A method for preparing indanol by asymmetric catalysis of dialkyl-substituted internal alkynes with rhodium metal

Abstract

The present invention relates to a method for the asymmetric cyclization reaction of unactivated internal alkynes catalyzed by metal rhodium using a newly developed chiral diene ligand. Under anhydrous and anaerobic conditions, an unactivated alkyne, a boric acid reagent, a rhodium catalyst, a chiral ligand, and a solvent are added, and the mixture is stirred overnight at room temperature to obtain 2,3-disubstituted indanol derivatives. The present invention uses a rhodium substance as a catalyst and a chiral diene substance as a ligand under mild conditions, solving the limitations when using unactivated alkynes as substrates before and improving the enantioselectivity of the product. The present invention is simple and easy to operate, the required substances in the method have low toxicity, are safe and environmentally friendly, and the product has a high conversion rate and is easy to store.

Description

Technical Field

[0001] The present invention belongs to the technical field of transition metal catalysis, and relates to a method for preparing indanol by rhodium-catalyzed asymmetric cyclization of dialkyl-substituted internal alkynes. Background Art

[0002] Indenal derivatives are an important class of carbocyclic compounds and are the core part of many natural products. They can be used to effectively synthesize a variety of biomolecules. For example, the natural product Euplectin has anti-tumor effects, Donpezil has therapeutic effects on Alzheimer's disease, Plerosin B extracted from marine blue algae and Pteris multifida has anti-inflammatory effects, and the natural product Puiflaive F is a potential anti-osteoporosis agent, etc.

[0003] In 2005, Hayashi developed the rhodium / diene-catalyzed regioselective synthesis of indanol, which can proceed with high yield and regioselectivity under mild conditions [Shintani, R.; Okamoto, K.; Hayashi, T. Chem. Lett., 2005, 34, 1294-1295.]. However, there are few reports on the enantioselective synthesis of indanol when using tetraoctyne as the reaction substrate. Especially when using chiral bidentate phosphorus as the ligand, the reaction hardly occurs.

[0004] Therefore, it is very meaningful to develop a new method for synthesizing enantiomerically enriched indanol. So we developed a new chiral diene ligand to participate in the rhodium-catalyzed asymmetric arylation reaction. Summary of the Invention

[0005] The purpose of this part is to outline some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this part, as well as in the abstract and title of the present application, to avoid obscuring the purpose of this part, the abstract, and the title. However, such simplifications or omissions shall not be used to limit the scope of the present invention.

[0006] In view of the above and / or problems existing in the prior art, the present invention is proposed.

[0007] Therefore, the purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for rhodium-catalyzed asymmetric cyclization of unactivated internal alkynes using a newly developed chiral diene ligand.

[0008] To solve the above technical problems, the present invention provides the following technical solution: A method for preparing indanol by rhodium-catalyzed asymmetric cyclization of dialkyl-substituted internal alkynes, comprising,

[0009] Including, under anhydrous and anaerobic conditions, adding unactivated alkyne, boric acid reagent, rhodium catalyst, chiral diene ligand and solvent, and stirring the reaction at room temperature to obtain the target product.

[0010] As a method for preparing indanol by asymmetric catalysis of dialkyl-substituted internal alkyne with rhodium metal in the present invention, it is characterized in that: the molar ratio of unactivated alkyne, boric acid reagent, rhodium catalyst and chiral diene ligand is 1∶1.5∶0.05∶0.055.

[0011] As a method for preparing indanol by asymmetric catalysis of dialkyl-substituted internal alkyne with rhodium metal in the present invention, it is characterized in that: the boric acid reagent is 2-formylphenylboronic acid.

[0012] As a method for preparing indanol by asymmetric catalysis of dialkyl-substituted internal alkyne with rhodium metal in the present invention, it is characterized in that: the unactivated alkyne is a simple alkyne such as 4-octyne and 5-decyne.

[0013] As a method for preparing indanol by asymmetric catalysis of dialkyl-substituted internal alkyne with rhodium metal in the present invention, it is characterized in that: the rhodium catalyst is commercially available [RhCl(cod)]2. As a method for the asymmetric cyclization reaction of unactivated internal alkyne catalyzed by rhodium metal using a newly developed chiral diene ligand in the present invention, it is characterized in that: the chiral ligand is a newly developed chiral diene ligand that has not been reported.

[0014] As a method for preparing indanol by asymmetric catalysis of dialkyl-substituted internal alkyne with rhodium metal in the present invention, it is characterized in that: the solvent includes 1,4-dioxane, potassium hydroxide, water

[0015] As a method for preparing indanol by asymmetric catalysis of dialkyl-substituted internal alkyne with rhodium metal in the present invention, it is characterized in that: the stirring at room temperature means stirring overnight at 25 °C.

[0016] Advantages of the present invention:

[0017] The present invention is simple and easy to operate, the required items in the method have low toxicity, are safe, environmentally friendly, have a wide substrate expansion range, good enantioselectivity, high yield and high reaction efficiency.

[0018] Both the raw materials and the catalyst used in the present invention are commercially available. By using a rhodium catalyst system involving a newly developed chiral diene ligand under mild conditions, enantiomerically enriched indanol compounds are obtained, which can be widely applied to various bioactive molecules and also provide more possibilities for rhodium-catalyzed asymmetric arylation reactions. Description of the drawings

[0019] To more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the accompanying drawings required for the description of the embodiments. Obviously, the accompanying drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other accompanying drawings can be obtained based on these drawings. Among them:

[0020] Figure 1 1H NMR spectrum of the product prepared in Example 1 of the present invention;

[0021] Figure 2 13C NMR spectrum of the product prepared in Example 1 of the present invention; Detailed implementation manners

[0022] To make the above objects, features, and advantages of the present invention more obvious and understandable, the following will provide a detailed description of the specific implementation manners of the present invention in combination with the embodiments of the specification.

[0023] In the following description, many specific details are set forth to fully understand the present invention. However, the present invention can also be implemented in other ways different from those described herein. Those skilled in the art can make similar generalizations without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0024] Secondly, the so-called "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that can be included in at least one implementation manner of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it an individual or alternative embodiment that is mutually exclusive with other embodiments.

[0025] Example 1

[0026] The reaction of rhodium-catalyzed 4-octyne with 2-formylphenylboronic acid is as follows:

[0027] A magnetic stir bar was placed in a 10 ml pressure bottle, and 0.15 mmol of 4-octyne and 0.225 mmol of 2-formylphenylboronic acid were placed in the bottle. Under nitrogen protection, 25 μl of KOH, 15 μl of water, and 0.5 ml of 1,4-dioxane were successively added to the reaction bottle. Stir at room temperature for 16 h, and 29.2 mg of the product was separated, with a yield of 90% and an ee value of 92%.

[0028] Yield = actual product mass / ideal product mass = 29.2 mg / (0.15 mmol × 216.3 mg·mol -1 )(relative molecular mass of the target product) = 90%

[0029] Characterize the product: 11H NMR (CDCl3, 600 MHz) δ 0.98 (td, J = 2.76, 7.32 Hz, 6H), 1.50 - 1.65 (m, 4H), 2.38 - 2.44 (m, 4H), 4.97 (d, J = 9.47 Hz, 1H), 7.13 - 7.17 (m, 2H), 7.25 - 7.27 (m, 1H), 7.47 (d, J = 7.17 Hz, 1H); 13 13C NMR (CDCl3, 151 MHz) δ 14.4, 21.8, 22.9, 27.3, 27.8, 118.7, 123.1, 124.9, 128.3, 137.9, 144.3, 145.0, 145.2.

[0030] HRMS (ESI) Calcd for C 15 H 20 O [M+H] + 217.1587, found 217.1584.

[0031] The structure formula of the product is:

[0032]

[0033] Example 2

[0034] The reaction of rhodium-catalyzed 4-octyne with 4-trifluoromethyl-2-formylphenylboronic acid is as follows:

[0035] A stir bar was placed in a 10 ml pressure bottle, and 0.15 mmol of 4-octyne and 0.225 mmol of 4-trifluoromethyl-2-formylphenylboronic acid were placed in the bottle. Under nitrogen protection, 25 μl of KOH, 15 μl of water, and 0.5 ml of 1,4-dioxane were successively added to the reaction bottle. Stir at room temperature for 16 h, and 34.1 mg of the product was separated, with a yield of 88% and an ee value of 96%.

[0036] Yield = actual product mass / ideal product mass = 34.1 mg / (0.15 mmol × 284.3 mg·mol -1 (relative molecular mass of the target product) = 88%

[0037] Characterize the product: 1 1H NMR (CDCl3, 600 MHz) δ 0.98 (t, J = 7.31 Hz, 6H), 1.52 - 1.67 (m, 4H), 2.42 - 2.44 (m, 4H), 5.01 (s, 1H), 7.22 (d, J = 7.80 Hz, 2H), 7.53 (d, J = 7.77 Hz, 1H), 7.69 (s, 1H); 1313C NMR (CDCl3, 151 MHz) δ 14.3, 14.3, 21.7, 22.8, 27.2, 27.9, 118.6, 119.9, 125.8, 127.2, 137.5, 145.4, 147.7, 148.4.

[0038] HRMS (ESI) Calcd for C 16 H 19 F3O [M+H] + 285.1461, found 285.1460.

[0039] The structural formula of the product is:

[0040]

[0041] Example 3

[0042] The reaction of rhodium-catalyzed 4-octyne with 4-hydroxy-2-formylphenylboronic acid is as follows:

[0043] A magnetic stir bar was placed in a 10 ml pressure bottle, and 0.15 mmol of 4-octyne and 0.225 mmol of 4-hydroxy-2-formylphenylboronic acid were added to the bottle. Under nitrogen protection, 25 μl of KOH, 15 μl of water, and 0.5 ml of 1,4-dioxane were successively added to the reaction bottle. Stir at room temperature for 16 h, and 34.1 mg of the product was obtained by separation, with a yield of 80% and an ee value of 86%.

[0044] Yield = actual product mass / ideal product mass = 34.1 mg / (0.1 mmol × 232.3 mg·mol -1 )(relative molecular mass of the target product) = 80%

[0045] Characterize the product: 1 1H NMR (CDCl3, 600 MHz) δ 0.94 - 0.97 (m, 6H), 1.40 - 1.63 (m, 4H), 2.32 - 2.38 (m, 4H), 4.90 (s, 1H), 6.70 - 6.72 (m, 1H), 6.96 - 6.97 (m, 1H), 7.01 (d, J = 2.1 Hz, 1H); 13 13C NMR (CDCl3, 151 MHz) δ 14.3, 14.3, 21.8, 22.9, 24.8, 27.4, 27.7, 111.8, 114.4, 119.3, 137.7, 142.7, 147.0, 154.0

[0046] HRMS (ESI) Calcd for C 15 H 20O2[M+H] + 233.1463, found 233.1466

[0047] The product structural formula is:

[0048]

[0049] Example 4

[0050] The reaction of rhodium-catalyzed 4-octyne with 4-dimethylamino-2-formylphenylboronic acid is as follows:

[0051] A magnetic stir bar was placed in a 10 ml pressure bottle, and 0.15 mmol of 4-octyne and 0.225 mmol of 4-dimethylamino-2-formylphenylboronic acid were added to the bottle. Under nitrogen protection, 25 μl of KOH, 15 μl of water, and 0.5 ml of 1,4-dioxane were successively added to the reaction bottle. Stir at room temperature for 16 h, and 31.1 mg of the product was obtained by separation, with a yield of 80% and an ee value of 85%.

[0052] Yield = actual product mass / ideal product mass = 31.1 mg / (0.1 mmol × 259.4 mg·mol -1 )(relative molecular mass of the target product) = 80%

[0053] Characterize the product: 1 H NMR(CDCl3, 400 MHz) δ 0.97(q, J = 6.57 Hz, 6H), 1.54 - 1.65(m, 4H), 2.33 - 2.40(m, 4H), 2.94(s, 6H), 4.93(s, 1H), 6.62(dd, J = 2.23, 8.16 Hz, 1H), 7.01 - 7.03(m, 2H); 13 C NMR(CDCl3, 151 MHz) δ 14.3, 14.4, 21.9, 23.0, 27.4, 27.7, 41.3, 109.7, 111.9, 119.0, 133.6, 137.8, 141.3, 146.7, 149.3.

[0054] HRMS(ESI) Calcd for C 17 H 25 NO[M+H] + 260.2009, found 260.2007

[0055] The product structural formula is:

[0056]

[0057] Example 5

[0058] The reaction of rhodium-catalyzed 4-octyne with 4-methoxy-2-formylphenylboronic acid is as follows:

[0059] A magnetic stir bar was placed in a 10 mL pressure bottle, and 0.15 mmol of 4-octyne and 0.225 mmol of 4-methoxy-2-formylphenylboronic acid were added to the bottle. Under nitrogen protection, 25 μL of KOH, 15 μL of water, and 0.5 mL of 1,4-dioxane were successively added to the reaction bottle. Stir at room temperature for 16 h, and 32.9 mg of the product was obtained by separation, with a yield of 89% and an ee value of 89%.

[0060] Yield = actual product mass / ideal product mass = 31.2 mg / (0.1 mmol × 246 mg·mol -1 )(relative molecular mass of the target product) = 88%

[0061] The product was characterized as follows: 1 1H NMR (CDCl3, 600 MHz) δ 97 (td, J = 2.19, 7.35 Hz, 6H), 1.49 - 1.64 (m, 4H), 2.34 - 2.41 (m, 4H), 3.82 (s, 3H), 4.94 (s, 1H), 6.78 (dd, J = 2.40, 8.14 Hz, 1H), 7.04 (d, J = 8.14 Hz 1H), 7.10 (d, J = 2.29 Hz, 1H); 13 13C NMR (CDCl3, 101 MHz) δ 14.3, 14.3, 21.8, 22.9, 27.4, 27.7, 55.6, 110.4, 112.9, 119.1, 137.0, 137.6, 143.0, 146.9, 158.1.

[0062] HRMS (ESI) Calcd for C 16 H 22 O2 [M + H] + 247.1693, found 247.1692

[0063] The structural formula of the product is:

[0064]

[0065] Example 6

[0066] The reaction of rhodium-catalyzed 4-octyne with 4-methyl-2-formylphenylboronic acid is as follows:

[0067] A magnetic stir bar was placed in a 10 mL pressure bottle, and 0.15 mmol of bromo-substituted diphenylacetylene and 0.225 mmol of boron-substituted o-cinnamone were added to the bottle. Under nitrogen protection, 25 μL of KOH, 15 μL of water, and 0.5 mL of 1,4-dioxane were successively added to the reaction bottle. The mixture was stirred at room temperature for 16 h, and 28 mg of the product was obtained by separation, with a yield of 81% and an ee value of 95%.

[0068] Yield = mass of actual product / mass of theoretical product = 28 mg / (0.1 mmol × 230.2 mg·mol -1 )(relative molecular mass of the target product) = 81%

[0069] The product was characterized as follows: 1 1H NMR (CDCl3, 600 MHz) δ 0.95 - 1.00 (m, 6H), 1.55 - 1.59 (m, 4H), 2.37 - 2.41 (m, 7H), 4.94 (s, 1H), 6.96 (d, J = 9.45 Hz, 2H), 7.35 (d, J = 7.26 Hz, 1H); 13 13C NMR (CDCl3, 151 MHz) δ 14.3, 14.4, 21.7, 21.8, 22.9, 27.3, 27.8, 119.6, 122.8, 125.4, 137.8, 138.1, 142.2, 144.5, 145.5.

[0070] HRMS (ESI) Calcd for C 16 H 22 O [M + H] + 231.1743, found 231.1742

[0071] The structural formula of the product is:

[0072]

[0073] Example 7

[0074] Provide: Screen the ligands used in the reaction and explain the change in the ee value.

[0075]

[0076]

[0077] Explanation: The size of the substituents at both ends of the diene ligand will produce different steric hindrance effects. The larger the substituent, the greater the influence on the insertion direction of the alkyne, and the higher the ee value of the product. Therefore, the result of selecting L9* as the ligand is the best.

[0078] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and they should all be covered within the scope of the claims of the present invention.

Claims

1. A method for preparing indanol by asymmetric catalysis of dialkyl-substituted internal alkynes with rhodium metal, which is characterized in that: Including, under anhydrous and anaerobic conditions, adding unactivated alkyne, boric acid reagent, rhodium catalyst, and stirring and reacting at room temperature in the presence of a chiral diene ligand and a solvent to obtain the target product; The boric acid reagent is 2-formylphenylboronic acid; The unactivated alkyne is 4-octyne or 5-decyne; The rhodium catalyst is [RhCl(coe)]2; The solvent includes 1,4-dioxane, potassium hydroxide, and water; The ligand is one of the following structural formulas: 。 2. The method for preparing indanol by asymmetric catalysis of dialkyl-substituted internal alkynes with rhodium metal as claimed in claim 1, wherein: The molar ratio of the unactivated alkyne, boric acid reagent, rhodium catalyst, and chiral diene ligand is 1∶1.5∶0.05∶0.

055.

3. The method for preparing indanol by asymmetric catalysis of dialkyl-substituted internal alkyne with rhodium metal as claimed in claim 1, wherein: The stirring at room temperature means stirring overnight at 25 °C.

Images