CN110407739B - Preparation method of (4, 6-diaryl-tetrahydropyridine-3-yl) (aryl) ketone - Google Patents
Preparation method of (4, 6-diaryl-tetrahydropyridine-3-yl) (aryl) ketone Download PDFInfo
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention relates to a preparation method of (4, 6-diaryl-tetrahydropyridine-3-yl) (aryl) ketone, which comprises the following steps: (1) mixing aryl propiolic alcohol, chalcone derivative, acid and a solvent, heating, and reacting under the reflux condition; (2) and adding an amine compound into a reaction system after the reaction is finished, and reacting for 9-17 hours under a reflux condition to obtain the (4, 6-diaryl-tetrahydropyridine-3-yl) (aryl) ketone. Compared with the prior art, the synthesis method has the advantages of simple method, mild condition, high yield, atom utilization rate of 100% and the like, greatly optimizes the synthesis of the compounds, and provides a brand new synthesis idea for the synthesis of compounds with similar structures.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of (4, 6-diaryl-tetrahydropyridine-3-yl) (aryl) ketone.
Background
In some documents already reported, we know that 4, 6-diaryl-tetrahydropyridin-3-yl) (aryl) methanones are an important framework in organic synthesis, and regarding the synthesis of the same kind of compound (2,4, 6-triphenyl-3, 4-dihydropyridine-1, 3(2H) -diyl) bis (benzophenone), pip and Wright finally synthesize the target compound by Grignard reaction, two self-additions and one Schottky-Bowman reaction of starting materials styryl cyanide and phenyl Grignard reagent. E.Piper and Geiger F Wright, JOC,1950, DIO: DOI:10.1021/ja01160a 068). Through the above reaction scheme, the synthesis method has more steps and needs format reagents to participate in the reaction, and the reaction conditions are relatively harsh (formula-1).
Pavel et al reported in 1979 a method for the synthesis of N-protected (4, 6-diaryl-1, 2,3, 4-tetrahydropyridin-3-yl) (aryl) methanones, but the starting material 1,3, 5-triphenyl-2-methylene-1, 5-pentanedione was relatively complex and difficult to obtain ((Pavel', G.V.and Tilichenko, M.N.; Khim.Geterotsikl.Soediin.Chemischer informationdienst 1979,10, formula-2).
Disclosure of Invention
The present invention aims to overcome the defects of the prior art and provide a novel preparation method of (4, 6-diaryl-tetrahydropyridine-3-yl) (aryl) ketone with 100% atom economy.
The purpose of the invention can be realized by the following technical scheme:
a process for the preparation of a (4, 6-diaryl-tetrahydropyridin-3-yl) (aryl) methanone comprising the steps of:
(1) mixing aryl propiolic alcohol, chalcone derivative, acid and a solvent, heating, and reacting under the reflux condition;
(2) and adding an amine compound into a reaction system after the reaction is finished, and reacting for 9-17 hours under a reflux condition to obtain the (4, 6-diaryl-tetrahydropyridine-3-yl) (aryl) ketone.
Wherein the aryl propiolic alcohol has the formula:
is 3-aryl substituted propargyl alcohol;
the molecular formula of the chalcone derivative is as follows:
the molecular formula of the amine compound is as follows: r4NH2；
The molecular formula of the (4, 6-diaryl-tetrahydropyridin-3-yl) (aryl) ketone is as follows:
the specific reaction equation of the invention is as follows:
the target product (4, 6-diaryl-tetrahydropyridine-3-yl) (aryl) ketone is obtained through the series Meyer-Schuster rearrangement reaction/conjugate addition reaction/second conjugate addition reaction, and the method is a brand new one-pot synthesis method, and has the advantages of easily obtained raw materials and simple operation; by adopting a series reaction, intermediate products generated by the Meyer-Schuster rearrangement reaction are continuously consumed, the forward reaction is facilitated, and the conversion of the reactant aryl propiolic alcohol is promoted; the key point is that the category of the raw materials is screened out, alkynol is easily converted into nucleophilic groups in the reaction, so that the reaction can be well carried out, two reactions in one pot can be smoothly carried out, and the yield of a target product is high.
In the invention, the reaction time with the amine compound in the step (2) is very critical, and if the reaction time is too short, the reaction is incomplete, and a large amount of intermediate products with chain structures are formed; if the reaction time is too long, side reactions increase, and the target compound is further converted into some cyclic compounds with small molecular weight, which also affects the yield of the target product.
More specifically, the R1Is phenyl, substituted phenyl, pyridyl, naphthyl or thienyl, preferably phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 4-methyl-phenyl, 4-phenyl, 4-methoxy-phenyl, 3-methoxy-phenyl, 2-naphthyl or 3-thienyl;
the R is2Is phenyl, substituted phenyl, pyridyl, naphthyl or thienyl, preferably 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl, 4-phenyl or 4-methoxy-phenyl;
the R is3Is phenyl, substituted phenyl, pyridyl, naphthyl or thienyl, preferably 4-chloro-phenyl, 4-methoxy-phenyl, 3-methoxy-phenyl or 2-methoxy-phenyl;
r4 is sulfonyl or acyl, preferably benzenesulfonyl, 4-nitro-benzenesulfonyl, 4-methoxy-benzenesulfonyl, 4-fluoro-benzenesulfonyl, 4-chloro-benzenesulfonyl, 4-methyl-benzenesulfonyl or benzoyl.
The molar ratio of the aryl propiolic alcohol, the chalcone derivative, the amine compound and the acid is 1 (1.00-2.00) to (0.10-1.00).
In the invention, the structure of the main product can be controlled by regulating the molar ratio of the aryl propiolic alcohol to the acid and the reaction time:
the molar ratio of the aryl propiolic alcohol to the acid is 1 (0.1-0.4), the reaction time in the step (2) is 9-11 hours, and the molecular formula of a main product is shown as a formula I;
the molar ratio of the aryl propiolic alcohol to the acid is 1 (0.4-0.8), the reaction time in the step (2) is 12-17 hours, and the molecular formula of a main product is shown as a formula II.
In the invention, the acid is used as a catalyst, specifically is Lewis acid, and is preferably one or more of trifluoromethanesulfonic acid, trifluoroacetic acid, ferric trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, copper trifluoromethanesulfonate, silver trifluoromethanesulfonate, scandium trifluoromethanesulfonate and ferric trichloride.
The solvent is one or more of dioxane, dichloroethane, benzotrifluoride, toluene, benzene, tetrahydrofuran or methanol. The method is carried out under the reflux condition, and the reflux temperature is the boiling point of the used solvent, so the reaction temperature of the method is related to the selected solvent and is 40-110 ℃.
In the step (1), the molar concentration of the aryl propiolic alcohol in the solvent is 1:5 mol/L-1: 10 mol/L.
And (3) adding water into the reaction solution to quench the reaction after the reaction in the step (2) is finished.
In the invention, the reaction time after the reactant amine is fed is the most critical step, when alkynol and chalcone just react, the amine is added into the reaction system, and different products can be obtained by controlling the reaction time in the step (2); the ratio of the reactants to the catalyst acid is the most important parameter, when the ratio of the catalyst acid in the ratio is too small, the reaction duration is prolonged, and the yield is reduced, and when the ratio of the catalyst in the ratio is too large, the self-coupling reaction of the alkynol is easily catalyzed, so that the yield of the main reaction is influenced.
Compared with the prior art, the invention has the following advantages:
(1) the method has the advantages of easily available raw materials, simple operation, mild conditions, convenient production and easy expanded production;
(2) the whole reaction path has 100% atomic utilization rate, no by-product is generated, and the method is green and environment-friendly;
(3) by optimizing the reaction conditions, the reaction yield is high, and the yield of the target product of more than 73 percent can be obtained.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
A process for the preparation of (4, 6-diaryl-tetrahydropyridin-3-yl) (aryl) methanones according to the equation:
among them, the synthesis of (4, 6-diaryl-tetrahydropyridin-3-yl) (aryl) methanone 4 or (4, 6-diaryl-tetrahydropyridin-3-yl) (aryl) methanone 5 can be specifically controlled by the amount of acid added and the reaction time, and thus, the preparation method is specifically divided into two preparation methods.
The method comprises the following steps: preparation of (4, 6-diaryl-tetrahydropyridin-3-yl) (aryl) methanone 4
The preparation method of the general (4, 6-diaryl-tetrahydropyridine-3-yl) (aryl) ketone 4 specifically comprises the following steps: adding 0.10mmol of aryl propiolic alcohol, 0.50-1.00 mL of solvent, 0.01-0.04 mmol of acid and 0.10-0.20 mmol of chalcone derivative into a 10mL sealed tube in sequence, heating, reacting under a reflux condition, monitoring the reaction by TLC, adding 0.10-0.20 mmol of amine compound after the aryl propiolic alcohol is completely reacted, reacting under the reflux condition for about 9-11 h, adding water into the reaction liquid to quench the reaction liquid, adding ethyl acetate to extract an organic phase, washing the obtained organic phase with saturated sodium chloride, drying anhydrous sodium sulfate, concentrating on a rotary evaporator, and purifying the obtained concentrated solution by column chromatography.
The second method comprises the following steps: preparation of (4, 6-diaryl-tetrahydropyridin-3-yl) (aryl) methanone 5
The preparation method of the general (4, 6-diaryl-tetrahydropyridine-3-yl) (aryl) ketone 5 specifically comprises the following steps: adding aryl propiolic alcohol (0.10mmol), a solvent (0.50-1.00 mL) and an acid (0.04-0.10 mmol) into a 10mL sealed tube in sequence, heating, reacting under a reflux condition, monitoring the reaction by TLC, adding an amine compound (0.10-0.20 mmol) after the aryl propiolic alcohol completely reacts, and reacting under the reflux condition. The reaction was monitored by TLC for approximately 12-17 h. Then adding water into the reaction solution to quench the reaction, adding ethyl acetate to extract an organic phase, washing the obtained organic phase with saturated sodium chloride, drying the organic phase with anhydrous sodium sulfate, concentrating the dried organic phase on a rotary evaporator, and purifying the obtained concentrated solution by column chromatography.
Wherein R is1Is phenyl, substituted phenyl, pyridyl, naphthyl or thienyl, preferably phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 4-methyl-phenyl, 4-phenyl, 4-methoxy-phenyl, 3-methoxy-phenyl, 2-naphthyl or 3-thienyl;
R2is phenyl, substituted phenyl, pyridyl, naphthyl or thienyl, preferably 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl, 4-phenyl or 4-methoxy-phenyl;
R3is phenyl, substituted phenyl, pyridyl, naphthyl or thienyl, preferably 4-chloro-phenyl, 4-methoxy-phenyl, 3-methoxy-phenyl or 2-methoxy-phenyl;
r4 is sulfonyl or acyl, preferably benzenesulfonyl, 4-nitro-benzenesulfonyl, 4-methoxy-benzenesulfonyl, 4-fluoro-benzenesulfonyl, 4-chloro-benzenesulfonyl, 4-methyl-benzenesulfonyl or benzoyl.
In the present invention, the acid is a catalyst, specifically a lewis acid, and its selection may be exemplified by trifluoromethanesulfonic acid, trifluoroacetic acid, iron trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, copper trifluoromethanesulfonate, silver trifluoromethanesulfonate, scandium trifluoromethanesulfonate, or iron trichloride.
The solvent can be selected from dioxane, dichloroethane, trifluorotoluene, toluene, benzene, tetrahydrofuran, and methanol.
The following are specific embodiments of the present invention.
The raw materials used in the examples are commercially available products, and therefore, no other contents need to be provided.
The catalyst, dioxane, dichloroethane, benzotrifluoride, toluene, benzene, tetrahydrofuran, ethyl acetate, petroleum ether, anhydrous sodium sulfate and the like used in the embodiments of the invention are all Chinese medicine reagents.
The information of the equipment and the manufacturers used in the embodiments of the present invention is as follows:
the stirrer is as follows: a Shanghai plum Yimpu MYPII-2 constant-temperature magnetic stirrer;
the circulating water pump is as follows: shanghai Yukang circulation multipurpose vacuum pump SHB-IIIA;
the rotary evaporator comprises: shanghai yukang rotary evaporator W.S 206B;
the oil pump is as follows: shanghai Yukang 2XZ-2 type rotary-vane vacuum pump;
the preparative HPLC was: shimadzu LC-20A.
Example 1
The preparation method of (4, 6-diphenyl-1-tosyl-1, 2,3, 4-tetrahydropyridine-3-yl) (phenyl) ketone comprises the following steps:
the preparation method refers to a first preparation method, and the specific types and the dosage of the aryl propiolic alcohol, the solvent, the catalyst, the chalcone compound and the amine are respectively as follows: phenyl propiolic alcohol (0.10mmol), 1, 2-dichloroethane (0.50mL), bismuth triflate (0.02mmol), chalcone (0.12mmol) and p-methylbenzenesulfonamide (0.12mmol), the reaction time after addition of the amine was 9 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C31H29NO3S([M+H]+):494.1790；found:494.1791。
The yield of the desired product was calculated to be 73%.
Example 2
The preparation method of (4, 6-diphenyl-1-methylsulfonyl-1, 2,3, 4-tetrahydropyridine-3-yl) (phenyl) ketone comprises the following steps:
the preparation method refers to the first preparation method, and the specific dosage and types of the aryl propargyl alcohol, the solvent, the acid, the chalcone compound and the amine are respectively as follows: phenylpropanol (0.10mmol), 1, 2-dichloroethane (1.0mL), copper trifluoromethanesulfonate (0.03mmol), chalcone (0.12mmol) and benzenesulfonamide (0.12mmol), and the reaction time after addition of the amine was 9 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C30H26NO3S([M+H]+):480.1633；found:480.1632。
The yield of the desired product was calculated to be 70%.
Example 3
The preparation method of 4, 6-diphenyl-1- (p-methoxybenzenesulfonyl) -1,2,3, 4-tetrahydropyridin-3-yl (phenyl) methanone comprises the following steps:
the preparation method refers to the first method, and the specific dosage and types of the aryl-substituted propargyl alcohol, the solvent, the acid, the chalcone compound and the amine are respectively as follows: phenylproparganol (0.10mmol), 1, 2-dichloroethane (0.50mL), ferric trifluoromethanesulfonate (0.03mmol), chalcone (0.12mmol) and p-methoxybenzenesulfonamide (0.15mmol), and the reaction time after addition of the amine was 9 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C31H28NO4S([M+H]+):510.1937；found:510.1936。
The yield of the desired product was calculated to be 69%.
Example 4
The preparation method of 4, 6-diphenyl-1- (p-fluorobenzenesulfonyl) -1,2,3, 4-tetrahydropyridine-3-yl (phenyl) ketone comprises the following steps:
the preparation method refers to the first preparation method, and the dosage of aryl-substituted propargyl alcohol, a solvent, an acid, a chalcone compound and an amine is respectively as follows: phenyl propiolic alcohol (0.10mmol), 1, 2-dichloroethane (1.00mL), trifluoromethanesulfonic acid (0.03mmol), chalcone (0.15mmol) and p-fluorobenzenesulfonamide (0.15mmol), the reaction time after addition of the amine was 10 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C30H25FNO3S([M+H]+):498.1539；found:498.153。
The yield of the desired product was calculated to be 72%.
Example 5
The preparation method of 4, 6-diphenyl-1- (p-chlorobenzenesulfonyl) -1,2,3, 4-tetrahydropyridine-3-yl (phenyl) ketone comprises the following steps:
the preparation method refers to the first method, and the specific dosage and types of the aryl-substituted propargyl alcohol, the solvent, the acid, the chalcone compound and the amine are respectively as follows: phenyl propargyl alcohol (0.10mmol), 1, 2-dichloroethane (0.80mL), ferric chloride (0.04mmol), chalcone (0.20mmol) and p-chlorobenzenesulfonamide (0.14mmol), and the reaction time after addition of the amine was 11 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C30H25ClNO3S([M+H]+):514.1244；found:514.1244。
The yield of the desired product was calculated to be 61%.
Example 6
The preparation method of 4, 6-diphenyl-1- (p-bromobenzenesulfonyl) -1,2,3, 4-tetrahydropyridin-3-yl (phenyl) methanone comprises the following steps:
the preparation method refers to the first method, and the specific dosage and types of the aryl-substituted propargyl alcohol, the solvent, the acid, the chalcone compound and the amine are respectively as follows: phenyl propiolic alcohol (0.10mmol), dioxane (0.50mL), silver triflate (0.03mmol), chalcone (0.04mmol) and p-bromobenzenesulfonamide (0.2mmol), the reaction time after addition of the amine was 11 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C30H25BrNO3S([M+H]+):558.0739；found:558.0738。
The yield of the desired product was calculated to be 63%.
Example 7
The preparation method of 4, 6-diphenyl-1- (p-nitrobenzenesulfonyl) -1,2,3, 4-tetrahydropyridine-3-yl (phenyl) ketone comprises the following steps:
the preparation method refers to the first method, and the specific dosage and types of the aryl-substituted propargyl alcohol, the solvent, the acid, the chalcone compound and the amine are respectively as follows: phenyl propiolic alcohol (0.10mmol), tetrahydrofuran (0.50mL), scandium triflate (0.30mmol), chalcone (0.12mmol) and p-nitrobenzenesulfonamide (0.12mmol), the reaction time after addition of the amine was 9 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C30H25N2O5S([M+H]+):525.1484；found:525.1483。
The yield of the desired product was calculated to be 59%.
Example 8
The preparation method of 4, 6-diphenyl-1- (methylsulfonyl) -1,2,3, 4-tetrahydropyridine-3-yl (phenyl) ketone comprises the following steps:
the preparation method refers to the first method, and the specific dosage and types of the aryl-substituted propargyl alcohol, the solvent, the acid, the chalcone compound and the amine are respectively as follows: phenyl propiolic alcohol (0.10mmol), toluene (0.50mL), bismuth triflate (0.03mmol), chalcone (0.15mmol) and methylsulfonamide (0.15mmol), the reaction time after addition of the amine was 9 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C25H24NO3S([M+H]+):418.1477；found:418.1477。
The yield of the desired product was calculated to be 51%.
Example 9
The preparation method of 4, 6-diphenyl-1- (benzoyl) -1,2,3, 4-tetrahydropyridine-3-yl (phenyl) ketone comprises the following steps:
the preparation method refers to the first method, and the specific dosage and types of the aryl-substituted propargyl alcohol, the solvent, the acid, the chalcone compound and the amine are respectively as follows: phenyl propiolic alcohol (0.10mmol), methanol (1.00mL), bismuth triflate (0.04mmol), chalcone (0.13mmol) and benzamide (0.13mmol), the reaction time after addition of the amine was 9 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C31H26NO2([M+H]+):444.1964；found:444.1963。
The yield of the desired product was calculated to be 53%.
Example 10
A method for preparing 4, 6-diphenyl-1- (benzene toluene sulfonyl) -1,2,3, 4-tetrahydropyridine-3-yl (p-tolyl) ketone, wherein the molecular formula of the target product is as follows:
the preparation method refers to the first method, and the specific dosage and types of the aryl-substituted propargyl alcohol, the solvent, the acid, the chalcone compound and the amine are respectively as follows: p-methylphenylpropynol (0.10mmol), 1, 2-dichloroethane (0.50mL), bismuth trifluoromethanesulfonate (0.02mmol), chalcone (0.12mmol) and p-toluenesulfonamide (0.20mmol), and the reaction time after addition of the amine was 9 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C32H30NO3S([M+H]+):508.1946；found:508.1945。
The yield of the desired product was calculated to be 67%.
Example 11
The preparation method of 4, 6-diphenyl-1- (benzene toluene sulfonyl) -1,2,3, 4-tetrahydropyridine-3-yl (naphthyl) ketone comprises the following steps:
the preparation method refers to the first method, and the specific dosage and types of the aryl-substituted propargyl alcohol, the solvent, the acid, the chalcone compound and the amine are respectively as follows: naphthopynol (0.10mmol), 1, 2-dichloroethane (0.50mL), bismuth trifluoromethanesulfonate (0.02mmol), chalcone (0.12mmol) and p-toluenesulfonamide (0.12mmol), and the reaction time after addition of the amine was 9 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C35H3NO3S([M+H]+):544.1946；found:544.1945。
The yield of the desired product was calculated to be 66%.
Example 12
The preparation method of 4, 6-diphenyl-1- (benzene tosyl) -1,2,3, 4-tetrahydropyridine-3-yl (thienyl) ketone comprises the following steps:
the preparation method refers to a first preparation method, and the specific types and the dosage of the aryl propiolic alcohol, the solvent, the catalyst, the chalcone compound and the amine are respectively as follows: the dosage and the type of the aryl-substituted propargyl alcohol, the solvent, the acid, the chalcone compound and the amine are respectively as follows: thiophene propargyl alcohol (0.10mmol), benzene (0.50mL), ferric chloride (0.03mmol), chalcone (0.12mmol) and p-toluenesulfonamide (0.12mmol), the reaction time after addition of the amine was 9 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C29H26NO3S2([M+H]+):500.1354；found:500.1354。
The yield of the desired product was calculated to be 68%.
Example 13
A preparation method of (6- (4-chloro-phenyl) -4-phenyl-1-p-toluenesulfonyl-1, 2,3, 4-tetrahydropyridin-3-yl) (phenyl) methanone, wherein the molecular formula of the target product is as follows:
the preparation process refers to the first method, and the specific dosage and types of the aryl-substituted propargyl alcohol, the solvent, the acid, the chalcone derivatives and the amine are respectively as follows: phenyl propiolic alcohol (0.10mmol), dioxane (0.50mL), copper triflate (0.03mmol), chalcone derivative (0.12mmol) and p-toluenesulfonamide (0.12mmol), the reaction time after addition of the amine was 9 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C31H27ClNO3S([M+H]+):528.1400；found:528.1399。
The yield of the desired product was calculated to be 67%.
Example 14
A preparation method of (6- (4-benzene-phenyl) -4-phenyl-1-p-toluenesulfonyl-1, 2,3, 4-tetrahydropyridine-3-yl) (phenyl) methanone comprises the following steps:
the preparation process refers to the first method, and the specific dosage and types of the aryl-substituted propargyl alcohol, the solvent, the acid, the chalcone derivatives and the amine are respectively as follows: phenyl propiolic alcohol (0.10mmol), dioxane (1.00mL), ferric triflate (0.02mmol), chalcone derivative (0.12mmol) and p-toluenesulfonamide (0.12mmol), and the reaction time after the addition of the amine was 9 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C37H32NO3S([M+H]+):570.2103；found:570.2102。
The yield of the desired product was calculated to be 69%.
Example 15
A preparation method of (4- (4-bromo-phenyl) -6-phenyl-1-p-toluenesulfonyl-1, 2,3, 4-tetrahydropyridin-3-yl) (phenyl) methanone, wherein the molecular formula of the target product is as follows:
the preparation process refers to the first method, and the specific dosage and types of the aryl-substituted propargyl alcohol, the solvent, the acid, the chalcone derivatives and the amine are respectively as follows: phenyl propiolic alcohol (0.10mmol), 1, 2-dichloroethane (1.00mL), bismuth trifluoromethanesulfonate (0.02mmol), a chalcone derivative (0.12mmol) and p-toluenesulfonamide (0.12mmol), and the reaction time after addition of the amine was 9 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C31H27BrNO3S([M+H]+):572.0895；found:572.0894。
The yield of the desired product was calculated to be 66%.
Example 16
A preparation method of (4- (4-methoxy-phenyl) -6-phenyl-1-p-toluenesulfonyl-1, 2,3, 4-tetrahydropyridine-3-yl) (phenyl) methanone comprises the following steps:
the preparation process refers to the first method, and the specific dosage and types of the aryl-substituted propargyl alcohol, the solvent, the acid, the chalcone derivatives and the amine are respectively as follows: phenyl propiolic alcohol (0.10mmol), 1, 2-dichloroethane (0.80mL), bismuth triflate (0.02mmol), chalcone derivative (0.12mmol) and p-toluenesulfonamide (0.12mmol), the reaction time after addition of the amine was 9 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C32H30NO4S([M+H]+):524.1896；found:524.1897。
The yield of the desired product was calculated to be 67%.
Example 17
The preparation method of (4, 6-diphenyl-1-p-toluenesulfonyl-1, 2,3, 4-tetrahydropyridin-3-yl) (3-methoxy-phenyl) methanone comprises the following steps:
the preparation process refers to the first method, and the specific dosage and types of the aryl-substituted propargyl alcohol, the solvent, the acid, the chalcone derivatives and the amine are respectively as follows: 3-Methoxyphenylpropiolic alcohol (0.10mmol), 1, 2-dichloroethane (1.00mL), bismuth trifluoromethanesulfonate (0.02mmol), a chalcone derivative (0.12mmol) and p-toluenesulfonamide (0.12mmol), and the reaction time after addition of the amine was 9 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C32H30NO4S([M+H]+):524.1896；found:524.1898。
The yield of the desired product was calculated to be 65%.
Example 18
The preparation method of (4, 6-diphenyl-2, 3,4, 5-tetrahydropyridine-3-yl) (phenyl) ketone comprises the following steps:
referring to the second preparation method, the specific types and the dosage of the aryl-substituted propargyl alcohol, the solvent, the catalyst, the chalcone compound and the amine are respectively as follows: phenyl propiolic alcohol (0.10mmol), 1, 2-dichloroethane (0.50mL), bismuth triflate (0.06mmol), chalcone (0.12mmol) and p-methylbenzenesulfonamide (0.12mmol), the reaction time after addition of the amine was 12 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C24H22NO([M+H]+):340.1701；found:340.1700。
The yield of the desired product was calculated to be 51%.
Example 19
The preparation method of (4, 6-diphenyl-2, 3,4, 5-tetrahydropyridine-3-yl) (p-toluene) ketone comprises the following steps:
referring to the second preparation method, the specific types and the dosage of the aryl-substituted propargyl alcohol, the solvent, the catalyst, the chalcone compound and the amine are respectively as follows: p-methylphenylpropynol (0.10mmol), 1, 4-dioxane (0.5mL), ferric triflate (0.06mmol), chalcone (0.10mmol) and p-methylbenzenesulfonamide (0.20mmol), and the reaction time after the addition of the amine was 15 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C25H24NO([M+H]+):354.1858；found:354.1856。
The yield of the desired product was calculated to be 53%.
Example 20
The preparation method of (6- (4-chlorphenyl) -4-phenyl-2, 3,4, 5-tetrahydropyridine-3-yl) (phenyl) ketone comprises the following steps:
referring to the second preparation method, the specific types and the dosage of the aryl-substituted propargyl alcohol, the solvent, the catalyst, the chalcone compound and the amine are respectively as follows: phenyl propynol (0.10mmol), methanol (0.50mL), copper triflate (0.06mmol) and chalcone derivative (0.20mmol) and p-methylbenzenesulfonamide (0.10mmol), the reaction time after addition of the amine was 15 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C24H21ClNO([M+H]+):374.1312；found:374.1311。
The yield of the desired product was calculated to be 48%.
Example 21
A preparation method of (4- (4-methoxyphenyl) -6-phenyl-2, 3,4, 5-tetrahydropyridine-3-yl) (phenyl) methanone comprises the following steps:
referring to the second preparation method, the specific types and the dosage of the aryl-substituted propargyl alcohol, the solvent, the catalyst, the chalcone compound and the amine are respectively as follows: phenyl propiolic alcohol (0.10mmol), tetrahydrofuran (0.50mL), bismuth triflate (0.06mmol), a chalcone derivative (0.10mmol) and p-methylbenzenesulfonamide (0.10mmol), the reaction time after addition of the amine was 17 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C25H24NO2([M+H]+):370.1807；found:370.1806。
The yield of the desired product was calculated to be 47%.
Example 22
A preparation method of (4- (4-methoxyphenyl) -6-phenyl-2, 3,4, 5-tetrahydropyridine-3-yl) (phenyl) methanone comprises the following steps:
referring to the second preparation method, the specific types and the dosage of the aryl-substituted propargyl alcohol, the solvent, the catalyst, the chalcone compound and the amine are respectively as follows: phenyl propiolic alcohol (0.10mmol), tetrahydrofuran (0.50mL), bismuth triflate (0.1mmol), a chalcone derivative (0.10mmol) and p-methylbenzenesulfonamide (0.10mmol), the reaction time after addition of the amine was 17 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C25H24NO2([M+H]+):370.1807；found:370.1806。
The yield of the desired product was calculated to be 36%.
Comparative example 1
The preparation method of (4, 6-diphenyl-1-tosyl-1, 2,3, 4-tetrahydropyridine-3-yl) (phenyl) ketone comprises the following steps:
the preparation method refers to a first preparation method, and the specific types and the dosage of the aryl propiolic alcohol, the solvent, the catalyst, the chalcone compound and the amine are respectively as follows: phenyl propiolic alcohol (0.10mmol), 1, 2-dichloroethane (0.50mL), bismuth triflate (0.02mmol), chalcone (0.12mmol) and p-methylbenzenesulfonamide (0.12mmol), the reaction time after addition of the amine was 4 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C31H29NO3S([M+H]+):494.1790；found:494.1791。
Simultaneously detecting a large amount of byproducts in the product, wherein the detection data is HRMS calculated for C31H30NO4S([M+H]+) 512.1896; 512.1895 is found. It is shown that the product contains a large amount of non-ring-closed by-products of the formula:
the yield of the target product is calculated to be 45%, and by comparing the data in comparative example 1 and the data in example 1, it can be found that when the reaction time is shorter, the intermediate chain product is not further closed to form the target product, which results in lower yield of the target product.
Comparative example 2
The preparation method of (4, 6-diphenyl-2, 3,4, 5-tetrahydropyridine-3-yl) (phenyl) ketone comprises the following steps:
referring to the second preparation method, the specific types and the dosage of the aryl-substituted propargyl alcohol, the solvent, the catalyst, the chalcone compound and the amine are respectively as follows: phenyl propiolic alcohol (0.10mmol), 1, 2-dichloroethane (0.50mL), bismuth triflate (0.06mmol), chalcone (0.12mmol) and p-methylbenzenesulfonamide (0.12mmol), the reaction time after addition of the amine was 18 hours.
Characterizing the synthesized product, and obtaining nuclear magnetic data of HRMS calculated for C24H22NO([M+H]+):340.1701；found:340.1700。
The yield of the desired product was calculated to be 41%. Comparing the data in comparative example 2 and example 18 (yield is 58%), it can be found that when the reaction time is too long, the yield of the synthesized target product is rather reduced, which indicates that the target product may further generate some cyclic compounds with small molecular weight under the action of the catalyst due to too long time, and also may affect the yield of the target product; in this example, the content of the intermediate (2-methylene-1, 3, 5-triaryl-1, 5-pentanedione) obtained in step (1) was checked by TLC, and it was found that the intermediate was completely converted after 17 hours of the reaction, and when the reaction time was further increased, carbonization was accelerated, resulting in a decrease in the yield of the objective product.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.
Claims (8)
1. A process for the preparation of (4, 6-diaryl-tetrahydropyridin-3-yl) (aryl) methanones, comprising the steps of:
(1) mixing aryl propiolic alcohol, chalcone derivative, acid and a solvent, heating, and reacting under the reflux condition;
(2) adding an amine compound into a reaction system after the reaction is finished, and reacting for 9-17 hours under a reflux condition to obtain the (4, 6-diaryl-tetrahydropyridine-3-yl) (aryl) ketone;
the aryl propiolic alcohol has the molecular formula:
the molecular formula of the chalcone derivative is as follows:
the acid is one or more of trifluoromethanesulfonic acid, ferric trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, copper trifluoromethanesulfonate, silver trifluoromethanesulfonate and scandium trifluoromethanesulfonate;
the molecular formula of the (4, 6-diaryl-tetrahydropyridin-3-yl) (aryl) ketone is as follows:
and/or
The R is1Is phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 4-methyl-phenyl, 4-phenyl, 4-methoxy-phenyl, 3-methoxy-phenyl, 2-naphthyl or 3-thienyl;
the R is2Is 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl, 4-phenyl or 4-methoxy-phenyl;
the R is3Is 4-chloro-phenyl, 4-methoxy-phenyl, 3-methoxy-phenyl or 2-methoxy-phenyl;
the R is4Is benzenesulfonyl, 4-nitro-benzenesulfonyl, 4-methoxy-benzenesulfonyl, 4-fluoro-benzenesulfonyl, 4-chloro-benzenesulfonyl, 4-methyl-benzenesulfonyl or benzoyl.
2. The method according to claim 1, wherein the amine compound has the formula: r4NH2。
3. The method of claim 1, wherein the molar ratio of the arylpropiolic alcohol, the chalcone derivative, the amine compound and the acid is 1 (1.00-2.00): (0.10-1.00).
4. The method for preparing (4, 6-diaryl-tetrahydropyridin-3-yl) (aryl) ketone according to claim 3, wherein the molar ratio of the aryl propiolic alcohol to the acid is 1 (0.1-0.4), the reaction time in the step (2) is 9-11 hours, and the formula of the main product is shown as formula I.
5. The method for preparing (4, 6-diaryl-tetrahydropyridin-3-yl) (aryl) ketone according to claim 3, wherein the molar ratio of the aryl propiolic alcohol to the acid is 1 (0.4-0.8), the reaction time in the step (2) is 12-17 hours, and the formula of the main product is shown as formula II.
6. The method according to claim 1, wherein the solvent is one or more selected from dioxane, dichloroethane, trifluorotoluene, toluene, benzene, tetrahydrofuran, and methanol.
7. The method according to claim 1, wherein the molar concentration of arylpropiolic alcohol in the solvent in the step (1) is 1:5mol/L to 1:10 mol/L.
8. The method according to claim 1, wherein water is added to the reaction mixture after the reaction of step (2) is completed to quench the reaction.
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