EP2598510A2 - Ligands for selective asymmetric hydroformylation - Google Patents
Ligands for selective asymmetric hydroformylationInfo
- Publication number
- EP2598510A2 EP2598510A2 EP11813250.5A EP11813250A EP2598510A2 EP 2598510 A2 EP2598510 A2 EP 2598510A2 EP 11813250 A EP11813250 A EP 11813250A EP 2598510 A2 EP2598510 A2 EP 2598510A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- crc
- amino
- hydroxyl
- amido
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000003446 ligand Substances 0.000 title claims description 52
- 238000007037 hydroformylation reaction Methods 0.000 title claims description 41
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 39
- 150000001336 alkenes Chemical class 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 239000003054 catalyst Substances 0.000 claims description 19
- -1 C6-Caryl Chemical group 0.000 claims description 18
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 18
- 125000003368 amide group Chemical group 0.000 claims description 18
- 230000015572 biosynthetic process Effects 0.000 claims description 15
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 238000003786 synthesis reaction Methods 0.000 claims description 14
- SJNALLRHIVGIBI-UHFFFAOYSA-N allyl cyanide Chemical compound C=CCC#N SJNALLRHIVGIBI-UHFFFAOYSA-N 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 7
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- 239000000470 constituent Substances 0.000 abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 27
- 150000001299 aldehydes Chemical class 0.000 description 26
- 125000000217 alkyl group Chemical group 0.000 description 17
- 239000010948 rhodium Substances 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 239000011550 stock solution Substances 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- ZOGYOOUMDVKYLM-UHFFFAOYSA-N phosphane phosphorous acid Chemical compound P.OP(O)O ZOGYOOUMDVKYLM-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 9
- LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical compound CCCCC=C LIKMAJRDDDTEIG-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 150000001298 alcohols Chemical class 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 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 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- GWLJTAJEHRYMCA-UHFFFAOYSA-N phospholane Chemical compound C1CCPC1 GWLJTAJEHRYMCA-UHFFFAOYSA-N 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 229910052703 rhodium Inorganic materials 0.000 description 5
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 229930015698 phenylpropene Natural products 0.000 description 4
- HJWLCRVIBGQPNF-UHFFFAOYSA-N prop-2-enylbenzene Chemical compound C=CCC1=CC=CC=C1 HJWLCRVIBGQPNF-UHFFFAOYSA-N 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- 238000004679 31P NMR spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- RVJBOIPTJJXRCT-UHFFFAOYSA-N diazaphospholidine Chemical group C1CPNN1 RVJBOIPTJJXRCT-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YBDBTBVNQQBHGJ-UHFFFAOYSA-N 1,2,3,4,5-pentafluoro-6-prop-2-enylbenzene Chemical compound FC1=C(F)C(F)=C(CC=C)C(F)=C1F YBDBTBVNQQBHGJ-UHFFFAOYSA-N 0.000 description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 2
- WBDAISHOLNEXDA-UHFFFAOYSA-N 1,2-diphenylphospholane Chemical group C1CCC(C=2C=CC=CC=2)P1C1=CC=CC=C1 WBDAISHOLNEXDA-UHFFFAOYSA-N 0.000 description 2
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-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
- 239000012298 atmosphere Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- DQTRYXANLKJLPK-UHFFFAOYSA-N chlorophosphonous acid Chemical compound OP(O)Cl DQTRYXANLKJLPK-UHFFFAOYSA-N 0.000 description 2
- 239000012973 diazabicyclooctane Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 2
- 238000007654 immersion Methods 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- PZMLXPJGXAXJGQ-UHFFFAOYSA-N iodophosphonous acid Chemical compound OP(O)I PZMLXPJGXAXJGQ-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- LFEAPEZKGMELNV-UHFFFAOYSA-N phospholane;phosphorous acid Chemical class OP(O)O.C1CCPC1 LFEAPEZKGMELNV-UHFFFAOYSA-N 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VCZQFJFZMMALHB-UHFFFAOYSA-N tetraethylsilane Chemical compound CC[Si](CC)(CC)CC VCZQFJFZMMALHB-UHFFFAOYSA-N 0.000 description 2
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- 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 2
- CVKMFSAVYPAZTQ-LURJTMIESA-N (2s)-2-methylhexanoic acid Chemical compound CCCC[C@H](C)C(O)=O CVKMFSAVYPAZTQ-LURJTMIESA-N 0.000 description 1
- GGQQNYXPYWCUHG-RMTFUQJTSA-N (3e,6e)-deca-3,6-diene Chemical compound CCC\C=C\C\C=C\CC GGQQNYXPYWCUHG-RMTFUQJTSA-N 0.000 description 1
- QXFGWQXNVDEWEE-UHFFFAOYSA-N 1,2-diphenylphospholane;phosphorous acid Chemical compound OP(O)O.C1CCC(C=2C=CC=CC=2)P1C1=CC=CC=C1 QXFGWQXNVDEWEE-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- FXPPNKAYSGWCQG-UHFFFAOYSA-N 2-acetoxypropanal Chemical compound O=CC(C)OC(C)=O FXPPNKAYSGWCQG-UHFFFAOYSA-N 0.000 description 1
- GXZALPSAOGRRNO-UHFFFAOYSA-N 2-methyl-3-(2,3,4,5,6-pentafluorophenyl)propan-1-ol Chemical compound OCC(C)CC1=C(F)C(F)=C(F)C(F)=C1F GXZALPSAOGRRNO-UHFFFAOYSA-N 0.000 description 1
- LTZKHYYXQWNXPU-UHFFFAOYSA-N 2-methyl-3-phenylpropan-1-ol Chemical compound OCC(C)CC1=CC=CC=C1 LTZKHYYXQWNXPU-UHFFFAOYSA-N 0.000 description 1
- HEPHYCJJLAUKSB-UHFFFAOYSA-N 2-methyl-3-phenylpropanal Chemical compound O=CC(C)CC1=CC=CC=C1 HEPHYCJJLAUKSB-UHFFFAOYSA-N 0.000 description 1
- LCFKURIJYIJNRU-UHFFFAOYSA-N 2-methylhexan-1-ol Chemical compound CCCCC(C)CO LCFKURIJYIJNRU-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical compound OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 1
- IQVAERDLDAZARL-UHFFFAOYSA-N 2-phenylpropanal Chemical compound O=CC(C)C1=CC=CC=C1 IQVAERDLDAZARL-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- GSDBCUROWGFXAT-UHFFFAOYSA-N 3-methyl-4-oxobutanenitrile Chemical compound O=CC(C)CC#N GSDBCUROWGFXAT-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- NECGOJWODZHPBU-UHFFFAOYSA-N 4-(2,3,4,5,6-pentafluorophenyl)butan-1-ol Chemical compound OCCCCC1=C(F)C(F)=C(F)C(F)=C1F NECGOJWODZHPBU-UHFFFAOYSA-N 0.000 description 1
- LDZLXQFDGRCELX-UHFFFAOYSA-N 4-phenylbutan-1-ol Chemical compound OCCCCC1=CC=CC=C1 LDZLXQFDGRCELX-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical class OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 125000004062 acenaphthenyl group Chemical group C1(CC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005157 alkyl carboxy group Chemical group 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 1
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 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
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000005331 diazinyl group Chemical group N1=NC(=CC=C1)* 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-M methanethiolate Chemical compound [S-]C LSDPWZHWYPCBBB-UHFFFAOYSA-M 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical compound [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003283 rhodium Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000010374 somatic cell nuclear transfer Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005413 thiopyridyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/49—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide
- C07C45/50—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide by oxo-reactions
- C07C45/505—Asymmetric hydroformylation
-
- 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
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
- B01J31/185—Phosphites ((RO)3P), their isomeric phosphonates (R(RO)2P=O) and RO-substitution derivatives thereof
-
- 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
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2495—Ligands comprising a phosphine-P atom and one or more further complexing phosphorus atoms covered by groups B01J31/1845 - B01J31/1885, e.g. phosphine/phosphinate or phospholyl/phosphonate ligands
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
- C07F9/65683—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine
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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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
-
- 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
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
- B01J2231/32—Addition reactions to C=C or C-C triple bonds
- B01J2231/321—Hydroformylation, metalformylation, carbonylation or hydroaminomethylation
-
- 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
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
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- 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
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/822—Rhodium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the invention relates to phosphine-phosphite ligands with a chiral phospholane (S,S)-diphenylphospholane and chiral or achiral biaryl phenols linked by a hydroxym ethyl bridge.
- the invention provides compounds of the formula 4:
- Olefin hydroformylation has been practiced industrially for decades for the production of commodity aldehyde intermediates. Since linear regioisomers are desired often, a major industrial focus has been the development of highly linear- selective ligands for rhodium-catalyzed hydroformylation. Several phosphorous- based ligands have been developed which exhibit sufficiently high regioselectivity for linear aldehydes for this methodology to be industrially applicable. Linear regioisomers are desired most often in the commodity chemicals sector. However, in organic synthesis of the more complex molecules used in the fine chemicals and pharmaceutical sector, there are demands for both linear and branched aldehyde regioisomers.
- the branched regioisomers of the aldehydes are also frequently preferred in optically active form; thus such products can be prepared by regioselective and enantioselective hydroformylation of olefins.
- the current state-of-the-art catalysts for enantioselective hydroformylation only deliver the branched aldehyde regioisomer for a select number of carefully chosen olefinic substrates.
- Ph-BPE has shown high activity and enantioselectivity for the asymmetric hydroformylation of selected olefins.
- Kelliphite a bisphosphite ligand was discovered to be effective for enantioselective hydroformylation after a comprehensive screen of novel ligands of this class.
- Binaphos an atropisomeric biaryl-based phosphine-phosphite has proven to be a prominent ligand for enantioselective hydroformylation with arguably the widest applicability demonstrated to date with high enantioselectivies observed with a range of terminal olefins bearing aryl, heteroaryl, alkenyl, heteroatom substituted groups, and a range of internal olefins. High enantioselectivity is a common feature in these reactions, with olefinic substrates chosen for their tendency to preferentially form the desired branched isomer giving regioselectivities of between 75% and in exceptional cases 99%.
- Rh catalysts derived from phosphine-phosphites give similar regioselectivity in the hydroformylation of olefins to simple achiral ligands such as triphenylphosphine or 1 ,2-bis-(diphenylphosphino)ethane.
- Phosphine-phosphites have been reported lacking the diphenylphospholane moiety.
- the invention provides compounds of the formula 4:
- the invention provides compounds of the formula 4:
- n and m are each independently an integer from 1 to 3;
- Ar are both independently C-6-Ci 4 aryl or Ci-Cgheteroaryl, which can be unsubstituted or substituted with one or more of the following groups: CrC 6 alkyl-, halogen, CrCehaloalkyl-, hydroxyl, hydroxyl(CrC 6 alkyl)-, H 2 N-, (C C 6 alkyl)amino-, di(Ci-C 6 alkyl)amino-, HO2C-, (CrC 6 alkoxy)carbonyl-, (d- C 6 alkyl)carboxyl-, di(CrC 6 alkyl)amido-, H 2 NC(0)-, (CrC 6 alkyl)amido-, or 0 2 N-; -Ar ⁇ -Ar 2 - is a bi(C 6 -Ci 4 aryl), bi(Ci-C 9 heteroaryl), or -(C 6 -Ci 4 aryl)-(Ci-
- the invention provides compound 3b (Fig. 3 crystal structure and Fig.4).
- Fig. 3 Crystal structure of diphenyl-phospholane-phosphite ligand 3b
- the invention provides compounds of the formulae 1 , 2a, 2b, and 3b.
- the invention provides a synthesis of 2-phenylpropanal from styrene and Syn gas in the presence of Rh catalysts derived from ligands of formula 4.
- the invention provides a synthesis of 3-methyl-4- oxobutanenitrile from allyl cyanide and Syn gas in the presence of Rh catalysts derived from ligands of formula 4.
- the invention provides a synthesis of 1 -oxopropan-2-yl acetate from vinyl acetate and Syn gas in the presence of Rh catalysts derived from ligands of formula 4.
- Table 1 are shown the results for the above hydroformylation of styrene using catalysts derived from ligands of type 4, which identified ligand 3b as the most enantioselective ligand.
- Table 1 Rh catalyzed hydroformylation of styrene
- Iigand1-3b (0.5%) , 1 mmol styrene, 3.5 ml_ toluene.
- the invention provides a regioselective synthesis of 2-methyl- 3-phenylpropan-1 -al from allyl benzene and Syngas in the presence of an Rh catalyst derived from ligands of type 4, under conditions where ligands outside the phospholane-phosphite class give no selectivity as shown in Table 2.
- BH 3 DMS is borane dimethyl sulfide complex ((CH 3 ) 2 S BH 3 ), DABCO is 1 ,4-diazabicyclo[2.2.2]octane, r. t. is room temperature, TMS-I is iodotrimethylsilane.
- % e. e means the enantiomeric excess of a substance, which is defined as the absolute difference between the mole fraction of each enantiomer.
- the number of carbon atoms present in a given group is designated "C x -C y ", where x and y are the lower and upper limits, respectively.
- a group designated as " ⁇ - ⁇ - ⁇ ” contains from 1 to 6 carbon atoms.
- the carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like. Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming from left to right the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
- arylalkyloxycabonyl refers to the group (C 6 -Ci 4 aryl)-(Ci-C 6 alkyl)-O- C(O)-. It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.
- the carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
- (Alkoxy)carbonyl refers to the group alkyl-O-C(O)-.
- Exemplary (Cr C 6 alkoxy)carbonyl groups include but are not limited to methoxy, ethoxy, n- propoxy, 1 -propoxy, n-butoxy, and t-butoxy.
- An (alkoxy)carbonyl group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, -NH 2 , (C C 6 alkyl)N-, (Ci-C 6 alkyl)(Ci-C 6 alkyl)N-, -N(C C 3 alkyl)C(0)(Ci- Cealkyl), -NHC(0)(Ci-C 6 alkyl), -NHC(0)H, -C(0)NH 2 , -C(0)NH(CrC 6 alkyl), - C(0)N(Ci-C 6 alkyl)(Ci-C 6 alkyl), -CN, C C 6 alkoxy, -C(0)OH, -C(0)0(C C 6 alkyl), - C(O)(d-C 6 alkyl), C 6 -C 14 aryl, C C 9 heteroaryl, C 3 -C 8 cycloalkyl, Ci-C 6 haloalkyl
- Alkyl- refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a C-
- C C 6 alkyl- groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
- An alkyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H 2 N-, (Ci-C 6 alkyl)amino-, di(Ci-C 6 alkyl)amino-, (C C- 6 alkyl)C(0)N(Cr C 3 alkyl)-, (C C 6 alkyl)carboxyamido-, HC(0)NH-, H 2 NC(O)-, (Ci-C 6 alkyl)NHC(0)-, di(Ci-C 6 alkyl)NC(O)-, NC-, hydroxyl, CrC 6 alkoxy-, CrC 6 alkyl-, HO 2 C-, (C C 6 alkoxy)carbonyl-, (CrC 6 alkyl)C(0)-, C 6 -C aryl-, C-i-Cgheteroaryl-, C 3 - Cscycloalkyl-, CrC 6 haloalkyl-, amino
- (Alkyl)amido- refers to a -C(0)NH- group in which the nitrogen atom of said group is attached to an alkyl group, as defined above.
- Representative examples of a (CrC 6 alkyl)amido group include, but are not limited to, - C(O)NHCH 3 , -C(0)NHCH 2 CH 3 , -C(0)NHCH 2 CH 2 CH 3 , -C(0)NHCH 2 CH 2 CH 2 CH 3l - C(0)NHCH 2 CH 2 CH 2 CH 2 CH 3 , -C(O)NHCH(CH 3 ) 2 , -C(0)NHCH 2 CH(CH 3 ) 2l - C(0)NHCH(CH 3 )CH 2 CH 3 , -C(O)NH-C(CH 3 ) 3 and -C(0)NHCH 2 C(CH 3 ) 3 .
- (Alkyl)amino- refers to an -NH group, the nitrogen atom of said group being attached to an alkyl group, as defined above.
- Representative examples of an (Ci-C 6 alkyl)amino- group include, but are not limited to CH 3 NH-, CH 3 CH 2 NH-, CH 3 CH 2 CH 2 NH-, CH 3 CH 2 CH 2 CH 2 NH-, (CH 3 ) 2 CHNH-, (CH 3 ) 2 CHCH 2 NH-, CH 3 CH 2 CH(CH 3 )NH- and (CH 3 ) 3 CNH-.
- An (alkyl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen, ⁇ 2 ⁇ -, (CrC 6 alkyl)amino-, di(CrC 6 alkyl)amino-, (Ci-C 6 alkyl)C(0)N(CrC 3 alkyl)-, (CrC 6 alkyl)carboxyamido-, HC(0)NH-, H 2 NC(0)-, (d-C 6 alkyl)NHC(0)-, di(C C 6 alkyl)NC(0)-, NC-, hydroxyl, C C 6 alkoxy-, C C 6 alkyl-, H0 2 C-, (C C 6 alkoxy)carbonyl-, (CrC 6 alkyl)C(0)-, C 6 -Ci 4 aryl-, Ci-Cgheteroaryl-, C 3 - Cscycloalkyl-, CrC 6 haloalkyl-, amino(
- Alkylcarboxy refers to an alkyl group, defined above, attached to the parent structure through the oxygen atom of a carboxyl (C(O)-O-) functionality.
- Examples of (CrC 6 alkyl)carboxy include acetoxy, ethylcarboxy, propylcarboxy, and isopentylcarboxy.
- Aryl- refers to an aromatic hydrocarbon group.
- Examples of an C 6 - Ci 4 aryl- group include, but are not limited to, phenyl, 1 -naphthyl, 2-naphthyl, 3- biphen-1 -yl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl.
- An aryl group can be unsubstituted or substituted with one or more of the following groups: CrC 6 alkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl(CrC 6 alkyl)-, H 2 N-, amino(C C 6 alkyl)-, di(CrC 6 alkyl)amino-, H0 2 C-, (Ci- C 6 alkoxy)carbonyl-, (C C 6 alkyl)carboxyl-, di(Ci-C 6 alkyl)amido-, H 2 NC(0)-, (C C 6 alkyl)amido-, or 0 2 N-.
- Di(alkyl)amido- refers to a -NC(O)- group in which the nitrogen atom of said group is attached to two alkyl groups, as defined above. Each alkyl group can be independently selected.
- Representative examples of a di(C C 6 alkyl)amido- group include, but are not limited to, -C(O)N(CH 3 ) 2 , - C(O)N(CH 2 CH 3 ) 2 , -C(O)N(CH 3 )CH 2 CH 3) -C(0)N(CH 2 CH 2 CH 2 CH 3 ) 2 , -C(0)N(CH 2 CH 3 )CH 2 CH 2 CH 3 , -C(0)N(CH 3 )CH(CH 3 ) 2l -C(O)N(CH 2 CH 3 )CH 2 CH(CH 3 ) 2 , - C(0)N(CH(CH 3 )CH 2 CH 3 ) 2> -C(O)N(CH 2 CH 3 )C(CH 3
- Di(alkyl)amino- refers to a nitrogen atom attached to two alkyl groups, as defined above. Each alkyl group can be independently selected.
- Representative examples of an di(CrC 6 alkyl)amino- group include, but are not limited to, - N(CH 3 ) 2 , -N(CH 2 CH 3 )(CH 3 ), -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , N(CH 2 CH 2 CH 2 CH 3 ) 2 , -N(CH(CH 3 ) 2 ) 2 , -N(CH(CH 3 ) 2 )(CH 3 ), -N(CH 2 CH(CH 3 ) 2 ) 2 , - NH(CH(CH 3 )CH 2 CH 3 ) 2 , -N(C(CH 3 ) 3 ) 2, -N(C(CH 3 ) 3 )(CH 3 ), and -N(CH 3 )(CH 2
- the two alkyl groups on the nitrogen atom when taken together with the nitrogen to which they are attached, can form a 3- to 7- membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with -N(H)-, -N(CrC 6 alkyl)-, -N(C 3 -C 8 cycloalkyl)-, -N(C 6 -C 4 aryl)-, -N(d- Cgheteroaryl)-, -N(amino(Ci-C 6 alkyl))-, -N(C 6 -Ci 4 arylamino)-, -O-, -S-, -S(O)-, or - S(0) 2 -.
- Halo or halogen refers to fluorine, chlorine, bromine, or iodine.
- Haloalkyl- refers to an alkyl group, as defined above, wherein one or more of the Ci-C 6 alkyl group's hydrogen atoms has been replaced with -F, -CI, - Br, or -I. Each substitution can be independently selected from -F, -CI, -Br, or -I.
- Ci-C 6 haloalkyl- group include, but are not limited to, -CH 2 F, -CCI 3 , -CF 3 , CH 2 CF 3 , -CH 2 CI, -CH 2 CH 2 Br, -CH 2 CH 2 I, -CH 2 CH 2 CH 2 F, - CH 2 CH 2 CH 2 CI, -CH 2 CH 2 CH 2 CH 2 Br, -CH 2 CH 2 CH 2 CH 2 I, -CH CH 2 CH 2 CH 2 CH 2 Br, - CH 2 CH 2 CH 2 CH 2 CH 2 I, -CH 2 CH(Br)CH 3 , -CH 2 CH(CI)CH 2 CH 3 , -CH(F)CH 2 CH 3 and - C(CH 3 ) 2 (CH 2 CI).
- Heteroaryl- refers to 5-10-membered mono and bicyclic aromatic groups containing at least one heteroatom selected from oxygen, sulfur, and nitrogen.
- monocyclic Ci -Cgheteroaryl- radicals include, but are not limited to, oxazinyl, thiazinyl, diazinyl, triazinyl, thiadiazoyi, tetrazinyl, imidazolyl, tetrazolyl, isoxazolyl, furanyl, furazanyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl, N-pyridyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.
- bicyclic C Cgheteroaryl- radicals include but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl, and indazolyl.
- the contemplated heteroaryl- rings or ring systems have a minimum of 5 members.
- Ci heteroaryl- radicals would include but are not limited to tetrazolyl
- C 2 heteroaryl- radicals include but are not limited to triazolyl, thiadiazoyi, and tetrazinyl
- Cgheteroaryl- radicals include but are not limited to quinolinyl and isoquinolinyl.
- a heteroaryl group can be unsubstituted or substituted with one or more of the following groups: C-i-C 6 alkyl-, halogen, CrC 6 haloalkyl-, hydroxyl, Ci-C 6 hydroxylalkyl-, H 2 N-, amino(Ci-C 6 alkyl), di(Ci-C 6 alkyl)amino-, -COOH, (CrC 6 alkoxy)carbonyl-, (CrC 6 alkyl)carboxyl-, di(CrC 6 alkyl)ainnido-, H 2 NC(0)-, (Ci-C 6 alkyl)amido-, or 0 2 N-.
- “Hydroxylalkyl-” refers to an alkyl group, as defined above, wherein one or more of the C-i-Cealkyl group's hydrogen atoms have been replaced with hydroxyl groups.
- Examples of hydroxyl (C Cealkyl)- moieties include, for example, - CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 OH, -CH 2 CH(OH)CH 3 , - CH(CH 3 )CH 2 OH and higher homologs.
- leaving group refers to an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a specified reaction.
- the leaving group is bromide.
- the leaving group is trimethylamine.
- the electrophilic nitration of benzene it is H + .
- the term has meaning only in relation to a specified reaction. Examples of leaving groups include, for example, carboxylates ⁇ i.e.
- EXAMPLE 6 Regioselective and enantioselective hydroformylation of Vinyl acetate. This reaction was run in an Argonaut Endeavour parallel autoclave system (AE). The vessels of the AE were flushed with Syngas. Stock solutions of [Rh(acac)(CO) 2 ] and ligand 3a were prepared as 1 mg per ml_ solution in toluene. 1 ml of the rhodium stock solution, (1 mg, 0.004 mmol, 0.4 mol%) and a stock solution equivalent to 0.005 mmol (0.5%) of ligand 3a were added into a well in the AE. The mixture was pressurized to 5 bar Syngas and heated at 50 °C for 40 minutes.
- the pressure was then vented and the apparatus cooled to room temperature.
- the require substrate (vinyl acetate 1 mmol) was then added also as a stock solution in toluene to bring the reaction vessel up to 3.5 ml_ volume.
- the apparatus was then purged three times with Syngas, placed at 2.5 bar pressure and heated to 60 °C at constant pressure for 4 hours, after which time no further Syngas uptake was used up (>99% conversion).
- the AE was then cooled and the reaction mixture analyzed by GC in the standard protocol using a beta- Dex 225 chiral column. This along with NMR revealed that the only product present was the branched aldehyde (B / L >99:1 ) and with an e. e.. of 83 %.
- EXAMPLE 7 Regioselective and enantioselective hydroformylation of styrene. This reaction was run in an Argonaut Endeavour parallel autoclave system (AE). The vessels of the AE were flushed with Syngas. Stock solutions of [Rh(acac)(CO) 2 ] and ligand 3a were prepared as 1 mg per mL solution in toluene. 1 ml of the rhodium stock solution, (1 mg, 0.004 mmol, 0.4 mol%) and a stock solution equivalent to 0.005 mmol (0.5%) of ligand 3a were added into a well in the AE. The mixture was pressurized to 5 bar Syngas and heated at 50 °C for 40 minutes.
- the pressure was then vented and the apparatus cooled to room temperature.
- the require substrate (styrene 1 mmol) was then added also as a stock solution in toluene to bring the reaction vessel up to 3.5 mL volume.
- the apparatus was then purged three times with Syngas, placed at 10 bar pressure and heated to 60 °C at constant pressure for 6 hours, after which time no further Syngas uptake was used up (>99% conversion).
- EXAMPLE 8 Regioselective and enantioselective hydroformylation of allyl cyanide. This reaction was run in an Argonaut Endeavour parallel autoclave system (AE). The vessels of the AE were flushed with Syngas. Stock solutions of [Rh(acac)(CO)2] and ligand 3a were prepared as 1 mg per ml_ solution in toluene. 1 ml of the rhodium stock solution, (1 mg, 0.004 mmol, 0.4 mol%) and a stock solution equivalent to 0.005 mmol (0.5%) of ligand 3a were added into a well in the AE. The mixture was pressurized to 5 bar Syngas and heated at 50 °C for 40 minutes.
- the pressure was then vented and the apparatus cooled to room temperature.
- the require substrate (allyl cyanide, 1 mmol) was then added also as a stock solution in toluene to bring the reaction vessel up to 3.5 mL volume.
- the apparatus was then purged three times with Syngas, placed at 10 bar pressure and heated to 30 °C at constant pressure for 14 hours, after which time no further Syngas uptake was used up (>99% conversion).
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Abstract
In an aspect, the invention provides compounds of the formula 4: wherein the constituent variables are defined herein.
Description
LIGANDS FOR SELECTIVE ASYMMETRIC HYDROFORMYLATION
INTRODUCTION
The invention relates to phosphine-phosphite ligands with a chiral phospholane (S,S)-diphenylphospholane and chiral or achiral biaryl phenols linked by a hydroxym ethyl bridge. In one aspect, the invention provides compounds of the formula 4:
4
wherein the constituent variables are defined below.
Olefin hydroformylation has been practiced industrially for decades for the production of commodity aldehyde intermediates. Since linear regioisomers are desired often, a major industrial focus has been the development of highly linear- selective ligands for rhodium-catalyzed hydroformylation. Several phosphorous- based ligands have been developed which exhibit sufficiently high regioselectivity for linear aldehydes for this methodology to be industrially applicable. Linear regioisomers are desired most often in the commodity chemicals sector. However, in organic synthesis of the more complex molecules used in the fine chemicals and pharmaceutical sector, there are demands for both linear and branched aldehyde regioisomers. In the latter case, the branched regioisomers of the aldehydes are also frequently preferred in optically active form; thus such products can be prepared by regioselective and enantioselective hydroformylation of olefins. The current state-of-the-art catalysts for enantioselective hydroformylation only deliver the branched aldehyde regioisomer for a select number of carefully chosen olefinic substrates. In the case of terminal olefins, these take the form R-CH=CH2 where Ar = aryl, heteroaryl or heteroatom, and XCH2CH=CH2 where X = heteroatom or CN. These catalysts deliver very poor regioselectivity in favor of the branched aldehydes for the hydroformylation of alkenes of type RCH2CH=CH2, where R refers to an aryl, heteroaryl or alkyl group
or functionalized derivative as defined herein. In addition, There is also an unmet need to attain extremely high regioselectivity (>99%) in the cases of olefins where the state of the art catalysts only provide moderate regioselectivity for the branched isomer. The invention described here addressed these unmet needs.
Significant advances in chiral ligand design have been made recently which have led to increased enantioselectivity in hydroformylation. Three such advances are Ph-BPE [Klosin et al, Angew. Chem. Int. Ed. 2005, 44, 5834], Kelliphite [Whiteker et al, J. Org. Chem., 2004, 6, 3277], and Binaphos [Takaya et al, J. Am. Chem. Soc, 1997, 1 19, 4413]. The structures of these three ligands are shown below in Figure 1 .
CR,S)-BINAPHOS Figure 1
Ph-BPE has shown high activity and enantioselectivity for the asymmetric hydroformylation of selected olefins. Kelliphite, a bisphosphite ligand was discovered to be effective for enantioselective hydroformylation after a comprehensive screen of novel ligands of this class. Binaphos, an atropisomeric
biaryl-based phosphine-phosphite has proven to be a prominent ligand for enantioselective hydroformylation with arguably the widest applicability demonstrated to date with high enantioselectivies observed with a range of terminal olefins bearing aryl, heteroaryl, alkenyl, heteroatom substituted groups, and a range of internal olefins. High enantioselectivity is a common feature in these reactions, with olefinic substrates chosen for their tendency to preferentially form the desired branched isomer giving regioselectivities of between 75% and in exceptional cases 99%. However, it has also been demonstrated that, in common with other types of hydroformylation catalyst, hydroformylation of an olefin of type RCH2CH=CH2 does not deliver the branched aldehyde selectively; in fact only around 25% of the aldehydes formed from a typical substrate, hex-1 -ene are the desired branched regioisomer as demonstrated in "Asymmetric hydroformylation catalyzed by an Rh(l)-(R,S)-BINAPHOS complex: substituent effects on the regioselectivity", J. Organomet. Chem. 1997, 527, 103. Research described in "Substituent Effect in Asymmetric Hydroformylation of Olefins Catalysed by Rhodium(l) Complexes of (fi,Sj-BINAPHOS Derivatives: A protocol for improvement of regio- and enantio-selectivities", Adv. Synth. Catal. 2001 , 343, 61 ; seeks to improve this situation, but only results in a poor 29.8% selectivity for enantioselective hydroformylation of hex-1 -ene. It is therefore widely known that Rh catalysts derived from phosphine-phosphites, up to now, give similar regioselectivity in the hydroformylation of olefins to simple achiral ligands such as triphenylphosphine or 1 ,2-bis-(diphenylphosphino)ethane. Despite many catalysts having been investigated for this transformation, this problem remained unsolved and is reflected in quotes from two authorative reviews; "the preferred formation of the branched aldehyde in particular for simple alkyl substituted alkenes is an unsolved problem" quoted from "Recent Advances in Chemo-, Regio- and Stereoselective Hydroformylation", Synthesis, 2001 , 1 , and similar conclusions in "Branched Selective Hydroformylation", Curr. Org. Chem. 2005, 9, 701 . There is a strong industrial demand for such branched aldehydes or products obtained directly from them as evidenced by less direct protocols described by "Hydrogenation Processes in the Synthesis of Perfumery Ingredients", Acc. Chem. Res. 2007, 40, 1312 and " The Synthesis of the High Potency Sweetener NC-
00637 Part 1 : The Synthesis of (S)-2-Methyl Hexanoic Acid", Org. Proc. Res. Dev. 2003, 7, 369.
Phosphine-phosphites have been reported lacking the diphenylphospholane moiety. The closest example is from Landis using a 1 ,2- benzene backbone and the diazaphospholane moiety for the phosphine, the best result for these ligands is 90% e. e. with b/l = 20 for styrene as referred to in "Highly Enantioselective Hydroformylation of Aryl Alkenes with Diazaphospholane Ligands", Organic Letters, 2008), 10(20), 4553;. Further examples of phosphine- phosphites that do not contain a phospholane moiety include "Asymmetric Hydroformylation Using Taddol-Based Chiral Phosphine-Phosphite Ligands", Organometallics 2010, 29(2), 478; "Asymmetric Hydroformylation of Olefins with Rh Catalysts Modified with Chiral Phosphine-Phosphite Ligands", Organometallics 2007, 26(25), 6428; "Synthesis of a chiral phosphite-phosphine ligand, its coordination behavior with rhodium(l) cation and the application in catalytic reaction", Zhongshan Daxue Xuebao, Ziran Kexueban, 2006, 45(4), 58; "Tuning of the structures of chiral phosphane-phosphites: application to the highly enantioselective synthesis of a-acyloxy phosphonates by catalytic hydrogenation", Chemistry-A European Journal 2007, 13(6), 1821 .
The research described in "Rhodium(l), Palladium(ll), and Platinum(ll) Complexes Containing New Mixed Phosphane-Phoshite Ligands - Effect of the Catalytic System stability on the Enantioselective Hydroformylation of Styrene", Eur. J. Inorg. Chem., 2002, 71 1 ; shows that chiral phosphine-phosphites containing a CH2O backbone but lacking a phospholane moiety are precedented, but do not give any notable enantioselectivity.
Despite the widespread nature of phosphine-phosphites, it is clear that there are no examples containing phospholane groups (as opposed to diazaphospholane groups) as the phosphine part of the ligand. Secondly, since there are no obvious leads to solve the problem of control of regioselectivity in hydroformylation of olefins of type RCH2CH=CH2, the examination of this distinct ligand class was examined, leading to the invention described herein. The hydroxymethyl bridge was selected as an initial starting backbone due to ease of synthesis. Thus, this family of ligands uses the diphenylphospholane moiety as
the phosphine donor and CH20 as the backbone. As a result they are easier to make than those phosphine-phosphites previously reported. More importantly, the results obtained using these ligands show that they have unique performance in producing the branched aldehyde in hydroformylation of olefins of type RCH2CH=CH2, and, in addition provide amongst the highest combination of regioselectivities and enantioselectivities observed in the hydroformylation of other olefin substrates. These ligands offer ease of synthesis, higher enantioselectivities, and higher regioselectivities.
SUMMARY
In one aspect, the invention provides compounds of the formula 4:
4
wherein the constituent variables are defined below.
DETAILED DESCRIPTION In one aspect, the invention provides compounds of the formula 4:
wherein n and m are each independently an integer from 1 to 3;
Ar are both independently C-6-Ci4aryl or Ci-Cgheteroaryl, which can be unsubstituted or substituted with one or more of the following groups: CrC6alkyl-, halogen, CrCehaloalkyl-, hydroxyl, hydroxyl(CrC6alkyl)-, H2N-, (C
C6alkyl)amino-, di(Ci-C6alkyl)amino-, HO2C-, (CrC6alkoxy)carbonyl-, (d- C6alkyl)carboxyl-, di(CrC6alkyl)amido-, H2NC(0)-, (CrC6alkyl)amido-, or 02N-; -Ar^-Ar2- is a bi(C6-Ci4aryl), bi(Ci-C9heteroaryl), or -(C6-Ci4aryl)-(Ci- Cgheteroaryl)- diradical, which can be unsubstituted or substituted with one or more of the following groups: CrC6alkyl-, halogen, d-Cehaloalkyl-, hydroxyl, hydroxyl(CrC6alkyl)-, H2N-, (C C6alkyl)amino-, di(C C6alkyl)amino-, H02C-, (C C6alkoxy)carbonyl-, (C C6alkyl)carboxyl-, di(Ci-C6alkyl)amido-, H2NC(0)-, (C C6alkyl)amido-, or O2N-.
In one aspect, the invention provides compound 3b (Fig. 3 crystal structure and Fig.4).
Fig. 3 Crystal structure of diphenyl-phospholane-phosphite ligand 3b In one aspect, the invention provides compounds of the formulae 1 , 2a, 2b, and 3b.
4
In one aspect the invention provides a synthesis of 2-phenylpropanal from styrene and Syn gas in the presence of Rh catalysts derived from ligands of formula 4.
In one aspect the invention provides a synthesis of 3-methyl-4- oxobutanenitrile from allyl cyanide and Syn gas in the presence of Rh catalysts derived from ligands of formula 4.
In one aspect the invention provides a synthesis of 1 -oxopropan-2-yl acetate from vinyl acetate and Syn gas in the presence of Rh catalysts derived from ligands of formula 4.
These results using in-situ formation Rh complexes of 3b are summarized
in Table 1 branched linear
In Table 1 are shown the results for the above hydroformylation of styrene using catalysts derived from ligands of type 4, which identified ligand 3b as the most enantioselective ligand.
Table 1 ; Rh catalyzed hydroformylation of styrene
3 T= 30 °C, S:G= 250:1 , Catalyst formed from 0.4 % [Rh(acac)(CO)2]
and Iigand1-3b (0.5%) , 1 mmol styrene, 3.5 ml_ toluene.
b calculated by GC of crude reaction mixture on a Beta Dex 225 chiral column.
c Initial Pressure = 10 bar
In one aspect the invention provides a regioselective synthesis of 2-methyl- 3-phenylpropan-1 -al from allyl benzene and Syngas in the presence of an Rh catalyst derived from ligands of type 4, under conditions where ligands outside the phospholane-phosphite class give no selectivity as shown in Table 2.
Table 2. Hydroformylation of allyl benzene, using a range of hydroformylation cataly
(L)
[a] Catalysts preformed from 0.4 % [Rh(acac)(CO)2] and 0.5 % bidentate ligand
or 1.2% monodentate ligand by stirring at 5 bar Syngas at 50 "C for 40 minutes
in toluene (3 ml), prior to running reactions at room temperature at 5 bar
initial syngas pressure for 3 days. Dppe = l,2-bis-(diphenylphosphino)ethane
[b] % Product determined by Ή NMR using tetraefhylsilane as internal standard.
[c] Determined by HPLC analysis of the alcohol formed after reduction with NaBH4 (Chiracel OD-H) [d] 53 % isolated yield of the corresponding alcohol over 2 steps.
[e] Reaction time of 4 hours at 30 °C.
In one aspect the invention provides a method by which the natural regioselectivity of the Rh catalyzed hydroformylation towards linear aldehydes from olefins of type RCH2CH=CH2 as previously defined is reversed towards the branched regioisomer by the use of phospholane-phosphites as ligands for the catalyst.
DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise. BH3DMS is borane dimethyl sulfide complex ((CH3)2S BH3), DABCO is 1 ,4-diazabicyclo[2.2.2]octane, r. t. is room temperature, TMS-I is iodotrimethylsilane. The term "% e. e." means the enantiomeric excess of a substance, which is defined as the absolute difference between the mole fraction of each enantiomer.
In general, the number of carbon atoms present in a given group is designated "Cx-Cy", where x and y are the lower and upper limits, respectively. For example, a group designated as "Ο-ι-Οβ" contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like. Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming from left to right the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycabonyl" refers to the group (C6-Ci4aryl)-(Ci-C6alkyl)-O- C(O)-. It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
"(Alkoxy)carbonyl" refers to the group alkyl-O-C(O)-. Exemplary (Cr C6alkoxy)carbonyl groups include but are not limited to methoxy, ethoxy, n- propoxy, 1 -propoxy, n-butoxy, and t-butoxy. An (alkoxy)carbonyl group can be
unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, -NH2, (C C6alkyl)N-, (Ci-C6alkyl)(Ci-C6alkyl)N-, -N(C C3alkyl)C(0)(Ci- Cealkyl), -NHC(0)(Ci-C6alkyl), -NHC(0)H, -C(0)NH2, -C(0)NH(CrC6alkyl), - C(0)N(Ci-C6alkyl)(Ci-C6alkyl), -CN, C C6alkoxy, -C(0)OH, -C(0)0(C C6alkyl), - C(O)(d-C6alkyl), C6-C14aryl, C C9heteroaryl, C3-C8cycloalkyl, Ci-C6haloalkyl-, C C6aminoalkyl-, -OC(0)(CrC6alkyl), Ci-C6carboxyamidoalkyl-, or -N02.
"Alkyl-" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a C-|-Ci0alkyl- group may have from 1 to 10 (inclusive) carbon atoms in it. In the absence of any numerical designation, "alkyl" is a chain (straight or branched) having 1 to 6 (inclusive) carbon atoms in it. Examples of C C6alkyl- groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. An alkyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H2N-, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino-, (C C-6alkyl)C(0)N(Cr C3alkyl)-, (C C6alkyl)carboxyamido-, HC(0)NH-, H2NC(O)-, (Ci-C6alkyl)NHC(0)-, di(Ci-C6alkyl)NC(O)-, NC-, hydroxyl, CrC6alkoxy-, CrC6alkyl-, HO2C-, (C C6alkoxy)carbonyl-, (CrC6alkyl)C(0)-, C6-C aryl-, C-i-Cgheteroaryl-, C3- Cscycloalkyl-, CrC6haloalkyl-, amino(Ci-C6alkyl)-, (CrC6alkyl)carboxyl-, C C6carboxyamidoalkyl-, or 02N-.
"(Alkyl)amido-" refers to a -C(0)NH- group in which the nitrogen atom of said group is attached to an alkyl group, as defined above. Representative examples of a (CrC6alkyl)amido group include, but are not limited to, - C(O)NHCH3, -C(0)NHCH2CH3, -C(0)NHCH2CH2CH3, -C(0)NHCH2CH2CH2CH3l - C(0)NHCH2CH2CH2CH2CH3, -C(O)NHCH(CH3)2, -C(0)NHCH2CH(CH3)2l - C(0)NHCH(CH3)CH2CH3, -C(O)NH-C(CH3)3 and -C(0)NHCH2C(CH3)3.
"(Alkyl)amino-" refers to an -NH group, the nitrogen atom of said group being attached to an alkyl group, as defined above. Representative examples of an (Ci-C6alkyl)amino- group include, but are not limited to CH3NH-, CH3CH2NH-, CH3CH2CH2NH-, CH3CH2CH2CH2NH-, (CH3)2CHNH-, (CH3)2CHCH2NH-, CH3CH2CH(CH3)NH- and (CH3)3CNH-. An (alkyl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen,
Η2Ν-, (CrC6alkyl)amino-, di(CrC6alkyl)amino-, (Ci-C6alkyl)C(0)N(CrC3alkyl)-, (CrC6alkyl)carboxyamido-, HC(0)NH-, H2NC(0)-, (d-C6alkyl)NHC(0)-, di(C C6alkyl)NC(0)-, NC-, hydroxyl, C C6alkoxy-, C C6alkyl-, H02C-, (C C6alkoxy)carbonyl-, (CrC6alkyl)C(0)-, C6-Ci4aryl-, Ci-Cgheteroaryl-, C3- Cscycloalkyl-, CrC6haloalkyl-, amino(CrC6alkyl)-, (CrC6alkyl)carboxyl-, C C6carboxyamidoalkyl-, or 02N-.
"Alkylcarboxy" refers to an alkyl group, defined above, attached to the parent structure through the oxygen atom of a carboxyl (C(O)-O-) functionality. Examples of (CrC6alkyl)carboxy include acetoxy, ethylcarboxy, propylcarboxy, and isopentylcarboxy.
"Aryl-" refers to an aromatic hydrocarbon group. Examples of an C6- Ci4aryl- group include, but are not limited to, phenyl, 1 -naphthyl, 2-naphthyl, 3- biphen-1 -yl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl. An aryl group can be unsubstituted or substituted with one or more of the following groups: CrC6alkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl(CrC6alkyl)-, H2N-, amino(C C6alkyl)-, di(CrC6alkyl)amino-, H02C-, (Ci- C6alkoxy)carbonyl-, (C C6alkyl)carboxyl-, di(Ci-C6alkyl)amido-, H2NC(0)-, (C C6alkyl)amido-, or 02N-.
"Di(alkyl)amido-" refers to a -NC(O)- group in which the nitrogen atom of said group is attached to two alkyl groups, as defined above. Each alkyl group can be independently selected. Representative examples of a di(C C6alkyl)amido- group include, but are not limited to, -C(O)N(CH3)2, - C(O)N(CH2CH3)2, -C(O)N(CH3)CH2CH3) -C(0)N(CH2CH2CH2CH3)2, -C(0)N(CH2 CH3)CH2CH2CH3, -C(0)N(CH3)CH(CH3)2l -C(O)N(CH2CH3)CH2CH(CH3)2, - C(0)N(CH(CH3)CH2CH3)2> -C(O)N(CH2CH3)C(CH3)3 and -C(O)N(CH2 CH3)CH2C(CH3)3.
"Di(alkyl)amino-" refers to a nitrogen atom attached to two alkyl groups, as defined above. Each alkyl group can be independently selected. Representative examples of an di(CrC6alkyl)amino- group include, but are not limited to, - N(CH3)2, -N(CH2CH3)(CH3), -N(CH2CH3)2, -N(CH2CH2CH3)2, N(CH2CH2CH2CH3)2, -N(CH(CH3)2)2, -N(CH(CH3)2)(CH3), -N(CH2CH(CH3)2)2, - NH(CH(CH3)CH2CH3)2, -N(C(CH3)3)2, -N(C(CH3)3)(CH3), and -N(CH3)(CH2CH3).
The two alkyl groups on the nitrogen atom, when taken together with the nitrogen to which they are attached, can form a 3- to 7- membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with -N(H)-, -N(CrC6alkyl)-, -N(C3-C8cycloalkyl)-, -N(C6-C 4aryl)-, -N(d- Cgheteroaryl)-, -N(amino(Ci-C6alkyl))-, -N(C6-Ci4arylamino)-, -O-, -S-, -S(O)-, or - S(0)2-.
"Halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.
"Haloalkyl-" refers to an alkyl group, as defined above, wherein one or more of the Ci-C6alkyl group's hydrogen atoms has been replaced with -F, -CI, - Br, or -I. Each substitution can be independently selected from -F, -CI, -Br, or -I. Representative examples of an Ci-C6haloalkyl- group include, but are not limited to, -CH2F, -CCI3, -CF3, CH2CF3, -CH2CI, -CH2CH2Br, -CH2CH2I, -CH2CH2CH2F, - CH2CH2CH2CI, -CH2CH2CH2CH2Br, -CH2CH2 CH2CH2 I, -CH CH2CH2CH2CH2Br, - CH2CH2CH2CH2CH2I, -CH2CH(Br)CH3, -CH2CH(CI)CH2CH3, -CH(F)CH2CH3 and - C(CH3)2(CH2CI).
"Heteroaryl-" refers to 5-10-membered mono and bicyclic aromatic groups containing at least one heteroatom selected from oxygen, sulfur, and nitrogen. Examples of monocyclic Ci -Cgheteroaryl- radicals include, but are not limited to, oxazinyl, thiazinyl, diazinyl, triazinyl, thiadiazoyi, tetrazinyl, imidazolyl, tetrazolyl, isoxazolyl, furanyl, furazanyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl, N-pyridyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl. Examples of bicyclic C Cgheteroaryl- radicals include but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl, and indazolyl. The contemplated heteroaryl- rings or ring systems have a minimum of 5 members. Therefore, for example, Ci heteroaryl- radicals would include but are not limited to tetrazolyl, C2heteroaryl- radicals include but are not limited to triazolyl, thiadiazoyi, and tetrazinyl, Cgheteroaryl- radicals include but are not limited to quinolinyl and isoquinolinyl. A heteroaryl group can be unsubstituted or substituted with one or more of the following groups: C-i-C6alkyl-, halogen, CrC6haloalkyl-, hydroxyl, Ci-C6hydroxylalkyl-, H2N-, amino(Ci-C6alkyl),
di(Ci-C6alkyl)amino-, -COOH, (CrC6alkoxy)carbonyl-, (CrC6alkyl)carboxyl-, di(CrC6alkyl)ainnido-, H2NC(0)-, (Ci-C6alkyl)amido-, or 02N-.
"Hydroxylalkyl-" refers to an alkyl group, as defined above, wherein one or more of the C-i-Cealkyl group's hydrogen atoms have been replaced with hydroxyl groups. Examples of hydroxyl (C Cealkyl)- moieties include, for example, - CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH(OH)CH2OH, -CH2CH(OH)CH3, - CH(CH3)CH2OH and higher homologs.
"Leaving group" refers to an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a specified reaction. For example, in the heterolytic solvolysis of benzyl bromide in acetic acid: the leaving group is bromide. In the reaction of N,N,N-trimethyl-1 -phenylmethanaminium ion with methanethiolate, the leaving group is trimethylamine. In the electrophilic nitration of benzene, it is H+. The term has meaning only in relation to a specified reaction. Examples of leaving groups include, for example, carboxylates {i.e. CH3COO~, CF3C02 ", or (CH3)2CH2COO~), F~ water, CI", ΒΓ, Γ, N3 ~ SCNT, trichloroacetimidate, thiopyridyl, tertiary amines (i.e. trimethylamine), phenoxides (i.e. o- nitrophenoxide), and sulfonates (/'. e. tosylate, mesylate, or triflate).
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
EXAMPLES
iylphospholane-CH2O moiety:
air stable ajr stable crystalline solid crystalline solid
Bisphosphite moiety:
1: R= H. Biphenyl
2a:R=H. ( -Binaphthyl
2b:R=H. (S Binaphthyl
3a: R= tBu. (i?)-BIPHEN
3b: R= ¾u. (S)-BIPHEN
Ligand formation:
ive
than chloridite
Preparation of ligand (3b)
To a Schlenk flask containing (S)-3,3'-di-teri-butyl-5,5',6,6'-tetramethyl-[1 ,Γ- biphenyl]-2,2'-diol] ((S)-BIPHEN) (2.00 g, 5.64 mmol) and triethylamine (1.65 mL, 1.20 g, 11.84 mmol, 2.1 eq.) was added phosphorus trichloride (517 μί, 814 mg, 5.92 mmol, 1.05 eq.) and the reaction stirred at room temperature overnight. The crude reaction mixture was then filtered under nitrogen atmosphere, toluene (3 x 5 mL portions) added to the residue, and removed under reduced pressure, to remove any residual phosphorus trichloride leaving a colorless solid. The crude 31P NMR (121.4 MHz, C6D6) spectrum showed a single peak at δΡ = 178.8 ppm, corresponding to (S)-BIPHEN chlorophosphite. In a glove box under a nitrogen atmosphere (S)-BIPHEN chlorophosphite (1.0 g, 2.39 mmol) from above was dissolved in toluene, excess trimethylsilyl iodide (1.5 mL, 2.11 g, 10.53 mmol) added and the reaction mixture allowed to stir for 2 hours at room temperature. The excess trimethylsilyl iodide was then removed under reduced pressure and toluene (3 x 5 mL portions) added to the residue and removed under reduced pressure, to remove any residual trimethylsilyl iodide. The crude 31P NMR (121.4 MHz, C6D6) spectrum showed two peaks, one at δρ = 178.8 ppm and another at δΡ = 222.1 ppm indicating only partial conversion to the desired iodo-phosphite (3). This mixture was used in the coupling step below to form ligand (3b), without further purification.
Step 2:
All procedures reactions were carried out in a glove box under a nitrogen atmosphere. To a Schlenk flask containing a solution of phospholane (707 mg, 2.39 mmol, 1 eq.) and a mixture of chloro- and iodo-phosphite (2.39 mmol) in toluene (10 ml_), was added 1 ,4-diazabicyclo-[2,2,2]-octane (DABCO, 1 .34 g, 1 1 .95 mmol, 5 eq.) and the solution allowed to stir at room temperature overnight. The product was isolated after filtration through silica as a pale yellow oil, which solidified to pale yellow crystals on standing. Yield: 547 mg, 0.84 mmol, (35%). etc25 = +387.1 ° (c = 0.41 , toluene); 31P NMR (121 .4 MHz, C6D6) δΡ = 139.3 (P1 ), 22.5 (P4); 1H NMR (400 MHz, C6D6) δΗ = 7.00-7.30 (m, 12H, ArCH), 4.09-4.21 (m, 1 H, C3H), 3.24-3.49 (m, 3H, C3H', C5H and C8H), 2.12-2.26 (m, 1 H, C6H or C7H), 2.09 (s, 3H, CH3), 2.08 (s, 3H, CH3), 1.83-1 .95 (m, 2H, C6H2 or C7H2), 1 .78 (s, 3H, CH3), .62 (s, 3H, CH3), 1 .50-1 .60 (m, H, C6H or C7H), 1 .50 (s, 9H, C(CH3)3), 1 .38 (s, 9H, C(CH3)3); 13C NMR (75.5 MHz, C6D6) 6C = 146.73, 146.68, 146.05, 146.03, 144.59, 44.40, 138.52, 138.50, 138.48, 138.45, 137.30, 135.32, 134.59, 132.66, 132.24, 132.19, 131 .62, 131 .27, 131 .24 (ArCquat.), 128.71 , 128.69, 128.62, 128.34, 128.25, 128.00, 127.96, 126.14, 126.12, 126.04, 126.02 (ArCH), 62.40 (dd, 1 JC-P = 29.0, 3.7 Hz, C3), 46.20 (d, 1 JC-P = 15.9 Hz, C5 or C8), 45.45 (d, 1 -P = 14.9 Hz, C5 or C8), 36.42 (C6 or C7), 32.67 (d, 2JC-P = 3.1 Hz, C6 or C7), 31 .76 (d, J = 5.0 Hz, C(CH3)3), 31 .29 (C(CH3)3), 20.4 (CH3), 20.37 (CH3), 16.74 (CH3), 16.45 (CH3).
EXAMPLE 2 Regioselective and enantioselective hydroformylation of allyl benzene.. [Rh(acac)(CO)2] (1 mg, 0.004 mmol, 0.4 mol%) was added into a vial, a stirring bar was added and the vial was sealed with a crimp cap a put under
inert atmosphere (N2). Two needles were pierced into the vial and this was introduced into the autoclave. The autoclave was then purged with three vacuum/N2 cycles. A solution of the ligand (Ligand 3a, 3.3 mg, 0.005 mmol, 0.5 mol%) in toluene (1 mL) from a stock solution was added using a syringe. The autoclave was then purged three times with syngas (50/50, CO/H2), pressurized to 5 bar, immersed into an oil bath preheated at 50 °C and stirred at 900 r.p.m for 40 minutes. After this time, the autoclave was cooled down to room temperature by partial immersion in cold water and the pressure released. A solution of alkene (allylbenzene, 118 mg, 133 μΙ, 1 mmol) and internal standard (tetraethylsilane, 30 μΙ) in toluene (1 mL) was added using a syringe. The autoclave was then pressurized back to the desired pressure (5 bar) and stirred at room temperature at 900 r.p.m. After the desired reaction time, (75 hours), the pressure was slowly released and the autoclave was opened. A small sample was taken and analyzed by 1H NMR (CDCI3) to calculate conversion (64%) and branched to linear ratio of the resulting aldehydes (4.00: 1). To determine enantioselectivity (e.e, = 90% for the branched aldehyde), the products were converted into the corresponding alcohols by NaBH4 reduction with the alcohol produce being obtained after work up (dichloromethane (5 mL), quenched with HCI aqueous (5 mL, 1 M), followed by 3 further extractions with dichloromethane (3x10 mL). The combined organic layers were dried over anhydrous MgS0 and the solvent was removed with a rotary evaporator to give the crude mixture which was purified by chromatography on using hexane/EtOAc 4:1 as eluent to give the branched and linear alcohols as a colorless oil (79 mg, 53%). [a]D rt = -12.2 (c 0.5, CHCI3) (for the branched alcohol).
NMR data for branched and linear alcohols.
2-methyl-3-phenylpropan-1-ol: 1H NMR (300 MHz, CDCI3): 6= 0.90 (3H, d, J = 6.8 Hz), 1.43 (1 H, br s), 1.87-1.99 (1 H, m), 2.41 (1 H, dd, J = 13.4, 8.1 Hz), 2.74 (1 H, dd, J = 13.4, 6.3 Hz), 3.46 (1 H, dd, J = 10.6, 6.0 Hz), 3.52 (1 H, dd, J = 10.6, 5.9 Hz), 7.14-7.28 (5H, m); MS (ES+): 173.1 ([MNa]+, 100%).
4-phenylbutan-1-ol:1H NMR (300 MHz, CDCI3): δ= 1.38 (1 H, br s), 1.55- 1.72 (4H, m), 2.62 (2H, t, J = 7.5 Hz), 3.64 (2H, t, J = 6.4 Hz), 7.15-7.28 (5H, m); MS (ES+): 173.1 ([MNa]+, 100%). The enantiomeric excess of the branched alcohol was determined by HPLC on a Chiralcel™ OD-H column, 250 x 4.6 mm, 95:5 n-hexane: 2-propanol, 0.5 ml/min, 210 nm, fR[(-)-(S), major] = 18.6 min, fo[(+)-(ft). minor] = 22.8 min, iR[linear] = 30.2 min.
EXAMPLE 3 Regioselective and enantioselective hydroformylation of hex-1-ene. [Rh(acac)(CO)2] (1 mg, 0.004 mmol, 0.4 mol%) was added into a vial, a stirring bar was added and the vial was sealed with a crimp cap and put under an inert atmosphere (N2). Two needles were pierced into the vial and this was introduced into the autoclave. The autoclave was then purged with three vacuum/N2 cycles. A solution of the ligand (Ligand 3a, 3.3 mg, 0.005 mmol, 0.5 mol%) in toluene (1 ml) from a stock solution was added using a syringe. The autoclave was then purged three times with syngas (50/50, CO/H2), pressurized to 5 bar, immersed into an oil bath preheated at 50 °C and stirred at 900 r.p.m for 40 min. After this time, the autoclave was cooled down to room temperature by partial immersion in cold water and the pressure released. A solution of alkene (1 - hexene, 84 mg, 124 μΙ, 1 mmol) and internal standard (tetraethylsilane, 30 μΙ) in toluene (1 ml) was added using a syringe. The autoclave was then pressurized back to the desired pressure (5 bar) and stirred at room temperature at 900 r.p.m. After the desired reaction time (46 h), the pressure was slowly realized and the autoclave was opened. A small sample was taken and analyzed by 1H NMR (CDCI3) to calculate conversion (70%) and branched to linear ratio of the resulting aldehydes (2.98: 1 ). To determine enantioselectivity (e. e. = 93% for the branched aldehyde), the products were converted into the Cbz-esters of the corresponding alcohols by reduction using NaBH4 and protection in the standard way. NMR data for branched and linear alcohols. [a]D 20 -1 1.6 (c 1.4, CHCI3, e. e. 93%)
2-methylhexan-1-ol: 1H NMR (300 MHz, CDCI3): δ= 0.89 (3H, t, J = 6.9 Hz), 0.91 (3H, d, J = 6.7 Hz), 1.05-1.67 (8H, m), 3.40 (1 H, dd, J = 10.5, 6.5 Hz), 3.50 (1 H, dd, J = 10.5, 5.8 Hz); MS (ES+): 139.1 ([MNa]+, 100%).
heptan-1-ol: H NMR (300 MHz, CDCI3): δ= 0.88 (3H, t, J = 6.4 Hz), 1.28- 1 .60 (1 1 H, m), 3.63 (2H, t, J = 6.6 Hz); MS (ES+): 139.1 ([MNa]+, 100%). The enantiomeric excess of the branched Cbz-derived alcohol was determined by HPLC on a tandem of Chiralpak™ AD-H, 250 x 4.6 mm, and Chiralcel™ OD-H, 250 x 4.6 mm, 99:1 n-hexane: 2-propanol, 0.5 ml/min, 210 nm, fR[(-)-(S), major] = 20.5 min, fR[(+)-(fl). minor] = 25.2 min, fR[linear] = 24.2 min.
EXAMPLE 4 Regioselective and enantioselective hydroformylation of pentafluoro-allyl benzene. Using a similar procedure as described in examples 2 and 3, but using pentafluoro-allylbenzene as substrate and a reaction temperature of 40 °C the branched aldehyde was again formed. After the desired reaction time (4 h), the pressure was slowly released and the autoclave was opened. A small sample was taken and analyzed by H NMR (CDCI3) to calculate conversion (90%) and branched to linear ratio of the resulting aldehydes (5.3: 1 ). To determine enantioselectivity (e. e.= 88% for the branched aldehyde), the aldehyde was reduced using NaBH4 in the standard way, with standard purification by chromatography on silica gel using hexane/EtOAc 4:1 as eluent to give the branched and linear alcohols as colorless oil (150 mg, 63%). [a]D 20 = - 8.7 (c 2.75, CHCI3, e. e. 88%);
(-)-2-methyl-3-(perfluorophenyl)propan-1 -ol. 1H NMR (400 MHz, CDCI3): δΗ = 0.92 (d, J = 6.8 Hz, 3H), 1 .77 (s, 1 H), 1 .89-2.01 (m, 1 H), 2.55 (ddt, J = 13.6, 8.4, 1 .7 Hz, 1 H), 2.85 (ddt, J = 13.6, 5.8, 1 .7 Hz, 1 H), 3.50 (dd, J = 8.9, 4.2 Hz, 1 H), 3.54 (dd, J = 8.9, 4.0 Hz, 1 H); 19F NMR (376 MHz, CDCI3): 5F = -163.6- -163.4 (m, 2F), -158.2 (t, J = 20.8 Hz, 1 F), -143.7—143.6 (m, 2F); 13C NMR (75 MHz, CDCI3): 5c = 16.0, 25.9, 36.2, 67.3, 1 13.7-1 14.0 (m), 136.1 -146.4 8 (m); MS (Cl+): 239.0 ([M-2H+H]+, 100%), 240 ([MH]+, 13), 250.0 ([M+NH4]+, 8); HRMS (CI+): m/z = 258.0914 [M+NH4]+, Ci0H13ONF5 requires 258.0912.
4-(perfluorophenyl)butan-1 -ol. H NMR (400 MHz, CDCI3): δΗ = 1 .46 (br s, 1 H), 1 .57-1 .72 (m, 4H), 2.72-2.75 (m, 2H), 3.67 (t, J = 6.2 Hz, 2H); 19F NMR
(376 MHz, CDCIs): δΡ = -163.5- -163.4 (m, 2F), -158.5 (t, J = 20.9 Hz, 1 F), - 144.9- -144.8 (m, 2F); 13C NMR (100 MHz, CDCI3): 5C = 22.0, 25.5, 32.0, 62.3, 1 14.7-1 15.0 (m), 136.1 -146.3 (m). The enantiomeric excess of the branched alcohol was determined by HPLC on a tandem series of Chiralpak™ AS-H, 250 x 4.6 mm, and Chiralpak AD-H columns, 250 x 4.6 mm, 99:1 n-hexane: 2-propanol, 0.5 mL/min, 210 nm, fR[(-), major] = 69.1 minutes, fo[(+), minor] = 74.0 minutes, fF near] = 97.2 minutes.
EXAMPLE 5 Regioselective and enantioselective hydroformylation of W-methyl-W-phenylbut-3-enamide. Using a similar procedure as described in examples 2 and 3, but using A/-methyl-/V-phenylbut-3-enamide as substrate and a reaction temperature of 15 °C, the branched aldehyde was again formed. After the desired reaction time (29 h), the pressure was slowly released and the autoclave was opened. A small sample was taken and analyzed by 1H NMR (CDCI3) to calculate conversion (71 %) and branched to linear ratio of the resulting aldehydes (4.5:1 ). To determine enantioselectivity (e. e.= 92% for the branched aldehyde), the aldehyde was reduced using NaBH4 in the standard way, with standard purification by chromatography on SiO2 using EtOAc as eluent to give the branched and linear alcohols as a colorless oil (1 13 mg, 55%). [a]D 20 -7.7 (c 0.85,
(-)-4-hydroxy- V,3-dimethyl-A/-phenylbutanamide. Purified by chromatography on silica gel using EtOAc as eluent to give the branched and linear alcohols as a colorless oil (1 13 mg, 55%). [α]ο20 -7.7 (c 0.85, CHCI3, e. e. 92%); 1H NMR (300 MHz, CDCI3): δ = 0.79 (d, J = 6.3 Hz, 3H), 2.00-2.21 (m, 3H), 3.24 (s, 3H), 3.29-3.34 (m, 2H), 3.50 (dd, J = 10.3, 3.4 Hz, 1 H), 7.14-7.18 (m, 2H), 7.30-7.43 (m, 3H); 13C NMR (75 MHz, CDCI3): δ = 17.2, 33.1 , 37.4, 38.9, 68.1 , 127.2, 127.8, 129.8, 143.9, 173.2; MS (ES+): 230.0 ([MNa]+, 100%); HRMS (ES+): m/z = 230.1 161 [MNa]\ Ci2H17NO2Na requires 230.1 157.
5-hydroxy-A/-methyl-A -phenylpentanamide. H NMR (300 MHz, CDCI3): δΗ = 1 .42-1 .51 (m, 2H), 1 .61 -1 .70 (m, 2H), 2.09 (t, J = 7.0 Hz, 2H), 2.24 (br s, 1 H),
3.25 (s, 3H), 3.54 (t, J = 6.3 Hz, 2H), 7.15-7.18 (m, 2H), 7.31 -7.44 (m, 3H); 13C NMR (75 MHz, CDCI3): 5C = 21 .2, 32.2, 33.6, 37.4, 62.0, 127.3, 127.9, 129.8, 144.1 , 173.3; MS (ES+): 230.0 ([MNa]+, 100%). The enantiomeric excess of the branched alcohol was determined by HPLC on a Chiralpak™ AD-H column, 250 x 4.6 mm, 93:7 n-hexane: 2-propanol, 0.5 mL/min, 254 nm, fo[(-), major] = 33.8 minutes, fFt[(+), minor] = 36.2 minutes, ^[linear] = 41 .2 minutes.
EXAMPLE 6: Regioselective and enantioselective hydroformylation of Vinyl acetate. This reaction was run in an Argonaut Endeavour parallel autoclave system (AE). The vessels of the AE were flushed with Syngas. Stock solutions of [Rh(acac)(CO)2] and ligand 3a were prepared as 1 mg per ml_ solution in toluene. 1 ml of the rhodium stock solution, (1 mg, 0.004 mmol, 0.4 mol%) and a stock solution equivalent to 0.005 mmol (0.5%) of ligand 3a were added into a well in the AE. The mixture was pressurized to 5 bar Syngas and heated at 50 °C for 40 minutes. The pressure was then vented and the apparatus cooled to room temperature. The require substrate (vinyl acetate 1 mmol) was then added also as a stock solution in toluene to bring the reaction vessel up to 3.5 ml_ volume. The apparatus was then purged three times with Syngas, placed at 2.5 bar pressure and heated to 60 °C at constant pressure for 4 hours, after which time no further Syngas uptake was used up (>99% conversion). The AE was then cooled and the reaction mixture analyzed by GC in the standard protocol using a beta- Dex 225 chiral column. This along with NMR revealed that the only product present was the branched aldehyde (B / L >99:1 ) and with an e. e.. of 83 %.
EXAMPLE 7: Regioselective and enantioselective hydroformylation of styrene. This reaction was run in an Argonaut Endeavour parallel autoclave system (AE). The vessels of the AE were flushed with Syngas. Stock solutions of [Rh(acac)(CO)2] and ligand 3a were prepared as 1 mg per mL solution in toluene. 1 ml of the rhodium stock solution, (1 mg, 0.004 mmol, 0.4 mol%) and a stock solution equivalent to 0.005 mmol (0.5%) of ligand 3a were added into a well in the AE. The mixture was pressurized to 5 bar Syngas and heated at 50 °C for 40 minutes. The pressure was then vented and the apparatus cooled to room temperature. The require substrate (styrene 1 mmol) was then added also as a stock solution in toluene to bring the reaction vessel up to 3.5 mL volume. The
apparatus was then purged three times with Syngas, placed at 10 bar pressure and heated to 60 °C at constant pressure for 6 hours, after which time no further Syngas uptake was used up (>99% conversion). The AE was then cooled and the reaction mixture analyzed by GC in the standard protocol using a beta-Dex 225 chiral column. This revealed >99% conversion to aldehydes, (B / L = 79.3:1 ) and with an e. e.. of 92 %.
EXAMPLE 8: Regioselective and enantioselective hydroformylation of allyl cyanide. This reaction was run in an Argonaut Endeavour parallel autoclave system (AE). The vessels of the AE were flushed with Syngas. Stock solutions of [Rh(acac)(CO)2] and ligand 3a were prepared as 1 mg per ml_ solution in toluene. 1 ml of the rhodium stock solution, (1 mg, 0.004 mmol, 0.4 mol%) and a stock solution equivalent to 0.005 mmol (0.5%) of ligand 3a were added into a well in the AE. The mixture was pressurized to 5 bar Syngas and heated at 50 °C for 40 minutes. The pressure was then vented and the apparatus cooled to room temperature. The require substrate (allyl cyanide, 1 mmol) was then added also as a stock solution in toluene to bring the reaction vessel up to 3.5 mL volume. The apparatus was then purged three times with Syngas, placed at 10 bar pressure and heated to 30 °C at constant pressure for 14 hours, after which time no further Syngas uptake was used up (>99% conversion). The AE was then cooled and the reaction mixture analyzed by 1H NMR spectroscopy utilizing enantiopure (fl)-1 -phenylpropan-1 -amine as a chiral derivatizing agent to facilitate calculation of enantiomeric excess, with the branched selectivity and conversion also measured using NMR. In some cases conversion, and branched to linear were also checked using chiral CG using an alpha-Dex 225 column. This revealed >99% conversion, a B : L = 10.0:1 and an e. e.. of 81 %.
Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other
changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
Claims
1. A compound of the formula 4:
4
wherein n and m are each independently an integer from 1 to 3;
Ar1 are both independently C6-Ci4aryl or Ci -Cgheteroaryl, which can be unsubstituted or substituted with one or more of the following groups: CrC6alkyl-, halogen, Ci-C6haloalkyl-, hydroxyl, hydroxyl(CrC6alkyl)-, H2N-, (C C6alkyl)amino-, di(Ci-C6alkyl)amino-, HO2C-, (Ci-C6alkoxy)carbonyl-, (C C6alkyl)carboxyl-, di(C C6alkyl)amido-, H2NC(0)-, (Ci-C6alkyl)amido-, or 02N-; and
-Ai^-Ar2- is a bi(C6-Ci4aryl), bi(Ci -Cgheteroaryl), or -(C6-Ci4aryl)-(C Cgheteroaryl)- diradical, which can be unsubstituted or substituted with one or more of the following groups: CrC6alkyl-, halogen, d-C6haloalkyl-, hydroxyl, hydroxyl(C C6alkyl)-, H2N-, (C C6alkyl)amino-, di(C C6alkyl)amino-, H02C-, (d- C6alkoxy)carbonyl-, (CrC6alkyl)carboxyl-, di(C C6alkyl)amido-, H2NC(O)-, (Ci- C6alkyl)amido-, or O2N-.
2. The compound of claim 1 , wherein -Ai^-Ar2- is a bi(C6-Ci4aryl) diradical, which can be unsubstituted or substituted with one or more of the following groups: C C6alkyl-, halogen, CrC6haloalkyl-, hydroxyl, hydroxyl(CrC6alkyl)-, H2N-, (C C6alkyl)amino-, di(Ci-C6alkyl)amino-, H02C-, (CrC6alkoxy)carbonyl-, (C C6alkyl)carboxyl-, di(CrC6alkyl)amido-, H2NC(0)-, (CrC6alkyl)amido-, or 02N-.
3. The compound of claim 2, wherein -Ai^-Ar2- is a biphenyl diradical, which can be unsubstituted or substituted with one or more of the following groups: C C6alkyl-, halogen, C C6haloalkyl-, hydroxyl, hydroxyl(CrC6alkyl)-, H2N-, (Ci- C6alkyl)amino-, di(CrC6alkyl)amino-, H02C-, (C-i-C6alkoxy)carbonyl-, (C C6alkyl)carboxyl-, di(CrC6alkyl)amidc~, H2NC(0)-, (Ci-C6alkyl)amido-, or 02N-.
4. The compound of claim 3, wherein -At^-Ar2- is a 2,2'-biphenyl diradical, which can be unsubstituted or substituted with one or more of the following groups: CrC6alkyl-, halogen, C-i-C6haloalkyl-, hydroxyl, hydroxyl(CrC6alkyl)-, H2N-, (d- C6alkyl)amino-, di(C C6alkyl)amino-, HO2C-, (CrC6alkoxy)carbonyl-, (C C6alkyl)carboxyl-, di(C C6alkyl)amido-, H2NC(0)-, (CrC6alkyl)amido-, or 02N-.
5. The compound of claim 4, wherein -Ar^-Ar2- is a 2,2'-biphenyl diradical, substituted with one or more CrC6alkyl- groups.
6. The compound of any one of claims 1 to 5, wherein Ar1 are both independently C6-Ci aryl.
7. The compound of any one of claims 1 to 6, wherein Ar1 are both phenyl.
8. The compound of any one of claims 1 to 7, wherein n and m are both 1.
9. The compound of any one of claims 1 to 8, which is of the formulae 1, 2a, 2b, 3a, or 3b:
1 -27-
1 1. A process for the synthesis of the ligands of formula 4 of claim 1 comprising:
4
wherein X is a leaving group.
12. A process for the asymmetric hydroformyiation of prochiral olefins in the presence of Rh catalysts derived from ligands of formula 4, of claim 1.
13. The process of claim 12, wherein the prochiral terminal olefin is RCH2CH=CH2, wherein R is C6-Caryl, d-Cgheteroaryl, or Ci-C-6alkyl, and any C6- Caryl, d-Cgheteroaryl, or CrC6alkyl radical, is optionally substituted by one or more with one or more of the following groups: halogen, H2N-, (CrC6alkyl)amino-, di(Ci-C6alkyl)amino-, (Ci-C6alkyl)C(0)N(Ci-C3alkyl)-, (Ci-C6alkyl)carboxyamido-, HC(0)NH-, H2NC(0)-, (CrC6alkyl)NHC(0)-, di(Ci-C6alkyl)NC(0)-, NC-, hydroxyl, CrC6alkoxy-, Ci-C6alkyl-, H02C-, (C C6alkoxy)carbonyl-, (C C6alkyl)C(O)-, C6- Ci4aryl-, CrCgheteroaryl-, C3-C8cycloalkyl-, CrC6haloalkyl-, amino(Ci-C6alkyl)-, (Ci-C6alkyl)carboxyl-, Ci-C6carboxyamidoalkyl-, or 02N-.
14. The process of claim 12, wherein the prochiral olefin is styrene and the hydroformyiation uses Syn gas in the presence of Rh catalysts derived from ligands of formul
15. The process of claim 12, wherein the prochiral olefin is allyl cyanide and the hydroformylation uses Syn gas in the presence of Rh catalysts derived from ligands of formula 4, the process comprising:
16. The process of claim 12, wherein the prochiral olefin is vinyl acetate and hydroformylation uses Syn gas in the presence of Rh catalysts derived from ligands of formula 4 the process comprising:
17. The process of claim 13, wherein the regioselectivity of the hydroformylation in favor of the linear aldehyde product is reversed towards the branched aldehyde product.
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| PCT/US2011/045897 WO2012016147A2 (en) | 2010-07-30 | 2011-07-29 | Ligands for selective asymmetric hydroformylation |
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| EP (1) | EP2598510A4 (en) |
| JP (1) | JP2013532691A (en) |
| WO (1) | WO2012016147A2 (en) |
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| CN104744514B (en) * | 2013-12-27 | 2018-03-23 | 中国科学院上海药物研究所 | A kind of chiral phosphorus alkene part, synthetic method and its application in asymmetric reaction |
| US9308527B2 (en) | 2014-03-17 | 2016-04-12 | Eastman Chemical Company | Phosphorous compounds useful as ligands and compositions and methods regarding them |
| US10144751B1 (en) * | 2017-11-28 | 2018-12-04 | Eastman Chemical Company | Highly isoselective catalyst for alkene hydroformylation |
| US10183961B1 (en) * | 2017-11-28 | 2019-01-22 | Eastman Chemical Company | Highly isoselective catalyst for alkene hydroformylation |
| AU2021268664A1 (en) | 2020-05-05 | 2022-10-20 | Nuvalent, Inc. | Heteroaromatic macrocyclic ether chemotherapeutic agents |
| EP4146205A4 (en) | 2020-05-05 | 2024-05-29 | Nuvalent, Inc. | Heteroaromatic macrocyclic ether chemotherapeutic agents |
| WO2022046421A1 (en) * | 2020-08-25 | 2022-03-03 | Eastman Chemical Company | Olefin hydroformylation processes using hydrocarbon solvents and fluorinated solvents in the presence of phospholane-phosphite ligands |
| US20230357115A1 (en) * | 2020-08-25 | 2023-11-09 | Eastman Chemical Company | Phospholane-phosphite ligands for alkene hydroformylation catalysts |
| WO2023056405A1 (en) | 2021-10-01 | 2023-04-06 | Nuvalent, Inc. | Solid forms, pharmaceutical compositions and preparation of heteroaromatic macrocyclic ether compounds |
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2011
- 2011-07-29 JP JP2013522001A patent/JP2013532691A/en not_active Ceased
- 2011-07-29 EP EP11813250.5A patent/EP2598510A4/en not_active Withdrawn
- 2011-07-29 WO PCT/US2011/045897 patent/WO2012016147A2/en active Application Filing
Non-Patent Citations (2)
| Title |
|---|
| GARY M. NOONAN ET AL: "Asymmetric Hydroformylation of an Enantiomerically Pure Bicyclic Lactam: Efficient Synthesis of Functionalised Cyclopentylamines", CHEMISTRY - A EUROPEAN JOURNAL, vol. 16, no. 43, 15 November 2010 (2010-11-15), pages 12788-12791, XP055083083, ISSN: 0947-6539, DOI: 10.1002/chem.201002233 * |
| See also references of WO2012016147A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2013532691A (en) | 2013-08-19 |
| WO2012016147A3 (en) | 2012-04-19 |
| WO2012016147A2 (en) | 2012-02-02 |
| EP2598510A4 (en) | 2014-02-26 |
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