Solvent-free protocol for amide bond formation via trapping of nascent phosphazenes with carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2011.03.069

A solvent-free synthesis of amides via the coupling of phosphazenes with carboxylic acids is reported. Increasing the rate of heating either by microwave irradiation or conventional heating results in multifold increase in the rate of amide bond formation. Synthesis of a library of amides including a potent antitumour candidate has been accomplished.

Full text of DOI:10.1016/j.tetlet.2011.03.069

Tetrahedron Letters 52 (2011) 2830–2833
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Tetrahedron Letters
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Solvent-free protocol for amide bond formation via trapping of nascent
phosphazenes with carboxylic acids
Murugan Sathishkumar, Poovan Shanmugavelan, Sangaraiah Nagarajan, Murugesan Maheswari,
⇑
Murugan Dinesh, Alagusundaram Ponnuswamy
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Tamilnadu 625-021, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A solvent-free synthesis of amides via the coupling of phosphazenes with carboxylic acids is reported.
Increasing the rate of heating either by microwave irradiation or conventional heating results in multifold
increase in the rate of amide bond formation. Synthesis of a library of amides including a potent antitu-
mour candidate has been accomplished.
Received 21 December 2010
Revised 10 March 2011
Accepted 16 March 2011
Available online 27 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Amide
Solvent-free
MW-irradiation/Glycerol bath
Amides are one of the important functional groups prevalent in
organic biomolecules. Further, the existence of carboxamido group
in more than 25% of known drugs1 and in potent drugs adds further
significance to amides in biological metabolism.
Though the more attractive microwave assisted organic synthe-
sis9 had replaced most of the time consuming conventional meth-
odologies, its applicability to amide bond formation is relatively
new. The results and systematic study in exploring the thermal
sources during our investigation are discussed (vide infra).
Initially, the one-pot synthesis of amide (3e) by coupling the
nascent phosphazenes (generated in situ from the secondary azide
(2b) and PPh3) with benzoic acid (1e) revealed that the solvent
with the highest boiling point is the most suitable (Table 1). In-
deed, in xylene under reflux (entry 3), the reaction is completed
in 5 h as compared to toluene (12 h, entry 2) and benzene (36 h,
entry 1).
Asaconsequenceofitsimportance,newerprotocolsforamidebond
formation have emerged. All the prevailing syntheses belong to the
solutionphasemethodology.Ofthese,themostfrequentlyandexten-
sivelyemployedmethodologyinvolvesdirectcouplingofamineswith
carboxylicacidsandcouplingreagents2,3(Scheme1).
Other approaches like aminocarbonylation4 of aryl halides with
amines and catalysis5 in amide bond formation have limitations,
such as loading of metal carbonyls/catalyst for large scale prepara-
tion and reactivation/reusability of deactivated catalyst which may
preclude the scope of their applicability.
From the above correlation indicating the thermal dependence
of the reaction rate, we envisaged that under solvent-free condi-
tion, the rate of amide (3e) formation could be enhanced by
An alternate solution phase protocol involves the coupling of
Staudinger’s phosphazenes6, generated from phosphines and or-
ganic azides, with carboxylic acids7 or its derivatives8 to afford car-
boxamide (Scheme 2). The limitations of this methodology are the
use of benzene (carcinogenic) as the solvent of choice, long reac-
tion time (3–36 h or even more)7a,b, and solubility problems that
arise with polar starting substrates.7a
coupling agent
R-COOH + R'-NH2
RCONHR'
solvents
Scheme 1.
We herein report a solvent-free protocol without the limitations
of the solution phase methodology. The stepwise variation in the
temperature has been accomplished with microwave synthesizer
in optimizing the temperature and time for an efficient synthesis
of amides.
R-COOH
benzene/ toluene
3 hours - 3 days
RCONHR'
R'-N3
Ph3P NR '
Phosphazene
Ph3P -N2
⇑
Corresponding author. Tel.: +91 9600868323.
E-mail address: ramradkrish@yahoo.co.in (A. Ponnuswamy).
Scheme 2.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.069

M. Sathishkumar et al. / Tetrahedron Letters 52 (2011) 2830–2833
2831
Table 1
Table 2
Effect of boiling point of solvents on the rate of the amide (3e) synthesis
Temperature/time optimization in solvent free micro-wave accelerated synthesis
(MAS)a of the amide (3e)
H
N3
solvent
reflux
N
COOH
PPh3
H
N3
N
O
COOH
+
+
O
solvent free
PPh
+
+
3
MW irradiation
1e
2b
3e
1e
3e
2b
Entry
Solvent
Bp (°C)
Reaction time (h)
Entry
Temp (°C)
Time (min)
Reaction progressb
1
2
3
4
5
Benzene
Toluene
Xylene
THF
Acetonitrile
80
111
144
66
36
12
5
>40
>36
Pzc
Amide
1
2
3
4
5
6
7
8
9
100
100
100
150
150
150
180
180
180
5
10
15
5
10
15
5
100
100
100
86
Nil
Nil
Nil
14
82
71
29
52
48
increasing the rate of heating via microwave irradiation. In fact, to
our delight, the perception was realized to be true (vide-infra). At
first, optimization of the reaction temperature and time for the sol-
vent-free synthesis of 3e was attempted (Table 2) by microwave
irradiation (CEM DISCOVER, Benchmate model, single-mode design
with inbuilt IR sensor).
74
26
10
15
30
70
—
>95
aA mixture of 1e (1.0 mmol), 2b (1.0 mmol), and PPh3 (1.1 mmol) was irradiated
with micro-wave.
Reaction progress monitored by 1H NMR.10
Phosphazenes.
b
c
The optimized temperature and time identified were 180 °C
(180 W) and 15 min (entry 9), respectively, thus resulting in a rapid
Table 3
Micro-wave accelerated synthesis (MAS) and glycerol bath accelerated synthesis (GBAS) of the amides (3)
solvent free
MW irradiation
(or)
R1N3
+
+
RCOOH
PPh
3
RCONHR1
3a-u
preheated Glycerol bath
180 oC, 15 min
2a-d
1a-m
R1 =
Br
d
a
c
b
Entry
1
R-(1a–m)
R1N3 (2a–d)
RCONHR1 (3a–x)
Yielda(%) MAS (GBAS)
O
O
CH3– 1a
2b
81 (79)
Ph
N
H
CH3
3a
N
Ph
Ph
2
3
CH3–CH2– 1b
2b
2b
83 (85)
80 (82)
H
CH3
3b
3c
O
CH2
N
H
1c
O
O
4
5
2b
2b
78 (81)
82 (80)
Ph
Ph
Ph
N
H
O
1d
3d
O
O
N
H
1e
3e
N
6
2b
H
78 (77)
Cl
1f
Cl
3f
(continued on next page)

2832
M. Sathishkumar et al. / Tetrahedron Letters 52 (2011) 2830–2833
Table 3 (continued)
Entry
R-(1a–m)
R1N3 (2a–d)
RCONHR1 (3a–x)
Yielda(%) MAS (GBAS)
O
Ph
Ph
N
7
8
2b
75 (72)
H
Br
Br
1g
3g
O
Cl
N
H
2b
84 (86)
1h
Cl
3h
O
H3CO
Ph
Ph
N
H
9
10
11
2b
2b
2b
88 (85)
79 (78)
75 (77)
1i
OCH3
3i
O
O
O
N
H
1j
3j
O
NH
1k
Ph
3k
O
CH2
N
12
2a
83 (86)
H
1c
3l
O
O
N
H
O
13
14
15
2a
2a
2a
80 (82)
84 (79)
81 (81)
1d
3m
O
N
H
1e
3n
O
N
H
Cl
Cl
1f
3o
O
N
H
16
2a
79 (81)
Br
Br
1g
3p
O
O2N
N
H
17
18
2a
2a
73 (75)
85 (79)
1l
NO2
3q
O
H3CO
N
H
1i
OCH3
3r

M. Sathishkumar et al. / Tetrahedron Letters 52 (2011) 2830–2833
2833
Table 3 (continued)
Entry
R-(1a–m)
R1N3 (2a–d)
RCONHR1 (3a–x)
Yielda(%) MAS (GBAS)
O
O
O
N
H
19
2a
77 (78)
1j
3s
OCH3
OCH3
OCH3
O
H3CO
H3CO
NH
b
20
21
2c
67 (69)
77 (81)
OCH3
#
1m
3t
H
N
CH2
2d
O
1c
Br
3u
a
Isolated yield.
Biologically potent compound.
b
Supplementary data
R1-N3
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.069.
O
RCONHR1
R-COOH
-
2
O
3a-u
1
RCOO
R
Ph3P NR1
+
Ph3P
Ph3P
+
+
NHR1
Ph3P NH R1
-N2
Phosphazene
Ph3PO
References and notes
Scheme 3. Plausible mechanism.
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S. Synthesis 2008, 2, 267.
3. Green Chemistry. Frontiers in Chemical Synthesis and Processes; Anastas, P. T.,
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Kasukhin, L. F. Tetrahedron 1992, 48, 1353.
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Urpi, F.; Vilarrasa, J. Tetrahedron Lett. 1986, 27, 4623.
8. (a) Shalev, D. E.; Chiacchiera, S. M.; Radkowsky, A. E.; Kosower, E. M. J. Org.
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increase of the reaction rate under microwave irradiation affording
an excellent yield of 3e as compared to the long reaction time
5–36 h) noted for the synthesis of 3e in solvents (Table 1). The
broad scope of the optimized MAS was established by conveniently
coupling three types of azides—primary, secondary, and aryl azides
(2a–d)11 with a variety of carboxylic acids viz aliphatic, aromatic,
heteroaromatic, and unsaturated carboxylic acids (1a–m)11 to
afford the respective amides (3a–u).12 Trimethoxycinnamic amide,
3t a potent inhibitor against four human tumor cell lines13 has been
obtained in good yield (Table 3).
Additionally an industrially prevalent glycerol bath, preheated
on a heating mantle to 180–190 °C, was used as an alternative to
microwave heating, to attain the optimum temperature for synthe-
sizing amides (3) under solvent-free condition. This was successful
affording identical yields (Table 3) as obtained in the MAS indicat-
ing the general applicability of GBAS.
The scale-up of the microwave accelerated and preheated glyc-
erol bath accelerated synthesis of amides 3e and 3f to 5 mmol and
15 mmol, respectively, was also performed successfully. In the
present study the rapid increase in the rate of amide bond forma-
tion is explained based on the high contacts/collapsing of polar
reactants in homogenous fused phase under solvent-free condi-
tion. The plausible mechanism (Scheme 3) is presented.
In conclusion, a solvent-free protocol for the synthesis of
amides via coupling of phosphazenes with carboxylic acids is sub-
mitted in view of a number of limitations associated with solution
phase synthesis. This methodology overcomes the limitations asso-
ciated with the solution phase approach.
9. Polshettiwar, V.; Varma, R. S. Acc. Chem. Res. 2008, 41, 629.
10. Reaction progress was monitored by 1H NMR from the disappearance of the
methine proton signal of –CHN@PPh3 (Phosphazenes) at 4.0 ppm and
appearance of methine signal of—CHNHCOR (amide) at 4.6 ppm.
11. All carboxylic acids (1a–m) and triphenyl phosphine used are of commercial
grade of high purity and preparation of organic azides (2a–d) are presented in
Supplementary data.
12. General Procedure: To a well ground intimate mixture of triphenyl phosphine
(1.1 mmol) and carboxylic acid, 1 (1.0 mmol) in a microwave vial (10 mL)
equipped with a magnetic stirring bar, the organic azide, 2 (1.0 mmol) was
added in drops while stirring. Stirring was continued until liberation of
nitrogen ceased and the reaction vessel was sealed with a septum. It was then
placed into the cavity of
a focused monomode microwave reactor (CEM
Discover, benchmate) and operated at 180 °C (temperature monitored by a
built-in IR sensor), power 80 W for 15 min. The reaction temperature was
maintained by modulating the power level of the reactor. Alternatively, the
microwave vial with the mixture was conventionally heated around 180 °C by
immersing in a preheated glycerol bath for 15 min. The reaction vessel was
then cooled to room temperature and the residue subjected to column
chromatography on silica (pet ether/ethyl acetate, 87:13). This resulted in the
isolation of pure amide, 3 Yield (67–88%).
Acknowledgments
The authors thank IRHPA, DST for providing 300 MHz NMR
instrument for recording the NMR spectra.
13. Yang, X. D.; Zeng, X. H.; Zhao, Y. H.; Wang, X. Q.; Pan, Z. Q.; Li, L.; Zhang, H. B. J.
Comb. Chem. 2010, 12, 307.