CN103819499A - Chiral secondary amine containing silica ether structure as well as preparation method and application of chiral secondary amine - Google Patents
Chiral secondary amine containing silica ether structure as well as preparation method and application of chiral secondary amine Download PDFInfo
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Abstract
The invention relates to a chiral secondary amine compound as shown in the formula (I), as well as a preparation method and application of the chiral secondary amine compound. The chiral secondary amine compound is synthesized through three steps of etherification, deprotection by hydrolysis and silanization. As shown in the formula (I), the chiral secondary amine compound containing a silica ether structure can be catalytically applied to an asymmetric organic reaction to obtain a product with optical selectivity. The chiral secondary amine compound contains functional groups such as pyrrolidyl and diaryl silicyl, and the synergy of the functional groups shows good chiral induction. The introduction of 4 styrene groups greatly improves the steric-hindrance of the catalyst, and meanwhile provides possibility for the further modification on the catalyst, for example, loading of the catalyst.
Description
(1) technical field
The present invention relates to a kind of chirality secondary amine compound of Novel siliceous oxygen ether structure, the invention still further relates to the preparation method of this novel chiral secondary amine compound and the application aspect synthetic at asymmetry catalysis.
(2) background technology
(J.Am.Chem.Soc. since asymmetric aldol reaction between the L-PROLINE of the report such as List in 2000 can highly selective catalytic molecular, 2000,122,2395-2396), be one of topmost study hotspot in asymmetric organocatalysis field take chiral proline and derivative thereof as the chirality secondary amine catalysis of representative.So far, existing many typical proline derivatives be designed, synthetic and for the various asymmetric reactions of catalysis.As the typical chirality secondary amine catalyst that contains silica ether structure, in the numerous reactions that participate at its catalysis aldehyde ketone, show excellent asymmetry catalysis performance, in chiral medicinal, agricultural chemicals, natural product and fine-chemical intermediate synthetic, obtained more and more potential using values that have.Therefore in recent years, the various chirality secondary-amine compounds containing silica ether structure occur like the mushrooms after rain, and have been applied in various asymmetric organic reactions.2005,
group and Hayashi group have reported respectively the application in series reaction as a kind of organic catalyst of diaryl dried meat ammonia alcohol silicon ether compound:
group development goes out secondary amines catalyst 1, and is applied to the asymmetric reaction of aldehyde and α-fluorination, and product has obtained 96% ee value (Angew.Chem.Int.Ed., 2005,44,794 – 797); The same year, the systematic study of Hayashi group catalyzer Cat1, Cat2 and Cat3 catalysis aldehyde react (Angew.Chem.Int.Ed., 2005,44,4212 – 4215) with nitroolefin.2006,
the Michael addition reaction of group has been used catalyzer Cat4 catalysis phenylacrolein and dimethyl malonate, obtained 94% ee value, and this synthetic method can be applied to (Angew.Chem.Int.Ed., 2006 in synthesizing of paroxetine, 45,4305 – 4309).2008, Ye seminar is take 1 as chiral catalyst, take 4-fluorobenzoic acid as acid additive, catalysis dimethyl malonate and a series of α, the Miacheal asymmetric reduction reaction of β-unsaturated aldehyde, has obtained adduct (Adv.Synth.Catal., 2008 of 99%ee value, 350,1383-1389).2009, Yu seminar of Zhejiang University was used catalyzer Cat5 catalysis p-met hoxycinnamic aldehyde and 5,5-dimethyl cyclohexane-1, the reaction (Tetrahedron2009,65,10016-10021) of 3-diketone, obtained being greater than the dr value of 25:1 and 84% ee value, and yield reaches 89%.2009, catalyzer 1 catalysis 2-(amyl group-3-oxygen for Ma seminar) reaction (Angew.Chem.Int.Ed. of acetaldehyde and (E)-N-(2-nitroethylene base) ethanamide, 2010,49,4656 – 4660), obtained 96%ee value and 80% yield, synthetic product is the pharmaceutical intermediate of GS-4104 (antiviral drug).2011, Tomkinson group is by comparing the catalytic activity of imidazolone and diaryl dried meat ammonia alcohol silica ethers catalyzer, diaryl dried meat ammonia alcohol silica ethers catalyzer 5 is for the D-A cycloaddition reaction of phenylacrolein and cyclopentadiene, normal-temperature reaction has obtained adduct (the Tetrahedron Lett. of 91%ee value, 2011,52,2783 – 2785).
Analyze the feature containing the secondary amines catalyst of chirality of silica ether structure, such catalyzer is mainly made up of two part functional groups: (1) tetramethyleneimine fragment is the basic skeleton of catalyzer, forming imines, enamine activation transition state with reaction substrate, is the key factor that asymmetric reaction is carried out smoothly; (2) chiral carbon atom connects a sterically hindered large group containing silica ether structure, and this is the key that asymmetric reaction can high optical selective be carried out, so can the numerous asymmetric reactions of highly-solid selectively ground catalysis.The present invention designs the secondary amines catalyst of chirality of a synthetic class Novel siliceous oxygen ether structure.
(3) summary of the invention
Primary and foremost purpose of the present invention is to provide a kind of chirality secondary amine compound containing silica ether structure.
Second object of the present invention is to provide the preparation method of the above-mentioned chirality secondary amine compound containing silica ether structure.
The 3rd object of the present invention is to provide the application of the above-mentioned chirality secondary amine compound containing silica ether structure in organic asymmetric catalysis.
A kind of chirality secondary amine compound containing silica ether structure of the present invention, its general formula is as shown in formula I:
In formula (I),
R
1, R
2independent is separately hydrogen, phenyl, 3,5-bis-trifluoromethyls, 3,5-diisopropyl phenyl, 3,5-di-tert-butyl-phenyl, 2,4, the alkyl of 6-trifluorophenyl, styryl or C1～C20;
R
3for hydrogen, TMS, triethyl silyl, tertiary butyl dimethylsilyl, dimethylphenylsilaneand base, tri-phenyl-silane base, phenylbenzene benzyl silylation.
Further, the structure optimization of the described chirality secondary amine compound containing silica ether structure is suc as formula compound shown in (I '):
Further, R
1, R
2independently be preferably separately phenyl or 3,5-, bis-trifluoromethyls.
Further, R
3be preferably TMS or triethyl silyl.
Further, R
1, R
2independently be preferably separately phenyl or 3,5-, bis-trifluoromethyls; R
3be preferably TMS.
Particularly, the described chirality secondary amine compound containing silica ether structure is as follows:
(1) (2S, 4R)-2-(phenylbenzene (trimethylsiloxy group) methyl)-4-(4-vinylbenzene oxygen base) tetramethyleneimine (I a),
(2) (I b) for tetramethyleneimine for-4-(4-vinylbenzene oxygen base) for (2S, 4R)-2-(two (two (trifluoromethyl) phenyl of 3,5-) (trimethylsiloxy group) methyl).
Second goal of the invention of the present invention is to provide a kind of method of simple to operate, reaction conditions is gentle, reaction yield is high, selectivity the is good synthetic described chirality secondary-amine compound containing silica ether structure.
The technical solution used in the present invention is as follows:
A kind of preparation method of the chirality secondary-amine compound containing silica ether structure; take formula (II) compound as starting raw material; successively by (a) etherificate, (b) hydrolysis deprotection and (c) three steps of silanization make the chirality secondary-amine compound containing silica ether structure shown in formula (I), reaction formula is as follows:
In formula I, formula (II), formula (III) or formula IV, R
1, R
2definition with the R in formula I
1, R
2, i.e. R
1, R
2independent is separately hydrogen, phenyl, 3,5-bis-trifluoromethyls, 3,5-diisopropyl phenyl, 3,5-di-tert-butyl-phenyl, 2,4, the alkyl of 6-trifluorophenyl, styryl or C1～C20;
R
3for hydrogen, TMS, triethyl silyl, tertiary butyl dimethylsilyl, dimethylphenylsilaneand base, tri-phenyl-silane base, phenylbenzene benzyl silylation.
Concrete, the preparation method of the described chirality secondary-amine compound containing silica ether structure, carries out as follows:
(a) etherificate: get sodium hydride powder and add compound shown in the formula II being dissolved in organic solvent A to be mixed under ice bath, be warmed up to 40 ℃-100 ℃ reaction 20-60min, under ice bath, add again the chloro-4-vinylbenzene of the 1-being dissolved in organic solvent A to react after 0.5 – 3h, be warming up to 40-100 ℃ and react again 0.5 – 3h, after reaction finishes, reaction solution obtains compound shown in formula III through separation and purification, described organic solvent A is N, N-dimethyl methyl acid amides (DMF), dimethyl sulfoxide (DMSO) (DMSO), tetrahydrofuran (THF) (THF), Isosorbide-5-Nitrae-dioxane or acetonitrile;
(b) hydrolysis deprotection: shown in the formula III that step (a) is made, compound is dissolved in organic solvent B, drip the aqueous solution of potassium hydroxide, at 30-70 ℃, react 12-36h, after reaction finishes, reaction solution acquires compound shown in formula IV through separation and purification; Described organic solvent B is ethanol, methylene dichloride, chloroform, ether, isopropyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, ethyl acetate, toluene, dimethylbenzene, acetonitrile, methyl alcohol, ethanol or Virahol;
(c) silanization: shown in the formula IV that step (b) is made, compound is dissolved in organic solvent C after being then added dropwise to triethylamine and mixing, adds R under ice bath
3then Cl alkane at room temperature react 12-36h, after question response is complete, reaction solution obtains compound shown in formula (I) through separation and purification, described organic solvent C is methylene dichloride 1,2-ethylene dichloride, 1,1,2-trichloroethane, chloroform, ether, isopropyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane.
Further, the method for the chirality secondary-amine compound containing silica ether structure of the present invention adds after in step (a), sodium hydride powder first being added to petroleum ether and stirring and being mixed shown in the formula II that is dissolved in organic solvent A in compound under ice bath again.
Further, in step (a), compound shown in formula II is with sodium hydride amount of substance than being 1:2-6, and compound shown in formula II is 1:2-6 with the chloro-4-vinylbenzene of 1-amount of substance ratio.
Further, the purification procedures of step (a) is specific as follows: after reaction finishes, the cancellation that adds water reaction, add again ether and the sherwood oil mixed organic solvents of arbitrary proportion to extract (preferred volume ratio ether: sherwood oil=2:1), obtain the precipitation that reduces pressure after desiccant dryness for organic phase A, product after precipitation carries out silica gel column chromatography, take volume ratio 5～15:100 ethyl acetate and sherwood oil mixed solution as eluent, collect the elutriant containing target components, precipitation obtains compound shown in formula III.
Further, in step (b), compound shown in described (III) is 1:4-10 with potassium hydroxide amount of substance ratio.
Further, purification procedures in step (b) is specific as follows: after reaction finishes, use ethyl acetate dilute reaction solution, wash with water again, get the precipitation that reduces pressure after desiccant dryness for organic phase B, the product after precipitation carries out silica gel column chromatography, take the ethyl acetate of volume ratio 5～15:100 and sherwood oil mixed solution as eluent, collect the elutriant containing target components, precipitation acquires compound shown in formula IV.
Further, in step (c), compound shown in described formula IV is 1:1-3 with triethylamine amount of substance ratio, compound and R shown in described formula IV
3cl amount of substance is than being 1:1-3.
Further, purification procedures in step (c) is specific as follows: after question response is complete, add methylene dichloride dilution, then washing, get the precipitation that reduces pressure after desiccant dryness for organic phase C, product after precipitation, take the ether of 10～30:100 and sherwood oil mixed solution as eluent, is collected the elutriant containing target components, and precipitation obtains compound shown in formula (I).
Further again, described step (a), step (b), the siccative described in step (c) is preferred anhydrous sodium sulphate all.
Further, organic solvent B in organic solvent A, step (b) in step of the present invention (a), in step (c), organic solvent C represents organic solvent, and A, B, C do not have specific connotation, is just the machine solvent used in differential responses step in order to difference.
Chirality secondary-amine compound containing silica ether structure of the present invention can be used as catalyzer and is applied in organic asymmetric reaction, obtains having the product of optical selective.
The invention provides the application of the described chirality secondary-amine compound containing silica ether structure in organic asymmetric reaction, described organic asymmetric reaction is Michael reaction, and reaction structure formula is as follows:
Compared with prior art, its beneficial effect is in the present invention:
(1) provide a kind of chirality secondary-amine compound of Novel siliceous oxygen ether structure, contained the functional group such as pyrrolidyl, diaryl silylation in this chipal compounds, each functional group synergy shows good chiral induction character;
The introducing of (2) 4 styrene groups has improved the sterically hindered of catalyzer greatly, is the further modification of this catalyzer simultaneously, as: load provides possibility;
(3) the chirality secondary-amine compound containing silica ether structure provided by the invention is as the application of catalyzer in organic asymmetric reaction, and organic asymmetric reaction is Michael reaction.Its advantage is that catalyst levels is few, reactive behavior is high, wide application, can be applicable to the synthetic of chiral medicinal, agricultural chemicals, natural product and fine-chemical intermediate.
(4) embodiment
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this.
Specific embodiments of the invention comprise:
The structure of described II a, II b, III a, III b, IV a, IV b, I a and I b compound is as follows:
Embodiment 1: the preparation of compound shown in chirality secondary amine compound formula III a
Sodium hydride powder 0.26g (11mmol) is added and in sherwood oil, stirs 10min, under ice bath, add the Compound I I a1.9g (5.5mmol) (being dissolved in DMF22mL) making, first at room temperature stir 20min, be then warming up to 60 ℃ of reaction 30min.Under ice bath, add after the chloro-4-vinylbenzene of 1-1.67g (11mmol) (being dissolved in DMF2mL) reaction 1h, be warming up to 60 ℃ of reaction half hours.After reaction finishes, (2ml) cancellation that first adds water reaction, after add diethyl ether (20ml) and sherwood oil (10ml) extracts, get subsequently the precipitation that reduces pressure after anhydrous sodium sulfate drying for organic phase.Product after precipitation is purified (moving phase is ethyl acetate/petroleum ether: 5%-10%-15%) with silica gel column chromatography, collects containing the compound elutriant shown in formula III a, and precipitation obtains target compound III a (1.66g, yield: 90%).Its specific rotatory power [α]
d 20=+33 °.
1H?NMR(500MHz,CDCl
3):δ=7.58-7.56(m,2H),7.45-7.42(m,2H),7.41-7.37(m,6H),7.35-7.27(m,4H),6.76-6.72(q,J=11.0,17.5Hz,1H),5.81-5.78(m,1H),5.31-5.28(m,1H),4.90-4.93(q,J=5.0,11.5Hz,1H),4.48(s,2H),4.18(t,J=5.5Hz,1H),4.08-4.05(q,J=5.5,12.5Hz,1H),3.38-3.35(m,1H),1.96-1.92(q,J=5.0,13.5Hz,1H),1.25-1.19(m,1H)ppm;
13C?NMR(125MHz,CDCl
3):δ=160.4,143.0,140.2,137.4,137.2,136.4(×2),128.7(×2),128.5(×2),128.0(×2),127.8,126.4(×2),126.1(×2),125.5(×2),114.2,85.8,78.4,71.1,67.5,53.8,36.2ppm;GC-MS:m/z411.2(100),165.1,91.1.HRMS:(ESI+)m/z?calcd?for?C
27H
26NO
3[M+H]
+412.1913,found412.1922.
Embodiment 2: the preparation of compound shown in chirality secondary amine compound formula III a
Sodium hydride powder 0.26g (11mmol) is added and in sherwood oil, stirs 10min, under ice bath, add the Compound I I a1.9g (5.5mmol) (being dissolved in DMSO22mL) making, first at room temperature stir 20min, be then warming up to 60 ℃ of reaction 30min.Under ice bath, add after the chloro-4-vinylbenzene of 1-1.67g (11mmol) (being dissolved in DMSO2mL) reaction 1h, be warming up to 60 ℃ of reaction half hours.After reaction finishes, (2ml) cancellation that first adds water reaction, after add diethyl ether (20ml) and sherwood oil (10ml) extracts, get subsequently the precipitation that reduces pressure after anhydrous sodium sulfate drying for organic phase.Product after precipitation is purified (moving phase is ethyl acetate/petroleum ether: 5%-10%-15%) with silica gel column chromatography, collects containing the compound elutriant shown in formula III a, and precipitation obtains target compound III a (1.48g, yield: 80%).Its specific rotatory power [α]
d 20=+33 °.
Embodiment 3: the preparation of compound shown in chirality secondary amine compound formula III b
Sodium hydride powder 0.26g (11mmol) is added and in sherwood oil, stirs 10min, under ice bath, add the Compound I I b3.37g (5.5mmol) (being dissolved in DMF22mL) making, first at room temperature stir 20min, be then warming up to 60 ℃ of reaction 30min.Under ice bath, add after the chloro-4-vinylbenzene of 1-1.67g (5.5mmol) (being dissolved in DMF2mL) reaction 1h, be warming up to 60 ℃ of reaction half hours.After reaction finishes, (2ml) cancellation that first adds water reaction, after add diethyl ether (20ml) and sherwood oil (10ml) extracts, the precipitation that reduces pressure after anhydrous sodium sulfate drying for organic phase subsequently.Product after precipitation is purified (moving phase is: ethyl acetate/petroleum ether: 5%-10%-15%) with silica gel column chromatography, collects containing the compound elutriant shown in formula III b, and precipitation obtains target compound III b (2.35g, yield: 70%).Its specific rotatory power [α]
d 20=+32 °.HRMS:(ESI+)m/zcalcd?for?C
31H
22F
12NO
3[M+H]
+684.1403,found684.1405.
Embodiment 4: the preparation of compound shown in chirality secondary amine compound formula III b
Sodium hydride powder 0.26g (11mmol) is added and in sherwood oil, stirs 10min, under ice bath, add the Compound I I b3.37g (5.5mmol) (being dissolved in DMSO22mL) making, first at room temperature stir 20min, be then warming up to 60 ℃ of reaction 30min.Under ice bath, add after the chloro-4-vinylbenzene of 1-1.67g (5.5mmol) (being dissolved in DMSO2mL) reaction 1h, be warming up to 60 ℃ of reaction half hours.After reaction finishes, (2ml) cancellation that first adds water reaction, after add diethyl ether (20ml) and sherwood oil (10ml) extracts, the precipitation that reduces pressure after anhydrous sodium sulfate drying for organic phase subsequently.Product after precipitation is purified (moving phase is: ethyl acetate/petroleum ether: 5%-10%-15%) with silica gel column chromatography, collects containing the compound elutriant shown in formula III b, and precipitation obtains target compound III b (1.85g, yield: 55%).Its specific rotatory power [α]
d 20=+32 °.
Embodiment 5: the preparation of compound shown in chirality secondary amine compound formula IV a
By in water-soluble potassium hydroxide 0.48g (8.5mmol) (1mL), be then added dropwise to the compound III a0.7g (1.7mmol) (being dissolved in ethanol (5mL)) making, at 45 ℃, react 24h.After reaction finishes, with 5ml ethyl acetate dilute reaction solution, then 10ml washing, get the precipitation that reduces pressure after organic phase 5g anhydrous sodium sulfate drying.Precipitation after product is purified (moving phase: ethyl acetate/petroleum ether: 5%-10%-15%) with silica gel column chromatography, collects containing compound elutriant shown in formula IV a, and precipitation, obtains target compound IV a(0.56g, yield: 86%).Its specific rotatory power [α]
d 20=+26 °.
1H?NMR(500MHz,CDCl
3):δ=7.62(d,J=7.0Hz,2H),7.53(t,J=1.0Hz,2H),7.43(d,J=8.5Hz,2H),7.36-7.30(m,6H),7.24-7.19(m,2H),6.79-6.73(q,J=10.5,17.5Hz,1H),5.78(d,J=17.5Hz,1H),5.28(d,J=11.0Hz,1H),4.63-4.60(q,J=6.5,9.5Hz,1H),4.49-4.44(m,2H),4.09-4.07(m,1H),3.20-3.16(m,2H),1.86-1.80(m,1H),1.74-1.70(m,1H)ppm;
13C?NMR(125MHz,CDCl
3):δ=147.8,145.0,138.0,137.1,136.6,128.3(×2),128.0(×2),127.8(×2),126.6,126.4,126.3(×2),126.0(×2),125.5(×2),113.9,79.5,76.9,70.6,63.5,52.6,33.0ppm;(ESI+)m/z386.28；HRMS:(ESI+)m/z?calcd?for?C
26H
28NO
2[M+H]
+386.2115,found386.2119.
Embodiment 6: the preparation of compound shown in chirality secondary amine compound formula IV a
By in water-soluble potassium hydroxide 0.48g (8.5mmol) (1mL), be then added dropwise to the compound III a0.7g (1.7mmol) (being dissolved in methyl alcohol (5mL)) making, at 45 ℃, react 24h.After reaction finishes, with 5ml ethyl acetate dilute reaction solution, then 10ml washing, get the precipitation that reduces pressure after organic phase 5g anhydrous sodium sulfate drying.Precipitation after product is purified (moving phase: ethyl acetate/petroleum ether: 5%-10%-15%) with silica gel column chromatography, collects containing compound elutriant shown in formula IV a, and precipitation, obtains target compound IV a(0.49g, yield: 75%).Its specific rotatory power [α]
d 20=+26 °.
Embodiment 7: the preparation of chirality secondary amine compound IV b
By in water-soluble potassium hydroxide 0.48g (8.5mmol) (1mL), be then added dropwise to the compound III b1.16g (1.7mmol) (being dissolved in ethanol (5mL)) making, at 45 ℃, react 24h.After reaction finishes, with ethyl acetate 5ml dilute reaction solution, then with 10ml washing, get the precipitation that reduces pressure after organic phase 5g anhydrous sodium sulfate drying.Precipitation after product is purified (moving phase: ethyl acetate/petroleum ether: 5%-10%-15%) with silica gel column chromatography, collects containing compound elutriant shown in formula IV b, and precipitation, obtains target compound IV b(0.91g, yield: 83%).Its specific rotatory power [α]
d 20=+28 °.HRMS:(ESI+)m/z?calcd?for?C
30H
24F
12NO
2[M+H]
+658.1610,found658.1615.
Embodiment 8: the preparation of chirality secondary amine compound IV b
By in water-soluble potassium hydroxide 0.48g (8.5mmol) (1mL), be then added dropwise to the compound III b1.16g (1.7mmol) (being dissolved in methyl alcohol (5mL)) making, at 45 ℃, react 24h.After reaction finishes, with ethyl acetate 5ml dilute reaction solution, then with 10ml washing, get the precipitation that reduces pressure after organic phase 5g anhydrous sodium sulfate drying.Precipitation after product is purified (moving phase: ethyl acetate/petroleum ether: 5%-10%-15%) with silica gel column chromatography, collects containing compound elutriant shown in formula IV b, and precipitation, obtains target compound IV b(0.88g, yield: 80%).Its specific rotatory power [α]
d 20=+28 °.
Embodiment 9: the preparation of chirality secondary amine compound I a
The compounds Ⅳ a0.38g (1mmol) making is dissolved in dry methylene chloride (5mL), then be added dropwise to triethylamine 0.13g (1.3mmol), stir after 15min, under ice bath, add trimethylchlorosilane 0.13g (1.2mmol), then at room temperature react 21h.After question response is complete, add methylene dichloride 5ml dilution, then 10ml washing.Get the precipitation that reduces pressure after organic phase 5g anhydrous sodium sulfate drying.Product after precipitation is purified (moving phase: ether/sherwood oil: 10%-20%-30%) with silica gel column chromatography, collects containing compound elutriant shown in formula I a, and precipitation, obtains target compound I a(0.306g, yield: 67%).Its specific rotatory power [α]
d 20=+33 °.
1H?NMR(500MHz,CDCl
3):δ=7.52-7.50(m,2H),7.41-7.38(m,4H),7.32-7.24(m,8H),6.77-6.71(q,J=11.0,18.0Hz,1H),5.77(d,J=18.0Hz,1H),5.26(d,J=10.5Hz,1H),4.42(t,J=5.5Hz,3H),3.84-3.83(m,1H),3.05-3.03(m,1H),2.88-2.85(m,1H),1.78-1.75(m,2H),0.06(s,9H)ppm;
13C?NMR(125MHz,CDCl
3):δ=146.5,145.3,138.1,137.0,136.6,128.5(×2),127.9(×2),127.7(×2),127.6(×2),127.5(×2),127.0,126.9,126.3(×2),113.8,82.8,79.0,70.6,63.8,52.8,34.3,2.2(×3)ppm;(ESI+)m/z458.21;HRMS:(ESI+)m/z?calcd?for?C
29H
36NO
2Si[M+H]
+458.2516,found458.2515.
Embodiment 10: the preparation of chirality secondary amine compound I a
The compounds Ⅳ a0.38g (1mmol) making is dissolved in dry trichloromethane (5mL), then be added dropwise to triethylamine 0.13g (1.3mmol), stir after 15min, under ice bath, add trimethylchlorosilane 0.13g (1.2mmol), then at room temperature react 21h.After question response is complete, add methylene dichloride 5ml dilution, then 10ml washing.Get the precipitation that reduces pressure after organic phase 5g anhydrous sodium sulfate drying.Product after precipitation is purified (moving phase: ether/sherwood oil: 10%-20%-30%) with silica gel column chromatography, collects containing compound elutriant shown in formula I a, and precipitation, obtains target compound I a(0.292g, yield: 64%).Its specific rotatory power [α]
d 20=+33 °.
Embodiment 11: the preparation of chirality secondary amine compound I b
The compounds Ⅳ b0.66g (1mmol) making is dissolved in dry methylene chloride (5mL), then be added dropwise to triethylamine 0.13g (1.3mmol), stir after 15min, under ice bath, add trimethylchlorosilane 0.13g (1.2mmol), then at room temperature react 21h.After question response is complete, add methylene dichloride 5ml dilution, then 10ml washing.Decompression precipitation after organic phase is dry with anhydrous sodium sulphate 5g.Product after precipitation is purified (moving phase: ether/sherwood oil: 10%-20%-30%) with silica gel column chromatography, collects containing compound elutriant shown in formula I b, and precipitation, obtains target compound I b(0.41g, yield: 56%).Its specific rotatory power [α]
d 20=+30 °.
1H?NMR(500MHz,CDCl
3):δ=8.02(s,2H),7.87-7.85(m,2H),7.78(s,2H),7.42-7.40(m,2H),7.29–7.25(m,2H),6.75–6.70(m,1H),5.78–5.75(m,1H),5.29–5.26(m,1H),4.53–4.40(m,3H),4.15–4.14(m,1H),3.06-3.04(m,1H),2.30-2.25(m,1H),2.07(s,1H),1.46-1.44(m,1H),0.92-0.86(m,1H),0.04(s,9H)ppm;(ESI+)m/z458.21;HRMS:(ESI+)m/z?calcd?for?C
33H
32F
12NO
2Si[M+H]
+730.2005,found730.2005.
Embodiment 12: the preparation of chirality secondary amine compound I b
The compounds Ⅳ b0.66g (1mmol) making is dissolved in dry trichloromethane (5mL), then be added dropwise to triethylamine 0.13g (1.3mmol), stir after 15min, under ice bath, add trimethylchlorosilane 0.13g (1.2mmol), then at room temperature react 21h.After question response is complete, add methylene dichloride 5ml dilution, then 10ml washing.Decompression precipitation after organic phase is dry with anhydrous sodium sulphate 5g.Product after precipitation is purified (moving phase: ether/sherwood oil: 10%-20%-30%) with silica gel column chromatography, collects containing compound elutriant shown in formula I b, and precipitation, obtains target compound I b(0.38g, yield: 52%).Its specific rotatory power [α]
d 20=+30 °.
Embodiment 13: the application of chirality secondary amine compound I a in asymmetric Michael1 reaction
10mL in vitro adds catalyzer I a0.005g(0.01mmol), 1,2-ethylene dichloride (0.25mL), phenylformic acid 0.001g(0.01mmol), to fluorine phenylacrolein 0.08g(0.5mmol), dimethyl malonate 0.03g(0.25mmol), stirring reaction 24h under room temperature.Then extract product (moving phase: ethyl acetate/petroleum ether: 10%-20%) with silica gel column chromatography, collect containing target product compound elutriant, precipitation, obtains target product (0.0627g, yield: 95%, ee value: 93%).Its specific rotatory power [α]
d 20=+29 °.
Embodiment 14: the application of chirality secondary amine compound I a in asymmetric Michael2 reaction
10mL in vitro adds catalyzer I a0.01g(0.0225mmol), ethanol (1mL), phenylformic acid 0.0006g(0.005mmol), phenylacrolein 0.02g(0.15mmol) and, Nitromethane 99Min. 0.03g(0.45mmol), stirring reaction 24h under room temperature.Then extract product (moving phase: ether/sherwood oil: 40%-50%-60%) with silica gel column chromatography, collect containing target product compound elutriant, precipitation, obtains target compound (0.0286g, yield: 99%, ee value 98%).Its specific rotatory power [α]
d 20=+30 °.
Embodiment 15: the application of chirality secondary amine compound I a in asymmetric Michael3 reaction
10mL in vitro adds nitrostyrolene 0.15g(0.1mmol), butyraldehyde-n 0.03g(0.4mmol), solvent (0.25mL, 1,2-ethylene dichloride: water=3:1), phenylformic acid 0.001g(0.01mmol), catalyst compound I a0.01g(0.02mmol), under normal temperature, stir 2 days.Then add ether, get organic phase precipitation after product silica gel column chromatography and purify (moving phase: ether/sherwood oil: 10%-20%-30%), collect containing target product compound elutriant, precipitation, obtains target compound (0.0218g, yield: 99%, ee value: 95%/37%, dr value: 2.1:1).Its specific rotatory power [α]
d 20=+32 °.
1H?NMR(500MHz,CDCl
3):δ=9.72(d,J=2.5Hz,1H),7.36-7.34(m,2H),7.31-7.28(m,1H),7.19-7.17(m,2H),4.74-4.70(q,J=4.5,12.5Hz,1H),4.66-4.61(q,J=10.0,13.0Hz,1H),3.84-3.77(m,1H),2.71-2.66(m,1H),1.55-1.46(m,2H),0.82(t,J=7.5Hz,3H)ppm;
13C?NMR(125MHz,CDCl
3):δ=203.1,136.8,129.1(×2),128.1,128.0(×2),78.5,53.4,42.8,20.4,10.7ppm;GC-MS:m/z145.1,117.1,104.1,91.1(100),77.1.
Embodiment 16: the application of chirality secondary amine compound I b in asymmetric Michael1 reaction
10mL in vitro adds catalyzer I a0.007g(0.01mmol), 1,2-ethylene dichloride (0.25mL), phenylformic acid 0.001g(0.01mmol), to fluorine phenylacrolein 0.08g(0.5mmol), dimethyl malonate 0.03g(0.25mmol), stirring reaction 24h under room temperature.Then extract product (moving phase: ethyl acetate/petroleum ether: 10%-20%) with silica gel column chromatography, collect containing target product compound elutriant, precipitation, obtains target product (0.036g, yield: 55%, ee value: 83%).Its specific rotatory power [α]
d 20=+24 °.
Embodiment 17: the application of chirality secondary amine compound I b in asymmetric Michael3 reaction
10mL in vitro adds nitrostyrolene 0.15g(0.1mmol), butyraldehyde-n 0.03g(0.4mmol), solvent (0.25mL, 1,2-ethylene dichloride: water=3:1), phenylformic acid 0.001g(0.01mmol), catalyst compound I b0.014g(0.02mmol), under normal temperature, stir 2 days.Then add ether, get organic phase precipitation after product silica gel column chromatography and purify (moving phase: ether/sherwood oil: 10%-20%-30%), collect containing target product compound elutriant, precipitation, obtains target compound (0.0218g, yield: 99%, ee value: 90%/50%, dr value: 3.1:1).Its specific rotatory power [α]
d 20=+29 °.
1H?NMR(500MHz,CDCl
3):δ=9.72(d,J=2.5Hz,1H),7.36-7.34(m,2H),7.31-7.28(m,1H),7.19-7.17(m,2H),4.74-4.70(q,J=4.5,12.5Hz,1H),4.66-4.61(q,J=10.0,13.0Hz,1H),3.84-3.77(m,1H),2.71-2.66(m,1H),1.55-1.46(m,2H),0.82(t,J=7.5Hz,3H)ppm;
13C?NMR(125MHz,CDCl
3):δ=203.1,136.8,129.1(×2),128.1,128.0(×2),78.5,53.4,42.8,20.4,10.7ppm;GC-MS:m/z145.1,117.1,104.1,91.1(100),77.1.
Claims (10)
1. containing a chirality secondary amine compound for silica ether structure, its general formula is as shown in (I):
In formula (I), R
1, R
2independent is separately hydrogen, phenyl, 3,5-bis-trifluoromethyls, 3,5-diisopropyl phenyl, 3,5-di-tert-butyl-phenyl, 2,4, the alkyl of 6-trifluorophenyl, styryl or C1～C20;
R
3for hydrogen, TMS, triethyl silyl, tertiary butyl dimethylsilyl, dimethylphenylsilaneand base, tri-phenyl-silane base, phenylbenzene benzyl silylation.
2. the chirality secondary amine compound containing silica ether structure as claimed in claim 1, the structure that it is characterized in that the described chirality secondary amine compound containing silica ether structure is suc as formula shown in (I '):
3. the chirality secondary amine compound containing silica ether structure as claimed in claim 1 or 2, is characterized in that described R
1, R
2independent is separately phenyl or 3,5-, bis-trifluoromethyls.
4. the chirality secondary amine compound containing silica ether structure as claimed in claim 1 or 2, is characterized in that described R
3for TMS or triethyl silyl.
5. the chirality secondary amine compound containing silica ether structure as claimed in claim 1, the structure that it is characterized in that the described chirality secondary amine compound containing silica ether structure suc as formula (I a) or formula (I b) shown in:
6. prepare the method for the chirality secondary amine compound containing silica ether structure as claimed in claim 1 for one kind; it is characterized in that described method is take formula (II) compound as starting raw material; successively by (a) etherificate, (b) hydrolysis deprotection and (c) three steps of silanization make the chirality secondary amine compound containing silica ether structure shown in formula (I), reaction formula is as follows:
In formula I, formula (II), (III) or formula IV, R
1, R
2definition with the R in formula I
1, R
2, i.e. R
1, R
2independent is separately hydrogen, phenyl, 3,5-bis-trifluoromethyls, 3,5-diisopropyl phenyl, 3,5-di-tert-butyl-phenyl, 2,4, the alkyl of 6-trifluorophenyl, styryl or C1～C20;
R
3for hydrogen, TMS, triethyl silyl, tertiary butyl dimethylsilyl, dimethylphenylsilaneand base, tri-phenyl-silane base, phenylbenzene benzyl silylation.
7. method as claimed in claim 6, the method described in it is characterized in that is carried out as follows:
(a) etherificate: get sodium hydride powder and add compound shown in the formula II being dissolved in organic solvent A to be mixed under ice bath, be warmed up to 40 ℃-100 ℃ reaction 20-60min, under ice bath, add again the chloro-4-vinylbenzene of the 1-being dissolved in organic solvent A to react after 0.5 – 3h, be warming up to 40-100 ℃ and react again 0.5 – 3h, after reaction finishes, reaction solution obtains compound shown in formula III through separation and purification, described organic solvent A is N, N-dimethyl methyl acid amides, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane or acetonitrile;
(b) hydrolysis deprotection: shown in the formula III that step (a) is made, compound is dissolved in organic solvent B, drip the aqueous solution of potassium hydroxide, at 30-70 ℃, react 12-36h, after reaction finishes, reaction solution acquires compound shown in formula IV through separation and purification; Described organic solvent B is ethanol, methylene dichloride, chloroform, ether, isopropyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, ethyl acetate, toluene, dimethylbenzene, acetonitrile, methyl alcohol, ethanol or Virahol;
(c) silanization: shown in the formula IV that step (b) is made, compound is dissolved in organic solvent C after being then added dropwise to triethylamine and mixing, adds R under ice bath
3then Cl alkane at room temperature react 12-36h, after question response is complete, reaction solution obtains compound shown in formula (I) through separation and purification, described organic solvent C is methylene dichloride 1,2-ethylene dichloride, 1,1,2-trichloroethane, chloroform, ether, isopropyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane.
8. the chirality secondary amine compound containing silica ether structure as claimed in claim 1 is applied in organic asymmetric reaction as catalyzer, obtains having the product of optical selective.
9. application as claimed in claim 8, is characterized in that described organic asymmetric reaction is Michael reaction.
10. application as claimed in claim 9, is characterized in that described Michael reaction is specially one of following:
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| CN106749296A (en) * | 2017-03-16 | 2017-05-31 | 浙江工业大学 | Asymmetric synthesis method of chiral furo [3,2-c ] chromene compound |
| JP2020131172A (en) * | 2019-02-25 | 2020-08-31 | 学校法人 名城大学 | Organic molecular catalyst and its use to achieve highly stereoselective asymmetric aldol reaction |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749296A (en) * | 2017-03-16 | 2017-05-31 | 浙江工业大学 | Asymmetric synthesis method of chiral furo [3,2-c ] chromene compound |
| CN106749296B (en) * | 2017-03-16 | 2019-04-09 | 浙江工业大学 | Asymmetric synthesis method of chiral furo [3,2-c ] chromene compound |
| JP2020131172A (en) * | 2019-02-25 | 2020-08-31 | 学校法人 名城大学 | Organic molecular catalyst and its use to achieve highly stereoselective asymmetric aldol reaction |
| JP7244905B2 (en) | 2019-02-25 | 2023-03-23 | 学校法人 名城大学 | Organocatalysts for highly stereoselective asymmetric aldol reactions and their applications |
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