CN104788415A - Method for asymmetrically synthesizing 4-nitromethyl-3-benzyl-3,4-dihydrocoumarin derivative - Google Patents

Method for asymmetrically synthesizing 4-nitromethyl-3-benzyl-3,4-dihydrocoumarin derivative Download PDF

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Publication number
CN104788415A
CN104788415A CN201510167107.XA CN201510167107A CN104788415A CN 104788415 A CN104788415 A CN 104788415A CN 201510167107 A CN201510167107 A CN 201510167107A CN 104788415 A CN104788415 A CN 104788415A
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benzyl
derivative
melilotine
nitromethyla
formula
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CN104788415B (en
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王启发
程青芳
张金彪
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Huaihai Institute of Techology
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Huaihai Institute of Techology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring

Abstract

The invention discloses a method for asymmetrically synthesizing a 4-nitromethyl-3-benzyl-3,4-dihydrocoumarin derivative. A reaction formula of the synthetic method is shown in the specification. In the reaction formula, R1 and R2 are groups on an aromatic ring; a catalyst is an oxazine benzotriazole tetrafluoroborate substance; alkali is acetate, carbonate, bicarbonate and organic amine of alkali metal. By means of the method, the variety of chiral dihydrocoumarin compounds is enriched, and an efficient and high-stereoselectivity asymmetric synthesis method is provided for synthesis of the chiral dihydrocoumarin derivative with two chiral centers.

Description

A kind of method of asymmetric synthesis 4-nitromethyla-3-benzyl-3,4-melilotine derivative
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to a kind of method of asymmetric synthesis 4-nitromethyla-3-benzyl-3,4-melilotine derivative.
Background technology
Chirality melilotine class material is that a class is extensively present in the natural lactone compound with important biomolecule activity, and its biological activity is varied, has antibacterial, anticoagulation, antitumor, multiple pharmacologically active and the effect such as AntiHIV1 RT activity, anti-inflammatory to people; Having at lower concentration to plant is growth hormone, is the double activity of growth inhibitor in high density; So, vast chemist controls synthetic method to its asymmetric chirality and constantly studies, in succession synthesize multiple chirality melilotine, but the chirality melilotine of bibliographical information is mostly containing a chiral centre, and chiral centre is mostly in C-4 position, for chirality melilotine bibliographical information less containing two chiral centres.
Compound containing nitro is also generally have bioactive compound, and nitro is easy to change into the groups such as amino, amide group, halogen, hydroxyl, but contains the also less of the synthesis bibliographical information of the chirality melilotine of nitro.
For employing Shou oxazine triazole Tetrafluoroboric acid Cabbeen is catalyzer, with 2-halo-3-aryl propionic aldehyde and alpha-hydroxy-2-nitro aromatic ethylene for the asymmetric synthesis of raw material one step is containing two chiral centres and chiral centre has no bibliographical information at 4-nitromethyla-3-benzyl-3, the 4-melilotine derivative of C-3 and C-4 position.
Summary of the invention
The invention provides a kind of method of asymmetric synthesis 4-nitromethyla-3-benzyl-3,4-melilotine derivative, the compound that the method obtains contains two chiral centres in C-3 and C-4 position.
Technical scheme of the present invention is summarized as follows:
By formula (II) compound 2-halo-3-aryl propionic aldehyde and formula (III) compound alpha-hydroxy-2-nitro aromatic ethylene in organic solvent, certain hour is reacted under chirality carbone catalyst and alkali effect, namely optically pure formula (I) compound 4-nitromethyla-3-benzyl-3,4-melilotine derivative is obtained after aftertreatment.
Synthetic route is:
In described reactant and product, R 1and R 2for hydrogen, C 1~ C 6alkyl, halogen, C 1~ C 4haloalkyl, C 1~ C 6alkoxyl group, nitro etc.
Described catalyzer Wei oxazine triazole Tetrafluoroboric acid Cabbeen salt, derived by amino acids material and obtain, the structure of catalyzer is:
Wherein, R 3and R 4for C 1~ C 4alkyl, C 1~ C 4haloalkyl, C 1~ C 4alkoxyl group, halogen etc.
Gai oxazine the carbene catalyzed efficiency of triazole Tetrafluoroboric acid is high, its consumption is only 5 ~ 10% of the amount of formula (II) combinations of materials.
Described alkali is alkali-metal acetate, carbonate or supercarbonate, organic amine etc., and the mol ratio of itself and formula (II) compound is 1.8 ~ 3: 1.
Described solvent is the conventional organic solvents such as tetrahydrofuran (THF), 2-methyltetrahydrofuran, toluene, benzene, methylene dichloride, ethylene dichloride, acetonitrile, organic ether.
The method has enriched the kind of chirality melilotine compounds, for the synthesis with bioactive chirality melilotine derivative provides a kind of efficient and method of asymmetric synthesis that stereoselectivity is high.
Embodiment
Below in conjunction with specific embodiment, further illustrate the present invention; Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.
Raw material used in embodiment or reagent, except special instruction, are analytical pure.
The synthesis of embodiment 1 (3R, 4R)-3-benzyl-4-nitromethyla-3,4-melilotine
Reaction formula is:
Under nitrogen protection, 5mmol2-chloro-3-phenylpropionaldehyde and 6mmol alpha-hydroxy-2-nitrostyrolene, 10mmol sodium-acetate, 0.3mmol catalyzer are added in strict dry reaction flask, then the 5mL methylene dichloride of absolute is injected reaction flask; sealing bottle cork; at 0 ~ 5 DEG C, react 4h, be then warming up to rt while stirring overnight, stopped reaction; filter salts; pressure reducing and steaming solvent, obtains crude product, and crude product is by silicagel column separating-purifying; obtain white solid, yield 88%.
By above-mentioned for trace obtained compound dissolution in isopropanol-hexane (1: 9) solvent, adopt Chiral liquid chromatography OD-H column chromatography, record this product d: r to be configured as 95: 5, ee value be 85%; 1h NMR (400Hz, ppm): 6.97-7.24 (m, 9H, ArH), 4.53-4.79 (m, 2H, CH 2), 3.38-3.42 (m, 1H, CH), 3.06-3.12 (m, 1H, CH), 2.72-2.89 (m, 2H, CH 2).
The synthesis of embodiment 2 (3R, 4R)-3-(4-chlorobenzyl)-7-chloro-4-nitromethyla-3,4-melilotine
Reaction formula is:
Under nitrogen protection; 5mmol 2-chloro-3-(4-chloro-phenyl-) propionic aldehyde and the chloro-2-of 6mmol 5-(2-nitroethylene base) phenol, 12mmol Potassium ethanoate, 0.4mmol catalyzer are added in strict dry reaction flask; then the 5mL cyclopentyl methyl ether of absolute is injected reaction flask; sealing bottle cork; 5h is reacted at 0 ~ 5 DEG C; then rt while stirring overnight is warming up to; stopped reaction; filter salts; pressure reducing and steaming solvent, obtains crude product, and crude product is by silicagel column separating-purifying; obtain white solid, yield 83%.
By above-mentioned for trace obtained compound dissolution in isopropanol-hexane (1: 9) solvent, adopt Chiral liquid chromatography OD-H column chromatography, recording d: the r of this product, to be configured as 93: 7, ee value be 89%; 1hNMR (400Hz, ppm): 7.27 (d, J=7.2Hz, 2H, ArH), 6.93-7.16 (m, 5H, ArH), 4.57-4.84 (m, 2H, CH 2), 3.32-3.45 (m, 1H, CH), 3.04-3.10 (m, 1H, CH), 2.64-2.83 (m, 2H, CH 2).

Claims (3)

1. the method for asymmetric synthesis 4-nitromethyla-3-benzyl-3, a 4-melilotine derivative, is characterized in that the reaction formula of this synthetic method is:
In described reaction formula, R 1and R 2for hydrogen, C 1~ C 6alkyl, halogen, C 1~ C 4haloalkyl, C 1~ C 6alkoxyl group, nitro.
2. the method for a kind of asymmetric synthesis 4-nitromethyla-3-benzyl-3,4-melilotine derivative according to claim 1, is characterized in that: described catalyzer Wei oxazine triazole Tetrafluoroboric acid Cabbeen salt, and the structure of catalyzer is:
In described catalyst structure, R 3and R 4for C 1~ C 4alkyl, C 1~ C 4haloalkyl, C 1~ C 4alkoxyl group, halogen; Its consumption is 5 ~ 10% of the amount of formula (II) combinations of materials.
3. a kind of asymmetric synthesis 4-nitromethyla-3-benzyl-3 according to claim 1, the method of 4-melilotine derivative, it is characterized in that: described alkali is alkali-metal acetate, carbonate, supercarbonate, organic amine, and the mol ratio of itself and formula (II) compound is 1.8 ~ 3: 1.
CN201510167107.XA 2015-03-31 2015-03-31 A kind of method of asymmetric synthesis 4 nitromethyla, 3 benzyl 3,4 dihydrocoumarin derivant Active CN104788415B (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105906649A (en) * 2016-05-12 2016-08-31 淮海工学院 Method for asymmetric synthesis of spiro-lactone compound containing chiral 5-hydroxy flavone unit
CN110452205A (en) * 2019-06-17 2019-11-15 天津农学院 A kind of preparation method for constructing 3- methene base -3,4- dihydrocoumarin framework compound

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Title
BOR-CHERNG HONG ET AL.: "Enantioselective organocatalytic domino Michael–acetalization–Henry reactions of 2-hydroxynitrostyrene and aldehyde for the synthesis of tetrahydro-6H-benzo[c]chromenones", 《ORG. BIOMOL. CHEM.》 *
CRAIG D. CAMPBELL ET AL.: "Catalytic enantioselective Steglich rearrangements using chiral N-heterocyclic carbenes", 《TETRAHEDRON: ASYMMETRY》 *
DENGFU LU ET AL.: "Organocatalytic Asymmetric Tandem Michael Addition-Hemiacetalization: A Route to Chiral Dihydrocoumarins,Chromanes, and 4H-Chromenes", 《J. ORG. CHEM.》 *
DHEVALAPALLY B. RAMACHARY ET AL.: "A general approach to high-yielding asymmetric synthesis of chiral 3-alkyl-4-nitromethylchromans via cascade Barbas–Michael and acetalization reactions", 《ORG. BIOMOL. CHEM.》 *
FAN LIU ET AL.: "Designing N-Heterocyclic Carbenes: Simultaneous Enhancement of Reactivity and Enantioselectivity in the Asymmetric Hydroacylation of Cyclopropenes", 《ANGEW. CHEM. INT. ED. 》 *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105906649A (en) * 2016-05-12 2016-08-31 淮海工学院 Method for asymmetric synthesis of spiro-lactone compound containing chiral 5-hydroxy flavone unit
CN110452205A (en) * 2019-06-17 2019-11-15 天津农学院 A kind of preparation method for constructing 3- methene base -3,4- dihydrocoumarin framework compound

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