Synthesis method of N, N-disubstituted enamine ester compound

Abstract

The invention relates to a synthesis method of an N, N-disubstituted enamine ester compound, and discloses a method for synthesizing the N, N-disubstituted enamine ester compound by taking phenylglycine ester and N, N-disubstituted amido malononitrile as substrates, copper acetate as a catalyst, chloranil as an oxidizing agent, hexamethylphosphoramide as an additive and acetonitrile as a solvent and reacting at 60 DEG C to obtain the N, N-disubstituted enamine ester compound. The invention discloses an N, N-disubstituted enamine ester compound. The method has good functional group tolerance, and an efficient and novel preparation method is provided for the N, N-disubstituted enamine ester compound.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing an N,N-disubstituted enamine ester compound. Background Art

[0002] β-Enaminones (esters) contain both strongly nucleophilic enamine structural units and electrophilic enone structural units, and have very rich reaction sites. They are an important class of organic synthons. As an important structural motif in a variety of natural products and bioactive molecules, enaminones have anti-inflammatory, anticonvulsant, antitumor and antibacterial effects. They are also important precursors for the preparation of chiral β-amino acid derivatives. The special structure of enaminones (esters) gives them outstanding value in drug synthesis applications and reaction catalysis, prompting researchers to develop a series of methods for synthesizing enaminones (esters). In addition to the classic ketoamine condensation reaction, many effective synthetic methods have been recorded in recent years under the promotion of transition metal catalysis, such as the amination of propargyl alcohol and alkynyl ketone (ester), NH olefination of amines and sulfonamides, and metal carbene-mediated reactions. Despite the above achievements, harsh reaction conditions or dangerous reagents are often required. Therefore, it is of great practical significance to develop more mild, efficient, green and economical synthetic strategies.

[0003] Among them, the carbon atom at the α-position of α-aminomalononitrile has strong nucleophilic ability due to the geminal dicyano electron-withdrawing effect, and can undergo nucleophilic addition or coupling reactions with many electron-deficient groups. Based on the understanding of the reactivity of N,N-disubstituted aminomalononitrile, we are prompted to further explore the synthetic uses of this type of synthetic precursor. N-arylglycine ester compounds are a very important module in organic synthesis. By chemically modifying N-arylglycine ester derivatives, a wide variety of glycine ester derivatives can be constructed, enriching the types of non-natural amino acid derivatives and promoting important developments in research fields such as biochemistry and synthetic chemistry. Summary of the invention

[0004] The purpose of the present invention is to improve the deficiencies of existing preparation and synthesis methods and to provide a method for synthesizing N,N-disubstituted enamine ester compounds with simple and efficient reaction conditions, wide substrate applicability and convenient operation.

[0005] The technical scheme of the present invention is: a substrate, an oxidant, a catalyst, and an additive are placed in a test tube, a solvent is added, and an N,N-disubstituted enamine ester compound is obtained under argon protection and room temperature. The reaction formula is as follows:

[0006]

[0007] (1)R 1is selected from the group consisting of a methyl group, a methoxy group, an isopropyl group, an ethyl group, a chlorine atom, a bromine atom, an iodine atom, a trifluoromethyl group, and a nitro group;

[0008] (2)R 2 Selected from methyl, phenyl, ethyl;

[0009] (3)R 3 Selected from ethyl, hexahydropyridinyl, morpholinyl, 2,6-dimethylmorpholinyl, phenyl, 2-methylphenyl, 2-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, benzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-fluorobenzyl, indolyl;

[0010] (4)R 4 Selected from ethyl, hexahydropyridinyl, morpholinyl, 2,6-dimethylmorpholinyl, methyl, indolyl;

[0011] (5) the organic solvent used is selected from 1,2-dichloroethane, n-heptane, toluene, acetonitrile, preferably acetonitrile;

[0012] (6) the oxidant used is selected from 2,2,6,6-tetramethyl-1-oxopiperidin-1-ium tetrafluoroborate, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide, tetrachlorobenzoquinone, MnO2 / O2, preferably tetrachlorobenzoquinone;

[0013] (7) The heating temperature used is selected from 0-80°C, preferably 60°C;

[0014] (8) The Lewis acid used is selected from copper iodide, copper acetate, aluminum chloride, silver trifluoromethanesulfonate, aluminum tris(trifluoromethanesulfonate), preferably copper acetate;

[0015] (9) The additive used is hexamethylphosphoric acid triamide;

[0016] (10) The molar mass ratio of each substance in the reaction is preferably: p-toluene glycine ester: N,N-disubstituted aminomalononitrile: copper acetate: hexamethylphosphoric triamide: tetrachlorobenzoquinone = 1:2.5:0.2:1:1.1. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] 1. Figure 1 The synthesis conditions of N, N-disubstituted enamine ester compounds;

[0018] 2. Figure 2 is the preparation reaction formula of compound 3a;

[0019] 3. Figure 3 is the preparation reaction formula of compound 3b;

[0020] 4. Figure 4 is the preparation reaction formula of compound 3c;

[0021] 5. Figure 5 is the preparation reaction formula of compound 3d;

[0022] 6. Figure 6 is the preparation reaction formula of compound 3e;

[0023] 7. Figure 7 is the preparation reaction formula of compound 3f;

[0024] 8. Figure 8 is the preparation reaction formula of compound 3g;

[0025] 9. Fig. 9 is the preparation reaction formula of compound 3h;

[0026] 10. Fig.10 is the preparation reaction formula of compound 3i;

[0027] 11. Fig.11 is the preparation reaction formula of compound 3j;

[0028] 12. Fig.12 is the preparation reaction formula of compound 3k;

[0029] 13. Fig.13 is the preparation reaction formula of compound 31;

[0030] 14. Fig.14 is the preparation reaction formula of compound 3m;

[0031] 15. Fig.15 is the preparation reaction formula of compound 3n;

[0032] 16. Fig.16 is the preparation reaction formula of compound 3o;

[0033] 17. Fig.17 is the preparation reaction formula of compound 3p;

[0034] 18. Fig.18 is the preparation reaction formula of compound 3q;

[0035] 19. Fig.19 is the preparation reaction formula of compound 3r;

[0036] 20. Fig. 20 is the preparation reaction formula of compound 3s;

[0037] twenty one. Fig.21 is the preparation reaction formula of compound 3t;

[0038] twenty two. Fig. 22 is the preparation reaction formula of compound 3u;

[0039] twenty three. Fig.23 This is the reaction formula for the preparation of compound 3v. DETAILED DESCRIPTION

[0040] The present invention is further described below through specific embodiments, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following embodiments, and all technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0041] Example 1: Phenylglycine ester (1a) and N,N-disubstituted aminomalononitrile (2a) are used as raw materials (reaction formula 1)

[0042]

[0043] At 60°C, in a MeCN (1.0 mL) solution under argon, phenylglycine ester 1a (33.0 mg, 0.2 mmol), N,N-dimethylaminocarbonitrile 2a (54.5 mg, 0.5 mmol), HMPA (35 μL, 0.2 mmol), tetrachlorobenzoquinone (54.1 mg, 0.22 mmol) and copper acetate (7.3 mg, 0.04 mmol) were added, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain product 3a.

[0044] The product detection data are as follows: yellow oily liquid, yield 65%.

[0045] 1 H NMR (400MHz, CDCl3) δ7.29–7.22(m,2H),7.01(tt,J=7.2,1.1Hz,1H),6.79–6.71(m,2H),6.58(s,1H),3.83(s,3H),2.58(s,3H); 13 C NMR (101MHz, CDCl3) δ163.8,140.0,131.3,128.9,122.6,118.2,114.4,111.3,52.8,42.0; HRMS (ESI) m / z: (M+Na) + calcdforC 13 H 15 N3NaO2 + 268.1060, found 268.1062.

[0046] Example 2: Toluene glycine ester (1b) and N,N-disubstituted aminomalononitrile (2a) are used as raw materials (reaction formula 2)

[0047]

[0048] Toluene glycinate 1b (35.8 mg, 0.2 mmol), N,N-dimethylaminocarbonitrile 2a (54.5 mg, 0.5 mmol), HMPA (35 μL, 0.2 mmol), tetrachlorobenzoquinone (54.1 mg, 0.22 mmol) and copper acetate (7.3 mg, 0.04 mmol) were added to a MeCN (1.0 mL) solution at 60 °C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain product 3b.

[0049] The product detection data are as follows: yellow oily liquid, yield 81%.

[0050] 1 H NMR (400MHz, CDCl3) δ7.09–7.03(m,2H),6.70–6.66(m,2H),6.62(s,1H),3.82(s,3H),2.55(s,6H),2.30(s,3H); 13 C NMR (101MHz, CDCl3) δ163.7, 137.4, 134.0, 132.6, 129.5, 118.8, 114.6, 109.4, 52.8, 42.3, 20.7; HRMS (ESI) m / z: (M+Na) + calcdforC 14 H 17 N3NaO2 + 282.1218, found 282.1219.

[0051] Example 3 Using 3-methylphenylglycine ester (1c) and N,N-disubstituted aminomalononitrile (2a) as raw materials (reaction formula 3)

[0052]

[0053] Toluene glycinate 1c (35.8 mg, 0.2 mmol), N,N-dimethylaminocarbonitrile 2a (54.5 mg, 0.5 mmol), HMPA (35 μL, 0.2 mmol), tetrachlorobenzoquinone (54.1 mg, 0.22 mmol) and copper acetate (7.3 mg, 0.04 mmol) were added to a MeCN (1.0 mL) solution at 60 °C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain product 3c.

[0054] The product detection data are as follows: yellow oily liquid, yield 73%.

[0055] 1 H NMR (400MHz, CDCl3) δ7.14(t,J=7.8Hz,1H),6.83(d,J=7.6Hz,1H),6.61–6.55(m,2H),6.54(m,1H),3.83(s,3H),2.58(s,6H),2.31(s,3H);; 13 C NMR (101MHz, CDCl3) δ163.9,140.0,139.0,132.3,128.8,123.6,119.0,115.3,114.5,110.8,52.8,42.1,21.4; HRMS (ESI) m / z: (M+Na) + Calculate for C 14 H 17 N3NaO2 + 282.1218, found 282.1218.

[0056] Implementation Case 4

[0057] Using 4-isopropylphenylglycine ester (1d) and N,N-disubstituted aminomalononitrile (2a) as raw materials (reaction formula 4):

[0058]

[0059] Toluene glycinate 1d (41.5 mg, 0.2 mmol), N,N-dimethylaminocarbonitrile 2a (54.5 mg, 0.5 mmol), HMPA (35 μL, 0.2 mmol), tetrachlorobenzoquinone (54.1 mg, 0.22 mmol) and copper acetate (7.3 mg, 0.04 mmol) were added to a MeCN (1.0 mL) solution at 60 °C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain product 3d.

[0060] The product detection data are as follows: yellow oily liquid, yield 77%.

[0061] 1 H NMR(400MHz, CDCl3) δ7.04(d,J=8.1Hz,2H),6.64(d,J=8.1Hz,2H),6.59(s, 1H),3.75(s,3H),2.86–2.72(m,1H),2.48(s,6H),1.16(s,3H),1.14(s,4H); 13 C NMR (101MHz, CDCl3) δ163.7,143.7,137.7,134.3,126.9,118.7,114.5,109.4,52.8,42.3,33.4,24.0; HRMS (ESI) m / z: (M+Na) + Calculate for C 16 H 21 N3NaO2 + 310.1531, found 310.1535.

[0062] Implementation Case 5

[0063] Using 4-methylphenylglycine ester (1e) and N,N-disubstituted aminomalononitrile (2a) as raw materials (reaction formula 5)

[0064]

[0065] Toluene glycinate 1e (48.3 mg, 0.2 mmol), N,N-dimethylaminocarbonitrile 2a (54.5 mg, 0.5 mmol), HMPA (35 μL, 0.2 mmol), tetrachlorobenzoquinone (54.1 mg, 0.22 mmol) and copper acetate (7.3 mg, 0.04 mmol) were added to a MeCN (1.0 mL) solution at 60 °C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain the product 3e.

[0066] The product detection data are as follows: yellow oily liquid, yield 47%.

[0067] 1 HNMR (400MHz, CDCl3) δ7.39–7.33(m,2H),7.25–7.20(m,1H),7.13–7.04(m,4H),6.81–6.76(m,2H),6.58(s,1H),2.64(s,6H),2.32(s,3H); 13 C NMR (101MHz, CDCl3) δ162.0,150.0,137.7,132.7,131.7,129.7,129.4,126.3,121.2,118.8,114.4,111.5,42.2,20.7; HRMS (ESI) m / z: (M+Na) + Calculate for C 19 H 19 N3NaO2 + 344.1375, found 344.1378.

[0068] Implementation Case 6

[0069] Using 4-ethylphenylglycine ester (1f) and N,N-disubstituted aminomalononitrile (2a) as raw materials (reaction formula 6)

[0070]

[0071] Toluene glycinate 1f (38.7 mg, 0.2 mmol), N,N-dimethylaminocarbonitrile 2a (54.5 mg, 0.5 mmol), HMPA (35 μL, 0.2 mmol), tetrachlorobenzoquinone (54.1 mg, 0.22 mmol) and copper acetate (7.3 mg, 0.04 mmol) were added to a MeCN (1.0 mL) solution at 60 °C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain the product 3f.

[0072] The product detection data are as follows: yellow oily liquid, yield 73%.

[0073] 1 H NMR (400MHz, CDCl3) δ7.12–7.06(m,2H),6.73–6.67(m,2H),6.65(s,1H),3.82(s,3H),2.64–2.57(m,2H),2.55(s,6H),1.21(t,J=7.6Hz,3H); 13 C NMR (101MHz, CDCl3) δ163.7,139.1,137.6,134.1,128.4,118.8,114.5,109.5,52.8,42.3,28.1,15.5; HRMS (ESI) m / z: (M+Na) + Calculate for C 15 H 19 N3NaO2 + 296.1375, found 296.1379.

[0074] Example 7: Using 4-methoxyphenylglycine ester (1g) and N,N-disubstituted aminomalononitrile (2a) as raw materials (reaction formula 7)

[0075]

[0076]

[0077] Toluene glycinate 1g (39.0mg, 0.2mmol), N,N-dimethylaminocarbonitrile 2a (54.5mg, 0.5mmol), HMPA (35μL, 0.2mmol), tetrachlorobenzoquinone (54.1mg, 0.22mmol) and copper acetate (7.3mg, 0.04mmol) were added to a MeCN (1.0mL) solution at 60°C under argon conditions, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain 3g of the product.

[0078] The product detection data are as follows: yellow oily liquid, yield 88%.

[0079] 1 H NMR (400MHz, CDCl3) δ6.83–6.74(m,4H),6.70(s,1H),3.79(s,3H),3.77(s,3H),2.52(s,6H); 13 C NMR (101MHz, CDCl3) δ163.5, 155.9, 135.9, 132.8, 121.1, 114.6, 114.1, 107.5, 55.3, 52.7, 42.3; HRMS (ESI) m / z: (M+Na) + calcdforC 14 H 17 N3NaO3 + 298.1168, found 298.1169.

[0080] Implementation Case 8

[0081] Using 4-methoxyphenylglycine ethyl ester (1h) and N,N-disubstituted aminomalononitrile (2a) as raw materials (reaction formula 8)

[0082]

[0083] Toluene glycinate 1h (41.9 mg, 0.2 mmol), N,N-dimethylaminocarbonitrile 2a (54.5 mg, 0.5 mmol), HMPA (35 μL, 0.2 mmol), tetrachlorobenzoquinone (54.1 mg, 0.22 mmol) and copper acetate (7.3 mg, 0.04 mmol) were added to a MeCN (1.0 mL) solution at 60 °C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain the product 3h.

[0084] The product detection data are as follows: yellow oily liquid, yield 71%.

[0085] 1 HNMR (400MHz, CDCl3) δ6.84–6.77(m,4H),6.72(s,1H),4.27(q,J=7.1Hz,2H),3.78(s,3H),2.51(s,6H),1.23(t,J=7.1Hz,3H); 13 C NMR (101MHz, CDCl3) δ163.0,156.2,137.3,132.9,121.7,114.7,114.1,107.0,62.4,55.5,42.5,13.7; HRMS (ESI) m / z: (M+Na) + calcdforC 15 H 19 N3NaO3 + 312.1324, found 312.1329.

[0086] Implementation Case 9

[0087] Using 4-methoxyphenylglycine methyl ester (1g) and N,N-disubstituted aminomalononitrile (2b) as raw materials (reaction formula 9)

[0088]

[0089] Toluene glycinate 1g (39.0mg, 0.2mmol), N,N-dimethylaminocarbonitrile 2b (68.6mg, 0.5mmol), HMPA (35μL, 0.2mmol), tetrachlorobenzoquinone (54.1mg, 0.22mmol) and copper acetate (7.3mg, 0.04mmol) were added to a MeCN (1.0mL) solution at 60°C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain product 3i.

[0090] The product detection data are as follows: yellow oily liquid, yield 45%.

[0091] 1 H NMR (400MHz, CDCl3) δ6.95 (s, 1H), 6.86–6.77 (m, 4H), 3.78 (s, 3H), 3.78 (s, 3H), 2.77 (q, J = 7.2Hz, 4H), 1.07 (t, J = 7.2Hz, 6H); 13 C NMR (101MHz, CDCl3) δ163.2, 156.6, 144.0, 133.1, 122.2, 114.7, 114.5, 102.1, 55.5, 52.9, 48.3, 13.0; HRMS (ESI) m / z: (M+Na) + calcdforC 16 H 21 N3NaO3 + 326.1481, found 326.1487.

[0092] Example 10: Using 4-methoxyphenylglycine methyl ester (1g) and N,N-disubstituted aminomalononitrile (2c) as raw materials (reaction formula 10)

[0093]

[0094] Toluene glycinate 1g (39.0mg, 0.2mmol), N,N-dimethylaminocarbonitrile 2c (74.6mg, 0.5mmol), HMPA (35μL, 0.2mmol), tetrachlorobenzoquinone (54.1mg, 0.22mmol) and copper acetate (7.3mg, 0.04mmol) were added to a MeCN (1.0mL) solution at 60°C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain product 3j.

[0095] The product detection data are as follows: yellow oily liquid, yield 67%.

[0096] 1 H NMR (400MHz, CDCl3) δ6.85–6.77(m,4H),6.72(s,1H),3.80(s,3H),3.79(s,3H),2.75–2.67(m,4H),1.55–1.40(m,6H); 13 C NMR (101MHz, CDCl3) δ163.6,156.3,137.2,132.5,122.1,115.1,114.1,106.5,55.5,52.9,51.3,25.7,23.4; HRMS (ESI) m / z: (M+Na) + calcdforC 17 H 21 N3NaO3 + 338.1481, found 338.1482.

[0097] Implementation Case 11

[0098] Using 4-methoxyphenylglycine methyl ester (1g) and N,N-disubstituted aminomalononitrile (2d) as raw materials (reaction formula 11)

[0099]

[0100] Toluene glycinate 1g (39.0mg, 0.2mmol), N,N-dimethylaminocarbonitrile 2d (75.6mg, 0.5mmol), HMPA (35μL, 0.2mmol), tetrachlorobenzoquinone (54.1mg, 0.22mmol) and copper acetate (7.3mg, 0.04mmol) were added to a MeCN (1.0mL) solution at 60°C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain the product 3k.

[0101] The product detection data are as follows: yellow oily liquid, yield 70%.

[0102] 1 HNMR (400MHz, CDCl3) δ6.82(s,4H),6.77(s,1H),3.83(s,3H),3.79(s,3H),3.56–3.50(m,4H),2.79–2.74(m,4H); 13 C NMR (101MHz, CDCl3) δ163.4,156.5,136.7,131.7,122.6,114.7,113.9,104.3,66.3,55.4,53.0,49.7; HRMS (ESI) m / z: (M+Na) + calcdforC 16 H 19 N3NaO4 + 340.1273, found 340.1273.

[0103] Example 12: Using 4-methoxyphenylglycine methyl ester (1g) and N,N-disubstituted aminomalononitrile (2e) as raw materials (reaction formula 12)

[0104]

[0105] Toluene glycinate 1g (39.0mg, 0.2mmol), N,N-dimethylaminocarbonitrile 2e (89.6mg, 0.5mmol), HMPA (35μL, 0.2mmol), tetrachlorobenzoquinone (54.1mg, 0.22mmol) and copper acetate (7.3mg, 0.04mmol) were added to a MeCN (1.0mL) solution at 60°C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain the product 3l.

[0106] The product detection data are as follows: yellow oily liquid, yield 64%.

[0107] 1 H NMR (400MHz, CDCl3) δ6.85–6.77(m,4H),6.71(s,1H),3.83(s,3H),3.79(s,3H),3.41–3 .31(m,2H),2.77–2.69(m,2H),2.36(dd,J=11.7,10.2Hz,2H),1.11(s,3H),1.10(s,3H); 13 C NMR (101MHz, CDCl3) δ163.6,156.5,136.0,131.8,122.5,114.8,113.9,104.5,71.3,55.5,55.0,53.0,18.8; HRMS (ESI) m / z: (M+Na) + calcdforC 18 H 23 N3NaO4 + 368.1586, found 368.1587.

[0108] Implementation Case 13

[0109] Using 4-methoxyphenylglycine methyl ester (1g) and N,N-disubstituted aminomalononitrile (2f) as raw materials (reaction formula 13)

[0110]

[0111] Toluene glycinate 1g (39.0mg, 0.2mmol), N,N-dimethylaminocarbonitrile 2f (85.6mg, 0.5mmol), HMPA (35μL, 0.2mmol), tetrachlorobenzoquinone (54.1mg, 0.22mmol) and copper acetate (7.3mg, 0.04mmol) were added to a MeCN (1.0mL) solution at 60°C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain the product 3m.

[0112] The product detection data are as follows: yellow oily liquid, yield 53%.

[0113] 1 H NMR (400MHz, CDCl3) δ7.25–7.19(m,2H),6.88(tt,J=7.3,1.1Hz,1H),6.71–6.66(m,6H),6.63(s,1H),3.90(s,3H),3.74(s,3H),3.01(s,3H); 13 C NMR (101MHz, CDCl3) δ163.2,156.9,144.7,139.2,131.5,129.1,122.9,120.3,116.4,114.9,113.8,98.8,55.5,53.3,37.3; HRMS (ESI) m / z: (M+Na) + Calculate for C 19 H 19 N3NaO3 + 360.1324, found 360.1325.

[0114] Implementation Case 14

[0115] Using 4-methoxyphenylglycine methyl ester (1g) and N,N-disubstituted aminomalononitrile (2g) as raw materials (reaction formula 14)

[0116]

[0117] Toluene glycinate 1g (39.0mg, 0.2mmol), N,N-dimethylaminocarbonitrile 2g (92.6mg, 0.5mmol), HMPA (35μL, 0.2mmol), tetrachlorobenzoquinone (54.1mg, 0.22mmol) and copper acetate (7.3mg, 0.04mmol) were added to a MeCN (1.0mL) solution at 60°C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain product 3n.

[0118] The product detection data are as follows: yellow oily liquid, yield 74%.

[0119] 1 HNMR (400MHz, CDCl3) δ7.15–7.06(m,2H),7.05–6.93(m,2H),6.79–6.73(m,2H),6. 67–6.60(m,2H),6.06(s,1H),3.79(s,3H),3.77(s,3H),3.13(s,3H),2.16(s,3H); 13 C NMR (101MHz, CDCl3) δ163.6,156.1,145.4,134.5,133.4,132.3,131.4,126.9,124. 9,121.8,120.8,115.8,114.3,105.7,55.5,52.9,40.4,18.5; HRMS(ESI)m / z:(M+Na) + calcdforC 20 H 21 N3NaO3 + 374.1481, found 374.1486.

[0120] Implementation Case 15

[0121] Using 4-methoxyphenylglycine methyl ester (1g) and N,N-disubstituted aminomalononitrile (2h) as raw materials (reaction formula 15)

[0122]

[0123] Toluene glycinate 1g (39.0mg, 0.2mmol), N,N-dimethylaminocarbonitrile 2h (102.8mg, 0.5mmol), HMPA (35μL, 0.2mmol), tetrachlorobenzoquinone (54.1mg, 0.22mmol) and copper acetate (7.3mg, 0.04mmol) were added to a MeCN (1.0mL) solution at 60°C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain the product 3o.

[0124] The product detection data are as follows: yellow oily liquid, yield 81%.

[0125] 1 HNMR(400MHz, CDCl3)δ7.37–7.32(m,1H),7.27–7.18(m,2H),7.10–7.03(m, 1H),6.81–6.72(m,4H),6.70(s,1H),3.78(s,3H),3.77(s,3H),3.07(s,3H); 13 C NMR (101MHz, CDCl3) δ163.1,156.4,144.6,139.9,132.9,130.4,129.2,127.9,12 5.9,123.5,121.4,115.9,114.4,102.6,55.4,53.0,40.5; HRMS(ESI)m / z:(M+Na) + calcdforC 19 H 18 ClN3NaO3 + 394.0934, found 394.0934.

[0126] Example 16 Using 4-methoxyphenylglycine methyl ester (1g) and N,N-disubstituted aminomalononitrile (2i) as raw materials (reaction formula 16)

[0127]

[0128] Toluene glycinate 1g (39.0mg, 0.2mmol), N,N-dimethylaminocarbonitrile 2i (94.6mg, 0.5mmol), HMPA (35μL, 0.2mmol), tetrachlorobenzoquinone (54.1mg, 0.22mmol) and copper acetate (7.3mg, 0.04mmol) were added to a MeCN (1.0mL) solution at 60°C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain the product 3p.

[0129] The product detection data are as follows: yellow oily liquid, yield 72%.

[0130] 1 H NMR (400MHz, CDCl3) δ6.93–6.86(m,2H),6.71(s,1H),6.69–6.62(m,4H),6.59–6.53(m,2H),3.90(s,3H),3.74(s,3H),2.98(s,3H); 13 C NMR (101MHz, CDCl3) δ163.2,158.5,156.8,156.1,140.8,137.4,131.2,122.7,116. 4,116.3,116.2,115.5,115.3,113.6,99.1,55.4,53.3,37.6; HRMS(ESI)m / z:(M+Na) + Calculate for C 19 H 18 FN3NaO3 + 378.1230, found 378.1232.

[0131] Implementation Case 17

[0132] Using 4-methoxyphenylglycine methyl ester (1g) and N,N-disubstituted aminomalononitrile (2j) as raw materials (reaction formula 17)

[0133]

[0134] Toluene glycinate 1g (39.0mg, 0.2mmol), N,N-dimethylaminocarbonitrile 2j (100.6mg, 0.5mmol), HMPA (35μL, 0.2mmol), tetrachlorobenzoquinone (54.1mg, 0.22mmol) and copper acetate (7.3mg, 0.04mmol) were added to a MeCN (1.0mL) solution at 60°C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain the product 3q.

[0135] The product detection data are as follows: yellow oily liquid, yield 54%.

[0136] 1 H NMR (400MHz, CDCl3) δ6.80–6.75(m,2H),6.72–6.67(m,2H),6.67–6.62(m,4H),6.61(s,1H),3.89(s,3H),3.76(s,3H),3.75(s,3H),3.00(s,3H); 13 C NMR (101MHz, CDCl3) δ163.4,156.6,154.1,138.7,137.1,131.8,122.4,117. 0,116.3,114.4,113.8,100.6,55.6,55.5,53.2,37.9; HRMS(ESI)m / z:(M+Na) + Calculate for C 20 H 21 N3NaO4 + 390.1430, found 390.1431.

[0137] Implementation Case 18

[0138] Using 4-methoxyphenylglycine methyl ester (1g) and N,N-disubstituted aminomalononitrile (2k) as raw materials (reaction formula 18)

[0139]

[0140] Toluene glycinate 1g (39.0mg, 0.2mmol), N,N-dimethylaminocarbonitrile 2k (92.6mg, 0.5mmol), HMPA (35μL, 0.2mmol), tetrachlorobenzoquinone (54.1mg, 0.22mmol) and copper acetate (7.3mg, 0.04mmol) were added to a MeCN (1.0mL) solution at 60°C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain product 3r.

[0141] The product detection data are as follows: yellow oily liquid, yield 60%.

[0142] 1 H NMR (400MHz, CDCl3) δ7.31–7.27(m,2H),7.27–7.24(m,2H),6.80–6.73(m,2H),6. 71(s,1H),6.64–6.57(m,2H),3.80(s,2H),3.77(s,3H),3.72(s,3H),2.56(s,3H); 13 C NMR (101MHz, CDCl3) δ163.1,156.5,140.7,136.8,132.8,129.1,128.4,127. 7,122.2,114.9,114.2,104.6,59.7,55.4,52.8,41.1; HRMS(ESI)m / z:(M+Na) + calcdforC 20 H 21 N3NaO3 + 374.1481, found 374.1489.

[0143] Example 19: Using 4-methoxyphenylglycine methyl ester (1 g) and N,N-disubstituted aminomalononitrile (2 l) as raw materials (reaction formula 19):

[0144]

[0145] Toluene glycinate 1g (39.0mg, 0.2mmol), N,N-dimethylaminocarbonitrile 2l (99.6mg, 0.5mmol), HMPA (35μL, 0.2mmol), tetrachlorobenzoquinone (54.1mg, 0.22mmol) and copper acetate (7.3mg, 0.04mmol) were added to a MeCN (1.0mL) solution at 60°C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain the product 3s.

[0146] The product detection data are as follows: yellow oily liquid, yield 82%.

[0147] 1 H NMR (400MHz, CDCl3) δ7.18–7.04(m,4H),6.79–6.72(m,2H),6.69(s,1H),6.63– 6.55(m,2H),3.77(s,3H),3.75(s,2H),3.73(s,3H),2.55(s,3H),2.30(s,3H); 13 C NMR (101MHz, CDCl3) δ163.2,156.5,140.6,137.4,133.7,132.9,129.1,129.1,1 22.1,114.9,114.2,104.9,59.4,55.4,52.8,41.0,21.1; HRMS(ESI)m / z:(M+Na) + calcdforC 21 H 23 N3NaO3 + 388.1637, found 388.1643.

[0148] Example 20: Using 4-methoxyphenylglycine methyl ester (1g) and N,N-disubstituted aminomalononitrile (2m) as raw materials (reaction formula 20)

[0149]

[0150] Toluene glycinate 1g (39.0mg, 0.2mmol), N,N-dimethylaminocarbonitrile 2m (109.8mg, 0.5mmol), HMPA (35μL, 0.2mmol), tetrachlorobenzoquinone (54.1mg, 0.22mmol) and copper acetate (7.3mg, 0.04mmol) were added to a MeCN (1.0mL) solution at 60°C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain the product 3t.

[0151] The product detection data are as follows: yellow oily liquid, yield 84%.

[0152] 1 H NMR (400MHz, CDCl3) δ7.25–7.16(m,4H),6.80–6.73(m,2H),6.69(s,1H),6.64–6.55(m,2H),3.77(s,3H),3.75(s,2H),3.72(s,3H),2.56(s,3H); 13 C NMR (101MHz, CDCl3) δ163.0,156.7,141.1,135.2,133.6,132.6,130.5,128. 5,122.3,114.8,114.3,104.1,58.9,55.4,52.9,41.3; HRMS(ESI)m / z:(M+Na) + Calculate for C 20 H 20 ClN3NaO3 + 408.1091, found 408.1094.

[0153] Example 21: Using 4-methoxyphenylglycine methyl ester (1g) and N,N-disubstituted aminomalononitrile (2n) as raw materials (reaction formula 21):

[0154]

[0155]

[0156] Toluene glycinate 1g (39.0mg, 0.2mmol), N,N-dimethylaminocarbonitrile 2n (101.6mg, 0.5mmol), HMPA (35μL, 0.2mmol), tetrachlorobenzoquinone (54.1mg, 0.22mmol) and copper acetate (7.3mg, 0.04mmol) were added to a MeCN (1.0mL) solution at 60°C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain the product 3u.

[0157] The product detection data are as follows: yellow oily liquid, yield 80%.

[0158] 1 H NMR (400MHz, CDCl3) δ7.26–7.19(m,2H),7.00–6.92(m,2H),6.80–6.74(m,2H),6. 72(s,1H),6.64–6.57(m,2H),3.77(s,3H),3.76(s,2H),3.72(s,3H),2.56(s,3H); 13 C NMR (101MHz, CDCl3) δ163.5,163.0,161.0,156.6,141.1,132.6,132.5,132.5,130.8,130. 7,122.2,115.4,115.1,114.8,114.3,104.0,58.8,55.4,52.9,41.2; HRMS(ESI)m / z:(M+Na) + calcdforC 20 H 20 FN3NaO3 + 392.1386, found 392.1387.

[0159] Implementation Case 22

[0160] Using 4-methoxyphenylglycine methyl ester (1g) and N,N-disubstituted aminomalononitrile (2n) as raw materials (reaction formula 22)

[0161]

[0162] Toluene glycinate 1h (39.0 mg, 0.2 mmol), N,N-dimethylaminocarbonitrile 2o (91.6 mg, 0.5 mmol), HMPA (35 μL, 0.2 mmol), tetrachlorobenzoquinone (54.1 mg, 0.22 mmol) and cupric acetate (7.3 mg, 0.04 mmol) were added to a MeCN (1.0 mL) solution at 60 °C under argon, and the reaction mixture was stirred for 10 hours. After the reaction was completed (monitored by thin layer chromatography), water was slowly added to quench the reaction mixture. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain the product 3v.

[0163] The product detection data are as follows: yellow oily liquid, yield 40%.

[0164] 1 H NMR(400MHz, CDCl3)δ7.12–7.01(m,2H),6.78(td,J=7.5,1.1Hz,1H),6.75–6.68(m,4H),6.67(s,1 H),6.44(d,J=7.8Hz,1H),3.90(s,3H),3.73(s,3H),3.62(t,J=8.3Hz,2H),2.91(t,J=8.3Hz,2H); 13 CNMR (101MHz, CDCl3) δ163.2,156.5,146.1,137.8,131.7,129.9,127.2,124.6,122 .4,120.4,115.1,113.8,109.6,97.0,55.5,53.2,51.7,28.3; HRMS(ESI)m / z:(M+Na) + Calculate for C 20 H 19 N3NaO3 + 372.1324, found 372.1319.

Claims

1. A method for synthesizing an N,N-disubstituted enamine ester compound, characterized in that phenylglycine ester and N,N-disubstituted aminomalononitrile are used as substrates, copper acetate is used as a catalyst, tetrachlorobenzoquinone is used as an oxidant, hexamethylphosphoric triamide is used as an additive, and acetonitrile is used as a solvent, and the N,N-disubstituted enamine ester compound is obtained by reaction at 60°C. The reaction formula is as follows: in: R 1 is selected from the group consisting of a methyl group, a methoxy group, an isopropyl group, an ethyl group, a chlorine atom, a bromine atom, an iodine atom, a trifluoromethyl group, and a nitro group; R 2 is selected from methyl, phenyl, ethyl; R 3 is selected from ethyl, hexahydropyridinyl, morpholinyl, 2,6-dimethylmorpholinyl, phenyl, 2-methylphenyl, 2-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, benzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-fluorobenzyl, indolyl; R 4 Selected from ethyl, piperidinyl, morpholinyl, 2,6-dimethylmorpholinyl, methyl, indolyl.

2. A method for synthesizing an N,N-disubstituted enamine ester compound according to claim 1, characterized in that: The organic solvent used is selected from 1,2-dichloroethane, n-heptane, toluene, and acetonitrile, preferably acetonitrile.

3. The method for synthesizing an N,N-disubstituted enamine ester compound according to claim 1, characterized in that: The oxidant used is selected from 2,2,6,6-tetramethyl-1-oxopiperidin-1-ium tetrafluoroborate, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide, tetrachlorobenzoquinone, MnO2 / O2, preferably tetrachlorobenzoquinone.

4. The method for synthesizing an N,N-disubstituted enamine ester compound according to claim 1, characterized in that: The heating temperature used is selected from 0-80°C, preferably 60°C.

5. The method for synthesizing an N,N-disubstituted enamine ester compound according to claim 1, characterized in that: The Lewis acid used is selected from copper iodide, copper acetate, aluminum chloride, silver trifluoromethanesulfonate, aluminum tris(trifluoromethanesulfonate), preferably copper acetate.

6. The method for synthesizing an N,N-disubstituted enamine ester compound according to claim 1, characterized in that: The additive used was hexamethylphosphoric triamide.

7. The method for synthesizing an N,N-disubstituted enamine ester compound according to claim 1, characterized in that: The molar mass ratio of each substance in the reaction is preferably: p-toluene glycine ester: N,N-disubstituted aminomalononitrile: copper acetate: hexamethylphosphoric triamide: tetrachlorobenzoquinone = 1:2.5:0.2:1:1.1.

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