Synthesis of 7-Azabenzisoselenazol-3(2H)-ones: A New Group of Selenium Containing Antimicrobials

Article abstract of DOI:10.1081/SCC-120025191

A convenient, general method for synthesis of various 2-substituted 7-azabenzisoselenazol-3(2H)-ones having pyridine ring condensed with selenazolone moiety is presented. It is based on the conversion of 2-chloronicotinic acid into 2-(chloroseleno)nicotin

Full text of DOI:10.1081/SCC-120025191

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Synthesis of 7-Azabenzisoselenazol- 3(2H)-ones: A New
Group of Selenium Containing Antimicrobials
a
a
a
Krystian Kloc , Irena Maliszewska & Jacek Młochowski
a
Institute of Organic Chemistry, Biochemistry and Biotechnology, Wrocław University of
Technology, Wrocław, Poland
Published online: 16 Aug 2006.
To cite this article: Krystian Kloc , Irena Maliszewska & Jacek Młochowski (2003): Synthesis of 7-Azabenzisoselenazol- 3(2H)-
ones: A New Group of Selenium Containing Antimicrobials, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:21, 3805-3815
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 21, pp. 3805–3815, 2003
Synthesis of 7-Azabenzisoselenazol-
(2H)-ones: A New Group of Selenium
Containing Antimicrobials
3
Krystian Kloc, Irena Maliszewska, and Jacek Mbochowski*
Institute of Organic Chemistry, Biochemistry, and
Biotechnology, Wroclaw University of Technology,
Wroclaw, Poland
ABSTRACT
A convenient, general method for synthesis of various 2-substituted
7-azabenzisoselenazol-3(2H)-ones having pyridine ring condensed
with selenazolone moiety is presented. It is based on the conversion
of 2-chloronicotinic acid into 2-(chloroseleno)nicotinic acid chloride
and its reaction with primary amines. The title compounds were
found in the antimicrobial assay in vitro to be highly active against
broad spectrum of bacteria and fungi.
Benzisoselenazol-3(2H)-ones are group of organoselenium com-
pounds extensively studied during last two decades as biological response
*
Correspondence: Jacek Mlochowski, Institute of Organic Chemistry,
Biochemistry, and Biotechnology, Wroclaw University of Technology, Wyb.
Wyspianskiego 27, 50-370 Wroclaw, Poland; E-mail: mlochowski@
´
kchf.ch.pwr.pl.
3
805
DOI: 10.1081/SCC-120025191
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3806
Kloc, Maliszewska, and Mbochowski
modifiers. The best known their representative is nontoxic
(
LD50 ¼ 6.8 g/kg) 2-phenylbenzisoselenazol-3(2H)-one named ebselen
(
living cells in the glutathione peroxidase-like way.
1) (Sch. 1). It is able to inactivate the oxygen species present in the
Different 2-
[
1,2]
substituted benzisoselenazol-3(2H)-ones were found as antiinflammatory
agents, immunomodifiers, cytokine inducers, enzyme inhibitors, and
[
2,7]
virucides.
More than ten years ago ebselen has been shown to possess
[
8]
antibacterial activity against Staphylococcus aureus and it has been
postulated that the antibacterial activity of ebselen and other selenium
compounds in vitro is due to their reactivity with an essential thiol
group.
o-substituted diaryldiselenides have been evaluated for their antifungal
[9]
Recently ebselen, some other benzisoselenazolones and
[
10]
and antibacterial properties.
Among different benzisoselenazolones only two azabenzisoselenazo-
lones (2e and 2f), having pyridine ring in a place of benzene ring, are
known. They have been obtained from nicotinamides by ortholithiation,
then methylselenylation, and finally cyclization with formation of Se-N
bond. The method used for their synthesis is limited to these com-
[11]
pounds. In our knowledge their biological activity has not been inves-
tigated. It seemed to be possible that introduction of nitrogen atom into
benzene ring should made the molecule more polar and noncovalent
interactions such/formation of hydrogen bonds between drug molecule
and biological receptor should took place. Both of these factors might
have an influence on the biological response in comparison to the ebselen.
In this article we present a general method for synthesis 7-azabenzi-
soselenazol-3(2H)-ones (2) (Sch. 1) and report their appreciable biological
activity against broad spectrum of bacteria and fungi.
The general strategy for synthesis of 7-azabenzisoselenazol-
(2H)-ones (2), presented in Sch. 2, is based on the conversion of
-chloronicotinic acid (3) into 2-(chloroseleno)nicotinoyl chloride (8)
3
2
and finally on the tandem acylation-selenylation of primary amino
group, present in aminoalkanes or aminoarenes, with this reagent.
Scheme 1.

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Synthesis of 7-Azabenzisoselenazol-3(2H)-ones
3807
Scheme 2.
Initially, 2-chloronicotinic acid (3) was converted to the acid
chloride 4 in usual way with thionyl chloride in the presence of dimethyl-
formamide as catalyst. The acid chloride 4 treated with potassium
tert-butoxylate in dry tetrahydrofurane on the ice/salt bath gave tert-
butyl-2-chloronicotinate (5). This oily ester could not be purified by
ꢀ
distillation because of its thermal instability (decomposed ca. 120 C
1
at 8 torr). Nevertheless H NMR spectrum made the evidence of its
purity and it was used in the next step of synthesis without purification.
In the next step the chlorine atom in ester 5 was substituted with
0
diselenide group and 2,2 -diselenobis(tert-butylnicotinate) (6) was
obtained by the reaction of compound 5 with freshly prepared dilithium
0
diselenide in dry tetrahydrofurane. Acid hydrolysis of ester 6 gave 2,2 -
diselenobis(nicotinics acid) (7). For this purpose methanesulfonic acid

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3808
Kloc, Maliszewska, and Mbochowski
was used as hydrolyzing agents since other common acids were less
active, the reaction proceeds more slowly, and yields of the acid were
substantially lower. The reaction of acid 7 with thionyl chloride in the
presence of catalytic amounts of dimethylformamide lead to 2-
(chloroseleno)nicotinoyl chloride (8). The last step of the synthesis was
similar to the tandem acylation-selenylation primary amino group with
[
4–7,12,13]
2
The reaction of dichloride 8 and ammonia or corresponding aliphatic, or
-(chloroseleno)benzoyl chloride reported in our earlier works.
ꢀ
aromatic amine in dry dichloromethane at ca. ꢁ15 C resulted in forma-
tion of desired 7-azabenzisoselenazol-3(2H)-one (2a) or its 2-substituted
alkyl and aryl derivatives 2b–2h. In the same manner diazaanalogues of
ebselen 2i and 2j were obtained. Both of them have one pyridine ring
condensed with isoselenazolone moiety while the second pyridine ring is
an substituent. Since in the reaction hydrochloric acid is eliminated,
ammonia or amine was used in threefold excess although in some
cases 2e–2j triethylamine was applied as a base.
The positive results of the reaction of 2-(chloroseleno)nicotinoyl
chloride (8) with primary aliphatic and aromatic amines lead to
supposition that it could be employed as versatile reagent for tandem
acylation-selenenylation of aminoacids, primary amides, and sulfona-
mides or compounds having active methylene groups similarly as earlier
[
6,12,15]
used its analogue 2-(chloroseleno)benzoyl chloride.
The ebselen (1) and 7-azabenzisoselenazol-3(2H)-ones (2a–j) were
tested against various bacteria and fungi strains (listed in
Experimental) in vitro. Only 2a and 2b were active against gram-negative
bacteria and none of them was active for Sarcina lutea strain. Most of
them (1, 2a–f, h) exhibited activity against Staphylococcus aureus
(
MIC ¼ 16–512 mg/mL). Usually resistant sporulating rods Bacillus
strains were very susceptible to the compounds 2a–e, h. Their activity
(
(
MIC ¼ 4–8 mg/mL) was substantially higher that found for ebselen
MIC ¼ 16–128 mg/mL). The compounds tested were generally inactive
against Candida albicans but the compounds 2a–e, h strongly inhibited
the growth of moulds—Aspergillus niger, Penicillum chrysogenum, and
Penicillum citrinum (MIC ¼ 2–32 mg/mL, for ebselen 128–256 mg/mL).
The broadest activity spectrum and lowest MIC values were observed
for the compounds 2a–c. These results support our supposition that
replacing of benzene ring in the benzisoselenazolone moiety by pyridine
ring enhances the biological response. The more extended biological
results and the details concerned to structure activity relationship will
be published elsewhere.

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Synthesis of 7-Azabenzisoselenazol-3(2H)-ones
EXPERIMENTAL
3809
General
Melting points: Digital Melting Point Apparatus Electrothermal IA
1
100. H NMR: Bruker 300-MHz spectrometer. IR (KBr pellets or CCl ):
9
Perkin-Elmer 2000 FT. All starting materials were purchased from
4
Aldrich Chem. Co. and Fluka. Ebselen (1) was obtained according to
[16]
[4]
ref. Tetrahydrofurane was dried as reported in ref. Dilithium disele-
nide was prepared directly before using from elemental lithium (0.36 g,
0
reported in ref.
.052 mol) and selenium powder (3.95 g, 0.050 mol) in the some way as
[16]
The antimicrobial activities of tested compounds were evaluated by
[
17]
the agar dilution method.
Nutrient Agar and Mycological Agar were
used for bacteria and fungi, respectively. Gram-positive bacterial species:
Staphylococcus aureus PCM 1944, Sarcina lutea PCM 1947, Bacillus
strains (B. Subtilis PCM 1949, B. Cereus, B. Megaterium, B.
Thuringensis), and gram-negative bacterial species. Escherichia coli
PCM 2057, Serratia marcescens PCM 549, Pseudomonas putida PCM
2124, and fungal strains: Candida albicans, Aspergillus niger, Penicillium
chrysogenum, Penicillium citrinum were used for the test.
Synthesis of 2-Chloronicotinoyl Chloride (4)
A suspension of 2-chloro-nicotinic acid (3) (31.52 g, 0.2 mol) and
dimethylformamide (5 drops) in thionyl chloride (200 mL) was refluxed
in moisture-free conditions for 4.5 h. After this period the excess of
thionyl chloride was evaporated in vacuo. The greasy residue was
dissolved in dichloromethane (200 mL), decolorized with charcoal, and
solvent was evaporated in vacuo. The solid residue recrystallized from
ꢀ
[18]
ꢀ
hexane gave pure 4. Yield 83% M.p. 39–44 C (ref. 39–44 C).
Synthesis of tert-Butyl 2-Chloronicotinate (5)
A solution of acid chloride 4 (33.5 g, 0.19 mol) in dry THF (50 mL)
was added dropwise during 1.5 h period to magnetically stirred, and
cooled on ice/salt bath, solution of potassium tert-butoxylate (22.45 g,
0
1
.2 mol) in dry THF (150 mL). The reaction was continued for additional
.5 h, most of the solvent (ca. 150 mL) was removed in vacuo and water
(200 mL) was added to the residue. The mixture was extracted with

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3810
Kloc, Maliszewska, and Mbochowski
dichloromethane (3 ꢂ 75 mL), combined extracts were dried with sodium
sulfate and the solvent was evaporated in vacuo. The residue was tri-
turated with four portions of hexane (100, 75, 50, and 50 mL). Hexane
was evaporated in vacuo and crude 5 was purified on silicagel column
using dichloromethane as an eluent. Yield 75%. Oil decomposed ca.
ꢀ
ꢁ1
20 C/8 Torr. IR (CCl ) 1736, 1713 cm (CO). H NMR (300 MHz,
4
1
1
CDCl ) ꢀ 1.62 (s, 9H, CH ), 7.30 (dd, 1H, J ¼ 7.7 and 4.8 Hz, ArH),
3
3
8
1
1
.05 (dd, 1H, J ¼ 7.7 and 1.9 Hz, ArH), 8.46 (dd, 1H, J ¼ 4.8 and
.9 Hz, ArH). Anal. calcd. for C H ClNO : C, 56.21; H, 5.66, Cl,
1
0
12
2
6.59, N, 6.56. Found: C, 56.26; H, 5.79; Cl, 16.30; N, 6.63.
0
Synthesis of 2,2 -Diselenobis(tert-butyl) Nicotinate (6)
The solution of ester 5 (10.68 g, 0.050 mol) in dry THF (60 mL) was
added dropwise for 1 h under argon into magnetically stirred freshly
prepared suspension of dilithium diselenide (0.052 mol) in dry THF
(
7
(
40 mL) cooled on the ice salt bath. The reaction was continued for
2 h (finally at room temperature), the mixture was poured into ice
ca. 400 g), carefully mixed and precipitated elemental selenium was
filtered off and washed with water. The filtrate was extracted with
dichloromethane (3 ꢂ 50 mL), combined extracts were decolorized with
charcoal, dried with sodium sulfate, and solvent was removed under
reduced pressure. The residue was recrystallized from chloroform-
ꢀ
hexane (1:1). Yield 59%. M.p. 190–195 C (decomposition). IR (KBr)
ꢁ
682 cm (CO). H NMR (300 MHz, CDCl ) ꢀ 1.65 (s, 18H, CH ),
3 3
1
1
1
7
1
.08 (dd, 2H, J ¼ 7.08 and 4.7 Hz, ArH), 8.13 (dd, 2H, J ¼ 7.8 and
.8 Hz, ArH), 8.47 (dd, 2H, J ¼ 4.7 and 1.8 Hz, ArH). Anal. calcd.
for C H N O Se : C, 46.0; H, 4.70; N, 5.45. Found: C, 46.55; H,
2
0
24
2
4
2
4
.60; N, 5.52.
0
Synthesis of 2,2 -Diselenobisnicotinic Acid (7)
Methanesulfonic acid (2.90 g, 30 mmol) was added to the solution
of ester 6 (3.86 g, 7.5 mmol) in dichloromethane at room temperature
and the reaction was continued for 12 days until the yellow mixture
decolorized. Colorless solid was filtered off, suspended in water
(150 mL) and filtered again (its color turned back to yellow), washed
with water and methanol, dried in the air and recrystallized from DMSO-
ꢀ
methanol (1:1). Yield 77%. M.p. 219–220 C (decomposition). IR (KBr):
1
ꢁ1
1
666 cm (CO). H NMR (DMSO-d ) ꢀ 7.34 (dd, 2H, J ¼ 7.6 and 4.8 Hz,
6

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Synthesis of 7-Azabenzisoselenazol-3(2H)-ones
3811
ArH), 8.25 (d, 2H, J ¼ 7.6 Hz, ArH), 8.59 (d, 2H, J ¼ 4.8 Hz, ArH), 13.95
(bs, 2H, COOH). Anal. calcd. for C H N O Se : C, 35.84; H, 2.01; N,
12 8 2 4 2
6
.97. Found: C, 35.72; H, 2.09; N, 6.78.
Synthesis of 2-(Chloroseleno)nicotinoyl Chloride (8)
A suspension of acid 7 (4.02 g, 10 mmol) in freshly distilled thionyl
chloride (25 mL) and one drop of dimethylformamide was refluxed in
moisture-free conditions for 8 h. After this period an additional portion
of thionyl chloride (20 mL) and DMF (one drop) was added to the mix-
ture and reaction was continued for 8 h. Thionyl chloride was removed
under reduced pressure, the residue was dissolved in dry dichloromethane
and solid was filtered off avoiding contact with air. From the filtrate
dichloromethane was evaporated in vacuo and the residue solidified in
the refrigerator was crude acid chloride 8 which directly was employed
in the next step without purification since its low stability. Yield 87%.
ꢀ
ꢁ1
1
M.p. decomposed above 50 C. IR (KBr): 1660 cm (CO). H NMR
300 MHz, CDCl ) ꢀ 7.46 (dd, 1H, J ¼ 8.0 and 4.7 Hz, ArH), 8.53 (dd,
(
3
1H, J ¼ 8.0 and 1.7 Hz, ArH), 8.95 (dd, 1H, J ¼ 4.7 and 1.7 Hz, ArH).
Anal. for C H Cl NOSe gave irreproducible results.
6
3
2
Syntheses of 7-Azabenzisoselenazol-3(2H)-ones (2a–j)
7
-Azobenzisoselenazol-3(2H)-one (2a). The moisture-free gaseous
ammonia was passed during 30 min through the solution of dichloride
(0.510 g, 2 mmol) in dry dichloromethane (40 mL) cooled on the ice/salt
8
bath. After this period a solvent and excess of ammonia were removed
under reduced pressure. Water (50 mL) was added to the residue and the
mixture was carefully magnetically stirred. The solid was filtered off and
ꢀ
recrystallized from dimethylformamide. Yield 64%. M.p. 258–259 C
ꢁ
1
decomposition). IR (KBr) 16.46 cm (CO). H NMR (300 MHz DMSO-
1
(
d ) ꢀ 7.51 (dd, 1H, J ¼ 7.7 and 4.7 Hz, ArH), 8.17(d, 1H, J ¼ 7.7 Hz,
6
ArH), 8.82 (d, 1H, J ¼ 4.7 Hz, ArH), 9.34 (bs, 1H, NH). Anal. calcd.
for C H N OSe: C, 36.20; H, 2.03; N, 14.06. Found: C, 36.06; H, 2.13;
6
4
2
N, 14.19.
-Methyl-7-azabenzisoselenazol-3(2H)-one (2b). The moisture-free
2
gaseous methylamine was passed during 1 h through the solution of
dichloride 8 (1.275 g, 5 mmol) in dry dichloromethane (60 mL) cooled
on the ice/salt bath. After this period the reaction mixture was washed
with water (3 ꢂ 50 mL), the layers were separated, the organic layer was
dried with sodium sulfate and the solvent was removed under reduced

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3812
Kloc, Maliszewska, and Mbochowski
pressure. The product was separated by silica gel chromatography (tri-
chloromethane), and recrystallized from dimethylsulfoxide-chloroform
ꢀ
ꢁ1
(
(
1:1). Yield 72%. M.p 227–229 C (decomposition). IR (KBr) 1626 cm
1
CO). H NMR (300 MHz, DMSO-d ) ꢀ 3.27 (s, 3H, CH ), 7.49 (dd, 1H,
6
3
J ¼ 7.7 and 4.7 Hz, ArH), 8.13 (d, 1H, J ¼ 7.7 Hz, ArH), 8.80 (d, 1H,
J ¼ 4.7 Hz, ArH). Anal. calcd. for C H N OSe: C, 39.08; H, 3.75; N,
7
6
2
1
3.02. Found: C, 39.23; H, 3.66; N, 13.10.
2
-Propyl-7-azabenzisoselenazol-3(2H)-one (2c). Propylamine (0.488 g,
.25 mmol) was dissolved in dry dichloromethane (10 mL) and then
8
ꢀ
cooled to ꢁ15 C solution was added dropwise to magnetically stirred
and cooled on ice/salt bath solution of dichloride 8 (0.637 g, 2.5 mmol)
in dichloromethane (30 mL) for 30 min and the reaction was continued
for additional 2 h. After this period the reaction mixture was washed
with water (3 ꢂ 20) mL and the layers were separated. The organic layer
was dried with sodium sulfate and the solvent was evaporated in vacuo.
The product was separated from the residue by silica gel chromatography
(
7
1
chloroform-ethyl acetate (5:1)) and recrystallized from hexane. Yield
ꢀ
ꢁ1
3%. M.p. 144–146 C (decomposition). IR (KBr) 1634 cm
(CO).
H NMR (300 MHz, DMSO-d ) ꢀ 0.88 (t, 3H, J ¼ 7.3 Hz, CH ) 1.63
6
3
(
7
sextet, 2H, J ¼ 7.2 Hz, CH CH ), 3.70 (t, 2H, J ¼ 7.2 Hz, CH CH ),
2
3
2
2
.50 (dd, 1H, J ¼ 7.7 and 4.7 Hz, ArH), 8.14 (dd, 1H, J ¼ 7.7 and 1.5 Hz,
ArH), 8.90 (dd, 1H, J ¼ 4.6 and 1.5 Hz, ArH). Anal. calcd. for
C H N OSe:C,44.82;H,4.18;N,11.62.Found:C,44.62;H,4.25;N,11.50.
9
10
2
2
the same manner as 2c using tert-butylamine (0.603 g, 8.25 mmol) as a
-tert-Butyl-7-azabenzisoselenazol-3(2H)-one (2d). It was obtained in
ꢀ
[11]
ꢀ
reagent. Yield 74%. M.p. 175–177 C (decomposition) (ref. 173–175 C).
-Cyclohexyl-7-azabenzisoselenazol-3(2H)-one (2e). It was obtained
in the same manner as 2c using cyclohexylamine (0.273 g, 2.75 mmol)
2
as a reagent and triethylamine (0.556 g, 5.50 mmol) as a base.
ꢀ
Recrystallized from ethyl ether. Yield 67%. M.p. 183–187 C. IR (KBr)
ꢁ
1
639, 1650 cm (CO). H NMR (300 MHz, DMSO-d ) ꢀ 1.15–1.22 (m,
1
1
6
1
H, CH ), 1.35–1.48 (m, 4H, CH ), 1.60–1.64 (m, 1H, CH ), 1.76–1.90
2
2
2
(
m, 4H, CH ), 4.27 (bs, 1H, CHN), 7.50 (dd, 1H, J ¼ 7.7 and 4.7 Hz,
2
ArH), 8.14 (dd, 1H, J ¼ 7.7 and 1.2 Hz, ArH), 8.79 (dd, 1H, J ¼ 4.7
and 1.2 Hz, ArH). Anal. calcd. for C H N OSe: C, 51.25; H, 5.02; N,
14
1
2
2
9
.96. Found: C, 51.30; H, 5.10; N, 10.03.
-Phenyl-7-azabenzisoselenazol-3(2H)-one (2f). It was obtained in the
same manner as 2c using aniline (0.256 g, 2.75 mmol) and triethylamine
2
(
0.556 g, 5.5 mmol). Recrystallized from chloroform-hexane (1:1). Yield
ꢀ
[11]
ꢀ
6
6%. M.p. 213–215 C (decomposition), (ref. 209–211 C).
-(4-Chloro)phenyl-7-azabenzisoselenazol-3(2H)-one (2g). It was
obtained in the same manner as 2c using 4-chloroaniline (0.351 g,
2

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Synthesis of 7-Azabenzisoselenazol-3(2H)-ones
3813
2
.75 mmol) and triethylamine (0.556 g, 5.50 mL). Recrystallized from
ꢀ
dimethylformamide. Yield 73%. M.p. 259–260 C (decomposition). IR
ꢁ
KBr) 1658 cm (CO). H NMR (300 MHz, DMSO-d ) ꢀ 7.52 (d, 2H,
6
1
1
(
J ¼ 6.8 Hz, ArH), 7.57 (dd, 1H, J ¼ 7.8 and 4.7 Hz, ArH), 7.69 (d, 2H,
J ¼ 6.8 Hz, ArH), 8.24 (dd, 1H, J ¼ 7.8 and 1.8 Hz, ArH), 8.88 (dd,
1
4
H, J ¼ 4.7 and 1.8 Hz, ArH). Anal. calcd. for C H ClN OSe: C,
1
2
7
2
6.55; H, 2.28; N, 11.45. Found: C, 46.38; H, 2.34; N, 11.30.
-(N,N-Diphenylamino)-7-azabenzisoselenazol-3(2H)-one(2h). To a
2
suspension of diphenylhydrazine hydrochloride (0.552 g, 2.5 mmol) in
dry chloromethane triethylamine (0.835 g, 8.75 mmol) was added
dropwise under vigorous stirring, and cooled on the ice/salt bath. Thus
obtained solution was treated with the solution of dichloride 8 (0.637 g,
2
3
3
.50 mmol) in dry dichloromethane (30 mL) added dropwise during
0 min. After this period the reaction was continued for additional
.5 h and the reaction mixture was worked up as for 2c, using dichlo-
romethane as an eluent for silica gel chromatography. Recrystallized
ꢀ
from chloroform-hexane (1:1). Yield 28%. M.p. 161–162 C (decomposi-
ꢁ
1
1
(CO). H NMR (300 MHz, DMSO-d6)
tion). IR (KBr) 1663 cm
ꢀ
7.07–7.10 (m, 6H, ArH), 7.31–7.36 (m, 4H, ArH), 7.53 (dd, 1H,
J ¼ 7.7 and 4.7 Hz, ArH), 8.24 (dd, 1H, J ¼ 7.7 and 1.5 Hz, ArH), 8.86
(
5
dd, 1H, J ¼ 4.7 and 1.5 Hz, ArH). Anal. calcd. for C H N OSe: C,
1
8
13
3
9.02; H, 3.58; N, 11.47. Found: C, 59.23; H, 3.28; N, 11.24.
-(2-Pyridinyl)-7-azabenzisoselenazol-3(2H)-one (2i). It was obtained
2
in the same manner as 2c using 2-aminopyridine (0.259 g, 2.75 mmol) and
triethylamine (0.566 g, 5.50 mmol). The crude product precipitated from
the reaction mixture was filtered, washed with dichloromethane (10 mL)
and water (20 mL), dried in air and recrystallized from chloroform. Yield
ꢀ
ꢁ1
7
2%. M.p. 221–223 C (decomposition). IR (KBr) 1651 cm
H NMR (300 MHz, DMSO-d ) ꢀ 7.23–7.24 (m, 1H, ArH), 7.54 (dd,
(CO).
1
6
1H, 7.8 and 4.7 Hz, ArH), 7.90–7.96 (m, 1H, ArH), 8.25 (dd, 1H, J ¼ 7.8
and 1.8 Hz, ArH), 8.42–8.45 (m, 1H, ArH), 8.57–8.61 (m, 1H, ArH), 8.88
(
dd, 1H, J ¼ 4.7 and 1.8 Hz, ArH). Anal. calcd. for C H N OSe: C,
1
1
7
3
4
7.84; H, 2.56, N, 15.22. Found: C, 47.65; H, 2.48; N, 15.11.
-(5-Chloro-2-pyridyl)-7-azabenzisoselenazol-3(2H)-one (2j). It was
obtained in the same manner as 2i using 5-chloro-2-aminopyridine
2
(0.354 g, 2.75 mmol) and triethylamine (0.566 g, 5.50 mmol). Recrystallized
from dimethylformamide. Yield 83%. M.p. 258–260 C (decomposition).
ꢀ
ꢁ
1
1
IR (KBr) 1663 cm (CO). H NMR (300 MHz, DMSO-d ) ꢀ 7.54 (dd, 1H,
6
J ¼ 7.8 and 4.7 Hz, ArH), 8.04 (dd, 1H, J ¼ 8.7 and 1.9 Hz, ArH), 8.24
(
d, 1H, J ¼ 7.8 Hz, ArH), 8.50 (s, 1H, ArH), 8.61 (d, 1H, J ¼ 8.7 Hz,
ArH), 8.87 (d, 1H, J ¼ 4.7 Hz, ArH). Anal. calcd. for C H ClN OSe: C,
11 6 3
4
2.53; H, 1.95; N, 11.41. Found: C, 42.37; H, 1.88; N, 11.28.

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3814
Kloc, Maliszewska, and Mbochowski
ACKNOWLEDGMENTS
This work was supported by the grant from Center Biomonitoring,
Biotechnology, and Preservation of Ecosystems of Lower Silesia.
REFERENCES
1
2
. Mugesh, G.; Singh, H.B. Synthetic organoselenium compounds as
an tioxidants: glutathione peroxidase activity. Chem. Soc. Rev.
2
000, 29 (5), 347–357.
. Mugesh, G.; du Mont W.-W.; Sies, H. Chemistry of biologically
important synthetic organoselenium compounds. Chem. Rev.
2
001, 101 (7), 2125–2179.
3
. Schewe, T. Molecular actions of ebselen—an antiinflammatory
antioxidant. Gen. Pharmac. 1995, 26 (6), 1153–1169.
4
. Mlochowski, J.; Kloc, K.; Syper, L.; Inglot, A.D.; Piasecki, E.
Aromatic and azaaromatic diselenides, benzisoselenazolones, and
related compounds as immunomodulators active in humans:
synthesis and properties. Liebigs Ann. Chem. 1993, (12), 1293–1244.
. Czyrski, J.A.; Inglot, A.D. Mitogenic activity of selenoorganic
compounds in human peripheral blood leucocytes. Experientia
5
6
1
991, 47, 95–97.
. Mlochowski, J.; Gryglewski, R.; Inglot, A.D.; Jakubowski, A.;
Juchniewicz, L.; Kloc, K. Synthesis and properties of 2-carbox-
yalkyl-1,2-benzisoselenazol-3(2H)-ones and related organoselenium
compounds as nitric oxide synthase inhibitors and cytokine inducers.
Liebigs Ann. 1996, (11), 1751–1755.
7
. Osajda, M.; Kloc, K.; Mlochowski, J.; Piasecki, E.; Rybka, K.
Bisbenzisoselenazol-3(2H)- ones a new group of ebselen analogues.
polish J. Chem. 2001, 75 (6), 823–830.
8
. Nozawa, R.T.; Yokota, R.; Fujimoto, R. Susceptibity of
methicillin-resistant aphylococcus aureus to the selenium-containing
compound 2-phenyl-1,2-benzisoselenazol-3(2H)-one
Antimicrob. Agents Chemother. 1989, 33 (8), 1388–1390.
(PZ51).
9
. Parnham, M.J.; Graf, E. Pharmacology of synthetic organic
selenium compounds. Prog. Drug. Res. 1991, 36, 9–47.
1
´
0. Bien, M.; Blaszczyk, B.; Kalinowska, K.; Mlochowski, J.; Inglot,
A.D. Antifungal activity of 2-(4-chlorophenyl-1,2-benzisoselenazol-
3
(2H)-one, the analog of ebselen. Arch. Immun. Ther. Exp. 1999,
7 (3), 185–193.
4

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Synthesis of 7-Azabenzisoselenazol-3(2H)-ones
3815
1
1. Lambert, C.; Hilbert, M.; Christiaens, L. Ortholithiation as a tool
for the synthesis of ebselen analogues. Synth. Commun. 1991, 21 (1),
5–98.
8
1
2. Osajda, M.; Mlochowski, J. The reactions of 2-(chloroseleno)-
benzoyl chloride with nucleophiles. Tetrahedron 2002, 58 (37),
7
531–7537.
1
3. Mhizha, S.; Mlochowski, J. Synthesis of 2-acyl- and 2-sulfonylben-
zisoselenazol-3(2H)-ones. Synth. Commun. 1997, 27 (2), 283–291.
4. Kloc, K.; Mlochowski, J. Selenylation acylation of ketones with
1
2-chloroselenobenzoyl chloride. A novel route to benzo[b]seleno-
phenes. Tetrahedron Lett. 2001, 42 (29), 4899–4902.
1
5. Kloc, K.; Osajda, M.; Mlochowski, J. 2-(Chloroseleno)benzoyl
chloride: a tandem reagent for selenenylation-acylation of C-H
Acids. Chem. Lett. 2001, (8), 826–827.
1
6. Giurg, M.; Mlochowski, J. Oxidative ring contraction of
cycloalkanones: a Facile method for synthesis of medium ring
cycloalkanecarboxylic acids. Synth. Commun. 1999, 29 (13),
2
281–2291.
1
7. Bistline, R.G.; Maurer, E.W.; Smith, F.D.; Linfield, W.M. Fatty
acid amides and anilides. Syntheses and antimicrobial properties.
J. Am. Oil Chem. Soc. 1980, 57 (2), 98–103.
1
8. Aldrich Handbook of Fine Chemicals and Laboratory Equipment,
2
003–2004; 448.
Received in Poland May 7, 2003

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