CN116283868A - Synthesis method of spiro [ benzofuran-cyclohexene ] compound - Google Patents

Synthesis method of spiro [ benzofuran-cyclohexene ] compound Download PDF

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CN116283868A
CN116283868A CN202310054770.3A CN202310054770A CN116283868A CN 116283868 A CN116283868 A CN 116283868A CN 202310054770 A CN202310054770 A CN 202310054770A CN 116283868 A CN116283868 A CN 116283868A
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benzofuran
spiro
cyclohexene
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王能中
邹坤
黄年玉
姚辉
刘明国
黄熠非
张雨霏
谭梦婷
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China Three Gorges University CTGU
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D307/00Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins

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Abstract

The invention discloses a synthesis method of spiro [ benzofuran-cyclohexene ] compounds, which takes benzofuran azadiene and allyl carbonate as reaction raw materials, and the spiro [ benzofuran-cyclohexene ] compounds are obtained through reaction under the action of an organic phosphine catalyst. The invention has the advantages that: the reaction is efficient, the yield is high, the organic phosphine catalyst is cheap and easy to obtain and stable, and no pungent smell exists; strong acid or strong alkali and an additional oxidation or reduction agent are not needed to be added in the reaction, so that the conditions are mild; the transition metal is not required to be used as a catalyst in the reaction, so that the method is economical, practical and environment-friendly; the reaction substrate is easy to prepare; the reaction efficiency is high after the reaction is amplified, and the method has practical value.

Description

Synthesis method of spiro [ benzofuran-cyclohexene ] compound
Technical Field
The invention belongs to the technical field of organic compound technology application, and in particular relates to a spiro [ benzofuran-cyclohexene ] compound and a high-efficiency convenient synthesis method thereof.
Background
The benzofuran spiro six-membered ring skeleton has a special structure, and the core skeleton of the benzofuran spiro six-membered ring skeleton is widely existing in compounds and medicines in the nature. For example, griseofulvin originally isolated from penicillium griseofulvin by oxford and his colleagues is an fda approved antifungal for the treatment of dermatophyte infections caused by different spore and ringworm bacteria. Filifolinol is a pharmacophore with this core backbone structure isolated from natural product Heliotropium filifolium, which has been demonstrated to have antiviral activity. Spirodesertol A is a compound extracted from the rhizome of Salvia officinalis, and cisplatin is used as positive control, which shows potent cytotoxicity to A-549, SMMC-7721 and MCF-7 cancer cell lines. In addition, various natural compounds containing benzofurans spiro six-membered ring skeletons have been found to have significant and novel biological activities.
Figure BDA0004060085480000011
Medicine and active molecule containing benzofuran spiro six-membered ring skeleton
The development of simple synthetic strategies for such frameworks has been a very interesting topic for the organic synthesis community, however few catalytic methods for synthesizing such frameworks have been reported, which are still highly challenging, and the aim of the present invention is to devise a simple and practical catalytic method for constructing such frameworks. Organophosphine catalysis is a very excellent catalyst in cyclization reactions and is often used as a high-efficiency catalyst for cyclization reactions. Therefore, the invention splits the parent nucleus structure into benzofuran azadiene and allyl carbonate, and constructs the parent nucleus structure through phosphine catalysis.
Disclosure of Invention
The invention innovatively realizes a method for efficiently constructing the benzofuran spiro six-membered ring skeleton. The inventor discovers that the benzofuranazadiene is a unique compound containing a benzofurane skeleton, and has the characteristics of stability, easiness in preparation and the like. In view of this, the present invention devised a reaction process for preparing spiro [ benzofuran-cyclohexene ] compounds by reacting a benzofuran azadiene with an allyl carbonate.
The synthesis method of the spiro [ benzofuran-cyclohexene ] compound provided by the invention takes benzofuran azadiene and allyl carbonate as reaction raw materials under the catalysis of an organic phosphine catalyst, and the corresponding conversion is effectively realized in a reaction solvent, so that the spiro [ benzofuran-cyclohexene ] compound shown in the formula (III) is prepared. Wherein the reaction process is represented by the following reaction formula (a):
Figure BDA0004060085480000021
in the above reaction formula, R 1 Is hydrogen or halogen atom substituted; r is R 2 Is benzene ring, naphthalene ring, substituted benzene ring; r is R 3 Is an alkyl or aryl-containing alkane.
Preferably, R 1 Is hydrogen, 5-fluorophenyl, 5-bromophenyl; r is R 2 Phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methoxyphenyl, 2-naphthyl, 3-fluorophenyl, 3-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-nitrophenyl; r is R 3 Is tert-butyl, isopropyl, cyclohexyl.
As shown in the reaction formula (a), the benzofuran azadiene shown in the formula (I) and allyl carbonate are used as reaction raw materials, and react in a reaction solvent under the action of an organic phosphine catalyst to obtain the spiro [ benzofuran-cyclohexene ] compound shown in the formula (III).
In the invention, the dosage ratio of the benzofuranazadiene shown in the formula (I) as the starting raw material to the allyl carbonate shown in the formula (II) is 1:1-1:2. Preferably, the dosage ratio of the two is 1:1.5.
In the invention, the solvent is any one or any combination of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetonitrile and toluene. Preferably, the solvent is acetonitrile.
The reaction temperature is 20-30 ℃;
the catalyst is PhEt 2 P、Ph 3 P、(4-FC 6 H 4 ) 3 P、(4-MeC 6 H 4 ) 3 P、Ph 2 CyP、Ph 2 MeP、Ph 2 EtP、PhMe 2 P、PhCy 2 P、Bu 3 P。
The synthesis reaction of the invention comprises the following steps:
the reaction of equation (a) comprises the steps of: adding benzofuran azadiene, allyl carbonate and acetonitrile into a reaction vessel, and stirring and reacting at 25 ℃ to obtain the spiro [ benzofuran-cyclohexene ] compound shown in the formula (III).
In one embodiment, as in equation (a), the synthesis of the present invention is carried out by adding benzofuran azadiene (X mmol), allyl carbonate (Y mmol), solvent (V mL) to reaction flask A and stirring the reaction system at 25deg.C for 12 hours. After the reaction is finished, the reaction system is cooled to room temperature, concentrated and separated by column chromatography to obtain the target product.
The invention also provides the spiro [ benzofuran-cyclohexene ] compound shown in the formula (III) prepared by the synthesis method,
Figure BDA0004060085480000031
wherein R is 1 Is hydrogen or halogen atom substituted; r is R 2 Is benzene ring, condensed ring, heterocycle, substituted benzene ring; r is R 3 Is an alkyl or aryl-containing alkane;
the invention also provides an application method of the spiro [ benzofuran-cyclohexene ] compound shown in the formula (III) in synthesizing potential medicaments containing benzofuran spiro six-membered ring frameworks.
The invention has the following advantages: a) The reaction is efficient, and the yield is high; b) The organic phosphine catalyst is cheap and easy to obtain, stable and has no pungent smell; c) Strong acid or strong alkali and an additional oxidation or reduction agent are not needed to be added in the reaction, so that the conditions are mild; d) The transition metal is not required to be used as a catalyst in the reaction, so that the method is economical, practical and environment-friendly; e) The reaction substrate is easy to prepare; f) The reaction efficiency is high after the reaction is amplified, and the method has practical value.
The invention takes benzofuran aza diene compound and allyl carbonate compound which are easy to prepare as reaction raw materials, and the spiro [ benzofuran-cyclohexene ] compound is obtained by reaction under the action of an organic phosphine catalyst. The reaction operation is simple, the reaction condition is mild, and the method is suitable for large-scale industrial production.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples, to which the present invention is not limited. Variations and advantages that would occur to one skilled in the art are included in the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is defined by the appended claims. The procedures, conditions, reagents, experimental methods, etc. for carrying out the present invention are common knowledge and common knowledge in the art, except for those specifically mentioned below, and the present invention is not particularly limited. The data presented in the examples below include specific operations and reaction conditions and products. The purity of the product was identified by nuclear magnetism.
The synthesis reaction of the aryl alkyl thioether compound comprises the following steps:
as shown in equation a: adding benzofuran azadiene, allyl carbonate and acetonitrile into a reaction vessel, and stirring at 25 ℃ for reaction to obtain the spiro [ benzofuran-cyclohexene ] compound shown in the formula (III). Concentrating, and separating by column chromatography to obtain the target product.
The spiro [ benzofuran-cyclohexene ] compounds shown in Table 1 are all synthesized by the method of the invention, and no publication has been made.
TABLE 1 novel spiro [ benzofuran-cyclohexene ] compounds of the invention
Figure BDA0004060085480000051
Figure BDA0004060085480000061
Figure BDA0004060085480000071
Example 1
Figure BDA0004060085480000072
After benzofuranazadiene (37.5 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, a reaction tube, was added tert-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) and then an organophosphine catalyst, phEt, were added 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 1 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 81 percent,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.41(s,1H),8.39(d,J=8.2Hz,1H),7.99(d,J=8.4Hz,2H),7.43–7.37(m,3H),7.02(d,J=4.4Hz,4H),6.99–6.90(m,2H),6.77(d,J=8.4Hz,1H),6.08(s,1H),5.34(s,1H),4.28(s,1H),2.98–2.86(m,1H),2.70(d,J=14.9Hz,1H),2.48(s,3H),1.01(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.9,171.7,170.1,163.3,143.5,138.9,138.7,138.4,134.3,130.5,129.5,128.8,127.4,126.9,126.6,121.9,119.2,117.5,112.5,101.4,90.7,82.1,50.4,38.3,29.7,27.5,21.6.HRMS(ESI)m/z:calcd.for C 32 H 31 NO 6 SNa + (M+Na) + 580.1764,found 580.1764.
example 2
Figure BDA0004060085480000073
After benzofuranazadiene (37.5 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, was added to the reaction tube, cyclohexylallyl carbonate (49) was added.0mg,0.15mmol,1.5 equiv.) followed by addition of the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give product 2 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 64%,9:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.38(s,1H),8.41(d,J=8.1Hz,1H),7.98(d,J=8.3Hz,2H),7.44–7.37(m,3H),7.03(d,J=4.3Hz,4H),7.01–6.92(m,2H),6.78(d,J=8.4Hz,1H),6.10(s,1H),5.36(s,1H),4.60–4.51(m,1H),4.33(s,1H),2.89(d,J=14.8Hz,1H),2.74(d,J=15.0Hz,1H),2.48(s,3H),1.25(s,4H),1.20(t,J=8.6Hz,2H),1.05–0.96(m,4H). 13 C NMR(100MHz,CDCl 3 )δ181.7,171.5,170.0,163.6,143.5,138.8,138.2,134.1,130.5,129.5,128.7,127.5,126.9,126.7,122.0,119.7,112.5,100.5,90.4,73.2,49.9,37.9,31.1,30.1,29.7,25.0,23.1,22.8,21.6.HRMS(ESI)m/z:calcd.for C 34 H 34 NO 6 S + (M+H) + 584.2101,found 584.2096.
example 3
Figure BDA0004060085480000081
After benzofuranazadiene (37.5 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, a catalyst, was added to the reaction tube, isopropyl allyl carbonate (40.1 mg,0.15mmol,1.5 equiv.) was added, followed by the organophosphine catalyst, phEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and the product 3 (eluent polarity: petroleum ether/ethyl acetate 20:1) was obtained after separation by column chromatography. Yield: 72%,7:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.29(s,1H),8.41(d,J=8.2Hz,1H),7.99(d,J=8.0Hz,2H),7.43–7.37(m,3H),7.02(d,J=4.3Hz,4H),6.98–6.91(m,2H),6.78(d,J=8.5Hz,1H),6.10(s,1H),5.36(s,1H),4.78–4.71(m,1H),4.32(s,1H),2.90(d,J=15.3Hz,1H),2.73(d,J=15.0Hz,1H),2.48(s,3H),1.01(d,J=6.2Hz,3H),0.42(d,J=6.2Hz,3H). 13 C NMR(100MHz,CDCl 3 )δ181.7,171.6,170.0,163.5,143.5,138.9,138.8,138.3,134.2,130.6,129.5,128.7,127.5,126.9,126.6,122.0,119.6,112.6,100.6,90.5,68.4,50.0,38.2,21.6,21.5,20.4.HRMS(ESI)m/z:calcd.for C 31 H 29 NO 6 SNa + (M+Na) + 566.1608,found 566.1590.
example 4
Figure BDA0004060085480000082
After adding 2-fluorobenzofuran azadiene (39.3 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 4 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 82%,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.41(s,1H),8.47(d,J=8.1Hz,1H),7.96(d,J=8.4Hz,2H),7.49–7.43(m,1H),7.36(d,J=7.8Hz,2H),7.19–7.15(m,1H),7.06–6.97(m,2H),6.93–6.83(m,3H),6.07(s,1H),5.34(s,1H),4.67(s,1H),2.89–2.82(m,1H),2.78(d,J=15.1Hz,1H),2.47(s,3H),1.07(s,9H). 13 C NMR(100MHz,CDCl 3 )δ180.5,171.4,169.7,163.8,160.9(d,J=247.7Hz),143.3,138.9,138.7,134.0,130.7,130.0,130.0,129.4,128.4(d,J=8.3Hz),126.9,126.0(d,J=14.0Hz),123.2(d,J=3.4Hz),122.1,119.6,116.9,114.8(d,J=22.9Hz),112.5,100.5,89.9,82.2,37.6,27.5,21.6.HRMS(ESI)m/z:calcd.for C 32 H 31 FNO 6 S + (M+H) + 576.1851,found 576.1841.
example 5
Figure BDA0004060085480000091
After adding 2-chlorobenzofuran azadiene (39.3 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, t-butyl allyl carbonate (45.0 m, etc.) was added to the reaction tubeg,0.15mmol,1.5 equiv.) then adding the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 5 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 61%,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.48(s,1H),8.52(d,J=8.1Hz,1H),7.90(d,J=8.1Hz,2H),7.49(t,J=7.8Hz,1H),7.33(d,J=8.1Hz,2H),7.26–7.20(m,2H),7.12–7.01(m,3H),6.86(d,J=8.4Hz,1H),6.05(s,1H),5.34(s,1H),4.87(s,1H),2.90(d,J=15.2Hz,1H),2.77(d,J=15.2Hz,1H),2.46(s,3H),1.11(s,9H). 13 C NMR(100MHz,CDCl 3 )δ180.3,171.5,169.7,164.2,143.2,138.9,138.7,137.1,135.5,133.9,130.7,129.9,129.3,129.1,128.1,126.8,126.0,122.2,119.9,116.7,112.7,100.8,89.4,82.4,43.5,36.8,27.6,21.6.HRMS(ESI)m/z:calcd.for C 32 H 30 ClNO 6 SNa + (M+Na) + 614.1375,found 614.1373.
example 6
Figure BDA0004060085480000092
After adding 2-bromobenzofuran azadiene (45.4 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) is added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 6 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 72 percent,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.54(s,1H),8.54(d,J=8.1Hz,1H),7.88(d,J=8.2Hz,2H),7.52(t,J=7.7Hz,1H),7.46(d,J=7.9Hz,1H),7.32(d,J=8.1Hz,2H),7.25–7.16(m,2H),7.09–6.99(m,2H),6.88(d,J=8.4Hz,1H),6.04(s,1H),5.33(s,1H),4.82(s,1H),2.96(d,J=15.3Hz,1H),2.71(d,J=15.4Hz,1H),2.45(s,3H),1.14(s,9H). 13 C NMR(100MHz,CDCl 3 )δ180.3,171.6,169.9,164.5,143.2,138.9,138.9,138.6,133.9,132.6,130.7,130.0,129.2,128.4,126.8,126.7,122.3,120.2,116.6,112.9,101.4,100.8,89.2,82.5,45.7,36.3,27.8,21.6.HRMS(ESI)m/z:calcd.for C 32 H 31 BrNO 6 S + (M+H) + 636.1050,found 636.1049.
example 7
Figure BDA0004060085480000101
After adding 2-methoxybenzofuran azadiene (40.5 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) is added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 7 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 56 percent,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.33(s,1H),8.43(d,J=8.1Hz,1H),7.94(d,J=8.3Hz,2H),7.44–7.39(m,1H),7.35(d,J=8.1Hz,2H),7.09(dd,J=7.6,1.7Hz,1H),7.04–6.99(m,1H),6.96(t,J=7.7Hz,1H),6.76–6.69(m,2H),6.58(d,J=8.0Hz,1H),6.03(s,1H),5.32(s,1H),4.88(s,1H),3.61(s,3H),2.83(q,J=15.1Hz,2H),2.46(s,3H),1.04(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.7,171.7,169.8,163.3,157.2,143.2,139.2,138.4,134.4,130.3,129.3,129.1,127.8,127.3,126.7,121.7,119.4,119.0,117.4,112.4,109.0,101.8,90.3,81.8,54.9,37.5,27.9,27.5,21.6.HRMS(ESI):calcd.for C 33 H 33 NO 7 SNa + (M+Na) + 610.1870,found 610.1884.
example 8
Figure BDA0004060085480000102
After adding 3-fluorobenzofuran azadiene (39.3 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) is added followed byInto organic phosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 8 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 80%,10:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.47(s,1H),8.42(d,J=8.1Hz,1H),7.99(d,J=8.3Hz,2H),7.47–7.41(m,1H),7.40(d,J=8.1Hz,2H),7.03–6.93(m,2H),6.84–6.74(m,3H),6.72–6.66(m,1H),6.09(s,1H),5.35(s,1H),4.28(s,1H),2.89(d,J=15.0Hz,1H),2.69(d,J=15.0Hz,1H),2.48(s,3H),1.05(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.4,171.5,169.9,163.7,162.2(d,J=245.0Hz),143.6,141.2(d,J=7.0Hz),139.0,134.0,130.6,130.0,129.5,128.8(d,J=8.1Hz),127.0,124.7(d,J=2.6Hz),122.1,119.6,115.5(d,J=22.2Hz),113.5(d,J=21.1Hz),112.5,100.7,90.4,82.3,50.0,38.3,27.6,21.6.HRMS(ESI)m/z:calcd.for C 32 H 31 FNO 6 S + (M+H) + 576.1851,found 576.1841.
example 9
Figure BDA0004060085480000111
After adding 3-methylbenzofuran azadiene (39.0 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 9 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 61, 13:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.40(s,1H),8.39(d,J=8.1Hz,1H),7.99(d,J=8.3Hz,2H),7.44–7.37(m,3H),6.94–6.87(m,2H),6.85–6.75(m,4H),6.08(s,1H),5.33(s,1H),4.24(s,1H),2.90(d,J=14.9Hz,1H),2.70(d,J=15.0Hz,1H),2.48(s,3H),2.15(s,3H),1.02(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.9,171.7,170.1,163.1,143.5,138.9,138.7,138.2,136.8,134.3,130.5,129.5,129.5,127.3,127.1,126.9,125.9,121.8,119.1,112.4,101.4,90.7,82.0,50.3,38.1,27.9,27.5,21.6,21.1.HRMS(ESI)m/z:calcd.for C 33 H 33 NO 6 SNa + (M+Na) + 594.1921,found 594.1917.
example 10
Figure BDA0004060085480000121
After adding 4-nitrobenzofuran azadiene (42.0 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 10 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 62 percent,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.55(s,1H),8.40(d,J=8.2Hz,1H),7.99(d,J=8.4Hz,2H),7.92(d,J=8.8Hz,2H),7.46–7.39(m,3H),7.24(d,J=8.8Hz,2H),6.96(t,J=7.7Hz,1H),6.77(d,J=8.4Hz,1H),6.13(s,1H),5.39(s,1H),4.41(s,1H),2.92(d,J=15.1Hz,1H),2.69(d,J=15.0Hz,1H),2.49(s,3H),1.02(s,9H). 13 C NMR(100MHz,CDCl 3 )δ180.8,171.1,169.6,169.2,164.4,146.7,146.6,143.9,139.3,138.5,133.6,130.7,129.6,127.0,122.6,122.6,120.3,117.1,112.4,99.8,90.1,82.8,50.2,38.4,27.9,27.7,21.6.HRMS(ESI)m/z:calcd.for C 32 H 30 N 2 O 8 SNa + (M+Na) + 625.1615,found 625.1613.
example 11
Figure BDA0004060085480000122
After adding 4-cyanobenzofuran azadiene (40.0 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butylallyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P(3.3mg,20 mol%) and stirred at a reaction temperature of 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 11 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 74 percent,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.54(s,1H),8.40(d,J=8.2Hz,1H),7.99(d,J=8.3Hz,2H),7.47–7.38(m,3H),7.34(d,J=8.5Hz,2H),7.18(d,J=8.4Hz,2H),7.00–6.94(m,1H),6.76(d,J=8.4Hz,1H),6.12(s,1H),5.38(s,1H),4.35(s,1H),2.91(d,J=15.2Hz,1H),2.67(d,J=15.0Hz,1H),2.49(s,3H),1.02(s,9H). 13 C NMR(100MHz,CDCl 3 )δ180.9,171.2,169.7,164.3,144.5,143.8,139.3,138.5,133.7,131.2,130.6,129.6,129.5,127.0,122.5,120.1,118.7,117.2,112.4,110.4,99.8,90.2,82.7,50.6,38.4,27.7,27.6,21.6.HRMS(ESI)m/z:calcd.for C 32 H 31 ClNO 6 S + (M+H) + 583.1897,found 583.1896.
example 12
Figure BDA0004060085480000131
After adding 4-trifluoromethylbenzofuran azadiene (44.3 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, to a reaction tube, t-butylallyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) is added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 12 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 74, 7:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.51(s,1H),8.40(d,J=8.2Hz,1H),7.99(d,J=8.3Hz,2H),7.45–7.38(m,3H),7.30(d,J=8.1Hz,2H),7.17(d,J=8.1Hz,2H),6.95(t,J=7.7Hz,1H),6.76(d,J=8.5Hz,1H),6.11(s,1H),5.37(s,1H),4.35(s,1H),2.92(d,J=15.1Hz,1H),2.70(d,J=15.0Hz,1H),2.49(s,3H),1.01(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.2,171.4,169.8,164.0,143.7,142.9,142.9,139.1,138.7,133.9,130.6,129.6,129.1,128.8,127.0,124.3(q,J=3.8Hz),122.3,121.4(q,J=270.2Hz)119.8,112.5,100.4,90.3,82.5,50.3,38.3,27.6,21.6.HRMS(ESI)m/z:calcd.for C 33 H 31 F 3 NO 6 S + (M+H) + 626.1819,found 626.1817.
example 13
Figure BDA0004060085480000132
After adding 4-fluorobenzofuran azadiene (44.3 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and the product 13 (eluent polarity: petroleum ether/ethyl acetate 20:1) was obtained after separation by column chromatography. Yield: 81 percent,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.42(s,1H),8.41(d,J=8.2Hz,1H),7.99(d,J=8.3Hz,2H),7.46–7.37(m,3H),7.03–6.93(m,3H),6.81–6.70(m,3H),6.08(s,1H),5.34(s,1H),4.28(s,1H),2.90(d,J=15.1Hz,1H),2.67(d,J=15.0Hz,1H),2.48(s,3H),1.05(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.7,171.5,170.0,163.5,161.6(d,J=245.0Hz),143.6,139.0,138.8,134.3(d,J=3.2Hz),134.1,130.5,130.2(d,J=7.9Hz),129.5,126.9,122.1,119.5,117.4,114.2(d,J=21.2Hz),101.1,90.6,82.2,49.7,38.3,29.7,27.6,21.6.HRMS(ESI)m/z:calcd.for C 32 H 30 FNO 6 SNa + (M+Na) + 598.1670,found 598.1669.
example 14
Figure BDA0004060085480000141
After adding 4-chlorobenzofuran azadiene (41.0 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. However, the method is thatThe reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 14 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 66%,10:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.45(s,1H),8.41(d,J=8.1Hz,1H),7.98(d,J=8.3Hz,2H),7.48–7.42(m,1H),7.39(d,J=8.0Hz,2H),7.05–6.94(m,5H),6.79(d,J=8.4Hz,1H),6.08(s,1H),5.34(s,1H),4.27(s,1H),2.88(d,J=14.8Hz,1H),2.67(d,J=15.0Hz,1H),2.48(s,3H),1.05(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.4,171.4,169.9,163.6,143.6,139.0,138.7,137.2,134.0,132.3,130.6,130.1,129.5,127.5,126.9,122.2,119.6,117.2,112.5,100.8,90.4,82.3,49.7,38.2,27.6,21.6.HRMS(ESI)m/z:calcd.for C 32 H 30 ClNO 6 SNa + (M+Na) + 614.1375,found 614.1374.
example 15
Figure BDA0004060085480000142
After adding 4-bromobenzofuran azadiene (45.4 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) is added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 15 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 72 percent,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.45(s,1H),8.41(d,J=8.2Hz,1H),7.98(d,J=8.3Hz,2H),7.49–7.42(m,1H),7.39(d,J=8.1Hz,2H),7.18(d,J=8.5Hz,2H),6.98(t,J=7.7Hz,1H),6.92(d,J=8.4Hz,2H),6.79(d,J=8.4Hz,1H),6.08(s,1H),5.34(s,1H),4.25(s,1H),2.88(d,J=15.0Hz,1H),2.68(d,J=15.0Hz,1H),2.48(s,3H),1.05(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.4,171.4,169.9,163.7,143.6,139.1,138.7,137.8,134.0,130.6,130.5,130.5,129.5,126.9,122.3,120.4,119.6,117.2,112.5,100.7,90.4,82.4,49.8,38.3,27.6,21.6.HRMS(ESI)m/z:calcd.for C 32 H 31 BrNO 6 S + (M+H) + 636.1050,found 636.1036.
example 16
Figure BDA0004060085480000151
After adding 4-methoxybenzofuran azadiene (40.5 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) is added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 16 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 70 percent,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.36(s,1H),8.41(d,J=8.0Hz,1H),7.98(d,J=8.3Hz,2H),7.45–7.36(m,3H),6.98–6.92(m,3H),6.80(d,J=8.4Hz,1H),6.61–6.56(m,2H),6.06(s,1H),5.32(s,1H),4.24(s,1H),3.65(s,3H),2.87(d,J=14.9Hz,1H),2.69(d,J=15.0Hz,1H),2.48(s,3H),1.05(s,9H). 13 C NMR(100MHz,CDCl 3 )δ182.0,171.7,170.1,163.1,158.3,143.5,138.9,138.8,134.3,130.7,130.5,129.8,129.5,126.9,122.0,119.1,117.4,112.9,112.6,101.6,90.8,82.0,55.2,49.4,38.1,27.6,21.6.HRMS(ESI)m/z:calcd.for C 33 H 33 NO 7 SNa + (M+Na) + 610.1870,found 610.1884.
example 17
Figure BDA0004060085480000152
After adding 1-naphthobenzofuran azadiene (42.6 mg,0.1mmol,1.0 equiv.) and acetonitrile (1.0 mL), a reaction solvent, to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) is added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 17 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield is good:45%,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.40(s,1H),8.39(d,J=8.1Hz,1H),7.99(d,J=8.3Hz,2H),7.44–7.37(m,3H),6.94–6.87(m,2H),6.85–6.75(m,4H),6.08(s,1H),5.33(s,1H),4.24(s,1H),2.90(d,J=14.9Hz,1H),2.70(d,J=15.0Hz,1H),2.48(s,3H),2.15(s,3H),1.02(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.9,171.7,170.1,163.1,143.5,138.9,138.7,138.2,136.8,134.3,130.5,129.5,129.5,127.3,127.1,126.9,125.9,121.8,119.1,112.4,101.4,90.7,82.0,50.3,38.1,27.9,27.5,21.6,21.1.HRMS(ESI)m/z:calcd.for C 36 H 34 NO 6 S + (M+H) + 608.2101,found 608.2100.
Example 18
Figure BDA0004060085480000161
After adding 5' -fluorofuran azadiene (39.3 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 18 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 90 percent,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.41(s,1H),8.10(d,J=6.3Hz,1H),7.99(d,J=8.3Hz,2H),7.40(d,J=8.1Hz,2H),7.14(td,J=8.9,2.8Hz,1H),7.05–6.98(m,5H),6.73(dd,J=9.1,3.9Hz,1H),6.08(s,1H),5.34(s,1H),4.27(s,1H),2.95–2.85(m,1H),2.69(d,J=15.0Hz,1H),2.49(s,3H),1.00(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.50(d,J=3.2Hz),171.59,166.40,163.15,156.77(d,J=241.8Hz),143.8,138.4,138.2,134.0,129.6,128.7,127.5,127.1,127.0,126.9,126.7,126.7,119.3,113.4(d,J=8.2Hz),101.2,91.8,82.2,50.6,38.3,27.5,21.7.HRMS(ESI)m/z:calcd.for C 32 H 30 FNO 6 SK + (M+K + )614.1409,found 614.1406.
example 19
Figure BDA0004060085480000162
After adding 5' -bromofuran azadiene (45.4 mg,0.1mmol,1.0 equiv.) and reaction solvent acetonitrile (1.0 mL) to a reaction tube, t-butyl allyl carbonate (45.0 mg,0.15mmol,1.5 equiv.) was added followed by the organophosphine catalyst PhEt 2 P (3.3 mg,20 mol%) was stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure and separated by column chromatography to give the product 19 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 46%,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ12.41(s,1H),8.53(s,1H),7.99(d,J=8.3Hz,2H),7.46(dd,J=8.9,2.1Hz,1H),7.40(d,J=8.1Hz,2H),7.06–6.97(m,5H),6.68(d,J=8.9Hz,1H),6.08(s,1H),5.33(s,1H),4.27(s,1H),2.89(d,J=14.8Hz,1H),2.68(d,J=15.0Hz,1H),2.49(s,3H),1.00(s,9H). 13 C NMR(100MHz,CDCl 3 )δ180.2,171.6,168.8,163.1,143.8,141.4,138.31,138.2,133.9,132.4,129.6,128.7,127.6,127.0,126.8,126.8,119.4,114.2,114.1,101.2,91.6,82.2,50.5,38.3,27.5,21.7.HRMS(ESI)m/z:calcd.for C 32 H 30 BrNO 6 SNa + (M+Na) + 658.0869,found 658.0863.
example 20
Figure BDA0004060085480000171
Potassium carbonate (10.2 mg,0.037mmol,1.0 equiv.) and methyl iodide (4.6. Mu.L, 0.074mmol,2.0 equiv.) were added to the reaction tube, followed by the addition of reaction solvent DMF (1.0 mL), and then the addition of compound 1 (20.5 mg,0.037mmol,1.0 equiv.) and stirring at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 20 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 78%,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ8.35(d,J=8.1Hz,1H),8.00(d,J=8.3Hz,2H),7.45–7.37(m,3H),7.10–7.05(m,2H),7.04–6.94(m,3H),6.93–6.87(m,1H),6.84(d,J=8.4Hz,1H),5.69(s,1H),5.18(s,1H),4.38(s,1H),3.80(s,3H),2.97(d,J=15.3Hz,1H),2.68(d,J=15.4Hz,1H),2.49(s,3H),1.04(s,9H). 13 C NMR(100MHz,CDCl 3 )δ181.5,170.3,164.7,155.6,143.6,138.8,138.7,135.4,134.1,130.5,129.7,129.5,127.6,127.3,127.0,121.9,120.6,117.3,116.1,112.6,90.8,81.0,62.0,52.3,39.4,27.4,21.6.HRMS(ESI):m/z calcd for C 33 H 34 NO 6 S + (M+H) + 572.2101,found 572.2113.
example 21
Figure BDA0004060085480000181
4-Methylthiophenol (9.3 mg,0.075mmol,1.5 equiv.) and triethylamine (6.9. Mu.L, 0.05mmol,1.0 equiv.) are added to the reaction tube followed by the addition of the reaction solvent CHCl 3 (1.0 mL) and then compound 11 (29.1 mg,0.05mmol,1.0 equiv.) were added and stirred at 25℃for 12 hours. The reaction solution was then freed from the solvent under reduced pressure, and separated by column chromatography to give the product 20 (eluent polarity: petroleum ether/ethyl acetate 20:1). Yield: 65 percent,>20:1d.r.; 1 H NMR(400MHz,CDCl 3 )δ8.36(d,J=8.2Hz,1H),7.93(d,J=8.3Hz,2H),7.62–7.56(m,1H),7.43(d,J=8.0Hz,2H),7.36(d,J=8.5Hz,2H),7.21(t,J=8.3Hz,4H),7.10(d,J=7.9Hz,2H),7.06–6.99(m,2H),4.21(d,J=13.5Hz,1H),3.85(d,J=13.4Hz,1H),3.50(dd,J=13.9,4.2Hz,1H),3.21–3.11(m,1H),2.76–2.60(m,2H),2.51(s,3H),2.34(s,3H),2.06(t,J=13.9Hz,1H),1.16(s,9H). 13 C NMR(100MHz,CDCl 3 )δ202.9,179.3,169.7,166.1,144.2,139.6,139.4,138.0,137.2,131.8,131.1,130.5,129.9,129.8,129.7,129.6,127.0,123.1,118.2,112.2,111.9,110.2,90.7,82.5,58.9,53.2,45.6,40.0,33.5,27.6,21.7,21.1.HRMS(ESI):m/z calcd for C 39 H 40 NO 6 S 2 + (M+H) + 707.2244,found 707.2253.。

Claims (6)

1. a synthesis method of spiro [ benzofuran-cyclohexene ] compounds is characterized in that benzofuran azadiene and allyl carbonate are used as reaction raw materials, and react in a reaction solvent under the catalysis of an organic phosphine catalyst to obtain spiro [ benzofuran-cyclohexene ] compounds shown as a formula (III); the reaction process is shown in a reaction formula (a);
Figure QLYQS_1
wherein R is 1 Is hydrogen or halogen atom substituted; r is R 2 Is benzene ring, naphthalene ring, substituted benzene ring; r is R 3 Is an alkyl or aryl-containing alkane.
2. The synthetic method according to claim 1, wherein the solvent is any one or any combination of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetonitrile, toluene.
3. The synthetic process according to claim 1, wherein the ratio of the starting benzofuranazadiene to allyl carbonate is 1:1 to 1:2.
4. The method of claim 1, wherein the reaction temperature is 20-30 ℃;
the catalyst is PhEt 2 P、Ph 3 P、(4-FC 6 H 4 ) 3 P、(4-MeC 6 H 4 ) 3 P、Ph 2 CyP、Ph 2 MeP、Ph 2 EtP、PhMe 2 P、PhCy 2 P、Bu 3 P.
5. A spiro [ benzofuran-cyclohexene ] compound prepared by the synthesis method according to any one of claims 1 to 4, which has the structure shown in formula (iii):
Figure QLYQS_2
wherein R is 1 Is hydrogen or halogen atom substituted; r is R 2 Is benzene ring, naphthalene ring, substituted benzene ring; r is R 3 Is an alkyl or aryl-containing alkane.
6. The spiro [ benzofuran-cyclohexene ] compound according to claim 5, wherein the structure is represented by formula (III):
Figure QLYQS_3
wherein R is 1 Any one selected from hydrogen, 5-fluorophenyl, 5-chlorophenyl and 5-bromophenyl;
R 2 any one selected from phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methoxyphenyl, 2-methylphenyl, 2-naphthyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-methoxyphenyl, 3-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-nitrophenyl, 4-methoxyphenyl;
R 3 selected from any one of methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclohexyl and benzyl.
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CN111961060A (en) * 2020-08-27 2020-11-20 遵义医科大学 Preparation method of spiroheterocyclic 2, 3-dihydrobenzofuran compound with optical activity
CN113354655A (en) * 2021-05-27 2021-09-07 张家港威胜生物医药有限公司 Bibenzo [5,6] spiroketal compound and preparation method thereof
CN113620918A (en) * 2021-08-18 2021-11-09 山东大学 Method for synthesizing spiro compound through Lewis acid catalyzed [3+2] cycloaddition reaction

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