CN106995461B - A kind of Phosphine ligands of the structure containing benzofuran and its preparation method and application - Google Patents
A kind of Phosphine ligands of the structure containing benzofuran and its preparation method and application Download PDFInfo
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- CN106995461B CN106995461B CN201710122111.3A CN201710122111A CN106995461B CN 106995461 B CN106995461 B CN 106995461B CN 201710122111 A CN201710122111 A CN 201710122111A CN 106995461 B CN106995461 B CN 106995461B
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Abstract
The present invention discloses a kind of Phosphine ligands and its preparation method and application of structure containing benzofuran, which is the compound or its enantiomer or raceme with chemical structural formula shown in formula (I).Phosphine ligands of the invention have introduced furan nucleus, and the cloud density of aromatic rings increases, and steric hindrance changes, so that the Phosphine ligands are applied has the characteristics that reactivity is good, yield is up to 99% in the Suzuki-Miyaura model reaction of palladium chtalyst.The Phosphine ligands of present invention structure containing benzofuran, synthetic method is simple, low in cost, and the palladium chtalyst Suzuki-Miyaura suitable for a variety of substrates reacts.
Description
Technical field
The invention belongs to the research and development of chemical catalysis field more particularly to phosphine complex, and in particular to one kind contains benzo
Phosphine ligands of furan structure and its preparation method and application.
Background technique
The Suzuki-Miyaura coupling reaction of palladium chtalyst is to generate that carbon-carbon bond is most effective, one of most straightforward approach,
It is widely used in the synthesis of the natural products containing biaryl structure, pharmaceutical intermediate and functional material, its advantage is that right
The scope of application of reaction substrate functional group is wider, and the organoboron reagent of one of reactant is with toxicity is low, stability is good, easy
In preparation the advantages that.Meanwhile asymmetric Suzuki-Miyaura coupling reaction becomes research hotspot in recent years, in palladium chtalyst
Axial chirality list phosphine system in terms of, Buchwald seminar (S)-KenPhos is ligand, Pd2(dba)3For palladium source, realize
The bromo- 2- naphthalene-phosphite ester of 1- is reacted with the catalysis asymmetry Suzuki-Miyaura of 2- alkylboronic acids.Qiu Liqin seminar
Design has synthesized bridge chain axial chirality phosphine oxide ligand and aminophosphine ligand in recent years, and the asymmetric Suzuki for applying to palladium chtalyst is anti-
It answers, while guaranteeing high yield, the enantioselectivity of most products is up to 90% or more.
In Suzuki-Miyaura reaction, ligand is of crucial importance the catalytic effect of reaction, research
It was found that: biphenyl class monophosphorus ligand Sphos (2- dicyclohexylphosphontetrafluoroborate -2', 6'- dimethoxy-biphenyl) can be suitably used for carbon-carbon bond formation
A plurality of types of aryl compounds are constructed, are used cooperatively with palladium, are demonstrated by high activity, and most of reaction energy in the reaction
It accesses in high yield.Then with the X-phos (2- dicyclohexyl phosphorus -2', 4', 6'- tri isopropyl biphenyl) of Sphos similar structures
It can be applied to the cross-coupling reaction of halogenated aryl, alkylene and heterocyclic aryl, generate C-N key, generate aryl amination product.
Kuang Fuer seminar has synthesized a series of monophosphorus ligands containing indole structure in 2007, is used for chlorinated aromatic hydrocarbons
Suzuki coupling reaction.In 2008, which designs again synthesized a series of other types of indoles monophosphorus ligands.
Different substrates and the requirement reacted to catalyst be not also identical, therefore the exploitation and application of various Novel Ligands
Research, either academic or application above suffer from important value.
Summary of the invention
The object of the present invention is to provide a kind of Novel phosphine ligand, which contains benzofuran structure.
It is a further object to provide the preparation methods of above-mentioned Phosphine ligands.
It is a further object to provide the applications of above-mentioned Phosphine ligands.
Above-mentioned purpose of the invention is achieved by following scheme:
A kind of Phosphine ligands of the structure containing benzofuran, the Phosphine ligands are the compounds with chemical structural formula shown in formula (I)
Or its enantiomer or raceme:
In formula,
R is aryl, alkyl, naphthenic base, heterocycle, substituted aryl, replaces alkyl, substituted cycloalkyl or substituted heterocyclic radical
In any one；
Y1~Y9For hydrogen, fluorine, chlorine, bromine, iodine, aryl, alkyl, alkoxy, amino, monoalkyl substituted amido, N, N- dioxane
Base substituted amido, naphthenic base, heterocycle, trifluoromethyl, trimethyl silicon substrate, triethyl group silicon substrate, triphenyl silicon substrate, substituted aryl,
Replace any one in alkyl, substituted cycloalkyl or substituted heterocyclic radical；Y1~Y9It is preferably all hydrogen.
Above-mentioned aryl is the aryl that carbon atom number is 6-20.
Abovementioned alkyl is the alkyl that carbon atom number is 1-20.
Above-mentioned naphthenic base is the naphthenic base of 3-8 member ring.
Above-mentioned heterocycle is the heterocycle that the carbon atom number of oxygen-containing, sulphur or nitrogen-atoms is 3-20.
Above-mentioned substituted aryl replaces the substitution in alkyl, substituted cycloalkyl and substituted heterocyclic radical to refer to containing halogen, trifluoro
The alkyl or carbon atom number that methyl, carbon atom number are 1-20 are any one in the alkoxy of 1-20.
Alkyl in above-mentioned alkoxy is the alkyl that carbon atom number is 1-20, constitutes its alkoxy (alcoxyl in the present invention
Base makees this definition).
The alkyl that alkyl in above-mentioned monoalkyl substituted amido is carbon atom number 1-20；
Alkyl in above-mentioned N, N- dialkyl group substituted amido is the alkyl that carbon atom number is 1-20.
The present invention is with Y1~Y9It is preferably all for hydrogen, the preparation method of compound shown in introduction type (I).
Step 1
Using beta naphthal as starting material, N- N-halosuccinimides are added, and (halogen of the N- N-halosuccinimides is
Iodine, bromine or chlorine), appropriate organic solvent and ammonium acetate, react 1~36h, after reaction purified processing at -10 DEG C~50 DEG C
It obtains compound 1 (halogenated beta naphthal), shown in the structural formula such as formula (II) of the compound 1:
X in above-mentioned formula (II) is iodine, bromine or chlorine.
In above-mentioned steps 1, the organic solvent be acetonitrile, toluene, benzene, dimethylbenzene, ether, ethyl alcohol, methanol, acetic acid, N,
Dinethylformamide, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, ethyl acetate, tetrahydrofuran, 1,4- dioxy six
Any one in ring, dimethyl sulfoxide, glycol dimethyl ether, glycol monoethyl ether or carbon disulfide；The beta naphthal and
The molar ratio of N- N-halosuccinimides is 1:(1~1.2)；The ammonium acetate and N- N-halosuccinimides react mole
Than for (0.01~1): 1.
In above-mentioned steps 1, the purification process is after reaction mixture revolving is removed solvent, by crude by column chromatography
Purifying obtains compound 1 (halogenated beta naphthal).
Step 2
Compound 1 is reacted in appropriate organic solvent with organic base, trifluoromethanesulfanhydride anhydride, reaction temperature is -20~20
DEG C, the reaction time is 1~36h, and purified processing obtains compound 2, the structural formula such as formula of the compound 2 after reaction
(III) shown in:
In above-mentioned steps 2, the reaction molar ratio of the compound 1 and organic base is 1:(1~5)；1 He of compound
The reaction molar ratio of trifluoromethanesulfanhydride anhydride is 1:(1~4)；The organic base be trimethylamine, triethylamine, tripropyl amine (TPA), tri-n-butylamine,
N, N- diisopropylethylamine, tetramethylethylenediamine, pyridine, N, N- lutidines, 1,4- lupetazin, 1- methyl piperidine,
Any one in 1- methylpyrrole or quinoline；The organic solvent is toluene, benzene, dimethylbenzene, ether, ethyl alcohol, methanol, second
Acid, N,N-dimethylformamide, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, ethyl acetate, tetrahydrofuran, 1,4- bis-
Any one in six ring of oxygen, dimethyl sulfoxide, glycol dimethyl ether, glycol monoethyl ether or carbon disulfide.
In above-mentioned steps 2, the purification process is that saturated sodium bicarbonate solution is first added into reaction mixture, is adjusted
PH separates organic phase, water phase organic solvent extracts three times, merges organic phase, by organic phase anhydrous sodium sulfate to meta-alkalescence
Dry 15min back spin boils off solvent, then purifies crude by column chromatography to obtain compound 2；In the extraction step, often
The volume ratio of organic solvent and liquid to be extracted is (0.1~2) when secondary extraction: 1.
Step 3
By compound 2 and formula (IV) described compound 3, organic base, palladium catalyst and ligand in appropriate organic solvent into
Row catalysis reaction, reaction temperature are 20~110 DEG C, and the reaction time is 1~60h, and purified processing obtains after reaction for catalysis
Compound 4, shown in the structural formula such as formula (V) of the compound 4:
In above-mentioned steps 3, the compound 2 is 1:(1~3 with the molar ratio of reacting of compound 3)；The compound 2 with
The reaction molar ratio of organic base is 1:(1~5)；The compound 2 is 1:(0.01~1 with the molar ratio of reacting of palladium catalyst)；
The compound 2 is 1:(0.01~1 with the molar ratio of reacting of ligand)；The organic base be trimethylamine, triethylamine, tripropyl amine (TPA),
Tri-n-butylamine, N, N- diisopropylethylamine, tetramethylethylenediamine, pyridine, N, N- lutidines, 1,4- lupetazin, 1- first
Any one in phenylpiperidines, 1- methylpyrrole or quinoline；The organic solvent be toluene, benzene, dimethylbenzene, ether, ethyl alcohol,
Methanol, acetic acid, N, N- dimethylformamide, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, ethyl acetate, tetrahydro furan
It mutters, any one in 1,4- dioxane, dimethyl sulfoxide, glycol dimethyl ether, glycol monoethyl ether or carbon disulfide；
The palladium catalyst is Pd (OAc)2、PdCl2Or Pd2(dba)3In any one；The ligand is dppb, dppp, dppf
Or Sphos, the dppb are bis- (diphenylphosphine) butane of Isosorbide-5-Nitrae-, the dppp is bis- (diphenylphosphine) propane of 1,3-, described
Dppf is bis- (diphenylphosphine) ferrocene of 1,1'-, the Sphos be 2- dicyclohexylphosphontetrafluoroborate -2 ', 6 '-dimethoxy-biphenyls.
In above-mentioned steps 3, the purification process is that reaction mixture is first cooled to room temperature, and organic solvent is then added
Dilution adds 1mol/L hydrochloric acid and separates organic phase, and water phase organic solvent extracts three times, merges organic phase, organic phase is used
The dry 15min back spin of anhydrous sodium sulfate boils off solvent, then purifies crude by column chromatography to obtain compound 4；The dilution
In step, the volume ratio of organic solvent and reaction mixture is (0.2~1): 1；1 mol/L hydrochloric acid of the addition separates organic
In the step of phase, the volume ratio of hydrochloric acid and organic base is 15:1；In the extraction step, every time extraction when organic solvent with to
The volume ratio of extract liquor is (0.1~2): 1.
Step 4
By compound 5 shown in compound 4 and formula (VI), (compound 5 is benzofuran -7- boric acid pinacol ester, originally
The compound 5 of invention uses commercial product), inorganic base, palladium catalyst and ligand prepare in appropriate organic solvent and suitable quantity of water
The volume ratio of in the mixed solvent progress catalyzed coupling reaction, the in the mixed solvent organic solvent and water is (1~100): 1, it urges
Changing reaction temperature is 20~100 DEG C, and the reaction time is 1~80h, and purified processing obtains compound 6 after reaction, described
Shown in the structural formula of compound 6 such as formula (VII).
In above-mentioned steps 4, the compound 4 is 1:(1~3 with the molar ratio of reacting of compound 5)；The compound 4 with
Reaction molar ratio 1:(1~5 of inorganic base)；The compound 4 is 1:(0.01~1 with the molar ratio of reacting of palladium catalyst)；Institute
It is 1:(0.01~1 that compound 4, which is stated, with the molar ratio of reacting of ligand)；The inorganic base is sodium hydroxide, potassium hydroxide, carbonic acid
Any one in sodium, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride or potassium phosphate；The organic solvent is toluene, benzene, two
Toluene, ether, ethyl alcohol, methanol, acetic acid, N,N-dimethylformamide, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, second
Acetoacetic ester, tetrahydrofuran, 1,4- dioxane, dimethyl sulfoxide, glycol dimethyl ether, glycol monoethyl ether or carbon disulfide
In any one；The palladium catalyst is Pd (OAc)2、PdCl2Or Pd2(dba)3In any one；The ligand is
Any one in dppb, dppp, dppf or Sphos.
In above-mentioned steps 4, the purification process is first to rotate reaction mixture to remove solvent, then by crude product through column
Chromatographic purifying obtains compound 6.
Step 5
Compound 6 and organic base, trichlorosilane are subjected to reduction reaction, reaction temperature 20 in appropriate organic solvent
~120 DEG C, the reaction time is 1~36h, and purified processing obtains compound 7, the structural formula of the compound 7 after reaction
Such as formula (I) (Y1~Y9When being hydrogen) shown in.
In above-mentioned steps 5, the compound 6 is 1:(1~20 with the molar ratio of reacting of trichlorosilane)；The organic base
Molar ratio of reacting with trichlorosilane is (1.5~3): 1；The organic base be trimethylamine, triethylamine, tripropyl amine (TPA), tri-n-butylamine,
N, N- diisopropylethylamine, tetramethylethylenediamine, pyridine, N, N- lutidines, 1,4- lupetazin, 1- methyl piperidine,
Any one in 1- methylpyrrole or quinoline；The organic solvent is toluene, benzene, dimethylbenzene, ether, ethyl alcohol, methanol, second
Acid, N,N-dimethylformamide, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, ethyl acetate, tetrahydrofuran, 1,4- bis-
Any one in six ring of oxygen, dimethyl sulfoxide, glycol dimethyl ether, glycol monoethyl ether or carbon disulfide.
In above-mentioned steps 5, the purification process is organic solvent diluting to be first added into reaction mixture, then use 1mol/
The sodium hydroxide solution of L filters after being quenched, and after filtrate is extracted three times with organic solvent, merges organic phase, successively by organic phase
After 1mol/L hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt water washing, then the dry 15min of anhydrous sodium sulfate is rotated
Crude by column chromatography is purified to obtain compound 7 after removing solvent；In the dilution step, organic solvent and reaction mixture
Volume ratio be (0.5~2): 1；In the extraction step, the volume ratio of organic solvent and liquid to be extracted is when extraction every time
(0.2~2): 1.
The present invention is with Y1~Y9It is preferably all for hydrogen, the mapping preparation of compound shown in introduction type (I).It is pressing
After obtaining the compound 6 of racemization shown in formula (VII) according to the above method, chiral resolution is carried out, reaction is then restored again and obtains
Optically pure chiral ligand, detailed process is as follows shown in structural formula:
Step 1
By HPLC method, using CHIRALPAK AD-H preparative chiral column to the compound 6 of racemization shown in formula (VII) into
Row is split, and respectively obtains optically pure (+) -6 or (-) -6；
Step 2
After obtaining (+) -6 or (-) -6, it is restored, respectively obtains (+) -7 and (-) -7, restoring method with it is above-mentioned
The raceme step 5 for preparing ligand is identical.
The Phosphine ligands of present invention structure containing benzofuran can be applied in palladium chtalyst Suzuki-Miyaura coupling reaction
In, when using chlorinated aromatic hydrocarbons perhaps aryl bromide as substrate with aryl boric acid or the aryl boric acid containing heterocycle carry out Suzuki-
Miyaura coupling reaction, the reactive applications ligand all have very high catalytic activity and yield under the catalysis of palladium.
Compared with prior art, the invention has the following beneficial effects:
1. the present invention innovatively develops the monophosphorus ligand containing benzofuran structure, synthetic method is simple, passes through
Ji, especially after having introduced furan nucleus, increases the cloud density of aromatic rings, changes steric hindrance, so that institute
Ligand have the advantages that reactivity is good, high income in the Suzuki-Miyaura model reaction of palladium chtalyst.
2. the present inventor is had found by experimental verification, whether the higher bromo-derivative of reactivity, or activity is poor
Chloro thing carries out for most of reaction substrates in the palladium of the ligand and 0.5~2mol% that add 0.5~2mol%
Suzuki-Miyaura reaction obtains good catalytic effect, part reaction yield is up in the case of reacting 0.5~14h
99%.
Specific embodiment
The present invention is further described through combined with specific embodiments below, but specific embodiment is not the present invention
Any restriction.
1 1- of embodiment (7 '-benzofuranyl) -2- diphenylphosphine naphthalene
The Y of the compound shown in formula (I)1~Y9It is hydrogen, when R is Ph, then the name of the compound is 1- (7 '-benzos
Furyl) -2- diphenylphosphine naphthalene, the preparation method of abbreviation L1, the compound includes the following steps:
The preparation of the bromo- beta naphthal of step 1 1-
17g (117.91mmol) beta naphthal is taken, 182mg (2.36mmol) ammonium acetate is dissolved in 200mL acetonitrile, is stirred several
After minute, 22.04g (123.81 mmol) N- bromo-succinimide is slowly added under ice bath, after adding, system is warmed to room temperature
About 4h is reacted, revolving goes crude by column chromatography after solvent to purify to obtain the bromo- beta naphthal of 1-, yield 80%.
Shown in the structural formula such as formula (II) of the bromo- beta naphthal of 1-, X is derived from Br.
The analysis result of the bromo- beta naphthal of 1-:1H NMR(400MHz,CDCl3) δ 8.06 (d, J=8.5Hz, 1H), 7.81
(d, J=8.1Hz, 1H), 7.77 (d, J=8.8Hz, 1H), 7.60 (t, J=7.7Hz, 1H), 7.42 (t, J=7.5Hz, 1H),
7.30 (d, J=8.8Hz, 1H), 5.95 (s, 1H).
The preparation of the bromo- 2- trifluoromethanesulfonate naphthalene of step 2 1-
The bromo- beta naphthal of 10g (44.83mmol) 1-, 7.09g (89.66mmol) anhydrous pyridine are taken, 150mL anhydrous two is dissolved in
In chloromethanes, under ice bath, nitrogen protection, it is slowly added to 18.97 g (67.24mmol) trifluoromethanesulfanhydride anhydride, after adding, is slowly risen
It is stayed overnight to normal-temperature reaction, saturated sodium bicarbonate solution is then added into reaction mixture, adjusted pH to meta-alkalescence, separated
Machine phase, then merge organic phase altogether three times with 20mL ethyl acetate aqueous phase extracted, organic phase is dry with anhydrous sodium sulfate
15min back spin boils off solvent, then purifies crude by column chromatography to obtain the bromo- 2- trifluoromethanesulfonate naphthalene 15.76g of 1-, produces
Rate is 99%.
Shown in the structural formula such as formula (III) of the bromo- 2- trifluoromethanesulfonate naphthalene of 1-, X is derived from Br.
The analysis result of the bromo- 2- trifluoromethanesulfonate naphthalene of 1-:1H NMR(400MHz,CDCl3) δ 8.34 (d, J=8.5Hz,
1H), 7.91 (d, J=8.7Hz, 2H), 7.72 (t, J=7.7Hz, 1H), 7.64 (t, J=7.5Hz, 1H), 7.46 (d, J=
9.0Hz,1H).19F NMR(377 MHz,CDCl3)δ-73.37(s)。
The preparation of step 3 (the bromo- 2- naphthalene of 1-) diphenyl phosphine oxide
Compound shown in the formula (IV) of the present embodiment uses diphenyl phosphine oxide.
The bromo- 2- trifluoromethanesulfonate naphthalene of 7.1g (20mmol) 1- and the diphenylphosphine oxygen of 4.85g (24mmol) are taken, then
5.24mL (30mmol) diisopropylethylamine, 460mg (0.5mmol) Pd is added2(dba)3It is molten with 412mg (1.0mmol) dppp
In about 100mL dry toluene, under nitrogen protection, it is warming up to 110 DEG C of reactions overnight, reaction mixture is then cooled to room
The dilution of 80mL ethyl acetate is added in temperature, adds 80mL 1mol/L hydrochloric acid and separates organic phase, then is extracted with 40mL ethyl acetate
Water phase merges organic phase altogether three times, and organic phase is boiled off solvent with the dry 15min back spin of anhydrous sodium sulfate, then will slightly be produced
Object obtains compound shown in 4.89g formula (V) through column chromatographic purifying, and X is derived from Br, and R is derived from Ph, yield 60%.
Product analysis result:1H NMR(400MHz,CDCl3)δ8.47–8.39(m,1H), 7.91–7.86(m,1H),
7.84-7.73 (m, 5H), 7.66 (dd, J=5.6,3.8Hz, 2H), 7.58 (t, J=7.2Hz, 2H), 7.51 (d, 1H), 7.49
(d, J=2.3Hz, 2H), 7.47 (d, J=3.1Hz, 1H), 7.44 (d, J=3.0Hz, 1H)13C NMR(101MHz,CDCl3)
δ 135.80,132.81,132.72,132.53,132.20,132.10,131.97,131.94,131.46, 131.24,
130.06,129.95,128.87,128.67,128.55,128.30,128.28,128.05, 127.62,127.51.31P NMR
(162MHz,CDCl3)δ31.55.
The preparation of step 4 [1- (7 '-benzofuranyl) -2- naphthalene] diphenyl phosphine oxide
Compound, 449 mg (1.84mmol) benzo furan shown in 375mg (0.92mmol) formula (V) are added in reaction flask
Mutter -7- boric acid pinacol ester, 585mg (2.76mmol) potassium phosphate, 42mg (0.046mmol) Pd2(dba)3And 38mg
(0.092mmol) Sphos, and the mixed solvent prepared by 7mL toluene and 0.7mL water is added, under nitrogen protection, it is warming up to 80
About 8h is reacted after DEG C, reaction mixture revolving is removed into solvent after reaction, then then prepares crude by column chromatography purifying
Compound shown in 274mg formula (VII) is obtained, R is derived from Br, yield 67%.
Product analysis result:1H NMR(400MHz,CDCl3) δ 7.99-7.90 (m, 2H), 7.74 (dd, J=11.3,
7.4Hz, 2H), 7.68 (dd, J=11.8Hz, 7.9Hz, 1H), 7.56 (t, J=7.3Hz, 1H), 7.48-7.42 (m, 2H),
7.38 (dd, J=12.1,7.8Hz, 5H), 7.32 (d, J=7.2Hz, 1H), 7.27 (d, J=8.3Hz, 2H), 7.19 (d, J=
7.6Hz, 1H), 7.13 (t, J=7.6Hz, 1H), 7.07-6.98 (m, 2H), 6.55 (d, J=1.8Hz, 1H)13C NMR
(101MHz,CDCl3)δ152.43,144.16,141.15,141.06, 134.73,134.71,133.48,132.84,
132.73,132.65,132.44,131.90,131.81, 131.60,131.34,131.31,130.74,130.54,
130.51,130.16,130.06,129.72, 128.79,128.67,128.54,128.26,128.14,128.05,
127.92,127.32,127.20, 127.06,126.97,126.37,122.26,121.71,121.40,121.35,
106.47.31P NMR (162MHz,CDCl3)δ27.88.
The preparation of step 5 1- (7 '-benzofuranyl) -2- diphenylphosphine naphthalene (L1)
Compound, 2.07 g (16mmol) N, N- diisopropyl shown in 356mg (0.8mmol) formula (VII) are added in reaction flask
Base ethamine and 20mL toluene under nitrogen protection, then add 1.08g (8mmol) trichlorosilane, 100 DEG C of heated overnight at reflux, instead
After answering, the dilution of 30mL ethyl acetate, mistake after being quenched with the sodium hydroxide solution of 1mol/L are added into reaction mixture
Filter is merged organic phase, organic phase is successively used to 1mol/L hydrochloric acid, saturated carbon altogether three times with 20mL ethyl acetate aqueous layer extracted
After sour hydrogen sodium solution and saturated common salt water washing, the dry 15min of anhydrous sodium sulfate, crude product is through column after then revolving removes solvent
Chromatographic purifying respectively obtains L1 309mg, yield 90%.
Product analysis result:1H NMR(400MHz,CDCl3) δ 7.91 (d, J=8.2Hz, 1H), 7.87 (d, J=
8.5Hz, 1H), 7.69 (dd, J=7.8,0.9Hz, 1H), 7.54-7.49 (m, 1H), 7.41-7.36 (m, 3H), 7.36-7.28
(m, 6H), 7.27-7.18 (m, 6H), 7.12 (d, J=7.3Hz, 1H), 6.80 (d, J=2.2Hz, 1H)13C NMR
(101MHz, CDCl3)δ145.08,133.81,133.68,133.62,133.48,129.84,128.39,128.37,
128.32,128.17,128.13,128.07,128.02,127.26,126.98,126.95,126.69, 126.55,
126.45,122.47,121.04,106.57.31P NMR(162MHz,CDCl3)δ -12.50。
2 1- of embodiment (7 '-benzofuranyl) -2- two (4- aminomethyl phenyl) phosphine naphthalene
The Y of the compound shown in formula (I)1~Y9It is hydrogen, when R is 4- aminomethyl phenyl, then the name of the compound is 1-
(7 '-benzofuranyl) -2- two (4- aminomethyl phenyl) phosphine naphthalene, the preparation method of abbreviation L2, the compound include the following steps:
Step 1 and 2 process referring to embodiment 1.
The preparation of two (4- aminomethyl phenyl) phosphine oxide of step 3 (the bromo- 2- naphthalene of 1-)
Compound shown in the formula (IV) of the present embodiment uses two (4- aminomethyl phenyl) phosphine oxides.
Take the bromo- 2- trifluoromethanesulfonate naphthalene of 7.1g (20mmol) 1- and two (the 4- methylbenzenes of 5.53g (24mmol)
Base) phosphine oxygen, add 5.2mL (30mmol) diisopropylethylamine, 460mg (0.5mmol) Pd2(dba)3And 412mg
(1.0mmol) dppp is dissolved in about 100mL dry toluene, under nitrogen protection, is warming up to 110 DEG C of reactions overnight, then will be anti-
It answers mixture to be cooled to room temperature, the dilution of 80mL ethyl acetate is added, adds 1 mol/L hydrochloric acid of 80mL and separates organic phase, then use
40mL ethyl acetate aqueous phase extracted merges organic phase altogether three times, and organic phase is boiled off with the dry 15min back spin of anhydrous sodium sulfate
Then solvent purifies crude by column chromatography to obtain compound shown in 4.53g formula (V), X is derived from Br, and R is derived from 4- methyl
Phenyl, yield 52%.
Product analysis result:1H NMR(400MHz,CDCl3)δ8.47–8.40(m,1H), 7.89–7.84(m,1H),
7.81 (d, J=8.4Hz, 1H), 7.64 (dd, J=11.9,8.0Hz, 1H), 7.44 (dd, J=11.4,8.6Hz, 1H), 7.30
(d, J=8.3Hz, 1H), 2.44 (s, 1H)13C NMR(101MHz,CDCl3)δ142.35,142.32,135.75,132.83,
132.75,132.19,132.09,131.82,130.78,130.15,130.04,129.87,129.83, 129.57,
129.39,129.26,128.71,128.47,128.26,128.17,128.07,127.47, 127.35,21.67.31P NMR
(162MHz,CDCl3)δ31.70.
The preparation of step 4 [1- (7 '-benzofuranyl) -2- naphthalene] two (4- aminomethyl phenyl) phosphine oxides
Compound, 449 mg (1.84mmol) benzo furan shown in 400mg (0.92mmol) formula (V) are added in reaction flask
Mutter -7- boric acid pinacol ester, 585mg (2.76mmol) potassium phosphate, 42mg (0.046mmol) Pd2(dba)3And 38mg
(0.092mmol) Sphos, and the mixed solvent prepared by 7mL toluene and 0.7mL water is added, under nitrogen protection, it is warming up to 80
About 8h is reacted after DEG C, reaction mixture revolving is removed into solvent after reaction, then then prepares crude by column chromatography purifying
Compound shown in 265mg formula (VII) is obtained, R is derived from 4- aminomethyl phenyl, yield 61%.
Product analysis result:1H NMR(400MHz,CDCl3) δ 7.94 (d, J=8.3Hz, 2H), 7.71 (dd, J=
11.7,8.8Hz, 1H), 7.64-7.53 (m, 4H), 7.41 (t, J=7.3 Hz, 2H), 7.36-7.30 (m, 2H), 7.27-7.22
(m, 3H), 7.22-7.19 (m, 1H), 7.17 (d, J=7.4Hz, 3H), 6.82 (d, J=6.4Hz, 2H), 6.56 (d, J=
1.1Hz, 1H),2.37(s,3H),2.20(s,3H).13C NMR(101MHz,CDCl3)δ152.46, 148.92,144.04,
143.98,141.49,141.12,140.62,140.54,134.65,134.21, 132.85,132.55,131.86,
131.76,131.63,130.43,130.38,130.15,130.05, 129.99,128.92,128.80,128.67,
128.59,128.36,128.08,128.03,127.90, 127.83,127.79,127.75,127.68,127.03,
126.94,126.80,126.69,126.33, 126.15,122.24,121.79,121.39,121.25,106.16,21.51,
21.34.31P NMR (162MHz,CDCl3)δ27.65.
The preparation of step 5 1- (7 '-benzofuranyl) (4- aminomethyl phenyl) the phosphine naphthalene of -2- two (L2)
Compound, 2.07 g (16mmol) N, N- diisopropyl shown in 378mg (0.8mmol) formula (VII) are added in reaction flask
Base ethamine and 20mL toluene under nitrogen protection, then add 1.08g (8mmol) trichlorosilane, 100 DEG C of heated overnight at reflux, instead
After answering, the dilution of 30mL ethyl acetate, mistake after being quenched with the sodium hydroxide solution of 1mol/L are added into reaction mixture
Filter is merged organic phase, organic phase is successively used to 1mol/L hydrochloric acid, saturated carbon altogether three times with 20mL ethyl acetate aqueous layer extracted
After sour hydrogen sodium solution and saturated common salt water washing, the dry 15min of anhydrous sodium sulfate, crude product is through column after then revolving removes solvent
Chromatographic purifying respectively obtains L2 336mg, yield 92%.
Product analysis result:1H NMR(400MHz,CDCl3) δ 7.90 (d, J=8.2Hz, 1H), 7.86 (d, J=
8.5Hz, 1H), 7.69 (d, J=7.8Hz, 1H), 7.54-7.48 (m, 1H), 7.40 (t, J=3.7Hz, 1H), 7.38-7.32
(m, 3H), 7.28 (t, J=7.5Hz, 1H), 7.21-7.12 (m, 5H), 7.12-7.08 (m, 2H), 7.04 (d, J=7.4Hz,
2H), 6.81 (d, J=2.1Hz, 1H), 2.38 (s, 3H), 2.33 (s, 3H)13C NMR(101MHz, CDCl3)δ153.16,
144.99,141.12,140.80,138.21,137.95,135.90,135.78, 134.42,134.31,134.28,
134.17,133.81,133.67,133.61,133.47,133.43, 132.65,132.59,129.80,129.20,
129.14,128.92,128.86,128.20,128.01, 127.22,127.02,126.98,126.54,126.35,
123.59,123.50,122.45,120.97, 106.53,21.35,21.29.31P NMR(162MHz,CDCl3)δ-14.04.
3 1- of embodiment (7 '-benzofuranyl) -2- two (3,5- di-tert-butyl-phenyl) phosphine naphthalene
The Y of the compound shown in formula (I)1~Y9 is hydrogen, R 3, when 5- di-tert-butyl-phenyl, then the name of the compound
Word is 1- (7 '-benzofuranyl) -2- two (3,5- di-tert-butyl-phenyl) phosphine naphthalene, abbreviation L3, the preparation method packet of the compound
Include following steps:
Step 1 and 2 process referring to embodiment 1.
The preparation of two (3,5- di-tert-butyl-phenyl) phosphine oxide of step 3 (the bromo- 2- naphthalene of 1-)
Compound shown in the formula (IV) of the present embodiment uses two (3,5- di-tert-butyl-phenyl) phosphine oxygen.
Take the bromo- 2- trifluoromethanesulfonate naphthalene of 7.1g (20mmol) 1- and two (3,5- bis- uncles of 10.24g (24mmol)
Butyl phenyl) phosphine oxygen, add 5.24mL (30mmol) diisopropylethylamine, 460mg (0.5mmol) Pd2(dba)3And 412mg
(1.0mmol) dppp is dissolved in about 100mL dry toluene, under nitrogen protection, is warming up to 110 DEG C of reactions overnight, then will be anti-
It answers mixture to be cooled to room temperature, the dilution of 80mL ethyl acetate is added, adds 80mL 1mol/L hydrochloric acid and separates organic phase, then use
40mL ethyl acetate aqueous phase extracted merges organic phase altogether three times, and organic phase is boiled off with the dry 15min back spin of anhydrous sodium sulfate
Then solvent purifies crude by column chromatography to obtain compound shown in 7.46g formula (V), X is derived from Br, and R is derived from 3,5- bis-
Tert-butyl-phenyl, yield 59%.
Product analysis result:1H NMR(400MHz,CDCl3) δ 8.44 (dd, J=6.3,3.4 Hz, 1H), 7.88 (d, J=
7.6Hz, 2H), 7.72-7.68 (m, 1H), 7.67-7.63 (m, 3H), 7.62 (s, 3H), 7.58 (d, J=1.2Hz, 2H),
1.29(s,36H).13C NMR(101 MHz,CDCl3)δ150.89,150.76,130.36,130.26,128.49,128.25,
128.04, 127.97,127.44,126.63,126.52,125.73,125.71,35.04,31.34.31P NMR (162MHz,
CDCl3)δ33.56.
The preparation of step 4 [1- (7 '-benzofuranyl) -2- naphthalene] two (3,5- di-tert-butyl-phenyl) phosphine oxides
Compound, 449 mg (1.84mmol) benzo furan shown in 581mg (0.92mmol) formula (V) are added in reaction flask
Mutter -7- boric acid pinacol ester, 585mg (2.76mmol) potassium phosphate, 42mg (0.046mmol) Pd2(dba)3And 38mg
(0.092mmol) Sphos, and the mixed solvent prepared by 7mL toluene and 0.7mL water is added, under nitrogen protection, it is warming up to 80
About 8h is reacted after DEG C, reaction mixture revolving is removed into solvent after reaction, then then prepares crude by column chromatography purifying
Compound shown in 413mg formula (VII) is obtained, R is derived from 3,5- di-tert-butyl-phenyl, yield 67%.
Product analysis result:1H NMR(400MHz,CDCl3) δ 7.93 (d, J=8.2Hz, 2H), 7.64 (s, 1H),
7.62-7.55 (m, 3H), 7.54 (s, 2H), 7.45-7.39 (m, 2H), 7.31 (s, 2H), 7.26 (d, J=8.3Hz, 2H),
7.22–7.08(m,2H),6.55(s,1H), 1.31(s,17H),1.20(s,18H).13C NMR(101MHz,CDCl3)δ
150.49, 150.38,149.71,149.59,144.56,129.13,128.74,128.62,127.99,127.65,
127.59,127.47,127.04,126.61,126.23,126.14,126.06,125.44,124.73, 124.62,
121.83,121.44,105.96,35.02,34.76,31.39,31.32.31P NMR (162MHz,CDCl3)δ28.43.
The preparation of step 5 1- (7 '-benzofuranyl) (3,5- di-tert-butyl-phenyl) the phosphine naphthalene of -2- two (L3)
Compound, 2.07 g (16mmol) N, N- diisopropyl shown in 536mg (0.8mmol) formula (VII) are added in reaction flask
Base ethamine and 20mL toluene under nitrogen protection, then add 1.08g (8mmol) trichlorosilane, 100 DEG C of heated overnight at reflux, instead
After answering, the dilution of 30mL ethyl acetate, mistake after being quenched with the sodium hydroxide solution of 1mol/L are added into reaction mixture
Filter is merged organic phase, organic phase is successively used to 1mol/L hydrochloric acid, saturated carbon altogether three times with 20mL ethyl acetate aqueous layer extracted
After sour hydrogen sodium solution and saturated common salt water washing, the dry 15min of anhydrous sodium sulfate, crude product is through column after then revolving removes solvent
Chromatographic purifying respectively obtains L3 476mg, yield 92%.
Product analysis result:1H NMR(400MHz,CDCl3) δ 7.90 (d, J=8.2Hz, 1H), 7.86 (d, J=
8.6Hz, 1H), 7.68 (d, J=7.8Hz, 1H), 7.50 (t, J=8.9Hz, 1H), 7.37 (d, J=1.9Hz, 5H), 7.29
(d, J=8.1Hz, 2H), 7.17 (d, J=8.1 Hz, 2H), 7.12 (d, J=7.3Hz, 1H), 7.07 (dd, J=11.2,
5.3Hz,2H),6.79(s, 1H),1.27(s,18H),1.23(s,18H).13C NMR(101MHz,CDCl3)δ144.96,
129.83,128.37,128.16,128.06,127.95,127.86,127.75,126.24,126.10, 122.36,
122.17,121.98,120.81,106.45,34.89,34.79,31.44,31.39.31P NMR(162MHz,CDCl3)δ-
9.45.
4 1- of embodiment (7 '-benzofuranyl) -2- two (3,5- di-t-butyl -4- methoxyphenyl) phosphine naphthalene
The Y of the compound shown in formula (I)1~Y9It is hydrogen, R 3, when 5- di-t-butyl -4- methoxyphenyl, then the change
The name for closing object is 1- (7 '-benzofuranyl) -2- two (3,5- di-t-butyl -4- methoxyphenyl) phosphine naphthalene, and abbreviation L4 should
The preparation method of compound includes the following steps:
Step 1 and 2 process referring to embodiment 1.
The preparation of step 3 (the bromo- 2- naphthalene of 1-) two (3,5- di-t-butyl -4- methoxyphenyl) phosphine oxide
Compound shown in the formula (IV) of the present embodiment uses two (3,5- di-t-butyl -4- methoxyphenyl) phosphine oxides.
Take the bromo- 2- trifluoromethanesulfonate naphthalene of 7.1g (20mmol) 1- and two (3,5- bis- uncles of 11.68g (24 mmol)
Butyl -4- methoxyphenyl) phosphine oxygen, add 5.2mL (30 mmol) diisopropylethylamine, 460mg (0.5mmol) Pd2
(dba)3It with 412mg (1.0 mmol) dppp, is dissolved in about 100mL dry toluene, under nitrogen protection, is warming up to 110 DEG C of reactions
Overnight, reaction mixture is then cooled to room temperature, the dilution of 80mL ethyl acetate is added, adds 80mL 1mol/L hydrochloric acid point
Organic phase out, then merge organic phase altogether three times with 40mL ethyl acetate aqueous phase extracted, organic phase is dry with anhydrous sodium sulfate
15min back spin boils off solvent, then purifies crude by column chromatography to obtain compound shown in 8.3g formula (V), and X is derived from Br,
R is derived from 3,5- di-t-butyl -4- methoxyphenyl, yield 60%.
Product analysis result:1H NMR(400MHz,CDCl3) δ 8.44 (dd, J=6.1,3.4 Hz, 1H), 7.90 (t, J=
7.4Hz, 2H), 7.77 (dd, J=10.7,8.9Hz, 1H), 7.68-7.63 (m, 2H), 7.60 (d, J=13.1Hz, 4H),
3.72(s,6H),1.36(s,36H).13C NMR(101MHz,CDCl3)δ162.74,162.71,144.09,143.96,
135.73, 132.66,131.34,131.08,130.96,130.34,130.25,128.51,128.29,128.02,
127.52,127.41,126.13,125.02,64.48,35.98,31.91.31P NMR(162MHz, CDCl3)δ33.20。
The system of two (3,5- di-t-butyl -4- methoxyphenyl) phosphine oxide of step 4 [1- (7 '-benzofuranyl) -2- naphthalene]
It is standby
Compound, 449 mg (1.84mmol) benzo furan shown in 637mg (0.92mmol) formula (V) are added in reaction flask
Mutter -7- boric acid pinacol ester, 585mg (2.76mmol) potassium phosphate, 42mg (0.046mmol) Pd2(dba)3And 38mg
(0.092mmol) Sphos, and the mixed solvent prepared by 7mL toluene and 0.7mL water is added, under nitrogen protection, it is warming up to 80
About 8h is reacted after DEG C, reaction mixture revolving is removed into solvent after reaction, then then prepares crude by column chromatography purifying
Compound shown in 436mg formula (VII) is obtained, R is derived from 3,5- di-t-butyl -4- methoxyphenyl, yield 65%.
Product analysis result:1H NMR(400MHz,CDCl3) δ 7.94 (t, J=7.3Hz, 2H), 7.64 (dd, J=
11.7,8.7Hz, 1H), 7.59 (d, J=12.2Hz, 2H), 7.54 (d, J=7.2Hz, 1H), 7.45 (t, J=8.1Hz, 2H),
7.30 (dd, J=9.9,4.0Hz, 4H), 7.18 (t, J=7.6Hz, 1H), 7.13 (d, J=8.6Hz, 1H), 6.59 (d, J=
2.1Hz,1H), 3.73(s,3H),3.60(s,3H),1.39(s,18H),1.28(s,18H).13C NMR(101 MHz,
CDCl3)δ162.17,161.96,161.80,152.92,144.60,143.60,143.48, 142.94,142.82,
140.76,140.68,134.58,133.01,132.90,131.92,130.92, 130.74,130.64,129.47,
129.36,128.97,128.77,128.65,128.03,127.64, 127.56,127.46,127.00,126.86,
126.64,126.39,126.03,125.79,122.03, 121.43,121.30,121.25,106.21,64.35,64.15,
35.96,35.86,35.68,35.60, 31.97,31.84.31P NMR(162MHz,CDCl3)δ28.71.
The system of step 5 1- (7 '-benzofuranyl) -2- two (3,5- di-t-butyl -4- methoxyphenyl) phosphine naphthalene (L4)
It is standby
Compound, 2.07 g (16mmol) N, N- diisopropyl shown in 584mg (0.8mmol) formula (VII) are added in reaction flask
Base ethamine and 20mL toluene under nitrogen protection, then add 1.08g (8mmol) trichlorosilane, 100 DEG C of heated overnight at reflux, instead
After answering, the dilution of 30mL ethyl acetate, mistake after being quenched with the sodium hydroxide solution of 1mol/L are added into reaction mixture
Filter is merged organic phase, organic phase is successively used to 1mol/L hydrochloric acid, saturated carbon altogether three times with 20mL ethyl acetate aqueous layer extracted
After sour hydrogen sodium solution and saturated common salt water washing, the dry 15min of anhydrous sodium sulfate, crude product is through column after then revolving removes solvent
Chromatographic purifying respectively obtains L4 525mg, yield 92%.
Product analysis result:1H NMR(400MHz,CDCl3) δ 7.90 (t, J=8.9Hz, 2H), 7.68 (d, J=
7.7Hz, 1H), 7.50 (s, 1H), 7.33 (dd, J=11.3,5.3Hz, 4H), 7.28 (d, J=7.5Hz, 1H), 7.14 (d, J
=7.8Hz, 3H), 7.05 (d, J=7.9 Hz, 2H), 6.77 (d, J=1.6Hz, 1H), 3.71 (s, 3H), 3.67 (s, 3H),
1.35(s,18H), 1.31(s,18H).13C NMR(101MHz,CDCl3)δ159.89,159.73,153.31, 144.89,
143.25,143.18,142.83,142.76,140.51,137.21,137.08,133.29, 132.72,132.63,
132.49,132.42,132.28,131.27,131.18,130.95,130.86, 129.42,127.95,127.70,
127.22,127.19,126.35,126.19,126.13,123.60, 123.51,122.36,120.80,106.43,64.25,
64.17,35.82,35.70,32.08,32.00. 31P NMR(162MHz,CDCl3)δ-11.60.
5 1- of embodiment (7 '-benzofuranyl) -2- two (3,5- di-t-butyl -4- methoxyphenyl) phosphine naphthalene enantiomer
For the present embodiment is with 1- (7 '-benzofuranyl) -2- two (3,5- di-t-butyl -4- methoxyphenyl) phosphine naphthalene,
The preparation of enantiomer is introduced, in addition the enantiomer preparation method of three kinds of ligands is referring to the embodiment.
Obtain [1- (7 '-benzofuranyl) -2- naphthalene] two (3,5- di-t-butyl -4- methoxyphenyl) oxygen of racemization
After phosphine (referred to as 6a), splits to obtain its a pair of of enantiomer by chiral HPLC, restores again to obtain optically pure ligand,
Specific steps are as follows:
The preparation of (+) -6a and (-) -6a
200mg raceme 6a is taken, by HPLC, it is split using CHIRALPAK AD-H chiral column, condition stream
Speed is 0.7L/min, and eluant, eluent is n-hexane and isopropanol, the retention time point of volume ratio 98:2, (+) -6a and (-) -6a
Not Wei 14.92min and 11.75min, split to obtain (+) -6a and 90mg (-) -6a of 80mg 99%ee by HPLC.It splits
Yield is respectively as follows: 80% and 90%.
Product interpretation of result: [α]D 25+ 54.4 (c=0.1, CHCl3), [α]D 25- 54.0 (c=0.1, CHCl3).Gained light
The nuclear magnetic spectrogram for learning homochiral enantiomer is identical as corresponding raceme.
The preparation of (+)-L4
4 method of ligand L of reducing preparation method and aforesaid compound 6a the reduction preparation racemization of optical voidness ligand (+)-L4
It is identical, but use optically pure (+) -6a for raw material.
Product interpretation of result: [α]D 25+ 40.2 (c=0.1, CHCl3).The nuclear magnetic spectrogram of gained optical homochiral enantiomer
It is identical as corresponding raceme.
The preparation of (-)-L4 can be obtained using the preparation method similar with (+)-L4.
Application of 6 Phosphine ligands of embodiment in Suzuki-Miyaura reaction
In glove box, the halogenated aryl hydrocarbon or heterocyclic arene compound, 2.0 mmol1- naphthalenylboronic acids, Pd of 1.0mmol are taken2
(dba)3, Phosphine ligands and 3.0mmol potassium phosphate in 7mL dry toluene, under nitrogen protection, after being warming up to 80 DEG C, react one section
Time, as a result as shown in table 1.
Above-mentioned Pd2(dba)3It is divided into three kinds: (1) 0.25mol% Pd with the dosage of Phosphine ligands2(dba)3, 0.5mol% phosphine
Ligand, or (2) 0.5mol%Pd2(dba)3, 1.0mol% Phosphine ligands, or (3) 1.0mol%Pd2(dba)3、
2.0mol% Phosphine ligands, specific dosage according to ligand dosage in table 1 subject to.
Comparative example 6.1
Use 2 '-methoxyl group -2-, two p-methylphenyl phosphine -1,1 ' dinaphthalene (L5) or 2 '-methoxyl group -2- dicyclohexylphosphontetrafluoroborates -
1,1 ' dinaphthalene (L6) replaces L1-L4, and be applied in Suzuki-Miyaura reaction: other reaction conditions are same as Example 6,
Reaction result is shown in Table 1.
Comparative example 6.2
With 2- dicyclohexyl phosphine -2', 6'- dimethoxy-biphenyl (L7) or the bis- Phenylphosphine -2' of 2-, 6'- dimethoxy-biphenyl
(L8) replace L1-L4 to be applied in Suzuki-Miyaura reaction: other reaction conditions are same as Example 6, and reaction result is shown in
Table 1.
Comparative example 6.3
With 2 '-two (3,5- di-t-butyl -4- methoxyphenyl) phosphine-(2,3) furans-[1,1 '] dinaphthalenes (L9) or [2-
(7 '-benzofuranyl) phenyl] bis- (3,5- di-t-butyl -4- methoxyphenyl) phosphines (L10) are applied to instead of L1-L4
In Suzuki-Miyaura reaction: other reaction conditions are same as Example 6, and reaction result is shown in Table 1.
Each embodiment Suzuki-Miyaura reaction result of table 1
Application of the 7 Phosphine ligands L1-L4 of embodiment in Suzuki-Miyaura reaction
In glove box, the bromo- 2- methoxynaphthalene of the 1- of 1.0mmol, 2.0mmol aryl boric acid, Pd are taken2(dba)3, phosphine matches
Body and 3.0mmol potassium phosphate are in 7mL dry toluene, under nitrogen protection, after being warming up to 80 DEG C, and reaction a period of time, as a result such as
Shown in table 2.
Above-mentioned Pd2(dba)3It is divided into two kinds: (1) 0.25mol% Pd with the dosage of Phosphine ligands2(dba)3, 0.5mol% phosphine
Ligand, or (2) 0.5mol%Pd2(dba)3, 1.0mol% Phosphine ligands, specific dosage show according to ligand dosage in table 2
It is quasi-.
Comparative example 7.1
L1-L4 is replaced to be applied in Suzuki-Miyaura reaction with L5-L6: other reaction conditions and 7 phase of embodiment
Together, reaction result is shown in Table 2.
Comparative example 7.2
L1-L4 is replaced to be applied in Suzuki-Miyaura reaction with L7-L8: other reaction conditions and 7 phase of embodiment
Together, reaction result is shown in Table 2.
Comparative example 7.3
L1-L4 is replaced to be applied in Suzuki-Miyaura reaction with L9-L10: other reaction conditions and 7 phase of embodiment
Together, reaction result is shown in Table 2.
Each embodiment Suzuki-Miyaura reaction result of table 2
Under identical reaction conditions, change Phosphine ligands respectively, test its catalysis reaction, for example above-mentioned table 1 of result and table
Shown in 2: the Phosphine ligands of a kind of structure containing benzofuran are for halogenated aryl hydrocarbon or heterocyclic arene and aryl boron synthesized by the present invention
The Suzuki-Miyaura coupling reaction of acid has very high catalytic activity and yield, and result is substantially better than right therewith substantially
The dinaphthalene monophosphorus ligand L5-L6 of ratio and dinaphthalene monophosphorus ligand L9, biphenyl monophosphorus ligand L8 with aphthofurans structure with
And the biphenyl monophosphorus ligand L10 with benzofuran structure, some ligands catalytic result are better than Sphos (L7).This is because furan
It mutters the introducing of ring, forms a big conjugated structure, thus regulate and control the steric hindrance of the complex formed with Pd (0) well, and
And the cloud density of oxygen atom is increased, the stability of the complex formed with Pd (0) is increased, reactivity is conducive to
Raising, and the group steric hindrance of the aryl institute band on the ligand phosphorus atoms is bigger, and the catalytic effect of ligand is more preferable.
Claims (9)
1. a kind of Phosphine ligands of structure containing benzofuran, it is characterised in that the Phosphine ligands are with chemical structural formula shown in formula (I)
Compound or its enantiomer or raceme:
In formula,
R is aryl, alkyl, naphthenic base, substituted aryl；
Y1~Y5And Y7~Y9For hydrogen, alkyl, alkoxy, N, N- dialkyl group substituted amido, replaces alkyl at trifluoromethyl；
Y6For H；
Above-mentioned aryl is the aryl that carbon atom number is 6-20；
Abovementioned alkyl is the alkyl that carbon atom number is 1-20；
Above-mentioned naphthenic base is the naphthenic base of 3-8 member ring；
Above-mentioned substituted aryl replaces the substitution in alkyl to refer to that halogen, trifluoromethyl, the alkyl that carbon atom number is 1-20 or carbon are former
Subnumber is the alkoxy of 1-20；
Alkyl in above-mentioned alkoxy is the alkyl that carbon atom number is 1-20, constitutes its alkoxy；Above-mentioned N, N- dialkyl group replace
Alkyl in amido is the alkyl that carbon atom number is 1-20.
2. the Phosphine ligands of the structure containing benzofuran according to claim 1, it is characterised in that the Y1~Y9For hydrogen.
3. a kind of preparation method of the Phosphine ligands of the structure containing benzofuran described in claim 2, it is characterised in that the preparation method
Include the following steps:
Step 1
Using beta naphthal as starting material, addition N- N-halosuccinimides, appropriate organic solvent and ammonium acetate, -10 DEG C~50 DEG C
1~36h of lower reaction, purified processing obtains compound 1 shown in formula (II) after reaction；
In formula (II): X is iodine, bromine or chlorine；
Step 2
Compound 1 shown in formula (II) is reacted in appropriate organic solvent with organic base, trifluoromethanesulfanhydride anhydride, reaction temperature be-
20~20 DEG C, the reaction time is 1~36h, and purified processing obtains compound 2 shown in formula (III) after reaction；
Step 3
By compound 2 shown in formula (III) with formula (IV) compound 3, organic base, palladium catalyst and ligand appropriate organic molten
Catalysis reaction is carried out in agent, reaction temperature is 20~110 DEG C, and the reaction time is 1~60h, is catalyzed purified place after reaction
Reason obtains compound 4 shown in formula (V)；
Step 4
By compound 4 shown in formula (V) and benzofuran -7- boric acid pinacol ester (compound 5), inorganic base, palladium catalyst and match
Body carries out catalyzed coupling reaction in the mixed solvent, and reaction temperature is 20~100 DEG C, and the reaction time is 1~80h, and reaction terminates
Compound 6 shown in formula (VII) is obtained by purification process；The mixed solvent is the body of organic solvent and water according to 1~100:1
Mixed solvent of the product than preparation；
Step 5
Compound 6 shown in formula (VII) and organic base, trichlorosilane are subjected to reduction reaction, reaction temperature in appropriate organic solvent
It is 20~120 DEG C, the reaction time is 1~36h, and purified processing obtains structure containing benzofuran shown in formula (I) after reaction
Phosphine ligands 7.
4. the preparation method of the Phosphine ligands of the structure containing benzofuran according to claim 3, it is characterised in that the step 1
In, organic solvent is acetonitrile, toluene, benzene, dimethylbenzene, ether, ethyl alcohol, methanol, acetic acid, n,N-Dimethylformamide, chlorobenzene, two
Chloromethanes, chloroform, carbon tetrachloride, ethyl acetate, tetrahydrofuran, 1,4- dioxane, dimethyl sulfoxide, glycol dinitrate
Ether, glycol monoethyl ether or carbon disulfide；The molar ratio of beta naphthal and N- N-halosuccinimides is 1:1~1.2；Ammonium acetate with
The reaction molar ratio of N- N-halosuccinimides is 0.01~1:1；Purification process is after reaction mixture revolving is removed solvent, to incite somebody to action
Crude by column chromatography purifies to obtain compound 1.
5. the preparation method of the Phosphine ligands of the structure containing benzofuran according to claim 3, it is characterised in that the step 2
In, the reaction molar ratio of compound 1 and organic base is 1:1~5；The reaction molar ratio of compound 1 and trifluoromethanesulfanhydride anhydride is 1:1
~4；Organic base be trimethylamine, triethylamine, tripropyl amine (TPA), tri-n-butylamine, N, N- diisopropylethylamine, tetramethylethylenediamine, pyridine, N,
N- lutidines, 1,4- lupetazin, 1- methyl piperidine, 1- methylpyrrole or quinoline；Organic solvent is toluene, benzene, two
Toluene, ether, ethyl alcohol, methanol, acetic acid, N,N-dimethylformamide, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, second
Acetoacetic ester, tetrahydrofuran, 1,4- dioxane, dimethyl sulfoxide, glycol dimethyl ether, glycol monoethyl ether or carbon disulfide；
Purification process is that saturated sodium bicarbonate solution is first added into reaction mixture, adjusts pH to meta-alkalescence, separates organic phase, water phase
Three times with organic solvent extraction, merge organic phase, organic phase is boiled off into solvent with the dry 15min back spin of anhydrous sodium sulfate, then
Crude by column chromatography is purified to obtain compound 2.
6. the preparation method of the Phosphine ligands of the structure containing benzofuran according to claim 3, it is characterised in that the step 3
In, compound 2 is 1:1~3 with the molar ratio of reacting of compound 3；Compound 2 is 1:1~5 with the molar ratio of reacting of organic base；
Compound 2 is 1:0.01~1 with the molar ratio of reacting of palladium catalyst；Compound 2 and ligand react molar ratio be 1:0.01~
1；Organic base is trimethylamine, triethylamine, tripropyl amine (TPA), tri-n-butylamine, N, N- diisopropylethylamine, tetramethylethylenediamine, pyridine, N, N-
Lutidines, 1,4- lupetazin, 1- methyl piperidine, 1- methylpyrrole or quinoline；Organic solvent is toluene, benzene, diformazan
Benzene, ether, ethyl alcohol, methanol, acetic acid, N,N-dimethylformamide, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, acetic acid
Ethyl ester, tetrahydrofuran, 1,4- dioxane, dimethyl sulfoxide, glycol dimethyl ether, glycol monoethyl ether or carbon disulfide；Palladium
Catalyst is Pd (OAc)2、PdCl2Or Pd2(dba)3；Ligand is bis- (diphenylphosphine) butane of 1,4-, 1,3- bis- (diphenylphosphines)
Bis- (diphenylphosphine) ferrocene of propane, 1,1'- or 2- dicyclohexylphosphontetrafluoroborate -2 ', 6 '-dimethoxy-biphenyls；Purification process is first will
Reaction mixture is cooled to room temperature, and organic solvent diluting is then added, and adds 1mol/L hydrochloric acid and separates organic phase, and water phase is with having
Solvent extracts three times, merges organic phase, and organic phase is boiled off solvent with the dry 15min back spin of anhydrous sodium sulfate, then will be thick
Product obtains compound 4 through column chromatographic purifying.
7. the preparation method of the Phosphine ligands of the structure containing benzofuran according to claim 3, it is characterised in that the step 4
In, compound 4 is 1:1~3 with the molar ratio of reacting of compound 5；Compound 4 reacts molar ratio 1:1~5 with inorganic base；Change
It is 1:0.01~1 that object 4, which is closed, with the molar ratio of reacting of palladium catalyst；Compound 4 is 1:0.01~1 with the molar ratio of reacting of ligand；
Inorganic base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride or potassium phosphate；Organic solvent
For toluene, benzene, dimethylbenzene, ether, ethyl alcohol, methanol, acetic acid, N,N-dimethylformamide, chlorobenzene, methylene chloride, chloroform,
Carbon tetrachloride, ethyl acetate, tetrahydrofuran, 1,4- dioxane, dimethyl sulfoxide, glycol dimethyl ether, glycol monoethyl ether
Or carbon disulfide；Palladium catalyst is Pd (OAc)2、PdCl2Or Pd2(dba)3；Ligand is bis- (diphenylphosphine) butane of 1,4-, 1,3-
Bis- (diphenylphosphine) propane, bis- (diphenylphosphine) ferrocene of 1,1'- or 2- dicyclohexylphosphontetrafluoroborate -2 ', 6 '-dimethoxy-biphenyls；It is pure
Change processing is first to rotate reaction mixture to remove solvent, then purifies crude by column chromatography to obtain compound 6.
8. the preparation method of the Phosphine ligands of the structure containing benzofuran according to claim 3, it is characterised in that the step 5
In, compound 6 is 1:1~20 with the molar ratio of reacting of trichlorosilane；Organic base and trichlorosilane react molar ratio be 1.5~
3:1；Organic base be trimethylamine, triethylamine, tripropyl amine (TPA), tri-n-butylamine, N, N- diisopropylethylamine, tetramethylethylenediamine, pyridine, N,
N- lutidines, 1,4- lupetazin, 1- methyl piperidine, 1- methylpyrrole or quinoline；Organic solvent is toluene, benzene, two
Toluene, ether, ethyl alcohol, methanol, acetic acid, N,N-dimethylformamide, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, second
Acetoacetic ester, tetrahydrofuran, 1,4- dioxane, dimethyl sulfoxide, glycol dimethyl ether, glycol monoethyl ether or carbon disulfide；
Purification process is that organic solvent diluting is first added into reaction mixture, then mistake after being quenched with the sodium hydroxide solution of 1mol/L
Filter after extracting filtrate three times with organic solvent, merges organic phase, organic phase is successively used to 1mol/L hydrochloric acid, unsaturated carbonate hydrogen
After sodium solution and saturated common salt water washing, then the dry 15min of anhydrous sodium sulfate is rotated crude by column chromatography after removing solvent
Purifying obtains compound 7.
9. the Phosphine ligands of the structure as claimed in claim 1 or 2 containing benzofuran are in palladium chtalyst Suzuki-Miyaura coupling reaction
Application.
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| JP2010053049A (en) * | 2008-08-26 | 2010-03-11 | Chiba Univ | Diphosphine compound, its transition metal complex and catalyst containing the transition metal complex and phosphine oxide compound and diphosphine oxide compound |
| CN105968137A (en) * | 2016-05-15 | 2016-09-28 | 中山大学 | Naphthofuran-structure-containing biaryl monophosphine ligands, and preparation method and application thereof |
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| CN1995047A (en) * | 2006-12-28 | 2007-07-11 | 上海交通大学 | Bidentate chiral phosphine complex intermediate with C2 symmetrical axle and its preparation method |
| JP2010053049A (en) * | 2008-08-26 | 2010-03-11 | Chiba Univ | Diphosphine compound, its transition metal complex and catalyst containing the transition metal complex and phosphine oxide compound and diphosphine oxide compound |
| CN105968137A (en) * | 2016-05-15 | 2016-09-28 | 中山大学 | Naphthofuran-structure-containing biaryl monophosphine ligands, and preparation method and application thereof |
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