CN104650018B - A kind of method preparing 2,3-disubstituted benzofuran analog derivative - Google Patents
A kind of method preparing 2,3-disubstituted benzofuran analog derivative Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 20
- -1 2,3-disubstituted benzofuran Chemical class 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 76
- 239000003054 catalyst Substances 0.000 claims abstract description 32
- 239000010948 rhodium Substances 0.000 claims abstract description 28
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 17
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims abstract description 11
- 150000002466 imines Chemical class 0.000 claims abstract description 8
- 150000001907 coumarones Chemical class 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000005843 halogen group Chemical group 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 230000004044 response Effects 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-trimethylbenzene Chemical compound CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- 239000000047 product Substances 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 238000004364 calculation method Methods 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 239000003208 petroleum Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229960001866 silicon dioxide Drugs 0.000 description 11
- 238000010183 spectrum analysis Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- OACNDCWDZGNLJV-UHFFFAOYSA-N 1-(4-methylphenyl)sulfonyl-4-phenyltriazole Chemical class C1=CC(C)=CC=C1S(=O)(=O)N1N=NC(C=2C=CC=CC=2)=C1 OACNDCWDZGNLJV-UHFFFAOYSA-N 0.000 description 9
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 8
- 238000006555 catalytic reaction Methods 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 6
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 4
- 238000006713 insertion reaction Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- FQPPKQWSXJIQCP-UHFFFAOYSA-N 1-(4-methylphenyl)sulfonyl-4-(2-phenylmethoxyphenyl)triazole Chemical class C(C1=CC=CC=C1)OC1=C(C=CC=C1)C=1N=NN(C=1)S(=O)(=O)C1=CC=C(C)C=C1 FQPPKQWSXJIQCP-UHFFFAOYSA-N 0.000 description 1
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical compound C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 description 1
- 0 C[C@]1C=C(C(C*)=C(*)O2)C2=CC=C1 Chemical compound C[C@]1C=C(C(C*)=C(*)O2)C2=CC=C1 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- 238000006898 Intramolecular Friedel-Crafts reaction Methods 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000005691 oxidative coupling reaction Methods 0.000 description 1
- 238000007243 oxidative cyclization reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 238000006722 reduction reaction Methods 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
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000007039 two-step reaction Methods 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
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the method that one prepares 2,3-disubstituted benzofuran analog derivatives, comprise the following steps: (1), under the effect of rhodium catalyst, 1-sulfonyl-1,2,3-triazoles compounds reacts and obtains imine intermediate；(2) at palladium/carbon catalyst and 1atm H2Under effect, the imine intermediate that step (1) obtains continues to be obtained by reacting 2,3-described disubstituted benzofuran analog derivatives.The inventive method reaction raw materials preparation method is simple, it is easy to preserving, react simple to operation, commodity rhodium catalyst used is less, can be substantially reduced cost.The method of the present invention can be used for the synthesis complex compound containing 2,3-disubstituted benzofuran structural framework.
Description
Technical field
The present invention relates to organic synthesis field, be specifically related to a kind of method being prepared 2,3-disubstituted benzofuran analog derivatives by two-step reaction under tetrabasic carboxylic acid two rhodium catalyst and palladium/carbon catalyst effect.
Background technology
Benzofuran structure is a very important organic heterocyclic structure of class, is important organic synthesis fragment, is also many skeletons having bioactive natural product.Such as, Cowart group (SynthesisandSARof5-Amino-and5-(Aminomethyl) benzofuranHistamineH3ReceptorAntagonistswithImprovedPote ncy.JMedChem.2005,48,6482-6490.) report with benzofuran structure be skeleton the synthesis of novel histamine receptor inhibitor and Effect study；And (InhibitionofLymphoidTyrosinePhosphatasebyBenzofuranSalic ylicAcids.JMedChem.2011,54,562-571) is as the application of the inhibitor of protein tyrosine phosphatase.For adapting to the research of drug screening and structure activity relationship, setting up the compound library being structural core with benzofuran, therefore develop new high-efficiency synthesis method has important meaning.
Traditional method synthesis benzofuran derivative can utilize intramolecular Friedel-Crafts reaction to realize (Palladium-Catalyzed α-ArylationofAryloxyketonesfortheSynthesisof2,3-Disubstitu tedBenzofurans).Transition metal-catalyzed development also promotes the appearance of new method, such as, recent report synthesizes new method (the Iron-CatalyzedTandemOxidativeCouplingandAnnulation:AnEff icientApproachtoConstructPolysubstitutedBenzofuransJ.Am. Chem.Soc.2008 of polysubstituted benzofuran with the phenol of ferrum catalysis and alpha-carbonyl esters oxidative coupling/cyclization, 131,17387-17393).While it is true, develop new synthetic method still have important value.
The terminal alkyne of the copper catalysis of development in recent years and the addition of sulfonyl nitrine obtain 1-sulfonyl-1, the reaction of 2,3-triazoles; yield is high, and reaction condition gentleness (EfficientSynthesisof1-Sulfonyl-1,2; 3-triazoles.Org.Lett.2010,12,4,952 4955).Rhodium catalysis the open loop denitrogenation of this compounds of catalysis can generate active α-imido grpup rhodium Cabbeen intermediate, and this be it provides favourable condition as application originated in organic synthesis of novel metal-carbene intermediate.The 1-sulfonyl-1 of rhodium catalysis; 2; the C-H insertion reaction of 3-triazole has applied in the synthesis of the sulfamide compound that β-position is chiral carbon; such as Fokin et al. (CatalyticAsymmetricC HInsertionsofRhodium (II) AzavinylCarbenes.J.Am.Chem.Soc.2011; 133,10352-10355).But utilize the sp of the 1-sulfonyl-1,2,3-triazoles compounds of rhodium catalysis3The reaction of the heterocycles such as c h bond insertion reaction synthesis benzofuran has no report.
Summary of the invention
The present invention provides the method that one prepares 2,3-disubstituted benzofuran analog derivatives, and the method raw material is easy to get, simple to operate, and yield is higher.
One prepares the method for 2,3-disubstituted benzofuran analog derivatives, comprises the following steps:
(1) under the effect of rhodium catalyst, 1-sulfonyl-1,2,3-triazoles compounds reacts and obtains imine intermediate；
The structure of described 1-sulfonyl-1,2,3-triazole class compounds is such as shown in formula II:
(2) under palladium/carbon catalyst effect and hydrogen effect, the imine intermediate that step (1) obtains continues to be obtained by reacting 2,3-described disubstituted benzofuran analog derivatives；
In formula I and formula II, R1For C1～C12One in alkyl, substituted or unsubstituted aryl, heteroaryl；R2For hydrogen, halogen atom or C1～C6Alkyl；R3For phenyl or p-methylphenyl.
Reaction equation is as follows:
The reaction principle of the method is: 1-sulfonyl-1; 2; the open loop denitrogenation under the effect of rhodium catalysis of 3-triazole class compounds forms α-imines Cabbeen rhodium reactive intermediate; the c h bond generation insertion reaction at this intermediate and oxygen atom ortho position generates the Dihydrobenzofuranes compound of functionalization; then under the effect of palladium catalyst, intramolecular elimination and reduction reaction generate 2,3-disubstituted benzofuran analog derivatives.
As preferably, described aryl is phenyl or naphthyl；Described heteroaryl is furyl or thienyl.
In the present invention, R1In aryl on substituent group independent selected from halo ,-CF3、C1～C4Alkyl, C1～C4Alkoxy carbonyl group or C1～C4Alkanoyl.Preferably, R1In aryl on substituent group independently selected from F, CF3, methyl, the tert-butyl group or methoxycarbonyl group.
Preferably, R in described 1-sulfonyl-1,2,3-triazoles compounds2Group for little steric hindrance improves reaction yield.
In step (1), the mol ratio of described rhodium catalyst and described 1-sulfonyl-1,2,3-triazoles compounds is 0.005～0.02:1；
In step (2), the mol ratio of described palladium/carbon catalyst and described 1-sulfonyl-1,2,3-triazoles compounds is 0.001～0.05:1, to improve the productivity of reaction.
Catalyst used is commercial product; the consumption of catalyst is less; N-sulfonyl-1 when reaction substrate amount is big; 2; the mol ratio of 3-triazole class compounds is 0.005 reaction yield is not significantly affected; as preferably, in step (1), described rhodium catalyst is tetraacethyl two rhodium, four sad two rhodiums, four pivalic acid two rhodiums or four (2-phthalimide group-3 Methylbutanoic acid) two rhodiums.
The reaction temperature of step (1) and step (2) is 80～120 DEG C；Response time is 1～4h.Generally, the response time is within 2 hours, to make substrate convert completely.Described reaction temperature is preferably 90～100 DEG C, more preferably 90 DEG C.
As preferably, the reaction of step (1) carries out in dichloromethane, chloroform, toluene, dimethylbenzene, sym-trimethylbenzene., ethyl acetate or 1,2-dichloroethanes, it is most preferred that for dichloromethane.；
The reaction of step (2) is at C1～C5Alkylol carries out.
As further preferably, after the reaction in step (1) completes, removing solvent obtains imine intermediate and is directly added into described C1～C5Alkylol and palladium/carbon catalyst, 1atmH2Lower 45 DEG C of reactions carrying out step (2).
Compared with prior art, the invention have the advantages that
The inventive method is obtained by reacting 2,3-disubstituted benzofuran analog derivatives with 1-sulfonyl-1,2,3-triazoles compounds, and preparation method is simple, and rhodium catalyst consumption is few, can be substantially reduced cost.The inventive method can be used for synthesizing a series of 2,3-disubstituted benzofuran analog derivatives.
Detailed description of the invention
Describe the present invention in detail below in conjunction with embodiment, but the present invention is not limited to this.
Embodiment 1
In the dry pressure reaction tube of 15mL, add 343mg 4-(2-ethoxyl phenenyl)-1-p-toluenesulfonyl-1,2,3-triazoles, 11.8mg Rh2(S-PTV)4The dichloromethane of (four (2-phthalimide group-3 Methylbutanoic acid) two rhodiums) and 3.0ml.Under a nitrogen, 90 DEG C of stirring reactions 4 hours.Reaction end is cooled to room temperature, removes dichloromethane solvent, adds anhydrous ethanol solvent, palladium/carbon catalyst (3%), 1atmH2Lower 45 DEG C are continued reaction 3h.Products therefrom is direct crosses silicagel column (volume ratio of petroleum ether and ethyl acetate is 10:1), obtains product 204mg, productivity 65%, and course of reaction is shown below:
The product that the present embodiment is prepared carries out nuclear magnetic resonance, NMR and mass spectral analysis:
1HNMR(400MHz,CDCl3): δ=7.71 (d, J=8.4Hz, 2H), 7.31 (d, J=8.0Hz, 1H), 7.23-7.27 (m, 3H), 7.19 (t, J=8.0Hz, 1H), 7.12-7.15 (m, 1H), 4.54 (br, 1H), 4.19 (d, J=5.2Hz, 2H), 2.41 (s, 3H), 2.31 (s, 3H)；
13CNMR(100MHz,CDCl3): δ=153.8,153.2,143.5,136.7,129.6,127.8,127.1,123.1,122.6,11 8.6,110.7,109.7,37.2,21.5,11.9；
HRMS: molecular formula is C17H17NO3S；Value of calculation is 315.0929；Detected value is 315.0926.
Embodiment 2
In the dry pressure reaction tube of 15mL, add 405mg 4-(2-benzyloxy-phenyl)-1-p-toluenesulfonyl-1,2,3-triazoles, 11.8mg Rh2(S-PTV)4The dichloromethane of (four (2-phthalimide group-3 Methylbutanoic acid) two rhodiums) and 3.0ml.Under a nitrogen, 90 DEG C of stirring reactions 2 hours.Reaction end is cooled to room temperature, removes dichloromethane solvent, adds anhydrous ethanol solvent, palladium/carbon catalyst (3%), 1atmH2Lower 45 DEG C are continued reaction 3h.Products therefrom is direct crosses silicagel column (volume ratio of petroleum ether and ethyl acetate is 10:1), obtains product 339mg, productivity 90%, and course of reaction is shown below:
The product that the present embodiment is prepared carries out nuclear magnetic resonance spectroscopy and mass spectral analysis:
1HNMR(400MHz,CDCl3): δ=7.76 (d, J=8.4Hz, 2H), 7.60-7.63 (m, 2H), 7.39-7.47 (m, 4H), 7.26-7.34 (m, 4H), 7.20 (t, J=7.2Hz, 1H), 4.56 (br, 1H), 4.43 (d, J=5.6Hz, 2H), 2.45 (s, 3H)；
13CNMR(400MHz,CDCl3): δ=153.9,153.4,143.7,136.3,129.7,129.1,128.9,128.7,127.3,12 7.2,124.9,123.1,119.4,111.2,110.1,37.7,21.6；
HRMS: molecular formula is C22H19NO3S；Value of calculation is 377.1086；Detected value is 377.1089.
Embodiment 3
In the dry pressure reaction tube of 15mL, add 419mg 4-(2-(4-tolyl) methoxyl group) phenyl-1-p-toluenesulfonyl-1,2,3-triazoles, 11.8mg Rh2(S-PTV)4The dichloromethane of (four (2-phthalimide group-3 Methylbutanoic acid) two rhodiums) and 3.0ml.Under a nitrogen, 90 DEG C of stirring reactions 2 hours.Reaction end is cooled to room temperature, removes dichloromethane solvent, adds anhydrous ethanol solvent, palladium/carbon catalyst (3%), 1atmH2Lower 45 DEG C are continued reaction 3h.Products therefrom is direct crosses silicagel column (volume ratio of petroleum ether and ethyl acetate is 10:1), obtains product 344mg, productivity 88%, and course of reaction is shown below:
The product that the present embodiment is prepared carries out nuclear magnetic resonance, NMR and mass spectral analysis:
1HNMR(400MHz,CDCl3): δ=7.76 (d, J=8.0Hz, 2H), 7.51 (d, J=8.0Hz, 2H), 7.45 (d, J=8.4Hz, 1H), 7.29-7.31 (m, 4H), 7.17-7.22 (m, 3H), 4.51 (br, 1H), 4.42 (d, J=5.6Hz, 2H), 2.46 (s, 3H), 2.41 (s, 3H)；
13CNMR(400MHz,CDCl3): δ=153.8,143.6,139.3,136.4,129.7,129.6,129.5,129.4,128.8,12 7.4,127.1,124.7,123.0,119.2,111.2,109.4,37.7,21.6,21.4；
HRMS: molecular formula is C23H21NO3S；Value of calculation is 391.1242；Detected value is 391.1244.
Embodiment 4
In the dry pressure reaction tube of 15mL, add 419mg 4-(2-(3-tolyl) methoxyl group) phenyl-1-p-toluenesulfonyl-1,2,3-triazoles, 11.8mg Rh2(S-PTV)4The dichloromethane of (four (2-phthalimide group-3 Methylbutanoic acid) two rhodiums) and 3.0ml.Under a nitrogen, 90 DEG C of stirring reactions 2 hours.Reaction end is cooled to room temperature, removes dichloromethane solvent, adds anhydrous ethanol solvent, palladium/carbon catalyst (3%), 1atmH2Lower 45 DEG C are continued reaction 3h.Products therefrom is direct crosses silicagel column (volume ratio of petroleum ether and ethyl acetate is 10:1), obtains product 348mg, productivity 89%, and course of reaction is shown below:
The product that the present embodiment is prepared carries out nuclear magnetic resonance, NMR and mass spectral analysis:
1HNMR(400MHz,CDCl3): δ=7.73 (d, J=8.0Hz, 2H), 7.38 (d, J=7.6Hz, 1H), 7.33 (d, J=7.6Hz, 1H), 7.25-7.30 (m, 3H), 7.16-7.21 (m, 2H), 4.66 (t, J=5.2Hz, 1H), 4.41 (d, J=5.2,2H), 2.43 (s, 3H), 2.38 (s, 3H)；
13CNMR(400MHz,CDCl3): δ=153.9,153.6,143.6,138.7,136.4,129.9,129.7,129.6,128.8,12 8.7,127.8,127.3,124.9,124.3,123.0,119.3,111.2,109.9,37.8,21.5,21.4；
HRMS: molecular formula is C23H21NO3S；Value of calculation is 391.1242；Detected value 391.1240.
Embodiment 5
In the dry pressure reaction tube of 15mL, add 439mg 4-(2-(4-chlorphenyl) methoxyl group) phenyl-1-p-toluenesulfonyl-1,2,3-triazoles, 11.8mg Rh2(S-PTV)4The dichloromethane of (four (2-phthalimide group-3 Methylbutanoic acid) two rhodiums) and 3.0ml.Under a nitrogen, 90 DEG C of stirring reactions 2 hours.Reaction end is cooled to room temperature, removes dichloromethane solvent, adds anhydrous ethanol solvent, palladium/carbon catalyst (3%), 1atmH2Lower 45 DEG C are continued reaction 3h.Products therefrom is direct crosses silicagel column (volume ratio of petroleum ether and ethyl acetate is 9:1), obtains product 285mg, productivity 57%, and course of reaction is shown below:
The product that the present embodiment is prepared carries out nuclear magnetic resonance, NMR and mass spectral analysis:
1HNMR(400MHz,CDCl3): δ=7.75 (d, J=8.0Hz, 2H), 7.56 (d, J=8.8Hz, 2H), 7.45 (d, J=8.0Hz, 1H), 7.29-7.39 (m, 6H), 7.18-7.22 (m, 1H), 4.57 (br, 1H), 4.39 (d, J=5.2Hz, 2H), 2.47 (s, 3H)；
13CNMR(100MHz,CDCl3): δ=153.8,152.2,143.8,136.2,135.1,129.7,129.1,128.6,128.4,12 8.1,127.3,125.2,123.2,119.3,111.2,110.4,37.6,21.6
HRMS: molecular formula is C22H18ClNO3S；Value of calculation is 411.0696；Detected value is 411.0700.
Embodiment 6
In the dry pressure reaction tube of 15mL, add 435mg 4-(2-(4-methoxyphenyl) methoxyl group) phenyl-1-p-toluenesulfonyl-1,2,3-triazoles, 11.8mg Rh2(S-PTV)4The dichloromethane of (four (2-phthalimide group-3 Methylbutanoic acid) two rhodiums) and 3.0ml.Under a nitrogen, 90 DEG C of stirring reactions 2 hours.Reaction end is cooled to room temperature, removes dichloromethane solvent, adds anhydrous ethanol solvent, palladium/carbon catalyst (3%), 1atmH2Lower 45 DEG C are continued reaction 3h.Products therefrom is direct crosses silicagel column (volume ratio of petroleum ether and ethyl acetate is 9:1), obtains product 280mg, productivity 70%, and course of reaction is shown below:
The product that the present embodiment is prepared carries out nuclear magnetic resonance, NMR and mass spectral analysis:
1HNMR (400MHz, CDCl3): δ=7.76 (d, J=8.0Hz, 2H), 7.56 (d, J=8.0Hz, 2H), 7.43 (d, J=8.4Hz, 1H), 7.26-7.31 (m, 4H), 7.15-7.18 (m, 1H), 6.92 (d, J=8.4Hz, 2H), 4.54 (br, 1H), 4.39 (d, J=5.2Hz, 2H), 3.86 (s, 3H), 2.46 (s, 3H)；
13CNMR (100MHz, CDCl3): δ=160.3,153.7,153.6,143.7,136.3,129.7,128.8,128.6,127.4,12 4.5,122.9,122.3,118.9,114.4,111.1,108.5,55.4,37.8,21.6；
HRMS: molecular formula C23H21NO4S；Value of calculation is 407.1191；Detected value is 407.1193.
Embodiment 7
In the dry pressure reaction tube of 15mL, add 435mg 4-(2-(3-trifluoromethyl) methoxyl group) phenyl-1-p-toluenesulfonyl-1,2,3-triazoles, 11.8mg Rh2(S-PTV)4The dichloromethane of (four (2-phthalimide group-3 Methylbutanoic acid) two rhodiums) and 3.0ml.Under a nitrogen, 90 DEG C of stirring reactions 2 hours.Reaction end is cooled to room temperature, removes dichloromethane solvent, adds anhydrous ethanol solvent, palladium/carbon catalyst (3%), 1atmH2Lower 45 DEG C are continued reaction 3h.Products therefrom is direct crosses silicagel column (volume ratio of petroleum ether and ethyl acetate is 9:1), obtains product 378mg, productivity 85%, and course of reaction is shown below:
The product that the present embodiment is prepared carries out nuclear magnetic resonance, NMR and mass spectral analysis:
1HNMR(400MHz,CDCl3): δ=7.95 (s, 1H), 7.81 (d, J=7.6Hz, 1H), 7.71 (d, J=8.0Hz, 2H), 7.64 (d, J=7.6Hz, 1H), 7.52 (t, J=7.6Hz, 1H), 7.47 (d, J=8.0Hz, 1H), 7.39 (d, J=7.6Hz, 1H), 7.32 (t, J=7.6Hz, 1H), 7.20-7.25 (m, 3H), 4.76 (t, J=5.2Hz, 1H), 4.41 (d, J=5.2Hz, 2H), 2.43 (s, 3H)；
13CNMR(100MHz,CDCl3): δ=153.9,151.5,143.8,136.1,131.6,131.3,130.5,130.2,129.7,12 9.4,128.4,127.2,125.6,125.5,124.0,123.9,123.3,119.6,111. 3,37.6,21.5；
HRMS: molecular formula C23H18F3NO3S；Value of calculation is 445.0959；Detected value is 445.0962.
Embodiment 8
In the dry pressure reaction tube of 15mL, add 423mg 4-(2-(3-fluorophenyl) methoxyl group) phenyl-1-p-toluenesulfonyl-1,2,3-triazoles, 11.8mg Rh2(S-PTV)4The dichloromethane of (four (2-phthalimide group-3 Methylbutanoic acid) two rhodiums) and 3.0ml.Under a nitrogen, 90 DEG C of stirring reactions 2 hours.Reaction end is cooled to room temperature, removes dichloromethane solvent, adds anhydrous ethanol solvent, palladium/carbon catalyst (3%), 1atmH2Lower 45 DEG C are continued reaction 3h.Products therefrom is direct crosses silicagel column (volume ratio of petroleum ether and ethyl acetate is 10:1), obtains product 348mg, productivity 88%, and course of reaction is shown below:
The product that the present embodiment is prepared carries out nuclear magnetic resonance, NMR and mass spectral analysis:
1HNMR(400MHz,CDCl3): δ=7.74 (d, J=8.0Hz, 2H), 7.46 (d, J=8.0Hz, 1H), 7.26-7.41 (m, 7H), 7.21 (t, J=7.6Hz, 1H), 7.09 (t, J=8.0Hz, 1H), 4.59 (br, 1H), 4.42 (d, J=5.2Hz, 2H), 2.45 (s, 3H)；
13CNMR(100MHz,CDCl3): δ=153.8,151.9,143.8,136.2,131.7,130.5,129.7,128.5,127.3,12 5.4,123.2,122.8,119.5,116.0,114.1,111.1,37.5,21.6；
HRMS: molecular formula C22H18FNO3S；Value of calculation is 395.0991；Detected value is 395.0991.
Embodiment 9
In the dry pressure reaction tube of 15mL, add 395mg 4-(2-(2-fluorophenyl) methoxyl group) phenyl-1-p-toluenesulfonyl-1,2,3-triazoles, 11.8mg Rh2(S-PTV)4The dichloromethane of (four (2-phthalimide group-3 Methylbutanoic acid) two rhodiums) and 3.0ml.Under a nitrogen, 90 DEG C of stirring reactions 2 hours.Reaction end is cooled to room temperature, removes dichloromethane solvent, adds anhydrous ethanol solvent, palladium/carbon catalyst (3%), 1atmH2Lower 45 DEG C are continued reaction 3h.Products therefrom is direct crosses silicagel column (volume ratio of petroleum ether and ethyl acetate is 10:1), obtains product 284mg, productivity 72%, and course of reaction is shown below:
The product that the present embodiment is prepared carries out nuclear magnetic resonance, NMR and mass spectral analysis:
1HNMR(400MHz,CDCl3): δ=7.72 (d, J=7.6Hz, 2H), 7.56-7.60 (m, 2H), 7.46 (d, J=8.0Hz, 1H), 7.38-7.42 (m, 1H), 7.31-7.35 (m, 1H), 7.22-7.26 (m, 4H), 7.11 (t, J=9.2Hz, 1H), 4.66 (br, 1H), 4.27 (d, J=6.0Hz, 2H), 2.42 (s, 3H)；
13CNMR(100MHz,CDCl3): δ=154.7,147.6,143.5,136.5,131.2,131.1,130.7,129.6,128.1,12 7.2,125.2,124.7,123.2,120.2,116.3,116.1,113.3,111.2,37.8,21.5；
HRMS: molecular formula C22H18FNO3S；Value of calculation is 395.0991；Detected value is 395.0988.
Embodiment 10
In the dry pressure reaction tube of 15mL, add 411mg 4-(2-(2-chlorphenyl) methoxyl group) phenyl-1-p-toluenesulfonyl-1,2,3-triazoles, 11.8mg Rh2(S-PTV)4The dichloromethane of (four (2-phthalimide group-3 Methylbutanoic acid) two rhodiums) and 3.0ml.Under a nitrogen, 90 DEG C of stirring reactions 2 hours.Reaction end is cooled to room temperature, removes dichloromethane solvent, adds anhydrous ethanol solvent, palladium/carbon catalyst (3%), 1atmH2Lower 45 DEG C are continued reaction 3h.Products therefrom is direct crosses silicagel column (volume ratio of petroleum ether and ethyl acetate is 10:1), obtains product 152mg, productivity 37%, and course of reaction is shown below:
The product that the present embodiment is prepared carries out nuclear magnetic resonance, NMR and mass spectral analysis:
1HNMR(400MHz,CDCl3): δ=7.70 (d, J=8.4Hz, 2H), 7.57 (d, J=7.6Hz, 1H), 7.45-7.48 (m, 2H), 7.40-7.42 (m, 2H), 7.32-7.37 (m, 2H), 7.23-7.27 (m, 3H), 4.60 (t, J=5.2Hz, 1H), 4.21 (d, J=5.2Hz, 2H), 2.42 (s, 3H)；
13CNMR(400MHz,CDCl3): δ=154.6,150.7,143.5,136.4,133.9,132.2,130.9,130.2,129.7,12 8.7,127.6,127.2,126.9,125.2,123.1,120.3,113.3,111.4,38.0,21.5；
HRMS: molecular formula C22H18ClNO3S；Value of calculation 411.0696；Detected value 411.0696.
Embodiment 11
In the dry pressure reaction tube of 15mL, add 411mg 4-(2-benzyloxy-5-chlorine) phenyl-1-p-toluenesulfonyl-1,2,3-triazoles, 11.8mg Rh2(S-PTV)4The dichloromethane of (four (2-phthalimide group-3 Methylbutanoic acid) two rhodiums) and 3.0ml.Under a nitrogen, 90 DEG C of stirring reactions 2 hours.Reaction end is cooled to room temperature, removes dichloromethane solvent, adds anhydrous ethanol solvent, palladium/carbon catalyst (3%), 1atmH2Lower 45 DEG C are continued reaction 3h.Products therefrom is direct crosses silicagel column (volume ratio of petroleum ether and ethyl acetate is 8:1), obtains product 304mg, productivity 74%, and course of reaction is shown below:
The product that the present embodiment is prepared carries out nuclear magnetic resonance, NMR and mass spectral analysis:
1HNMR(400MHz,CDCl3): δ=7.75 (d, J=8.0Hz, 2H), 7.60-7.62 (m, 2H), 7.45 (d, J=8.4Hz, 1H), 7.39-7.41 (m, 3H), 7.27-7.32 (m, 3H), 7.19 (t, J=7.6Hz, 1H), 4.57 (br, 1H), 4.42 (d, J=5.2Hz, 2H), 2.45 (s, 3H)；
13CNMR(100MHz,CDCl3): δ=153.8,153.4,143.7,136.3,129.7,129.1,128.9,128.7,127.3,12 7.2,124.9,123.0,119.4,111.2,110.0,37.7,21.6；
HRMS: molecular formula C22H18ClNO3S；Value of calculation 411.0696；Detected value 411.0694.
Claims (5)
1. the method preparing 2,3-disubstituted benzofuran analog derivatives, it is characterised in that comprise the following steps:
(1) under the effect of rhodium catalyst, 1-sulfonyl-1,2,3-triazoles compounds reacts and obtains imine intermediate；
The structure of described 1-sulfonyl-1,2,3-triazole class compounds is such as shown in formula II:
(2) under palladium/carbon catalyst and hydrogen effect, the imine intermediate that step (1) obtains reacts and obtains 2,3-described disubstituted benzofuran analog derivatives；
In formula I and formula II, R1For C1～C12One in alkyl, substituted or unsubstituted aryl, described aryl is phenyl or naphthyl, R1In aryl on substituent group independent selected from halo ,-CF3Or C1～C4Alkyl；R2For hydrogen, halogen atom or C1～C6Alkyl；R3For phenyl or p-methylphenyl；
In step (1), described rhodium catalyst is four (2-phthalimide group-3 Methylbutanoic acid) two rhodiums.
2. the method preparing 2,3-disubstituted benzofuran analog derivatives as claimed in claim 1, it is characterised in that in step (1), the mol ratio of described rhodium catalyst and described 1-sulfonyl-1,2,3-triazoles compounds is 0.005～0.02:1；
In step (2), the mol ratio of described palladium/carbon catalyst and described 1-sulfonyl-1,2,3-triazoles compounds is 0.001～0.05:1, and the pressure of hydrogen is 1.0 atmospheric pressure.
3. the method preparing 2,3-disubstituted benzofuran analog derivatives as claimed in claim 1, it is characterised in that the reaction temperature of step (1) and step (2) is 80～120 DEG C；Response time is 1～4h.
4. preparation 2 as claimed in claim 1, the method of 3-disubstituted benzofuran analog derivative, it is characterized in that, the reaction of step (1) carries out in dichloromethane, chloroform, toluene, dimethylbenzene, sym-trimethylbenzene., ethyl acetate or 1,2-dichloroethanes；
The reaction of step (2) is at C1～C5Alkylol carries out.
5. the method preparing 2,3-disubstituted benzofuran analog derivatives as claimed in claim 4, it is characterised in that after the reaction in step (1) completes, removing solvent obtains imine intermediate and is directly added into described C1～C5Alkylol and palladium/carbon catalyst, at 1atmH2The reaction of step (2) is carried out under existence.
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