α-Thioureidoalkylation of functionally substituted ureas: I. Tandem cyclization and esterification in reactions of N-(carboxyalkyl)ureas with 1,3-dialkyl-4,5-dihydroxy-4,5-diphenylimidazolidine-2-thiones in alcohols

Article abstract of DOI:10.1134/S1070428011100204

Acid-catalyzed reactions of N-(carboxyalkyl)ureas with 1,3-dialkyl-4,5- dihydroxy-4,5-diphenylimidazolidine- 2-thiones in methanol or propan-2-ol led to the formation of previously unknown ω-(4,6-dialkyl- 2-oxo-3a,6a-diphenyl- 5-thioxooctahydroimidazo[4,5-d]imidazol-1-yl)alkanoic acids and their methyl and isopropyl esters. The structure of some esters was proved by X-ray analysis. Methyl (4,6-diethyl-2-oxo-3a,6adiphenyl- 5-thioxooctahydroimidazo[4,5-d] imidazol-1-yl)acetate showed anxiolytic effect. Pleiades Publishing, Ltd., 2011.

Full text of DOI:10.1134/S1070428011100204

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 10, pp. 1564–1571. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © V.V. Baranov, G.A. Gazieva, Yu.V. Nelyubina, A.N. Kravchenko, N.N. Makhova, 2011, published in Zhurnal Organicheskoi Khimii,
2011, Vol. 47, No. 10, pp. 1535–1542.
α-Thioureidoalkylation of Functionally Substituted Ureas:
I. Tandem Cyclization and Esterification in Reactions
of N-(Carboxyalkyl)ureas with 1,3-Dialkyl-4,5-dihydroxy-
4,5-diphenylimidazolidine-2-thiones in Alcohols
V. V. Baranova, G. A. Gazievaa, Yu. V. Nelyubinab, A. N. Kravchenkoa, and N. N. Makhovaa
a Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences,
Leninskii pr. 47, Moscow, 119991 Russia
e-mail: kani@ioc.ac.ru
b Nesmeyanov Institute of Organometallic Compounds, Russian Academy of Sciences,
ul. Vavilova 28, Moscow, 119991 Russia
Received March 27, 2010
Abstract—Acid-catalyzed reactions of N-(carboxyalkyl)ureas with 1,3-dialkyl-4,5-dihydroxy-4,5-diphenyl-
imidazolidine-2-thiones in methanol or propan-2-ol led to the formation of previously unknown ω-(4,6-dialkyl-
2-oxo-3a,6a-diphenyl-5-thioxooctahydroimidazo[4,5-d]imidazol-1-yl)alkanoic acids and their methyl and iso-
propyl esters. The structure of some esters was proved by X-ray analysis. Methyl (4,6-diethyl-2-oxo-3a,6a-
diphenyl-5-thioxooctahydroimidazo[4,5-d]imidazol-1-yl)acetate showed anxiolytic effect.
DOI: 10.1134/S1070428011100204
with 4,5-dihydroxy-4,5-diphenylimidazolidin-2-ones:
when these reactions were carried out in alcohols
(methanol or propan-2-ol) the cyclization process lead-
ing to N-(carboxyalkyl)glycolurils was accompanied
by esterification [13]. Analogous reactions of ureas
with 4,5-dihydroxy-4,5-diphenylimidazolidine-2-
thiones were not reported.
Glycolurils (I, octahydroimidazo[4,5-d]imidazole-
2,5-diones) exhibit a broad spectrum of biological
activity [1–4], in particular neurotropic [1], while
2,4,6,8-tetramethylglycoluril (Mebicar) is used in med-
ical practice as minor tranquilizer [2]. 1,5-Diphenyl-
glycolurils affect hepatic cytochrome P-450-dependent
monooxygenase system [3]. Only a few examples of
synthesis of thio analogs of glycolurils (5-thioxoocta-
hydroimidazo[4,5-d]imidazol-2-ones II) were reported
[5–7], though these compounds may also be important
from the practical viewpoint. On the one hand (accord-
ing to PASS), they could exhibit diverse pharmaco-
logical activity related to their effect on the central
nervous system. On the other hand, it is known that,
e.g., dithiopiracetam (III) possesses a higher nootropic
activity than does Piracetam [8]. Therefore, synthesis
of glycoluril thio analogs seems to be an important
problem.
In the present work we examined the condensation
of 1,3-dialkyl-4,5-dihydroxy-4,5-diphenylimidazoli-
dine-2-thiones IVa and IVb with ureido acids Va–Vd
with a view to synthesize glycoluril thio analogs VI as
potential biologically active substances. Reactions of
ureas with 4,5-dihydroxy-4,5-diphenylimidazolidin-2-
R1
R4
R1
R4
R5
R5
N
N
N
N
O
O
S
O
N
R2
N
R3
N
R2
N
R3
R6
R6
Glycolurils I can be synthesized by reaction of
ureas with 4,5-dihydroxyimidazolidine-2-ones. In par-
ticular, reactions of N-alkyl- [9], N-(carboxyalkyl)-
[10], N-(hydroxyalkyl)- [11], and N-(aminoalkyl)ureas
[12] were reported. We recently described some specif-
icities of the condensation of N-(carboxyalkyl)ureas
I
II
S
O
N
N
H2N
H2N
S
O
III
Piracetam
1564

α-THIOUREIDOALKYLATION OF FUNCTIONALLY SUBSTITUTED UREAS: I.
1565
ones are usually carried out in water, lower alcohols, or
their mixtures, depending on the solubility of the reac-
tants, under conditions of acid catalysis (HCl) [9–13].
The condensation of acids Va–Vd with imidazolidine-
thiones IVa and IVb were performed by heating the
reactants in boiling methanol or propan-2-ol (com-
pounds IV are insoluble in water) in the presence of
concentrated hydrochloric acid over a period of 1, 2, or
3 h. It was found that the formation of bicyclic thio-
glycolurils VIa–VIh was accompanied by esterifica-
tion of the carboxy group [14] so that the major prod-
ucts were the corresponding methyl and isopropyl
esters VIIa–VIIf and VIIIa–VIIIh (Scheme 1). The
1H NMR spectra of esters VII and VIII lacked down-
field signals assignable to OH proton in carboxy group
(δ 12 ppm), but signals from MeO or i-PrO group were
present. We succeeded in detecting and isolating only
thioglycolurils VIa and VIe in the reactions of N-car-
bamoylglycine (Va) with compounds IVa and IVb in
isopropyl alcohol; in both cases, esters VIIIa and
VIIIe were also formed. The ratio of acids VI and
esters VIII changed during the process. Complete
esterification of the carboxy group in VIa and VIb
required 8 or 10 h, respectively, which may be related
to steric structure of both initial reactants and thiogly-
colurils VIa and VIe. All ureido acids Va–Ve reacted
with compound IVa in boiling ethanol, whereas com-
pound IVb reacted only with acids Va and Vb to
produce methyl esters VIIe and VIIf, respectively.
Compounds IVa and IVb turned out to be more reac-
tive in propan-2-ol, and isopropyl esters VIIIa–VIIIh
were formed from all ureido acids Va–Vd. The best
yields of esters VIIa, VIIb, VIIe, and VIIIb (65, 59,
73, and 58%, respectively) were obtained by heating
the reactants over a period of 1 h; compounds VIId,
VIIf, VIIId, and VIIIh (35, 57, 65, and 77%, respec-
tively) required heating over a period of 2 h; and esters
VIIc, VIIIc, VIIIf, and VIIIg (51, 70, 66, and 67%,
respectively) were isolated after heating for 3 h. When
the reaction time was shortened from 1 h to 15 min, the
yields of the corresponding esters were considerably
lower, while initial ureido acids Va–Vd were partly
recovered from the reaction mixtures.
In all cases, the reactions were accompanied by side
processes. Hydrolysis of compounds IVa and IVb to
the corresponding ureas and benzil was observed in all
reactions (Scheme 2, a), while other side reactions
occurred only in some cases. 4,5-Dimethoxy-1,3-di-
methyl-4,5-diphenylimidazolidine-2-thione (IX) was
formed in methanol (Scheme 2, b), and it did not react
with ureido acids. In the reactions of acids Va–Vd with
compound IVb in isopropyl alcohol previously un-
Scheme 1.
R1
R1
Ph
Ph
Ph
H
N
H
N
N
N
i-PrOH
+
S
O
S
O
N
R1
N
N
R1
N
R1
Ph
Ph
Ph
—
H
( )n
COOPr-i
COOH
N
OH
OH
H2N
N
COOH
( )n
+
VIIIa–VIIIc, VIIIe–VIIIg
VIa, VIe
S
O
N
R1
R1
Ph
H
N
N
MeOH
IVa, IVb
Va–Vc
S
O
N
N
Ph
R1
( )n
COOMe
VIIa–VIIc, VIIe, VIIf
R1
Ph
H
N
O
N
H
N
R2OH
S
O
H2N
+
IVa, IVb
COOR2
N
COOH
H
N
N
H
N
Ph
R1
O
O
Vd
VIId, VIIId, VIIIh
IV, R1 = Me (a), Et (b); V, n = 1 (a), 2 (b), 3 (c); VI, R1 = Me (a), Et (e); VII, VIII, R1 = Me, n = 1 (a), 2 (b), 3 (c), R1 = Et,
n = 1 (e), 2 (f), 3 (g); VII, R1 = R2 = Me (d); VIII, R1 = Me, R2 = i-Pr (d), R1 = Et, R2 = i-Pr (h).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 10 2011

BARANOV et al.
1566
Scheme 2.
Me
Ph
Ph
N
OMe
OMe
b
S
N
S
O
Me
a
R1
R1
Ph
+
IX
IVa, IVb
N
N
Ph
H
H
Et
Et
O
O
N
N
c
S
Ph
Ph
X
H
N
O
H
N
d
H2N
COOH
O
N
H
O
Va
XI
known 1,3-diethyl-5,5-diphenyl-2-thioxoimidazolidin-
4-one (X) was formed (Scheme 2, c). In addition,
prolonged heating of acid Va with imidazolidinethione
IVa (8 h) or compound IVb (10 h) in isopropyl alcohol
resulted in the formation of well known hydantoin XI
via cyclization of the initial acid [9] (Scheme 2, d).
orientation of the isopropoxycarbonyl group with
respect to the bicyclic fragment is similar to that found
for structurally related compound XIII which was pre-
sumed to crystallize as racemate taking into account
steric repulsion between the carboxypropyl and ethyl
substituents in chiral associate [15].
We succeeded in obtaining single crystals suitable
for X-ray analysis only from isopropyl esters VIIIc
and VIIIg. According to the X-ray diffraction data,
these compounds crystallized as racemates (space
group P1). Thioglycolurils VIIIc and VIIIg were char-
acterized by slightly different molecular structures,
though their geometric parameters were consistent
with those typical of structurally related compounds
[9–13, 15, 16]. The imidazolidine rings in molecule
VIIIc have twist conformation with the C1 and C3
atoms deviating by 0.096(3)–0.167(3) and 0.149(3)–
0.211(3) Å, respectively, from the plane formed by the
other atoms in the ring. The imidazolidine rings in
molecule VIIIg have envelope conformation, and
deviations of the C3 and C1 atoms were 0.341(3) and
0.331(3) Å, respectively. The dihedral angle between
the mean-square planes of the imidazolidine rings is
64.3(2)° in VIIIc and 68.6(2)° in VIIIg; in both mole-
cules the phenyl groups on C1 and C3 are oriented cis
with respect to each other. The isopropoxycarbonyl-
propyl groups on the N3 atom in VIIIc and VIIIg have
similar synclinal conformations with the torsion angle
C19C20C21C22 equal to 70.9(2)° (VIIIc) or 78.0(2)°
(VIIIg). The carbonyl group is synperiplanar to the
C21–C20 bond: the torsion angle O2C22C21C20 is 6.2 and
13.5° for VIIIc and VIIIg, respectively. Furthermore,
Et
Me
Ph
H
N
H
N
N
N
N
O
O
O
O
N
N
N
COOH
Ph
Et
Me
COOMe
XIII
XIV
In fact, molecules VIIIc and VIIIg in crystal are
linked to form centrosymmetric dimers by medium-
strength hydrogen bond N4–H···O1 [N···O 2.8714(18)
and 2.852(2) Å, ∠NHO 164 and 174° for VIIIc and
VIIIg, respectively]. These dimers are linked to each
other via numerous weak C–H · · · O, C–H · · · S,
C–H···H–C, and C–H···π (for VIIIc) contacts leading
to formation of three-dimensional network.
Pharmacological testing of methyl (4,6-diethyl-2-
oxo-3a,6a-diphenyl-5-thioxooctahydroimidazo[4,5-d]-
imidazol-1-yl)acetate (VIIa) and methyl (4,6-dimeth-
yl-2,5-dioxo-3a,6a-diphenyloctahydroimidazo[4,5-d]-
imidazol-1-yl)acetate (XIV) [13] taken for comparison
showed that both compounds are almost nontoxic
(LD50 > 1000 mg/kg). Glycoluril XIV revealed no
appreciable neuroprotective effect on the behavior of
animals exposed to hypoxic stress, while thioglycoluril
VIIa exhibited anxiolytic effect.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 10 2011

α-THIOUREIDOALKYLATION OF FUNCTIONALLY SUBSTITUTED UREAS: I.
1567
C25
C25
C23
C24
O3
C23
O3
C22
C24
C21
C22
O2
C21
C20
O2
C20
O1
C19
S1
C18
C19
N3
C18A
O1
C4
N2
N3
C18
C3
C2
C4
N2
S1
N1
C17A
N4
C2
N4
C17
C12
C3
C11
C16
C11
C1
C5
C13
C14
C12
N1
C1
C5
C16
C17
C13
C15
C6
C10
C15
C14
C10
C6
C9
C7
C8
VIIIc
C9
C7
C8
VIIIg
Molecular structures of isopropyl 4-(4,6-dimethyl-2-oxo-3a,6a-diphenyl-5-thioxooctahydroimidazo[4,5-d]imidazol-1-yl)butanoate
(VIIIc) and isopropyl 4-(4,6-diethyl-2-oxo-3a,6a-diphenyl-5-thioxooctahydroimidazo[4,5-d]imidazol-1-yl)butanoate (VIIIg) accord-
ing to the X-ray diffraction data
EXPERIMENTAL
Pharmacological assays were performed at the In-
stitute of Technical Chemistry (Ural Division, Russian
Academy of Sciences) in 20–22-g white outbred mice.
The H and 13C NMR spectra were recorded on
a Bruker AM-300 spectrometer at 300.13 and
75.5 MHz, respectively using DMSO-d6 as solvent and
tetramethylsilane as internal reference. The melting
points were determined on a Sanyo Gallenkamp melt-
ing point apparatus. The X-ray diffraction data for
compounds VIIIc and VIIIg were obtained on a Smart
1000 CCD diffractometer (MoKα irradiation, graphite
monochromator, ω-scanning). The structures were
solved by the direct method and were refined by F2hkl
by the least-squares procedure in full-matrix aniso-
tropic approximation. Hydrogen atoms in the NH
groups were localized by Fourier difference syntheses
of electron density. The positions of hydrogen atoms in
methyl and methylene groups were calculated on the
basis of geometry considerations. The positions of all
hydrogen atoms were refined according to the riding
model. The principal crystallographic data and refine-
ment parameters are given in table. All calculations
were performed using SHELXTL PLUS software
package [17].
1
1,3-Dialkyl-4,5-dihydroxy-4,5-diphenylimidazoli-
dine-2-thiones IVa and IVb were synthesized by con-
densation of N,N′-dimethyl- and N,N′-diethylthioureas
with 1,2-diphenylethane-1,2-dione [18, 19]. Ureido
acids Va–Vd were obtained by reaction of the corre-
sponding amino acids [glycine, β-alanine, γ-amino-
butyric acid, and N-(aminoacetyl)glycine] with potas-
sium cyanate [20].
Thioglycolurils VIa and VIe (general procedure).
A solution of 4 mmol of imidazolidinethione IVa or
IVb and 4 mmol of ureido acid Va in 40 ml of
isopropyl alcohol containing 0.6 ml of concentrated
hydrochloric acid was heated for 1 h under reflux. The
mixture was evaporated to dryness, the residue was
treated with diethyl ether to remove benzil, the precip-
itate (a mixture of compounds VIa and VIIIa or VIe
and VIIIe) was treated with 5 ml of 5% aqueous alkali
under stirring over a period of 5 min at room tempera-
ture, and the precipitate (ester VIIIa or VIIIe) was
filtered off. The filtrate was acidified to pH 1 by
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 10 2011

BARANOV et al.
1568
Principal crystallographic data and refinement parameters
for compounds VIIIc and VIIIg
adding concentrated hydrochloric acid, and the precip-
itate (acid VIa or VIe) was filtered off.
(4,6-Dimethyl-2-oxo-3a,6a-diphenyl-5-thioxo-
Parameter
VIIIc
VIIIg
octahydroimidazo[4,5-d]imidazol-1-yl)acetic acid
Formula
C25H30N4O3S C27H34N4O3S
1
(VIa). Yield 0.62 g (39%), mp 297–299°C. H NMR
Molecular weight
Temperature, K
Crystal system
Space group
Z
466.59
120
494.64
100
spectrum, δ, ppm: 2.92 s and 3.01 s (3H each, NMe),
3.54 d and 4.01 d (1H each, CH2, J = 18 Hz), 6.60–
6.90 m (4H, Harom), 6.93–7.17 m (6H, Harom), 8.90 s
(1H, NH), 12.69 br.s (1H, COOH). 13C NMR spec-
trum, δC, ppm: 31.04 and 32.28 (NMe), 43.63 (CH2),
86.61 and 90.19 (C3a, C6a); 127.21, 127.84, 128.02,
128.40, 128.61, 128.82, 132.46, 134.17 (Carom); 158.25
(C5), 170.05 (COOH), 183.15 (C2). Found, %:
C 60.54; H 5.19; N 14.19; S 8.00. C20H20N4O3S. Cal-
culated, %: C 60.59; H 5.08; N 14.13; S 8.09.
Triclinic
P-1
Triclinic
P-1
2
2
a, Å
08.5592(6)
11.2734(7)
9.2016(15)
9.7183(16)
b, Å
c, Å
12.9535(8) 15.919(3)000
α, deg
75.9490(10)
87.0650(10)
93.158(8)
β, deg
90.050(10)
[2-(4,6-Dimethyl-2-oxo-3a,6a-diphenyl-5-thioxo-
octahydroimidazo[4,5-d]imidazol-1-yl)-1-oxoethyl-
amino]acetic acid (VIe). Yield 0.32 g (18%), mp 288–
γ, deg
V, Å3
82.4420(10) 113.261(6)00
1201.73(13)
1.289
1305.4(4)
1.258
1
d
calc, g/cm3
290°C. H NMR spectrum, δ, ppm: 2.91 s and 2.95 s
μ, cm–1
1.690
1.590
(3H each, NMe), 3.52 d and 4.15 d (1H each, CH2, J =
17.3 Hz), 3.68–3.85 m (2H, CH2), 6.60–6.93 m (4H,
F(000)
0496
0528
Harom), 6.95–7.20 m (6H, Harom), 8.09 t (1H, NH, J =
2θmax, deg
0058
0058
5.5 Hz), 8.88 s (1H, NH), 12.55 br.s (1H, COOH).
13C NMR spectrum, δC, ppm: 30.95 and 32.30 (NMe),
40.65 (CH2), 44.28 (CH2), 86.46 and 90.37 (C3a, C6a);
127.56, 128.01, 128.40, 128.58, 128.78, 132.38,
134.18 (Carom); 158.37 and 167.90 (C=O), 170.98
(COOH), 183.07 (C=S). Found, %: C 58.20; H 5.16;
N 15.41; S 7.14. C22H23N5O4S. Calculated, %:
C 58.26; H 5.11; N 15.44; S 7.07.
Total number of reflections
13251
14476
Number of independent
reflections
06346
04615
00302
06917
04327
00320
Number of reflections
with I > 2σ(I)
Number of refined
parameters
R1
0.0519
0.1092
1.0070
0.0563
0.1417
1.0080
Methyl and isopropyl (4,6-dialkyl-2-oxo-3a,6a-
diphenyl-5-thioxooctahydroimidazo[4,5-d]imidazol-
1-yl)alkanoates VIIa–VIIf and VIIIa–VIIIh (general
procedure). A solution of 4 mmol of compound IVa or
IVb and 4 mmol of ureido acid Va–Vd in 20 ml of
methanol or 40 ml of propan-2-ol containing 0.6 ml of
concentrated hydrochloric acid was heated for 1 h (in
the synthesis of VIIa, VIIb, VIIe, and VIIIb), 2 h (in
the synthesis of VIId, VIIf, VIIId, and VIIIh), 3 h (in
the synthesis of VIIc, VIIIc, VIIIf, and VIIIg), 8 h (in
the synthesis of VIIIa), or 10 h (in the synthesis of
VIIIe). The mixture was kept for 3 days at room tem-
perature, and the precipitate was filtered off, washed
on a filter with diethyl ether to remove benzil, and
recrystallized from methanol. After separation of ester
VIIIe–VIIIh, the filtrate was kept for 3 days, and the
precipitate of hydantoin X was filtered off.
wR2
Goodness of fit
Residual electron density,
0.369/–0.270 0.753/–0.597
e×Å–3 (dmax/dmin
)
spectrum, δ, ppm: 2.93 s and 2.98 s (3H each, NMe),
3.65 s (3H, OMe), 3.77 d and 4.25 d (1H each, CH2,
J = 17.8 Hz), 6.62–6.99 m (4H, Harom), 7.01–7.23 m
(6H, Harom), 8.92 s (1H, NH). 13C NMR spectrum, δC,
ppm: 31.01 and 32.31 (NMe), 43.47 (CH2), 52.03
(OMe), 86.74 and 90.11 (C3a, C6a); 127.18, 127.76,
128.05, 128.42, 128.67, 128.85, 132.28, 133.98 (Carom);
158.18 (C2), 169.30 (COO), 183.00 (C5). Found, %:
C 61.36; H 5.39; N 13.68; S 7.74. C21H22N4O3S. Cal-
culated, %: C 61.44; H 5.40; N 13.65; S 7.81.
Methyl 3-(4,6-dimethyl-2-oxo-3a,6a-diphenyl-
5-thioxooctahydroimidazo[4,5-d]imidazol-1-yl)pro-
panoate (VIIb). Yield 1.00 g (59%), mp 205–207°C.
1H NMR spectrum, δ, ppm: 2.42–2.54 m (1H, CH2),
Methyl (4,6-dimethyl-2-oxo-3a,6a-diphenyl-5-
thioxooctahydroimidazo[4,5-d]imidazol-1-yl)acetate
1
(VIIa). Yield 1.07 g (65%), mp 292–294°C. H NMR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 10 2011

α-THIOUREIDOALKYLATION OF FUNCTIONALLY SUBSTITUTED UREAS: I.
1569
2.67–2.77 m (1H, CH2), 2.90 s and 3.08 s (3H each,
NMe), 3.01–3.11 m (1H, CH2), 3.56 s (3H, OMe),
3.64–3.75 m (1H, CH2), 6.58–6.90 m (4H, Harom),
6.92–7.21 m (6H, Harom), 8.85 s (1H, NH). 13C NMR
spectrum, δC, ppm: 30.76 and 32.63 (NMe), 33.52
(CH2), 38.27 (CH2), 51.45 (OMe), 86.69 and 90.52
(C3a, C6a); 128.10, 128.44, 128.74, 128.86, 132.19,
133.59 (Carom); 158.56 (C2), 170.99 (COO), 182.96
(C5). Found, %: C 62.19; H 5.74; N 13.27; S 7.40.
C22H24N4O3S. Calculated, %: C 62.24; H 5.70;
N 13.20; S 7.55.
C6a); 127.05, 127.22, 127.43, 127.79, 128.00, 128.33,
128.86, 129.06, 132.44, 134.25 (Carom); 158.28 (C2);
169.28 (COO); 182.94 (C5). Found, %: C 62.88;
H 5.94; N 12.82; S 7.27. C23H26N4O3S. Calculated, %:
C 62.99; H 5.98; N 12.78; S 7.31.
Methyl 3-(4,6-diethyl-2-oxo-3a,6a-diphenyl-5-
thioxooctahydroimidazo[4,5-d]imidazol-1-yl)propa-
noate (VIIf). Yield 1.03 g (57%), mp 230–232°C.
1H NMR spectrum, δ, ppm: 1.16 t (3H, Me, J =
6.6 Hz), 1.32 t (3H, Me, J = 7.4 Hz), 2.50– 2.70 m
(2H, CH2), 3.01–3.16 m (1H, CH2), 3.11–3.26 m (1H,
CH2), 3.40–3.47 m (1H, CH2), 3.44–3.52 m (1H, CH2),
3.57 s (3H, OMe), 3.54–3.71 m (1H, CH2), 3.68–
3.86 m (1H, CH2), 6.68–6.92 m (4H, Harom), 6.94–
7.25 m (6H, Harom), 8.71 s (1H, NH). 13C NMR spec-
trum, δC, ppm: 13.50, 14.39 (Me); 33.57, 37.68, 40.38
(CH2); 51.50 (OCH3); 87.21, 91.66 (C3a, C6a); 126.98,
127.16, 127.71, 127.94, 128.05, 128.33, 128.91,
129.03, 132.21, 133.80 (Carom); 158.61 (C2); 171.03
(COO); 182.61 (C5). Found, %: C 63.74; H 6.28;
N 12.37; S 7.01. C24H28N4O3S. Calculated, %:
C 63.69; H 6.24; N 12.38; S 7.09.
Methyl 4-(4,6-dimethyl-2-oxo-3a,6a-diphenyl-
5-thioxooctahydroimidazo[4,5-d]imidazol-1-yl)-
butanoate (VIIc). Yield 0.89 g (51%), mp 227–229°C.
1H NMR spectrum, δ, ppm: 1.56–1.73 m (1H, CH2),
1.84–1.97 m (1H, CH2), 2.26–2.38 m (2H, CH2), 2.72–
2.82 m (1H, CH2), 2.93 s and 3.09 s (3H, NMe), 3.36–
3.57 m (1H, CH2), 3.54 s (3H, OMe), 6.60–6.93 m
(4H, Harom), 6.95–7.26 m (6H, Harom), 8.75 s (1H, NH).
13C NMR spectrum, δC, ppm: 24.47 (CH2), 30.45
(CH2), 30.61 and 32.60 (NMe), 41.54 (CH2), 51.24
(OMe), 86.70 and 90.55 (C3a, C6a); 127.00, 128.12,
128.37, 128.74, 128.79, 132.37, 133.55 (Carom); 158.61
(C2), 172.83 (COO), 182.90 (C5). Found, %: C 63.08;
H 5.95; N 12.72; S 7.25. C23H26N4O3S. Calculated, %:
C 62.99; H 5.98; N 12.78; S 7.31.
Isopropyl (4,6-dimethyl-2-oxo-3a,6a-diphenyl-5-
thioxooctahydroimidazo[4,5-d]imidazol-1-yl)acetate
(VIIIa). Yield 1.38 g (79%), mp 239–241°C. 1H NMR
spectrum, δ, ppm: 1.19 d and 1.22 d (3H each, Me, J =
6.4 Hz), 2.94 s and 3.00 s (3H each, NMe), 3.73 d and
4.19 d (1H each, CH2, J = 17.8 Hz), 4.85–4.98 m (1H,
OCH), 6.60–6.93 m (4H, Harom), 6.95–7.20 m (6H,
Methyl [2-(4,6-dimethyl-2-oxo-3a,6a-diphenyl-5-
thioxooctahydroimidazo[4,5-d]imidazol-1-yl)-1-oxo-
ethylamino]acetate (VIId). Yield 0.65 g (35%),
mp 271–273°C. 1H NMR spectrum, δ, ppm: 2.91 s and
2.96 s (3H each, NMe), 3.58 d and 4.16 d (1H each,
CH2, J = 16.9 Hz), 3.62 s (3H, OMe), 3.74–3.93 m
(2H, CH2), 6.60–6.93 m (4H, Harom), 6.95–7.20 m (6H,
Harom), 8.21 t (1H, NH, J = 6.7 Hz), 8.87 s (1H, NH).
13C NMR spectrum, δC, ppm: 30.95 and 32.22 (NMe),
40.59 (CH2), 44.29 (CH2), 51.64 (OMe), 86.48 and
90.37 (C3a, C6a); 127.17, 128.01, 128.41, 128.58,
128.79, 132.38, 134.18 (Carom); 158.36 and 168.08
(CO), 170.08 (COO), 183.08 (C=S). Found, %:
C 59.19; H 5.34; N 15.03; S 6.75. C23H25N5O4S. Cal-
culated, %: C 59.08; H 5.39; N 14.98; S 6.86.
H
arom), 8.94 s (1H, NH). 13C NMR spectrum, δC, ppm:
21.39 and 21.45 (Me), 30.99 and 32.27 (NMe), 43.84
(CH2), 68.35 (OCH), 86.76 and 90.04 (C3a, C6a);
127.16, 127.76, 128.03, 128.38, 128.65, 128.82,
132.35, 134.04 (Carom); 158.15 (C2), 168.15 (COO),
183.14 (C5). Found, %: C 62.94; H 5.85; N 12.80;
S 7.36. C23H26N4O3S. Calculated, %: C 62.99; H 5.98;
N 12.78; S 7.31.
Isopropyl 3-(4,6-dimethyl-2-oxo-3a,6a-diphenyl-
5-thioxooctahydroimidazo[4,5-d]imidazol-1-yl)pro-
panoate (VIIIb). Yield 1.05 g (58%), mp 190–192°C.
1H NMR spectrum, δ, ppm: 1.16 d (6H, Me, J =
6.2 Hz), 2.36–2.47 m and 2.61–2.71 m (1H each,
CH2), 2.92 s and 3.09 s (3H each, NMe), 3.00–3.10 m
and 3.49–3.59 m (1H each, CH2), 3.64–3.74 m (1H,
OCH), 6.60–6.93 m (4H, Harom), 6.95–7.20 m (6H,
Methyl (4,6-diethyl-2-oxo-3a,6a-diphenyl-5-
thioxooctahydroimidazo[4,5-d]imidazol-1-yl)acetate
1
(VIIe). Yield 1.28 g (73%), mp 215–217°C. H NMR
H
arom), 8.86 s (1H, NH). 13C NMR spectrum, δC, ppm:
spectrum, δ, ppm: 1.15–1.29 m (6H, Me), 3.05–3.76 m
(4H, CH3CH2), 3.66 s (3H, OMe), 3.77 d and 4.28 d
(1H each, CH2, J = 17.8 Hz), 6.76–6.94 m (4H, Harom),
6.96–7.23 m (6H, Harom), 8.80 s (1H, NH). 13C NMR
spectrum, δC, ppm: 13.54 and 14.19 (Me); 39.69,
40.11, 42.99 (CH2); 52.13 (OMe); 87.48, 91.03 (C3a,
21.49 (Me), 30.75 and 32.65 (NMe), 33.98 (CH2),
38.16 (CH2), 67.42 (OCH), 86.72 and 90.48 (C3a, C6a);
127.06, 127.31, 127.77, 128.10, 128.44, 128.74,
128.86, 132.19, 133.57 (Carom); 158.54 (C2), 170.09
(COO), 182.95 (C5). Found, %: C 63.76; H 6.22;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 10 2011

BARANOV et al.
1570
N 12.35; S 7.11. C24H28N4O3S. Calculated, %:
C 63.69; H 6.24; N 12.38; S 7.09.
Isopropyl 3-(4,6-diethyl-2-oxo-3a,6a-diphenyl-5-
thioxooctahydroimidazo[4,5-d]imidazol-1-yl)propa-
noate (VIIIf). Yield 1.27 g (66%), mp 197–199°C.
1H NMR spectrum, δ, ppm: 1.15 t (3H, Me, J =
6.9 Hz), 1.16 d (6H, Me, J = 6.3 Hz), 1.32 t (3H, Me,
J = 6.8 Hz), 2.41–2.65 m (2H, CH2), 3.01–3.14 m (1H,
CH2), 3.11–3.23 m (2H, CH2), 3.35–3.45 m (1H, CH2),
3.43–3.56 m (2H, CH2), 3.59–3.69 m (1H, CH2), 3.71–
3.82 m (1H, CH2), 4.79–4.92 m (1H, OCH), 6.63–
6.95 m (4H, Harom), 6.97–7.23 m (6H, Harom), 8.70 s
(1H, NH). 13C NMR spectrum, δC, ppm: 13.47, 14.37
(Me); 21.57 (2C, Me); 34.00, 37.59, 39.36 (CH2);
67.45 (OCH); 87.24, 91.64 (C3a, C6a); 127.31, 127.77,
128.06, 128.31, 128.91, 129.03, 132.30, 133.89
(Carom); 158.58 (C2); 170.09 (COO); 182.68 (C5).
Found, %: C 64.90; H 6.76; N 11.63; S 6.72.
C26H32N4O3S. Calculated, %: C 64.97; H 6.71;
N 11.66; S 6.67.
Isopropyl 4-(4,6-dimethyl-2-oxo-3a,6a-diphenyl-
5-thioxooctahydroimidazo[4,5-d]imidazol-1-yl)-
butanoate (VIIIc). Yield 1.30 g (70%), mp 186–
1
188°C. H NMR spectrum, δ, ppm: 1.11 d and 1.12 d
(3H, Me, J = 5.9 Hz), 1.55–1.70 m (1H, CH2), 1.82–
1.96 m (1H, CH2), 2.24–2.28 m (2H, CH2), 2.71–
2.81 m (1H, CH2), 2.93 s and 3.09 s (3H each, NMe),
3.39–3.52 m (1H, CH2), 4.75–4.89 m (1H, CH), 6.60–
6.93 m (4H, Harom), 6.95–7.20 m (6H, Harom), 8.78 s
(1H, NH). 13C NMR spectrum, δC, ppm: 21.53 (Me),
24.57 (CH2), 30.65 (NMe), 31.05 (CH2), 32.65 (NMe),
41.59 (CH2), 67.09 (OCH), 86.70 and 90.58 (C3a, C6a);
127.03, 128.14, 128.40, 128.77, 128.82, 132.38,
133.58 (Carom); 158.65 (C2), 171.88 (COO), 182.91
(C5). Found, %: C 64.33; H 6.53; N 11.97; S 6.90.
C25H30N4O3S. Calculated, %: C 64.35; H 6.48;
N 12.01; S 6.87.
Isopropyl 4-(4,6-diethyl-2-oxo-3a,6a-diphenyl-5-
thioxooctahydroimidazo[4,5-d]imidazol-1-yl)buta-
noate (VIIIg). Yield 1.32 g (67%), mp 187–189°C.
1H NMR spectrum, δ, ppm: 1.13 d (6H, Me, J =
6.2 Hz), 1.17 t and 1.33 t (3H each, Me, J = 7 Hz),
1.71–1.81 m (1H, CH2), 2.24–2.29 m (2H, CH2), 2.83–
2.96 m (1H, CH2), 3.00–3.14 m (1H, CH2), 3.18–
3.32 m (1H, CH2), 3.44–3.54 m (1H, CH2), 3.57–
3.68 m (1H, CH2), 3.75–3.87 m (1H, CH2), 4.78–
4.91 m (1H, OCH), 6.67–6.92 m (4H, Harom), 6.94–
7.24 m (6H, Harom), 8.61 s (1H, NH). 13C NMR spec-
trum, δC, ppm: 13.52, 14.55 (Me); 21.52 (2C, Me);
24.56, 31.14, 38.98, 39.17, 40.94 (CH2); 66.96 (OCH);
87.10, 91.80 (C3a, C6a); 127.20, 127.74, 128.07,
128.18, 128.88, 128.93, 132.44, 133.91 (Carom); 158.71
(C2); 171.83 (COO); 182.74 (C5). Found, %: C 65.68;
H 6.90; N 11.20; S 6.43. C27H34N4O3S. Calculated, %:
C 65.56; H 6.93; N 11.33; S 6.48.
Isopropyl [2-(4,6-dimethyl-2-oxo-3a,6a-diphenyl-
5-thioxooctahydroimidazo[4,5-d]imidazol-1-yl)-1-
oxoethylamino]acetate (VIIId). Yield 1.29 g (65%),
1
mp 225–227°C. H NMR spectrum, δ, ppm: 1.18 d
(6H, Me, J = 5.9 Hz), 2.91 s and 2.95 s (3H each,
NMe), 3.52 d and 4.16 d (1H each, CH2, J = 16.9 Hz),
3.71–3.88 m (2H, CH2), 4.83–4.95 m (1H, OCH),
6.60–6.93 m (4H, Harom), 6.95–7.20 m (6H, Harom),
8.23 t (1H, NH, J = 5.7 Hz), 8.90 s (1H, NH).
13C NMR spectrum, δC, ppm: 21.52 (Me), 30.92 and
32.30 (NMe), 40.91 (CH2), 44.29 (CH2), 67.98 (OCH),
86.49 and 90.36 (C3a, C6a); 127.16, 128.02, 128.42,
128.61, 128.81, 132.41, 134.19 (Carom); 158.37 and
168.04 (C=O), 169.13 [C(O)O], 183.07 (C=S). Found,
%: C 60.66; H 5.93; N 14.10; S 6.39. C25H29N5O4S.
Calculated, %: C 60.59; H 5.90; N 14.13; S 6.47.
Isopropyl (4,6-diethyl-2-oxo-3a,6a-diphenyl-5-
thioxooctahydroimidazo[4,5-d]imidazol-1-yl)acetate
(VIIIe). Yield 1.29 g (69%), mp 199–201°C. 1H NMR
spectrum, δ, ppm: 1.11–1.31 m (12H, Me), 3.03–
3.19 m (1H, CH2), 3.24–3.35 m and 3.53–3.67 m (1H
each, CH2), 3.65– 3.76 m (2H, CH2), 3.77 d and 4.11 d
(1H each, CH2, J = 17.6 Hz), 4.88–5.00 m (1H, OCH),
6.70–6.93 m (4H, Harom), 6.95–7.25 m (6H, Harom),
8.82 s (1H, NH). 13C NMR spectrum, δC, ppm: 13.56,
14.11 (Me); 21.48 (2C, Me); 39.78, 40.00, 43.53
(CH2); 68.34 (OCH); 87.38, 91.07 (C3a, C6a); 127.43,
127.78, 127.85, 128.23, 128.75, 128.93, 132.47,
134.33 (Carom); 158.19 (C2); 168.05 (COO); 182.85
(C5). Found, %: C 64.41; H 6.46; N 11.93; S 6.90.
C25H30N4O3S. Calculated, %: C 64.35; H 6.48;
N 12.01; S 6.87.
Isopropyl [2-(4,6-diethyl-2-oxo-3a,6a-diphenyl-5-
thioxooctahydroimidazo[4,5-d]imidazol-1-yl)-1-oxo-
ethylamino]acetate (VIIIh). Yield 1.61 g (77%),
mp 211–213°C. 1H NMR spectrum, δ, ppm: 1.16 t (3H,
Me, J = 7.3 Hz), 1.19 d (3H, Me, J = 5.5 Hz), 1.19 d
(3H, Me, J = 6.4 Hz), 1.27 t (3H, Me, J = 6.4 Hz),
3.09–3.27 m (2H, CH2), 3.57–3.70 m (2H, CH2), 3.75–
3.89 m (4H, CH2), 4.82–4.97 m (1H, OCH), 6.76–
6.98 m (4H, Harom), 7.00–7.29 m (6H, Harom), 8.15 t
(1H, NH, J = 5.5 Hz), 8.75 s (1H, NH). 13C NMR
spectrum, δC, ppm: 13.51, 14.04 (Me); 21.50 (2C, Me);
25.44, 40.87, 43.79 (CH2); 67.96 (OCH); 87.11, 91.35
(C3a, C6a); 127.51, 127.74, 128.03, 128.20, 128.62,
128.85, 132.45, 134.44 (Carom); 158.39, 167.91 (C=O);
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 10 2011

α-THIOUREIDOALKYLATION OF FUNCTIONALLY SUBSTITUTED UREAS: I.
1571
8. Granik, V.G., Lekarstva (Medicines), Moscow: Vuzov-
169.09 (COO); 182.94 (C=S). Found, %: C 61.99;
H 6.46; N 13.30; S 6.01. C27H33N5O4S. Calculated, %:
C 61.93; H 6.35; N 13.37; S 6.12.
skaya Kniga, 2001, p. 150.
9. Kravchenko, A.N., Sigachev, A.S., Maksareva, E.Yu.,
Gazieva, G.A., Trunova, N.S., Lozhkin, B.V., Pivi-
na, T.S., Il’in, M.M., Lysenko, K.A., Nelyubina, Yu.V.,
Davankov, V.A., Lebedev, O.V., Makhova, N.N., and
Tartakovskii, V.A., Izv. Ross. Akad. Nauk, Ser. Khim.,
2005, p. 680.
10. Kravchenko, A.N., Lysenko, K.A., Chikunov, I.E.,
Belyakov, P.A., Il’in, M.M., Baranov, V.V., Nelyubi-
na, Yu.V., Davankov, V.A., Pivina, T.S., Makhova, N.N.,
and Antipin, M.Yu., Izv. Ross. Akad. Nauk, Ser. Khim.,
2009, p. 390.
11. Kravchenko, A.N., Sigachev, A.S., Belyakov, P.A.,
Il’in, M.M., Lysenko, K.A., Davankov, V.A., Lebe-
dev, O.V., Makhova, N.N., and Tartakovskii, V.A., Izv.
Ross. Akad. Nauk, Ser. Khim., 2009, p. 1229.
12. Gazieva, G.A., Lozhkin, P.V., Baranov, V.V., Nelyubi-
na, Yu.V., Kravchenko, A.N., and Makhova, N.N., Izv.
Ross. Akad. Nauk, Ser. Khim., 2009, p. 2408.
1,3-Diethyl-5,5-diphenyl-2-thioxoimidazolidin-
4-one (X). Yield 0.05–0.08 g (4–6%), mp 133–135°C.
1H NMR spectrum, δ, ppm: 0.46 t (3H, Me, J = 7 Hz),
1.15 t (3H, Me, J = 7.3 Hz), 3.71–3.84 m (2H, CH2),
3.78–3.89 m (2H, CH2), 7.12–7.23 m (4H, Harom),
7.43–7.54 m (6H, Harom). 13C NMR spectrum, δC, ppm:
11.70 and 12.67 (Me), 36.57 and 40.24 (CH2), 76.21
(C5); 127.96, 129.10, 129.16, 135.72 (Carom); 173.41
(C4), 179.69 (C2). Found, %: C 70.26; H 6.19; N 8.67;
S 9.93. C19H20N2OS. Calculated, %: C 70.34; H 6.21;
N 8.63; S 9.88.
This study was performed under financial support
by the Chemistry and Materials Science Department of
the Russian Academy of Sciences (program “Medi-
cinal and Biomolecular Chemistry,” no. OKh-9).
13. Baranov, V.V., Nelyubina, Yu.V., Kravchenko, A.N., and
Makhova, N.N., Izv. Ross. Akad. Nauk, Ser. Khim.,
2010, p. 1395.
REFERENCES
1. Lebedev, O.V., Khmel’nitskii, L.I., Epishina, L.V., Suvo-
rova, L.I., Zaikonnikova, I.V., Zimakova, I.E., Kir-
shin, S.V., Karpov, A.M., Chudnovskii, V.S., Povstya-
noi, M.V., and Eres’ko, V.A., Tselenapravlennyi poisk
novykh neirotropnykh preparatov (Purposeful Search for
New Neurotropic Agents), Riga: Zinatne, 1983, p. 81.
14. Organikum. Organisch-chemisches Grundpraktikum,
Becker, H. et al., Eds., Berlin: Wissenschaften, 1976,
15th edn., p. 554.
15. Lyssenko, K.A., Golovanov, D.G., Kravchenko, A.N.,
Shikunov, I.E., Lebedev, O.V., and Makhova, N.N.,
Mendeleev Commun., 2004, p. 105.
16. Kravchenko, A.N., Maksareva, E.Yu., Belyakov, P.A,
Sigachev, A.S., Chegaev, K.Yu., Lysenko, K.A., Lebe-
dev, O.V., and Makhova, N.N., Izv. Ross. Akad. Nauk,
Ser. Khim., 2003, p. 180.
17. Sheldrick, G.M., SHELXTL v. 5.10, Structure Deter-
mination Software Suit, Madison, Wisconsin, USA:
Bruker AXS, 1998.
2. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
Moscow: Novaya Volna, 2010, 16th ed., vol. 1, p. 86.
3. Bakibaev, A.A., Akhmedzhanov, R.R., Yagovkin, A.Yu.,
Novozheeva, T.P., Filimonov, V.D., and Saratikov, A.S.,
Khim.-Farm. Zh., 1993, vol. 27, no. 6, p. 29.
4. Vikharev, Yu.B., Anikina, L.V., Chikunov, I.E., Siga-
chev, A.S., Kravchenko, A.N., Shklyaev, Yu.V., and
Makhova, N.N., Vopr. Biol. Med. Farm. Khim., 2006,
no. 2, p. 12.
18. Broan, C.J., Butler, A.R., Reed, D., and Sadler, I.H.,
J. Chem. Soc., Perkin Trans. 2, 1989, p. 731.
5. Eres’ko, V.A., Epishina, L.V., Lebedev, O.V., Povstya-
noi, M.V., Khmel’nitskii, L.I., and Novikov, S.S., Izv.
Akad. Nauk SSSR, Ser. Khim., 1980, p. 1594.
19. Baranov, V.V., Nelyubina, Yu.V., Lysenko, K.A., and
Kravchenko, A.N., Mendeleev Commun., 2009, vol. 19,
p. 211.
6. Slezak, F.B., Bluestone, H., Magee, T.A., and Wotiz, J.H.,
J. Org. Chem., 1962, vol. 27, p. 2181.
7. Verner, J., Taraba, J., and Potacek, M., Tetrahedron Lett.,
20. Kravchenko, A.N., Chikunov, I.E., Chegaev, K.A., and
Baranov, V.V., Sintezy organicheskikh soedinenii (Syn-
theses of Organic Compounds), Egorov, M.P., Ed.,
Moscow: Maks, 2008, vol. 3, p. 143.
2002, vol. 43, p. 4833.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 10 2011