CN117603121A - C (sp) of indol-3-one 3 ) Process for preparing-H aminated derivatives - Google Patents
C (sp) of indol-3-one 3 ) Process for preparing-H aminated derivatives Download PDFInfo
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- CN117603121A CN117603121A CN202311294899.8A CN202311294899A CN117603121A CN 117603121 A CN117603121 A CN 117603121A CN 202311294899 A CN202311294899 A CN 202311294899A CN 117603121 A CN117603121 A CN 117603121A
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- ethyl acetate
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- 238000000034 method Methods 0.000 title claims abstract description 16
- FGFUBBNNYLNVLJ-UHFFFAOYSA-N indol-3-one Chemical compound C1=CC=C2C(=O)C=NC2=C1 FGFUBBNNYLNVLJ-UHFFFAOYSA-N 0.000 title description 4
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims abstract description 80
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000003960 organic solvent Substances 0.000 claims abstract description 4
- 239000007800 oxidant agent Substances 0.000 claims abstract description 4
- 230000001590 oxidative effect Effects 0.000 claims abstract description 4
- 239000001301 oxygen Substances 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 138
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 150000005626 indol-3-ones Chemical class 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 238000005576 amination reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- 239000003208 petroleum Substances 0.000 description 22
- 239000011541 reaction mixture Substances 0.000 description 22
- 238000002390 rotary evaporation Methods 0.000 description 22
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 20
- AUMJJQZNOVOCGY-UHFFFAOYSA-N 1-acetyl-2h-indol-3-one Chemical compound C1=CC=C2N(C(=O)C)CC(=O)C2=C1 AUMJJQZNOVOCGY-UHFFFAOYSA-N 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- -1 indolone compound Chemical class 0.000 description 6
- 230000000694 effects Effects 0.000 description 4
- UOIWOHLIGKIYFE-UHFFFAOYSA-N n-methylpentan-1-amine Chemical compound CCCCCNC UOIWOHLIGKIYFE-UHFFFAOYSA-N 0.000 description 4
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ZXWCKKSSCIFVBT-UHFFFAOYSA-N 1-(3-fluorophenyl)-n-methylmethanamine Chemical compound CNCC1=CC=CC(F)=C1 ZXWCKKSSCIFVBT-UHFFFAOYSA-N 0.000 description 1
- QCBJCECRIFTTGY-UHFFFAOYSA-N 1-acetyl-5-fluoro-2h-indol-3-one Chemical compound FC1=CC=C2N(C(=O)C)CC(=O)C2=C1 QCBJCECRIFTTGY-UHFFFAOYSA-N 0.000 description 1
- DZHOQDSNRADAKS-UHFFFAOYSA-N 1-acetyl-5-methyl-2h-indol-3-one Chemical compound CC1=CC=C2N(C(=O)C)CC(=O)C2=C1 DZHOQDSNRADAKS-UHFFFAOYSA-N 0.000 description 1
- UTBULQCHEUWJNV-UHFFFAOYSA-N 4-phenylpiperidine Chemical compound C1CNCCC1C1=CC=CC=C1 UTBULQCHEUWJNV-UHFFFAOYSA-N 0.000 description 1
- VJWIXTLPDOVKPN-UHFFFAOYSA-N Gelsemine Natural products CN1CC2(C=C)C3CC4OC3C1C2CC45C(=O)Nc6ccccc56 VJWIXTLPDOVKPN-UHFFFAOYSA-N 0.000 description 1
- RVOLLKGLJIUGLG-UHFFFAOYSA-N Horsfiline Natural products C12=CC(OC)=CC=C2NC(=O)C21CCN(C)C2 RVOLLKGLJIUGLG-UHFFFAOYSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- HYGWNUKOUCZBND-UHFFFAOYSA-N azanide Chemical compound [NH2-] HYGWNUKOUCZBND-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- NNGAQKAUYDTUQR-UHFFFAOYSA-N cyclohexanimine Chemical compound N=C1CCCCC1 NNGAQKAUYDTUQR-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- XIWBSOUNZWSFKU-UHFFFAOYSA-N ethyl piperidine-3-carboxylate Chemical compound CCOC(=O)C1CCCNC1 XIWBSOUNZWSFKU-UHFFFAOYSA-N 0.000 description 1
- NFYYATWFXNPTRM-QJICHLCESA-N gelsemine Chemical compound OC1=NC2=CC=CC=C2[C@@]21[C@H]1[C@H]3[C@H]4CO[C@@H]2C[C@H]4[C@]1(C=C)CN3C NFYYATWFXNPTRM-QJICHLCESA-N 0.000 description 1
- RVOLLKGLJIUGLG-ZDUSSCGKSA-N horsfiline Chemical compound C12=CC(OC)=CC=C2NC(=O)[C@@]21CCN(C)C2 RVOLLKGLJIUGLG-ZDUSSCGKSA-N 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 1
- 150000005624 indolones Chemical class 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a preparation method of a C (sp 3) -H aminated derivative of indole-3 ketone, which comprises the following steps: the method comprises the steps of taking oxygen in air as an oxidant, taking potassium iodide as a catalyst, dissolving indole-3 ketone in an organic solvent, reacting for 12 hours at room temperature, and purifying to obtain a C (sp 3) -H amination product of the indole-3 ketone. The preparation method has the advantages that the preparation of the reaction raw materials is simple, the reaction is carried out at room temperature, only one step is needed, the reaction is simple, and the method is one of the main methods for generating a complex molecule from two simple molecules.
Description
Technical Field
The invention belongs to the field of organic synthesis, and relates to a novel method for preparing a C (sp 3) -H aminated derivative of indole-3 ketone by using a common metal catalyst.
Background
Indolone as one of the nitrogen-containing aromatic heterocyclic compounds plays an important role in pharmaceutical chemistry and drug discovery, such as antibacterial, antitumor, anticancer, antiviral, antihypertensive, antipsychotic, and the like. In addition, the indolone compound combines the pharmacodynamic structure of natural macromolecular alkaloids such as Gelsemine, horsfiline, can prepare specific catalysts for directionally selecting and synthesizing spiro indolone derivatives with optical activity, and has good pharmacodynamic activity and biological activity. Based on the widespread use of indolone derivatives, in recent years, a large number of direct C (sp 3) -H functionalities have been carried out at the C2 position of nucleophilic indol-3-ones, such as acyloxylation, hydroxylation, bromination, and asymmetric amination reactions. Despite these ongoing efforts, methods of selective C-N bond formation are still rarely established. Therefore, the preparation of C (sp 3) -H aminated derivatives of indol-3-ones is particularly important, which is one of the main methods for generating a complex molecule from two simple molecules.
Disclosure of Invention
The invention provides a preparation method of a C (sp 3) -H aminated derivative of indole-3 ketone, which has the advantages of stable and easily available reaction substrate, mild reaction condition and simple operation.
A process for the preparation of a C (sp 3) -H aminated derivative of indol-3-one comprising: taking oxygen in air as an oxidant and potassium iodide as a catalyst, performing direct oxidation and amination reaction in ethyl acetate solvent, and then performing post-treatment such as concentration and purification to obtain the C (sp 3) -H aminated derivative of the indole-3 ketone;
the structure of the C (sp 3) -H aminated derivative of the indole-3 ketone is shown as a formula (I):
the structure of the indole-3 ketone derivative is shown as a formula (II):
R 1 independently selected from one of hydrogen, halogen and nitro, preferably a hydrogen atom;
R 2 and R is 3 Independently selected from C 1 ～C 5 Alkyl, cycloalkyl, C 1 ～C 5 Alkoxycarbonyl, C 1 ～C 5 Alkanoyloxy, phenyl, benzyl or halogen-substituted benzyl, said phenyl or benzylThe substituent on the radical is halogen; or said R 2 And R is 3 Forms a substituted or unsubstituted 5-8 membered ring with the attached N, the substituents on the 5-8 membered ring being C 1 ～C 5 Alkoxycarbonyl or phenyl.
Preferably, the secondary amine is one of the following compounds:
. In practice, the amount of catalyst is not critical and an excess of catalyst is generally added, preferably in a molar ratio of 1:0.05 to 1:0.2 with respect to the potassium iodide catalyst.
The reaction temperature is 25-80 ℃, the reaction time is 6-12h, the conversion rate of raw materials can be improved by prolonging the reaction time, but the conversion rate is increased along with the increase of the temperature, but the decomposition of products is reduced, the yield is not beneficial to the improvement, and the reaction temperature is preferably 25-50 ℃, and is most preferably 25 ℃; the reaction time is optimally 12h.
The organic solvent is one of acetonitrile, toluene, tetrahydrofuran, 1, 4-dioxane, dichloromethane and ethyl acetate, preferably ethyl acetate.
The synthesis reaction equation is as follows:
wherein R is 1 、R 2 And R is 3 Is defined as above.
The synthetic reaction principle is as follows: under air conditions, the catalyst KI is oxidized to [ IOn] - (n=1 or 2) attacks the C2 position of the indol-3 ketone, while the amine is converted to an amine anion, which reacts with the indol-3 ketone cation to form a C (sp 3) -H aminated derivative of the indol-3 ketone.
Compared with the prior art, the invention has the following advantages:
the method of the invention takes indole-3 ketone as a substrate to react and synthesize the C (sp 3) -H aminated derivative of indole-3 ketone, the reaction raw materials are cheap and easy to obtain, oxygen in the air is taken as an oxidant, potassium iodide is taken as a catalyst, the reaction can be carried out in one step, the reaction is carried out at room temperature, the reaction steps are simplified, and the preparation method is simple.
Detailed Description
The present invention will be described in detail with reference to specific examples, but the present invention is not limited thereto.
Example 1
In a dry pressure-resistant tube, 35.04mg of N-acetyl-3-indolinone, 34.85mg of morpholine and 6.64mg of potassium iodide were added, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 5:1), 28mg of a product is obtained, the yield is 54%, and the reaction process is shown as the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 )δ8.47(d,J＝8.1Hz,1H),7.63(t,J＝8.3Hz,2H),7.17(t,J＝7.4Hz,1H),4.56(s,1H),3.70–3.59(m,4H),3.06–2.87(m,2H),2.66–2.58(m,2H),2.46(s,3H).
13 C NMR(101MHz,CDCl 3 )δ197.99,170.24,153.59,137.90,124.34,123.27,122.98,117.93,79.97,67.14,47.00,23.76.
example 2
In a dry pressure-resistant tube, 35.04mg of N-acetyl-3-indolinone, 34.85mg of morpholine and 6.64mg of potassium iodide were added, and 1.5mL of acetonitrile was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 5:1), 24mg of a product is obtained, the yield is 47%, and the reaction process is shown as the following formula:
example 3
In a dry pressure-resistant tube, 35.04mg of N-acetyl-3-indolinone, 34.85mg of morpholine and 6.64mg of potassium iodide were added, and 1.5mL of methylene chloride was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 5:1), 24mg of a product is obtained, the yield is 46%, and the reaction process is shown as the following formula:
example 4
In a dry pressure-resistant tube, 35.04mg of N-acetyl-3-indolinone, 34.85mg of morpholine and 6.64mg of potassium iodide were added, and 1.5mL of tetrahydrofuran was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, cooling to room temperature, concentrating by rotary evaporation, and purifying by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 5:1) to obtain 18mg of a product, wherein the yield is 35%, and the reaction process is shown as the following formula:
the results of examples 1 to 4 show that the solvent has an important effect on the reaction yield, and the ethyl acetate has the best reaction effect.
Example 5
In a dry pressure-resistant tube, 35.04mg of N-acetyl-3-indolinone, 34.85mg of morpholine and 6.00mg of sodium iodide were added, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 5:1), 26mg of a product is obtained, the yield is 50%, and the reaction process is shown as the following formula:
example 6
In a dry pressure-resistant tube, 35.04mg of N-acetyl-3-indolinone, 34.85mg of morpholine and 14.77mg of tetrabutylammonium iodide were added, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 5:1), 21mg of a product is obtained, the yield is 40%, and the reaction process is shown as the following formula:
the results of examples 1, 5 and 6 show that the catalyst has an important effect on the reaction yield, and that the potassium iodide has the best reaction effect.
Example 7
In a dry pressure-resistant tube, 35.04mg of N-acetyl-3-indolinone, 34.85mg of morpholine and 6.64mg of potassium iodide were added, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at 40℃for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 5:1), 25mg of a product is obtained, the yield is 48%, and the reaction process is shown as the following formula:
example 8
70.08mg of N-acetyl-3-indolinone, 17.42mg of morpholine and 6.64mg of potassium iodide were added to a dry pressure-resistant tube, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction, cooling to room temperature, concentrating by rotary evaporation, purifying by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 5:1) to obtain 41mg of a product, the yield is 78%, and the reaction process is shown as the following formula:
example 9
70.08mg of N-acetyl-3-indolinone, 17.03mg of piperidine and 6.64mg of potassium iodide were added to a dry pressure-resistant tube, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 6:1), 30mg of a product is obtained, the yield is 58%, and the reaction process is shown as the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 )δ8.51(d,J＝8.2Hz,1H),7.64(dd,J＝10.1,4.5Hz,2H),7.18(t,J＝7.5Hz,1H),4.57(s,1H),2.96–2.85(m,2H),2.65–2.53(m,2H),2.47(s,3H),1.58–1.44(m,6H).
13 C NMR(101MHz,CDCl 3 )δ198.87,170.59,153.56,137.69,124.08,123.09,117.89,80.92,47.84,26.23,24.24,23.72.
example 10
70.08mg of N-acetyl-3-indolinone, 32.25mg of 4-phenylpiperidine and 6.64mg of potassium iodide were added to a dry pressure-resistant tube, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 6:1), 32mg of a product is obtained, the yield is 48%, and the reaction process is shown as the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 )δ8.52(d,J＝8.3Hz,1H),7.68–7.63(m,2H),7.33–7.26(m,2H),7.20–7.16(m,4H),4.64(s,1H),3.41(td,J＝11.8,2.3Hz,1H),3.17(d,J＝11.6Hz,1H),2.74(d,J＝10.6Hz,1H),2.58–2.48(m,4H),2.31(td,J＝11.7,2.4Hz,1H),1.97–1.91(m,1H),1.79–1.68(m,2H),1.59(qd,J＝12.3,4.0Hz,1H).
13 C NMR(101MHz,CDCl 3 )δ198.69,170.51,153.60,145.81,137.82,128.50,126.79,126.34,124.20,123.18,123.07,117.97,80.53,50.38,44.78,42.37,34.18,33.15,23.81.
example 11
70.08mg of N-acetyl-3-indolinone, 31.44mg of ethyl 3-piperidinecarboxylate and 6.64mg of potassium iodide were added to a dry pressure-resistant tube, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 4:1), 54mg of a product is obtained, the yield is 82%, and the reaction process is shown as the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 )δ8.48(t,J＝8.4Hz,1H),7.65–7.59(m,2H),7.15(t,J＝7.5Hz,1H),4.58(s,0.48H),(minor diastereomer),4.56(s,0.52H),4.17–3.99(m,2H),3.21–2.91(m,2H),2.87–2.41(m,3H),2.40(s,1.44H),(minor diastereomer),2.39(s,1.56H),1.77(d,J＝3.0Hz,1H),1.73–1.61(m,2H),1.53–1.42(m,1H),1.24(t,J＝7.1Hz,1.56H),1.18(t,J＝7.1Hz,1.44H),(minor diastereomer).
13 C NMR(101MHz,CDCl 3 )δ198.34,198.20,173.50,173.28,170.52,170.33,153.68,153.61,137.85,124.23,124.15,123.28,123.22,122.97,122.93,117.98,117.92,80.49,80.38,60.65,60.51,49.94,48.31,47.94,46.59,41.76,41.52,26.40,26.19,24.32,24.16,23.72,23.67,14.18.
example 12
70.08mg of N-acetyl-3-indolinone, 20.23mg of 4-hydroxypiperidine and 6.64mg of potassium iodide were added to a dry pressure-resistant tube, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 1:1), 21mg of a product is obtained, the yield is 39%, and the reaction process is shown as the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,DMSO)δ8.36(d,J＝8.3Hz,1H),7.74–7.68(m,1H),7.64–7.56(m,1H),7.24–7.18(m,1H),5.01(s,1H),4.57(d,J＝3.9Hz,1H),3.42(td,J＝8.6,4.3Hz,1H),2.95–2.86(m,1H),2.80(t,J＝9.4Hz,1H),2.69–2.59(m,1H),2.35(s,3H),2.17(dd,J＝9.5,8.1Hz,1H),1.76–1.58(m,2H),1.29(dddd,J＝16.2,13.0,8.0,4.2Hz,2H).
13 C NMR(101MHz,DMSO)δ199.34,170.67,153.61,138.11,124.43,123.25,117.55,79.99,66.48,43.18,35.29,34.79,23.82.
example 13
70.08mg of N-acetyl-3-indolinone, 37.25mg of N-Boc-piperazine and 6.64mg of potassium iodide were added to a dry pressure-resistant tube, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction, cooling to room temperature, concentrating by rotary evaporation, purifying by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 3:1) to obtain 67mg of a product with the yield of 93%, wherein the reaction process is shown in the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 )δ8.49(d,J＝8.5Hz,1H),7.65–7.68(m,2H),7.20(t,J＝7.5Hz,1H),4.64(s,1H),3.41(s,4H),2.91–2.92(m,2H),2.66–2.54(m,2H),2.48(s,3H),1.45(s,9H).
13 C NMR(101MHz,CDCl 3 )δ197.88,170.23,154.42,153.57,137.96,123.30,122.87,117.95,79.94,79.89,46.52,28.38,23.81.
example 14
70.08mg of N-acetyl-3-indolinone, 19.84mg of cyclohexylimine and 6.64mg of potassium iodide were added to a dry pressure-resistant tube, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 8:1), 35mg of a product is obtained, the yield is 64%, and the reaction process is shown as the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 )δ8.50(d,J＝8.7Hz,1H),7.62(t,J＝7.6Hz,2H),7.15(t,J＝7.5Hz,1H),4.64(s,1H),3.00–2.90(m,2H),2.80–2.71(m,2H),2.48(s,3H),1.64–1.50(m,8H).
13 C NMR(101MHz,CDCl 3 )δ199.81,170.60,153.33,137.73,124.01,123.27,123.08,118.10,81.35,49.68,29.47,26.94,23.92.
example 15
70.08mg of N-acetyl-3-indolinone, 20.24mg of N-methyl-N-pentylamine and 6.64mg of potassium iodide were added to a dry pressure-resistant tube, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction, cooling to room temperature, concentrating by rotary evaporation, purifying by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 6:1) to obtain 37mg of a product with the yield of 68%, wherein the reaction process is shown as the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 )δ8.49(d,J＝8.7Hz,1H),7.68–7.57(m,2H),7.15(t,J＝7.4Hz,1H),4.62(s,1H),2.72–2.58(m,2H),2.43(s,3H),2.36(s,3H),1.51–1.42(m,2H),1.29–1.20(m,4H),0.86(t,J＝6.9Hz,3H).
13 C NMR(101MHz,CDCl 3 )δ199.24,170.54,153.49,137.72,124.07,123.18,123.05,117.99,80.48,51.24,35.25,29.23,27.36,23.75,22.47,14.03.
example 16
70.08mg of N-acetyl-3-indolinone, 21.43mg of N-methylaniline and 6.64mg of potassium iodide were added to a dry pressure-resistant tube, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction, cooling to room temperature, concentrating by rotary evaporation, purifying by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 5:1) to obtain 19mg of a product, the yield is 33%, and the reaction process is shown as the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 )δ8.58(d,J＝8.3Hz,1H),7.72(dd,J＝15.2,7.5Hz,2H),7.31(t,J＝7.9Hz,2H),7.23(t,J＝7.5Hz,1H),7.02(d,J＝8.2Hz,2H),6.92(t,J＝7.3Hz,1H),5.75(s,1H),2.72(s,3H),2.20(s,3H).
13 C NMR(101MHz,CDCl 3 )δ197.32,170.22,153.21,147.99,138.30,129.67,124.50,123.79,122.91,120.35,118.50,115.24,76.54,32.45,24.53.
example 17
70.08mg of N-acetyl-3-indolinone, 27.83mg of N-methyl-3-fluorobenzylamine and 6.64mg of potassium iodide were added to a dry pressure-resistant tube, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction, cooling to room temperature, concentrating by rotary evaporation, purifying by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 5:1) to obtain 53mg of a product with the yield of 84%, wherein the reaction process is shown as the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 )δ8.49(d,J＝8.3Hz,1H),7.71–7.61(m,2H),7.31–7.26(m,1H),7.19(t,J＝7.5Hz,1H),7.08(d,J＝7.6Hz,1H),7.02(d,J＝9.6Hz,1H),6.95(td,J＝8.4,2.3Hz,1H),4.73(s,1H),3.87(s,2H),2.46(s,3H),2.31(s,3H).
13 C NMR(101MHz,CDCl 3 )δ198.72,170.26,164.18,161.73,153.65,140.20(d,J＝6.9Hz),137.96,129.98(d,J＝8.2Hz),124.62(d,J＝2.6Hz),124.33,123.14(d,J＝10.9Hz),118.15,115.77(d,J＝21.2Hz),114.54(d,J＝20.9Hz),78.91,55.28,35.60,23.90.
19 F NMR(376MHz,CDCl 3 )δ-113.10.
example 18
In a dry pressure-resistant tube, 83.85mg of 1-acetyl-6-chloroindolin-3-one, 17.42mg of morpholine and 6.64mg of potassium iodide were added, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 6:1), 31mg of a product is obtained, the yield is 53%, and the reaction process is shown as the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCL 3 )δ8.55(s,1H),7.59(d,J＝8.2Hz,1H),7.17(dd,J＝8.2,1.6Hz,1H),4.59(s,1H),3.70–3.62(m,4H),3.04–2.91(m,2H),2.66–2.59(m,2H),2.47(s,3H).
13 C NMR(101MHz,CDCL 3 )δ196.62,170.24,153.93,144.48,125.03,124.18,121.30,118.27,80.34,67.10,47.00,23.75.
example 19
In a dry pressure-resistant tube, 83.85mg of 1-acetyl-6-chloroindolin-3-one, 20.24mg of N-methyl N-pentylamine and 6.64mg of potassium iodide were added, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 12:1), 33mg of a product is obtained, the yield is 54%, and the reaction process is shown as the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCL 3 )δ8.57(d,J＝0.8Hz,1H),7.56(d,J＝8.2Hz,1H),7.14(dd,J＝8.2,1.3Hz,1H),4.65(s,1H),2.72–2.57(m,2H),2.43(s,3H),2.36(s,3H),1.48(dd,J＝14.4,7.2Hz,2H),1.32–1.27(m,2H),1.24(dd,J＝10.5,3.6Hz,2H),0.87(t,J＝6.9Hz,3H).
13 C NMR(101MHz,CDCL 3 )δ197.88,170.58,153.81,144.23,124.75,123.96,121.52,118.30,80.89,51.25,35.25,29.22,27.34,23.72,22.48,14.04.
example 20
In a dry pressure-resistant tube, 77.27mg of 1-acetyl-5-fluoroindolin-3-one, 24.23mg of N-methylbenzylamine and 6.64mg of potassium iodide were added, and 1.5mL of ethyl acetate was further added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 8:1), 38mg of a product is obtained, the yield is 60%, and the reaction process is shown as the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCL 3 )δ8.52(dd,J＝8.9,4.1Hz,1H),7.38–7.27(m,7H),4.76(s,1H),3.89(s,2H),2.41(s,3H),2.30(s,3H).
13 C NMR(101MHz,CDCL 3 )δ198.42(d,J＝2.0Hz),170.16,159.15(d,J＝247.5Hz),150.08,137.20,129.25,128.51,127.71,124.90(d,J＝24.2Hz),124.31(d,J＝8.1Hz),119.82(d,J＝8.1Hz),108.64(d,J＝23.2Hz),79.20,55.87,35.57,23.75.
19 F NMR(376MHz,CDCL 3 )δ-117.09.
example 21
In a dry pressure-resistant tube, 75.69mg of 1-acetyl-5-methylindolin-3-one, 24.23mg of N-methylbenzylamine and 6.64mg of potassium iodide were added, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 8:1), 35mg of a product is obtained, the yield is 57%, and the reaction process is shown as the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCL 3 )δ8.34(s,1H),7.57(d,J＝7.8Hz,1H),7.33–7.26(m,5H),7.00(d,J＝7.8Hz,1H),4.71(s,1H),3.89(d,J＝11.0Hz,2H),2.45(s,3H),2.43(s,3H),2.29(s,3H).
13 C NMR(101MHz,CDCL 3 )δ199.07,170.20,151.84,138.90,137.53,134.20,129.21,128.46,127.58,123.28,122.80,117.93,79.07,55.83,35.50,23.84,20.77.
example 22
In a dry pressure-resistant tube, 88.07mg of 1-acetyl-6-nitroindolin-3-one, 17.42mg of morpholine and 6.64mg of potassium iodide were added, and 1.5mL of ethyl acetate was added to dissolve the above solid, and the resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction is finished, the mixture is cooled to room temperature, concentrated by rotary evaporation and purified by a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 5:1), 17mg of a product is obtained, the yield is 27%, and the reaction process is shown as the following formula:
nuclear magnetic resonance analysis was performed on the product prepared in this example:
1 H NMR(400MHz,CDCL 3 )δ9.32(d,J＝1.3Hz,1H),8.02(dd,J＝8.3,1.9Hz,1H),7.81(d,J＝8.3Hz,1H),4.70(s,1H),3.71–3.64(m,4H),3.02–2.94(m,2H),2.68–2.61(m,2H),2.51(s,3H).
13 C NMR(101MHz,CDCL 3 )δ197.25,170.20,153.62,153.54,126.28,124.12,119.23,113.36,80.61,67.00,47.02,23.67。
Claims (6)
1. a process for the preparation of a C (sp 3) -H aminated derivative of indol-3-one, comprising: potassium iodide is used as a catalyst, oxygen in the air is used as an oxidant, the indole-3 ketone derivative reacts with secondary amine in an organic solvent, and after the reaction is finished, the concentration and purification are carried out to obtain a C (sp 3) -H aminated derivative of the indole-3 ketone;
the structure of the C (sp 3) -H aminated derivative of the indole-3 ketone is shown as a formula (I):
the structure of the indole-3 ketone derivative is shown as a formula (II):
the structure of the secondary amine is shown as a formula (II I):
R 1 independently selected from one of hydrogen, halogen and nitro;
R 2 and R is 3 Independently selected from C 1 ～C 5 Alkyl, cycloalkyl, C 1 ～C 5 Alkoxycarbonyl, C 1 ～C 5 Alkanoyloxy, phenyl, benzyl or halogen substituted benzyl, the substituents on said phenyl or benzyl being halogen; or said R 2 And R is 3 Forms a substituted or unsubstituted 5-8 membered ring with the attached N, the substituents on the 5-8 membered ring being C 1 ～C 5 Alkoxycarbonyl or phenyl.
2. The process for the preparation of C (sp 3) -H aminated derivatives of indol-3 ketones according to claim 1, wherein said secondary amine is one of the following compounds:
3. a process for the preparation of an aminated C (sp 3) -H derivative of indol-3-ones according to claim 1, wherein R 1 Is hydrogen.
4. The process for the preparation of C (sp 3) -H aminated derivatives of indol-3-ones according to claim 1, characterized in that the molar ratio of said indol-3-one derivatives to said catalyst KI is between 1:0.05 and 1:0.2.
5. The process for the preparation of a C (sp 3) -H aminated derivative of indol-3-ones according to claim 1, wherein the reaction temperature is 25 ℃ to 80 ℃ and the reaction time is 6 to 12H.
6. The process for the preparation of C (sp 3) -H aminated derivatives of indol-3-ones according to claim 1, wherein the organic solvent is at least one of acetonitrile, toluene, tetrahydrofuran, 1, 4-dioxane, dichloromethane and ethyl acetate.
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