Direct amidation of carboxylic acids with amines under microwave irradiation using silica gel as a solid support

Article abstract of DOI:10.1039/c5gc00189g

A highly improved and green methodology for the direct amidation of carboxylic acids with amines using silica gel as a solid support and catalyst is described. The scope of this method is exemplified by the use of several aliphatic, aromatic, unsaturated and fatty acids. The reaction is also applied to different primary and secondary amines. Typically, the amines should be aliphatic, but aromatic amines can be used as well, though with lower yields. Several experiments to illustrate the selectivity of this methodology were also carried out with several more functionalized acids and amines. This approach is a substantial improvement over other previously described methods in amide synthesis.

Full text of DOI:10.1039/c5gc00189g

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Journal Name
RSCPublishing
ARTICLEꢀ
Direct amidation of carboxylic acids with amines
under microwave irradiation using silica gel as a solid
support
Cite this: DOI:
10.1039/x0xx00000x
Andrea Ojeda-Porras,a Alejandra Hernández-Santanaa and Diego Gamba-
Sánchez*a
Received 00th January 2012,
Accepted 00th January 2012
A highly improved and green methodology for the direct amidation of carboxylic acids with
amines using silica gel as a solid support and catalyst is described. The scope of this method is
exemplified by the use of several aliphatic, aromatic, unsaturated and fatty acids. The reaction
is also applied to different primary and secondary amines. Typically, the amines should be
aliphatic, but aromatic amines can be used as well, though with lower yields. Several
experiments to illustrate the selectivity of this methodology were also carried out with several
more functionalized acids and amines. This approach is a substantial improvement over other
previously described methods in amide synthesis.
DOI: 10.1039/x0xx00000x
www.rsc.org/
acids with amines is a potential complementary procedure to
eliminate some of the reported synthetic challenges. This
Introductionꢀ
Amides are undeniably one of the most important functional
groups in organic chemistry; they are present in many naturally
occurring molecules, synthetic polymers, peptides, and
pharmaceutical agents, among others.1 Traditionally, amides
have been prepared by coupling activated carboxylic acid
derivatives and amines,2 from carboxylic acids using
stoichiometric amounts of condensing reagents3 and more
reaction has been neglected for many years principally because
of the long reaction times and high temperatures needed.16
Currently, microwave irradiation has proven to be efficient at
reducing the reaction times in many organic transformations.17
One of the first examples where microwaves have been
successfully applied to reduce the reaction time is the
esterification reaction of carboxylic acids with alcohols.18 Our
aim was to extend the use of microwaves to the amidation
reaction, and we report herein our principal results in this area,
which appear very promising as a more general and easier
method for amide synthesis than those currently in use.
recently by innovative methods such as transamidation,3c,
4
employing carbamates as the amine source,5 via S-
nitrosothiacids,6 oxidative amidation of aldehydes,7 very
recently via sulfynilamides8 and amidation of esters,9 in
addition to the more well-known named reactions.10 Despite all
these existing methodologies, new synthetic efforts have been
made in order to obtain amides directly from carboxylic acids
without using any coupling reagent. The main motivation for
the development of new methods is the reduction of waste,
leading to a more eco-friendly or green process. The formation
of an amide moiety by classical methods is one of the most
used procedures in the pharmaceutical industry.11 However, as
acknowledged ten years ago by the ACS, poor atom economy
in amide synthesis is one of the most important challenges to
overcome in synthetic organic chemistry.11c
Previous work
O
H2O
O
NH2
R1
R1
R
N
H
R
OH
Acid
Amine
Loupy18: M.W., solvent free, limited to aliphatic acids and aliphatic amines
Clark19: Reflux of toluene,K60 catalyst, limited to aliphatic acids.
Komura20: Reflux of toluene,MCM-41 catalyst, limited to fatty acids and
long-chain amines.
This work
O
H
N
O
All of methodologies mentioned above have significant
drawbacks, including the generation of by-products or residues,
the cost of the coupling reagents and/or the limited scope of
substrates. The use of catalytic boron derivatives,12 other
homogeneous13 or heterogeneous14 catalysts and/or enzymes15
has emerged as powerful alternatives to the traditional
amidation process. Thus, the thermal amidation of carboxylic
Silica Gel
M.W
R1
R1
R2
H2O
R
N
R
OH
R2
Acid
Amine
Aliphatic, aromatic, fatty and unsaturated acids.
Aliphatic, aromatic primary and secondary amines.
Schemeꢀ1.ꢀComparisonꢀbetweenꢀpreviousꢀandꢀpresentꢀwork.ꢀ
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Previous investigations using microwaves in amide synthesis 2), and the azeotropic removal of water only moderately
were reviewed recently19 and include the use of the Ritter increased the obtained yield but diminished the reaction time
reaction10a and the amidation of esters.9b Furthermore, a considerably (entry 3). We decided to use Fe(III) salts as an
previous work reported by Loupy and co-workers20 showed the addition to our previously reported work;4 however, even
first microwave-assisted synthesis of amides from carboxylic though effective, the reaction did not exhibit better yields (entry
acids. Unfortunately, this reaction is restricted to aliphatic acids 4). We were delighted to see that the combination of
and primary aliphatic amines, and with only activated aromatic microwave heating and the use of silica gel as a solid support
amines being reactive, the method has a very limited substrate effectively catalyzed the reaction, affording a much better yield
scope. Clark and co-workers.21 recently used a heterogeneous in a shorter reaction time (entry 6) than the reaction in the
silica-based catalyst for amidation reactions, which absence of any catalyst or additive (entry 7). The reaction time
demonstrated a better scope but with longer reaction times, the is comparable with the reaction performed under solvent-free
use of azeotropic removal of the water by-product, and the need conditions and microwave heating, but the yield was improved
for very high temperatures to activate the catalyst. Komura and by almost 20 % (entries 5 and 6).
co-workers22 used
mesoporous silica MCM-41 with fatty acids and long-chain scope of this method by investigating a variety of different
a very similar approach employing With these promising results, we decided to further explore the
amines (Scheme 1).
acids.
Table 2. Reaction of benzylamine with different acids.a
ResultsꢀandꢀDiscussionꢀ
O
O
O
Silica gel
These three results reported previously inspired us to explore a
combination of techniques avoiding the use of solvent for a
more eco-friendly method. The use of silica gel as a solid
support for microwave-assisted synthesis has been previously
shown to be effective in other reaction types.23 Hence, we
anticipated that the same approach could be applied
successfully using chromatographic silica gel and microwave
heating as a new approach in amide synthesis.
Ph
Ph
NH2
R
N
H
Ph
Ph
M.W. 80 min
R
OH
O
O
N
H
N
H
H
N
H
Ph
6; 83 % (quantb)
4; 78 %
5; 85 %
O
O
O
In our initial studies, an α,β-unsaturated acid and benzylamine
was used as a model reaction. Cinnamic acid was chosen
because only a few examples exist in the literature where
unsaturated acids are used as substrates for direct amidation.24
This may be a consequence of the two electrophilic sites
present, which may participate in competitive Michael
reactions.
Ph
N
H
Ph
F3C
N
H
Ph
N
Ph
H
8; 96 %
9; 94 %
7; 94 %
O
O
N
H
Ph
N
H
Ph
7
7
11; quantc
10; 86 %
a. All reactions were performed with 1.5 mmol of acid and 1.5 mmol of amine
supported on 1.0 g of silica gel 60 and irradiated for 4 cycles of 20 min at
130ºC. b. The reaction was performed using malonic acid. c. The reaction was
performed using 1.95 mmol of acid and 1.5 mmol of amine.
Table 1. Optimization of the microwave-assisted amidation reaction
conditions.
O
O
Ph
NH2
Table 2 shows that in terms of acid compatibility, the reaction
is quite general. Saturated aliphatic acids reacted very well
(products 4-7), and even small acids such as formic and acetic
acid still afforded good yields (products 5 and 6). Benzoic acid
was used as a representative example of aromatic acids and
proved to work much better than expected. In fact, looking in
detail at all previous direct amidation protocols, aromatic acids
generally give the lowest yields. However, in our case, the
combination of benzoic acid with the primary aliphatic amines
worked very well to obtain product 8 (see below) with excellent
yields. Highly acidic trifluoroacetic acid showed good
reactivity and to the best of our knowledge is the first example
of direct trifluoroacetylation with a free acid (product 9). Long-
chain acids also worked as expected and afforded the desired
product 10 in good yield. Surprisingly, using malonic acid did
not produce double or single amidation; instead, product 6
(acetylation product) was the only isolated product, even when
a large excess of amine was used. We believe that the product is
Ph
N
H
Ph
Ph
OH
2 (1.0 equiv.)
Conditions
3
1 (1.0 equiv.)
Entry
Time
5 h
36 h
3 h
Yield (%)
1
2
3
4
5
6
B(OH)3, p-xylene refluxa
20 % w.t silica-gel, p-xylene reflux
20 % w.t silica-gel, p-xylene refluxa
FeCl3, p-xylene reflux
69
50
79
68
73
94
27 h
Microwave heating solvent freeb
Microwave heating silica gel as
supportb
40 min
40 min
7
p-xylene at refluxa
48 h
20
The reaction was performed with a Dean-Stark trap. b.The acid and the
amine were heated under microwave irradiation at 130ºC.
a.
Before exploring microwave heating and the use of silica gel,
we examined several other systems for comparison to
demonstrate the advantages of our approach. Boric acid has
been described as an effective catalyst for amidation.13a The
reaction in the presence of boric acid proceeded smoothly with
a 69 % yield (entry 1). Silica gel also proved to be useful (entry
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formed after the decarboxylation of the first formed It should be noted that all reactions performed using crotonic
monoamide. Other unsaturated acids such as crotonic acid are acid were prepared using a small excess of acid (1.3 equiv.);
also active, and the product was obtained in quantitative yield otherwise, the Michael addition product on the amide resulted,
1
(product 11).
as observed by H NMR of the crude product. However, the
The next step to show reaction generality was to explore acid excess was enough to avoid the Michael product
different amines. We decided not to use a specific acid in order formation, and simple amides were the only observed product
to illustrate that many combinations are possible. Table 3 shows after treatment.
the results obtained for the amide synthesis using a variety of The unsaturated acids also reacted with aromatic primary
carboxylic acids with aliphatic, aromatic primary and secondary amines (products 16 and 17). The reaction between aniline and
amines.
cinnamic acid is slower than the reactions of the same acid with
The reaction between unsaturated acids and aliphatic primary other amines; this causes partial oxidation of aniline and
amines (products 12 and 13) was successful with the products consequently low yields. We decided to use freshly distilled
obtained in excellent yield, even when a more functionalized aniline and make its addition in portions of 0.3 equivalents after
amine (product 13) was used.
each microwave irradiation. Using this slight modification we
were able to obtain product 16 in good yield. Nevertheless,
inactivated amines such as o-nitroaniline did not react, and the
starting material was recovered even when the temperature or
reaction time was increased. As mentioned above, the use of
aromatic acids in direct amidation processes has always been a
drawback. In our case, benzoic acid reacted very well with
aliphatic primary amines (products 8 and 18), with secondary
amines (product 19) and with aromatic amines (product 20).
However, in this case, the reaction with inactivated aromatic
primary amines (p-nitroaniline) was unsuccessful. Ortho-
substituted benzoic acid is also reactive despite its more
hindered environment (product 21).
Table 3. Amidation of carboxylic acids with amines.
O
O
R1
R2
Silica gel
R2
N
H
R
N
M.W. 80 min
R
OH
R1
O
O
N
Ph
N
H
Ph
O
N
H
12 ; 98 %
13; 86 %
O
O
Ph
Ph
N
H
Ph
N
N
H
N
16; 65 %b
14; 88 %
It has to be noted that products 15 and 17 are successful
examples where both solid reagents were used.
15; 85 %a
O
OMe
Isovaleric acid showed very good reactivity with aniline
(product 22) and p-methoxyaniline (product 23). Other aliphatic
saturated acids were also active with secondary (product 24)
and aromatic (product 25) amines. All acids discussed
previously showed no reactivity with hindered secondary
amines; nevertheless, the use of formic acid in combination
with the secondary amine diphenylamine afforded the desired
amide in good yield (product 26). Surprisingly, the use of
dicyclohexylamine only allowed us to isolate the desired amide
in low yield (product 27). Fatty acids and secondary amines are
also a reactive couple (product 28); in addition, long β,γ-
unsaturated acids proved to be active (product 29), although the
conjugated isomer was isolated in 15 % yield.
As mentioned above, amide synthesis is one of the most used
reactions in organic chemistry laboratories in both academia
and industry. One of the principal reasons for the widespread
use of amidation is the synthesis of peptides. In our case, the
reaction of several acids with amino acid (glycine and
phenylalanine) methyl esters did not afford the desired amide.
On the other hand, free amino acids were completely
unreactive. We also tried N-protection with an acetyl group and
with BOC. Unfortunately, in those cases, only mixtures of
unidentified polar products were obtained.
O
Ph
N
H
Ph
O
N
H
18; 96 %
17; 76 %
I
O
O
Ph
Ph
N
N
H
Ph
N
H
19; 64 % (96 %c)
20; 84 %
21; 77 %
OMe
O
O
O
Ph
N
H
N
H
N
24; 62 %
22; 98 %
23; 75 % (93 %b)
O
H
O
H
O
N
Ph
N
N
H
Ph
Ph
25; 63 %
26; 77 %
27; 16 %
O
O
N
N
H
Ph
4
7
7
28; 92 %
29; 70 %
a.
The reaction was performed using 1.95 mmol of acid and 1.5 mmol of
b.
amine.
The reaction was performed using freshly distilled aniline and
making 4 additions of 0.3 equivalents each one, after each irradiation. c. based
on the recovered starting material.
We have shown that our method is more general, more versatile
and less expensive than other existing procedures. In addition,
this method fulfils at least six out of the twelve principles of
green chemistry.25 They are 1) prevention, 2) atom economy, 3)
less hazardous chemical synthesis, 5) safer solvents and
The unsaturated acids also reacted with secondary (product 14)
and heteroaromatic (product 15) amines, with very good results.
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auxiliaries, 8) reduced derivatives and 12) inherently safer
chemistry for accident prevention. In addition, two additional
principles can be considered: 6) design for energy efficiency
and 9) catalysis. The energy efficiency of microwave synthesis
has been recently analyzed and discussed by Moseley and
Kappe.26 The authors concluded, and we agree, that each
reaction has to be evaluated before automatically labelled as
“green” in terms of energy use. We are at present evaluating the
energy efficiency of this method compared with the other
methods previously described. Nevertheless, more recently,
Török and co-workers27 demonstrated that solid-supported
reactions under microwave irradiation are generally more
energy efficient than those using conventional heating.
Concerning the ninth principle, which suggests the use of a
catalyst, it is evident that silica gel has an additional effect and
that microwaves are not the only factor responsible for these
results (Table 1, entries 5 and 6). We strongly believe that this
effect does not result from the heat transfer of the solid support
alone but instead that there is a catalytic effect, as reinforced by
entries 2 and 3 in Table 1, where the use of catalytic amounts of
silica improves the yield in comparison to the use of
conventional heating of the reagents without any additive or
catalyst (entry 7). To provide further evidence to support our
hypothesis, we are currently working on a mechanistic
proposal. In conclusion, 6 out of the 12 principles of green
chemistry are fulfilled using our approach for amide synthesis,
with the potential for another 2 principles to be satisfied,
pending future results.
a.
OH
O
OH
O
Silica Gel
M.W
+
H2O
+
OH
N
H
Ph
H2N
Ph
30 (1.0 equiv.)
OH
2 (1.3 equiv)
32; (69 %)
H
N
O
b.
O
Ph
+
Silica Gel
M.W
+
H2O
H2N
Ph
NH2
31 (1.0 equiv.)
Schemeꢀ2.ꢀReactionsꢀofꢀcarboxylicꢀacidsꢀcontainingꢀaꢀnucleophilicꢀsite.ꢀ
NH2
33; (66 %)
2 (1.3 equiv)
Having studied more functionalized acids, we were interested
in investigating the reaction selectivity. To this end, we can
speculate from the results shown in Table 3 that primary
aliphatic amines are the preferred substrate in this
methodology. We were therefore interested in what would
happen when two different amines are present in the reaction
medium.
To explore this scenario, we conducted two experiments. In the
first experiment, a primary 35 and a secondary amine 36 were
used (Scheme 3a). As expected, the amide formation occurred
only with the primary amine 18 (89%).
a.
The last factor we evaluated in this study was selectivity. To
this end, we conducted a series of experiments that are listed
below.
The first experiment was the evaluation of carboxylic acids
with two electrophilic sites. For this experiment, we chose
chloroacetic and oxoacetic acid to study in independent
H2N
+
O
O
35
Silica Gel
M.W
+
H2O
Ph
OH
Ph
N
H
NH
36
34
18 (89 %)
b.
experiments
with
benzylamine.
Unfortunately,
both
H2N
+
O
O
35
experiments were unsuccessful, and the desired amides were
not observed. Only mixtures of polar inseparable products were
obtained.
Silica Gel
M.W
Ph
OH
+ H2O
Ph
N
H
NH2
34
18 (91 %)
Following from these results, we were interested in the
evaluation of the reactivity of carboxylic acids containing a
nucleophilic site. The chosen compounds were salicylic acid 30
and p-aminobenzoic acid 31. Each of these two compounds
may react with itself to produce esters or amides, respectively.
To avoid or minimize this possibility, we used 1.3 equivalents
of amine (Scheme 2). The reaction of salicylic acid with
benzylamine (Scheme 2a) afforded the desired amide 32 in 69
% yield as the only observed product. On the other hand, the
reaction with aminobenzoic acid produced a slightly lower
yield (66 %) of amide 33. These results are very encouraging,
showing the versatility of our method.
37
Schemeꢀ3.ꢀSelectivityꢀbetweenꢀamines.ꢀꢀ
The second test (Scheme 3b) demonstrates the competition
between aromatic and aliphatic amines. In this experiment, 1.0
equivalent of n-butylamine 35 and 1.0 equivalent of aniline 37
were mixed with 1.0 equivalent of benzoic acid 34 and
supported in 1.0 g of silica gel. After irradiation for 3 periods of
20 min, only amide 18 was isolated in very good yield (91 %),
showing that the reaction is completely selective to primary
aliphatic amines.
Lastly, to complete our evaluation of the selectivity in this
reaction, the use of amines with an additional nucleophilic site
was explored. To this end, we used ethanolamine 38 and
aminothiophenol 40.
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reduced pressure, and the reaction mixture was transferred to a
microwave tube. The mixture was then placed in a CEM
microwave reactor and subjected to 20 min cycles using a
power of 200 W, maintaining a constant temperature of 130 °C,
and a hold time of 2 min. The reaction mixture was then
allowed to cool to room temperature, sonicated for 20 min with
30 ml of ethyl acetate, and filtered, and the silica was washed
with another 30 ml of ethyl acetate. The organic phase was
washed with a saturated solution of NaHCO3 and HCl (10 %),
dried over MgSO4, and filtered, and the solvent was removed
under reduced pressure to obtain the pure product. In some
cases, flash chromatography was needed, as indicated in the
characterization data.
a.
O
O
HO
OH
Silica Gel
M.W
+
NH2
NH2
Ph
N
H
+
H2O
Ph
OH
OH
38
SH
34
39; (53 %)
b.
O
S
N
Silica Gel
M.W
+
2H2O
+
H
40
41
42; (34 %)
Schemeꢀ4.ꢀReactionꢀofꢀbenzoicꢀacidꢀandꢀbinucleophilicꢀamines.ꢀ
Scheme 4a depicts the reaction between benzoic acid 34 and
ethanolamine 38. As expected, the more nucleophilic nitrogen
was preferred over the oxygen, and consequently, the amide 39
was the only isolated product with acceptable yield (53 %).
This result was also observed by Orru and co-workers using
microwave heating, but at higher temperatures.24
When the competition is between the sulfur and nitrogen, the
only isolated product was benzothiazole 42 in low yield (34 %).
We strongly believe that the amide formation is the first step of
this reaction sequence, followed by the rapid dehydration of the
amide as described previously4, as no traces of amide were
Characterization of representative products
N-Benzyl-3-phenyl-acrylamide (3)
Following the general procedure, the compound was isolated
and analysis of the sample indicated 94 % yield (335 mg). mp:
1
107 °C (Lit.28 106-107 °C). H NMR (400 MHz, CDCl3) δ
(ppm) 7.66 (d, J = 15.6 Hz, 1H), 7.25-7.48 (m, 10H), 6.43 (d, J
= 15.7 Hz, 1H), 6.15 (s, 1H), 4.55 (d, J = 5.7 Hz, 2H). 13C
NMR (101 MHz, CDCl3) δ (ppm) 165.8, 141.4, 138.2, 134.8,
129.7, 128.8, 128.7, 127.9, 127.7, 127.6, 120.5, 43.9. IR: 3267,
3028, 1652, 1616, 1543 cm-1. MS (EI): 237 [M]+ (44), 131
(100), 103 (79), 91 (21), 77 (39).
1
observed by H NMR even after stopping the reaction at low
conversion. On the other hand two control experiments were
carried out using thiophenol and formic or acetic acid, in both
cases no traces of thioester was observed. Accordingly, we can
conclude that the reaction is completely selective towards
nitrogen when other nucleophilic atoms (oxygen or sulfur) are
present in the amine. Nevertheless, o-substituted aromatic
amines are less reactive compared with unsubstituted or p-
substituted anilines.
N-Benzyl-2,2,2-trifluoro-acetamide (9)
Following the general procedure, the compound was isolated
and analysis of the sample indicated 94 % yield (286 mg). mp:
1
69 °C (Lit.29 70-71 °C). H NMR (400 MHz, CDCl3) δ (ppm)
7.48 – 7.21 (m, 5H), 6.65 (s, 1H), 4.47 – 4.58 (m, 2H). 13C
NMR (101 MHz, CDCl3) δ (ppm) 157.2 (q, JC-F=37.3 Hz),
135.9, 129.1, 128.3, 128.0, 115.9 (q, JC-F=287.9 Hz), 44.0. IR:
3302, 3109, 1702, 1560 cm-1. MS (EI): 203 [M]+ (52), 134 (28),
91 (100).
Experimentalꢀ
N-Butyl-2-iodo-benzamide (21)
General Information
Following the general procedure, the compound was isolated
and analysis of the sample indicated 77 % yield (350 mg). mp:
90-92 °C (Lit.30 94-96 °C). 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.85 (d, J = 7.8 Hz, 1H), 7.36 (dd, J = 5.4, 1.8 Hz, 2H),
7.06-7.09 (m, 1H), 3.42 - 3.47 (m, 2H), 1.67 – 1.56 (m, 2H),
1.44 (dd, J = 15.2, 7.4 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ (ppm) 169.3, 142.6, 139.8, 130.9,
128.2, 128.1, 92.4, 39.8, 31.4, 20.2, 13.7. IR: 3275, 2947, 2865,
1637, 1547 cm-1. MS (EI): 303 [M]+ (11), 261 (31), 231 (100),
203 (23), 105 (22), 76 (42).
Proton nuclear magnetic resonance (1H NMR) spectra were
recorded on a 400 MHz spectrometer. The chemical shifts are
expressed in parts per million (ppm) referenced to TMS. The
data are reported as follows: δ, chemical shift; multiplicity
(recorded as br, broad; s, singlet; d, doublet; t, triplet; q,
quadruplet; quint, quintuplet and m, multiplet), coupling
constants (J in Hertz, Hz) and integration. Carbon nuclear
magnetic resonance (13C NMR) spectra were recorded on the
same instrument at 101 MHz. The chemical shifts are expressed
in parts per million (ppm), referenced to TMS. Infrared spectra
(IR) are reported in terms of absorption frequency (ν, cm-1)
using KBr. Mass spectrometry (MS) was performed in electron
impact (EI; 70 eV) mode. Mass spectra are reported as m/z.
High-resolution mass spectrometry (HRMS) was performed on
a Q-TOF LC/MS instrument.
Conclusionsꢀ
In conclusion, we have developed a versatile, simple, general
and green method for the direct amidation of carboxylic acids
with amines. The selectivity of this methodology was proved
using several examples, and it constitutes one of the more
efficient and simple methods for amide synthesis described to
date. The most significant advantages are the use of
inexpensive chromatographic silica gel without any special
treatment or activation and the use of microwave heating.
Typical procedure for amide synthesis
Amine (1.5 mmol) and carboxylic acid (1.5 mmol) were
dissolved in ethyl acetate (15 ml) before silica gel 60 230-400
mesh (1.0 g) was added. The solvent was then removed under
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Green Chemistry
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ARTICLEꢀ
JournalꢀNameꢀ
DOI: 10.1039/C5GC00189G
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The Chemistry Department and the Faculty of Science of the
Universidad de los Andes supported this work. A.O.-P.
acknowledges the Universidad de los Andes and especially the
Chemistry Department for the fellowship. We also
acknowledge Dr. Jaime Portilla for the access to the
microwaves equipment, Mr. Edwin Guevara for the mass
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15.
Notesꢀandꢀreferencesꢀ
a
Laboratory of Organic Synthesis, Bio and Organocatalysis, Chemistry
Department, Universidad de los Andes, Cra 1 No. 18A-12; Q:305, Bogotá
111711, Colombia
† Electronic Supplementary Information (ESI) available: [Experimental
procedures, characterization data and copies of all 1H NMR and 13C NMR
spectra]. See DOI: 10.1039/b000000x/
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Green Chemistry
View Article Online
DOI: 10.1039/C5GC00189G
Acids:
Aromatic and aliphatic
O
O
H2O
R
OH
R2
R
N
H
N
Silica Gel
R1
R1
R2
R: H, Alkyl, Aryl and Alkenyl
R1 and/or R2: H, Alkyl and Aryl
Amines:
Primary and secondary
MICROWAVES
32 examples, up to quantitative yield
A highly improved methodology for the direct amidation of carboxylic acids with amines using silica gel as a solid
support and catalyst is described. Several examples using aliphatic, aromatic, unsaturated and fatty acids combined with
primary and secondary amines are shown.