Tetrahedron Letters
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.).
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).
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.