A method and application of synthesizing N-aryl ketimine by acid-catalyzed ketal method

Abstract

The invention discloses a method and application of synthesizing N-aryl ketone imine by an acid-catalyzed ketal method, wherein the method uses Lewis acid or organic acid as a catalyst, and generates N-aryl ketone imine by condensation of aromatic amine and ketal under heating conditions. The advantage of the method is that the condensation reaction of aromatic amine and alkyl ketone with poor nucleophilicity due to electrical or steric reasons still has excellent reaction effect. The method is simple to operate, has high raw material conversion rate, good reaction selectivity, high product yield and good quality. It can be applied to the efficient synthesis of the herbicide dimethenamid.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis methodology, and specifically relates to a method for synthesizing N-aryl ketimine by an acid-catalyzed ketal method and application thereof. Background Art

[0002] As an important organic intermediate, N-aryl ketone imine compounds can participate in various types of reactions, such as the formation of tetrahydropyridine by aza-Diels-Alder reaction, the formation of oxaziridine by reaction with m-chloroperbenzoic acid, the formation of quinoline by Povarov reaction, and the important intermediate of reductive amination reaction. In addition, as the most common ligand in ligand chemistry, N-aryl ketone imine can form a variety of metal complexes with a wide range of metal elements, and has important application value in the field of metal catalysis. The asymmetric reductive amination reaction involving N-aryl ketone imine is the most commonly used method for preparing chiral secondary amines in industry, and is widely used in the synthesis of pharmaceutical and pesticide intermediates, such as the synthesis of chiral pesticide propidol (Kindor) (WO 9521151, WO 9705095). The typical method for preparing ketone imine is through the dehydration condensation reaction of primary amine and ketone. Since the reaction equilibrium is more inclined to the ketone and amine side, azeotropic reflux water separation or the use of molecular sieve dehydrating agents is required during the reaction. For N-aryl ketimine compounds, due to the lone pair of electrons of the nitrogen atom and the conjugation of the aromatic ring, the nucleophilicity is weakened, especially when the ortho position of the aromatic amine carries a large steric substituent, the condensation reaction is usually difficult to carry out. Even if tetra(ethoxy)titanium, titanium tetrachloride and other activating reagents (Org. Lett. 2019, 21, 9699; Dalton Trans. 2007, 40, 4565.) or stoichiometric dehydrating agents (J. Organomet. Chem. 2009, 694, 1380; New J. Chem. 2005, 29, 385.) are added, the condensation reaction efficiency is still low, and the post-processing is cumbersome and the imine yield is low, which is not suitable for large-scale preparation. Summary of the invention

[0003] The purpose of the present invention is to provide a method and application of synthesizing N-aryl ketimines by a ketal method catalyzed by a Lewis acid or an organic acid, in view of the fact that aromatic amines have poor nucleophilicity and are difficult to react with ketone compounds for dehydration condensation to generate N-aryl ketimine compounds due to electrical or steric reasons.

[0004] In order to achieve the above object, the present invention adopts the following technical solutions:

[0005] A method for synthesizing N-aryl ketimine by an acid-catalyzed ketal method, wherein the method uses Lewis acid or organic acid as a catalyst, and under heating conditions, condenses aromatic amine and ketal to generate N-aryl ketimine, and the reaction formula is as follows:

[0006]

[0007] In the reaction formula: Ar is selected from phenyl, thienyl, pyridyl, furyl, pyrrolyl, or the aromatic ring carries a single or multiple substituents: halogen, alkyl, alkoxy, phenyl or benzyl;

[0008] Among them, R 1 and R 2 are selected from alkyl, phenyl, benzyl, thienyl, pyridyl, furyl, pyrrolyl, or the aromatic ring has the following substituents: halogen, alkyl, alkoxy, phenyl or benzyl, R 1 , R 2 Same or different;

[0009] R 3 The 5-membered or 6-membered cyclic ketal is selected from methyl, ethyl, propyl, butyl or 1,2-disubstituted ethyl or 1,3-disubstituted propyl.

[0010] Furthermore, the solvent used in the method is selected from toluene, xylene, 1,2-dichloroethane, chloroform, ethyl acetate, acetonitrile, dioxane or tetrahydrofuran.

[0011] Furthermore, the molar ratio of the aromatic amine to the ketal is 1:(1.0-3.0).

[0012] Furthermore, the molar ratio of the acid catalyst to the aromatic amine is (0.1% to 5%):1.

[0013] Further, the Lewis acid or organic acid catalyst includes tin dichloride, ferric chloride, bismuth trifluoromethanesulfonate, scandium trifluoromethanesulfonate or p-toluenesulfonic acid;

[0014] The molar ratio of the acid catalyst to the aromatic amine is (0.5% to 5%):1.

[0015] Further, the Ar is selected from phenyl, thienyl, or the aromatic ring has the following substituents: chlorine, alkyl or alkoxy;

[0016] The R 1 and R 2 are selected from alkyl, phenyl, benzyl or the aromatic ring has the following substituents: halogen, alkyl or alkoxy, R 1 , R 2 Same or different;

[0017] The R 3 Selected from methyl or ethyl.

[0018] Further, the aromatic amine is selected from 2,4-dimethyl-3-aminothiophene, 2,6-dimethylaniline or 2-methyl-6-ethylaniline;

[0019] The molar ratio of the aromatic amine, ketal, acid catalyst and solvent is 1:(1.1-2.0):(0.005-0.05):(3-10).

[0020] Further, the solvent is selected from toluene, 1,2-dichloroethane, chloroform or tetrahydrofuran;

[0021] The heating reaction temperature is (60-120)°C.

[0022] The invention also discloses N-aryl ketimine synthesized by the method for synthesizing N-aryl ketimine by the acid-catalyzed ketal method.

[0023] The invention also discloses a method for synthesizing N-aryl ketimine by an acid-catalyzed ketal method and its application in the synthesis of the herbicide dimethenamid

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The present invention uses Lewis acid or organic acid as a catalyst, and generates N-aryl ketone imine by condensation of aromatic amine and ketal under heating conditions. The advantage of this method is that it is not only applicable to the condensation of common aromatic amine and alkyl ketone, but also has excellent reaction effect for the condensation reaction of aromatic amine and alkyl ketone with poor nucleophilicity due to electrical or steric reasons. This method is simple to operate, has high raw material conversion rate, good reaction selectivity, high product yield, good quality, simple operation, less three wastes, suitable for large-scale preparation, and can be applied to organic synthesis methodology and the synthesis of medicine and pesticide intermediates. DETAILED DESCRIPTION

[0026] The present invention is further described below in conjunction with embodiments, the purpose of which is to provide a better understanding of the essential features of the present invention as embodied in the contents of the present invention. Therefore, the examples given should not be regarded as limiting the scope of protection of the present invention.

[0027] The experimental steps of the present invention are as follows:

[0028] (1) Preparation of ketal: Add ketone, trialkyl orthoformate, p-toluenesulfonic acid and alkyl alcohol solvent into a round-bottom flask with a reflux condenser, and heat to react for 2 to 4 hours at a heating temperature of 60°C to 100°C; monitor the reaction in the gas phase, and stop the reaction when the raw material ketone is less than 5%. The reaction formula is as follows (2):

[0029]

[0030] Ketone R 1 , R 2 The groups are the same or different and are selected from alkyl, phenyl, benzyl, or the aromatic ring further carries the following substituents: halogen, alkyl, alkoxy; R 3 The group is selected from methyl and ethyl;

[0031] The alkyl alcohol is selected from methanol and ethanol; the molar ratio of ketone, trialkyl orthoformate, p-toluenesulfonic acid and alkyl alcohol is 1:(1-3):(0.005-0.05):(3-10).

[0032] The reaction solution is cooled to room temperature. For alkyl ketone substrates that are liquid at room temperature, the solvent and excess orthoformate are distilled off, and then the ketal product is obtained by reduced pressure distillation. For aryl ketone substrates that are solid at room temperature, the ketal product is precipitated in the reaction solution, filtered, and washed with methanol. The obtained solid is the ketal product.

[0033] (2) Preparation of N-aryl ketone imine: Add aromatic amine, ketal, acid catalyst and solvent into a round-bottom flask with a reflux condenser, and heat to react for 2 to 4 hours at a temperature of 70°C to 110°C; monitor the reaction in the gas phase, and stop the reaction when the raw aromatic amine is less than 5%. The reaction formula is as follows (1):

[0034]

[0035] The Ar group of the aromatic amine is selected from phenyl or thienyl, or the aromatic ring has the following substituents: chlorine, alkyl, alkoxy; the Lewis acid or organic acid catalyst is selected from tin dichloride, bismuth trifluoromethanesulfonate or p-toluenesulfonic acid; the solvent is selected from toluene, 1,2-dichloroethane, chloroform, tetrahydrofuran; the molar ratio of aromatic amine, ketal, acid catalyst and solvent is 1: (1.1-2.0): (0.005-0.05): (3-10).

[0036] The reaction solution is cooled to room temperature. For N-aryl ketimine which is liquid at room temperature, the solvent and excess ketal are distilled off, and then the N-aryl ketimine product is obtained by reduced pressure distillation. For N-aryl ketimine which is solid at room temperature, the solvent is concentrated by a rotary evaporator, and the obtained solid crude product is recrystallized using a solvent such as chloroform, toluene, ethyl acetate, etc. according to the different physicochemical properties of the product to obtain the N-aryl ketimine product.

[0037] Examples 1 to 4 respectively provide examples of preparing different ketals, Examples 5 to 7 respectively provide examples of preparing different N-aryl ketone imine products, and Examples 8 and 9 provide examples of preparing the herbicide dimethinaton.

[0038] Example 1

[0039] This example gives an example of preparing ketal: 1,2,2-trimethoxypropane (1a):

[0040]

[0041] The method comprises: adding 8.8 g of methoxyacetone, 11.7 g of trimethyl orthoformate, 190 mg of p-toluenesulfonic acid monohydrate and 20 mL of methanol into a 100 mL round-bottom flask with a reflux condenser, heating and reacting for 2.5 hours, monitoring the reaction by gas phase, stopping the reaction when the conversion rate of the raw material methoxyacetone is 98%, distilling to separate methanol and excess trimethyl orthoformate, and then distilling under reduced pressure to obtain 12.6 g of ketal product 1,2,2-trimethoxypropane, with a yield of 94.0% and a content of 98.0%.

[0042] Example 2

[0043] This example gives an example of preparing ketal: 2,2-diethoxy-1-methoxypropane (1b):

[0044]

[0045] The method comprises: adding 8.8 g of methoxyacetone, 17.7 g of triethyl orthoformate, 190 mg of p-toluenesulfonic acid monohydrate and 20 mL of ethanol into a 100 mL round-bottom flask with a reflux condenser, heating and reacting for 4 hours, monitoring the reaction in gas phase, stopping the reaction when the conversion rate of the raw material methoxyacetone is 96%. Distilling out methanol and excess triethyl orthoformate, and then distilling under reduced pressure to obtain 15.0 g of ketal product 2,2-diethoxy-1-methoxypropane, with a yield of 92.5% and a content of 97.6%.

[0046] Example 3

[0047] This example gives an example of preparing ketal: bis(3,5-di-tert-butylphenyl)dimethoxymethane (1c):

[0048]

[0049] The method comprises: adding 8.2 g of bis(3,5-di-tert-butylphenyl) ketone, 2.4 g of trimethyl orthoformate, 38 mg of p-toluenesulfonic acid monohydrate and 20 mL of methanol into a 50 mL round-bottom flask with a reflux condenser, heating for reaction for 2 hours, monitoring the reaction by gas phase, and stopping the reaction when the conversion rate of the raw material bis(3,5-di-tert-butylphenyl) ketone is 97%. The reaction solution is cooled to room temperature, the product ketal is precipitated in the reaction solution, filtered, and washed with methanol, and the obtained solid is the ketal product bis(3,5-di-tert-butylphenyl) dimethoxymethane 8.6 g, with a yield of 95.0% and a content of 95.0%.

[0050] Example 4

[0051] This example gives an example of preparing ketal: 1,3-bis(4-methoxyphenyl)-2,2-dimethoxypropane (1d):

[0052]

[0053] The method comprises: adding 5.4 g of 1,3-bis(4-methoxyphenyl)acetone, 2.4 g of trimethyl orthoformate, 38 mg of p-toluenesulfonic acid monohydrate and 20 mL of methanol into a 50 mL round-bottom flask with a reflux condenser, heating for reaction for 2 hours, monitoring the reaction by gas phase, stopping the reaction when the conversion rate of the raw material bis(3,5-di-tert-butylphenyl)ketone is 98%. The reaction solution is cooled to room temperature, the product ketal is precipitated in the reaction solution, filtered, and washed with methanol, and the obtained solid is the ketal product 1,3-bis(4-methoxyphenyl)-2,2-dimethoxypropane 6.0 g, with a yield of 96.5% and a content of 96.2%.

[0054] Example 5

[0055] This example shows the preparation of N-aryl ketimine 2a:

[0056]

[0057] The method comprises: adding 8.9 g of 2,4-dimethyl-3-aminothiophene, 11.3 g of acetal 1a, 265.4 mg of tin dichloride and 20 mL of 1,2-dichloroethane into a round-bottom flask with a reflux condenser, heating and reacting for 4 hours, monitoring the reaction by gas phase, stopping the reaction when the raw material 2,4-dimethyl-3-aminothiophene is less than 5%. The reaction solution is cooled to room temperature, the solvent is separated by distillation, and then reduced pressure distillation is performed to obtain 12.5 g of N-aryl ketimine product 2a, with a yield of 90.2% and a content of 94.6%.

[0058] Example 6

[0059] This example shows the preparation of N-aryl ketimine 2b:

[0060]

[0061] 1.5 g 2-methylaniline, 7.6 g ketal 1c, 53.1 mg tin dichloride and 5 mL 1,2-dichloroethane were added to a 25 mL pressure tube and heated for 2 hours. The reaction was monitored by gas phase. The raw material 2-methylaniline was less than 5%, and the reaction was stopped. The reaction solution was cooled to room temperature, and the solvent was concentrated using a rotary evaporator. The obtained solid crude product was recrystallized using ethyl acetate to obtain 6.4 g N-aryl ketimine product 2b, with a yield of 92.0% and a content of 97.0%.

[0062] Example 7

[0063] This example shows the preparation of N-aryl ketimine 2c

[0064]

[0065] 1.2 g 2,6-dimethylaniline, 3.8 g ketal 1d, 37.9 mg tin dichloride and 5 mL 1,2-dichloroethane were added to a 25 mL pressure tube and heated for 2.5 hours. The reaction was monitored by gas phase. The raw material 2-methylaniline was less than 5%, and the reaction was stopped. The reaction solution was cooled to room temperature, and the solvent was concentrated using a rotary evaporator. The obtained solid crude product was recrystallized using ethyl acetate to obtain 3.4 g N-aryl ketimine product 2c, with a yield of 91.0% and a content of 96.0%.

[0066] Example 8

[0067] This example shows the preparation of 2,4-dimethyl-3-aminothiophene derivative (3)

[0068]

[0069] 3.9 g of imine 2a obtained in Example 5 was dissolved in 20 mL of methanol, 1.1 g of sodium borohydride was added in batches at 0°C, and the reaction was allowed to proceed at room temperature for 3 hours. The reaction was monitored by TLC, and the reaction was stopped when the raw material imine 2a was completely converted. Ice water was slowly added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was concentrated and distilled under reduced pressure to obtain 3.7 g of product 3, with a yield of 92.0% and a content of 98.5%.

[0070] The NMR data of the product are as follows: 1 H NMR (500MHz, CDCl3): δppm 6.604 (s, 1H), 3.360 (s, 1H), 3.323-3.312 (dd, 2H), 3.281-3.234 (m, 1H), 2.992 (s, 1H), 2.288 (s, 3H), 2.099 (s, 3H), 1.144-1.131 (d, 3H). 13 C NMR (125MHz, CDCl3): δppm 141.650, 133.338, 121.919, 115.911, 76.328, 59.034, 53.042, 18.539, 14.439, 12.695.

[0071] Example 9

[0072] This example provides the preparation of the herbicide dimethinatonil:

[0073]

[0074] 3.0 g of the product 3 obtained in Example 8 and 2.0 g of triethylamine were dissolved in 30 mL of dichloromethane, and 1.9 g of chloroacetyl chloride was added dropwise at 0°C. The reaction was allowed to react at room temperature for 4 hours. The reaction was monitored by TLC. The raw material 3 was completely converted and the reaction was stopped. Sodium bicarbonate solution was added to quench the reaction, and dichloromethane was used for extraction. The organic phase was concentrated and distilled under reduced pressure to obtain 3.4 g of the product dimethenamid, with a yield of 82.0% and a content of 99.0%.

[0075] The NMR data of the product are as follows. The product is a pair of diastereoisomers: 1 H NMR (500MHz, CDCl3): δppm6.795 (s, 1H), 6.794 (s, 1H), 4.554-4.515 (m, 1H), 4.455-4.416 (m, 1H), 3.670-3.630 (m, 4H), 3.603-3.509 (m, 2H), 3.38 7-3.313(m,2H),3.282(s,3H),3.252(s,3H),2.336(s,3H),2.321(s,3H) , 2.065(s, 3H), 2.048(s, 3H), 1.199-1.185(d, 3H), 1.118-1.104(d, 3H). 13 C NMR (125MHz, CDCl3): δppm 167.080,167.035,137.073,136.797,135.169,135.147,134.381,133.886,118.283,118.254,74.44 3,74.240,58.528,58.480,54.833,54.090,42.676,15.583,15.060,14.554,14.278,13.825,13.351.

[0076] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. Application of the method for synthesizing N-aryl ketimine by acid-catalyzed ketal method in the synthesis of herbicide dimethenamid, characterized in that: The app includes: N-aryl ketimine is dissolved in methanol, sodium borohydride is added in batches at 0°C, reacted at room temperature for 3 hours, the reaction is monitored by TLC, the N-aryl ketimine is completely converted, the reaction is stopped, ice water is slowly added to quench the reaction, dichloromethane is extracted, the organic phase is concentrated, and the product is obtained by distillation under reduced pressure; then the above-prepared product and triethylamine are dissolved in dichloromethane, chloroacetyl chloride is added dropwise at 0°C, the reaction is reacted at room temperature for 4 hours, TLC is monitored, the reaction is stopped when the raw material is completely converted; sodium bicarbonate solution is added to quench the reaction, dichloromethane is extracted, the organic phase is concentrated, and distillation under reduced pressure is performed to obtain the product dimethenamid; The method for synthesizing N-aryl ketone imine by acid-catalyzed ketal method uses an acid catalyst to condense aromatic amine and ketal under heating conditions to generate N-aryl ketone imine; The molar ratio of the aromatic amine, ketal, acid catalyst and solvent is 1: (1.1-2.0): (0.005-0.05): (3-10); The heating reaction temperature is 60-120°C; The reaction formula of this method is as follows: ； In the reaction formula: The acid catalyst is tin dichloride; The solvent is selected from toluene, 1,2-dichloroethane, chloroform or tetrahydrofuran; represents aromatic amine, wherein the aromatic amine is 2,4-dimethyl-3-aminothiophene; represents a ketal, wherein the ketal is ; represents N-aryl ketimine, wherein the N-aryl ketimine is .

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