CN112125843B - A kind of preparation method of 3-hydroxymethyl-4-phenyl-3,4-dihydroquinolinone compound - Google Patents

Abstract

The invention discloses a preparation method of 3-hydroxymethyl-4-phenyl-3,4-dihydroquinolinone compound. The method uses acetonitrile as a reaction medium, and potassium monopersulfate promotes N-methyl-N-aryl-2-phenylacrylamide to undergo epoxidation-intramolecular Friedel-Crafts alkylation series reaction to generate 3-hydroxymethyl ‑4‑phenyl‑3,4‑dihydroquinolinone compound; the method has the advantages of mild conditions, simple operation, environmental protection, easy availability of raw materials, excellent compatibility of substrate functional groups, and high reaction yield.

Description

A kind of preparation method of 3-hydroxymethyl-4-phenyl-3,4-dihydroquinolinone compound

technical field

The invention relates to a preparation method of a 3-hydroxymethyl-4-phenyl-3,4-dihydroquinolinone compound, in particular to potassium monopersulfate promoting N - Epoxidation of methyl-N-aryl-2-phenylacrylamide-intramolecular Friedel-Crafts alkylation to synthesize 3-hydroxymethyl-4-phenyl-3,4-dihydroquinolinone The compound method belongs to the technical field of organic intermediate synthesis.

Background technique

3,4-Dihydroquinolinones exist in a variety of natural products and synthetic drugs, and have good biological and pharmacological activities. The development of new preparation methods for these compounds has important research significance. The hydroxymethyl functional group can effectively improve the metabolic stability and bioavailability of biologically active molecules, and the development of new synthetic methods for heterocyclic compounds containing hydroxymethyl functional groups is of great significance for drug research and development. The synthesis of 3,4-dihydroquinolinones containing hydroxymethyl functional group has positive research significance for the development and utilization of drug molecules containing 3,4-dihydroquinolinone skeletons. N-methyl-N-aryl-2-phenylacrylamide is an inexpensive and readily available acrylamide derivative and is a synthetic intermediate widely used in synthetic chemistry and medicinal chemistry.

But so far, there is no literature report on the direct synthesis of 3-hydroxymethyl-4-phenyl-3,4-dicarbonate from N-methyl-N-aryl-2-phenylacrylamide which is cheap and easy to obtain. Methods of Hydroquinolinone Compounds.

SUMMARY OF THE INVENTION

Aiming at the preparation method of 3-hydroxymethyl-4-phenyl-3,4-dihydroquinolinone compound that has not been reported in the prior art, the object of the present invention is to provide a kind of using cheap potassium monopersulfate as Reaction accelerator, N-methyl-N-aryl-2-phenylacrylamide as raw material, potassium monopersulfate promotes epoxidation of N-methyl-N-aryl-2-phenylacrylamide- A method for the synthesis of 3-hydroxymethyl-4-phenyl-3,4-dihydroquinolinone compounds by intramolecular Friedel-Crafts alkylation series reaction, the method does not require additional transition metal catalysis and acid additives, and has high performance under mild conditions. The yield obtains the 3-hydroxymethyl-4-phenyl-3,4-dihydroquinolinone compound, and the raw materials are cheap and easy to obtain, the cost is low, the reaction conditions are simple and safe, the environment is friendly, and the industrial production and application are favorable.

In order to achieve the above technical purpose, the present invention provides a preparation method of 3-hydroxymethyl-4-phenyl-3,4-dihydroquinolinone compound, the method is to combine N-methyl-N-aryl Epoxidation of -2-phenylacrylamide and potassium monopersulfate in acetonitrile medium-intramolecular Friedel-Crafts alkylation series reaction to generate 3-hydroxymethyl-4-phenyl-3,4-dihydroquinoline Linone compounds;

The N-methyl-N-aryl-2-phenylacrylamide has the structure of formula 1:

The 3-hydroxymethyl-4-phenyl-3,4-dihydroquinolinone compound has the structure of formula 2:

in,

R is hydrogen, a C ₁ -C ₅ alkyl group, a C ₁ -C ₅ alkoxy group, or a halogen substituent.

The R substituent of the present invention is mainly a group introduced by N-methyl-N-aryl-2-phenylacrylamide, which is a common substituent, and the substitution position of the substituent on the benzene ring is not limited, Common substituents such as alkyl substituents, alkoxy substituents, halogen substituents and the like. The length of the alkyl chain of the alkyl substituent has little effect on the reaction. Common alkyl substituents are C ₁ -C ₅ alkyl groups, such as methyl, ethyl, propyl, etc., with 3 carbon atoms. The above alkyl groups also include isomers, such as branched alkyl groups, such as isobutyl, etc.; the alkyl chain length of the alkoxy substituent is not limited, and common alkoxy substituents are C ₁ ~ C ₅ alkoxy groups, such as methoxy, ethoxy, propoxy, etc., and alkoxy groups with 3 or more carbon atoms also include isomers, such as branched alkoxy groups , such as isobutoxy, etc.; halogen substituents, such as fluorine, chlorine, bromine or iodine substituents.

As a preferred solution, the potassium monopersulfate is 1.2 to 2 times the molar amount of N-methyl-N-aryl-2-phenylacrylamide. If the ratio of potassium monopersulfate is too low, the yield of the target product is obviously reduced, and if the ratio of potassium monopersulfate is too high, the yield of the target product is not significantly improved.

As a preferred solution, the concentration of N-methyl-N-aryl-2-phenylacrylamide in the acetonitrile medium is 0.1-0.5 mol/L.

As a preferred solution, the reaction temperature of the epoxidation-intramolecular Friedel-Crafts alkylation series reaction is 80-100° C., and the reaction time is 18-30 hours. Further preferably, the reaction temperature of the epoxidation-intramolecular Friedel-Crafts alkylation series reaction is 85-95° C., and the reaction time is 22-26 hours. The reaction temperature is too low, mainly due to the incomplete reaction of the raw materials, resulting in a low yield. For example, if the reaction temperature is lowered to 80 ° C, the yield is reduced to about 56% after 24 hours of reaction, and the reaction temperature is too high. As a result, the yield of the target product is reduced. For example, when the reaction temperature is increased to 100 °C, the yield is reduced to about 69% after 24 hours of reaction, and a higher yield can be obtained when the reaction temperature is around 90 °C.

The present invention is by the route of the epoxidation of the N-methyl-N-aryl-2-phenylacrylamide promoted by potassium monopersulfate-intramolecular Friedel-Crafts alkylation series reaction as follows:

The present invention also proposes a reasonable reaction mechanism, taking the epoxidation of N-methyl-N-aryl-2-phenylacrylamide promoted by potassium monopersulfate as an example-intramolecular Friedel-Crafts alkylation series reaction as an example Be specific. Under heating conditions, potassium monopersulfate is used as an oxidant to oxidize the alkenyl group of N-methyl-N-aryl-2-phenylacrylamide (1) to undergo epoxidation reaction to generate epoxy intermediate 2 and potassium hydrogen sulfate. The proton-activated epoxy intermediate 2 of potassium bisulfate generates intermediate 3, which undergoes intramolecular Friedel-Crafts alkylation to generate intermediate 4, and finally, intermediate 4 undergoes dehydroaromatization to obtain the target product 3-hydroxymethyl -4-Phenyl-3,4-dihydroquinolinone compound (5)

Relative to the prior art, the beneficial technical effects brought by the technical solution of the present invention:

1) Potassium monopersulfate of the present invention has dual effects, simultaneously as oxidant and acid accelerator;

2) The present invention does not need transition metal catalysts and external acid additives;

3) The N-methyl-N-aryl-2-phenylacrylamide of the present invention has wide selectivity and good functional group compatibility;

4) The two raw materials of the present invention are cheap and easy to obtain, the reaction conditions are mild, the operation is simple and convenient, and have excellent application value.

Description of drawings

Fig. 1 is the hydrogen nuclear magnetic spectrum of 3-hydroxymethyl-4-phenyl-3,4-dihydroquinolinone compound;

Figure 2 is a carbon nuclear magnetic spectrum of 3-hydroxymethyl-4-phenyl-3,4-dihydroquinolinone compound.

Detailed ways

The following specific examples are intended to further illustrate the content of the present invention, rather than limit the protection scope of the claims of the present invention.

The following reactions serve as standard reaction conditions:

The specific operation steps are as follows: in a 10 mL round-bottomed flask, add N-methyl-N-aryl-2-phenylacrylamide (0.5 mmol), potassium monopersulfate, and a solvent (2.5 mL) in sequence. The obtained mixed solution was stirred and reacted under heating condition, and the reaction progress was tracked by thin layer chromatography, and the reaction time was 24 hours. After the reaction, the yield was analyzed by crude NMR spectroscopy.

Comparative Example:

In the following table, the control experimental groups 1 to 13 are all reacted according to the above reaction equation, and the product yields under different reaction conditions are as follows:

In the above table, experimental groups 1-8 investigated the epoxidation-intramolecular Friedel-Crafts alkylation series reaction of N-methyl-N-aryl-2-phenylacrylamide promoted by potassium monopersulfate as reaction medium Experiments show that the reaction medium is the key to whether the reaction can proceed. Using common organic solvents such as dichloroethane, toluene, dimethyl sulfoxide, N,N-dimethylformamide, ethyl acetate, tetrahydrofuran and benzonitrile as the reaction medium, the reaction can hardly be carried out. Acetonitrile is the best reaction medium for this reaction and is irreplaceable.

In the above table, experimental groups 1, 9-10 investigated the use amount of potassium monopersulfate on the epoxidation of N-methyl-N-aryl-2-phenylacrylamide promoted by potassium monopersulfate-Molecular The influence of the internal reaction of the alkylation series reaction, it is shown by experiments that the usage of 1.5 stoichiometric equivalents is the optimum usage of potassium monopersulfate of this reaction, and the potassium monopersulfate consumption is too low to be unfavorable for the carrying out of the reaction, and If the dosage is too high, the target parameter yield does not increase significantly.

In the above table, experimental groups 1, 11-12 investigated the epoxidation-intramolecular Friedel-Crafts alkylation of N-methyl-N-aryl-2-phenylacrylamide promoted by potassium monopersulfate at reaction temperature The effect of the series reaction, through experiments show that 90 ℃ is the best reaction temperature for this reaction. The reaction temperature is too low, mainly due to the incomplete reaction of the raw materials, resulting in a low yield. For example, if the reaction temperature is lowered to 80 ° C, the yield is reduced to about 56% after 24 hours of reaction, and the reaction temperature is too high. As a result, the yield of the target product is reduced. For example, when the reaction temperature is increased to 100° C., the yield is reduced to about 69% after 24 hours of reaction, and a higher yield can be obtained when the reaction temperature is around 90%.

In the above table, the experimental group 13 has investigated the effect of potassium monopersulfate on the epoxidation of N-methyl-N-aryl-2-phenylacrylamide-intramolecular Friedel-Crafts alkylation series reaction. The reaction cannot occur without potassium monopersulfate, indicating that potassium monopersulfate is a necessary condition for the reaction.

Examples 1 to 4

The following examples 1 to 4 are all reacted according to the following reaction equations, mainly to investigate the yield situation of different substrates reacting under optimal conditions:

The specific operation steps are as follows: in a 10 mL round-bottomed flask, add N-methyl-N-aryl-2-phenylacrylamide (0.5 mmol), potassium monopersulfate (0.75 mmol), and acetonitrile (2.5 mL) in turn. . The obtained mixed solution was stirred and reacted at 90°C, and the reaction progress was tracked by a thin-layer chromatography plate, and the reaction time was generally 24 hours. After the reaction, the extract was concentrated in a rotary evaporator, and purified by column chromatography on silica gel using petroleum ether/ethyl acetate as the eluent.

Example 1

Compound 1, 70% yield, 3-hydroxy-1-methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one;

¹ H NMR (400MHz, CDCl ₃ , ppm) δ 7.47-7.43 (m, 2H), 7.39-7.28 (m, 4H), 7.07 (dd, J=8.1, 1.2Hz, 1H), 6.98 (td, J ＝7.6,1.2Hz,1H),6.66(dt,J＝7.8,1.4Hz,1H), 4.52(d,J＝13.2Hz,1H),4.12(d,J＝13.2Hz,1H),3.90(s ,1H),3.51(s,3H);

¹³ C NMR (100MHz, CDCl ₃ , ppm) δ 171.5, 138.9, 138.0, 129.3, 129.0, 128.5, 128.2, 128.1, 127.7, 123.9, 114.9, 70.0, 49.3, 30.5;

HRMS(ESI) m/z Calcd for C ₁₆ H ₁₅ NO ₂ ⁺ [M ⁺ ]: 253.1103; found: 253.1105.

Example 2

Compound 2, 76% yield,

3-hydroxy-1,6-dimethyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one;

¹ H NMR (400MHz, CDCl ₃ , ppm) δ 7.48-7.44 (m, 2H), 7.40-7.36 (m, 1H), 7.35- 7.30 (m, 2H), 7.10 (d, J=8.4Hz, 1H ),6.96(d,J＝8.4Hz,1H),6.45(s,1H),4.48(d,J＝13.6Hz,1H),4.08(d,J＝13.6Hz,1H),3.92(d,1H) ), 3.48(s, 3H), 2.18(s, 3H);

¹³ C NMR (100MHz, CDCl ₃ , ppm) δ 171.3, 138.1, 136.5, 133.6, 129.3, 129.0, 129.0, 128.6, 127.9, 127.6, 114.8, 70.1, 49.3, 30.5, 20.7

HRMS(ESI) m/z Calcd for C ₁₇ H ₁₇ NO ₂ ⁺ [M ⁺ ]: 267.1259; found: 267.1261.

Example 3

Compound 3, 80% yield,

3-hydroxy-6-methoxy-1-methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one;

¹ H NMR (400MHz, CDCl ₃ , ppm) δ 7.44 (t, J=7.3Hz, 2H), 7.38-7.31 (m, 3H), 6.99 (d, J=8.8Hz, 1H), 6.82-6.79 ( m,1H),6.22(dd,J=2.9,1.3Hz,1H),4.48(d,J=13.2Hz,1H),4.07(d,J=13.2Hz,1H),3.93(d,1H,) ,3.64(s,3H),3.48(s,3H);

¹³ C NMR (100MHz, CDCl ₃ , ppm) δ 170.9, 156.0, 137.8, 132.4, 129.8, 129.2, 129.0, 127.7, 115.9, 115.2, 112.1, 69.9, 55.4, 49.4, 30.7;

HRMS(ESI) m/z Calcd for C ₁₇ H ₁₇ NO ₃ ⁺ [M ⁺ ]: 283.1208; found: 283.1211.

Example 4

Compound 4, 65% yield,

6-bromo-3-hydroxy-1-methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one;

¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 7.49-7.38 (m, 4H), 7.32-7.29 (m, 2H), 6.93 (d, J=8.8 Hz, 1H), 6.76 (dd, J=2.4 ,1.3Hz,1H),4.48(d,J=12.8Hz,1H),4.09(d,J=13.6Hz,1H),3.84(d,1H),3.48(s,3H);

¹³ C NMR (100MHz, CDCl ₃ , ppm) δ 171.2, 138.0, 137.0, 131.3, 131.2, 130.2, 129.3, 129.1, 128.0, 117.0, 116.6, 69.8, 49.1, 30.6

HRMS (ESI) m/z Calcd for C ₁₆ H ₁₄ BrNO ₂ ⁺ [M ⁺ ]: 331.0208; found: 331.0210.

Claims (5)

1. a preparation method of 3-hydroxy-4-phenyl-3,4-dihydroquinolinone compound is characterized in that: N -methyl- N -aryl-phenylacrylamide and hydrogen monopersulfate Potassium undergoes epoxidation in acetonitrile medium-intramolecular Friedel-Crafts alkylation series reaction to generate 3-hydroxy-4-phenyl-3,4-dihydroquinolinone compound; The N -methyl- N -aryl-phenylacrylamide has the structure of formula 1:

Formula 1 The 3-hydroxy-4-phenyl-3,4-dihydroquinolinone compound has the structure of formula 2:

Formula 2 in, R is hydrogen, a C ₁ -C ₅ alkyl group, a C ₁ -C ₅ alkoxy group or a halogen substituent. 2. the synthetic method of a kind of 3-hydroxyl-4-phenyl-3,4-dihydroquinolinone compound according to claim 1, is characterized in that: described potassium hydrogen monopersulfate is N -methyl - 1.2 to 2 times the molar amount of N -aryl-phenylacrylamide. 3. the synthetic method of a kind of 3-hydroxyl-4-phenyl-3,4-dihydroquinolinone compound according to claim 1, is characterized in that: N -methyl- N -aryl-phenyl The concentration of acrylamide in acetonitrile medium is 0.1~0.5mol/L. 4. the synthetic method of a kind of 3-hydroxyl-4-phenyl-3,4-dihydroquinolinone compound according to any one of claim 1～3, it is characterized in that: described epoxidation-molecule The reaction temperature of the in-line alkylation reaction is 80 to 100° C., and the reaction time is 18 to 30 hours. 5. the synthetic method of a kind of 3-hydroxyl-4-phenyl-3,4-dihydroquinolinone compound according to claim 4, is characterized in that: described epoxidation-intramolecular fusco-alkyl The reaction temperature of the tandem reaction is 85-95° C., and the reaction time is 22-26 hours.

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