CN118047805A - 一种钯催化合成Danishefsky-Diene的方法 - Google Patents
一种钯催化合成Danishefsky-Diene的方法 Download PDFInfo
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- CN118047805A CN118047805A CN202410104490.3A CN202410104490A CN118047805A CN 118047805 A CN118047805 A CN 118047805A CN 202410104490 A CN202410104490 A CN 202410104490A CN 118047805 A CN118047805 A CN 118047805A
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- Prior art keywords
- palladium
- diene
- mmol
- synthesizing
- ligand
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 title claims abstract description 81
- 229910052763 palladium Inorganic materials 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 39
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 30
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- 239000000758 substrate Substances 0.000 claims abstract description 54
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 239000003513 alkali Substances 0.000 claims abstract description 20
- 239000003960 organic solvent Substances 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- -1 propargyl alcohol ester Chemical class 0.000 claims abstract description 13
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- 150000001993 dienes Chemical class 0.000 claims abstract description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 7
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 230000008030 elimination Effects 0.000 claims abstract description 4
- 238000003379 elimination reaction Methods 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 51
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- 239000003446 ligand Substances 0.000 claims description 32
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [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 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 17
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 17
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 5
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 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
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 239000007983 Tris buffer Substances 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 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
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 3
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [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 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- PAGZTSLSNQZYEV-UHFFFAOYSA-L 2,2-dimethylpropanoate;palladium(2+) Chemical compound [Pd+2].CC(C)(C)C([O-])=O.CC(C)(C)C([O-])=O PAGZTSLSNQZYEV-UHFFFAOYSA-L 0.000 claims description 2
- JSGVZVOGOQILFM-UHFFFAOYSA-N 3-methoxy-1-butanol Chemical compound COC(C)CCO JSGVZVOGOQILFM-UHFFFAOYSA-N 0.000 claims description 2
- WVYWICLMDOOCFB-UHFFFAOYSA-N 4-methyl-2-pentanol Chemical compound CC(C)CC(C)O WVYWICLMDOOCFB-UHFFFAOYSA-N 0.000 claims description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 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
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- HNQXCHVZYRDHJN-UHFFFAOYSA-N cyanosilicon Chemical compound [Si]C#N HNQXCHVZYRDHJN-UHFFFAOYSA-N 0.000 claims description 2
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 claims description 2
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 2
- HDULBKVLSJEMGN-UHFFFAOYSA-N dicyclohexylphosphane Chemical compound C1CCCCC1PC1CCCCC1 HDULBKVLSJEMGN-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- UJNZOIKQAUQOCN-UHFFFAOYSA-N methyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C)C1=CC=CC=C1 UJNZOIKQAUQOCN-UHFFFAOYSA-N 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims description 2
- JYVLIDXNZAXMDK-UHFFFAOYSA-N pentan-2-ol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 claims 2
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 claims 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 claims 1
- 229940035437 1,3-propanediol Drugs 0.000 claims 1
- 235000011187 glycerol Nutrition 0.000 claims 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000000926 separation 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 130
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- 239000011541 reaction mixture Substances 0.000 description 16
- 238000013375 chromatographic separation Methods 0.000 description 15
- 238000002156 mixing Methods 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 15
- XRBCRPZXSCBRTK-UHFFFAOYSA-N phosphonous acid Chemical compound OPO XRBCRPZXSCBRTK-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 238000004293 19F NMR spectroscopy Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 238000001308 synthesis method Methods 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- 241001090476 Castoreum Species 0.000 description 2
- 238000005698 Diels-Alder reaction Methods 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- HRDCVMSNCBAMAM-UHFFFAOYSA-N 3-prop-2-ynoxyprop-1-yne Chemical compound C#CCOCC#C HRDCVMSNCBAMAM-UHFFFAOYSA-N 0.000 description 1
- VVBXKASDRZXWON-UHFFFAOYSA-N N=[PH3] Chemical compound N=[PH3] VVBXKASDRZXWON-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- CFBGXYDUODCMNS-UHFFFAOYSA-N cyclobutene Chemical compound C1CC=C1 CFBGXYDUODCMNS-UHFFFAOYSA-N 0.000 description 1
- SHALBPKEGDBVKK-VOTSOKGWSA-N danishefsky's diene Chemical compound CO\C=C\C(=C)O[Si](C)(C)C SHALBPKEGDBVKK-VOTSOKGWSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 238000006464 oxidative addition reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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Abstract
本申请公开了一种钯催化合成Danishefsky‑Diene的方法,包括以下步骤:在有机溶剂中,以炔丙醇酯作为反应底物,钯作为催化剂,水作为质子源,碱促进氢的消除来合成含有两个氧原子取代的共轭二烯(Danishefsky‑Diene)。本发明在反应过程中使用炔丙醇酯,与钯催化剂进行配位,以较高的收率,优异的选择性得到目标产物。整个方法简单易行且安全,从商业可得的原料出发,历经两步即可实现Danishefsky‑Diene的合成,在优化的反应条件之下,目标产品分离后产率可以高达74%,是一种通用、高效、经济和环境友好的合成Danishefsky‑Diene的方法。
Description
技术领域
本申请涉及催化合成技术和精细化学品合成技术领域,特别是涉及一种钯催化合成Danishefsky-Diene的方法。
背景技术
1-甲氧基-3-三甲基硅氧基-1,3-丁二烯被称为Danishefsky-Diene,其二烯骨架上有两个含氧的供电子取代基。在迪尔斯-阿尔德(Diels-Alder,DA)环加成反应中,Danishefsky-Diene与缺电子烯烃具有高反应活性,从而能够以高度区域和立体可控的方式生成氧官能化的六元环化合物,因此合成Danishefsky-Diene是非常有用的。一般来说,DA反应的区域和立体选择性通常会受到取代基数和共轭双键的立体化学的影响。具有吸引力的是,Danishefsky-Diene具有高度富电子效应的特点,并且由于两个含氧取代基的限定而具有可预测的区域和立体化学结果,因此其立体选择性制备的高效方法至关重要。
发明内容
解决的技术问题:
本申请需要解决的技术问题是传统合成Danishefsky-Diene存在产物结构单一不利于修饰,产物的立体选择性不好以及合成方法比较局限等问题,基于现有技术的不足,本申请提供一种钯催化合成Danishefsky-Diene的方法,该方法围绕钯催化的炔丙醇酯,通过氧化加成的反应的模式,高立体选择性地实现了Danishefsky-Diene的合成,为复杂天然产物以及具有生物活性分子的合成提供了简单方便,快捷高效的策略。
技术方案:
一种钯催化合成Danishefsky-Diene的方法,在有机溶剂中,以炔丙醇酯作为反应底物,钯作为催化剂与配体L进行配位,水作为质子源,碱促进氢的消除来合成含有两个氧原子取代的共轭二烯Danishefsky-Diene;反应通式表示如下:
式中:R为取代或非取代芳基和杂芳基,R1为烷基羰基和/或芳基羰基,R2为烷基和/或硅烷基,L代表配体。
作为本申请的一种优选技术方案:所述R表示取代或者非取代芳基、含N、O、S的杂芳基,其芳环上的取代基选自氢、C1~C20的烷基、C1~C20卤取代烷基、C1~C20烷基羰基、硝基、羟基、氰基、硅基、氨基、硫基中的一种或几种。
作为本申请的一种优选技术方案:所述R1表示C1~C20的烷基羰基、C1~C20卤取代烷基羰基、C1~C20芳基羰基、C1~C20卤取代芳基基羰基中的一种或几种。
作为本申请的一种优选技术方案:所述R2表示C1~C20的烷基、C1~C20卤取代烷基中的一种或几种。
作为本申请的一种优选技术方案:所述配体为双齿手性N配体、双齿手性P配体、双齿手性N、P配体、单齿手性N配体中的一种或几种。
作为本申请的一种优选技术方案:所述钯选自醋酸钯、新戊酸钯、四(三苯基膦)钯、二(三叔丁基膦)钯、三(双环己基膦)二氯化钯、双(三邻甲苯膦)二氯化钯、双(甲基二苯基膦)二氯化钯、双(乙腈)二氯化钯、二(苯腈)二氯化钯、双(二亚苄基丙酮)钯、三(二亚苄基丙酮)二钯中的一种或几种。
作为本申请的一种优选技术方案:所述有机溶剂选自甲醇、乙醇、乙二醇、正丙醇、异丙醇、1,3-丙二醇、甘油、正丁醇、异丁醇、叔丁醇、三氟乙醇、2-甲基-2-丁醇、3-甲氧基丁醇、仲丁醇、叔戊醇、4-甲基-2-戊醇、异戊醇、2-戊醇、3-戊醇、环戊醇、正戊醇、聚乙二醇200-10000、乙腈、苯腈、甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、二甲亚砜、N,N二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二甲基丙烯基脲、N-甲基吡咯烷酮、乙酸乙酯、1,4-二氧六环、四氢呋喃中的一种或几种。
作为本申请的一种优选技术方案:所述炔丙醇酯、钯、配体的摩尔比为1:(0.1~0.3):(0.1~0.3)。
作为本申请的一种优选技术方案:碱为无机碱和/或有机碱,无机碱选自碳酸钠、碳酸铯、碳酸钾、氢氧化钠中的一种或几种;有机碱选自三乙胺、二环己基胺、吡啶、哌啶,2,6-二甲基吡啶中的一种或几种。
作为本申请的一种优选技术方案:所述合成含有两个氧原子取代的共轭二烯Danishefsky-Diene的温度为40-70℃,时间为10-20小时,反应氛围为氮气条件下。
本申请的技术原理是:本发明的方法中钯催化剂具有催化活性高,选择性强,催化剂制作方便的特点,反应过程中通过金属钯与炔丙醇酯氧化加成的模式,亲核试剂进攻形成环丁烯钯中间体,质子开环形成烯丙基钯中间体,碱促进β-H消除,从而以优异的产率和高立体择性得到目标产物;本申请合成的含有两个氧原子取代的共轭二烯Danishefsky-Diene与亲二烯体发生环化反应,合成天然产物和药物分子的关键中间体:六元环的骨架,从而存在进一步转化为药物分子castoreum的一种成分,triketide以及iso-Hajos-Parrish Ketone等的潜质。
有益效果:
本申请所述一种钯催化合成Danishefsky-Diene的方法采用以上技术方案与现有技术相比,具有以下技术效果:
1、本发明提供了一种新型的Danishefsky-Diene的合成方法,该方法从商业可得原料出发只需两步反应,即可获得高立体选择性Danishefsky-Diene;反应条件温和,选择性高、产率高;底物官能团相容性好,适用范围广;是一种通用、高效、经济和环境友好的合成Danishefsky-Diene类化合物的方法;
2、本发明采用全新的反应模式来合成Danishefsky-Diene:通过氧化加成的模式,经历环丁烯钯中间体,Π-烯丙基钯中间体这两个关键步骤。此策略弥补了先前合成方法产物结构单一,选择性不好的缺点。此反应对复杂的底物也能取得理想的催化效果;
3、本发明的方法合成Danishefsky-Diene类化合物的后续应用迪尔斯-阿尔德反应可以为药物或生物活性分子提供合成的关键中间体,有广泛应用于药物分子和天然化合物的合成的潜质;
4、传统合成Danishefsky-Diene的策略大多是从羰基化合物出发,获得的Danishefsky-Diene不利于后期修饰,且获得的立体选择性均小于十比一,无法获得单一产物。本发明的方法合成Danishefsky-Diene类化合物从炔丙醇酯出发,可修饰位点较多,且为单一高立体选择性产物。
具体实施方式
根据下述实施例,可以更好地理解本发明。然而,本领域的技术人员容易理解,实施例所描述的内容仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径或通过下面方法简单制备获得。
初始底物通过如下方法合成或者商业购买:
其中,R,R1,R2与最终底物产物上取代基相同。
在氮气条件下,50mL反应瓶中依次加入炔丙基醚(5.0mmol,1.00equiv)、四氢呋喃(17mL,0.3M),室温下混合均匀后,将反应瓶置于0℃,反应混合物在0℃下逐滴加入正丁基锂,在0℃下反应10分钟;10分钟后,将醛(5mmol,1.0equiv)在0℃下逐滴加入反应体系中,随后将反应瓶移置室温反应1小时,1小时后,将反应瓶置于0℃,逐滴加入酰氯(6mmol,1.2equiv),随后移置室温反应2小时;反应2小时后用水淬灭,用乙酸乙酯萃取,真空旋干层析分离得到目标产物。
底物一:
1H NMR(400MHz,CDCl3):δ7.48–7.47(m,2H),7.37–7.35(m,3H),6.46(s,1H),4.38(s,2H),1.21(s,9H),0.90(s,9H),0.10(s,6H).13C NMR(100MHz,CDCl3):δ177.24,137.42,128.74,128.65,127.41,85.82,81.69,65.48,51.91,38.88,27.12,25.89,18.36,-4.99.HRMS(ESI):Calcd 361.2194 for C21H33O3Si[M+H]+;Found:361.2193.
底物二:
1H NMR(400MHz,CDCl3):δ7.66–7.61(m,1H),7.34–7.30(m,1H),7.19–7.14(m,1H),7.08–7.03(m,1H),6.68(s,1H),4.38(s,2H),1.20(s,9H),0.89(s,9H),0.10(s,6H).13C NMR(100MHz,CDCl3):δ176.93,161.47,158.98,130.72,130.64,129.29,129.26,124.78,124.65,124.32,124.28,115.86,115.65,86.01,80.63,60.00,51.90,38.89,27.12,25.88,18.35,-5.00.19F NMR(376MHz,CDCl3):δ-117.55.HRMS(ESI):Calcd 379.2099 forC21H32FO3Si[M+H]+;Found:379.2104.
底物三:
1H NMR(400MHz,CDCl3):δ7.43(d,J=8.5Hz,2H),7.34(d,J=8.5Hz,2H),6.42(s,1H),4.38(s,2H),1.20(s,9H),0.89(s,9H),0.10(s,6H).13C NMR(100MHz,CDCl3):δ177.15,136.00,134.69,128.89,128.88,86.20,81.21,64.81,51.86,38.87,27.09,25.88,18.36,-5.00.HRMS(ESI):Calcd 395.1804 for C21H32ClO3Si[M+H]+;Found:395.1809.
底物四:
1H NMR(400MHz,CDCl3):δ8.04(d,J=8.1Hz,2H),7.55(d,J=8.1Hz,2H),6.49(s,1H),4.37(s,2H),3.91(s,3H),1.20(s,9H),0.88(s,9H),0.08(s,6H).13C NMR(100MHz,CDCl3):δ177.05,166.72,142.21,130.47,130.00,127.29,86.46,81.01,64.94,52.30,51.83,38.88,27.08,25.85,18.33,-5.02.HRMS(ESI):Calcd 419.2249 for C23H35O5Si[M+H]+;Found:419.2252.
底物五:
1H NMR(400MHz,CDCl3):δ7.64–7.59(m,4H),6.49(s,1H),4.38(s,2H),1.22(s,9H),0.89(s,9H),0.10(s,6H).13C NMR(100MHz,CDCl3):δ-62.48.δ177.12,141.32,131.08,130.76,130.43,127.70,125.79,125.75,125.71,125.68,122.71,86.63,80.90,64.80,51.85,38.93,27.11,25.87,18.37,-5.01.19F NMR(376MHz,CDCl3):δ-62.66.HRMS(ESI):Calcd 429.2068 for C22H32F3O3Si[M+H]+;Found:429.2071.
底物六:
1H NMR(400MHz,CDCl3):δ7.39–7.34(m,2H),7.19–7.14(m,2H),6.43(s,1H),4.38(s,2H),2.36(s,3H),1.20(s,9H),0.90(s,9H),0.11(s,6H).13C NMR(100MHz,CDCl3):δ177.31,138.63,134.57,129.34,127.46,81.88,65.44,51.94,38.88,27.15,25.92,21.35,18.38,-4.96.HRMS(ESI):Calcd 375.2350 for C22H35O3Si[M+H]+;Found:375.2345.
底物七:
1H NMR(400MHz,CDCl3):δ7.43(d,J=8.7Hz,2H),6.89(d,J=8.7Hz,2H),6.41(s,1H),4.38(s,2H),3.81(s,3H),1.19(s,9H),0.90(s,9H),0.11(s,6H).13C NMR(100MHz,CDCl3):δ177.35,159.97,129.72,129.05,113.99,85.61,81.93,65.29,55.44,51.95,38.88,27.14,25.92,18.39,-4.95.HRMS(ESI):Calcd 408.2564 for C22H38NO4Si[M+NH4]+;Found:408.2560.
底物八:
1H NMR(400MHz,CDCl3):δ7.31(d,J=3.9Hz,1H),7.20(d,J=3.9Hz,1H),6.96–6.95(m,1H),6.70(s,1H),4.40(s,2H),1.20(s,9H),0.91(s,9H),0.13(s,6H).13C NMR(100MHz,CDCl3):δ177.09,140.34,127.21,126.75,126.65,85.36,80.97,60.95,51.83,38.85,27.06,25.89,18.36,-4.98.HRMS(ESI):Calcd 367.1758 for C19H31O3SSi[M+H]+;Found:367.1755.
底物九:
1H NMR(400MHz,CDCl3):δ8.26(s,1H),7.71(d,J=8.6Hz,1H),6.75(d,J=8.6Hz,1H),6.41(s,1H),4.37(s,2H),3.94(s,3H),1.18(s,9H),0.89(s,9H),0.10(s,6H).13C NMR(100MHz,CDCl3):δ177.19,164.47,146.42,138.18,126.28,86.15,81.08,63.30,53.74,51.84,38.89,27.10,25.90,18.38,-4.98.HRMS(ESI):Calcd 392.2252 for C21H34NO4Si[M+H]+;Found:392.2257.
底物十:
1H NMR(400MHz,CDCl3):δ7.24–7.20(m,2H),7.04–7.02(m,1H),6.41(s,1H),4.38(s,2H),1.20(s,9H),0.89(s,9H),0.10(s,6H).13C NMR(100MHz,CDCl3):δ177.14,143.98,143.95,134.33,133.76,131.79,129.25,123.25,109.08,86.45,81.05,64.96,51.84,38.88,27.09,25.87,18.38,-5.00.19F NMR(376MHz,CDCl3):δ-49.70.HRMS(ESI):Calcd441.1904 for C22H31F2O5Si[M+H]+;Found:441.1909.
底物十一:
1H NMR(400MHz,CDCl3):δ7.51–7.49(m,2H),7.38–7.35(m,3H),6.48(s,1H),4.18(s,2H),3.37(s,3H),1.22(s,9H).13C NMR(100MHz,CDCl3):δ177.24,137.27,128.81,128.70,127.38,83.39,82.86,65.41,59.97,57.70,38.86,27.07.HRMS(ESI):Calcd278.1750 for C16H24NO3[M+NH4]+;Found:278.1751.
底物十二:
1H NMR(400MHz,CDCl3):δ7.53–7.50(m,2H),7.39–7.32(m,8H),6.50(s,1H),4.60(s,2H),4.25(s,2H),1.23(s,9H).13C NMR(100MHz,CDCl3):δ177.30,137.37,137.33,128.86,128.75,128.58,128.35,128.06,127.43,83.63,83.08,71.62,65.52,57.41,38.92,27.14.HRMS(ESI):Calcd 354.2063 for C22H28NO3[M+NH4]+;Found:354.2056.
底物十三:
1H NMR(400MHz,CDCl3):δ7.52–7.50(m,2H),7.40–7.34(m,3H),6.49(s,1H),4.39(s,2H),2.10(s,3H),0.89(s,9H),0.10(s,6H).13C NMR(100MHz,CDCl3):δ169.90,137.05,129.04,128.74,127.85,86.16,81.44,65.77,51.89,25.90,21.19,18.39,-5.03.HRMS(ESI):Calcd 336.1989 for C18H30NO3Si[M+NH4]+;Found:336.1990.
底物十四:
1H NMR(400MHz,CDCl3):δ8.09–8.06(m,2H),7.62–7.55(m,3H),7.46–7.36(m,5H),6.75(s,1H),4.41(s,2H),0.89(s,9H),0.10(s,6H).13C NMR(100MHz,CDCl3):δ165.51,137.16,133.37,130.02,129.91,129.02,128.77,128.51,127.83,86.41,81.51,66.31,51.94,25.91,18.39,-5.01.HRMS(ESI):Calcd 381.1881 for C23H29O3Si[M+H]+;Found:381.1878.
底物十五:
1H NMR(400MHz,CDCl3):δ7.49–7.47(m,2H),7.38–7.33(m,3H),6.47(s,1H),4.45(s,2H),1.21(s,9H),1.12–1.09(m,3H),1.06–1.05(m,18H).13C NMR(100MHz,CDCl3):δ177.26,137.52,128.71,128.64,127.42,85.97,81.49,65.53,52.19,38.90,27.13,18.03,17.84,12.42,12.14.HRMS(ESI):Calcd 403.2663 for C24H39O3Si[M+H]+;Found:403.2666.
下述实施例中全部的底物和产物的具体结构见表1。
实施例1:
一种钯催化合成Danishefsky-Diene化合物1的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物一(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在50℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物1,其产率为74%。1H NMR(400MHz,CDCl3):δ7.34–7.32(m,2H),7.28–7.24(m,2H),7.18–7.14(m,1H),6.59(d,J=11.8Hz,1H),6.00(s,1H),5.77(d,J=11.8Hz,1H),1.31(s,9H),0.93(s,9H),0.17(s,6H).13C NMR(100MHz,CDCl3):δ175.02,144.94,143.32,134.83,128.43,128.15,126.76,115.69,109.25,39.16,27.37,25.54,18.30,-5.28.HRMS(ESI):Calcd 361.2194 for C21H33O3Si[M+H]+;Found:369.2184.
实施例2
一种钯催化合成Danishefsky-Diene化合物2的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物二(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在50℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物2,其产率为56%。1H NMR(400MHz,CDCl3):δ7.49–7.45(m,1H),7.17–7.12(m,1H),7.04–6.97(m,2H),6.65(d,J=11.7Hz,1H),6.13(s,1H),5.80(d,J=11.7Hz,1H),1.27(s,9H),0.93(s,9H),0.17(s,6H).13C NMR(100MHz,CDCl3):δ175.07,161.16,158.69,146.54,144.10,129.70,128.48,128.40,123.60,123.56,122.94,122.81,115.56,115.34,109.23,107.73,107.68,39.30,27.43,25.65,18.41,-5.15.19FNMR(376MHz,CDCl3):δ-115.27.HRMS(ESI):Calcd 379.2099 for C21H32FO3Si[M+H]+;Found:379.2096.
实施例3
一种钯催化合成Danishefsky-Diene化合物3的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物三(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在50℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物3,其产率为51%。1H NMR(400MHz,CDCl3):δ7.28–7.21(m,4H),6.63(d,J=11.7Hz,1H),5.94(s,0H),5.75(d,J=11.7Hz,1H),1.30(s,9H),0.92(s,9H),0.16(s,6H).13C NMR(100MHz,CDCl3):δ175.03,145.64,143.90,133.49,132.43,129.74,128.47,114.55,109.17,39.30,27.48,25.65,18.42,-5.17.HRMS(ESI):Calcd395.1804for C21H32ClO3Si[M+H]+;Found:395.1799.
实施例4
一种钯催化合成Danishefsky-Diene化合物4的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物四(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在50℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物4,其产率为57%。13C NMR(100MHz,CDCl3):δ174.99,167.00,146.99,144.62,139.72,129.61,128.29,128.08,114.85,109.22,52.13,39.32,27.46,25.61,18.40,-5.19.HRMS(ESI):Calcd 419.2249 for C23H35O5Si[M+H]+;Found:419.2244.
实施例5
一种钯催化合成Danishefsky-Diene化合物5的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物五(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在50℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物5,其产率为53%。1H NMR(400MHz,CDCl3):δ7.52–7.42(m,4H),6.68(d,J=11.7Hz,1H),6.02(s,1H),5.77(d,J=11.7Hz,1H),1.31(s,9H),0.93(s,9H),0.17(s,6H).13C NMR(100MHz,CDCl3):δ175.01,146.97,144.67,138.62,128.59,125.27,125.24,125.20,125.16,114.36,109.05,39.34,27.46,25.63,18.42,-5.17.19FNMR(376MHz,CDCl3):δ-62.48.HRMS(ESI):Calcd 429.2068 for C22H32F3O3Si[M+H]+;Found:429.2058.
实施例6
一种钯催化合成Danishefsky-Diene化合物6的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物六(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在50℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物6,其产率为76%。1H NMR(400MHz,CDCl3):δ7.25(d,J=8.0Hz,2H),7.08(d,J=7.9Hz,2H),6.60(d,J=11.8Hz,1H),5.96(s,1H),5.76(d,J=11.8Hz,1H),2.30(s,3H),1.32(s,9H),0.92(s,9H),0.16(s,6H).13C NMR(100MHz,CDCl3):δ175.14,144.42,143.06,136.66,132.09,129.03,128.44,115.81,109.52,39.30,27.54,25.68,21.35,18.43,-5.15.HRMS(ESI):Calcd 375.2350 for C22H35O3Si[M+H]+;Found:375.2349.
实施例7
一种钯催化合成Danishefsky-Diene化合物7的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物七(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在50℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物7,其产率为71%。1H NMR(400MHz,CDCl3):δ7.27(d,J=8.5Hz,2H),6.81(d,J=8.8Hz,2H),6.55(d,J=11.8Hz,1H),5.94(s,1H),5.72(d,J=11.8Hz,1H),3.78(s,3H),1.32(s,9H),0.92(s,9H),0.16(s,6H).13C NMR(100MHz,CDCl3):δ175.19,158.53,143.68,142.72,129.78,127.68,115.41,113.77,109.52,55.35,39.31,27.55,25.68,18.43,-5.15.HRMS(ESI):Calcd 391.2299 for C22H35O4Si[M+H]+;Found:391.2301.
实施例8
一种钯催化合成Danishefsky-Diene化合物8的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物八(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在50℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物8,其产率为61%。1H NMR(400MHz,CDCl3):δ7.21–7.19(m,1H),6.95(s,2H),6.59(d,J=11.9Hz,1H),6.26(s,1H),5.74(d,J=11.9Hz,1H),1.42(s,9H),0.92(s,9H),0.16(s,9H).13C NMR(100MHz,CDCl3):δ175.56,143.43,143.38,137.26,127.06,126.71,125.44,110.19,109.00,39.51,27.82,25.67,18.42,-5.13.HRMS(ESI):Calcd 367.1758 for C19H31O3SSi[M+H]+;Found:367.1768.
实施例9
一种钯催化合成Danishefsky-Diene化合物9的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物九(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在50℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物9,其产率为64%。1H NMR(400MHz,CDCl3):δ8.11–8.10(m,1H),7.60–7.57(m,1H),6.66(m,1H),6.61(d,J=11.8Hz,1H),5.90(s,1H),5.75(d,J=11.8Hz,1H),3.90(s,3H),1.30(s,9H),0.92(s,9H),0.16(s,6H).13C NMR(100MHz,CDCl3):δ175.16,162.82,146.86,145.20,143.52,138.20,124.37,112.03,110.36,109.07,53.62,39.34,27.51,25.66,18.43,-5.16.HRMS(ESI):Calcd 392.2252 for C21H34NO4Si[M+H]+;Found:392.2251.
实施例10
一种钯催化合成Danishefsky-Diene化合物10的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物十(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在50℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物10,其产率为67%。1H NMR(400MHz,CDCl3):δ7.13(s,1H),7.02–6.89(m,2H),6.64(d,J=11.7Hz,1H),5.94(s,1H),5.74(d,J=11.7Hz,1H),1.32(s,9H),0.92(s,9H),0.16(s,6H).13C NMR(100MHz,CDCl3):δ175.04,145.48,144.00,143.89,142.37,131.72,131.23,124.18,114.38,109.27,109.09,108.97,39.30,27.45,25.62,18.42,-5.18.19F NMR(376MHz,CDCl3):δ-50.07.
实施例11
一种钯催化合成Danishefsky-Diene化合物11的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物十一(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在50℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物11,其产率为60%。1H NMR(400MHz,CDCl3):δ7.36–7.30(m,2H),7.29–7.27(m,2H),7.20–7.18(m,1H),6.69(d,J=12.6Hz,1H),6.06(s,1H),5.59(d,J=12.6Hz,1H),1.31(s,9H).13C NMR(100MHz,CDCl3):δ175.37,149.46,144.77,134.83,128.51,128.30,126.94,115.84,101.87,56.63,39.28,27.45.HRMS(ESI):Calcd261.1485 for C16H21O3[M+H]+;Found:261.1483.
实施例12
一种钯催化合成Danishefsky-Diene化合物12的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物十二(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在50℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物12,其产率为66%。1H NMR(400MHz,CDCl3):δ7.41–7.33(m,7H),7.29–7.25(m,2H),7.19–7.15(m,1H),6.71(d,J=12.6Hz,1H),6.06(s,1H),5.72(d,J=12.6Hz,1H),4.83(s,2H),1.28(s,9H).13C NMR(100MHz,CDCl3):δ175.32,148.33,144.70,136.26,134.86,128.81,128.55,128.45,128.32,127.91,126.99,116.16,103.63,72.16,39.28,27.45.HRMS(ESI):Calcd 337.1798 for C22H25O3[M+H]+;Found:337.1792.
实施例13
一种钯催化合成Danishefsky-Diene化合物13的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物十三(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在70℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物13,其产率为62%。1H NMR(400MHz,CDCl3):δ7.37–7.35(m,2H),δ7.31–7.27(m,2H),7.19–7.14(m,1H),6.63(d,J=11.7Hz,1H),5.96(s,1H),5.77(d,J=11.7Hz,1H),2.23(s,3H),0.93(s,9H),0.18(s,6H).13C NMR(100MHz,CDCl3):δ168.16,145.02,143.89,134.98,128.60,128.32,127.00,115.44,109.22,25.66,21.03,18.40,-5.13.
实施例14
一种钯催化合成Danishefsky-Diene化合物14的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物十四(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在50℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物14,其产率为54%。1H NMR(400MHz,CDCl3):δ8.20–8.18(m,2H),7.68–7.64(m,1H),7.55–7.51(m,2H),7.40–7.38(m,2H),7.21–7.17(m,2H),7.13–7.11(m,1H),6.66(d,J=11.8Hz,1H),6.08(s,1H),5.86(d,J=11.7Hz,1H),0.89(s,9H),0.11(s,6H).13C NMR(100MHz,CDCl3):δ163.87,144.98,144.00,134.86,133.81,130.22,129.36,128.87,128.59,128.33,126.94,115.79,109.21,25.62,18.35,-5.19.HRMS(ESI):Calcd 381.1881 for C23H29O3Si[M+H]+;Found:381.1873.
实施例15
一种钯催化合成Danishefsky-Diene化合物15的方法,在氮气条件下,25mL史莱克管中依次加入四(三苯基膦)钯(0.03mmol)作为催化剂,底物十五(0.3mmol)作为反应底物,亚膦酰胺配体L(0.03mmol),水(6mmol)作为质子源,2,6-二甲基吡啶(1mmol)作为碱,1,4二氧六环(3mL)作为有机溶剂。
室温下混合均匀后,反应混合物在50℃下反应16h。反应结束,直接层析分离(石油醚:乙酸乙酯V/V=100∶1)得到化合物15,其产率为61%。1H NMR(400MHz,CDCl3):7.37–7.35(m,2H),7.30–7.26(m,2H),7.20–7.16(m,1H),6.73(d,J=11.6Hz,1H),6.02(s,1H),5.82(d,J=11.6Hz,1H),1.32(s,9H),1.20–1.15(m,3H),1.12–1.10(m,18H).13C NMR(100MHz,CDCl3):δ175.08,145.20,143.95,135.00,128.54,128.24,126.81,115.63,109.25,39.23,27.48,17.72,11.98.HRMS(ESI):Calcd 403.2663 for C24H39O3Si[M+H]+;Found:403.2654.
实施例1~15的原料和产物结构式及对应的实验结果如下表1所示:
表1
本申请合成的含有两个氧原子取代的共轭二烯Danishefsky-Diene与亲二烯体发生环化反应,合成天然产物和药物分子的关键中间体:六元环的骨架,从而存在进一步转化为药物分子castoreum的一种成分,triketide以及iso-Hajos-Parrish Ketone等的潜质。
对比例1
对比例1与实施例1的方法相同,不同之处在于:不加入钯催化剂,目标产物产率为0。
对比例2
对比例2与实施例1的方法相同,不同之处在于:不加入配体L,目标产物产率为5%。
对比例3
对比例3与实施例1的方法相同,不同之处在于:使用烷基炔丙醇酯作为底物,目标产物产率为0。
以上所述,仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,虽然本发明已以较佳实施例揭露如上,然而并非用以限定本发明,本发明中的各种钯催化剂理论上都能炔丙醇酯形成环丁烯钯物种,从而有利于反应的顺利进行;取代基的修饰只是一定程度上影响反应,不对反应的发生起决定作用。任何熟悉本专业的技术人员不难理解,在不脱离本发明技术方案范围内,当可进行变动或修饰得到相应的实施例,例如对于所述的取代基可在本发明范围内进行替换、改变或修饰,均可以实现本发明方法。但凡是未脱离本发明技术方案的宗旨,依据本发明的对以上实施例所作的任何修改、修饰或等同与等效的变化,均仍属于本发明技术方案的范围内。
Claims (10)
1.一种钯催化合成Danishefsky-Diene的方法,其特征在于:在有机溶剂中,以炔丙醇酯作为反应底物,钯作为催化剂与配体L进行配位,水作为质子源,碱促进氢的消除来合成含有两个氧原子取代的共轭二烯Danishefsky-Diene;反应通式表示如下:
式中:R为取代或非取代芳基和杂芳基,R1为烷基羰基和/或芳基羰基,R2为烷基和/或硅烷基,L代表配体。
2.根据权利要求1所述的一种钯催化合成Danishefsky-Diene的方法,其特征在于:所述R表示取代或者非取代芳基、含N、O、S的杂芳基,其芳环上的取代基选自氢、C1~C20的烷基、C1~C20卤取代烷基、C1~C20烷基羰基、硝基、羟基、氰基、硅基、氨基、硫基中的一种或几种。
3.根据权利要求1所述的一种钯催化合成Danishefsky-Diene的方法,其特征在于:所述R1表示C1~C20的烷基羰基、C1~C20卤取代烷基羰基、C1~C20芳基羰基、C1~C20卤取代芳基基羰基中的一种或几种。
4.根据权利要求1所述的一种钯催化合成Danishefsky-Diene的方法,其特征在于:所述R2表示C1~C20的烷基、C1~C20卤取代烷基中的一种或几种。
5.根据权利要求1所述的一种钯催化合成Danishefsky-Diene的方法,其特征在于,所述配体为双齿手性N配体、双齿手性P配体、双齿手性N、P配体、单齿手性N配体中的一种或几种。
6.根据权利要求1所述的一种钯催化合成Danishefsky-Diene的方法,其特征在于:所述钯选自醋酸钯、新戊酸钯、四(三苯基膦)钯、二(三叔丁基膦)钯、三(双环己基膦)二氯化钯、双(三邻甲苯膦)二氯化钯、双(甲基二苯基膦)二氯化钯、双(乙腈)二氯化钯、二(苯腈)二氯化钯、双(二亚苄基丙酮)钯、三(二亚苄基丙酮)二钯中的一种或几种。
7.根据权利要求1所述的一种钯催化合成Danishefsky-Diene的方法,其特征在于,所述有机溶剂选自甲醇、乙醇、乙二醇、正丙醇、异丙醇、1,3-丙二醇、甘油、正丁醇、异丁醇、叔丁醇、三氟乙醇、2-甲基-2-丁醇、3-甲氧基丁醇、仲丁醇、叔戊醇、4-甲基-2-戊醇、异戊醇、2-戊醇、3-戊醇、环戊醇、正戊醇、聚乙二醇200-10000、乙腈、苯腈、甲苯、丙酮、二氯甲烷、1,2-二氯乙烷、二甲亚砜、N,N二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二甲基丙烯基脲、N-甲基吡咯烷酮、乙酸乙酯、1,4-二氧六环、四氢呋喃中的一种或几种。
8.根据权利要求1所述的一种钯催化合成Danishefsky-Diene的方法,其特征在于,所述炔丙醇酯、钯、配体的摩尔比为1:(0.1~0.3):(0.1~0.3)。
9.根据权利要求1所述的一种钯催化合成Danishefsky-Diene的方法,其特征在于:碱为无机碱和/或有机碱,无机碱选自碳酸钠、碳酸铯、碳酸钾、氢氧化钠中的一种或几种;有机碱选自三乙胺、二环己基胺、吡啶、哌啶,2,6-二甲基吡啶中的一种或几种。
10.根据权利要求1所述的一种钯催化合成Danishefsky-Diene的方法,其特征在于:所述合成含有两个氧原子取代的共轭二烯Danishefsky-Diene的温度为40-70℃,时间为10-20小时,反应氛围为氮气条件下。
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