CN102964195B - Method for preparing second-level and third-level substituted amide - Google Patents

Abstract

The invention provides a method for preparing secondary and tertiary substituted amides, using a base catalyst to catalyze the reaction of nitriles and amines under air or inert gas conditions, the reaction temperature is 100-200°C, and the reaction time is 24-24°C. 72 hours, the mol ratio of raw material nitrile and raw material amine is 3～1:1～3; The raw material amine is primary amine or secondary amine; The solvent of reaction is water or ammoniacal liquor; Described alkali catalyst is LiOH, NaOH, KOH, CsOH, t-BuOK, t-BuONa, Mg(OH) ₂ or Ca(OH) ₂ . The alkali catalyst used in the present invention can be purchased directly, the catalyst is cheap, easy to get, stable, not afraid of water or oxygen, low toxicity, good water solubility, and low consumption, can be easily dissolved in water and removed after the reaction, in addition The reaction conditions are equivalent to the metal catalyzed method, easy to operate, no organic solvent is needed for the reaction, and the greenest water is used as the solvent, so this method can also greatly reduce the possible pollution of the environment caused by the organic solvent.

Description

A method for preparing secondary and tertiary substituted amides

technical field

The invention belongs to the field of chemical synthesis, in particular to a method for preparing secondary and tertiary substituted amides.

Background technique

The amide bond or amide functional group is one of the most important functional groups in life chemistry and synthetic chemistry. Amide compounds are important organic synthesis reagents and synthetic intermediates widely used in many fields such as drug synthesis and material research and development. Since amide bonds are ubiquitous in bioactive compounds, improving amide synthesis methods or amide bond formation methods to overcome the shortcomings of traditional methods has become the hottest research field and the most important research goal in the pharmaceutical synthesis industry. Therefore, the research on the synthesis method of substituted amides has received special attention in recent years, and a series of catalytic methods have been reported using various raw materials to synthesize amides to replace the past reactions using coupling reagents, dehydrating reagents, or activation. substances such as acid chlorides. At the same time, many top international journals such as Nature, Chem.Soc.Rev., etc. have recently reviewed the synthesis methods of amides, and have also made certain prospects for the synthesis of amides.

Although the hydrolysis of nitrile compounds is a direct, economical and convenient method for preparing unsubstituted amides, and there are many reports in the literature, the use of nitriles as stable and easily available raw materials is used to synthesize secondary and tertiary compounds containing substituents. There are still very few methods for grade amides. Similar to the hydrolysis reaction of nitriles, the known methods of reacting nitriles with amines to synthesize substituted amides mostly use catalysts of noble metals such as platinum (Pt), ruthenium (Ru) or cerium (Ce), but these reactions still require high temperature (above 160°C), some also require a large excess of one of the reactants (greater than 2 equivalents). Although the method of noble metal catalysis has been improved compared with the traditional method, the method of using precious metal catalysts that are not easy to obtain, difficult to synthesize, unstable, highly toxic, have heavy metal residues, and excessive reactants obviously still has many shortcomings, especially not applicable for the synthesis of pharmaceuticals and bioactive compounds. A recent report of a cheap metal iron (Fe) catalyzed method, but the method needs to use 10mol% ferric nitrate nonahydrate [Fe(NO ₃ ) ₃ 9H ₂ O], 8 equivalents of nitrile or 6-8 equivalents of amine Effective reaction, so in fact the amount of catalyst used is large and the utilization rate of raw materials is very low. In addition, there is a case of zinc (Zn) catalysis reported to improve the Fe-catalyzed method, but this method needs to use 10 mol% Lewis acid Zn(OTf) ₂ as catalyst, 10 mol% hydroxylamine hydrochloride (NH ₂ OH·HCl) as cocatalyst, and 2 equivalents of starting nitrile. Obviously, Zn(OTf) ₂ , which is difficult to obtain and easily hydrolyzed, is relatively expensive, and the catalyst system is also relatively complicated. In addition, excessive nitrile needs to be used, which also leads to very limited application potential of this method.

Therefore, the synthesis of secondary and tertiary substituted amides by catalyzing the reaction of nitriles with amines using low-toxicity, non-toxic catalysts or even without the participation of transition metals is worth studying.

Contents of the invention

The present invention aims at the deficiencies of the above-mentioned prior art, and provides a method for preparing secondary and tertiary substituted amides with little environmental pollution and high efficiency.

The present invention is achieved through the following technical solutions:

A method for preparing secondary and tertiary substituted amides, using a base catalyst to catalyze the reaction of nitriles and amines under air or inert gas conditions, the reaction temperature is 100-200 ° C, the reaction time is 24-72 hours, the reaction The formula is:

in:

The molar ratio of the raw material nitrile to the raw material amine is 3~1:1~3; the raw material amine is primary or secondary amine;

R ¹ is various functional groups substituted in 2-, 3-, or 4-phenyl or various substituted aryl groups, substituted furan, substituted thiophene, substituted pyridine and other substituted heteroaryl groups, or various carbon chain lengths and branched chain substituted alkyl groups;

R ² and R ³ are benzyl, heterobenzyl substituted by hydrogen or various functional groups, or various substituted, various carbon chain lengths and branched chain substituted alkyl, cycloalkyl;

The solvent of reaction is water or ammoniacal liquor;

The base catalyst is LiOH, NaOH, KOH, CsOH, t-BuOK, t-BuONa, Mg(OH) ₂ or Ca(OH) ₂ .

Preferably, the base catalyst is CsOH.

Preferably, the amount of the base catalyst is 1-200mol%.

Preferably, the amount of the base catalyst is 10-20mol%.

Preferably, the inert gas is nitrogen.

Preferably, the reaction temperature is 160°C.

Preferably, the reaction time is 48 hours.

Preferably, the solvent for the reaction is water.

The present invention starts from cheap, stable and easy-to-obtain nitriles and amines, and uses a suitable catalyst to carry out the reaction of nitriles and amines without the participation of a transition metal catalyst, thereby realizing a low-environmental pollution and high-efficiency secondary And a new method for the synthesis of tertiary substituted amides.

The base catalyst used in the present invention can be purchased directly. Compared with other methods reported in the literature, this method has a catalyst that is cheap, easy to get, stable, not afraid of water or oxygen, low toxicity, good water solubility, and low dosage, and can be easily dissolved in water and removed after the reaction. The conditions are equivalent to those of the metal-catalyzed method, and it is easy to operate. The reaction does not require an organic solvent, and the greenest water is used as a solvent. Therefore, this method can also greatly reduce the possible pollution of the environment caused by the organic solvent. All in all, this method does not require high reaction conditions and has a good application prospect.

Detailed ways

The following embodiments will help to understand the present invention, but are not limited to the content of the present invention.

Example 1:

Preparation of N-Benzylbenzamide by Reaction of Benzonitrile and Benzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), PhCN (2mmol), benzylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen protection, seal and heat Reaction at 160°C for 48h. The conversion rate of the reaction was determined to be 99% by GC-MS. The product was separated and purified by column chromatography, and the separation yield was 58%. ¹ H NMR (500MHz, d ₆ -DMSO): δ9.05(t, J=6.0Hz, 1H), 7.91(d, J=7.5Hz, 2H), 7.56-7.53(m, 1H), 7.50-7.47 (m, 2H), 7.34-33 (m, 4H), 7.27-7.24 (m, 1H), 4.50 (d, J=6.0Hz, 2H). ¹³ C NMR (125.4MHz, d ₆ -DMSO): δ166 .2, 139.7, 134.3, 131.2, 128.28, 128.24, 127.20, 127.17, 126.7, 42.6. MS(EI): m/z(%) 212(13), 211(82), 210(25), 107(3 ), 106(9), 105(100), 104(4), 91(9), 79(4), 78(5), 77(42), 76(2), 65(4), 51(11 ), 50(3).

Example 2:

Preparation of N-benzyl p-methylbenzamide by the reaction of p-methylbenzonitrile and benzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), p-toluonitrile (2mmol), benzylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen After protection, seal and heat to 160°C for 48h. The conversion rate of the reaction was 83% as measured by GC-MS. The product was separated and purified by column chromatography, and the separation yield was 50%. ¹ H NMR (500MHz, d ₆ -DMSO): δ7.68(d, J=8.0Hz, 2H), 7.36-7.34(m, 4H), 7.31-7.28(m, 1H), 7.22(d, J= 8.0Hz, 2H), 6.40(b, 1H), 4.64(d, J=6.0Hz, 2H), 2.39(s, 3H). ¹³ C NMR (125.4MHz, d ₆ -DMSO): δ167.3, 141.9 , 138.3, 131.6, 129.3, 128.8, 127.9, 127.6, 127.0, 44.1, 21.4. MS(EI): m/z(%) 226(6), 225(41), 120(7), 119(100), 107(2), 92(2), 91(28), 89(2), 77(2), 65(6).

Example 3:

Preparation of N-benzyl m-methylbenzamide by the reaction of m-methylbenzonitrile and benzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), m-toluonitrile (2mmol), benzylamine (2mmol, 1equiv.) to the reaction tube in turn, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen After protection, seal and heat to 160°C for 48h. GC-MS showed that the reaction conversion rate was 75%. The product was separated and purified by column chromatography, and the separation yield was 60%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.61(s, 1H), 7.56-7.54(m, 1H), 7.35-7.33(m, 4H), 7.29-7.27(m, 3H), 6.47(b, 1H), 4.62(d, J=5.5Hz, 2H), 2.37(s, 3H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ167.5, 138.4, 138.3, 134.4, 132.2, 128.7, 128.4, 127.9 , 127.7, 127.6, 123.9, 44.1, 21.3. MS (EI): m/z (%) 226 (8), 225 (50), 107 (2), 106 (3), 104 (2), 92 (20 ), 91(100), 89(3), 77(4), 65(15), 63(3), 51(5), 50(3), 43(2), 41(2).

Example 4:

Preparation of N-benzyl-3-chlorobenzamide by the reaction of m-chlorobenzonitrile and benzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), m-chlorobenzonitrile (2mmol), benzylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen gas protection Back sealing is heated to 160 DEG C and reacts 48h. GC-MS showed that the reaction conversion rate was 80%. The product was separated and purified by column chromatography, and the separation yield was 70%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.77(t, J=2.0Hz, 1H), 7.65(d, J=7.5Hz, 1H), 7.47-7.45(m, 1H), 7.37-7.33(m , 5H), 7.32-7.29 (m, 1H), 6.42 (b, 1H), 4.63 (d, J=6.0Hz, 2H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ166.0, 137.9, 136.2 , 134.8, 131.6, 129.9, 128.9, 128.0, 127.8, 127.4, 125.0, 44.3. MS(EI): m/z(%) 248(2), 247(12), 246(6), 245(37), 210(4), 142(2), 141(34), 140(7), 139(100), 113(6), 111(17), 107(2), 77(3), 75(4).

Example 5:

Preparation of N-benzyl p-bromobenzamide by reaction of p-bromoxynil and benzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), p-bromoxynil (2mmol), benzylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen gas protection Back sealing is heated to 160 DEG C and reacts 48h. The conversion rate of the reaction was 98% as measured by GC-MS. The product was separated and purified by column chromatography, and the separation yield was 65%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.65(d, J=8.5Hz, 2H), 7.56(d, J=8.5Hz, 2H), 7.37-7.29(m, 5H), 6.37(b, 1H ), 4.62 (d, J=5.5Hz, 2H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ166.4, 137.9, 133.2, 131.9, 128.9, 128.6, 128.0, 127.8, 126.3, 44.3.MS (EI ): m/z(%) 292(8), 291(51), 290(9), 289(53), 186(8), 185(99), 184(8), 183(100), 157( 25), 155(25), 108(3), 107(4), 106(4), 104(5), 77(8), 76(13), 75(7), 50(3)

Embodiment 6:

Preparation of N-benzyl-4-pyridinecarboxamide by reaction of 4-cyanopyridine and benzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), 4-cyanopyridine (2mmol), benzylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen After protection, seal and heat to 160°C for 48h. The conversion rate of the reaction was 91% as measured by GC-MS. The product was separated and purified by column chromatography, and the separation yield was 83%. ¹ H NMR (500MHz, CDCl ₃ ): δ8.68(d, J=5.0Hz, 2H), 7.62-7.61(m, 2H), 7.37-7.31(m, 5H), 6.81(b, 1H), 4.63 (d, J=6.0Hz, 2H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ165.5, 150.5, 141.5, 137.5, 128.9, 128.0, 127.9, 121.0, 44.3. MS(EI): m/z (%) 213(15), 212(100), 211(23), 183(2), 168(2), 155(3), 107(6), 106(54), 104(7), 91( 10), 79(10), 78(22), 77(6), 65(3), 51(8), 50(2), 28(3).

Embodiment 7:

Preparation of N-benzyl-2-chloro-4-pyridinecarboxamide by the reaction of 2-chloro-4-cyanopyridine and benzylamine

CsOH·H ₂ O (0.0336g, 10mol%), 2-chloro-4-cyanopyridine (2mmol), benzylamine (2mmol, 1equiv.), and water (0.5mL) were added successively into the reaction tube as a solvent, Sealed and heated to 160° C. for reaction 48h after evacuating and nitrogen protection. GC-MS showed that the reaction conversion rate was 75%. The product was separated and purified by column chromatography, and the separation yield was 60%. ¹ H NMR (500MHz, CDCl ₃ ): δ8.46(d, J=5.0Hz, 1H), 7.65(s, 1H), 7.53(dd, J=5.0Hz, J=1.0Hz, 1H), 7.38- 7.31 (m, 5H), 6.66 (b, 1H), 4.61 (d, J=5.5Hz, 2H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ164.1, 152.5, 150.5, 144.5, 137.2, 128.9 , 128.04, 128.00, 122.0, 119.8, 44.4. MS (EI): m/z (%) 249 (5), 248 (28), 247 (21), 246 (100), 245 (27), 211 (42 ), 210(12), 182(7), 169(7), 139(10), 135(11), 111(11), 107(27), 106(8), 85(9), 80(12 ), 79(7), 69(19), 53(9), 52(9).

Embodiment 8:

Preparation of N-Benzylthiophene-2-Carboxamide by Reaction of 2-cyanothiophene and Benzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), 2-cyanothiophene (2mmol), benzylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen After protection, seal and heat to 160°C for 48h. The conversion rate of the reaction was determined to be 99% by GC-MS. The product was separated and purified by column chromatography, and the separation yield was 50%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.51(dd, J=3.5Hz, J=1.0Hz, 1H), 7.47(dd, J=5.0Hz, J=1.0Hz, 1H), 7.36-7.34( m, 4H), 7.32-7.27(m, 1H), 7.06(dd, J=4.0Hz, J=5.0Hz, 1H), 6.31(b, 1H), 4.61(d, J=5.5Hz, 2H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ161.8, 138.8, 138.1, 130.0, 128.8, 128.2, 128.0, 127.7, 127.6, 44.0. MS (EI): m/z (%) 219 (4), 218 (11), 217(72), 216(4), 113(8), 112(13), 111(100), 106(42), 105(12), 104(7), 91(20), 84 (10), 83(11), 79(8), 77(11), 65(10), 51(8), 39(24).

Embodiment 9:

Preparation of N-Benzylcyclopropylformamide by Reaction of Cyclopropylcarbonitrile and Benzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), cyclopropylcarbonitrile (2mmol), benzylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen After protection, seal and heat to 160°C for 48h. The conversion rate of the reaction was 98% as measured by GC-MS. The product was separated and purified by column chromatography, and the separation yield was 53%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.35-7.27(m, 5H), 5.96(b, 1H), 4.45(d, J=6.0Hz, 2H), 1.38-1.33(m, 1H), 1.02 -0.99 (m, 2H), 0.76-0.72 (m, 2H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ173.4, 138.5, 128.7, 127.8, 127.5, 43.9, 14.8, 7.2. MS (EI) : m/z(%) 176(8), 175(56), 174(13), 160(6), 146(9), 132(10), 131(26), 130(8), 117(12 ), 116(7), 107(8), 106(48), 105(12), 104(100), 92(8), 91(94), 79(12), 77(18), 69(45 ), 65(22), 59(12), 55(9), 51(15), 50(6), 41(57), 39(34), 28(12), 27(5).

Example 10:

Preparation of N-Benzylvaleramide by Reaction of Valeronitrile and Benzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), valeronitrile (2mmol), benzylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen to protect and seal Heated to 160°C for 48h. GC-MS showed that the reaction conversion rate was 80%. The product was separated and purified by column chromatography, and the separation yield was 60%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.35-7.26(m, 5H), 5.82(b, 1H), 4.42(d, J=6.0Hz, 2H), 2.21(t, J=7.5Hz, 2H ), 1.66-1.60 (m, 2H), 1.39-1.31 (m, 2H), 0.92 (t, J=7.5Hz, 2H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ173.0, 138.5, 128.7 , 127.8, 127.5, 43.6, 36.5, 27.9, 22.4, 13.8. MS (EI): m/z (%) 192 (6), 191 (42), 148 (18), 130 (3), 107 (33) , 106(100), 105(13), 104(4), 103(3), 92(3), 91(29), 85(2), 79(10), 77(4), 65(4) , 58(5), 43(10), 42(3), 28(2).

Example 11:

Preparation of N-benzylphenylacetamide by the reaction of phenylacetonitrile and benzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), phenylacetonitrile (2mmol), benzylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen to protect and seal Heated to 160°C for 48h. GC-MS showed that the reaction conversion rate was 70%. The product was separated and purified by column chromatography, and the separation yield was 45%. ¹ H NMR (500MHz, d ₆ -DMSO): δ7.36-7.24(m, 8H), 7.17(d, J=7.0Hz, 2H), 5.73(b, 1H), 4.41(d, J=6.0Hz , 2H), 3.62(s, 2H). ¹³ C NMR (125.4MHz, d ₆ -DMSO): δ170.8, 138.1, 134.8, 129.5, 129.1, 128.7, 127.5, 127.44, 127.42, 43.9, 43.6.MS ( EI): m/z(%)226(8), 225(50), 107(2), 106(3), 104(2), 92(20), 91(100), 89(3), 77 (4), 65(15), 63(3), 51(5), 50(2), 43(2), 41(2).

Example 12:

Preparation of N-p-methylbenzylbenzamide by reaction of benzonitrile and p-methylbenzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), PhCN (2mmol), p-methylbenzylamine (2mmol, 1equiv.) to the reaction tube in turn, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen gas protection Back sealing is heated to 160 DEG C and reacts 48h. GC-MS measured the conversion rate of the reaction to be 78%. The product was separated and purified by column chromatography, and the separation yield was 50%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.78(d, J=8.5Hz, 2H), 7.51-7.48(m, 1H), 7.4-7.40(m, 2H), 7.26-7.24(m, 2H) , 7.16(d, J=8.0Hz, 2H), 6.41(b, 1H), 4.60(d, J=5.5Hz, 2H), 2.34(s, 3H). ¹³ C NMR(125.4MHz, CDCl ₃ ): δ167.3, 137.4, 135.1, 134.5, 131.5, 129.5, 128.6, 128.0, 126.9, 43.9, 21.1. MS (EI): m/z (%) 226 (8), 225 (44), 210 (10), 156(22), 120(8), 113(6), 106(10), 105(100), 104(28), 79(6), 78(10), 77(58), 56(8), 51(17), 50(5), 42(7).

Example 13:

Preparation of N-o-methylbenzylbenzamide by reaction of benzonitrile and o-methylbenzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), PhCN (2mmol), o-methylbenzylamine (2mmol, 1equiv.) to the reaction tube in turn, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen gas protection Back sealing is heated to 160 DEG C and reacts 48h. GC-MS showed that the reaction conversion was 80%. The product was separated and purified by column chromatography, and the separation yield was 70%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.77(d, J=7.0Hz, 2H), 7.48-7.46(m, 1H), 7.42-7.38(m, 2H), 7.28(d, J=7.0Hz , 1H), 7.22-7.18(m, 3H), 6.35(b, 1H), 4.61(d, J=5.5Hz, 2H), 2.36(s, 3H). ¹³ CNMR (125.4MHz, CDCl ₃ ): δ167 .3, 136.6, 135.8, 134.4, 131.5, 130.6, 128.7, 128.6, 127.9, 127.0, 126.3, 42.3, 19.1. MS(EI): m/z(%) 226(8), 225(44), 210( 10), 156(22), 120(8), 113(6), 106(10), 105(100), 104(28), 103(6), 79(6), 78(10), 77( 58), 56(8), 51(17), 50(5), 42(7), 39(4).

Example 14:

Preparation of N-p-Fluorobenzylbenzamide by Reaction of Benzonitrile and p-Fluorobenzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), PhCN (2mmol), p-fluorobenzylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen to protect Sealed and heated to 160 ° C for 48h. The conversion rate of the reaction was determined to be 99% by GC-MS. The product was separated and purified by column chromatography, and the separation yield was 70%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.78(d, J=7.0Hz, 2H), 7.52-7.49(m, 1H), 7.45-7.42(m, 2H), 7.34-7.31(m, 2H) , 7.05-7.01 (m, 2H), 6.44 (b, 1H), 4.61 (d, J=6.0Hz, 2H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ167.4, 162.3 (d, J _cF =245.3Hz), 134.3, 134.1 (d, J _cF =3.3Hz), 131.7, 129.6 (d, J _cF =8.2Hz), 128.6, 126.9, 115.6 (d, J _cF =21.4Hz), 43.4.MS ( EI): m/z (%) 230(3), 229(20), 228(7), 200(6), 108(7), 106(7), 105(100), 104(8), 103 (7), 77(47), 76(5), 70(7), 67(8), 57(7), 55(11), 54(6), 51(10), 43(12), 41 (14), 39(8).

Example 15:

Preparation of N-m-chlorobenzylbenzamide by reaction of benzonitrile and m-chlorobenzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), PhCN (2mmol), m-chlorobenzylamine (2mmol, 1equiv.) to the reaction tube in turn, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen to protect Sealed and heated to 160 ° C for 48h. The conversion rate of the reaction was determined to be 99% by GC-MS. The product was separated and purified by column chromatography, and the separation yield was 58%. ¹ H NMR (500MHz, CDCl ₃ ): ¹ H NMR (500MHz, CDCl ₃ ): δ7.79(d, J=7.5Hz, 2H), 7.53-7.49(m, 1H), 7.45-7.41(m, 2H ), 7.33(s, 1H), 7.27-7.22(m, 3H), 6.58(b, 1H), 4.61(d, J=5.5Hz, 2H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ167. 4, 140.3, 134.6, 134.1, 131.7, 130.0, 128.6, 127.8, 127.7, 126.9, 125.9, 43.4. ¹³ C NMR (125.4MHz, CDCl ₃ ): δ167.4, 140.3, 134.6, 134.1, 131.7, 130.0, 1 , 127.8, 127.7, 126.9, 125.9, 43.4. MS (EI): m/z (%) 247 (5), 246 (2), 245 (14), 211 (10), 210 (63), 106 (8 ), 105(100), 78(4), 77(46), 76(2), 51(8).

Example 16:

Preparation of N-o-chlorobenzylbenzamide by the reaction of benzonitrile and o-chlorobenzylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), PhCN (2mmol), o-chlorobenzylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen to protect Sealed and heated to 160 ° C for 48h. The conversion rate of the reaction was determined to be 99% by GC-MS. The product was separated and purified by column chromatography, and the separation yield was 65%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.78(d, J=7.0Hz, 2H), 7.51-7.37(m, 5H), 7.25-7.23(m, 2H), 6.67(b, 1H), 4.74 -4.72(m, 2H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ167.4, 135.7, 134.4, 133.8, 131.7, 130.6, 129.7, 129.2, 128.7, 127.3, 127.1, 42.2. MS(EI): m/z(%)247(5), 246(2), 245(14), 211(10), 210(63), 106(8), 105(100), 78(4), 77(46) , 76(2), 51(8).

Example 17:

Preparation of N-n-Butylbenzamide by Reaction of Benzonitrile and n-Butylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), PhCN (2mmol), n-butylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen to protect Sealed and heated to 160 ° C for 48h. The conversion rate of the reaction was 93% as measured by GC-MS. The product was separated and purified by column chromatography, and the separation yield was 60%. ¹ H NMR (500MHz, d ₆ -DMSO): δ8.44(b, 1H), 7.85-7.83(m, 2H), 7.53-7.49(m, 1H), 7.47-7.44(m, 2H), 3.29- 3.25(m, 2H), 1.54-1.48(m, 2H), 1.37-1.29(m, 2H), 0.91(t, J=7.5Hz, 3H). ¹³ C NMR (125.4MHz, d ₆ -DMSO): δ166.1, 134.7, 130.9, 128.2, 127.1, 38.8, 31.2, 19.6, 13.7. MS(EI): m/z(%) 178(2), 177(13), 176(2), 148(4) , 136(3), 135(15), 134(11), 106(8), 105(100), 78(3), 77(32), 76(2), 51(9), 50(3) .

Example 18:

Preparation of N-isobutylbenzamide by Reaction of Benzonitrile and Isobutylamine

Add CsOH·H2O (0.0336g, 10mol%), PhCN (2mmol), isobutylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen protection, seal and heat Reaction at 160°C for 48h. GC-MS showed that the reaction conversion rate was 87%. The product was separated and purified by column chromatography, and the separation yield was 68%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.77(d, J=7.5Hz, 2H), 7.48-7.45(m, 1H), 7.41-7.37(m, 2H), 6.61(b, 1H), 3.25 (t, J=6.5Hz, 2H), 1.92-1.87(m, 1H), 0.95(d, J=7.0Hz, 6H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ167.8, 134.9, 131.3 , 128.5, 126.9, 47.4, 28.6, 20.2. MS (EI): m/z (%) 225 (9), 134 (8), 121 (2), 106 (4), 105 (53), 104 (23 ), 92(4), 91(11), 77(21), 65(5), 51(6), 39(3), 38(4), 36(11), 30(100), 28(2 ).

Example 19:

Preparation of N-cyclohexylbenzamide by Reaction of Benzonitrile and Cyclohexylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), PhCN (2mmol), cyclohexylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen to protect and seal Heated to 160°C for 48h. GC-MS showed that the reaction conversion rate was 75%. The product was separated and purified by column chromatography, and the separation yield was 30%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.75(d, J=7.5Hz, 2H), 7.50-7.40(m, 3H), 5.99(b, 1H), 4.01-3.95(m, 1H), 2.05 -2.02(m, 2H), 1.78-1.74(m, 2H), 1.67-1.64(m, 1H), 1.48-1.39(m, 2H), 1.28-1.20(m, 3H). ¹³ C NMR (125.4MHz , CDCl ₃ ): δ166.6, 135.2, 131.2, 128.5, 126.8, 48.7, 33.2, 25.6, 24.9. MS (EI): m/z (%) 176 (4), 175 (36), 174 (28) , 146(8), 106(7), 105(100), 78(4), 77(49), 70(9), 68(4), 55(4), 51(16), 50(6) , 44(4), 43(6), 41(16).

Example 20:

Preparation of N-octylbenzamide by reaction of benzonitrile and n-octylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), PhCN (2mmol), n-octylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen to protect Sealed and heated to 160 ° C for 48h. GC-MS showed that the reaction conversion rate was 85%. The product was separated and purified by column chromatography, and the separation yield was 70%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.75(d, J=7.0Hz, 2H), 7.50-7.46(m, 1H), 7.43-7.40(m, 2H), 6.25(b, 1H), 3.46 -3.42(m, 2H), 1.64-1.58(m, 2H), 1.31-1.27(m, 10H), 0.89-0.86(t, J=7.0Hz, 3H). ¹³ C NMR (125.4MHz, CDCl ₃ ) : δ167.5, 134.9, 131.3, 128.5, 126.8, 40.1, 31.8, 29.7, 29.3, 29.2, 27.0, 22.6, 14.1. MS (EI): m/z (%) 190 (2), 176 (7), 162(8), 149(3), 148(10), 135(26), 134(22), 122(7), 106(8), 105(100), 79(2), 78(2), 77(31), 55(7), 51(5), 43(12), 41(12).

Example 21:

Preparation of N-2-Phenylethylbenzamide by Reaction of Benzonitrile and 2-Phenylethylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), PhCN (2mmol), 2-phenylethylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen After protection, seal and heat to 160°C for 48h. GC-MS showed that the reaction conversion rate was 56%. The product was separated and purified by column chromatography, and the separation yield was 51%. ¹ H NMR (500MHz, d ₆ -DMSO): δ8.55(t, J=5.5Hz, 1H), 7.81(d, J=7.0Hz, 2H), 7.53-7.50(m, 1H), 7.47-7.44 (m, 2H), 7.31-7.28(m, 2H), 7.24(d, J=7.0Hz, 2H), 7.22-7.19(m, 1H), 3.51-3.47(m, 2H), 2.85(t, J =7.5Hz, 2H). ¹³ C NMR (125.4MHz, d ₆ -DMSO): δ166.2, 139.5, 134.6, 131.0, 128.6, 128.3, 128.2, 127.1, 126.0, 40.8, 35.1. MS (EI): m /z(%)225(9), 134(8), 121(2), 106(4), 105(53), 104(23), 92(4), 91(11), 77(21), 65(5), 51(6), 39(3), 38(4), 36(11), 30(100), 28(2).

Example 22:

Preparation of N-1-Phenylethylbenzamide by Reaction of Benzonitrile and 1-Phenylethylamine

Add CsOH·H ₂ O (0.0336g, 10mol%), PhCN (2mmol), 1-phenylethylamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen After protection, seal and heat to 160°C for 48h. GC-MS showed that the conversion rate of the reaction was 45%. The product was separated and purified by column chromatography, and the separation yield was 25%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.77(d, J=7.0Hz, 2H), 7.51-7.48(m, 1H), 7.44-7.35(m, 6H), 7.30-7.27(m, 1H) , 6.31 (b, 1H), 5.37-5.31 (m, 1H), 1.61 (d, J=7.0Hz, 3H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ166.6, 143.1, 134.6, 131.5, 128.8, 128.6, 127.5, 126.9, 126.3, 49.2, 21.7. MS (EI): m/z (%) 225 (9), 134 (8), 121 (2), 106 (4), 105 (53), 104(23), 92(4), 91(11), 77(21), 65(5), 51(6), 39(3), 38(4), 36(11), 30(100), 28(2).

Example 23:

Preparation of N-2-Hydroxyethylbenzamide by Reaction of Benzonitrile and Ethanolamine

Add CsOH·H ₂ O (0.0336g, 10mol%), PhCN (2mmol), ethanolamine (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as a solvent, vacuumize and fill with nitrogen protection, seal and heat to React at 160°C for 48h. GC-MS showed that the reaction conversion rate was 80%. The product was separated and purified by column chromatography, and the separation yield was 65%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.74(d, J=7.5Hz, 2H), 7.45-7.42(m, 1H), 7.34-7.31(m, 2H), 4.38(b, 1H), 3.72 (t, J=5.0Hz, 2H), 3.53-3.50 (m, 2H), 3.15 (b, 1H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ168.9, 134.0, 131.6, 128.5, 127.0, 61.5, 42.7. MS(EI): m/z(%) 165(2), 147(14), 135(4), 134(9), 122(20), 117(8), 106(9), 105(100), 104(3), 78(6), 77(67), 76(5), 51(28), 50(10), 40(4), 33(9), 32(4), 31(3).

Example 24:

Preparation of N-Benzoyltetrahydropyrrole by Reaction of Benzonitrile and Tetrahydropyrrole

Add CsOH·H ₂ O (0.0336g, 10mol%), PhCN (2mmol), tetrahydropyrrole (2mmol, 1equiv.) to the reaction tube in sequence, then add water (0.5mL) as solvent, vacuumize and fill with nitrogen to protect and seal Heated to 160°C for 48h. GC-MS showed that the reaction conversion rate was 77%. The product was separated and purified by column chromatography, and the separation yield was 65%. ¹ H NMR (500MHz, CDCl ₃ ): δ7.48-7.46(m, 2H), 7.36-7.34(m, 3H), 3.60(t, J=7.0Hz, 2H), 3.37(t, J=6.5Hz , 2H), 1.94-1.88 (m, 2H), 1.85-1.79 (m, 2H). ¹³ C NMR (125.4MHz, CDCl ₃ ): δ169.7, 137.2, 129.7, 128.2, 127.0, 49.6, 46.1, 26.3 , 24.4.MS(EI): m/z(%) 176(5), 175(34), 174(23), 147(3), 146(17), 106(9), 105(100), 104 (13), 78(5), 77(55), 76(2), 70(4), 56(2), 51(12), 50(3).

Claims (7)

1. A method for preparing secondary and tertiary substituted amides, characterized in that, under air or inert gas conditions, a base catalyst is used to catalyze the reaction of nitriles and amines, the reaction temperature is 100～200°C, and the reaction time is 24 ~72 hours, the reaction formula is: in: The molar ratio of the raw material nitrile to the raw material amine is 3-1:1-3; the raw material amine is a primary amine or a secondary amine; R ¹ is substituted aryl, substituted heteroaryl, or alkyl; R ² and R ³ are hydrogen or benzyl substituted by various functional groups, or various substituted, various carbon chain lengths and branched chain substituted alkyl, cycloalkyl; The solvent of reaction is water or ammoniacal liquor; The base catalyst is CsOH. 2. The method for preparing secondary and tertiary substituted amides according to claim 1, characterized in that the amount of the base catalyst is 1-200 mol%. 3. The method for preparing secondary and tertiary substituted amides according to claim 1, characterized in that the amount of the base catalyst is 10-20 mol%. 4. The method for preparing secondary and tertiary substituted amides according to claim 1, wherein the inert gas is nitrogen. 5. The method for preparing secondary and tertiary substituted amides according to claim 1, characterized in that the reaction temperature is 160°C. 6. The method for preparing secondary and tertiary substituted amides according to claim 1, characterized in that, the reaction time is 48 hours. 7. The method for preparing secondary and tertiary substituted amides according to claim 1, characterized in that the solvent of the reaction is water.