Polyethylene glycol-promoted dialkyl, aryl/heteroaryl phosphonates

Article abstract of DOI:10.1080/00397911.2010.518279

A new, straightforward polyethylene glycol-promoted method for Michaelis-Arbuzov rearrangement has been described.

Full text of DOI:10.1080/00397911.2010.518279

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Polyethylene Glycol–Promoted Dialkyl,
Aryl/Heteroaryl Phosphonates
K. Reddi Mohan Naidu a , E. Dadapeer a , C. Bhupendra Reddy a , A.
Janardhan Rao a , C. Suresh Reddy a & C. Naga Raju a
a Department of Chemistry, Sri Venkateswara University, Tirupati,
India
Available online: 01 Jun 2011
To cite this article: K. Reddi Mohan Naidu, E. Dadapeer, C. Bhupendra Reddy, A. Janardhan Rao,
C. Suresh Reddy & C. Naga Raju (2011): Polyethylene Glycol–Promoted Dialkyl, Aryl/Heteroaryl
Phosphonates, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:23, 3462-3468
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Synthetic Communications1, 41: 3462–3468, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.518279
POLYETHYLENE GLYCOL–PROMOTED DIALKYL,
ARYL/HETEROARYL PHOSPHONATES
K. Reddi Mohan Naidu, E. Dadapeer, C. Bhupendra Reddy,
A. Janardhan Rao, C. Suresh Reddy, and C. Naga Raju
Department of Chemistry, Sri Venkateswara University, Tirupati, India
GRAPHICAL ABSTRACT
Abstract A new, straightforward polyethylene glycol–promoted method for Michaelis–
Arbuzov rearrangement has been described.
Keywords Aryl=heteroaryl phosphonates; dialkyl; PEG-600
INTRODUCTION
The Michaelis–Arbuzov rearrangement is one of the most versatile pathways
for the formation of carbon–phosphorus bonds and their diverse biological
activity.[1,2] Two main flaws that preclude wider use of this reaction are the drastic
reaction are conditions such as long reaction time in high temperatures and the
formation of a mixture of phosphorylated products,[3] which consequently decrease
the yield of the desired product. To overcome these drawbacks, many catalysts such
as iodine,[4] alkali–metal-iodide,[5] trimethyl silylhalide (TMSX),[6] BF3 ꢀ OEt2,[7] and
ionic liquid[8] have been tried, but none of them was found to be satisfactory. The
present method for the Arbuzov reaction in polyethylene glycol (PEG) overcomes
these difficulties. PEG has many advantages such as thermal stability and recover-
ability; it is environmentally benign and a biologically acceptable medium for drug
delivery not only as an ecofriendly solvent but also as a catalyst.[9]
SYNTHESIS AND DISCUSSION
In the present procedure, trialkyl phosphite (2), a safe and easy reagent to
handle, has been employed as an effective phosphite ion source, and neither
Received April 22, 2010.
Address correspondence to C. Naga Raju, Department of Chemistry, Sri Venkateswara University,
Tirupati 517502, India. E-mail: rajuchamarthi10@gmail.com
3462

SYNTHESIS OF ORGAN PHOSPHORUS COMPOUNDS
3463
additives are needed nor promoters to enhance this reaction because PEG serves as
an ecofriendly medium and also acts as a reaction-promoting catalyst under mild
conditions.
To date, it is the first feasible method for the Arbuzov reaction of various
alkyl=aryl=heteroaryl halides with trialkyl phosphite in PEG medium. The advan-
tages are many: simple and mild experimental conditions, less reaction time, cost-
effectiveness due to recyclability of PEG, and applicability to various substituted
alkyl, aryl, and heterocyclic halide substrates. It is an innovative and efficient green
chemical approach to synthesize phosphonates while avoiding hazardous solvents
and toxic reagents.
The synthetic route for the new alkyl, aryl, and heterocyclic phosphonates
(3a–l) in good yields (72–82%) involved reaction of alkyl, aryl, and heterocyclic
halides (1a–l) with trialkyl phosphites (2) in PEG at 50–60 ꢁC (Scheme 1). The chemi-
1
cal structures of 3a–l were confirmed by elemental analysis; infrared (IR); H, 13C,
and 31P NMR; and mass spectral data. The methoxy protons gave two distinct doub-
lets in the region of d 3.78–3.63 (J ¼ 10.9–10.2 Hz), 3.72–3.40 (J ¼ 10.9–10.2 Hz),[10]
indicating their magnetic nonequivalence, and the methyleneoxy protons resonated
as multiplets at d (4.21–4.01).[11] The methoxy carbon chemical shifts appeared as
a doublet at d 59.0–52.5 (d, J ¼ 6.7–6.4 Hz).[10] Similarly in diethyl phosphonate,
the methyleneoxy carbons also resonated as a doublet at d 62.3–61.4 (d, J ¼
6.9 Hz).[11] The 31P NMR signals were observed in the range 19.2–26.2 ppm.[11]
Liquid chromatography=mass spectrometry (LCMS) data were recorded for 3a,
3c, 3f, 3i, and 3l, and they gave Mþꢀ ions at their respective m=z values.
EXPERIMENTAL
Chemistry
Chemicals purchased from Sigma-Aldrich, Merck, and Lancaster were used as
such without further purification. All solvents used for spectroscopic and other
physical studies were of reagent grade and were further purified as described in the
literature methods.[12] IR spectra were recorded as KBr pellets and Nujol mulls on
1
a Perkin-Elmer 283 unit. H, 13C, and 31P NMR spectra were recorded on a Bruker
1
400-MHz NMR spectrometer operating at 400 MHz for H, 100 MHz for 13C, and
161.9 MHz for 31P NMR in CDCl3 and referenced to tetramethylsilane (TMS) (1H
and 13C) and 85% H3PO4(31P), respectively. LCMS mass spectra were recorded on
a Jeol SX102 DA=600 mass spectrometer. Elemental analyses were performed on a
Thermo Finnigan Insturment at University of Hyderabad, Hyderabad, India.
Scheme 1.

3464
K. R. M. NAIDU ET AL.
Table 1. Synthesis of phosphonate derivatives
Compound
3a
R
R1
Me
3b
Et
3c
Me
Et
3d
3e
3f
Me
Et
3g
3h
Me
Et
3i
3j
Me
Et
3k
3l
Me
Et

SYNTHESIS OF ORGAN PHOSPHORUS COMPOUNDS
3465
General Procedure for the Preparation of 3a–l
A mixture of alkyl=aryl halide (1 mmol), trialkyl phosphite (1.3 mmol), and
PEG-600 (3 g) were placed in a 50-mL round-bottomed flask, and the mixture was
stirred at 50–60 ꢁC for 2–4 h. The reaction progress was monitored by thin-layer chro-
matography (TLC) (ethyl acetate–hexane, 3:7). After completion of the reaction, the
reaction mixture was cooled in a dry ice–acetone bath to precipitate the PEG and
extract it with ether. The ether extract was dried over MgSO4 and evaporated. The
resulting product, though seen as a single compound by TLC, was further purified
by passing it over a column of silica gel. The recovered PEG was reused.
Selected Data
Dimethyl-4-chloro-2-nitrophenylphosphonate (3a). Yield 81%, semisolid;
1H NMR (CDCl3): d 7.68 (1H, d, J ¼ 6.9 Hz, Ar-H), 7.38 (1H, s, Ar-H), 7.31 (1H, d,
J ¼ 7.8 Hz, Ar-H), 3.78 (3H, d, J ¼ 10.5 Hz, -OCH3), 3.72 (3H, d, J ¼ 10.2 Hz,
-OCH3); 13C NMR: 148.2, 135.4, 130.4, 128.9, 122.2, 117.6, 52.5 (d, J ¼ 6.2 Hz,
-OCH3); P NMR: d 24.3; IR (KBr) cmꢂ1: 1243 (P O), 1018 (P-C); LCMS m=z:
31
=
264 (100, Mþꢀ), 266 (32, M þ 2). Anal. calcd. for C8H9NO5PCl: C, 36.24; H, 3.39;
N, 5.28. Found: C, 36.20; H, 3.36; N, 5.22.
Diethyl-4-chloro-2-nitrophenylphosphonate (3b). Yield 82%, semisolid;
1H NMR (CDCl3): d 7.57 (1H, d, J ¼ 8.1 Hz, Ar-H), 7.26 (1H, s, Ar-H), 7.20 (1H,
d, J ¼ 6.9 Hz, Ar-H), 4.16–4.01 (4H, m, -OCH2), 1.18 (6H, t, J ¼ 5.1 Hz, -CH3);
13C NMR: 149.1, 134.6, 131.2, 129.2, 122.7, 116.4, 61.4 (d, J ¼ 5.9 Hz, -OCH2),
16.7 (-CH3); 31P NMR: d 26.2; IR (KBr) cmꢂ1: 1234 (P O), 971 (P-C); Anal. calcd.
=
for C10H13NO5PCl: C, 40.95; H, 4.43; N, 4.77. Found: C, 40.92; H, 4.38; N, 4.72.
Dimethyl-4-nitrobenzylphosphonate (3c). Yield 77%, semisolid; 1H NMR
(CDCl3): d 8.11 (2H, d, J ¼ 8.3 Hz, Ar-H), 8.01 (2H, d, J ¼ 8.2 Hz, Ar-H), 3.64 (3H,
d, J ¼ 10.9 Hz, -OCH3), 3.50 (3H, d, J ¼ 10.9 Hz, -OCH3), 3.22–3.06 (2H, q, -P-CH2);
13C NMR: 147.2, 139.2, 130.7, 123.9, 53.2 (d, J ¼ 6.7 Hz, -OCH3), 33.7 (P-CH2); 31
P
þꢀ
NMR: d 23.2; IR (KBr) cmꢂ1: 1237 (P O), 967 (P-C); LCMS m=z: 245 (M ). Anal.
calcd. for C9H12NO5P: C, 44.08; H, 4.89; N, 5.71. Found: C, 43.98; H, 4.86; N, 5.68.
=
1
Diethyl-4-nitrobenzylphosphonate (3d). Yield 80%, semisolid; H NMR
(CDCl3): d 8.14 (2H, d, J ¼ 7.9 Hz, Ar-H), 8.03(2H, d, J ¼ 8.1 Hz, Ar-H), 4.12–
4.02 (4H, m, -OCH2), 3.25–3.03 (2H, q, -P-CH2), 1.20 (6H, t, J ¼ 5.6 Hz, -CH3);
13C NMR: 146.7, 139.5, 130.4 123.4, 62.3 (d, J ¼ 6.9 Hz, -OCH2), 34.2 (P-CH2),
16.0 (-CH3); 31P NMR: d 24.2; IR (KBr) cmꢂ1: 1249 (P O), 1027 (P-C). Anal. calcd.
=
for C11H16NO5P: C, 48.35; H, 5.86; N, 5.12. Found: C, 48.30; H, 5.79; N, 5.04.
Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl-phosphonate
1
(3e). Yield 72%, semisolid; H NMR (CDCl3): d 8.20 (2H, s, -NH), 6.71 (1H, d,
J ¼ 7.5 Hz, Ar-H), 3.62 (3H, d, J ¼ 10.2 Hz, -OCH3), 3.56 (3H, d, J ¼ 10.8 Hz,
-OCH3); 31P NMR: d 21.3; IR (KBr) cmꢂ1: 3412 (-NH), 1726 (C O), 1261
=
=
(P O), 1031 (P-C); Anal. calcd. for C6H9N2O5P: C, 32.72; H, 4.09; N, 12.72. Found:
C, 32.65; H, 4.03; N, 12.65.

3466
K. R. M. NAIDU ET AL.
Diethyl-2, 4-dioxo-1,2,3,4-tetrahydropyrimidine-5-yl-phosphonate (3f).
Yield 76%, semisolid; 1H NMR (CDCl3): d 8.20 (2H, s, -NH), 6.79 (1H, d,
J ¼ 7.5 Hz, Ar-H), 4.21–4.13 (4H, m, -OCH2), 1.14 (6H, t, J ¼ 7.1 Hz, -CH3); 31P
NMR: d19.2; IR (KBr) cmꢂ1: 3380 (-NH), 1716 (C O), 1237 (P O), 954 (P-C);
LCMS m=z; 248 (Mþꢀ). Anal. calcd. for C8H13N2O5P: C, 38.70; H, 5.24; N, 11.29.
Found: C, 38.64; H, 5.19; N, 11.21.
=
=
Dimethyl-3-amino pyridin-2-yl phosphonate (3g). Yield 80%, semisolid;
1H NMR (CDCl3): d 8.12 (1H, d, J ¼ 8.2 Hz, Ar-H), 7.55 (1H, t, J ¼ 7.6 Hz,
Ar-H), 7.12 (1H, d, J ¼ 6.5 Hz, Ar-H), 5.91 (2H, s, -NH2), 3.62 (3H, d, J ¼ 10.5 Hz,
-OCH3), 3.42 (3H, d, J ¼ 10.2 Hz, -OCH3); 13C NMR: 145.1, 143.2, 129.2, 126.1,
123.9, 59.0 (d, J ¼ 6.4 Hz, -OCH3); 31P NMR: d 20.3; IR (KBr) cmꢂ1: 3365
=
(-NH2), 1240 (P O), 960 (P-C). Anal. calcd. for C7H11N2O3P: C, 41.58; H, 5.44;
N, 13.86. Found: C, 41.50; H, 5.40; N, 13.81.
1
Diethyl-3-amino pyridin-2-yl phosphonate (3h). Yield 81%, semisolid; H
NMR (CDCl3): d 8.14 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.61 (1H, t, J ¼ 7.2 Hz, Ar-H), 7.10
(1H, d, J ¼ 6.9 Hz, Ar-H), 5.99 (2H, s, -NH2), 4.15–4.09 (4H, m, -OCH2), 1.21 (6H, t,
J ¼ 6.2 Hz, -CH3); 31P NMR: d 21.5; IR (KBr) cmꢂ1: 3352 (-NH2), 1232 (P O), 1012
=
(P-C). Anal. calcd. for C9H15N2O3P: C, 46.95; H, 6.52; N, 12.17. Found: C, 46.89; H,
6.44; N, 12.10.
Dimethyl-2-amino-6-methylpyrimidin-4-yl-phosphonate (3i). Yield 78%,
semisolid; 1H NMR (CDCl3): d 6.80 (1H, s, Ar-H), 5.50 (2H, s, -NH2), 3.68 (3H, d,
J ¼ 10.6 Hz, -OCH3), 3.40 (3H, d, J ¼ 10.5 Hz, -OCH3), 2.59 (3H, s, -CH3); 31P
NMR: d 20.9; IR (KBr) cmꢂ1: 3344 (-NH2), 1211 (P O), 980 (P-C); LCMS m=z:
=
217 (Mþꢀ). Anal. calcd. for C7H12N3O3P: C, 38.70; H, 5.52; N, 19. 35. Found: C,
38.65; H, 5.49; N, 19.30.
Diethyl-2-amino-6-methylpyrimidin-4-yl-phosphonate (3j). Yield 82%,
1
semisolid; H NMR (CDCl3): d 6.79 (1H, s, Ar-H), 5.55 (2H, s, -NH2), 4.20–4.12
(4H, m, -OCH2) 2.41 (3H, s, -CH3), 1.18 (6H, t, J ¼ 10.5 Hz, -CH2-CH3); 31P
NMR: d 21.5; IR (KBr) cmꢂ1: 3336 (-NH2), 1220 (P O), 960 (P-C). Anal. calcd.
for C9H16N3O3P: C, 44.08; H, 6.53; N, 17.14. Found: C, 43.97; H, 6.50; N, 17.11.
=
Dimethyloxiran-2-ylmethylphosphonate (3k). Yield 70%, semisolid; 1H
NMR (CDCl3): d 3.64 (3H, d, J ¼ 10.2 Hz, -OCH3), 3.42 (3H, d, J ¼ 10.1 Hz,
-OCH3), 2.62–2.54 (2H, m, -CH2), 2.41–2.39 (1H, m, -CH), 2.10–2.02 (2H, m,
-CH2-P); 31P NMR: d 22.9; IR (KBr) cmꢂ1: 1242 (P O), 975 (P-C). Anal. calcd.
=
for C5H11O4P: C, 36.14; H, 6.62. Found: C, 36.08; H, 6.59.
Diethyloxiran-2-ylmethylphosphonate (3l). Yield 73%, semisolid; 1H
NMR (CDCl3): d 4.20–4.13 (4H, m, -OCH2), 2.65-2.53 (2H, m, -CH2), 2.45–2.32
(1H, m, -CH), 2.20–2.11 (2H, m, -CH2-P), 1.12 (6H, t, J ¼ 10.2 Hz, -CH2-CH3);
þꢀ
31P NMR: d 22.0; IR (KBr) cmꢂ1; 1235 (P O), 980 (P-C); LCMS m=z: 194 (M ).
=
Anal. calcd. for C7H15O4P: C, 43.29; H, 7.73. Found: C, 43.23; H, 7.69.

SYNTHESIS OF ORGAN PHOSPHORUS COMPOUNDS
3467
CONCLUSION
An efficient, ecofriendly green synthesis of novel alkyl, aryl, and heterocyclic
phosphonates was achieved by a one-pot, two-component reaction between alkyl,
aryl, and heteroaryl halides and trialkyl phosphite in PEG, which served both as
reaction medium and as a catalyst. This procedure was environmentally friendly
and inexpensive, and the catalyst is recyclable, making it an attractive protocol over
the existing procedures for the synthesis of phosphonates.
ACKNOWLEDGMENTS
The authors express their thanks to the University Grants Commission, New
Delhi, for sanctioning a major research project [F. No. 34-356=2008(SR)] and Prof.
C. D. Reddy, Department of Chemistry, Sri Venkateswara University, Tirupati, for
his help and invaluable discussions.
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