Homoallylamine compounds and methods for their preparation

Abstract

The application discloses a high allylamine compound, and relates to a one-step synthesis of a series of high allyl compounds with application prospects by using an air-stable allyl potassium trifluoroborate reagent as an allylation reagent, selecting cheap and readily available rose Bengal as a catalyst, and irradiating with a commercially available visible light LED light source. The synthesis method has the advantages of short steps, simple operation, mild conditions, wide substrate range, no participation of additives and metals, and environmental friendliness.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a class of high-allylamine compounds, and also to a method for preparing the above-mentioned compounds. Background Technology

[0002] Homoallylamine compounds are a special structural unit, serving as important components in many natural products and pharmaceutical active molecules. For example, the alkaloid angustifoline extracted from narrow-leaved lupin and the proteasome inhibitor eponemycin, which has anticancer effects, contain homoallylamine structural fragments. Homoallylamine compounds are also an important class of intermediates; the allyl moiety can undergo various transformations, such as epoxidation, dihydroxylation, and halogenation of the double bond, yielding a variety of derivatives. Therefore, the synthesis of these compounds has long been a research hotspot for chemists and pharmacologists.

[0003] The addition of allyl metal complexes to the carbon-nitrogen double bond of imines is one of the most effective methods for obtaining high allylamines. However, allyl metal reagents are sensitive to water and oxygen and are not easy to store in air. They need to be freshly prepared using allyl haloalkanes and stoichiometric metal reducing reagents. In addition, the amine needs to be oxidized to imine. Although this traditional method has a wide range of applications, it requires the substrate to be prepared in advance, which is cumbersome and uneconomical, and causes environmental pollution and waste of resources. Therefore, there is an urgent need to develop greener and more environmentally friendly methods.

[0004] To address the aforementioned issues, this invention proposes applying visible light-promoted allylation reactions to the synthesis of high-allylamine compounds. Visible light, as a safe, inexpensive, abundant, and renewable source of chemical potential, promotes chemical reactions that meet the requirements of organic chemists for atom economy and environmental friendliness. Summary of the Invention

[0005] The purpose of this invention is to provide a high-allylamine compound, which is a fragment of natural products and drug molecules, as well as an important synthetic intermediate.

[0006] The second objective of this invention is to provide a method for preparing the above-mentioned high-allylamine compounds, which overcomes the problems of uneconomical and environmentally unfriendly practices of existing preparation methods, such as the need for pre-functionalization of raw materials and the requirement for the participation of transition metals.

[0007] The first technical solution adopted in this invention is a high-allylamine compound, the structure of which is shown in general formula 3 below:

[0008]

[0009] In Formula 3, R1 is a C1-C12 alkyl group, R2 is H, a C1-C3 alkyl group, a methoxy group, or a halogen, and n is 1-3.

[0010] The second technical solution adopted in this invention is a method for preparing the above-mentioned high-allylamine compounds, the specific steps of which are as follows:

[0011] Step 1: Dissolve the tertiary amine compound and potassium allyl trifluoroborate in chloroform solvent, and react them in one step under blue light irradiation and Bengal rose red catalysis to obtain the reaction mixture. The reaction formula is as follows:

[0012]

[0013] In the above formula, R1 is a C1 to C12 alkyl group, R2 is H, C1 to C3 alkyl group, methoxy group, or halogen, and n is 1 to 3;

[0014] Step 2: Add distilled water to the reaction mixture and extract with chloroform three times to obtain the organic phase. Wash the organic phase with saturated sodium chloride and dry it with anhydrous sodium sulfate for half an hour. Remove the solvent with a rotary evaporator and purify by silica gel column chromatography to obtain the high-allylamine compounds.

[0015] The invention is further characterized in that,

[0016] In step 1, the reaction temperature is room temperature and the reaction time is 12–48 h.

[0017] The molar ratio of the tertiary amine compound and potassium allyl trifluoroborate is 1:1.

[0018] The amount of Bengal rose red used is 1-5 mol% of the amount of the tertiary amine compound.

[0019] In step 1, the amount of chloroform added is 5-10 mL per 1 mmol of tertiary amine compound.

[0020] The blue light refers to a commercially available 10W blue light lamp with a wavelength of 465-475nm.

[0021] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0022] (1) The high-allylamine compounds of the present invention are fragments of natural products and drug molecules, as well as important synthetic intermediates.

[0023] (2) In this invention, potassium allyl trifluoroborate, which is stable in air, is used as the allylation reagent. Inexpensive and readily available Bengal rose red is selected as the catalyst. A series of high allyl compounds with application prospects are synthesized in one step by irradiation with commercially available visible light LED light source. The synthesis method has the advantages of short steps, simple operation, mild conditions, wide substrate range, no additives and no metal participation. Attached Figure Description

[0024] Figure 1This is the 1H NMR spectrum of 2-allyl-1-phenylpyrrolidine prepared in Example 1 of this invention;

[0025] Figure 2 This is the carbon NMR spectrum of 2-allyl-1-phenylpyrrolidine prepared in Example 1 of this invention.

[0026] Figure 3 This is the 1H NMR spectrum of 2-allyl-1-(4-bromophenyl)pyrrolidine prepared in Example 2 of this invention;

[0027] Figure 4 This is the carbon NMR spectrum of 2-allyl-1-(4-bromophenyl)pyrrolidine prepared in Example 2 of this invention;

[0028] Figure 5 This is the 1H NMR spectrum of 2-allyl-1-(3-methoxyphenyl)pyrrolidine prepared in Example 3 of this invention;

[0029] Figure 6 This is the carbon NMR spectrum of 2-allyl-1-(3-methoxyphenyl)pyrrolidine prepared in Example 3 of this invention;

[0030] Figure 7 This is the 1H NMR spectrum of 2-allyl-1-(3,5-dimethylphenyl)pyrrolidine prepared in Example 4 of this invention;

[0031] Figure 8 This is the carbon NMR spectrum of 2-allyl-1-(3,5-dimethylphenyl)pyrrolidine prepared in Example 4 of this invention;

[0032] Figure 9 This is the 1H NMR spectrum of 2-allyl-1-phenylpiperidine prepared in Example 5 of this invention;

[0033] Figure 10 This is the carbon NMR spectrum of 2-allyl-1-phenylpiperidine prepared in Example 5 of this invention;

[0034] Figure 11 This is the 1H NMR spectrum of 2-allyl-1-phenylhexamethyleneimine prepared in Example 6 of this invention;

[0035] Figure 12 This is the carbon NMR spectrum of 2-allyl-1-phenylhexamethyleneimine prepared in Example 6 of this invention;

[0036] Figure 13 This is the 1H NMR spectrum of N-(but-3-en-1-yl)-N-methylaniline prepared in Example 7 of this invention;

[0037] Figure 14 This is the carbon NMR spectrum of N-(but-3-en-1-yl)-N-methylaniline prepared in Example 7 of this invention;

[0038] Figure 15 This is the 1H NMR spectrum of N-(but-3-en-1-yl)-N-isobutylaniline prepared in Example 8 of this invention;

[0039] Figure 16 This is the carbon NMR spectrum of N-(but-3-en-1-yl)-N-isobutylaniline prepared in Example 8 of this invention. Detailed Implementation

[0040] The present invention will now be described in detail with reference to specific embodiments.

[0041] A high-allylamine compound of the present invention has the structure shown in general formula 3 below:

[0042]

[0043] In Formula 3, R1 is a C1-C12 alkyl group, R2 is H, a C1-C3 alkyl group, a methoxy group, or a halogen, and n is 1-3.

[0044] The specific steps for synthesizing the above-mentioned allylamine compounds are as follows:

[0045] Step 1: Dissolve the tertiary amine compound and potassium allyl trifluoroborate in chloroform solvent at a molar ratio of 1:1. Under the irradiation of a commercially available 10W blue light lamp and catalysis by Bengal rose red, a one-step reaction is carried out to obtain the reaction mixture. The reaction formula is as follows:

[0046]

[0047] In the above formula, R1 is a C1 to C12 alkyl group, R2 is H, a C1 to C3 alkyl group, a methoxy group, or a halogen, and n is 1 to 3;

[0048] The reaction conditions were as follows: room temperature and 12–48 h. The amount of Bengal rose red used was 1–5 mol% of the amount of the tertiary amine compound. The amount of chloroform added was 5–10 mL per 1 mmol of the tertiary amine compound. The blue light wavelength was 465–475 nm.

[0049] Step 2: Add distilled water to the reaction mixture and extract with chloroform three times to obtain the organic phase. Wash the organic phase with saturated sodium chloride and dry it with anhydrous sodium sulfate for half an hour. Remove the solvent with a rotary evaporator and purify by silica gel column chromatography to obtain the high-allylamine compounds.

[0050] The present invention will be further described in detail below with reference to the embodiments:

[0051] Example 1

[0052] 0.2 mmol of 1-phenylpyrrolidine, 0.2 mmol of allyl trifluoroborate, and 10.2 mg of Bengal rose red were added to a 10 mL reaction flask equipped with a magnetic stirrer. Then, 2.0 mL of chloroform was added to the reaction system, and the mixture was stirred for 12 h under 10 W blue light irradiation. After the reaction was completed, 10 mL of distilled water was added, and the reaction mixture was extracted three times with 10 mL of chloroform. The organic phase was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate for half an hour, and the solvent was removed by rotary evaporation. The remaining reactants were purified by silica gel column chromatography to obtain 2-allyl-1-phenylpyrrolidine 3a in 73% yield.

[0053]

[0054] In the above examples, the product 2-allyl-1-phenylpyrrolidine 3a is a yellow oily liquid; the eluent is ethyl acetate:petroleum ether (1:50, Rf=0.50).

[0055] like Figure 1 and Figure 2 The NMR data for the products are shown below: ¹H NMR (400MHz, CDCl₃) δ 7.25–7.19 (m, 2H), 6.66 (t, J = 7.3Hz, 1H), 6.59 (d, J = 8.2Hz, 2H), 5.83 (ddt, J = 17.2, 10.2, 7.0Hz, 1H), 5.16–5.05 (m, 2H), 3.80–3.70 (m, 1H), 3.43 (td, J = 9.0, 8.2, 2.4Hz, 1H), 3.20–3.11 (m, H), 2.54–2.46 (m, 1H), 2.11–1.85 (m, 5H); ¹³C NMR (101MHz, CDCl3) δ147.2,135.8,129.4,117.0,115.5,112.0,58.1,48.5,37.5,29.9,23.4.

[0056] Example 2

[0057] 0.2 mmol of 1-(4-bromophenyl)pyrrolidine, 0.2 mmol of allyl trifluoroborate, and 6.1 mg of Bengal rose red were added to a 10 mL reaction flask equipped with a magnetic stirrer. Then, 1.0 mL of chloroform was added to the reaction system, and the mixture was stirred for 12 h under 10 W blue light irradiation. After the reaction was complete, 10 mL of distilled water was added, and the reaction mixture was extracted three times with 10 mL of chloroform. The organic phase was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate for half an hour, and the solvent was removed by rotary evaporation. The remaining reactants were purified by silica gel column chromatography to give 2-allyl-1-(4-bromophenyl)pyrrolidine 3b in 69% yield.

[0058]

[0059] In the above examples, the product 2-allyl-1-(4-bromophenyl)pyrrolidine 3b is a yellow oily liquid; eluent: ethyl acetate: petroleum ether (1:50, Rf=0.50).

[0060] like Figure 3 and Figure 4 The NMR data of the products are shown below: 1H NMR (400MHz, CDCl3) δ7.30–7.25(m,2H),6.46–6.40(m,2H),5.85–5.74(m,1H),5.13–5.06(m,2H),3.73–3.68(m,1H),3.40–3.35(m,1H),3.15–3.09(m,1H),2.47–2.41 (m,1H),2.09–1.88(m,5H); 13C NMR (101MHz, CDCl3) δ146.1,135.4,131.9,117.3,113.6,107.3,58.2,48.5,37.2,29.9,23.4.

[0061] Example 3

[0062] 0.2 mmol of 1-(3-methoxyphenyl)pyrrolidine, 0.2 mmol of allyl trifluoroborate, and 10.2 mg of Bengal rose red were added to a 10 mL reaction flask equipped with a magnetic stirrer. Then, 2.0 mL of chloroform was added to the reaction system, and the mixture was stirred for 24 h under 10 W blue light irradiation. After the reaction was complete, 10 mL of distilled water was added, and the reaction mixture was extracted three times with 10 mL of chloroform. The organic phase was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate for half an hour, and the solvent was removed by rotary evaporation. The remaining reactants were purified by silica gel column chromatography to give 2-allyl-1-(3-methoxyphenyl)pyrrolidine 3c, with a yield of 62%.

[0063]

[0064] The product 2-allyl-1-(3-methoxyphenyl)pyrrolidine 3c is a yellow oily liquid; eluent: ethyl acetate: petroleum ether (1:50, Rf=0.50).

[0065] like Figure 5 and Figure 6The NMR data for the products are shown below: ¹H NMR (400MHz, CDCl₃) δ 7.13 (t, J = 8.2Hz, ¹H), 6.23 (td, J = 8.2, 2.2Hz, 2H), 6.14 (t, J = 2.2Hz, 1H), 5.87–5.76 (m, ¹H), 5.16–5.01 (m, 2H), 3.80 (s, 3H), 3.78–3.70 (m, 1H), 3.41 (td, J = 8.0, 2.4Hz, 1H), 3.19–3.13 (m, 1H), 2.56–2.45 (m, 1H), 2.12–1.84 (m, 5H); ¹³C NMR (101MHz, CDCl3) δ160.9,148.5,135.8,130.0,117.1,105.3,100.5,98.4,58.3,55.2,48.5,37.5,29.9,23.3.

[0066] Example 4

[0067] 0.2 mmol of 1-pyrrolidine, 0.2 mmol of allyl trifluoroborate, and 10.2 mg of Bengal rose red were added to a 10 mL reaction flask equipped with a magnetic stirrer. Then, 1.2 mL of chloroform was added to the reaction system, and the mixture was stirred for 48 h under 10 W blue light irradiation. After the reaction was complete, 10 mL of distilled water was added, and the reaction mixture was extracted three times with 10 mL of chloroform. The organic phase was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate for half an hour, and the solvent was removed by rotary evaporation. The remaining reactants were purified by silica gel column chromatography to give 2-allyl-1-(3,5-dimethylphenyl)pyrrolidine 3d, with a yield of 62%.

[0068]

[0069] The product 2-allyl-1-(3,5-dimethylphenyl)pyrrolidine 3d is a yellow oily liquid; eluent: ethyl acetate: petroleum ether (1:50, Rf=0.50).

[0070] like Figure 7 and Figure 8The NMR data of the products are shown below: ¹H NMR (400MHz, CDCl₃) δ 6.34 (s, ¹H), 6.22 (s, 2H), 5.89–5.76 (m, ¹H), 5.17–5.01 (m, 2H), 3.76–3.70 (m, ¹H), 3.48–3.35 (m, 1H), 3.17–3.10 (m, 1H), 2.54–2.43 (m, 1H), 2.27 (s, 6H), 2.12–1.80 (m, 5H); ¹³C NMR (101MHz, CDCl₃) δ 147.4, 138.0, 135.9, 117.6, 116.9, 109.9, 58.0, 48.5, 37.7, 29.8, 23.3, 21.9.

[0071] Example 5

[0072] 0.2 mmol of 1-phenylpiperidine, 0.2 mmol of allyl trifluoroborate potassium, and 2.0 mg of Bengal rose red were added to a 10 mL reaction flask equipped with a magnetic stirrer. Then, 2.0 mL of chloroform was added to the reaction system, and the mixture was stirred for 24 h under 10 W blue light irradiation. After the reaction was complete, 10 mL of distilled water was added, and the reaction mixture was extracted three times with 10 mL of chloroform. The organic phase was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate for half an hour, and the solvent was removed by rotary evaporation. The remaining reactants were purified by silica gel column chromatography to give 2-allyl-1-phenylpiperidine 3e in 34% yield.

[0073]

[0074] The product 2-allyl-1-phenylpiperidine 3e is a yellow oily liquid; eluent: ethyl acetate: petroleum ether (1:50, Rf=0.50).

[0075] like Figure 9 and Figure 10The NMR data for the products are shown below: ¹H NMR (400MHz, CDCl₃) δ 7.26–7.20 (m, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.79 (t, J = 8.0 Hz, 1H), 5.81–5.61 (m, 1H), 5.07–4.93 (m, 2H), 3.88–3.78 (m, 1H), 3.32 (dt, J = 12.0, 4.0 Hz, 1H), 3.0–2.9 (m, 1H), 2.41–2.12 (m, 2H), 1.77–1.57 (m, 6H); ¹³C NMR (101MHz, CDCl3) δ151.1,136.5,129.2,118.8,116.9,116.6,55.9,44.4,31.8,27.4, 25.8,19.3.

[0076] Example 6

[0077] 0.2 mmol of 1-phenylhexamethyleneimine, 0.2 mmol of allyl trifluoroborate, and 10.2 mg of Bengal rose red were added to a 10 mL reaction flask equipped with a magnetic stirrer. Then, 2.0 mL of chloroform was added to the reaction system, and the mixture was stirred for 24 h under 10 W blue light irradiation. After the reaction was complete, 10 mL of distilled water was added, and the reaction mixture was extracted three times with 10 mL of chloroform. The organic phase was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate for half an hour, and the solvent was removed by rotary evaporation. The remaining reactants were purified by silica gel column chromatography to give 2-allyl-1-phenylhexamethyleneimine 3f in 71% yield.

[0078]

[0079] The product 2-allyl-1-phenylhexamethyleneimine 3f is a yellow oily liquid; eluent: ethyl acetate: petroleum ether (1:50, Rf=0.50).

[0080] like Figure 11 and Figure 12The NMR data for the products are shown below: ¹H NMR (400MHz, CDCl₃) δ 7.27–7.16 (m, 2H), 6.68 (d, J = 8.0Hz, 2H), 6.61 (t, J = 8.0Hz, 1H), 5.90–5.77 (m, 1H), 5.13–5.01 (m, 2H), 3.70–3.62 (m, 1H), 3.48 (dt, J = 16.0, 4.0Hz, 1H), 3.12–3.15 (m, 1H), 2.44–2.34 (m, 1H), 2.26–2.09 (m, 2H), 1.83–1.18 (m, 7H); ¹³C NMR (101MHz, CDCl3) δ148.4,135.6,129.5,116.9,114.7,110.5,56.9,43.3,38.1,34.7,30.1,27.4,25.5.

[0081] Example 7

[0082] 0.2 mmol N,N-dimethylaniline, 0.2 mmol potassium allyl trifluoroborate, and 8.1 mg Bengal rose red were added to a 10 mL reaction flask equipped with a magnetic stirrer. Then, 2.0 mL of chloroform was added to the reaction system, and the mixture was stirred for 48 h under 10 W blue light irradiation. After the reaction was complete, 10 mL of distilled water was added, and the reaction mixture was extracted three times with 10 mL of chloroform. The organic phase was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate for half an hour, and the solvent was removed by rotary evaporation. The remaining reactants were purified by silica gel column chromatography to obtain N-(but-3-en-1-yl)-N-methylaniline in a yield of 47%.

[0083]

[0084] Product: 3g of N-(but-3-en-1-yl)-N-methylaniline, a yellow oily liquid; eluent: ethyl acetate: petroleum ether (1:50, Rf=0.50).

[0085] like Figure 13 and 14 The NMR data of the products are shown below: ¹H NMR (400MHz, CDCl₃) δ 7.27–7.19 (m, 2H), 6.76–6.63 (m, 3H), 5.88–5.78 (m, 1H), 5.17–4.96 (m, 2H), 3.44–3.31 (m, 2H), 2.93 (s, 3H), 2.39–2.25 (m, 2H); ¹³C NMR (101MHz, CDCl₃) δ 149.2, 136.1, 129.3, 116.5, 116.2, 112.3, 52.5, 38.4, 31.2.

[0086] Example 8

[0087] 0.2 mmol N-isobutyl-N-methylaniline, 0.2 mmol allyl trifluoroborate, and 10.2 mg Bengal rose red were added to a 10 mL reaction flask equipped with a magnetic stirrer. Then, 2.0 mL of chloroform was added to the reaction system, and the mixture was stirred for 48 h under 10 W blue light irradiation. After the reaction was complete, 10 mL of distilled water was added, and the reaction mixture was extracted three times with 10 mL of chloroform. The organic phase was washed with 10 mL of saturated sodium chloride, dried over anhydrous sodium sulfate for half an hour, and the solvent was removed by rotary evaporation. The remaining reactants were purified by silica gel column chromatography to obtain N-(but-3-en-1-yl)-N-isobutylaniline (3 h), with a yield of 89%.

[0088]

[0089] The product N-(but-3-en-1-yl)-N-isobutylaniline was a yellow oily liquid after 3 hours; eluent: ethyl acetate: petroleum ether (1:50, Rf=0.50).

[0090] like Figure 15 and Figure 16 The NMR data of the products are shown below: ¹H NMR (400MHz, CDCl₃) δ 7.24–7.18 (m, 2H), 6.74–6.60 (m, 3H), 5.87–5.77 (m, 1H), 5.15–4.99 (m, 2H), 3.43–3.29 (m, 2H), 3.06 (d, J = 8.0Hz, 2H), 2.38–2.26 (m, 2H), 2.10–1.99 (m, 1H), 0.92 (d, J = 6.8Hz, 6H); ¹³C NMR (101MHz, CDCl₃) δ 148.2, 136.1, 129.3, 116.4, 115.5, 112.2, 59.3, 51.6, 31.0, 27.2, 20.5.

Claims

1. A method for preparing a high-allylamine compound, characterized in that: The specific steps are as follows: Step 1: Dissolve the tertiary amine compound and potassium allyl trifluoroborate in chloroform solvent, and react them in one step under blue light irradiation and Bengal rose red catalysis to obtain the reaction mixture. The specific reaction formula is as follows: ； In the above formula, R1 is a C1 to C12 alkyl group, R2 is H, a C1 to C3 alkyl group, a methoxy group, or a halogen, and n is 1 to 3; Step 2: Add distilled water to the reaction mixture and extract with chloroform three times to obtain the organic phase. Wash the organic phase with saturated sodium chloride and dry it with anhydrous sodium sulfate for half an hour. Remove the solvent with a rotary evaporator and purify by silica gel column chromatography to obtain the high-allylamine compounds.

2. The method for preparing the high-allylamine compound according to claim 1, characterized in that: The reaction temperature in step 1 is room temperature, and the reaction time is 12 to 48 hours.

3. The method for preparing the high-allylamine compound according to claim 2, characterized in that: The molar ratio of the tertiary amine compound and potassium allyl trifluoroborate is 1:

1.

4. The method for preparing the high-allylamine compound according to claim 2, characterized in that: The amount of Bengal rose red used is 5 mol of the amount of tertiary amine compound.

5. The method for preparing the high-allylamine compound according to claim 2, characterized in that: The amount of chloroform added in step 1 is 5 to 10 mL of chloroform per 1 mmol of tertiary amine compound.

6. The method for preparing the high-allylamine compound according to claim 2, characterized in that: The blue light source is a commercially available 10W blue light lamp with a wavelength of 465–475 nm.

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