CN108774216A - A kind of list tooth Pei Wei oxazoline ligands and its preparation method and application - Google Patents
A kind of list tooth Pei Wei oxazoline ligands and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to a kind of Dan Chi oxazoline ligands and its preparation method and application, Dan Chi oxazolines of the invention realize the asymmetric hydrogen carbon functional groupization reaction of the disactivation alkene of double guiding of palladium chtalyst.Applying can efficiently realize that the asymmetric coupling reaction of the positions C3-, the Stereoselective reaction that can be up to 90%ee obtain the product of γ-addition in various types of indoles.And the chiral oxazoline ligand can efficiently be prepared using cheap amino acid, and synthetic method is very simple, be the important research progress of chiral ligand research field.The ligand can be applied to efficiently synthesize the medicine intermediate containing chiral molecules, be conducive to quickly prepare chemicals, power-assisted new drug development.
Description
Technical field
The invention belongs to medicine intermediates to synthesize field, and in particular to a kind of list tooth Pei Wei oxazoline ligands and its preparation side
Method and application.
Background technology
Chipal compounds are to be widely present, and have been developed as treating the effective of various diseases in native compound
Drug.And native compound is far from being enough for the demand of social development, so need our chemistry return home synthesis it is various
The needs of chiral molecules of various kinds is to meet us.Traditional organic synthesis can not synthesize single chiral compound, need
Complicated disassembler can just obtain single chipal compounds.Therefore asymmetric syntheses is to obtain single chiral compound most
Effective means have obtained very huge development in recent years.Nobel chemistry Prize authorizes American scientist William within 2001
Knowles, Barry summer Price and Japanese Scientists Ryoji Noyori, with commendation, they are made in " chiral catalysis " field
The contribution gone out.It is enough to find out that asymmetry catalysis is a field that is extremely important and urgently continuing development.
So-called asymmetry catalysis is exactly the catalyst using a determining single configuration, to realize to reaction substrate
Selectivity control.And in metal catalytic, metallic atom itself is that do not have chirality, therefore a kind of efficient method is exactly
Use chiral ligand of the chiral molecules synthesis with single chiral present in natural.And the design synthesis of chiral ligand is not right
Claim the key link in catalysis, only synthesizes various chiral ligands, could realize the diversity of asymmetric syntheses, from
And obtain more useful chipal compounds.
It is known that , oxazolines be it is a kind of have be widely used general chiral ligand, and develop many well-known
The three of ligand, such as bisoxazoline ligand (BOX, PyBOX), the N of bidentate, N-, the ligands such as P-N, S-N and Tang Yong academician's development
The multiple tooth coordination oxazoline ligands such as oxazoline ligand, since multiple tooth coordination effectively can be formed efficiently with metal center
Chiral catalyst provides effective chiral environment, and the efficient asymmetric syntheses of all kinds of chemical reactions may be implemented.Due to its height
The chiral environment ability of constructing of effect is that Dan Chi oxazoline ligands institute is irrealizable, therefore the development of Dan Chi oxazoline ligands is always
Very slowly.
But single tooth oxazoline ligand is a kind of chiral ligand more simple and easy to get, but its application is limited to very much,
It is reported almost without being reacted about the catalysis of Dan Chi oxazoline ligands.Therefore, design novel Dan Chi oxazoline ligands and by its profit
For being very important in effective asymmetric catalysis, it can be used for synthesizing all kinds of drug molecules containing chiral centre
And medicine intermediate molecule, the foreground with very important significance of scientific research and commercial Application.
Invention content
In view of the deficiencies of the prior art, it is an object of the present invention to provide a kind of single tooth Pei Wei oxazoline ligands and its preparation sides
Method and application, list tooth of the present invention with position oxazoline ligand can for the first time and be efficiently applied to alkene asymmetric function dough reaction
In, and achieve the stereoselectivity of highest 90%ee.
The general structure of a kind of list tooth Pei Wei oxazoline ligands, the list tooth Pei Wei oxazoline ligands is as follows：
Wherein, R1For-CH3；R2For in H, phenyl, 3,5- bis trifluoromethyl phenyls, pentafluorophenyl group or p-methoxyphenyl
It is a kind of；R3For H or-CH3；
The present invention also provides ligand L 1 or the preparation methods of the mono- tooth Pei Wei oxazoline ligands of L2, include the following steps：
(1) in the corresponding halogen organic solvent of nonpolarity, by Formulas I compound represented, Formula II compound represented, have
Machine acid catalyst is according to 1:1.2-2.0：The mol ratio of 0.05-0.1 is uniformly mixed, the back flow reaction 10-24 under 50-100 degree
Hour, it isolates and purifies, obtains formula III compound represented, specific synthetic route is as follows：
Further, the halogen organic solvent of nonpolarity in the step (1) is in 1,2- dichloroethanes or dichloromethane
One kind；The organic acid catalyst is acetic acid, formic acid, propionic acid, phenylic acid, one kind in adjacent phenyl acid；
Further, the reaction in step (1) can also carry out under nitrogen protection.
The present invention also provides ligand L 3, the preparation method of the mono- tooth Pei Wei oxazoline ligands of L4, L5 or L6, including following steps
Suddenly：
(1) in the corresponding halogen organic solvent of nonpolarity, by Formulas I compound represented, Formula II compound represented, have
Machine acid catalyst is according to 1:1.2-2.0：The mol ratio of 0.05-0.1 is uniformly mixed, the back flow reaction 10-24 under 50-100 degree
Hour, it isolates and purifies, obtains formula III compound represented, specific synthetic route is as follows：
(2) in corresponding benzene series organic solvent, by halogen compound, iodate shown in formula III compound represented, formula IV
Cuprous, N, N'- dimethyl -1,2- cyclohexanediamine, potassium phosphate are according to 1:1.1-2.0:0.05-0.2:0.10-0.4:1.2-2.0
Mol ratio reacts 6-24 hours under 40-90 degree, obtains ligand shown in Formula V, and specific synthetic route is as follows：
Further, the halogen organic solvent of nonpolarity in the step (1) is in 1,2- dichloroethanes or dichloromethane
One kind；The organic acid catalyst is acetic acid, formic acid, propionic acid, benzoic acid, one kind in o-toluic acid；The step
(2) the benzene series organic solvent in is one kind in toluene, dimethylbenzene or chlorobenzene.
Further, the reaction in step (1) or step (2) can also carry out under nitrogen protection, and can obtain compared with
The better yield of air and quality.
The present invention also provides the applications of single tooth Pei Wei oxazoline ligands, include the following steps：By substrate shown in Formula IV,
One kind in nucleopilic reagent, palladium catalyst, ligand shown in L1-L6, adjacent Phenylbenzoic acid (o-PBA) and alcohol system organic solvent are pressed
According to 1:1.5:0.1:0.3:1.0 molar ratio mixing, is stirred at room temperature 30 minutes, then reacts 48 on the heat block of 60oC
Hour.Reaction solution is cooled to room temperature, obtains Formula VII compound represented, and the ee values of Formula VII compound represented are 60-
90%.
Further, alcohol system organic solvent is one kind in methanol, ethyl alcohol or isopropanol；The palladium catalyst is vinegar
Sour palladium catalyst, dibenzoic acid palladium catalyst；The nucleopilic reagent is substituted indole.
Further, the application response of single tooth Pei Wei oxazoline ligands can also carry out under protection of argon gas.
Advantageous effect
List tooth Pei Wei oxazoline ligands of the present invention are relative to multidentate ligand, and simple and easy to get, preparation method is efficient, have it solely
Special chiral control activity, applies the high selectivity in asymmetric reaction.
The Dan Chi oxazolines of the present invention realize the asymmetric hydrogen carbon official of the disactivation alkene of double guiding of the first palladium chtalyst
The energy dough reaction various types of indoles of can efficiently realize the asymmetric coupling reaction of the positions C3-, can be with up to
The Stereoselective reaction of 90%ee obtains the product of γ-addition.And the chiral oxazoline ligand can use cheap ammonia
Base acid is efficiently prepared, and synthesis is very simple, can be efficiently applied to efficiently synthesize the medicine intermediate containing chiral molecules, is
The important research of Dan Chi oxazoline ligands is in progress.
Description of the drawings
Fig. 1 is that the hydrogen of L1 ligands is composed；
Fig. 2 is that the carbon of L1 ligands is composed；
Fig. 3 is that the hydrogen of L2 ligands is composed；
Fig. 4 is that the carbon of L2 ligands is composed；
Fig. 5 is that the hydrogen of L3 ligands is composed；
Fig. 6 is that the carbon of L3 ligands is composed；
Fig. 7 is that the hydrogen of L4 ligands is composed；
Fig. 8 is that the carbon of L4 ligands is composed；
Fig. 9 is that the hydrogen of L5 ligands is composed；
Figure 10 is that the carbon of L5 ligands is composed；
Figure 11 is that the hydrogen of L6 ligands is composed；
Figure 12 is that the carbon of L6 ligands is composed；
Figure 13 is the hydrogen spectrum of Formula VII compound represented in embodiment 9-14；
Figure 14 is the carbon spectrum of Formula VII compound represented in embodiment 9-14；
The spectrogram that Figure 15 is the HPLC of asymmetric products shown in Formula VII in embodiment 12；
The spectrogram that Figure 16 is the HPLC of racemic product shown in Formula VII in embodiment 12；
Figure 17 is the hydrogen spectrum of Formula VII compound represented in embodiment 15-20；
Figure 18 is the carbon spectrum of Formula VII compound represented in embodiment 15-20；
The spectrogram that Figure 19 is the HPLC of asymmetric products shown in Formula VII in embodiment 18；
The spectrogram that Figure 20 is the HPLC of racemic product shown in Formula VII in embodiment 18；
Figure 21 is the reaction mechanism figure of asymmetric reaction shown in embodiment 9-20.
Specific implementation mode
With reference to embodiment, this practicality is expanded on further.
Embodiment 1
1 corresponding preparation method of ligand L is in the present invention：
(1) in 1,2- dichloroethane solvents, shown in Formulas I compound represented in following reaction equation, Formula II
Compound, acetate catalyst are according to 1:1.2：0.1 mol ratio is uniformly mixed, back flow reaction 10 hours under 100 degree, cooling
To room temperature, be extracted with ethyl acetate after system is spin-dried for and wash with water again, merge organic phase afterwards, using anhydrous sodium sulfate into
Row drying, then concentrated silicagel column can take product, and product takes faint yellow solid (60% yield) after can recrystallizing.
Formula III compound represented (i.e. ligand L 1) is obtained, specific synthetic route is as follows：
The corresponding hydrogen spectrum and carbon modal data (as shown in Figure 1 and Figure 2) of ligand L 1 are as follows：
1H NMR (400MHz, Chloroform-d) δ 8.22 (s, 1H), 7.60 (d, J=7.8Hz, 1H), 7.33 (d, J=
8.1Hz, 1H), 7.18 (t, J=7.5Hz, 1H), 7.13-7.05 (m, 2H), 4.10 (t, J=7.5Hz, 1H), 2.97 (qd, J=
14.9,7.4Hz, 2H), 1.97 (s, 3H), 1.34 (d, J=7.7Hz, 6H)13C NMR (101MHz, Chloroform-d) δ
163.63,136.41,127.56,122.44,121.92,119.22,118.77,113.28,111.26,86.31,73.84,
28.69,27.15,21.80,14.75.
Embodiment 2
2 corresponding preparation method of ligand L is in the present invention：
(1) in 1,2- alkane solvents containing chloromethane, shown in Formulas I compound represented in following reaction equation, Formula II
Compound, benzoic acid catalyst are according to 1:2.0：0.05 mol ratio is uniformly mixed, back flow reaction 10 hours under 50 degree, point
It from purifying, after being cooled to room temperature, is extracted with ethyl acetate after system is spin-dried for and washes with water again, merge organic phase afterwards, use
Anhydrous sodium sulfate is dried, then concentrated silicagel column can take product, and product takes pale yellow colored solid after can recrystallizing
Body (70% yield).Formula III compound represented (i.e. ligand L 2) is obtained, specific synthetic route is as follows：：
Ligand L 2 corresponds to hydrogen spectrum and carbon modal data (as shown in Figure 3, Figure 4) is as follows：
(Rf=0.3, n-hexane:Ethyl acetate=1:1(v/v)).1H NMR (400MHz, Chloroform-d) δ 8.07
(s, 1H), 7.64 (d, J=7.9Hz, 1H), 7.36 (d, J=8.1Hz, 1H), 7.20 (t, J=7.6Hz, 1H), 7.13 (t, J=
7.5Hz, 1H), 7.04 (s, 1H), 4.49 (t, J=7.4Hz, 1H), 4.18 (t, J=8.9Hz, 1H), 3.98 (t, J=7.9Hz,
1H), 3.24 (dd, J=14.6,5.0Hz, 1H), 2.79 (dd, J=14.6,8.8Hz, 1H), 1.98 (d, J=1.5Hz, 3H)
.13C NMR (101MHz, Chloroform-d) δ 165.19,136.40,127.63,122.39,122.03,119.35,
118.82,111.95,111.26,72.46,66.59,31.59,14.06.HRMS (ESI) m/z Calcd for C13H15N2O+
[M+H+]:215.1179, found:215.1182.
Embodiment 3
2 corresponding preparation method of ligand L is identical as the reactant used in embodiment 2 in the present embodiment, only reacts item
The difference of part, it is specific as follows：
In 1,2- alkane solvents containing chloromethane, by chemical combination shown in Formulas I compound represented in following reaction equation, Formula II
Object, benzoic acid catalyst are according to 1:1.5：0.08 mol ratio is uniformly mixed, back flow reaction 15 hours under 80 degree, and separation is pure
Change, after being cooled to room temperature, is extracted with ethyl acetate after system is spin-dried for and washes with water again, merge organic phase afterwards, use is anhydrous
Sodium sulphate is dried, then concentrated silicagel column can take product, and product takes faint yellow solid after can recrystallizing
(75% yield) obtains formula III compound represented (i.e. ligand L 2).
Embodiment 4
The phase of ligand L 2 corresponding preparation method and the reactant and reaction condition that are used in embodiment 3 in the present embodiment
Together, it differs only in the present embodiment and carries out under protection of argon gas, the yield for obtaining ligand L 2 is faint yellow solid (80%
Yield).
Embodiment 5
In toluene solvant, ligand L 2 prepared by embodiment 3 is as reactant, iodobenzene, cuprous iodide, N, N'- diformazans
Base -1,2- cyclohexanediamine, potassium phosphate are according to 1:1.1:0.05:0.10:1.2 mol ratio is reacted 24 hours under 40 degree, cold
But it to being diluted with ethyl acetate after room temperature, is concentrated after filtering, pale yellow oily liquid is obtained to get to L3 via column chromatography method
Shown in ligand (75% yield), specific synthetic route is as follows：
Ligand L 3 corresponds to hydrogen spectrum and carbon modal data (as shown in Figure 5, Figure 6) is as follows：
(Rf=0.2, n-hexane:Ethyl acetate=1:1(v/v)).1H NMR (400MHz, Chloroform-d) δ 7.71-
7.65 (m, 1H), 7.56 (dd, J=7.9,1.1Hz, 1H), 7.54-7.45 (m, 4H), 7.38-7.29 (m, 1H), 7.26-7.13
(m, 3H), 4.58-4.46 (m, 1H), 4.23 (t, J=8.9Hz, 1H), 4.02 (t, J=8.5Hz, 1H), 3.28 (dd, J=
14.6,5.1,1.1Hz, 1H), 2.84 (dd, J=14.6,8.8Hz, 1H), 1.99 (s, 3H)13C NMR (101MHz,
Chloroform-d) 165.13 δ, 139.82,136.19,129.70,129.16,126.35,126.02,124.25,122.71,
120.18,119.30,113.47,110.68,72.50,66.62,31.52,14.14.HRMS (ESI) m/z Calcd for
C19H19N2O+[M+H+]:291.1492, found:291.1493.
If keeping under identical reaction condition, it is distinguished as being reacted under protection of argon gas, then the yield of ligand L 3 can obtain
To 80%.
Embodiment 6
In xylene solvent, ligand L 2 prepared by embodiment 4 is as reactant, 3,5- bis trifluoromethyls iodobenzene, iodine
Change cuprous, N, N'- dimethyl -1,2- cyclohexanediamine, potassium phosphate are according to 1:2.0:0.2:0.4:2.0 mol ratio, at 90 degree
Lower reaction 6 hours, is diluted with ethyl acetate after being cooled to room temperature, is concentrated after filtering, white solid is obtained via column chromatography method,
Ligand shown in L4 (77% yield) is obtained, specific synthetic route is as follows：
Ligand L 4 corresponds to hydrogen spectrum and carbon modal data (as shown in Figure 7, Figure 8) is as follows：
(Rf=0.4, n-hexane:Ethyl acetate=1:1(v/v)).1H NMR (400MHz, Chloroform-d) δ 7.99
(d, J=1.5Hz, 2H), 7.84 (s, 1H), 7.73 (dt, J=7.7,1.0Hz, 1H), 7.58-7.52 (m, 1H), 7.34 (td, J
=8.3,7.1Hz, 1H), 7.30-7.24 (m, 2H), 4.62-4.50 (m, 1H), 4.31 (t, J=9.4Hz, 1H), 4.04 (t, J
=8.5Hz, 1H), 3.23 (dd, J=14.7,5.8Hz, 1H), 2.92 (dd, J=14.7,7.8Hz, 1H), 2.02 (d, J=
1.3Hz, 3H)13C NMR (101MHz, Chloroform-d) δ 165.36,141.31,135.75,133.92,133.58,
133.24,132.91,129.84,127.12,125.16,124.41,123.85,123.74,123.70,123.66,123.63,
121.69,121.39,119.91,119.49,119.45,119.41,119.38,118.98,115.98,110.00,77.48,
77.16,76.84,72.40,66.39,31.39,14.12.19F NMR (376MHz, Chloroform-d) δ -62.89 (s, Ar-
CF3) the ee values of products are analyzed via HPLC, the chiral column used is：Chiralpak IC column (n-hexanes：Isopropyl
Alcohol=85:15,1.0mL/min, T=30 DEG C, 254nm), TR=4.38min (minor), 4.65min (major):>99.5%
ee.HRMS(ESI)m/zCalcd for C21H17N2OF6 +[M+H+]:427.1240, found:427.1242.
If keeping under identical reaction condition, it is distinguished as being reacted under protection of argon gas, then the yield of ligand L 4 can obtain
To 87%.
Embodiment 7
In corresponding xylene solvent, ligand L 2 prepared by embodiment 4 is sub- as reactant, five fluorine iodobenzenes, iodate
Copper, N, N'- dimethyl -1,2- cyclohexanediamine, potassium phosphate are according to 1:1.5:0.1:0.3:1.5 mol ratio, it is anti-under 50 degree
It answers 14 hours, is diluted with ethyl acetate after being cooled to room temperature, concentrated after filtering, colorless oil liquid is obtained via column chromatography method
For body to get to ligand shown in L5 (40% yield), specific synthetic route is as follows：
Ligand L 5 corresponds to hydrogen spectrum and carbon modal data (as shown in Figure 9, Figure 10) is as follows：
HNMR (400MHz, Chloroform-d) δ 7.72-7.65 (m, 1H), 7.31-7.26 (m, 1H), 7.25-7.20
(m, 1H), 7.11-7.05 (m, 1H), 7.02 (s, 1H), 4.58-4.46 (m, 1H), 4.24 (t, J=8.9Hz, 1H), 3.99
(dd, J=8.5,7.2Hz, 1H), 3.29-3.18 (m, 1H), 2.86 (dd, J=14.8,8.1Hz, 1H), 1.98 (d, J=
1.3Hz, 3H)13C NMR (101MHz, Chloroform-d) δ 165.30,144.80,139.48,136.69,128.78,
126.04,123.56,121.15,119.47,115.55,110.32,72.23,66.24,31.19,14.02.19F NMR
(376MHz, Chloroform-d) δ -144.92, -145.31, -154.42, -154.42, -154.47, -154.53, -
160.49, -160.51, -160.55, -160.57, -160.61, -160.63 (m, Ar-F) .HRMS (ESI) m/z Calcd for
C19H14N2OF5 +[M+H+]:381.1021, found:381.1024.
If keeping under identical reaction condition, it is distinguished as being reacted under protection of argon gas, then the yield of ligand L 5 can obtain
To 56%.
Embodiment 8
In xylene solvent, ligand L 2 prepared by embodiment 3 as reactant, to methoxyl group iodobenzene, cuprous iodide,
N, N'- dimethyl -1,2- cyclohexanediamine, potassium phosphate are according to 1:1.6:0.15:0.3:1.7 mol ratio is reacted under 70 degree
20 hours, diluted with ethyl acetate after being cooled to room temperature, concentrated after filtering, via column chromatography method obtain white solid to get
To ligand shown in L6 (82% yield), specific synthetic route is as follows：
Ligand L 6 corresponds to hydrogen spectrum and carbon modal data is as follows (as shown in Figure 11, Figure 12)：
1H NMR (400MHz, Chloroform-d) δ 7.67 (d, J=7.7Hz, 1H), 7.44 (d, J=8.1Hz, 1H),
7.41-7.36 (m, 2H), 7.21 (t, J=7.5Hz, 1H), 7.19-7.11 (m, 2H), 7.02 (d, J=8.5Hz, 2H), 4.59-
4.46 (m, 1H), 4.23 (t, J=8.9Hz, 1H), 4.02 (t, J=7.9Hz, 1H), 3.88 (d, J=0.9Hz, 3H), 3.28
(dd, J=14.6,5.0Hz, 1H), 2.83 (dd, J=14.6,8.8Hz, 1H), 2.00 (d, J=1.5Hz, 3H)13C NMR
(101MHz, Chloroform-d) δ 165.10,158.18,136.64,132.82,128.74,126.38,125.87,
122.48,119.87,119.18,114.81,112.77,110.52,72.52,66.66,55.70,31.52,14.15.HRMS
(ESI)m/z Calcd for C20H21N2O2 +[M+H+]:321.1598, found:321.1601.
If keeping under identical reaction condition, it is distinguished as being reacted under protection of argon gas, then the yield of ligand L 6 can obtain
To 88%.
Embodiment 9-14
The present invention also provides application of single tooth Pei Wei oxazoline ligands in asymmetric reaction, specifically include following step
Suddenly：
Shown in the corresponding N- methyl indols of substrate, nucleopilic reagent shown in Formula IV, palladium acetate catalyst, (L1-L6)
Any one of ligand, o-PBA and methanol solvate are according to 1:1.5:0.1:0.3:1.0 molar ratio mixing, is stirred at room temperature
It 30 minutes, is then reacted 48 hours on 60 DEG C of heat block.Reaction solution is cooled to room temperature, is then spin-dried for reaction system dense
After contracting three times with dichloromethane extraction, then saturated sodium bicarbonate is used respectively, saturated salt solution cleans three times, merges organic phase, makes
It is dried with anhydrous sodium sulfate, the isolated product of silica gel column chromatography is used after being spin-dried for, obtains Formula VII compound represented, and formula
The ee values of VII compounds represented are 60-86%.
Wherein, the corresponding hydrogen of embodiment 9-14 compound of formula VTI is composed with carbon modal data (as shown in Figure 13, Figure 14) such as
Under：
1H NMR (400MHz, Chloroform-d) δ 9.67 (s, 1H), 8.77 (dd, J=7.5,1.6Hz, 1H), 8.75
(dd, J=4.3,1.7Hz, 1H), 8.15 (dd, J=8.3,1.7Hz, 1H), 7.68 (dt, J=7.9,1.0Hz, 1H), 7.59-
7.46 (m, 2H), 7.43 (dd, J=8.3,4.2Hz, 1H), 7.33-7.24 (m, 1H), 7.20 (ddd, J=8.2,6.8,
1.2Hz, 1H), 7.07 (ddd, J=8.0,6.9,1.1Hz, 1H), 6.90 (s, 1H), 3.73 (s, 3H), 3.19 (q, J=
7.1Hz, 1H), 2.54 (td, J=7.2,2.0Hz, 2H), 2.34-2.17 (m, 2H), 1.44 (d, J=7.0Hz, 3H)13C NMR
(101MHz,Chloroform-d)δ172.20,148.15,138.45,137.36,136.45,134.73,128.06,
127.58,127.28,125.52,121.65,121.58,121.38,119.72,119.66,118.70,116.49,109.34,
77.48,77.16,76.84,36.55,33.33,32.75,30.82,22.22.
HRMS(ESI)m/z Calcd for C13H24N3O+[M+H+]:358.1914,found:358.1917.
The ee values of compound shown in Formula VII are analyzed via HPLC, and the chiral column used is：ChiralcelAD-H
Column (n-hexanes：Isopropanol=94:6,1.0mL/min, T=30 DEG C, 254nm), TR=21.77min (major),
24.80min(minor):93:7er.
Wherein, disappear shown in the spectrogram (Figure 15) of the HPLC of asymmetric products shown in Formula VII and Formula VII in embodiment 12
Revolve the spectrogram (Figure 16) of the HPLC of product；It can be seen that the yield and ee values that 4 catalytic asymmetric reaction of ligand L generates are all fine.
Asymmetric reaction principle is as shown in figure 21, and reaction mechanism is：1. palladium selectivity Yu oxazoline ligands first
In conjunction with active palladium catalyst (IN1) is generated, it is then combined .2. alkene with substrate and is coordinated with Pd, is selected under the action of o-PBA
The dissociation acetate of selecting property, to which selectivity obtains crucial chiral control intermediate (IN2), subsequent nucleopilic reagent indoles selection
Property attack alkene, formed intermediate (IN3), go palladium that final product is obtained by the reaction finally by proton, be completed at the same time catalyst
Regeneration cycle
The key effect pattern of ligand is that the nitrogen-atoms on oxazole ring in ligand is coordinated with metal Pd, on oxazole ring
Methyl plays the effect for distinguishing substrate steric hindrance, and the indole ring effect in ligand has two aspects, first aspect secondary to pass through with Pd
Grade rail effect stablizes chiral control intermediate, and second aspect is to provide chiral environment, and steric hindrance can occur with substrate.
Indole ring N- substituent group main functions are exactly to adjust the electrical of indole ring, and can there are electronics heaps with the quinoline ring in substrate
Product effect.
The difference of the ligand mode of action：L1 ligands make the structure of ligand occur in the effect for being primarily due to two methyl
Variation, coordination angle compression is serious, causes the active force of remaining Binding Capacity to become smaller, eventually leads to the reduction and selection of its yield
The reduction of property.L2 ligands mainly since there is no active forces with substrate by the N-H of indoles in coordination, make the intermediate compound I N2 to be formed
Conformation without stabilization, chiral control ability reduces, but the ability of itself and Pd coordinations is eager to excel compared with L1, therefore its yield can be kept
Higher level, selectivity are medium.L3 is substituted by phenyl relative to L2, the N of indoles, but phenyl belongs to electron rich with quinoline ring
Aromatic ring, between there are repulsive interactions, therefore make its stability reduction, selectively can be down slightly.L4 will replace relative to L3
Group changes 3,5- bis trifluoromethyl phenyls into, belongs to electron deficient aromatic ring, can form stronger effect with the quinoline ring in substrate
Power reaches best chiral control to stablize the conformation of key intermediate.L5 is relative to L4, and the group of pentafluorophenyl group is more
Electron deficient causes the effect of ligand and quinoline ring too strong, its structure is made to be distorted, its chiral control ability is caused substantially to drop
It is low.P-methoxyphenyl is electron-donating group in L6, belongs to electron rich aromatic ring, unfavorable to selectivity, but-OMe therein has
There is certain coordination effect, certain Stable conformation can be played the role of, to improve selectivity.
Embodiment 15-20
The present invention also provides application of single tooth Pei Wei oxazoline ligands in asymmetric reaction, specifically include following step
Suddenly：
It will match shown in the corresponding indoles of substrate, nucleopilic reagent, dibenzoic acid palladium catalyst, (L1-L6) shown in Formula IV
Any one of body, o-PBA and methanol solvate are according to 1:1.5:0.1:0.3:1.0 molar ratio mixing, is stirred at room temperature 30
Minute, then reacted 48 hours on 60 DEG C of heat block.Reaction solution is cooled to room temperature, then is spin-dried for concentrating by reaction system
Afterwards three times with dichloromethane extraction, then saturated sodium bicarbonate is used respectively, saturated salt solution cleans three times, merges organic phase, uses
Anhydrous sodium sulfate is dried, and the isolated product of silica gel column chromatography is used after being spin-dried for, obtains Formula VII compound represented, and Formula VII
The ee values of compound represented are 65-90%.
| Embodiment | Corresponding ligand | Yield/% of Formula VII compound | Ee values/% of Formula VII compound |
| Embodiment 15 | L1 | 54 | 65 |
| Embodiment 16 | L2 | 94 | 84 |
| Embodiment 17 | L3 | 86 | 78 |
| Embodiment 18 | L4 | 95 | 90 |
| Embodiment 19 | L5 | 91 | 79 |
| Embodiment 20 | L6 | 90 | 82 |
Difference for methyl and ethyl：Difference lies in the groups of ethyl for methyl group, and steric hindrance is larger,
The chiral space that remaining ligand binding is formed is compacter, and without chiral leakage occurs, therefore its chiral selectivity is relative to methyl
For can improve.By the research of other substrates, it is found that substituent group is bigger, the chiral control of the reaction is better.
Wherein, the corresponding hydrogen of embodiment 15-20 compound of formula VTI is composed with carbon modal data (as shown in Figure 17, Figure 18) such as
Under：1H NMR (400MHz, Chloroform-d) δ 9.64 (s, 1H), 8.76 (d, J=7.5Hz, 1H), 8.73 (dd, J=4.1,
1.8Hz, 1H), 8.18-8.10 (m, 1H), 8.08 (s, 1H), 7.67 (d, J=7.9Hz, 1H), 7.57-7.45 (m, 2H), 7.42
(ddd, J=8.3,4.3,1.4Hz, 1H), 7.36 (d, J=8.1Hz, 1H), 7.17 (t, J=7.6Hz, 1H), 7.06 (t, J=
7.5Hz, 1H), 7.02 (s, 1H), 2.91 (ddd, J=11.4,9.3,6.0Hz, 1H), 2.59-2.40 (m, 2H), 2.39-2.28
(m, 1H), 2.28-2.14 (m, 1H), 1.83 (t, J=7.3Hz, 2H), 0.86 (td, J=7.4,1.4Hz, 3H)
13C NMR(101MHz,Chloroform-d)δ172.35,148.11,138.35,136.77,136.39,
134.62,127.98,127.49,127.17,121.83,121.68,121.62,121.41,119.60,119.08,118.83,
116.44,111.34,77.48,77.16,76.84,38.46,36.49,31.20,29.21,12.38.
HRMS(ESI)m/z Calcd for C23H24N3O+[M+H+]:358.1914,found:358.1917.
The ee values of compound shown in Formula VII are analyzed via HPLC, and the chiral column used is：Phenomenex
Cellulose-1 column (n-hexanes：Isopropanol=80:20,1.0mL/min, T=30 DEG C, 254nm), TR=16.09min
(major),18.19min(minor):94:6er. wherein, the spectrum of the HPLC of asymmetric products shown in Formula VII in embodiment 18
Scheme the spectrogram (Figure 20) of the HPLC of racemic product shown in (Figure 19) and Formula VII；It can be seen that 4 catalytic asymmetric reaction of ligand L
The yield and ee values of generation are all fine.
Embodiment 21-26
The present invention provides application response condition of single tooth Pei Wei oxazoline ligands in asymmetric reaction and embodiment 15-
20 is essentially identical, and the reaction differed only in the present embodiment carries out under protection of argon gas.
| Embodiment | Corresponding ligand | Yield/% of Formula VII compound | Ee values/% of Formula VII compound |
| Embodiment 21 | L1 | 34 | 67 |
| Embodiment 22 | L2 | 64 | 86 |
| Embodiment 23 | L3 | 56 | 80 |
| Embodiment 24 | L4 | 52 | 92 |
| Embodiment 25 | L5 | 60 | 81 |
| Embodiment 26 | L6 | 63 | 84 |
As can be seen that the asymmetric reaction of the present invention can be such that the yield of compound slightly declines in nitrogen protection, but can make
The ee values of Formula VII compound further increase, and reason is that a small amount of oxygen in air may be golden with Pd in the reaction system
Belong to coordination, is competed to be formed with chiral ligand, to make the ee values of product reduce.
Claims (8)
1. a kind of list tooth Pei Wei oxazoline ligands, it is characterized in that：The structural formula of the list tooth Pei Wei oxazoline ligands is as follows：
。
2. a kind of list tooth Pei Wei oxazoline ligands, it is characterized in that：The structural formula of the list tooth Pei Wei oxazoline ligands is as follows：
。
3. according to a kind of preparation method of any single tooth Pei Wei oxazoline ligands of claim 1-2, characterized in that including
Following steps：
(1) in the corresponding halogen organic solvent of nonpolarity, by Formulas I compound represented, Formula II compound represented, organic acid
Catalyst is according to 1:1.2-2.0：The mol ratio of 0.05-0.1 is uniformly mixed, back flow reaction 10-24 hours under 50-100 degree,
It isolates and purifies, obtains ligand compound shown in formula III, specific synthetic route is as follows：
4. a kind of preparation method of single tooth Pei Wei oxazoline ligands according to claim 3, characterized in that including following step
Suddenly：The halogen organic solvent of nonpolarity in the step (1) is one kind in 1,2- dichloroethanes or dichloromethane；It is described organic
Acid catalyst is one kind in the acid such as acetic acid, sulfuric acid, formic acid, hydrochloric acid.
5. according to a kind of preparation method of any single tooth Pei Wei oxazoline ligands of claim 4, characterized in that step
(1) reaction in can also carry out under nitrogen protection.
6. according to a kind of application of any single tooth Pei Wei oxazoline ligands of claim 1-2, characterized in that including following
Step：Ligand, adjacent Phenylbenzoic acid and alcohol system shown in substrate, nucleopilic reagent, palladium catalyst, formula III shown in Formula IV are had
Solvent is according to 1:1.5:0.1:0.3:1.0 molar ratio mixing, is stirred at room temperature 30 minutes, then in 60 DEG C of heat block
Upper reaction 48 hours.Reaction solution is cooled to room temperature, Formula VII compound represented, and the ee of Formula VII compound represented are obtained
Value is 60-90%；Specific synthetic route is as follows：
7. a kind of application of single tooth Pei Wei oxazoline ligands according to claim 6, characterized in that the alcohol system is organic molten
Agent is one kind in methanol, ethyl alcohol or isopropanol；The palladium catalyst is palladium acetate catalyst, dibenzoic acid palladium catalyst；Institute
It is substituted indole to state nucleopilic reagent.
8. a kind of application of single tooth Pei Wei oxazoline ligands according to claim 6, characterized in that the list tooth Pei Wei Evil
The application response of oxazoline ligand can also carry out under protection of argon gas.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1201793A (en) * | 1998-07-09 | 1998-12-16 | 华东理工大学 | Quinolinoxazole compound |
| CN1549818A (en) * | 2001-08-09 | 2004-11-24 | �������⻯ѧƷ�ع�����˾ | Isoxazoline derivatives as P, N ligands |
| CN103159693A (en) * | 2012-09-26 | 2013-06-19 | 上海大学 | Chiral aryl-substituted phenyl-1,3-oxazoline compound and synthesis method thereof |
| CN105601626A (en) * | 2015-11-04 | 2016-05-25 | 浙江大学 | Preparation method of 2-substituted oxazoline-containing derivative |
-
2018
- 2018-05-29 CN CN201810531622.5A patent/CN108774216A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1201793A (en) * | 1998-07-09 | 1998-12-16 | 华东理工大学 | Quinolinoxazole compound |
| CN1549818A (en) * | 2001-08-09 | 2004-11-24 | �������⻯ѧƷ�ع�����˾ | Isoxazoline derivatives as P, N ligands |
| CN103159693A (en) * | 2012-09-26 | 2013-06-19 | 上海大学 | Chiral aryl-substituted phenyl-1,3-oxazoline compound and synthesis method thereof |
| CN105601626A (en) * | 2015-11-04 | 2016-05-25 | 浙江大学 | Preparation method of 2-substituted oxazoline-containing derivative |
Non-Patent Citations (1)
| Title |
|---|
| 张成路等: "含噁唑啉环的苯并咪唑卡宾配体的设计合成及其在催化加成反应中的应用研究", 《辽宁师范大学学报(自然科学版)》 * |
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