The amide bond is an important building unit naturally or synthetically occurring1,2. It is present as a key in many important natural products and man-made compounds2. For example, N-acylalkylenediamines3 react with 4-amino-2-chloro-6,7-dimethoxyquinazolines to give a variety of antihypertensive agents4.

The synthesis of amides from carboxylic esters is a transformation of general synthetic interest which in many cases needs harsh conditions (temperature, reaction periods) or the use of strong catalysts5,6.

However, the enormous growth in the use of microwave irradiation this last decade in synthetic organic chemistry7 inspired us to study this reaction. A recently described synthesis of N-acylalkylenediamines from the corresponding carboxylic esters and alkylene diamines, which requires prolonged reaction times (3-16 h)8 and also synthesis of N-arylamines9, prompts us to report our results on preparations under solvent-free conditions which proceed in a much shorter time (2-3 min).

For the synthesis of primary amides, the reactions were carried out using an ester (1 eq), formamide (3 eq) and solid potassium tert-butoxide (t-BuOK) (1 eq) and the reaction mixture was submitted to microwave irradiation (MWI) in a focused microwave oven (Synthewave 402®)10.
 

a The yield refers to isolated products which exhibit physical and spectral properties (NMR spectra) in agreement with the assigned structures.
 

While the syntheses of secondary amides are realized from esters (1 eq) and butylamine (1 eq), tertiary amides result from esters (1 eq) and secondary amines (1 eq) with adjusted amounts of (t-BuOK) as shown in table 2 for the following reactions.
 

a The irradiation power is monitored for the desired temperature. b The yield refers to isolated products which exhibit physical and spectral properties (NMR spectra) in agreement with the assigned structures. c Reaction in an oil bath (D) previously set at the temperature of the microwave experiments. (d: days; h: hours).
 
 

We observe that the reaction yields are lower for dimethyl malonate either with alicyclic or cyclic amines when compared to other esters (entries 13-15).

The structures of the amides were assigned on the basis of their 1H NMR spectra and comparison with literature data.

We compared the results of the present synthesis using microwave with classical heating during the same time. It is noteworthy that after 3 minutes in the same conditions, the yields under classical heating are in the range of traces. In table 2 we report in the last column the yields after a longer heating period to allow a comparison.

In conclusion, microwave irradiation accelerates considerably the process of condensation as compared with classical heating.
 

EXPERIMENTAL SECTION :

NMR spectra were measured on a Bruker FT AM 200 spectrometer using CDCl3 as solvent and TMS as internal standard.

General Procedure for the preparation of amides

Method A (MWI)

The typical procedure for the substituted amides synthesis is as follows: potassium tert-butoxide (1eq, 5.10-3 mol or 0.5 or 0.25 eq) was added to a premixed mixture of amines (1eq) and esters (1eq) in the (Ø:2.5 cm) reactor of a focused microwave oven (Synthewave 402)10 and irradiated for the specified temperature and time (see Tables 1-2). On completion of the reaction, the mixture was extracted with CH2Cl2.

After evaporation of the solvent, the resulting mixture was analyzed by 1H NMR.

Method B (Conventional)

Reactions are performed in the same conditions using an oil bath previously set at the temperature measured in the microwave oven. As this study was done only for the comparison, the products were not isolated and the ratio were determinated by 1H NMR.

Acetamide ¹¹:

Yield : 80%; Solid, mp: 78°-80°C,1H NMR (200 MHz, CDCl3): d: 1.6 (s,2H, NH2); 2.0 (s, 3H,CH3).

Phenylacetamide ¹²:

Yield : 79%; Solid, mp: 154-157°C,1H NMR (200 MHz, CDCl3): d: 1.95 (s,2H,CH2); 4.69 (s,2H,NH2); 7.10 à 7.25 (m, 5H, phenyl).

Cyanoacetamide ¹³:

Yield : 71%; Solid, mp: 120-122°C,1H NMR (200 MHz, CDCl3): d: 3.08 (s,2H,NH2); 3.40 (s, 2H, CH2).

Cinnamamide ¹⁴:

Yield : 84 %; Solid, mp: 140-148°C,1H NMR (200 MHz, CDCl3): d: 3.49 (s, 2H,NH2); 6.45 à 7.65 (dd, CH=CH); 7.35 ( m, 5H, phenyl).

Methylmalonamide ¹⁵:

Yield : 43%; Solid, mp: 216°-217°C,1H NMR (200 MHz, CDCl3): d: 3.76 (s, 2H,NH2); 3.50 (s, 3H, CH3); 1.67 ( s, 2H, CH2).

N-Butyl acetamide ¹⁶:

Yield : 70%; Brown paste, bp: 229°C (lit),1H NMR (200 MHz, CDCl3): d: 3.40 (t,1H,NH); 0.87 (t, 3H, CH3); 1.40 ( m, 4H, CH2-CH2); 1.95 ( s, 3H, CH3-CO).

N-Butyl 2-phenylacetamide ¹⁷:

Yield : 97%; Solid, mp: 105°C (114°C lit.) 1H NMR (200 MHz, CDCl3): d: 7.3 ( m, 5H, phenyl); 4.55 ( s, 2H, -CH2-CO); 1.40 ( m, 4H, CH2-CH2); 0.9 (t, 3H, CH3)

N-Butyl 2-cyanoacetamide ¹⁸:

Yield : 60%; Solid, mp: 148°-150C,1H NMR (200 MHz, CDCl3): d: 3.90 (t,1H,NH-CH2); 3.45 ( s, 2H, -CH2-CO); 1.65 ( q, 4H, CH2-CH2); 0.9 (t, 3H, CH3).

N-Butyl cinnamamide ¹⁹:

Yield : 61%; Solid, mp: 58°-60°C,1H NMR (200 MHz, CDCl3): d: 1.01 à 1.95 (d Butyl); 3.80 ( t, 1H, NH-); 6.5 à 7.7 (dd, CH=CH); 7.35 ( m, 5H, phenyl).

N,N-dibutyl malonamide²⁰:

Yield : 17%; Liquid, bp: 46°-48°C/mmHg (lit.) 1H NMR (200 MHz, CDCl3): d: 0.77 à 1.85 (d Butyl); 3.75 ( t, 1H, NH-); 3.95 (s,2H, CH2); 4.02 (s, 3H, -CH3).

1-Acetylpiperidine²¹:

Yield : 74%; Solid, mp: 85°-87°C,1H NMR (200 MHz, CDCl3): d : 1.55 (m,6H,H2H3H4); 3.05 (t, 4H, H1H5); 3.45 (s, 3H, -CH3).

1-(Phenylacetyl)piperidine²²:

Yield : 70%; Solid, mp: 52°-54°C/16mmHg (lit.) 1H NMR (200 MHz, CDCl3): d: 1.60 (m,6H,H2H3H4); 3.20 (t, 4H, H1H5); 3.9 (s, 2H, -CH2); 7.25 ( m, 5H, phenyl).

1-(Cyanoacetyl)piperidine²³:

Yield : 75%; Solid, mp: 88°-90°C,1H NMR (200 MHz, CDCl3): d: 1.60 (m,6H,H2H3H4); 3.20 (t, 4H, H1H5); 3.50 (s, 2H, -CH2).

3-Phenyl-1-(piperidin-1-yl)propenone²⁴:

Yield : 75%; Solid, mp: 45°-47°C,1H NMR (200 MHz, CDCl3): d: 1.55 (m,6H,H2H3H4); 3.05 ( t, 4H, H1H5); 6.45 à 7.6 (dd, CH=CH); 7.35 (m, 5H, phenyl).

Methyl 3-oxo-3-(piperidin-1-yl)propanonate²⁵:

Yield : 41%; Liquid, bp: 75°-76°C (lit.) 1H NMR (200 MHz,CDCl3):

d:1.55 (m,6H,H2H3H4); 3.05 (t, 4H, H1H5); 3.7 (s, 2H, -CH2); 3.9 (s, 3H, -CH3).

N-Acetylpyrrolidine²⁶:

Yield : 69%; Liquid, bp: 53°-54°C (lit.) 1H NMR (200 MHz, CDCl3): d: 1.9

(m,4H,H2H3); 3.5 (t, 4H, H1H4); 3.75 (s, 3H, -CH3).

1-(Phenylacetyl)pyrrolidine²⁷:

Yield : 63%; Liquid, bp: 47°-50°C (lit.) 1H NMR (200 MHz, CDCl3): d: 1.85

(m,4H,H2H3); 3.45 (t, 4H, H1H4); 3.99 (s, 2H, -CH2); 7.4 (m, 5H, phenyl).

1-(Cyanoacetyl)pyrrolidine²⁸:

Yield : 78%; Solid, mp: 35°-37°C,1H NMR (200 MHz, CDCl3): d: 1.95 (m,4H,H2H3); 3.45 (t, 4H, H1H4); 3.80 (s, 2H, -CH2).

1-Cinnamoylpyrrolidine²⁹:

Yield : 68%; Solid, mp: 47°-49°C,1H NMR (200 MHz, CDCl3): d: 1.85 (m,4H,H2H3); 3.3 (t, 4H, H1H4); 6.5 à 7.7 (dd, -CH=CH-); 7.5 (m, 5H, phenyl).

Methyl 3-oxo-3-(pyrrolidin-1-yl)propanoate³⁰:

Yield : 51%; Liquid, bp: 65°-67°C (lit.) 1H NMR (200 MHz, CDCl3): d: 1.85 (m,4H,H2H3); 3.25 (t, 4H, H1H4); 3.75 (s, 2H, -CH2); 3.95 (s, 3H, -CH3).
 

References