Method for preparing beta-chloro alkenyl amide derivative without catalyst at room temperature

Abstract

The invention belongs to the technical field of organic synthesis, and particularly discloses a novel method for preparing and synthesizing series of beta-chloro-alkenyl amides with diversified structures and derivatives of the beta-chloro-alkenyl amides under the conditions of room temperature and no catalyst. In the invention, cheap and easily available commercial chlorides, such as N-chlorosuccinimide, are used as chlorination reagents to react with alkenyl amide compounds containing different substituent groups under the conditions of room temperature and no catalyst, so as to efficiently synthesize the series of functionalized beta-chloroalkenyl amides and the derivatives of the series of functionalized beta-chloroalkenyl amides. The raw materials involved in the invention can be obtained through commercialized purchase or simple preparation, the reaction post-treatment process flow is simple and convenient to operate, the environmental pollution risk is avoided, and the product is easy to separate and purify. Products can be provided for related fields of biological medicines, photoelectric functional materials and the like, and the method has good industrial application potential.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, relates to the synthesis of beta-chloroenamide derivatives, and particularly relates to a method for preparing beta-chloroenamide derivatives without a catalyst at room temperature. Background Art

[0002] Enamides are an important class of structural units, widely present in many medicines, pesticides, natural products, and active biological molecules, and exhibit excellent physiological activity. In addition, enamides are also an important class of synthons, which are widely used in organic synthesis research and realize a series of important synthetic transformation reactions. However, the reaction systems reported so far have many defects, such as the use of precious metal catalysts, harsh reaction conditions, narrow substrate range, excessive addition of additives, etc., which greatly limit the industrial application of such reactions. Therefore, it is urgent to develop a simple, green, efficient and practical new synthetic strategy to achieve efficient transformation of enamide compounds. Among these transformation reactions, the direct carbon-hydrogen bond chlorination reaction of enamide substrates to prepare β-chloroenamide compounds with high added value has not been reported yet. Therefore, exploring the development of a simple, efficient and mild reaction system, using simple and easy-to-prepare enamide derivatives as starting materials, reacting with cheap and readily available chlorination reagents at room temperature, and accurately and efficiently preparing and synthesizing β-chloroenamide compounds has important research value and application potential. As is known to all, N-chlorosuccinimide (NCS) is a cheap, readily available, commercial chlorination reagent with the characteristics of high reaction efficiency, mild reaction conditions, and high reaction selectivity, which makes it particularly suitable for large-scale industrial production. However, the use of N-chloro compounds as chlorination reagents to prepare β-chloroenamide compounds has not been reported. Summary of the invention

[0003] In view of the deficiencies of the prior art, the purpose of the present invention is to provide a method for preparing β-chloroenamide derivatives without catalyst at room temperature. The present invention uses cheap and readily available N-chloro compounds such as N-chlorosuccinimide as chlorination reagents, and eneamide derivatives containing a variety of different substituents, and efficiently synthesizes a series of multifunctionalized β-chloroenamides and their derivatives at room temperature and without catalyst. The present invention has many advantages such as mild reaction conditions, simple and readily available raw materials, no need for catalysts, and simple operation. It provides a simple and efficient new synthesis method for the precise synthesis of β-chloroenamide derivatives, enriches the synthesis strategy of such compounds, and has important research value and industrial application potential.

[0004] The present invention is achieved through the following technical solutions:

[0005] A method for preparing β-chloroolefinamide derivatives without catalyst at room temperature, comprising the following steps

[0006] In an organic solvent, an enamide derivative 1 containing different substituents is used as a raw material, and a chlorination reagent 2 is used to react under stirring at room temperature and without a catalyst, and the reaction is tracked by TLC until the reaction is complete. The reaction solution is post-treated to obtain β-chloroenamide and its derivatives shown in formula 3;

[0007] The chemical reaction equation is:

[0008]

[0009] In the enamide derivatives, R is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, methoxy, benzyloxy, thiomethoxy, trifluoromethoxy, (hetero)aryl or halogen atom, and can be monosubstituted, disubstituted or trisubstituted; R 1 is selected from acetyl, propionyl, isobutyryl, benzoyl, etc.; R 2 Selected from methyl, ethyl, benzyl, isopropyl or allyl;

[0010] The chlorination agent is selected from N-chlorosuccinimide, N-chloro-o-sulfonylbenzoic acid imide, N-chlorophthalimide, tert-butyl hypochlorite, 1-chloro-1,2-benzidoyl-3-one or 1-chloro-1,3-dihydro-3,3-dimethyl-1,2-benzidoyloxypentane and the like.

[0011] A further improvement of the present invention is:

[0012] The organic solvent is selected from tetrahydrofuran, toluene, acetonitrile, acetone, dichloromethane, dimethyl sulfoxide, 1,2-dichloroethane, 1,4-dioxane or N,N-dimethylformamide.

[0013] Preferably, the chlorination agent is N-chlorosuccinimide.

[0014] Preferably, the organic solvent is 1,4-dioxane.

[0015] Further, the molar ratio of the enamide derivative to the chlorination agent is 1:1.5 to 2.5;

[0016] Furthermore, 1.5 to 2.5 mL of an organic solvent is required per 1 mmol of the enamide derivative.

[0017] Furthermore, the room temperature is 20-30° C., and the reaction time is 12-18 hours.

[0018] Preferably, the reaction temperature is 25°C.

[0019] Furthermore, during TLC tracking, the developing solvent used was V 石油醚 :V 乙酸乙酯 =8~12:1.

[0020] Furthermore, the post-treatment process is as follows: after the reaction is completed, the organic phase is washed with water, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure, and then subjected to silica gel column chromatography to obtain an oily liquid β-chloroenamide derivative.

[0021] Further, the column chromatography eluent is V 石油醚 :V 乙酸乙酯 =8~12:1.

[0022] The beneficial effects of the present invention are:

[0023] The invention has many characteristics, such as the starting materials, reaction reagents and the like involved in the invention are simple and easy to obtain, the reaction system is simple, the reaction conditions are extremely mild, the post-reaction treatment operation is convenient, the product is easy to separate, and the like. The invention is particularly suitable for preparing and synthesizing a variety of highly functionalized β-chloroenamides and their derivatives, and is suitable for large-scale industrial production. A series of β-chloroenamides and their derivatives can be prepared and synthesized with high efficiency and high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 For N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3a 1 H-NMR spectrum;

[0025] Figure 2 For N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3a 13 C-NMR spectrum;

[0026] Figure 3 For N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3b 1 H-NMR spectrum;

[0027] Figure 4 For N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3b 13 C-NMR spectrum;

[0028] Figure 5 For N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3c 1 H-NMR spectrum;

[0029] Figure 6 For N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3c 13 C-NMR spectrum;

[0030] Figure 7 N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3d 1 H-NMR spectrum;

[0031] Figure 8 N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3d 13 C-NMR spectrum;

[0032] Fig. 9 N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3d 19 F-NMR spectrum;

[0033] Fig.10 N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3e 1 H-NMR spectrum;

[0034] Fig.11 N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3e 13 C-NMR spectrum;

[0035] Fig.12 For N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3f 1 H-NMR spectrum;

[0036] Fig.13 For N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3f 13 C-NMR spectrum;

[0037] Fig.14 N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3g 1 H-NMR spectrum;

[0038] Fig.15 N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3g 13 C-NMR spectrum;

[0039] Fig.16 N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3g 19 F-NMR spectrum;

[0040] Fig.17 For N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3h 1 H-NMR spectrum;

[0041] Fig.18 For N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3h 13 C-NMR spectrum;

[0042] Fig.19 For N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3i1 H-NMR spectrum;

[0043] Fig. 20 For N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3i 13 C-NMR spectrum;

[0044] Fig.21 For N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide 3i 19 F-NMR spectrum. DETAILED DESCRIPTION

[0045] The present invention is described in detail below in conjunction with specific embodiments.

[0046] The present invention provides a novel method for preparing and synthesizing a series of β-chloroenamide compounds with diversified structures at room temperature and without catalyst. In the present invention, a cheap and readily available N-chloro compound is used as a chlorination reagent, and an enamide derivative containing a plurality of different substituents is stirred and reacted at room temperature to efficiently synthesize a series of multifunctional β-chloroenamides and their derivatives.

[0047] The chlorination reagent in the present invention can be one of: N-chlorosuccinimide, N-chloro-o-sulfonylbenzoimide, N-chlorophthalimide, tert-butyl hypochlorite, 1-chloro-1,2-benzidoyl-3-one, 1-chloro-1,3-dihydro-3,3-dimethyl-1,2-benzidooxypentane, among which N-chlorosuccinimide 2 has the best reaction effect.

[0048] The reaction solvent may be one of tetrahydrofuran, toluene, acetonitrile, acetone, dichloromethane, 1,2-dichloroethane, 1,4-dioxane, dimethyl sulfoxide and N,N-dimethylformamide, among which 1,4-dioxane has the best effect.

[0049] In a specific embodiment, the present invention mixes an olefin amide derivative 1 containing different substituents with N-chlorosuccinimide 2, adds 1,4-dioxane and stirs at room temperature for 15 hours, and the reaction is separated by post-treatment to obtain a series of β-chloroolefin amide derivatives 3, wherein R can be: hydrogen, methyl, ethyl, isopropyl, tert-butyl, methoxy, benzyloxy, thiomethoxy, trifluoromethoxy, (hetero)aryl, halogen atom (fluorine, chlorine, bromine, iodine), etc., and can be monosubstituted, disubstituted or even trisubstituted; R 1 is acetyl, propionyl, isobutyryl, benzoyl, etc.; R 2 It is methyl, ethyl, benzyl, isopropyl, allyl, etc.; the reaction equation is as follows:

[0050]

[0051] The present invention synthesized the following compounds in specific embodiments:

[0052]

[0053]

[0054] Example 1: Preparation and synthesis of N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide derivative 3a:

[0055]

[0056] In a 25 mL round-bottom flask with magnetic stirring, N-benzyl-N-(1-aryl-alkenyl)acetamide 1a (0.251 g, 1.0 mmol), N-chlorosuccinimide 2 (0.266 g, 2.0 mmol) and 1,4-dioxane (2.0 mL) were added and the reaction was stirred at room temperature for 15 h. The reaction was analyzed by TLC (developing solvent V 石油醚 :V 乙酸乙酯 =10:1) to detect the reaction of the raw material until it disappears. After the reaction is completed, the organic phase is washed with water (3×10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a viscous crude product, which is then chromatographed on a silica gel column (eluent: V 石油醚 :V 乙酸乙酯 =10:1) to obtain an oily liquid, which was identified by nuclear magnetic resonance and high-resolution mass spectrometry as: N-benzyl-N-(2-chloro-1-aryl-alkenyl)acetamide derivative 3a in a yield of 87%.

[0057] Spectral analysis data 3a:

[0058] Oily liquid, 1 H NMR (400MHz, CDCl3) δ7.55(d,J=6.1Hz,2H),7.46-7.41(m,3H),7.31-7.25(m,3H),7.22-7.19(m,2H),5.95(s,1H),4.52(s,1H),2.20(s,1H); 13 C NMR (100MHz, CDCl3) δ170.68,140.15,136.84,132.13,129.61,128.97,128.64,128.44,127.54,125.84,118.80,49.40,22.06; HRMS (ESI-TOF) [M+H] + calculated for C 17 H 17 ClNO:286.0993,found:286.0996.

[0059] Example 2: Synthesis of Compound 3b

[0060] 1a in Example 1 was replaced by 1b, and other operating conditions were the same as those in Example 1, with a yield of 80%.

[0061]

[0062] Spectral analysis data 3b:

[0063] Oily liquid, 1 H NMR (400MHz, CDCl3) δ7.34-7.22(m,7H),7.15-7.13(m,2H),6.14(s,1H),4.44(s,2H),2.38(s,3H),2.19(s,3H); 13 C NMR (100MHz, CDCl3) δ170.56,137.81,137.04,130.83,129.46,129.07,128.84,128.43 ,128.11,128.01,127.31,125.93,118.74,48.48,22.25,19.70; HRMS(ESI-TOF)[M+Na] + calculated for C 18 H 18 ClNONa:322.0969,found:322.0971.

[0064] Example 3: Synthesis of Compound 3c

[0065] 1c was used to replace 1a in Example 1, and other operating conditions were the same as those in Example 1. The yield was 86%.

[0066]

[0067] Spectral analysis data 3c:

[0068] Oily liquid, 1 H NMR (400MHz, CDCl3) δ7.65 (d, J = 8.7Hz, 1H), 7.37-7.32 (m, 1H), 7.29-7.23 (m, 5H), 7.20-7.16 (m, 2H), 6.19 (s, 1H), 4.48 (s, 2H), 2.40 (s, 3H); 13C NMR (100MHz, CDCl3) δ170.81,140.50,136.90,133.76,133.14,132.35,130.92 ,128.34,127.35,127.29,123.13,119.65,48.68,22.68; HRMS(ESI-TOF)[M+K] + calculated for C 17 H 15 ClBrNOK:401.9657,found:401.9657.

[0069] Example 4: Synthesis of Compound 3d

[0070] 1d was used to replace 1a in Example 1, and other operating conditions were the same as those in Example 1, and the yield was 89%.

[0071]

[0072] Spectral analysis data 3d:

[0073] Oily liquid, 1 H NMR (400MHz, CDCl3) δ7.44-7.39(m,1H),7.29-7.25(m,4H),7.22-7.12(m,4H),6.09(s,3H),4.50(s,3H),2.27(s,2H); 13 C NMR (100MHz, CDCl3) δ170.48, 160.10 (d, J = 252.0Hz), 136.72, 136.39, 131.63 (d, J = 8.5Hz), 130.98 (d, J = 2.4Hz), 128.75, 128.40, 127.45, 124.18 (d, J = 3.5Hz), 121.37, 120.43 (d, J = 13.6Hz), 116.39 (d, J = 22.0Hz), 49.02, 22.12; 19 FNMR(376MHz, CDCl3)δ-110.36; HRMS(ESI-TOF)[M+K] + calculated for C 17 H 15 ClFNOK:342.0458,found:342.0460.

[0074] Example 5: Synthesis of Compound 3e

[0075] 1e was used to replace 1a in Example 1, and other operating conditions were the same as those in Example 1, and the yield was 69%.

[0076]

[0077] Spectral analysis data 3e:

[0078] Oily liquid, 1 H NMR (400MHz, CDCl3) δ7.38-7.28(m,4H),7.23-7.20(m,2H),7.14-7.09(m,2 H),6.97-6.94(m,1H),5.95(s,1H),4.53(s,2H),3.81(s,3H),2.19(s,3H); 13 C NMR (100MHz, CDCl3) δ170.64,159.62,140.05,136.87,133.49,129.71,128.99,128.4 4,127.54,120.93,118.94,114.97,114.40,55.30,49.51,22.06; HRMS(ESI-TOF)[M+K] + calculated for C 18 H 18 ClNO2K:354.0658,found:354.0654.

[0079] Example 6: Synthesis of Compound 3f

[0080] 1f was used to replace 1a in Example 1, and other operating conditions were the same as those in Example 1, and the yield was 83%.

[0081]

[0082] Spectral analysis data 3f:

[0083] Oily liquid, 1 H NMR (400MHz, CDCl3) δ7.53 (s, 1H), 7.44-7.37 (m, 3H), 7.28 (t, J = 8.5Hz, 3H), 7.20-7.18 (m, 2H), 6.00 (s, 1H), 4.53 (s, 2H), 2.19 (s, 3H); 13 C NMR (100MHz, CDCl3) δ170.52,139.01,136.58,134.73,134.07,129.94,129.73,128 .96,128.55,128.52,127.69,126.78,120.00,49.54,22.06; HRMS(ESI-TOF)[M+Na] + calculated for C17 H 15 Cl2NONa:342.0423,found:342.0423.

[0084] Example 7: Synthesis of Compound 3g

[0085] 1g was used to replace 1a in Example 1, and other operating conditions were the same as those in Example 1, with a yield of 90%.

[0086]

[0087] Spectral analysis data 3g:

[0088] Oily liquid, 1 H NMR (400MHz, CDCl3) δ7.44-7.39(m,1H),7.33-7.26(m,5H),7.22-7.18(m,2H),7.12(t,J=8.3Hz,1H),5.99(s,1H),4.53(s,2H),2.18(s,3H); 13 C NMR (100MHz, CDCl3) δ170.54, 162.68 (d, J = 247.0Hz), 139.08, 136.63, 134.40 (d, J = 7.5Hz), 130.31 (d, J = 8.2Hz), 128.98, 128.52, 127.68, 124.23 (d, J = 2.6Hz), 119.95, 116.68 (d, J = 21.2Hz), 115.69 (d, J = 23.0Hz), 49.55, 22.02; 19 F NMR(376MHz, CDCl3)δ-111.52; HRMS(ESI-TOF)[M+Na] + calculated for C 17 H 15 ClFNONa:326.0718,found:326.0716.

[0089] Example 8: Synthesis of Compound 3h

[0090] 1a in Example 1 was replaced by 1h, and other operating conditions were the same as those in Example 1, with a yield of 77%.

[0091]

[0092] Spectrum analysis data 3h:

[0093] Oily liquid, 1H NMR (400MHz, CDCl3) δ7.49(d,J=8.6Hz,2H),7.41(d,J=8.6Hz,2H),7.28(t,J=7.7Hz,3H),7.19-7.19(m,1H),5.97(s,1H),4.52(s,1H),2.18(s,2H); 13 C NMR(100MHz, CDCl3)δ170.60,139.24,136.64,135.55,130.65,129.97,128.99,128.53,127.69,119.37,49.50,22.08; HRMS(ESI-TOF)[M+K] + calculated for C 17 H 15 Cl2NOK:358.0162,found:358.0163.

[0094] Example 9: Synthesis of Compound 3i

[0095] 1i was used to replace 1a in Example 1, and other operating conditions were the same as those in Example 1, and the yield was 92%.

[0096]

[0097] Spectral analysis data 3i:

[0098] Oily liquid, 1 H NMR (400MHz, CDCl3) δ7.56-7.52(m,2H),7.28(t,J=7.4Hz,3H),7.19-7.10(m,4H),5.95(s,1H),4.52(s,2H),2.19(s,3H); 13 C NMR (100MHz, CDCl3) δ170.61, 163.02 (d, J = 251.0Hz), 139.31, 136.70, 130.70 (d, J = 8.4Hz), 128.97,128.51,128.20(d,J=2.8Hz),127.65,118.73,115.83(d,J=21.8Hz),49.44,22.07; 19 F NMR(376MHz, CDCl3)δ-109.93; HRMS(ESI-TOF)[M+H] + calculated for C 17 H 16 ClFNO:304.0899,found:304.0901.

[0099] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing β-chloroenamide derivatives without catalyst at room temperature, characterized in that: The method comprises the following steps: in an organic solvent, using an enamide derivative 1 containing different substituents as a raw material, stirring and reacting at room temperature and without a catalyst under the action of a chlorinating reagent 2, tracking the reaction by TLC until the reaction is complete, and post-treating the reaction solution to obtain a β-chloroenamide and its derivatives shown in formula 3; The chemical reaction equation is: In the enamide derivatives, R is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, methoxy, benzyloxy, thiomethoxy, trifluoromethoxy, (hetero)aryl or halogen atom, which may be monosubstituted, disubstituted or trisubstituted; R 1 is selected from acetyl, propionyl, isobutyryl, benzoyl; R 2 is selected from methyl, ethyl, benzyl, isopropyl or allyl; The chlorination agent is selected from N-chlorosuccinimide, N-chloro-o-sulfonylbenzamide, N-chlorophthalimide, tert-butyl hypochlorite, 1-chloro-1,2-benzidoyl-3-one or 1-chloro-1,3-dihydro-3,3-dimethyl-1,2-benzidoyloxolane.

2. The method for preparing β-chloroenamide derivatives without catalyst at room temperature according to claim 1, characterized in that: The organic solvent is selected from tetrahydrofuran, toluene, acetonitrile, acetone, dichloromethane, dimethyl sulfoxide, 1,2-dichloroethane, 1,4-dioxane or N,N-dimethylformamide.

3. The method for preparing β-chloroenamide derivatives without catalyst at room temperature according to claim 1, characterized in that: The chlorination agent is N-chlorosuccinimide.

4. The method for preparing β-chloroenamide derivatives without catalyst at room temperature according to claim 2, characterized in that: The organic solvent is 1,4-dioxane.

5. The method for preparing β-chloroenamide derivatives without catalyst at room temperature according to claim 1, characterized in that: The molar ratio of the enamide derivative to the chlorination reagent is 1:1.5-2.

5.

6. The method for preparing β-chloroenamide derivatives without catalyst at room temperature according to claim 1, characterized in that: 1.5 to 2.5 mL of organic solvent is required per 1 mmol of the enamide derivative.

7. The method for preparing β-chloroenamide derivatives without catalyst at room temperature according to claim 1, characterized in that: The room temperature is 20-30°C, and the reaction time is 12-18h.

8. The method for preparing β-chloroenamide derivatives without catalyst at room temperature according to claim 1, characterized in that: When TLC is used, the developing solvent is V 石油醚 :V 乙酸乙酯 =8~12:

1.

9. The method for preparing β-chloroenamide derivatives without catalyst at room temperature according to claim 1, characterized in that: The post-treatment process is as follows: after the reaction is completed, the organic phase is washed with water, dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure, and then subjected to silica gel column chromatography to obtain an oily liquid β-chloroenamide derivative.

10. The method for preparing β-chloroenamide derivatives without catalyst at room temperature according to claim 9, characterized in that: The column chromatography eluent is V 石油醚 :V 乙酸乙酯 =8~12:1.

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