CN110903215B - Polysubstituted benzene compound and its synergistic catalytic preparation method - Google Patents
Polysubstituted benzene compound and its synergistic catalytic preparation method Download PDFInfo
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- CN110903215B CN110903215B CN201910377931.6A CN201910377931A CN110903215B CN 110903215 B CN110903215 B CN 110903215B CN 201910377931 A CN201910377931 A CN 201910377931A CN 110903215 B CN110903215 B CN 110903215B
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- -1 Polysubstituted benzene compound Chemical class 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 title abstract description 17
- 230000002195 synergetic effect Effects 0.000 title abstract description 6
- 230000003197 catalytic effect Effects 0.000 title description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 66
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 25
- 229910001544 silver hexafluoroantimonate(V) Inorganic materials 0.000 claims abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 49
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 claims description 29
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 claims description 28
- 229940117916 cinnamic aldehyde Drugs 0.000 claims description 27
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- 239000000758 substrate Substances 0.000 claims description 22
- QHPQWRBYOIRBIT-UHFFFAOYSA-N 4-tert-butylphenol Chemical compound CC(C)(C)C1=CC=C(O)C=C1 QHPQWRBYOIRBIT-UHFFFAOYSA-N 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N CHCl3 Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 15
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 150000002825 nitriles Chemical class 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 239000003054 catalyst Substances 0.000 description 20
- 239000000047 product Substances 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 238000010523 cascade reaction Methods 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- OEVXGSUDJYKUQX-UHFFFAOYSA-N 2-aminobenzene-1,3-dicarbonitrile Chemical compound NC1=C(C#N)C=CC=C1C#N OEVXGSUDJYKUQX-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000006845 Michael addition reaction Methods 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 6
- 238000005972 Thorpe-Ziegler reaction Methods 0.000 description 6
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 235000011181 potassium carbonates Nutrition 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 6
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 229910052723 transition metal Inorganic materials 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 229910052709 silver Inorganic materials 0.000 description 4
- 150000003624 transition metals Chemical class 0.000 description 4
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 3
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical class OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 3
- 238000006114 decarboxylation reaction Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000004332 silver Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- WYJOVVXUZNRJQY-UHFFFAOYSA-N 2-Acetylthiophene Chemical compound CC(=O)C1=CC=CS1 WYJOVVXUZNRJQY-UHFFFAOYSA-N 0.000 description 2
- AXCXHFKZHDEKTP-NSCUHMNNSA-N 4-methoxycinnamaldehyde Chemical compound COC1=CC=C(\C=C\C=O)C=C1 AXCXHFKZHDEKTP-NSCUHMNNSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- XUHWJLMOAFPKEV-UHFFFAOYSA-N Sepiol Chemical compound OC1=C(O)C(OC)=CC=C1C1=CC2=CC=C(O)C=C2OC1 XUHWJLMOAFPKEV-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- LAQPNDIUHRHNCV-UHFFFAOYSA-N isophthalonitrile Chemical compound N#CC1=CC=CC(C#N)=C1 LAQPNDIUHRHNCV-UHFFFAOYSA-N 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 125000002560 nitrile group Chemical group 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- CDUQMGQIHYISOP-RMKNXTFCSA-N (e)-2-cyano-3-phenylprop-2-enoic acid Chemical compound OC(=O)C(\C#N)=C\C1=CC=CC=C1 CDUQMGQIHYISOP-RMKNXTFCSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- MLIREBYILWEBDM-UHFFFAOYSA-M 2-cyanoacetate Chemical compound [O-]C(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-M 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000005899 aromatization reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- FCFXSHWIQVTCQE-UHFFFAOYSA-N cyano(phenyl)cyanamide Chemical class N#CN(C#N)C1=CC=CC=C1 FCFXSHWIQVTCQE-UHFFFAOYSA-N 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 238000006452 multicomponent reaction Methods 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- AXCXHFKZHDEKTP-UHFFFAOYSA-N para-methoxycinnamaldehyde Natural products COC1=CC=C(C=CC=O)C=C1 AXCXHFKZHDEKTP-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- NLFIMXLLXGTDME-UHFFFAOYSA-N propyl 2-cyanoacetate Chemical compound CCCOC(=O)CC#N NLFIMXLLXGTDME-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000007832 transition metal-catalyzed coupling reaction Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一类多取代苯化合物及其协同催化制备方法。所述方法包括化合物
Description
技术领域technical field
本发明涉及药物化学领域，具体而言，本发明涉及吡咯烷和AgSbF6协同催化肉桂醛与氰乙酸衍生物，发生多米诺反应合成多取代苯的方法。The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing polysubstituted benzene by domino reaction of pyrrolidine and AgSbF6 in synergistic catalysis of cinnamaldehyde and cyanoacetic acid derivatives.
背景技术Background technique
由于多取代苯环单元广泛存在于天然产物、药物分子、新功能材料中，并在有机合成化学中作为重要中间体发挥重要作用。同时多取代苯类化合物是有机化学、天然产物化学及高分子化学中的重要化合物，并作为许多天然活性化合物的基本骨架，以及许多具有药理活性的杂环化合物的合成中间体，它在药物化学中扮演重要角色。例如，中国专利CN101654401A公开了具有
另一方面，多米诺骨牌反应[4]由于具有能够缩短反应过程、减少原料浪费、环境友好性和良好的原子经济性的特点而成为热点。近年来，一些小组开发了通过一系列多米诺方法合成多取代苯的有效方法。例如，在2007年，Deng等人报道了在碱性条件下烷基二烯丙二腈与硝基烯烃的一系列串联反应，得到多取代的苯。[5a]2011年，Fan等人通过1，2-丙二烯酮与氰基乙酸酯的串联反应合成高度官能化的苯。[5b]2013年，Li的研究小组报道了第一个磷化氢催化的多米诺反应，用γ-CH3取代的烯醇化物和共轭二烯烃合成功能化苯。[5c]2015年，Chi等报道了第一例NHC催化的[4+2]形式的多米诺反应合成多取代芳烃。[5d] On the other hand, the domino reaction [4] has become a hot spot due to its features of shortening the reaction process, reducing raw material waste, environmental friendliness, and good atom economy. In recent years, several groups have developed efficient methods for the synthesis of polysubstituted benzenes through a series of domino methods. For example, in 2007, Deng et al. reported a series of tandem reactions of alkyldiallylononitriles with nitroalkenes under basic conditions to give polysubstituted benzenes. [5a] In 2011, Fan et al. synthesized highly functionalized benzene through the tandem reaction of 1,2-propadienone with cyanoacetate. [5b] In 2013, Li's research group reported the first phosphine-catalyzed domino reaction to synthesize functionalized benzenes with γ - CH substituted enolates and conjugated dienes. [5c] In 2015, Chi et al. reported the first NHC-catalyzed [4+2] domino reaction to synthesize polysubstituted aromatic hydrocarbons. [5d]
在过去的几十年中，化学家开发了多种通过碱催化合成2，6-二氰基苯的多组分多米诺反应方法。[7-8]从机理上看，这些策略可分为三种主要的反应类型。其中之一是由迈克尔加成和Thorpe-Ziegler环合α，β-不饱和化合物合成苯环。Sepiol和Milart[8a]以芳基亚甲基丙二腈和1-芳基亚乙基丙二腈为原料在哌啶催化的条件下制备2，6-二氰基苯胺，产率中等至良好。使用类似的策略，其他化学家[8]也合成了各种多取代的2，6-二氰基苯胺。Over the past few decades, chemists have developed a variety of multicomponent domino reaction methods for the base-catalyzed synthesis of 2,6-dicyanobenzene. [7-8] Mechanistically, these strategies can be classified into three main reaction types. One of them is the synthesis of benzene rings by Michael addition and Thorpe-Ziegler cyclization of α,β-unsaturated compounds. Sepiol and Milart [8a] Preparation of 2,6-dicyanoaniline from arylmethylenemalononitrile and 1-arylethylenemalononitrile under piperidine-catalyzed conditions in moderate to good yields . Using a similar strategy, other chemists [8] have also synthesized various polysubstituted 2,6-dicyanoanilines.
第二种机理是依次经过Adol缩合、迈克尔加成、Knoevenagel缩合和Thorpe-Ziegler环化来实现，其中α，β-不饱和化合物是原位形成的。Yu和Velasco[9a]报道，当丙二腈与苯甲醛和乙醛反应时，可合成2，6-二氰基苯。Borate[9b]报道，在吗啉存在下，对各种芳基醛，烷基醛和丙二腈进行了表征，得到2，6-二氰基苯胺作为次要产物。Rong等[9c]发现，不同的醛类和酮类与丙二腈研磨后，与固体氢氧化钠一起，可以顺利地生成取代的2，6-二氰基苯胺。由Rong group[9d，e，f，g]，Zhou等[9h]和Shaterian等也描述了类似的策略[9i]，用来合成以后所需的2，6-二氰基苯胺。王等[9j]和Banerjee等[9k]分别报道了一种微波和二氧化硅纳米粒子促进多组分反应，使醛、酮和丙二腈平行合成各种取代的二氰基苯胺。The second mechanism is achieved sequentially through Adol condensation, Michael addition, Knoevenagel condensation and Thorpe-Ziegler cyclization, in which α,β-unsaturated compounds are formed in situ. Yu and Velasco [9a] reported that 2,6-dicyanobenzene can be synthesized when malononitrile is reacted with benzaldehyde and acetaldehyde. Borate [9b] reported that various arylaldehydes, alkylaldehydes and malononitriles were characterized in the presence of morpholine to give 2,6-dicyanoaniline as a secondary product. Rong et al. [9c] found that substituted 2,6-dicyanoanilines could be successfully generated together with solid sodium hydroxide after grinding different aldehydes and ketones with malononitrile. A similar strategy was also described by Rong group [9d, e, f, g] , Zhou et al. [9h] and Shaterian et al. [9i] for the synthesis of the later desired 2,6-dicyanoaniline. Wang et al. [9j] and Banerjee et al. [9k] respectively reported a microwave and silica nanoparticle-promoted multicomponent reaction for the parallel synthesis of various substituted dicyanoanilines from aldehydes, ketones, and malononitriles.
第三种类型的机理是依次经过Knoevenagel凝聚，Michael加成和Thorpe-Ziegler环化来实现。Hassan等人[10a]通过使用甲基2-噻吩基酮，丙二腈和α-氰基肉桂酸酯作为起始原料，研究了含有3-噻吩基取代基的2，6-二氰基苯胺的合成。类似地，其他课题组[10b-h]也合成了一系列2，6-二氰基苯胺和衍生物。The third type of mechanism is achieved sequentially through Knoevenagel condensation, Michael addition and Thorpe-Ziegler cyclization. Hassan et al. [10a] investigated 2,6-dicyanoanilines containing 3-thienyl substituents by using methyl 2-thienyl ketone, malononitrile and α-cyanocinnamate as starting materials Synthesis. Similarly, other research groups [10b-h] also synthesized a series of 2,6-dicyanoanilines and derivatives.
第四种类型的机理是依次经过迈克尔加成，Knoevenagel凝聚和Thorpe-Ziegler环化来实现。(1)Kandeel等课题组[11a-c]研究了在碱性条件下丙二腈与各种乙炔酮的反应，得到2，6-二氰基苯胺和衍生物。(2)Khaidem等课题组[11d-i]研究了在碱存在下丙二腈与各种α，β-不饱和酮的反应，得到2，6-二氰基苯胺和衍生物。然而，到目前为止，已知的关于α，β-不饱和醛[11g，11h]的研究证明该策略的有效性并不好。The fourth type of mechanism is achieved sequentially through Michael addition, Knoevenagel condensation and Thorpe-Ziegler cyclization. (1) The research group of Kandeel et al. [11a-c] studied the reaction of malononitrile with various acetylene ketones under alkaline conditions to obtain 2,6-dicyanoaniline and derivatives. (2) The research group of Khaidem et al. [11d-i] studied the reaction of malononitrile with various α, β-unsaturated ketones in the presence of bases to obtain 2,6-dicyanoaniline and derivatives. However, the known studies on α,β-unsaturated aldehydes [11g, 11h] so far demonstrate the effectiveness of this strategy is not good.
更重要的是，上述方法经常遇到一些缺点：(1)有害的副产品，如氰化物盐和HCN，这可能对环境造成污染和对人体造成损害；(2)底物的范围有限，因为丙二腈是唯一含氰基的资源；(3)α，β-不饱和醛成功参与这种反应仍然是一个挑战；(4)可替代的高效催化体系是有限的，它不能满足合成多取代苯的需要。为了克服上述不足，我们希望通过脱羧多米诺反应，选取市售的具有多种氰基乙酸酯的α，β-不饱和醛，通过有机催化剂和过渡金属催化剂的协同催化首次合成出多取代苯环。过渡金属和有机分子结合进行协同催化，可以通过金属催化剂和有机催化剂同时或依次地活化和重组多个化学键，实现新的转化。这一概念在有机合成反应中具有巨大的应用前景，这在后来由金属/有机二元催化剂体系加速转化中证明了这一点。[13]在该方案中，AgSbF6用作金属催化剂，吡咯烷用作有机催化剂。本申请参考下述文献，下述文献全部引入本申请并作参考。More importantly, the above methods often suffer from some disadvantages: (1) harmful by-products, such as cyanide salts and HCN, which may cause pollution to the environment and damage to humans; (2) the limited range of substrates, because C Dinitrile is the only resource containing cyano groups; (3) the successful participation of α,β-unsaturated aldehydes in this reaction is still a challenge; (4) alternative efficient catalytic systems are limited, which cannot meet the requirements for the synthesis of polysubstituted benzenes needs. In order to overcome the above shortcomings, we hope to synthesize polysubstituted benzene rings for the first time through the decarboxylation domino reaction, select commercially available α, β-unsaturated aldehydes with various cyanoacetates, and synergistically catalyze organic catalysts and transition metal catalysts. . Transition metals and organic molecules are combined for synergistic catalysis, and new transformations can be achieved by activating and recombining multiple chemical bonds simultaneously or sequentially through metal catalysts and organic catalysts. This concept holds great promise in organic synthesis reactions, which was later demonstrated in accelerated transformations by metal/organic binary catalyst systems. [13] In this scheme, AgSbF was used as the metal catalyst and pyrrolidine was used as the organic catalyst. The present application refers to the following documents, all of which are incorporated herein by reference.
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[14](a)Gotoh，H.；Ishikawa，H.；Hayashi，Y.，Org.Lett.，2007，9，5307-5309.(b)Product 6 was confirmed by H1-NMR.[14] (a) Gotoh, H.; Ishikawa, H.; Hayashi, Y., Org. Lett., 2007, 9, 5307-5309. (b) Product 6 was confirmed by H 1 -NMR.
[15]Product 7 was confirmed by H1-NMR，C13-NMR and HR-MS.[15]Product 7 was confirmed by H 1 -NMR, C 13 -NMR and HR-MS.
[16]We performed Sc(OTf)3，Yb(OTf)3，Ce(OTf)3，Sm(OTf)3，La(OTf)3，In(OTf)3Bi(OTf)3and other lewis acid as the additiyes to active the nitrile group，butthe yield had not been improved.These experiments indicated that silver saltin the reaction not only active the carbon-nitrogen triple bond，but also playan important role in decarboxylation process(See from the SI).For someexamples of decarboxylation catalyzed by silver：(a)Josep Cornella，CarolinaSanchez，David Banawa and Igor Larrosa，Chem.Commun.，2009，7176-7178.(b)PengfeiLu，Carolina Sanchez，Josep Cornella，and Igor Larrosa，Org.Lett.，2009，11，5710-5713.(c)Sukalyah Bhadra，Wojciech I.Dzik，and Lukas J.Goossen，J.Am.Chem.Soc.，2012，134，9938-9941.[16] We performed Sc(OTf) 3 , Yb(OTf) 3 , Ce(OTf) 3 , Sm(OTf) 3 , La(OTf) 3 , In(OTf) 3 Bi(OTf) 3 and other lewis acid as the additiyes to active the nitrile group, but the yield had not been improved. These experiments indicated that silver salt in the reaction not only active the carbon-nitrogen triple bond, but also playan important role in decarboxylation process (See from the SI). For some examples of decarboxylation catalyzed by silver: (a) Josep Cornella, Carolina Sanchez, David Banawa and Igor Larrosa, Chem. Commun., 2009, 7176-7178. (b) Pengfei Lu, Carolina Sanchez, Josep Cornella, and Igor Larrosa, Org. Lett. , 2009, 11, 5710-5713. (c) Sukalyah Bhadra, Wojciech I. Dzik, and Lukas J. Goossen, J. Am. Chem. Soc., 2012, 134, 9938-9941.
发明内容SUMMARY OF THE INVENTION
本发明的目的之一提供了一类多取代苯化合物。One of the objects of the present invention provides a class of polysubstituted benzene compounds.
本发明的另一目的在提供了上述多取代化合物的制备方法。Another object of the present invention is to provide a preparation method of the above-mentioned polysubstituted compound.
本发明还有一目的是提供了上述化合物的用途。Another object of the present invention is to provide the use of the above-mentioned compounds.
为实现上述目的，本发明采用了下述技术方案：To achieve the above object, the present invention has adopted the following technical solutions:
一种多取代苯化合物，所述化合物如下述式I所示：A kind of polysubstituted benzene compound, described compound is shown in following formula I:
其中，R1选自甲基、乙基、丙基或
其中一个优选地的技术方案为：One of the preferred technical solutions is:
优选地R1为
优选地，R3选自F、Cl、Br；R2选自Et；Preferably, R 3 is selected from F, Cl, Br; R 2 is selected from Et;
更优选地，R3选自H、Me、OMe；R2选自Et。More preferably, R 3 is selected from H, Me, OMe; R 2 is selected from Et.
另一优选的技术方案为：Another preferred technical solution is:
优选地，R1为
优选地，R3选自H、Me或OMe；R2选自Me、n-Pr或i-Pr；Preferably, R 3 is selected from H, Me or OMe; R 2 is selected from Me, n-Pr or i-Pr;
更优选地，R3选自H；R2选自n-Pr、i-Pr或苄基。More preferably, R3 is selected from H; R2 is selected from n - Pr, i-Pr or benzyl.
所述式I化合物选自下述具体化合物：The compound of formula I is selected from the following specific compounds:
本发明还提供了所述化合物的制备方法，其包括下述步骤：化合物
所述碱性试剂选自碳酸钠、碳酸钾、碳酸铯、三乙胺或DBU中的一种或几种；优选碳酸钾；The alkaline reagent is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or DBU; preferably potassium carbonate;
优选地，反应温度为70～100℃；更优选75～85℃；反应时间12小时。Preferably, the reaction temperature is 70-100°C; more preferably 75-85°C; the reaction time is 12 hours.
优选地，反应体系中还存在有机溶剂，所述有机溶剂选自CHCl3、DCE、THF、甲苯、EtOH、DMSO或DMF中的一种或几种。更优选CHCl3。优选在惰性气氛下进行，更优选在氮气下进行。Preferably, an organic solvent also exists in the reaction system, and the organic solvent is selected from one or more of CHCl 3 , DCE, THF, toluene, EtOH, DMSO or DMF. More preferred is CHCl3 . It is preferably carried out under an inert atmosphere, more preferably under nitrogen.
优选地，反应体系中还存在PTBP。Preferably, PTBP is also present in the reaction system.
优选地，所述方法包括化合物
更优选地，所述方法包括在摩尔量为肉桂醛底物摩尔量的10％的AgSbF6、摩尔量为肉桂醛底物摩尔量的20％的吡咯烷、摩尔量为肉桂醛底物摩尔量的10％的PTBP、摩尔量为肉桂醛底物摩尔量的200％的K2CO3存在下，在CHCl3中，80℃下生成式I化合物的步骤。More preferably, the method comprises AgSbF 6 in a molar amount of 10% of the molar amount of the cinnamaldehyde substrate, pyrrolidine in a molar amount of 20% of the molar amount of the cinnamaldehyde substrate, and a molar amount of the cinnamaldehyde substrate in a molar amount. The steps of generating the compound of formula I in the presence of 10% PTBP and 200% K 2 CO 3 in the molar amount of the cinnamaldehyde substrate molar amount in CHCl 3 at 80°C.
本发明具有以下优点The present invention has the following advantages
1.反应活性高，反应完全，分离方便，能获得高的收率。1. High reactivity, complete reaction, convenient separation and high yield.
2.金属催化剂与有机催化剂的协同使用，提高反应效率，操作简便。2. The synergistic use of metal catalysts and organic catalysts improves the reaction efficiency and is easy to operate.
3.多米诺反应条件温和，反应在70～100℃下进行。3. The domino reaction conditions are mild, and the reaction is carried out at 70-100 °C.
4、比较传统的合成方法，此方法采用少量的银催化剂和吡咯烷作为协同催化剂，可以得到大量的多取代苯衍生物，合成路线简短，原子经济性高，底物适用范围广泛，具有很高的实用价值。4. Compared with the traditional synthesis method, this method uses a small amount of silver catalyst and pyrrolidine as a synergistic catalyst to obtain a large number of polysubstituted benzene derivatives. The synthesis route is short, the atom economy is high, and the substrate is suitable for a wide range. practical value.
本发明还提供了前述化合物在制备多取代苯化合物方面的应用。The present invention also provides the application of the aforementioned compounds in the preparation of polysubstituted benzene compounds.
实施例Example
下面通过实施例对本发明作进一步说明。应该理解的是，本发明实施例所述方法仅仅是用于说明本发明，而不是对本发明的限制，在本发明的构思前提下对本发明制备方法的简单改进都属于本发明要求保护的范围。实施例中用到的所有原料和溶剂均为市售产品。The present invention will be further described below through examples. It should be understood that the methods described in the embodiments of the present invention are only used to illustrate the present invention, rather than to limit the present invention, and simple improvements to the preparation method of the present invention under the concept of the present invention all belong to the scope of protection of the present invention. All raw materials and solvents used in the examples are commercially available products.
实施例1：化合物3aa的制备：Example 1: Preparation of compound 3aa:
在25毫升圆底烧瓶中加入肉桂醛1a(0.25毫摩尔，33毫克)，氰乙酸乙酯2a(2毫摩尔，226毫克)，碳酸钾(0.5毫摩尔，69毫克)，六氟锑酸银(0.05毫摩尔，17毫克)，四氢吡咯(0.05毫摩尔，4毫克)，对叔丁基苯酚(0.025毫摩尔，4毫克)，溶解在3毫升三氯甲烷中，在氮气保护下80℃搅拌12小时。反应完成后将混合溶液冷却至室温，用饱和食盐水和二氯甲烷萃取3次(10毫升/次)，将有机相合并后用无水硫酸钠干燥。最后通过硅胶柱层析法分离(淋洗剂为石油醚和乙酸乙酯，体积比为30∶1-20∶1)，得到目标产物多取代苯3aa(收率63％)。In a 25 mL round bottom flask were added cinnamaldehyde 1a (0.25 mmol, 33 mg), ethyl cyanoacetate 2a (2 mmol, 226 mg), potassium carbonate (0.5 mmol, 69 mg), silver hexafluoroantimonate (0.05 mmol, 17 mg), tetrahydropyrrole (0.05 mmol, 4 mg), p-tert-butylphenol (0.025 mmol, 4 mg), dissolved in 3 mL of chloroform at 80°C under nitrogen Stir for 12 hours. After the completion of the reaction, the mixed solution was cooled to room temperature, extracted three times with saturated brine and dichloromethane (10 ml/time), and the organic phases were combined and dried over anhydrous sodium sulfate. Finally, it was separated by silica gel column chromatography (the eluent was petroleum ether and ethyl acetate, the volume ratio was 30:1-20:1) to obtain the target product polysubstituted benzene 3aa (yield 63%).
根据实施例1类似的制备方法，改变不同的反应条件，探讨最优反应条件。结果列于表1中。According to the preparation method similar to Example 1, different reaction conditions were changed to explore the optimal reaction conditions. The results are listed in Table 1.
表1.肉桂醛1a和氰基乙酸乙酯2a之间的多米诺反应的优化Table 1. Optimization of the domino reaction between cinnamaldehyde 1a and ethyl cyanoacetate 2a
a)反应条件：1a(0.25毫摩尔)，2a(2毫摩尔)，[M](0.05毫摩尔)，有机催化剂(0.05毫摩尔)，碱(0.5毫摩尔)，氮气保护，反应温度80℃，反应时间12小时。a) Reaction conditions: 1a (0.25 mmol), 2a (2 mmol), [M] (0.05 mmol), organic catalyst (0.05 mmol), base (0.5 mmol), nitrogen protection, reaction temperature 80°C , the reaction time is 12 hours.
b)分离产率.b) Isolated yield.
c)氧气气氛下。c) Under an oxygen atmosphere.
d)PTBP(0.025毫摩尔)加入到反应体系中；PTBP＝对叔丁基苯酚。d) PTBP (0.025 mmol) was added to the reaction system; PTBP = p-tert-butylphenol.
e)1a(10毫摩尔，1.32克)。e) 1a (10 mmol, 1.32 g).
结果与讨论：Results and discussion:
最初选择肉桂醛1a和氰基乙酸乙酯2a作为模型底物，以探索和优化一系列多米诺反应。当反应用15％Ag2O和20％吡咯烷(以肉桂醛底物计)作为催化剂，在DCE中以温度为80℃的条件反应12h时，我们很高兴地发现所需的多取代苯环3aa以38％的收率时生成(项目1，表1)。然后，使用其他过渡金属催化剂，如CuBr、CuBr2、Pd(OAc)2、Rh(PPh3)Cl2、Ir(cod)2Cl2、Sc(OTf)3和Yb(OTf)3，发现AgSbF6是这些过渡金属盐中的产率最高的(项目5与项目1-4相比，表1)。在不存在银催化剂的情况下未观察到期望的产物3aa(项目6，表1)。接下来，我们筛选了有机催化剂(项目7-9，表1)，实验表明吡咯烷能提供48％的最好收率的所需产物3aa(项目7，表1)。在不存在有机催化剂的情况下，3aa的产率明显降低(项目15，表1)。当使用其他碱而不是K2CO3时，获得了较低的3aa产率(项目10-13，表1)。除此之外，如果从反应体系中除去碱，则所需产物3aa的产率降低至痕量(项目14，表1)。还考察了溶剂对多米诺骨牌反应的影响，证明CHCl3优于DCE、THF、甲苯、EtOH、DMSO和DMF(项目16，表1)。接下来，我们在O2条件下进行反应，3aa的产率略有下降(表1；项目17)。当反应体系中加入10％的PTBP(对叔丁基苯酚)时(以肉桂醛底物计)，收率高达63％(表1；项目18)。筛选反应条件后，可以得出结论，反应的最优条件是10％的AgSbF6、20％的吡咯烷作为催化剂，10％的PTBP作为添加剂、2当量的K2CO3与1a、1b在CHCl3中进行，反应温度为80℃。Cinnamaldehyde 1a and ethyl cyanoacetate 2a were initially chosen as model substrates to explore and optimize a range of domino reactions. When the reaction was carried out in DCE at 80°C for 12 h using 15% Ag 2 O and 20% pyrrolidine (based on cinnamaldehyde substrate) as catalysts, we were pleased to find the desired polysubstituted benzene ring 3aa was produced in 38% yield (entry 1, Table 1). Then, using other transition metal catalysts such as CuBr, CuBr2, Pd(OAc )2 , Rh( PPh3 )Cl2, Ir(cod )2Cl2, Sc(OTf)3 and Yb (OTf) 3 , AgSbF was found 6 was the highest yield of these transition metal salts (entry 5 compared to entries 1-4, Table 1). The desired product 3aa was not observed in the absence of silver catalyst (entry 6, Table 1). Next, we screened organocatalysts (Items 7-9, Table 1) and experiments showed that pyrrolidine provided the best yield of 48% of the desired product 3aa (Item 7, Table 1). In the absence of the organocatalyst, the yield of 3aa was significantly reduced (entry 15, Table 1). Lower yields of 3aa were obtained when other bases than K2CO3 were used (entries 10-13, Table 1). In addition to this, if the base was removed from the reaction system, the yield of the desired product 3aa was reduced to trace amounts (entry 14, Table 1). The effect of solvent on the domino reaction was also examined, demonstrating that CHCl3 is superior to DCE, THF, toluene, EtOH, DMSO, and DMF (Item 16, Table 1). Next, we carried out the reaction under O conditions and the yield of 3aa decreased slightly (Table 1 ; entry 17). When 10% PTBP (p-tert-butylphenol) was added to the reaction system (based on cinnamaldehyde substrate), the yield was as high as 63% (Table 1; entry 18). After screening the reaction conditions, it can be concluded that the optimal conditions for the reaction are 10% AgSbF 6 , 20% pyrrolidine as catalyst, 10% PTBP as additive, 2 equiv of K 2 CO 3 with 1a, 1b in CHCl 3 , and the reaction temperature was 80 °C.
实施例2：化合物3ba化合物的制备：Example 2: Preparation of compound 3ba compound:
在25毫升圆底烧瓶中加入对甲氧基肉桂醛1b(0.25毫摩尔，41毫克)，氰乙酸乙酯2a(2毫摩尔，226毫克)，碳酸钾(0.5毫摩尔，69毫克)，六氟锑酸银(0.05毫摩尔，17毫克)，四氢吡咯(0.05毫摩尔，4毫克)，对叔丁基苯酚(0.025毫摩尔，4毫克)，溶解在3毫升三氯甲烷中，在氮气保护下80℃搅拌12小时。反应完成后将混合溶液冷却至室温，用饱和食盐水和二氯甲烷萃取3次(10毫升/次)，将有机相合并后用无水硫酸钠干燥。最后通过硅胶柱层析法分离(淋洗剂为石油醚和乙酸乙酯，体积比为30∶1-20∶1)，得到目标产物多取代苯3ba(收率68％)。In a 25 mL round-bottom flask, add p-methoxycinnamaldehyde 1b (0.25 mmol, 41 mg), ethyl cyanoacetate 2a (2 mmol, 226 mg), potassium carbonate (0.5 mmol, 69 mg), six Silver fluoroantimonate (0.05 mmol, 17 mg), tetrahydropyrrole (0.05 mmol, 4 mg), p-tert-butylphenol (0.025 mmol, 4 mg), dissolved in 3 mL of chloroform under nitrogen Stir under protection at 80°C for 12 hours. After the completion of the reaction, the mixed solution was cooled to room temperature, extracted three times with saturated brine and dichloromethane (10 ml/time), and the organic phases were combined and dried over anhydrous sodium sulfate. Finally, it is separated by silica gel column chromatography (eluent is petroleum ether and ethyl acetate, the volume ratio is 30:1-20:1) to obtain the target product polysubstituted benzene 3ba (yield 68%).
按照实施例2类似的制备方法，按照下式反应式，采用不同的原料制备表2中的化合物。According to the similar preparation method of Example 2, according to the following reaction formula, the compounds in Table 2 were prepared by using different raw materials.
表2.以不同α，β-不饱和醛为原料制备的化合物Table 2. Compounds prepared from different α,β-unsaturated aldehydes
a)反应条件：1(0.25毫摩尔)，2(2毫摩尔)，AgSbF6(0.05毫摩尔)，吡咯烷(0.05毫摩尔)，K2CO3(0.25毫摩尔)，PTBP(0.025毫摩尔)，氮气存在下，80℃，12h，分离产率。a) Reaction conditions: 1 (0.25 mmol), 2 (2 mmol), AgSbF 6 (0.05 mmol), pyrrolidine (0.05 mmol), K 2 CO 3 (0.25 mmol), PTBP (0.025 mmol) ), in the presence of nitrogen, 80 °C, 12 h, isolated yield.
结果与讨论：Results and discussion:
在优化的反应条件下，我们考察了该方法的通用性和适用范围。我们发现一系列肉桂醛衍生物1a-j能够顺利地与氰基乙酸乙酯2a进行多米诺反应，得到所需产物3aa-ja，产率为39-68％(表2)。在这一反应中，似乎对肉桂醛上的官能团的电子密度敏感。具有p-位上电子基团(例如CH3O-和CH3-)的肉桂醛的表现优于具有电子基团(如F-和NO2-)的肉桂醛。值得一提的是，当采用脂肪族α，β-不饱和醛1h-j时，成功构建了所需的多取代苯，这为合成多种烷基化苯提供了一种新的策略。这种方法是Friedel-Crafts反应的一个很好的补充，因为当芳香环上的基团电子失活时，很难进行Friedel-Crafts反应。Under the optimized reaction conditions, we examined the generality and applicability of this method. We found that a series of cinnamaldehyde derivatives 1a-j could be successfully domino-reacted with ethyl cyanoacetate 2a to afford the desired products 3aa-ja in 39-68% yields (Table 2). In this reaction, it appears to be sensitive to the electron density of the functional groups on cinnamaldehyde. Cinnamaldehydes with electronic groups in the p-position (eg CH3O- and CH3- ) performed better than cinnamaldehydes with electronic groups (eg F- and NO2-). It is worth mentioning that the desired polysubstituted benzenes were successfully constructed when aliphatic α,β-unsaturated aldehydes 1h-j were employed, which provides a new strategy for the synthesis of various alkylated benzenes. This method is a good complement to the Friedel-Crafts reaction, because it is difficult to carry out the Friedel-Crafts reaction when the group on the aromatic ring is electronically deactivated.
实施例3：化合物3ac的制备：Example 3: Preparation of compound 3ac:
在25毫升圆底烧瓶中加入肉桂醛1a(0.25毫摩尔，33毫克)，氰乙酸丙酯2c(2毫摩尔，254毫克)，碳酸钾(0.5毫摩尔，69毫克)，六氟锑酸银(0.05毫摩尔，17毫克)，四氢吡咯(0.05毫摩尔，4毫克)，对叔丁基苯酚(0.025毫摩尔，4毫克)，溶解在3毫升三氯甲烷中，在氮气保护下80℃搅拌12小时。反应完成后将混合溶液冷却至室温，用饱和食盐水和二氯甲烷萃取3次(10毫升/次)，将有机相合并后用无水硫酸钠干燥。最后通过硅胶柱层析法分离(淋洗剂为石油醚和乙酸乙酯，体积比为30∶1-20∶1)，得到目标产物多取代苯3ac(收率65％)。In a 25 mL round bottom flask, add cinnamaldehyde 1a (0.25 mmol, 33 mg), propyl cyanoacetate 2c (2 mmol, 254 mg), potassium carbonate (0.5 mmol, 69 mg), silver hexafluoroantimonate (0.05 mmol, 17 mg), tetrahydropyrrole (0.05 mmol, 4 mg), p-tert-butylphenol (0.025 mmol, 4 mg), dissolved in 3 mL of chloroform at 80°C under nitrogen Stir for 12 hours. After the completion of the reaction, the mixed solution was cooled to room temperature, extracted three times with saturated brine and dichloromethane (10 ml/time), and the organic phases were combined and dried over anhydrous sodium sulfate. Finally, it was separated by silica gel column chromatography (the eluent was petroleum ether and ethyl acetate, the volume ratio was 30:1-20:1) to obtain the target product polysubstituted benzene 3ac (yield 65%).
按照实施例3类似的制备方法，按照下式反应式，采用不同的原料制备表3中的化合物。According to the similar preparation method of Example 3, according to the following reaction formula, the compounds in Table 3 were prepared by using different raw materials.
表3.以不同氰基乙酸烷基酯为原料制备的化合物Table 3. Compounds prepared from different alkyl cyanoacetates
a)反应条件：1(0.25毫摩尔)，2(2毫摩尔)，AgSbF6(0.05毫摩尔)，吡咯烷(0.05毫摩尔)，K2CO3(0.25毫摩尔)，PTBP(0.025毫摩尔)，氮气存在下，80℃，12h，分离产率。a) Reaction conditions: 1 (0.25 mmol), 2 (2 mmol), AgSbF 6 (0.05 mmol), pyrrolidine (0.05 mmol), K 2 CO 3 (0.25 mmol), PTBP (0.025 mmol) ), in the presence of nitrogen, 80 °C, 12 h, isolated yield.
b)反应中2为1.25毫摩尔。b) 2 is 1.25 mmol in the reaction.
c)反应中2为0.75毫摩尔。c) 2 is 0.75 mmol in the reaction.
此外，还考察了不同氰基乙酸烷基酯2与肉桂醛及其衍生物1的多米诺反应。实验表明，该反应对甲酯、丙酯、异丙酯、正丁酯、叔丁酯和苄酯等不同的酯类均有良好的耐受性。在这个反应中，当用氰基乙酸烷基酯对4-位上带有甲氧基的肉桂醛进行配位反应时，可以顺利地得到所需产物3。In addition, the domino reactions of different alkyl cyanoacetates 2 with cinnamaldehyde and its derivatives 1 were also investigated. Experiments show that the reaction is well tolerated for different esters such as methyl, propyl, isopropyl, n-butyl, tert-butyl and benzyl esters. In this reaction, when the cinnamaldehyde bearing a methoxy group at the 4-position is coordinated with an alkyl cyanoacetate, the desired product 3 can be successfully obtained.
本申请所制备的部分化合物核磁数据如下所示：The NMR data of some compounds prepared in this application are as follows:
1H NMR(CDCl3，400MHz)δ：8.12(d，J＝8.0Hz，1H)，7.57-7.55(m，2H)，7.51-7.45(m，3H)，6.73(d，J＝8.0Hz，2H)，4.41-4.35(m，2H)，1.43(t，J＝7.2Hz，3H). 1 H NMR (CDCl 3 , 400 MHz) δ: 8.12 (d, J=8.0 Hz, 1H), 7.57-7.55 (m, 2H), 7.51-7.45 (m, 3H), 6.73 (d, J=8.0 Hz, 2H), 4.41-4.35 (m, 2H), 1.43 (t, J=7.2Hz, 3H).
1H NMR(CDCl3，400MHz)δ：8.09(d，J＝8.0Hz，1H)，7.53(d，J＝8.0Hz，2H)，7.26(s，1H)，7.01(d，J＝8.0Hz，2H)，6.70(d，J＝8.0Hz，2H)，4.38(d，J＝8.0Hz，2H)，3.86(s，3H)，1.42(t，J＝8.0Hz，3H). 1 H NMR (CDCl 3 , 400 MHz) δ: 8.09 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 2H), 7.26 (s, 1H), 7.01 (d, J=8.0 Hz) , 2H), 6.70 (d, J=8.0Hz, 2H), 4.38 (d, J=8.0Hz, 2H), 3.86 (s, 3H), 1.42 (t, J=8.0Hz, 3H).
1H NMR(CDCl3，400MHz)δ：8.12(d，J＝8.0Hz，1H)，7.47(d，J＝8.0Hz，2H)，7.12(d，J＝16.0Hz，2H)，6.62(d，J＝8.0Hz，3H)，4.34-4.28(m，2H)，1.36(t，J＝8.0Hz，3H). 1 H NMR (CDCl 3 , 400 MHz) δ: 8.12 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.12 (d, J=16.0 Hz, 2H), 6.62 (d , J=8.0Hz, 3H), 4.34-4.28 (m, 2H), 1.36 (t, J=8.0Hz, 3H).
1H NMR(CDCl3，400MHz)δ：8.04(d，J＝8.0Hz，1H)，7.48(t，J＝8.0Hz，4H)，6.74(t，J＝8.0Hz，2H)，4.41-4.36(m，2H)，1.43(t，J＝8.0Hz，3H). 1 H NMR (CDCl 3 , 400 MHz) δ: 8.04 (d, J=8.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 4H), 6.74 (t, J=8.0 Hz, 2H), 4.41-4.36 (m, 2H), 1.43 (t, J=8.0Hz, 3H).
1H NMR(CDCl3，400MHz)δ：8.12(d，J＝8.0Hz，1H)，7.62(d，J＝8.0Hz，2H)，7.41(d，J＝6.0Hz，2H)，6.74(m，3H)，4.41-4.36(m，2H)，1.43(t，J＝8.0Hz，3H). 1 H NMR (CDCl 3 , 400 MHz) δ: 8.12 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 2H), 7.41 (d, J=6.0 Hz, 2H), 6.74 (m , 3H), 4.41-4.36 (m, 2H), 1.43 (t, J=8.0Hz, 3H).
1H NMR(CDCl3，400MHz)δ：8.36(d，J＝8.0Hz，1H)，8.18(d，J＝8.0Hz，1H)，7.74(d，J＝8.0Hz，2H)，6.79(m，3H)，4.43-4.38(m，2H)，1.44(t，J＝8.0Hz，3H). 1 H NMR (CDCl 3 , 400 MHz) δ: 8.36 (d, J=8.0 Hz, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 2H), 6.79 (m , 3H), 4.43-4.38 (m, 2H), 1.44 (t, J=8.0Hz, 3H).
1H NMR(CDCl3，400MHz)δ：7.84(s，1H)，6.39(s，2H)，4.37-4.31(m，2H)，2.83(m，2H)，2.23(s，3H)，1.41(t，J＝8.0Hz，3H)，1.23(t，J＝8.0Hz，3H). 1 H NMR (CDCl 3 , 400 MHz) δ: 7.84 (s, 1H), 6.39 (s, 2H), 4.37-4.31 (m, 2H), 2.83 (m, 2H), 2.23 (s, 3H), 1.41 ( t, J=8.0Hz, 3H), 1.23 (t, J=8.0Hz, 3H).
1H NMR(CDCl3，400MHz)δ：7.97(d，J＝8.0Hz，1H)，6.54(d，J＝8.0Hz，3H)，4.37-4.31(m，2H)，2.48(s，3H)，1.40(m，J＝8.0Hz，3H). 1 H NMR (CDCl 3 , 400 MHz) δ: 7.97 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 3H), 4.37-4.31 (m, 2H), 2.48 (s, 3H) , 1.40(m, J=8.0Hz, 3H).
1H NMR(CDCl3，400MHz)δ：7.92(d，J＝8.0Hz，1H)，6.48(d，J＝8.0Hz，3H)，4.30-4.24(m，2H)，2.68(t，J＝8.0Hz，2H)，1.65-1.60(m，2H)，1.33(t，J＝8.0Hz，3H)，0.93(t，J＝8.0Hz，3H). 1 H NMR (CDCl 3 , 400 MHz) δ: 7.92 (d, J=8.0 Hz, 1H), 6.48 (d, J=8.0 Hz, 3H), 4.30-4.24 (m, 2H), 2.68 (t, J= 8.0Hz, 2H), 1.65-1.60 (m, 2H), 1.33 (t, J=8.0Hz, 3H), 0.93 (t, J=8.0Hz, 3H).
1H NMR(CDCl3，400MHz)δ：8.10(d，J＝8.0Hz，1H)，7.57-7.55(m，2H)，7.51-7.45(m，3H)，6.73(d，J＝8.0Hz，3H)，3.92(s，3H). 1 H NMR (CDCl 3 , 400 MHz) δ: 8.10 (d, J=8.0 Hz, 1H), 7.57-7.55 (m, 2H), 7.51-7.45 (m, 3H), 6.73 (d, J=8.0 Hz, 3H), 3.92(s, 3H).
1H NMR(CDCl3，400MHz)δ：8.12(d，J＝8.0Hz，1H)，7.57-7.55(m，2H)，7.50-7.45(m，3H)，6.73(d，J＝8.0Hz，3H)，4.30(t，J＝8.0Hz，2H)，1.83-1.78(m，2H)，1.06(t，J＝8.0Hz，3H). 1 H NMR (CDCl 3 , 400 MHz) δ: 8.12 (d, J=8.0 Hz, 1H), 7.57-7.55 (m, 2H), 7.50-7.45 (m, 3H), 6.73 (d, J=8.0 Hz, 3H), 4.30(t, J=8.0Hz, 2H), 1.83-1.78(m, 2H), 1.06(t, J=8.0Hz, 3H).
1H NMR(DMSO-d6，400MHz)δ：8.07(d，J＝8.0Hz，1H)，7.55(t，J＝8.0Hz，5H)，7.26(s，2H)，6.78(d，J＝8.0Hz，1H)，5.20-5.12(m，1H)，1.35(d，J＝8.0Hz，6H). 1 H NMR (DMSO-d 6 , 400 MHz) δ: 8.07 (d, J=8.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 5H), 7.26 (s, 2H), 6.78 (d, J= 8.0Hz, 1H), 5.20-5.12 (m, 1H), 1.35 (d, J=8.0Hz, 6H).
1H NMR(DMSO-d6，400MHz)δ：8.04(d，J＝8.0Hz，1H)，7.55(d，J＝8.0Hz，2H)，7.22(s，2H)，7.10(d，J＝12.0Hz，2H)，6.76(d，J＝12.0Hz，1H)，5.20-5.11(m，1H)，3.83(s，3H)，1.34(d，J＝8.0Hz，6H). 1 H NMR (DMSO-d 6 , 400 MHz) δ: 8.04 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.22 (s, 2H), 7.10 (d, J= 12.0Hz, 2H), 6.76 (d, J=12.0Hz, 1H), 5.20-5.11 (m, 1H), 3.83 (s, 3H), 1.34 (d, J=8.0Hz, 6H).
1H NMR(CDCl3，400MHz)δ：8.11(d，J＝8.0Hz，1H)，7.56(t，J＝8.0Hz，2H)，7.50-7.45(m，2H)，6.73(d，J＝8.0Hz，3H)，4.34(t，J＝8.0Hz，2H)，1.80-1.73(m，2H)，1.51-1.46(m，2H)，1.01(t，J＝8.0Hz，3H). 1 H NMR (CDCl 3 , 400 MHz) δ: 8.11 (d, J=8.0 Hz, 1H), 7.56 (t, J=8.0 Hz, 2H), 7.50-7.45 (m, 2H), 6.73 (d, J= 8.0Hz, 3H), 4.34 (t, J=8.0Hz, 2H), 1.80-1.73 (m, 2H), 1.51-1.46 (m, 2H), 1.01 (t, J=8.0Hz, 3H).
1H NMR(CDCl3，400MHz)δ：8.07(d，J＝8.0Hz，1H)，7.53(d，J＝8.0Hz，2H)，7.01(d，J＝8.0Hz，2H)，6.71(d，J＝8.0Hz，2H)，3.91(d，J＝20.0Hz，6H). 1 H NMR (CDCl 3 , 400 MHz) δ: 8.07 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 6.71 (d , J=8.0Hz, 2H), 3.91 (d, J=20.0Hz, 6H).
1H NMR(CDCl3，400MHz)δ：8.15(d，J＝8.0Hz，1H)，7.55-7.36(m，9H)，6.72(d，J＝8.0Hz，2H)，5.36(d，J＝8.0Hz，2H). 1 H NMR (CDCl 3 , 400 MHz) δ: 8.15 (d, J=8.0 Hz, 1H), 7.55-7.36 (m, 9H), 6.72 (d, J=8.0 Hz, 2H), 5.36 (d, J= 8.0Hz, 2H).
1H NMR(CDCl3，400MHz)δ：8.11(d，J＝8.0Hz，1H)，7.53-7.35(m，7H)，7.00(d，J＝8.0Hz，2H)，6.80-6.66(m，3H)，5.34(s，2H)，3.85(s，3H). 1 H NMR (CDCl 3 , 400 MHz) δ: 8.11 (d, J=8.0 Hz, 1H), 7.53-7.35 (m, 7H), 7.00 (d, J=8.0 Hz, 2H), 6.80-6.66 (m, 3H), 5.34(s, 2H), 3.85(s, 3H).
1H NMR(CDCl3，400MHz)δ：8.10(d，J＝8.0Hz，1H)，7.42-7.40(m，3H)，7.33-7.31(m，2H)，7.10(d，J＝8.0Hz，2H)，6.65(d，J＝8.0Hz，2H)，4.41-4.36(m，2H)，1.43(t，J＝8.0Hz，3H). 1 H NMR (CDCl 3 , 400 MHz) δ: 8.10 (d, J=8.0 Hz, 1H), 7.42-7.40 (m, 3H), 7.33-7.31 (m, 2H), 7.10 (d, J=8.0 Hz, 2H), 6.65 (d, J=8.0Hz, 2H), 4.41-4.36 (m, 2H), 1.43 (t, J=8.0Hz, 3H).
对照实验：没有吡咯烷的标准条件下(eq.1)的制备过程：Control experiment: Preparation process under standard conditions (eq.1) without pyrrolidine:
在25毫升圆底烧瓶中加入肉桂醛1a(0.25毫摩尔，33毫克)，氰乙酸乙酯2a(2毫摩尔，226毫克)，碳酸钾(0.25毫摩尔，35毫克)，六氟锑酸银(0.025毫摩尔，9毫克)，溶解在3毫升三氯甲烷中，在氮气保护下80℃搅拌12小时。反应完成后将混合溶液冷却至室温，经过液质联用技术检测，没有发现相应的目标产物多取代苯3aa。In a 25 mL round bottom flask were added cinnamaldehyde 1a (0.25 mmol, 33 mg), ethyl cyanoacetate 2a (2 mmol, 226 mg), potassium carbonate (0.25 mmol, 35 mg), silver hexafluoroantimonate (0.025 mmol, 9 mg), dissolved in 3 mL of chloroform, and stirred at 80°C for 12 hours under nitrogen protection. After the completion of the reaction, the mixed solution was cooled to room temperature, and the corresponding target product polysubstituted benzene 3aa was not found through the detection by liquid chromatography-mass spectrometry.
按照(eq.1)类似的制备方法，按照下式反应式，采用不同的原料以及条件制备相应化合物，并探讨最优条件。According to the similar preparation method of (eq.1), according to the following reaction formula, the corresponding compounds are prepared by using different raw materials and conditions, and the optimal conditions are discussed.
为了深入了解多米诺骨牌反应的机理，进行了一系列实验。在没有吡咯烷的标准条件下(eq.1)，对2a和1a的底物进行了处理，未检测到所需的产物3aa。类似地，我们分别在不存在AgSbF6(eq.2)和K2CO3(eq.3)的情况下进行反应，得到低产率或无产率的3aa。这些实验表明，吡咯烷、AgSbF6和K2CO3在该反应中起重要的作用。然后，在标准条件(eq.4)下使用4和2b，未发现所需的产物3aa。根据上述实验，我们得出的结论是，反应可能首先涉及迈克尔加成，然后是Knoevenagel缩合和Thorpe-Ziegler环化。为了验证我们的假设，我们根据文献使用1a和硝基甲烷获得迈克尔加成产物6，[14]然后将1a(8eq)不经分离注入反应体系中，在标准条件下产生所需产物7[15]产率为40％。To gain insight into the mechanism of the domino reaction, a series of experiments were performed. Substrates of 2a and 1a were processed under standard conditions without pyrrolidine (eq. 1) and the desired product 3aa was not detected. Similarly, we performed the reactions in the absence of AgSbF6 (eq. 2 ) and K2CO3 (eq. 3 ), respectively, to give 3aa in low or no yield. These experiments show that pyrrolidine, AgSbF 6 and K 2 CO 3 play important roles in this reaction. Then, using 4 and 2b under standard conditions (eq. 4), the desired product 3aa was not found. From the above experiments, we conclude that the reaction may first involve Michael addition followed by Knoevenagel condensation and Thorpe-Ziegler cyclization. To test our hypothesis, we used 1a and nitromethane to obtain the Michael addition product 6 according to the literature, [14] and then injected 1a (8eq) into the reaction system without separation to yield the desired product 7 under standard conditions [15 ] The yield was 40%.
根据上述不同化合物的制备以及不同反应条件的优化，我们推断本申请所述反应的机理如下：According to the preparation of the above-mentioned different compounds and the optimization of different reaction conditions, we infer that the mechanism of the reaction described in this application is as follows:
基于上述实验结果和文献，[8，9]在上述反应式中描述了多米诺反应的可能机理。最初，1a和2a可以在K2CO3存在下形成迈克尔加成产物8。然后以吡咯烷作为有机催化剂，在8和1b之间发生Knoevenagel缩合得到9。当AgSbF6活化腈基时，中间体10易于通过分子内Thorpe-Ziegler反应形成11。随后，在K2CO3或AgSbF6 [16]的存在下，11转化为12，同时HCOOEt被消除。最后，中间体12涉及芳构化过程并生成了3aa。Based on the above experimental results and literature, [8, 9] described the possible mechanism of the domino reaction in the above reaction formula. Initially, 1a and 2a can form Michael addition product 8 in the presence of K2CO3. Knoevenagel condensation between 8 and 1b then gave 9 using pyrrolidine as an organic catalyst. When AgSbF6 activates the nitrile group, the intermediate 10 readily forms 11 via the intramolecular Thorpe-Ziegler reaction. Subsequently, 11 was converted to 12 in the presence of K2CO3 or AgSbF6 [ 16 ] , while HCOOEt was eliminated. Finally, intermediate 12 was involved in the aromatization process and yielded 3aa.
综上所述，通过吡咯烷作为有机催化剂，以AgSbF6作为过渡金属催化剂，经迈克尔加成，Knoevenagel缩合，Thorpe-Ziegler型环化脱羧。所用原料都是市售的α，β-不饱和醛和各种氰基乙酸酯，为合成多取代苯提供了一种具有更加环保、操作简单和实际可行性的方法。To sum up, the Thorpe-Ziegler-type cyclodecarboxylation was performed by Michael addition, Knoevenagel condensation, and AgSbF6 as transition metal catalyst via pyrrolidine as an organic catalyst. The raw materials used are all commercially available α,β-unsaturated aldehydes and various cyanoacetates, which provide a more environmentally friendly, simple and practical method for synthesizing polysubstituted benzene.
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