ES2392875A1 - Hydrogenation catalysts enantioselectiva based on phosphines-chiral phosphites linked to polystyrene resins. (Machine-translation by Google Translate, not legally binding) - Google Patents
Hydrogenation catalysts enantioselectiva based on phosphines-chiral phosphites linked to polystyrene resins. (Machine-translation by Google Translate, not legally binding) Download PDFInfo
- Publication number
- ES2392875A1 ES2392875A1 ES201130904A ES201130904A ES2392875A1 ES 2392875 A1 ES2392875 A1 ES 2392875A1 ES 201130904 A ES201130904 A ES 201130904A ES 201130904 A ES201130904 A ES 201130904A ES 2392875 A1 ES2392875 A1 ES 2392875A1
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- Spain
- Prior art keywords
- compound
- structural formula
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- catalyst
- phosphine
- Prior art date
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- Granted
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- 239000003054 catalyst Substances 0.000 title claims abstract description 58
- 238000005984 hydrogenation reaction Methods 0.000 title claims abstract description 20
- 229920005990 polystyrene resin Polymers 0.000 title claims abstract description 9
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 239000003446 ligand Substances 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 36
- -1 phosphino group Chemical group 0.000 claims abstract description 28
- 239000010948 rhodium Substances 0.000 claims abstract description 27
- ZOGYOOUMDVKYLM-UHFFFAOYSA-N phosphane phosphorous acid Chemical compound P.OP(O)O ZOGYOOUMDVKYLM-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 21
- 125000003118 aryl group Chemical group 0.000 claims abstract description 20
- 239000004793 Polystyrene Substances 0.000 claims abstract description 18
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 18
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229920002223 polystyrene Polymers 0.000 claims abstract description 10
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 9
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 9
- 229910052751 metal Inorganic materials 0.000 claims abstract description 9
- 239000002184 metal Substances 0.000 claims abstract description 9
- 229910052707 ruthenium Inorganic materials 0.000 claims abstract description 9
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical group C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims abstract description 8
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 8
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002202 Polyethylene glycol Chemical group 0.000 claims abstract description 6
- 229920001223 polyethylene glycol Chemical group 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 4
- 125000003827 glycol group Chemical group 0.000 claims abstract description 4
- 150000001336 alkenes Chemical class 0.000 claims description 27
- 230000008569 process Effects 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 14
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 239000002243 precursor Substances 0.000 claims description 8
- 229920005989 resin Polymers 0.000 claims description 8
- 239000011347 resin Substances 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- 229920001577 copolymer Polymers 0.000 claims description 7
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 6
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000012018 catalyst precursor Substances 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 150000004703 alkoxides Chemical class 0.000 claims description 4
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000012429 reaction media Substances 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 230000004913 activation Effects 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 238000004873 anchoring Methods 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical group OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- BUYVJWVYKPKZEX-DWVXZKBMSA-N (1z,5z)-cycloocta-1,5-diene;(z)-4-hydroxypent-3-en-2-one;rhodium Chemical compound [Rh].C\C(O)=C\C(C)=O.C\1C\C=C/CC\C=C/1 BUYVJWVYKPKZEX-DWVXZKBMSA-N 0.000 claims description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 claims description 2
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 239000004593 Epoxy Substances 0.000 claims description 2
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- GGRQQHADVSXBQN-FGSKAQBVSA-N carbon monoxide;(z)-4-hydroxypent-3-en-2-one;rhodium Chemical compound [Rh].[O+]#[C-].[O+]#[C-].C\C(O)=C\C(C)=O GGRQQHADVSXBQN-FGSKAQBVSA-N 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- 150000004696 coordination complex Chemical class 0.000 claims description 2
- 150000001993 dienes Chemical class 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 125000002524 organometallic group Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 4
- 230000000694 effects Effects 0.000 claims 4
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical group CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims 3
- 239000002638 heterogeneous catalyst Substances 0.000 claims 3
- 238000007037 hydroformylation reaction Methods 0.000 claims 3
- 244000309464 bull Species 0.000 claims 2
- 238000006467 substitution reaction Methods 0.000 claims 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 125000003710 aryl alkyl group Chemical group 0.000 claims 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims 1
- 229910001914 chlorine tetroxide Inorganic materials 0.000 claims 1
- DQTRYXANLKJLPK-UHFFFAOYSA-N chlorophosphonous acid Chemical class OP(O)Cl DQTRYXANLKJLPK-UHFFFAOYSA-N 0.000 claims 1
- 229920006037 cross link polymer Polymers 0.000 claims 1
- 125000004663 dialkyl amino group Chemical group 0.000 claims 1
- 150000002118 epoxides Chemical class 0.000 claims 1
- 150000002170 ethers Chemical class 0.000 claims 1
- 239000012634 fragment Substances 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims 1
- 150000003003 phosphines Chemical group 0.000 claims 1
- 229910052723 transition metal Inorganic materials 0.000 claims 1
- 150000003624 transition metals Chemical class 0.000 claims 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 239000002131 composite material Substances 0.000 abstract 1
- 229920006163 vinyl copolymer Polymers 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 239000012071 phase Substances 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 150000002924 oxiranes Chemical class 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound 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
- RYIOLWQRQXDECZ-UHFFFAOYSA-N phosphinous acid Chemical compound PO RYIOLWQRQXDECZ-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000010908 decantation Methods 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LYXHWHHENVLYCN-QMDOQEJBSA-N (1z,5z)-cycloocta-1,5-diene;rhodium;tetrafluoroborate Chemical compound [Rh].F[B-](F)(F)F.C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 LYXHWHHENVLYCN-QMDOQEJBSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- HRJABHWZEQHPFS-UHFFFAOYSA-N [1-[2-(12,14-dioxa-13-phosphapentacyclo[13.8.0.02,11.03,8.018,23]tricosa-1(15),2(11),3,5,7,9,16,18,20,22-decaen-13-yloxy)naphthalen-1-yl]naphthalen-2-yl]-diphenylphosphane Chemical compound O1C=2C=CC3=CC=CC=C3C=2C(C2=CC=CC=C2C=C2)=C2OP1OC1=CC=C2C=CC=CC2=C1C(C1=CC=CC=C1C=C1)=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 HRJABHWZEQHPFS-UHFFFAOYSA-N 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- CCRCUPLGCSFEDV-UHFFFAOYSA-N cinnamic acid methyl ester Natural products COC(=O)C=CC1=CC=CC=C1 CCRCUPLGCSFEDV-UHFFFAOYSA-N 0.000 description 2
- 239000013065 commercial product Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 239000002815 homogeneous catalyst Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- CTKINSOISVBQLD-GSVOUGTGSA-N (R)-Glycidol Chemical compound OC[C@@H]1CO1 CTKINSOISVBQLD-GSVOUGTGSA-N 0.000 description 1
- CTKINSOISVBQLD-VKHMYHEASA-N (S)-Glycidol Chemical compound OC[C@H]1CO1 CTKINSOISVBQLD-VKHMYHEASA-N 0.000 description 1
- CHRJZRDFSQHIFI-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;styrene Chemical compound C=CC1=CC=CC=C1.C=CC1=CC=CC=C1C=C CHRJZRDFSQHIFI-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000005427 anthranyl group Chemical group 0.000 description 1
- 235000019568 aromas Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 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
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 239000011982 enantioselective catalyst Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000007210 heterogeneous catalysis Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000003622 immobilized catalyst Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- CCRCUPLGCSFEDV-BQYQJAHWSA-N methyl trans-cinnamate Chemical compound COC(=O)\C=C\C1=CC=CC=C1 CCRCUPLGCSFEDV-BQYQJAHWSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000001814 trioxo-lambda(7)-chloranyloxy group Chemical group *OCl(=O)(=O)=O 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/14—Phosphorus; Compounds thereof
- B01J27/185—Phosphorus; Compounds thereof with iron group metals or platinum group metals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- 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
- C07F15/0073—Rhodium 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
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Abstract
Description
Catalizadores de hidrogenación enantioselectiva basados en fosfinas-fosfitos quirales enlazados a resinas de poliestireno Enantioselective hydrogenation catalysts based on chiral phosphines-phosphites bound to polystyrene resins
SECTOR DE LA TÉCNICA SECTOR OF THE TECHNIQUE
El objeto de la presente invención es un catalizador para reacciones de hidrogenación enantioselectiva soportado sobre un polímero de poliestireno, su procedimiento de preparación, su utilización en reacciones de hidrogenación asimétrica, preferentemente de olefinas, y su reutilización. El catalizador presenta un ligando fosfinafosfito quiral enlazado covalentemente a una resina de poliestireno. The object of the present invention is a catalyst for enantioselective hydrogenation reactions supported on a polystyrene polymer, its preparation process, its use in asymmetric hydrogenation reactions, preferably of olefins, and its reuse. The catalyst has a chiral phosphine phosphite ligand covalently bonded to a polystyrene resin.
Mediante el uso de estos catalizadores pueden prepararse diversas clases de compuestos quirales con elevada pureza enantiomérica. Entre ellos pueden destacarse los a- y los �-aminoácidos que tienen gran interés para la industria farmacéutica. Otros compuestos quirales accesibles mediante el uso de estos catalizadores pueden tener interés para otros sectores como el agroquímico o el de los aromas. Various kinds of chiral compounds with high enantiomeric purity can be prepared by using these catalysts. Among them, the a- and �-amino acids that are of great interest to the pharmaceutical industry can be highlighted. Other chiral compounds accessible through the use of these catalysts may be of interest to other sectors such as agrochemicals or aromas.
ESTADO DE LA TÉCNICA STATE OF THE TECHNIQUE
La actividad biológica de muchas moléculas quirales está relacionada con su configuración, y este fenómeno tiene una importancia capital en diversos sectores industriales como el farmacéutico, el agroquímico y en el de la perfumería. Por ello, existe una demanda muy importante de procedimientos eficientes para la preparación de productos quirales en estado enantiopuro (Thayer, A. M. Chemical and Engineering News 2007, 85, 19). Entre diversas estrategias para la preparación de productos enantiopuros, el uso de catalizadores basados en complejos metálicos quirales constituye una de las estrategias principales. Estos catalizadores han ofrecido la solución más conveniente en la síntesis industrial de un gran número de compuestos quirales (Blaser, H. U. Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and Solutions, Wiley 2004). The biological activity of many chiral molecules is related to its configuration, and this phenomenon is of paramount importance in various industrial sectors such as pharmaceutical, agrochemical and perfumery. Therefore, there is a very important demand for efficient procedures for the preparation of chiral products in the enantiopuro state (Thayer, A. M. Chemical and Engineering News 2007, 85, 19). Among various strategies for the preparation of enantiopuro products, the use of catalysts based on chiral metal complexes is one of the main strategies. These catalysts have offered the most convenient solution in the industrial synthesis of a large number of chiral compounds (Blaser, H. U. Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and Solutions, Wiley 2004).
En la búsqueda de catalizadores eficientes, juega un papel central el desarrollo de ligandos quirales con características electrónicas, estéricas y estereoquímicas adecuadas. En el campo de las reacciones de hidrogenación catalítica enantioselectiva, se han utilizado principalmente tres tipos de ligandos: quelatantes con simetría C2, quelatantes con simetría C1 (también llamados heterobifuncionales) y monodentados. En la mejora de las aplicaciones existentes o del desarrollo de nuevas aplicaciones, el uso de catalizadores basados en ligandos heterobifuncionales es una estrategia muy prometedora porque da acceso a catalizadores con estructuras y características de reactividad diferentes a las que generan los ligandos de los otros dos tipos. Recientemente, por ejemplo, mediante el uso de catalizadores de este tipo se ha descrito la primera hidrogenación con elevada enantioselectividad de un substrato olefínico no funcionalizado (A. Pfaltz Science 2006, 311, 642). In the search for efficient catalysts, the development of chiral ligands with suitable electronic, steric and stereochemical characteristics plays a central role. In the field of enantioselective catalytic hydrogenation reactions, three types of ligands have been used mainly: chelators with C2 symmetry, chelators with C1 symmetry (also called heterobifunctional) and monodentate. In the improvement of existing applications or the development of new applications, the use of catalysts based on heterobifunctional ligands is a very promising strategy because it gives access to catalysts with structures and reactivity characteristics different from those generated by ligands of the other two types . Recently, for example, the use of catalysts of this type has described the first hydrogenation with high enantioselectivity of a non-functionalized olefinic substrate (A. Pfaltz Science 2006, 311, 642).
El objeto de la presente invención se basa en un tipo de ligandos heterobifuncionales quirales denominados fosfina-fosfito. Se ha observado que diversos catalizadores de rodio homogéneos, basados en ligandos de este tipo, ofrecen excelentes resultados en la hidrogenación enantioselectiva de diversos tipos de olefinas (A. Vidal-Ferran, Chem. Eur. J. 2010, 16, 6495; A. Pizzano, Organometallics 2002, 21, 4611; Chem. Eur. J. 2008, 14, 9856). The object of the present invention is based on a type of chiral heterobifunctional ligands called phosphine-phosphite. It has been observed that various homogeneous rhodium catalysts, based on ligands of this type, offer excellent results in the enantioselective hydrogenation of various types of olefins (A. Vidal-Ferran, Chem. Eur. J. 2010, 16, 6495; A. Pizzano, Organometallics 2002, 21, 4611; Chem. Eur. J. 2008, 14, 9856).
Los catalizadores homogéneos enantioselectivos actúan en una fase líquida en la que al final de la reacción coexisten con el producto de la reacción. Por ello, el aislamiento del producto requiere efectuar la separación del catalizador. Esta etapa, dependiendo de las características del producto (p.e solubilidad, punto de ebullición), puede conllevar una dificultad importante, especialmente en reacciones a escala industrial. El uso de versiones de catalizadores homogéneos soportados en un sólido constituye una solución a este inconveniente. Estos catalizadores, con una elección adecuada del soporte y del procedimiento de anclaje del catalizador al soporte, pueden mostrar una reactividad similar al catalizador homogéneo. Además, los catalizadores soportados pueden separarse fácilmente del medio de reacción mediante una simple filtración. Además, el catalizador soportado tiene ventajas adicionales. Puede ser reutilizado en la reacción catalítica, multiplicando de este modo su productividad y también puede utilizarse en reactores de flujo. La inmovilización del catalizador requiere, por lo general, la funcionalización del ligando quiral, lo que puede suponer un importante esfuerzo sintético. Por consiguiente, el uso de ligandos soportados que puedan sintetizarse con facilidad supone una importante ventaja. Homogeneous enantioselective catalysts act in a liquid phase in which at the end of the reaction they coexist with the reaction product. Therefore, product isolation requires separation of the catalyst. This stage, depending on the characteristics of the product (e.g. solubility, boiling point), can lead to significant difficulty, especially in reactions on an industrial scale. The use of homogeneous catalyst versions supported on a solid constitutes a solution to this drawback. These catalysts, with a suitable choice of the support and of the method of anchoring the catalyst to the support, can show a reactivity similar to the homogeneous catalyst. In addition, supported catalysts can be easily separated from the reaction medium by simple filtration. In addition, the supported catalyst has additional advantages. It can be reused in the catalytic reaction, thereby multiplying its productivity and can also be used in flow reactors. The immobilization of the catalyst generally requires the functionalization of the chiral ligand, which can be an important synthetic effort. Therefore, the use of supported ligands that can be easily synthesized is an important advantage.
Se conocen varios ejemplos de catalizadores de hidrogenación de olefinas anclados sobre soportes de diferente naturaleza. Un grupo de ellos se basa en la interacción no covalente entre complejos catiónicos y resinas aniónicas (Barbaro Chem. Eur. J. 2006, 12, 5666) o sólidos inorgánicos aniónicos (Augustine J. Mol. Cat. A: 2004, 216, 189). Este procedimiento es muy simple, aunque está limitado a la inmovilización de complejos catiónicos. Por otro lado también se han estudiado catalizadores en los que los ligandos están unidos a polímeros solubles (Chan Tetrahedron: Asymmetry 2001, 12, 1241). Esta aproximación cuenta con la ventaja de que la reacción transcurre en fase homogénea, aunque la separación del catalizador requiere su precipitación, que constituye un procedimiento menos ventajoso que el de separación de un catalizador heterogeneizado. (Leadbeater Chem. Rev. 2002, 102, 3217). Por otra parte también se han utilizado catalizadores enlazados, mediante enlaces covalentes, tanto a sólidos Several examples of hydrogenation catalysts of olefins anchored on supports of different nature are known. A group of them is based on the non-covalent interaction between cationic complexes and anionic resins (Barbaro Chem. Eur. J. 2006, 12, 5666) or anionic inorganic solids (Augustine J. Mol. Cat. A: 2004, 216, 189 ). This procedure is very simple, although it is limited to the immobilization of cationic complexes. On the other hand, catalysts have also been studied in which the ligands are bound to soluble polymers (Chan Tetrahedron: Asymmetry 2001, 12, 1241). This approach has the advantage that the reaction takes place in a homogeneous phase, although the separation of the catalyst requires its precipitation, which constitutes a less advantageous procedure than the separation of a heterogeneized catalyst. (Leadbeater Chem. Rev. 2002, 102, 3217). On the other hand, linked catalysts have also been used, by covalent bonds, both to solids
inorgánicos (Song Chem. Rev. 2002, 102, 3495) como a polímeros orgánicos (Leadbeater Chem. Rev. 2002, 102, 3217). En cada caso, el enlace del ligando quiral al soporte requiere de diversas etapas de síntesis, que requieren bien la funcionalización adicional del ligando o del soporte y su condensación. Según el tipo de ligando, uno u otro tipo de soporte puede facilitar la preparación del ligando soportado. inorganic (Song Chem. Rev. 2002, 102, 3495) as to organic polymers (Leadbeater Chem. Rev. 2002, 102, 3217). In each case, the binding of the chiral ligand to the support requires various stages of synthesis, which require either the additional functionalization of the ligand or the support and its condensation. Depending on the type of ligand, one or another type of support may facilitate the preparation of the supported ligand.
En la bibliografía se han descrito diversos catalizadores de rodio para la hidrogenación de olefinas enlazados a soportes poliméricos (Bayston J.Org. Chem. 1998, 63, 3137; Gilbertson Tetrahedron 1999, 55, 11609; Kamer Angew. Chem. Int. Ed. 2008, 47, 6602 y Eur. J. Org. Chem. 2009, 5796). Estos catalizadores se han utilizado sólo en reacciones de hidrogenación de substratos estándar y no se han empleado en la hidrogenación de substratos con mayor interés sintético. Various rhodium catalysts for the hydrogenation of olefins bound to polymeric supports have been described in the literature (Bayston J.Org. Chem. 1998, 63, 3137; Gilbertson Tetrahedron 1999, 55, 11609; Kamer Angew. Chem. Int. Ed. 2008, 47, 6602 and Eur. J. Org. Chem. 2009, 5796). These catalysts have been used only in hydrogenation reactions of standard substrates and have not been used in the hydrogenation of substrates with greater synthetic interest.
Debe por otro lado mencionarse un precedente de catalizadores basados en ligandos fosfina-fosfito soportados (Nozaki J. Am. Chem. Soc. 1998, 120, 4051). En particular se trata de versiones de los ligandos denominados BINAPHOS enlazados a poliestireno que poseen un grado de entrecruzamiento muy elevado, en torno al 50 %. No se conocen precedentes del uso de estos catalizadores en reacciones de hidrogenación catalítica enantioselectiva. La preparación de estos ligandos BINAPHOS soportados requiere la síntesis de diversos derivados vinílicos fosforados que suponen un importante esfuerzo sintético. On the other hand, a precedent of catalysts based on supported phosphine-phosphite ligands should be mentioned (Nozaki J. Am. Chem. Soc. 1998, 120, 4051). In particular, these are versions of the polystyrene bonded BINAPHOS ligands that have a very high degree of crosslinking, around 50%. There are no known precedents for the use of these catalysts in enantioselective catalytic hydrogenation reactions. The preparation of these supported BINAPHOS ligands requires the synthesis of various phosphorus vinyl derivatives that involve an important synthetic effort.
La presente invención utiliza como soporte resinas basadas en poliestireno, unidas mediante un enlace covalente al ligando quiral. Los ligandos que se describen en la presente invención se pueden preparar a partir del glicidol, que es un producto comercial en cualquiera de sus dos enantiómeros, y una resina de poliestireno bromobutilada, que es también un producto comercial, así como reactivos fosforados que se sintetizan en una etapa a partir de productos comerciales. El procedimiento de síntesis es también muy versátil y permite variar fácilmente y de una manera sistemática la estructura del ligando quiral, aspecto que agiliza notablemente el proceso de optimización del catalizador The present invention uses polystyrene-based resins as support, bonded by a covalent bond to the chiral ligand. The ligands described in the present invention can be prepared from glycidol, which is a commercial product in any of its two enantiomers, and a bromobutylated polystyrene resin, which is also a commercial product, as well as phosphorized reagents that are synthesized. in a stage from commercial products. The synthesis procedure is also very versatile and allows the chiral ligand structure to be varied easily and systematically, an aspect that significantly speeds up the catalyst optimization process
A partir de los precedentes puede concluírse que el desarrollo de catalizadores inmovilizados basados en ligandos fosfinas-fosfitos quirales pueden tener un gran interés, ya que idealmente pueden aunar niveles de enantioselectividad y reactividad catalítica elevados junto con las ventajas prácticas que aportan los catalizadores soportados. Finalmente, y por su relación con el contenido de la presente invención debe mencionarse que se ha descrito la preparación de ligandos fosfina-fosfito homógeneos con una estructura similar a los considerados en la invención (A. Vidal-Ferran, Chem. Eur. J. 2010, 16, 6495), estos ligandos y su uso en reacciones de hidrogenación catalitico se han recogido en una patente (WO 2009/030626 A1). From the foregoing it can be concluded that the development of immobilized catalysts based on chiral phosphine phosphite ligands can be of great interest, since they can ideally combine high levels of catalytic enantioselectivity and reactivity together with the practical advantages provided by supported catalysts. Finally, and because of its relation to the content of the present invention, it should be mentioned that the preparation of homologous phosphine-phosphite ligands with a structure similar to those considered in the invention has been described (A. Vidal-Ferran, Chem. Eur. J. 2010, 16, 6495), these ligands and their use in catalytic hydrogenation reactions have been included in a patent (WO 2009/030626 A1).
DESCRIPCIÓN DE LA INVENCIÓN DESCRIPTION OF THE INVENTION
La presente invención se refiere a un compuesto de fórmula estructural L1 caracterizado porque comprende un ligando fosfina-fosfito enlazado a poliestireno, un centro estereogénico en el carbono al grupo fosfino, y donde R1, R2, R3a y R3b son independientemente grupos arilo o alquilo lineales, ramificados o cíclicos, siendo preferente que R3a y R3b sean iguales, X es una cadena alquílica o una cadena de polietilenglicol y PS es un copolímero de vinil y divinilbenceno enlazado mediante uno de sus anillos aromáticos al sustituyente X. The present invention relates to a compound of structural formula L1 characterized in that it comprises a phosphine-phosphite ligand linked to polystyrene, a stereogenic carbon center to the phosphino group, and where R1, R2, R3a and R3b are independently linear aryl or alkyl groups , branched or cyclic, with R3a and R3b being the same, X is an alkyl chain or a polyethylene glycol chain and PS is a vinyl and divinylbenzene copolymer linked by one of its aromatic rings to the substituent X.
R2 R1 R2 R1
P P
R3a R3a
X X
OOR
OPS PAHO
OP O OP O
R3b R3b
L1 L1
De acuerdo con un modo de realización preferente, el compuesto de fórmula estructural L1 de la presente invención se caracteriza porque PS es un copolímero de estireno y divinilbenceno en el que este copolímero está unido al ligando fosfina-fosfito a través del sustituyente X según la estructura L2, en la que m varía entre 0.01 y 0.30, n varía entre 0.70 y 0.98, y p entre 0.01 y 0.10, siendo la suma de m, n y p igual a 1.00. According to a preferred embodiment, the compound of structural formula L1 of the present invention is characterized in that PS is a styrene and divinylbenzene copolymer in which this copolymer is attached to the phosphine-phosphite ligand through substituent X according to the structure L2, in which m varies between 0.01 and 0.30, n varies between 0.70 and 0.98, and p between 0.01 and 0.10, with the sum of m, n and p being equal to 1.00.
De forma aún más preferentemente, m varía entre 0.10 y 0.20, n varía entre 0.7 y 0.98, y p entre 0.01 y 0.05, siendo la suma de m, n y p igual a 1.00. Even more preferably, m varies between 0.10 and 0.20, n varies between 0.7 and 0.98, and p between 0.01 and 0.05, the sum of m, n and p being equal to 1.00.
De acuerdo con un modo de realización preferente adicional, el compuesto de fórmula estructural L1 de la 5 presente invención, donde PS puede tener una estructura L2 tal como se ha definido anteriormente, se caracteriza porque X es una cadena alquílica C1-C5 o una cadena de polietilenglicol. According to a further preferred embodiment, the compound of structural formula L1 of the present invention, where PS can have a structure L2 as defined above, is characterized in that X is a C1-C5 alkyl chain or a chain of polyethylene glycol.
De acuerdo con otro modo de realización preferente, el compuesto de la presente invención se caracteriza porque R1 y R2 se eligen entre el grupo formado por isopropilo, ciclohexilo, fenilo, 4-metilfenilo y 3,5-dimetilfenilo; y el grupo P(OR3a)(OR3b) corresponde a la estructura According to another preferred embodiment, the compound of the present invention is characterized in that R1 and R2 are selected from the group consisting of isopropyl, cyclohexyl, phenyl, 4-methylphenyl and 3,5-dimethylphenyl; and the group P (OR3a) (OR3b) corresponds to the structure
P P
que comprende un grupo bifenilo con quiralidad axial en el que R4 es hidrógeno o alquilo. comprising a biphenyl group with axial chirality in which R4 is hydrogen or alkyl.
Preferentemente R4 es hidrógeno o un alquilo C1-C10, más preferentemente hidrógeno o terc-butilo. Preferably R4 is hydrogen or a C1-C10 alkyl, more preferably hydrogen or tert-butyl.
De acuerdo con otro modo de realización preferente, el compuesto de fórmula estructural L1 de la presente invención se caracteriza porque R1 y R2 se eligen entre el grupo formado por isopropilo, ciclohexilo, fenilo, 415 metilfenilo y 3,5-dimetilfenilo; y el grupo P(OR3a)(OR3b) corresponde a la estructura According to another preferred embodiment, the compound of structural formula L1 of the present invention is characterized in that R1 and R2 are selected from the group consisting of isopropyl, cyclohexyl, phenyl, 415 methylphenyl and 3,5-dimethylphenyl; and the group P (OR3a) (OR3b) corresponds to the structure
que comprende un grupo binaftilo con quiralidad axial en el que R5 es hidrógeno o alquilo. comprising a binaphthyl group with axial chirality in which R5 is hydrogen or alkyl.
Preferentemente, R5 es hidrógeno o alquilo C1-C10 más preferentemente hidrógeno o metilo. Preferably, R5 is hydrogen or C1-C10 alkyl more preferably hydrogen or methyl.
De acuerdo con otro modo de realización, el compuesto de fórmula estructural L1 de la presente invención 20 se caracteriza porque R1 y R2 se eligen entre el grupo formado por isopropilo, ciclohexilo, fenilo, 4-metilfenilo y 3,5dimetilfenilo; y el grupo P(OR3a)(OR3b)corresponde a la estructura According to another embodiment, the compound of structural formula L1 of the present invention is characterized in that R1 and R2 are selected from the group consisting of isopropyl, cyclohexyl, phenyl, 4-methylphenyl and 3,5-dimethylphenyl; and the group P (OR3a) (OR3b) corresponds to the structure
que comprende un grupo binaftilo parcialmente hidrogenado con quiralidad axial, en el que R6 es hidrógeno o alquilo. comprising a partially hydrogenated binaphthyl group with axial chirality, wherein R6 is hydrogen or alkyl.
Preferentemente R6 es hidrógeno o un alquilo C1-C10, más preferentemente hidrógeno, terc-butilo o metilo. Preferably R6 is hydrogen or a C1-C10 alkyl, more preferably hydrogen, tert-butyl or methyl.
De acuerdo con otro modo de realización preferente, el compuesto de fórmula estructural L1 de la presente 5 invención se caracteriza porque R1 y R2 se eligen entre el grupo formado por isopropilo, ciclohexilo, fenilo, 4metilfenilo y 3,5-dimetilfenilo; y el grupo P(OR3a)(OR3b)corresponde a la estructura According to another preferred embodiment, the compound of structural formula L1 of the present invention is characterized in that R1 and R2 are selected from the group consisting of isopropyl, cyclohexyl, phenyl, 4-methylphenyl and 3,5-dimethylphenyl; and the group P (OR3a) (OR3b) corresponds to the structure
R7 R7
que comprende un grupo dialquilo cíclilo con dos centros estereogénicos, en el que R7 es un grupo arilo. which comprises a cyclyl dialkyl group with two stereogenic centers, wherein R7 is an aryl group.
Preferentemente, R7 se elige entre el grupo formado por fenilo, 3,5-dimetilfenilo, 1-naftilo, 2-naftilo y 910 antranilo. Preferably, R7 is selected from the group consisting of phenyl, 3,5-dimethylphenyl, 1-naphthyl, 2-naphthyl and 910 anthranyl.
Un aspecto adicional de la presente invención es un catalizador que comprende un metal elegido entre rodio, rutenio e iridio y el compuesto de fórmula estructural L1 tal como se describe en la presente solicitud de patente. Preferentemente, el catalizador comprende rodio y el compuesto de fórmula estructural L1 de la presente invención. A further aspect of the present invention is a catalyst comprising a metal chosen from rhodium, ruthenium and iridium and the compound of structural formula L1 as described in the present patent application. Preferably, the catalyst comprises rhodium and the compound of structural formula L1 of the present invention.
15 Otro aspecto adicional de la presente invención es un procedimiento de obtención del compuesto de fórmula estructural L1 que comprende las etapas de: Another additional aspect of the present invention is a process for obtaining the compound of structural formula L1 comprising the steps of:
a) reacción de un epóxido soportado de fórmula L4 con una fuente de fosfina secundaria de fórmula – P(R1)(R2), donde R1 y R2 tienen el mismo significado que en L1, opcionalmente en presencia de una base; y a) reaction of a supported epoxide of formula L4 with a secondary phosphine source of formula-P (R1) (R2), where R1 and R2 have the same meaning as in L1, optionally in the presence of a base; Y
R2 R1 R2 R1
P P
OX OX
X+ -P(R1)(R2)OPS OPS X + -P (R1) (R2) OPS OPS
O OR
H H
L4 L3L4 L3
b) reacción del compuesto hidroxifosfina de fórmula L3 obtenido en la etapa anterior con un compuesto de fórmula Y-P(OR3a)(OR3b), donde Y es un halógeno y R3a y R3b tienen el mismo significado que en L1, en presencia de una base. b) reaction of the hydroxyphosphine compound of formula L3 obtained in the previous step with a compound of formula Y-P (OR3a) (OR3b), where Y is a halogen and R3a and R3b have the same meaning as in L1, in the presence of a base.
R2 R2 R2 R2
R1 R1
R1 R1
P P
P P
- PS $
- X O O H + Y-P(OR3a)(OR3b) PS X O O P O O R3a R3b X OR Or h + Y-P (OR3a) (OR3b) $ X OR OR P O o R3a R3b
- L3 L3
- L1 L1
De acuerdo con un modo de realización preferente, el procedimiento de obtención del compuesto de fórmula estructural L1 de la presente invención puede utilizar como fuente de fosfina secundaria Z-P(R1)(R2) o ZP(BH3)(R1)(R2), donde Z se elige entre hidrógeno o un metal alcalino, alcalinotérreo o Zn, preferentemente Na, Li, K, Mg o Zn; y R1 y R2 tienen el mismo significado que en L1. According to a preferred embodiment, the process for obtaining the compound of structural formula L1 of the present invention can use ZP (R1) (R2) or ZP (BH3) (R1) (R2) as a secondary phosphine source, where Z is chosen from hydrogen or an alkali metal, alkaline earth metal or Zn, preferably Na, Li, K, Mg or Zn; and R1 and R2 have the same meaning as in L1.
Cuando Z es hidrógeno, la etapa a) tiene lugar en presencia de una base, preferentemente un alquillitio. When Z is hydrogen, step a) takes place in the presence of a base, preferably an alkyl lithium.
De acuerdo con otro modo de realización preferente, la etapa a) del procedimiento de obtención del compuesto de fórmula estructural L1 de la presente invención tiene lugar en un disolvente orgánico adecuado, más preferentemente este disolvente puede ser un éter como, por ejemplo, THF o éter dietílico. According to another preferred embodiment, step a) of the process for obtaining the compound of structural formula L1 of the present invention takes place in a suitable organic solvent, more preferably this solvent can be an ether such as THF or diethyl ether.
De acuerdo con otro modo de realización preferente, la etapa a) del procedimiento de obtención del compuesto de fórmula estructural L1 tal como se ha descrito anteriormente puede tener lugar entre -20 y -80 ºC. According to another preferred embodiment, step a) of the process for obtaining the compound of structural formula L1 as described above can take place between -20 and -80 ° C.
De acuerdo con otro modo de realización preferente, la etapa a) del procedimiento de obtención del compuesto de fórmula estructural L1 tal como se ha descrito anteriormente puede tener lugar en atmósfera inerte, más preferentemente en atmósfera de nitrógeno o argón. According to another preferred embodiment, step a) of the process for obtaining the compound of structural formula L1 as described above can take place in an inert atmosphere, more preferably in a nitrogen or argon atmosphere.
Adicionalmente, el procedimiento de obtención del compuesto de fórmula estructural L1 de la presente invención puede incluir una etapa adicional de tratamiento de la hidroxifosfina soportada de fórmula L3 con agua y un alcohol, más preferentemente con agua y metanol. Additionally, the process for obtaining the compound of structural formula L1 of the present invention may include an additional step of treating the supported hydroxyphosphine of formula L3 with water and an alcohol, more preferably with water and methanol.
De acuerdo con otro modo de realización preferente, el compuesto Y-P(OR3a)(OR3b) utilizado en la etapa b) se caracteriza porque Y es cloro. According to another preferred embodiment, the compound Y-P (OR3a) (OR3b) used in step b) is characterized in that Y is chlorine.
De acuerdo con otro modo de realización preferente, la etapa b) del procedimiento de obtención del compuesto de fórmula estructural L1 de la presente invención puede tener lugar en presencia de una base orgánica, preferentemente piridina o trietilamina. According to another preferred embodiment, step b) of the process for obtaining the compound of structural formula L1 of the present invention can take place in the presence of an organic base, preferably pyridine or triethylamine.
De acuerdo con otro modo de realización preferente, la etapa b) del procedimiento de obtención del compuesto de fórmula estructural L1 tal como se ha descrito anteriormente puede tener lugar en un disolvente orgánico adecuado, preferentemente en diclorometano, tolueno o THF. According to another preferred embodiment, step b) of the process for obtaining the compound of structural formula L1 as described above can take place in a suitable organic solvent, preferably in dichloromethane, toluene or THF.
De acuerdo con otro modo de realización preferente, la etapa b) del procedimiento de obtención del compuesto de fórmula estructural L1 tal como se ha descrito anteriormente puede tener lugar en un intervalo de temperatura entre -20 y 100 ºC. According to another preferred embodiment, step b) of the process for obtaining the compound of structural formula L1 as described above can take place in a temperature range between -20 and 100 ° C.
De acuerdo con otro modo de realización preferente, la etapa b) del procedimiento de obtención del compuesto de fórmula estructural L1 tal como se ha descrito anteriormente puede tener lugar en atmósfera inerte, preferentemente en atmósfera de nitrógeno o argón. According to another preferred embodiment, step b) of the process for obtaining the compound of structural formula L1 as described above can take place in an inert atmosphere, preferably in a nitrogen or argon atmosphere.
De acuerdo con otro modo de realización preferente, el procedimiento de obtención del compuesto de fórmula estructural L1 de la presente invención puede incluir, cuando la fuente de fosfina secundaria es ZP(BH3)(R1)(R2), una etapa de desboronación. Preferentemente en esta etapa adicional se utiliza un agente de desboronación como, por ejemplo, DABCO o dietilamina. According to another preferred embodiment, the process for obtaining the compound of structural formula L1 of the present invention may include, when the secondary phosphine source is ZP (BH3) (R1) (R2), an overflow stage. Preferably, at this additional stage, an overflow agent is used, such as DABCO or diethylamine.
Adicionalmente, el procedimiento de obtención del compuesto de fórmula estructural L1 de la presente invención puede comprender una etapa adicional de lavado con un disolvente orgánico adecuado, preferentemente diclorometano, THF, éter dietílico o tolueno, para obtener el compuesto de fórmula estructural L1. Additionally, the process for obtaining the compound of structural formula L1 of the present invention may comprise an additional washing step with a suitable organic solvent, preferably dichloromethane, THF, diethyl ether or toluene, to obtain the compound of structural formula L1.
El epóxido enlazado a la resina de poliestireno de fórmula L4, se puede obtener por condensación del glicidol con una resina de poliestireno funcionalizada, como por ejemplo, pero no exclusivamente, las resinas comerciales que contienen sustituyentes bromo butilo, o polietilenglicol. The epoxy bonded to the polystyrene resin of formula L4 can be obtained by condensation of glycidol with a functionalized polystyrene resin, such as, but not exclusively, commercial resins containing bromine butyl substituents, or polyethylene glycol.
Otro aspecto adicional de la presente invención es el procedimiento de obtención del catalizador que comprende un metal elegido entre rodio, rutenio e iridio y el compuesto de fórmula estructural L1 de la presente invención. Dicho procedimiento comprende la reacción del del compuesto de fórmula L1 tal como se define en la presente solicitud de patente con un complejo metálico precursor del metal elegido entre rodio, rutenio e iridio. Preferentemente, el complejo metálico precursor comprende rodio. Another additional aspect of the present invention is the process for obtaining the catalyst comprising a metal chosen from rhodium, ruthenium and iridium and the compound of structural formula L1 of the present invention. Said process comprises the reaction of the compound of formula L1 as defined in the present patent application with a metal precursor complex of the metal chosen from rhodium, ruthenium and iridium. Preferably, the precursor metal complex comprises rhodium.
De acuerdo con un modo de realización preferente, el precursor metálico de rodio puede comprender ligandos como carboxilato, alcóxido, haluro, alquilo, arilo, olefina o diolefina. Preferentemente, el complejo precursor puede ser [Rh(COD)Cl]2, [Rh(COD)2]X´ o Rh(acac)(CO)2 Rh(acac)(COD), donde X´ es un contranión, preferentemente BF4-, ClO4-, SbF6-, CF3SO3-o BAr4-, y donde Ar representa arilo, COD representa 1,5-ciclooctadieno y acac representa acetilacetonato. According to a preferred embodiment, the rhodium metal precursor may comprise ligands such as carboxylate, alkoxide, halide, alkyl, aryl, olefin or diolefin. Preferably, the precursor complex can be [Rh (COD) Cl] 2, [Rh (COD) 2] X´ or Rh (acac) (CO) 2 Rh (acac) (COD), where X´ is a counterion, preferably BF4-, ClO4-, SbF6-, CF3SO3-or BAr4-, and where Ar represents aryl, COD represents 1,5-cyclooctadiene and acac represents acetylacetonate.
Otro aspecto adicional de la presente invención es la utilización del catalizador de rodio, rutenio o iridio definido anteriormente en la hidrogenación asimétrica de olefinas, cetonas e iminas mediante catálisis heterogénea. Another additional aspect of the present invention is the use of the rhodium, ruthenium or iridium catalyst defined above in the asymmetric hydrogenation of olefins, ketones and imines by heterogeneous catalysis.
De acuerdo con un modo de realización preferente, el catalizador de rodio, rutenio o iridio definido anteriormente se puede utilizar en la hidrogenación asimétrica de olefinas. According to a preferred embodiment, the rhodium, ruthenium or iridium catalyst defined above can be used in the asymmetric hydrogenation of olefins.
Mas preferentemente, el procedimiento de hidrogenación de olefinas de la presente invención comprende las siguientes etapas: More preferably, the olefin hydrogenation process of the present invention comprises the following steps:
- --
- (a) adición previa de un precursor del catalizador en el medio de reacción, (a) prior addition of a catalyst precursor in the reaction medium,
- --
- (b) adición de la olefina a hidrogenar disuelta en un disolvente orgánico, (b) adding the olefin to be hydrogenated dissolved in an organic solvent,
- --
- (c) activación del precursor del catalizador por reacción, (c) activation of the catalyst precursor by reaction,
- --
- (d) reacción de la olefina con el catalizador, (d) reaction of the olefin with the catalyst,
- --
- (e) separación del catalizador por métodos físicos, (e) catalyst separation by physical methods,
- --
- (f) reutilización del catalizador mediante la adición de una nueva disolución de olefina, seguida de las (f) catalyst reuse by adding a new olefin solution, followed by the
etapas c) a e). stages c) to e).
Preferentemente, la olefina puede disolverse en diclorometano, tetrahidrofurano, 2-metiltetrahidrofurano, benceno, tolueno, metanol o mezclas. Así mismo, la concentración de olefina en dicho disolvente orgánico puede variar entre 0.01 M y 2 M. Preferably, the olefin can be dissolved in dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, toluene, methanol or mixtures. Likewise, the concentration of olefin in said organic solvent can vary between 0.01 M and 2 M.
Se prefiere que el precursor del catalizador se active por reacción con hidrógeno. De forma más preferente la activación puede tener lugar a una presión entre 1 y 100 atmósferas, y de forma aún más preferente a una temperatura entre -20 y 100 ºC. It is preferred that the catalyst precursor is activated by reaction with hydrogen. More preferably, the activation can take place at a pressure between 1 and 100 atmospheres, and even more preferably at a temperature between -20 and 100 ° C.
Preferentemente, el compuesto hidrogenado obtenido se separa del medio de reacción por decantación o filtración del catalizador insoluble. Preferably, the hydrogenated compound obtained is separated from the reaction medium by decantation or filtration of the insoluble catalyst.
De acuerdo con un modo de realización preferente, las olefinas que se hidrogenan por el procedimiento de la presente invención tienen una estructura L5 According to a preferred embodiment, the olefins that are hydrogenated by the process of the present invention have an L5 structure
R8 R8
L5 L5
donde where
R8 R9 y R10 son independientemente H; grupos arilo; alquilo lineal, ramificado o cíclico, donde los grupos arilo o alquilo están opcionalmente funcionalizados; COOH; COOR12 donde R12 es alquilo o arilo; CN; o P(O)(OR13)2 donde R13 es H, alquilo o arilo; R8 R9 and R10 are independently H; aryl groups; linear, branched or cyclic alkyl, where the aryl or alkyl groups are optionally functionalized; COOH; COOR12 where R12 is alkyl or aryl; CN; or P (O) (OR13) 2 where R13 is H, alkyl or aryl;
Y es un átomo de oxígeno, un grupo NH o CH2; Y is an oxygen atom, an NH or CH2 group;
y R11 es un grupo alquilo arilo, alcóxido, arilóxido o dialquilamino. EJEMPLO 1. Anclaje del Glicidol en una resina de poliestireno. Síntesis del epóxido soportado (R)-4 and R11 is an aryl, alkoxide, aryloxide or dialkylamino alkyl group. EXAMPLE 1. Anchoring glycidol in a polystyrene resin. Synthesis of the supported epoxide (R) -4
0.53 g de suspensión de hidruro de sodio en aceite mineral (suspensión al 60 %, 13.3 mmol) se lavan con THF (10 0.53 g of sodium hydride suspension in mineral oil (60% suspension, 13.3 mmol) are washed with THF (10
5 mL), se secan a vacío y se suspenden en dimetiformamida (15 mL). Sobre la suspensión enfriada a 0 ºC se añade (R)-Glicidol (0,987g, 13,3mmol) gota a gota. La mezcla se agitó a 0º C mediante el uso de un agitador suspendido durante 1 h y posteriormente añadida sobre una suspensión de 3.0 g de polímero estireno-divinilbenceno con 1 % de entrecruzamiento funcionalizado (1.1 mmol/g de resina) con grupos bromobutilo. La mezcla resultante se agitó durante 3 días a temperatura ambiente y posteriormente se dejó decantar la resina. El líquido sobrenadante se 5 mL), dried in vacuo and suspended in dimethylformamide (15 mL). On the suspension cooled to 0 ° C (R) -Glycidol (0.987g, 13.3mmol) is added dropwise. The mixture was stirred at 0 ° C by using a stirrer suspended for 1 h and subsequently added on a 3.0 g suspension of styrene-divinylbenzene polymer with 1% functionalized crosslinking (1.1 mmol / g resin) with bromobutyl groups. The resulting mixture was stirred for 3 days at room temperature and then the resin was allowed to decant. The supernatant liquid is
10 eliminó y el sólido obtenido se trató con 25 mL de metanol. El sólido volvió a separarse por decantación y posteriormente se lavó con porciones de 10 mL de metanol (2), dimetilformamida (2), tetrahidrofurano (2), éter dietílico (2) y diclorometano (2) y finalmente secado a vacío. Rendimiento 2,48 g (83 %). RMN 13C{1H} (fase gel, 75 MHz, CDCl3, ppm) 5 = 27.8, 29.2, 35.5, 40.4, 44.1, 50.7, 71.28, 76.5, 128.0. 10 removed and the solid obtained was treated with 25 mL of methanol. The solid was separated again by decantation and subsequently washed with 10 mL portions of methanol (2), dimethylformamide (2), tetrahydrofuran (2), diethyl ether (2) and dichloromethane (2) and finally dried under vacuum. Yield 2.48 g (83%). 13C NMR {1H} (gel phase, 75 MHz, CDCl3, ppm) 5 = 27.8, 29.2, 35.5, 40.4, 44.1, 50.7, 71.28, 76.5, 128.0.
EJEMPLO 2. Síntesis del epóxido soportado (S)-4. EXAMPLE 2. Synthesis of the supported epoxide (S) -4.
El epóxido (S)-4 se preparó a partir del (S)-glicidol de manera análoga a la descrita en la preparación del epóxido (R)-4. Rendimiento: 83 %. Epoxide (S) -4 was prepared from (S) -glycidol analogously to that described in the preparation of epoxide (R) -4. Yield: 83%.
EJEMPLO 3. Síntesis de la hidroxifosfina (R)-3. EXAMPLE 3. Synthesis of hydroxyphosphine (R) -3.
Sobre una suspensión de 1.0 g (1,1 mmol) del epóxido (R)-4 en 15 mL de tetrahidrofurano agitada por medio de un agitador suspendido, se añade una disolución de difenilfosfina (0,282; 1,68mmol; 1,5eq) en tetrahidrofurano (20 mL). La mezcla resultante se enfrió a -78 ºC y sobre la misma se añadio lentamente n-BuLi (1,05ml 1,6M en hexano). Se 5 deja a la mezcla alcanzar la temperatura ambiente y se agita durante 16 h. El sólido resultante se separa por decantación, se trató con una gota de agua desoxigenada y metanol (10 mL), se agitó la mezcla resultante durante 0,5 h y el sobrenadante se separó por decantación. El sólido resultante se lavó con porciones de 10 mL de metanol (2), tetrahidrofurano (3), diclorometano (2), éter dietílico (2) y finalmente secado a vacío. Rendimiento 1,08 g (90 %). RMN 13C{1H} (fase gel, 75 MHz, CDCl3, ppm) 5 = 28.0, 29.3, 33.0, 35.6, 46.0, 68.5, 71.2, 75.1, 128.6, 132.5, 138.4. On a suspension of 1.0 g (1.1 mmol) of the epoxide (R) -4 in 15 mL of tetrahydrofuran stirred by means of a suspended stirrer, a diphenylphosphine solution (0.282; 1.68mmol; 1.5eq) is added in tetrahydrofuran (20 mL). The resulting mixture was cooled to -78 ° C and n-BuLi (1.05ml 1.6M in hexane) was added slowly thereto. The mixture is allowed to reach room temperature and stirred for 16 h. The resulting solid is separated by decantation, treated with a drop of deoxygenated water and methanol (10 mL), the resulting mixture is stirred for 0.5 h and the supernatant is separated by decantation. The resulting solid was washed with 10 mL portions of methanol (2), tetrahydrofuran (3), dichloromethane (2), diethyl ether (2) and finally dried under vacuum. Yield 1.08 g (90%). 13C NMR {1H} (gel phase, 75 MHz, CDCl3, ppm) 5 = 28.0, 29.3, 33.0, 35.6, 46.0, 68.5, 71.2, 75.1, 128.6, 132.5, 138.4.
10 RMN 31P{1H} (fase gel, 121 MHz, CDCl3, ppm) 5 = -24.0. 10 NMR 31P {1H} (gel phase, 121 MHz, CDCl3, ppm) 5 = -24.0.
EJEMPLO 4. Síntesis de la hidroxifosfina (S)-3. EXAMPLE 4. Synthesis of hydroxyphosphine (S) -3.
0.01 0.01
(S)-3(S) -3
OH OH
PPh2 PPh2
La hidroxifosfina (S)-3 se preparó a partir del epóxido (S)-4 de manera análoga a la descrita en la síntesis del compuesto (R)-3. Rendimiento 90 %. RMN 13C{1H} (fase gel, 75 MHz, CDCl3, ppm) 5 = 25.6, 27.9, 29.3, 33.0, 35.6, 15 40.5, 45.7, 46.0, 68.0, 68.5, 71.3, 75.2, 128.6, 132.8, 138.5. RMN 31P{1H} (fase gel, 121 MHz, CDCl3, ppm) 5 = Hydroxyphosphine (S) -3 was prepared from epoxide (S) -4 in a manner analogous to that described in the synthesis of compound (R) -3. 90% yield. 13C NMR {1H} (gel phase, 75 MHz, CDCl3, ppm) 5 = 25.6, 27.9, 29.3, 33.0, 35.6, 15 40.5, 45.7, 46.0, 68.0, 68.5, 71.3, 75.2, 128.6, 132.8, 138.5. NMR 31P {1H} (gel phase, 121 MHz, CDCl3, ppm) 5 =
24.1. 24.1.
EJEMPLO 5. Preparación del ligando fosfina-fosfito soportado (R,S)-1 Sobre una suspensión de la hidroxifosfina soportada (R)-3 y el (S)-3,3’-di-terc-butil-5,5’,6,6’,7,7’,8,8’-octahidro-1,1’binafto-2,2’-diil fosfocloridito (0.17 g, 0.37 mmol, 2.0 eq) suspendidos en diclorometano (20 mL), se añadió trietilamina (0.056 g, 0,56mmol, 3.0 equiv) y 4-dimetilaminopiridina (0.022 g, 1.0 eq). La mezcla se calentó a 50 ºC y se mantuvo a reflujo durante 24 h. La resina se filtró y se lavó con porciones de 10 mL de diclorometano (2) y éter dietílico (3) y se secó bajo vacío (0.24 g, 99 %). RMN 13C{1H} (fase gel, 75 MHz, CDCl3, ppm) 5 = 23.1, 27.3, 27.5, 29.7, 31.4, 31.6, 33.4, 34.7, 35.7, 40.6, 73.0, 127.3, 128.6, 133.0, 138.4, 144.8. 31P{1H} (fase gel, 121 MHz, CDCl3, ppm) 5 = -24.0, 136.4. EXAMPLE 5. Preparation of the supported phosphine-phosphite ligand (R, S) -1 On a suspension of the supported hydroxyphosphine (R) -3 and the (S) -3,3'-di-tert-butyl-5.5 ' , 6.6 ', 7.7', 8.8'-octahydro-1,1'binafto-2,2'-diyl phosphochloridite (0.17 g, 0.37 mmol, 2.0 eq) suspended in dichloromethane (20 mL), is added triethylamine (0.056 g, 0.56 mmol, 3.0 equiv) and 4-dimethylaminopyridine (0.022 g, 1.0 eq). The mixture was heated at 50 ° C and refluxed for 24 h. The resin was filtered and washed with 10 mL portions of dichloromethane (2) and diethyl ether (3) and dried under vacuum (0.24 g, 99%). 13C NMR {1H} (gel phase, 75 MHz, CDCl3, ppm) 5 = 23.1, 27.3, 27.5, 29.7, 31.4, 31.6, 33.4, 34.7, 35.7, 40.6, 73.0, 127.3, 128.6, 133.0, 138.4, 144.8. 31P {1H} (gel phase, 121 MHz, CDCl3, ppm) 5 = -24.0, 136.4.
EJEMPLO 6. Preparación del ligando fosfina-fosfito soportado (S,S)-1 EXAMPLE 6. Preparation of the supported phosphine-phosphite ligand (S, S) -1
Sobre una suspensión de la hidroxifosfina (S)-3 (0.2 g, 0.18 mmol) y el (S)-3,3’-di-terc-butil-5,5’,6,6’,7,7’,8,8’octahidro-1,1’-binafto-2,2’-diil fosfocloridito (0.17 g, 0.37 mmol, 2.0 eq) suspendidos en diclorometano (20 mL), se añadió piridina (0.044 g, 0,56mmol, 3.0 equiv) y 4-dimetilaminopiridina (0.022 g, 1.0 eq). La mezcla se calentó a 50 ºC y se mantuvo a reflujo durante 24 h. La resina se filtró y se lavó con porciones de 10 mL de diclorometano (2) y On a suspension of hydroxyphosphine (S) -3 (0.2 g, 0.18 mmol) and (S) -3,3'-di-tert-butyl-5.5 ', 6.6', 7.7 ', 8,8'octahydro-1,1'-binaphto-2,2'-diyl phosphochloridite (0.17 g, 0.37 mmol, 2.0 eq) suspended in dichloromethane (20 mL), pyridine (0.044 g, 0.56mmol, 3.0 equiv) and 4-dimethylaminopyridine (0.022 g, 1.0 eq). The mixture was heated at 50 ° C and refluxed for 24 h. The resin was filtered and washed with 10 mL portions of dichloromethane (2) and
15 éter dietílico (3) y se secó bajo vacío (0.24 g, 98 %). RMN 13C{1H} (fase gel, 75 MHz, CDCl3, ppm) 5 = 23.1, 27.3, 27.5, 29.4, 29.7, 31.4, 31.6, 34.7, 35.7, 40.5, 71.1, 73.5, 127.5, 128.5, 132.7, 137.8, 145.0. 31P{1H} (fase gel, 121 MHz, CDCl3, ppm) 5 = -23.5, 135.8. 15 diethyl ether (3) and dried under vacuum (0.24 g, 98%). 13C NMR {1H} (gel phase, 75 MHz, CDCl3, ppm) 5 = 23.1, 27.3, 27.5, 29.4, 29.7, 31.4, 31.6, 34.7, 35.7, 40.5, 71.1, 73.5, 127.5, 128.5, 132.7, 137.8, 145.0. 31P {1H} (gel phase, 121 MHz, CDCl3, ppm) 5 = -23.5, 135.8.
EJEMPLO 7. Preparación de un complejo de rodio con un ligando fosfina fosfito soportado. Síntesis del complejo {[Rh(COD)[(S,S)-1]}BF4. EXAMPLE 7. Preparation of a rhodium complex with a phosphite supported phosphite ligand. Synthesis of the complex {[Rh (COD) [(S, S) -1]} BF4.
Sobre una suspensión de la fosfina-fosfito soportado (S,S)-1 (0,24 g, 0,182 mmol) en diclorometano (5 mL) se añadió una disolución de [Rh(COD)2]BF4 (0,074 g, 0,182 mmol, 1.0 eq) en diclorometano (5 mL). La suspensión resultante se agitó durante 1 h. Se añadio una cantidad adicional de [Rh(COD)2]BF4 (0,005 g, 0,012 mmol). La On a suspension of the supported phosphine-phosphite (S, S) -1 (0.24 g, 0.182 mmol) in dichloromethane (5 mL) a solution of [Rh (COD) 2] BF4 (0.074 g, 0.182 mmol) was added , 1.0 eq) in dichloromethane (5 mL). The resulting suspension was stirred for 1 h. An additional amount of [Rh (COD) 2] BF4 (0.005 g, 0.012 mmol) was added. The
5 suspensión resultante se filtró y el sólido se lavó con porciones de 10 mL de diclorometano (3), éter dietílico (2) y se secó bajo vacío. El complejo soportado se obtuvo como un sólido de color naranja (0.29 g, 97 %). RMN 13C{1H} (fase gel, 75 MHz, CD2Cl2, ppm) 5 = 23.3, 27.6, 29.0, 30.0, 30.8, 32.0, 32.5, 35.4, 41.1, 68.0, 72.2, 75.0, 76.7, 96.7, 108.1, 110.9, 129.1, 135.4, 144.4. 31P{1H} (fase gel, 121 MHz, CD2Cl2, ppm) 5 = 10.8, 122.1. The resulting suspension was filtered and the solid was washed with 10 mL portions of dichloromethane (3), diethyl ether (2) and dried under vacuum. The supported complex was obtained as an orange solid (0.29 g, 97%). 13C NMR {1H} (gel phase, 75 MHz, CD2Cl2, ppm) 5 = 23.3, 27.6, 29.0, 30.0, 30.8, 32.0, 32.5, 35.4, 41.1, 68.0, 72.2, 75.0, 76.7, 96.7, 108.1, 110.9, 129.1, 135.4, 144.4. 31P {1H} (gel phase, 121 MHz, CD2Cl2, ppm) 5 = 10.8, 122.1.
EJEMPLO 8. Procedimiento característico de hidrogenación enantioselectiva. EXAMPLE 8. Characteristic procedure of enantioselective hydrogenation.
10 En un reactor de presión de vidrio de tipo Fischer-Porter equipado con un agitador magnético se añade catalizador de rodio {[Rh(COD)[(S,S)-1]}BF4. (2mg, 1,23μmol) y a continuación una disolución de (Z)-N-acetamido cinamato de metilo (0.027 g; 0,12 mmol, S/C=100) disuelto en 2mL de 2 metiltetrahidrofurano. El reactor se presurizó a 4 atm y la reacción se mantuvo en agitación durante 24 h. A continuación se detuvo la agitación y se separó el líquido sobrenadante por decantación. La disolución obtenida se evaporó hasta sequedad. El análisis mediante RMN de 1H 10 A rhodium catalyst {[Rh (COD) [(S, S) -1]} BF4 is added to a Fischer-Porter glass pressure reactor equipped with a magnetic stirrer. (2mg, 1.23μmol) and then a solution of (Z) -N-acetamido methyl cinnamate (0.027g; 0.12mmol, S / C = 100) dissolved in 2mL of 2 methyltetrahydrofuran. The reactor was pressurized at 4 atm and the reaction was kept under stirring for 24 h. The stirring was then stopped and the supernatant liquid was separated by decantation. The solution obtained was evaporated to dryness. 1 H NMR analysis
15 indica la formación del éster metílico de la N-Acetylfenilalanina con una conversión del 97 %. El exceso enantiomérico de este producto (82 % ee) se determinó por cromatografía HPLC con una columna quiral (Chiralcel OD-H, n-hexano:isopropanol 90:10, 1.0 mL/min). t1(R)= 9.7 min), t2(S) = 12.2 min. 15 indicates the formation of the methyl ester of N-Acetylfenylalanine with a conversion of 97%. The enantiomeric excess of this product (82% ee) was determined by HPLC chromatography with a chiral column (Chiralcel OD-H, n-hexane: isopropanol 90:10, 1.0 mL / min). t1 (R) = 9.7 min), t2 (S) = 12.2 min.
EJEMPLO 9. Reutilización del catalizador en una hidrogenación enantioselectiva. EXAMPLE 9. Reuse of the catalyst in an enantioselective hydrogenation.
Al sólido resultante del ejemplo 8 tras la reacción de hidrogenación, se añade una disolución de (Z)-N-acetamido To the solid resulting from Example 8 after the hydrogenation reaction, a solution of (Z) -N-acetamido is added
20 cinamato de metilo (0.027 g; 0,12 mmol, S/C=100) disuelto en 2mL. La mezcla resultante se agita durante 24 h y el producto de la reacción se purifica y analiza como se ha descrito en el ejemplo 5. En el segundo ciclo el rendimiento de la reacción es del 94 % y el exceso enantiomérico del 82 % ee. El solido resultante vuelve a utilizarse en un tercer ciclo de reacción de hidrogenación, que conduce al producto de la reacción con una conversión del 85 % y un exceso enantiomérico del 70 % ee. 20 methyl cinnamate (0.027 g; 0.12 mmol, S / C = 100) dissolved in 2mL. The resulting mixture is stirred for 24 h and the reaction product is purified and analyzed as described in Example 5. In the second cycle the reaction yield is 94% and the enantiomeric excess of 82% ee. The resulting solid is reused in a third hydrogenation reaction cycle, which leads to the reaction product with a conversion of 85% and an enantiomeric excess of 70% ee.
Claims (21)
- 4.Four.
- Un compuesto de fórmula estructural L1 según una cualquiera de las reivindicaciones 1 a 3, caracterizado porque X es una cadena alquílica C1-C5 o una cadena de polietilenglicol. A compound of structural formula L1 according to any one of claims 1 to 3, characterized in that X is a C1-C5 alkyl chain or a polyethylene glycol chain.
- 5.5.
- Un compuesto de fórmula estructural L1 según una cualquiera de las reivindicaciones 1 a 4, caracterizado porque R3a y R3b son iguales. A compound of structural formula L1 according to any one of claims 1 to 4, characterized in that R3a and R3b are the same.
- 9.9.
- Un compuesto de fórmula estructural L1 según la reivindicación 8, caracterizado porque R5 es hidrógeno o metilo. A compound of structural formula L1 according to claim 8, characterized in that R5 is hydrogen or methyl.
- 10.10.
- Un compuesto de fórmula estructural L1 según una cualquiera de las reivindicaciones 1 a 5, caracterizado porque R1 y R2 se eligen entre el grupo formado por isopropilo, ciclohexilo, fenilo, 4-metilfenilo y 3,5-dimetilfenilo; y el grupo P(OR3a)(OR3b) corresponde a la estructura A compound of structural formula L1 according to any one of claims 1 to 5, characterized in that R1 and R2 are selected from the group consisting of isopropyl, cyclohexyl, phenyl, 4-methylphenyl and 3,5-dimethylphenyl; and the group P (OR3a) (OR3b) corresponds to the structure
- 11.eleven.
- Un compuesto de fórmula estructural L1 según la reivindicación 10, caracterizado porque R6 se elige entre hidrógeno, terc-butilo y metilo. A compound of structural formula L1 according to claim 10, characterized in that R6 is selected from hydrogen, tert-butyl and methyl.
- 12.12.
- Un compuesto de fórmula estructural L1 según una cualquiera de las reivindicaciones 1 a 5, caracterizado A compound of structural formula L1 according to any one of claims 1 to 5, characterized
- 21.twenty-one.
- Utilización del catalizador tal como se define en una cualquiera de las reivindicaciones 14 o 15 para la hidrogenación asimétrica mediante catálisis heterogénea de olefinas. Use of the catalyst as defined in any one of claims 14 or 15 for asymmetric hydrogenation by heterogeneous olefin catalysis.
- 22. 22
- Utilización del catalizador según la reivindicación 21, caracterizado porque el procedimiento de hidrogenación de olefinas comprende las siguientes etapas: -(a) adición previa de un precursor del catalizador en el medio de reacción, -(b) adición de la olefina a hidrogenar disuelta en un disolvente orgánico, -(c) activación del precursor del catalizador por reacción, -(d) reacción de la olefina con el catalizador, -(e) separación del compuesto hidrogenado, Use of the catalyst according to claim 21, characterized in that the olefin hydrogenation process comprises the following steps: - (a) prior addition of a catalyst precursor in the reaction medium, - (b) addition of the olefin to be hydrogenated dissolved in an organic solvent, - (c) activation of the catalyst precursor by reaction, - (d) reaction of the olefin with the catalyst, - (e) separation of the hydrogenated compound,
- 23.2. 3.
- Utilización de un catalizador según una cualquiera de las reivindicaciones 21 o 22, caracterizado porque las olefinas a hidrogenar tienen una estructura L5 Use of a catalyst according to any one of claims 21 or 22, characterized in that the olefins to be hydrogenated have an L5 structure
- Categoría Category
- 56 Documentos citados Reivindicaciones afectadas 56 Documents cited Claims Affected
- Y Y
- WO 2009030626 A1 (INSTITUT CATALÀ D’INVESTIGACIÓ QUÍMICA) 12.03.2009, todo el documento. 1-23 WO 2009030626 A1 (INSTITUT CATALÀ D’INVESTIGACIÓ QUÍMICA) 12.03.2009, the whole document. 1-23
- Y Y
- K. NOZAKI et al., “Asymmetric hydroformylation of olefins in a highly crosslinked polymer matrixes”, Bull. Chem. Soc. Jpn., 1999, vol. 72, nº 8, páginas 1911-1918. 1-23 K. NOZAKI et al., "Asymmetric hydroformylation of olefins in a highly crosslinked polymer matrixes", Bull. Chem. Soc. Jpn., 1999, vol. 72, No. 8, pages 1911-1918. 1-23
- A TO
- I. ARRIBAS et al., ”Chiral phosphine-phosphite ligands with a substituted ethane backbone. Influence of conformational effects in rhodium-catalyzed asymmetric olefin hydrogenation and hydroformylation reactions”, Organometallics, 2010, vol. 29, nº 22, páginas 5791-5804. 1-23 I. TOP et al., ”Chiral phosphine-phosphite ligands with a substituted ethane backbone. Influence of conformational effects in rhodium-catalyzed asymmetric olefin hydrogenation and hydroformylation reactions ”, Organometallics, 2010, vol. 29, no. 22, pages 5791-5804. 1-23
- A TO
- T. ROBERT et al., “Phenol-derived chiral phosphine-phosphite ligands in the rhodium-catalyzed enantioselective hydrogenation of functionalized olefins”, Tetrahedron: Asymmetry, 2010, vol. 21, páginas 2671-2674. 1-23 T. ROBERT et al., "Phenol-derived chiral phosphine-phosphite ligands in the rhodium-catalyzed enantioselective hydrogenation of functionalized olefins", Tetrahedron: Asymmetry, 2010, vol. 21, pages 2671-2674. 1-23
- A TO
- D. J. BAYSTON et al., “Preparation and use of a polymer supported BINAP hydrogenation catalyst”, Journal Organic Chemistry, 1998, vol. 63, nº 9, páginas 3137-3140. 1-23 D. J. BAYSTON et al., "Preparation and use of a polymer supported BINAP hydrogenation catalyst", Journal Organic Chemistry, 1998, vol. 63, No. 9, pages 3137-3140. 1-23
- Categoría de los documentos citados X: de particular relevancia Y: de particular relevancia combinado con otro/s de la misma categoría A: refleja el estado de la técnica O: referido a divulgación no escrita P: publicado entre la fecha de prioridad y la de presentación de la solicitud E: documento anterior, pero publicado después de la fecha de presentación de la solicitud Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application
- El presente informe ha sido realizado • para todas las reivindicaciones • para las reivindicaciones nº: This report has been prepared • for all claims • for claims no:
- Fecha de realización del informe 15.10.2012 Date of completion of the report 15.10.2012
- Examinador E. Dávila Muro Página 1/4 Examiner E. Dávila Muro Page 1/4
- Novedad (Art. 6.1 LP 11/1986) Novelty (Art. 6.1 LP 11/1986)
- Reivindicaciones Reivindicaciones 1-23 SI NO Claims Claims 1-23 IF NOT
- Actividad inventiva (Art. 8.1 LP11/1986) Inventive activity (Art. 8.1 LP11 / 1986)
- Reivindicaciones Reivindicaciones 1-23 SI NO Claims Claims 1-23 IF NOT
- Documento Document
- Número Publicación o Identificación Fecha Publicación Publication or Identification Number publication date
- D01 D01
- WO 2009030626 A1 12.03.2009 WO 2009030626 A1 03/12/2009
- D02 D02
- K. NOZAKI et al., Bull. Chem. Soc. Jpn., 1999, vol. 72, nº 8, páginas 1911-1918 K. NOZAKI et al., Bull. Chem. Soc. Jpn., 1999, vol. 72, No. 8, pages 1911-1918
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Non-Patent Citations (4)
| Title |
|---|
| D. J. BAYSTON et al., ¿Preparation and use of a polymer supported BINAP hydrogenation catalyst¿, Journal Organic Chemistry, 1998, vol. 63, nº 9, páginas 3137-3140 * |
| I. ARRIBAS et al.,¿Chiral phosphine-phosphite ligands with a substituted ethane backbone. Influence of conformational effects in rhodium-catalyzed asymmetric olefin hydrogenation and hydroformylation reactions¿, Organometallics, 2010, vol. 29, nº 22, páginas 5791-5804 * |
| K. NOZAKI et al., ¿Asymmetric hydroformylation of olefins in a highly crosslinked polymer matrixes¿, Bull. Chem. Soc. Jpn., 1999, vol. 72, nº 8, páginas 1911-1918 * |
| T. ROBERT et al., ¿Phenol-derived chiral phosphine-phosphite ligands in the rhodium-catalyzed enantioselective hydrogenation of functionalized olefins¿, Tetrahedron: Asymmetry, 2010, vol. 21, páginas 2671-2674 * |
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