CN109721523B - Indoline derivative and preparation method thereof - Google Patents
Indoline derivative and preparation method thereof Download PDFInfo
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- CN109721523B CN109721523B CN201811578478.7A CN201811578478A CN109721523B CN 109721523 B CN109721523 B CN 109721523B CN 201811578478 A CN201811578478 A CN 201811578478A CN 109721523 B CN109721523 B CN 109721523B
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- 125000003387 indolinyl group Chemical class N1(CCC2=CC=CC=C12)* 0.000 title claims abstract 8
- 238000002360 preparation method Methods 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 20
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical class NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000007800 oxidant agent Substances 0.000 claims abstract description 13
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims abstract description 12
- 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 abstract description 11
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 10
- GJBRNHKUVLOCEB-UHFFFAOYSA-N tert-butyl benzenecarboperoxoate Chemical compound CC(C)(C)OOC(=O)C1=CC=CC=C1 GJBRNHKUVLOCEB-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000001590 oxidative effect Effects 0.000 claims abstract description 9
- 150000002978 peroxides Chemical class 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000000654 additive Substances 0.000 claims abstract description 7
- 230000000996 additive effect Effects 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 2
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 abstract description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 abstract description 4
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 abstract description 4
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 abstract description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 abstract description 2
- 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 abstract description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 abstract description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 abstract description 2
- XMNIXWIUMCBBBL-UHFFFAOYSA-N 2-(2-phenylpropan-2-ylperoxy)propan-2-ylbenzene Chemical compound C=1C=CC=CC=1C(C)(C)OOC(C)(C)C1=CC=CC=C1 XMNIXWIUMCBBBL-UHFFFAOYSA-N 0.000 abstract description 2
- CDVAIHNNWWJFJW-UHFFFAOYSA-N 3,5-diethoxycarbonyl-1,4-dihydrocollidine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C CDVAIHNNWWJFJW-UHFFFAOYSA-N 0.000 abstract description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 abstract description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 abstract description 2
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 abstract description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 abstract description 2
- 229940011182 cobalt acetate Drugs 0.000 abstract description 2
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 abstract description 2
- FJDJVBXSSLDNJB-LNTINUHCSA-N cobalt;(z)-4-hydroxypent-3-en-2-one Chemical compound [Co].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FJDJVBXSSLDNJB-LNTINUHCSA-N 0.000 abstract description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 abstract description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 abstract description 2
- YQHLDYVWEZKEOX-UHFFFAOYSA-N cumene hydroperoxide Chemical compound OOC(C)(C)C1=CC=CC=C1 YQHLDYVWEZKEOX-UHFFFAOYSA-N 0.000 abstract description 2
- 229940045803 cuprous chloride Drugs 0.000 abstract description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 abstract description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 abstract description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 abstract description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 abstract description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 abstract description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 abstract description 2
- 229910001958 silver carbonate Inorganic materials 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- -1 nitrogen-containing heterocyclic compounds Chemical class 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 150000002476 indolines Chemical class 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 238000002390 rotary evaporation Methods 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 238000001308 synthesis method Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 4
- 238000010758 carbon-nitrogen bond forming reactions Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000007306 functionalization reaction Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 238000010499 C–H functionalization reaction Methods 0.000 description 2
- 208000003251 Pruritus Diseases 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000007803 itching Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BQPIYDUNTQHZBF-UHFFFAOYSA-N n,n-difluorocarbamoyl fluoride Chemical compound FN(F)C(F)=O BQPIYDUNTQHZBF-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- SKNGHROBOKBHGJ-UHFFFAOYSA-N 2-methoxyiminoacetamide Chemical compound CON=CC(N)=O SKNGHROBOKBHGJ-UHFFFAOYSA-N 0.000 description 1
- CWPKTBMRVATCBL-UHFFFAOYSA-N 3-[1-[1-[(2-methylphenyl)methyl]piperidin-4-yl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound CC1=CC=CC=C1CN1CCC(N2CCC(CC2)N2C(NC3=CC=CC=C32)=O)CC1 CWPKTBMRVATCBL-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 239000005465 B01AC22 - Prasugrel Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 206010060840 Ischaemic cerebral infarction Diseases 0.000 description 1
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 1
- 208000036071 Rhinorrhea Diseases 0.000 description 1
- 206010039101 Rhinorrhoea Diseases 0.000 description 1
- 206010048908 Seasonal allergy Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 1
- 229960003856 argatroban Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001539 azetidines Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 description 1
- 229960002881 clemastine Drugs 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- OZMXYFCTLVMXEU-UHFFFAOYSA-N formamide 2H-triazole Chemical compound N1N=NC=C1.C(=O)N OZMXYFCTLVMXEU-UHFFFAOYSA-N 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000022084 motor paralysis Diseases 0.000 description 1
- NFAUULBAHCDQIL-UHFFFAOYSA-N n'-[2-(4-methylphenyl)ethyl]oxamide Chemical compound CC1=CC=C(CCNC(=O)C(N)=O)C=C1 NFAUULBAHCDQIL-UHFFFAOYSA-N 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 201000005111 ocular hyperemia Diseases 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- 201000004338 pollen allergy Diseases 0.000 description 1
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 1
- 229960004197 prasugrel Drugs 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 150000003236 pyrrolines Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 206010041232 sneezing Diseases 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Abstract
The invention provides a method for synthesizing indoline derivatives, which comprises the steps of taking oxamide derivatives as raw materials, adding a catalyst, and under the conditions of a solvent, a peroxide oxidant and an additive, realizing an oxamide-induced intramolecular C-N bonding reaction to synthesize the indoline derivatives, wherein the solvent is one of 1, 2-dichloroethane, chlorobenzene, toluene, m-xylene, mesitylene, dimethyl sulfoxide, 1, 4-dioxane, tert-amyl alcohol or hexafluoroisopropanol; the catalyst is one of palladium chloride, palladium acetate, cobalt acetate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, cobalt acetylacetonate, ferric acetylacetonate, nickel chloride or copper acetate; the peroxide oxidant is one of cumyl hydroperoxide, di-tert-butyl peroxide, tert-butyl peroxybenzoate, dicumyl peroxide and tert-butyl peroxide; the additive is one of silver carbonate, benzoquinone, potassium persulfate, cuprous chloride, ferric chloride or N-methylmorpholine oxide.
Description
Technical Field
The invention relates to an indoline derivative and a preparation method thereof, belonging to the technical field of organic synthesis.
Background
Heterocyclic compounds, especially nitrogen-containing heterocyclic compounds, are very important compounds which are generally important molecular skeletons of natural substances and pharmaceutical molecules. The nitrogen-containing heterocyclic compound has wide application in medicine and pesticide chemistry. For example, physostigmine is used primarily in the treatment of glaucoma, and can constrict the pupil and lower intraocular pressure. The clemastine is mainly used for the phenomena of skin redness and itching caused by various anaphylactic reactions, and rhinorrhea, sneezing, eye redness and itching and the like caused by pollen allergy and cold. Argatroban is an anticoagulant and is mainly used for ischemic cerebral infarction within 48 hours of attack and improvement of nervous symptoms (motor paralysis) of patients in acute stage. Prasugrel is mainly used for treating cardiovascular and cerebrovascular diseases such as heart failure, stroke, unstable angina pectoris and the like. In addition, the nitrogen-containing heterocycle is also applied to the aspects of metal catalytic materials and fuel sensitized solar cells due to the characteristics that the nitrogen-containing heterocycle is easy to carry out structural modification and is convenient for introducing various groups. Therefore, the formation of C-N bond to construct the nitrogen-containing heterocyclic compound skeleton is of crucial importance in synthetic chemistry. Transition metal catalyzed C-H bond functionalization has been an effective, versatile method of constructing complex molecules for the last few decades. The targeting, also called Ligand-Directed (Ligand-Directed) or complexation-Directed (Coordination-Directed), is that a molecule requiring C-H activation and a transition metal can form a relatively stable cyclic metal intermediate by virtue of the complexation between the Ligand and the transition metal through an existing group having Coordination ability in the molecule, so that a C-M bond is formed at an expected position, and a functionalization reaction further occurs. Among many reports, C — H bond activation with the aid of a directing group has attracted considerable attention due to its good selection and functional group tolerance.
At present, many synthetic methods for synthesizing indoline derivatives have been reported. In 2008, Yu project group first discovered a targeting group of trifluoroformamide, which can be applied to ortho-iodination of phenylethylamine to achieve selective functionalization of C — H bond. On this basis, they further succeeded in synthesizing indoline derivatives (Li, j. -j.; Mei, t. -s.; Yu, j. -q.angelw.chem.int.ed.2008, 47,6452.). After a while, the Yu topic group reported a breakthrough development. They use Ce (SO)4)2Or F+As strong oxidizing agents instead of copper salts[15]The phenethylamine protected by the trifluoroformamide is taken as a substrate to be directly synthesized in one stepIndoline derivatives are provided. However, 10 to 15 mol% of palladium (II) and a large amount of oxidizing agent (Mei, T. -S.; Wang, X.; Yu, J. -Q.J.Am.chem.Soc.2009,131,10806.) are required to achieve this conversion.
In 2011, Chen and Daugulis project groups reported picolinamide-directed palladium-catalyzed C (sp), respectively2) -H and C (sp)3) Intramolecular ammoniation reaction of-H, all using PhI (OAc)2As an oxidant, a series of azetidine and pyrroline derivatives ((a) He, G.; ZHao, Y.; Zhang, S.; Lu, C.; Chen, G.J.Am.Chem.Soc.2012,134,3.(b) Nadres, E.T.; Daugulis, O.J.Am.Chem.Soc.2012,134,7.) are synthesized through five-membered ring palladium transition states and six-membered ring palladium transition states respectively, so that C-N bonding of a challenging aliphatic amine substrate is realized. Subsequently, Chen subject group found that oxygen has a certain inhibitory effect on cyclization reaction of amine substrates (He, G.; Lu C.; Zhao, Y.; Nack, W.A.; Chen, G.Org.Lett.2012,14,2944.), and they succeeded in synthesizing nitrogen-containing heterocyclic derivatives by modifying experimental conditions using argon as a reaction atmosphere, and under the reaction conditions, the catalyst dosage is less and the temperature is lower.
2012, the Shi topic group Pd (OAc)2Is catalyst, PhI (OAc)2As an oxidant, 1,2, 3-triazole formamide is a guide group, and an intramolecular C-N bond forming reaction is realized (Ye, X.; He, Z.; Ahmed, T.; Weise, K.; Akhmedov, N.G.; Petersen, J.L.; Shi, X.Chem.Sci.2013,4,3712.). In 2013, the Ma project group uses 2-methoxyiminoacetamide as a positioning group to realize amination reaction of 2-esterphenethylamine derivatives (He, Y-P.; Zhang, C.; Fan, M.; Wu, Z.; Ma, D.org.Lett.2015,17,496.). In this system, when PhI (OAc) is used2When used as an oxidizing agent, the reaction is not good in yield and by-products of the acyl oxidation are also present.
In 2014, Shi subject group realized palladium-catalyzed ammoniation reactions of phenethylamines, amphetamines and aliphatic amines with oxamides as targeting groups, forming five-and six-membered heterocycles ((a) Wang, Q.; Han, J.; Wang, C.; Zhang, J.Y; Huang, Z.B.; Shi, D.Q.; Zhao, Y.S.Chem.Sci.2014,5,4962.(b) Han, J.; Liu, P.; Wang, C.; Wang, Q.; Zhang, J.Y; Zhao, Y.W.; Shi, D.Q.; Huang Z.B.; Zhao, Y.S.O.; Wang, Z.B.rg.lett.2014,16,5682.). Despite the many advantages of this method, PhI (OAc)2Expensive and not readily available, so that the reaction can still be improved, the invention utilizes cheap and easily available peroxide TBPB instead of expensive PhI (OAc)2As the oxidizing agent, also can well realize palladium catalyzed oxamide induced intramolecular C-N bond forming reaction, so as to synthesize the indoline derivative.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for synthesizing indoline derivatives, which utilizes a small amount of catalyst and under mild reaction conditions, reduces reaction steps, shortens reaction time and improves yield. In order to solve the technical problems, the technical scheme of the invention is as follows: an indoline derivative, which is characterized in that: has a structure shown in formula IV:
wherein R is preferably-CH3、-OCH3Any one of-F, -Br or-Cl.
The invention provides a method for synthesizing indoline derivatives, which takes oxamide derivatives as raw materials, adds a catalyst, and realizes an oxamide-induced intramolecular C-N bond forming reaction under the conditions of a solvent, a peroxide oxidant and an additive to synthesize the indoline derivatives shown in formula IV.
The preferred synthesis method of the invention is that the molar ratio of the oxamide derivative to the catalyst is 1: 0.025.
In the preferred synthesis method of the present invention, the solvent is preferably one of 1, 2-dichloroethane, chlorobenzene, toluene, m-xylene, mesitylene, dimethyl sulfoxide, 1, 4-dioxane, tert-amyl alcohol and hexafluoroisopropanol. More preferably hexafluoroisopropanol.
In the preferable synthesis method of the invention, the catalyst is one of palladium chloride, palladium acetate, cobalt acetate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, cobalt acetylacetonate, ferric acetylacetonate, nickel chloride or copper acetate. Palladium acetate is preferred.
In the preferred synthesis method of the invention, the peroxide oxidant is one of cumyl hydroperoxide, di-tert-butyl peroxide, tert-butyl peroxybenzoate, dicumyl peroxide and tert-butyl peroxide. Tert-butyl peroxybenzoate is preferred.
In the preferred synthesis method of the invention, the additive is one of silver carbonate, benzoquinone, potassium persulfate, cuprous chloride, ferric chloride or N-methylmorpholine oxide. Potassium persulfate is preferred.
In the preferable synthesis method, the reaction temperature is 80-120 ℃, and the reaction time is 8-16 h; the preferred reaction temperature is 100 ℃ and the reaction time is 12 h.
The method for realizing the invention is listed as follows: the method for synthesizing indoline derivatives comprises the steps of taking compounds of an amine derivative formula I and a formula II as raw materials, taking triethylamine as a catalyst to synthesize an oxamide derivative formula III, taking the compound of the formula III as the raw material, adding the catalyst, and under the conditions of a solvent, a peroxide oxidant and an additive, realizing an oxamide-induced intramolecular C-N bonding reaction to synthesize indoline and derivatives thereof, namely an indoline derivative formula IV, wherein the specific synthetic route is as follows:
the invention has the advantages that: the synthesis process of the invention utilizes a C-H activation/cyclization method and uses palladium acetate as a catalyst to realize oxamide-induced intramolecular C-N bond forming reaction to synthesize the indoline derivative. Wherein the compounds N, N-diisopropyl-2- (4-bromoindol-1-yl) -2-oxyacetamide (IVa), N-diisopropyl-2- (4-fluoroindol-1-yl) -2-oxyacetamide (IVb), N-diisopropyl-2- (5-methoxyindol-1-yl) -2-oxyacetamide (IVc), N-diisopropyl-2- (5-bromoindol-1-yl) -2-oxyacetamide (IVd), N-diisopropyl-2- (6-methylindol-1-yl) -2-oxyacetamide (IVe), N, N-diisopropyl-2- (4, 6-dichloroindol-1-yl) -2-oxyacetamide (IVf) having the following structure:
Detailed Description
Example 1
Will N1,N1-diisopropyl-N2Adding (0.2mmol) of- (2-bromophenylethyl) oxamide into a reaction tube, adding a palladium acetate catalyst (2.5 mol%) and tert-butyl peroxybenzoate (3 equivalents) and potassium persulfate (1 equivalent), adding hexafluoroisopropanol (0.5mL), sealing the reaction tube, putting the mixture into an oil bath, stirring and reacting at 100 ℃ for 12 hours, cooling the reaction system to room temperature after the reaction is finished, performing suction filtration and rotary evaporation drying after a solid is separated out, purifying by using a silica gel column chromatography, and taking ethyl acetate and petroleum ether (1:15) as eluent to obtain a target product N, N-diisopropyl-2- (4-bromoindol-1-yl) -2-oxyacetamide (IVa): the yield is 81%; 1H NMR (400MHz, CDCl3) δ:8.12(d, J ═ 8.4Hz,0.77H),7.22-7.01(m,2.22H),4.19-4.10(m,2H),3.94-3.90(m,1H),3.55-3.52(m,1H),3.20-3.13(m,2H),1.56-1.50(m,6H),1.26-1.15(m,6H).13C NMR(100MHz,CDCl3)δ:163.7,162.8,132.5,129.5,129.1,127.6,127.1,119.5,116.0,51.1,50.7,47.5,46.2,46.0,29.7,28.3,21.0,20.7,20.2,20.0.
Example 2
Following the procedure of example 1, N1,N1-diisopropyl-N2Adding (0.2mmol) of- (2-fluorophenethyl) oxamide into a reaction tube, adding a palladium acetate catalyst (2.5mol percent), tert-butyl peroxybenzoate (3 equivalents) and potassium persulfate (1 equivalent), adding hexafluoroisopropanol (0.5mL), sealing the reaction tube, putting the mixture into an oil bath, stirring and reacting at 100 ℃ for 12 hours, cooling the reaction system to room temperature after the reaction is finished, performing suction filtration and rotary evaporation drying after a solid is separated out, purifying by silica gel column chromatography by using ethyl acetate and petroleum ether (1:15) as eluent to obtain a target product N, N-diisopropyl-2- (4-fluoroindol-1-yl) -2-oxyacetamide (IVb): the yield is 84%;1H NMR(400MHz,CDCl3)δ:7.96(d,J＝8.4Hz,0.67H),7.23-7.21(m,1.24H),7.14-7.10(m,0.24H),6.97-6.95(m,0.24H),6.82-6.75(m,0.85H),4.23-4.13(m,2H),3.95-3.72(m,1H),3.58-3.20(m,1H),3.24-3.16(m,2H),1.57-1.50(m,6H),1.27-1.16(m,6H).13C NMR(100MHz,CDCl3)δ:164.1,163.7,162.4,160.2,157.7,144.2,144.1,129.6,129.6,129.3,129.3,118.2,117.9,113.1,113.0,111.6,111.4,111.1,110.9,109.0,109.0,51.0,50.6,48.4,47.2,46.1 45.91,24.5,23.0,20.9,20.6,20.1,19.9.
example 3
Following the procedure of example 1, N1,N1-diisopropyl-N2Adding (0.2mmol) of- (3-methoxyphenethyl) oxamide into a reaction tube, adding a palladium acetate catalyst (2.5mol percent), tert-butyl peroxybenzoate (3 equivalents) and potassium persulfate (1 equivalent), adding hexafluoroisopropanol (0.5mL), sealing the reaction tube, putting the mixture into an oil bath, stirring and reacting at 100 ℃ for 12 hours, cooling the reaction system to room temperature after the reaction is finished, performing suction filtration and rotary evaporation drying after solid is separated out, purifying by silica gel column chromatography by taking ethyl acetate and petroleum ether (1:15) as eluent to obtain a target product N, N-diisopropyl-2- (5-methoxyindol-1-yl) -2-oxyacetamide (IVc): the yield is 71%;1H NMR(400MHz,CDCl3)δ:8.05(d,J＝8.8Hz,0.75H),7.06(d,J＝9.2Hz,0.26H),6.75-6.69(m,1H),4.12-4.03(m,2H),3.95-3.88(m,1H),3.75-3.73(m,3H),3.53-3.47(m,1H),3.15-3.04(m,2H),1.54-1.46(m,6H),1.22-1.10(m,6H).13C NMR(100MHz,CDCl3)δ:164.6,164.1,161.9,161.8,157.1,156.9,135.4,134.6,133.5,133.3,117.8,113.9,112.3,112.1,111.5,111.0,55.7,55.6,50.9,50.5,48.1,46.9,45.9,45.8,28.3,27.0,20.9,20.6,20.1,19.9.
example 4
Following the procedure of example 1, N1,N1-diisopropyl-N2- (3-bromochlorophenylethyl) oxamide (0.2mmol) is added into a reaction tube, then a palladium acetate catalyst (2.5mol percent), tert-butyl peroxybenzoate (3 equivalents) and potassium persulfate (1 equivalent) are added, hexafluoroisopropanol (0.5mL) is added, the reaction tube is sealed, the mixture is put into an oil bath and stirred at 100 ℃ for reaction for 12 hours, after the reaction is finished, the reaction system is cooled to room temperature, and after solids are precipitated, suction filtration is carried out,Performing rotary evaporation and drying, performing silica gel column chromatography, and purifying by using ethyl acetate and petroleum ether (1:15) as eluent to obtain a target product N, N-diisopropyl-2- (5-bromoindol-1-yl) -2-oxyacetamide (IVd): the yield is 66%;1H NMR(400MHz,CDCl3)δ:7.79(d,J＝7.6Hz,0.72H),7.31-7.19(m,2H),6.99(d,J＝8.8Hz,0.26H),4.12-4.04(m,2H),3.89-3.84(m,1H),3.66-3.48(m,1H),3.17-3.09(m,2H),1.52-1.45(m,6H),1.22-1.11(m,6H).13C NMR(100MHz,CDCl3)δ:164.1,163.6,162.4,140.9,139.0,135.3,134.2,130.4,130.2,128.8,127.9,118.4,117.1,116.8,114.5,51.0,50.6,48.0,46.8,46.0,45.9,27.9,26.5,20.9,20.6,20.1,19.9.
example 5
Following the procedure of example 1, N1,N1-diisopropyl-N2Adding (0.2mmol) of (4-methylphenylethyl) oxamide into a reaction tube, adding a palladium acetate catalyst (2.5mol percent), tert-butyl peroxybenzoate (3 equivalents) and potassium persulfate (1 equivalent), adding hexafluoroisopropanol (0.5mL), sealing the reaction tube, putting the mixture into an oil bath, stirring and reacting at 100 ℃ for 12 hours, cooling the reaction system to room temperature after the reaction is finished, performing suction filtration and rotary evaporation drying after solid is separated out, purifying by silica gel column chromatography by taking ethyl acetate and petroleum ether (1:15) as eluent to obtain a target product N, N-diisopropyl-2- (6-methylindol-1-yl) -2-oxyacetamide (IVe): the yield is 79 percent;1H NMR(400MHz,CDCl3)δ:8.04(s,0.61H),7.11-7.04(m,1.27H),6.91-6.83(m,0.92H),4.19-4.06(m,2H),3.97-3.71(m,1H),3.56-3.51(m,1H),3.16-3.08(m,2H),2.35-2.28(m,3H),1.60-1.50(m,6.40H),1.25-1.07(m,5.79H).13C NMR(100MHz,CDCl3)δ:164.5,164.0,162.4,162.3,141.8,139.8,137.5,137.3,129.8,128.9,125.4,125.2,125.0,124.4,117.8,113.9,50.9,50.5,48.3,46.9,45.9,45.7,27.7,26.3,21.5,21.3,20.8,20.5,20.1,19.8.
example 6
Following the procedure of example 1, N1,N1-diisopropyl-N2- (2, 4-Dichlorophenethyl) oxamide (0.2mmol) was added to the reaction tube, followed by palladium acetate catalyst (2.5 mol%) and tert-butyl peroxybenzoate (3 equiv.) to give a solutionAnd potassium persulfate (1 equivalent), adding hexafluoroisopropanol (0.5mL), sealing the reaction tube, putting the mixture into an oil bath, stirring and reacting at 100 ℃ for 12 hours, cooling the reaction system to room temperature after the reaction is finished, performing suction filtration and rotary evaporation drying after a solid is separated out, purifying by silica gel column chromatography to obtain a target product N, N-diisopropyl-2- (4, 6-dichloroindol-1-yl) -2-oxyacetamide (IVf) by taking ethyl acetate and petroleum ether (1:15) as eluent: the yield is 69%;1H NMR(400MHz,CDCl3)δ:8.13-8.12(m,0.6H),7.26-7.25(m,0.39H),7.08-7.03(m,1H),4.21-4.13(m,2H),3.93-3.88(m,1H),3.70-3.52(m,1H),3.19-3.12(m,2H),1.61-1.49(m,6H),1.26-1.17(m,6H).13C NMR(100MHz,CDCl3)δ:163.8,163.3,162.8,162.4,143.7,141.9,134.3,131.8,130.9,130.1,129.0,124.4,123.8,115.9,112.2,51.2,50.8,48.2,46.9,46.4,46.1,27.3,25.9,21.0,20.8,20.2,19.9.
after screening of reaction conditions for many times, considering the effect of the reaction and the principle of green chemistry, as the optimization, hexafluoroisopropanol is determined as a solvent, palladium acetate is determined as a catalyst, and the oxamide derivative and the catalyst are reacted for 12 hours at the reaction temperature of 100 ℃ according to the molar ratio of 1:0.025, so that the yield of the obtained target product is highest.
The foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed.
Claims (4)
1. A method for synthesizing indoline derivatives, wherein the derivatives have the structure shown in formula IV:
the method isThe method comprises the steps of taking an oxamide derivative as a raw material, adding a catalyst, and under the conditions of a solvent, a peroxide oxidant and an additive, realizing an oxamide-induced intramolecular C-N bonding reaction to synthesize an indoline derivative shown in a formula IV; the peroxide oxidant is tert-butyl peroxybenzoate, the additive is potassium persulfate, and the catalyst is palladium acetate; the solvent is hexafluoroisopropanol; wherein the structural formula of the oxamide derivative is as follows:
wherein R is-CH3、-OCH3Any one of-F, -Br or-Cl; wherein-OA is
2. A process for the synthesis of indoline derivatives according to claim 1 wherein the molar ratio of oxamide derivative to catalyst is 1: 0.025.
3. The method for synthesizing indoline derivatives according to claim 1, wherein the reaction temperature is 80-120 ℃ and the reaction time is 8-16 h.
4. The method for synthesizing indoline derivatives according to claim 1, wherein the reaction temperature is 100 ℃ and the reaction time is 12 hours.
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Non-Patent Citations (5)
| Title |
|---|
| Easily accessible auxiliary for palladium-catalyzed intramolecular amination of C(sp2)-H and C(sp3)-H bonds at δ- and ε-positions;Chao Wang，等;《Angewandte Chemie, International Edition》;20140722;第53卷(第37期);9884-9888 * |
| Oxalyl amide assisted palladium-catalyzed synthesis of pyrrolidones via carbonylation of γ-C(sp3)-H bonds of aliphatic amine substrates;Chao Wang，等;《Chemical Science》;20150519;第6卷(第8期);4610-4614 * |
| Palladium-Catalyzed Carbonylation of β‑Arylethylamide Directed by Oxalyl Amide in the Presence of Carbon Monoxide;Li Zhang，等;《Journal of Organic Chemistry》;20160523;第81卷;5256-5262 * |
| Palladium-Catalyzed Oxalyl Amide-Directed γ-Arylation of Aliphatic Amines;Jian Han，等;《Journal of Organic Chemistry》;20150826;第80卷(第18期);9297-9306 * |
| Pd-Catalyzed regioselective sequential meta-, ortho-C-H functionalization of arenes: a predictable approach to the synthesis of polysubstituted β-arylethylamines;Jian Han，等;《Organic & Biomolecular Chemistry》;20170530;第15卷(第24期);5112-5116 * |
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Application publication date: 20190507 Assignee: NANTONG WANNIANCHANG PHARMACEUTICAL Co.,Ltd. Assignor: JIANGSU University OF TECHNOLOGY Contract record no.: X2023980054244 Denomination of invention: A dihydroindole derivative and its preparation method Granted publication date: 20211221 License type: Common License Record date: 20231227 |