A method for asymmetric hydrogenation of an amide directed naphthalene compound to synthesize tetrahydronaphthalene compounds

Abstract

The application discloses a method for synthesizing tetrahydronaphthalene compounds through asymmetric hydrogenation of amide-oriented naphthalene compounds. The method realizes high-yield and high-enantiomeric-selectivity synthesis of tetrahydronaphthalene compounds through asymmetric hydrogenation of amide-oriented naphthalene compounds catalyzed by 5%-10% ruthenium and a biphosphine ligand. The catalyst used in the application is cheap and easy to obtain, and the reaction condition is relatively mild, and excellent yield and enantiomeric selectivity can be obtained, and the application has potential practical value.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric catalytic synthesis and relates to a method for the asymmetric hydrogenation synthesis of tetrahydronaphthalene compounds by amide-directed naphthalene compounds, providing a method for the synthesis of tetrahydronaphthalene compounds with high enantioselectivity. Technical Background

[0002] Asymmetric hydrogenation of aromatic carbocyclic compounds provides a concise and efficient route for the synthesis of chiral cyclic compounds. Compared with other aromatic carbocyclic compounds, the asymmetric hydrogenation of naphthalene rings faces challenges not only in strong aromaticity and difficulty in controlling enantioselectivity, but also in controlling regioselectivity. Currently, only a few examples of transition metal-catalyzed homogeneous asymmetric hydrogenation of naphthalene rings have been reported. In 2012, Kuwano's group first achieved ruthenium-catalyzed asymmetric hydrogenation of 2-naphthalene ethers, yielding a series of centrally chiral tetrahydronaphthalene compounds with good to excellent enantioselectivity. To control the regioselectivity of the reaction, the substrate range was mainly concentrated on symmetrical 2,6-disubstituted naphthalene compounds. Ten years later, Researcher Yonggui Zhou of the Dalian Institute of Chemical Physics achieved the kinetic resolution of 1-substituted naphthalenes through hydrogenation using rhodium and bisphosphine ligands as catalysts, constructing a series of axially chiral biaryl compounds. In the same year, Chirik's group reported the asymmetric hydrogenation of heteroatom-free naphthalene compounds catalyzed by molybdenum and pincer ligands, yielding a series of decahydronaphthalene compounds. However, excellent enantioselectivity was only achieved when the 2 and 6 positions of the naphthalene ring were methyl or ethyl. In summary, current asymmetric hydrogenation of naphthalene rings mainly focuses on symmetrical naphthalene ring compounds or axially chiral naphthalene ring compounds. High regio- and enantioselective asymmetric hydrogenation of asymmetric naphthalene ring compounds has not yet been achieved. (Reference 1: (a) Urban, S.; Ortega, N.; Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 3803-3806. (b) Kuwano, R.; M orioka, R.; Kashiwabara, M.; Kameyama, N. Angew. Chem. Int. Ed. 2012, 51, 4136-4139. (c) Viereck, P.; Hie rlmeier,G.;Tosatti,P.;Pabst,TP;Puentener,K.Chirik,PJJAm.Chem.Soc.2022,144,11203-11214.(d) Ding, Y.-X.; Zhu, Z.-H.; Chen, M.-W.; Yu, C.-B.; Zhou, Y.-G. Angew. Chem. Int. Ed. 2022, 61, e202205623.). Summary of the Invention

[0003] To address the challenge of asymmetric hydrogenation of naphthalene ring compounds, this invention provides a method for the asymmetric hydrogenation synthesis of tetrahydronaphthalene rings via amide-directed hydrogenation. An amide-directing group is introduced into the naphthalene ring compound. Through the interaction between the directing group and a chiral ruthenium catalyst, the interaction between the naphthalene ring and the catalyst is enhanced, thereby achieving highly stereoselective and regioselective hydrogenation of the naphthalene ring. This invention is simple and practical to operate, uses readily available raw materials, exhibits good enantioselectivity, high yield, and the reaction is green, atom-economical, environmentally friendly, and has potential practical value.

[0004] The technical solution of the present invention is as follows:

[0005] A method for the asymmetric hydrogenation synthesis of tetrahydronaphthalene compounds via amide-directed naphthalene compounds, wherein the method uses a complex of ruthenium, chiral bisphosphine and an acid as a catalyst, and 2-substituted naphthalene compounds as substrates to asymmetricly hydrogenate and synthesize chiral tetrahydronaphthalene compounds.

[0006] The reaction formula is as follows:

[0007]

[0008] In the formula:

[0009] R is a C1-C10 alkyl, aryl, methoxy, benzyl, or halogen, and C1-C10 alkyl includes methyl, ethyl, and propyl;

[0010] R 1 It is a C1-C10 alkyl, aryl, methoxy, benzyl, or halogen, and C1-C10 alkyl includes methyl, ethyl, and propyl;

[0011] Ar is a benzene ring or an aromatic ring containing substituents, wherein the substituents are C1-C10 alkyl, aryl, methoxy, benzyl or halogen, and C1-C10 alkyl includes methyl, ethyl, propyl;

[0012] n is 1 or 2;

[0013] The catalyst is a complex of a ruthenium metal precursor, a chiral bisphosphine ligand, and an acid.

[0014] Based on the above technical solution, preferably, the reaction solvent is an organic solvent, which is one or more of 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, trifluoroethanol, and isopropanol; preferably isopropanol.

[0015] Based on the above technical solutions, the preferred reaction temperature is 25-70℃, preferably 60℃; the reaction time is 24-120 hours, preferably 72 hours; and the hydrogen pressure is 400-1000psi, preferably 800psi.

[0016] Based on the above technical solution, preferably, the molar ratio of 2-substituted naphthalene compound, ruthenium precursor, chiral bisphosphine ligand and acid is 1:0.01:0.011:0.02-1:0.2:0.22:0.4, and more preferably 1:0.1:0.11:0.2; the amount of organic solvent used is 0.5-6 mL of organic solvent per 0.05-0.4 mmol of 2-substituted naphthalene compound, and more preferably 2 mL of organic solvent per 0.20 mmol of 2-substituted naphthalene compound.

[0017] Based on the above technical solutions, preferably, the ruthenium precursor is bis(2-methylallyl)(1,5-cyclooctadiene)ruthenium(II).

[0018] Based on the above technical solution, preferably, the chiral bisphosphine ligand is (R)-(+)-(6,6'-dimethoxybiphenyl-2,2'-yl)bis(diphenylphosphine)L1, (S,S,R ax (R)-C3*-TunePhos L2, (+)-1,2-bis((2S,5S)-2,5-dimethylphosphine)benzene L3, (1R,1'R,2S,2'S)-2,2'-di-tert-butyl-2,3,2'3'-tetrahydro-1H,1'H-(1,1')diisophosphine L4, (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocene]ethyldicyclohexylphosphine L5, (R)-4,12-bis(diphenylphosphino)[2.2]p-cycloarane L6, preferably (R)-4,12-bis(diphenylphosphino)[2.2]p-cycloarane L6.

[0019] Based on the above technical solutions, preferably, the acid is one of tetrafluoroboric acid (HBF4), hexafluorophosphate, trifluoroacetic acid, and trifluoromethanesulfonic acid.

[0020] Based on the above technical solution, preferably, the catalyst is prepared by stirring a ruthenium precursor, a chiral bisphosphine ligand, and an acid in a solvent at room temperature for 10-60 minutes under nitrogen or argon protection. The solvent is one or more of 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, trifluoroethanol, and isopropanol, preferably isopropanol.

[0021] Based on the above technical solution, preferably, the specific reaction steps of the method are as follows: adding 2-substituted naphthalene compounds, in-situ prepared catalysts and solvents into a reaction flask, placing the reaction flask into a high-pressure reactor, introducing H2 to react and obtain hydrogenated products, and purifying them to obtain pure products.

[0022] Based on the above technical solution, preferably, the purification step is as follows: after releasing hydrogen gas, the solvent is evaporated, and the pure product is obtained by column chromatography.

[0023] The method of this invention enables the asymmetric hydrogenation of amide-directed naphthalene compounds catalyzed by ruthenium (5%-10% ruthenium and bisphosphine ligands), yielding tetrahydronaphthalene compounds with central chirality in high yield and with high enantioselectivity (enantiomeric excess up to 92%). This invention features high enantioselectivity, simple and practical operation, readily available raw materials, inexpensive and readily available catalysts, mild reaction conditions, excellent yields, low energy consumption, environmental friendliness, and potential practical value.

[0024] Beneficial effects

[0025] 1. The raw materials are simple and readily available, the catalyst is easy to prepare, and the reaction operation is simple and practical.

[0026] 2. It has high reactivity, complete conversion of raw materials, convenient separation, and can obtain high-purity products.

[0027] 3. It exhibits good regional selectivity and enantioselectivity.

[0028] 4. The reaction conditions are mild and environmentally friendly. Detailed Implementation

[0029] The present invention is described in detail below through embodiments, but the present invention is not limited to the embodiments described below.

[0030] References for the synthesis of 2-substituted naphthalene compounds in the following examples: (a) Strasser, M.; Cooper, P.; Devald, B.; Paynea, T. Helv. Chimica Acta 1988, 71, 1156-1176. (b) Zhao, W.; Huang, L.; Guan, Y.; Wulff, W. Angew. Chem. Int. Ed. 2014, 53, 3436-3441. (c) Li, C.; Zhao, P.; Li, R.; Zhang, B.; Zhao, W. Angew. Chem. Int. Ed. 2020, 59, 10913-10917. (d) Hama, T.; Culkin, DA.; Hartwig, J. F. A. M. Chem. Soc. 2006, 128, 4976-4985.

[0031] Examples 1-13

[0032] Condition optimization: changing the organic solvent, temperature, and type of chiral ligand.

[0033] In a reaction flask, 0.01 mmol (5.0 mol%) of bis(2-methylallyl)(1,5-cyclooctadiene)ruthenium(II), 0.011 mmol (5.5 mol%) of chiral ligand L, and 0.02 mmol (10 mol%) of tetrafluoroboric acid were added. After purging with nitrogen, 1 mL of solvent was added, and the mixture was stirred at room temperature for 30 minutes to prepare the catalyst in situ. In a glove box, a reaction flask pre-filled with substrate 2-substituted naphthalene 1a (0.20 mmol) was added to the in-situ prepared catalyst and 1 mL of solvent. The flask was placed in an autoclave, and hydrogen gas (800 psi) was introduced. The reaction was carried out at a controlled temperature for 24 hours. After cooling to room temperature, hydrogen gas was slowly released, the solvent was removed by rotary evaporation, and the pure product was obtained by column chromatography.

[0034] The organic solvent, temperature, and type of chiral ligand are shown in Table 1; ee represents enantioselectivity.

[0035]

[0036] Table 1.2 - Optimization of asymmetric hydrogenation reaction conditions for substituted naphthalene 1a

[0037]

[0038]

[0039] Examples 14-24

[0040] Condition optimization: changing the organic solvent, acid, reaction time, and catalyst dosage.

[0041] In a reaction flask, di(2-methylallyl)(1,5-cyclooctadiene)ruthenium(II) (x mol%), chiral ligand L6 (1.1 x mol%), and acid (2 x mol%) were added. After purging with nitrogen, 1 mL of solvent was added, and the mixture was stirred at room temperature for 30 minutes to prepare the catalyst in situ. In a glove box, a reaction flask pre-filled with substrate 2-substituted naphthalene 1b (0.20 mmol) was added to the in-situ prepared catalyst and 1 mL of solvent. The flask was placed in an autoclave, and hydrogen gas (800 psi) was introduced. The reaction was carried out at 60 °C for a certain time. After cooling to room temperature, hydrogen gas was slowly released, the solvent was removed by rotary evaporation, and the pure product was obtained by column chromatography.

[0042] Organic solvents, temperature, and types of chiral ligands are considered, with specific results shown in Table 2; ee represents enantioselectivity.

[0043]

[0044] Table 2.2 - Optimization of asymmetric hydrogenation reaction conditions for substituted naphthalene 1b

[0045]

[0046] Examples 25-36

[0047] Asymmetric hydrogenation of 2-substituted naphthalene.

[0048] Di(2-methylallyl)(1,5-cyclooctadiene)ruthenium(II) (0.02 mmol, 10 mol%), (R)-4,12-bis(diphenylphosphino)[2.2]-p-cycloarane L6 (0.022 mmol, 11 mol%), and tetrafluoroborate (0.04 mmol, 20 mol%) were added to a reaction flask, purged with nitrogen, and 1 mL of isopropanol was added. The mixture was stirred at room temperature for 30 minutes to prepare the catalyst in situ. In a glove box, a reaction flask containing substrate 2-substituted naphthalene 1 (0.20 mmol) was placed, and the in-situ prepared catalyst and 1 mL of isopropanol were added. The flask was then placed in a high-pressure reactor, and hydrogen gas (800 psi) was introduced. The reaction was carried out at 60 °C for 72 hours. The mixture was then cooled to room temperature, and hydrogen gas was slowly released. The solvent was removed by rotary evaporation, and the pure product was obtained by column chromatography.

[0049] Examples of 13 different tetrahydronaphthalene compounds 2 were obtained by changing only the type of 1 containing a 2-substituted naphthalene compound. The specific types of compounds changed are as follows:

[0050]

[0051] The reaction temperature for 2h, 2k, 2l, and 2m is 80℃, and the reaction time for 2k-m is 120 hours.

[0052] The absolute configuration of 2c was determined by X-ray diffraction to be S. The CCDC number is 2123701.

[0053] _____________________________________________________________________

[0054] (-)-N,N-Diethyl-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide(2b):

[0055]

[0056]

[0057]

[0058]

Claims

1. A method for the asymmetric hydrogenation synthesis of tetrahydronaphthalene compounds via amide-directed naphthalene compounds, characterized in that, The method uses a complex of ruthenium, chiral bisphosphine, and acid as a catalyst, and 2-substituted naphthalene compounds as substrates to synthesize chiral tetrahydronaphthalene compounds through asymmetric hydrogenation. The reaction formula is as follows: or In the formula: R is a C1-C10 alkyl, aryl, methoxy, benzyl, or halogen. R 1 It is a C1-C10 alkyl, aryl, methoxy, benzyl, or halogen group; Ar is a benzene ring or an aromatic ring containing a substituent, wherein the substituent is a C1-C10 alkyl, aryl, methoxy, benzyl, or halogen. n is 1 or 2; The reaction solvent is an organic solvent, namely one or more of 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, and isopropanol; the reaction temperature is 25-70 ℃; the reaction time is 24-120 hours; and the hydrogen pressure is 400-1000 psi. The catalyst is a complex of a ruthenium metal precursor, a chiral bisphosphine ligand, and an acid. The ruthenium precursor is di(2-methylallyl)(1,5-cyclooctadiene)ruthenium(II); the chiral bisphosphine ligand is ( R )-4,12-bis(diphenylphosphino)[2.2]p-cycloarane; the acid is one of tetrafluoroboric acid, hexafluorophosphate, and trifluoromethanesulfonic acid; The catalyst is prepared by stirring a ruthenium precursor, a chiral bisphosphine ligand, and an acid in a solvent at room temperature for 10-60 minutes under nitrogen or argon protection.

2. The method according to claim 1, characterized in that: The molar ratio of 2-substituted naphthalene compounds, ruthenium precursor, chiral bisphosphine ligand, and acid is 1:0.01:0.011:0.02-1:0.2:0.22:0.4, and the amount of organic solvent used is 0.5-6 mL per 0.05-0.4 mmol of 2-substituted naphthalene compound.

3. The method according to claim 1, characterized in that, The specific reaction steps of the method are as follows: 2-substituted naphthalene compounds, in-situ prepared catalysts and solvents are added to a reaction flask, the reaction flask is placed in a high-pressure reactor, H2 is introduced to react and hydrogenate the product, and then purified to obtain a pure product.

4. The method according to claim 1, characterized in that, The purification steps are as follows: after releasing hydrogen gas, the solvent is evaporated, and the pure product is obtained by column chromatography.

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