CN111517934B - Gamma-alkenyl ketone and synthetic method thereof - Google Patents

Gamma-alkenyl ketone and synthetic method thereof Download PDF

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CN111517934B
CN111517934B CN202010079545.1A CN202010079545A CN111517934B CN 111517934 B CN111517934 B CN 111517934B CN 202010079545 A CN202010079545 A CN 202010079545A CN 111517934 B CN111517934 B CN 111517934B
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邢栋
谢丽玉
杨海见
段燕红
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Abstract

The invention discloses a gamma-alkenyl ketone and a preparation method thereof, which takes simple cyclic ketone such as cyclopentanone or acyclic methyl ketone, and 1-phenyl-1-propyne as raw materials to obtain a target product with high yield, high regioselectivity and high enantioselectivity under the condition of the existence of an organic solvent, a catalyst, an additive and a ligand. The method has the advantages of atom economy, high regioselectivity, high enantioselectivity and the like, and can realize the high-efficiency conversion from cheap basic organic chemicals to high-added-value gamma-alkenyl ketone. The gamma-alkenyl ketone synthesized by the invention is a potential synthesis intermediate, and has potential application prospect in fine chemical synthesis and drug intermediate synthesis.

Description

Gamma-alkenyl ketone and synthetic method thereof
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to gamma-alkenyl ketone and a synthesis method thereof.
Background
C-H bond is one of the most common functional groups in organic compounds, and the activation of the C-H bond is an effective method for constructing C-C and is very important in organic synthesis. This mild and selective conversion mode is widely used in the field of chemical synthesis. The chemical synthesis of the C-H bond activation strategy can simplify raw materials, shorten reaction flow, realize the target product which is difficult to prepare by the conventional method, is one of the most economical, concise and efficient ways, and accords with the development trend of modern green synthetic chemistry.
Over the past few decades, significant progress has been made in the catalysis of allylic substitutions with transition metals. However, this method also has disadvantages, such as the need for a substrate containing a leaving group or the need for a more reactive substrate. Trost and Yamamoto in the late 1990 s and early 2000 s developed an atom-efficient route to linear allyl products using predominantly allene or methyl-substituted internal alkynes to effect nucleophile allylation under Pd catalysis (angelw. Chem., int. Ed. Engl.1992,31,1335-1336.; j.am. Chem. Soc.1994,116, 6019-6020.). Later on, breit topic group developed a series of selective C-O, C-S, C-N and C-C bond syntheses by introducing various nucleophiles to alkyne and allene through selecting proper rhodium/bidentate phosphine catalyst. However, the synthesis of C-C bonds is realized, beta-keto acids or 1, 3-diketone are mainly used as substrates, the construction of C-C bonds of simple ketones is not realized, and asymmetric synthesis is not realized (J.Am.chem.Soc.2011, 133,2386-2389.; J.Am.chem.Soc.2014,136,16124-16127.; chem.Eur.J.2016, 22,6547-6551.; J.Am.chem.Soc.2014,136, 862-865).
Disclosure of Invention
The invention aims to overcome the defects in the prior art and discloses an economic, green, efficient and high-selectivity alpha-alkylation reaction of simple ketone and 1-phenyl-1-propyne with wide substrate range, wherein the required alpha-allylation target product 3a, namely the gamma-alkenyl ketone, is obtained in 93% yield by using an additive under the conditions of a catalyst and a ligand, and the alpha-allylation target product has excellent regioselectivity and enantioselectivity.
The invention provides a synthesis method of gamma-alkenyl ketone, which comprises the steps of taking ketone (ketone compound) shown in a formula (1 a) and 1-phenyl-1-propyne shown in a formula (2 a) as reaction raw materials to react in the presence of an organic solvent, a catalyst, an additive and a ligand to obtain gamma-alkenyl ketone shown in a formula (3 a); the reaction is shown in the following reaction formula (A):
Figure BDA0002379778500000021
wherein:
R 1 is one of the following groups, including hydrogen, chain alkane containing oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom for substitution, cycloalkyl, phenyl substituted by alkyl, phenyl containing oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom for substitution, phenyl substituted by aromatic ring or aromatic heterocyclic ring, aromatic heterocyclic ring;
R 2 is hydrogen; or when R 2 When not hydrogen, the formula (1 a) is various cyclic ketones containing cyclopentanone and cyclohexanone and having 5 to 15 carbon atoms, cyclic ketones containing substitution of oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, cyclic ketones containing substitution of various aromatic rings or aromatic heterocyclic rings;
R 3 is one of the following groups, including chain alkane, chain alkane containing oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom for substitution, cycloalkyl, phenyl substituted by alkyl, phenyl containing oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom for substitution, phenyl substituted by aromatic ring or aromatic heterocyclic ring, and aromatic heterocyclic ring.
Preferably, the first and second electrodes are formed of a metal,
R 1 is one of the groups comprising hydrogen, C1-C6 alkyl, phenyl, C1-C6 alkyl substituted phenyl, N, N-dimethyl substituted phenyl, fluoro substituted phenyl, trifluoromethyl substituted phenyl, C1-C6 alkoxy substituted phenyl, naphthyl, furyl, thienyl, ferrocenyl;
R 2 is a hydrogen atom; or when R is 2 When not hydrogen, formula (1 a) includes cyclopentanone, cyclohexaneThe cyclic ketones with 5-15 carbon atoms, the cyclic ketones containing oxygen atoms, nitrogen atoms, boron atoms, silicon atoms and halogen atoms, and the cyclic ketones containing various aromatic rings or aromatic heterocyclic rings;
R 3 is one of the groups comprising C1-C6 alkyl, phenyl, C1-C6 alkyl substituted phenyl, N, N-dimethyl substituted phenyl, fluoro substituted phenyl, trifluoromethyl substituted phenyl, C1-C6 alkoxy substituted phenyl, naphthyl, furyl, thienyl, ferrocenyl.
It is further preferred that the first and second liquid crystal display panels,
R 1 is one of the following groups, including hydrogen, n-propyl, isopropyl, phenyl, p-methylphenyl, m-methoxyphenyl, p-trifluoromethylphenyl;
R 2 is hydrogen;
R 3 is hydrogen, p-phenylphenyl, p-methylphenyl, p-tert-butylphenyl, p-methoxyphenyl, p-fluorophenyl, p-chlorophenyl, o-methylphenyl, m-methoxyphenyl, 2-naphthylphenyl, m-fluorophenyl, 2- (1, 4-benzoxano) phenyl.
In the present invention, the ketone-ketone compound includes acetone, cyclopentanone, cyclohexanone, 2-pentanone, 3-methyl 2-pentanone, 4-dimethylcyclohexanone, 4-phenylcyclohexanone, beta-tetralone, acetophenone, various substituted phenyl methyl ketones, and the like.
In the invention, the organic solvent is one or more of 1, 2-dichloroethane, toluene, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, CPME, ethyl acetate, methanol and ethanol; preferably, it is 1, 2-dichloroethane.
In the present invention, the catalyst is a monovalent metal rhodium catalyst, preferably, [ Rh (cod) Cl ]2.
In the invention, the ligand has a bidentate ligand or monodentate ligand with coordination effect with rhodium, and the bidentate ligand is a bidentate phosphorus-containing ligand, preferably BIPHEP or DTBM-MeOBIPHEP.
In the present invention, the additives include: acids, amines, and/or phenols. Wherein, acid and amine must be included in the reaction system, further, the addition of phenol helps to improve the reaction yield, but the addition of phenol is not essential. Wherein the acid is one or more of benzoic acid, C1-C6 alkyl substituted benzoic acid, halogen atom substituted benzoic acid, isophthalic acid and diphenyl phosphate; preferably diphenyl phosphate. The amine is one or more of piperidine, pyrrole and morpholine; preferably, morpholine. The phenol is one or more of various alkyl substituted phenols such as 2, 6-dimethylphenol, 2, 6-di-tert-butylphenol, 2, 6-diisopropylphenol and the like; preferably, it is 2, 6-dimethylphenol.
In the present invention, when the ketone is cyclopentanone, the molar ratio of ketone to alkyne to acid to amine to phenol to metal catalyst to ligand is: 1 (1-3), 0.1-1, 0.1-0.5, 0.1-1, 0.01-0.1, 0.02-0.2; the adding amount of the organic solvent is 1mL/mmol ketone;
if the ketone is not cyclopentanone, the molar ratio of ketone to alkyne to acid to amine to phenol to metal catalyst to ligand is: (1-3) 1 (0.1-1): 0.1-0.5): 0.1-1): 0.01-0.1): 0.02-0.2; the amount of the organic solvent added was 1mL/mmol of ketone.
Specifically, when the ketone is cyclopentanone, the preferred molar ratio of ketone to alkyne to acid to amine to phenol to metal catalyst to ligand is: 1; the adding amount of the organic solvent is 1mL/mmol ketone; when the ketone is not cyclopentanone, the preferred molar ratio of ketone to alkyne to acid to amine to phenol to metal catalyst to ligand is: 3; the amount of the organic solvent added was 1mL/mmol of ketone.
In the invention, the reaction temperature is 90-130 ℃; preferably, it is 110 ℃.
In the invention, the reaction time is 2-72h; preferably 24h.
The synthesis method of the invention also comprises the following post-treatment steps: carrying out column chromatography on the crude reaction liquid obtained by the reaction by using a solution with a volume ratio of diethyl ether to petroleum ether =1 = 40-1
The method for separating and purifying the crude product in the method comprises the step of performing column chromatography on the crude reaction liquid by using a mobile phase with a volume ratio of diethyl ether to petroleum ether = 1-1.
The method adopts acid, amine and/or phenol as additives, avoids the use of alkali metal strong base which is easy to cause waste and pollutant in the prior art, not only ensures that a reaction system is green and has low pollution, but also ensures that the reaction can occur under more neutral and mild conditions, can realize wider substrate functional group compatibility, and is suitable for the atom economic conversion from industrial basic chemical reagents of acetone, 2-pentanone and the like to enantiomorphic gamma-alkenyl ketone with high added value.
The chemical reaction mechanism involved in the present invention is shown in the following formula (B): enamine intermediate 1-A generated by secondary amine and ketone 1 under the catalysis of acid, meanwhile, alkyne generates allene 2-A under the action of rhodium metal catalyst, and then is converted into pi-allyl rhodium intermediate 2-B, enamine intermediate 1-A attacks pi-allyl rhodium intermediate 2-B, carbon-carbon bond is generated to obtain intermediate 1-B, and alpha-allylation product 3 is further obtained by hydrolysis.
Figure BDA0002379778500000041
The invention also provides gamma-alkenyl ketone, the structure of which is shown as the formula (3 a):
Figure BDA0002379778500000042
wherein: r is 1 Is one of the following groups, including hydrogen, chain alkane containing oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom for substitution, cycloalkyl, phenyl substituted by alkyl, phenyl containing oxygen atom, nitrogen atom, boron atom and silicon atom and halogen atom for substitution, phenyl substituted by aromatic ring or aromatic heterocyclic ring, aromatic heterocyclic ring;
R 2 is hydrogen; or when R is 2 When not hydrogen, the formula (1 a) is various cyclic ketones containing 5 to 15 carbon atoms including cyclopentanone and cyclohexanone, cyclic ketones substituted by oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, and cyclic ketones substituted by various aromatic rings or aromatic heterocyclic rings;
R 3 is one of the following groups, including chain alkane, chain alkane containing oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom for substitution, cycloalkyl, phenyl substituted by alkyl, phenyl containing oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom for substitution, phenyl substituted by aromatic ring or aromatic heterocyclic ring, and aromatic heterocyclic ring.
Preferably, R 1 Is one of the following groups, including hydrogen, C1-C6 alkyl, phenyl, C1-C6 alkyl substituted phenyl, N, N-dimethyl substituted phenyl, fluoro substituted phenyl, trifluoromethyl substituted phenyl, C1-C6 alkoxy substituted phenyl, naphthyl, furyl, thienyl, ferrocenyl;
R 2 is a hydrogen atom; or when R is 2 When not hydrogen, the formula (1 a) is various cyclic ketones containing 5 to 15 carbon atoms including cyclopentanone and cyclohexanone, cyclic ketones substituted by oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, and cyclic ketones substituted by various aromatic rings or aromatic heterocyclic rings;
R 3 is one of the groups listed below, including C1-C6 alkyl, phenyl, C1-C6 alkyl substituted phenyl, N, N-dimethyl substituted phenyl, fluoro substituted phenyl, trifluoromethyl substituted phenyl, C1-C6 alkoxy substituted phenyl, naphthyl, furyl, thienyl, ferrocenyl.
The invention also provides the gamma-alkenyl ketone which is synthesized and prepared according to the method and is shown in the formula (3 a).
In the present invention, the gamma-alkenyl ketones include various gamma-alkenyl ketones derived from cyclopentanone, cyclohexanone, substituted cyclohexanone, various aliphatic methyl ketones, substituted aryl methyl ketones, and also include various beta-substituted aryl groups (examples 1 to 25 hereinafter).
The invention also provides application of the gamma-alkenyl ketone in preparing the compound 7 and/or preparing the compound 8.
Figure BDA0002379778500000051
The method has the advantages of atom economy, high regioselectivity, high enantioselectivity and the like, and can realize the high-efficiency conversion from cheap basic organic chemicals to high-added-value gamma-alkenyl ketone. The gamma-alkenyl ketone synthesized by the invention is a potential synthesis intermediate, and has potential application prospect in fine chemical synthesis and drug intermediate synthesis.
The invention also has the following beneficial effects: aryl methyl alkyne is used as an allyl precursor to replace an allylation reagent with a leaving group which is usually required in the traditional method, so that the reaction steps are simplified, and no by-product is generated; meanwhile, an acid/secondary amine synergistic catalysis system is adopted, and the process of generating the enamine intermediate on site through a synergistic catalyst effectively overcomes the defect that equivalent metal strong base such as LDA, liHMDS, KHMDS and the like is required in the traditional method, and has great advantages in reducing environmental pollution and optimizing reaction conditions. Meanwhile, the method is suitable for one-step conversion from basic chemical actual acetone to corresponding gamma-alkenyl ketone with high added value, and has potential application prospect in fine chemical synthesis.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples, but the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art are intended to be included within the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is to be determined by the appended claims. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
Example 1:
Figure BDA0002379778500000061
to a 4-mL high temperature pretreated vial equipped with a stirrer was added [ Rh (cod) Cl] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), howeverAnd then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was capped tightly, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction is finished, the mixed product is cooled to room temperature, diluted by ethyl acetate, and the diluted solution is filtered by a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid, in 93% yield. 1 H NMR(400MHz,CDCl 3 )δ7.36–7.21(m,4H),7.18(d,J＝7.6Hz,1H),6.28–6.15(ddd,J＝17.3Hz,0.7H),6.11–5.98(m,0.3H),5.23–5.03(m,2H),3.96(dd,J＝8.5,4.1Hz,0.3H),3.90(q,J＝6.3Hz,0.7H),2.64–2.48(m,1H),2.40–2.21(m,1H),2.21–1.84(m,3H),1.83–1.66(m,1.5H),1.64–1.51(m,0.5H). 13 C NMR(101MHz,CDCl 3 )δ219.65,219.12,141.18,139.67,137.30,128.84,128.51,127.91,126.57,126.44,117.43,115.11,54.64,53.07,48.60,48.30,38.95,38.72,26.43,25.70,20.66,20.51.IR(KBr):2956,2927,2362,2342,1737,1453,1258,1151,1002cm -1 .
Example 2:
Figure BDA0002379778500000062
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), and then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction is finished, the mixed product is cooled to room temperature, diluted by ethyl acetate, and the diluted solution is filtered by a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 80% yield. The product characterization data was the same as in example 1.
Example 3:
Figure BDA0002379778500000071
to a 4-mL high temperature pretreated vial equipped with a stirrer was added [ Rh (cod) Cl] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid with a yield of 83%. 1 H NMR(400MHz,CDCl 3 )7.57–7.41(m,4H),7.40–7.30(m,2H),7.30–7.20(m,2H),7.20–7.13(m,1H),6.15(ddd,J＝17.2,10.3,7.0Hz,0.5H),5.97(ddd,J＝16.5,10.3,8.3Hz,0.5H),5.17–4.99(m,2H),3.90(dd,J＝8.4,4.2Hz,0.5H),3.86(t,J＝6.1Hz,0.5H),2.60–2.43(m,1H),2.31–2.09(m,1H),2.08–1.61(m,4H),1.59–1.47(m,1H). 13 C NMR(101MHz,CDCl 3 )δ218.10,140.70,139.23,138.51,136.19,128.21,127.70,127.28,126.19,126.14,126.11,125.97,125.95,125.9,116.50,114.23,53.56,52.10,47.27,46.92,37.91,37.71,25.40,24.73,19.64,19.50.IR(KBr):2917,2849,2368,2338,2361,1967,1728,1275cm -1 .HRMS:calcd.C 20 H 20 ONa[M+Na] + :299.1412.Found:299.1440.
Example 4:
Figure BDA0002379778500000081
to a 4-mL high temperature pretreated vial equipped with a stirrer was added [ Rh (cod) Cl] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 95% yield. 1 H NMR(400MHz,CDCl 3 )δ7.36–7.21(m,4H),7.18(d,J＝7.6Hz,1H),6.28–6.15(ddd,J＝17.3Hz,0.7H),6.11–5.98(m,0.3H),5.23–5.03(m,2H),3.96(dd,J＝8.5,4.1Hz,0.3H),3.90(q,J＝6.3Hz,0.7H),2.64–2.48(m,1H),2.40–2.21(m,1H),2.21–1.84(m,3H),1.83–1.66(m,1.5H),1.64–1.51(m,0.5H). 13 C NMR(101MHz,CDCl 3 )δ219.65,219.12,141.18,139.67,137.30,128.84,128.51,127.91,126.57,126.44,117.43,115.11,54.64,53.07,48.60,48.30,38.95,38.72,26.43,25.70,20.66,20.51.IR(KBr):2956,2927,2362,2342,1737,1453,1258,1151,1002cm -1 .C 15 H 18 ONa[M+Na] + :237.1255.Found:237.1239.
Example 5:
Figure BDA0002379778500000082
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). Mixing small bottleCovered tightly, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 85% yield. 1 H NMR(400MHz,CDCl 3 )δ7.39–7.25(m,2H),7.24–7.08(m,2H),6.21(ddd,J＝17.3,10.4,7.1Hz,0.3H),6.03(ddd,J＝17.0,10.3,8.5Hz,0.7H),5.19–5.03(m,2H),3.96(dd,J＝8.5,4.0Hz,0.7H),3.87(dd,J＝7.1,5.4Hz,0.3H),2.62–2.47(m,1H),2.39–1.87(m,4.5H),1.85–1.57(m,1.5H),1.32(d,J＝6.1Hz,9H). 13 C NMR(101MHz,CDCl 3 )δ219.32,149.17,139.87,139.55,137.37,128.37,127.47,125.39,125.18,117.32,114.88,54.72,53.15,48.03,47.94,38.98,38.74,34.39,31.39,31.37,26.46,25.59,20.69,20.53.IR(KBr):2949,2924,2357,2341,1736,1269,1151,919cm -1 .C 18 H 24 ONa[M+Na] + :279.1725.Found:279.1743.
Example 6:
Figure BDA0002379778500000091
to a 4-mL high temperature pretreated vial equipped with a stirrer was added [ Rh (cod) Cl] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product is colorless liquidBody, yield 93%. 1 H NMR(400MHz,CDCl 3 )δ7.11–6.95(m,2H),6.82–6.70(m,2H),6.09(ddd,J＝17.2,10.4,6.7Hz,0.6H),5.92(ddd,J＝17.1,10.2,8.1Hz,0.4H),5.09–4.90(m,2H),3.82–3.76(m,1H),3.71(d,J＝4.9Hz,2H),2.50–2.36(m,1H),2.28–2.10(m,1H),2.10–1.74(m,3H),1.72–1.58(m,1.5H),1.53–1.42(m,0.5H). 13 C NMR(101MHz,CDCl 3 )δ218.86,218.28,157.13,138.91,136.67,133.56,132.07,128.79,127.83,116.01,113.75,112.81,112.58,54.19,54.15,53.64,52.09,46.79,46.31,37.95,37.72,25.16,24.73,19.61,19.49.IR(KBr):2961,2919,2368,2356,1734,1510,1247,1179,916cm -1 .HRMS:calcd.C 15 H 18 O 2 Na[M+Na] + :253.1204.Found:253.1215.
Example 7:
Figure BDA0002379778500000101
to a 4-mL high temperature pretreated vial equipped with a stirrer was added [ Rh (cod) Cl] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. 0.2mL of DCE,1a (1eq, 0.2mmol) and morpholine (4.4. Mu.L, 25 mol%) were then added followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid, in 77% yield. 1 H NMR(400MHz,CDCl 3 )δ7.17–7.09(m,1H),7.09–7.01(m,1H),6.98–6.83(m,2H),6.15–6.01(m,0.5H),5.96–5.83(m,0.5H),5.13–4.92(m,2H),3.82(dd,J＝8.4,4.2Hz,1H),2.53–2.35(m,1H),2.30–2.13(m,1H),2.10–1.88(m,2H),1.85–1.74(m,1H),1.72–1.40(m,2H). 13 C NMR(101MHz,CDCl 3 )δ218.11,217.62,163.07,162.91,160.63,160.47,144.26,144.19,142.81,142.74,128.93,128.85,128.72,128.63,123.50(d,J＝2.8Hz),122.53(d,J＝2.7Hz),114.66(t,J＝10.6Hz),112.55,112.36(d,J＝4.0Hz),112.18,53.32,51.98,47.29(d,J＝1.9Hz),46.86(d,J＝1.7Hz),37.79,37.61,25.39,24.66,19.58,19.45.IR(KBr):2984,2361,1736,1372,1233,1043,937cm -1 .HRMS:calcd.C 14 H 15 FONa[M+Na] + :219.1185.Found:219.1699.
Example 8:
Figure BDA0002379778500000102
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was capped tightly, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 70% yield. 1 H NMR(400MHz,CDCl 3 )δ7.23–7.15(m,2H),7.10(d,J＝8.7Hz,1H),7.05–7.00(m,1H),6.13–6.02(m,0.5H),5.95–5.83(m,0.5H),5.13–4.94(m,2H),3.81(t,J＝5.1Hz,1H),2.53–2.44(m,0.5H),2.44–2.35(m,0.5H),2.30–2.14(m,1H),2.09–1.89(m,2H),1.85–1.60(m,2.5H),1.48–1.35(m,0.5H). 13 C NMR(101MHz,CDCl 3 )δ218.25,217.71,138.58,138.06,135.95,129.23,128.27,127.57,127.38,116.65,114.55,53.31,51.99,47.05,46.42,37.81,37.64,25.22,24.77,19.57,19.47.IR(KBr):2956,1732,1600,1490,1274,1151,1090,1013cm -1 .HRMS:calcd.C 14 H 15 ClO[M]:218.1107.Found:218.1103.
Example 9:
Figure BDA0002379778500000111
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. 0.2mL of DCE,1a (1eq, 0.2mmol) and morpholine (4.4. Mu.L, 25 mol%) were then added followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 87% yield. 1 H NMR(400MHz,CDCl 3 )δ7.20–7.14(m,1H),7.12–7.03(m,3H),6.13(ddd,J＝17.2,10.3,7.0Hz,0.4H),5.89(ddd,J＝17.1,10.2,8.0Hz,0.6H),5.03–4.77(m,2H),4.13(dd,J＝8.0,4.1Hz,0.6H),3.74–3.65(m,0.4H),2.55(q,J＝8.7Hz,0.5H),2.39–2.15(m,5H),2.13–2.05(m,1H),2.04–1.93(m,1H),1.92–1.82(m,1H),1.75–1.59(m,1H),1.43(m,0.5H). 13 C NMR(101MHz,CDCl 3 )δ217.96,139.99,138.77,136.28,134.75,129.64,129.54,127.06,125.98,125.20,125.16,125.03,124.93,116.01,113.96,52.88,51.65,43.94,42.77,37.67,37.53,27.84,25.01,19.64,19.41,18.92,18.60.IR(KBr):2955,2920,2369,2355,1736,1489,1454,1273,1150,996cm -1 .HRMS:calcd.C 15 H 18 ONa[M+Na] + :237.1255.Found:237.1239.
Example 10:
Figure BDA0002379778500000121
directional dress4-mL high temperature pretreated vials with stirrer were charged sequentially with [ Rh (cod) Cl] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was capped tightly, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction is finished, the mixed product is cooled to room temperature, diluted by ethyl acetate, and the diluted solution is filtered by a short silica gel column to remove metal ions. Decompression rotary evaporation to remove solvent, coarse nuclear magnetism detection, product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 76% yield. 1 H NMR(400MHz,CDCl 3 )δ7.21–7.06(m,1H),6.78–6.60(m,3H),6.10(ddd,J＝14.6,10.4,7.0Hz,0.4H),5.92(ddd,J＝16.9,10.3,8.4Hz,0.6H),5.10–4.94(m,2H),3.89–3.67(m,4H),2.54–2.36(m,1H),2.36–1.75(m,4H),1.75–1.41(m,2H). 13 C NMR(101MHz,CDCl 3 )δ218.13,158.59,143.29,143.14,135.98,135.84,128.43,119.16,116.63,116.52,112.87,110.43,54.95,54.13,53.63,47.51,47.44,37.92,24.62,22.23,19.62.HRMS:calcd.C 15 H 18 O 2 [M+H] + :253.1204.Found:253.1215.
Example 11:
Figure BDA0002379778500000122
to a 4-mL high temperature pretreated vial equipped with a stirrer was added [ Rh (cod) Cl] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction is finished, cooling the mixed product to room temperature, diluting the mixed product with ethyl acetate, and diluting the diluted solutionFiltering with short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 52% yield. 1 H NMR(400MHz,CDCl 3 )δ7.25–7.13(m,1H),6.99–6.78(m,3H),6.14–6.02(m,0.4H),6.00–5.81(m,0.6H),5.18–4.95(m,2H),3.91–3.78(m,1H),2.55–2.38(m,1H),2.30–2.16(m,1H),2.10–1.90(m,2H),1.87–1.58(m,2,5H),1.50–1.39(m,0.5H). 13 C NMR(101MHz,CDCl 3 )δ218.11,217.62,137.90,135.64,128.93,128.85,128.72,123.50(d,J＝2.8Hz),122.53(d,J＝2.7Hz),116.87,114.66(t,J＝10.6Hz),113.89,113.67,112.55,112.36(d,J＝4.0Hz),112.18,53.32,51.98,47.30,47.28,46.87,37.79,37.61,25.39,24.66,19.58,19.45.IR(KBr):2961,2918,2363,2340,1735,1612,1586,1273,1149.cm -1 .HRMS:calcd.C 14 H 15 FONa[M+Na] + :219.1185.Found:219.1699.
Example 12:
Figure BDA0002379778500000131
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Decompression rotary evaporation to remove solvent, coarse nuclear magnetism detection, product regioselectivity>20:1. Column chromatography of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 72% yield. 1 H NMR(400MHz,CDCl 3 )δ7.86–7.63(m,4H),7.52–7.31(m,3H),6.33(ddd,J＝17.1,10.4,6.7Hz,0.5H),6.15(ddd,J＝17.0,10.3,8.3Hz,0.5H),5.29–5.10(m,2H),4.14(dd,J＝8.3,4.2Hz,0.5H),4.11–4.06(m,0.5H),2.74–2.59(m,1H),2.42–2.24(m,1H),2.23–1.85(m,3H),1.83–1.68(m,1.5H),1.65–1.53(m,0.5H). 13 C NMR(101MHz,CDCl 3 )δ219.65,219.12,142.64,139.67,137.30,128.84,128.51,128.31,127.91,126.57,126.44,117.43,115.11,54.64,53.07,48.60,48.30,38.95,38.72,26.43,25.70,20.66,20.51.IR(KBr):2920,2356,1735,1599,1259,1157,1047,786.cm -1 .HRMS:calcd.C 18 H 18 ONa[M+Na] + :273.1255.Found:273.1246.
Example 13:
Figure BDA0002379778500000141
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), then transferred into a glove box. 0.2mL of DCE,1a (1eq, 0.2mmol) and morpholine (4.4. Mu.L, 25 mol%) were then added followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction is finished, the mixed product is cooled to room temperature, diluted by ethyl acetate, and the diluted solution is filtered by a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 68% yield. 1 H NMR(400MHz,CDCl 3 )δ6.84–6.61(m,3H),6.15(ddd,J＝17.2,10.4,7.0Hz,0.5H),5.96(ddd,J＝17.0,10.3,8.3Hz,0.5H),5.20–5.01(m,2H),4.25(d,J＝4.2Hz,4H),3.84(dd,J＝8.4,4.2Hz,0.5H),3.81–3.75(m,0.5H),2.58–2.42(m,1H),2.38–2.21(m,1H),2.19–1.69(m,4.5H),1.64–1.52(m,0.5H). 13 C NMR(101MHz,CDCl 3 )δ219.67,219.20,143.31,139.77,137.35,135.96,134.50,121.78,120.79,117.43,117.25,117.17,116.96,116.56,114.88,64.40,64.35,64.32,64.30,54.63,53.09,47.85,47.60,38.95,38.72,26.43,25.66,20.66,20.52.IR(KBr):2927,2877,2362,1732,1505,1283,1255,1125,1067cm -1 .C 16 H 18 O 3 Na[M+Na] + :281.1154.Found:281.1131.
Example 14:
Figure BDA0002379778500000142
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. 0.2mL of DCE,1a (1eq, 0.2mmol) and morpholine (4.4. Mu.L, 25 mol%) were then added followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 57% yield. 1 H NMR(400MHz,CDCl 3 )δ7.26–7.08(m,5H),5.97(ddd,J＝17.5,10.3,7.5Hz,0.6H),5.81(ddd,J＝16.9,10.1,9.1Hz,0.4H),5.05–4.88(m,2H),3.73(t,J＝8.9Hz,0.4H),3.65(dd,J＝9.6,7.6Hz,0.6H),2.76–2.66(m,1H),2.40–2.14(m,2H),2.11–1.81(m,2H),1.76–1.68(m,1H),1.65–1.48(m,2.5H),1.32–1.23(m,0.5H). 13 C NMR(101MHz,CDCl 3 )δ139.07,138.18,127.52,127.39,126.79,125.48,125.20,115.18,113.88,54.35,54.20,48.31,47.99,41.30,41.05,30.90,30.58,27.50,27.34,23.34,22.69.IR(KBr):2926,2363,1709,1275,1261,1125,914,764.cm -1 .
Example 15:
Figure BDA0002379778500000151
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), then transferred into a glove box. 0.2mL of DCE,1a (1eq, 0.2mmol) and morpholine (4.4. Mu.L, 25 mol%) were then added followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction is finished, the mixed product is cooled to room temperature, diluted by ethyl acetate, and the diluted solution is filtered by a short silica gel column to remove metal ions. Decompression rotary evaporation to remove solvent, coarse nuclear magnetism detection, product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 65% yield. 1 H NMR(400MHz,CDCl 3 )δ7.28–7.02(m,10H),6.07(ddd,J＝17.3,10.4,6.8Hz,0.5H),5.83(ddd,J＝17.0,10.1,9.1Hz,0.5H),5.06–4.83(m,2H),3.83(t,J＝8.3Hz,0.5H),3.76–3.66(m,0.5H),3.08–2.88(m,2H),2.60–2.23(m,2.5H),2.19–2.10(m,1H),1.93–1.77(m,1.5H),1.67(q,J＝12.9Hz,0.5H),1.55–1.40(m,0.5H). 13 C NMR(101MHz,CDCl 3 )δ210.34,209.46,143.58,143.36,142.61,140.36,139.31,137.57,127.67,127.58,127.49,127.40,127.38,126.83,125.72,125.66,125.62,125.53,125.38,125.12,115.64,114.01,53.57,53.04,47.65,47.18,42.77,42.65,41.57,41.25,38.82,37.88,34.93,34.24.IR(KBr):2949,2355,1712,1493,1452,1264,1146,917.cm-1.HRMS:calcd.C 21 H 22 ONa[M+Na] + :313.1568.Found:313.1569.
Example 16:
Figure BDA0002379778500000161
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Decompression rotary evaporation to remove solvent, coarse nuclear magnetism detection, product regioselectivity>20:1. Column chromatography of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 54% yield. 1 H NMR(400MHz,CDCl 3 )δ7.23–7.06(m,5H),6.04(ddd,J＝17.2,10.4,6.8Hz,0.5H),5.79(ddd,J＝17.4,9.6Hz,0.5H),5.04–4.81(m,2H),3.74(t,J＝8.4Hz,0.5H),3.64(t,J＝7.6Hz,0.5H),2.96–2.82(m,1H),2.52–2.33(m,1H),2.22–2.09(m,1H),1.82–1.75(m,0.5H),1.68–1.52(m,2H),1.41–1.31(m,1H),1.22–1.17(m,0.5H),1.13(s,1.5H),1.09(s,1.5H),0.95(s,1.5H),0.82(s,1.5H). 13 C NMR(101MHz,CDCl 3 )δ211.77,210.89,139.59,137.99,127.71,127.35,127.30,126.80,125.27,125.01,115.27,113.81,49.47,49.03,47.68,47.06,44.42,43.34,39.78,39.32,38.24,37.91,30.51,30.23,30.02,29.96,23.65,23.61.IR(KBr):2956,2926,2316,1711,1452,1275,1149,1002,914.cm -1 .HRMS:calcd.C 17 H 22 ONa[M+Na] + :265.1568.Found:265.1555.
Example 17:
Figure BDA0002379778500000171
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. 0.2mL of DCE,1a (1eq, 0.2mmol) and morpholine (4.4. Mu.L, 25 mol%) were then added followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction is finished, the mixed product is cooled to room temperature, diluted by ethyl acetate and dilutedThe solution was filtered through a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 60% yield. 1 H NMR(400MHz,CDCl 3 )δ7.22–6.94(m,7H),6.73–6.62(m,2H),6.16(ddd,J＝16.9,10.3,8.9Hz,0.6H),6.02(ddd,J＝16.9,10.2,9.3Hz,0.4H),5.12–4.92(m,2H),3.94(q,J＝8.2,7.5Hz,1H),3.65(dd,J＝13.5,6.5Hz,1H),2.87–2.76(m,0.5H),2.74–2.64(m,0.5H),2.61–2.55(m,0.5H),2.52–2.38(m,1H),2.38–2.24(m,1.5H). 13 C NMR(101MHz,CDCl 3 )δ211.91,211.61,141.02,140.14,139.16,137.50,137.19,137.00,134.65,130.15,129.88,128.43,128.27,128.23,127.91,127.84,127.13,127.10,126.91,126.89,126.31,126.17,117.12,116.24,61.46,60.35,54.47,53.79,38.31,37.82,27.12,26.74.IR(KBr):2919,2316,2356,1737,1710,1454,1230,1044cm -1 .HRMS:calcd.C 19 H 18 O[M]:262.1358.Found:262,1326.
Example 18:
Figure BDA0002379778500000172
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. 0.2mL of DCE,1a (1eq, 0.2mmol) and morpholine (4.4. Mu.L, 25 mol%) were then added followed by 2a (1.25eq, 0.25mmol). The vial was capped tightly, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 26% yield. 1 H NMR(400MHz,CDCl 3 )δ7.34–7.28(m,2H),7.25–7.19(m,3H),5.98(ddd,J＝17.1,10.3,6.8Hz,1H),5.10–4.99(m,2H),3.92(q,J＝7.2Hz,1H),2.93–2.79(m,2H),2.10(s,3H). 13 C NMR(101MHz,CDCl 3 )δ206.05,141.73,139.49,127.58,126.56,125.58,113.58,47.95,43.50,29.65.IR(KBr):2920,2850,2360,1680,1600,1455,1256,1014.cm -1 .
Example 19:
Figure BDA0002379778500000181
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was capped tightly, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid with a yield of 25%. 1 H NMR(400MHz,CDCl 3 )δ7.25–7.17(m,2H),7.17–7.07(m,3H),5.97–5.80(m,1H),4.95(t,J＝14.3Hz,2H),3.86(q,J＝7.3Hz,1H),2.81–2.67(m,2H),2.32–2.14(m,2H),1.53–1.40(m,2H),0.76(td,J＝7.4,1.9Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ208.16,141.91,139.64,127.54,127.52,126.59,125.51,113.50,47.07,44.50,43.46,15.95,12.63.IR(KBr):2955,2920,2356,1716,1455,1262,916cm -1 .
Example 20:
Figure BDA0002379778500000182
to 4-m equipped with a stirrerL high temperature pretreated Vial was charged with [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Decompression rotary evaporation to remove solvent, coarse nuclear magnetism detection, product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 47% yield. 1 H NMR(400MHz,CDCl 3 )δ7.24–7.17(m,2H),7.15–7.10(m,3H),5.89(ddd,J＝17.2,10.4,6.8Hz,1H),5.02–4.88(m,2H),3.86(q,J＝7.2Hz,1H),2.80–2.67(m,2H),2.20–2.07(m,2H),2.06–1.95(m,1H),0.76(dd,J＝6.6,2.9Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ207.80,141.91,139.66,127.52,126.62,125.50,113.50,51.61,47.51,43.39,23.30,21.49,21.47.IR(KBr):2985,2369,2310,1984,1715,1683,199,1275.cm -1 .
Example 21:
Figure BDA0002379778500000191
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was capped tightly, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Decompression rotary evaporation to remove solvent, coarse nuclear magnetism detection, product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 38% yield. 1 H NMR(400MHz,CDCl 3 )δ7.89–7.82(m,2H),7.49–7.44(m,1H),7.40–7.34(m,2H),7.25–7.16(m,4H),7.15–7.09(m,1H),5.97(ddd,J＝17.1,10.4,6.8Hz,1H),5.01–4.89(m,2H),4.10–4.01(m,1H),3.40–3.25(m,2H). 13 C NMR(101MHz,CDCl 3 )δ197.21,142.10,139.61,136.06,132.00,127.54,127.02,126.67,125.51,113.68,43.48,42.97.IR(KBr):2926,2355,1682,1597,1448,1260,1022,988.cm -1 .
Example 22:
Figure BDA0002379778500000201
to a 4-mL high temperature pretreated vial equipped with a stirrer was added [ Rh (cod) Cl] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. 0.2mL of DCE,1a (1eq, 0.2mmol) and morpholine (4.4. Mu.L, 25 mol%) were then added followed by 2a (1.25eq, 0.25mmol). The vial was capped tightly, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 27% yield. 1 H NMR(400MHz,CDCl 3 )δ7.76(d,J＝8.1Hz,2H),7.25–7.10(m,7H),5.97(ddd,J＝17.1,10.3,6.7Hz,1H),5.03–4.90(m,2H),4.06(q,J＝7.0Hz,1H),3.37–3.22(m,2H),2.32(s,3H). 13 C NMR(101MHz,CDCl 3 )δ218.37,217.96,138.75,136.25,134.91,134.73,129.62,129.52,127.03,125.96,125.18,124.91,116.01,113.95,52.86,51.63,43.92,42.74,37.66,27.83,24.98,19.63,19.39,18.91,18.59.IR(KBr):2984,2361,2016,1736,1372,1233,1043.cm -1 .
Example 23:
Figure BDA0002379778500000202
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), then transferred into a glove box. 0.2mL of DCE,1a (1eq, 0.2mmol) and morpholine (4.4. Mu.L, 25 mol%) were then added followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid with a yield of 32%. 1 H NMR(400MHz,CDCl 3 )δ7.46–7.42(m,1H),7.38(dd,J＝2.7,1.6Hz,1H),7.30–7.18(m,5H),7.16–7.10(m,1H),7.02(ddd,J＝8.3,2.7,0.9Hz,1H),5.97(ddd,J＝17.2,10.4,6.8Hz,1H),5.03–4.92(m,2H),4.06(m,1H),3.76(s,3H),3.39–3.24(m,2H). 13 C NMR(101MHz,CDCl 3 )δ197.03,158.77,142.10,139.61,137.44,128.52,127.56,126.67,125.52,119.64,118.56,113.69,111.22,54.40,43.55,43.10.IR(KBr):2926,2362,1683,1597,1427,1262,1030,993.cm -1 .
Example 24:
Figure BDA0002379778500000211
to a 4-mL high temperature pretreated vial equipped with a stirrer was added [ Rh (cod) Cl] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), then transferred into a glove box. Followed by addition of 0.2mL of DCE,1a (1eq, 0.2mmol) andlin (4.4. Mu.L, 25 mol%) followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Decompression rotary evaporation to remove solvent, coarse nuclear magnetism detection, product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 27% yield. 1 H NMR(400MHz,CDCl 3 )δ7.46–7.42(m,1H),7.38(dd,J＝2.7,1.6Hz,1H),7.30–7.18(m,5H),7.16–7.10(m,1H),7.02(ddd,J＝8.3,2.7,0.9Hz,1H),5.97(ddd,J＝17.2,10.4,6.8Hz,1H),5.03–4.92(m,2H),4.06(m,1H),3.76(s,3H),3.39–3.24(m,2H). 13 C NMR(101MHz,CDCl 3 )δ197.03,158.77,142.10,139.61,137.44,128.52,127.56,126.67,125.52,119.64,118.56,113.69,111.22,54.40,43.55,43.10.IR(KBr):2926,2362,1683,1597,1427,1262,1030,993.cm -1 .
Example 25:
Figure BDA0002379778500000221
to a 4-mL high temperature pretreated vial equipped with a stirrer was added [ Rh (cod) Cl] 2 (4.9mg,5mol％)，BIPHEP(5.2mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Removing solvent by reduced pressure rotary evaporation, performing crude nuclear magnetic detection, and performing product regioselectivity>20:1. Column chromatography separation of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid in 34% yield. 1 H NMR(400MHz,CDCl 3 )δ7.21(d,J＝7.6Hz,2H),7.17–7.05(m,3H),6.07(ddd,J＝17.3,8.5Hz,0.6H),5.87–5.73(ddd,J＝17.6,0.4Hz,0H),5.09–4.94(m,2H),3.79(t,J＝8.1Hz,0.4H),3.67(t,J＝7.4Hz,0.6H),2.82(m,1H),2.36–2.195(m,1H),2.14–1.88(m,2H),1.83–1.59(m,3H),1.49–1.39(m,3H),1.30–1.16(m,9H),1.15–1.08(m,3H),1.07–1.01(m,3H),0.96(d,J＝8.3Hz,5H),0.85–0.75(m,12H),0.59(s,1H),0.55(s,2H). 13 C NMR(101MHz,CDCl 3 )δ210.61,209.92,142.83,140.87,139.53,138.08,127.70,127.30,127.27,126.88,125.22,125.00,115.24,113.91,55.25,55.21,55.11,52.97,52.73,49.88,49.44,47.99,47.65,47.38,47.11,44.83,44.49,43.92,42.65,41.59,41.54,38.89,38.78,38.47,35.48,35.41,35.09,34.75,34.72,34.23,34.18,30.71,30.60,27.68,27.19,26.98,23.19,23.16,22.80,21.79,21.53,20.58,20.35,17.62,17.57,11.62,11.60,11.06,11.01.IR(KBr):2943,2852,1737,1696,1587,1466,1373,1075.cm -1 .HRMS:calcd.C 36 H 54 O[M+H] + :503.4253.Found:503.4298.
Example 26:
Figure BDA0002379778500000222
to a 4-mL high temperature pretreated vial equipped with a stir bar was added [ Rh (cod) Cl ] in sequence] 2 (4.9mg,5mol％)，DTBM-MeOBIPHEP(13.4mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), which was then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was closed, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Decompression rotary evaporation to remove solvent, coarse nuclear magnetism detection, product regioselectivity>20:1. Column chromatography of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid, in 92% yield. The diastereoselectivity of the product was 94/95. High performance liquid chromatography chiral analysis, dr: 1.8; er:94, 6/95, chiralcel IF, containing 0.2% by weight of a total ofA solution of isopropanol in n-hexane at a flow rate of 1.0mL/min, λ =217nm, t R (major)＝18.720min,t R (minor)＝21.862min,t R (major)＝26.388min,t R (minor)＝27.967min.
Example 27:
Figure BDA0002379778500000231
to a 4-mL high temperature pretreated vial equipped with a stirrer was added [ Rh (cod) Cl] 2 (4.9mg,5mol％)，DTBM-MeOBIPHEP(13.4mg,10mol％)，(PhO) 2 POOH (5mg, 10mol%), 2, 6-dimethylphenol (12.2mg, 50mol%), then transferred into a glove box. Followed by 0.2mL of DCE,1a (1eq, 0.2 mmol) and morpholine (4.4. Mu.L, 25 mol%), followed by 2a (1.25eq, 0.25mmol). The vial was capped tightly, removed from the glove box and heated at 110 ℃ for 24 hours. After the reaction, the mixed product was cooled to room temperature, diluted with ethyl acetate, and the diluted solution was filtered through a short silica gel column to remove metal ions. Decompression rotary evaporation to remove solvent, coarse nuclear magnetism detection, product regioselectivity>20:1. Column chromatography of the crude product (silica gel, PE/Et) 2 O =100, 1 to 60) to obtain a pure product. The product was a colorless liquid with a yield of 95%. The diastereoselectivity of the product was 95/91. Chiral analysis by high performance liquid chromatography, dr: 1.8; er:95 R (major)＝17.465min,t R (minor)＝22.253min,t R (minor)＝23.722min,t R (major)＝26.032min.
Based on the gamma-alkenyl ketone in each example, the researchers of the invention further perform applicable derivatization on partial products aiming at the main structure of the gamma-alkenyl ketone so as to prove the practicability of the patent products, and the specific structure and the synthesis steps are as follows:
application example 1: use of gamma-alkenyl ketones of formula (3 a) for the synthesis of compound 7
Figure BDA0002379778500000241
To a flame dried round bottom flask was added the gamma-alkenyl ketone obtained in example 1 (63mg, 0.31mmol, 1eq) followed by 2mL THF and the reaction mixture was cooled to 0 deg.C. Slowly add 1M BH3.SMe at 0 ℃ 2 THF solution (0.32mL, 1.6mmol, 5eq). After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 1 hour. Next, the reaction mixture was cooled to 0 ℃ and 3M NaOH solution (2mL, 5eq) was slowly added, followed by 30% H 2 O 2 (2 mL). The reaction was heated to 60 ℃ for 2 hours. After cooling to room temperature, the reaction mixture was washed with Et 2 And (4) extracting. The combined organic layers were over anhydrous MgSO 4 Dried, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography to afford compound 5.
To compound 5 (58mg, 0.31mmol) was added 3mL CH 2 Cl 2 Freshly distilled N, N-diisopropylethylamine (0.80mL, 4.84mmol) was added via syringe at 0 ℃. After 10 min, dimethylsulfoxide (0.50ml, 6.74mmol) was added to the reaction mixture via syringe and the solution was stirred for an additional 10 min. Sulfur trioxide-pyridine complex (0.44g, 2.76mmol) was then added in one portion. The reaction was allowed to proceed at 0 ℃ for 1 hour, after which TLC analysis indicated complete consumption of starting material. The reaction was diluted with 25mL of dichloromethane and 25mL of 0.1M HCl. The layers were separated and the aqueous phase was back-extracted four times with 25mL of dichloromethane. The combined organic layers were washed with 25mL of saturated sodium bicarbonate solution and then with 25mL of brine. The clear colorless solution was washed with brine, dried over sodium sulfate and concentrated to give a yellow oil. The oil was purified by silica gel chromatography to give the desired compound 6 as a clear colorless oil
Compound 6 (24mg, 0.11mmol) was added to a solution of acetonitrile (1.5 mL) and stirred for a while. Hydroxylamine hydrochloride (24mg, 0.33mmol) was then added and the lid closed and the mixture was heated to 80 ℃ where it was stirred overnight. The next day, the reaction was cooled to room temperature and acetonitrile was removed under reduced pressure. The dark solid was then dissolved in 3mL of saturated K 2 CO 3 /H 2 Aqueous O solution (1. To be combined withNa for organic layer 2 SO 4 Dried and concentrated in vacuo. The crude residue was purified by silica gel chromatography to give compound 7.
Figure BDA0002379778500000242
1 H NMR(400MHz,CDCl 3 )δ8.40(d,J＝5.2Hz,1H),7.52–7.36(m,5H),7.10(d,J＝5.2Hz,1H),3.07(m,4H),2.11(m,2H). 13 C NMR(101MHz,CDCl 3 )δ166.36,147.84,145.36,138.73,134.45,128.59,128.24,128.17,120.64,34.60,30.86,23.43.
Application example 2: use of gamma-alkenyl ketones of formula (3 a) in the synthesis of compound 8
Figure BDA0002379778500000251
A flame-dried 25-mL round-bottomed flask was charged with (S) -CBS (1.0M toluene solution) (140. Mu.l, 0.38mmol,3.0 eq) THF (2 mL), and the solution was cooled to 0 ℃ under flow, to which was added N 2 And BH 3 ·SMe 2 (1.0M in THF) (92. Mu.l, 0.09mmol,2.0 eq). The reaction mixture was stirred for 5 minutes. The gamma-alkenyl ketone obtained in example 20 (11mg, 0.05mmol, 1.0eq) was added dropwise through a syringe. After stirring for 20 min, the reaction mixture was quenched with water and allowed to warm to room temperature and extracted with diethyl ether (3 × 1 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by silica gel flash column chromatography (eluting with petroleum ether/diethyl ether =20/1 to 10/1) to afford compound 8 as a colorless oil. By passing 1 H NMR spectroscopic analysis determined diastereoselectivity of compound 8 and enantioselectivity of compound 8 by chiral HPLC analysis.
The present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art are intended to be included within the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is to be determined by the appended claims.

Claims (9)

1. A method for synthesizing gamma-alkenyl ketone is characterized in that under the condition that an organic solvent, a catalyst, an additive and a ligand exist, ketone shown as a formula (1 a) and 1-phenyl-1-propyne shown as a formula (2 a) are used as reaction raw materials to carry out reaction to obtain gamma-alkenyl ketone shown as a formula (3 a); the catalyst is a monovalent rhodium metal catalyst; the ligand is a bidentate ligand or monodentate ligand having a coordination effect with rhodium; the additive is acid and amine, wherein the acid is one of benzoic acid, C1-C6 alkyl substituted benzoic acid, halogen atom substituted benzoic acid, isophthalic acid and diphenyl phosphate; the amine is one of piperidine, pyrrole and morpholine; the reaction is shown in the following reaction formula (A):
Figure DEST_PATH_IMAGE001
reaction formula (A);
wherein:
R 1 is one of the following groups, including hydrogen, chain alkane containing oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom for substitution, cycloalkyl, phenyl substituted by alkyl, phenyl containing oxygen atom, nitrogen atom, boron atom and silicon atom and halogen atom for substitution, phenyl substituted by aromatic ring or aromatic heterocyclic ring, aromatic heterocyclic ring;
R 2 is hydrogen; or when R is 2 When not hydrogen, the formula (1 a) is various cyclic ketones containing cyclopentanone and cyclohexanone and having 5 to 15 carbon atoms, cyclic ketones containing substitution of oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, cyclic ketones containing substitution of various aromatic rings or aromatic heterocyclic rings;
R 3 is one of the following groups, including phenyl, alkyl substituted phenyl, phenyl substituted by oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, and phenyl substituted by aromatic ring or aromatic heterocyclic ring.
2. The method of synthesis according to claim 1,
R 1 is one of the following groups, including hydrogen, C1-C6 alkyl, phenyl, C1-C6 alkyl substituted phenyl, N, N-dimethyl substituted phenyl, fluoro substituted phenyl, trifluoromethyl substituted phenyl, C1-C6 alkoxy substituted phenyl, naphthyl, furyl, thienyl, ferrocenyl;
R 2 is a hydrogen atom; or when R 2 When not hydrogen, the formula (1 a) is various cyclic ketones containing 5 to 15 carbon atoms including cyclopentanone and cyclohexanone, cyclic ketones substituted by oxygen atom, nitrogen atom, boron atom, silicon atom and halogen atom, and cyclic ketones substituted by various aromatic rings or aromatic heterocyclic rings;
R 3 is one of the following groups, including phenyl, C1-C6 alkyl substituted phenyl, N, N-dimethyl substituted phenyl, fluoro substituted phenyl, trifluoromethyl substituted phenyl, C1-C6 alkoxy substituted phenyl.
3. The method of synthesis of claim 1, wherein the additive further comprises phenol; the phenol is one of unsubstituted or substituted phenol, and the substituted phenol comprises one of 2, 6-dimethylphenol, 2, 6-dimethoxyphenol, 2, 6-di-tert-butylphenol and 2, 6-diisopropylphenol.
4. The method of claim 1, wherein the organic solvent is one or more of 1, 2-dichloroethane, toluene, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether, CPME, ethyl acetate, methanol, ethanol.
5. The synthesis method according to claim 1, characterized in that the catalyst is [ Rh (cod) Cl [ ]] 2 。
6. The synthesis method of claim 3, wherein when the ketone is cyclopentanone, the molar ratio of ketone to alkyne to acid to amine to phenol to metal catalyst to ligand is: 1 (1-3) (0.1-1) (0.1-0.5) (0.1-1) (0.01-0.1) (0.02-0.2); the adding amount of the organic solvent is 1mL/mmol ketone;
when the ketone is not cyclopentanone, the molar ratio of ketone to alkyne to acid to amine to phenol to metal catalyst to ligand is: (1-3) 1 (0.1-1): (0.1-0.5): 0.1-1): 0.01-0.1): 0.02-0.2); the amount of the organic solvent added was 0.33 ml/mmol of ketone.
7. The method of synthesis according to claim 6,
when the ketone is cyclopentanone, the molar ratio of ketone to alkyne to acid to amine to phenol to metal catalyst to ligand is: 1.25; the adding amount of the organic solvent is 1mL/mmol ketone;
if the ketone is not cyclopentanone, the molar ratio of ketone to alkyne to acid to amine to phenol to metal catalyst to ligand is: 3; the amount of the organic solvent added was 1mL/mmol of ketone.
8. The method of claim 1, wherein the reaction temperature is from 90 to 130 ℃ o C; the reaction time is 2-72 hours.
9. The synthetic method of claim 1, further comprising a post-treatment step, wherein the crude reaction solution obtained by the reaction is subjected to column chromatography by using a solution with a volume ratio of diethyl ether to petroleum ether =1 to 60 to 1.
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Citations (1)

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Publication number Priority date Publication date Assignee Title
CN101085726A (en) * 2007-06-29 2007-12-12 中国科学院上海有机化学研究所 Method for synthesizing 1,3-disubstitute-4-penten-1-one

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101085726A (en) * 2007-06-29 2007-12-12 中国科学院上海有机化学研究所 Method for synthesizing 1,3-disubstitute-4-penten-1-one

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
[(CH2CH)2Al(μ-OCH2CH2NMe2)]2: a vinylalane reagent suitable for conjugate additions to α,β-unsaturated ketones;HerbertSchumann等;《Tetrahedron Letters》;20010806;第32卷(第42期);第5406页表2 *
Enolonium Species—Umpoled Enolates;Shlomy Arava等;《Angewandte Chemie》;20171231;第56卷(第10期);第2602页表2 *
The stereoselectivity of ketal Claisen rearrangements with ketals of simple cyclic ketones;G.WilliamDaub等;《Tetrahedron Letters》;19861231;第52卷(第27期);第6312页 *

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