RU2602501C1 - Method of producing 3-furylpropane-1-on - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry - obtaining derivatives of 3-furylpropane-1-on derivatives of formula 1a-j, where R¹-R⁴ have following values:

which involves reaction of 2-methylfuran with available α,β-unsaturated carbonyl compounds in presence of copper (II) bromide in 1,2-dichloroethane at room temperature during 4 hours.

EFFECT: these compounds are of interest in synthesis of pharmaceutical substances.

1 cl, 2 tbl, 11ex

Description

The invention relates to the field of organic chemistry - the preparation of 3-furylpropan-1-one derivatives of interest in the synthesis of pharmaceutical substances.

The invention relates to the development of a method for the preparation of 3-furylpropan-1-one derivatives of the general formula 1a-k, which can be used as starting materials for the synthesis of 4-aryl-4-oxobutanoic acids - kinurenin-3-hydrolase inhibitors having a neuroprotective effect [ Giordani, A .; Pevarello, P .; Cini, M .; Bormetti, R .; Greco, F .; Toma, S .; Speciale, C; Varasi. M. Bioorg. Med. Chem. Lett, 1998, 8, 2907].

Existing methods for the synthesis of derivatives of 3-furylpropan-1-ones are based on the reaction of conjugated addition of furans to α, β-unsaturated carbonyl compounds. However, the implementation of this approach, as a rule, requires the use of catalysts based on metal salts of the platinum group [J.J. Hirner, D.J. Faizi, S.A. Blum, J. Am. Chem. Soc, 2014,136, 4740-4745; X. Zhang, X.Q. Yu, X.J. Feng, M. Bao, Synlett, 2012, 23, 1605-1608] or special conditions (high pressure, low temperature) [Jenner, G .; Gacem, B. J. Phys. Org. Chem. 2003,16,265; Hanessian, S .; Stoffman, E.J.L .; Mi, X.L .; Renton, P. Org. Lett., 2011, 13, 840]. On the other hand, methods based on the use of available Bronsted acids [Dyker, G .; Muth, E .; Hashmi, A.S.K .; Ding, L. Adv. Synth. Catal. 2003, 345, 1247] or Lewis [Hashmi, A.S.K .; Schwarz, L .; Choi, J.-H .; Frost, T.M. Angew. Chem. Int. Ed., 2000, 39, 2285; D.A. Evans, K.R. Fandrick, H.J. Song, K.A. Scheidt, R. Xu, J. Am. Chem. Soc, 2007, 129, 10029-10041]. However, the use of the latter is limited by the presence of reaction-sensitive functional groups in the starting substrates.

The disadvantages of the described methods include a limited scope, the use of expensive catalysts based on precious or rare-earth metals, and the use of specific reaction conditions. Thus, the development of a simple and effective method for the synthesis of 3-furylpropan-1-ones derivatives using an available catalyst under mild reaction conditions with the possibility of introducing a variety of functional groups into the structure of the final product is an urgent task.

The objective of the invention is the development of a new effective method for producing a variety of derivatives of 3-furylpropan-1-one under mild conditions, which allows to expand the range of potentially biologically active substances, and which are convenient starting compounds for the synthesis of substituted 4-aryl-4-oxobutanoic acids.

The technical result is the development of a new method for producing a wide range of 3-furylpropan-1-ones, based on the reaction of conjugated addition of 2-methylfuran to α, β-unsaturated carbonyl compounds.

The proposed method is based on the previously described method for the synthesis of 3-furylpropanone derivatives by the interaction of 2-methylfuran with α, β-unsaturated carbonyl compounds in the presence of catalytic amounts of copper (II) triflate [Bulbule, V.J .; Deshpande, V.H .; Bedekar, A.V. J. Chem. Research (S), 2000, 220]. The disadvantages of this method include the limited scope of the reaction, moderate yields of reaction products, and the need to use easily hydrolyzed and expensive copper (II) triflate.

The technical result is achieved by the interaction of α, β-unsaturated ketones with 2-methylfuran in 1,2-dichloroethane at room temperature in the presence of available copper (II) bromide for 4 hours.

The yields of the reaction products and the spectral characteristics of the obtained 3-furylpropan-1-ones 1a-k are shown in Table 1.

The technical result obtained opens the way to a wide range of derivatives of 3-furylpropan-1-one 1, making it possible to introduce various substituents into the structure of the final products.

Thus, the set of essential features set forth in the claims, allows to achieve the desired technical result.

Examples of the proposed method for producing 3- (5-methylfur-2-yl) -1,3-diphenylpropan-1-one 1a.

Example 1

A mixture of 0.540 g of benzylideneacetophenone (2.6 mmol), 0.585 ml of 2-methylfuran (6.5 mmol), 0.058 g of copper (II) bromide (0.26 mmol) and 8.5 ml of 1,2-dichloroethane was stirred on a magnetic stirrer at room temperature for 4 hours. The reaction mass is filtered through a thin layer of silica gel (Macherey-Nagel brand, fraction 40-63 μm), washed with CH ₂ Cl ₂ (10 ml) and the solvent is removed under reduced pressure. Task 3- (5-furo-2-yl) -1,3-diphenylpropane-1-one was isolated by column chromatography on silica gel (brand Macherey-Nagel, fraction 40-63 um), eluting with - CH ₂ Cl ₂ / petroleum ether (1: 9). Yield 73% (0.552 g).

R _f = 0.40 (ethyl acetate / petroleum ether 1: 4)

¹ H NMR spectrum (CDCl ₃ ), (δ, ppm, and KSSB, J, Hz): 2.23 (s, 3H, Me), 3.54 (dd, J = 16.9 Hz, 7.2 Hz, 1H, CH ₂ ) , 3.80 (dd, J = 16.9 Hz, 7.2 Hz, 1H, CH ₂ ), 4.80 (t, J = 7.2 Hz, 1H, CH), 5.85 (br s, 1H, H _Fur ), 5.91 (br s , 1H, H _Fur ), 7.20-7.26 (m, 1H, H _Ar ), 7.28-7.36 (m, 4H, H _Ar ), 7.42-7.47 (m, 2H, H _Ar ), 7.53-7.57 (m, 1H , H _Ar ), 7.92-7.98 (m, 2H, H _Ar ).

¹³ C NMR spectrum (CDCl ₃ ), (δ, ppm): 13.6, 40.6, 43.9, 106.1, 106.6, 126.8, 128.0 (2С), 128.2 (2С), 128.6 (2С), 128.7 (2С), 133.1, 137.3, 142.4, 151.2, 155.0, 197.8.

Example 2

A mixture of 0.540 g of benzylideneacetophenone (2.6 mmol), 0.585 ml of 2-methylfuran (6.5 mmol), 0.065 g of CuSO ₄ · 5H ₂ O (0.26 mmol) and 8.5 ml of 1,2-dichloroethane is stirred on a magnetic stirrer at room temperature for 4 hours . The reaction mass is filtered through a thin layer of silica gel (Macherey-Nagel brand, fraction 40-63 μm), washed with CH ₂ Cl ₂ (10 ml) and the solvent is removed under reduced pressure. The target 3- (5-methylfur-2-yl) -1,3-diphenylpropan-1-one was isolated by silica gel column chromatography (Macherey-Nagel brand, fraction 40-63 μm), eluent CH ₂ Cl ₂ / petroleum ether (1: 9). Yield 0%.

Example 3

A mixture of 0.540 g of benzylideneacetophenone (2.6 mmol), 0.585 ml of 2-methylfuran (6.5 mmol), 0.047 g of Cu (OAc) ₂ (0.26 mmol) and 8.5 ml of 1,2-dichloroethane was stirred on a magnetic stirrer at room temperature for 4 hours. The reaction mass is filtered through a thin layer of silica gel (Macherey-Nagel brand, fraction 40-63 μm), washed with CH ₂ Cl ₂ (10 ml) and the solvent is removed under reduced pressure. The target 3- (5-methylfur-2-yl) -1,3-diphenylpropan-1-one was isolated by silica gel column chromatography (Macherey-Nagel brand, fraction 40-63 μm), eluent CH ₂ Cl ₂ / petroleum ether (1: 9). Yield 0%.

Example 4

A mixture of 0.540 g of benzylideneacetophenone (2.6 mmol), 0.585 ml of 2-methylfuran (6.5 mmol), 0.035 g of CuCl ₂ (0.26 mmol) and 8.5 ml of 1,2-dichloroethane was stirred on a magnetic stirrer at room temperature for 4 hours. The reaction mass is filtered through a thin layer of silica gel (Macherey-Nagel brand, fraction 40-63 μm), washed with CH ₂ Cl ₂ (10 ml) and the solvent is removed under reduced pressure. The target 3- (5-methylfur-2-yl) -1,3-diphenylpropan-1-one was isolated by silica gel column chromatography (Macherey-Nagel brand, fraction 40-63 μm), eluent CH ₂ Cl ₂ / petroleum ether (1: 9). Yield 48% (0.362 g).

Example 5

A mixture of 0.540 g of benzylideneacetophenone (2.6 mmol), 0.585 ml of 2-methylfuran (6.5 mmol), 0.049 ml of HBr (43% w / w, 0.26 mmol) and 8.5 ml of 1,2-dichloroethane was stirred on a magnetic stirrer at room temperature for 4 hours. The reaction mass is filtered through a thin layer of silica gel (Macherey-Nagel brand, fraction 40-63 μm), washed with CH ₂ Cl ₂ (10 ml) and the solvent is removed under reduced pressure. The target 3- (5-methylfur-2-yl) -1,3-diphenylpropan-1-one was isolated by silica gel column chromatography (Macherey-Nagel brand, fraction 40-63 μm), eluent CH ₂ Cl ₂ / petroleum ether (1: 9). Yield 52% (0.393 g).

Example 6

A mixture of 0.540 g of benzylideneacetophenone (2.6 mmol), 0.585 ml of 2-methylfuran (6.5 mmol), 0.021 ml of HCl (38% w / w, 0.26 mmol) and 8.5 ml of 1,2-dichloroethane was stirred on a magnetic stirrer at room temperature for 4 hours. The reaction mixture is filtered through a thin pad of silica gel (grade Macherey-Nagel, fraction 40-63 micron), washed with CH ₂ Cl ₂ (10 mL) and the solvent removed under reduced pressure. The target 3- (5-methylfur-2-yl) -1,3-diphenylpropan-1-one was isolated by silica gel column chromatography (Macherey-Nagel brand, fraction 40-63 μm), eluent CH ₂ Cl ₂ / petroleum ether (1: 9). Yield 18% (0.136 g).

Example 7

A mixture of 0.540 g of benzylideneacetophenone (2.6 mmol), 0.585 ml of 2-methylfuran (6.5 mmol), 0.015 ml of glacial acetic acid (0.26 mmol) and 8.5 ml of 1,2-dichloroethane was stirred on a magnetic stirrer at room temperature for 4 hours. The reaction mass is filtered through a thin layer of silica gel (Macherey-Nagel brand, fraction 40-63 μm), washed with CH ₂ Cl ₂ (10 ml) and the solvent is removed under reduced pressure. Task 3- (5-furo-2-yl) -1,3-diphenylpropane-1-one was isolated by column chromatography on silica gel (brand Macherey-Nagel, fraction 40-63 um), eluting with - CH ₂ Cl ₂ / petroleum ether (1: 9). Yield 5% (0.038 g).

Example 8

A mixture of 0.540 g of benzylideneacetophenone (2.6 mmol), 0.585 ml of 2-methylfuran (6.5 mmol), 0.058 g of copper (II) bromide (0.26 mmol) and 8.5 ml of 1,4-dioxane was stirred on a magnetic stirrer at room temperature for 4 hours. The reaction mixture is filtered through a thin pad of silica gel (grade Macherey-Nagel, fraction 40-63 micron), washed with CH ₂ Cl ₂ (10 mL) and the solvent removed under reduced pressure. The target 3- (5-methylfur-2-yl) -1,3-diphenylpropan-1-one was isolated by silica gel column chromatography (Macherey-Nagel brand, fraction 40-63 μm), eluent CH ₂ Cl ₂ / petroleum ether (1: 9). Yield 0%.

Example 9

A mixture of 0.540 g of benzylideneacetophenone (2.6 mmol), 0.585 ml of 2-methylfuran (6.5 mmol), 0.058 g of copper (II) bromide (0.26 mmol) and 8.5 ml of dimethylformamide was stirred on a magnetic stirrer at room temperature for 4 hours. The reaction mass is filtered through a thin layer of silica gel (Macherey-Nagel brand, fraction 40-63 μm), washed with CH ₂ Cl ₂ (10 ml) and the solvent is removed under reduced pressure. The target 3- (5-methylfur-2-yl) -1,3-diphenylpropan-1-one was isolated by silica gel column chromatography (Macherey-Nagel brand, fraction 40-63 μm), eluent CH ₂ Cl ₂ / petroleum ether (1: 9). Yield 0%.

Example 10

A mixture of 0.540 g of benzylideneacetophenone (2.6 mmol), 0.585 ml of 2-methylfuran (6.5 mmol), 0.058 g of copper (II) bromide (0.26 mmol) and 8.5 ml of 1,2-dichloroethane was stirred on a magnetic stirrer at room temperature for 3 hours. The reaction mass is filtered through a thin layer of silica gel (Macherey-Nagel brand, fraction 40-63 μm), washed with CH ₂ Cl ₂ (10 ml) and the solvent is removed under reduced pressure. Task 3- (5-furo-2-yl) -1,3-diphenylpropane-1-one was isolated by column chromatography on silica gel (brand Macherey-Nagel, fraction 40-63 um), eluting with - CH ₂ Cl ₂ / petroleum ether (1: 9). Yield 50% (0.378 g).

Example 11

A mixture of 0.540 g of benzylideneacetophenone (2.6 mmol), 0.585 ml of 2-methylfuran (6.5 mmol), 0.058 g of copper (II) bromide (0.26 mmol) and 8.5 ml of 1,2-dichloroethane was stirred on a magnetic stirrer at room temperature for 12 hours. The reaction mass is filtered through a thin layer of silica gel (Macherey-Nagel brand, fraction 40-63 μm), washed with CH ₂ Cl ₂ (10 ml) and the solvent is removed under reduced pressure. The target 3- (5-methylfur-2-yl) -1,3-diphenylpropan-1-one was isolated by silica gel column chromatography (Macherey-Nagel brand, fraction 40-63 μm), eluent CH ₂ Cl ₂ / petroleum ether (1: 9). Yield 72% (0.554 g).

Table 2 shows the effect of the reaction conditions on the yield of 3- (5-methylfur-2-yl) -1,3-diphenylpropan-1-one 1a (examples 1-11).

As can be seen from table 2, the result, namely, obtaining 3- (5-methyl-fur-2-yl) -1,3-diphenylpropan-1-one 1a, with the highest possible yield can be achieved by stirring a mixture of the starting compounds at room temperature in 1,2-dichloroethane in the presence of 10 mol.% copper (II) bromide for 4 hours. The use of such catalysts as CuSO ₄ , Cu (OAc) ₂ , CuCl ₂ , HBr, HCl or AcOH in 1,2-dichloroethane at room temperature, as well as the replacement of the solvent with DMF or 1,4-dioxane, does not allow one to isolate the target product with higher output.

Thus, by method 1, a number of derivatives of 3- (5-methylfur-2-yl) -1,3-diphenylpropan-1-one 1a-k were obtained in yields of 42-83%.

Claims (1)

The method of obtaining derivatives of 3-furylpropan-1-ones of the General formula 1,

characterized in that a mixture of available α, β-unsaturated carbonyl compounds, 2-methylfuran, copper (II) bromide is stirred in 1,2-dichloroethane at room temperature for 4 hours.