CN102432636A - Triphenylphosphine oxide connecting bisoxazoline ligand, preparation method and application thereof - Google Patents

Triphenylphosphine oxide connecting bisoxazoline ligand, preparation method and application thereof Download PDF

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CN102432636A
CN102432636A CN201110255694XA CN201110255694A CN102432636A CN 102432636 A CN102432636 A CN 102432636A CN 201110255694X A CN201110255694X A CN 201110255694XA CN 201110255694 A CN201110255694 A CN 201110255694A CN 102432636 A CN102432636 A CN 102432636A
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bisoxazoline
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CN102432636B (en
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杜大明
靳宇
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Beijing Institute of Technology BIT
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Abstract

The invention discloses a triphenylphosphine oxide connecting bisoxazoline ligand, a preparation method and an application thereof and belongs to the technical field of organic synthesis and chiral catalysts. A structural formula of the triphenylphosphine oxide connecting bisoxazoline ligand provided by the invention is shown as formula I. The variety of the bisoxazoline ligand is increased, and the application of the bisoxazoline ligand in the chiral synthesis technology and other fields is widened. The invention also provides the preparation method for the triphenylphosphine oxide connecting bisoxazoline ligand. According to the preparation method, a derivative of bromophenyl-2-oxazoline or o-bromobenzaldehyde glycol acetal is reacted with magnesium, thereby obtaining a corresponding Grignard reagent, and then the Grignard reagent is reacted with phenylphosphonyl dichloride (PhPOCl2), and after the follow-up treatment is performed, the ligand is obtained. The invention also provides the application of the ligand. The ligand and palladium can be compounded into a chiral bisoxazoline metallic complex compound which is used for catalyzing an asymmetric allyl alkylation reaction.

Description

A kind of triphenylphosphinc oxide connects the bisoxazoline part
Technical field
The present invention relates to a kind of triphenylphosphinc oxide and connect the bisoxazoline part, belong to organic synthesis and technical field of chiral catalysts.
Background technology
Oxazoline and verivate thereof are the five member ring heterocyclic compounds of one type of important nitrogenous, oxygen, have widespread use in fields such as medicine, agricultural chemicals and materials.In recent years, structure diversity, chiral source are easy to get, asymmetry catalysis is induced advantages such as performance is good because the chirality bisoxazoline has as part, become very important one type of chiral ligand in the asymmetry catalysis study on the synthesis field.Further; The chirality bisoxazoline metal complex that said chirality bisoxazoline part and transition metal form; Multiple asymmetric catalysis (McManus, the H.A. such as nucleophilic addition, free radical addition reaction, Henry reaction, Michael addition, Friedel-Crafts alkylated reaction, Aldol reaction that can be used for cyclopropanization reaction, ethylenimine reaction, allyl substitution reaction, Diels-Alder reaction, allyl oxidation reaction, aldehyde; Guiry, P.J.Chem.Rev.2004,104,4151).Yet, because the variety of organic reaction type and substrate, can be applicable to that the quantity of chiral ligand or catalyzer of the multiple organic chemical reactions of catalysis is very limited.Therefore, design and synthetic chiral ligand and catalyzer with high catalytic activity, and to develop new chiral ligand compound be very important.
With optically active amino acids or chiral amino alcohol is reactant, can conveniently obtain the chiral oxazoline part of two configurations.The oxazoline preparation method who has known comprises that two carboxylic acids close ring, make (Ghosh, A.K. such as two carboxylic acids and the direct Guan Huan of amino alcohol through using special reagent through two hydroxyl amide intermediate; Mathivanan, P.; Cappiello, J.Tetrahedron:Asymmetry 1998,9, and 1).The thionyl chloride or the POCl3 of the use severe corrosive that has in the aforesaid method, serious to equipment corrosion; The reagent that the use that has is relatively more expensive is like dibutyl tin dichloride, diethylaminosulfurtrifluoride (DAST), uneconomical also not environmental protection.
In the organic synthesis field, phosphoroso-group has obtained widespread use as one type of important hydrogen bond receptor at crystal engineering and field of materials.And Li Yong oxazoline part and triphenylphosphinc oxide group combine to be connected the bisoxazoline part and also not to see bibliographical information to obtain triphenylphosphinc oxide, therefore need design to synthesize a kind of novel bifunctional chiral ligand compound.
Summary of the invention
Kind and limited amount to prior art Zhong bisoxazoline part; Be applicable to the few problem of amount of ligand in the multiple asymmetric catalysis of catalysis; One of the object of the invention is to provide a kind of triphenylphosphinc oxide to connect the bisoxazoline part; Increase the kind of bisoxazoline part, expand bisoxazoline part in chirality synthetic technology and other Application for Field.
Two of the object of the invention is to provide a kind of triphenylphosphinc oxide to connect the preparation method of bisoxazoline part, and said method can prepare chirality and be connected the bisoxazoline part with achiral triphenylphosphinc oxide.
Three of the object of the invention is to provide a kind of triphenylphosphinc oxide to connect the purposes of bisoxazoline part, and said part can form chirality bisoxazoline metal complex with the transition metal palladium, is used for the asymmetric allyl group alkylated reaction of catalysis.
For realizing above-mentioned purpose, technical scheme of the present invention is following:
A kind of triphenylphosphinc oxide connects the bisoxazoline part, and the chemical structural formula of said part is suc as formula shown in the I:
Figure BDA0000088044880000021
Wherein, R 1Be hydrogen, methyl, sec.-propyl, the tertiary butyl, phenyl or benzyl; R 2Be hydrogen or phenyl;
Wherein, said part has chiral centre, is levoisomer, dextrorotatory isomer or racemic modification; Wherein, levoisomer and dextrorotatory isomer are enantiomer, and the equal amount of mixture of two enantiomers is a racemic modification; The chemical structural formula of said racemic modification, levoisomer and dextrorotatory isomer is identical, and three-dimensional arrangement is different with rotary light performance.
A kind of triphenylphosphinc oxide of the present invention connects the preparation method of bisoxazoline, and concrete preparation process is following:
Method 1:
When said triphenylphosphinc oxide connects R in the bisoxazoline part chemical structural formula 1Be hydrogen, methyl, sec.-propyl, the tertiary butyl or benzyl; R 2During for hydrogen, preparation process is following: with bromophenyl-2-oxazoline verivate (Zhou, Q.-L.; Pfaltz, A.Tetrahedron 1994,50,4467-78; Sedelmeier, J.; Hammerer, T.; Bolm, C.Org.Lett.2008,10,917-920.) obtain corresponding Grignard reagent, promptly with the MAGNESIUM METAL 99 reaction! oxazoline-2-yl) the phenyl-magnesium-bromide verivate; Said Grignard reagent and benzene phosphinylidyne dichloro (PhPOCl 2) reaction, obtain a kind of triphenylphosphinc oxide of the present invention and connect the bisoxazoline part;
Concrete preparation process is following:
1. noble gas protection adds magnesium chips and THF (THF) down in reactor drum, the mixture of 45～55 ℃ of following dripping bromine phenyl-2-oxazoline verivates and THF, and backflow is 1～12 hour after dropwising, and obtains corresponding Grignard reagent; 2. be cooled to room temperature, drip the mixture of benzene phosphinylidyne dichloro and THF, stirring at normal temperature reaction 12～24 hours; 3. water cancellation reaction; Use dichloromethane extraction; Behind the organic phase 1 usefulness saturated nacl aqueous solution washing separatory that obtains; Obtain organic phase 2,, obtain a kind of triphenylphosphinc oxide of the present invention and connect the bisoxazoline part organic phase 2 usefulness anhydrous sodium sulfate dryings, concentrated after silica gel column chromatography separates;
Wherein, said magnesium chips amount of substance: bromophenyl-2-oxazoline verivate amount of substance=1: 1;
Said bromophenyl-2-oxazoline verivate amount of substance: amount of substance=2.5～3 of benzene phosphinylidyne dichloro: 1;
It is the mixed solvent of methylene dichloride and methyl alcohol that said silica gel column chromatography separates developping agent; The volume of methylene dichloride: the volume of methyl alcohol=50: 1;
THF uses as solvent in reaction process;
The preparation chemical equation is following, and the chemical structural formula of wherein said bromophenyl-2-oxazoline verivate is suc as formula shown in the II, and the chemical structural formula of corresponding Grignard reagent is shown in formula III; R in formula II and the formula III 1Be hydrogen, methyl, sec.-propyl, the tertiary butyl or benzyl; R 2Be hydrogen:
Figure BDA0000088044880000031
Wherein, Preferably 1. in noble gas protection down, in reactor drum, add magnesium chips, THF and 10～30mg iodine, the mixture of 45～55 ℃ of following dripping bromine phenyl-2-oxazoline verivates and THF; Dropwise the back and refluxed 1～12 hour, obtain corresponding Grignard reagent.
Method 2:
When said triphenylphosphinc oxide connects R in the bisoxazoline part chemical structural formula 1Be hydrogen, methyl, sec.-propyl, the tertiary butyl, phenyl or benzyl; R 2During for hydrogen or phenyl, preparation process is following: with adjacent bromobenzaldehyde Glycol Acetal (Peters, M.V.; Stoll, R.S.; Goddard, R.; Buth, G.; Hecht, S.J.Org.Chem.2006,71 (20), 7840-7845.) obtain corresponding grignard reagent, i.e. 2-(1,3-dioxolane-2-yl) phenyl-magnesium-bromide with the MAGNESIUM METAL 99 reaction; Said Grignard reagent and the reaction of benzene phosphinylidyne dichloro obtain two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxides; That said two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxide obtains through deprotection is corresponding 2,2 '-(phenyl Asia phosphoryl) two phenyl aldehydes; Said 2,2 '-(the inferior phosphoryl of phenyl) two phenyl aldehydes and amino alcohol reaction after, obtain a kind of triphenylphosphinc oxide connection bisoxazoline part of the present invention through N-bromo-succinimide (NBS) oxidation;
Concrete preparation process is following:
Step 1,1. noble gas protection adds magnesium chips and THF down in reactor drum, and 45～55 ℃ of mixtures that drip adjacent bromobenzaldehyde Glycol Acetal and THF down dropwise back backflow 1～12 hour, obtain corresponding Grignard reagent; 2. be cooled to room temperature, drip the mixed solution of benzene phosphinylidyne dichloro and THF, stirring at normal temperature reaction 5～24 hours; 3. water cancellation reaction; Use dichloromethane extraction; Behind the organic phase 1 usefulness saturated nacl aqueous solution that the obtains washing separatory, obtain organic phase 2, with organic phase 2 usefulness anhydrous sodium sulfate dryings, concentratedly separate through silica gel column chromatography; Obtain containing two [2-(1, the 3-dioxolane-2-yl) phenyl] phenylphosphine oxides of phosphorus oxygen functional group dialdehyde protection product;
Step 2, two [2-(1, the 3-dioxolane-2-yl) phenyl] phenylphosphine oxides, tosic acid and the acetone that obtain in the step 1 are added in the reactor drum, add entry after the dissolving, temperature control to 70～90 ℃.Thin-layer chromatography monitoring reaction progress is treated to stop heating after said two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxide disappears, stir, and is chilled to after the room temperature except that desolvating.The residuum that obtains separates through silica gel column chromatography, obtain 2,2 '-(the inferior phosphoryl of phenyl) two phenyl aldehydes;
Step 3, with obtain in the step 22; 2 '-(phenyl inferior phosphoryl) two phenyl aldehydes, chiral amino alcohol,
Figure BDA0000088044880000041
molecular sieve (
Figure BDA0000088044880000042
MS) are added in the reactor drum with methylene dichloride, and stirring at normal temperature was reacted 12～24 hours.Add N-bromo-succinimide (NBS) after the cooling in batches; React after 1～2 hour, remove by filter white solid, filtrating is respectively with saturated sodium bicarbonate, saturated sodium pyrosulfate solution and saturated nacl aqueous solution washing; Behind the anhydrous magnesium sulfate drying; Concentrate to remove and desolvate, remaining oily matter separates through silica gel column chromatography, obtains a kind of triphenylphosphinc oxide of the present invention and connects the bisoxazoline part;
Wherein, the amount of substance of magnesium chips described in the step 1: adjacent bromobenzaldehyde Glycol Acetal amount of substance=1: 1; Said adjacent bromobenzaldehyde Glycol Acetal amount of substance: the amount of substance of benzene phosphinylidyne dichloro=2: 1; It is the mixed solvent of sherwood oil and ETHYLE ACETATE that said silica gel column chromatography separates developping agent; Sherwood oil volume: the volume of ETHYLE ACETATE=1: 1; THF uses as solvent in reaction process;
The amount of substance of two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxides described in the step 2: the amount of substance of tosic acid: the volume of acetone=5～6mmol: 1mmol: 40ml; Preferably water: the volume of acetone=1: 100; It is the mixed solvent of sherwood oil and ETHYLE ACETATE that said silica gel column chromatography separates developping agent; Sherwood oil volume: the volume of ETHYLE ACETATE=1: 1;
Described in the step 32,2 '-(the inferior phosphoryl of phenyl) two phenyl aldehyde amount of substances: chiral amino alcohol amount of substance: the quality of
Figure BDA0000088044880000051
molecular sieve: the volume=1mmol of methylene dichloride: 2mmol: 1～1.5g: 10ml; Said NBS amount of substance: 2,2 '-(the inferior phosphoryl of phenyl) two phenyl aldehyde amount of substances=2～2.5: 1; It is the mixed solvent of sherwood oil and ETHYLE ACETATE that said silica gel column chromatography separates developping agent, sherwood oil: the volume of ETHYLE ACETATE=1: 2;
The preparation chemical equation is following; Wherein the chemical structural formula of adjacent bromobenzaldehyde Glycol Acetal described in the step 1 is suc as formula shown in the IV, and the chemical structural formula of corresponding Grignard reagent is suc as formula shown in the V, and two described in the step 2 [2-(1; 3-dioxolane-2-yl) phenyl] chemical structural formula of phenylphosphine oxide is suc as formula shown in the VI; Said 2,2 '-chemical structural formula of (the inferior phosphoryl of phenyl) two phenyl aldehydes is suc as formula shown in the VII, R in the chiral amino alcohol wherein 1Be hydrogen, methyl, sec.-propyl, the tertiary butyl, phenyl or benzyl; R 2Be hydrogen or phenyl:
Figure BDA0000088044880000052
Wherein, Preferably 1. middle noble gas protection adds magnesium chips, THF and 10～30mg iodine, 45～55 ℃ of mixtures that drip adjacent bromobenzaldehyde Glycol Acetal and THF down down in reactor drum; Dropwise the back and refluxed 1～12 hour, obtain corresponding Grignard reagent.
A kind of triphenylphosphinc oxide of the present invention connects the purposes of bisoxazoline part, and said triphenylphosphinc oxide connects the bisoxazoline part can form the bisoxazoline metal complex with the transition metal palladium, is used for the asymmetric allyl group alkylated reaction of catalysis.
Beneficial effect
1. triphenylphosphinc oxide bisoxazoline part of the present invention combines oxazoline and two types of important molecular structure fragments of triphenylphosphinc oxide, and a kind of novel bifunctional chiral part is provided; Wherein the two keys of oxygen phosphorus have the function that forms hydrogen bond as Lewis alkali, and gold belongs to and the coordination of oxazole woods forms Lewis acid, thereby realize the effect of double function ligand; Said triphenylphosphinc oxide connects the kind that the bisoxazoline part enriches oxazoline part, expands the application of oxazoline part in chipal compounds catalysis is synthetic;
2. the preparation method of triphenylphosphinc oxide bisoxazoline part of the present invention; Have raw materials usedly be easy to get, temperature of reaction is low, mild condition, the simple advantage of method; Adopt Dan oxazoline unit coupling or dialdehyde to use the NBS oxidation, severe corrosive reagent such as thionyl chloride of having avoided using in two carboxylic acid methods or POCl3.And can be through selecting the amino alcohol of different sources for use, the preparation chirality is connected the bisoxazoline part with achiral triphenylphosphinc oxide;
3. triphenylphosphinc oxide of the present invention connects the bisoxazoline part as part, can form the chirality complex compound catalyst with transition metal ion, and have good catalytic performance; Triphenylphosphinc oxide connection bisoxazoline part of the present invention is processed metallic palladium complex compound chiral catalyst can be used for the asymmetric allyl group alkylated reaction of catalysis; Said complex compound chiral catalyst has catalytic activity and stereoselectivity preferably in the allyl group alkylated reaction of allyl acetic acid ester derivative and malonic ester, enantioselectivity reaches 94%ee; Through studying the catalytic activity of said complex compound chiral catalyst, can further develop the asymmetry catalysis compound method efficient, that selectivity is good.
Embodiment
Describe the present invention in detail through specific embodiment below:
Embodiment 1
(4S, 4 ' S)-2,2 '-preparation method of [(phenyl inferior phosphoryl) two-2,1-phenylene] two [(4-benzyl)-2-oxazolines], said method steps is following:
Under the argon shield, in being furnished with the 25ml there-necked flask of constant pressure funnel and prolong, add clean dried magnesium chips (72mg, 3mmol), the THF (2ml) and the granule iodine (20mg) that heavily steamed.Under 50 ℃, drip (4S)-4-benzyl-2-(2-bromophenyl) oxazoline (948.6mg, THF 3mmol) (2ml) solution; After dropwising, refluxed 2 hours, obtain corresponding Grignard reagent.Be cooled to room temperature, and dropping benzene phosphinylidyne dichloro (195mg, THF 1mmol) (2ml) solution, after dropwising, stirring at normal temperature 12 hours.With the 10ml shrend reaction of going out, (3 * 10ml) extraction separatory behind the organic phase 1 usefulness saturated nacl aqueous solution that the obtains washing separatory, obtain organic phase 2 to use methylene dichloride then.With organic phase 2 usefulness anhydrous sodium sulfate dryings, concentrated through the silica gel column chromatography separation, developping agent is the mixed solvent of methylene dichloride and methyl alcohol; The volume ratio of methylene dichloride and methyl alcohol is 50: 1, obtains a kind of triphenylphosphinc oxide of the present invention and connects De bisoxazoline part, is (4S; 4 ' S)-2,2 '-[(the inferior phosphoryl of phenyl) two-2,1-phenylene] two [(4-benzyl)-2-oxazolines]; Its stereostructural formula is shown in the Ia, heavy 205.9mg, and productive rate is 35%; Be yellow powder, 52～54 ℃ of fusing points, specific rotatory power [α] D 20=-70.4 (c 1.00, CH 2Cl 2).Nucleus magnetic hydrogen spectrum (500MHz, CDCl 3): δ 2.58 (dd, J=9.0,13.5Hz, 2H, CH 2), 3.03-3.08 (m, 2H, CH 2), 3.73 (t, J=8.0Hz, 1H, CH), 3.78 (t, J=8.0Hz, 1H, CH 3), 3.97-4.01 (m, 2H, CH), 4.15-4.23 (m, 1H, CH), 4.29-4.38 (m, 1H, CH), 7.13 (d; J=7.0Hz, 2H, ArH), 7.17 (d, J=7.5Hz, 2H, ArH), 7.19-7.31 (m, 6H, ArH), 7.38-7.42 (m; 2H, ArH), 7.44-7.49 (m, 3H, ArH), 7.53-7.60 (m, 4H, ArH), 7.79 (d, J=7.5Hz, 1H; ArH), 7.81 (d, J=7.5Hz, 1H, ArH), 7.86 (dd, J=3.5,7.5Hz, 2H, ArH). high resolution mass spectrum (EI): calculated value C 38H 34N 2O 3P [M+H] +597.23016, measured value: 597.22906.
Said method reaction formula is following, wherein said (4S)-4-benzyl-2-(stereostructural formula of 2-bromophenyl) oxazoline is suc as formula shown in the IIa, and the stereostructural formula of corresponding Grignard reagent is suc as formula shown in the IIIa:
Figure BDA0000088044880000071
Embodiment 2
(4S, 4 ' S)-2,2 '-preparation method of [(phenyl inferior phosphoryl) two-2,1-phenylene] two [(4-sec.-propyl)-2-oxazolines], said method steps is following:
Under the nitrogen protection, in being furnished with the 25ml there-necked flask of constant pressure funnel and prolong, add clean dried magnesium chips (199mg, 8.29mmol), the THF (2ml) and the granule iodine (10mg) that heavily steamed.Under 50 ℃, drip (4S)-4-sec.-propyl-2-(2-bromophenyl) oxazoline (2.222mg, THF 8.29mmol) (2ml) solution; After dropwising, refluxed 2 hours, obtain corresponding Grignard reagent.Be cooled to room temperature, and dropping benzene phosphinylidyne dichloro (538mg, THF 2.76mmol) (2ml) solution, after dropwising, stirring at normal temperature 12 hours.With the 10ml shrend reaction of going out, (3 * 10ml) extraction separatory behind the organic phase 1 usefulness saturated nacl aqueous solution that the obtains washing separatory, obtain organic phase 2 to use methylene dichloride then.With organic phase 2 usefulness anhydrous sodium sulfate dryings, concentrated through the silica gel column chromatography separation, developping agent is the mixed solvent of methylene dichloride and methyl alcohol; The volume ratio of methylene dichloride and methyl alcohol is 50: 1, obtains a kind of triphenylphosphinc oxide of the present invention and connects De bisoxazoline part, is (4S; 4 ' S)-2,2 '-[(the inferior phosphoryl of phenyl) two-2,1-phenylene] two [(4-sec.-propyl)-2-oxazolines]; Its stereostructural formula is shown in the Ib, heavy 709mg, and productive rate is 51%; Be yellow powder, 47～49 ℃ of fusing points, specific rotatory power [α] D 20=-58.0 (c 1.00, CH 2Cl 2), nucleus magnetic hydrogen spectrum 1H NMR (400MHz, CDCl 3): δ 0.77 (d, J=6.4Hz, 3H, CH 3), 0.80 (d, J=6.0Hz, 3H, CH 3), 0.86 (d, J=5.6Hz, 3H, CH 3), 0.91 (d, J=5.6Hz, 3H, CH 3), 1.66 (br s, 2H, CH), 3.52-3.54 (m, 1H), 3.69-3.76 (m, 3H), 4.00 (br s, 2H), 7.41-7.63 (m, 10H, ArH), 7.83-7.85 (m, 3H) .HRMS (EI): calcd.for C 30H 34N 2O 3P [M+H] +501.23016, found:501.23062.
Said method reaction formula is following, wherein said (4S)-4-sec.-propyl-2-(stereostructural formula of 2-bromophenyl) oxazoline is suc as formula shown in the IIb, and the stereostructural formula of corresponding Grignard reagent is suc as formula shown in the IIIb:
Figure BDA0000088044880000081
Embodiment 3
(4S, 4 ' S)-2,2 '-preparation method of [(phenyl inferior phosphoryl) two-2,1-phenylene] two [(the 4-tertiary butyl)-2-oxazolines], said method steps is following:
Under the nitrogen protection, in being furnished with the 25ml there-necked flask of constant pressure funnel and prolong, add clean dried magnesium chips (68mg, 2.85mmol), the THF (2ml) and the iodine (30mg) that heavily steamed.Under 50 ℃, drip (the 4S)-4-tertiary butyl-2-(2-bromophenyl) oxazoline (804.9mg, THF 2.85mmol) (2ml) solution; After dropwising, refluxed 2 hours, obtain corresponding Grignard reagent.Be cooled to room temperature, and dropping benzene phosphinylidyne dichloro (195mg, THF 1mmol) (2ml) solution, after dropwising, stirring at normal temperature 12 hours.With the 10ml shrend reaction of going out, (3 * 10ml) extraction separatory behind the organic phase 1 usefulness saturated nacl aqueous solution that the obtains washing separatory, obtain organic phase 2 to use methylene dichloride then.With organic phase 2 usefulness anhydrous sodium sulfate dryings, concentrated through the silica gel column chromatography separation, developping agent is the mixed solvent of methylene dichloride and methyl alcohol; The volume ratio of methylene dichloride and methyl alcohol is 50: 1, obtains a kind of triphenylphosphinc oxide of the present invention and connects the bisoxazoline part, is (4S; 4 ' S)-2,2 '-[(the inferior phosphoryl of phenyl) two-2,1-phenylene] two [(the 4-tertiary butyl)-2-oxazolines]; Its stereostructural formula is shown in the Ic, heavy 264mg, and productive rate is 50%; Be yellow powder, 69～71 ℃ of fusing points, specific rotatory power [α] D 20=-106.8 (c 1.00, CH 2Cl 2).Nucleus magnetic hydrogen spectrum (400MHz, CDCl 3): δ 0.79 (s, 9H, 3CH 3), 0.83 (s, 9H, 3CH 3), 3.46 (t, J=8.8Hz, 1H, CH), 3.67 (t, J=8.8Hz, 1H, CH), 3.85 (t, J=8.8Hz, 4H, CH), 7.42-7.52 (m, 8H, ArH), 7.67-7.73 (m, 1H, ArH), 7.79-7.89 (m, 4H, ArH). high resolution mass spectrum (EI): calculated value C 32H 38N 2O 3P [M+H] +529.26146, measured value: 529.26207.
Said method reaction formula is following, wherein said (the 4S)-4-tertiary butyl-2-(stereostructural formula of 2-bromophenyl) oxazoline is suc as formula shown in the IIc, and the stereostructural formula of corresponding Grignard reagent is suc as formula shown in the IIIc:
Figure BDA0000088044880000091
Embodiment 4
(4S, 4 ' S)-2,2 '-preparation method of [(phenyl inferior phosphoryl) two-2,1-phenylene] two [(4-phenyl)-2-oxazolines], said method steps is following:
1) under the argon shield; In being furnished with the 100ml there-necked flask of constant pressure funnel and prolong; Add clean dried magnesium chips (427.2mg, 17.8mmol), the THF (6ml) and the iodine (20mg) that heavily steamed, under 50 ℃; Drip adjacent bromobenzaldehyde Glycol Acetal (4.08g, THF 17.8mmol) (6ml) solution.After dropwising, refluxed 2 hours, obtain corresponding Grignard reagent.Be cooled to room temperature, drip benzene phosphinylidyne dichloro (1.735g, THF 8.9mmol) (6ml) solution.After dropwising, stirring at normal temperature reaction 12 hours.With the 20ml shrend reaction of going out, (3 * 20ml) extraction separatory behind the organic phase 1 usefulness saturated nacl aqueous solution that the obtains washing separatory, obtain organic phase 2 to use methylene dichloride then.With organic phase 2 usefulness anhydrous sodium sulfate dryings, concentrated through the silica gel column chromatography separation, developping agent is the mixed solvent of sherwood oil and ETHYLE ACETATE; The volume ratio of sherwood oil and ETHYLE ACETATE is 1: 1, obtains two [2-(1, the 3-dioxolane-2-yl) phenyl] phenylphosphine oxides of dialdehyde protection product, heavy 2.819g, and productive rate is 75%, is yellow solid, 157～160 ℃ of fusing points.
2) take by weighing by 1) in obtain two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxides (4.581g, 10.85mmol) and tosic acid (NBS, 0.356g 2mmol) place the 250ml round-bottomed flask, use the 80ml acetone solution.After treating two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxides and tosic acid dissolving, adding 0.8ml zero(ppm) water is controlled oil bath temperature to 80 ℃, stirring and refluxing 2 hours.Thin-layer chromatography monitoring reaction progress, question response is complete, after promptly two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxides disappear, can stop heating, stirring, be chilled to room temperature after vacuum rotary steam desolvate.Residuum separates through silica gel column chromatography, and developping agent is the mixed solvent of sherwood oil and ETHYLE ACETATE; The volume ratio of sherwood oil and ETHYLE ACETATE is 1: 1,2,2 '-(phenyl inferior phosphoryl) two phenyl aldehydes, heavy 2.865g, productive rate is 79%, is yellow solid, 170～172 ℃ of fusing points.
3) in the 25ml round-bottomed flask, add by 2) in obtain 2,2 '-(the inferior phosphoryl of phenyl) two phenyl aldehydes (334.3mg, 1mmol); (S)-benzene glycinol (302.4mg; 2mmol),
Figure BDA0000088044880000101
molecular sieve (1g) and 10ml methylene dichloride, stirring at normal temperature 12 hours; Question response is complete; Ice bath cooling, add in three batches the N-bromo-succinimide (356mg, 2mmol).React after 1 hour, remove by filter white solid, filtrating is washed anhydrous magnesium sulfate drying with saturated sodium bicarbonate, saturated sodium pyrosulfate solution and saturated nacl aqueous solution respectively.Vacuum rotary steam desolvates, and remaining oily matter separates through silica gel column chromatography, and developping agent is the mixed solvent of sherwood oil and ETHYLE ACETATE; The volume ratio of sherwood oil and ETHYLE ACETATE is 1: 2, obtains a kind of triphenylphosphinc oxide of the present invention and connects De bisoxazoline part, is (4S; 4 ' S)-2,2 '-[(the inferior phosphoryl of phenyl) two-2,1-phenylene] two [(4-phenyl)-2-oxazolines]; Its stereostructural formula is Id, heavy 146mg, and productive rate is 26%; Be white powder, 89～91 ℃ of fusing points, [α] D 20=-53.2 (c 0.50, CH 2Cl 2). 1H?NMR(400MHz，CDCl 3)：δ3.83-3.97(m，2H，CH)，4.37-4.53(m，2H，CH)，4.91-5.13(m，2H，CH)，7.18-7.27(m，8H，ArH)，7.37-7.65(m，10H，ArH)，7.69-7.84(m，3H，ArH)，7.96-7.81(m，2H，ArH).HRMS(EI)：calcd.for?C 36H 30N 2O 3P[M+H]569.19886，found：569.19923.
Said method reaction formula is following; Wherein the chemical structural formula of adjacent bromobenzaldehyde Glycol Acetal described in the step 1) is suc as formula shown in the IV; The chemical structural formula of corresponding Grignard reagent is suc as formula shown in the V, step 2) described in the chemical structural formula of two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxides suc as formula shown in the VI; Said 2,2 '-chemical structural formula of (the inferior phosphoryl of phenyl) two phenyl aldehydes is suc as formula shown in the VII:
Figure BDA0000088044880000111
Embodiment 5
(4S, 5R, 4 ' S, 5 ' R)-2,2 '-preparation method of [(phenyl inferior phosphoryl) two-2,1-phenylene] two [(4, the 5-phenylbenzene)-2-oxazolines], said method steps is following:
1) with the 1st among the embodiment 4) step;
2) with the 2nd among the embodiment 4) step;
3) in the 250ml round-bottomed flask, add by 2) in obtain 2,2 '-(the inferior phosphoryl of phenyl) two phenyl aldehydes (2.674g, 8mmol); (1S, 2R)-2-amino-1,2-phenylbenzene ethanol (3.413g; 16mmol), molecular sieve (8g) and 100ml methylene dichloride, stirring at normal temperature 12 hours; Question response is complete; Ice bath cooling, add in five batches the N-bromo-succinimide (3.56g, 20mmol).React after 1 hour, remove by filter white solid, filtrating is washed anhydrous magnesium sulfate drying with saturated sodium bicarbonate, saturated sodium pyrosulfate solution and saturated nacl aqueous solution respectively.Decompression is revolved and is desolvated, and remaining oily matter separates through silica gel column chromatography, and developping agent is the mixed solvent of sherwood oil and ETHYLE ACETATE; The volume ratio of sherwood oil and ETHYLE ACETATE is 1: 2, obtains a kind of triphenylphosphinc oxide of the present invention and connects the bisoxazoline part, is (4S, 5R; 4 ' S, 5 ' R)-2,2 '-[(the inferior phosphoryl of phenyl) two-2,1-phenylene] two [(4; The 5-phenylbenzene)-the 2-oxazoline], its stereostructural formula is Ie, heavy 1.852g, and productive rate is 32%; Be white powder, 117～119 ℃ of fusing points, specific rotatory power [α] D 20=-303.2 (c 0.50, CH 2Cl 2).Nucleus magnetic hydrogen spectrum (400MHz, CDCl 3): δ 5.29 (d, J=10.0Hz, 1H, CH), 5.45 (d, J=10.0Hz, 1H, CH); 5.70 (d, J=9.2Hz, 2H, CH), 6.60 (d, J=6.0Hz, 2H, ArH); 6.72 (s, 2H, ArH), 6.83-6.96 (m, 13H, ArH), 7.12-7.42 (m; 10H), and 7.60-7.71 (m, 3H), 7.89-7.97 (m, 2H), 8.22-8.24 (m, 1H). high resolution mass spectrum (EI): calculated value C 48H 38N 2O 3P [M+H] +721.26146, measured value: 721.26131.
The reaction formula of said method is following, wherein described in the step 3) 2,2 '-chemical structural formula of (the inferior phosphoryl of phenyl) two phenyl aldehydes is suc as formula shown in the VII:
Figure BDA0000088044880000121
Embodiment 6
Triphen oxygen phosphorus connects the catalytic asymmetric allyl group alkylated reaction of palladium complex of bisoxazoline part, and catalytic step is following:
In round-bottomed flask, add [Pd (η 3-C 3H 5) Cl] 2(4.6mg, 0.0125mmol) with embodiment 5 in resulting (4S, 5R, 4 ' S; 5 ' R)-2,2 '-[(the inferior phosphoryl of phenyl) two-2,1-phenylene] two [(4, the 5-phenylbenzene)-2-oxazoline] (21.6mg; 0.03mmol), argon shield adds trichloromethane (2ml) down, and 40 ℃ were stirred 0.5 hour.Adding acetate-(E)-1, (126.2mg, 0.5mmol) the back restir is 10 minutes for 3-diphenylprop-2-alkene-1-alcohol ester.Add subsequently methyl-malonate (0.17ml, 1.5mmol), N, the two silica-based ethanamides of front three (BSA) of O-(0.37ml, 1.5mmol) with anhydrous acetic acid potassium (KOAc) (10mg, 0.1mmol).Acetate-(E)-1,3-diphenylprop-2-alkene-1-alcohol ester obtains the mixed solution of crude product and solvent to reacting completely in the thin-layer chromatography tracking.In said mixed solution, add 10ml water, (3 * 10ml) layerings merge organic phase and use anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain crude product with dichloromethane extraction.Crude product is through silica gel chromatography; Eluent is the mixed solvent of sherwood oil and ETHYLE ACETATE, wherein sherwood oil: the volume ratio of ETHYLE ACETATE is 20: 1, obtains colorless oil product 2-[(1S; 2E)-1; 3-phenylbenzene-2-propenyl] dimethyl maleate 162mg, productive rate is 99%, specific rotatory power [α] D 20=-3.7 (c 1.00, CH 2Cl 2), recording enantioselectivity by HPLC is 92%ee.
Reaction formula is shown below; Wherein said acetate-(E)-1; The chemical structural formula of 3-diphenylprop-2-alkene-1-alcohol ester is suc as formula shown in the VIII, and the chemical structural formula of said methyl-malonate is suc as formula shown in the IX, said 2-[(1S; 2E)-1,3-phenylbenzene-2-propenyl] stereostructural formula of dimethyl maleate is suc as formula shown in the X:
Figure BDA0000088044880000131
The part that under room temperature or 40 ℃ of conditions, obtains with embodiment 1～5 is by same method experiment, and the gained catalytic result is listed in table 1.
Table 1. triphen oxygen phosphorus connects the catalytic asymmetric allyl group alkylated reaction of bisoxazoline palladium complex
Figure BDA0000088044880000132
In sum, more than being merely preferred embodiment of the present invention, is not to be used to limit protection scope of the present invention.All within spirit of the present invention and principle, any modification of being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.

Claims (7)

1. a triphenylphosphinc oxide connects the bisoxazoline part, and it is characterized in that: the chemical structural formula of said part is suc as formula shown in the I:
Wherein, R 1Be hydrogen, methyl, sec.-propyl, the tertiary butyl, phenyl or benzyl; R 2Be hydrogen or phenyl.
2. a kind of triphenylphosphinc oxide according to claim 1 connects the bisoxazoline part, and it is characterized in that: said part has chiral centre, is levoisomer, dextrorotatory isomer or racemic modification.
3. the preparation method of a triphenylphosphinc oxide connection bisoxazoline part as claimed in claim 1 is characterized in that: R in said part chemical structural formula 1Be hydrogen, methyl, sec.-propyl, the tertiary butyl or benzyl; R 2During for hydrogen, concrete preparation process is following:
1. noble gas protection adds magnesium chips and THF down in reactor drum, and the mixture of 45～55 ℃ of following dripping bromine phenyl-2-oxazoline verivates and THF dropwises back backflow 1～12 hour, obtains corresponding Grignard reagent; 2. be cooled to room temperature, drip the mixture of benzene phosphinylidyne dichloro and THF, stirring at normal temperature reaction 12～24 hours; 3. water cancellation reaction; Use dichloromethane extraction, behind the organic phase 1 usefulness saturated nacl aqueous solution washing separatory that obtains, obtain organic phase 2; With organic phase 2 usefulness anhydrous sodium sulfate dryings, concentrated, obtain a kind of triphenylphosphinc oxide and connect the bisoxazoline part after silica gel column chromatography separates;
Wherein, said magnesium chips amount of substance: bromophenyl-2-oxazoline verivate amount of substance=1: 1;
Said bromophenyl-2-oxazoline verivate amount of substance: amount of substance=2.5～3 of benzene phosphinylidyne dichloro: 1;
It is the mixed solvent of methylene dichloride and methyl alcohol that said silica gel column chromatography separates developping agent; The volume of methylene dichloride: the volume of methyl alcohol=50: 1;
Said preparation feedback chemical equation is following, and the chemical structural formula of wherein said bromophenyl-2-oxazoline verivate is suc as formula shown in the II, and the chemical structural formula of corresponding Grignard reagent is shown in formula III; R in formula II and the formula III 1Be hydrogen, methyl, sec.-propyl, the tertiary butyl or benzyl; R 2Be hydrogen:
Figure FDA0000088044870000021
4. a kind of triphenylphosphinc oxide according to claim 3 connects the preparation method of bisoxazoline part; It is characterized in that: 1. the noble gas protection down; In reactor drum, add magnesium chips, THF and 10～30mg iodine; The mixture of 45～55 ℃ of following dripping bromine phenyl-2-oxazoline verivates and THF dropwises the back and refluxed 1～12 hour, obtains corresponding Grignard reagent.
5. the preparation method of a triphenylphosphinc oxide connection bisoxazoline part as claimed in claim 1 is characterized in that: R in said part chemical structural formula 1Be hydrogen, methyl, sec.-propyl, the tertiary butyl, phenyl or benzyl; R 2During for hydrogen or phenyl, concrete preparation process is following:
Step 1,1. noble gas protection adds magnesium chips and THF down in reactor drum, and 45～55 ℃ of mixtures that drip adjacent bromobenzaldehyde Glycol Acetal and THF down dropwise back backflow 1～12 hour, obtain corresponding Grignard reagent; 2. be cooled to room temperature, drip the mixed solution of benzene phosphinylidyne dichloro and THF, stirring at normal temperature reaction 5～24 hours; 3. dichloromethane extraction is used in water cancellation reaction, behind the organic phase 1 usefulness saturated nacl aqueous solution washing separatory that obtains; Obtain organic phase 2; With organic phase 2 usefulness anhydrous sodium sulfate dryings, concentrated, obtain two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxides after silica gel column chromatography separates;
Step 2, two [2-(1, the 3-dioxolane-2-yl) phenyl] phenylphosphine oxides, tosic acid and the acetone that obtain in the step 1 are added in the reactor drum, add entry after the dissolving, temperature control to 70～90 ℃.Thin-layer chromatography monitoring reaction progress, question response stop heating fully, stir, and are chilled to room temperature and remove and desolvate, and the residuum that obtains separates through silica gel column chromatography, obtain 2,2 '-(the inferior phosphoryl of phenyl) two phenyl aldehydes;
Step 3, with obtain in the step 22; 2 '-(phenyl inferior phosphoryl) two phenyl aldehydes, chiral amino alcohol,
Figure FDA0000088044870000022
molecular sieve are added in the reactor drum with methylene dichloride, and stirring at normal temperature was reacted 12～24 hours.The cooling back adds the N-bromo-succinimide; React after 1～2 hour, remove by filter white solid, filtrating is respectively with saturated sodium bicarbonate, saturated sodium pyrosulfate solution and saturated nacl aqueous solution washing; Behind the anhydrous magnesium sulfate drying; Concentrate to remove and desolvate, remaining oily matter separates through silica gel column chromatography, obtains a kind of triphenylphosphinc oxide and connects the bisoxazoline part;
Wherein, the amount of substance of magnesium chips described in the step 1: adjacent bromobenzaldehyde Glycol Acetal amount of substance=1: 1; Said adjacent bromobenzaldehyde Glycol Acetal amount of substance: the amount of substance of benzene phosphinylidyne dichloro=2: 1; It is the mixed solvent of sherwood oil and ETHYLE ACETATE that said silica gel column chromatography separates developping agent; Sherwood oil volume: the volume of ETHYLE ACETATE=1: 1;
The amount of substance of two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxides described in the step 2: the amount of substance of tosic acid: the volume of acetone=5～6mmol: 1mmol: 40ml; Preferably water: the volume of acetone=1: 100; It is the mixed solvent of sherwood oil and ETHYLE ACETATE that said silica gel column chromatography separates developping agent; Sherwood oil volume: the volume of ETHYLE ACETATE=1: 1;
Described in the step 32,2 '-(the inferior phosphoryl of phenyl) two phenyl aldehyde amount of substances: chiral amino alcohol amount of substance: the quality of
Figure FDA0000088044870000031
molecular sieve: the volume=1mmol of methylene dichloride: 2mmol: 1～1.5g: 10ml; Said N-bromo-succinimide amount of substance: 2,2 '-(the inferior phosphoryl of phenyl) two phenyl aldehyde amount of substances=2～2.5: 1; It is the mixed solvent of sherwood oil and ETHYLE ACETATE that said silica gel column chromatography separates developping agent, sherwood oil: the volume of ETHYLE ACETATE=1: 2;
The preparation chemical equation is following; Wherein the chemical structural formula of adjacent bromobenzaldehyde Glycol Acetal described in the step 1 is suc as formula shown in the IV, and the chemical structural formula of corresponding Grignard reagent is suc as formula shown in the V, and two described in the step 2 [2-(1; 3-dioxolane-2-yl) phenyl] chemical structural formula of phenylphosphine oxide is suc as formula shown in the VI; Said 2,2 '-chemical structural formula of (the inferior phosphoryl of phenyl) two phenyl aldehydes is suc as formula shown in the VII, R in the chiral amino alcohol wherein 1Be hydrogen, methyl, sec.-propyl, the tertiary butyl, phenyl or benzyl; R 2Be hydrogen or phenyl:
Figure FDA0000088044870000032
6. a kind of triphenylphosphinc oxide according to claim 5 connects the preparation method of bisoxazoline part; It is characterized in that: 1. the noble gas protection down; In reactor drum, add magnesium chips, THF and 10～30mg iodine; 45～55 ℃ of mixtures that drip adjacent bromobenzaldehyde Glycol Acetal and THF down dropwise the back and refluxed 1～12 hour, obtain corresponding Grignard reagent.
7. a triphenylphosphinc oxide as claimed in claim 1 connects the purposes of bisoxazoline part, and it is characterized in that: said part and palladium formation bisoxazoline metal complex are used for the asymmetric allyl group alkylated reaction of catalysis.
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CN107033342A (en) * 2017-04-25 2017-08-11 清华大学 A kind of preparation method of the solid supported chiral bisoxazoline parts of PEG
CN111606868A (en) * 2020-06-23 2020-09-01 温州大学新材料与产业技术研究院 Preparation method of bidentate oxazoline chiral ligand
CN114181256A (en) * 2020-09-15 2022-03-15 上海交通大学 Chiral bisoxazoline-alkynyl phosphine ligand and preparation and application thereof

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107033342A (en) * 2017-04-25 2017-08-11 清华大学 A kind of preparation method of the solid supported chiral bisoxazoline parts of PEG
CN107033342B (en) * 2017-04-25 2019-04-30 清华大学 A kind of preparation method of the immobilized chiral double oxazoline ligands of PEG
CN111606868A (en) * 2020-06-23 2020-09-01 温州大学新材料与产业技术研究院 Preparation method of bidentate oxazoline chiral ligand
CN111606868B (en) * 2020-06-23 2023-02-17 温州大学新材料与产业技术研究院 Preparation method of bidentate oxazoline chiral ligand
CN114181256A (en) * 2020-09-15 2022-03-15 上海交通大学 Chiral bisoxazoline-alkynyl phosphine ligand and preparation and application thereof
CN114181256B (en) * 2020-09-15 2023-07-25 上海交通大学 Chiral bisoxazoline-alkynyl phosphine ligand, preparation and application thereof

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