s-triazene based fluorous coupling reagent for direct amide synthesis

Article abstract of DOI:10.1016/j.tetlet.2015.02.078

Abstract A new simple and efficient fluorous coupling reagent TriTFET (2,4,6-tris-(2,2,2-trifluoro-ethoxy)-[1,3,5] triazene) has been designed and synthesized for the direct amidation. The use of 5 mol % of TriTFET is good for the amide synthesis from carboxylic acids with amines in moderate to excellent yields (72-96%).

Full text of DOI:10.1016/j.tetlet.2015.02.078

Accepted Manuscript
s-Triazene based fluorous coupling reagent for direct amide synthesis
Shrawan Kumar Mangawa, Sangram Keshari Bagh, Kumkum Sharma, Satish
K. Awasthi
PII:
S0040-4039(15)00359-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.078
TETL 45948
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 January 2015
17 February 2015
17 February 2015
Please cite this article as: Mangawa, S.K., Bagh, S.K., Sharma, K., Awasthi, S.K., s-Triazene based fluorous coupling
reagent for direct amide synthesis, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.02.078
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Shrawan Kumar Mangawa, Sangram Keshari Bagh, Kumkum Sharma, Satish K. Awasthi*

1
Tetrahedron Letters
journal homepage: www.els evier.com
s-Triazene based fluorous coupling reagent for direct amide synthesis
Shrawan Kumar Mangawa, Sangram Keshari Bagh, Kumkum Sharma, Satish K. Awasthi*
a Chemical Biology Laboratory, Department of Chemistry, University of Delhi, Delhi-110007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A new simple and efficient fluorous coupling reagent TriTFET (2,4,6-Tris-(2,2,2-trifluoro-
ethoxy)-[1,3,5] triazene) has been designed and synthesized for the direct amidation. The use of
5 mol % of TriTFET is good for the amide synthesis from carboxylic acids with amines in
moderate to excellent yields (72-96 %).
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Fluorous coupling reagent
Carboxylic Acids
Amines
Amides
Introduction
A simple and elegant approach for amide bond formation is
often overlooked as a contemporary challenge in organic
chemistry because of the widespread occurrence of amide bond
in drugs, biomacromolecules, natural and synthetic polymers.1-2
Amide bonds are more common in wide array of clinical drugs,
for example; Bupivacaine, Mepivacaine, Lidocaine and
Paracetamol (Figure 1). High polarity, stability and
conformational flexibility allow versatile usage of amide bond
for many applications.
All the reported methods have some limitations, such as long
reaction time, limited substance scope, modest yields, expensive
coupling reagents and cumbersome work-up procedures.8
Literature survey reveals that s-triazene based micelles has been
widely used as powerful catalysts for many coupling reactions.7e,
7f, 9 It is also used for amide coupling reactions between acids and
amines. However, under similar conditions, s-triazine and long
alkyl chain acid did not form micelles, hence no amide bond
formation. For example; octanoate does not form micelles with s-
triazine based reagent, therefore no amide bond formation with
long chain acids. Thus, simple, efficient and economic approach
for amide bond formation is still need in modern organic
chemistry.
H
N
H
N
H
N
O
CH3
HCl H2O
N
N
N
O
N
H
O
O
HO
Bupivacaine
Paracetamol
Mepivacaine
Lidocaine
O
CF3
O
O
P
O
O
Figure 1. Amide linkage containing clinical drugs
C8H17
O
N
N
OMe
O
P
Cl
N
NH3 Cl
N
P
O
CF3 N
O
N
O
O
N
N
S
N
Amide bond formation can occur via variety of chemical
methods as well as enzymatic methods.3 Direct approaches,
metal-based catalytic approaches and use of suitable coupling
reagents forms the bulk of reported procedures.4-5 Further, for
coupling between carboxylic acids and amines organocatalytic
conditions have also been used in the presence of functionalized
arylboronic acids and triphenylphosphines.6 In addition, various
acylating reagents such as thionyl chlorides, or coupling reagents
TfO
OMe
c
H3C
N
H3C
F3C
a
OH
d
b
Figure 2. Amide coupling reagents (a) phosphorous containing
reagent (b) VB catalyst (c) s-triazene base miceller reagent (d)
TriTFET
Recently, we have reported a variety of effective catalytic
systems for the synthesis of biological active molecule.10 In this
context, we further designed a new, stable fluorous coupling
reagent TriTFET (Figure 2d). In this work TriTFET was utilized
as a new coupling reagent for direct amidation from a large array
of amines and carboxylic acids in acetonitrile under mild
conditions and in lesser time. The coupling reagent was easily
synthesized using commercially available s-triazene and
trifluoroethanol in single step. Authenticity of TriTFET was
such
as
1-hydroxybenzotriazole
(HOBt)7a,
1,
1-
carbonyldiimidazole (CDI)7b, Uronium,7c and Phosphonium
salts,7d triazene based micelles7e and thymine hydrochloride7f are
generally utilized for activation of carboxylic acid in amide bond
formation (Figure 2a-c).
Corresponding author. Tel.: +91 1127667794 Ext. 134 Email.
satishpna@gmail.com, skawasthi@chemistry.du.ac.in

2
Tetrahedron Letters
confirmed by 1H, 13C and 19F NMR spectroscopy (See
supporting info).
Table 2. Optimization of the reaction conditionsa using
different amount of reagent loadings in acetonitrile
S.No.
Mol% of TriTFET
Yield (%)
Initially, we optimized the favorable reaction conditions, such
as best reaction solvent system, temperature and requisite amide
coupling reagent for better results. To optimize the reaction
conditions for the synthesis of amide bond, we conducted test
reactions using phenylacetic acid and benzyl amine in different
reaction conditions (Table 1). We selected three types of solvents
viz; green solvent (ethanol), non polar solvent (toluene) and polar
solvent (CHCl3, DMF, DMSO, ACN). When we attempted the
reaction of acid with amine in presence of 5 mol % of catalyst in
ethanol at 80 °C yielded 30% of the desired product in 4 hours
(Table 1, entry 2). Subsequently, we carried out the above
reaction in non-polar solvent (toluene) at 90 °C gave 40% of
product after 4 hours (Table 1, entry 3). Reaction of phenylacetic
acid and benzyl amine in CHCl3 at 60 °C gave trace amount of
the desired product. Among polar solvents, we first selected
acetonitrile due to ease of work up procedure. Interestingly,
reaction of phenylacetic acid and benzyl amine in the presence
of 5 mol % of TriTFET in acetonitrile at 60 °C gave 95 % of
product after 2 hours (Table 1, entry 5) thus highlighting the role
of TriTFET as a coupling reagent. Further studies in other polar
solvents such as (1,4-dioxane, DMF and DMSO) revealed that
the reactions were sluggish giving poor yields (Table 1, entries
4,6,7). Therefore, we selected acetonitrile as solvent choice for
reaction due to lower boiling points, easy work up and high yield
of product.
1
2
3
4
5
6
7
--------
NR
30
50
95
80
60
50
1
2
5
10
15
20
aReaction conditions: Compound 2 (1 mmol), benzyl amine (1mmol),
coupling reagent 5 mol %. bIsolated yields. Optimized reaction condition is in
bold.
Moreover, we also compared the feasibility of amide
synthesis with previously known methods which are summarized
in Table 3. Most of the reported methods worked at higher
temperature or longer reaction time compared to TriTFET
catalyzed method. In entry 1 (Table 3), amidation proceeded
without any catalyst but it occurs at high temperature and longer
reaction time. Other catalysts mentioned in the Table 3 require
high temperature, longer reaction time, and gave moderate yields
(Table 4, entries 1-8). Interestingly, s-triazine based catalyst
works at low temperature, shorter reaction time (Table 3, entry
7). But it suffers from cumbersome synthesis of catalyst. CAL-B
also works at low temperature and longer reaction time and gave
moderate to good yields (Table 3, entry 8). On the other hand, in
this work synthesis of TriTFET catalyst is more economical. It
requires low temperature, shorter reaction time, and moderate to
excellent yields. (Table 3, entry 7). On comparison, it appears
that TriTFET is better than existing catalysts.
Scheme 1. Synthesis of amide 2a using phenylacetic acid and
benzyl amine
TriTFET
(5 mol%)
H
N
OH
H2N
Table 3.
+
O
Solvents
Temp
O
Comparative overview of the present method with little
previously known methods
Table 1. Optimization of the reaction conditionsa using
S.
No.
Catalyst
Temp
(°C)
110
Time Yield
(h)
Ref.
different solvents
S. No.
(%)
Solvent
Temp
(0C)
60
Time
Yieldb
(%)
Trace
30
(h)
4
1
2
Without catalyst
22
90
5b
1
2
3
4
CHCl3
Ethanol
PhMe
Nano-sulfated
TiO2
115
6-12
h
70-98 11b
80
4
3
4
5
6
Boronic acid
ZrCl4
100
110
120
175
16-24 44-73 6a
90
6
40
4-24
5-24
7h
70-94
40-99
80
8
8
8
1,4-
Dioxane
90
8
65
Zeolite-Hy
5
6
7
ACN
60
2
8
8
95
85
75
Phosphorous
catalyzed
DMF
110
7
Triazene based 25
miceller catalyst
1-4
16-88
8
DMSO
120
aReaction conditions: Compound 2 (1 mmol), benzylamine (1 mmol),
coupling reagent 5 mol %. bIsolated yields. Optimized reaction condition is
shown in bold.
8
CAL-B
40
20-30 60-90 11a
9
TriTFET
60
2-3
95
Current
study
The next step was the optimization of coupling reagent
loading for achieving high yield of amide synthesis. We carried
out reaction with 1, 2, 5, 10, 15 & 20 mol % of catalyst. It is
evident from the Table 2 that increase of calayst loading from 1
to 5 mole % result in increase in the yield of the desired product
(Table 2, entries 2-4). Further increase of calatyst loading from 5
mol % to 20 mole % leads to decrease in the yield of final
product from 90 % to 50 %. In fact the observation reveals that
on increasing the amount of catalyst from 10 mol% to 20 mol%,
the reaction mixture becomes cloudy and sticky mass formed
instantly, thus it is impossible to stir the reaction for longer time
consequently incomplete synthesis provides lesser yield (Table 2,
entries 5-7). It means that 5 mol % of TriTFET is optimum
amount for catalytic activity in amide synthesis. (Table 2, entry
4).
Thus, using optimized reacton conditions i.e. 5 mol % of
catalyst, in acetonitrile at 60 °C, we then successfully synthesized
a variety of substituted amides using different carboxylic acids
and amine derivatives (Scheme 2). The results are summarized in
Table 4. In all the studied examples, the aromatic and aliphatic
amines (Primary and secondary) could react smoothly to give the
corresponding amide derivatives in good to excellent yields (76
to 95%). However, a synthesis of dipeptide between suitably
protected α-amino acids under similar reaction conditions were
unsuccessful.

3
Scheme 2. Synthesis of amide derivatives using acids and amines
Table 4. Synthesis of amide derivatives from carboxylic acids and amines using TriTFET
S. No.
Carboxylic Acids
Amines
Amides
Product
1a
Time (h)
Yield %
92
1
COOH
O
H2N
2
N
H
NC
NC
2
3
COOH
O
H2N
H2N
2a
3a
2
2
95
72
N
H
O
O
H3C
N
H
H3C OH
4
O
COOH
H2N
4a
5a
3
4
90
86
N
H
OHC
OHC
O2N
5
6
O
COOH
H2N
N
H
O2N
CH3
7
COOH
O
H2N
CH3
6
6a
7a
2
2
95
94
N
H
7
8
9
O
O
COOH
COOH
CH3
15
H2N
H2N
CH3
14
N
H
CH3
17
CH3
16
N
H
8a
9a
2
2
82
88
COOH
H
N
H2N
H2N
O
10
11
O
COOH
COOH
10a
11a
3
83
93
N
H
N
N
Cl
Cl
Cl
H
N
H2N
3.5
O
Cl
O
12
13
14
H3C COOH
9
H2N
N
H
H3C
8
12a
13a
15a
4
4
81
76
O
NHBoc
COOH
COOH
NHBoc
H2N
N
H
2.5
86
N
H
N
O
15
COOH
16a
2
84
N
H
CH3
N
CH3
O

4
16
Tetrahedron
COOH
COOH
17a
18a
19a
2.5
84
88
80
N
N
H
O
17
18
O
Ph
H
N
N
N
3
O
Ph
N
H
O
COOH
O
O
3.5
N
N
H
aReaction conditions 1mmol of acids and 1mmol of amines in the acetonitrile
solvent using 5 mol % of TriTFET .bIsolated yield.
References and notes
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Figure 3. Activation of acids using TriTFET
On the basis of the represented results, a mechanism is
proposed for the direct amidation. Acids first activated with
TriTFET to give intermediate stages. Finally, amine combines
with an acid molecule to produce corresponding amide by
regenerating the TriTFET as a catalytically active species.
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In conclusion, we successfully synthesized a variety of
functional amides through direct amidation of acids and amines
(primary and secondary) in moderate to excellent yield (72-95%)
by a new fluorous reagent under mild conditions. The scope of
this methodology has been demonstrated in (i) primary and
secondary aliphatic amines (ii) aromatic amines with carboxylic
acids (aliphatic and aromatic). Moreover, it is also useful for the
synthesis of amide bond between long alkyl chain acid and
amine. Considering the economic attractiveness and operational
simplicity, we strongly believe that the procedure is of important
synthetic value for access to a variety of functionalized amides.
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Acknowledgments
SKM is thankful to CSIR, India for providing fellowship.
SKA acknowledges the University of Delhi, Delhi, India for
financial support. Authors are thankful to USIC, University of
Delhi for Spectral data.
Supplementary Material
Experimental protocols and copies of 1H and 13C NMR spectra of
all compounds are provided.