Synthesis of O,O-dialkyl 2-oxo-2-(4-(selenomorpho-linosulfonyl)phenylamino) ethylphosphonate

Article abstract of DOI:10.1080/10426500701793212

A series of O,O-dialkyl 2-oxo-2-(4-(seleomorpholinosulfonyl)phenylamino) ethy lphosphonate were synthesized by reactions of 2-chloro-N-(4- (seleomorpholino sulfonyl)phenyl)acetamide with dialkylphosphite in the presence of sodium hydride. The structure of all new compounds has been confirmed by 1H NMR,31P NMR, IR, Mass spectroscopy and elemental analyses. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500701793212

This article was downloaded by: [University of Calgary]
On: 05 October 2014, At: 16:00
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Synthesis of O,O-Dialkyl 2-
Oxo-2-(4-(Selenomorpho-
Linosulfonyl)Phenylamino)Ethylpho
Fang Wang a , Liming Hu b , Xiaopeng Li b , Xuemei
Xu b & Hongguang Du a
a College of Science Beijing University of Chemical
Technology , Beijing, 100029, China
b College of Life Sciences and Bioengineering ,
Beijing University of Technology , Beijing, 100022,
China
Published online: 20 Jun 2008.
To cite this article: Fang Wang , Liming Hu , Xiaopeng Li , Xuemei Xu &
Hongguang Du (2008) Synthesis of O,O-Dialkyl 2-Oxo-2-(4-(Selenomorpho-
Linosulfonyl)Phenylamino)Ethylphosphonate, Phosphorus, Sulfur, and Silicon and the
Related Elements, 183:2-3, 610-616, DOI: 10.1080/10426500701793212
To link to this article: http://dx.doi.org/10.1080/10426500701793212
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any

losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 183:610–616, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701793212
Synthesis of O,O-Dialkyl 2-Oxo-2-(4-(Selenomorpho-
Linosulfonyl)Phenylamino)Ethylphosphonate
Fang Wang,1 Liming Hu,2 Xiaopeng Li,2 Xuemei Xu,2
and Hongguang Du3
1College of Science Beijing University of Chemical Technology, Beijing
100029, China
2College of Life Sciences and Bioengineering, Beijing University of
Technology, Beijing 100022, China
3College of Science Beijing University of Chemical Technology, Beijing
100029, China
A
series of O,O-dialkyl 2-oxo-2-(4-(seleomorpholinosulfonyl)phenylamino)ethy
lphosphonate were synthesized by reactions of 2-chloro-N-(4-(seleomorpholino sul-
fonyl)phenyl)acetamide with dialkylphosphite in the presence of sodium hydride.
1
31
The structure of all new compounds has been confirmed by H NMR, P NMR, IR,
Mass spectroscopy and elemental analyses.
Keywords Dialkyl phosphite; selenomorpholine; phosphonate; synthesis
INTRODUCTION
Since selenium was found to be an active center of glutathione
peroxidase(GSH-Px), which can catalyze and decompose liquid hy-
droperoxide or hydrogen peroxide, the study of selenium biological ac-
tivity has developed rapidly.1−2 Selenoorganic compound, such as Eb-
selen, with the function against biological damage caused in vivo by
reactive hydroperoxides,3−7 which increased a striking interest in de-
veloping new seleoorganic compound for therapy. These compounds
have been potentially used in a variety of fields varying from medicinal
to agriculture application.8−10 In our pervious work, many selenoor-
ganic compounds were synthesized and exhibited excellent pharma-
cological effect.11−13 Recently, the antibiotic activity and plant sys-
temic activity of selenomor pholine derivatives were studied in our
Address correspondence to Liming Hu, College of Life Sciences and Bioengineering,
Beijing University of Technology, Beijing 100022, China. E-mail: huliming@bjut.edu.cn
610

O,O-Dialkyl 2-Oxo-2-(4-(Selenomorpho-Linosulfonyl) Phenylamino)
611
Lab.14−15 In this work, we present the synthesis of O,O-dialkyl 2-oxo-
2-(4-(seleomorpholinosulfonyl)-phenyl-amino)ethylphosphonate.
RESULTS AND DISCUSSION
Synthesis of O,O-dialkyl 2-oxo-2-
(4-(selenomorpholinosulfonyl)
phenylamino) Ethyl Phosphonate
A general synthesis of the title compounds 7 is described by a mul-
tistep route outlined in Scheme 1. The synthesis of selenomorpholine
started from selenium and utilized a synthetic sequence previously re-
ported from our laboratory.16 Acylation of aniline followed by sulfona-
tion with sulfuric chloride gave 4-acetamidobenzene-1-sulfonyl chloride
2, which was coupled to selenomorpholine to give 3. Ac-deprotection
with aqueous sodium hydroxide followed by reaction with 2-chlorlacetyl
chloride afforded the desired 2-chloro-N-(4-(selenomorpholinosulfonyl)-
phenyl)acetamide 5, which reacted with dialkyl phosphite in the pres-
ence of sodium hydride to give title compounds 7.
1
The structure of 7 was confirmed by H NMR, 31P NMR, IR, Mass
1
spectroscopy and elemental analyses. In the H NMR spectra of com-
pound 7, the proton in PCH appeared as a doublet in the range of δ
3.0–3.2 ppm (2 JPH=20.4–21.4Hz). The chemical shift of labile proton
in the NH of compound 7 is 9.5–10.0 ppm, which can disappear slowly
when deuterated. The 31P NMR spectra of 7 revealed a singlet at the
range of δ19.1–22.6 ppm. The IR spectra of compound 7 showed the ex-
istence of the group P O(1233–1281cm−1) and C O(1685–1699cm−1).
The EI-MS spectra of 7 demonstrated the molecular ion peak (M+).
Other ions were consistent with their structures and can be clearly
assigned. Because there are two major isotopes of selenium (approxi-
mate ratio 2:1), the fragmental ion abundance ratio which contain two
isotopes of selenium is 2:1.
EXPERIMENTAL
The melting points were determined on a hot stage apparatus and un-
corrected, Elemental analyses were performed on a CHN Carlo Erba
element analyzer. 1H NMR spectra were recorded with a Varian XL-200
spectrometer, TMS was used as an internal standard for 1H NMR and
85% H3PO4 was used as an external standard for 31P NMR. The IR
spectra were measured by a NICOLET AVATAR360 instrument. Mass
spectra were recorded with a HP-5988A spectrometer.

612
F. Wang et al.
SCHEME 1
The reagents and solvents were available commercially and purified
according to conventional methods; column chromatography was per-
formed on silica gel (10–40 µ, Hai Yang Chemical Factory of Qingdao).
Unless other noted, all solvents were dried over Na2SO4 or MgSO4, and
the solvent was removed in a rotary evaporator under reduce pressure,
chromatography was performed on silica gel.
N-phenylacetamide 1,17 4-acetamidobenzene-1-sulfonyl chloride 218
and dialkylphos- phate 619 have been prepared following literature
methods.
N-(4-(Selenomorpholinosulfonyl)phenyl)acetamide (3)
To a stirred solution of selenomorpholine (3.0 g, 20 mmol) and dry pyri-
dine (10 mL) at room temperature under a nitrogen atmosphere, 4-
acetamidobenzene-1-sulfonyl chloride (5.2 g, 22 mmol) was added over
a period of 0.5 h, and was heated at 100◦C for 1 h. The resulting mix-
ture was quenched with ice and water. A light yellow precipitate was
produced. The crude product was filtered and washed with water and
purified by recrystallization in ethanol as a white solid (m.p. 89–91◦C,
yield, 74%).

O,O-Dialkyl 2-Oxo-2-(4-(Selenomorpho-Linosulfonyl) Phenylamino)
613
4-(Selenomorpholinosulfonyl)benzeneamine (4)
A solution of N-(4-(selenomorpholinosulfonyl)phenyl)acetamide (1.75 g,
5 mmol) and 10% sodium hydroxide solution (20 mL) was refluxed un-
der stirring for 1h and then allowed to cool to room temperature. The
reaction mixture was neutralized with 6M hydrochloric acid solution
to pH 8. The reaction mixture was cooled, and the precipitate was fil-
tered off and washed with hot water. The crude product was purified
by recrystallization in ethanol to provide compound 4 (1.35 g). White
1
crystal, m.p.201–202◦C; yield 88%. HNMR (δ,ppm,CDCl3) 2.71 (t,4H
SeCH2,3 JHH =4.8Hz), 3.43 (t,4H,NCH2,3 JHH =4.8Hz), 4.17 (s,2H,NH),
6.64 (d,2H,Ar H), 7.45 (d,2H,Ar H),MS(M/z,%) 306 (M+,4.2).
2-Chloro-N-(4-(selenomorpholinosulfonyl)phenyl)
Acetamide (5)
A mixture of 4-(selenomorpholinosulfonyl)benzeneamine (3.06 g, 10
mmol) in chloroform (20 mL) and triethylamine (1.2 g, 12 mmol) was
treated with 2-chloroacetyl chloride (1.13 g, 10 mmol) in chloroform (5
mL) and stirred for 1 h under 2◦C, and standing for overnight at room
temperature. The reaction mixture was washed with water. The organic
layer was separated and dried over sodium sulfate, and filtered. The fil-
trate was concentrated under reduced pressure, and the crude product
was purified by recrystallization in ethanol to provide compound 5 as a
white solid (2.7 g, 71%).
O,O-Dialkyl 2-oxo-2-(4-(selenomorpholinosulfonyl)
phenylamino) Ethylphosphonate (7a–g)
General procedure
A solution of dialkyl phosphite (5 mmol) in dry petroleum ether (20
mL) was treated with 60% sodium hydroxide (0.22 g, 5.5 mmol). The
reaction mixture was stirred at room temperature for1 h and concen-
trated under reduced pressure till half volume. Then the mixture was
cooled under ice bathe to 5◦C, a solution of 2-chloro-N-(4-(selenomor-
pholinosulfonyl)phenyl)acetamide (1.91 g, 5.5 mmol)) in acetonitrile (20
mL) was added dropwise and the reaction was allowed to proceed at
70◦C for 3 h. Then the reaction mixture was cooled to room temperature
and washed with water and extracted with chloroform. The combined
organic extracts were dried (Na2SO4), filtered, and concentrated under
reduced pressure. The residue was purified by flash column chroma-
tography (silica gel, 15% acetone in petroleum ether) to provide title
compounds 7.

614
F. Wang et al.
O,O-Dimethyl- 2-oxo-2-(4-(selenomorpholinosulfonyl)
phenylamino) ethylphos- phonate(7a)
1
Light yellow solid, yield, 42%, m.p. 60–62◦C. H NMR (δ,ppm): 2.69–
2.77 (m,4H,SeCH2), 3.09 (d,2H,PCH2,2 JPH =20.4Hz), 3.52–3.57 (m,
4H,NCH2), 3.77 (d,6H,OCH3,3 JPH=10.7Hz), 7.44–7.78 (m,4H,Ph), 9.53
(s,1H, NH) . IR (cm−1): 1697 (νC O), 1253 (νP O), 1159 (νS O), 1027
(νP−O−C) MS (M/z,%): 456 (M+, 0.43), 306 (2.07), 242 (8.31), 151 (6.32),
123 (8.74), 109 (15.95), 78 (23.51), 63 (25.72), 42 (100). 31PNMR(δ,ppm):
22.15. Anal. Calcd. for C14H21N2O6PSSe (456): C, 36.90; H, 4.65; N 6.15;
found, C, 36.72; H, 4.71; N, 6.19.
O,O-Diethyl- 2-oxo-2-(4-(selenomorpholinosulfonyl)
phenylamino) ethylphosphonate (7b)
Light yellow solid, yield, 48%, m.p. 74–77◦C. 1H NMR(δ,ppm):
1.38 (t,6H,CH3,3 JHH=6.8Hz), 2.72 (m,4H, SeCH2), 3.08 (d,2H,PCH2,
2 JPH=21.4Hz), 3.45 (m,4H,NCH2), 4.12–4.26 (m, 4H, OCH2), 7.53–
7.64 (m,4H,Ph), 9.66 (s, 1H,NH). IR (cm−1): 1696 (νC O), 1233 (νP O),
1160 (νS O), 1026 (νP
C). MS(M/z,%): 484 (M+, 0.21), 335 (1.49), 272
O
(7.77), 179 (5.23), 150 (19.51), 108 (15.97), 92 (17.85), 63 (20.92), 42
(10031PNMR(δ,ppm): 22.64. Anal. Calcd. for C16H25N2O6PSSe (484): C,
39.76; H, 5.21; N 5.80; found, C, 39.48; H, 5.29; N, 6.01.
O,O-Di(n-propyl)-2-oxo-2-(4-(selenomorpholinosulfonyl)
phenylamino) ethylphos- phonate (7c)
Light yellow solid, yield, 56%, m.p. 88-91◦C. 1H NMR (δ,ppm):
0.99 (t,6H,CH3,3 JHH=7.2Hz), 1.73 (m,4H, CH2CH3,3 JHH=6.8Hz),
2.71 (m,4H, SeCH2,3 JHH=5.3Hz), 3.15 (d,2H,PCH2,2 JPH=21.4Hz),
3.41 (m,4H,NCH2,3 JHH=4.9Hz), 4.05–4.15 (m,4H,OCH2,3 JHH=6.8Hz),
7.46–7.61 (m,4H,Ph), 9.66 (s, 1H,NH). IR (cm−1): 1698 (νC O), 1233
(νP O), 1161 (νS O), 1007 (νP−O−C). MS (M/z,%): 512 (M+, 0.24),
362 (1.37), 298 (6.32), 207 (16.63), 179 (6.17), 150 (17.05), 106
(20.45), 63 (26.37), 42 (100). 31PNMR(δ,ppm): 22.23. Anal. Calcd. for
C18H29N2O6PSSe (512): C, 42.28; H, 5.72; N 5.48; found, C, 42.41; H,
5.74; N, 5.56.
O,O-Di(iso-propyl)- 2-oxo-2-(4-(selenomorpholinosulfonyl)
phenylamino) ethylphos- phonate (7d)
1
Light yellow solid, yield, 39%, m.p. 67–69◦C. H NMR (δ,ppm): 1.36
(dd,12H,CH3,3 JHH=6.0Hz,4 JPH=1.94Hz,) 2.69–2.75 (m,4H, SeCH2),
3.03 (d,2H,PCH2,2 JPH=21.4Hz), 3.41-3.47 (m,4H,NCH2), 4.69-4.80

O,O-Dialkyl 2-Oxo-2-(4-(Selenomorpho-Linosulfonyl) Phenylamino)
615
(m,2H,OCH), 7.52–7.64 (m,4H,Ph), 9.74 (s,1H,NH). IR (cm−1): 1696
(νC O), 1234 (νP O), 1160 (νS O), 1000 (νP
C). MS(M/z,%): 512
O
(M+, 0.13), 362 (2.38), 298 (8.39), 179 (4.32), 150 (20.39), 106
(22.81), 63 (28.74), 42 (100). 31PNMR(δ,ppm): 20.15. Anal. Calcd. for
C18H29N2O6PSSe (512): C, 42.28; H, 5.72; N 5.48; found, C, 42.43; H,
5.68; N, 5.51.
O,O-Di(n-butyl)- 2-oxo-2-(4-(selenomorpholinosulfonyl)
phenylamino) ethylphosphonate (7e)
Light yellow solid, yield, 69%, m.p. 97–99◦C. 1H NMR (δ,ppm):
0.93 (t,6H,CH3,3 JHH=6.8Hz), 1.31–1.49 (m,4H, CH2CH3,3 JHH=7.2Hz),
1.61–1.76 (m, 4H,OCH2 CH2,3 JHH=7.0Hz), 2.69–2.74 (m,4H,SeCH2,
3 JHH=4.9Hz), 3.06 (d, 2H,PCH2,2 JPH=21.4Hz), 3.42–3.47 (m,4H,
3
NCH2, JHH=4.9Hz), 4.05-4.16 (m,4H,OCH2,3 JHH=6.8Hz), 7.47–7.73
(m,4H,Ph), 9.58 (s,1H,NH). IR (cm−1): 1699 (νC O), 1281 (νP O), 1159
(νS O), 1026 (νP
C). MS (M/z,%): 540 (M+, 0.11), 390 (2.41), 235
O
(10.37), 207 (10.91), 193 (14.36), 150 (35.75), 136 (2.95), 63 (27.14), 57
(100). 31PNMR (δ,ppm): 22.30. Anal. Calcd. for C20H33N2O6PSSe (540):
C, 44.53; H, 6.17; N 5.19; found, C, 44.38; H, 6.14; N, 5.21.
O,O-Di(iso-butyl)-2-oxo-2-(4-(selenomorpholinosulfonyl)
phenylamino) ethylphosphonate (7f )
Light yellow solid, yield, 47%, m.p.83–86◦C. 1H NMR (δ,ppm):
0.93 (d,6H,CH3,3 JHH=6.8Hz), 1.34 (d,6H,CH3,3 JHH=6.6Hz), 1.61–
1.74 (m,2H, CH), 2.69 (m,4H,SeCH2,3 JHH=5.8Hz), 3.00 (d,2H,
PCH2,2 JPH=20.4Hz), 3.46 (m,4H, NCH2,3 JHH= 5.4Hz), 4.49–4.55
(m,4H,OCH2,3 JHH=5.8Hz), 7.57–7.68 (m,4H, Ph), 9.55 (s, 1H,NH).
IR (cm−1): 1695 (νC O), 1233 (νP O), 1160 (νS O), 997 (νP
C).
O
MS (M/z,%): 540 (M+,0.27), 390 (4.64), 333 (7.30), 242 (33.90), 207
(30.24), 150 (1.79), 42 (100). 31PNMR (δ,ppm): 20.75. Anal. Calcd. for
C20H33N2O6PSSe (540): C, 44.53; H, 6.17; N 5.19; found, C, 44.69; H,
6.23; N, 5.18.
O,O-Di(benzyl)- 2-Oxo-2-(4-(Selenomorpholinosulfonyl)
phenylamino) ethylphosphonate (7g )
Light yellow solid, yield, 45%, m.p.103–106◦C. 1H NMR (δ,ppm):
2.68–2.74 (m,4H,SeCH2), 3.14 (d,2H,PCH2,2 JPH=21.4Hz), 3.38–3.43
(m, 4H,NCH2), 4.98–5.07 (m,4H,OCH2), 7.32–7.68 (m,14H,Ph), 10.04
(s,1H,NH). IR (cm−1): 1685 (νC O), 1236 (νP O), 1162 (νS O), 1012
(νP−O−C). MS (M/z,%)608: C, ,0.14, 458 (1.37), 390 (4.64), 305 (4.23),

616
F. Wang et al.
275 (7.82), 170 (2.56), 150 (4.37), 91 (100), 77 (53,4), 63 (27.6). 31PNMR
(δ,ppm): 19.06. Anal. Calcd. for C26H29N2O4PSSe (608): C, 62.18; H,
5.03; N4.51; found, C, 62.31; H, 5.09; N, 4.46.
REFERENCES
[1] X. L. Ji, W. X. Hu, J. P.Cheng, et al, Ecotoxicology and Environmental Safety, 64 ,
171 (2006).
[2] M. P. Bansal P. Kaur, Indian Journal of Experimental Biology, 43 , 1119 (2005).
[3] J. K. Pearson and R. J.Boyd, Journal of Physical Chemistry A, 110, 8979 (2006).
[4] Filipovska, G. F.Kelso, S. E.Brown, et al, Journal of Biological Chemistry,280, 24113
(2005).
[5] M. Giurg and H. M. Wojtowicz, J Polish Journal of Chemistry,76, 537 (2002).
[6] W. Sattler, M. Maiorino, and R. Stocker, Archives of Biochemistry and Biophysics,
309, 214 (1994).
[7] M. Maiorino, A. Roveri, M. Coassin et al., Biochemical Pharmacology, 37, 2267
(1988).
[8] P. Smrkolj, M. Germ, I. Kreft et al. Journal of Experimental Botany, 57, 3595 (2006).
[9] R. J. Robbins, A- S.Keck, G. Banuelos, et al, Journal of Medicinal Food, 8, 204 (2005).
[10] A. C. Pappas, F. S. Karadas, F. Peter, et al, Journal of Trace Elements in Medicine
and Biology, 20, 155 (2006).
[11] L. M. Hu, Z. Y Chen, S. M. Lu, et al, Phosphorus, Sulfur and Silicon and the Related
Elements ,179, 1065 (2004).
[12] X. Li, Y. Liu, J. Wu, et al, Thermochimica Acta, 387, 57 (2002).
[13] L. M. Hu, J. H.Feng, Z. Y. Chen, et al, Chinese Journal of Chemistry, 21, 1642 (2003).
[14] J. Wu, F. J.Gong, Z. Y. Huang, et al, Journal of Plant Nutrition, 23, 349 (2000).
[15] X. Li, C. Y. Zheng, S- S. Qu, et al, Journal of Wuhan University of Technology,
Materials Science Edition, 17, 90 (2002).
[16] J. Wu, X. F. Liu, H. S. Xu, et al. Wuhan University Journal of Natural Sciences, 5,
89. (2000).
[17] J. M.Zhou, M. Lin, and L. F.Yang, Journal of Xiamen University(Natural Science),
42, 679 (2003).
[18] G. Blotny, Tetrahedron Letters, 44, 1499 (2003).
[19] A. K. Misra and J. B.Lal, Indian Journal of Applied Chemistry, 28, 187 (1965).