Silica-supported 2,4,6-trichloro-1,3,5-triazine as an efficient reagent for direct conversion of carboxylic acids to amides under solvent-free conditions

Article abstract of DOI:10.1080/10426500601047214

A very simple and efficient solvent-free method for the direct conversion of carboxylic acids to primary, secondary, tertiary alkyl, and aromatic amides in the presence of the corresponding ammonium salts, silica-supported 2,4,6-trichloro-1,3,5-triazine, and triethylamine is described. The reactions proceed rapidly at room temperature, and the products are obtained in moderate to excellent yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500601047214

This article was downloaded by: [University of Delaware]
On: 11 June 2012, At: 03:24
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Silica-Supported 2,4,6-
Trichloro-1,3,5-triazine as an
Efficient Reagent for Direct
Conversion of Carboxylic Acids
to Amides Under Solvent-Free
Conditions
Ali Khalafi-Nezhad a , Abdolkarim Zare a , Abolfath
Parhami a , Mohammad Navid Soltani Rad b &
Gholam Reza Nejabat c
a Department of Chemistry, Shiraz University, Shiraz,
Iran
b Department of Chemistry, Shiraz University of
Technology, Shiraz, Iran
c Department of Chemistry, Shiraz University, Shiraz,
Iran
Available online: 30 Jan 2007
To cite this article: Ali Khalafi-Nezhad, Abdolkarim Zare, Abolfath Parhami,
Mohammad Navid Soltani Rad & Gholam Reza Nejabat (2007): Silica-Supported 2,4,6-
Trichloro-1,3,5-triazine as an Efficient Reagent for Direct Conversion of Carboxylic
Acids to Amides Under Solvent-Free Conditions, Phosphorus, Sulfur, and Silicon and
the Related Elements, 182:3, 657-666
To link to this article: http://dx.doi.org/10.1080/10426500601047214
PLEASE SCROLL DOWN FOR ARTICLE

Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

Phosphorus, Sulfur, and Silicon, 182:657–666, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601047214
Silica-Supported 2,4,6-Trichloro-1,3,5-triazine as an
Efficient Reagent for Direct Conversion of Carboxylic
Acids to Amides Under Solvent-Free Conditions
Ali Khalafi-Nezhad
Abdolkarim Zare
Abolfath Parhami
Department of Chemistry, Shiraz University, Shiraz, Iran
Mohammad Navid Soltani Rad
Department of Chemistry, Shiraz University of Technology, Shiraz, Iran
Gholam Reza Nejabat
Department of Chemistry, Shiraz University, Shiraz, Iran
A very simple and efficient solvent-free method for the direct conversion of carboxylic
acids to primary, secondary, tertiary alkyl, and aromatic amides in the presence of
the corresponding ammonium salts, silica-supported 2,4,6-trichloro-1,3,5-triazine,
and triethylamine is described. The reactions proceed rapidly at room temperature,
and the products are obtained in moderate to excellent yields.
Keywords 2,4,6-Trichloro-1,3,5-triazine; amide; ammonium salt; carboxylic acid;
solvent-free
INTRODUCTION
Solvent-free organic reactions have been applied as a useful technol-
ogy in organic synthesis.1 The solid-state technique often leads to a
large reduction in reaction time, increased yields, easier workup, and
matches with green chemistry protocols, and it may enhance the regio-
and stereoselectivity of reactions.1
The amide function is significant in organic and biological
chemistry. Amides are important as pharmaceuticals2a as well as
Received November 30, 2005; accepted August 23, 2006.
We thank Shiraz University and the Shiraz University of Technology Research Coun-
cils, Shiraz, Iran, for financial support of this work. We are also grateful to Prof. H.
Sharghi for helpful discussion and to Mr. H. Sajedian Fard for running the NMR spectra.
Address correspondence to Ali Khalafi-Nezhad, Department of Chemistry, College of
Sciences, Shiraz University, Shiraz 71454, Iran. E-mail: khalafi@chem.susc.ac.ir
657

658
A. Khalafi-Nezhad et al.
agrochemicals.2b The conversion of carboxylic acids to amides is
one of the important transformations in organic synthesis.3 In gen-
eral, the conversion of carboxylic acids to carboxamides requires
an activation of the carboxyl group. This can be achieved by con-
version of the carboxyl group to a more reactive group such as acyl
halide, mixed anhydride, acyl azide, and active ester, or through
in situ–activation by coupling reagents including N, N-dicyclohexyl
carbodiimide (DCC),4 TiCl4,5 activated phosphate,6 Sn[N(TMS)2]2,7 N-
halosuccinimide/PPh3,8 trichloroacetonitrile/PPh3,9 tert-butyl-3-(3,4-
dihydrobenzotriazine-4-on)yl carbonate (Boc-Odhbt),10 ArB(OH)2,11
Lawesson’s reagent,12
(R2N)2Mg,13
SO2ClF,14
chlorosulfonyl
isocyanate,15 and 2-mercaptopyridone-1-oxide based uronium salts.16
There have been several reports on the transformation of carboxylic
acids to amides under solvent-free conditions.17 Recently, we reported
a new method for the direct conversion of carboxylic acids to various
amides under solvent-free conditions.18a To the best of our knowledge,
there is no other report for the direct transformation of carboxylic acids
to all kinds of amides including primary, secondary, tertiary alkyl, and
aromatic amides by this means. Along with our previous work on the
direct conversion of carboxylic acids to amides17d,18a and also in ex-
tension of our previous studies on solvent-free organic reactions,17d,18
we report here an efficient, rapid, and simple method for the direct
conversion of carboxylic acids to primary, secondary, tertiary alkyl, and
aromatic amides in the presence of the corresponding ammonium salts,
silica-mediated 2,4,6-trichloro-1,3,5-triazine (TCT), and triethylamine
under solvent-free conditions at r.t. (Scheme 1).
O
O
SiO2-TCT/NEt3
r.t., 1 min
R1R2NH2Cl
+
R
NR1R2
R
OH
R1, R2 = H, Aryl, Alkyl
R = Aryl, Alkyl
SCHEME 1
50–87%
2,4,6-trichloro-1,3,5-triazine was chosen as a condensing agent be-
cause this compound and its derivatives have been used as very ef-
ficient reagents for the activation of carboxyl groups in the prepara-
tion of esters,19a peptides,19a−c amides,19a−d as well as acyl azides.19e
This reagent has also been used for the synthesis of amides; however,
its application was restricted to conversion in solution. Moreover, this
amidation reaction needed long reaction times.
Instead of amines, ammonium salts were employed in the reaction
because (a) ammonium salts of gaseous or volatile amines such as am-
monia, methyl amine, and dimethyl amine can be easily used in the

Silica-Supported Solvent-Free Amide Synthesis
659
TABLE I The Effect of Different Ammonium
Salts on the Amidation Reaction of Benzoic
Acid in the Presence of SiO2-TCT and
Triethylamine at R.T.
Ammonium salt
Time (min)
Yield (%)a
NH4Cl
NH4I
NH4NO3
NH4OAc
(NH4)2SO4
(NH4)2CO3
1
1
10
10
10
10
82
74
67
71
63
69
aThe yield refers to a pure isolated product.
reaction; and (b) amines are hazardous compounds, and application of
their salts decreases environmental pollution.
RESULTS AND DISCUSSION
To determine the optimal reaction conditions, we have selected the con-
version of benzoic acid to benzamide as a model reaction. Different
ammonium salts in the presence of silica-mediated TCT and triethy-
lamine were examined in the reaction. The results are summarized in
Table I. As indicated in Table I, ammonium chloride was the most suit-
able source for in situ–generation of ammonia. In another study, a set
of different bases was considered in order to evaluate their capabilities
(Table II). As is shown in Table II, the best results were obtained when
TABLE II The Influence of Bases on the
Results of the Reaction of Benzoic Acid
With Ammonium Chloride in the
Presence of SiO2-TCT at R.T.
Base
Time (min)
Yield (%)a
NEt3
NBu3
NMM
DMAP
DBU
1
1
1
10
10
10
15
30
30
82
71
74
65
70
67
42
8
DBN
DABCO
K2CO3
Cs2CO3
11
aThe yield refers to a pure isolated product.

660
A. Khalafi-Nezhad et al.
TABLE III The Effect of Various Supports on the
Amidation of Benzoic Acid in the Presence of TCT and
Triethylamine
Support
T (◦C)
Time (min)
Yield(%)a
—
—
SiO2
r.t.
70
r.t.
r.t.
70
70
70
70
70
60
30
1
10
10
10
10
10
10
13
24
82
37
49
61
47
33
42
Basic Al2O3
Neutral Al2O3
Clay
Molecular sieve 0.3 nm
Montmorillonite K-10
Graphite
aThe yield refers to a pure isolated product.
triethylaminewas used; therefore, triethylamine was the base of choice
in all reactions. The influence of the supporting material on the result
of the reaction was also investigated. The results are in Table III. As
becomes clear from Table III, the absence of support in the reaction
medium gave low yields of the product even on longer reaction times
and higher temperatures. Thus, the support had a remarkable effect on
the progress of the reaction. Among the examined supports, silica gel
showed the best results.
To investigate the versatility and applicability of this method, the
amidation reaction was investigated with various structurally diverse
carboxylic acids and ammonium salts. As shown in Table IV, the re-
actions proceeded efficiently, and the desired amides were obtained in
moderate to excellent yields.
We have also studied the effect of electron-donating and electron-
withdrawing substituents at the aromatic ring of the carboxylic acid on
the result of the reaction. As Table IV demonstrates, electron-donating
substituents lowered the yield, while electron-withdrawing substituent
(NO2) increased the reaction yield. Moreover, the presence of a nitrogen
atom in the aromatic ring of the acid increased the yield of the amides
(Table IV). The presence of halogen atoms (Cl or Br) at the aromatic
ring of the acid had no significant effect on the result of the reaction.
Interestingly, no Michael addition-side products were observed when
cinnamic and crotonic acid were used (Table IV).
We have extended our reaction to sterically hindered and aromatic
ammonium salts. As shown in Table IV, these ammonium salts afforded
the corresponding amides in high yields. The procedure works also with
aliphatic and dicarboxylic acids.

661

662

663

664
A. Khalafi-Nezhad et al.
O
O
O
N
Ph
O
O
Ph
O
O
Ph
Cl
O
Cl
N
-
+
N
N
N
N
PhCOO NHEt3
O
N
N
N
+
+
N
Cl
N
O
Ph
N
Cl
Cl
Cl
O
Ph
O
Ph
1
2
3
O
O
HN
NH
NH4Cl, NEt3
+
Ph
NH2
O
N
H
O
SCHEME 2
We suggest that the reaction proceeds via the intermediates 1, 2,
and 3 (Scheme 2). They are formed by the nucleophilic attack of the
carboxylate anion to the 2,4,6-trichloro-1,3,5-triazine and further re-
act with the amine, which is generated from the reaction of the cor-
responding ammonium salt and triethylamine, providing the carbox-
amide. To explore the formation of intermediates 1–3 during the reac-
tion, a mixture of benzoic acid, TCT, and silica gel were reacted with
triethylamine. Intermediates 1, 2, and 3 could be observed on a TLC
plate; however, they could not be separated and purified using the con-
ventional techniques such as column chromatography or recrystaliza-
tion. The subsequent addition of ammonium chloride and triethylamine
showed the disappearance of the intermediates and the formation of
benzamide.
In summary, we have developed a cheap, rapid, and solvent-free
method for the direct conversion of carboxylic acids to all sorts of amides
at r.t. with moderate to excellent yields.
EXPERIMENTAL
All chemicals were obtained from Merck (Darmstadt, Germany) or
Fluka (Buchs, Switzerland). Solvents were purified and dried according
to the reported methods and stored over molecular sieves.20 Progress
of the reactions was followed with TLC using silica gel SILG/UV 254
plates. Silica gel 60, 0.063–0.200 mm (70–230 mesh American Stan-
dards Testing Methods (ASTM)) was used for column chromatogra-
1
phy and support. H NMR spectra (250 MHz) were recorded with on
a Bruker Avance DPX-250 FT-NMR spectrometer. Melting points were
¨
determined on a BUCHI B-545 apparatus in open capillary tubes and
are uncorrected.

Silica-Supported Solvent-Free Amide Synthesis
665
Procedure for the Preparation of Silica-Supported TCT
Silica gel (8.00 g) was mixed with a solution of TCT (1.84 g, 10 mmol)
in anhydrous CH2Cl2 (50 mL). Evaporation of the solvent gave a white
powder, which was used as the coupling agent.
General Procedure for the Direct Conversion of Carboxylic
Acids to Amides Using TCT as a Condensing Agent
In a mortar, a mixture of carboxylic acid (1 mmol), the respective am-
monium salt (2 mmol), and silica-mediated TCT (0.49 g) was crushed
vigorously to give a homogeneous mass. The mixture was transferred
into a test tube, and then triethylamine (0.40 g, 4 mmol) was added
dropwise. After 1 min, the reaction mixture was suspended in ethyl
acetate (50 mL), and filtered, and the filtrate was washed with 0.02 N
solution of HCl (2 × 50 mL) and water (2 × 50 mL). The organic layer
was separated and dried with MgSO4. The solvent was evaporated, and
the crude product was purified by column chromatography on silica gel
with ethyl acetate/n-hexane (1:1).
REFERENCES
[1] (a) K. Tanaka and F. Toda, Chem. Rev., 100, 1025 (2000) (b) K. Tanaka, Solvent-Free
Organic Synthesis (Wiley-VCH, Weinheim, 2004).
[2] (a) M. Negwer and H.-G. Scharnow, Organic-Chemical Drugs and Their Synonyms,
8th ed., p. 4254 (Wiley-VCH, Weinheim, Berlin, 2001); (b) G. W. A. Milne, CRC
Handbook of Pesticides (CRC Press, Boca Raton, Florida, 1995).
[3] J. March, in Advanced Organic Chemistry, 5th ed., pp. 508–510 (Wiley, New York,
2001); (b) B. M. Trost, in Comprehensive Organic Synthesis, Vol. 6, 381–417 (Perg-
amon Press, Oxford, 1991).
[4] J. C. Sheehan and G. P. Hess, J. Am. Chem. Soc., 77, 1067 (1955).
[5] J. D. Wilson, C. F. Hobbs, and H. J. Weingarten, J. Org. Chem., 15, 1542 (1970).
[6] T. Yasuhara, Y. Nagaoka, and K. Tomioka, J. Chem. Soc., Perkin Trans. 1, 7, 2901
(2000).
[7] C. Burnell-Curty and E. J. Roskamp, Tetrahedron Lett., 34, 5193 (1993).
[8] P. Froyen, Synth. Commun., 959 (1995).
[9] D. O. Jang, D. J. Park, and J. Kim, Tetrahedron Lett., 40, 5323 (1999).
[10] Y. Basel and A. Hassner, Tetrahedron Lett., 43, 2529 (2002).
[11] K. Ishihara, S. Ohara, and H. Yamamoto, J. Org. Chem., 61, 4196 (1996).
[12] M. Thorsen, T. P. Andersen, U. Pedersen, B. Yde, S.-O. Lawesson, and H. F. Hansen,
Tetrahedron, 41, 5633 (1985).
[13] R. Sanchez, G. Vest, and L. Depres, Synth. Commun., 19, 2909 (1989).
[14] G. A. Olah, S. C. Narang, and A. G. Garcia-Luna, Synthesis, 8, 661 (1980).
[15] K. S. Keshavamurthy, Y. D. Vankar, and D. N. Dhar, Synthesis, 6, 506 (1982).
[16] M. A. Baile´n, R Chinchilla, D. J. Dodsworth, and C. Najera´, Tetrahedron Lett., 41,
9809 (2000).

666
A. Khalafi-Nezhad et al.
[17] (a) B. W. Baldwin, T. Hirose, and Z. H. Wang, Chem. Commun., 2669 (1996); (b)
R. S. Varma and K. P. Naicker, Tetrahedron Lett., 40, 6177 (1999); (c) L. Perreux,
A. Loupy, and F. Volatron, Tetrahedron, 58, 2155 (2002); (d) A. Khalafi-Nezhad, B.
Mokhtari, and M. N. Soltani Rad, Tetrahedron Lett., 44(39), 7325 (2003).
[18] (a) A. Khalafi-Nezhad, A. Parhami, M. N. Soltani Rad, and A. Zarea, Tetrahe-
dron Lett., 46, 6879 (2005); (b) A. Khalafi-Nezhad, A. Zarea, M. N. Soltani Rad,
B. Mokhtari, and A. Parhami, Synthesis, 419 (2005); (c) A. Khalafi-Nezhad, M.
N. Soltani Rad, and A. Khoshnood, Synthesis, 583 (2004); (d) A. Khalafi-Nezhad and
B. Mokhtari, Tetrahedron Lett., 45, 6737 (2004); (e) A. Khalafi-Nezhad, M. N. Soltani
Rad, and G. H. Hakimelahi, Helv. Chim. Acta, 86, 2396 (2003); (f) A. Khalafi-Nezhad,
F. Alamdari, and N. Zekri, Tetrahedron, 56, 7503 (2000); (g) A. Khalafi-Nezhad and
A. Hashemi, J. Chem. Res., Synop., 36, 720 (1999).
[19] (a) M. K. Venkataraman and D. R. Wagle, Tetrahedron Lett., 20, 3037 (1979); (b) W.
Markowicz and R. Dembinski, Synthesis, 80 (2004); (c) H. L. Rayle and L. Fellmeth,
Org. Proc. Res. Develop., 3, 172 (1999); (d) Z. J. Kaminski, P. Paneth, and J. Rudzinski,
J. Org. Chem., 63, 4242 (1998); (e) B. P. Bandgar and S. S. Pandit, Tetrahedron Lett.,
43(18), 3413 (2002).
[20] A. I. Vogel, in Practical Organic Chemistry, pp. 161-176 (Longman, Green and Co.,
London, 1954).
[21] The Combined Chemical Dictionaries on CD-Rom, Version 6.1, Chapman and Hall,
2003.
[22] S. T. Chen, S. H. Wu, and K. T. Wang, Synthesis, 1, 37 (1989).