Synthesis of 2-phosphono alkyl 1,2-benzisoselenazol-3(2H)-ones

Article abstract of DOI:10.1080/10426500214892

A series of 2-phosphonoalkyl 1,2-benzisoselenazol-3(2H)-ones were designed and synthesized via reaction 2-chloroselenobenzoyl chloride with 1-hydrazinobenzyl phosphonate. The structures of all new compounds were confirmed by spectroscopic methods and microanalyses.

Full text of DOI:10.1080/10426500214892

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of 2-Phosphono Alkyl 1,2-
Benzisoselenazol-3(2H)-ones
Liming Hu a b , Shengmei Lu a , Fengling Yang a , Juhong Feng a , Zhaojie Liu a , Hansheng Xu
b & Hongwu He a
a Central China Normal University, Wuhan, China
b Wuhan University, Wuhan, China
Published online: 27 Oct 2010.
To cite this article: Liming Hu , Shengmei Lu , Fengling Yang , Juhong Feng , Zhaojie Liu , Hansheng Xu & Hongwu He (2002)
Synthesis of 2-Phosphono Alkyl 1,2-Benzisoselenazol-3(2H)-ones, Phosphorus, Sulfur, and Silicon and the Related Elements,
177:12, 2785-2790, DOI: 10.1080/10426500214892
To link to this article: http://dx.doi.org/10.1080/10426500214892
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:2785–2790
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290146776
SYNTHESIS OF 2-PHOSPHONO ALKYL
1,2-BENZISOSELENAZOL-3(2H)-ONES
Liming Hu,a,b Shengmei Lu,a Fengling Yang,a Juhong Feng,a
Zhaojie Liu,a Hansheng Xu,b and Hongwu Hea
Central China Normal University, Wuhan, Chinaa and
Wuhan University, Wuhan, Chinab
(Received April 2, 2002; accepted May 10, 2002)
A series of 2-phosphonoalkyl 1,2-benzisoselenazol-3(2H)-ones were de-
signed and synthesized via reaction 2-chloroselenobenzoyl chloride with
1-hydrazinobenzyl phosphonate. The structures of all new compounds
were confirmed by spectroscopic methods and microanalyses.
Keywords: 1-Hydrazinobenzyl phosphonate; cyclization; ebselen
INTRODUCTION
In recent years, biologically active organoselenium compounds have
been attracting considerable interest due to their unique and diverse po-
tential of pharmacological importance, such as antitumor,1 antiviral,2
and antiinflammatory.3 The discovery of the essential role played
by seleno-organic compound ebselen (2-phenyl-1,2-benzisoselenazol-
3(2H)-one) in the activity of the enzyme glutathione peroxidase (GSH-
Px) against biological damage caused in vivo by reactive hydroper-
oxides, increased a striking interest in developing organoselenium
compounds for therapy.4 In our previous articles, a number of amino
acid ester derivatives of benzisoselenazolone were synthesized and
these compounds exhibited excellent pharmacological effects.5 Here we
report the synthesis of some 2-phosphonoalkyl 1,2-benzisoselenazol-
3(2H)-ones 5. The easily accessible 1-hydroxyalkylphosphonates re-
acted with mesyl chloride to give 1-mesyloxyalkylphosphonates 1,
which were allowed to react with hydrazine hydrate to produce 1-
hydrazinoalkylphosphonates 2 in satisfactory yields. Compounds 5
were obtained by compounds 2 reacting with 2-chloroselenobenzoyl
Address correspondence to L. Hu, Institute of Organic Synthesis, Central China
Normal University, Wuhan 430 079, China. E-mail: jinxiuh@ccnu.edu.cn
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L. Hu et al.
chloride 4. The preliminary anticancer tests in vitro were carried out
by the conventional method.
RESULTS AND DISCUSSION
Synthesis of 2-Phosphonoalkyl-1,2-benzisoselenazol-
3(2H)-ones
The title compounds 5 were synthesized by a multistep route outlined
in Scheme 1.
SCHEME 1
Preparation of the 1-hydrazinoalkylphosphonates 2 was readily ac-
complished in three-step sequence (40–50% overall yield) starting from
aldehyde and diethyl phosphite.6 First, 1-hydroxyalkylphosphonates
can be synthesized by the solid-catalyzed condensation of diethyl phos-
phite and aldehyde. Then, 1-hydroxyalkylphosphonates reacted with
mesyl chloride to give 1-mesyloxyalkylphosphonates 1. With the me-
syloxy substituent as a good leaving group, compounds 1 could be
converted to other types of phosphonates. With hydrazine hydrate
as the nucleophile, 1-hydrazinoalkylphosphonates 2 can be synthe-
sized in good yield. Santaniello et al.7 have reported that the reduc-
ing power of sodium borohydride in polyethylene glycols is enhanced

Synthesis of 2-Phosphono Alkyl 1,2-Benzisoselenazol-3(2H)-ones
2787
and able to reduce carbonyl compounds. Similarly, under the PEG-
KBH4 reaction system, 1 mmol of selenium was efficiently reduced to
Se Se2 anion by only 0.018 mmol of KBH4, catalyzed by PEG-600
in aqueous NaOH. Thus, Se Se2 anion was allowed to react with
2-carboxybenzenediazonium chloride, and the reaction mixture was
then acidified to give 2,20-diselenobis(benzoic acid) 3 in a yield of 90%.
3 was treated with excess thionyl chloride to provide the intermedi-
ate 2-(chloroseleno)benzoyl chloride 4 in a yield of 80%. The reaction
of 4 with each 1-hydrazinoalkylphosphonate was carried out under the
ether-water-NaHCO3 reaction system in the presence of phase transfer
catalyst Bu4NBr to give products 5 in a yield of 45–78%.
The Structures of the Products
1
The structure of all compounds prepared were confirmed by H NMR,
31P NMR, IR, MS spectroscopy, and elemental analysis. In the 1H
NMR spectra of 5, the chemical shift of H atom in CH(R = aryl) is
in the range of 6.13–6.31. Owing to the deshielding effect of the
-benzene ring, these chemical shifts are much bigger than those of
CH(R=alkyl), which are in the range of 3.35–4.06. Moreover, the H
atom in CH(R=aryl) appears as double doublet due the coupling ef-
fects of the P atom and H in NH (2JPCH = 21.0–23.0 Hz, 3JHNCH = 11.0–
12.6 Hz) while that when R=alkyl exhibits complicated peaks due to
the phosphorus atom coupling, C H coupling and N H coupling. The
IR spectra of compounds 5 show normal stretching absorption bands,
indicating the existence of groups C O(1644–1658 cm 1), P O(1248–
1257 cm 1), and N H(3337–3354 cm 1). The EI-MS spectra of 5 record
the existence of molecular ion peaks, indicating that the heterocycle
skeletons are of some stability, the major MS peaks, particularly m/e
199, 156, 137 are common to all compounds, other ion peaks were con-
sistent with their structures and can be clearly assigned. Because there
are two major isotope of selenium (approximatively 2:1), the ion which
contain two isotopes of selenium abundance ratio is about 2:1.
EXPERIMENTAL
Elemental analyses were performed with CHN PE983 elementary an-
alyzer. NMR spectra were taken on Varian XL200 spectrometer, TMS
1
was used as an internal standard for H NMR, and 85% H3PO4 was
used as an external standard for 31P NMR. Mass spectra were recorded
on a Hewlett-Packard 5988A instrument. IR spectra were recorded on a
NICOLET AVATAR360. Melting points were determined with a model
X4 apparatus and are uncorrected.

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2-Chloroseleno benzoyl chloride 48 and 1-hydrazinobenzyl phospho-
nate 26 have been prepared following literature methods.
2-Phosphonoalkyl 1,2-Benzisoselenazol-3(2H)-ones 5
To a stirred mixture of -hydrazinobenzyl phosphonate (5 mmol), potas-
sium bicarbonate (16 mmol) and tetrabutylammonium bromide (cat-
alytic amount) in H2O(10 mL)-ether(25 mL) system cooled with an ice
bath was added a solution of 2-chloroseleno benzoyl chloride 2 (5 mmol)
in 20 mL of ether over 30 min. Then the mixture was stirred for an
additional 7 h at room temperature. The organic product was extracted
with ether, and the layers were separated. Combined organic extracts
were dried (Na2SO4), and the solvent was removed under reduced pres-
sure. The residue was purified by column chromatography on silica gel,
eluting with ethyl acetate/petroleum ether.
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