CN107056795A - A kind of loop coil hydroxyindole pentamethylene and β lactones compound synthesis methods - Google Patents
A kind of loop coil hydroxyindole pentamethylene and β lactones compound synthesis methods Download PDFInfo
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- CN107056795A CN107056795A CN201710171412.5A CN201710171412A CN107056795A CN 107056795 A CN107056795 A CN 107056795A CN 201710171412 A CN201710171412 A CN 201710171412A CN 107056795 A CN107056795 A CN 107056795A
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- 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
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Abstract
It is specially that beta-unsaturated ketone acid esters is reactant, using N-heterocyclic carbine as catalyst with phenyl unsaturated aldehyde, reaction obtains loop coil hydroxyindole pentamethylene and β the invention discloses a kind of synthetic method of compound in loop coil hydroxyindole pentamethylene and β‑Interior compound.Method raw material disclosed by the invention is simple and easy to get, and reaction condition is gentle, post-processes simple and convenient, applicable substrate spectrum extensively, and high income, cis-selectivity and enantioselectivity are high；Thus the intermediate that obtained product can be used to synthetic drug and insecticide is synthesized.
Description
Technical field
The present invention relates to the synthesis of loop coil producing oxindoles compound, and in particular to and a kind of loop coil hydroxyindole pentamethylene and β-interior
The process for catalytic synthesis of compound.
Background technology
Loop coil producing oxindoles compound is widely existed in natural products, with antiviral, sterilization, inhibitory enzyme activity,
The significant physiology such as anti-oxidant and radiation proof, antitumor and pharmacological activity.It is also indispensable in many drug molecules simultaneously
Important feature unit, therefore paid close attention to by many scientists.And simultaneously β-interior lipoid substance also has life well to pentamethylene
Thing activity and medical value, but leave away a molecule carbon dioxide because decarboxylation easily occurs for the product and be difficult to obtain.Therefore develop
The structure that this two class all has bioactivity and pharmacological action is come together to synthesis of chiral loop coil hydroxyl Yin by efficient method
Diindyl pentamethylene and β-interior compound have attracted the great interest of many chemists, but its synthetic method is not reported.
In organic synthesis field, the synthetic method by organic catalysis is a kind of synthesis hand that is efficient, having economic value
The method of property compound.It is widely used in the synthesis of various Complex Chiral Compounds nearly ten years.Loop coil oxindole compounds
Synthesis is exactly the focus of a research, such as nitro compds and the hydroxyindole of three substitutions under thiocarbamide catalysis derived from golden pheasant soda
The Michael-Henry cascade reactions of derivative, this method can obtain hydroxyindole with good yield, outstanding enantioselectivity
Derivative cyclopentane derivatives.The synthetic method of loop coil oxindole derivatives is relatively common in the prior art, but loop coil hydroxyindole
Pentamethylene and β-lactones compound synthesis method are not reported also, because stable pentamethylene and β-lactones product is difficult
Arrive, quaternary cyclic lactone is easy to open loop, obtain the cyclopentene product after decarboxylation.In fact, beta-propiolactone be not only it is exceedingly useful
Building block, for example synthesize the carboxylic acid, polyester, Oxygenic heterocyclic compounds of various straight chains（H. Nguyen, G. Ma, T.
Gladysheva, T. Fremgen, D. Romo, J. Org. Chem. 2011, 76, 2-12.）；Beta-propiolactone is in itself
The intermediate of medicine, resin and fibre modifier is may be used as, the disinfection sanitizer of blood plasma, vaccine is also used as, it derives
Thingβ- mercaptopropionic acid is the raw material of PVC stabilizer and medicine.
Therefore necessary a kind of simple, efficient synthesizing spiro hydroxyindole pentamethylene and the β-interior compound found
Synthetic method, this method enantioselectivity and cis-selectivity are outstanding, while required substrate is easily-synthesized, cheap and easy to get, catalysis
Agent high catalytic efficiency, reaction condition is gentle, simple to operate.
The content of the invention
It is an object of the invention to provide loop coil hydroxyindole pentamethylene and the process for catalytic synthesis of β-interior compound；Lead to first
The efficient synthesizing spiro hydroxyindole pentamethylene of N-heterocyclic carbine and β-lactones structural compounds are crossed, structure is novel, it is to avoid existing
The defect that technology ester bond is departed from form of carbon dioxide.
To achieve the above object of the invention, the technical solution adopted by the present invention is：A kind of loop coil hydroxyindole pentamethylene and β-interior
The synthetic method of compound, with phenyl unsaturated aldehyde, beta-unsaturated ketone acid esters is reactant, using N-heterocyclic carbine as catalyst,
Reaction obtains loop coil hydroxyindole pentamethylene and β-Interior compound；
The chemical structural formula of the phenyl unsaturated aldehyde is, wherein R1It is selected from：2- methoxyl groups, 3- nitros,
One kind in 4- methoxyl groups, chlorine, nitro, bromine, cyano group, the chlorine substituents of 2,4- bis-；
The chemical structural formula of the beta-unsaturated ketone acid esters is, wherein R2For 5- methyl, methoxyl group, fluorine, 7- first
Base or 5,6- difluoros；R3For methyl, pi-allyl, benzyl；
The loop coil hydroxyindole pentamethylene and β-The structural formula of interior compound is：
。
In the present invention, the catalyst is N-heterocyclic carbine, and its chemical structural formula is as follows：
In above-mentioned technical proposal, course of reaction is included in 0 DEG C, and catalyst, phenyl unsaturated aldehyde, no are sequentially added into reaction bulb
Saturation keto ester, 4 molecular sieves, solvent, magnetic agitation are reacted, and after reaction terminates, crude product passes through simple column chromatography
（Eluant, eluent is preferably ethyl acetate: petroleum ether=1：5~1:10）It can obtain target product；Product prepared by the present invention is first
Retain quaternary lactonic ring, so that as many antibacterials, antitumor, resisting HIV, antivirotic and enzyme suppression
The analog of preparation, there is huge potential using value.
The reaction is carried out in ethers, benzene class or alcohols solvent；Such as dichloromethane, ether, tetrahydrofuran, first
Enter in benzene, 1,2- dichloroethanes, paraxylene, mesitylene, meta-xylene, ortho-xylene, 1,4- dioxane or methanol
OK, wherein during using mesitylene as solvent, cooperation N-heterocyclic carbine is catalyst reaction best results.
With molar amount, the consumption of the catalyst is the 5-20% of beta-unsaturated ketone acid esters；The consumption of phenyl unsaturated aldehyde is
1.5 times of beta-unsaturated ketone acid esters；It is preferred that scheme in, the consumption of the catalyst is the 10% of beta-unsaturated ketone acid esters consumption.
In the present invention, the reaction temperature is 0 DEG C, and the time is 24 hours.
It is preferred that, the reaction is carried out in the presence of 4 molecular sieves.
The invention also discloses according to above-mentioned loop coil hydroxyindole pentamethylene and β-The synthetic method synthesis of interior compound
Loop coil hydroxyindole pentamethylene and β-Interior compound, it is to avoid the defect that prior art ester bond is all departed from form of carbon dioxide,
Success closes CC keys, so as to form four-membered ring lactonic ring, achieves unexpected technique effect.
The efficient synthesizing spiro hydroxyindole pentamethylene of first passage N-heterocyclic carbine of the present invention and β-lactones structural compounds,
Thus disclose N-heterocyclic carbine and prepare loop coil hydroxyindole pentamethylene and β-Application in interior compound.Also disclose simultaneously
N-heterocyclic carbine is in the application and phenyl unsaturated aldehyde being catalyzed during phenyl unsaturated aldehyde reacts with beta-unsaturated ketone acid esters and/or not
Saturation keto ester is preparing loop coil hydroxyindole pentamethylene and β-Application in interior compound；The loop coil hydroxyindole pentamethylene is simultaneously
β-The structural formula of interior compound is：
。
Above-mentioned course of reaction is as follows：
Because above-mentioned technical proposal is used, the present invention has following advantages compared with prior art:
It is catalyst that 1. the present invention is realized by reactant, N-heterocyclic carbine of phenyl unsaturated aldehyde and beta-unsaturated ketone acid esters first
The method of synthesizing spiro hydroxyindole pentamethylene and β-interior compound, this method is easy to operate, high income, enantioselectivity and non-
Enantioselectivity is good；
2. the post-reaction treatment of synthesizing spiro hydroxyindole pentamethylene disclosed in this invention and β-lactones is simple, reaction belongs to
Aldol-Lactonizationization is reacted, and does not have accessory substance generation in system；Prior art ester bond is avoided all with carbon dioxide
The defect that form departs from, successfully closes CC keys, so as to form four-membered ring lactonic ring, achieves unexpected technique effect；
3. the method suitable substrates scope of synthesizing spiro hydroxyindole pentamethylene disclosed by the invention and β-interior compound is very wide, former
Material be industrialization, product cheap and easy to get, it is pollution-free；And functional group compatibility is high, cis-selectivity is outstanding, yield
It is high.
Embodiment
With reference to embodiment, the invention will be further described:
Embodiment one
The chemical structural formula of N-heterocyclic carbine is as follows：
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1a（19.8mg, 0.15
mmol）, 2a (26 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, is reacted under the conditions of 0 DEG C
24 hours, reaction system passed through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:5）It can obtain target product
3a （21.1 mg）, white solid, yield is 54%,>99/1 dr, 91% ee；Antibacterials can be prepared.
N-heterocyclic carbine is sequentially added in reaction bulb（1.85 mg, 0.005 mmol）It is used as catalyst, and 1a
（19.8mg, 0.15 mmol）, 2a (26 mg, 0.1 mmol), 4 molecular sieves（5mg）, 0.5 mL mesitylene is added, 0
Reacted 24 hours under the conditions of DEG C, reaction system passes through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:5）
Obtain target product 3a（15.2 mg）, white solid, yield is 39%,>99/1 dr, 90% ee.
N-heterocyclic carbine is sequentially added in reaction bulb（7.4 mg, 0.02 mmol）It is used as catalyst, and 1a（19.8mg,
0.15 mmol）, 2a (26 mg, 0.1 mmol), 4 molecular sieves（20 mg）, 0.5 mL mesitylene is added, in 0 DEG C of condition
Lower reaction 24 hours, reaction system passes through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:5）It can obtain mesh
Mark product 3a（20.3 mg）, white solid, yield is 52%,>99/1 dr, 90% ee.
Product 3a is analyzed, it is as a result as follows：[Daicel Chiralcel OJ-H, hexane/ are determined with HPLC
iPrOH (90:10), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 11.70, t
(minor) = 13.29]; [α]20 D = –38.9 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d)
δ 7.44 (dd, J = 7.2, 1.2 Hz, 1H), 7.23 (dd, J = 7.6, 1.2 Hz, 1H), 7.20 – 7.06
(m, 4H), 6.91 – 6.89 (m, 2H), 6.57 (d, J = 7.6 Hz, 1H), 4.97 (d, J = 8.0 Hz,
1H), 4.43 (q, J = 7.2 Hz, 2H), 4.00 (d, J = 8.4 Hz, 1H), 3.26 (d, J = 14.8
Hz, 1H), 2.81 (s, 3H), 2.72 (d, J = 14.8 Hz, 1H), 1.41 (t, J = 7.2 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 176.7, 169.0, 166.9, 143.2, 133.3, 128.7, 127.6,
127.5, 127.1, 126.7, 122.5, 122.2, 107.8, 83.6, 65.4, 63.6, 62.3, 54.1, 39.4,
25.2, 13.6. IR (neat, cm-1):3056,2965,2323,1982,1836,1748,1733,1699,
1469,1298,1093,1066,1056,808. HRMS (ESI): calcd. for C23H21NO5H+ [M + H] +
392.1492; found: 392.1498。
Embodiment two
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1b（24.3mg, 0.15
mmol）, 2a (26 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, is reacted under the conditions of 0 DEG C
24 hours, reaction system passed through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:5）It can obtain target product
3b （23.9 mg）, white solid, yield is 57%,>99/1 dr, 91% ee, can prepare antineoplastic.
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1b（24.3mg,
0.15 mmol）, 2a (26 mg, 0.1 mmol), 0.5 mL mesitylene of addition, reaction 24 hours under the conditions of 0 DEG C, reaction
System passes through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:5）It can obtain target product 3b（20.8mg）,
White solid, yield is 51%,>99/1 dr, 88% ee.
Product 3b is analyzed, it is as a result as follows：[Daicel Chiralcel AD-H, hexane/ are determined with HPLC
iPrOH (90:10), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 11.51, t
(minor) = 17.35]; [α]20 D = –51.7 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d)
δ 7.48 (d, J = 7.6 Hz, 1H), 7.24 – 7.19 (m, 1H), 7.15 – 7.06 (m, 3H), 6.80
(t, J = 7.6 Hz, 1H), 6.64 (t, J = 7.2 Hz, 2H), 4.73 (d, J = 6.0 Hz, 1H), 4.54
(d, J = 6.4 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 3.51 (s, 3H), 3.31 (d, J =
15.2 Hz, 1H), 2.90 (s, 3H), 2.66 (d, J = 15.2 Hz, 1H), 1.40 (t, J = 7.2 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 176.5, 169.3, 167.2, 156.8, 142.7, 129.3,
128.5, 128.1, 127.7, 123.9, 123.5, 122.1, 119.8, 109.9, 107.3, 85.2, 65.1,
63.8, 62.2, 54.5, 47.9, 39.9, 25.4, 13.6. IR (neat, cm-1):2924,1830,1716,
1601,1491,1483,1286,1102,902,750. HRMS (ESI): calcd. for C24H23NO6H+ [M +
H] + 422.1598; found: 422.1612。
Embodiment three
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1b（26.5mg, 0.15
mmol）, 2a (26 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, is reacted under the conditions of 0 DEG C
24 hours, reaction system passed through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target product
3c （28.3 mg）, white solid, yield is 65%,>99/1 dr, 86% ee, can prepare enzyme inhibitor.
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1b（26.5mg,
0.15 mmol）, 2a (26 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL tetrahydrofurans are added, in 0 DEG C of condition
Lower reaction 24 hours, reaction system passes through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain mesh
Mark product 3c（20.6mg）, white solid, yield is 47%,>99/1 dr, 81% ee.
Product 3c is analyzed, it is as a result as follows：[Daicel Chiralcel OD-H, hexane/ are determined with HPLC
iPrOH (80:20), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 15.64, t
(minor) = 12.77]; [α]20 D = 88.1 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d)
δ 8.03 (dt, J = 7.2, 2.4 Hz, 1H), 7.72 (s, 1H), 7.49 (dd, J = 7.6, 1.2 Hz,
1H), 7.39 – 7.34 (m, 2H), 7.31 – 7.29 (m, 1H), 7.19 (td, J = 7.6, 1.2 Hz,
1H), 6.64 (d, J = 7.6 Hz, 1H), 4.95 (d, J = 8.0 Hz, 1H), 4.45 (q, J = 7.2 Hz,
2H), 4.10 (d, J = 8.0 Hz, 1H), 3.31 (d, J = 15.2 Hz, 1H), 2.87 (s, 3H), 2.75
(d, J = 15.2 Hz, 1H), 1.43 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
176.1, 168.2, 166.6, 147.4, 142.9, 136.0, 133.2, 129.3, 128.8, 126.1, 123.1,
122.6, 122.3, 122.3, 108.2, 83.5, 65.0, 63.7, 62.6, 53.2, 39.8, 25.4, 13.6.
IR (neat, cm-1):3095,1830,1711,1605,1455,1434,1267,1124,901,741.
HRMS (ESI): calcd. for C23H20N2O7H+ [M + H] + 437.1343; found: 437.1355。
Example IV
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1d（24.3mg, 0.15
mmol）, 2a (26 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, is reacted under the conditions of 0 DEG C
24 hours, reaction system passed through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target product
3d （26.5 mg）, white solid, yield is 63%,>99/1 dr, 86% ee.
Product 3d is analyzed, it is as a result as follows：[Daicel Chiralcel AD-H, hexane/ are determined with HPLC
iPrOH (90:10), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 13.35, t
(minor) = 17.93]; [α]20 D = –73.9 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d)
δ 7.42 (dd, J = 7.6, 1.2 Hz, 1H), 7.23 (dd, J = 7.6, 1.2 Hz, 1H), 7.13 (td, J
= 7.6, 1.2 Hz, 1H), 6.84 – 6.82 (m, 2H), 6.62 – 6.58 (m, 3H), 4.90 (d, J =
8.4 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 3.95 (d, J = 8.4 Hz, 1H), 3.69 (s,
3H), 3.24 (d, J = 14.8 Hz, 1H), 2.84 (s, 3H), 2.69 (d, J = 14.8 Hz, 1H), 1.41
(t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 176.9, 169.0, 167.0, 158.7,
143.2, 128.7, 128.3, 126.9, 125.3, 122.5, 122.1, 113.0, 107.8, 83.5, 65.4,
63.8, 62.3, 54.7, 53.6, 39.4, 25.2, 13.6. IR (neat, cm-1):2981,1834,1750,
1607,1375,1264,1071,905,761,674. HRMS (ESI): calcd. for C24H23NO6H+ [M +
H] + 422.1598; found: 422.1604。
Embodiment five
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1e（26.5mg, 0.15
mmol）, 2a (26 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, is reacted under the conditions of 0 DEG C
24 hours, reaction system passed through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target product
3e （30.9 mg）, white solid, yield is 71%,>99/1 dr, 91% ee.
Product 3e is analyzed, it is as a result as follows：[Daicel Chiralcel OD-H, hexane/ are determined with HPLC
iPrOH (90:10), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 26.35, t
(minor) = 42.06]; [α]20 D = 68.2 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d)
δ 7.97 (d, J = 8.8, 1H), 7.49 – 7.46 (m, 1H), 7.30 (td, J = 7.6, 1.2 Hz, 1H),
7.18 (td, J = 7.6, 0.8 Hz, 1H), 7.12 – 7.10 (m, 1H), 6.63 (d, J = 7.6 Hz,
1H), 4.97 (d, J = 8.4 Hz, 1H), 4.45 (q, J = 7.2 Hz, 2H), 4.09 (d, J = 8.0 Hz,
1H), 3.30 (d, J = 15.2 Hz, 1H), 2.85 (s, 3H), 2.75 (d, J = 14.8 Hz, 1H), 1.42
(t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 176.1, 168.2, 166.5, 147.1,
142.9, 140.9, 129.3, 128.3, 125.9, 123.0, 122.8, 122.2, 108.2, 83.5, 65.3,
63.5, 62.5, 53.3, 39.8, 25.4, 13.6. IR (neat, cm-1):2987,2922,1792,1740,
1616,1541,1319,1123,668. HRMS (ESI): calcd. for C23H20N2O7H+ [M + H] +
437.1343; found: 437.1357。
Embodiment six
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1f（24.9mg, 0.15
mmol）, 2a (26 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, is reacted under the conditions of 0 DEG C
24 hours, reaction system passed through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target product
3f （26.7 mg）, white solid, yield is 63%,>99/1 dr, 91% ee.
Product 3f is analyzed, it is as a result as follows：[Daicel Chiralcel AD-H, hexane/ are determined with HPLC
iPrOH (90:10), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 11.52, t
(minor) = 13.30]; [α]20 D = –27.4 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d)
δ 7.43 (dd, J = 7.2, 1.2 Hz, 1H), 7.28 – 7.24 (m, 1H), 7.14 (td, J = 7.6, 0.8
Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 7.6
Hz, 1H), 4.91 (d, J = 8.4 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 3.96 (d, J = 8.0
Hz, 1H), 3.25 (d, J = 15.2 Hz, 1H), 2.85 (s, 3H), 2.70 (d, J = 15.0 Hz, 1H),
1.41 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 176.5, 168.7, 166.8,
143.1, 133.46, 131.9, 128.9, 128.6, 127.8, 126.4, 122.7, 122.1, 108.0, 83.5,
65.3, 63.6, 62.4, 53.3, 39.5, 25.3, 13.6. IR (neat, cm-1): 2933, 1772, 1613,
1576, 1471, 1329, 1141, 1013, 720, 631. HRMS (ESI): calcd. for C23H20ClNO5H+ [M
+ H] + 426.1103; found: 426.1120。
Embodiment seven
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1g（31.3mg, 0.15
mmol）, 2a (26 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, is reacted under the conditions of 0 DEG C
24 hours, reaction system passed through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target product
3g （28.1 mg）, white solid, yield is 60%,>99/1 dr, 90% ee.
Product 3g is analyzed, it is as a result as follows：[Daicel Chiralcel AD-H, hexane/ are determined with HPLC
iPrOH (90:10), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 14.50, t
(minor) = 12.17]; [α]20 D = 14.9 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d)
δ 7.42 (dd, J = 7.2 Hz, 0.8 Hz, 1H), 7.25 – 7.21 (m, 3H), 7.15 (td, J = 7.6
Hz, 0.8 Hz, 1H), 6.79 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.0 Hz, 1H), 4.90 (d,J = 8.4 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 3.95 (d, J = 8.4 Hz, 1H), 3.25 (d,J = 14.8 Hz, 1H), 2.86 (s, 3H), 2.70 (d, J = 15.2 Hz, 1H), 1.41 (t, J = 6.8
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 176.5, 168.6, 166.7, 143.1, 132.5, 130.8,
129.0, 128.9, 126.4, 122.7, 122.1, 121.7, 108.0, 83.4, 65.2, 63.6, 62.4,
53.4, 39.6, 25.3, 13.6. IR (neat, cm-1): 3037, 2992, 1756, 1630, 1546, 1341,
1210, 1014, 765. HRMS (ESI): calcd. for C23H20BrNO5H+ [M + H] +470.0598; found:
470.0608。
Embodiment eight
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1h（23.5mg, 0.15
mmol）, 2a (26 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, is reacted under the conditions of 0 DEG C
24 hours, reaction system passed through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target product
3h （28.7 mg）, white solid, yield is 69%,>99/1 dr, 93% ee.
Product 3h is analyzed, it is as a result as follows：[Daicel Chiralcel AD-H, hexane/ are determined with HPLC
iPrOH (90:10), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 29.59, t
(minor) = 38.27]; [α]20 D = 1246.7 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 7.47 (dd, J = 7.6, 1.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.31 – 7.27
(m, 1H), 7.17 (td, J = 7.6, 1.2 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.63 (d, J
= 7.6 Hz, 1H), 4.95 (d, J = 8.0 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 4.06 (d, J
= 8.0 Hz, 1H), 3.28 (d, J = 15.2 Hz, 1H), 2.84 (s, 3H), 2.75 (d, J = 15.2 Hz,
1H), 1.41 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 176.2, 168.3, 166.6,
142.9, 138.9, 131.4, 129.2, 128.1, 126.0, 122.9, 122.3, 117.8, 111.5, 108.1,
83.5, 65.3, 63.3, 62.5, 53.4, 39.6, 25., 13.6. IR (neat, cm-1): 2961, 2922,
1843, 1736, 1670, 1521, 1419, 1321, 1206, 990, 790. HRMS (ESI): calcd. for
C24H20N2O5H+ [M + H] + 417.1445; found: 417.1465。
Embodiment nine
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1i（30.0mg, 0.15
mmol）, 2a (26 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, is reacted under the conditions of 0 DEG C
24 hours, reaction system passed through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target product
3i （31.2 mg）, white solid, yield is 68%,>99/1 dr, 97% ee.
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1i（30.0mg,
0.15 mmol）, 2a (26 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL methanol is added, it is anti-under the conditions of 0 DEG C
Answer 24 hours, reaction system passes through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target production
Thing 3i（25.8 mg）, white solid, yield is 56%,>99/1 dr, 91% ee.
Product 3i is analyzed, it is as a result as follows：[Daicel Chiralcel AD-H, hexane/ are determined with HPLC
iPrOH (90:10), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 9.06, t
(minor) = 18.54]; [α]20 D = 11.4 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d)
δ 7.51 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.29 – 7.16 (m, 3H),
7.11 (t, J = 7.6 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 4.69 (d, J = 11.2 Hz,
1H), 4.43 (d, J = 7.6 Hz, 2H), 3.24 (d, J = 14.8 Hz, 1H), 2.99 (s, 3H), 2.71
(d, J = 15.2 Hz, 1H), 1.41 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
176.1, 167.9, 166.8, 142.7, 134.5, 133.8, 131.8, 129.3, 128.9, 128.8, 127.2,
126.8, 123.9, 122.6, 107.7, 84.23 65.5, 64.1, 62.5, 48.5, 40.5, 25.6, 13.6.
IR (neat, cm-1): 2972, 2918, 1800, 1715, 1636, 1507, 1457, 1338, 762, 669.
HRMS (ESI): calcd. for C23H19Cl2NO5H+ [M + H] + 460.0713; found: 460.0718。
Embodiment ten
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1i（30.0mg, 0.15
mmol）, 2b (28.5 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, it is anti-under the conditions of 0 DEG C
Answer 24 hours, reaction system passes through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target production
Thing 3j（30.5 mg）, white solid, yield is 63%,>99/1 dr, 83% ee.
Product 3j is analyzed, it is as a result as follows：[Daicel Chiralcel AD-H, hexane/ are determined with HPLC
iPrOH (90:10), flow rate:1.0 mL·min-1 , λ = 254 nm, t (major) = 6.74, t
(minor) = 13.48]; [α]20 D = 68.6 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d)
δ 7.52 (dd, J = 7.6, 1.2 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.23 (td, J =
8.0, 1.2 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 8.4, 2.0 Hz, 1H),
7.10 (td, J = 7.6, 1.2 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.56 – 5.47 (m,
1H), 5.03 (dd, J = 14.4, 1.2 Hz, 1H), 4.78 (d, J = 7.2 Hz, 1H), 4.73 – 4.68
(m, 2H), 4.49 – 4.38 (m, 2H), 4.36 – 4.30 (m, 1H), 3.91 (dd, J = 16.4, 5.6
Hz, 1H), 3.26 (d, J = 15.2 Hz, 1H), 2.74 (d, J = 15.2 Hz, 1H), 1.40 (t, J =
7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 176.0, 167.9, 166.7, 142.0, 134.6,
133.8, 131.3, 129.9, 129.7, 128.9, 128.8, 126.9, 126.5, 124.1, 122.5, 117.0,
108.7, 83.9, 65.4, 64.5, 62.5, 47.9, 41.6, 40.8, 13.6. IR (neat, cm-1): 2921,
2850, 1832, 1738, 1703 1641, 1541, 1467, 1325, 1218, 1101, 967, 826, 755,
689. HRMS (ESI): calcd. for C25H21Cl2NO5H+ [M + H] + 486.0870; found: 486.0880。
Embodiment 11
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1i（30.0mg, 0.15
mmol）, 2c (33.5 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, it is anti-under the conditions of 0 DEG C
Answer 24 hours, reaction system passes through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target production
Thing 3k（29.4 mg）, white solid, yield is 55%,>99/1 dr, 73% ee.
Product 3k is analyzed, it is as a result as follows：[Daicel Chiralcel AD-H, hexane/ are determined with HPLC
iPrOH (90:10), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 8.32, t
(minor) = 27.46]; [α]20 D = –159.0 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 7.53 (dd, J = 7.2, 1.2 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.23 – 7.17
(m, 4H), 7.15 (dd, J = 8.0, 1.2 Hz, 1H), 7.08 (td, J = 7.6, 1.2 Hz, 1H), 7.03
(dd, J = 8.8, 2.4 Hz, 1H), 6.81 – 6.76 (d, J = 6.0 Hz, 2H), 6.54 (d, J = 7.6
Hz, 1H), 4.95 (d, J = 15.6 Hz, 1H), 4.83 (d, J = 7.6 Hz, 1H), 4.77 (d, J =
7.2 Hz, 1H), 4.48 – 4.39 (m, 3H), 3.31 (d, J = 15.2 Hz, 1H), 2.78 (d, J =
15.2 Hz, 1H), 1.41 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 176.5,
168.0, 166.7, 142.1, 134.7, 134.3, 133.8, 131.1, 129.8, 129.0, 128.9, 128.2,
127.1, 127.1, 126.4, 126.2, 124.2, 122.5, 108.8, 83.6, 65.5, 64.8, 62.5,
47.4, 43.1, 41.2, 13.6. IR (neat, cm-1): 2920, 2849, 1843, 1736, 1609, 1488,
1363, 1175, 1024, 857, 721. HRMS (ESI): calcd. for C29H23Cl2NO5H+ [M + H] +
536.1026; found: 536.1031。
Embodiment 12
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1i（30.0mg, 0.15
mmol）, 2d (27.3 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, it is anti-under the conditions of 0 DEG C
Answer 24 hours, reaction system passes through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target production
Thing 3l（30.3 mg）, white solid, yield is 62%,>99/1 dr, 99% ee.
Product 3l is analyzed, it is as a result as follows：[Daicel Chiralcel OD-H, hexane/ are determined with HPLC
iPrOH (95:5), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 13.95, t
(minor) = 20.37]; [α]20 D = 138 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ
7.40 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.17 (dd, J = 8.8, 2.4
Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 8.4, 2.4 Hz, 1H), 6.59 (d, J
= 8.4 Hz, 1H), 4.67 (q, J = 7.2 Hz, 2H), 4.47 – 4.39 (m, 2H), 3.82 (s, 3H),
3.25 (d, J = 15.2 Hz, 1H), 2.97 (s, 3H), 2.68 (d, J = 15.2 Hz, 1H), 1.41 (t,J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 175.6, 167.9, 166.8, 155.8, 136.0,
134.4, 133.8, 131.9, 129.4, 128.9, 128.3, 126.8, 113.8, 110.8, 108.2, 84.3,
65.6, 64.4, 62.5, 55.4, 48.6, 40.5, 25.7, 13.6. IR (neat, cm-1): 2924, 1830,
1743, 1601, 1558, 1435, 1234, 902. HRMS (ESI): calcd. for C24H21Cl2NO6H+ [M +
H] + 490.0819; found: 490.0822。
Embodiment 13
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1i（30.0mg, 0.15
mmol）, 2e (28.9 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, it is anti-under the conditions of 0 DEG C
Answer 24 hours, reaction system passes through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target production
Thing 3m（29.8 mg）, white solid, yield is 63%,>99/1 dr, 89% ee.
Product 3m is analyzed, it is as a result as follows：[Daicel Chiralcel AD-H, hexane/ are determined with HPLC
iPrOH (90:10), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 7.11, t
(minor) = 11.03]; [α]20 D = –50.4 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d)
δ 7.40 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.19 – 7.15 (m, 2H),
7.05 (d, J = 8.8 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 4.68 (q, J = 9.2 Hz, 2H),
4.67 – 4.39 (m, 2H), 3.23 (d, J = 15.2 Hz, 1H), 2.96 (s, 3H), 2.69 (d, J =
15.2 Hz, 1H), 2.35 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 176.0, 167.9, 166.9, 140.3, 134.4, 133.7, 132.2, 131.8, 129.3, 129.0,
128.9, 127.0, 126.7, 124.8, 107.4, 84.2, 65.5, 64.3, 62.4, 48.4, 40.4, 25.6,
20.7, 13.6. IR (neat, cm-1): 2924, 1831, 1716, 1653, 1541, 1506, 1419, 1334,
1220, 1151, 970, 701. HRMS (ESI): calcd. for C24H21Cl2NO5H+ [M + H] + 474.0870;
found: 474.0875。
Embodiment 14
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1a（19.8mg, 0.15
mmol）, 2e (28.9 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, it is anti-under the conditions of 0 DEG C
Answer 24 hours, reaction system passes through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target production
Thing 3n（21.8 mg）, white solid, yield is 52%,>99/1 dr, 79% ee.
Product 3n is analyzed, it is as a result as follows：[Daicel Chiralcel AD-H, hexane/ are determined with HPLC
iPrOH (90:10), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 26.29, t
(minor) = 42.68]; [α]20 D = –86.3 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d)
δ 7.52 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.23 (t, J = 7.6 Hz,
1H), 7.18 (s, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.65
(d, J = 8.0 Hz, 1H), 5.56 – 5.47 (m, 1H), 5.02 (d, J = 10.0 Hz, 1H), 4.78 (d,J = 7.2 Hz, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.72 (t, J = 6.8 Hz, 2H), 4.47 –
4.38 (m, 4H), 4.34 (d, J = 16.8 Hz, 1H), 3.91 (d, J = 17.2 Hz, 1H), 3.26 (d,J = 14.8 Hz, 1H), 2.75 (d, J = 15.2 Hz, 1H), 1.40 (t, J = 7.2 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 176.4, 169.0, 166.9, 155.8, 136.6, 133.4, 128.0, 127.6,
127.5, 127.2, 113.0, 109.5, 108.2, 83.6, 65.7, 63.7, 62.3, 55.4, 54.1, 39.6,
25.3, 13.6. IR (neat, cm-1): 2924, 1840, 1747, 1614, 1471, 1352, 1206, 1177,
1145, 1047, 789. HRMS (ESI): calcd. for C24H23NO6H+ [M + H] + 422.1598; found:
422.1608。
Embodiment 15
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1i（30.0mg, 0.15
mmol）, 2f (27.7 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, it is anti-under the conditions of 0 DEG C
Answer 24 hours, reaction system passes through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target production
Thing 3o（26.7 mg）, white solid, yield is 56%,>99/1 dr, 96% ee.
Product 3o is analyzed, it is as a result as follows：[Daicel Chiralcel AD-H, hexane/ are determined with HPLC
iPrOH (90:10), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 10.42, t
(minor) = 16.22]; [α]20 D = –20.8 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d)
δ 7.38 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 8.0, 2.4 Hz, 1H), 7.21 (d, J = 2.0
Hz, 1H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 6.98 (td, J = 8.8, 2.8 Hz, 1H), 6.62
(dd, J = 8.8, 4.4 Hz, 1H), 4.68 (q, J = 4.0 Hz 1H), 4.47 – 4.40 (m, 2H), 3.26
(d, J = 15.2 Hz, 1H), 2.98 (s, 3H), 2.69 (d, J = 15.2 Hz, 1H), 1.41 (t, J =
7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 175.7, 167.5, 166.7, 160.0, 157.6,
138.6, 134.4, 133.9, 131.5, 129.3, 129.0, 128.8, 128.7, 126.8, 115.3, 115.0,
112.5, 112.2, 108.4, 108.3, 84.2, 65.5, 64.2, 64.2, 62.6, 48.5, 40.4, 25.7,
13.6. IR (neat, cm-1): 2980, 1840, 1740, 1613, 1493, 1303, 1179, 1023, 982.
HRMS (ESI): calcd. for C323H18Cl2FNO5H+ [M + H] + 478.0619; found: 478.0619。
Embodiment 16
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1i（30.0mg, 0.15
mmol）, 2g (29.5 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, it is anti-under the conditions of 0 DEG C
Answer 24 hours, reaction system passes through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target production
Thing 3p（28.7 mg）, white solid, yield is 58%,>99/1 dr, 94% ee.
Product 3p is analyzed, it is as a result as follows：[Daicel Chiralcel OD-H, hexane/ are determined with HPLC
iPrOH (80:20), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 7.94, t
(minor) = 9.69]; [α]20 D = 22.6 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ
7.40 (t, J = 7.6 Hz,1H), 7.35 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H),
7.20 (dd, J = 8.8, 2.4 Hz, 1H), 6.54 (dd, J = 9.6, 6.4 Hz, 1H), 4.64 (s, 2H),
4.47 – 4.41 (m, 2H), 3.24 (d, J = 15.2 Hz, 1H), 2.96 (s, 3H), 2.66 (d, J =
15.6 Hz, 1H), 1.42 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 175.7,
167.4, 166.7, 134.3, 134.1, 131.5, 130.1, 129.3, 129.0, 126.9, 122.8, 114.2,
114.0, 98.3, 98.0, 84.2, 65.4, 63.6, 62.6, 48.8, 40.4, 25.9, 13.6. IR (neat,
cm-1):2923,2851,2361,1842,1714,1623,1507,1412,1351,1260,1220,1189,
1061,903. HRMS (ESI): calcd. for C23H17Cl2F2NO5H+ [M + H] + 496.0525; found:
496.0533。
Embodiment 17
N-heterocyclic carbine is sequentially added in reaction bulb（3.7 mg, 0.01 mmol）It is used as catalyst, and 1i（30.0mg, 0.15
mmol）, 2h (27.3 mg, 0.1 mmol), 4 molecular sieves（10 mg）, 0.5 mL mesitylene is added, it is anti-under the conditions of 0 DEG C
Answer 24 hours, reaction system passes through simple column chromatography（Eluant, eluent is ethyl acetate：Petroleum ether=1:10）It can obtain target production
Thing 3q（28.1 mg）, white solid, yield is 60%,>99/1 dr, 94% ee.
Product 3q is analyzed, it is as a result as follows：[Daicel Chiralcel OD-H, hexane/ are determined with HPLC
iPrOH (80:20), flow rate: 1.0 mL·min-1 , λ = 254 nm, t (major) = 7.94, t
(minor) = 9.69]; [α]20 D = 22.6 (c 1, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ
7.40 (t, J = 7.6 Hz,1H), 7.35 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H),
7.20 (dd, J = 8.8, 2.4 Hz, 1H), 6.54 (dd, J = 9.6, 6.4 Hz, 1H), 4.64 (s, 2H),
4.47 – 4.41 (m, 2H), 3.24 (d, J = 15.2 Hz, 1H), 2.96 (s, 3H), 2.66 (d, J =
15.6 Hz, 1H), 1.42 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 175.7,
167.4, 166.7, 134.3, 134.1, 131.5, 130.1, 129.3, 129.0, 126.9, 122.8, 114.2,
114.0, 98.3, 98.0, 84.2, 65.4, 63.6, 62.6, 48.8, 40.4, 25.9, 13.6. IR (neat,
cm-1):2923,2851,2361,1842,1714,1623,1507,1412,1351,1260,1220,1189,
1061,903. HRMS (ESI): calcd. for C23H17Cl2F2NO5H+ [M + H] + 496.0525; found:
496.0533。
Claims (10)
1. a kind of loop coil hydroxyindole pentamethylene and β-The synthetic method of interior compound, it is characterised in that comprise the following steps：With
Phenyl unsaturated aldehyde, beta-unsaturated ketone acid esters is reactant, using N-heterocyclic carbine as catalyst, and reaction obtains loop coil hydroxyindole ring penta
Alkane and β-Interior compound；
The chemical structural formula of the phenyl unsaturated aldehyde is, wherein R1Selected from 2- methoxyl groups, 3- nitros, 4-
One kind in methoxyl group, chlorine, nitro, bromine, cyano group, the chlorine substituents of 2,4- bis-；
The chemical structural formula of the beta-unsaturated ketone acid esters is, wherein R2For 5- methyl, methoxyl group, fluorine, 7- methyl
Or 5,6- difluoros；R3For methyl, pi-allyl or benzyl；
The loop coil hydroxyindole pentamethylene and β-The structural formula of interior compound is：
。
2. loop coil hydroxyindole pentamethylene and β according to claim 1-The synthetic method of interior compound, it is characterised in that:
The reaction is carried out in ethers, benzene class or alcohols solvent.
3. loop coil hydroxyindole pentamethylene and β according to claim 2-The synthetic method of interior compound, it is characterised in that:Institute
State reaction dichloromethane, ether, tetrahydrofuran, toluene, 1,2- dichloroethanes, paraxylene, mesitylene, meta-xylene,
Carried out in ortho-xylene, 1,4- dioxane or methanol.
4. loop coil hydroxyindole pentamethylene and β according to claim 1-The synthetic method of interior compound, it is characterised in that:With
Molar amount, the consumption of the catalyst is the 5-20% of beta-unsaturated ketone acid esters；The consumption of phenyl unsaturated aldehyde is unsaturated ketone acid
1.5 times of ester.
5. loop coil hydroxyindole pentamethylene and β according to claim 1-The synthetic method of interior compound, it is characterised in that:Institute
It is 0 DEG C to state reaction temperature, and the time is 24 hours.
6. loop coil hydroxyindole pentamethylene and β according to claim 1-The synthetic method of interior compound, it is characterised in that:Institute
Reaction is stated to carry out in the presence of 4 molecular sieves.
7. loop coil hydroxyindole pentamethylene and β according to claim 1-The loop coil hydroxyl Yin of the synthetic method synthesis of interior compound
Diindyl pentamethylene is simultaneouslyβ-Interior compound.
8. N-heterocyclic carbine is preparing loop coil hydroxyindole pentamethylene and β-Application in interior compound；Or N-heterocyclic carbine exists
It is catalyzed the application during phenyl unsaturated aldehyde reacts with beta-unsaturated ketone acid esters.
9. loop coil hydroxyindole pentamethylene described in claim 7 and β-Interior compound is preparing antibacterials, antineoplastic, resisted
Application in human immunodeficiency virus medicine, antivirotic and enzyme inhibitor.
10. phenyl unsaturated aldehyde and/or beta-unsaturated ketone acid esters are preparing loop coil hydroxyindole pentamethylene simultaneouslyβ-In interior compound
Using.
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| WO2018176350A1 (en) * | 2017-03-31 | 2018-10-04 | 苏州大学张家港工业技术研究院 | SYNTHESIS METHOD FOR SPIRO HYDROXYINDOLE CYCLOPENTANE β-INTRA-ESTER COMPOUND |
| CN110551136A (en) * | 2019-09-16 | 2019-12-10 | 贵州大学 | preparation method and application of chiral spiro compound containing indole skeleton and catalyzed by N-heterocyclic carbene |
| CN113321657A (en) * | 2021-02-01 | 2021-08-31 | 南京工业大学 | Fluoro/fluoroalkyl 1, 3-dione compounds and method for synthesizing chiral compounds having fluoro/alkyl fluoro quaternary carbon centers |
| CN114478558A (en) * | 2022-01-24 | 2022-05-13 | 郑州大学 | Enantiomer-pure tetrahydrofuran spiro-oxoindole derivative and preparation method and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018176350A1 (en) * | 2017-03-31 | 2018-10-04 | 苏州大学张家港工业技术研究院 | SYNTHESIS METHOD FOR SPIRO HYDROXYINDOLE CYCLOPENTANE β-INTRA-ESTER COMPOUND |
| CN110551136A (en) * | 2019-09-16 | 2019-12-10 | 贵州大学 | preparation method and application of chiral spiro compound containing indole skeleton and catalyzed by N-heterocyclic carbene |
| CN110551136B (en) * | 2019-09-16 | 2022-05-17 | 贵州大学 | Preparation method and application of chiral spiro compound containing indole skeleton and catalyzed by N-heterocyclic carbene |
| CN113321657A (en) * | 2021-02-01 | 2021-08-31 | 南京工业大学 | Fluoro/fluoroalkyl 1, 3-dione compounds and method for synthesizing chiral compounds having fluoro/alkyl fluoro quaternary carbon centers |
| CN114478558A (en) * | 2022-01-24 | 2022-05-13 | 郑州大学 | Enantiomer-pure tetrahydrofuran spiro-oxoindole derivative and preparation method and application thereof |
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