CN111647018A - Preparation method of phosphorus center chiral compound - Google Patents
Preparation method of phosphorus center chiral compound Download PDFInfo
- Publication number
- CN111647018A CN111647018A CN202010501171.8A CN202010501171A CN111647018A CN 111647018 A CN111647018 A CN 111647018A CN 202010501171 A CN202010501171 A CN 202010501171A CN 111647018 A CN111647018 A CN 111647018A
- Authority
- CN
- China
- Prior art keywords
- group
- alkyl
- nmr
- phenyl
- phosphorus
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 35
- 229910052698 phosphorus Inorganic materials 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- -1 2-pyridyl diaryl phosphine oxides Chemical class 0.000 claims abstract description 70
- 150000001336 alkenes Chemical class 0.000 claims abstract description 13
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 11
- 239000003446 ligand Substances 0.000 claims abstract description 11
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 claims abstract description 11
- 150000001413 amino acids Chemical class 0.000 claims abstract description 10
- 150000002940 palladium Chemical class 0.000 claims abstract description 10
- 238000006772 olefination reaction Methods 0.000 claims abstract description 9
- 239000007800 oxidant agent Substances 0.000 claims abstract description 9
- 230000001590 oxidative effect Effects 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 229910001923 silver oxide Inorganic materials 0.000 claims description 7
- 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 6
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 claims description 5
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 5
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 5
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 4
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000005561 phenanthryl group Chemical group 0.000 claims description 4
- 239000011574 phosphorus Substances 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001725 pyrenyl group Chemical group 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical group [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 239000012429 reaction media Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- MHUMCPFRVONXMM-UHFFFAOYSA-N 4-methyl-1-(4-methyl-2-phenylphenyl)sulfonyl-2-phenylbenzene Chemical group C=1C(C)=CC=C(S(=O)(=O)C=2C(=CC(C)=CC=2)C=2C=CC=CC=2)C=1C1=CC=CC=C1 MHUMCPFRVONXMM-UHFFFAOYSA-N 0.000 claims 1
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 claims 1
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 198
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 170
- 239000000203 mixture Substances 0.000 description 87
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 82
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 81
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 69
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
- 238000003786 synthesis reaction Methods 0.000 description 45
- 230000015572 biosynthetic process Effects 0.000 description 44
- 239000012074 organic phase Substances 0.000 description 43
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 42
- 238000005160 1H NMR spectroscopy Methods 0.000 description 42
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 42
- 238000010898 silica gel chromatography Methods 0.000 description 41
- 239000011734 sodium Substances 0.000 description 39
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 27
- 239000011780 sodium chloride Substances 0.000 description 27
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 27
- 239000003208 petroleum Substances 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- 238000010828 elution Methods 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- KTHDTJVBEPMMGL-VKHMYHEASA-N N-acetyl-L-alanine Chemical compound OC(=O)[C@H](C)NC(C)=O KTHDTJVBEPMMGL-VKHMYHEASA-N 0.000 description 16
- KTHDTJVBEPMMGL-UHFFFAOYSA-N N-acetyl-L-alanine Natural products OC(=O)C(C)NC(C)=O KTHDTJVBEPMMGL-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 15
- 229940071536 silver acetate Drugs 0.000 description 15
- 239000012299 nitrogen atmosphere Substances 0.000 description 14
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 13
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 10
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- SZXBQTSZISFIAO-ZETCQYMHSA-N (2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C SZXBQTSZISFIAO-ZETCQYMHSA-N 0.000 description 6
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 5
- QKJAZPHKNWSXDF-UHFFFAOYSA-N 2-bromoquinoline Chemical compound C1=CC=CC2=NC(Br)=CC=C21 QKJAZPHKNWSXDF-UHFFFAOYSA-N 0.000 description 4
- DTQFYZAIOBOXCO-UHFFFAOYSA-N COc1ccc(cc1)[P](=O)c1ccc(OC)cc1 Chemical compound COc1ccc(cc1)[P](=O)c1ccc(OC)cc1 DTQFYZAIOBOXCO-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 3
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000006254 arylation reaction Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- YWWZASFPWWPUBN-UHFFFAOYSA-N 1-bromoisoquinoline Chemical compound C1=CC=C2C(Br)=NC=CC2=C1 YWWZASFPWWPUBN-UHFFFAOYSA-N 0.000 description 2
- PZSISEFPCYMBDL-UHFFFAOYSA-N 2-bromo-3-methylpyridine Chemical compound CC1=CC=CN=C1Br PZSISEFPCYMBDL-UHFFFAOYSA-N 0.000 description 2
- SOHDPICLICFSOP-UHFFFAOYSA-N 2-bromo-6-methylpyridine Chemical compound CC1=CC=CC(Br)=N1 SOHDPICLICFSOP-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VCKQRKMYCBNCSF-UHFFFAOYSA-N Fc1ccc(cc1)[P](=O)c1ccc(F)cc1 Chemical compound Fc1ccc(cc1)[P](=O)c1ccc(F)cc1 VCKQRKMYCBNCSF-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 1
- LRFZIPCTFBPFLX-SSDOTTSWSA-N (2s)-3,3-dimethyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)C(C)(C)C LRFZIPCTFBPFLX-SSDOTTSWSA-N 0.000 description 1
- KTZVZZJJVJQZHV-UHFFFAOYSA-N 1-chloro-4-ethenylbenzene Chemical compound ClC1=CC=C(C=C)C=C1 KTZVZZJJVJQZHV-UHFFFAOYSA-N 0.000 description 1
- JWVTWJNGILGLAT-UHFFFAOYSA-N 1-ethenyl-4-fluorobenzene Chemical compound FC1=CC=C(C=C)C=C1 JWVTWJNGILGLAT-UHFFFAOYSA-N 0.000 description 1
- WPMHMYHJGDAHKX-UHFFFAOYSA-N 1-ethenylpyrene Chemical compound C1=C2C(C=C)=CC=C(C=C3)C2=C2C3=CC=CC2=C1 WPMHMYHJGDAHKX-UHFFFAOYSA-N 0.000 description 1
- DNWSVXHWEWBVSJ-UHFFFAOYSA-N 2-diphenylphosphorylpyridine Chemical compound C=1C=CC=CC=1P(C=1N=CC=CC=1)(=O)C1=CC=CC=C1 DNWSVXHWEWBVSJ-UHFFFAOYSA-N 0.000 description 1
- SCWURGBJGRXNOA-UHFFFAOYSA-N 2-diphenylphosphorylquinoline Chemical compound C=1C=CC=CC=1P(C=1N=C2C=CC=CC2=CC=1)(=O)C1=CC=CC=C1 SCWURGBJGRXNOA-UHFFFAOYSA-N 0.000 description 1
- KXYAVSFOJVUIHT-UHFFFAOYSA-N 2-vinylnaphthalene Chemical compound C1=CC=CC2=CC(C=C)=CC=C21 KXYAVSFOJVUIHT-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- JLBJTVDPSNHSKJ-UHFFFAOYSA-N 4-Methylstyrene Chemical compound CC1=CC=C(C=C)C=C1 JLBJTVDPSNHSKJ-UHFFFAOYSA-N 0.000 description 1
- BGGDZDRRHQTSPV-UHFFFAOYSA-N 4-ethenyl-n,n-diphenylaniline Chemical compound C1=CC(C=C)=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 BGGDZDRRHQTSPV-UHFFFAOYSA-N 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- KGHDWPBBOUJUEF-UHFFFAOYSA-N COC1=CC=C(C=C1)[PH2]=O Chemical compound COC1=CC=C(C=C1)[PH2]=O KGHDWPBBOUJUEF-UHFFFAOYSA-N 0.000 description 1
- IEZLCNLEPOROKK-UHFFFAOYSA-N COc1cccc(c1)[P](=O)c1cccc(OC)c1 Chemical compound COc1cccc(c1)[P](=O)c1cccc(OC)c1 IEZLCNLEPOROKK-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ICYMNRZVLLTNSE-UHFFFAOYSA-N Cc1ccc(cc1)[P](=O)c1ccc(C)cc1 Chemical compound Cc1ccc(cc1)[P](=O)c1ccc(C)cc1 ICYMNRZVLLTNSE-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- KKUKTXOBAWVSHC-UHFFFAOYSA-N Dimethylphosphate Chemical compound COP(O)(=O)OC KKUKTXOBAWVSHC-UHFFFAOYSA-N 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005466 alkylenyl group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- UCQFCFPECQILOL-UHFFFAOYSA-N diethyl hydrogen phosphate Chemical compound CCOP(O)(=O)OCC UCQFCFPECQILOL-UHFFFAOYSA-N 0.000 description 1
- GCSJLQSCSDMKTP-UHFFFAOYSA-N ethenyl(trimethyl)silane Chemical compound C[Si](C)(C)C=C GCSJLQSCSDMKTP-UHFFFAOYSA-N 0.000 description 1
- UJTPZISIAWDGFF-UHFFFAOYSA-N ethenylsulfonylbenzene Chemical compound C=CS(=O)(=O)C1=CC=CC=C1 UJTPZISIAWDGFF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical group [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 239000002699 waste material Substances 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/62—Isoquinoline or hydrogenated isoquinoline ring systems
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a preparation method of a phosphorus center chiral compound, which specifically comprises the following steps: in the presence of an oxidant, a palladium salt and an N-single protection chiral amino acid ligand, carrying out C-H bond olefination reaction on 2-pyridyl diaryl phosphine oxide shown in a formula (II) and olefin derivatives shown in a formula (III) to generate a phosphorus center chiral compound shown in a formula (I). The method has better adaptability to various 2-pyridyl diaryl phosphine oxides and different substituent groups in olefin, especially olefin with larger steric hindrance, and has stable yield and excellent enantioselectivity.
Description
Technical Field
The invention relates to the technical field of asymmetric chemical synthesis, in particular to a preparation method of a phosphorus center chiral compound.
Background
Chiral phosphorus compounds have played an important role as chiral ligands and catalysts in various types of asymmetric catalytic reactions. Since the difficulty in constructing the phosphorus chiral center is great, chemists have focused more on the construction of the chiral carbon skeleton in the early stage of research, and the phosphorus chiral center is often ignored.
Over the last decade, great efforts have been made by chemists to maintain constant efforts in the asymmetric synthesis of chiral compounds at the phosphorus center, particularly in the preparation of such compounds by novel asymmetric catalytic reactions. Such as cross-coupling reactions of secondary phosphine oxides with aromatic hydrocarbons containing a leaving group, and the like. However, the related synthetic routes often require the preparation of a substrate containing a functional group in advance, and the atom economy and step economy of the reaction routes are poor. In addition, these catalytic reactions suffer from problems such as limited range of substrates, low turnover and low stereoselectivity.
It is well known that the C-H bond is a chemical bond that is widely present in various types of organic compounds. The C-H bond activation strategy is known as an effective method for directly and quickly constructing C-C bonds and C-heteroatom bonds, the economical efficiency of reaction atoms is improved, meanwhile, the synthetic route is greatly shortened, the waste emission is reduced, and the method belongs to a green chemical process.
With the continuous and intensive research of chemists in the field in recent years, a plurality of efficient catalytic systems have been developed, regioselective and stereoselective functionalization is realized on a substrate aryl C-H bond with a specific structure, and the synthesis of a phosphorus center chiral compound is successfully realized. Higher yields and enantioselectivities were achieved in the catalytic Synthesis of phosphorus-centered chiral compounds by using intramolecular asymmetric arylC-H bond Arylation as described by Staglair et al (Palladium-catalysis Enantioselective C-H Arylation for the Synthesis of P-Stereogenic compounds, Angew. chem. int. Ed.2015,54,6265). Korean-Foster et al synthesized a series of phosphorus-centered chiral compounds using phosphoramide directed intermolecular asymmetric arylC-H bond Arylation reactions with moderate to good yields and excellent enantioselectivity (Palladium-Catalyzed Enantioselective Synthesis of P-stereospecific phosphonic acid via Desymmetic C-H aryl, J.Am.chem.Soc.,2015,137,632).
However, no report has been found on the study of synthesizing chiral compounds at phosphorus centers by using the transition metal to catalyze the enantioselective C-H bond olefination reaction between molecules starting from achiral raw materials.
Disclosure of Invention
The invention provides a preparation method of a phosphorus center chiral compound, which is characterized in that under the existence of a complex formed by an oxidant, palladium salt and an N-single protection chiral amino acid ligand, 2-pyridyl diaryl phosphine oxide and an olefin derivative are used as raw materials to carry out intermolecular asymmetric C-H bond olefination reaction to synthesize the phosphorus center chiral compound.
The technical scheme provided by the invention for solving the technical problems is as follows:
a preparation method of a phosphorus center chiral compound comprises the following steps that in the presence of an oxidant, a palladium salt and an N-single protection chiral amino acid ligand, C-H bond olefination reaction is carried out on 2-pyridyl diaryl phosphine oxide shown in a formula (II) and an olefin derivative shown in a formula (III) to generate the phosphorus center chiral compound shown in the formula (I);
wherein,
m is 0, 1,2, 3 or 4;
n is 0, 1,2 or 3;
R1is H, C1～6Alkyl or C6～10Aryl radical, said C1～10Alkyl or C6～10Aryl is optionally substituted by 1-3 halogens, methyl, OH or NH2Substitution; or two adjacent R1Together with the pyridyl group to which it is attached to form a quinolinyl group;
R2is H, halogen, C1～6Alkyl radical, C1～6Alkoxy or C6～10Aryl radical, said C1～6Alkyl radical, C1～6Alkoxy or C6～10Aryl is optionally substituted by 1-3 halogens, methyl, OH or NH2Substitution; or two adjacent R2Together with the phenyl group to which it is attached form a naphthyl group;
R3is H, C1～6Alkyl, -C (═ O) O-C1～6Alkyl radical, C1～6alkyl-CHO, -C (═ O) -C1～6Alkyl, -P (═ O) - (O-C)1～6Alkyl radical)3、-S(＝O)2-C1～6Alkyl, -S (═ O)2-C6～20Aryl, -Si (C)1～6Alkyl radical)3、C6～20Aryl radical, said C6～20Aryl is optionally substituted by 1-3 of halogen, methyl, heteroaryl, OH, NH2or-N (Ph)2Substituted, said C1～6Alkyl, -S (═ O)2-C6～20Aryl, -Si (C)1～6Alkyl radical)3Optionally substituted by 1-3 halogens, methyl, OH or NH2And (4) substitution.
Preferably, R is1Is H, C1～4Alkyl or phenyl, said C1～4The alkyl or phenyl is optionally substituted with 1-3 halogens.
Preferably, R is1Is H, methyl, tert-butyl or phenyl, and the methyl, tert-butyl or phenyl is optionally substituted by 1-3 halogens.
Two adjacent R1Together with the pyridyl group to which it is attached form a quinolinyl group, said quinolinyl group being
The two adjacent R2Together with the phenyl group to which they are attached form a naphthyl group, said naphthyl group being
Preferably, R is2Is H, halogen, C1～4Alkyl radical, C1～4Alkoxy or phenyl, said C1～4Alkyl radical, C1～4The alkoxy or phenyl is optionally substituted with 1 to 3 halogens.
Preferably, R is2Is H, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy or phenyl, the methyl, ethylPropyl, methoxy, ethoxy, propoxy or phenyl optionally substituted with 1 to 3 halogens.
In the preparation process of the phosphorus center chiral compound, olefin with large steric hindrance can also smoothly react. Preferably, R is3Is H, methyl ester, ethyl ester, n-butyl ester, tert-butyl ester, p-methoxyphenyl, p-nitrophenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-methylphenyl, phenylsulfonyl, dimethyl phosphate, diethyl phosphate, trimethylsilyl, diphenylaminophenyl, naphthyl, anthryl, phenanthryl, pyrenyl or
The naphthyl, anthryl, phenanthryl or pyrenyl group is optionally substituted by 1-3 halogens.
The palladium salt is palladium acetate, palladium bis (acetylacetonate), palladium trifluoroacetate, palladium tetrakis (acetonitrile) tetrafluoroborate or palladium chloride.
The N-single protection chiral amino acid ligand is
The oxidant is copper acetate, silver carbonate, silver oxide or benzoquinone.
The reaction temperature of the C-H bond olefination reaction is 40-80 ℃, and the reaction time is 6-48H.
The reaction medium of the C-H bond olefination reaction is methanol, tetrahydrofuran, tert-amyl alcohol, toluene or hexafluoroisopropanol. The solvent is preferably tert-amyl alcohol, in which case the reaction gives the desired product in higher yield and enantioselectivity.
The preparation method of the phosphorus center chiral compound also comprises the following post-treatment steps, after the reaction is finished, the mixture is diluted by water, and after extraction, an organic phase is separated by silica gel column chromatography to obtain the phosphorus center chiral compound shown in the formula (I).
The concentration of the 2-pyridyl diaryl phosphine oxide shown in the formula (II) is 0.1-0.5 mol/L solution.
The molar ratio of the oxidant to the 2-pyridyl diaryl phosphine oxide shown in the formula (II) is 1.1-3: 1.
the molar ratio of the palladium salt to the 2-pyridyl diaryl phosphine oxide shown in the formula (II) is 0.01-0.1: 1.
the molar ratio of the N-single protection chiral amino acid ligand to the 2-pyridyl diaryl phosphine oxide shown in the formula (II) is 0.01-0.2: 1.
the mol ratio of the olefin derivative shown in the formula (III) to the 2-pyridyl diaryl phosphine oxide shown in the formula (II) is 1.1-3: 1.
the molar ratio of the oxidant, the palladium salt, the N-single protection chiral amino acid ligand, the 2-pyridyl diaryl phosphine oxide shown in the formula (II) and the olefin derivative shown in the formula (III) is 1.1-3: 0.01-0.1: 0.01-0.2: 1: 1.1 to 3.
Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, including variations of deuterium and hydrogen, so long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., ═ O), it means that two hydrogen atoms are substituted. The keto substitution does not occur on the aromatic group.
The term "optionally substituted" means that it may or may not be substituted, and the kind and number of the substituents may be arbitrary on the basis of chemical realizability.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent, unless otherwise specified. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
Unless otherwise specified, the term "C1-10Alkyl "is intended to mean a straight-chain or branched radical derived from 1To a saturated hydrocarbon group consisting of 8 carbon atoms. Said C is1-10The alkyl group comprising C1-10、C1-9、C1-8、C1-6、C1-5、C1-4、C1-3、C1-2、C2-6、C2-4、C10、C9、C8、C7、C6And C5Alkyl, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C1-10Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, heptyl, octyl, and the like.
Compounds are named according to the conventional naming principles in the art or using software, and commercially available compounds are referred to by the supplier's catalog name.
Compared with the prior art, the invention has the advantages that:
1. the catalyst palladium salt and the N-single protection chiral amino acid ligand of the preparation method are commercial reagents, and the raw materials of the 2-pyridyl diaryl phosphine oxide and the olefin derivative are cheap and easy to obtain.
2. The preparation method has the advantages of good yield and enantioselectivity, simple operation, and convenient post-treatment, and the crude product is subjected to rapid column chromatography for impurity removal and then is subjected to reduced pressure concentration to obtain a pure product.
3. The preparation method has better adaptability to various 2-pyridyl diaryl phosphine oxides and different substituent groups in olefin, especially olefin with larger steric hindrance, stable yield and excellent enantioselectivity.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers.
Example 1: synthesis of diphenyl (pyridin-2-yl) phosphine oxide
To a 100mL Schlenk reaction flask, diphenylphosphine oxide (4.04g,20mmol), 2-bromopyridine (2.38mL,25mmol), and K were added in this order under a nitrogen atmosphere2CO3(3.45g,25mmol)。Ni(PPh3)2Cl2(261.7mg,0.4mmol), DMF (15mL), and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 1:1 elution, and suction-dried to give a white solid (3.77g,13.5mmol) with a yield of 67.5%.
1H NMR(400MHz,CDCl3)8.75(d,J＝3.9Hz,1H),8.29(t,J＝6.4Hz,1H),7.90(dd,J＝11.6,7.7Hz,4H),7.84–7.72(m,1H),7.55–7.37(m,6H),7.37–7.24(m,1H)。
13C NMR(101MHz,CDCl3)156.3(d),150.1(d),136.2(d),132.2(d),132.1(d),131.9(d),128.3(d),128.2(s),125.3(d)。
HRMS(ESI):m/z:[M+H]+calculated for C17H15NOP:280.0886,Found:280.0891。
Example 2 Synthesis of (3-methylpyridin-2-yl) diphenylphosphine oxide
To a 100mL Schlenk reaction flask, diphenylphosphine oxide (4.04g,20mmol), 2-bromo-3-methylpyridine (2.79mL,25mmol), K were added in this order under a nitrogen atmosphere2CO3(3.45g,25mmol)。Ni(PPh3)2Cl2(261.7mg,0.4mmol), DMF (15mL), and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the mixture was chromatographed on silica gel column, petroleum ether/ethyl acetate 1:1, and dried to give a white solid (4.04g,13.8mmol) in 69 yield.2％。
1H NMR(400MHz,CDCl3)8.50(d,J＝4.1Hz,1H),7.85–7.68(m,4H),7.61–7.36(m,7H),7.27(dd,J＝7.9,4.2Hz,1H),2.65(s,3H)。
13C NMR(101MHz,CDCl3)153.3(d),146.5(d),140.6(d),139.3(d),132.89(d),132.1(d),131.7(d),128.3(d),125.1(d),19.2(s)。
HRMS(ESI):m/z:[M+H]+calculated for C18H16NOP:294.0970,Found:294.1044。
Example 3: synthesis of diphenyl (quinolin-2-yl) phosphine oxide
To a 100mL Schlenk reaction flask, diphenylphosphine oxide (4.04g,20mmol), 2-bromoquinoline (5.21mL,25mmol), K were added under a nitrogen atmosphere2CO3(3.45g,25mmol)，Ni(PPh3)2Cl2(654.2mg,1mmol), DMF (15mL), and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 1:1 elution, and suction-dried to give a white solid (3.62g,11mmol) with a yield of 55%.
1H NMR(400MHz,CDCl3)8.32(ddd,J＝20.7,8.3,4.0Hz,2H),8.15(d,J＝8.5Hz,1H),8.07–7.90(m,4H),7.84(d,J＝8.2Hz,1H),7.78–7.66(m,1H),7.59(t,J＝7.5Hz,1H),7.54–7.34(m,6H)。
13C NMR(101MHz,CDCl3)157.1(d),148.1(d),136.2(d),132.5(d),132.2(d),131.9(d),130.2(d),128.3(d),128.2(s),127.9(d),123.4(d).31P NMR(202MHz,CDCl3)20.59(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C21H14F2NOP:352.0971,Found:352.0863。
Example 4: synthesis of bis (4-fluorophenyl) (quinolin-2-yl) phosphine oxide
To a 100mL Schlenk reaction flask, bis (p-fluoro) phenylphosphoric oxide (4.76g,20mmol), 2-bromoquinoline (5.21mL,25mmol), K was added under a nitrogen atmosphere2CO3(4.14g,30mmol)，Ni(PPh3)2Cl2(261.7mg,0.4mmol), DMF (15mL), and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 2:1 elution, and suction-dried to give a white solid (4.20g,11.5mmol), yield 57.5%.
1H NMR(400MHz,CDCl3)8.34(d,J＝3.9Hz,2H),8.14(d,J＝8.5Hz,1H),7.99(ddd,J＝11.4,7.9,5.8Hz,4H),7.88(d,J＝8.2Hz,1H),7.77(t,J＝7.7Hz,1H),7.63(t,J＝7.5Hz,1H),7.14(t,J＝8.2Hz,4H)。
13C NMR(101MHz,CDCl3)166.43(s),163.88(s),157.31(s),155.99(s),148.22(s),148.00(s),136.41(s),134.92–134.25(m),130.24(d,J＝10.2Hz),128.82(s),128.35(d,J＝9.6Hz),127.88(d,J＝19.5Hz),123.32(s),123.10(s),115.77(dd,J＝21.4,13.3Hz)。
HRMS(ESI):m/z:[M+Na]+calculated for C21H14F2NOP:388.0781,Found:388.0674。
Example 5: synthesis of bis (4-fluorophenyl) (3-methylpyridin-2-yl) phosphine oxide
Under nitrogen atmosphere, bis (p-fluorophenyl) phosphorus oxide (0.952g,5mmol), 1-bromoisoquinoline (1.04g,5mmol), and K were sequentially added to a 100mL Schlenk reaction flask2CO3(1.38g,10mmol)，Ni(PPh3)2Cl2(159.3mg,0.25mmol), DMF (5mL) and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate,the mixture was chromatographed on a silica gel column eluting with petroleum ether/ethyl acetate 2:1 and dried by suction to give a white solid (1.10g,3mmol) in 60% yield.
1H NMR(400MHz,CDCl3)9.42(d,J＝8.5Hz,1H),8.62(d,J＝5.5Hz,1H),7.90–7.82(m,5H),7.76(dd,J＝5.6,2.8Hz,1H),7.71(d,J＝7.2Hz,1H),7.65(dd,J＝11.4,4.1Hz,1H),7.14(td,J＝8.7,2.1Hz,4H)。
13C NMR(101MHz,CDCl3)166.30(s),163.79(s),155.95(s),154.63(s),136.22(d,J＝7.4Hz),134.70(s),131.58(d,J＝22.6Hz),130.80(s),129.41(s),128.41(d,J＝22.3Hz),127.21(d,J＝24.2Hz),123.28(s),115.72(dd,J＝21.3,13.2Hz)。
HRMS(ESI):m/z:[M+Na]+calculated for C21H14F2NOP:388.0781,Found:388.0674。
Example 6: synthesis of bis (4-fluorophenyl) (6-methylpyridin-2-yl) phosphine oxide
To a 100mL Schlenk reaction flask, bis (p-fluorophenyl) phosphorus oxide (0.952g,5mmol), 2-bromo-6-methylpyridine (0.68mL,6mmol), K were added in that order under a nitrogen atmosphere2CO3(1.38g,10mmol)。Ni(PPh3)Cl2(159.25mg,0.25mmol), DMF (5mL) and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 2:1 elution, and suction-dried to give a white solid (0.89g,2.7mmol) with a yield of 54%.
1H NMR(400MHz,CDCl3)8.00(t,J＝6.7Hz,1H),7.85(ddd,J＝11.4,8.2,5.9Hz,4H),7.66(td,J＝7.7,4.2Hz,1H),7.18(d,J＝9.6Hz,1H),7.06(dd,J＝8.6,7.2Hz,4H),2.51(s,3H)。
13C NMR(101MHz,CDCl3)166.35(s),163.83(s),159.26(d,J＝19.4Hz),136.39(s),134.64(d,J＝10.1Hz),129.01(s),127.91(s),125.42(d,J＝20.0Hz),115.67(dd,J＝21.3,13.0Hz),24.65(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C18H14F2NOP:352.0789,Found:352.0763。
Example 7: synthesis of bis (4-methoxyphenyl) (pyridin-2-yl) phosphine oxide
To a 100mL Schlenk reaction flask, bis (p-methoxyphenyl) phosphorus oxide (0.952g,5mmol), 2-bromopyridine (0.60mL,6mmol), K were added under a nitrogen atmosphere2CO3(1.38g,10mmol)。Ni(PPh3)Cl2(159.25mg,0.25mmol), DMF (5mL) and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 2:1 elution, and suction-dried to give a white solid (0.85g,2.5mmol) with a yield of 50%.
1H NMR(400MHz,CDCl3)8.68(d,J＝3.6Hz,1H),8.20(t,J＝6.4Hz,1H),7.80–7.64(m,5H),7.29(s,1H),6.87(d,J＝7.5Hz,4H),3.74(s,6H)。
13C NMR(101MHz,CDCl3)162.47(s),136.12(s),133.94(s),128.21(s),125.06(s),124.08(s),122.97(s),114.03(s),113.90(s),55.30(d)。
HRMS(ESI):m/z:[M+Na]+calculated for C19H18NO3P:362.1026,Found:362.0917。
Example 8: synthesis of bis (4-methoxyphenyl) (3-methylpyridin-2-yl) phosphine oxide
To a 100mL Schlenk reaction flask, bis (p-methoxy) phenylphosphine oxide (0.952g,5mmol), 2-bromo-3-methylpyridine (0.60mL,6mmol), K were added in that order under a nitrogen atmosphere2CO3(1.38g,10mmol)。Ni(PPh3)Cl2(159.25mg,0.25mmol)DMF (5mL) and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 2:1 elution, and suction-dried to give a white solid (0.88g,2.5mmol) with a yield of 50%.
1H NMR(400MHz,CDCl3)8.49(d,J＝4.4Hz,1H),7.66(dd,J＝11.2,8.7Hz,4H),7.62–7.50(m,2H),6.94(dd,J＝8.7,2.0Hz,4H),3.82(s,6H),2.64(s,3H).13C NMR(101MHz,CDCl3)162.21(s),154.72(s),153.38(s),140.17(s),139.16(s),133.83(s),124.94(s),123.83(s),113.85(d),55.27(s),19.29(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C20H20NO3P:376.1181,Found:376.1073。
Example 9: synthesis of bis (4-methoxyphenyl) (6-methylpyridin-2-yl) phosphine oxide
To a 100mL Schlenk reaction flask, bis (p-methoxyphenyl) phosphorus oxide (0.952g,5mmol), 2-bromo-6-methylpyridine (0.60mL,6mmol), and K were added in this order under a nitrogen atmosphere2CO3(1.38g,10mmol)。Ni(PPh3)Cl2(159.3mg,0.25mmol), DMF (5mL) and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 2:1 elution, and suction-dried to give a white solid (0.93g,2.65mmol), 53% yield.
1H NMR(400MHz,CDCl3)9.41(t,J＝6.6Hz,1H),9.21(dd,J＝11.3,8.7Hz,4H),9.10(td,J＝7.7,4.0Hz,1H),8.62(d,J＝7.6Hz,1H),8.36(dd,J＝8.7,2.1Hz,4H),5.23(s,6H),3.98(s,3H)。
13C NMR(101MHz,CDCl3)162.36(d),159.10(d),155.82(d),136.15(s),134.00(d),125.12(d),123.77(d),113.86(d),100.00(s),55.28(d,),24.63(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C20H20NO3P:376.1181,Found:376.1075。
Example 10: synthesis of bis (4-methoxyphenyl) (quinolin-2-yl) phosphine oxide
To a 100mL Schlenk reaction flask, bis (p-methoxyphenyl) phosphorus oxide (0.952g,5mmol), 2-bromoquinoline (1.25g,6mmol), and K were added in that order under a nitrogen atmosphere2CO3(1.38g,10mmol)。Ni(PPh3)Cl2(159.3mg,0.25mmol), DMF (5mL) and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 2:1 elution, and suction-dried to give a white solid (0.82g,2.1mmol) with a yield of 42%.
1H NMR(400MHz,CDCl3)8.27–8.18(m,1H),8.12(s,1H),8.02(s,1H),7.83(dd,J＝14.3,5.6Hz,4H),7.69–7.47(m,2H),7.38(d,J＝6.5Hz,1H),6.83(d,J＝1.9Hz,4H),3.67–3.53(m,6H)。
13C NMR(101MHz,CDCl3)162.36(d),158.37(s),157.07(s),148.10(s),147.89(s),136.12(d),133.98(dd),130.02(s),127.92(d,),124.23(s),123.14(s),122.94(s),113.89(d),55.16(d)。
HRMS(ESI):m/z:[M+Na]+calculated for C23H20NO3P:412.1181,Found:412.1073。
Example 11: synthesis of isoquinolin-1-yl bis (4-methoxyphenyl) phosphine oxide
Under nitrogen atmosphere, bis (p-methoxyphenyl) phosphorus oxide (0.952g,5mmol), 1-bromoisoquinoline (1.04g,6mmol), K were added to a 100mL Schlenk reaction flask2CO3(1.38g,10mmol)。Ni(PPh3)Cl2(159.3mg,0.25mmol), DMF (5mL) and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluting with petroleum ether/ethyl acetate 2:1, and dried by suction to give a white solid (0.86g,2.2mmol) with a yield of 44%.
1H NMR(400MHz,CDCl3)9.43(d,J＝8.5Hz,1H),8.61(d,J＝5.5Hz,1H),7.85(d,J＝8.1Hz,1H),7.78–7.69(m,6H),7.65–7.59(m,1H),6.95(dd,J＝8.8,2.2Hz,4H),3.82(s,6H)。
13C NMR(101MHz,CDCl3)162.29(s),157.27(s),136.12(s),134.09(s),131.56(s),130.55(s),128.19(s),127.19(s),125.03(s),123.92(s),122.85(s),113.94(s),113.81(s),55.27(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C23H20NO3P:412.1181,Found:412.1071。
Example 12: synthesis of quinolin-2-yl di-p-tolyl phosphine oxide
To a 100mL Schlenk reaction flask, bis (p-methylphenyl) phosphorus oxide (1.15g,5mmol), 2-bromoquinoline (1.04g,6mmol), and K were added in that order under a nitrogen atmosphere2CO3(1.38g,10mmol)。Ni(PPh3)Cl2(159.3mg,0.25mmol), DMF (5mL) and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 2:1 elution, and suction-dried to give a white solid (0.61g,1.7mmol), yield 34%.
1H NMR(400MHz,CDCl3)8.21(qd,J＝8.4,4.0Hz,1H),8.05(d,J＝8.5Hz,1H),7.76(dd,J＝11.6,8.1Hz,4H),7.65–7.55(m,2H),7.52–7.41(m,2H),7.36(td,J＝7.4,2.7Hz,1H),7.17–7.13(m,3H),2.28(d,J＝8.3Hz,6H)。
13C NMR(101MHz,CDCl3)158.21(s),156.92(s),148.16(d),142.24(d),136.06(d),132.13(dd),130.33(s),129.89(d),129.05(d),128.77(s),128.52(d),128.23–127.78(m),123.30(d),21.60(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C23H20NOP:380.1283,Found:380.1176。
Example 13: synthesis of bis (3-methoxyphenyl) (pyridin-2-yl) phosphine oxide
To a 100mL Schlenk reaction flask, bis (m-methoxyphenyl) phosphorus oxide (0.952g,5mmol), 2-bromopyridine (0.60mL,6mmol), and K were added in that order under a nitrogen atmosphere2CO3(1.38g,10mmol)。Ni(PPh3)Cl2(159.3mg,0.25mmol), DMF (5mL) and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 2:1 elution, and suction-dried to give a white solid (0.61g,1.7mmol), yield 34%.
1H NMR(400MHz,CDCl3)8.77(d,J＝4.0Hz,1H),8.25(t,J＝6.7Hz,1H),7.86–7.78(m,1H),7.43(dd,J＝10.8,9.2Hz,4H),7.39–7.30(m,3H),7.03(d,J＝7.3Hz,2H),3.77(s,6H)。
13C NMR(101MHz,CDCl3)159.38(d),156.42(d),150.16(d),136.13(d),133.47(d),129.56(d),128.31(d),125.27(d),124.44(d),118.17(d),116.75(d),55.39(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C19H18NO3P:362.1024,Found:362.0925。
Example 14: synthesis of bis ([1,1' -biphenyl ] -4-yl) (pyridin-2-yl) phosphine oxide
Under nitrogenTo a 100mL Schlenk reaction flask under an atmosphere were added bis (p-phenylphenyl) phosphorus oxide (1.77g,5mmol), 2-bromopyridine (0.60mL,6mmol), K2CO3(1.38g,10mmol)。Ni(PPh3)Cl2(159.3mg,0.25mmol), DMF (5mL) and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 4:1 elution, and suction-dried to give a white solid (0.99g,2.3mmol), yield 46%.
1H NMR(400MHz,CDCl3)8.84(d,J＝4.5Hz,1H),8.41–8.35(m,1H),8.00(dd,J＝11.6,8.3Hz,4H),7.90(ddd,J＝7.7,6.2,3.8Hz,1H),7.69(dd,J＝8.3,2.6Hz,4H),7.62–7.57(m,4H),7.48–7.42(m,5H),7.41–7.35(m,2H)。
13C NMR(101MHz,CDCl3)150.23(d),144.74(d),140.07(s),136.28(d),132.64(d),132.11(d),131.37(s),130.32(s),128.92(s),128.62–128.16(m),128.08(s),127.44–126.97(m),125.36(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C29H22NOP:454.1493,Found:454.1333。
Example 15: synthesis of bis (naphthalen-1-yl) (pyridin-2-yl) phosphine oxides
To a 100mL Schlenk reaction flask, bis (o-phenylphenyl) phosphorus oxide (1.51g,5mmol), 2-bromopyridine (0.60mL,6mmol), K were added in that order under a nitrogen atmosphere2CO3(1.38g,10mmol)。Ni(PPh3)Cl2(159.3mg,0.25mmol), DMF (5mL) and stirred at 90 ℃ for 24 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 4:1 elution, and suction-dried to give a white solid (0.80g,2.1mmol) with a yield of 42%.
1H NMR(400MHz,CDCl3)8.74(d,J＝8.4Hz,2H),8.68(d,J＝4.5Hz,1H),8.49–8.45(m,1H),8.02(d,J＝8.2Hz,2H),7.90(d,J＝8.1Hz,2H),7.61–7.35(m,10H)。
13C NMR(101MHz,CDCl3)157.68(s),156.36(s),150.02(d),136.46(d),133.83(dd),133.24(d),129.13(d),128.83(s),127.78(s),127.56(d),127.25(s),126.37(s),125.23(d),124.55(s),124.41(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C25H18NOP:402.1125,Found:402.1017。
Example 16: synthesis of ethyl 3- (2- (phenyl (pyridin-2-yl) phosphoryl) phenyl) acrylate
A25 mL Schlenk reaction flask was charged with diphenylene-2-yl phosphine oxide (83.7mg,0.3mmoL), ethyl acrylate (45.1mg,0.45mmoL), palladium acetate (3.4mg,0.015mmoL), silver carbonate (165.5mg,0.6mmoL), Ac-Ala-OH (3.9mg,0.03mmoL), and dissolved thoroughly with methanol (3 mL). The mixture was stirred at room temperature for 10 minutes, then at 80 ℃ for 24 h. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 1:1 elution, and suction-dried to give a white solid with a yield of 65%.
1H NMR(400MHz,CDCl3)8.72(d,J＝4.3Hz,1H),8.38(t,J＝6.6Hz,1H),8.26(d,J＝15.7Hz,1H),8.01(dd,J＝11.5,7.8Hz,2H),7.86(dd,J＝11.2,7.9Hz,1H),7.72–7.57(m,1H),7.57–7.31(m,7H),6.09(d,J＝15.7Hz,1H),4.15(q,J＝7.1Hz,2H),1.28(t,J＝6.9Hz,3H)。
13C NMR(101MHz,CDCl3)165.91(s),156.60(d),150.04(d),142.81(d),139.03(d),136.28(d),133.53(d),132.81(s),132.38(d),132.20–131.54(m),130.61(s),129.56(d),129.00–128.62(m),128.43(t),127.82(d),125.29(s),121.22(d),60.36(s),14.29(s)。
HRMS(ESI):m/z:[M+H]+calculated for C22H21NO3P:378.1254,Found:378.1249。
The enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 80: 20, 0.5mL/min, 254nm, 98% ee). The major enantiomer tr was 11.45 min and the minor enantiomer tr was 12.57 min.
[α]D 20＝70.60(c＝0.012,CHCl3)。
Example 17: synthesis of ethyl 3- (2- (((3-methylpyridin-2-yl) (phenyl) phosphoryl) phenyl) acrylate
To a 25mL Schlenk reaction flask was added (3-methylpyridin-2-yl) diphenylphosphinone oxide (87.9mg,0.3mmoL), ethyl acrylate (45.1mg,0.45mmoL), palladium acetate (3.4mg,0.015mmoL), copper acetate (108.9mg,0.6mmoL), Ac-Ala-OH (3.9mg,0.03mmoL), and methanol (2mL) was added to dissolve thoroughly. The solution was stirred at room temperature for 10 minutes, then at 50 ℃ for 48 h. The mixture was diluted with ethyl acetate (20mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 1:1 elution, and suction-dried to give a yellow solid in a yield of 57%.
1H NMR(400MHz,CDCl3)8.45(d,J＝4.3Hz,1H),8.19(d,J＝15.7Hz,1H),7.88(dt,J＝18.9,9.6Hz,2H),7.62(dd,J＝7.6,4.1Hz,1H),7.58–7.32(m,8H),7.25–7.22(m,1H),6.11(d,J＝15.7Hz,1H),4.11(dt,J＝12.4,7.1Hz,2H),2.75(s,3H),1.25(t,J＝7.1Hz,6H)。
13C NMR(101MHz,CDCl3)165.88(d),146.67(d,),144.13(s),143.08(d),140.67(d),139.25(d),138.58(s),134.37(s),133.35(s),132.72(dd),132.13(d),129.43(s),128.83(d),128.37(t),127.65(d),124.94(s),120.83(s),60.33(s),19.20(s),14.24(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C23H22NO3P:414.1337,Found:414.1231。
The enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol 80: 20, 0.5mL/min, 254nm, 99.5% ee). The major enantiomer tr was 8.90 min and the minor enantiomer tr was 10.48 min.
[α]D 20＝12.40(c＝0.027,CHCl3)。
Example 18: synthesis of ethyl 3- (2- (phenyl (quinolin-2-yl) phosphoryl) phenyl) acrylate
A25 mL Schlenk reaction flask was charged with diphenylene (quinolin-2-yl) phosphine oxide (101.7mg,0.3mmoL), ethyl acrylate (45.1mg,0.45mmoL), palladium acetate (3.4mg,0.015mmoL), silver carbonate (91mg,0.33mmoL), Ac-Ala-OH (3.9mg,0.03mmoL), and dissolved thoroughly with methanol (3 mL). The solution was stirred at room temperature for 10 minutes, then at 60 ℃ for 48 h. The mixture was diluted with ethyl acetate (20mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 1:1 elution, and suction-dried to give a yellow solid with a yield of 59%.
1H NMR(400MHz,CDCl3)8.39(ddd,J＝24.5,8.4,4.0Hz,3H),8.11–7.96(m,3H),7.87(d,J＝8.1Hz,1H),7.77–7.70(m,1H),7.70–7.58(m,3H),7.49(ddd,J＝11.4,9.9,5.6Hz,5H),7.38(d,J＝7.3Hz,1H),6.07(d,J＝15.7Hz,1H),4.11(q,J＝7.1Hz,2H),1.26–1.21(m,3H)。
13C NMR(101MHz,CDCl3)165.96(s),143.28(s),136.26(s),133.65(s),132.49(d),132.44(s),132.30(s),132.06(s),130.29(s),130.09(s),128.88(s),128.42(s),128.30(s),127.88(s),127.72(s),123.71(s),123.49(s),121.08(s),60.33(s),14.25(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C26H22NO3P:450.1337,Found:450.1230。
The enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol 80: 20, 0.5mL/min, 254nm, 97% ee). The major enantiomer tr was 11.57 min and the minor enantiomer tr was 12.64 min.
[α]D 20＝16.31(c＝0.005,CHCl3)。
Example 19: synthesis of butyl-3- (5-fluoro-2- ((4-fluorophenyl) (3-methylpyridin-2-yl) phosphoryl) phenyl) acyl acrylate
To a 25mL Schlenk reaction flask was added bis (4-fluorophenyl) (3-methylpyridin-2-yl) phosphine oxide (98.7mg,0.3mmoL), butyl acrylate (76.9mg,0.60mmoL), palladium acetate (3.4mg,0.015mmoL), silver oxide (173.8mg,0.75mmoL), Boc-Val-OH (6.5mg,0.03mmoL), and methanol (1mL) was added to dissolve well. The solution was stirred at room temperature for 10 minutes, then at 60 ℃ for 36 h. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, eluted with petroleum ether/ethyl acetate 1:1 and then dried by suction to give a yellow solid with a yield of 59%.
1H NMR(400MHz,CDCl3)8.36(d,J＝3.6Hz,1H),8.04(d,J＝15.7Hz,1H),7.83–7.74(m,2H),7.52–7.46(m,1H),7.25(ddd,J＝24.6,13.4,6.2Hz,4H),7.08(t,J＝8.0Hz,2H),6.96(t,J＝7.9Hz,1H),6.03(d,J＝15.7Hz,1H),4.01(t,J＝6.4Hz,2H),2.64(s,3H),1.55–1.49(m,2H),1.27(dd,J＝14.9,7.3Hz,2H),0.85(t,J＝7.2Hz,3H)。
13C NMR(101MHz,CDCl3)166.07(s),165.72(s),163.75(d),153.36(s),152.01(s),146.71(d),141.63(s),140.88(s),140.66(s),139.44(d),135.14(dd),129.48(d,J＝103.1Hz),127.40(d,J＝106.7Hz),125.24(s),122.13(s),115.77(dd),115.04(s),64.44(s),30.65(s),19.08(s),13.69(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C25H24F2NO3P:478.1462,Found:478.1354。
The enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 80: 20, 0.5mL/min, 254nm, 98% ee). The major enantiomer tr was 11.21 min and the minor enantiomer tr was 13.51 min.
[α]D 20＝79.41(c＝0.002,CHCl3)。
Example 20: (E) synthesis of butyl (E) -3- (5-fluoro-2- (((4-fluorophenyl) (6-methylpyridin-2-yl) phosphoryl) phenyl) acrylate
To a 25mL Schlenk reaction flask was added bis (4-fluorophenyl) (6-methylpyridin-2-yl) phosphine oxide (98.7mg,0.3mmoL), butyl acrylate (76.9mg,0.60mmoL), palladium acetate (3.4mg,0.015mmoL), silver oxide (173.8mg,0.75mmoL), Boc-Val-OH (6.5mg,0.03mmoL), and methanol (3mL) was added to dissolve well. The solution was stirred at room temperature for 10 minutes, then at 60 ℃ for 24 h. The mixture was diluted with ethyl acetate (20mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 1:1 elution, and suction-dried to give a yellow solid with a yield of 52%.
1H NMR(400MHz,CDCl3)8.26(d,J＝15.8Hz,1H),8.13(t,J＝6.6Hz,1H),7.95(ddd,J＝11.3,8.7,5.6Hz,2H),7.74(td,J＝7.7,4.3Hz,1H),7.67–7.55(m,1H),7.31–7.21(m,3H),7.14(td,J＝8.8,2.2Hz,2H),7.05(t,J＝8.1Hz,1H),6.08(d,J＝15.7Hz,1H),4.11(t,J＝6.7Hz,2H),2.52(s,3H),1.61(dd,J＝14.6,6.8Hz,2H),1.38(dd,J＝15.0,7.4Hz,2H),0.95(t,J＝7.4Hz,3H)。
13C NMR(101MHz,CDCl3)165.72(s),159.25(d),154.78(d,J＝136.1Hz),142.01(s),136.40(s),134.87(s),129.09–128.58(m),128.15(s),127.95–127.65(m),126.00(s),125.79(s),125.32(s),122.21(s),115.93(s),115.79(s),115.58(s),64.47(s),30.70(s),24.48(s),19.12(s),13.72(s).
HRMS(ESI):m/z:[M+Na]+calculated for C25H24F2NO3P:478.1462,Found:478.1355。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol 80: 20, 0.5mL/min, 254nm, 84% ee); m/z (MH +). The major enantiomer tr was 14.61 min and the minor enantiomer tr was 17.43 min.
[α]D 20＝46.83(c＝0.004,CHCl3)。
Example 21: synthesis of butyl-3- (5-fluoro-2- ((4-fluorophenyl) (quinolin-2-yl) phosphoryl) phenyl) acrylate
To a 25mL Schlenk reaction flask was added bis (4-fluorophenyl) (quinolin-2-yl) phosphine oxide (147.3mg,0.3mmoL), butyl acrylate (76.9mg,0.60mmoL), palladium acetate (3.4mg,0.015mmoL), silver oxide (173.8mg,0.75mmoL), Boc-Val-OH (6.5mg,0.03mmoL), and THF (3mL) was added to dissolve well. The solution was stirred at room temperature for 10 minutes, then at 40 ℃ for 48 h. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 1:1 elution, and suction-dried to give a yellow solid with a yield of 52%.
1H NMR(400MHz,CDCl3)9.39(d,J＝8.4Hz,1H),8.55(d,J＝5.5Hz,1H),8.12(d,J＝15.7Hz,1H),7.94–7.85(m,3H),7.73(dd,J＝8.5,5.7Hz,2H),7.69–7.61(m,1H),7.44–7.28(m,2H),7.19–7.10(m,2H),7.03(t,J＝8.2Hz,1H),6.07(d,J＝15.7Hz,1H),3.99–3.82(m,2H),1.45–1.35(m,2H),1.22(dd,J＝14.9,7.3Hz,2H),0.85(t,J＝7.3Hz,3H)。
13C NMR(101MHz,CDCl3)166.30(d),165.48(s),163.77(d),155.81(s),154.48(s),141.71(d),141.51–141.25(m),136.20(d),135.76–134.92(m),131.59(s),131.36(s),130.80(s),130.03(s),128.94(s),128.54(s),128.06(s),127.35(s),127.05(s),123.38(s),122.37(s),115.84(dd),115.00(dd),64.31(s),30.44(s),18.98(s),13.69(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C28H24F2NO3P:514.1462,Found:514.1357
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol 80: 20, 0.5mL/min, 254nm, 84% ee); the major enantiomer tr was 16.96 min and the minor enantiomer tr was 23.33 min.
[α]D 20＝50.35(c＝0.018,CHCl3)。
Example 22: synthesis of butyl-3- (5-fluoro-2- ((4-fluorophenyl) (isoquinolin-1-yl) phosphoryl) phenyl) acrylate
To a 25mL Schlenk reaction flask was added bis (4-fluorophenyl) (isoquinolin-1-yl) phosphine oxide (147.3mg,0.3mmoL), butyl acrylate (76.9mg,0.60mmoL), palladium acetate (3.4mg,0.015mmoL), silver oxide (173.8mg,0.75mmoL), Boc-Val-OH (6.5mg,0.03mmoL), and THF (6mL) was added and dissolved thoroughly. The solution was stirred at room temperature for 10 minutes, and then at 40 ℃ for 36 hours. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 1:1 elution, and suction-dried to give a yellow solid with a yield of 52%.
1H NMR(400MHz,CDCl3)8.33(d,J＝15.0Hz,2H),8.07(d,J＝9.0Hz,1H),8.05–7.97(m,3H),7.88(d,J＝7.7Hz,1H),7.76(t,J＝7.7Hz,1H),7.67–7.61(m,2H),7.15(s,3H),7.07(t,J＝8.1Hz,1H),6.08(d,J＝15.7Hz,1H),4.08(t,J＝6.7Hz,2H),1.62–1.56(m,2H),1.35(dd,J＝12.9,5.1Hz,2H),0.93(t,J＝7.4Hz,3H)。
13C NMR(101MHz,CDCl3)165.66(s),135.00(s),130.19(s),128.51(s),127.93(s),122.37(s),115.82(s),64.47(s),30.67(s),19.10(s),13.71(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C28H24F2NO3P:514.1462,Found:514.1356。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol 90: 10, 0.5mL/min, 254nm,% ee); the major enantiomer tr was 42.10 min and the minor enantiomer tr was 45.47 min.
[α]D 20＝120(c＝0.0006,CHCl3)。
Example 23: synthesis of butyl 3- (5-methoxy-2- (((4-methoxyphenyl) (pyridin-2-yl) phosphoryl) phenyl) acrylate
To a 25mL Schlenk reaction flask was added bis (4-methoxyphenyl) (pyridin-2-yl) phosphine oxide (98.7mg,0.3mmoL), butyl acrylate (76.9mg,0.60mmoL), palladium acetate (3.4mg,0.015mmoL), benzoquinone (97.3mg,0.9mmoL), Boc-Val-OH (6.5mg,0.03mmoL), and THF (0.5mL) was added and dissolved thoroughly. The solution was stirred at room temperature for 10 minutes, then at 80 ℃ for 24 h. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 1:1 elution, and suction-dried to give a yellow solid with a yield of 56%.
1H NMR(400MHz,CDCl3)8.70(d,J＝4.1Hz,1H),8.33(t,J＝6.6Hz,1H),8.21(d,J＝15.7Hz,1H),7.93–7.78(m,3H),7.42–7.30(m,2H),7.08(s,1H),6.96(d,J＝6.9Hz,2H),6.84(d,J＝8.4Hz,1H),6.08(d,J＝15.7Hz,1H),4.08(t,J＝6.6Hz,2H),3.83(d,J＝2.2Hz,6H),1.61(dd,J＝14.6,6.9Hz,2H),1.39(dd,J＝15.0,7.4Hz,2H),0.95(t,J＝7.4Hz,3H)。
13C NMR(101MHz,CDCl3)164.07(s),160.52(d),148.08(s),147.89(s),140.93(d),138.99(s),134.20(d),133.62(d),132.24(d),126.46(s),126.26(s),123.05(s),121.07(s),119.35(s),112.09(s),111.96(s),111.47(d),62.33(s),53.39(d),28.74(s),17.17(s),11.80(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C26H28NO5P:488.1705,Found:488.1596。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol 75: 25, 1mL/min, 254nm, 99.9% ee); m/z (MH +). The major enantiomer tr was 11.54 min and the minor enantiomer tr was 23.5 min.
Example 24: synthesis of butyl-3- (5-methoxy-2- ((4-methoxyphenyl) (3-methylpyridin-2-yl) phosphoryl) phenyl) acrylate
To a 25mL Schlenk reaction flask was added bis (4-methoxyphenyl) (pyridin-2-yl) phosphine oxide (105.9mg,0.3mmoL), butyl acrylate (76.9mg,0.60mmoL), palladium acetate (3.4mg,0.015mmoL), benzoquinone (97.3mg,0.9mmoL), Boc-Val-OH (6.5mg,0.03mmoL), and THF (3mL) was added and dissolved thoroughly. The solution was stirred at room temperature for 10 minutes, then at 80 ℃ for 24 h. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography, petroleum ether/ethyl acetate 1:1 elution, and suction-dried to give a yellow solid with a yield of 56%.
1H NMR(400MHz,CDCl3)8.44(d,J＝4.1Hz,1H),8.14(d,J＝15.7Hz,1H),7.75(dd,J＝10.9,8.8Hz,2H),7.56–7.49(m,1H),7.30(d,J＝8.6Hz,1H),7.22(d,J＝3.0Hz,1H),7.11(s,1H),6.96(d,J＝6.8Hz,2H),6.84(d,J＝8.6Hz,1H),6.10(d,J＝15.7Hz,1H),4.06(t,J＝6.6Hz,2H),3.83(d,J＝1.7Hz,6H),2.70(s,3H),1.62–1.54(m,2H),1.34(dd,J＝15.0,7.4Hz,2H),0.92(t,J＝7.4Hz,3H)。
13C NMR(101MHz,CDCl3)166.16(s),162.40(s),162.13(s),153.31(s),146.59(d),143.13(d),140.46(s),140.25(s),139.14(d),134.82(d),134.35(d),126.22(s),124.79(s),123.62(s),120.88(s),113.94(t),113.26(d),64.26(s),55.34(d),30.68(s),19.21(d),13.77(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C27H30NO5P:502.1863,Found:502.1753。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol 93: 7, 0.6mL/min, 254nm, 99.9% ee); m/z. The major enantiomer tr was 27.00 min and the minor enantiomer tr was 30.25 min.
[α]D 20＝53.59(c＝0.005,CHCl3)。
Example 25: synthesis of butyl-3- (5-methoxy-2- ((4-methoxyphenyl) (6-methylpyridin-2-yl) phosphoryl) phenyl) acrylate
To a 25mL reaction tube was added bis (4-methoxyphenyl) (6-methylpyridin-2-yl) phosphine oxide (105.9mg,0.3mmoL), butyl acrylate (76.9mg,0.60mmoL L), palladium bis (acetylacetonate) (9.1mg,0.03mmoL), Boc-Phe-OH (15.9mg,0.06mmoL), silver acetate (150.2mg,0.9mmoL), and isopropanol (3mL) was added. The reaction tube was moved to an 80 ℃ oil bath for reaction for 48 h. The mixture was diluted with ethyl acetate (20mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 67% yield.
1H NMR(400MHz,CDCl3)8.27(d,J＝15.7Hz,1H),8.08(t,J＝6.6Hz,1H),7.86(dd,J＝11.1,8.7Hz,2H),7.68(td,J＝7.7,4.1Hz,1H),7.52(dd,J＝13.1,8.6Hz,1H),7.18(d,J＝7.7Hz,1H),7.07(d,J＝2.5Hz,1H),6.96–6.91(m,2H),6.86(d,J＝8.6Hz,1H),6.07(d,J＝15.7Hz,1H),4.08(t,J＝6.7Hz,2H),3.82(d,J＝3.4Hz,6H),2.51(s,3H),1.65–1.57(m,2H),1.38(dd,J＝14.9,7.4Hz,2H),0.94(t,J＝7.4Hz,3H)。
13C NMR(101MHz,CDCl3)166.16(s),162.33(d),158.92(d),156.76(s),155.43(s),143.55(d),140.86(d),136.13(d),135.69(d),134.20(d),125.51(d),124.88(d),123.87(s),122.78(s),120.93(s),113.88(dd),113.30(d),64.26(s),55.33(d),30.72(s),24.53(s),19.14(s),13.76(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C27H30NO5P:502.1863,Found:502.1754。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 85: 15, 0.8mL/min, 254nm, 99.9% ee); m/z (MH +). The major enantiomer tr was 26.52 min and the minor enantiomer tr was 31.59 min.
[α]D 20＝19.23(c＝0.007,CHCl3)。
Example 26: synthesis of butyl-3- (5-methoxy-2- ((4-methoxyphenyl) (quinolin-2-yl) phosphoryl) phenyl) acrylate
To a 25mL reaction tube was added bis (4-methoxyphenyl) (quinolin-2-yl) phosphine oxide (116.7mg,0.3mmoL), butyl acrylate (76.9mg,0.60mmoL), palladium bis (acetylacetonate) (9.1mg,0.03mmoL), Ac-Ala-OH (7.9mg,0.06mmoL), silver acetate (150.2mg,0.9mmoL), and isopropanol (3mL) was added. The reaction tube was moved to an 80 ℃ oil bath for reaction for 48 h. The mixture was diluted with ethyl acetate (20mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 67% yield.
1H NMR(400MHz,CDCl3)9.35(d,J＝8.5Hz,1H),8.48(d,J＝5.5Hz,1H),8.09(d,J＝15.7Hz,1H),7.81–7.68(m,3H),7.62(t,J＝5.7Hz,2H),7.55(t,J＝7.5Hz,1H),7.30–7.17(m,1H),7.08–7.02(m,1H),6.87(dd,J＝8.7,2.0Hz,2H),6.76(d,J＝8.5Hz,1H),6.01(d,J＝15.7Hz,1H),3.75(d,J＝4.1Hz,6H),1.35–1.26(m,2H),1.13(dd,J＝15.0,7.4Hz,2H),0.77(t,J＝7.3Hz,3H)。
13C NMR(101MHz,CDCl3)165.94(s),162.48(d),162.23(d),156.50(d),143.08(d),141.71(d),140.73(d),136.12(d),135.03(d),134.42(d),131.36(d),130.52(s),128.17(s),127.49(s),127.18(s),126.14(s),125.06(s),123.66(s),122.87(d),122.56(s),121.12(s),113.95(dd),113.37(d),64.11(s),55.34(d),30.44(s),18.98(s),13.71(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C30H30NO5P:538.1862,Found:538.1752。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol 75: 25, 1mL/min, 254nm, 87.4% ee); m/z (MH +). The major enantiomer tr was 9.99 min and the minor enantiomer tr was 20.45 min.
[α]D 20＝17.83(c＝0.005,CHCl3)。
Example 27: synthesis of butyl-3- (2- (isoquinolin-1-yl (4-methoxyphenyl) phosphoryl) -5-methoxyphenyl) acrylate
To a 25mL reaction tube was added isoquinolin-1-ylbis (4-methoxyphenyl) phosphine oxide (116.7mg,0.3mmoL), butyl acrylate (76.9mg,0.60mmoL), palladium bis (acetylacetonate) (9.1mg,0.03mmoL), Ac-Ala-OH (7.9mg,0.06mmoL), silver acetate (150.2mg,0.9mmoL), and methanol (3mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 48 h. The mixture was diluted with ethyl acetate (20mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 56% yield.
1H NMR(400MHz,CDCl3)8.34(qd,J＝8.4,3.9Hz,3H),8.07(d,J＝8.5Hz,1H),7.92(dd,J＝11.0,8.8Hz,2H),7.84(d,J＝8.1Hz,1H),7.75–7.50(m,4H),7.09(s,1H),6.95(d,J＝6.9Hz,2H),6.87(d,J＝8.6Hz,1H),6.07(d,J＝15.7Hz,1H),4.05(t,J＝6.6Hz,2H),3.82(d,J＝4.5Hz,6H),1.61–1.53(m,2H),1.33(dd,J＝14.9,7.5Hz,2H),0.91(t,J＝7.4Hz,3H)。
13C NMR(101MHz,CDCl3)163.79(s),160.19(d),156.10(s),154.78(s),145.73(d),141.10(d),138.61(d,),133.85(d),133.46(d),132.03(d),129.82(d),127.99(s),127.66(s),126.23(d),125.69(d),125.49–125.40(m),121.53(s),121.18(d),121.04–120.93(m),120.16(s),118.82(s),111.68(dd),111.08(d),61.97(s),53.06(d),28.39(s),16.83(s),11.47(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C30H30NO5P:538.1862,Found:538.1755。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol 75: 25, 1mL/min, 254nm, 99.3% ee); the major enantiomer tr was 12.92 min and the minor enantiomer tr was 32.82 min.
[α]D 20＝15.42(c＝0.003,CHCl3)。
Example 28: (E) synthesis of butyl (E) -3- (2- (isoquinolin-3-yl (p-tolyl) phosphoryl) -5-methylphenyl) acrylate
To a 25mL reaction tube was added isoquinolin-1-ylbis (4-methylphenyl) phosphine oxide (107.1mg,0.3mmoL), butyl acrylate (115.4mg,0.9mmoL), palladium tetrakis (acetonitrile) tetrafluoroborate (6.7mg,0.015), Ac-Ala-OH (3.9mg,0.03mmoL), silver acetate (150.2mg,0.9mmoL), and methanol (0.6mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 32 h. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give a product in 68% yield.
1H NMR(400MHz,CDCl3)8.35–8.19(m,3H),7.99(d,J＝8.5Hz,1H),7.85–7.75(m,3H),7.64(t,J＝7.2Hz,1H),7.56–7.42(m,2H),7.35(d,J＝3.1Hz,1H),7.18(d,J＝6.1Hz,2H),7.10(d,J＝7.8Hz,1H),6.01(d,J＝15.7Hz,1H),3.97(t,J＝6.6Hz,2H),2.30(s,6H),1.54–1.45(m,2H),1.26(dd,J＝15.0,7.4Hz,2H),0.84(t,J＝7.4Hz,3H)。
13C NMR(101MHz,CDCl3)163.82(s),155.77(s),154.47(s),145.78(s),145.57(s),141.15(d),140.27(s),140.07(s),136.59(d),133.79(d),131.51(d),130.10(d),127.96(s),127.59(s),127.23(d),126.74(d),126.13(d),125.78(s),125.48(s),121.28(s),121.07(s),118.39(s),61.82(s),28.35(s),19.23(d),16.77(s),11.42(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C30H30NO3P:506.1963,Found:506.1856。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 90/10, 0.5mL/min, 254nm, 70% ee); the major enantiomer tr was 14.6 min and the minor enantiomer tr 16.0 min.
[α]D 20＝39.69(c＝0.013,CHCl3)。
Example 29: (E) synthesis of butyl (E) -3- (4-methoxy-2- (((3-methoxyphenyl) (pyridin-2-yl) phosphoryl) phenyl) acrylate
To a 25mL reaction tube was added bis (3-methoxyphenyl) (pyridin-2-yl) phosphine oxide (101.7mg,0.3mmoL), butyl acrylate (115.4mg,0.9mmoL), palladium acetate (6.7mg,0.03mmoL), Ac-Ala-OH (7.9mg,0.06mmoL), silver acetate (150.2mg,0.9mmoL), and methanol (2mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 48 h. The mixture was diluted with ethyl acetate (20mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 62% yield.
1H NMR(400MHz,CDCl3)8.73(d,J＝4.4Hz,1H),8.34(t,J＝6.7Hz,1H),8.18(d,J＝15.7Hz,1H),7.89–7.82(m,1H),7.56(ddd,J＝18.7,10.4,6.5Hz,3H),7.38(dt,J＝7.5,3.9Hz,2H),7.09–6.98(m,3H),6.04(d,J＝15.7Hz,1H),4.07(t,J＝6.7Hz,2H),3.81(s,3H),3.73(s,3H),1.60(dd,J＝14.6,6.9Hz,2H),1.37(dd,J＝15.0,7.5Hz,2H),0.94(t,J＝7.4Hz,3H)。
13C NMR(101MHz,CDCl3)166.38(s),159.90(s),159.75(s),159.53(s),159.38(s),150.16(s),149.97(s),142.25(d),136.31(d),130.96(s),129.52(dd),128.67(s),128.46(s),125.35(s),124.70(d),119.67(d),119.04(s),118.65(s),117.32(s),116.72(d),64.14(s),55.41(d),30.73(s),19.14(s),13.77(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C26H28NO5P:488.1704,Found:488.1596。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 85/15, 0.5mL/min, 254nm, 93.3% ee); the major enantiomer tr was 18.7 min and the minor enantiomer tr was 22.2 min.
[α]D 20＝36.50(c＝0.005,CHCl3)。
Example 30: butyl (E) -3- (4- ([ [1,1 '-biphenyl ] -4-yl (pyridin-2-yl) phosphoryl) - [1,1' -biphenyl ] -3-yl) acyl acrylate
To a 25mL reaction tube was added bis ([1,1' -biphenyl ] -4-yl) (pyridin-2-yl) phosphine oxide (129.3mg,0.3mmol), butyl acrylate (115.4mg,0.9mmol), palladium acetate (2.0mg,0.009mmol), Ac-Ala-OH (2.4mg,0.018mmol), silver acetate (150.2mg,0.9mmol), and methanol (1.5mL) was added. The reaction tube was moved to a 50 ℃ oil bath for reaction for 36 h. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 67% yield.
1H NMR(400MHz,CDCl3)8.77(d,J＝4.2Hz,1H),8.43(t,J＝6.6Hz,1H),8.33(d,J＝15.7Hz,1H),8.09(dd,J＝11.1,8.3Hz,2H),7.89(d,J＝3.1Hz,1H),7.82(d,J＝2.8Hz,1H),7.71(d,J＝6.2Hz,2H),7.64–7.56(m,6H),7.46(t,J＝7.3Hz,4H),7.42–7.36(m,3H),6.20(d,J＝15.7Hz,1H),4.09(t,J＝6.6Hz,2H),1.67–1.57(m,2H),1.39(dd,J＝14.9,7.4Hz,2H),0.94(t,J＝7.3Hz,3H)。
13C NMR(101MHz,CDCl3)165.98(s),157.45(s),156.13(s),150.11(d),145.20(s),144.83(s),142.96(d),139.98(s),139.64(d),139.45(s),136.37(d),134.21(d),132.91(d),131.34(s),130.32(s),128.90(t),128.48(d),128.15(s),127.72–126.89(m),126.65(d),125.33(s),121.59(s),64.33(s),30.73(s),19.14(s),13.74(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C36H32NO3P:580.2120,Found:580.2013。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 85/15, 0.5mL/min, 254nm, 99.9% ee); the major enantiomer tr was 29.3 min and the minor enantiomer tr was 25.2 min.
[α]D 20＝33.96(c＝0.006,CHCl3)。
Example 31: (E) synthesis of butyl (E) -3- (1- (naphthalen-1-yl (pyridin-2-yl) phosphoryl) naphthalen-2-yl) acrylate
To a 25mL reaction tube was added bis (naphthalen-1-yl) (pyridin-2-yl) phosphine oxide (113.7mg,0.3mmoL), butyl acrylate (38.5mg,0.3mmoL), palladium chloride (5.3mg,0.03mmoL), Ac-Ala-OH (7.9mg,0.06mmoL), silver acetate (150.2mg,0.9mmoL), and methanol (1mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 48 h. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 34% yield.
1H NMR(400MHz,CDCl3)9.13(d,J＝8.6Hz,1H),8.69(d,J＝4.4Hz,1H),8.45–8.38(m,1H),8.30(d,J＝8.5Hz,1H),8.09(d,J＝15.7Hz,1H),8.01–7.92(m,2H),7.87–7.79(m,3H),7.62–7.53(m,1H),7.50–7.40(m,3H),7.39–7.32(m,3H),7.32–7.26(m,1H),5.50(d,J＝15.8Hz,1H),4.00–3.88(m,2H),1.59–1.50(m,2H),1.34(dd,J＝14.8,7.4Hz,2H),0.93(t,J＝7.4Hz,3H)。
13C NMR(101MHz,CDCl3)165.67(s),158.19(s),156.88(s),150.23(d),146.05(d),139.69(d),136.47(d),134.88(d),134.14–133.32(m),133.25(s),132.35(d),131.56(s),130.54(s),129.02(s),128.91–128.38(m),128.38–127.84(m),127.17(d),126.59(dd),125.81(dd,),125.28–125.17(m),124.68(d),120.38(s),118.21(s),64.01(s),30.62(s),19.15(s),13.79(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C32H28NO3P:528.1807,Found:528.1702。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 85/15, 0.5mL/min, 254nm, 98% ee); m/z. The major enantiomer tr was 21.6 min and the minor enantiomer tr 16.2 min.
[α]D 20＝75.76(c＝0.011,CHCl3)。
Example 32: (E) synthesis of t-butyl (E) -3- (2- (((3-methylpyridin-2-yl) (phenyl) phosphoryl) phenyl) acrylate
To a 25mL reaction tube were added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg,0.3mmol), tert-butyl acrylate (115.4mg,0.9mmol), bis (acetylacetonato) palladium (9.1mg,0.03mmol), Cbz-Val-OH (15.1mg,0.06mmol), silver acetate (150.2mg,0.9mmol), and HFIP (3mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 32 h. The mixture was diluted with ethyl acetate (20mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 56% yield.
1H NMR(400MHz,CDCl3)8.37(d,J＝4.4Hz,1H),7.98(d,J＝15.7Hz,1H),7.78(dd,J＝11.5,7.9Hz,2H),7.55–7.35(m,7H),7.29(dd,J＝18.6,5.5Hz,2H),7.20–7.14(m,1H),5.93(d,J＝15.7Hz,1H),2.65(s,3H),1.35(s,9H)。
13C NMR(101MHz,CDCl3)165.27(s),153.99(s),152.66(s),146.75(s),146.55(s),142.16(d),140.70(s),140.49(s),139.12(dd),133.93(s),133.14–132.43(m),132.33(s),131.85(dd),128.41(dd),127.69(d),124.91(d),122.98(s),80.25(s),28.07(s),19.29(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C25H26NO3P:442.1650,Found:442.1542。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 80/20, 0.5mL/min, 254nm, 99.9% ee); the major enantiomer tr was 7.8 min and the minor enantiomer tr was 6.7 min.
[α]D 20＝68.41(c＝0.006,CHCl3)。
Example 33: (E) synthesis of (3-methylpyridin-2-yl) (phenyl) (2-styrylphenyl) phosphine oxide
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg,0.3mmol), styrene (62.5mg,0.6mmol), palladium acetate (3.4mg,0.015mmol), BOC-Val-OH (6.5mg,0.03), silver acetate (150.2mg,0.9mmol), and toluene (3mL) was added. The reaction tube was moved to a 45 ℃ oil bath for reaction for 48 h. The mixture was diluted with ethyl acetate (15mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 88% yield.
1H NMR(400MHz,CDCl3)8.42(d,J＝4.4Hz,1H),7.86(dd,J＝11.5,7.7Hz,2H),7.73(dd,J＝7.7,4.4Hz,1H),7.67(d,J＝16.0Hz,1H),7.54–7.39(m,6H),7.29–7.12(m,8H),6.80(d,J＝16.0Hz,1H),2.68(s,3H)。
13C NMR(101MHz,CDCl3)154.52(s),153.19(s),146.68(s),146.48(s),141.67(d),140.39(s),140.17(s),139.14(d),137.04(s),133.16–132.46(m),132.01(d),131.87–131.23(m),131.16(s),130.61(s),129.22(s),128.50–127.98(m),127.72(s),127.42(d),127.00–126.35(m),124.85(d),19.24(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C26H22NOP:418.1439,Found:418.1334。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 80/20, 0.5mL/min, 254nm, 99.9% ee); m/z. The major enantiomer tr was 13.9 min and the minor enantiomer tr 16.2 min.
[α]D 20＝73.33(c＝0.006,CHCl3)。
Example 34: (E) synthesis of (3-methylpyridin-2-yl) (2- (4-methylstyryl) phenyl) (phenyl) phosphine oxide
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg,0.3mmoL), p-methylstyrene (53mg,0.45mmoL), palladium tetrakis (acetonitrile) tetrafluoroborate (2.7mg,0.006mmoL), Ac-Ala-OH (1.6mg,0.012mmoL), silver acetate (150.2mg,0.9mmoL), and hexafluoroisopropanol: ethylene glycol dimethyl ether is 1:1(3 mL). The reaction tube was moved to a 40 ℃ oil bath for 48 hours. The mixture was diluted with ethyl acetate (20mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 77% yield.
1H NMR(400MHz,CDCl3)8.43(d,J＝4.4Hz,1H),7.86(dd,J＝11.5,7.7Hz,2H),7.73(dd,J＝7.7,4.4Hz,1H),7.61(d,J＝16.0Hz,1H),7.53–7.40(m,7H),7.18–7.09(m,4H),7.05(d,J＝7.9Hz,2H),6.79(d,J＝16.0Hz,1H),2.68(s,3H),2.31(s,3H)。
13C NMR(101MHz,CDCl3)154.62(s),153.29(s),146.67(s),146.47(s),141.81(d),140.35(s),140.14(s),139.11(d),137.63(s),134.29(s),132.95(d),132.62(d),131.97(s),131.54(d),131.03(s),130.46(s),129.12(s),128.14(d),126.87–126.13(m),124.82(s),21.24(s),19.25(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C27H24NOP:432.1596,Found:432.1489。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 80/20, 0.5mL/min, 254nm, 96% ee); the major enantiomer tr was 13.3 min and the minor enantiomer tr was 11.9 min.
[α]D 20＝32.00(c＝0.009,CHCl3)。
Example 35: (E) synthesis of (2- (4-fluorophenylethenyl) phenyl) (3-methylpyridin-2-yl) (phenyl) phosphine oxide
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg,0.3mmol), p-fluorostyrene (54.9mg,0.45mmol), palladium acetate (6.7mg,0.03mmol), Cbz-Val-OH (15.1mg,0.06mmol), silver acetate (55.1mg,0.33mmol), and methanol (2mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 48 h. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 74% yield.
1H NMR(400MHz,CDCl3)8.34(d,J＝4.3Hz,1H),7.77(dd,J＝11.5,7.7Hz,2H),7.62(dd,J＝7.6,4.3Hz,1H),7.53(d,J＝16.0Hz,1H),7.46–7.27(m,7H),7.13–7.05(m,3H),6.85(t,J＝8.5Hz,2H),6.67(d,J＝16.0Hz,1H),2.59(s,3H)。
13C NMR(101MHz,CDCl3)162.38(d,J＝247.5Hz),153.83(d,J＝134.2Hz),146.56(d),141.57(d),140.40(s),140.19(s),139.14(d),133.26(d),133.13–132.67(m),132.57(d),132.02(d),131.68(dd),130.59(s),129.87(s),128.22(t),127.30(d),126.81(d),126.47(d),124.85(d),115.46(s),115.25(s),19.23(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C26H21FNOP:436.1345,Found:436.1247。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol-90/10, 1mL/min, 254nm, 99.9% ee); the major enantiomer tr was 21.2 min and the minor enantiomer tr was 14.3 min.
[α]D 20＝67.14(c＝0.007,CHCl3)。
Example 36: (E) synthesis of (2- (4-chlorostyryl) phenyl) (3-methylpyridin-2-yl) (phenyl) phosphine oxide
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg,0.3mmoL), p-chlorostyrene (62.4mg,0.45mmoL), palladium acetate (6.7mg,0.03mmoL), Ac-Ala-OH (7.9mg,0.06mmoL), silver oxide (83.4mg,0.36mmoL), and methanol (2mL) was added. The reaction tube was moved to a 40 ℃ oil bath for 28 h. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 71% yield.
1H NMR(400MHz,CDCl3)8.34(d,J＝4.3Hz,1H),7.81–7.72(m,2H),7.62(dd,J＝13.9,6.7Hz,2H),7.46–7.28(m,6H),7.23–7.16(m,1H),7.16–7.03(m,5H),6.67(d,J＝16.0Hz,1H),2.60(s,3H)。
13C NMR(101MHz,CDCl3)154.42(s),153.09(s),146.69(s),146.49(s),141.34(d),140.42(s),140.21(s),139.18(d),135.58(s),133.30(s),133.13–132.41(m),132.03(d),131.71(d),130.74(s),129.70(s),128.60(s),128.10(dd),126.98(d),126.53(d),124.89(d),19.25(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C26H21ClNOP:452.1049,Found:452.0944。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 80/20, 0.5mL/min, 254nm, 99.8% ee); m/z. The major enantiomer tr was 16.7 min and the minor enantiomer tr was 27.8 min.
[α]D 20＝42.83(c＝0.015,CHCl3)。
Example 37: (E) synthesis of (3-methylpyridin-2-yl) (2- (2- (naphthalen-2-yl) vinyl) phenyl) (phenyl) phosphine oxide
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg,0.3mmol), 2-vinylnaphthalene (92.5mg,0.6mmol), bis (acetylacetonato) palladium (9.1mg,0.03mmol), Boc-Tle-OH (13.9mg,0.06mmol), silver acetate (50mg,0.3mmol), and tert-amyl alcohol (2mL) was added. The reaction tube was moved to a 40 ℃ oil bath for 48 hours. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 64% yield.
1H NMR(400MHz,CDCl3)8.44(d,J＝4.1Hz,1H),7.90(dd,J＝11.3,7.5Hz,2H),7.84–7.69(m,5H),7.60(s,1H),7.58–7.37(m,9H),7.28(dd,J＝14.2,6.6Hz,2H),7.16–7.10(m,1H),6.97(d,J＝16.0Hz,1H),2.71(s,3H)。
13C NMR(101MHz,CDCl3)146.73(s),146.53(s),141.63(s),140.41(s),140.19(s),139.17(d),134.61(s),133.47(s),133.00(d),132.64(d),132.07(s),131.72(s),131.14(s),128.45–127.74(m),127.65(s),126.86(d),126.50(d),126.23(s),125.97(s),124.85(s),123.79(s),19.29(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C30H24NOP:468.1596,Found:468.149。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 80/20, 0.5mL/min, 254nm, 99.9% ee); the major enantiomer tr was 18.6 min and the minor enantiomer tr was 23.6 min.
[α]D 20＝72.05(c＝0.008,CHCl3)。
Example 38: (E) synthesis of (3-methylpyridin-2-yl) (phenyl) (2- (2- (trimethylsilyl) vinyl) phenyl) phosphine oxide
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg,0.3mmoL), trimethylvinylsilane (60mg,0.6mmoL), palladium trifluoroacetate (10mg,0.03mmoL), Ac-Ala-OH (7.9mg,0.06mmoL L), silver acetate (150.2mg,0.9mmoL), and tetrahydrofuran (3mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 48 h. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 70% yield.
1H NMR(400MHz,CDCl3)8.34(d,J＝4.3Hz,1H),7.77–7.67(m,2H),7.57(dd,J＝7.6,4.3Hz,1H),7.48–7.29(m,6H),7.16(ddd,J＝14.6,13.2,7.4Hz,3H),6.16(d,J＝18.7Hz,1H),2.59(s,3H),-0.20(s,9H)。
13C NMR(101MHz,CDCl3)156.04(s),154.71(s),148.20(s),147.99(s),144.33(d),143.69(d),141.88(s),141.67(s),140.65(d),134.70(s),134.15(dt),133.45(d),133.13(t),132.83(s),131.81(s),129.60(d),128.51(d),128.10(d),126.30(d),20.85(s),0.00(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C23H26NOPSi:414.1521,Found:414.1402。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 90/10, 0.5mL/min, 254nm, 99.3% ee); m/z. The major enantiomer tr was 9.9 min and the minor enantiomer tr was 8.7 min.
[α]D 20＝37.05(c＝0.027,CHCl3)。
Example 40: (E) synthesis of (3-methylpyridin-2-yl) (phenyl) (2- (2- (phenylsulfonyl) ethenyl) phenyl) phosphine oxide
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg,0.3mmoL), phenylvinylsulfone (151.4mg,0.9mmoL), palladium acetate (6.7mg,0.03mmoL), Ac-Ala-OH (7.9mg,0.06mmoL), silver acetate (150.2mg,0.9mmoL), and tert-amyl alcohol (3mL) was added. The reaction tube was moved to an 80 ℃ oil bath for reaction for 48 h. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 87% yield.
1H NMR(400MHz,CDCl3)8.43(d,J＝4.4Hz,1H),8.23(d,J＝15.2Hz,1H),7.84–7.74(m,4H),7.62–7.45(m,10H),7.37(dd,J＝7.7,4.6Hz,2H),7.31–7.27(m,1H),6.68(d,J＝15.2Hz,1H),2.74(s,3H)。
13C NMR(101MHz,CDCl3)146.81(s),146.61(s),141.60(d),141.01(s),140.79(s),140.31(s),139.60(d),133.19(d,J＝10.7),132.46(d),132.02(d),129.67(d),129.20(s),128.54(d),128.12(d),127.80(s),125.29(s),19.18(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C26H22NOPS:482.1058,Found:482.0949。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 80/20, 0.5mL/min, 254nm, 97.3% ee); m/z. The major enantiomer tr was 32.7 min and the minor enantiomer tr was 28.2 min.
[α]D 20＝36.81(c＝0.011,CHCl3)。
Example 41: (E) synthesis of (2- (4- (4- (diphenylamino) styryl) phenyl) (3-methylpyridin-2-yl) (phenyl) phosphine oxide
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg,0.3mmoL), N, N-diphenyl-4-vinylaniline (122.1mg,0.45mmoL), palladium tetrakis (acetonitrile) tetrafluoroborate (6.7mg,0.015mmoL), Ac-Ala-OH (7.9mg,0.06mmoL), benzoquinone (32.4mg,0.9mmoL), and methanol (3mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 45 h. The mixture was diluted with ethyl acetate (20mL), washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and concentrated under reduced pressure to give the product in 56% yield.
1H NMR(400MHz,CDCl3)8.33(d,J＝4.3Hz,1H),7.76(dd,J＝11.1,7.7Hz,2H),7.64(dd,J＝7.6,4.4Hz,1H),7.45–7.30(m,7H),7.16(t,J＝7.7Hz,5H),7.08(ddd,J＝7.3,4.4,2.5Hz,1H),7.01–6.91(m,8H),6.84(d,J＝8.5Hz,2H),6.70(d,J＝16.0Hz,1H),2.57(s,3H)。
13C NMR(101MHz,CDCl3)154.72(s),153.39(s),147.47(d),146.72(s),146.51(s),141.83(d),140.34(s),140.13(s),139.16(d),133.03(d),132.62(d),132.17–131.84(m),131.63(d),131.23(d),130.55(s),130.21(s),129.31(s),128.18(d),127.71(s),126.35(dd),125.70(d),124.87(d),124.56(s),123.13(d),19.32(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C38H31N2OP:582.2179,Found:582.2066。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 80/20, 0.6mL/min, 365nm, 99.9% ee); the major enantiomer tr was 104.9 min and the minor enantiomer tr was 56.8 min.
[α]D 20＝30.55(c＝0.014,CHCl3)。
Example 42: (E) synthesis of (3-methylpyridin-2-yl) (phenyl) (2- (2- (pyridin-1-yl) ethenyl) phenyl) phosphine oxide
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg,0.3mmoL), 1-vinylpyrene (102.6mg,0.45mmoL), palladium acetate (6.7mg,0.03mmoL), Ac-Ala-OH (7.9mg,0.06mmoL), silver acetate (150.2mg,0.9mmoL), and tert-amyl alcohol (3mL) was added. The reaction tube was moved to a 70 ℃ oil bath for reaction for 48 h. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in a yield of 72%.
1H NMR(400MHz,CDCl3)8.43(d,J＝4.3Hz,1H),8.29(d,J＝9.3Hz,1H),8.16(d,J＝7.3Hz,2H),8.08–7.88(m,11H),7.62(t,J＝7.5Hz,1H),7.51–7.42(m,4H),7.34(dd,J＝7.3,4.7Hz,2H),7.05(ddd,J＝7.3,4.4,2.6Hz,1H),2.68(s,3H)。
13C NMR(101MHz,CDCl3)142.15(d),140.48(s),140.26(s),139.10(d),133.01(d),132.69(d),132.12(s),131.92–131.33(m),131.29–130.85(m),130.85–130.75(m),130.55(d),128.40–128.08(m),127.39(d),126.95(d),125.96(s),125.30(s),124.89(dd),124.03(s),123.01(s),19.22(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C36H26N2OP:542.1752,Found:542.1644。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 80/20, 0.6mL/min, 365 nm); the major enantiomer tr was 30.1 min and the minor enantiomer tr was 60.9 min.
[α]D 20＝62.82(c＝0.013,CHCl3)。
Example 43: (E) synthesis of (2- (4- (5, 5-difluoro-1, 3,7, 9-tetramethyl-5H-4 l4,5l 4-dipyrrolo [1, 2-c: 2', 1' -f ] [1,3,2] -boro-azepin-10-yl) styryl) phenyl) (3-methylpyridin-2-yl) (phenyl) phosphine oxide
To a 25mL reaction tube was added (3-methylpyridin-2-yl) diphenylphosphine oxide (87.9mg,0.3mmol),5, 5-difluoro-1, 3,7, 9-tetramethyl-10- (4-vinylphenyl) -5H-4l4,5l 4-dipyrrolo [1, 2-c: 2', 1' -f ] [1,3,2] Diazaboronamine (210mg,0.6mmoL), palladium tetrakis (acetonitrile) tetrafluoroborate (13.3mg,0.03), Ac-Ala-OH (7.9mg,0.06mmoL), silver carbonate (248.2mg,0.9mmoL), and further tert-amyl alcohol (3mL) was added. The reaction tube was moved to a 40 ℃ oil bath for reaction for 48 h. The mixture was diluted with ethyl acetate (10mL), washed with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was subjected to silica gel column chromatography and then concentrated under reduced pressure to give the product in 70% yield.
1H NMR(400MHz,CDCl3)8.43(d,J＝4.0Hz,1H),7.91–7.71(m,4H),7.57–7.25(m,10H),7.16(d,J＝7.9Hz,3H),6.82(d,J＝16.0Hz,1H),5.98(s,2H),2.69(s,3H),2.55(s,6H),1.40(s,6H)。
13C NMR(101MHz,CDCl3)155.49(s),146.73(s),146.52(s),143.01(s),141.49(s),140.48(s),139.15(d),137.76(s),134.21(s),132.92(d),132.60(d),132.12(s),131.71(s),131.38(s),130.29(s),128.68(s),128.21(d),127.37(s),127.26–126.73(m),126.70(s),124.80(s),121.22(s),31.94(s),29.72(s),29.34(s),27.23(s),22.71(s),19.27(s),14.58(s),14.14(s),1.05(s)。
HRMS(ESI):m/z:[M+Na]+calculated for C39H35BF2N3OP:642.2658,Found:642.2645。
Enantiomeric excess was determined by UPLC (Chiralpak INB column) (hexane: 2-propanol ═ 80/20, 0.5mL/min, 254nm, 96.5% ee); the major enantiomer tr is 39.886 min and the minor enantiomer tr is 27.001 min.
Claims (10)
1. A preparation method of a phosphorus center chiral compound is characterized by comprising the following steps:
under the existence of an oxidant, palladium salt and an N-single protection chiral amino acid ligand, carrying out C-H bond olefination reaction on 2-pyridyl diaryl phosphine oxide shown in a formula (II) and olefin derivatives shown in a formula (III) to generate a phosphorus center chiral compound shown in a formula (I);
wherein,
m is 0, 1,2, 3 or 4;
n is 0, 1,2 or 3;
R1is H, C1～6Alkyl or C6～10Aryl radical, said C1～10Alkyl or C6～10Aryl is optionally substituted by 1-3 halogens, methyl, OH or NH2Substitution; or two adjacent R1Together with the pyridyl group to which it is attached to form a quinolinyl group;
R2is H, halogen, C1～6Alkyl radical, C1～6Alkoxy or C6～10Aryl radical, said C1～6Alkyl radical, C1～6Alkoxy or C6～10Aryl is optionally substituted by 1-3 halogens, methyl, OH or NH2Substitution; or two adjacent R2Together with the phenyl group to which it is attached form a naphthyl group;
R3is H, C1～6Alkyl, -C (═ O) O-C1～6Alkyl, -C1～6alkyl-CHO, -C (═ O) -C1～6Alkyl, -P (═ O) - (O-C)1～6Alkyl radical)3、-S(＝O)2-C1～6Alkyl, -S (═ O)2-C6～20Aryl, -Si (C)1～6Alkyl radical)3Or C6～20An aryl group, a heteroaryl group,
said C6～20Aryl is optionally substituted by 1-3 of halogen, methyl, heteroaryl, OH, NH2or-N (Ph)2Substituted, said C1～6Alkyl, -S (═ O)2-C6～20Aryl, -Si (C)1～6Alkyl radical)3Optionally substituted by 1-3 halogens, methyl, OH or NH2And (4) substitution.
2. The method for preparing chiral compounds of phosphorus center as claimed in claim 1, wherein R is3Is H, methyl ester, ethyl ester, n-butyl ester, tert-butyl ester, p-methoxyphenyl, p-nitrophenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-methylphenyl,
Phenyl sulfone group, trimethyl phosphate, triethyl phosphate, trimethylsilyl group, diphenylaminophenyl group, naphthyl group, anthryl group, phenanthryl group or pyrenyl group, wherein the naphthyl group, anthryl group, phenanthryl group or pyrenyl group is optionally substituted by 1-3 halogens, heteroaryl or-N (Ph)2And (4) substitution.
3. The method for preparing chiral compounds of phosphorus center as claimed in claim 1, wherein R is1Is H, methyl, tert-butyl or phenyl, the methyl, tert-butyl or phenyl is optionally substituted by 1-3 halogens; said R2Is H, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy or phenyl, and the methyl, ethyl, propyl, methoxy, ethoxy, propoxy or phenyl is optionally substituted by 1-3 halogens.
4. The method for preparing a phosphorus central chiral compound according to any one of claims 1 to 3, wherein the palladium salt is palladium acetate, palladium bis (acetylacetonate), palladium trifluoroacetate, palladium tetrakis (acetonitrile) tetrafluoroborate or palladium chloride.
5. The method for preparing the chiral compound of phosphorus center according to any one of claims 1 to 3, wherein the N-mono-protected chiral amino acid ligand is
6. The method for preparing a phosphorus-centered chiral compound according to any one of claims 1 to 3, wherein the oxidant is copper acetate, silver carbonate, silver oxide or benzoquinone.
7. The method for preparing the chiral compound of phosphorus center according to any one of claims 1 to 3, wherein the reaction temperature of C-H bond olefination is 40-80 ℃ and the reaction time is 6-48H.
8. The method for preparing the chiral compound of phosphorus center according to any one of claims 1 to 3, wherein the reaction medium for C-H bond olefination is methanol, tetrahydrofuran, tert-amyl alcohol, toluene or hexafluoroisopropanol.
9. The method for preparing a phosphorus-centered chiral compound according to any one of claims 1 to 3, wherein the molar ratio of the oxidant, the palladium salt, the N-mono-protected chiral amino acid ligand and the 2-pyridyldiarylphosphine oxide represented by formula (II) is 1.1 to 3: 0.01-0.1: 0.01-0.2: 1.
10. the method for preparing a phosphorus-centered chiral compound according to any one of claims 1 to 3, wherein the molar ratio of the 2-pyridyldiarylphosphine oxide represented by the formula (II) to the olefin derivative represented by the formula (III) is 1: 1.1 to 3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010501171.8A CN111647018B (en) | 2020-06-04 | 2020-06-04 | Preparation method of phosphorus center chiral compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010501171.8A CN111647018B (en) | 2020-06-04 | 2020-06-04 | Preparation method of phosphorus center chiral compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111647018A true CN111647018A (en) | 2020-09-11 |
| CN111647018B CN111647018B (en) | 2023-04-07 |
Family
ID=72351130
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010501171.8A Active CN111647018B (en) | 2020-06-04 | 2020-06-04 | Preparation method of phosphorus center chiral compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111647018B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113512065A (en) * | 2021-08-13 | 2021-10-19 | 浙江工业大学 | Chiral secondary phosphorus oxide pre-ligand and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107226827A (en) * | 2017-04-16 | 2017-10-03 | 杭州师范大学 | A kind of preparation method of chiral phosphorus fluorenes oxide |
| CN108558927A (en) * | 2018-04-24 | 2018-09-21 | 杭州师范大学 | A kind of silicon Stereocenter chipal compounds and its synthetic method |
-
2020
- 2020-06-04 CN CN202010501171.8A patent/CN111647018B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107226827A (en) * | 2017-04-16 | 2017-10-03 | 杭州师范大学 | A kind of preparation method of chiral phosphorus fluorenes oxide |
| CN108558927A (en) * | 2018-04-24 | 2018-09-21 | 杭州师范大学 | A kind of silicon Stereocenter chipal compounds and its synthetic method |
Non-Patent Citations (2)
| Title |
|---|
| CHANG-SHENG WAN 等: "Ruthenium-Catalyzed C−H Bond Alkylation of Arylphosphine Oxides with Alkenes: A Straightforward Access to Bifunctional Phosphorous Ligands with a Pendent Carboxylate", 《CHEMCATCHEM》 * |
| 林燕: "构建磷及硅手性中心的过渡金属催化失对称反应研究", 《中国优秀硕士学位论文全文数据库工程科技Ⅰ辑》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113512065A (en) * | 2021-08-13 | 2021-10-19 | 浙江工业大学 | Chiral secondary phosphorus oxide pre-ligand and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111647018B (en) | 2023-04-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Chelucci et al. | Chiral P, N-ligands with pyridine-nitrogen and phosphorus donor atoms. Syntheses and applications in asymmetric catalysis | |
| US8558017B2 (en) | Ruthenium (II) catalysts for use in stereoselective cyclopropanations | |
| CN100482644C (en) | Chiral diene ligand, synthesis method and its application in asymmetric reaction | |
| CN114315917B (en) | Chiral ferrocene PNNO tetradentate ligand and application thereof in asymmetric hydrogenation reaction | |
| CA2559242A1 (en) | Cycloolefin phosphine ligands and their use in catalysis | |
| CN105732725A (en) | Chiral tridentate nitrogen-phosphine-oxygen ligands and application of related ligands in asymmetric catalytic reactions | |
| CN105732387B (en) | The method of novel C -2` phase transfer catalyst photooxidation beta-dicarbonyl compound asymmetry 'alpha '-hydroxylation | |
| CN112920221B (en) | Chiral phosphoric acid with spiro-bis-dihydrobenzothiole skeleton and preparation method and application thereof | |
| CN111647018B (en) | Preparation method of phosphorus center chiral compound | |
| CN110494439B (en) | Chiral biphenyl diphosphine ligand and preparation method thereof | |
| CN109503670B (en) | Chiral monophosphine ligand WJ-Phos of ferrocene skeleton, preparation method and application | |
| CN109232650B (en) | Chiral 1-phospha norbornadiene derivative and synthesis method thereof | |
| CN101445517A (en) | Phosphoramidite monophosphine ligand and preparation method and application thereof | |
| CN104744514B (en) | A kind of chiral phosphorus alkene part, synthetic method and its application in asymmetric reaction | |
| CN115448949A (en) | Synthesis method of chiral allyl phosphine compound | |
| WO2003040149A2 (en) | Asymmetric catalysis based on chiral phospholanes and hydroxyl phospholanes | |
| JP2001526111A (en) | Catalyst compositions based on chiral ligands having molybdenum, tungsten or chromium and methods for asymmetric alkylation of allylic substrates | |
| Chelucci et al. | Chiral thienylpyridines as N–S ligands for asymmetric catalysis: Palladium-catalyzed allylic alkylation and copper-catalyzed cyclopropanation reactions | |
| CN111039767B (en) | Method for preparing deuterated aldehyde by using triazole carbene as catalyst | |
| CN107880022B (en) | Chiral imidazole pyridine amide-containing compound and preparation method and application thereof | |
| CN107459533B (en) | Benzimidazole-indole skeleton phosphine ligand and preparation method and application thereof | |
| CN104945434A (en) | (2-disubstituted phosphino-phenyl)-1-alkyl-indol-phosphine ligand and synthetic method and application thereof | |
| CN109666041A (en) | The chiral monophosphorus ligand HP-Phos and preparation method and application of a kind of hexichol ether skeleton | |
| CN113214110B (en) | Preparation method of alpha-substituted-beta-hydroxy nitrile compound and derivative thereof | |
| CN114773229B (en) | 1,6 Diene compound and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |