CN111187142B - Method for enantioselective aryl alkynylation of olefin - Google Patents

Method for enantioselective aryl alkynylation of olefin Download PDF

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CN111187142B
CN111187142B CN202010016009.7A CN202010016009A CN111187142B CN 111187142 B CN111187142 B CN 111187142B CN 202010016009 A CN202010016009 A CN 202010016009A CN 111187142 B CN111187142 B CN 111187142B
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enantioselective
aryl
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alkene
alkynylation
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CN111187142A (en
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张国柱
雷光月
张瀚文
陈斌
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Shanghai Institute of Organic Chemistry of CAS
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    • C07C2/00—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms
    • C07C2/86—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon
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    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/272—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by addition reactions
    • C07C17/275—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by addition reactions of hydrocarbons and halogenated hydrocarbons
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    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton

Abstract

The invention provides an alkene enantioselective aryl alkynylation method, and relates to the technical field of drug intermediate synthesis; specifically, the alkene, diaryl iodonium salt and terminal alkyne perform enantioselective arylethynylation reaction under the synergistic action of a copper catalyst and a ligand, three reactants perform coupling reaction under mild reaction conditions, the reactant range is wide, the 1, 2-diaryl-3-butyne compound with high comprehensive value is synthesized, and the reaction yield and the chiral purity are high.

Description

Method for enantioselective aryl alkynylation of olefin
Technical Field
The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a method for enantioselective aryl alkynylation of olefin.
Background
Sphingosine-1-Phosphate (Sphingosine-1-Phosphate S1P) is a lysophospholipid with important biological activity, which plays a key role as a signal molecule in many biological processes such as cell survival, growth, differentiation and migration. Sphingosine-1-phosphate is stored at relatively high concentrations in human platelets, which lack enzymes capable of catabolizing sphingosine-1-phosphate, which is released directly into the blood stream upon activation by physiological stimuli such as growth factors, cytokines, and receptor agonists and antigens. Sphingosine-1-phosphate plays a key role in platelet aggregation and thrombosis, but aggravates cardiovascular diseases, on the one hand, and sphingosine-1-phosphate, at relatively high concentrations in High Density Lipoproteins (HDL), is beneficial for atherogenesis, on the other hand. For example, recent studies have shown that sphingosine-1-phosphate, together with other blood-soluble lipids, such as sphingosylphosphorylcholine and lysosulfate, is a significant benefit in the clinical efficacy of HDL by stimulating vascular endothelium to produce a potent anti-atherosclerotic signaling molecule, nitric oxide. In addition, sphingosine-1-phosphate, like lysophosphatidic acid, is also a marker for certain types of cancer, and there is evidence that its role in cell division or proliferation may have an impact on cancer development. The current study of sphingosine-1-phosphate is a research hotspot for medical researchers, and there has been a growing active search for therapeutic intervention of sphingosine-1-phosphate in metabolism with the aim of alleviating the effects of diseases and disorders by modulating S1P.
As sphingosine-1-phosphate receptor modulators, the novel azetidine derivatives of international patent WO2012074926a1 disclose a group of novel azetidine derivatives which are potent and selective for sphingosine-1-phosphate as receptor modulators useful in the treatment of a variety of diseases associated with modulation of sphingosine-1-phosphate receptors. This patent discloses an important intermediate for the synthesis of novel azetidine derivatives, the synthetic route of which is:
Figure BDA0002358901800000021
the synthesis steps are complicated, the product is low in yield and low in chiral purity due to multi-step reaction, the yield of the final product, namely the novel azetidine derivative is low, the production cost of the novel azetidine derivative is high, and the novel azetidine derivative is not favorable for popularization and application as the sphingosine-1-phosphate portable regulator.
Disclosure of Invention
The invention aims to provide a method for alkene enantioselective aryl alkynylation, which can prepare 1, 2-diaryl-3-butyne series compounds by one-step reaction with chiral selectivity under mild reaction conditions, can prepare important intermediates of novel azacyclic derivatives of sphingosine-1-phosphate receptor modulators by the synthetic route disclosed by the invention, and has high reaction yield and chiral purity.
In order to achieve the above purpose, the invention provides the following technical scheme: a method for alkene enantioselective aryl alkynylation comprises the steps of carrying out enantioselective aryl alkynylation reaction on terminal alkene A, terminal alkyne B and diaryl iodonium salt C in an environment containing a catalyst and a ligand to generate 1, 2-diaryl-3-butyne D;
the specific synthetic route is as follows:
Figure BDA0002358901800000031
wherein the terminal olefin A has the formula wherein the radical R1Is aryl, heterocyclic or aliphatic radical, terminal alkyne B being a radical R in the formula2Is aryl, heterocycle, cycloalkyl, cycloalkenyl or TMS, a radical R in the formula of diaryliodonium salt C3Is aryl, heterocycle or-CF3。
Further, the equivalent ratio of the terminal alkene a, terminal alkyne B, and diaryliodonium salt C is 1.0: 2.0: 1.25.
further, the ligand is
Figure BDA0002358901800000032
Figure BDA0002358901800000033
Further, the catalyst is copper catalyst, and the copper catalyst is CuI, CuBr, CuCl, CuOAc, Cu (MeCN)4PF6And CuCN.
Further, the terminal alkene A, the terminal alkyne B, and the diaryliodonium salt C are subjected to enantioselective arylethynylation in a solvent containing a catalyst and a ligand, wherein the solvent is one or more of methanol, toluene, DME, acetonitrile, DMF, THF, and dioxane.
Further, a basic salt is dissolved in the solvent, and the basic salt is Cs2CO3、Na2CO3、Li2CO3、K2CO3、K3PO4、NaHCO3、KHCO3Or K2HPO4。
Further, the equivalent ratio of catalyst, ligand and basic salt in the solvent is 0.05: 0.05: 2.0.
according to the technical scheme, the method for enantioselectively arylethynylation of the olefin has the following beneficial effects:
the invention discloses a method for alkene enantioselective aryl alkynylation, olefin, diaryl iodonium salt and terminal alkyne are subjected to enantioselective aryl alkynylation reaction under the action of a copper catalyst, three reactants are subjected to coupling reaction under mild reaction conditions, the range of the reactants is wide, 1, 2-diaryl-3-butyne series compounds with high comprehensive value are synthesized, the reaction yield is high, and the chiral purity is also high. The key point of the success of synthesizing the 1, 2-diaryl-3-butyne series compounds in one step through the coupling reaction is that a chiral BOPA ligand is applied in the set reaction conditions, and the invention provides a novel method for generating phenyl free radicals under the action of a high-valence copper catalyst.
Compared with the synthesis scheme of the prior art which adopts a multi-step reaction, the synthesis method disclosed by the invention can directly carry out the one-step reaction, and has the advantages of mild reaction conditions, high yield and high chiral purity; the application in preparing the novel nitrogen heterocyclic derivative of the sphingosine-1-phosphate receptor regulator reduces the manufacturing cost of the novel nitrogen heterocyclic derivative and is beneficial to the popularization of the novel nitrogen heterocyclic derivative.
It should be understood that all combinations of the foregoing concepts and additional concepts described in greater detail below can be considered as part of the inventive subject matter of this disclosure unless such concepts are mutually inconsistent.
The foregoing and other aspects, embodiments and features of the present teachings can be more fully understood from the following description taken in conjunction with the accompanying drawings. Additional aspects of the present invention, such as features and/or advantages of exemplary embodiments, will be apparent from the description which follows, or may be learned by practice of specific embodiments in accordance with the teachings of the present invention.
Drawings
The drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. Embodiments of various aspects of the present invention will now be described, by way of example, with reference to the accompanying drawings, in which:
FIG. 1 is a nuclear magnetic hydrogen spectrum of product D1 of example 1 of the present invention;
FIG. 2 is a nuclear magnetic carbon spectrum of product D1 of example 1 according to the present invention;
FIG. 3 is a high performance liquid chromatogram of product D1 of example 1 according to the present invention;
FIG. 4 is a nuclear magnetic hydrogen spectrum of product D2 of example 2 of the present invention;
FIG. 5 is a nuclear magnetic carbon spectrum of product D2 of example 2 according to the present invention;
FIG. 6 is a high performance liquid chromatogram of product D2 of example 2 according to the invention;
FIG. 7 is a graph of the selection of products corresponding to different terminal olefins A and their yields in examples of the present invention;
FIG. 8 is a graph showing the selection of products corresponding to different terminal alkynes B and diaryliodonium salts C and their yields in examples of the present invention;
FIG. 9 is a reaction scheme of a synthetic route of the present invention;
FIG. 10 is a preferred synthetic scheme of the present invention.
Detailed Description
In order to better understand the technical content of the present invention, specific embodiments are described below with reference to the accompanying drawings.
In this disclosure, aspects of the present invention are described with reference to the accompanying drawings, in which a number of illustrative embodiments are shown. Embodiments of the present disclosure are not intended to include all aspects of the present invention. It should be appreciated that the various concepts and embodiments described above, as well as those described in greater detail below, may be implemented in any of numerous ways, as the disclosed concepts and embodiments are not limited to any one implementation. In addition, some aspects of the present disclosure may be used alone, or in any suitable combination with other aspects of the present disclosure.
The invention aims to provide a method for alkene enantioselective aryl alkynylation, which aims to prepare 1, 2-diaryl-3-butyne series compounds by one-step reaction with chiral selectivity under mild reaction conditions, has simple reaction steps and high reaction yield and chiral purity of products, and is favorable for preparation, popularization and application of the novel azacyclic derivative of the sphingosine-1-phosphate receptor modulator when the synthetic method is applied to preparation of an important intermediate of the novel azacyclic derivative of the sphingosine-1-phosphate receptor modulator.
The invention discloses a method for alkene enantioselective aryl alkynylation, which specifically comprises the following steps: carrying out enantioselective arylethynylation on terminal olefin A, terminal alkyne B and diaryl iodonium salt C in an environment containing a catalyst and a ligand to generate 1, 2-diaryl-3-butyne D;
the specific synthetic route is as follows:
Figure BDA0002358901800000061
wherein the terminal olefin A has the formula wherein the radical R1Is aryl, heterocyclic or aliphatic radical, terminal alkyne B being a radical R in the formula2Is aryl, heterocycle, cycloalkyl, cycloalkenyl or TMS (tetramethylsilane), diaryliodonium salt C in the formula3Is aryl, heterocycle or-CF3. The catalyst is copper catalyst selected from CuI, CuBr, CuCl, CuOAc and Cu (MeCN)4PF6And CuCN; the ligand is
Figure BDA0002358901800000062
Figure BDA0002358901800000063
The first 9 ligands are sequentially marked as iPr-Cbzbox, iBu-Cbzbox and PhCH2-Cbzbox, Ph-Cbzbox, Et-Cbzbox, tBu-Cbzbox, iPr-BOPA, Ph-BOPA and tBu-BOPA.
Specifically, enantioselective arylethynylation reaction of terminal alkene A, terminal alkyne B and diaryl iodonium salt C is carried out in a solvent containing a catalyst and a ligand, wherein the solvent is one or more of methanol, toluene, DME, acetonitrile, DMF, THF and dioxane; the solvent is dissolved with basic salt which makes the solvent alkaline, and the basic salt is Cs2CO3、Na2CO3、Li2CO3、K3CO3、K3PO4、NaHCO3、KHCO3And K2HPO4One or more of (a).
When the method is specifically implemented, the reaction condition is mild, and the reaction can be carried out at room temperature; in addition, in order to ensure that reactants do not react with external environment elements in the reaction process, the reaction is operated under the anhydrous and oxygen-free conditions, the enantioselective arylethynylation reaction disclosed by the invention is carried out under an inert gas protection system, such as a nitrogen system and an argon system, and the nitrogen system is directly adopted in the embodiment of the specification.
The specific operation process of the synthetic route of the method for alkene enantioselective aryl alkynylation comprises the following steps: in a dry sealed tube, the ligand (0.05 eq), basic salt (2.0 eq) and copper catalyst (0.05 eq) were completely dissolved in the solvent at room temperature; stirring the mixture for a while under nitrogen atmosphere, then adding terminal alkene (1.0 equivalent), terminal alkyne (2.0 equivalents) and diaryliodonium salt (1.25 equivalents) in order, sealing the opening of the sealed tube after the addition of reactants is completed; the mixture was stirred at room temperature for 24 hours, the reaction was monitored by TLC plates until the reaction was complete and the product was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluent.
The process for enantioselective arylalkynylation of olefins according to the invention is described in more detail below with reference to specific examples.
Example 1
In a dry sealed tube, the ligand tBu-BOPA (0.037mmol, 0.05 eq.), basic salt K2CO3(0.4mmol, 2.0 equiv.) and a copper catalyst (Cu (MeCN)4PF60.05 eq) was dissolved in anhydrous acetonitrile (2.0mL) at room temperature; stirring the mixture for 10min under a nitrogen atmosphere, then sequentially adding p-methylstyrene (0.2mmol, 1.0 equivalent), phenylacetylene (0.4mmol, 2.0 equivalent) and diphenyliodonium hexafluorophosphate (0.25mmol, 1.25 equivalent), and sealing the opening of the sealing tube by using a teflon diaphragm after the reactants are added; the mixture was stirred at room temperature for 24 hours, the reaction was monitored by TLC plate until completion, and the product was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluent; the product D1 was obtained as a colorless oil, 46.2mg, 0.16mmol, yield 78%, enantiomeric excess 86%.
Figure BDA0002358901800000071
The NMR and HPLC chromatograms of the product D1 are shown in FIGS. 1 to 3,1H NMR(400MHz,CDCl3)δ7.45–7.38(m,2H),7.35–7.27(m,8H),7.25(d,J＝7.7Hz,2H),7.18(d,J＝7.7Hz,2H),4.09(t,J＝7.3Hz,1H),3.14(d,J＝7.3Hz,2H),2.39(s,3H)。
13C NMR(100MHz,CDCl3)δ139.0,138.3,136.4,131.5,129.5,129.1,128.1,128.0,127.7,127.5,126.4,123.7,91.2,84.1,45.1,40.4,21.1.IR(neat)cm-1
Figure BDA0002358901800000082
3059,2920,1690,1601,1492,1450,1316,1177,1023,807,755,693,559,524.HRMS:m/z(EI)calculated[M]+:296.1565,found:296.1562。
HPLC(Chiralcel OD-H column,hexanes:i-PrOH＝100:0,0.8mL/min,210nm),tminor＝25.9min,tmajor＝29.4min,ee＝86％.[α]D 25＝5.4,(c＝0.47,CHCl3)。
example 2
Except for example 1, where reactant A was replaced with 4-acetoxystyrene (0.2mmol, 1.0 equiv.) and the conditions were otherwise unchanged, the product D2 was obtained as a colorless oil, 56.4mg, 0.17mmol, yield 83%, enantiomeric excess 89%.
Figure BDA0002358901800000081
The NMR and HPLC chromatograms of the product D2 are shown in FIGS. 4 to 6:1H NMR(400MHz,CDCl3)δ7.90(d,J＝7.9Hz,2H),7.35–7.27(m,4H),7.23–7.19(m,3H),7.18–7.12(m,3H),7.05(d,J＝6.9Hz,2H),4.05(t,J＝7.1Hz,1H),3.82(s,3H),3.10–2.97(m,2H)。
13C NMR(100MHz,CDCl3)δ166.9,146.4,138.2,131.5,129.7,129.5,128.8,128.2,128.1,128.0,127.8,126.6,123.3,90.0,84.7,52.0,44.7,40.7.IR(neat)cm-1
Figure BDA0002358901800000083
3060,2949,1718,1691,1605,1491,1435,1275,1178,1106,1018,936,857,756,694,559,485.HRMS:m/z(ESI)calculated[M+Na]+:363.1361,found:363.1355。
HPLC(Chiralcel OD-H column,hexanes:i-PrOH＝98:2,0.8mL/min,210nm),tminor＝8.9min,tmajor＝9.9min,ee＝89％.[α]D 25＝8.1,(c＝0.15,CHCl3)。
example 3
Except for example 1, where reactant A was replaced with p-trifluoromethylstyrene (0.2mmol, 1.0 equiv.) and the other conditions were unchanged, the product D3 was obtained as a colorless oil, 55.3mg, 0.16mmol, yield 86% and enantiomeric excess 86%.
Figure BDA0002358901800000091
The results of the nuclear magnetic spectrum and the high performance liquid chromatography data of the product D3 are as follows:1H NMR(400MHz,CDCl3)δ7.56(d,J＝7.9Hz,2H),7.44(d,J＝8.0Hz,2H),7.41–7.35(m,2H),7.32–7.19(m,6H),7.14(d,J＝7.1Hz,2H),4.13(t,J＝7.2Hz,1H),3.19–3.05(m,2H)。
13C NMR(100MHz,CDCl3)δ140.2,138.1,131.5,129.5,129.2(q,J＝32.3Hz),128.3,128.1,128.1,128.0,126.7,125.4(q,J＝3.0Hz),124.2(q,J＝270.1Hz),123.2,89.9,84.8,44.8,40.1.19F NMR(376MHz,CDCl3)δ-62.2(s,3F).IR(neat)cm-1
Figure BDA0002358901800000092
3063,2924,1692,1600,1492,1450,1413,1321,1163,1118,1065,1016,833,754,693,603,530.HRMS:m/z(EI)calculated[M]+:350.1282,found:350.1287。
HPLC(Chiralcel OD-H column,hexanes:i-PrOH＝99.2:0.8,0.35mL/min,210nm),tminor＝15.2min,tmajor＝15.9min,ee＝86％.[α]D 25＝4.9,(c＝0.28,CHCl3)。
example 4
Different from example 1 in that the reactant A was replaced by p-styrene (0.2mmol, 1.0 equivalent), and other conditions were not changed, the product D4 was obtained as a colorless oil, 40.6mg, 0.14mmol, yield 72%, enantiomeric excess 87%.
Figure BDA0002358901800000101
The results of the nuclear magnetic spectrum and the high performance liquid chromatography data of the product D4 are as follows:1H NMR(400MHz,CDCl3)δ7.49–7.42(m,4H),7.41–7.28(m,9H),7.26(d,J＝7.2Hz,2H),4.15(t,J＝7.2Hz,1H),3.19(d,J＝7.2Hz,2H)。
13C NMR(100MHz,CDCl3)δ141.2,138.8,131.5,129.5,128.4,128.1,128.0,127.8,127.7,126.8,126.4,123.6,90.9,84.3,45.1,40.8.IR(neat)cm-1
Figure BDA0002358901800000103
3059,2921,1688,1597,1490,1449,1271,1175,1070 1026,913,843,754,691,559,513.HRMS:m/z(EI)calculated[M]+:282.1409,found:282.1411。
HPLC(Chiralcel OD-Hcolumn,hexanes:i-PrOH＝100:0,0.8mL/min,210nm),tminor＝34.0min,tmajor＝30.7min,ee＝87％.[α]D 25＝103.8(c＝0.05,CHCl3)。
example 5
Except for example 1, where reactant A was replaced with p-phenylstyrene (0.2mmol, 1.0 equiv.) and the conditions were otherwise unchanged, the product D5 was obtained as a colorless oil, 53.7mg, 0.15mmol, yield 75%, enantiomeric excess 89%.
Figure BDA0002358901800000102
The results of the nuclear magnetic spectrum and the high performance liquid chromatography data of the product D5 are as follows:1H NMR(400MHz,CDCl3)δ7.56(dd,J＝16.7,7.7Hz,4H),7.45–7.37(m,5H),7.36–7.15(m,9H),4.11(t,J＝7.2Hz,1H),3.14(d,J＝7.2Hz,2H)。
13C NMR(100MHz,CDCl3)δ140.8,140.4,139.7,138.8,131.5,129.5,128.7,128.2,128.1,128.0,127.8,127.2,127.1,127.0,126.5,123.6,90.8,84.4,45.0,40.5.IR(neat)cm-1
Figure BDA0002358901800000112
3057,2921,1688,1599,1516,1486,1448,1405,1284,1111,912,833,756,691,569,509.HRMS:m/z(EI)calculated[M]+:358.1722,found:358.1732。
HPLC(Chiralcel OD-H column,hexanes:i-PrOH＝99.5:0.5,0.8mL/min,210nm),tminor＝13.7min,tmajor＝15.7min,ee＝89％.[α]D 25＝7.0,(c＝0.33,CHCl3)。
in summary, the structures for adjusting the terminal olefin of the reactant A shown in examples 1 to 5 also include other terminal olefins containing different groups R1The terminal olefin and the terminal alkyne of,The product, yield and enantiomeric excess of the diaryliodonium salts after reaction are all reported on the structure shown in FIG. 7.
The invention further discloses compounds having different radicals R2Corresponding reactant B, different radicals R3The corresponding reactant C reacts with the terminal olefin to produce different products, yields and enantiomeric excess values, the results of which are shown in FIG. 8.
To further investigate the effect of setting conditions on the preparation of the 1, 2-diaryl-3-butyne series of compounds according to the invention, example 6, example 7, example 8 and example 9 investigated the effect of different ligands, different copper catalysts, different solvents and different basic salts, respectively, on the product yield and the enantiomeric excess.
Example 6: ligand screening
The method selects p-methylstyrene, phenylacetylene and diphenyliodonium hexafluorophosphate to react, has the following reaction formula, selects 12 ligands of L1-L11 and 2,2, 2-terpyridine to carry out experiments, and verifies the influence of the ligands on the yield and the enantiomeric excess value of a product D1, and the results are shown in Table 1.
Figure BDA0002358901800000111
Figure BDA0002358901800000121
Combining the yield and the enantiomeric excess value shown in the table 1, the product yield and the enantiomeric excess value corresponding to the ligand L9 are the highest, the high enantiomeric excess value indicates that the chiral purity of the product is high, the ligand L9 is selected as the ligand with the best verification effect, and the ligand L9 is used for selecting the better copper catalyst.
TABLE 1 ligand screening
Figure BDA0002358901800000122
Example 7: catalyst screening
Selecting p-methylstyrene, phenylacetylene and diphenyliodonium hexafluorophosphate to react, wherein the reaction formula is as follows, and selecting CuI, CuBr, CuCl, CuOAc and Cu (MeCN)4PF6And CuCN 6 copper catalyst experiments, and the effects of the catalysts on the yield and the enantiomeric excess of the product D1 are verified, and the results are shown in Table 2.
Figure BDA0002358901800000123
TABLE 2 catalyst screening
Figure BDA0002358901800000131
Combining the yields and enantiomeric excesses shown in Table 2, the copper catalyst having better catalytic effect is Cu (MeCN)4PF6Ligand L9, catalyst Cu (MeCN)4PF6Further solvent screening was performed.
Example 8: solvent screening
The p-methylstyrene, phenylacetylene and diphenyliodonium hexafluorophosphate are selected to react, the reaction formula is as follows, 7 solvent experiments including methanol, toluene, DME, acetonitrile, DMF, THF and dioxane are selected, and the influence of the solvent on the yield and enantiomeric excess of the product D1 is verified, and the results are shown in Table 3.
Figure BDA0002358901800000132
TABLE 3 solvent screening
Figure BDA0002358901800000133
As is clear from the data in Table 3, the product yield and enantiomeric excess obtained are high when acetonitrile is used as solvent, and ligand L9 and catalyst Cu (MeCN)4PF6And further carrying out basic salt screening on the solvent acetonitrile.
Example 8: basic salt screening
Selecting p-methylstyrene, phenylacetylene and diphenyliodonium hexafluorophosphate to react, wherein the reaction formula is as follows, and Cs is selected2CO3、Na2CO3、Li2CO3、K2CO3、K3PO4、NaHCO3、KHCO3And K2HPO4In total, 8 basic salt experiments were performed to verify the effect of the basic salt on the yield and enantiomeric excess of the product D1, and the results are shown in table 4.
Figure BDA0002358901800000141
TABLE 4 basic salt screening
Figure BDA0002358901800000142
The data from the basic salt screen shown in Table 4 indicate K2CO3Has better promoting effect on the alkene enantioselective aryl alkynylation.
In summary, the reaction mechanism for obtaining the present invention is shown in FIG. 9 in examples 1 to 8.
The reaction mechanism of the present invention is shown in FIG. 9, in which Cu (I) X reacts with ligand Ln in an alkaline environment to form complex Cu (I) Ln. Then in alkaline environment, the complex Cu (I) Ln reacts with alkyne to generate [ LnCu (I) (C ≡ CR)]-K+(M)，[LnCu(I)(C≡CR)]-K+(M) is oxidized by diaryliodonium salts to give Cu (II) particles, LnCu (II) (C.ident.CR) (N), constituting aryl groups. In summary, the preferred synthetic route of the method for enantioselective arylalkynylation of olefins according to the present invention is shown in FIG. 10.
The invention discloses a method for alkene enantioselective aryl alkynylation, which can be directly modified into the following synthetic route for the process steps of synthesizing an important intermediate of a novel nitrogen heterocyclic derivative in a sphingosine-1-phosphate receptor regulator by using the novel nitrogen heterocyclic derivative disclosed in international patent WO2012074926A 1:
Figure BDA0002358901800000143
compared with the reaction steps disclosed in the international patent, the synthesis route is directly completed by one step through the existing 5-step reaction, the reaction conditions are mild, the yield of the product is high, and the enantiomeric excess value is also high.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, the protection scope of the present invention should be determined by the appended claims.

Claims (1)

1. A method for alkene enantioselective aryl alkynylation is characterized in that terminal alkene A, terminal alkyne B and diaryl iodonium salt C are subjected to enantioselective aryl alkynylation reaction in a solvent containing a catalyst and a ligand and dissolved with basic salt to generate 1, 2-diaryl-3-butyne D;
the equivalent ratio of terminal alkene a, terminal alkyne B and diaryliodonium salt C is 1.0: 2.0: 1.25;
the equivalent ratio of catalyst, ligand and basic salt in the solvent is 0.05: 0.05: 2.0;
the specific compounds, solvents, catalysts, ligands, basic salts and corresponding reaction products of the terminal alkene a, terminal alkyne B, diaryl iodonium salt C are shown in the following table:
Figure FDA0002962763310000011
Figure FDA0002962763310000021
Figure FDA0002962763310000031
Figure FDA0002962763310000041
Figure FDA0002962763310000051
Figure FDA0002962763310000061
Figure FDA0002962763310000071
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CN103339095A (en) * 2010-12-03 2013-10-02 阿勒根公司 Alkyne and alkene derivatives as sphingosine 1-phosphate-1 receptor modulators
CN110627610A (en) * 2019-08-29 2019-12-31 南方科技大学 Method for synthesizing alkyne by catalyzing asymmetric cross coupling

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A general asymmetric copper-catalysed Sonogashira C(sp(3))-C(sp) coupling;Dong,Xiao-Yang 等;《NATURE CHEMISTRY》;20191231;第11卷(第12期);第1159-1161页table1-3 *
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