RU2317986C2 - Method for preparing 2-methyl-5-substituted 1,3,4-oxadiazoles - Google Patents

Abstract

FIELD: organic chemistry, chemistry of heterocyclic compounds.

SUBSTANCE: invention relates to heterocyclic compounds possessing the potential biological activity, in particular, to a method for synthesis of 2-methyl-5-substituted 1,3,4-oxadiazoles. Invention describes a method for synthesis of 2-methyl-5R-substituted 1,3,4-oxadizoles wherein R means aryl, hetaryl or alkyl by the cyclization reaction of tributylstannyl derivatives of tetrazole in the presence of aliphatic acid anhydrides by the following scheme:

. Method provides preparing 2-methyl-1,3,4-oxadiazoles substituted with bulky substitutes at position 5 by simplified technology.

EFFECT: improved and simplified method of synthesis.

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Description

The present invention relates to the field of chemistry of heterocyclic compounds with potential biological activity, in particular to a method for producing 2-methyl-5-substituted-1,3,4-oxadiazoles. Such aromatic derivatives of 1,3,4-oxadiazoles are a class of chemically stable and heat-resistant polymers, possess luminescent properties, are part of liquid-crystalline films, conductive polymer compositions [N. Weijuan, S. Jianhua, Ch. Kongchang, T. He Chemistry Letters, 26 (1), 101, 1997].

The closest analogue is a method for producing 2,5-diphenyl-1,3,4-oxadiazole by intramolecular cyclization of 1,2-diphenylhydrazine with phosphorus oxychloride when heated without solvent [Methods for obtaining chemically pure reagents and preparations. Issue 2, p. 57, Moscow, 1961].

The disadvantages of the method adopted for the prototype are the inaccessibility of the synthesis of 1,3,4-oxadiazoles having bulky substituents, or inaccessibility (instability of the corresponding acyl hydrazides).

The objective of the invention is to remedy these disadvantages in the preparation of 1,3,4-oxadiazoles.

The present invention provides a method for producing 2-methyl-5-substituted-1,3,4-oxadiazoles of the general formula:

where R is aryl, hetaryl or alkyl, wherein the tributylstannyl derivatives of tetrazole are cyclized in the presence of aliphatic acid anhydride.

To obtain these 1,3,4-oxadiazoles, pre-obtained tributylstannyl derivatives of tetrazole are used, cyclization of which with aliphatic acid anhydrides allows to obtain 2,5-disubstituted-1,3,4-oxadiazoles in one stage according to the following scheme:

Example 1

Obtaining 2,5-diphenyl-1,3,4-oxadiazole in a known manner.

In a 0.5 L flask equipped with a mechanical stirrer and reflux condenser, a solution of 10 g of 98% hydrazine hydrate in 200 ml of dry pyridine was placed and 56 g of benzoyl chloride was slowly added dropwise to it. After the addition of all benzoyl chloride is complete, the mixture is boiled for 20 minutes, and then the contents of the flask are poured into cold water (500-600 ml). The precipitated colorless crystalline product is filtered off, washed on the filter with water and dried. The yield of 1,2-dibenzoylhydrazine quantitative, so pl. 237 ° C. 24 g of 1,2-dibenzoylhydrazine are mixed with 80 ml of phosphorus oxychloride and boiled in a 250 ml flask under reflux for 1 h, and the whole substance in the form of a suspension passes into solution. After that, 40 ml of phosphorus oxychloride are distilled off, and the residue is carefully poured into five times the amount of cold water. The precipitated colorless crystalline precipitate was filtered off, washed with water and dried, yield 19 g (91% of theory), mp 137 ° C.

The method of obtaining 2 and 3

Example 2

General procedure for the preparation of compounds 2.

Dissolved in 20 ml of o-xylene (0.02 mol) sodium azide (0.02 mol) tributyltin chloride and heated at boiling point for 5 hours. Cool to room temperature. Then add (0.0065 mol) of nitrile 1a-s and heat at a boiling point for another 15 hours. Control over the reaction is carried out by TLC (Silufol UV-254, EA-CCl _{4 system} (1: 4)). The hot solution is filtered from inorganic salts. Cool to room temperature. Poured into cold petroleum ether or hexane. Washed several times with hot heptane.

Example 3

According to the methodology obtained:

Based on benzonitrile - 5-phenyl-1- (tributylstannyl) -1H-1,2,3,4-tetraazole 2a - mp. 66-68 ° C. [M. Casey, Ch. Moody, Ch. Rees, J. Chem. Soc., Perkin Trans. 1, 1933 (1984)].

Example 4

Based on 3-cyanindole - 3- [1- (Tributylstannyl) -1H-1,2,3,4-tetraazol-5-yl] -1H-indole 2b. T. pl. 148-150 ° C. ¹ NMR spectrum of CD ₃ CN (d, ppm, J / Hz); 9.60 (broad s, 1H, NH); 8.28 (m, 1H, H (4) _Ind ); 7.85 (d, 1H, H (2) _Ind , J = 2.75); 7.51 (m, 1H, H (7) _Ind ); 7.24 (m, 1H, H (6) _Ind ); 7.19 (m, 1H, H (5) _Ind ); 1.68-1.36 (m, 12H, (CH ₂ ) ₆ ); 0.89 (t, 9H, (CH ₃ ) ₃ , J = 7.15). Mass spectrum (EU, 70 eV), m / z (I _rel (%)): 474 [M] ⁺ (10). Found (%): C, 52.89; H, 6.87; N, 14.41; C ₂₁ H ₃₃ N ₅ Sn. Calculated (%): C, 53.19; H, 7.01; N, 14.77.

Example 5

7.43 (м., 2Н, Н(2,6)_ph); 7.37 (м., 1Н, H(4)_Ind); 7.31 (м., 1Н, H(7)_Ind); 7.22 (м., 2Н, Н(3,5)_ph); 7.12 (м., 1Н, Н(4)_ph); 7.09 (м., 1Н, H(2)_Ind); 7.01 (м., 1Н, H(6)_Ind); 6.85 (м., 1Н, H(5)_Ind); 5.86 (с., 1Н, CH);

Масс-спектр (ЭУ, 70 эВ), m/z (I_отн (%)): 563 [M]⁺ (15), 206 [IndCHPh]⁺ (100). Найдено (%):С, 59.59; Н, 6.97; N, 12.41; C₂₈H₃₉N₅Sn. Вычислено (%): С, 59.39; Н, 7.07; N, 12.56.Based on 2- (1H-indol-3-yl) -2-phenylacetonitrile - 3-phenyl [1- (tributylstannyl) -1H-1,2,3,4-tetraazol-5-yl] methyl-1H-indole 2c - T. pl. 199.5-200.5 ° C (isopropanol). ¹ H NMR Spectrum DMSO-d ⁶ (d, ppm, J / Hz);

7.43 (m, 2H, H (2.6) _ph ); 7.37 (m, 1H, H (4) _Ind ); 7.31 (m, 1H, H (7) _Ind ); 7.22 (m, 2H, H (3.5) _ph ); 7.12 (m. 1H, H (4) _ph ); 7.09 (m, 1H, H (2) _Ind ); 7.01 (m, 1H, H (6) _Ind ); 6.85 (m, 1H, H (5) _Ind ); 5.86 (s, 1H, CH);

Mass spectrum (EU, 70 eV), m / z (I _rel (%)): 563 [M] ⁺ (15), 206 [IndCHPh] ⁺ (100). Found (%): C, 59.59; H, 6.97; N, 12.41; C ₂₈ H ₃₉ N ₅ Sn. Calculated (%): C, 59.39; H, 7.07; N, 12.56.

General procedure for obtaining 3a-s

Compounds 2a-c (0.0062 mol) were dissolved in 40 ml of acetic anhydride. Heated at boiling point 9 hours. Acetic anhydride is distilled off on a rotary evaporator. The residue is washed several times with heptane.

Recrystallized from isopropyl alcohol.

Example 6

According to the methodology obtained:

2-Methyl-5-phenyl-1,3,4-oxadiazole 3a - mp. 65-68 ° C (isopropanol). NMR spectrum ¹ H CD ₃ CN (d, ppm, J / Hz); 8.01 (m, 2H, o-Ph); 7.6 (m, 3H, mp-Ph); 2.55 (s, 3H, CH ₃ ). Mass spectrum (EU, 70 eV), m / z (I _rel (%)): 160 [M] ⁺ . Found (%): C, 74.42; H, 5.03; N, 14.22; C ₉ H ₈ N ₂ O. Calculated (%): C, 74.72; H, 5.23; N, 14.52.

Example 7

1- [3- (5-Methyl-1,3,4-oxadiazol-2-yl) -1H-indol-1-yl] -1-ethanone 3b. T. pl. 176-178 ° C (isopropanol). NMR spectrum ¹ H CD ₃ CN (d, ppm, J / Hz); 8.45 (m, 1H, H (7) _Ind ); 8.25 (m, 1H, H (2) _Ind ); 8.25 (m, 1H, H (4) _Ind ); 7.49 (m, 1H, H (6) _Ind ); 7.43 (m, 1H, H (5) _Ind ); 2.68 (s, 3H, CH ₃ ); 2.57 (s, 3H, CH ₃ ). Mass spectrum (EU, 70 eV), m / z (I _rel (%)): 240 [M] ⁺ (45), 199 [M-ССОН ₃ ] ⁺ (100). Found (%): C, 69.74; H, 4.82; N, 10.86. C ₁₄ H ₁₂ N ₂ O ₂ . Calculated (%): C, 69.99; H, 5.03; N, 11.66.

Example 8

7.42 (м., 1Н, H(7)_Ind); 7.35 (м., 1Н, H(4)_Ind); 7.3-7.4 (м., 5Н, Ph); 7.16 (д., 1Н, H(2)_Ind, J=2.56); 7.13 (м., 1Н, H(6)_Ind); 6.99 (м., 1Н, H(5)_Ind); 5.94 (с., 1Н, СН); 2.43 (с., 3Н, СН₃). Масс-спектр (ЭУ, 70 эВ), m/z (I_отн (%)): 289 [M]⁺ (100), 206 [IndCHPh]⁺ (95). Найдено (%): С, 74.44; Н, 5.12; N, 14.26. C₁₈H₁₅N₃O. Вычислено (%): С, 74.72; Н, 5.23; N, 14.52.3 - [(5-Methyl-1,3,4-oxadiazol-2-yl) (phenyl) methyl] -1H-indole 3c. T. pl. 185-186 ° C (isopropanol). NMR spectrum ¹ H CD ₃ CN (d, ppm, J / Hz);

7.42 (m, 1H, H (7) _Ind ); 7.35 (m, 1H, H (4) _Ind ); 7.3-7.4 (m, 5H, Ph); 7.16 (d, 1H, H (2) _Ind , J = 2.56); 7.13 (m. 1H, H (6) _Ind ); 6.99 (m, 1H, H (5) _Ind ); 5.94 (s, 1H, CH); 2.43 (s, 3H, CH ₃ ). Mass spectrum (EU, 70 eV), m / z (I _rel (%)): 289 [M] ⁺ (100), 206 [IndCHPh] ⁺ (95). Found (%): C, 74.44; H, 5.12; N, 14.26. C ₁₈ H ₁₅ N ₃ O. Calculated (%): C, 74.72; H, 5.23; N, 14.52.

As can be seen from the above examples, the developed method allows for the production of 2-methyl-5-substituted-1,3,4-oxadiazoles of various structures containing alkyl, aryl and hetaryl substituents in the 5-position of the 1,3,4-oxadiazole ring using a simple technology .

Claims (1)

The method of obtaining 2-methyl-5-substituted-1,3,4-oxadiazoles of the General formula

where R is aryl, hetaryl or alkyl, characterized in that the tributylstannyl derivatives of tetrazole are subjected to cyclization in the presence of aliphatic acid anhydride.