CN114029086B - 一种轴手性萘-吡咯类膦催化剂及其制备方法与应用 - Google Patents
一种轴手性萘-吡咯类膦催化剂及其制备方法与应用 Download PDFInfo
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- 239000003054 catalyst Substances 0.000 title claims abstract description 74
- -1 naphthalene-pyrrole phosphine Chemical compound 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 98
- 150000001875 compounds Chemical class 0.000 claims abstract description 97
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 60
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 25
- 238000003756 stirring Methods 0.000 claims abstract description 23
- 239000002994 raw material Substances 0.000 claims abstract description 21
- 238000005859 coupling reaction Methods 0.000 claims abstract description 5
- 238000006459 hydrosilylation reaction Methods 0.000 claims abstract description 5
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 129
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 114
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 46
- 239000011259 mixed solution Substances 0.000 claims description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 33
- 238000004809 thin layer chromatography Methods 0.000 claims description 33
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- 238000010898 silica gel chromatography Methods 0.000 claims description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 239000011261 inert gas Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000007810 chemical reaction solvent Substances 0.000 claims description 13
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 239000000654 additive Substances 0.000 claims description 10
- 230000000996 additive effect Effects 0.000 claims description 10
- 239000003446 ligand Substances 0.000 claims description 10
- 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 10
- 238000001914 filtration Methods 0.000 claims description 9
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- 239000005052 trichlorosilane Substances 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical compound Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- BZLZKLMROPIZSR-UHFFFAOYSA-N triphenylsilicon Chemical compound C1=CC=CC=C1[Si](C=1C=CC=CC=1)C1=CC=CC=C1 BZLZKLMROPIZSR-UHFFFAOYSA-N 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 5
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 claims description 5
- DPGHISRNNOYQGP-UHFFFAOYSA-N 1-(1,2,3,4,4a,5,6,7-octahydronaphthalen-1-yl)naphthalene Chemical group C1=CC=C2C(C3CCCC4C3=CCCC4)=CC=CC2=C1 DPGHISRNNOYQGP-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N binaphthyl group Chemical group C1(=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
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- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 claims description 3
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical group P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims 1
- 239000011698 potassium fluoride Substances 0.000 claims 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 abstract description 16
- 229910000073 phosphorus hydride Inorganic materials 0.000 abstract description 8
- 238000007040 multi-step synthesis reaction Methods 0.000 abstract 1
- 230000003287 optical effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 90
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 25
- 239000000047 product Substances 0.000 description 22
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 238000012512 characterization method Methods 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- 238000004252 FT/ICR mass spectrometry Methods 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- 239000000376 reactant Substances 0.000 description 17
- 238000002844 melting Methods 0.000 description 14
- 230000008018 melting Effects 0.000 description 14
- 239000002808 molecular sieve Substances 0.000 description 14
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 14
- 229940126214 compound 3 Drugs 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 12
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- 238000004679 31P NMR spectroscopy Methods 0.000 description 4
- CLPHAYNBNTVRDI-UHFFFAOYSA-N ditert-butyl propanedioate Chemical compound CC(C)(C)OC(=O)CC(=O)OC(C)(C)C CLPHAYNBNTVRDI-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- HVAMZGADVCBITI-UHFFFAOYSA-M pent-4-enoate Chemical compound [O-]C(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-M 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SLLGVCUQYRMELA-UHFFFAOYSA-N chlorosilicon Chemical compound Cl[Si] SLLGVCUQYRMELA-UHFFFAOYSA-N 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- AONJIZKDDQFWRD-UHFFFAOYSA-N 1,5-bis(4-methoxyphenyl)-2-(2-methylprop-1-enyl)-3-propan-2-ylpentane-1,5-dione Chemical compound C1=CC(OC)=CC=C1C(=O)CC(C(C)C)C(C=C(C)C)C(=O)C1=CC=C(OC)C=C1 AONJIZKDDQFWRD-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0255—Phosphorus containing compounds
- B01J31/0267—Phosphines or phosphonium compounds, i.e. phosphorus bonded to at least one carbon atom, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, the other atoms bonded to phosphorus being either carbon or hydrogen
- B01J31/0268—Phosphonium compounds, i.e. phosphine with an additional hydrogen or carbon atom bonded to phosphorous so as to result in a formal positive charge on phosphorous
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Abstract
本发明公开了一种轴手性萘‑吡咯类膦催化剂及其制备方法与应用,该膦催化剂的结构如式6所示;以式1、式2化合物为原料,在手性磷酸催化剂作用下搅拌反应得式3化合物;再以式3化合物为原料,经多步合成得到式6化合物。该膦催化剂可用于催化不对称硅氢化氧化反应或不对称偶联反应。本发明制备轴手性萘‑吡咯类膦催化剂的方法操作简便、反应条件温和、原料经济易得,且制备得到的轴手性萘‑吡咯类膦催化剂的光学纯度高,产率高,应用前景好。
Description
技术领域
本发明涉及有机化学合成技术领域,具体涉及一种轴手性萘-吡咯类膦催化剂及其制备方法与应用。
背景技术
手性膦催化剂是一类应用非常广泛的催化剂,可以用于催化各种类型的有机化学反应。然而手性膦催化剂大部分是含有碳手性中心的膦催化剂,轴手性膦催化剂的报道却屈指可数,且往往局限于联芳基轴手性膦催化剂。因此,开发新型的轴手性膦催化剂用于催化不对称反应的基础研究和工业生产具有不可忽视的意义。
发明内容
本发明的目的之一是提供一种轴手性萘-吡咯类膦催化剂,满足催化不对称反应的基础研究和工业生产的需要。
本发明的目的之二是提供上述轴手性萘-吡咯类膦催化剂的制备方法,反应条件温和、成本低、收率高、对映选择性高。
本发明的目的之三是提供上述轴手性萘-吡咯类膦催化剂在催化不对称反应中的应用。
为实现上述目的,本发明采用的技术方案如下:
第一方面,本发明提供一种轴手性萘-吡咯类膦催化剂,其化学结构如式6所示:
式中,R1选自氢、C1-C4烷基、C1-C4烷氧基、卤素中的一种;R2选自氢、C1-C4烷基、C1-C4烷氧基、卤素中的一种;R3选自芳基、杂芳基、烷基中的一种;R4选自芳基、杂芳基、烷基中的一种;R5选自芳基、杂芳基、烷基中的一种;R6选自芳基、杂芳基、烷基中的一种。
第二方面,本发明还提供上述轴手性萘-吡咯类膦催化剂的制备方法,具体步骤如下:
(1)以式1化合物和式2化合物为反应原料,以二氯甲烷、乙酸乙酯、甲苯、丙酮或乙腈中的一种或两种作为溶剂,手性磷酸为催化剂,在0-40℃搅拌反应,TLC跟踪反应至结束,过滤、浓缩、纯化即制得式3化合物;其中,式1化合物和式2化合物的反应摩尔比为1:1.2至2:1;
(2)惰性气体氛围下,以式3化合物、三氟甲磺酸酐为原料,以二氯甲烷为反应溶剂,加入N,N-二异丙基乙胺,在0℃搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取,浓缩、纯化即制得式4化合物;
(3)惰性气体氛围下,以式4化合物、二级膦氧化物为原料,二甲基亚砜(DMSO)为反应溶剂,二异丙基乙胺作为有机碱,醋酸钯和1,4-双(二苯膦)丁烷(DPPB)分别作为催化剂和配体,在120℃搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取,浓缩、纯化即制得式5化合物;
(4)惰性气体氛围下,以式5化合物、三氯硅烷为原料,甲苯(toluene)为反应溶剂,三乙胺作为有机碱,在120℃搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取,浓缩、纯化即制得式6化合物;
其中,所述的式1化合物的结构式为所述的式2化合物的结构式为所述的式3化合物的结构式为所述的式4化合物的结构式为所述的式5化合物的结构式为式中,R1选自氢、C1-C4烷基、C1-C4烷氧基、卤素中的一种;R2选自氢、C1-C4烷基、C1-C4烷氧基、卤素中的一种;R3选自芳基、杂芳基、烷基中的一种;R4选自芳基、杂芳基、烷基中的一种;R5选自芳基、杂芳基、烷基中的一种;R6选自芳基、杂芳基、烷基中的一种;
所述的手性磷酸选自联萘骨架衍生物、八氢联萘骨架衍生物、螺环骨架衍生物中的一种或两种;所述的联萘骨架衍生物的结构式为式中G选自9-蒽基、9-菲基、2,4,6-三异丙基苯基、三苯基硅基、4-氯苯基、2-萘基或1-萘基中的一种;所述的八氢联萘骨架衍生物的结构式为式中G’选自9-蒽基、9-菲基、2,4,6-三异丙基苯基、三苯基硅基、4-氯苯基、2-萘基或1-萘基中的一种;所述的螺环骨架衍生物的结构式为式中G”选自9-蒽基、9-菲基、2,4,6-三异丙基苯基、三苯基硅基、4-氯苯基、2-萘基或1-萘基中的一种。
其反应路线如下:
优选的,步骤(1)纯化采用硅胶柱层析,洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液;步骤(2)纯化采用硅胶柱层析,洗脱剂为体积比1:1的石油醚和二氯甲烷混合溶液;步骤(3)纯化采用硅胶柱层析,洗脱剂为体积比2:1的石油醚与乙酸乙酯混合溶液;步骤(4)纯化采用硅胶柱层析,洗脱剂为体积比5:1的石油醚与乙酸乙酯混合溶液。
第三方面,本发明还提供轴手性萘-吡咯类膦催化剂在苯乙烯的不对称硅氢化氧化反应中的应用。
具体步骤是:在惰性气体保护下,以苯乙烯为原料,烯丙基氯化钯为催化剂,式6a轴手性萘-吡咯类膦为配体,加入三氯硅氢,0℃搅拌反应数小时,通过蒸馏方式制得式8中间体;以蒸馏制得的式8中间体为原料,加入过氧化氢(H2O2)、氟化钾(KF)、碳酸氢钾(KHCO3),室温条件下搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取、浓缩、纯化即得式9化合物。
反应式如下:
第四方面,本发明还提供轴手性萘-吡咯类膦催化剂在不对称偶联反应中的应用。
在惰性气体保护下,以式10烯丙基醋酸酯、式11丙二酸二叔丁酯为原料,乙腈(CH3CN)为溶剂,烯丙基氯化钯为催化剂,式6a轴手性萘-吡咯类膦为配体,醋酸锂(LiOAc)为无机碱,N,O-双三甲硅基乙酰胺(BSA)为添加剂,-20℃搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取、浓缩、纯化即得式12化合物。
反应式如下:
与现有技术相比,本发明具有如下有益效果:
1.本发明的一种新型轴手性萘-吡咯类膦催化剂,不仅可应用于苯乙烯的催化不对称硅氢化氧化反应,还可应用于烯丙基醋酸酯和丙二酸二叔丁酯的催化不对称偶联反应中,说明本发明合成的轴手性萘-吡咯类膦催化剂在多类型催化不对称反应中具有应用价值。
2.本发明的一种新型轴手性萘-吡咯类膦催化剂的合成方法,采用手性磷酸作为催化剂,可获得高的对映选择性;本合成方法中,产物的对映选择性高、收率高、反应过程温和、原料廉价,适宜工业化生产;可采用多种类的底物作为反应物,获得结构多样性的新型轴手性萘-吡咯类膦催化剂。
具体实施方式
下面结合附图和具体实施例对本发明作进一步详细说明。
下述实施例中,除非另有说明,所述的实验方法通常按照常规条件或制造厂商建议的条件实施。
以下实施例中所述式1化合物可采用文献Angew.Chem.Int.Ed.2019,58,15104报道的方法制备;式2化合物可采用文献Nat.Commun.2017,8,1;Org.Biomol.Chem.2021,19,4992报道的方法制备;所述手性磷酸催化剂以及其他试剂均可通过市售购买的方式获得。
实施例1
在3毫升二氯甲烷中加入0.1毫摩尔的式1a化合物与0.12毫摩尔的式2a化合物作为反应物,100毫克分子筛作为添加剂,0.01毫摩尔的手性磷酸作为催化剂,在20℃反应4小时,TLC跟踪反应至结束,过滤除去分子筛,用乙酸乙酯洗涤滤饼,得到的滤液浓缩之后通过硅胶柱层析(洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液)分离,即得到轴手性化合物3aa。
上述反应中,催化剂手性磷酸结构式如下:
产物3aa的结构表征数据如下:
产率:78%(48.0mg),白色固体,熔点:137-139℃;[α]D 20=-37.8(c=0.75,acetone);1H NMR(400MHz,CDCl3)δ7.82–7.76(m,2H),7.49(d,J=8.0Hz,1H),7.33–7.27(m,5H),7.25–7.20(m,2H),7.18–7.10(m,3H),7.06–6.98(m,3H),6.96–6.88(m,4H),6.81(s,1H),6.35(d,J=8.8Hz,2H),5.45(s,1H),3.83(s,3H),3.81(s,3H),3.63(s,3H);13C NMR(100MHz,CDCl3)δ159.5,159.2,152.1,143.1,134.8,134.6,134.4,133.0,131.7,129.6,129.4,129.0,128.6,127.9,126.4,125.3,124.1,123.1,122.7,121.1,120.0,116.9,114.2,113.1,111.1,98.5,75.3,55.4,55.2;IR(KBr):3426,3053,2833,2050,1507,1462,1336,1250,858,584cm-1;ESI FTMS exact mass calcd for(C42H33NO4-H)-requires m/z614.2337,found m/z 614.2336;The enantiomeric excess:93%,HPLC (DaicelChiralpak IA,正己烷/异丙醇=70/30,flow rate 1.0mL/min,T=30℃,254nm):tR=6.493(minor),tR=10.606(major).
在惰性气体氛围下,0.5毫摩尔的式3aa化合物和1.0毫摩尔的三氟甲磺酸酐(Tf2O)作为反应物,以二氯甲烷为反应溶剂,加入1.5毫摩尔的N,N-二异丙基乙胺,在0℃搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取,浓缩有机相,硅胶柱层析纯化(洗脱剂为体积比1:1的石油醚和二氯甲烷混合溶液)即制得式4a化合物。
产物4a的结构表征数据如下:
产率:91%(340.4mg),白色固体,熔点:76–78℃;[α]D 20=27.5(c=0.28,acetone);1H NMR(400MHz,CDCl3)δ7.97–7.90(m,2H),7.88(d,J=9.2Hz,1H),7.56–7.51(m,1H),7.44–7.39(m,1H),7.39–7.34(m,2H),7.25–7.19(m,4H),7.13–7.06(m,2H),7.04–6.99(m,1H),6.97–6.90(m,4H),6.90–6.84(m,2H),6.79(s,1H),6.37(d,J=8.4Hz,2H),3.85–3.77(m,6H),3.66(s,3H);13C NMR(100MHz,CDCl3)δ159.3,159.2,159.1,145.9,143.0,140.6,134.7,134.2,133.9,133.1,132.5,131.5,131.4,129.6,129.4,128.6,128.0,127.7,127.2,126.8,125.9,124.9,122.1,121.1,119.7,119.3,114.0,113.9,113.0,110.8,98.5,75.3,55.4,55.3,55.2;IR(KBr):3546,3054,2930,2340,1569,1509,1028,888,691,557cm-1;ESI FTMS exact mass calcd for(C43H32F3NO6S+Na)+requires m/z770.1794,found m/z 770.1797;The enantiomeric excess:93%,HPLC(DaicelChiralpak AD-H,正己烷/异丙醇=95/5,flow rate 1.0mL/min,T=30℃,254nm):tR=5.490(minor),tR=7.670(major).
在惰性气体氛围下,0.1毫摩尔的式4a化合物和0.4毫摩尔的二苯基氧膦(Ph2P(O)H)作为反应物,以二甲亚砜(DMSO)为反应溶剂,0.03摩尔的醋酸钯(Pd(OAc)2)和0.03摩尔的1,4-双(二苯膦)丁烷(DPPB)分别作为催化剂和配体,0.5毫摩尔的N,N-二异丙基乙胺为有机碱,在120℃搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取,浓缩有机相,硅胶柱层析纯化(洗脱剂为体积比2:1的石油醚与乙酸乙酯混合溶液)即制得式5a化合物。
产物5a的结构表征数据如下:
产率:79%(63.5mg),白色固体,熔点:96-98℃;[α]D 20=38.5(c=0.20,acetone);1H NMR(400MHz,CDCl3)δ7.91(d,J=8.4Hz,1H),7.84(d,J=8.8Hz,1H),7.76–7.72(m,1H),7.60–7.51(m,3H),7.42–7.33(m,3H),7.31–7.26(m,4H),7.21(s,1H),7.18–7.14(m,1H),7.13–7.02(m,3H),7.02–6.94(m,5H),6.87(d,J=8.8Hz,2H),6.82–6.71(m,4H),6.48–6.42(m,1H),6.40–6.34(m,2H),6.31(d,J=8.0Hz,1H),3.79(s,3H),3.74(s,3H),3.69(s,3H);13C NMR(100MHz,CDCl3)δ158.7,158.6,157.8,145.4,140.6,137.2,137.1,134.8,134.6,134.5,133.6,133.4,133.2,132.8,132.6,132.2,132.0,131.9,131.6,131.5,131.0,130.5,129.3,129.2,129.0,128.9,128.2,128.1,127.8,127.7,127.6,127.4,127.3,127.0,126.9,126.7,126.6,121.1,120.6,120.2,118.7,113.2,112.6,111.4,110.1,102.2,74.8,55.4,55.3,55.2;31P NMR(162MHz,CDCl3)δ27.20(s);IR(KBr):3050,2833,2359,1606,1508,1200,1027,830,720cm-1;ESIFTMSexactmasscalcdfor(C54H42NO4P+H)+requires m/z800.2924,found m/z800.2925;The enantiomeric excess:93%,HPLC(Daicel Chiralpak IC,正己烷/异丙醇=85/15,flow rate1.0mL/min,T=30℃,254nm):tR=16.447(minor),tR=19.533(major).
在惰性气体氛围下,0.1毫摩尔的式5a化合物和1.0毫摩尔的三氯硅烷(HSiCl3)作为反应物,以1.0毫升甲苯(toluene)为反应溶剂,2.5毫摩尔的三乙胺为有机碱,在120℃搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取,浓缩有机相,硅胶柱层析纯化(洗脱剂为体积比5:1的石油醚与乙酸乙酯混合溶液)即制得式6a化合物。
产物6a的结构表征数据如下:
产率:81%(63.4mg),白色固体,熔点:74-76℃;[α]D 20=-95.3(c=0.51,acetone);1H NMR(400MHz,CDCl3)δ7.94–7.87(m,2H),7.73(d,J=8.4Hz,1H),7.55–7.50(m,1H),7.43–7.36(m,3H),7.31–7.27(m,1H),7.26–7.19(m,3H),7.17–7.11(m,2H),7.05–6.94(m,6H),6.93–6.81(m,6H),6.79–6.74(m,2H),6.65–6.55(m,4H),6.37(d,J=6.4Hz,2H),3.84–3.72(m,6H),3.70(s,3H);13CNMR(100MHz,CDCl3)δ159.2,158.7,157.6,142.2,138.7,137.2,136.2,134.5,134.3,134.1,133.9,133.5,132.9,132.8,132.3,129.4,129.1,128.9,128.4,128.1,128.0,127.8,127.5,127.4,127.2,126.4,126.3,125.8,121.3,120.6,119.0,113.2,113.0,111.4,110.5,74.7,55.4,55.3,55.2;31P NMR(162MHz,CDCl3)δ-12.59(s);IR(KBr):3048,2928,2833,2363,1608,1510,1250,1025,695,548cm-1;ESIFTMS exact mass calcd for(C54H42NO3P+H)+requires m/z784.2975,found m/z784.2965;The enantiomeric excess:93%,HPLC(Daicel Chiralpak IA,正己烷/异丙醇=95/5,flow rate 1.0mL/min,T=30℃,254nm):tR=6.373(minor),tR=13.236(major).
实施例2
在5毫升二氯甲烷和乙酸乙酯的混合溶液中加入0.1毫摩尔的式1a化合物与0.12毫摩尔的式2b化合物作为反应物,0.015毫摩尔的手性磷酸作为催化剂,在20℃反应10小时,TLC跟踪反应至结束,得到的滤液浓缩之后通过硅胶柱层析(洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液)分离,即得到轴手性化合物3ab。
上述反应中,催化剂手性磷酸结构式如下:
产物3ab的结构表征数据如下:
产率:98%(60.4mg),白色固体,95:5dr;熔点:133-135℃;[α]D 20=-145.1(c=0.37,acetone);1H NMR(400MHz,CDCl3)δ7.82–7.76(m,2H),7.56(d,J=7.6Hz,1H),7.44–7.39(m,1H),7.32–7.27(m,2H),7.25–7.21(m,2H),7.20–7.16(m,2H),7.15–7.08(m,4H),7.06–6.98(m,5H),6.81(d,J=8.4Hz,2H),6.36(d,J=8.8Hz,2H),5.39(s,1H),3.77(s,3H),3.72(s,3H),3.63(s,3H);13C NMR(100MHz,CDCl3)δ159.4,158.9,157.7,152.1,143.1,138.1,135.4,135.2,134.4,133.2,132.0,129.5,129.4,128.9,128.6,128.1,128.0,127.9,126.9,126.3,125.4,124.4,123.1,122.5,121.3,121.0,119.9,116.8,113.8,113.2,113.0,111.7,111.2,98.2,75.0,55.5,55.2;IR(KBr):3054,2962,2834,1596,1558,1256,1024,908,746,696cm-1;ESI FTMS exact mass calcd for(C42H33NO4-H)-requires m/z614.2337,found m/z614.2338;The enantiomeric excess:94%,HPLC(DaicelChiralpak OD-H,正己烷/异丙醇=95/5,flow rate 0.5mL/min,T=30℃,254nm):tR=18.767(minor),tR=20.930(major).
在惰性气体氛围下,0.5毫摩尔的式3ab化合物和1.0毫摩尔的三氟甲磺酸酐(Tf2O)作为反应物,以二氯甲烷为反应溶剂,加入1.5毫摩尔的N,N-二异丙基乙胺,在0℃搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取,浓缩有机相,硅胶柱层析纯化(洗脱剂为体积比1:1的石油醚和二氯甲烷混合溶液)即制得式4b化合物。
产物4b的结构表征数据如下:
产率:92%(344.5mg);白色固体;>95:5dr;熔点:106–108℃;[α]D 20=-179.9(c=0.74,acetone);1H NMR(400MHz,CDCl3)δ8.00(d,J=8.4Hz,1H),7.93(d,J=8.0Hz,1H),7.87(d,J=9.2Hz,1H),7.58–7.53(m,1H),7.47–7.38(m,2H),7.27(s,1H),7.26–7.21(m,2H),7.21–7.15(m,3H),7.08–6.98(m,5H),6.97–6.93(m,2H),6.83–6.74(m,2H),6.39(d,J=8.4Hz,2H),3.79–3.71(m,6H),3.67(s,3H);13C NMR(100MHz,CDCl3)δ159.2,158.9,157.7,146.1,143.2,138.9,135.6,134.7,133.9,133.4,132.5,131.5,129.4,129.3,128.6,128.5,128.1,128.0,127.8,127.2,127.0,126.8,125.8,125.3,122.0,121.3,120.9,119.7,119.2,113.4,113.0,111.6,111.1,98.3,75.3,55.4,55.2;IR(KBr):3048,2836,2048,1609,1509,1251,1032,831,638cm-1;ESI FTMS exact mass calcd for(C43H32F3NO6S+Na)+requires m/z700.1794,found m/z700.1776;The enantiomericexcess:93%,HPLC(Daicel Chiralpak OD-H,正己烷/异丙醇=99/1,flow rate 0.2mL/min,T=30℃,254nm):tR=49.843(major),tR=53.133(minor).
在惰性气体氛围下,0.1毫摩尔的式4b化合物和0.4毫摩尔的二苯基氧膦(Ph2P(O)H)作为反应物,以二甲亚砜(DMSO)为反应溶剂,0.03摩尔的醋酸钯(Pd(OAc)2)和0.03摩尔的1,4-双(二苯膦)丁烷(DPPB)分别作为催化剂和配体,0.5毫摩尔的N,N-二异丙基乙胺为有机碱,在120℃搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取,浓缩有机相,硅胶柱层析纯化(洗脱剂为体积比2:1的石油醚与乙酸乙酯混合溶液)即制得式5b化合物。
产物5b的结构表征数据如下:
产率:74%(59.1mg),白色固体,>95:5dr;熔点:119-121℃;[α]D 20=-79.1(c=0.33,acetone);1H NMR(400MHz,CDCl3)δ7.92(d,J=8.0Hz,1H),7.82(d,J=8.4Hz,1H),7.76(dd,J=8.8,2.4Hz,1H),7.62–7.55(m,3H),7.43–7.36(m,2H),7.35–7.27(m,4H),7.25–7.22(m,2H),7.15–7.07(m,3H),7.00–6.88(m,7H),6.87–6.83(m,1H),6.82–6.75(m,3H),6.73(s,1H),6.56–6.50(m,1H),6.48–6.43(m,1H),6.36(d,J=8.8Hz,2H),3.83(s,3H),3.80(s,3H),3.68(s,3H);13CNMR(100MHz,CDCl3)δ159.1,158.8,158.7,145.3,140.3,140.2,139.0,136.1,134.7,134.6,134.5,133.4,133.1,133.0,132.9,132.8,132.1,131.9,131.8,131.4,131.3,131.1,130.4,129.2,129.1,128.9,128.8,128.2,128.1,127.9,127.8,127.7,127.5,127.3,127.0,126.8,126.7,126.5,120.9,120.6,118.7,113.9,113.6,112.6,109.9,102.6,74.9,55.4,55.3;31P NMR(162MHz,CDCl3)δ26.9;IR(KBr):3049,2833,2358,1607,1508,1248,1025,744,542cm-1;ESI FTMS exact mass calcdfor(C54H42NO4P+Na)+requires m/z822.2744,found m/z822.2719;The enantiomericexcess:93%,HPLC(Daicel Chiralpak IC,正己烷/异丙醇=90/10,flow rate 0.5mL/min,T=30℃,254nm):tR=32.990(major),tR=37.297(minor).
在惰性气体氛围下,0.1毫摩尔的式5b化合物和1.0毫摩尔的三氯硅烷(HSiCl3)作为反应物,以1.0毫升甲苯(toluene)为反应溶剂,2.5毫摩尔的三乙胺为有机碱,在120℃搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取,浓缩有机相,硅胶柱层析纯化(洗脱剂为体积比5:1的石油醚与乙酸乙酯混合溶液)即制得式6b化合物。
产物6b的结构表征数据如下:
产率:85%(66.6mg),>95:5dr,白色固体,熔点:119.0-121℃;[α]D 20=-18.2(c=0.29,acetone);1H NMR(400MHz,CDCl3)δ7.90(d,J=8.0Hz,2H),7.75(d,J=8.4Hz,1H),7.56–7.50(m,1H),7.47–7.37(m,3H),7.34–7.28(m,2H),7.22–7.17(m,1H),7.16–7.09(m,2H),7.09–6.82(m,14H),6.79(s,1H),6.74–6.52(m,4H),6.38(d,J=8.4Hz,2H),3.91–3.75(m,6H),3.70(s,3H);13C NMR(100MHz,CDCl3)δ159.3,159.0,142.1,139.4,139.1,139.0,138.8,138.6,138.5,137.5,137.3,135.3,134.1,134.0,133.9,133.8,133.7,133.5,133.1,132.9,132.7,131.5,129.8,129.5,129.4,129.1,128.1,128.0,127.9,127.8,127.6,127.4,126.5,126.4,125.4,121.5,120.9,119.0,114.0,113.7,113.0,110.3,105.7,105.6,74.7,55.3;31P NMR(162MHz,CDCl3)δ-12.22(s);IR(KBr):3051,2833,2360,1606,1509,1246,1070,747,532cm-1;ESI FTMS exact mass calcd for(C54H42NO3P+Na)+requires m/z806.2794,found m/z 806.2754;The enantiomeric excess:93%,HPLC(Daicel Chiralpak AD-H,正己烷/异丙醇=90/10,flow rate1.0mL/min,T=30℃,254nm):tR=3.526(major),tR=4.860(minor).
实施例3
在3毫升二氯甲烷中加入0.1毫摩尔的式1b化合物与0.12毫摩尔的式2a化合物作为反应物,100毫克分子筛作为添加剂,0.01毫摩尔的手性磷酸作为催化剂,在20℃反应4小时,TLC跟踪反应至结束,过滤除去分子筛,用乙酸乙酯洗涤滤饼,得到的滤液浓缩之后通过硅胶柱层析(洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液)分离,即得到轴手性化合物3ba。
上述反应中,催化剂手性磷酸同实施例1。
产物3ba的结构表征数据如下:
产率:84%(54.5mg);白色固体;熔点:128-130℃;[α]D 20=-63.0(c=1.04,acetone);1H NMR(400MHz,CDCl3)δ7.84–7.74(m,2H),7.49–7.39(m,1H),7.32–7.27(m,2H),7.25–7.22(m,4H),7.20(s,1H),7.16(d,J=8.8Hz,1H),7.06(s,2H),7.00(d,J=8.4Hz,2H),6.96–6.90(m,4H),6.84(s,1H),6.36(d,J=8.4Hz,2H),5.35(s,1H),3.83(s,3H),3.82(s,3H),3.63(s,3H);13C NMR(100MHz,CDCl3)δ159.5,159.3,152.1,144.4,140.3,134.5,134.2,133.0,131.2,129.9,129.2,129.0,128.7,128.0,126.6,126.0,124.9,123.7,123.2,123.0,120.3,116.9,114.2,113.1,112.3,111.8,98.1,75.4,55.4,55.2;IR(KBr):3745,2930,2833,2359,1507,1251,1058,963,830,551cm-1;ESI FTMS exact mass calcdfor(C42H32ClNO4-H)-requires m/z648.1947,found m/z648.1943;The enantiomericexcess:93%,determined by HPLC(Daicel Chiralpak IB,正己烷/异丙醇=70/30,flowrate1.0mL/min,T=30℃,254nm):tR=6.980(major),tR=8.477(minor).
实施例4
在3毫升二氯甲烷中加入0.1毫摩尔的式1c化合物与0.12毫摩尔的式2a化合物作为反应物,100毫克分子筛作为添加剂,0.01毫摩尔的手性磷酸作为催化剂,在20℃反应4小时,TLC跟踪反应至结束,过滤除去分子筛,用乙酸乙酯洗涤滤饼,得到的滤液浓缩之后通过硅胶柱层析(洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液)分离,即得到轴手性化合物3ca。
上述反应中,催化剂手性磷酸结构同实施例1。
产物3ca的结构表征数据如下:
产率:71%(44.8mg),白色固体,熔点:123-125℃;[α]D 20=-57.2(c=0.43,acetone);1H NMR(400MHz,CDCl3)δ7.82–7.75(m,2H),7.49(d,J=7.6Hz,1H),7.31–7.27(m,3H),7.25–7.19(m,3H),7.17(d,J=8.8Hz,1H),7.07–7.02(m,2H),7.00–6.92(m,4H),6.92–6.86(m,3H),6.79(s,1H),6.33(d,J=8.8Hz,2H),5.46(s,1H),3.82(s,3H),3.81(s,3H),3.62(s,3H),2.30(s,3H);13C NMR(100MHz,CDCl3)δ159.4,159.2,152.1,143.2,139.7,134.7,134.5,133.3,133.1,129.5,129.3,129.0,128.6,127.9,126.3,125.3,124.3,123.1,120.6,116.8,114.1,113.3,113.0,110.7,97.8,75.2,55.4,55.2,21.4;IR(KBr):3854,2930,2833,2362,1508,1251,1175,830,779,590cm-1;ESI FTMS exact mass calcdfor(C43H35NO4-H)-requires m/z628.2493,found m/z628.2496;The enantiomericexcess:91%,determined by HPLC(Daicel Chiralpak IB,正己烷/异丙醇=95/5,flowrate 1.0mL/min,T=30℃,254nm):tR=20.693(minor),tR=23.470(major).
实施例5
在3毫升二氯甲烷中加入0.1毫摩尔的式1d化合物与0.12毫摩尔的式2c化合物作为反应物,100毫克分子筛作为添加剂,0.01毫摩尔的手性磷酸作为催化剂,在20℃反应4小时,TLC跟踪反应至结束,过滤除去分子筛,用乙酸乙酯洗涤滤饼,得到的滤液浓缩之后通过硅胶柱层析(洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液)分离,即得到轴手性化合物3dc。
上述反应中,催化剂手性磷酸结构同实施例1。
产物3dc的结构表征数据如下:
产率:97%(59.8mg),白色固体,熔点:127-129℃;[α]D 20=-69.7(c=1.28,acetone);1H NMR(400MHz,CDCl3)δ7.81–7.74(m,2H),7.42(d,J=7.2Hz,1H),7.30–7.27(m,2H),7.25–7.20(m,4H),7.16–7.10(m,3H),7.04(d,J=7.6Hz,2H),7.01–6.91(m,6H),6.87(s,1H),6.85–6.79(m,2H),5.33(s,1H),3.84(s,3H),3.83(s,3H);13C NMR(100MHz,CDCl3)δ159.4,159.3,152.0,143.7,140.2,134.9,134.3,134.2,131.6,131.1,129.8,129.2,129.0,128.7,128.6,128.0,126.5,125.0,123.8,123.2,121.9,120.7,116.9,114.3,113.1,112.4,110.8,98.8,75.6,55.4;IR(KBr):2930,2835,2360,1607,1509,1279,1030,831,751,591cm-1;ESI FTMS exact mass calcd for(C41H30ClNO3-H)-requires m/z618.1841,found m/z618.1842;The enantiomeric excess:94%,determined by HPLC(Daicel Chiralpak IB,正己烷/异丙醇=70/30,flow rate 1.0mL/min,T=30℃,254nm):tR=5.103(major),tR=5.920(minor).
实施例6
在3毫升二氯甲烷中加入0.1毫摩尔的式1d化合物与0.12毫摩尔的式2d化合物作为反应物,100毫克分子筛作为添加剂,0.01毫摩尔的手性磷酸作为催化剂,在20℃反应4小时,TLC跟踪反应至结束,过滤除去分子筛,用乙酸乙酯洗涤滤饼,得到的滤液浓缩之后通过硅胶柱层析(洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液)分离,即得到轴手性化合物3dd。
上述反应中,催化剂手性磷酸结构同实施例1。
产物3dd的结构表征数据如下:
产率:88%(57.8mg),白色固体,熔点:150-152℃;[α]D 20=-73.9(c=1.59,acetone);1H NMR(400MHz,CDCl3)δ7.86–7.74(m,2H),7.40(d,J=8.0Hz,1H),7.31–7.27(m,1H),7.25–7.20(m,5H),7.17–7.10(m,3H),7.02–6.91(m,7H),6.87(s,1H),6.79(d,J=8.4Hz,2H),5.30(s,1H),3.84(s,3H),3.83(s,3H);13CNMR(100MHz,CDCl3)δ159.5,159.4,152.0,143.0,141.7,135.0,134.2,134.1,133.8,131.5,130.7,130.0,129.8,129.2,129.1,129.0,128.9,128.5,128.1,127.8,126.6,124.8,123.3,121.9,120.9,116.9,114.4,112.0,110.8,98.9,75.6,55.4;IR(KBr):2953,2929,2360,1607,1507,1252,1032,830,707,590cm-1;ESI FTMS exact mass calcd for(C41H29Cl2NO3-H)-requires m/z652.1451,found m/z652.1430;The enantiomeric excess:96%,determined by HPLC(Daicel Chiralpak IB,正己烷/异丙醇=70/30,flow rate 1.0mL/min,T=30℃,254nm):tR=5.176(major),tR=5.910(minor).
实施例7
在3毫升二氯甲烷中加入0.1毫摩尔的式1a化合物与0.12毫摩尔的式2e化合物作为反应物,100毫克分子筛作为添加剂,0.01毫摩尔的手性磷酸作为催化剂,在20℃反应4小时,TLC跟踪反应至结束,过滤除去分子筛,用乙酸乙酯洗涤滤饼,得到的滤液浓缩之后通过硅胶柱层析(洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液)分离,即得到轴手性化合物3ae。
上述反应中,催化剂手性磷酸结构同实施例1。
产物3ae的结构表征数据如下:
产率:82%(48.4mg),白色固体,熔点:66-68℃;[α]D 20=-81.4(c=0.81,acetone);1H NMR(400MHz,CDCl3)δ7.87(d,J=8.8Hz,1H),7.82(d,J=7.6Hz,1H),7.48(d,J=8.0Hz,1H),7.33–7.27(m,5H),7.25–7.21(m,3H),7.17–7.10(m,2H),7.05–6.99(m,1H),6.97–6.87(m,7H),6.65–6.59(m,1H),5.49(s,1H),3.82(s,3H),3.81(s,3H);13C NMR(100MHz,CDCl3)δ159.3,159.2,152.3,142.7,140.4,134.6,134.5,133.0,132.0,131.4,131.3,129.9,129.5,129.4,129.3,129.0,128.0,126.7,126.51,125.3,124.9,123.7,123.2,122.8,121.1,120.0,117.0,114.1,113.0,111.0,98.4,75.1,55.4;IR(KBr):3501,3054,2928,2834,2359,1704,1508,1251,1031,787,585cm-1;ESI FTMS exact mass calcdfor(C39H29NO3S+H)+requires m/z592.1941,found m/z 592.1928;The enantiomericexcess:90%,determined by HPLC (Daicel Chiralpak OD-H,正己烷/异丙醇=70/30,flow rate1.0mL/min,T=30℃,254nm):tR=5.883(major),tR=11.323(minor).
实施例8
在3毫升二氯甲烷中加入0.1毫摩尔的式1a化合物与0.12毫摩尔的式2f化合物作为反应物,100毫克分子筛作为添加剂,0.01毫摩尔的手性磷酸作为催化剂,在20℃反应4小时,TLC跟踪反应至结束,过滤除去分子筛,用乙酸乙酯洗涤滤饼,得到的滤液浓缩之后通过硅胶柱层析(洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液)分离,即得到轴手性化合物3af。
上述反应中,催化剂手性磷酸结构同实施例1。
产物3af的结构表征数据如下:
产率:53%(29.0mg),白色固体,熔点:71-73℃;[α]D 20=-46.0(c=0.35,acetone);1H NMR(400MHz,CDCl3)δ7.90–7.79(m,2H),7.60–7.53(m,1H),7.38–7.29(m,3H),7.24(s,1H),7.22–7.14(m,4H),7.14–7.06(m,2H),7.05–6.98(m,1H),6.95–6.83(m,4H),6.23(s,1H),5.60(s,1H),3.82(s,3H),3.80(s,3H),1.19–1.11(m,1H),0.57–0.37(m,3H),0.33–0.25(m,1H);13C NMR(100MHz,CDCl3)δ159.2,159.1,152.3,145.6,137.2,136.3,134.8,134.6,132.8,131.9,131.8,129.5,129.2,129.1,129.0,128.0,126.3,125.5,123.1,122.3,120.7,119.8,116.9,114.0,112.6,111.0,97.2,75.3,55.4,7.9,7.6,7.4;IR(KBr):3048,2961,2834,2359,2341,1597,1508,830,745,585cm-1;ESI FTMS exact masscalcd for(C38H31NO3+H)+requires m/z550.2377,foundm/z550.2353;The enantiomericexcess:82%,determined by HPLC (Daicel Chiralpak AD-H,正己烷/异丙醇=90/10,flow rate 1.0mL/min,T=30℃,254nm):tR=6.760(minor),tR=8.260(major).
实施例9
在5毫升二氯甲烷和乙酸乙酯的混合溶液中加入0.1毫摩尔的式1a化合物与0.12毫摩尔的式2g化合物作为反应物,0.015毫摩尔的手性磷酸作为催化剂,在20℃反应10小时,TLC跟踪反应至结束,得到的滤液浓缩之后通过硅胶柱层析(洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液)分离,即得到轴手性化合物3ag。
上述反应中,催化剂手性磷酸结构同实施例2。
产物3ag的结构表征数据如下:
产率:56%(33.0mg),白色固体,91:9dr;m.p.141-143℃;[α]D 20=+10.6(c=0.60,acetone);1H NMR(400MHz,CDCl3)δ7.82–7.72(m,2H),7.53–7.47(m,1H),7.39(s,1H),7.35(d,J=5.2Hz,2H),7.32–7.27(m,4H),7.25–7.20(m,2H),7.18–7.11(m,3H),7.10–6.98(m,4H),6.93(d,J=8.8Hz,2H),6.89–6.79(m,3H),5.38(s,1H),3.82(s,3H);13C NMR(100MHz,CDCl3)δ159.6,152.1,142.7,141.9,140.2,136.0,134.9,134.8,134.4,133.1,131.3,130.6,130.2,129.7,129.4,129.0,128.4,128.3,128.0,127.7,127.3,126.5,126.2,125.2,123.1,121.4,120.3,116.9,114.4,112.8,111.0,99.3,75.5,55.5;IR(KBr):3506,3056,2930,1594,1510,1253,1029,833,745,694cm-1;ESI FTMS exact mass calcd for(C40H28ClNO2-H)-requires m/z588.1736,found m/z588.1747;The enantiomeric excess:95%,determined by HPLC(Daicel Chiralpak AD-H,正己烷/异丙醇=70/30,flowrate1.0mL/min,T=30℃,254nm):tR=4.266(major),tR=6.990(minor).
实施例10
在5毫升二氯甲烷和乙酸乙酯的混合溶液中加入0.1毫摩尔的式1a化合物与0.12毫摩尔的式2h化合物作为反应物,0.015毫摩尔的手性磷酸作为催化剂,在20℃反应10小时,TLC跟踪反应至结束,得到的滤液浓缩之后通过硅胶柱层析(洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液)分离,即得到轴手性化合物3ah。
上述反应中,催化剂手性磷酸结构同实施例2。
产物3ah的结构表征数据如下:
产率:91%(53.2mg),白色固体,88:12dr;m.p.148-150℃;[α]D 20=+11.8(c=0.94,acetone);1H NMR(400MHz,CDCl3)δ7.81–7.74(m,2H),7.50(d,J=8.0Hz,1H),7.37–7.27(m,4H),7.25–7.18(m,3H),7.16–7.11(m,2H),7.10–7.06(m,2H),7.05–6.98(m,2H),6.97–6.88(m,6H),6.86–6.80(m,2H),5.44(s,1H),3.82(s,3H),3.76(s,3H);13C NMR(100MHz,)δ159.9,159.4,152.0,142.9,141.2,140.8,135.5,134.9,134.4,133.0,131.5,131.2,129.9,129.6,129.5,129.0,128.2,127.9,127.6,127.3,126.3,125.2,123.0,122.8,121.1,120.5,120.1,116.8,114.3,114.2,112.9,111.2,98.8,75.8,55.4,55.3;IR(KBr):3054,2931,2834,1598,1510,1253,1032,830,760,697cm-1;ESI FTMS exact masscalcd for(C41H31NO3-H)-requires m/z584.2231,found m/z584.2230;The enantiomericexcess:91%,determined by HPLC (Daicel Chiralpak IA,正己烷/异丙醇=85/15,flowrate 1.0mL/min,T=30℃,254nm):tR=6.253(major),tR=11.493(minor).
实施例11
在5毫升二氯甲烷和乙酸乙酯的混合溶液中加入0.1毫摩尔的式1a化合物与0.12毫摩尔的式2i化合物作为反应物,0.015毫摩尔的手性磷酸作为催化剂,在20℃反应10小时,TLC跟踪反应至结束,得到的滤液浓缩之后通过硅胶柱层析(洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液)分离,即得到轴手性化合物3ai。
上述反应中,催化剂手性磷酸结构同实施例2。
产物3ai的结构表征数据如下:
产率:94%(62.1mg),白色固体,92:8dr;m.p.135-137℃;[α]D 20=-114.8(c=0.80,acetone);1H NMR(400MHz,CDCl3)δ7.81(d,J=8.4Hz,2H),7.52(d,J=8.4Hz,1H),7.45–7.40(m,1H),7.33(s,1H),7.31–7.27(m,1H),7.25–7.21(m,2H),7.19–7.12(m,4H),7.11–7.07(m,2H),7.06–7.00(m,3H),6.94(s,4H),6.81(d,J=8.8Hz,2H),5.35(s,1H),3.77(s,3H),3.72(s,3H);13C NMR(100MHz,CDCl3)δ159.0,157.7,152.0,142.3,139.8,135.3,134.9,134.4,133.0,131.5,130.8,130.6,129.7,129.6,129.0,128.9,128.2,128.0,127.9,126.5,126.4,125.1,123.2,122.8,122.1,121.4,121.0,120.1,116.8,113.8,112.8,111.8,111.3,100.0,98.4,75.2,55.5,55.3;IR(KBr):3052,2930,2834,1597,1509,1249,1027,918,783,510cm-1;ESI FTMS exact mass calcd for(C41H30BrNO3-H)-requires m/z662.1336,found m/z 662.1339;The enantiomeric excess:91%,determined by HPLC(Daicel Chiralpak AD-H,正己烷/异丙醇=98/2,flow rate 1.0mL/min,T=30℃,254nm):tR=15.216(major),tR=19.813(minor).
实施例12
在5毫升二氯甲烷和乙酸乙酯的混合溶液中加入0.1毫摩尔的式1a化合物与0.12毫摩尔的式2j化合物作为反应物,0.015毫摩尔的手性磷酸作为催化剂,在20℃反应10小时,TLC跟踪反应至结束,得到的滤液浓缩之后通过硅胶柱层析(洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液)分离,即得到轴手性化合物3aj。
上述反应中,催化剂手性磷酸结构同实施例2。
产物3aj的结构表征数据如下:
产率:76%(46.6mg),白色固体,94:6dr;m.p.143-145℃;[α]D 20=-94.8(c=0.46,acetone);1H NMR(400MHz,CDCl3)δ7.83–7.77(m,2H),7.53–7.48(m,1H),7.45–7.39(m,1H),7.34–7.27(m,4H),7.18–7.15(m,1H),7.14–7.09(m,4H),7.06–7.01(m,4H),7.00–6.95(m,2H),6.81(d,J=8.4Hz,2H),6.35(d,J=8.4Hz,2H),5.27(s,1H),3.78(s,3H),3.72(s,3H),3.63(s,3H);13C NMR(100MHz,CDCl3)δ159.5,159.1,157.7,152.2,144.5,138.6,135.4,134.4,134.3,133.6,131.7,129.8,129.7,129.1,128.6,128.1,127.9,126.6,126.0,125.1,124.1,123.3,123.0,121.4,120.3,116.9,113.9,113.1,112.5,112.1,111.8,98.0,75.3,55.5,55.3,55.2;IR(KBr):3054,2961,2834,1606,1508,1252,1030,934,861,585cm-1;ESI FTMS exact mass calcd for(C42H33NO4-H)-requires m/z 614.2337,found m/z614.2341;The enantiomeric excess:95%,determined by HPLC(Daicel ChiralpakIB,正己烷/异丙醇=95/5,flow rate 1.0mL/min,T=30℃,254nm):tR=7.456(minor),tR=9.203(major).
实施例13
在5毫升二氯甲烷和乙酸乙酯的混合溶液中加入0.1毫摩尔的式1a化合物与0.12毫摩尔的式2k化合物作为反应物,0.015毫摩尔的手性磷酸作为催化剂,在20℃反应10小时,TLC跟踪反应至结束,得到的滤液浓缩之后通过硅胶柱层析(洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液)分离,即得到轴手性化合物3ak。
上述反应中,催化剂手性磷酸结构同实施例2。
产物3ak的结构表征数据如下:
产率:79%(48.9mg),白色固体,95:5dr;m.p.122-124℃;[α]D 20=-147.0(c=0.54,acetone);1H NMR(400MHz,CDCl3)δ7.80(d,J=8.8Hz,2H),7.53(d,J=8.0Hz,1H),7.46–7.40(m,1H),7.35(s,1H),7.31–7.27(m,2H),7.25–7.21(m,1H),7.18–7.12(m,4H),7.10–7.08(m,3H),7.06–7.01(m,3H),6.99–6.92(m,2H),6.82(d,J=8.4Hz,2H),6.77–6.71(m,1H),5.35(s,1H),3.78(s,3H),3.73(s,3H);13C NMR(100MHz,CDCl3)δ159.1,157.7,152.0,142.3,140.2,135.3,134.8,134.4,133.6,133.5,133.0,131.5,129.9,129.6,129.1,128.7,128.3,128.0,127.9,127.5,126.5,126.4,125.4,125.1,123.1,122.8,121.4,121.0,120.1,116.8,113.9,112.7,111.8,111.3,100.0,98.5,75.2,55.5,55.3;IR(KBr):3056,2929,2834,1596,1488,1429,1338,1108,1026,745cm-1;ESI FTMS exact masscalcd for(C41H30ClNO3-H)-requires m/z618.1841,found m/z618.1840;Theenantiomeric excess:92%,determined by HPLC (Daicel Chiralpak IB,正己烷/异丙醇=95/5,flow rate 1.0mL/min,T=30℃,254nm):tR=6.840(minor),tR=7.790(major).
实施例14
在惰性气体氛围下,1.0毫摩尔的式7化合物和2.0毫摩尔的三氯硅烷(HSiCl3)作为反应物,以1.0毫升甲苯(toluene)为反应溶剂,0.005摩尔的烯丙基氯化钯([PdCl(π-allyl)]2)和0.02摩尔的6a分别作为催化剂和配体,在0℃搅拌反应数小时,通过蒸馏方式制得式8中间体;
以蒸馏制得的式8中间体为原料,5毫升四氢呋喃和5毫升甲醇混合溶液作为溶剂,加入12.0毫摩尔的过氧化氢(H2O2)、6.0毫摩尔的氟化钾(KF)、9.0毫摩尔的碳酸氢钾(KHCO3),室温条件下搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取,浓缩有机相,硅胶柱层析纯化(洗脱剂为体积比3:1的石油醚与乙酸乙酯混合溶液)即制得式9化合物。
产物9的结构表征数据如下:
产率:56%(68.3mg),无色油状,[α]D 20=-36.2(c=0.78,CHCl3);1H NMR(400MHz,CDCl3)δ7.42–7.32(m,4H),7.32–7.26(m,1H),4.88(q,J=6.4Hz,1H),2.14(s,1H),1.49(d,J=6.4Hz,3H);13C NMR(100MHz,CDCl3)δ145.9,128.5,127.5,125.5,70.4,25.2;IR(KBr):3366,3063,2973,1452,1204,1099,1029,761,700,541cm-1;The enantiomeric excess:85%,HPLC (Daicel Chiralpak AD-H,正己烷/异丙醇=95/5,flow rate 0.6mL/min,T=30℃,254nm):tR=14.787(minor),tR=17.227(major).
实施例15
在惰性气体保护下,0.1毫摩尔的式10烯丙基醋酸酯、0.3毫摩尔的式11丙二酸二叔丁酯为原料,1.5毫升乙腈(CH3CN)为溶剂,0.005摩尔的烯丙基氯化钯([PdCl(π-allyl)]2)和0.01摩尔的6a分别作为催化剂和配体,0.02毫摩尔的醋酸锂(LiOAc)为无机碱,0.3毫摩尔的N,O-双三甲硅基乙酰胺(BSA)为添加剂,在室温下搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取,浓缩有机相,硅胶柱层析纯化(洗脱剂为体积比5:1的石油醚与乙酸乙酯混合溶液)即制得式12化合物。
产物12的结构表征数据如下:
产率:91%(37.1mg),无色油状,[α]D 20=-14.8(c=0.24,acetone);1H NMR(400MHz,CDCl3)δ7.34–7.27(m,7H),7.26–7.15(m,3H),6.45(d,J=15.6Hz,1H),6.37–6.29(m,1H),4.19–4.12(m,1H),3.74(d,J=10.8Hz,1H),1.42(s,9H),1.22(s,9H);13C NMR(100MHz,CDCl3)δ167.3,166.8,140.8,137.1,131.3,130.2,128.5,128.2,127.4,126.9,126.3,81.8,81.6,59.4,49.1,28.0,27.6;IR(KBr):3061,2979,2360,1730,1478,1246,1369,1141,745,698.531cm-1;ESI FTMS exact mass calcd for(C26H32O4+Na)+requires m/z431.2193,found m/z 431.2182;The enantiomeric excess:91%,HPLC(DaicelChiralpak IA,正己烷/异丙醇=90/10,flow rate 1.0mL/min,T=30℃,254nm):tR=5.667(minor),tR=7.163(major).
本发明制备轴手性萘-吡咯类膦催化剂的方法,收率高,操作简便、反应条件温和、原料经济易得。本发明制备得到的轴手性萘-吡咯类膦催化剂通过实例被证明可应用于苯乙烯不对称硅氢化氧化反应中以及烯丙基醋酸酯和丙二酸二叔丁酯催化不对称偶联反应中,表现出优秀的效果。
Claims (8)
1.一种轴手性萘-吡咯类膦催化剂的制备方法,其特征在于,具体步骤如下:
(1)以式1化合物和式2化合物为反应原料,以二氯甲烷、乙酸乙酯、甲苯、丙酮或乙腈中的一种或两种作为溶剂,手性磷酸为催化剂,在0-40℃搅拌反应,TLC跟踪反应至结束,过滤、浓缩、纯化即制得式3化合物;其中,式1化合物和式2化合物的反应摩尔比为1:1.2至2:1;
(2)惰性气体氛围下,以式3化合物、三氟甲磺酸酐为原料,以二氯甲烷为反应溶剂,加入N,N-二异丙基乙胺,在0℃搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取,浓缩、纯化即制得式4化合物;
(3)惰性气体氛围下,以式4化合物、二级膦氧化物为原料,二甲基亚砜为反应溶剂,二异丙基乙胺作为有机碱,醋酸钯和1,4-双(二苯膦)丁烷分别作为催化剂和配体,在120℃搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取,浓缩、纯化即制得式5化合物;
(4)惰性气体氛围下,以式5化合物、三氯硅烷为原料,甲苯为反应溶剂,三乙胺作为有机碱,在120℃搅拌反应,TLC跟踪反应至完全,乙酸乙酯萃取,浓缩、纯化即制得式6化合物;
其中,所述的式1化合物的结构式为所述的式2化合物的结构式为所述的式3化合物的结构式为所述的式4化合物的结构式为所述的式5化合物的结构式为所述的式6化合物的结构式为式中,R1选自氢、C1-C4烷基、C1-C4烷氧基、卤素中的一种;R2选自氢、C1-C4烷基、C1-C4烷氧基、卤素中的一种;R3选自芳基、杂芳基、烷基中的一种;R4选自芳基、杂芳基、烷基中的一种;R5选自芳基、杂芳基、烷基中的一种;R6选自芳基、杂芳基、烷基中的一种;
3.根据权利要求1所述的轴手性萘-吡咯类膦催化剂的制备方法,其特征在于,步骤(1)纯化采用硅胶柱层析,洗脱剂为体积比1:2的石油醚和二氯甲烷混合溶液;步骤(2)纯化采用硅胶柱层析,洗脱剂为体积比1:1的石油醚和二氯甲烷混合溶液;步骤(3)纯化采用硅胶柱层析,洗脱剂为体积比2:1的石油醚与乙酸乙酯混合溶液;步骤(4)纯化采用硅胶柱层析,洗脱剂为体积比5:1的石油醚与乙酸乙酯混合溶液。
4.权利要求1至3任一项所述的制备方法制得的轴手性萘-吡咯类膦催化剂。
6.根据权利要求5所述的应用,其特征在于,所述的式6化合物的用量为2mol%。
8.根据权利要求7所述的应用,其特征在于,所述的式6化合物的用量为10mol%。
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