Aliphatic amine deamination functionalization method

Abstract

The invention discloses a deamination functionalization method of aliphatic amine, which comprises the following steps: reacting aliphatic amine shown as a formula (I) with a nucleophilic reagent in the presence of acid and a solvent to generate a deamination functionalization product shown as a formula (III), wherein R1, R2 and R3 groups are independently selected from hydrogen, hydroxyl, alkyl, alkoxy, alkanoyl, alkoxycarbonyl, alkyl sulfinyl, alkyl sulfonyl, aryl sulfonyl, aryl, heteroaryl and phenylalkyl, or two or three of the R1, R2 and R3 groups form a non-aromatic ring cage compound; fG is a functional group for the nucleophilic reagent to participate in the reaction. The method has the advantages of cheap and easily available raw materials, simple reaction conditions, wide substrate applicability and the like.

Description

[0001] This application is a divisional application of the invention patent filed on January 8, 2026, with application number 202610019645.2 and invention title "A method for deamination functionalization of aliphatic amines or aliphatic nitroamines". Technical Field

[0002] This invention relates to the field of chemical synthesis technology, and in particular to a method for the deamination and functionalization of aliphatic amines. Background Technology

[0003] Alkyl functionalization reactions are a persistent research hotspot in synthetic chemistry. Over the past century, alkyl halides and fatty alcohols have been extensively studied as ideal building blocks for synthesis due to their abundant sources. Notably, research reports on fatty amines—another important alkylating agent—are remarkably scarce. Utilizing fatty amines as alkyl sources and developing related deamination methodologies plays a crucial role in drug development and enhancing synthetic diversity.

[0004] To date, only a few deamination methodologies have been reported. These deamination strategies mainly originate from transformations related to the alkyl radical pathway, and they provide new insights into the construction of carbon-halogen and carbon-carbon bonds.

[0005] For example, Chinese patent document CN111892489B discloses a method for the difluoroalkylation of aliphatic amines after deamination. The method uses readily available aliphatic amine of formula A as a raw material, reacting it with tetrafluoroborate pyran salt of formula B under heating or room temperature conditions to obtain alkylpyridinium salt of formula C. Subsequently, under light irradiation, using commercially available [Ir(dtbbpy)(ppy)2]PF6 as a catalyst and difluoroenol silyl ether D as the difluoroalkylating agent, various difluoroalkyl-substituted alkanes and cycloalkanes and their derivatives are obtained. The reaction process is as follows: .

[0006] Chinese patent document CN118108572A discloses a method for synthesizing alkyl trifluoromethyl compounds. Using alkylamine compounds as raw materials, the method involves selectively deaminating and trifluoromethylating the alkylamine compounds in the presence of a deamination reagent, a trifluoromethylating reagent, a catalyst, and a ligand to obtain alkyl trifluoromethyl compounds. The reaction process is as follows: .

[0007] However, using aliphatic amines as synthons to construct other equally important carbon-oxygen, carbon-nitrogen, and carbon-sulfur bonds remains impossible. Furthermore, the reported methods generally suffer from high reagent costs and complex procedures, hindering the application of aliphatic amines.

[0008] In summary, current research on deamination reactions is still limited by the narrow range of applicable substrates and applications. Therefore, developing a novel, simple, and universally applicable deamination functionalization methodology is of great value in broadening the application scope of aliphatic amines. Summary of the Invention

[0009] This invention provides a method for the deamination functionalization of aliphatic amines or aliphatic nitroamines, which has the advantages of inexpensive and readily available raw materials, simple reaction conditions, and wide substrate applicability.

[0010] The technical solution of the present invention is as follows: A method for deamination functionalization of aliphatic amines or aliphatic nitroamines, comprising: reacting an aliphatic amine of formula (I) or an aliphatic nitroamine of formula (II) with a nucleophile in the presence of an acid and a solvent to generate a deamination functionalized product of formula (III), wherein the reaction formula is: ; Among them, R 1 R 2 R 3 Each group is independently selected from hydrogen, hydroxyl, amino, alkyl, alkoxy, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, aryl, heteroaryl, phenylalkyl, or R. 1 R 2 R 3 Two or three of the groups form a non-aromatic ring, cage-like compound; FG is a functional group in which nucleophiles participate in the reaction.

[0011] In this invention, the aliphatic amines represented by formula (I) or aliphatic nitroamines represented by formula (II) can be any primary, secondary, tertiary, and benzylic substitutions.

[0012] Preferred, R 1 R 2 R 3 Each group is independently selected from hydrogen, amino, C1-C 20 Alkyl, alkoxy, alkanoyl, alkoxycarbonyl, aryl, heteroaryl, phenylalkyl, wherein the heteroaryl group contains 1 to 3 heteroatoms each independently selected from oxygen, nitrogen, and sulfur; wherein the amino, C1-C 20 Alkyl, alkoxy, alkanoyl, alkoxycarbonyl, aryl, heteroaryl, and phenylalkyl may optionally be substituted by 0 or more substituents selected from the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, nitro, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and phenylalkyl. Or R 1 R 2R 3 Two or three of the groups form a non-aromatic ring, cage-like compound, wherein the non-aromatic ring, cage-like compound is optionally substituted by 0 or more substituents selected from the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, nitro, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, phenylalkyl.

[0013] Preferred, R 1 R 2 R 3 Each group is independently selected from hydrogen, C1-C 20 Alkyl, phenyl C1-C6 alkyl; Or R 1 R 2 R 3 Two of the groups form a non-aromatic ring, which contains 0 to 3 heteroatoms each independently selected from oxygen, nitrogen, and sulfur; the non-aromatic ring is optionally substituted by 0 or more substituents selected from the following: aryl, heteroaryl, cycloalkyl, heterocycloalkyl, phenylalkyl; Or R 1 R 2 R 3 The group comprises three cage-like compounds, wherein the cage-like compounds are optionally substituted by 0 or more substituents selected from the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, nitro, aryl, heteroaryl, cycloalkyl, heterocycloalkyl.

[0014] Preferably, the fatty amines represented by formula (I) are selected from: ; The aliphatic nitrosamines represented by formula (II) are selected from: .

[0015] Preferably, FG is selected from halogens, alkyl groups, aromatic groups, R4O-, R5S-, R6Se-, and R7R8N-. R4, R5, and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cyano, aromatic, aromatic alkyl, halothionyl, and acyl. R7 and R8 are independently selected from hydrogen, sulfonyl, and acyl groups, or R7 and R8 form a non-aromatic ring or benzene is not an aromatic ring. The non-aromatic ring contains 1 to 3 heteroatoms, each independently selected from oxygen, nitrogen, and sulfur.

[0016] Preferably, the nucleophile is a halogen nucleophile, an oxygen nucleophile, a nitrogen nucleophile, a sulfur nucleophile, a selenium nucleophile, or an aromatic nucleophile.

[0017] Preferably, the nucleophilic reagent is selected from: .

[0018] More preferably, the molar amount of the nucleophile is 100% to 500% of the molar amount of the fatty amine or fatty nitroamine.

[0019] Preferably, the acid is at least one selected from concentrated nitric acid, trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, perchloric acid, hydrobromic acid, and hydroiodic acid.

[0020] Preferably, the concentrated nitric acid has a mass fraction of 65%-68%.

[0021] Preferably, the molar amount of acid is 50% to 600% of the molar amount of fatty amine or fatty nitroamine.

[0022] Preferably, the solvent is 1,2-dichloroethane, hexafluoroisopropanol, methanol, or trifluoroethanol.

[0023] More preferably, the molar amount of solvent is 9500% to 24720% of the molar amount of fatty amine or fatty nitroamine.

[0024] Preferably, the reaction temperature is 0~100℃ and the reaction time is 0.1~10h.

[0025] The reaction was carried out under stirring conditions.

[0026] Preferably, when the reaction substrate is an aliphatic amine as shown in formula (I), the aliphatic amine and the nucleophile react in the presence of an acid, a catalyst and a solvent, wherein the catalyst is at least one of 4-dimethylaminopyridine, potassium thiocyanate and lithium bromide.

[0027] This invention provides a novel method for the deamination functionalization of aliphatic amines and aliphatic nitroamines. In the presence of acid and solvent, aliphatic amines or aliphatic nitroamines undergo deamination coupling with a nucleophilic reagent to obtain alkyl-functionalized products.

[0028] Compared with the prior art, the beneficial effects of the present invention are as follows: The method of the present invention can efficiently realize the deamination functionalization reaction of aliphatic amines and aliphatic nitroamines, while other groups in the aliphatic amine or aliphatic nitroamine molecule can be retained.

[0029] The method of this invention has the advantages of inexpensive and readily available raw materials, simple reaction conditions, and wide applicability of substrates, which meets the requirements for developing green and environmentally friendly chemistry. Detailed Implementation

[0030] The present invention will be further described in detail below with reference to the embodiments. It should be noted that the embodiments described below are intended to facilitate the understanding of the present invention and do not limit it in any way.

[0031] Embodiments of the present invention provide a novel method for the deamination functionalization of aliphatic amines or aliphatic nitroamines. The method includes the following steps: reacting an aliphatic amine (I) or aliphatic nitroamine (II) with a nucleophile in the presence of an acid and a solvent to generate a deamination functionalized product (III): ;

[0032] Among them, R 1 R 2 R 3 Each group can be independently hydrogen, substituted or unsubstituted alkyl, aryl, etc. In this context, FG represents the functional group in which the nucleophile participates in the reaction; According to embodiments of the present invention, the alkyl group in the aliphatic amine (I) or aliphatic nitroamine (II) in the above method steps can be any primary, secondary, tertiary, or benzylic substitution.

[0033] According to embodiments of the present invention, the above-mentioned fatty amine (I) and fatty nitroamine (II) are selected from one of the following, but are not limited thereto: .

[0034] According to embodiments of the present invention, the nucleophilic reagent described above is selected from one of the following, but is not limited thereto: .

[0035] According to embodiments of the present invention, the solvent is selected from, but not limited to, one of the following: 1,2-dichloroethane, hexafluoroisopropanol, methanol, and trifluoroethanol.

[0036] According to embodiments of the present invention, the acid is selected from one, but not limited to, concentrated nitric acid (65%-68% by mass), trifluoromethanesulfonic acid, and methanesulfonic acid.

[0037] According to embodiments of the present invention, the molar amount of the nucleophile is 100% to 500% of the molar amount of the fatty amine (I) or fatty nitroamine (II).

[0038] According to an embodiment of the present invention, the molar amount of acid is 50% to 600% of the molar amount of aliphatic amine (I) or aliphatic nitroamine (II).

[0039] According to an embodiment of the present invention, in the method steps, the molar amount of solvent is 9500% to 24720% of the molar amount of aliphatic amine (I) or aliphatic nitroamine (II).

[0040] According to an embodiment of the present invention, in the method step, the reaction is stirred under heating at 0 to 100 °C for 1 hour.

[0041] In the embodiments disclosed in this invention, aliphatic amines or aliphatic nitroamines are coupled with nucleophiles in the presence of acid and solvent to obtain deamination-functionalized products. The deamination-functionalization reaction of aliphatic amines can be used to synthesize alkane-functionalized products, which will facilitate the development of related drugs and the synthesis of related compounds. For example, the small molecule drugs containing amino groups, Sitagliptin and Oseltamivir, can achieve amino conversion using the method of this invention, which can be used for post-modification of drugs to find new and highly effective drugs. Furthermore, the deamination-functionalization reaction in this invention can be used as a conventional synthetic method for the synthesis of drug molecules; for example, the product P19 obtained in Example 19 of this invention can be used as a precursor for the drug molecule Adapalene.

[0042] Example 1: ; The specific steps include: dissolving 4-[4-[(5S)-5-(aminomethyl)-2-carbonyl-3-azolidinyl]phenyl]-3-morpholinone S1 (59 mg, 1.0 equivalent) and 4-dimethylaminopyridine (61 mg, 2.5 equivalent) in 2 mL of 1,2-dichloroethane, then adding concentrated nitric acid solution (23.3 mg, 1.2 equivalent, 65%–68% by mass) at room temperature and stirring for 10 min. Finally, adding thionyl chloride N1 (60 mg, 2.5 equivalent) to the reaction system, heating the mixture to 100 °C and continuing the reaction for 1 h. After the reaction is complete, cooling to room temperature and adding 1 mL of saturated sodium bicarbonate solution to quench the reaction. Dichloromethane was added to the quenched solution, and the organic phase was extracted and separated (repeated 3 times). The organic phase was washed with 10 g of saturated brine and allowed to stand for separation. After separation, the organic phase was dried and concentrated, and then separated by column chromatography (PE:Acetone = 1:2 (volume ratio)) to obtain 4-[4-[(5S)-5-(chloromethyl)-2-carbonyl-3-azoloalkyl]phenyl]-3-morpholinone P1, with a yield of 81%. The product was then subjected to... 1 H NMR and 13 C NMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 8.9Hz, 2H), 4.94 – 4.84 (m, 1H), 4.34 (s, 2H), 4.17 (t, J = 9.0 Hz, 1H), 4.06 –4.01 (m, 2H), 3.96 (dd,J = 9.1, 5.7 Hz, 1H), 3.80 – 3.72 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 166.0, 153.0, 136.5, 135.7, 125.4, 118.2, 70.0, 67.7, 63.3, 48.8, 47.2, 43.7.

[0043] Example 2: ; The specific steps include: dissolving 1-amine-adamantane S2 (75.6 mg, 1.0 equivalent) and 4-dimethylaminopyridine (152.7 mg, 2.5 equivalent) in 5 mL of 1,2-dichloroethane, adding concentrated nitric acid solution (58.2 mg, 1.2 equivalent, 65%–68% by mass) at room temperature, and stirring for 10 min. Finally, adding sulfoxide N2 (260 mg, 2.5 equivalent) to the reaction system, heating the mixture to 70 °C, and continuing the reaction for 1 h. After the reaction is complete, cooling to room temperature, and quenching the reaction with 1 mL of saturated sodium bicarbonate solution. Adding dichloromethane to the quenched solution, extracting and separating the organic phase (repeated 3 times), washing the organic phase with 20 g of saturated brine, allowing it to stand for separation, drying and concentrating the separated organic phase, and then separating it by column chromatography (PE: DCM = 95:5 (volume ratio)) to obtain 1-adamantane bromide P2 in 55% yield. To the product 1 H NMR and 13 C NMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 2.36 (d, J = 2.9 Hz, 6H), 2.13 – 2.05 (m,3H), 1.72 (t, J = 2.9 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ 66.9, 49.5, 35.7, 32.7.

[0044] Example 3: ; The specific steps include: dissolving 1-amine adamantane S2 (15.2 mg, 1.0 equivalent) and potassium thiocyanate (9.8 mg, 1 equivalent) in 1 mL of 1,2-dichloroethane; adding concentrated nitric acid solution (58.2 mg, 6 equivalent, 65%–68% by mass) at room temperature and stirring for 10 min; finally adding deionized water N3 (7.2 mg, 4 equivalent) to the reaction system; heating the mixture to 100 °C and continuing the reaction for 1 h; after the reaction is complete, cooling to room temperature; and quenching the reaction with 1 mL of saturated sodium bicarbonate solution; adding dichloromethane to the quenched solution; extracting and separating the organic phase (repeated 3 times); washing the organic phase with 5 g of saturated brine; allowing the mixture to stand and separate the layers; drying and concentrating the separated organic phase; and obtaining 1-adamantane P3 by column chromatography (PE: EtOAc = 75:25 (volume ratio)) with a yield of 59%. The product was then subjected to… 1 H NMR and 13 CNMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 2.13 (s, 3H), 1.70 (d, J = 2.8 Hz, 6H), 1.67– 1.55 (m, 6H), 1.54 (s, 1H). 13 C NMR (100 MHz, CDCl3) δ 68.4, 45.5, 36.2, 30.9.

[0045] Example 4: ; The specific steps included: dissolving hexadecylamine S5 (24.2 mg, 1.0 equivalent) and lithium bromide (34.7 mg, 4 equivalent) in 1 mL of 1,2-dichloroethane, adding concentrated nitric acid solution (58.2 mg, 6 equivalent, 65%–68% by mass) at room temperature, and stirring for 10 min. Finally, adding acetic acid N4 (60 mg, 10 equivalent) to the reaction system, heating the mixture to 100 °C, and continuing the reaction for 1 h. After the reaction was complete, cooling to room temperature, and quenching the reaction with 1 mL of saturated sodium bicarbonate solution. Adding dichloromethane to the quenched solution, extracting and separating the organic phase (repeated 3 times), washing the organic phase with 5 g of saturated brine, allowing it to stand for separation, separating the organic phase, drying and concentrating, and separating by column chromatography (PE:EtOAc = 10:90 (volume ratio)) to obtain hexadecyl acetate P4 in a yield of 42%. The product was then subjected to… 1 H NMR and 13 CNMR characterization, the characterization results are as follows: 1 H NMR (400MHz, CDCl3) 4.04 (t, J =6.8 Hz, 2 H), 2.04 (s, 3 H), 1.48–1.62 (m, 2 H), 1.25–1.34 (m, 26 H), 0.87 (t, J = 6.8 Hz, 3 H) 13 C NMR (100 MHz, CDCl3) δ 171.4, 64.8, 32.1, 29.8, 29.8, 29.7, 29.7,29.5, 29.4, 28.7, 26.1, 22.8, 21.2, 14.3.

[0046] Example 5: ; The specific steps include: dissolving diphenylmethylamine S3 (18.5 mg, 1.0 equivalent) and potassium thiocyanate (9.7 mg, 1 equivalent) in 1 mL of 1,2-dichloroethane, adding concentrated nitric acid solution (58.2 mg, 6 equivalent, mass fraction 65%–68%) at room temperature, and stirring for 10 min. Finally, sodium benzoate N5 (43 mg, 3 equivalent) is added to the reaction system, and the mixture is heated to 80 °C and reacted for 1 h. After the reaction is complete, it is cooled to room temperature, and 1 mL of saturated sodium bicarbonate solution is added to quench the reaction. Dichloromethane is added to the quenched solution, and the organic phase is extracted (repeated 3 times). The organic phase is washed with 5 g of saturated brine, allowed to stand for separation, and the separated organic phase is dried and concentrated. Diphenylmethyl ester P5 is obtained by column chromatography (PE: EtOAc = 10:90 (volume ratio)) with a yield of 43%. The product is then subjected to… 1 H NMR and 13 C NMR characterization, the characterization results are as follows: 1 H NMR (400MHz, CDCl3) δ 8.16 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.4Hz, 1H), 7.50-7.43 (m, 6H), 7.32-7.28 (t, J = 7.5 Hz, 4H), 7.30 (t, J = 7.1 Hz, 2H), 7.13 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 165.7, 140.4, 133.3, 130.4, 129.9, 128.7, 128.6, 128.1, 127.3, 77.6.

[0047] Example 6: ; The specific steps included: dissolving diphenylmethylamine S3 (91.5 mg, 1.0 equivalent) and lithium bromide (173.7 mg, 4 equivalent) in 5 mL of methanol, adding concentrated nitric acid solution (291 mg, 6 equivalent, 65%–68% by mass) at room temperature, and stirring for 10 min. The mixture was then heated to 100 °C and reacted for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and 2 mL of saturated sodium bicarbonate solution was added to quench the reaction. Methanol was removed by concentration, and dichloromethane was added to the aqueous phase containing the product. The organic phase was extracted and separated (repeated 3 times). The organic phase was washed with 10 g of saturated brine, allowed to stand for separation, and then dried and concentrated. The product was then separated by column chromatography (PE: EtOAc = 15:85 (volume ratio)) to obtain (methoxymethylene)diphenyl P6 in 64% yield. The product was then subjected to further analysis. 1 H NMR and 13 C NMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.39 – 7.17 (m, 10H), 5.23 (s, 1H), 3.36 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 142.2, 128.5, 127.5, 127.0, 85.5, 57.1.

[0048] Example 7: ; The specific steps include: dissolving diphenylmethylamine S3 (18.5 mg, 1.0 equivalent) and potassium thiocyanate (9.7 mg, 1 equivalent) in 1 mL of 1,2-dichloroethane, adding concentrated nitric acid solution (58.2 mg, 6 equivalent, 65%–68% by mass) at room temperature, and stirring for 10 min. Finally, adding 4-phenylbutanol N7 (75 mg, 5 equivalent) to the reaction system, heating the mixture to 80 °C, and continuing the reaction for 1 h. After the reaction is complete, cooling to room temperature, and quenching the reaction with 1 mL of saturated sodium bicarbonate solution. Adding dichloromethane to the quenched solution, extracting and separating the organic phase (repeated 3 times), washing the organic phase with 5 g of saturated brine, allowing it to stand for separation, separating the organic phase, drying and concentrating, and separating by column chromatography (PE: EtOAc = 10:90 (volume ratio)) to obtain (4-phenylbutoxymethylene)diphenyl P7 in 51% yield. The product was then subjected to… 1 H NMR and 13 C NMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.29 – 7.07 (m, 15H), 5.24 (s, 1H), 3.39 (t, J = 6.1 Hz, 2H), 2.57 – 2.51 (m, 2H), 1.69-1.59 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 142.7, 142.7, 128.6, 128.5, 128.4, 127.5,127.1, 125.8, 83.8, 69.1, 35.8, 29.6, 28.2.

[0049] Example 8: ; The specific steps included: dissolving 1-amine-adamantane S2 (75.6 mg, 1.0 equivalent) and lithium bromide (173.7 mg, 4 equivalent) in 5 mL of hexafluoroisopropanol; adding concentrated nitric acid solution (291 mg, 6 equivalent, 65%–68% by mass) at room temperature and stirring for 10 min; and finally heating the mixture to 100 °C and reacting for 1 h. After the reaction was complete, cooling to room temperature and quenching the reaction with 2 mL of saturated sodium bicarbonate solution. Methanol was removed by concentration, and dichloromethane was added to the aqueous phase containing the product. The organic phase was extracted and separated (repeated 3 times). The organic phase was washed with 10 g of saturated brine, allowed to stand for separation, and then dried and concentrated. 1-[(1,1,1,3,3,3-hexafluoroprop-2-yl)oxy]adamantane P8 was obtained by column chromatography (PE: DCM = 95:5 (volume ratio)) with a yield of 45%. The product was then subjected to… 1 H NMR and 13 CNMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.40 (hept, J = 6.1 Hz, 1H), 2.22 (s, 3H), 1.79 (d, J = 2.9 Hz, 6H), 1.71 – 1.56 (m, 6H). 13 C NMR (100 MHz, CDCl3) δ 78.7, 68.1 (hept, J = 32.4 Hz), 41.8, 36.0,31.0.

[0050] Example 9: ; The specific steps include: N- Cyclohexylnitroamine S7 (14.5 mg, 1.0 equivalent) and 4-cyanophenol N9 (24 mg, 2 equivalent) were dissolved in 1 mL of 1,2-dichloroethane. Trifluoromethanesulfonic acid (30 mg, 2 equivalent) was added at room temperature, and the mixture was heated to 80 °C and reacted for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and 1 mL of saturated sodium bicarbonate solution was added to quench the reaction. Dichloromethane was added to the quenched solution, and the organic phase was extracted (repeated 3 times). The organic phase was washed with 5 g of saturated brine, allowed to stand for separation, and then dried and concentrated. 4-(cyclohexyloxy)benzonitrile P9 was obtained by column chromatography (PE:DCM = 66:34 (v / v)) in a yield of 37%. The product was then subjected to further analysis. 1 H NMR and13 C NMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.8 Hz, 2H), 6.92 (d, J =9.2Hz, 2H), 4.36-4.28 (m, 1H), 2.05-1.93 (m, 2H), 1.88-1.73 (m, 2H), 1.68-1.48(m, 3H), 1.48-1.30 (m, 3H). 13 C NMR (100 MHz, CDCl3) δ 161.2, 133.9, 119.4, 116.1, 103.2, 75.6, 31.4, 25.4, 23.5.

[0051] Example 10: ; The specific steps include: N- Cyclohexylnitroamine S7 (14.5 mg, 1.0 equivalent) and 5,5-dimethyl-1,3-cyclohexanedione N10 (28 mg, 2 equivalent) were dissolved in 1 mL of 1,2-dichloroethane. Trifluoromethanesulfonic acid (15 mg, 1 equivalent) was added at room temperature, and the mixture was heated to 70 °C and reacted for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and 1 mL of saturated sodium bicarbonate solution was added to quench the reaction. Dichloromethane was added to the quenched solution, and the organic phase was extracted (repeated 3 times). The organic phase was washed with 5 g of saturated brine, allowed to stand for separation, and then dried and concentrated. The product was separated by column chromatography (PE: EtOAC = 80:20 (v / v)) to give 3-(cyclohexyloxy)-5,5-dimethylcyclohexyl-2-en-1-one P10 in 60% yield. The product was then subjected to... 1 H NMR and 13 C NMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 5.35 (s, 1H), 4.19-4.11 (m, 1H), 2.24 (s,2H), 2.20 (s, 2H), 1.97 – 1.87 (m, 2H), 1.79 – 1.70 (m, 2H), 1.58-1.51 (m,1H), 1.52 – 1.40 (m, 2H), 1.40 – 1.26 (m, 3H), 1.06 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 200.0, 175.4, 101.9, 76.4, 50.8, 43.5, 32.6, 31.2, 29.8, 28.4, 25.5, 23.7.

[0052] Example 11: ; The specific steps include: 1- N - Nitrofurantoin S7 (19.6 mg, 1.0 equivalent) and N Acetylcysteine ​​methyl ester N11 (35.5 mg, 2 equivalents) was dissolved in 1 mL of 1,2-dichloroethane. Trifluoromethanesulfonic acid (15 mg, 1 equivalent) was then added at room temperature, and the mixture was heated to 70 °C and reacted for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and 1 mL of saturated sodium bicarbonate solution was added to quench the reaction. Dichloromethane was added to the quenched solution, and the organic phase was extracted (repeated 3 times). The organic phase was washed with 5 g of saturated brine, allowed to stand for separation, and then dried and concentrated. The methyl group was obtained by column chromatography (PE: EtOAC = 50:50 (v / v)). N -Acetyl-S-(adamantane-1-yl)cysteine ​​P11, yield 99%. The product was subjected to... 1 H NMR and 13 C NMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 6.31 (d, J = 7.4 Hz, 1H), 4.83 (dt, J = 7.7,4.8 Hz, 1H), 3.75 (s, 3H), 3.03 – 2.91 (m, 2H), 2.02 (s, 6H), 1.79 (d, J =2.0 Hz, 6H), 1.72 – 1.59 (m, 6H). 13 C NMR (100 MHz, CDCl3) δ 171.4, 169.9, 52.8, 52.1, 44.9, 43.4, 36.2, 29.7, 27.9, 23.3.

[0053] Example 12: ; The specific steps include: dissolving 12.2 mg of 2-phenylethylamine S3 (1.0 equivalent) and potassium thiocyanate (39 mg, 4 equivalent) in 1 mL of 1,2-dichloroethane; adding concentrated nitric acid solution (58.2 mg, 6 equivalent, 65%–68% by mass) at room temperature and heating to 70 °C for 1 h; cooling to room temperature and quenching the reaction with 1 mL of saturated sodium bicarbonate solution; adding dichloromethane to the quenched solution and extracting the organic phase (repeated 3 times); washing the organic phase with 5 g of saturated brine and allowing it to stand for separation; drying and concentrating the separated organic phase; and then separating it by column chromatography (PE: DCM = 66:34 (volume ratio)) to obtain (2-thiocyanoethyl)benzene P12 in a yield of 47%. The product was then subjected to… 1 HNMR and 13 C NMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.38-7.32 (m, 2H), 7.29 (d, J = 7.2 Hz, 1H), 7.23 (d, J = 7.1 Hz, 2H), 3.21 – 3.16 (m, 2H), 3.14-3.10 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 137.8, 129.0, 128.8, 127.4, 112.2, 36.2,35.3.

[0054] Example 13: ; The specific steps include: N- Cyclohexylnitroamine S7 (14.5 mg, 1.0 equivalent) and 4-nitrophenylthiophenol N13 (31 mg, 2 equivalent) were dissolved in 1 mL of 1,2-dichloroethane. Trifluoromethanesulfonic acid (15 mg, 1 equivalent) was added at room temperature, and the mixture was heated to 70 °C and reacted for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and 1 mL of saturated sodium bicarbonate solution was added to quench the reaction. Dichloromethane was added to the quenched solution, and the organic phase was extracted (repeated 3 times). The organic phase was washed with 5 g of saturated brine, allowed to stand for separation, and then dried and concentrated. Cyclohexyl(4-nitrophenyl)thione P13 was obtained by column chromatography (PE:DCM = 66:34 (v / v)) in 80% yield. The product was then subjected to further analysis. 1 H NMR and 13 C NMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4Hz, 2H), 3.30-3.36 (m, 1H), 2.02-2.05 (m, 2H), 1.78-1.81 (m, 2H), 1.64-1.67(m, 1H), 1.24-1.46 (m, 5H). 13 C NMR (100 MHz, CDCl3) δ 147.1, 145.2, 127.7, 124.1, 44.9, 33.0, 26.0, 25.7.

[0055] Example 14: ; The specific steps include: N- Cyclohexylnitroamine S7 (14.5 mg, 1 equivalent) and thiobenzoic acid N14 (27.6 mg, 2 equivalent) were dissolved in 1 mL of 1,2-dichloroethane. Trifluoromethanesulfonic acid (15 mg, 1 equivalent) was then added at room temperature, and the mixture was heated to 70 °C and reacted for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched by adding 1 mL of saturated sodium bicarbonate solution. Dichloromethane was added to the quenched solution, and the organic phase was extracted (repeated 3 times). The organic phase was washed with 5 g of saturated brine, allowed to stand for separation, and then dried and concentrated. The product was then separated by column chromatography (PE:DCM = 66:34 (v / v)) to obtain thiobenzoic acid S-cyclohexyl ester P14 in 39% yield. The product was then subjected to further analysis. 1 HNMR and 13 C NMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.2 Hz, 2H), 7.53 (t, J = 7.6Hz, 1H), 7.42 (t, J = 8.0 Hz, 2H), 3.76-3.70 (m, 1H), 2.04- 2.01 (m, 2H), 1.76-1.73 (m, 3H), 1.63-1.60 (m, 2H), 1.56-1.43 (m, 2H), 1.35-1.28 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ 191.9, 137.6, 133.2, 128.6, 127.2, 42.6, 33.3, 26.1, 25.7.

[0056] Example 15: ; The specific steps include: N- Cyclohexylnitroamine S7 (14.5 mg, 1.0 equivalent) and phenylselenoyl alcohol N15 (31.4 mg, 2 equivalent) were dissolved in 1 mL of 1,2-dichloroethane. Trifluoromethanesulfonic acid (15 mg, 1 equivalent) was added at room temperature, and the mixture was heated to 70 °C and reacted for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and 1 mL of saturated sodium bicarbonate solution was added to quench the reaction. Dichloromethane was added to the quenched solution, and the organic phase was extracted (repeated 3 times). The organic phase was washed with 5 g of saturated brine, allowed to stand for separation, and then dried and concentrated. Cyclohexyl(phenyl)selenoyl alcohol P15 was obtained by column chromatography (PE:DCM = 95:5 (v / v)) in 71% yield. The product was then subjected to further analysis. 1 H NMR and 13 C NMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.55-7.53 (m, 2H), 7.26-7.23 (m, 3H), 3.27-3.22 (m, 1H), 2.03-2.00 (m, 2H), 1.75-1.72 (m, 2H), 1.62-1.58 (m, 1H), 1.55-1.46 (m, 2H), 1.36-1.33 (m, 1H), 1.29-1.24 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 134.8, 129.4, 128.9, 127.3, 43.3, 34.32, 26.9, 25.8.

[0057] Example 16: ; The specific steps include: dissolving diphenylmethylamine S3 (18.5 mg, 1.0 equivalent) and potassium thiocyanate (9.7 mg, 1 equivalent) in 1 mL of 1,2-dichloroethane; adding concentrated nitric acid solution (58.2 mg, 6 equivalent, 65%–68% by mass) at room temperature and stirring for 10 min; finally adding methyl 1H-indazole-3-carboxylate N16 (52.8 mg, 3 equivalent) to the reaction system; heating the mixture to 80 °C and continuing the reaction for 1 h; after the reaction is complete, cooling to room temperature and quenching the reaction with 1 mL of saturated sodium bicarbonate solution. Dichloromethane was added to the quenched solution, and the organic phase was extracted and separated (repeated 3 times). The organic phase was washed with 5 g of saturated brine and allowed to stand for separation. After separation, the organic phase was dried and concentrated, and then separated by column chromatography (PE: EtOAc = 75:25 (v / v)) to obtain methyl 1-diphenylmethyl-1H-indazole-3-carboxylate P16, with a yield of 41%. The product was then subjected to... 1 H NMR and 13 C NMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.85(d, J = 8.5 Hz, 1H), 7.41 - 7.29 (m, 12H), 4.06 (s, 3H) 13 C NMR (100 MHz, CDCl3) δ 147.7, 139.5, 128.8, 128.4, 127.9, 126.2,125.3, 123.5, 121.5, 119.1, 67.7, 52.0.

[0058] Example 17: ; The specific steps include: N- Cyclohexylnitroamine S7 (29 mg, 2 equivalents) and p-toluenesulfonamide N15 (17.1 mg, 1 equivalent) were dissolved in 1 mL of 1,2-dichloroethane. Trifluoromethanesulfonic acid (15 mg, 1 equivalent) was then added at room temperature, and the mixture was heated to 70 °C and reacted for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and 1 mL of saturated sodium bicarbonate solution was added to quench the reaction. Dichloromethane was added to the quenched solution, and the organic phase was extracted (repeated 3 times). The organic phase was washed with 5 g of saturated brine, allowed to stand for separation, and the separated organic phase was dried and concentrated. The final product was obtained by column chromatography (PE:DCM = 95:5 (v / v)).N -Cyclohexyl-4-toluenesulfonamide P17, yield 75%. The product was subjected to... 1 H NMR and 13 C NMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.84-7.65 (m, 2H), 7.32-7.27 (m, 2H), 4.71(d, J = 7.4 Hz, 1H), 3.20-3.02 (m, 1H), 2.42 (s, 3H), 1.79-1.69 (m, 2H), 1.67-1.57 (m, 2H), 1.55-1.43 (m, 1H), 1.31-1.01 (m, 5H). 13 C NMR (100 MHz, CDCl3) δ 143.2, 138.6, 129.7, 127.0, 52.7, 34.0, 25.2, 24.7, 21.6.

[0059] Example 18: ; The specific steps include: dissolving diphenylmethane S3 (18.5 mg, 1.0 equivalent) and potassium thiocyanate (9.7 mg, 1 equivalent) in 1 mL of 1,2-dichloroethane, adding concentrated nitric acid solution (58.2 mg, 6 equivalent, mass fraction 65%–68%) at room temperature, and stirring for 10 min. Finally, adding benzamide N16 (36.3 mg, 3 equivalent) to the reaction system, heating the mixture to 100 °C, and continuing the reaction for 1 h. After the reaction is complete, cooling to room temperature, and quenching the reaction with 1 mL of saturated sodium bicarbonate solution. Adding dichloromethane to the quenched solution, extracting and separating the organic phase (repeated 3 times), washing the organic phase with 5 g of saturated brine, allowing it to stand for layering, separating the organic phase, drying and concentrating, and then separating by column chromatography (PE: EtOAc = 75:25 (volume ratio)) to obtain... N -Diphenylmethylbenzamide P18, yield 19%. The product was subjected to... 1 HNMR and 13 C NMR characterization, the characterization results are as follows: 1H NMR (400 MHz, CDCl3) δ 7.86 - 7.76 (m, 2H), 7.53 - 7.47 (m, 1H), 7.45 - 7.38 (m, 2H), 7.38 - 7.25 (m, 10H), 6.75 (d, J = 7.5 Hz, 1H), 6.45 (d, J = 7.8 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 166.5, 141.5, 134.2, 131.7, 128.8, 128.7, 127.6, 127.5, 127.1, 57.5.

[0060] Example 19: ; The specific steps include: 1- N 1-Nitro-2-methoxyphenyl)adamantane S7 (19.6 mg, 1.0 equivalent) and 4-bromoanisole N19 (56.1 mg, 3 equivalent) were dissolved in 1 mL of 1,2-dichloroethane. Methanesulfonic acid (9.7 mg, 1 equivalent) was added at room temperature, and the mixture was heated to 70 °C and reacted for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and 1 mL of saturated sodium bicarbonate solution was added to quench the reaction. Dichloromethane was added to the quenched solution, and the organic phase was extracted (repeated 3 times). The organic phase was washed with 5 g of saturated brine, allowed to stand for separation, and then dried and concentrated. 1-(5-bromo-2-methoxyphenyl)adamantane P19 was obtained by column chromatography (PE: DCM = 80:20 (v / v)) in 73% yield. The product was then subjected to further analysis. 1 H NMR and 13 C NMR characterization, the characterization results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.23 – 7.17 (m, 2H), 6.66 (d, J = 8.5 Hz,1H), 3.74 (s, 3H), 1.98 (s, 9H), 1.69 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 158.0, 140.9, 129.9, 129.4, 113.4, 113.4, 55.3, 40.4, 37.3, 37.1, 29.1.

[0061] The embodiments described above provide a detailed explanation of the technical solutions and beneficial effects of the present invention. It should be understood that the above descriptions are merely specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, additions, and equivalent substitutions made within the scope of the principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for deamination functionalization of aliphatic amines, characterized in that, include: The aliphatic amine and nucleophile shown in formula (I) react in the presence of acid and solvent to produce the deamination functionalized product shown in formula (III), as follows: ； Among them, R 1 R 2 R 3 Each group is independently selected from hydrogen, hydroxyl, alkyl, alkoxy, alkanoyl, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, aryl, heteroaryl, phenylalkyl, or R 1 R 2 R 3 Two or three of the groups form a non-aromatic ring, cage-like compound; FG is a functional group in which nucleophiles participate in the reaction.

2. The method for deamination and functionalization of aliphatic amines according to claim 1, characterized in that, R 1 R 2 R 3 Each group is independently selected from hydrogen, C1-C 20 Alkyl, alkoxy, alkanoyl, alkoxycarbonyl, aryl, heteroaryl, phenylalkyl, wherein the heteroaryl group contains 1 to 3 heteroatoms each independently selected from oxygen, nitrogen, and sulfur; wherein the amino, C1-C 20 Alkyl, alkoxy, alkanoyl, alkoxycarbonyl, aryl, heteroaryl, and phenylalkyl may optionally be substituted by 0 or more substituents selected from the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, nitro, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and phenylalkyl. or R 1 R 2 R 3 Two or three of the groups form a non-aromatic ring, cage-like compound, wherein the non-aromatic ring, cage-like compound is optionally substituted by 0 or more substituents selected from the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, nitro, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, phenylalkyl.

3. The method for deamination functionalization of aliphatic amines according to claim 1, characterized in that, R 1 R 2 R 3 Each group is independently selected from hydrogen, C1-C 20 Alkyl, phenyl C1-C6 alkyl; or R 1 R 2 R 3 Two of the groups form a non-aromatic ring, which contains 0 to 3 heteroatoms each independently selected from oxygen, nitrogen, and sulfur; the non-aromatic ring is optionally substituted by 0 or more substituents selected from the following: aryl, heteroaryl, cycloalkyl, heterocycloalkyl, phenylalkyl; or R 1 R 2 R 3 The group comprises three cage-like compounds, wherein the cage-like compounds are optionally substituted by 0 or more substituents selected from the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, cyano, nitro, aryl, heteroaryl, cycloalkyl, heterocycloalkyl.

4. The method for deamination functionalization of aliphatic amines according to any one of claims 1 to 3, characterized in that, The fatty amines represented by formula (I) are selected from: ； The aliphatic nitrosamines represented by formula (II) are selected from: 。 5. The method for deamination functionalization of aliphatic amines according to claim 1, characterized in that, FG is selected from halogens, alkyl groups, aromatic groups, R4O-, R5S-, R6Se-, and R7R8N-. R4, R5, and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cyano, aromatic, aromatic alkyl, halothionyl, and acyl. R7 and R8 are independently selected from hydrogen, sulfonyl, and acyl groups, or R7 and R8 form a non-aromatic ring or benzene is not an aromatic ring. The non-aromatic ring contains 1 to 3 heteroatoms, each independently selected from oxygen, nitrogen, and sulfur.

6. The method for deamination and functionalization of aliphatic amines according to claim 1, characterized in that, The nucleophile is a halogen nucleophile, an oxygen nucleophile, a nitrogen nucleophile, a sulfur nucleophile, a selenium nucleophile, or an aromatic nucleophile.

7. The method for deamination functionalization of aliphatic amines according to claim 1 or 6, characterized in that, The nucleophilic reagents mentioned are selected from: 。 8. The method for deamination functionalization of aliphatic amines according to claim 1 or 7, characterized in that, The molar amount of the nucleophile is 100% to 500% of the molar amount of the fatty amine.

9. The method for deamination and functionalization of aliphatic amines according to claim 1, characterized in that, The acid mentioned is concentrated nitric acid.

10. The method for deamination functionalization of aliphatic amines according to claim 1 or 8, characterized in that, The molar amount of acid is 50% to 600% of the molar amount of fatty amine or fatty nitroamine.

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