Microwave-assisted preparation of amides using a stable and reusable mesoporous carbonaceous solid acid

Article abstract of DOI:10.1039/b821392p

An efficient and green microwave assisted protocol to prepare amides from amines via N-acylation using acidic polysaccharide derived mesoporous materials provides quantitative yields of amides in short reaction times.

Full text of DOI:10.1039/b821392p

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www.rsc.org/greenchem | Green Chemistry
Microwave-assisted preparation of amides using a stable and reusable
mesoporous carbonaceous solid acid
Rafael Luque,* Vitaly Budarin, James H. Clark* and Duncan J. Macquarrie
Received 28th November 2008, Accepted 13th January 2009
First published as an Advance Article on the web 29th January 2009
DOI: 10.1039/b821392p
An efficient and green microwave assisted protocol to
prepare amides from amines via N-acylation using acidic
polysaccharide derived mesoporous materials provides
quantitative yields of amides in short reaction times.
We have previously reported the preparation of acidic
R
polysaccharide-derived mesoporous materials (Starbon acids)
and their activity in a range of acid catalysed reactions
ꢀ
1
5–17
16
15
including esterifications,
etherifications, alkylations, and
acylations under microwave irradiation.
Inspired by the reported results of Narender et al. and
15
7a
Introduction
7b
Choudary et al. that employed solid acids in the acylation of
amines under conventional heating, we aimed to bring together
the advantages of using a highly active and reusable water tol-
Amide bond formations are one of the most important transfor-
1
mations carried out in pharmaceutical synthesis, accounting
ꢀ
R
for 65% of all preliminary screening reactions in industrial
erant solid acid (Starbon acid) as well as a microwave assisted
protocol that is believed to enhance the rates of reactions as well
as improving yields and potentially influencing selectivities in
2
medicinal chemistry laboratories as recently reported. Amides
also represent a very important family of intermediates widely
employed in the preparation of fine chemicals, cosmetics and
18,19
organic synthesis.
Herein, we report the efficient and atom
1–3
food additives. However, the majority of the current employed
protocols to form amides involve the use of stoichiometric
activated toxic and corrosive reagents (e.g. acid anhydrides
and/or acyl chlorides) with poor atom economy that generate
economic preparation of amides via N-acylation of primary and
ꢀ
R
secondary amines under microwave irradiation using a Starbon
acid as catalyst and acetic acid as the acylation reagent.
4,5
considerable waste. Furthermore, an excess of these reagents
is normally needed to achieve optimum amide yields and the
reaction is water-sensitive with the efficient removal of water
Experimental
ꢀR
Starbons acids were synthesized as recently reported in the
5,6
being a critical factor in the systems.
15–17
◦
literature.
The material carbonised at 400 C (herein after
The development of cleaner syntheses are key to reducing the
ꢀR
referred to as Starbon -400) was chosen for its ideal hydrophilic-
ity/hydrophobicity ratio and subsequently functionalised by
2
environmental impact of amide formations. In this regard, the
direct reaction of amines with carboxylic acids remains the most
suspending in H
h at 80 C. After sulfonation, the solid acid was washed with
2
SO (10 mL acid/g material) and heated for
4
2,6,7
attractive approach.
These types of reactions are arguably
◦
4
best carried out without catalysis where possible, however,
reaction conditions remain harsh in order to accomplish direct
distilled water until the washings were neutral, conditioned in
◦
◦
boiling toluene (150 C, 4 h) and water (100 C, 3 h) and finally
8
amide formation.
◦
oven dried overnight (100 C) before being tested in the catalytic
reaction. Sulfonated materials are denoted as Starbon -400-
A range of greener catalytic methodologies have been reported
ꢀR
for the preparation of amides. These include the N-acylation
SO H.
3
7,9
of amines with organic acids (Scheme 1), the use of solid
A typical N-acylation was carried out by reacting 2 mmol of
1
0
supported reagents (e.g. polymer-bound acylating agents),
the amine with 2 mmol acetic acid and 0.1 g catalyst in a tube
6,11
arylboronic or boronic acid derivatives,
and the use of
Many different catalysts have been
reported for the acylation of amines including transition metal
◦
using microwave radiation at 300 W (120–130 C maximum
5,10,12,13
microwave irradiation.
temperature reached) for 1–10 minutes. A general procedure to
isolate the formed amides was performed as follows: the residue
was then redissolved in DCM (5 mL), washed with brine (5 mL),
diluted HCl (5 mL), brine (5 mL), diluted NaOH (5 mL), brine
14
7c
salts, immobilised ionic liquids on mesoporous materials, and
7
solid acid catalysts.
(
5 mL), dried over MgSO4, and the solvent evaporated under
ꢀ
R
vacuum to yield the corresponding amide. Starbon acids were
reused after every reaction run. For this, the solid acids were
filtered off from the mixture after reaction completion, washed
◦
with methanol and acetone and dried at 100 C prior to their
Scheme 1 Catalysed N-acylation of amines using organic acids.
reuse in the reaction.
Microwave experiments were carried out in a CEM-
DISCOVER model with PC control and monitored by sampling
aliquots of reaction mixture that were subsequently analysed by
GC/GC-MS using an Agilent 6890 N GC model equipped, with
Green Chemistry Centre of Excellence, The University of York,
Heslington, YO10 5DD, York, UK. E-mail: jhc1@york.ac.uk,
q62alsor@uco.es; Fax: +44 1904 432705; Tel: +44 1904 432865
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a 7683B series autosampler, fitted with a DB-5 capillary column
and an FID detector. Experiments were conducted in a closed
vessel (pressure controlled) under continuous stirring.
Table 1 R N-Acylation of a range of amines with acetic acid using
ꢀ
Starbon -400-SO
3
H as catalyst and acetic acid as acylating agent under
a
microwave irradiation
c
Time/ Conversion
S
amide
Entry Amine
Product
min
(mol%)
(mol%)
Results and discussion
b
Blank
15
<10
>98
The use of acetic acid in the N-acylation reaction instead
of the corrosive acetyl chloride and the lachrymator acetic
anhydride provides many advantages from both economical
and environmental standpoints, and water is the only by-
product. The N-acylation of aniline (primary amine) was chosen
as reaction test to compare the activity of a range of solid
acid catalysts including acidic clays, zeolites and Al-MCM-1
materials. The results are shown in Fig. 1. Initially, a 1:1 ratio
amine:acetic acid, 0.1 g catalyst, maximum microwave power
output (300 W) and 15 min irradiation were selected as reaction
1
2
10
2
90 (87)
>99
>98
>99 (92)
3
4
5
6
2
3
3
5
>99 (95)
>95 (89)
89 (83)
>99
>99
>99
>99
15
conditions, in a similar way to previously reported results.
87 (79)
7
8
9
0.6
3
>99 (94)
>99 (94)
>99 (92)
>98
>99
>99
1
Fig. 1 Conversion and selectivity to amide (Sel Amide) of various solid
acids in the N-acylation of aniline with acetic acid [Reaction conditions:
1
1
0
1
15
15
77
68
>99
>99
2
mmol aniline, 2 mmol AcOH, 0.1 g cat., microwave, 300 W (maximum
◦
power), 130 C (maximum temperature reached), 15 min].
1
2
15
82
>95
Blank runs in the absence of catalyst provided almost no
conversion of starting material after microwaving for 15 min
a
2
mmol amine, 2 mmol AcOH, 0.1 g Starbon-400-SO
3
H, microwave,
(
Table 1, Blank).
◦
3
00 W (maximum power output), 130 C (maximum temperature
Quantitative conversion of the starting material was found
b
c
reached). Blank reaction in the absence of catalyst. Isolated yields,
where appropiate, are given in brackets.
in less than 15 min reaction under microwave irradiation using
ꢀ
R
Starbon -400-SO H. Comparatively, the reaction rates using
3
other solid acids were found to be between 5 to 10 times slower
ꢀ
R
ꢀR
than that of the Starbon acid. With Starbon acid being
the optimum catalyst for the reaction, the next step was to
optimise the reaction parameters. As expected, a decrease in
the microwave power and/or catalyst loading had a detrimental
effect on the amide yield. Interestingly, the selectivity to amide
was not significantly altered by changing these parameters and
in general all solid acids were extremely selective to amide
formation. The time of microwave irradiation and the catalyst
loading were probably the most important parameters in the
A wide variety of primary and secondary aromatic, aliphatic
and cyclic hindered and unhindered amines were effectively and
selectively converted into their corresponding amides under mild
conditions and with short times of reaction (0.5 to 15 min).
Of note was also the remarkable tolerance of the reaction to
susbtituents (from electron withdrawing to electron donating
groups) and functionalities in the amines. The water-tolerant
ꢀ
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partially hydrophilic Starbon acid is believed to push the
equilibrium forward to the formation of amides without the
need to remove the water generated in the acylation (which
normally reverses the equilibrium and destroys the amide).
This property may be due to the Starbons unusual starch-
like structure which is still present at low temperatures of
ꢀ
R
reaction. For most of the solid acids (excluding Starbon ), rea-
sonable conversions (>50%) were only achieved at significantly
longer times of irradiation (45 min and over) and/or doubling
the quantities of catalyst (from 0.1 to 0.2 g).
In an attempt to broaden the scope of the methodology, a
range of amines were employed as starting materials in the
acylation reaction. The results are summarised in Table 1.
◦
20
carbonisation (<400 C); this is consistent with our previous
ꢀ
R
21
observation of Starbon catalytic activity in water. In order
to demonstrate the true scope of the proposed methodology,
4
60 | Green Chem., 2009, 11, 459–461
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Table 2 R N-Acylation of benzylamine with a range of acids using
solid acid exhibited remarkably improved activities compared
to commercially available alternatives.
ꢀ
a
Starbon -400-SO
3
H as catalyst under microwave irradiation
b
Conversion
S
amide
Entry
Acid
C–COOH
Time/min
(mol%)
(mol%)
Notes and references
1
2
H
3
0.6
5
>99 (94)
94 (89)
>98
>99
1 (a) T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 2nd Ed., John Wiley and Sons Inc., New York, 1999;
(
b) R. C. Larock, Comprehensive Organic Transformations, Wiley-
3
4
5
90 (86)
>98
VCH, New York, 1999.
2
3
4
5
D. J. Constable, P. J. Dunne, J. D. Haysler, G. R. Humphrey, J. L.
Leazer, Jr., R. J. Linderman, K. Lorenz, J. Mansley, B. A. Pearlman,
A. Wells, A. Zaks and T. Y. Zhang, Green Chem., 2007, 9, 411–420.
(a) P. J. Dunn, S. Galvin and K. Hettenbach, Green Chem., 2004, 6,
c
15
>99
75
5
6
10
10
>99 (92)
>99
>99
4
3–48; (b) R. Vaidyanathan, V. G. Kalthod, D. P. Ngo, J. M. Manley
and S. P. Lapekas, J. Org. Chem., 2004, 69, 2565–2568.
(a) J. Mc Nulty, V. Krishnamoorthy and A. Robertson, Tetrahedron
Lett., 2008, 49, 6344–6347; (b) S. Naik, G. Bhattacharjya, B. Talukdar
and B. K. Patel, Eur. J. Org. Chem., 2004, 1254–1260.
88 (84)
C. A. G. N. Montalbetti and V. Falque, Tetrahedron, 2005, 61, 10827–
1
0852.
a
2
mmol benzylamine, 2 mmol acid, 0.1 g Starbon-400-SO
3
H, mi-
6 K. Arnold, A. S. Batsanov, B. Davies and A. Whiting, Green Chem.,
2008, 10, 124–134.
◦
crowave, 300 W (maximum power output), 130 C (maximum tempera-
b
ture reached). Isolated yields, where appropriate, are given in brackets.
7 (a) N. Narender, P. Srinivasu, S. J. Kulkarni and K. V. Raghavan,
Green Chem., 2000, 2, 104–105; (b) B. M. Choudary, V. Bhaskar,
M. Lakshmi Kantam, K. Koteswara Rao and K. V. Raghavan,
Catal. Lett., 2001, 74, 207–211; (c) S. M. Coman, M. Florea, V. I.
Parvulescu, V. David, A. Medvedovici, D. De Vos, P. A. Jacobs, G.
Poncelet and P. Grange, J. Catal., 2007, 249, 359–369.
c
Selectivity to diamide.
a range of carboxylic acids were employed as reagents in the
N-acylation of benzylamine (Amine Entry 7, Table 1). Results
included in Table 2 proved the applicability of the protocol,
as the Starbon acid afforded quantitative yields of amides
in less than 15 min of microwave irradiation. Of note were
results obtained using succinic acid (1,4, butanedioic acid) in
the reaction (Table 2, entry 4). Quantitative yield of diamide
could be obtained in less than 30 min reaction under microwave
irradiation.
8
(a) D. Davidson and P. Newman, J. Am. Chem. Soc., 1952, 74, 1515–
1516; (b) B. S. Jursic and Z. Zdravkovski, Synth. Commun., 1993, 23,
2761–2770.
ꢀ
R
9
M. Basanagouda, M. V. Kulkarni, R. G. Kalkhambkar and G. M.
Kulkarni, Synth. Commun., 2008, 38, 2929–2940.
10 (a) E. Petricci, C. Mugnaini, M. Radi, F. Corelli and M. Botta,
J. Org. Chem., 2004, 69, 7880–7887; (b) D. R. Sauer, D. Kalvin and
K. M. Phelan, Org. Lett., 2003, 5, 4721–4724; (c) E. Petricci, M.
Botta, F. Corelli and C. Mugnaini, Tetrahedron Lett., 2002, 43, 6507–
6
509.
The highly active sulfonated starbon was easily recovered from
the reaction mixture whereupon the reaction rates returned to
the background values. The recovered Starbon could be added
to fresh substrate solutions giving almost identical activity and
selectivity to the amides after 3 reuses to that observed in the
11 (a) K. Arnold, B. Davies, R. L. Giles, C. Grosjean, G. E. Smith and A.
Whiting, Adv. Synth. Catal., 2006, 348, 813–820; (b) S. W. Coghlan,
R. L. Giles, J. A. K. Howard, M. R. Probert, G. E. Smith and A.
Whiting, J. Organomet. Chem., 2005, 690, 4784–4793; (c) K. Ishihara,
S. Kondo and H. Yamamoto, Org. Synth., 2002, 79, 176–185.
12 X. J. Wang, Q. Yang, F. Liu and Q. D. You, Synth. Commun., 2008,
38, 1028–1035.
3 (a) C. Goretzki, A. Krlej, C. Steffens and H. Ritter, Macromol. Rapid
Commun., 2004, 25, 513–516; (b) A. R. Hajipour and M. Ghasemi,
Indian J. Chem. B: Org. Chem. Incl. Med. Chem., 2001, 40, 504–507;
ꢀ
R
first run (e.g. 3rd Starbon acid reuse, aniline + acetic acid, 87%
1
conversion, 99% selectivity to the amide compared to the 90%
ꢀ
R
conversion, 99% selectivity obtained for fresh Starbon acid).
The catalyst is very stable under the reaction conditions, in good
agreement with previously reported results that already proved
the outstanding properties of this acidic polysaccharide-derived
(
(
c) A. Loupy and F. Volatron, Tetrahedron, 2002, 58, 2155–2162;
d) F. Massicot, R. Plantier-Royon, C. Portella, D. Saleur and A.
Sudha, Synthesis, 2001, 2441–2444; (e) M. P. Vazquez-Tato, Synlett,
993, 506.
14 A. K. Chakraborti and R. Gulhane, Tetrahedron Lett., 2003, 44,
749–6753.
1
15–17,20,21
mesoporous material.
6
1
1
1
1
5 V. Budarin, R. Luque, J. H. Clark and D. J. Macquarrie, Chem.
Commun., 2007, 634–636.
Conclusions
6 R. Luque, V. Budarin, J. H. Clark and D. J. Macquarrie, Appl. Catal.,
B, 2008, 82, 157–162.
7 V. Budarin, J. H. Clark, R. Luque, D. J. Macquarrie, A. Koutinas
and C. Webb, Green Chem., 2007, 9, 992–995.
8 (a) C. O. Kappe, Chem. Soc. Rev., 2008, 37, 1127–1139; (b) C. O.
Kappe, A. Stadler, Microwaves in Organic and Medicinal Chemistry,
Wiley-VCH, Weinheim, 2005; (c) C. O. Kappe, Angew. Chem., Int.
Ed., 2004, 43, 6250–6284.
In conclusion, our efficient, atom economic and environmentally
friendly protocol allowed the preparation of a wide range of
intermediates for pharmaceuticals (e.g. acetanilide and N-acetyl-
p-aminophenol) and fine chemicals. A variety of amides were
successfully prepared from a range of amines and acids used as
reagents in a 1:1 ratio, in a protocol that was demonstrated
to be independent of the substrate combination and, most
importantly, of the efficient removal of water that has been
19 (a) Micowaves in Organic Synthesis, ed. A. Loupy, 2nd, Wiley-VCH,
2
006; (b) Microwave-assisted Organic Synthesis, ed. P. Lidstr o¨ m and
J. P. Tierney, Blackwell Scientific, 2004.
2
2
0 V. Budarin, J. H. Clark, J. J. E. Hardy, R. Luque, K. Milkowski,
S. J. Tavener and A. J. Wilson, Angew. Chem., Int. Ed., 2006, 45,
3782–3786.
1 R. Luque, C. S. K. Lin, C. Du, D. J. Macquarrie, A. Kouti-
nas, R. Wang, C. Webb and J. H. Clark, Green Chem., 2009,
DOI: 10.1039/b813409j.
22
reported to be critical in order to achieve high amide yields. The
ꢀ
R
Starbon acid is a renewable and environmentally compatible
catalyst that can easily be obtained from biomass, and has proven
to be highly active, selective and reusable in the N-acylation
of amines with acetic acid under microwave irradiation. Our
22 L. C. Chan and B. G. Cox, J. Org. Chem., 2007, 72, 8863–8869.
This journal is © The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 459–461 | 461