CN1760198A - New type spirocyclic phosphic ester, preparation method and application in asymmetric addition reaction - Google Patents
New type spirocyclic phosphic ester, preparation method and application in asymmetric addition reaction Download PDFInfo
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- CN1760198A CN1760198A CN 200510015985 CN200510015985A CN1760198A CN 1760198 A CN1760198 A CN 1760198A CN 200510015985 CN200510015985 CN 200510015985 CN 200510015985 A CN200510015985 A CN 200510015985A CN 1760198 A CN1760198 A CN 1760198A
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Abstract
A spirocyclosulphite is prepared from spirocyclodiphenol through three methods. Its spirodihydroindene structure has axial chirality, so said compound has two mutamers: levo- and dextro- spirocyclosulphite compounds. It can be used for the asymmetrical addition reaction of aldehyde and imine with high stereo activity.
Description
Technical field
The present invention relates to a kind of novel chiral spirocyclo mono-phosphorus part, is a kind of C of having specifically
2The spirocyclic phosphic ester of symmetry axis and preparation method, with and application in the asymmetric reduction reaction of aldehyde and imines.
Background technology
Phosphorous chiral ligand occupies critical role in asymmetric catalysis, they all show outstanding chiral induction ability (Ohkuma, T. in many transition metal-catalyzed reactions; Kitamura, M.; Noyori, R.Catalytic AsymmetricSynthesis, Wiley, New York, 2000).Major part in the phosphorous chiral ligand of report all is a bitooth ligand at present, for example DIOP, DIPAMP, BINAP, DuPhos etc., its successful Application in asymmetric catalysis has made that the research of monodentate phosphorus ligand is ignored by people since a very long time, successfully monodentate MOP part is applied to the catalytic allyl substitution reaction of Pd (Uozumi, Y up to Hayashi in 1991 etc.; Hayashi, T.J, Am, Chem.Soc.1991,113,9987), people just pay attention to again gradually to the research of monophosphorous ligand.Recent years, many novel chiral monophosphorous ligands are synthesized out, and in many asymmetric catalysis very high enantioselectivity is arranged all (Ansell, J; Wills, M.Chem.Soc.Rev.2002,31,259).
To with regard to the asymmetric reduction reaction of aldehyde and imines,, be to use existing monophosphorous ligand still can not obtain ideal results with regard to the catalytic boric acid of Rh (I), mainly show as enantioselectivity low (Sakai, M. though people have done a lot of research work; Ueda, M.; Miyaura, N.Angew.Chem.Int.Ed.1998,37,3279), perhaps have only substrate could obtain result (Kuriyama, M. preferably to particular type; Soeta, T.; X.-Y., Hao; Q.Chen, Tomioka, K.J, Am, Chem.Soc.2004,126,8128).Boric acid is important source material (Spencer, the C.M. of synthesis of chiral medicine to the asymmetric adduct of aldehyde and imines; Foulds, D.; Peter, D.H.Drugs 1993,46, and 1055; Sakurai, S.; Ogawa, N.; Suzuki, T.; Kato, K.; Ohashi, T.; Yasuda, S.; Kato, H.; Ito, Y.Chem.Pharm.Bull.1996,44,765), thus the high enantioselectivity that will realize this type of reaction just must exploitation new, chiral monophosphorous ligand efficiently.
Summary of the invention
Purpose of the present invention is intended to for overcoming the shortcoming of prior art, and a kind of novel monodentate spirocyclic phosphic ester part with spiro indan structure is provided; Another object of the present invention provides three kinds of synthetic methods of the above-mentioned novel spirocyclo mono-phosphorus part with spiro indan structure; In addition, the present invention also provides the purposes of the above-mentioned novel spirocyclo mono-phosphorus part with spiro indan structure, promptly, in the asymmetric catalysis such as asymmetric addition of aryl boric acid, make catalyzer, can obtain very high enantioselectivity aldehyde and imines with transition metal complexes such as rhodiums.
The present invention discloses a kind of novel spirocyclic phosphic ester for achieving the above object, it is characterized in that it is the compound with following chemical structure of general formula:
Wherein: n=0～3, R
1Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group, phenyl, substituted-phenyl and haloalkyl, substituting group quantity is 1～5), 1-naphthyl, 2-naphthyl, diphenyl methyl etc.; R
2Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group, phenyl, substituted-phenyl and haloalkyl, substituting group quantity is 1～5), 1-naphthyl, 2-naphthyl, halogen, cyano group; Described alkyl is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl etc., and described alkoxyl group is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy etc.
Described spirocyclic phosphic ester is process for racemic spiro cyclic phosphites-(±)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-alkyl phosphorous acid ester and (±)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-aromatic yl phosphite.
Described spirocyclic phosphic ester is dextrorotation spirocyclic phosphic ester-(R)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-alkyl phosphorous acid ester and (R)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-aromatic yl phosphite.
Described spirocyclic phosphic ester is left-handed spirocyclic phosphic ester-(S)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-alkyl phosphorous acid ester and (S)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-aromatic yl phosphite.
New type spirocyclic phosphic ester of the present invention can synthesize by following method:
Method 1: is 1: 1～4 with volution diphenol (SPINOL) and phosphorus trichloride with mol ratio, toluene is solvent, temperature-20～80 a ℃ following reaction generated the intermediate phosphoryl chloride in 1～24 hour, at room temperature reacted 1～24 hour generation spirocyclic phosphic ester with oxy-compound then under the effect of alkali.
Method 2: with volution diphenol (SPINOL) under the effect of alkali and alkoxyl group phosphorus dichloride or aryloxy phosphorus dichloride be 1: 1～4 with mol ratio, CH
2Cl
2Be solvent, temperature-20～80 a ℃ following reaction generated spirocyclic phosphic ester in 1～24 hour.
Method 3: is 1: 1～4 with mol ratio with volution diphenol (SPINOL) and hexamethyl phosphoramidite in nitrogen gas stream, temperature range O～150 ℃, solvent is that benzene or toluene reacted 1～24 hour, generate Spirocyclophophorousamine amine, and then through synthesizing corresponding spirocyclic phosphic ester with the exchange of alcohol or phenol.
Spiro indan structure in the spirocyclic phosphic ester has axial chirality, so have two optically active isomers, one is the dextrorotation spirocyclic phosphic ester, and it two is left-handed spirocyclic phosphic ester, and the equal amount of mixture of these two optically active isomers then becomes the process for racemic spiro cyclic phosphites.Therefore, in fact the said spirocyclic phosphic ester of the present invention comprises racemic modification, dextrorotatory form and levo form.Racemic modification, dextrorotatory form and levo form have identical chemical structure of general formula, but have different three-dimensional arrangements and rotary light performance.
The application of spirocyclic phosphic ester of the present invention, it is characterized in that this compound makes rhodium (I) complex compound and be used for the asymmetric reduction reaction of aryl boric acid to aldehyde as catalyzer in solvent, catalyst levels is 0.01～10%, temperature of reaction is-20～80 ℃, reaction times is 1～48 hour, reaction solvent is water or organic solvent such as ethylene dichloride, dioxane, dimethyl second diether, toluene, methyl alcohol etc. also can be by water and organic solvent such as ethylene dichloride, dioxane, dimethyl second diether, toluene, the mixed solvent of two or more composition in the methyl alcohol etc.Its reaction formula is:
Wherein:
N=0～3, R
1Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group, phenyl, substituted-phenyl and haloalkyl, substituting group quantity is 1～5), 1-naphthyl, 2-naphthyl, diphenyl methyl; R
2Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group, phenyl, substituted-phenyl and haloalkyl, substituting group quantity is 1～5), 1-naphthyl, 2-naphthyl, halogen, cyano group; Described alkyl is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, and described alkoxyl group is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy.R
3, R
4, R
5Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group and halogen, replacing radix is 1～5), 1-naphthyl, 2-naphthyl, furyl, thienyl, pyrryl substituting group.
The application of spirocyclic phosphic ester of the present invention, it is characterized in that this compound makes rhodium (I) complex compound and be used for the asymmetric reduction reaction of aryl boric acid to imines as catalyzer in solvent, catalyst levels is 0.01～10%, temperature of reaction is-20～80 ℃, reaction times is 1～48 hour, reaction solvent is water or organic solvent such as ethylene dichloride, dioxane, dimethyl second diether, toluene, methyl alcohol etc. also can be by water and organic solvent such as ethylene dichloride, dioxane, dimethyl second diether, toluene, the mixed solvent of two or more composition in the methyl alcohol etc.Its reaction formula is:
Wherein:
N=0～3, R
1Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group, phenyl, substituted-phenyl and haloalkyl, substituting group quantity is 1～5), 1-naphthyl, 2-naphthyl, diphenyl methyl; R
2Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group, phenyl, substituted-phenyl and haloalkyl, substituting group quantity is 1～5), 1-naphthyl, 2-naphthyl, halogen, cyano group; Described alkyl is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, and described alkoxyl group is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy.R
3, R
4, R
5Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group and halogen, replacing radix is 1～5), 1-naphthyl, 2-naphthyl, furyl, thienyl, pyrryl substituting group.
The spirocyclo mono-phosphorus part can be raceme, also can be (R)-isomer or (S)-isomer.
The preparation method of this rhodium catalyst is simple, and spirocyclo mono-phosphorus part of the present invention and the complexing of monovalence rhodium compound can be obtained.Described monovalence rhodium compound can be Rh (acac) (CH
2CH
2)
2, Rh (COD)
2BF
4, Rh (COD)
2PF
6, Rh (COD)
2SnF
6, Rh (COD)
2OTf, [Rh (COD) (CH
3CN)] BF
4, Rh (acac) (CO)
2, [RH (COD) Cl]
2, [RhCl (CH
2CH
2)]
2Deng.
This rhodium catalyst can obtain by following preparation method:
In organic solvents such as ethylene dichloride, dioxane, dimethyl second diether, toluene, methyl alcohol, 1 normal monovalence rhodium compound, 2～3 normal spirocyclo mono-phosphorus parts of the present invention obtained the corresponding metal rhodium catalyst in 0.5～5 hour-20～80 ℃ of reactions.
Spirocyclic phosphic ester of the present invention is a raw material with the volution diphenol, and it is simple to have synthetic method, and group is constructed characteristics easily.Because spirocyclic phosphic ester of the present invention and the formed complex compound of rhodium have suitable configuration, therefore be applied to aryl boric acid as catalyzer the addition reaction of aldehyde is shown high stereoselectivity, e.e. value can reach 87%, best result (the 41%ee that is better than the type reaction finding report, see:Sakai, M.; Ueda, M.; Miyaura, N.Angew.Chem.Int.Ed.1998,37,3279).Products therefrom---chirality diarylcarbinols is the important medicinal intermediates of a class, as can be used for synthetic drugs ((+)-(R)) neobenodine.
Aryl boric acid is that a class is stable, inexpensive, the commercialization reagent of the various functional groups that are easy to carry, be that nucleophilic reagent substitutes responsive, valuable aryl zinc, aryl titanium and be difficult for the addition reaction that reagent such as synthetic aryl-boric acid ester is used for imines with the aryl boric acid be an important subject (Kuriyama, the M. of organic synthesis; Soeta, T.; Hao, X.Y.; Chen, O.; Tomioka, K.J.Am.Chem.Soc.2004,126,8128; Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T.J.Am.Chem.Soc.2004,126,13584).To the addition reaction of imines in can obtain enantioselectivity up to 96% as catalyzer at aryl boric acid with spirocyclic phosphic ester of the present invention and the formed complex compound of rhodium.Products therefrom---chirality diaryl methylamine is the important medicinal intermediates of a class, as can be used for synthetic drugs (S)-cetirizine.
Embodiment
To help further to understand the present invention by following embodiment, but not limit content of the present invention.Preparation method of the present invention can be further as follows with the preparation process embodiment of representation compound:
Embodiment 1:(R)-and O, the preparation of O '-[7,7 '-(1,1 '-spiro indan)]-O-methyl phosphorous acid ester
Under nitrogen atmosphere, to be equipped with 308mg (1.2mmol) (R)-add 263mg (2.6mmol) triethylamine in the reaction flask of volution diphenol, 15mL methylene dichloride, stir down and in reaction flask, drip methoxyl group phosphorus dichloride 174mg (1.3mmol) in 0 ℃, keep 0 ℃ of reaction 0.5 hour, again room temperature reaction 3 hours.Gained reaction solution removal of solvent under reduced pressure, the residuum n-hexane dissolution, through diatomite filtration, remove behind the solvent white solid 318mg.Yield: 85%.Fusing point: 135-137 ℃.[α]
D 20=-522.8 (c 0.5, CH
2Cl
2);
1H NMR: δ 7.21-7.14 (m, 2H, Ar-H), 7.06 (t, J=8Hz, 2H, Ar-H), 6.92 (d, J=7.8Hz, 1H, Ar-H), 6.78 (d, J=7.8Hz, 1H, Ar-H), 3.46 (d, J=10.1Hz, 3H, CH
3), 3.12-3.01 (m, 2H, CH
2), 2.85-2.78 (m, 2H, CH
2), 2.26-2.20 (m, 2H, CH
2) 2.03-1.96 (m, 2H, CH
2);
13C NMR: δ 146.2,145.8,145.7,144.2, and 142.7,140.3,128.7,128.2,122.1,121.9,121.7,121.5,59.3,52.0,38.6,38.2,31.1,30.7;
31PNMR: δ 123.5 (s); MS (EI) m/z 312 (M
+); Ultimate analysis (theoretical value) C
18H
17O
3P:C 69.49 (69.23); H 5.70 (5.49).
Embodiment 2:(R)-and O, the O '-[preparation of 7,7 '-(1,1 '-spiro indan)-O-phenyl phosphites
Under nitrogen atmosphere, to be equipped with 308mg (1.2mmol) (R)-add 263mg (2.6mmol) triethylamine in the volution diphenol, 15mL reaction of toluene bottle, stir down and in reaction flask, drip phosphorus trichloride 178mg (1.3mmol) in 0 ℃, again room temperature reaction 20 hours, through diatomite filtration, in gained filtrate, add phenol 113mg (1.2mmol), stir and add triethylamine 152mg (1.5mmol) down, room temperature reaction 3 hours, remove and to desolvate, residuum through silica gel column chromatography (eluent be ethyl acetate/petroleum ether=1: 10) white solid 336mg.Yield: 75%.104～105 ℃ of fusing points.[α]
D 25=+72 (c 0.5, CHCl
3).
1H NMR: δ 7.35-6.77 (m, 11H), 3.12-3.03 (m, 2H), 2.87-2.80 (m, 2H), 2.28-2.22 (m, 2H), 2.07-2.00 (m, 2H).
13C NMR: δ 151.2,145.1,144.7,143.8,142.3,141.9,138.7,128.7,127.6,126.9,123.2,122.8,121.1,120.9,120.6,119.7,118.5,58.2,37.5,36.9,29.9,29.4,28.6.
31P NMR: δ 120.5.HR-MS (FAB) (theoretical value) C
23H
19O
3P+H:375.1144 (375.1140).
Embodiment 3:(R)-and O, the preparation of O '-[7,7 '-(1,1 '-spiro indan)]-O-tertiary butyl phosphorous acid ester
With the phenol among the trimethyl carbinol replacement embodiment 2, the preparation method is identical with embodiment 2, gets (R)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-tertiary butyl phosphorous acid ester, white solid, yield: 65%.Fusing point: 57-58 ℃.[α]
D 20＝+80(c0.5，CHCl
3)。
1H NMR: δ 7.20-6.76 (m, 6H), 3.08-3.02 (m, 2H), 2.85-2.81 (m, 2H), 2.24-2.18 (m, 2H), 2.04-2.00 (m, 2H), 1.48 (s, 9H).
13C NMR: δ 145.1,14.8,144.4,142.9, and 142.0,139.1,127.3,126.2,121.8,120.8,120.5,119.9,58.0,37.4,36.9,29.9 9.5.
31P NMR: δ 128.1.HR-MS (FAB) (theoretical value) C
21H
23O
3P+H:355.1463 (355.1457).
Embodiment 4:(R)-and O, the preparation of O '-[7,7 '-(1,1 '-spiro indan)]-O-diphenyl methyl phosphorous acid ester
With the phenol among the diphenyl-carbinol replacement embodiment 2, the preparation method is identical with embodiment 2, gets (R)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-diphenyl methyl phosphorous acid ester, white solid, yield: 43%.Fusing point: 77-79 ℃.[α]D25＝+218(c 0.53，CHCl
3)。
1H NMR: δ 7.31-6.30 (m, 16H), 6.153 (d, 1H), 3.13-1.91 (m, 8H).
13CNMR: δ 146.4,145.9,145.5,144.0,143.8, l42.8,141.8,141.7,139.9,128.3,128.2,127.9,127.6,127.5,127.4,126.6,123.3,122.6,121.7,121.1,79.2,19.0,59.1,38.5,37.9,31.0,30.5.
31PNMR: δ 126.4.HR-MS (FAB) (theoretical value) C
30H
25O
3P:464.1546 (464.1541).
Embodiment 5:(S)-and O, the O '-[preparation of 7,7 '-(1,1 '-spiro indan)-O-4-p-methoxy-phenyl phosphorous acid ester
Replace (R)-volution diphenol among the embodiment 2 with (S)-volution diphenol, with the phenol among the p methoxy phenol replacement embodiment 2, the preparation method is identical with embodiment 2, get (S)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-4-p-methoxy-phenyl phosphorous acid ester, white solid, yield: 68%.Fusing point: 118-120 ℃ of .[α]
D 20=-170.0 (c 0.5, CH
2Cl
2); 1HNMR: δ 7.25-7.21 (m, 1H, Ar-H), 7.18-7.08 (m, 5H, Ar-H), 7.01-6.99 (d, J=8Hz, 1H, Ar-H), 6.89-6.86 (d, J=9.2Hz, 2H, Ar-H), 6.83-6.81 (d, J=8 Hz, 1H, Ar-H), 3.97 (s, 3H, CH
3), 3.17-3.05 (m, 2H, CH
2), 2.89-2.83 (m, 2H, CH
2), 2.30-2.26 (m, 2H, CH
2), 2.11-2.00 (m, 2H, CH
2);
13CNMR: δ 156.0,146.0,145.9,145.8, and 145.0,144.9,143.5,143.4,142.9,139.9,128.5,127.8,122.0,121.7,121.6,120.6,120.5,114.8,59.2,55.6,38.6,37.9,30.9,30.5;
31PNMR: δ 120.9 (s); MS (EI) m/z 404 (M
+);
Ultimate analysis (theoretical value) C
24H
21O
4P:C, 71.34 (71.28); H, 5.38 (5.23).
Embodiment 6:(S)-and O, the preparation of O '-[7,7 '-(1,1 '-spiro indan)]-O-2-trifluoromethyl phosphorous acid ester
Replace (R)-volution diphenol among the embodiment 2 with (S)-volution diphenol, with the phenol among the o-trifluoromethyl phenol replacement embodiment 2, the preparation method is identical with embodiment 2, get (S)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-2-trifluoromethyl phosphorous acid ester, white solid, yield: 50%.Fusing point: 125-127 ℃ of .[α]
D 20=-238.4 (c 0.5, CH
2Cl
2);
1H NMR: δ 7.62 (d, J=7.5 Hz, 1H, Ar-H), 7.48 (t, J=7.5Hz, 1H, Ar-H), 7.27-7.06 (m, 6H, Ar-H), 6.97 (t, J=7.5Hz, 2H, Ar-H), 3.18-3.02 (m, 2H, CH
2), 2.90-2.81 (m, 2H, CH
2), 2.30-2.24 (m, 2H, CH
2), 2.08-1.98 (m, 2H, CH
2);
13C NMR: δ 150.3,146.4,145.7,144.6, and 143.9,143.8,143.2,139.7,133.4,128.8,128.2,127.5,127.4,124.7,123.8,122.5,121.9,120.9,120.8,59.5,38.9,38.1,31.2,30.7;
31P NMR: δ 124.8 (s); MS (EI) m/z 442 (M
+); Ultimate analysis (theoretical value) C
24H
18F
3O
3P:C, 65.24 (65.16); H, 3.83 (4.10).
Embodiment 7:(S)-O, the preparation of O '-[7,7 '-(1,1 '-spiro indan)]-O-4-trifluoromethyl phosphorous acid ester replaces (R)-volution diphenol among the embodiment 2 with (S)-volution diphenol, with the phenol among the p-trifluoromethyl-phenol replacement embodiment 2, the preparation method is identical with embodiment 2, gets (S)-O, O '-[7,7 '-(1,1 '-spiro indan)]-and O-4-trifluoromethyl phosphorous acid ester, white solid, yield: 73%.Fusing point: 71-73 ℃ of .[α]
D 20=-159.2 (c 0.5, CH
2Cl
2);
1HNMR: δ 7.59 (d, J=9.0Hz, 2H, Ar-H), 7.26-7.07 (m, 6H, Ar-H), 6.99 (d, J=8.3Hz, 1H, Ar-H), 6.71 (t, J=6.8Hz, 1H, Ar-H), 3.18-3.03 (m, 2H, CH
2), 2.90-2.82 (m, 2H, CH
2), 2.30-2.24 (m, 2H, CH
2), 2.10-1.97 (m, 2H, CH
2);
13C NMR: δ 155.2,146.4,146.1,144.7, and 144.6,143.5,143.4,143.0,139.9,128.9,128.1,127.3,122.6,122.0,121.9,121.8,120.0,1 19.9,59.5,38.8,38.2,31.2,30.7;
31PNMR: δ 118.3 (s); MS (EI) m/z442 (M
+); Ultimate analysis (theoretical value) C
24H
18F
3O
3P:C, 65.48 (65.16); H, 4.16 (4.10).
Embodiment 8:(S)-and O, O '-[7,7 '-(1,1 '-spiro indan)]-and O-2, the preparation of 6-di-t-butyl-4-p-methoxy-phenyl phosphorous acid ester replaces (R)-volution diphenol among the embodiment 2 with (S)-volution diphenol, with 2,6-di-t-butyl-4-methoxyphenol replaces the phenol among the embodiment 2, and the preparation method is identical with embodiment 2, gets (S)-O, O '-[7,7 '-(1,1 '-spiro indan)]-and O-2,6-di-t-butyl-4-p-methoxy-phenyl phosphorous acid ester, white solid, yield: 50%.Fusing point: 125-127 ℃ of .[α]
D 20=-272.6 (c 0.5, CH
2Cl
2);
1HNMR: δ 7.25 (s, 1H, Ar-H), 7.17-7.09 (m, 4H, Ar-H), 6.98 (m, 2H, Ar-H), 6.74 (d, J=7.8Hz, 1H, Ar-H), 3.11-3.03 (m, 2H, CH
2), 2.87-2.80 (m, 2H, CH
2), 2.27-2.22 (m, 5H), 2.03-1.95 (m, 2H, CH
2), 1.27 (s, 18H, CH
3);
13C NMR: δ 146.0,145.7,145.3,145.0, and 144.9,144.7,143.2,143.0,140.2,136.0,132.0,128.5,128.2,128.1,125.7,122.7,121.9,121.4,59.5,39.1,38.0,36.1,34.4,33.0,32.4,31.1,30.7,30.5,21.3;
31P NMR: δ 124.8 (s); MS (EI) m/z 500 (M
+); Ultimate analysis (theoretical value) C
32H
37O
3P:C, 76.91 (76.78); H, 7.62 (7.45).
Embodiment 9:(S)-and O, O '-[7,7 '-(1,1 '-spiro indan)]-O-3, the preparation of 5-di-tert-butyl-phenyl phosphorous acid ester
Replace (R)-volution diphenol among the embodiment 2 with (S)-volution diphenol, with 3,5-di-tert-butyl phenol replaces the phenol among the embodiment 2, and the preparation method is identical with embodiment 2, gets (S)-O, O '-[7,7 '-(1,1 '-spiro indan)]-and O-3,5-di-tert-butyl-phenyl phosphorous acid ester, white solid, yield: 73%.Fusing point: 88-90 ℃ of .[α]
D 20=-366.6 (c0.5, CH
2Cl
2);
1H NMR: δ 7.25 (d, J=8.2Hz, 2H, Ar-H), 7.18-6.97 (m, 6H, Ar-H), 6.72 (d, J=6.5Hz 1H, Ar-H), 3.14-3.03 (m, 2H, CH
2), 2.88-2.79 (m, 2H, CH
2), 2.30-2.22 (m, 2H, CH
2), 2.05-1.92 (m, 2H, CH
2), 1.28 (s, 18H, CH
3);
13C NMR: δ 147.4,146.1,145.8,144.9, and 144.8,144.6,143.4,143.2,140.2,128.5,128.1,127.4,123.2,122.6,121.9,121.8,121.4,58.5,39.1,36.2,33.0,31.1,30.7,30.5;
31P NMR: δ 124.7 (s); MS (EI) m/z 486 (M
+); Ultimate analysis (theoretical value) C
31H
35O
3P:C, 76.36 (76.52); H, 7.38 (7.25).
Embodiment 10:(R)-and O, O '-[7,7 '-(1,1 '-spiro indan)]-O-2, the preparation of 6-3,5-dimethylphenyl phosphorous acid ester
With 2, the 6-xylenol replaces the phenol among the embodiment 2, and the preparation method is identical with embodiment 2, gets (R)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-2,6-3,5-dimethylphenyl phosphorous acid ester, white solid, yield: 76%.Fusing point: 143-145 ℃ of .[α]
D 25=+324 (c 0.5, CH
2Cl
2);
1H NMR:7.25-6.81 (m, 9H), 3.16-3.04 (m, 2H), 2.90-2.81 (m, 2H), 2.31-2.26 (m, 2H), 2.24 (s, 6H), 2.09-2.0 (m, 2H).
13C NMR: δ 149.2,146.2,145.8,145.1, and 144.1,144.0,143.2,140.2,130.8,129.1,128.6,127.8,124.5,123.0,122.1,121.9,121.8,121.6,59.5,38.9,38.1,31.2,30.7,18.0;
31P NMR: δ 122.7; HR-MS (FAB) (theoretical value) C
25H
23O
3P+H:403.1447 (403.1457).
Embodiment 11:(S)-and O, the preparation of O '-[7,7 '-(1,1 '-spiro indan)]-O-1-naphthyl phosphorous acid ester
Replace (R)-volution diphenol among the embodiment 1 with (S)-volution diphenol, with the methoxyl group phosphorus dichloride among the 1-naphthyloxy phosphorus dichloride replacement embodiment 1, the preparation method is identical with embodiment 1, get (S)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-1-naphthyl phosphorous acid ester, white solid, yield: 81%.Fusing point: 121-123 ℃ .[a]
D 20=-86.6 (c 0.5, CH
2Cl
2);
1H NMR: δ 8.04 (d, J=7.8Hz, 1H, Ar-H), 7.82 (d, J=7.8Hz, 1H, Ar-H), 7.62 (d, J=7.8Hz, 1H, Ar-H), 7.52-7.32 (m, 3H, Ar-H), 7.25-7.20 (m, 2H, Ar-H), and 7.16-7.08 (m, 3H, Ar-H), 6.99 (d, J=7.8Hz, 1H, Ar-H), 6.93 (d, J=7.0Hz, 1H, Ar-H), 3.18-3.06 (m, 2H, CH
2), 2.91-2.85 (m, 2H, CH
2), 2.31-2.27 (m, 2H, CH
2), 2.12-2.02 (m, 2H, CH
2);
13C NMR: δ 148.6,146.3,146.0,145.0, and 143.9,143.2,140.1,135.5,128.8,128.2,127.8,126.9,126.1,125.7,124.0,122.7,122.3,122.0,121.9,113.8,113.6,108.8,59.5,38.9,38.2,31.2,30.8;
31P NMR: δ 119.7 (s); MS (EI) m/z 424 (M
+); Ultimate analysis (theoretical value) C
27H
21O
3P:C, 76.67 (76.41); H, 4.95 (4.99).
Embodiment 12:(S)-and O, the preparation of O '-[7,7 '-(1,1 '-spiro indan)]-O-2-naphthyl phosphorous acid ester
Replace (R)-volution diphenol among the embodiment 1 with (S)-volution diphenol, with the methoxyl group phosphorus dichloride among the 2-naphthyloxy phosphorus dichloride replacement embodiment 1, the preparation method is identical with embodiment 1, get (S)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-2-naphthyl phosphorous acid ester, white solid, yield: 85%.Fusing point: 113-115 ℃ of .[α]
D 20=-70.2 (c 0.5, CH
2Cl
2);
1H NMR: δ 7.82-7.77 (m, 3H, Ar-H), 7.56 (s, 1H, Ar-H), 7.50-7.40 (m, 2H, Ar-H), 7.27-7.22 (m, 3H, Ar-H), 7.13-7.01 (m, 3H, Ar-H), 6.81 (d, J=7.8Hz, 1H, Ar-H), 3.17-3.05 (m, 2H, CH
2), 2.90-2.83 (m, 2H, CH
2), 2.30-2.26 (m, 2H, CH
2), 2.11-2.00 (m, 2H, CH
2);
13C NMR: δ 150.2,146.3,146.0,145.0, and 143.7,143.1,140.1,134.2,130.6,130.1,128.9,128.1,127.9,127.4,126.9,125.1,122.4,122.2,121.9,120.8,115.3,115.2,59.5,38.3,38.2,31.2,30.8;
31P NMR: δ 119.7 (s); MS (EI) m/z424 (M
+); Ultimate analysis (theoretical value) C
27H
21O
3P:C, 76.26 (76.4); H, 5.02 (4.99).
The catalytic aryl boric acid of embodiment 13:Rh (I) is to the asymmetric reduction reaction of aldehyde
(with (S)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-2-naphthyl phosphorous acid ester and [RhCl (CH
2CH
2)
2]
2The complex catalysis phenyl-boron dihydroxide that forms and the addition reaction of 1-naphthaldehyde are example)
Add 0.37mg (1.9 μ mol, 1mol%) [RhCl (CH in the nitrogen atmosphere downhill reaction bottle
2CH
2)
2]
2(1.7mg 4 μ mol) (S)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-2-naphthyl phosphorous acid ester (embodiment 12) and 1mL toluene, stirring at room reaction 0.5 hour is reduced to 0 ℃, adds 1mL water, phenyl-boron dihydroxide 47mg (0.38mmol), KF 22mg (0.38mmol), 1-naphthaldehyde 30mg (0.19mmol), keep 0 ℃ of reaction 7 hours, reaction solution obtains target product through dichloromethane extraction, dried over mgso through the silica gel column chromatography separation.The product optical purity is measured with HPLC.
Gained experimental result 1 (the aryl boric acid R that sees the following form
3B (OH)
2Middle R
3=Ph, 4-Me-Ph, 4-F-Ph, 4-Ac-Ph, 3-MeO-Ph, 4-Ph-Ph are example; Aldehyde R
4R among the CHO
4=1-Naphthyl, 2-Me-Ph, 2-Cl-Ph, 2-Br-Ph, 4-MeO-Ph, 4-Cl-Ph are example).
Table 1: aryl boric acid is to the asymmetric reduction reaction experimental result of aldehyde
| R 4 | R 3 | Reaction times (h) | Yield (%) | ee (％) | |
| 1 2 3 4 5 6 7 8 9 10 11 | 1-Naphthyl 2-Me-Ph 2-Cl-Ph 2-Br-Ph 4-MeO-Ph 4-Cl-Ph 2-Cl-Ph 2-Cl-Ph 2-Cl-Ph 2-Cl-Ph 2-Br-Ph | Ph Ph Ph Ph Ph Ph 4-Me-Ph 4-F-Ph 4-Ac-Ph 3-MeO-Ph 4-Ph-Ph | 7 7 5 5 12 4 6 9 10 8 8 | 95 94 97 96 90 94 94 98 88 91 94 | 80(R) 80(R) 82(R) 83(R) 65(R) 62(R) 84 83 85 80 87 |
The catalytic aryl boric acid of embodiment 14:Rh (I) is to the asymmetric reduction reaction of imines
(with (R)-O, O '-[7,7 '-(1,1 '-spiro indan)]-O-phenyl phosphites and Rh (acac) (CH
2CH
2)
2The complex catalysis phenyl-boron dihydroxide that forms is an example with the addition reaction of (4-chloro-phenyl-)-methene base-4-Methyl benzenesulfonyl imines)
Add 1.5mg (5.7 μ mol, 3mol%) Rh (acac) (CH in the nitrogen atmosphere downhill reaction bottle
2CH
2) 2, (4.7mg 12.5 μ mol) (R)-O, O '-[7,7 '-(1,1 '-spiro indan)]-and O-phenyl phosphites (embodiment 2) and 1mL toluene, stirring at room reaction 0.5 hour adds 1mL water, phenyl-boron dihydroxide 47mg (0.38mmol), KF 44mg (0.76mmol), (4-chloro-phenyl-)-methene base-4-Methyl benzenesulfonyl imines 55mg (0.19mmol), room temperature reaction 48 hours.Reaction solution obtains target product through dichloromethane extraction, dried over mgso through the silica gel column chromatography separation.The product optical purity is measured with HPLC.
Gained experimental result 2 (the aryl boric acid R that see the following form
3B (OH)
2Middle R
3=Ph, 4-Me-Ph, 4-F-Ph, 4-MeO-Ph are example; Aldehyde R
5CH=NSO
2R among the Ph-4-Me
5=4-Cl-Ph, 4-Me-Ph, 4-F-Ph, 2-Cl-Ph, 2-Br-Ph, 1-Naphthyl are example).
Table 2: aryl boric acid is to the asymmetric reduction reaction experimental result of imines
| R 5 | R 3 | Reaction times (h) | Yield (%) | ee (％) | |
| 1 2 3 4 5 6 7 8 9 | 4-Cl-Ph 4-Me-Ph 4-F-Ph 2-Cl-Ph 2-Br-Ph 1-Naphthyl Ph Ph Ph | Ph Ph Ph Ph Ph Ph 4-Me-Ph 4-F-Ph 4-MeO-Ph | 48 48 48 48 48 48 48 48 48 | 91 81 90 83 79 76 79 63 71 | 93 94 94 95 93 96 92 94 96 |
Claims (10)
1. new type spirocyclic phosphic ester is characterized in that having following structural formula:
Wherein: n=0～3, R
1Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group, phenyl, substituted-phenyl and haloalkyl, substituting group quantity is 1～5), 1-naphthyl, 2-naphthyl, diphenyl methyl; R
2Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group, phenyl, substituted-phenyl and haloalkyl, substituting group quantity is 1～5), 1-naphthyl, 2-naphthyl, halogen, cyano group; Described alkyl is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, and described alkoxyl group is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy.
2. according to the described spirocyclic phosphic ester of claim 1, it is characterized in that it is process for racemic spiro cyclic phosphites-(±)-O, O '-[7,7 '-(1,1 '-spiro indan)]-and O-alkyl phosphorous acid ester and (±)-O, O '-[7,7 '-(1,1 '-spiro indan)]-the O-aromatic yl phosphite.
3. according to the described spirocyclic phosphic ester of claim 1, it is characterized in that it is dextrorotation spirocyclic phosphic ester-(R)-O, O '-[7,7 '-(1,1 '-spiro indan)]-and O-alkyl phosphorous acid ester and (R)-O, O '-[7,7 '-(1,1 '-spiro indan)]-the O-aromatic yl phosphite.
4. according to the described spirocyclic phosphic ester of claim 1, it is characterized in that it is left-handed spirocyclic phosphic ester-(S)-O, O '-[7,7 '-(1,1 '-spiro indan)]-and O-alkyl phosphorous acid ester and (S)-O, O '-[7,7 '-(1,1 '-spiro indan)]-the O-aromatic yl phosphite.
5. the preparation method of the new type spirocyclic phosphic ester of a claim 1, it is characterized in that it is that volution diphenol and phosphorus trichloride are 1: 1～4 with mol ratio, temperature-20～80 a ℃ following reaction generated the intermediate phosphoryl chloride in 1～24 hour, at room temperature reacted 1～24 hour generation spirocyclic phosphic ester with oxy-compound then under the effect of alkali.Its reactions steps is as follows:
6. the preparation method of the new type spirocyclic phosphic ester of a claim 1, it is characterized in that it be the volution diphenol under the effect of alkali and alkoxyl group phosphorus dichloride or aryloxy phosphorus dichloride be 1: 1～4 with mol ratio, temperature-20～80 ℃ down reaction generated spirocyclic phosphic ester in 1～24 hour.Its reactions steps is as follows:
7. the preparation method of the new type spirocyclic phosphic ester of a claim 1, it is characterized in that it is that volution diphenol and hexamethyl phosphoramidite are 1: 1～4 with mol ratio in nitrogen gas stream, 0～150 ℃ of temperature range, solvent is that benzene or toluene reacted 1～24 hour, generate Spirocyclophophorousamine amine, and then through synthesizing corresponding spirocyclic phosphic ester with the exchange of alcohol or phenol.Its reactions steps is as follows:
8. the application of the new type spirocyclic phosphic ester of a claim 1 in the asymmetric reduction reaction of aldehyde, it is characterized in that this compound makes rhodium (I) complex compound and be used for the asymmetric reduction reaction of aryl boric acid to aldehyde as catalyzer in solvent, catalyst levels is 0.01～10%, temperature of reaction is-20～80 ℃, and the reaction times is 1～48 hour.
Wherein:
N=0～3, R
1Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group, phenyl, substituted-phenyl and haloalkyl, substituting group quantity is 1～5), 1-naphthyl, 2-naphthyl, diphenyl methyl; R
2Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group, phenyl, substituted-phenyl and haloalkyl, substituting group quantity is 1～5), 1-naphthyl, 2-naphthyl, halogen, cyano group; Described alkyl is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl; Described alkoxyl group is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy; R
3, R
4, R
5Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group and halogen, replacing radix is 1～5), 1-naphthyl, 2-naphthyl, furyl, thienyl, pyrryl substituting group.
9. the application of the new type spirocyclic phosphic ester of a claim 1 in the asymmetric reduction reaction of imines, it is characterized in that this compound makes rhodium (I) complex compound and be used for the asymmetric reduction reaction of aryl boric acid to imines as catalyzer in solvent, catalyst levels is 0.01～10%, temperature of reaction is-20～80 ℃, and the reaction times is 1～48 hour.
Wherein:
N=0～3, R
1Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group, phenyl, substituted-phenyl and haloalkyl, substituting group quantity is 1～5), 1-naphthyl, 2-naphthyl, diphenyl methyl; R
2Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group, phenyl, substituted-phenyl and haloalkyl, substituting group quantity is 1～5), 1-naphthyl, 2-naphthyl, halogen, cyano group; Described alkyl is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl; Described alkoxyl group is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy; R
3, R
4, R
5Be C
1～C
6Alkyl, phenyl, substituted-phenyl (substituting group on the phenyl is C
1～C
6Alkyl, alkoxyl group and halogen, replacing radix is 1～5), 1-naphthyl, 2-naphthyl, furyl, thienyl, pyrryl substituting group.
10. according to claim 8 and the described application of claim 9, it is characterized in that described solvent is water or organic solvent: ethylene dichloride, dioxane, dimethyl second diether, toluene, methyl alcohol, also can be by water and organic solvent: two or more mixed solvent formed in ethylene dichloride, dioxane, dimethyl second diether, toluene, the methyl alcohol.
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