Synthesis of α1-oxindole-α-hydroxyphosphonates under catalyst-free conditions using polyethylene glycol (PEG-400) as an efficient and recyclable reaction medium

Article abstract of DOI:10.1016/j.tetlet.2012.01.045

A simple, efficient, eco-friendly, and cost-effective method has been developed for the synthesis of α¹-oxindole-α- hydroxyphosphonate derivatives (3a-o) by a one-pot reaction of isatins (1a-o) with trialkyl phosphites (2a-o) under catalyst-free-conditions using inexpensive, non-toxic polyethylene glycol (PEG-400) in excellent yields (82-92%). The present methodology offers an environmental acceptability; low cost, high yields, and recyclability of the PEG-400 are the important features of this protocol.

Full text of DOI:10.1016/j.tetlet.2012.01.045

Tetrahedron Letters 53 (2012) 1699–1700
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Synthesis of a a-hydroxyphosphonates under catalyst-free
1-oxindole-
conditions using polyethylene glycol (PEG-400) as an efficient and
recyclable reaction medium
Lingaiah Nagarapu a, , Raghu Mallepalli b, U. Nikhil Kumar a, P. Venkateswarlu a, Rajashaker Bantu a,
⇑
Lingappa Yeramanchi b
a Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500 607, India
b Department of Chemistry, Sri Venkateswara University, Tirupati 517502, India
a r t i c l e i n f o
a b s t r a c t
A simple, efficient, eco-friendly, and cost-effective method has been developed for the synthesis of a1
oxindole-a-hydroxyphosphonate derivatives (3a–o) by a one-pot reaction of isatins (1a–o) with trialkyl
phosphites (2a–o) under catalyst-free-conditions using inexpensive, non-toxic polyethylene glycol (PEG-
400) in excellent yields (82–92%). The present methodology offers an environmental acceptability; low
cost, high yields, and recyclability of the PEG-400 are the important features of this protocol.
Ó 2012 Elsevier Ltd. All rights reserved.
-
Article history:
Received 1 November 2011
Revised 9 January 2012
Accepted 10 January 2012
Available online 2 February 2012
Keywords:
Isatins
Triethyl phosphate
a
1-oxindole-
a-hydroxyphosphonates
Polyethylene glycol
Catalyst free conditions
a
-Hydroxyphosphonates motifs have remarkable biological
catalysts. Hence, there is a need to develop a rapid, efficient, and
environmentally benign synthetic protocol for the synthesis of
activities1 such as antiviral, antibacterial, anticancer, and also use-
ful as synthetic intermediates of
a
-substituted phosphonyl com-
a
-hydroxyphosphonate derivatives under catalyst-free conditions.
In recent years, PEG has emerged as a powerful phase transfer
pounds.2 In addition these derivatives are widely used in the
pharmaceutical applications, such as enzyme inhibitors of rennin,
EPSP synthase, and HIV protease.3 These derivatives also show
activities such as antibacterial, anti-inflammatory, laxative agents,
growth hormones, and new targets for cancer chemotherapy.4
Furthermore, these derivatives have been used in the preparation
catalyst and performs many useful organic transformations under
mild reaction conditions. Moreover, PEG is inexpensive, easy to
handle, thermally stable, non-toxic, and recyclable in various or-
ganic transformations, such as synthesis of b-amino sulfides,
2-substituted benzimidazoles, bis-benzimidazoles, 3,4-dihydro-
pyrimidinones, b-keto sulfides, and dibenz[b,f]-1,4-oxazapine
etc.9 This inspired us to focus on the aspect of synthesis of biolog-
ically active pyrrole derivatives under catalyst free conditions by
using PEG as an eco-friendly and recyclable media. In continuation
of our studies toward the development of novel methodologies10,11
of
a-ketophosphonates, a-aminophosponates, and 1,2-diketones
from acid chlorides.5
Several different strategies for the synthesis of substituted
-hydroxy phosphonates are known, the most common protocol
a
is the reaction of aldehydes or ketones with dialkyl or trialkyl
phosphites in the presence of acidic or basic catalysts,6,7 Mean-
while, tris(trimethylsilyl)phosphite was also used to synthesize
herein we report for the first time synthesis of
a a-
1-oxindole-
hydroxyphosphonates derivatives by using PEG-400 as a recyclable
medium without adding any organic solvent and catalyst. To the
best of our knowledge there are no reports for the synthesis of
a
-hydroxy phosphonates but it requires elevated temperature
under anhydrous reaction conditions.8
However, many of these methods are associated with various
drawbacks such as use of metal catalysts, harsh reaction condi-
tions, tedious experimental procedures, unsatisfactory yields, long
reaction times, and usage of expensive and moisture sensitive
a a-hydroxyphosphonate derivatives by using PEG-400
1-oxindole-
as a reaction medium under catalyst-free conditions (Scheme 1).
To explore the scope of this reaction for the synthesis of a1
-
oxindole-a-hydroxyphosphonate derivatives, different substituted
isatins were reacted with trialkyl phosphites with PEG-400 as the
reaction medium (Scheme 2, Table 1). In general, all the reactions
were very clean, and the
derivatives were obtained in high yields under these conditions.12
a a-hydroxyphosphonate
1-oxindole-
⇑
Corresponding author. Tel.: +91 40 27191509; fax: + 91 40 27193382.
E-mail address: lnagarapuiict@yahoo.com (L. Nagarapu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.045

1700
L. Nagarapu et al. / Tetrahedron Letters 53 (2012) 1699–1700
O
P
tages of this protocol. PEG-400 mediated reactions are very useful
both from economical and environmental points of view.
OH
O
OR
OR
OR
OR
PEG-400
10h, 50 0
C
+
RO
P
N
H
O
N
H
O
Acknowledgments
R = Et, Me
1-oxindole-
a-hydroxy phosphonates.
The authors are thankful to J. S. Yadav, Director, IICT, for his
kind permission and support. We also thank UGC-BSR New Delhi
for financial assistance.
Scheme 1. PEG mediated synthesis of
a
References and notes
PEG
O
1. Stowasser, B.; Budt, K.-H.; Jian-Qi, L.; Peyman, A.; Ruppert, D. Tetrahedron Lett.
1992, 33, 6625; For a review about the biological activity of amino phosphonic
acids, see Kafarski, P.; Lejczak, B. Phosphorus, Sulfur, Silicon 1991, 63, 193.
2. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
3. Hirschmann, R.; Smith, A. B., III; Taylor, C. M.; Benkovic, P. A.; Taylor, S. D.;
Yager, K. M.; Sprengeler, P. A.; Benkovic, S. J. Science 1994, 265, 234; Patel, D. V.;
Rielly-Gauvin, K.; Ryono, D. E.; Free, C. A.; Rogers, W. L.; Smith, S. A.; DeForrest,
J. M.; Oehl, R. S.; Petrillo, E. W. J. Med. Chem. 1995, 38, 4557.
4. Garrido, F.; Ibanez, J.; Gonalons, E.; Giraldez, A. Eur. J. Med. Chem. 1975, 10, 143;
Tokunaga, T.; Hume, W. E.; Nagamine, J.; Kawamura, T.; Taiji, M.; Nagata, R.
Bioorg. Med. Chem. Lett. 2005, 15, 1789; Popp, F. D. J. Heterocycl. Chem. 1984, 21,
1367; Pajouhesh, H.; Parsons, R.; Popp, F. D. J. Pharm. Sci. 1983, 72, 318; Yong, S.
R.; Ung, A. T.; Pyne, S. G.; Skelton, B. W.; White, A. H. Tetrahedron 2007, 63,
5579.
5. Firouzabadi, H.; Iranpoor, N.; Sobhani, S.; Amoozgar, Z. Synthesis 2004, 1771;
Kaboudin, B. Tetrahedron Lett. 2003, 44, 1051; Firouzabadi, H.; Iranpoor, N.;
Sobhani, S. Synth. Commun. 2004, 34, 1463; Iorga, B.; Eymery, F.; Savignac, P.
Tetrahedron 1999, 55, 2671.
O R
O
O
PEG
O
O
PEG
OR
P OR
OR
N
R
O
N
R
N
R
:
P OR
OR
upon
workup
OH
OH
P OR
O
O
P OR
+
R-PEG
OR
OR
N
R
O
N
R
O
Scheme 2. Plausible mechanism for the synthesis of
a a-hydroxy
1-oxindole-
phosphonates.
6. Texier-Boullet, F.; Lequitte, M. Tetrahedron Lett. 1986, 27, 3515; Alexander, C.
W.; Albiniak, P. A.; Gibson, L. R. Phosphorus, Sulfur, Silicon 2000, 167, 205; Saito,
B.; Egami, H.; Katsuki, T. J. Am. Chem. Soc. 1978, 2007, 129; Texier-Boullet, F.;
Foucaud, A. Synthesis 1982, 916; Dodda, R.; Zhao, C.-G. Org. Lett. 2006, 8, 4911;
Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron: Asymmetry 1993, 4, 1779.
7. Tajbakshi, M.; Heydari, A.; Khalizadeh, M. A.; Lakouraj, M. M.; Zamenian, B.;
Khaksar, S. Synlett 2007, 2347; Shankar, J.; Karnakar, K.; Srinivas, B.; Nageswar,
Y. V. D. Tetrahedron Lett. 2010, 51, 3938; Azizi, N.; Saidi, M. R. Phosphorus, Sulfur,
Silicon 2003, 178, 1255; Heydari, A.; Arefi, A.; Khaksar, S.; Tajbakhsh, M. Catal.
Commun. 2006, 7, 982; Goldeman, W.; Soroka, M. Synthesis 2006, 3019.
8. Evans, D. A.; Hurst, K. M.; Takacs, J. M. J. Am. Chem. Soc. 1978, 100, 3467.
9. Dickerson, T. J.; Reed, N. N.; Janda, K. D. Chem. Rev. 2002, 102, 3325.
10. Suryakiran, N.; Srikanth Reddy, T.; Ashalatha, K.; Lakshman, M.;
Venkateswarlu, Y. Tetrahedron Lett. 2006, 47, 3853.
Table 1
PEG-400 mediated synthesis of
a
1-oxindole-
a
-hydroxy phosphonatesa
O
P
OH
O
R
R
OR2
OR2
OR2
OR2
OR2
PEG-400
50 0C, 10 h
P
+
N
R1
1a-o
O
N
O
R2
2a-o
3a-o
Entry
R
R1
R2
Yieldb (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
H
H
H
H
H
H
H
H
Me
Ph
Et
Et
Et
Et
Et
Et
Et
Et
90
87
89
82
85
87
84
86
83
85
92
89
86
84
86
Me
OMe
F
Cl
Br
NO2
H
H
H
H
11. Nagarapu, L.; Raghu, M.; Lingappa, Y. Tetrahedron Lett. 2011, 52, 3401;
Nagarapu, L.; Raghu, M.; Glory, A.; Lingappa, Y. Eur. J. Chem. 2010, 1, 228; L.
Nagarapu, M. Raghu, Y. Lingappa, Eur. J. Chem. in press.; Nagarapu, L.; Raghu,
M.; Lingappa, Y. Synlett 2011, 2730.
12. General Procedure for the Synthesis of
a a-hydroxyphosphonate by
1-oxindole-
using PEG as the reaction medium: A mixture of isatin (1.0 mmol) and trialkyl
phosphite (1.0 mmol) was taken in 5 mL of polyethylene glycol, and stirred at
50 °C for 10 h. After completion of the reaction, as monitored by TLC, the
reaction mass was poured into water and extracted into ethyl acetate. The
organic layer was removed under reduced pressure, and the crude product was
purified by column chromatography. The recovered PEG can be reused for a
number of cycles without any significant loss of activity.
Et
Et
–CH2Ph
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Br
F
Data of representative examples:
Diethyl 3-hydroxy-2-oxoindolin-3-ylphosphonate (Table 1, entry1): Pale yellow
NO2
solid; Yield 92%; mp 142–144 °C ; IR: 3201, 2987, 1730, 1621, 1473,1395 cmÀ1
;
a
1H NMR (200 MHz, CDCl3) d 8.20 (s, 1H), 7.34–7.24 (m, 2H), 6.94–6.89 (m, 2H),
4.49–3.99 (m, 4H), 1.54–1.10 (m, 6H),; 13C NMR (75 MHz,CDCl3) d 160.95,
138.61, 130.69, 125.72, 123.92, 112.44, 64.81, 63.18, 16.07, 14.1; MS m/z (ESI);
309 [M+Na] +. HRMS m/z calcd for C12H16NO5NaP 309.1029; found 309.1027.
Diethyl 3-hydroxy-5-methyl-2-oxoindolin-3-ylphosphonate (Table 1, entry 2):
brown semisolid; Yield 91%; IR: 3203, 2985, 2858, 1733, 1627, 1492, 1247,
Reaction conditions: Isatin (1 mmol), trialkyl phosphite (1 mmol), PEG (5 mL),
50 °C, 10 h.
b
Isolated yields.
Isatin bearing electron-donating groups (Me, OMe) and electron-
withdrawing groups (NO2) gave the desired products in quantita-
tive yields in 10 h (Table 1, entries b, c, q, l, o). Results show that
the substituent groups did not play any significant role in the reac-
tivity of the substrate.
1035 cmÀ1 1H NMR (200 MHz, CDCl3): d 8.14 (s,1H), 7.49–7.07 (m, 2H), 6.99–
;
6.56 (m, 1H), 4.28–3.93 (m, 4H), 3.73 (s,1H), 2.07 (s, 3H), 1.51–0.88 (m, 6H),;
13C NMR (75 MHz,CDCl3): d 169.16, 138.73, 132.80, 130.90, 126.97, 110.03,
72.65, 64.61, 29.67, 20.98, 15.96; MS m/z (ESI); 322 [M+Na]+. HRMS m/z calcd
for C13H18NO5NaP 322.0820; found 322.0819.
Diethyl 3-hydroxy-5-nitro-2-oxoindolin-3-ylphosphonate( Table 1, entry 7): Pale
yellow solid; Yield 93%; mp 144–146 °C; IR: 3179, 2991, 2114, 1751, 1627,
In conclusion, we have developed an efficient and facile method
for the synthesis of
1523, 1342 cmÀ1 1H NMR (200 MHz, CDCl3): d 9.14 (s, 1H), 8.44-8.18 (m, 2H),
;
a a-hydroxyphosphonate deriva-
1-oxindole-
6.97–6.88 (m,1H), 4.58–3.85 (m, 4H), 1.75–1.02 (m, 6H); 13C
NMR(75 MHz,CDCl3): d 170.25, 159.25, 136.29, 127.46, 122.00, 110.43, 71.79,
64.99, 29.68, 15.72; 31P NMR, d: 19.59MS m/z (ESI); 331 [M+H]+. HRMS m/z
calcd for C12H15N2O7NaP 353.054; found 353.0500.
tives by the treatment of the corresponding isatins with trialkyl
phosphites by using PEG-400 as a recyclable medium without
the addition of any additive or organic co-solvent under catalyst-
free conditions. The mild reaction conditions, less expensive reac-
tion medium, operational simplicity, and high yields are the advan-
Dimethyl 3-hydroxy-5-methyl-2-oxoindolin-3-ylphosphonate (Table 1, entry 12):
Orange oil liquid; Yield 92%; 1H NMR (200 MHz, CDCl3): d 8.40 (s, 1H), 7.39–
7.25 (m, 1H), 7.16–7.05 (m, 1H), 6.75–6.83 (m, 1H), 3.91–3.80 (m, 6H), 3.80 (s,
OH), 2.29 (s, 3H); MS m/z (ESI); 318 [M+H]+.