CN111995561A - High-yield preparation method of polychlorinated methyl indoline without metal catalyst - Google Patents
High-yield preparation method of polychlorinated methyl indoline without metal catalyst Download PDFInfo
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- CN111995561A CN111995561A CN202010927888.9A CN202010927888A CN111995561A CN 111995561 A CN111995561 A CN 111995561A CN 202010927888 A CN202010927888 A CN 202010927888A CN 111995561 A CN111995561 A CN 111995561A
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- Prior art keywords
- methyl
- reaction
- polychlorinated
- indoline
- metal catalyst
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- FIRXFHJQGIIJDB-UHFFFAOYSA-N 1-methyl-2,3-dihydroindole Chemical class C1=CC=C2N(C)CCC2=C1 FIRXFHJQGIIJDB-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 239000003054 catalyst Substances 0.000 title claims abstract description 12
- 229910052751 metal Inorganic materials 0.000 title claims abstract description 11
- 239000002184 metal Substances 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003999 initiator Substances 0.000 claims abstract description 13
- 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 claims abstract description 11
- 150000001336 alkenes Chemical class 0.000 claims abstract description 11
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 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
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- HGTUJZTUQFXBIH-UHFFFAOYSA-N (2,3-dimethyl-3-phenylbutan-2-yl)benzene Chemical group C=1C=CC=CC=1C(C)(C)C(C)(C)C1=CC=CC=C1 HGTUJZTUQFXBIH-UHFFFAOYSA-N 0.000 claims 1
- 238000000605 extraction Methods 0.000 claims 1
- 238000010791 quenching Methods 0.000 claims 1
- 230000000171 quenching effect Effects 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 15
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002904 solvent Substances 0.000 abstract description 6
- 150000003254 radicals Chemical class 0.000 abstract description 4
- 238000000034 method Methods 0.000 description 12
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 9
- 239000007800 oxidant agent Substances 0.000 description 9
- 238000007363 ring formation reaction Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- -1 allylic arylamines Chemical class 0.000 description 8
- 150000002476 indolines Chemical class 0.000 description 8
- XHMYLHSZUIFINI-UHFFFAOYSA-N 1-(trichloromethyl)-2,3-dihydroindole Chemical compound C1CN(C2=CC=CC=C21)C(Cl)(Cl)Cl XHMYLHSZUIFINI-UHFFFAOYSA-N 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- HLPQKSWDOUSJDT-UHFFFAOYSA-N 1-(dichloromethyl)-2,3-dihydroindole Chemical compound C1CN(C2=CC=CC=C21)C(Cl)Cl HLPQKSWDOUSJDT-UHFFFAOYSA-N 0.000 description 5
- 230000001590 oxidative effect Effects 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000004342 Benzoyl peroxide Substances 0.000 description 4
- 235000019400 benzoyl peroxide Nutrition 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000005394 methallyl group Chemical group 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 3
- 238000010523 cascade reaction Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- YIVJZNGAASQVEM-UHFFFAOYSA-N Lauroyl peroxide Chemical compound CCCCCCCCCCCC(=O)OOC(=O)CCCCCCCCCCC YIVJZNGAASQVEM-UHFFFAOYSA-N 0.000 description 2
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000002015 acyclic group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- XKRFBSDTIKDVGQ-UHFFFAOYSA-N 2-(trichloromethyl)-1h-indole Chemical compound C1=CC=C2NC(C(Cl)(Cl)Cl)=CC2=C1 XKRFBSDTIKDVGQ-UHFFFAOYSA-N 0.000 description 1
- UQRLKWGPEVNVHT-UHFFFAOYSA-N 3,5-dichloroaniline Chemical compound NC1=CC(Cl)=CC(Cl)=C1 UQRLKWGPEVNVHT-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
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- QHAFKQOFQVSWCE-UHFFFAOYSA-N 3-methylindol-2-one Chemical class C1=CC=CC2=NC(=O)C(C)=C21 QHAFKQOFQVSWCE-UHFFFAOYSA-N 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910002567 K2S2O8 Inorganic materials 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 229960001413 acetanilide Drugs 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000002277 benzylpenicilloyl group Chemical group C(=O)(O)[C@@H]1N[C@H](SC1(C)C)[C@@H](C(=O)*)NC(CC1=CC=CC=C1)=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000007265 chloromethylation reaction Methods 0.000 description 1
- 125000004966 cyanoalkyl group Chemical group 0.000 description 1
- 125000003074 decanoyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 1
- 239000012969 di-tertiary-butyl peroxide Substances 0.000 description 1
- RNPXCFINMKSQPQ-UHFFFAOYSA-N dicetyl hydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(=O)OCCCCCCCCCCCCCCCC RNPXCFINMKSQPQ-UHFFFAOYSA-N 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- ZJULYDCRWUEPTK-UHFFFAOYSA-N dichloromethyl Chemical compound Cl[CH]Cl ZJULYDCRWUEPTK-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- LQFLWKPCQITJIH-UHFFFAOYSA-N n-allyl-aniline Chemical class C=CCNC1=CC=CC=C1 LQFLWKPCQITJIH-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 235000019394 potassium persulphate Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tert-butyl alcohol Substances CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention relates to a high-yield preparation method of polychlorinated methyl indoline without a metal catalyst. Uses non-activated olefin as free radical acceptor, dicumyl peroxide (DCP) as initiator, and dichloromethane, chloroform and carbon tetrachloride as cheap solvent. The reaction does not need a metal catalyst, and has the advantages of simple operation, mild conditions, low cost, wide substrate application range and the like.
Description
The invention is a divisional application, and the patent application numbers of the parent case are as follows: 201910155183.7, filing date: year 2019, 03, month 01, with patent names: a preparation method of polychlorinated methyl indoline without a metal catalyst.
Technical Field
The invention relates to the field of chemistry, in particular to a preparation method of high-yield polychlorinated methyl indoline without a metal catalyst.
Background
Halogens are widely present in medicine and active molecular structures, and halogen-containing compounds are also frequently used as synthetic substrates in the chemical industry. Up to now, it has been found that the introduction of more than 5000 halogen-containing natural products into the structure of natural or synthetic drugs has a profound effect on their biological activity and physicochemical properties. Among them, the polychlorinated methyl structure often occurs in alkaloids, which have unique biological activities, and thus, many chemical and pharmaceutical chemists have studied new synthetic methods to construct the polychlorinated methyl structure. Walsh et al describe a novel class of halogenase-catalyzed halogenation of non-activated aliphatic carbon centers. Zakaarian et al, catalyzed by ruthenium and titanium, undergo stereoselective haloalkylation of N-acyl oxazolinones. In addition, several groups have studied the dichloro or trichlorochloromethylation of olefins to synthesize polychlorinated methyl indolones. Although the chloromethylation reaction has made some progress, polychlorinated methylated nonactivated olefins remain important methods for building molecular diversity, and introducing polychlorinated methyl groups into reactive molecular structures remains a challenging task.
Indoline skeletons are widely present in natural and synthetic active compound structures, and finding a simple synthetic method for synthesizing indoline skeletons remains a research focus of organic and pharmaceutical chemists. However, the synthesis of indolines is mainly limited by dearomatization of the indole and the synthesis of indolines by acyclic substrates is also quite limited. More recently, the beam group has used the alkene of allylic arylamines as a radical acceptor for CF3CH2-a phosphate group, a cyanoalkyl group to the indoline. In 2018, the pan topic is combined into polychlorinated methyl indoline, but the group uses dilauroyl peroxide (LPO) which is an expensive oxidant, has too large molecular weight, generates a large amount of macromolecular waste, is not economical in terms of atom economy, and generates a large amount of molecular waste which causes relative difficulty in separation and purification. And the method has poor substrate universality and narrow substrate range, for example, an N-protecting group cannot be sulfonyl or aroyl. Other possibilities are explored for this purpose.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of polychlorinated methyl indoline without a metal catalyst.
The technical scheme for solving the technical problems is as follows:
the invention provides a preparation method of polychlorinated methyl indoline without a metal catalyst, which is characterized in that unactivated olefin reacts with chlorinated alkane under the condition of taking dicumyl peroxide as an initiator to obtain the polychlorinated methyl indoline.
Further, the chlorine-containing alkane is a dichloromethyl or trichloromethyl reagent.
Further, the equation for the reaction is:
Further, the molar ratio of the dicumyl peroxide to the dicumyl peroxide is 1: 3.
Further, the alkane containing chlorine is one of dichloromethane, chloroform and carbon tetrachloride.
Further, the reaction temperature of the reaction was 120 ℃ and the reaction time was 3 hours. .
The invention has the beneficial effects that: the invention provides a metal-free catalytic polychlorinated methyl/cyclization tandem reaction of unactivated olefin, which can synthesize polychlorinated methylated indoline in one step. In addition, CHCl is used3、CH2Cl2And CCl4And the like, taking cheap solvents as polychlorinated methyl reagents, synthesizing dichloromethylindoline and trichloromethylindoline, and presenting exo selectivity. The method has the advantages of simple operation, mild conditions, low cost, wide substrate range and the like. Compared with the modes of using LPO and the like, the invention breakthroughly uses DCP as an oxidant, has low price, small molecular weight and good atom economy, does not interfere separation and purification, uses DCP as the oxidant and uses a substrate application rangeThe circumference is wider.
Further, it is generally considered that the reaction efficiency using DCP as the oxidizing agent should be lower than that using LPO as the oxidizing agent. However, in the case of using DCP in the present invention, since DCP has a small molecular weight, it is excellent in atomic economy, the waste generated has a small molecular weight, it is easy to handle, and the reaction efficiency obtained by using DCP as an oxidizing agent is higher than that obtained by using LPO as an oxidizing agent, that is, the technical effect obtained in the present invention is not expected.
In addition, experiments on the synthesis of polychlorinated methylated indolines by polychlorinated methyl/cyclization tandem reactions of unactivated olefins were conducted in the present invention, and it was unexpectedly found that the synthesis of indolines from acyclic raw materials can be achieved while having good functional group tolerance properties using a specific catalyst. Under the action of cheap DCP, the N-allylaniline compounds undergo a series polychlorinated methyl/cyclization reaction to generate polychlorinated methyl indoline with exo selectivity. The method has the advantages of simple operation, mild conditions, low cost, wide substrate range and the like. Compared with modes such as LPO and the like, DCP is used as an oxidant in a breakthrough manner, the method is low in price, small in molecular weight and good in atom economy, cannot interfere with separation and purification, is higher in reaction efficiency and is wider in substrate application range due to the fact that DCP is used as the oxidant.
Detailed Description
The principles and features of this invention are described below in conjunction with embodiments, which are included to explain the invention and not to limit the scope of the invention.
The invention provides a preparation method of polychlorinated methyl indoline without a metal catalyst, which is characterized in that unactivated olefin reacts with chlorinated alkane under the condition of taking dicumyl peroxide as an initiator to obtain the polychlorinated methyl indoline. The chlorine-containing alkane is a dichloromethyl or trichloromethyl reagent. Preferably one of dichloromethane, chloroform and carbon tetrachloride.
The equation for the reaction is:
wherein R is1Is H or methyl, R2Is one of H, halogen, methyl or phenyl, PG is COR3、SO2R4Or C1-6One of the alkyl groups of (1), R3Is methyl, ethyl, n-C7H15、n-C9H19、n-C11H23、n-C17H35t-Bu (tert-butyl) or tert-butoxy, R4Is methyl or ethyl. The molar ratio of the dicumyl peroxide to the dicumyl peroxide is 1: 3. The reaction temperature of the reaction was 120 ℃ and the reaction time was 3 hours.
The invention provides a metal-free catalytic polychlorinated methyl/cyclization tandem reaction of unactivated olefin, which can synthesize polychlorinated methylated indoline in one step. In addition, CHCl is used3、CH2Cl2And CCl4And the like, taking cheap solvents as polychlorinated methyl reagents to synthesize dichloromethylindoline and trichloromethylindoline. The method has the advantages of simple operation, mild conditions, low cost, wide substrate range and the like.
Example 1
When R is1Is CH3，R2Is H, PG is acetyl (Ac-or CH)3CO-), the specific equation of the reaction is,
the procedure was carried out in 35ml of a dry Schlenk flask, successively adding N- (2-methylallyl) -N-phenylacetylarylamine 1a1(95mg, 0.5mmol), DCP (405mg, 1.5mmol) and then CHCl3(5.0ml), the mixture was stirred at 120 ℃ for 3 hours, and saturated water Na was added to complete the reaction2S2O3(2.0ml) and water (20.0ml) quenched with CH2Cl2Extracted three times (10.0 ml). The combined organic phases are distilled under reduced pressure and chromatographed on a silica gel column (silica gel as stationary phase, petroleum ether-ethyl acetate 30: 1 as eluent).This gave trichloromethylindoline 2a1(133 mg). The yield of the trichloromethyl indoline is 87%.
Example 2
Will be R in example 11、R2The PG and PG were replaced by different groups and the reaction was carried out according to the procedure, molar ratio and reaction conditions in example 1 to obtain the products and their yields shown in the following Table.
TABLE 1 when the reactant is CHCl3When R is1、R2Products obtained when PG is a different group and yields thereof
Based on the data in table 1, the optimization conditions, and the examination of the substrate range of the reaction, a series of allylarylamine substrates can synthesize the target product trichloromethylindoline in the next step under the optimization conditions, such as: when the benzene ring of N- (2-methyl allyl) acetanilide is para-connected with electron-donating or electron-withdrawing group and CHCl3The trichloromethylated indoline 2a2-4 can be obtained with the yield of 61-77%. We examined Protecting Groups (PGs) on nitrogen and were able to obtain propionyl-substituted indolines 2b1, 2 in high yields of 87% and 77%, respectively. The pivaloyl substituted allylarylamine can be used for successfully obtaining the corresponding indoline 2c with 76% yield. For the protecting group on nitrogen, we examined various long chain groups, octanoyl, decanoyl, dodecanoyl and stearoylThe groups are not affected by steric hindrance, and the corresponding trichloromethyl indoline 2d1-2 and 2e1-3 can be successfully obtained with the yield of 57-88%. The indoline 2f can be successfully obtained by using the allyl arylamine substituted by Boc to participate in the reaction. Benzoyl and 3-chlorobenzoyl substituted indolines 2g1, 2 can also be prepared in moderate yield. Protecting groups on Nitrogen We also investigated sulfonyl-, methanesulfonyl-and ethanesulfonyl-substituted allylarylamines and CHCl3Can react smoothly, and obtain the corresponding trichloromethyl indoline 2h, 2i1-3 with 49-77 percent. The substituent group on the benzene ring of the allylarylamine is not only in para position, and the N- (3, 5-dichloroaniline) -N- (2-methylallyl) octanoamide is not influenced by steric hindrance and is very active, so that the indoline 2j can be obtained with high yield of 96%. However, for the 2-chloro substitution reaction on the benzene ring of 2-methylallyl arylamine, we tried that the protecting groups on the nitrogen are propionyl and octanoyl, which are not separated into the target product and may be the cause of steric hindrance.
Both exo and endo mode cyclization processes are favored in this reaction according to the Bowdin's rule. Therefore, the present invention was initially studied using a 2-methylallyl substrate to avoid endo-mode cyclization reactions. After exo selectivity was achieved in all of the above reactions, further studies were conducted on the methyl-free substituted allylanilide polychlorinated methylation/cyclization reaction. Allylarylamine R1With H, a perfect exo product can be obtained. Meanwhile, N-allylphenyl acetamide, N-allyl-N- (4-chlorophenyl) acetamide and N-allyl-N-phenyloctanamide are explored, so that 5-exo-trig product 2I1-3 can be obtained with the yield of 40-71%, and 6-17% trichloromethyl indole 2I1 '-3' can be obtained, the generation of indole compounds can be further oxidation of indoline products, and endo-trig products are not found.
Example 3
The solvent from example 1 was changed to methylene chloride except that R was changed1、R2The products obtained with PG and their yields are given in the following table.
TABLE 2 when the reactant is CH2Cl2When R is1、R2Is different from PGThe product of (4) and the yield thereof
In table 2, the reaction conditions: 1(0.5mmol), CH2Cl2(5mL)，DCP(1.5mmol，3equiv)，120℃，3h。
Based on the above experimental results, it is reasonable to think that dichloromethylindoline can be synthesized by using dichloromethane in series dichloromethylation/cyclization reaction. Methylene chloride has proven to be more reactive as a dichloromethyl radical reagent and has been shown to give dichloromethylindoline in very high yields, and dichloromethylindoline obtained using methylene chloride as a solvent also exhibits very good functional group tolerance.
Comparative example
Following the experimental procedure of example 1, DCP was replaced with other initiators to give the products in the following yields.
Table 3 comparative examples of different initiators
Solvent and as a source of trichloromethyl radicals, the reaction conditions were explored (table 3). First, by using benzoyl peroxide (BPO, number 1) as an initiator, and reacting 1a1 with 3 times the amount of BPO at 120 ℃ for 3 hours, indoline 2a1 was obtained in 62% yield. To further improve the reaction efficiency, we optimized the initiator, and it is desirable that we react 1a1 with CHCl3 at 120 ℃ for 3 hours with 3 times the amount of DCP as initiator to obtain 2a1 in 87% yield. Tert-butanol peroxide (TBHP, Nos. 2 and 3) in an amount of 3 times was less effective than DCP (No. 4). When 3 times the amount of potassium persulfate (K2S2O8, No. 5) andpotassium hydrogen persulfate (O.times.one, No. 6) did not react. 3 times of m-chloroperoxybenzoic acid (mCPBA, No. 7) and diiodo (I) pentoxide were added2O5No. 8) as an initiator, only a decomposition product of the substrate 1a1 was obtained. When DCP is used as the optimized initiator, the reaction temperature and the amount are further optimized. When the reaction temperature was lowered to 80 ℃, no reaction occurred even if the reaction time was prolonged. When the amount of DCP is reduced, the yield of the target product is not improved. The initiator can be BPO, TBHP, DTBP, TBPB or DCP, the temperature is not lower than 120 ℃, and the indoline product can be obtained when the amount of the DCP is more than twice.
In conclusion, the invention discloses a novel method for generating polychlorinated methyl indoline with higher yield by using the series polychlorinated methylation free radical/cyclization reaction of non-activated olefin of allyl arylamine without metal catalysis. The method adopts a cheap common reagent as a polychlorinated methyl chloride source, and DCP as a free radical initiator. The method has the obvious advantages of mild conditions, simple operation, low cost and wide substrate application range. The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (1)
1. A preparation method of polychlorinated methyl indoline with high yield and without metal catalyst is characterized in that under the condition of taking dicumyl peroxide as initiator, non-activated olefin reacts with chlorinated alkane to obtain polychlorinated methyl indoline; the chlorine-containing alkane is dichloromethane and chloroform; the equation for the reaction is:
the above-mentioned
The mol ratio of the dicumyl peroxide to the dicumyl peroxide is 1:3, wherein
The proportion of the catalyst to the alkane containing chlorine is 0.5mmol:5ml, the reaction temperature is 120 ℃, and the reaction time is 3 hours; saturated water for reaction completion Na2S2O3And water quenching with CH2Cl2Extraction was carried out three times.
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| CHANGDUO PAN等: "Metal-free radical cascade chloromethylation of unactivated alkenes: synthesis of polychlorosubstituted indolines", 《ORG. BIOMOL. CHEM.》 * |
| YUNFEI TIAN等: "Metal-free radical cascade dichloromethylation of activated alkenes using CH2Cl2: highly selective activation of the C-H bond", 《RSC ADV.》 * |
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