CN108864189A - 亚磺酰胺类手性单膦配体及其制备方法和应用 - Google Patents
亚磺酰胺类手性单膦配体及其制备方法和应用 Download PDFInfo
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- CN108864189A CN108864189A CN201810707194.7A CN201810707194A CN108864189A CN 108864189 A CN108864189 A CN 108864189A CN 201810707194 A CN201810707194 A CN 201810707194A CN 108864189 A CN108864189 A CN 108864189A
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- alkyl
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- chiral
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- 239000003446 ligand Substances 0.000 title claims abstract description 60
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims description 9
- PIZNQHDTOZMVBH-UHFFFAOYSA-N thionylimide Chemical class N=S=O PIZNQHDTOZMVBH-UHFFFAOYSA-N 0.000 title abstract description 3
- -1 halogenated aryl allyl ether Chemical compound 0.000 claims abstract description 37
- 230000009467 reduction Effects 0.000 claims abstract description 16
- 238000007341 Heck reaction Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- 238000007259 addition reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 230000015572 biosynthetic process Effects 0.000 claims description 20
- 238000003786 synthesis reaction Methods 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 229910052723 transition metal Inorganic materials 0.000 claims description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 9
- 239000003638 chemical reducing agent Chemical group 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000012298 atmosphere Substances 0.000 claims description 5
- 229910000085 borane Inorganic materials 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 4
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- 150000004696 coordination complex Chemical class 0.000 claims description 4
- 239000012973 diazabicyclooctane Substances 0.000 claims description 4
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 claims description 4
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 3
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 3
- QAZLUNIWYYOJPC-UHFFFAOYSA-M sulfenamide Chemical compound [Cl-].COC1=C(C)C=[N+]2C3=NC4=CC=C(OC)C=C4N3SCC2=C1C QAZLUNIWYYOJPC-UHFFFAOYSA-M 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- FJLUATLTXUNBOT-UHFFFAOYSA-N 1-Hexadecylamine Chemical compound CCCCCCCCCCCCCCCCN FJLUATLTXUNBOT-UHFFFAOYSA-N 0.000 claims description 2
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 claims description 2
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical class C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 claims description 2
- LTHNHFOGQMKPOV-UHFFFAOYSA-N 2-ethylhexan-1-amine Chemical compound CCCCC(CC)CN LTHNHFOGQMKPOV-UHFFFAOYSA-N 0.000 claims description 2
- JOZZAIIGWFLONA-UHFFFAOYSA-N 3-methylbutan-2-amine Chemical compound CC(C)C(C)N JOZZAIIGWFLONA-UHFFFAOYSA-N 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 2
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims description 2
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 claims description 2
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 claims description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 2
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 2
- RBYGDVHOECIAFC-UHFFFAOYSA-L acetonitrile;palladium(2+);dichloride Chemical compound [Cl-].[Cl-].[Pd+2].CC#N.CC#N RBYGDVHOECIAFC-UHFFFAOYSA-L 0.000 claims description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N allylamine Natural products NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 claims description 2
- WXNOJTUTEXAZLD-UHFFFAOYSA-L benzonitrile;dichloropalladium Chemical compound Cl[Pd]Cl.N#CC1=CC=CC=C1.N#CC1=CC=CC=C1 WXNOJTUTEXAZLD-UHFFFAOYSA-L 0.000 claims description 2
- 230000000903 blocking effect Effects 0.000 claims description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- YQLZOAVZWJBZSY-UHFFFAOYSA-N decane-1,10-diamine Chemical compound NCCCCCCCCCCN YQLZOAVZWJBZSY-UHFFFAOYSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 claims description 2
- JRBPAEWTRLWTQC-UHFFFAOYSA-N dodecylamine Chemical compound CCCCCCCCCCCCN JRBPAEWTRLWTQC-UHFFFAOYSA-N 0.000 claims description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 claims description 2
- HKUFIYBZNQSHQS-UHFFFAOYSA-N n-octadecyloctadecan-1-amine Chemical compound CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC HKUFIYBZNQSHQS-UHFFFAOYSA-N 0.000 claims description 2
- QNIVIMYXGGFTAK-UHFFFAOYSA-N octodrine Chemical compound CC(C)CCCC(C)N QNIVIMYXGGFTAK-UHFFFAOYSA-N 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- AOHJOMMDDJHIJH-UHFFFAOYSA-N propylenediamine Chemical compound CC(N)CN AOHJOMMDDJHIJH-UHFFFAOYSA-N 0.000 claims description 2
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims 2
- OBNDGIHQAIXEAO-UHFFFAOYSA-N [O].[Si] Chemical compound [O].[Si] OBNDGIHQAIXEAO-UHFFFAOYSA-N 0.000 claims 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 2
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 claims 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 229910052786 argon Inorganic materials 0.000 claims 1
- 230000008859 change Effects 0.000 claims 1
- 150000002240 furans Chemical class 0.000 claims 1
- 239000007789 gas Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 10
- 238000006555 catalytic reaction Methods 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 7
- 230000009257 reactivity Effects 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 78
- 230000005311 nuclear magnetism Effects 0.000 description 31
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 28
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 14
- 238000001228 spectrum Methods 0.000 description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 238000004949 mass spectrometry Methods 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- 150000003003 phosphines Chemical class 0.000 description 5
- 0 C*S(N1C(*)C(CCCCC2)C2*(*)*(C)C1)O Chemical compound C*S(N1C(*)C(CCCCC2)C2*(*)*(C)C1)O 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- WQONPSCCEXUXTQ-UHFFFAOYSA-N 1,2-dibromobenzene Chemical compound BrC1=CC=CC=C1Br WQONPSCCEXUXTQ-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
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- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
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Abstract
本发明公开了一类亚磺酰胺类手性单膦配体,所述手性单膦配体为(式1)所示化合物本发明还公开了该类配体的合成方法,所述方法包括:以(式2)R1R2PH·BH3、(式3)(式4)和(式5)R5X为原料,进行取代反应、加成反应“一锅法”制备所述配体。该配体(式1)的对映异构可以通过使用(式4)的对映异构体实现。本发明通过使用两种构型的手性亚磺酰亚胺“一锅法”可得到所述两种光学纯的手性单膦配体(S,Rs)和(R,Ss)。本发明还公开了所述配体在催化邻卤代芳基烯丙基醚分子内不对称还原Heck反应中的应用,具有很高的反应活性和立体选择性,具有广泛的应用价值。
Description
技术领域
本发明属于有机化学技术领域,涉及新型亚磺酰胺类手性单膦配体及其制备方法和应用,具体涉及一类新型的手性单膦配体及其制备方法和应用。
背景技术
手性在自然界中广泛存在,是自然界的基本属性之一。在生物体内,蛋白质、核苷酸、糖等生物分子绝大多数都是手性分子。手性物质就如同人们的左右手一样,两个对映异构体互为镜像却不能完全重合。看似相近的两个对映体却往往具有不同的光学性质、物理化学性质以及不同甚至截然相反的生物活性,如手性乙胺丁醇。它的(S,S)构型异构体可以治疗结核病,而(R,R)构型异构体却可以致盲。可见,合成光学纯的分子不仅是化学界的挑战,对于人类医药健康、生物、材料和环境等方面也有极其重要的意义。手性化合物的获得方法主要有以下几种:天然产物的分离、底物或手性试剂的诱导、外消旋化合物的拆分以及不对称催化。不对称催化合成无论是从经济适用性还是环境保护性方面考虑,都具有较大的优势,数十年来一直是研究的热点和前沿。在2001年,诺贝尔化学奖被授予Knowles、Noyori和Sharpless三位化学家,以表彰他们在不对称催化研究领域做出的杰出贡献。
不对称催化的核心问题是设计合成具有高效、高活性以及高选择性的催化剂,而手性配体是手性催化剂产生不对称诱导的源泉。迄今为止,膦配体是研究最多、应用最广泛的配体,现已陆续合成出几千个手性膦配体,以BINAP为代表的手性膦配体的成功,极大地推动了手性膦配体的研究与应用。然而,原料昂贵、合成路线长、产率低、改造难等难题很大程度上制约着手性膦配体的发展。寻找一种原料低廉、环境友好、易于改造、便于高效合成的手性配体的体系具有非常好的应用前景。目前,本课题组先后开发了Ming-Phos(Angew.Chem.Int.Ed.2014,53,4350;Angew.Chem.,Int.Ed.2016,55,6324;ACSCatal.2015,5,7488;ACS Catal.2017,7,210)、Xiao-Phos(Angew.Chem.Int.Ed.2015,54,6874)、Wei-Phos(Angew.Chem.Int.Ed.2015,54,14853)、Peng-Phos(Angew.Chem.Int.Ed.2016,55,13316)和PC-Phos(Angew.Chem.,Int.Ed.2017,56,15905;J.Am.Chem.Soc.2018,140,3467)等多种新型手性单膦配体(催化剂)。本课题组一直致力于原料低廉、环境友好、易于改造、便于高效合成的手性单膦配体的开发。
发明内容
本发明的目的是提供一类亚磺酰胺手性单膦配体及制备方法和应用,通过“一锅法”即可高效、高选择性及低成本的制备所述手性单膦配体。
本发明提供的一类亚磺酰胺手性单膦配体,为如下(式1)的化合物:
上述(式1)中:
(式1)中,Ar选自R1、R2、R4分别独立选自C1~C12的烷烃基、C1~C10的烷氧基、R3选自C1~C12的烷烃基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基、 ORw或SRw;R5选自氢、C1~C12的烷烃基、其中,Rx和Rx′分别独立选自氢、卤素、C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基;Ry、Ry′、Ry″、Rz、Rz′和Rw分别独立选自C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基;n选自1~5的整数。
作为一种优选方案,上述式(1)中的Ar选自R1、R2同时选自C1~C12的烷烃基、R3选自C1~C12的烷烃基、C1~C10的硅氧基、C1~C10的酯基或R4选自C1~C12的烷烃基、R5选自氢、C1~C12的烷烃基、其中Rx和Rx′分别独立选自氢、卤素、C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基。
作为一种优选方案,上述(式1)中的Ar选自苯基;R1、R2同时选自C1~C12的烷烃基、R3选自C1~C12的烷烃基或R4选自叔丁基;R5选自甲基。其中Rx和Rx′分别独立选自氢、C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基。
作为进一步优选方案,上述(式1)中的R1、R2同时选自C1~C12的烷烃基、作为进一步优选方案,上述(式1)中的Ar选自作为更进一步优选方案,所述手性单膦配体选自如下化合物:
其中:Cy为环己基;Ph为苯基;Me为甲基。
本发明还提供了(式1)手性单膦配体的制备方法,采取如下方案:
在溶剂中,一定温度下,第一步:将(式2)R1R2PH·BH3在BuLi作用下与(式3)进行反应,生成中间体第二步:然后中间体和(式4)进行加成反应,得到中间体第三步:再然后中间体和(式5)R5X进行取代反应,得到中间体第四步:再在有机胺的作用下,脱去硼烷保护基团,得到手性单膦配体(S,Rs),反应过程如下反应式(I)所示:
其中,各基团的定义如上(式1)所述;优选地,Ar、R1、R2、R3、R4的含义同上(式1)所述,X为卤素。
其中,所述溶剂选自干燥的二氯甲烷、乙醚、二丁醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、甲苯、二甲苯、苯、氯苯、氟苯、氯仿、正己烷;优选地,为干燥的四氢呋喃。
其中,所述第一步和第二步反应的温度为-78℃~30℃;优选地,为-78℃~-50℃。
其中,所述第一步、第二步、第三步反应的时间为10分钟~10小时;优选地,为1~2小时。
其中,所述第三步反应的温度为-78℃~30℃;优选地,为-20℃~20℃。
其中,所述第四步反应的温度为-10℃~130℃;优选地,为40℃~90℃。
其中,所述第四步反应的时间为10分钟~30小时;优选地,为2~10小时。
其中,所述BuLi的作用为和卤素X进行交换、进行取代反应;所述BuLi包括n-BuLi、s-BuLi、t-BuLi。
其中,所述第四步有机胺选自Et3N、DBU、DABCO、甲胺、一丙胺、2-丙烯胺、叔丁胺、癸胺、二甲胺、二丙胺、环丙胺、二异丁胺、十二胺、三甲胺、三丙胺、正丁胺、己胺、十六胺、一乙胺、异丙胺、二正丁胺、2-乙基己胺、十八胺、二乙胺、二异丙胺、异丁胺、己二胺、二硬脂胺、三乙胺、1,2-二甲基丙胺、仲丁胺、三辛胺、1,5-二甲基己胺、乙二胺、1,2-丙二胺、1,4-丁二胺、1,10-癸二胺。
其中,所述第一步、第二步、第三步和第四步反应中,(式2)、(式3)、BuLi、(式4)、(式5)和有机胺的摩尔比为(1~10)∶(1~10)∶(1~10)∶(1~10)∶(1~100)∶(5~100);优选地,为1∶1∶2∶3∶5∶15。
本发明还提供了所述手性单膦配体用于邻卤代芳基烯丙基醚分子内不对称还原Heck反应中的应用,所述手性单膦配体具有如(式1)的化合物。
本发明还提供了所述邻卤代芳基烯丙基醚分子内不对称还原Heck反应合成苯并二氢呋喃类化合物的方法,将如上所述的手性单膦配体与过渡金属盐形成金属配合物溶液,然后在还原剂的作用下催化邻卤代芳基烯丙基醚不对称还原Heck反应,合成所述苯并二氢呋喃化合物。所述手性单膦配体为(式1)的化合物或所述(式1)化合物的对映体。
如上所述的手性单膦配体用于催化邻卤代芳基烯丙基醚分子内不对称还原Heck反应的应用中,以及合成苯并二氢呋喃类化合物的方法中:
作为一种优选方案,首先使所述手性单膦配体与过渡金属盐形成配合物,然后用于催化邻卤代芳基烯丙基醚分子内不对称还原Heck反应。
作为进一步优选方案,所述配合物的制备包括如下步骤:在惰性气氛下,将所述手性单膦配体与过渡金属盐加入到有机溶剂中,在-10~150℃搅拌,反应0.1~20小时,形成配合物溶液,向配合物溶液中加入邻卤代芳基烯丙基醚和还原剂,在-90~190℃条件下进行分子内不对称还原Heck反应,合成所述苯并二氢呋喃类化合物。
作为更进一步优选方案,所述手性单膦配体和过渡金属盐的摩尔比为100∶1,以(1~10)∶1最佳。
作为更进一步优选方案,所述过渡金属盐为Pd盐。
作为更进一步优选方案,所述Pd盐包括Pd(OAc)2、PdCl2、Pd(MeCN)2Cl2、Pd(PPh3)4、Pd(TFA)2、[Pd(ally)Cl]2、Pd(dba)2、Pd2(dba)3、Pd2(dba)3·CHCl3、Pd(PhCN)2Cl2、Pd(OTf)2、Pd(OTs)2、Pd(MeCN)2(BF4)2。
作为更进一步优选方案,所述还原剂选自碱(Et3N、DBU、DABCO、Bn2NH、Bu3N、Pr2NH、K2CO3、Na2CO3、KOH、NaOH、Cs2CO3、Li2CO3、CsOH、LiOH、NaOtBu、KOtBu、LiOtBu)与水、甲醇、乙醇、异丙醇、丁醇或甲酸的混合物。
作为更进一步优选方案,所述惰性气氛为氩气气氛或者氮气气氛;所述有机溶剂选自二氯甲烷、乙醚、二丁醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、甲苯、二甲苯、苯、氯苯、氟苯、氯仿。
将所述配合物用于催化邻卤代芳基烯丙基醚分子内不对称还原Heck反应的操作如下:在惰性气氛下,将所制备的所述配体与钯的配合物溶液加入到邻卤代芳基烯丙基醚和还原剂中,在-90~190℃条件下进行环化反应。
不对称还原Heck反应中,所述邻卤代芳基烯丙基醚、还原剂与所述配体和钯的配合物的摩尔比为(1~10000)∶(1~100000)∶1;优选地,所述邻卤代芳基烯丙基醚、还原剂与所述配体和钯的配合物的摩尔比为(20~100)∶(20~300)∶1。
所述邻卤代芳基烯丙基醚可以是结构如(式6)所示的化合物:
上述(式6)中:R选自氢、卤素、硝基、氰基、炔基、C1~C10的烷烃基、C1~C10的烷氧基、C1~C10的酯基、C1~C10的烷酰基或C1~C10的酰胺基;R1选自C1~C10的烷烃基、C1~C10的烷氧基、C1~C10的烷酰基或C1~C10的酯基、取代苄基;优选地,R选自氢、卤素、硝基、氰基、C1~C5的烷烃基、C1~C5的烷氧基、C1~C10的酯基、C1~C5的酰胺基;R1选自C1~C10的烷烃基、C1~C10的烷氧基、其中,Rx和Rx′分别独立选自氢、卤素、C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基;n选自1~5的整数。
与现有技术相比,本发明具有如下有益效果:(1)本发明提供了一类新型手性单膦配体,首次报道了所述手性单膦配体与过渡金属盐形成配合物用于邻卤代芳基烯丙基醚的不对称还原Heck反应,具有很高的反应活性和立体选择性,可使环化产物:的产率为70%-97%,对映体过量(ee)为88%-95%。(2)本发明提供的手性单膦配体的制备方法,克服了现有技术中合成含膦手性配体时,原料昂贵、合成路线冗长、反应试剂毒性大、对映异构体的合成难度大、产率低等缺陷,本发明通过一锅法即可制备高催化活性的手性膦配体,收率为40%-99%,适合规模化生产,具有非常好的实用价值。
具体实施方式
结合以下具体实施例,对本发明作进一步的详细说明。实施本发明的过程、条件、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。
下述实施例提供了上述手性单膦配体(式1)的具体实施例为:
实施例11a(S,Rs)的合成
在一个250mL的干燥的单支口瓶,在氮气氛围下加入二环己基膦的硼烷络合物(8mmol)和干燥的甲苯与四氢呋喃的混合溶剂(50ml),在-78℃下搅拌10分钟后,滴加正丁基锂(1.0eq.,8mL,1.6M).继续搅拌1.5小时,加入邻二溴苯(8mmol),随后再加入正丁基锂(8mmol,1.6M)。30分钟加入(9.6mmol),然后升至室温,搅拌过夜。之后,再将反应体系中加入三氟甲磺酸甲酯(12mmol)。随后,选干溶剂,加入Et2NH(8mL),50℃搅拌过夜,旋干,柱层析纯化,得产率为50%。氢谱核磁(300MHz,CDCl3)δ7.76-7.72(m,1H),7.49-7.38(m,2H),7.30-7.27(m,1H),7.25-7.15(m,5H),6.87(d,J=10.1Hz,1H),2.57(s,3H),1.91-1.41(m,11H),1.28-0.85(s,20H).膦谱核磁(122MHz,CDCl3)δ-16.88.碳谱核磁(126MHz,CDCl3)δ147.11(d,J=22.1Hz),139.98,134.97(d,J=21.1Hz),133.04(d,J=3.2Hz),130.59,128.71,128.11(d,J=4.9Hz),127.88,127.13,126.54,70.11(d,J=31.9Hz),58.54,34.70(dd,J=12.9,2.2Hz),30.72-29.93(m),29.40(dd,J=17.5,10.0Hz),27.15-26.96(m),26.24(d,J=27.6Hz),24.06.高分辨率质谱理论数据C30H45NOPS:m/z(%):498.2959(M+H+),实验数据:498.2954。
实施例21b(S,Rs)的合成
具体操作参考实施例1,所用原料为产率为55%。氢谱核磁(300MHz,CDCl3)δ7.73-7.69(m,1H),7.48-7.37(m,2H),7.28-7.23(m,1H),7.07-7.01(m,4H),6.82(d,J=10.1Hz,1H),2.56(s,3H),2.27(s,3H),1.91-0.87(m,31H).膦谱核磁(122MHz,CDCl3)δ-16.88.碳谱核磁(126MHz,CDCl3)δ147.37(d,J=22.2Hz),137.02,136.71,134.93(d,J=21.1Hz),132.95(d,J=3.2Hz),130.41,128.65,128.57,128.10(d,J=4.9Hz),126.43,69.79(d,J=31.6Hz),58.49,34.67(dd,J=22.3,13.1Hz),30.63(d,J=18.0Hz),29.98-29.34(m),27.17-26.55(m),26.26(d,J=24.5Hz),24.09,21.00.高分辨率质谱理论数据C30H45NOPS:m/z(%):512.3116(M+H+),实验数据:512.3120。
实施例31c(S,Rs)的合成(参考方案一)
具体操作参考实施例1,所用原料为产率为43%。氢谱核磁(300MHz,CDCl3)δ7.77-7.73(m,1H),7.49-7.40(m,2H),7.31-7.28(m,1H),7.15-7.11(m,2H),6.94-6.83(m,3H),2.56(s,3H),1.89-1.45(m,11H),1.23-0.85(m,20H).膦谱核磁(122MHz,CDCl3)δ-17.02.氟谱核磁(282MHz,CDCl3)δ-115.16(tt,J=8.1,5.0Hz).碳谱核磁(126MHz,CDCl3)δ161.86(d,J=246.5Hz),146.90(d,J=22.1Hz),135.84(d,J=3.3Hz),134.84(d,J=21.4Hz),133.22(d,J=3.3Hz),132.37(d,J=8.1Hz),128.92,127.76(d,J=4.8Hz),126.73,114.70(d,J=21.3Hz),69.58(d,J=32.2Hz),58.62,34.69(dd,J=25.9,12.9Hz),30.53-28.91(m),29.36(dd,J=25.1,9.6Hz),27.03-26.85(m),26.23(d,J=26.4Hz),24.06.高分辨率质谱理论数据C30H45NOPS:m/z(%):516.2865(M+H+),实验数据:516.2860。
实施例41d(S,Rs)的合成
具体操作参考实施例1,所用原料为总产率为56%。氢谱核磁(300MHz,CDCl3)δ8.36(d,J=8.5Hz,1H),8.13-8.09(m,1H),7.82(d,J=8.1Hz,1H),7.70(d,J=8.2Hz,1H),7.65-7.58(m,2H),7.54-7.46(m,3H),7.34-7.29(m,1H),7.25-7.20(m,1H),6.99(d,J=7.2Hz,1H),2.65(s,3H),1.90-1.65(m,5H),1.31-0.45(s,26H).膦谱核磁(122MHz,CDCl3)δ-16.64.碳谱核磁(126MHz,CDCl3)δ147.23(d,J=21.8Hz),135.77,135.54(d,J=21.9Hz),133.81,133.01(d,J=3.0Hz),131.52,130.66,128.74(d,J=4.6Hz),128.64,128.48,128.27,126.43,126.28,125.54,124.58(d,J=1.6Hz),124.39,66.09(d,J=34.6Hz),58.44,34.15(dd,J=49.5,13.6Hz),30.76,30.53-28.91(m),27.03-26.85(m),26.19(d,J=48.8Hz),23.92.高分辨率质谱理论数据C34H47NOPS:m/z(%):548.3110(M+H+),实验数据:548.3114。
实施例51e(S,Rs)的合成
具体操作参考实施例1,所用原料为总产率为58%。氢谱核磁(300MHz,CDCl3)δ7.78-7.74(m,1H),7.45-7.37(m,2H),7.24-7.21(m,1H),7.00(s,2H),6.74(d,J=10.4Hz,1H),3.57(s,3H),2.56(s,3H),1.88-0.78(d,J=88.5Hz,49H).膦谱核磁(122MHz,CDCl3)δ-17.35.碳谱核磁(126MHz,CDCl3)δ158.46,147.29(d,J=22.2Hz),142.42,135.02(d,J=20.6Hz),133.57,133.00(d,J=3.2Hz),129.66,128.58,127.53(d,J=4.9Hz),126.42,70.24(d,J=32.8Hz),64.16,58.35,35.58,35.03(dd,J=13.2,7.9Hz),31.98,30.59(dd,J=17.6,5.1Hzl,30.22,29.48-29.14(m),27.12-26.14(m),24.01.高分辨率质谱理论数据C39H63NO2PS:m/z(%):640.4312(M+H+),实验数据:640.4303。
实施例61f(S,Rs)的合成
具体操作参考实施例1,所用原料为总产率为52%。氢谱核磁(500MHz,CDCl3)δ7.43(dd,J=13.2,7.4Hz,1H),7.36-7.31(m,1H),7.30-7.25(m,1H),4.34(s,1H),2.73(s,3H),1.79-1.71(m,4H),1.69-1.55(m,6H),1.50-1.35(m,15H),1.18(s,9H).膦谱核磁(202MHz,CDCl3)δ-15.62.碳谱核磁(125MHz,CDCl3)δ142.45(d,J=16.2Hz),135.88(d,J=15.3Hz),128.28,127.16,125.81(d,J=21.0Hz),124.55,63.60,58.20(d,J=15.3Hz),33.84,29.17(d,J=11.5Hz),28.38(d,J=22.9Hz),26.53,26.28,21.85,19.43.高分辨率质谱理论数据C25H43NOPS:m/z(%):436.2803(M+H+),实验数据:436.2807。
实施例71g(S,Rs)的合成
具体操作参考实施例1,所用原料为总产率为44%。氢谱核磁(500MHz,CDCl3)δ7.67(d,J=7.5Hz,1H),7.40(dd,J=13.2,7.5Hz,1H),7.34(t,J=7.4Hz,1H),7.26(t,J=7.5Hz,1H),4.06(s,1H),2.71(s,3H),1.90-1.79(m,4H),1.67-1.40(m,18H),1.31(s,9H),1.02(s,9H).膦谱核磁(202MHz,CDCl3)δ-15.62.碳谱核磁(125MHz,CDCl3)δ141.79(d,J=16.2Hz),134.56(d,J=15.3Hz),129.12,127.00,123.86,114.61(d,J=21.0Hz),75.89(d,J=15.3Hz),63.60,35.23,34.63,29.17(d,J=11.4Hz),28.38(d,J=22.9Hz),27.17,26.53,26.28,21.85.高分辨率质谱理论数据C28H49NOPS:m/z(%):478.3272(M+H+),实验数据:478.3275。
实施例81h(S,Rs)的合成
其他操作参考实施例1,所用膦试剂为总产率为41%。氢谱核磁(500MHz,CDCl3)δ7.90-7.87(m,1H),7.51-7.31(m,5H),7.28-7.15(m,3H),5.53(s,1H),2.72(s,3H),1.24(s,9H),1.07(s,18H).膦谱核磁(202MHz,CDCl3)δ21.36.碳谱核磁(125MHz,CDCl3)δ141.58(d,J=15.3Hz),136.77,134.04(d,J=16.2Hz),128.99,128.40,127.87,127.84,126.64,125.07,117.78(d,J=21.0Hz),69.26(d,J=15.3Hz),63.60,34.07,29.90(d,J=12.4Hz),29.73(d,J=23.8Hz),21.85.高分辨率质谱理论数据C26H41NOPS:m/z(%):446.2646(M+H+),实验数据:446.2643。
实施例91i(S,Rs)的合成
其他操作参考实施例1,所用卤代烃为BnBr,总产率为49%。氢谱核磁(500MHz,CDCl3)δ7.80-7.78(m,1H),7.73(d,J=7.2Hz,2H),7.49-7.42(m,1H),7.37-7.15(m,10H),5.51(s,1H),4.94(d,J=12.5Hz,1H),4.28(d,J=12.5Hz,1H),2.40-2.33(m,1H),2.02-1.80(m,4H),1.79-1.30(m,16H),1.00(s,10H).膦谱核磁(202MHz,CDCl3)δ-15.62.碳谱核磁(125MHz,CDCl3)δ136.94,136.87,136.51(d,J=16.2Hz),134.61(d,J=16.2Hz),128.93,128.66,128.41(2C),128.18,127.84,127.64,126.96,125.36,108.91(d,J=21.0Hz),65.75(d,J=15.3Hz),63.82,49.89,29.17(d,J=11.5Hz),28.38(d,J=22.9Hz),26.53,26.28,21.85.高分辨率质谱理论数据C36H49NOPS:m/z(%):574.3272(M+H+),实验数据:574.3275。
实施例101j(S,Rs)的合成
其他操作参考实施例1,所用卤代烃为3-溴丙烯,总产率为42%。氢谱核磁1H NMR(500MHz,CDCl3)δ7.75(dd,J=7.3,3.2Hz,3H),7.47-7.39(m,1H),7.35-7.29(m,2H),7.27-7.16(m,3H),6.00(dd,J=16.7,10.3Hz,1H),5.55(s,1H),5.27(dd,J=13.8,10.2Hz,1H),5.14(dd,J=16.7,13.7Hz,1H),3.85(d,J=12.3Hz,1H),3.60(d,J=12.5Hz,1H),1.92-1.82(m,4H),1.74-1.53(m,6H),1.46-1.28(m,12H),1.2l(s,9H).膦谱核磁(202MHz,CDCl3)δ-15.62.碳谱核磁(125MHz,CDCl3)δ136.94,136.51(d,J=16.2Hz),135.85,134.61(d,J=16.2Hz),128.93,128.41,128.18,127.84,126.96,125.36,117.55,108.91(d,J=21.0Hz),65.83(d,J=15.3Hz),63.82,48.21,29.17(d,J=11.5Hz),28.38(d,J=22.9Hz),26.53,26.28,21.85.高分辨率质谱理论数据C32H47NOPS:m/z(%):524.3116(M+H+),实验数据:524.3113。
实施例111k(S,Rs)的合成
其他操作参考实施例1,所用卤代烃为3-溴丙炔,总产率为40%。氢谱核磁(500MHz,CDCl3)δ7.53-7.46(m,3H),7.41-7.29(m,3H),7.28-7.16(m,3H),5.00(s,1H),4.53(d,J=12.5Hz,1H),3.76(d,J=12.5Hz,1H),2.97(s,1H),1.92-1.82(m,4H),1.72-1.57(m,10H),1.49-1.39(m,6H),1.34(s,2H),1.30(s,9H).31P NMR(202MHz,CDCl3)δ-15.62.13C NMR(125MHz,CDCl3)δ136.94,136.51(d,J=16.2Hz),134.61(d,J=16.2Hz),128.93,128.41,128.18,127.84,126.96,125.36,108.91(d,J=21.0Hz),74.98,65.78,65.75(d,J=15.2Hz),63.82,31.61,29.17(d,J=11.4Hz),28.38(d,J=22.9Hz)26.53,26.28,21.85.高分辨率质谱理论数据C32H45NOPS:m/z(%):522.2959(M+H+),实验数据:522.2961。
实施例121e(R,Ss)的合成
其他操作参考实施例1,所用原料为总产率为53%。氢谱核磁(300MHz,CDCl3)δ7.78-7.74(m,1H),7.45-7.37(m,2H),7.24-7.21(m,1H),7.00(s,2H),6.74(d,J=10.4Hz,1H),3.57(s,3H),2.56(s,3H),1.88-0.78(d,J=88.5Hz,49H).膦谱核磁(122MHz,CDCl3)δ-17.35.碳谱核磁(126MHz,CDCl3)δ158.46,147.29(d,J=22.2Hz),142.42,135.02(d,J=20.6Hz),133.57,133.00(d,J=3.2Hz),129.66,128.58,127.53(d,J=4.9Hz),126.42,70.24(d,J=32.8Hz),64.16,58.35,35.58,35.03(dd,J=13.2,7.9Hz),31.98,30.59(dd,J=17.6,5.1Hz),30.22,29.48-29.14(m),27.12-26.14(m),24.01.高分辨率质谱理论数据C39H63NO2PS:m/z(%):640.4312(M+H+),实验数据:640.4303。
实施例13邻卤代芳基烯丙基醚分子内不对称还原Heck反应
将实施例1所得的手性单膦配体1a(S,Rs):与Pd盐形成的配合物用于反应的催化,具体操作为:在氩气气氛中,将手性单膦配体1a(S,Rs)(0.022mmol)和[PdCl(ally)]2(0.05mmol)加入经无水无氧处理过的反应管中,加入邻卤代芳基烯丙基醚和甲酸钠,维持在室温,通过TLC检测,底物全部转化后,过滤,滤液浓缩至1mL,柱层析分析其产率,HPLC分析其对映体过量值(ee)。
具体催化反应如下反应式(II)所示:
柱层析分析得知:目标产物产率66%:HPLC分析得知:ee=71%
目标产物的1H NMR(500MHz,CDCl3)δ7.25-7.20(m,3H),7.14-7.11(m,1H),7.01-6.98(m,2H),6.94-6.92(m,1H),6.87-6.84(m,1H),6.76(d,J=8.0Hz,1H),4.49(d,J=8.7Hz,1H),4.05(d,J=8.7Hz,1H),2.91-2.84(m,2H),1.35(s,3H).13C NMR(126MHz,CDCl3)δ159.47,137.51,134.78,130.32,128.14,127.89,126.42,123.30,120.24,109.66,81.84,46.58,46.19,24.55.低分辨率质谱实验数据(EI):m/z(%)=224(M+,3.25),133(100);高分辨率质谱理论数据[C16H16O]+:224.1201实验数据:224.1203.手性通过HPLC测定,使用IA手性柱(hexanes,0.5mL/min,220nm);小的对映异构体保留时间17.9min,大的对映异构体保留时间24.6min.[α]D 25=15.9(c=0.25,CHCl3)。
实施例14-26
考察本发明所述的手性单膦配体1与Pd盐Pd盐形成的配合物,阴离子、配体R3取代基、反应温度及溶剂对反应的影响,具体操作及其余条件均参照实施例19所述。各实施例的反应条件及实验结果详见表1所示。
表1实施例16-31的反应条件和反应结果
通过实施例14-16,说明1e(S,Rs)为最合适的配体,以68%产率,84%ee得到目标产物;通过实施例16-20,说明Pd2(dab)3·CHCl3为最合适的钯盐,以73%产率,89%ee得到目标产物;通过实施例20-25,说明甲苯与甲醇的混合溶剂为最合适的溶剂,以85%产率,92%ee得到目标产物;通过实施例25-26,说明90℃为最合适的温度,以82%产率,95%ee得到目标产物。
实施例27-36
考察本发明所述的底物的普适性,具体操作及其余条件均参照实施例26所述。各实施例的反应条件及实验结果详见表2所示。
催化反应如下式式(III)所示:
表2实施例32-36的反应条件和反应结果
通过实施例27-36,在催化邻卤代芳基烯丙基醚分子内不对称还原Heck反应的应用中,所述配体有很好的底物普适性,且具有很高的反应活性和立体选择性。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。
Claims (10)
1.一类亚磺酰胺手性单膦配体,其特征在于,所述手性单膦配体为如下(式1)所示的化合物:
(式1)中,Ar选自R1、R2、R4分别独立选自C1~C12的烷烃基、C1~C10的烷氧基、R3选自C1~C12的烷烃基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基、 ORw或SRw;R5选自氢、C1~C12的烷烃基、
其中,Rx和Rx′分别独立选自氢、卤素、C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基;Ry、Ry′、Ry″、Rz、Rz′和Rw分别独立选自C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基;n选自1~5的整数。
2.如权利要求1所述的手性单膦配体,其特征在于,其结构如下(式1)所示的化合物:
Ar选自R1、R2同时选自C1~C12的烷烃基、 R3选自C1~C12的烷烃基、C1~C10的硅氧基、C1~C10的酯基或R4选自C1~C12的烷烃基、R5独立选自氢、C1~C12的烷烃基、其中Rx和Rx′分别独立选自氢、卤素、C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基。
3.一种权利要求1所述的手性单膦配体的制备方法,其特征在于,
在溶剂中,步骤一:将(式2)R1R2PH·BH3在BuLi作用下与(式3)进行反应,生成中间体步骤二:然后中间体和(式4)进行加成反应,得到中间体步骤三:再然后中间体和(式5)R5X进行取代反应,得到中间体步骤四:再在有机胺的作用下,脱去硼烷保护基团,得到手性单膦配体(S,Rs),反应过程如下反应式(I)所示:
反应式(I)中,Ar选自R1、R2、R4分别独立选自C1~C12的烷烃基、C1~C10的烷氧基、R3选自C1~C12的烷烃基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基、 ORw或SRw;R5选自氢、C1~C12的烷烃基、
其中,Rx和Rx′分别独立选自氢、卤素、C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基;Ry、Ry′、Ry″、Rz、Rz′和Rw分别独立选自C1~C12的烷烃基、C1~C10的烷氧基、C1~C10的硅氧基、C1~C10的烷酰基、C1~C10的酯基、C1~C10的磺酸酯基;n选自1~5的整数;
其中,所述溶剂选自干燥的二氯甲烷、乙醚、二丁醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、甲苯、二甲苯、苯、氯苯、氟苯、氯仿、正己烷;
所述第一步和第二步反应的温度为-78℃~30℃;
所述第一步、第二步、第三步反应的时间为10分钟~10小时;
所述第三步反应的温度为-78℃~30℃;
所述第四步反应的温度为-10℃~130℃;
所述第四步反应的时间为10分钟~30小时;
所述BuLi的作用为和卤素X进行交换、进行取代反应;所述BuLi包括n-BuLi、s-BuLi、t-BuLi;
所述第四步有机胺选自Et3N、DBU、DABCO、甲胺、一丙胺、2-丙烯胺、叔丁胺、癸胺、二甲胺、二丙胺、环丙胺、二异丁胺、十二胺、三甲胺、三丙胺、正丁胺、己胺、十六胺、一乙胺、异丙胺、二正丁胺、2-乙基己胺、十八胺、二乙胺、二异丙胺、异丁胺、己二胺、二硬脂胺、三乙胺、1,2-二甲基丙胺、仲丁胺、三辛胺、1,5-二甲基己胺、乙二胺、1,2-丙二胺、1,4-丁二胺、1,10-癸二胺;
所述第一步、第二步、第三步和第四步反应中,(式2)、(式3)、BuLi、(式4)、(式5)和有机胺的摩尔比为(1~10):(1~10):(1~10):(1~10):(1~100):(5~100)。
4.如权利要求1所述的手性单膦配体(式1)的对映异构通过使用(式4)的对映异构体实现。
5.一种权利要求1所述的手性单膦配体在催化邻卤代芳基烯丙基醚分子内不对称还原Heck反应中的应用。
6.如权利要求5所述的应用,其特征在于,所述手性单膦配体在催化邻卤代芳基烯丙基醚分子内不对称还原Heck反应合成苯并二氢呋喃类化合物。
7.如权利要求6所述的应用,其特征在于,所述合成苯并二氢呋喃类化合物是:将所述的手性单膦配体与过渡金属盐形成金属配合物溶液,然后催化邻卤代芳基烯丙基醚分子内不对称还原Heck反应,合成所述苯并二氢呋喃类化合物,具体包括:
在惰性气氛下,将所述手性单膦配体和过渡金属盐加入到有机溶剂中,在-10~50℃反应0.1~20小时,形成金属配合物溶液,向该金属配合物溶液中加入邻卤代芳基烯丙基醚和还原剂,在20~200℃条件下进行分子内不对称还原Heck反应,合成所述苯并二氢呋喃类化合物,其中:
所述邻卤代芳基烯丙基醚与金属配合物的摩尔比为(10~10000):1;
所述还原剂与邻卤代芳基烯丙基醚的摩尔比为(10~10000):1;
所述手性单膦配体与过渡金属盐的摩尔比为(1~100):1。
8.根据权利要求7所述的应用,其特征在于,所述惰性气氛为氩气或者氮气气氛;所述有机溶剂选自二氯甲烷、乙醚、二丁醚、甲基叔丁基醚、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、甲苯、二甲苯、苯、氯苯、氟苯、氯仿、甲醇、乙醇、丙醇、异丙醇或正丁醇。
9.根据权利要求7所述的应用,其特征在于,所述过渡金属盐为Pd盐,所述Pd盐选自Pd(OAc)2、PdCl2、Pd(MeCN)2Cl2、Pd(PPh3)4、Pd(TFA)2、[Pd(ally)Cl]2、Pd(dba)2、Pd2(dba)3、Pd2(dba)3·CHCl3、Pd(PhCN)2Cl2、Pd(OTf)2、Pd(OTs)2或Pd(MeCN)2(BF4)2。
10.根据权利要求7所述的应用,其特征在于,所述还原剂选自碱与水、甲醇、乙醇、异丙醇、丁醇或甲酸的的混合物;
其中,所述碱为Et3N、DBU、DABCO、Bn2NH、Bu3N、Pr2NH、K2CO3、Na2CO3、KOH、NaOH、Cs2CO3、Li2CO3、CsOH、LiOH、NaOtBu、KOtBu或LiOtBu;
其中,所述碱与水、甲醇、乙醇、异丙醇、丁醇或甲酸的摩尔比为1:1~100。
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