CN116621802A - Method for synthesizing 3, 4-dibenzoisocoumarin and derivatives thereof through palladium-catalyzed cascade cyclization reaction - Google Patents
Method for synthesizing 3, 4-dibenzoisocoumarin and derivatives thereof through palladium-catalyzed cascade cyclization reaction Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000007363 ring formation reaction Methods 0.000 title claims abstract description 19
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 39
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 18
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 239000003446 ligand Substances 0.000 claims abstract description 7
- 229910003002 lithium salt Inorganic materials 0.000 claims abstract description 7
- 159000000002 lithium salts Chemical class 0.000 claims abstract description 7
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 7
- 230000003197 catalytic effect Effects 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 239000012429 reaction media Substances 0.000 claims abstract description 3
- 150000001559 benzoic acids Chemical class 0.000 claims abstract 3
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 44
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 42
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 23
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 22
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C SACNIGZYDTUHKB-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 claims description 2
- 125000005561 phenanthryl group Chemical group 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- GEPJPYNDFSOARB-UHFFFAOYSA-N tris(4-fluorophenyl)phosphane Chemical compound C1=CC(F)=CC=C1P(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 GEPJPYNDFSOARB-UHFFFAOYSA-N 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 25
- 230000015572 biosynthetic process Effects 0.000 abstract description 24
- IQZZFVDIZRWADY-UHFFFAOYSA-N isocoumarin Chemical compound C1=CC=C2C(=O)OC=CC2=C1 IQZZFVDIZRWADY-UHFFFAOYSA-N 0.000 abstract description 17
- 239000000758 substrate Substances 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 4
- 239000007800 oxidant agent Substances 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract description 3
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 120
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- 238000005481 NMR spectroscopy Methods 0.000 description 40
- 238000004440 column chromatography Methods 0.000 description 40
- 239000000047 product Substances 0.000 description 40
- 238000003756 stirring Methods 0.000 description 40
- -1 lactone compound Chemical class 0.000 description 39
- 239000012074 organic phase Substances 0.000 description 38
- 150000001875 compounds Chemical class 0.000 description 23
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 238000012512 characterization method Methods 0.000 description 20
- 238000001035 drying Methods 0.000 description 20
- 239000003480 eluent Substances 0.000 description 20
- 238000001914 filtration Methods 0.000 description 20
- 238000010438 heat treatment Methods 0.000 description 20
- 239000012046 mixed solvent Substances 0.000 description 20
- 239000003208 petroleum Substances 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- 238000005406 washing Methods 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 20
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 150000002512 isocoumarins Chemical class 0.000 description 10
- 238000010586 diagram Methods 0.000 description 8
- WILOFNBKMCNOPK-UHFFFAOYSA-N tert-butyl 2-(2-phenylethynyl)benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1C#CC1=CC=CC=C1 WILOFNBKMCNOPK-UHFFFAOYSA-N 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- VUVIRKAVBZITDO-UHFFFAOYSA-N 1-bromonaphthalene-2-carboxylic acid Chemical compound C1=CC=CC2=C(Br)C(C(=O)O)=CC=C21 VUVIRKAVBZITDO-UHFFFAOYSA-N 0.000 description 1
- KJKUTYSDSVMXDM-UHFFFAOYSA-N 2-(2-bromophenyl)-1-phenylethanone Chemical compound BrC1=CC=CC=C1CC(=O)C1=CC=CC=C1 KJKUTYSDSVMXDM-UHFFFAOYSA-N 0.000 description 1
- HWFCHCRFQWEFMU-UHFFFAOYSA-N 2-bromo-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(Br)=C(C(O)=O)C=C1OC HWFCHCRFQWEFMU-UHFFFAOYSA-N 0.000 description 1
- USMQLFCVCDEXAK-UHFFFAOYSA-N 2-bromo-4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1Br USMQLFCVCDEXAK-UHFFFAOYSA-N 0.000 description 1
- ZZYYOHPHSYCHQG-UHFFFAOYSA-N 2-bromo-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(Br)=C1 ZZYYOHPHSYCHQG-UHFFFAOYSA-N 0.000 description 1
- ODHJOROUCITYNF-UHFFFAOYSA-N 2-bromo-5-methoxybenzoic acid Chemical compound COC1=CC=C(Br)C(C(O)=O)=C1 ODHJOROUCITYNF-UHFFFAOYSA-N 0.000 description 1
- ZXMISUUIYPFORW-UHFFFAOYSA-N 2-bromo-5-methylbenzoic acid Chemical compound CC1=CC=C(Br)C(C(O)=O)=C1 ZXMISUUIYPFORW-UHFFFAOYSA-N 0.000 description 1
- DMEZDDHJCUHENA-UHFFFAOYSA-N 8-bromonaphthalene-1-carboxylic acid Chemical compound C1=CC(Br)=C2C(C(=O)O)=CC=CC2=C1 DMEZDDHJCUHENA-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- UUDYWELSMJWOIM-UHFFFAOYSA-N isochromen-6-one Chemical compound O1C=CC2=CC(=O)C=CC2=C1 UUDYWELSMJWOIM-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229910052716 thallium Inorganic materials 0.000 description 1
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
Abstract
The invention discloses a method for synthesizing 3, 4-dibenzo-isocoumarin and derivatives thereof by palladium catalytic cascade cyclization reaction, which takes an organic solvent as a reaction medium, takes o-alkynyl benzoate and o-halogenated benzoic acid as raw materials, reacts under the action of a palladium catalyst, phosphine ligand, lithium salt and alkali, and is separated and purified to obtain the 3, 4-dibenzo-isocoumarin and derivatives thereof. The invention can promote the conversion of palladium (0) into palladium (II) to participate in circulation without adding an additional oxidant, realizes the synthesis of fused isocoumarin which cannot be prepared by the traditional method, and has wide substrate application range and good chemical selectivity.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 3, 4-dibenzoisocoumarin and derivatives thereof by catalyzing o-alkynyl benzoate and o-halogenated benzoic acid with palladium.
Background
Isocoumarin is a lactone compound with a benzo chromene ketone skeleton structure, and is widely distributed in nature and various. Scientific researches show that the isocoumarin derivative not only has physiological and biological activities such as antibiosis, antiphlogosis, anticancer, protease activity inhibition, inoxidizability and the like, but also is a key intermediate in the process of synthesizing heterocyclic compounds. Recent studies have shown that isocoumarin derivatives have significant anticancer activity. In order to study the structure-activity relationship of the compounds, it is important to develop a medicament with practical value and develop a more efficient method for constructing the skeleton.
The study on isocoumarins has been traced back to the 70 s of the last century, and so far, many synthetic methods of isocoumarins have been developed, and more classical methods of chroman catalytic oxidation, cyclocondensation, indene oxidation, etc. have been developed. Among them, the metal catalysis method is the most commonly used method for synthesizing isocoumarin, and the most commonly used catalyst mainly comprises thallium, palladium, lithium and complexes thereof. In recent years, palladium-catalyzed cascade cyclization has attracted great interest due to its high efficiency and diversity in building complex molecules, and has become a highly efficient strategy for building multicyclic backbones.
In 2012, the Li group reports cascade reactions of 2-alkynyl benzoate and electron-deficient olefins under palladium catalysis to synthesize 4-substituted isocoumarins. The Lu group reported in 2016 that palladium catalyzes the intramolecular cascade cyclization of orthoalkynyl benzoates to rapidly synthesize fused isocoumarins. The Jiang subject group establishes an efficient and reliable 3-substituted isocoumarin synthesis method in 2017 through palladium-catalyzed nucleophilic addition/oxidation cyclization reaction of bromoalkyne and benzoic acid. In the same year, zhu group reported that phenyl formate reacted with 2-bromobenzyl phenyl ketone under palladium catalysis to rapidly synthesize 3, 4-disubstituted isocoumarins. However, the above methods for synthesizing isocoumarin derivatives have the following problems: 1. the raw materials need halogenation and the atom utilization rate is low; 2. poor chemical selectivity and limited substrate application range; 3. the reaction yield is not high and the byproducts are more.
Therefore, it is important to develop a synthetic method of isocoumarin derivatives with wide application range of the substrate starting from cheap and easily available substrates.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a method for synthesizing 3, 4-dibenzoisocoumarin and derivatives thereof by palladium catalytic cascade cyclization reaction, which can promote palladium (0) to be converted into palladium (II) to participate in circulation without adding an additional oxidant, realizes the synthesis of fused isocoumarin which cannot be prepared by the traditional method, and has wide substrate application range and good chemical selectivity.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
the method for synthesizing 3, 4-dibenzoisocoumarin and derivatives thereof by palladium catalytic cascade cyclization reaction takes an organic solvent as a reaction medium, takes o-alkynyl benzoate and o-halogenated benzoic acid as raw materials, reacts under the action of a palladium catalyst, phosphine ligand, lithium salt and alkali, and obtains the 3, 4-dibenzoisocoumarin and derivatives thereof after separation and purification, wherein the reaction equation is shown in a formula 1:
wherein R is 1 、R 2 And R is 3 Independently selected from hydrogen atoms, halogen atoms, C 1 ～C 8 Alkyl, C of (2) 1 ～C 8 Alkoxy, cyano, nitro, aryl, heteroaryl or C containing substituents 1 ～C 8 May be one or more and is not limited in position.
The halogen atom refers to fluorine, chlorine or bromine.
The above C 1 ～C 8 Alkyl of (2) means a straight or branched chain saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms such as methyl, ethyl, isopropyl, t-butyl, etc.;
the above C 1 ～C 8 The alkoxy group of (a) means a group having an oxygen atom attached to the terminal of an alkyl group having 1 to 8 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
The aryl group includes phenyl, naphthyl, anthryl, phenanthryl or C-containing 1 ～C 8 Alkyl, C of (2) 1 ～C 8 At least one of an alkoxy group, a halogen atom, a cyano group, and a nitro groupThe phenyl group of the substituent may have one or more substituents, and the substituted position is not limited.
The heterocyclic aryl includes five-membered or six-membered ring substituents such as furan, thiophene, pyridine and the like, and the substituent may be one or more, and the substituted position is not limited.
The above substituent-containing C 1 ～C 8 An alkyl group of (C) may contain a halogen atom or a C atom on any one of carbon atoms 1 ～C 8 At least one substituent selected from the group consisting of alkoxy, cyano, nitro, aryl and heteroaryl.
X is a halogen atom, such as one of fluorine, chlorine and bromine.
Preferably, the palladium catalyst is one or more of tetrakis (triphenylphosphine) palladium, palladium acetate, palladium trifluoroacetate, bis (triphenylphosphine) palladium dichloride, palladium bromide and palladium chloride.
Preferably, the phosphine ligand is selected from one or more of 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl, triphenylphosphine, tricyclohexylphosphine, tris (4-fluorophenyl) phosphine, 2-dicyclohexylphosphine-2 ',6' -diisopropyloxy-1, 1' -biphenyl and 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl.
Preferably, the base is selected from one or more of cesium carbonate, potassium phosphate and potassium t-butoxide.
Preferably, the lithium salt is selected from one or more of lithium chloride, lithium bromide and lithium acetate.
Preferably, the organic solvent is selected from one or more of N, N-dimethylacetamide, dimethylsulfoxide, N-dimethylformamide, acetonitrile and 1, 4-dioxane.
Preferably, the molar ratio of the orthoalkynyl benzoate, the orthohalogenated benzoic acid, the palladium catalyst, the phosphine ligand and the lithium salt to the alkali is 1:2-3:0.05-0.1:0.1-0.2:2-4:2-4.
Preferably, the reaction temperature is 90-140 ℃ and the reaction time is 8-16 h.
The invention has the advantages that:
compared with the traditional method for constructing isocoumarin by palladium catalytic cascade cyclization, the method can promote the conversion of palladium (0) into palladium (II) to participate in circulation without adding an additional oxidant; the synthesis of fused isocoumarin which can not be prepared by the traditional method, in particular to the synthesis of 3, 4-dibenzoisocoumarin, has good chemical selectivity, no isomer and single configuration.
Drawings
FIG. 1 shows a compound prepared in example 1 of the present invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 2 shows a compound prepared in example 1 of the present invention 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 3 shows a compound prepared in example 4 of the present invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 4 is a diagram of a compound prepared in example 4 of the present invention 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 5 shows a compound prepared in example 5 of the present invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 6 shows a compound prepared in example 5 of the present invention 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 7 is a schematic illustration of a compound prepared in accordance with example 7 of the present invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 8 is a diagram of a compound prepared in example 7 of the present invention 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 9 is a diagram of a compound prepared in example 9 of the present invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 10 is a diagram of a compound prepared in example 9 of the present invention 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 11 is a diagram of a compound prepared in example 10 of the present invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 12 is a diagram of a compound prepared in example 10 of the present invention 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 13 is a schematic illustration of a compound prepared in accordance with example 11 of the present invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 14 is a schematic illustration of a compound prepared in accordance with example 11 of the present invention 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 15 is a schematic illustration of a compound prepared in example 12 of the present invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 16 shows a compound prepared in example 12 of the present invention 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 17 is a diagram showing a compound prepared in example 17 of the present invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 18 is a diagram showing a compound prepared in example 17 of the present invention 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 19 is a drawing of a compound prepared in example 19 of the present invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 20 is a drawing of a compound prepared in example 19 of the present invention 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 21 is a drawing of a compound prepared in example 20 of the present invention 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 22 shows a compound prepared in example 20 of the present invention 13 Nuclear magnetic resonance spectrum of C-NMR.
Detailed Description
In order to make the technical solution of the present invention better understood by those skilled in the art, the present invention will be further described in detail with reference to specific embodiments, but the scope of the present invention is not limited thereto.
Example 1
Synthesis of 6H-tribenzo [ c, f, H ] chromen-6-one (3 a)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of o-bromobenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- (phenylethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 74%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.71-8.67(m,2H),8.63(d,J＝9.5Hz,2H),8.53(dd,J＝17,8.5Hz,2H),7.88-7.85(m,1H),7.77-7.75(m,1H),7.72-7.69(m,1H),7.67-7.61(m,3H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.22,146.68,135.46,134.29,131.29,130.55,128.90,128.87,128.07,127.62,127.57,127.14,126.55,126.12,126.02,123.64,123.60,123.12,122.49,122.45,110.11.
example 2
Synthesis of 8-methyl-6H-tribenzo [ c, f, H ] chromen-6-one (3 b)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of o-bromobenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 5-methyl-2- (phenylethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 80%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.66–8.64(m,1H),8.62–8.61(m,1H),8.58(d,J＝8.5Hz,2H),8.38(d,J＝8.0Hz,1H),8.28(d,J＝2.0Hz,1H),7.73–7.66(m,2H),7.64–7.61(m,3H),2.53(s,3H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.35,146.18,138.38,135.46,132.91,131.05,130.34,128.83,128.63,127.71,127.49,127.04,126.48,126.03,125.99,123.67,123.59,123.01,122.44,122.32,110.18.
example 3
Synthesis of 8-chloro-6H-tribenzo [ c, f, H ] chromen-6-one (3 c)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of o-bromobenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 5-chloro-2- (phenylethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 38%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.68–8.66(m,1H),8.61–8.55(m,3H),8.48(d,J＝2.0Hz,1H),8.41(d,J＝8.5Hz,1H),7.78–7.74(m,1H),7.71–7.66(m,3H),7.56(dd,J＝10,2.0Hz,1H).
13 C NMR(CDCl 3 ,125MHz)δ＝160.44,147.48,141.29,136.85,132.13,131.55,129.35,128.93,128.85,128.44,127.70,127.50,127.20,126.37,126.25,125.52,125.40,123.75,123.34,123.26,122.53,120.67,109.09.
example 4
Synthesis of 8-methoxy-6H-tribenzo [ c, f, H ] chromen-6-one (3 d)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of o-bromobenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 5-methoxy-2- (phenylethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove solvent, separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1-10:1: ethyl acetate mixed solvent, yield 63%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.59–8.57(m,1H),8.53–8.48(m,3H),8.3(d,J＝9.0Hz,1H),7.84(d,J＝2.5Hz,1H),7.68–7.62(m,2H),7.60–7.54(m,2H),7.34(dd,J＝9.0,3.0Hz,1H),3.95(s,3H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.28,159.19,145.41,130.80,128.91,128.45,128.20,127.65,127.53,127.05,126.04,123.81,123.70,123.64,123.44,122.84,122.47,111.28,110.20,55.89.
example 5
Synthesis of 8-fluoro-6H-tribenzo [ c, f, H ] chromen-6-one (3 e)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of o-bromobenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 5-fluoro-2- (phenylethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 41%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.61(d,J＝7.5Hz,1H),8.54–8.42(m,4H),8.09(d,J＝9.0Hz,1H),7.72–7.58(m,4H),7.53–7.49(m,1H).
13 C NMR(CDCl 3 ,125MHz)δ＝162.56,160.57,160.21,146.16,131.92,131.12,128.95,128.87,127.65,127.25,126.26,125.69,123.69,123.37,122.97,122.48,122.41,122.23,116.19,116.01,109.46.
example 6
Synthesis of 12-methyl-6H-tribenzo [ c, f, H ] chromen-6-one (3 f)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of 2-bromo-5-methylbenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- (phenylethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 57%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.51(dd,J＝8.0,1.5Hz,1H),8.48–8.44(m,3H),8.41(d,J＝8.0Hz,1H),8.31(s,1H),7.82–7.78(m,1H),7.68–7.65(m,1H),7.61(td,J＝8.5,1.5Hz,1H),7.59–7.56(m,1H),7.39(dd,J＝8.5,1.5Hz,1H),2.53(s,3H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.17,146.66,136.94,135.48,134.85,134.14,131.25,130.44,129.64,128.83,128.75,127.87,127.64,127.60,127.01,126.57,126.42,125.96,125.69,125.22,123.46,123.12,123.01,122.34,122.21,109.76,21.94.
example 7
Synthesis of 13-methyl-6H-tribenzo [ c, f, H ] chromen-6-one (3 g)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of 2-bromo-4-methylbenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- (phenylethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 64%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.55(dd,J＝8.0,1.5Hz,2H),8.49–8.45(m,3H),8.40(s,1H),7.84–7.80(m,1H),7.71–7.68(m,1H),7.67–7.63(m,1H),7.59(t,J＝7.5Hz,1H),7.42(dd,J＝8.5,2.0Hz,1H),2.60(s,3H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.25,146.13,135.78,135.54,134.18,131.01,130.49,128.91,128.84,128.66,127.92,127.37,126.49,125.84,125.33,125.24,123.66,123.46,123.05,122.43,110.03,21.74.
example 8
Synthesis of 12-methoxy-6H-tribenzo [ c, f, H ] chromen-6-one (3H)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of 2-bromo-5-methoxybenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- (phenylethynyl) benzoate, 2mL of DMF, and a stirrer was added. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying with anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove solvent, separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1-10:1: ethyl acetate mixed solvent, yield 62%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.50–8.45(m,4H),8.40(d,J＝8.0Hz,1H),7.98(d,J＝2.5Hz,1H),7.81–7.78(m,1H),7.67–7.64(m,1H),7.59–7.56(m,2H),7.20(dd,J＝9.5,3.0Hz,1H),3.93(s,3H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.15,158.68,147.22,135.57,134.23,131.38,130.59,129.03,128.95,127.95,126.49,125.84,125.19,123.11,122.94,122.51,122.35,121.95,114.54,109.64,108.79,55.55.
example 9
Synthesis of 12, 13-dimethoxy-6H-tribenzo [ c, f, H ] chromen-6-one (3 i)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of 2-bromo-4, 5-dimethoxybenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- (phenylethynyl) benzoate, and 2mL of DMF, and a stirrer was added. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 10:1: ethyl acetate mixed solvent, yield 50%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.58–8.50(m,3H),8.45(d,J＝8.0Hz,1H),8.05(s,1H),7.98(s,1H),7.87–7.84(m,1H),7.73–7.70(m,1H),7.65–7.60(m,2H),4.13(s,3H),4.05(s,3H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.29,149.45,148.45,145.90,135.75,134.23,130.79,130.74,128.64,128.00,126.61,125.63,123.61,123.21,122.79,122.58,122.31,122.06,109.86,107.22,104.40,56.11,56.03.
example 10
Synthesis of 13-chloro-6H-tribenzo [ c, f, H ] chromen-6-one (3 j)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of 2-bromo-4-chlorobenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- (phenylethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 63%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.60–8.56(m,3H),8.51(d,J＝7.5Hz,2H),8.42(d,J＝8.0Hz,1H),7.89–7.86(m,1H),7.77–7.71(m,2H),7.64(t,J＝7.5Hz,1H),7.58(dd,J＝9.0,2.0Hz,1H).
13 C NMR(CDCl 3 ,125MHz)δ＝160.93,146.75,135.11,134.49,132.23,130.75,130.25,129.21,128.37,128.28,127.46,126.34,126.03,124.00,123.37,123.26,122.59,122.52,109.85.
example 11
Synthesis of 2H-dibenzo [ c, H ] naphtho [2,1-f ] chromen-2-one (3 k)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of 1-bromo-2-naphthoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- (phenylethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 46%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.93–8.87(m,2H),8.72–8.70(m,1H),8.50(dd,J＝7.5,1.5Hz,1H),8.44(d,J＝8.5Hz,1H),8.40(d,J＝8.0Hz,1H),7.99(dd,J＝7.0,2.0Hz,1H),7.85–7.79(m,2H),7.70–7.59(m,5H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.20,146.48,135.36,134.22,132.51,130.78,130.63,129.88,128.20,128.15,127.93,127.90,126.89,126.82,126.75,126.39,126.26,126.17,123.73,123.07,122.54,110.28.
example 12
Synthesis of 6H-benzo [6,7] naphtho [1',8':3,4,5] cyclohepta [1,2-c ] isochromen-6-one (3 l)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of 8-bromo-1-naphthoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- (phenylethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 40%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.35(d,J＝7.5Hz,1H),8.19–8.17(m,1H),7.83–7.77(m,3H),7.57–7.44(m,7H),7.10–7.05(m,2H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.93,149.42,142.03,140.51,139.13,136.39,134.05,133.84,133.58,131.07,130.80,130.25,129.65,129.43,128.23,127.67,127.61,127.47,127.41,126.92,126.53,124.75,124.34,121.82,117.02.
example 13
Synthesis of 2-methyl-6H-tribenzo [ c, f, H ] chromen-6-one (3 m)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of o-bromobenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- (p-tolylethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 64%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.66–8.62(m,2H),8.52–8.47(m,3H),8.37(s,1H),7.86–7.82(m,1H),7.63–7.58(m,3H),7.51(d,J＝8.5Hz,1H),2.63(s,3H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.35,146.96,139.11,135.67,134.27,131.47,130.56,129.26,128.68,127.84,127.02,126.45,126.01,125.94,123.63,123.08,122.39,122.33,121.51,109.32,22.30.
example 14
Synthesis of 1-methyl-6H-tribenzo [ c, f, H ] chromen-6-one (3 n)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of o-bromobenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- (3-methylphenylethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 51%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.61–8.58(m,2H),8.51–8.43(m,3H),8.36(d,J＝9.5Hz,1H),7.86–7.82(m,1H),7.61–7.58(m,3H),7.54–7.51(m,1H),2.58(s,3H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.39,146.03,137.67,135.60,134.26,130.63,130.53,129.20,128.96,127.98,127.23,126.69,126.57,126.02,123.58,123.41,122.63,122.43,109.95,21.69.
example 15
Synthesis of 2-methoxy-6H-tribenzo [ c, f, H ] chromen-6-one (3 o)
To the reaction tube were added, in order, 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of o-bromobenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- ((4-methoxyphenyl) ethynyl) benzoate, 2mL of DMF, and a stirrer was added. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 60%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.59–8.58(m,1H),8.54–8.52(m,1H),8.47–8.44(m,3H),7.90(d,J＝2.5Hz,1H),7.81(t,J＝7.0Hz,1H),7.60–7.55(m,3H),7.26(dd,J＝9.0,2.5Hz,1H),4.02(s,3H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.30,160.25,146.93,135.71,134.22,133.07,130.49,128.24,128.20,127.52,127.20,126.19,125.97,125.71,124.92,123.61,121.97,117.82,116.90,108.03,104.43,55.54.
example 16
Synthesis of 1-methoxy-6H-tribenzo [ c, f, H ] chromen-6-one (3 p)
To the reaction tube were added, in order, 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of o-bromobenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- ((3-methoxyphenyl) ethynyl) benzoate, 2mL of DMF, and a stirrer was added. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 53%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.59(d,J＝8.0Hz,1H),8.55–8.46(m,4H),7.88–7.83(m,2H),7.62–7.55(m,3H),7.31(dd,J＝9.0,3.0Hz,1H),4.01(s,3H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.31,159.16,146.24,135.54,134.29,130.53,128.96,128.09,126.73,126.47,126.15,126.13,126.03,125.60,124.89,124.27,123.08,122.45,119.83,110.65,102.79,55.85.
example 17
Synthesis of 2-chloro-6H-tribenzo [ c, f, H ] chromen-6-one (3 q)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of o-bromobenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- (4-chlorophenyl ethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 35%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.62(d,J＝6.5Hz,1H),8.55(d,J＝8.5Hz,1H),8.52–8.48(m,4H),7.87(t,J＝8.0Hz,1H),7.67–7.61(m,4H).
13 C NMR(CDCl 3 ,125MHz)δ＝160.90,146.23,135.32,135.20,134.42,132.40,130.68,128.34,128.14,128.07,127.82,126.56,126.39,126.11,124.77,123.73,122.48,122.34,121.96,110.34.
example 18
Synthesis of 4-chloro-6H-tribenzo [ c, f, H ] chromen-6-one (3 r)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of o-bromobenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- (2-chlorophenyl ethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 40%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.57–8.55(m,1H),8.53–8.49(m,2H),8.46(dd,J＝8.0,1.5Hz,1H),8.39(d,J＝8.5Hz,1H),7.85–7.81(m,1H),7.71(d,J＝8.0Hz,1H),7.64–7.59(m,3H),7.55(t,J＝8.0Hz,1H).
13 C NMR(CDCl 3 ,125MHz)δ＝160.29,146.14,135.00,134.05,134.02,131.69,131.12,130.10,128.51,128.45,128.35,127.68,127.45,126.99,126.51,125.98,124.14,122.31,121.69,120.92,111.65.
example 19
Synthesis of 2-ethyl-6H-tribenzo [ c, f, H ] chromen-6-one (3 s)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of o-bromobenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- (4-ethylphenylethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, yield 70%.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.69–8.67(m,1H),8.65–8.63(m,1H),8.53–8.48(m,3H),8.40(s,1H),7.86–7.82(m,1H),7.64–7.58(m,3H),7.55(dd,J＝8.5,2.0Hz,1H),2.93(q,J＝8.0Hz,2H),1.40(t,J＝7.5Hz,3H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.38,146.97,145.38,135.68,134.27,131.54,130.56,128.81,128.18,127.85,127.02,126.45,126.03,125.93,123.65,123.22,122.33,121.74,121.19,109.36,29.60,15.74.
example 20
Synthesis of 2-tert-butyl-6H-tribenzo [ c, f, H ] chromen-6-one (3 t)
To the reaction tube were successively added 0.02mmol of palladium chloride, 0.04mmol of XPhos, 0.6mmol of o-bromobenzoic acid, 0.6mmol of cesium carbonate, 0.8mmol of lithium bromide, 0.2mmol of tert-butyl 2- (4-tert-butylphenylethynyl) benzoate, 2mL of DMF and a stirrer. After the reactor was then left to react at 120℃with stirring for 12 hours, the heating and stirring were stopped and the reactor was cooled to room temperature. Washing the reaction solution with saturated saline water, extracting with ethyl acetate, merging organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain a target product, wherein the used column chromatography eluent is petroleum ether with the volume ratio of 30:1: ethyl acetate mixed solvent, 67% yield.
The structural characterization data of the obtained product are as follows:
1 H NMR(CDCl 3 ,500MHz)δ＝8.75–8.73(m,1H),8.68–8.66(m,1H),8.63(d,J＝2.0Hz,1H),8.55(t,J＝9.0Hz,2H),8.50(dd,J＝8.0,1.5Hz,1H),7.87–
7.83(m,1H),7.78(dd,J＝9.0,2.0Hz,1H),7.68–7.63(m,2H),7.62–7.59(m,1H),1.52(s,9H).
13 C NMR(CDCl 3 ,125MHz)δ＝161.43,152.14,146.93,135.69,134.30,131.18,130.59,129.15,127.91,127.88,126.99,126.47,126.11,125.97,125.95,123.59,122.98,122.36,121.53,118.35,109.52,35.50,31.46.
Claims (9)
1. a method for synthesizing 3, 4-dibenzoisocoumarin and derivatives thereof by palladium catalytic cascade cyclization reaction is characterized in that: organic solvent is used as reaction medium, o-alkynyl benzoate and o-halogenated benzoic acid are used as raw materials, the raw materials react under the action of palladium catalyst, phosphine ligand, lithium salt and alkali, and 3, 4-dibenzoisocoumarin is obtained after separation and purification, and the reaction equation is shown in formula 1:
wherein R is 1 、R 2 And R is 3 Independently selected from hydrogen atoms, halogen atoms, C 1 ～C 8 Alkyl group of (C),C 1 ～C 8 Alkoxy, cyano, nitro, aryl, heteroaryl or C containing substituents 1 ～C 8 One of the alkyl groups of (a); x is a halogen atom.
2. The method for synthesizing 3, 4-dibenzoisocoumarin and its derivatives by palladium-catalyzed cascade cyclization according to claim 1, wherein the method comprises the steps of: the halogen atom is fluorine, chlorine or bromine;
the aryl group comprises phenyl, naphthyl, anthryl, phenanthryl or C-containing 1 ～C 8 Alkyl, C of (2) 1 ～C 8 Phenyl of at least one substituent among alkoxy, halogen atom, cyano and nitro;
the heteroaryl group includes five-membered or six-membered ring substituents;
the substituent-containing C 1 ～C 8 The alkyl group of (2) being an alkyl chain containing a halogen atom, C 1 ～C 8 C of at least one substituent in alkoxy, cyano, nitro, aryl, heteroaryl 1 ～C 8 Alkyl of (a);
and X is fluorine, chlorine or bromine.
3. The method for synthesizing 3, 4-dibenzoisocoumarin and its derivatives by palladium-catalyzed cascade cyclization according to claim 1 or 2, characterized in that: the palladium catalyst is one or more of tetra (triphenylphosphine) palladium, palladium acetate, trifluoroacetate palladium, di (triphenylphosphine) palladium dichloride, palladium bromide and palladium chloride.
4. The method for synthesizing 3, 4-dibenzoisocoumarin and its derivatives by palladium-catalyzed cascade cyclization according to claim 1 or 2, characterized in that: the phosphine ligand is selected from one or more of 2-dicyclohexylphosphine-2 ',4',6' -triisopropyl biphenyl, triphenylphosphine, tricyclohexylphosphine, tri (4-fluorophenyl) phosphine, 2-dicyclohexylphosphine-2 ',6' -diisopropyloxy-1, 1' -biphenyl and 2-di-tert-butyl phosphino-2 ',4',6' -triisopropyl biphenyl.
5. The method for synthesizing 3, 4-dibenzoisocoumarin and its derivatives by palladium-catalyzed cascade cyclization according to claim 1 or 2, characterized in that: the base is selected from one or more of cesium carbonate, potassium phosphate and potassium tert-butoxide.
6. The method for synthesizing 3, 4-dibenzoisocoumarin and its derivatives by palladium-catalyzed cascade cyclization according to claim 1 or 2, characterized in that: the lithium salt is selected from one or more of lithium chloride, lithium bromide and lithium acetate.
7. The method for synthesizing 3, 4-dibenzoisocoumarin and its derivatives by palladium-catalyzed cascade cyclization according to claim 1 or 2, characterized in that: the organic solvent is selected from one or more of N, N-dimethylacetamide, dimethyl sulfoxide, N-dimethylformamide, acetonitrile and 1, 4-dioxane.
8. The method for synthesizing 3, 4-dibenzoisocoumarin and its derivatives by palladium-catalyzed cascade cyclization according to claim 1 or 2, characterized in that: the molar ratio of the o-alkynyl benzoate to the o-halogenated benzoic acid to the palladium catalyst to the phosphine ligand to the lithium salt to the alkali is 1:2-3:0.05-0.1:0.1-0.2:2-4:2-4.
9. The method for synthesizing 3, 4-dibenzoisocoumarin and its derivatives by palladium-catalyzed cascade cyclization according to claim 1 or 2, characterized in that: the reaction temperature is 90-140 ℃ and the reaction time is 8-16 h.
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