Synthesis of tetrasubstituted isoselenoureas

Full text of DOI:10.1134/S0012500810010039

ISSN 0012ꢀ5008, Doklady Chemistry, 2010, Vol. 430, Part 1, pp. 8–10. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.N. Proshin, I.V. Serkov, S.O. Bachurin, 2010, published in Doklady Akademii Nauk, 2010, Vol. 430, No. 2, pp. 58–60.
CHEMISTRY
Synthesis of Tetrasubstituted Isoselenoureas
A. N. Proshin, I. V. Serkov, and Corresponding Member of the RAS S. O. Bachurin
Received August 4, 2009
DOI: 10.1134/S0012500810010039
In recent years, the chemistry of organoselenium correcting agents and cognitive enhancers [10], and
can act as NO synthase inhibitors [11].
We developed a method for the synthesis of seleꢀ
noureas and Se,N,N,N'ꢀtetrasubstituted acyclic isoseꢀ
lenourea derivatives based on them as bioisosteric anaꢀ
logues of isothioureas. As the starting compounds for
compounds has been one of vigorously developing
areas of bioorganic and medicinal chemistry. Recent
studies demonstrated that selenium is an important
component in functioning of many biological systems.
No wonder that during the last 20 years organic seleꢀ
nium derivatives have ceased to be uncommon comꢀ
pounds. Moreover, they are of interest not only as
chemical compounds with unique properties but also
as biologically active agents, which exhibit antioxidant
[1] and antibacterial [2] activities. Low plasma conꢀ
centration of selenium is a risk factor at various pathoꢀ
logical processes including cancer [3–6], cardiovascuꢀ
lar diseases [7], and osteoarthritis and AIDS [8, 9].
the synthesis, we used 4ꢀisopropylaniline and
dine ( , Scheme 1. These anilines were converted to
formamides ( ) by reaction with formic acid [12], and
then aryl selenocyanates ( ) were prepared by refluxꢀ
ing a mixture of formamides ( ), phosgene, and seleꢀ
nium (powder) in toluene in the presence of triethyꢀ
lamine [13]. The aryl isoselenates ( ) were made to
react with dibenzylamines ( ) to give selenoureas ( ).
The latter were alkylated with methyl or ethyl iodide to
give final isoselenoureas ( ). Thus, we developed an
approach to the synthesis of arylselenoureas and their
pꢀtoluiꢀ
1
2
3
2
3
4
5
Isothioureas is a class of compounds widely used in
the synthesis of medications. Proper isothioureas have
6
a clearꢀcut protective action and can be used as neuroꢀ alkylated iso analogues.
R4
R3
O
H
Se
H
N
C
NH2
NH
N
R2
COCl
Se
HCO H
2
4
2
R1
R1
R1
1
2
3
R3
R3
R2
R2
H
N
N
N
N
5
R I
· HI
Se
Se
R1
R5
R1
R4
R4
5a–5d
6a–6f
1 2 3 4 5
R = Me, i-Pr; R = H, Me; R = H, OMe; R = H, OMe, F; R = Me, Et
Scheme 1.
Institute of Physiologically Active Substances, Russian Academy of Sciences, Chernogolovka, Moscow oblast,
142432 Russia
8

SYNTHESIS OF TETRASUBSTITUTED ISOSELENOUREAS
9
EXPERIMENTAL
N
ꢀ(4ꢀFluorobenzyl)ꢀ
isopropylphenyl)selenourea
R3 = H, R4 = F). Light yellow powder. mp = 165–
167 C. MS (
): 454 (M + H). 1H NMR (CDCl3),
ppm: 7.20 (13H, m, Harom), 6.22 (1H, q, CH), 4.78
(1 H, d, = 17.0 Hz, СНН), 4.62 (1H, d, = 17.0 Hz,
СНН), 2.85 (1H, m, CH), 1.65, (3H, d, = 7.2 Hz,
CH3), 1.18 (6H, d, = 7.3 Hz, 2 СН3).
SeꢀMethylꢀ ꢀdibenzylꢀ 'ꢀ(4ꢀisopropylpheꢀ
N
ꢀ(1ꢀphenylꢀ1ꢀethyl)ꢀ
(
N'ꢀ(4ꢀ
5d; R1 = iꢀPr, R2 = Me,
1
The H NMR spectra were recorded on a Bruker
CPXꢀ200 instrument (Germany), the chemical shifts
°
m
/
z
δ
,
are presented on the
δ
scale with respect to Me4Si.
Mass spectra were recorded on a Finnigan 4021
instrument. Melting points were determined on a
Boetius hot stage and were not corrected. The soluꢀ
tions were concentrated on a rotary evaporator in a
water jet pump vacuum.
Synthesis of arylselenoureas (5) and isoselenoureas nyl)isoselenourea hydroiodide
(
6a; R1 = iꢀPr, R2 = R3 =
(6) (general procedure). A solution of aniline
(0.1 mol) in 95% formic acid (20 mL) was refluxed for
30 min and the solvent was evaporated. The residue
was dissolved in Et2O and washed with AcOH (5%)
water, and a solution of NaHCO3 (5%). The aqueous
layer was extracted with Et2O, the organic extracts
were combined and dried over anhydrous MgSO4. The
drying agent was filtered off and the filtrate was conꢀ
centrated. The residue was crystallized from an
J
J
J
J
×
N
,
N
N
R4 = H, R5 = Me). Light brown powder, mp 142–
1
1
145
(CDCl3),
Harom), 5.22 (4H, s, 2
°
C. MS (
m/
z
): 435 (M – Me + 2H). H NMR
δ
, ppm: 11.35 (1H, br s, NH), 7.32 (14H, m,
СН2), 2.74 (1H, m, CH),
2
×
2.12 (3H, s, SeCH3), 1.25 (6H, d,
CH3).
J
= 3.5 Hz, 2
×
SeꢀEthylꢀ
nyl)isoselenourea hydroiodide (6b; R1 =
R4 = H, R5 = Et). Light brown powder, mp 138–
140 C. MS ( ): 450 (M + H), 422 (M – Et + 2H).
1H NMR (CDCl3),
, ppm: 11.28 (1H, br s, NH), 7.25
(14H, m, Harom), 5.23 (4H, s, 2 СН2), 2.84 (1H, m,
CH), 2.59 (2H, q, = 3.8 Hz, SeCH2), 1.27 (3H, t,
= 3.8 Hz, SeCH2CH3), 1.24 (6H, d, = 3.5 Hz, 2
N,Nꢀdibenzylꢀ
N
'ꢀ(4ꢀisopropylpheꢀ
i
ꢀPr, R2 = R3 =
EtOH/H2O mixture. The resulting arylformamide
(0.04 mol) was dissolved in anhydrous toluene
(100 mL), and at 0 C, Et3N (0.16 mol) and selenium
2
°
m/z
δ
°
×
(powder, 0.04 mol) were added with intense stirring.
Then, a 20% solution of phosgene in toluene (30 g,
0.06 mol) was added dropwise over a period of 30 min,
J
J
J
×
and the reaction mixture was refluxed for 8 h. Then, CH3).
the suspension was filtered and washed with toluene
SeꢀMethylꢀ
nourea hydroiodide
H). Light brown powder, mp 85–87
N
,
N
(
ꢀdibenzylꢀ
6c; R1 = R5 = Me, R2 = R3 = R4 =
C. MS ( ): 394
(M – Me + 2H). H NMR (CDCl3), , ppm: 11.37
(1H, br s, NH), 7.30 (14H, m, Harom), 5.27 (4H, s,
СН2), 2.23 (3H, s, ArCH3), 2.10 (3H, s, SeCH3).
SeꢀMethylꢀ ꢀbis(4ꢀmethoxybenzyl)ꢀ 'ꢀ(4ꢀ
tolyl)isoselenourea hydroiodide
6d; R1 = R5 = Me,
R2 = H, R3 = R4 = OMe). Light brown powder, mp
95–98 C. 1H NMR (CDCl3),
, ppm: 11.24 (1H, br.s.,
NH), 7.07 (12H, m, Harom), 5.15 (4H, s, 2 СН2),
3.80 (6H, s, 2 СН3), 2.22 (3H, s, ArCH3), 2.08
(3H, s, SeCH3).
SeꢀMethylꢀ
ethyl)ꢀ 'ꢀ(4ꢀisopropylphenyl)isoselenourea hydroioꢀ
dide
6e; R1 = ꢀPr, R2 = R5 = Me, R3 = H, R4 = F).
Yellowish oil. 1H NMR (CDCl3),
, ppm: 11.30 (1H,
br s, NH), 7.20 (13H, m, Harom), 6.22 (1H, q, CH),
N'ꢀ(4ꢀtolyl)isoseleꢀ
(2
×
50 mL), and the organic layer was concentrated.
The residue was purified by column chromatography
on silica gel with petroleum ether as the eluent. The
yield of aryl selenocyanates
cocyanate (0.01 mol) was dissolved in toluene
(10 mL), dibenzylamine (0.01 mol) was added, and
the mixture was refluxed for 1 h. The mixture was
cooled, the precipitated selenourea was filtered off
and dissolved in dry acetone (10 mL), and alkyl iodide
(0.007 mol) was added. The precipitated crystals of
isoselenourea
from dioxane.
°
m/z
1
δ
3 was 40–50%. Aryl seleꢀ
3
2
×
4
N,N
N
5
(
δ
6 were filtered off and recrystallized
×
×
O
N,NꢀDibenzylꢀN'ꢀ(4ꢀisopropylphenyl)selenourea
(
5a; R1 =
i
ꢀPr, R2 = R3 = R4 = H). Light yellow powꢀ
Nꢀ(4ꢀfluorobenzyl)ꢀNꢀ(1ꢀphenylꢀ1ꢀ
1
der, mp 135–137
NMR (CDCl3),
(4H, s,
3.5 Hz,
°
C. MS (
m/
z): 422 (M + H). H
N
δ
, ppm: 7.35 (14H, m, Harom), 5.20
(
i
2
2
×
СН2), 2.91 (1H, m, CH), 1.28 (6H, d,
СН3).
J =
δ
×
N,NꢀDibenzylꢀN'ꢀ(4ꢀtolyl)selenourea (
5b; R1 =
5.22 (1H, d,
16.2 Hz, СНН); 2.91 (1H, m, CH), 2.02 (3H, d,
J
= 16.2 Hz, СНН), 5.12 (1H, d,
J
J
=
=
Me, R2 = R3 = R4 = H). Grayishꢀbrown powder, mp
1
85–87
(CDCl3),
CH2), 2.33 (3H, s, ArCH3).
°
C. MS (
m/
z
): 394 (M + H). H NMR
7.2 Hz, CH3), 1.98 (3H, s, SeCH2CH3), 1.22 (6H, d,
= 3.5 Hz, 2 СН3).
SeꢀEthylꢀ1ꢀ(4ꢀfluorobenzyl)ꢀ
ethyl)ꢀ 'ꢀ(4ꢀisopropylphenyl)isoselenourea hydroioꢀ
dide
6f; R1 = ꢀPr, R2 = Me, R3 = H, R4 = F, R5 = Et).
Yellowish oil. MS (
): 454 (M – Et + 2H). 1H NMR
, ppm: 11.25 (1H, br s, NH), 7.20 (13H, m,
= 16.2 Hz,
δ
, ppm: 7.35 (14H, m, Harom), 5.20 (4H, s,
J
×
2
×
Nꢀ(1ꢀphenylꢀ1ꢀ
N
,
N
ꢀBis(4ꢀmethoxybenzyl)ꢀ
5c, R1 = Me, R2 = H, R3 = R4 = OMe). Yellowish oil.
): 454 (M + H). 1H NMR (CDCl3),
MS ( , ppm:
7.10 (12H, m, Harom), 5.21 (4H, s, 2 СН2), 3.85 (6H, (CDCl3),
s, 2 СН3), 2.25 (3H, s, ArCH3). Harom), 6.28 (1H, q, CH), 5.23 (1H, d, J
N'ꢀ(4ꢀtolyl)selenourea
N
(
(
i
m
/
z
δ
m/z
×
δ
×
O
DOKLADY CHEMISTRY Vol. 430
Part 1
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10
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6. ElꢀSayed, W.M., AboulꢀFadl, T., Lamb, J.G., et al.,
СНН), 5.13 (1H, d,
J
= 16.2 Hz, СНН); 2.91 (1H, m,
Chem. Biol. Inter, 2006, vol. 162, p. 31.
CH), 2.53 (2H, q,
= 7.2 Hz, CH3), 1.29 (3H, t,
SeCH2CH3), 1.22 (6H, d, = 3.5 Hz,
J = 3.8 Hz, SeCH2), 2.01 (3H, d,
J
J
= 3.8 Hz,
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2
×
СН3).
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