Green synthesis method for preparing chiral alpha-aminoketone under illumination

Abstract

The invention discloses a green synthesis method for preparing chiral alpha-aminoketone under illumination, which comprises the following steps: adding a nitro-aromatic compound, an alpha-hydroxy arone compound, a boron-linked reagent and a chiral phosphoric acid reagent into a solvent, and reacting for 1-24 hours under the illumination of 427-440nm. The method adopts a photocatalysis strategy, does not need to add a photocatalyst, and is mild in reaction condition, simple in operation step, green, environment-friendly, high in enantioselectivity and good in functional group tolerance. Blue LEDs are used as reaction energy, so that the method is green and environment-friendly, the energy utilization rate is high, and conversion from optical energy to chemical energy can be efficiently realized. The prepared chiral alpha-aminoketone can be widely applied to the fields of medicine, synthesis industry and the like, can effectively reduce the economic cost, and is environment-friendly.

Description

Technical Field

[0001] The invention relates to the field of organic chemical synthesis, and in particular to a green synthesis method for preparing chiral α-amino ketone under light irradiation. Background Art

[0002] Chiral α-amino ketones are widely present in drugs and bioactive molecules and are a very important class of pharmacodynamic functional groups. Therefore, achieving their efficient enantioselective synthesis is an important and challenging topic in the field of organic chemical synthesis. For the enantioselective synthesis of α-amino ketone compounds, the main progress currently relies heavily on electrophilic or nucleophilic amination reactions. However, the asymmetric electrophilic α-amination of ketoenolates usually leads to the formation of mixed enolates of dialkyl ketones, and requires specific nitrogen electrophilic reagents (such as azodicarboxylates) to provide products, which requires additional transformations to provide synthetically useful compounds; the nucleophilic α-amination method using free amines as nitrogen sources requires additional steps to prepare α-functionalized carbonyl compounds, such as α-bromocyclic ketones, α-diazoketones, and α-carbonyl sulfonylation, etc. The products need further transformation to be used as valuable synthetic building blocks, so the step economy and ease of operation of this type of synthetic method need to be further improved. Summary of the invention

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

[0004] In order to achieve the above object, the technical solution adopted by the present invention is:

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

[0006] Add nitroaromatic compounds, α-hydroxyaromatic ketone compounds, biboron reagents and chiral phosphoric acid reagents into a solvent and react under light of 427-440 nm for 1 to 24 hours.

[0007] Preferably, the nitroaromatic compound has the 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 20Heteroalkenyl, C3-C 20 Cycloalkenyl, C3-C 20 Heterocycloalkenyl, C2-C 20 Alkynyl, C2-C 20 Heteroalkynyl, C3-C 20 Cycloalkynyl, C3-C 20 Heterocycloalkynyl, 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 ) alkyl, alkyloxycarbonylalkyl, or a hydrogen atom substituent.

[0010] Further 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 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 20 Heteroalkenyl, C3-C 20 Cycloalkenyl, C3-C 20 Heterocycloalkenyl, C2-C 20 Alkynyl, C2-C 20 Heteroalkynyl, C3-C 20 Cycloalkynyl, C3-C 20 Heterocycloalkynyl, 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 ) alkyl, alkyloxycarbonylalkyl, or a hydrogen atom substituent.

[0014] Preferably, the biboron reagent is at least one of the compounds represented by the following structural formulas:

[0015]

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

[0017]

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

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

[0020] Preferably, the molar ratio of the nitroaromatic compound, the α-hydroxyaromatic ketone compound, the biboron 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] The second aspect of the present invention provides a chiral α-amino ketone compound, which is prepared by the method for preparing chiral α-amino ketone under light irradiation.

[0023] The third aspect of the present invention provides the use of the chiral α-amino ketone compound in the preparation of a pharmaceutical intermediate.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] 1. The reaction system is simple, and there is no need to prepare complex photocatalysts in advance. The overall reaction system can be strictly metal-free, the reaction process is safe and controllable, and the preparation and production process is simplified.

[0026] 2. Using blue LEDs as reaction energy is green and environmentally friendly with high energy utilization rate, and can efficiently realize the conversion of light energy into chemical energy.

[0027] 3. The reactants are simple and commercially available raw materials, which are cheap and easy to obtain. Such reactants do not need additional modification and protection before the reaction and can be directly used in the preparation and production, which simplifies the operation steps and shortens the reaction route.

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

[0029] The specific embodiments of the present invention are further described below. It should be noted that the description of these embodiments is used to help understand the present invention, but does not constitute a limitation of the present invention. In addition, the technical features involved in each embodiment of the present invention described below can be combined with each other as long as they do not conflict with each other.

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

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

[0032] Example 1

[0033] Add nitrobenzene (0.4mmol, 1.0eq), 2-hydroxy-2-phenylacetophenone (1.2mmol, 3.0eq), biboronic acid pinacol ester (1.2mmol, 3.0eq), S-3,3'-bis(triphenylsilyl)binaphthol phosphonate (0.02mmol, 0.05eq) and toluene (1mL) into a dry 4mL sample bottle. After sealing the sample bottle, stir evenly at room temperature, then stir on a stirrer and irradiate with 427nm LEDs. The reaction time is 1 to 24h. After the reaction is completed, the filtrate is dried and separated by column chromatography to obtain the target product with a yield of 81% and an enantiomeric excess of 90%.

[0034]

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

[0036] The results of the relevant characterization analysis are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.91(d,J=8.4Hz,2H),7.45(t,J=7.4Hz,1H),7.35(q,J=7.4Hz,4H),7 .22–7.17(m,2H),7.12(t,J=7.3Hz,1H),7.05(t,J=7.9Hz,2H),6.62(d,J=8.4Hz,3H),5.96(s,1H). 13 C NMR (126MHz, Chloroform-d) δ197.11,146.16,137.74,135.12,133.52,129.25,129.07,128.88,128.70,128.14,128.11,117.87,113.53,62.76.

[0037] Example 2

[0038] The preparation method thereof refers to the preparation method of 2-anilino-1,2-diphenylacetone in Example 1, except that p-methylnitrobenzene (0.4 mmol) is used instead of nitrobenzene. After the reaction is completed, the filtrate is dried by rotary evaporation and separated by column chromatography to obtain the target product with a yield of 78% and an enantiomeric excess of 90%.

[0039]

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

[0041] The results of the relevant characterization analysis are as follows: 1H NMR(500MHz,Chloroform-d)δ7.91(d,J=7.3Hz,2H),7.44(t,J=7.4Hz,1H),7.37–7.31(m,4H),7.18(q,J=6. 1,4.8Hz,2H),7.11(t,J=7.3Hz,1H),6.86(d,J=8.0Hz,2H),6.53(d,J=8.3Hz,2H),5.94(s,1H),2.11(s,3H). 13 CNMR(126MHz,Chloroform-d)δ197.33,143.83,137.85,133.44,129.92,129 .75,129.04,128.86,128.67,128.16,128.07,127.24,113.90,63.24,20.37.

[0042] Example 3

[0043] The preparation method thereof refers to the preparation method of 2-anilino-1,2-diphenylacetone in Example 1, except that 4-nitrochlorobenzene (0.4 mmol) is used instead of nitrobenzene. After the reaction is completed, the filtrate is dried by rotary evaporation and separated by column chromatography to obtain the target product with a yield of 73% and an enantiomeric excess of 91%.

[0044]

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

[0046] The results of the relevant characterization analysis are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.91(d,J=7.4Hz,2H),7.46(t,J=7.4Hz,1H),7.35(t,J=8.4Hz,4H), 7.20(q,J=6.8,6.2Hz,2H),7.14(d,J=7.2Hz,1H),6.99(d,J=8.7Hz,2H),6.52(s,2H),5.91(s,1H). 13 C NMR (126MHz, Chloroform-d) δ196.68,144.61,137.25,134.88,133.68,129.17,129.10,128.89,128.75,128.30,128.11,122.48,114.67,62.74.

[0047] Example 4

[0048] The preparation method thereof refers to the preparation method of 2-anilino-1,2-diphenylethanone in Example 1, except that 1-nitronaphthalene (0.4 mmol) is used instead of nitrobenzene. After the reaction is completed, the filtrate is dried by rotary evaporation and separated by column chromatography to obtain the target product with a yield of 84% and an enantiomeric excess of 95%.

[0049]

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

[0051] The results of the relevant characterization analysis are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.99(d,J=8.1Hz,1H),7.93(d,J=7.7Hz,2H),7.67(d,J=7.8Hz,1H),7.41(d,J=7.6Hz,3 H),7.39–7.34(m,2H),7.33(d,J=7.5Hz,2H),7.16(t,J=7.1Hz,2H),7.10(d,J=13.0Hz,3H),6.48(s,1H),6.08(s,1H). 13 C NMR(126MHz,Chloroform-d)δ197.20,141.22,137.57,135.18,134.51,133.57,129.09,128.96,1 28.74,128.64,128.22,128.20,126.34,125.88,124.97,123.74,120.33,117.95,105,71,62.96.

[0052] Example 5

[0053] The preparation method thereof refers to the preparation method of 2-anilino-1,2-diphenylacetone in Example 1, except that 4-nitrobiphenyl (0.4 mmol) is used instead of nitrobenzene. After the reaction is completed, the filtrate is dried by rotary evaporation and separated by column chromatography to obtain the target product with a yield of 70% and an enantiomeric excess of 93%.

[0054]

[0055] Product: 2-([1,1'-biphenyl]-4-ylamino)-1,2-diphenyl-ethanone

[0056] The results of the relevant characterization analysis are as follows: 1H NMR(500MHz,Chloroform-d)δ7.99(d,J=7.4Hz,2H),7.48(td,J=13.3,11.5,7.5Hz,5H),7.39(dt,J=15.1,7.2 Hz, 6H), 7.27 (t, J = 7.6Hz, 2H), 7.21 (dd, J = 14.8, 7.3Hz, 2H), 6.73 (d, J = 8.5Hz, 2H), 6.05 (s, 1H), 5.52 (s, 1H). 13 CNMR(126MHz,Chloroform-d)δ196.98,145.55,141.17,137.67,135.06,133.60,130.78, 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 invention are described in detail above, but the present invention is not limited to the described embodiments. For those skilled in the art, various changes, modifications, substitutions and variations of these embodiments are made without departing from the principles and spirit of the present invention, and still fall within the protection scope of the present invention.

Claims

1. A method for preparing chiral α-amino ketone under light irradiation, It is characterized in that The following steps are involved: Add nitroaromatic compounds, α-hydroxyaromatic ketone compounds, biboron reagents and chiral phosphoric acid reagents into a solvent and react under light of 427-440 nm for 1 to 24 hours.

2. The method for preparing chiral α-amino ketone under light according to claim 1, It is characterized in that The structural formula of the nitroaromatic compound is: Among them, R 1 , R 2 , R 3 , R 4 and R 5 Same or different C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl, C 3 -C 20 Heterocycloalkynyl, C 1 -C 20 Alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, aryl (C 1 -C 20 ) alkyl, heteroaryl (C 1 -C 20 ) alkyl, C 2 -C 20 Alkenyl (C 1 -C 20 ) alkyl, C 2 -C 20 Alkynyl (C 1 -C 20 ) alkyl, cyano (C 1 -C 20 ) alkyl, alkyloxycarbonylalkyl, or a hydrogen atom substituent.

3. The method for preparing chiral α-amino ketone under light according to claim 2, It is characterized in that The nitroaromatic compound includes one of nitrobenzene, p-methylnitrobenzene, 4-nitrochlorobenzene, 1-nitronaphthalene and 4-nitrobiphenyl.

4. The method for preparing chiral α-amino ketone under light according to claim 1, It is characterized in that The structural formula of the α-hydroxy aromatic ketone compound is: Among them, R 6 , R 7 , R 8 , R 9 , R 10 and R 11 Same or different C 1 -C 20 Alkyl, C 1 -C 20 Heteroalkyl, C 3 -C 20 Cycloalkyl, C 3 -C 20 Heterocycloalkyl, C 2 -C 20 Alkenyl, C 2 -C 20 Heteroalkenyl, C 3 -C 20 Cycloalkenyl, C 3 -C 20 Heterocycloalkenyl, C 2 -C 20 Alkynyl, C 2 -C 20 Heteroalkynyl, C 3 -C 20 Cycloalkynyl, C 3 -C 20 Heterocycloalkynyl, C 1 -C 20 Alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, aryl (C 1 -C 20 ) alkyl, heteroaryl (C 1 -C 20 ) alkyl, C 2 -C 20 Alkenyl (C 1 -C 20 ) alkyl, C 2 -C 20 Alkynyl (C 1 -C 20 ) alkyl, cyano (C 1 -C 20 ) alkyl, alkyloxycarbonylalkyl, or a hydrogen atom substituent.

5. The method for preparing chiral α-amino ketone under light according to claim 1, It is characterized in that The biboron reagent is at least one of the compounds shown in the following structural formula:

6. The method for preparing chiral α-amino ketone under light according to claim 1, It is characterized in that The chiral phosphoric acid reagent is at least one of the compounds represented by the following formulas (I)-(VI): Among them, R 12 , R 13 , R 14 , R 15 , R 16 and R 17 is hydrogen, halogen, triphenylsilyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, anthracenyl, substituted anthracenyl, phenanthryl, substituted phenanthryl, pyrene, substituted pyrene; the substituents on phenyl, naphthyl, anthracenyl, phenanthryl and pyrene are the same or different from any one of alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, heteroalkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, heteroalkynyl, cycloalkynyl, heterocycloalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxyl, thiol, aldehyde, sulfonic acid, carboxyl, acyl halide, ester, amide, amino, imino, nitro, cyano and nitroso.

7. The method for preparing chiral α-amino ketone under light according to claim 1, It is characterized in that The solvent is at least one of acetonitrile, benzene, toluene, ethylbenzene, o-xylene, m-xylene, p-xylene, chlorobenzene, trifluorotoluene, anisole, ethyl ether, dimethyl ether, n-hexane and tetrahydrofuran.

8. The method for preparing chiral α-amino ketone under light according to claim 1, It is characterized in that The molar ratio of the nitroaromatic compound, the α-hydroxyaromatic ketone compound, the biboron reagent and the chiral phosphoric acid reagent is 1:(1-3):(1-3):(0.05-0.15).

9. A chiral α-amino ketone compound, It is characterized in that The chiral α-amino ketone is prepared by the method for preparing chiral α-amino ketone under light irradiation according to any one of claims 1 to 8.

10. Use of the chiral α-amino ketone compound according to claim 9 in the preparation of a pharmaceutical intermediate.

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