Microwaves-assisted solvent-free synthesis of N-acetamides by amidation or aminolysis

Article abstract of DOI:10.1016/j.tetlet.2008.02.170

The preparation of acetamides directly from amines and an acetyl donor under microwaves without any catalyst is described. The inexpensive, solvent free, and fast reaction conditions are the important features of this procedure.

Full text of DOI:10.1016/j.tetlet.2008.02.170

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3004–3008
Microwaves-assisted solvent-free synthesis of N-acetamides
by amidation or aminolysis
´
´ `
Clotilde Ferroud , Marie Godart, Stephane Ung, Helene Borderies, Alain Guy
Conservatoire National des Arts et Me´tiers, Laboratoire de Transformations Chimiques et Pharmaceutiques, UMR CNRS 7084,
Case 303, 2 rue Conte´, 75003 Paris, France
Received 21 December 2007; revised 27 February 2008; accepted 29 February 2008
Available online 6 March 2008
Abstract
The preparation of acetamides directly from amines and an acetyl donor under microwaves without any catalyst is described. The
inexpensive, solvent free, and fast reaction conditions are the important features of this procedure.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Acetamides; Solvent-free conditions; Microwave-assisted synthesis; Regiocontrol
The stable and polar amide functionality is an important
unit among the organic molecules present in natural-occur-
ring materials (e.g., peptides and proteins). It is also found
in many synthetic substances as intermediates or as active
pharmaceutical products or prodrugs.1
selectivity of reactions. The application of microwave tech-
nology in the amide solvent-free synthesis is not frequently
described in the literature.4 In this Letter, we highlight that
to improve efficiency and reduce waste production, the
microwaves offer mild methods to prepare amides directly
from non-activated carboxylic acids and amines in the
absence of coupling reagents and solvents.
In a recent review bearing with the very complex ther-
mal and non-thermal effects of microwave irradiation, De
la Hoz emphasized that the microwave radiation is a very
polarizing field and may stabilize polar transition states
and intermediates.4k In the case of the solvent-free uncata-
lyzed amidations of acids, Loupy and Perreux has shown a
microwave effect, attributed to the increase of polarity dur-
ing the course of the reaction, due to the development of a
dipole in the transition state.4d
In order to screen the uncatalyzed amidation under
microwave-assisted solvent-free conditions of primary
amines, we performed the reaction with 1.2 equiv of acetic
acid, acetyl chloride or various esters as acyl donors in a
DiscoverTM microwave synthesizer. Neat compounds were
mixed in a sealed microwave reaction tube and irradiated
under 25 W for few seconds to few minutes. The reactions
were monitored by GC–MS analysis, and the purity of the
desired products was evaluated by NMR spectroscopy.5
Due to its interest in organic synthesis, the preparation
of amides from the corresponding amines is an important
and well-known transformation. The most popular meth-
ods for the synthesis of carboxamides involve the conver-
sion of carboxylic acid to a more reactive functional
group or an in situ activation by using coupling reagents.2
Although good results are obtained with both approaches,
they need often expensive coupling reagents, which lead to
the formation of by-products requiring further separations.
Over the last years, a large number of publications and
reviews have clearly shown that many types of chemical
transformations can be carried out successfully under
microwaves (MW) conditions.3 Most importantly, micro-
wave processing frequently leads to dramatically reduced
reaction times, higher yields, less formation of by-products,
easier work-up matching with the goal of green chemistry,
solvent-free organic transformations, atom economy, and
Corresponding author. Tel.: +33 1 40 27 24 02; fax: +33 1 42 71 05 34.
E-mail address: ferroud@cnam.fr (C. Ferroud).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.170

C. Ferroud et al. / Tetrahedron Letters 49 (2008) 3004–3008
3005
In the case of primary amines 1–3, all the tested acyl-
ating agents are very efficient for rapid amidation. The
reactions were generally achieved within 3 min and the
yields were excellent, typically higher than 84% and often
quantitative.
The reactions were performed on a 2 mmol scale. All the
microwave-assisted amidation reactions studied proved to
be ‘directly scalable’: about identical yields were obtained
on a 2 mmol and 20 mmol scale without needing new devel-
opment of the reactional conditions.5 With microwave
heating, the amidation was completed in 1 h (entries 1
and 8) or almost completed (entries 3, 4, and 5) in a shorter
time compared to that of conventional heating.
Differentially substituted polyamine moieties are found
as either key pharmacophoric element or an important
structural scaffold in a large number of biochemical targets
across all the therapeutic areas.6 Selective acetylation of the
less hindered amino group in polyamines is often required.
The quest for complete control over efficient and selective
introduction of functionality is still a challenging problem.
In the absence of inherent steric or electronic influences,
conditions that are generally required for monoacetylation
are either the use of excess diamine to avoid a statistical
distribution of products (starting diamine, mono- and
diacetylated products), or the reaction of one amine moiety
by the use of structurally sophisticated selective acetylating
agents which are not in accordance with the concept of
atom economy.7
We expected that this process could provide practical
and rapid preparative procedures for the selective acylation
of polyamines. The previously described conditions (i.e.,
2 W, 90 °C or 10 W, 130 °C) were applied to the amidation
of N-cyclohexylpropylenediamine 9, N-propylpropylenedi-
amine 10, and dibutylamine 11 with acetic acid, in order to
study the competition between primary amine versus sec-
ondary amine, to evaluate the reactivity of secondary
amines, and to optimize the conditions of acetylation
(Table 3).
With our goal in mind, we have chosen to carry our
studies further with acetic acid, an acylating agent of
choice, affording only water as a by-product. Most of the
microwave-assisted amidations are performed at high tem-
perature (150–300 °C).4 In a preliminary study, we exam-
ined the temperature effect on the reaction of acetic acid
and dodecylamine and we observed that whatever the watt-
age (P = 2–25 W) was, the amidation occurred as soon as
the temperature (T) reached 80–90 °C (in less than
5 min). This is of interest for reactions involving thermi-
cally unstable compounds. Then, we checked the better
conditions (P, T) to achieve the reaction (Fig. 1). The
results from all these experiments show that the amidation
reaction with dodecylamine 1 and a slight excess of acetic
acid (1.2 equiv) can be performed under low wattage since
the required temperature (90 °C) is rapidly reached. It
should be noticed that after 30 min under 1 W, the temper-
ature reached only 80 °C and no reaction occurred.
The reaction was quantitative in 5–15 min under 3–
25 W, and required 2 h under 2 W. Table 2 shows the
extension of these conditions to the quantitative acylation
of aliphatic amines under low conditions of temperature
and wattage. The reactions were performed with various
primary amines 1–4 in the presence of 1.2 equiv of acetic
acid at 90 °C under 2 W (MW) or by conventional heating
in a thermostated oil bath (D: refluxing acetic acid, 115 °C)
(Table 2). Wattage was automatically adjusted so as to
maintain the desired temperature.
O
O
MW
CH3-(CH2)11-NH2
+
H3C
OH
H3C
NH (CH2)11-CH3
100
90
80
70
60
50
40
30
20
10
0
P = 1W
P = 2W
P = 3W
P = 5W
P = 10W
P = 25W
0
5
10
15
20
25
30
35
Time (min)
Fig. 1. Temperature effect on the acetamidation of dodecylamine 1 by acetic acid.

3006
C. Ferroud et al. / Tetrahedron Letters 49 (2008) 3004–3008
The results showed that, in all cases, the reactions
130 °C under 10 W to give 96% of the expected acetamide
14. These results were confirmed in the case of piperazine
proceeded cleanly, and the less hindered acetylated prod-
ucts N-[3-(cyclohexylamino)propyl]-acetamide 12 and
N-[3-(propylamino) propyl]-acetamide 13 were selectively
formed in high yields. These results confirm the interest
of our method in regard to the monofunctionalization
methods described previously requiring complex acylating
agents for the same discrimination.7
O
R
NH2
H
O
O
MW
We then decided to find better conditions to perform the
acetylation of secondary amines in order to check the selec-
tivity of their monoacetylation. Under the conditions
described by Orru and co-workers,4h a low selectivity
between primary amine versus secondary amine (respec-
tively 85:15) was observed for diamine 9 (entry 1, i.e.,
200 W, 1 h, 200 °C), compared to total discrimination that
we obtained in 1 h at 130 °C under 10 W. The acetylation
of the secondary N,N-dibutylamine 11 required 2 h at
R
N
O
O
R
N
H
H
R
NH2
Scheme 1. Microwave-assisted stoichiometric acetamidation of amines by
vinyl acetate.
Table 1
Microwave-assisted acetylation of primary amines
O
O
MW
R-NH2
+
H3C
R'
H3C
NH R
R=alkyl, benzyl
R'=Cl, OH, Oalkyl
AcCla
Yield
AcOHb
AcOCH@CH2
AcOMec
Time Yield
AcOtBuc
AcOEtc
c
Time
(s)
Time
(s)
Yield
(%)
Time
(s)
Yield
(%)
Time
(s)
Yield
(%)
Time
Yield
(%)
(%)
(s)
(%)
(s)
Dodecylamine 1
Benzylamine 2
Cyclohexylamine 3
180
120
1800
100
99
100
30
30
60
100
100
100
10
10
15
100
100
100
15
15
30
93
96
91
60
60
120
97
84
37
150
150
150
87
72
22
a
100 °C, 25 W.
150 °C, 100 W.
200 °C, 200 W.
b
c
Table 2
Microwave-assisted amidation of primary amine under mild conditions
O
O
2W
R
NH2
1-4
1eq
+
90 ºC
H3C
OH
H3C
NH R
5-8
1.2eq
Entry
R
Scale (mmol)
Reaction time (h)
Ratioa amine/product (%)
MW
D
1
2
3
1 CH3–(CH2)11
-
2
20
20
1
2
6
1/5
0/100
15/85
4/96
87/13
47/53
4
5
2 Benzyl-
2
20
1
5
2/6
3/7
4/8
11/89
10/90
69/31
22/78
6
7
3 Cyclohexyl-
2
2
1
1
93/7
0/100b
8
4 CH2@CH–CH2-
2
1
0/100c
78/22c
Ratio was determined by GC–MS spectroscopy and confirmed by 1H NMR.5
10 W, 130 °C, 1 h.
a
b
c
Ratio was determined only by NMR spectroscopy because of the volatility of the allylamine.

C. Ferroud et al. / Tetrahedron Letters 49 (2008) 3004–3008
3007
Table 3
Selective acetylation of primary amines versus secondary amines
Entry
Amine (2 mmol)
Conditions
Starting material
Mono
Di
By-products
2 W, 90 °C, 1 h
D: 115 °C, 1 h
10 W, 130 °C, 1 h
200 W, 200 °C, 1 h
31
94
0
12
13
14
69
6
100
85
0
NH
NH2
NH2
0
0
15a
1
9
0
2 W, 90 °C, 1 h
D: 115 °C, 1 h
5 W, 110 °C, 1 h
10 W, 130 °C, 1 h
43
100
8
45
0
72.5
0
0
3
13
NH
2
3
10
16.5
6.5
0
78
15.5
2 W, 90 °C, 1 h
Db: 130 °C, 1 h
10 W, 130 °C, 1 h
10 W, 130 °C, 2 h
Db: 130 °C, 2 h
93
100
38
4
100
7
0
62
96
0
11
HN
4
15c
10 W, 130 °C, 1 hd
200 W, 200 °C, 1 h
0
0
16
57
27
43
73
H
N
N H
a
Conditions described by Orru and co-workers.4h
In sealed tube.
b
c
Ratio amine 15/AcOH:1/2.
d
Because acetic acid did not mix well with piperazine even at 130 °C in a sealed tube, the reaction was not performed under classical heating.
15 for which, in the presence of 2 equiv of acetic acid, an
emitted power of 10 W was required for a total conversion
but no selectivity was observed. The results depicted in
Table 3 show the unreactivity of the secondary amines
9–11 under classical thermal conditions and thus confirm
the influence of the microwave irradiation.
ditions, and shorter reaction times accompanied by a clea-
ner reaction profile compared to those obtained under
Table 4
Vinyl acetate: a green reagent for quantitative selective monofunctional-
ization of amines
From the preliminary results given in Table 1, it clearly
appeared that vinyl acetate 17 was also of interest as an
acyl donor. We decided to explore its potentiality in selec-
tive monoacetylation of polyamines (Table 4).
O
O
2W
CH -CHO
+
N R
H
3
R
NH2
+
H3C
O
H3C
90 ºC
1-4, 9-10
17
When the reaction was performed at room temperature
without any microwave activation, a rapid transfer of acyl
was observed in a few seconds but a twofold excess of amine
was required. These results show that the amine reacts by
two different pathways. The reaction of the primary amine
with vinyl acetate leads in a first step to the formation of the
acetamide together with the formation of acetaldehyde as
the by-product which reacts in situ with the excess amine
to give the corresponding imine. On the other hand, under
microwave activation, the hydrolysis of the intermediate
imine (probably favored by a polar transition state) under-
goes rapidly and allows a stoichiometric reaction. Thus, the
starting amine re-formed by the imine hydrolysis can react
again with the unreacted vinyl acetate to lead to the forma-
tion of the acetamide and so on until the overall consump-
tion of the vinyl acetate (Scheme 1).
1eq
1.2eq
5-8, 12-13
Entry
Amine/conditions
Starting material
Product
CH3–(CH2)11–NH2
2 mmol (1 h)
20 mmol (1 h)
1
5
100
100
1
2
0
0
NH2
2
6
3
4
2 mmol (1 h)
20 mmol (1 h)
0
0
100
100
NH2
3
7
5
6
2 mmol
0
0
100
4
8
NH2
2 mmol
100
The analysis of the results depicted in Tables 2–4 shows
a similar reactivity of the amines studied with either acetic
acid or vinyl acetate (2 W, 90 °C) except for the two cyclo-
hexylamines 3 and 9 for which more drastic conditions
were required to achieve the acetylation with acetic acid
(Table 2, entries 6, 7 and Table 3, entry 1). No explanation
can be given to account of this discrepancy.
NH
NH2
NH2
9
12
7
2 mmol
NH
2 mmol
0
0
100
13
10
8
84:16a
a
In conclusion, all the tests carried out under microwave
activation show higher product yields, milder reaction con-
Ratio of acetylation of primary amine versus secondary respectively
determined by GC–MS spectrometry.

3008
C. Ferroud et al. / Tetrahedron Letters 49 (2008) 3004–3008
Gelens, E.; Smeets, L.; Sliedregt, L.; Van Steen, B.; Kruse, C.; Leurs,
R.; Orru, R. V. Tetrahedron Lett. 2005, 46, 3751–3754; (i) Massicot, F.;
Plantier-Royon, R.; Portella, C.; Saleur, D.; Sudha, A. Synthesis 2001,
16, 2441–2444; (j) Perreux, L.; Loupy, A.; Delmotte, M. Tetrahedron
2003, 59, 2185–2189; (k) de la Hoz, A.; Diaz-Ortiz, A.; Moreno, A.
Chem. Soc. Rev. 2005, 34, 164–178; (l) Karis, N.; Loughlin, W.;
Jenkins, I. Tetrahedron 2007, 63, 12303–12309.
thermal conditions. However, at this stage we have not
investigated further to conclude to a specific microwave
effect which is still a controversial topic. Concerning the
selectivity, the monoacetylation of polyamines, obtained
under these conditions, is broadly equivalent to those
described in the literature with more sophisticated reagents
and shows still the interest of the use of the microwaves in
organic synthesis.
5. Typical procedure: In a capped 10 mL MW-vessel, the carboxylic acid
(or the carboxylic acid derivative) (2.4 mmol, 1.2 equiv) and the amine
(2 mmol) were mixed. The tube was positioned in the irradiation cavity
and the mixture was heated with stirring under microwave irradiation
to 90 °C with 2 W of power and held for about 1 h (reactions on a
2 mmol scale realized in sealed CEM 10 mL microwave reaction vials
and reactions carried out on a 20 mmol scale in the open-vessel were all
performed with a CEM DiscoverÒ single mode microwave reactor
equipped with a 300 W power source). After completion, upon cooling
to ambient temperature, the conversion was directly determined by
GC–MS analyses (Agilent 6890 N Gas Chromatograph equipped with
a column HP-5MS (30 m  250 lm  0.25 lm). The mass spectra
resulting from ionization by electronic impact (EI-LRMS) were
acquired on an Agilent 5973 Network MSD). A consecutive work up
was simply performed by dissolving the reaction mixture in dichloro-
methane and then concentrated under vacuum in order to eliminate
either the acetic acid or the vinyl acetate in excess. The purity of the
final products was controlled by 1H NMR. Characterization data were
consistent with that of previously described products.8
6. (a) Rynbrandt, R.; Schmidt, F. J. Med. Chem. 1971, 14, 54–56; (b)
Chou, W.-C.; Tan, C.-W.; Chen, S.-F.; Ku, H. J. Org. Chem. 1998, 63,
10015–10017; (c) Altamura, M.; Canfarini, F.; Catalioto, R.-M.; Guidi,
A.; Pasqui, F.; Renzetti, A.; Triolo, A.; Maggi, C. Bioorg. Med. Chem.
Lett. 2002, 2945–2948.
7. (a) Murakami, Y.; Kondo, K.; Miki, K.; Aldyama, Y.; Watanabe, T.;
Yokoyama, Y. Tetrahedron Lett. 1997, 38, 3751–3754; (b) Bender, J.;
Meanwell, N.; Wang, T. Tetrahedron 2002, 58, 3111–3128.
8. N-Dodecylacetamide 5 [3886-80-4]: (a) El Seoud, M.; Vieira, R.; El
Seoud, O. J. Org. Chem. 1982, 47, 5137–5141; (b) Helgen, C.; Bochet,
C. Heterocycles 2006, 67, 797–805; N-Benzylacetamide 6 [588-46-5]: (a)
Kita, Y.; Akai, S.; Ajimura, N.; Yoshigi, M.; Tsugoshi, T.; Yasuda, H.;
Tamura, Y. J. Org. Chem. 1986, 51, 4150–4158; (b) Kondo, K.; Iida,
T.; Fujita, H.; Suzuki, T.; Yamaguchi, K.; Murakami, Y. Tetrahedron
2000, 56, 8883–8891. N-(Cyclohexyl)-acetamide 7 [1124-53-4]: (a)
Becker, J.; Zinger, B.; Yatziv, S. J. Org. Chem. 1987, 52, 2783–2789;
Allylacetamide 8 [692-33-1]: Idoux, J.; Scandrett, J.; Sikorski, J. J. Am.
Chem. Soc. 1977, 99, 4577–4583; (b) Gottlieb, H.; Cheung, H. J. Chem.
Res. (S) 1979, 11, 370–374; N-[3-(Cyclohexylamino)propyl]-acetamide
12 [128459-11-0]: Kikugawa, Y.; Mitsui, K.; Sakamoto, T.; Kawase,
M.; Tamiya, H. Tetrahedron Lett. 1990, 31, 243–246; N-[3-(propyl-
amino)propyl]-acetamide 13 [4189-54-2]: Ref. 71; N,N-Dibutyl-
acetamide 14 [1563-90-2]: Fritz, H.; Hug, P.; Sauter, H.; Winkler, T.;
Logemann, E. Org. Magn. Reson. 1977, 9, 108–112.
References and notes
1. (a) Brown, W. Idrugs 1999, 2(10), 1059–1068; (b) Albericio, F. Curr.
Opin. Chem. Biol. 2004, 8, 211–221.
2. (a) Beckwith, A. In The Chemistry of Amides: Synthesis of Amides;
Patai, S., Ed.; Interscience: New York, 1970; pp 74–167; (b) Labelle,
M.; Gravel, D. Chem. Commun. 1985, 3, 105–106; (c) Handbook of
Reagents for Organic Synthesis. Reagents for Glycoside, Nucleotide and
Peptide Synthesis; Crich, David, Ed.; John Wiley
& Sons Ltd:
Chichester, West Sussex, England, 2005; (d) Burnell-Curty, C.;
Roskamp, E. J. Tetrahedron Lett. 1993, 34, 5193–5196; (e) Froyen,
P. Synth. Commun. 1995, 25, 959–968; (f) Thorsen, J. D.; Andersen, T.
P.; Pedersen, U.; Yde, B.; Leweson, S. Tetrahedron 1985, 41, 5633–
5636; (g) Basel, Y.; Hassner, A. Tetrahedron Lett. 2002, 43, 2529–2533;
(h) Bailen, M. A.; Chinchilla, R.; Dodsworth, D. J.; Najera, C.
Tetrahedron Lett. 2000, 41, 9809–9813; (i) Guo, Z.; Dowdy, E.; Li, W.-
S.; Polniaszek, R.; Delaney, E. Tetrahedron Lett. 2001, 42, 1843–1845;
(j) Machetti, F.; Bucelli, I.; Kappe, C. O.; Guarna, A. J. Comb. Chem.
2007, 9, 454–461.
3. For reviews on microwave chemistry, see: (a) Caddick, S. Tetrahedron
1995, 51, 10403–10432; (b) Lidstrom, P.; Tierney, J.; Wathey, B.;
Westman, J. Tetrahedron 2001, 57, 9225–9283; (c) Hayes, B. L.
Microwave Synthesis: Chemistry at the Speed of Light; CEM
Publishing: Matthews, NC, 2002; (d) Loupy, A. Microwaves in Organic
Synthesis; Wiley-VCH: Weinheim, Germany, 2002; (e) Kappe, C. O.
Angew. Chem., Int. Ed. 2004, 43, 6250–6284; (f) Hayes, B. L.
Aldrichim. Acta 2004, 37(2), 66–76; (g)Microwave Assisted Organic
Synthesis; Tierney, J. P., Lidstro¨m, P., Eds.; Blackwell Publishing:
Oxford, UK, 2005; (h) Kappe, C. O.; Stadler, A. Microwaves in
Organic and Medicinal Chemistry; Wiley-VCH: Weinheim, Germany,
2005; (i) Roberts, B. A.; Strauss, C. R. Acc. Chem. Res. 2005, 38, 653–
661.
4. (a) Vazquez-Tato, M. Synlett 1993, 556; (b) Baldwin, B.; Hirose, T.;
Wang, Z. Chem. Commun. 1996, 2269–2670; (c) Varma, R.; Naicker,
K. Tetrahedron Lett. 1999, 40, 6177–6180; (d) Perreux, L.; Loupy, A.
Tetrahedron 2001, 57, 9199–9223; (e) Perreux, L.; Loupy, A.; Volatron,
F. Tetrahedron 2002, 58, 2155–2162; (f) Sauer, D.; Kalvin, D.; Phelan,
K. Org. Lett. 2003, 5, 4721–4724; (g) Khalafi-Nezhad, A.; Mokhtari,
B.; Navid Soltani Rad, M. Tetrahedron Lett. 2003, 44, 7325–7328; (h)