CN115093368A - Method for preparing quinoline-2, 4-diketone derivative by copper-catalyzed cyclization/oxidation cleavage of alpha-bromocarbonyl alkyne - Google Patents
Method for preparing quinoline-2, 4-diketone derivative by copper-catalyzed cyclization/oxidation cleavage of alpha-bromocarbonyl alkyne Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000007363 ring formation reaction Methods 0.000 title claims abstract description 12
- 150000001345 alkine derivatives Chemical class 0.000 title claims abstract description 10
- IRFHMTUHTBSEBK-QGZVFWFLSA-N tert-butyl n-[(2s)-2-(2,5-difluorophenyl)-3-quinolin-3-ylpropyl]carbamate Chemical compound C1([C@H](CC=2C=C3C=CC=CC3=NC=2)CNC(=O)OC(C)(C)C)=CC(F)=CC=C1F IRFHMTUHTBSEBK-QGZVFWFLSA-N 0.000 title claims abstract description 9
- 230000003647 oxidation Effects 0.000 title description 5
- 238000007254 oxidation reaction Methods 0.000 title description 5
- 238000003776 cleavage reaction Methods 0.000 title description 2
- 230000007017 scission Effects 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- 239000010949 copper Substances 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000012298 atmosphere Substances 0.000 claims abstract description 16
- 238000007248 oxidative elimination reaction Methods 0.000 claims abstract description 12
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 229910052802 copper Inorganic materials 0.000 claims abstract description 8
- 239000003446 ligand Substances 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 6
- -1 alkyne compound Chemical class 0.000 claims abstract description 4
- 230000009471 action Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 87
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 15
- 238000004440 column chromatography Methods 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 15
- 239000003208 petroleum Substances 0.000 claims description 15
- YZMVLKJJJCMVGX-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline-2,4-dione Chemical class C1=CC=C2NC(=O)CC(=O)C2=C1 YZMVLKJJJCMVGX-UHFFFAOYSA-N 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 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 125000000484 butyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- WPTCSQBWLUUYDV-UHFFFAOYSA-N 2-quinolin-2-ylquinoline Chemical compound C1=CC=CC2=NC(C3=NC4=CC=CC=C4C=C3)=CC=C21 WPTCSQBWLUUYDV-UHFFFAOYSA-N 0.000 claims description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- RMSGQZDGSZOJMU-UHFFFAOYSA-N 1-butyl-2-phenylbenzene Chemical group CCCCC1=CC=CC=C1C1=CC=CC=C1 RMSGQZDGSZOJMU-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
- 125000006163 5-membered heteroaryl group Chemical class 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 125000005059 halophenyl group Chemical group 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims 1
- 229940076286 cupric acetate Drugs 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 12
- 239000000758 substrate Substances 0.000 abstract description 4
- 238000003756 stirring Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 15
- 230000035484 reaction time Effects 0.000 description 13
- 239000012156 elution solvent Substances 0.000 description 11
- 238000012512 characterization method Methods 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 3
- 238000005520 cutting process Methods 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- KMMHZIBWCXYAAH-UHFFFAOYSA-N 4-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(Br)C=C1 KMMHZIBWCXYAAH-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000006464 oxidative addition reaction Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for preparing quinoline-2, 4-diketone derivative by copper-catalyzed cyclization/oxidative cleavage of alpha-bromocarbonyl alkyne includes adding alpha-bromocarbonyl alkyne compound into water under air atmosphere, stirring, cyclizing under the action of copper catalyst, ligand and alkaline substance, and oxidative cleavage until the raw materials react completely to obtain quinoline-2, 4-diketone derivative. The method has the advantages of wide application range of reaction substrates, simplicity, high efficiency and green and mild conditions, and is particularly suitable for industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis, relates to preparation of quinoline-2, 4-dione derivatives, and particularly relates to a method for preparing quinoline-2, 4-dione derivatives by copper-catalyzed alpha-bromocarbonyl alkyne cyclization/oxidative cleavage.
Background
Quinoline-2, 4-dione derivatives are very important structural units in various natural products and medicines, and the existing preparation method is generally an intramolecular cyclization reaction of acyl chloride/aldehyde and halogenated alkane.
Copper catalysts are extremely important in catalytic chemistry because of the many characteristics of the copper atom, such as Lewis acids, pi-acids, single electron modifiers, two electron modifiers, and the like. In recent years, copper-mediated alkyne conversion has been extensively studied and broadly classified into coupling, cyclization, oxidative cleavage, addition, and the like because of their diverse reactivity, electrical properties, and rigidity of carbon-carbon triple bonds. In particular the combinatorial strategy of cyclization/oxidative cleavage is a relatively well-developed field, however the uncontrollable nature of this sequence process makes this research field challenging. We therefore envisage the selective synthesis of quinoline-2, 4-dione derivatives using copper-catalysed highly selective cyclisation/oxidative cleavage of a-bromocarbyne alkynes.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for preparing a quinoline-2, 4-dione derivative by copper-catalyzed cyclization/oxidative cleavage of alpha-bromocarbonyl alkyne, which takes a green and efficient alpha-bromocarbonyl alkyne compound as a raw material to prepare the target product quinoline-2, 4-dione derivative in high selectivity and high yield under mild conditions through a selective cyclization/oxidative cleavage reaction.
In order to achieve the purpose, the invention adopts the technical scheme that: a method for preparing quinoline-2, 4-diketone derivatives by copper-catalyzed alpha-bromocarbonyl alkyne cyclization/oxidation cutting comprises the steps of adding an alpha-bromocarbonyl alkyne compound shown in a formula 1 into water in an air atmosphere, stirring, cyclizing and oxidation cutting under the action of a copper catalyst, a ligand and a basic substance until raw materials completely react to obtain the quinoline-2, 4-diketone derivatives shown in a formula I, wherein the reaction formula is as follows:
wherein, in formula 1, Y ═ N; r 1 Selected from hydrogen, C 1 -C 2 Alkyl or halogen; r 2 Selected from substituted or unsubstituted phenyl, 4-6 membered heteroaryl or C 1 -C 4 An alkyl group; r is 3 Selected from benzyl, allyl or C 1 -C 2 An alkyl group.
Preferably, R is 2 Selected from phenyl, by halogen or C 1 -C 4 Alkyl-substituted phenyl, 5-membered heteroaryl or butyl; further, R 2 Selected from phenyl, halophenyl, butylphenyl, thienyl or butyl.
Preferably, the copper catalyst is one or a mixture of copper bromide, copper acetate or copper trifluoromethanesulfonate, and is preferably copper trifluoromethanesulfonate. The ligand is one or a mixture of 1,10-phen, 2'-Dipyridyl or 2,2' -Biquinoline, and preferably 1, 10-phen. The alkaline substance is one or a mixture of potassium carbonate, triethylamine or diisopropylethylamine, and preferably is diisopropylethylamine.
Preferably, the reaction temperature is 60 ℃. The dosage of the copper catalyst is 20 mol%, the dosage of the ligand is 30 mol%, and the dosage of the alkaline substance is 2 equivalents.
After completion of the reaction, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (petroleum ether and ethyl acetate were mixed at a volume ratio of 5:1 as an eluent) to give a quinoline-2, 4-dione derivative.
The invention provides a method for preparing quinoline-2, 4-diketone derivatives by alpha-bromocarbonyl alkyne cyclization/oxidative cleavage, which prepares and obtains a series of target products in a green solvent water system with high yield. The method has the advantages of wide application range of reaction substrates, greenness and high efficiency, and is particularly suitable for industrial production.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and starting materials, if not otherwise specified, are commercially available and/or may be prepared according to known methods.
Examples 1-7 are experiments optimized for reaction conditions.
Example 1
To a Schlenk flask was added α -bromocarbonylalkyne of formula 1a (70.0mg,0.2mmol), CuBr 2 (8.8mg,20mol％)、1,10-Phen(10.8mg,30mol％)、K 2 CO 3 (55.2mg,2.0eq) and water (1.0mL), then the reactor is stirred under the condition of 60 ℃ air atmosphere, the progress of the reaction is monitored by TLC until the raw materials disappear (the reaction time is 36 hours), after the reaction is finished, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, filtered and decompressed and concentrated to remove the solvent, and the residue is separated by column chromatography (the elution solvent is petroleum ether/ethyl acetate is 5:1) to obtain a target product I-1 (51% yield); product structure characterization data are: 1 H NMR(500MHz,CDCl 3 )δ:8.02-8.00(m,1H),7.65-7.62(m,1H),7.20-7.16(m,2H),3.47(s,3H),1.49(s,6H)； 13 C NMR(126MHz,CDCl 3 )δ:197.7,174.3,143.1,135.8,128.2,123.0,119.9,114.7,53.2,29.9,23.9。
example 2
Cu(OAc) 2 Replace CuBr 2 Otherwise, the procedure was as in example 1, giving the desired product I-1 in a yield of 48%.
Example 3
Cu(OTf) 2 Replace CuBr 2 The rest conditions are the same as those in example 1 to obtain the target product I-The yield of 1 was 55%.
Example 4
The yield of the target product I-1 was 31% under the same conditions as in example 3 except that 1,10-Phen was replaced with 2,2' -Dipyridyl.
Example 5
The yield of the target product I-1 was 5% under the same conditions as in example 3 except that 1,10-Phen was replaced with 2,2' -Biquinoline.
Example 6
Et 3 N replaces K 2 CO 3 Otherwise, the same procedure as in example 3 was repeated, whereby the desired product I-1 was obtained in a yield of 71%.
Example 7
i-Pr 2 NEt substituted for K 2 CO 3 Otherwise, the same procedure as in example 3 gave the desired product I-1 in 85% yield.
As can be seen from the above examples 1-7, the optimum reaction conditions are those of example 7, i.e. the catalyst copper trifluoromethanesulfonate, ligand 1,10-Phen, base i-Pr 2 NEt (2.0eq), solvent water, under 60 ℃ nitrogen atmosphere stirring reaction. On the basis of obtaining the optimal reaction conditions, the inventor further selects alpha-bromocarbonyl acetylene compounds with different substituents as raw materials under the optimal reaction conditions to develop a high-selectivity cyclization/oxidation cutting reaction method.
Example 8
To a Schlenk flask was added α -bromocarbonylalkyne of formula 1b (73.8mg,0.2mmol), Cu (OTf) 2 (14.4mg,20mol％)、1,10-Phen(10.8mg,30mol％)、i-Pr 2 NEt (51.7mg,2.0eq) and water (1.0mL), then the reactor was stirred at 60 ℃ under an air atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 36 hours), after completion of the reaction, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: petroleum ether/ethyl acetate)Ester 5:1) to give the target product I-2 (85% yield); product structure characterization data are: 1 H NMR(400MHz,CDCl 3 ):7.80(s,1H),7.43(d,J＝8.4Hz,1H),7.07(d,J＝8.4Hz,1H),3.45(s,3H),2.37(s,3H),1.48(s,6H)； 13 C NMR(101MHz,CDCl 3 ):198.0,174.2,140.9,136.6,132.8,128.1,119.7,114.7,53.1,29.9,23.9,20.4；HRMS m/z(ESI)calcd for C 13 H 16 NO 2 ([M+H] + )218.1176,found 218.1170。
example 9
To a Schlenk flask was added α -bromocarbonylalkyne of formula 1c (74.6mg,0.2mmol), Cu (OTf) 2 (14.4mg,20mol％)、1,10-Phen(10.8mg,30mol％)、i-Pr 2 NEt (51.7mg,2.0eq) and water (1.0mL), then the reactor is stirred to react under the condition of 60 ℃ air atmosphere, the progress of the reaction is monitored by TLC until the raw materials disappear (the reaction time is 36 hours), after the reaction is finished, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, filtered and decompressed and concentrated to remove a solvent, and the residue is separated by column chromatography (the elution solvent is petroleum ether/ethyl acetate is 5:1) to obtain a target product I-3 (80% yield); product structure characterization data are: 1 H NMR(400MHz,CDCl 3 ):7.69-7.66(m,1H),7.37-7.32(m,1H),7.18-7.14(m,1H),3.47(s,3H),1.49(s,6H)； 13 C NMR(101MHz,CDCl 3 ):196.9,173.8,158.5(d,J C-F ＝245.9Hz),139.5,122.8(d,J C-F ＝23.5Hz),121.1(d,J C-F ＝6.3Hz),116.6(d,J C-F ＝7.1Hz),114.0(d,J C-F ＝23.4Hz),53.1,30.2,23.9； 19 F NMR(376MHz,CDCl 3 ):-119.6；HRMS m/z(ESI)calcd for C 12 H 13 FNO 2 ([M+H] + )222.0925,found 222.0927。
example 10
To a Schlenk flask was added α -bromocarbonylalkyne of formula 1d (77.8mg,0.2mmol), Cu (OTf) 2 (14.4mg,20mol％)、1,10-Phen(10.8mg,30mol％)、i-Pr 2 NEt (51.7mg,2.0eq) and water (1.0mL), then the reactor is stirred to react under the condition of 60 ℃ air atmosphere, the progress of the reaction is monitored by TLC until the raw materials disappear (the reaction time is 36 hours), after the reaction is finished, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, filtered and decompressed and concentrated to remove a solvent, and the residue is separated by column chromatography (the elution solvent is petroleum ether/ethyl acetate is 5:1) to obtain a target product I-4 (81% yield); product structure characterization data are: 1 H NMR(400MHz,CDCl 3 ):7.95(s,1H),7.59-7.56(m,1H),7.12(d,J＝9.2Hz,1H),3.46(s,3H),1.49(s,6H)； 13 C NMR(101MHz,CDCl 3 ):196.6,173.9,141.6,135.4,128.8,127.7,121.0,116.4,53.3,30.1,23.8；HRMS m/z(ESI)calcd for C 12 H 13 ClNO 2 ([M+H] + )238.0629,found 238.0635。
example 11
To a Schlenk flask was added α -bromocarbonylalkyne of formula 1e (73.8mg,0.2mmol), Cu (OTf) 2 (14.4mg,20mol％)、1,10-Phen(10.8mg,30mol％)、i-Pr 2 NEt (51.7mg,2.0eq) and water (1.0mL), then the reactor is stirred to react under the condition of 60 ℃ air atmosphere, the progress of the reaction is monitored by TLC until the raw materials disappear (the reaction time is 36 hours), after the reaction is finished, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, filtered and decompressed and concentrated to remove a solvent, and the residue is separated by column chromatography (the elution solvent is petroleum ether/ethyl acetate is 5:1) to obtain a target product I-5 (84% yield); product structure characterization data are: 1 H NMR(400MHz,CDCl3):7.90(d,J＝7.6Hz,1H),7.00(d,J＝8.8Hz,1H),6.97(s,1H),3.46(s,3H),2.46(s,3H),1.48(s,6H)； 13 C NMR(101MHz,CDCl3):197.3,174.6,147.2,143.2,128.3,124.1,117.6,115.2,52.9,29.8,24.0,22.4；HRMS m/z(ESI)calcd for C 13 H 16 NO 2 ([M+H] + )218.1176,found 218.1170。
example 12
To a Schlenk bottle was added α -bromocarbonylalkyne of formula 1f (74.6mg,0.2mmol), Cu (OTf) 2 (14.4mg,20mol％)、1,10-Phen(10.8mg,30mol％)、i-Pr 2 NEt (51.7mg,2.0eq) and water (1.0mL), then the reactor is stirred to react under the condition of 60 ℃ air atmosphere, the progress of the reaction is monitored by TLC until the raw materials disappear (the reaction time is 36 hours), after the reaction is finished, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, filtered and decompressed and concentrated to remove a solvent, and the residue is separated by column chromatography (the elution solvent is petroleum ether/ethyl acetate is 5:1) to obtain a target product I-6 (78% yield); the product structural characterization data are: 1 H NMR(400MHz,CDCl 3 ):8.06-8.02(m,1H),6.90-6.86(m,2H),3.45(s,3H),1.49(s,6H)； 13 C NMR(101MHz,CDCl 3 ):196.2,174.4,167.4(d,J C-F ＝256.6Hz),145.4(d,J C-F ＝11.7Hz),131.2(d,J C-F ＝11.2Hz),116.4,110.4(d,J C-F ＝22.3Hz),102.4(d,J C-F ＝27.6Hz),53.1,30.1,24.0； 19 F NMR(376MHz,CDCl 3 ):-99.5；HRMS m/z(ESI)calcd for C 12 H 13 FNO 2 ([M+H] + )222.0925,found 222.0931。
example 13
A Schlenk flask was charged with α -bromocarbonylalkyne of formula 1g (77.8mg,0.2mmol), p-bromobenzenesulfonyl chloride of formula 2a (102.2mg,0.4mmol), Cu (OTf) 2 (14.4mg,20mol％)、1,10-Phen(10.8mg,30mol％)、i-Pr 2 NEt (51.7mg,2.0eq) and water (1.0mL), then the reactor was put under an air atmosphere at 60 ℃Stirring the mixture to react under the condition, monitoring the reaction progress by TLC until the raw materials disappear (the reaction time is 36 hours), extracting the reaction liquid by ethyl acetate after the reaction is finished, drying an organic phase by anhydrous sodium sulfate, filtering and concentrating under reduced pressure to remove a solvent, and separating the residue by column chromatography (an elution solvent is petroleum ether/ethyl acetate which is 5:1) to obtain a target product I-7 (79% yield); product structure characterization data are: 1 H NMR(400MHz,CDCl 3 ):7.95(d,J＝8.0Hz,1H),7.17-7.14(m,2H),3.46(s,3H),1.49(s,6H)； 13 C NMR(101MHz,CDCl 3 ):196.5,174.3,144.1,142.1,129.6,123.3,118.2,115.0,53.2,30.0,23.9。
example 14
To a Schlenk flask was added α -bromocarbonylalkyne of formula 1h (82.2mg,0.2mmol), Cu (OTf) 2 (14.4mg,20mol％)、1,10-Phen(10.8mg,30mol％)、i-Pr 2 NEt (51.7mg,2.0eq) and water (1.0mL), then the reactor was stirred under an air atmosphere at 60 ℃, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 36 hours), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: petroleum ether/ethyl acetate ═ 5:1) to obtain the target product I-1 (86% yield).
Example 15
To a Schlenk flask was added α -bromocarbonylalkyne of formula 1i (86.6mg,0.2mmol), Cu (OTf) 2 (14.4mg,20mol％)、1,10-Phen(10.8mg,30mol％)、i-Pr 2 NEt (51.7mg,2.0eq) and water (1.0mL), then the reactor was stirred for reaction at 60 ℃ under an air atmosphere, the progress of the reaction was monitored by TLC until the starting material disappeared (the reaction time was 36 hours), and after completion of the reaction, the reaction solution was extracted with ethyl acetateThe organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate 5:1) to give the desired product I-1 (81% yield).
Example 16
To a Schlenk bottle was added α -bromocarbonylalkyne of formula 1h (87.4mg,0.2mmol), Cu (OTf) 2 (14.4mg,20mol％)、1,10-Phen(10.8mg,30mol％)、i-Pr 2 NEt (51.7mg,2.0eq) and water (1.0mL), then the reactor was stirred under an air atmosphere at 60 ℃ to react, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 36 hours), after completion of the reaction, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting solvent: petroleum ether/ethyl acetate 5:1) to give the target product I-1 (73% yield).
Example 17
To a Schlenk flask was added α -bromocarbonylalkyne of formula 1i (67.0mg,0.2mmol), Cu (otf) 2 (14.4mg,20mol％)、1,10-Phen(10.8mg,30mol％)、i-Pr 2 NEt (51.7mg,2.0eq) and water (1.0mL), then the reactor was stirred under an air atmosphere at 60 ℃, the progress of the reaction was monitored by TLC until the starting material disappeared (reaction time was 36 hours), after the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: petroleum ether/ethyl acetate: 5:1) to obtain the target product I-1 (81% yield).
Example 18
To a Schlenk flask was added α -bromocarbonylalkyne of formula 1j (86.2mg,0.2mmol), Cu (OTf) 2 (14.4mg,20mol％)、1,10-Phen(10.8mg,30mol％)、i-Pr 2 NEt (51.7mg,2.0eq) and water (1.0mL), then the reactor is stirred to react under the condition of 60 ℃ air atmosphere, the progress of the reaction is monitored by TLC until the raw materials disappear (the reaction time is 36 hours), after the reaction is finished, the reaction liquid is extracted by ethyl acetate, an organic phase is dried by anhydrous sodium sulfate, filtered and decompressed and concentrated to remove a solvent, and the residue is separated by column chromatography (the elution solvent is petroleum ether/ethyl acetate is 5:1) to obtain a target product I-8 (84% yield); product structure characterization data are: 1 H NMR(500MHz,CDCl 3 ):8.01-7.99(m,1H),7.48-7.45(m,1H),7.33(t,J＝7.5Hz,2H),7.28-7.23(m,3H),7.13(t,J＝7.5Hz,1H),7.05(d,J＝8.0Hz,1H),5.27(s,2H),1.58(s,6H)； 13 C NMR(126MHz,CDCl 3 ):197.6,174.6,142.5,136.2,135.7,129.0,128.3,127.5,126.3,123.2,120.2,115.6,53.4,46.3,23.9；HRMS m/z(ESI)calcd for C 18 H 18 NO 2 ([M+H] + )280.1332,found 280.1338。
example 19
To a Schlenk bottle was added α -bromocarbonylyne of formula 1k (76.2mg,0.2mmol), Cu (OTf)2(14.4mg,20 mol%), 1,10-Phen (10.8mg,30 mol%), i-Pr 2 NEt (51.7mg,2.0eq) and water (1.0mL), then the reactor is stirred to react under the condition of 60 ℃ air atmosphere, the progress of the reaction is monitored by TLC until the raw material disappears (the reaction time is 36 hours), after the reaction is completed, the reaction liquid is extracted by ethyl acetate, the organic phase is dried by anhydrous sodium sulfate, filtered and decompressed and concentrated to remove the solvent, and the residue is separated by column chromatography (the elution solvent is petroleum ether/ethyl acetate is 5:1) to obtain the target product I-9 (84% yield); product structure characterization data are: 1 H NMR(500MHz,CDCl 3 ):8.01-7.99(m,1H),7.60-7.57(m,1H),7.16(t,J＝7.5Hz,1H),7.12(d,J＝8.5Hz,1H),5.93-5.88(m,1H),5.25-5.18(m,2H),4.68-4.66(m,2H),1.51(s,6H)； 13 C NMR(126MHz,CDCl 3 ):197.7,174.0,142.3,135.7,131.7,128.2,123.1,120.1,116.9,115.4,53.3,44.9,23.8；HRMS m/z(ESI)calcd for C 14 H 16 NO 2 ([M+H] + )230.1176,found 230.1172。
example 20 control experiment to study reaction mechanism
To clarify the source of oxygen atoms in the oxidative cleavage reaction, several control experiment examples 20 were carried out. Substrate 1a with Cu (OTf) 2 、1,10-Phen、i-Pr 2 NEt in dry MeCN and O 2 The reaction was carried out under ambient conditions and the expected product I-1 was formed in 79% yield, indicating that the newly formed oxygen atom in the oxidative cleavage reaction may be derived from O 2 . Further, each at 15.0 equivalents of H under standard conditions 2 18 O, air ( 16 O 2 ) And treatment of the substrate 1a and 16 o-labeled product I-1, I-1 determined by GC-MS analysis 16 O is the main product, which also confirms that the oxygen atom of the newly formed carbonyl group in the product I-1 is derived from O in the air 2 。
It follows that the possible reaction mechanism of the present invention can be deduced as shown in the following formula:
the embodiments described above are only preferred embodiments of the invention and are not exhaustive of the possible implementations of the invention. Any obvious modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the spirit and scope of the present invention.
Claims (8)
1. A method for preparing quinoline-2, 4-diketone derivatives by copper-catalyzed alpha-bromocarbonyl alkyne cyclization/oxidative cleavage is characterized in that an alpha-bromocarbonyl alkyne compound shown in a formula 1 is added into water in an air atmosphere, stirred and cyclized and oxidatively cleaved under the action of a copper catalyst, a ligand and a basic substance to prepare the quinoline-2, 4-diketone derivatives, wherein the reaction formula is as follows:
wherein, in formula 1, Y ═ N; r is 1 Selected from hydrogen, C 1 -C 2 Alkyl or halogen; r 2 Selected from substituted or unsubstituted phenyl, 4-6 membered heteroaryl or C 1 -C 4 An alkyl group; r 3 Selected from benzyl, allyl or C 1 -C 2 An alkyl group.
2. The method of claim 1, wherein R is 2 Selected from phenyl, by halogen or C 1 -C 4 Alkyl-substituted phenyl, 5-membered heteroaryl or butyl.
3. The method of claim 2, wherein R is 2 Selected from phenyl, halophenyl, butylphenyl, thienyl or butyl.
4. The method according to claim 1, wherein the copper catalyst is one or more of cupric bromide, cupric acetate or copper trifluoromethanesulfonate.
5. The method according to claim 1, wherein the ligand is one or more of 1,10-phen, 2'-Dipyridyl or 2,2' -Biquinoline.
6. The method according to claim 1, wherein the basic substance is one or more of potassium carbonate, triethylamine or diisopropylethylamine.
7. The process according to claim 1, wherein the reaction temperature is 60 ℃.
8. The process according to any one of claims 1 to 7, wherein after completion of the reaction, the reaction solution is extracted with ethyl acetate, the organic phase is dried over anhydrous sodium sulfate and then filtered and concentrated under reduced pressure to remove the solvent, and the residue is separated by column chromatography using a mixture of ethyl acetate and petroleum ether as an eluent to obtain the quinoline-2, 4-dione derivative.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000031074A2 (en) * | 1998-11-19 | 2000-06-02 | Eli Lilly And Company Limited | Indole derivatives and their use as serotonin receptor ligands |
| CN113429330A (en) * | 2021-06-09 | 2021-09-24 | 宁波大学 | Method for preparing 2-pyrrolidone derivative through three-component serial cyclization reaction under catalysis of copper |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000031074A2 (en) * | 1998-11-19 | 2000-06-02 | Eli Lilly And Company Limited | Indole derivatives and their use as serotonin receptor ligands |
| CN113429330A (en) * | 2021-06-09 | 2021-09-24 | 宁波大学 | Method for preparing 2-pyrrolidone derivative through three-component serial cyclization reaction under catalysis of copper |
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| Title |
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| CAIZHI WU等: "Cobalt-Catalyzed Enantioselective Hydroboration/Cyclization of 1, 7- Enynes: Asymmetric Synthesis of Chiral Quinolinones Containing Quaternary Stereogenic Centers", ANGEW. CHEM. INT. ED., vol. 58, pages 8882 - 8886 * |
| HONGJIAN SONG等: "Self-Induced Stereoselective in Situ Trifluoromethylation: Preparation of Spiro[indoline-3, 3′-quinoline] via Palladium-Catalyzed Cascade Reaction", ORG. LETT., vol. 16, pages 3240 - 3243 * |
| QING-QING KANG等: "Copper-catalyzed switchable cyclization of alkynetethered α-bromocarbonyls: selective access to quinolin-2-ones and quinoline-2, 4-diones", ORG. CHEM. FRONT., vol. 9, pages 6617 - 6623 * |
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