阅读说明：本技术 含三氟甲基的螺[4,5]癸烷类化合物及其制备方法 (Trifluoromethyl-containing spiro [4,5] decane compound and preparation method thereof ) 是由 韩贵芳 刘阳平 宋玉光 赵一霖 王雪 于 2021-10-22 设计创作，主要内容包括：本发明公开了含三氟甲基的螺[4,5]癸烷类化合物及其制备方法,包括以下步骤：(1)在惰性氛围下,室温条件下将催化剂与配体溶于有机溶剂中反应；(2)加入苯酚衍生物和碱,在一定温度下发生反应；(3)加入三氟甲基源,控制反应温度和时间直至苯酚衍生物反应完全。本发明提供的含三氟甲基的螺[4,5]癸烷类化合物的制备方法具有成本低、可重复性好、环境友好等特点,并且制备得到的含三氟甲基的螺[4,5]癸烷类化合物不仅是重要的有机合成砌块,而且是天然产物和活性成分的重要骨架。(The present invention discloses spiro [4,5] containing trifluoromethyl]The decane compound and the preparation method thereof comprise the following steps: (1) dissolving a catalyst and a ligand in an organic solvent for reaction under the inert atmosphere and room temperature; (2) adding a phenol derivative and alkali, and reacting at a certain temperature; (3) a trifluoromethyl source is added and the reaction temperature and time are controlled until the phenol derivative reaction is complete. The spiro [4,5] containing trifluoromethyl provided by the invention]The preparation method of the decane compound has the characteristics of low cost, good repeatability, environmental friendliness and the like, and the prepared trifluoromethyl-containing spiro [4,5]Decane compounds are not only important organic synthetic building blocks, but also important skeletons of natural products and active ingredients.)

1. the spiro [4,5] decane compound containing trifluoromethyl has the following structural formula:

wherein the content of the first and second substances,

R₁selected from hydrogen, halogen, alkyl, alkoxy or ester groups;

R₂、R₃selected from ester groups or alkylcarbonyloxy groups;

R₄selected from alkyl or aryl.

2. A method for producing a trifluoromethyl group-containing spiro [4,5] decane-based compound according to claim 1, comprising the steps of:

(1) dissolving a catalyst and a ligand in an organic solvent for reaction under the inert atmosphere and room temperature;

(2) adding a phenol derivative and alkali, and reacting at a certain temperature;

(3) a trifluoromethyl source is added and the reaction temperature and time are controlled until the phenol derivative reaction is complete.

3. The method according to claim 2, wherein the catalyst in the step (1) is Fe (acac)₃、Fe(acac)₂、FeCl₂、Fe(OTf)₂Or FeBr₂(ii) a The ligand is 2,2 ' -bipyridyl, 4 ' -dimethoxy-2, 2 ' -bipyridyl, 6 ' -dimethyl-2, 2 ' -bipyridyl, terpyridine, 1, 2-bis (diphenylphosphino) ethane or N-methylpyrrolidone; the organic solvent is dichloromethane or 1, 2-dichloroethane.

4. The method of claim 3, wherein the catalyst is Fe (acac)₃(ii) a The ligand is 2, 2' -bipyridine.

5. The method according to claim 2, wherein the reaction time in the step (1) is 0.5 to 3 hours; the alkali in the step (2) is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, 2, 6-di-tert-butylpyridine or N, N-diisopropylethylamine, the reaction temperature is 20-200 ℃, and the reaction time is 0.5-3 hours; the reaction temperature in the step (3) is 30-200 ℃, and the reaction time is 1-48 hours.

6. The method according to claim 5, wherein the reaction time in the step (1) is 0.5 to 1 hour; the alkali in the step (2) is potassium tert-butoxide, the reaction temperature is 20-80 ℃, and the reaction time is 0.5-2 hours; the reaction temperature in the step (3) is 40-100 ℃, and the reaction time is 12-36 hours.

7. The method of claim 2, further comprising adding an aqueous solution to quench the reaction after the reaction is completed, and purifying after extraction.

8. The production process according to any one of claims 2 to 7, wherein the molar ratio of the phenol derivative, the trifluoromethyl source, the catalyst, the base and the ligand is 1:1.5:0.2:0.5: 0.4.

9. The method of claim 8, wherein the phenol derivative is of formula II:

wherein the content of the first and second substances,

R₁、R₂、R₃、R₄is as defined in claim 1.

10. The method of claim 8, wherein the trifluoromethyl source is of formula III or iv.

Technical Field

The invention belongs to the technical field of organic matter synthesis, and particularly relates to a spiro [4,5] decane compound containing trifluoromethyl and a preparation method thereof.

Background

The fluorine-containing spiro compound is not only an important organic synthetic block, but also an important skeleton of natural products and active ingredients. Because the trifluoromethyl group has unique properties, the introduction of the trifluoromethyl group into an organic molecule can obviously change the properties of the molecule, such as stability, lipophilicity, bioavailability and the like, and therefore, the development of a reaction for efficiently and sustainably introducing the trifluoromethyl group into the molecule has important research value in the fields of medicines, materials and the like. And spiro [4,5] decane is a complex cyclic molecule having a three-dimensional structure, and is widely present in natural products as well as bioactive components. The trifluoromethyl group is introduced into the spiro [4,5] decane, so that on one hand, the physicochemical property of the spiro [4,5] decane is improved, and the drug property of the spiro [4,5] decane is further improved; on the other hand, the spiro [4,5] decane structure containing trifluoromethyl is also an important synthetic block in organic synthesis. However, there are almost no natural trifluoromethyl group-containing spiro [4,5] decanes in nature, and it is necessary to develop organic synthesis methods. The method for constructing the trifluoromethyl-containing all-carbon spiro [4,5] decane compound is only reported, so that the development of a method for efficiently preparing the trifluoromethyl-containing spiro [4,5] decane compound is urgently needed.

Iron is large in storage amount in nature, has small harm to the environment and human bodies, is more economical and green compared with copper, but a method for constructing a compound containing trifluoromethyl by activating Togni's reagent by iron is rarely reported.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a spiro [4,5] decane compound containing trifluoromethyl, which has the following structural formula:

wherein the content of the first and second substances,

R₁selected from hydrogen, halogen, alkyl, alkoxy or ester groups;

R₂、R₃selected from ester groups or alkylcarbonyloxy groups;

R₄selected from alkyl or aryl.

In certain embodiments，R₁Selected from hydrogen, chlorine, bromine, fluorine, methyl, methoxy or ethoxycarbonyl.

In certain embodiments, R₂Selected from methoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl.

In certain embodiments, R₃Selected from methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or acetyl.

In certain embodiments, R₄Selected from methyl, phenyl, tolyl or bromophenyl.

The invention further provides a preparation method of the trifluoromethyl-containing spiro [4,5] decane compound, which comprises the following steps:

(1) dissolving a catalyst and a ligand in an organic solvent for reaction under the inert atmosphere and room temperature; (2) adding phenol derivative and alkali, and reacting at a certain temperature; (3) a trifluoromethyl source is added and the reaction temperature and time are controlled until the phenol derivative reaction is complete.

In certain embodiments, the catalyst in step (1) is Fe (acac)₃、Fe(acac)₂、FeCl₂、Fe(OTf)₂Or FeBr₂。

In certain embodiments, the catalyst in step (1) is Fe (acac)₃。

In certain embodiments, the ligand in step (1) is 2,2 ' -bipyridine, 4 ' -dimethoxy-2, 2 ' -bipyridine, 6 ' -dimethyl-2, 2 ' -bipyridine, terpyridine, 1, 2-bis (diphenylphosphino) ethane, or N-methylpyrrolidone.

In certain embodiments, the ligand in step (1) is 2, 2' -bipyridine.

In certain embodiments, the organic solvent in step (1) is dichloromethane or 1, 2-dichloroethane.

In certain embodiments, the reaction time in step (1) is from 0.5 to 3 hours.

In certain embodiments, the reaction time in step (1) is from 0.5 to 1 hour.

In certain embodiments, the base in step (2) is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, 2, 6-di-tert-butylpyridine or N, N-diisopropylethylamine.

In certain embodiments, the base in step (2) is potassium tert-butoxide.

In certain embodiments, the reaction temperature in step (2) is from 20 to 200 ℃.

In certain embodiments, the reaction temperature in step (2) is from 20 to 80 ℃.

In certain embodiments, the reaction time in step (2) is from 0.5 to 3 hours.

In certain embodiments, the reaction time in step (2) is from 0.5 to 2 hours.

In certain embodiments, the reaction temperature in step (3) is from 30 to 200 ℃.

In certain embodiments, the reaction temperature in step (3) is from 40 to 100 ℃.

In certain embodiments, the reaction time in step (3) is from 1 to 48 hours.

In certain embodiments, the reaction time in step (3) is from 12 to 36 hours.

In some embodiments, the method further comprises adding an aqueous solution to quench the reaction after the reaction is completed, and purifying after extraction.

In certain embodiments, the aqueous solution of the quenching reaction is a 2M HCl solution, a 2M citric acid aqueous solution, or a saturated sodium carbonate aqueous solution.

In certain embodiments, the aqueous solution of the quenching reaction is 2M HCl solution or 2M citric acid aqueous solution.

In certain embodiments, the specific process of extractive purification is: adding water solution for quenching reaction, washing, layering to obtain organic phase, extracting water phase with dichloromethane, mixing organic phases, drying, distilling under reduced pressure to remove organic solvent, and performing column chromatography to obtain spiro [4,5] decane compound containing trifluoromethyl.

In certain embodiments, the molar ratio of the phenol derivative, the trifluoromethyl source, the catalyst, the base, and the ligand is 1:1.5:0.2:0.5: 0.4.

In certain embodiments, the phenol derivative is of formula II:

wherein the content of the first and second substances,

R₁selected from hydrogen, halogen, alkyl, alkoxy or ester groups;

R₂、R₃selected from ester groups or alkylcarbonyloxy groups;

R₄selected from alkyl or aryl.

In certain embodiments, the trifluoromethyl source is formula III or formula iv.

In certain embodiments, the trifluoromethyl source is formula III.

The invention has the beneficial effects that:

(1) compared with the reported preparation method, the preparation method does not use noble metal and toxic metal as catalysts, the used catalysts are more green, economic and low in toxicity, and the preparation method is low in cost and good in repeatability.

(2) The method has the advantages of green, economic, mild and efficient reaction conditions, simple operation, high yield and easy separation of products.

(3) The spiro [4,5] decane compound containing trifluoromethyl prepared by the invention has good functional group tolerance and high regioselectivity, is not only an important organic synthetic building block, but also has potential bioactivity.

Detailed Description

The invention is explained below with reference to specific examples.

The compounds in the following examples were prepared by the following reaction equation:

the preparation method comprises the following steps: adding a catalyst, a ligand and an organic solvent into a 25ml reaction tube in an inert atmosphere, and reacting for 0.5-3 hours at room temperature; adding phenol derivative II and alkali, heating to 20-200 deg.C, and reacting for 0.5-3 hr; and adding trifluoromethyl source III or IV, heating to 30-200 ℃, and reacting for 1-48 hours until the phenol derivative II is completely reacted. Adding water solution to quench reaction, washing, separating to obtain an organic phase, extracting the water phase with dichloromethane, combining the organic phases, drying with anhydrous sodium sulfate, removing the organic solvent by reduced pressure distillation, and purifying by column chromatography to obtain the spiro [4,5] decane compound containing trifluoromethyl.

Wherein the catalyst is selected from Fe (acac)₃、Fe(acac)₂、FeCl₂、Fe(OTf)₂Or FeBr₂(ii) a The ligand is selected from 2, 2-bipyridine, 4 '-dimethoxy-2, 2' -bipyridine, 6 '-dimethyl-2, 2' -bipyridine, terpyridine, 1, 2-bis (diphenylphosphino) ethane or N-methylpyrrolidone; the organic solvent is selected from dichloromethane or 1, 2-dichloroethane; the base is selected from potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, 2, 6-di-tert-butylpyridine or N, N-diisopropylethylamine; the aqueous solution of the quenching reaction is selected from a 2M HCl solution, a 2M citric acid aqueous solution or a saturated sodium carbonate aqueous solution; the molar ratio of the phenol derivative, the trifluoromethyl source, the catalyst, the base and the ligand is 1:1.5:0.2:0.5: 0.4.

Example 1

Diethyl 4-methyl-8-oxo-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylate (a):

iron acetylacetonate (21.28mg,0.06mmol), 2' -bipyridine (18.72mg,0.12mmol) and 1, 2-dichloroethane (5ml) were charged into a 25ml reaction tube under an inert atmosphere, and reacted at room temperature for 0.5 hour; further adding a phenol derivative(96mg,0.3mmol) and potassium tert-butoxide (16.8mg,0.15mmol), heated to 60 ℃ for 1 hour; then trifluoromethyl source III (148.5mg,0.45mmol) is added, the temperature is raised to 80 ℃, and the reaction 2 is carried out4 hours until the reaction of the phenol derivative II was completed. Adding 2M hydrochloric acid to quench reaction, washing, separating to obtain organic phase, extracting water phase with dichloromethane, mixing organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove organic solvent, and purifying by column chromatography to obtain spiro [4,5] containing trifluoromethyl]A decane compound (formula a).

The product was a colorless oil in 90% yield.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ6.97(dd,J＝10.4,3.2Hz,1H),6.85(dd,J＝10.4,3.2Hz,1H),6.41(dd,J＝10.4,1.6Hz,1H),6.32(dd,J＝10.4,1.6Hz,1H),4.31–4.19(m,4H),3.04(d,J＝14.8Hz,1H),2.89(d,J＝15.2Hz,1H),2.58(d,J＝15.2Hz,1H),2.25(d,J＝14.8Hz,1H),2.13–2.03(m,1H),1.93–1.83(m,1H),1.30–1.23(m,9H)；¹⁹F NMR(377MHz,CDCl₃)δ-59.84；¹³C NMR(101MHz,CDCl₃) δ 184.7,172.0,171.6,150.0,149.3,131.7,129.5,126.6(q, J-277.4 Hz),62.5,62.4,58.6,54.9,48.9,45.5,41.3,41.1(q, J-28.3 Hz),22.1,14.0, 14.0; HRMS (ESI) theoretical value C₁₉H₂₄F₃O₅[M+H]⁺: 389.1570, test value: 389.1566.

example 2

4-methyl-8-oxo-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylic acid dimethyl ester (b):

ferrous chloride (7.6mg,0.06mmol), terpyridine (27.96mg,0.12mmol) and dichloromethane (5ml) were added to a 25ml reaction tube under an inert atmosphere and reacted at room temperature for 1 hour; further adding a phenol derivative(87.6mg,0.3mmol) and 2, 6-di-tert-butylpyridine (28.65mg,0.15mmol), and heating to 80 deg.C for reaction for 2 hr; further adding trifluoromethyl source IV (142.2mg,0.45mmol), heating to 100 ℃, and reacting for 12 hours until the phenol derivative II is completely reacted.Adding 2M citric acid aqueous solution to quench reaction, washing, separating to obtain organic phase, extracting water phase with dichloromethane, mixing organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove organic solvent, and purifying by column chromatography to obtain spiro [4,5] containing trifluoromethyl]A decane compound (formula b).

The product was a white solid in 79% yield and a melting point of 106-107 ℃.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ6.96(dd,J＝10.4,3.2Hz,1H),6.84(dd,J＝10.4,3.2Hz,1H),6.41(dd,J＝10.4,1.6Hz,1H),6.32(dd,J＝10.4,1.6Hz,1H),3.80(s,3H),3.78(s,3H),3.03(d,J＝15.2Hz,1H),2.88(d,J＝14.8Hz,1H),2.62(d,J＝15.2Hz,1H),2.30–2.25(m,1H),2.14–2.03(m,1H),1.94–1.84(m,1H),1.24(s,3H)；¹⁹F NMR(377MHz,CDCl₃)δ-59.85；¹³C NMR(101MHz,CDCl₃) δ 184.7,172.4,172.1,149.8,149.1,131.8,129.5,126.5(q, J-277.4 Hz),58.5,54.9,53.6,53.5,48.9,45.5,41.3,41.1(q, J-27.8 Hz), 22.2; HRMS (ESI) theoretical value C₁₇H₂₀F₃O₅[M+H]⁺: 361.1257, test value: 361.1253.

example 3

4-methyl-8-oxo-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylic acid diisopropyl ester (c):

in an inert atmosphere, Fe (OTf)₂(21.24mg,0.06mmol), N-methylpyrrolidone (11.88mg,0.12mmol) and methylene chloride (5ml) were charged into a 25ml reaction tube and reacted at room temperature for 2 hours; further adding a phenol derivative(104.4mg,0.3mmol) and N, N-diisopropylethylamine (19.35mg,0.15mmol), and the reaction was carried out at 30 ℃ for 3 hours; further, trifluoromethyl source IV (142.2mg,0.45mmol) was added, the temperature was raised to 40 ℃ and the reaction was carried out for 36 hours until the completion of the reaction of phenol derivative II. Is added intoQuenching reaction with sodium carbonate aqueous solution, washing, separating to obtain organic phase, extracting water phase with dichloromethane, mixing organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove organic solvent, and purifying by column chromatography to obtain spiro [4,5] containing trifluoromethyl]Decane compound (formula c).

The product was a white solid with a yield of 97% and a melting point of 83-85 ℃.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ6.98(dd,J＝10.4,3.2Hz,1H),6.86(dd,J＝10.4,3.2Hz,1H),6.40(dd,J＝10.4,1.2Hz,1H),6.31(dd,J＝10.4,1.2Hz,1H),5.15–5.01(m,2H),3.03(d,J＝14.8Hz,1H),2.88(d,J＝14.8Hz,1H),2.53(d,J＝14.8Hz,1H),2.19(d,J＝14.8Hz,1H),2.15–2.03(m,1H),1.95–1.82(m,1H),1.30–1.19(m,15H)；¹⁹F NMR(377MHz,CDCl₃)δ-59.82；¹³C NMR(101MHz,CDCl₃) δ 184.8,171.5,171.1,150.1,149.4,131.7,129.4,126.6(q, J ═ 279.5Hz),70.1,70.0,58.8,54.9,48.9,45.5,41.4,41.1(q, J ═ 27.8Hz),22.1,21.5,21.5,21.4, 21.4; HRMS (ESI) theoretical value C₂₁H₂₈F₃O₅[M+H]⁺: 417.1883, test value: 417.1881.

example 4

Diethyl 7, 9-dimethoxy-4-methyl-8-oxy-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylate (d):

the preparation method is the same as example 1In place of example 1To obtain the targetA compound (I) is provided.

The product was a white solid in 48% yield and a melting point of 146-.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ5.99(d,J＝2.4Hz,1H),5.75(d,J＝2.4Hz,1H),4.31–4.20(m,4H),3.71(s,3H),3.67(s,3H),3.13(d,J＝14.8Hz,1H),2.96(d,J＝15.2Hz,1H),2.53(d,J＝15.2Hz,1H),2.17(d,J＝14.8Hz,1H),2.14–2.01(m,1H),1.89–1.79(m,1H),1.30–1.24(m,9H)；¹⁹F NMR(377MHz,CDCl₃)δ-59.74；¹³C NMR(101MHz,CDCl₃) δ 175.6,172.4,171.8,152.3,150.7,126.8(q, J ═ 279.3Hz),117.4,115.6,62.4,62.3,58.3,55.4,55.3,53.2,48.6,45.4,43.1,41.0(q, J ═ 27.6Hz),22.6, 14.0; HRMS (ESI) theoretical value C₂₁H₂₈F₃O₇[M+H]⁺: 449.1782, test value: 449.1776.

example 5

Diethyl 4,7, 9-trimethyl-8-oxo-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylate (e):

the preparation method is the same as example 1Instead of that in example 1Thus obtaining the target compound.

The product was a white solid with a yield of 88% and a melting point of 85-87 ℃.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ6.70(s,1H),6.60(s,1H),4.30–4.20(m,4H),2.99(d,J＝14.8Hz,1H),2.88(d,J＝14.8Hz,1H),2.53(d,J＝14.8Hz,1H),2.18(d,J＝14.8Hz,1H),2.11–2.00(m,1H),1.93(d,J＝0.8Hz,3H),1.91(d,J＝0.8Hz,3H),1.85–1.76(m,1H),1.31–1.21(m,9H)；¹⁹F NMR(377MHz,CDCl₃)δ-59.77；¹³C NMR(101MHz,CDCl₃) δ 186.1,172.1,171.9,145.1,144.3,137.7,135.3,125.8(q, J ═ 279.9Hz),62.3,62.2,58.6,54.2,48.6,45.4,41.4,41.0(q, J ═ 27.4Hz),22.3,16.6,16.5,14.0, 14.0; HRMS (ESI) theoretical value C₂₁H₂₈F₃O₅[M+H]⁺: 417.1883, respectively; found, test value: 417.1880.

example 6

Diethyl 7, 9-di-tert-butyl-4-methyl-8-oxo-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylate (f):

the preparation method is the same as example 1Instead of that in example 1Thus obtaining the target compound.

The product was a white solid with a yield of 61% and a melting point of 37-40 ℃.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ6.60(d,J＝2.8Hz,1H),6.48(d,J＝2.8Hz,1H),4.29–4.20(m,4H),2.97(d,J＝14.8Hz,1H),2.86(d,J＝14.8Hz,1H),2.52(d,J＝14.8Hz,1H),2.23(d,J＝14.8Hz,1H),2.05–1.90(m,1H),1.77–1.67(m,1H),1.31–1.26(m,6H),1.24(s,9H),1.22(s,9H),1.19(s,3H)；¹⁹F NMR(377MHz,CDCl₃)δ-59.67；¹³C NMR(101MHz,CDCl₃) δ 184.5,171.1,171.0,149.0,146.6,139.8,139.2,125.8(q, J ═ 279.7Hz),61.2,61.2,57.6,52.1,47.8,44.6,41.1,39.8(q, J ═ 27.3Hz),34.2,34.1,28.5,28.4,21.2,13.0, 13.0; HRMS (ESI) theoretical value C₂₇H₄₀F₃O₅[M+H]⁺: 501.2822, test value: 501.2822.

example 7

Diethyl 7, 9-dichloro-4-methyl-8-oxo-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylate (g)

The preparation method is the same as example 1Instead of that in example 1Thus obtaining the target compound.

The product was a white solid in 99% yield and a melting point of 140-141 ℃.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ7.23(d,J＝2.8Hz,1H),7.07(d,J＝2.8Hz,1H),4.31–4.21(m,4H),3.10(d,J＝15.2Hz,1H),2.86(d,J＝15.2Hz,1H),2.64(d,J＝15.2Hz,1H),2.33(d,J＝15.2Hz,1H),2.17–2.03(m,1H),2.01–1.85(m,1H),1.31–1.25(m,9H)；¹⁹F NMR(377MHz,CDCl₃)δ-59.74；¹³C NMR(101MHz,CDCl₃) δ 172.1,171.7,171.2,146.1,145.3,133.7,132.1,126.2(q, J ═ 279.7Hz),62.8,62.6,58.5,58.1,50.1,45.4,41.3,41.2(q, J ═ 28.2Hz),22.4,14.0, 14.0; HRMS (ESI) theoretical value C₁₉H₂₂Cl₂F₃O₅[M+H]⁺: 457.0791, respectively; test values are: 457.0789.

example 8

Diethyl 7, 9-dibromo-4-methyl-8-oxo-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylate (h):

the preparation method is the same as example 1Instead of that in example 1Thus obtaining the target compound.

The product was a white solid in 97% yield and a melting point of 142-.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ7.48(d,J＝2.8Hz,1H),7.32(d,J＝2.8Hz,1H),4.30–4.22(m,4H),3.08(d,J＝15.2Hz,1H),2.85(d,J＝14.8Hz,1H),2.64(d,J＝15.2Hz,1H),2.35(d,J＝14.8Hz,1H),2.17–2.03(m,1H),2.02–1.88(m,1H),1.30–1.25(m,9H)；¹⁹F NMR(377MHz,CDCl₃)δ-59.72；¹³C NMR(101MHz,CDCl₃) δ 171.7,171.6,171.2,150.5,149.8,126.3(q, J ═ 279.6Hz),124.1,122.3,62.8,62.6,60.7,58.5,49.9,45.4,41.2(q, J ═ 28.1Hz),40.9,40.8,22.4,14.0, 14.0; HRMS (ESI) theoretical value C₁₉H₂₂Br₂F₃O₅[M+H]⁺: 546.9760, respectively; test values are: 546.9756.

example 9

Diethyl 7-methoxy-4-methyl-8-oxy-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylate (i):

the preparation method is the same as example 1Instead of that in example 1Thus obtaining the target compound.

The product was a white solid in 50% yield with dr 1: 0.9.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ6.99(dd,J＝10.0,2.4Hz,0.5H),6.88(dd,J＝10.0,2.8Hz,1H),6.44(d,J＝10.0Hz,1H),6.34(d,J＝10.0Hz,0.5H),5.92(d,J＝2.8Hz,1H),5.68(d,J＝2.8Hz,0.5H),4.32–4.18(m,6H),3.70(s,1.5H),3.67(s,3H),3.14(d,J＝14.8Hz,1H),3.05(d,J＝15.2Hz,0.5H),2.98–2.88(m,1.5H),2.61–2.50(m,1.5H),2.27–2.17(m,1.5H),2.16–2.00(m,1.5H),1.93–1.79(m,1.5H),1.31–1.24(m,13.5H)；¹⁹F NMR(377MHz,CDCl₃)δ-59.78,-59.80；¹³C NMR(101MHz,CDCl₃) δ 180.0,172.3,172.0,171.8,171.7,152.7,151.2,150.5,149.6,131.1,128.7,126.7(q, J ═ 279.8Hz),116.9,115.3,62.4,62.3,58.6,58.3,55.7,55.0,54.9,49.1,48.4,45.6,45.3,42.3,42.0,41.3(q, J ═ 28.0Hz),22.4,22.3, 14.0; HRMS (ESI) theoretical value C₂₀H₂₆F₃O₆[M+H]⁺: 419.1676, respectively; test values are: 419.1674.

example 10

Diethyl 4, 6-dimethyl-8-oxo-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylate (j):

the preparation method is the same as example 1Alternative example 1Thus obtaining the target compound.

The product was a colorless oil in 32% yield, dr 1: 0.7.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ6.91(s,1H),6.89(s,1H),6.34–6.30(m,2H),6.29–6.28(m,1H),6.16(s,1H),4.34–4.19(m,8H),3.36(d,J＝15.2Hz,1H),3.15(d,J＝16.0Hz,1H),2.96(d,J＝15.2Hz,1H),2.84(d,J＝14.8Hz,1H),2.58(d,J＝16.8Hz,1H),2.52–2.46(m,1H),2.25(d,J＝15.2Hz,1H),2.16(d,J＝0.8Hz,3H),2.14–2.04(m,2H),2.02(d,J＝1.2Hz,3H),1.99–1.77(m,3H),1.33–1.19(m,18H)；¹⁹F NMR(377MHz,CDCl₃)δ-59.51,-59.58；¹³C NMR(101MHz,CDCl₃) δ 185.4,185.4,172.2,172.1,172.0,170.9,159.2,158.5,153.7,151.5,132.5,130.7,129.1,128.8,126.7(q, J ═ 279.6Hz),126.5(q, J ═ 279.9Hz),62.6,62.5,62.4,60.6,58.3,58.1,50.6,50.1,46.1,45.9,40.7(q, J ═ 27.9Hz),40.7(q, J ═ 27.6Hz),39.9,38.4,24.8,24.1,23.9,23.3, 14.0; HRMS (ESI) theoretical value C₂₀H₂₆F₃O₅[M+H]⁺: 403.1727, respectively; test values are: 403.1722.

example 11

Diethyl 7-fluoro-4-methyl-8-oxo-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylate (k):

the preparation method is the same as example 1Alternative example 1Thus obtaining the target compound.

The product was a white solid in 84% yield, dr ═ 1:1.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ7.02(dd,J＝10.4,2.8Hz,1H),6.89(dd,J＝10.0,2.7Hz,1H),6.57(dd,J＝14.0,2.8Hz,1H),6.48–6.33(m,3H),4.34–4.15(m,8H),3.14–3.03(m,2H),2.92–2.82(m,2H),2.64–2.56(m,2H),2.31–2.26(m,2H),2.20–2.02(m,2H),1.97–1.81(m,2H),1.32–1.22(m,18H)；¹⁹F NMR(377MHz,CDCl₃)δ-59.80(s,CF₃),-59.84(s,CF₃),-124.95(s,F),-127.59(s,F)；¹³C NMR(101MHz,CDCl₃)δ177.6,177.5,177.4,177.3,171.9,171.8,171.5,171.4,156.4,155.2,153.7,152.5,150.7,150.7,150.0,131.0,131.0,128.8,128.8,126.4(q,J＝279.5Hz),125.7,125.6,124.6,124.4,,62.6,62.6,62.5,58.5,58.4,56.5,56.4,49.5,48.9,45.5,45.3,41.1(q, J ═ 27.9Hz),41.0(q, J ═ 27.9Hz),22.3,22.2,14.0, 14.0; HRMS (ESI) theoretical value C₁₉H₂₃F₄O₅[M+H]⁺: 407.1476, respectively; test values are: 407.1471.

example 12

Diethyl 7-chloro-4-methyl-8-oxo-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylate (l):

the preparation method is the same as example 1Instead of that in example 1Thus obtaining the target compound.

The product was a white solid in 78% yield, dr 1:1.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ7.19(d,J＝2.8Hz,1H),7.06–6.99(m,2H),6.88(dd,J＝10.4,3.2Hz,1H),6.50(d,J＝10.0Hz,1H),6.41(d,J＝10.0Hz,1H),4.31–4.19(m,8H),3.10(d,J＝4.0Hz,1H),3.06(d,J＝4.0Hz,1H),2.88(d,J＝15.2Hz,2H),2.63(d,J＝9.6Hz,1H),2.60(d,J＝9.2Hz,1H),2.35–2.25(m,2H),2.16–2.02(m,2H),1.97–1.85(m,2H),1.30–1.22(m,18H)；¹⁹F NMR(377MHz,CDCl₃)δ-59.75,-59.83；¹³C NMR(101MHz,CDCl₃) δ 177.8,177.8,171.8,171.8,171.5,171.4,150.1,149.5,146.0,145.1,134.9,133.2,130.5,128.3,126.4(q, J ═ 279.5Hz),62.7,62.6,62.5,58.6,58.5,57.5,57.3,49.7,49.3,45.5,45.3,41.3,41.2,41.2(q, J ═ 28.0Hz),41.1(q, J ═ 28.0Hz),29.7,22.3,14.0, 14.0; HRMS (ESI) theoretical value C₁₉H₂₃F₃ClO₅[M+H]⁺: 423.1181, respectively; test values are: 423.1179.

example 13

Diethyl 7-bromo-4-methyl-8-oxo-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylate (m):

the preparation method is the same as example 1Alternative example 1Thus obtaining the target compound.

The product was a white solid in 74% yield, dr ═ 1: 0.9.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ7.45(d,J＝2.8Hz,1H),7.32(d,J＝2.8Hz,1H),7.03(dd,J＝10.2,2.8Hz,1H),6.89(dd,J＝10.2,2.8Hz,1H),6.50(d,J＝10.2Hz,1H),6.41(d,J＝10.2Hz,1H),4.33–4.17(m,8H),3.13–3.02(m,2H),2.88(d,J＝15.2Hz,2H),2.67–2.56(m,2H),2.36–2.25(m,2H),2.17–2.03(m,2H),1.99–1.84(m,2H),1.31–1.21(m,18H)；¹⁹F NMR(377MHz,CDCl₃)δ-59.74,-59.82；¹³C NMR(101MHz,CDCl₃) δ 177.7,177.6,171.8,171.8,171.4,171.3,150.4,150.1,149.6,149.4,130.0,127.8,126.8,126.4(q, J ═ 279.5Hz),125.0,62.7,62.6,62.5,58.6,58.5,58.4,58.3,49.6,49.3,45.5,45.3,41.2(q, J ═ 27.9Hz),41.1(q, J ═ 28.0Hz),41.1,41.0,22.3, 14.0; HRMS (ESI) theoretical value C₁₉H₂₃BrF₃NaO₅[M+Na]⁺: 489.0495, test value: 489.0490.

example 14

2, 2-diethyl 7-methyl 4-methyl-8-oxo-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2, 7-tricarboxylate (n):

the preparation method is the same as example 1Alternative example 1Thus obtaining the target compound.

The product was a colorless oil in 20% yield, dr 1:1.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ7.66(d,J＝3.2Hz,1H),7.54(d,J＝3.2Hz,1H),6.96(dd,J＝10.4,3.2Hz,1H),6.82(dd,J＝10.4,3.2Hz,1H),6.45(d,J＝10.4Hz,1H),6.36(d,J＝10.4Hz,1H),4.30–4.15(m,8H),3.87(s,6H),3.12(d,J＝15.2Hz,1H),3.03(d,J＝14.8Hz,1H),2.90(d,J＝14.4Hz,1H),2.71–2.58(m,2H),2.37–2.25(m,2H),2.14–2.03(m,2H),2.02–1.83(m,3H),1.31–1.24(m,18H)；¹⁹F NMR(376MHz,CDCl₃)δ-59.73,-59.85；¹³C NMR(101MHz,CDCl₃) δ 180.3,171.8,171.7,171.5,171.3,171.2,164.6,164.6,154.9,154.7,148.4,147.8,134.0,132.2,132.0,130.0,126.6(q, J ═ 279.8Hz),62.7,62.6,62.5,60.4,58.8,58.7,55.2,55.1,52.6,52.6,49.9,49.8,45.5,45.5,41.7,41.5,41.2(q, J ═ 28.1Hz),41.3,41.1(q, J ═ 27.8Hz),22.2,22.0,14.2,14.0,14.0, 13.9; HRMS (ESI) theoretical value C₂₁H₂₆F₃O₅[M+H]⁺: 447.1625, test value: 447.1624.

example 15

Diethyl 8-oxo-4-phenyl-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylate (o):

the preparation method is the same as example 1Alternative example 1Thus obtaining the target compound.

The product was a white solid with a yield of 72% and a melting point of 84-86 ℃.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ7.25–7.19(m,5H),7.16(dd,J＝10.4,3.2Hz,1H),6.66(dd,J＝10.4,3.2Hz,1H),6.51(dd,J＝10.4,2.0Hz,1H),5.90(dd,J＝10.4,2.0Hz,1H),4.35–4.19(m,4H),3.83(d,J＝15.6Hz,1H),3.31(d,J＝15.2Hz,1H),3.07(d,J＝15.6Hz,1H),2.92–2.80(m,1H),2.79–2.66(m,1H),2.12(d,J＝15.2Hz,1H),1.32–1.24(m,6H)；¹⁹F NMR(377MHz,CDCl₃)δ-58.27；¹³CNMR(101MHz,CDCl₃) δ 184.9,171.9,171.6,150.3,148.6,140.8,131.9,128.5,128.4,127.7,126.0(q, J ═ 280.5Hz),125.3,62.7,62.5,57.3,55.6,55.1,42.8,40.3(q, J ═ 26.4Hz),38.9,14.0, 13.9; HRMS (ESI) theoretical value C₂₄H₂₆F₃O₅[M+H]⁺: 451.1727, test value: 451.1723.

example 16

Diethyl 8-oxo-4- (p-tolyl) -4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylate (p):

the preparation method is the same as example 1Alternative example 1Thus obtaining the target compound.

The product was a white solid in 85% yield and a melting point of 123-124 ℃.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ7.15(dd,J＝10.4,3.2Hz,1H),7.11–6.99(m,4H),6.66(dd,J＝10.4,3.2Hz,1H),6.49(dd,J＝10.4,2.0Hz,1H),5.91(dd,J＝10.4,2.0Hz,1H),4.37–4.16(m,4H),3.80(d,J＝15.2Hz,1H),3.28(d,J＝15.2Hz,1H),3.05(d,J＝15.2Hz,1H),2.86–2.66(m,2H),2.27(s,3H),2.11(d,J＝15.2Hz,1H),1.32–1.24(m,6H)；¹⁹F NMR(377MHz,CDCl₃)δ-58.25；¹³C NMR(101MHz,CDCl₃) δ 185.0,172.0,171.6,150.5,148.8,137.7,137.3,131.8,129.0,128.4,126.0(q, J ═ 280.8Hz),125.1,62.6,62.5,57.3,55.6,54.9,42.7,40.3(q, J ═ 26.4Hz),38.9,20.9,14.0, 13.9; HRMS (ESI) theoretical value C₂₅H₂₈F₃O₅[M+H]⁺: 465.1883, test value: 465.1883.

example 17

Diethyl 4- (4-bromophenyl) -8-oxo-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2, 2-dicarboxylate (q):

the preparation method is the same as example 1Alternative example 1Thus obtaining the target compound.

The product was a white solid in 65% yield and a melting point of 149-151 ℃.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ7.36(d,J＝8.4Hz,2H),7.13(dd,J＝10.4,3.2Hz,1H),7.08(d,J＝8.8Hz,2H),6.63(dd,J＝10.4,3.2Hz,1H),6.51(dd,J＝10.4,2.0Hz,1H),5.94(dd,J＝10.4,2.0Hz,1H),4.41–4.13(m,4H),3.76(d,J＝15.6Hz,1H),3.32(d,J＝15.2Hz,1H),3.04(d,J＝15.6Hz,1H),2.91–2.78(m,1H),2.73–2.60(m,1H),2.11(d,J＝15.3Hz,1H),1.34–1.23(m,6H)；¹⁹F NMR(377MHz,CDCl₃)δ-58.21；¹³C NMR(101MHz,CDCl₃) δ 184.6,171.8,171.4,149.8,148.2,140.0,132.2,131.6,128.8,127.0,125.8(q, J ═ 280.5Hz),121.8,62.7,62.6,57.2,55.4,54.7,42.7,40.2(q, J ═ 26.5Hz)38.9,14.0, 13.9; HRMS (ESI) theoretical value C₂₄H₂₅F₃BrO₅[M+H]⁺: 529.0832, respectively; test values are: 529.0829.

example 18

Ethyl 2-acetyl-4-methyl-8-oxy-4- (2,2, 2-trifluoroethyl) spiro [4.5] decane-6, 9-diene-2-carboxylate (r):

the preparation method is the same as example 1Alternative example 1Thus obtaining the target compound.

The product was a colorless oil in 67% yield, dr 1:1.

The characterization data for the product are:¹H NMR(400MHz,CDCl₃)δ6.97(dd,J＝10.4,3.2Hz,1H),6.88–6.81(m,2H),6.73(dd,J＝10.4,3.2Hz,1H),6.40(dd,J＝10.4,1.6Hz,2H),6.32(dd,J＝10.4,2.0Hz,1H),6.28(dd,J＝10.4,2.0Hz,1H),4.31–4.23(m,4H),3.05(d,J＝14.8Hz,1H),2.93(d,J＝14.8Hz,1H),2.89–2.77(m,2H),2.53–2.41(m,2H),2.22(s,3H),2.18(s,3H),2.14–2.03(m,4H),1.95–1.81(m,2H),1.35–1.20(m,12H)；¹⁹F NMR(377MHz,CDCl₃)δ-59.80,-59.82；¹³C NMR(101MHz,CDCl₃) δ 201.3,200.9,184.7,184.7,172.6,172.5,150.0,149.7,149.2,149.2,131.7,131.7,129.5,129.4,126.5(q, J ═ 279.8Hz),65.4,65.1,62.7,62.6,55.0,54.8,49.0,48.8,43.5,41.2(q, J ═ 32.7Hz),41.0(q, J ═ 27.9Hz),39.3,39.3,26.2,26.1,22.3,22.0,14.0, 14.0; HRMS (ESI) theoretical value C₁₈H₂₂F₃O₄[M+H]⁺: 359.1465, respectively; test values are: 359.1463.