CN109734610B - Meta-substituted phenol compound and preparation method and application thereof - Google Patents
Meta-substituted phenol compound and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- -1 phenol compound Chemical class 0.000 title claims description 10
- 150000002989 phenols Chemical class 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 238000005859 coupling reaction Methods 0.000 claims abstract description 7
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 38
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 16
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 15
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 15
- IICNXSSJTABWGY-UHFFFAOYSA-N 3-(4-bromoanilino)phenol Chemical compound Oc1cccc(Nc2ccc(Br)cc2)c1 IICNXSSJTABWGY-UHFFFAOYSA-N 0.000 claims description 11
- NDACNGSDAFKTGE-UHFFFAOYSA-N 3-hydroxydiphenylamine Chemical compound OC1=CC=CC(NC=2C=CC=CC=2)=C1 NDACNGSDAFKTGE-UHFFFAOYSA-N 0.000 claims description 11
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 8
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 8
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 8
- 229940112669 cuprous oxide Drugs 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 239000011630 iodine Substances 0.000 claims description 8
- 239000007800 oxidant agent Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 5
- 230000000996 additive effect Effects 0.000 claims description 5
- UBXYXCRCOKCZIT-UHFFFAOYSA-N biphenyl-3-ol Chemical compound OC1=CC=CC(C=2C=CC=CC=2)=C1 UBXYXCRCOKCZIT-UHFFFAOYSA-N 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 4
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims description 3
- MEJYXDZTSTYXNP-UHFFFAOYSA-N 3-(4-methoxyphenyl)phenol Chemical compound C1=CC(OC)=CC=C1C1=CC=CC(O)=C1 MEJYXDZTSTYXNP-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- DMVOXQPQNTYEKQ-UHFFFAOYSA-N biphenyl-4-amine Chemical group C1=CC(N)=CC=C1C1=CC=CC=C1 DMVOXQPQNTYEKQ-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 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 21
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- 238000006356 dehydrogenation reaction Methods 0.000 description 11
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 11
- 235000010290 biphenyl Nutrition 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- 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 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 238000013375 chromatographic separation Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- RVWUHFFPEOKYLB-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxidopiperidin-1-ium Chemical compound CC1(C)CCCC(C)(C)[NH+]1[O-] RVWUHFFPEOKYLB-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000004071 biological effect Effects 0.000 description 4
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- 235000010338 boric acid Nutrition 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 150000001412 amines Chemical group 0.000 description 3
- 230000000975 bioactive effect Effects 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 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 description 2
- RHDYQUZYHZWTCI-UHFFFAOYSA-N 1-methoxy-4-phenylbenzene Chemical compound C1=CC(OC)=CC=C1C1=CC=CC=C1 RHDYQUZYHZWTCI-UHFFFAOYSA-N 0.000 description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 2
- QYTDEUPAUMOIOP-UHFFFAOYSA-N TEMPO Chemical class CC1(C)CCCC(C)(C)N1[O] QYTDEUPAUMOIOP-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001555 benzenes Chemical group 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000007336 electrophilic substitution reaction Methods 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- VRQVVMDWGGWHTJ-CQSZACIVSA-N methotrimeprazine Chemical compound C1=CC=C2N(C[C@H](C)CN(C)C)C3=CC(OC)=CC=C3SC2=C1 VRQVVMDWGGWHTJ-CQSZACIVSA-N 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 229910001958 silver carbonate Inorganic materials 0.000 description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical compound CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 description 1
- WIJQCPIRWXSWQG-UHFFFAOYSA-N 1,2-benzothiazol-3-amine Chemical compound C1=CC=C2C(N)=NSC2=C1 WIJQCPIRWXSWQG-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical class NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 1
- QURGRYZJKCDXKY-UHFFFAOYSA-N 3-(4-methoxyanilino)phenol Chemical compound C1=CC(OC)=CC=C1NC1=CC=CC(O)=C1 QURGRYZJKCDXKY-UHFFFAOYSA-N 0.000 description 1
- CWLKGDAVCFYWJK-UHFFFAOYSA-N 3-aminophenol Chemical compound NC1=CC=CC(O)=C1 CWLKGDAVCFYWJK-UHFFFAOYSA-N 0.000 description 1
- 229940018563 3-aminophenol Drugs 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
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- 239000003570 air Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
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- 150000001502 aryl halides Chemical class 0.000 description 1
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- 125000005619 boric acid group Chemical group 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
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- 210000004027 cell Anatomy 0.000 description 1
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- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
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- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 1
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
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- 229940042053 methotrimeprazine Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
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- 229950000688 phenothiazine Drugs 0.000 description 1
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- 235000011056 potassium acetate Nutrition 0.000 description 1
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- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
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Abstract
The invention relates to the field of organic synthesis, in particular to a meta-substituted phenol derivative molecule and a preparation method and application thereof. The invention discloses a preparation method of a meta-substituted phenol molecule, which comprises the step of carrying out multiple oxidative dehydrogenation coupling reaction on a compound shown as a formula I and a compound shown as a formula II to obtain a compound shown as a formula III. The invention provides a meta-substituted phenol derivative molecule and a preparation method and application thereof, and solves the technical problems of high synthesis reaction cost, low reaction stability and complex reaction of the meta-substituted phenol derivative molecule in the prior art.
Description
Technical Field
The invention relates to the field of organic synthesis, and in particular relates to a meta-substituted phenol compound and a preparation method and application thereof.
Background
Phenol and derivatives thereof are important organic substances, play an important role in the modern chemical and biological medicine industries, and are core structures of many bioactive compounds. Phenol and its derivatives can also be used as common laboratory solvents, reagents and disinfectants, and biologically, the protein on the chromosome in the plant cell can be separated from DNA by the phenol aqueous solution and used as DNA stain for biological experiments. Substituted phenol derivatives are common and important chemicals, widely used in the preparation of high value pharmaceuticals, agrochemicals, polymers, bioactive compounds and other fine and large chemicals. Substituted phenol derivatives typically have three positions at which substitution can occur: ortho-, meta-and para-positions of the phenolic hydroxyl group, wherein the synthesis of ortho-or para-substituted phenol derivatives is easily achieved using classical electrophilic substitution reactions due to the strong electron-directing action of the hydroxyl group, but meta-substituted phenol derivatives are difficult to produce by simple reactions. The meta-phenol derivatives are important in the synthesis of bioactive molecules, for example, 3- ((4-methoxyphenyl) amino) phenol is an important oxidative stain, levopromethazine is synthesized as a phenothiazine antipsychotic from (R) -3- (2-methoxy-10H-phenothiazin-10-yl) -N, N, 2-trimethylpropan-1-amine, which is a meta-phenol derivative, 6- (3-aminophenoxy) benzo [ d ] isothiazol-3-amine is important in the medical treatment of endothelial diseases, and 6- (3-aminophenoxy) -2H-benzo [ b ] [1,4] oxazin-3 (4H) -one is important in the high-risk operation as a drug for treating vascular defects.
The traditional method for constructing meta-substituted phenol is complicated in process, phenolic hydroxyl is often required to be alkylated, amino is introduced at para position to serve as a positioning group, meta-substitution reaction is carried out, finally amino is eliminated through diazotization reaction, and the C-O double bond is broken by hydroiodic acid to obtain the phenolic hydroxyl again. The synthesis of meta-substituted phenol derivatives is difficult by simple C-H activation or electrophilic substitution. As a traditional means for constructing the compounds, the method has some defects, such as complex synthetic process, narrow substrate range and pre-preparation of initial substrates, so that the development of a direct and universal method for constructing the meta-substituted phenol from simple and easily available raw materials is still expected.
Against this background, professor Buchwald 2009 developed a universal, efficient process, using various metal catalyst systems of Cu and Pd, for the selective O-and N-arylation of unprotected aminophenols using aryl halides; professor Shannon s.stahl in 2012 reported that cyclohexanone was directly oxidatively dehydrogenated intramolecular multiple times in the presence of metallic palladium and a nitrogen-containing additive to form phenols substituted at each position; professor Parthasarathi Das and professor Patrick y.s.lam 2017 realized the structure of cross-coupling with 3-aminophenol and boric acid as raw materials to produce meta-substituted phenol under the catalysis of copper. Although some progress has been made in the synthesis of meta-substituted phenol derivative molecules by the prior art, it is believed that it would be of great utility to develop a process for the multiple dehydrogenation coupling of meta-substituted phenol derivative molecules catalyzed by inexpensive metals, with TBHP as the oxidant, using inexpensive and readily available starting materials.
Dehydrogenation reactions help to produce product molecules with high pharmaceutical activity and material utility from a simple feedstock. The catalytic dehydrogenation mainly uses a metal catalyst to migrate and insert C-H bonds in raw materials to be broken, so as to achieve the aim of dehydrogenation. However, the C-C bond has a smaller energy and is more easily cleaved than the C-H bond, and a suitable catalyst must be selected so that only the C-H bond is cleaved without cleaving the C-C bond for the purpose of dehydrogenation. The dehydrogenation reaction can increase the unsaturation degree of the reaction product, thereby having high-efficiency reaction activity and being widely applied to important processes in organic synthesis. The method has been realized before, and uses a plurality of metal catalysts to synergistically catalyze to obtain the functionalized meta-substituted phenol derivative, but the used system catalyst has more types and less dehydrogenation times. We believe that the ability to achieve multiple dehydrogenation reactions over a single catalyst remains a significant challenge.
Therefore, the technical problems to be solved by the technical personnel in the field are solved, such as the incapability of using a single catalyst to perform multiple dehydrogenation reactions, the high cost of the synthesis reaction and the poor stability in the prior art.
Disclosure of Invention
The invention provides a meta-substituted phenol derivative molecule and a preparation method and application thereof, and solves the technical problems of high synthesis reaction cost, low reaction stability and complex reaction of the meta-substituted phenol derivative molecule in the prior art.
The invention provides a preparation method of a meta-substituted phenol derivative molecule, which comprises the following steps:
carrying out multiple oxidative dehydrogenation coupling reactions on a compound shown as a formula I and a compound shown as a formula II to obtain a compound shown as a formula III, wherein the formula I:
formula II: R-X; formula III:
wherein R is selected from one of saturated alkyl, phenyl, substituted phenyl and cyclane;
x is selected from amines or boric acids.
Preferably, the catalyst of the reaction is selected from one or more of copper acetate, copper trifluoromethanesulfonate, cuprous halide, cupric halide, cuprous oxide and cupric oxide.
Preferably, the molar ratio of the compound shown in the formula I to the compound shown in the formula II is 3: 1-1: 3.
More preferably, the molar ratio of the compound of formula (I) to the compound of formula (II) is 1: 2.
Preferably, the molar ratio of the catalyst to the catalyst shown in the formula I is 0.01-0.5%.
More preferably, the amount of catalyst is 5 mol% to 10 mol%, even more preferably 5 mol% and 10 mol%, most preferably 10 mol% of the amount of compound of formula (I).
Preferably, the method further comprises an oxidizing agent;
the oxidant is one or more of air, oxygen, copper acetate, silver carbonate, potassium persulfate, tetramethylpiperidine oxynitride, tert-butyl hydroperoxide and tert-butyl peroxide.
More preferably, the oxidizing agent is t-butyl hydroperoxide and tetramethylpiperidine nitroxide (TEMPO).
Preferably, the composition also comprises an additive;
the additive is one or more of elementary iodine, silver acetate, silver carbonate, silver nitrate, sodium acetate, lithium carbonate, potassium carbonate, cesium carbonate or potassium acetate.
More preferably, the additive is elemental iodine.
Preferably, the reaction is carried out in an inert solvent selected from one or more of toluene, tetrahydrofuran, 1, 4-dioxane, N '-dimethylformamide, N' -dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile and 1, 2-dichloroethane.
More preferably, the inert solvent is toluene.
More preferably, the amount of the inert solvent is 0.5mL to 3 mL.
More preferably, the amount of the inert solvent used is 2 mL.
Preferably, the reaction temperature is 60-120 ℃;
the reaction time is 6-24 h.
More preferably, the reaction temperature is 100 ℃ and the reaction time is 10 hours.
In the embodiment of the invention, after the reaction is finished, the method further comprises the following steps: after the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (4) carrying out chromatographic separation on the crude product by using a prepared silica gel plate to obtain the product. Wherein the selected developing agent or eluent is petroleum ether, and the volume ratio of the petroleum ether to the ethyl acetate is 10: 1.
the invention also provides a meta-substituted phenol molecule prepared by the preparation method.
The invention also provides application of the meta-substituted phenol molecule or the meta-substituted phenol molecule obtained by the preparation method in medicines and/or materials.
The preparation method provided by the invention utilizes the metal catalyst and the oxidant to carry out oxidation reaction, can form combination of various bonds in a single operation, realizes multiple dehydrogenation coupling reaction of taking cheap metal cuprous salt as the catalyst and taking cyclohexanone and amines or boric acid into consideration, obtains multi-substituted meta-substituted phenol derivative molecules, and simultaneously meets the requirements of green and sustainable chemistry. In addition, the chemical reagent is used for oxidation reaction, so that the advantages of good selectivity, simple process, convenience, flexibility and the like can be achieved, and especially the expected effect can be achieved in the field of pharmaceutical chemicals. In addition, the invention relates to a method for rapidly obtaining the complex molecular meta-substituted phenol derivative by combining oxidative coupling and dehydrogenation reactions and utilizing a transition metal catalytic reaction in the process of continuously paying attention to the dehydrogenation coupling reaction, thereby further developing the application in biomedicine and materials.
The invention provides a preparation method of a meta-substituted phenol molecule, which takes substituted cyclohexanone and amines or boric acid as raw materials to react under the action of a catalyst and an oxidant in the presence of an inert solvent. The meta-substituted phenol molecule obtained by the preparation method is a brand new meta-substituted phenol molecule, and can be widely applied to the fields of medicines and materials.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without inventive exercise.
FIG. 1 shows NMR spectra of 3- (phenylamino) phenol (3a) provided in example 1 of the present invention1H, spectrogram;
FIG. 2 shows NMR spectra of 3- (phenylamino) phenol (3a) according to example 1 of the present invention13C, spectrum;
FIG. 3 shows NMR spectra of 3- ((4-bromophenyl) amino) phenol (3b) provided in example 2 of the present invention1H, spectrogram;
FIG. 4 shows NMR spectra of 3- ((4-bromophenyl) amino) phenol (3b) provided in example 2 of the present invention13C, spectrum;
FIG. 5 shows 3- ([1,1' -biphenyl ] provided in example 3 of the present invention]-4-ylamino) phenol (3c) nuclear magnetic resonance1H, spectrogram;
FIG. 6 shows 3- ([1,1' -biphenyl ] provided in example 3 of the present invention]-4-ylamino) phenol (3c) nuclear magnetic resonance13C, spectrum;
FIG. 7 shows [1,1' -biphenyl ] provided in example 4 of the present invention]-3-alcohol (3d) nuclear magnetic resonance1H, spectrogram;
FIG. 8 shows [1,1' -biphenyl ] provided in example 4 of the present invention]-3-alcohol (3d) nuclear magnetic resonance13C, spectrum;
FIG. 9 shows 4 '-methoxy- [1,1' -biphenyl ] provided in example 5 of the present invention]-3-alcohol (3e) nuclear magnetic resonance1H, spectrogram;
FIG. 10 shows 4 '-methoxy- [1,1' -biphenyl ] provided in example 5 of the present invention]-3-alcohol (3e) nuclear magnetic resonance13C, spectrum;
FIG. 11 shows the NMR of m-cresol (3f) as provided in example 6 of the present invention1H, spectrogram;
FIG. 12 shows the NMR of m-cresol (3f) as provided in example 6 of the present invention13And C, spectrum.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Other embodiments, which can be derived by one of ordinary skill in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The meta-substituted phenol derivative molecule, the preparation method thereof and the raw materials and reagents used in the application can be purchased from the market.
The meta-substituted phenol derivative molecule provided by the present invention, and the preparation method and application thereof are further described below.
Example 13- (phenylamino) phenol (3a)
Cyclohexanone 1(59.2mg,0.50mmol), aniline 2a (18.6mg,0.20mmol), cuprous oxide (21.0mg,0.15mmol), t-butyl hydroperoxide (135.2mg, 1.5mmol), 2,2,6, 6-tetramethylpiperidine oxide (9.4mg,0.06mmol), iodine (135.2mg, 0.3mmol), toluene (toluene,2.0mL) were added sequentially to a 15mL Schlenk reaction tube under an atmospheric oxygen atmosphere and reacted at 120 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 10: 1 to yield the product 3- (phenylamino) phenol (3 a): white solid, yield 51% (47.2 mg).
The hydrogen nuclear magnetic resonance spectrum measurement result of the 3- (phenylamino) phenol (3a) is as follows:1H NMR(400MHz,CDCl3)δ7.43-7.39(m,2H),7.22(dd,J＝2.0Hz,8.0Hz,3H),7.09(t,J＝7.2Hz,1H),6.75-6.70(m,2H),6.52(d,J＝8.0Hz,1H),5.83(brs,1H),5.27(brs,1H)。
the carbon nuclear magnetic resonance spectrum measurement result of the 3- (phenylamino) phenol (3a) is as follows:13C NMR(101MHz,CDCl3)δ156.6,144.9,142.6,130.3,129.3,121.4,118.6,109.9,107.7,104.0。
the embodiment of the invention can efficiently and simply obtain the meta-substituted phenylaminol with potential biological activity, provides a new method for constructing the C-N bond at the meta position of the benzene ring, and provides the possibility of subsequent conversion for the subsequent meta-substituted phenylaminol with high biological activity and material application potential.
Example 23- ((4-bromophenyl) amino) phenol (3b)
Cyclohexanone 1(58.8mg,0.60mmol), p-bromoaniline 2b (34.4mg,0.20mmol), cuprous oxide (21.0mg,0.15mmol), t-butyl hydroperoxide (162.2mg, 1.8mmol), 2,2,6, 6-tetramethylpiperidine oxide (18.8mg,0.12mmol), iodine (270.4mg, 0.6mmol), toluene (toluene,2.5mL) were added sequentially to a 15mL Schlenk reaction tube under an atmospheric oxygen atmosphere and reacted at 120 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 10: 1 to yield the product 3- ((4-bromophenyl) amino) phenol (3 b): white solid, yield 51% (80.8 mg).
The hydrogen nuclear magnetic resonance spectrum measurement result of the 3- ((4-bromophenyl) amino) phenol (3b) is as follows:1H NMR(400MHz,CDCl3)δ7.34(d,J＝8.4Hz,2H),7.11(t,J＝8.0Hz,1H),6.95(d,J＝8.8Hz,2H),6.59(d,J＝8.0Hz,1H),6.54(s,1H),6.41(dd,J＝1.6Hz,8.0Hz,1H),5.67(brs,1H),5.09(brs,1H)。
the carbon Nuclear Magnetic Resonance (NMR) spectrum measurement result of the 3- ((4-bromophenyl) amino) phenol (3b) is as follows:13C NMR(101MHz,CDCl3)δ156.6,144.2,141.8,132.2,130.4,119.8,113.1,110.3,108.3,104.5。
the embodiment of the invention can efficiently obtain the meta-substituted aniline with potential biological activity, and the reaction is compatible with the substituted phenyl functional group, thereby providing convenience for subsequent conversion, such as various coupling reactions, and further obtaining the more functionalized derivative.
Example 33- ([1,1' -Biphenyl ] -4-ylamino) phenol (3c)
Cyclohexanone 1(29.4mg,0.30mmol), 4-amino-1, 1' -biphenyl 2c (18.6mg,0.20mmol), cuprous oxide (21.0mg,0.15mmol), t-butyl hydroperoxide (135.2mg, 1.5mmol), 2,2,6, 6-tetramethylpiperidine oxide (9.4mg,0.06mmol), iodine (135.2mg, 0.3mmol), toluene (tolene, 2.0mL) were added sequentially to a 15mL Schlenk reaction tube under an atmospheric oxygen atmosphere and reacted at a temperature of 80 ℃ for 20 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 10: 1, obtaining the product 3- ([1,1' -biphenyl ] -4-ylamino) phenol (3 c): white solid, yield 62% (56.1 mg).
3- ([1,1' -Biphenyl)]-4-ylamino) phenol (3c) as determined by NMR spectroscopy:1H NMR(400MHz,CDCl3)δ7.58(d,J＝7.6Hz,2H),7.44(t,J＝7.6Hz,2H),7.35(dd,J＝7.2Hz,14.4Hz,2H),7.31(s,1H),7.20(d,J＝7.6Hz,1H),7.13(t,J＝8.0Hz,1H),7.07(d,J＝8.0Hz,1H),6.67(d,J＝8.0Hz,1H),6.60(s,1H),6.41(d,J＝7.6Hz,1H),5.70(brs,1H)。
3- ([1,1' -Biphenyl)]-4-ylamino) phenol (3c) having the following NMR carbon spectrum:13C NMR(101MHz,CDCl3)δ155.6,144.8,143.0,142.5,141.0,130.4,129.4,127.1,120.3,117.4,117.2,110.1,107.9,104.3。
the embodiment of the invention can efficiently obtain the substituted phenol amine with potential biological activity and condensed ring-fused meta-substituent, and the reaction is compatible with the substituted phenyl functional group, thereby providing convenience for subsequent conversion and obtaining the more functionalized derivative.
Example 4[1,1' -Biphenyl ] -3-ol (3d)
Cyclohexanone 1(7.2mg,0.10mmol), phenylboronic acid 2d (24.3mg,0.20mmol), cuprous oxide (4.8mg,0.04mmol), tert-butyl hydroperoxide (86.1mg, 0.6mmol), 2,2,6, 6-tetramethylpiperidine oxide (3.1mg,0.02mmol), iodine (44.2mg, 0.1mmol), toluene (toluene,1.0mL) were added sequentially to a 15mL Schlenk reaction tube under an atmospheric oxygen atmosphere and reacted at 90 ℃ for 18 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 10: 1, to obtain the product [1,1' -biphenyl ] -3-ol (3 d): white solid, yield 44% (7.48 mg).
[1,1' -Biphenyl]-the hydrogen nuclear magnetic resonance spectrum of the 3-alcohol (3d) is as follows:1H NMR(400MHz,CDCl3)δ7.58(d,J＝7.2Hz,2H),7.45(t,J＝7.2Hz,2H),7.39-7.35(m,1H),7.32(d,J＝7.6Hz,1H),7.20(d,J＝7.6Hz,1H),7.11(t,J＝2.0Hz,1H),6.86(dd,J＝1.6Hz,8.0Hz,1H),5.87(brs,1H)。
[1,1' -Biphenyl]-the carbon nuclear magnetic resonance spectrum of the 3-alcohol (3d) is as follows:13C NMR(101MHz,CDCl3)δ155.8,142.9,140.6,130.0,128.7,127.4,127.0,119.7,114.2。
the embodiment of the invention can efficiently obtain the molecules of the phenol derivatives with the meta-position substitution being benzene rings, and can well convert the molecules into the molecules in medicines and materials continuously modified on the meta-position substituted benzene rings.
Example 54 '-methoxy- [1,1' -biphenyl ] -3-ol (3e)
Cycloacetone 1(70.2mg,0.50mmol), p-methoxyphenylboronic acid 2e (60.4mg,0.40mmol), cuprous oxide (21.3mg,0.17mmol), tert-butyl hydroperoxide (182.2mg, 2.0mmol), 2,2,6, 6-tetramethylpiperidine oxide (1.6mg,0.01mmol), iodine (221.2mg, 0.5mmol), toluene (tolene, 2.0mL) were added to a 15mL Schlenk reaction tube in this order under an atmospheric oxygen atmosphere and reacted at 90 ℃ for 18 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 50: 1 to give the product 4 '-methoxy- [1,1' -biphenyl ] -3-ol (3 e): pale yellow solid, yield 76% (100.0 mg).
4 '-methoxy- [1,1' -biphenyl]-the hydrogen nuclear magnetic resonance spectrum of the 3-alcohol (3e) is as follows:1H NMR(400MHz,CDCl3)δ7.54-7.51(m,2H),7.33(t,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),7.09(t,J＝2.4Hz,1H),6.98-6.95(m,2H),6.87-6.84(m,1H),3.86(s,3H)。
4 '-methoxy- [1,1' -biphenyl]-the carbon nuclear magnetic resonance spectrum of the 3-alcohol (3e) is as follows:13C NMR(100MHz,CDCl3)δ159.9,159.2,142.3,133.6,129.7,128.2,119.3,114.1,112.5,112.0,55.3。
the embodiment of the invention can efficiently obtain the molecule of the meta-substituted phenol with the methoxy structure, and can well convert the molecule into the molecule in the medicine and the material which are continuously modified on the meta-substituted benzene ring in the next step.
EXAMPLE 6 m-cresol (3f)
Cycloacetone 1(35.1mg,0.25mmol), methylboronic acid 2f (14.9mg,0.25mmol), cuprous oxide (21.3mg,0.15mmol), tert-butylhydroperoxide (182.2mg, 2.0mmol), 2,2,6, 6-tetramethylpiperidine oxide (1.6mg,0.01mmol), iodine (221.2mg, 0.5mmol), toluene (toluene,2.0mL) were added sequentially to a 15mL Schlenk reaction tube under an atmospheric oxygen atmosphere, and reacted at 120 ℃ for 10 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 50: 1, obtaining the product m-cresol (3 f): pale yellow solid, yield 76% (100.0 mg).
The nuclear magnetic resonance hydrogen spectrum measurement result of the m-cresol (3f) is as follows:1H NMR(400MHz,CDCl3)δ7.08-7.03(m,1H),6.70(d,J＝7.6Hz,1H),6.62(d,J＝6.4Hz,2H),6.25(brs,1H),2.12(s,3H)。
the nuclear magnetic resonance carbon spectrum measurement result of the m-cresol (3f) is as follows:13C NMR(100MHz,CDCl3)δ154.9,139.8,129.4,121.7,116.1,112.4,21.1。
the embodiment of the invention can efficiently obtain the molecule of the meta-substituted phenol with the aliphatic structure, and can well convert the meta-substituted phenol into the molecule of a medicine or a material with a linear meta-position.
The above-mentioned embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the same; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (5)
1. A method for preparing a meta-substituted phenol derivative molecule, comprising:
carrying out multiple oxidative dehydrogenation coupling reactions on a compound of a formula I and a compound of a formula II to obtain a compound of a formula III;
wherein the compound of formula I is selected from cyclohexanone;
the compound of formula II is one selected from aniline, p-bromoaniline, 4-amino-1, 1' -biphenyl, phenylboronic acid, p-methoxyphenylboronic acid and methylboronic acid;
the compound of formula III is selected from one of 3- (phenylamino) phenol, 3- ((4-bromophenyl) amino) phenol, 3- ([1,1 '-biphenyl ] -4-ylamino) phenol, [1,1' -biphenyl ] -3-ol, 4 '-methoxy- [1,1' -biphenyl ] -3-ol and m-cresol;
the catalyst for the reaction is selected from cuprous oxide;
the oxidant for the reaction is selected from 2,2,6, 6-tetramethyl piperidine oxynitride and tert-butyl hydroperoxide;
the reactive additive is selected from elemental iodine.
2. The preparation method according to claim 1, wherein the molar ratio of the compound of formula I to the compound of formula II is 3:1 to 1: 3.
3. The method of claim 1, wherein the molar ratio of the catalyst to the compound of formula I is 0.01% to 0.5%.
4. The method according to claim 1, wherein the reaction is carried out in an inert solvent selected from one or more of toluene, tetrahydrofuran, 1, 4-dioxane, N '-dimethylformamide, N' -dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile and 1, 2-dichloroethane.
5. The method according to claim 1, wherein the reaction temperature is 60 ℃ to 120 ℃;
the reaction time is 6-24 h.
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