CN114773253A - Preparation method of polysubstituted arylamine compound - Google Patents

Abstract

The invention belongs to the field of pharmaceutical chemical intermediates and related chemical technologies, and provides a method for preparing a polysubstituted aromatic amine compound. Under the following conditions, react with an amine compound in an anhydrous organic solvent to obtain the corresponding polysubstituted aromatic amine compound. The beneficial effects of the present invention are that the method has a short synthetic route, mild reaction conditions, simple operation and high yield; the obtained aromatic amine product can be subjected to various functionalizations, such as bromination reaction, and the reaction product can be applied to various functional materials and Synthesis of drug molecules.

Description

A kind of preparation method of polysubstituted aromatic amine compound

technical field

The invention belongs to the field of pharmaceutical chemical intermediates and related chemical technologies, and provides an efficient preparation method of polysubstituted aromatic amine compounds.

Background technique

Because of their unique electronic properties, arylamine compounds have important application value in the fields of medicine, natural products, and luminescent materials, and are widely present in existing drug molecules. The construction of polysubstituted aromatic amines is particularly important.

The reported synthetic methods for synthesizing aromatic amine compounds are divided into two types according to the type of catalytic system. One is the direct nitration and reduction method using aromatic hydrocarbons as raw materials without metal catalysts. However, the reaction requires a large amount of metal reagents (such as iron powder), excess acid reagents, and harsh reaction conditions. These factors severely limit the application of this method in the construction of polysubstituted aromatic amines, and are also harmful to the environment. The other is a coupling reaction catalyzed by transition metal palladium, copper, etc., using aromatic hydrocarbons as raw materials. The most common are Buchwald-Hartwig cross-coupling reaction [Org Process Res Dev, 2019, 23(8): 1478-83], Ullmann amination reaction [Prog Chem, 2018, 30(9): 1257-97; Chem Soc Rev, 2014, 43(10):3525-50], Chan-Lam amination reaction [Chem Rev, 2019, 119(24):12491-523].

In the Buchwald-Hartwig cross-coupling reaction, in the presence of palladium catalysts, halogenated aromatic hydrocarbons can react with different amines to construct aromatic amine compounds. However, after years of development, there is still no catalytic system that can be used for the construction of different aromatic amine substrates, and only halogenated aromatic hydrocarbons are reacted with amines.

Ullmann reaction, the use of halogenated aromatic hydrocarbons and different amine compounds in the presence of excess copper catalyst to achieve the construction of aromatic amine compounds. However, the high reaction temperature, complex ligand system and ambiguous reaction mechanism limit the application of Ullmann reaction in the construction of polysubstituted aromatic amines.

In Chan-Lam amination reaction, in the presence of copper catalyst, boronic acid compounds and amine compounds are used to construct aromatic amine compounds. However, the reaction requires an equivalent amount of oxidant as an auxiliary and must use an organic boronic acid reagent as a substrate, which limits the application of the Chan-Lam amination reaction in the construction of polysubstituted aromatic amines.

In recent years, the method of constructing functional molecules by transition metal dearomatization strategy has become more and more promising due to its mild reaction conditions and easy preparation of complex functional molecules. Up to now, there has been no report on the synthesis method of directly obtaining polysubstituted arylamines using benzyl halides and their derivatives as reaction substrates.

SUMMARY OF THE INVENTION

The invention provides a preparation method of a polysubstituted aromatic amine compound. The preparation method has the advantages of mild reaction conditions, good reaction selectivity, wide substrate range and the like.

The technical scheme of the present invention is as follows:

An efficient preparation method of polysubstituted aromatic amine compounds is characterized in that, using benzyl halide and derivatives thereof as raw materials, under the joint action of alkali, palladium catalyst and ligand, in anhydrous organic solvent, The corresponding polysubstituted aromatic amine compounds can be prepared by reacting with nitrogen-containing compounds. The synthetic route is as follows:

The reaction temperature was 40°C, and the reaction time was 12h;

R ¹ is selected from hydrogen, aryl;

R ² is selected from hydrogen, methoxy, aryl;

R ³ is aryl;

R ⁴ is alkyl;

R ⁵ is alkyl;

X is selected from chlorine, bromine;

The molar ratio of benzyl halide and its derivatives to base is 1:4;

The molar ratio of benzyl halide and its derivatives to metal catalyst is 1:0.05;

The molar ratio of benzyl halide and its derivatives to ligand is 1:0.2;

The molar concentration of benzyl halide and its derivatives is 0.06mmol/mL;

The molar ratio of benzyl halide and its derivative to amine compound is 1:2;

The amine compounds are monoamine compounds and diamine compounds;

Described alkali is sodium hydride;

Described metal catalyst is palladium acetate, two (acetylacetonate) palladium;

The ligands include tris(2-furyl)phosphorus, tris[2-(5-methylfuryl)]phosphine, tris[2-(5-ethylfuryl)]phosphine, tris(2-thiophene) base) phosphine;

Described anhydrous organic solvent is tetrahydrofuran;

Separation methods include column chromatography, recrystallization, etc.;

Commonly used solvents for recrystallization include n-hexane, petroleum ether, acetone, and water.

When the product is separated by column chromatography, silica gel or neutral alumina can be used as the stationary phase, and the developing solvent is generally a pure solvent, such as petroleum ether, n-hexane, dichloromethane, ethyl acetate, methanol; or two. It is obtained by mixing different polar solvents, such as ethyl acetate-petroleum ether, ethyl acetate-n-hexane, dichloromethane-petroleum ether, methanol-ethyl acetate, methanol-dichloromethane.

The beneficial effects of the present invention are that the synthesis route of the method is short, the reaction conditions are mild, the operation is simple and the yield is high; the obtained amination product can be subjected to various functionalizations, such as bromination reaction, and the reaction product can be applied to various functional materials and Synthesis of drug molecules.

Description of drawings

FIG. 1 is the ¹ H nuclear magnetic spectrum of 4,4-difluoro-1-(4-methyl-3-phenylphenyl)piperidine in Example 1. FIG.

2 is a ¹³ C nuclear magnetic spectrum of 4,4-difluoro-1-(4-methyl-3-phenylphenyl)piperidine in Example 1.

FIG. 3 is the ¹ H nuclear magnetic spectrum of 2-phenyl-4-(4-benzoylpiperazinyl)toluene in Example 2. FIG.

4 is a ¹³ C nuclear magnetic spectrum of 2-phenyl-4-(4-benzoylpiperazinyl)toluene in Example 2.

FIG. 5 is the ¹ H nuclear magnetic spectrum of 5-methoxy-4-morpholinyl-2-phenyltoluene in Example 3. FIG.

FIG. 6 is a ¹³ C nuclear magnetic spectrum of 5-methoxy-4-morpholinyl-2-phenyltoluene in Example 3. FIG.

FIG. 7 is a ¹ H nuclear magnetic spectrum of 4-morpholinyl-2,5-diphenyltoluene in Example 4. FIG.

FIG. 8 is a ¹³ C nuclear magnetic spectrum of 4-morpholinyl-2,5-diphenyltoluene in Example 4. FIG.

FIG. 9 is the ¹ H nuclear magnetic spectrum of 4-morpholinyl-2-(4-methoxyphenyl)toluene in Example 5. FIG.

FIG. 10 is the ¹³ C nuclear magnetic spectrum of 4-morpholinyl-2-(4-methoxyphenyl)toluene in Example 5. FIG.

FIG. 11 is the ¹ H nuclear magnetic spectrum of 4-morpholinyl-2-phenyltoluene in Comparative Example 1. FIG.

FIG. 12 is a ¹³ C nuclear magnetic spectrum of 4-morpholinyl-2-phenyltoluene in Comparative Example 1. FIG.

Detailed ways

The preparation method of the polysubstituted aromatic amine compound of the present invention has the advantages of low raw material price, few reaction steps, mild reaction conditions, simple operation and high reaction yield.

The present invention will be further described below in conjunction with specific embodiments. These examples are only intended to illustrate the present invention and not to limit the scope of the present invention. Simple replacements or improvements made to the present invention by those skilled in the art all fall within the technical solutions protected by the present invention.

Example 1: Synthesis of 4,4-difluoro-1-(4-methyl-3-phenylphenyl)piperidine

In a 25 mL reactor, sodium hydride (0.0224 g, 1.2 mmol) was added, and after nitrogen replacement three times, anhydrous tetrahydrofuran (5 mL) was added, and 4,4-difluoropiperidine (0.0727 g, 0.6 mmol) was added under stirring. , and after stirring for one hour, tris(2-furyl)phosphine (0.0139g, 0.06mmol), palladium acetate (0.0034g, 0.015mmol), 2-phenylbenzyl chloride (0.0608g, 0.3mmol) were successively added thereto; The mixture was reacted at 40°C for 12 hours. Column chromatography (silica gel, 200-300 mesh; developing solvent, petroleum ether/ethyl acetate = 3/1, v/v) to obtain 4,4-difluoro-1-(4-methyl-3-benzene phenyl) piperidine 0.074 g, 86% yield.

4,4-二氟-1-(4-甲基-3-苯基苯基)哌啶

4,4-Difluoro-1-(4-methyl-3-phenylphenyl)piperidine

Colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.29 (m, 2H), 7.28-7.21 (m, 3H), 7.08 (d, J=8.3Hz, 1H), 6.81-6.74 (m, 2H), 3.27–3.21 (m, 4H), 2.10 (s, 3H), 2.06–1.95 (m, 4H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 148.3, 142.8, 142.3, 131.1, 129.1, 128.1, 126.9 , 118.7, 116.0, 47.2 ( ² J _CF = 5.0 Hz), 33.7 ( ¹ J _CF = 22.8 Hz), 19.5. ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ-97.6. IR (neat): υ _max 3056, 2966 ,2938,2831,1609,1561,1342,1197,925,773,703,633cm ^-1 ; HRMS(ESI) m/z calcd for C ₁₈ H ₂₀ F ₂ N[M+H] ⁺ :288.1558,found:288.1550.

Example 2: Synthesis of 2-phenyl-4-(4-benzoylpiperazinyl)toluene

In a 25 mL reactor, sodium hydride (0.0224 g, 1.2 mmol) was added, after nitrogen replacement three times, anhydrous tetrahydrofuran (5 mL) was added, and 1-benzoylpiperazine was added under stirring, and after stirring for two hours, added thereto Tris[2-(5-methylfuryl)]phosphine (0.0165g, 0.06mmol), bis(acetylacetonate)palladium (0.0046g, 0.015mmol), 2-phenylbenzyl chloride (0.0608g, 0.3mmol) were added successively ); the mixture was reacted at 40°C for 12 hours. Column chromatography separation (silica gel, 200-300 mesh; developing solvent, petroleum ether/ethyl acetate=1/1, v/v) to obtain 2-phenyl-4-(4-benzoylpiperazinyl)toluene 0.076 g, 71% yield.

2-苯基-4-(4-苯甲酰基哌嗪基)甲苯

2-Phenyl-4-(4-benzoylpiperazinyl)toluene

White solid. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.41–7.30 (m, 7H), 7.28–7.21 (m, 3H), 7.11 (d, J=8.3 Hz, 1H), 6.78 (d, J= 25.9Hz, 2H), 3.69(d, J=214.3Hz, 4H), 3.11(d, J=87.8Hz, 4H), 2.11(s, 3H). ¹³ C NMR(151MHz, CDCl ₃ )δ170.4,149.0, 142.7,142.2,135.7,131.1,129.9,129.1,128.6,128.1,127.2,126.9,118.6,116.0,50.2,47.7,42.1,19.5.IR(KBr):υ _max 3019,2954,2924,1637,1431 , 1264, 1156, 1013, 942, 737, 704 cm ^-1 ; HRMS(ESI) m/zcalcd for C ₂₄ H ₂₅ N ₂ O[M+H] ⁺ : 357.1961, found: 357.1951.

Example 3: Synthesis of 5-methoxy-4-morpholinyl-2-phenyltoluene

Sodium hydride (0.0224 g, 1.2 mmol) was added, and after nitrogen replacement three times, anhydrous tetrahydrofuran (5 mL) was added, and morpholine (0.0523 g, 0.6 mmol) was added under stirring. After stirring for one hour, tri[ 2-(5-Ethylfuryl)]phosphine (0.0190g, 0.06mmol), bis(acetylacetonate)palladium (0.0046g, 0.015mmol), 5-methoxy-2-phenylbenzyl chloride (0.0698g, 0.3 mmol); the mixture was reacted at 40°C for 12 hours. Column chromatography separation (silica gel, 200-300 mesh; developing solvent, petroleum ether/ethyl acetate=10/1, v/v) to obtain 5-methoxy-4-morpholinyl-2-phenyltoluene 0.045 g, 53% yield.

5-甲氧基-4-吗啉基-2-苯基甲苯

5-Methoxy-4-morpholinyl-2-phenyltoluene

Colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42–7.37 (m, 2H), 7.34–7.28 (m, 3H), 6.80 (s, 1H), 6.76 (s, 1H), 3.93–3.86 ( m, 7H), 3.11–3.02 (m, 4H), 2.24 (s, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 151.3, 142.0, 138.9, 134.4, 129.9, 129.4, 128.1, 126.5, 119.8, 113.4, 67.2,55.6,51.4,20.1.IR(neat):υ _max 2955,2852,2816,1605,1513,1490,1233,1119,1050,870,704,563cm ^-1 ; HRMS(ESI)m/z calcd for C ₁₈ H ₂₂ NO ₂ [M+H] ⁺ :284.1645,found:284.1638.

Example 4: Synthesis of 4-morpholino-2,5-diphenyltoluene

Sodium hydride (0.0224 g, 1.2 mmol) was added, and after nitrogen replacement three times, anhydrous tetrahydrofuran (5 mL) was added, and morpholine (0.0523 g, 0.6 mmol) was added under stirring, and after stirring for one hour, three ( 2-Furyl)phosphine (0.0139 g, 0.06 mmol), bis(acetylacetonate)palladium (0.0046 g, 0.015 mmol), 2,5-diphenylbenzyl chloride (0.0836 g, 0.3 mmol); mixture at 40°C The reaction was carried out for 12 hours. Column chromatography separation (silica gel, 200-300 mesh; developing solvent, petroleum ether/ethyl acetate=15/1, v/v), 0.050 g of 4-morpholino-2,5-diphenyltoluene was obtained, the product was rate 51%.

4-吗啉基-2,5-二苯基甲苯

4-Morpholinyl-2,5-diphenyltoluene

Yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77–7.72 (m, 2H), 7.51–7.41 (m, 7H), 7.37–7.33 (m, 1H), 7.23 (s, 1H), 6.95 ( s, 1H), 3.67–3.62 (m, 4H), 2.89–2.85 (m, 4H), 2.31 (s, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 147.8, 141.9, 141.7, 140.7, 133.9, 133.6 ,129.6,129.2,128.9,128.3,128.2,127.0,126.9,119.7,67.0,51.7,19.6.IR(KBr):υ _max 3056,3023,2852,1781,1683,1600,1512,1483,1446,1118, 773,701cm ^-1 ; HRMS (ESI) m/z calcd for C ₂₃ H ₂₄ NO[M+H] ⁺ : 330.1852, found: 330.1846.

Example 5: Synthesis of 4-morpholino-2-(4-methoxyphenyl)toluene

Sodium hydride (0.0224 g, 1.2 mmol) was added, and after nitrogen replacement three times, anhydrous tetrahydrofuran (5 mL) was added, and morpholine (0.0523 g, 0.6 mmol) was added under stirring, and after stirring for one hour, three ( 2-Thienyl)phosphine (0.0168 g, 0.06 mmol), palladium acetate (0.0034 g, 0.015 mmol), 2-(4-methoxyphenyl)benzyl chloride (0.0698 g, 0.3 mmol); mixture at 40°C The reaction was carried out for 12 hours. Column chromatography separation (silica gel, 200-300 mesh; developing solvent, petroleum ether/ethyl acetate=15/1, v/v) to obtain 4-morpholino-2-(4-methoxyphenyl)toluene 0.047 g, 55% yield.

4-吗啉基-2-(4-甲氧基苯基)甲苯

4-Morpholinyl-2-(4-methoxyphenyl)toluene

Colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.29 (d, J=7.8 Hz, 2H), 7.20 (d, J=8.2 Hz, 1H), 7.02–6.96 (m, 2H), 6.88–6.82 (m, 2H), 3.91–3.86 (m, 7H), 3.21–3.16 (m, 4H), 2.23 (s, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 158.6, 149.4, 142.2, 134.8, 131.0, _HRMS (ESI )m/z calcd for C ₁₈ H ₂₂ NO ₂ [M+H] ⁺ :284.1645,found:284.1638.

Comparative Example 1: Synthesis of 4-morpholinyl-2-(4-methoxyphenyl)toluene

The existing synthesis method of [J Am Chem Soc, 2012, 134(12):5492-5495]4-[1-(4-methylnaphthyl)]morpholine was used. In a 25 mL reactor, sodium hydride (0.0480 g, 2.0 mmol) and tetrakis(triphenylphosphine) palladium (0.029 g, 0.025 mmol) were added, and after nitrogen replacement three times, anhydrous tetrahydrofuran (5 mL) was added under nitrogen protection, Morpholine (0.0871 g, 1.0 mmol) and 1-chloromethylnaphthalene (0.0883 g, 0.5 mmol) were added under stirring, stirred at room temperature for 12 hours, and separated by column chromatography (silica gel, 200-300 mesh; developing solvent, petroleum ether/ Ethyl acetate=10/1, v/v) to obtain 0.084 g of 4-[1-(4-methylnaphthyl)]morpholine with a yield of 74%.

An attempt was made to synthesize 4-morpholino-2-phenyltoluene using the existing method in [J Am Chem Soc, 2012, 134(12):5492-5495]. In a 25 mL reactor, sodium hydride (0.0480 g, 2.0 mmol) and tetrakis(triphenylphosphine) palladium (0.029 g, 0.025 mmol) were added, and after nitrogen replacement three times, anhydrous tetrahydrofuran (5 mL) was added under nitrogen protection, Morpholine (0.0871 g, 1.0 mmol) and 2-phenylbenzyl chloride (0.1013 g, 0.5 mmol) were added with stirring, and the mixture was stirred at room temperature for 12 hours. Column chromatography separation (silica gel, 200-300 mesh; developing solvent, petroleum ether/ethyl acetate=10/1, v/v) to obtain 0.011 g of 4-morpholino-2-phenyltoluene, yield 9% .

4-(4-吗啉基)-2-苯基甲苯

4-(4-Morpholinyl)-2-phenyltoluene

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.33 (t, J=7.5 Hz, 2H), 7.29-7.22 (m, 3H), 7.10 (d, J=8.3 Hz, 1H), 6.77 (dd, J= 8.3, 2.8Hz, 1H), 6.73 (d, J=2.8Hz, 1H), 3.82–3.76 (m, 4H), 3.10–3.04 (m, 4H), 2.11 (s, 3H). ¹³ C NMR (151MHz) ,CDCl ₃ )δ149.3,142.6,142.4,131.0,129.1,128.1,127.0,126.8,117.5,114.9,67.0,49.8,19.5.IR(neat):υ _max 3048,3023,2954,2848,1609,1488,1449 , 1377, 1336, 1122, 945, 704 cm ^-1 ; HRMS(ESI) m/z calcd for C ₁₇ H ₂₀ NO[M+H] ⁺ : 254.1539, found: 254.1535.

Comparative Example 2: Synthesis of 4-morpholino-2-phenyltoluene

Experimental conditions: In a 25 mL reactor, add a base (1.2 mmol), after nitrogen replacement three times, add an anhydrous solvent (5 mL), and add morpholine (0.0523 g, 0.6 mmol) under stirring, and after stirring for one hour, add The ligand (0.06 mmol), the metal catalyst (0.015 mmol), and 2-phenylbenzyl chloride (0.0608 g, 0.3 mmol) were sequentially added therein; the mixture was reacted at 40° C. for 12 hours. The product yield was determined by NMR of the reaction solution. The experimental results are shown in the table. The product purification method is the same as that in Example 4.

Claims (6)

1. a preparation method of a polysubstituted aromatic amine compound, is characterized in that, with containing benzyl halide and derivative thereof as raw material, under the effect of metal catalyst, ligand, alkali, in anhydrous organic solvent, Amine compounds are combined with raw materials to obtain polysubstituted aromatic amine compounds. The synthetic route is as follows:

The reaction temperature was 40°C, and the reaction time was 12 hours; R ¹ is selected from hydrogen, aryl; R ² is selected from hydrogen, methoxy, aryl; R ³ is aryl; R ⁴ is alkyl; R ⁵ is alkyl; X is selected from chlorine, bromine; The molar ratio of benzyl halide and its derivatives to base is 1:4; The molar ratio of benzyl halide and its derivatives to metal catalyst is 1:0.05; The molar ratio of benzyl halide and its derivatives to ligand is 1:0.2; The molar concentration of benzyl halide and its derivatives is 0.06mmol/mL; The molar ratio of the benzyl halide and its derivatives to the amine compound is 1:2. 2 . The preparation method according to claim 1 , wherein the amine compound includes a monoamine compound and a diamine compound. 3 . 3. preparation method as described in claim 1 is characterized in that, described alkali is sodium hydride. 4. The preparation method according to claim 1, wherein the metal catalyst comprises palladium acetate and bis(acetylacetonate) palladium. 5. The preparation method according to claim 1, wherein the ligand comprises tris(2-furyl) phosphorus, tris[2-(5-methylfuryl)]phosphine, tris[ 2-(5-ethylfuryl)]phosphine, tris(2-thienyl)phosphine. 6. The preparation method according to claim 1, wherein the anhydrous solvent is tetrahydrofuran.

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