RU2831365C1 - Method of producing 2-methyl-3-propylindole - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, specifically to a method of producing 2-methyl-3-propylindole, which can be used as a repellent in marine antifouling material against living organisms, for synthesis of indole derivatives and photochromic dyes. Method is characterized by that 2-methyl-3-propylindole is obtained by reacting aniline with 1,2-propanediol in the presence of granular zeolite Y_h in H-form with a hierarchical porous structure, in autoclave at 260 °C, molar ratio of aniline : 1,2-propanediol = 1:2-5, in presence of 5-20 wt.% catalyst H-Y_h, for 6-9 hours.

EFFECT: simplification of heterogeneous catalytic synthesis of end product from available and safe raw material.

1 cl, 1 tbl, 6 ex

Description

The proposed invention relates to the field of organic chemistry, in particular to a method for producing 2-methyl-3-propylindole ( 1 ).

2-Methyl-3-propylindole is used as a repellent in marine antifouling material against living organisms [ Patents JPH10259101A; JP4092621 ]; for the synthesis of indole derivatives with anti-arteriosclerotic and anti-inflammatory effects [ Patent JP2006001926 ], photochromic dyes [ Patent DE19646820A1 ].

In the literature [ EB Landstrom [et al.] // Organic Letters. – 2020. – Vol. 22. – No. 16. – P. 6543-6546 ] a method for obtaining 2-methyl-3-propylindole ( 1 ) using aqueous micellar catalysis is described:

In the first stage, phenyl trifluoromethanesulfonate reacted with a hydrazine derivative in the presence of a catalytic system based on a palladium complex Pd (0.5 mol%) using phosphine tBuBrettPhos (0.5 mmol), sodium tert-butoxide NaOt-Bu (2 mmol) (45 °C, 16 h, argon). A derivative of polyoxyethanyl-α-tocopheryl succinate, TPGS-750-M (2 wt. % in H ₂ O), was used as a surfactant. In the second stage, ethanol (0.2 M), sulfuric acid and 2-hexanone (hydrazine derivative: 2-hexanone:H ₂ SO ₄ = 1:2:3 mol/mol) were added, the reaction was carried out for 24 h under boiling conditions. The disadvantages of the above-described method are the use of many expensive components, multi-stage nature and long synthesis.

Authors [H.-D. Xia [et al.] // Organic Letters. – 2018. – Vol. 20. – No. 13. – P. 4052-4056] synthesized 2-methyl-3-propylindole1with a yield of 80% two-stage synthesis:

First, intramolecular condensation of benzamide 3 was carried out to obtain indole derivative 2 (catalyst based on hypervalent iodine (phenyliodonio)sulfamate, H ₂ O, CH ₃ CN, 60 °C, 2 h), then the nitrogen group was deprotected (catalyst – N ₂ H ₄ ⋅H ₂ O, EtOH, 36 h under boiling conditions). The disadvantages of this method are multi-stage and long synthesis, use of precursor, narcotic and psychotropic substances as a solvent.

The authors [ S. Banerjee, E. Barnea, AL Odom // Organometallics. – 2008. – Vol. 27. – Titanium-Catalyzed Hydrohydrazination with Monosubstituted Hydrazines. – No. 5. – P. 1005-1014 ] synthesized indole 1, starting from 1-hexyne and phenylhydrazine, with a yield of 87% using two catalysts:

First, a Ti-containing catalytic system (toluene, 80 °C, 4.5 h) was used as a catalyst, then zinc chloride ZnCl ₂ (100 °C, 24 h) was added. The disadvantages of this method are: the use of a complex titanium complex as a catalyst, a relatively expensive and explosive reagent (1-hexine), poisonous phenylhydrazine, multi-stage, long synthesis.

Compound 1 was synthesized in a similar reaction with a yield of 82% [ NT Patil, A. Konala // European Journal of Organic Chemistry. – 2010. – Vol. 2010. – No. 35. – P. 6831-6839 ] in the presence of a binary catalytic system consisting of an organometallic complex of gold and p-toluenesulfonic acid Ph ₃ PAuNTf ₂ /pTSA H ₂ O (toluene, 100 °C). The disadvantages of this method are the use of a complex and expensive gold complex as a catalyst, a relatively expensive and explosive reagent (1-hexyne), and poisonous phenylhydrazine.

Using the traditional method of synthesizing indoles from phenylhydrazine and 2-hexanone (Fischer reaction), the authors [J. Selby [et al.] // The Journal of Organic Chemistry. – 2020. – Vol. 85. – No. 19. – P. 12227-12242] alkylindole was obtained1with exit 87%:

Synthesis conditions: acetic acid catalyst, 120 °C – 6 hours, then room temperature – 18 hours. The disadvantages of this method are the use of an expensive reagent (2-hexanone), toxic phenylhydrazine, and long synthesis.

The use of homogeneous catalysts in the above methods leads to a multi-stage process, complex separation of products from catalysts, and the impossibility of their reuse. Heterogeneous catalysts are free of these disadvantages.

In the work [ L.-L. Cao [et al.] // Tetrahedron Letters. – 2011. – Vol. 52. – No. 22. – P. 2837-2839 ] 2-methyl-3-propylindole 1 was obtained by reduction of 2-methyl-α-ethylindole-3-methanol under the action of a 5% Pd/C catalyst, benzoic acid in a hydrogen atmosphere in the presence of tetrahydrofuran (THF):

The yield of the target product 1 was 91%. The disadvantages of this method include the use of an expensive reagent (2-methyl-α-ethylindole-3-methanol), the use of hydrogen, and the need to remove benzoic acid.

2-Methyl-3-propylindole 1 was obtained in 62% yield in the presence of sodium borohydride on the polymeric base PS-BH ₄ [ E. Chiurchiù, A. Palmieri, M. Petrini // Arkivoc. – 2019. – Vol. 2019. – No. 4. – P. 69-79 ] by decomposition of the sulfo derivative of indole 4 (40 min, 2 atm, room temperature):

The authors propose to obtain the arylsulfonylalkyl derivative of indole 4 using the method [ A. Palmieri, M. Petrini // The Journal of Organic Chemistry. – 2007. – Vol. 72. – No. 5. – P. 1863-1866 ] by reacting 2-methylindole, p-toluenesulfonic acid and aldehyde. The disadvantages of this method include the multi-stage nature of the process.

In the work [ MP Prochazka [et al.] // Acta Chemica Scandinavica. – 1990. – Vol. 44. – P. 610-613 ] indole 1 was synthesized with a yield of 86% in the presence of powdered zeolite grade Y-82 (Union Carbide) by the Fischer synthesis. The zeolite (6 g) was mixed with xylene (solvent, 40 ml) for 5 min, then 2-hexanone was added and the suspension was stirred for 1 h. Phenylhydrazine was added (2-hexanone: phenylhydrazine = 1:1 mol/mol), the reaction was carried out under boiling conditions (~130-140 °C) for 3 h. The disadvantages of this method include the use of large quantities of catalyst, toxic phenylhydrazine, and large volumes of solvent.

The objective of the present invention is to develop an efficient heterogeneous catalytic method for synthesizing 2-methyl-3-propylindole.

The solution to this problem is achieved by the fact that the synthesis of alkylindole ( 1 ) is carried out by the interaction of aniline with 1,2-propanediol in the presence of granulated zeolite of the FAU structural type in the H-form with a high degree of crystallinity, having a micro-meso-macroporous structure (HY _h ). The reaction is carried out in an autoclave at 260 °C, with a molar ratio of aniline: 1,2-propanediol = 1: 2-5, in the presence of 5-20 wt.% of the HY _h catalyst, for 6-9 hours.

The main product of the reaction of aniline with 1,2-propanediol in the presence of zeolite catalyst HY _h is 2-methyl-3-propylindole 1 :

In addition to the target product 1 , 3-methyl-2-ethylquinoline (X), 3-methyl-2-ethyl-N-phenyl-1,2,3,4-tetrahydroquinoline-4-amine (THQA), 3,4-dimethyl-1-phenylpyrrole (P), alkylanilines, and alcohol conversion products were found in the reaction mixture. The by-product N-heterocyclic compounds are valuable raw materials for the production of drugs, corrosion inhibitors, polymers, etc. [ Vandekerckhove S.; D'hooghe, M. Bioorganic & Medicinal Chemistry, 2015; 23(16), 5098 – 5119; Chitra S.; Saranya J.; Lavanya, K. Corrosion Reviews, 2018; 36(4), 365-371; A. K. Diaw; A. Yassar; D. Gningue-Sall; J.-J. Aaron/Arkivoc(2009), 2008(17), 122-144; 8. S. Tarkuk; E. Sahmetlioglu; C. Tanyeli; I.M. Akhmedov; L. Toppare (2006), 51(25), 5412–5419 ].

Using two inexpensive reagents – 1,2-propanediol and aniline – the syntheses of 3-methylindole (skatole) [ Wenhui L.; Xinghai L.; Dongyan L.; Lei S.; Qi S. Chin. J. Catal, 2009; 30(12), 1287–1290; Yang H.; Wenhui L.; Dongyan L.; Jing L.; Lei S.; Qi S. Journal of Natural Gas Chemistry, 2009;18, 445–448; China Patent 107540595, 106278985 ] and 2-methylindole [ Lee H.; Yi C.S. Organometallics, 2019; 35(11), 1973–1977; Charvieux A.; Hammoud AA; Duclos M.-Ch.; Duguet N.; Métay E. Tetrahedron Letters, 2021; 78, 153270; Zhang M.; Xie F.; Wang XiaoTing; Yan F.; Wang T.; Chen M.; Ding Yu. RSC Adv., 2013; 3, 6022–6029 ]. There are no references in the literature to the synthesis of 2-methyl-3-propylindole 1 by the reaction of 1,2-propanediol with aniline.

Zeolite HY _h is synthesized in the form of granules without binders; its granules are single intergrowths of zeolite crystals and have a degree of crystallinity close to 100%. The porous structure of the granules consists of the microporous structure of the Y zeolite itself and the mesoporous structure formed between the intergrowths of crystals. A significant advantage of zeolite HY _h over highly dispersed zeolites is that it is synthesized in granules. The granulated catalyst has better physical properties: it does not dust, does not cake, is easily dispersed and is easily separated from the reaction mass by filtration (unlike the highly dispersed catalyst, which quickly clogs the filter or passes through the filter cloth).

Granulated zeolites are usually synthesized by mixing highly dispersed zeolite with a binder, and then forming the resulting mixture into granules. The introduction of a binder into the granules reduces the adsorption capacity and catalytic activity of zeolites compared to highly dispersed zeolites, and in some cases it is not possible to ensure the mechanical strength of the granulated materials obtained in this way. The HY _h catalyst granules are 100% zeolite Y and do not contain a binder.

Zeolite HY _h has a combined micro-meso-macroporous crystalline structure, which is highly stable and does not deteriorate during the ion exchange of Na ⁺ cations to H ⁺ .

The use of the proposed method has the following advantages over known methods:

1) Inexpensive, accessible, stable reagents are used for synthesis.

2) The reaction is carried out in the presence of a heterogeneous catalyst – zeolite HY _h with a hierarchical porous structure.

3) Zeolite is used in the form of granules.

4) The zeolite catalyst is easily separated from the reaction mass and can be reused.

5) The above-mentioned reactions are carried out in the presence of solvents, which are used in large volumes; in the proposed method, there is no solvent, therefore, the stage of its separation and purification is not required.

The granulated zeolite catalyst HY _h is synthesized in the Na-form using the method described in [ Travkina OS, Agliullin MR, Filippova NA, Khazipova AN, Danilova IG, Grigor'eva NG, Narender N, Pavlov ML, Kutepov BI // RSC Advances. 7 (2017) 32581-32590; Russian Federation Patents No. 2540086, No. 2553876 ]. By ion exchange from a NH ₄ NO ₃ solution, the Na-Y _h zeolite is converted into the NH ₄ -form; subsequent calcination at 540 ^o C for 4 hours converts it into the H-form.

The reaction is carried out in an autoclave at 260 °C, with a molar ratio of aniline: 1,2-propanediol = 1: 2-5, in the presence of 5-20% HY _h catalyst, for 6-9 hours.

The reaction products are extracted with methylene chloride and analyzed using high-performance liquid chromatography (HPLC) on a SHIMADZU modular instrument with an SPD-20a spectrophotometric detector. Recording conditions: column – Agilent C18 (4.6⋅250 mm), eluent-CH ₃ CN/H ₂ O - 80/20, eluent feed rate - 1 ml/min.

The invention is illustrated by the following examples.

EXAMPLE 1 .

0.2 g (2.2 mmol) of aniline, 0.8 g (11.0 mmol) of 1,2-propanediol and 0.1 g (10% by weight based on the initial mixture) of zeolite HY _h are loaded into a metal autoclave, the autoclave is hermetically sealed and placed in a thermostatically controlled cabinet. The reaction is carried out at a temperature of 260°C for 6 h with continuous rotation of the autoclave.

After completion of the reaction, the autoclave is cooled to room temperature, the reaction products are extracted with dichloromethane, and after distilling off the solvent, they are analyzed by high-performance liquid chromatography.

The conversion of aniline is 99%, the selectivity for the formation of 2-methyl-3-propylindole 1 is 55%.

EXAMPLES 2-6. Similar to example 1. The conditions and results of the examples are presented in the table.

Table

Synthesis of 2-methyl-3-propylindole 1 in the presence of hierarchical zeolite HY _h

(temperature 260°C)

No. Time, h Aniline: 1,2-propanediol, mol/mol Amount of catalyst, % by weight Aniline conversion,
% Selectivity, % 1 X TGHA P Other 1 6 1:5 10 99 55 22 5 8 10 2 6 1:3 10 99 50 20 5 7 18 3 6 1:2 10 95 44 18 5 6 27 4 6 1:3 5 81 49 14 10 8 19 5 6 1:3 20 99 45 19 4 8 24 6 9 1:3 10 99 45 22 2 7 24

3-methyl-2-ethylquinoline (X), 3-methyl-2-ethyl-N-phenyl-1,2,3,4-tetrahydroquinoline-4-amine (THQA),

3,4-dimethyl-1-phenylpyrrole (P).

Claims (1)

A method for producing 2-methyl-3-propylindole, characterized in that 2-methyl-3-propylindole is obtained by reacting aniline with 1,2-propanediol in the presence of granulated zeolite Y _h in the H-form with a hierarchical porous structure, in an autoclave at 260°C, with a molar ratio of aniline:1,2-propanediol = 1:2-5, in the presence of 5-20 wt.% of catalyst HY _h , for 6-9 hours.