CN107715909B - Pentaerythritol-supported proline catalyst and preparation method and application thereof - Google Patents
Pentaerythritol-supported proline catalyst and preparation method and application thereof Download PDFInfo
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- CN107715909B CN107715909B CN201710820861.8A CN201710820861A CN107715909B CN 107715909 B CN107715909 B CN 107715909B CN 201710820861 A CN201710820861 A CN 201710820861A CN 107715909 B CN107715909 B CN 107715909B
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- 239000003054 catalyst Substances 0.000 title claims abstract description 57
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 title claims abstract description 41
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title abstract description 16
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 claims abstract description 29
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 claims abstract description 22
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 16
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 claims abstract description 14
- 229930182821 L-proline Natural products 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- TXBCBTDQIULDIA-UHFFFAOYSA-N 2-[[3-hydroxy-2,2-bis(hydroxymethyl)propoxy]methyl]-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(CO)(CO)COCC(CO)(CO)CO TXBCBTDQIULDIA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229930182820 D-proline Natural products 0.000 claims abstract description 12
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- WVDGSSCWFMSRHN-QMMMGPOBSA-N 1-o-tert-butyl 2-o-methyl (2s)-pyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C WVDGSSCWFMSRHN-QMMMGPOBSA-N 0.000 claims abstract description 11
- MZMNEDXVUJLQAF-MQWKRIRWSA-N 1-o-tert-butyl 2-o-methyl (2s)-4-hydroxypyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C MZMNEDXVUJLQAF-MQWKRIRWSA-N 0.000 claims abstract description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 69
- 229960002429 proline Drugs 0.000 claims description 31
- -1 4-p-hydroxyphenoxy-N-Boc-proline methyl ester Chemical compound 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 239000003208 petroleum Substances 0.000 claims description 12
- 150000001299 aldehydes Chemical class 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- 239000002798 polar solvent Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 claims description 5
- 238000006683 Mannich reaction Methods 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
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-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
- 239000000243 solution Substances 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- 239000012047 saturated solution Substances 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000007127 saponification reaction Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 5
- JFFVHJDYRGZLIR-UHFFFAOYSA-N [3-hydroxy-2,2-bis(hydroxymethyl)propyl] 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OCC(CO)(CO)CO)C=C1 JFFVHJDYRGZLIR-UHFFFAOYSA-N 0.000 abstract description 3
- 125000006239 protecting group Chemical group 0.000 abstract description 2
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 229940059574 pentaerithrityl Drugs 0.000 description 18
- 238000005406 washing Methods 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 6
- 239000000969 carrier Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- DKESASVLMZGECV-UHFFFAOYSA-N 4-hydroxy-4-(4-nitrophenyl)butan-2-one Chemical compound CC(=O)CC(O)C1=CC=C([N+]([O-])=O)C=C1 DKESASVLMZGECV-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical group O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 2
- 239000000412 dendrimer Substances 0.000 description 2
- 229920000736 dendritic polymer Polymers 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- PMMYEEVYMWASQN-IUYQGCFVSA-N trans-4-hydroxy-D-proline Chemical group O[C@@H]1CN[C@@H](C(O)=O)C1 PMMYEEVYMWASQN-IUYQGCFVSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000006668 aldol addition reaction Methods 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- OIYLDISFBUJSNS-UHFFFAOYSA-N non-5-enal Chemical compound CCCC=CCCCC=O OIYLDISFBUJSNS-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- 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
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/04—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/10—Formation of amino groups in compounds containing carboxyl groups with simultaneously increasing the number of carbon atoms in the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- 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
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract
The invention discloses a pentaerythritol-supported proline catalyst and a preparation method and application thereof. The catalyst is L/D-proline carried by pentaerythritol and L/D-proline carried by dipentaerythritol. The preparation method of the catalyst comprises the following steps: respectively reacting N-Boc-4-hydroxyproline methyl ester and mono (bi) pentaerythritol with p-toluenesulfonyl chloride to prepare 4-p-toluenesulfonate-N-Boc-proline methyl ester and mono (bi) pentaerythritol p-toluenesulfonate; 4-p-toluenesulfonate-N-Boc-proline methyl ester sequentially reacts with hydroquinone and mono (di) pentaerythritol p-toluenesulfonate to obtain mono (di) pentaerythritol supported N-Boc-proline methyl ester; the pentaerythritol supported proline catalyst is prepared by removing protective groups and saponifying. The catalyst can catalyze Aldol, Mannich and other asymmetric reactions. The catalyst is recycled for 6 times, and the catalytic activity is not reduced.
Description
Technical Field
The invention relates to the field of catalytic organic synthesis, and in particular relates to a pentaerythritol-supported proline catalyst and a preparation method and application thereof.
Background
Among numerous organic catalysts, chiral proline catalysts have attracted much attention due to their high performance and high stereoselectivity exhibited in many asymmetric organic synthesis reactions, however, chiral proline catalysts catalyze asymmetric reactions with large amounts and are difficult to recycle. Therefore, researchers select chiral proline catalysts to be loaded on different carriers, and the loaded catalysts are conveniently separated, purified and reused by utilizing the property of the carriers which are convenient to recover.
The pentaerythritol has a plurality of hydroxyl groups in the molecule, has small molecular weight, and has higher load capacity and more accurate molecular structure than other carriers such as polystyrene, modified silica gel, PEG and the like. The pentaerythritol with the structure of the dendrimer can have the same functional action as the traditional dendrimer carrier without algebraic growth. Pentaerythritol is one of the carriers, has larger supporting capacity compared with the traditional carriers such as polyethylene glycol, polystyrene and the like, can be simply recovered from catalytic reaction in a precipitation and filtration mode, and is an ideal soluble catalyst carrier. The invention supports chiral proline on a pentaerythritol carrier, and aims to solve the problem of recycling of a chiral proline catalyst and enhance the catalytic efficiency.
Disclosure of Invention
The invention aims to provide a pentaerythritol-supported proline catalyst and a preparation method and application thereof.
The pentaerythritol-supported proline catalyst provided by the invention is pentaerythritol-supported L-proline, pentaerythritol-supported D-proline, dipentaerythritol-supported L-proline and dipentaerythritol-supported D-proline, and has the following structures:
the invention also provides a preparation method of the pentaerythritol-supported proline catalyst, which comprises the following steps:
a. preparing 4-p-toluenesulfonato-N-Boc-proline methyl ester from N-Boc-4-hydroxyproline methyl ester and p-toluenesulfonyl chloride under the action of alkali;
b. mono (di) pentaerythritol and paratoluensulfonyl chloride are used for preparing mono (di) pentaerythritol paratoluenesulfonate under the action of alkali;
c. 4-p-toluenesulfonato-N-Boc-proline methyl ester reacts with hydroquinone under the action of alkali to obtain 4-p-hydroxyphenoxy-N-Boc-proline methyl ester;
d. 4-p-hydroxyphenoxy-N-Boc-proline methyl ester reacts with mono (di) pentaerythritol p-toluenesulfonate under the action of alkali to prepare mono (di) pentaerythritol supported N-Boc-proline methyl ester;
e. the mono (di) pentaerythritol supported N-Boc-proline methyl ester is subjected to Boc group removal and then NaOH saponification to prepare the pentaerythritol supported proline catalyst.
The synthetic route is as follows:
in the preparation method of the pentaerythritol-supported proline catalyst, the alkali in the steps a and b is pyridine and triethylamine; the alkali in the steps c and d is cesium carbonate, potassium carbonate and sodium carbonate; the molar ratio of the 4-p-toluenesulfonate-N-Boc-proline methyl ester to the hydroquinone in the step c is 1: 1; and in the step e, the reagent for removing the Boc protecting group of the N-Boc-proline methyl ester supported by the mono (bi) pentaerythritol is a saturated solution of hydrogen chloride and an organic solvent and a dichloromethane solution of trifluoroacetic acid.
After the Mannich reaction of the asymmetric Aldol catalyzed by the catalyst is finished, ether or petroleum ether is added into a reaction system, the catalyst can be separated out, and can be recycled for 6 times through filtration and purification, and the catalytic activity is not reduced.
The invention also provides an application of the pentaerythritol-supported proline catalyst. The catalyst catalyzes asymmetric Aldol and Mannich reaction in a polar solvent.
In the application, the catalyst and aldehyde or aldehyde and ketone are dissolved in a polar solvent solution, stirred for a certain time at room temperature, added with ether or petroleum ether, filtered, recovered, concentrated and purified to obtain the corresponding Aldol product. The reaction formula is shown as follows:
in the formula, R1，R2，R3Each independently is H, alkyl.
Dissolving the catalyst and aldehyde, ketone, p-anisidine or aldehyde, aldehyde and p-anisidine in a polar solvent, stirring for a certain time at room temperature, adding diethyl ether or petroleum ether, filtering, recovering the catalyst, concentrating the filtrate, and purifying to obtain the corresponding Mannich product. The reaction formula is shown as follows:
in the formula, R1，R2，R3Each independently is H, alkyl.
The invention has the following beneficial effects: the related pentaerythritol supported proline catalyst has the advantages of simple synthetic route, high yield and wide application, and can catalyze asymmetric Aldol and Mannich reactions of various substrates. High product yield, good enantioselectivity, easy catalyst recovery, 6 times of cyclic utilization and unchanged catalytic activity.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
examples 1-4 illustrate the synthesis of the pentaerythritol supported proline catalyst.
Examples 5-9 illustrate the use of the pentaerythritol supported proline catalyst in an asymmetric Aldol, Mannich, etc. reaction.
Example 1
Preparation of pentaerythritol-supported L-proline catalyst (1):
1.66g (14mmol) of p-toluenesulfonyl chloride was charged into a 100mL reaction flask, 13mL of dried pyridine was added, the mixture was stirred at room temperature until the solid was completely dissolved, the temperature of the system was lowered to about 5 ℃, 2.33g (12mmol) of L-N-Boc-4-hydroxyproline methyl ester was added in portions, and the mixture was stirred at room temperature for 8 hours. And adding 10ml of water into the system, stirring for 2 hours, performing suction filtration, and performing column chromatography purification to obtain the L-4-p-toluenesulfonate-N-Boc-proline methyl ester with the yield of 69.5%. 2.04g (10.7mmol) of paratoluensulfonyl chloride is added into a 250mL reaction bottle, 13mL of dried pyridine is added, the mixture is stirred at room temperature until the solid is completely dissolved, the temperature of the system is reduced to about 5 ℃ in an ice bath, 0.34g (2.5mmol) of monopentaerythritol is added in batches, and the mixture is stirred at room temperature for 8 hours. 50mL of water was added to the system, and the reaction was carried out for 2 hours, followed by suction filtration, washing of the solid with water, dissolution in methylene chloride, and precipitation in methanol to obtain 1.45g of pentaerythritol sulfonate as a white powder in a yield of 78%. Mp of 148.5-150 deg.C.
3.99g (10mmol) L-4-p-toluenesulfonate-N-Boc-proline methyl ester, 1.10g (10mmol) hydroquinone and 3.9g (12mmol) cesium carbonate were added to 10mL dry DMF and reacted at 60 ℃ for 24h, pH was adjusted with dilute hydrochloric acid 3, the solvent was distilled off under reduced pressure, 10mL CH was added2Cl2Dissolving, washing with saturated saline solution, drying, concentrating, and purifying by column chromatography to obtain L-4-p-hydroxyphenoxy-N-Boc-proline methyl ester with yield of 87%.
16.17g (48mmol) L-4-p-hydroxyphenoxy-N-Boc-proline methyl ester, 7.69g (10mmol) pentaerythritol sulfonate and 16.9g (52mmol) caesium carbonate were added to 100mL dry DMF and reacted at 60 ℃ for 24h, the solvent was evaporated off under reduced pressure and 100mL CH was added2Cl2Dissolving, washing with saturated saline, drying, concentrating and vacuum drying to obtain pentaerythritol-supported L-N-Boc-proline methyl ester with the yield of 82%.
Adding 5g of pentaerythritol-supported L-N-Boc-proline methyl ester into 50mL of dichloromethane saturated solution of hydrogen chloride, stirring for 3h at 0 ℃, evaporating to dryness under reduced pressure, adding 20mL of 1mol/L NaOH solution into the residue, stirring for 1h at room temperature, adjusting pH to 6.3 with dilute hydrochloric acid, concentrating under reduced pressure to one third of the original volume, adding diethyl ether, precipitating, filtering, washing with diethyl ether, and drying in vacuum to obtain the pentaerythritol-supported L-proline catalyst (1) with the yield of 78%.
Example 2
Preparation of pentaerythritol-supported D-proline catalyst (2):
a pentaerythritol-supported D-proline catalyst (2) was obtained in 80% yield by the procedure of example 1, except that L-4-hydroxyproline was replaced with D-4-hydroxyproline.
Example 3
Preparation of dipentaerythritol-supported L-proline catalyst (3):
a dipentaerythritol sulfonate was prepared in 79% yield by the procedure of example 1 using 0.56g (2.5mmol) of dipentaerythritol in place of 0.34g (2.5mmol) of monopentaerythritol and 3.06g (16.0mmol) of p-toluenesulfonyl chloride in place of 2.04g (10.7mmol) of p-toluenesulfonyl chloride;
a dipentaerythritol-supported L-N-Boc-proline methyl ester was prepared in 81% yield by the procedure of example 1, using 24.25g (72mmol) of L-4-p-hydroxyphenoxy-N-Boc-proline methyl ester, 11.51g (10mmol) of dipentaerythritol sulfonate and 27.95g (86mmol) of cesium carbonate in place of 16.17g (48mmol) of L-4-p-hydroxyphenoxy-N-Boc-proline methyl ester, 7.69g (10mmol) of pentaerythritol sulfonate and 16.9g (52mmol) of cesium carbonate.
Dipentaerythritol supported L-proline catalyst (3) was prepared as in example 1 using dipentaerythritol sulfonate and dipentaerythritol supported L-N-Boc-proline methyl ester.
Example 4
Preparation of dipentaerythritol-supported D-proline catalyst (4):
example 3 was carried out using D-4-hydroxyproline in place of L-4-hydroxyproline to obtain a dipentaerythritol-supported D-proline catalyst (4).
Example 5
Preparation of 4-hydroxy-4- (4' -nitrophenyl) -2-butanone:
adding 20mg of pentaerythritol-supported L-proline (1) into 2mL of acetone and 5mL of DMSO, adding 151mg (1 mmol) of 4-nitrobenzaldehyde, reacting at room temperature for 10h, adding 20mL of petroleum ether, filtering, washing with petroleum ether, recovering catalyst (1), concentrating the filtrate, separating the product with silica gel chromatography column (eluent: petroleum ether: ethyl acetate = 3: 1), and obtaining the Aldol product 4-hydroxy-4- (4' -nitro-4) methyl-benzaldehydePhenyl) -2-butanone 200mg with a yield of 68% [ α ]]D 25= +60˚ (c 1, CHCl3), e.e.: 76%, Mp: 60-62.5℃。1H-NMR (300MHz, CDCl3) δ2.22 (s, 3H), 2.85 (m, 2H), 3.57 (d, J = 3.3Hz,1H), 5.27 (m, 1H), 7.54 (d, J = 8.7Hz, 2H), 8.21 (d, J = 8.7Hz, 2H)。
Adding 30mg of L-proline into 2mL of acetone and 5mL of DMSO, adding 151mg (1 mmol) of 4-nitrobenzaldehyde, reacting for 4h at room temperature, concentrating the filtrate, separating the product by a silica gel chromatography column (eluent: petroleum ether: ethyl acetate = 3: 1) to obtain 200mg of Aldol product 4-hydroxy-4- (4' -nitrophenyl) -2-butanone, obtaining the yield of 68%, e.e.: 76%
Example 6
Preparation of 4- (4-methoxyanilino) -4- (4-nitrophenyl) -butanone-2:
weighing dipentaerythritol-supported L-proline (3) 25mg, 4-nitrobenzaldehyde 755mg (5mmol), 4-methoxyaniline 615 mg (5mmol) and acetone/DMF (1: 4) into a 50mL reaction bottle, stirring at 4 ℃ for 12h, adding diethyl ether 20mL, filtering, washing with diethyl ether, recovering catalyst (3), washing the filtrate with saturated saline solution for 3 times, and washing the organic layer with anhydrous Na2SO4Drying, concentrating under reduced pressure, and separating the product with silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3: 1) to obtain Mannich product 4- (4-methoxyanilino) -4- (4-nitrophenyl) -butanone-2 with 50% yield [ α ]]D 25= -81.7˚ (c 1, CHCl3), ee:94%;Mp:164-168℃;1H-NMR(300MHz, CDCl3) δ2.13 (s,3H), 2.93（d,2H）, 3.69 (s, 3H),4.85 (t, J=6.3Hz, 1H), 6.44 (m,2H), 6.67 (m,2H), 7.54 (m,2H), 8.16 (m,2H)。
Example 7
Preparation of (3R, 4R,5R,6S) -6-ethyl-3, 5-dimethyl-tetrahydro-2H-pyran-2, 4-diol:
weighing pentaerythritol-supported L-proline (1) 20mg, propionaldehyde 580mg (10mmol) and 5ml of DMF (diethyl formamide) and adding into a reaction flask, stirring at 4 ℃ for 24 hours, adding diethyl ether 20ml, filtering, washing with diethyl ether, recovering the catalyst (1), washing an organic phase with saturated saline solution, drying, filtering, concentrating a filtrate, and purifying by column chromatography to obtain an Aldol addition productAdding 5ml of DMF, 20mg of pentaerythritol-supported D-proline (2) and 580mg of propionaldehyde (10mmol), stirring at 4 ℃ for 24H, adding 20ml of diethyl ether, filtering, washing with diethyl ether, recovering the catalyst (2), washing an organic phase with saturated brine, drying, filtering, concentrating a filtrate, separating a product by using a silica gel chromatographic column (eluent: petroleum ether: ethyl acetate = 2: 1) to obtain a hexose Aldol product (3R, 4R,5R,6S) -6-ethyl-3, 5-dimethyl-tetrahydro-2H-pyran-2, 4-diol, wherein the total yield is 33%, [ α ]]D 25= -10.7˚ (c 2, CHCl3), ee:>99%；1H-NMR(300MHz, CDCl3) δ0.95 (m, 6H), 1.06 (d, J = 7.2Hz, 3H),1.47 (m,2H), 1.63(m, 2H), 2.09 (m, 1H), 2.58 (bs,1H)。
Example 8
Preparation of ethyl (2R, 3R) -3-formyl-2- (4-methoxyanilino) nonyl-5-eneacetate:
20mg of dipentaerythritol-supported D-proline (4), 2.07g (10mmol) of ethyl 2- (4-methoxyphenylimine) acetate, 1.69g (10mmol) of 5-nonenenylaldehyde and 10mL of THF/H were weighed2O (9: 1) was added to the reaction flask, stirred at room temperature for 24 hours, added with 20ml of diethyl ether, filtered, washed with diethyl ether, recovered catalyst (4), the filtrate was concentrated, and the product was separated by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 4: 1) to give Mannich-allylated product (2R, 3R) -3-formyl-2- (4-methoxyanilino) nonyl-5-eneacetic acid ethyl ester in 89% yield and dr>19:1 (syn/anti), ee:>99%；1H-NMR(300MHz, CDCl3) δ0.96 (s,3H), 1.30 (s,3H),1.31-1.35 (m,6H), 1.97-2.38 (m, 4H), 3.25 (m,1H),3.67 (m,1H), 3.73 (s,3H),4.1 (t,2H), 5.48 (m,2H), 6.32-6.56 (m, 4H), 9.72 (s,1H)。
Example 9
And (3) testing the recycling performance of the catalyst:
the procedure of example 8 was repeated, except that the catalyst was recovered, dissolved in a volume of ethyl acetate, precipitated with diethyl ether, filtered and purified 1 time, and dried, and then recycled for asymmetric Mannich-allylation of ethyl 2- (4-methoxyphenylimine) acetate and 5-nonenal (Table 1). The results show that the catalyst is recycled 6 times without activity reduction. The catalysts (2-4) have the same recycling effect.
Claims (8)
1. A pentaerythritol-supported proline catalyst characterized by comprising: pentaerythritol-supported L-proline, pentaerythritol-supported D-proline, dipentaerythritol-supported L-proline or dipentaerythritol-supported D-proline, the structures of which are shown below:
2. the method for producing a pentaerythritol-supported proline catalyst according to claim 1, characterized by comprising the steps of:
a. preparing 4-p-toluenesulfonato-N-Boc-proline methyl ester from N-Boc-4-hydroxyproline methyl ester and p-toluenesulfonyl chloride under the action of alkali;
b. mono/dipentaerythritol and p-toluenesulfonyl chloride are used for preparing mono/dipentaerythritol p-toluenesulfonate under the action of alkali;
c. 4-p-toluenesulfonato-N-Boc-proline methyl ester reacts with hydroquinone under the action of alkali to obtain 4-p-hydroxyphenoxy-N-Boc-proline methyl ester;
d. 4-p-hydroxyphenoxy-N-Boc-proline methyl ester reacts with mono/dipentaerythritol p-toluenesulfonate under the action of alkali to prepare mono/dipentaerythritol supported N-Boc-proline methyl ester;
e. the mono/dipentaerythritol supported N-Boc-proline methyl ester is subjected to Boc group removal and then NaOH saponification to prepare the pentaerythritol supported proline catalyst, and the synthetic route is shown as follows:
3. the method according to claim 2, wherein the base used in steps a and b is pyridine or triethylamine.
4. The method of claim 2, wherein the base used in steps c and d is cesium carbonate, potassium carbonate, or sodium carbonate.
5. The method of claim 2, wherein the molar ratio of 4-p-toluenesulfonate-N-Boc-proline methyl ester to hydroquinone in step c is 1: 1.
6. The method according to claim 2, wherein the Boc-removing reagent of N-Boc-proline methyl ester supported on mono/dipentaerythritol in step e is a saturated solution of hydrogen chloride and an organic solvent, and a dichloromethane solution of trifluoroacetic acid.
7. The catalyst of claim 1 applied to an asymmetric Aldol, asymmetric Mannich reaction in a polar solvent.
8. Use according to claim 7, characterized in that it comprises the following steps: dissolving a catalyst and aldehyde or aldehyde and ketone in a polar solvent, stirring for a certain time at room temperature, adding ether or petroleum ether, filtering, recovering the catalyst, concentrating and purifying the filtrate to obtain a corresponding Aldol product, wherein the reaction formula is shown as follows:
in the formula, R1，R2，R3Each independently is H, alkyl;
dissolving a catalyst and aldehyde, ketone, p-anisidine or aldehyde, aldehyde and p-anisidine in a polar solvent, stirring for a certain time at room temperature, adding diethyl ether or petroleum ether, filtering, recovering the catalyst, concentrating the filtrate, and purifying to obtain a corresponding Mannich product, wherein the reaction formula is as follows:
in the formula, R1，R2，R3Each independently is H, alkyl.
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