RU2754735C1 - Method for preparation of 3,5-disubstituted 1,2,4-oxadiazoles containing alkenyl fragment - Google Patents

Abstract

FIELD: chemical industry.SUBSTANCE: invention relates to a method for producing 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment, which consists in the interaction of pre-dissolved and activated carboxylic acids and amidoximes with the formation of O-acylamidoximes and subsequent intramolecular cyclodehydration of the obtained O-acylamidoximes in the presence of finely ground KOH at a temperature of 20-25°C, with the release of the target product by known methods. The synthesis is carried out continuously in one reactor for 70-80 minutes, N,N-dimethylacetamide (N,N-DMAA) is used as a solvent, and intramolecular cyclodehydration is carried out by gradually adding a 2-fold excess of finely ground KOH to the reaction mixture relative to each initial component, i.e. at the ratio: carboxylic acids : amidoximes : KOH = 1:1:2 (mol).EFFECT: method for obtaining 3,5-disubstituted 1,2,4-oxadiazoles with a high yield has been developed. 3,5-disubstituted-1,2,4-oxadiazoles containing an alkenyl fragment can be used in various directions of organic synthesis, in particular, the synthesis of aziridines, active components of pharmaceuticals, agricultural chemicals, liquid crystal materials or intermediates in organic synthesis.1 cl, 1 tbl, 13 ex

Description

The invention relates to the field of production of 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment, of the general formula:

3,5-Disubstituted 1,2,4-oxadiazoles containing an alkenyl moiety can be used in various areas of organic synthesis, in particular, in the synthesis of aziridines, active ingredients of pharmaceuticals, agricultural chemicals, liquid crystal materials or intermediates in organic synthesis.

There is a known method for the preparation of 3,5-disubstituted 1,2,4-oxadiazoles, in which O-acylamidoxime is subjected to a cyclization reaction in the presence of at least one inorganic basic compound (for example, phosphate) and at least one phase transition catalyst ( eg Crown Ether) [JP 2010070528A, published 02.04.2010]. The disadvantages of this method are the multistage synthesis and the time duration of 5-8 hours.

There is also known a method of obtaining 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment, described in the application RU 2012140908 (published 03/27/2014, bull. No. 9), including the following steps: 1) 3,4-dialkoxycinnamic acid activated with 1, H-carbonyldiimidazole (CDI) at a temperature of 20-35 ° C in a solvent selected from toluene, N, N-dimethylformamide (DMF, DMF) and tetrahydrofuran (THF, THF) to obtain the corresponding activated form; 2) reacting the activated (in step 1) compound with a substituted amidoxime to obtain the corresponding O-acylamidoxime; 3) O-acylamidoxime (obtained in step 2) is dehydrated by treatment with 1,1'-carbonyldiimidazole in a solvent selected from toluene, DMF and THF at 50-140 ° C for 6-12 hours to obtain the corresponding 3.5 -disubstituted 1,2,4-oxadiazole containing an alkenyl fragment. The disadvantages of this method are the large number of stages - 5; high temperature at stage 3 (50-140 ° C), which is critical in the synthesis of oxadiazoles with an alkenyl fragment; the duration of the synthesis in time. The target product yield is low, 20-30%.

Closest to the claimed is a method for producing 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment described in the article by Tarasenko Μ., Sidneva V., Belova., Romanycheva Α., Sharonova T., Baykov S. , Shetnev N., Kofanov E., Kuznetsov M. An efficient yn-thesis and antimicrobial evaluation of 5-alkenyl- and 5 styryl-1,2,4-oxadiazoles // ARKIVOC. 2018, partvii, p. 458-470, which we have chosen as a prototype. In accordance with this method, 3,5 disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment are obtained in two stages, each of which uses different solvents. In the first stage, O-acylation of substituted amidoximes with substituted carboxylic acids is carried out to form O-acylamidoximes. In this case, the carboxylic acid is dissolved at a temperature of 20-25 ° C in 1,4-dioxane and activators are added - triethylamine (TEA, TEA) and ethyl chloroformate, a solution of substituted amidoxime in 1,4-dioxane is added to the mixture and the reaction mixture is stirred at a temperature of 20 -25 ° C for 15 minutes. Then the solvent is evaporated under reduced pressure, water is added to the remaining mass, while a precipitate is formed, which is filtered off and washed with water. The second stage consists in carrying out intramolecular cyclodehydration of the O-acylamidoximes obtained in the first stage with the formation of 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment in the potassium hydroxide / dimethyl sulfoxide (KOH / DMSO) system. In this case, O-acylamidoxime obtained in the first stage is added to a suspension of finely ground KOH in DMSO. At the initial moment, the content of finely ground KOH is maximum, and local overheating of intermediate and target products is very likely. Finely ground KOH is taken in an equimolar ratio, relative to each initial component, i.e. Carboxylic acids: Amidoximes: KOH = 1: 1: 1 (mol).

The reaction mixture is stirred at a temperature of 20-25 ° C for 10-60 minutes, then diluted with cold water, and a precipitate is obtained, which is filtered off, washed with cold water and dried in air at a temperature of 20-25 ° C. The disadvantage of this method is the duration of the synthesis time, 15-20 hours, and a relatively low yield of the target product - 10-35%.

The objective of the present invention is to develop an effective method for the preparation of 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment, namely, to shorten the synthesis time and increase the yield of the target product.

The task is achieved by the fact that a method is proposed for the preparation of 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment by the interaction of previously dissolved and activated carboxylic acids and amidoximes with the formation of O-acylamidoximes and subsequent intramolecular cyclodehydration of the obtained O-acylamidoximes in the presence of finely ground KOH at a temperature of 20-25 ° C, followed by the isolation of the target product in a known manner, which has the following distinctive features:

- synthesis of 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment is carried out continuously in one reactor for 70-80 minutes, without intermediate isolation of O-acylamidoximes;

- N, N-dimethylacetamide (N, N-DMAA) is used as a solvent;

- intramolecular cyclodehydration of O-acylamidoximes with the formation of 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment is carried out by gradually adding to the reaction mixture a 2-fold excess of finely ground KOH relative to each starting component, i.e. at a ratio of carboxylic acids: amidoximes: KOH = 1: 1: 2 (mol).

The process of obtaining 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment is carried out as follows.

The carboxylic acid is activated by adding TEA and ethyl chloroformate for 10-30 minutes at a temperature of 20-25 ° C. The synthesis of O-acylamidoxime is carried out within 10-60 minutes. Intramolecular cyclodehydration of O-acylamidoximes with the formation of 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment is carried out by the gradual addition of a 2-fold excess of finely ground KOH to the reaction mixture at a ratio of carboxylic acids: amidoximes: KOH = 1: 1: 2 (mol), stirred for 10-40 minutes. In the proposed method, the addition of finely ground KOH to the reaction mixture is carried out gradually, thus, the process of intramolecular cyclodehydration proceeds under mild conditions, there are no local overheating of O-acylamidoxime when finely ground KOH interacts with the water released during dehydration. This is especially important in the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment to prevent polymerization and increase the yield of target products. The total reaction time is 70-80 minutes. The synthesized 3,5-disubstituted 1,2,4-oxadiazole containing an alkenyl fragment is precipitated with water, filtered off, washed with water and dried. The yield of the target product is 65-85%.

Thus, the proposed set of distinctive features allows us to solve the problem and obtain a new technical result, which consists in a significant increase in the yield of the target product up to 65-85%, creating softer synthesis conditions, reducing the staging and time of the synthesis to 70-80 minutes.

The invention is illustrated by the following examples:

Example 1. Obtaining 3-phenyl-5- (2-phenylethenyl) -1,2,4-oxadiazole is carried out as follows. 0.37 g (2.5 mmol) of 3-phenyl-propenoic acid is dissolved in 2 ml of N, N-dimethylacetamide (N, N-DMAA), 0.30 g (3.0 mmol) of triethylamine and 0.33 g (3.0 mmol) of ethyl chloroformate are added , stirred for 20 minutes at a temperature of 20-25 ° C. Add 0.34 g (2.5 mmol) of N-hydroxybenzimidamide, stir for 20 minutes at a temperature of 20-25 ° C. Gradually, 0.28 g (5.0 mmol) of finely ground KOH is added to the reaction mixture, and the mixture is stirred for 20 minutes at a temperature of 20-25 ° C. The mixture is poured into 20 ml of water, filtered off and the precipitate is dried. The yield of 3-phenyl-5- (2-phenylethenyl) -1,2,4-oxadiazole is 67%.

T. pl. 93-94 ° C.

IR ν, cm ⁺¹ : 1644, (CH = CH), 1593 (C = N), 1175 (C-O), 971 (CH = CH, trans).

¹ H NMR (400 MHz, CDCl ₃ ) δ, ppm, DHz): 7.08 (d, J = 16.4, 1H), 7.43-7.45 (m, 3H), 7.50-7.52 (m, 3H), 7.61 -7.63 (m, 2H), 7.90 (d, J = 16.4, 1H), 8.12-8.15 (m, 2H).

¹³ С NMR (101 MHz, CDCl ₃ ), δ, ppm: 110.3, 127.0, 127.5, 127.9, 128.9, 129.1, 130.5, 131.2, 134.5, 142.7, 168.7, 175.3.

Examples 2-13. The preparation of other 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment by the general formula (I) is carried out analogously to example 1. The conditions and results are shown in Table 1 of the Appendix.

Claims (1)

A method of obtaining 3,5-disubstituted 1,2,4-oxadiazoles containing an alkenyl fragment by the interaction of previously dissolved and activated carboxylic acids and amidoximes with the formation of O-acylamidoximes and subsequent intramolecular cyclodehydration of the obtained O-acylamidoximes in the presence of finely ground KOH at a temperature of 20-25 ° C, followed by the isolation of the target product in a known manner, characterized in that the reaction is carried out continuously in one reactor for 70-80 minutes, N, N-dimethylacetamide is used as a solvent, and intramolecular cyclodehydration is carried out by gradually adding 2-fold excess of finely ground KOH relative to each starting component, i. e. at a ratio of carboxylic acids: amidoximes: KOH = 1: 1: 2 (mol).