CN109563029B - 用于制备二氢茚酮类的方法 - Google Patents
用于制备二氢茚酮类的方法 Download PDFInfo
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- CN109563029B CN109563029B CN201780049982.5A CN201780049982A CN109563029B CN 109563029 B CN109563029 B CN 109563029B CN 201780049982 A CN201780049982 A CN 201780049982A CN 109563029 B CN109563029 B CN 109563029B
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- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical class C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 title description 11
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 238000000034 method Methods 0.000 claims abstract description 47
- -1 amino compound Chemical class 0.000 claims abstract description 41
- 238000002360 preparation method Methods 0.000 claims description 18
- 238000005580 one pot reaction Methods 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 8
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229940124530 sulfonamide Drugs 0.000 claims description 6
- 150000003456 sulfonamides Chemical class 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 229920002554 vinyl polymer Polymers 0.000 claims description 5
- 150000004657 carbamic acid derivatives Chemical class 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 238000006317 isomerization reaction Methods 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 69
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 239000000203 mixture Substances 0.000 description 33
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 25
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 24
- 239000003921 oil Substances 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 238000010992 reflux Methods 0.000 description 22
- 229920006395 saturated elastomer Polymers 0.000 description 22
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 18
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 15
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- FAVMIAXKDIUAKF-UHFFFAOYSA-N 2-methyl-6-(2-methylpropyl)-2,3-dihydroinden-1-one Chemical compound CC(C)CC1=CC=C2CC(C)C(=O)C2=C1 FAVMIAXKDIUAKF-UHFFFAOYSA-N 0.000 description 14
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 239000012043 crude product Substances 0.000 description 13
- 238000004821 distillation Methods 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N 3-phenylprop-2-enal Chemical class O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 229910052709 silver Inorganic materials 0.000 description 4
- 239000004332 silver Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- LXCNIWIHIQTKFZ-FMIVXFBMSA-N (e)-2-methyl-3-[4-(2-methylpropyl)phenyl]prop-2-enal Chemical compound CC(C)CC1=CC=C(\C=C(/C)C=O)C=C1 LXCNIWIHIQTKFZ-FMIVXFBMSA-N 0.000 description 3
- MHQIZLXEJZNBQI-UHFFFAOYSA-N 1h-inden-1-amine Chemical compound C1=CC=C2C(N)C=CC2=C1 MHQIZLXEJZNBQI-UHFFFAOYSA-N 0.000 description 3
- JJARVPPFJKHTKJ-UHFFFAOYSA-N 6-ethyl-2-methyl-2,3-dihydroinden-1-one Chemical compound CCC1=CC=C2CC(C)C(=O)C2=C1 JJARVPPFJKHTKJ-UHFFFAOYSA-N 0.000 description 3
- QHKFBWKOHWQEFW-UHFFFAOYSA-N 7-bromo-2-methyl-2,3-dihydroinden-1-one Chemical compound C1=CC(Br)=C2C(=O)C(C)CC2=C1 QHKFBWKOHWQEFW-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000007848 Bronsted acid Substances 0.000 description 3
- VOEXDIJTELPPTQ-UHFFFAOYSA-N C(C(C)C)C1=CC=C2C=C(C(C2=C1)NC(C)=O)C Chemical compound C(C(C)C)C1=CC=C2C=C(C(C2=C1)NC(C)=O)C VOEXDIJTELPPTQ-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IQHLLUZHVYLDHG-UHFFFAOYSA-N 2-ethyl-6-(2-methylpropyl)-2,3-dihydroinden-1-one Chemical compound C(C)C1C(C2=CC(=CC=C2C1)CC(C)C)=O IQHLLUZHVYLDHG-UHFFFAOYSA-N 0.000 description 2
- UCONRJSUTSLMAA-UHFFFAOYSA-N 2-methyl-6-(3-methylbutyl)-2,3-dihydroinden-1-one Chemical compound C(CC(C)C)C1=CC=C2CC(C(C2=C1)=O)C UCONRJSUTSLMAA-UHFFFAOYSA-N 0.000 description 2
- AHMJTIYXKJRVFF-UHFFFAOYSA-N 4-bromo-2-methyl-2,3-dihydroinden-1-one Chemical compound O=C1C(C)CC2=C1C=CC=C2Br AHMJTIYXKJRVFF-UHFFFAOYSA-N 0.000 description 2
- GMWXCOYOQNIWPE-UHFFFAOYSA-N 5-bromo-2-methyl-2,3-dihydroinden-1-one Chemical compound BrC1=CC=C2C(=O)C(C)CC2=C1 GMWXCOYOQNIWPE-UHFFFAOYSA-N 0.000 description 2
- GMJKJIUETGRADG-UHFFFAOYSA-N 6-bromo-2-methyl-2,3-dihydroinden-1-one Chemical compound C1=C(Br)C=C2C(=O)C(C)CC2=C1 GMJKJIUETGRADG-UHFFFAOYSA-N 0.000 description 2
- GVIAHNSBJYXHAR-UHFFFAOYSA-N 6-methyl-2-propan-2-yl-2,3-dihydroinden-1-one Chemical compound C(C)(C)C1C(C2=CC(=CC=C2C1)C)=O GVIAHNSBJYXHAR-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L Zinc bromide Inorganic materials Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 125000005466 alkylenyl group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 229940117916 cinnamic aldehyde Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 235000019645 odor Nutrition 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- UHDVDAVDGABLBC-JYRVWZFOSA-N (2e)-3-methyl-2-[(4-methylphenyl)methylidene]butanal Chemical compound CC(C)C(\C=O)=C/C1=CC=C(C)C=C1 UHDVDAVDGABLBC-JYRVWZFOSA-N 0.000 description 1
- WAJNQADTYWMLJA-PKNBQFBNSA-N (E)-3-(4-butan-2-ylphenyl)-2-methylprop-2-enal Chemical compound C(C)(CC)C1=CC=C(C=C1)/C=C(/C=O)\C WAJNQADTYWMLJA-PKNBQFBNSA-N 0.000 description 1
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 1
- ORERKZSAOICFMM-VMPITWQZSA-N (e)-3-(3-bromophenyl)-2-methylprop-2-enal Chemical compound O=CC(/C)=C/C1=CC=CC(Br)=C1 ORERKZSAOICFMM-VMPITWQZSA-N 0.000 description 1
- RNBCQLCYZIHPON-SOFGYWHQSA-N (e)-3-(4-bromophenyl)-2-methylprop-2-enal Chemical compound O=CC(/C)=C/C1=CC=C(Br)C=C1 RNBCQLCYZIHPON-SOFGYWHQSA-N 0.000 description 1
- LBJVUCHTVWQXJT-CSKARUKUSA-N (e)-3-(4-ethylphenyl)-2-methylprop-2-enal Chemical compound CCC1=CC=C(\C=C(/C)C=O)C=C1 LBJVUCHTVWQXJT-CSKARUKUSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- KWRSKZMCJVFUGU-UHFFFAOYSA-N 1h-inden-1-ol Chemical class C1=CC=C2C(O)C=CC2=C1 KWRSKZMCJVFUGU-UHFFFAOYSA-N 0.000 description 1
- YKIWSTMAKMOTHZ-UHFFFAOYSA-N 1h-inden-1-yl carbamate Chemical compound C1=CC=C2C(OC(=O)N)C=CC2=C1 YKIWSTMAKMOTHZ-UHFFFAOYSA-N 0.000 description 1
- IACNXKGUXUXLQS-UHFFFAOYSA-N 1h-indene-1-sulfonamide Chemical compound C1=CC=C2C(S(=O)(=O)N)C=CC2=C1 IACNXKGUXUXLQS-UHFFFAOYSA-N 0.000 description 1
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- QWZAOSKLFKAEOK-UHFFFAOYSA-N 3,3-dimethyl-2h-inden-1-one Chemical class C1=CC=C2C(C)(C)CC(=O)C2=C1 QWZAOSKLFKAEOK-UHFFFAOYSA-N 0.000 description 1
- SUISZCALMBHJQX-UHFFFAOYSA-N 3-bromobenzaldehyde Chemical compound BrC1=CC=CC(C=O)=C1 SUISZCALMBHJQX-UHFFFAOYSA-N 0.000 description 1
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 1
- 241001647745 Banksia Species 0.000 description 1
- QCUTXHBBCBLRKO-UHFFFAOYSA-N C(C(C)C)C1=CC=C2C=C(C(C2=C1)NS(=O)(=O)C)C Chemical compound C(C(C)C)C1=CC=C2C=C(C(C2=C1)NS(=O)(=O)C)C QCUTXHBBCBLRKO-UHFFFAOYSA-N 0.000 description 1
- JUCOAYOPWHBSID-UHFFFAOYSA-N C(C(C)C)C=1C=C2C(=C(CC2=CC=1)C)NC(C)=O Chemical compound C(C(C)C)C=1C=C2C(=C(CC2=CC=1)C)NC(C)=O JUCOAYOPWHBSID-UHFFFAOYSA-N 0.000 description 1
- ALKQXXHQAHUCMW-UHFFFAOYSA-N C(C(C)C)C=1C=C2C(=C(CC2=CC=1)C)NS(=O)(=O)C Chemical compound C(C(C)C)C=1C=C2C(=C(CC2=CC=1)C)NS(=O)(=O)C ALKQXXHQAHUCMW-UHFFFAOYSA-N 0.000 description 1
- 235000015655 Crocus sativus Nutrition 0.000 description 1
- 244000124209 Crocus sativus Species 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 229910003074 TiCl4 Inorganic materials 0.000 description 1
- AXMVYSVVTMKQSL-UHFFFAOYSA-N UNPD142122 Natural products OC1=CC=C(C=CC=O)C=C1O AXMVYSVVTMKQSL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001853 cinnamic aldehyde derivatives Chemical class 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- IRORNFAADORSTL-UHFFFAOYSA-N ethyl N-[2-methyl-6-(2-methylpropyl)-1H-inden-1-yl]carbamate Chemical compound C(C(C)C)C1=CC=C2C=C(C(C2=C1)NC(OCC)=O)C IRORNFAADORSTL-UHFFFAOYSA-N 0.000 description 1
- DGBRHQBTTDOLMQ-UHFFFAOYSA-N ethyl N-[2-methyl-6-(2-methylpropyl)-3H-inden-1-yl]carbamate Chemical compound C(C(C)C)C=1C=C2C(=C(CC2=CC=1)C)NC(OCC)=O DGBRHQBTTDOLMQ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- IYOOLUIMTICUMP-UHFFFAOYSA-N methyl N-[2-methyl-6-(2-methylpropyl)-1H-inden-1-yl]carbamate Chemical compound C(C(C)C)C1=CC=C2C=C(C(C2=C1)NC(OC)=O)C IYOOLUIMTICUMP-UHFFFAOYSA-N 0.000 description 1
- FAKPZBRXBPBTDC-UHFFFAOYSA-N methyl N-[2-methyl-6-(2-methylpropyl)-3H-inden-1-yl]carbamate Chemical compound C(C(C)C)C=1C=C2C(=C(CC2=CC=1)C)NC(OC)=O FAKPZBRXBPBTDC-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000004248 saffron Substances 0.000 description 1
- 235000013974 saffron Nutrition 0.000 description 1
- 238000000526 short-path distillation Methods 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
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Abstract
形成式(I)的化合物的方法,包括以下步骤:使氨基化合物H2NR加成到式(II)的化合物上,然后进行环化、异构化和水解。
Description
本发明涉及有机合成领域。它提供了制备二氢茚酮类(indanones)的新方法,所述二氢茚酮类是式I的化合物:
特别地,它提供了由α-取代的肉桂醛制备式I的化合物的方法。
一些二氢茚酮类在文献中被描述为有用的香料成分。例如,WO03072533A1描述了3,3-二甲基二氢茚酮类在香料中的应用,其具有革香、木香和藏红花样气味。US3,944,679公开了当给予到烟草、食品和饮料香精中时,2-和3-烷基取代的二氢茚酮类具有类似香豆素的气味。
通常,二氢茚酮类的合成途径有些复杂,并且制备必须在几个单独的步骤中进行,增加了所述化合物的成本。
在US7,250,528B2中公开了由肉桂醛类合成茚酚酯类和茚酚醚类。所述化合物可进一步转化为相应的二氢茚酮类(Womack,G.B.等人;J.Org.Chem.2009,74,5738-5741;Womack,G.B.等人;J.Org.Chem.2007,72,7046-7049)。
或者,二氢茚酮类可以通过茚基磺酰胺(Fan,X.等人;Chem.Comm.2014,50,4119-4122)或茚基氨基甲酸酯(Kraft,W.M.;J.Am.Chem.Soc.1948,70,3569-3571)以逐步转化的方式从肉桂醛类获得。
仍然需要提供简单且成本有效的制备式I的化合物的方法。
本发明在第一方面提供制备式(I)的化合物的方法
所述方法包括以下步骤:
a)使氨基化合物H2NR加成到式(II)的化合物上
然后环化成式(III)的化合物;
其中式(II)的化合物中的波状键表示相邻双键的未指定的构型;和
所述氨基化合物H2NR选自烷基酰胺类、磺酰胺类和氨基甲酸酯类;
b)使式(III)的化合物异构化成式(IV)的化合物;
c)使式(IV)的化合物水解成式(I)的化合物;
其中,在式(I)、(II)、(III)和/或(IV)的化合物中,
R1表示甲基,乙基,乙烯基,直链、支链或环状C3-10烷基或烯基,或苯基,其是任选取代的;
R2、R3、R4、R5和R6各自独立地表示氢原子,甲基,乙基,乙烯基,甲氧基,乙氧基,乙烯氧基,直链、支链或环状C3-10烷基、烯基或烷氧基,卤原子或苯基,其是任选取代的。
通常,这种任选取代的苯基可带有一个或多个例如选自直链、支链或环状烷基、烯基或烷氧基或卤素原子的取代基。
在该方法的步骤a)中,式(II)的α-取代的肉桂醛与氨基化合物H2NR进行缩合反应,然后立即环化成式(III)的茚基胺中间体化合物:
式(II)的化合物中的波状键表示相邻双键的未指定构型。这意味着式(II)的化合物可以作为E-或Z-化合物存在,或作为异构体混合物存在。
氨基化合物H2NR选自磺酰胺类、氨基甲酸酯类或烷基酰胺类。
在其中氨基化合物H2NR选自磺酰胺类的实施方案中,R特别表示-SO2Me、-SO2Et或-SO2PhMe。
在上述氨基化合物H2NR中,磺酰胺类是最昂贵的;然而,当在该方法的步骤a)中使用时,反应快速进行。
在其中氨基化合物H2NR选自氨基甲酸酯类的实施方案中,R特别表示-CO2Me或-CO2Et。
当选择氨基甲酸酯类作为氨基化合物H2NR时,反应可能导致极少的副产物或几乎没有副产物。
在其中氨基化合物H2NR选自烷基酰胺类的实施方案中,R特别表示-(CO)Me或-(CO)Et。
烷基酰胺类是所提及的氨基化合物H2NR中最便宜的替代物,但是根据该方法的步骤a)的反应较慢。然而,该反应产生了良好的收率。这在现有技术的知识中是令人惊讶的(Fan,X.等人;Chem.Comm.2014,50,4119-4122),在现有技术中使用苯甲酰胺(R=-(CO)Ph)的类似反应未能得到所需产物。
相对于式(II)的化合物的摩尔量,氨基化合物H2NR可以1.0至1.2、优选1.05至1.1摩尔当量使用。氨基化合物的最佳浓度取决于其性质并且取决于进一步的反应条件。
步骤a)的缩合反应例如由路易斯酸或另一种活化剂催化,所述路易斯酸可以选自(但不限于)FeCl3、ZnCl2、AlCl3、TiCl4、BF3、ZnBr2,所述另一种活化剂例如为POCl3、PCl5或TfOH。所述化合物可以是无水形式(例如FeCl3)或还可以是水合物形式(例如FeCl3·6H2O),除了那些在水存在下不稳定的酸。
路易斯酸可以催化或化学计量的量使用或甚至过量使用。优选地,相对于式(II)的化合物的摩尔量,催化剂的用量为0.01至0.5,或甚至0.1至0.2摩尔当量。然而,催化剂的最佳浓度取决于催化剂的性质并且取决于进一步的反应条件。
在本发明的一个方面,步骤a)的缩合反应的催化剂是路易斯酸,特别是FeCl3。
在本发明的一个方面,步骤a)优选在选自甲苯、二甲苯、苯、二氯甲烷、1,2-二氯乙烷、EtOAc、MeOAc或乙腈的溶剂中进行。
所需的溶剂的量取决于反应参与者(reaction partners)的溶解度,并且特别是取决于式(II)的化合物的溶解度。出于经济原因,优选溶剂的用量低,例如起始醛(g)对溶剂(ml)的比例为1:10,或1:7,或1:4,或1:3,或甚至1:1.5。
该方法的步骤a)可在室温下进行。或者,可将反应混合物加热至65℃或75℃,或加热至回流,并且最佳温度取决于所选择的溶剂和/或所使用的催化剂。通常,升高的温度可能缩短反应时间。
取决于式(II)的化合物中芳环上的取代基R3至R6,环化步骤可以得到一种式(III)的化合物或两种异构体的混合物。例如,如果在式(II)的化合物中仅在苯环的3位上有取代基,例如R4=Me且R3、R5和R6=H,则可以得到两种异构体。两种异构体均可以在后续步骤中进一步转化。
在该方法的步骤b)中,发生式(III)的茚基胺中间体化合物至式(IV)的中间体化合物的异构化:
异构化在碱例如稀释的含水碱的存在下或在醇溶液中,以不同的浓度,例如1mol/L、2mol/L或32%进行。优选地,碱是碱金属碱(alkali base),例如NaOH。或者,可以使用在有机溶剂如EtOAc中的Et3N或其它胺如DABCO。
相对于式(II)的化合物的摩尔量,碱可以0.5至2.5、优选0.89至1.7、更优选1.5摩尔当量使用。使用较高量的碱可以缩短反应时间。
在该方法的步骤c)中,将式(IV)的中间体化合物水解成所需的式I的二氢茚酮化合物:
水解优选通过用布朗斯台德酸处理来进行。它可能在升高的温度下加速。
优选地,所用的布朗斯台德酸是H2SO4或HCl,并且它以浓缩或以稀释的形式使用。
相对于式(II)的化合物的摩尔量,布朗斯台德酸可以1.0至3.0、优选1.1至2.7、更优选1.7的摩尔当量使用。
在一个具体实施方案中,该方法的步骤a)、b)和c)在一锅法中进行
其中,在式(I)和/或(II)的化合物中,
R1表示甲基,乙基,乙烯基,直链、支链或环状C3-10烷基或烯基,或苯基,其是任选取代的;
R2、R3、R4、R5和R6各自独立地表示氢原子,甲基,乙基,乙烯基,甲氧基,乙氧基,乙烯氧基,直链、支链或环状C3-10烷基、烯基或烷氧基,卤原子或苯基,其是任选取代的。
这种一锅法使得能够更快地合成二氢茚酮类,因为只需要对最终的式(I)的化合物进行一个后处理和/或纯化步骤而不是进行三个后处理和/或纯化步骤。因此,还可以减少溶剂的消耗,使得该方法对环境友好并且进一步降低成本。
此外,一锅法可以提供比逐步法的总收率更高的收率。
此外,由于茚基胺中间体━式(III)和(IV)的化合物━是固体而最终产物是油,使用三步-一锅法来避免分离这些中间体可能是更方便的。
在本发明的一个方面,上述方法可用于获得分子量不大于300g/mol的式(I)的化合物。这些化合物是特别有用的香料。
在本发明的一个方面,上述方法可用于获得式(I)的化合物,其中在式(I)、(II)、(III)和/或(IV)的化合物中,R1选自甲基、乙基、丙基和异丙基。
在本发明的另一方面,上述方法可用于获得式(I)的化合物,其中在式(I)、(II)、(III)和/或(IV)的化合物中,R2选自H和甲基。
在本发明的另一方面,上述方法可用于获得式(I)的化合物,其中在式(I)、(II)、(III)和/或(IV)的化合物中,R3、R4、R5和R6独立地选自H,甲基,乙基,丙基,异丙基,环丙基,丁基,异丁基,仲丁基,叔丁基,环丁基,戊基,异戊基,环戊基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,Cl,Br,I和苯基,其是任选取代的。
特别地,所述方法可用于使氨基化合物与在苯环上具有吸电子基团例如卤素原子如Cl、Br、I的式(II)的化合物反应,然后进一步将其转化为相应的二氢茚酮。这是令人惊讶的,因为在Fan,X.等人(Chem.Comm.2014,50,4119-4122)描述的条件下加成反应失败。
在本发明的另一方面,上述方法可用于获得式(I)的化合物,其中在式(I)、(II)、(III)和/或(IV)的化合物中,R3、R4、R5和R6中的至少一个是H,而该基团的其它取代基独立地选自甲基,乙基,乙烯基,甲氧基,乙氧基,乙烯氧基,直链、支链或环状C3-10烷基、烯基或烷氧基,卤素或苯基,其是任选取代的。
在本发明的另一方面,上述方法可用于获得式(I)的化合物,其中在式(I)、(II)、(III)和/或(IV)的化合物中,R3、R4、R5和R6中的至少两个或三个表示H,而该基团的其它取代基独立地选自甲基,乙基,乙烯基,甲氧基,乙氧基,乙烯氧基,直链、支链或环状C3-10烷基、烯基或烷氧基,卤素或苯基,其是任选取代的。
在本发明的一个具体实施方案中,上述方法可用于获得式(I)的化合物,其中在式(I)、(II)、(III)和/或(IV)的化合物中,
R1选自甲基、乙基、丙基和异丙基;
R2选自H和甲基;且
R3、R4、R5和R6独立地选自H,甲基,乙基,丙基,异丙基,环丙基,丁基,异丁基,仲丁基,叔丁基,环丁基,戊基,异戊基,环戊基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,Cl,Br,I和苯基,其是任选取代的。
在本发明的另一方面,上述方法可用于获得式(I)的化合物,其中在式(II)的化合物中,R3、R5和R6表示H,且R4选自H,甲基,乙基,丙基,异丙基,环丙基,丁基,异丁基,仲丁基,叔丁基,环丁基,戊基,异戊基,环戊基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,Cl,Br,I和苯基,其是任选取代的。在这种情况下,上述方法将得到式(I)的化合物的区域异构体混合物。
在本发明的另一方面,上述方法可用于获得式(I)的化合物,所述化合物选自6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮和2-异丙基-6-甲基-2,3-二氢-1H-茚-1-酮。
现在参考以下非限制性实施例进一步描述本发明。这些实施例仅用于说明的目的,并且应理解,本领域技术人员可以进行变化和修改。
实施例
实施例1:6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮的制备━使用氨基甲酸甲酯(MeOCONH2)的逐步合成
步骤1:(6-异丁基-2-甲基-1H-茚-1-基)氨基甲酸甲酯
将氨基甲酸甲酯(39.4g,0.519mol,1.05eq)和(E)-3-(4-异丁基苯基)-2-甲基丙烯醛(脱氢银醛,100g,0.494mol,1-2%(Z)-异构体)在二氯乙烷(400ml)中的混合物加热至35℃,并将所得溶液用三氯化铁(8.27g,0.049mol,0.1eq.)处理。将所得混合物加热至回流(79℃),搅拌2小时,冷却至15℃,用EtOAc(100ml)处理,并用1N HCl水溶液(80ml)洗涤。将有机相用饱和NaHCO3水溶液(50ml)洗涤两次,用饱和NaCl水溶液(50ml)洗涤两次,用MgSO4干燥,过滤,并蒸发溶剂。将粗产物(120g,棕色固体)用己烷(300ml)研磨,过滤,用己烷(150ml)洗涤,并干燥,得到(6-异丁基-2-甲基-1H-茚-1-基)氨基甲酸甲酯(91g,92%纯度,略带棕色固体,71%收率)。
Rf(己烷/MTBE 10:1):0.25;1H-NMR(400MHz,CDCl3):δ7.19(br.s,1H),7.05(br.d,J=7.6,1H),7.01(br.d,J=7.3,1H),6.35(br.s,1H),5.20(br.d,J=9.8,1H),4.65(br.d,J=9.5,1H),3.78(br.s,OMe),2.46(d,J=7.1,CH2),2.02(s,Me),1.85(hept.,J=6.7,1H),0.91(d,J=6.6,CMe2);13C-NMR(100MHz,CDCl3):δ157.78(s),145.72(s),144.22(s),141.08(s),138.60(s),128.84(d),127.47(d),124.15(d),119.62(d),60.41(d),52.44(q),45.34(t),30.38(d),22.35(2q),13.96(q);MS(EI):260(10),259(53),244(5),227(10),216(47),202(29),185(21),184(100),170(14),156(42),142(43),141(96),128(26),115(32)。
步骤2:(5-异丁基-2-甲基-1H-茚-3-基)氨基甲酸甲酯
在50℃下,用2M NaOH水溶液(87ml,0.174mol,0.5eq.)逐滴处理(6-异丁基-2-甲基-1H-茚-1-基)氨基甲酸甲酯(90g,0.347mol)在MeOH(230ml)中的溶液,同时将反应温度升至回流温度以允许搅拌。将所得混合物在回流下搅拌2小时,冷却,用冰(100g)处理,并用MTBE(1升)萃取。将有机相用饱和NH4Cl水溶液(100ml)洗涤,用饱和NaCl水溶液(100ml)洗涤两次,用MgSO4干燥,过滤,并蒸发溶剂。将粗产物(85.5g,棕色固体)用己烷(300ml)研磨,过滤,用己烷(150ml)洗涤,并干燥,得到(5-异丁基-2-甲基-1H-茚-3-基)氨基甲酸甲酯(74.5g,89%纯度,略带棕色固体,74%收率)。
Rf(己烷/MTBE 10:1):0.13;1H-NMR(400MHz,CDCl3):δ7.23(br.d,J=7.3,1H),6.96(br.s,1H),6.92(br.dd,J=1.4,7.5,1H),6.13(br.s,1H),3.76(br.s,OMe),3.27(br.s,CH2),2.49(d,J=7.1,CH2),2.04(s,Me),1.86(hept.,J=6.7,1H),0.90(d,J=6.6,CMe2);13C-NMR(100MHz,CDCl3):δ157.07(br.s),142.57(s),139.73(s),138.22(s),135.65(br.s),131.00(br.s),125.38(d),122.99(d),118.20(br.d),52.54(q),45.53(t),40.27(t),30.42(d),22.37(2q),13.77(br.q)。
MS(EI):260(6),259(34),244(4),227(25),216(29),202(18),185(17),184(100),170(23),156(29),142(28),141(56),128(20),115(22)。
步骤3:6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮
将(5-异丁基-2-甲基-1H-茚-3-基)氨基甲酸甲酯(73g,0.28mol)在甲醇(70ml)和35%硫酸水溶液(87g,0.31mol,1.1eq.)中的悬浮液在回流(80℃)下加热1小时,冷却,并用MTBE(100ml)萃取。将有机相用2M HCl水溶液洗涤,并将合并的水相用MTBE(70ml)萃取两次。将合并的有机相用饱和NaHCO3水溶液(100ml)洗涤,用饱和NaCl水溶液(100ml)洗涤,过滤,并将滤液用MgSO4干燥,过滤,并蒸发溶剂。将粗产物(53g)用短程Vigreux蒸馏装置(0.1mbar,油浴温度:155至175℃,蒸馏头温度98-115℃)蒸馏,得到6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮(49.5g,99.6%纯度,黄色油状物,87%收率)。
Rf(己烷/MTBE 10:1):0.48;1H-NMR(400MHz,CDCl3):δ7.53(br.s,1H),7.38(dd,J=1.5,7.8,1H),7.34(br.dm,J=0.7,7.8,1H),3.35(m,1H),2.75-2.64(m,2H),2.52(d,J=7.1,CH2),1.87(hept.,J=6.7,1H),1.30(d,J=7.6,Me),0.90(d,J=6.6,CMe2);13C-NMR(100MHz,CDCl3):δ209.5(s),151.0(s),141.0(s),136.3(s),135.9(d),126.0(d),123.9(d),44.8(t),42.2(d),34.5(t),30.1(d),22.2(2q),16.2(q);MS(EI):203(5),202(34),187(8),160(71),159(100),145(26),141(6),131(14),129(11),128(14),116(12),115(27),91(13),77(6)。
经过3个步骤的收率:46%
实施例2a:6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮的制备━使用氨基甲酸甲酯(MeOCONH2)的一锅法合成
将(E)-3-(4-异丁基苯基)-2-甲基丙烯醛(脱氢银醛,5g,24.7mmol,1-2%(Z)-异构体)和氨基甲酸甲酯(2g,26mmol,1.05eq.)在甲苯(20ml)中的混合物用三氯化铁(0.4g,2.47mmol,0.1eq.)处理,并在回流温度下加热30min。然后将反应混合物冷却至45℃,用2NNaOH水溶液(11ml)和甲醇(5ml)处理,并在回流温度下搅拌21小时。将所得混合物冷却至55℃,用浓H2SO4(1.85g)处理,在回流温度下搅拌10小时,并冷却至20℃。将水相分离并将有机相用MTBE(25ml)稀释,并用2N HCl水溶液洗涤。将合并的水相用MTBE(10ml)萃取两次,并将合并的有机相用饱和NaHCO3水溶液(10ml)洗涤,用饱和NaCl水溶液(10ml)洗涤两次,用MgSO4干燥,过滤,并蒸发溶剂。将粗产物(5.6g,棕色油状物)使用库格尔若(Kugelrohr)装置(150-200℃,0.08-0.1mbar)蒸馏,得到如实施例1中所表征的6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮(3.97g,93%纯度,黄色油状物,74%收率)。
实施例2b:可替代地,可以应用以下条件:
将(E)-3-(4-异丁基苯基)-2-甲基丙烯醛(脱氢银醛,20g,99mmol,1-2%(Z)-异构体)、三氯化铁(2.455g,14.8mmol,0.15eq.)和甲苯(8ml)的混合物加温至73-75℃并用氨基甲酸甲酯(7.5g,99mmol,1.0eq.)在甲苯(22ml)中的温热溶液(40℃)逐滴处理(25min)。将所得混合物在75℃下加热80min,首先用甲醇(15ml),然后用32%NaOH水溶液(18.54g,1.5eq.)逐滴处理,并在回流温度(60℃)下搅拌30min。将所得混合物用浓H2SO4(17.35g,1.7eq.)处理,在回流温度(60℃)下搅拌30min,冷却至20℃,用己烷(40ml)和2M HCl水溶液(60ml)处理。将水相分离并将有机相用MTBE(25ml)稀释,并用2N HCl水溶液洗涤。将合并的水相用己烷(25ml)萃取三次,并将合并的有机相用饱和NaHCO3水溶液(50ml)洗涤,用饱和NaCl水溶液(50ml)洗涤两次,用MgSO4干燥,过滤,并蒸发溶剂。将粗产物(20.1g,棕色油状物)使用短程蒸馏装置(120-180℃,0.08mbar)蒸馏,得到6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮(16.2g,95%纯度,黄色油状物,77%收率)。
实施例3:6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮的制备━使用氨基甲酸乙酯(EtOCONH2)的一锅法合成
将(E)-3-(4-异丁基苯基)-2-甲基丙烯醛(脱氢银醛,3g,14.8mmol,1-2%(Z)-异构体)和氨基甲酸乙酯(1.3g,14.8mmol,1eq.)在甲苯(30ml)中的混合物用三氯化铁(360mg,2.2mmol,0.15eq.)处理,并在回流温度下加热50min。然后将反应混合物冷却至10℃,用2N NaOH水溶液(10ml)和甲醇(11ml)处理,并在回流温度下搅拌4小时。将所得混合物冷却至15℃,用浓HCl(2.5ml)处理,在回流温度下搅拌13小时,冷却,并倒入冰中。将水相分离并用MTBE萃取三次。将合并的有机相用饱和NaHCO3水溶液洗涤,用饱和NaCl水溶液洗涤两次,用MgSO4干燥,过滤,并蒸发溶剂。将粗产物(3.94g,棕色油)使用库格尔若装置(170-190℃,0.1mbar)蒸馏,得到如在实施例1中所表征的6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮(3g,84%纯度,黄色油状物,84%收率)。
中间体1((6-异丁基-2-甲基-1H-茚-1-基)氨基甲酸乙酯):
1H-NMR(400MHz,CDCl3):δ7.18(br.s,1H),7.02(br.d,J=7.6,1H),6.97(br.d,J=7.6,1H),6.33(br.m,1H),5.18(br.d,J=9.8,1H),4.69(br.d,J=9.8,1H),4.20(q,J=7.1,OCH2),2.44(d,J=7.3,CH2),1.99(s,Me),1.83(hept.,J=6.7,1H),1.27(d,J=7.1,Me)。0.89(d,J=6.6,CMe2);13C-NMR(100MHz,CDCl3):δ157.4(s),145.8(s),144.3(s),141.0(s),138.4(s),128.7(d),124.1(d),119.5(br.d),61.1(t),60.3(d),45.3(t),30.3(d),22.3(2q),14.5(q),13.9(br.q);MS(EI):274(10),273(52),258(2),244(13),230(22),227(15),216(10),200(16),185(23),184(100),170(16),156(35),142(41),141(77),128(26),115(30)。
中间体2((5-异丁基-2-甲基-1H-茚-3-基)氨基甲酸乙酯):
1H-NMR(400MHz,CDCl3):δ7.25(br.d,J=7.3,1H),6.99(br.s,1H),6.94(br.dd,J=1.3,7.5,1H),6.22(br.s,1H),4.23(q,J=7.1,14.2,O CH2),3.29(br.s,CH2),2.51(d,J=7.1,CH2),2.06(s,Me),1.88(hept.,J=6.7,1H),1.23(t,J=7.0,Me)。0.92(d,J=6.6,CMe2);13C-NMR(100MHz,CDCl3):δ157.5(br.s),142.7(s),139.8(s),138.3(s),135.4(br.s),131.1(br.s),125.4(d),123.0(d),118.3(br.d),61.4(br.t),45.6(t),40.3(t),30.5(d),22.4(2q),14.6(q),13.9(br.q);MS(EI):274(5),273(27),244(7),230(9),227(34),216(4),200(9),185(18),184(100),170(24),156(20),142(20),141(37),128(17),115(17)。
实施例4:6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮的制备━使用甲磺酰胺(MeSO2NH2)的一锅法锅合成
将(E)-3-(4-异丁基苯基)-2-甲基丙烯醛(脱氢银醛,50g,247mmol,1-2%(Z)-异构体)和甲磺酰胺(25.2g,260mmol,1.05eq.)在甲苯(300ml)中的混合物用三氯化铁(4.13g,24.7mmol,0.1eq.)处理,并在回流温度(98℃)下加热4小时。然后将反应混合物冷却至25℃,用甲醇(50ml)和2N NaOH水溶液(144ml)处理,并搅拌2.5小时。将所得混合物用浓HCl(53ml)逐滴处理,在回流温度下搅拌24小时,冷却,并倒入冰中。将水相分离并用MTBE萃取三次。将合并的有机相用饱和NaHCO3水溶液洗涤,用饱和NaCl水溶液洗涤两次,用MgSO4干燥,过滤,并蒸发溶剂。将粗产物(57g,棕色油状物)使用短程Vigreux蒸馏装置(蒸馏头温度100℃,0.06mbar)蒸馏(油浴温度120-130℃),得到如实施例1中所表征的6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮(36.1g,85%纯度,黄色油状物,61%收率)。
中间体1(N-(6-异丁基-2-甲基-1H-茚-1-基)甲磺酰胺):
1H-NMR(400MHz,CDCl3):δ7.24(br.s,1H),7.01(br.d,J=7.3,1H),6.98(br.dd,J=1.2,7.6,1H),6.34(br.m,1H),4.73(br.d,J=9.8,1H),4.50(br.d,J=9.8,1H),3.10(s,SO2Me),2.45(d,J=7.1,CH2),2.05-2.04(2d,J=1.0,Me),1.84(hept.,J=6.7,1H),0.90(d,J=6.6,Me),0.89(d,J=6.6,Me);13C-NMR(100MHz,CDCl3):δ144.4(s),143.6(s),140.6(s),138.9(s),129.2(d),127.9(d),124.3(d),119.9(d),62.5(d),45.3(t),42.4(q),30.3(d),22.3(2q),14.0(q);MS(EI):279(20),264(1),236(2),200(89),199(17),184(7),172(9),157(33),156(100),142(24),141(24),130(18),128(21),115(20)。
中间体2(N-(5-异丁基-2-甲基-1H-茚-3-基)甲磺酰胺):
1H-NMR(400MHz,CDCl3):δ7.25(br.dm,J=7.8,1H),7.15(br.s,1H),6.96(br.dd,J=1.5,7.6,1H),6.42(br.s,1H),3.32(br.s,CH2),2.99(s,SO2Me),2.51(d,J=7.1,CH2),2.18(s,Me),1.86(hept.,J=6.7,1H),0.90(d,J=6.6,CMe2);13C-NMR(100MHz,CDCl3):δ142.2(s),142.0(s),140.1(s),138.1(s),130.2(s),125.9(d),123.3(d),118.4(d),45.4(t),40.5(q),40.5(t),30.4(d),22.3(2q),14.0(q);MS(EI):279(24),264(1),237(4),236(4),200(100),172(13),158(40),156(50),142(27),130(35),116(15),115(20)。
实施例5:6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮的制备━使用乙酰胺(MeCONH2)的一锅法合成
将(E)-3-(4-异丁基苯基)-2-甲基丙烯醛(脱氢银醛,1g,4.94mmol,1-2%(Z)-异构体)和乙酰胺(0.32g,5.42mmol,1.1eq.)在甲苯(10ml)中的混合物用三氯化铁(180mg,1.1mmol,0.2eq.)处理,并在回流温度(104℃)下加热24小时。然后将反应混合物冷却至10℃,用2N NaOH水溶液(3ml)处理,并在20℃下搅拌2小时并在回流温度下搅拌2.5小时。将所得混合物用浓HCl(1ml)处理,在回流温度下搅拌15小时,冷却,并倒入冰中。将水相分离并用MTBE萃取两次。将合并的有机相用饱和NaHCO3水溶液洗涤,用饱和NaCl水溶液洗涤两次,用MgSO4干燥,过滤,并蒸发溶剂。将粗产物(1.1g,棕色油)使用库格尔若装置(170-190℃,0.1mbar)蒸馏,得到如在实施例1中所表征的6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮(0.93g,84%纯度,黄色油状物,65%收率)。
实施例6:6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮的制备━使用乙酰胺(MeCONH2)的逐步合成
步骤1:N-(6-异丁基-2-甲基-1H-茚-1-基)乙酰胺
将乙酰胺(1.6g,27.1mmol,1.1eq。)和(E)-3-(4-异丁基苯基)-2-甲基丙烯醛(脱氢银醛,5g,24.7mmol,1-2%(Z)-异构体)在甲苯(50ml)中的混合物加热至50℃,并将所得溶液用三氯化铁(0.80g,4.94mmol,0.2eq.)处理。将所得混合物加热至回流(100℃),搅拌20小时,冷却至60℃,用EtOAc(20ml)处理,并用1N HCl水溶液(10毫升)洗涤。将有机相用饱和NaHCO3水溶液(10ml)洗涤,用饱和NaCl水溶液(10ml)洗涤三次,并将最终的有机相(悬浮液)过滤,并将固体用EtOAc洗涤并干燥,得到纯的N-(6-异丁基-2-甲基-1H-茚-1-基)乙酰胺(1.86g,31%收率),为浅棕色固体。将滤液用MgSO4干燥,过滤,并蒸发溶剂。将粗产物(3.26g,棕色固体)用己烷(20ml)研磨,冷却至5℃,过滤,用冷己烷(10ml)洗涤,并干燥,得到另外的N-(6-异丁基-2-甲基-1H-茚-1-基)乙酰胺(2.58g,100%纯度,43%收率;总收率:74%),为浅棕色固体。
Rf(己烷/MTBE 11:1):0.33;1H-NMR(400MHz,CDCl3):δ7.14(br.s,1H),7.05(br.d,J=7.5,1H),6.98(br.d,J=7.5,1H),6.37(br.s,1H),5.53(br.d,J=9.3,1H),5.48(br.d,J=9.4,1H),2.47(d,J=7.1,CH2),2.08(s,Me),1.97(br.s,COMe),1.83(hept.,J=6.7,1H),0.89(d,J=6.6,CMe2);13C-NMR(100MHz,CDCl3):δ170.71(s),145.69(s),144.35(s),141.45(s),138.63(s),128.83(d),127.81(d),124.21(d),119.68(d),58.63(d),45.36(t),30.41(d),23.41(q),22.38(2q),14.09(q);MS(EI):244(5),243(30),201(8),200(10),186(14),185(17),184(100),158(31),144(47),143(30),142(26),141(73),128(16),115(21),43(49)。
步骤2:N-(5-异丁基-2-甲基-1H-茚-3-基)乙酰胺
在20℃下,将N-(6-异丁基-2-甲基-1H-茚-1-基)乙酰胺(2g,8.22mmol)在MeOH(20ml)中的悬浮液用2M NaOH水溶液(2ml,4.0mmol,0.49eq.)逐滴处理,并将所得悬浮液加热至回流。将所得溶液在回流下搅拌1小时,冷却,用水(5ml)处理,并用MTBE(20ml)萃取。将有机相用饱和NH4Cl水溶液(10ml)洗涤,用饱和NaCl水溶液(10ml)洗涤,用MgSO4干燥,过滤,并蒸发溶剂。将粗产物(2g,棕色固体)用己烷(20ml)研磨,冷却至5℃,过滤,用冷己烷(10ml)洗涤,并干燥,得到N-(5-异丁基-2-甲基)-1H-茚-3-基)乙酰胺(1.73g,100%纯度,87%收率),为浅棕色固体。
Rf(己烷/MTBE 1:1):0.12;1H-NMR(400MHz,CDCl3):δ(主要旋转异构体,60%)7.23(br.d,J=8.0,1H),6.99(br.d,J=8.0,1H),6.94-6.90(m,1H),6.78-6.66(br.s,1H),3.30(br.s,CH2),2.49(d,J=7.3,CH2),2.24(s,Me),2.03(br.s,COMe),1.86(hept.,J=6.7,1H),0.896(d,J=6.6,CMe2)。δ(次要旋转异构体,40%)7.29(br.d,J=7.3,1H),6.94-6.90(m,2H),6.57-6.47(br.s,1H),3.34(br.s,CH2),2.51(d,J=7.3,CH2),2.09(br.s,COMe),1.92(s,Me),1.86(hept.,J=6.7,1H),0.901(d,J=6.6,CMe2);13C-NMR(100MHz,CDCl3):δ(主要旋转异构体,60%)168.48(s),142.48(s),139.78(s),138.42(s),136.76(s),131.37(s),125.46(d),123.07(d),118.27(d),45.60(t),40.48(t),30.48(d),23.54(q),22.44(2q),14.19(q)。δ(次要旋转异构体,40%)173.34(s),142.80(s),140.44(s),139.86(s),136.03(s),133.13(s),126.03(d),123.41(d),118.43(d),45.48(t),40.23(t),30.48(d),22.37(2q),20.23(q),13.55(q);MS(EI):244(6),243(36),201(8),200(16),186(21),185(15),184(100),158(38),144(60),143(41),142(24),141(49),128(16),115(17),43(59)。
步骤3:6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮
将N-(5-异丁基-2-甲基-1H-茚-3-基)乙酰胺(1.4g,5.75mmol)在甲醇(14ml)和35%硫酸水溶液(1.72ml,6.33mmol,1.1eq.)中的悬浮液在回流(65℃)下加热5小时,冷却,用MTBE(20ml)稀释,并用水(5ml)洗涤。将有机相用2M HCl水溶液洗涤,并将合并的水相用MTBE(20ml)萃取两次。将合并的有机相用饱和NaHCO3水溶液(10ml)洗涤,用饱和NaCl水溶液(10ml)洗涤,用MgSO4干燥,过滤,并蒸发溶剂。将粗产物(1.17g,棕色油状物)使用库格尔若蒸馏装置(0.09mbar,100-150℃)蒸馏,得到如实施例1中所表征的6-异丁基-2-甲基-2,3-二氢-1H-茚-1-酮(1.03g,100%纯度,89%收率),为浅黄色油状物。
经过3个步骤的收率:57%
实施例7:6-溴-2-甲基-2,3-二氢-1H-茚-1-酮的制备━使用甲磺酰胺(MeSO2NH2)的一锅法合成
向(E)-3-(4-溴苯基)-2-甲基丙烯醛(50.0g,222mmol,在NaOH存在下,在EtOH和水中,根据Unterhalt,B.;Eljabour,S.Archiv Pharmazie 1986,319,666-71,由对溴苯甲醛和丙醛制备)在甲苯(200ml)中的溶液中添加甲磺酰胺(25.4g,267mmol,1.2eq.)和氯化铁(III)(7.21g,44.4mmol,0.2eq.)。搅拌混合物并加热至95℃保持16小时。在起始醛完全耗尽后,将反应冷却,用甲醇(200ml)和氢氧化钠(22.21g,555mmol,2.5eq.)在水(70ml)中的溶液处理,并在室温下搅拌2小时。然后将所得混合物用甲醇(200ml)和逐滴加入的浓HCl(54.7ml,37%,666mmol,3.0eq.)处理,加热至85℃,并搅拌过夜。冷却后,加入水(200ml),并将溶液用MTBE(150ml)萃取三次。将合并的有机层用盐水洗涤,用MgSO4干燥,过滤并浓缩。残余物经快速色谱法(硅胶,己烷/MTBE 50:1)得到浅黄色固体(23g),将其蒸馏(球-球(bulb-to-bulb)蒸馏装置,150℃,0.08mbar),得到6-溴-2-甲基-2,3-二氢-1H-茚-1-酮(20g,96%纯度,38%收率),为浅黄色固体。
Rf(己烷/MTBE 10:1):0.3;1H-NMR(300MHz,CDCl3):δ7.86(br.s,1H),7.67(dd,J=8.1,1.7,1H),7.34(br.d,J=8.1,1H),3.35(dd,J=17.2,7.7,1H),2.83-2.62(m,2H),1.31(d,J=7.4,Me);13C-NMR(75MHz,CDCl3):δ207.7(s),151.9(s),138.1(s),137.3(d),128.2(d),126.8(d),121.5(s),42.4(d),34.6(t),16.1(q);MS(EI):226(68),224(70),211(97),209(100),198(10),196(11),183(10),181(8),170(4),156(3),145(21),128(4),115(68),102(22),89(20),75(12),63(15)。
实施例8:4-溴-2-甲基-2,3-二氢-1H-茚-1-酮的制备━使用甲磺酰胺(MeSO2NH2)的一锅法合成
向(E)-3-(2-溴苯基)-2-甲基丙烯醛(70.0g,80%纯度,249mmol,由邻溴苯甲醛和丙醛在NaOH的存在下在MeOH和水中根据Li,W.-D.Z.;Duo,W.-G;Zhuang,C.-H.Org.Lett.2011,13,3538-41制备)在甲苯(200ml)中的溶液中添加甲磺酰胺(28.4g,299mmol,1.2eq.)和氯化铁(III)(8.07g,49.8mmol,0.2eq.)。将混合物搅拌并加热至65℃保持16小时。在起始醛完全耗尽后,将反应冷却,用甲醇(200ml)和氢氧化钠(24.88g,622mmol,2.5eq.)在水(80ml)中的溶液处理,并在室温下搅拌2小时。然后将所得混合物用甲醇(200ml)和逐滴加入的浓HCl(63ml,37%,746mmol,3.0eq.)处理,加热至85℃,并搅拌过夜。冷却后,加入水(200ml),并将溶液用MTBE(150ml)萃取三次。将合并的有机层用盐水洗涤,用MgSO4干燥,过滤并浓缩。残余物经快速色谱法(硅胶,己烷/MTBE 50:1)得到淡黄色油状物(34g),将其蒸馏(球-球蒸馏装置,130℃,0.11mbar),得到4-溴-2-甲基-2,3-二氢-1H-茚-1-酮(32g,61%收率),为黄色固体。
Rf(己烷/MTBE 10:1):0.3;1H-NMR(300MHz,CDCl3):δ7.75(d,J=7.7,1H),7.70(d,J=7.6,1H),7.28(t,J=7.6,1H),3.35(dd,J=17.5,7.7,1H),2.83-2.67(m,1H),2.66(dd,J=17.6,3.8,1H),1.34(d,J=7.4,Me);13C-NMR(75MHz,CDCl3):δ208.5(s),153.2(s),138.4(s),137.4(d),129.2(d),122.8(d),122.2(s),42.0(d),36.0(t),16.2(q);MS(EI):226(51),224(53),211(97),209(100),198(10),198(4),196(5),183(7),181(6),170(3),168(3),156(1),145(14),128(3),127(3),115(61),102(16),89(18),75(11),63(14)。
实施例9:5-和7-溴-2-甲基-2,3-二氢-1H-茚-1-酮的制备━使用甲磺酰胺(MeSO2NH2)的一锅法合成
与实施例7和8类似,按照以下顺序处理在甲苯(200ml)中的(E)-3-(3-溴苯基)-2-甲基丙烯醛(60.0g,267mmol,以80%收率和98%纯度由间溴苯甲醛和丙醛在NaOH存在下在甲醇和水中制备):首先用甲磺酰胺(30.4g,320mmol,1.2eq.)/氯化铁(III)(8.65g,53.3mmol,0.2eq.)在65℃下处理16小时,然后用在水(70ml)中的甲醇(200ml)/氢氧化钠(26.7g,666mmol,2.5eq.)在室温下处理2h,最后用甲醇(200ml)/浓HCl(24.3ml,37%,800mmol,3.0eq.)在85℃下处理过夜,进行后处理和残余物的快速色谱法(硅胶,己烷/MTBE50:1)后,得到5-和7-溴-2-甲基-2,3-二氢-1H-茚-1-酮(33.3g,57%收率)的85:15混合物,为黄色油状物。蒸馏(球-球蒸馏装置,150℃,0.08mbar)得到5-和7-溴-2-甲基-2,3-二氢-1H-茚-1-酮的85:15混合物(30g,50%收率),为黄色油状物。
Rf(己烷/MTBE 10:1):0.3;1H-NMR(300MHz,CDCl3):δ7.65-7.35(m,3H),3.46-3.28(m,1H),2.83-2.67(m,1H),2.79-2.62(m,2H),1.32(d,J=7.2,0.45H,Me),1.30(d,J=7.2,2.55H,Me);13C-NMR(75MHz,CDCl3):δ(5-溴-异构体)208.0(s),155.0(s),135.2(s),131.0(d),130.0(s),129.8(d),125.2(d),42.0(d),34.6(t),16.2(q);δ(7-溴-异构体)206.2(s),156.1(s),135.1(d),133.6(s),132.4(d),125.6(d),119.7(s),42.7(d),34.1(t),16.3(q);MS(EI):5-溴-异构体:226(50),224(52),211(97),209(100),198(5),196(6),183(9),181(8),170(2),168(3),156(3),154(2),145(16),128(5),127(3),115(50),102(21),89(17),75(12),63(14);7-溴-异构体:226(57),224(59),211(97),209(100),198(10),198(4),196(5),183(6),181(5),170(2),168(2),156(2),145(10),128(3),115(51),102(20),89(16),75(11),63(11)。
实施例10:2-乙基-6-异丁基-2,3-二氢-1H-茚-1-酮的制备━使用甲磺酰胺(MeSO2NH2)的一锅法合成
向(E)-3-(4-异丁基苯基)-2-甲基丙烯醛(5.35g,24.7mmol)在甲苯(50ml)中的溶液中添加甲磺酰胺(2.82g,29.7mmol)和氯化铁(III)(0.80g,4.9mmol)。将混合物搅拌并加热至65℃。在醛完全消耗(通过GC监测)后,将反应冷却至室温。然后加入甲醇(30ml)和氢氧化钠(2.47g,61.8mmol)在水(20ml)中的溶液,将混合物在室温下搅拌2小时。加入另外的甲醇(30ml)和硫酸(3.95mL,74.2mmol),将混合物加热至70℃并搅拌过夜。加入水(100ml),并将溶液用MTBE(100ml×3)萃取。将合并的有机层用盐水洗涤,用MgSO4干燥,过滤并浓缩,得到粗产物。将残余物通过硅胶色谱法(己烷/MTBE=50:1)纯化,得到4.0g产物,为浅黄色油状物。将油状物通过库格尔若装置(0.15mbar,160℃)蒸馏,得到2-乙基-6-异丁基-2,3-二氢-1H-茚-1-酮,为无色油状物(2.60g,48.6%收率)。
1H NMR(300MHz,CDCl3):δ7.52(s,1H),7.34-7.40(m,2H),3.28(dd,J=17.1,7.8Hz,1H),2.78(dd,J=17.1,3.9Hz,1H),2.58-2.65(m,1H),2.52(d,J=7.2Hz,2H),1.80-2.04(m,2H),1.46-1.60(m,1H),1.01(t,J=7.5Hz,3H),0.90(d,J=6.6Hz,6H)ppm;13C NMR(75MHz,CDCl3):δ209.2(s),151.5(s),141.1(s),137.0(s),136.0(d),126.1(d),123.8(d),49.2(d),44.9(t),32.0(t),30.2(d),24.5(t),22.3(2q),11.7(q)ppm;GC/MS(EI):m/z(%):216(7)[M+],188(100),173(33),145(36),131(20),91(7),77(7)。
实施例11:2-异丙基-6-甲基-2,3-二氢-1H-茚-1-酮的制备━使用甲磺酰胺(MeSO2NH2)的一锅法合成
向(E)-3-甲基-2-(4-甲基亚苄基)丁醛(3.00g,15.9mmol)在甲苯(100ml)中的溶液中添加甲磺酰胺(2.27g,23.9mmol)和氯化铁(III)(0.388g,2.39mmol)。将混合物搅拌并加热至80℃。在醛完全消耗(通过TLC监测)后,将反应冷却并加入甲醇(30.0ml)和氢氧化钠(1.27g,31.9mmol)的水(10.0ml)溶液,将混合物在室温下搅拌2小时。加入另外的甲醇(30ml)和氯化氢(3.78ml,39.8mmol),将混合物加热至70℃并搅拌过夜。加入水(200ml),并将溶液用MTBE(150×3ml)萃取。将合并的有机层用盐水洗涤,用MgSO4干燥,过滤并浓缩,得到粗产物。残余物经硅胶色谱法(己烷/MTBE=50:1)纯化,得到0.8g产物,为浅黄色油状物。将油状物通过库格尔若装置(0.12mbar,140℃)蒸馏,得到0.500g产物,为无色油状物(收率26.7%)。
1H NMR(300MHz,CDCl3):δ7.53(s,1H),7.31-7.44(m,2H),3.09(dd,J=17.1,9.0Hz,1H),2.83-2.90(m,1H),2.64-2.68(m,1H),2.36-2.42(m,3H),1.04(d,J=6.9Hz,3H),0.78(d,J=6.6Hz,3H)ppm;13C NMR(75MHz,CDCl3):δ209.0(s),151.6(s),137.8(s),137.1(s),135.8(d),126.2(d),123.5(d),53.4(d),29.1(d),27.8(t),21.0(q),20.9(q),17.3(q)ppm;GC/MS(EI):m/z(%):188(2)[M+],173(3),146(100),131(21),115(12),91(5),77(4)。
实施例12:6-乙基-2-甲基-2,3-二氢-1H-茚-1-酮的制备━使用甲磺酰胺(MeSO2NH2)的一锅法合成
根据实施例11中的通用方法制备,(E)-3-(4-乙基苯基)-2-甲基丙烯醛(5.0g,28.7mmol)、甲磺酰胺(4.09g,43.0mmol)和氯化铁(III)(0.931g,5.74mmol)的反应和随后通过库格尔若装置(150℃/0.12mbar)的蒸馏,得到6-乙基-2-甲基-2,3-二氢-1H-茚-1-酮,为无色油状物(1.30g,26.0%收率)。
1H NMR(300MHz,CDCl3):δ7.58(s,1H),7.34-7.44(m,2H),3.35(dd,J=18.0,8.7Hz,1H),2.65-2.73(m,1H),2.64-2.68(m,4H),1.22-1.31(m,6H)ppm;13C NMR(75MHz,CDCl3):δ209.6(s),151.1(s),143.7(s),136.5(s),135.0(d),126.3(d),122.6(d),42.3(d),34.6(t),28.5(t),16.3(q),15.6(q)ppm;GC/MS(EI):m/z(%):174(60)[M+],159(100),145(23),131(32),115(22),91(13),77(7)。
实施例13:6-(仲丁基)-2-甲基-2,3-二氢-1H-茚-1-酮的制备━使用甲磺酰胺(MeSO2NH2)的一锅法合成
根据实施例11中的通用方法制备,(E)-3-(4-(仲丁基)苯基)-2-甲基丙烯醛(5.00g,14.8mmol)、甲磺酰胺(1.69g,17.8mmol)和氯化铁(III)(0.481g,2.97mmol)的反应和随后通过库格尔若装置(150℃/0.08mbar)的蒸馏,得到6-乙基-2-甲基-2,3-二氢-1H-茚-1-酮,为无色油状物(1.00g,33.3%收率)。
(两种异构体的混合物)1H NMR(300MHz,CDCl3):δ7.59(s,1H),7.38-7.44(m,2H),3.32-3.41(m,1H),2.66-2.73(m,3H),1.58-1.63(m,2H),1.31(d,J=7.2Hz,3H),1.25(d,J=6.9Hz,3H),0.81ppm(t,J=7.2Hz,3H)ppm;13C NMR(75MHz,CDCl3):δ209.8(s),151.3(s),147.2(s),136.5(s),134.4(d),134.3(d),126.3(d),121.9(d),121.9(d),42.4(d),41.4(d),34.6(t),31.1(t),21.9(q),16.3(q),12.2(q)ppm;GC/MS(EI):m/z(%):202(30)[M+],187(5),173(100),159(7),117(27),91(8),77(4)。
实施例14:6-异戊基-2-甲基-2,3-二氢-1H-茚-1-酮的制备━使用甲磺酰胺(MeSO2NH2)的一锅法合成
根据实施例11中的通用方法制备,(E)-3-(4-异戊基苯基)-2-甲基丙烯醛(5.00g,18.5mmol)、甲磺酰胺(2.11g,22.2mmol)和氯化铁(III)(0.600g,3.70mmol)的反应和随后通过库格尔若装置(162℃/0.10mbar)的蒸馏,得到6-异戊基-2-甲基-2,3-二氢-1H-茚-1-酮,为无色油状物(1.30g,32.5%收率)。
1H NMR(300MHz,CDCl3):δ7.57(s,1H),7.32-7.42(m,2H),3.34(dd,J=18.0,8.7Hz,1H),2.62-2.70(m,4H),1.46-1.62(m,3H),1.29(d,J=7.2Hz,3H),0.93(d,J=6.9Hz,6H)ppm;13C NMR(75MHz,CDCl3):δ209.5(s),151.0(s),142.5(s),136.5(s),135.4(q),126.3(q),123.1(q),42.3(d),40.8(t),34.6(t),33.3(t),27.5(d),22.5(2q),16.3(q)ppm;GC/MS(EI):m/z(%):216(80)[M+],201(30),187(1),159(98),132(100),118(55),104(55),91(23),77(8)。
Claims (4)
1.用于制备式(I)的化合物的方法
包括以下步骤:
a)使氨基化合物H2NR加成到式(II)的化合物上
然后环化成式(III)的化合物;
其中波状键表示相邻双键的未指定的构型;和
所述氨基化合物H2NR选自烷基酰胺类、磺酰胺类和氨基甲酸酯类;
b)使式(III)的化合物异构化成式(IV)的化合物;
c)使式(IV)的化合物水解成式(I)的化合物;
其中,在式(I)、(II)、(III)和/或(IV)的化合物中,
R1表示甲基,乙基,乙烯基,直链、支链或环状C3-10烷基或烯基,或苯基,其是任选取代的;且
R2、R3、R4、R5和R6各自独立地表示氢原子,甲基,乙基,乙烯基,甲氧基,乙氧基,乙烯氧基,直链、支链或环状C3-10烷基、烯基或烷氧基,卤原子或苯基,其是任选取代的,和
其中所述方法以一锅法进行。
2.权利要求1的方法,其中所述氨基化合物H2NR是烷基酰胺类,且R表示-(CO)Me或-(CO)Et。
3.权利要求1的方法,其中所述氨基化合物H2NR是磺酰胺,且R表示-SO2Me、-SO2Et或-SO2PhMe。
4.权利要求1的方法,其中所述氨基化合物H2NR是氨基甲酸酯,且R表示-CO2Me、-CO2Et。
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ssembly of indenamine derivatives through in situ formed N-sulfonyliminium ion initiated cyclization;Xiaohui Fan等;《Chem. Commun.》;20140225;第50卷;第4119- 4122页 * |
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