Catalyst and solvent-free, ultrasound promoted rapid protocol for the one-pot synthesis of α-aminophosphonates at room temperature

Article abstract of DOI:10.1016/j.tetlet.2012.07.123

An ultrasound promoted easy, efficient, and environment friendly process has been devised for the synthesis of α-aminophosphonates within seconds through a one-pot three-component condensation of the aldehydes, amines, and triethylphosphite. The desired products were obtained in excellent yields and in high purity under solvent-free and catalyst-free conditions. Study with various aldehydes and amines reveals that ultrasound radiation plays a key role in the direct synthesis of α-aminophosphonates. 2012 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2012.07.123

Tetrahedron Letters 53 (2012) 5497–5502
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalyst and solvent-free, ultrasound promoted rapid protocol for the
one-pot synthesis of a-aminophosphonates at room temperature
Bashir Dar a, Amrinder Singh a, Akshya Sahu a, Praveen Patidar a, Arup Chakraborty a, Meena Sharma b,
,
⇑
Baldev Singh a,
⇑
a Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu and Kashmir, India
b Department of Chemistry, University of Jammu, Jammu and Kashmir 180004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An ultrasound promoted easy, efficient, and environment friendly process has been devised for the syn-
thesis of -aminophosphonates within seconds through a one-pot three-component condensation of the
aldehydes, amines, and triethylphosphite. The desired products were obtained in excellent yields and in
high purity under solvent-free and catalyst-free conditions. Study with various aldehydes and amines
reveals that ultrasound radiation plays a key role in the direct synthesis of a-aminophosphonates.
Received 5 June 2012
Revised 26 July 2012
Accepted 28 July 2012
Available online 3 August 2012
a
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
a-Aminophosphonates
Ultrasonication
One pot
Neat
Catalyst free
The structural resemblance of
-amino acids has brought them to the center of immense attention
a
-aminophosphonates with
Cd(ClO4)2 Â H2O,25 Nano Fe3O4,26 Although, these approaches are
a
satisfactory for three component, one-pot synthesis of a-amino-
in recent years.1
a-Aminophosphonates are among the most stud-
phosphonates, nevertheless the utilization of toxic solvents,
ied bioactive compounds which are reported to possess antitumor,2
anti-inflammatory,3 and antibiotic4 activities. Their potential as
good enzyme inhibitors,5 herbicides,6 peptide mimetics,7 fungi-
cides,8 insecticides9 plant growth regulators10 etc is also well
documented. The assortment of possibilities of practical use of
R
O
NH2
CH
O
O
O
neat,
)))))
HN
4
P
a
a
-aminophosphonates has stimulated considerable interest toward
-aminophosphonate chemistry and a plethora of synthetic meth-
P
+
+
O
O
O
r.t.
20-45 s
R
R'
ods have been reported for their preparation. Three-component
condensation of an amine, aldehyde, and diethylphosphite or
triethylphosphite is the most common and convenient method to
construct such significant scaffold. Generally, these transformations
are mediated by catalysts such as ZrCl4,11 InCl3,12 MgBr2,13
TaCl5–SiO2.14
1
3
2
R'
Scheme 1.
The major drawback of the above mentioned processes, particu-
larly those utilizing a single-pot procedure and involving moisture
sensitive Lewis acids, is catalyst deactivation by water released dur-
ing the reaction process.15 This undesirable characteristic has been
circumvented to some extent with the development of some cata-
lytic systems like NbCl5,16 mesoporous aluminosilicate nanocage,17
Silica sulfuric acid,18 Al(H2PO4)3,19 Ce(OTf)4,20 CeCl3Á7H2O,21
BF3–SiO2,22 MoO2Cl2,23 Choline chlorideÁ2ZnCl2 ionic liquid,24
Table 1
Condensation of 4-chloroaniline, 4-chlorobenzaldehyde and triethylphosphite under
different reaction conditions
Entry
Condition
Solvent
Time
Yielda (%)
1
2
3
4
5
6
30 °C without sonication
30 °C without sonication
30 °C with sonication
30 °C with sonication
Reflux without sonication
Acetonitrile
No solvent
No solvent
Acetonitrile
No solvent
Acetonitrile
18 h
18 h
20 s
20 s
2 h
Traces
Traces
99
79
10
Reflux without sonication
2 h
30
⇑
Corresponding authors. Tel.: +91 2572002; fax: +91 2548607.
E-mail address: drbaldev1@gmail.com (B. Singh).
a
HPLC yield.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.123

5498
B. Dar et al. / Tetrahedron Letters 53 (2012) 5497–5502
Table 2
the exercise of these approaches. The development of a simple and
Effect of Solvents on the condensation of 4-chloroaniline, 4-chlorobenzaldehyde and
triethylphosphite under ultrasonication
inexpensive procedure for one-pot synthesis of
nate is needed.
a-aminophospho-
Entry
Solvent
Time (S)
Yielda (%)
Ultrasound assisted synthesis of organic compounds is a well
established protocol and has been authenticated as a substitute en-
ergy source for organic reactions ordinarily accomplished through
heating.27 Many homogeneous and heterogeneous reactions can
be conducted smoothly by sonication to afford improved yields
and increased selectivities.28 Therefore, ultrasound irradiation has
been established as an important technique in organic synthesis.
Taking advantage of this energy source some researchers have
recently reported the ultrasound mediated solvent-free synthesis
1
2
3
4
5
6
7
8
Solvent-free
Hexane
Ethyl acetate
Tetrahydrofuran (THF)
Dimethylformamide
Acetone
Acetonitrile
Methanol
Toluene
20
20
20
20
20
20
20
20
20
20
20
20
99
90
89
86
85
82
79
79
76
73
72
65
9
10
11
12
Dichloromethane
Ethanol
Water
of
a-aminophosphonates from aryl amines, aryl aldehydes, and
triethylphosphite using different catalysts.29
To make this process more efficient, we herein describe the ultra-
sound promoted procedure with rapid kinetics under mild condi-
tions, good atom-efficiency, simple work-up, and easy purification
a
HPLC yield.
undesirable reaction conditions, expensive reagents, lengthened
reaction times, costly catalysts, and formation of side products limit
procedure for the synthesis of a-aminophosphonates with different
Table 3
Ultrasound promoted condensation of anilines, benzaldehydes and triethylphosphite under solvent free and catalyst free conditions
Entry
Aldehyde
Amine
Product
Time (S)
Yield (%)
Cl
O
NH2
CH
O
P
O
HN
1
20
99
O
Cl
Cl
Cl
4a
Cl
NH2
Cl
O
CH
OCH3
O
P
O
HN
O
2
45
86
H3CO
OCH3
OCH3
H3CO
Cl
OCH3
4b
O
NH2
Cl
CH
O
O
N
HN
P
O
3
20
81
N
H3C
CH3
H3C
Cl
CH3
4c
NH2
Cl
O
O
O
HN
P
4
20
84
O
4d

B. Dar et al. / Tetrahedron Letters 53 (2012) 5497–5502
5499
Table 3 (continued)
Entry
Aldehyde
Amine
Product
Time (S)
Yield (%)
Cl
NH2
O
O
O
P
O
Br
5
20
80
HN
O
O
Cl
Br
4e
Cl
NH2
Cl
O
O
O
O
P
Piperonal
O
HN
6
20
87
O
O
O
4f
Cl
NH2
Cl
HO
O
P
O
7
20
84
O
HN
O
OH
4g
Cl
NH2
Cl
Cl
O
Cl
O
O
8
20
92
HN
P
O
Cl
Cl
4h
Cl
NH2
Cl
O
O
P
O
F
HN
9
25
95
O
F
4i
Cl
NH2
CH3
O
O
O
HN
P
10
20
96
O
Cl
Cl
4j
(continued on next page)

5500
B. Dar et al. / Tetrahedron Letters 53 (2012) 5497–5502
Table 3 (continued)
Entry
Aldehyde
Amine
Product
Time (S)
Yield (%)
Cl
NH2
O
F
O
P
O
11
20
91
HN
O
F
F
Cl
F
4k
CH3
NH2
CH3
O
O
O
HN
P
12
20
20
30
95
87
88
O
H3CO
H3CO
H3CO
OCH3
4l
F
F
O
NH2
F
O
O
O
F
13
HN
P
O
O
F
F
OCH3
4m
F
O
NH2
O
O
HN
P
14
O
F
OCH3
4n
4o
4p
F
NH2
O
O
O
15
20
91
HN
P
F
O
CH3
O
NH2
CH3
O
P
O
16
25
88
HN
O

B. Dar et al. / Tetrahedron Letters 53 (2012) 5497–5502
5501
Table 3 (continued)
Entry
Aldehyde
Amine
Product
Time (S)
Yield (%)
F
F
NH2
F
O
O
17
20
87
O
P
F
F
O
O
HN
O
F
4q
Cl
NH2
O
O
O
18
4 h
Traces
O
HN
P
O
CH3
NH2
4r
Cl
O
P
19
5 h
No reaction
O
HN
Cl
O
CH3
NH2
4s
O
O
P
O
HN
20
4 h
Traces
O
CH3
4t
species of aryl amines, aryl aldehydes, and triethylphosphite in cat-
alyst free and solvent-free conditions (Scheme 1).
their comparison with the solvent-free approach proved that bet-
ter results are obtained in solvent-free conditions (Table 2, entry
1–12).
We investigated the solvent-free and catalyst-free ultrasound
promoted multicomponent synthesis of
a
-aminophosphonates at
Once, the reaction conditions were optimized we further at-
tempted to understand the general reactivity of other carbonyl
compounds and amines. To study the scope and the limitations
of this novel method, we investigated the reaction using several
electron-donating and electron-withdrawing substituted benzal-
dehydes as well as amine with triethylphosphite under solvent-
free conditions. The reaction was found to be compatible with var-
ious functional groups such as Cl, Br, F, OMe, OEt, NO2, and OH with
excellent chemoselectivity. Various aromatic aldehydes containing
electron donating or electron withdrawing functional groups were
treated with various amines and did not show any remarkable dif-
ference in the yield of the desired products. The results are given in
Table 3 which shows that all the reactions preceded clean, to give
room temperature. Initially, we attempted one pot coupling of 4-
chloroaniline (1 mmol), 4-chlorobenzaldehyde (1 mmol) and tri-
ethylphosphite (1.3 mmol) as the model reaction to optimize the
reaction conditions. To our surprise the reaction proceeded effi-
ciently with 100% conversion to afford the corresponding a-amin-
ophosphonate (99% yields) within dramatically shorter time (20 s)
at room temperature (Table 1, entry 3).30 The products were puri-
fied through recrystallization without applying any chromato-
graphic technique. This avoids use of large quantities of volatile
organic solvents usually required for work-up and purification in
many existing procedures. When the reaction was carried out with
and without solvents at room temperature exclusive of exposing to
ultrasonic radiations, merely traces of the product were observed
even after 18 h. (Table 1, entry 1–2). In the absence of ultrasound
radiations increased temperature also could not enhance the reac-
tion rate or product yield (Table 1, entry 5–6). Evidently, the sono-
chemical effect might be the key factor to the high efficiency of the
one-pot and solvent-free reactions. Screening of different solvents
such as water, ethanol, methanol, dichloromethane, N,N-diethyl-
formamide, toluene, hexane and acetonitrile for this reaction and
the corresponding a-aminophosphonate. It was observed that ani-
line substituted with electron withdrawing group requires less
time than the amine substituted with electron donating group.
Similar observation is noticed in case of aromatic aldehydes when
they are attached with electron withdrawing and electron
donating groups. Furthermore increase in the reaction time of low-
er yielding reactions (e.g., Table 3, entry 2) could not bring any sig-
nificant improvement in the yield of the product (Fig. 1).

5502
B. Dar et al. / Tetrahedron Letters 53 (2012) 5497–5502
Figure 1. Effect of reaction time on the yield of 4b.
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der sonication without using any catalyst. Based on the results of
this study, it seems that the ultrasound irradiations are sufficient
to draw this reaction in the absence of any catalyst with decreased
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reaction times and improved yields of
Though the protocol is general but is not universal, because the
-aminophosphonates obtained from corresponding ketones were
a-aminophosphonates.
a
very less in yield under these conditions. When aldehydes were re-
placed with ketones the yields were found to be very less even
after 4–5 h (Table 3, entry 18–20). Here the products from aceto-
phenone and cyclohexanone were obtained in traces, acetone
shows no reaction.
In conclusion we report an ultrasound promoted, catalyst free
and solvent-free efficient, convenient, methodology for the synthe-
sis of
a-aminophosphonates with short reaction time, good to
25. Dindulkar, S. D.; Reddy, M. V.; Jeong, Y. T. Catal. Commun. 2012, 17, 114.
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excellent yields, and high selectivity.
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Acknowledgements
We are grateful to the authorities of M/S Indian Institute of Inte-
grated Medicine (IIIM), canal road, Jammu for providing necessary
facilities and good environment to carry out the research work. We
are also thankful to CSRI-DELHI for the financial support.
30. Typical procedure for one-pot synthesis of a-aminophosphonates: A mixture of an
aniline (1 mmol) and an aldehyde (1 mmol) was taken with triethylphosphite
(1.3 mmol) in a 5 ml glass test tube (Scheme 1) with total reaction volume 0.4–
0.5 ml approximately. The reaction mixture was placed at room temperature for
specified time under ultrasonic irradiation, performed in a Bandelin Sonorex
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Super RK 510
H
ultrasonic bath with Inner tank dimensions l  w  d:
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was monitored by TLC (silica gel) using ethyl acetate–hexane as eluent. After
completion of the reaction (as indicated by TLC), the mixture was quenched
with water and extracted with ethyl acetate, dried (MgSO4) then concentrated
under reduced pressure to afford the crude product. The crude product thus
obtained was purified by the process of crystallization and the spectral data (1H,
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