Synthesis method of 2-amino-3-trifluoromethyl naphthoquinone compound

Abstract

The invention discloses a synthesis method of a 2-amino-3-trifluoromethyl naphthoquinone compound, which comprises the following steps: by taking a 1, 4-naphthoquinone compound, a Togni reagent and alkylamine as substrates, stirring in the dark at room temperature under the promotion of a proper amount of alkali to realize the construction of the 2-amino-3-trifluoromethyl naphthoquinone compound. The synthesis method has the prominent advantages that the substrate is cheap and easy to obtain, the reaction condition is mild, the operation is simple, the product is diversified and the like, and the synthesis method can be applied to derivative modification of drug molecules such as doxazosin (Doxazosin), levocetirizine (Levocetirizine), risperidone (Risperidone), desloratadine (Desloratadine) and paroxetine (Paroxetine).

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and in particular to a method for synthesizing 2-amino-3-trifluoromethylnaphthoquinone compounds. Background Art

[0002] Naphthoquinone compounds are the most basic type of organic chemical raw materials, showing broad application prospects in fields such as organic synthesis, functional materials, and pesticides (Nat. Prod. Rep. 2012, 29, 513; J. Mater. Chem. A 2016, 4, 11179; Org. Lett. 2010, 12, 5554; Org. Lett. 2013, 15, 2080; J. Med. Chem. 2013, 56, 1007). At present, a large number of studies have shown that when an amino group is introduced into naphthoquinone, the resulting 2-aminonaphthoquinone compounds exhibit excellent antibacterial and anticancer activities, such as 20S protease inhibitors, histone deacetylase (HDAC) inhibitors, reactive oxygen species, etc. (J. Med. Chem. 1969, 12, 181; Bioorg. Med. Chem. 2002, 10, 1947; J. Med. Chem. 1983, 26, 570; Bioorg. Med. Chem. 2010, 18, 5576; Bioorg. Med. Chem. Lett. 2012, 22, 2772; ACS Chem. Biol. 2012, 7, 331; J. Med. Chem. 2016, 59, 5209; Bioorg. Med. Chem. 2009, 17, 634; Chem. Biodiversity 2014,11,341). 2-Aminonaphthoquinone compounds can also be used as an effective photocatalyst (Org.Lett.2021,23,519). In addition, since the introduction of trifluoromethyl groups into organic molecules will cause some unique changes in their physical and chemical properties, this feature makes trifluoromethyl-containing organic molecules exhibit good biological and pharmaceutical activities. Therefore, trifluoromethyl-containing 2-aminonaphthoquinone compounds, such as 2-amino-3-trifluoromethylnaphthoquinone compounds, will have the dual characteristics of 2-aminonaphthoquinone compounds and trifluoromethyl-containing compounds. However, there is only one case report on the synthesis of 2-amino-3-trifluoromethylnaphthoquinone by coupling trifluoromethylsulfinic acid zinc with 2-aminonaphthoquinone catalyzed by ferrous sulfate (J.Org.Chem.2017,82,6795). This method requires the use of ferrous sulfate as a transition metal catalyst and explosive tert-butyl hydroperoxide as an oxidant, which seriously hinders the further synthetic application of this method. The report found that 2-amino-3-trifluoromethyl naphthoquinone compounds have good anti-tumor activity and can effectively inhibit the growth of human alveolar basal epithelial cells A549, human liver cancer cell line HepG2 and human KB cell line. In view of the importance of 2-amino-3-trifluoromethyl naphthoquinone compounds, the present invention is expected to disclose a three-component free radical coupling reaction of naphthoquinone, Togni reagent and amine without any external catalyst, so as to efficiently and greenly construct 2-amino-3-trifluoromethyl naphthoquinone compounds.There is no relevant literature or patent report on this method yet. Summary of the invention

[0003] In order to overcome the deficiencies in the above-mentioned prior art, the present invention provides a method of using naphthoquinone compounds (I) and amines (III) as starting materials for the reaction and Togni reagent (II) as a trifluoromethyl source, and under the promotion of a base, olefin bifunctionalization strategy can effectively construct 2-amino-3-trifluoromethyl naphthoquinone compounds (IV). The method does not require the use of any catalyst, and the target compound can be constructed by stirring in the dark at room temperature.

[0004] The object of the present invention is achieved in that:

[0005] A method for synthesizing 2-amino-3-trifluoromethylnaphthoquinone compounds, characterized in that it comprises the following synthesis steps:

[0006] The naphthoquinone compound of structure (I), the Togni reagent of structure (II), the amine of structure (III) and an appropriate amount of base are dissolved in a solvent, and stirred at room temperature in the dark to obtain a 2-amino-3-trifluoromethyl naphthoquinone compound having structure (IV):

[0007]

[0008] The specific structure of IV is:

[0009]

[0010] Preferably, the organic solvent is acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate or toluene;

[0011] Preferably, the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, triethylenediamine or triethylamine; and the inorganic base is potassium acetate, potassium phosphate or cesium carbonate.

[0012] Beneficial effects: Compared with the related technologies in the field of existing chemical synthesis, the present invention realizes for the first time the trifluoromethyl-amino difunctionalization reaction of naphthoquinone without the addition of an external transition metal catalyst and an oxidant. In the dark, naphthoquinone (I) undergoes Michael addition with amine (III) to generate 2-aminohydronaphthoquinone, and the generated 2-aminohydronaphthoquinone is in situ oxidized by naphthoquinone (I) to 2-aminonaphthoquinone, while 1,4-naphthalene diol is generated. Togni reagent (II) oxidizes the obtained 1,4-naphthalene diol to naphthoquinone (I) through a single electron transfer process and generates trifluoromethyl radicals and 2-iodobenzoic acid. Subsequently, the trifluoromethyl radical is added to 2-amino-1,4-naphthoquinone to obtain a 2-amino-3-trifluoromethylnaphthoquinone carbon radical, which is further oxidized by Togni reagent (II) and deprotonated under the action of a base to generate the final 2-amino-3-trifluoromethylnaphthoquinone compound. This method has the outstanding advantages of cheap and readily available substrates, mild reaction conditions, simple operation, and diversified products. It can be applied to the derivatization and modification of drug molecules such as doxazosin, levocetirizine, risperidone, desloratadine, and paroxetine, and can easily achieve gram-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1a , 1b and 1c are respectively the hydrogen nuclear magnetic resonance spectrum, carbon spectrum and fluorine spectrum of the 2-amino-3-trifluoromethylnaphthoquinone target compound 1 prepared according to Example 1 of the present invention;

[0014] Figure 2a , 2b 2c and 2d are respectively the hydrogen nuclear magnetic resonance spectrum, carbon spectrum and fluorine spectrum of the 2-amino-3-trifluoromethylnaphthoquinone target compound 4 prepared according to Example 2 of the present invention;

[0015] Figure 3a , 3b and 3c are respectively the hydrogen nuclear magnetic resonance spectrum, carbon spectrum and fluorine spectrum of the 2-amino-3-trifluoromethylnaphthoquinone target compound 5 prepared according to Example 3 of the present invention;

[0016] Figure 4a , 4b 4c and 4d are respectively the hydrogen nuclear magnetic resonance spectrum, carbon spectrum and fluorine spectrum of the 2-amino-3-trifluoromethylnaphthoquinone target compound 13 prepared according to Example 4 of the present invention.

[0017] Figure 5a , 5b5c and 5d are respectively the hydrogen nuclear magnetic resonance spectrum, carbon spectrum and fluorine spectrum of the 2-amino-3-trifluoromethylnaphthoquinone target compound 22 prepared according to Example 5 of the present invention.

[0018] Figure 6a , 6b and 6c are respectively the hydrogen nuclear magnetic resonance spectrum, carbon spectrum and fluorine spectrum of the 2-amino-3-trifluoromethylnaphthoquinone target compound 27 prepared according to Example 6 of the present invention.

[0019] Figure 7a , 7b 7c and 7d are respectively the hydrogen nuclear magnetic resonance spectrum, carbon spectrum and fluorine spectrum of the 2-amino-3-trifluoromethylnaphthoquinone target compound 28 prepared according to Example 7 of the present invention.

[0020] Figure 8a , 8b and 8c are respectively the hydrogen nuclear magnetic resonance spectrum, carbon spectrum and fluorine spectrum of the 2-amino-3-trifluoromethylnaphthoquinone target compound 29 prepared according to Example 8 of the present invention.

[0021] Figure 9a , 9b and 9c are respectively the hydrogen nuclear magnetic resonance spectrum, carbon spectrum and fluorine spectrum of the 2-amino-3-trifluoromethylnaphthoquinone target compound 32 prepared according to Example 9 of the present invention.

[0022] Fig.10a , 10b 10a and 10b are respectively the hydrogen nuclear magnetic resonance spectrum, carbon spectrum and fluorine spectrum of the 2-amino-3-trifluoromethylnaphthoquinone target compound 33 prepared according to Example 10 of the present invention. DETAILED DESCRIPTION

[0023] The present invention will be further described below in conjunction with the accompanying drawings and embodiments:

[0024] A method for synthesizing 2-amino-3-trifluoromethylnaphthoquinone compounds, characterized in that it comprises the following synthesis steps:

[0025] The naphthoquinone compound of structure (I), the Togni reagent of structure (II), the amine of structure (III) and an appropriate amount of base are dissolved in a solvent, and stirred at room temperature in the dark to obtain a 2-amino-3-trifluoromethyl naphthoquinone compound having structure (IV):

[0026]

[0027] The specific structure of IV is:

[0028]

[0029] Preferably, the organic solvent is acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate or toluene;

[0030] Preferably, the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, triethylenediamine or triethylamine; and the inorganic base is potassium acetate, potassium phosphate or cesium carbonate.

[0031] Example 1

[0032] 0.4mmol 1,4-naphthoquinone, 0.5mmol Toogni reagent, 0.2mmol morpholine, 0.24mmol 1,8-diazabicyclo[5.4.0]undec-7-ene and 1mL acetonitrile were added to a clean and dry 10mL glass reaction tube, and the reaction mixture was stirred at room temperature in the dark for 16 hours. After the reaction was completed, the reaction solvent was removed by a rotary evaporator, and the residue was separated by a silica gel column using petroleum ether and ethyl acetate as eluents to obtain the target product as an orange-yellow solid with a yield of 78%.

[0033] NMR data: 1 H NMR (600MHz, CDCl3): δ [ppm] = 8.08-8.07 (dd, J = 7.8, 0.8Hz, 1H), 7.99-7.97 (dd, J = 7.8, 0.9Hz, 1H), 7.75-7.72 (t d,J=7.8,0.8Hz,1H),7.69-7.66(td,J=7.8,0.9Hz,1H),3.87-3.85(t,J=4.6Hz,4H),3.70-3.68(t,J=4.4Hz,4H); 13 C{ 1 H}NMR (150MHz, CDCl3): δ [ppm] = 183.4, 181.0, 151.8, 134.8, 133.3, 132.1, 131.6, 126.9, 126.2, 123.4 (q, J CF =272.7Hz),111.3(q,J CF =28.4Hz),67.4,54.1; 19 F NMR (564MHz, CDCl3): δ [ppm] = -56.7 (s, 3F).

[0034] The hydrogen nuclear magnetic resonance spectrum of the product prepared in this example is as follows Figure 1a As shown, the carbon NMR spectrum is Figure 1b As shown, the NMR fluorine spectrum is Figure 1c As shown in the figure, it can be confirmed that the obtained product is the target compound 1.

[0035] Example 2

[0036] 0.4mmol 1,4-naphthoquinone, 0.5mmol Toogni reagent, 0.2mmol N-cyclopropylcarbonylpiperazine, 0.24mmol 1,8-diazabicyclo[5.4.0]undec-7-ene and 1mL acetonitrile were added to a clean and dry 10mL glass reaction tube, and the reaction mixture was stirred at room temperature in the dark for 16 hours. After the reaction was completed, the reaction solvent was removed by a rotary evaporator, and the residue was separated by a silica gel column using petroleum ether and ethyl acetate as eluents to obtain the target product as an orange-yellow solid with a yield of 67%.

[0037] NMR data: 1 H NMR (600MHz, CDCl3): δ [ppm] = 8.10-8.08 (dd, J = 7.8, 0.9Hz, 1H), 8.02-8.00 (dd, J = 7.9, 0.9Hz, 1H), 7.77-7.74 (td, J = 7.8, 0.9Hz, 1H), 7.71 -7.69(td,J=7.9,0.9Hz,1H),3.90(s,2H),3.83(s,2H),3.68(s,2H),3.62(s,2H),1.76-1.72(m,1H),1.03-1.01(m,2H),0.83-0.80(m,2H); 13 C{ 1 H}NMR (150MHz, CDCl3): δ [ppm] = 183.2, 181.1, 172.4, 151.9, 134.9, 133.5, 132.0, 131.5, 127.0, 126.3, 123.2 (q, J CF =271.2Hz),112.6(q,J CF =28.5Hz),53.5,53.4,46.0,42.7,11.0,7.9; 19 F NMR (564MHz, CDCl3): δ [ppm] = -56.8 (s, 3F).

[0038] The hydrogen nuclear magnetic resonance spectrum of the product prepared in this example is as follows Figure 2a As shown, the carbon NMR spectrum is Figure 2b As shown, the NMR fluorine spectrum is Figure 2c As shown in the figure, it can be confirmed that the obtained product is the target compound 4.

[0039] Example 3

[0040] 0.4mmol 1,4-naphthoquinone, 0.5mmol Toogni reagent, 0.2mmol N-tert-butyloxycarbonylpiperazine, 0.24mmol 1,8-diazabicyclo[5.4.0]undec-7-ene and 1mL acetonitrile were added to a clean and dry 10mL glass reaction tube, and the reaction mixture was stirred at room temperature in the dark for 16 hours. After the reaction was completed, the reaction solvent was removed by a rotary evaporator, and the residue was separated by a silica gel column using petroleum ether and ethyl acetate as eluents to obtain the target product as an orange-yellow solid with a yield of 71%.

[0041] NMR data: 1 H NMR (600MHz, CDCl3): δ [ppm] = 8.09-8.08 (d, J = 7.6Hz, 1H), 8.00-7.99 (d, J = 7.7Hz, 1H ),7.76-7.73(t,J=7.6Hz,1H),7.70-7.67(t,J=7.7Hz,1H),3.62(s,8H),1.47(s,9H); 13 C{ 1 H} NMR (150MHz, CDCl3): δ [ppm] = 183.2, 181.1, 154.5, 152.0, 134.8, 133.4, 132.1, 131.6, 126.9, 126.2, 123.3 (q, J CF =272.2Hz),112.2(q,J CF =28.4Hz),80.6,53.4,44.7,43.6,28.5; 19 F NMR (564MHz, CDCl3): δ [ppm] = -56.7 (s, 3F).

[0042] The hydrogen nuclear magnetic resonance spectrum of the product prepared in this example is as follows Figure 3a As shown, the carbon NMR spectrum is Figure 3b As shown, the NMR fluorine spectrum is Figure 3c As shown in the figure, it can be confirmed that the obtained product is the target compound 5.

[0043] Example 4

[0044] 0.4mmol 1,4-naphthoquinone, 0.5mmol Toogni reagent, 0.2mmol tetrahydroisoquinoline, 0.24mmol 1,8-diazabicyclo[5.4.0]undec-7-ene and 1mL acetonitrile were added to a clean and dry 10mL glass reaction tube, and the reaction mixture was stirred at room temperature in the dark for 16 hours. After the reaction was completed, the reaction solvent was removed by a rotary evaporator, and the residue was separated by a silica gel column using petroleum ether and ethyl acetate as eluents to obtain the target product as an orange-yellow solid with a yield of 56%.

[0045] NMR data: 1 H NMR (600MHz, CDCl3): δ [ppm] = 8.10-8.08 (d, J = 7.7Hz, 1H), 7.98-7.96 (d, J = 7.7Hz, 1H), 7.74-7.71 (t, J = 7.8Hz, 1H), 7.66-7.64 (t, J =7.8Hz,1H),7.22-7.15(m,3H),7.06-7.05(d,J=6.8Hz,1H),4.77(s,2H),4.12-4.10(t,J=5.6Hz,2H),3.14-3.12(t,J=5.7Hz,2H); 13 C{ 1 H}NMR (150MHz, CDCl3): δ [ppm] = 183.6, 180.6, 153.0, 134.8, 133.5, 133.1, 132.8,132.2,131.5,128.9,127.3,126.7,126.6,126.2,126.0,123.8(q,J CF =275.2Hz),109.3(q,J CF =28.8Hz),56.6(q,J CF =4.5Hz),50.0,29.0; 19 F NMR (564MHz, CDCl3): δ [ppm] = -55.9 (s, 3F).

[0046] The hydrogen nuclear magnetic resonance spectrum of the product prepared in this example is as follows Figure 4a As shown, the carbon NMR spectrum is Figure 4b As shown, the NMR fluorine spectrum is Figure 4c As shown in the figure, it can be confirmed that the obtained product is the target compound 13.

[0047] Example 5

[0048] 0.4mmol 1,4-naphthoquinone, 0.5mmol Toogni reagent, 0.2mmol n-butylamine, 0.24mmol 1,8-diazabicyclo[5.4.0]undec-7-ene and 1mL acetonitrile were added to a clean and dry 10mL glass reaction tube, and the reaction mixture was stirred at room temperature in the dark for 16 hours. After the reaction, the reaction solvent was removed by a rotary evaporator, and the residue was separated by a silica gel column using petroleum ether and ethyl acetate as eluents to obtain the target product as an orange-yellow solid with a yield of 67%.

[0049] NMR data: 1 H NMR (600MHz, CDCl3): δ [ppm] = 8.17-8.15 (dd, J = 7.8, 0.8Hz, 1H), 8.07-8.06 (d, J = 8.0Hz, 1H), 7.80-7.77 (td, J = 8.0, 0.9Hz, 1H), 7.67-7.64(td,J=7.9,0.9Hz,1H),6.63(s,1H),3.42(s,2H),1.70-1.65(m,2H),1.45-1.39(m,2H),0.96-0.94(t,J=6.9Hz,3H); 13 C{ 1 H}NMR (150MHz, CDCl3): δ [ppm] = 181.4, 179.4, 147.2, 135.9, 133.4, 132.7, 129.2, 126.9, 47.0 (q, J CF =5.7Hz),32.2,19.9,13.7; 19 F NMR (564MHz, CDCl3): δ [ppm] = -52.0 (s, 3F).

[0050] The hydrogen nuclear magnetic resonance spectrum of the product prepared in this example is as follows Figure 5a As shown, the carbon NMR spectrum is Figure 5b As shown, the NMR fluorine spectrum is Figure 5c As shown in the figure, it can be confirmed that the obtained product is the target compound 22.

[0051] Example 6

[0052] 0.4mmol 1,4-naphthoquinone, 0.5mmol Toogni reagent, 0.5mmol ammonia water, 0.24mmol 1,8-diazabicyclo[5.4.0]undec-7-ene and 1mL acetonitrile were added to a clean and dry 10mL glass reaction tube, and the reaction mixture was stirred at room temperature in the dark for 16 hours. After the reaction was completed, the reaction solvent was removed by a rotary evaporator, and the residue was separated by a silica gel column using petroleum ether and ethyl acetate as eluents to obtain the target product as an orange-yellow solid with a yield of 56%.

[0053] NMR data: 1 H NMR (600MHz, CDCl3): δ [ppm] = 8.19-8.17 (dd, J = 7.9, 0.8Hz, 1H), 8.11-8.09 (dd, J = 8.0, 0.9Hz, 1H ),7.82-7.80(td,J=8.0,0.9Hz,1H),7.71-7.68(td,J=7.9,1.0Hz,1H),6.49(s,1H),6.02(s,1H); 13 C{ 1 H}NMR (150MHz, CDCl3): δ [ppm] = 180.3, 179.0, 145.9, 135.9, 133.0, 132.9, 129.5, 127.0, 126.8, 124.9 (q, J CF =273.2Hz); 19 F NMR (564MHz, CDCl3): δ [ppm] = -55.8 (s, 3F).

[0054] The hydrogen nuclear magnetic resonance spectrum of the product prepared in this example is as follows Figure 6a As shown, the carbon NMR spectrum is Figure 6b As shown, the NMR fluorine spectrum is Figure 6c From the spectrum, it can be confirmed that the obtained product is the target compound 27.

[0055] Example 7

[0056] 0.4mmol 1,4-anthraquinone, 0.5mmol Toogni reagent, 0.2mmol morpholine, 0.24mmol 1,8-diazabicyclo[5.4.0]undec-7-ene and 1mL acetonitrile were added to a clean and dry 10mL glass reaction tube, and the reaction mixture was stirred at room temperature in the dark for 16 hours. After the reaction was completed, the reaction solvent was removed by a rotary evaporator, and the residue was separated by a silica gel column using petroleum ether and ethyl acetate as eluents to obtain the target product as an orange-red solid with a yield of 32%.

[0057] NMR data: 1 H NMR (600MHz, CDCl3): δ [ppm] = 8.58 (s, 1H), 8.52 (s, 1H), 8.04-8.00 (m, 2H), 7.69-7.64(m,2H),3.90-3.88(t,J=4.4Hz,4H),3.76-3.75(t,J=4.5Hz,4H); 13 C{ 1 H}NMR (150MHz, CDCl3): δ [ppm] = 183.2, 180.8, 152.9, 135.5, 134.7, 130.1, 129.9, 129.7, 129.3, 128.3, 128.1, 123.5 (q, J CF =244.2Hz),112.7(q,J CF =28.4Hz),67.5,54.1; 19 F NMR (564MHz, CDCl3): δ [ppm] = -56.8 (s, 3F).

[0058] The hydrogen nuclear magnetic resonance spectrum of the product prepared in this example is as follows Figure 7a As shown, the carbon NMR spectrum is Figure 7b As shown, the NMR fluorine spectrum is Figure 7c As shown in the figure, it can be confirmed that the obtained product is the target compound 28.

[0059] Example 8

[0060] 0.4mmol 1,4-naphthoquinone, 0.5mmol Togni reagent, 0.2mmol doxazosin intermediate, 0.24mmol 1,8-diazabicyclo[5.4.0]undec-7-ene and 1mL acetonitrile were added to a clean and dry 10mL glass reaction tube, and the reaction mixture was stirred at room temperature in the dark for 16 hours. After the reaction was completed, the reaction solvent was removed by a rotary evaporator, and the residue was separated by a silica gel column using petroleum ether and ethyl acetate as eluents to obtain the target product as an orange-yellow solid with a yield of 72%.

[0061] NMR data: 1H NMR (600MHz, CDCl3): δ [ppm] = 8.11-8.09 (m, 1H), 8.03-8.01 (m, 1H), 7.78-7 .76(td,J=7.7,0.9Hz,1H),7.73-7.70(td,J=7.7,0.9Hz,1H),6.92-6.85(m ,4H),4.87-4.85(dd,J=8.0,2.5Hz,1H),4.53-4.50(dd,J=11.8,2.5Hz,1H) ,4.37-4.33(dd,J=11.8,8.0Hz,1H),4.05-4.00(m,2H),3.83-3.58(m,6H); 13 C{ 1 H}NMR (150MHz, CDCl3): δ [ppm] = 183.1, 181.1, 165.3, 151.7, 143.3, 142.3, 135.0, 133.6, 132.0, 131.5, 127.0, 126.3, 123.1 (q, J CF =275.3Hz),122.6,121.8,117.6,117.3,113.3(q,J CF =28.3Hz),70.7,65.1,53.6,53.3,46.5,42.7; 19 F NMR (564MHz, CDCl3): δ [ppm] = -56.9 (s, 3F).

[0062] The hydrogen nuclear magnetic resonance spectrum of the product prepared in this example is as follows Figure 8a As shown, the carbon NMR spectrum is Figure 8b As shown, the NMR fluorine spectrum is Figure 8c As shown in the figure, it can be confirmed that the obtained product is the target compound 29.

[0063] Example 9

[0064] 0.4mmol 1,4-naphthoquinone, 0.5mmol Toogni reagent, 0.2mmol desloratadine, 0.24mmol 1,8-diazabicyclo[5.4.0]undec-7-ene and 1mL acetonitrile were added to a clean and dry 10mL glass reaction tube, and the reaction mixture was stirred at room temperature in the dark for 16 hours. After the reaction was completed, the reaction solvent was removed by a rotary evaporator, and the residue was separated by a silica gel column using petroleum ether and ethyl acetate as eluents to obtain the target product as an orange-yellow solid with a yield of 62%.

[0065] NMR data: 1H NMR (600MHz, CDCl3): δ[ppm]=8.39-8.38(m,1H),8.06-8.03(m,1H),7.97-7.95(m,1H),7.71-7.67(m,1H),7.66-7.61(m,1H),7.45-7.4 3(m,1H),7.16-7.08(m,4H),3.87-3.82(t,J=14.3Hz,2H),3.44-3.33(m,4H),2.88-2.74(m,3H),2.70-2.65(m,1H),2.54-2.51(m,2H); 13 C{ 1 H}NMR (150MHz, CDCl3): δ [ppm] = 183.2, 181.0, 156.7, 152.3, 146.8, 139.7, 137.8, 137.4, 135 .9,135.0,134.7,133.5,133.2,132.2,131.6,130.6,129.1,126.9,126.3,126.1,123.5(q,J CF =269.7Hz),122.5,111.1(q,J CF =28.6Hz),54.9,54.5,31.9,31.8,31.7,31.6; 19 F NMR (564MHz, CDCl3): δ [ppm] = -56.5 (s, 3F).

[0066] The hydrogen nuclear magnetic resonance spectrum of the product prepared in this example is as follows Figure 9a As shown, the carbon NMR spectrum is Figure 9b As shown, the NMR fluorine spectrum is Fig.9c From the spectrum, it can be confirmed that the obtained product is the target compound 32.

[0067] Example 10

[0068] 0.4mmol 1,4-naphthoquinone, 0.5mmol Toogni reagent, 0.2mmol paroxetine, 0.24mmol 1,8-diazabicyclo[5.4.0]undec-7-ene and 1mL acetonitrile were added to a clean and dry 10mL glass reaction tube, and the reaction mixture was stirred at room temperature in the dark for 16 hours. After the reaction was completed, the reaction solvent was removed by a rotary evaporator, and the residue was separated by a silica gel column using petroleum ether and ethyl acetate as eluents to obtain the target product as an orange-yellow solid with a yield of 68%.

[0069] NMR data: 1H NMR (600MHz, CDCl3): δ [ppm] = 8.12-8.11 (dd, J = 7.7, 0.8Hz, 1H), 8.04-8.03 (dd, J = 7.7, 0.8Hz, 1H), 7.77-7.74 (td, J = 7.8, 0.8 Hz,1H),7.71-7.68(td,J=7.7,0.8Hz,1H),7.18-7.16(m,2H),7.00-6.97(t,J=8.7Hz,2H),6.63-6.62(d,J=8.6Hz,1H),6.374 -6.370(d,J=2.4Hz,1H),6.16-6.14(dd,J=8.6,2.4Hz,1H),5.88(s,2H),4.30-4.27(m,1H),4.02-4.00(d,J=13.1Hz,1H),3.6 7-3.65(dd,J=9.5,2.8Hz,1H),3.51-3.37(m,3H),2.94-2.89(m,1H),2.48-2.43(m,1H),2.10-2.03(m,1H),1.96-1.94(m,1H); 13 C{ 1 H}NMR (150MHz, CDCl3): δ [ppm] = 183.4, 181.2, 161.8 (d, J CF =243.4Hz),154.2,152.2,148.3,141.9,138.3,134.8,133.3,132.2,131.7,128.9(q,J CF =7.7Hz),126.9,126.2,123.5(q,J CF =277.1Hz),115.7(d,J CF =20.8Hz),111.8(q,J CF =28.3Hz),108.0,105.6,101.3,98.1,68.5,56.9,54.8,43.4,43.0,34.8; 19 F NMR (564MHz, CDCl3): δ [ppm] = -56.7 (s, 3F), -115.5 (s, 1F).

[0070] The hydrogen nuclear magnetic resonance spectrum of the product prepared in this example is as follows Fig.10a As shown, the carbon NMR spectrum is Fig.10b As shown, the NMR fluorine spectrum is Fig.10c As shown in the figure, it can be confirmed that the obtained product is the target compound 33.

[0071] In one embodiment, the present invention provides a method for synthesizing 2-amino-3-trifluoromethyl naphthoquinone compounds, 1,4-naphthoquinone can act as a substrate and a catalyst, and Togni reagent can act as a substrate and an oxidant, realizing the trifluoromethyl-amino difunctionalization reaction of naphthoquinone without an external transition metal catalyst and an oxidant. This method has the outstanding advantages of cheap and readily available substrates, mild reaction conditions, simple operation, and diversified products. In order to better illustrate the rationality and novelty of the present invention, the approximate reaction mechanism is as follows:

[0072]

[0073] Naphthoquinone (I) reacts with amine (III) to form 2-aminohydronaphthoquinone, which is then in situ oxidized by naphthoquinone (I) to 2-aminohydronaphthoquinone, while 1,4-naphthalenediol is produced. Togni reagent (II) oxidizes the resulting 1,4-naphthalenediol to naphthoquinone (I) via a single electron transfer process and produces trifluoromethyl radicals and 2-iodobenzoic acid. Subsequently, the trifluoromethyl radical adds to 2-amino-1,4-naphthoquinone to form 2-amino-3-trifluoromethylnaphthoquinone carbon radical, which is further oxidized by Togni reagent (II) and deprotonated by a base to form the final 2-amino-3-trifluoromethylnaphthoquinone compound.

[0074] The above is an explanation of the preferred embodiments of the present invention to enable those skilled in the art to implement or use the present invention. Some modifications to these embodiments will be apparent to those skilled in the art. The general principles defined herein may be implemented in other embodiments without departing from the scope or spirit of the present invention. Therefore, the scope of the present invention is not limited by the specific embodiments described above.

Claims

1. A method for synthesizing 2-amino-3-trifluoromethylnaphthoquinone compounds, characterized in that: The synthesis steps include: The naphthoquinone compound of structure (I), the Togni reagent of structure (II), the amine of structure (III) and an appropriate amount of base are dissolved in a solvent, and stirred at room temperature in the dark to obtain a 2-amino-3-trifluoromethyl naphthoquinone compound having structure (IV): The specific structure of IV is:

2. A method for synthesizing 2-amino-3-trifluoromethylnaphthoquinone compounds according to claim 1, characterized in that: Preferably, the organic solvent is acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate or toluene.

3. A method for synthesizing 2-amino-3-trifluoromethylnaphthoquinone compounds according to claim 1, characterized in that: Preferably, the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-dimethylaminopyridine, triethylenediamine or triethylamine; and the inorganic base is potassium acetate, potassium phosphate or cesium carbonate.

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