CN105820174A - Polysubstituted thienoindole derivative and preparation method thereof - Google Patents
Polysubstituted thienoindole derivative and preparation method thereof Download PDFInfo
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- CN105820174A CN105820174A CN201610218479.5A CN201610218479A CN105820174A CN 105820174 A CN105820174 A CN 105820174A CN 201610218479 A CN201610218479 A CN 201610218479A CN 105820174 A CN105820174 A CN 105820174A
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- arh
- cyclohexyl
- thieno
- indole
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- 238000002360 preparation method Methods 0.000 title claims description 13
- KWQMJXZUGBNSOY-UHFFFAOYSA-N 1h-thieno[2,3-g]indole Chemical class C1=C2SC=CC2=C2NC=CC2=C1 KWQMJXZUGBNSOY-UHFFFAOYSA-N 0.000 title abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 239000002904 solvent Substances 0.000 claims abstract description 16
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000002527 isonitriles Chemical class 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- 229910052759 nickel Inorganic materials 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- -1 methoxyl group Chemical group 0.000 claims description 16
- SHWZFQPXYGHRKT-FDGPNNRMSA-N (z)-4-hydroxypent-3-en-2-one;nickel Chemical compound [Ni].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O SHWZFQPXYGHRKT-FDGPNNRMSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- 241001597008 Nomeidae Species 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 150000003577 thiophenes Chemical class 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 150000007984 tetrahydrofuranes Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 63
- 238000004440 column chromatography Methods 0.000 abstract description 11
- 238000000034 method Methods 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000000047 product Substances 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 239000012043 crude product Substances 0.000 abstract 2
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 238000001816 cooling Methods 0.000 abstract 1
- 239000000706 filtrate Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 11
- 238000007789 sealing Methods 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000012265 solid product Substances 0.000 description 10
- XYZMOVWWVXBHDP-UHFFFAOYSA-N cyclohexyl isocyanide Chemical compound [C-]#[N+]C1CCCCC1 XYZMOVWWVXBHDP-UHFFFAOYSA-N 0.000 description 8
- MLAXVEHWMLUSFO-UHFFFAOYSA-N indol-2-imine Chemical class C1=CC=CC2=NC(=N)C=C21 MLAXVEHWMLUSFO-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- 229940117953 phenylisothiocyanate Drugs 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- MTCDZEJRPZTGIK-UHFFFAOYSA-N 2H-thieno[2,3-b]indole Chemical class S1C=2C(=CC1)C1=CC=CC=C1N=2 MTCDZEJRPZTGIK-UHFFFAOYSA-N 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- RDKFRGLXFKQDIT-UHFFFAOYSA-N 5-cyclopropyl-5-isothiocyanatocyclohexa-1,3-diene Chemical compound C1(CC1)C1(CC=CC=C1)N=C=S RDKFRGLXFKQDIT-UHFFFAOYSA-N 0.000 description 1
- VNDRRFQFJVFMDG-UHFFFAOYSA-N C1=CC=C(C(=C1)C#CC2=CC=C(C=C2)N=C=S)N=C=S Chemical compound C1=CC=C(C(=C1)C#CC2=CC=C(C=C2)N=C=S)N=C=S VNDRRFQFJVFMDG-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 238000006647 Pauson-Khand annulation reaction Methods 0.000 description 1
- QKFJKGMPGYROCL-UHFFFAOYSA-N Phenyl isothiocyanate Natural products S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 1
- UMYVESYOFCWRIW-UHFFFAOYSA-N cobalt;methanone Chemical compound O=C=[Co] UMYVESYOFCWRIW-UHFFFAOYSA-N 0.000 description 1
- 229920001940 conductive polymer Polymers 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005518 electrochemistry Effects 0.000 description 1
- 238000005401 electroluminescence Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000002808 molecular sieve Substances 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
- 238000000746 purification Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
The invention discloses a method for preparing a polysubstituted thienoindole derivative, and the method belongs to the technical field of organic synthesis. The method comprises the following steps: adding ortho-alkynyl isothiocyanate and isonitrile into a reactor; under the catalysis of nickel, heating an obtained mixture in a solvent, cooling an obtained reaction product to a room temperature after completing the reaction, extracting a system by ethyl acetate, then concentrating a filtrate by a rotary evaporator to obtain a crude product, and finally separating the crude product by a column chromatography to obtain a product. The method for preparing the polysubstituted thienoindole derivative, which is provided by the invention, is scientific and reasonable, the productivity is relatively high and the product is purified easily.
Description
Technical field
The invention belongs to technical field of organic synthesis, particularly to the preparation method of a kind of polysubstituted 2H-thieno [2,3-b] indole derivatives.
Background technology
Thieno indole derivatives be a class common there is biological activity and heterocyclic compound that pharmacologically active is widely present in natural product.A lot of thieno indole derivatives have biological activity and the pharmacologically actives such as sterilization, resisting hypertension, antidepressant, antiallergic, malaria, antitumor, as 2H-thieno [2,3-b] indole derivatives can be converted into a kind of compound controlling rice seedlings activity further.
The synthesis application of thieno indole derivatives has exceeded field of medicaments, gradually extends to technical field of material chemistry, as high-performance conductive polymer and organic electroluminescence device etc. are prepared in thieno indole derivatives electrochemistry copolymerization.
Thieno indole derivatives has extensive use in these fields so that the synthesis of these compounds has the meaning of particular importance.
The preparation method of thieno indole derivatives has:
1) PeterLanger synthetic method: 3-halo chromone, beta-keto acyl amine and 1,3-indoline-2-thioketone reacts, obtains thieno indole derivatives.
2) TakashiOtani synthetic method: 2-alkyl phenyl isothiocyanate is cyclization under trifluoromethanesulfonic acid is catalyzed, and obtains thieno indole derivatives.
3) TakaoSaito synthetic method: adjacent alkynyl isothiocyanate, under the catalysis of carbonyl cobalt or molybdenum carbonyl, obtains thieno indole derivatives by Pauson-Khand reaction.
Utilizing said method to prepare thieno indole derivatives in the lab, there is obvious shortcoming: 1) synthesis step is many, complex operation, catalytic metal expensive.2) reaction is carried out under strong acid or strong alkaline condition, big for environment pollution；3) portion of reagent toxicity is big, severe reaction conditions.
Summary of the invention
In order to overcome above-mentioned the deficiencies in the prior art, the invention provides a kind of polysubstituted thiophene diindyl derivant and preparation method thereof.
A kind of polysubstituted thiophene diindyl derivant, has a structure shown in formula I:
In formula I, wherein R1Selected from cyclohexyl, normal-butyl, the tert-butyl group, 2,6-3,5-dimethylphenyl；R2Selected from fluorine atom, chlorine atom, bromine atoms, saturated three-membered ring, the tert-butyl group, thienyl, phenyl, substituted aryl, substituted radical therein is fluorine atom, chlorine atom, methyl, methoxyl group；R3Selected from hydrogen atom, fluorine atom, chlorine atom, methyl, methoxyl group；R4Selected from hydrogen atom, fluorine atom, chlorine atom, methyl.
By adjacent alkynyl isothiocyanate and isonitrile, under nickel is catalyzed, solvent obtains after reacting by heating a kind of polysubstituted thiophene diindyl derivant；This preparation method below equation II represents:
The Raney nickel selected is nickel acetylacetonate, the consumption of nickel acetylacetonate is the 0.3% of the amount of adjacent alkynyl isothiocyanate materials, and the molar ratio of adjacent alkynyl isothiocyanate and isonitrile is 1.0:1.2, and the solvent of selection is oxolane, reaction temperature is 80 DEG C, and the response time is 5h.
The invention have the benefit that the synthetic method of the polysubstituted thiophene diindyl derivant that the present invention provides is scientific and reasonable, 2H-thieno [2, the 3-b] indole derivatives obtaining having various substituent group can be synthesized；And also it is simple to have synthetic method, productivity is higher, product is prone to the features such as purification.
Accompanying drawing explanation
Fig. 1 is the compound of embodiment 5 preparation1HNMR、13CNMR collection of illustrative plates；
Fig. 2 is the compound of embodiment 7 preparation1HNMR、13CNMR collection of illustrative plates；
Fig. 3 is the compound of embodiment 10 preparation1HNMR、13CNMR collection of illustrative plates；
Detailed description of the invention
The present invention is described in more detail with specific embodiment below in conjunction with the accompanying drawings:
Test method described in following embodiment, if no special instructions, is conventional method；Described reagent and material, if no special instructions, the most commercially obtain.
Solvent used in following embodiment all processes through anhydrous and oxygen-free or adds the molecular sieve after activating before using and carries out simple process.
Embodiment 1:(Z)-N-cyclohexyl-3-phenyl-2H-thieno [2,3-b] indole-2-amine (R in structural formula I1=cyclohexyl, R2=phenyl, R3=hydrogen atom, R4=hydrogen atom)
2-phenylacetylene base-phenyl isothiocyanate (1.0mmol is added in 25mL round-bottomed flask, 235mg), cyclohexyl isonitrile (1.2mmol, 153uL) with nickel acetylacetonate (0.003mmol, 0.88mg), add the oxolane that 3.0mL heavily steams, after sealing mouth, put into reaction 5h in the oil bath of 80 DEG C.After reaction completely, it is cooled to room temperature, system is extracted with ethyl acetate, then solvent is evaporated with Rotary Evaporators, residue obtains purity red solid product (Z)-N-cyclohexyl-3-phenyl-2H-thieno [2, the 3-b] indole-2-amine 336mg more than 99% through column chromatography for separation (200-300 mesh silica gel) (petrol ether/ethyl acetate=20/1) and separates productivity 96%.
(Z) Structural Identification of-N-cyclohexyl-3-phenyl-2H-thieno [2,3-b] indole-2-amine:
1HNMR(CDCl3, 500MHz): δ=1.26 1.35 (m, 1H, CH2),1.40–1.47(m,2H,CH2),1.61–1.70(m,4H,2×CH2),1.82–1.87(m,4H,2×CH2), 3.40 3.44 (m, 1H, CH), 6.9 (t, J=7.5Hz, 1H, ArH), 7.32 (t, J=7.6Hz, 1H, ArH), 7.41 (d, J=7.6Hz, 1H, ArH), 7.51 7.55 (m, 3H, ArH), 7.60 (d, J=7.5Hz, 1H, ArH), 7.74 7.76 (m, 2H, ArH)；13CNMR(CDCl3, 125MHz): δ=24.1,25.4,33.3,69.5,119.9,123.10,124.3,125.6,128.2,130.1,130.7,131.4,131.6,142.6,147.4,161.1,161.2,175.2.HRMS (ESI-TOF, [M+H]+):calcdforC22H20FN2S,345.1425,found345.1428
Embodiment 2:(Z)-N-cyclohexyl-3-(4-fluorophenyl)-2H-thieno [2,3-b] indole-2-imines (R in structural formula I1=cyclohexyl, R2=to fluorophenyl, R3=hydrogen atom, R4=hydrogen atom)
(3-fluorophenyl) acetenyl-phenyl isothiocyanate (1.0mmol is added in 25mL round-bottomed flask, 253mg), cyclohexyl isonitrile (1.2mmol, 153uL) with nickel acetylacetonate (0.003mmol, 0.88mg), add the oxolane that 3.0mL heavily steams, after sealing mouth, put into reaction 5h in the oil bath of 80 DEG C.After reaction completely, it is cooled to room temperature, system is extracted with ethyl acetate, then solvent is evaporated with Rotary Evaporators, residue obtains purity red solid product (Z)-N-cyclohexyl-3-(4-fluorophenyl)-2H-thieno [2, the 3-b] indole-2-imines 294mg more than 99% through column chromatography for separation (200-300 mesh silica gel) (petrol ether/ethyl acetate=20/1) and separates productivity 95%.
(Z) Structural Identification of-N-cyclohexyl-3-(4-fluorophenyl)-2H-thieno [2,3-b] indole-2-imines:
1HNMR(CDCl3, 500MHz): δ=1.23 1.35 (m, 1H, CH2),1.38–1.46(m,2H,CH2),1.58–1.67(m,4H,2×CH2),1.79–1.85(m,4H,2×CH2), 3.37 3.42 (m, 1H, CH), 6.98 (t, J=7.6Hz, 1H, ArH), 7.20 (t, J=8.7Hz, 2H, ArH), 7.31 (t, J=7.6Hz, 1H, ArH), 7.39 (d, J=7.7Hz, 1H, ArH), 7.54 (d, J=7.5Hz, 1H, ArH), 7.72-7.75 (m, 2H, ArH)；13CNMR(CDCl3,125MHz)；δ=24.1,25.5,33.4,69.4,115.5 (d, JC-F=21.6Hz), 120.0,123.0,124.4,125.5,127.4,131.7,132.8,141.3,147.3,16 1.2,161.2,163.7 (d, JC-F=251.4Hz), 175.0.HRMS (ESI-TOF, [M+H]+):calcdforC22H20FN2S,363.1331,found363.1342.
Embodiment 3:(Z)-N-cyclohexyl-5-fluoro-3-phenyl-2H-thieno [2,3-b] indole-2-amine (R in structural formula I1=cyclohexyl, R2=phenyl, R3=fluorine atom, R4=hydrogen atom)
The fluoro-2-of 4-(phenylene-ethynylene)-phenyl isothiocyanate (1.0mmol is added in 25mL round-bottomed flask, 253mg), cyclohexyl isonitrile (1.2mmol, 153uL) with nickel acetylacetonate (0.003mmol, 0.88mg), add the oxolane that 3.0mL heavily steams, after sealing mouth, put into reaction 5h in the oil bath of 80 DEG C.After reaction completely, it is cooled to room temperature, system is extracted with ethyl acetate, then solvent is evaporated with Rotary Evaporators, residue obtains purity red solid product (Z)-N-cyclohexyl-5-fluoro-3-phenyl-2H-thieno [2, the 3-b] indole-2-amine 330mg more than 99% through column chromatography for separation (200-300 mesh silica gel) (petrol ether/ethyl acetate=20/1) and separates productivity 93%.
(Z) Structural Identification of-N-cyclohexyl-5-fluoro-3-phenyl-2H-thieno [2,3-b] indole-2-amine:
1HNMR(CDCl3, 500MHz): δ=1.24 1.35 (m, 1H, CH2),1.39–1.46(m,2H,CH2),1.61–1.67(m,4H,2×CH2),1.80–1.86(m,4H,2×CH2),3.39–3.43(m,1H,CH),7.00(td,1J=8.8Hz,2J=2.4Hz, 1H, ArH), 7.28 (dd,1J=8.2Hz,2J=2.4Hz, 1H, ArH), 7.31 7.33 (m, 1H, ArH), 7.52 7.54 (m, 3H, ArH), 7.70 7.71 (m, 2H, ArH)；13CNMR(CDCl3,125MHz)；δ=24.0,25.5,33.4,69.5,110.7 (d, JC-F=26.3Hz), 117.4 (d, JC-F=22.3Hz), 120.2,126.8,128.4,130.4,130.6,131.1,143.9,146.8,157.2,15 9.1,160.1 (d, JC-F=244.0Hz), 160.9,174.7.HRMS (ESI-TOF, [M+H]+):calcdforC22H20FN2S,363.1331,found363.1339
Embodiment 4:(Z)-N-cyclohexyl-3-(4-methoxyphenyl)-2H-thieno [2,3-b] indole-2-amine (R in structural formula I1=cyclohexyl, R2=p-methoxyphenyl, R3=hydrogen atom, R4=hydrogen atom)
(3-methoxyphenyl)-acetenyl-phenyl isothiocyanate (1.0mmol is added in 25mL round-bottomed flask, 265mg), cyclohexyl isonitrile (1.2mmol, 153uL) with nickel acetylacetonate (0.003mmol, 0.88mg), add the oxolane that 3.0mL heavily steams, after sealing mouth, put into reaction 5h in the oil bath of 80 DEG C.After reaction completely, it is cooled to room temperature, system is extracted with ethyl acetate, then solvent is evaporated with Rotary Evaporators, residue obtains purity red solid product (Z)-N-cyclohexyl-3-(4-methoxyphenyl)-2H-thieno [2, the 3-b] indole-2-amine 289mg more than 99% through column chromatography for separation (200-300 mesh silica gel) (petrol ether/ethyl acetate=20/1) and separates productivity 81%.
(Z) Structural Identification of-N-cyclohexyl-3-(4-methoxyphenyl)-2H-thieno [2,3-b] indole-2-amine:
1HNMR(CDCl3, 500MHz): δ=1.25 1.35 (m, 1H, CH2),1.39–1.47(m,2H,CH2),1.60–1.67(m,4H,2×CH2),1.80–1.87(m,4H,2×CH2),2.44(s,3H,OCH3), 3.39-3.43 (m, 1H, CH), 6.98 (t, J=7.6Hz, 1H, ArH), 7.29 7.32 (m, 2H, ArH), 7.39 7.42 (m, 2H, ArH), 7.52 7.55 (m, 2H, ArH), 7.58 (d, J=7.4Hz, 1H, ArH)；13CNMR(CDCl3,125MHz)；δ=21.4,24.1,25.5,33.4,69.4,119.9,123.1,124.3,125.8,127.9,1 28.1,130.8,131.3,131.5,137.8,142.9,147.3,161.2,175.2.HRM S (ESI-TOF, [M+H]+):calcdforC23H23N2OS,375.1531,found375.1529
Embodiment 5:(Z)-N-cyclohexyl-3-(p-methylphenyl)-2H-thieno [2,3-b] indole-2-amine (R in structural formula I1=cyclohexyl, R2=p-methylphenyl, R3=hydrogen atom, R4=hydrogen atom)
(4-tolyl)-acetenyl-phenyl isothiocyanate (1.0mmol is added in 25mL round-bottomed flask, 249mg), cyclohexyl isonitrile (1.2mmol, 153uL) with nickel acetylacetonate (0.003mmol, 0.88mg), add the oxolane that 3.0mL heavily steams, after sealing mouth, put into reaction 5h in the oil bath of 80 DEG C.After reaction completely, it is cooled to room temperature, system is extracted with ethyl acetate, then solvent is evaporated with Rotary Evaporators, residue obtains purity red solid product (Z)-N-cyclohexyl-3-(p-methylphenyl)-2H-thieno [2, the 3-b] indole-2-amine 302mg more than 99% through column chromatography for separation (200-300 mesh silica gel) (petrol ether/ethyl acetate=20/1) and separates productivity 84%.
(Z) Structural Identification of-N-cyclohexyl-3-(p-methylphenyl)-2H-thieno [2,3-b] indole-2-amine:
1HNMR(CDCl3, 500MHz): δ=1.26 1.34 (m, 1H, CH2),1.39–1.46(m,2H,CH2),1.59–1.67(m,4H,2×CH2),1.80–1.86(m,4H,2×CH2),2.45(s,3H,CH3), 3.38 3.43 (m, 1H, CH), 6.98 (t, J=7.5Hz, 1H, ArH), 7.29 7.33 (m, 3H, ArH), 7.39 (d, J=7.7Hz, 2H, ArH), 7.61 (d, J=7.4Hz, 1H, ArH), 7.65 (d, J=8.0Hz, 2H, ArH)；13CNMR(CDCl3,125MHz)；δ=21.6,24.1,25.5,33.4,69.5,119.8,123.1,124.3,125.7,128.5,1 29.0,130.7,131.4,140.5,142.8,146.9,161.0,161.4,175.1.HRM S (ESI-TOF, [M+H]+):calcdforC23H23N2S,359.1582,found359.1576
Embodiment 6:(Z)-N-cyclohexyl-3-cyclopropyl-2H-thieno [2,3-b] indole-2-amine (R in structural formula I1=cyclohexyl, R2=cyclopropyl, R3=hydrogen atom, R4=hydrogen atom)
1-cyclopropyl-phenyl isothiocyanate (1.0mmol is added in 25mL round-bottomed flask, 199mg), cyclohexyl isonitrile (1.2mmol, 153uL) with nickel acetylacetonate (0.003mmol, 0.88mg), add the oxolane that 3.0mL heavily steams, after sealing mouth, put into reaction 5h in the oil bath of 80 DEG C.After reaction completely, it is cooled to room temperature, system is extracted with ethyl acetate, then solvent is evaporated with Rotary Evaporators, residue obtains purity red solid product (Z)-N-cyclohexyl-3-cyclopropyl-2H-thieno [2, the 3-b] indole-2-amine 294mg more than 99% through column chromatography for separation (200-300 mesh silica gel) (petrol ether/ethyl acetate=20/1) and separates productivity 95%.
(Z) Structural Identification of-N-cyclohexyl-3-cyclopropyl-2H-thieno [2,3-b] indole-2-amine:
1HNMR(CDCl3, 500MHz): δ=1.21 1.28 (m, 2H, CH2),1.34–1.46(m,3H,CH2),1.57–1.64(m,4H,2×CH2),1.71–1.75(m,2H,CH2),1.81–1.82(m,4H,2×CH2), 2.42 2.47 (m, 1H, CH), 3.28 3.32 (m, 1H, CH), 7.07 (t, J=7.5Hz, 1H, ArH), 7.29 (t, J=7.7Hz, 1H, ArH), 7.38 (d, J=7.8Hz, 1H, ArH), 7.62 (d, J=7.4Hz, 1H, ArH)；13CNMR(CDCl3,125MHz)；δ=11.2,13.0,23.9,25.6,33.4,68.8,119.8,122.9,124.2,125.9,13 0.3,145.6,150.0,160.6,161.0,174.5.HRMS (ESI-TOF, [M+H]+):calcdforC19H21N2S,309.1425,found309.1432
Embodiment 7:(Z)-N-cyclohexyl-3-(trimethyl silyl)-2H-thieno [2,3-b] indole-2-amine (R in structural formula I1=cyclohexyl, R2=trimethyl is silica-based, R3=hydrogen atom, R4=hydrogen atom)
(2-isothiocyanatophenyl)-Ethynyl-trimethyl silane (1.0mmol is added in 25mL round-bottomed flask, 231mg), cyclohexyl isonitrile (1.2mmol, 153uL) with nickel acetylacetonate (0.003mmol, 0.88mg), add the oxolane that 3.0mL heavily steams, after sealing mouth, put into reaction 5h in the oil bath of 80 DEG C.After reaction completely, it is cooled to room temperature, system is extracted with ethyl acetate, then solvent is evaporated with Rotary Evaporators, residue obtains purity red solid product (Z)-N-cyclohexyl-3-(trimethyl silyl)-2H-thieno [2, the 3-b] indole-2-amine 201mg more than 99% through column chromatography for separation (200-300 mesh silica gel) (petrol ether/ethyl acetate=20/1) and separates productivity 59%.
(Z) Structural Identification of-N-cyclohexyl-3-(trimethyl silyl)-2H-thieno [2,3-b] indole-2-amine:
1HNMR(CDCl3, 500MHz): δ=0.46 (s, 9H, 3 × CH3),1.38–1.45(m,3H,CH2),1.61–1.66(m,3H,CH2),1.82–1.84(m,4H,2×CH2), 3.37 3.38 (m, 1H, CH), 7.06 (t, J=7.4Hz, 1H, ArH), 7.29 7.36 (m, 2H, ArH), 7.74 (d, J=7.5Hz, 1H, ArH)；13CNMR(CDCl3,125MHz)；δ=0.7,23.9,25.6,33.4,68.8,119.8,124.2,125.2,126.4,131.4,14 9.8,159.1,161.6,166.5,177.8.HRMS (ESI-TOF, [M+H]+):calcdforC19H25SiN2S,341.1508,found341.1501.
Embodiment 8:(Z)-N-cyclohexyl-6-methyl-3-phenyl-2H-thieno [2,3-b] indole-2-amine (R in structural formula I1=cyclohexyl, R2=phenyl, R3=hydrogen atom, R4=methyl)
4-methyl isophthalic acid-(phenethyl)-phenyl isothiocyanate (1.0mmol is added in 25mL round-bottomed flask, 249mg), cyclohexyl isonitrile (1.2mmol, 153uL) with nickel acetylacetonate (0.003mmol, 0.88mg), add the oxolane that 3.0mL heavily steams, after sealing mouth, put into reaction 5h in the oil bath of 80 DEG C.After reaction completely, it is cooled to room temperature, system is extracted with ethyl acetate, then solvent is evaporated with Rotary Evaporators, residue obtains purity red solid product (Z)-N-cyclohexyl-6-methyl-3-phenyl-2H-thieno [2, the 3-b] indole-2-amine 334mg more than 99% through column chromatography for separation (200-300 mesh silica gel) (petrol ether/ethyl acetate=20/1) and separates productivity 91%.
(Z) Structural Identification of-N-cyclohexyl-6-methyl-3-phenyl-2H-thieno [2,3-b] indole-2-amine:
1HNMR(CDCl3, 500MHz): δ=1.19 1.28 (m, 1H, CH2),1.32–1.39(m,2H,CH2),1.55–1.60(m,3H,CH2),1.73–1.79(m,4H,2×CH2),2.31(s,3H,CH3), 3.31-3.35 (m, 1H, CH), 6.71 (d, J=7.6Hz, 1H, ArH), 7.14 (s, 1H, ArH), 7.20 (s, 1H, ArH), 7.39 (d, J=7.7Hz, 1H, ArH), 7.42-7.45 (m, 3H, ArH), 7.65-7.67 (m, 2H, ArH)；13CNMR(CDCl3,125MHz)；δ=22.1,24.1,25.5,33.4,69.4,120.8,122.9,124.9,128.2,129.9,1 30.7,131.6,141.3,142.5,147.5,161.2,161.5,175.5.HRMS (ESI-TOF, [M+H]+):calcdforC23H23N2S,359.1582,found359.1576
Embodiment 9:(Z) and-N-normal-butyl-3-phenyl-2H-thieno [2,3-b] indole-2-amine (in structural formula I, R1=normal-butyl, R2=phenyl, R3=hydrogen atom, R4=hydrogen atom)
2-phenylene-ethynylene-phenyl isothiocyanate (1.0mmol is added in 25mL round-bottomed flask, 235mg), normal-butyl isonitrile (1.2mmol, 99.8mg) with nickel acetylacetonate (0.003mmol, 0.88mg), add the oxolane that 3.0mL heavily steams, after sealing mouth, put into reaction 5h in the oil bath of 80 DEG C.After reaction completely, it is cooled to room temperature, system is extracted with ethyl acetate, then solvent is evaporated with Rotary Evaporators, residue obtains purity red solid product (Z)-N-normal-butyl-3-phenyl-2H-thieno [2, the 3-b] indole-2-amine 290mg more than 99% through column chromatography for separation (200-300 mesh silica gel) (petrol ether/ethyl acetate=20/1) and separates productivity 94%.
(Z) Structural Identification of-N-normal-butyl-3-phenyl-2H-thieno [2,3-b] indole-2-amine:
1HNMR(CDCl3, 500MHz): δ=0.97 (t, J=7.3Hz, 3H, CH3), 1.46 (hexa, J=7.6Hz, 2H, CH2), 1.79 (penta, J=7.2Hz, 2H, CH2), 3.77 (t, J=6.9Hz, 2H, CH2), 6.98 (t, J=7.5Hz, 1H, ArH), 7.31 (t, J=7.6Hz, 1H, ArH), 7.40 (d, J=7.7Hz, 1H, ArH), 7.48 7.54 (m, 3H, ArH), 7.56 (d, J=7.5Hz, 1H, ArH), 7.70 7.72 (m, 2H, ArH)；13CNMR(CDCl3,125MHz)；δ=13.9,19.5,20.7,32.4,60.1,111.2,120.0,123.2,124.5,125.5,1 27.8,128.3,130.2,130.5,131.2,131.7,142.5,147.5,157.8,161 .1,164.0,175.0.HRMS (ESI-TOF, [M+H]+):calcdforC20H19N2S,319.1269,found319.1258
Embodiment 10:(Z) and-N-(2,6-3,5-dimethylphenyl)-3-phenyl-2H-thieno [2,3-b] indole-2-imines (in structural formula I, R1=2,5-3,5-dimethylphenyl, R2=phenyl, R3=hydrogen atom, R4=hydrogen atom)
2-phenylacetylene base-phenyl isothiocyanate (1.0mmol is added in 25mL round-bottomed flask, 235mg), 2,5-3,5-dimethylphenyl isonitrile (1.2mmol, 113mg) with nickel acetylacetonate (0.003mmol, 0.88mg), add the oxolane that 3.0mL heavily steams, after sealing mouth, put into reaction 5h in the oil bath of 80 DEG C.After reaction completely, it is cooled to room temperature, system is extracted with ethyl acetate, then solvent is evaporated with Rotary Evaporators, residue obtains purity red solid product (the Z)-N-(2 more than 99% through column chromatography for separation (200-300 mesh silica gel) (petrol ether/ethyl acetate=20/1), 6-3,5-dimethylphenyl)-3-phenyl-2H-thieno [2,3-b] indole-2-imines 242mg separates productivity 66%.
(Z) Structural Identification of-N-(2,6-3,5-dimethylphenyl)-3-phenyl-2H-thieno [2,3-b] indole-2-imines:
1HNMR(CDCl3, 500MHz): δ=2.13 (s, 6H, 2 × CH3), 6.99 7.04 (m, 2H, ArH), 7.07 7.09 (m, 2H, ArH), 7.32 (t, J=7.6Hz, 1H, ArH), 7.38 (d, J=7.6Hz, 1H, ArH), 7.53 7.61 (m, 4H, ArH), 7.86 (d, J=6.9Hz, 2H, ArH)；13CNMR(CDCl3,125MHz)；δ=18.1,120.3,123.6,124.9,125.2,125.6,125.8,128.2,128.6,130 .4,130.7,132.3,141.3,148.6,149.7,161.3,168.0,175.4.HRMS (ESI-TOF, [M+H]+):calcdforC24H19N2S,367.1269,found367.1258。
Claims (3)
1. a preparation method for polysubstituted thiophene diindyl derivant, described polysubstituted thiophene diindyl derivant has a structure shown in formula I:
In formula I, wherein R1Selected from cyclohexyl, normal-butyl, the tert-butyl group, 2,6-3,5-dimethylphenyl；R2Selected from fluorine atom, chlorine atom, bromine atoms, saturated three-membered ring, the tert-butyl group, thienyl, phenyl, substituted aryl, substituted radical therein is fluorine atom, chlorine atom, methyl, methoxyl group；R3Selected from hydrogen atom, fluorine atom, chlorine atom, methyl, methoxyl group；R4Selected from hydrogen atom, fluorine atom, chlorine atom, methyl；It is characterized in that, by adjacent alkynyl isothiocyanate and isonitrile, under nickel is catalyzed, solvent obtains after reacting by heating the polysubstituted thiophene diindyl derivant shown in formula I；This preparation method below equation represents:
Preparation method the most according to claim 1, it is characterized in that selected Raney nickel is nickel acetylacetonate, the consumption of nickel acetylacetonate is the 0.3% of the amount of adjacent alkynyl isothiocyanate materials, and the molar ratio of adjacent alkynyl isothiocyanate and isonitrile is 1.0:1.2.
Preparation method the most according to claim 1, it is characterised in that selected solvent is oxolane, reaction temperature is 80 DEG C, and the response time is 5h.
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| CN106432131A (en) * | 2016-09-22 | 2017-02-22 | 青岛科技大学 | Preparation method of tri-imine thiazole derivative |
| CN108947997A (en) * | 2018-08-09 | 2018-12-07 | 山东博苑医药化学有限公司 | The copper catalysis series connection cyclization that a kind of oxygen participates in constructs N-5- carbonyl thiazole indoles |
| CN114225967A (en) * | 2021-11-26 | 2022-03-25 | 华南理工大学 | Self-healing load type zirconium-based metal organic framework and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009205074A (en) * | 2008-02-29 | 2009-09-10 | Kyocera Mita Corp | Electrophotographic photoreceptor |
| CN105218553A (en) * | 2015-10-14 | 2016-01-06 | 李乃温 | A kind of synthetic method of pharmaceutical intermediate pyrrolo-indole compounds |
-
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Patent Citations (2)
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|---|---|---|---|---|
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| CN105218553A (en) * | 2015-10-14 | 2016-01-06 | 李乃温 | A kind of synthetic method of pharmaceutical intermediate pyrrolo-indole compounds |
Non-Patent Citations (3)
| Title |
|---|
| QIAN GAO，等: "Cobalt(II )/silver relay catalytic isocyanide insertion/cycloaddition cascades: a new access to pyrrolo[2,3-b]indoles", 《CHEM. COMMUN.》 * |
| TAKAO SAITO，等: "Tr ifl ic acid-promoted cycloisomerization of 2-alkynylphenyl isothiocyanates and isocyanates: a novel synthetic method for a variety of indole derivatives", 《ORG. BIOMOL. CHEM.》 * |
| ZHEN ZHANG，等: "Cyclization of Alkyne−Azide with Isonitrile/CO via Self-Relay Rhodium Catalysis", 《ORGANIC LETTERS》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432131A (en) * | 2016-09-22 | 2017-02-22 | 青岛科技大学 | Preparation method of tri-imine thiazole derivative |
| CN106432131B (en) * | 2016-09-22 | 2018-06-05 | 青岛科技大学 | A kind of preparation method of three imines thiazole |
| CN108947997A (en) * | 2018-08-09 | 2018-12-07 | 山东博苑医药化学有限公司 | The copper catalysis series connection cyclization that a kind of oxygen participates in constructs N-5- carbonyl thiazole indoles |
| CN114225967A (en) * | 2021-11-26 | 2022-03-25 | 华南理工大学 | Self-healing load type zirconium-based metal organic framework and preparation method and application thereof |
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