Aromatic methylamine denitrification alkylation method
Through the electron spin center transfer strategy mediated by boron radicals, the denitrogenation alkylation reaction of arylmethylamine is achieved, solving the problems of poor atomic economy and the use of toxic reagents in the prior art, and providing a new method with excellent atomic economy.
Patent Information
- Application Number
- CN202411775411.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-05
- Publication Date
- 2025-02-25
AI Technical Summary
In the prior art, in the process of realizing the carbon-nitrogen bond denitrogenation of organic amines, there are problems such as poor atomic economy and the need to use toxic tin reagents.
The electron spin center transfer strategy was adopted to carry out the denitrogenation alkylation reaction of arylmethylamine through a boron radical-mediated two-step method, avoiding the use of toxic tin reagents and expensive transition metals.
The organic amine denitrogenation alkylation reaction with excellent atomic economy has been achieved, providing a new route for functional molecules synthesis, and avoiding the disadvantages of using toxic reagents.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for denitrogenation alkylation of aromatic methylamine. Background Art
[0002] Organic amines are an important biological substance and chemical intermediate that are widely present in nature, bulk chemicals, etc. The study of the reaction properties of organic amine carbon-nitrogen bonds is a hot topic in material science. Nitrogen and carbon sources can be obtained by breaking the carbon-nitrogen bonds of organic amines, providing an effective way to synthesize diverse chemicals. However, since nitrogen atoms contain lone pairs of electrons, the electron cloud density is large, the carbon-nitrogen bond length is short, it is not easy to be polarized, and the bond energy is high, breaking the carbon-nitrogen bond is extremely challenging. Research in this area has always been a difficulty and focus of synthetic chemistry research.
[0003] The use of free radical reactions is an effective way to break carbon-nitrogen bonds. Currently, there are two main ways to use free radical reactions to break carbon-nitrogen bonds: 1) converting the primary amino group into isonitrile, and then using toxic tin radicals to achieve Barton deamination reaction (Barton, DHR, Aldrichimica Acta ., 1990, 23 , 3.); 2) Converting organic amines into quaternary ammonium salts (Da-Gang Yu, J. Am. Chem. Soc. , 2018, 140 , 17338.), Katrizky salt (Yi Wang, Nat. Commun. , 2021, 12 , 6745.), diazonium salts (Mahdavi, M., New J. Chem .2022, 46 , 10814.; Ritter, T., Science , 2024, 384 ,446-452.) etc. to increase the polarizability of the carbon-nitrogen bond, and then directly or by using photocatalysis or electrocatalysis technology to break the carbon-nitrogen bond to generate the corresponding carbon free radicals, thereby achieving the purpose of functionalization of the carbon-nitrogen bond. Despite the above methods, the denitrogenation functionalization reaction of the carbon-nitrogen bond still faces the disadvantages of needing to use toxic tin reagents, poor atom economy, and poor stability of the reaction raw materials. Therefore, developing a method with good atom economy and easy preparation of raw materials is still the focus of research in the field of organic synthesis technology.
[0004]
[0005] Spin-center-shift (SCS) is an effective way to break carbon-hetero bonds. Although great progress has been made in this area, there is only one case of using the SCS process to break carbon-nitrogen bonds. In 2011, Ollivier et al. used the SCS strategy to develop a visible light-catalyzed high ring strain α -Ketoazapine carbon-nitrogen bond cleavage (C. Ollivier, Angew. Chem. Int. Ed. 2011, 50, 4463.). Therefore, if a universal method for denitrogenation and alkylation of carbon-nitrogen bonds can be developed using the SCS strategy, it will not only provide a new method for the conversion of organic amines into functional molecules, but also develop new application scenarios for electron spin center transfer.
[0006] Summary of the invention
[0007] The purpose of the present invention is to provide a method for denitrogenation alkylation of aromatic methylamines to overcome the above-mentioned defects of the prior art. The present invention utilizes the electron spin center transfer strategy to develop a new boron radical-mediated denitrogenation functionalization method for organic amines, which can provide a new route for the synthesis of functional molecules. Compared with the methods that have been reported, the present invention has the advantages of excellent atom economy, no need to use expensive transition metals, no need to use toxic organotin reagents, etc.
[0008] The method for denitrogenation alkylation of aromatic methylamines of the present invention adopts a two-step method, comprising the following steps: Step 1: Under a nitrogen atmosphere, an aromatic methylamine substrate and a base are added to solvent 1, and then methylsulfonyl chloride is added dropwise to the system in an ice-water bath environment. After the addition is completed, the reaction is continued for 4 hours; after the reaction is completed, ice water is added to quench the reaction, the reaction solution is extracted with dichloromethane, and washed with saturated brine, and the collected organic phase is recrystallized from a dichloromethane and petroleum ether system to obtain an aromatic methylsulfonamide methyl compound.
[0009] In step 1, the aromatic methylamine substrate is methyl 4-aminomethylbenzoate, methyl 4-(1-aminoethyl)benzoate or butyl-3-en-1-yl 4-(1-aminomethyl)benzoate, the base is triethylamine, and the solvent 1 is dichloromethane.
[0010] Furthermore, the molar ratio of the aromatic methylamine substrate, the base and the methanesulfonyl chloride is 1.0:1.3:1.1.
[0011] The synthetic route of this step is as follows:
[0012] Step 2: Under nitrogen atmosphere, the aromatic methyl sulfonamide methyl compound obtained in step 1, aromatic vinyl, borane, thiol, and free radical initiator are added to solvent 2, and reacted at 120° C. for 12 hours. The reaction endpoint is determined by thin layer chromatography spot plate, and then a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 50:1 is used as an eluent, and separation and purification is performed on a silica gel column to obtain an aromatic methylamine denitrogenation alkylation product.
[0013] In step 2, the ethylene is 4-methoxystyrene, vinylferrocene, 4-(4-vinylphenyl)morpholine, 4-allyloxystyrene, methyl 4-vinylbenzoate or 2-ethyl-1-butene, the borane is dimethylaminopyridine-borane, the thiol is 2,6-dimethylthiophenol, and the free radical initiator is di-tert-butyl peroxide.
[0014] Furthermore, the molar ratio of the arylmethylsulfonylamide methyl compound, arylethylene, borane, thiol and free radical initiator is 1.0:8.0:3.5:0.2:0.5. The concentration of the arylmethylsulfonylamide methyl compound in the reaction system is controlled at 0.1 mol / L.
[0015] In step 2, the solvent 2 is composed of acetonitrile and water in a volume ratio of 15:1.
[0016] The synthetic route of this step is as follows:
[0017] The overall synthetic route is shown below:
[0018] The present invention realizes the boron radical-mediated denitrogenation alkylation reaction of organic amines for the first time, providing a new method for carbon-nitrogen bond functionalization. This reaction can not only solve the drawbacks of poor atom economy and the need to use toxic tin reagents in the conversion of organic amine carbon-nitrogen bonds, but can also be applied to the field of drug synthesis to directly prepare related drugs or as drug intermediates (World Intellectual Property Organization, WO9611902 A1, Breault, GA, 1996-04-25).
[0019] DETAILED DESCRIPTION
[0020] The organic synthesis technology scheme involved in the present invention will be described in more detail and clearly below in conjunction with the embodiments of the present invention. Obviously, the series of embodiments described below are only a part of the present invention, not all embodiments. Other embodiments obtained by ordinary technicians in the field without creative work on the basis of any embodiment reported in the present invention belong to the protection scope of the present invention. Embodiment 1: 1. The synthesis steps of methyl 4-(methylsulfonamidomethyl)benzoate are as follows:
[0021]
[0022] Under nitrogen atmosphere, methyl 4-aminomethylbenzoate (51.4 mmol) and triethylamine (1.3 equivalents) were added to 200 mL of dichloromethane solvent, and then methylsulfonyl chloride (1.1 equivalents) was added dropwise to the reaction in an ice-water bath. After the addition was complete, the reaction was continued at room temperature for 4 hours. After the reaction was completed, ice water was added to quench the reaction and the reaction was extracted three times with dichloromethane. The obtained organic phase was washed twice with saturated brine, and the obtained organic phase was concentrated using a rotary evaporator. The residue was recrystallized from a dichloromethane and petroleum ether system to obtain methyl 4-(methylsulfonamidomethyl)benzoate.
[0023] The yield was 64%, white solid; 1 H NMR (400 MHz, CDCl3) δ 2.88 (3H, s), 3.91 (3H,s), 4.37 (2H, d, J = 6.4 Hz), 5.06 (1H, br s), 7.38-7.46 (2H, m), 7.98-8.05(2H, m); 13 C NMR (100 MHz, CDCl3) δ 41.1, 46.7, 52.2, 127.7, 129.9, 130.1, 141.9, 166.6. 2. The synthesis steps of methyl 4-[3-(4-methoxyphenyl)propyl]benzoate are as follows:
[0024]
[0025] Under nitrogen atmosphere, methyl 4-(methylsulfonamidomethyl)benzoate (0.2997 mmol), 4-methoxystyrene (8.0 equivalents), p-lutidine-borane (3.5 equivalents), 2,6-dimethylthiophenol (0.2 equivalents) and di-tert-butyl peroxide (0.5 equivalents) were added to a mixed solvent of acetonitrile: water = 15:1, and the reaction was stirred at 120 °C for 12 hours. The reaction endpoint was determined by thin layer chromatography. Then, the product was separated and purified by silica gel column using a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 50:1 as eluent to obtain methyl 4-[3-(4-methoxyphenyl)propyl]benzoate.
[0026] Yield 74%, yellow oily liquid; 1 H NMR (500 MHz, CDCl3) δ 1.88-1.97 (2H, m), 2.58(2H, t, J = 7.8 Hz), 2.67 (2H, t, J = 7.8 Hz), 3.78 (3H, s), 3.89 (3H, s), 6.83 (2H, d, J = 8.0 Hz), 7.08 (2H, d, J = 8.0 Hz), 7.23 (2H, d, J = 8.0 Hz),7.95 (2H, d, J = 8.0 Hz); 13 C NMR (125 MHz, CDCl3) δ 32.8, 34.3, 35.3, 51.9, 55.2, 113.7, 127.7, 128.4, 129.2, 129.6, 133.9, 147.9, 157.7, 167.1.
[0027] Neuromodulator B can be obtained by replacing an olefin similar to that in this example. The examples in this invention are intended to illustrate the excellent functional group compatibility and substrate applicability of the reaction. Embodiment 2:
[0028] The synthesis steps of methyl 4-(3-ferrocenylpropyl)benzoate in this embodiment are as follows:
[0029] Under nitrogen atmosphere, methyl 4-(methylsulfonamidomethyl)benzoate (0.2994 mmol), vinyl ferrocene (8.0 equivalents), p-lutidine-borane (3.5 equivalents), 2,6-dimethylthiophenol (0.2 equivalents) and di-tert-butyl peroxide (0.5 equivalents) were added to a mixed solvent of acetonitrile: water = 15:1, and the reaction was stirred at 120 °C for 12 hours. The reaction endpoint was determined by thin layer chromatography. Then, a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 50:1 was used as an eluent, and the product was separated and purified on a silica gel column to obtain methyl 4-(3-ferrocenylpropyl)benzoate.
[0030] Yield 70%, orange-yellow oily liquid; 1 H NMR (400 MHz, CDCl3) δ 1.80-1.90 (2H, m),2.36 (2H, t, J = 7.8 Hz), 2.69 (2H, t, J = 7.6 Hz), 3.90 (4H, s), 4.05 (5H,s), 7.20-7.29 (2H, m), 7.91-8.01 (2H, m); 13 C NMR (100 MHz, CDCl3) δ 29.1, 32.3, 35.7, 52.0, 67.1, 68.0, 68.4, 88.6, 127.7, 128.4, 129.7, 148.0, 167.2. Embodiment 3:
[0031] The synthesis steps of methyl 4-[3-(4-morpholinephenyl)propyl]benzoate in this embodiment are as follows:
[0032] Under nitrogen atmosphere, methyl 4-(methylsulfonamidomethyl)benzoate (0.2994 mmol), 4-(4-vinylphenyl)morpholine (8.0 equivalents), p-lutidine-borane (3.5 equivalents), 2,6-dimethylthiophenol (0.2 equivalents) and di-tert-butyl peroxide (0.5 equivalents) were added to a mixed solvent of acetonitrile:water = 15:1, and the reaction was stirred at 120 °C for 12 hours. The reaction endpoint was determined by thin layer chromatography. Then, the product was separated and purified by silica gel column using a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 50:1 as the eluent to obtain methyl 4-[3-(4-morpholinephenyl)propyl]benzoate.
[0033] Yield 67%, colorless oily liquid; 1H NMR (500 MHz, CDCl3) δ 1.88-1.98 (2H, m), 2.57(2H, t, J = 7.5 Hz), 2.68 (2H, t, J = 7.5 Hz), 3.12 (4H, t, J = 4.0 Hz), 3.83(4H, t, J = 4.0 Hz), 3.89 (3H, s), 6.82-6.88 (2H, m), 7.05-7.12 (2H, m), 7.21-7.26 (2H, m), 7.92-7.98 (2H, m); 13 C NMR (125 MHz, CDCl3) δ 32.7, 34.3,35.3, 49.6, 51.9, 66.9, 115.8, 127.6, 128.4, 129.0, 129.6, 133.5, 147.9,149.4, 167.1. Embodiment 4:
[0034] The synthesis steps of methyl 4-{3-[4-(allyloxy)phenyl]propyl}benzoate in this embodiment are as follows:
[0035] Under nitrogen atmosphere, methyl 4-(methylsulfonamidomethyl)benzoate (0.3003 mmol), 4-allyloxystyrene (8.0 equivalents), p-lutidine-borane (3.5 equivalents), 2,6-dimethylthiophenol (0.2 equivalents) and di-tert-butyl peroxide (0.5 equivalents) were added to a mixed solvent of acetonitrile: water = 15:1, and the reaction was stirred at 120°C for 12 hours. The reaction endpoint was determined by thin layer chromatography. Then, the product was separated and purified by silica gel column using a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 50:1 as the eluent to obtain methyl 4-{3-[4-(allyloxy)phenyl]propyl}benzoate.
[0036] Yield 66%, colorless oily liquid; 1 H NMR (500 MHz, CDCl3) δ 1.89-1.99 (2H, m), 2.59(2H, t, J = 7.8 Hz), 2.69 (2H, t, J = 7.8 Hz), 3.91 (3H, s), 4.52 (2H, ddd, J= 5.0, 1.6, 1.6 Hz), 5.28 (1H, ddt, J = 10.5, 1.5, 1.5 Hz), 5.41 (1H, ddt, J = 17.5, 1.5, 1.5 Hz), 6.01-6.12 (1H, m), 6.82-6.88 (2H, m), 7.04-7.11 (2H,m), 7.22-7.28 (2H, m), 7.91-7.99 (2H, m); 13 C NMR (125 MHz, CDCl3) δ 32.8,34.4, 35.3, 51.9, 68.8, 114.6, 117.5, 127.7, 128.4, 129.3, 129.7, 133.5,134.2, 147.9, 156.8, 167.1. Embodiment 5:
[0037] The synthesis steps of methyl 4-[1-(methylsulfonylamino)ethyl]benzoate in this embodiment are as follows:
[0038] Under nitrogen atmosphere, methyl 4-aminomethylbenzoate (28.0 mmol) and triethylamine (1.3 equivalents) were added to 100 mL of dichloromethane solvent, and then methylsulfonyl chloride (1.1 equivalents) was added dropwise to the reaction in an ice-water bath. After the addition was complete, the reaction was continued at room temperature for 4 hours. After the reaction was completed, ice water was added to quench the reaction and the reaction was extracted three times with dichloromethane. The obtained organic phase was washed twice with saturated brine, and the obtained organic phase was concentrated using a rotary evaporator. The residue was recrystallized from a dichloromethane and petroleum ether system to obtain methyl 4-[1-(methylsulfonylamino)ethyl]benzoate.
[0039] The yield was 66%, white solid; 1 H NMR (400 MHz, CDCl3) δ 1.54 (3H, d, J = 6.8Hz), 2.65 (3H, s), 3.92 (3H, s), 4.65-4.77 (1H, m), 5.03 (1H, d, J = 6.8 Hz),7.39-7.47 (2H, m), 8.00-8.08 (2H, m); 13C NMR (100 MHz, CDCl3) δ 23.9, 41.9, 52.2, 53.4, 126.3, 129.8, 130.3, 147.5, 166.6. Embodiment 6:
[0040] The synthesis steps of methyl 4-[4-(4-methoxyphenyl)butan-2-yl]benzoate in this embodiment are as follows:
[0041] Under nitrogen atmosphere, methyl 4-[1-(methylsulfonylamino)ethyl]benzoate (0.2993 mmol), 4-methoxystyrene (8.0 equivalents), p-lutidine-borane (3.5 equivalents), 2,6-dimethylthiophenol (0.2 equivalents) and di-tert-butyl peroxide (0.5 equivalents) were added to a mixed solvent of acetonitrile: water = 15:1, and the reaction was stirred at 120°C for 12 hours. The reaction endpoint was determined by thin layer chromatography. Then, the product was separated and purified by silica gel column using a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 50:1 as the eluent to obtain methyl 4-[4-(4-methoxyphenyl)butan-2-yl]benzoate.
[0042] Yield 69%, colorless oily liquid; 1 H NMR (500 MHz, CDCl3) δ 1.27 (3H, d, J = 7.0Hz), 1.83-1.95 (2H, m), 2.37-2.50 (2H, m), 2.71-2.82 (1H, m), 3.78 (3H, s), 3.91 (3H, s), 6.77-6.84 (2H, m), 6.99-7.06 (2H, m), 7.21-7.30 (2H, m), 7.94-8.01 (2H, m); 13 C NMR (125 MHz, CDCl3) δ 22.2, 32.8, 39.4, 39.9, 51.9, 55.2, 113.7, 127.1, 128.0, 129.2, 129.8, 134.2, 152.9, 157.7, 167.1. Embodiment 7:
[0043] The synthesis steps of methyl 4-{4-[4-(methoxycarbonyl)phenyl]butan-2-yl}benzoate in this embodiment are as follows:
[0044] Under nitrogen atmosphere, methyl 4-[1-(methylsulfonylamino)ethyl]benzoate (0.2993 mmol), methyl 4-vinylbenzoate (8.0 equivalents), p-lutidine-borane (3.5 equivalents), 2,6-dimethylthiophenol (0.2 equivalents) and di-tert-butyl peroxide (0.5 equivalents) were added to a mixed solvent of acetonitrile: water = 15:1, and the reaction was stirred at 120°C for 12 hours. The reaction endpoint was determined by thin layer chromatography. Then, the product was separated and purified by silica gel column using a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 50:1 as eluent to obtain methyl 4-{4-[4-(methoxycarbonyl)phenyl]butan-2-yl}benzoate.
[0045] Yield 41%, colorless oily liquid; 1 H NMR (500 MHz, CDCl3) δ 1.29 (3H, d, J = 7.0Hz), 1.94 (2H, dd, J = 7.5, 7.5 Hz), 2.44-2.61 (2H, m), 2.71-2.83 (1H, m), 3.89 (3H, s), 3.91 (3H, s), 7.11-7.20 (2H, m), 7.19-7.29 (2H, m), 7.89-7.98(2H, m), 7.96-8.04 (2H, m); 13 C NMR (125 MHz, CDCl3) δ 22.2, 33.9, 39.3, 39.6,52.0, 52.0, 127.1, 127.9, 128.2, 128.4, 129.7, 129.9, 147.7, 152.4, 167.1,167.1. Embodiment 8:
[0046] The synthesis steps of 4-(methylsulfonylaminomethyl)benzoic acid but-3-en-1-yl ester in this embodiment are as follows:
[0047] Under nitrogen atmosphere, 4-(1-aminomethyl)benzoic acid but-3-en-1-yl ester (9.86 mmol) and triethylamine (1.3 equivalents) were added to 50 mL of dichloromethane solvent, and then methylsulfonyl chloride (1.1 equivalents) was added dropwise to the reaction in an ice-water bath. After the addition was complete, the reaction was continued at room temperature for 4 hours. After the reaction was completed, ice water was added to quench the reaction and extracted three times with dichloromethane. The obtained organic phase was washed twice with saturated brine, concentrated using a rotary evaporator, and separated and purified by silica gel column using a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 5:1 as the eluent to obtain 4-(methylsulfonylaminomethyl)benzoic acid but-3-en-1-yl ester.
[0048] Yield 71%, colorless transparent liquid; 1 H NMR (400 MHz, CDCl3) δ 2.46-2.56 (2H, m), 2.86(3H, s), 4.31-4.39 (4H, m), 5.10 (1H, ddt, J = 10.0, 1.6, 1.6 Hz), 5.16 (1H,br s), 5.17 (1H, ddt, J = 17.2, 1.6, 1.6 Hz), 5.78-5.93 (1H, m), 7.37-7.45(2H, m), 7.97-8.04 (2H, m); 13 C NMR (100 MHz, CDCl3) δ 33.1, 41.1, 46.7, 64.1, 117.4, 127.6, 130.0, 130.1, 133.9, 141.9, 166.1. Embodiment 9:
[0049] The synthesis steps of 4-[3-(4-methoxyphenyl)propyl]benzoic acid but-3-ene-1-yl ester in this embodiment are as follows:
[0050] Under nitrogen atmosphere, 4-(methylsulfonylaminomethyl)benzoic acid but-3-en-1-yl ester (0.3000 mmol), 4-methoxystyrene (8.0 equivalents), p-lutidine-borane (3.5 equivalents), 2,6-dimethylthiophenol (0.2 equivalents) and di-tert-butyl peroxide (0.5 equivalents) were added to a mixed solvent of acetonitrile: water = 15:1, and the reaction was stirred at 120°C for 12 hours. The reaction endpoint was determined by thin layer chromatography. Then, the product was separated and purified by silica gel column using a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 50:1 as the eluent to obtain 4-[3-(4-methoxyphenyl)propyl]benzoic acid but-3-en-1-yl ester.
[0051] Yield 58%, colorless oily liquid; 1 H NMR (400 MHz, CDCl3) δ 1.87-1.98 (2H, m), 2.47-2.55 (2H, m), 2.58 (2H, t, J = 7.6 Hz), 2.68 (2H, t, J = 7.6 Hz), 3.78(3H, s), 4.35 (2H, t, J = 6.8 Hz), 5.10 (1H, dtt, J = 10.2, 1.4, 1.4 Hz),5.17 (1H, dtt, J = 17.0, 1.4, 1.4 Hz), 5.76-5.98 (1H, m), 6.77-6.89 (2H, m), 7.02-7.16 (2H, m), 7.16-7.31 (2H, m), 7.88-8.01 (2H, m); 13 C NMR (100 MHz, CDCl3) δ 32.8, 33.1, 34.3, 35.3, 55.2, 63.8, 113.7, 117.2, 127.9, 128.4, 129.3, 129.6, 133.9, 134.1, 147.9, 157.7, 166.6. Embodiment 10:
[0052] The synthesis steps of methyl 4-(3-ethylpentyl)benzoate in this embodiment are as follows:
[0053] Under nitrogen atmosphere, methyl 4-(methylsulfonamidomethyl)benzoate (0.2993 mmol), 2-ethyl-1-butene (8.0 equivalents), p-dimethylpyridine-borane (3.5 equivalents), 2,6-dimethylthiophenol (0.2 equivalents) and di-tert-butyl peroxide (0.5 equivalents) were added to a mixed solvent of acetonitrile: water = 15:1, and the mixture was stirred at 120 °C for 12 hours. The reaction endpoint was determined by thin layer chromatography. Then, the mixture was separated and purified by silica gel column using a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 50:1 as the eluent to obtain methyl 4-(3-ethylpentyl)benzoate.
[0054] Yield 31%, colorless oily liquid; 1 H NMR (400 MHz, CDCl3) δ 0.86 (6H, t, J = 7.2Hz), 1.29-1.40 (4H, m), 1.53-1.62 (3H, m), 2.52-2.78 (2H, m), 3.90 (3H, s), 7.22-7.26 (2H, m), 7.91-7.98 (2H, m); 13 C NMR (100 MHz, CDCl3) δ 10.8, 25.2, 33.2, 34.4, 40.0, 52.0, 127.5, 128.4, 129.6, 149.0, 167.2. Embodiment 11:
[0055] The synthesis steps of methyl 4-[3-(4-acetylphenyl)propyl]benzoate in this embodiment are as follows:
[0056] Under nitrogen atmosphere, methyl 4-(methylsulfonamidomethyl)benzoate (0.3000 mmol), N-(4-vinylphenyl)acetamide (8.0 equivalents), p-lutidine-borane (3.5 equivalents), 2,6-dimethylthiophenol (0.2 equivalents) and di-tert-butyl peroxide (0.5 equivalents) were added to a mixed solvent of acetonitrile: water = 15:1, and the mixture was stirred at 120 °C for 12 hours. The reaction endpoint was determined by thin layer chromatography. Then, the mixture was separated and purified by silica gel column using a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 10:1 as the eluent to obtain methyl 4-[3-(4-acetylphenyl)propyl]benzoate.
[0057] Yield 45%, white solid; 1H NMR (500 MHz, CDCl3) δ 1.87-1.97 (2H, m), 2.14(3H, s), 2.59 (2H, t, J = 7.5 Hz), 2.66 (2H, t, J = 7.5 Hz), 3.89 (3H, s), 7.07-7.12 (2H, m), 7.20-7.25 (2H, m), 7.39-7.44 (2H, m), 7.66 (1H, s), 7.92-7.97 (2H, m); 13 C NMR (125 MHz, CDCl3) δ 24.5, 32.6, 34.7, 35.3, 52.0, 120.2,127.8, 128.5, 128.9, 129.7, 135.9, 137.9, 147.9, 167.3, 168.6.
[0058] Neuromodulator A can be obtained by replacing an olefin similar to that in this example. The examples in this invention are intended to illustrate the excellent functional group compatibility and substrate applicability of the reaction.
Claims
1. A method for denitrogenation alkylation of aromatic methylamines, characterized in that The steps include: Step 1: under a nitrogen atmosphere, an aromatic methylamine substrate and a base are added to solvent 1, and methylsulfonyl chloride is added dropwise to the system in an ice-water bath, and the reaction is continued after the addition is completed; after the reaction is completed, ice water is added to quench the reaction, the reaction solution is extracted with dichloromethane, and washed with saturated brine, and the collected organic phase is recrystallized to obtain an aromatic methylsulfonamide methyl compound; Step 2: under nitrogen atmosphere, the arylmethylsulfonamide methyl compound obtained in step 1, arylethylene, borane, thiol, and free radical initiator are added to solvent 2, reacted at 120° C., the reaction endpoint is determined by thin layer chromatography, and then separated and purified by silica gel column to obtain the denitrogenation alkylation product of arylmethylamine; The synthetic route is as follows: 。 2. The method according to claim 1, characterized in that: In step 1, the aromatic methylamine substrate is methyl 4-aminomethylbenzoate, methyl 4-(1-aminoethyl)benzoate or methyl 4-(1-aminomethyl)benzoate but-3-en-1-yl ester, and the base is triethylamine.
3. The method according to claim 2, characterized in that: The molar ratio of the aromatic methylamine substrate, the base and the methanesulfonyl chloride is 1.0:1.3:1.
1.
4. The method according to claim 1, characterized in that: In step 2, the aromatic vinyl is 4-methoxystyrene, vinylferrocene, 4-(4-vinylphenyl)morpholine, 4-allyloxystyrene or methyl 4-vinylbenzoate.
5. The method according to claim 1, characterized in that: In step 2, the borane is dimethylaminopyridine-borane, the thiol is 2,6-dimethylbenzenethiol, and the free radical initiator is di-tert-butyl peroxide.
6. The method according to claim 4 or 5, characterized in that: The molar ratio of the arylmethylsulfonylamidemethyl compound, arylethylene, borane, thiol and free radical initiator is 1.0:8.0:3.5:0.2:0.
5.
7. The method according to claim 1, characterized in that: In step 2, the solvent 2 is composed of acetonitrile and water in a volume ratio of 15:1.