Application of des catalyst on ortho-amino bromide and synthesis method of ortho-amino bromide

Abstract

The application relates to application of a DES catalyst to ortho-amino bromide and a synthesis method of the ortho-amino bromide. The method specifically comprises the following steps: synthesizing a deep eutectic solvent (DES) in a proportion of a choline chloride: citric acid molar ratio of 1:1, taking a chalcone as a substrate, taking the DES as a catalyst, reacting at 40-100 DEG C for 1-3 hours to prepare, and obtaining the amino bromide through extraction, drying, reduced pressure distillation and column separation. In the application, the DES has high catalytic activity, a small dosage and high reaction yield.

Description

Technical Field

[0001] This invention relates to the application of a catalyst in the preparation of ortho-amino bromides and a novel preparation method thereon, and more specifically, to a novel method for preparing ortho-amino bromides by catalyzing an amine bromide addition reaction using a deep eutectic solvent. Background Technology

[0002] Ortho-amino bromides are a class of bifunctional compounds in which both halogens and amino groups are located in adjacent positions. Because the amino group is nucleophilic and the halogen is easily removed and replaced by other nucleophiles, they are widely used synthetic intermediates in organic synthesis. Generally, these compounds can be obtained by the ammonia halogenation of alkenes, simultaneously introducing an amino group and a halogen onto the C=C junction.

[0003] Ortho-amino halides not only serve as bioactive secondary metabolites [1] Widely found in nature, they are also used to treat diseases due to their significant biological activity. For example: (1) virantmycin, a natural product with high antibiotic activity; (2) keramadine, a 5-hydroxytryptamine receptor antagonist that can specifically counteract vasoconstriction in isolated rabbit arteries induced by 5-hydroxytryptamine; (3) palau'amine, a proteasome inhibitor; (4) chlorambucil, a chemotherapeutic agent that works through DNA alkylation; (5) GABA-AT inhibitors, which can be used to treat a variety of neurological diseases, including epilepsy. Ortho-amino halides are also an important class of organic synthesis intermediates. 2 For example, under certain conditions, intramolecular nucleophilic substitution reactions can occur to form aziridine propane, and then a series of heterocyclic compounds can be synthesized through ring-opening and ring-closing reactions of aziridine propane; since halogens are excellent leaving groups, they can undergo nucleophilic substitution reactions with other nucleophiles to form new compounds (such as α,β-dehydroamino acid derivatives, lactams, amino alcohols). [3] (etc.); under certain conditions, ortho-amino halides can also undergo hydrogen halide elimination reactions to form aminoenes. [4] This leads to the Diels-Alder reaction. Currently, the amine halogenation of alkenes is widely used in organic synthesis. [5] Drug molecule construction and structural modification of natural products 6 ]middle.

[0004] Although the discovery of numerous effective catalysts has expanded the scope of research on ammonia halide addition reactions at the alkene bond, the use of some catalysts remains inconvenient, such as the need for inert gas protection in some reactions. 5Otherwise, moisture in the air will deactivate the catalyst, limiting the widespread industrial application of this method; most catalysts currently used are applied in large quantities, especially transition metals and heavy metals, which can leave trace amounts of heavy metals in the product, thus limiting the application of ammonia halide addition reactions in drug synthesis; some catalysts, although highly effective, are toxic. 7 This also limits its application in ammonia halide addition reactions. 8 Therefore, catalyst screening has been an important research topic in this field from the very beginning. Continuing to discover catalysts that are easy to operate, require small amounts, are non-toxic, and are inexpensive will undoubtedly remain a very important task in future research. Summary of the Invention

[0005] The purpose of this invention is to address the shortcomings of current technologies, such as high catalyst toxicity, high corrosivity, severe environmental pollution, poor catalyst stability, and difficulty in reusing catalysts, by providing an acidic ionic liquid catalyst for the synthesis of ortho-amino halides. This catalyst possesses advantages such as high activity, selectivity, and recyclability. Using this catalyst, the yield of ortho-amino bromides in amine halide addition reactions is high.

[0006] The general reaction formula of this invention is:

[0007]

[0008] The technical solution of this invention is: a process for preparing p-chalcone compounds by catalytic addition reaction of amine halides using a deep eutectic solvent, comprising the following steps:

[0009] Chalcone, p-toluenesulfonamide (TsNH2), and N-bromosuccinimide (NBS) were used as reactants, and DES was used as a catalyst. DES was prepared as a deep eutectic solvent from choline chloride (ChCl) and citric acid (CA) in a molar ratio of 1:1.

[0010] In the method described above, preferably, based on 1 mol of chalcone compound as a standard, the amount of DES ([ChCl][CA]) is 1-3 mol, more preferably 1.5 mol, the amount of TsNH2 is 0.5-3 mol, more preferably 2 mol, and the amount of NBS is 0.5-2 mol, more preferably 1 mol.

[0011] According to the method described above, DES can be reused 4 times.

[0012] The above methods are simple to follow after the reaction; the ortho-amino halide can be obtained by direct extraction, drying, vacuum distillation, and column separation.

[0013] Compared with traditional methods, the present invention has the following advantages: the reaction conditions are mild and easy to operate. The present invention can be carried out at 40-100℃ and the reaction can be completed in 1-3 hours. The acidic ionic liquid catalyst has strong stability, is non-volatile, has high catalytic activity, can be recycled, requires a small amount, and has a high reaction yield. Attached Figure Description

[0014] Figure 1 This is the hydrogen NMR spectrum of the product of this invention. Detailed Implementation

[0015] The present invention is described in detail below through specific embodiments, but this does not limit the scope of protection of the present invention. Unless otherwise specified, the experimental methods used in the present invention are all conventional methods, and the experimental equipment, materials, reagents, etc. used can be purchased from chemical companies.

[0016] In the following examples, chalcone, p-toluenesulfonamide, and N-bromosuccinimide were used as reactants, and DES was used as a catalyst. DES was prepared as a deep eutectic solvent from choline chloride and citric acid in a 1:1 molar ratio. The 1H NMR spectra of the products in the following examples are shown below. Figure 1 As shown. 1 HNMR (500MHz, Chloroform-d)δ

[0017] 8.06(d,J=8.2Hz,2H),7.72(d,J=8.2Hz,2H),7.63(t,J=7.6Hz,1H),7.49(t,J=7.8Hz,2H),7.37 -7.31(m,5H),7.23(d,J=8.2Hz,2H),4.52(d,J=4.3Hz,1H),4.29(d,J=4.4Hz,1H),2.40(s,3H).

[0018] Example 1

[0019] Experimental method: 1 mmol chalcone, 1 mmol p-toluenesulfonamide, and 1 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 1 mmol DES[ChCl][CA]. The mixture was magnetically stirred in an oil bath at 40 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 2.5 hours.

[0020] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 58%.

[0021]

[0022] Example 2

[0023] Experimental method: 1 mmol chalcone, 1 mmol p-toluenesulfonamide, and 1 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 1 mmol DES[ChCl][CA]. The mixture was magnetically stirred in an oil bath at 60 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 2.5 hours.

[0024] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 70%.

[0025]

[0026] Example 3

[0027] Experimental method: 1 mmol chalcone, 1 mmol p-toluenesulfonamide, and 1 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 1 mmol DES[ChCl][CA]. The mixture was magnetically stirred in an oil bath at 80 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 2.5 hours.

[0028] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 57%.

[0029]

[0030] Example 4

[0031] Experimental method: 1 mmol chalcone, 1 mmol p-toluenesulfonamide, and 1 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 1 mmol DES[ChCl][CA]. The mixture was magnetically stirred in an oil bath at 100 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 2.5 hours.

[0032] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 38%.

[0033]

[0034] Example 5

[0035] Experimental method: 1 mmol chalcone, 2 mmol p-toluenesulfonamide, and 1 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 1 mmol DES[ChCl][CA]. The mixture was magnetically stirred in an oil bath at 60 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 1.5 hours.

[0036] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 75%.

[0037]

[0038] Example 6

[0039] Experimental method: 1 mmol chalcone, 1 mmol p-toluenesulfonamide, and 2 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 1 mmol DES[ChCl][CA]. The mixture was magnetically stirred in an oil bath at 60 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 1.5 hours.

[0040] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 73%.

[0041]

[0042] Example 7

[0043] Experimental method: 2 mmol chalcone, 1 mmol p-toluenesulfonamide, and 1 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 1 mmol DES[ChCl][CA]. The mixture was magnetically stirred in an oil bath at 60 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 1.5 hours.

[0044] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 66%.

[0045]

[0046] Example 8

[0047] Experimental method: 1 mmol chalcone, 2 mmol p-toluenesulfonamide, and 1 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 0.5 mmol DES[ChCl][CA]. The mixture was magnetically stirred in an oil bath at 60 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 1.5 hours.

[0048] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 68%.

[0049]

[0050] Example 9

[0051] Experimental method: 1 mmol chalcone, 2 mmol p-toluenesulfonamide, and 1 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 1.5 mmol DES[ChCl][CA]. The mixture was magnetically stirred in an oil bath at 60 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 1.5 hours.

[0052] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 80%.

[0053]

[0054] Example 10

[0055] Experimental method: 1 mmol chalcone, 2 mmol p-toluenesulfonamide, and 1 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 2 mmol DES[ChCl][CA]2. The mixture was magnetically stirred in an oil bath at 60 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 1.5 hours.

[0056] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 75%.

[0057]

[0058] Example 11

[0059] Experimental method: 1 mmol chalcone, 2 mmol p-toluenesulfonamide, and 1 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 2.5 mmol DES[ChCl][CA]2. The mixture was magnetically stirred in an oil bath at 60 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 1.5 hours.

[0060] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 73%.

[0061]

[0062] Example 12

[0063] Experimental method: 1 mmol chalcone, 2 mmol p-toluenesulfonamide, and 1 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 3 mmol DES[ChCl][CA]. The mixture was magnetically stirred in an oil bath at 60 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 1.5 hours.

[0064] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 72%.

[0065]

[0066] Example 13

[0067] Experimental method: 1 mmol chalcone, 2 mmol p-toluenesulfonamide, and 1 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 1.5 mmol DES[ChCl][CA]. The mixture was magnetically stirred in an oil bath at 60 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 1 hour.

[0068] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 65%.

[0069]

[0070] Example 14

[0071] Experimental method: 1 mmol chalcone, 2 mmol p-toluenesulfonamide, and 1 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 1.5 mmol DES[ChCl][CA]. The mixture was magnetically stirred in an oil bath at 60 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 2 hours.

[0072] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 81%.

[0073]

[0074] Example 15

[0075] Experimental method: 1 mmol chalcone, 2 mmol p-toluenesulfonamide, and 1 mmol N-bromosuccinimide were added to a 50 mL three-necked flask, followed by 1.5 mmol DES[ChCl][CA]. The mixture was magnetically stirred in an oil bath at 60 °C, and the reaction progress was monitored by thin-layer chromatography. The reaction was complete after 3 hours.

[0076] Post-processing: Add 20 ml of ethyl acetate to the system after the reaction is complete, and then wash the diluted organic phase three times with water (15 ml) and saturated brine (15 ml) respectively. Dry the organic layer with anhydrous sodium sulfate, and distill the organic solvent under reduced pressure to obtain the crude product. After column separation, a white solid was obtained with a yield of 81%.

[0077]

[0078] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

[0079] References

[0080] [1]Gordon W.Gribble.Occurrence ofHalogenatedAlkaloids[J].TheAlkaloids,2012,71:1-165

[0081] [2] Yoshio Ueno, Shoji Takemura, Yoshiko Ando, ​​Hiromi Terauchi. Reaction of N-Halosulfonamide.

[0082] [3]Chen Dianjun,Guo Li,Liu Junying,Kirtane Sameer,CannonJohn F.,LiGuigen.Functionalization ofα,β-UnsaturatedEsters andKetones:AFacile andHighlyStereoselective One-PotApproach to N-Protectedα,β-DehydroaminoAcidDerivatives[J].Organic Letters,2005,7(5):921–924.

[0083] [4] Chen Zhanguo, Liu Dee, Li Wenli, Liu Yali. Synthesis of functionalized enamines (IV): Sodium acetate rapidly promotes the reaction of β,β-dicyanostyrene derivatives with NBS to the corresponding enamines [J]. Journal of Chemical Research in Chinese Universities, 2014, 35(11): 2360-2365.

[0084] [5]YeungYingYeung,Gao Xuri,CoreyE.J..AGeneral Process for theHaloamidation ofOlefins,Scope and Mechanism.[J].ChemInform,2006,37(48):9644–9645.

[0085] [6]Hans H.Baer,WernerRank.TheAddition ofN-Bromoacetamide to 2,3-UnsaturatedNitro Sugars,aNewApproach to 2,3-Diamino Sugars.SynthesisofDerivatives of2,3-Diamino-2,3-dideoxy-D-mannose and-D-talose.[J].CanadianJournal ofChemistry,1974,52(12):2257-2267.

[0086] [7]Xin Qi,Sang-Hyeup Lee,JiYoung Kwon,Youngmee Kim,Sung-Jin Kim,Yoon-Sik Lee,JuyoungYoon.Aminobromination ofUnsaturatedPhosphonates.[J].ChemInform,2004,35(13):.

[0087] [8]Yi-NingWang,Adiseshu Kattuboina,TengAi,Diya Banerjee,GuigenLi.Chelation-controlled asymmetric aminohalogenation reaction[J].TetrahedronLetters,2007,48(44):7894-7898.

Claims

1. The application of DES in the catalytic synthesis of ortho-amino bromides, characterized in that, Using chalcone, p-toluenesulfonamide, and N-bromosuccinimide as substrates, and DES (a deep eutectic solvent prepared from choline chloride and citric acid in a 1:1 molar ratio) as a catalyst, the synthesis of ortho-amino bromide was catalyzed. DES was reused throughout the catalytic reaction. The product structure is as follows: 。 2. A method for synthesizing ortho-amino bromide, characterized in that, Using chalcone, p-toluenesulfonamide, and N-bromosuccinimide as reactants and DES as catalyst, based on 1 mol of chalcone as the standard, the amount of p-toluenesulfonamide is 0.5-3 mol, and the amount of N-bromosuccinimide is 0.5-2 mol. An addition reaction is carried out at 40-100℃ for 1-3 h to prepare ortho-amino bromide. DES is a deep eutectic solvent prepared from choline chloride and citric acid in a 1:1 molar ratio. The molar ratio of chalcone to DES is 1:1-3. The product structure is as follows: 。 3. The synthesis method according to claim 2, characterized in that, The optimal reaction yield was achieved using 2 mol of p-toluenesulfonamide and 1 mol of N-bromosuccinimide.

Images