RU2609028C1 - Method of producing 2, 2, 4-trimethyl-1, 2-dihydroquinoline - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2,2,4-trimethyl-1,2-dihydroquinoline by condensation of aniline with acetone in presence of a heterogeneous catalyst, characterised by that catalyst used is micro-meso-macroporous zeolite H-Y-MMM and reaction is carried out at temperature 60–230 °C, catalyst concentration 5–20 % and reaction time of 6–23 hours.

EFFECT: novel method of producing 2,2,4-trimethyl-1,2-dihydroquinoline, which is widely used in production of highly effective medicinal preparations, chelating agents, sorbents, cyan dyes, is widely used in synthesis of fungicides, pesticides, alkaloids, etc.

1 cl, 1 tbl, 6 ex

Description

The invention relates to the field of organic chemistry, in particular to a method for the preparation of quinoline derivatives, namely 2,2,4-trimethyl-1,2-dihydroquinoline.

The dihydroquinoline fragment is present in many natural compounds, most of which have biological activity [1. Balayer A., Sévenet T., Schaller N., Hamid A., Hadi A., Chiaroni A., Riche C. & Païs M. Dihydroquinoline-type Alkaloids from Bhesa Paniculata, Celastraceae // Natural Product Lellers. - 1993. - V. - 2 (1). - P. 61-67; 2. Abe F .; Yamauchi, T .; Shibuya, H .; Kitagawa, I .; Yamashita. Indole Alkaloids from the Leaves of Alstonia villosa in Sunbawa // M. Chem. Pharm. Bull. - 1998. - 46. - P. 1235-1238]. For example, 2,2,4 substituted 1,2-dihydroquinolines were used as potent substances with antibacterial, antidiabetic and anti-inflammatory effects [3. Jay V. Johnson, Barbara S. Rauckman, David P. Baccanari, and Barbara Roth. 2,4-Diamino-5-benzylpyrimidines and Analogues as Antibacterial Agents, 1,2-Dihydroquinolylmethyl Analogues with High Activity and Specificity for Bacterial Dihydrofolate Reductase // Med. Chem. - 1989. - 32. - P. 1942-1949; 4. Pat. JP No. 042823701992; 5. Dillard R. D., Pravey D. E., Benslay D. N. Synthesis and anti-inflammatory activity of some 2,2-dimethyl-1,2-dihydroquinolines // J. Med. Chem. - 1973. - V. 16. - P. 251-253; 6. Maria-Elena Theoclitou * and Leslie A. Robinson. Novel facile synthesis of 2,2,4 substituted 1,2-dihydroquinolines via a modified Skraup reaction // Tetrahedron Letters. - 2002. - 43. - P. 3907-3910].

Derivatives of dihydroquinolines can be used as lipid peroxidation inhibitors [7. Pat. USA No. 5411969], HMG-CoA reductase [8. Pat. US No. 568808], a bile acid transporter inhibitor [9. Pat. WO No. 0134570 A1], progesterone agonists and antagonists [10. Pat.WO No. 9619458; 11. Pat. WO No. 9941256].

The polymer of 2,2,4-trimethyl-1,2-dihydroquinoline [12. Y. Liu, Q. Gao, L. Liu and S. Li. Investigated on the Rubber Antioxidant 2,2,4-Trimethyl-1,2-dihydroquinoline Polymer // Asian Journal of Chemistry. - 2013. - V. 25. - No. 6. - P. 2956-2958] used as an antioxidant in the manufacture of rubber.

Dihydroquinolines can be synthesized by Skraup cyclization, which consists in the interaction of aniline and a carbonyl compound in the presence of iodine (or bromine) at 145 ° C for 2-3 days [13. Vaughan, W.R. 2,4-Dimethylquinoline // Org. Synth. - 1955. - 3. - P. 329-334; 14. Pat. JP No. 55,040,661; 15. Lugovik B.A., Yudin L.G., Kost A.N., Technology of the reaction of acetone with aniline // Zh. Prikl. Khim. - 1965. - 38. - P. 216].

A number of works are devoted to the simplification of this method [16. Durgadas S., Chatare V.K., Mukkanti K., Pal S. Ceric Ammonium Nitrate: An Efficient Catalyst for One-Pot Synthesis of 2,2,4-Trimethyl-1,2-dihydroquinolines // Letters in Organic Chemistry. - 2010. - V. 7. - P. 306-310; 17. Kundu D., Kundu S.K., Majee A., Hajra A. A Facile Synthesis of 2,2,4-Trisubstituted-1,2-dihydroquinolines Catalyzed by Zinc Triflate under Solvent-free Conditions // J. Chin. Chem. Soc. - 2008. - V. 55. - P. 1186-1190; 18. Kiss A., Potor A., Hell Z. Heterogeneous Catalytic Solvent-free Synthesis of Quinoline. Derivatives via the Friedlander Reaction // Catal Lett. - 2008. - 125. - P. 250-253; 19. A. Hegedüs, Z. Hell, T. Vargadi, A. Potor and I. Gresitsb. A new synthesis of 1,2-dihydroquinolines via cyclocondensation using zeolite catalyst // Catalysis Letters. - 2007.- V. 117, - 3-4].

In the works [12; 20. Liu Yu, Gao qinyu, Liu Lianxin, and Shi guangxia. Study on the Industrial Process of Rubber Anti-oxidant RD // Journal of the Korean Chemical Society. - 201. - V. 55. - No. 5] the mechanism of the reaction of aniline with acetone with the formation of 2,2,4-trimethyl-1,2-dihydroquinoline and its subsequent polymerization was studied. In the synthesis of dihydroquinoline and its oligomers, it is proposed to use BF ₃ ⋅O (C ₂ H ₅ ) ₂ [12], AlBr ₃ or HCl [20] as a catalyst. The reaction is exothermic, therefore it is necessary to control that the temperature does not exceed 50 ° C.

The reaction mechanism in the presence of BF ₃ ⋅ О (С ₂ Н ₅ ) ₂ can be represented in the form of the following scheme:

In the presence of HCl, aniline with acetone react according to the scheme:

Disadvantages:

1. Multi-stage;

2. Corrosive environment;

3. The formation of wastewater;

4. The ethereal boron trifluoride is poisonous;

5. The formation of fluorine-containing waste.

In addition, p-aminobenzenesulfonic acid [15], benzenesulfonic acid [21] can be used as a catalyst for the synthesis of dihydroquinoline by the interaction of aniline with acetone. Pat. JP No. 56.014.516; 22. Pat. GB No. 764,957], p-toluenesulfonic acid [23. R.W. Layer, Synthesis of 1,3,5-trialkylbenzenes from anils of methyl alkyl ketones // J. Org. Chem. - 1981. - 46. - P. 4552-4555; 24. Pat. JP No. 57.011.968]. In this case, di-, tri- and tetramers of 2,2,4-trimethyl-1,2-dihydroquinoline are formed.

Disadvantages:

1. Complex separation of the catalyst from the reaction mass;

2. The inability to reuse the catalyst;

3. It is necessary to remove the generated water.

A method for the synthesis of dihydroquinoline under the action of silicotungsten acid (H ₄ [SiW ₁₂ O ₄₀ ]) [25. R. Kamakshi, BSR Reddy. Synthesis of 2,2,4-dihydroquinolines using heteropolyacid as a catalyst. // Catalysis Communications. - 2007. - 8. P. 825-828]. The synthesis is carried out by the interaction of aromatic amines with ketones at a molar ratio of reagents 1: 2.7 (mol), the boiling point of the solvent (acetone, acetonitrile, dichloromethane, chloroform or toluene) for 4-10 hours, the concentration of the catalyst is 2 mol%. Then the reaction mixture was cooled, the solvent was evaporated. The concentrated reaction mixture was diluted with chloroform and washed with water (3 * 20 ml). The organic layer was separated and dried over anhydrous sodium sulfate. Then it is concentrated and purified by column chromatography. The yield of 1,2-dihydroquinolines is 77-94%. The highest yields were obtained using acetonitrile as a solvent.

Disadvantages:

1. The use of several solvents in large volumes;

2. The multi-stage method;

3. The formation of wastewater;

4. The inability to use the catalyst repeatedly.

In [6], the authors propose the synthesis of 2,2,4-trimethyl-1,2-dihydroquinoline in the presence of scandium triflate Sc (OTf) ₃ (0.05 mmol) in a solvent of CH ₃ CN at room temperature for 2-6 h under the influence of microwave radiation. The reaction mixture was extracted with dimethyl sulfoxide. When aniline and acetone are involved in the reaction in a molar ratio of 1: 600, the yield of 2,2,4-trimethyl-1,2-dihydroquinoline is 65%. In the case of using substituted anilines, the yield of dihydroquinolines is 78-98%.

Disadvantages:

1. High cost of Sc based catalyst;

2. The reaction proceeds in an environment of a solvent used in large quantities;

3. The multi-stage method.

The reaction of aniline with acetone can be carried out in the presence of Zn (OTf) ₃ in an amount of 5-10 mol. % [17] at room temperature, without solvent for 22 hours. The yield of dihydroquinoline is 70-80%. Raising the reaction temperature to 70% reduces the reaction time by half. The reaction mass is extracted with diethyl ether.

Disadvantages:

1. The difficulty of removing the catalyst from the reaction mass;

2. The need to remove solvent after extraction;

3. Multi-stage.

The authors of [26. Satoshi Kamiguchi, Ikuko Takahashi, Hideki Kurokawa, Hiroshi Miura, Teiji Chihara. Vapor-phase synthesis of 1,2-dihydro-2,2,4-trimethylquinolines from anilines and acetone over group 5-7 metal halide clusters as catalysts // Applied Catalysis A. - 2006. - 309. - P. 70-75 ] a method for producing 2,2,4-trimethyl-1,2-dihydroquinoline by the interaction of aniline (feed rate of 0.091 ml / h) with acetone (0.147 ml / h) by the action of clusters based on niobium halides is proposed. The synthesis is carried out in a reactor with a fixed catalyst bed (30 mg), in a stream of hydrogen, at 300 ° C for 1 h. The most active was [(Nb ₆ Cl ₁₂ ) Cl ₂ (Н ₂ О) ₄ ] ⋅4H ₂ O, on which the selectivity for the formation of dihydroquinoline was 71.7%. As a by-product, N-isopropylidenaniline (16%) is formed at aniline conversion of 34%.

Disadvantages:

1. The use of complex, expensive and inaccessible catalytic systems;

2. Low catalyst activity.

Polyhedral oligomeric silsesquioxanes (POSS) are used as a catalyst for the synthesis of dihydroquinolines [27. Ganapati D. Yadav, Rahul P. Kumbhar, Saumydeep Helder. A Facile Solvent-Free Skraup Cyclization Reaction for Synthesis of 2,2,4-trimethyl-1,2-dihydroquinoline // I.RE.CH.E. - 2012. - V. 4. - N.6], which is a class of three-dimensional organo-inorganic hybrids with the general formula (RSiO _1,5 ) _n , where R = Н, alkyl-, aryl-, halogen; n is an integer ≥4. The reaction is carried out at 140-170 ° C in an autoclave, the molar ratio of aniline: acetone = 1: 3-9, the amount of catalyst is 0.01-0.03 g / cm ³ . Aniline conversion reaches 94%. The authors did not indicate the yield of the target products.

Disadvantages:

1. The synthesis of the catalyst is complex and multi-stage.

Since the beginning of the 21st century, work has been actively carried out on the use of zeolites as catalysts for the gas-phase condensation of carbonyl compounds with aniline [28. Aguilar J., Corma A., Melo F.V. and Sastre E. Alkylation of biphenyl with propylene using acid catalysts // Catal. Today. - 2000. - V. 55. - P. 225; 29. Jin D.F., Hou Z.Y., Zhang L.W., Zheng X.M., Selective synthesis of para-para-dimethyldiphenylmeme over H-Beta zeolite // Catal. Today. - 2008. - V. 131. - P. 378-384; 30. Pat. US No. 5,700,942].

The authors of [19] proposed a method for producing 2,2,4-trimethyl-1,2-dihydroquinoline by the reaction of aniline with acetone in a solvent of toluene under the action of catalyst E4a (250% of the catalyst per aniline) for 6 hours. Catalyst E4a was obtained based on natural zeolite clinoptilonite (composition in terms of oxides: SiO ₂ - 73.0%, Al ₂ O ₃ - 11.2%, Fe ₂ O ₃ 1.17%, K ₂ O - 5.12%, Na ₂ O - 0.38%, CaO - 2.20 %, MgO - 0.44%) by ion exchange of Ca, Mg, K cations for ammonium ions and subsequent calcination in order to obtain a decationized form of zeolite. Fe and Al cations are practically not removed during ion exchange. Reaction conditions: 110 ° C, the mass content of the catalyst per aniline is 250%, the molar ratio of aniline: acetone: toluene is 1: 5: 45. The reaction is carried out in a glass heated reactor with a stirrer, reflux condenser and thermometer. In the presence of catalyst E4a, the yield of 2,2,4-trimethyl-1,2-dihydroquinoline is 96%.

The disadvantages of this method include:

1. The use of catalyst in large quantities (250% of the catalyst per aniline), which significantly degrades the efficiency of the method.

2. A large amount of solvent (molar ratio of aniline: toluene = 1:45) leads to an increase in the volume of equipment used and creates problems in the separation and regeneration of the solvent.

3. The catalyst is prepared on the basis of natural zeolite. The latter, as a rule, are characterized by instability of the mineralogical and chemical composition, porous structure, strength indicators, thermal stability, ability to ion exchange, and other important characteristics. Natural zeolites, in addition to the main mineral, also contain accompanying ones, such as sand, clay, quartz. The composition and amount of metal cations present in them can vary significantly.

The present invention is to develop a more efficient method for the synthesis of 2,2,4-trimethyl-1,2-dihydroquinoline under the action of zeolite catalysts.

This goal is achieved by the fact that the method of producing 2,2,4-trimethyl-1,2-dihydroquinoline by condensation of aniline with acetone is carried out according to the invention in the presence of a granule-free zyolite catalyst HY-MMM having a micro-meso-macroporous structure at temperature 60-230 ° C, a catalyst concentration of 5-20% and a reaction time of 6-23 hours. The molar ratio of aniline: acetone is 1: 5.

The formation of 2,2,4-trimethyl-1,2-dihydroquinoline from aniline and acetone can be represented in the form of a scheme [31. Liu Y., Gao Q., Liu L. and Li S. Investigated on the Rubber Antioxidant 2,2,4-Trimethyl-1,2-dihydroquinoline Polymer // Asian Journal of Chemistry. - 2013. - V. 25. - No. 6. - P. 2956-2958]:

Zeolite Y-MMM is synthesized in the form of granules without binders [32. RF patent No. 2412903]. Its granules are single intergrowths of zeolite crystals and have a crystallinity degree close to 100%. The porous structure of the granules consists of a microporous structure of the zeolite itself and a meso-macroporous structure formed between intergrowths of crystals. The use of micro-mesoporous zeolites in the synthesis of quinolines is unknown.

A comparative analysis of the proposed solution with the prototype shows that the claimed method differs from the prototype in that in the synthesis of 2,2,4-trimethyl-1,2-dihydroquinoline by the reaction of aniline with acetone, a HY-MMM zeolite catalyst granulated without binders is used . The synthesis is carried out at 60-230 ° C. Aniline conversion reaches 100%, the selectivity for the formation of 2,2,4-trimethyl-1,2-dihydroquinoline is 60-68%. A by-product of the reaction is N-phenylpropan-2-imine [N- (1-methylidene) aniline], which is a valuable chemical compound.

Imines are known to be important intermediates in the synthesis of biologically active N-containing compounds, such as β-lactams, dyes, fragrances, pharmaceuticals, fungicides and agricultural chemicals [33. Martin S.F. Recent applications of imines as key intermediates in the synthesis of alkaloids and novel nitrogen heterocycles // Pure Appl. Chem. - 2009. - V. 81. - No. 2. - P. 195-204].

Using the proposed method allows you to:

1. To carry out the reaction of aniline with acetone at a significantly lower catalyst concentration (5-20%);

2. Do not use solvents;

3. The use of a synthetic zeolite catalyst having a stable chemical and phase composition, physico-chemical characteristics, will allow to obtain stable and reproducible results, including high aniline conversion and a sufficiently high yield of 2,2,4-trimethyl-1,2-dihydroquinoline;

4. In the process, a valuable chemical compound is formed - N-phenylpropan-2-imine, the yield of which can be controlled by changing the reaction conditions.

The proposed method is as follows.

Aniline, acetone and 5-20% of the zeolite catalyst H-Y-MMM (based on the mixture of aniline: acetone taken in a molar ratio of 1: 2) were loaded into the ampoule. A sealed ampoule was placed in an autoclave, which was hermetically sealed and heated to a predetermined temperature for the required time. After the reaction, the autoclave was cooled to room temperature, the ampoule was opened. The reaction mass was filtered off from the catalyst.

The reaction products were analyzed by gas-liquid chromatography on a chromatograph with a flame ionization detector (steel packed column 3 m long, phase 15% polyethylene glycol on HMDS chromaton, analysis temperature 50-180 ° C with programmed heating 8 ° C / min, detector temperature 200 ° С, evaporator temperature 200 ° С, carrier gas - helium - 30 ml / min).

Mass spectra were obtained on a SHIMADZU GCMS-QP2010Plus chromatography-mass spectrometer (SPB-5 phase, capillary column 30 m × 0.25 mm, carrier gas — helium, programming temperature from 40 to 300 ° C at a rate of 8 ° C / min, evaporation temperature 280 ° С, ion source temperature 200 ° С, ionization energy 70 eV).

Identification of the products was carried out by comparing the chromato-mass spectra and chromatographic behavior of the isolated and standard compounds of quinoline and its derivatives. The spectral characteristics of 2,2,4-trimethyl-1,2-dihydroquinoline correspond to the literature data given in [19].

The proposed method is illustrated by the following examples.

EXAMPLE 1

0.2 g (0.002 mol) of aniline, 0.58 g (0.01 mol) of acetone and 0.06 g of the HY-MMM zeolite catalyst (15% by weight based on the mixture of aniline: acetone taken in molar) were loaded into the ampoule 1: 2 ratio). The sealed ampoule was placed in an autoclave, which was heated at 230 ° C for 23 h. After the reaction, the autoclave was cooled to room temperature, the ampoule was opened. The reaction mass was filtered off from the catalyst and analyzed by gas-liquid chromatography. Aniline conversion was 97%, and the selectivity for the formation of 2,2,4-trimethyl-1,2-dihydroquinoline was 66%.

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

Claims (1)

The method of producing 2,2,4-trimethyl-1,2-dihydroquinoline by condensation of aniline with acetone in the presence of a heterogeneous catalyst, characterized in that the catalyst is used micro-meso-macroporous zeolite HY-MMM and the reaction is carried out at a temperature of 60-230 ° C, a catalyst concentration of 5-20% and a reaction time of 6-23 hours