A green synthetic method for the preparation of chiral alpha-amino ketones under illumination

Abstract

The application discloses a green synthesis method for preparing chiral alpha-amino ketone under illumination, and comprises the following steps: adding a nitroaromatic compound, an alpha-hydroxy aryl ketone compound, a boron reagent and a chiral phosphoric acid reagent into a solvent, and reacting under illumination of 427-440 nm for 1-24 hours. The application adopts a photocatalysis strategy, does not need to add an external photocatalyst, has mild reaction conditions, simple operation steps, is green and environment-friendly, has high enantioselectivity and good functional group tolerance. Blue LEDs are used as reaction energy sources, which are green and environment-friendly and have high energy utilization rate, and can efficiently realize conversion of light energy into chemical energy. The prepared chiral alpha-amino ketone can be widely used in the fields of medicine and synthetic industry, can effectively reduce economic cost, and is environment-friendly.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic chemical synthesis, in particular to a green synthesis method for preparing chiral alpha-amino ketone under light irradiation. BACKGROUND

[0002] Chiral alpha-amino ketone is widely present in drugs and bioactive molecules, and is a very important pharmacophore. Therefore, achieving efficient enantioselective synthesis is an important challenge in the field of organic chemical synthesis. The main progress in the enantioselective synthesis of alpha-amino ketone compounds is highly dependent on electrophilic or nucleophilic amination reactions. However, asymmetric electrophilic alpha-amination of ketone enolate usually leads to the formation of mixed enolates of dialkyl ketones, and requires specific nitrogen electrophiles (such as azodicarboxylate) to provide products, which requires additional transformations to provide synthetically useful compounds; nucleophilic alpha-amination methods using free amines as nitrogen sources require additional steps to prepare alpha-functionalized carbonyl compounds such as alpha-bromocyclic ketones, alpha-diazo ketones and alpha-carbonyl sulfonylation, and the products need to be further transformed to be used as valuable synthetic building blocks, so the step economy and operation simplicity of this type of synthesis method need to be further improved. SUMMARY

[0003] The purpose of the present application is to overcome the problems in the prior art, and to provide a method for preparing chiral alpha-amino ketone under light irradiation, so as to overcome the technical problems of limited application range, complex steps and complicated operation of the prior art.

[0004] In order to achieve the above-mentioned purpose, the technical scheme adopted by the present application is:

[0005] The first aspect of the present application provides a method for preparing chiral alpha-amino ketone under light irradiation, comprising the following steps:

[0006] The nitroarene compound, the alpha-hydroxy aryl ketone compound, the diboron reagent and the chiral phosphoric acid reagent are added to the solvent, and the reaction is carried out under light irradiation at 427-440 nm for 1-24 h.

[0007] Preferably, the nitroarene compound has the following structural formula:

[0008]

[0009] wherein R1, R2, R3, R4 and R5 are the same or different C1-C 20 alkyl, C1-C 20 heteroalkyl, C3-C 20 cycloalkyl, C3-C 20 heterocycloalkyl, C2-C 20 alkenyl, C2-C 20Heterene group, C3-C 20 Cycloalkenyl, C3-C 20 Heterocyclic alkenyl, C2-C 20 alkynyl group, C2-C 20 heteroyne group, C3-C 20 Cycloalkynyl, C3-C 20 Heterocyclic alkyne group, C1-C 20 Alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, aryl (C1-C) 20 )alkyl, heteroaryl (C1-C 20 )alkyl, C2-C 20 alkenyl (C1-C) 20 )alkyl, C2-C 20 alkynyl (C1-C) 20 )alkyl, cyano (C1-C 20 Any one of alkyl, alkyloxycarbonyl, or hydrogen atom substituent.

[0010] More preferably, the nitroaromatic compound includes one of nitrobenzene, p-methylnitrobenzene, 4-nitrochlorobenzene, 1-nitronaphthalene, and 4-nitrobiphenyl.

[0011] Preferably, the structural formula of the α-hydroxy aromatic ketone compound is:

[0012]

[0013] Among them, R6, R7, R8, R9, R 10 and R 11 For the same or different C1-C 20 Alkyl, C1-C 20 Heteroalkyl, C3-C 20 cycloalkyl, C3-C 20 Heterocyclic alkyl, C2-C 20 alkenyl, C2-C 20 Heterene group, C3-C 20 Cycloalkenyl, C3-C 20 Heterocyclic alkenyl, C2-C 20 alkynyl group, C2-C 20 heteroyne group, C3-C 20 Cycloalkynyl, C3-C 20 Heterocyclic alkyne group, C1-C 20 Alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, aryl (C1-C) 20 )alkyl, heteroaryl (C1-C 20 )alkyl, C2-C 20 alkenyl (C1-C) 20 )alkyl, C2-C20 alkynyl (C1-C) 20 )alkyl, cyano (C1-C 20 Any one of alkyl, alkyloxycarbonyl, or hydrogen atom substituent.

[0014] Preferably, the boron reagent is at least one of the compounds shown in the following structural formulas:

[0015]

[0016] Preferably, the chiral phosphoric acid reagent is at least one of the compounds shown in formulas (I)-(VI):

[0017]

[0018] Among them, R 12 R 13 R 14 R 15 R 16 and R 17 The substituents on the phenyl, naphthyl, triphenylsilyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, anthracene, substituted anthracene, phenanthryl, substituted phenanthryl, pyrene, substituted pyrene are any one of the following: alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, heteroalkynyl, cycloalkynyl, heterocycloalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxyl, mercapto, aldehyde, sulfonic acid, carboxyl, acyl halide, ester, amide, amino, imino, nitro, cyano, nitroso.

[0019] Preferably, the solvent is at least one selected from acetonitrile, benzene, toluene, ethylbenzene, o-xylene, m-xylene, p-xylene, chlorobenzene, trifluorotoluene, anisole, diethyl ether, dimethyl ether, n-hexane, and tetrahydrofuran.

[0020] Preferably, the molar ratio of the nitroaromatic compound, the α-hydroxy ketone compound, the boron reagent, and the chiral phosphoric acid reagent is 1:(1-3):(1-3):(0.05-0.15).

[0021] In some specific embodiments of the present invention, the light source used for the reaction illumination is a Kessil lamp.

[0022] A second aspect of the present invention provides a chiral α-amino ketone compound, prepared by the method for preparing chiral α-amino ketones under light irradiation.

[0023] A third aspect of the present invention provides the use of the chiral α-aminoketone compound in the preparation of pharmaceutical intermediates.

[0024] Compared with the prior art, the present application has the following advantages:

[0025] 1. The reaction system is simple, and no complex photocatalyst needs to be prepared in advance, so that the whole reaction system can be strictly metal-free, the reaction process is safe and controllable, and the preparation and production process is simplified.

[0026] 2. Blue LEDs are used as the reaction energy source, which is green and has high energy utilization rate, and can efficiently realize the conversion of light energy to chemical energy.

[0027] 3. The reactants are simple and commercially available materials, which are low in price and easy to obtain, and do not need to be additionally modified and protected before reaction, so that they can be directly used for preparation and production, thereby simplifying the operation steps and shortening the reaction route.

[0028] 4. The required reaction conditions are mild and economical, and have good industrial application prospect. Due to the progressiveness of the method for preparing chiral α-amino ketones under light, the method can be widely used in the fields of medicine and synthesis industry, can effectively reduce the economic cost, and is friendly to the environment. DETAILED DESCRIPTION

[0029] The specific embodiments of the present application will be further described below. It should be noted that the description of the embodiments is used to help understand the present application, but does not constitute a limitation on the present application. In addition, the technical features involved in each embodiment of the present application described below can be combined with each other as long as there is no conflict.

[0030] The experimental methods in the following examples are all conventional methods unless otherwise specified, and the test materials used in the following examples are all commercially available unless otherwise specified.

[0031] The compounds and derivatives involved in the embodiments of the present application are all named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstract Service, located in Columbus, Ohio) naming system.

[0032] Example 1

[0033] In a dry 4 mL sample vial, add nitrobenzene (0.4 mmol, 1.0 eq), 2-hydroxy-2- phenylacetophenone (1.2 mmol, 3.0 eq), pinacol diboronic acid (1.2 mmol, 3.0 eq), S-3,3'- bis(triphenylsilyl)binol phosphonate (0.02 mmol, 0.05 eq) and toluene (1 mL). After the sample vial is sealed, it is stirred uniformly at room temperature, then stirred on a stirrer and irradiated with 427 nm LEDs, and the reaction time is 1-24 h. After the reaction is completed, the filtrate is rotary evaporated, column chromatography is performed to separate, and the target product is obtained in a yield of 81% and an enantiomeric excess of 90%.

[0034]

[0035] Product: 2-anilino-1,2-diphenyl-ethanone

[0036] The relevant characterization analysis results are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.91 (d, J = 8.4 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.35 (q, J = 7.4 Hz, 4H), 7.22-7.17 (m, 2H), 7.12 (t, J = 7.3 Hz, 1H), 7.05 (t, J = 7.9 Hz, 2H), 6.62 (d, J = 8.4 Hz, 3H), 5.96 (s, 1H). 13 C NMR (126 MHz, Chloroform-d) δ 197.11, 146.16, 137.74, 135.12, 133.52, 129.25, 129.07, 128.88, 128.70, 128.14, 128.11, 117.87, 113.53, 62.76.

[0037] Example 2

[0038] The preparation method is the same as that of 2-anilino-1,2-diphenyl-ethanone in Example 1, except that p-methyl nitrobenzene (0.4 mmol) is used instead of nitrobenzene, and after the reaction is completed, the filtrate is rotary evaporated, column chromatography is performed to separate, and the target product is obtained in a yield of 78% and an enantiomeric excess of 90%.

[0039]

[0040] Product: 2-[(4-methylphenyl)amino]-1,2-diphenyl-ethanone

[0041] The relevant characterization analysis results are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.91 (d, J = 7.3 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.37 - 7.31 (m, 4H), 7.18 (q, J = 6.1, 4.8 Hz, 2H), 7.11 (t, J = 7.3 Hz, 1H), 6.86 (d, J = 8.0 Hz, 2H), 6.53 (d, J = 8.3 Hz, 2H), 5.94 (s, 1H), 2.11 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 196.68, 144.61, 137.25, 134.88, 133.68, 129.17, 129.10, 128.89, 128.75, 128.30, 128.11, 122.48, 114.67, 62.74.

[0042] Example 3

[0043] The preparation method refers to the preparation method of 2-anilino-1,2-diphenyl- ethanone in Example 1, except that 4-nitrochlorobenzene (0.4 mmol) is used instead of nitrobenzene, and the filtrate is rotary dried after the reaction is completed, and column chromatography is used for separation to obtain the target product at a yield of 73% and an enantiomeric excess of 91%.

[0044]

[0045] Product: 2-((4-chlorophenyl)amino)-1,2-diphenyl-ethanone

[0046] The relevant characterization analysis results are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.91 (d, J = 7.3 Hz, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.37 - 7.31 (m, 4H), 7.18 (q, J = 6.1, 4.8 Hz, 2H), 7.11 (t, J = 7.3 Hz, 1H), 6.86 (d, J = 8.0 Hz, 2H), 6.53 (d, J = 8.3 Hz, 2H), 5.94 (s, 1H), 2.11 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 196.68, 144.61, 137.25, 134.88, 133.68, 129.17, 129.10, 128.89, 128.75, 128.30, 128.11, 122.48, 114.67, 62.74.

[0047] Example 4

[0048] The preparation method refers to the preparation method of 2-anilino-1,2-diphenyl- ethanone in Example 1, except that 1-nitronaphthalene (0.4 mmol) is used instead of nitrobenzene, and after the reaction is completed, the filtrate is rotary evaporated, column chromatography is used for separation, and the target product is obtained at a yield of 84% and an enantiomeric excess of 95%.

[0049]

[0050] Product: 2-(naphthalen-1-ylamino)-1,2-diphenyl-ethanone

[0051] The relevant characterization analysis results are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.99 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 7.7 Hz, 2H), 7.67 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 7.6 Hz, 3H), 7.39 - 7.34 (m, 2H), 7.33 (d, J = 7.5 Hz, 2H), 7.16 (t, J = 7.1 Hz, 2H), 7.10 (d, J = 13.0 Hz, 3H), 6.48 (s, 1H), 6.08 (s, 1H). 13 C NMR (126 MHz, Chloroform-d) δ 197.20, 141.22, 137.57, 135.18, 134.51, 133.57, 129.09, 128.96, 128.74, 128.64, 128.22, 128.20, 126.34, 125.88, 124.97, 123.74, 120.33, 117.95, 105, 71, 62.96.

[0052] Example 5

[0053] The preparation method refers to the preparation method of 2-anilino-1,2-diphenyl- ethanone in Example 1, except that 1-nitronaphthalene (0.4 mmol) is used instead of nitrobenzene, and after the reaction is completed, the filtrate is rotary evaporated, column chromatography is used for separation, and the target product is obtained at a yield of 84% and an enantiomeric excess of 95%.

[0054]

[0055] Product: 2-(naphthalen-1-ylamino)-1,2-diphenyl-ethanone

[0056] The relevant characterization analysis results are as follows: 1H NMR (500 MHz, Chloroform-d) δ 7.99 (d, J = 7.4 Hz, 2H), 7.48 (td, J = 13.3, 11.5, 7.5 Hz, 5H), 7.39 (dt, J = 15.1, 7.2 Hz, 6H), 7.27 (t, J = 7.6 Hz, 2H), 7.21 (dd, J = 14.8, 7.3 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 6.05 (s, 1H), 5.52 (s, 1H). 13 CNMR (126 MHz, Chloroform-d) δ 196.98, 145.55, 141.17, 137.67, 135.06, 133.60, 130.78, 129.15, 128.92, 128.74, 128.64, 128.21, 128.17, 127.97, 126.31, 126.12, 113.78, 62.74.

[0057] The embodiments of the present application described above are merely given as examples, but the present application is not limited to the above examples. Various changes, modifications, replacements, and variations of the embodiments can be made by those skilled in the art without departing from the principles and spirit of the present application, and still fall within the scope of the present application.

Claims

1. A process for the preparation of chiral α-amino ketones under illumination, characterized in that, The method comprises the following steps: adding a nitroarene compound, an alpha-hydroxy aryl ketone compound, a boron reagent and a chiral phosphoric acid reagent into a solvent, and reacting under light irradiation at 427-440 nm for 1-24 h; the nitroarene compound is selected from one of nitrobenzene, p-methyl nitrobenzene, 4-nitrochlorobenzene, 1-nitro naphthalene and 4-nitro biphenyl, the alpha-hydroxy aryl ketone compound is 2-hydroxy-2-phenyl acetophenone, the boron reagent is pinacol diboron, and the chiral phosphoric acid reagent is S-3,3'-bis(triphenylsilyl) binaphthyl phosphonate.

2. The process for the photochemical preparation of chiral α-amino ketones according to claim 1, characterized in that, the solvent is at least one of acetonitrile, benzene, toluene, ethylbenzene, o-xylene, m-xylene, p-xylene, chlorobenzene, trifluorotoluene, anisole, diethyl ether, dimethyl ether, n-hexane and tetrahydrofuran.

3. The process for the photochemical preparation of chiral α-amino ketones according to claim 1, characterized in that, the molar ratio of the nitroarene compound, the alpha-hydroxy aryl ketone compound, the boron reagent and the chiral phosphoric acid reagent is 1:(1-3):(1-3):(0.05-0.15).

4. The process for the photochemical preparation of chiral α-amino ketones according to claim 1, characterized in that, the chiral alpha-amino ketone is selected from one of the following structural formulae:

Images