Solvent-free preparation of amides from acids and primary amines under microwave irradiation

Article abstract of DOI:10.1016/S0040-4020(02)00085-6

Synthesis of amides via pyrolysis of the salts obtained by mixing neat primary amines and carboxylic acids were realized under solvent-free conditions within short times and appreciable yields under microwave activation. The evident specific non-thermal microwave effects are attributed to polarity increase during the course of the reaction, due to development of a dipole in the transition state.

Full text of DOI:10.1016/S0040-4020(02)00085-6

TETRAHEDRON
Pergamon
Tetrahedron ꢀ8 52002) 21ꢀꢀ±2162
Solvent-free preparation of amides from acids and primary
amines under microwave irradiation
a a,p
Laurence Perreux, Andr e Loupy and Fran cË ois Volatron
b
a
Laboratoire des R e actions S e lectives sur Supports, Universit e Paris-Sud, CNRS, ICMO, UMR 8615, B aà timent 410,
1405Orsay Cedex, France
9
Laboratoire de Chimie Physique, Universit e Paris-Sud, 91405Orsay Cedex, France
b
Received 26 July 2001;revised 19 October 2001;accepted 27 December 2001
AbstractÐSynthesis of amides via pyrolysis of the salts obtained by mixing neat primary amines and carboxylic acids were realized under
solvent-free conditions within short times and appreciable yields under microwave activation. The evident speci®c non-thermal microwave
effects are attributed to polarity increase during the course of the reaction, due to development of a dipole in the transition state. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
However, this method usually suffers from rather harsh
conditions with respect to temperature and reaction times.
There is considerable interest in the formation of amides by
the direct combination of carboxylic acids and amines, as
the methods employed may also be utilized in peptide and
lactam synthesis. In general, the formation of carboxamides
from amines and carboxylic acids implies the activation of the
In recent developments, the use of microwave irradiation
5MW) to simplify and improve classic organic reactions
8
±10
has become a very popular method,
because it often
leads to higher yields, cleaner reactions and shorter reaction
times. In connection with solvent-free conditions, MW
methods result in ef®cient and safe technology, `Green
1
carboxyl group. The most common methods involve either
conversion of carboxylic acid to a more reactive functional
group such as an acyl chloride, mixed anhydride, acyl azide or
active esters, or via an in situ activation of carboxyl group by
some coupling reagents such as carbodiimides.2,3 More
recently, new systems were recommended such as titanium
1
0,11
Chemistry'.
Microwave activation has been used with a great deal of
success in several cases of amide synthesis by direct irradia-
tion of amine±carboxylic acid mixtures. They involved
4
or divalent tin reagents of type Sn5N5TMS) ) , treatment
2
2
1
2
with equivalent amounts of triphenylphosphine and N-halo-
succinimides such as NBS. or with trichloroacetonitrile.
different kinds of catalysts such as K-10 montmorillonite,
imidazole, zeolite-HY, polyphosphoric acid, p-tolue-
ꢀ
6
13
14
1ꢀ
1
6
17
nesulfonic acid, TaCl -silica gel, KF±alumina and silica
ꢀ
1
gel. In a few cases, reactions were performed in the
absence of catalyst for the synthesis of aromatic amides,
2-oxazolines and imides from dicarboxylic acids.
8
With the aim of simpli®cation of the procedures, especially
in order to avoid the preliminary and often expensive
synthesis of coupling reagents, pyrolitic preparations of
amides should be considered as the most interesting method
for their syntheses in the absence of any catalyst and
1
9
2
0
21
This set of reactions was carried out using domestic micro-
wave ovens, i.e. without any control of temperature and
emitted power. There was no comparison provided with
conventional heating 5K) under identical conditions
7
solvent. It consists of the pyrolysis of the corresponding
salts obtained by mixture of the amine and the carboxylic
acid 5Eq. 51)).
5medium, temperature, time, pressure) to check for possible
RCO H + R'NH2
speci®c purely non-thermal microwave effects. To this
purpose, we have studied the synthesis of typical amides
by pyrolysis of the salts obtained quasi-instantaneously
from mixtures of an amine and a carboxylic acid. Reactions
were performed under mechanical stirring to avoid macro-
2
∆
ꢀ1†
-
+
RCO , NH R'
RCONHR'
2
3
H O
2
2
2
scopic hot spots, using a monomode reactor with focused
Keywords: amides synthesis;microwave irradiation;solvent-free reaction;
polarity;pyrolysis of salts.
10
w
waves 5Prolabo Synthewave 402) with accurate control
of power and temperature 5by infrared detection or with an
optical ®bre) during the course of the reaction. Experiments
p
Corresponding author. Tel.: 133-1-69-1ꢀ-76-ꢀ0;fax: 133-1-69-1ꢀ-46-
79;e-mail: aloupy@icmo.u-psud.fr
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020502)0008ꢀ-6

21ꢀ6
L. Perreux et al. / Tetrahedron 58 ꢀ2002) 2155±2162
were then repeated, for sake of comparison with microwave
activation, under exactly the same conditions including
similar pro®les of rises in temperature by conventional
heating 5using a thermostated oil bath).
other reagent 51 or 2) is highly favourable, especially in the
case of benzoic acid, as it allowed for noticeable improve-
ment in yields.
Under these conditions, very important speci®c purely non-
thermal microwave effects were evidenced, especially in the
case of benzoic acid amidation under similar conventional
heating pro®les of temperature increase 5Fig. 1).
2. Results
Experiments were carried out without catalyst 5in contrast to
ester aminolysis which could be realized either under
neutral or basic conditions and studied elsewhere under
microwave irradiation ) with conjugated and non-
conjugated carboxylic acids and amines. The reaction
temperature selected was 1ꢀ08C in order to favour shifting
of the equilibrium by water removal 5Eq. 52)).
0
2.2. Reaction of the n-octylamine ꢀ2, R ˆn-C
H )
17
8
2
3
ꢀTable 2)
Table 2. Reaction of n-octylamine with RCO
5
2
H at 1ꢀ08C within 30 min
scale: 3 mmol) under microwave activation 5MW) or classical heating 5K)
0
0
RCO H 1 R NH O RCONHR 1 H O
2
ꢀ2†
2
2
a
Yields 5%3)
R
Relative amount 1/2
1
2
3
RˆC H , C H CH , n-C H ;
6
ꢀ
6
ꢀ
2
9
19
MW
K
0
R ˆC H , p-CH OC H , C H CH , n-C H .
6
ꢀ
3
6
4
6
ꢀ
2
8
17
C
6
H
ꢀ
1:1
1
3
2
±
±
±
23
41
3ꢀ
ꢀ4
68
46
:1.ꢀ
1.ꢀ:1
1:1
0
2.1. Reaction of benzylamine ꢀ2, R ˆC H CH ) with
several carboxylic acids ꢀTable 1)
6
5
2
10
ꢀ4
82
ꢀ2
63
68
ꢀ2
C H CH
6
ꢀ
2
1
:1.ꢀ
Table 1. Reaction of benzylamine with RCO H at 1ꢀ08C 5scale: 3 mmol)
2
under microwave activation 5MW) or by conventional heating in a thermo-
stated oil bath 5K)
1.ꢀ:1
1:1
1:1.ꢀ
9 19
n-C H
1
.ꢀ:1
a
Yields 5%3)
R
Reaction time 5min) Relative amount 1/2
a
In isolated products.
MW
K
C
C
6
H
H
ꢀ
ꢀ
30
1:1
10
80
7ꢀ
ꢀ1
80
92
93
80
8ꢀ
10
8
3
3
0
0
1:1.ꢀ
1.ꢀ:1
1:1
Under these conditions, benzoic acid failed to react regard-
less of the relative amount of acid/amine used. Quite
excellent yields were obtained in the two next cases but
only phenylacetic acid revealed the intervention of speci®c
microwave effects.
17
24
63
40
72
34
49
6
CH
2
10
3
3
3
0
0
0
1:1
1:1.ꢀ
1.ꢀ:1
1:1
n-C
9
H
19
10
30
1:1
When considering the most favourable conditions, one can
establish the following sequence for the different acid
reactivities:
a
In isolated products.
In all cases, good to excellent yields were obtained within
0 min of microwave exposure. The excess of one or the
3
n-C H CO H $ C H CH CO H q C H CO H
2
9
19
2
6
ꢀ
2
2
6
ꢀ
1
1
1
1
1
80
60
40
20
00
300
2
50
200
150
100
temperature (˚C)
power (Watts)
8
6
4
2
0
0
0
0
0
5
0
0
0
100
200
300
400
500
600
t (s)
Figure 1. Pro®le of rise in temperature under microwave irradiation by modulation of emitted power for the reaction of benzoic acid with benzylamine
1/2ˆ1:1.ꢀ).
5

L. Perreux et al. / Tetrahedron 58 ꢀ2002) 2155±2162
21ꢀ7
0
2
.3. Reaction of aniline ꢀ2, R ˆC H ) ꢀTable 3)
3.1. Mechanistic considerations
6
5
2
Table 3. Reaction of aniline with RCO H at 1ꢀ08C 5scale: 3 mmol) under
At room temperature, mixing of an amine and a carboxylic
acid leads to the rapid formation of the corresponding
ammonium salt by an acid±base equilibrium 5Eq. 53)).
microwave activation 5MW) or classical heating 5K)
a
Yields 5%3)
R
Reaction time 5min) Relative amount 1/2
MW
K
0
2
2
1
RCO H 1 R NH O RCO ; NH R
0
ꢀ3†
2
2
3
C
C
6
H
H
ꢀ
120
30
1:1.ꢀ
1:1
12
40
40
ꢀ2
14
40
34
±
6
ꢀ
CH
2
33
41
4ꢀ
±
3ꢀ
30
Subsequently, the pyrolysis of this salt leads to amide
formation by equilibrium retrogradation and subsequent
nucleophilic attack of the amine on the carbonyl group.
This process needs temperatures higher than 1008C for
water elimination 5Eq. 54)).
3
3
30
0
0
1:1.ꢀ
1.ꢀ:1
1:1.ꢀ
1:1
n-C
9
H
19
120
120
1:1.ꢀ
a
In isolated products.
- +
RCO , NH R'
RCO H
2
3
2
ꢀ
4†
+
R'NH2
RCONHR'
Poor to moderate yields were obtained in the case of aniline.
They were only slightly modi®ed by extending reaction
times or changing the amounts of reagents.
H2O
Different factors can be considered to justify the relative
reactivities of amines and carboxylic acids:
0
2
.4. Reaction of p-methoxyaniline ꢀ2, R ˆp-CH OC H )
3
6
4
ꢀ
Table 4)
In a ®rst approach, amide formation could be favoured by
displacement to the right of the previous equilibrium
Table 4. Reaction of p-methoxyaniline with RCO H at 1ꢀ08C 5scale:
2
mmol) under microwave activation 5MW) or classical heating 5K)
3
5Eq. 53)).
a
Yields 5%3)
R
Reaction time 5min) Relative amount 1/2
2
4
MW
K
Table 5. pK values for amines and carboxylic acid
C
6
6
H
ꢀ
ꢀ
30
1:1
29
33
28
62
68
69
8ꢀ
23
34
ꢀ8
71
86
18
32
2ꢀ
44
ꢀ9
ꢀ9
74
20
28
30
33
70
n-C H NH
17
C H CH NH
2
p-CH OC H NH
4
C H NH
ꢀ
8
2
6
ꢀ
2
3
6
2
6
2
3
3
0
0
1:1.ꢀ
1.ꢀ:1
1:1
1:1.ꢀ
1.ꢀ:1
1:1.ꢀ
1:1
1.ꢀ:1
1:1.ꢀ
1:1.ꢀ
1:1.ꢀ
pKb 3.3ꢀ
4.67
8.66
n-C
9.40
C
H
CH
2
30
C
6
H
ꢀ
CO
2
H
C
6
H
ꢀ
CH
2
2
CO H
9
H
19CO
2
H
3
3
0
0
pK
a
4.21
4.31
4.89
120
9 19
n-C H
30
3
3
6
0
0
0
From pK values for amines and carboxylic acids 5Table ꢀ),
one can expect rather similar behaviours of the different
120
carboxylic acids due to their close pK values and a large
a
a
In isolated products.
in¯uence of the amine structure between aliphatic 5pK <3±
b
ꢀ) and the less basic aromatic ones 58±10). As the experi-
Yields were signi®cantly enhanced due to the electron-
donating effect of the methoxy group. These experiments
correlated better with phenylacetic and decanoic acid
experiments with evidence for some rather limited speci®c
microwave effects.
mental sequences 5Tables 1±4) are clearly different from the
ones we can expect from these predictions, this possible
in¯uence on the position of acid±base equilibrium has to
be rejected.
3.2. Nucleophilic attack of amine on carbonyl group
ꢀEq. ꢀ4))
3. Discussion
It constitutes the rate-determining step and occurs by the
attack of nitrogen atom on carbonyl group of the acid
In the examples described in Tables 1±4, one can conclude
that good to excellent yields of amides 5except in some
cases with benzoic acid) can be obtained by simple mixing
of reagents under microwave irradiation with reduced
reaction times 510±30 min). Signi®cant differences in
reactivities were observed according to the structures of
the reagents:
5Scheme 1).
Ab initio calculations 5geometry, charges and orbital levels)
have allowed us the conclusion that this reaction occurs
2
ꢀ
presumably under orbital control as there is no connection
with charge densities on N and C atoms of amine and acid,
respectively. Conversely, good correlations are obtained
with the relative energy levels of the molecular orbitals
Carboxylic acid : n-C H CO H $ C H CH CO H
2
9
19
2
6
ꢀ
2
2
6
@
C H CO H
6 ꢀ 2
5MOs) involved in the electronic transfer 5Scheme 2).
These are the occupied N-non-bonding orbital 5n )
N
Amines :
C H CH NH . n-C H NH
6 ꢀ 2 2 8 17 2
p
describing the amine lone pair and the empty p
on the carboxyl moiety.
orbital
CvO
2
7
.
p-CH OC H NH . C H NH
2
3
6
4
2
6
ꢀ

21ꢀ8
L. Perreux et al. / Tetrahedron 58 ꢀ2002) 2155±2162
Scheme 1. Mechanism for nucleophilic attack of amine on carboxylic acid.
Scheme 3. Electrophilic assistance to nucleophilic attack by amine.
3.4. On the possibility of p-stacking
When each reagent 5amine and acid) bears an aromatic ring
in adequate relative position to give possible p±p inter-
2
8
Ê
actions at distances 3±4 A, p-stacking can be involved.
They are shown to play an important role especially under
solvent-free conditions
2
9,30
where they can be developed
with their optimal magnitude as restrictions imposed by
solvent±substrate interactions are minimal 5Scheme 4).
Scheme 2. Energy diagram representing the interactions between the
different reactants.
The highest n orbitals of the amines are found for non-
N
conjugated compounds that indeed correspond to the most
reactive species. Due to conjugation with the orbitals of the
phenyl ring, the n orbital is lowered in energy in the case of
N
aniline which is the less reactive species. Similar trends are
series: when conjugation with the phenyl
rises in energy. As a conse-
p
found in the p
ring MOs occurs, the p
CvO
p
Scheme 4. Approach showing an optimal magnitude of p±p interactions.
CvO
quence, benzoic acid is predicted to be the less reactive
species.
This may be the case of two benzylic reagents, i.e. benzyl-
amine and phenylacetic acid 5Scheme 4). This phenomenon
allows for a stabilization of the transition state 5TS) of the
reaction thus leading to a decrease in activation energy and
therefore enhancement in yields.
3
.3. In¯uence of the excess of one reagent
The most striking case concerns the in¯uence of the ratio of
1
/2 for the reaction of benzoic acid with benzylamine 5Table
). Among some other possibilities, the most simple and
1
To support the possibility of p-stacking, molecular model-
ling calculations 5MP3 type which is the most adapted
method to describe hydrogen bonding and the interactions
between non-bonding atomsÐHyperchem program) were
done on N-benzylbenzamide. The most stable form is the
one where overlapping between p systems is involved
adapted interpretation for this observation lies in the possi-
bility of complexation by hydrogen bonding of the carbonyl
group of RCO H with the excess of either amine or acid.
2
This provides some explanation of its electrophilic assis-
tance to nucleophilic attack by N atom 5Scheme 3).
5Scheme ꢀ).
1
3a
A similar observation was made by Baldwin et al. with
respects to the reaction of benzylamine with benzoic acid
under microwave activation. They have shown that the addi-
tion of one equivalent of imidazole induced an increase in
the yields 5from 13 to 61%). This secondary amine did not
react with the carboxylic acid but electrophilically assisted
the carbonyl group.
3.5. Interpretation of speci®c microwave effects
Very important speci®c non-thermal microwave effects are
evidenced in the majority of the reactions concerned. They
seem to be increasingly important in the case of sluggish
reactions. For instance, they allow for an improvement in

L. Perreux et al. / Tetrahedron 58 ꢀ2002) 2155±2162
21ꢀ9
generates polar species prone to interact strongly with
microwave radiation which induces a noticeable rise in
temperature 5Scheme 7).
The pro®les of the elevation in temperature obtained under
microwave irradiation are representative of the polarity of
the reactants as they interact strongly with the electro-
magnetic ®eld. The amine and the carboxylic acid interact
weakly with microwave radiation, as the temperatures
obtained, after 30 min of microwave exposure, are 12ꢀ
and 808C, respectively. On the other hand, there is a signi®-
cant enhancement in the polarity with the liquid ammonium
carboxylate and amide, i.e. when above their melting point
517ꢀ and 1228C, respectively).
Scheme 5. Optimized geometry for N-benzylphenylacetamide.
yields from 8±17% 5conventional heating) to 7ꢀ±80%
5microwave activation) in the reaction of benzoic acid and
benzylamine.
It is evident that the effect lies in the enhancement by micro-
wave radiation of nucleophilic attack by the nitrogen atom
on the carbonyl group 5the rate-determining step) as the
temperature 51ꢀ08C) allows for a water removal regardless
the mode of activation.
The increase in the polarity of the system provided by the
ammonium carboxylate thus strongly favours to the reaction
as well as the formation of polar amide during the course of
the reaction.
These effects can be easily understood by considering the
possible microwave activation affects by dipole±dipole
interactions according to mechanistic considerations and
to an increase of the polarity of the system during the
0
00
Some measurements of dielectric characteristics 51 and 1 )
are in progress to support these hypotheses.
3
1
progress of the reaction 5Scheme 1).
4. Conclusion
It is well established that microwave±materials interactions
3
2
are increased with the polarity of the materials. As the TS
is consequently more polar than the ground state 5GS), its
stabilization is more affected 5by dipole±dipole interactions
with the electromagnetic ®eld), thus resulting in a decrease
in activation energy 5Scheme 6).
Pyrolysis of salts obtained by mixing neat primary amines
and carboxylic acids were, in a great majority of cases,
realized under solvent-free conditions within short times
and appreciable yields with microwave activation. The
evident speci®c non-thermal microwave effects are
attributed to enhancements in microwave±materials inter-
action due to polarity increase during the progress of the
reaction. Further experiments including dielectric character-
It is important here to state that the preliminary formation of
ammonium salts be considered of prime interest as it
Scheme 6. Relative stabilizations of a more polar TS when compared to GS 5polar mechanism).
Scheme 7. Pro®le of rise in temperature of the different reactants for the reaction of benzylamine with benzoic acid when submitted to microwaves 5emitted
powerˆ300 W).

2160
L. Perreux et al. / Tetrahedron 58 ꢀ2002) 2155±2162
3
CDCl ): d 4.6ꢀ 5s, 2H), 6.40 5br s, 1H), 7.40 5m, 8H),
7.80 5d, 2H, Jˆ8.0 Hz).
istics measurements and theoretical approaches are under
progress.
3
5
.3.2. N-Benzylphenylacetamide. 3ꢀ53, RˆC H CH ,
0
6 ꢀ 2
6
ꢀ
2
5
. Experimental
.1. Theoretical calculations
Ab initio calculations were performed at the RHF level
R ˆC H CH ): mpˆ118±1208C 5lit. mpˆ118±1198C);
1
H NMR 52ꢀ0 MHz, CDCl ): d 3.46 5s, 2H), 4.2ꢀ 5s, 2H),
3
1
3
7.27 5m, 10H), 8.60 5br s, 1H); C NMR 562.ꢀ MHz,
5
CDCl ): d 43.48, 43.64, 127.19, 127.27, 127.39, 128.ꢀ2,
3
128.86, 129.29, 134.89, 138.19, 170.62.
3
3
using the Gaussian set of programs. The polarized split-
valence basis set 6-31G5d) was used throughout.
Geometries of amines and acids were fully optimized.
Characterizations of the optimized extrema were performed
by frequencies calculations.
0
5.3.3. N-Benzyldecanamide. 53, RˆC H , R ˆC H CH ):
9
19
6
ꢀ
2
1
mpˆ60±628C; H NMR 5200 MHz, CDCl ): d 0.8ꢀ 5t, 3H,
3
Jˆ3.4 Hz), 1.24 5m, 12H), 1.6ꢀ 5m, 2H), 2.20 5t, 2H,
Jˆ3.9 Hz), 4.43 5d, 2H, Jˆ2.8 Hz), ꢀ.60 5br s, 1H), 7.30
1
m, ꢀH); C NMR 562.ꢀ MHz, CDCl ): d 14.0, 22.ꢀ9,
3
5
3
5
.2. Reactants and equipment
2ꢀ.74, 29.29, 29.38, 31.80, 36.72, 43.ꢀ2, 127.36, 127.72,
28.60, 173.01. HRMS: calcd 261.41, found 261.21.
1
The microwave reactor was
5
a
Synthewave 402 from Prolabo) with focused waves
monomode system
w
36
0
): d 0.9 5t, 3H,
5.3.4. N-Octylbenzamide. 53, RˆC
H
, R ˆC
H17):
8
6
ꢀ
1
operating at 2.4ꢀ GHz. The temperature was controlled
throughout the reaction and evaluated by an infrared detec-
tor which indicated the surface temperature 5the IR probe
was calibrated by tuning the emissivity factor using a
thermo-couple introduced into the reaction mixture).
Temperature was maintained constant at a chosen value
by modulation of emitted MW power 5Fig. 1). Mechanical
stirring during the irradiation period provided good homo-
geneity 5power and temperature). Data gathering and treat-
ment was performed by a computer. All reactions were
performed in cylindrical Pyrex open vessels.
mpˆ39±418C; H NMR 5200 MHz, CDCl
3
Jˆ6.6 Hz), 1.3ꢀ 5m, 10H), 1.60 5m, 2H), 3.40 5t, 1H,
Jˆ6.4 Hz), 3.4ꢀ 5t, 1H, Jˆ6.6 Hz), 6.0ꢀ 5br s, 1H), 7.4ꢀ
1
3
5m, 3H), 7.7ꢀ 5d, 2H, Jˆ8.0 Hz); C NMR 5ꢀ0 MHz,
CDCl ): d 13.90, 22.48, 28.91, 29.07, 29.17, 29.ꢀꢀ, 31.66,
3
40.04, 126.92, 128.26, 131.06, 134.81, 167.ꢀ1.
5.3.5. N-Octylphenylacetamide. 53, RˆC
H
ꢀ
CH
,
2
6
0
1
R ˆC
H
8
17): mpˆ61±648C; H NMR 52ꢀ0 MHz, CDCl
):
3
d 0.8ꢀ 5t, 3H, Jˆ6.6 Hz), 1.10±1.ꢀ0 5m, 10H), 1.4ꢀ 5m,
2H), 3.10 5t, 1H, Jˆ6.3 Hz), 3.1ꢀ 5t, 1H, Jˆ6.7 Hz), 3.ꢀꢀ
1
s, 2H), ꢀ.03 5br s, 1H), 7.30 5m, ꢀH); C NMR 562.ꢀ MHz,
3
5
In order to compare microwave irradiation with conven-
tional heating, the reactions were performed under similar
experimental conditions 5weight of reactants, time and
temperature) using a thermostated oil bath. The temperature
was measured by the insertion of a Quick digital thermo-
meter into the reaction mixture and the rate of the tempera-
ture rise was adjusted to be the same as to that measured
under microwave irradiation.
CDCl ): d 13.79, 22.26, 2ꢀ.36, 31.37, 36.4ꢀ, 43.27, 127.1ꢀ,
3
127.ꢀ3, 128.43, 134.ꢀ6, 173.16;HRMS: calcd 247.38,
found 247.19.
0
5.3.6. N-Octyldecanamide. 53, RˆC
H
19, R ˆC
H17):
9
8
1
mpˆ63±648C; H NMR 5200 MHz, CDCl
): d 0.8ꢀ 5t,
6H, Jˆ6.6 Hz), 1.2ꢀ 5m, 22H), 1.4ꢀ±1.6ꢀ 5m, 4H), 2.1ꢀ
3
5t, 2H, Jˆ7.ꢀ Hz), 3.20 5t, 1H, Jˆ6.3 Hz), 3.2ꢀ 5t, 1H,
1
3
Jˆ6.ꢀ Hz), 7.40 5br s, 1H); C NMR 5ꢀ0 MHz, CDCl ): d
3
1
13
H and C NMR spectra were recorded at 200 and ꢀ0 MHz,
13.78, 22.40, 2ꢀ.77, 26.81, 29.16, 31.60, 36.46, 39.27,
173.28.
and at 2ꢀ0 and 62.ꢀ MHz 5Br uÈ ker WP 200, WP 2ꢀ0, respec-
tively). Chemical shifts are given in ppm down®eld from
internal standard tetramethylsilane 5dˆ0.00 ppm).
3
0
5.3.7. N-Phenylbenzamide. 53, RˆC H , R ˆC H ):
6
ꢀ
6
ꢀ
commercial compound.
5
.3. General procedure for the synthesis of amides
5
.3.8. N-Phenylphenylacetamide. 53, RˆC H CH ,
6
ꢀ
2
0
37
1
Synthesis of amides was performed under microwave
irradiation or conventional heating. In a Pyrex cylindrical
open reactor adapted to the Synthewave reactor, 3 mmol of
amine were mixed with 3 mmol of carboxylic acid. The
mixture was then homogenized and subjected to microwave
irradiation with mechanical stirring. At the end of irradia-
tion, the reaction mixture was cooled to room temperature
and extracted with chloroform. The extracts were washed
successively with a solution of 2 M HCl 5ꢀ0 mL) and a
R ˆC
H
6
ꢀ
): mpˆ117±1198C 5lit. mpˆ117±1188C); H
): d 3.6ꢀ 5s, 2H), 7.0ꢀ±7.3ꢀ 5m,
NMR 52ꢀ0 MHz, CDCl
10H).
3
0
5.3.9. N-Phenyldecanamide. 53, RˆC
H
9
19, R ˆC
H ):
6 ꢀ
1
mpˆ6ꢀ±668C; H NMR 5200 MHz, CDCl
): d 0.8ꢀ 5t,
3H, Jˆ6.4 Hz), 1.2ꢀ 5m, 12H), 1.72 5m, 2H), 2.3ꢀ 5t, 2H,
3
Jˆ7.ꢀ Hz), 7.10 5t, 2H, Jˆ7.8 Hz), 7.30 5t, 1H, Jˆ7.8 Hz),
1
3
7.ꢀ0 5t, 2H, Jˆ7.9 Hz); C NMR 562.ꢀ MHz, CDCl
): d
3
solution of ꢀ% NaHCO 5ꢀ0 mL). The organic layer was
3
14.03, 22.ꢀ6, 2ꢀ.68, 29.22, 29.3ꢀ, 31.78, 37.62, 120.00,
124.03, 128.77, 138.06, 172.03;HRMS: calcd 247.38,
found 247.19.
dried over MgSO4 and concentrated under vacuum.
The crude product was puri®ed by simple washing with
pentane.
5
.3.10. N-ꢀp-Methoxyphenyl)benzamide. 53, RˆC H ,
0
OC H
3 6 4
6
ꢀ
1
0
5
.3.1. N-Benzylbenzamide. 53, RˆC H , R ˆC H CH ):
R ˆp-CH
): mpˆ162±1638C, H NMR 5200 MHz,
6
ꢀ
6
ꢀ
2
3
4
1
mpˆ10ꢀ±1078C 5lit. mpˆ10ꢀ8C); H NMR 52ꢀ0 MHz,
DMSO): d 3.7ꢀ 5s, 3H), 6.9ꢀ 5d, 2H, Jˆ8.9 Hz), 7.ꢀ0 5m,

L. Perreux et al. / Tetrahedron 58 ꢀ2002) 2155±2162
2161
3
5
H), 7.70 5d, 2H, Jˆ8.9 Hz), 7.9ꢀ 5d, 2H, Jˆ8.0 Hz), 10.1ꢀ
3. Lawrence, R. H.;Biller, S. A.;Fryszman, O. M.;Poss, M. A.
Synthesis 1997, ꢀꢀ3.
1
br s, 1H); C NMR 5ꢀ0 MHz, DMSO): d ꢀꢀ.13, 113.71,
3
1
1
6
22.00, 127.ꢀꢀ, 128.32, 131.3ꢀ, 132.34, 13ꢀ.07, 1ꢀꢀ.ꢀꢀ,
6ꢀ.13;Anal. calcd for C 14H NO : C, 73.99;H, ꢀ.77;N,
.16;O, 14.08. Found: C, 73.47;H, ꢀ.78;N, 6.04;O, 14.01.
4. Burnell-Curty, C.;Roskamp, E. J. Tetrahedron Lett. 1993, 34,
ꢀ193.
ꢀ. Froyen, P. Synth. Commun. 1995, 25, 9ꢀ9.
13
2
6
. Jang, D. O.;Park, D. J.;Kim, J. Tetrahedron Lett. 1999, 40,
ꢀ323.
5
.3.11.
N-ꢀp-Methoxyphenyl)phenylacetamide.
0
53,
H
1
RˆC H CH , R ˆp-CH OC H ): mpˆ124±12ꢀ8C,
7. Jursic, B. S.;Zdravkovski, Z. Synth. Commun. 1993, 23, 2761.
8. Abramovich, R. Org. Prep. Proced. Int. 1991, 23, 683.
9. Caddick, S. Tetrahedron 1995, 51, 10403.
6
ꢀ
2
3
6
4
NMR 5200 MHz, DMSO): d 3.70 5s, ꢀH), 6.90 5d, 2H,
Jˆ8.9 Hz), 7.3ꢀ 5m, ꢀH), 7.6ꢀ 5d, 2H, Jˆ8.9 Hz), 10.1ꢀ
1
br s, 1H); C NMR 5ꢀ0 MHz, DMSO): d 43.38, ꢀꢀ.02,
3
5
10. Loupy, A.;Petit, A.;Hamelin, J.;Texier-Boullet, F.;
Jacquault, P.;MatheÂ, D. Synthesis 1998, 1213.
11. Varma, R. S. Green Chem. 1999, 1, 43.
1
1
13.81, 120.86, 126.48, 128.27, 129.12, 132.47, 136.23,
ꢀꢀ.32, 168.74;HRMS: calcd 241.29, found 241.11.
1
2. Ruault, P.;Pilard, J. F.;Touaux, B.;Texier-Boullet, F.;
Hamelin, J. Synlett 1994, 93ꢀ.
5
.3.12. N-ꢀp-Methoxyphenyl)decanamide. 53, RˆC H ,
9
19
0
DMSO): d 0.8ꢀ 5m, 3H), 1.2ꢀ 5m, 12H), 1.70 5m, 2H),
1
R ˆp-CH OC H ): mpˆ102±1038C, H NMR 5200 MHz,
3
6
4
13. 5a) Baldwin, B. W.;Hirose, T.;Wang, Z. H. J. Chem. Soc.,
Chem. Commun. 1996, 2669. 5b) Hirose, T.;Baldwin, B. W.;
Wang, Z. H. Jpn. Kokai Tokkyo Koho 1998, 10036294 Chem.
Abstr., 1998, 128, 180333.
2
.30 5t, 2H, Jˆ7.ꢀ Hz), 3.80 5s, 3H), 6.7ꢀ 5d, 2H,
1
3
Jˆ8.8 Hz), 7.40 5d, 2H, Jˆ8.8 Hz), 8.3ꢀ 5br s, 1H); C
NMR 5ꢀ0 MHz, DMSO): d 13.96, 22.ꢀ2, 2ꢀ.73, 29.21,
2
1
1
4. Gadhwal, S.;Prakash Dutta, M.;Boruah, A.;Prajapati, D.;
Sandhu, J. S. Indian J. Chem. 1998, 37B, 72ꢀ.
9.34, 31.73, 37.2ꢀ, ꢀꢀ.21, 113.74, 121.94, 131.26,
ꢀ6.04, 171.99;HRMS: calcd 277.41, found 277.20.
1
ꢀ. El'Tsov, A. V.;Martynova, V. P.;Sokolova, N. B.;Dmitrieva,
N. N.;Brykov, A. S. Russ. J. Gen. Chem. 1995, 65, 4ꢀ4.
16. Hajipour, A. R.;Ghasemi, M. Indian J. Chem. ꢀB) 2001, 40,
5
.3.13. N-Phenethylbenzamide. 53, RˆC H CH ,
6
ꢀ
2
0
1
R ˆC H CH CH ): mpˆ94±968C, H NMR 52ꢀ0 MHz,
6
ꢀ
2
2
ꢀ04.
17. Chandrasekhar, S.;Takhi, M.;Uma, G.
997, 38, 8089.
CDCl ): d 2.70 5t, 2H, Jˆ6.9 Hz), 3.40 5t, 1H, Jˆ6.8 Hz),
3
Tetrahedron Lett.
3
.4ꢀ 5t, 1H, Jˆ6.9 Hz), 3.ꢀ0 5s, 2H), 6.00 5br s, 1H), 7.0ꢀ 5d,
1
1
3
2
CDCl ): d 3ꢀ.17, 40.ꢀ0, 43.37, 126.10, 126.89, 128.26,
H, Jˆ7.7 Hz), 7.2ꢀ 5m, 8H); C NMR 562.ꢀ MHz,
1
8. Marquez, H.;Plutin, A.;Rodriguez, Y.;Perez, E.;Loupy, A.
Synth. Commun. 2000, 30, 1067.
9. Vasquez-Tato, M. P. Synlett 1993, ꢀ06.
3
128.43, 128.ꢀ9, 129.08, 134.73, 138.ꢀ1, 170.8ꢀ;HRMS:
calcd 239.31, found 239.13.
1
2
2
0. Marrero-Terrero, A. L.;Loupy, A. Synlett 1996, 24ꢀ.
1. Seijas, J. A.;Vasquez-Tato, M. P.;Montserrat Martinez, M.;
Nunez-Corredoira, G. J. Chem. Res. ꢀS) 1999, 420.
2. 5a) Stuerga, D.;Gaillard, P. Tetrahedron 1996, 52, ꢀꢀ0ꢀ.
5
.3.14. N-Benzylhydrocinnamide. 53, RˆC H CH CH ,
0
H NMR 5200 MHz,
6 ꢀ 2
6
ꢀ
2
2
1
R ˆC H CH ): mpˆ84±868C,
2
CDCl ): d 2.ꢀ0 5t, 2H, Jˆ7.7 Hz), 2.9ꢀ 5t, 2H, Jˆ7.6 Hz),
3
5b) Stuerga, D.;Gaillard, P. J. Microwave Power Electrom.
Energy 1996, 31, 87.
1
3
4 C
NMR 5ꢀ0 MHz, CDCl ): d 31.41, 37.77, 42.ꢀ0, 12ꢀ.88,
.30 5d, 2H, Jˆꢀ.7 Hz), ꢀ.60 5br s, 1H), 7.2ꢀ 5m, 10H);
3
2
2
3. Loupy, A.;Perreux, L. Unpublished results.
4. Howard, P. H.;Meylan, W. M. In Handbook of Physical
Properties of Organic Chemicals;Lewis, E., Ed.;CRC:
New York, 1997.
126.93, 127.23, 128.09, 128.21, 140.ꢀꢀ, 172.08;Anal.
calcd for C H NO: C, 80.30;H, 7.16;N, ꢀ.8ꢀ;O, 6.69.
Found: C, 79.81;H, 7.1ꢀ;N, ꢀ.98;O, 6.89.
1
6
17
2
2
ꢀ. Fleming, I. Frontier Orbitals and Organic Chemical
Reactions;Wiley: London, 1976;pp ꢀ±32.
5
.3.15. N-Phenethylhydrocinnamide. 53, RˆC H CH CH ,
6
ꢀ
2
2
0
1
R ˆC H CH CH ): mpˆ98±1008C, H NMR 52ꢀ0 MHz,
6
ꢀ
2
2
6. To simplify the calculations, we modelled methylamine and
acetic acid for octylamine and decanoic acid, respectively 5a
long chain does not modify the results).
CDCl ): d 2.4ꢀ 5t, 2H, Jˆ6.6 Hz), 2.70 5t, 2H, Jˆ6.7 Hz),
3
2
.9ꢀ 5t, 2H, Jˆ6.6 Hz), 3.40 5t, 1H, Jˆ6.6 Hz), 3.4ꢀ 5t, 1H,
Jˆ6.7 Hz), ꢀ.30 5br s, 1H), 7.0ꢀ 5m, 2H), 7.20 5m, 8H);
2
7. These orbitals may not be the frontier orbitals strictly
speaking: for instance, the LUMO in phenylacetic acid is a
molecular orbital located on the phenyl ring as the HOMO in
the case of the benzylamine.
Anal. calcd for C H NO: C, 80.60;H, 7.ꢀ6;N, ꢀ.ꢀ3;O,
1
7
19
6
.32. Found: C, 80.48;H, 7.ꢀ7;N, ꢀ.ꢀ9;O, 6.ꢀ1.
2
2
3
8. Jones, G. B.;Chapmann, B. J. Synthesis 1995, 47ꢀ.
9. Loupy, A.;Zaparucha, A. Tetrahedron Lett. 1993, 30, 333.
0. Diez-Barra, E.;de la Hoz, A.;Merino, S.;Sanchez-Verdu, P.
Tetrahedron Lett. 1997, 38, 23ꢀ9.
Acknowledgements
We sincerely thank `Electricit e de France' 5E.D.F.),
Research and Development DivisionÐ77818 Moret sur
Loing CedexÐ5France) and especially Dr Michel
MONEUSE and Dr Karine BURLE for their appreciated
3
3
3
1. Loupy, A.;Perreux, L.;Liagre, M.;Burle, K.;Moneuse, M.
Pure Appl. Chem. 2001, 73, 161.
2. Gedye, R. N.;Smith, F. E.;Westaway, K. C. Can. J. Chem.
®
nancial and scienti®c support.
1
998, 66, 17.
3. Frisch, M. J.;Trucks, G. W.;Schlegel, H. B.;Scuseria, G. E.;
Robb, M. A.;Cheeseman, J. R.;Zakrzewski, V. G.;
Montgomery, J. A.;Stratmann, R. E.;Burant, J. C.;Dapprich,
S.;Millam, J. M.;Daniels, A. D.;Kudin, K. N.;Strain, M. C.;
Farkas, O.;Tomasi, J.;Barone, V.;Cossi, M.;Cammi, R.;
Mennucci, B.;Pomelli, C.;Adamo, C.;Clifford, S.;
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