RU2646222C2 - Method of producing 2-[(oxyphenyl)methyl]butane-1,4-diols - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to the method of producing 2-[(oxyphenyl)methyl]butane-1,4-diols of the general formula (1a-d)

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a) R₁=R₃=H, R₂=OMe; b) R₁=H, R₂=R₃=OMe; c) R₁=H, R₂=OMe, R₃=OH; d) R₁=R₂=R₃=OMe, which are used in the synthesis γ-butyrolactones, lignans, 3-(arylmethyl) pyrrolidines. The method consists in the reaction of allylarene with triethylaluminum (AlEt₃) in the presence of a catalyst Cp₂ZrCl₂ followed by oxidation and hydrolysis. Herewith substituted allylbenzene (allylanisole, 4-allyl-1,2-dimethoxybenzene, 4-allyl-2-methoxyphenol (eugenol), 5-allyl-1,2,3-trimethoxybenzene) are used as allylarene, the reaction is conducted at a molar ratio of allylarene: AlEt₃: [Zr] = 50:(150-180):(1-2), at a temperature of 22°C and an atmospheric pressure for 16 hours in toluene, the subsequent oxidation is carried out with dry O₂ for 24 h, and the hydrolysis is carried out using the 10% HCl solution.

EFFECT: increasing the output of target products.

1 tbl, 19 ex

Description

The invention relates to a method for producing β-substituted 1,4-butanediols, specifically to a method for producing 2 - [(hydroxyphenyl) methyl] butane-1,4-diols of general formula (1a-d):

The developed method opens up a new path to the production of practically important 2-benzyl substituted 1,4-butanediols used in the synthesis of γ-butyrolactones, lignans ([1] Dhal R., Landais Y., Lebrun A., Robin J.-P., Tetrahedron 1994, V. 50, No. 4, P. 1153-1164; [2] Ward RS Recent advances in the chemistry of lignans. In the book: Studies in Natural Products Chemistry (Ed. By Atta-ur-Rahman), 2000, V. 24, Part E, P.739-798; [3] Ito ML, Shiibashi A., Ikariya T., Chem. Commun., 2011, V. 47, P. 2134-2136), as well as 3- ( arylmethyl) -pyrrolidines ([4] patent EP 562185 A1).

The known method ([5] Shao L., Miyata Sh., Muramatsu H., Kawano H., Ishii Y., Saburi M, Uchida Y., J. Chem. Soc. Perkin Trans. 1990. - V. 1. - P. 1441-1445) for the preparation of 2 - [(hydroxyphenyl) methyl] butane-1,4-diols in 80-85% yield by reduction of benzyl substituted succinic acids with LiAlH ₄ in THF while boiling in a nitrogen atmosphere for 1 h according to the scheme :

The disadvantages of the method include the use of hard-to-reach benzyl substituted succinic acids as starting compounds.

The known method ([6] Ito M., Ootsuka T., Watari R., Shiibashi A., Himizu A., Ikariya T., J. Am. Chem. Soc, 2011, V. 133, P. 4240-4242, patents WO 2010/004883 A1, EP 2298723 A1) for the preparation of 2-phenyl-1,4-butanediol in the hydrogenation of 3-phenyltetrahydrofuran-2-one with molecular hydrogen at a pressure of 5 MPa in the presence of KO ^t BU and a Cp * RuCl catalyst N- * C ₂ -N) in isopropyl alcohol at a temperature of 100 ° C for 12-15 hours:

As disadvantages, the necessity of carrying out the reaction at high pressure and temperature, as well as the use of expensive ruthenium catalyst and hard-to-reach benzyl substituted γ-butyrolactones, should be noted.

A known method ([7] Kamlage S., Sefkow M., Zimmermann N., Peter MG, Synlett, 2002, No. 1, P. 77-80) synthesis of 2 - [(hydroxyphenyl) methyl] butane-1,4- diols 1d, e, gk by reduction of 2-benzyl-1,4-butenediols with H ₂ at a pressure of 100 bar with a substrate conversion of 100% in the presence of 3-5 mol. % Ir (I) -phosphinoxazoline catalysts for 2 hours according to the scheme:

The disadvantages of the method include the use of hard-to-reach 2-benzylbut-2-en-1,4-diols as starting compounds, the use of an expensive iridium-based catalyst, and the reaction at high pressure.

Closest to the invention is the method ([8] Dzhemilev U.M., Ibragimov A.G., Zolotarev A.P., Musloukhov PP, Tolstikov G.A., Izv. AN SSSR, Ser. Chem. - 1990. - No. 10. - S. 2831-2841) for the preparation of 2-benzyl-1,4-diol (1g) in the reaction of AlEt ₃ with allylbenzene in the presence of a Cp ₂ ZrCl ₂ catalyst taken in the molar ratio alkene: AlEt ₃ : Cp ₂ ZrCl ₂ = 100: 120: 2, for 10 hours at room temperature, followed by oxidation of the reaction mass with dry air and hydrolysis with an aqueous solution of NaOH:

The known method does not allow to obtain 2 - [(hydroxyphenyl) methyl] butane-1,4-diols (1a-d) in sufficient yield.

Thus, in the literature there is no information on the single-reactor synthesis of 2 - [(hydroxyphenyl) methyl] butane-1,4-diols (1a-d) from substituted allylbenzenes, and the existing method leads to a low yield of target products.

The objective of the invention is to develop a one-reactor method for producing 2 - [(hydroxyphenyl) methyl] butane-1,4-diols (1a-d) in the reaction of substituted allylbenzenes with triethylaluminum (AlEt ₃ ) in the presence of a Cp ₂ ZrCl ₂ catalyst, followed by dry oxidation of the reaction mass O ₂ and hydrolysis with HCl.

The essence of the method consists in the interaction of substituted allylbenzenes (allylanizole, 4-allyl-1,2-dimethoxybenzene, 4-allyl-2-methoxyphenol (eugenol), 5-allyl-1,2,3-trimethoxybenzene) with triethylaluminum (AlEt ₃ ) in the presence of a Cp ₂ ZrCl ₂ catalyst, taken in an alkene: AlEt ₃ molar ratio: [Zr] = 50: (150-180) :( 1-2) in an argon atmosphere at room temperature (~ 22 ° C) and atmospheric pressure in toluene for 16 hours, followed by oxidation with dry O ₂ and hydrolysis with a 10% HCl solution. The yield of the target product (la-d) is 60-65%. The reaction proceeds according to the scheme:

2-Benzyl-1,4-butanediols (1a-d) are formed as a result of two-step synthesis without isolation of intermediate products. In the first stage, oxygen-containing allylbenzenes, AlEt ₃ and Cp ₂ ZrCl _{2 are used} as a catalyst. In the second stage, gaseous oxygen is used. In the presence of other organoaluminum compounds (for example, AlMe ₃ , AlBu ⁱ ₃ , Et ₂ AlCl), the desired products (la-d) are not formed. The use of other transition metal complexes as catalysts, for example, ZrCl ₄ , Zr (acac) ₄ , Cp ₂ TiCl ₂ , Pd (acac) ₂ , Ni (acac) ₂ , does not lead to the formation of 2-benzyl-1,4-butanediols ( 1a-d). The use of other oxidizing agents, for example, H ₂ O ₂ in KOH, leads to a decrease in yield (1a-d) (Table 1). An increase in the temperature of the oxidation reaction to 40 ° C or the addition of catalytic amounts of Ti (O ⁱ Pr) ₄ during oxidation does not significantly increase the yield (1a-d).

The reaction was carried out with stirring on a magnetic stirrer, at a temperature of ~ 22 ° C. At temperatures above 40 ° C, the rate of adverse reactions increases. Lowering the temperature reduces the yield (1a-d) and also increases the reaction time.

The reaction in the presence of a catalyst Cp ₂ ZrCl ₂ more than 4 mol. % with respect to olefin does not lead to a significant increase in the yield of the target product (1a-d). The decrease in catalyst concentration of less than 2 mol. % causes a decrease in the reaction rate and the yield of alcohols (1a-d).

A change in the ratio of starting reagents in the direction of decreasing the initial concentration of AlEt ₃ leads to a decrease in the reaction rate and yield of the target product (1a-d). An increase in the initial concentration of AlEt ₃ does not lead to a significant increase in yield (1a-d).

Significant differences of the proposed method:

1. The proposed method is based on the use of substituted allylbenzenes (allylanizole, 4-allyl-1,2-dimethoxybenzene, 4-allyl-2-methoxyphenol (eugenol), 5-allyl-1,2,3-trimethoxybenzene as starting reagents). The reaction takes place in toluene. In the known method, unsubstituted allylbenzene is used. The reaction is analogous without solvent.

2. In the proposed method, dry O _{2 is used} , and hydrolysis is carried out using a 10% HCl solution. In the known method, dry air is used in the oxidation step, and the reaction mass is hydrolyzed with an aqueous solution of NaOH.

3. The proposed method uses a molar ratio of the starting reagents alkene: AlEt ₃ : [Zr] = 50: (150-180) :( 1-2), whereas in the known methods the ratio of alkene: AlEt ₃ : [Zr] is 100: 120: 2.

The proposed method has the following advantages:

1. The method provides the desired products - 2 - [(hydroxyphenyl) methyl] butane-1,4-diols with a yield of 60-65%).

The method is illustrated by the following example:

General technique. In a 10 ml glass reactor mounted on a magnetic stirrer, 0.06-0.12 mmol of Cp ₂ ZrCl ₂ catalyst, 3 mmol of substituted allylbenzene and 9-10.8 mmol of AlEt ₃ (25% solution in toluene) are placed in an argon atmosphere. The reaction is carried out at a temperature of 20-22 ° C with continuous stirring for 16 hours. The flask was cooled to 0 ° C and dry O _{2 was} bubbled in for 2 hours. The reaction mass was then stirred in an oxygen atmosphere for another 24 hours. The resulting mixture was hydrolyzed with a 10% HCl solution. The product is extracted with diethyl ether. The organic layer was dried over Na ₂ SO ₄ . The resulting alcohols are isolated by column chromatography on silica gel. The yield 1a-d is 60-65%.

Example 1. In a 10 ml glass reactor mounted on a magnetic stirrer, 35 mg (0.12 mmol) of Cp ₂ ZrCl ₂ catalyst, 0.46 ml of allylanizole and 5.8 ml of AlEt ₃ (25% solution in toluene) were placed under argon atmosphere. The reaction is carried out at a temperature of 20-22 ° C with continuous stirring for 16 hours. The flask was cooled to 0 ° C and dry O _{2 was} bubbled in for 2 hours. The reaction mass was then stirred in an oxygen atmosphere for another 24 hours. The resulting mixture was hydrolyzed with a 10% HCl solution. The product is extracted with diethyl ether. The organic layer was dried over Na ₂ S0 ₄ . The product was isolated by silica gel column chromatography. Get alcohol 1A with a yield of 65% (Table. 1, No. 4).

Examples 2, 3 and 4 for 4-allyl-1,2-dimethoxybenzene, 4-allyl-2-methoxyphenol and 5-allyl-1,2,3-trimethoxybenzene are carried out analogously to example 1. The results are shown in table 1: No. 11 , 14 and 17.

Spectral characteristics 1a-d.

2 - [(4-Methoxyphenyl) methyl] butane-1,4-diol (1a). ¹ H NMR (400.13 MHz, CDCl ₃ ) δ _H 1.49-1.61 (m, CHCHHO, 1H), 1.61-1.72 (m, CHCHHO, 1H), 1.84-1.97 (m, CH, 1H), 2.47 (dd, ² J = 13.6 Hz, ³ J = Hz, CHHPh, 1H), 2.59 (dd, ² J = 13.6 Hz, ³ J = Hz, CHHPh, 1H), 3.42 (dd, ² J = 10.8 Hz, ³ J = 7.2 Hz , OCHHCH, 1H), 3.52-3.64 (m, OCHHCHCH ₂ CHHO, 2H), 3.65-3.75 (m, CH ₂ CHHO, 1H), 3.78 (s, OCH ₃ , 3H), 6.82 (d, ³ J = 8.4 Hz, Ph, 2H), 7.08 (d, ³ J = 8.4 Hz, Ph, 2H). ¹³ C NMR (100.62 MHz, CDCl ₃ ) δ _C 35.2 (C ³ ), 37.2 (C ⁵ ), 41.4 (C ² ), 55.2 (OCH ₃ ), 60.8 (C ⁴ ), 65.4 (C ¹ ), 113.8, 130.0, 132.4, 157.8 (Ph).

2 - [(3,4-Dimethoxyphenyl) methyl] butane-1,4-diol (1b). ¹ H NMR (400.13 MHz, CDCl ₃ ) δ _H 1.52-1.64 (m, CHCHH, 1H), 1.66-1.76 (m, CHCHH, 1H), 1.90-2.00 (m, CH, 1H), 2.49 (dd, ² J = 14.0 Hz, ³ J = 7.60 Hz, CHHPh, 1H), 2.61 (dd, ² J = 14.0 Hz, ³ J = 6.4 Hz, CHHPh, 1H), 3.47 (dd, ² J = 10.8 Hz, ³ J = 6.8 Hz, OCHHCH, 1H), 3.58-3.68 (m, OCHHCHCH ₂ CHHO, 2H), 3.72-3.80 (m, CH ₂ CHHO, 1H), 3.85 (s, OCH ₃ , 3H), 3.86 (s, OCH ₃ , 3H), 6.67-6.73 (m, Ph, 2H), 6.78 (d, ³ J = 8.8 Hz, Ph, 1H). ¹³ C NMR (100.62 MHz, CDCl ₃ ) δ _C 35.3 (C ³ ), 37.9 (C ⁵ ), 41.3 (C ² ), 55.86 (OCH ₃ ), 55.91 (OCH ₃ ), 61.0 (C ⁴ ), 65.5 ( C ¹ ), 111.2, 112.3, 121.1, 132.9, 147.3, 148.8 (Ph).

2 - [(3-Hydroxy-4-methoxy-phenyl) methyl] butane-1,4-diol (1c). NMR ¹ H (400.13 MHz, CDCl ₃ ) δ _H 1.56-1.68 (m, CHCHH, 1H), 1.69-1.80 (m, CHCHH, 1H), 1.93-2.03 (m, CH, 1H), 2.51 (dd, ² J = 14.0 Hz, ³ J = 6.8 Hz, CHHPh, 1H), 2.63 (dd, ² J = 14.0 Hz, ³ J = 7.6 Hz, CHHPh, 1H), 3.53 (dd, 2J = 11.2 Hz, ³ J = 7.2 Hz, OCHHCH, 1H), 3.52-3.64 (m, OCHHCHCH ₂ CHHO, 2H), 3.77-3.86 (m, CH ₂ CHHO, 1H), 3.90 (s, OCH ₃ , 3H), 6.68 (d, ³ J = 7.8 Hz, Ph, 1H), 6.70 (s, Ph, 1H), 6.85 (d, ³ J = 7.8 Hz, Ph, 1H). ¹³ C NMR (100.62 MHz, CDCl ₃ ) δ _C 35.2 (C ³ ), 38.0 (C ⁵ ), 41.4 (C ² ), 55.9 (OCH ₃ ), 61.2 (C ⁴ ), 65.6 (C ¹ ), 111.5, 114.4, 121.7, 132.1, 143.9, 146.4 (Ph).

2 - [(3,4,5-Trimethoxyphenyl) methyl] butane-1,4-diol (1d). ¹ H NMR (400.13 MHz, CDCl ₃ ) δ _H 1.57-1.70 (m, CHCHH, 1H), 1.71-1.83 (m, CHCHH, 1H), 1.95-2.08 (m, CH, 1H), 2.53 (dd, ² J = 10.6 Hz, ³ J = 7.6 Hz, CHHPh, 1H), 2.65 (dd, ² J = 10.6 Hz, ³ J = 7.4 Hz, CHHPh, 1H), 3.55 (dd, ² J = 10.6 Hz, ³ J = 4.8 Hz, OCHHCH, 1H), 3.66-3.73 (m, OCHHCH, 1H, 2H), 3.66-3.75 (m, CH ₂ CHHO, 1H), 3.79-3.82 (m, CH ₂ CHHO, 1H), 3.87 (s , OCH ₃ , 6H), 3.85 (s, OCH ₃ , 3H), 6.41 (s, Ph, 2H). ¹³ C NMR (100.62 MHz, CDCl ₃ ) δ _C 35.3 (C ³ ), 38.7 (C ⁵ ), 41.2 (C ² ), 56.1 (OCH ³ ), 60.9 (C ⁴ ), 61.2 (OCH ₃ ), 65.6 ( C ¹ ), 106.0, 136.1, 153.1 (Ph).

Claims (3)

The method of obtaining 2 - [(hydroxyphenyl) methyl] butane-1,4-diols of General formula (1a-d):

the interaction of allylarene with triethylaluminum (AlEt ₃ ) in the presence of a Cp ₂ ZrCl ₂ catalyst, followed by oxidation and hydrolysis, characterized in that substituted allylbenzenes (allylanizole, 4-allyl-1,2-dimethoxybenzene, 4-allyl-2- methoxyphenol (eugenol), 5-allyl-1,2,3-trimethoxybenzene), the reaction is carried out at a molar ratio of allylarene: AlEt ₃ : [Zr] = 50: (150-180) :( 1-2), temperature 22 ° C and atmospheric pressure for 16 hours in toluene, subsequent oxidation is carried out with dry O ₂ for 24 hours, hydrolysis is carried out using 10% sol RA HCl.