CN116715643A - Preparation method of hydrogenated dibenzofuran compound - Google Patents
Preparation method of hydrogenated dibenzofuran compound Download PDFInfo
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- CN116715643A CN116715643A CN202310542994.9A CN202310542994A CN116715643A CN 116715643 A CN116715643 A CN 116715643A CN 202310542994 A CN202310542994 A CN 202310542994A CN 116715643 A CN116715643 A CN 116715643A
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- -1 hydrogenated dibenzofuran compound Chemical class 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 57
- 150000004826 dibenzofurans Chemical class 0.000 claims abstract description 53
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- 238000005859 coupling reaction Methods 0.000 claims abstract description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 43
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 33
- 150000002828 nitro derivatives Chemical class 0.000 claims description 21
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 20
- 229910052763 palladium Inorganic materials 0.000 claims description 19
- 239000003446 ligand Substances 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 12
- 150000007530 organic bases Chemical class 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- 239000003960 organic solvent Substances 0.000 claims description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 5
- JSZOAYXJRCEYSX-UHFFFAOYSA-N 1-nitropropane Chemical compound CCC[N+]([O-])=O JSZOAYXJRCEYSX-UHFFFAOYSA-N 0.000 claims description 4
- KQDJTBPASNJQFQ-UHFFFAOYSA-N 2-iodophenol Chemical compound OC1=CC=CC=C1I KQDJTBPASNJQFQ-UHFFFAOYSA-N 0.000 claims description 4
- FGLBSLMDCBOPQK-UHFFFAOYSA-N 2-nitropropane Chemical compound CC(C)[N+]([O-])=O FGLBSLMDCBOPQK-UHFFFAOYSA-N 0.000 claims description 4
- ZPTVNYMJQHSSEA-UHFFFAOYSA-N 4-nitrotoluene Chemical compound CC1=CC=C([N+]([O-])=O)C=C1 ZPTVNYMJQHSSEA-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 150000001925 cycloalkenes Chemical class 0.000 claims description 4
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 claims description 4
- 238000002156 mixing Methods 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 4
- CZGCEKJOLUNIFY-UHFFFAOYSA-N 4-Chloronitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1 CZGCEKJOLUNIFY-UHFFFAOYSA-N 0.000 claims description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- HTJWUNNIRKDDIV-UHFFFAOYSA-N bis(1-adamantyl)-butylphosphane Chemical compound C1C(C2)CC(C3)CC2CC13P(CCCC)C1(C2)CC(C3)CC2CC3C1 HTJWUNNIRKDDIV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 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 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
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- PWUBONDMIMDOQY-UHFFFAOYSA-N acetonitrile;hydrochloride Chemical compound Cl.CC#N PWUBONDMIMDOQY-UHFFFAOYSA-N 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 239000007787 solid Substances 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 8
- 125000006481 2-iodobenzyl group Chemical group [H]C1=C([H])C(I)=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 6
- 238000005910 aminocarbonylation reaction Methods 0.000 abstract description 4
- 238000010523 cascade reaction Methods 0.000 abstract description 4
- 238000007363 ring formation reaction Methods 0.000 abstract description 4
- 230000004071 biological effect Effects 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000012512 characterization method Methods 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-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
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BFCFYVKQTRLZHA-UHFFFAOYSA-N 1-chloro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Cl BFCFYVKQTRLZHA-UHFFFAOYSA-N 0.000 description 1
- CSIFGMFVGDBOQC-UHFFFAOYSA-N 3-iminobutanenitrile Chemical compound CC(=N)CC#N CSIFGMFVGDBOQC-UHFFFAOYSA-N 0.000 description 1
- 238000006617 Intramolecular Heck reaction Methods 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- JZDKETLGZNAINJ-UHFFFAOYSA-H [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mo+6] Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mo+6] JZDKETLGZNAINJ-UHFFFAOYSA-H 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical group C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of a hydrogenated dibenzofuran compound, belonging to the technical field of organic synthesis. According to the invention, 2- (2-iodobenzyl) cyclohexane-1-ketone compounds are used as reaction substrates, cyclization reaction is carried out under the catalysis of a catalyst, and hydrogenation dibenzofuran compounds with wide biological activity can be prepared efficiently and at high temperature only through one step through intramolecular coupling reaction and aminocarbonylation tandem reaction; meanwhile, the preparation raw materials adopted by the invention are low in price, simple and easy to obtain, and are suitable for large-scale production of hydrogenated dibenzofuran compounds.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a hydrogenated dibenzofuran compound.
Background
Hydrogenated dibenzofurans have fused tricyclic structures, a common structural feature in natural products. Hydrogenated dibenzofurans are an important structural unit as the core skeleton of a number of drug molecules or bioactive molecules; therefore, how to construct hydrogenated dibenzofurans concisely and efficiently has led to intensive thinking by many organic chemists.
In recent years, many methods for constructing hydrogenated dibenzofuran skeleton are available, such as Angewandte ChemieInternational Edition,2011, 50 (35): 8161-8166 utilizes an intramolecular oxygen Michael addition reaction to synthesize hydrogenated dibenzofuran; organic Letters,2012, 14 (11): 2714-2717 by intramolecular Heck reaction; the Journal of Organic Chemistry,2015, 80 (3): 1952-1956 hydrogenated dibenzofurans are synthesized using rhodium catalyzed [ (3+2) +1] cycloaddition. However, the above-mentioned processes for synthesizing hydrogenated dibenzofurans all require complex substrates, are not highly economical in atoms, and are severely complicated in reaction conditions.
Aiming at the defects existing in the preparation process of the hydrogenated dibenzofuran compounds, the preparation method of the hydrogenated dibenzofuran compounds with mild reaction conditions and simple and easily obtained reaction substrates is the key point of the current research.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method of hydrogenated dibenzofuran compounds, wherein the preparation process has mild reaction conditions, and the reaction substrate is simple and easy to obtain, and the prepared hydrogenated dibenzofuran compounds have higher yield.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
in a first aspect, the present invention provides a method for preparing a hydrogenated dibenzofuran compound, wherein the structural formula of the hydrogenated dibenzofuran compound is shown as the following formula (II), and the method comprises the following steps:
s1, carrying out a coupling reaction on a compound with a structural formula (I) and a nitro compound under the action of a palladium catalyst, a phosphine ligand and an organic base to obtain a mixed solution, wherein the temperature of the coupling reaction is 120 ℃;
s2, purifying the mixed solution obtained in the step S1 to obtain the hydrogenated dibenzofuran compound;
wherein R in formula (II) is alkyl or aryl.
In the prior art, complex substrates are needed for synthesizing the hydrogenated dibenzofuran compounds, so that the preparation process of the hydrogenated dibenzofuran compounds is difficult and is not suitable for mass production and application; the invention uses the compound shown in the formula (I) as a reaction substrate, and the compound is subjected to cyclization reaction under the action of palladium catalysts, phosphine ligands and organic alkali, and the hydrogenated dibenzofuran compound with wide bioactivity can be efficiently prepared by only one step through intramolecular coupling and aminocarbonylation tandem reaction.
The inventors found through experiments that the coupling of the present invention at a temperature of 120 ℃ can lead to a more complete reaction.
As a preferred embodiment of the process for the preparation of hydrogenated dibenzofurans of the present invention, R in formula (II) is selected from one of n-propyl, isopropyl, substituted or unsubstituted phenyl;
as a more preferred embodiment of the process for the preparation of hydrogenated dibenzofurans of the present invention, the substituted phenyl group is tolyl or chlorophenyl.
As a preferred embodiment of the process for producing a hydrogenated dibenzofuran compound of the present invention, in the step S1, the nitro compound is nitromethane, nitropropane, nitroisopropane, nitrobenzene, para-nitrotoluene, or nitrochlorobenzene; the R group of the hydrogenated dibenzofuran compound of the invention is different according to the choice of the nitro compound.
As a preferred embodiment of the process for producing a hydrogenated dibenzofuran compound of the present invention, in the step S1, the palladium-based catalyst is palladium dichloride (PdCl 2 ) Palladium acetate (Pd (OAc)) 2 ) Palladium trifluoroacetate (Pd (TFA) 2 ) Diacetonitrile palladium chloride (Pd (CH) 3 CN) 2 Cl 2 ) Or tetrakis (triphenylphosphine) palladium (Pd (PPh) 3 ) 4 )。
As a more preferred embodiment of the process for producing a hydrogenated dibenzofuran compound of the present invention, the palladium-based catalyst is PdCl 2 The inventor passes through bigThe amount experiments show that the palladium catalyst can improve the yield of the finally obtained hydrogenated dibenzofuran compounds.
As a preferred embodiment of the process for producing hydrogenated dibenzofurans of the present invention, in the step S1, the phosphine ligand is triphenylphosphine (PPh 3 ) Diphenyl-1-pyrene phosphine (dppp), 1 '-binaphthyl-2, 2' -Bisdiphenylphosphine (BINAP), n-butyldi (1-adamantyl) phosphine (BuPAd) 2 ) Or bis (2-diphenylphosphinophenyl) ether (DPEPhos).
As a more preferred embodiment of the process for the preparation of hydrogenated dibenzofurans of the present invention, the phosphine ligand is PPh 3 The inventor finds through a large number of experiments that the yield of the finally obtained hydrogenated dibenzofuran compound can be higher by adopting the phosphine ligand.
As a preferred embodiment of the method for producing a hydrogenated dibenzofuran compound of the present invention, in the step S1, the compound of the formula (I) is a 2- (2-iodobenzyl) cyclohexane-1-one compound.
As a more preferable embodiment of the method for producing a hydrogenated dibenzofuran-based compound of the present invention, the method for producing a 2- (2-iodobenzyl) cyclohexane-1-one-based compound comprises the steps of:
a1, carrying out addition reaction on o-iodophenol and cycloolefin oxide in an organic solvent, and separating after the reaction is finished to obtain a light yellow oily substance with a structural formula (III);
a2, reacting the light yellow oily substance with the structural formula (III) in the step A1 with oxalyl chloride in an organic solvent, and separating after the reaction is finished to obtain a light yellow oily substance with the structural formula (IV);
a3, reacting the light yellow oily substance with the structural formula (IV) in the step A2 with methyl triphenylphosphine bromide and n-butyllithium organic solvent, and separating after the reaction is finished to obtain a compound with the structural formula (I);
as the most preferable embodiment of the preparation method of the hydrogenated dibenzofuran compound, the preparation method of the 2- (2-iodobenzyl) cyclohexane-1-ketone compound comprises the following steps:
a1, dissolving o-iodophenol and cycloolefin oxide in an N, N-Dimethylformamide (DMF) solvent under the anaerobic condition, then adding cesium carbonate, heating to 110 ℃, stirring for 24 hours, and separating after the reaction is finished to obtain a light yellow oily substance with a structural formula (III);
a2, dissolving oxalyl chloride in anhydrous dichloromethane under the anaerobic condition, slowly dropwise adding a dichloromethane solution of dimethyl sulfoxide at the temperature of minus 78 ℃, dropwise adding a dichloromethane solution of the light yellow oily substance of the structural formula (III) in the step S1, stirring and mixing, dropwise adding triethylamine, continuously stirring for 2 hours, recovering to room temperature, adding water, and separating to obtain the light yellow oily substance of the structural formula (IV);
a3, adding methyl triphenylphosphine bromide into anhydrous THF, dropwise adding 2.5M n-butyllithium at the temperature of minus 78 ℃, moving the reaction system to room temperature, stirring for h, cooling to the temperature of minus 78 ℃, dropwise adding tetrahydrofuran solution of light yellow oily substance of the structural formula (IV), moving the reaction system to room temperature, reacting for 1 hour, cooling to the temperature of 0 ℃, adding water, and separating to obtain the compound of the structural formula (I);
the preparation process of the 2- (2-iodobenzyl) cyclohexane-1-ketone compound is shown as the following formula:
as a preferred embodiment of the method for producing a hydrogenated dibenzofuran compound of the present invention, the step S1 is specifically: mixing palladium catalyst and phosphine ligand in a container, adding organic solution of the compound of the structural formula (I), nitro compound and organic base into the container under anaerobic condition, sealing the container, and reacting at 120-125 ℃ for 20-22h to obtain a mixed solution.
As a more preferred embodiment of the process for producing a hydrogenated dibenzofuran compound of the present invention, the organic base is diisopropylethylamine.
As a more preferable embodiment of the process for preparing hydrogenated dibenzofuran-based compounds of the present invention, the oxygen-free environment of step S1 is created by filling the vessel with carbon monoxide by adding hexahydroxy molybdenum, and then evacuating the vessel from the atmosphere by vacuum.
As a more preferable embodiment of the method for preparing the hydrogenated dibenzofuran compound of the present invention, the molar ratio of the compound of structural formula (I), the nitro compound, the organic base, the palladium catalyst and the phosphine ligand is structural formula (I), the nitro compound, the organic base, the palladium catalyst and the phosphine ligand=0.2:0.6:0.3:0.01:0.02.
As a preferred embodiment of the method for producing a hydrogenated dibenzofuran compound of the present invention, the step S2 is specifically: and (3) cooling the mixed solution obtained in the step (S1) to room temperature, releasing carbon monoxide in a container, filtering, concentrating under reduced pressure, and purifying by using a column chromatography method to obtain the hydrogenated dibenzofuran compound.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, 2- (2-iodobenzyl) cyclohexane-1-ketone compounds are used as reaction substrates, cyclization reaction is carried out under the catalysis of a catalyst, and hydrogenation dibenzofuran compounds with wide biological activity can be prepared efficiently and at high temperature only through one step through intramolecular coupling reaction and aminocarbonylation tandem reaction; meanwhile, the preparation raw materials adopted by the invention are low in price, simple and easy to obtain, and are suitable for large-scale production of hydrogenated dibenzofuran compounds.
Drawings
FIG. 1 shows the structural formula and the yield of the hydrogenated dibenzofuran compounds;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the hydrogenated dibenzofuran compound of formula (134) of the present invention;
FIG. 3 is a nuclear magnetic resonance spectrum of the hydrogenated dibenzofuran compound of formula (134) of the present invention;
FIG. 4 is a nuclear magnetic resonance hydrogen spectrum of the hydrogenated dibenzofuran compound of formula (134 a) of the present invention;
FIG. 5 is a nuclear magnetic resonance spectrum of the hydrogenated dibenzofuran compound of formula (134 a) of the present invention;
FIG. 6 is a nuclear magnetic resonance hydrogen spectrum of the hydrogenated dibenzofuran compound of formula (134 b) of the present invention;
FIG. 7 is a nuclear magnetic resonance spectrum of the hydrogenated dibenzofuran compound of formula (134 b) of the present invention;
FIG. 8 is a nuclear magnetic resonance hydrogen spectrum of the hydrogenated dibenzofuran compound of formula (134 c) of the present invention;
FIG. 9 is a nuclear magnetic resonance spectrum of the hydrogenated dibenzofuran compound of formula (134 c) of the present invention;
FIG. 10 is a nuclear magnetic resonance hydrogen spectrum of the hydrogenated dibenzofuran compound of formula (134 d) of the present invention;
FIG. 11 is a nuclear magnetic resonance spectrum of the hydrogenated dibenzofuran compound of formula (134 d) of the present invention;
FIG. 12 is a nuclear magnetic resonance hydrogen spectrum of the hydrogenated dibenzofuran compound of formula (134 e) of the present invention;
FIG. 13 is a nuclear magnetic resonance spectrum of the hydrogenated dibenzofuran compound of formula (134 e) of the present invention.
Detailed Description
For a better description of the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to the following specific examples.
The reagents, methods and apparatus employed in the present invention, unless otherwise specified, are all conventional in the art.
Example 1
An embodiment of the method for preparing a hydrogenated dibenzofuran compound according to the present invention includes the following steps:
s1, adding 0.01mmol of palladium dichloride, 0.02mmol of triphenylphosphine and 0.6mmol of molybdenum hexacarbonyl into a 15mL pressure-resistant tube, vacuumizing for 10min, and repeatedly filling N 2 3 times, followed by 0.2mmol of the compound of formula (I) in THF, 0.6mmol of nitromethane, 0.3mmol of the diiso-formPropylethylamine and 0.3mmol of water, then sealing the pressure-resistant tube, placing the pressure-resistant tube on a heating module preheated to 120 ℃, and stirring for 20 hours to obtain a mixed solution;
s2, cooling the mixed solution obtained in the step S1 to room temperature, releasing carbon monoxide, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain the hydrogenated dibenzofuran compound.
In this embodiment, the preparation method of the compound of structural formula (I) comprises the following steps:
a1, dissolving 20.0mmol of o-iodophenol and 24.0mmol of cycloolefin oxide in 12.0mL of anhydrous DMF under the protection of nitrogen, then adding 60.0mmol of cesium carbonate, heating the reaction system to 110 ℃, refluxing and stirring for 24 hours, adding 20.0mL of ethyl acetate and 20.0mL of water for quenching reaction, extracting the obtained water phase with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating by using a silica gel column chromatography (the filling phase is petroleum ether: ethyl acetate=10:1) to obtain a light yellow oily substance with the structural formula (III);
a2, dissolving 19.52mmol of oxalyl chloride in 27.9mL of anhydrous dichloromethane under the protection of nitrogen, slowly dropwise adding 2.8mL of a dichloromethane solution of dimethyl sulfoxide with the molar concentration of 7.1M at the temperature of minus 78 ℃, then dropwise adding 16.27mmol of a dichloromethane solution of the light yellow oily substance with the structural formula (III) in the step S1 with the molar concentration of 0.6M, stirring for 1.5h, then dropwise adding 78.10mmol of triethylamine, continuing stirring for 2h, recovering to room temperature, adding 100mL of water, quenching, extracting the water phase obtained by the reaction with dichloromethane, washing the organic phase with saturated saline, then drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating by silica gel column chromatography (the filling phase is petroleum ether: ethyl acetate=10:1) to obtain the light yellow oily substance with the structural formula (IV);
a3, adding 34.96mmol of methyltriphenylphosphine bromide into 38.0mL of anhydrous THF, dropwise adding 13.4mL of 2.5M n-butyllithium at-78 ℃, moving the reaction system to room temperature, stirring for 2h, cooling to-78 ℃, dropwise adding 12.2mL of tetrahydrofuran solution of a light yellow oily substance of a structural formula (IV), moving the reaction system to room temperature, reacting for 1h, cooling to 0 ℃, adding water for quenching, extracting the obtained water phase with ethyl acetate, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating to obtain the compound of the structural formula (I) by silica gel column chromatography (the filling phase is petroleum ether: ethyl acetate=1:0);
the preparation process of the 2- (2-iodobenzyl) cyclohexane-1-ketone compound is shown as the following formula:
the yield of the hydrogenated dibenzofuran compound (134) of this example is: 86%, the structural characterization is shown in fig. 2 and 3, and the structural characterization data are as follows: 1 H NMR(500MHz，Chloroform-d)δ7.15(td，J＝7.7，1.4Hz，1H)，7.11(dd，J＝7.4，1.4Hz，1H)，6.89(td，J＝7.4，1.0 Hz，1H)，6.82(d，J＝7.9Hz，1H)，5.19(s，1H)，4.68(t，J＝6.6，5.2Hz，1H)，2.68(d，J＝4.8Hz，3H)，2.50-2.37(m，2H)，1.98-1.90(m，2H)，1.89-1.81(m，1H)，1.72-1.62(m，1H)，1.59-1.47(m，2H)，1.43-1.34(m，1H)，1.32-1.21(m，1H).
13 C NMR(126MHz，CDCl 3 )δ170.8，158.8，134.0，128.5，122.6，120.5，110.6，86.3，46.6，45.9，32.O，27.2，26.2，20.6，20.1.
the structural formula is shown as the following formula (134);
example 2
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the nitro compound was nitropropane, and the other steps were the same as in example 1.
The preparation of the compound of formula (I) described in this example is identical to that described in example 1.
The yield of the hydrogenated dibenzofuran compound (134 a) of this example was: 77, the structural characterization is shown in fig. 4 and 5, and the structural characterization data are as follows: 1 H NMR(500MHz，Chloroform-d)δ7.18-7.07(m，2H)，6.87(t，J＝7.4，1.0Hz，1H)，6.80(d，J＝7.9Hz，1H)，5.28(s，1H)，4.68(t，J＝6.3，5.1Hz，1H)，3.16-2.98(m，2H)，2.51-2.36(m，2H)，1.96-1.86(m，2H)，1.86-1.79(m，1H)，1.73-1.65(m，1H)，1.57-1.44(m，2H)，1.42-1.31(m，3H)，1.28-1.23(m，1H)，0.77(t，J＝7.4Hz，3H).
13 C NMR(126MHz，CDCl 3 )δ170.0，158.9，134.1，128.5，122.6，120.5，110.6，86.2，46.5，45.7，41.1，32.3，26.9，22.6，20.5，19.9，11.2.
the structural formula is shown as the following formula (134 a):
example 3
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the nitro compound is nitroisopropane, and the rest steps are the same as in the example 1.
The preparation of the compound of formula (I) described in this example is identical to that described in example 1.
The yield of the hydrogenated dibenzofuran compound (134 b) of this example was: 49%, as shown in fig. 6 and 7, the structural characterization data are as follows: 1 H NMR(500MHz，Chloroform-d)δ7.17-7.09(m，2H)，6.88(t，J＝7.4，1.0Hz，1H)，6.81(d，J＝8.0Hz，1H)，4.97(s，1H)，4.68(t，J＝6.5，5.1Hz，1H)，3.99-3.89(m，1H)，2.46-2.32(m，2H)，1.97-1.88(m，2H)，1.86-1.78(m，1H)，1.71-1.62(m，1H)，1.58-1.46(m，2H)，1.42-1.33(m，1H)，1.31-1.21(m，1H)，1.01(d，J＝6.6Hz，3H)，0.94(d，J＝6.5Hz，3H).
13 C NMR(126MHz，CDCl 3 )δ169.1，158.9，133.9，128.5，122.8，120.4，110.6，86.3，46.6，46.3，41.1，32.1，27.0，22.5，22.5，20.4，19.8.
the structural formula is shown as the following formula (134 b):
example 4
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the nitro compound was nitrobenzene, and the rest of the steps were the same as in example 1.
The preparation of the compound of formula (I) described in this example is identical to that described in example 1.
The yield of the hydrogenated dibenzofuran compound (134 c) of this example was: 55%, the structural characterization is shown in fig. 8 and 9, and the structural characterization data are as follows: 1H NMR (500 MHz, chloroform-d) delta 7.23-7.15 (m, 4H), 7.14-7.06 (m, 2H), 6.99 (t, J=6.9, 1.5Hz, 1H), 6.91-6.82 (m, 2H), 6.77 (d, J=7.9 Hz, 1H), 4.63 (t, J=6.7, 5.3Hz, 1H), 2.52 (q, J=13.8 Hz, 2H), 1.96-1.85 (m, 2H), 1.85-1.78 (m, 1H), 1.63-1.54 (m, 1H), 1.52-1.41 (m, 2H), 1.35-1.25 (m, 1H), 1.24-1.18 (m, 1H).
13C NMR(126MHz，CDCl3)δ168.5，158.9，137.4，133.5，128.8，128.8，124.3，122.8，120.7，119.9，110.9，86.4，47.3，46.9，31.9，27.2，20.6，20.0.
The structural formula is shown as the following formula (134 c):
example 5
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the nitro compound was p-nitrotoluene, and the other steps were the same as in example 1.
The preparation of the compound of formula (I) described in this example is identical to that described in example 1.
The yield of the hydrogenated dibenzofuran compound (134 d) of this example is: 70%, the structural characterization is shown in fig. 10 and 11, and the structural characterization data are as follows: 1H NMR (500 MHz, chloroform-d) delta 7.22-7.13 (m, 4H), 7.06 (d, J=8.2 Hz, 2H), 6.92 (t, J=7.4, 0.9Hz, 1H), 6.85 (d, J=7.9 Hz, 1H), 6.66 (s, 1H), 4.70 (t, J=6.8, 5.3Hz, 1H), 2.66-2.54 (m, 2H), 2.28 (s, 3H), 2.06-1.85 (m, 3H), 1.71-1.61 (m, 1H), 1.55-1.50 (m, 1H), 1.44-1.23 (m, 3H).
13C NMR(126MHz，CDCl3)δ168.4，158.9，134.9，133.9，133.6，129.3，128.7，122.8，120.6，120.0，110.8，86.4，47.2，46.9，31.9，27.2，20.8，20.6，20.0.
The structural formula is shown as the following formula (134 d):
example 6
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the nitro compound was p-nitrochlorobenzene, and the rest of the steps were the same as in example 1.
The preparation of the compound of formula (I) described in this example is identical to that described in example 1.
The yield of the hydrogenated dibenzofuran compound (134 e) of this example is: 54%, as shown in fig. 12 and 13, the structural characterization data are as follows: 1H NMR (500 MHz, chloroform-d) delta 7.23-7.18 (m, 5H), 7.15 (dd, J=7.4, 1.4Hz, 1H), 6.93 (td, J=7.4, 1.0Hz, 1H), 6.85 (d, J=7.9, 0.7Hz, 1H), 6.63 (s, 1H), 4.68 (t, J=6.9, 5.4Hz, 1H), 2.64-2.56 (m, 2H), 2.09-2.02 (m, 1H), 2.01-1.92 (m, 1H), 1.90-1.83 (m, 1H), 1.68-1.61 (m, 1H), 1.55-1.51 (m, 1H), 1.41-1.24 (m, 3H).
13C NMR(126MHz，CDCl3)δ168.5，158.9，136.0，133.2，129.2，128.9，128.8，122.7，121.0，120.7，111.0，86.4，47.6，47.0，31.9，27.3，20.6，20.1.
The structural formula is shown as the following formula (134 e):
example 7
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the nitro compound was nitropropane, and the other steps were the same as in example 1.
The preparation of the compound of formula (I) described in this example is identical to that described in example 1.
The yield of the hydrogenated dibenzofuran compound (134 f) in this example is: 67%, the structural characterization data are as follows: 1H NMR (500 MHz, chlorofOrm-d) delta 7.14-7.05 (m, 2H), 6.84 (td, J=7.4, 1.0Hz, 1H), 6.71 (d, J=8.0, 0.8Hz, 1H), 5.36 (s, 1H), 5.19 (d, J=5.8 Hz, 1H), 3.19-3.11 (m, 1H), 3.07-2.99 (m, 1H), 2.73-2.54 (m, 2H), 2.02-1.86 (m, 4H), 1.74-1.65 (m, 1H), 1.49-1.39 (m, 1H), 1.37-1.29 (m, 2H), 0.79 (t, J=7.4 Hz, 3H).
13C NMR(126MHz，CDCl3)δ170.2，160.3，132.7，128.6，123.2，120.3，109.1，92.6，55.5，45.6，41.1，40.8，35.2，24.2，22.6，11.2.
The structural formula is shown as the following formula (134 f):
example 8
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the nitro compound is nitroisopropane, and the rest steps are the same as in the example 1.
The preparation of the compound of formula (I) described in this example is identical to that described in example 1.
The yield of hydrogenated dibenzofuran compound (134 g) described in this example is: 66%, the structural characterization data is as follows: 1H NMR (500 MHz, chloroform-d) delta 7.13-7.06 (m, 2H), 6.85 (t, J=7.4, 1.0Hz, 1H), 6.72 (d, J=7.9 Hz, 1H), 5.19 (d, J=5.9 Hz, 1H), 5.05 (s, 1H), 4.00-3.88 (m, 1H), 2.59 (dd, J=81.2, 14.1Hz, 2H), 2.06-1.96 (m, 2H), 1.96-1.84 (m, 2H), 1.73-1.65 (m, 1H), 1.50-1.38 (m, 1H), 1.01 (d, J=6.5 Hz, 3H), 0.90 (d, J=6.5 Hz, 3H).
13C NMR(126MHz，CDCl3)δ169.3，160.5，132.6，128.6，123.2，120.3，109.2，92.4，55.6，45.9，41.1，40.9，35.2，24.2，22.5，22.3。
The structural formula is shown as the following formula (134 g):
example 9
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the nitro compound was nitrobenzene, and the rest of the steps were the same as in example 1.
The preparation of the compound of formula (I) described in this example is identical to that described in example 1.
The yield of the hydrogenated dibenzofuran compound (134 h) in this example is: 60%, structural characterization data were as follows: 1H NMR (500 MHz, chloroform-d) delta 7.25-7.14 (m, 4H), 7.11-7.03 (m, 3H), 7.02-6.96 (m, 1H), 6.81 (t, J=7.4, 1.0Hz, 1H), 6.67 (d, J=8.3, 1.0Hz, 1H), 5.12 (d, J=5.8 Hz, 1H), 2.85-2.64 (m, 2H), 1.99-1.94 (m, 2H), 1.93-1.83 (m, 2H), 1.69-1.61 (m, 1H), 1.45-1.33 (m, 1H).
13C NMR(126MHz，CDCl3)δ168.7，160.4，137.4，132.5，128.9，128.8，124.4，123.3，120.6，120.0，109.3，92.7，55.6，46.6，40.8，35.2，24.2.
The structural formula is shown as the following formula (134 h):
example 10
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the nitro compound was p-nitrotoluene, and the other steps were the same as in example 1.
The preparation of the compound of formula (I) described in this example is identical to that described in example 1.
The yield of the hydrogenated dibenzofuran compound (134 i) of this example is: 60%, structural characterization data were as follows: 1H NMR (500 MHz, chloroform-d) delta 7.16-7.09 (m, 3H), 7.08-7.03 (m, 2H), 6.97 (d, J=8.2 Hz, 2H), 6.79 (t, J=7.4 Hz, 1H), 6.66 (d, J=8.2 Hz, 1H), 5.12 (d, J=5.8 Hz, 1H), 2.79-2.62 (m, 2H), 2.20 (s, 3H), 1.95-1.81 (m, 3H), 1.68-1.60 (m, 1H), 1.46-1.33 (m, 1H), 1.21-1.15 (m, 1H).
13C NMR(126MHz，CDCl3)δ168.6，160.3，134.9，134.0，132.6，129.3，128.7，123.4，120.5，120.2，109.2，92.7，60.4，55.6，46.4，40.6，35.2，24.2，20.8.
The structural formula is shown as the following formula (134 i):
example 11
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the nitro compound was p-nitrochlorobenzene, and the rest of the steps were the same as in example 1.
The preparation of the compound of formula (I) described in this example is identical to that described in example 1.
The yield of the hydrogenated dibenzofuran compound (134 j) of this example was: 76, structural characterization data were as follows: 1H NMR (500 MHz, chloroform-d) delta 7.21 (s, 4H), 7.18-7.14 (m, 2H), 6.95 (s, 1H), 6.92-6.88 (m, 1H), 6.76 (d, J=7.9 Hz, 1H), 5.17 (d, J=5.9 Hz, 1H), 2.92 (d, J=14.6 Hz, 1H), 2.74 (d, J=14.7 Hz, 1H), 2.11-2.02 (m, 2H), 2.01-1.90 (m, 2H), 1.78-1.70 (m, 1H), 1.53-1.43 (m, 1H).
13C NMR(126MHz，CDCl3)δ168.7，160.4，136.0，132.3，129.1，128.9，128.8，123.3，121.2，120.6，116.2，109.4，92.6，55.6，46.6，40.8，35.2，24.2.
The structural formula is shown as the following formula (134 j):
example 12
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the palladium catalyst is Pd (OAc) 2 The remaining steps were identical to those of example 1; the yield of the hydrogenated dibenzofuran compound (134) of this example is: 56%.
Example 13
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the palladium catalyst is Pd (TFA) 2 The remaining steps were identical to those of example 1; the yield of the hydrogenated dibenzofuran compound (134) of this example is: 80%.
Example 14
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the palladium catalyst is Pd (CH) 3 CN) 2 Cl 2 The remaining steps were identical to those of example 1; the yield of the hydrogenated dibenzofuran compound (134) of this example is: 68%.
Example 15
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the palladium catalyst is Pd (PPh 3 ) 4 The other steps are the same as those of the actual processExample 1 was consistent; the yield of the hydrogenated dibenzofuran compound (134) of this example is: 80%.
Example 16
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the phosphine ligand is dppp, and the rest steps are consistent with the embodiment 1; the yield of the hydrogenated dibenzofuran compound (134) of this example is: 40%.
Example 17
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, phosphine ligand is BINAP, and the rest steps are consistent with the embodiment 1; the yield of the hydrogenated dibenzofuran compound (134) of this example is: 16%.
Example 18
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, the phosphine ligand is BuPAd 2 The remaining steps were identical to those of example 1; the yield of the hydrogenated dibenzofuran compound (134) of this example is: 64%.
Example 19
This example differs from the process for the preparation of hydrogenated dibenzofurans described in example 1 only in that: in the step S1, phosphine ligand is DPEPho, and the rest steps are consistent with the embodiment 1; the yield of the hydrogenated dibenzofuran compound (134) of this example is: 84%.
According to the invention, 2- (2-iodobenzyl) cyclohexane-1-ketone compounds are used as reaction substrates, cyclization reaction is carried out under the catalysis of a catalyst, and hydrogenation dibenzofuran compounds with wide biological activity can be prepared efficiently and at high temperature only through one step through intramolecular coupling reaction and aminocarbonylation tandem reaction; meanwhile, the preparation raw materials adopted by the invention are low in price, simple and easy to obtain, and are suitable for large-scale production of hydrogenated dibenzofuran compounds.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted equally without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. The preparation method of the hydrogenated dibenzofuran compound is characterized by comprising the following steps of:
s1, carrying out a coupling reaction on a compound shown in a structural formula (I) and a nitro compound under the action of a palladium catalyst, a phosphine ligand and an organic base to obtain a mixed solution, wherein the temperature of the coupling reaction is 120 ℃;
s2, purifying the mixed solution obtained in the step S1, wherein the solid obtained after purification is the hydrogenated dibenzofuran compound;
wherein R in formula (II) is alkyl or aryl.
2. The process for the preparation of hydrogenated dibenzofurans according to claim 1 wherein R in formula (II) is selected from one of n-propyl, isopropyl, substituted or unsubstituted phenyl;
preferably, R is methyl substituted tolyl or chlorophenyl.
3. The process for the preparation of hydrogenated dibenzofurans according to claim 1, wherein in step S1, the nitro compound is nitromethane, nitropropane, nitroisopropane, nitrobenzene, para-nitrotoluene or para-nitrochlorobenzene.
4. The process for preparing hydrogenated dibenzofuran compounds according to claim 1, wherein said palladium catalyst in step S1 is palladium dichloride, palladium acetate, palladium trifluoroacetate, palladium bis acetonitrile chloride or tetrakis (triphenylphosphine) palladium.
5. The process for producing hydrogenated dibenzofuran compounds according to claim 1, wherein said palladium catalyst in step S1 is palladium dichloride.
6. The process for the preparation of hydrogenated dibenzofurans according to claim 1, wherein in step S1 the phosphine ligand is triphenylphosphine, diphenyl-1-pyrene phosphine, 1 '-binaphthyl-2, 2' -bisdiphenylphosphine, n-butyldi (1-adamantyl) phosphine or bis (2-diphenylphosphinophenyl) ether.
7. The process for the preparation of hydrogenated dibenzofurans according to claim 1, wherein in step S1 the phosphine ligand is triphenylphosphine.
8. The process for the preparation of hydrogenated dibenzofuran compounds according to claim 1, wherein said process for the preparation of compounds of formula (I) in step S1 comprises the steps of:
a1, carrying out addition reaction on o-iodophenol and cycloolefin oxide in an organic solvent, and separating after the reaction is finished to obtain a compound shown in a structural formula (III);
a2, reacting the compound shown in the structural formula (III) in the step A1 with oxalyl chloride in an organic solvent, and separating after the reaction is finished to obtain a compound shown in the structural formula (IV);
a3, reacting the compound shown in the structural formula (IV) in the step A2 with methyl triphenylphosphine bromide and n-butyllithium organic solvent, and separating after the reaction is finished to obtain a compound shown in the structural formula (I);
9. the process for the preparation of hydrogenated dibenzofuran compounds according to claim 1, characterized in that said step S1 is specifically: mixing a palladium catalyst and a phosphine ligand, then mixing an organic solution of a compound of a structural formula (I), a nitro compound and an organic base under an anaerobic condition, and reacting for 20-22 hours at a temperature of 120-125 ℃ after sealing to obtain a mixed solution;
preferably, the organic base is diisopropylethylamine.
10. The process for the preparation of hydrogenated dibenzofuran compounds according to claim 9, wherein the molar ratio of said compound of formula (I), nitro compound, organic base, palladium catalyst and phosphine ligand is formula (I) to nitro compound to organic base to palladium catalyst to phosphine ligand=0.2:0.6:0.3:0.01:0.02.
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