(ESI+):Calculated for C13H13NNaO2 ([M+Na]+):238.0838,Found:238.0847.
example 7
To a dried Schlenk tube were added β, β -disubstituted enamine derivative 7a (62.8mg,0.2mmol), palladium acetate (4.5mg, 0.02mmol), (S) -4-tert-butyl-2- (2- (diphenylphosphino) phenyl) -4, 5-dihydrooxazole (62mg, 0.16mmol), and lithium tert-butoxide (24.0mg,0.3mmol) in this order under a nitrogen atmosphere. Ether (2.0mL,0.1M) was then added via syringe and the reaction mixture reacted at 85 ℃ for 40h, then the solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether 1:3(v/v) to give product 7b in 48% yield, with an er value of 91/9 as determined by HPLC. [ Daicel Chiralpak OD-H column (25 cm. times.0.46 cm ID),nhexane/iPrOH＝80/20,0.7mL/min,254 nm；tminor＝10.9min,tmajor＝11.7min].1H NMR(500MHz,CDCl3)δ 6.95-6.86(m,2H),4.69(dd,J＝7.8,6.6Hz,2H),2.82(dt,J＝13.5,8.0 Hz,1H),2.63-2.50(m,1H),2.55(s,3H),2.39(s,3H)；13C NMR(125 MHz,CDCl3)δ176.0(d,J＝3.4Hz),172.9,161.1(d,J＝245.6Hz), 150.1,140.2(d,J＝9.3Hz),132.2(d,J＝8.6Hz),117.2(d,J＝22.8Hz), 106.8(d,J＝25.4Hz),66.2,64.3(d,J＝2.4Hz),31.4,17.0,16.5.HRMS m/z(ESI+):Calculated for C13H12FNNaO2([M+Na]+):256.0744,Found: 256.0754.
example 8
To a dried Schlenk tube were added β, β -disubstituted enamine derivative 8a (59.2mg,0.2mmol), palladium acetate (18.0mg, 0.08mmol), (S) -4-tert-butyl-2- (2- (diphenylphosphino) phenyl) -4, 5-dihydrooxazole (9.3mg, 0.024mmol), and tripotassium phosphate (63.7mg,0.3mmol) in this order under a nitrogen atmosphere. Then adding 1, 4-dioxygen through a syringeHexacyclic ring (2.0mL,0.1M), the reaction mixture was reacted at 85 ℃ for 40h, then the solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether 1:3(v/v) to give product 8b in 43% yield with an er value of 94/6 as determined by HPLC. [ Daicel Chiralpak C2 column (25 cm. times.0.46 cm ID),nhexane/iPrOH＝80/20,0.7mL/min, 254nm；tminor＝18.9min,tmajor＝26.1min].1H NMR(500MHz,CDCl3) δ7.63(d,J＝7.8Hz,1H),7.40(td,J＝7.7,1.1Hz,1H),7.36(d,J＝7.4 Hz,1H),7.23(td,J＝7.5,0.8Hz,1H),4.79-4.63(m,2H),2.83(dt,J＝ 13.4,8.1Hz,1H),2.75-2.54(m,3H),1.41(t,J＝7.3Hz,3H)；13C NMR (125MHz,CDCl3)δ181.8,173.6,155.5,139.1,129.4,126.2,121.3, 120.8,66.3,63.7,31.6,23.6,10.3.HRMS m/z(ESI+):Calculated for C13H14NO2([M+H]+):216.1019,Found:216.1028.
example 9
To a dried Schlenk tube were added in this order, under a nitrogen atmosphere, β -disubstituted enamine derivative 9a (68.8mg,0.2mmol), palladium acetate (4.5mg, 0.02mmol), (S) -4-tert-butyl-2- (2- (diphenylphosphino) phenyl) -4, 5-dihydrooxazole (9.3mg, 0.02mmol), and sodium carbonate (21.2mg,0.2 mmol). Tetrahydrofuran (2.0mL,0.1M) was then added via syringe and the reaction mixture reacted at 85 ℃ for 40h, then the solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether 1:3(v/v) to give product 9b in 74% yield, with an er value of 93/7 as determined by HPLC. [ Daicel Chiralpak AS column (25 cm. times.0.46 cm ID),nhexane/iPrOH＝80/20,0.7mL/min,254 nm；tmajor＝20.0min,tminor＝22.0min].1H NMR(500MHz,CDCl3)δ 7.91-7.84(m,2H),7.74(d,J＝7.7Hz,1H),7.49(ddd,J＝8.7,3.3,1.6 Hz,3H),7.46-7.40(m,2H),7.28(td,J＝7.5,0.9Hz,1H),4.88-4.74(m, 2H),3.02(dt,J＝13.4,9.7Hz,1H),2.48(ddd,J＝13.4,6.8,3.1Hz,1H)；13C NMR(125MHz,CDCl3)δ175.5,174.2,155.0,140.4,131.4,131.2, 129.7,129.1,128.3,126.8,121.7,121.0,66.6,62.0,33.1.HRMS m/z (ESI+):Calculated for C17H13NNaO2([M+Na]+):286.0838,Found: 286.0845.
examples 1 to 9 relate to experimental results corresponding to the synthesis method of specific chiral spiro [ furan-3, 3' -indolenine ] -2-one compounds shown in table 1:
TABLE 1 Palladium catalyzed Synthesis of chiral spiro [ furan-3, 3' -indolenine]-2-keto reaction results[a]
[a]The reaction conditions are shown in the examples;[b]the isolation yield.
The foregoing is merely a few specific embodiments of the present invention, which are described in detail and specific, but the scope of the present invention is not limited thereto. Any changes or substitutions that may be easily made by those skilled in the art within the technical scope of the present disclosure are intended to be included within the scope of the present disclosure. Therefore, the protection scope of the present invention should be subject to the appended claims.
Claims (9)
1. A preparation method of chiral spiro [ furan-3, 3 '-indolenine ] -2-ketone compounds is characterized in that beta, beta-disubstituted enamine derivatives shown in formula (1) are used as raw materials, under the combined action of a palladium catalyst, a ligand and an alkaline compound, the reaction is carried out in an organic solvent at the temperature of 40-140 ℃, after the reaction is finished, the chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compounds shown in formula (2) are obtained through post-treatment, and the reaction general formula is as follows:
in the formula: r1Selected from alkyl, alkoxy, trifluoromethyl or halogenOne of the elements; r2Is alkyl or phenyl.
2. The chiral spiro [ furan-3, 3' -indolenine of claim 1]Process for the preparation of (E) -2-keto compounds, characterized in that R is1The alkyl in (A) is selected from C1-C10 straight chain or branched chain alkane, R1The alkoxy in (1) is selected from C1-C10 straight chain or branched chain alkoxy, R1The halogen in (A) is selected from one of fluorine, chlorine or bromine; r2The alkyl in (1) is selected from C1-C10 straight chain or branched chain alkane.
3. The method for preparing chiral spiro [ furan-3, 3' -indolenine ] -2-one compound according to claim 1, wherein the organic solvent is any one selected from dichloromethane, dichloroethane, toluene, m-xylene, methanol, ethanol, methyl tert-butyl ether, diethyl ether, tetrahydrofuran and 1, 4-dioxane, the ratio of the volume of the organic solvent to the amount of the beta, beta-disubstituted enamine derivative is 1-6: 1, the volume unit is ml, and the amount of the substance is mmol.
4. The process for preparing chiral spiro [ furan-3, 3' -indolenine ] -2-one compound according to claim 1, characterized in that the palladium catalyst is any one selected from the group consisting of palladium tetrakistriphenylphosphine, bis (tri-tert-butylphosphino) palladium, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, palladium acetate, diacetonitrile palladium dichloride, and allylpalladium chloride dimer.
5. The chiral spiro [ furan-3, 3' -indolenine of claim 1]A process for preparing (E) -2-ketone compounds, characterized in that the ligand is selected from (S) -Bn-Phox, (S) -onetBu-Phox、(S)-iPr-Phox、(S)-Ph-Phox、(S,Sp)-Bn-Phosferrox、(S,Sp)-tBu-Phosferrox、(S,Sp)-iPr-Phosferrox、(S,Sp) Any one of-Ph-Phosferrox.
6. The process for preparing chiral spiro [ furan-3, 3' -indolenine ] -2-one compound according to claim 1, characterized in that the basic compound is selected from any one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium acetate, potassium phosphate, disodium hydrogen phosphate, sodium carbonate, potassium carbonate or cesium carbonate.
7. The method for preparing chiral spiro [ furan-3, 3' -indolenine ] -2-one compound according to claim 1, wherein the molar ratio of the beta, beta-disubstituted enamine derivative, the palladium catalyst, the ligand and the basic compound is 1: 0.1-0.4: 0.1-0.8: 1-5.
8. The method for preparing chiral spiro [ furan-3, 3' -indolenine ] -2-one compound according to claim 1, characterized in that the reaction temperature is 60-100 ℃ and the reaction time is 20-72 h.
9. The process for the preparation of chiral spiro [ furan-3, 3' -indolenine ] -2-one compounds as claimed in claim 1, characterized by the post-treatment steps of: after the reaction is finished, removing the organic solvent by rotary evaporation, and then carrying out column chromatography separation to obtain a target product; the mobile phase of the column chromatography is a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-10: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011438913.3A CN112375086A (en) | 2020-12-11 | 2020-12-11 | Preparation method of chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011438913.3A CN112375086A (en) | 2020-12-11 | 2020-12-11 | Preparation method of chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112375086A true CN112375086A (en) | 2021-02-19 |
Family
ID=74590702
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011438913.3A Pending CN112375086A (en) | 2020-12-11 | 2020-12-11 | Preparation method of chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112375086A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115746001A (en) * | 2022-09-19 | 2023-03-07 | 浙江工业大学 | Preparation method of chiral pyrrolizine-3-ketone compound |
| CN116041359A (en) * | 2022-12-30 | 2023-05-02 | 成都大学 | Seven-membered indole spiro heterocyclic chiral derivative constructed by palladium catalysis |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100041900A1 (en) * | 2008-08-13 | 2010-02-18 | Kuang Ta Foods Co., Ltd | Isolation of lactam compound from adlay bran and its use on anti-proliferative cancer cells |
| CN104744484A (en) * | 2015-03-25 | 2015-07-01 | 浙江工业大学 | 3-furan[2,3-b] pyridine-4-indol maleimide derivatives as well as preparation and application thereof |
| CN106243118A (en) * | 2016-06-17 | 2016-12-21 | 南京理工大学 | A kind of GSH sensor based on rhodamine B, preparation method and application |
| CN107298684A (en) * | 2017-06-15 | 2017-10-27 | 浙江工业大学 | The method of intramolecular synthesizing spiro indolone |
| CN108440549A (en) * | 2018-04-04 | 2018-08-24 | 苏州大学 | The synthetic method of spiro indole class compound |
| US20190169209A1 (en) * | 2014-08-21 | 2019-06-06 | Boehringer Ingelheim International Gmbh | New spiro[3h-indole-3,2'-pyrrolidin]-2(1h)-one compounds and derivatives as mdm2-p53 inhibitors |
-
2020
- 2020-12-11 CN CN202011438913.3A patent/CN112375086A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100041900A1 (en) * | 2008-08-13 | 2010-02-18 | Kuang Ta Foods Co., Ltd | Isolation of lactam compound from adlay bran and its use on anti-proliferative cancer cells |
| US20190169209A1 (en) * | 2014-08-21 | 2019-06-06 | Boehringer Ingelheim International Gmbh | New spiro[3h-indole-3,2'-pyrrolidin]-2(1h)-one compounds and derivatives as mdm2-p53 inhibitors |
| CN104744484A (en) * | 2015-03-25 | 2015-07-01 | 浙江工业大学 | 3-furan[2,3-b] pyridine-4-indol maleimide derivatives as well as preparation and application thereof |
| CN106243118A (en) * | 2016-06-17 | 2016-12-21 | 南京理工大学 | A kind of GSH sensor based on rhodamine B, preparation method and application |
| CN107298684A (en) * | 2017-06-15 | 2017-10-27 | 浙江工业大学 | The method of intramolecular synthesizing spiro indolone |
| CN108440549A (en) * | 2018-04-04 | 2018-08-24 | 苏州大学 | The synthetic method of spiro indole class compound |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115746001A (en) * | 2022-09-19 | 2023-03-07 | 浙江工业大学 | Preparation method of chiral pyrrolizine-3-ketone compound |
| CN116041359A (en) * | 2022-12-30 | 2023-05-02 | 成都大学 | Seven-membered indole spiro heterocyclic chiral derivative constructed by palladium catalysis |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Lv et al. | Aromatization-driven cascade [1, 5]-hydride transfer/spirocyclization promoted by fluorinated alcohols | |
| CN112375086A (en) | Preparation method of chiral spiro [ furan-3, 3' -indolenine ] -2-ketone compound | |
| CN111171037B (en) | Chiral spiro 3,2' -pyrrolidine oxindole skeleton compound, preparation method and application thereof, intermediate and preparation method thereof | |
| Xu et al. | Pd‐catalyzed asymmetric intramolecular arylative dearomatization of para‐aminophenols | |
| Mardjan et al. | A tunable copper-catalyzed multicomponent reaction towards alkaloid-inspired indole/lactam polycycles | |
| Wang et al. | Iridium-catalyzed asymmetric hydrogenation of 2-substituted 1, 4-benzodioxines | |
| CN112916042A (en) | Chiral quaternary ammonium salt phase transfer catalyst based on tetramethyl spiroindane skeleton and preparation method thereof | |
| Reddy et al. | A concise approach for central core of trigolutes: Total synthesis of trigolute B and 3-epi-trigolute B and analogues | |
| Paul et al. | Redox-annulations of cyclic amines with electron-deficient o-tolualdehydes | |
| Dong et al. | Stereoselective Synthesis of Dihydrofuranoindoles via the Friedel–Crafts Alkylation/Annulation Cascade Process | |
| Sun et al. | Pd-Catalyzed asymmetric decarboxylation for the construction of spiro [4.5] deca-6, 9-dien-8-ones featuring vicinal quaternary carbons | |
| Chaudhari et al. | Polymer‐supported phosphoric‐acid catalysed enantioselective pictet‐spengler cyclisation for the synthesis of quaternary tryptolines in batch/continuous flow | |
| CN111057080B (en) | Preparation method of boron-containing indolinone derivative | |
| Keivanloo et al. | Novel one-pot synthesis of 1-alkyl-2-(aryloxy) methyl-1 H-pyrrolo [2, 3-b] quinoxalines via copper-free Sonogashira coupling reaction | |
| Das et al. | Annulations involving 1-indanones to access fused-and spiro frameworks | |
| Zhao et al. | Palladium-catalyzed desymmetric [2+ 2+ 2] cycloaddition of 1, 6-enyne and alkyne | |
| Jiang et al. | Synthesis of optically pure pyrroloquinolones via Pictet–Spengler and Winterfeldt reactions | |
| CN110590644A (en) | Chiral 1, 2-dihydropyridine compounds and preparation method and application thereof | |
| CN107522645B (en) | Method for preparing polysubstituted pyrrole compound | |
| JP2001526111A (en) | Catalyst compositions based on chiral ligands having molybdenum, tungsten or chromium and methods for asymmetric alkylation of allylic substrates | |
| CN109384705A (en) | A kind of synthetic method of benzo [a] carbazole of gold catalysis | |
| CN115746001A (en) | Preparation method of chiral pyrrolizine-3-ketone compound | |
| CN111704576A (en) | Synthesis method and application of axial chiral 9-aryl tetrahydroacridine | |
| Tang et al. | N-Heterocyclic Carbene Catalyzed Reaction of 2-(2-Aroylvinyl) cinnamaldehydes with α, β-Unsaturated Imines: An Efficient Method for the Stereoselective Synthesis of Highly Functionalized Indane Derivatives | |
| Panda et al. | Transition‐Metal Catalyzed [4+ 2]‐Cycloaddition Reactions: A Sexennial Update |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210219 |