144
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 1, January, 2013
Proshin et al.
С(4)
ysis of the compounds obtained was performed on a CHN anaꢀ
lyzer (Carlo Erba).
С(3)
F
С(5)
Synthesis of 1ꢀarylꢀ3ꢀ(2ꢀcyclohexꢀ1ꢀenylethyl)selenoureas
5a—d. A solution of substituted aryl isoselenocyanate 3a—d
(0.01 mol) in diethyl ether (20 mL) was added dropwise to
a stirred solution of amine 4 (1.25 g, 0.01 mol) in diethyl ether
(20 mL). The reaction mixture was stirred at room temperaꢀ
ture for 2—5 h until a precipitate formed. The precipitate
was filtered off and dried to give analytically pure selenoꢀ
ureas 5a—d.
1ꢀ(2ꢀCyclohexꢀ1ꢀenylethyl)ꢀ3ꢀphenylselenourea (5a). Yield
83%, light brown crystals, m.p. 110—112 C. Found (%): C, 58.63;
H, 6.56; N, 9.12. C15H20N2Se. Calculated (%): C, 58.47; H, 6.62;
N, 9.24. 1H NMR, : 1.55 (m, 4 H, CH2CH2); 1.87 (m, 4 H,
CH2C=CHCH2); 2.23 (t, 2 H, NHCH2CH2, J = 6.3 Hz); 3.75
(q, 2 H, NHCH2CH2, J = 6.3 Hz); 5.31 (s, 1 H, C=CH); 6.34
(br.s, 1 H, NHCH2); 7.20 (m, 2 H, Harom); 7.43 (m, 3 H, Harom);
8.12 (br.s, 1 H, NH).
1ꢀ(3ꢀChloroꢀ4ꢀmethylphenyl)ꢀ3ꢀ(2ꢀcyclohexꢀ1ꢀenylethyl)seꢀ
lenourea (5b). Yield 82%, light brown crystals, m.p. 147—149 C.
Found (%): C, 54.02; H, 5.95; N, 7.87. C16H21N2ClSe. Calcuꢀ
lated (%): C, 53.82; H, 6.03; N, 7.99. 1H NMR, : 1.49 (m, 4 H,
CH2CH2); 1.83 (m, 4 H, CH2C=CHCH2); 2.19 (t, 2 H,
NHCH2CH2, J = 6.3 Hz); 2.36 (s, 3 H, Me); 3.71 (q, 2 H,
NHCH2CH2, J = 6.3 Hz); 5.30 (s, 1 H, C=CH); 6.24 (br.s, 1 H,
NHCH2); 6.98 (dd, 1 H, Harom, J = 2.0 Hz, J = 8.2 Hz); 7.19
(d, 1 H, Harom, J = 8.2 Hz); 7.25 (d, 1 H, Harom, J = 2.0 Hz);
8.04 (br.s, 1 H, NH).
С(12)
N(1)
N(2)
С(2)
С(1)
С(6)
С(7)
С(11)
С(10)
С(8)
Se
С(9)
С(13)
Fig. 3. Structure 11c in the crystal.
Table 1. Effects of compounds 5a—d on the antiradical activity
and Fe3+ꢀinitiated peroxide oxidation of lipids (POL) in rat brain
homogenates
b
Comꢀ
pound
I (%)a
IC50
AA (%)c
/mol L–1
5a
5b
5c
5d
87.27 6.22
81.35 7.09
86.02 6.99
77.04 12.28
1.93 1.63
2.12 0.69
2.20 0.93
3.77 1.19c
45.5 0.38
23.2 0.99
20.38 1.20
29.94 0.86
1ꢀ(2ꢀCyclohexꢀ1ꢀenylethyl)ꢀ3ꢀ(4ꢀfluorophenyl)selenourea (5c).
Yield 85%, light brown crystals, m.p. 157—159 C. Found (%):
C, 55.39; H, 5.89; N, 8.61. C15H19N2FSe. Calculated (%):
C, 55.55; H, 5.78; N, 8.71. 1H NMR, : 1.48 (m, 4 H, CH2CH2);
1.81 (m, 4 H, CH2C=CHCH2); 2.17 (t, 2 H, NHCH2CH2,
J = 6.3 Hz); 3.69 (q, 2 H, NHCH2CH2, J = 6.3 Hz); 5.24
(s, 1 H, C=CH); 6.10 (br.s, 1 H, NHCH2); 7.15 (m, 4 H, Harom);
8.10 (br.s, 1 H, NH).
a I is the POL inhibition (% of that in the control group).
b Compounds 7a—d and 11a—c show themselves inactive under
these experimental conditions.
c Antiradical activity (DPPH assay) (% of that in the control
group).
bicyclic isoselenoureas 7a—d and 11a—c can neither scavꢀ
enge radicals nor affect the peroxide oxidation of lipids
(POL) in rat brain homogenates (Table 1). Selenoureas
10a—c were not tested for biological activity because of
their in situ rearrangement into isoselenoureas 11a—c that
preclude them from being isolated.
To sum up, we developed a synthetic approach to biꢀ
cyclic isoselenoureas containing the 1,3ꢀselenazine ring,
namely, 1ꢀselenaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀylamines 7
and 3ꢀselenaꢀ1ꢀazabicyclo[3.3.1]nonꢀ2ꢀylideneamines 11.
We demonstrated that intramolecular Seꢀalkylation of
selenoureas gives cyclic isoselenoureas, with dramatic
changes in their biological redox activity. Note that the
starting selenoureas 5a—d are comparable in antioxidant
activity with the wellꢀknown antioxidants trolox and ionol.8
1ꢀ(2ꢀCyclohexꢀ1ꢀenylethyl)ꢀ3ꢀ(4ꢀisopropylphenyl)selenoꢀ
urea (5d). Yield 80%, light brown crystals, m.p. 87—89 C.
Found (%): C, 61.88; H, 7.50; N, 8.02. C18H26N2Se. Calculatꢀ
1
ed (%): C, 61.99; H, 7.44; N, 7.93. H NMR, : 1.25 (d, 6 H,
CH(CH3)2, J = 6.8 Hz); 1.47 (m, 4 H, CH2CH2); 1.80 (m, 4 H,
CH2C=CHCH2); 2.16 (t, 2 H, NHCH2CH2, J = 6.3 Hz); 2.90
(m, 1 H, CHMe2); 3.69 (q, 2 H, NHCH2CH2, J = 6.3 Hz); 5.24
(s, 1 H, C=CH); 6.25 (br.s, 1 H, NHCH2); 7.15 (m, 4 H, Harom);
7.99 (br.s, 1 H, NH).
Synthesis of Nꢀsubstituted 1ꢀselenaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀ
enꢀ2ꢀylamines 7a—d. Selenourea 5a—d was suspended in 48%
aqueous HBr (10 mL). The resulting suspension was refluxed for
5 h. After completion of the reaction, the mixture was cooled
and diluted with water (20 mL). The product was extracted with
CH2Cl2 (3×15 mL). The combined organic extracts were washed
with water and brine, dried with anhydrous Na2SO4, filtered,
and concentrated in vacuo. The residue was recrystallized from
propanꢀ2ꢀol to give Nꢀsubstituted 1ꢀselenaꢀ3ꢀazaspiro[5.5]ꢀ
undecꢀ2ꢀenꢀ2ꢀylamine hydrobromide 7a—d.
Experimental
Nꢀ(1ꢀSelenaꢀ3ꢀazaspiro[5.5]undecꢀ2ꢀenꢀ2ꢀyl)aniline hydroꢀ
bromide (7a). Yield 79%, light brown crystals, m.p. 147—149 C.
Found (%): C, 46.41; H, 5.45; N, 7.22. C15H21N2SeBr. Calcuꢀ
lated (%): C, 46.22; H, 5.33; N, 7.31. 1H NMR, : 1.37 (m, 3 H,
C(9)H2, C(10)HH); 1.69 (m, 5 H, C(11)HH, C(10)HH, C(8)H2,
C(7)HH); 2.14 (m, 4 H, C(11)HH, C(7)HH, C(5)H2); 3.71
1
H NMR spectra were recorded on a Bruker CXPꢀ200 inꢀ
strument (Germany) in CDCl3. Chemical shifts are referenced
to Me4Si. Melting points were determined on a Boetius hot stage
and are given uncorrected. Solutions were concentrated on
a rotary evaporator in a water aspirator vacuum. Elemental analꢀ