CN1803760A - N-arylation process with hydrazone as ligand in aqueous phase system - Google Patents
N-arylation process with hydrazone as ligand in aqueous phase system Download PDFInfo
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- CN1803760A CN1803760A CN 200610033067 CN200610033067A CN1803760A CN 1803760 A CN1803760 A CN 1803760A CN 200610033067 CN200610033067 CN 200610033067 CN 200610033067 A CN200610033067 A CN 200610033067A CN 1803760 A CN1803760 A CN 1803760A
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- reaction
- acylhydrazone
- aqueous phase
- phase system
- arylation
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- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000006254 arylation reaction Methods 0.000 title claims abstract description 20
- 239000008346 aqueous phase Substances 0.000 title claims description 12
- 239000003446 ligand Substances 0.000 title abstract description 3
- 150000007857 hydrazones Chemical class 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- -1 hydrazone compound Chemical class 0.000 claims abstract description 19
- 150000001502 aryl halides Chemical class 0.000 claims abstract description 15
- 238000010438 heat treatment Methods 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
- 239000013543 active substance Substances 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 239000010949 copper Substances 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 229910052802 copper Inorganic materials 0.000 claims description 4
- 125000003431 oxalo group Chemical group 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910017052 cobalt Inorganic materials 0.000 claims description 2
- 239000010941 cobalt Substances 0.000 claims description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 2
- XXUJMEYKYHETBZ-UHFFFAOYSA-N ethyl 4-nitrophenyl ethylphosphonate Chemical compound CCOP(=O)(CC)OC1=CC=C([N+]([O-])=O)C=C1 XXUJMEYKYHETBZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 229910052748 manganese Inorganic materials 0.000 claims description 2
- 239000011572 manganese Substances 0.000 claims description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims 1
- 150000001412 amines Chemical class 0.000 abstract description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 abstract description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 abstract description 3
- 238000005859 coupling reaction Methods 0.000 abstract description 3
- 239000002585 base Substances 0.000 abstract description 2
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 abstract 1
- 229910019142 PO4 Inorganic materials 0.000 abstract 1
- 229910052783 alkali metal Inorganic materials 0.000 abstract 1
- 150000001340 alkali metals Chemical class 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 150000002390 heteroarenes Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract 1
- 239000010452 phosphate Substances 0.000 abstract 1
- 239000004094 surface-active agent Substances 0.000 abstract 1
- 230000001052 transient effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 238000005406 washing Methods 0.000 description 22
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 18
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 238000003810 ethyl acetate extraction Methods 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229960001866 silicon dioxide Drugs 0.000 description 11
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 10
- 230000003197 catalytic effect Effects 0.000 description 10
- 230000006837 decompression Effects 0.000 description 10
- 238000004821 distillation Methods 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 9
- 230000002194 synthesizing effect Effects 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000006887 Ullmann reaction Methods 0.000 description 3
- 150000004982 aromatic amines Chemical class 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 150000008431 aliphatic amides Chemical class 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 229910052728 basic metal Inorganic materials 0.000 description 2
- 150000003818 basic metals Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- LIJJGMDKVVOEFT-UHFFFAOYSA-N n-benzyl-4-methoxyaniline Chemical compound C1=CC(OC)=CC=C1NCC1=CC=CC=C1 LIJJGMDKVVOEFT-UHFFFAOYSA-N 0.000 description 2
- BISSQVWYQNHTIH-UHFFFAOYSA-N n-benzyl-n-phenylacetamide Chemical compound C=1C=CC=CC=1N(C(=O)C)CC1=CC=CC=C1 BISSQVWYQNHTIH-UHFFFAOYSA-N 0.000 description 2
- GTWJETSWSUWSEJ-UHFFFAOYSA-N n-benzylaniline Chemical compound C=1C=CC=CC=1CNC1=CC=CC=C1 GTWJETSWSUWSEJ-UHFFFAOYSA-N 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 150000003016 phosphoric acids Chemical class 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- PIMNFNXBTGPCIL-UHFFFAOYSA-N 1-(2-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1Br PIMNFNXBTGPCIL-UHFFFAOYSA-N 0.000 description 1
- XNLOIFUGGCCEQX-UHFFFAOYSA-N 1-(4-methoxyphenyl)imidazole Chemical class C1=CC(OC)=CC=C1N1C=NC=C1 XNLOIFUGGCCEQX-UHFFFAOYSA-N 0.000 description 1
- PEBHYIWLEXUDPC-UHFFFAOYSA-N 1-(4-methoxyphenyl)piperidine Chemical class C1=CC(OC)=CC=C1N1CCCCC1 PEBHYIWLEXUDPC-UHFFFAOYSA-N 0.000 description 1
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 1
- ORPVVAKYSXQCJI-UHFFFAOYSA-N 1-bromo-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Br ORPVVAKYSXQCJI-UHFFFAOYSA-N 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical class CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical compound [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Chemical compound CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- KEVOWRWHMCBERP-UHFFFAOYSA-N n-benzyl-4-methylaniline Chemical compound C1=CC(C)=CC=C1NCC1=CC=CC=C1 KEVOWRWHMCBERP-UHFFFAOYSA-N 0.000 description 1
- QBSRKOBMKFOHOS-UHFFFAOYSA-N n-benzyl-4-nitroaniline Chemical compound C1=CC([N+](=O)[O-])=CC=C1NCC1=CC=CC=C1 QBSRKOBMKFOHOS-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The provided N-arylation method in water phase system for C-N coupling reaction comprises: using aryl halide and amine or nitrogen-contained heteroaromatic compound as material and water as solvent, heating traditionally or with microwave; using the carbonate, fluoride, phosphate and hydrate of alkali metal or alkali earth metal as base; with transient metal catalysis, adding surfactant to promote the C-N coupling reaction with acylated hydrazone compound as ligand. This invention just needs mild reaction condition, and has wide application.
Description
Technical field
The present invention relates to chemical field, especially a kind of method of N-arylation reaction.
Technical background
Arylamines is the important compound of a class, extensively is present in to have in the natural of physiologically active and the non-natural product, and the research that the C-N key is formed reaction causes that people pay attention to widely.
The Ullmann reaction of carbon-nitrogen cross-coupling was from existing so far history (Ley, the S.V. for a long time of reported first in 1903; Thomas, A.W.Angew.Chem.Int.Ed.2003,42,5400 reach relevant quoted passage).Because this reaction is normally in high boiling polar solvent, carry out under at the copper powder of high temperature, catalytic amount or equivalent as the condition of catalyzer, thereby there is long reaction time, the subsequent disposal difficulty of reaction, the not high drawback of reaction product complexity and reaction yield.Nineteen eighty-three, people such as Migita have found that the earliest the catalytic C-N key of Pd forms reaction (Kosugi, M.; Kameyama, M.; Migita, T.Chem.Lett.1983,927), 1994, Buchwald and Hartwig developed the catalytic C-N key of Pd simultaneously independently and have formed reaction ((a) Guram, A.S.; Buchwald, S.L.J.Am.Chem.Soc.1994,116,7901; (b) Paul, F.; Patt, J.; Hartwig, J.E.J.Am.Chem.Soc.1994,116,5969).Adopt the catalytic C-N key of Pd to form the more traditional Ullmann reaction of reaction and have condition gentleness relatively, reacting phase is to advantage such as simple, need to use high boiling organic solvent but also exist, toxicity is bigger, the price height, and to the shortcomings such as dependency of unstable and hypertoxic organophosphorus ligand, therefore, in recent years, the catalytic Ullmann of Cu reacts the very big development of having got back.People's such as Buckwald patent PCT/US02/12785 (WO02/085838) and Ley, S.V. and; Thomas, the summary of A.W. (Ley, S.V.; Thomas, A.W.Angew.Chem.Int.Ed.2003,42,5400) in introduced the formation method of the C-N key under the copper katalysis.By adding suitable part, use the Cu salt of catalytic amount, the Ullmann reaction can be carried out under comparatively gentle condition.Yet, no matter adopt which kind of metal catalyst, the N-arylation reaction of being reported in these documents is normally carried out in organic solvent.On the other hand, reaction takes the long application that has also seriously hindered high-throughput bioactivity screening in present medicine and the agricultural chemicals R﹠D process.Therefore, the objective requirement that to invent a kind of quick, eco-friendly reaction process be current such reaction will have good application prospects.
People such as Pell ó n have reported the catalytic C-N linked reaction of copper in the aqueous solution ((a) Pell ó n, R.F.; Carrasco, R.; Rod é s, L.Synth.Comm.1993,23 (10), 1447; (b) Pell ó n, R.F.; Est é vez-Braun, A.; Docampo, M.L.; Mart í n, A.; Ravelo, A.G.Synlett 2005, (10), 1606), have the aryl halides of carboxyl and the reaction of amine but only be confined to the ortho position.People such as Twieg reported cuprous iodide catalytic be synthetic method (Lu, the Z. of arylamines in the aqueous solution of part with the 2-dimethylaminoethanol; Twieg, R.J.Tetrahedron Lett.2005,46,2997), but only be confined to aromatic halogenate and amino acid or with certain water miscible short-chain fat amine is arranged and has the reaction of the aliphatic amide of hydroxyl.Reported the linked reaction of aromatic halogenate and ammoniacal liquor or short-chain alkyl amine in the catalytic aqueous solution of copper sulfate in the European patent EP 0549263.But above-mentioned reaction all can only be carried out at specific compound, thereby can not promote the use of.And people such as Buchwald have reported formation reaction (Huang, the X. of C-N key in the catalytic aqueous solution of Pd; Anderson, K.W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S.L.J.Am.Chem.Soc.2003,125,6653) there is defective because of the cost of its catalyst system.
The present invention is under Guangdong Province's natural science fund assistance, and the research that provides a kind of quick, eco-friendly N-arylation method to carry out is provided.
Summary of the invention
The objective of the invention is to overcome the shortcoming that exists in the prior art C-N linked reaction method, provide a kind of easy, quick, reaction conditions is gentle, the N-arylation method of wide application range of substrates, environmental friendliness, process economy.
The present invention is the formation method of C-N key in a kind of aqueous solution.It is characterized in that with aryl halides and amine or nitrogen heterocyclic ring aromatic compound be raw material, with water as solvent, adopt and reflux or the microwave-assisted heating, carbonate, fluorochemical, phosphoric acid salt and oxyhydroxide with basic metal or alkaline-earth metal are alkali, by adding tensio-active agent, under transition metal-catalyzed condition, use the C-N linked reaction of acylhydrazone compounds as part.
Involved reaction can adopt following reaction formula to represent among the present invention:
Wherein X-can be a bromine or iodine.
R represents 2-on the halo aromatic ring, 3-, and the substituting group of 4-position, or represent two on the aromatic ring to replace or multi-substituent, and can be H ,-NO
2,-CN ,-COOH ,-COOR, ethanoyl, alkyl, alkoxyl group, aryl, halogen, trifluoromethyl etc. but not only be confined to these substituting groups.
R
1R
2NH contains straight or branched alkyl, C
5-C
7Cycloalkyl, benzyl, (substituting group is an alkyl to substituted benzyl, alkoxyl group etc.) etc. Armeen, secondary amine, or five to the heptatomic cyclic secondary amine, or contains the primary amine of aromatic substituent (aromatic substituent is benzene or has alkyl, substituent benzene such as alkoxyl group).
R
1R
2NH contains NH to arrive seven membered heterocyclic class aromatic compound at intra-annular five, as imidazoles, pyrroles, pyrazoles etc.
Concrete reaction process of the present invention is: catalyzer, part, aryl halides, amine, alkali, tensio-active agent and water are added in microwave reaction pipe or the round-bottomed flask successively, and the mode that adopts microwave-assisted heating or common heating bath to reflux stirs reacting by heating down; After reaction finished, separating reaction mixed solution and purifying obtained N-arylation product.
Described separating reaction mixed solution and purifying can be used ethyl acetate extraction, washing, and the saturated common salt washing, anhydrous magnesium sulfate drying filters, precipitation, reaction mixture is purified through the silicagel column column chromatography for separation, gets N-arylation product.
Below the inventive method is further described:
(1) is reaction solvent with water, has good environmental compatibility;
(2) the reaction heating can be adopted the mode that microwave-assisted heating or common heating bath reflux.During the microwave-assisted heating, temperature of reaction is 60-180 ℃, is preferably 80-150 ℃, and the reaction times is 1-30min, is preferably 2-10min; Or adopt common heating bath, and temperature of reaction is 50-100 ℃, is preferably 60-100 ℃, the reaction times is 0.5-24h, is preferably 2-12h;
(3) reactant aryl halides can be that replace or non-replacement, and reactant amine can be primary amine or secondary amine, can be aromatic amine, aliphatic amide or nitrogen-containing heterocycle compound; The mol ratio of aryl halides and amine is preferably 1: 1 to 1: 4;
(4) employed part is the acylhydrazone compounds, can be single acylhydrazone or two acylhydrazone compounds, as oxalyl dihydrazone, benzoyl hydrazone, phenylacetyl hydrazone, naphthalene acetyl hydrazone etc.; The mol ratio of used part and catalyzer is preferably 1: 2 to 2: 1;
(5) can use the salt of copper, cobalt, iron, zinc, manganese and title complex to make catalyzer, the mol ratio of catalyzer and substrate aryl halides is preferably 1: 20 to 1: 1;
(6) used alkali can be carbonate, phosphoric acid salt, fluorochemical, borate and the oxyhydroxide of basic metal or alkaline-earth metal or the compound that can be converted into respective compound in water; The mol ratio of alkali and substrate aryl halides is preferably 1: 1 to 3: 1;
(7) employed tensio-active agent can be quaternary ammonium salts, dodecane sulfonate class, PEG class but not only be confined to these tensio-active agents; The mol ratio of tensio-active agent and substrate aryl halides is preferably 1: 20 to 1: 1.
That carbon provided by the invention-nitrogen coupling reaction method has is simple to operate, the reaction times is short, temperature is low, product simply is easy to separate and characteristics such as environmental friendliness.Especially with water as reaction solvent, adopt the type of heating of microwave-assisted, with the reacting phase ratio of reporting in the document of the same type, effectively shorten the reaction times, improved the environment friendly that reacts, conform to the requirement of Green Chemistry development more, may have broad application prospects aspect preparing at the high-throughput of natural product, medicine and agricultural chemicals.
Embodiment
Below in conjunction with embodiment content of the present invention is described further.
Synthesizing of embodiment 1:N-phenylbenzylamine
With 8mg (0.1mmol) CuO, 55mg (0.2mmol) bisoxalydihydrazone, 102mg (0.5mmol) iodobenzene, 160mg (1.5mmol) benzylamine, 56mg (1.0mmol) KOH, 8.1mg (0.025mmol) TBAB, 1.5ml H
2O adds in the 8ml microwave reaction pipe, and 100W reacts 2min under 130 ℃ of conditions.After reaction stops, using ethyl acetate extraction, washing, saturated common salt washing, behind the anhydrous magnesium sulfate drying, filter the filtrate decompression distillation, purify by [eluent: petrol ether/ethyl acetate (50: 1)] through the silicagel column column chromatography for separation, get N-phenylbenzylamine 82mg, yield 90%.
MS (the ESI source, m/z): 184 (M
++ 1);
1H NMR (CDCl
3, 300MHz) δ 7.32 (dd, J=7.2,6.6Hz, 4H), 7.24-7.26 (m, 1H), 7.15 (t, J=7.8,2H), 6.69 (t, J=7.2Hz, 1H), 6.61 (d, J=7.8,2H), 4.31 (s, 2H), 3.97 (brs, 1H).
Synthesizing of embodiment 2:N-p-nitrophenyl benzylamine
With 37mg (0.25mmol) FeSO
4, 70mg (0.25mmol) bisoxalydihydrazone, 102mg (0.5mmol) be to the nitro bromobenzene, 54mg (0.5mmol) benzylamine, 228mg (1.5mmol) CsF, 68mg (0.25mmol) SDS-Na, 1.5ml H
2O adds in the 8ml microwave reaction pipe, and 100W reacts 10min under 80 ℃ of conditions.After reaction stops, using ethyl acetate extraction, washing, saturated common salt washing, behind the anhydrous magnesium sulfate drying, filter the filtrate decompression distillation, purify by [eluent: petrol ether/ethyl acetate (5: 1)] through the silicagel column column chromatography for separation, get N-p-nitrophenyl benzylamine 51mg, yield 45%.
MS (the ESI source, m/z): 229 (M
++ 1);
1H NMR (CDCl
3, 300MHz) δ 8.07 (d, J=9Hz, 2H), 7.31-7.39 (m, 5H), 6.56 (d, J=9Hz, 2H), 4.85 (brs, 1H), 4.42 (s, 2H).
Synthesizing of embodiment 3:N-p-methoxyphenyl benzylamine
With 13mg (0.05mmol) CuSO
4.5H
2O, 20mg (0.1mmol) diacetone base oxalyl dihydrazone, 94mg (0.5mmol) be to the methoxyl group bromobenzene, 214mg (2.0mmol) benzylamine, 69mg (0.5mmol) K
2CO
3, 161mg (0.5mmol) TBAB, 1.5ml H
2O adds in the 8ml microwave reaction pipe, and 100W reacts 5min under 130 ℃ of conditions.After reaction stops, using ethyl acetate extraction, washing, saturated common salt washing, behind the anhydrous magnesium sulfate drying, filter the filtrate decompression distillation, purify by [eluent: petrol ether/ethyl acetate (30: 1)] through the silicagel column column chromatography for separation, get N-p-methoxyphenyl benzylamine 98mg, yield 92%.
MS (the ESI source, m/z): 214 (M
++ 1);
1H NMR (CDCl
3, 300MHz) δ 7.27-7.37 (m, 5H), 6.74-6.78 (m, 2H), 6.60-6.64 (m, 2H), 4.28 (s, 2H), 3.73 (s, 3H).
Synthesizing of embodiment 4:N-p-methylphenyl benzylamine
With 38mg (0.2mmol) CuI, 111mg (0.4mmol) bisoxalydihydrazone, 171mg (1.0mmol) be to the methyl bromobenzene, 321mg (3.0mmol) benzylamine, 168mg (3.0mmol) KOH, 32.2mg (0.1mmol) TBAB, 10ml H
2O adds in the 50ml round-bottomed flask, reflux 10h.After reaction stops, using ethyl acetate extraction, washing, saturated common salt washing, behind the anhydrous magnesium sulfate drying, filter the filtrate decompression distillation, purify by [eluent: petrol ether/ethyl acetate (50: 1)] through the silicagel column column chromatography for separation, get N-p-methylphenyl benzylamine 162mg, yield 82%.
MS (the ESI source, m/z): 198 (M
++ 1);
1H NMR (CDCl
3, 300MHz) δ 7.24-7.36 (m, 5H), 6.96 (d, J=7.8Hz, 2H), 6.54 (d, J=8.1Hz, 2H), 4.29 (s, 2H), 3.88 (brs, 1H), 2.22 (s, 3H).
Embodiment 5:N, N-diphenylamine synthetic
With 16mg (0.2mmol) CuO, 50mg (0.2mmol) dicyclo pentanone oxalyl dihydrazone, 78mg (0.5mmol) bromobenzene, 214mg (2.0mmol) benzylamine, 212mg (1.0mmol) K
3PO
4, 161mg (0.5mmol) TBAB, 1.5ml H
2O adds in the 8ml microwave reaction pipe, and 100W reacts 5min under 150 ℃ of conditions.After reaction stops, using ethyl acetate extraction, washing, saturated common salt washing, behind the anhydrous magnesium sulfate drying, filter, the filtrate decompression distillation is through silicagel column column chromatography for separation purification [eluent: petrol ether/ethyl acetate (30: 1)], get N, N-diphenylamine 6l mg, yield 72%.
MS (the ESI source, m/z): 170 (M
++ 1);
1H NMR (CDCl
3, 300MHz) δ 7.30-7.25 (m, 4H), 7.09 (d, J=7.6Hz, 4H), 6.94 (t, J=7.3Hz, 2H), 5.98 (s, 1H).
Synthesizing of embodiment 6:N-p-methoxyphenyl piperidines
With 40mg (0.5mmol) CuO, 70mg (0.25mmol) bisoxalydihydrazone, 94mg (0.5mmol) be to the methoxyl group bromobenzene, 85mg (1.0mmol) piperidines, 40mg (1.0mmol) NaOH, 81mg (0.25mmol) TBAB, 1.5ml H
2O adds in the 8ml microwave reaction pipe, and 100W reacts 5min under 120 ℃ of conditions.After reaction stops, using ethyl acetate extraction, washing, saturated common salt washing, behind the anhydrous magnesium sulfate drying, filter the filtrate decompression distillation, purify by [eluent: petrol ether/ethyl acetate (20: 1)] through the silicagel column column chromatography for separation, get N-p-methoxyphenyl piperidines 74mg, yield 77%.
MS (the ESI source, m/z): 192 (M
++ 1);
1H NMR (CDCl
3, 300MHz) δ 6.91-6.87 (m, 2H), 6.83-6.79 (m, 2H), 3.75 (s, 3H), 3.01 (t, J=5.4Hz, 4H), 1.75-1.68 (m, 4H), 1.57-1.50 (m, 2H).
Synthesizing of embodiment 7:N-p-methoxyphenyl-N-n-propyl amine
With 14mg (0.1mmol) Cu
2O, 46mg (0.2mmol) pimelinketone phenylacetyl hydrazone, 187mg (1.0mmol) be to the methoxyl group bromobenzene, 236mg (4.0mmol) Tri N-Propyl Amine, 112mg (2.0mmol) KOH, 322mg (1.0mmol) TBAB, 10ml H
2O adds in the 50ml round-bottomed flask, reflux 6h.After reaction stops, using ethyl acetate extraction, washing, saturated common salt washing, behind the anhydrous magnesium sulfate drying, filter the filtrate decompression distillation, purify by [eluent: petrol ether/ethyl acetate (30: 1)] through the silicagel column column chromatography for separation, get N-p-methoxyphenyl-N-n-propyl amine 83mg, yield 50%.
MS (the ESI source, m/z): 166 (M
++ 1);
1H NMR (CDCl
3, 300MHz) δ 6.74 (d, J=8.7Hz, 2H) 6.55 (d, J=8.7Hz, 2H), 3.73 (s, 3H), 3.02 (t, J=7.1Hz, 2H), 1.66-1.58 (m, 2H), 0.99 (t, J=7.4Hz, 3H).
Synthesizing of embodiment 8:N-p-methoxyphenyl imidazoles
With 27mg (0.2mmol) CuCl
2, 28mg (0.1mmol) bisoxalydihydrazone, 94mg (0.5mmol) be to the methoxyl group bromobenzene, 136mg (2.0mmol) imidazoles, 326mg (1.0mmol) Cs
2CO
3, 161mg (0.5mmol) TBAB, 1.5ml H
2O adds in the 8ml microwave reaction pipe, and 100W reacts 10min under 150 ℃ of conditions.After reaction stops, using ethyl acetate extraction, washing, saturated common salt washing, behind the anhydrous magnesium sulfate drying, filter the filtrate decompression distillation, purify by [eluent: petrol ether/ethyl acetate (10: 1)] through the silicagel column column chromatography for separation, get N-p-methoxyphenyl imidazoles 55mg, yield 63%.
MS (the ESI source, m/z): 175 (M
++ 1);
1H NMR (CDCl
3, 300MHz) δ 7.78 (s, 1H), 7.31 (d, J=8.0Hz, 2H), 7.20 (d, J=8.0Hz, 2H), 7.00 (s, 1H), 6.98 (s, 1H), 3.85 (s, 3H).
Synthesizing of embodiment 9:N-p-methoxyphenyl benzylamine
With 13mg (0.05mmol) CuSO
4.5H
2O, 20mg (0.1mmol) dicyclohexyl oxalyl dihydrazone, 94mg (0.5mmol) be to the methoxyl group bromobenzene, 214mg (2.0mmol) benzylamine, 69mg (0.5mmol) K
2CO
3, 161mg (0.5mmol) TBAB, 1.5ml H
2O adds in the 8ml microwave reaction pipe, and 100W reacts 5min under 60 ℃ of conditions.After reaction stops, using ethyl acetate extraction, washing, saturated common salt washing, behind the anhydrous magnesium sulfate drying, filter the filtrate decompression distillation, purify by [eluent: petrol ether/ethyl acetate (30: 1)] through the silicagel column column chromatography for separation, get N-p-methoxyphenyl benzylamine 66mg, yield 62%.
Embodiment 10:N-is synthetic to the acetyl phenylbenzylamine
With 2mg (0.025mmol) CuO, 14mg (0.05mmol) bisoxalydihydrazone, 100mg (0.5mmol) be to the ethanoyl bromobenzene, 160mg (1.5mmol) benzylamine, 56mg (1.0mmol) KOH, 8.1mg (0.025mmol) TBAB, 10ml H
2O adds in the 50ml round-bottomed flask, is heated to 50 ℃ of reaction 2h.After reaction stops, using ethyl acetate extraction, washing, saturated common salt washing, behind the anhydrous magnesium sulfate drying, filter the filtrate decompression distillation, purify by [eluent: petrol ether/ethyl acetate (5: 1)] through the silicagel column column chromatography for separation, get N-acetyl phenylbenzylamine 34mg, yield 30%.
MS (the ESI source, m/z): 226 (M
++ 1);
1H NMR (CDCl
3, 300MHz) δ 7.82 (d, J=8.7Hz, 2H), 7.39-7.29 (m, 5H), 6.60 (, J=8.7Hz, 2H), 4.41 (s, 2H), 2.51 (s, 3H).
Claims (10)
1. one kind is the N-arylation method in the aqueous phase system of part with the acylhydrazone, may further comprise the steps:
1) with water as solvent, aryl halides, aminated compounds, catalyzer, part, alkali, tensio-active agent are added in the reaction vessel, stir reacting by heating down, reaction expression is as follows:
Wherein X-is a bromine or iodine;
R on the aryl halides represents 2-on the halo aromatic ring, 3-, and the substituting group of 4-position, or represent two on the aromatic ring to replace or multi-substituent;
R
1R
2NH is one of following: contain the straight or branched alkyl, the cycloalkyl of C5-C7, benzyl, Armeen, the secondary amine of substituted benzyl (substituting group is an alkyl, alkoxyl group etc.) etc.; Or five to the heptatomic cyclic secondary amine; Or contain the primary amine of aromatic substituent (aromatic substituent is benzene or has alkyl, substituent benzene such as alkoxyl group); Or contain NH at intra-annular five to seven membered heterocyclic class aromatic compound;
Described part is the acylhydrazone compounds;
Described catalyzer is metal-salt and compound thereof.
2) after reaction finished, separating reaction mixed solution and purifying obtained N-arylation product.
2. as claimed in claim 1 is N-arylation method in the aqueous phase system of part with the acylhydrazone, and it is characterized in that: described step 1) adopts the microwave-assisted heating, and temperature of reaction is 60-180 ℃, and the reaction times is 1-30min.
3. as claimed in claim 1 is N-arylation method in the aqueous phase system of part with the acylhydrazone, and it is characterized in that: described step 1) adopts common heating bath, and temperature of reaction is 50-100 ℃, and the reaction times is 0.5-24h.
4. as claimed in claim 1 is N-arylation method in the aqueous phase system of part with the acylhydrazone, and it is characterized in that: the mol ratio of described aryl halides and aminated compounds is 1: 1 to 1: 4.
5. the N-arylation method in the aqueous phase system as claimed in claim 1 is characterized in that: described catalyzer is one of following: the salt of copper, cobalt, iron, zinc, manganese and title complex.
As claim 1 or 5 described be N-arylation method in the aqueous phase system of part with the acylhydrazone, it is characterized in that: the mol ratio of described catalyzer and aryl halides is 1: 20 to 1: 1.
7. in the aqueous phase system as claimed in claim 1 is the N-arylation method of part with the acylhydrazone, it is characterized in that: described part is single acylhydrazone or acyl two hydrazone compounds, comprises oxalyl dihydrazone, benzoyl hydrazone, phenylacetyl hydrazone, naphthalene acetyl hydrazone.
As claim 1 or 6 or 7 described be N-arylation method in the aqueous phase system of part with the acylhydrazone, it is characterized in that: the mole of described part and catalyzer is 1: 2 to 2: 1.
9. as claimed in claim 1 is N-arylation method in the aqueous phase system of part with the acylhydrazone, and it is characterized in that: the mol ratio of described alkali and aryl halides is 1: 1 to 3: 1.
10. as claimed in claim 1 is N-arylation method in the aqueous phase system of part with the acylhydrazone, and it is characterized in that: the mol ratio of described tensio-active agent and aryl halides is 1: 20 to 1: 1.
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| CN101774874B (en) * | 2010-01-25 | 2013-05-29 | 中山大学 | N-arylating method using pyrrole-2-hydrazide compound as ligand in aqueous phase system |
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| CN111848441A (en) * | 2020-07-28 | 2020-10-30 | 朱翠萍 | N-substituted benzoyl hydrazone compound and preparation method and application thereof |
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| CN101691318B (en) * | 2009-06-29 | 2013-05-29 | 中山大学 | N-arylation method taking substituted adipic dihydrazide as ligand in aqueous phase system |
| CN101774874B (en) * | 2010-01-25 | 2013-05-29 | 中山大学 | N-arylating method using pyrrole-2-hydrazide compound as ligand in aqueous phase system |
| CN103739417A (en) * | 2013-09-29 | 2014-04-23 | 中山大学 | Method for synthesizing aromatic primary amine in circulating water phase system |
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| CN105949075A (en) * | 2016-06-24 | 2016-09-21 | 江苏倍合德化工有限公司 | Synthesis method of mefenamic acid |
| CN111848441A (en) * | 2020-07-28 | 2020-10-30 | 朱翠萍 | N-substituted benzoyl hydrazone compound and preparation method and application thereof |
| CN111848441B (en) * | 2020-07-28 | 2023-02-17 | 山东中新科农生物科技有限公司 | N-substituted benzoyl hydrazone compound and preparation method and application thereof |
| CN115872894A (en) * | 2022-11-15 | 2023-03-31 | 上海慧聚药业有限公司 | Synthesis of non-ionic contrast agents |
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