New access to thioglycolurils by condensation of 4,5-dihydroxyimidazolidin-2-ones(thiones) with HSCN

Article abstract of DOI:10.1016/j.tetlet.2015.09.071

A general and highly effective protocol for the direct synthesis of mono- and dithioglycolurils containing various substituents at the 1,3-nitrogen atoms has been developed based on the condensation of easily accessible dihydroxyimidazolidin-2-ones with HSCN under mild reactions conditions.

Full text of DOI:10.1016/j.tetlet.2015.09.071

Tetrahedron Letters 56 (2015) 6085–6088
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New access to thioglycolurils by condensation of 4,5-
dihydroxyimidazolidin-2-ones(thiones) with HSCN
b,
a
a
Vladimir V. Baranov a, , Yulia V. Nelyubina , Angelina N. Kravchenko , Natalya G. Kolotyrkina ,
⇑
⇑
Ksenia A. Biriukova a
a N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation
b A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2015
Revised 7 September 2015
Accepted 17 September 2015
Available online 21 September 2015
A general and highly effective protocol for the direct synthesis of mono- and dithioglycolurils containing
various substituents at the 1,3-nitrogen atoms has been developed based on the condensation of easily
accessible dihydroxyimidazolidin-2-ones with HSCN under mild reactions conditions.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Thioglycolurils
Imidazolidin-2-one(thione)
HSCN
Condensation
Nitrogen- and sulfur-containing fused heterocycles have a
broad range of biological activities and are attractive compounds
for medicinal chemistry.1 Bicyclic structures containing a C–C-
bridgehead imidazolidin-2-one(thione) moiety fused with imida-
zolidin-2-one,2 tetrahydrothiophene,3 pyrrolidine4 and tetrahydro-
furan5 motifs are important classes of compounds in
pharmaceutical chemistry. Some of these compounds constitute
the core structures of commercial drugs such as biotin (which
show antimicrobial, antidiabetic and antibacterial activities).3
Our research group has significant experience in the synthesis of
similar heterocyclic systems, including tetrahydroimidazo[4,5-d]
imidazole-2,5(1H,3H)-diones(glycolurils), of which the best known
is the tranquilizer mebicar (1,3,4,6-tetramethylglycoluril).2a
Analogues of mebicar are also important: albicar (1,4-diethyl-3,6-
dimethylglycoluril) and bicaret (1,3,4,6-tetraethylglycoluril), have
passed several preclinical and laboratory tests.2d–g Therefore, the
development of new strategies for the synthesis of heterocyclic
compounds incorporating the imidazolidin-2-one(thione) moiety
fused with any nitrogen- or sulfur-containing heterocycles repre-
sent a challenging task for organic and medical chemistry.
R
Ph
H
N
N
KSCN/AcOH
*
X
S
*
MeOH, reflux, 2h
N
O
R
Ph
Ph
1, 2a,b
R
N
OH
OH
*
X
*
N
Me
Ph
Ph
3, 4a,b
R
N
S
KSCN/TFA
*
S
NH
*
THF, reflux, 5h
N
O
(for 4a)
Ph
5
1, 3 X=O, R=Me
2, 4 X=S, (a) R=Me, (b) R=Et
Me
Scheme 1. Reactions of 4,5-Ph2DHI 3 and 4,5-Ph2DHIT 4 with KSCN/H+.
prepared by the reaction of either 4,5-dihydroxy-4,5-diphenylimi-
dazolidin-2-one (4,5-Ph2DHI) 3 or the analogous thiones (4,5-Ph2-
DHIT) 4a,b with KSCN/AcOH in MeOH. The reaction of 4,5-Ph2DHIT
4b with KSCN/TFA in THF has been previously reported,7 furnishing
heterocyclic system 5, in which the imidazolidine ring was fused
with an oxathiazoline ring (Scheme 1).
Recently, we reported difficult to synthesize bicyclic hetero-
cyclic structures 1 and 2, in which the imidazolidin-2-one(thione)
ring was fused with an oxazolidine ring.6 These compounds were
⇑
Corresponding authors. Fax: +7 499 135 5328 (V.V.B.), +7 095 135 5085 (Y.V.N.).
E-mail addresses: kani@server.ioc.ac.ru (V.V. Baranov), unelya@xrlab.ineos.ac.ru
Unfortunately, both of these reactions afforded only a limited
number of structures 1, 2a,b and 5 and therefore, it was of interest
(Y.V. Nelyubina).
http://dx.doi.org/10.1016/j.tetlet.2015.09.071
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

6086
V. V. Baranov et al. / Tetrahedron Letters 56 (2015) 6085–6088
R1
N
R1
to extend the range of initial DHI and DHIT substrates used in the
reaction with KSCN.
H
N
OH
OH
N
*
*
*
*
KSCN/HCl
MeOH
During the last decades, mono- and dithioglycolurils 8 and 9
have attracted the attention of many chemists. Dithioglycolurils
9 have found use as organocatalysts for the Boc protection of ami-
X
X
S
N
R2
N
R2
N
H
nes8 or for the -monobromination of 1,3-dicarbonyl compounds9
a
while monothioglycolurils have been applied as building blocks for
the synthesis of semithiobambusurils.10 Both thioglycoluril types
have been used in the template-directed crossed-Claisen conden-
sation,11 and as molecular clips.12 However, known methods for
their synthesis are limited,11b,12–15 and recently developed meth-
ods generally consist of a large number of steps.16,17 Herein, we
present a new, effective synthetic route to access monothiogly-
colurils (5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-ones) 8
6a-g, 7a-k
8a-g, 9a-k
6, 8 X = O
7, 9 X = S
R1, R2 = H, Alk, Ph
Scheme 2. Synthesis of monothioglycolurils 8 and dithioglycolurils 9.
Table 1
and
dithioglycolurils
(tetrahydroimidazo[4,5-d]imidazole-2,5
Screening of conditions for the synthesis of thioglycoluril 8a
(1H,3H)-dithiones) 9 based on the reaction of DHI 6 and DHIT 7
with KSCN in MeOH (water, acetone) in the presence of hydrochlo-
ric acid (Scheme 2).
We began our investigation by optimizing the reaction condi-
tions for the preparation of model thioglycoluril 8a from the reac-
tion of DHI 6a with KSCN. A variety of acids, solvents, reactant
molar ratios and temperatures were screened (Table 1).
Me
Me
H
N
OH
OH
N
N
*
KSCN/H
O
O
S
N
N
N
H
*
Me
Me
6a
8a
In water, the yield of thioglycoluril 8a increased (27–28%) as the
KSCN/DHI 6a molar ratio was increased (Table 1, entries 2, 3). The
use of acetone as the solvent further increased the yield of 8a to
35% (Table 1, entry 4). The replacement of water by MeOH was
found to have the greatest influence on the yield of 8a; therefore
the reaction duration and nature of the acid used were next exam-
ined (Table 1, entries 5–9). The optimal conditions for the forma-
tion of thioglycoluril 8a (78%) were determined as heating a
solution of DHI 6a (1.0 equiv) with KSCN (2.25 equiv) and HCl
(2.25 equiv) in MeOH for 30 min (Table 1, entry 6).
Entry
Solvent
Acid
T (°C)
Time (min)
KSCN equiva
Yield (%)
1
2
3
4
5
6
7
8
9
H2O
H2O
H2O
Me2CO
MeOH
MeOH
MeOH
MeOH
MeOH
HCl
HCl
HCl
HCl
HCl
HCl
HCl
AcOH
TFA
80
80
80
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
30
30
30
30
10
30
60
30
30
1.25
2.25
3.25
2.25
2.25
2.25
2.25
2.25
2.25
15
27
28
35
37
78
69
34
40
a
KSCN/acid molar ratio (1:1).
Table 2
Substrates scope for the synthesis of thioglycolurils 8 and 9
R1
N
R1
R1
NH
H
OH
O
N
N
*
*
*
KSCN/HCl
X
X
X
S
NH
N
R2
N
R2
N
H
O
OH
*
R2
10a-g, 11a-k
6a-g, 7a-k
8a-g, 9a-k
Entry
DHI or DHIT
R1
R2
X
Conditions
8, 9
Yield (%) (lit)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
7a
7b
7c
7d
7e
7f
Me
H
Et
Me
Et
Me
H
Me
Et
Me
H
Ph
Me
Et
Me
H
Et
Ph
Ph
t-Bu
c-C6H11
Me
Et
Et
H
Ph
Ph
O
O
O
O
O
O
O
S
S
S
S
S
S
S
S
S
S
S
i
i
i
i
8a
8b
8c
8d
8e
8f
8g
9a
9b
9c
9d
9e
9f
78 (7115a
)
68 (5–2415a
)
67
42
57
21a
74
89
78
81
70
82
69
64
53
67
92
60
i
ii
ii
i
i
i
iii
iii
iii
iii
iii
iii
iii
iii
9
10
11
12
13
14
15
16
17
18
7g
7h
7i
7j
7k
Ph
Ph
Ph
Me
Ph
9g
9h
9i
9j
9k
(CH2)2OH
(CH2)3OH
H
H
(i) KSCN (2.25 equiv), HCl (2.25 equiv), H2O, 80 °C, 30 min.
(ii) KSCN (2.25 equiv), HCl (2.25 equiv), MeOH, reflux, 30 min.
(iii) KSCN (2.25 equiv), HCl (2.25 equiv), acetone, reflux, 30 min.
a
The second product in this reaction was 1-(tert-butyl)-3-methyl-4-thioxoimidazolidin-2-one 12.

V. V. Baranov et al. / Tetrahedron Letters 56 (2015) 6085–6088
6087
R
R
R
OH
*
N
N
N
H
X
X
X
-H2O
N
N
N
*
OH
OH
OH
R
R
R
3, 4
carbenium-iminium cation A
NCS
N
R
R
R
H
N
OH
NH2
OH
N
N
N
C
H2O
C
S
X
X
X
S
-CSO
N
N
N
OH
OH
R
R
R
D
C
B
HNCS
NH2
S
R
R
H
R
H
S
N
N
N
N
NH
OH
H
N
X
X
S
NH2
X
-H2O
N
N
N
H
-H
N
R
R
R
E
F
8, 9
X=O, S
Scheme 3. Plausible mechanism for the formation of thioglycolurils 8 and 9.
In order to extend the reaction to the synthesis of a series of
thioglycolurils 8 and 9, the range of examined DHI 6a–g and DHIT
7a–k compounds was expanded. These compounds were easily
accessible by the condensation of ureas and thioureas, respectively,
with glyoxal in water with gentle heating.10,18
Conclusion
In conclusion, we have developed a new, facile and efficient
synthetic route to thioglycolurils using easily accessible reagents,
DHI, DHIT, KSCN and HCl, proceeding under mild conditions.19 This
method proved to be suitable for the synthesis of both mono- and
dithioglycolurils 8 and 9, but it was especially effective for the syn-
thesis of dithioglycolurils 9, which were previously less accessible
than thioglycolurils 8. The advantages of this method are opera-
tional simplicity, step economy and the use of environmentally
friendly reagents. The developed method provides a powerful tool
for the synthesis of an extensive series of thioglycoluril derivatives
that have previously been difficult to synthesize.
Having a wide range of DHI 6a–g and DHIT 7a–k compounds
in hand, we investigated their reaction with KSCN/HCl under
the optimized conditions (Table 2). It was established that these
conditions were only suitable for DHI 6a–e and DHIT 7a–c
(Table 2, entries 1–5, 8–10). Because DHI 6f and 6g were poorly
soluble in MeOH, water was used as a replacement solvent
(Table 2, entries 6, 7). Acetone was used instead of MeOH for
the successful synthesis of dithioglycolurils 9d–k from DHIT
7d–k (Table 2, entries 11–18).
The structures of all novel compounds were confirmed by 1H
and 13C NMR spectroscopy and high-resolution mass spectrometry.
Single crystal X-Ray diffraction was performed for compounds 8a,c,
9b,c, 7a,c and 12 [CCDC 1050192–1050198 contains supplemen-
tary crystallographic data for these compounds].
Acknowledgment
We gratefully acknowledge Russian Foundation for Basic
Research (Grant no 14-03-00556 A) for the funding of this
research.
A plausible mechanism for the formation of thioglycolurils 8 or
9 is outlined in Scheme 3. Initially, formation of the carbenium–
iminium cation A, followed by nucleophilic attack by the NCS anion
furnishes adduct B with the OH and NCS groups located on differ-
ent sides of the imidazolidinone ring. This trans-orientation of the
OH and NCS groups prevents the intramolecular cyclization of
intermediate B to give the imidazothiazole ring. Addition of water
to the NCS group gives unstable hydroxycarbamothioic O-acid C
which after elimination of the CSO fragment gives aminol D. Addi-
tion of HNCS to the NH2 group of intermediate D generates the
thiourea containing intermediate E. Finally, protonation of the
OH group of intermediate E and subsequent elimination of H2O
forms cation F which undergoes intramolecular cyclization to fur-
nish the desired thioglycolurils 8 or 9.
Supplementary data
Supplementary data (experimental procedures, analytical and
spectral data of all synthesized compounds, X-ray data) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2015.09.071.
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dihydroxyimidazolidin-2-one(thione) 6 or 7 (0.01 mol) and KSCN (2.19 g,
0.0225 mol) in MeOH (for 8a–e, 9a–c) (30 mL) or Me2CO (for 9d–k) (35 mL) at
room temperature. The precipitate was filtered and washed with MeOH or
Me2CO, respectively. The filtrate was heated at reflux for 30 min with stirring.
Then the reaction mixture was cooled and kept for 12–48 h at rt to furnish a
precipitate. The precipitate was filtered and washed with MeOH or Me2CO to
give product 8a–e or 9a–k.
Synthesis of monothioglycoluril 8f. Hydrochloric acid (35.5%) (2 ml, 0.0225 mol)
was added to a solution of 1-(tert-butyl)-4,5-dihydroxy-3-methylimidazolidin-2-
one 6f (1.88 g, 0.01 mol) and KSCN (2.19 g, 0.0225 mol) in H2O (20 mL) at rt. The
reaction mixture was stirred at 80 °C for 30 min and cooled. The white precipitate
of 1-(tert-butyl)-3-methyl-4-thioxoimidazolidin-2-one 12 was filtered, and
monothioglycoluril 8f was precipitated from the filtrate after standing for 24 h
at rt. Both precipitates were recrystallized from MeOH.
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Synthesis of monothioglycoluril 8g. Hydrochloric acid (35.5%) (2 mL, 0.0225 mol)
was added to a solution of 1-cyclohexyl-4,5-dihydroxyimidazolidin-2-one 6g
(2.00 g, 0.01 mol) and KSCN (2.19 g, 0.0225 mol) in H2O (20 mL) at rt. The reaction
mixture was stirred at 80 °C for 30 min, cooled, and kept for 12–48 h at rt to give a
white precipitate of 8g. The precipitate was filtered and washed with MeOH.
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