New heterocyclic selenenamides: 1,2,4-benzoselenadiazin-3(4H)-ones and 1,3,2-benzodiselenazoles

Article abstract of DOI:10.1016/S0040-4039(02)00684-6

Two groups of selenium-containing heterocycles having new, unique 1,2,4-benzoselenadiazine and 1,3,2-diselenazole ring systems with an endocyclic selenenamide C-N moiety are presented. The first type was obtained by oxidative cyclization of 2,2′-diselenobis(phenylureas) and the second type by the reaction of 1,2-di(bromoseleno)benzene with primary amines.

Full text of DOI:10.1016/S0040-4039(02)00684-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4071–4074
New heterocyclic selenenamides:
1,2,4-benzoselenadiazin-3(4H)-ones and 1,3,2-benzodiselenazoles
Krystian Kloc, Jacek Młochowski,* Karol Osajda, Ludwik Syper and Halina Wo´jtowicz
Institute of Organic Chemistry, Biochemistry and Biotechnology, Wrocław University of Technology, Wyb. Wyspian´skiego 27,
50-370 Wrocław, Poland
Received 12 March 2002; revised 26 March 2002; accepted 5 April 2002
Abstract—Two groups of selenium-containing heterocycles having new, unique 1,2,4-benzoselenadiazine and 1,3,2-diselenazole
ring systems with an endocyclic selenenamide C–N moiety are presented. The first type was obtained by oxidative cyclization of
2,2%-diselenobis(phenylureas) and the second type by the reaction of 1,2-di(bromoseleno)benzene with primary amines. © 2002
Elsevier Science Ltd. All rights reserved.
Selenium-containing heterocycles, particularly those
having the endocyclic selenenamide Se–N moiety and
related diaryl diselenides play an important role in
medicinal biology as biological response modifiers.1
Some of them, particularly 2-phenyl-1,2-benzisoselena-
zol-3(2H)-one (ebselen) its derivatives and analogues,
were found as glutathione peroxidase mimics, anti-
inflammatory, antiatherosclerotic, anticancer, antimi-
crobial and antiviral agents as well as immuno-
stimulants, cytokine inducers and nitric oxide synthase
inhibitors.2 Moreover, the ebselen and camphor derived
selenenamide, and bis[2-(phenylcarbamoyl)phenyl] dise-
lenides were used as efficient oxygen-transfer catalysts
for hydroperoxide oxidation the different groups of
organic compounds such as sulfides, thiols, ketazines,
aldazines, oximes, N,N-dimethylhydrazones, aldehydes
and alkylarenes.2h,3
In this work, we present a simple approach for the
synthesis of two different groups of heterocycles having
new selenium and nitrogen-containing six- and five-
membered 1,2,4-benzoselenadiazine and 1,3,2-ben-
zodiselenazole ring systems.
2-Substituted
1,2,4-benzoxaselenadiazin-3(4H)-ones
(1a–c) were synthesized starting from 1-chloro-2-
nitrobenzene 3. Compound 3 was treated with dilithium
diselenide in an aprotic medium according to the proce-
dure reported earlier,4 to give bis(2-nitrophenyl) dise-
lenide 4 which was reduced with hydrazine, in the
presence of catalytic Ni (Raney) to afford bis(2-
aminophenyl) diselenide 5.5,6 Both amino groups were
converted to the corresponding aminocarbamoyl by
treatment of 5 with isocyanates.7 The 2,2%-diseleno-
bis(phenylureas) (6a–c) thus formed were oxidatively
Scheme 1.
Keywords: organoselenium compounds; benzoselenadiazinone; benzoselenadiazinthiones; benzodiselenazoles; selenenamides.
* Corresponding author. Tel.: +48-71-3202419; fax: +48-71-3284064; e-mail: mlochowski@kchf.ch.pwr.wroc.pl
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00684-6

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K. Kloc et al. / Tetrahedron Letters 43 (2002) 4071–4074
Scheme 2.
cyclized to the final products 1a–c (Scheme 1).8
A
References
comparison of the 1H NMR spectra of substrates 6
and products 1 indicated that only one pair of NH
protons remained (primary observed at ca. 6.7 ppm),
and that the multiplicity of the NCH proton signal in
the spectra of compounds having N-alkyl substituents
(1a–c) was decreased. This evidence confirmed that
oxidative elimination of a hydrogen atom and ring
closure had occurred. Benzoyl peroxide was used as
the oxidant of choice since it had successfully been
used earlier for Se–N bond formation in other hetero-
cyclic ring systems.9 Nevertheless, it was observed
that the reaction was limited to diselenides of type 6
which are soluble in benzene or toluene. 2,2%-Dise-
lenobis(phenylureas) having an aryl substituent
1. For a review of bioactive organoselenium compounds,
see: (a) Sies, H. Free Radic. Biol. Med. 1993, 14, 313–323;
(b) Schewe, T. Gen. Pharmac. 1995, 26, 1153–1169; (c)
Mugesh, G.; Singh, H. B. Chem. Soc. Rev. 2000, 29,
347–357; (d) Mugesh, G.; du Mont W.-W.; Sies, H.
Chem. Rev. 2001, 101, 2125–2179.
2. (a) Muller, A.; Cadenas, E.; Graf, P.; Sies, H. Biochem.
Pharmacol. 1984, 33, 3235–3240; (b) Wendel, A.; Fausel,
M.; Safayachi, H.; Tiegs, G.; Otter, R. Biochem. Pharma-
col. 1984, 33, 3241–3245; (c) Reich, H. J.; Jasperse, C. P.
J. Am. Chem. Soc. 1987, 109, 5549–5551; (d) Inglot, D.;
Zielin´ska-Jenczylik, J.; Piasecki, E.; Syper, L.;
Młochowski, J. Experientia 1990, 46, 308–311; (e)
Jaquemin, V.; Christiaens, L. E.; Renson, M. J.; Evers,
M. J.; Dereu, N. Tetrahedron Lett. 1992, 33, 3863–3867;
(f) Młochowski, J.; Kloc, K.; Syper, L.; Inglot, A. D.;
Piasecki, E. Liebigs Ann. Chem. 1993, 1239–1244; (g)
Młochowski, J.; Gryglewski, R. J.; Inglot, A. D.; Juch-
niewicz, L.; Kloc, K. Liebigs Ann. Chem. 1996, 1751–
1755; (h) Back, T. G.; Dyck, B. P. J. Am. Chem. Soc.
1997, 119, 2079–2083; (i) Chandiere, J.; Erdelmeier, I.;
Montet, M.; Yadan, J. C. Phosphorus, Sulfur Silicon
1998, 136–138, 467–470; (j) Bien´, M.; Błaszczyk, B.;
Kalinowska, K.; Młochowski, J.; Inglot, A. D. Arch.
Immun. Ther. Exp. 1999, 47, 185–193; (k) Osajda, M.;
Kloc, K.; Młochowski, J.; Piasecki, E.; Rybka, K. Polish
J. Chem. 2001, 75, 823–830.
(phenyl,
4-nitrophenyl,
3-chlorophenyl,
3,4-
dichlorophenyl) on the terminal nitrogen atom of the
urea moiety were insoluble in these solvents and
remained unreacted.
Replacement of the aminocarbamoyl group by an
aminothiocarbamoyl
bis(phenylthiourea) 6d soluble in benzene. Thus, com-
pound 6d, obtained from diselenide and
phenylisothiocyanate, was smoothly converted into
the expected 2-phenyl-1,2,4-benzoxaselenadiazin-
group
made
2,2%-diseleno-
5
3(4H)-thione 1d by oxidation with benzoyl peroxide.
The lack of one pair of NH protons (primary
observed in the 1H NMR spectrum of the substrate
6d at 8.33 ppm) supports the proposed cyclic struc-
ture of the product 1d.
3. (a) Młochowski, J.; Giurg, M.; Kubicz, E.; Said, S. B.
Synth. Commun. 1996, 26, 291–300; (b) Młochowski, J.
Phosphorus, Sulfur Silicon 1998, 136–138, 191–204; (c)
Wo´jtowicz, H.; Brza˛szcz, M.; Kloc, K.; Młochowski, J.
Tetrahedron 2001, 57, 9743–9748.
Starting from poly(bis-1,2-phenylene) diselenide 7,
prepared recently in our laboratory,10 2-substituted
1,3,2-benzodiselenazoles (2a–e) were synthesized. The
diselenide 7, brominated with elemental bromine, gave
1,2-di(bromoseleno)benzene 811,12 which was subse-
quently treated with primary alkylamines to produce
the desired heterocycles 2 (Scheme 2).13 Their 1H
NMR spectra and elemental analyses support the
proposed structures. The analogous reaction of 8 with
aromatic amines (aniline, 4-nitroaniline) gave no posi-
tive results since the corresponding products 2 could
not be isolated due to their instability.
4. Syper, L.; Młochowski, J. Tetrahedron 1988, 44, 6119–
6130.
5. To a solution of diselenide 4 (18.0 g, 45 mmol) in
propanol (150 ml) heated to 95°C, Raney nickel (ca. 10 g)
was added and then hydrazine monohydrate (15 ml, 300
mmol) was added dropwise and the mixture was stirred
for 3 h. The reaction was continued for an additional 2 h
and the hot mixture was filtered. The solvent was evapo-
rated in vacuo and the residue was recrystallized from
ethanol. Compound 5: yield 71%, bright orange-red
prisms, mp 83.2°C (Ref. 6 83.5°C).
6. Matti, J. Bull. Soc. Chim. Fr. 1940, 7, 617–621.
7. The mixture of amine 5 (3.42 g, 10 mmol) and the
corresponding isocyanate or isothiocyanate (30 mmol)
was heated for 2–30 h at 80°C until it solidified. The
excess of reagent was evaporated in vacuo and the crude
product was recrystallized from toluene to give pure
(6a–d). Compound 6a: yield 81%, mp 174–175°C, yellow
Acknowledgements
This work was supported by the Polish State Com-
mittee for scientific research (Grant No 3 TO9A 097
17).

K. Kloc et al. / Tetrahedron Letters 43 (2002) 4071–4074
4073
1
CH2), 1.50 (m, 2H, CH2), 1.63–1.72 (m, 2H, CH2), 3.72
(t, 1H, J=10.9 Hz, CHN), 6.88 (d, 2H, J=7.5 Hz,
ArH), 7.09 (t, 1H, J=7.5 Hz, ArH), 7.31 (d, 1H, J=7.5
Hz, ArH), 9.23 (s, 1H, ArNH). IR (KBr) 3325, 3082,
2930, 2852, 1650. Anal. calcd for C13H16N2OSe: C,
52.89; H, 5.46; N, 9.49. Found: C, 52.38; H, 5.21; N,
9.65%. Compound 1d: yield 52%, mp 128–129°C, white
prisms. 1H NMR (300 MHz, DMSO-d6, l, ppm) 6.99–
7.05 (m, 2H, ArH), 7.27–7.38 (m, 3H, ArH), 7.57 (d, 1H,
J=8.1 Hz, ArH), 7.82 (t, 3H, J=8.4 Hz, ArH), 10.43 (s,
1H, ArNH). IR (KBr): 3180, 3082, 2957, 1625, 1559,
1428, 1289, 1266, 744, 675. Anal. calcd for C13H10N2SSe:
C, 51.15; H, 3.30; N, 9.18. Found: C, 50.96; H, 3.63; N,
9.62%.
prisms. H NMR (300 MHz, DMSO-d6, l, ppm) 0.88 (t,
6H, J=7.3 Hz, CH3), 1.40–1.47 (m, 4H, CH2), 2.99–3.31
(m, 4H, CH2N), 6.76 (t, 2H, J=7.4 Hz, NH), 6.89 (t,
2H, J=7.5 Hz, ArH), 7.21 (t, 2H, J=7.5 Hz, ArH), 7.49
(d, 2H, J=8.0 Hz, ArH), 7.59 (d, 2H, J=8.0 Hz, ArH),
8.01 (s, 2H, ArNH). IR (KBr) 3306, 3097, 2958, 2931,
2872, 1639. Anal. calcd for C20H26N4O2Se2: C, 46.86; H,
5.11; N, 10.94. Found: C, 46.99; H, 5.20; N, 11.12.
Compound 6b: yield 80%, mp 155–157°C, bright yellow
1
prisms. H NMR (300 MHz, DMSO-d6, l, ppm) 0.87 (t,
6H, J=7.2 Hz, CH3), 1.17–1.29 (m, 4H, CH2), 1.39–1.49
(m, 4H, CH2), 3.28 (m, 4H, CH2N), 6.72 (t, 2H, J=7.4
Hz, NH), 6.97 (t, 4H, J=7.4 Hz, ArH), 7.21 (t, 2H,
J=7.7 Hz, ArH), 7.40 (d, 2H, J=7.7 Hz, ArH), 8.01 (s,
2H, ArNH). IR (KBr) 3305, 3093, 2952, 2929, 2870,
1641. Anal. calcd for C22H30N4O2Se2: C, 48.87; H, 5.60;
N, 10.37%. Found: C, 49.01; H, 5.73; N, 10.58%. Com-
pound 6c: yield 75%, mp 210–211°C bright yellow
prisms. 1H NMR (300 MHz, DMSO-d6, l, ppm) 0.98–
1.56 (m, 12H, CH2), 1.64–1.67 (m, 4H, CH2), 1.79–1.82
(m, 4H, CH2), 3.41–3.45 (m, 2H, CH), 6.72 (d, 2H,
J=7.7 Hz, NH), 6.88 (t, 2H, J=7.2 Hz, ArH), 7.21 (t,
2H, J=7.2 Hz, ArH), 7.48 (d, 2H, J=7.2 Hz, ArH), 7.61
(d, 2H, J=7.7 Hz, ArH), 7.94 (s, 2H, ArNH). IR (KBr)
3322, 3083, 2952, 2929, 2852, 1643. Anal. calcd for
C26H34N4O2Se2: C, 52.68; H, 5.77; N, 9.46. Found: C,
52.35; H, 5.42; N, 9.55%. Compound 6d: yield 82%, mp
9. (a) Fong, M. C.; Schiesser, C. H. Tetrahedron Lett. 1995,
3, 7329–7332; (b) Mhizha, M. Tetrahedron 1997, 53,
17751–17760; (c) Kloc, K.; Młochowski, J. Eur. J. Org.
Chem. 1999, 67–91.
10. For the synthesis of poly(bis-1,2-phenylene) diselenide
see: Giurg, M.; Said, S. B.; Syper, L.; Młochowski, J.
Synth. Commun. 2001, 31, 3151–3159.
11. A solution of bromine (8.9 g, 56 mmol) in dry 1,2-
dichloromethane (100 ml) was added dropwise to a sus-
pension of diselenide 7 (11.7 g, 50 mmol) at ice–salt bath
temperature in the same solvent (250 ml) over 1 h. The
reaction was stirred at room temperature for 24 h, the
solvent and excess bromine were evaporated in vacuo.
The residue was recrystallized from 1,2-dichloromethane
to yield 8 (60%) as bright dark red plates, mp 146–147°C
with decomp. (Ref. 12 139–141°C).
1
121–122°C yellow prisms. H NMR (300 MHz, DMSO-
d6, l, ppm) 6.94–6.99 (m, 4H, ArH), 7.23–7.30 (m, 6H,
ArH), 7.45 (d, 4H, J=7.7 Hz, ArH), 7.55 (d, 2H, J=7.7
Hz, ArH), 7.70 (d, 2H, J=8.1 Hz, ArH), 8.33 (s, 2H,
ArNH), 9.23 (s, 2H, ArNH). IR(KBr) 3451, 3179, 3118,
3047, 2935, 2856, 1624, 1558, 1450, 1241, 1220, 743, 699.
Anal. calcd for C26H22N4S2Se2: C, 50.98; H, 3.62; N,
9.14. Found: C, 51.14; H, 3.73; N, 9.21%.
12. Lambert, C.; Christiaens, L. Tetrahedron Lett. 1984, 25,
833–834.
13. A solution of compound 8 (0.788 g, 2.0 mmol) in dry
1,2-dichloromethane (20 ml) was added dropwise to a
stirred solution of amine (6.3 mmol) at ice–salt bath
temperature in the same solvent (80 ml) over a 30 min
period. The reaction was continued at a temperature
maintained below −5°C for 2 h, then the mixture was
washed with water (3×20 ml). The layers were separated,
the organic layer was dried over sodium sulfate and the
solvent was evaporated in vacuo without heating. The
residue was pure product 2. Compound 2a: yield 87%,
8. A magnetically stirred solution of 2,2%-diselenobis(phenyl-
urea) (6a–c) or 2,2%-diselenobis(phenylthiourea) (6d) (1
mmol) and benzoyl peroxide (1.1 mmol) in dry benzene
(30 ml) was heated to 80°C for 20 h. After this period
the solvent was evaporated in vacuo. The products 1
were isolated from the residue by column chromatogra-
phy on silica gel using hexane–ethyl acetate (4:1) as
eluent and recrystallized from toluene. Compound 1a:
1
yellow oil. H NMR (300 MHz, CDCl3, l, ppm) 0.87 (t,
1
yield 65%, mp 106–107°C, yellow prisms. H NMR (300
3H, J=7.5 Hz, CH3), 1.49 (sextet, 2H, J=7.2 Hz, -CH2-),
3.16 (t, 2H, J=7.2 Hz, CH2N), 7.21 (dd, 2H, J=5.6 and
3.2 Hz, ArH), 7.45 (dd, 2H, J=5.6 and 3.2 Hz, ArH);
IR (film) 3052, 2958, 2930, 2870, 1559, 1427, 741. Anal.
calcd for C9H11NSe2: C, 37.13; H, 3.81; N, 4.81. Found:
C, 37.04; H, 3.74; N, 5.00%. Compound 2b: yield 90%,
MHz, DMSO-d6, l, ppm) 0.81 (t, 3H, J=7.3 Hz, CH3),
1.42–1.55 (m, 2H, CH2), 3.25 (t, 2H, J=7.0 Hz, CH2N),
6.97 (t, 2H, J=7.6 Hz, ArH), 7.15 (t, 1H, J=7.3 Hz,
ArH), 7.4 (d, 1H, J=7.6 Hz, ArH), 9.27 (s, 1H, ArNH).
IR (KBr) 3304, 3104, 2957, 2872, 1664. Anal. calcd for
C10H12N2OSe: C, 47.07; H, 4.74; N, 10.98. Found: C,
46.94; H, 4.53; N, 11.11%. Compound 1b: yield 68%, mp
1
yellow oil. H NMR (300 MHz, CDCl3, l, ppm) 0.88 (t,
3H, J=7.2 Hz, CH3), 1.30 (sextet, 2H, J=7 Hz, CH2),
1.45 (q, 2H, J=7.2 Hz, CH2), 3.18 (t, 2H, J=7.2 Hz,
CH2N), 7.21 (dd, 2H, J=5.5 and 3.2 Hz, ArH), 7.45 (dd,
2H, J=5.5 and 3.2 Hz, ArH) IR (film) 3052, 2956, 2929,
2869, 1559, 1427, 741. Anal. calcd for C10H13NSe2: C,
39.36; H, 4.29; N, 4.59 Found: C, 39.04; H, 4.31; N,
4.80%. Compound 2c: yield 96%, yellow oil. 1H NMR
(300 MHz, CDCl3, l, ppm) 0.88 (d, 6H, J=6.7 Hz,
CH3), 1.66–1.79 (m, 1H, CH), 3.00 (d, 2H, J=6.7 Hz,
CH2), 7.20 (dd, 2H, J=5.4 and 3.3 Hz, ArH), 7.45 (dd,
2H, J=5.4 and 3.3 Hz, ArH). IR (film) 3052, 2956, 2929,
1
108–109°C, yellow prisms. H NMR (300 MHz, DMSO-
d6, l, ppm) 0.85 (t, 3H, J=7.2 Hz, CH3), 1.16–1.26 (m,
2H, CH2), 1.41–1.46 (m, 2H, CH2), 3.25 (t, 2H, J=7.0
Hz, CH2N), 6.95 (d, 2H, J=7.3 Hz, ArH), 7.16 (t, 1H,
J=7.7 Hz, ArH), 7.39 (d, 1H, J=7.7 Hz, ArH), 9.25 (s,
1H, ArNH). IR (KBr) 3309, 3084, 2987, 2965, 2872,
1645. Anal. calcd for C11H14N2OSe: C, 49.08; H, 5.24;
N, 10.41. Found: C, 48.91; H, 5.12; N, 10.83%. Com-
pound 1c: yield 54%, mp 96–98°C, white prisms. 1H
NMR (300 MHz, DMSO-d6, l, ppm) 1.13–1.38 (m, 6H,

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K. Kloc et al. / Tetrahedron Letters 43 (2002) 4071–4074
2869, 1559, 1427, 741. Anal. calcd for C10H13NSe2: C,
39.36; H, 4.29; N, 4.59. Found: C, 39.60; H, 4.60; N,
4.80%. Compound 2d: yield 81%, yellow prisms, mp
4.85%. Compound 2e: yield 86%, yellow oil. 1H NMR
(300 MHz, CDCl3, l, ppm) 0.86 (t, 3H, J=7.5 Hz, CH3),
0.96 (d, 3H, J=6.3 Hz, CH3), 1.16–1.36 (m, 1H, CH2),
1.54–1.63 (m, 1H, CH2), 2.78 (m, 1H, CH3), 7.15 (dd, 2H,
J=5.7 and 3.3 Hz, ArH), 7.39 (dd, 2H, J=5.7 and 3.3
Hz, ArH). IR (film) 3052, 2928, 2872, 1558, 1427, 741.
Anal. calcd for C10H13NSe2: C, 39.36; H, 4.29; N, 4.59.
Found: C, 39.30; H, 4.10; N, 4.88%.
1
59–61°C. H NMR (300 MHz, CDCl3, l, ppm) 1.09 (s,
9H, CH3), 7.14 (dd, 2H, J=5.6 and 3.2 Hz, ArH), 7.40
(dd, 2H, J=5.6 and 3.2 Hz, ArH). IR (KBr) 3048, 2967,
2923, 1555, 1423, 741. Anal. calcd for C10H13NSe2: C,
39.36; H, 4.29; N, 4.59. Found: C, 39.32; H, 4.50; N,