CN111704571A - Preparation method of optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde - Google Patents

Preparation method of optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde Download PDF

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CN111704571A
CN111704571A CN202010697480.7A CN202010697480A CN111704571A CN 111704571 A CN111704571 A CN 111704571A CN 202010697480 A CN202010697480 A CN 202010697480A CN 111704571 A CN111704571 A CN 111704571A
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indole
cyclopentane
optically active
formaldehyde
spiro
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刘志平
肖军安
黎金莲
成秀亮
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Nanning Normal University
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

The invention provides a preparation method of optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde, which comprises the following steps: the preparation method comprises the steps of taking vinyl oxindole spiro-propane and olefine aldehyde as raw materials, adding the raw materials into a solvent, respectively adding secondary amine, palladium salt, a ligand and an additive, stirring the mixture at room temperature, then removing the solvent, and purifying by a flash column chromatography to obtain the optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde. The 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde prepared by the method has the characteristics of mild reaction conditions, simple process, controllable optical activity, high yield and the like.

Description

Preparation method of optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde
Technical Field
The invention relates to the field of synthesis of oxindole derivatives. More particularly, the invention relates to a preparation method of optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde.
Background
Oxindole spiro rings are the core frameworks of many bioactive natural products and drug molecules, and the strategy of methods for efficiently constructing these frameworks has attracted extensive attention in the synthetic chemistry community. To date, several effective synthetic methods have been reported, such as 1, 3-dipolar cycloaddition, ring-opening [3+2] -cyclization and tandem [3+2] -cyclization of cyclopropane, and the like. Although these methods have greatly facilitated the development of the isatin conversion chemistry, the search for efficient stereoselective construction of spiro-oxidised indole backbones is still imminent.
Cyclic ternary synthons, such as donor-acceptor cyclopropane (DAC) and ethylene oxide, have received great attention due to their diverse reactivity. In particular, such synthetic blocks comprising two consecutive stereocenters (i.e., spiro ternary synthons) can be used to open a ring by [3+ n ]]-cyclization to efficiently construct spiro molecules. For example, in 2017 Zhou and colleagues reported the use of Ni (OTf)2Chiral BOX ligand catalytic system for catalyzing enantioselectivity [3+3 ] of nitrone and spiro propane oxindole]-cycloaddition reaction. In 2018, Tang task group reports that the series dearomatization reaction catalyzed by oxidizing indole spiro-oxirane with chiral phosphoric acid and 2-naphthol is used for constructing a spiro-oxindole skeleton. These methods are very efficient in enantioselectively synthesizing oxindole derivatives, but their yields often do not exceed 50%. To avoid the generation of kinetic resolution products and to increase the yield of the target cycloaddition product, achiral catalysts can be used instead of chiral catalysts to activate the spirocyclic ternary synthon. Based on preliminary findings from the subject group, it is envisaged herein that a concerted catalytic strategy may be a solution to the current challenge.
Disclosure of Invention
An object of the present invention is to solve at least the above problems and/or disadvantages and to provide at least the advantages described hereinafter.
Still another object of the present invention is to provide a process for preparing optically active 2-arylspiro [ cyclopentane-1, 3' -indole ] -3-carbaldehyde, which can improve the yield of the synthesized indole derivatives and has excellent enantioselectivity.
To achieve these objects and other advantages in accordance with the present invention, there is provided a process for preparing optically active 2-arylspiro [ cyclopentane-1, 3' -indole ] -3-carbaldehyde, comprising the steps of:
using vinyl oxindole spiropropane and olefine aldehyde as raw materials, adding the raw materials into a solvent, respectively adding secondary amine, palladium salt, a ligand and an additive, stirring the mixture at room temperature, then removing the solvent, and purifying by a flash column chromatography to obtain optically active 2-aryl spirocyclo [ cyclopentane-1, 3' -indole ] -3-formaldehyde;
the optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde has the following general structure: the general formula I and the general formula II,
general formula I:
Figure BDA0002591831840000021
general formula II:
Figure BDA0002591831840000022
wherein R is1Is an aryl group.
Preferably, the solvent is tetrahydrofuran, acetonitrile, N-dimethylformamide, toluene or methanol.
Preferably, the secondary amine is L-proline, a Michaelis catalyst and
Figure BDA0002591831840000023
a catalyst.
Preferably, the ligand is tris (2-furyl) phosphine or Xantphos.
Preferably, the additive is acetic acid.
Preferably, flash column chromatography is performed using petroleum ether: ethyl acetate 19:1-9: 1.
Preferably, the ratio of vinyloxindole spiropropane, enal and solvent is 0.1 mmol: 0.1-0.3 mmol: 1-3mL, the amount of the substance added with the secondary amine is 20-25 mol%, the amount of the substance added with the palladium salt is 5-8 mol%, the amount of the substance added with the ligand is 10-15 mol%, and the amount of the substance added with the additive is 20-30 mol%.
Preferably, the preparation method of the ethylene oxoindole spiro propane comprises the following steps:
step 1: to an ethanol solution of the nitrogen-protected isatin derivative was added hydrazine hydrate, the mixture was heated under reflux for 4-6 hours, then the ethanol was removed, the residue was extracted twice with ethyl acetate and washed with brine, and the combined organic phases were dried and concentrated to give a crude product of reduction.
Step 2: to the above-mentioned anhydrous tetrahydrofuran from which the crude product was reduced, sodium hydride was added in small portions, and the mixture was stirred at room temperature for 5 to 10 minutes, followed by further addition of 1, 4-dibromo-2-butene in portions. The reaction mixture was stirred at room temperature for 10-15 minutes, after completion of the reaction, the excess sodium hydride was quenched by addition of water, the residue was extracted twice with ethyl acetate and washed with brine, the organic phase was dried and concentrated in vacuo, purified by flash column chromatography with petroleum ether: the resulting residue was purified with ethyl acetate 19:1-9:1 to give the vinyloxindole spiropropane.
The invention at least comprises the following beneficial effects: the method can realize the directional ring opening of the spiro propane under mild conditions, further complete the efficient construction of the 2-aryl spiro [ cyclopentane-1, 3 '-indole ] -3-formaldehyde, and ensure that the reaction for synthesizing the 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde has the characteristics of mild reaction conditions, simple process, controllable optical activity, high yield and the like.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Drawings
FIG. 1 is a schematic representation of compounds 3-5b1H NMR spectrum;
FIG. 2 is a schematic representation of compounds 3-5b13C NMR spectrum;
FIG. 3 is a drawing of compounds 3-6b1H NMR spectrum;
FIG. 4 is a schematic representation of compounds 3-6b13C NMR spectrum;
FIG. 5 is a schematic representation of compounds 3-6d1H NMR spectrum;
FIG. 6 is a schematic representation of compounds 3-6d13C NMR spectrum;
FIG. 7 shows compounds 3-6h1H NMR spectrum;
FIG. 8 is of compounds 3-6h13C NMR spectrum;
FIG. 9 is an X-ray structural drawing of compounds 3-6 f. .
Detailed Description
The present invention is further described in detail below with reference to the attached drawings so that those skilled in the art can implement the invention by referring to the description text.
A preparation method of optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde comprises the following steps:
using vinyl oxindole spiropropane and olefine aldehyde as raw materials, adding the raw materials into a solvent, respectively adding secondary amine, palladium salt, a ligand and an additive, stirring the mixture at room temperature for 40-50 hours, then removing the solvent, and purifying by a flash column chromatography to obtain optically active 2-aryl spirocyclo [ cyclopentane-1, 3' -indole ] -3-formaldehyde;
the chemical reaction formula is as follows:
Figure BDA0002591831840000041
wherein R is1Is an aryl group.
Example 1
Taking 0.1mmol of vinyl oxindole spiro-propane and 0.1mmol of olefine aldehyde as raw materials, adding the raw materials into 1mL of tetrahydrofuran, respectively adding 20 mol% of secondary amine, 5 mol% of palladium salt, 10 mol% of ligand and 20 mol% of additive, stirring the mixture at room temperature for 48h, then removing the solvent, and purifying by flash column chromatography to obtain optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde;
the optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde has the following general structure: the general formula I and the general formula II,
general formula I:
Figure BDA0002591831840000042
general formula II:
Figure BDA0002591831840000043
wherein R is1＝4-FC6H4。
The product of this example was in 88% yield, dr 57:43, 87/73% ee.
Characterization data:
Figure BDA0002591831840000051
Hz,1H),7.72-7.74(m,1H),7.09-7.18(m,5H),6.94(d,J＝7.6Hz,4H),6.53-6.60(m,3H),6.06-6.15(m,1H),5.30(d,J＝16.8Hz,1H),5.15(d,J＝10.0Hz,1H),4.89(d,J＝16.0Hz,1H),4.45(d,J＝16.4Hz,1H),4.28-4.33(m,1H),4.19-4.22(m,1H),3.86-3.95(m,1H),2.40-2.43(m,1H),2.19-2.25(m,1H)；13C NMR(DMSO-d6,100MHz)203.9,178.2,161.9(d,J＝241.0Hz),142.8,139.3,136.1,133.0,130.8,130.0,128.6,127.5,126.9,123.5,123.1,117.1,115.2(d,J＝21.0Hz),109.3,59.4,56.9,52.2,42.6.
Figure BDA0002591831840000052
(d,J＝7.2Hz,1H),7.20-7.21(m,3H),7.02-7.13(m,2H),6.83-6.93(m,6H),6.65(d,J＝7.6Hz,1H),6.02-6.11(m,1H),5.32(d,J＝16.8Hz,1H),5.16(d,J＝10.0Hz,1H),4.99(d,J＝16.0Hz,1H),4.67(d,J＝16.0Hz,1H),4.12-4.22(m,2H),3.87-3.93(m,1H),2.26-2.31(m,1H),2.13-2.18(m,1H)；13C NMR(DMSO-d6,100MHz)203.7,178.1,162.8,160.4,142.2,138.8,136.3,133.0,130.2(d,J＝8.0Hz),128.8,128.5,127.7,127.3,125.2,122.7,117.4,115.0(d,J＝21.0Hz),109.5,59.6,57.4,53.0,43.6,43.2；HRMS(TOF-ESI+)m/z:calcd for C28H24FNNaO2[M+H]+448.1683,found 448.1768.
example 2
Taking 0.1mmol of vinyl oxindole spiro-propane and 0.2mmol of olefine aldehyde as raw materials, adding the raw materials into 2mL of toluene, respectively adding 25 mol% of secondary amine, 8 mol% of palladium salt, 15 mol% of tri (2-furyl) phosphine and 30 mol% of additive, stirring the mixture for 40h at room temperature, then removing the solvent, and purifying by a flash column chromatography to obtain optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde;
the optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde has the following general structure: the general formula I and the general formula II,
general formula I:
Figure BDA0002591831840000061
general formula II:
Figure BDA0002591831840000062
wherein R is1＝3-BrC6H4。
The product of this example was in 50% yield, dr 74:26, 0/56% ee.
Characterization data:
Figure BDA0002591831840000063
7.73-7.74(m,1H),7.40(d,J＝7.6Hz,1H),7.13-7.16(m,6H),7.03-7.07(m,1H),6.88-6.90(m,1H),6.62(d,J＝6.8Hz,1H),6.54-6.55(m,1H),6.04-6.13(m,1H),5.30(d,J＝16.8Hz,1H),5.16(d,J＝10.0Hz,1H),4.92(d,J＝16.4Hz,1H),4.44(d,J＝16.0Hz,1H),4.35(t,J＝10.8Hz,1H),4.20(d,J＝11.2Hz,1H),3.87-3.96(m,1H),2.40-2.46(m,1H),2.18-2.24(m,1H)；
13C NMR(DMSO-d6,100MHz)203.7,178.1,142.8,139.8,139.3,136.1,130.7,130.6,128.9,128.7,127.5,126.8,123.5,123.1,121.9,117.1,109.3,59.3,56.6,52.3,42.8.
Figure BDA0002591831840000071
J＝7.2Hz,1H),7.22-7.29(m,4H),7.09-7.13(m,3H),7.00-7.05(m,1H),6.91-6.98(m,4H),6.63(d,J＝7.6Hz,1H),6.01-6.10(m,1H),5.32(d,J＝17.2Hz,1H),5.15-5.18(m,1H),5.03(d,J＝16.0Hz,1H),4.66(d,J＝16.0Hz,1H),4.17-4.25(m,2H),3.85-3.94(m,1H),2.25-2.28(m,1H),2.14-2.19(m,1H)；13C NMR(DMSO-d6,100MHz)203.5,178.0,142.2,139.8,138.8,136.3,131.2,130.7,130.4,129.0,128.6,127.6,127.4,127.1,125.2,122.6,121.7,117.4,109.6,59.6,57.2,53.0,43.6,43.3.
example 3
Taking 0.1mmol of vinyl oxindole spiro-propane and 0.2mmol of olefine aldehyde as raw materials, adding the raw materials into 2mL of methanol, respectively adding 25 mol% of secondary amine, 8 mol% of palladium salt, 15 mol% of Xantphos and 30 mol% of additive, stirring the mixture at room temperature for 40h, then removing the solvent, and purifying by flash column chromatography to obtain optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde;
the optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde has the following general structure: the general formula I and the general formula II,
general formula I:
Figure BDA0002591831840000072
general formula II:
Figure BDA0002591831840000073
wherein R is1＝4-MeC6H4。
The product of this example was obtained in 90% yield, dr 59:41, 89/84% ee.
Characterization data:
Figure BDA0002591831840000081
7.70-7.72(m,1H),7.07-7.17(m,5H),6.81-6.92(m,4H),6.59-6.61(m,2H),6.49-6.51(m,1H),6.06-6.15(m,1H),5.28(d,J＝16.8Hz,1H),5.15(d,J＝10.0Hz,1H),4.90(d,J＝16.4Hz,1H),4.44(d,J＝16.4Hz,1H),4.16-4.30(m,2H),3.85-3.94(m,1H),2.38-2.43(m,1H),2.20-2.27(m,4H)；13C NMR(DMSO-d6,100MHz)204.1,178.3,142.9,139.3,136.6,136.1,133.7,131.0,129.1,128.7,128.5,128.1,127.4,126.9,123.4,122.9,116.9,109.2,59.4,57.0,52.8,42.7,21.1.
Figure BDA0002591831840000082
J＝7.2Hz,1H),7.17-7.21(m,3H),7.00-7.11(m,3H),6.89(d,J＝6.8Hz,2H),6.82(d,J＝5.2Hz,3H),6.60(d,J＝7.6Hz,1H),6.03-6.12(m,1H),5.30(d,J＝16.8Hz,1H),5.15(d,J＝10.0Hz,1H),5.00(d,J＝16.0Hz,1H),4.66(d,J＝16.0Hz,1H),4.08-4.21(m,2H),3.82-3.91(m,1H),2.23-2.32(m,2H),2.15(s,3H)；13C NMR(DMSO-d6,100MHz)203.9,178.2,142.2,138.8,136.4,136.2,133.7,131.2,128.9,128.3,127.2,125.2,122.6,117.3,109.5,59.7,57.5,53.4,43.7,43.5,43.1,21.0.
example 4
Taking 0.1mmol of vinyl oxindole spiro-propane and 0.3mmol of olefine aldehyde as raw materials, adding the raw materials into 3mL of tetrahydrofuran, respectively adding 21 mol% of secondary amine, 6 mol% of palladium salt, 10 mol% of tri (2-furyl) phosphine and 25 mol% of additive, stirring the mixture at room temperature for 50h, then removing the solvent, and purifying by flash column chromatography to obtain optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde;
the optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde has the following general structure: the general formula I and the general formula II,
general formula I:
Figure BDA0002591831840000091
general formula II:
Figure BDA0002591831840000092
wherein R is1＝2-naphthyl。
The product of this example was in 81% yield, dr 53:47, 97/80% ee.
Characterization data:
Figure BDA0002591831840000093
＝2.4Hz,1H),7.80-785(m,2H),7.68-7.70(m,1H),7.56-7.62(m,2H),7.45-7.51(m,2H),7.10-7.17(m,2H),6.87-6.98(m,2H),6.42-6.51(m,3H),6.30(d,J＝7.6Hz,2H),6.10-6.17(m,1H),5.33(d,J＝17.2Hz,1H),5.16-5.19(m,1H),4.88(d,J＝16.0Hz,1H),4.49-4.55(m,1H),4.25-4.41(m,2H),3.93-4.01(m,1H),2.45-2.50(m,1H),2.27-2.32(m,1H)；13C NMR(DMSO-d6,100MHz)204.0,178.3,142.8,139.4,135.8,134.7,133.2,132.8,131.0,128.6,128.3,127.8,126.5,126.2,123.5,123.0,109.2,59.5,56.8,53.1,43.0,42.6.
Figure BDA0002591831840000101
1H),7.76-7.77(m,2H),7.67-7.70(m,1H),7.53-7.55(m,3H),7.43-7.45(m,2H),7.03-7.05(m,4H),6.79(t,J＝7.6Hz,2H),6.71-6.73(m,1H),6.49-6.51(m,1H),6.08-6.17(m,1H),5.35(d,J＝17.2Hz,1H),5.18-5.20(m,1H),5.02(d,J＝16.0Hz,1H),4.59(d,J＝16.4Hz,1H),4.41(d,J＝12.0Hz,1H),4.29-4.35(m,1H),3.94-3.98(m,1H),2.33-2.38(m,1H),2.18-2.23(m,1H)；13C NMR(DMSO-d6,100MHz)203.8,178.2,142.2,138.8,136.0,134.6,133.0,132.5,131.1,128.6,128.4,128.1,127.8,127.6,127.5,127.4,126.9,126.5,126.3,125.3,122.6,117.4,109.5,59.9,57.5,53.8,43.9,43.5,43.2,31.4,22.6.
example 5
Taking 0.1mmol of vinyl oxindole spiro-propane and 0.3mmol of olefine aldehyde as raw materials, adding the raw materials into 3mL of tetrahydrofuran, respectively adding 23 mol% of L-proline, 7 mol% of palladium acetate, 12 mol% of tri (2-furyl) phosphine and 30 mol% of acetic acid, stirring the mixture at room temperature for 48h, then removing the solvent, and purifying by a flash column chromatography to obtain optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde;
the optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde has the following general structure: the general formula I and the general formula II,
general formula I:
Figure BDA0002591831840000102
general formula II:
Figure BDA0002591831840000103
wherein R is1＝3,4-diCl C6H4。
The product of this example was in 55% yield, dr 60:40, 94/67% ee.
Characterization data:
Figure BDA0002591831840000111
1.6Hz,1H),7.73-7.75(m,1H),7.26-7.28(m,1H),7.12-7.18(m,6H),6.99(s,1H),6.84(d,J＝7.6Hz,1H),6.54-6.62(m,3H),6.03-6.13(m,1H),5.30(d,J＝16.8Hz,1H),5.16(d,J＝10.4Hz,1H),4.92(d,J＝16.0Hz,1H),4.42-4.46(m,1H),4.33-4.39(m,1H),4.21(d,J＝11.2Hz,1H),3.90-3.96(m,1H),2.40-2.46(m,1H),2.18-2.24(m,1H)；13C NMR(DMSO-d6,100MHz)203.7,178.1,142.8,139.6,139.3,136.1,133.2,130.6,130.3,128.9,128.7,127.8,127.7,127.5,127.1,126.8,123.5,123.1,117.1,109.3,59.3,56.6,53.2,42.7.
Figure BDA0002591831840000112
mg,0.067mmol)；m.p.130-132℃；1H NMR(DMSO-d6,400MHz)9.75(s,1H),7.69(d,J＝7.2Hz,1H),7.21-7.23(m,3H),7.09-7.15(m,2H),7.03-7.07(m,2H),6.97(s,1H),6.92-6.94(m,2H),6.87(d,J＝7.6Hz,1H),6.63(d,J＝7.6Hz,1H),6.01-6.10(m,1H),5.32(d,J＝16.8Hz,1H),5.17(d,J＝10.0Hz,1H),5.02(d,J＝16.0Hz,1H),4.66(d,J＝16.0Hz,1H),4.17-4.26(m,2H),3.85-3.94(m,1H),2.25-2.30(m,1H),2.17(dd,J＝7.6,12.8Hz,1H)；13CNMR(DMSO-d6,100MHz)203.5,178.0,142.2,139.5,138.7,136.2,133.0,130.7,130.1,129.0,128.6,128.2,127.7,127.5,127.1,125.2,122.6,117.5,109.6,59.5,57.2,53.0,43.3.
example 6
Taking 0.1mmol of vinyl oxindole spiro-propane and 0.3mmol of enal as raw materials, adding the raw materials into 3mL of acetonitrile, respectively adding 20 mol% of a Mimi-ren catalyst, 5 mol% of palladium acetate, 10 mol% of tri (2-furyl) phosphine and 20 mol% of acetic acid, stirring the mixture at room temperature for 45h, then removing the solvent, and purifying by a fast column chromatography to obtain optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde;
the optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde has the following general structure: the general formula I and the general formula II,
general formula I:
Figure BDA0002591831840000121
general formula II:
Figure BDA0002591831840000122
wherein R is1＝2-ClC6H4。
The product of this example was obtained in 53% yield, dr 70:30, 16/94% ee.
Characterization data:
Figure BDA0002591831840000123
7.54-7.68(m,2H),7.31-7.36(m,1H),6.91-7.24(m,8H),6.76(d,J＝6.8Hz,1H),6.55(d,J＝7.2Hz,1H),6.00-6.14(m,1H),5.09-5.34(m,2H),4.80-4.95(m,2H),4.51(d,J＝16.0Hz,1H),4.17-4.22(m,1H),3.93-4.08(m,1H),5.32(d,J＝17.2Hz,1H),5.16-5.19(m,1H),4.89-4.93(m,1H),4.68-4.78(m,2H),2.20-2.42(m,1H)；13C NMR(DMSO-d6,100MHz)203.5,178.3,142.6,138.9,136.2,135.3,134.4,129.9,129.7,129.1,129.0,128.9,128.0,127.5,127.1,124.8,122.6,109.1,59.2,58.3,47.7,43.2,42.8.
Figure BDA0002591831840000124
1H),7.57(d,J＝7.2Hz,1H),7.24-7.26(m,1H),7.20-7.22(m,3H),7.12-7.14(m,1H),7.06(t,J＝7.6Hz,2H),6.93-7.00(m,4H),6.60(d,J＝7.6Hz,1H),6.22-6.31(m,1H),5.32(d,J＝17.2Hz,1H),5.16-5.19(m,1H),4.89-4.93(m,1H),4.68-4.78(m,2H),4.15-4.20(m,1H),3.86-3.92(m,1H),2.31(d,J＝7.2Hz,2H)；13C NMR(DMSO-d6,100MHz)202.9,178.7,142.5,138.8,136.4,135.2,134.3,131.3,130.1,129.6,128.9,128.8,128.4,127.6,127.2,126.5,125.7,122.3,109.2,60.1,58.0,48.8,44.4,43.7,43.3.
example 7
Taking 0.1mmol of vinyl oxindole spiropropane and 0.15mmol of olefine aldehyde as raw materials, adding the raw materials into 1mL of tetrahydrofuran, and respectively adding the raw materials
Figure BDA0002591831840000134
Figure BDA0002591831840000134
20 mol% of catalyst, 5 mol% of palladium acetate, 10 mol% of tri (2-furyl) phosphine and 20 mol% of acetic acid, stirring the mixture for 48h at room temperature, removing the solvent, and purifying by flash column chromatography to obtain the optically active 2-aryl spiro [ cyclopentane-1, 3' -indole]-3-formaldehyde;
the optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde has the following general structure: the general formula I and the general formula II,
general formula I:
Figure BDA0002591831840000131
general formula II:
Figure BDA0002591831840000132
wherein R is1＝2-furyl。
The product of this example was in 77% yield, dr 53:47, 46/90% ee.
Characterization data:
Figure BDA0002591831840000133
7.64(d,J＝7.2Hz,1H),7.31(s,1H),7.23-7.25(m,3H),7.10-7.19(m,2H),6.93(d,J＝6.4Hz,2H),6.68(d,J＝7.6Hz,1H),6.24(s,1H),5.98-6.07(m,1H),5.87(d,J＝2.8Hz,1H),5.27(d,J＝17.2Hz,1H),5.14(d,J＝10.0Hz,1H),4.94(d,J＝16.0Hz,1H),4.59(d,J＝16.0Hz,1H),4.32(t,J＝10.8Hz,1H),4.08-4.14(m,1H),3.87-3.94(m,1H),2.29-2.34(m,1H),2.18-2.23(m,1H)；13C NMR(DMSO-d6,100MHz)203.7,178.0,152.1,142.9,142.4,138.8,136.4,130.9,129.0,128.5,127.6,127.2,123.2,117.2,110.6,109.2,106.9,57.9,56.6,46.5,42.7.
Figure BDA0002591831840000141
7.42(d,J＝7.6Hz,1H),7.33-7.36(m,2H),7.23-7.28(m,3H),7.17(s,1H),7.10(t,J＝7.6Hz,1H),6.93-6.96(m,1H),6.75(d,J＝7.6Hz,1H),6.00-6.08(m,2H),5.84-5.85(m,1H),5.30(d,J＝16.8Hz,1H),5.07-5.17(m,2H),4.78-4.82(m,1H),4.32(d,J＝11.2Hz,1H),3.98-4.04(m,1H),3.79-3.84(m,1H),2.20-2.26(m,1H),2.05-2.10(m,1H)；13C NMR(DMSO-d6,100MHz)203.2,178.2,152.3,142.3,138.2,136.6,131.1,129.0,128.3,127.7,127.4,124.8,122.5,117.6,110.4,109.4,106.8,57.8,56.9,46.4,44.1,43.7,43.3.
example 8
Taking 0.1mmol of vinyl oxindole spiropropane and 0.15mmol of olefine aldehyde as raw materials, adding the raw materials into 1.5mL of tetrahydrofuran, and respectively adding the raw materials
Figure BDA0002591831840000144
Figure BDA0002591831840000144
20 mol% of catalyst, 5 mol% of palladium acetate, 10 mol% of tri (2-furyl) phosphine and 20 mol% of acetic acid, stirring the mixture for 48h at room temperature, removing the solvent, and purifying by flash column chromatography to obtain the optically active 2-aryl spiro [ cyclopentane-1, 3' -indole]-3-formaldehyde;
the optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde has the following general structure: the general formula I and the general formula II,
general formula I:
Figure BDA0002591831840000142
general formula II:
Figure BDA0002591831840000143
wherein R is1＝2-thienyl。
The product of this example was in 64% yield, dr 61:39, 79/83% ee.
Characterization data:
Figure BDA0002591831840000151
1H),7.71(d,J＝6.8Hz,1H),7.12-7.24(m,6H),6.83-6.85(m,1H),6.59-6.70(m,4H),6.00-6.09(m,1H),5.28(d,J＝16.4Hz,1H),5.14(d,J＝9.6Hz,1H),4.90(d,J＝16.4Hz,1H),4.46-4.54(m,2H),4.19-4.25(m,1H),3.85-3.94(m,1H),3.35-3.40(m,1H),2.22-2.28(m,1H)；13C NMR(DMSO-d6,100MHz)203.7,177.9,143.3,139.7,139.1,136.2,130.5,128.9,128.8,127.4,127.2,126.9,125.1,125.0,123.5,123.4,123.0,117.2,109.3,59.3,58.8,58.4,48.4,42.9,42.7,42.3.
Figure BDA0002591831840000152
7.63(d,J＝7.2Hz,1H),7.27-7.31(m,1H),7.14-7.22(m,4H),7.04-7.07(m,1H),6.89-6.96(m,2H),6.70-6.76(m,2H),6.55-6.62(m,1H),5.99-6.08(m,1H),5.23-5.31(m,1H),5.11-5.16(m,1H),4.88-5.01(m,1H),4.71-4.78(m,1H),4.38-4.53(m,1H),3.83-3.95(m,2H),2.11-2.30(m,2H)；13C NMR(DMSO-d6,100MHz)203.6,177.7,144.3,142.6,140.0,139.7,139.0,138.4,136.2,130.8,130.4,128.9,128.7,127.6,127.1,126.9,126.7,126.1,125.4,125.2,125.0,123.1,122.8,117.5,109.6,108.7,59.7,59.5,59.2,58.5,49.2,43.8,43.2,43.0.
example 9
The preparation of the vinyloxindole spirocyclopropanes used in examples 1-8 comprises the following steps:
step 1: to a solution of the nitrogen-protected isatin derivative (20mmol) in ethanol (0.1M) was added hydrazine hydrate (3.1mL,50mmol, 2.5 equivalents, 80% aqueous solution). The mixture was heated under reflux for 4 hours, then the ethanol was removed, and the residue was extracted twice with ethyl acetate and washed with brine. The combined organic phases were dried and concentrated to give a crude product of reduction.
Step 2: to the crude product reduced as described above in anhydrous tetrahydrofuran was added sodium hydride (2.0g, 50mmol, 2.5 equiv., 60% dispersion in mineral oil) in small portions, the mixture was stirred at room temperature for 5 minutes, and then 1, 4-dibromo-2-butene (4.7g, 22mmol, 1.1 equiv.) was further added in portions. The reaction mixture was stirred at room temperature for 10 minutes and after completion of the reaction (monitored by TLC), water (5mL) was added to quench the excess sodium hydride. The residue was extracted twice with ethyl acetate and washed with brine. The organic phase was dried and concentrated in vacuo. By flash column chromatography with petroleum ether: purifying the resulting residue with ethyl acetate 19:1-9:1 to give the vinyloxindole spiropropane;
the chemical reaction is as follows:
Figure BDA0002591831840000161
while embodiments of the invention have been disclosed above, it is not intended to be limited to the uses set forth in the specification and examples. It can be applied to all kinds of fields suitable for the present invention. Additional modifications will readily occur to those skilled in the art. It is therefore intended that the invention not be limited to the exact details and illustrations described and illustrated herein, but fall within the scope of the appended claims and equivalents thereof.

Claims (8)

1. The preparation method of the optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde is characterized by comprising the following steps:
adding vinyl oxindole spiropropane and olefine aldehyde serving as raw materials into a solvent, respectively adding secondary amine, palladium salt, a ligand and an additive, stirring the mixture at room temperature, then removing the solvent, and purifying by a flash column chromatography to obtain the optically active 2-aryl spirocyclo [ cyclopentane-1, 3' -indole ] -3-formaldehyde;
the optically active 2-aryl spiro [ cyclopentane-1, 3' -indole ] -3-formaldehyde has the following general structure: the general formula I and the general formula II,
general formula I:
Figure FDA0002591831830000011
general formula II:
Figure FDA0002591831830000012
wherein R is1Is an aryl group.
2. The process for producing an optically active 2-arylspiro [ cyclopentane-1, 3' -indole ] -3-carbaldehyde according to claim 1, wherein the solvent is tetrahydrofuran, acetonitrile, N-dimethylformamide, toluene, or methanol.
3. The optically active 2-arylspiro [ cyclopentane-1, 3' -indole of claim 1]A preparation method of (E) -3-formaldehyde, which is characterized in that the secondary amine is L-proline, a Migmelin catalyst and
Figure FDA0002591831830000013
-Hayashi catalyst.
4. The process for preparing an optically active 2-arylspiro [ cyclopentane-1, 3' -indole ] -3-carbaldehyde according to claim 1, wherein the ligand is tris (2-furyl) phosphine or xanthphos.
5. The process for preparing an optically active 2-arylspiro [ cyclopentane-1, 3' -indole ] -3-carbaldehyde according to claim 1, wherein the additive is acetic acid.
6. The process for producing an optically active 2-arylspiro [ cyclopentane-1, 3' -indole ] -3-carbaldehyde according to claim 1, wherein the flash column chromatography is performed using petroleum ether: ethyl acetate 19:1-9: 1.
7. The process for preparing optically active 2-arylspiro [ cyclopentane-1, 3' -indole ] -3-carbaldehyde according to claim 1, wherein the ratio of vinyloxoindole spiropropane, enal and solvent is 0.1 mmol: 0.1-0.3 mmol: 1-3mL, the amount of the substance added with the secondary amine is 20-25 mol%, the amount of the substance added with the palladium salt is 5-8 mol%, the amount of the substance added with the ligand is 10-15 mol%, and the amount of the substance added with the additive is 20-30 mol%.
8. The process for preparing optically active 2-arylspiro [ cyclopentane-1, 3' -indole ] -3-carbaldehyde according to claim 1, wherein the process for preparing vinyloxoindole spiropropane comprises the steps of:
step 1: adding hydrazine hydrate to an ethanol solution of a nitrogen-protected isatin derivative, heating the mixture under reflux for 4-6 hours, then removing the ethanol, extracting the residue twice with ethyl acetate and washing with brine, drying the combined organic phases and concentrating to obtain a crude reduction product;
step 2: to the above-mentioned anhydrous tetrahydrofuran from which the crude product was reduced, sodium hydride was added in small portions, the mixture was stirred at room temperature for 5 to 10 minutes, then 1, 4-dibromo-2-butene was further added in portions, the reaction mixture was stirred at room temperature for 10 to 15 minutes, after completion of the reaction, the excess sodium hydride was quenched by addition of water, the residue was extracted twice with ethyl acetate and washed with brine, the organic phase was dried and concentrated in vacuo, and purified by flash column chromatography with petroleum ether: the resulting residue was purified with ethyl acetate 19:1-9:1 to give the vinyloxindole spiropropane.
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