Simple and catalyst-free synthesis of oxoindolin-3-yl phosphonates

Article abstract of DOI:10.1021/cc900169p

An efficient, simple, and catalyst-free synthesis of dialkyl or diaryl 3-(dicyanomethyl)-2-oxoindolin-3-ylphosphonates by the reaction of dialkyl or diaryl phosphites and oxoindolin-3-ylidenemalononitriles under solvent-free conditions is reported. The reaction of imino isatins with dialkyl or diaryl phosphites results in the formation of dialkyl or diaryl 2-oxo-3-(arylamino) indolin-3-ylphosphonates.

Full text of DOI:10.1021/cc900169p

J. Comb. Chem. 2010, 12, 295–297
295
Simple and Catalyst-Free Synthesis of Oxoindolin-3-yl Phosphonates
Ghazaleh Imani Shakibaei,† Saadi Samadi,† Ramin Ghahremanzadeh,‡ and
Ayoob Bazgir*,†
Department of Chemistry, Shahid Beheshti UniVersity, G.C., P.O. Box 19396-4716, Tehran, Iran, and
Nanobiotechnology Research Center, AVicenna Research Institute, ACECR, Tehran, Iran
ReceiVed October 27, 2009
An efficient, simple, and catalyst-free synthesis of dialkyl or diaryl 3-(dicyanomethyl)-2-oxoindolin-3-
ylphosphonates by the reaction of dialkyl or diaryl phosphites and oxoindolin-3-ylidenemalononitriles under
solvent-free conditions is reported. The reaction of imino isatins with dialkyl or diaryl phosphites results in
the formation of dialkyl or diaryl 2-oxo-3-(arylamino)indolin-3-ylphosphonates.
1. Introduction
cleophilic addition of phosphites to imines is convenient and
is usually activated by catalyst.28
Isatin and derivatives have been demonstrated to be
versatile starting materials for the synthesis of heterocyclic
and noncyclic, natural products, and analogues, as well as
for the synthesis of potentially important compounds with
biological activities.1 Oxindoles are well-known among these
compounds. Oxindoles are useful as antibacterial, antiflam-
matory, and laxative drugs.2,3 Furthermore, this heterocyclic
compounds have been isolated from plant.4 Therefore, a
number of methods have been reported for the synthesis of
oxindole derivatives.5-8
Considering the above reports and as part of our program
that aims to develop new selective and environmentally
friendly methodologies for the preparation of heterocyclic
compounds,29 we report herein, the synthesis of oxoindolin-
3-yl phosphonates by efficient and catalyst-free methods.
2. Results and Discussion
We found that a mixture of 2-(2-oxoindolin-3-ylidene)ma-
lononitriles 1a-f and dialkyl or diaryl phosphites 2a-d in
the absence of any catalyst at 50 °C for 1.5-5 h under
solvent-free conditions, afforded dialkyl or diaryl 3-(dicya-
nomethyl)-2-oxoindolin-3-ylphosphonates 3a-r in good
yields (Scheme 1). The results are summarized in Table 1.
Several 2-(2-oxoindolin-3-ylidene)malononitriles carrying
different substituents worked well, mostly leading to good
yields of products. Another advantage of this method is its
efficiency for the high yield synthesis of products from
dialkyl or diaryl phosphites.
To the best of our knowledge, this new procedure provides
the first example of a catalyst-free synthesis of dialkyl or
diaryl 3-(dicyanomethyl)-2-oxoindolin-3-ylphosphonate de-
rivatives. The reactions under catalyst- and solvent-free
conditions are considerably safe, nontoxic, environmentally
friendly, and inexpensive. The absence of catalyst for the
reaction allows avoiding the use of moisture sensitive and
heavy metal Lewis acids. This method, based on catalyst-
free reaction under solvent-free conditions, is the most simple
and convenient and would be applicable for the synthesis of
different types of dicyanomethyl-oxoindolin-3-ylphospho-
nates.
Organophosphorus compounds have found a wide range
of application in the areas of industrial, agricultural, and
medicinal chemistry because of their biological and physical
properties, as well as their utility as synthetic intermediates.9-11
R-Functionalized phosphonic acids are valuable intermediates
for the preparation of medicinal compounds and synthetic
intermediates.12-14 Natural products containing P-C bonds
also show interesting biological activities.15,16
Among various methods to generate P-C bonds, the
addition of P(O)-H bonds across alkenes is one of the most
utilized approaches.17 There are three general approaches:
(a) the phospha-Michael reaction of activated alkenes, most
commonly promoted by catalysts17-21 or microwave irradia-
tion,22 (b) the addition to inactivated olefins, promoted by
radical initiators,23 and (c) the hydrophosphorylation of
inactivated alkenes catalyzed by transition metals.24,25
The synthesis of R-amino phosphonates exhibiting high
biological activity has recently attracted a lot of attention.26
Because of their structural analogy with R-amino acids, this
type of organophosphorous compounds are widely used for
the development of new inhibitors of enzymes, neuroactive
compounds, antibiotics, and plant-growth regulators.27 Thus,
a variety of synthetic approaches are desirable to synthesize
R-amino phosphonates. Of the methods available, the nu-
Due to the biological importance of R-amino phospho-
nates, we extended the reaction of dialkyl or diaryl phosphites
2 with various imino isatins 4 under similar conditions,
furnishing the respective dialkyl or diaryl 2-oxo-3-(arylami-
no)indolin-3-ylphosphonates 5a-z in good yields (Scheme
2). The results are summarized in Table 2. The imino isatins
carrying both electron-withdrawing and electron-releasing
substituents were also converted to their corresponding
* To whom correspondence should be addressed. E-mail: a_bazgir@
sbu.ac.ir.
† Shahid Beheshti University.
‡ Avicenna Research Institute.
10.1021/cc900169p  2010 American Chemical Society
Published on Web 01/28/2010

296 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Shakibaei et al.
Scheme 1. Synthesis of Dialkyl or Diaryl 3-(Dicyanomethyl)-2-oxoindolin-3-ylphosphonates 3
Scheme 2. Synthesis of Dialkyl or Diaryl 2-Oxo-3-(arylamino)indolin-3-ylphosphonates 5
Table 1. Synthesis of Dialkyl or Diaryl 3-(Dicyanomethyl)-2-
oxoindolin-3-ylphosphonates 3
Table 2. Synthesis of Dialkyl or Diaryl 2-Oxo-3-
(arylamino)indolin-3-ylphosphonates 5
products 3
R
X
R′
Et
Et
Et
Et
time (h)
yield (%)
products 5
R
X
R′
Et
Ar
time (min) yield (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
H
H
H
H
NO2
Br
H
H
H
NO2
Br
Br
H
H
H
NO2
Br
H
2
2.5
3
1.5
1.5
2
1
2.5
2
1.5
3
4.5
3
82
80
78
86
83
81
80
79
83
80
78
82
78
80
84
81
80
86
a
b
c
d
e
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
20
25
88
88
91
87
88
90
95
90
89
88
86
87
89
88
90
89
85
91
91
95
94
90
78
89
97
96
PhCH2
Me
H
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-NO2-C6H4
4-Et-C6H4
20
15
30
30
H
H
Et
Me
Me
Me
Me
Me
Me
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
C6H5
C6H5
f
PhCH2
Me
H
g
h
i
j
k
l
m
n
o
p
q
r
4-Br-C6H4
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-Br-C6H4
4-Me-C6H4
4-Cl-C6H4
4-MeO-C6H4
4-NO2-C6H4
4-Cl-C6H4
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-MeO-C6H4
4-Me-C6H4
4-Me-C6H4
C6H5
20
50
70
60
50
95
Me
Me
Me
Me
PhCH2
PhCH2
PhCH2
PhCH2
H
H
Me
H
PhCH2
Me
H
100
100
80
100
90
5
2.5
2
5
3
H
H
H
Br Et
Br Et
Br Et
H
H
H
H
H
H
H
H
H
H
NO2
110
100
85
70
80
s
t
Me
PhCH2
PhCH2
Me
Me
Me
i-Pr
i-Pr
u
v
w
x
y
z
dialkyl or diaryl 2-oxo-3-(arylamino)indolin-3-ylphosphonate
derivatives in relatively similar times and yields (Table 2).
The workup of these very clean reactions involves only a
simple washing step (diethyl ether) to remove unreacted
starting materials. For further purification, the residue
recrystallized from EtOH-H2O. Using this simple purification
protocol the desired products are obtained in high purity.
Compounds 3 and 5 are stable solids whose structures were
established by IR, 1H, 31P and 13C NMR spectroscopy, mass
spectrometry and elemental analysis.
H
H
H
H
100
90
60
C6H5 C6H5
C6H5 4-Me-C6H4
Br C6H5 4-Me-C6H4
70
time (Table 1 and Table 2). After completion of reaction, as
indicated by TLC, the reaction mixture was washed with
diethyl ether (5 mL) and residue recrystallized from EtOH-
H2O (1:3) to afford the pure product.
In conclusion, an efficient, atom-economical, and simple
method for the preparation of dialkyl or diaryl 3-(dicyanom-
ethyl)-2-oxoindolin-3-ylphosphonates and dialkyl or diaryl
2-oxo-3-(arylamino)indolin-3-ylphosphonates using readily
available starting materials under solvent-free conditions was
reported. Prominent among the advantages of this new
catalyst-free method are the operational simplicity, good
yields, and the easy workup procedures employed.
Acknowledgment. We gratefully acknowledge financial
support from the Research Council of Shahid Beheshti
University.
Supporting Information Available. Experimental pro-
cedures and IR, 1H NMR, and 13C NMR spectra for
compounds 3 and 5. This material is available free of charge
via the Internet at http://pubs.acs.org.
References and Notes
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e)malononitrile or imino isatin (1 mmol) and dialkyl or diaryl
phosphite (1.1 mmol) was stirred at 50 °C for an appropriate

Oxoindolin-3-yl Phosphonates
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 297
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