CN104650145A

CN104650145A - Chiral phosphorous ligand as well as metal catalyst containing ligand and application of chiral phosphorous ligand and catalyst

Info

Publication number: CN104650145A
Application number: CN201510063960.7A
Authority: CN
Inventors: 汤文军; 李承喜
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 2015-02-06
Filing date: 2015-02-06
Publication date: 2015-05-27

Abstract

The invention relates to a chiral phosphorous ligand as well as a metal catalyst containing the ligand and an application of the chiral phosphorous ligand and the catalyst, and particularly discloses a bidentate phosphine-phosphonate ligand compound or an enantiomer, a despinner or a diastereoisomer thereof, wherein the bidentate phosphine-phosphonate ligand compound has a structure as shown in formula I in the specification. The invention further discloses a transition metal catalyst containing the bidentate phosphine-phosphonate ligand compound and an application of the transition metal catalyst to catalyzing coupling reaction for synthesizing noncyclic alkyl aromatic hydrocarbon.

Description

Chiral phosphine ligand and comprise the metal catalyst of this part and their application

Technical field

The present invention relates to metal catalyst field.More particularly, the present invention relates to novel bidentate phosphine-phosphine oxygen ligand compound and comprise the metal catalyst of this ligand compound and they the large steric hindrance aryl halide of efficient catalytic and branched-chain alkyl boric acid Suzuki-Miyaura linked reaction and synthesizing the application in gossypol novel method.

Background technology

The direct coupling of transition metal-catalyzed lower carbon-carbon bond is the important method of the phenolic compound that a series of alkyl of synthesis replaces, and the application in drug research is increasingly extensive.But the carbon-carbon bond coupling of existing method to large steric hindrance still has larger limitation, institute applicable effective catalyst and part still rarely found.Especially to the C―C bond formation between large steric hindrance aryl and alkyl, lack efficient method, its major cause is that the β-hydrogen in alkyl exists, and existing reaction method can cause the generation of a large amount of reduction and isomerization by product.Therefore, development efficiently large coupling between steric hindrance alkyl and aryl still also exists many problem in science, is a major challenge in organic synthesis and drug research.

Many have the natural product of important physiologically active and medicine to there is large steric hindrance substituted aryl structure (as gossypol (gossypol), pottery tower diphenol (totaradiol), Arisaema balansae Engl. grass kind element (prionitin), total shape Root of Racemose Inula quinone (royleanone), perovskone etc.At present, this kind of large steric hindrance substituted aryl structure obtains through number step mainly through paying gram acylations, and make to there is reaction preference in this way bad, productive rate is lower.One of the most efficient and direct synthesizing mean for natural product and medicine is by the linked reaction one-step synthesis large steric hindrance alkyl substituting aromatic base structure between a large steric hindrance alkyl and aryl.

In sum, this area needs to develop a kind of ligand compound and the catalyzer thereof that can realize the direct coupling of carbon-carbon bond between large steric hindrance alkyl and aryl in a hurry.

Summary of the invention

The object of the present invention is to provide a kind of bidentate phosphine-phosphine oxygen ligand compound or its enantiomorph, raceme or diastereomer.

The present invention also aims to provide a kind of transition metal complex of being formed by described bidentate phosphine-phosphine oxygen ligand compound and transition metal tM or transition metal halide complexing or its enantiomorph, raceme or diastereomer.

The present invention also aims to provide a kind of method catalyzing and synthesizing gossypol.

A first aspect of the present invention, provides a kind of bidentate phosphine-phosphine oxygen ligand compound or its enantiomorph, raceme or diastereomer, and described bidentate phosphine-phosphine oxygen ligand compound has structure shown in formula I:

In formula,

R is selected from H, halogen ,-ORa ,-NRaRb, the substituted or unsubstituted alkyl of C1-C10, the substituted or unsubstituted alkoxyl group of C1-C4, the substituted or unsubstituted cycloalkyl of C3-C30, substituted or unsubstituted aryl, the substituted or unsubstituted heteroatomic 5-8 unit heterocycle being selected from N, O, S containing 1-3;

Each Ra and Rb may be the same or different, and is respectively independently selected from the substituted or unsubstituted alkyl of H, C1-C6, the substituted or unsubstituted alkoxyl group of C1-C4, the substituted or unsubstituted cycloalkyl of C3-C10, substituted or unsubstituted aryl;

R ' is selected from halogen, the substituted or unsubstituted alkyl of C1-C10, the substituted or unsubstituted cycloalkyl of C3-C30, substituted or unsubstituted aryl;

Each R " may be the same or different, is respectively independently selected from halogen, the substituted or unsubstituted alkyl of C1-C10, the substituted or unsubstituted cycloalkyl of C3-C30, substituted or unsubstituted aryl;

Wherein, the described one or more hydrogen atoms replaced on expression group are selected from the substituting group replacement of lower group: halogen, C1-C3 alkyl, C1-C4 haloalkyl, amino, hydroxyl.

In another preference, describedly replace 1-5 of representing on group, preferably 1-3 hydrogen atom is selected from the substituting group replacement of lower group: halogen, C1-C3 alkyl, C1-C4 haloalkyl, amino, hydroxyl.

In another preference, described replacement, represents that 1-5 (preferably 1-3) hydrogen atom on group is selected from the substituting group replacement of lower group: halogen, C1-C3 alkyl, C1-C4 haloalkyl, amino, hydroxyl.

In another preference, described bidentate phosphine-phosphine oxygen ligand compound is such as formula shown in (Ia):

In formula,

R, R ' and R " as first aspect present invention define.

In another preference, R is selected from H, halogen ,-ORa ,-NRaRb, the substituted or unsubstituted alkyl of C1-C10, the substituted or unsubstituted cycloalkyl of C3-C30, substituted or unsubstituted aryl, the substituted or unsubstituted heteroatomic 5-8 unit heterocycle being selected from N, O, S containing 1-3.

In another preference, R is selected from H, halogen ,-ORa ,-NRaRb, the unsubstituted alkyl of C1-C6, unsubstituted aryl, the unsubstituted heteroatomic 5-8 unit heterocycle being selected from N, O, S containing 1-3.

In another preference, described aryl is phenyl.

In another preference, described 5-8 unit heterocycle is

In another preference, R, R ' and R " in be one or morely selected from the substituted or unsubstituted alkyl of C1-C10.

In another preference, R, R ' and R " in be one or morely selected from the unsubstituted alkyl of C1-C10, be preferably the tertiary butyl.

In another preference, R, R ' and R " in two or three be identical.

In another preference, described bidentate phosphine-phosphine oxygen ligand compound has structure shown in formula II:

In formula, R as first aspect present invention define.

In another preference, described bidentate phosphine-phosphine oxygen ligand compound has following chemical structural formula:

A second aspect of the present invention, provide a kind of transition metal complex or its enantiomorph, raceme or diastereomer, described transition metal complex is formed by the bidentate phosphine-phosphine oxygen ligand compound described in first aspect present invention and transition metal tM or transition metal halide complexing.

In another preference, described transition metal halide consists of tM-N-X.

In another preference, described transition metal tM is selected from lower group: Rh, Ru, Ni, Ir, Pd, Cu, Pt, Co, Au or its combination.

In another preference, described transition metal is Pd.

In another preference, described X is halogen, is preferably: F, Cl, Br.

In another preference, described N is not particularly limited, for forming element and/or the group of transition metal halide tM-N-X with transition metal tM and halogen X arbitrarily.

In another preference, described N is 1,5-cyclooctadiene, polyimide-osmanthus acyl group.

In another preference, described transition metal halide tM-N-X is selected from lower group: muriate, bromide.

In another preference, described transition metal halide tM-N-X is muriate.

In another preference, described transition metal halide tM-N-X is (1,5-cyclooctadiene) palladium chloride (II) (Pd (COD) Cl ₂), (polyimide-osmanthus acyl group) Palladous chloride (II) dimer or its combination.

In another preference, described transition metal complex is compound or their enantiomorph, raceme or the diastereomer with following chemical structural formula C3 or C4.

A third aspect of the present invention, provides the preparation method of the phosphine of bidentate shown in the formula I described in a kind of first aspect present invention-phosphine oxygen ligand compound,

Described method comprises the steps:

A () in organic solvent, is carried out optionally single phosphine oxygen double bond reduction reaction to formula e compound, thus is formed the phosphine of bidentate shown in formula I-phosphine oxygen ligand compound,

In various, R, R ' and R " as first aspect present invention define.

In another preference, organic solvent described in step (a) is selected from lower group: toluene, tetrahydrofuran (THF), anhydrous diethyl ether or its combination.

In another preference, step (a) temperature of reaction is 40-100 DEG C, is preferably 50-90 DEG C, is more preferably 60-90 DEG C.

In another preference, step (a) reaction times is 3-48 hour, is preferably 5-24 hour, is more preferably 12-18 hour.

In another preference, step (a) carries out optionally single phosphine oxygen double bond reduction reaction under trichlorosilane and triethylamine exist, and obtains the phosphine of bidentate shown in formula I-phosphine oxygen ligand compound.

In another preference, step (a) is carried out under an inert atmosphere, is preferably nitrogen atmosphere.

In another preference, step (a) is reacted products therefrom and is also passed through washing and/or drying and/or filter and/or chromatographic step.

In another preference, described washing solution used is saturated NaCl solution.

In another preference, described drying siccative used is anhydrous sodium sulphate.

In another preference, described chromatography chromatography column used is neutral alumina column.

In another preference, described chromatography eluent used is the mixture of the mixture of the mixture of the mixture of EA and MeOH, normal hexane and ethyl acetate, normal hexane and methyl tertiary butyl ether, normal hexane and ether.

A fourth aspect of the present invention, provides the preparation method of transition metal complex described in a kind of second aspect present invention, and described method comprises the steps:

B () in organic solvent, the phosphine of bidentate shown in formula I-phosphine oxygen ligand compound described in first aspect present invention and transition metal halide generation metal-complexing react, thus form transition metal complex described in second aspect present invention,

In various, R, R ' and R " as first aspect present invention define;

TM is transition metal, is selected from lower group: Rh, Ru, Ni, Ir, Pd, Cu, Pt, Co, Au or its combination;

X is halogen, is preferably: F, Cl, Br.

In another preference, organic solvent described in step (b) is selected from lower group: toluene, tetrahydrofuran (THF), anhydrous diethyl ether or its combination.

In another preference, described transition metal halide tM-N-X is (1,5-cyclooctadiene) palladium chloride (I I) (Pd (COD) Cl ₂), (polyimide-osmanthus acyl group) Palladous chloride (II) dimer or its combination.

In another preference, the mass ratio of the phosphine of bidentate described in step (b)-phosphine oxygen ligand compound and described transition metal halide tM-N-X is 10:1, is preferably 5:1, is more preferably 3:1.

In another preference, the mol ratio of the phosphine of bidentate described in step (b)-phosphine oxygen ligand compound and described transition metal halide tM-N-X is 10:1, is preferably 4:1, is more preferably 3:1.

In another preference, the equivalence ratio of the phosphine of bidentate described in step (b)-phosphine oxygen ligand compound and described transition metal halide tM-N-X is 8:1, is preferably 5:1, is more preferably 3:1.

In another preference, described reaction is carried out under an inert atmosphere, is preferably nitrogen atmosphere.

In another preference, described temperature of reaction is 10-60 DEG C, is preferably 10-40 DEG C, is more preferably 15-35 DEG C.

In another preference, described temperature of reaction is room temperature.

In another preference, the described reaction times is 0.5-12 hour, is preferably 0.5-8 hour, is more preferably 2.5-6 hour.

In another preference, after step (b), also comprise filtration gained solution obtain transition metal complex described in second aspect present invention.

A fifth aspect of the present invention, provides a kind of material combination, and described material combination comprises following component:

1) the first packaging, described first packing pack is containing the first component, and described first component is the bidentate phosphine described in first aspect present invention-phosphine oxygen ligand compound;

2) the second packaging, described second packing pack is containing second component, and described second component is transition metal halide.

In another preference, described transition metal halide consists of tM-N-X.

In another preference, described transition metal tM is Pd.

In another preference, described X is halogen, is preferably: F, Cl, Br.

In another preference, described N is 1,5-cyclooctadiene, polyimide-osmanthus acyl group or its combination.

In another preference, described transition metal halide tM-N-X is muriate.

In another preference, the mass ratio of described first packaging and the second packaging is 10:1, and being preferably 5:1, is more preferably 3:1.

In another preference, the mol ratio of described first packaging and the second packaging is 10:1, and being preferably 6:1, is more preferably 4:1.

In another preference, the equivalence ratio of described first packaging and the second packaging is 8:1, and being preferably 5:1, is more preferably 3:1.

A sixth aspect of the present invention, provides the purposes of material combination described in transition metal complex described in bidentate phosphine-phosphine oxygen ligand compound described in a kind of first aspect present invention or second aspect present invention or fifth aspect present invention, for the preparation of transition-metal catalyst.

A seventh aspect of the present invention, provides a kind of catalyzer, and described catalyzer has the one or more features being selected from lower group:

1) comprise the bidentate phosphine-phosphine oxygen ligand compound described in first aspect present invention or be made up of the bidentate phosphine described in first aspect present invention-phosphine oxygen ligand compound;

2) comprise transition metal complex described in second aspect present invention or be made up of transition metal complex described in second aspect present invention;

3) comprise material combination described in fifth aspect present invention or be made up of material combination described in fifth aspect present invention.

In another preference, described catalyzer is used for arylalkyl Suzuki-Miyaura linked reaction.

A eighth aspect of the present invention, provides a kind of method catalyzing and synthesizing acyclic alkyl groups aromatic hydrocarbons, described method with material combination described in transition metal complex described in second aspect present invention or fifth aspect present invention for catalyzer.

In another preference, material combination described in fifth aspect present invention generates transition metal complex described in second aspect present invention in reaction process.

In another preference, described catalysis is carried out under organic solvent and/or mineral alkali exist.

In another preference, described organic solvent is selected from lower group: toluene, tetrahydrofuran (THF), anhydrous diethyl ether or its combination.

In another preference, described mineral alkali is selected from lower group: one hypophosphite monohydrate potassium, potassiumphosphate, sodium tert-butoxide.

In another preference, described catalysis is carried out under an inert atmosphere, is preferably nitrogen atmosphere.

In another preference, described acyclic alkyl groups aromatic hydrocarbons is non-annularity one-level alkylaromatic hydrocarbon or non-annularity secondary alkyl aromatic hydrocarbons.

In another preference, described acyclic alkyl groups aromatic hydrocarbons is preferably gossypol, oestrone or its combination.

In another preference, described acyclic alkyl groups aromatic hydrocarbons is obtained through described catalyzed reaction by aryl halide and alkylboronic acids compound.

In another preference, described aryl halide refers to comprise at least one aromatic yl group and at least one substituent organic compound.

In another preference, described aromatic yl group is selected from lower group:

In another preference, described substituting group is selected from lower group; The substituted or unsubstituted alkyl of H, halogen, C1-C10 ,-CN ,-ORa ,-NO ₂, carbonyl, substituted or unsubstituted amino, aldehyde radical, substituted or unsubstituted carboxyl ,-OTf;

Ra is independently selected from the substituted or unsubstituted alkyl of H, C1-C6, the substituted or unsubstituted alkoxyl group of C1-C4, the substituted or unsubstituted cycloalkyl of C3-C10, substituted or unsubstituted aryl;

Wherein, the described one or more hydrogen atoms replaced on expression group are selected from the substituting group replacement of lower group: halogen, C1-C3 alkyl, C1-C4 haloalkyl, amino, hydroxyl, phenyl ring.

In another preference, described alkylboronic acids compound refers to Ra-B (OH) ₂;

In another preference, described alkylboronic acids compound is one-level or secondary chain alkylboronic acids.

In another preference, described aryl halide refers to

Wherein,

refer to substituted or unsubstituted aryl;

X is selected from lower group: F, Cl, Br;

Wherein, the described one or more hydrogen atoms replaced on expression group are selected from the substituting group replacement of lower group: the substituted or unsubstituted alkyl of H, halogen, C1-C10, C1-C4 haloalkyl ,-CN ,-ORa ,-NO ₂, carbonyl, substituted or unsubstituted amino, aldehyde radical, substituted or unsubstituted carboxyl ,-OTf, hydroxyl, phenyl ring;

In another preference, described in be selected from lower group:

In another preference, described aryl halide refers to

Wherein,

A is C or N;

R1, R2 and R3 may be the same or different, and are respectively independently selected from the substituted or unsubstituted alkyl of H, C1-C10 ,-CN ,-ORa ,-NO ₂, substituted or unsubstituted carboxyl, substituted or unsubstituted amino, carbonyl, aldehyde radical;

The number of R3 is 1-3;

R1 and R3 or R2 and R3 and adjacent at least two carbon atom jointly forms the 5-7 saturated or undersaturated aromatic ring of unit or is selected from the heterocycle of N, O, S containing 1-2;

X is selected from lower group: F, Cl, Br.

In another preference, described method is carried out according to following reaction:

Wherein, x and Ra as defined above.

In another preference, in above-mentioned reaction with Ra-B (OH) ₂mass ratio be 10:1, being preferably 5:1, is more preferably 3:1.

In another preference, in above-mentioned reaction with Ra-B (OH) ₂mol ratio be 5:1, being preferably 3:1, is more preferably 1:5.

In another preference, in described reaction with Ra-B (OH) ₂equivalence ratio be 5:1, being preferably 3:1, is more preferably 1:5.

In another preference, described in described reaction, the mass ratio of aryl halide and described transition metal complex is 120:1, is preferably 110:1, is more preferably 100:1.

In another preference, described in described reaction, the mol ratio of aryl halide and described transition metal complex is 120:1, is preferably 100:1, is more preferably 60:1.

In another preference, described in described reaction, the equivalence ratio of aryl halide and described transition metal complex is 120:1, is preferably 100:1, is more preferably 60:1.

In another preference, described in described reaction, the mass ratio of aryl halide and described material combination is 120:1, is preferably 100:1, is more preferably 60:1.

In another preference, described in described reaction, the mol ratio of aryl halide and described material combination is 120:1, is preferably 100:1, is more preferably 60:1.

In another preference, described in described reaction, the equivalence ratio of aryl halide and described material combination is 120:1, is preferably 100:1, is more preferably 60:1.

In another preference, the temperature of reaction of described reaction is 50-200 DEG C, is preferably 80-150 DEG C, is more preferably 80-120 DEG C.

In another preference, the reaction times of described reaction is 5-24 hour, is preferably 5-15 hour, is more preferably 5-10 hour.

In another preference, described aryl halide has following chemical structural formula:

In another preference, described alkylboronic acids compound has following chemical structural formula:

In another preference, described acyclic alkyl groups aromatic hydrocarbons has following chemical structural formula:

Wherein, thickened portion represents and is derived from described alkylboronic acids compound R a-B (OH) ₂ra-group.

A ninth aspect of the present invention, provides a kind of method catalyzing and synthesizing gossypol, and described method utilizes material combination described in transition metal complex described in second aspect present invention or fifth aspect present invention to be catalyzer, catalyzes and synthesizes gossypol in organic solvent.

In another preference, in described method, use the linked reaction of catalyst aryl halide and alkylboronic acids compound described in seventh aspect present invention.

Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.

Accompanying drawing explanation

Fig. 1 is transition metal complex C3 (Pd (1) Cl prepared by the embodiment of the present invention 3 ₂) X-ray crystallogram.

Fig. 2 is transition metal complex C4 (Pd (2) Cl prepared by the embodiment of the present invention 4 ₂) X-ray crystallogram.

Fig. 3 is the X-ray crystallogram of compound r in the embodiment of the present invention 6.

Fig. 4 is the online infrared signature spectrogram of the embodiment of the present invention 9.

Fig. 5 is the online infrared speed of reaction graphic representation of the embodiment of the present invention 10.

Embodiment

The present inventor is through long-term and deep research, unexpectedly prepare a kind of part realizing the catalyzer of the direct coupling of carbon-carbon bond between large steric hindrance alkyl and aryl, and the catalyzer using this part to prepare has high catalytic efficiency, the coupling reaction process of the carbon-carbon bond between large steric hindrance alkyl and aryl can be simplified, and then simplify a series of with the synthesis of the above-mentioned reaction drug molecule that is committed step, there is very high practicality, significantly can reduce reaction cost, shorten reaction time, use in the catalytic process of this catalyzer simultaneously and produce without other unwanted by products.Based on above-mentioned discovery, contriver completes the present invention.

Term

As used herein, term " bidentate phosphine of the present invention-phosphine oxygen ligand compound ", " ligand compound of the present invention ", " bidentate phosphine-phosphine oxygen ligand compound ", " bidentate phosphine ligands compound ", " ligand compound " or " part " are used interchangeably, and all refer to have the compound of structural formula shown in formula I:

In formula,

As used herein, term " the substituted or unsubstituted alkyl of C1-C10 " represents the radical of saturated aliphatic alkyl containing 10 carbon atoms at the most of straight or branched, such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl, tertiary hexyl, heptyl, different heptyl, octyl group and iso-octyl.Similarly, " the substituted or unsubstituted alkoxyl group of C1-C4 " represents the alkyl as hereinbefore defined connected by Sauerstoffatom, as methoxyl group, oxyethyl group, propoxy-, butoxy etc.

As used herein, term " the substituted or unsubstituted cycloalkyl of C3-C30 " represents the radical of saturated aliphatic alkyl containing 30 carbon atoms at the most of ring-type.

As used herein, term " halogen " comprises F, Cl, Br or I.

As used herein, term " aryl " represents to have the substituting group of the character of aromatic ring structure, the aryl of such as C6-C30, the present invention can aryl include but not limited to: phenyl, naphthyl, anthryl etc.In the present invention; aryl comprises substituted or unsubstituted aryl, wherein replaces the substituting group replacement that the one or more hydrogen atoms referred on group are selected from lower group: halogen, C1-C3 alkyl, C3 ~ C10 cycloalkyl, C1-C4 haloalkyl, hydroxyl, carboxyl, aldehyde radical, acyl group, amino.

As used herein, term " aryl halide " expression comprises at least one aromatic yl group and at least one substituent organic compound.

As used herein, term " Palladium (II) (pi-cinnamyl) Chloride Dimer " and " [Pd (cinnamyl) Cl] ₂" all refer to (polyimide-osmanthus acyl group) Palladous chloride (II) dimer.

Bidentate phosphine-phosphine oxygen ligand compound

The invention provides a kind of bidentate phosphine-phosphine oxygen ligand compound or its enantiomorph, raceme or diastereomer, described bidentate phosphine-phosphine oxygen ligand compound has structure shown in formula I:

In formula,

Particularly, described bidentate phosphine-phosphine oxygen ligand compound is such as formula shown in (Ia):

In formula,

R, R ' and R are " as defined above.

In another preference, R is selected from H, halogen ,-ORa ,-NRaRb, the unsubstituted alkyl of C1-C6, unsubstituted aryl, the unsubstituted heteroatomic 5-8 unit heterocycle being selected from N, O, S containing 1-3;

In another preference, described aryl is phenyl.

In another preference, described 5-8 unit heterocycle is

In another preference, R, R ' and R " in two or three be identical.

Typically, described bidentate phosphine-phosphine oxygen ligand compound has structure shown in formula II:

In formula, R is as defined above.

Transition metal complex

Present invention also offers a kind of transition metal complex or its enantiomorph, raceme or diastereomer, described transition metal complex is formed by bidentate phosphine-phosphine oxygen ligand compound of the present invention and transition metal tM or transition metal halide complexing.

In another preference, described transition metal halide consist of tM-N-X.

Typically, described transition metal tM comprises (but being not limited to): Rh, Ru, Ni, Ir, Pd, Cu, Pt, Co, Au or its combination.

Typically, described transition metal is Pd.

Typically, described X is halogen, comprises (but being not limited to): F, Cl, Br.

In the present invention, described N is not particularly limited, for forming element and/or the group of transition metal halide tM-N-X with transition metal tM and halogen X arbitrarily.

Typically, described N comprises (but being not limited to): 1,5-cyclooctadiene, polyimide-osmanthus acyl group.

Typically, described transition metal halide tM-N-X comprises (but being not limited to): muriate, bromide.

Typically, described transition metal halide tM-N-X comprises (but being not limited to): (1,5-cyclooctadiene) palladium chloride (II) (Pd (COD) Cl ₂), (polyimide-osmanthus acyl group) Palladous chloride (II) dimer or its combination.

In the present invention, described transition metal complex is compound or their enantiomorph, raceme or the diastereomer with following chemical structural formula C3 or C4.

The preparation method of bidentate phosphine-phosphine oxygen ligand compound

Present invention also offers the preparation method of bidentate phosphine-phosphine oxygen ligand compound shown in a kind of described formula I,

Described method comprises the steps:

In various, R, R ' and R are " as defined above.

Typically, organic solvent described in step (a) comprises (but being not limited to): toluene, tetrahydrofuran (THF), anhydrous diethyl ether or its combination.

Typically, described chromatography eluent used comprises (but being not limited to): the mixture of the mixture of the mixture of the mixture of EA and MeOH, normal hexane and ethyl acetate, normal hexane and methyl tertiary butyl ether, normal hexane and ether.

The preparation method of transition metal complex

Present invention also offers a kind of preparation method of described transition metal complex, described method comprises the steps:

B () in organic solvent, there is metal-complexing reaction in the phosphine-phosphine oxygen ligand compound of bidentate shown in formula I of the present invention and transition metal halide tM-N-X, thus forms transition metal complex of the present invention,

In various, R, R ' and R are " as hereinbefore defined;

TM, X are as hereinbefore defined.

Typically, organic solvent described in step (b) comprises (but being not limited to): toluene, tetrahydrofuran (THF), anhydrous diethyl ether or its combination.

In another preference, described temperature of reaction is room temperature.

In another preference, after step (b), also comprise filtration gained solution obtain described transition metal complex.

Material combination

Present invention also offers a kind of material combination, described material combination comprises following component:

1) the first packaging, described first packing pack is containing the first component, and described first component is described bidentate phosphine-phosphine oxygen ligand compound;

Catalyzer

Present invention also offers the purposes of a kind of described bidentate phosphine-phosphine oxygen ligand compound or described transition metal complex or described material combination, for the preparation of transition-metal catalyst.

In the present invention, described catalyzer has the one or more features being selected from lower group:

1) comprise bidentate of the present invention phosphine-phosphine oxygen ligand compound or be made up of bidentate phosphine of the present invention-phosphine oxygen ligand compound;

2) comprise transition metal complex of the present invention or be made up of transition metal complex of the present invention;

3) comprise material combination of the present invention or be made up of material combination of the present invention.

Catalyze and synthesize the method for acyclic alkyl groups aromatic hydrocarbons

Present invention also offers a kind of method catalyzing and synthesizing acyclic alkyl groups aromatic hydrocarbons, described method with transition metal complex of the present invention or material combination of the present invention for catalyzer.

In another preference, material combination of the present invention generates transition metal complex of the present invention in reaction process.

In the present invention, described organic solvent and described mineral alkali are not particularly limited, and can select this area conventional material, or prepare by ordinary method, or obtain from market purchase.

Typically, described organic solvent comprises (but being not limited to): toluene, tetrahydrofuran (THF), anhydrous diethyl ether or its combination.

Typically, described mineral alkali comprises (but being not limited to): a hypophosphite monohydrate potassium, potassiumphosphate, sodium tert-butoxide.

Typically, described acyclic alkyl groups aromatic hydrocarbons comprises (but being not limited to): non-annularity one-level alkylaromatic hydrocarbon, non-annularity secondary alkyl aromatic hydrocarbons.

Particularly, described acyclic alkyl groups aromatic hydrocarbons is obtained through described catalyzed reaction by aryl halide and alkylboronic acids compound.

Typically, described aryl halide refers to comprise at least one aromatic yl group and at least one substituent organic compound.

Typically, described aromatic yl group comprises (but being not limited to):

Typically, described substituting group comprises (but being not limited to); The substituted or unsubstituted alkyl of H, halogen, C1-C10 ,-CN ,-ORa ,-NO ₂, carbonyl, substituted or unsubstituted amino, aldehyde radical, substituted or unsubstituted carboxyl ,-OTf;

In another preference, described aryl halide refers to

Wherein,

refer to substituted or unsubstituted aryl;

X is selected from lower group: F, Cl, Br;

Typically, described in comprise (but being not limited to):

Typically, described aryl halide refers to

Wherein,

A is C or N;

The number of R3 is 1-3;

X is selected from lower group: F, Cl, Br.

Wherein, x and Ra as defined above.

Application

Utilize transition metal complex of the present invention or material combination of the present invention to be catalyzer, can multi-medicament be catalyzed and synthesized, as gossypol, oestrone etc.

1) method of gossypol is catalyzed and synthesized

Present invention also offers a kind of method catalyzing and synthesizing gossypol, described method utilizes transition metal complex of the present invention or material combination of the present invention to be catalyzer, catalyzes and synthesizes gossypol in organic solvent.

Typically, the reaction process catalyzing and synthesizing gossypol in the present invention is as follows:

Compared with prior art, the present invention has following major advantage:

(1) the direct coupling of the carbon-carbon bond between large steric hindrance alkyl and aryl can be realized containing the catalyzer of bidentate phosphine of the present invention-phosphine oxygen ligand compound;

(2) catalyzer containing bidentate phosphine of the present invention-phosphine oxygen ligand compound has high catalytic efficiency;

(3) greatly can simplify the coupling reaction process of the carbon-carbon bond between large steric hindrance alkyl and aryl, and then simplify a series of with the synthesis of the above-mentioned reaction drug molecule that is committed step;

(4) greatly can simplify the coupling reaction process of the carbon-carbon bond between large steric hindrance alkyl and aryl, and then realize a series of with the rear modification of the above-mentioned reaction drug molecule that is committed step;

(5) there is very high practicality, significantly can reduce reaction cost, shorten reaction time;

(6) use in the catalytic process of catalyzer of the present invention and produce without other unwanted by products;

(7) use reaction conditions in the catalytic process of catalyzer of the present invention gentleer.

Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, the usually conveniently conditioned disjunction condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and number calculate by weight.

Unless otherwise defined, all specialties used in literary composition and scientific words and one skilled in the art the same meaning be familiar with.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.

Embodiment 1

Prepare bidentate phosphine-phosphine oxygen ligand compound L4

1. synthetic compound b

Compound a (1.23g, 8.15mmol, 1.1equiv) is dissolved in 15mL tetrahydrofuran (THF), is cooled to 0 DEG C, slowly drip n-Butyl Lithium (3.20mL, 8.15mmol, 1.1equiv), stir 1 hour at 0 DEG C.Tertiary butyl phosphorus dichloride (the 1.18g dissolved with tetrahydrofuran (THF) (15mL) is slowly added afterwards in 0 DEG C of downhill reaction system, 7.41mmol, 1.0equiv), reaction system is moved to after stirred at ambient temperature reacts 4 hours and add 3mL water, react 3 hours under room temperature.At room temperature in reaction system, dropwise add sodium hydroxide solution (2M, 7.4mL, 14.82mmol, 2.0equiv) with formaldehyde solution (37%, 1.60mL, 3.0equiv), the temperature of guarantee system is all the time lower than 30 DEG C, and afterwards, reaction system was in stirred at ambient temperature 3 hours.In reaction system, add dilute hydrochloric acid (6M) regulate PH=2.0, add 20mL water and 10mL methylene dichloride, separatory, with dichloromethane extraction three times, merge organic phase, dry, concentrated, column chromatography for separation obtains white solid product b (1.81g, 6.36mmol, 78%).

Compound b: ¹h NMR (500MHz, CDCl ₃) δ 7.39 (dt, J=8.2,1.9Hz, 1H), 6.91 (m, 1H), 6.64 ~ 6.66 (m, 1H), 4.24 (d, J=13.8Hz, 1H), 4.14 (br s, 1H), 4.04 ~ 4.08 (m, 1H), 3.74 (d, J=2.2Hz, 3H), 2.70 (s, 3H), 2.69 (s, 3H), 1.11 (dd, J=15.3,2.2Hz, 9H); ¹³c NMR (125MHz, CDCl ₃) δ 162.0 (d, J=40.8Hz), 133.9,115.0 (d, J=7.3Hz), 113.7 (d, J=79.0Hz), 110.1,107.3 (d, J=6.3Hz), 59.1 (d, J=66.9Hz), 55.4,47.4,35.3 (d, J=65.8Hz), 24.9; ³¹p NMR (162MHz, CDCl ₃) δ 51.6; ESI-MS:m/z 286.2 [M+H] ⁺, 308.2 [M+Na] ⁺; HRMS (ESI) calculated for [M+H, C ₁₄h ₂₅n ₁o ₃p ₁] ⁺: 286.1571; Found:286.1567.

2. synthetic compound c

Under nitrogen protection condition, in the reaction tubes that compound b (1.00g, 3.51mmol, 1.0equiv) be housed, slowly drip Hydrogen bromide (48%in water, 10mL), reaction system is heated to 120 DEG C of stirring reactions 20 hours.Then, reaction system is cooled to 0 DEG C, slowly adding sodium hydroxide solution regulates PH to be about 9, backward system in add methylene dichloride separatory, aqueous phase continues with dichloromethane extraction three times, merge organic phase, drying, concentrated, column chromatography for separation obtains white solid product c (0.76g, 2.81mmol, 80%).

Compound c: ¹h NMR (500MHz, CDCl ₃) δ 12.07 (s, 1H), 7.38 (t, J=8.2Hz, 1H), 6.89 (dd, J=7.9,4.1Hz, 1H), 6.78 (dd, J=8.3,3.2Hz, 1H), 5.94 (m, 1H), 4.34 (m, 2H), 2.70 (s, 3H), 2.61 (s, 3H), 1.22 (d, J=15.2Hz, 9H); ¹³cNMR (125MHz, CDCl ₃) δ 166.2,156.7,134.8 (d, J=1.6Hz), 117.0 (d, J=6.2Hz), 112.9 (d, J=7.9Hz), 108.3 (d, J=77.6Hz), 59.8 (d, J=67.5Hz), 50.5,45.4,35.5 (d, J=62.9Hz), 24.4; ³¹p NMR (162MHz, CDCl ₃) δ 65.4; ESI-MS:m/z 272.3 [M+H] ⁺, 294.3 [M+Na] ⁺; HRMS (ESI) calculated for [M+H, C ₁₃h ₂₃n ₁o ₃p ₁] ⁺: 272.1418; Found:272.1410.

3. synthetic compound d

Get a Schlenk pipe to dry, add compound c (0.33g, 1.22mmol, 1.0equiv), substitute nitrogen three times, add THF (2.0mL) to dissolve, triphenylphosphine (0.38g, 1.47mmol, 1.2equiv) and diethyl azodiformate (0.37g is added in reaction system, 1.83mmol, 1.5equiv).Reaction system is concentrated after 3 hours in stirred at ambient temperature, and column chromatography for separation obtains white solid product d (0.26g, 1.04mmol, 85%).

Compound d: ¹h NMR (400MHz, CDCl ₃) δ 7.29 (t, J=8.1Hz, 1H), 6.39 ~ 6.46 (m, 2H), 4.29 ~ 4.51 (m, 2H), 2.99 (s, 6H), 1.17 (d, J=16.0Hz, 9H); ¹³c NMR (100MHz, CDCl ₃) δ 166.5 (d, J=18.1Hz), 157.1 (d, J=2.59Hz), 135.6,109.7 (d, J=6.7Hz), 106.0 (d, J=5.3Hz), (103.9 d, J=51.5Hz), 64.5 (d, J=64.1Hz), 44.6,34.9 (d, J=72.1Hz), 24.5; ³¹p NMR (162MHz, CDCl ₃) δ 66.5 (s); EI-MS:m/z 253.0 [M] ⁺; HRMS (EI) m/z calcd for C ₁₃h ₂₀nO ₂p (M ⁺): 253.1232, found:253.1231.

4. synthetic compound e

Get a Schlenk pipe to dry, add compound d (100mg, 0.39mmol), substitute nitrogen three times, add THF (2ml), temperature is down to-78 DEG C, slowly drips LDA (0.22ml, 2Min THF, 1.1equiv) ,-78 DEG C are reacted one hour.In reaction system, slowly add di-t-butyl phosphorus chloride (0.08ml, 0.43mmol, 1.1equiv) ,-78 DEG C are reacted one hour, react one hour under moving to room temperature.Be cooled to 0 DEG C, slowly drip hydrogen peroxide (5ml, 30%), under room temperature, reaction one hour, adds methylene dichloride layering, is separated organic phase, and dry concentrated rear column chromatography for separation (EA:MeOH=10:1) obtains Verbindung.

Verbindung: ¹h NMR (400MHz, CDCl ₃) δ 7.32 (t, J=8.0Hz, 1H), 6.53 (dd, J=8.1,4.5Hz, 1H), 6.46 (dd, J=8.2,2.4Hz, 1H), 4.90 (dd, J=10.0,5.7Hz, 1H), 2.95 (s, 6H), 1.42 (d, J=13.4Hz, 9H), 1.40 (d, J=14.3Hz, 9H), 1.25 (d, J=16.3Hz, 9H); ¹³c NMR (125MHz, CDCl ₃) δ 164.3,157.6 (d, J=2.3Hz), 135.5, (110.9 d, J=6.7Hz), 106.4 (d, J=5.2Hz), (70.1 dd, J=45.2,5.1Hz), 45.0, (38.0 d, J=57.2Hz), 37.1 (dd, J=54.5,6.7Hz), 36.3 (d, J=77.3Hz), 27.6,26.8,25.4; ³¹p NMR (162MHz, CDCl ₃) δ 62.0 (d, J=8.5Hz, 1P), 61.7 (d, J=8.4Hz, 1P); EI-MS:m/z 413.0 [M] ⁺; HRMS (EI) m/zcalcd for C ₂₁h ₃₇nO ₃p ₂(M ⁺): 413.2246, found:413.2245.

5. synthetic ligands L4

Verbindung (0.36g, 0.87mmol) is put into Schlenk pipe, after substituting nitrogen three times, adds THF (4mL).HSiCl is added in this reaction system ₃(0.44ml, 4.35mmol, 5equiv) and TEA (1.2ml, 8.7mmol, 10equiv).This reaction system return stirring 24 hours, is cooled to room temperature final vacuum and drains THF.30% aqueous sodium hydroxide solution (4mL) is dropwise added in reaction system, hydrogen is had to produce in dropping process, this reaction system heated and stirred in 60 DEG C is added Me-THF (4mL) wherein after 30 minutes, wash with water (4mL × 3) after being separated organic phase, after saturated NaCl solution washing, add anhydrous sodium sulfate drying.Filter, drain to obtain product (160mg).

Ligand L 4: ¹h NMR (400MHz, CDCl ₃) δ 7.15 (t, J=8.0Hz, 1H), 6.44 (dd, J=8.0,3.7Hz, 1H), 6.40 (d, J=8.0Hz, 1H), 5.39 (dd, J=7.7,3.4Hz, 1H), 2.93 (s, 6H), 1.43 (d, J=13.0,9H), 1.23 (d, J=13.6Hz, 9H), 0.98 (d, J=12.3Hz, 9H); ¹³c NMR (100MHz, CDCl ₃) δ 164.9 (d, J=1.35Hz), 155.8 (d, J=12.0Hz), 132.0,113.1 (dd, J=21.7,1.6Hz), 109.5, (d, J=6.5Hz), 103.9,79.2 (dd, J=61.7,45.9Hz), 43.0,42.9,37.0 (dd, J=13.8,1.4Hz), 36.5 (dd, J=13.6,1.4Hz), 34.2 (dd, J=24.9,8.2Hz), 27.5 (d, J=4.7Hz), 27.2,26.9 (d, J=14.5Hz); ³¹p NMR (162MHz, CDCl ₃) δ 57.4 (d, J=39.9Hz), 5.1 (d, J=39.9Hz); EI-MS:m/z 397.1 [M] ⁺; HRMS (EI) m/z calcd forC ₂₁h ₃₇nO ₂p ₂(M ⁺): 397.2300, found:397.2305.

Embodiment 2

Prepare bidentate phosphine-phosphine oxygen ligand compound L3

1. synthetic ligands L3

Compound f (0.38g, 1.00mmol, 1.0equiv) is put into Schlenk pipe, after substituting nitrogen three times, adds toluene (5mL).HSiCl is added in this reaction system ₃(0.51ml, 5.00mmol, 5.0equiv) and TEA (1.40mL, 10.00mmol, 10.0equiv).Stir 12 hours at this reaction system 80 DEG C of temperature, be cooled to room temperature final vacuum and drain toluene.30% aqueous sodium hydroxide solution (20mL) is dropwise added in reaction system, hydrogen is had to produce in dropping process, this reaction system heated and stirred in 60 DEG C was cooled to room temperature after 30 minutes, add MTBE (20mL × 3) extraction wherein, merge and be organicly added to anhydrous sodium sulfate drying.Filter, drained neutral alumina column and obtain white solid L3 (0.35g, 0.91mmol, 96%).

Ligand L 3: ¹h NMR (400MHz, CDCl ₃) δ 7.21 (t, J=8.1Hz, 1H), 6.44 ~ 6.48 (m, 2H), 5.47 (dd, J=7.6,3.2Hz, 1H), 3.82 (s, 3H), 1.42 (d, J=13.1Hz, 9H), 1.20 (d, J=13.6Hz, 9H), 1.02 (d, J=12.4Hz, 9H); ¹³c NMR (125MHz, CDCl ₃) δ 164.7 (d, J=8.0Hz), 161.7 (d, J=12.7Hz), 132.4,110.7 (d, J=17.9Hz), 104.4,103.2 (d, J=1.3Hz), 80.5 (dd, J=61.7,47.0Hz), 55.5,36.9 (d, J=4.0Hz), 36.5 (d, J=5.3Hz), 33.0 (dd, J=25.0,7.5Hz), 27.4 (d, J=5.5Hz), 27.1 (d, J=4.8Hz), 27.1 (d, J=10.0Hz); ³¹p NMR (162MHz, CDCl ₃) δ 57.1 (d, J=40.1Hz), 2.3 (d, J=40.3Hz); EI-MS:m/z 384.0 [M] ⁺; HRMS (EI) m/z calcd for C ₂₀h ₃₄o ₃p ₂(M ⁺): 384.1983, found:384.1986.

Embodiment 3

Prepare transition metal complex Pd (1) Cl ₂

Ligand 1 (100mg, 0.26mmol, 2.2equiv) and solid Pd (COD) Cl is added in the 20mL Schlenk pipe adding stirrer ₂(34mg, 0.12mmol, 1equiv).Add THF (1mL) after substituting nitrogen three times, the solution obtained at room temperature stirs two hours.In mixed solution, add anhydrous diethyl ether (3mL), stirred at ambient temperature filters after half an hour, obtains yellow solid (90mg, 0.26mmol, 62%).

The product obtained adds methylene dichloride and ether dissolution (1:3) after drying, separates out radial slice-type crystal, single crystal samples sample presentation is done X-diffraction analysis after being placed on overnight at room temperature.

Pd(1)Cl ₂: ¹H NMR(400MHz,CDCl ₃)δ7.49(dt,J＝8.3,0.67Hz,1H),6.62(dd,J＝8.2,4.8Hz,1H),6.53(dd,J＝8.3,1.1Hz,1H),5.68(d,J＝9.0Hz,1H),3.87(s,3H),1.56(d,J＝15.2Hz,9H),1.49(d,J＝14.7Hz,9H),1.40(d,J＝18.0Hz,9H)； ¹³C NMR(125MHz,CDCl ₃)δ164.6(dd,J＝4.6,1.2Hz),162.9(d,J＝5.3Hz),137.0,106.1(d,J＝6.1Hz),105.1(d,J＝4.5Hz),100.7(d,J＝42.9Hz),78.5(dd,J＝53.3,7.1Hz),56.2,39.2(dd,J＝13.6,4.2Hz),38.1(d,J＝47.6Hz),37.4(dd,J＝51.5,3.9Hz),27.4,27.2(d,J＝5.1Hz),26.8； ³¹P NMR(162MHz,CDCl ₃)δ100.0(d,J＝14.3Hz),65.4(d,J＝14.2Hz)；EI-MS:m/z 561.6.

Embodiment 4

Prepare transition metal complex Pd (2) Cl ₂

Part 2 (40mg, 0.10mmol, 2.2equiv) and solid Pd (COD) Cl is added in the 20mL Schlenk pipe adding stirrer ₂(13.1mg, 0.05mmol, 1.0equiv).Add THF (1mL) after substituting nitrogen three times, the solution obtained at room temperature stirs two hours.In mixed solution, add anhydrous diethyl ether (3mL), stirred at ambient temperature filters after half an hour, obtains yellow solid (30mg, 0.052mmol, 52%).

Pd(2)Cl ₂: ¹H NMR(500MHz,CDCl ₃)δ7.42(t,J＝8.0Hz,1H),6.74(dd,J＝7.8,5.0Hz,1H),6.49(d,J＝8.1Hz,1H),5.78(dd,J＝5.5,3.2Hz,1H),3.24(s,6H),1.72(d,J＝14.7Hz,9H),1.30(d,J＝15.0Hz,9H),1.29(d,J＝17.6Hz,9H)； ¹³C NMR(100MHz,CDCl ₃)δ164.1(d,J＝3.1Hz),158.8,136.1,113.1,105.1,104.3(d,J＝37.1Hz),78.3(dd,J＝46.9,5.7Hz),46.1,40.2(dd,J＝13.6,5.2Hz),38.0(dd,J＝50.4,1.2Hz),37.7(d,J＝48.3Hz),27.2,26.7,26.6(d,J＝3.8Hz)； ³¹P NMR(162MHz,CDCl ₃)δ100.1(d,J＝13.4Hz),63.2(d,J＝13.3Hz).

Embodiment 5

Bidentate phosphine-phosphine oxygen ligand compound L4 modifies estrone

1. synthetic compound g

The Schlenk pipe getting a 250mL is dried, add compound f (3.0g, 11.1mmol, 1.0equiv), N-bromo acetamide (1.68g, 12.2mmol, 1.1equiv), substitute nitrogen three times, sealing, add dehydrated alcohol (120mL), stirred at ambient temperature eight hours.Add water in reaction system, separate out white solid, filter, after washing with water, obtain white products g (2.5g, 7.2mmol, 72%).

2. synthetic compound h

The Schlenk pipe getting a 250mL is dried, and adds compound g (1.5g, 4.3mmol, 1.0equiv), Anhydrous potassium carbonate (2.97g, 21.5mmol, 5.0equiv), substitute nitrogen three times, sealing, adds anhydrous alcohol solution, methyl iodide (4.0ml is slowly added in reaction system, 64.5mmol, 15.0equiv), stirred at ambient temperature 12 hours.Add water in reaction system and methylene dichloride separatory, and with dichloromethane extraction three times (100ml*3), merge organic phase, anhydrous sodium sulfate drying, filters, concentrated, column chromatography for separation obtains white solid product h (1.41g, 3.87mmol, 90%).

[α] _D ²⁷＝62.5°(c＝0.20,CHCl ₃).

Compound h: ¹h NMR (400MHz, CDCl ₃) δ 7.24 (d, J=8.6Hz, 1H), 6.76 (d, J=8.6Hz, 1H), 3.88 (s, 3H), 3.02 ~ 3.08 (m, 1H), 2.70 ~ 2.79 (m, 1H), 2.48 ~ 2.55 (m, 1H), 2.38 ~ 2.40 (m, 1H), 2.29 (m, 1H), 1.95 ~ 2.20 (m, 4H), 1.36 ~ 1.69 (m, 6H), 0.90 (s, 3H); ¹³c NMR (125MHz, CDCl ₃) δ 220.7,154.0,137.5,134.2,124.8,114.8,109.1,56.3,50.4,47.9,44.2,37.5,35.9,31.5,31.1,26.7,26.1,21.6,13.8; EI-MS:m/z 362.0 [M] ⁺; HRMS (EI) m/z calcd for C ₁₉h ₂₃brO ₂(M ⁺): 362.0881, found:362.0879.

3. synthetic compound i

The Schlenk pipe getting a 10mL is dried; add compound h (36.0mg; 0.10mmol; 1.0equiv); sec.-propyl boric acid (18.0mg; 0.20mmol, 2.0equiv), a hypophosphite monohydrate potassium (70.0mg; 0.30mmol; 3.0equiv), (polyimide-osmanthus acyl group) Palladous chloride (II) dimer (0.001mmol, 0.01equiv) and ligand L 4 (0.002mmol; 0.02equiv; Pd/ part mol ratio: 1/2), substitutes nitrogen three times, sealing.Add toluene (2mL).Reaction system is warming up to 110 DEG C of reactions 8 hours, is cooled to room temperature, adds water (10mL) and methylene dichloride (10mL), separatory, merges organic phase, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains white solid product i (87%).

Known after tested, in products therefrom, branched product and chain proportion of by-product are 11:1.

[α] _D ²⁵＝56.7°(c＝0.45,CHCl ₃).

Compound i: ¹h NMR (500MHz, CDCl ₃) δ 7.15 (d, J=8.7Hz, 1H), 6.75 (d, J=8.7Hz, 1H), 3.80 (s, 3H), 3.30 (br s, 1H), 2.95 ~ 2.99 (m, 1H), 2.79 ~ 2.86 (m, 1H), 2.48 ~ 2.54 (m, 1H), 2.38 ~ 2.42 (m, 1H), 2.24 ~ 2.28 (m, 1H), 2.11 ~ 2.19 (m, 1H), 2.04 ~ 2.10 (m, 2H), 1.95 ~ 1.97 (m, 1H), 1.46 ~ 1.67 (m, 6H), 1.32 (d, J=7.0Hz, 6H), 0.91 (s, 3H); ¹³c NMR (100MHz, CDCl ₃) δ 221.1,157.0,134.8,133.9,132.4,123.6,109.4,55.2,50.6,47.9,44.6,37.3,35.9,31.7,27.6,27.4,27.1,26.3,21.6,20.4,13.8; EI-MS:m/z 326.0 [M] ⁺; HRMS (EI) m/z calcd for C ₂₂h ₃₀o ₂(M ⁺): 326.2246, found:326.2244.

Embodiment 6

Synthetic drugs molecule gossypol (Gossypol)

1. synthetic compound k

Get a Schlenk pipe to dry, add compound j (5.0g, 43.8mmol, 1equiv), substitute nitrogen three times, add THF (50ml), temperature is down to-78 DEG C, slowly drips LDA (2.0M in THF, 24mL, 48.21mmol, 1.1equiv) ,-78 DEG C are reacted one hour.In reaction system, slowly add TMSCl (6.75mL, 52.6mmol, 1.2equiv) ,-78 DEG C are reacted 20 minutes, react one hour under moving to room temperature.Reaction solution is spin-dried for, again dissolves with pentane (60mL), cross diatomite and remove precipitation, be spin-dried for obtain crude product k (6.76g, 36.3mmol, 83%).

Compound k: ¹h NMR (300MHz, C ₆d ₆) δ 5.13 (d, J=2.0Hz, 1H), 4.86 (d, J=1.2Hz, 1H), 4.36 (s, 1H), 3.03 (s, 3H), 2.17 (s, 3H) .0.18 (s, 9H); ¹³c NMR (101MHz, C ₆d ₆) δ 157.60,140.26,108.44,81.84,54.67,23.90,0.43.

2. synthetic compound m

The Schlenk pipe getting a 250mL is dried, and adds compound l (5.0g, 25.5mmol, 1equiv), 30% hydrogen peroxide (3.5ml, 33.2mmol, 1.3equiv), substitutes nitrogen three times, and sealing, adds dissolve with methanol.Cool the temperature to 0 DEG C, in reaction system, slowly add sulfuric acid (0.5ml), stirred at ambient temperature 1 hour.Saturated sodium bicarbonate solution cancellation reaction is added in reaction system, add methylene dichloride separatory, and with dichloromethane extraction three times (50ml*3), merge organic phase, anhydrous sodium sulfate drying, filter, concentrated, column chromatography for separation obtains yellow liquid product m (4.5g, 24.5mmol, 96%).

Compound m: ¹h NMR (500MHz, CDCl ₃) δ 6.61 (d, J=9.0Hz, 1H), 6.54 (d, J=9.0Hz, 1H), 5.57 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.79 (s, 3H); ¹³c NMR (125MHz, CDCl ₃) δ 147.0,143.5,142.4,140.6,108.7,107.8,61.3,61.0,56.6; EI-MS:m/z 184.1 [M] ⁺; HRMS (EI) m/z calcd for C ₉h ₁₂o ₄(M ⁺): 184.0736, found:187.0734.

3. synthetic compound n

The Schlenk pipe getting a 250mL is dried, and adds compound m (3.0g, 16.3mmol, 1equiv) and CuCl ₂(2.19g, 16.3mmol, 1equiv).Add ethyl acetate (35mL) and water (17.5ml).Temperature is risen to 70 DEG C, stir 3 hours under the environment of oxygen.Add methylene dichloride separatory, and with dichloromethane extraction three times (40ml*3), merge organic phase, anhydrous sodium sulfate drying, filter, concentrated, column chromatography for separation obtains yellow oily product n (1.7g, 10.1mmol, 62%).

Compound n: ¹h NMR (500MHz, CDCl ₃) δ 6.60 (s, 2H), 4.02 (s, 6H); ¹³c NMR (125MHz, CDCl ₃) δ 184.1,145.1,134.6,61.3.

4. synthetic compound o

The Schlenk pipe getting a 100mL is dried, and adds compound n (1.62g, 9.25mmol, 2equiv), adds methylene dichloride (22mL) and dissolves.Under room temperature, compound k (0.9g, 4.84mmol, 1equiv) is slowly added drop-wise in reaction system, stirred at ambient temperature 20 hours.In reaction system, add acetic acid (0.57mL, 10.65mmol, 2.2equiv), stirred at ambient temperature 30 minutes, is spin-dried for reaction solution, and direct column chromatography for separation obtains yellow solid product o.

Compound o: ¹h NMR (500MHz, CDCl ₃) δ 7.53 (s, 1H), 7.03 (s, 1H), 4.07 (s, 3H), 4.03 (s, 3H), 3.96 (s, 3H), 2.43 (s, 3H); ¹³c NMR (125MHz, CDCl ₃) δ 182.4,180.8,159.9,148.3,146.3,145.8,133.1,120.1,118.4,116.3,61.5,61.2,56.6,22.3; EI-MS:m/z 262.0 [M] ⁺; HRMS (EI) m/z calcd for C ₁₄h ₁₄o ₅(M ⁺): 262.0841, found:262.0845.

5. synthetic compound p

The Schlenk pipe getting a 100mL is dried, and adds compound o (5.0g, 19.1mmol, 1.0equiv), substitutes nitrogen three times, adds methylene dichloride (40mL) and dissolves.Be cooled to 0 DEG C, slowly drip Et ₃siH (9.2mL, 57.3mmol, 3equiv) and PBr ₃(5.5ml, 57.3mmol, 3.0equiv).React the cancellation that adds water in 6 hours under room temperature, dichloromethane extraction three times, merge organic phase, anhydrous sodium sulfate drying, filters, concentrated, column chromatography (eluent: n-hexane/ethyl acetate=15/1) is separated and obtains white solid product p (3.93g, 15.8mmol, 83%).

Compound p: ¹h NMR (500MHz, CDCl ₃) δ 9.25 (s, 1H), 7.04 (s, 1H), 6.60 (s, 1H), 6.47 (s, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.92 (s, 3H), 2.40 (s, 3H); ¹³c NMR (125MHz, CDCl ₃) δ 155.8,153.8,147.1,135.1,133.9,132.9,119.8,109.5,104.7,97.9,60.8,56.1,55.7,21.9; EI-MS:m/z 248.2 [M] ⁺; HRMS (EI) m/z calcd for C ₁₄h ₁₆o ₄(M ⁺): 248.1049, found:248.1050.

6. synthetic compound q

Get a 100mL Schlenk pipe dry, add compound p (600mg, 2.42mmol, 1.0equiv) and, substitute nitrogen three times, add THF (5mL) dissolving.NBS (480mg, 2.70mmol, 1.1equiv) is slowly added at 0 DEG C.Be warming up to room temperature, the stirring reaction cancellation that adds water in 2 hours, dichloromethane extraction three times, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated, column chromatography (eluent: n-hexane/ethyl acetate=20/1) is separated and obtains white solid product q (90mg, 1.50mmol, 62%).

Compound q: ¹h NMR (500MHz, CDCl ₃) δ 9.47 (s, 1H), 7.60 (s, 1H), 6.61 (s, 1H), 4.05 (s, 3H), 3.99 (s, 3H), 3.95 (s, 3H), 2.47 (s, 3H); ¹³c NMR (125MHz, CDCl ₃) δ 155.9,151.8,147.5,137.7,136.4,130.9,119.9,111.9,106.4,104.2,61.3,61.1,56.5,22.3; ESI-MS:m/z 329.2 [M+H] ⁺, 351.3 [M+Na] ⁺; HRMS (ESI) calculatedfor [M+Na, C ₁₄h ₁₅br ₁na ₁o ₄] ⁺: 349.0053; Found:349.0046.

7. synthetic compound r

The Schlenk pipe getting a 20mL is dried, add compound q (100mg, 0.31mmol, 1.0equiv), substitute nitrogen three times, add methylene dichloride (2mL) and dissolve, add triethylamine (0.3mL, 1.53mmol, 5.0equiv), be cooled to-78 DEG C and slowly add Tf ₂o (0.15mL, 0.34mmol, 1.1equiv).Reaction system stirring reaction at-78 DEG C adds water (5mL) cancellation after 1 hour, dichloromethane extraction three times, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated, column chromatography (eluent: n-hexane/ethyl acetate=100/1) is separated and obtains white solid product r (139mg, 0.30mmol, 99%).

Compound r: ¹h NMR (500MHz, CDCl ₃) δ 7.66 (s, 1H), 6.76 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 3.97 (s, 3H), 2.51 (s, 3H); ¹³c NMR (125MHz, CDCl ₃) δ 154.3,150.4,144.0,138.1,137.9,130.9,118.8 (q, J=318.4Hz, 1C), 118.8,115.7,115.0,108.9,61.9,61.2,55.4,22.2; ¹⁹f NMR (376MHz, CDCl ₃) δ 73.8; ESI-MS:m/z 461.2 [M+H] ⁺, 481.3 [M+Na] ⁺; HRMS (ESI) calculated for [M+Na, C ₁₅h ₁₄br ₁f ₃na ₁o ₆s ₁] ⁺: 480.9545; Found:480.9539.

The X-ray crystallogram of compound r is shown in Fig. 3.

8. synthetic compound s

The Schlenk pipe getting a 10mL is dried, add compound r (46mg, 0.10mmol, 1.0equiv), sec.-propyl boric acid (17mg, 0.20mmol, 2.0equiv), hypophosphite monohydrate potassium (70.0mg, a 0.30mmol, 3.0equiv), [Pd (cinnamyl) Cl] ₂(0.26mg, 0.0005mmol, 1mol%Pd) and ligand L 4 (0.77mg, 0.002mmol, 2mol%), substitutes nitrogen three times, sealing.Add toluene (2mL).Reaction system is warming up to 110 DEG C of reactions 8 hours, be cooled to room temperature, add water (10mL) and methylene dichloride (10mL), separatory, merge organic phase, anhydrous sodium sulfate drying, concentrated, column chromatography for separation obtains white solid product s (86%, identify that iPr:nPr ratio is 9.6:1 through nuclear-magnetism).

Compound s: ¹h NMR (500MHz, CDCl ₃) δ 7.51 (s, 1H), 6.70 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.91 (s, 3H), 3.89 (m, 1H), 2.48 (s, 3H), 1.48 (d, J=7.3Hz, 6H); ¹³c NMR (150MHz, CDCl ₃) δ 154.7,144.2,136.9,135.7,131.2,119.0 (q, J=318.6Hz, 1C), 116.7,116.3,115.0,107.8,61.4,55.3,27.3,22.6,22.1; ¹⁹f NMR (376MHz, CDCl ₃) δ 73.9; ESI-MS:m/z 423 [M+H] ⁺; HRMS (ESI) calculated for [M+H, C ₁₈h ₂₁f ₃na ₁o ₆s ₁] ⁺: 423.1089; Found:423.1094.

9. synthetic compound t

The autoclave getting a 100mL is dried, and adds compound s (40mg, 0.095mmol, 1.0equiv); Triethylamine (0.04mL, 0.28mmol, 3.0equiv) and 10%Pd/C (40mg), add methyl alcohol (1mL).Be warming up to 60 DEG C to react 4 hours under 100psi hydrogen atmosphere.Reaction system is cooled to room temperature, filters, concentrated, column chromatography for separation obtains white solid product t (25.7mg, 0.094mmol, 99%).

Compound t: ¹h NMR (400MHz, CDCl ₃) δ 7.47 (s, 2H), 6.60 (s, 1H), 3.97 (s, 3H), 3.97 (s, 3H), 3.93 (br s, 1H), 3.88 (s, 3H), 2.49 (s, 3H), 1.49 (d, J=7.2Hz, 6H); ¹³c NMR (100MHz, CDCl ₃) δ 154.8,151.3,134.8,132.8,128.8,121.5,116.0,115.7,105.3,100.0,61.1,55.5,55.5,26.9,22.7,22.1; EI-MS:m/z 274.4 [M] ⁺; HRMS (EI) m/z calcd for C ₁₇h ₂₂o ₃(M ⁺): 274.1569, found:274.1570.

Comparative example 1

Different ligands catalysis large steric hindrance arylalkyl linked reaction

The Schlenk pipe getting a 10mL is dried; add compd A (0.10mmol; 1.0equiv); sec.-propyl boric acid B (0.20mmol; 2.0equiv); one hypophosphite monohydrate potassium (0.30mmol; 3.0equiv); (polyimide-osmanthus acyl group) Palladous chloride (I I) dimer (1%mmol; 0.01equiv) and part (2%mmol, 0.02equiv, palladium/part mol ratio is 1/2); substitute nitrogen three times, sealing.Add toluene (2mL).Reaction system is warming up to 110 DEG C of reactions 8 hours, be cooled to room temperature, add water (10mL) and methylene dichloride (10mL), separatory, merge organic phase, anhydrous sodium sulfate drying, concentrated, with HPLC detection reaction yield after sampling, column chromatography for separation obtains white solid product, through the ratio of nuclear magnetic data assay products C and by product D, E, acquired results is in table 1.

Table 1

Wherein,

L1 is

L2 is

^[a]reaction conditions: nitrogen environment, using toluene as solvent, adds 1mol% (polyimide-osmanthus acyl group) Palladous chloride (II) dimer and 2mol% part, with K ₃pO ₄h ₂o, as alkali, reacts 8 hours under 110 DEG C of conditions. ^[b]yield is detected by the HPLC of C-18. ^[c]separation yield.

As can be seen from Table 1, although use L1, BI-DIME and Antphos higher as the catalyst system activity of part, the selectivity of product and isomerization by product is also bad, and generates debrominate by product.Ligand L 2, L3 of the present invention all has comparatively high reaction activity, and wherein, ligand L 3 shows higher reaction preference owing to having larger steric hindrance, can effectively suppress β-H eliminating rate and debrominate reduction to eliminate side reaction approach.

Embodiment 7

The research of ligand L 3 substrate different from L4 catalysis

The Schlenk pipe getting a 10mL is dried; add aryl halide (0.10mmol; 1.0equiv); alkyl boron reagent (0.20mmol; 2.0equiv); one hypophosphite monohydrate potassium (0.30mmol; 3.0equiv); (polyimide-osmanthus acyl group) Palladous chloride (II) dimer (1%mmol; 0.01equiv) and part (2%mmol, 0.02equiv, palladium/part mol ratio is 1/2); substitute nitrogen three times, sealing.Add toluene (2mL).Reaction system is warming up to 110 DEG C of reactions 8 hours, be cooled to room temperature, add water (10mL) and methylene dichloride (10mL), separatory, merge organic phase, anhydrous sodium sulfate drying, concentrated, with HPLC detection reaction yield after sampling, column chromatography for separation obtains white solid product, through the ratio of nuclear magnetic data assay products and by product, acquired results is in table 2, and wherein thickened portion represents and is derived from described alkylboronic acids compound R a-B (OH) ₂ra-group.

As can be seen from Table 2, use the catalyst system of catalyzer of the present invention to have the substrate scope of application widely, ligand L 3 has higher activity and functional group compatibility in the linked reaction of large steric hindrance aryl halide and alkylboronic acids.

Embodiment 8

The research of ligand L 2, the different substrate of L3 with L4 catalysis

The Schlenk pipe getting a 10mL is dried; add aryl halide (0.10mmol; 1.0equiv); alkylboronic acids reagent (0.20mmol; 2.0equiv); one hypophosphite monohydrate potassium (0.30mmol; 3.0equiv); (polyimide-osmanthus acyl group) Palladous chloride (II) dimer (1%mmol; 0.01equiv) and part (2%mmol, 0.02equiv, palladium/part mol ratio is 1/2); substitute nitrogen three times, sealing.Add toluene (2mL).Reaction system is warming up to 110 DEG C of reactions 8 hours, be cooled to room temperature, add water (10mL) and methylene dichloride (10mL), separatory, merge organic phase, anhydrous sodium sulfate drying, concentrated, with HPLC detection reaction yield after sampling, column chromatography for separation obtains white solid product, through the ratio of nuclear magnetic data assay products and by product, acquired results is in table 3.

Table 2

^astandard conditions (unless stated otherwise): aromatic bromide (0.25mmol); the sec.-propyl boric acid (2) of 1.5equiv; (polyimide-osmanthus acyl group) Palladous chloride (II) dimer of 0.5mol%, the K of the L3 of 2mol%, 3.0equiv ₃pO ₄h ₂o, toluene, 100 DEG C, 12h. ^bthe separation yield of iPrAr. ^cthe ratio of iPr/nPr is detected by carbon 18 Reversed Phase High Performance or nuclear-magnetism. ^duse ligand L 4.

Table 3

^astandard conditions (unless stated otherwise): aromatic bromide (0.25mmol); the sec.-propyl boric acid (2) of 1.5equiv; (polyimide-osmanthus acyl group) Palladous chloride (II) dimer of 0.5mol%, the K of the L4 of 2mol%, 3.0equiv ₃pO ₄h ₂o, toluene, 100 DEG C, 12h. ^bthe separation yield of iPrAr. ^cthe ratio of iPr/nPr is detected by carbon 18 Reversed Phase High Performance or nuclear-magnetism. ^duse ligand L 2. ^euse ligand L 3.

As can be seen from Table 3, use the catalyst system of catalyzer of the present invention to have the substrate scope of application widely, in the linked reaction of the large steric hindrance aryl halide that ligand L 4 replaces at ortho position bifunctional and alkylboronic acids, there is higher activity and functional group compatibility.

Embodiment 9

Catalyst levels is studied

Linked reaction (solvent: toluene, temperature of reaction: 110 DEG C) for bromo-3, the 5-dimethoxy benzaldehydes of 4-and sec.-propyl boric acid have employed the detections such as online infrared detection and HPLC, to explore the consumption of minimum catalyzer.

The online infrared signature spectrogram of gained is shown in Fig. 4, and as can be seen from Figure 4, the aldehyde carbonyl of bromo-3, the 5-dimethoxy benzaldehydes of raw material 4-is at 1704cm ^-1the stretching vibration infrared absorption peak at place is obvious, and the aldehyde carbonylic stretching vibration infrared absorption peak of product is at 1618cm ^-1locate obvious.And reaction start after, raw material reduces fast, the generation of product corresponding proportion, and whole reaction quickly, reached balance in about 20 minutes.Now, detect through HPLC and show that this reaction terminates, productive rate 98%, demonstrate the high efficiency of this catalyst system.

Embodiment 10

Catalyst efficient studies

Use 1mmol% respectively, the catalyzer of 0.5mmol% and 0.1mmol% reacts at identical conditions, and carries out Real-Time Monitoring with infrared online to reaction system, and coordinates HPLC to carry out record to experimental result.

Online infrared speed of reaction graphic representation is shown in Fig. 5, and HPLC test data is in table 4.Associative list 4 and Fig. 5, can find out, when 1mmol% catalytic amount, react and terminate within the very short time (20min), target product productive rate is up to 98%; When 0.5mmol% catalytic amount, reaction can reach very high productive rate (96%) equally, but reaction time comparatively 1mmol% catalytic amount time to grow, be about two and one-half-hours; And when the amount of reduction catalyzer is to 0.1mmol%, react after 24 hours, productive rate only has 30%.And can find out that from Fig. 5 reaction stopped four and a half hours time further.Above-mentioned experimental result shows that the consumption of catalyzer lowly can reach 0.5mmol%, and this also shows that this ligand catalysis system has high catalytic efficiency.

Table 4

The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.

Claims

1. bidentate phosphine-phosphine oxygen ligand compound or its enantiomorph, raceme or a diastereomer, is characterized in that, described bidentate phosphine-phosphine oxygen ligand compound has structure shown in formula I:

In formula,

2. bidentate phosphine-phosphine oxygen ligand compound as claimed in claim 1, it is characterized in that, described bidentate phosphine-phosphine oxygen ligand compound is such as formula shown in (Ia):

In formula,

R, R ' and R " as claim 1 define;

Preferably, described bidentate phosphine-phosphine oxygen ligand compound has structure shown in formula II:

In formula, R as claim 1 define;

Preferably, described bidentate phosphine-phosphine oxygen ligand compound has following chemical structural formula:

3. transition metal complex or its enantiomorph, raceme or a diastereomer, is characterized in that, described transition metal complex is formed by bidentate phosphine-phosphine oxygen ligand compound according to claim 1 and transition metal tM or transition metal halide complexing.

4. a preparation method for the phosphine of bidentate shown in formula I according to claim 1-phosphine oxygen ligand compound,

It is characterized in that, described method comprises the steps:

In various, R, R ' and R " as claim 1 define.

5. a preparation method for transition metal complex described in claim 3, is characterized in that, described method comprises the steps:

B () in organic solvent, the phosphine of bidentate shown in formula I-phosphine oxygen ligand compound described in claim 1 and transition metal halide generation metal-complexing react, thus form transition metal complex described in claim 3,

In various, R, R ' and R " as claim 1 define;

X is halogen, is preferably: F, Cl, Br.

6. a material combination, is characterized in that, described material combination comprises following component:

1) the first packaging, described first packing pack is containing the first component, and described first component is bidentate according to claim 1 phosphine-phosphine oxygen ligand compound;

7. a purposes for material combination described in transition metal complex described in bidentate phosphine-phosphine oxygen ligand compound described in claim 1 or claim 3 or claim 6, is characterized in that, for the preparation of transition-metal catalyst.

8. a catalyzer, is characterized in that, described catalyzer has the one or more features being selected from lower group:

1) comprise bidentate according to claim 1 phosphine-phosphine oxygen ligand compound, or be made up of bidentate phosphine according to claim 1-phosphine oxygen ligand compound;

2) comprise transition metal complex described in claim 3, or be made up of transition metal complex described in claim 3;

3) comprise material combination described in claim 6, or be made up of material combination described in claim 6.

9. catalyze and synthesize a method for acyclic alkyl groups aromatic hydrocarbons, it is characterized in that, described method with material combination described in transition metal complex described in claim 3 or claim 6 for catalyzer.

10. catalyze and synthesize a method for gossypol, it is characterized in that, described method utilizes material combination described in transition metal complex described in claim 3 or claim 6 to be catalyzer, catalyzes and synthesizes gossypol in organic solvent.