α-Ureidoalkylation of 1,3-bis(hydroxymethyl)-imidazolidin-2-one

Article abstract of DOI:10.1007/s10593-007-0217-4

The α-ureidoalkylation of imidazolidine-2,4-dione, urea, carboxylic acid amides, and sulfonamides has been studied using 1,3-bis(hydroxymethyl)- imidazolidin-2-one as ureidoalkylating agent. Methods have been developed for the synthesis of 1,3-bis(2,4-dioxoimidazolidin-1-ylmethyl)-, 1,3-bis(acetylaminomethyl)-, 1,3-bis(benzoylaminomethyl)-, 1,3- bis(phenylsulfonylaminomethyl)-, and 1,3-bis(p-toluenesulfonylaminomethyl) imidazolidin-2-ones.

Full text of DOI:10.1007/s10593-007-0217-4

Chemistry of Heterocyclic Compounds, Vol. 43, No. 11, 2007
α-UREIDOALKYLATION
OF 1,3-BIS(HYDROXYMETHYL)-
IMIDAZOLIDIN-2-ONE
G. A. Gazieva, P. V. Lozhkin, and A. N. Kravchenko
The α-ureidoalkylation of imidazolidine-2,4-dione, urea, carboxylic acid amides, and sulfonamides has
been studied using 1,3-bis(hydroxymethyl)-imidazolidin-2-one as ureidoalkylating agent. Methods have
been developed for the synthesis of 1,3-bis(2,4-dioxoimidazolidin-1-ylmethyl)-, 1,3-bis(acetyl-
aminomethyl)-, 1,3-bis(benzoylaminomethyl)-, 1,3-bis(phenylsulfonylaminomethyl)-, and 1,3-bis(p-
toluenesulfonylaminomethyl)imidazolidin-2-ones.
Keywords: 1,3-bis(R-aminomethyl)imidazolidin-2-ones, 1,3-bis(hydroxymethyl)imidazolidin-2-one,
1,3-bis(2,4-dioxoimidazolidin-1-yl)methylimidazolidin-2-one, α-ureidoalkylation.
Derivatives of imidazolidin-2-one display antispasmodic, analgetic, herbicidal, and other forms of
activity [1-4]. In the course of several years we have broadly investigated the α-ureidoalkylation of alkyl-,
hydroxyalkyl, and carboxyalkylureas, sulfamides, thiosemicarbazides, and aminoguanidine using 4,5-dihydroxy-
imidazolidin-2-ones as ureidoalkylating reagents and have developed general methods for the directed synthesis
of 1,3,4,6-tetrahydroimidazo[4.5-d]imidazole-2,5-diones [5-7] and their heteroanalogs [8, 9] substituted at the
nitrogen atom.
The aim of the present work is the investigation of the α-ureidoalkylation of 2,4-dioxoimidazolidine,
ureas, sulfamides, and acid amides using 1,3-bis(hydroxymethyl)imidazolidin-2-one (1). It is known that
compound 1 is used for cross-linking cellulose [10] and also covalent fixing on cellulose fibers of dyestuffs
containing nucleophilic groups in the molecule, including –NHR and –NHCOR. However a check on the
reaction process was effected only by UV and IR spectroscopic methods of the obtained powders [11].
O
HOH2C
N
N CH2OH
1
Furthermore, by the reaction of imidazolidin-2-one (ethylene urea) with formaldehyde in acid medium in
a variant of the one-stage synthesis (without isolating the N-hydroxymethyl derivatives of ethylene urea),
analogs of cucurbiturils [12] and linear oligomers [13, 14], have been obtained and used for cross-linking or
stabilizing polymers. There are isolated examples in the literature of aminomethylation of ethylene urea with
N-hydroxymethyl or N-methoxymethyl derivatives of amines [14, 15].
__________________________________________________________________________________________
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991; e-mail:
gaz@server.ioc.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1655-1659,
November, 2007. Original article submitted February 20, 2007.
1406
0009-3122/07/4311-1406©2007 Springer Science+Business Media, Inc.

In the first stage we studied the α-ureidoalkylation of 2,4-dioxoimidazolidine (hydantoin). Choice of
hydantoin 2 as a model compound was due to the fact that the NH group of hydantoin, located between two
carbonyl groups, is distinguished by a low reactivity, which enables avoidance of the formation of oligomers and
polymers reported in the literature [12-14]. Reactions were carried out by a procedure analogous to the
α-ureidoalkylation of ethylene urea with 4,5-dihydroxyimidazolidin-2-ones [16], under conditions of acid
catalysis during 1 h on boiling equimolar quantities of the reactants in methanol, water, and a water–isopropyl
1
alcohol mixture. Solids were isolated in all cases, the H and 13C NMR spectra of which corresponded to the
expected 1,3-bis(2,4-dioxoimidazolidin-1-ylmethyl)imidazolidin-2-one (3). The signal of the NH groups protons
was located at 10.86 ppm and corresponds to the signal of a proton at a nitrogen atom situated between two
carbonyl groups. The intensities of the signals of the protons of the methylene and ethylene groups, being
singlets, and also the NH groups, correspond completely to the structure of compound 3.
O
O
O
O
MeOH, HCl
boiling, 1 h
HN
O
NH
HN
O
N
N
2
1
N
N
NH
O
+
2
3
The yields of product 3 in methanol (70), water (64), and in the water-isopropyl alcohol mixture (59%)
were comparable. Analogous results were obtained on carrying the reaction of bis(hydroxymethyl)ethylene urea
1 with acetamide 4 in these solvents.
In the reaction of compound 1 with acid amides 4-7 in methanol in the presence of HCl the previously
undescribed 1,3-bis(acetylaminomethyl)imidazolidin-2-one (8), 1,3-bis(benzoylaminomethyl)imidazolidin-2-one
(9), 1,3-bis(phenylsulfonylaminomethyl)imidazolidin-2-one (10), and 1,3-bis(p-toluenesulfonylamino-
methyl)imidazolidin-2-one (11) were obtained.
O
X
X
X
2 H2N
4–7
N
N
1
N
N
+
H
H
8–11
4, 8 X = C(O)Me; 5, 9 X = C(O)Ph; 6, 10 X = SO2Ph; 7, 11 X = Ts
TABLE 1. Characteristics of Compounds 3, 8-11, 18
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C (solvent)
Yield, %
С
H
N
S
3
С11H14N6O5
С9H16N4O3
42.60
42.58
4.56
4.55
27.07
27.09
302-304
(DMSO-H2O, 1:1)
68-71
62-64
48-50
39-42
62-65
60-63
8
47.35
47.36
64.77
64.76
7.09
7.07
5.70
5.72
24.56
24.55
15.91
15.90
164-166 (MeOH)
9
С19H20N4O3
С17H20N4O5S2
С19H24N4O5S2
С7H12N4O6
207-209 (MeOH)
10
11
18
48.12
48.10
4.74
4.75
13.21
13.20
15.08
15.11
188-191
(Me2CO-CHCl3, 1:3)
50.41
50.43
33.85
33.88
5.34
5.35
4.90
4.87
12.39
12.38
22.56
22.57
14.15
14.17
198-200
(Me2CO-H2O, 1:1)
210-212 (H2O)
1407

TABLE 2. Spectral Characteristics of Compounds 3, 8-11, 17, 18
Com-
pound
1Н NMR spectrum, δ, ppm (J, Hz)
13C NMR spectrum, δ, ppm (J, Hz)
3
8
3.30 (4H, s, 2CH2); 3.86 (4H, s, 2CH2);
4.60 (4H, s, 2CH2); 10.86 (2H, br. s, 2NH)
40.8 (CH2), 50.0 (CH2), 50.5 (CH2),
157.5 (C=O), 159.6 (C=O), 171.9 (C=O)
1.79 (6H, s, 2CH3); 3.21 (4H, s, 2CH2);
4.41 (4H, d, J = 6.1, 2CH2);
8.38 (2H, t, J = 6.1, 2NH)
9
3.33 (4H, s, 2CH2); 4.70 (4H, d, J = 6.1, 2CH2); 41.6 (CH2), 48.5 (CH2), 127.4 (C6H5),
7.46 (6H, m, C6H5); 7.86 (4H, d, J = 6.7, C6H5);
9.01 (2H, t, J = 6.1, 2NH)
128.3 (C6H5), 131.5 (C6H5),
133.7 (C6H5), 158.9 (C=O), 167.1 (C=O)
10
11
17
18
2.79 (4H, s, 2CH2); 4.23 (4H, d, J = 6.1, 2CH2);
7.57 (6H, m, C6H5); 7.74 (4H, d, J = 7.4, C6H5);
8.37 (2H, t, J = 6.1, 2NH)
2.38 (6H, s, 2CH3); 2.88 (4H, s, 2CH2);
4.23 (4H, s, 2CH2); 7.37 (4H, d, J = 7.1, Ts);
7.65 (4H, d, J = 7.1, Ts); 8.22 (2H, br. s, 2NH) 142.6 (Ts), 157.5 (C=O)
20.9 (CH3), 39.8 (CH2), 51.8 (CH2),
126.2 (Ts), 129.4 (Ts), 138.6 (Ts),
4.43 (2H, t, J = 6.1, CH2); 6.82-6.92 (4H, m,
2H(C6H5)+2NH); 7.21 (4H, t, J = 7.4, C6H5);
7.37 (4H, d, J = 7.4, C6H5); 8.61 (2H, s, 2NH)
3.69 (4H, d, J = 5.5, 2CH2);
4.24 (2H, t, J = 5.8, CH2); 6.28 (2H, br. s, 2NH);
6.72 (2H, t, J = 5.8, 2NH)
On introducing urethane 12, ureas 13, 14, and butylsulfamide 15 into analogous reactions, products were
formed the 1H NMR spectra of which did not contain signals for the protons of the ethylene urea fragment, but in
them there were signals for the ethyl group of urethane 12, the phenyl fragment of urea 13, the ethoxycarbonyl
fragment of the N-carbamoylglycine 14, or the butyl group of sulfamide 15, for the NH groups of all the
compounds listed, and triplet signals for protons at 4.12-4.41 ppm. From their chemical shifts they may be
assigned to CH2 groups protons linking the fragments of the initial compounds 12-15. The intensities of all the
groups of protons correspond to the structure of methylene bisderivatives 16-19. This fact indicates that the
urethane, ureas, and butylsulfamide were condensed not with compound 1, but with formaldehyde. This may be
explained by the reversible hydroxymethylation reaction, due to which a certain amount of formaldehyde is
always present in solutions of compound 1.
CH2O
YNHCH2NHY
NH2
Y
16–19
12–15
12, 16 Y = COOEt, 13, 17 Y = CONHPh, 14, 18 Y = CONHCH2COOH,
15, 19 Y = SO2NHBu
Methylenebiscarbamates, ureas, and sulfamides, including compounds 16, 17, and 19 have been
obtained as by-products, initial, or intermediate products in the synthesis of various linear and heterocyclic
compounds [17-21].
Study of the α-ureidoalkylation of hydantoin, ureas, and acid amides with 1,3-bis(hydroxy-
methyl)imidazolidin-2-one 1 therefore led to the previously unknown 1,3-disubstituted imidazolidin-2-ones,
which has confirmed the possibility of using 1,3-bis(hydroxymethyl)imidazolidin-2-one as a ureidoalkylating
agent.
1408

EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on a Bruker AM-300 spectrometer (at 300 and 75 MHz
respectively) in DMSO-d6, internal standard was TMS. Melting points were determined on a Gallenkamp
instrument (Sanyo).
α-Ureidoalkylation with 1,3-Bis(hydroxymethyl)imidazolidin-2-one (1) (General Method).
Compound 1 (0.73 g, 5 mmol) and the appropriate compound 2, 4-7, 12-15 (10 mmol) were dissolved in
methanol (5 ml), conc. HCl (2 drops) was added and the mixture was boiled for 1 h. After cooling the reaction
mixture, the precipitated solid compound 3, 8-11, 16-19 was filtered off, and recrystallized. Compound 10
(Rf = 0.23, for benzenesulfamide Rf = 0.48) was purified by column chromatography on silica gel (40/100) using
acetone–chloroform, 1:3. The characteristics of the obtained compounds are given in Tables 1 and 2.
Bis(ethoxycarbonylamino)methane 16. Yield 15-17%; mp 130-132oC (MeOH) (lit. mp 130°C from
n-C6H14 [17]).
1,1′-Methylenebis(3-phenylurea) 17. Yield 48-53%; mp 222-223°C (MeOH) (lit. mp 210-211°C [18],
mp 221-223oC [19]).
1,1′-Methylenebis(3-butylsulfamide) 19. Yield 7-9%; mp 136-138°C (MeOH) (lit. mp 124oC from
Et2O [20]).
The data of 1H NMR spectra of compounds 16 and 19 correspond to those given in [17, 20].
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