CN102432636B - Triphenylphosphine oxide connecting bisoxazoline ligand, preparation method and application thereof - Google Patents
Triphenylphosphine oxide connecting bisoxazoline ligand, preparation method and application thereof Download PDFInfo
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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
Technical field
The present invention relates to a kind of triphenylphosphinc oxide Lian Jie bisoxazoline part and its preparation method and application, belong to organic synthesis and technical field of chiral catalysts.
Background technology
Oxazoline and derivative thereof are the five member ring heterocyclic compounds of important nitrogenous, the oxygen of a class, have widespread use in fields such as medicine, agricultural chemicals and materials.In recent years, because hand bisoxazoline has the advantages such as structure diversity, chiral source are easy to get, asymmetry catalysis induction performance is good as part, become a very important class chiral ligand in asymmetry catalysis study on the synthesis field.Further, the Shou bisoxazoline metal complex that described Shou bisoxazoline part and transition metal form, can be used for multiple asymmetric catalysis (McManus, the H.A. such as nucleophilic addition, Radical Addition, Henry reaction, Michael addition, Friedel-Crafts alkylated reaction, Aldol reaction of cyclopropanization reaction, ethylenimine reaction, allyl substitution reaction, Diels-Alder reaction, allyl oxidation reaction, aldehyde; Guiry, P.J.Chem.Rev.2004,104,4151).But, due to the diversity of organic reaction type and substrate, can be applicable to the chiral ligand of the multiple organic chemical reactions of catalysis or the quantity of catalyzer is very limited.Therefore, design and synthetic chiral ligand and the catalyzer with high catalytic activity, and to develop new chiral ligand compound be very important.
Taking optically active amino acids or chiral amino alcohol as reactant, can conveniently obtain the chiral oxazoline part of two configurations.The oxazoline preparation method who has known comprises that two carboxylic acids are through two hydroxyl amide intermediate pass ring, by using special reagent to make (Ghosh, the A.K. such as two carboxylic acids and the direct Guan Huan of amino alcohol; Mathivanan, P.; Cappiello, J.Tetrahedron:Asymmetry 1998,9,1).Thionyl chloride or the phosphorus oxychloride of the use severe corrosive having in aforesaid method are serious to equipment corrosion; The reagent that some uses are more expensive, as dibutyl tin dichloride, diethylaminosulfurtrifluoride (DAST), uneconomical also not environmental protection.
In organic synthesis field, phosphoroso-group is widely applied at crystal engineering and Material Field as the important hydrogen bond receptor of a class.And Li Yong oxazoline ligand is combined to obtain triphenylphosphinc oxide Lian Jie bisoxazoline part with triphenylphosphinc oxide group and is yet there are no bibliographical information, therefore need the synthetic a kind of novel bifunctional chiral ligand compound of design.
Summary of the invention
For kind and the limited amount of prior art Zhong bisoxazoline part, be applicable to the few problem of amount of ligand in the multiple asymmetric catalysis of catalysis, one of object of the present invention is to provide a kind of triphenylphosphinc oxide Lian Jie bisoxazoline part, increase the kind of bisoxazoline part, expand the application of bisoxazoline part in chirality synthetic technology and other field.
Two of object of the present invention is to provide a kind of preparation method of triphenylphosphinc oxide Lian Jie bisoxazoline part, and described method can be prepared chirality and achiral triphenylphosphinc oxide Lian Jie bisoxazoline part.
Three of object of the present invention is to provide a kind of purposes of triphenylphosphinc oxide Lian Jie bisoxazoline part, and described part can form Shou bisoxazoline metal complex with transition metal palladium, for the asymmetric allyl group alkylated reaction of catalysis.
For achieving the above object, technical scheme of the present invention is as follows:
A kind of triphenylphosphinc oxide Lian Jie bisoxazoline part, the chemical structural formula of described part is suc as formula shown in I:
Wherein, R
1for hydrogen, methyl, sec.-propyl, the tertiary butyl, phenyl or benzyl; R
2for hydrogen or phenyl;
Wherein, described 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 racemic modification; The chemical structural formula of described racemic modification, levoisomer and dextrorotatory isomer is identical, and three-dimensional arrangement is different with rotary light performance.
The preparation method of a kind of triphenylphosphinc oxide Lian Jie bisoxazoline of the present invention, concrete preparation process is as follows:
Method 1:
As R in described triphenylphosphinc oxide Lian Jie bisoxazoline part chemical structural formula
1for hydrogen, methyl, sec.-propyl, the tertiary butyl or benzyl; R
2during for hydrogen, preparation process is as follows: by bromophenyl-2-oxazoline derivant (Zhou, Q.-L.; Pfaltz, A.Tetrahedron 1994,50,4467-78; Sedelmeier, J.; Hammerer, T.; Bolm, C.Org.Lett.2008,10,917-920.) react with MAGNESIUM METAL obtain corresponding Grignard reagent, i.e. (oxazoline-2-yl) phenyl-magnesium-bromide derivative; Described Grignard reagent and benzene phosphinylidyne dichloro (PhPOCl
2) reaction, obtain a kind of triphenylphosphinc oxide Lian Jie bisoxazoline part of the present invention;
Concrete preparation process is as follows:
1. under noble gas protection, in reactor, add magnesium chips and tetrahydrofuran (THF) (THF), drip the mixture of bromophenyl-2-oxazoline derivant and THF at 45～55 DEG C, dropwise rear backflow 1～12 hour, obtain 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, with dichloromethane extraction, after the organic phase 1 use saturated nacl aqueous solution washing separatory obtaining, obtain organic phase 2, separate through silica gel column chromatography by organic phase 2 use anhydrous sodium sulfate dryings, after concentrated, obtain a kind of triphenylphosphinc oxide of the present invention and connect and connect bisoxazoline part;
Wherein, described magnesium chips amount of substance: bromophenyl-2-oxazoline derivant amount of substance=1: 1;
Described bromophenyl-2-oxazoline derivant 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 described silica gel column chromatography separates developping agent; The volume of methylene dichloride: volume=50 of methyl alcohol: 1;
THF uses as solvent in reaction process;
Preparation chemical equation is as follows, and the chemical structural formula of wherein said bromophenyl-2-oxazoline derivant is suc as formula shown in II, and the chemical structural formula of corresponding Grignard reagent is as shown in formula III; R in formula II and formula III
1for hydrogen, methyl, sec.-propyl, the tertiary butyl or benzyl; R
2for hydrogen:
Wherein, preferably 1. under noble gas protection, in reactor, add magnesium chips, tetrahydrofuran (THF) and 10～30mg iodine, drip the mixture of bromophenyl-2-oxazoline derivant and tetrahydrofuran (THF) at 45～55 DEG C; dropwise rear backflow 1～12 hour, obtain corresponding Grignard reagent.
Method 2:
As R in described triphenylphosphinc oxide Lian Jie bisoxazoline part chemical structural formula
1for hydrogen, methyl, sec.-propyl, the tertiary butyl, phenyl or benzyl; R
2during for hydrogen or phenyl, preparation process is as follows: by o-bromobenzaldehye Glycol Acetal (Peters, M.V.; Stoll, R.S.; Goddard, R.; Buth, G.; Hecht, S.J.Org.Chem.2006,71 (20), 7840-7845.) react with MAGNESIUM METAL and obtain corresponding grignard reagent, i.e. 2-(1,3-dioxolane-2-yl) phenyl-magnesium-bromide; Described Grignard reagent reacts with benzene phosphinylidyne dichloro and obtains two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxides; Described two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxide obtains corresponding 2,2 '-(the sub-phosphoryl of phenyl) two phenyl aldehydes through deprotection; After described 2,2 '-(the sub-phosphoryl of phenyl) two phenyl aldehydes react with amino alcohol, obtain a kind of triphenylphosphinc oxide Lian Jie bisoxazoline part of the present invention through N-bromo-succinimide (NBS) oxidation;
Concrete preparation process is as follows:
Step 1,1. under noble gas protection, in reactor, add magnesium chips and THF, drip the mixture of o-bromobenzaldehye Glycol Acetal and THF at 45～55 DEG C, dropwise rear 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, with dichloromethane extraction, after the organic phase 1 use saturated nacl aqueous solution washing separatory obtaining, obtain organic phase 2, by organic phase 2 use anhydrous sodium sulfate dryings, concentrated separate through silica gel column chromatography, obtain containing two [2-(1, the 3-dioxolane-2-yl) phenyl] phenylphosphine oxides of Lin Yang functional group dialdehyde protection product;
Step 2, two [2-(1, the 3-dioxolane-2-yl) phenyl] phenylphosphine oxides, tosic acid and the acetone that in step 1, obtain are added in reactor, after dissolving, add water, temperature control to 70～90 DEG C.Thin-layer chromatography monitoring extent of reaction, treats after described two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxide disappears to stop heating, stir, and is chilled to after room temperature except desolventizing.The residuum obtaining separates through silica gel column chromatography, obtains 2,2 '-(the sub-phosphoryl of phenyl) two phenyl aldehydes;
Step 3, by 2,2 '-(phenyl sub-phosphoryl) the two phenyl aldehydes that obtain in step 2, chiral amino alcohol,
molecular sieve (
mS) and methylene dichloride be added in reactor, stirring at normal temperature reaction 12～24 hours.After cooling, add N-bromo-succinimide (NBS) in batches, react after 1～2 hour, remove by filter white solid, filtrate is respectively with saturated sodium bicarbonate, saturated sodium pyrosulfate solution and saturated nacl aqueous solution washing, after anhydrous magnesium sulfate drying, concentrated except desolventizing, remaining oily matter separates through silica gel column chromatography, obtains a kind of triphenylphosphinc oxide of the present invention and even connects bisoxazoline part;
Wherein, the amount of substance of magnesium chips described in step 1: o-bromobenzaldehye Glycol Acetal amount of substance=1: 1; Described o-bromobenzaldehye Glycol Acetal amount of substance: amount of substance=2 of benzene phosphinylidyne dichloro: 1; It is the mixed solvent of sherwood oil and ethyl acetate that described silica gel column chromatography separates developping agent; Sherwood oil volume: volume=1 of ethyl acetate: 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 step 2: the amount of substance of tosic acid: the volume=5～6mmol of acetone: 1mmol: 40ml; Preferably water: volume=1 of acetone: 100; It is the mixed solvent of sherwood oil and ethyl acetate that described silica gel column chromatography separates developping agent; Sherwood oil volume: volume=1 of ethyl acetate: 1;
2,2 '-(the sub-phosphoryl of phenyl) two phenyl aldehyde amount of substances described in step 3: chiral amino alcohol amount of substance:
the quality of molecular sieve: the volume=1mmol of methylene dichloride: 2mmol: 1～1.5g: 10ml; Described NBS amount of substance: 2,2 '-(the sub-phosphoryl of phenyl) two phenyl aldehydes amount of substance=2～2.5: 1; It is the mixed solvent of sherwood oil and ethyl acetate that described silica gel column chromatography separates developping agent, sherwood oil: volume=1 of ethyl acetate: 2;
Preparation chemical equation is as follows; wherein the chemical structural formula of the Glycol Acetal of o-bromobenzaldehye described in step 1 is suc as formula shown in IV; the chemical structural formula of corresponding Grignard reagent is suc as formula shown in V; two [2-(1 described in step 2; 3-dioxolane-2-yl) phenyl] chemical structural formula of phenylphosphine oxide is suc as formula shown in VI; the chemical structural formula of described 2,2 '-(the sub-phosphoryl of phenyl) two phenyl aldehydes is suc as formula shown in VII, wherein R in chiral amino alcohol
1for hydrogen, methyl, sec.-propyl, the tertiary butyl, phenyl or benzyl; R
2for hydrogen or phenyl:
Wherein, preferably 1. under noble gas protection, in reactor, add magnesium chips, tetrahydrofuran (THF) and 10～30mg iodine, drip the mixture of o-bromobenzaldehye Glycol Acetal and tetrahydrofuran (THF) at 45～55 DEG C; dropwise rear backflow 1～12 hour, obtain corresponding Grignard reagent.
The purposes of a kind of triphenylphosphinc oxide Lian Jie bisoxazoline part of the present invention, described triphenylphosphinc oxide Lian Jie bisoxazoline part can form bisoxazoline metal complex with transition metal palladium, for the asymmetric allyl group alkylated reaction of catalysis.
Beneficial effect
1. triphenylphosphinc oxide bisoxazoline part of the present invention combines oxazoline and the important molecular structure fragment of triphenylphosphinc oxide two classes, 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; Described triphenylphosphinc oxide Lian Jie bisoxazoline part enriches the kind of oxazoline ligand, expands the application of oxazoline ligand in chipal compounds catalyzes and synthesizes;
2. the preparation method of triphenylphosphinc oxide bisoxazoline part of the present invention, have be raw materials usedly easy to get, temperature of reaction is low, mild condition, the simple advantage of method, adopt the unit coupling of Dan oxazoline or dialdehyde to be oxidized with NBS, avoided the severe corrosive such as thionyl chloride or the phosphorus oxychloride reagent using in two carboxylic acid methods.And can be by selecting the amino alcohol of different sources, preparation chirality and achiral triphenylphosphinc oxide Lian Jie bisoxazoline part;
3. triphenylphosphinc oxide Lian Jie bisoxazoline part of the present invention, as part, can form chirality complex compound catalyst with transition metal ion, and have good catalytic performance; Triphenylphosphinc oxide Lian Jie bisoxazoline part of the present invention is made to metallic palladium complex compound chiral catalyst and can be used for the asymmetric allyl group alkylated reaction of catalysis, described complex compound chiral catalyst has good catalytic activity and stereoselectivity in the allyl group alkylated reaction of allyl acetic acid ester derivative and malonic ester, and enantioselectivity reaches 94%ee; By studying the catalytic activity of described complex compound chiral catalyst, can further develop the asymmetry catalysis synthetic method efficient, selectivity is good.
Embodiment
Describe the present invention in detail below by specific embodiment:
Embodiment 1
The preparation method of (4S, 4 ' S)-2,2 '-[(the sub-phosphoryl of phenyl) two-2,1-phenylene] two [(4-benzyl)-2-oxazolines], described method steps is as follows:
Under argon shield, in the 25ml there-necked flask of being furnished with constant pressure funnel and prolong, add the magnesium chips (72mg, 3mmol) of clean dried, the heavily THF (2ml) and the granule iodine (20mg) that steamed.At 50 DEG C, drip (4S)-4-benzyl-2-(THF (2ml) solution of 2-bromophenyl) oxazoline (948.6mg, 3mmol); After dropwising, reflux 2 hours, obtain corresponding Grignard reagent.Be cooled to room temperature, drip THF (2ml) solution of benzene phosphinylidyne dichloro (195mg, 1mmol), after dropwising, stirring at normal temperature 12 hours.With the 10ml shrend reaction of going out, then use methylene dichloride (3 × 10ml) extraction separatory, after the organic phase 1 use saturated nacl aqueous solution washing separatory obtaining, obtain organic phase 2.By organic phase 2 use anhydrous sodium sulfate dryings, concentrated through 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; obtaining a kind of triphenylphosphinc oxide of the present invention and connect bisoxazoline part, is (4S, 4 ' S)-2; 2 '-[(the sub-phosphoryl of phenyl) two-2; 1-phenylene] two [(4-benzyl)-2-oxazolines], its stereostructural formula is shown in Ia, heavy 205.9mg; productive rate is 35%; for yellow powder, 52～54 DEG C 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.
Described method chemical equation is as follows, wherein said (4S)-4-benzyl-2-(stereostructural formula of 2-bromophenyl) oxazoline is suc as formula shown in IIa, and the stereostructural formula of corresponding Grignard reagent is suc as formula shown in IIIa:
Embodiment 2
The preparation method of (4S, 4 ' S)-2,2 '-[(the sub-phosphoryl of phenyl) two-2,1-phenylene] two [(4-sec.-propyl)-2-oxazolines], described method steps is as follows:
Under nitrogen protection, in the 25ml there-necked flask of being furnished with constant pressure funnel and prolong, add the magnesium chips (199mg, 8.29mmol) of clean dried, the heavily THF (2ml) and the granule iodine (10mg) that steamed.At 50 DEG C, drip (4S)-4-sec.-propyl-2-(THF (2ml) solution of 2-bromophenyl) oxazoline (2.222mg, 8.29mmol); After dropwising, reflux 2 hours, obtain corresponding Grignard reagent.Be cooled to room temperature, drip THF (2ml) solution of benzene phosphinylidyne dichloro (538mg, 2.76mmol), after dropwising, stirring at normal temperature 12 hours.With the 10ml shrend reaction of going out, then use methylene dichloride (3 × 10ml) extraction separatory, after the organic phase 1 use saturated nacl aqueous solution washing separatory obtaining, obtain organic phase 2.By organic phase 2 use anhydrous sodium sulfate dryings, concentrated through 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; obtaining a kind of triphenylphosphinc oxide of the present invention and connect bisoxazoline part, is (4S, 4 ' S)-2; 2 '-[(the sub-phosphoryl of phenyl) two-2; 1-phenylene] two [(4-sec.-propyl)-2-oxazolines], its stereostructural formula is shown in Ib, heavy 709mg; productive rate is 51%; for yellow powder, 47～49 DEG C 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.
Described method chemical equation is as follows, wherein said (4S)-4-sec.-propyl-2-(stereostructural formula of 2-bromophenyl) oxazoline is suc as formula shown in IIb, and the stereostructural formula of corresponding Grignard reagent is suc as formula shown in IIIb:
Embodiment 3
The preparation method of (4S, 4 ' S)-2,2 '-[(the sub-phosphoryl of phenyl) two-2,1-phenylene] two [(the 4-tertiary butyl)-2-oxazolines], described method steps is as follows:
Under nitrogen protection, in the 25ml there-necked flask of being furnished with constant pressure funnel and prolong, add the magnesium chips (68mg, 2.85mmol) of clean dried, the heavily THF (2ml) and the iodine (30mg) that steamed.At 50 DEG C, drip (the 4S)-4-tertiary butyl-2-(THF (2ml) solution of 2-bromophenyl) oxazoline (804.9mg, 2.85mmol); After dropwising, reflux 2 hours, obtain corresponding Grignard reagent.Be cooled to room temperature, drip THF (2ml) solution of benzene phosphinylidyne dichloro (195mg, 1mmol), after dropwising, stirring at normal temperature 12 hours.With the 10ml shrend reaction of going out, then use methylene dichloride (3 × 10ml) extraction separatory, after the organic phase 1 use saturated nacl aqueous solution washing separatory obtaining, obtain organic phase 2.By organic phase 2 use anhydrous sodium sulfate dryings, concentrated through 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; obtaining a kind of triphenylphosphinc oxide Lian Jie bisoxazoline part of the present invention, is (4S, 4 ' S)-2; 2 '-[(the sub-phosphoryl of phenyl) two-2; 1-phenylene] two [(the 4-tertiary butyl)-2-oxazolines], its stereostructural formula is shown in Ic, heavy 264mg; productive rate is 50%; for yellow powder, 69～71 DEG C 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.
Described method chemical equation is as follows, wherein said (the 4S)-4-tertiary butyl-2-(stereostructural formula of 2-bromophenyl) oxazoline is suc as formula shown in IIc, and the stereostructural formula of corresponding Grignard reagent is suc as formula shown in IIIc:
Embodiment 4
The preparation method of (4S, 4 ' S)-2,2 '-[(the sub-phosphoryl of phenyl) two-2,1-phenylene] two [(4-phenyl)-2-oxazolines], described method steps is as follows:
1) under argon shield; in the 100ml there-necked flask of being furnished with constant pressure funnel and prolong; add the magnesium chips (427.2mg of clean dried; the THF (6ml) 17.8mmol), heavily steaming and iodine (20mg); at 50 DEG C; drip THF (6ml) solution of o-bromobenzaldehye Glycol Acetal (4.08g, 17.8mmol).After dropwising, reflux 2 hours, obtain corresponding Grignard reagent.Be cooled to room temperature, drip THF (6ml) solution of benzene phosphinylidyne dichloro (1.735g, 8.9mmol).After dropwising, stirring at normal temperature reaction 12 hours.With the 20ml shrend reaction of going out, then use methylene dichloride (3 × 20ml) extraction separatory, after the organic phase 1 use saturated nacl aqueous solution washing separatory obtaining, obtain organic phase 2.By organic phase 2 use anhydrous sodium sulfate dryings, concentrated through silica gel column chromatography separation, developping agent is the mixed solvent of sherwood oil and ethyl acetate; The volume ratio of sherwood oil and ethyl 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 DEG C of fusing points.
2) take by 1) in two [2-(1 of obtaining, 3-dioxolane-2-yl) phenyl] phenylphosphine oxide (4.581g, 10.85mmol) and tosic acid (NBS, 0.356g, 2mmol) be placed in 250ml round-bottomed flask, use 80ml acetone solution.After treating that two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxides and tosic acid dissolve, add 0.8ml distilled water, control oil bath temperature to 80 DEG C, stirring and refluxing 2 hours.Thin-layer chromatography monitoring extent of reaction, question response is complete, after two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxides disappear, can stop heating, stir, and is chilled to vacuum rotary steam desolventizing after room temperature.Residuum separates through silica gel column chromatography, and developping agent is the mixed solvent of sherwood oil and ethyl acetate; The volume ratio of sherwood oil and ethyl acetate is 1: 1, obtains 2,2 '-(the sub-phosphoryl of phenyl) two phenyl aldehydes, heavy 2.865g, and productive rate is 79%, is yellow solid, 170～172 DEG C of fusing points.
3) in 25ml round-bottomed flask, add by 2) in 2,2 '-(phenyl sub-phosphoryl) two phenyl aldehydes (334.3mg, 1mmol) of obtaining, (S)-benzene glycinol (302.4mg, 2mmol),
molecular sieve (1g) and 10ml methylene dichloride, stirring at normal temperature 12 hours, question response is complete, and ice bath is cooling, adds in three batches N-bromo-succinimide (356mg, 2mmol).React after 1 hour, remove by filter white solid, filtrate is washed with saturated sodium bicarbonate, saturated sodium pyrosulfate solution and saturated nacl aqueous solution respectively, anhydrous magnesium sulfate drying.Vacuum rotary steam desolventizing, remaining oily matter separates through silica gel column chromatography, and developping agent is the mixed solvent of sherwood oil and ethyl acetate; The volume ratio of sherwood oil and ethyl acetate is 1: 2; obtaining a kind of triphenylphosphinc oxide of the present invention and connect bisoxazoline part, is (4S, 4 ' S)-2; 2 '-[(the sub-phosphoryl of phenyl) two-2; 1-phenylene] two [(4-phenyl)-2-oxazolines], its stereostructural formula is Id, heavy 146mg; productive rate is 26%; for white powder, 89～91 DEG C 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.
Described method chemical equation is as follows; wherein step 1) described in the chemical structural formula of o-bromobenzaldehye Glycol Acetal suc as formula shown in IV; the chemical structural formula of corresponding Grignard reagent is suc as formula shown in V; step 2) described in two [2-(1; 3-dioxolane-2-yl) phenyl] chemical structural formula of phenylphosphine oxide is suc as formula shown in VI; the chemical structural formula of described 2,2 '-(the sub-phosphoryl of phenyl) two phenyl aldehydes is suc as formula shown in VII:
Embodiment 5
The preparation method of (4S, 5R, 4 ' S, 5 ' R)-2,2 '-[(the sub-phosphoryl of phenyl) two-2,1-phenylene] two [(4,5-phenylbenzene)-2-oxazolines], described method steps is as follows:
1) with the 1st in embodiment 4) step;
2) with the 2nd in embodiment 4) step;
3) in 250ml round-bottomed flask, add by 2) in 2,2 '-(phenyl sub-phosphoryl) two phenyl aldehydes (2.674g, 8mmol) of obtaining; (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, and ice bath is cooling, adds in five batches N-bromo-succinimide (3.56g, 20mmol).React after 1 hour, remove by filter white solid, filtrate is washed with saturated sodium bicarbonate, saturated sodium pyrosulfate solution and saturated nacl aqueous solution respectively, anhydrous magnesium sulfate drying.Desolventizing is revolved in decompression, and remaining oily matter separates through silica gel column chromatography, and developping agent is the mixed solvent of sherwood oil and ethyl acetate; The volume ratio of sherwood oil and ethyl acetate is 1: 2, obtains a kind of triphenylphosphinc oxide Lian Jie bisoxazoline part of the present invention, is (4S; 5R, 4 ' S, 5 ' R)-2; 2 '-[(the sub-phosphoryl of phenyl) two-2,1-phenylene] two [(4,5-phenylbenzene)-2-oxazolines]; its stereostructural formula is Ie; heavy 1.852g, productive rate is 32%, is white powder; 117～119 DEG C 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), 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 chemical equation of described method is as follows, wherein step 3) described in the chemical structural formula of 2,2 '-(phenyl sub-phosphoryl) two phenyl aldehydes suc as formula shown in VII:
Embodiment 6
The asymmetric allyl group alkylated reaction of the palladium complex catalysis of triphen oxygen phosphorus Lian Jie bisoxazoline part, catalytic step is as follows:
In round-bottomed flask, add [Pd (η
3-C
3h
5) Cl]
2(4.6mg; (the 4S that obtains 0.0125mmol) and in embodiment 5; 5R, 4 ' S, 5 ' R)-2; 2 '-[(the sub-phosphoryl of phenyl) two-2; 1-phenylene] two [(4,5-phenylbenzene)-2-oxazoline] (21.6mg, 0.03mmol); under argon shield, add trichloromethane (2ml), 40 DEG C are stirred 0.5 hour.Add acetic acid-(E)-1, after 3-diphenylprop-2-alkene-1-alcohol ester (126.2mg, 0.5mmol), stir again 10 minutes.Add subsequently dimethyl malonate (0.17ml, 1.5mmol), N, the two trimethylsilyl ethanamides (BSA) (0.37ml, 1.5mmol) of O-and anhydrous acetic acid potassium (KOAc) (10mg, 0.1mmol).Thin-layer chromatography is followed the tracks of acetic acid-(E)-1, and 3-diphenylprop-2-alkene-1-alcohol ester, to reacting completely, obtains the mixed solution of crude product and solvent.In described mixed solution, add 10ml water, with dichloromethane extraction (3 × 10ml) layering, merge organic phase anhydrous sodium sulfate drying, remove solvent under reduced pressure, obtain crude product.Crude product is through silica gel chromatography, eluent is the mixed solvent of sherwood oil and ethyl acetate, wherein sherwood oil: the volume ratio of ethyl acetate is 20: 1, obtain 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 acetic acid-(E)-1, the chemical structural formula of 3-diphenylprop-2-alkene-1-alcohol ester is suc as formula shown in VIII, the chemical structural formula of described dimethyl malonate is suc as formula shown in IX, described 2-[(1S, 2E)-1,3-phenylbenzene-2-propenyl] stereostructural formula of dimethyl maleate is suc as formula shown in X:
Under room temperature or 40 DEG C of conditions, test in the same way with the part that embodiment 1～5 obtains, gained catalytic result is listed in table 1.
The asymmetric allyl group alkylated reaction of table 1. triphen oxygen phosphorus Lian Jie bisoxazoline palladium complex catalysis
In sum, these are only preferred embodiment of the present invention, be not intended to limit protection scope of the present invention.Within the spirit and principles in the present invention all, any amendment of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (2)
1. prepare suc as formula the triphenylphosphinc oxide shown in I and connect a method that connects bisoxazoline part, it is characterized in that: concrete preparation process is as follows:
1. under noble gas protection, in reactor, add magnesium chips and tetrahydrofuran (THF), drip the mixture of bromophenyl-2-oxazoline derivant and tetrahydrofuran (THF) at 45～55 DEG C, dropwise rear backflow 1～12 hour, obtain corresponding Grignard reagent; 2. be cooled to room temperature, drip the mixture of benzene phosphinylidyne dichloro and tetrahydrofuran (THF), stirring at normal temperature reaction 12～24 hours; 3. water cancellation reaction, with dichloromethane extraction, after the organic phase 1 use saturated nacl aqueous solution washing separatory obtaining, obtain organic phase 2, separate through silica gel column chromatography by organic phase 2 use anhydrous sodium sulfate dryings, after concentrated, obtain a kind of triphenylphosphinc oxide and connect and connect bisoxazoline part;
Wherein, described magnesium chips amount of substance: bromophenyl-2-oxazoline derivant amount of substance=1:1;
Described bromophenyl-2-oxazoline derivant amount of substance: the amount of substance=2.5～3:1 of benzene phosphinylidyne dichloro;
It is the mixed solvent of methylene dichloride and methyl alcohol that described silica gel column chromatography separates developping agent; The volume of methylene dichloride: the volume=50:1 of methyl alcohol;
Described preparation feedback chemical equation is as follows, and the chemical structural formula of wherein said bromophenyl-2-oxazoline derivant is suc as formula shown in II, and the chemical structural formula of corresponding Grignard reagent is suc as formula shown in III; Wherein, R
1for hydrogen, methyl, sec.-propyl, the tertiary butyl or benzyl; R
2for hydrogen:
2. prepare suc as formula the triphenylphosphinc oxide shown in I and connect a method that connects bisoxazoline part, it is characterized in that: concrete preparation process is as follows:
Step 1,1. under noble gas protection, in reactor, add magnesium chips and tetrahydrofuran (THF), drip the mixture of o-bromobenzaldehye Glycol Acetal and tetrahydrofuran (THF) at 45～55 DEG C, dropwise rear backflow 1～12 hour, obtain corresponding Grignard reagent; 2. be cooled to room temperature, drip the mixed solution of benzene phosphinylidyne dichloro and tetrahydrofuran (THF), stirring at normal temperature reaction 5～24 hours; 3. water cancellation reaction, with dichloromethane extraction, after the organic phase 1 use saturated nacl aqueous solution washing separatory obtaining, obtain organic phase 2, separate through silica gel column chromatography by organic phase 2 use anhydrous sodium sulfate dryings, after concentrated, obtain two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxides;
Step 2, two [2-(1, the 3-dioxolane-2-yl) phenyl] phenylphosphine oxides, tosic acid and the acetone that in step 1, obtain are added in reactor, after dissolving, add water, temperature control to 70～90 DEG C; Thin-layer chromatography monitoring extent of reaction, question response stops heating completely, stirs, and is chilled to room temperature except desolventizing, and the residuum obtaining separates through silica gel column chromatography, obtains the two phenyl aldehydes of 2,2'-(the sub-phosphoryl of phenyl);
Step 3, by step 2, obtain 2, the two phenyl aldehydes of 2'-(phenyl sub-phosphoryl), amino alcohol,
molecular sieve and methylene dichloride are added in reactor, stirring at normal temperature reaction 12～24 hours; After cooling, add N-bromo-succinimide, react after 1～2 hour, remove by filter white solid, filtrate is respectively with saturated sodium bicarbonate, saturated sodium pyrosulfate solution and saturated nacl aqueous solution washing, after anhydrous magnesium sulfate drying, concentrated except desolventizing, remaining oily matter separates through silica gel column chromatography, obtains a kind of triphenylphosphinc oxide and even connects bisoxazoline part;
Wherein, the amount of substance of magnesium chips described in step 1: o-bromobenzaldehye Glycol Acetal amount of substance=1:1; Described o-bromobenzaldehye Glycol Acetal amount of substance: the amount of substance=2:1 of benzene phosphinylidyne dichloro; It is the mixed solvent of sherwood oil and ethyl acetate that described silica gel column chromatography separates developping agent; Sherwood oil volume: the volume=1:1 of ethyl acetate;
The amount of substance of two [2-(1,3-dioxolane-2-yl) phenyl] phenylphosphine oxides described in step 2: the amount of substance of tosic acid: the volume=5～6mmol:1mmol:40ml of acetone; Water: the volume=1:100 of acetone; It is the mixed solvent of sherwood oil and ethyl acetate that described silica gel column chromatography separates developping agent; Sherwood oil volume: the volume=1:1 of ethyl acetate;
Described in step 32, the two phenyl aldehyde amount of substances of 2'-(the sub-phosphoryl of phenyl): amino alcohol amount of substance:
the quality of molecular sieve: the volume=1mmol:2mmol:1～1.5g:10ml of methylene dichloride; The two phenyl aldehyde amount of substance=2～2.5:1 of described N-bromo-succinimide amount of substance: 2,2'-(the sub-phosphoryl of phenyl); It is the mixed solvent of sherwood oil and ethyl acetate that described silica gel column chromatography separates developping agent, sherwood oil: the volume=1:2 of ethyl acetate;
Preparation chemical equation is as follows, wherein the chemical structural formula of the Glycol Acetal of o-bromobenzaldehye described in step 1 is suc as formula shown in IV, the chemical structural formula of corresponding Grignard reagent is suc as formula shown in V, two [2-(1 described in step 2,3-dioxolane-2-yl) phenyl] chemical structural formula of phenylphosphine oxide is suc as formula shown in VI, described 2, the chemical structural formula of the two phenyl aldehydes of 2'-(the sub-phosphoryl of phenyl) is suc as formula shown in VII, and the chemical structural formula of amino alcohol is suc as formula shown in VIII; Wherein, R
1for hydrogen, methyl, sec.-propyl, the tertiary butyl, phenyl or benzyl; R
2for hydrogen or phenyl:
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