Synthesis method of alpha-amino nitrile based on N, N-disubstituted amino malononitrile

Abstract

The invention designs a synthesis method of alpha-amino nitrile based on N, N-disubstituted amino malononitrile, and discloses that aldehyde and N, N-disubstituted amino malononitrile are taken as substrates, acetic acid is taken as an activating agent, water is taken as a solvent, the alpha-amino nitrile is obtained through reaction at 120 / 80 DEG C, the reaction condition is mild, and the alpha-amino nitrile has good functional group tolerance. The method is simple in reaction condition, wide in substrate applicability and convenient to operate, and overcomes the defects in the prior art.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing alpha-amino nitrile based on N,N-disubstituted aminomalononitrile. Background Art

[0002] α-Aminonitriles are unique motifs in many natural products, clinical drugs, and bioactive molecules. They are also an important class of synthetic precursors that can be converted into a series of valuable organic compounds, such as α-amino acids, 1,2-diamines, α-amino aldehydes / alcohols, ketones, and a series of nitrogen-containing heterocyclic compounds (e.g., indoles, pyrroles, imidazolides, etc.). In view of the above-mentioned important uses of α-aminonitriles, the construction of such fragments has always been a hot topic in the field of synthetic chemistry. The development of alternative reaction modes that can simultaneously install amino and cyano fragments on the same carbon atom with a low toxic cyanide source is still very much needed and has important significance for the field of organic synthesis. Considering the specific structure of N,N-disubstituted aminomalononitriles, it is very important to develop a synthetic method for α-aminonitriles based on N,N-disubstituted aminomalononitriles, which is of great significance for the synthesis and structural diversity of multiple α-aminonitriles and the study of the activity of related compounds. Summary of the invention

[0003] The purpose of the present invention is to overcome the defects of the existing preparation technology and provide a method for synthesizing α-amino nitrile with simple reaction conditions, wide substrate applicability and convenient operation.

[0004] The technical scheme of the present invention is: aldehyde 1 and N, N-disubstituted aminomalononitrile 2 are used as substrates, acetic acid is used as an activator, and water is used as a solvent, and the reaction is carried out at 120 / 80°C to obtain α-aminonitrile, and the reaction formula is as follows:

[0005]

[0006] (1)R 1 is selected from hydrogen, methyl, ethyl, butyl, tert-butylmethylene, isopropylmethylene, cyclopentyl, cyclohexyl, styryl, phenethyl, phenyl, 2-methylphenyl, 2-bromophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-bromophenyl, 3-chlorophenyl, 3-fluorophenyl, 4-methylphenyl, 4-chlorophenyl, 4-iodophenyl, 4-biphenyl, 4-trifluoromethylphenyl, 4-(N,N-dimethyl)phenyl, 2-bromo-4-methylphenyl, 2-bromo-5-methoxyphenyl, 5-bromo-2-methoxyphenyl, 2,3-dichlorophenyl, naphthyl, thiophene, furan;

[0007] (2)R 2 Selected from methyl, chloro, methoxy;

[0008] (3) Ar is selected from phenyl and thiophene;

[0009] (4) the solvent used is selected from toluene, tetrahydrofuran, chlorobenzene, DMF, acetonitrile, methanol, n-hexane, dibromomethane, carbon tetrachloride, chloroform, DCE, dichloromethane, ethyl acetate, toluene, trimethyl orthoformate, triethyl orthoformate, water and a mixed solvent of the above-mentioned organic solvents and water in any proportion, preferably water;

[0010] (5) the acid used is selected from acetic acid, citric acid, formic acid, methanesulfonic acid, camphorsulfonic acid, phosphoric acid, benzoic acid, p-toluenesulfonic acid, benzenesulfonic acid, phthalic acid, disodium hydrogen phosphate, dipotassium hydrogen phosphate, propionic acid, preferably acetic acid;

[0011] (6) The reaction temperature is selected from 60-140°C, preferably 120°C and 80°C. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] 1. Figure 1 It is the general synthetic formula of aromatic α-amino nitrile;

[0013] 2. Figure 2 is the general synthetic formula of alkyl α-amino nitrile;

[0014] 3. Figure 3 is the preparation reaction formula of compound 3a;

[0015] 4. Figure 4 is the preparation reaction formula of compound 3b;

[0016] 5. Figure 5 is the preparation reaction formula of compound 3c;

[0017] 6. Figure 6 is the preparation reaction formula of compound 3d;

[0018] 7. Figure 7 is the preparation reaction formula of compound 3e;

[0019] 8. Figure 8 is the preparation reaction formula of compound 3f;

[0020] 9. Fig. 9 is the preparation reaction formula of compound 3g;

[0021] 10. Fig.10 is the preparation reaction formula of compound 3h;

[0022] 11. Fig.11 is the preparation reaction formula of compound 3i;

[0023] 12. Fig.12 is the preparation reaction formula of compound 3j;

[0024] 13. Fig.13 is the preparation reaction formula of compound 3k;

[0025] 14. Fig.14 is the preparation reaction formula of compound 31;

[0026] 15. Fig.15 is the preparation reaction formula of compound 3m;

[0027] 16. Fig.16 is the preparation reaction formula of compound 3n;

[0028] 17. Fig.17 is the preparation reaction formula of compound 3o;

[0029] 18. Fig.18 is the preparation reaction formula of compound 3p;

[0030] 19. Fig.19 is the preparation reaction formula of compound 3q;

[0031] 20. Fig. 20 is the preparation reaction formula of compound 3r;

[0032] twenty one. Fig.21 is the preparation reaction formula of compound 3s;

[0033] twenty two. Fig. 22 is the preparation reaction formula of compound 3t;

[0034] twenty three. Fig.23 is the preparation reaction formula of compound 3u;

[0035] twenty four. Fig.24 is the preparation reaction formula of compound 3v;

[0036] 25. Fig.25 is the preparation reaction formula of compound 3w;

[0037] 26. Fig.26 is the preparation reaction formula of compound 3x;

[0038] 27. Fig. 27 is the preparation reaction formula of compound 3y;

[0039] 28. Fig.28 is the preparation reaction formula of compound 3z;

[0040] 29. Fig.29 is the preparation reaction formula of compound 3aa;

[0041] 30. Fig.30 is the preparation reaction formula of compound 3ab;

[0042] 31. Fig.31is the preparation reaction formula of compound 3ac;

[0043] 32. Fig.32 is the preparation reaction formula of compound 3ad;

[0044] 33. Fig.33 is the preparation reaction formula of compound 3ae;

[0045] 34. Fig.34 is the reaction formula for preparing compound 3af;

[0046] 35. Fig.35 is the preparation reaction formula of compound 3ag;

[0047] 36. Fig.36 is the preparation reaction formula of compound 3ah;

[0048] 37. Fig.37 is the preparation reaction formula of compound 3ai;

[0049] 38. Fig.38 is the preparation reaction formula of compound 3aj;

[0050] 39. Fig.39 is the preparation reaction formula of compound 3ak;

[0051] 40. Fig.40 is the preparation reaction formula of compound 3a1;

[0052] 41. Fig.41 This is the reaction formula for the preparation of compound 3am. DETAILED DESCRIPTION

[0053] 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.

[0054] Example 1: Using aromatic aldehyde substrate 1 and N,N-disubstituted aminomalononitrile 2 as raw materials:

[0055]

[0056] Add N,N-disubstituted aminomalononitrile (0.24mmol, 2.0equiv.), aromatic aldehyde (0.12mmol, 1.0equiv.), glacial acetic acid (0.24mmol, 2.0equiv.) in a sealed tube, add a magnetic stirrer, and 1ml of distilled water to disperse the reactants evenly. Stir in a 120℃ oil bath until the reaction is completed. Use TLC to monitor whether the reaction is complete. After the reaction is completed, cool the system to room temperature, slowly add saturated sodium bicarbonate solution until no bubbles are generated, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and then wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate in vacuo. Separate and purify by silica gel flash column chromatography (EA:PE=1:100) to obtain α-amino nitrile.

[0057] Implementation Case 2

[0058] Using alkyl aldehyde substrate 1 and N,N-disubstituted aminomalononitrile 2 as raw materials:

[0059]

[0060] Add N,N-disubstituted aminomalononitrile (0.36mmol, 3.0equiv.), alkylaldehyde (0.12mmol, 1.0equiv.), glacial acetic acid (0.36mmol, 3.0equiv.) in a sealed tube, add a magnetic stirrer, and 1ml of distilled water to disperse the reactants evenly. Stir in an 80℃ oil bath until the reaction is completed. Use TLC to monitor whether the reaction is complete. After the reaction is completed, cool the system to room temperature, slowly add saturated sodium bicarbonate solution until no bubbles are generated, extract the aqueous phase with ethyl acetate three times, combine the organic phases and wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate in vacuo. Separate and purify by silica gel flash column chromatography (EA:PE=1:100) to obtain α-amino nitrile.

[0061] Implementation Case 3

[0062] Using benzaldehyde substrate 1a and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0063]

[0064] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), benzaldehyde (12.7 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3a was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0065] The product testing data are as follows:

[0066] White solid, yield 99%, melting point 64-65℃.

[0067] 1 H NMR(400MHz, CDCl3)δ7.59(d,J=6.8Hz,2H),7.49-7.41(m,3H),7.36(t,J=8.0H z, 2H), 7.06 (d, J = 8.0Hz, 2H), 7.01 (t, J = 8.0Hz, 1H), 5.88 (s, 1H), 2.77 (s, 3H).

[0068] 13 C NMR (100MHz, CDCl3) δ149.0,133.3,129.4,129.0,129.0,127.1,121.1,116.6,116.1,58.5,34.5.

[0069] HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 15 N2223.1235, Found 223.1239.

[0070] Implementation Case 4

[0071] Using 2-fluorobenzaldehyde substrate 1b and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0072]

[0073] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 2-fluorobenzaldehyde (15.3 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3b was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0074] The product testing data are as follows:

[0075] Colorless liquid, yield 86%.

[0076] 1 H NMR (400MHz, CDCl3) δ7.65-7.61(m,1H),7.47-7.41(m,1H),7.37-7.32(m,2H),7.27-7.23(m,1 H),7.19-7.14(m,1H),7.10(d,J=8.4Hz,2H),7.01(t,J=6.2Hz,1H),6.02(s,1H),2.78(s,3H).

[0077] 13 C NMR(100MHz,CDCl3)δ160.6(d,J cf =250.0Hz),148.9,131.4(d,J cf =8.0Hz),129.9(d,J cf =8.0Hz),129.4,124.3(d,J cf =16.0Hz),121.8,121.0,127.7(d,J cf =14.0Hz),117.7,116.2(d,J cf =20.0Hz),115.3,54.4,34.2.

[0078] 19 F NMR (377MHz, CDCl3) δ-116.1.

[0079] HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 14FN2282.0793, Found 282.0799.

[0080] Implementation Case 5

[0081] Using 2-bromobenzaldehyde substrate 1c and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0082]

[0083] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 2-bromobenzaldehyde (22.2 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3c was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0084] The product testing data are as follows:

[0085] White solid, yield 93%, melting point 85-87℃.

[0086] 1 H NMR (400MHz, CDCl3) δ7.73(d,J=7.6Hz,1H),7.68(d,J=7.6Hz,1H),7.44(t,J=7.6Hz,1H), 7.37-7.32(m,3H),7.13(d,J=7.6Hz,2H),7.01(t,J=7.2Hz,1H),5.98(s,1H),2.74(s,3H).

[0087] 13 C NMR (100MHz, CDCl3) δ148.7,134.0,132.4,130.9,130.6,129.4,127.7,124.2,121.5,117.1,115.9,58.7,34.4.

[0088] HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 14BrN2301.0335,303.0314,Found301.0343,303.0323.

[0089] Implementation Case 6

[0090] Using 2-methylbenzaldehyde substrate 1d and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0091]

[0092] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 2-methylbenzaldehyde (14.4 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3d was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0093] The product testing data are as follows:

[0094] White solid, yield 68%, melting point 106-108℃.

[0095] 1 H NMR (400MHz, CDCl3) δ7.69 (d, J = 7.4 Hz, 1H), 7.38-7.24 (m, 5H), 7.07 (d, J = 8.8 Hz, 2H), 6.99 (t, J = 8.0 Hz, 1H), 5.85 (s, 1H), 2.69 (s, 3H), 2.33 (s, 3H).

[0096] 13 C NMR (100MHz, CDCl3) δ148.8,137.1,131.3,131.1,129.5,129.4,128.8,126.3,121.1,116.4,116.4,56.4,34.1,19.0.

[0097] HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 17 N2237.1386,Found 237.1393.

[0098] Implementation Case 7

[0099] Using 2-methoxybenzaldehyde substrate 1e and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0100]

[0101] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 2-methoxybenzaldehyde (16.3 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3e was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0102] The product testing data are as follows:

[0103] White solid, yield 91%, melting point 114-115℃.

[0104] 1 H NMR (400MHz, CDCl3) δ7.58(d,J=7.6Hz,1H),7.43(t,J=7.8Hz,1H),7.35(t,J=8.0Hz,1H),7.13(d ,J=8.0Hz,2H),7.06(t,J=7.6Hz,1H),7.00-6.97(m,2H),6.13(s,1H),3.88(s,3H),2.79(s,3H).

[0105] 13 C NMR (100MHz, CDCl3) δ157.0,149.4,130.8,129.5,129.2,121.6,121.0,120.5,117.1,116.3,111.2,55.7,54.6,33.7.

[0106] HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 17 N2O 253.1335, Found 253.1342.

[0107] Implementation Case 8

[0108] Using 3-fluorobenzaldehyde substrate 1f and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0109]

[0110] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 3-fluorobenzaldehyde (15.3 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120 °C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3f was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0111] The product testing data are as follows:

[0112] White solid, yield 56%, melting point 58-60℃.

[0113] 1 H NMR (400MHz, CDCl3) δ7.46-7.26(m,5H),7.14-7.10(m,1H),7.05-6.99(m,3H),5.83(s,1H),2.78(s,3H).

[0114] 13 C NMR(100MHz,CDCl3)δ163.1(d,J cf =246.0Hz),148.9,136.1(d,J cf =7.0Hz),130.7(d,J cf =8.0Hz),129.5,122.7(d,J cf =8.0Hz),121.5,116.9,116.2(d,J cf =21.0Hz),115.7,114.3(d,J cf =24.0Hz),58.4,34.8.

[0115] 19 F NMR (377MHz, CDCl3) δ-111.3.

[0116] HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 14 FN2241.1136, Found 241.1143.

[0117] Implementation Case 9

[0118] Take 3-chlorobenzaldehyde substrate 1g and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0119]

[0120]

[0121] Add N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 3-chlorobenzaldehyde (16.9 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) in the sealed tube, add a magnetic stirrer, 1 ml of distilled water to disperse the reactants evenly, stir in a 120 ° C oil bath until the reaction is completed, and use TLC to monitor whether the reaction is complete. After the reaction is completed, the system is cooled to room temperature, and a saturated sodium bicarbonate solution is slowly added until no bubbles are generated. The aqueous phase is extracted three times with ethyl acetate, and the organic phases are combined and washed with saturated brine. The organic phase is dried over anhydrous sodium sulfate and concentrated in vacuo. 3 g is separated and purified by silica gel flash column chromatography (EA: PE = 1: 100).

[0122] The product testing data are as follows:

[0123] Pale yellow solid, yield 63%, melting point 40-42°C.

[0124] 1 H NMR (400MHz, CDCl3) δ7.59-7.57(m,1H),7.49-7.45(m,1H),7.42-7.33(m,4H),7.05-6.99(m,3H),5.81(s,1H),2.77(s,3H).

[0125] 13 C NMR (100MHz, CDCl3) δ148.9,135.6,135.2,130.3,129.6,129.4,127.3,125.3,121.3,116.9,115.6,58.4,34.8.

[0126] HRMS(ESI)m / z:[M+H] + Calcd for C15 H 14 ClN2257.0840,Found 257.0847.

[0127] Implementation Case 10

[0128] Using 3-bromobenzaldehyde substrate 1h and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0129]

[0130] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 3-bromobenzaldehyde (22.2 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to evenly disperse the reactants. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3h was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0131] The product testing data are as follows:

[0132] Pale yellow liquid, yield 79%.

[0133] 1 H NMR (400MHz, CDCl3) δ7.74(s,1H),7.57-7.51(m,2H),7.38-7.31(m,3H),7.06-7.00(m,3H),5.81(s,1H),2.77(s,3H).

[0134] 13 C NMR (100MHz, CDCl3) δ148.9,135.8,132.3,130.6,130.1,129.5,125.8,123.2,121.6,116.9,115.5,58.3,34.8.

[0135] HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 14 BrN2301.0335,303.0314,Found301.0344,303.0323. Implementation Case 11

[0136] Using 3-methylbenzaldehyde substrate 1i and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0137]

[0138] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 3-methylbenzaldehyde (14.4 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3i was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0139] The product testing data are as follows:

[0140] Pale yellow liquid, yield 79%.

[0141] 1 H NMR (400MHz, CDCl3) δ7.38-7.31(m,5H),7.23(d,J=8.0Hz,1H),7.05(d,J=8.0Hz,2H),6.99(t,J=8.0Hz,1H),5.84(s,1H),2.76(s,3H),2.41(s,3H).

[0142] 13 C NMR (100MHz, CDCl3) δ149.1,138.9,133.3,129.8,129.5,128.9,127.8,124.2,121.1,116.6,116.2,58.5,34.5,21.4.

[0143] HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 17 N2237.1386,Found 237.1393.

[0144] Implementation Case 12

[0145] Using 3-methoxybenzaldehyde substrate 1j and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0146]

[0147] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 3-methoxybenzaldehyde (16.3 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3j was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0148] The product testing data are as follows:

[0149] Pale yellow liquid, yield 57%.

[0150] 1 H NMR (400MHz, CDCl3) δ7.38-7.33(m,3H),7.16(d,J=8.0Hz,1H),7.10(s,1H),7.04(d,J=8.4H z, 2H), 6.99 (t, J = 7.4Hz, 1H), 6.94 (dd, J = 8.4Hz, 1H), 5.84 (s, 1H), 3.83 (s, 3H), 2.77 (s, 3H).

[0151] 13 C NMR (100MHz, CDCl3) δ160.2,149.1,134.9,130.1,129.5,121.1,119.3,116.6,116.1,114.6,112.7,58.5,55.4,34.6.

[0152] HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 17 N2O 253.1335, Found 253.1342.

[0153] Example 13 Using 4-chlorobenzaldehyde substrate 1k and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0154]

[0155] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 4-chlorobenzaldehyde (16.9 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3k was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0156] The product testing data are as follows:

[0157] White solid, yield 79%, melting point 90-92℃.

[0158] 1 H NMR (400MHz, CDCl3) δ7.52-7.50(m,2H),7.44-7.41(m,2H),7.37-7.32(m,2H),7.05-6.99(m,3H),5.80(s,1H),2.75(s,3H).

[0159] 13 C NMR (100MHz, CDCl3) δ148.9,135.1,132.0,129.5,129.3,128.5,121.5,117.0,115.8,58.3,34.8.

[0160] HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 14 ClN2257.0840,Found 257.0847.

[0161] Example 14 Using 4-iodobenzaldehyde substrate 11 and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0162]

[0163] Add N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 4-iodobenzaldehyde (27.8 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) in a sealed tube, add a magnetic stirrer, and 1 ml of distilled water to disperse the reactants evenly. Stir in a 120°C oil bath until the reaction is complete. Use TLC to monitor whether the reaction is complete. After the reaction is completed, cool the system to room temperature, slowly add a saturated sodium bicarbonate solution until no bubbles are generated, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and then wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate in vacuo. Separate and purify 3l by silica gel flash column chromatography (EA:PE=1:100).

[0164] The product testing data are as follows:

[0165] White solid, yield 80%, melting point 102-104°C.

[0166] 1 H NMR (400MHz, CDCl3) δ7.80-7.77(m,2H),7.37-7.30(m,4H),7.04-6.99(m,3H),5.77(s,1H),2.75(s,3H).

[0167] 13 C NMR (100MHz, CDCl3) δ148.9,138.2,133.2,129.5,129.0,121.5,116.9,115.7,94.9,58.4,34.8.

[0168] HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 14 IN2349.0196,Found 349.0207.

[0169] Example 15 Using 4-trifluoromethylbenzaldehyde substrate 1m and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0170]

[0171] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 4-trifluoromethylbenzaldehyde (20.9 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to evenly disperse the reactants. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3m was separated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0172] The product testing data are as follows:

[0173] White solid, yield 58%, melting point 69-70℃.

[0174] 1 H NMR (400MHz, CDCl3) δ7.72(s,4H),7.38-7.34(m,2H),7.06-7.01(m,3H),5.87(s,1H),2.77(s,3H).

[0175] 13 C NMR(100MHz,CDCl3)δ148.8,137.5,131.5(q,J cf =33.0Hz),129.6,127.6,126.1(q,J cf =3.5Hz),123.7(d,J cf =271.0Hz),121.7,117.0,115.5,58.6,35.0.

[0176] 19 F NMR (377 MHz, CDCl3) δ -62.7.

[0177] HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 14 F3N2291.1104, Found 291.1110.

[0178] Example 16 Using 4-methylbenzaldehyde substrate 1n and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0179]

[0180] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 4-methylbenzaldehyde (14.4 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to evenly disperse the reactants. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3n was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0181] The product testing data are as follows:

[0182] White solid, yield 70%, melting point 92-93°C.

[0183] 1 H NMR(400MHz, CDCl3)δ7.58(d,J=8.0Hz,2H),7.50-7.46(m,2H),7.38(d,J=8.0Hz,2H) ,7.17(d,J=7.6Hz,2H),7.12(t,J=7.4Hz,2H),5.96(s,1H),2.88(s,3H),2.53(s,3H).

[0184] 13 C NMR (100MHz, CDCl3) δ149.1,139.0,130.4,129.7,129.5,127.1,121.0,116.7,116.3,58.3,34.4,21.1.

[0185] HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 17 N2237.1386, Found 237.1386.

[0186] Implementation Case 17

[0187] Using 4-phenylbenzaldehyde substrate 1o and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0188]

[0189] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 4-phenylbenzaldehyde (21.9 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3o was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0190] The product testing data are as follows:

[0191] White solid, yield 85%, melting point 97-98℃.

[0192] 1 H NMR (400MHz, CDCl3) δ7.69-7.61(m,6H),7.47(t,J=7.4Hz,2H),7.41-7.34(m ,3H),7.08(d,J=8.0Hz,2H),7.01(t,J=7.4Hz,1H),5.91(s,1H),2.80(s,3H).

[0193] 13 C NMR (100MHz, CDCl3) δ149.1,142.1,140.1,132.3,129.5,128.9,127.8,127.7,127.6,127.1,121.2,116.8,116.2,58.4,34.6.

[0194] HRMS(ESI)m / z:[M+H] + Calcd for C 21 H 19 N2299.1543,Found 299.1548.

[0195] Implementation Case 18

[0196] Using 4-methoxybenzaldehyde substrate 1p and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0197]

[0198] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 4-methoxybenzaldehyde (16.3 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3p was separated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0199] The product testing data are as follows:

[0200] White solid, yield 95%, melting point 65-67℃.

[0201] 1 H NMR (400MHz, CDCl3) δ7.46 (d, J = 8.4 Hz, 2H), 7.36-7.32 (m, 2H), 7.04 (d, J = 8.0 Hz, 2H), 7.00-6.93 (m, 3H), 5.80 (s, 1H), 3.84 (s, 3H), 2.74 (s, 3H).

[0202] 13 C NMR (100MHz, CDCl3) δ160.1,149.1,129.5,128.5,125.3,121.1,116.8,116.4,114.3,58.1,55.4,34.4.

[0203] HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 17 N2O 253.1335, Found 253.1342.

[0204] Example 19 Using 4-dimethylaminobenzaldehyde substrate 1q and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0205]

[0206] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 4-dimethylaminobenzaldehyde (17.9 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3q was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0207] The product testing data are as follows:

[0208] Yellow liquid, yield 65%.

[0209] 1 H NMR (400MHz, CDCl3) δ7.37-7.31(m,4H),7.05-7.03(m,2H),6.98-6.94(m,1H),6.76-6.72(m,2H),5.79(s,1H),2.99(s,6H),2.73(s,3H).

[0210] 13 C NMR (100MHz, CDCl3) δ150.8,149.3,129.4,128.2,120.8,120.3,116.7,116.6,112.3,57.9,40.4,34.1.

[0211] HRMS(ESI)m / z:[M+H] + Calcd for C 17 H 20 N3266.1652, Found 266.1658.

[0212] Example 20 Using 2-bromo-4-methylbenzaldehyde substrate 1r and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0213]

[0214] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 2-bromo-4-methylbenzaldehyde (23.9 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to evenly disperse the reactants. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3r was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0215] The product testing data are as follows:

[0216] Yellow solid, yield 60%, melting point 117-118°C.

[0217] 1 H NMR (400MHz, CDCl3) δ7.60(d,J=7.6Hz,1H),7.50(s,1H),7.37-7.32(m,2H),7.22(d,J=8.0H z, 1H), 7.13 (d, J = 8.0Hz, 2H), 6.99 (t, J = 7.4Hz, 1H), 5.94 (s, 1H), 2.72 (s, 3H), 2.38 (s, 3H).

[0218] 13 C NMR (100MHz, CDCl3) δ148.8,141.5,134.4,130.4,129.3,128.4,123.9,121.4,117.1,116.1,58.5,34.2,20.8.

[0219] HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 16 BrN2315.0491,317.0471,Found315.0499,317.0478.

[0220] Implementation Case 21

[0221] Using 2,3-dichlorobenzaldehyde substrate 1s and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0222]

[0223] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 2,3-dichlorobenzaldehyde (21.0 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3s was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0224] The product testing data are as follows:

[0225] Yellow liquid, yield 67%.

[0226] 1 H NMR (400MHz, CDCl3) δ7.64(d,J=7.6Hz,1H),7.58(d,J=8.1Hz,1H),7.38-7.32( m, 3H), 7.10 (d, J = 8.0Hz, 2H), 7.02 (t, J = 7.3Hz, 1H), 6.02 (s, 1H), 2.76 (s, 3H).

[0227] 13 C NMR (100MHz, CDCl3) δ148.6,134.5,133.1,132.7,131.6,129.5,128.5,127.4,121.8,117.2,115.5,57.4,34.7.

[0228] HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 13 Cl2N2291.0450,Found 291.0459.

[0229] Implementation Case 22

[0230] Using 5-bromo-2-methoxybenzaldehyde substrate 1t and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0231]

[0232] Add N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 5-bromo-2-methoxybenzaldehyde (25.8 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) in a sealed tube, add a magnetic stirrer, and 1 ml of distilled water to disperse the reactants evenly. Stir in a 120°C oil bath until the reaction is complete. Use TLC to monitor whether the reaction is complete. After the reaction is completed, cool the system to room temperature, slowly add saturated sodium bicarbonate solution until no bubbles are generated, extract the aqueous phase three times with ethyl acetate, combine the organic phases, and then wash with saturated brine. Dry the organic phase with anhydrous sodium sulfate and concentrate in vacuo. Purify 3t by silica gel flash column chromatography (EA:PE=1:100).

[0233] The product testing data are as follows:

[0234] White solid, yield 77%, melting point 119-121°C.

[0235] 1 H NMR (400MHz, CDCl3) δ7.65 (d, J=2.4Hz, 1H), 7.51 (dd, J1=8.8Hz, J2=2.4Hz, 1H), 7.35-7.30 (m, 2H), 7.0 7(d,J=8.0Hz,2H),6.98(t,J=8.2Hz,1H),6.85(d,J=8.8Hz,1H),6.02(s,1H),3.85(s,3H),2.80(s,3H).

[0236] 13 C NMR (100MHz, CDCl3) δ156.1,149.1,133.5,132.0,129.3,123.8,121.2,117.1,115.7,113.0,112.8,56.1,54.3,34.0.

[0237] HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 16 BrN2O 331.0441,333.0420,Found331.0450,333.0428.

[0238] Implementation Case 23

[0239] Using 2-bromo-5-methoxybenzaldehyde substrate 1u and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0240]

[0241] Add N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 2-bromo-5-methoxybenzaldehyde (25.8 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) in the sealed tube, add a magnetic stirrer, 1 ml of distilled water to disperse the reactants evenly, stir in a 120 ° C oil bath until the reaction is completed, and use TLC to monitor whether the reaction is complete. After the reaction is completed, the system is cooled to room temperature, and a saturated sodium bicarbonate solution is slowly added until no bubbles are generated. The aqueous phase is extracted three times with ethyl acetate, and the organic phases are combined and washed with saturated brine. The organic phase is dried over anhydrous sodium sulfate and concentrated in vacuo. 3u is separated and purified by silica gel flash column chromatography (EA: PE = 1: 100).

[0242] The product testing data are as follows:

[0243] White solid, yield 62%, melting point 103-105℃.

[0244] 1 H NMR (400MHz, CDCl3) δ7.66 (d, J=2.4Hz, 1H), 7.51 (dd, J1=8.8Hz, J2=2.4Hz, 1H), 7.35-7.30 (m, 2H), 7.07 (d,J=10.8Hz,2H),6.98(t,J=8.0Hz,1H),6.85(d,J=8.8Hz,1H),6.03(s,1H),3.85(s,3H),2.80(s,3H).

[0245] 13 C NMR (100MHz, CDCl3) δ156.1,149.1,133.4,131.9,129.3,123.8,121.2,117.1,115.7,113.0,112.8,56.0,54.3,34.0.

[0246] HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 16 BrN2O[M+H] + :331.0441,333.0420,Found331.0448,333.0429.

[0247] Implementation Case 24 Using 2-naphthylbenzaldehyde substrate 1v and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0248]

[0249] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), 2-naphthylbenzaldehyde (18.7 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3v was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0250] The product testing data are as follows:

[0251] White solid, yield 96%, melting point 137-138°C.

[0252] 1 H NMR(400MHz, CDCl3)δ8.10(s,1H),7.92-7.87(m,3H),7.59-7.54(m,3H),7.39-7 .35(m,2H),7.10(d,J=8.0Hz,2H),7.00-6.99(m,1H),6.01(s,1H),2.78(s,3H).

[0253] 13 C NMR (100MHz, CDCl3) δ149.2,133.4,133.0,130.8,129.5,129.2,128.2,127.7,127.0,126.9,126.6,124.3,121.2,116.8,116.2,58.8,34.6.

[0254] HRMS(ESI)m / z:[M+H] + Calcd for C 19 H 17 N2273.1392, Found 273.1395.

[0255] Example 25 Using furan-2-carboxaldehyde substrate 1w and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0256]

[0257] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), furan-2-carboxaldehyde (11.5 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3w was separated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0258] The product testing data are as follows:

[0259] Colorless liquid, yield 80%.

[0260] 1 H NMR (400MHz, CDCl3) δ7.48 (d, J = 1.2Hz, 1H), 7.36-7.31 (m, 2H), 7.04-6.97 ( m, 3H), 6.10 (d, J = 3.2Hz, 1H), 6.43-6.42 (m, 1H), 5.78 (s, 1H), 2.84 (s, 3H).

[0261] 13 C NMR (100MHz, CDCl3) δ148.4,146.3,144.0,129.4,121.6,117.2,114.8,110.7,110.7,53.1,34.8.

[0262] HRMS(ESI)m / z:[M+H] + Calcd for C 13 H 13 N2O 213.1022, Found 213.1024.

[0263] Implementation Case 26

[0264] Using thiophene-2-carboxaldehyde substrate 1x and N-phenyl-N-methylmalononitrile 2a as raw materials:

[0265]

[0266] N-phenyl-N-methylmalononitrile (41.1 mg, 0.24 mmol, 2.0 equiv.), thiophene-2-carboxaldehyde (13.4 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3x was separated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0267] The product testing data are as follows:

[0268] Yellow solid, yield 82%, melting point 62-64°C.

[0269] 1 H NMR (400MHz, CDCl3) δ7.39-7.31(m,4H),7.07-7.00(m,4H),5.92(s,1H),2.83(s,3H).

[0270] 13 C NMR (100MHz, CDCl3) δ148.7,137.5,129.5,127.4,127.3,126.9,121.9,117.5,115.6,55.3,34.8.

[0271] HRMS(ESI)m / z:[M+H] + Calcd for C 13 H 13 N2S229.0794,Found 229.0800.

[0272] Implementation Case 27

[0273] Using paraformaldehyde substrate 1y and N-(4-methylphenyl)-N-methylmalononitrile 2b as raw materials:

[0274]

[0275]

[0276] N-(4-methylphenyl)-N-methylmalononitrile (200.0 mg, 1.08 mmol, 9.0 equiv.), paraformaldehyde (10.8 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (63 μl, 1.08 mmol, 9.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 80 °C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3y was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0277] The product testing data are as follows:

[0278] Brown liquid, yield 88%.

[0279] 1 H NMR (400MHz, CDCl3) δ7.15-7.13(m,2H),6.83-6.79(m,2H),4.13(s,2H),2.97(s,3H),2.30(s,3H).

[0280] 13 C NMR (100MHz, CDCl3) δ145.7,130.0,129.9,115.6,115.5,77.5,77.1,76.8,42.8,39.5,20.4.

[0281] HRMS(ESI)m / z:[M+H] + Calcd for C 10 H 13 N2161.1074,Found 161.1075.

[0282] Implementation Case 28

[0283] Using acetaldehyde substrate 1z and N-(4-methylphenyl)-N-methylmalononitrile 2b as raw materials:

[0284]

[0285] N-(4-methylphenyl)-N-methylmalononitrile (66.7 mg, 0.36 mmol, 3.0 equiv.), acetaldehyde (5.3 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (21 μl, 0.36 mmol, 3.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to evenly disperse the reactants. The mixture was stirred in an oil bath at 80 °C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3z was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0286] The product testing data are as follows:

[0287] Yellow liquid, yield 32%.

[0288] 1 H NMR (400MHz, CDCl3) δ7.13 (d, J = 8.4Hz, 2H), 6.93-6.89 (m, 2H), 4.54 (q, J = 7.2Hz, 1H), 2.89 (s, 3H), 2.31 (s, 3H), 1.59 (d, J = 7.2Hz, 3H).

[0289] 13 C NMR (100MHz, CDCl3) δ146.7,131.0,129.8,118.4,117.9,77.3,77.0,76.7,49.8,34.7,20.4,17.8.

[0290] HRMS(ESI)m / z:[M+H] + Calcd for C 11 H 15 N2175.1230, found 175.1233.

[0291] Implementation Case 29

[0292] Using n-valeraldehyde substrate 1aa and N-(4-methylphenyl)-N-methylmalononitrile 2b as raw materials:

[0293]

[0294] N-(4-methylphenyl)-N-methylmalononitrile (66.7 mg, 0.36 mmol, 3.0 equiv.), n-valeraldehyde (10.3 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (21 μl, 0.36 mmol, 3.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 80 °C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3aa was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0295] The product testing data are as follows:

[0296] Yellow liquid, yield 43%.

[0297] 1 H NMR (400MHz, CDCl3) δ7.11 (d, J = 8.4Hz, 2H), 6.86 (d, J = 8.8Hz, 2H), 4.35 (t, J = 8.0Hz, 1H) ,2.85(s,3H),2.23(s,3H),1.93-1.87(m,2H),1.52-1.36(m,4H),0.94(t,J=9.6Hz,3H).

[0298] 13 C NMR (100MHz, CDCl3) δ147.3,130.7,129.9,118.1,117.6,77.3,77.0,76.7,55.0,34.7,31.5,27.9,22.1,20.5,13.8.

[0299] HRMS(ESI)m / z:[M+H] + Calcd for C 14 H 21 N2217.1700,Found 217.1699.

[0300] Implementation Case 30 Using 3,3-dimethylbutyraldehyde substrate 1ab and N-(4-methylphenyl)-N-methylmalononitrile 2b as raw materials:

[0301]

[0302] N-(4-methylphenyl)-N-methylmalononitrile (66.7 mg, 0.36 mmol, 3.0 equiv.), 3,3-dimethylbutyraldehyde (12.0 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (21 μl, 0.36 mmol, 3.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 80 °C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3ab was purified by silica gel flash column chromatography (EA:PE=1:100).

[0303] The product testing data are as follows:

[0304] Yellow liquid, yield 55%.

[0305] 1 H NMR (400MHz, CDCl3) δ7.12 (d, J = 8.0Hz, 2H), 6.90-6.87 (m, 2H), 4.46-4.43 (m, 1H ),3.77(s,3H),2.80(s,3H),1.91-1.80(m,2H),1.82-1.67(m,2H),1.03(s,9H).

[0306] 13 C NMR (100MHz, CDCl3) δ147.1,130.8,129.9,118.8,117.6,77.3,77.0,76.7,51.7,45.4,34.9,30.5,29.4,20.5.

[0307] HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 23 N2231.1856, Found 231.1851.

[0308] Implementation Case 31

[0309] Using cyclopentylcarboxaldehyde substrate 1ac and N-(4-methylphenyl)-N-methylmalononitrile 2b as raw materials:

[0310]

[0311] N-(4-methylphenyl)-N-methylmalononitrile (66.7 mg, 0.36 mmol, 3.0 equiv.), cyclopentylcarboxaldehyde (11.8 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (21 μl, 0.36 mmol, 3.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 80 °C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3ac was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0312] The product testing data are as follows:

[0313] Yellow liquid, yield 48%.

[0314] 1 H NMR (400MHz, CDCl3) δ7.10(d,J=8.4Hz,2H),6.86(d,J=8.8Hz,2H),4.03(d,J=8.0Hz,1H),2.86(s,3H),2. 53-1.43(m,1H),2.29(s,3H),2.05-1.95(m,1H),1.86-1.78(m,1H),1.75-1.56(m,4H),1.49-1.41(m,2H).

[0315] 13 C NMR (100MHz, CDCl3) δ147.5,130.5,129.8,118.0,117.4,77.3,77.0,76.7,60.1,41.4,34.8,30.3,29.6,25.2,25.0,20.4.

[0316] HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 21 N2229.1700,Found 229.1698.

[0317] Implementation Case 32

[0318] Cyclohexylcarboxaldehyde substrate 1ad and N-(4-methylphenyl)-N-methylmalononitrile 2b were used as raw materials:

[0319]

[0320] N-(4-methylphenyl)-N-methylmalononitrile (66.7 mg, 0.36 mmol, 3.0 equiv.), cyclohexylcarboxaldehyde (13.5 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (21 μl, 0.36 mmol, 3.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 80 °C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3ad was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0321] The product testing data are as follows:

[0322] Yellow liquid, yield 60%.

[0323] 1 H NMR (400MHz, CDCl3) δ7.14(d,J=8.0Hz,2H),7.00-6.87(m,2H),4.11(d,J=10.8Hz,1H),2.87(s,3H),2.3 3(s,3H),2.14-2.03(m,2H),1.97-1.75(m,4H),1.43-1.22(m,3H),1.20-1.09(m,1H),1.04-0.94(m,1H).

[0324] 13 C NMR (100MHz, CDCl3) δ147.5,129.7,129.7,117.1,116.7,77.3,77.0,76.7,60.8,38.7,34.3,30.1,29.4,26.0,25.4,25.3,20.3.

[0325] HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 23 N2243.1856, Found 243.1859.

[0326] Implementation Case 33

[0327] Using trans-cinnamaldehyde substrate 1ae and N-(4-methylphenyl)-N-methylmalononitrile 2b as raw materials:

[0328]

[0329] N-(4-methylphenyl)-N-methylmalononitrile (66.7 mg, 0.36 mmol, 3.0 equiv.), trans-cinnamaldehyde (15.9 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (21 μl, 0.36 mmol, 3.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 80 °C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3ae was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0330] The product testing data are as follows:

[0331] Yellow liquid, yield 44%.

[0332] 1 H NMR (400MHz, CDCl3) δ7.33-7.29(m,2H),7.24-7.20(m,3H),7.10(d,J=8.0Hz,2H),6.93( d,J=8.4Hz,2H),5.71(t,J=8.0Hz,1H),3.70(d,J=8.0Hz,2H),3.06(s,3H),2.27(s,3H).

[0333] 13 C NMR (100MHz, CDCl3) δ144.0,139.0,133.2,129.8,128.7,128.3,126.54,125.5,122.7,121.5,114.7,40.3,35.6,20.6.

[0334] HRMS(ESI)m / z:[M+H] + Calcd for C 18 H 19 N2263.1543,Found 263.1549.

[0335] Implementation Case 34

[0336] Using phenylpropanaldehyde substrate 1af and N-(4-methylphenyl)-N-methylmalononitrile 2b as raw materials:

[0337]

[0338] N-(4-methylphenyl)-N-methylmalononitrile (66.7 mg, 0.36 mmol, 3.0 equiv.), phenylpropanaldehyde (16.1 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (21 μl, 0.36 mmol, 3.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to evenly disperse the reactants. The mixture was stirred in an oil bath at 80 °C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3af was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0339] The product testing data are as follows:

[0340] Yellow liquid, yield 90%.

[0341] 1 H NMR (400MHz, CDCl3) δ7.32-7.29(m,2H),7.25-7.23(m,1H),7.20-7.18(m,2H),7.07(d,J=8.4Hz,2H),6. 79-6.75(m,2H),4.28(t,J=8.0Hz,1H),2.86(s,3H),2.83-2.80(m,2H),2.27(s,3H),2.24-2.18(m,2H).

[0342] 13 C NMR (100MHz, CDCl3) δ147.0,139.5,130.9,129.8,129.6,128.7,128.5,126.5,117.8,117.6,112.6,53.8,34.8,33.1,31.5,20.4.

[0343] HRMS(ESI)m / z:[M+H] + Calcd for C 18 H 21 N2265.1705,Found 265.1709.

[0344] Implementation Case 35

[0345] Using benzaldehyde substrate 1a and N-(4-methylphenyl)-N-methylmalononitrile 2b as raw materials:

[0346]

[0347] N-(4-methylphenyl)-N-methylmalononitrile (44.5 mg, 0.24 mmol, 2.0 equiv.), benzaldehyde (12.7 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to evenly disperse the reactants. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3ag was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0348] The product testing data are as follows:

[0349] Yellow liquid, yield 94%.

[0350] 1 H NMR (400MHz, CDCl3) δ7.59-7.57(m,2H),7.47-7.41(m,3H),7.15(d,J=8.4Hz,2H),6.99-6.96(m,2H),5.78(s,1H),2.71(s,3H),2.32(s,3H).

[0351] 13 C NMR (100MHz, CDCl3) δ147.0,133.5,131.0,130.0,129.0,129.0,127.0,117.4,116.1,59.4,34.8,20.5.

[0352] HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 17 N2237.1386,Found 237.1393.

[0353] Implementation Case 36

[0354] Using benzaldehyde substrate 1a and N-(4-chlorophenyl)-N-methylmalononitrile 2c as raw materials:

[0355]

[0356]

[0357] N-(4-chlorophenyl)-N-methylmalononitrile (49.4 mg, 0.24 mmol, 2.0 equiv.), benzaldehyde (12.7 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3ah was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0358] The product testing data are as follows:

[0359] Yellow liquid, yield 54%.

[0360] 1 H NMR (400MHz, CDCl3) δ7.55-7.53(m,2H),7.47-7.42(m,3H),7.31-7.27(m,2H),6.98-6.95(m,2H),5.79(s,1H),2.74(s,3H).

[0361] 13 C NMR (100MHz, CDCl3) δ147.6,133.0,129.4,129.2,129.1,127.1,126.3,118.1,115.9,58.7,34.9.

[0362] HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 14 ClN2257.0840,Found 257.0847.

[0363] Implementation Case 37

[0364] Using benzaldehyde substrate 1a and N-(4-methoxyphenyl)-N-methylmalononitrile 2d as raw materials:

[0365]

[0366] N-(4-methoxyphenyl)-N-methylmalononitrile (48.3 mg, 0.24 mmol, 2.0 equiv.), benzaldehyde (12.7 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3ai was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0367] The product testing data are as follows:

[0368] White solid, yield 77%, melting point 56-58°C.

[0369] 1 H NMR (400MHz, CDCl3) δ7.59-6.90(m,9H),5.61(s,1H),3.80(s,3H),2.68(s,3H).

[0370] 13 C NMR (100MHz, CDCl3) δ155.3,143.2,133.6,129.0,128.9,127.4,120.3,116.1,114.7,61.1,55.6,35.6.

[0371] HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 17 N2O 253.1341, Found 253.1344.

[0372] Implementation Case 38

[0373] Using 4-chlorobenzaldehyde substrate 1k and N-(4-methylphenyl)-N-methylmalononitrile 2b as raw materials:

[0374]

[0375] N-(4-methylphenyl)-N-methylmalononitrile (44.5 mg, 0.24 mmol, 2.0 equiv.), benzaldehyde (16.9 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3aj was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0376] The product testing data are as follows:

[0377] White solid, yield 84%, melting point 111-113°C.

[0378] 1 H NMR (400MHz, CDCl3) δ7.53-7.50(m,2H),7.43-7.40(m,2H),7.15(d,J=8.0Hz,2H),6.98-6.94(m,2H),5.70(s,1H),2.70(s,3H),2.32(s,3H).

[0379] 13 C NMR (100MHz, CDCl3) δ146.8,135.1,132.1,131.4,130.0,129.2,128.6,117.7,115.8,59.1,35.0,20.5.

[0380] HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 16 ClN2271.0997, Found 271.1005.

[0381] Implementation Case 39

[0382] Using isovaleraldehyde substrate 1ag and N-(4-methoxyphenyl)-N-methylmalononitrile 2d as raw materials:

[0383]

[0384] N-(4-methoxyphenyl)-N-methylmalononitrile (72.4 mg, 0.36 mmol, 3.0 equiv.), isovaleraldehyde (10.3 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (21 μl, 0.36 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3ak was isolated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0385] The product testing data are as follows:

[0386] Colorless liquid, yield 65%.

[0387] 1 H NMR (400MHz, CDCl3) δ7.02-7.00(m,2H),6.89-6.85(m,2H),4.27(t,J=8.0H z,1H),3.77(s,3H),2.80(s,3H),1.94-1.84(m,1H),0.99(d,J=6.4Hz,3H).

[0388] 13 C NMR (100MHz, CDCl3) δ155.0,143.3,120.5,117.9,114.3,77.3,77.0,76.7,55.2,54.6,40.2,35.7,24.4,22.1,21.9.

[0389] HRMS(ESI)m / z:[M+H] + Calcd for C 14 H 21 N2O 233.1649, Found 233.1653.

[0390] Embodiment 40 uses benzaldehyde substrate 1a and 2-(3,4-dihydroisoquinoline-2(1H)-yl)malononitrile 2e as raw materials:

[0391]

[0392] 2-(3,4-dihydroisoquinolin-2(1H)-yl)malononitrile (47.3 mg, 0.24 mmol, 2.0 equiv.), benzaldehyde (12.7 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3al was separated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0393] The product testing data are as follows:

[0394] White solid, yield 30%, melting point 84-85℃.

[0395] 1 H NMR (400MHz, CDCl3) δ7.63-7.61(m,2H),7.45-7.40(m,3H),7.16-7.11(m, 3H),7.01-6.99(m,1H),5.08(s,1H),3.83-3.75(m,2H),3.02-2.81(m,4H).

[0396] 13 C NMR (100MHz, CDCl3) δ133.7,133.6,133.0,129.0,128.8,128.7,127.8,126.6,126.4,125.8,115.3,62.3,52.4,47.5,29.3.

[0397] HRMS(ESI)m / z:[M+H] + Calcd for C 17 H 17 N2249.1392, Found 249.1398.

[0398] Implementation Case 41

[0399] Using 2-chlorobenzaldehyde substrate 1ah and 2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)malononitrile 2f as raw materials:

[0400]

[0401] 2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)malononitrile (48.8 mg, 0.24 mmol, 2.0 equiv.), benzaldehyde (16.7 mg, 0.12 mmol, 1.0 equiv.), glacial acetic acid (14 μl, 0.24 mmol, 2.0 equiv.) were added to the sealed tube in sequence, and a magnetic stirrer and 1 ml of distilled water were added to disperse the reactants evenly. The mixture was stirred in an oil bath at 120°C until the reaction was completed. TLC was used to monitor whether the reaction was complete. After the reaction was completed, the system was cooled to room temperature, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. 3am was separated and purified by silica gel flash column chromatography (EA:PE=1:100).

[0402] The product testing data are as follows:

[0403] White solid, yield 49%, melting point 124-126℃.

[0404] 1 H NMR (400MHz, CDCl3) δ7.72-7.68(m,1H),7.47-7.43(m,1H),7.39-7.35(m,2H),7.08(d,J =5.2Hz,1H),6.70(d,J=5.2Hz,1H),5.32(s,1H),3.79(d,J=13.6Hz,1H),3.66(d,J=14.0 Hz,1H),3.00-2.82(m,4H).

[0405] 13 C NMR (100 MHz, CDCl3) δ132.9,132.5,130.8,130.6,130.5,103.0,126.8,125.1,123.1,115.2,59.2,49.4,47.8,25.6.

[0406] HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 14 ClN2S 289.0566,Found 289.0571.

Claims

1. A method for synthesizing α-amino nitrile based on N,N-disubstituted aminomalononitrile, characterized in that formanilide is used as an initial substrate, and N,N-disubstituted aminomalononitrile substrate 2 is synthesized by conventional transformation within 2 steps, acetic acid is used as an activator, water is used as a solvent, and aldehyde 1 is reacted at 120°C to obtain α-amino nitrile 3, and the reaction formula is as follows: in: R 1 R is selected from hydrogen, methyl, ethyl, butyl, tert-butylmethylene, isopropylmethylene, cyclopentyl, cyclohexyl, styryl, phenethyl, phenyl, 2-methylphenyl, 2-bromophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-bromophenyl, 3-chlorophenyl, 3-fluorophenyl, 4-methylphenyl, 4-chlorophenyl, 4-iodophenyl, 4-biphenyl, 4-trifluoromethylphenyl, 4-(N,N-dimethyl)phenyl, 2-bromo-4-methylphenyl, 2-bromo-5-methoxyphenyl, 5-bromo-2-methoxyphenyl, 2,3-dichlorophenyl, naphthyl, thiophene, furan; 2 is selected from methyl, chloro, methoxy; Ar is selected from phenyl, thiophene.

2. A method for synthesizing α-amino nitrile based on N,N-disubstituted aminomalononitrile according to claim 1, characterized in that: The acid used is selected from acetic acid, citric acid, formic acid, methanesulfonic acid, camphorsulfonic acid, phosphoric acid, benzoic acid, p-toluenesulfonic acid, benzenesulfonic acid, phthalic acid, disodium hydrogen phosphate, dipotassium hydrogen phosphate, propionic acid, preferably acetic acid.

3. A method for synthesizing α-amino nitrile based on N,N-disubstituted aminomalononitrile according to claim 1, characterized in that: The solvent used is selected from toluene, tetrahydrofuran, chlorobenzene, DMF, acetonitrile, methanol, n-hexane, dibromomethane, carbon tetrachloride, chloroform, DCE, dichloromethane, ethyl acetate, trimethyl orthoformate, triethyl orthoformate, water and a mixed solvent of the above-mentioned organic solvent and water in any proportion, preferably water.

4. A method for synthesizing α-amino nitrile based on N,N-disubstituted aminomalononitrile according to claim 1, characterized in that: The reaction temperature used is selected from 60-140°C, preferably 120°C and 80°C.

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