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Synthetic method of trifluoromethyl-containing spiro indoline or acetal

A technology of trifluoromethylspirocyclic indoline and trifluoromethylspirocyclic acetal, which is applied in the field of compound synthesis and achieves the effects of high chemistry, good functional group compatibility, and good economic and environmental significance

Pending Publication Date: 2019-01-18
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a field with broad development prospects, de-aromatization still rarely involves the participation of carbon dioxide. Therefore, it will be a very challenging task to realize the de-aromatization of carbon dioxide, a new type of carbon dioxide conversion reaction.

Method used

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  • Synthetic method of trifluoromethyl-containing spiro indoline or acetal
  • Synthetic method of trifluoromethyl-containing spiro indoline or acetal
  • Synthetic method of trifluoromethyl-containing spiro indoline or acetal

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Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0070] 3'-Benzyl-1-(pyrimidin-2-yl)-2-(trifluoromethyl)spiro[indoline-3,5'-oxazolidinin]-2'-one

[0071] Preparation of 3'-benzyl-1-(pyrimidin-2-yl)-2-(trifluoromethyl)spiro[indoline-3,5'-oxazolidin]-2'-one (hereinafter referred to as compound 2a) (Description: indole Line compound 2a means that the compound is prepared from substrate 1a, and the names of other indoline compounds are consistent with it)

[0072]

[0073] Optimum selection of reaction conditions in table 1 [a]

[0074]

[0075]

[0076] [a] Reaction conditions: 1a (0.2mmol), 1 atmosphere of CO 2 , second-generation Togni reagent (0.4mmol), base (0.4mmol), copper catalyst (0.02mmol), solvent (2mL), room temperature (rt), 16 hours. [b] Yields are isolated yields. [c] Second generation Togni reagent (0.3 mmol). [d] Second generation Togni reagent (0.35 mmol). Pym = 2-pyrimidinyl. TMG = tetramethylguanidine. DABCO = 1,4-diazabicyclo[2.2.2]octane. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene. DBN = 1,5-...

Embodiment 1-2 to Embodiment 1-19

[0082] Preparation of Example 1-2 to Example 1-19 Indoline Compound 2b-2s

[0083] The specific operation is as follows: the synthesis steps are consistent with the synthesis steps of compound 2a.

[0084] The preparation of table 2 indoline compounds [a]

[0085]

[0086]

[0087] [a] Reaction condition 1 (0.2mmol), 1 atmosphere CO 2 , second generation Togni reagent (0.35mmol), DBN (0.4mmol), tetraethylcyanide copper hexafluorophosphate (0.02mmol), MeCN (2mL), room temperature, 16 hours; isolated yield; all diastereomers Body selectivity (dr value) greater than 19:1, except product 2n (dr=11:1, 19 The results obtained by F-NMR analysis). [b] DMSO was used as solvent, the second generation Togni reagent (0.40mmol), 24 hours.

[0088] 3'-Butyl-1-(pyrimidin-2-yl)-2-(trifluoromethyl)spiro[indoline-3,5'-oxazolidinin]-2'-one (2b)

[0089] 3'-butyl-1-(pyrimidin-2-yl)-2-(trifluoromethyl)spiro[indoline-3,5'-oxazolidin]-2'-one

[0090] 2H),3.54–3.32(m,2H),1.73–1.64(m,2H)...

Embodiment 3

[0198] The gram-scale synthesis of embodiment 3 product 4a

[0199] The specific operation is: in the glove box, place the weighed tetraethylcyanide copper hexafluorophosphate (149mg, 0.40mmol, 0.10equiv) and the second generation Togni reagent (2.53g, 8mmol, 2.0equiv) in sequence in advance The baked 25ml Shrek tube equipped with a stirrer, then tighten the reaction tube and take it out of the glove box, and replace it with carbon dioxide gas for three times, and then under the carbon dioxide gas flow, add the substituted furan substrate 3a ( 766mg, 5.0mmol, 1.0equiv), anhydrous acetonitrile (40mL), DBU (1.20mL, 8.0mmol, 2.0equiv). After the addition operation was completed, the reaction tube was tightened in an atmosphere of carbon dioxide at atmospheric pressure, and then it was placed on a stirrer at room temperature and stirred for 16 hours. After the reaction, the reaction solution was removed from the reaction solvent on a rotary evaporator, and then the residue was se...

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Abstract

The invention provides a synthetic method of trifluoromethyl-containing spiro indoline or acetal. The synthetic method comprises the steps as follows: a substituted indole substrate or a substituted furan substrate reacts in a solvent in the presence of CO2, a copper catalyst, alkali and a trifluoro methylation reagent to obtain the trifluoromethyl-containing spiro indoline or trifluoromethyl-containing spiro acetal. A trifluoromethyl-containing spiro indoline and spiro acetal compound is constructed under redox neutral and mild conditions, and besides, greenhouse gas CO2 is utilized in the synthetic method, so that the synthetic method has better economic and environment significance. The obtained trifluoromethyl-containing spiro indoline and spiro acetal compound has high chemical areasand diastereoisomer selectivity and has the advantages of better functional group compatibility, wider substrate range and high probability of gram-grade scale synthesis.

Description

technical field [0001] The invention belongs to the field of compound synthesis, and in particular relates to a synthesis method of trifluoromethyl spirocyclic indoline or acetal. Background technique [0002] In recent years, due to the wide application of heterocyclic compounds in fields such as medical materials, their synthesis has received more and more attention. Indole derivatives are an important part of aromatic heterocycles, and their dearomatization products such as indolenine and indoline are important structural units in alkaloids. They have been studied as therapeutic agents with important biological activity against cancer, inflammation and hypertension. Since the middle of the twentieth century, many chemists have devoted themselves to the synthesis of indole dearomatization products and made many outstanding contributions. At present, the dearomatization of indole has been systematically studied, and a variety of complex nitrogen-containing heterocyclic mo...

Claims

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Application Information

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IPC IPC(8): C07D498/10C07D498/20
CPCC07B2200/07C07D498/10C07D498/20
Inventor 余达刚李静叶剑衡颜思顺周文俊宋磊鞠涛殷珠宝张振
Owner SICHUAN UNIV
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