Synthesis method of chiral trifluoromethyl allyl tertiary alcohol compound

Abstract

The invention relates to a synthesis method of a chiral trifluoromethyl allyl tertiary alcohol compound, which comprises the following steps: under the protection of nitrogen, taking alkyne and trifluoromethyl ketone as raw materials, taking metal cobalt salt and an organic ligand as catalysts, taking Hanus ester as a reducing agent, and reacting in the presence of excessive organic solvent, photosensitizer and organic alkali to obtain the chiral trifluoromethyl allyl tertiary alcohol compound. And carrying out illumination reaction to obtain the chiral trifluoromethyl allyl tertiary alcohol compound. The method has the advantages of simple and easily available reaction raw materials and reagents, mild and easily controlled conditions, high atom economy, no need of noble metal catalysis, wide substrate application range, high regioselectivity, stereoselectivity and enantioselectivity, and wide application prospect.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis methods, and in particular to a method for synthesizing a chiral trifluoromethyl allyl tertiary alcohol compound. Background Technology

[0002] Organofluorine chemistry is a rapidly developing field with a wide range of applications, potentially impacting all sectors of society. In fact, fluorine plays a crucial role in pharmaceuticals, veterinary medicine, agricultural chemistry, and materials science. Particularly relevant is the emergence of drug candidates characterized by fluorine atoms, which often exhibit promising therapeutic effects. Therefore, the introduction of one or more fluorine atoms is a routine strategy in every new drug discovery and development program (Thayer, AMChem. Eng. News 2006, 84, 15; O'Hagan, D.; Harper, DBJ Fluorine Chem. 1999, 100, 127; Ma, J.-A.; Cahard, DJ Fluorine Chem. 2007, 128, 975). It is well known that the presence of fluorine functional groups in bioactive molecules profoundly alters their physicochemical and biological properties through changes in their spatial, electronic, lipophilic, and metabolic characteristics. The promising therapeutic effects of drugs characterized by fluorine atoms in humans and animals have spurred research into new discoveries in medicinal chemistry; however, constructing fluorine-containing compounds remains highly challenging. In particular, stereocontrol of the carbon center characterized by trifluoromethyl groups is an extremely challenging task (Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1.; Dale, JA; Dull, DL; Mosher, H.S. J. J. G. Chem. 1969, 34, 2543.).

[0003] Currently, the construction of chiral trifluoromethyl allyl tertiary alcohol compounds is mainly achieved through one-step addition of nucleophiles to trifluoromethyl ketones or by allylation catalyzed with rhodium (which cannot achieve optical activity), or by inducing the synthesis of chiral trifluoromethyl allyl tertiary alcohol compounds using chiral substrates (Zhang, F., Liu, Z., Liu, J., 1,8-Diazabicyclo[5.4.0]undec-7-ene(DBU)Catalyzed Regiospecific and Diastereoselective Reaction of Chiral N-(tert-Butanesulfinyl)ketimines and α,β-Unsaturated Trifluoromethyl Ketones. Chin. J. Chem. 2011, 29, 2727-2731.; Lee, K., Silverio, DL, Torker, S., Robbins, DW, Haeffner, F., Hoveyda, AHCatalytic enantioselective addition of organoboron reagents to fluoroketones controlled by electrostaticinteractions.Nat.Chemistry 2016,8,768–777.;Liu,Z.-Q.,Liang,C.,Luo,Z.,Wu,Y.-F.,Hong,C.-M.,Li,Q.-H.,Liu,T.-L.Transfer Vinylation and Dienylation viaRhodium(I)-Catalyzed Deketonation of Allylic Alcohols.ACS Catal.2022,12,7030-7036.,Mu,B.-S.,Gao,Y.,Yang,F.-M.,Wu,W.-B.,Zhang,Y.,Wang,X.,Yu,J.-S.,Zhou,J.The Bifunctional Silyl Reagent Me2(CH2Cl)SiCF3 Enables HighlyEnantioselective Ketone Trifluoromethylation and Related Tandem Processes. Angew. Chem. Int. Ed. 2022, 61, e202208861.).However, there are currently no reports on the synthesis of chiral trifluoromethyl allyl alcohol compounds by reacting simple terminal alkynes and trifluoromethyl ketones in the presence of a reducing agent. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for synthesizing chiral trifluoromethyl allyl tertiary alcohol compounds that has a wide substrate range, high atom economy, and does not require noble metal catalysis.

[0005] To address the aforementioned problems, the present invention provides a method for synthesizing a chiral trifluoromethyl allyl tertiary alcohol compound, characterized in that: the synthesis method refers to preparing a chiral trifluoromethyl allyl tertiary alcohol compound as shown in general formula III by photocatalysis under nitrogen protection, using alkynes represented by general formula I and trifluoromethyl ketones represented by general formula II as raw materials, cobalt salt and organic ligands as catalysts, and hans ester as a reducing agent, in the presence of excess organic solvent, photosensitizer and organic base;

[0006] General formula I: General Formula II: General Formula III:

[0007] In the formula: R 1 R 2 Each is independently selected from substituted or unsubstituted C1-C. 11 Alkyl, substituted or unsubstituted C6-C 10 cycloalkyl, substituted or unsubstituted C1-C 28 The R group is one of the following: aryl, halogen, hydroxyl, ester, amide, alkoxy, aryloxy, ferrocene, silicon-containing, boron-containing, aldehyde, ketone carbonyl, or mercapto. 1 R 2 Similarities or differences.

[0008] The reaction formula is as follows:

[0009]

[0010] The R 1 R 2 Each is independently selected from one of the following: phenyl, alkyl-substituted phenyl, heterocyclic phenyl, hydroxy-substituted phenyl, ester-substituted phenyl, halogen-substituted phenyl, ketone-substituted phenyl, aldehyde-substituted phenyl, aryl-substituted phenyl, alkoxy-substituted phenyl, aryloxy-substituted phenyl, various aromatic heterocycles, naphthyl, cyclohexenyl, methyl, long-chain alkyl, cyclic alkyl, hydroxy-substituted alkyl, aryl-substituted alkyl, ester-substituted alkyl, halogen-substituted alkyl, cyano-substituted alkyl, alkoxy-substituted alkyl, and aryloxy-substituted alkyl.

[0011] The mass ratio of the alkyne to the trifluoromethyl ketone is 1:100 to 100:1.

[0012] The cobalt salts are CoBr2, CoCl2, CoI2, Co(NO3)2·6H2O, Co(BF4)2·6H2O, CoSO4·H2O, Co2(CO)8, Co(acac)2, Co(OAc)2, CoC2O4, and Cp. * One of Co(CO)I2, Cp2CoPF6, CoCO3, CoBr2·DME, and Co3(PO4)2 is used in an amount of 5% or 10% of the molar mass of the alkyne substrate.

[0013] The organic ligand is selected from one of chiral monophosphorus ligands, chiral diphosphorus ligands, chiral nitrogen-phosphorus ligands, chiral monodentate nitrogen ligands, and chiral bidentate nitrogen ligands, and its amount is 10% or 20% of the molar mass of the alkyne substrate.

[0014] The amount of Hans ester used is 2.0 times the stoichiometric amount of the alkyne substrate.

[0015] The organic solvent is one or more selected from n-butyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide, acetonitrile, toluene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl acetate, methanol, anhydrous ethanol, or isopropanol.

[0016] The photosensitizer refers to 2,4,5,6-tetrakis(9H-carbazole-9-yl)isophthalonitrile (4CzIPN), 2,4,5,6-tetrakis(3,6-diphenyl-9H-carbazole-9-yl)isophthalonitrile (4CzIPN-Ph), 2,4,5,6-tetrakis(3,6-dibromo-9H-carbazole-9-yl)isophthalonitrile (4CzIPN-Br), and 2,4,5,6-tetrakis(3,6-di-tert-butyl-9H-carbazole-9-yl)isophthalonitrile (4CzIPN- t Bu), 3,4,5,6-tetrakis(3,6-dibromo-9H-carbazole-9-yl)phthalonitrile (4CzPN-Br), 3,4,5,6-tetrakis(3,6-di-tert-butyl-9H-carbazole-9-yl)phthalonitrile (4CzPN- t Bu), 3,4,5,6-tetra(3,6-diphenyl-9H-carbazole-9-yl)phthalonitrile (4CzPN-Ph), 2,3,5,6-tetra(3,6-di-tert-butyl-9H-carbazole-9-yl)terephthalonitrile (4CzTPN), 2,3,5,6-tetra(3,6-di-tert-butyl-9H-carbazole-9-yl)terephthalonitrile (4CzTPN-Ph), 2,3,5,6-tetra(3,6-di-tert-butyl-9H-carbazole-9-yl)terephthalonitrile (4CzTPN- tBu), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (3DPA2FBN), 2,4,5,6-tetra(diphenylamino)-isophthalonitrile (4DPAIPN), tris(2,2′-bipyridine)ruthenium di(hexafluorophosphate) (Ru(bpy)3(PF6)2), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][1,10-phenanthroline]iridium di(hexafluorophosphate) ([Ir(dF(CF3)ppy)2phen)]PF6), bis[2,4 One of the following: (-difluorophenyl)-5-methylpyridine][2,2'-bi(tetra-tert-butylpyridine)]iridium di(hexafluorophosphate) ([Ir(dFMeppy)2dtbbpy)]PF6), FAC-IR(2-phenylpyridinyl)3 (fac-Ir(ppy)3), and (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridinyl)phenyl]iridium(III)hexafluorophosphate ([Ir(ppy)2(dtbbpy)]PF6), is used in an amount of 2% of the molar mass of the alkyne substrate.

[0017] The organic base is one of diisopropylethylamine, triethylamine, trimethylamine, dicyclohexylmethylamine, and diisopropylamine, and its amount is 12% of the molar mass of the alkyne substrate.

[0018] The photo-reaction refers to a reaction at room temperature with stirring for 20 hours under the illumination of a 5-watt blue LED lamp.

[0019] Compared with the prior art, the present invention has the following advantages:

[0020] 1. This invention uses inexpensive cobalt salt as a catalyst, terminal alkynes and trifluoromethyl ketones as raw materials, and Hans ester as a reducing agent to prepare chiral trifluoromethyl allyl tertiary alcohol compounds through photo-irradiation reaction in the presence of organic solvents, photosensitizers, and organic bases. Not only are the raw materials inexpensive and readily available, and the reaction conditions mild and easy to control, but the reaction also has excellent regioselectivity, stereoselectivity, and enantioselectivity. It is currently the most competitive method for synthesizing chiral trifluoromethyl allyl alcohol compounds.

[0021] 2. This invention has high atom economy, does not require precious metal catalysis, and has a wide range of applicable substrates, thus having broad application prospects. Detailed Implementation

[0022] A method for synthesizing a chiral trifluoromethyl allyl tertiary alcohol compound, wherein the method refers to the reaction under nitrogen protection, using alkynes of general formula I and trifluoromethyl ketones of general formula II as raw materials, cobalt salt and organic ligands as catalysts, and hans ester as reducing agent, in the presence of excess organic solvent, photosensitizer and organic base, and under irradiation with a 5-watt blue LED lamp at room temperature with stirring for 20 hours, to obtain a chiral trifluoromethyl allyl tertiary alcohol compound as shown in general formula III;

[0023] General Formula I: General Formula II: General Formula III:

[0024] In the formula: R 1 R 2 Each is independently selected from substituted or unsubstituted C1-C. 11 Alkyl, substituted or unsubstituted C6-C 10 cycloalkyl, substituted or unsubstituted C1-C 28 The R group is selected from one of the following groups: aryl, halogen, hydroxyl, ester, amide, alkoxy, aryloxy, ferrocene, silicon-containing, boron-containing, aldehyde, ketone carbonyl, and mercapto. 1 R 2 Similarities or differences.

[0025] Where: R 1 R 2 Each is independently selected from one of the following: phenyl, alkyl-substituted phenyl, heterocyclic phenyl, hydroxy-substituted phenyl, ester-substituted phenyl, halogen-substituted phenyl, ketone-substituted phenyl, aldehyde-substituted phenyl, aryl-substituted phenyl, alkoxy-substituted phenyl, aryloxy-substituted phenyl, various aromatic heterocycles, naphthyl, cyclohexenyl, methyl, long-chain alkyl, cyclic alkyl, hydroxy-substituted alkyl, aryl-substituted alkyl, ester-substituted alkyl, halogen-substituted alkyl, cyano-substituted alkyl, alkoxy-substituted alkyl, and aryloxy-substituted alkyl. Preferred: one of phenylacetylene, p-methylphenylacetylene, 3-hydroxyphenylacetylene, methyl 3-ethynylbenzoate, 2-chlorophenylacetylene, 4-ethynylbiphenyl, 3-ethynylthiophene, 1-ethynylcyclohexene, propyne, 1-hexyne, cyclohexyne, 2,2,2,4'-tetrafluoroacetophenone, 3'-methoxy-2,2,2-trifluoroacetophenone, 2,2,2,2'-tetrafluoroacetophenone, 2-2,2,2-trifluoronaphthyl acetophenone, 2,2,2-trifluoro-1-(6-methoxypyridin-3-yl)acetophenone, 1,1,1-trifluoro-3-phenylpropanone, and 1,1,1-trifluoro-4-(4-tolyl)-2-butanone.

[0026] The mass ratio (g / g) of alkyne to trifluoromethyl ketone is 1:100 to 100:1.

[0027] The metallic cobalt salts are CoBr2, CoCl2, CoI2, Co(NO3)2·6H2O, Co(BF4)2·6H2O, CoSO4·H2O, Co2(CO)8, Co(acac)2, Co(OAc)2, CoC2O4, and Cp. *One of Co(CO)I2, Cp2CoPF6, CoCO3, CoBr2·DME, and Co3(PO4)2 is used in an amount of 5% or 10% of the molar mass of the alkyne substrate.

[0028] The organic ligand is selected from one of chiral monophosphorus ligands, chiral diphosphorus ligands, chiral nitrogen-phosphorus ligands, chiral monodentate nitrogen ligands, and chiral bidentate nitrogen ligands, and its amount is 10% or 20% of the molar mass of the alkyne substrate.

[0029] The amount of Hans ester used was 2.0 times the stoichiometric amount of the alkyne substrate.

[0030] The organic solvent is one or more of the following: n-butyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide, acetonitrile, toluene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl acetate, methanol, anhydrous ethanol, or isopropanol.

[0031] Photosensitizers refer to 2,4,5,6-tetrakis(9H-carbazole-9-yl)isophthalonitrile (4CzIPN), 2,4,5,6-tetrakis(3,6-diphenyl-9H-carbazole-9-yl)isophthalonitrile (4CzIPN-Ph), 2,4,5,6-tetrakis(3,6-dibromo-9H-carbazole-9-yl)isophthalonitrile (4CzIPN-Br), and 2,4,5,6-tetrakis(3,6-di-tert-butyl-9H-carbazole-9-yl)isophthalonitrile (4CzIPN- t Bu), 3,4,5,6-tetrakis(3,6-dibromo-9H-carbazole-9-yl)phthalonitrile (4CzPN-Br), 3,4,5,6-tetrakis(3,6-di-tert-butyl-9H-carbazole-9-yl)phthalonitrile (4CzPN- t Bu), 3,4,5,6-tetra(3,6-diphenyl-9H-carbazole-9-yl)phthalonitrile (4CzPN-Ph), 2,3,5,6-tetra(3,6-di-tert-butyl-9H-carbazole-9-yl)terephthalonitrile (4CzTPN), 2,3,5,6-tetra(3,6-di-tert-butyl-9H-carbazole-9-yl)terephthalonitrile (4CzTPN-Ph), 2,3,5,6-tetra(3,6-di-tert-butyl-9H-carbazole-9-yl)terephthalonitrile (4CzTPN- tBu), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (3DPA2FBN), 2,4,5,6-tetra(diphenylamino)-isophthalonitrile (4DPAIPN), tris(2,2′-bipyridine)ruthenium di(hexafluorophosphate) (Ru(bpy)3(PF6)2), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][1,10-phenanthroline]iridium di(hexafluorophosphate) ([Ir(dF(CF3)ppy)2phen)]PF6), bis[2,4 One of the following: (-difluorophenyl)-5-methylpyridine][2,2'-bi(tetra-tert-butylpyridine)]iridium di(hexafluorophosphate) ([Ir(dFMeppy)2dtbbpy)]PF6), FAC-IR(2-phenylpyridinyl)3 (fac-Ir(ppy)3), and (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridinyl)phenyl]iridium(III)hexafluorophosphate ([Ir(ppy)2(dtbbpy)]PF6), is used in an amount of 2% of the molar mass of the alkyne substrate.

[0032] The organic base is one of diisopropylethylamine, triethylamine, trimethylamine, dicyclohexylmethylamine, or diisopropylamine, and its amount is 12% of the molar mass of the alkyne substrate.

[0033] Example 1:

[0034] Chiral (4,4,4-trifluoro-3-(trifluoromethyl)but-1-ene-1,3-diyl)diphenyl ether was prepared from phenylacetylene and 2,2,2-trifluoro-1-phenylethane-1-one under different chiral ligands:

[0035]

[0036] Under nitrogen protection, cobalt chloride (0.02 mmol), chiral ligand L (0.02 mmol), 2,4,5,6-tetratetra(3,6-dibromo-9H-carbazole-9-yl)isophthalonitrile (4CzIPN-Br, 0.004 mmol), dicyclohexylmethylamine (0.024 mmol), diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (Hans ester, HE, 0.4 mmol), tetrahydrofuran (2 mL), phenylacetylene (0.2 mmol), and 2,2,2-trifluoro-1-phenylethane-1-one (0.4 mmol) were added to a 25 mL reaction tube. The tube was sealed and the reaction was stirred at room temperature for 20 hours under a 5-watt blue LED lamp.

[0037] After the reaction was completed, dodecane was added as an internal standard. The yield and regioselectivity of the product were determined by GC-MS, the stereoselectivity of the reaction was determined by NMR, and the enantioselectivity of the product was determined by HPLC. The results are shown in Table 1.

[0038] Table 1. Yields and selectivity of different chiral ligands

[0039]

[0040]

[0041] As shown in Table 1, L1 to L15 can all yield the product (4,4,4-trifluoro-3-(trifluoromethyl)but-1-ene-1,3-diyl)diphenyl in low yields. The products have moderate to excellent enantioselectivity as well as excellent regioselectivity and stereoselectivity.

[0042] Example 2:

[0043] Chiral (4,4,4-trifluoro-3-(trifluoromethyl)but-1-ene-1,3-diyl)diphenyl was prepared from phenylacetylene and 2,2,2-trifluoro-1-phenylethane-1-one in different solvents:

[0044]

[0045] Under nitrogen protection, cobalt chloride (0.02 mmol), chiral ligand (S)-2-(2-(bis(3,5-dimethylphenyl)phosphino)-5-methoxyphenyl)-4-(tert-butyl)-4,5-dihydrooxazole (L1, 0.02 mmol), 2,4,5,6-tetra(3,6-dibromo-9H-carbazole-9-yl)isophthalonitrile (4CzIPN-Br, 0.004 mmol), dicyclohexylmethylamine (0.024 mmol), diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate (Hans ester, HE, 0.4 mmol), tetrahydrofuran (2 mL), phenylacetylene (0.2 mmol), and 2,2,2-trifluoro-1-phenylethane-1-one (0.4 mmol) were added to a 25 mL reaction tube. Seal the test tube and stir it at room temperature for 20 hours under the illumination of a 5-watt blue LED light.

[0046] After the reaction was completed, dodecane was added as an internal standard. The yield and regioselectivity of the product were determined by GC-MS, the stereoselectivity of the reaction was determined by NMR, and the enantioselectivity of the product was determined by HPLC. The results are shown in Table 2.

[0047] Table 2 Yields and selectivity of different organic solvents

[0048]

[0049]

[0050] Note: aCoI2 (0.02 mmol), b 10℃.

[0051] As shown in Table 2, N,N-dimethylformamide can significantly enhance the reaction activity, yielding the product (4,4,4-trifluoro-3-(trifluoromethyl)but-1-ene-1,3-diyl)diphenyl with moderate yield and excellent enantioselectivity, as well as excellent regioselectivity and stereoselectivity. The reaction activity is further enhanced when cobalt iodide is used as a catalyst, and the enantioselectivity increases slightly when the reaction temperature is lowered.

[0052] Example 3:

[0053] Chiral (4,4,4-trifluoro-3-(trifluoromethyl)but-1-ene-1,3-diyl)diphenyl was prepared from phenylacetylene and 2,2,2-trifluoro-1-phenylethane-1-one under different photosensitizers:

[0054]

[0055] Under nitrogen protection, cobalt iodide (0.02 mmol), chiral ligand (S)-2-(2-(bis(3,5-dimethylphenyl)phosphino)-5-methoxyphenyl)-4-(tert-butyl)-4,5-dihydrooxazole (L1, 0.02 mmol), photosensitizer (0.004 mmol), dicyclohexylmethylamine (0.024 mmol), diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate (Hans ester, HE, 0.4 mmol), N,N-dimethylformamide (2 mL), phenylacetylene (0.2 mmol), and 2,2,2-trifluoro-1-phenylethane-1-one (0.4 mmol) were added to a 25 mL reaction tube. The tube was sealed and the reaction was stirred at room temperature for 20 hours under a 5-watt blue LED lamp.

[0056] After the reaction was completed, dodecane was added as an internal standard. The yield and regioselectivity of the product were determined by GC-MS, the stereoselectivity of the reaction was determined by NMR, and the enantioselectivity of the product was determined by HPLC. The results are shown in Table 3.

[0057] Table 3. Yields and selectivity of different photosensitizers

[0058] Serial Number photosensitizer Yield (%) Regional selectivity Stereoselectivity Enantiomerism 1 <![CDATA[4CzPN- t This]]> 58 >99:1 >19:1 91 2 4CzPN-Br 60 >99:1 >19:1 91 3 4CzPN-Ph 70 >99:1 >19:1 91 5 4CzPN 66 >99:1 >19:1 91 6 <![CDATA[4CzIPN- t This]]> 63 >99:1 >19:1 91 7 4CzIPN-Br 66 >99:1 >19:1 91 8 4CzIPN-Ph 61 >99:1 >19:1 91 9 4CzTPN-Ph 63 >99:1 >19:1 91 10 <![CDATA[4CzTPN- t This]]> 48 >99:1 >19:1 91 11 4DPAIPN 53 >99:1 >19:1 91 12 3DPA2FBN 62 >99:1 >19:1 91 13 <![CDATA[Ru(bpy)3(PF6)2]]> 52 >99:1 >19:1 91 14 <![CDATA[[Ir(dF(CF3)ppy)2phen)]PF6]]> 44 15:85 >19:1 91 15 <![CDATA[[Ir(dFMeppy)2dtbbpy)]PF6]]> 31 10:90 >19:1 91 16 <![CDATA[fac-Ir(ppy)3]]> 51 >99:1 >19:1 91 17 <![CDATA[[Ir(ppy)2(dtbbpy)]PF6]]> 70 >99:1 >19:1 91

[0059] As shown in Table 3, 4CzPN-Ph significantly enhances the reaction activity as a photosensitizer, yielding the product (4,4,4-trifluoro-3-(trifluoromethyl)but-1-ene-1,3-diyl)diphenyl with excellent yield and enantioselectivity, and exhibiting excellent regioselectivity and stereoselectivity.

[0060] Example 4:

[0061] Chiral (4,4,4-trifluoro-3-(trifluoromethyl)but-1-ene-1,3-diyl)diphenyl catalysis was prepared from arylalkynes and various trifluoromethyl ketones:

[0062]

[0063] Under nitrogen protection, cobalt iodide (0.02 mmol), chiral ligand (S)-2-(2-(bis(3,5-dimethylphenyl)phosphino)-5-methoxyphenyl)-4-(tert-butyl)-4,5-dihydrooxazole (L1, 0.02 mmol), 2,4,5,6-tetra(3,6-dibromo-9H-carbazole-9-yl)isophthalonitrile (4CzIPN-Br, 0.004 mmol), dicyclohexylmethylamine (0.024 mmol), diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate (Hans ester, HE, 0.4 mmol), N,N-dimethylformamide, aryl alkyne (0.2 mmol), and trifluoromethyl ketone (0.4 mmol) were added to a 25 mL reaction tube. The tube was sealed and the reaction was stirred at room temperature for 20 hours under a 5-watt blue LED lamp. After removing the solvent under reduced pressure, the residue is directly separated by column chromatography to obtain the product. The obtained product can be further separated by thin-layer chromatography or column chromatography. The developing solvent used in this thin-layer chromatography and column chromatography method is a mixture of polar and non-polar solvents. Preferably, the solvent can be a mixture of ethyl acetate-petroleum ether, dichloromethane-petroleum ether, etc., with a volume ratio (ml / ml) of polar solvent: non-polar solvent = 1:2-10. For example: ethyl acetate: petroleum ether = 1:2-10, dichloromethane-petroleum ether = 1:2-10.

[0064] The regioselectivity and stereoselectivity of the reaction were determined by NMR, and the enantioselectivity was determined by HPLC. The results are shown in Table 4.

[0065] Table 4. Yields and selectivity of different trifluoromethyl ketones

[0066]

[0067]

[0068] As can be seen from Table 4, various aryl alkynes and aryl trifluoromethyl ketones are compatible with this reaction and have excellent enantioselectivity, stereoselectivity and regioselectivity. However, the enantioselectivity of the reaction with alkyl trifluoromethyl ketones will decrease significantly.

[0069] Example 5:

[0070] Chiral (4,4,4-trifluoro-3-(trifluoromethyl)but-1-ene-1,3-diyl)diphenyl catalysis was prepared from alkylalkynes and various trifluoromethyl ketones under cobalt catalysis.

[0071]

[0072] Under nitrogen protection, cobalt chloride (0.02 mmol), chiral ligand (2S,4S)-(-)-2,4-bis(diphenylphosphine)pentane ((S,S)-BDPP) 0.02 mmol, 2,4,5,6-tetra(9H-carbazole-9-yl)isophthalonitrile (4CzIPN, 0.004 mmol), dicyclohexylmethylamine (0.024 mmol), diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate (Hans ester, HE, 0.4 mmol), tetrahydrofuran (2 mL), alkyl alkyne (0.2 mmol), and trifluoromethyl ketone (0.4 mmol) were added to a 25 mL reaction tube. The tube was sealed and the reaction was stirred at room temperature for 20 hours under a 5-watt blue LED lamp. After removing the solvent under reduced pressure, the residue was directly separated by column chromatography to obtain the product. The obtained product can be separated by thin-layer chromatography or column chromatography. The developing solvent used in this thin-layer chromatography and column chromatography method is a mixture of polar and nonpolar solvents. Preferably, the solvent can be a mixture of ethyl acetate-petroleum ether, dichloromethane-petroleum ether, etc., with a volume ratio (ml / ml) of polar solvent: nonpolar solvent = 1:2-10. For example: ethyl acetate: petroleum ether = 1:2-10, dichloromethane-petroleum ether = 1:2-10.

[0073] The regioselectivity and stereoselectivity of the reaction were determined by NMR, and the enantioselectivity was determined by HPLC. The results are shown in Table 5.

[0074] Table 5. Yields and selectivity of different trifluoromethyl ketones

[0075]

[0076] As can be seen from Table 5, various alkyl alkynes and aryl trifluoromethyl ketones are compatible with this reaction and have excellent enantioselectivity, stereoselectivity and regioselectivity. However, the enantioselectivity of the reaction with alkyl trifluoromethyl ketones will decrease significantly.

[0077] It should be noted that the above preferred embodiments are merely illustrative of the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for synthesizing a chiral trifluoromethyl allylic tertiary alcohol compound, characterized by: The synthesis method refers to that under nitrogen protection, the alkynol shown in the general formula I and the trifluoromethyl ketone shown in the general formula II are used as raw materials, a cobalt metal salt and an organic ligand are used as a catalyst, a Hans ester is used as a reducing agent, in the presence of an excess of an organic solvent, a photosensitizer and an organic base, a chiral trifluoromethyl allyl tertiary alcohol compound shown in the general formula III is prepared through a light irradiation reaction. The general formula I: The general formula II: The general formula III: wherein: R 1 , R 2 are each independently selected from one of substituted or unsubstituted C1-C 11 alkyl, substituted or unsubstituted C6-C 10 cycloalkyl, substituted or unsubstituted C1-C 28 aryl, a halogen atom, a hydroxyl group, an ester group, an amide group, an alkoxy group, an aryloxy group, a ferrocenyl group, a silicon-containing group, a boron-containing group, an aldehyde group, a ketone carbonyl group, a mercapto group, and R 1 , R 2 are the same or different.

2. The method for synthesizing a chiral trifluoromethyl allyl tertiary alcohol compound as described in claim 1, characterized in that: said R 1 , R 2 each independently is selected from one of phenyl, alkyl substituted phenyl, heterocumaryl phenyl, hydroxyl substituted phenyl, ester substituted phenyl, halogen substituted phenyl, ketone substituted phenyl, aldehyde substituted phenyl, aryl substituted phenyl, alkoxy substituted phenyl, aryloxy substituted phenyl, various aryl heterocycles, naphthyl, cyclohexenyl, methyl, long chain alkyl, cyclic alkyl, hydroxyl substituted alkyl, aryl substituted alkyl, ester substituted alkyl, halogen substituted alkyl, cyano substituted alkyl, alkoxy substituted alkyl, aryloxy substituted alkyl.

3. The method for synthesizing a chiral trifluoromethyl allyl tertiary alcohol compound as described in claim 1, characterized in that: The mass ratio of the alkynol to the trifluoromethyl ketone is 1:100-100:

1.

4. The method for synthesizing a chiral trifluoromethyl allyl tertiary alcohol compound as described in claim 1, characterized in that: CoBr2, CoCl2, CoI2, Co(NO3)2-6H2O, Co(BF4)2-6H2O, CoSO4-H2O, Co2(CO)8, Co(acac)2, Co(OAc)2, CoC2O4, CpCo(CO)2, Co(CO)I2, Cp2CoPF6, CoCO3, CoBr2-DME, Co3(PO4)2, in an amount of 5% or 10% of the molar mass of the alkyne substrate. * CoBr2, CoCl2, CoI2, Co(NO3)2-6H2O, Co(BF4)2-6H2O, CoSO4-H2O, Co2(CO)8, Co(acac)2, Co(OAc)2, CoC2O4, CpCo(CO)2, Co(CO)I2, Cp2CoPF6, CoCO3, CoBr2-DME, Co3(PO4)2, in an amount of 5% or 10% of the molar mass of the alkyne substrate.

5. The method for synthesizing a chiral trifluoromethyl allyl tertiary alcohol compound as described in claim 1, characterized in that: The organic ligand is selected from one of a chiral monophosphorus ligand, a chiral biphosphorus ligand, a chiral nitrogen phosphorus ligand, a chiral monodentate nitrogen ligand and a chiral bidentate nitrogen ligand, and the amount of the organic ligand is 10% or 20% of the molar mass of the alkynol substrate.

6. The method for synthesizing a chiral trifluoromethyl allyl tertiary alcohol compound as described in claim 1, characterized in that: The amount of the Hans ester is 2.0 times the chemical equivalent of the alkynol substrate.

7. The method for synthesizing a chiral trifluoromethyl allyl tertiary alcohol compound as described in claim 1, characterized in that: The organic solvent is one or more of n-butyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide, acetonitrile, toluene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl acetate, methanol, anhydrous ethanol or isopropanol.

8. The method for synthesizing a chiral trifluoromethyl allyl tertiary alcohol compound as described in claim 1, characterized in that: The photosensitizer is one of 2,4,5,6-tetrakis(9H-carbazol-9-yl)isophthalonitrile, 2,4,5,6-tetrakis(3,6-diphenyl-9H-carbazol-9-yl)isophthalonitrile, 2,4,5,6-tetrakis(3,6-dibromo-9H-carbazol-9-yl)isophthalonitrile, 2,4,5,6-tetrakis(3,6-di-tert-butyl-9H-carbazol-9-yl)isophthalonitrile, 3,4,5,6-tetrakis(3,6-dibromo-9H-carbazol-9-yl)phthalonitrile, 3,4,5,6-tetrakis(3,6-di-tert-butyl-9H-carbazol-9-yl)phthalonitrile, 3,4,5,6-tetrakis(3,6-diphenyl-9H-carbazol-9-yl)phthalonitrile, 2,3,5,6-tetrakis(3,6-di-tert-butyl-9H-carbazol-9-yl)terephthalonitrile, 2,3,5,6-tetrakis(3,6-diphenyl-9H-carbazol-9-yl)terephthalonitrile, 2,3,5,6-tetrakis(3,6-di-tert-butyl-9H-carbazol-9-yl)terephthalonitrile, 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile, 2,4,5,6-tetrakis(diphenylamino)isophthalonitrile, tris(2,2'-bipyridine)ruthenium dichloride hexafluorophosphate, bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][1,10-phenanthroline]iridium dichloride hexafluorophosphate, bis[2-(2,4-difluorophenyl)-5-methylpyridine][2,2'-bi(tetra-tert-butylpyridine)]iridium dichloride hexafluorophosphate, FAC-IR(2-phenylpyridyl)3, (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, and the amount of the photosensitizer is 2% of the molar mass of the alkynol substrate.

9. The method for synthesizing a chiral trifluoromethyl allyl tertiary alcohol compound as described in claim 1, characterized in that: The organic base is one of diisopropylethylamine, triethylamine, trimethylamine, dicyclohexylmethylamine and diisopropylamine, and the amount of the organic base is 12% of the molar mass of the alkynol substrate.

10. The method for synthesizing a chiral trifluoromethyl allyl tertiary alcohol compound as described in claim 1, characterized in that: The photoreaction refers to stirring the reaction at room temperature for 20 hours under irradiation of a 5-watt blue LED lamp. The photoreaction refers to stirring the reaction at room temperature for 20 hours under irradiation of a 5-watt blue LED

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