CN112250708B - 一种含蒽二聚体骨架配体及其制备方法和在金属催化反应中的应用 - Google Patents
一种含蒽二聚体骨架配体及其制备方法和在金属催化反应中的应用 Download PDFInfo
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- CN112250708B CN112250708B CN201910663384.8A CN201910663384A CN112250708B CN 112250708 B CN112250708 B CN 112250708B CN 201910663384 A CN201910663384 A CN 201910663384A CN 112250708 B CN112250708 B CN 112250708B
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- 239000003446 ligand Substances 0.000 title claims abstract description 56
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 title claims description 59
- 238000002360 preparation method Methods 0.000 title claims description 9
- 238000006555 catalytic reaction Methods 0.000 title claims description 6
- 239000000539 dimer Substances 0.000 title description 14
- 229910052751 metal Inorganic materials 0.000 title description 7
- 239000002184 metal Substances 0.000 title description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 29
- 238000007006 Miyaura reaction Methods 0.000 claims abstract description 11
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 claims abstract description 11
- 238000006411 Negishi coupling reaction Methods 0.000 claims abstract description 8
- 238000006254 arylation reaction Methods 0.000 claims abstract description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 7
- 238000005580 one pot reaction Methods 0.000 claims abstract description 7
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 96
- -1 hydroxy, nitro, amino Chemical group 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 150000004696 coordination complex Chemical class 0.000 claims description 16
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 14
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 14
- 238000005859 coupling reaction Methods 0.000 claims description 13
- 229910052744 lithium Inorganic materials 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 13
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 238000005658 halogenation reaction Methods 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 2
- 125000002827 triflate group Chemical class FC(S(=O)(=O)O*)(F)F 0.000 claims 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 abstract description 45
- 238000006471 dimerization reaction Methods 0.000 abstract description 19
- 229910000073 phosphorus hydride Inorganic materials 0.000 abstract description 18
- 239000002904 solvent Substances 0.000 abstract description 11
- 239000003054 catalyst Substances 0.000 abstract description 8
- 239000000758 substrate Substances 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
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- 150000001454 anthracenes Chemical class 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000005885 boration reaction Methods 0.000 abstract description 2
- 238000005271 boronizing Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract description 2
- 238000007832 transition metal-catalyzed coupling reaction Methods 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- MWPLVEDNUUSJAV-LSMJWXKXSA-N anthracene Chemical group [13CH]1=[13CH][13CH]=[13CH][13C]2=CC3=CC=CC=C3C=[13C]21 MWPLVEDNUUSJAV-LSMJWXKXSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 235000011056 potassium acetate Nutrition 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- 239000011261 inert gas Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000004809 Teflon Substances 0.000 description 4
- 229920006362 Teflon® Polymers 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 4
- 239000004810 polytetrafluoroethylene Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
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- 229910000160 potassium phosphate Inorganic materials 0.000 description 3
- 235000011009 potassium phosphates Nutrition 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
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- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
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- 125000006651 (C3-C20) cycloalkyl group Chemical group 0.000 description 1
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- XMWJLKOCNKJERQ-UHFFFAOYSA-N 1-bromoanthracene Chemical compound C1=CC=C2C=C3C(Br)=CC=CC3=CC2=C1 XMWJLKOCNKJERQ-UHFFFAOYSA-N 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
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- UUDYBRGMAFZKMY-UHFFFAOYSA-N 2-fluoro-2,3-dihydroinden-1-one Chemical compound C1=CC=C2C(=O)C(F)CC2=C1 UUDYBRGMAFZKMY-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
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- LNJZJDLDXQQJSG-UHFFFAOYSA-N 2-phenylpyrazine Chemical compound C1=CC=CC=C1C1=CN=CC=N1 LNJZJDLDXQQJSG-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- KJQVHOFAWISYDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-b]pyridazine Chemical compound C1=CC=NN2C(Br)=CN=C21 KJQVHOFAWISYDO-UHFFFAOYSA-N 0.000 description 1
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- PIWNKSHCLTZKSZ-UHFFFAOYSA-N 8-bromoquinoline Chemical compound C1=CN=C2C(Br)=CC=CC2=C1 PIWNKSHCLTZKSZ-UHFFFAOYSA-N 0.000 description 1
- FYGANPJAPOLXNE-UHFFFAOYSA-N 8-naphthalen-1-ylquinoline Chemical compound C1=CN=C2C(C=3C4=CC=CC=C4C=CC=3)=CC=CC2=C1 FYGANPJAPOLXNE-UHFFFAOYSA-N 0.000 description 1
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
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- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
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- VFHDCDDYMMQCBF-UHFFFAOYSA-M [Cl-].[Zn+]C1=CC=CC=C1 Chemical compound [Cl-].[Zn+]C1=CC=CC=C1 VFHDCDDYMMQCBF-UHFFFAOYSA-M 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
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- 150000001336 alkenes Chemical class 0.000 description 1
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- JUTIJVADGQDBGY-UHFFFAOYSA-N anthracene photodimer Chemical group C12=CC=CC=C2C2C(C3=CC=CC=C33)C4=CC=CC=C4C3C1C1=CC=CC=C12 JUTIJVADGQDBGY-UHFFFAOYSA-N 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000005046 dihydronaphthyl group Chemical group 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000004146 energy storage Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 125000005549 heteroarylene group Chemical group 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
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 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
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- HUMMCEUVDBVXTQ-UHFFFAOYSA-N naphthalen-1-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=CC=CC2=C1 HUMMCEUVDBVXTQ-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 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
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000011907 photodimerization Methods 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005551 pyridylene group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910052703 rhodium 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
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000011232 storage material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005556 thienylene group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明提供一类如下式I所示的蒽二聚衍生物含膦配体,其可以用于一系列过渡金属催化的偶联反应,例如Miyaura反应、Suzuki‑Miyaura反应、Negishi反应和羰基α‑芳基化反应,尤其是用低用量的催化体系就可以催化底物的硼化反应(Miyaura反应)、Suzuki‑Miyaura反应、Negishi反应和羰基α‑芳基化反应,这有利于在药物合成领域的应用。所述含膦配体还可以用于底物的一锅Miyaura硼化/Suzuki偶联反应,并且在第二步不需要额外的添加催化剂和溶剂,一锅法就可以得到目标产物,极大地提高了反应效率,有利于经济友好和可持续发展。
Description
技术领域
本发明涉及有机光化学合成和金属催化领域,具体涉及一种含蒽二聚体骨架配体及其制备方法和在金属催化反应中的应用。
背景技术
蒽及其衍生物在长波紫外光(300-400nm)照射下在9,10位发生[4+4]光二聚反应是最早被发现研究的光化学反应之一。蒽光二聚体骨架虽然已被应用于主客体识别、分子开关和能量存储材料等领域,但在有机合成中的应用目前仍十分有限。
手性配体和催化剂是不对称催化合成领域的重要化合物,因此开发新型手性骨架配体成为促进不对称反应方法学重要研究方向,并且凝聚巨大的研究、应用和商业价值。目前使用手性蒽二聚体衍生物作为配体或催化剂在合成方法学中的应用尚未见报道。
综上所述,合成具有独特立体结构的蒽二聚衍生物配体或催化剂,进而基于此开发更加友好、原子经济的催化偶联反应新方法,这对社会发展具有重大的意义。
发明内容
为解决上述技术问题,本发明首先提供如下式I所示的蒽二聚衍生物含膦配体,其对映异构体,消旋体或非对映异构体:
其中,Q1、Q2相同或不同,彼此独立地选自H或PR1R2,R1、R2相同或不同,彼此独立地选自无取代,或任选被一个,两个或更多个Ra取代的如下基团:C1-10烷基,C1-10烷氧基,C3-20环烷基,3-20元杂环基,C6-20芳基,3-20元杂芳基,条件是Q1、Q2不同时为H;
Q3、Q4相同或不同,彼此独立地选自H,羟基,硝基,氨基,无取代或任选被一个,两个或更多个Rb取代的如下基团:C1-10烷基,C1-10烷氧基;
Ra、Rb相同或不同,彼此独立地选自羟基,硝基,氨基,C1-10烷基,C1-10烷氧基。
根据本发明的实施方案,式I中,Q1、Q2相同或不同,彼此独立地选自H或PR1R2,R1、R2相同或不同,彼此独立地选自C1-6烷基,C3-8环烷基,C1-6烷氧基,C6-12芳基,3-12元杂芳基,条件是Q1、Q2不同时为H;
Q3、Q4相同或不同,彼此独立地选自H,羟基,氨基,C1-6烷基,C1-6烷氧基。
作为优选的实施方案,式I选自如下式3a或3b所示的结构,其中R相同或不同,彼此独立地选自C1-6烷基,C3-8环烷基,C1-6烷氧基,C6-12芳基,3-12元杂芳基,R基团的下标表示有2个R基团;
作为实例,式I所示的蒽二聚衍生物含膦配体选自如下化合物:
本发明还提供如上所述式I所示的蒽二聚衍生物含膦配体的制备方法,包括如下方法中的至少一种:
方法一、
a1)化合物I-1与化合物I-2反应得到化合物I-3;
a2)将步骤a1)制备的化合物I-3与烷基锂或碱土金属单质及化合物PR1R2X3反应得到式I所示的蒽二聚衍生物含膦配体;
方法二、
b1)化合物I-1与烷基锂或碱土金属单质及化合物PR1R2X3反应得到化合物I-4;
b2)将步骤b1)制备的化合物I-4与化合物I-2反应得到式I所示的蒽二聚衍生物含膦配体;
方法三、
c1)蒽与化合物I-2反应得到化合物I-5;
c2)将步骤c1)制备的化合物I-5进行卤化反应,得到化合物I-6;
c3)将步骤c2)制备的化合物I-6与烷基锂或碱土金属单质及化合物PR1R2X3反应得到式I所示的蒽二聚衍生物含膦配体;
方法四、
d1)化合物I-1先与烷基锂或碱土金属单质及化合物PR1R2X3反应,产物再与双氧水反应得到化合物I-7;
d2)将步骤d1)制备的化合物I-7与化合物I-2反应得到化合物I-8;
d3)将步骤d2)制备的化合物I-8经还原得到式I所示的蒽二聚衍生物含膦配体;
其中,X1、X2相同或不同,彼此独立地选自H或卤素,条件是X1、X2不同时为H;
X3选自卤素;
基团Y1、Y2相同或不同,彼此独立地选自H或P(O)R1R2,条件是基团Y1、Y2不同时为H;
Q1、Q2、Q3、Q4、R1、R2具有如上所述的定义。
根据本发明的实施方案,所述烷基锂选自正丁基锂,叔丁基锂或其混合物;所述碱土金属单质选自镁单质。
根据本发明的实施方案,步骤a1)、b2)、c1)、d2)在>320nm的紫外光照射下进行。
根据本发明的实施方案,步骤a1)中化合物I-1与化合物I-2、步骤b2)中化合物I-4与化合物I-2、步骤c1)中蒽与化合物I-2、步骤d2)中化合物I-7与化合物I-2的摩尔比相同或不同,彼此独立地为1:(1~15),优选1:(1~10)。
根据本发明的实施方案,步骤a1)、b2)、c1)、d2)在惰性气体氛围中进行。
根据本发明的实施方案,步骤a2)、b1)、c3)及步骤d1)中化合物I-1与烷基锂或碱土金属单质及化合物PR1R2X3的反应温度相同或不同,彼此独立地在-30℃以下的低温条件下进行,优选在-70℃以下的条件下进行。
根据本发明的实施方案,步骤a2)、b1)、c3)、d1)在惰性气体氛围中进行。
根据本发明的实施方案,步骤a2)中化合物I-3与烷基锂或碱土金属单质及化合物PR1R2X3、步骤b1)中化合物I-1与烷基锂或碱土金属单质及化合物PR1R2X3、步骤c3)中化合物I-6与烷基锂或碱土金属单质及化合物PR1R2X3、步骤d1)中化合物I-1与烷基锂或碱土金属单质及化合物PR1R2X3的摩尔比相同或不同,彼此独立地为1:(1~5):(1~10),优选1:(1~3):(1~5)。
根据本发明的实施方案,步骤c2)的卤化反应中,使用的卤化试剂选自三氯化铁/卤素(Cl、Br或I)单质的混合物,或N-溴代丁二酰亚胺(NBS)。
根据本发明的实施方案,步骤d3)中还原反应在有机胺和卤代硅烷的存在下进行,例如在三乙胺和三氯硅烷的存在下进行。
根据本发明的实施方案,步骤d3)中化合物I-8与有机胺和卤代硅烷的摩尔比为1:(1~15):(1~10)。
根据本发明的实施方案,步骤d3)在惰性气体氛围中进行。
式I化合物可具有手性,例如当式I化合物为3a或者3b(其中两个基团-PR2不同)时,其为手性化合物。
因此本发明还提供一种式I化合物的拆分方法,包括如下步骤:将式I化合物用双氧水进行氧化,之后将得到的氧化产物进行手性色谱拆分,再将拆分得到的光学纯氧化产物还原,得到光学纯的式I化合物。
进一步的,本发明还提供消旋体3a的拆分方法,包括如下步骤:将如上方法一至四任一方法制备得到的消旋体3a先使用双氧水进行氧化得到消旋体4a,再将消旋体4a进行手性色谱拆分,分离得到旋光纯的4a,最后将旋光纯的4a分别进行还原得到旋光纯的3a。
本发明还提供如上所述式I所示的蒽二聚衍生物含膦配体在金属催化偶联反应中的用途。
根据本发明的实施方案,所述金属催化偶联反应选自Miyaura反应、Suzuki-Miyaura反应、Negishi反应、羰基α-芳基化、和Miyaura硼化/Suzuki偶联。
所述Miyaura反应是指芳基、杂芳基或烯基卤代物或三氟磺酸酯衍生物与联二硼酸频哪醇酯发生偶联反应,制备得到相应的硼酸频哪醇酯。
所述Suzuki-Miyaura反应为芳基、杂芳基或烯基硼酸或硼酸酯与氯、溴、碘代芳烃或烯烃发生交叉偶联。
所述Negishi反应为不饱和有机锌试剂和芳基、杂芳基或烯基卤化物等进行的偶联反应。
根据本发明的实施方案,在所述金属催化偶联反应中,式I所示的蒽二聚衍生物含膦配体与金属形成金属配合物,所述金属为Rh、Ru、Ni、Ir、Pd、Cu、Pt、Fe、Co、Cu中的至少一种。
优选的,所述金属配合物中还可以包括其他配体。
在一个实施方式中,将本发明所述式I所示的含磷配体与已知的金属配合物(例如如下所示的Pd G4二聚体)反应形成含有式I的金属配合物,将该配合物用于催化偶联反应。
例如化合物11与Pd G4二聚体形成的配位结构11-Pd G4。
根据本发明的实施方案,所述Miyaura反应的产物可以作为Suzuki-Miyaura反应的原料。
本发明还提供式I所示的蒽二聚衍生物含膦配体催化Miyaura反应的方法,包括如下步骤:
S1)将如上所述式I所示的蒽二聚衍生物含膦配体与已知的金属配合物混合,制备得到含有式I配体的金属配合物;
S2)将芳基、杂芳基或烯基卤代物或三氟磺酸酯衍生物与联硼酸频那醇酯在碱、步骤S1)制备得到的含有式I配体的金属配合物的存在下制备相应的硼酸频哪醇酯。
根据本发明的实施方案,步骤S1)和步骤S2)在惰性气体氛围下进行。
根据本发明的实施方案,步骤S2)所述的碱选自氟化钾,碳酸钾,醋酸钾,碳酸钠,磷酸钾,氟化铯等中的至少一种,优选醋酸钾。
根据本发明的实施方案,步骤S2)反应的温度为60-100℃,优选90℃;反应时间为12-48h,优选24h;反应溶剂选自二甲基甲酰胺,四氢呋喃,二氧六环,二甲基亚砜,2-甲基四氢呋喃或它们的混合溶剂;优选2-甲基四氢呋喃。
本发明还提供式I所示的蒽二聚衍生物含膦配体一锅法催化Suzuki-Miyaura反应制备偶联产物的方法,包括如下步骤:
S1’)将如上所述式I所示的蒽二聚衍生物含膦配体与已知的金属配合物混合,制备得到含有式I配体的金属配合物;
S2’)将芳基、杂芳基或烯基卤代物或三氟磺酸酯衍生物与联硼酸频那醇酯在碱,步骤S1’)制备的含有式I配体的金属配合物的存在下制备相应的硼酸频哪醇酯;
S3’)向步骤S2’)制备的硼化产物体系中加入芳基、杂芳基或烯基卤代物中的一种反应得到偶联产物。
根据本发明的实施方案,步骤S1’)、步骤S2’)、步骤S3’)在惰性气体氛围下进行。
根据本发明的实施方案,步骤S2’)所述的碱选自氟化钾,碳酸钾,醋酸钾,碳酸钠,磷酸钾,氟化铯等中的至少一种,优选醋酸钾。
根据本发明的实施方案,步骤S2’)反应的温度为60-100℃,优选90℃;反应时间为12-48h,优选24h;反应溶剂选自二甲基甲酰胺,四氢呋喃,二氧六环,二甲基亚砜,2-甲基四氢呋喃或它们的混合溶剂;优选2-甲基四氢呋喃。
术语解释和说明
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、优选地定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当属于本申请记载的范围。
除非另有说明,本申请中基团的上标为基团标记,下标一般指该基团的个数。
“任选……取代”为被任意取代基取代或未取代。
本发明单独使用或用作后缀或前缀的“C1-10烷基”意指支链和直链饱和脂族烃基,其具有1至10个碳原子(或若提供了碳原子的具体数目,则指该具体数目)的支链和直链饱和脂族烃基。例如,所述烷基可以为C1-6烷基,所述“C1-6烷基”表示具有1、2、3、4、5、6个碳原子的烷基。烷基的实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基、1,2-二甲基丁基、2-乙基己基、3-乙基己基、2-己基癸基等,以及上述基团的全部异构形式。
术语“C1-10烷氧基”指C1-10烷基-O-,其中C1-10烷基具有如上所述的定义。
本发明使用的术语“C3-20环烷基”意指饱和的烃环,其可包括稠合或桥接的多环***。环烷基在其环结构中优选具有3至20个碳原子。优选地,环烷基在其环结构中具有3、4、5或6个碳原子。例如,“C3-6环烷基”表示例如环丙基、环丁基、环戊基或环己基的基团。
本发明使用的术语“3-20元杂环基”指包含3至20个原子的饱和、不饱和或部分饱和的单环、二环或三环(除非另有说明),其中1、2、3、4或5个环原子选自氮、硫或氧,除非另有说明,其可通过碳或氮来连接,其中-CH2-基团任选被-C(O)-代替;及其中除非另有相反说明,环氮原子或环硫原子任选被氧化以形成N-氧化物或S-氧化物或环氮原子任选被季铵化;其中环中的-NH任选被乙酰基、甲酰基、甲基或甲磺酰基取代;及环任选被一个或多个卤素取代。应该理解的是,当杂环基中S原子和O原子的总数超过1时,这些杂原子不彼此相邻。若所述杂环基为二环或三环。
术语“C6-20芳基”应理解为表示具有6~20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环,优选“C6-14芳基”。术语“C6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-14芳基”),特别是具有6个碳原子的环(“C6芳基”),例如苯基;或联苯基,或者是具有9个碳原子的环(“C9芳基”),例如茚满基或茚基,或者是具有10个碳原子的环(“C10芳基”),例如四氢化萘基、二氢萘基或萘基,或者是具有13个碳原子的环(“C13芳基”),例如芴基,或者是具有14个碳原子的环(“C14芳基”),例如蒽基。
术语“5-20元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5~20个环原子且包含1-5个独立选自N、O和S的杂原子,例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5、6、7、8、9、10、11、12、13或14个环原子,特别是5或6或9或10个碳原子,且其包含1-5个,优选1-3个独立选自N、O和S的杂原子并且,另外在每一种情况下可为苯并稠合的。特别地,杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物,例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并***基、吲唑基、吲哚基、异吲哚基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等,以及它们的苯并衍生物,例如喹啉基、喹唑啉基、异喹啉基等;或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
除非另有说明,杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式,例如其位置异构体。因此,对于一些说明性的非限制性实例,吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基;噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基。
本发明中,当所述结构具有手性时,除非明确说明是光学纯外,所涉及的化合物以及所画结构均指外消旋物,或者手性异构体的混合物。
有益效果
1、本发明提供一类式I所示的蒽二聚衍生物含膦配体,其可以用于一系列过渡金属催化的偶联反应,例如Miyaura反应、Suzuki-Miyaura反应、Negishi反应和羰基α-芳基化反应,尤其是用低用量的催化体系就可以催化底物的硼化反应(Miyaura反应)、Suzuki-Miyaura反应、Negishi反应和羰基α-芳基化反应,这有利于在药物合成领域的应用。所述含膦配体还可以用于底物的一锅Miyaura硼化/Suzuki偶联反应,并且在第二步不需要额外的添加催化剂和溶剂,一锅法就可以得到目标产物,极大地提高了反应效率,有利于经济友好和可持续发展。
2、本发明利用蒽或取代蒽的[4+4]光反应,以廉价易得的商业可用原料制备得到式I所示的蒽二聚衍生物含膦配体,制备方法简单,产物收率较高。
3、本发明制备的含蒽二聚体骨架含膦配体,反应活性很高,即用少量的配体就能够高产率得到偶联反应产物,底物普适性尤其是对于杂环底物的偶联反应适用性很好,这有助于开发更加友好、原子经济的反应新体系,对社会发展具有重大的研究意义。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
实施例1
消旋体蒽二聚体骨架的单膦配体11的制备方法,包括如下合成步骤:
在充满氮气的手套箱中,将蒽(1.46g,8.17mmol,10.0equiv),1-溴蒽(210mg,0.817mmol,1equiv)和脱气的甲苯(68mL)加入到150mL玻璃厚壁压力瓶中。将厚壁瓶盖上盖子,从手套箱中转出,并在氙灯照射下在110℃下搅拌24小时。将混合物冷却至室温并借助于二氯甲烷(50mL)通过短硅藻土过滤。然后减压除去溶剂。使用硅胶柱色谱法纯化,得到白色固体化合物10(305mg,86%收率)(消旋体)。
1H NMR(400MHz,CDCl3)δ7.18-7.16(m,1H),7.01(dd,J=8.0Hz,1.1Hz,1H),6.97-6.78(m,12H),6.66(dd,J=7.7Hz,7.7Hz,1H),5.06(d,J=11.0Hz,1H),4.59(d,J=11.1Hz,1H),4.55-4.51(m,2H);
13C NMR(101MHz,CDCl3)δ146.1,143.7,143.4,143.3,143.2,143.1,142.6,129.4,127.7,127.3,127.25,127.20,127.1,127.01,126.99,126.3,126.2,126.05,126.03,125.9,125.84,125.80,125.6,123.5,54.1,53.9,52.8,52.6。
在空气条件下,将化合物10(292mg,0.673mmol)加入到装有磁子的100mL圆底烧瓶中。用橡胶塞密封烧瓶,抽真空并用氮气回填(三个循环),然后加入无水四氢呋喃(35mL)。将所得溶液在-78℃下搅拌5分钟。接下来,在-78℃下将正丁基锂(2.5M,正己烷溶液,0.34mL,0.84mmol,1.25equiv)缓慢加入烧瓶中。将混合物在-78℃下搅拌1.5小时,然后在-78℃下通过注射器加入二苯基氯化磷(296mg,1.34mmol,2.00equiv,在1mL四氢呋喃溶液中)溶液。将反应混合物在-78℃下搅拌1.5小时,然后在25℃下搅拌15小时。将反应混合物用去离子水(10mL)淬灭并转移至分液漏斗中。将水相用二氯甲烷(10mL)萃取三次。将合并的有机相用饱和食盐水洗涤,经无水硫酸钠干燥。减压除去溶剂。使用硅胶柱色谱法纯化,得到白色固体化合物配体11(177mg,49%收率)。
1H NMR(400MHz,CDCl3)δ7.41-7.36(m,3H),7.34-7.28(m,2H),7.25-7.11(m,5H),7.00(d,J=7.2Hz,1H),6.95-6.85(m,5H),6.84-6.74(m,5H),6.75-6.70(m,2H),6.58(d,J=7.2Hz,1H),6.44-6.38(m,1H),5.36(dd,J=11.0Hz,5.9Hz,1H),4.67(d,J=11.0Hz,1H),4.61-4.53(m,2H);
13C NMR(101MHz,CDCl3)δ148.9,148.6,144.25,144.19,143.75,143.72,143.7,143.2,137.1,136.7,136.6,134.7,134.5,133.5,133.4,130.7,128.9,128.7,128.6,128.54,128.47,128.4,128.3,127.5,127.22,127.19,127.16,127.11,127.08,126.9,126.8,126.0,125.9,125.71,125.68,125.6,54.2,53.0,50.9,50.7;
31P NMR(162MHz,CDCl3)δ-11.9。
实施例2
手性蒽二聚体骨架的单膦配体11的制备方法,包括如下合成步骤:
将化合物10(218mg,0.500mmol)采用实施例1中相同的方法制备得到化合物11(消旋体)。再将得到的化合物11粗产物溶解在装有磁子和二氯甲烷(30mL)的100mL圆底烧瓶中。在0℃下将过氧化氢(30%水溶液,0.15mL,1.5mmol,3.0equiv)加入到反应混合物中。将反应混合物升温并在25℃下搅拌3小时,然后倒入含有去离子水(10mL)的分液漏斗中。将水层用二氯甲烷(10mL)萃取三次。将合并的有机相用饱和食盐水洗涤,用无水硫酸钠干燥,并真空浓缩。使用硅胶柱色谱法纯化,得到白色固体化合物12(消旋体)(153mg,55%产率)。
1H NMR(400MHz,CDCl3)δ7.62-7.41(m,9H),7.39-7.30(m,2H),7.08(d,J=7.6Hz,1H),6.97-6.86(m,5H),6.84-6.72(m,5H),6.65(dd,J=7.2Hz,7.2Hz,1H),6.48-6.40(m,1H),6.26(d,J=7.2Hz,1H),5.43(d,J=10.8Hz,1H),4.86(d,J=10.8Hz,1H),4.61(d,J=11.2Hz,1H),4.55(d,J=11.2Hz,1H);
13C NMR(101MHz,CDCl3)δ149.6,149.5,146.25,146.15,143.71,143.67,143.5,143.3,142.9,132.7,132.6,132.5,132.0,131.9,131.8,131.4,131.3,130.3,130.2,129.3,128.7,128.6,128.5,127.5,127.3,127.2,127.0,126.8,126.2,125.7,125.63,125.61,125.53,125.46,125.0,124.9,54.2,53.7,51.61,51.56;
31P NMR(162MHz,CDCl3)δ32.8。
使用配备有Daicel OD柱(5cm ID×25cm)的制备型SFC(NovaSep SuperSep 20-30***)用于外消旋化合物12(1.02g)的拆分。色谱分离条件:CO2/(CH3OH和CH3CN,体积比为1:1)=67/33(g/g),120g/min,36℃。
峰1,(Rp)-12:保留时间:2.7分钟;0.483g,收率47%。(绝对构型由X射线晶体确定)
峰2,(Sp)-12:保留时间:3.9分钟;0.453g,收率44%。
分析HPLC使用Daicel OD柱(0.46cm I.D.×25cm L),色谱分离条件:正己烷:i-PrOH=95:5,1.0mL/min。
保留时间:峰1,(Rp)-12:10.9分钟;峰2,(Sp)-12:22.5分钟。
在充满氮气的手套箱中,将光学纯化合物(Sp)-12(55.7mg,0.100mmol)和脱气的甲苯(10mL)加入装有搅拌磁子的40mL玻璃反应瓶中。然后将三乙胺(0.10mL,0.700mmol,7.0equiv)和三氯硅烷(0.05mL,0.500mmol,5.0equiv)加入到反应瓶中。将反应瓶用聚四氟乙烯的隔膜盖密封,从手套箱中转出,并在115℃下搅拌24小时。将反应混合物冷却至室温,与二氯甲烷(5mL)混合,用饱和碳酸氢钠水溶液(0.20mL)淬灭,并搅拌30分钟。接下来,将混合物直接加载到硅胶柱上,用1:2石油醚/二氯甲烷(200mL)洗脱,得到纯净的白色固体化合物(Sp)-11(48.1mg,89%产率)。采用上述相同的方法还制备得到光学纯化合物(Rp)-11。
实施例3
将手性蒽二聚体骨架的单膦配体(Rp)-11应用于不对称催化反应,包括如下步骤:
在充满氮气的手套箱中,1-(2,6-二溴-4-甲基苯基)萘(37.6mg,0.10mmol),苯基硼酸(14.6mg,0.12mmol,1.20equiv),无水碳酸钾(20.7mg,0.15mmol,1.50equiv),Pd2(dba)3(2.3mg,0.0025mmol,0.025equiv),配体(Rp)-11(3.2mg,0.006mmol,0.060equiv)和甲苯(1mL)分别加入装有磁子的4mL反应瓶中,将反应瓶用聚四氟乙烯的盖子密封并移出手套箱。将反应混合物在25℃剧烈搅拌15小时。然后借助乙酸乙酯(10mL)将混合物通过短硅胶过滤,减压除去溶剂,使用硅胶柱色谱法(石油醚)纯化,得到白色固体13(14.6mg,39%产率)。使用Daicel OD柱的HPLC分析确定对映体比率为66:34(正己烷/i-PrOH=99:1,流速=1.0mL/min,对映体多的tR=5.0min,对映体少的tR=6.0分钟)。
实施例4
蒽二聚体骨架的单膦配体11和Pd G4二聚体形成的配合物,包括如下步骤:
(Ms:甲磺酰基)
在充满氮气的手套箱中,将Pd G4二聚体(15.4mg,0.02mmol),配体11(消旋体)(21.6mg,2.0equiv,0.04mmol)和无水2-MeTHF(5mL)加入装有40mL的反应瓶中。将反应瓶用聚四氟乙烯的盖子密封并移出手套箱。将反应混合物在25℃剧烈搅拌1小时后,减压下除去溶剂,然后加入戊烷(6mL),接着在25℃下超声处理30秒。通过离心(10000rpm,3分钟)分离所得悬浮液,并用移液管小心地移除上清液。戊烷洗涤-超声-离心处理重复三次。减压干燥得到的沉淀,为淡黄色固体11-Pd G4(31.2mg)。
1H NMR(400MHz,CD2Cl2)δ8.46(t,J=5.8Hz,1H),7.97(d,J=7.2Hz,1H),7.81(dd,J=7.1,1.9Hz,1H),7.60-7.41(m,5H),7.31(d,J=7.3Hz,1H),7.26-7.01(m,8H),7.02-6.86(m,7H),6.86-6.66(m,5H),6.65-6.39(m,4H),5.93(d,J=7.3Hz,1H),5.44(d,J=10.9Hz,1H),5.21(d,J=10.9Hz,1H),4.77(d,J=11.2Hz,1H),4.67(d,J=11.2Hz,1H),2.83(dd,J=5.8,3.0Hz,3H),2.72(s,3H);
13C NMR(101MHz,CD2Cl2)δ149.8,144.4,144.3,144.0,143.7,143.1,143.0,142.7,141.4,138.6,137.7,137.6,136.2,136.1,133.5,133.0,132.8,131.0,130.2,129.7,128.9,128.8,128.75,128.5,128.10,128.05,127.99,127.91,127.8,127.2,126.97,126.87,126.77,126.5,126.23,126.15,126.09,125.87,125.7,125.5,125.2,125.11,125.07,124.98,123.2,122.2,54.6,52.3,51.7,51.7,40.4,40.2。
31P NMR(162MHz,CD2Cl2)δ35.0。
实施例5
蒽二聚体骨架的单膦配体11(消旋体)应用于Miyaura反应,包括如下步骤:
在充满氮气的手套箱中,将Pd G4二聚体(2.0mg,0.0026mmol),配体11(3.2mg,0.0059mmol)和无水2-MeTHF(1.0mL)加入到48mL玻璃厚壁压力容器中,将此混合物在手套箱中在室温下搅拌15分钟。然后依次加入3-溴苯并噻吩(1.065g,5.0mmol,1.0equiv),联硼酸频那醇酯(1.60g,6.3mmol,1.26equiv),无水醋酸钾(980mg,10.0mmol,2.00equiv)和无水2-MeTHF(24.0mL)到反应瓶中。将反应瓶用盖子盖上从手套箱中转出,并在90℃剧烈搅拌24小时。将反应混合物冷却至室温,借助乙酸乙酯(100mL)通过短硅胶过滤。然后减压除去溶剂,使用硅胶柱层析纯化,得到白色固体3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷)苯并噻吩(1.092g,84%产率)。
实施例6
蒽二聚体骨架的单膦配体11(消旋体)应用于Suzuki-Miyaura反应,包括如下步骤:
在充满氮气的手套箱中,将Pd G4二聚体(1.9mg,0.0025mmol),配体11(3.2mg,0.006mmol)和无水乙二醇二甲醚(1.0mL)加入装配有磁子的4mL反应瓶中。将混合物在手套箱中室温下搅拌15分钟,得到0.005M的11-Pd G4溶液。然后,在手套箱中,将8-溴喹啉(83.2mg,0.40mmol),1-萘硼酸(82.5mg,0.48mmol,1.20equiv),无水磷酸钾(169.3mg,0.800mmol,2.00equiv),11-Pd G4(0.005M,0.4mL,0.0050equiv)和无水醇二甲醚(3.6mL)分别加入装有磁子的20mL反应瓶中,且用聚四氟乙烯的盖子密封并移出手套箱。将反应混合物在80℃剧烈搅拌24小时。反应结束后将混合物冷却至室温并借助乙酸乙酯(10mL)进行短硅胶过滤。减压除去溶剂,使用硅胶柱层析纯化,得到浅黄色固体8-萘基喹啉(100.3mg,98%产率)。
实施例7
蒽二聚体骨架的单膦配体11(消旋体)应用于Negishi反应,包括如下步骤:
在充满氮气的手套箱中,将Pd G4二聚体(1.9mg,0.0025mmol),配体11(消旋体)(3.2mg,0.006mmol)和无水四氢呋喃(1.0mL)加入装有磁子的4mL反应瓶中。将混合物在手套箱中室温下搅拌15分钟,得到0.005M的11-Pd G4溶液。接着,在手套箱中,将2-溴吡嗪(63.6mg,0.400mmol),11-Pd G4(0.005M,0.4mL,0.0050equiv)和无水四氢呋喃(1.6mL)的溶液分别加入到20mL反应瓶中,用聚四氟乙烯的盖子密封并移出手套箱。反应混合物在0℃剧烈搅拌5分钟,然后再通过注射器在0℃下将苯基氯化锌溶液(0.40M四氢呋喃溶液,2.0mL,2.00equiv)逐滴加入反应混合物中。隔膜帽的穿孔用真空脂覆盖。并将得到的混合物在0℃下搅拌24小时。反应结束后,将混合物温热至室温并借助乙酸乙酯(10mL)短硅胶过滤,减压除去溶剂。使用硅胶柱层析纯化,得到白色固体2-苯基吡嗪(59.3mg,95%产率)。
实施例8
蒽二聚体骨架的单膦配体11(消旋体)应用于羰基α-芳基化反应,包括如下步骤:
在充满氮气的手套箱中,将Pd G4二聚体(1.9mg,0.0025mmol),配体11(消旋体)(3.2mg,0.006mmol)和无水乙二醇二甲醚(1.0mL)分别加入装有磁子的4mL反应瓶中。将混合物在手套箱中室温下搅拌15分钟,得到0.005M的11-Pd G4溶液。然后,在手套箱中,将4-甲基溴苯(68.4mg,0.400mmol),2-氟-2,3-二氢-1H-茚-1-酮(90.1mg,0.60mmol,1.50equiv),无水氟化铯(120.8mg,0.800mmol,2.00equiv),11-Pd G4(0.005M,0.4mL,0.0050equiv)和无水乙二醇二甲醚(1.6mL)加入装有磁子的20mL反应瓶中。将反应瓶用聚四氟乙烯的盖子密封并移出手套箱。并将反应混合物在80℃剧烈搅拌48小时。然后将混合物冷却至室温并借助于乙酸乙酯(10mL)短硅胶过滤,减压除去溶剂。使用硅胶柱层析纯化,得到白色固体2-氟-2-(对甲基苯)-2,3-二氢-1H-茚-1-酮(80.6mg,84%产率)。
实施例9
蒽二聚体骨架的单膦配体11(消旋体)应用于杂环底物的的一锅Miyaura硼化/Suzuki偶联反应,并且在第二步不需要额外的添加催化剂和溶剂,包括如下步骤:
步骤一:在充满氮气的手套箱中,将Pd G4二聚体(1.9mg,0.0025mmol),配体11(3.2mg,0.006mmol)和无水2-甲基四氢呋喃(1.0mL)分别加入装有磁子的4mL反应瓶中。将混合物在手套箱中室温下搅拌15分钟,得到0.005M的11-Pd G4溶液。然后,在手套箱中,5-溴-2-三氟甲基吡啶(90.4mg,0.400mmol),联硼酸频那醇酯(122mg,0.480mmol,1.20equiv),无水醋酸钾(78.5mg,0.800mmol,2.00equiv),11-Pd G4溶液(0.005M,0.4mL,0.005equiv)和无水2-甲基四氢呋喃(1.6mL)分别加入装有磁子的20mL反应瓶中。将反应瓶用聚四氟乙烯的盖子密封,从手套箱中转出,并在90℃下剧烈搅拌24小时。反应结束后,将反应瓶(保持密封)冷却至室温。
步骤二:将来自步骤一的反应瓶转移至充满氮气的手套箱中。然后,将3-溴咪唑并[1,2-b]哒嗪(118.8mg,0.60mmol,1.5equiv)和碳酸钾(110.4mg,0.800mmol,2.0equiv)分别加入到反应瓶中。反应瓶用聚四氟乙烯的盖子密封并移出手套箱。再通过注射器添加脱氧的去离子水(0.4mL)。隔膜帽的穿孔用真空脂覆盖。将反应混合物在90℃剧烈搅拌48小时。然后将混合物冷却至室温,用去离子水(10mL)淬灭反应并转移至分液漏斗中。将水相用CH2Cl2(10mL)萃取三次,饱和食盐水洗涤,合并有机相用无水硫酸钠干燥并减压浓缩。使用硅胶柱层析纯化,得到白色固体3-(6-(三氟甲基)吡啶-3-基)咪唑并[1,2-b]哒嗪(68.6mg,65%产率)。
1H NMR(400MHz,CDCl3)δ9.38(s,1H),8.67(dd,J=8.3,2.0Hz,1H),8.46(d,J=4.3Hz,1H),8.22(s,1H),8.07(d,J=9.1Hz,1H),7.78(d,J=8.2Hz,1H),7.18(dd,J=9.1,4.3Hz 1H);
13C NMR(101MHz,CDCl3)δ147.5,146.6(q,J=34.9Hz),143.5,134.2,134.0,127.9,126.5,123.0,120.4(q,J=3.1Hz),120.3,117.7,117.5;
19F NMR(377MHz,CDCl3)δ-67.8。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.如下式I所示的化合物,其对映异构体,消旋体或非对映异构体:
其中,Q1、Q2相同或不同,彼此独立地选自H或PR1R2,R1、R2相同或不同,彼此独立地选自无取代,或任选被一个,两个或更多个Ra取代的C6-12芳基,条件是Q1、Q2不同时为H;
Q3、Q4相同或不同,彼此独立地选自H,羟基,硝基,氨基,无取代或任选被一个,两个或更多个Rb取代的如下基团:C1-10烷基,C1-10烷氧基;
Ra、Rb相同或不同,彼此独立地选自羟基,硝基,氨基,C1-10烷基,C1-10烷氧基。
2.根据权利要求1所述的化合物,其对映异构体,消旋体或非对映异构体,其特征在于,Q3、Q4相同或不同,彼此独立地选自H,羟基,氨基,C1-6烷基,C1-6烷氧基。
3.根据权利要求1或2所述的化合物,其对映异构体,消旋体或非对映异构体,其特征在于,式I选自如下式3a或3b所示的结构,其中R相同或不同,彼此独立地选自C6-12芳基,R基团的下标表示有2个R基团;
4.根据权利要求3所述的化合物,其对映异构体,消旋体或非对映异构体,其特征在于,选自如下化合物:
5.权利要求1-4任一项所述的化合物,其对映异构体,消旋体或非对映异构体的制备方法,其特征在于,包括如下方法中的至少一种:
方法一、
a1)化合物I-1与化合物I-2反应得到化合物I-3;
a2)将步骤a1)制备的化合物I-3与烷基锂或碱土金属单质及化合物PR1R2X3反应得到式I所示的化合物;
方法二、
b1)化合物I-1与烷基锂或碱土金属单质及化合物PR1R2X3反应得到化合物I-4;
b2)将步骤b1)制备的化合物I-4与化合物I-2反应得到式I所示的化合物;
方法三、
c1)蒽与化合物I-2反应得到化合物I-5;
c2)将步骤c1)制备的化合物I-5进行卤化反应,得到化合物I-6;
c3)将步骤c2)制备的化合物I-6与烷基锂或碱土金属单质及化合物PR1R2X3反应得到式I所示的化合物;
方法四、
d1)化合物I-1先与烷基锂或碱土金属单质及化合物PR1R2X3反应,产物再与双氧水反应得到化合物I-7;
d2)将步骤d1)制备的化合物I-7与化合物I-2反应得到化合物I-8;
d3)将步骤d2)制备的化合物I-8经还原得到式I所示的化合物;
其中,X1、X2相同或不同,彼此独立地选自H或卤素,条件是X1、X2不同时为H;
X3选自卤素;
基团Y1、Y2相同或不同,彼此独立地选自H或P(O)R1R2,条件是基团Y1、Y2不同时为H;
Q1、Q2、Q3、Q4、R1、R2具有权利要求1-4任一项所述的定义。
6.一种权利要求1-4任一项所述的式I化合物的拆分方法,其特征在于,包括如下步骤:当所述式I化合物为手性化合物时,将式I化合物用双氧水进行氧化,之后将得到的氧化产物进行手性色谱拆分,再将拆分得到的光学纯氧化产物还原,得到光学纯的式I化合物。
7.权利要求1-4任一项所述式I所示的化合物,其对映异构体,消旋体或非对映异构体在金属催化偶联反应中的用途,其中,所述式I化合物作为配体用于金属催化偶联反应中。
8.根据权利要求7所述的用途,其特征在于,所述金属催化偶联反应选自Miyaura反应、Suzuki-Miyaura反应、Negishi反应、羰基α-芳基化和Miyaura硼化/Suzuki偶联。
9.权利要求1-4任一项所述式I所示的化合物,其对映异构体,消旋体或非对映异构体催化Miyaura反应的方法,其特征在于,包括如下步骤:
S1)将式I所示的化合物,其对映异构体,消旋体或非对映异构体与金属配合物混合,制备得到含有式I化合物作为配体的金属配合物;
S2)将芳基、杂芳基或烯基卤代物或三氟磺酸酯衍生物与联硼酸频那醇酯在碱、步骤S1)制备得到的含有式I配体的金属配合物的存在下制备相应的硼酸频哪醇酯。
10.权利要求1-4任一项所述式I所示的化合物,其对映异构体,消旋体或非对映异构体一锅法催化Suzuki-Miyaura反应制备偶联产物的方法,其特征在于,包括如下步骤:
S1’)将式I所示的化合物,其对映异构体,消旋体或非对映异构体与已知的金属配合物混合,制备得到含有式I化合物作为配体的金属配合物;
S2’)将芳基、杂芳基或烯基卤代物或三氟磺酸酯衍生物与联硼酸频那醇酯在碱,步骤S1’)制备的含有式I配体的金属配合物的存在下制备相应的硼酸频哪醇酯;
S3’)向步骤S2’)制备的硼化产物体系中加入芳基、杂芳基或烯基卤代物中的一种反应得到偶联产物。
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