CN116693529A - Synthesis method of 2-aza [2.2.2] octane compound - Google Patents
Synthesis method of 2-aza [2.2.2] octane compound Download PDFInfo
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- -1 octane compound Chemical class 0.000 title claims abstract description 27
- 238000001308 synthesis method Methods 0.000 title abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000002904 solvent Substances 0.000 claims abstract description 27
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 239000003513 alkali Substances 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 17
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical class CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 14
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 claims description 12
- 238000010189 synthetic method Methods 0.000 claims description 7
- YYAQOJILQOVUSK-UHFFFAOYSA-N n,n'-diphenylpropanediamide Chemical class C=1C=CC=CC=1NC(=O)CC(=O)NC1=CC=CC=C1 YYAQOJILQOVUSK-UHFFFAOYSA-N 0.000 claims description 5
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- WURBFLDFSFBTLW-UHFFFAOYSA-N benzil Chemical compound C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 150000002894 organic compounds Chemical class 0.000 abstract description 3
- 150000002576 ketones Chemical class 0.000 abstract description 2
- JLBJTVDPSNHSKJ-UHFFFAOYSA-N 4-Methylstyrene Chemical compound CC1=CC=C(C=C)C=C1 JLBJTVDPSNHSKJ-UHFFFAOYSA-N 0.000 abstract 1
- 230000007613 environmental effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- 238000004440 column chromatography Methods 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 14
- 230000008020 evaporation Effects 0.000 description 11
- 238000000926 separation method Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000006352 cycloaddition reaction Methods 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 238000006617 Intramolecular Heck reaction Methods 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 238000010523 cascade reaction Methods 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- CPSUAFUQJBJMPO-UHFFFAOYSA-N 2-phenylpropanediamide Chemical compound NC(=O)C(C(N)=O)C1=CC=CC=C1 CPSUAFUQJBJMPO-UHFFFAOYSA-N 0.000 description 1
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical class O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 230000000724 leishmaniacidal effect Effects 0.000 description 1
- 125000000346 malonyl group Chemical group C(CC(=O)*)(=O)* 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- RFCMRQCFUIALCR-UHFFFAOYSA-N n,n'-bis(2-chlorophenyl)propanediamide Chemical compound ClC1=CC=CC=C1NC(=O)CC(=O)NC1=CC=CC=C1Cl RFCMRQCFUIALCR-UHFFFAOYSA-N 0.000 description 1
- XZWOXAMUBVDXBL-UHFFFAOYSA-N n,n'-bis(3-chlorophenyl)propanediamide Chemical compound ClC1=CC=CC(NC(=O)CC(=O)NC=2C=C(Cl)C=CC=2)=C1 XZWOXAMUBVDXBL-UHFFFAOYSA-N 0.000 description 1
- UWWFXRVMMDRCCS-UHFFFAOYSA-N n,n'-bis(4-chlorophenyl)propanediamide Chemical compound C1=CC(Cl)=CC=C1NC(=O)CC(=O)NC1=CC=C(Cl)C=C1 UWWFXRVMMDRCCS-UHFFFAOYSA-N 0.000 description 1
- MSEFNNYTRUIQHL-UHFFFAOYSA-N n,n'-bis(4-methoxyphenyl)propanediamide Chemical compound C1=CC(OC)=CC=C1NC(=O)CC(=O)NC1=CC=C(OC)C=C1 MSEFNNYTRUIQHL-UHFFFAOYSA-N 0.000 description 1
- OBZHMICJQVRDOF-UHFFFAOYSA-N n,n'-di(quinolin-8-yl)propanediamide Chemical compound C1=CN=C2C(NC(CC(=O)NC=3C4=NC=CC=C4C=CC=3)=O)=CC=CC2=C1 OBZHMICJQVRDOF-UHFFFAOYSA-N 0.000 description 1
- RETNWOLYVHIWJJ-UHFFFAOYSA-N n,n'-dinaphthalen-1-ylpropanediamide Chemical compound C1=CC=C2C(NC(CC(=O)NC=3C4=CC=CC=C4C=CC=3)=O)=CC=CC2=C1 RETNWOLYVHIWJJ-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of a 2-azacyclo [2.2.2] octane compound, and belongs to the technical field of organic compound synthesis. The 2-azacyclo [2.2.2] octane compound is synthesized in one step by taking an N, N' -di (phenyl) malonamide compound and bis (methyl styrene) ketone as raw materials, potassium tert-butoxide as alkali and ethanol as a solvent. The compound is an important organic compound and is widely applied. The synthesis method has the advantages of environmental friendliness, simplicity in operation, low price and the like.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a synthesis method of a 2-aza [2.2.2] octane compound.
Background
The synthesis of 2-aza [2.2.2] octane has attracted considerable attention, and the nitrogen-containing heterocyclic backbone is the core backbone of many natural alkaloids and bioactive molecules. The 2-aza [2.2.2] octane skeleton has also found wide application in the fields of total synthesis of natural compounds, pharmaceutical chemistry, and peptide mimetic design, among others. In addition, 2-aza [2.2.2] octane derivatives have been reported to have a wide range of pharmacological actions, such as anti-addiction, antifungal or anti-lipase, anti-HIV-1, anticholinesterase and leishmanicidal activities. Because of its broad biological activity, efforts are continually being made to develop atomic economic strategies for constructing these complex compounds.
At present, a great deal of literature reports on the synthesis of 2-aza- [2.2.2] octane derivatives, and from the standpoint of synthetic strategies, these methods can be classified into the following categories:
the first is the construction of a bicyclic scaffold based on the differentiation of an intramolecular functional group, cyclisation by intramolecular nucleophilic attack of one of two identical functional groups present in the molecule, leading to group differentiation and formation of the bicyclic scaffold, such as literature: A.V.Tymtsunik, S.O.Kokhan, Y.M.Ivon, I.V.Komarov, O.O.Grygorenko.RSC Advances 2016,6 (27), 22737-22748 construction of 2-aza [2.2.2] octane by dearomatization of substituted aromatic hydrocarbons, such as literature: L.Gong, J.H.Hogg, J.Collier, R.S.Wilhelm, C.Soderberg.Bioorg.Med.Chem.Lett.2003,13,3597-3600, but such synthetic methods can only give a single structure, substrate expansion is greatly limited.
The second category is Diels-Alder (IEDDA) 4+2 cycloaddition to form 2-aza [2.2.2] octane, IEDDA cycloaddition using electron-deficient 2-pyridone, such as literature: R.C.Conyers, J.R.Mazzone, M.A.Siegler, G.H.Posner.Tetrahedron Lett.2016,57,3344-3348.2 cycloaddition of pyranones, such as in: G.H.Posner, T.D.Nelson, C.M.Kinter, K.Afarinkia.Tetrahedron Lett.1991,32,5295-5298 the formation of separable lactones under mild conditions without extrusion of carbon dioxide, which can lead to the loss of substantial stereochemical information.
The third class is intramolecular Heck cyclization tandem reactions that build bridged N-heterocyclic compounds, such as literature: y.xu, Y.Wang, M Li.Chin.J.Org.chem.2021,41,3073-3082. However, such synthetic methods use transition metal catalysis and the reaction conditions are relatively stringent.
The importance of 2-aza [2.2.2] octanes can be found in chemical disciplines, and with applications such as drug/bioactivity studies, polymerization studies, etc., as well as a basis for larger, more complex organic molecules, the need for new ways to obtain these ideal molecules is expanding. Although there are reported methods for synthesizing 2-aza [2.2.2] octane compounds, the problems are also obvious, such as intramolecular Heck cyclization tandem reaction, transition metal catalysis is used in the route for constructing bridged N-heterocyclic compounds, and the reaction needs to be carried out under anhydrous and anaerobic conditions. Therefore, the development of a greener, simple and effective synthetic method of the 2-aza [2.2.2] octane compound still has important practical significance.
Disclosure of Invention
In order to solve the technical problems, the invention provides a synthesis method of a 2-aza [2.2.2] octane compound. A green, simple and efficient method for synthesizing the 2-aza [2.2.2] octane compounds is established. In order to achieve the purpose, the method provided by the invention is carried out under the metal-free condition, and the 2-aza [2.2.2] octane compound can be obtained in high yield through one-step reaction, so that the substrate is cheap, the steps are simple, and the operation is easy.
To achieve the above object, the present invention provides a 2-azacyclo [2.2.2]The synthesis process of octane compounds with N, N' -di (phenyl) malonamide and methyl styryl ketone as material and potassium tert-butoxide as material t BuOK) as a base and ethanol (EtOH) as a solvent to synthesize 2-azacyclo [2.2.2] in one step]Octane compounds, the reaction route is as follows:
the substituent R is selected from-4-Me-C 6 H 4 、-3-Me-C 6 H 4 、-2-Me-C 6 H 4 Phenyl (-Ph), -4-OMe-C 6 H 4 、-4-Cl-C 6 H 4 、-3-Cl-C 6 H 4 、-2-Cl-C 6 H 4 、-4-CO 2 Et-C 6 H 4 Quinoline (8-AQ), alpha-Naphthalene (alpha-napthalene) or benzyl (Bn).
The synthesis method of the invention not only can further enrich the synthesis method of the 2-aza [2.2.2] octane compounds, but also provides more candidate methods for industrial screening. The reaction of the invention only needs one step, and the N, N' -di (phenyl) malonamide compound and the methyl styrene ketone are easy-to-obtain chemicals, and preferably, when 1.2 equivalent of the methyl styrene ketone, 0.6 equivalent of the tertiary potassium butoxide and 3mL of ethanol are used, the reaction is carried out to generate the 2-nitrogen heterocyclic ring [2.2.2] octane compound.
Preferably, the molar ratio of N, N '-bis (phenyl) malonamide to the methyl styrene ketone is 1:1.2, for example, when the molar number of N, N' -bis (phenyl) malonamide is 0.3mmol, the molar number of methyl styrene ketone is 0.36mmol.
Preferably, the N, N '-di (phenyl) malonamide compound is a symmetrical N, N' -di (phenyl) malonamide compound.
Preferably, the structural formula of the N, N' -di (phenyl) malonamide compound is as follows:
the substituent R is selected from-4-Me-C 6 H 4 、-3-Me-C 6 H 4 、-2-Me-C 6 H 4 、-Ph、-4-OMe-C 6 H 4 、-4-Cl-C 6 H 4 、-3-Cl-C 6 H 4 、-2-Cl-C 6 H 4 、-4-CO 2 Et-C 6 H 4 8-AQ, alpha-naphalene or Bn.
Preferably, the reaction is carried out under air conditions.
Preferably, the reaction temperature is 60 ℃.
Preferably, the method further comprises the steps of removing the solvent by reduced pressure evaporation after the reaction is finished, and separating by column chromatography to obtain the target product 2-aza [2.2.2] octane compounds.
Compared with the prior art, the invention has the following advantages and technical effects:
the searching of a synthetic method which has simple reaction conditions, effective method, wide application range and green economy is an important direction in the field of the production of the compounds.
In the method, the reaction step is only one step, the synthetic method has few steps, low raw materials, easy acquisition, low technical difficulty and easy operation. The synthesis method of the invention avoids the process of using multi-step reaction and simultaneously avoids the use of metal catalysts, and the target product can be obtained only by evaporating the solvent under reduced pressure after the reaction is finished and separating the solvent by column chromatography.
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the invention described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from consideration of the specification of the present invention. The specification and examples of the present invention are exemplary only.
As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to.
Example 1
N was added to a 15mL pressure-resistant tube 1 ,N 3 Di-p-tolylpropanediamide (85 mg,0.3 mmol), methyl styryl ketone (84 mg,0.36 mmol), potassium tert-butoxide (20.2 mg,0.18 mmol) and 3mL of ethanol as solvent, stirring for 1 hour at 60 ℃ under air condition, monitoring the reaction process by using TCL, removing the solvent by reduced pressure evaporation after the reaction, and separating by column chromatography to obtain white solid: 147mg, 95% yield.
White solid, yield 95%. 1 H NMR(400MHz,CDCl 3 )δ10.71(d,J＝12.4Hz,1H),7.39–7.37(m,2H),7.34–7.32(m,2H),7.29(d,J＝7.6Hz,4H),7.21(t,J＝7.2Hz,4H),7.16–7.12(m,2H),6.82(d,J＝8.0Hz,2H),6.75–6.71(m,2H),4.04–3.98(m,2H),2.76–2.70(m,2H),2.41(s,3H),2.37–2.33(m,2H),2.16(s,3H). 13 C NMR(101MHz,CDCl 3 )δ170.8,167.2,141.3,138.1,134.3,133.8,132.0,130.0,128.9,128.7,128.5,128.1,127.3,121.3,86.4,58.1,45.9,43.4,21.3,20.9.
Example 2
N was added to a 15mL pressure-resistant tube 1 ,N 3 Di-m-tolylpropanediamide (85 mg,0.3 mmol), methyl styryl ketone (84 mg,0.36 mmol), potassium tert-butoxide (20.2 mg,0.18 mmol) and 3mL of ethanol as solvent, stirring for 1 hour at 60 ℃ under air condition, monitoring the reaction process by using TCL, removing the solvent by reduced pressure evaporation after the reaction, and separating by column chromatography to obtain white solid: 142mg, yield: 92%.
White solid, yield: 92%. 1 H NMR(600MHz,CDCl 3 )δ10.75(s,1H),7.45(t,J＝7.8Hz,1H),7.34–7.30(m,6H),7.27(d,J＝7.8Hz,1H),7.24(t,J＝7.8Hz,4H),7.16(t,J＝7.2Hz,2H),6.92(t,J＝7.8Hz,1H),6.73(t,J＝7.8Hz,2H),6.70(s,1H),4.03(dd,J＝10.8,4.8Hz,2H),3.31(s,1H),2.76(t,J＝12.6Hz,2H),2.46(s,3H),2.40–2.36(m,2H),2.13(s,3H). 13 C NMR(101MHz,CDCl 3 )δ170.8,167.1,141.3,139.4,138.1,136.9,134.6,129.4,129.2,128.7,128.2,128.1,127.3,125.7,125.0,121.8,118.2,86.4,58.1,46.0,43.6,21.6,21.3.
Example 3
N was added to a 15mL pressure-resistant tube 1 ,N 3 Dio-tolylpropanediamide (85 mg,0.3 mmol), tolylstyryl ketone (84 mg,0.36 mmol), potassium tert-butoxide (20.2 mg,0.18 mmol) and 3mL of ethanol as solvent, stirring at 60deg.C for 1 hr under air condition, monitoring the reaction process with TCL, evaporating under reduced pressure to remove solvent after the reaction, and separating by column chromatography to obtain white solid: 140mg, 90% yield.
White solid, yield: 90%. 1 H NMR(400MHz,DMSO)δ11.06(s,1H),7.39–7.33(m,6H),7.29–7.25(m,6H),7.19–7.16(m,2H),7.11(d,J＝8.0Hz,1H),6.97(d,J＝7.6Hz,1H),6.92(t,J＝7.6Hz,1H),6.86–6.82(m,2H),4.15(dd,J＝11.2,6.8Hz,1H),4.00(dd,J＝10.4,5.6Hz,1H),2.81(dd,J＝24.0,11.6Hz,2H),2.30–2.25(m,1H),2.23(s,3H),2.10–2.05(m,1H),1.67(s,3H). 13 C NMR(151MHz,DMSO)δ171.3,167.7,144.1,142.5,137.9,136.1,136.0,131.1,130.2,129.4,129.0,128.9,128.8,128.5,128.2,127.7,127.5,127.0,126.7,126.2,87.0,56.2,48.2,45.7,44.4,43.5,20.0,17.5.
Example 4
N was added to a 15mL pressure-resistant tube 1 ,N 3 Phenyl malonamide (76 mg,0.3 mmol), methyl styrene ketone (84 mg,0.36 mmol), potassium tert-butoxide (20.2 mg,0.18 mmol) in 3mL ethanol as solvent, stirring at 60 ℃ for 1 hour under air condition, monitoring the reaction process with TCL, evaporating the solvent under reduced pressure after the reaction, and separating by column chromatography to obtain white solid: 138mg, yield: 94%.
White solid, yield: 94%. 1 H NMR(400MHz,CDCl 3 )δ10.70(s,1H),7.60–7.57(m,2H),7.53–7.48(m,3H),7.33(d,J＝7.2Hz,4H),7.23(d,J＝8.0Hz,3H),7.15(t,J＝7.2Hz,2H),7.07–7.03(m,2H),6.92(dd,J＝7.6,2.8Hz,3H),4.12(dd,J＝11.2,5.2Hz,2H),2.83(t,J＝12.4Hz,2H),2.69(s,1H),2.39(dd,J＝10.4,5.2Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ170.7,167.1,141.2,137.0,134.6,129.4,128.8,128.7,128.4,128.3,128.1,127.4,124.1,121.1,86.5,58.3,46.0,43.5.
Example 5
N was added to a 15mL pressure-resistant tube 1 ,N 3 Bis (4-methoxyphenyl) malonamide (94 mg,0.3 mmol), methyl styryl ketone (84 mg,0.36 mmol) and potassium tert-butoxide (20.2 mg,0.18 mmol) were stirred for 1 hour at 60 ℃ in air with 3mL of ethanol, the reaction process was monitored by TCL, the solvent was removed by evaporation under reduced pressure after the completion of the reaction, and the white solid was obtained by column chromatography separation: 159mg, yield: 97%.
White solid, yield: 97%. 1 H NMR(400MHz,CDCl 3 )δ10.66(s,1H),7.43–7.41(m,2H),7.29(d,J＝7.6Hz,4H),7.23(t,J＝7.2Hz,4H),7.17(t,J＝7.2Hz,2H),7.03–7.01(m,2H),6.70–6.82(m,2H),6.56(d,J＝8.8Hz,2H),4.00–3.97(m,2H),3.82(s,3H),3.66(s,3H),2.71(t,J＝11.2Hz,2H),2.36(dd,J＝11.6,4.8Hz,2H). 13 C NMR(151MHz,CDCl 3 )δ170.9,167.1,159.2,156.3,141.4,130.04,129.8,128.7,128.1,127.3,127.2,122.9,114.6,113.6,86.3,58.1,55.6,55.3,45.9,43.4.
Example 6
N was added to a 15mL pressure-resistant tube 1 ,N 3 Bis (4-chlorophenyl) malonamide (97 mg,0.3 mmol), methyl styryl ketone (84 mg,0.36 mmol), t-butanolPotassium (20.2 mg,0.18 mmol), 3mL ethanol is used as solvent, the mixture is stirred for 1 hour under the condition of air at the temperature of 60 ℃, the reaction process is monitored by TCL, the solvent is removed by reduced pressure evaporation after the reaction is finished, and the white solid is obtained by column chromatography separation: 153mg, yield: 92%.
White solid, yield: 92%. 1 H NMR(400MHz,CDCl 3 )δ10.65(s,1H),7.54(d,J＝8.4Hz,2H),7.44(d,J＝8.8Hz,2H),7.27(s,1H),7.25–7.22(m,7H),7.19–7.14(m,2H),7.01(d,J＝8.8Hz,2H),6.87(d,J＝8.8Hz,2H),4.10(dd,J＝12.4,5.2Hz,2H),2.81(dd,J＝23.6,12.4Hz,3H),2.37(dd,J＝10.4,5.2Hz,2H). 13 C NMR(151MHz,CDCl 3 )δ170.8,167.1,140.8,135.5,134.2,132.9,130.0,129.5,129.2,128.8,128.5,127.9,127.6,122.1,86.6,58.4,45.9,43.4.
Example 7
N was added to a 15mL pressure-resistant tube 1 ,N 3 Bis (3-chlorophenyl) malonamide (97 mg,0.3 mmol), methyl styryl ketone (84 mg,0.36 mmol) and potassium tert-butoxide (20.2 mg,0.18 mmol) were stirred for 1 hour at 60 ℃ in air with 3mL of ethanol, the reaction was monitored by TCL, the solvent was removed by evaporation under reduced pressure after the completion of the reaction, and the white solid was obtained by column chromatography separation: 160mg, yield: 96%.
White solid, yield: 96%. 1 H NMR(600MHz,CDCl 3 )δ10.75(s,1H),7.54(t,J＝1.8Hz,1H),7.47–7.40(m,3H),7.24–7.21(m,8H),7.18–7.15(m,2H),7.00(t,J＝2.4Hz,1H),6.93(t,J＝8.4Hz,1H),6.89(ddd,J＝8.4,1.8,1.2Hz,1H),6.64–6.62(m,1H),3.96(dd,J＝10.8,5.4Hz,2H),3.93(s,1H),2.74(dd,J＝12.6,11.4Hz,2H),2.38–2.35(m,2H). 13 C NMR(101MHz,CDCl 3 )δ170.7,167.6,140.8,137.8,135.8,134.7,133.9,130.1,129.4,129.1,128.9,128.4,127.9,127.6,127.1,124.6,121.5,119.3,86.9,58.4,46.0,43.3.
Example 8
N was added to a 15mL pressure-resistant tube 1 ,N 3 Bis (2-chlorophenyl) malonamide (97 mg,0.3 mmol), methyl styryl ketone (84 mg,0.36 mmol) and potassium tert-butoxide (20.2 mg,0.18 mmol) were stirred for 1 hour at 60 ℃ in air with 3mL of ethanol, the reaction was monitored by TCL, the solvent was removed by evaporation under reduced pressure after the completion of the reaction, and the white solid was obtained by column chromatography separation: 145mg, yield: 87%.
White solid, yield: 87%. 1 H NMR(600MHz,CDCl 3 )δ11.09(s,1H),7.58(dd,J＝7.2,1.8Hz,1H),7.49(d,J＝7.2Hz,2H),7.43–7.38(m,4H),7.35(d,J＝7.2Hz,2H),7.27(t,J＝7.8Hz,2H),7.22(t,J＝7.2Hz,2H),7.19(t,J＝7.2Hz,1H),7.15(t,J＝7.2Hz,1H),7.09(dd,J＝7.8,1.2Hz,1H),6.97–6.95(m,1H),6.84(td,J＝7.8,1.8Hz,1H),4.12(dd,J＝10.8,6.0Hz,1H),4.06(dd,J＝11.4,6.0Hz,1H),3.29(s,1H),2.82–2.70(m,3H),2.23(ddd,J＝13.2,6.0,3.6Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ171.7,167.6,141.6,141.2,134.2,133.9,133.6,131.3,130.8,129.9,128.9,128.8,128.6,128.3,128.1,127.6,127.3,126.6,125.3,124.9,123.6,87.4,57.3,47.4,47.3,43.3.
Example 9
To a 15mL pressure-resistant tube were added diethyl 4,4' - (malonyl bis (azadiyl)) dibenzoate (119 mg,0.3 mmol), methyl styryl ketone (84 mg,0.36 mmol) and potassium tert-butoxide (20.2 mg,0.18 mmol), 3mL of ethanol was used as a solvent, and the mixture was stirred at 60℃for 1 hour under air condition, the reaction was monitored by TCL, the solvent was removed by evaporation under reduced pressure after the completion of the reaction, and a white solid was obtained by column chromatography separation: 173mg, yield: 91%.
White solid, yield: 91%. 1 H NMR(600MHz,CDCl 3 )δ10.88(s,1H),8.07(d,J＝8.4Hz,2H),7.71(d,J＝9.0Hz,2H),7.57(d,J＝8.4Hz,2H),7.26(d,J＝7.8Hz,4H),7.20(t,J＝7.8Hz,4H),7.13(t,J＝7.2Hz,2H),7.04(d,J＝8.4Hz,2H),4.63(s,1H),4.36(q,J＝7.2Hz,2H),4.24(q,J＝7.2Hz,2H),4.07(dd,J＝10.8,4.8Hz,2H),2.82(t,J＝12.0Hz,2H),2.49(dd,J＝12.0,4.8Hz,2H),1.39(t,J＝7.2Hz,3H),1.30(t,J＝7.2Hz,3H). 13 C NMR(151MHz,CDCl 3 )δ170.6,167.5,166.3,166.3,141.1,140.9,139.0,130.3,130.2,129.3,128.8,128.6,127.9,127.6,125.7,119.7,87.1,61.5,60.8,58.7,46.0,43.2,14.3,14.3.
Example 10
N was added to a 15mL pressure-resistant tube 1 ,N 3 Bis (quinolin-8-yl) malonamide (107 mg,0.3 mmol), methyl styryl ketone (84 mg,0.36 mmol) and potassium tert-butoxide (20.2 mg,0.18 mmol) were stirred for 1 hour at 60 ℃ with 3mL of ethanol as a solvent under air conditions, the reaction process was monitored by TCL, the solvent was removed by evaporation under reduced pressure after the completion of the reaction, and the white solid was obtained by column chromatography separation: 159mg, yield: 90%.
White solid, yield: 90%. 1 H NMR(600MHz,DMSO)δ12.46(s,1H),9.00(dd,J＝3.6,1.8Hz,1H),8.56–8.54(m,2H),8.49(d,J＝7.8Hz,1H),8.15–8.14(m,2H),8.02(d,J＝7.8Hz,2H),7.89–7.88(m,1H),7.85–7.82(m,1H),7.67(dd,J＝8.4,4.2Hz,1H),7.43–7.41(m,3H),7.37–7.34(m,2H),7.19(t,J＝7.8Hz,2H),7.14(t,J＝7.8Hz,2H),7.02(t,J＝7.2Hz,1H),6.97(t,J＝7.2Hz,1H),6.60(s,1H),4.20(dd,J＝11.2,5.4Hz,1H),4.10(dd,J＝10.2,6.0Hz,1H),3.10–3.06(m,1H),2.85(t,J＝12.0Hz,1H),2.67(t,J＝11.4Hz,1H),2.39–2.36(m,1H). 13 C NMR(151MHz,DMSO)δ170.2,168.8,150.7,149.1,146.3,143.3,143.1,138.7,137.0,136.4,135.3,135.1,131.2,130.0,129.4,128.8,128.5,128.2,128.0,127.1,127.1,127.0,126.9,122.4,122.0,121.9,116.9,87.4,58.6,48.2,47.6,43.6.
Example 11
N was added to a 15mL pressure-resistant tube 1 ,N 3 Bis (naphthalen-1-yl) malonamide (106 mg,0.3 mmol), methyl styryl ketone (84 mg,0.36 mmol) and potassium tert-butoxide (20.2 mg,0.18 mmol) were stirred for 1 hour at 60 ℃ with 3mL of ethanol as a solvent under air condition, the reaction process was monitored by TCL, the solvent was removed by evaporation under reduced pressure after the completion of the reaction, and a white solid was obtained by column chromatography separation: 129mg, yield: 73%.
White solid, yield: 73%. 1 H NMR(600MHz,DMSO)δ11.64(s,1H),8.06(t,J＝7.8Hz,2H),7.78(d,J＝7.8Hz,2H),7.74(t,J＝7.8Hz,1H),7.69(d,J＝7.2Hz,1H),7.55(t,J＝7.8Hz,4H),7.40–7.24(m,12H),7.16(t,J＝7.2Hz,1H),7.11(d,J＝8.4Hz,1H),6.95(s,1H),4.37(dd,J＝11.4,6.0Hz,1H),4.12(dd,J＝10.8,6.0Hz,1H),2.99(t,J＝12.6Hz,1H),2.90(t,J＝12.6Hz,1H),2.48–2.46(m,1H),2.32–2.30(m,1H). 13 C NMR(151MHz,DMSO)δ172.7,168.3,144.4,142.3,134.5,133.8,133.7,132.8,132.0,129.2,129.1,128.8,128.5,127.7,127.6,127.3,127.2,126.7,126.6,126.6,126.4,126.3,125.9,125.0,124.2,121.2,119.4,87.7,56.3,48.3,45.7,43.9.
Example 12
N was added to a 15mL pressure-resistant tube 1 ,N 3 Dibenzylamide (85 mg,0.3 mmol), methyl styryl ketone (84 mg,0.36 mmol) and potassium tert-butoxide (20.2 mg,0.18 mmol) are stirred for 1 hour under the condition of air and 60 ℃ by taking 3mL of ethanol as a solvent, the reaction process is monitored by TCL, the solvent is removed by reduced pressure evaporation after the reaction is finished, and the white solid is obtained by column chromatography separation: 148mg, yield: 96%.
White solid, yield: 96%. 1 H NMR(600MHz,DMSO)δ9.14–9.12(m,1H),7.43(d,J＝7.2Hz,2H),7.32(t,J＝7.8Hz,2H),7.26–7.21(m,6H),7.17–7.15(m,3H),7.12(s,1H),7.07(ddd,J＝20.4,13.2,7.2Hz,3H),6.89(d,J＝7.2Hz,4H),4.84(d,J＝14.4Hz,1H),4.71(d,J＝15.0Hz,1H),4.18(dd,J＝15.6,7.2Hz,1H),3.96(dd,J＝15.0,4.8Hz,1H),3.87(dd,J＝10.8,4.8Hz,1H),3.36(dd,J＝11.4,6.0Hz,1H),2.78(t,J＝12.6Hz,1H),2.28(td,J＝12.6,3.0Hz,1H),2.11(dd,J＝12.0,6.0Hz,1H),1.86–1.84(m,1H). 13 C NMR(151MHz,DMSO)δ172.1,167.8,145.0,140.4,139.6,139.3,129.5,128.9,128.7,128.6,128.5,128.4,128.2,127.5,127.2,126.9,126.3,85.0,57.3,46.1,44.6,42.6,42.5,42.3,37.9.
The present invention is not limited to the above-mentioned embodiments, and any changes or substitutions that can be easily understood by those skilled in the art within the technical scope of the present invention are intended to be included in the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope of the claims.
Claims (6)
1. A method for synthesizing 2-aza [2.2.2] octane compounds is characterized in that N, N' -di (phenyl) malonamide compounds and methyl styryl ketone are used as raw materials, potassium tert-butoxide is used as alkali, ethanol is used as a solvent, and the 2-aza [2.2.2] octane compounds are synthesized in one step.
2. The method according to claim 1, wherein the molar ratio of the N, N' -bis (phenyl) malonamide compound to the benzil is 1:1.2.
3. The method according to claim 2, wherein the N, N '-di (phenyl) malonamide compound is an N, N' -di (phenyl) malonamide compound.
4. A method of synthesis according to claim 3, wherein the N, N' -bis (phenyl) malonamides are of the formula:
the substituent R is selected from-4-Me-C 6 H 4 、-3-Me-C 6 H 4 、-2-Me-C 6 H 4 Phenyl, -4-OMe-C 6 H 4 、-4-Cl-C 6 H 4 、-3-Cl-C 6 H 4 、-2-Cl-C 6 H 4 、-4-CO 2 Et-C 6 H 4 Quinoline, alpha-naphthalene or benzyl.
5. The synthetic method of claim 1 wherein the reaction is carried out under air conditions.
6. The synthetic method of claim 1 wherein the reaction temperature is 60 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107586272A (en) * | 2016-07-06 | 2018-01-16 | 浙江圣效化学品有限公司 | A kind of bicyclic [2.2.2] Octane derivatives of polysubstituted benzo and preparation method thereof |
| CN112204006A (en) * | 2017-11-02 | 2021-01-08 | 卡里科生命科学有限责任公司 | Modulators of integrated stress pathways |
| CN114195671A (en) * | 2021-12-27 | 2022-03-18 | 河南师范大学 | Asymmetric malonanilide compound and synthesis method thereof |
| CN116693530A (en) * | 2023-06-09 | 2023-09-05 | 河南师范大学 | Synthesis method of bridged dicyclolactam compound |
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| CN107586272A (en) * | 2016-07-06 | 2018-01-16 | 浙江圣效化学品有限公司 | A kind of bicyclic [2.2.2] Octane derivatives of polysubstituted benzo and preparation method thereof |
| CN112204006A (en) * | 2017-11-02 | 2021-01-08 | 卡里科生命科学有限责任公司 | Modulators of integrated stress pathways |
| CN114195671A (en) * | 2021-12-27 | 2022-03-18 | 河南师范大学 | Asymmetric malonanilide compound and synthesis method thereof |
| CN116693530A (en) * | 2023-06-09 | 2023-09-05 | 河南师范大学 | Synthesis method of bridged dicyclolactam compound |
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