CN115286573A - Green synthesis method of 1-alkoxy isoquinoline compound - Google Patents
Green synthesis method of 1-alkoxy isoquinoline compound Download PDFInfo
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- CN115286573A CN115286573A CN202210941005.9A CN202210941005A CN115286573A CN 115286573 A CN115286573 A CN 115286573A CN 202210941005 A CN202210941005 A CN 202210941005A CN 115286573 A CN115286573 A CN 115286573A
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- alkoxyisoquinoline
- choline chloride
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- -1 1-alkoxy isoquinoline compound Chemical class 0.000 title claims abstract description 46
- 238000001308 synthesis method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 239000002904 solvent Substances 0.000 claims abstract description 30
- 230000005496 eutectics Effects 0.000 claims abstract description 27
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzenecarbonitrile Natural products N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- VAYTZRYEBVHVLE-UHFFFAOYSA-N 1,3-dioxol-2-one Chemical compound O=C1OC=CO1 VAYTZRYEBVHVLE-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000654 additive Substances 0.000 claims abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000000996 additive effect Effects 0.000 claims abstract description 10
- 238000010499 C–H functionalization reaction Methods 0.000 claims abstract description 9
- 239000010941 cobalt Substances 0.000 claims abstract description 9
- 229910017052 cobalt Inorganic materials 0.000 claims abstract description 9
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000007259 addition reaction Methods 0.000 claims abstract description 4
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 24
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 claims description 19
- 235000019743 Choline chloride Nutrition 0.000 claims description 19
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 claims description 19
- 229960003178 choline chloride Drugs 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 17
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 14
- 229960003237 betaine Drugs 0.000 claims description 13
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 7
- 150000005486 1-alkoxyisoquinolines Chemical group 0.000 claims description 3
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000005751 Copper oxide Substances 0.000 claims description 2
- 229910018286 SbF 6 Inorganic materials 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229940011182 cobalt acetate Drugs 0.000 claims description 2
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical group [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 claims description 2
- 229910000431 copper oxide Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940071536 silver acetate Drugs 0.000 claims description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 2
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 2
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 claims 2
- 229960000583 acetic acid Drugs 0.000 claims 1
- 235000011054 acetic acid Nutrition 0.000 claims 1
- 150000008359 benzonitriles Chemical class 0.000 claims 1
- 229960005150 glycerol Drugs 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 150000001868 cobalt Chemical class 0.000 abstract description 8
- 125000000524 functional group Chemical group 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 3
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 239000000374 eutectic mixture Substances 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000004064 recycling Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000000047 product Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000000376 reactant Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- AFWHVAFMAIDVTH-UHFFFAOYSA-N 1-methoxyisoquinoline Chemical compound C1=CC=C2C(OC)=NC=CC2=C1 AFWHVAFMAIDVTH-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- RZIAABRFQASVSW-UHFFFAOYSA-N Isoquinoline N-oxide Chemical compound C1=CC=CC2=C[N+]([O-])=CC=C21 RZIAABRFQASVSW-UHFFFAOYSA-N 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 150000002537 isoquinolines Chemical class 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 238000006053 organic reaction Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- QPXSLAHGOWGTMB-UHFFFAOYSA-N 1,5-dimethoxyisoquinoline Chemical compound N1=CC=C2C(OC)=CC=CC2=C1OC QPXSLAHGOWGTMB-UHFFFAOYSA-N 0.000 description 1
- DEWRCDDRJOMEOX-UHFFFAOYSA-N 1-(2,2,2-trifluoroethoxy)isoquinoline Chemical compound FC(COC1=NC=CC2=CC=CC=C12)(F)F DEWRCDDRJOMEOX-UHFFFAOYSA-N 0.000 description 1
- XDXCBCXNCQGZPG-UHFFFAOYSA-N 1-(2-iodophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1I XDXCBCXNCQGZPG-UHFFFAOYSA-N 0.000 description 1
- NLBFKZSJIHFJPA-UHFFFAOYSA-N 1-methoxy-6-methylisoquinoline Chemical compound CC1=CC=C2C(OC)=NC=CC2=C1 NLBFKZSJIHFJPA-UHFFFAOYSA-N 0.000 description 1
- RCBQGORSOSQECB-UHFFFAOYSA-N 4-chloro-1-methoxyisoquinoline Chemical compound C1=CC=C2C(OC)=NC=C(Cl)C2=C1 RCBQGORSOSQECB-UHFFFAOYSA-N 0.000 description 1
- PHIVVOIRMMJXNL-UHFFFAOYSA-N 5-chloro-1-methoxyisoquinoline Chemical compound C1=CC=C2C(OC)=NC=CC2=C1Cl PHIVVOIRMMJXNL-UHFFFAOYSA-N 0.000 description 1
- 239000002028 Biomass Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012363 selectfluor Substances 0.000 description 1
- 238000002691 topical anesthesia Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and discloses a green synthesis method of a 1-alkoxy isoquinoline compound, which comprises the steps of taking a benzonitrile compound and alcohol as initial raw materials for reaction, taking a eutectic mixture as a solvent, carrying out addition reaction, and then carrying out intramolecular C-H activation/cyclization reaction with vinylene carbonate under the action of a cobalt catalyst and an additive to prepare the 1-alkoxy isoquinoline compound. The invention has the advantages of simple and easily obtained starting materials, low price, high reaction selectivity and product yield, excellent compatibility of substrate functional groups, repeated recycling of a eutectic solvent/cobalt salt catalytic system and great reduction of production cost.
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and relates to a green synthesis method of a 1-alkoxy isoquinoline compound.
Background
The isoquinoline structure is an important organic composition structure, and most compounds containing the structure segment have excellent biological and pharmacological activities, such as antifungal activity, antitumor activity, antiviral activity and the like, so the isoquinoline structure has wide application in the fields of medicine and other related fields. Among them, the 1-alkoxy isoquinoline compound has better clinical application. For example, quinicaine, which is used for topical anesthesia, is more than 1000 times more anesthetized than cocaine and is less toxic. Therefore, in recent years, research on synthesis of 1-alkoxy-containing isoquinoline compounds is increasing at home and abroad.
The traditional synthesis of azacyclic ethers mainly comprises the reaction of azacyclic halides with alcohols under the action of strong alkali, however, the reaction temperature is high, and the yield is low. Londregan et al reported that synthesis of 1-alkoxyisoquinoline compounds was achieved under basic conditions using an isoquinoline N-oxide as a starting material and a trispyrrolidinylphosphonium bromide hexafluorophosphate (PyBroP) salt as an accelerator (org. Lett.,2016,18, 1362-1365. This method requires the use of relatively expensive trispyrrolidinylphosphonium bromide hexafluorophosphate (Aldrich, 280 yuan/g) and multi-step synthesis of substituent-containing isoquinoline N-oxide starting material.
In recent years, intramolecular C — H activation/cyclization by the "one-pot" method has received considerable attention from researchers. For example, hua Ruimao et al, starting from a diphenylene alkyne, a nitrile and an alcohol, achieved 1-alkoxy-3, 4-diaryl substituted isoquinoline compounds (J.Org.Chem., 2021,86, 8862-8872) over a rhodium catalyst. The reaction requires the use of expensive rhodium catalysts and the alkynes need to be of symmetrical structure.
In addition, the general synthetic methods of 1-alkoxyisoquinoline compounds reported in the above methods, in which all of the positions 3,4 of the 1-alkoxyisoquinoline compounds have corresponding substituent groups, and no substituent group is found in the positions 3,4, are rarely reported. In the prior art, the synthesis method of the 1-alkoxy isoquinoline compound generally needs to use a toxic and volatile organic solvent as a reaction medium, and the used catalyst is expensive. The organic solvent, catalyst and additives are difficult to recover, which not only causes environmental pollution, but also results in high reaction cost. In view of the important characteristic that the 1-alkoxy isoquinoline compound without the substituent at the 3,4 position can introduce diversified functionalization through other reactions, the development of a green synthesis method of the 1-alkoxy isoquinoline compound without the substituent at the 3,4 position, which has the advantages of simple raw material, high reaction activity, good universality, low reaction cost and environmental friendliness, is necessary.
Disclosure of Invention
Aiming at the defects of the synthesis method of the 1-alkoxy isoquinoline compound in the prior art, the invention aims to provide a green synthesis method for preparing the 1-alkoxy isoquinoline compound by taking a benzonitrile compound and alcohol as initial raw materials for reaction, taking a eutectic as a solvent, carrying out addition reaction, and then carrying out intramolecular C-H activation/cyclization reaction with vinylene carbonate under the action of a cobalt catalyst and an additive.
In order to achieve the purpose, the invention adopts the technical scheme that:
a green synthetic method of 1-alkoxy isoquinoline compound, using benzonitrile compound and alcohol as initial raw materials of reaction, using eutectic as solvent, performing addition reaction, and then performing intramolecular C-H activation/cyclization reaction with vinylene carbonate under the action of cobalt catalyst and additive to prepare 1-alkoxy isoquinoline compound;
the reaction route is as follows:
in the 1-alkoxyisoquinoline compounds of the invention, R 1 Hydrogen, methyl, methoxy, halogen, cyano, ester, trifluoromethyl, nitro, and the like. The position of the substituent is not limited, and can be ortho, meta or para。
Further, R 2 Is C 1 ～C 4 Straight or branched chain alkyl, trifluoroethyl, allyl, and the like. The 3,4 position of the 1-alkoxyisoquinoline has no substituent. R 1 And R 2 The selection of the type and the position of the substituent group has no obvious influence on the yield of the target product, and experiments show that various substituent groups can basically ensure that the yield of the target product is over 80 percent.
As a preferable embodiment, the eutectic solvent is selected from any one of choline chloride/acetic acid, choline chloride/malonic acid, choline chloride/glycerin, betaine/hexafluoroisopropanol. The preferable choline chloride/acetic acid eutectic solvent consists of choline chloride and acetic acid according to a molar ratio of 1. The preferable choline chloride/malonic acid eutectic solvent consists of choline chloride and malonic acid according to a molar ratio of 1. The preferable choline chloride/glycerol eutectic solvent consists of choline chloride and glycerol according to a molar ratio of 1. The preferable betaine/hexafluoroisopropanol eutectic solvent consists of betaine and hexafluoroisopropanol in a molar ratio of 1. In the eutectic solvents, 1-alkoxy isoquinoline compounds can be generated smoothly, the yield of the target product is over 60 percent, betaine/hexafluoroisopropanol is the best eutectic solvent for the reaction, and particularly when the betaine/hexafluoroisopropanol are composed according to a molar ratio of 1. The amount of the eutectic solvent used in the present invention is in accordance with the amount of the conventional solvent added, for example, the concentration of 1-alkoxyisoquinoline in the eutectic solvent is 0.05 to 0.2mol/L, preferably 0.05 to 0.1mol/L.
Further, the cobalt catalyst is cobalt acetate, cpCo (CO) I 2 And [ CoCp (CH) 3 CN) 3 ](SbF 6 ) 2 One kind of (1). In a further preferred technical scheme, the dosage of the cobalt salt catalyst is at least 2.5% of the mol dosage of the cyanobenzene. The optimal dosage of the cobalt salt catalyst is 5 percent equivalent, and when the dosage of the cobalt salt catalyst is increased, the yield of the target product is not obviously increased; when the dosage of the cobalt salt catalyst is reduced, the yield of the target product is obviously reduced; more preferably 2.5 to 10%.
The additive is used as an oxidant and is one of copper acetate, copper oxide, silver acetate and silver carbonate. Further preferably, the dosage of the additive is 10 to 30mol percent of the cyanobenzene. The optimum amount of the additive is 20mol%.
The green synthesis method of the 1-alkoxy isoquinoline compound comprises the following steps: alcohol: vinylene carbonate molar ratio is 1:10 to 20:3 to 5.
Further preferred is a technical scheme that benzonitrile: alcohol: vinylene carbonate molar ratio is 1:20:3.
the intramolecular C-H activation/cyclization reaction conditions are as follows: reacting for 12-24 h at 90-120 ℃. The temperature is most preferably about 110 ℃, the time is most preferably 12h, the temperature is further increased or the reaction time is prolonged, and the yield of the target product is not increased.
After the intramolecular C-H activation/cyclization reaction is finished, an organic solvent is adopted for extraction, the 1-alkoxy isoquinoline compound is separated, and the raffinate is a eutectic solvent, a cobalt salt catalyst and an additive and can be repeatedly used. Organic solvents such as ethyl acetate, and the like.
The invention has the advantages and beneficial effects that:
1. the invention provides a universal green synthesis method of a 1-alkoxy isoquinoline compound, and provides a new idea for the actual synthesis of the compound.
2. The method adopts the biomass eutectic solvent as a reaction medium and the cobalt salt as a catalyst, has the advantages of low price, easily available source and environmental friendliness, and the eutectic solvent/cobalt salt system can be recycled for more than 6 times.
3. The reaction substrate used in the invention is convenient in source, and the benzonitrile, the alcohol and the vinylene carbonate are all industrial products, and the price is very low. Good functional group compatibility, wide substrate application range and high yield.
4. The invention provides a green synthesis method of a 3, 4-position unsubstituted 1-alkoxy isoquinoline compound, and a new functional group can be introduced into the 3, 4-position by other organic reaction means, so that the construction of a series of 1-alkoxy isoquinoline compounds can be realized, and the product diversity is met.
Detailed Description
The present invention is not limited to the following embodiments, and those skilled in the art can implement the present invention in other various embodiments or make simple changes or modifications in the design and concept of the present invention based on the disclosure of the present invention, and fall into the protection scope of the present invention. It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict.
Comparative example:
the intramolecular C-H activation/cyclization reaction (as a standard reaction) occurs under the action of the eutectic solvent and cobalt catalyst under optimal conditions according to the following reaction formula:
the specific operation steps are as follows: a clean, dry 25mL round bottom flask was charged with benzonitrile (0.5 mmol), methanol (10 mmol), vinylene carbonate (1.5 mmol), cp. Multidot. Co (CO) I 2 (5 mol%), copper acetate (20 mol%), eutectic solvent betaine/hexafluoroisopropanol (5 mL), heating the obtained mixed solution at 110 ℃ for reaction for 12 hours, cooling the reaction solution to room temperature after the reaction is finished, extracting the reactant with ethyl acetate, and purifying by column chromatography with Petroleum Ether (PE)/Ethyl Acetate (EA) as an eluent and silica gel (200-mesh sieve).
The following control experimental groups 1 to 19 are described by comparison with reference to standard reaction conditions:
the experimental groups 1 to 5 in the above table investigate the reaction of different catalystsThe experimental data show that the three cobalt catalysts have certain catalytic activity on the reaction, the yield is over 65 percent, and Cp & ltco & gt (CO) I 2 When the amount is 5mol%, the reaction effect is best 92%.
The effect of the additives on the reaction was examined in experimental groups 6 to 9, with the best effect of copper acetate.
The influence of different eutectic solvents, compositions and amounts on the reaction was examined in experimental groups 10-16. Among them, betaine/hexafluoroisopropanol works best as a solvent. The optimal molar ratio of betaine to hexafluoroisopropanol in the eutectic solvent is 1. In addition, the dosage of betaine/hexafluoroisopropanol has certain influence on the reaction, the yield of the target product cannot be reduced when the dosage is too high, but the yield of the target product can be reduced to a certain extent when the dosage is too low, and the concentration of reactants is preferably ensured to be in a concentration range of 0.05-0.1 mol/L.
The experimental groups 17 to 19 investigate the influence of different reaction time and temperature on the reaction, the reaction temperature is most preferably about 110 ℃, and when the temperature is further increased, the yield of the target product is not increased; when the reaction temperature is reduced, the yield of the target product is obviously reduced; the reaction time is further prolonged, and the yield of the target product is not increased.
The following examples 1 to 6 were carried out according to the standard reactions described above:
the specific operation steps are as follows: a clean, dry 25mL round bottom flask was charged with, in order, aromatic nitrile (0.5 mmol), alcohol (10 mmol), vinylene carbonate (1.5 mmol), cp. Co (CO) I 2 (5 mol%), copper acetate (20 mol%), eutectic solvent betaine/hexafluoroisopropanol (5 mL), heating the obtained mixed solution at 110 ℃ for reaction for 12 hours, cooling the reaction solution to room temperature after the reaction is finished, extracting the reactant with ethyl acetate, using Petroleum Ether (PE)/Ethyl Acetate (EA) as eluent, and adopting silica gel (200 300) as eluentMesh screen) was purified by column chromatography.
Example 1
1 H NMR(500MHz,CDCl 3 )δ8.26(ddd,J＝0.8,2.0,8.2Hz,1H),8.01(d,J＝6.2Hz,1H),7.73(dt,J＝0.8,8.2Hz,1H),7.65(ddd,J＝1.6,7.0,8.2Hz,1H),7.53(ddd,J＝1.2,7.0,8.2Hz,1H),7.21(dd,J＝0.8,5.9Hz,1H),4.15(s,3H).
13 C NMR(125MHz,CDCl 3 )δ160.9,139.6,137.8,130.4,126.5,126.0,124.1,119.8,114.9,53.6.
Example 2
1 H NMR(500MHz,CDCl 3 )δ8.32(dd,J＝1.2,8.2Hz,1H),8.00(d,J＝5.9Hz,1H),7.73(d,J＝8.2Hz,1H),7.66(ddd,J＝1.2,6.6,8.2Hz,1H),7.54(ddd,J＝1.6,6.9,8.3Hz,1H),7.22(d,J＝5.5Hz,1H),6.23(tdd,J＝5.4,10.6,17.2Hz,1H),5.51(qd,J＝1.6,17.3Hz,1H),5.32(qd,J＝1.4,10.5Hz,1H),5.07(td,J＝1.6,5.5Hz,2H).
13 C NMR(125MHz,CDCl 3 )δ160.1,139.6,137.9,133.5,130.4,126.5,125.7,124.1,119.7,117.1,115.0,66.7.
Example 3
1 H NMR(500MHz,CDCl 3 )δ8.30(ddd,J＝0.8,2.0,8.6Hz,1H),7.98(d,J＝5.9Hz,1H),7.78(d,J＝8.2Hz,1H),7.71(ddd,J＝1.2,6.6,8.2Hz,1H),7.60(ddd,J＝1.2,6.9,8.3Hz,1H),7.32(dd,J＝0.8,5.9Hz,1H),4.97(q,J＝8.6Hz,2H).
13 C NMR(125MHz,CDCl 3 )δ158.7,139.3,138.4,131.2,128.3,127.5,126.5,125.5,124.2,122.8.
Example 4
1 H NMR(500MHz,CDCl 3 )δ8.18(d,J＝7.5Hz,1H),8.09(d,J＝7.4Hz,1H),7.28–7.19(m,2H),7.03(dd,J＝7.5,1.1Hz,1H),4.06(s,3H),2.50(s,3H).
13 C NMR(125MHz,CDCl 3 )δ158.1,143.6,138.0,137.7,128.6,126.2,125.8,120.5,117.3,54.4,21.7.
Example 5
1 H NMR(500MHz,CDCl 3 )δ8.17(d,J＝7.3Hz,1H),7.39(d,J＝1.4Hz,1H),7.27(dd,J＝7.5,1.4Hz,1H),7.19(dd,J＝7.5,1.4Hz,1H),6.94(dd,J＝7.5,1.5Hz,1H),4.06(s,3H),3.81(s,3H).
13 C NMR(125MHz,CDCl 3 )δ159.6,156.2,139.3,132.1,127.9,121.0,119.8,115.6,110.2,56.1,54.4.
Example 6
1 H NMR(500MHz,CDCl 3 )δ8.36(d,J＝7.5Hz,1H),8.15(dd,J＝7.5,1.4Hz,1H),7.50(d,J＝7.5Hz,1H),7.41(dd,J＝7.5,1.4Hz,1H),7.31(t,J＝7.5Hz,1H),4.06(s,3H).
13 C NMR(125MHz,CDCl 3 )δ156.2,144.5,138.4,133.5,128.7,127.8,124.0,119.8,112.8,54.4.
Example 7
The specific operation steps are as follows: a clean, dry 25mL round bottom flask was charged with benzonitrile (0.5 mmol), methanol (10 mmol), vinylene carbonate (1.5 mmol), cp. Multidot. Co (CO) I 2 (5 mol%), copper acetate (20 mol%), eutectic solvent betaine/hexafluoroisopropanol (5 mL), heating the obtained mixed solution at 110 ℃ for reaction for 12 hours, cooling the reaction solution to room temperature after the reaction is finished, extracting reactants with ethyl acetate, and analyzing the yield of products by nuclear magnetism. And sequentially adding new cyanobenzene (0.5 mmol), methanol (10 mmol) and vinylene carbonate (1.5 mmol) into the raffinate, heating the reaction system at 110 ℃ for 12 hours, extracting reactants by using ethyl acetate after the reaction is finished, and analyzing the yield of the product by nuclear magnetism. Repeated 5 times in sequence.
| Number of cycles | 1 | 2 | 3 | 4 | 5 | 6 |
| Yield of | 92％ | 91％ | 90％ | 88％ | 86％ | 85％ |
The 3,4-unsubstituted 1-alkoxy isoquinoline compound synthesized by the invention can introduce a new functional group into the 3,4 position by other organic reaction means, thereby realizing the construction of a series of 1-alkoxy isoquinoline compounds and meeting the product diversity, such as the following examples:
example 8
The method comprises the following steps of (1) performing chloro-functionalization reaction on the 4-position of a 1-methoxyisoquinoline compound, wherein the reaction formula is as follows:
the specific operation steps are as follows: 1-methoxyisoquinoline (0.4 mmol), acetyliodobenzene (0.6 mmol), ethyl chloroformate (2 mmol) and dichloroethane (2 mL) were sequentially added to a 10mL round-bottomed flask, the resulting mixture was heated at 50 ℃ for reaction for 6 hours, after the reaction was completed, the reaction mixture was cooled to room temperature, and the reaction product was extracted with ethyl acetate and purified by column chromatography using Petroleum Ether (PE)/Ethyl Acetate (EA) as an eluent and silica gel (200 mesh).
1 H NMR(500MHz,CDCl 3 )δ8.25(dd,J＝7.5,1.4Hz,1H),8.08(s,1H),8.02(dd,J＝7.5,1.4Hz,1H),7.62(td,J＝7.5,1.5Hz,1H),7.47(td,J＝7.5,1.4Hz,1H),4.06(s,3H).
13 C NMR(125MHz,CDCl 3 )δ156.5,142.9,131.1,129.7,126.6,126.0,124.3,123.9,123.3,54.4.
Example 9
The site 3 amination reaction of the 1-methoxyisoquinoline compound is as follows:
the specific operation steps are as follows: 1-methoxyisoquinoline (0.4 mmol), benzotriazole (0.8 mmol), copper acetate (0.04 mmol), selectfluor (0.6 mmol), potassium carbonate (0.8 mmol) and nitromethane (3 mL) are sequentially added into a 10mL round-bottom flask, the obtained mixed solution is heated at 120 ℃ for reaction for 12 hours, after the reaction is finished, the reaction solution is cooled to room temperature, reactants are extracted by ethyl acetate, and the mixture is purified by column chromatography by silica gel (200-mesh sieve) by using Petroleum Ether (PE)/Ethyl Acetate (EA) as an eluent.
1 H NMR(500MHz,CDCl 3 )δ8.27(dd,J＝7.5,1.2Hz,1H),7.97(ddd,J＝10.5,9.6,2.6Hz,3H),7.64–7.52(m,2H),7.51–7.34(m,3H),4.06(s,3H).
13 C NMR(125MHz,CDCl 3 )δ152.0,144.5,142.8,137.8,134.3,130.5,129.3,128.2,126.4,126.3,124.8,118.2,116.6,115.3,106.1,54.4.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the technical principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A green synthesis method of a 1-alkoxy isoquinoline compound is characterized by comprising the following steps: taking benzonitrile compounds and alcohol as initial raw materials for reaction, taking eutectic as a solvent, performing addition reaction, and then performing intramolecular C-H activation/cyclization reaction with vinylene carbonate under the action of a cobalt catalyst and an additive to prepare 1-alkoxy isoquinoline compounds;
the reaction route is as follows:
wherein R is 1 Is a substituent at an arbitrary position of the benzene ring, and R 1 One selected from hydrogen, methyl, methoxy, halogen, cyano, ester, trifluoromethyl and nitro; and the 3,4 position of the 1-alkoxyisoquinoline has no substituent.
2. The green synthesis method of a 1-alkoxyisoquinoline compound according to claim 1, characterized in that: in the alcohol, the substituent R 2 Is C 1 ～C 4 Or one of a linear or branched alkyl group, trifluoroethyl group, and allyl group.
3. A green synthesis method of a 1-alkoxyisoquinoline compound according to claim 1, characterized in that: the eutectic solvent is any one of choline chloride and acetic acid, choline chloride and malonic acid, choline chloride and glycerol, betaine and hexafluoroisopropanol.
4. A green synthesis method of a 1-alkoxyisoquinoline compound according to claim 3, characterized in that:
the mol ratio of choline chloride to acetic acid in the eutectic solvent of choline chloride and acetic acid is 1;
the mol ratio of choline chloride to malonic acid in the choline chloride and malonic acid eutectic solvent is 1;
the mol ratio of choline chloride to glycerol in the eutectic solvent of choline chloride and glycerol is 1;
the mol ratio of choline chloride to hexafluoroisopropanol in the eutectic solvent of betaine and hexafluoroisopropanol is 1.
5. A green synthesis method of a 1-alkoxyisoquinoline compound according to claim 1, characterized in that: the cobalt catalyst is cobalt acetate, cpCo (CO) I 2 Or [ CoCp (CH) 3 CN) 3 ](SbF 6 ) 2 Any one of them.
6. A green synthesis method of a 1-alkoxyisoquinoline compound according to claim 1, characterized in that: the additive is any one of copper acetate, copper oxide, silver acetate and silver carbonate.
7. A green synthesis process of a 1-alkoxyisoquinoline compound according to any of claims 1 to 6, characterized in that: the cyanobenzene compound comprises the following components: alcohol: the mol ratio of vinylene carbonate is 1:10 to 20:3 to 5.
8. A green synthesis process of a 1-alkoxyisoquinoline compound according to any of claims 1 to 6, characterized in that: the dosage of the cobalt catalyst is 2.5-10 mol% of the cyanobenzene.
9. A green synthesis process of a 1-alkoxyisoquinoline compound according to any of claims 1 to 6, characterized in that: the dosage of the additive is 10-30 mol% of benzonitrile.
10. A green synthesis method of a 1-alkoxyisoquinoline compound according to claim 1, characterized in that: the intramolecular C-H activation/cyclization reaction conditions are as follows: reacting for 12-24 h at 90-120 ℃.
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