CN114405547A - 金属络合物 - Google Patents
金属络合物 Download PDFInfo
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- CN114405547A CN114405547A CN202111499881.2A CN202111499881A CN114405547A CN 114405547 A CN114405547 A CN 114405547A CN 202111499881 A CN202111499881 A CN 202111499881A CN 114405547 A CN114405547 A CN 114405547A
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- Prior art keywords
- metal complex
- trans
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- ppm
- complex
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- 229910052751 metal Inorganic materials 0.000 title abstract description 36
- 239000002184 metal Substances 0.000 title abstract description 32
- 150000004696 coordination complex Chemical class 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 22
- 230000008569 process Effects 0.000 claims abstract description 11
- 230000003197 catalytic effect Effects 0.000 claims abstract description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 172
- 239000000460 chlorine Substances 0.000 claims description 82
- -1 perfluoroate Chemical compound 0.000 claims description 81
- 239000010948 rhodium Substances 0.000 claims description 54
- 239000000203 mixture Substances 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 31
- 229910052703 rhodium Inorganic materials 0.000 claims description 23
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical group [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 23
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 239000011541 reaction mixture Substances 0.000 claims description 16
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical group I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 10
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 8
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 8
- 239000011630 iodine Substances 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical group [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 7
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical group [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical group [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 6
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 5
- 125000000129 anionic group Chemical group 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical group [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 4
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Chemical compound Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 claims description 4
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- LLYCMZGLHLKPPU-UHFFFAOYSA-M perbromate Chemical compound [O-]Br(=O)(=O)=O LLYCMZGLHLKPPU-UHFFFAOYSA-M 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical group OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical group [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 3
- 235000021317 phosphate Nutrition 0.000 claims description 3
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical class OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 2
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims description 2
- 150000001642 boronic acid derivatives Chemical class 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 229910001919 chlorite Inorganic materials 0.000 claims description 2
- 229910052619 chlorite group Inorganic materials 0.000 claims description 2
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical group OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 claims description 2
- ZCDOYSPFYFSLEW-UHFFFAOYSA-N chromate(2-) Chemical compound [O-][Cr]([O-])(=O)=O ZCDOYSPFYFSLEW-UHFFFAOYSA-N 0.000 claims description 2
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 claims description 2
- BLBIZNCSZLTDPW-UHFFFAOYSA-N dihydrogenphosphite Chemical compound OP(O)[O-] BLBIZNCSZLTDPW-UHFFFAOYSA-N 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical group [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- AAUNBWYUJICUKP-UHFFFAOYSA-N hypoiodite Chemical compound I[O-] AAUNBWYUJICUKP-UHFFFAOYSA-N 0.000 claims description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical group [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims description 2
- 150000004767 nitrides Chemical class 0.000 claims description 2
- 150000003891 oxalate salts Chemical class 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-M oxalate(1-) Chemical compound OC(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-M 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 2
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 claims description 2
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical class O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims description 2
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 2
- 150000003892 tartrate salts Chemical class 0.000 claims description 2
- 150000004764 thiosulfuric acid derivatives Chemical class 0.000 claims description 2
- 150000004763 sulfides Chemical class 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 33
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 10
- 239000001257 hydrogen Substances 0.000 abstract description 10
- 238000006555 catalytic reaction Methods 0.000 abstract description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 94
- 239000002904 solvent Substances 0.000 description 77
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 238000006243 chemical reaction Methods 0.000 description 52
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 41
- 229910052741 iridium Inorganic materials 0.000 description 39
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 37
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 36
- 150000003254 radicals Chemical class 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 27
- 125000004432 carbon atom Chemical group C* 0.000 description 24
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 24
- 239000000725 suspension Substances 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 150000003839 salts Chemical class 0.000 description 22
- 125000001424 substituent group Chemical group 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
- 150000001412 amines Chemical class 0.000 description 20
- 229910052736 halogen Inorganic materials 0.000 description 20
- 239000003446 ligand Substances 0.000 description 20
- 238000004458 analytical method Methods 0.000 description 19
- 150000002367 halogens Chemical group 0.000 description 19
- 238000000746 purification Methods 0.000 description 19
- UILZQFGKPHAAOU-ARJAWSKDSA-N (z)-2-bromobut-2-ene Chemical compound C\C=C(\C)Br UILZQFGKPHAAOU-ARJAWSKDSA-N 0.000 description 18
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 17
- 125000004429 atom Chemical group 0.000 description 17
- 239000011737 fluorine Substances 0.000 description 17
- 229910052731 fluorine Inorganic materials 0.000 description 17
- 238000010992 reflux Methods 0.000 description 17
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 16
- 239000007832 Na2SO4 Substances 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 15
- 239000013078 crystal Substances 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 150000002430 hydrocarbons Chemical group 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 14
- 239000012071 phase Substances 0.000 description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 13
- 229910052799 carbon Inorganic materials 0.000 description 13
- 125000005842 heteroatom Chemical group 0.000 description 13
- 239000000758 substrate Substances 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000012230 colorless oil Substances 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 150000002503 iridium Chemical class 0.000 description 11
- 150000002825 nitriles Chemical group 0.000 description 11
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 10
- 229910052744 lithium Inorganic materials 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 125000004122 cyclic group Chemical group 0.000 description 9
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 9
- 230000007935 neutral effect Effects 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 8
- 150000004985 diamines Chemical class 0.000 description 8
- 125000002524 organometallic group Chemical group 0.000 description 8
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000007126 N-alkylation reaction Methods 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 125000005647 linker group Chemical group 0.000 description 6
- 125000001979 organolithium group Chemical group 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 5
- 238000004293 19F NMR spectroscopy Methods 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 238000011068 loading method Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 150000003283 rhodium Chemical class 0.000 description 5
- 150000003333 secondary alcohols Chemical class 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 4
- 229910021638 Iridium(III) chloride Inorganic materials 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000000539 dimer Substances 0.000 description 4
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 4
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 4
- 125000004437 phosphorous atom Chemical group 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 150000003138 primary alcohols Chemical class 0.000 description 4
- 150000003141 primary amines Chemical class 0.000 description 4
- 229910052707 ruthenium Inorganic materials 0.000 description 4
- 229930195734 saturated hydrocarbon Natural products 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 4
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 3
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- 125000001054 5 membered carbocyclic group Chemical group 0.000 description 3
- ADLVDYMTBOSDFE-UHFFFAOYSA-N 5-chloro-6-nitroisoindole-1,3-dione Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1C(=O)NC2=O ADLVDYMTBOSDFE-UHFFFAOYSA-N 0.000 description 3
- 125000004008 6 membered carbocyclic group Chemical group 0.000 description 3
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Images
Classifications
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- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0033—Iridium compounds
-
- 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
- C07F17/00—Metallocenes
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- 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
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
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Abstract
Description
本申请为国际申请PCT/GB2016/053986于2018年6月19日进入中国国家阶段、申请号为201680074493.0、发明名称为“金属络合物”的分案申请。
技术领域
本发明涉及金属络合物。金属络合物包含固定剂配体。金属络合物可在催化反应中用作催化剂。催化反应可为自动转移过程,例如氢借用。
背景技术
在文献中,已报道非均相催化剂和均相催化剂促进氢自动转移过程或氢借用。非均相催化剂具有优于均相催化剂的一些优点,诸如它们更容易从反应混合物中回收。然而,通常需要高压和高温,因此,均相催化剂的使用经常允许反应在比非均相催化剂更低的温度发生并且具有更高的选择性。
Grigg和他的同事在1981年报道了第一次通过均相催化的氢借用反应(R.Grigg,T.R.B.Mitchell,S.Sutthivaiyakit和N.Tongpenyai,J.Chem.Soc.Chem.Commun.,1981,611-612)。作者利用原位产生的金属-膦络合物和预先形成的金属-膦催化剂实现了通过醇对胺的N-烷基化。已经检查了铱、钌和络合物,并且使用预先形成的铑-膦络合物RhH(PPh3)4获得了最好的结果。底物范围仅限于相对易挥发的醇。
自从Grigg等人报道的该第一个示例以来,已经做出了很大的努力来开发用于胺的烷基化的更好的催化剂。其它几种络合物在氢借用反应中合成并被测试。提供最佳活性和收率的催化剂包括基于钌的催化剂。
1982年,Murahashi和他的同事证明,脂肪族胺是使用[RuH2(PPh3)4]催化剂对醇(S.-I.Murahashi,K.Kondo和T.Hakata,Tetrahedron Lett.,1982,23,229-232)和用[RuCl2(PPh3)3]对芳基胺进行N-烷基化的有力底物。这两个示例中的底物范围仍然非常有限,并且反应条件苛刻,需要高温(180℃)。
最近,已经报道了更好的催化剂体系。Williams和他的同事们证明,通过添加双(二苯基膦基)二茂铁(dppf)或DPEphos而活化的[Ru(对甲基异丙基苯)Cl2]2是通过伯醇对胺进行烷基化的活性催化剂体系(总结在M.H.S.A.Hamid,C.L.Allen,G.W.Lamb,A.C.Maxwell,H.C.Maytum,A.J.A.Watson和J.M.J.Williams,J.Am.Chem.Soc.,2009,131,1766-1774中)。添加添加剂、一种膦配体对于实现良好的收率是极为重要的。当单独使用[Ru(对甲基异丙基苯)Cl2]2作为催化剂时,N-烷基化进行缓慢。该催化剂体系表现出对官能团的宽泛的耐受性,但当仲醇用作底物时,它不起作用。添加另外的配体以促进反应是不希望的。此外,不希望依赖添加剂来提供可行的反应速率。因此,本发明的某些实施方案的目的是去除对包含额外配体的需要。
Beller和他的同事们进一步改进了这种钌络合物族,报道[Ru3(CO)12]利用伯醇和仲醇促进伯胺和仲胺的N-烷基化(A.Tillack,D.Hollmann,D.Michalik和M.Beller,Tetrahedron Lett.,2006,47,8881-8885,以及A.Tillack,D.Hollmann,K.Mevius,D.Michalik,S.和M.Beller,European J.Org.Chem.,2008,4745-4750)。为了获得更高的收率,以催化剂量加入膦配体。
二聚体铱络合物η5-(五甲基环戊二烯基)二氯化铱(III)[Cp*IrCl2]2也已用于氢借用中(综述参见K.Fujita和R.Yamaguchi,Synlett,2005,560-571)。这种铱二聚体已被有效地用于伯胺和仲胺的N-烷基化反应。可使用伯醇和仲醇,尽管对于大体积的底物,催化剂负载增加高达铱的5mol%以获得高收率的产物。可耐受的官能团相当宽泛,并且包括吸电子基团和供电子基团,诸如醚、酯、卤素、硝基和腈基。
其它铱络合物,诸如二聚体[Cp*IrI2]2、(SCRAM)在质子溶剂中显示出更好的活性,诸如水和叔戊醇。
第一个示例中之一是二聚体[Cp*IrI2]2,(SCRAM),其在水中具有良好的收率并且在不添加碱的情况下进行(O.Saidi,A.J.Blacker,M.M.Farah,S.P.Marsden和J.M.J.Williams,Chem.Commun.,2010,46,1541-1543)。
最近,单体铱催化剂在使用水作为溶剂的N-烷基化反应中显示出高活性(R.Kawahara,K.Fujita和R.Yamaguchi,Adv.Synth.Catal.,2011,353,1161-1168)。底物范围广泛;然而,为了获得高收率需要高浓度(7M),并且仲醇可有效地仅用于伯胺的烷基化。
为了改善用于氢借用的催化剂的活性,研究了新的含有N-杂环卡宾(NHC)的铱络合物(A.da Costa,M.Viciano,M.Sanaú,S.Merino,J.Tejeda,E.Peris和B.Royo,Organometallics,2008,27,1305-1309;A.Prades,R.Corberán,M.Poyatos和E.Peris,Chem.-A Eur.J.,2008,14,11474-11479;D.Gnanamgari,E.L.O.Sauer,N.D.Schley,C.Butler,C.D.Incarvito和R.H.Crabtree,Organometallics,2009,28,321-325)。用这些催化剂获得的收率与用[Cp*IrCl2]2获得的结果相当,但底物范围更受限制。
通常,铱二聚体[Cp*IrCl2]2被认为是用于氢借用工艺的有效催化剂。
本发明旨在提供优选具有改进的催化活性的替代金属络合物。本发明的目的是提供一种金属络合物,其在催化反应中具有改善(即减少)的金属络合物负载。本发明的另一个目的是提高包含本发明的金属络合物的催化反应的速率。本发明旨在实现这些改进,其对底物上的官能团、底物上的取代基、伯醇或仲醇、以及伯胺或仲胺具有高耐受性,底物、醇和胺存在于由本发明的金属络合物介导的催化反应中。现有技术的金属络合物已经证明对溶剂有限的耐受性。因此,本发明旨在提供在一系列溶剂中(诸如在极性溶剂、偶极溶剂和非极性溶剂例如水和其它非质子溶剂、DMF、NMP或DMSO中)具有催化活性的金属络合物。本发明的某些实施方案旨在潜在地提供制备手性胺的对映选择性方法学。
本发明满足了上述目的中的一些或全部,并克服了现有技术的问题。
发明内容
根据本发明,提供了一种具有固定剂配体的金属络合物。固定剂配体可为取代或未取代的环戊二烯基烷基胺,例如四甲基-环戊二烯基烷基胺。在本发明的第一方面中,提供了式(I)的金属络合物,
其中
M为过渡金属;
L1和L2独立地选自:卤素、腈、胺、膦、亚磷酸酯、磺酸酯、N-杂环卡宾或者5元或6元杂环环,或者L1和L2一起为二齿配体,其选自:二胺、二膦、二亚磷酸酯、二磺酸酯、氨基酸或其衍生物、氨基醇、氨基磺酰胺、N-杂环卡宾、二酮酸酯和取代或未取代的联吡啶,
其中L1和L2基团为未取代的或任选被卤素、C1-4烷基、C1-4卤代烷基、-ORA、-NRARB、-CN、-SO2RA取代;
R1和R2各自独立地表示H、取代或未取代的:C1-14烷基、C1-14卤代烷基、C3-8碳环和3元至8元杂环环、苯基取代的C1-14烷基、氟标记或固体载体,
或者R1和R2一起形成3元至8元杂环环;
R3和R4各自独立地选自:H、卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基和-ORA1;
或者R3和R4与它们所连接的共有的、相邻的或不相邻的碳原子一起形成3元至8元碳环(任选5元或6元碳环),
或者R1和R2中的一个以及R3和R4中的一个与它们所连接的原子一起形成3元至8元杂环环;
R5选自卤素、C1-6烷基、C1-6卤代烷基和C3-6环烷基、C6芳基或者5元或6元杂芳基
或者两个相邻的R5基团与它们所连接的原子一起形成5元或6元碳环;
p为0或1或更大;
n选自1至10;
m选自0、1、2、3或4;
RA、RB和RA1在每次出现时独立地选自:H、C1-6烷基或C1-6卤代烷基。
对于本领域技术人员显而易见的是,取决于p的值,式(I)的金属络合物可为非离子或阳离子分子。当p为0时,式(I)的金属络合物是非离子的。当p为1或2时,金属络合物是阳离子的。在实施方案中,p为0或2。在实施方案中,p为0。在实施方案中,p为2。当p为1或2时,金属络合物可为根据式(II)的化合物。因此,本发明提供根据式(II)的化合物:
其中X为1、2或3个阴离子分子,p为1或更大,并且其它基团具有本文其它地方定义的定义。
X可选自任何1、2或3个合适的单阴离子、双阴离子或三阴离子分子。X可选自氢氧化物、氟化物、氯化物、溴化物、碘化物、乙酸盐、甲酸盐、氟酸盐、亚氟酸盐、溴酸盐、亚溴酸盐、碘酸盐、亚碘酸盐、氯酸盐、亚氯酸盐、碳酸氢盐、次氟酸盐、次氯酸盐、次溴酸盐、次碘酸盐、全氟化物、高氯酸盐、高溴酸盐、高碘酸盐、铬酸盐、氰酸盐、氰化物、磷酸二氢盐、亚磷酸二氢盐、硝酸盐、草酸氢盐、硫酸氢盐、亚硫酸氢盐、高锰酸盐、亚硝酸盐、硫氰酸盐、氢化物、六氟磷酸盐、六氟化抗薄荷酸盐(hexafluoroantiminate)、四氟硼酸盐、过氧化物、[B[3,5-(CF3)2C6H3]4]-(BARF)、B(C6F5)4 -,Al(OC(CF3)3)4 -。硫酸盐、亚硫酸盐、硫化物、过硫酸盐、硫代硫酸盐、连二亚硫酸盐、磷酸氢盐、亚磷酸氢盐、偏硅酸盐、碳酸盐、过碳酸盐、草酸盐、苯甲酸盐、酒石酸盐、硼酸盐、硼化物、柠檬酸盐、次磷酸盐、氮化物、磷酸盐、磷化物和亚磷酸盐。
任选地,X可为选自氟化物、氯化物、溴化物、碘化物、六氟磷酸盐、六氟锑酸盐或四氟硼酸盐的1、2或3种(任选1种或2种)阴离子分子。
优选地,X可表示1或2个阴离子分子的存在。分子的数量取决于金属络合物上的电荷和阴离子上的电荷。例如,p可为2,因此金属络合物具有+2的电荷,并且阴离子可为上述任何X,任选地氟化物、氯化物、溴化物、碘化物、六氟磷酸盐、六氟化抗薄荷酸盐或四氟硼酸盐,它们都具有-1电荷;因此,X可表示2Cl、2PF6、2BF4或2SbF6。
同样,p可为1,因此X可表示Cl、PF6、BF4或SbF6中的每一者之一。
X可表示Cl、PF6、BF4、SbF6、2Cl、2PF6、2BF4或2SbF6。
任选地,R5为C1-6烷基,例如甲基。任选地,m为0或4,例如4。
在一个优选的实施方案中,m为4且R5为甲基。因此,式(I)的环戊二烯基环可为四甲基环戊二烯基环。因此,在一个优选的实施方案中,式(I)的金属络合物是根据式(III)的金属络合物:
本文公开的任何阳离子化合物还可包含X,其为1、2或3(任选1或2)个阴离子分子。式(III)的金属络合物可为根据式(IVa)或(IVb)的金属络合物:
M可为钌、铑、铱、钴、镍、钯、铂、铁或锇。M可为钌、铑、铱、钴、镍、钯或铂。在一个优选的实施方案中,M为铱或铑。任选地,M为铱。
在其中化合物为根据式(IVa)的化合物的实施方案中,M为铱并且n为3。在其中化合物为根据式(IVb)的化合物的实施方案中,M为铱或铑。在其中化合物为根据式(IVb)的化合物的实施方案中,M为铱或铑,并且X表示1或2个选自本文其它地方的X的定义的阴离子,例如Cl、PF6、BF4、SbF6、2Cl、2PF6、2BF4或2SbF6。
L1和L2可独立地选自:卤素、腈、胺、膦或者5元或6元杂环环,或者L1和L2一起为二齿配体,其选自:二胺、二膦和取代或未取代的联吡啶,
其中L1和L2基团是未取代的或任选被卤素、C1-4烷基、C1-4卤代烷基、-ORA、-NRARB、-CN、-SO2RA取代。
L1和L2独立地选自:卤素、C1-10烷基腈、C6-10芳基腈、C3-10环烷基腈、C5-10杂芳基腈、C3-10杂环烷基腈、联吡啶、C1-10烷基胺、C6-10芳基胺、C3-10环烷基胺、C5-10杂芳基胺、C3-10杂环烷基胺、C1-10烷基膦、C6-10芳基膦、C3-10环烷基膦、C5-10杂芳基膦、C3-10杂环烷基膦、C1-10烷基磺酸盐、C6-10芳基磺酸盐、C3-10环烷基磺酸盐、C5-10杂芳基磺酸盐、C3-10杂环烷基磺酸盐、C3-6环烷基膦、C1-10烷基磺酸酯、N-杂环卡宾或吡咯基、吡唑基、咪唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基,或者L1和L2一起为选自以下的二齿配体:联吡啶、C1-10烷基二胺、C6-10芳基二胺、C3-10环烷基二胺、C5-10杂芳基二胺、C3-10杂环烷基二胺、C1-10烷基二膦、C6-10芳基二膦、C3-10环烷基二膦、C5-10杂芳基二膦、C3-10杂环烷基二膦、C1-10烷基二磺酸盐、C6-10芳基二磺酸盐、C3-10环烷基二磺酸盐、C5-10杂芳基二磺酸盐、C3-10杂环烷基二磺酸盐、氨基酸(涵盖所有20种蛋白原氨基酸、非天然的α-氨基酸诸如苯基甘氨酸和叔亮氨酸和β-氨基酸诸如3-氨基丙酸)或其衍生物、N-杂环卡宾(包括咪唑啉亚基、亚咪唑啉亚基、噻唑亚基、恶唑亚基、三唑亚基、苯并咪唑亚基、吡咯烷亚基、“异常”咪唑烷或二酰氨卡宾碳烯、以及二酮酸酯诸如乙酰丙酮化物、1-芳基-1,3-丁烷二酮酸酯、1-杂芳基-1,3-丁烷二酮酸酯、1,3-二芳基-1,3-丙二酮酸酯、1,3-二杂芳基-1,3-丙二酮酸酯和1-芳基,3-杂芳基-1,3-丙二酮酸酯;
其中L1和L2基团为未取代的或任选被卤素、C1-4烷基、C1-4卤代烷基、-ORA、-NRARB、-CN、-SO2RA取代。
L1和L2可独立地选自:卤素、C1-10烷基腈、C6-10芳基腈、C1-10烷基胺、C6-10芳基胺、膦或者5元或6元杂环环,或者L1和L2一起为二齿配体,其选自:C1-10烷基二胺、C6-10芳基二胺、二膦和取代或未取代的联吡啶;
其中L1和L2基团是未取代的或任选被卤素、C1-4烷基、C1-4卤代烷基、-ORA、-NRARB、-CN、-SO2RA取代。
L1和L2可独立地选自:卤素、C1-10烷基腈、C6-10芳基腈、C1-10烷基胺、C6-10芳基胺、膦或者5元或6元杂环环,或者L1和L2一起为二齿配体,其选自:C1-10烷基二胺、C6-10芳基二胺、C1-10烷基二膦和取代或未取代的联吡啶;
其中L1和L2基团是未取代的或任选被卤素、C1-4烷基、C1-4卤代烷基、-ORA、-NRARB、-CN、-SO2RA取代。
L1和L2独立地选自:卤素、C1-10烷基腈、或者5元或6元杂芳基环,或者L1和L2一起为联吡啶或C1-10烷基二膦(例如Ph2PCH2PPh2)。
L1和L2独立地选自:氯、碘、乙腈或吡啶,或者L1和L2一起为联吡啶或Ph2PCH2PPh2。
在一个优选的实施方案中,L1和L2为氯、碘或乙腈。
在实施方案中,p可为0、1、2或3。任选地,p可为0或2。
其中p为0时,L1和L2优选为卤素,例如Cl。其中p为2时,L1和L2优选为乙腈。
当p不为0时,L1和L2可为能够与金属中心形成配价共价键的配体。因此,当p不为0时,M-L1和M-L2键可为配价共价键。
R1和R2可独立地选自:H、甲基、乙基、苯基、苄基、异丙基、叔丁基、氟标记、固体载体,或者R1和R2中的一个以及R3和R4中的一个与它们所连接的原子一起形成5元或6元杂环环。在一个实施方案中,R1为H并且R2选自:H、甲基、乙基、苯基、苄基、异丙基、叔丁基、氟标记、固体载体,或者R2以及R3和R4中的一个与它们所连接的原子一起形成5元或6元杂环环。氟标记可为CH2CH2OCH2CH2C8F17。
R1、R3和R4可为H并且R2可选自:H、甲基、乙基、苯基、苄基、异丙基、叔丁基、氟标记和固体载体,或者R2和在邻近N原子的原子上带有R1和R2的R3,一起与R2和R3所连接的原子一起形成5元或6元杂环环。
或者,R1和R2可独立地选自H、甲基、乙基、苯基、苄基、异丙基、叔丁基、氟标记或固体载体,并且R3和R4各自独立地选自:H、甲基、丙基、异丙基、环丙基或叔丁基,或者R3和R4与它们所连接的共有的、相邻的或不相邻的碳原子一起形成5元或6元碳环。
优选地,R1和R2选自H和Me。在实施方案中,R1和R2中的至少一个为H。因此,在实施方案中,本发明不涵盖其中R1和R2都不是H的络合物。
R3和R4可为H、C1-6烷基、环烷基、苯基或者5元或6元杂芳基环,或者R1和R2中的一个以及R3和R4中的一个与它们所连接的原子一起形成3元至8元环,或者R3和R4以及它们所连接的共有的、相邻的或不相邻的碳原子一起形成3元至8元(优选5元或6元)的环烷基或亚环烷基环或苯环。R3和R4可为H、甲基、丙基、异丙基、环丙基或叔丁基。优选地,R3和R4为H和异丙基。在实施方案中,n为1至6,任选1至4。
在一个优选的实施方案中,n为2、3或4。特别优选的是n为3。在实施方案中,n为3且R3和R4为H。在某些实施方案中,当p为0时,n为3,当p不为0时,n为3至6。
如本领域技术人员将会理解的,在R3和R4和它们所连接的共有碳原子形成环的情况下,该环将具有螺环的外观。例如,诸如如下所示的结构:
如本领域技术人员将理解的那样,在R3和R4与它们所连接的相邻碳原子形成环的情况下,该环可具有以下所示结构的外观,例如:
如本领域技术人员将理解的那样,在R3和R4与它们所连接的不相邻碳原子形成环的情况下,该环可具有以下所示结构的外观,例如:
在一个优选的实施方案中,式(I)的金属络合物是根据式(V)的金属络合物:
在一个优选的实施方案中,L1和L2是氯、碘或乙腈,R1和R2选自H和Me,并且p为0或2。在一个优选的实施方案中,L1和L2为氯、碘或乙腈,R1和R2选自H和Me,并且p为0或2,并且当p为2时,X存在并且X表示2Cl或2SbF6。
本发明的金属络合物是:
如上所示的阳离子物质还可包含如上定义的X。具体地,X可为2Cl-或2SbF6 -。X可为2BF4 -、2PF6 -、2Cl-或2SbF6 -。
本发明的金属络合物是:
本发明的特别优选的金属络合物是:
在一个实施方案中,本发明的金属络合物不是:
在实施方案中,当p为0时,M不为铑。在本发明的一个实施方案中,当p为0时,M为铱,并且当p为2时,M为铱或铑。
在本发明的一个方面中,提供了一种催化方法。该催化方法包括将本发明的金属络合物加入反应混合物中。该反应混合物还任选地包含溶剂和至少一种(优选至少2种)起始物质。起始物质任选地为胺和醇。胺任选地为伯脂族胺、伯芳族胺、伯杂芳族胺、仲二脂族胺、仲二芳族胺、仲二杂芳族胺、仲芳基(杂芳基)胺、仲烷基/芳族胺、仲烷基/杂芳族胺、伯磺酰胺、仲N-烷基磺酰胺、仲N-芳基磺酰胺、仲N-杂芳基磺酰胺、伯磺酰胺、仲N-烷基磺酰胺、仲N-芳基磺酰胺、仲N-杂芳基磺酰胺、伯氨基甲酸酯、仲N-烷基氨基甲酸酯、仲N-芳基氨基甲酸酯、仲N-杂芳基氨基甲酸酯、伯酰胺、仲N-烷基酰胺、仲N-芳基酰胺、仲N-杂芳酰胺、伯脲、仲N-烷基脲、仲N-芳基脲、仲N-杂芳基脲。醇可为伯脂族、烯丙型、苄型或杂苄型、或仲脂族、仲苄型、仲杂苄型或仲烯丙型。醇和胺组分可另外包含官能取代,包括卤素、烷基基团、醇、烷氧基基团、游离胺、烷基胺、羰基基团、羧基基团、烯烃、腈、硫化物、亚砜、砜、亚磺酰胺、磺酰胺、氨基甲酸酯、脲和酰胺。
该方法可任选地进一步包括产生产物的步骤。任选地,产物是N-烷基化产物,例如胺。
溶剂可为任何工业上适用的溶剂,例如但不限于在Henderson等人,Green Chem.,2011,13,854中讨论的那些。任选地,溶剂可选自:甲苯、1,4-二氧杂环己烷、2-甲基四氢呋喃、乙腈、叔戊醇、叔丁醇、乙酸异丙酯、二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮、水以及它们的混合物。
附图说明
下面参照附图进一步描述本发明的实施方案,其中:
图1是示出具有不同N取代基的本发明的金属络合物和比较络合物的反应速率的图。
图2是示出具有不同的抗衡离子的本发明的金属络合物和比较络合物的反应速率的图。
图3a和图3b是示出铱络合物和铑络合物在两种不同溶剂中的反应速率的图。
图4是示出本发明的铱络合物和比较铱络合物在一系列溶剂中的收率的柱状图。
图5是示出铑络合物和比较铑络合物在一系列溶剂中的收率的柱状图。
图6a-d是示出铱络合物和比较铱络合物在不同溶剂中的反应速率的图。
图7示出了本发明的铱络合物的一些底物范围和官能团容限与比较络合物[Cp*IrCl2]2的一些数据。
图8和图9是示出中性和离子铱络合物以及中性和离子铑络合物的反应速率的图。
图10是示出本发明的铱络合物和比较铱络合物在一系列溶剂中的收率的柱状图。
图11a-c是示出铱络合物的温度依赖性的图。
图12和图13是示出不同铱络合物加载量的反应速率的图。
图14是示出链长对催化活性的影响的图。
具体实施方式
以下给出了本申请中使用的术语的定义。本文中未定义的任何术语具有普通含义,因为技术人员会理解该术语。
术语“卤”是指周期表第17族中的一种卤素。该术语尤其指氟、氯、溴和碘。优选地,该术语是指碘或氯。
术语“烷基”是指直链或支链的烃链。烷基环可为含有1、2、3、4、5、6、7、8、9、10、11、12、13或14个碳原子的“C1-14烷基”。例如,术语“烷基”涵盖甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基和正己基。亚烷基基团同样可为直链或支链的,并且可具有两个与分子其余部分连接的位置。此外,亚烷基基团可例如对应于本段中列举的那些烷基基团之一。烷基和亚烷基基团可为未取代的或被一个或多个取代基取代。下面描述可能的取代基。烷基基团的取代基可为卤素,例如氟、氯、溴和碘、OH、C1-6烷氧基。
术语“烷氧基”是指通过氧与分子连接的烷基基团。这包括其中烷基部分可为直链或支链并且可含有例如C1-6烷氧基1、2、3、4、5或6个碳原子的部分,例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基和正己基。因此,烷氧基基团可为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和正己氧基。烷氧基基团的烷基部分可为未取代的或被一个或多个取代基取代。下面描述可能的取代基。烷基基团的取代基可为卤素,例如氟、氯、溴和碘、OH、C1-6烷氧基。
术语“C1-4卤代烷基”或“C1-6卤代烷基”是指被至少一个在每次出现时独立选择的卤素原子例如氟、氯、溴和碘取代的烃链。卤素原子可存在于烃链上的任何位置。例如,“C1-4卤代烷基”或“C1-6卤代烷基”可指氯甲基,氟甲基,三氟甲基,氯乙基例如1-氯甲基和2-氯乙基,三氯乙基例如1,2,2-三氯乙基、2,2,2-三氯乙基,氟乙基例如1-氟甲基和2-氟乙基,三氟乙基例如1,2,2-三氟乙基和2,2,2-三氟乙基,氯丙基,三氯丙基,氟丙基,三氟丙基。
术语“C2-6烯基”是指含有至少一个双键并具有2、3、4、5或6个碳原子的支链或直链的烃链。双键可作为E或Z异构体存在。双键可位于烃链的任何可能的位置。例如,“C2-6烯基”可为乙烯基、丙烯基、丁烯基、丁二烯基、戊烯基、戊二烯基、己烯基和己二烯基。
术语“C2-6炔基”是指含有至少一个三键且具有2、3、4、5或6个碳原子的支链或直链的烃链。三键可位于烃链的任何可能的位置。例如,“C2-6炔基”可为乙炔基、丙炔基、丁炔基、戊炔基和己炔基。
术语“C1-6杂烷基”是指含有1、2、3、4、5或6个碳原子和位于链中任何碳之间或者在链的末端的至少一个选自N、O和S的杂原子的支链或直链的烃链。例如,烃链可含有一个或两个杂原子。C1-6杂烷基可通过碳或杂原子与分子的其余部分键合。例如,“C1-6杂烷基”可为C1-6 N-烷基、C1-6 N,N-烷基或C1-6 O-烷基。
术语“碳环”是指饱和或不饱和的含碳环系。“碳环”体系可为单环或稠合多环环系,例如双环或三环。“碳环”部分可含有3至14个碳原子,例如单环环系中的3至8个碳原子和多环环系中的7至14个碳原子。“碳环”涵盖环烷基部分、环烯基部分、芳基环系和包括芳族部分的稠合环系。
术语“杂环”是指含有至少一个选自N、O或S的杂原子的饱和或不饱和的环系。“杂环”体系可含有1、2、3或4个杂原子,例如1或2个。“杂环”体系可为单环或稠合多环环系,例如双环或三环。“杂环”部分可含有3至14个碳原子,例如单环体系中的3至8个碳原子和多环体系中的7至14个碳原子。“杂环”涵盖杂环烷基部分、杂环烯基部分和杂芳族部分。例如,杂环基团可为环氧乙烷、氮丙啶、氮杂环丁烷、氧杂环丁烷、四氢呋喃、吡咯烷、咪唑啉、琥珀酰亚胺、吡唑烷、噁唑烷、异噁唑烷、噻唑烷、异噻唑烷、哌啶、吗啉、硫代吗啉、哌嗪和四氢吡喃。
术语“C3-8环烷基”是指含有3、4、5、6、7或8个碳原子的饱和烃环体系。例如,“C3-8环烷基”可为环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
术语“C3-6环烯基”或“C3-8环烯基”分别指含有3、4、5或6个碳原子或3、4、5、6、7或8个碳原子的不饱和烃环体系,其不是芳族的。该环可包含多于一个双键,条件是环系不是芳族的。例如,“C3-8环烷基”可为环丙烯基、环丁烯基、环戊烯基、环戊二烯基、环己烯基、环己二烯基、环庚烯基、环庚二烯基、环辛烯基和环己二烯基。
术语“C3-10杂环烷基”是指含有3、4、5、6、7或8个碳原子和在环内选自N、O和S的至少一个杂原子的饱和烃环体系。例如,可存在1、2或3个杂原子,任选1或2个。“C3-10杂环烷基”可通过任何碳原子或杂原子键合到分子的其余部分。“C3-10杂环烷基”可具有一个或多个,例如,一个或两个键与分子的其余部分键合:这些可通过环中的任何原子键合。例如,“C3-10杂环烷基”可为环氧乙烷、氮丙啶、氮杂环丁烷、氧杂环丁烷、四氢呋喃、吡咯烷、咪唑啉、琥珀酰亚胺、吡唑烷、噁唑烷、异噁唑烷、噻唑烷、异噻唑烷、哌啶、吗啉、硫代吗啉、哌嗪和四氢吡喃。
术语“C3-10杂环烯基”是指含有3、4、5、6、7或8个碳原子和在环内选自N、O和S的至少一个杂原子的不饱和烃环体系(不是芳族的)。例如,可存在1、2或3个杂原子,任选1或2个。“C3-10杂环烯基”可通过任何碳原子或杂原子键合到分子的其余部分。“C3-10杂环烯基”可具有一个或多个,例如,一个或两个键与分子的其余部分键合:这些可通过环中的任何原子键合。例如,“C3-10杂环烷基”可为四氢吡啶、二氢吡喃、二氢呋喃、吡咯烷。
当作为整体应用于取代基时,术语“芳族”是指在环或环体系内共轭π体系中具有4n+2个电子的单环或多环体系,其中所有对共轭π体系有贡献的原子在同一平面中。
术语“芳基”是指芳族烃环体系。该环体系在一个环内共轭π体系中有4n+2个电子,所有对共轭π体系有贡献的原子都在同一个平面中。例如,“芳基”可为苯基和萘基。芳基体系本身可被其它基团取代。
术语“杂芳基”是指在单环内或在稠合环系内具有选自O、N和S的至少一个杂原子的芳香烃环体系。环或环体系在共轭π体系中具有4n+2个电子,其中所有对共轭π体系有贡献的原子都在同一平面中。例如,“杂芳基”可为咪唑、噻吩、呋喃、噻蒽、吡咯、苯并咪唑、吡唑、吡嗪、吡啶、嘧啶和吲哚。
所谓的“酰基”是指例如通过除去羟基基团由有机酸衍生的有机基团,例如具有式R-C(O)-的基团,其中R可选自H、C1-6烷基、C3-8环烷基、苯基、苄基或苯乙基基团,例如R为H或C1-3烷基。在一个实施方案中,酰基是烷基-羰基。酰基基团的示例包括但不限于甲酰基、乙酰基、丙酰基和丁酰基。具体的酰基基团是乙酰基。
所谓的“膦”是指具有连接到磷原子上的三个有机基团的有机磷化合物,例如三苯基膦、三环己基膦或双环己基苯基膦。膦可为与三个相同基团或三个不同基团连接的磷原子,例如膦可为P(RC)3,或者膦可连接到三个不同基团(PRC1RC2RC3)或两个相同基团和另一个不同的基团(PRC1(RC2)2)。因此,本发明的任何化合物的膦可为PRC1RC2RC3,其中RC1、RC2和RC3在每次出现时各自独立地选自:C1-10烷基、C6-10芳基、C3-10环烷基、C5-10杂芳基和C3-10杂环烷基。任选地,RC1、RC2和RC3在每次出现时各自独立地选自:C6-10芳基、C3-10环烷基,例如苯基和环己基。
“二膦”类似地是具有两个磷原子的有机磷化合物,每个磷原子具有2个有机取代基,并且还有一个取代基与两个磷原子相连,例如2,2'-双(二苯基膦基)-1,1'-联萘(BINAP)。因此,二膦可为RC1RC2P-RD-PRC4RC5),其中RC1、RC2、RC4和RC5在每次出现时各自独立地选自:C1-10烷基、C6-10芳基、C3-10环烷基、C5-10杂芳基和C3-10杂环烷基,并且RD选自C1-10亚烷基、C6-10亚芳基、C3-10亚环烷基、C5-10亚杂芳基、C3-10亚杂环烷基、双-C6-10亚芳基、双-C3-10亚环烷基、双-C5-10亚杂芳基和双-C3-10亚杂环烷基。任选地,RC1、RC2、RC4和RC5在每次出现时各自独立地选自:C1-10烷基、C6-10芳基、C3-10环烷基,并且RD选自C1-10亚烷基、C6-10亚芳基、C3-10亚环烷基、双-C6-10亚芳基、双-C3-10亚环烷基,例如苯基、环己基萘基和联苯基。
“二齿配体”是具有能够键合到金属中心的两个原子的单分子。二齿配位体可为腈、胺、膦或磺酸酯,本领域技术人员将会理解,单胺基团等的存在将导致分子被称为胺。因此,作为胺的二齿配体例如可包含单个胺基(作为与金属中心连接的第一点)和相同或不同的官能团(作为与金属中心连接的第二点)。
“氟标记”是高度氟化的基团。荧光标记被充分氟化以提供对氟化溶剂或氟化固相萃取的亲和力。氟标记可直接键合到金属络合物上,或者连接基团可存在于金属络合物和氟标记之间。例如,氟标记可为C8F17。示例性的氟标记和连接基为CH2CH2OCH2CH2C8F17。
在部分被取代的情况下,其可在化学上可能且与原子价态要求一致的部分上的任何点处被取代。该部分可被一个或多个取代基例如1、2、3或4个取代基取代;任选在基团上存在1或2个取代基。当存在两个或更多个取代基时,取代基可相同或不同。取代基可选自:OH、NHR、脒基、胍基、羟基胍基、甲脒基、异硫脲基、脲基、巯基、C(O)H、酰基、酰氧基、羧基、磺基、氨磺酰基、氨基甲酰基、氰基、偶氮、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C3-8环烷基、C2-6烯基、C2-6炔基、芳基、杂芳基或烷芳基。当待取代的基团是烷基基团时,取代基可为=O。R可选自H、C1-6烷基、C3-8环烷基、苯基、苄基或苯乙基基团,例如R为H或C1-3烷基。当部分被两个或更多个取代基取代并且两个取代基相邻时,相邻的取代基可与取代基取代的部分的原子一起形成C4-8环,其中C4-8环是具有4、5、6、7或8个碳原子的饱和的或不饱和的烃环或具有4、5、6、7或8个碳原子和1、2或3个杂原子的饱和或不饱和的烃环。
取代基仅存在于化学上可能的位置,本领域技术人员能够在没有不适当努力的情况下确定(实验上或理论上)哪些取代是化学上可能的而哪些不是。
本发明考虑了本发明的金属络合物的盐。这些可包括金属络合物的酸加成盐和碱盐。这些可为化合物的酸加成盐和碱盐。此外,本发明考虑了这些化合物的溶剂化物。这些可为化合物的水合物或其它溶剂化形式。
合适的酸加成盐由形成无毒盐的酸形成。示例包括乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、羟苯酰苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、1,5-萘二磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、糖酸盐、硬脂酸盐、琥珀酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
合适的碱盐由形成无毒盐的碱形成。示例包括铝、精氨酸、苄星、钙、胆碱、二乙胺、二乙醇胺、甘氨酸、赖氨酸、镁、葡甲胺、乙醇胺、钾、钠、氨基丁三醇和锌盐。也可形成酸和碱的半酸盐,例如半硫酸盐和半钙盐。关于合适的盐的综述,参见Stahl和Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,Weinheim,Germany,2002)。
式(I)的金属络合物的盐可通过三种方法中的一种或多种来制备:
(i)通过使本发明的化合物与所需的酸或碱反应;
(ii)从本发明化合物的合适前体除去酸或碱不稳定的保护基团或通过使用所需的酸或碱来开环合适的环状前体例如内酯或内酰胺;
(iii)通过与合适的酸或碱反应或通过合适的离子交换柱将本发明化合物的一种盐转化成另一种盐;
(iv)或通过盐置换。
所有三种反应通常在溶液中进行。所得盐可沉淀出来并通过过滤收集,或者可通过蒸发溶剂来回收。所得盐中的离子化程度可从完全离子化到几乎不离子化。
本发明的金属络合物可以非溶剂化和溶剂化形式存在。术语“溶剂化物”在本文中用于描述包含本发明的化合物和化学计量量的一种或多种药学上可接受的溶剂分子(例如乙醇)的分子络合物。当所述溶剂是水时使用术语“水合物”。
在下文中,对任何式的金属络合物的所有提及都包括对其盐、溶剂化物和络合物的提及以及其盐的溶剂化物和络合物。
本发明的金属络合物包括本文定义的多个式的金属络合物,包括如下文所定义的所有多晶型物和晶体习性和异构体(包括光学、几何和互变异构体)和本发明的同位素标记的金属络合物。
本发明还包括本发明的所有工业上可接受的同位素标记的金属络合物,其中一个或多个原子被具有相同原子序数的原子置换,但原子质量或质量数不同于自然中发现的最常见的原子量或质量数。
适合包含在本发明的金属络合物中的同位素的示例包括氢的同位素诸如2H和3H,碳的同位素诸如11C、13C和14C,氯的同位素诸如36Cl,氟的同位素诸如18F,碘的同位素诸如123I和125I,氮的同位素诸如13N和15N,氧的同位素诸如15O、17O和18O,磷的同位素诸如32P,以及硫的同位素诸如35S。
对于本发明的金属络合物的制备方法的一些步骤,可能需要保护不希望发生反应的潜在反应性官能团,并因此裂解所述保护基团。在这种情况下,可使用任何相容的保护基。特别是可使用保护和脱保护的方法,诸如T.W.Greene(Protective Groups in OrganicSynthesis,A.Wiley-Interscience Publication,1981)或P.J.Kocienski(Protectinggroups,Georg Thieme Verlag,1994)中描述的那些。前述方法中使用的所有上述反应和新颖起始物质的制备是针对其性能或制备的常规的且适合的试剂和反应条件,以及分离所需产物的工序对于本领域技术人员而言是众所周知的参考文献先例以及这方面的示例和准备。
而且,本发明的金属络合物以及用于其制备的中间体可根据各种公知的方法诸如例如结晶或色谱来纯化。本发明的金属络合物可以单一晶体形式或以晶体形式的混合物存在,或者它们可为无定形的。
实施例
使用本发明的催化剂金属络合物进行醇胺化反应的一般合成工序。在氮气下向搅拌的铱络合物实施例3(4.4mg,0.01mmol)的甲苯(0.5mL)悬浮液中加入相应的醇(1.0mmol)和相应的胺(1.0mmol)。所得溶液在110℃加热18小时。在减压下除去溶剂并通过过滤或通过快速色谱法纯化以得到产物胺。
配体和配体前体的合成
中间体1:N-Boc-4-(2'-氨乙基)-3,5-二甲基-庚-2,5-二烯-4-醇
用己烷洗涤锂丝(516mg,74.0mmol),切成小块并悬浮于Et2O(15mL)中。将2-溴-2-丁烯(1.8mL,18mmol,顺式和反式异构体的混合物)一次性加入混合物中并搅拌直至反应开始,通过溶剂的回流观察;滴加另一等分的2-溴-2-丁烯(2.0mL,20mmol)在Et2O(10mL)中的溶液以保持温和回流。将悬浮液在室温搅拌2小时,并且然后冷却至-78℃。逐滴加入N-Boc-β-丙氨酸甲酯(2.40g,12.0mmol)在Et2O(10mL)中的溶液,将混合物温热至室温,搅拌过夜并小心加入饱和NH4Cl水溶液(60mL)来猝灭。分离各相并将产物用Et2O(2×30mL)萃取。合并的有机萃取物用Na2SO4干燥并在减压下除去溶剂。通过快速色谱(SiO2,用己烷-EtOAc(95:5)洗脱)纯化,得到中间体1,为无色油状物,为反式-反式和顺式-反式异构体的1:1混合物,其不经任何其它纯化直接使用(1.50g,5.30mmol,44%)。
Rf=0.30(己烷-EtOAc 80:20);1H NMR(500MHz,CDCl3,δ/ppm):5.65-5.59(2H,m,对于反式-反式异构体为2CH),5.44-5.34(2H,m,对于反式-顺式异构体为2CH),5.18-5.10(2H,m,2NH),3.30-3.22(4H,m,2H-2’),1.95-1.86(4H,m,2H-1’),1.77(6H,s,2CH3),1.69-1.60(18H,m,6CH3),1.44(18H,s,2C(CH3)3);13C NMR(125MHz,CDCl3,δ/ppm):156.1(C(O)),139.7(CqCH3),139.0(CqCH3),137.7(CqCH3),123.1(对于反式-顺式异构体为CH),118.6(对于反式-反式异构体为CH),80.7(C(CH3)3),79.8(C-4),78.9(C-4),39.1(C-1’),36.7(C-2’),28.4(C(CH3)3),23.3(CH3),22.7(CH3),14.7(CH3),14.4(CH3),13.2(CH3),12.5(CH3);IR(νmax,纯净,cm-1):3387(N-H和O-H),2976,2933,1696(C=O),1509,1452,1366,1279,1250,1173;HRMS(ESI+)m/z:对于C16H29NNaO3(M+Na+)计算的:306.2040,实测的:306.2034。
中间体2:N-Boc-4-(3'-氨丙基)-3,5-二甲基-庚-2,5-二烯-4-醇
用己烷洗涤锂丝(340mg,48.6mmol),切成小块并悬浮于Et2O(10mL)中。逐滴加入2-溴-2-丁烯(2.4mL,24mmol,顺式和反式异构体的混合物)在Et2O(10mL)中的溶液,并将该悬浮液在室温搅拌2小时。逐滴加入溶解于Et2O(8.0mL)中的N-Boc-2-吡咯烷酮(1.50g,8.10mmol),将混合物在室温搅拌2小时,并通过小心加入饱和NH4Cl水溶液(40mL)猝灭。分离两相并将产物用Et2O(3×20mL)萃取。合并的有机相用Na2SO4干燥并在减压下除去溶剂。通过快速色谱(SiO2,用己烷-EtOAc(90:10至80:20)洗脱)纯化,得到中间体2,为无色油状物,为反式-反式和反式-顺式异构体的混合物(主要级分(反式-顺式)/次要级分(反式-反式):2/1),其不经任何其它纯化而使用(1.10g,5.70mmol,70%)。
Rf=0.60(己烷-EtOAc 70:30);1H NMR(500MHz,CDCl3,δ/ppm):5.58(2H,dq,J=1.0,6.5Hz,对于反式-反式异构体为2CH),5.35(2H,dq,J=1.0,6.5Hz,对于反式-顺式异构体为2CH),4.59(2H,br s,2NH),3.14(4H,br s,2H-3’),1.84-1.81(2H,m,2OH),1.76-1.75(4H,m,2H-1’),1.67-1.59(24H,m,8CH3),1.53-1.49(4H,m,2H-2’),1.43(18H,s,2C(CH3)3);13C NMR(125MHz,CDCl3,δ/ppm):156.1(C(O)),140.0(CqCH3),139.5(CqCH3),138.0(CqCH3),122.7(对于反式-顺式异构体为CH),122.6(对于反式-顺式异构体为CH),118.3(对于反式-反式异构体为CH),80.6(C(CH3)3),79.5(C-4),79.0(C-4),41.1(C-3’),36.8(C-1’),35.0(C-1’),28.4(C(CH3)3),24.5(C-2’),24.2(C-2’),23.4(CH3),22.8(CH3),14.7(CH3),14.4(CH3),13.2(CH3),12.6(CH3);HRMS(ESI+)m/z:对于C17H31NNaO3(M+Na+)计算的:320.2196,实测的:320.2200。与文献值一致的光谱数据(M.Ito,N.Tejima,M.Yamamura,Y.Endo和T.Ikariya,Organometallics,2010,29,1886-1889)。
中间体3:N-Boc-4-(4'-氨丁基)-3,5-二甲基-庚-2,5-二烯-4-醇
用己烷洗涤锂丝(4.37mg,63.0mmol),切成小块并悬浮于Et2O(10mL)中。将2-溴-2-丁烯(1.3mL,13mmol,顺式和反式异构体的混合物)一次性加入混合物中并搅拌直至反应开始,通过溶剂的回流观察;逐滴加入另一等份的2-溴-2-丁烯(2.0mL,20mmol)在Et2O(10mL)中的溶液,并将该悬浮液在室温搅拌2小时。逐滴加入N-Boc-2-哌啶酮(3.00g,15.0mmol)在Et2O(20mL)中的溶液,将该混合物搅拌1小时并通过小心加入饱和NH4Cl水溶液(60mL)猝灭。分离各相并将产物用Et2O(2×30mL)萃取。合并的有机相用Na2SO4干燥并在减压下除去溶剂。通过快速色谱(SiO2,用己烷-EtOAc(90:10)洗脱)纯化,得到中间体3,为无色油状物,为反式-反式和反式-顺式异构体的混合物(主要级分(反式-顺式)/次要级分(反式-反式):3/2),其不经任何其它纯化而使用(940mg,3.00mmol,20%)。
Rf=0.50(己烷-EtOAc 70:30);1H NMR(500MHz,CDCl3,δ/ppm):5.57(2H,q,J=6.5Hz,对于反式-反式异构体为2CH),5.34(2H,dq,J=1.3,7.5Hz,对于反式-顺式异构体为2CH),4.54(2H,br s,2NH),3.12(4H,br s,2H-4’),1.84-1.71(6H,m,2H-1’和2OH),1.69-1.60(24H,m,8CH3),1.53-1.46(8H,m,4CH2),1.44(18H,s,2C(CH3)3);13C NMR(125MHz,CDCl3,δ/ppm):156.1(C(O)N),140.2(CqCH3),139.6(CqCH3),138.1(CqCH3),122.5(对于反式-顺式异构体为CH),122.4(对于反式-顺式异构体为CH),118.9(对于反式-反式异构体为CH),118.1(对于反式-反式异构体为CH),80.8(C(CH3)3),79.4(C-4),79.1(C-4),40.4(C-4’),39.4(C-1’),37.6(C-1’),28.4(C(CH3)3),23.4(CH3),22.8(CH3),20.7(CH2),20.5(CH2),14.8(CH3),14.4(CH3),13.4(CH3),13.2(CH3),12.6(CH3),12.4(CH3);IR(νmax,纯净,cm-1):3364(N-H和O-H),2975,2933,2865,1695(C=O),1515,1454,1366,1251,1172,1003;HRMS(ESI+)m/z:对于C18H33NNaO3(M+Na+)计算的:334.2353,实测的:334.2357。
中间体4:N-Boc-N-甲基-4-(3'-氨基丙基)-3,5-二甲基-庚-2,5-二烯-4-醇
用己烷洗涤锂丝(150mg,22.0mmol),切成小块并悬浮于Et2O(10mL)中。逐滴加入2-溴-2-丁烯(1.2mL,12mmol,顺式和反式异构体的混合物)在Et2O(10mL)中的溶液,并将该悬浮液在室温搅拌2小时。逐滴加入N-Boc-N-甲基-4-氨基丁酸甲酯(1.20g,5.19mmol)在Et2O(10mL)中的溶液,在室温搅拌90分钟并小心加入饱和NH4Cl水溶液(40mL)猝灭。分离各相并将产物用Et2O(3×20mL)萃取。合并的有机萃取物用Na2SO4干燥并在减压下除去溶剂。通过快速色谱法(SiO2,用己烷-EtOAc(90:10)洗脱)纯化,得到中间体4,为在反式-反式和反式-顺式顺式异构体的1:1混合物中的无色油状物,其不经任何其它纯化而使用(540mg,1.74mmol,33%)。
Rf=0.40(己烷-EtOAc 80:20);1H NMR(500MHz,CDCl3,δ/ppm):5.62-5.56(2H,m,对于反式-反式异构体为2CH),5.42-5.30(2H,m,对于反式-顺式异构体为2CH),3.27-3.24(4H,m,2H-3’),2.87(6H,br s,2H-1”),1.86-1.76(4H,m,2H-1’),1.74(2H,s,2OH),1.69-1.61(18H,m,6CH3),1.62-1.59(4H,m,2CH2),1.46(24H,s,2CH3和2C(CH3)3);13C NMR(125MHz,CDCl3,δ/ppm):156.0(C(O)N),140.1(CqCH3),139.6(CqCH3),138.1(CqCH3),122.5(CH),119.0(CH),118.2(CH),80.7(C(CH3)3),79.1(C-4),51.6(C-3’),34.0(C-1”),29.7(C-1’),28.4(C(CH3)3),23.4(CH3),22.8(CH3),21.9(C-2’),14.8(CH3),14.4(CH3),13.4(CH3),13.2(CH3),12.6(CH3),12.4(CH3);IR(νmax,纯净,cm-1):3474(O-H),2973,2931,1759(C=O),1695(C=C),1481,1454,1395,1365,1171;HRMS(ESI+)m/z:对于C18H33NNaO3(M+Na+)计算的:334.2353,实测的:334.2349。
中间体5:4-(3'-二甲基氨基丙基)-3,5-二甲基-庚-2,5-二烯-4-醇
用己烷洗涤锂丝(530mg,76.0mmol),切成小块并悬浮于Et2O(10mL)中。将2-溴-2-丁烯(1.5mL,15mmol,顺式和反式异构体的混合物)一次性加入混合物中并搅拌直至反应开始,通过溶剂的回流观察;逐滴加入另一等份的2-溴-2-丁烯(2.5mL,25mmol)在Et2O(15mL)中的溶液,并将该悬浮液在室温搅拌2小时。逐滴加入N,N-二甲基-4-氨基丁酸乙酯(2.80g,18.0mmol)在Et2O(15mL)中的溶液,在室温搅拌60分钟并小心加入饱和NH4Cl水溶液(50mL)猝灭。分离各相并将产物用Et2O(2×40mL)萃取。合并的有机相用Na2SO4干燥并在减压下除去溶剂。通过快速色谱法(SiO2,用己烷-EtOAc(60:40至0:100)洗脱)纯化,得到中间体5,为无色油状物,作为反式-反式和反式-顺式顺式异构体的1:1混合物,其不经任何其它纯化而使用(1.70g,7.54mmol,41%)。
Rf=0.38(DCM-MeOH 80:20);1H NMR(500MHz,CDCl3,δ/ppm):5.65(2H,q,J=5.7Hz,对于反式-反式异构体为2CH),5.58(1H,q,J=6.5Hz,对于反式-顺式异构体为CH),5.40(1H,q,J=7.3Hz,对于反式-顺式异构体为CH),2.33-2.28(4H,m,2CH2),2.24(6H,s,2H-1”),2.20(6H,s,2H-1”),2.07-1.91(4H,m,2CH2),1.83-1.61(18H,m,6CH3),1.59-1.51(4H,m,2CH2),1.49-1.46(6H,m,2CH3);13CNMR(125MHz,CDCl3,δ/ppm):139.8(CqCH3),139.0(CqCH3),138.8(CqCH3),122.9(对于反式-顺式异构体为CH),118.5(对于反式-反式异构体为CH),117.5(对于反式-顺式异构体为CH),79.8(C-4),78.9(C-4),60.6(C-3’),45.1(C-1”),37.6(C-1’),36.4(C-1’),23.6(CH3),22.1(CH2),21.9(CH2),14.8(CH3),13.5(CH3),13.3(CH3),12.5(CH3),12.4(CH3);IR(νmax,纯净,cm-1):3394(O-H),2944,2919,2859,2821,2779,1459,1378,1039,1014;HRMS(ESI+)m/z:对于C14H28NO(M+H+)计算的:226.2165,实测的:226.2167。
中间体6:N,N-二甲基-3-(四甲基环戊二烯基)丙-1-胺盐酸盐
向搅拌的中间体5(970mg,4.30mmol)在甲醇(2.5mL)中的溶液加入2M HCl在Et2O(2.6mL,5.2mmol)中的溶液。将该溶液在室温搅拌2小时,并且在减压下除去溶剂。所得黄色沉淀(1.14g)不经任何其它纯化用于以下反应。通过快速色谱法(SiO2,用DCM-MeOH(90:10)洗脱)纯化少量粗物质(478mg),得到中间体6,为浅黄色固体,用于表征的异构体混合物(239mg,0.984mmol,55%)。
Rf=0.50(DCM-MeOH 90:10);mp 117.5-118.6℃(DCM-Et2O);1HNMR(500MHz,CDCl3,δ/ppm):8.54(1H,br s,NH),2.73-2.66(2H,m,H-1),2.68-2.41(1H,m,CH),2.59-2.53(6H,m,2H-1’),2.48-2.23(2H,m,CH2),1.92-1.63(2H,m,CH2),1.80-1.75(9H,m,3CH3),0.98(3H,d,J=7.5Hz,CH3);13C NMR(125MHz,CDCl3,δ/ppm):139.7(CqCH3),139.6(CqCH3),139.0(CqCH3),136.7(CqCH3),136.4(CqCH3),136.1(CqCH3),134.5(CqCH3),133.9(CqCH3),132.9(CqCH3),58.6(C-1),58.2(C-1),55.3(CH),51.6(CH),49.1(CH),43.7(C-1’),43.6(C-1’),43.5(CH2),43.3(CH2),25.8(CH2),25.1(CH2),24.7(CH2),23.3(CH2),22.9(CH2),14.2(CH3),11.9(CH3),11.8(CH3),11.6(CH3),11.3(CH3),11.0(CH3);IR(νmax,纯净,cm-1):3403(N-H),2961,2856,2763,2580,2517,2479,1655,1487,1443,1377,1172,1058,1041,1020,1006;HRMS(ESI+)m/z:对于C14H26N(M+H+)计算的:208.2060,实测的:208.2062。
中间体7:4-(2’-1H”,1H”,2H”,2H”-全氟癸氧基乙酰氨基)丁酸乙酯
向搅拌的DMAP(3.48g,28.5mmol)、N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐(2.73g,14.3mmol)和4-氨基丁酸乙酯盐酸盐(1.59g,9.50mmol)在DCM(160mL)中的悬浮液在0℃以小等分试样(4.96g,9.50mmol)加入1H’1H’,2H’,2H’-全氟癸氧基乙酸。将反应混合物在室温温热并搅拌18小时。在减压下除去溶剂,将残余物溶于EtOAc(100mL)和1M HCl水溶液(100mL)中,并且分离两相。将产物用EtOAc(3×100mL)萃取,并且合并的有机萃取物用盐水(100mL)洗涤并用Na2SO4干燥。在减压下除去溶剂,得到中间体7,为无色油状物(5.77g,9.09mmol,96%)。
1H NMR(500MHz,CDCl3,δ/ppm):6.67(1H,br s,NH),4.13(2H,q,J=7.0Hz,OCH2),3.98(2H,s,H-2’),3.83(2H,t,J=6.4Hz,H-1”),3.35(2H,q,J=7.0Hz,H-4),2.52-2.42(2H,m,H-2”),2.36(2H,t,J=7.2Hz,H-2),1.87(2H,ap五峰,J=7.1Hz,H-3),1.25(3H,t,J=7.0Hz,CH3);13C NMR(125MHz,CDCl3,δ/ppm):173.2(C-1或C-1’),168.9(C-1或C-1’),70.5(C-2’),63.5(C-1”),60.5(OCH2),38.3(C-4),31.7(C-2),31.4(t,J=21.7Hz,C-2”),24.6(C-3),14.1(CH3),未观察到8个碳(7×CF2,1×CF3);19F NMR(282MHz,CDCl3,δ/ppm):-80.8(t,J=10.0Hz),-113.2(五峰,J=14.4Hz),-121.6,-121.9,-122.7,-123.6,-126.1,未观察到1个氟;IR(νmax,纯净,cm-1):3339(N-H),2938,1732(C=O),1666(C=O),1536,1446,1372,1348,1325,1235,1199,1144,1116,1029;HRMS(ESI+)m/z:对于C18H19F17NO4(M+H+)计算的:636.1037,实测的:636.1041。
中间体8:4-((2’-1H”,1H”,2H”,2H”-全氟十二烷氧基乙基)氨基)丁酸乙酯
在-78℃向搅拌的中间体7(2.20g,3.47mmol)和2-氟吡啶(328μL,3.82mmol)在DCM(8.0mL)中的溶液逐滴加入三氟甲磺酸酐(613μL,3.64mmol)。将该溶液在-78℃搅拌10分钟,并且然后在0℃温热。逐滴加入三乙基硅烷(610μL,3.82mmol),将溶液在0℃搅拌10分钟并在室温搅拌5小时。加入2,6-二甲基-1,4-二氢吡啶-3,5-二羧酸二乙酯(1.23g,4.86mmol)并将所得混合物搅拌15小时,然后用DCM(15mL)和饱和NaHCO3水溶液(10mL)猝灭。将两相分离并将产物用DCM(2×30mL)萃取。合并的有机相用Na2SO4干燥并在减压下除去溶剂。通过快速色谱(SiO2,用DCM-MeOH(95:5)洗脱)纯化得到中间体8,为无色油状物(688mg,1.11mmol,32%)。
Rf=0.35(DCM-MeOH 90:10);1H NMR(500MHz,CDCl3,δ/ppm):4.12(2H,q,J=7.0Hz,OCH2),3.75(2H,t,J=6.8Hz,H-1”),3.61(2H,t,J=5.0Hz,H-2’),3.35(1H,br s,NH),2.84(2H,t,J=5.0Hz,H-1’),2.73(2H,t,J=7.2Hz,H-4),2.47-2.38(2H,m,H-2”),2.73(2H,t,J=7.2Hz,H-2),1.87(2H,ap五峰,J=7.2Hz,H-3),1.24(3H,t,J=7.0Hz,CH3);13C NMR(125MHz,CDCl3,δ/ppm):173.4(C-1),69.8(C-2’),62.9(C-1”),60.4(OCH2),48.8(C-4或C-1’),48.6(C-4或C-1’),32.0(C-2),31.5(t,J=21.3Hz,C-2”),24.6(C-3),14.1(CH3),未观察到8个碳(7×CF2,1×CF3);19F NMR(282MHz,CDCl3,δ/ppm):-80.8(t,J=9.9Hz),-113.4,-121.7,-121.9,-122.7,-123.6,-126.1,未观察到1个氟;IR(νmax,纯净,cm-1):3342(N-H),2935,1729(C=O),1656,1543,1444,1370,1348,1199,1145,1134,1016,1029;HRMS(ESI+)m/z:对于C18H20F17NNaO3(M+Na+)计算的:644.1064,实测的:644.1066。
中间体9:4-(N-Boc-(2’-1H”,1H”,2H”,2H”-全氟癸氧基乙基)氨基)丁酸乙酯
在0℃向搅拌的二碳酸二叔丁酯(600mg,2.73mmol)在DCM(8.0mL)中的溶液加入中间体8(1.54g,2.49mmol)在DCM(4.0mL)中的溶液。将溶液在0℃搅拌30分钟,并且然后在室温搅拌16小时。在减压下除去溶剂并通过快速色谱(SiO2,用己烷-EtOAc(85:15)洗脱)纯化,得到中间体9,为无色油状物(1.30g,1.80mmol,72%)。
Rf=0.36(己烷-EtOAc 80:20);1H NMR(500MHz,CDCl3,δ/ppm):4.12(2H,q,J=7.0Hz,OCH2),3.72(2H,t,J=6.7Hz,H-1”),3.57(2H,br s,H-1’或H-2’),3.37(2H,br s,H-1’或H-2’),3.27(2H,br s,H-4),2.44-2.32(2H,m,H-2”),2.28(2H,t,J=7.3Hz,H-2),1.84(2H,ap五峰,J=7.3Hz,H-3),1.45(9H,s,C(CH3)3),1.25(3H,t,J=7.0Hz,CH3);13C NMR(125MHz,CDCl3,δ/ppm):173.2(C-1),155.6(C(O)N),79.6(C(CH3)3),69.9&69.7(CH2,旋转异构体),62.9(CH2),60.3(CH2),47.7&47.2(CH2,旋转异构体),46.9(CH2),31.6(t,J=21.2Hz,C-2”),31.5(C-2),28.4(C(CH3)3),23.9&23.5(CH2,旋转异构体),14.2(CH3),未观察到8个碳(7×CF2,1×CF3);19F NMR(282MHz,CDCl3,δ/ppm):-80.8(t,J=10.0Hz),-113.4(五峰,J=15.5Hz),-121.7,-121.9,-122.7,-123.6,-126.1,未观察到1个氟;IR(νmax,纯净,cm-1):2980,2935,1736(C=O),1729,1693(C=O),1656,1543,1479,1444,1413,1370,1367,1348,1236,1201,1199,1144,1134,1132,1116,1030;HRMS(ESI+)m/z:对于C23H29F17NO5(M+H+)计算的:722.1769,实测的:722.1778。
中间体10:4-(N-Boc-(2”-1H”’,1H”’,2H”’,2H”’-全氟癸氧基乙基)氨基丙基)-3,
5-二甲基-庚-2,5-二烯-4-醇
用己烷洗涤锂丝(300mg,43.2mmol),切成小块并悬浮于Et2O(10mL)中。将2-溴-2-丁烯(1.0mL,10mmol,顺式和反式异构体的混合物)一次性加入混合物中并搅拌直至反应开始,通过溶剂的回流观察;逐滴加入另一等份的2-溴-2-丁烯(1.33mL,13.0mmol)在Et2O(10mL)中稀释的溶液,并将该悬浮液在室温搅拌2小时。通过用薄荷醇(1.0mmol)和2,2'-联吡啶(0.1mmol)滴定来测定有机锂的浓度。将中间体9(1.35g,1.87mmol)溶于Et2O(10mL)并在-78℃冷却。逐滴加入滴定的有机锂(7.48mmol),并且将溶液在-78℃搅拌30分钟,然后升温至室温持续60分钟。加入饱和NH4Cl水溶液(15mL)并分离两相。用Et2O(3×50mL)萃取水相,合并的有机萃取物用Na2SO4干燥并在减压下除去溶剂。通过快速色谱法(SiO2,用己烷-EtOAc(90:10至85:15)洗脱)纯化,得到中间体10,为浅黄色油状物,为反式-反式和反式-顺式异构体的1:1混合物(849mg,1.08mmol,58%)。通过色谱法纯化后得到反式-反式异构体的纯级分,并已用于表征。
Rf=0.36(己烷-EtOAc 80:20);1H NMR(500MHz,CDCl3,δ/ppm):5.63-5.59(2H,m,H-2和H-6),3.75-3.70(2H,m,H-1”’),3.57(2H,br s,H-1”或H-2”),3.37(2H,br s,H-1”或H-2”),3.26(2H,br s,H-3’),2.46-2.33(2H,m,H-2”’),1.86-1.58(10H,m,2CH2和2CH3),1.55-1.44(15H,m,2CH3和C(CH3)3);13C NMR(125MHz,CDCl3,δ/ppm):155.7(C(O)N),138.1(CqCH3),118.9(CH),80.3(C-4),79.4(C(CH3)3),69.8(CH2),62.9(C-1”’),48.8(CH2),46.7(CH2),31.6(t,J=21.2Hz,C-2”’),28.4(C(CH3)3),22.9(CH2),12.3(CH3),11.6(CH3),未观察到9个碳(1×CH2,7×CF2,1×CF3);19F NMR(282MHz,CDCl3,δ/ppm):-80.7(t,J=9.7Hz),-113.4,-121.7,-121.9,-122.7,-123.6,-126.1,未观察到1个氟;IR(νmax,纯净,cm-1):3449(O-H),2976,1674(C=O),1479,1416,1367,1237,1202,1170,1144,1006;HRMS(ESI+)m/z:对于C29H38F17NNaO4(M+Na+)计算的:810.2422,实测的:810.2417。
中间体11:(R)-N-Boc-4-(3’-氨基-3’-异丙基)丙基-3,5-二甲基-庚-2,5-二烯-
4-醇
用己烷洗涤锂丝(300mg,43.2mmol),切成小块并悬浮于Et2O(10mL)中。将2-溴-2-丁烯(1.0mL,10mmol,顺式和反式异构体的混合物)一次性加入混合物中并搅拌直至反应开始,通过溶剂的回流观察;逐滴加入另一等份的2-溴-2-丁烯(1.3mL,13mmol)在Et2O(10mL)中的溶液,并将该悬浮液在室温搅拌2小时。通过用薄荷醇(1.0mmol)和2,2'-联吡啶(0.1mmol)滴定来测定有机锂的浓度。在Et2O(6.0mL)中稀释(R)-N-叔丁氧羰基-5-异丙基-2-吡咯烷酮(根据Smrcina等人,Tetrahedron,1997,53,12867制备)(500mg,2.20mmol)并在0℃冷却。逐滴加入滴定的有机锂(4.40mmol),将溶液在0℃搅拌30分钟,然后升温至室温持续60分钟。小心加入饱和NH4Cl水溶液(30mL),并分离两相。将产物用Et2O(2×30mL)萃取。合并的有机相用Na2SO4干燥并在减压下除去溶剂。通过快速色谱(SiO2,用己烷-EtOAc(90:10)洗脱)纯化,得到中间体11,为无色油状物,为反式-反式和反式-顺式异构体的混合物(主要级分(反式-顺式)/次要级分(反式-反式):3/1),其不经进一步纯化而使用(184mg,0.542mmol,25%)。
Rf=0.74(己烷-EtOAc 80:20);[α]D=+7.8(c=1.0,CHCl3);1H NMR(500MHz,CDCl3,δ/ppm):5.57(2H,q,J=6.2Hz,对于反式-反式异构体为2CH),5.43-5.27(2H,m,对于反式-顺式异构体为2CH),4.30(2H,br s,2NH),3.49-3.37(2H,m,2H-3’),1.96-1.51(30H,m,8CH3和2CH2和2H-1”),1.43(18H,s,2C(CH3)3),1.39-1.16(4H,m,2CH2),0.91-0.85(12H,m,4H-2”);13C NMR(125MHz,CDCl3,δ/ppm):156.2(C(O)),140.2(CqCH3),139.7(CqCH3),138.2(CqCH3),122.6(CH),122.5(CH),122.4(CH),118.1(CH),80.8(C(CH3)3),79.5(C-4),78.8(C-4),56.1(C-3’),36.3(CH2),34.3(CH2),32.5(CH2),28.4(C(CH3)3),27.0(CH2),26.6(CH2),23.5(CH2),22.8(CH3),19.2(CH2),17.8(CH2),14.8(CH3),14.7(CH3),14.4(CH3),13.2(CH3),12.6(CH3);HRMS(ESI+)m/z:对于C20H37NNaO3(M+Na+)计算的:362.2666,实测的:362.2672。
中间体12:4-(3'-二乙基氨基丙基)-3,5-二甲基-庚-2,5-二烯-4-醇
用己烷洗涤锂丝(470mg,67.0mmol),切成小块并悬浮于Et2O(15mL)中。将2-溴-2-丁烯(1.6mL,16mmol,顺式和反式异构体的混合物)一次性加入混合物中并搅拌直至反应开始,通过溶剂的回流观察;逐滴加入另一等份的2-溴-2-丁烯(2.0mL,20mmol)在Et2O(15mL)中的溶液,并将该悬浮液在室温搅拌2小时。逐滴加入N,N-二乙基-4-氨基丁酸乙酯(3.00g,16.0mmol)在Et2O(10mL)中的溶液,在室温搅拌90分钟并小心加入饱和NH4Cl水溶液(100mL)猝灭。分离各相并将产物用Et2O(2×40mL)萃取。合并的有机萃取物用Na2SO4干燥并在减压下除去溶剂。通过快速色谱法(SiO2,用己烷-EtOAc(80:20至0:100)洗脱)纯化,得到中间体12,为无色油状物,作为反式-反式和反式-顺式异构体的1:1混合物,其不经任何其它纯化而使用(3.70g,14.7mmol,92%)。
Rf=0.39(DCM-MeOH 90:10);1H NMR(500MHz,CDCl3,δ/ppm):5.63(2H,q,J=6.7Hz,对于反式-反式异构体为2CH),5.59-5.55(1H,m,对于反式-顺式异构体为CH),5.38(1H,q,J=7.2Hz,对于反式-顺式异构体为CH),2.56-2.48(8H,m,4H-1”),2.45-2.35(4H,m,2H-3’),2.04-1.87(4H,m,2CH2),1.78-1.73(4H,m,2CH2),1.64-1.46(24H,m,8CH3),1.04-0.99(12H,m,4H-2”);13C NMR(125MHz,CDCl3,δ/ppm):139.9(CqCH3),139.3(CqCH3),122.5(对于反式-顺式异构体为CH),118.3(对于反式-反式异构体为CH),117.4(对于反式-顺式异构体为CH),79.7(C-4),79.0(C-4),54.4(C-3’),54.1(C-3’),45.8(C-1”),45.6(C-1”),37.5(C-1’),36.4(C-1’),23.7(CH3),21.8(CH2),21.6(CH2),14.8(CH3),14.2(CH3),13.4(CH3),13.2(CH3),12.6(CH3),10.5(C-2”),10.2(C-2”);IR(νmax,纯净,cm-1):3408(O-H),2970,2813,2813,1455,1377,1293,1195,1066;HRMS(ESI+)m/z:对于C16H32NO(M+H+)计算的:254.2478,实测的:254.2484。
中间体13:N,N-二乙基-3-(四甲基环戊二烯基)丙-1-胺
由Ito等人报道的用于合成环戊二烯基的一般方法的稍微修改版本(Organometallics,2010,29,1886)制备如下。向搅拌的中间体12(1.29g,5.09mmol)在甲醇(3.0mL)中的溶液加入2M HCl在Et2O(3.0mL,6.0mmol)中的溶液。将所得溶液在室温搅拌4小时,并且在减压下除去溶剂。通过快速色谱法纯化(Al2O3 pH 9.5±0.5,用DCM-MeOH(99:1)洗脱),得到中间体13,为三种异构体(705mg,2.99mmol,60%)的未解析混合物中的浅黄色油状物。
Rf=0.60(中性氧化铝,DCM-MeOH 95:5);1H NMR(500MHz,CDCl3,δ/ppm):2.65-2.40(1H,m,CH),2.52(4H,q,J=7.3Hz,2H-1’),2.47-2.41(2H,m,H-1),2.35-2.11(2H,m,H-3),1.82-1.77(9H,m,3CH3),1.75-1.78(2H,m,H-2),1.05-0.96(9H,m,CH3和2H-2’);13C NMR(125MHz,CDCl3,δ/ppm):142.2(CqCH3),138.4(CqCH3),138.3(CqCH3),138.1(CqCH3),135.6(CqCH3),135.3(CqCH3),134.5(CqCH3),134.0(CqCH3),133.6(CqCH3),55.9(CH),53.4(CH2),53.1(CH2),52.7(CH2),52.0(CH2),51.5(CH),49.4(CH),46.9(C-1’),27.8(CH2),26.7(CH2),25.6(CH2),24.3(CH2),23.7(CH2),22.4(CH2),21.0(CH2),14.2(CH3),14.1(CH3),11.8(CH3),11.7(CH3),11.6(CH3),11.1(CH3),11.0(CH3);IR(νmax,纯净,cm-1):2968,2934,2870,2799,1742,1656,1445,1381,1294,1201,1070;HRMS(ESI+)m/z:对于C16H30N(M+H+)计算的:236.2373,实测的:236.2376。
中间体14:N-Boc-4-(4'-氨丁基)-3,5-二甲基-庚-2,5-二烯-4-醇
用己烷洗涤锂丝(437mg,63.0mmol),切成小块并悬浮于Et2O(10mL)中。将2-溴-2-丁烯(1.3mL,13mmol,顺式和反式异构体的混合物)一次性加入混合物中并搅拌直至反应开始,通过溶剂的回流观察;逐滴加入另一等份的2-溴-2-丁烯(2.0mL,20mmol)在Et2O(10mL)中的溶液,并将该悬浮液在室温搅拌2小时。逐滴加入N-Boc-2-哌啶酮(3.00g,15.0mmol)在Et2O(20mL)中的溶液,将该混合物搅拌1小时并通过小心加入饱和NH4Cl水溶液(60mL)猝灭。分离各相并将产物用Et2O(2×30mL)萃取。合并的有机相用Na2SO4干燥并在减压下除去溶剂。通过快速色谱法(SiO2,用己烷-EtOAc(90:10)洗脱)纯化,得到中间体14,为无色油状物,为反式-反式和反式-顺式异构体的混合物(主要级分(反式-顺式)/次要级分(反式-反式):3/2),其不经任何其它纯化而使用(940mg,3.00mmol,20%)。
Rf=0.50(己烷-EtOAc 70:30);1H NMR(500MHz,CDCl3,δ/ppm):5.57(2H,q,J=6.5Hz,对于反式-反式异构体为2CH),5.34(2H,dq,J=1.3,7.5Hz,对于反式-顺式异构体为2CH),4.54(2H,br s,2NH),3.12(4H,br s,2H-4’),1.84-1.71(6H,m,2H-1’和2OH),1.69-1.60(24H,m,8CH3),1.53-1.46(8H,m,4CH2),1.44(18H,s,2C(CH3)3);13C NMR(125MHz,CDCl3,δ/ppm):156.1(C(O)N),140.2(CqCH3),139.6(CqCH3),138.1(CqCH3),122.5(对于反式-顺式异构体为CH),122.4(对于反式-顺式异构体为CH),118.9(对于反式-反式异构体为CH),118.1(对于反式-反式异构体为CH),80.8(C(CH3)3),79.4(C-4),79.1(C-4),40.4(C-4’),39.4(C-1’),37.6(C-1’),28.4(C(CH3)3),23.4(CH3),22.8(CH3),20.7(CH2),20.5(CH2),14.8(CH3),14.4(CH3),13.4(CH3),13.2(CH3),12.6(CH3),12.4(CH3);IR(νmax,纯净,cm-1):3364(N-H和O-H),2975,2933,2865,1695(C=O),1515,1454,1366,1251,1172,1003;HRMS(ESI+)m/z:对于C18H33NNaO3(M+Na+)计算的:334.2353,实测的:334.2357。
中间体15:2-{(4E/Z)-3-[(2E)-丁-2-烯-2-基]-3-羟基-4-甲基己-4-烯-1基}吡
咯烷-1-羧酸-(S)-叔丁酯
用己烷洗涤锂丝(300mg,43.2mmol),切成小块并悬浮于Et2O(10mL)中。将2-溴-2-丁烯(1.0mL,10mmol,顺式和反式异构体的混合物)一次性加入混合物中并搅拌直至反应开始,通过溶剂的回流观察。此后,逐滴加入其余的2-溴-2-丁烯(1.3mL,13mmol)在Et2O(10mL)中的溶液,并将该悬浮液在室温搅拌1小时。通过用薄荷醇(1.0mmol)和2,2'-联吡啶(0.1mmol)滴定来测定有机锂的浓度。将(2S)-N-叔丁氧羰基-2-(3'-甲氧基-3'-氧代-1'-丙基)吡咯烷(Org.Lett.,2008,10,3045)(100mg,0.40mmol)在Et2O(3.0mL)中稀释并在-78℃冷却。逐滴加入滴定的有机锂(1.60mmol),将溶液搅拌5分钟,然后升温至室温并搅拌90分钟。小心加入饱和NH4Cl水溶液(25mL),并分离两相。将产物用Et2O(3×20mL)萃取。合并的有机相用Na2SO4干燥并在减压下除去溶剂。通过快速色谱法(SiO2,用己烷-EtOAc(80:20)洗脱)纯化,得到中间体15,为在反式-反式和反式-顺式顺式异构体的3:1混合物中的无色油状物,其不经进一步纯化而使用(91mg,0.27mmol,61%)。
Rf=0.32(己烷-EtOAc 80:20);[α]D=-30.5(c=1.0,CHCl3);1H NMR(500MHz,CDCl3,δ/ppm):5.61(2H,q,J=6.6,对于反式-反式异构体为2CH),5.40-5.31(2H,m,对于反式-顺式异构体为2CH),3.43-3.38(2H,m,2NCH),3.36-3.31(4H,m,4NHCH2),1.93-1.77(10H,m,2×CH3和2×CH2),1.73-1.55(30H,m,10×CH3),1.35-1.25(4H,m,2×CH2);13C NMR(125MHz,CDCl3,δ/ppm):154.8,139.5,138.3,137.8,122.5,122.5,118.9,78.9,57.5,56.9,46.4,46.1,33.1,30.8,28.7,28.5,23.7,23.4,23.2,14.8,14.4,13.4,13.2,12.3(从CqOH缺失的一个C信号);HRMS(ESI+)m/z:对于C20H35NNaO3(M+Na+)计算的:360.2515,实测的:360.2509。
金属络合物合成
实施例1:RhCl2[η5:η1-C5(CH3)4(CH2)3N(CH2CH2OCH2CH2C8F17)H]
向搅拌的中间体10(386mg,0.490mmol)在甲醇(4.0mL)中的溶液加入RhCl3·水合物(51mg,0.25mmol)。将该混合物加热回流20小时,并且在减压下除去溶剂。通过快速色谱法(SiO2,用DCM-MeOH(97:3至95:5)洗脱)纯化,得到标题化合物,为红色固体(74mg,88μmol,35%)。
Rf=0.53(DCM-MeOH 97:3);mp 133.3-134.6℃(DCM-己烷,v/v=1/2);1H NMR(500MHz,CDCl3,δ/ppm):3.85-3.76(1H,m,CH2),3.73-3.49(4H,m,2CH2),2.91-2.84(1H,m,CH2),2.79-2.67(2H,m,CH2),2.45-2.31(2H,m,H-2”),2.25-1.91(4H,m,2CH2),1.76(3H,s,CH3),1.73(3H,s,CH3),1.67(3H,s,CH3),1.64(3H,s,CH3);13C NMR(125MHz,CDCl3,δ/ppm):103.0(d,J=7.5Hz,CqRh),94.3(d,J=8.8Hz,CqRh),93.2(d,J=8.0Hz,CqRh),92.0(d,J=9.1Hz,CqRh),85.1(d,J=9.6Hz,CqRh),69.0(C-3),62.7(CH2),50.7(CH2),48.3(CH2),31.4(t,J=21.2Hz,C-2”),27.0(CH2),19.4(CH2),9.9(CH3),9.4(CH3),9.1(CH3),9.1(CH3),未观察到8个碳(7×CF2,1×CF3);19F NMR(282MHz,CDCl3,δ/ppm):-80.8(t,J=9.8Hz),-113.3,-121.6,-121.9,-122.7,-123.5,-126.1,未观察到1个氟;IR(νmax,纯净,cm-1):3272(N-H),2918,1487,1440,1370,1331,1243,1200,1145,1114,1006;HRMS(ESI+)m/z:对于C24H27F17 35ClNORh(M-Cl-,100%)计算的:806.0559,实测的:806.0552,对于C24H27F17 37ClNORh(M-Cl-,35%)计算的:808.0539,实测的:808.0533;分析:对于C24H27Cl2F17NORh计算的:C,34.22;H,3.23;N,1.66;实测的:C,34.40;H,3.20;N,1.60。
实施例2:[Rh{η5:η1-C5(CH3)4(CH2)3NH2}{CH3CN}2][SbF6]2
向搅拌的已知的铑络合物[Cl2Rh{η5:η1-C5(CH3)4(CH2)3NH2}](Ito等人,Organometallics,2010,29,1886)(50mg,0.14mmol)在乙腈(4.0mL)中的溶液加入六氟锑酸银(96mg,0.28mmol)。将混合物在70℃加热24小时,通过垫过滤粗制物,用MeCN洗涤并在减压下除去溶剂。通过从MeCN-Et2O(v/v=1/2)中结晶纯化,得到标题化合物,为黄色粉末(71mg,90μmol,61%)。通过从MeCN-Et2O(v/v=1/2)重结晶获得单晶。
mp>250℃(MeCN);1H NMR(500MHz,DMSO,δ/ppm):4.22(2H,br s,NH2),2.59(2H,brs,H-3),2.17-2.11(2H,m,H-1),2.06-2.01(8H,m,H-2和2CH3CN),1.70(6H,s,2CH3),1.44(6H,s,2CH3);13C NMR(125MHz,DMSO,δ/ppm):119.0(C≡N),102.7-101.4(m,CqRh),86.1-85.2(m,CqRh),41.3(C-3),29.8(C-2),18.7(C-1),7.4(CH3),7.2(CH3),2.1(CH3CN),未观察到一个碳(CqRh);IR(νmax,纯净,cm-1):3328(N-H),3284(N-H),2321,2291,1594,1455,1370,1163,1083,1021;HRMS(ESI+)m/z:对于C12H20F6NRh121Sb(M-[SbF6 -]-2MeCN,100%)计算的:515.9593,实测的:515.9588;对于C12H20F6NRh123Sb(M-[SbF6 -]-2MeCN,68%)计算的:517.9598,实测的:517.9590;分析:对于C16H26F12N3RhSb2计算的:C,23.02;H,3.14;N,5.03;实测的:C,23.20;H,3.10;N,4.90。
实施例3:IrCl2[η5:η1-C5(CH3)4(CH2)3NH2]
向搅拌的IrCl3·水合物(670mg,2.24mmol)和NaHCO3(190mg,2.24mmol)在甲醇(15mL)中的悬浮液加入中间体2(1.34g,4.48mmol)。将微波加热以130℃的设定温度在120psi的压力下施加到反应混合物2小时,并在室温冷却后,在减压下除去溶剂。通过快速色谱(SiO2,用DCM-MeOH(98:2)洗脱)纯化,得到标题化合物,为黄色固体(427mg,0.968mmol,44%)。通过从DCM-己烷(v/v=1/3)重结晶获得单晶。
Rf=0.67(DCM-MeOH 90:10);mp>250℃(DCM-己烷,v/v=1/3);1H NMR(500MHz,CDCl3,δ/ppm):3.94(2H,br s,NH2),2.72-2.68(2H,m,H-3),2.18(2H,t,J=6.3Hz,H-1),1.96-1.91(2H,m,H-2),1.78(6H,s,2CH3),1.67(6H,s,2CH3);13C NMR(125MHz,CDCl3,δ/ppm):90.8(CqIr),88.7(CqIr),41.9(C-3),30.7(C-2),19.2(C-1),9.2(CH3),9.0(CH3),未观察到一个碳(CqIr);IR(νmax,纯净,cm-1):3234(N-H),3153(N-H),2948,2877,1593,1444,1376,1269,1240,1165,1083,1038;HRMS(ESI+)m/z:对于C12H20 35Cl191IrN(M-Cl-,50%)计算的:404.0885,实测的:404.0883;对于C12H20 37Cl191IrN和C12H20 35Cl193IrN(M-Cl-,100%)计算的:406.0900,实测的:406.0901;对于C13H22 37Cl193IrN(M-Cl-,26%)计算的:408.0879,实测的:408.0878;分析:对于对于C12H20Cl2IrN计算的:C,32.65;H,4.57;N,3.17;Cl,16.06;实测的:C,32.95;H,4.50;N,3.00,Cl,16.00。
实施例4:IrCl2[η5:η1-C5(CH3)4(CH2)3N(CH3)H]
向搅拌的IrCl3·水合物(70mg,0.23mmol)和NaHCO3(20mg,0.23mmol)在甲醇(3.0mL)中的悬浮液加入中间体4(143mg,0.46mmol)。将微波加热以140℃的设定温度在200psi的压力下施加到反应混合物2小时,并在室温冷却后,在减压下除去溶剂。通过快速色谱法(SiO2,用DCM-MeOH(98:2)洗脱)纯化,得到标题化合物,为黄色固体(32mg,0.070mmol,30%)。通过从DCM缓慢重结晶获得单晶。
Rf=0.47(DCM-MeOH 90:10);mp 186.4-187.0℃(DCM-己烷);1H NMR(500MHz,CDCl3,δ/ppm):4.22(1H,br s,NH),2.86-2.81(1H,m,HA-3),2.77-2.73(1H,m,HB-3),2.72(3H,d,J=6.0Hz,NCH3),2.24-2.17(1H,m,CH2),2.15-2.10(2H,m,CH2),2.00-1.93(1H,m,CH2),1.71(3H,s,CH3),1.70(3H,s,CH3),1.66(3H,s,CH3),1.64(3H,s,CH3);13C NMR(125MHz,CDCl3,δ/ppm):97.5(CqIr),85.7(CqIr),85.4(CqIr),53.3(C-3),39.6(NCH3),26.1(CH2),19.3(CH2),9.3(CH3),9.2(CH3),9.1(CH3),9.0(CH3),未观察到两个碳(CqIr);IR(νmax,纯净,cm-1):3178(N-H),2990,2970,2923,1738,1455,1374,1228,1217,1064,1028;HRMS(ESI+)m/z:对于C13H22 35Cl191IrN(M-Cl-,50%)计算的:418.1041,实测的:418.1044;对于C13H22 37Cl191IrN和C13H22 35Cl193IrN(M-Cl-,100%)计算的:420.1056,实测的:420.1052;对于C13H22 37Cl193IrN(M-Cl-,23%)计算的:422.1035,实测的:422.1029;分析:对于C13H22Cl2IrN计算的:C,34.28;H,4.87;N,3.08;Cl,15.57;实测的:C,34.40;H,4.80;N,3.00;Cl,15.30。
实施例5:Ir2Cl4[η5-C5(CH3)4(CH2)3NMe2·HCl]2
向搅拌的IrCl3·水合物(100mg,0.334mmol)在甲醇(3.0mL)中的悬浮液加入中间体6(321mg,1.32mmol)。将微波加热以120℃的设定温度在90psi的压力下施加到反应混合物1小时。从所得的混合物中过滤橙色固体并在减压下干燥,得到标题化合物,为橙色粉末(155mg,0.153mmol,93%)。盐酸盐的形成通过比较NMR信号与文献(Organometallics,2010,29,1886)中报道的类似络合物来确定。
1H NMR(500MHz,DMSO,δ/ppm):10.11(2H,br s,NH),3.11-3.08(4H,m,2H-3),2.72(12H,s,4NCH3),2.10(4H,t,J=8.3Hz,2H-1),1.84-1.79(4H,m,2H-2),1.70(12H,s,4CH3),1.64(12H,s,4CH3);13C NMR(125MHz,DMSO,δ/ppm):94.1(CqIr),92.1(CqIr),89.9(CqIr),56.1(C-3),42.0(NCH3),22.1(C-2),20.2(C-1),8.3(CH3),8.2(CH3);IR(νmax,纯净,cm-1):3011,1453,1406,1375,1031;HRMS(ESI+)m/z:对于C28H48 35Cl2 37Cl191Ir2N2和C28H48 35Cl3 191Ir193IrN2(M-[2HCl]-Cl-,63%)计算的:901.2102,实测的:901.2112;对于C28H48 35Cl37Cl2 191Ir2N2、C28H48 35Cl2 37Cl191Ir193IrN2和C28H48 35Cl37Cl193Ir2N2(M-[2HCl]-Cl-,100%)计算的:903.2106,实测的:903.2109;对于C28H48 37Cl3 191Ir2N2、C28H48 35Cl37Cl2 191Ir193IrN2和C28H48 35Cl2 37Cl193Ir2N2(M-[2HCl]-Cl-,65%)计算的:905.2097,实测的:905.2102;分析:对于C28H50Cl6Ir2N2计算的:C,33.24;H,4.98;N,2.77;Cl,21.02;实测的:C,33.10;H,4.90;N,2.60;Cl,20.60。
实施例6:IrCl2[η5:η1-C5(CH3)4(CH2)3N(CH3)2]
向实施例5(107mg,0.106mmol)在DCM(10mL)中的悬浮液加入叔丁醇钾(25mg,0.22μmol),并将反应混合物在室温搅拌15小时。将混合物通过垫过滤,用DCM洗涤并在减压下除去溶剂。从DCM-己烷中结晶,得到标题化合物,为橙色固体(93mg,0.20mmol,90%)。通过从DCM-己烷(v/v=1/2)缓慢重结晶获得单晶。
Rf=0.90(DCM-MeOH 90:10);mp 198.3-199.5℃(DCM-己烷,v/v=1/2);1H NMR(500MHz,CDCl3,δ/ppm):2.77(6H,s,2NCH3),2.60-2.58(2H,m,H-3),2.15-2.08(4H,m,2CH2),1.60(6H,s,2CH3),1.59(6H,s,2CH3);13C NMR(125MHz,CDCl3,δ/ppm):89.1(CqIr),84.7(CqIr),80.6(CqIr),64.2(C-3),52.7(NCH3),25.3(CH2),19.0(CH2),9.3(CH3),9.1(CH3);IR(νmax,纯净,cm-1):2917,1477,1448,1435,1375,1029,1002;HRMS(ESI+)m/z:对于C14H24 35Cl191IrN(M-Cl-,49%)计算的:432.1198,实测的:432.1197;对于C14H24 37Cl191IrN和C14H24 35Cl193IrN(M-Cl-,100%)计算的:434.1213,实测的:434.1215;对于C14H24 37Cl193IrN(M-Cl-,27%)计算的:436.1195,实测的:436.1193;分析:对于C14H24Cl2IrN计算的:C,35.82;H,5.15;N,2.98;Cl,15.10;实测的:C,36.20;H,5.15;N,2.90;Cl,14.75。
实施例7:IrI2[η5:η1-C5(CH3)4(CH2)3NH2]
向搅拌的实施例3(70mg,0.16mmol)在脱气的丙酮(10mL)中的溶液加入碘化钠(52mg,0.35mmol)。将反应混合物加热回流18小时,冷却至室温,并且在减压下除去溶剂。将残余物溶于DCM(20mL)和水(15mL)中,并且分离两相。将产物用DCM(2×20mL)萃取,合并的有机相用盐水(40mL)洗涤并用Na2SO4干燥。在减压下除去溶剂。通过从DCM-己烷中(v/v=1/2)结晶纯化,得到标题化合物,为橙色固体(72mg,0.12mmol,75%)。
Rf=0.88(DCM-MeOH 90:10);mp>250℃(DCM);1H NMR(500MHz,CDCl3,δ/ppm):3.92(2H,br s,NH2),2.58-2.54(2H,m,H-3),2.20(2H,t,J=6.3Hz,H-1),2.05(6H,s,2CH3),1.92(6H,s,2CH3),1.85-1.81(2H,m,H-2);13C NMR(125MHz,CDCl3,δ/ppm):89.8(CqIr),89.7(CqIr),81.1(CqIr),42.5(C-3),29.1(C-2),19.3(C-1),12.2(CH3),10.1(CH3);IR(νmax,纯净,cm-1):3214(N-H),3139(N-H),2908,1579,1458,1371,1309,1262,1157,1070,1022;HRMS(ESI+)m/z:对于C12H20I191IrN(M-I-,64%)计算的:496.0241,实测的:496.0237;对于C12H20I193IrN(M-I-,100%)计算的:498.0264,实测的:498.0263;分析:对于C12H20I2IrN计算的:C,23.09;H,3.23;N,2.24;实测的:C,23.55;H,3.30;N,2.20。C元素分析数据超出范围(±0.4),但是迄今为止的最佳值。
实施例8:IrI2[η5:η1-C5(CH3)4(CH2)3N(CH3)2]
向搅拌的实施例6(93mg,0.20mmol)在脱气的丙酮(12mL)中的溶液加入碘化钠(66mg,0.44mmol)。将反应混合物回流加热17小时,冷却至室温,并在减压下除去溶剂。将残余物溶于DCM(30mL)和水(30mL)中,并且分离两相。将产物用DCM(2×30mL)萃取,合并的有机相用Na2SO4干燥并在减压下除去溶剂。通过从DCM-己烷(v/v=1/2)中结晶进行纯化,得到标题化合物,为亮红色晶体(125mg,0.192mmol,96%)。
mp 203.0-204.7℃(CHCl3);1H NMR(500MHz,CDCl3,δ/ppm):3.13(6H,s,2NCH3),2.57(2H,br s,H-3),2.05(4H,s,2CH2),1.87(6H,s,2CH3),1.82(6H,s,2CH3);13C NMR(125MHz,CDCl3,δ/ppm):88.0(CqIr),86.7(CqIr),85.1(CqIr),64.9(C-3),58.9(NCH3),24.9(CH2),18.4(CH2),12.4(CH3),11.0(CH3);IR(νmax,纯净,cm-1):2906,1452,1439,1374,1364,1029;HRMS(ESI+)m/z对于C14H24I191IrN(M-I-,54%)计算的:524.0554,实测的:524.0551;对于C14H24I193IrN(M-I-,100%)计算的:526.0578,实测的:526.0574;分析:对于C14H24I2IrN计算的:C,25.78;H,3.71;N,2.15;I,38.91;实测的:C,26.15;H,3.70;N,2.00;I,38.45。I元素分析数据超出范围(±0.4),但是迄今为止的最佳值。
实施例9:(R)-IrCl2[η5:η1-C5(CH3)4(CH2)2(CH(CH(CH3)2)NH2]
向搅拌的IrCl3·水合物(80mg,0.27mmol)和NaHCO3(23mg,0.27mmol)在甲醇(3.0mL)中的悬浮液加入中间体11(184mg,0.542mmol)。将微波加热以125℃的设定温度在130psi的压力下施加到反应混合物2小时,并冷却至室温后,在减压下除去溶剂。通过快速色谱法(SiO2,用DCM-MeOH(97:3)洗脱)纯化,然后从DCM-己烷(v/v=1/3)中结晶,得到标题化合物,为黄色固体(35mg,0.072mmol,27%)。通过从DCM-己烷(v/v=1/3)重结晶获得单晶。
Rf=0.71(DCM-MeOH 95:5);[α]D=-12.18(c=1.0,CHCl3);mp250.8-252.9℃(分解,DCM-己烷,v/v=1/3);1H NMR(500MHz,CDCl3,δ/ppm):4.08(1H,br s,NH),3.27(1H,brs,NH),2.43-2.30(2H,m,H-3和HA-1),2.19-2.02(2H,m,HB-1和HA-2),1.94-1.82(1H,m,H-1’),1.78(3H,s,CH3),1.77(3H,s,CH3),1.69(6H,s,2CH3),1.57-1.42(1H,m,HB-2),0.98-0.95(6H,m,2H-2’);13C NMR(125MHz,CDCl3,δ/ppm):90.6(CqIr),90.2(CqIr),90.0(CqIr),59.2(C-3),33.4(C-2),33.3(C-1’),20.3(C-1),18.2(C-2’),18.1(C-2’),9.3(CH3),9.1(CH3),9.0(CH3),8.9(CH3),未观察到两个碳(CqIr);IR(νmax,纯净,cm-1):3299(N-H),3207(N-H),2962,2920,2876,1575,1478,1455,1369,1338,1282,1261,1186,1168,1102,1059,1034;HRMS(ESI+)m/z:对于C15H26 37Cl191IrN和C15H26 35Cl193IrN(M-Cl-,100%)计算的:448.1369,实测的:448.1368;分析:对于C15H26Cl2IrN计算的:C,37.26;H,5.42;N,2.90;Cl,14.67;实测的:C,37.60;H,5.40;N,2.80;Cl,14.40。
实施例10:[Ir{η5:η1-C5(CH3)4(CH2)3NH2}{联吡啶}][Cl]2
向搅拌的实施例3(70mg,0.16mmol)在氯仿(3.0mL)中的溶液加入2,2’-联吡啶(25mg,0.16mmol)。将反应混合物在室温搅拌过夜,并将溶剂缓慢蒸发至其体积的一半。过滤所得沉淀,得到标题化合物,为浅黄色晶体(90mg,0.15mmol,94%)。通过从氯仿缓慢结晶获得单晶。
mp 197.6-199.2℃(分解,CHCl3);1H NMR(500MHz,MeOD,δ/ppm):8.92(2H,d,J=5.7Hz,2H-5’),8.65(2H,d,J=8.0Hz,2H-2’),8.30(2H,ap dt,J=8.0,1.4Hz,2H-3’),7.84(2H,ddd,J=8.0,5.7,1.3Hz,2H-4’),2.49-2.45(2H,m,H-3),2.44-2.41(2H,m,H-1),1.96-1.92(2H,m,H-2),1.80(6H,s,2CH3),1.41(6H,s,2CH3);13C NMR(125MHz,MeOD,δ/ppm):157.4(C-1’),153.6(C-5’),142.5(C-3’),130.6(C-4’),126.0(C-2’),101.2(CqIr),97.5(CqIr),80.3(CqIr),43.1(C-3),29.7(C-2),19.4(C-1),8.2(CH3),8.1(CH3);IR(νmax,纯净,cm-1):3448(N-H),3365(N-H),3116,3043,1698,1607,1472,1446,1314,1210,1162,1076,1033;HRMS(ESI+)m/z:对于C22H28 191IrN3(M-2Cl-,56%)计算的:262.5939,实测的:262.5944;对于C22H28 193IrN3(M-2Cl-,100%)计算的:263.5951,实测的:263.5960;分析:对于C22H28Cl2IrN3·2H2O计算的:C,41.70;H,5.09;N,6.63;Cl,11.19;实测的:C,41.60;H,5.40;N,6.20;Cl,11.20。N元素分析数据超出范围(±0.4),但是迄今为止的最佳值。
实施例11:[Ir{η5:η1-C5(CH3)4(CH2)3NH2}{CH3CN}2][SbF6]2
向搅拌的实施例3(120mg,0.272mmol)在乙腈(8.0mL)中的溶液加入六氟锑酸银(200mg,0.582mmol)。将混合物在室温搅拌4小时,通过垫过滤粗制物,用MeCN洗涤并在减压下除去溶剂。通过从DCM中沉淀纯化,得到标题化合物,为浅黄色粉末(174mg,0.188mmol,70%)。通过从MeCN-Et2O(v/v=1/4)重结晶获得单晶。
mp>250℃(MeCN-Et2O,v/v=1/4);1H NMR(500MHz,CD3CN,δ/ppm):4.38(2H,br s,NH2),2.60-2.56(2H,m,H-3),2.30-2.25(2H,m,H-1),1.97(6H,s,2CH3CN),1.92-1.87(2H,m,H-2),1.86(6H,s,2CH3),1.65(6H,s,2CH3);13C NMR(125MHz,CD3CN,δ/ppm):100.6(CqIr),98.9(CqIr),81.4(CqIr),42.7(C-3),29.8(C-2),18.9(C-1),9.4(CH3),9.1(CH3),未观察到两个碳(C≡N和CH3CN);IR(νmax,纯净,cm-1):3313(N-H),3274(N-H),2946,2315,1654,1597,1457,1365,1279,1191,1083,1030;HRMS(ESI+)m/z:对于C12H20F6N191Ir121Sb(M-[SbF6 -]-2MeCN,43%)计算的:604.0139,实测的:604.0139;对于C12H20F6N191Ir123Sb和C12H20F6N193Ir121Sb(M-[SbF6 -]-2MeCN,100%)计算的:606.0156,实测的:606.0157;对于C12H20F6N193Ir123Sb(M-[SbF6 -]-2MeCN,53%)计算的:608.0167,实测的:608.0164;分析:对于C16H26F12N3IrSb2计算的:C,20.80;H,2.84;N,4.55;实测的:C,21.20;H,2.80;N,4.50。
实施例12:Rh2Cl4[η5-C5(CH3)4(CH2)3NEt2·HCl]2
向搅拌的中间体13(182mg,0.672mmol)在甲醇(5.0mL)中的溶液加入RhCl3·水合物(70mg,0.33mmol)。将反应混合物加热回流22小时,冷却至室温,并在减压下除去溶剂。从DCM-己烷(v/v=1/3)中结晶,得到标题化合物,为红色固体(130mg,0.147mmol,89%)。盐酸盐的形成通过比较NMR信号与文献(Organometallics,2010,29,1886)中报道的类似络合物来确定。
mp>250℃(MeOH);1H NMR(500MHz,DMSO,δ/ppm):10.14(2H,br s,2NH),3.09-3.06(12H,m,6NCH2),2.22(4H,t,J=8.3Hz,2H-1),1.84-1.80(4H,m,2H-2),1.70(12H,s,4CH3),1.63(12H,s,4CH3),1.19(12H,t,J=7.3Hz,4NCH2CH3);13C NMR(125MHz,DMSO,δ/ppm):100.1(d,J=8.8Hz,CqRh),99.1(d,J=7.5Hz,CqRh),97.9(d,J=8.0Hz,CqRh),50.2(NCH2),46.0(NCH2),21.4(C-2),20.5(C-1),8.6(CH3),8.4(CH3),未观察到一个碳(CH3);IR(νmax,纯净,cm-1):3214,3140,2933,2856,2756,2724,1581,1491,1453,1370,1355,1309,1263,1157,1114,1070,1023;分析:对于C32H58Cl6N2Rh2计算的:C,43.22;H,6.57;N,3.15;实测的:C,43.65;H,6.35;N,2.90。C元素分析数据超出期望范围(±0.4),但是迄今为止的最佳值。
实施例13:RhCl2[η5:η1-C5(CH3)4(CH2)3N(CH2CH3)H]
向实施例12(40mg,50μmol)在DCM(5.0mL)中的悬浮液加入叔丁醇钾(11mg,0.10mmol)。将混合物在室温搅拌72小时,通过垫过滤,用DCM洗涤并在减压下除去溶剂。通过快速色谱法(SiO2,用DCM-MeOH(99:1)洗脱)纯化,得到标题化合物,为橙色固体(6mg,16μmol,16%)。
Rf=0.57(DCM-MeOH 90:10);mp 175.1-176.4℃(DCM);1H NMR(500MHz,CDCl3,δ/ppm):3.58-3.53(1H,m,HA-3),3.30(1H,br s,NH),2.84-2.73(2H,m,NCH2),2.68-2.61(1H,m,HB-3),2.19-1.99(4H,m,2CH2),1.77(3H,s,CH3),1.72(3H,s,CH3),1.67(3H,s,CH3),1.62(3H,s,CH3),1.10(3H,t,J=7.3Hz,CH3);13C NMR(125MHz,CDCl3,δ/ppm):105.1(d,J=7.5Hz,CqRh),94.8(d,J=8.8Hz,CqRh),93.1(d,J=8.8Hz,CqRh),90.1(d,J=7.5Hz,CqRh),83.8(d,J=8.8Hz,CqRh),45.3(NCH2),44.6(NCH2),26.0(C-2),19.3(C-1),13.7(CH3),9.9(CH3),9.4(CH3),9.3(CH3),9.2(CH3);IR(νmax,纯净,cm-1):3469(N-H),3217(N-H),2917,1651,1448,1374,1063,1028;HRMS(ESI+)m/z:对于C14H24 35ClNRh(M-Cl-,100%)计算的:344.0640,实测的:344.0640。
实施例14:Rh2Cl4[η5-C5(CH3)4(CH2)4NH3Cl]2
向搅拌的中间体14(298mg,0.964mmol)在甲醇(8.0mL)中的溶液加入RhCl3·水合物(100mg,0.478mmol)。将反应混合物加热回流22小时,然后冷却至室温,并在减压下除去溶剂。从MeOH-Et2O(v/v=1/2)中结晶,得到标题化合物,为橙色固体(65mg,0.081mmol,34%)。盐酸盐的形成通过比较NMR信号与文献(Organometallics,2010,29,1886)中报道的类似络合物来确定。
1H NMR(500MHz,DMSO,δ/ppm):8.05(6H,br s,2NH3),2.75(4H,br s,2H-4),2.15(4H,br s,2H-1),1.67(12H,s,4CH3),1.63-1.57(16H,m,2CH2和4CH3),1.48(4H,br s,2CH2);13C NMR(125MHz,DMSO,δ/ppm):99.4(d,J=7.5Hz,CqRh),99.3(d,J=7.5Hz,CqRh),99.1(d,J=7.5Hz,CqRh),38.3(C-4),26.9(CH2),23.9(CH2),22.7(C-1),8.7(CH3),8.6(CH3);IR(νmax,纯净,cm-1):3370(N-H),3100(N-H),2965,2914,1706,1591,1567,1479,1400,1367,1024;HRMS(ESI+)m/z:对于C26H44N2Rh2 35Cl3(M-[2HCl]-Cl-,100%)计算的:695.0675,实测的:695.0673,对于C26H44N2Rh2 35Cl2 37Cl(M-[2HCl]-Cl-,100%)计算的:697.0649,实测的:697.0647;对于C26H44N2Rh2 35Cl37Cl2(M-[2HCl]-Cl-,33%)计算的:699.0627,实测的:699.0620。
实施例15:RhCl2[η5:η1-C5(CH3)4(CH2)4NH2]
向搅拌的实施例14(52mg,0.065mmol)在DCM(10mL)中的溶液加入叔丁醇钾(16mg,0.14mmol),并将混合物在室温搅拌72小时。将其通过垫过滤,用DCM洗涤并在减压下除去溶剂。通过快速色谱法(SiO2,用DCM-MeOH(97:3)洗脱)纯化,得到标题化合物,为橙色固体(14mg,38μmol,29%)。
Rf=0.53(DCM-MeOH 90:10);1H NMR(500MHz,CDCl3,δ/ppm):3.23-3.19(2H,m,H-4),2.87(2H,br s,NH2),2.11-2.09(2H,m,CH2),2.07-2.01(2H,m,CH2),1.86-1.79(2H,m,CH2),1.66(6H,s,2CH3),1.64(6H,s,2CH3);13C NMR(125MHz,CDCl3,δ/ppm):100.9(d,J=11.3Hz,CqRh),96.7(d,J=10.0Hz,CqRh),89.3(d,J=10.0Hz,CqRh),43.9(C-4),28.9(CH2),22.9(CH2),21.5(CH2),9.7(CH3),9.0(CH3);HRMS(ESI+)m/z:对于C13H22NRh35Cl(M-Cl-,100%)计算的:330.0490,实测的:330.0492,对于C13H22NRh37Cl(M-Cl-,33%)计算的:332.0461,实测的:332.0457。
实施例16:RhI2[η5:η1-C5(CH3)4(CH2)3NH2]
向搅拌的已知(Organometallics,2010,29,1886)铑络合物RhCl2[η5:η1-C5(CH3)4(CH2)3NH2](30mg,85μmol)在已脱气的丙酮(5.0mL)中的溶液加入碘化钠(28mg,0.19mmol)。将反应混合物加热回流20小时,然后冷却至室温,并在减压下除去溶剂。将残余物溶于DCM(15mL)中,用水(2×15mL)和盐水(15mL)洗涤。将有机相用Na2SO4干燥并在减压下除去溶剂。通过快速色谱(SiO2,用DCM-MeOH(98:2)洗脱)纯化,得到标题化合物,为暗红色固体(27mg,0.050mmol,60%)。
Rf=0.87(DCM-MeOH 90:10);mp>250℃(DCM-己烷,v/v=1/2);1H NMR(500MHz,CDCl3,δ/ppm):3.17(2H,br s,NH2),2.56-2.53(2H,m,H-3),2.17-2.13(2H,m,H-1),2.14(6H,s,2CH3),2.00(6H,s,2CH3),1.94-1.89(2H,m,H-2);13C NMR(125MHz,CDCl3,δ/ppm):97.5(d,J=7.5Hz,CqRh),97.0(d,J=7.5Hz,CqRh),90.5(d,J=7.5Hz,CqRh),40.0(C-3),28.8(C-2),19.5(C-1),12.7(CH3),10.6(CH3);IR(νmax,纯净,cm-1):3223(N-H),3149(N-H),2942,2908,1580,1458,1370,1354,1145,1129,1015,924;HRMS(ESI+)m/z:对于C12H20NRhI(M-I-)计算的:407.9690,实测的:407.9693;分析:对于C12H20I2NRh计算的:C,26.96;H,3.77;N,2.62;实测的:C,27.50;H,3.80;N,2.50。C元素分析数据超出期望范围(±0.4),但是迄今为止的最佳值。
实施例17:(R)-IrCl2[η5:η1-C5(CH3)4(CH2)2CH{CH2CH2CH2}NH]
在甲醇(3.0mL)中制备IrCl3水合物(70mg,0.20mmol)和NaHCO3(19.7mg,0.20mmol)的搅拌悬浮液并置于氮气下。将中间体15(158mg,0.50mmol)加入悬浮液中。将微波加热在125℃的设定温度以130psi的压力施加2小时。此后,在减压下除去溶剂。通过硅胶色谱法(洗脱剂DCM/MeOH,95:5)纯化,得到黄色固体(42.9mg,0.10mmol,38%)。通过使用DCM/己烷(v/v=1:3)重结晶获得单晶。
Rf=0.51(DCM/MeOH,95:5).mp(分解)250.6-251.5℃(DCM-己烷,v/v=1/3)。1HNMR(500MHz,CDCl3,δ/ppm):(非对映异构体的混合物)4.59-4.57(1H,m,NH),3.78-3.72(1H,m,CH2),3.43-3.29(2H,m,CH2),3.12-3.07(1H,m,NCH),2.87-2.77(1H,m,CH2),2.66-2.58(1H,m,CH),2.41-1.78(14H,m,14CH2),1.73-1.71(24H,m,24CH3),1.53-1.46(2H,m,CH2)(缺失1×NH信号);13C NMR(125MHz,CDCl3,δ/ppm):(非对映异构体的混合物)95.2(CqIr),93.0(CqIr),91.6(CqIr),89.9(CqIr),89.0(CqIr),88.6(CqIr),85.0(CqIr),81.9(CqIr),63.8(NCH),59.8(NCH),49.8(CH2),48.6(CH2),35.0(CH2),31.4(CH2),31.3(CH2),31.2(CH2),23.2(CH2),22.9(CH2),20.4(CH2),20.2(CH2),9.2(Cp*CH3),9.1(Cp*CH3),9.1(Cp*CH3),9.1(Cp*CH3),9.0(Cp*CH3),9.0(Cp*CH3),8.9(Cp*CH3),8.9(Cp*CH3),缺失2CqIr信号。IR(νmax,纯净,cm-1):3427,3150,2959,2920,2854,1451,1368,700;HRMS(ESI+)m/z:对于C15H24 35Cl191IrN(M-Cl-,50%)计算的:444.1204,实测的:444.1198;对于C15H24 37Cl191IrN和C15H24 35Cl193IrN(M-Cl-,100%)计算的:446.1201,实测的:446.1213;对于C15H24 37Cl193IrN(M-Cl-,26%)计算的:448.1197,实测的:448.1195;对于C15H24Cl2IrN分析计算的:C,37.42%;H,5.02%;N,2.91%;实测的:C,37.00%;H,4.90%;N,2.80%。
实施例18:[Ir{η5:η1-C5(CH3)4(CH2)3NH2}{2,4-二氟-N-苯基吡啶酰胺}][PF6]
将实施例3(50mg,0.11mmol)和2,4-二氟-N-苯基吡啶酰胺(30.4mg,0.13mmol)在乙醇(20mL)中的悬浮液搅拌并回流30分钟。加入NH4PF6(42.4mg,0.26mmol)在乙醇(10mL)中的溶液并将混合物回流过夜。冷却至室温后,过滤其余的固体,并且在减压下从滤液中除去溶剂。通过从EtOH/己烷中沉淀纯化,得到标题化合物,为亮黄色粉末(63.5mg,0.0848mmol,77%)。通过从MeOH/Et2O中重结晶来实现单晶。
1H NMR(500MHz,CD3OD,δ/ppm):8.80(1H,d,J=5.3Hz,H-4),8.27(1H,td,J=7.7,1.3Hz,H-6),8.15(1H,d,J=7.9Hz,H-7),7.86(1H,ddd,J=7.4,5.7,1.4Hz,H-5),7.41-7.12(2H,m,H-8,H-10),7.08(1H,br s,H-9),2.81(1H,br s,H-3),2.52-2.44(2H,m,H-3,H-1),2.24(1H,m,H-1),2.09(1H,m,H-2),1.88,(3H,s,CH3),1.85(1H,br s,H-2),1.57(3H,s,CH3),1.45(3H,s,CH3),0.89(3H,s,CH3);13C NMR(125MHz,CD3OD,δ/ppm):211.0(CO),154.5(Cq-Py),152.9(C-4),141.9(C-6),130.8(C-5),128.1(C-7),112.8(C-9),105.4(C-10),98.1(C-8),91.4(Cq-Ir),86.2(Cq-Ir),43.7(C-3),30.3(C-2),19.9(C-1),8.6(CH3),未观察到其它碳原子;IR(vmax,纯净,cm-1):3589(N-H),3111(N-H),1629,1603,1501,840,557;HRMS(ESI+)m/z:对于C24H27F2 191IrN3O(M-PF6 -,60%)计算的:602.1728,实测的:602.1722;对于C24H27F2 193IrN3O(M-PF6 -,100%)计算的:604.1751,实测的:604.1749。
实施例19:[Ir{η5:η1-C5(CH3)4(CH2)3NH2}{4-氟-N-苯基-2-甲硫基吡啶酰胺}]
[PF6]2
将实施例3(50mg,0.11mmol)和4-氟-N-苯基-2-甲硫基吡啶酰胺(32mg,0.13mmol)在乙醇(20mL)中的悬浮液搅拌并回流30分钟。加入NH4PF6(42.4mg,0.26mmol)在乙醇(10mL)中的溶液并将混合物回流过夜。冷却至室温后,过滤其余的固体,并且在减压下从滤液中除去溶剂。通过从EtOH/己烷中沉淀纯化,得到标题化合物,为亮橙色粉末(78.6mg,0.10mmol,94%)。通过从EtOH/己烷中重结晶获得单晶。
1H NMR(500MHz,CD3OD,δ/ppm):8.14(1H,dd,J=7.9,1.1Hz,H-7),8.01(1H,t,J=7.8Hz,H-6),7.74(1H,dd,J=7.7,1.5Hz,H-5),7.17(4H,m,H-8-11),2.99(3H,s,CH3-4),2.82(1H,m,H-3),2.38(2H,m,H-3,H-1),2.17(1H,m,H-1),2.10(3H,s,CH3),2.01(1H,m,H-2),1.84(1H,m,H-2),1.61(3H,s,CH3),1.43(3H,s,CH3),1.36(3H,s,CH3);13C NMR(125MHz,CD3OD,δ/ppm):197.0(CS),163.6(Cq-F),140.8(C-6),129.1(C-5),124.7(C-7),123.3(C-8,C-11),116.6(C-9,C-10),91.1(Cq-Ir),88.5(Cq-Ir),88.0(Cq-Ir),81.9(Cq-Ir),44.7(C-3),30.5(C-2),29.9(CH3-4),20.0(C-1),10.7(CH3),9.4(CH3),9.1(CH3),8.3(CH3),未观察到其它碳原子;IR(νmax,纯净,cm-1):3315(N-H),3271(N-H),3128,3044,1601,1543,1509,1470,1405,1237,1190,1162,1044,837,762,556;HRMS(ESI+)m/z:对于C25H30F191IrN3S(M-H-2PF6 -,60%)计算的:614.1750,实测的:614.1737;对于C25H30F193IrN3S(M-H-2PF6 -,100%)计算的:616.1774,实测的:616.1762。
实施例20:[Ir{η5:η1-C5(CH3)4(CH2)3NH2}{dppm}][BF4]2
搅拌实施例3(50mg,0.11mmol)、双(二苯基膦基)甲烷(42.3mg,0.11mmol)和NaBF4(24.2mg,0.22mmol)在乙醇(10mL)中的悬浮液并加热回流过夜。冷却至室温后,在减压下除去溶剂,并且将残余物用甲醇处理并过滤。再次在减压下除去滤液中的溶剂。通过从MeOH/Et2O沉淀来纯化,得到标题化合物,为浅黄色粉末(72.7mg,0.078mmol,71%)。通过从MeOH/Et2O或MeCN/Et2O中重结晶来实现单晶。
1H NMR(500MHz,CD3OD,δ/ppm):7.74(6H,m,Ph),7.67(6H,m,Ph),7.58(4H,m,Ph),7.38(4H,m,Ph),5.49(2H,s,H-4),2.69(2H,m,H-3),2.33(6H,t,J=4.0Hz,2CH3),2.23(2H,m,H-1),1.95(2H,m,H-2),1.26(6H,m,2CH3);13C NMR(125MHz,CD3OD,δ/ppm):134.6(Ph),133.5(Ph),133.1(Ph),131.7(Ph),130.9(Ph),99.3(Cq-Ir),54.9(C-4),42.4(C-3),26.0(C-2),19.9(C-1),10.7(CH3),9.1(CH3),未观察到其它碳原子;31P NMR(121MHz,CD3OD,δ/ppm):-46.3;IR(vmax,纯净,cm-1):3391(N-H),1574,1437,1097,1058,721,699,650,621,541,508;HRMS(ESI+)m/z:对于C37H41 191IrNP2(M-H-2BF4 -,60%)计算的:752.2320,实测的:752.2335;对于C37H41 193IrNP2(M-H-2BF4 -,100%)计算的:754.2343,实测的:754.2341。
实施例21:[IrCl{η5:η1-C5(CH3)4(CH2)3NH2}{吡啶}][BF4]
搅拌实施例3(50mg,0.11mmol)和NaBF4(24.2mg,0.22mmol)在乙醇(5mL)中的悬浮液,并加入吡啶(18μL,0.22mmol)。将混合物加热回流过夜。冷却至室温后,过滤混合物并在减压下除去溶剂。通过从MeOH/Et2O沉淀来纯化,得到标题化合物,为浅黄色粉末(43.6mg,0.076mmol,69%)。通过从MeOH/Et2O中重结晶来实现单晶。
1H NMR(500MHz,CD3OD,δ/ppm):8.83(2H,m,H-4),8.04(1H,tt,J=7.7,1.6Hz,H-6),7.61(2H,m,H-5),2.86(1H,m,H-3),2.60(1H,m,H-3),2.34(2H,m,H-1),2.05(2H,m,H-2),1.76(3H,s,CH3),1.66(3H,s,CH3),1.62(3H,s,CH3),1.15(3H,s,CH3);13C NMR(125MHz,CD3OD,δ/ppm):154.8(C-4),140.8(C-6),128.2(C-5),96.6(Cq-Ir),93.8(Cq-Ir),90.1(Cq-Ir),83.1(Cq-Ir),77.8(Cq-Ir),43.6(C-3),30.3(C-2),19.8(C-1),9.1(CH3),8.8(CH3),8.7(CH3),8.2(CH3);IR(vmax,纯净,cm-1):3276(N-H),3221(N-H),1579,1449,1058,1020,767,697,551,527,518;HRMS(ESI+)m/z:对于C12H20Cl191IrN(M-Py-BF4 -,60%)计算的:404.0890,实测的:404.0879;对于C12H20Cl193IrN(M-Py-BF4 -,100%)计算的:406.0914,实测的:406.0897。
实施例22:铱催化剂-N-取代基的作用
将实施例3、4和6的金属络合物与比较例金属络合物[Cp*IrCl2]2一起进行如上所示的反应。测量每种金属络合物随时间的收率并示于图1中。简单的氨基(实施例3)和甲氨基(实施例4)金属络合物几乎同等活性,并且比[Cp*IrCl2]2活性更高。与[Cp*IrCl2]2相比,叔胺衍生的催化剂实施例6具有稍微降低的速率;然而,24小时后的最终转化率是相当的。
实施例23:铱催化剂:抗衡离子的作用
实施例3和实施例7的金属络合物与[Cp*IrCl2]2一起进行上述反应。测量每种金属络合物随时间的收率并示于图2中。二氯络合物比二碘络合物活性更高,呈现的反应速率更快。然而,两种络合物在24小时提供几乎相同的最终收率。实施例3和实施例7都比比较络合物[Cp*IrCl2]2显著更有活性。
实施例24:中性铑和铱络合物的比较
实施例3的金属络合物在两种不同的溶剂甲苯和叔戊醇中进行上述反应。在上面的方案中显示的等同的已知铑催化剂进行相同的反应。图3a(甲苯)和图3b(叔戊醇)显示了两种反应随时间的收率。实施例3的铱催化剂相比等同的铑络合物可靠地活性更高,尽管差异性能的程度显示出一些溶剂敏感性。
实施例25:铱络合物-溶剂耐受性
用上述反应在许多溶剂中测试实施例3的金属络合物和比较络合物[Cp*IrCl2]2。图4示出了两种络合物在每种溶剂中24小时后的最终收率。在所有溶剂(除TBME之外)中,本发明的金属络合物的最终收率较高。
类似地,实施例13的已知铑金属络合物在一系列溶剂中在与上述相同的反应中但用不同的溶剂进行测试。收率示于图5中。比较铑催化剂与铱催化剂的收率,本发明的铱络合物显著优于等同的铑络合物。
图6a-d示出了实施例3的金属络合物在选择上述测试的溶剂体系中随时间的收率。如通过24小时的绝对转化(图4)或单独的动力学分析(图6a-d)所测量的,实施例3的络合物显示出比[Cp*IrCl2]2更好的溶剂耐受性。
实施例26:使用铱催化剂的底物范围
图7示出了一系列官能团的底物耐受性和收率。反应条件如下:
以下字母表示对于如图7中所示的某些化合物的该一般工序的偏离:a在130℃进行的反应;b使用2当量的胺;c使用2当量的乙醇;d使用2摩尔%的铱。实施例3的络合物实现了较宽的底物范围;在某些情况下明显证明[Cp*IrCl2]2的优越性能。
实施例27:铑中性催化剂与离子催化剂的比较
实施例2的离子铑络合物和实施例13中首先示出的铑络合物进行上述反应。反应速率图如图8所示。实施例2的离子铑络合物显示出比已知的中性铑络合物高的反应速率。
实施例28:铱中性催化剂与离子催化剂的比较
以与上述实施例27类似的方式,将中性铱络合物(实施例3)和离子铱络合物(实施例11)用于上述反应。反应速率如图9所示。离子铱络合物(实施例11)比中性二氯化物络合物活性显著更高,而中性络合物转而比比较络合物[Cp*IrCl2]2活性显著更高,参见图1和图2。
实施例29:铱络合物-溶剂耐受性
如实施例14中那样,在一系列溶剂中测试实施例11的离子络合物。与图4和实施例14中所示的结果相比,图10中示出了24小时后具有离子络合物的反应的最终收率。该离子络合物显示出与二氯化物络合物至少一样宽的溶剂相容性,并且通常更具活性。
实施例30:铱催化剂的温度性能
实施例3的铱催化剂、实施例11的离子络合物和比较络合物[Cp*IrCl2]2在不同温度范围内进行上述反应。所得的反应速率显示在图11a(实施例3)、图11b(实施例11)和图11c(比较络合物)中。实施例3的络合物比比较络合物[Cp*IrCl2]2在较低温度似乎对反应较不敏感。该离子络合物(实施例11)显示出低至80℃的良好活性,其在80℃比比较配合物在110℃具有更好的活性。
实施例31:铱络合物-在低催化剂负载下的性能
在上面示出的反应条件下,实施例3和实施例11的金属络合物在24小时内提供了优异(接近完全)的转化率,分别为0.1摩尔%Ir和0.075摩尔%Ir的负载量。图12和图13示出了结果。相比之下,比较络合物[Cp*IrCl2]2在2摩尔%下不能达到100%的转化率,参见图1和图2。
实施例32:n(连接基团中的连接基长度)对催化活性的影响
研究了链长度对铑催化剂的催化活性的影响。针对比较铑二聚体[Cp*RhCl2]2测试了三种具有连接配体的催化剂,其中连接基具有不同的长度(n=2、3和4)。测试了具有2、3和4个碳原子的连接碳链长度的络合物。在连接基团链中具有三个碳原子的络合物(n=3(图14中o=1))的催化活性显著优于其它测试的连接配体和比较二聚体的催化活性。数据如图14所示。
在本说明书的整个说明书和权利要求书中,词语“包括”和“包含”及其变体意指“包括但不限于”,并且它们不旨在(并且不)排除其它部分、添加剂、组分、整数或步骤。贯穿本说明书的描述和权利要求书,单数涵盖复数,除非上下文另有要求。具体地,在使用不定冠词时,除非上下文另有要求,否则说明书应被理解为考虑复数以及单数。
结合本发明的具体方面、实施方案或实施例描述的特征、整体、特性、化合物、化学部分或基团应被理解为适用于本文所述的任何其它方面、实施方案或实施例,除非与此不兼容。本说明书(包括权利要求、摘要和附图)中公开的所有特征和/或如此公开的任何方法或过程的所有步骤可以任何组合来组合,除了组合之外,其中至少一些此类特征和/或步骤是相互排斥的。本发明不限于任何前述实施方案的细节。本发明延伸到本说明书(包括权利要求书、摘要和附图)中公开的特征的任何新颖特征或任何新颖组合,或如此公开的任何方法或过程的任何新颖内容或任何新颖组合。
读者的注意力是针对与本申请相关的与本说明书同时提交或在本说明书之前提交的所有文件和文献,并且这些文件和文献在本说明书中公开供公众查阅,并且所有这些文件和文献的内容通过引用并入本文。
Claims (12)
3.根据权利要求2所述的金属络合物,其中p为2。
4.根据权利要求2所述的金属络合物,其中X选自氢氧化物、氟化物、氯化物、溴化物、碘化物、乙酸盐、甲酸盐、氟酸盐、亚氟酸盐、溴酸盐、亚溴酸盐、碘酸盐、亚碘酸盐、氯酸盐、亚氯酸盐、碳酸氢盐、次氟酸盐、次氯酸盐、次溴酸盐、次碘酸盐、全氟酸盐、高氯酸盐、高溴酸盐、高碘酸盐、铬酸盐、氰酸盐、氰化物、磷酸二氢盐、亚磷酸二氢盐、硝酸盐、草酸氢盐、硫酸氢盐、亚硫酸氢盐、高锰酸盐、亚硝酸盐、硫氰酸盐、氢化物、六氟磷酸盐、六氟锑酸盐、四氟硼酸盐、[B[3,5-(CF3)2C6H3]4]-、B(C6F5)4 -、Al(OC(CF3)3)4 -、硫酸盐、亚硫酸盐、硫化物、过硫酸盐、硫代硫酸盐、磷酸氢盐、亚磷酸氢盐、偏硅酸盐、碳酸盐、过碳酸盐、草酸盐、苯甲酸盐、酒石酸盐、硼酸盐、硼化物、柠檬酸盐、次磷酸盐、氮化物、磷酸盐、磷化物和亚磷酸盐。
5.根据权利要求4所述的金属络合物,其中X为氟化物、氯化物、溴化物、碘化物、六氟磷酸盐、六氟锑酸盐或四氟硼酸盐。
6.根据权利要求1-5任一项所述的金属络合物,其中R5为甲基。
7.根据权利要求1-5任一项所述的金属络合物,其中m为0或4。
8.根据权利要求1-5任一项所述的金属络合物,其中R2,以及R3和R4中的一个,与它们所连接的原子一起形成5元或6元杂环环。
9.根据权利要求1-5任一项所述的金属络合物,其中n为3。
12.一种催化方法,包括将根据权利要求1-11任一项所述的金属络合物加入反应混合物中。
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