A new route to 1,4-disubstituted 5-thioxoperhydroimidazo[4,5-d]imidazol-2-ones

Article abstract of DOI:10.1016/S0040-4039(02)00893-6

1,4-Disubstituted 5-thioxoperhydroimidazo[4,5-d]imidazol-2-ones were prepared by one-pot criss-cross cycloaddition reactions of 1,4-disubstituted 1,4-diazabuta-1,3-dienes with HNCS and HNCO generated in situ from potassium salts by acetic acid.

Full text of DOI:10.1016/S0040-4039(02)00893-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4833–4836
A new route to 1,4-disubstituted
-thioxoperhydroimidazo[4,5-d]imidazol-2-ones
†
5
a
b
a,
Ji rˇ ´ı Verner, Jan Taraba and Milan Pot a´ cˇ ek *
a
Department of Organic Chemistry, Faculty of Science, Masaryk University of Brno, Kotl a´ rˇ sk a´ 2, 611 37 Brno, Czech Republic
Department of Inorganic Chemistry, Faculty of Science, Masaryk University of Brno, Kotl a´ rˇ sk a´ 2, 611 37 Brno, Czech Republic
b
Received 15 February 2002; revised 3 May 2002; accepted 10 May 2002
Abstract—1,4-Disubstituted 5-thioxoperhydroimidazo[4,5-d]imidazol-2-ones were prepared by one-pot criss-cross cycloaddition
reactions of 1,4-disubstituted 1,4-diazabuta-1,3-dienes with HNCS and HNCO generated in situ from potassium salts by acetic
acid. © 2002 Elsevier Science Ltd. All rights reserved.
Structures with carbamide fragments have a broad
spectrum of biological activity. For example, 1,3,4,6-
tetramethylperhydroimidazo[4,5 - d]imidazol - 2,5 - dione
was successfully used as a day-time tranquilizer and
was introduced into medical practice in 1979 under the
trimethylsilylisothiocyanate with symmetrical 1,4-diaza-
buta-1,3-dienes derived from aromatic and aliphatic
amines (Scheme 2). The criss-cross addition on 1a in
THF with trimethylsilylisothiocyanate affords 1,4-
dicyclohexylperhydroimidazo [4,5-d]imidazol-2,5-dithi-
one 4a in 53% yield, and its oxidation with 30% H O
1
name Mebicar.
2
2
4
gave 2a in 75% yield. Reaction of 1b with trimethyl-
silylisothiocyanate (dioxane, 3 h) afforded 4b (24%) at
Symmetrical compounds with this skeleton (2 or 4)
were prepared either by a condensation of N-substi-
tuted ureas with glyoxal under acidic catalysis or by a
criss-cross addition on 1.
4
room temperature.
For example, N-(t-butyl)urea with glyoxal and HCl
2
catalyst forms 2 in a 62% yield (Scheme 1).
Reactions of 1,4-diazabuta-1,3-dienes 1 are rare in the
3
literature. Thus, Sakamoto et al. described the reaction
of 1,1%-biisoquinolines with aryl and benzoyl iso-
cyanates. Takahashi described the reaction of
Scheme 2.
4
On the other hand, criss-cross cycloadditions on 2,3-
diazabuta-1,3-dienes are well documented. In 1917
5
Bailey and Moore described the reaction between some
aromatic aldazines and thiocyanic acid or cyanic acid in
acetic acid. The reaction was carried out by a slow
addition of potassium thiocyanate or cyanate into a
solution of the aldazine in acetic acid. Similarly Schantl
6
et al. prepared criss-cross products from various
Scheme 1.
aliphatic ketazines by a slow addition of an acetic acid
solution of the ketazine into aqueous potassium cya-
nate. The molar ratio of acetic acid and cyanate was
Keywords: criss-cross; cycloaddition; glyoxalimine; 1,4-diazabuta-1,3-
diene; 5-thioxoperhydroimidazo[4,5-d]imidazol-2-one.
1
:1, in slight excess over the azine. Such a modification
*
Corresponding author. Tel.: +420-5-41129306; fax: +420-5-
1211214; e-mail: potacek@chemi.muni.cz
Dedicated to Professor Jaroslav Jonas on the occasion of his 65th
birthday.
was used in order to avoid exposure of the already
formed criss-cross adduct to an acidic environment
which would cause its decomposition.
4
†
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00893-6

4
834
J. Verner et al. / Tetrahedron Letters 43 (2002) 4833–4836
In our communication we would like to report a new
and quick method for the preparation of mixed deriva-
tives, 5-thioxoperhydroimidazo[4,5-d]imidazol-2-ones 3,
substituted at positions 1 and 4 (Scheme 3). To the best
of our knowledge, this is the only method for the
synthesis of these substances.
butadienes 1a–c were prepared from glyoxal and the
corresponding amines.
7
When we tried to prepare criss-cross adducts from
simple aliphatic or aromatic 1,4-diazabuta-1,3-dienes 1
5
and HNCS or HNCO according to Bailey’s or
6
Shantl’s method, only traces of the desired products
were obtained. In some cases, the major isolated
product was the corresponding salt of the amine due to
the instability of substituted 1,4-diazabuta-1,3-dienes 1
in acid (Scheme 4).
Slow addition of the substituted 1,4-diazabuta-1,3-diene
1
into potassium isocyanate dissolved in carefully dried
acetic acid, improved the procedure. Due to the large
difference in reactivity between HNCS and HNCO, we
were able to obtain mixed cycloadducts 3 (Scheme 3) in
a one-pot procedure, when substituted 1,4-diazabuta-
1
,3-dienes 1 were added to a mixture of both acids. We
examined the influence of concentration, as well as
Scheme 3.
We attempted to synthesize these products by criss-
cross cycloaddition of HNCS and HNCO with 1,4-di-
substituted 1,4-diazabuta-1,3-dienes 1. The diaza-
Scheme 4.
Table 1. Effect of reactant concentration ratio upon composition of the reaction mixture after reaction of 1a with HNCO
and HNCS
1
a starting concentration c=0.1 mol/l (ambient temperature), 1 h
cKNCS (mol/l)
cKNCO (mol/l)
2a (mol%)
3a (mol%)
4a (mol%)
Overall yield [%]
47
42
56
52
0.10
0.10
0.10
0.10
0.10
0.15
0.21
0.40
2
3
3
7
56
65
81
82
42
32
16
11
a
a
3
0 min.
Table 2. Effect of temperature upon composition of the reaction mixture after reaction of 1a with HCNO and HCNS
a starting concentration c=0.1 mol/l (cKNCS=0.1 mol/l, cKNCO=0.2 mol/l), 1 h
1
Temperature (°C)
2a (mol%)
3a (mol%)
4a (mol%)
Overall yield (%)
1
3
4
5
0
5
3
4
3
63
70
71
33
26
26
45
49
47
Table 3. Composition of reaction mixtures after reaction of 1a–c with mixtures of acids in ratio cHNCO/cHNCS=2, (reaction
time 1 h)
R
2 (mol%)
3 (mol%)
4 (mol%)
Overall yield (%)
1a
1a
1b
1c
Cyclohexyl
Cyclohexyl
3
3
0
0
71
84
96
76
26
13
4
47
60
43
54
a
4-Methoxyphenyl
b
t-Butyl
24
a
3
0 min, cKNCO=0.25 mol/l, cKNCS=0.25 mol/l, cdiene=0.125 mol/l.
b
Vigorous agitation.

J. Verner et al. / Tetrahedron Letters 43 (2002) 4833–4836
4835
temperature, upon the composition of the reaction mix-
ture from 1a with the mixture of HCNO and HCNS.
Results are summarized in Tables 1 and 2.
References
1. Lebedev, O. V.; Khmel’nitskii, L. I.; Epishina, L. V.;
Suvorova, L. I.; Zaikonnikova, I. V.; Zimakova, I. E.;
Kirshin, S. V.; Karpov, A. M.; Chudnovskii, V. S.; et al.
The Directed Search for Neutropic Agents; Riga, 1983; pp.
81–93.
Based on the results shown in Table 1, the ratio of
concentrations cHNCO/cHNCS=2 was used for further
experiments.
2
. Bakibaev, A. A.; Akhmedzhanov, R. R.; Yagovkin, A.
Yu.; Novozheeva, T. P.; Filimonov, V. D.; Saratikov, A.
S. Pharm. Chem. J. (Engl. Transl.) 1993, 27, 401–406;
Khim. Farm. Zh. 1993, 27, 29–33.
. Sakamoto, M.; Tomimatsu, Y.; Miyazawa, K.; Tokoro, K.
Yakugaku Zasshi. 1972, 92, 1462–1467; Chem. Abstr. 1973,
The major products under these conditions were mixed
criss-cross cycloadducts 3, which were separated, for
analysis, on a silica gel column (CH Cl /acetone 5:1)
2
2
8
and characterized. Compositions of final mixtures were
analyzed by H NMR spectra and the results are pre-
3
1
sented in Table 3.
78, 97610(v).
4
5
. Takahashi, M.; Miyadai, S. Heterocycles 1990, 31, 883.
. Bailey, J. R.; Moore, N. H. J. Am. Chem. Soc. 1917, 39,
In the NMR spectrum of symmetrical molecules 2a and
4
a there was only one signal for the protons H-3a and
279–291.
H-6a, as a singlet with double intensity, l=5.26 ppm
and l=5.66 ppm, respectively. In the mixed derivative
6. Schantl, J. G.; Gstach, H.; Hebeisen, P.; Lanznaster, N.
Tetrahedron 1985, 41, 5525–5528.
3
a, the signals of these protons differ in chemical shift
7
8
. tom Dieck, H.; Renk, I. W. Chem. Ber. 1971, 104, 92–109.
. Melting points were measured on a Boetius Rapido
PHMK 73/2106 (W a¯ getechnik) instrument. TLC was car-
ried out on Silufol (Kavalier); detection was made by
(
l=5.40 ppm, l=5.52 ppm), and their coupling con-
3
stant JH3a–H6a=8.9 Hz suggests a cis orientation. The
second coupling with the proton at the neighboring
nitrogen atom appears for only one of the H-3a and
Fluotes Universal (Quazlampen, Hanau) or in I vapors.
‡
3
2
H-6a proton signals. This coupling with JH3a–H3=2
NMR spectra were recorded on Bruker Avance 300.
Hz disappears after addition of D O. The stereochem-
2
1
,4-Dicyclohexyl-5-thioxoperhydroimidazo[4,5-d]imidazol-2-
one (3a)
Mp 290–292°C. H NMR (300 MHz, DMSO-d ): 1.16–
istry of the structure 3a has been proved by X-ray
9
analysis. The crystal packing of 3a is shown in Fig. 1.
1
6
1
.80 (m, 20H), 3.38–3.45 (m, 1H), 4.11–4.19 (m, 1H), 5.40
We propose that the substituted 1,4-diazabuta-1,3-
dienes 1 react with the more reactive species in the
reaction mixture i.e. thiocyanic acid, forming an inter-
mediate (1+1 adduct), which then reacts with cyanic
acid present in excess. Under properly chosen condi-
tions product 3 predominates and the reaction repre-
sents a facile method for the preparation of such a
mixed product.
(
d, 1H, J=8.9 Hz), 5.52 (dd, 1H, J=8.9 Hz, J=2.0 Hz),
13
7
.54 (s, 1H, CO-NH), 8.94 (s, 1H, CS-NH). C NMR
(
75.5 MHz, DMSO-d ): 24.7, 25.3, 28.6, 28.9, 30.8, 31.1,
6
5
1.2, 54.3, 67.5, 67.6 (OꢀC-N-CH-CH-N-CꢀS), 67.6 (OꢀC-
N-CH-CH-N-CꢀS), 158.3 (CꢀO), 181.0 (CꢀS). MS (70 eV)
m/z (%): 325 (5), 323 (20), [M] 322 (8), 167 (9), 166 (100),
+
1
1
57 (16), 98 (63), 84 (75).
,4-Di(4-methoxyphenyl)-5-thioxoperhydroimidazo[4,5-d]-
imidazol-2-one (3b)
Mp 290–291°C (dec.). H NMR (300 MHz, DMSO-d6):
.76 (s, 3H, OCH ), 3.79 (s, 3H, OCH ), 5.96 (d, 1H,
1
3
3
3
J=8.3 Hz, OꢀC-N-CH-CH-N-CꢀS), 6.04 (d, 1H, J=8.3
Hz, OꢀC-N-CH-CH-N-CꢀS), 6.93 (2H, d, J=8.6 Hz,
ArH), 6.98 (2H, d, J=8.6 Hz, ArH), 7.32 (2H, d, J=8.6
Hz, ArH), 7.45 (2H, d, J=8.6 Hz, ArH), 8.20 (s, 1H,
13
CO-NH), 9.72 (s, 1H, CS-NH). C NMR (75.5 MHz,
DMSO-d ): 55.3 (Ar-OCH ), 55.3 (Ar-OCH ), 69.5 (OꢀC-
6
3
3
N-CH-CH-N-CꢀS), 72.0 (OꢀC-N-CH-CH-N-CꢀS), 115.0
Ar), 115.0 (Ar), 122.4 (Ar), 128.9 (Ar), 130.5 (Ar-N),
(
1
1
30.6 (Ar-N), 155.9 (Ar-O), 156.6 (Ar-O), 158.1 (CꢀO),
82.0 (CꢀS). MS (70 eV) m/z (%): 372 (8), 371 (21), 370
+
[M] (99), 311 (17), 267 (18), 253 (20), 222 (25), 221 (37),
205 (31), 190 (31), 165 (49), 150 (45), 149 (94), 134 (100).
1,4-Di(t-butyl)-5-thioxoperhydroimidazo[4,5-d]imidazol-2-
one (3c)
Mp 259–260°C. H NMR (300 MHz, DMSO-d ): 1.33 (s,
1
6
9
H, C-CH ), 1.56 (s, 9H, C-CH ), 5.42 (d, 1H, J=8.3 Hz,
3
3
OꢀC-N-CH-CH-N-CꢀS), 5.57 (dd, 1H, J=8.3 Hz, J=2.0
Hz, OꢀC-N-CH-CH-N-CꢀS), 7.50 (s, 1H, OꢀC-NH), 8.86
Figure 1. Crystal packing of compound 3a.
13
(
s, 1H, SꢀC-NH). C NMR (75.5 MHz, DMSO-d ): 28.0
6
(
OꢀC-N-C(CH ) ), 28.3 (SꢀC-N-C(CH ) ), 52.3 (OꢀC-N-
3
3
3 3
‡
1
H NMR (300 MHz) Bruker Avance in DMSO-d , at 600 MHz in
C(CH ) ), 55.6 (SꢀC-N-C(CH ) ), 68.2 (OꢀC-N-CH-CH-
N-CꢀS), 69.4 (OꢀC-N-CH-CH-N-CꢀS), 158.8 (CꢀO), 182.0
3 3
3 3
6
CD COCD3 both couplings are visible.
3

4
836
J. Verner et al. / Tetrahedron Letters 43 (2002) 4833–4836
+
(
2
(
CꢀS). MS (70 eV) m/z (%): 273 (4), 272 (14), [M] 270 (100),
refined assuming a ‘ride-on’ model. Data are deposited in
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 179213.
13 (10), 199 (42), 157 (25), 140 (42), 125 (36), 116 (28), 100
25).
9
. The X-ray data of 3a were collected on a KUMA KM-4
CCD kappa-axis diffractometer using a graphite monochro-
,
matized Mo–Ka radiation (u=0.71073 A). The structure
was solved by direct methods (Sheldrick, G. M. SHELX-97
program package; University of G o¨ ttingen, 1997; Sheldrick,
G. M. SHELXTL V 5.1; Bruker AXS GmbH.) Non-hydro-
gen atoms were refined anisotropically while hydrogen
atoms were inserted in calculated positions and isotropically
The crystal structure is composed of 3a molecules and water
which are bound into a two dimensional network by a
system of four types of hydrogen bonds: N(6)ꢁH···O(51)=
C(5) (2.876 A) between two enantiomers of the molecules
,
of 3a forming dimers. These dimers are further connected
by hydrogen bonds of water molecules through N(3)ꢁH···O
(2.868 A
).
), OꢁH···O(51)ꢀC (2.755 A), and OꢁH···S(21) (3.263
, ,
A
,