Method for preparing secondary amine derivative through acid-promoted intramolecular hydrogen transfer reductive amination

Abstract

The invention provides a method for preparing a secondary amine derivative by acid-promoted intramolecular hydrogen transfer reductive amination, which comprises the following steps: reacting a 2-dihydro nitrogen fused ring aniline derivative with aldehydes under the conditions of room temperature and normal pressure by using Bronsted acid as a catalyst to obtain the secondary amine derivative. The reaction does not need an additional reducing hydrogen source and can be carried out at room temperature and normal pressure, the reaction process is simple, raw materials are cheap and easy to obtain, the yield is high, and the method is an efficient, safe and environment-friendly production process.

Description

Technical Field

[0001] This application belongs to the field of organic synthesis technology, and in particular relates to a method for preparing secondary amine derivatives by acid-promoted intramolecular hydrogen transfer reductive amination. Background Technology

[0002] Secondary amines, also known as imines or secondary amines, are an important class of fine chemicals widely used in pharmaceutical active molecules and organic functional materials. Examples include antimalarial drugs, anti-asthmatic drugs, transition metal catalyst ligands, and organic light-emitting materials. Therefore, efficient and environmentally friendly synthetic methods for secondary amines have attracted widespread attention from researchers.

[0003] Due to the diverse applications of secondary amines, the synthesis of these compounds and their derivatives has become a hot topic, particularly the development of simple, efficient, and mild methods for synthesizing them. Currently reported synthetic methods mainly include the following: Chusov et al. reported a novel reductive amination method without a catalyst, using only sodium hypophosphite (NaH2PO2·H2O). By directly mixing 0.5–1.0 equivalents of reducing agent with 1.0–2.0 equivalents of amine and 1.0 equivalent of carbonyl compound, the reaction was carried out at 130–200 °C, successfully yielding the corresponding secondary amine, with phosphate as a byproduct.

[0004] This method has drawbacks such as high temperature, limited heat-sensitive functional groups, and easy mixing of polyamines. Furthermore, the reducing agent sodium hypophosphite has low solubility, the reaction is heterogeneous, and scale-up is difficult. J. Org. Chem., 2025, 90 , 11081-11090.).

[0005] Zhang et al. reported an intramolecular asymmetric reductive amination using secondary amines as the nitrogen source. Iridium / bisphosphine ligands + Ti(OiPr)4, reacted at 50 atm H2 and 25 °C for 24 h, cyclized pyridinylaminoketone hydrochloride into a chiral tertiary amine heterocycle in one step, achieving an ee of up to 99% and a broad substrate range. Ti(OiPr)4 promoted reversible imine / enamine condensation, generating crowded imine cations. High enantiomeric control was achieved through ionic hydrogenation of the iridium-hydrogen complex via directional hydrogen transfer. This method also has significant drawbacks: it requires high-pressure hydrogen at 50 atm, placing high demands on equipment; the catalyst precursor and custom ligands are not commercially available, resulting in high preparation costs and difficulties. Org. Lett .,2025, 27 , 6726-6731.).

[0006] Shao et al. reported a chiral phosphoric acid-catalyzed asymmetric reductive amination to construct axially chiral styrene-type allylamines. The product was obtained in 3 days at room temperature via imine-transfer hydrogenation and kinetic resolution of 1-enal-substituted 2-naphthol with an aromatic amine in a CPA / Hantzsch ester system. This method is simple, has a broad substrate base, and is under mild conditions. However, the reaction requires a stoichiometric Hantzsch ester, has low atom economy, and a relatively long reaction time. Org.Chem.Front., 2022 , 9 , 764-770.).

[0007] While the above reactions can effectively synthesize secondary amines and their derivatives, they also have several drawbacks: the use of additional reducing hydrides, such as hydrogen or borohydrides, introduces a series of high-pressure conditions, increasing the risk of the reaction to some extent; the use of transition metal or noble metal catalysts increases the cost of the synthesis process and the environmental pollution caused by the metals; and some reactions require temperatures as high as 200°C. o C does not conform to the development trend and requirements of green synthesis. Summary of the Invention

[0008] The purpose of this application is to provide a method for preparing secondary amine derivatives by acid-promoted intramolecular hydrogen transfer reductive amination, which aims to solve the problems of additional hydrogen source use, catalyst contamination, and high reaction temperature mentioned in the background art.

[0009] A method for preparing secondary amine derivatives by acid-promoted intramolecular hydrogen transfer reductive amination involves using Brønsted acid as a catalyst, and reacting a 2-dihydro-nitrogen-fused-cyclic aniline derivative with an aldehyde under room temperature and atmospheric pressure conditions to yield the secondary amine derivative; the reaction formula is as follows: , Among them, R 1 and R 2 Each substituent is independently selected from one of hydrogen, halogen, amino, carboxyl, ester, acyl, cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; R 3 It is a substitute for an aryl or alkyl group.

[0010] The technical advantages of this application are as follows: This invention rapidly condenses an aldehyde and a 2-dihydronitrogen-fused-cyclic aniline derivative under the promotion of Brønsted acid, followed by an intramolecular hydrogen transfer reducing amination reaction to obtain a secondary amine derivative with higher added value. This process does not require an additional reducing hydrogen source or high reaction pressure and can be rapidly obtained at room temperature and atmospheric pressure. The process is simple, safe, environmentally friendly, and has a short reaction time, yielding a high amount of secondary amine derivatives, thus possessing potential industrial application value. Attached Figure Description

[0011] Figure 1 The above is the 1H NMR spectrum of compound 3aa in the examples; Figure 2 The image shows the carbon NMR spectrum of compound 3aa in the examples; Figure 3 The above is the 1H NMR spectrum of compound 3ab in the examples; Figure 4 The image shows the carbon NMR spectrum of compound 3ab in the examples; Figure 5 The above is the 1H NMR spectrum of compound 3ba in the examples; Figure 6 The image shows the carbon NMR spectrum of compound 3ba in the examples; Figure 7 The image shows the carbon NMR spectrum of compound 3ca in the examples; Figure 8 The image shows the carbon NMR spectrum of compound 3ca in the examples. Detailed Implementation

[0012] The embodiments of the technical solution of this application will now be described in detail with reference to the accompanying drawings. These embodiments are only used to more clearly illustrate the technical solution of this application and are therefore merely examples, and should not be used to limit the scope of protection of this application.

[0013] A method for preparing secondary amine derivatives via acid-promoted intramolecular hydrogen transfer reductive amination is described, using Brønsted acid as a catalyst. Under room temperature and atmospheric pressure conditions, a 2-dihydro-nitrogen-fused-cyclic aniline derivative reacts with aldehydes to yield the secondary amine derivative. The reaction formula is as follows: , Among them, R 1 and R 2 Each substituent is independently selected from one of hydrogen, halogen, amino, carboxyl, ester, acyl, cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; R 3 It is a substitute for an aryl or alkyl group.

[0014] The 2-dihydronitrogen-fused-ring aniline derivative described in this application has a fused ring at position 2 of the aniline ring, and the ring connected to the aniline ring is a heterocycle containing a nitrogen-hydrogen bond located at position 2 of the heterocycle. After the reaction, the hydrogen on the nitrogen-hydrogen bond undergoes transfer reduction of the imine.

[0015] In a preferred embodiment, the Brønsted acid is selected from one of benzenesulfonic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, 1-heptanesulfonic acid, dodecylbenzenesulfonic acid, difluoroacetic acid, hydrochloric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid.

[0016] In a preferred embodiment, the molar ratio of the Brønsted acid to the aldehyde is (0.1 to 3.0): 1.

[0017] In a preferred embodiment, the molar ratio of the aldehyde to the 2-dihydronitrogen-fused-ring aniline derivative is 1:(0.9~3.0).

[0018] In a preferred embodiment, the reaction time is 5 min to 5 h.

[0019] In a preferred embodiment, the reaction is carried out in a solvent selected from one of hexafluoroisopropanol, trifluoroethanol, N,N-dimethylformamide, water, methanol, ethanol, acetonitrile, benzene, xylene, ethyl acetate, toluene, tetrahydrofuran, 1,4-dioxane, and dimethyl sulfoxide.

[0020] In a preferred embodiment, the 2-dihydro-nitrogen-fused-cyclic aniline derivative is selected from one of 2-dihydropyrroloquinoxalinylaniline, 2-(5,6-dihydrophenanthridine-6-yl)aniline, 2-(2,3-dihydrobenzo[d]oxazol-2-yl)aniline, 2-(1,2-dihydroquinazin-2-yl)aniline, 2-(2,3-dihydrobenzo[d]thiazolyl)aniline, 2-(2,3-dihydro-1H-benzo[d]imidazolyl)aniline, or a 2-(1,2-dihydroquinazolin-2-yl)aniline derivative.

[0021] In addition, the following are the structural formulas of some of the 2-dihydronitrogen-fused-ring aniline derivatives obtained in this application. The reaction solution containing the secondary amine derivative obtained from the reaction was concentrated under reduced pressure, purified by silica gel column chromatography, or directly filtered or pulped, and then vacuum dried to obtain the secondary amine derivative. The technical solutions and effects of this application will be further illustrated below through specific embodiments.

[0022] Example 1 Reactants: 2-dihydropyrroloquinoxalinylaniline, benzaldehyde; Solvent: dichloromethane; Catalyst: Trifluoromethanesulfonic acid; Reaction formula: .

[0023] 0.24 mmol of 2-dihydropyrroloquinoxalinylaniline 1a, 4 mL of dichloromethane, 0.3 mmol of trifluoromethanesulfonic acid, and 0.2 mmol of benzaldehyde 2a were added to a 10 mL reactor. A magnetic stir bar was added, and the reaction was carried out at room temperature for 15 min. The reaction was monitored by TLC. After the reaction was completed, the pH was adjusted by adding an appropriate amount of triethylamine to the system, and the reaction was quenched by stirring. The solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified by silica gel chromatography using petroleum ether:dichloromethane at a volume ratio of 5:1. N -benzyl-2-(pyrrole[1,2-) α Quinoxalo-4-yl)aniline 3aa, bright yellow solid, separation yield 95%.

[0024] Structural identification of compound 3aa: Nuclear magnetic resonance data: 1 H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 2.6 Hz, 1H), 7.92 ~ 7.77 (m,3H), 7.54 ~ 7.46 (m, 2H), 7.45 ~ 7.39 (m, 3H), 7.36 ~ 7.28 (m, 3H), 7.24 (d, J = 7.3 Hz, 1H), 7.02 (d, J = 3.9 Hz, 1H), 6.89 (dd, J = 4.0, 2.7 Hz, 1H), 6.80 (dt, J = 7.3, 3.1 Hz, 2H), 4.46 (s, 2H). 13 C NMR (125 MHz, CDCl3) δ :154.6, 147.4, 139.5, 135.3, 131.0, 130.5, 129.4, 128.6, 127.4, 127.3, 127.1, 127.0, 125.8, 125.3, 120.5, 115.8, 114.8, 114.0, 113.7, 111.9, 109.9, 47.7. Compound 3aa 1 H NMR, 13 C NMR such as Figure 1 ,like Figure 2 As shown in the figure, the analysis results indicate that the obtained target product has the correct structure.

[0025] Example 2 Reactants: 2-dihydropyrroloquinoxalinylaniline, 2-bromobenzaldehyde; Solvent: dichloromethane; Catalyst: Trifluoromethanesulfonic acid; Reaction formula: .

[0026] 2-Dihydropyrroloquinoxalinylaniline 1a (0.24 mmol), dichloromethane (4 mL), trifluoromethanesulfonic acid (0.3 mmol), and 2-bromobenzaldehyde 2b (0.2 mmol) were added to a 10 mL reactor. A magnetic stir bar was added, and the reaction was carried out at room temperature for 15 min. The reaction was monitored by TLC. After the reaction was completed, the pH was adjusted by adding an appropriate amount of triethylamine to the system, and the reaction was quenched by stirring. The solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified by silica gel chromatography using petroleum ether:dichloromethane at a volume ratio of 2:1. N -(2-Bromobenzyl)-2-(pyrrole[1,2-) α Quinazolin-4-yl)aniline 3ab, a bright yellow solid, with a separation yield of 97%.

[0027] Structural identification of compound 3ab: Nuclear magnetic resonance data: 1 H NMR (500 MHz, CDCl3) δ 8.00 (dd, J = 2.8, 1.3 Hz, 1H), 7.95 ~ 7.86(m, 2H), 7.84 (dd, J = 7.8, 1.6 Hz, 1H), 7.62 (s, 1H), 7.56 (dd, J = 8.0, 1.2Hz, 1H), 7.54 ~ 7.49 (m, 1H), 7.49 ~ 7.41 (m, 2H), 7.29 (ddd, J = 8.5, 7.3,1.6 Hz, 1H), 7.26 ~ 7.22 (m, 1H), 7.11 (td, J = 7.6, 1.7 Hz, 1H), 7.03 (dd, J = 3.9, 1.3 Hz, 1H), 6.90 (dd, J = 4.0, 2.7 Hz, 1H), 6.81 (t, J= 7.4 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 4.51 (s, 2H). 13 C NMR (125 MHz, CDCl3) δ : 154.5,147.1, 138.3, 135.3, 132.7, 131.0, 130.5, 129.5, 128.8, 128.5, 127.6, 127.5,127.1, 125.8, 125.3, 123.2, 120.7, 116.1, 114.9, 114.0, 113.7, 112.0, 109.9,47.9. Compound 3ab 1 H NMR, 13 C NMR such as Figure 3 ,like Figure 4 As shown in the figure, the analysis results indicate that the obtained target product has the correct structure.

[0028] Example 3 Reactant: 2-(7-(4-(tert-butyl)phenyl)-4,5-dihydropyrrolo[1,2- α Quinoxalo-4-yl)aniline, benzaldehyde; Solvent: dichloromethane; Catalyst: Trifluoromethanesulfonic acid; Reaction formula: .

[0029] 2-(7-(4-(tert-butyl)phenyl)-4,5-dihydropyrrolo[1,2- α Quinoxalo-4-yl)aniline 1L (0.24 mmol), dichloromethane (4 mL), trifluoromethanesulfonic acid (0.3 mmol), and benzaldehyde 2a (0.2 mmol) were added to a 10 mL reactor. A magnetic stir bar was added, and the reaction was carried out at room temperature for 15 min. The reaction was monitored by TLC. After the reaction was completed, an appropriate amount of triethylamine was added to the system to adjust the pH, and the reaction was quenched by stirring. The solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified by silica gel chromatography using petroleum ether:dichloromethane at a volume ratio of 3:1. N -benzyl-2-(7-(4-(tert-butyl)phenyl)pyrrolo[1,2- α Quinoxalo-4-yl)aniline 3ba, a bright yellow solid, with a separation yield of 96%.

[0030] Structural identification of compound 3ba: Nuclear magnetic resonance data: 1 H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 2.2 Hz, 1H), 7.99 (dd, J =2.8, 1.3 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.84 (dd, J = 7.7, 1.6 Hz, 1H), 7.75 (dd, J = 8.5, 2.1 Hz, 1H), 7.58 (dd, J = 56.9, 8.1 Hz, 5H), 7.43 (d, J =7.6 Hz, 2H), 7.32 (dt, J = 12.1, 8.0 Hz, 3H), 7.26 (d, J = 3.8 Hz, 1H), 7.06~ 7.01 (m, 1H), 6.90 (dd, J = 4.1, 2.7 Hz, 1H), 6.83 ~ 6.77 (m, 2H), 4.46 (s, 2H), 1.39 (s, 9H). 13 C NMR (125 MHz, CDCl3) δ : 154.8, 125.5, 147.5, 147.5,139.5, 138.0, 137.0, 135.6, 130.9, 130.4, 128.6, 127.2, 127.1, 126.9, 126.6,126.1, 126.0, 125.8, 125.7, 120.4, 115.7, 114.8, 114.0, 111.8, 109.9, 47.7,34.5, 31.3. Compound 3ba 1 H NMR, 13 C NMR such as Figure 5 ,like Figure 6 As shown in the figure, the analysis results indicate that the obtained target product has the correct structure.

[0031] Example 4 Reactants: 2-(7-(4-fluorophenyl)-4,5-dihydropyrrole[1,2-a]quinoxalin-4-yl)aniline, benzaldehyde; Solvent: dichloromethane; Catalyst: Trifluoromethanesulfonic acid; Reaction formula: .

[0032] 1 L (0.24 mmol) of 2-(7-(4-fluorophenyl)-4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)aniline, 4 mL of dichloromethane, 0.3 mmol of trifluoromethanesulfonic acid, and 0.2 mmol of benzaldehyde were added to a 10 mL reactor. A magnetic stir bar was added, and the reaction was carried out at room temperature for 15 min. The reaction was monitored by TLC. After the reaction was completed, the pH was adjusted by adding an appropriate amount of triethylamine to the system, and the reaction was quenched by stirring. The solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified by silica gel chromatography using petroleum ether:dichloromethane at a volume ratio of 7:1. N -benzyl-2-(7-(4-fluorophenyl)pyrrole[1,2-] α Quinoxalo-4-yl)aniline 3ca, a bright yellow solid, with a separation yield of 94%.

[0033] Structural identification of compound 3ca: Nuclear magnetic resonance data: 1 H NMR (500 MHz, CDCl3) δ : 8.02 ~ 7.95 (m, 2H), 7.90 (d, J = 8.5 Hz, 1H), 7.86 (dd, J = 7.9, 1.7 Hz, 1H), 7.70 ~ 7.57 (m, 4H), 7.43 (d, J = 7.1Hz, 2H), 7.32 (dtd, J = 7.4, 5.4, 2.5 Hz, 3H), 7.25 (d, J = 5.0 Hz, 1H), 7.18(t, J = 8.6 Hz, 2H), 7.05 (dd, J = 4.1, 1.3 Hz, 1H), 6.91 (dd, J = 4.1, 2.7Hz, 1H), 6.81 (dt, J = 7.3, 3.1 Hz, 2H), 4.47 (s, 2H). 13C NMR (125 MHz, CDCl3) δ 163.4, 161.7, 155.0, 147.5, 139.4, 137.2, 136.1, 136.1, 135.5, 131.0, 130.5, 128.6, 128.5, 127.3, 127.2, 127.0, 126.2, 125.9, 125.6, 120.2,115.8, 115.7, 114.8, 114.1, 114.1, 111.9, 110.1, 47.7. Compound 3ca 1 H NMR, 13 C NMR such as Figure 7 ,like Figure 8 As shown in the figure, the analysis results indicate that the obtained target product has the correct structure.

[0034] The present invention also synthesized compounds 3ac-3ah and 3ba-3ea using the same method. Please refer to Table 1 for the structural formulas, yields, and characterization data of the compounds.

[0035] Table 1. Structural formulas, yields, and NMR data of the synthesized compounds: The method for preparing secondary amine derivatives in this application is compared with existing methods for preparing secondary amine derivatives, and the results are shown in Table 2: Table 2: Comparison of different methods for preparing secondary amine derivatives Reference 1 comes from J. Org. Chem., 2025, 90, 11081-11090 Reference 2 is from Org. Lett., 2025, 6726-6731 Reference 3 comes from J. Org. Chem., 2025, 90, 10392-10401 Reference 4 is from Org. Lett., 2025, 27, 4322-4326. As can be seen from Table 2, the preparation method of this application can significantly reduce the reaction time and reaction temperature, while eliminating the need for an additional hydrogen source and significantly improving the yield of secondary amine derivatives.

[0036] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A method for the acid-promoted intramolecular hydrogen transfer reductive amination to prepare secondary amine derivatives, characterized in that: The reaction formula is as follows: wherein, the Bronsted acid is selected from one of benzene sulfonic acid, trifluoroacetic acid, trichloroacetic acid, methane sulfonic acid, trifluoromethane sulfonic acid, 1-heptane sulfonic acid, dodecyl benzene sulfonic acid, difluoroacetic acid, hydrochloric acid, phosphoric acid, hydrobromic acid and hydroiodic acid. ， wherein, wherein R 1 and R 2 each substituent is independently selected from one of hydrogen, halogen, amino, carboxyl, ester, acyl, cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; R 3 is one of the substituents of aryl or alkyl.

2. The acid-promoted intramolecular hydrogen transfer reductive amination process for the preparation of secondary amine derivatives according to claim 1, characterized in that: The molar ratio of the Bronsted acid to the aldehyde is (0.1-3.0):

1.

3. The acid-promoted intramolecular hydrogen transfer reductive amination process for the preparation of secondary amine derivatives according to claim 1, characterized in that: The molar ratio of the aldehyde to the 2-dihydroazepinyl aniline derivative is 1:(0.9-3.0).

4. The acid-promoted intramolecular hydrogen transfer reductive amination process for the preparation of secondary amine derivatives according to claim 1, characterized in that, The reaction time is 5 min to 5 h.

5. The acid-promoted intramolecular hydrogen transfer reductive amination process for the preparation of secondary amine derivatives according to claim 1, characterized in that: The reaction solution containing the secondary amine derivative is subjected to vacuum concentration, silica gel column purification, filtration or beating operation, and vacuum drying to obtain the secondary amine derivative.

6. The method of preparing secondary amine derivatives by acid-promoted intramolecular hydrogen transfer reductive amination according to claim 1, characterized in that: The reaction is carried out in a solvent selected from hexafluoroisopropanol, trifluoroethanol, N , N - one of dimethylformamide, water, methanol, ethanol, acetonitrile, benzene, xylene, ethyl acetate, toluene, tetrahydrofuran, 1,4-dioxane, dimethylsulfoxide.

7. The acid-promoted intramolecular hydrogen transfer reductive amination process for the preparation of secondary amine derivatives according to claim 1, characterized in that: The secondary amine derivative is selected from one of the group consisting of 2- dihydropyrroloquinoxalinyl aniline, 2-(5,6-dihydrophenanthridin-6-yl)aniline, 2-(2,3- dihydrobenzo[ d ]oxazol-2-yl)aniline, 2-(1,2-dihydroquinolizin-2-yl)aniline, 2-(2,3-dihydrobenzo[ d ]thiazol-2-yl)aniline, 2-(2,3-dihydro-1 H-benzo[ d ]imidazol-2-yl)aniline or 2-(1,2-dihydroquinazolin-2-yl)aniline derivative.

8. The acid-promoted intramolecular hydrogen transfer reductive amination process for the preparation of secondary amine derivatives according to claim 1, characterized in that: ​

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