CN106831862B - 一类手性桥连的轴手性单膦配体及其制备方法 - Google Patents
一类手性桥连的轴手性单膦配体及其制备方法 Download PDFInfo
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- CN106831862B CN106831862B CN201611183532.9A CN201611183532A CN106831862B CN 106831862 B CN106831862 B CN 106831862B CN 201611183532 A CN201611183532 A CN 201611183532A CN 106831862 B CN106831862 B CN 106831862B
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- Prior art keywords
- compound
- chiral
- reaction
- ligand
- decanediol
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- 239000003446 ligand Substances 0.000 title claims abstract description 76
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- -1 aryl boric acid Chemical compound 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 12
- 238000005557 chiral recognition Methods 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 14
- 230000035484 reaction time Effects 0.000 claims description 12
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 7
- 235000011009 potassium phosphates Nutrition 0.000 claims description 7
- 229910052723 transition metal Inorganic materials 0.000 claims description 7
- 150000003624 transition metals Chemical class 0.000 claims description 7
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 230000001335 demethylating effect Effects 0.000 claims description 5
- 150000002009 diols Chemical class 0.000 claims description 5
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 claims description 5
- 239000005052 trichlorosilane Substances 0.000 claims description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 5
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 4
- RXYPXQSKLGGKOL-UHFFFAOYSA-N 1,4-dimethylpiperazine Chemical compound CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 claims description 4
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 4
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- OWBTYPJTUOEWEK-UHFFFAOYSA-N (-)-(2R,3R)--2,3-butanediol Natural products CC(O)C(C)O OWBTYPJTUOEWEK-UHFFFAOYSA-N 0.000 claims description 3
- SSJXIUAHEKJCMH-WDSKDSINSA-N (1s,2s)-cyclohexane-1,2-diamine Chemical compound N[C@H]1CCCC[C@@H]1N SSJXIUAHEKJCMH-WDSKDSINSA-N 0.000 claims description 3
- GTCCGKPBSJZVRZ-WHFBIAKZSA-N (2s,4s)-pentane-2,4-diol Chemical compound C[C@H](O)C[C@H](C)O GTCCGKPBSJZVRZ-WHFBIAKZSA-N 0.000 claims description 3
- OWBTYPJTUOEWEK-QWWZWVQMSA-N (R,R)-butane-2,3-diol Chemical compound C[C@@H](O)[C@@H](C)O OWBTYPJTUOEWEK-QWWZWVQMSA-N 0.000 claims description 3
- 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 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 3
- PWMWNFMRSKOCEY-QMMMGPOBSA-N (1r)-1-phenylethane-1,2-diol Chemical compound OC[C@H](O)C1=CC=CC=C1 PWMWNFMRSKOCEY-QMMMGPOBSA-N 0.000 claims description 2
- VCVOSERVUCJNPR-RFZPGFLSSA-N (1r,2r)-cyclopentane-1,2-diol Chemical compound O[C@@H]1CCC[C@H]1O VCVOSERVUCJNPR-RFZPGFLSSA-N 0.000 claims description 2
- VCVOSERVUCJNPR-SYDPRGILSA-N (1r,2s)-cyclopentane-1,2-diol Chemical compound O[C@H]1CCC[C@H]1O VCVOSERVUCJNPR-SYDPRGILSA-N 0.000 claims description 2
- IHPDTPWNFBQHEB-KBPBESRZSA-N (1s,2s)-1,2-diphenylethane-1,2-diol Chemical compound C1([C@H](O)[C@@H](O)C=2C=CC=CC=2)=CC=CC=C1 IHPDTPWNFBQHEB-KBPBESRZSA-N 0.000 claims description 2
- OHMBHFSEKCCCBW-PHDIDXHHSA-N (2R,5R)-hexanediol Chemical compound C[C@@H](O)CC[C@@H](C)O OHMBHFSEKCCCBW-PHDIDXHHSA-N 0.000 claims description 2
- PAXWQLGKYISPNH-HTQZYQBOSA-N (2R,7R)-octane-2,7-diol Chemical compound C[C@H](CCCC[C@@H](C)O)O PAXWQLGKYISPNH-HTQZYQBOSA-N 0.000 claims description 2
- TUVOFCSJXRZIOZ-RKDXNWHRSA-N (2R,8R)-nonane-2,8-diol Chemical compound C[C@H](CCCCC[C@@H](C)O)O TUVOFCSJXRZIOZ-RKDXNWHRSA-N 0.000 claims description 2
- NJPZORYXXMZSGU-NXEZZACHSA-N (2R,9R)-decane-2,9-diol Chemical compound C[C@@H](O)CCCCCC[C@@H](C)O NJPZORYXXMZSGU-NXEZZACHSA-N 0.000 claims description 2
- OZIMXLFSRSPFAS-BQBZGAKWSA-N (2S,6S)-heptane-2,6-diol Chemical compound C[C@@H](CCC[C@H](C)O)O OZIMXLFSRSPFAS-BQBZGAKWSA-N 0.000 claims description 2
- PAXWQLGKYISPNH-YUMQZZPRSA-N (2S,7S)-octane-2,7-diol Chemical compound C[C@@H](CCCC[C@H](C)O)O PAXWQLGKYISPNH-YUMQZZPRSA-N 0.000 claims description 2
- NJPZORYXXMZSGU-UWVGGRQHSA-N (2S,9S)-decane-2,9-diol Chemical compound C[C@@H](CCCCCC[C@H](C)O)O NJPZORYXXMZSGU-UWVGGRQHSA-N 0.000 claims description 2
- YSRSBDQINUMTIF-SNVBAGLBSA-N (2r)-decane-1,2-diol Chemical compound CCCCCCCC[C@@H](O)CO YSRSBDQINUMTIF-SNVBAGLBSA-N 0.000 claims description 2
- GTCCGKPBSJZVRZ-RFZPGFLSSA-N (2r,4r)-pentane-2,4-diol Chemical compound C[C@@H](O)C[C@@H](C)O GTCCGKPBSJZVRZ-RFZPGFLSSA-N 0.000 claims description 2
- OZIMXLFSRSPFAS-RNFRBKRXSA-N (2r,6r)-heptane-2,6-diol Chemical compound C[C@@H](O)CCC[C@@H](C)O OZIMXLFSRSPFAS-RNFRBKRXSA-N 0.000 claims description 2
- YSRSBDQINUMTIF-JTQLQIEISA-N (2s)-decane-1,2-diol Chemical compound CCCCCCCC[C@H](O)CO YSRSBDQINUMTIF-JTQLQIEISA-N 0.000 claims description 2
- OHMBHFSEKCCCBW-WDSKDSINSA-N (2s,5s)-hexane-2,5-diol Chemical compound C[C@H](O)CC[C@H](C)O OHMBHFSEKCCCBW-WDSKDSINSA-N 0.000 claims description 2
- TUVOFCSJXRZIOZ-IUCAKERBSA-N (2s,8s)-nonane-2,8-diol Chemical compound C[C@H](O)CCCCC[C@H](C)O TUVOFCSJXRZIOZ-IUCAKERBSA-N 0.000 claims description 2
- OTIAABPRCRPHFC-RKDXNWHRSA-N (3R,7R)-nonane-3,7-diol Chemical compound CC[C@H](CCC[C@@H](CC)O)O OTIAABPRCRPHFC-RKDXNWHRSA-N 0.000 claims description 2
- FLCSUDIUYHCGGZ-NXEZZACHSA-N (3R,8R)-decane-3,8-diol Chemical compound CC[C@H](CCCC[C@@H](CC)O)O FLCSUDIUYHCGGZ-NXEZZACHSA-N 0.000 claims description 2
- OTIAABPRCRPHFC-IUCAKERBSA-N (3S,7S)-nonane-3,7-diol Chemical compound CC[C@@H](CCC[C@H](CC)O)O OTIAABPRCRPHFC-IUCAKERBSA-N 0.000 claims description 2
- FLCSUDIUYHCGGZ-UWVGGRQHSA-N (3S,8S)-decane-3,8-diol Chemical compound CC[C@@H](CCCC[C@H](CC)O)O FLCSUDIUYHCGGZ-UWVGGRQHSA-N 0.000 claims description 2
- POFSNPPXJUQANW-PHDIDXHHSA-N (3r,4r)-hexane-3,4-diol Chemical compound CC[C@@H](O)[C@H](O)CC POFSNPPXJUQANW-PHDIDXHHSA-N 0.000 claims description 2
- BQWORYKVVNTRAW-RNFRBKRXSA-N (3r,5r)-heptane-3,5-diol Chemical compound CC[C@@H](O)C[C@H](O)CC BQWORYKVVNTRAW-RNFRBKRXSA-N 0.000 claims description 2
- BCKOQWWRTRBSGR-HTQZYQBOSA-N (3r,6r)-octane-3,6-diol Chemical compound CC[C@@H](O)CC[C@H](O)CC BCKOQWWRTRBSGR-HTQZYQBOSA-N 0.000 claims description 2
- POFSNPPXJUQANW-WDSKDSINSA-N (3s,4s)-hexane-3,4-diol Chemical compound CC[C@H](O)[C@@H](O)CC POFSNPPXJUQANW-WDSKDSINSA-N 0.000 claims description 2
- BQWORYKVVNTRAW-BQBZGAKWSA-N (3s,5s)-heptane-3,5-diol Chemical compound CC[C@H](O)C[C@@H](O)CC BQWORYKVVNTRAW-BQBZGAKWSA-N 0.000 claims description 2
- BCKOQWWRTRBSGR-YUMQZZPRSA-N (3s,6s)-octane-3,6-diol Chemical compound CC[C@H](O)CC[C@@H](O)CC BCKOQWWRTRBSGR-YUMQZZPRSA-N 0.000 claims description 2
- MBEWGVZBETVWKJ-UWVGGRQHSA-N (4S,7S)-decane-4,7-diol Chemical compound CCC[C@@H](CC[C@H](CCC)O)O MBEWGVZBETVWKJ-UWVGGRQHSA-N 0.000 claims description 2
- VDZVHCDRFIJZKX-RKDXNWHRSA-N (4r,6r)-nonane-4,6-diol Chemical compound CCC[C@@H](O)C[C@H](O)CCC VDZVHCDRFIJZKX-RKDXNWHRSA-N 0.000 claims description 2
- VDZVHCDRFIJZKX-IUCAKERBSA-N (4s,6s)-nonane-4,6-diol Chemical compound CCC[C@H](O)C[C@@H](O)CCC VDZVHCDRFIJZKX-IUCAKERBSA-N 0.000 claims description 2
- FUGIIBWTNARRSF-NXEZZACHSA-N (5r,6r)-decane-5,6-diol Chemical compound CCCC[C@@H](O)[C@H](O)CCCC FUGIIBWTNARRSF-NXEZZACHSA-N 0.000 claims description 2
- PUPZLCDOIYMWBV-SCSAIBSYSA-N (R)-butane-1,3-diol Chemical compound C[C@@H](O)CCO PUPZLCDOIYMWBV-SCSAIBSYSA-N 0.000 claims description 2
- IHPDTPWNFBQHEB-ZIAGYGMSSA-N (R,R)-hydrobenzoin Chemical compound C1([C@@H](O)[C@H](O)C=2C=CC=CC=2)=CC=CC=C1 IHPDTPWNFBQHEB-ZIAGYGMSSA-N 0.000 claims description 2
- PUPZLCDOIYMWBV-BYPYZUCNSA-N (S)-butane-1,3-diol Chemical compound C[C@H](O)CCO PUPZLCDOIYMWBV-BYPYZUCNSA-N 0.000 claims description 2
- OWBTYPJTUOEWEK-IMJSIDKUSA-N (S,S)-butane-2,3-diol Chemical compound C[C@H](O)[C@H](C)O OWBTYPJTUOEWEK-IMJSIDKUSA-N 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- XULIXFLCVXWHRF-UHFFFAOYSA-N 1,2,2,6,6-pentamethylpiperidine Chemical compound CN1C(C)(C)CCCC1(C)C XULIXFLCVXWHRF-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 claims description 2
- FLUVVESHOANMOG-UHFFFAOYSA-N 1-cyclodecyldiazecane Chemical compound C1CCCCCCCCC1N1NCCCCCCCC1 FLUVVESHOANMOG-UHFFFAOYSA-N 0.000 claims description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- LDJXFZUGZASGIW-UHFFFAOYSA-L 2-diphenylphosphanylethyl(diphenyl)phosphane;palladium(2+);dichloride Chemical compound Cl[Pd]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 LDJXFZUGZASGIW-UHFFFAOYSA-L 0.000 claims description 2
- 125000003860 C1-C20 alkoxy group Chemical group 0.000 claims description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- XDODWINGEHBYRT-YUMQZZPRSA-N [(1r,2r)-2-(hydroxymethyl)cyclohexyl]methanol Chemical compound OC[C@@H]1CCCC[C@H]1CO XDODWINGEHBYRT-YUMQZZPRSA-N 0.000 claims description 2
- XDODWINGEHBYRT-OCAPTIKFSA-N [(1s,2r)-2-(hydroxymethyl)cyclohexyl]methanol Chemical compound OC[C@H]1CCCC[C@H]1CO XDODWINGEHBYRT-OCAPTIKFSA-N 0.000 claims description 2
- INVRLGIKFANLFP-PHDIDXHHSA-N [(4r,5r)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol Chemical compound CC1(C)O[C@H](CO)[C@@H](CO)O1 INVRLGIKFANLFP-PHDIDXHHSA-N 0.000 claims description 2
- INVRLGIKFANLFP-WDSKDSINSA-N [(4s,5s)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol Chemical compound CC1(C)O[C@@H](CO)[C@H](CO)O1 INVRLGIKFANLFP-WDSKDSINSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical group Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 claims description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 2
- PFURGBBHAOXLIO-OLQVQODUSA-N cis-cyclohexane-1,2-diol Chemical compound O[C@H]1CCCC[C@H]1O PFURGBBHAOXLIO-OLQVQODUSA-N 0.000 claims description 2
- PFURGBBHAOXLIO-WDSKDSINSA-N cyclohexane-1,2-diol Chemical compound O[C@H]1CCCC[C@@H]1O PFURGBBHAOXLIO-WDSKDSINSA-N 0.000 claims description 2
- XXECWTBMGGXMKP-UHFFFAOYSA-L dichloronickel;2-diphenylphosphanylethyl(diphenyl)phosphane Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 XXECWTBMGGXMKP-UHFFFAOYSA-L 0.000 claims description 2
- ZBQUMMFUJLOTQC-UHFFFAOYSA-N dichloronickel;3-diphenylphosphaniumylpropyl(diphenyl)phosphanium Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1[PH+](C=1C=CC=CC=1)CCC[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 ZBQUMMFUJLOTQC-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- 229960000948 quinine Drugs 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- PFURGBBHAOXLIO-PHDIDXHHSA-N trans-cyclohexane-1,2-diol Chemical compound O[C@@H]1CCCC[C@H]1O PFURGBBHAOXLIO-PHDIDXHHSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000006651 (C3-C20) cycloalkyl group Chemical group 0.000 claims 2
- MOILFCKRQFQVFS-OORONAJNSA-N (1s,3r,4s,5s)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1[C@H]2C(C)(C)[C@@H]1C[C@@H](O)[C@]2(O)C MOILFCKRQFQVFS-OORONAJNSA-N 0.000 claims 1
- SSYDTHANSGMJTP-ZXZARUISSA-N (3s,4r)-oxolane-3,4-diol Chemical compound O[C@H]1COC[C@H]1O SSYDTHANSGMJTP-ZXZARUISSA-N 0.000 claims 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims 1
- 230000007704 transition Effects 0.000 claims 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 abstract description 51
- 239000004305 biphenyl Substances 0.000 abstract description 26
- 235000010290 biphenyl Nutrition 0.000 abstract description 26
- 230000000694 effects Effects 0.000 abstract description 9
- 238000000926 separation method Methods 0.000 abstract description 4
- 239000004215 Carbon black (E152) Substances 0.000 abstract description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 abstract description 2
- 239000004327 boric acid Substances 0.000 abstract description 2
- 229930195733 hydrocarbon Natural products 0.000 abstract description 2
- 230000003287 optical effect Effects 0.000 abstract description 2
- 238000010898 silica gel chromatography Methods 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 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 8
- 238000004679 31P NMR spectroscopy Methods 0.000 description 6
- AMWIBYDUYRJBLM-KGZKBUQUSA-N [O].C[C@H](CC[C@@H](C)O)O Chemical compound [O].C[C@H](CC[C@@H](C)O)O AMWIBYDUYRJBLM-KGZKBUQUSA-N 0.000 description 6
- 238000006555 catalytic reaction Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XCGLJABEWPHFMX-UHFFFAOYSA-N (4-methoxy-2-propan-2-ylphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C(C(C)C)=C1 XCGLJABEWPHFMX-UHFFFAOYSA-N 0.000 description 3
- YVBFQTIEWXWDKZ-UHFFFAOYSA-N 3-methoxy-2-(2-methoxyphenyl)phenol Chemical group COC1=CC=CC=C1C1=C(O)C=CC=C1OC YVBFQTIEWXWDKZ-UHFFFAOYSA-N 0.000 description 3
- 229910021580 Cobalt(II) chloride Inorganic materials 0.000 description 3
- 229910021577 Iron(II) chloride Inorganic materials 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- WXUAQHNMJWJLTG-UHFFFAOYSA-N 2-methylbutanedioic acid Chemical compound OC(=O)C(C)CC(O)=O WXUAQHNMJWJLTG-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229960001270 d- tartaric acid Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QSAWQNUELGIYBC-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-dicarboxylic acid Chemical compound OC(=O)[C@@H]1CCCC[C@H]1C(O)=O QSAWQNUELGIYBC-PHDIDXHHSA-N 0.000 description 1
- PWMWNFMRSKOCEY-MRVPVSSYSA-N (1s)-1-phenylethane-1,2-diol Chemical compound OC[C@@H](O)C1=CC=CC=C1 PWMWNFMRSKOCEY-MRVPVSSYSA-N 0.000 description 1
- QSAWQNUELGIYBC-WDSKDSINSA-N (1s,2s)-cyclohexane-1,2-dicarboxylic acid Chemical compound OC(=O)[C@H]1CCCC[C@@H]1C(O)=O QSAWQNUELGIYBC-WDSKDSINSA-N 0.000 description 1
- ROEQGIFOWRQYHD-UHFFFAOYSA-N (2-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC=C1B(O)O ROEQGIFOWRQYHD-UHFFFAOYSA-N 0.000 description 1
- KTZUVUWIBZMHMC-UHFFFAOYSA-N (2-propan-2-ylphenyl)boronic acid Chemical compound CC(C)C1=CC=CC=C1B(O)O KTZUVUWIBZMHMC-UHFFFAOYSA-N 0.000 description 1
- ACTRVOBWPAIOHC-LWMBPPNESA-N (2r,3r)-2,3-bis(sulfanyl)butanedioic acid Chemical compound OC(=O)[C@@H](S)[C@H](S)C(O)=O ACTRVOBWPAIOHC-LWMBPPNESA-N 0.000 description 1
- FJWGRXKOBIVTFA-LWMBPPNESA-N (2r,3r)-2,3-dibromobutanedioic acid Chemical compound OC(=O)[C@@H](Br)[C@H](Br)C(O)=O FJWGRXKOBIVTFA-LWMBPPNESA-N 0.000 description 1
- PIYZBBVETVKTQT-LURJTMIESA-N (2s)-2-(2-methylpropyl)butanedioic acid Chemical compound CC(C)C[C@H](C(O)=O)CC(O)=O PIYZBBVETVKTQT-LURJTMIESA-N 0.000 description 1
- ACTRVOBWPAIOHC-JCYAYHJZSA-N (2s,3s)-2,3-bis(sulfanyl)butanedioic acid Chemical compound OC(=O)[C@H](S)[C@@H](S)C(O)=O ACTRVOBWPAIOHC-JCYAYHJZSA-N 0.000 description 1
- FJWGRXKOBIVTFA-JCYAYHJZSA-N (2s,3s)-2,3-dibromobutanedioic acid Chemical compound OC(=O)[C@H](Br)[C@@H](Br)C(O)=O FJWGRXKOBIVTFA-JCYAYHJZSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 1
- WXUAQHNMJWJLTG-VKHMYHEASA-N (S)-methylsuccinic acid Chemical compound OC(=O)[C@@H](C)CC(O)=O WXUAQHNMJWJLTG-VKHMYHEASA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- DLVPKRMLAXQBGK-UHFFFAOYSA-N 2-iodo-3-methoxyphenol Chemical compound COC1=CC=CC(O)=C1I DLVPKRMLAXQBGK-UHFFFAOYSA-N 0.000 description 1
- XFTRTWQBIOMVPK-RXMQYKEDSA-N D-citramalic acid Chemical compound OC(=O)[C@@](O)(C)CC(O)=O XFTRTWQBIOMVPK-RXMQYKEDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 229910006069 SO3H Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 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
- AXYSDZQJEIAXBL-UHFFFAOYSA-N bis(oxomethylidene)iron Chemical compound O=C=[Fe]=C=O AXYSDZQJEIAXBL-UHFFFAOYSA-N 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- BEENOGKCXKWOBB-UHFFFAOYSA-M chlorocopper;triphenylphosphane Chemical compound [Cu]Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 BEENOGKCXKWOBB-UHFFFAOYSA-M 0.000 description 1
- XFTRTWQBIOMVPK-UHFFFAOYSA-N citramalic acid Chemical compound OC(=O)C(O)(C)CC(O)=O XFTRTWQBIOMVPK-UHFFFAOYSA-N 0.000 description 1
- SYTWXWRJCLAZFP-UHFFFAOYSA-L cobalt(2+);2-diphenylphosphanylethyl(diphenyl)phosphane;dichloride Chemical compound Cl[Co]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 SYTWXWRJCLAZFP-UHFFFAOYSA-L 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000012649 demethylating agent Substances 0.000 description 1
- ZXTCSIQSHINKKY-UHFFFAOYSA-L dichloroiron;2-diphenylphosphanylethyl(diphenyl)phosphane Chemical compound Cl[Fe]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 ZXTCSIQSHINKKY-UHFFFAOYSA-L 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000006459 hydrosilylation reaction Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 229940116298 l- malic acid Drugs 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- HUMMCEUVDBVXTQ-UHFFFAOYSA-N naphthalen-1-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=CC=CC2=C1 HUMMCEUVDBVXTQ-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65525—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring
- C07F9/65527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- 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
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
- B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
-
- 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
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
- B01J2231/4211—Suzuki-type, i.e. RY + R'B(OR)2, in which R, R' are optionally substituted alkyl, alkenyl, aryl, acyl and Y is the leaving group
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- B—PERFORMING OPERATIONS; TRANSPORTING
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Abstract
本发明公开了一类手性桥连的轴手性单膦配体及其制备方法。本发明以联苯为骨架，通过精确的手性识别和控制，获得既具有桥连的手性链又具有轴手性的光学纯配体，合成方法简单、经济，通过硅胶柱层析分离方法即可分离纯化，避免了繁杂的手性拆分过程，所得手性配体在考察的模型反应中具有反应活性高、对映选择性好等优点；尤其在钯催化溴代杂环芳烃与芳基硼酸的不对称Suzuki反应中效果优秀。
Description
技术领域
本发明属于化学催化领域，具体地说，涉及一类手性单膦配体及其制备方法。
背景技术
在不对称催化反应中，配体的影响极其关键，由于配体没有通用性，底物结构的变化，常常会导致催化剂活性和对映选择性的显著改变，这就需要合适的配体与底物相互匹配。因此手性配体的设计合成与新的催化反应无疑都是不对称催化开发研究的热点(Noyori,R；Ohkuma,T.Angew.Chem.Int.Ed.2002,41,2008–2022.)，前者着重新配体的设计合成，后者则进行新反应的探索。手性膦配体是不对称催化过程中应用最广泛、最为成功的几类配体之一，在不对称催化的发展中起着至关重要的作用。在手性双膦配体中，已发现配体的二面角对不对称氢化的活性和对映选择性有着重要影响，合适的二面角往往能得到很好的对映选择性(Zhang,X.；et al.J.Org.Chem.2000,65,6223.Chan,A.S.C.；etal.J.Am.Chem.Soc.2006,128,5955.)。近年来，手性单膦配体特别是联芳基单膦配体，由于其广泛的手性诱导能力尤其在不对称C-C键形成方面的强大能力而备受关注，1991年Hayashi等合成了(S)-2-二苯基膦-2'-甲氧基-1,1'-联萘(MeO-MOP)，并成功应用于非官能团烯烃的不对称硅氢化反应中(Uozumi,Y；Hayashi,T.J.Am.Chem.Soc.1991,113,9887-9888.)。2000年Buchwald等开发了一系列轴手性联萘单磷配体(Yin,J.；Buchwald,S.L.J.Am.Chem.Soc.2000,122,12051.)，并成功应用于不对称Suzuki偶联反应中。邱立勤等人相继开发了二面角可调的手性联苯基O,P-单膦配体和N,P-单膦配体(Org.Lett.2012,14,1966；Adv.Synth.Catal.2012,354,239；CN102516300A；CN102532196A.)，应用于不对称Suzuki偶联反应时，获得了比联萘基单膦配体MOP及上述Buchwald配体更佳的效果。但不对称Suzuki偶联反应底物对配体的要求非常严格，应用已有配体获得成功的催化实例还非常有限，对杂环化合物以及大位阻联芳的不对称偶联，目前还缺乏有效的配体和催化体系，急需开发新型手性配体和催化体系来解决手性联芳基化合物的不对称催化合成这一热点难题。
发明内容
本发明的目的在于提供一类骨架新颖的手性单膦配体。
本发明的另一目的在于提供所述手性单膦配体及其制备方法。
本发明的另一目的在于提供所述手性单膦配体的应用。
本发明的上述目的通过如下技术方案予以实现：
一类手性桥连的轴手性单膦配体，其结构式如下：
其中，R为C1-20的芳基、C1-20的烷基、C1-20的环烷基、C1-20的杂环基以及取代芳基、取代烷基、取代环烷基或取代杂环基；R1、R2为氢、C1-20的芳基、C1-20的烃氧基、C1-20的烷基、C1-20的环烷基、C1-20的杂环基、氨基、卤素、-Bn、-COOH、-COOMe、-COOEt、-COOiPr、-COOtBu、-COOBn、-OH、-CF3、三甲基硅基、三乙基硅基、三苯基硅基、-SO3H及其对应的钠和钾之类的盐以及取代芳基、取代烷基、取代环烷基、取代杂环基或取代氨基中的任意一种；前述取代基任意选自C1-20的芳基、C1-20的烃氧基、C1-20的烷基、C1-20的环烷基、C1-20的杂环基、-CF3、卤素基团；R1出现在苯环的2'、3'、4'或5'位，但2'位不包含氨基、取代氨基、羟基、取代羟基，R2出现在苯环的3、4或5位；
所述
为含有中心手性的侧链，并有控制二面角大小的功能；所述
为由
脱去Lg(离去或部分离去的基团)后得到，所述Lg为羟基、羧基、酰氯、卤素、甲基磺酸酯、对甲基苯磺酸酯或三氟甲基磺酸酯；
所述
为碳原子个数为1～20；
在上述的轴手性单膦配体中，所述
为(2R,3R)-2,3-丁二醇、(2S,3S)-2,3-丁二醇、(1S,2S)-1,2-二苯乙二醇、(1R,2R)-1,2-二苯乙二醇、(2R,3R)-1,4-二苄氧基丁二醇、(2S,3S)-1,4-二苄氧基丁二醇、(2R,4R)-2,4-戊二醇、(2S,4S)-2,4-戊二醇、(2R,5R)-2,5-己二醇、(2S,5S)-2,5-己二醇、(3R,4R)-3,4-己二醇、(3S,4S)-3,4-己二醇、(3S)-1,3-丁二醇、(3R)-1,3-丁二醇、(R)-(-)-1-苯乙烷-1,2-二醇、(S)-(+)-1-苯乙烷-1,2-二醇、(R)-1,2-癸二醇、(S)-1,2-癸二醇、(2S,9S)-2,9-癸二醇、(2R,9R)-2,9-癸二醇、(3S,8S)-3,8-癸二醇、(3R,8R)-3,8-癸二醇、(4S,7S)-4,7-癸二醇、(5R,6R)-5,6-癸二醇、(5S,6S)-4,6-癸二醇、顺式-1,2-环己二醇、(1R,2R)-反-1,2-环己二醇、(1S,2S)-反-1,2-环己二醇、(1R,2R)-反-1,2-环戊二醇、(1S,2S)-反-1,2-环戊二醇、顺式-1,2-环戊二醇、(1S,2S,3R,5S)-(+)-2,3-蒎烷二醇、(3S,5S)-(+)-3,5-庚烷二醇、(3R,5R)-(-)-3,5-庚烷二醇、(2S,6S)-2,6-庚烷二醇、(2R,6R)-2,6-庚烷二醇、cis-3,4-四氢呋喃二醇(3R,6R)-3,6-辛二醇、(3S,6S)-3,6-辛二醇、(2R,7R)-2,7-辛二醇、(2S,7S)-2,7-辛二醇、(2R,8R)-2,8-壬二醇、(2S,8S)-2,8-壬二醇、(3R,7R)-3,7-壬二醇、(3S,7S)-3,7-壬二醇、(4R,6R)-4,6-壬二醇、(4S,6S)-4,6-壬二醇、顺-1,2-环己二甲醇、反-1,2-环己二甲醇、(+)-2,3-O-异亚丙基-L-苏糖醇、(-)-2,3-O-异亚丙基-D-苏糖醇这些手性二醇或(R)-2,2’-联萘酚、(S)-2,2’-联萘酚；或前述手性二醇的甲磺酸酯、对甲基苯磺酸酯或三氟甲基磺酸酯；或(R)-2,2’-联萘二羧酸、(S)-2,2’-联萘二羧酸、L-酒石酸、D-酒石酸、(2R,3R)-2,3-二溴丁二酸、(2S,3S)-2,3-二溴丁二酸、(2R,3R)-2,3-二巯丁二酸、(2S,3S)-2,3-二巯丁二酸、(S)-(-)-2-异丁基丁二酸、(+)-二-对甲氧苯酰-D-酒石酸、(-)-二-对甲氧苯酰-L-酒石酸、(1R,2R)-1,2-环己烷二甲酸、(1S,2S)-1,2-环己烷二甲酸、(R)-(-)-柠苹酸、(S)-(+)-柠苹酸、L-苹果酸、D-苹果酸、(R)-(+)-甲基琥珀酸或(S)-(-)-甲基琥珀酸这些手性二羧酸；或前述手性二羧酸所对应的酰氯；或前述手性二羧酸还原所对应的手性二醇及由其衍生的甲磺酸酯、对甲基苯磺酸酯或三氟甲基磺酸酯。
上述轴手性单膦配体的制备方法，包括如下步骤：
当R1和R2为氢时，式Ⅰ或式II化合物由如下方法制备得到：
(1)该类化合物以2-碘-3-甲氧基苯酚为起始原料，在无机碱与过渡金属存在下，在有机溶剂或水或有机溶剂/水混合溶剂中，化合物1与化合物2发生偶联反应，得到化合物3；反应温度20～100℃，反应时间1～50小时；
(2)在有机溶剂中，在氮原子上含有孤对电子的有机碱存在下，化合物3和三氟甲基磺酸酐反应得到相应的三氟甲基磺酸酯4；化合物4和三氟甲基磺酸酐的摩尔比为1:1～1:4；反应温度-25～40℃，反应时间1～24小时；
(3)在过渡金属、膦配体形成的配合物催化剂存在的条件下，化合物4与R2P(O)H在有机溶剂中反应制备化合物5；化合物4和R2P(O)H的摩尔比为1:1～1:5，化合物4与过渡金属、膦配体形成的配合物催化剂的摩尔比为100:1～1:1；反应温度60～130℃，反应时间1～40小时；
(5)在氮原子上含有孤对电子的有机碱存在的条件下，化合物5在有机溶剂中经三氯硅烷还原制得化合物6；化合物5和三氯硅烷的摩尔比为1:1～1:30；反应温度60～140℃，反应时间7～40小时；
(6)在去甲基试剂与有机溶剂存在的条件下，化合物6脱去甲基得到化合物7；化合物与去甲基试剂的摩尔比为1:2～1:20，反应温度为-80～30℃，反应时间为1～40小时；
(7)在无机碱存在下，在有机溶剂中，化合物7与化合物8发生成环反应，反应具有精确的手性识别和控制能力，无需经过繁杂的手性拆分过程，就可得到同时具有中心手性和轴手性的单膦配体9或10；反应温度为20～100℃，反应时间1～50小时。
在上述轴手性单膦配体的制备方法中，所述氮原子上含有孤对电子的有机碱优选为三甲胺、三乙胺、二异丙基乙胺、四甲基乙二胺、N,N-二甲基苯胺、N,N-二乙基苯胺、三丙胺、三丁胺、吡啶、N,N-二甲基吡啶、1,4-二氮杂二环[2,2,2]辛烷、二氮杂二环十二烷、1,4二甲基哌嗪、1-甲基哌啶、1-甲基吡咯、奎宁、1-甲基吗啉或1-甲基-2,2,6,6-四甲基哌啶；
所述无机碱优选为氢氧化钠、氢氧化钾、碳酸钾、碳酸铯、碳酸钠、磷酸钾或氟化铯；
所述有机溶剂优选为乙醚、乙腈、苯、甲苯、二甲苯、二甲基亚砜、四氢呋喃、甲基叔丁基醚、乙二醇甲醚、乙二醇二甲醚、二氯甲烷、二氯乙烷、氯仿、二硫化碳、四氯化碳、1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或N-甲基吡咯烷酮；
所述去甲基试剂优选为三氯化铝，三氯化硼，三溴化硼或三甲基碘硅烷。
在上述轴手性单膦配体的制备方法中，所述过渡金属、膦配体组成的配合物催化剂优选为：(CuMe)2(dppe)、CuCl(PPh3)3、FeCl2(dppe)、FeCl2(PPh3)3、FeCl3(PPh3)3、FeCl2(dppp)、FeCl2(dppb)、Fe(CO)2(PPh3)3、CoCl2(PPh3)3、CoCl2(dppe)、CoCl2(dppp)、CoCl2(dppb)、NiCl2(dppe)、NiCl2(dppp)、NiCl2(dppb)、PdCl2(dppe)、PdCl2(dppp)、PdCl2(dppb)、Pd(OAc)2(dppe)、Pd(OAc)2(dppp)或Pd(OAc)2(dppb)；
其中：
当R1或R2为非氢时，其制备方法为先在化合物1或化合物2上引入相应的取代基团，其余步骤与上述相同，得到相应手性单膦配体。
与现有技术相比，本发明具有如下有益效果：本发明所涉及的手性单膦配体的制备以联苯为骨架，通过精确的手性识别和控制，获得既具有桥连的手性链又具有轴手性的光学纯配体，合成方法简单、经济，通过硅胶柱层析分离方法即可分离纯化，避免了繁杂的手性拆分过程，所得手性配体在考察的模型反应中具有反应活性高、对映选择性好等优点；尤其在钯催化卤代杂环芳烃与芳基硼酸的不对称Suzuki反应中效果优秀，如使用MeO-MOP作为配体时仅得到收率78％、32％ee(对映体过量值)的目标产物，又如使用BINAP作为配体时，该反应不能进行，而在相同的条件下用本发明制备的(S)-[6,6’-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯代替，则可以得到82％的收率和81％ee(对映体过量值)的目标产物(实施例4)，其结果也明显优于使用之前开发的手性联苯基O,P-单膦配体和N,P-单膦配体(CN102516300A，CN102532196A)所获之结果，这一点在实施例4的对比例2-7中可以体现。利用本发明制备的手性单膦配体在钯催化2-亚磷酸二乙酯-1-溴喹啉与2-异丙基4-甲氧基苯硼酸的不对称Suzuki反应中，可得到53％的收率和高达96％ee(对映体过量值)的目标产物。
具体实施方式
实施例1：以制备(R)-[6,6'-((S,S)-2,3-丁二醇氧)]-2-二苯基膦联苯为例
6,6'-二甲氧基-2-羟基联苯的制备：
在氮气保护下，将15g(60mmol)2-碘-3-甲氧基苯酚1,13.68g(90mmol)2-甲氧基苯硼酸,24.84g(180mmol)碳酸钾，538mg(2.4mmol)醋酸钯悬浮在150mL N,N-二甲基甲酰胺(DMF)与150mL水中，升温至50℃，搅拌24小时，减压蒸去DMF和水，反应剩余物倒入1mol/L的盐酸中，用乙酸乙酯萃取3次，合并有机相。有机相用无水硫酸镁干燥，蒸去溶剂后粗产物经柱层析纯化得到10.2g产物6,6'-二甲氧基-2-羟基联苯，产率为74％。
产品分析结果：1H NMR(400MHz,CDCl3):δ7.41-7.45(m,1H),7.27-7.33(m,2H),7.08-7.13(m,2H),6.71(d,J＝8.0Hz,1H),6.62(d,J＝8.0Hz,1H),3.84(s,3H),3.76(s,3H).13C NMR(100MHz,CDCl3):δ157.78,157.09,154.22,133.11,129.78,129.20,129.15,121.24,121.11,111.73,111.69,108.91,103.47,103.43,55.88.ESI-HRMS Calcd.forC14H14O3[M+Na]+:253.0835,found 253.0837.
6,6'-二甲氧基-2-三氟甲磺酰氧基联苯的制备：
6,6'-二甲氧基-2-羟基联苯13.5g(58.7mmol)溶于90mL无水吡啶中，冰浴下缓慢加入三氟甲基磺酸酐33.1g(117.4mmol)。滴加完毕后冰浴下反应1小时，缓慢升温至室温，反应过夜，反应结束后减压蒸去吡啶，剩余物稀释到200mL乙酸乙酯中，然后依次用5％的盐酸、饱和碳酸氢钠、饱和食盐水洗涤，有机相用无水硫酸镁干燥，蒸去溶剂后粗产物经柱层析纯化得到20.2g产物6,6'-二甲氧基-2-三氟甲磺酰氧基联苯，产率95％。
产品分析结果：1H NMR(400MHz,CDCl3):δ7.38-7.49(m,2H),7.22-7.25(m,1H),7.01-7.09(m,4H),3.80(s,6H).13C NMR(100MHz,CDCl3):δ158.56,157.06,148.32,132.16,129.96,129.15,121.64,120.19,120.06,119.91,116.72,113.20,110.96,110.74,56.28,55.23.ESI-HRMS Calcd.for C15H13F3O5S[M+Na]+:385.0328,found 385.0335.
6,6'-二甲氧基-2-二苯基氧膦联苯的制备
在氮气保护下，5g(13.8mmol)6,6'-二甲氧基-2-三氟甲磺酰氧基联苯、5.58g(27.6mmol)二苯基膦氧、1.18g(2.76mmol)1,4-双二苯基膦丁烷(dppb)、618mg(2.76mmol)醋酸钯加入反应瓶中，然后加入8mL二异丙基乙胺和50mL二甲基亚砜，升温至110℃，反应12小时。反应结束后剩余物稀释到200mL的乙酸乙酯中，用水、1N稀盐酸、饱和碳酸氢钠、饱和食盐水洗涤。有机层用无水硫酸镁干燥，蒸出溶剂后粗产品经柱层析纯化得5.48g产物6,6'-二甲氧基-2-二苯基氧膦联苯，产率96％。
产品分析结果：1H NMR(400MHz,CDCl3):δ7.69-7.73(m,2H),7.28-7.49(m,8H),7.19-7.24(m,2H),7.06-7.16(m,3H),6.82(t,J＝8.0Hz,1H),6.32(d,J＝8.0Hz,1H),3.71(s,3H),3.42(s,3H).13C NMR(100MHz,CDCl3):δ158.25,158.11,156.52,134.22,133.74,133.27,133.20,132.91,132.77,132.71,132.67,132.23,132.11,132.02,131.13,131.11,130.90,130.80,130.55,130.52,129.18,128.17,128.14,128.02,127.54,127.42,125.98,125.86,124.08,124.04,119.27,114.80,114.78,108.93,56.22,54,20(observedcomplexity due to P-C splitting).31P NMR(162MHz,CDCl3):δ27.15.ESI-HRMSCalcd.for C26H23O3P [M+H]+:415.1458,found 415.1466.
6,6'-二甲氧基-2-二苯基膦联苯的制备
在氮气保护下，将4.14g(10mmol)6,6'-二甲氧基-2-二苯基氧膦联苯悬浮在100mL干燥的甲苯中，加入二异丙基乙胺38.7g(300mmol)、三氯硅烷13.5g(100mmol)。将反应瓶转移到油浴中升温至110℃，回流16小时，冷却至室温后，加入100mL乙酸乙酯稀释，用1N的氢氧化钠水溶液终止反应，过滤，用乙酸乙酯萃取水层。合并有机相用稀盐酸、饱和碳酸氢钠溶液、饱和食盐水洗涤，无水硫酸镁干燥。蒸出溶剂后粗产品经柱层析纯化得3.58g产物6,6'-二甲氧基-2-二苯基膦联苯，产率90％。
产品分析结果：1H NMR(400MHz,CDCl3):δ7.24-7.35(m,12H),7.02(d,J＝8.0Hz,2H),6.91-6.94(m,1H),6.85(d,J＝8.0Hz,1H),6.72-6.75(m,1H),3.77(s,3H),3.49(s,3H).13C NMR(100MHz,CDCl3):δ157.34,157.25,157.10,139.11,139.00,138.10,137.98,137.63,137.51,133.94,133.87,133.74,133.56,131.96,131.93,128.94,128.37,128.27,128.25,128.18,128.07,128.04,127.97,126.32,126.24,125.92,119.80,111.52,110.39,55.99,55,01(observed complexity due to P-C splitting).31P NMR(162MHz,CDCl3):δ-13.05.ESI-HRMS Calcd.for C26H23O2P[M+H]+:399.1508,found 399.1525.
6,6'-二羟基-2-二苯基膦联苯的制备
在氮气保护下，将3.17g(8mmol)6,6'-二甲氧基-2-二苯基膦联苯溶解在50mL干燥的二氯甲烷中，低温冷却至-70℃后缓慢加入26g(104mmol)三溴化硼，搅拌0.5小时后缓慢升至室温反应24小时。冰浴下缓慢加入水淬灭反应，用二氯甲烷萃取水层，合并有机相用饱和食盐水洗涤，无水硫酸镁干燥，蒸出溶剂后粗产品经柱层析纯化得2.55g产物6,6'-二羟基-2-二苯基膦联苯，产率86％。
产品分析结果：1H NMR(400MHz,CDCl3):δ7.29-7.42(m,7H),7.20-7.27(m,5H),7.05(d,J＝8.0Hz,1H),6.98(d,J＝8.0Hz,1H),6.78-7.82(m,2H),6.66-6.69(m,1H),5.11(s,2H).13C NMR(100MHz,CDCl3):δ154.06,153.99,153.46,140.37,140.25,136.51,136.40,136.35,136.25,133.97,133.94,130.83,128.85,128.80,128.52,128.45,128.39,128.31,126.77,126.46,125.84,120.96,120.32,120.24,116.42,116.38(observedcomplexity due to P-C splitting).31P NMR(162MHz,CDCl3):δ-12.26.ESI-HRMSCalcd.for C24H19O2P[M+H]+:371.1195,found 371.1207.
(R)-[6,6'-((S,S)-2,3-丁二醇氧)]-2-二苯基膦联苯的制备
在氮气保护下，将1.2g(3.24mmol)6,6'-二羟基-2-二苯基膦联苯，2.43g(7.45mmol)碳酸铯悬浮在80mL干燥的N,N-二甲基甲酰胺(DMF)中，在温度为80℃条件下搅拌1小时。然后将(2R,3R)-2,3-丁二醇的甲基磺酸酯1.68g(6.83mmol)溶解在40mL干燥的DMF中，在4小时内缓慢滴加到反应液中。反应液在温度为80℃条件下继续搅拌24小时，减压蒸去DMF。反应剩余物倒入1mol/L的盐酸中，用乙酸乙酯萃取3次，合并有机相。有机相用无水硫酸镁干燥，蒸去溶剂后粗产物经柱层析纯化得到0.34g产物(R)-[6,6'-((S,S)-2,3-丁二醇氧)]-2-二苯基膦联苯，产率为25％。
产品分析结果：1H NMR(400MHz,CDCl3):δ7.38-7.46(m,5H),7.20-7.35(m,6H),7.11-7.17(m,3H),7.06(d,J＝8.0Hz,1H),6.99(t,J＝8.0Hz,1H),6.85-6.87(m,1H),3.85-3.98(m,2H),1.39-1.42(m,6H).13C NMR(100MHz,CDCl3):δ159.08,159.00,158.87,138.21,138.08,137.98,137.81,137.71,134.28,134.08,133.69,133.49,131.56,131.47,130.54,130.27,129.85,128.99,128.77,128.64,128.13,128.09,128.02,122.77,122.47,121.88,86.44,85.50,19.12,19.04(observed complexity due to P-C splitting).31P NMR(162MHz,CDCl3):δ-12.25.ESI-HRMS Calcd.for C28H25O2P[M+H]+:425.1665,found425.1682.[α]D 25＝-28.4(c＝0.5,CH2Cl2).
实施例2：以制备(S)-[6,6'-((2R,4R)-2,4-戊二醇氧)]-2-二苯基膦联苯为示例
在氮气保护下，将1.2g(3.24mmol)6,6'-二羟基-2-二苯基膦联苯，2.43g(7.45mmol)碳酸铯悬浮在80mL干燥的N,N-二甲基甲酰胺(DMF)中，在温度为80℃条件下搅拌1小时。然后将(2S,4S)-2,4-戊二醇的对甲基苯基磺酸酯2.67g(6.48mmol)溶解在40mL干燥的DMF中，在4小时内缓慢滴加到反应液中。反应液在温度为80℃条件下继续搅拌30小时，减压蒸去DMF。反应剩余物倒入1mol/L的盐酸中，用乙酸乙酯萃取3次，合并有机相。有机相用无水硫酸镁干燥，蒸去溶剂后粗产物经柱层析纯化得到0.31g产物(S)-[6,6'-((2R,4R)-2,4-戊二醇氧)]-2-二苯基膦联苯，产率为22％。
产品分析结果：1H NMR(400MHz,CDCl3):δ7.35-7.43(m,5H),7.21-7.24(m,5H),7.10-7.17(m,4H),7.06(d,J＝8.0Hz,1H),6.91(t,J＝8.0Hz,1H),6.70-6.74(m,1H),4.54-4.65(m,2H),1.71-1.94(m,2H),1.37-1.39(m,6H).13C NMR(100MHz,CDCl3):δ157.69,157.61,156.99,138.04,137.92,137.71,137.58,137.43,136.92,136.64,134.40,134.20,133.82,133.62,131.58,131.51,129.85,129.78,128.78,128.61,128.55,128.48,128.23,128.09,128.01,127.95,127.88,121.37,118.00,117.13,75.67,74.45,41.01,22.63,22.09(observed complexity due to P-C splitting).31P NMR(162MHz,CDCl3):δ-12.42.ESI-HRMS Calcd.for C29H27O2P[M+H]+:439.1821；found 439.1823.[α]D 25＝+108.9(c＝0.5,CH2Cl2).
实施例3：以制备(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯为示例
在氮气保护下，将1.2g(3.24mmol)6,6'-二羟基-2-二苯基膦联苯，2.43g(7.45mmol)碳酸铯悬浮在80mL干燥的N,N-二甲基甲酰胺(DMF)中，在温度为80℃条件下搅拌1小时。然后将(2S,5S)-2,4-己二醇的对甲基苯基磺酸酯2.76g(6.48mmol)溶解在40mL干燥的DMF中，在4小时内缓慢滴加到反应液中。反应液在温度为80℃条件下继续搅拌30小时，减压蒸去DMF。反应剩余物倒入1mol/L的盐酸中，用乙酸乙酯萃取3次，合并有机相。有机相用无水硫酸镁干燥，蒸去溶剂后粗产物经柱层析纯化得到0.61g产物(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯，产率为42％。
产品分析结果：1H NMR(400MHz,CDCl3):δ7.38-7.45(m,5H),7.11-7.24(m,7H),7.07-7.09(m,1H),7.01-7.03(m,1H),6.79-6.84(m,2H),6.60-6.63(m,1H),4.40-4.48(m,2H),1.81-1.84(m,2H),1.55-1.59(m,2H),1.29-1.36(m,6H).13C NMR(100MHz,CDCl3):δ157.24,157.17,156.81,138.44,138.31,137.90,137.82,137.78,137.70,134.81,134.49,134.29,133.78,133.58,132.24,132.17,128.82,128.55,128.45,128.38,128.06,127.88,127.85,127.75,127.45,126.35,119.56,114.61,113.83,79.68,78.68,33.24,33.11,21.62,21.47(observed complexity due to P-C splitting).31P NMR(162MHz,CDCl3):δ-11.41.ESI-HRMS Calcd.for C30H29O2P[M+H]+:453.1978,found 453.1981.[α]D 25＝+85.8(c＝0.5,CH2Cl2).
实施例4(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯在不对称Suzuki反应中的应用
在手套箱中将2-亚磷酸二乙酯-1-溴喹啉、(1.0mmol,1.0equiv)、萘硼酸2.0equiv)、Pd2(dba)3(2mol％)、配体(S)-[6,6’-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯(4.8mol％)、磷酸钾(3equiv)、6mL四氢呋喃置于15mL烘干的单口瓶中，封闭瓶口，40℃下搅拌40小时。经柱层析分离后收率为82％，HPLC分析对映体过量值为81％ee。
对比例1
以(R)-MeO-MOP代替(S)-[6,6’-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯作为配体，重复实施例4。
MeO-MOP作为配体时仅得到78％的收率和32％ee(对映体过量值)的目标产物。
对比例2
以(R)-[6,6'-((S,S)-2,3-丁二醇氧)]-2-二苯基膦-2'-甲氧基联苯代替(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯作为配体，重复实施例4。
(R)-[6,6'-((S,S)-2,3-丁二醇氧)]-2-二苯基膦-2'-甲氧基联苯作为配体时得到65％的收率和49％ee(对映体过量值)的目标产物。
对比例3
以(R)-[6,6'-((S,S)-2,3-丁二醇氧)]-2-二(3,5-二甲基苯基)膦-2'-甲氧基联苯代替(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯作为配体，重复实施例4。
(R)-[6,6'-((S,S)-2,3-丁二醇氧)]-2-二(3,5-二甲基苯基)膦-2'-甲氧基联苯作为配体时得到73％的收率和61％ee(对映体过量值)的目标产物。
对比例4
以(R)-[6,6'-((S,S)-2,3-丁二醇氧)]-2-二(3,5-二叔丁基苯基)膦-2'-甲氧基联苯代替(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯作为配体，重复实施例4。
(R)-[6,6'-((S,S)-2,3-丁二醇氧)]-2-二(3,5-二叔丁基苯基)膦-2'-甲氧基联苯作为配体时得到78％的收率和61％ee(对映体过量值)的目标产物。
对比例5
以(S)-[6,6'-((2R,4R)-2,4-戊二醇氧)]-2-二(3,5-二叔丁基苯基)膦-2'-甲氧基联苯代替(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯作为配体，重复实施例4。
(S)-[6,6'-((2R,4R)-2,4-戊二醇氧)]-2-二(3,5-二叔丁基苯基)膦-2'-甲氧基联苯作为配体时得到74％的收率和42％ee(对映体过量值)的目标产物。
对比例6
以(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二(3,5-二叔丁基苯基)膦-2'-甲氧基联苯代替(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯作为配体，重复实施例4。
(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二(3,5-二叔丁基苯基)膦-2'-甲氧基联苯作为配体时得到68％的收率和28％ee(对映体过量值)的目标产物。
对比例7
以(S)-[6,6'-((2R,4R)-2,4-戊二醇氧)]-2-二苯基膦2'-(N,N-二甲基)联苯代替(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯作为配体，重复实施例4。
(S)-[6,6'-((2R,4R)-2,4-戊二醇氧)]-2-二苯基膦2'-(N,N-二甲基)联苯作为配体时得到69％的收率和46％ee(对映体过量值)的目标产物。
与实施例4相同的实验条件，替换不同的膦配体，并测量其在催化不对称Suzuki反应中的应用效果，结果如表1所示：
表1
实施例5(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯在不对称Suzuki反应中的应用
在手套箱中将2-亚磷酸二乙酯-1-溴喹啉、(1.0mmol,1.0equiv)、4-苯基-1-萘硼酸2.0equiv)、Pd2(dba)3(2mol％)、配体(S)-[6,6’-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯(4.8mol％)、磷酸钾(3equiv)、6mL四氢呋喃置于15mL烘干的单口瓶中，封闭瓶口，40℃下搅拌40小时。经柱层析分离后收率为85％，HPLC分析对映体过量值为87％ee。
实施例6(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯在不对称Suzuki反应中的应用
在手套箱中将2-亚磷酸二乙酯-1-溴喹啉、(1.0mmol,1.0equiv)、2-异丙基苯硼酸2.0equiv)、Pd2(dba)3(2mol％)、配体(S)-[6,6’-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯(4.8mol％)、磷酸钾(3equiv)、6mL乙二醇二甲醚置于15mL烘干的单口瓶中，封闭瓶口，40℃下搅拌60小时。经柱层析分离后收率为83％，HPLC分析对映体过量值为88％ee。
实施例7(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯在不对称Suzuki反应中的应用
在手套箱中将2-亚磷酸二乙酯-1-溴喹啉、(1.0mmol,1.0equiv)、2-异丙基4-甲氧基苯硼酸2.0equiv)、Pd2(dba)3(2mol％)、配体(S)-[6,6’-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯(4.8mol％)、磷酸钾(3equiv)、6mL乙二醇二甲醚置于15mL烘干的单口瓶中，封闭瓶口，40℃下搅拌72小时。经柱层析分离后收率为53％，HPLC分析对映体过量值为96％ee。
实施例8(S)-[6,6'-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯在不对称Suzuki反应中的应用
在手套箱中将2-亚磷酸二乙酯-1-溴喹啉、(1.0mmol,1.0equiv)、2-异丙基4-甲氧基苯硼酸2.0equiv)、Pd2(dba)3(2mol％)、配体(S)-[6,6’-((2R,5R)-2,5-己二醇氧)]-2-二苯基膦联苯(4.8mol％)、磷酸钾(3equiv)、6mL乙二醇二甲醚置于15mL烘干的单口瓶中，封闭瓶口，40℃下搅拌72小时。经柱层析分离后收率为57％，HPLC分析对映体过量值为90％ee。
Claims (6)
1.一类手性桥连的轴手性单膦配体，其结构式如下：
其中，R为C5-20的芳基、C1-20的烷基、C3-20的环烷基以及取代芳基、取代烷基、取代环烷基；R1、R2为氢、C5-20的芳基、C1-20的烃氧基、C1-20的烷基、C3-20的环烷基、卤素、-Bn、-CF3、三甲基硅基、三乙基硅基、三苯基硅基以及取代芳基、取代烷基、取代环烷基或取代氨基中的任意一种；前述取代基任意选自C5-20的芳基、C1-20的烃氧基、C1-20的烷基、C3-20的环烷基、-CF3、卤素基团；R1出现在苯环的3'、4'或5'位，R2出现在苯环的3、4或5位；
所述
为含有中心手性的侧链，其碳原子个数为3～20，由
脱去Lg后得到，所述Lg为羟基、甲基磺酸酯、对甲基苯磺酸酯或三氟甲基磺酸酯；所述
具体为(2R,3R)-2,3-丁二醇、(2S,3S)-2,3-丁二醇、(1S,2S)-1,2-二苯乙二醇、(1R,2R)-1,2-二苯乙二醇、(2R,3R)-1,4-二苄氧基丁二醇、(2S,3S)-1,4-二苄氧基丁二醇、(2R,4R)-2,4-戊二醇、(2S,4S)-2,4-戊二醇、(2R,5R)-2,5-己二醇、(2S,5S)-2,5-己二醇、(3R,4R)-3,4-己二醇、(3S,4S)-3,4-己二醇、(3S)-1,3-丁二醇、(3R)-1,3-丁二醇、(R)-(-)-1-苯乙烷-1,2-二醇、(S)-(+)-1-苯乙烷-1,2-二醇、(R)-1,2-癸二醇、(S)-1,2-癸二醇、(2S,9S)-2,9-癸二醇、(2R,9R)-2,9-癸二醇、(3S,8S)-3,8-癸二醇、(3R,8R)-3,8-癸二醇、(4S,7S)-4,7-癸二醇、(5R,6R)-5,6-癸二醇、(5S,6S)-4,6-癸二醇、顺式-1,2-环己二醇、(1R,2R)-反-1,2-环己二醇、(1S,2S)-反-1,2-环己二醇、(1R,2R)-反-1,2-环戊二醇、(1S,2S)-反-1,2-环戊二醇、顺式-1,2-环戊二醇、(1S,2S,3R,5S)-(+)-2,3-蒎烷二醇、(3S,5S)-(+)-3,5-庚烷二醇、(3R,5R)-(-)-3,5-庚烷二醇、(2S,6S)-2,6-庚烷二醇、(2R,6R)-2,6-庚烷二醇、cis-3,4-四氢呋喃二醇(3R,6R)-3,6-辛二醇、(3S,6S)-3,6-辛二醇、(2R,7R)-2,7-辛二醇、(2S,7S)-2,7-辛二醇、(2R,8R)-2,8-壬二醇、(2S,8S)-2,8-壬二醇、(3R,7R)-3,7-壬二醇、(3S,7S)-3,7-壬二醇、(4R,6R)-4,6-壬二醇、(4S,6S)-4,6-壬二醇、顺-1,2-环己二甲醇、反-1,2-环己二甲醇、(+)-2,3-O-异亚丙基-L-苏糖醇、(-)-2,3-O-异亚丙基-D-苏糖醇这些手性二醇；或前述手性二醇的甲磺酸酯、对甲基苯磺酸酯或三氟甲基磺酸酯。
2.权利要求1所述的轴手性单膦配体的制备方法，其特征在于包括如下步骤：
当R1和R2为氢时，式Ⅰ或式II化合物由如下方法制备得到：
(1)该类化合物以2-碘-3-甲氧基苯酚为起始原料，在无机碱与过渡金属存在下，在有机溶剂或水或有机溶剂/水混合溶剂中，化合物1与化合物2发生偶联反应，得到化合物3；反应温度20～100℃，反应时间1～50小时；
(2)在有机溶剂中，在氮原子上含有孤对电子的有机碱存在下，化合物3和三氟甲基磺酸酐反应得到相应的三氟甲基磺酸酯4；化合物4和三氟甲基磺酸酐的摩尔比为1:1～1:4；反应温度-25～40℃，反应时间1～24小时；
(3)在过渡金属、膦配体形成的配合物催化剂存在的条件下，化合物4与R2P(O)H在有机溶剂中反应制备化合物5；化合物4和R2P(O)H的摩尔比为1:1～1:5，化合物4与过渡金属、膦配体形成的配合物催化剂的摩尔比为100:1～1:1；反应温度60～130℃，反应时间1～40小时；
(5)在氮原子上含有孤对电子的有机碱存在的条件下，化合物5在有机溶剂中经三氯硅烷还原制得化合物6；化合物5和三氯硅烷的摩尔比为1:1～1:30；反应温度60～140℃，反应时间7～40小时；
(6)在去甲基试剂与有机溶剂存在的条件下，化合物6脱去甲基得到化合物7；化合物与去甲基试剂的摩尔比为1:2～1:20，反应温度为-80～30℃，反应时间为1～40小时；
(7)在无机碱存在下，在有机溶剂中，化合物7与化合物8发生成环反应，反应具有精确的手性识别和控制能力，无需经过繁杂的手性拆分过程，就可得到同时具有中心手性和轴手性的单膦配体9或10；反应温度为20～100℃，反应时间1～50小时。
3.如权利要求2所述的制备方法，其特征在于，所述氮原子上含有孤对电子的有机碱为三甲胺、三乙胺、二异丙基乙胺、四甲基乙二胺、N,N-二甲基苯胺、N,N-二乙基苯胺、三丙胺、三丁胺、吡啶、N,N-二甲基吡啶、1,4-二氮杂二环[2,2,2]辛烷、二氮杂二环十二烷、1,4二甲基哌嗪、1-甲基哌啶、1-甲基吡咯、奎宁、1-甲基吗啉或1-甲基-2,2,6,6-四甲基哌啶；
所述无机碱为氢氧化钠、氢氧化钾、碳酸钾、碳酸铯、碳酸钠、磷酸钾或氟化铯；
所述有机溶剂为乙醚、乙腈、苯、甲苯、二甲苯、二甲基亚砜、四氢呋喃、甲基叔丁基醚、乙二醇甲醚、乙二醇二甲醚、二氯甲烷、二氯乙烷、氯仿、二硫化碳、四氯化碳、1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或N-甲基吡咯烷酮；
所述去甲基试剂为三氯化铝，三氯化硼，三溴化硼或三甲基碘硅烷。
4.如权利要求2-3任一项所述的制备方法，其特征在于，所述过渡金属、膦配体组成的配合物催化剂为：NiCl2(dppe)、NiCl2(dppp)、NiCl2(dppb)、PdCl2(dppe)、PdCl2(dppp)、PdCl2(dppb)、Pd(OAc)2(dppe)、Pd(OAc)2(dppp)或Pd(OAc)2(dppb)；
其中：
5.权利要求2所述的制备方法，其特征在于包括如下步骤：
当R1或R2为非氢时，其制备方法为先在化合物1或化合物2上引入相应的取代基团，其余步骤与权利要求3相同，得到相应的手性单膦配体。
6.权利要求1所述的轴手性单膦配体在钯催化的不对称Suzuki反应中的应用。
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