A preparation method of triflate of para C-H bond of an aromatic amine compound

Abstract

The present application relates to the field of organic chemical synthesis, in particular to a preparation method of para-C-H bond triflate of arylamine compound, comprising the following steps: under low temperature conditions, dissolving arylamine compound a, high-valence iodine reagent and trifluoromethanesulfonic acid in a solvent to carry out esterification reaction, after the reaction is completed, the reaction system is treated to obtain the arylamine product b of para-triflate; the present application uses arylamine as a substrate, realizes the triflate of para-C-H bond of aromatic ring through PIFA and TfOH mediation, avoids the multi-step synthesis of traditional phenolic route, reduces reagent consumption and operation time; especially when the substrate is an unprotected arylamine, N-acylation protection and subsequent deprotection steps are not needed, the pre-functionalization link is avoided, the step economy is improved; moreover, the product prepared by the present application provides a dual functional group synthon with amino modification site and coupling site for subsequent construction of complex nitrogen-containing compounds, greatly widening the product derivatization approach.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis, specifically to a method for preparing aromatic amine compounds by para-CH bond trifluoromethanesulfonation. Background Technology

[0002] Aryl trifluoromethanesulfonates (Ar-OTf) are an important class of synthetic intermediates. Due to the strong electron-withdrawing effect of the trifluoromethanesulfonyl group, the -OTf group is considered an excellent class of "pseudo-halogenated" compounds, exhibiting reactivity comparable to aryl bromides. They can readily participate in various palladium-catalyzed cross-coupling reactions, such as the Suzuki-Miyaura, Stille, and Buchwald-Hartwig reactions. Therefore, aryl trifluoromethanesulfonates can transform the relatively inert CO system into friendly substrates capable of participating in diverse aryl editing, showing broad application prospects in organic synthesis, medicinal chemistry, and functional materials.

[0003] However, current methods for preparing aryl trifluoromethanesulfonates almost entirely rely on the reaction of phenolic compounds with electrophilic trifluoromethanesulfonating agents, with trifluoromethanesulfonic anhydride being the core reagent. To improve regioselectivity and functional group compatibility, expensive N-phenylbis(trifluoromethanesulfonyl)imide is also frequently used. These synthetic routes using phenol derivatives as starting materials generally suffer from lengthy reaction processes and difficulties in constructing the target product.

[0004] On the other hand, the functionalization of the aromatic ring CH bond of aromatic amines has been a long-standing research focus in the field of organic synthesis. Traditional aromatic ring CH functionalization of aromatic amines, especially para-sulfonation reactions, highly rely on a "protection-functionalization-deprotection" strategy. For example, the direct CH functionalization of aniline usually requires the use of an N-protecting group to control chemoselectivity. Specifically, Liu Huan reported in his master's thesis that, under the oxidation of iodobenzene trifluoroacetate, acetanilide (N-acetyl protected form) as a substrate reacted with benzenesulfonic acid / p-toluenesulfonic acid to obtain para-substituted sulfonates with high selectivity. Amélie Pialat et al. also used acetanilide as a substrate and reacted it with silver trifluoromethanesulfonate under iodine(III) oxidation conditions to prepare para-trifluoromethanesulfonated acetanilide compounds (Pialat et al., Org. Lett., 2013, 15, 1764). Although the above methods achieve para-selective sulfonation or trifluoromethanesulfonation, they still rely on the traditional route of N-protection-functionalization-deprotection, which is lengthy, has limited overall yield, and the amino group in the product is still in a protected state, which limits its direct use in the construction of complex molecules containing free amino groups. Summary of the Invention

[0005] To address the problems of substrate limitations, lengthy processes in phenolic routes, and reliance on protection / deprotection strategies in existing methods for preparing aryl trifluoromethanesulfonates, this invention proposes a method for preparing trifluoromethanesulfonates by para-CH bond esterification of aromatic amine compounds. This method not only features mild reaction conditions, simple operation, and readily available raw materials, but also significantly improves the economic efficiency of the process.

[0006] The technical solution adopted in this invention is as follows: A method for preparing para-CH bond trifluoromethanesulfonate esterification of aromatic amine compounds, comprising the following steps: under conditions of -20~25℃, aromatic amine compound a, [bis(trifluoroacetoxy)iodo]benzene (PIFA), and trifluoromethanesulfonic acid (TfOH) are mixed in an organic solvent to carry out an esterification reaction. After the reaction is completed, the reaction system is post-treated to obtain para-trifluoromethanesulfonate esterified aromatic amine product b.

[0007] Furthermore, the aromatic amine compound has the following structural formula: , In this configuration, an amino group is attached to the 1-position of the benzene ring, and an R group is attached to the amino group. 1 R is attached to the 2 and 6 positions of the benzene ring, respectively. 2 The benzene ring has R atoms attached to the 3 and 5 positions respectively. 3 The fourth position of the benzene ring is a hydrogen atom; R 1 Selected from hydrogen, alkyl, acyl, or alkylene; and when R 1 When R is alkylene, 1 The other end is attached to the 2 or 6 position of the benzene ring to form a nitrogen-containing fused heterocycle; Two Rs 2 Each is independently selected from hydrogen, alkyl, halogen, or alkylene; and when any R 2 When R is alkylene, 2 The other end is meta-connected to the adjacent benzene ring, forming a fused ring; Two Rs 3 Each is independently selected from hydrogen, alkyl, or halogen; and R 1 With R 2 They do not form a ring at the same time.

[0008] Furthermore, the molar ratio of the aromatic amine compound, [bis(trifluoroacetoxy)iodide]benzene, and trifluoromethanesulfonic acid is 1:(0.8~1.5):(2.5~4.0), and the esterification reaction time is 0.5~2 h.

[0009] Preferably, the molar ratio of aromatic amine compound, [bis(trifluoroacetoxy)iodide]benzene and trifluoromethanesulfonic acid is 1:1.1:3, the esterification reaction temperature is -20°C, and the esterification reaction time is 1 h.

[0010] Furthermore, the solvent is selected from dichloromethane (DCM), 1,2-dichloroethane (DCE) or trichloromethane, preferably dichloromethane.

[0011] Furthermore, the post-processing includes quenching, extraction, washing, drying, vacuum concentration, and column chromatography purification.

[0012] Further, the quenching agent is a saturated sodium bicarbonate solution; the extractant is dichloromethane and purified water; the detergent is a saturated sodium chloride solution; the desiccant is anhydrous sodium sulfate; and the eluent for column chromatography purification is petroleum ether and ethyl acetate.

[0013] Furthermore, the volume ratio of petroleum ether to ethyl acetate is 8:1 to 5:1, preferably 5:1.

[0014] The present invention also provides a para-trifluoromethanesulfonated aromatic amine product, which is prepared by any of the above preparation methods.

[0015] The para-trifluoromethanesulfonated aromatic amine product has the following structural formula: .

[0016] Compared with the prior art, the beneficial effects of the present invention are: (1) This invention uses aromatic amines as substrates and achieves trifluoromethanesulfonation of the para-CH bond of the aromatic ring through PIFA and TfOH mediation. This not only expands the substrate range of aryl trifluoromethanesulfonate preparation methods but also avoids the multi-step synthesis of traditional phenolic routes, reducing reagent consumption and operation time. It features mild reaction conditions and readily available raw materials. In particular, when the substrate is an unprotected aromatic amine, it also eliminates the need for N-acylation protection and subsequent deprotection steps, further avoiding the cumulative yield loss caused by separation and purification in the protection / deprotection steps and improving the efficiency of the process.

[0017] (2) The product prepared by this invention is an aryl trifluoromethanesulfonate with a free amino group retained. The leaving ability of -OTf is far superior to that of -OTs or -OSO2Ph, enabling it to participate efficiently in various palladium-catalyzed cross-coupling reactions; simultaneously, the free amino group can independently undergo acylation, alkylation, and other derivatization reactions. The product prepared by this invention provides bifunctional synthons with both amino modification sites and coupling sites for the subsequent construction of complex nitrogen-containing compounds, greatly broadening the product derivatization pathway. Attached Figure Description

[0018] Figure 1 Product 1b prepared in Example 1 of the present invention 1 H NMR; Figure 2 Product 1b prepared in Example 1 of the present invention13 C NMR; Figure 3 Product 1b prepared in Example 1 of the present invention 19 F NMR; Figure 4 Product 4b prepared in Example 4 of this invention 1 H NMR; Figure 5 Product 4b prepared in Example 4 of this invention 13 C NMR; Figure 6 Product 4b prepared in Example 4 of this invention 19 F NMR) Figure 7 The product 11b prepared in Example 11 of the present invention 1 H NMR; Figure 8 The product 11b prepared in Example 11 of the present invention 13 C NMR; Figure 9 The product 11b prepared in Example 11 of the present invention 19 F NMR; Figure 10 The product 14b prepared in Example 14 of this invention 1 H NMR; Figure 11 The product 14b prepared in Example 14 of this invention 13 C NMR; Figure 12 The product 14b prepared in Example 14 of the present invention 19 F NMR) Figure 13 The product 19b prepared in Example 19 of the present invention 1 H NMR; Figure 14 The product 19b prepared in Example 19 of the present invention 13 C NMR; Figure 15 The product 19b prepared in Example 19 of the present invention 19 F NMR. Detailed Implementation

[0019] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0020] It should be noted that, in this invention, "unprotected aromatic amine compounds" refers to compounds in which the hydrogen on the amino group is not replaced by protecting groups such as acyl, sulfonyl, or alkoxycarbonyl groups, i.e., the amino group is in the form of free -NH2 or -NHR.

[0021] Example 1 The reaction formula is as follows: At -20℃, 1a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) were mixed with 3 mL DCM and reacted for 1 h. Saturated sodium bicarbonate solution was then slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 1b, with a separation yield of 78%. The NMR spectral characterization data of product 1b are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.13 – 6.97 (m,2H), 6.72 – 6.61 (m, 2H), 3.81 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ146.57, 141.72, 122.33, 118.9z(q, J = 321 Hz), 115.63. 19 F NMR (376 MHz, Chloroform-d) δ -72.78. Example 2 The reaction formula is as follows: At -20℃, 2a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) were mixed with 3 mL DCM and reacted for 1 h. Saturated sodium bicarbonate solution was then slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 2b, with a yield of 76%. The NMR spectral characterization data of product 2b are as follows: 1 H NMR (400 MHz, CDCl3) δ 6.99 – 6.88 (m, 2H), 6.64 (d, J = 8.54 Hz, 1H), 3.74 (s, 2H), 2.17 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 144.74, 141.52, 123.74, 123.08, 118.9z (q, J = 321 Hz), 115.14, 17.61. 19 F NMR (376 MHz, Chloroform-d) δ -72.85. HRMS (ESI): m / z [M +H] + calcd for Chemical Formula: C8H8F3NO3S: 256.0250; found: 256.0254. Example 3 The reaction formula is as follows: At -20℃, 3a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) were mixed with 3 mL of DCM and reacted for 1 h. Saturated sodium bicarbonate solution was then slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 3b, with a yield of 67%. The NMR spectral characterization data of product 3b are as follows: 1H NMR (400 MHz, Chloroform-d) δ 6.86 (s, 2H), 3.85 (s, 2H), 2.18 (s, 6H). 13 C NMR (101 MHz, Chloroform- d ) δ 142.88, 140.90,122.84, 120.68, 118.9(q, J = 321 Hz), 17.82. 19 F NMR (376 MHz, Chloroform- d ) δ -72.94. HRMS (ESI): m / z [M + H] + calcd for Chemical Formula: C9H 11 F3NO3S:270.0406; found: 270.0412. Example 4 The reaction formula is as follows: At -20℃, 4a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) were mixed with 3 mL DCM and reacted for 1 h. Saturated sodium bicarbonate solution was then slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 4b, with a yield of 66%. The NMR spectral characterization data of product 4b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.26 (s, 2H), 6.95 (d, J = 8.6 Hz, 1H), 4.05 (s, 2H), 2.80 (q, J = 7.5 Hz, 2H), 1.56 (t, J =7.5 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d) δ 144.16, 141.99, 129.41, 120.99,119.56, 118.9(q, J = 321 Hz), 115.56, 23.95, 12.46. 19 F NMR (376 MHz, Chloroform- d ) δ -72.85. HRMS (ESI): m / z [M + H] + calcd for Chemical Formula:C9H 11 F3NO3S: 270.0403; found: 270.0403. Example 5 The reaction formula is as follows: At -20℃, 5a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) were mixed with 3 mL of DCM and reacted for 1 h. Saturated sodium bicarbonate solution was then slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 5b, with a yield of 51%. The NMR spectral characterization data of product 5b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 6.93 (d, J = 7.6Hz, 2H), 6.64 (dt, J = 9.2, 1.5 Hz, 1H), 3.75 (s, 2H), 2.48 – 2.40 (m, 2H), 1.65 (dq, J = 14.8, 7.4 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ144.28, 141.80, 128.02, 122.06, 119.62, 118.9(q, J= 321 Hz),115.74, 77.37, 33.20, 21.35, 14.02. 19 F NMR (376 MHz, Chloroform- d ) δ -72.82.HRMS (ESI): m / z [M + H] + calcd for Chemical Formula: C 10 H 13 F3NO3S: 284.0563; found: 284.0560. Example 6 The reaction formula is as follows: At -20℃, 6a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) were mixed with 3 mL of DCM and reacted for 1 h. Saturated sodium bicarbonate solution was then slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 6b, with a yield of 63%. The NMR spectral characterization data of product 6b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.09 (d, J = 2.9Hz, 1H), 6.93 (dd, J = 8.7, 2.9 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 3.95 (s, 2H), 1.41 (s, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ 144.73, 141.97, 135.18,119.87, 119.57, 118.9(q, J = 321 Hz), 117.94, 34.49, 29.23. 19 F NMR (376 MHz, Chloroform- d) δ -72.89. HRMS (ESI): m / z [M + H] + calcd for Chemical Formula: C 11 H 15 F3NO3S: 298.0719; found: 298.0712. Example 7 The reaction formula is as follows: At -20℃, 7a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) were mixed with 3 mL of DCM and reacted for 1 h. Saturated sodium bicarbonate solution was then slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 7b, with a yield of 68%. The NMR spectral characterization data of product 7b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.00 (d, J = 2.9Hz, 1H), 6.91 (dd, J = 8.7, 2.9 Hz, 1H), 6.64 (d, J = 8.7 Hz, 1H), 3.79 (s,2H), 2.85 (hept, J = 6.8 Hz, 1H), 1.25 (d, J = 6.8 Hz, 6H). 13 C NMR (101 MHz, Chloroform- d ) δ 143.51, 142.31, 134.12, 119.33, 118.64, 118.9(q, J = 321 Hz),116.11, 27.99, 21.95. 19 F NMR (376 MHz, Chloroform- d ) δ -72.86. HRMS (ESI): m / z[M + H] +calcd for Chemical Formula: C 10 H 13 F3NO3S: 284.0563; found: 284.0562 Example 8 The reaction formula is as follows: At -20℃, 8a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) were mixed with 3 mL DCM and reacted for 1 h. Saturated sodium bicarbonate solution was then slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 8b, with a yield of 20%. The NMR spectral characterization data of product 8b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.21 (d, J = 2.8Hz, 1H), 7.00 (dd, J = 8.9, 2.8 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 4.21 (s, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 143.35, 140.54, 122.65, 120.98, 119.02,118.8(q, J = 321 Hz), 115.62. 19 F NMR (376 MHz, Chloroform- d ) δ -72.65. HRMS(ESI): m / z [M + H] + calcd for Chemical Formula: C7H6ClF3NO3S: 275.9704; found:275.9701. Example 9 The reaction formula is as follows: At -20℃, 9a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) were mixed with 3 mL of DCM and reacted for 1 h. Saturated sodium bicarbonate solution was then slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 9b, with a yield of 77%. The NMR spectral characterization data of product 9b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 6.99 (d, J = 8.7Hz, 1H), 6.53 (d, J = 2.9 Hz, 1H), 6.48 (dd, J = 8.7, 2.9 Hz, 1H), 3.73 (s, 2H), 2.28 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 146.33, 140.78, 131.90,122.20, 120.38, 118.8(q, J = 320 Hz), 117.51, 113.34, 16.56. 19 F NMR (376 MHz, Chloroform- d ) δ -73.86. Example 10 The reaction formula is as follows: At -20℃, 10a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) and 3 mL DCM were mixed and reacted for 1 h. Saturated sodium bicarbonate solution was slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 10b, with a separation yield of 70%. The NMR spectral characterization data of product 10b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.00 (d, J = 8.7 Hz, 1H), 6.59 (d, J = 2.9 Hz, 1H), 6.51 (dd, J = 8.8, 2.9 Hz, 1H), 3.82(s, 2H), 2.64 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 145.95, 140.42, 137.77, 122.19, 118.7(q, J = 320 Hz). 116.19,113.66, 23.16, 13.98. 19 F NMR (376 MHz, Chloroform- d ) δ -74.01. HRMS (ESI): m / z[M + H] + calcd for C9H 11 F3NO3S: 270.0406; found: 270.0408. Example 11 The reaction formula is as follows: At -20℃, 11a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) and 3 mL DCM were mixed and reacted for 1 h. Saturated sodium bicarbonate solution was then slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 8:1 as eluent to obtain product 11b, with a yield of 61%. The NMR spectral characterization data of product 11b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 6.37 (s,2H), 3.62 (s, 2H), 2.27 (s, 6H). 13 C NMR (101 MHz, Chloroform- d ) δ 145.68,139.08, 132.30, 118.6(q, J = 321 Hz). 115.47, 17.16. 19 F NMR (376 MHz, Chloroform- d ) δ -73.65. HRMS (ESI): m / z [M + H] + calcd for C9H 11 F3NO3S:270.0406; found: 270.0407. Example 12 The reaction formula is as follows: At -20℃, 12a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) and 3 mL DCM were mixed and reacted for 1 h. Saturated sodium bicarbonate solution was slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 8:1 as eluent to obtain product 12b, with a yield of 61%. The NMR spectral characterization data of product 12b are as follows:1 H NMR (400 MHz, Chloroform- d ) δ 6.90 (s,1H), 6.51 (s, 1H), 3.66 (s, 2H), 2.25 (s, 3H), 2.12 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 144.48, 140.38, 129.11, 122.88, 121.24, 118.8(q, J = 321 Hz). 19 F NMR (376 MHz, Chloroform- d ) δ -73.91. HRMS (ESI): m / z [M + H] + calcd forC9H 11 F3NO3S: 270.0406; found: 270.0402. Example 13 The reaction formula is as follows: At -20℃, 13a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) and 3 mL DCM were mixed and reacted for 1 h. Saturated sodium bicarbonate solution was slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 8:1 as eluent to obtain product 13b, with a yield of 68%. The NMR spectral characterization data of product 13b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 6.92 (d, J = 8.8 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 3.84 (s, 2H), 2.26 (s, 3H), 2.10 (s, 3H). 13 C NMR (101 MHz, Chloroform- d) δ 144.43, 141.18, 129.98, 122.71, 119.29,118.9(q, J = 320 Hz), 113.15, 13.73, 13.55. 19 F NMR (376 MHz, Chloroform- d ) δ -73.79. HRMS (ESI): m / z [M + H] + calcd for C9H 11 F3NO3S: 270.0407; found:270.0405. Example 14 The reaction formula is as follows: At -20℃, 14a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) and 3 mL DCM were mixed and reacted for 1 h. Saturated sodium bicarbonate solution was slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 14b, with a yield of 55%. The NMR spectral characterization data of product 14b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 6.99 (d, J= 8.8 Hz, 1H), 6.61 (d, J = 2.9 Hz, 1H), 6.49 (dd, J = 8.8, 2.9 Hz, 1H), 3.76(s, 2H), 3.19 (hept, J = 6.8 Hz, 1H), 1.22 (d, J = 6.9 Hz, 6H). 13 C NMR (101MHz, Chloroform- d ) δ 146.60, 142.34, 139.39, 122.17, 120.3, 118.8(q, J = 320Hz), 113.41, 113.28, 27.23, 23.19. 19 F NMR (376 MHz, Chloroform-d ) δ -73.96. Example 15 The reaction formula is as follows: At -20℃, 15a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) and 3 mL DCM were mixed and reacted for 1 h. Saturated sodium bicarbonate solution was slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 15b, with a yield of 67%. The NMR spectral characterization data of product 15b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.09 (d, J = 8.7 Hz, 1H), 6.70 (d, J = 2.9 Hz, 1H), 6.50 (dd, J = 8.8, 2.9 Hz, 1H), 3.74(s, 2H), 1.39 (s, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ 145.69, 142.74,141.48, 122.31, 118.5(q, J = 320 Hz), 114.60, 113.22, 34.77, 30.41. 19 F NMR (376MHz, Chloroform- d ) δ -74.39. HRMS (ESI): m / z [M + H] + calcd for C 11 H 15 F3NO3S:298.0720; found: 298.0715 Example 16 The reaction formula is as follows: At -20℃, 16a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) and 3 mL DCM were mixed and reacted for 1 h. Saturated sodium bicarbonate solution was slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 16b, with a yield of 60%. The NMR spectral characterization data of product 16b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 6.87 (d, J = 8.6 Hz, 1H), 6.47 (d, J = 8.6 Hz, 1H), 3.67 (s, 2H), 3.02 (t, J = 7.5 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.16 (p, J = 7.5 Hz, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 142.43, 138.66, 137.48, 131.12, 120.05, 118.8(q, J = 320 Hz),113.49, 30.66, 30.23, 24.67. 19 F NMR (376 MHz, Chloroform- d ) δ -73.69. HRMS(ESI): m / z [M + H] + calcd for C 10 H 11 F3NO3S: 282.0407; found: 282.0405. Example 17 The reaction formula is as follows: At -20℃, 17a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) and 3 mL DCM were mixed and reacted for 1 h. Saturated sodium bicarbonate solution was slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 17b, with a yield of 73%. The NMR spectral characterization data of product 17b are as follows: 1 H NMR (400 MHz, Chloroform- d 6.90 (d, J =8.69 Hz, 1H), 6.50 (d, J = 8.71 Hz, 1H), 3.68 (s, 2H), 2.75 (t, J = 6.21 Hz, 2H), 2.43 (t, J = 6.36 Hz, 2H), 1.90 – 1.82 (m, 2H), 1.81 – 1.73 (m, 2H). 13 CNMR (101 MHz, Chloroform- d ) δ 144.25, 140.67, 131.11, 123.53, 118.76, 118.7(q, J = 320 Hz), 112.19, 24.43, 24.19, 22.14, 21.69. 19 F NMR (376 MHz, Chloroform- d ) δ -73.99. HRMS (ESI): m / z [M + H] + calcd for C 11 H 13 F3NO3S:296.0563; found: 296.0563. Example 18 The reaction formula is as follows: At -20℃, 18a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) and 3 mL DCM were mixed and reacted for 1 h. Saturated sodium bicarbonate solution was slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 18b, with a yield of 65%. The NMR spectral characterization data of product 18b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.45 –7.31 (m, 2H), 7.03 – 6.93 (m, 2H), 1.95 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 168.65, 145.42, 138.05, 122.11, 121.14, 120.44, 117.25, 24.71. Example 19 The reaction formula is as follows: At -20℃, 19a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) and 3 mL DCM were mixed and reacted for 1 h. Saturated sodium bicarbonate solution was slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 19b, with a yield of 68%. The NMR spectral characterization data of product 19b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 6.99 (dd, J = 2.6, 1.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.6 Hz, 1H), 6.55 (d, J= 8.5 Hz, 1H), 3.62 (t, J = 8.5 Hz, 2H), 3.06 (t, J = 8.5 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 151.58, 142.00, 131.22, 120.24, 118.9(q, J = 321 Hz), 118.11, 108.90,47.87, 29.78. 19 F NMR (376 MHz, Chloroform- d ) δ -72.82. HRMS (ESI): m / z [M + H] + calcd for C9H9F3NO3S: 268.0250; found: 268.0251. Example 20 The reaction formula is as follows: At -20℃, 20a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) and 3 mL DCM were mixed and reacted for 1 h. Saturated sodium bicarbonate solution was slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 20b, with a yield of 51%. The NMR spectral characterization data of product 20b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 7.11 –7.04 (m, 2H), 6.59 – 6.52 (m, 2H), 3.92 (s, 1H), 2.83 (s, 3H). 13 C NMR (101MHz, Chloroform- d ) δ 49.12, 140.83, 122.12, 118.9(q, J = 321 Hz), 112.62, 30.75. 19 F NMR (376 MHz, Chloroform-d ) δ -72.81. HRMS (ESI): m / z [M + H] + calcdfor C8H9F3NO3S: 256.0250; found: 256.0247. Example 21 The reaction formula is as follows: At -20℃, 21a (0.5 mmol), PIFA (0.55 mmol), TfOH (1.5 mmol) and 3 mL DCM were mixed and reacted for 1 h. Saturated sodium bicarbonate solution was slowly added dropwise, and the reaction was monitored by thin-layer chromatography (TLC) until termination. The reaction mixture was then transferred to a 250 mL separatory funnel and extracted with DCM (15 mL × 3) and purified water. The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography using petroleum ether / ethyl acetate = 5:1 as eluent to obtain product 21b, with a yield of 60%. The NMR spectral characterization data of product 21b are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 6.83 (dt, J = 5.7, 2.2 Hz, 2H), 6.44 – 6.35 (m, 1H), 4.01 (s, 1H), 3.33 – 3.28 (m, 2H), 2.75 (t, J = 6.4 Hz, 2H), 1.97 – 1.88 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ144.69, 140.32, 122.27, 122.05, 118.9(q, J = 321 Hz), 119.63, 114.16, 41.76,27.10, 21.40. 19 F NMR (376 MHz, Chloroform- d ) δ -72.89. HRMS (ESI): m / z [M + H] + calcd for C 10 H 11 F3NO3S: 282.0407; found: 282.0407. Example 22 The difference between this embodiment and Example 1 is that the esterification reaction temperature was 25°C. The obtained product was confirmed by NMR to be 1b, with a separation yield of 58%.

[0022] Example 23 The difference between this embodiment and Example 1 is that the esterification reaction temperature was 0°C. The obtained product was confirmed as 1b by NMR, with a separation yield of 63%.

[0023] Example 24 The difference between this embodiment and Example 1 is that the PIFA content is 0.4 mmol. The obtained product was confirmed as 1b by NMR, with a separation yield of 52%.

[0024] Example 25 The difference between this embodiment and Example 1 is that the PIFA content is 0.75 mmol. The obtained product was confirmed as 1b by NMR, with a separation yield of 50%.

[0025] Example 26 The difference between this embodiment and Example 1 is that the TfOH content is 1.25 mmol. The obtained product was confirmed as 1b by NMR, with a separation yield of 61%.

[0026] Example 27 The difference between this embodiment and Example 1 is that the TfOH concentration was 2 mmol. The obtained product was confirmed as 1b by NMR, with a separation yield of 66%.

[0027] Example 28 The difference between this embodiment and Example 1 is that the esterification reaction time was 0.5 h. The obtained product was confirmed as 1b by NMR, with a separation yield of 51%.

[0028] Example 29 The difference between this embodiment and Example 1 is that the esterification reaction time was 2 hours. The obtained product was confirmed by NMR to be 1b, with a separation yield of 74%.

[0029] Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that the PIFA content was 0.25 mmol. The obtained product was confirmed as 1b by NMR, with a separation yield of only 16%. This indicates that the reaction efficiency is significantly reduced when the amount of PIFA is less than 0.8 equivalents of the substrate.

[0030] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that the amount of TfOH was 0.5 mmol. Nuclear magnetic resonance (NMR) analysis revealed that product 1b was not obtained, with a separation yield of 0%. This indicates that the reaction cannot proceed effectively when the amount of TfOH is too low.

[0031] Reaction mechanism Taking Example 1 as an example, a preliminary exploration was conducted into the possible mechanism of the trifluoromethanesulfonation reaction of the para-CH bond in the aromatic amine compounds of the present invention. First, a free radical inhibition experiment was used to clarify whether the present invention involves a free radical mechanism: 1 mmol of the free radical inhibitors TEMPO, BHT, and 1,4-benzoquinone were added to the reaction system of Example 1, respectively, to obtain three sets of parallel control experiments. The specific reaction routes are as follows: The separation yields were 32% with the addition of TEMPO, 37% with the addition of BHT, and 28% with the addition of 1,4-benzoquinone. The results indicate that the presence of free radical inhibitors did not completely suppress the formation of the target product; the reaction proceeded smoothly, with only a decrease in yield. Based on these results, the possibility of the reaction proceeding via a free radical intermediate pathway can be ruled out, indicating that the reaction belongs to an ionic electrophilic substitution pathway.

[0032] Based on the above experimental results, this invention proposes the following possible reaction mechanism: Substrate 1a preferentially reacts with trifluoromethanesulfonic acid to generate aniline trifluoromethanesulfonate intermediate Anil-1; simultaneously, PIFA, as an electrophilic oxidant capable of activating electron-rich aromatic rings, forms a more reactive high-valent iodine species under the promotion of TfOH, which causes intermediate Anil-1 to form intermediate Anil-2. Subsequently, the trifluoromethanesulfonate ion in the system selectively acts on the para-carbon of intermediate Anil-2, because this site is electrophilic and has minimal steric hindrance due to activation by high-valent iodine; at the same time, iodobenzene and (trifluoro)acetate ions leave, thereby generating trifluoromethanesulfonate intermediate Anil-3 of product 1b. Finally, under the alkaline action of saturated sodium bicarbonate solution, the ammonium salt on intermediate Anil-3 is neutralized, the amino group is restored to a free state, and the trifluoromethanesulfonate ion is released, yielding product 1b.

[0033] All parts not disclosed in this invention are prior art, and their specific structures, materials, and working principles will not be described in detail. Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing an aromatic amine compound by para-CH bond trifluoromethanesulfonation, characterized in that, Includes the following steps: An esterification reaction was carried out by mixing aromatic amine compounds, [bis(trifluoroacetoxy)iodide]benzene, and trifluoromethanesulfonic acid in an organic solvent at -20 to 25 °C. After the reaction was completed, the reaction system was post-treated to obtain the para-trifluoromethanesulfonated aromatic amine product.

2. The method for preparing an aromatic amine compound by para-CH bond trifluoromethanesulfonation according to claim 1, characterized in that, The aromatic amine compounds have the following structural formulas: ， In this configuration, an amino group is attached to the 1-position of the benzene ring, and an R group is attached to the amino group. 1 R is attached to the 2 and 6 positions of the benzene ring, respectively. 2 The benzene ring has R atoms attached to the 3 and 5 positions respectively. 3 The fourth position of the benzene ring is a hydrogen atom; R 1 Selected from hydrogen, alkyl, acyl, or alkylene; and when R 1 When R is alkylene, 1 The other end is attached to the 2 or 6 position of the benzene ring to form a nitrogen-containing fused heterocycle; Two Rs 2 Each is independently selected from hydrogen, alkyl, halogen, or alkylene; and when any R 2 When R is alkylene, 2 The other end is meta-connected to the adjacent benzene ring, forming a fused ring; Two Rs 3 Each is independently selected from hydrogen, alkyl, or halogen; and R 1 With R 2 They do not form a ring at the same time.

3. The method for preparing an aromatic amine compound by para-CH bond trifluoromethanesulfonation according to claim 1, characterized in that, The molar ratio of the aromatic amine compound, [bis(trifluoroacetoxy)iodide]benzene, and trifluoromethanesulfonic acid is 1:(0.8~1.5):(2.5~4.0), and the esterification reaction time is 0.5~2 h.

4. The method for preparing an aromatic amine compound by para-CH bond trifluoromethanesulfonation according to claim 1, characterized in that, The organic solvent is selected from dichloromethane, 1,2-dichloroethane, or trichloromethane.

5. The method for preparing an aromatic amine compound by para-CH bond trifluoromethanesulfonation according to claim 1, characterized in that: The post-processing includes quenching, extraction, washing, drying, vacuum concentration, and column chromatography purification.

6. The method for preparing an aromatic amine compound by para-CH bond trifluoromethanesulfonation according to claim 5, characterized in that: The quenching agent is a saturated sodium bicarbonate solution; the extractant is dichloromethane (DCM) and purified water; the detergent is a saturated sodium chloride solution; the desiccant is anhydrous sodium sulfate; and the eluent for column chromatography purification is petroleum ether and ethyl acetate.

7. The method for preparing an aromatic amine compound by para-CH bond trifluoromethanesulfonation according to claim 6, characterized in that: The volume ratio of petroleum ether to ethyl acetate is 8:1 to 5:

1.

8. A para-trifluoromethanesulfonated aromatic amine product, characterized in that, It is prepared by the preparation method according to any one of claims 1-7.

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