A convenient synthesis of 3-amino-4-imino(thioxo)-imidazolidin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2004.07.134

Subsequent treatment of diethylphosphonopropyl α-aminonitriles with 1,1′-carbonyldiimidazole or 1,1′-carbonyl-di-(1,2,4-triazole) and hydrazines afforded substituted 3-amino-4-imino-imidazolidin-2-ones. Their acidic hydrolysis and their reactions with hydrogen sulfide are described.

Full text of DOI:10.1016/j.tetlet.2004.07.134

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7049–7051
A convenient synthesis of
3-amino-4-imino(thioxo)-imidazolidin-2-ones
Thomas Kurz* and Khalid Widyan
Institute of Pharmacy, University of Hamburg, Bundesstrasse 45, 20146 Hamburg, Germany
Received 25 June 2004; revised 26 July 2004; accepted 28 July 2004
Available online 13 August 2004
Abstract—Subsequent treatment of diethylphosphonopropyl a-aminonitriles with 1,10-carbonyldiimidazole or 1,10-carbonyl-di-
(1,2,4-triazole) and hydrazines afforded substituted 3-amino-4-imino-imidazolidin-2-ones. Their acidic hydrolysis and their reactions
with hydrogen sulfide are described.
Ó 2004 Elsevier Ltd. All rights reserved.
O
1. Introduction
O
NO2
O
HN
O
N N
The chemistry and properties of hydantoins and their
derivatives have been investigated for more than
140years. The hydantoin moiety represents an impor-
tant pharmacophore, which is present in various biolog-
ically active compounds. Over the past decades intensive
research effort in industry and academia has been dedi-
cated to the structural modification of hydantoins and
their derivatives. Novel lead structures and drug candi-
dates have emerged from this research and different
types of hydantoin derivatives have been introduced
into the market as pharmaceuticals.
HN
NH
O
Nitrofurantoin
Phenytoin
H
N
S
O
OH
N
H
OH
OH
OH
The 1-aminohydantoin Nitrofurantoin1,2 is an anti-
microbial drug for the treatment of urinary tract infec-
tions, while its analog Dantrolene1,2 represents a
well-known skeletal muscle relaxant. Another 1-amino-
hydantoin, Azimilide,1,2 is a promising drug candidate
for the treatment of cardiac arrhythmia. Phenytoin,3 a
5,5-diphenyl-imidazolidin-2,4-dione, is an anticonvul-
sant used for the treatment of epilepsy.
Thiohydantoin
Figure 1. Selected hydantoin derivatives.
In recent years considerable effort has been devoted to
the development of novel and more efficient methods
for the preparation of hydantoin derivatives. Besides
conventional multi-step methods, one-pot,1 solid-phase2
and microwave-assisted6 approaches have been pub-
lished. Our group reported the synthesis of 3-aralkoxy-
4-imino-imidazolidin-2-ones7 by treatment of a-cyano-
methyl substituted aralkoxyureas with anhydrous
EtOH–HCl as well as their base catalyzed Dimroth rear-
rangement into 4-aralkoxy-imino-imidazolidin-2-ones.
We now describe a practical and efficient synthetic path-
way for the preparation of 3-amino-4-imino(thioxo)-
imidazolidin-2-ones (4, 5).
Sulfahydantoin4 acts as a serine protease inhibitor and
the glucopyranosylidene-spiro-thiohydantoin5 is an effi-
cient inhibitor of muscle and liver glycogen phosphoryl-
ases (Fig. 1).
Keywords: Diethylphosphonopropyl a-aminonitriles; 1,10-Carbonyldi-
imidazole; 1,10-Carbonyl-di-(1,2,4-triazole); Hydrazines; 3-Amino-4-
imino(thioxo)-imidazolidin-2-ones.
*
Corresponding author. Tel.: +49 040 42838 3467; fax: +49 040 42838
6573; e-mail: kurz@chemie.uni-hamburg.de
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.134

7050
T. Kurz, K. Widyan / Tetrahedron Letters 45 (2004) 7049–7051
1
2. Results and discussion
lidin-2-ones took place. Furthermore, IR, H and 13C
NMR data of compounds 4 were consistent with those
obtained for 3-aralkoxy-4-imino-imidazolidine-2-ones.
a-Aminonitriles (1a–d) have been prepared by Strecker
synthesis and were used for the preparation of 4 after
1
13
structure confirmation by H and C NMR.7,8 Coup-
ling of diethylphosphonopropyl a-aminonitriles (1a–d)
with 1,10-carbonyldiimidazole (CDI) or 1,10-carbonyl-
di-(1,2,4-triazole) (CDT) in dry THF furnished the azo-
lide-intermediates (2), which were converted into the
open-chained intermediates (3) by treatment with vari-
ous hydrazines. Nucleophilic attack of the semicarb-
azide nitrogen to the nitrile carbon in refluxing THF
in the presence of triethylamine afforded 3-amino-4-
imino-imidazolidin-2-ones (4a–f,i,j) in 59–73% yield.
However, ring closure of N-substituted intermediates
3g,h failed under similar reaction conditions. Finally,
their cyclization was accomplished in the presence of
sodium hydride in dry THF (Scheme 1).
During the reaction the formation of intermediates 3,
which are characterized by a sharp (C@O) band at
1670–1680cmꢀ1 was monitored by IR spectroscopy.
The disappearance of the (CN) band in the IR spectra
at 2231cmꢀ1 and the appearance of a new sharp absorp-
tion band at 1745–1760cmꢀ1 clearly indicated the for-
mation of 4 (Table 1).
Thionation of 4a,g,i by hydrogen sulfide in dry dichloro-
methane in the presence of dry pyridine afforded 3-amino-
4-thioxo-imidazolidin-2-ones (5a,g,i) while the acidic
hydrolysis of 4a furnished the imidazolidin-2,4-dione
6a (Scheme 2).7,9
Finally, dealkylation of phosphonic esters 4a, 5a and 6a
with bromotrimethylsilane gave phosphonic acids 7, 8,
9. (Scheme 3). The phosphonic acid group is present in
various pharmaceuticals and pesticides and represents
an important pharmacophore and carboxylic acid bio-
isoster.10,11 The introduction of a phosphonic acid func-
tionality offers access to water soluble hydantoin
derivatives.
In contrast to 3-aralkoxy-4-imino-imidazolidin-2-ones,
which underwent Dimroth rearrangement to 4-aralkoxy-
imino-imidazolidin-2-ones in the presence of triethyl-
amine,7 3-amino-4-imino-imidazolidin-2-ones (4) are
solid and stable compounds. According to NMR and
IR spectra, recorded from the crude reaction mixtures,
no Dimroth rearrangement of 4 to 4-hydrazono-imidazo-
O
P
O
P
R1
R1
O
P
NH
R1
N
R3
R4
CN
O
i
CN
EtO
EtO
EtO
EtO
EtO
EtO
Y
N
N
N
N
NH
R2
R2
R2
N
O
2
4a,g,i
1a-d
i
ii
ii
O
P
S
O
O
O
P
R1
N
R1
R3
NH
O
P
R1
Ph
P
R3
R4
CN
EtO
EtO
EtO
EtO
iii
R3
R4
EtO
EtO
N
N
N
N
H
EtO
EtO
R4
N
N
N
N
N
N
H
R2
R2
O
N
H
O
R2
O
O
5a: 85%
5g: 80%
5i: 83%
6a: 90%
4a-j
3
Scheme 1. Synthesis of 3-amino-4-imino-imidazolidin-2-ones (4a–j).
Reagents and conditions: (i) CDI or CDT; (ii) H2N–NR3R4; (iii) Et3N/
heating or THF, NaH; Y = CH, N.
Scheme 2. Thionation and acidic hydrolysis of 4. Reagents and
conditions: (i) H2S, pyridine, CH2Cl2; (ii) 20% HCl/THF.
Table 1. Synthesis of 3-amino-4-imino-imidazolidin-2-ones (4a–j) from a-aminonitriles (1a–d)
4
R1
R2
R3
R4
4 Yield (%)
a
b
c
d
e
f
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
C6H5
73
65
63
62
60
71
59
57
65
60
H
4-F–C6H4
H
t-Bu
H
H
H
2-Pyridyl
–(CH2)5–
–(CH2)5–
–(CH2)5–
C6H5
H
g
h
i
CH3
C3H5
H
H
j
H
H
–(CH2)5–

T. Kurz, K. Widyan / Tetrahedron Letters 45 (2004) 7049–7051
7051
8. Varlet, J. M.; Fabre, G.; Sauveur, F.; Collignon, N.;
Savignac, P. Tetrahedron 1981, 37, 1377–1384.
9. Sternberg, J. A.; Adams, J. B. DuPont de Nemours, 1992;
EP 503798, Chem. Abstr. 1993, 118, 80921u.
10. Kuroda, Y.; Okuhara, M.; Goto, T.; Okamoto, M.;
Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J.
Antibiot. 1980, 33, 29–35.
X
O
P
X
O
P
Ph
Ph
i
EtO
EtO
HO
HO
N
N
H
N
N
H
N
N
H
O
H
O
7 : X = NH, 75%
8 : X = O, 80%
9 : X = S, 90%
4a, 5a, 6a
X = NH, O, S
11. Morphy, J. R.; Beeley, N. R. A.; Boyce, B. A.; Leonard,
J.; Mason, B.; Millican, A.; Millar, K.; OÔConnell, J. P.;
Porter, J. Bioorg. Med. Chem. Lett. 1994, 4, 2747–2752.
12. Procedure for the preparation of 3-amino-4-imino-imidaz-
olidin-2-ones (4a–f,i,j). A solution of a-amino- nitriles (1a–
d) (10mmol) in anhydrous THF (10mL) was added
dropwise over a period of 10min to a suspension of 1,10-
carbonyldiimidazole or 1,10-carbonyl-di-(1,2,4-triazole)
(10.5mmol) in anhydrous THF (10mL) under ice cooling.
After stirring at room temperature for 10min a solution of
the appropriate hydrazine (10mmol) was added dropwise
and the reaction mixture was stirred at room temperature
for 3h. The solvent was removed under reduced pressure,
triethylamine (2.5mL) was added and the reaction mixture
was heated to 60–70°C until a sharp band in the IR
spectra appears at 1745–1760cmꢀ1. After cooling to room
temperature the reaction mixture was dissolved in EtOAc
and washed with brine and water. The organic layer was
dried over MgSO4, concentrated and the remaining oil was
crystallized from EtOAc/hexane to give 4a–f,i,j as colorless
solids. Due to its higher reactivity, CDT was used in case
of a-aminonitriles derived from ketones.
Scheme 3. Synthesis of phosphonic acids 7, 8, 9. Reagents and
conditions: (i) TMSBr/CH2Cl2 then THF/H2O.
In summary, we have developed the first synthetic
method for the preparation of substituted 3-amino-4-
imino-imidazolidin-2-ones.12,13 Our novel one-pot proto-
col allows the introduction of different types of substitu-
ents in the 1, 3 and 5 positions of the imidazolidin
nucleus. In addition, compounds 4 are valuable precur-
sors for the synthesis of 3-amino-4-thioxo-imidazolidin-
2-ones (5) and 3-amino-imidazolidin-2,4-diones (6).14
Currently we are investigating the Dimroth rearrange-
ment of compounds 4 and the reactivity of the imino
group. The results of these investigations will be
reported in due course.
13. Typical experimental data for compounds 4a. Diethyl 2-(4-
imino-5-methyl-2-oxo-3-phenylaminio-imidazolidin-5-yl)eth-
ylphosphonate. Colorless solid (73%). Mp 169°C (EtOAc/
Acknowledgements
hexane); IR (KBr): m = 3213, 1755, 1680, 1225, 1032cmꢀ1
;
The authors thank Prof. Dr. D. Geffken for his valuable
help in the preparation of this manuscript.
1H NMR (DMSO-d6) d: 1.24 (t, J = 7.07Hz, 6H), 1.37 (s,
3H), 1.41–1.98 (m, 4H), 3.89–4.08 (m, 4H), 6.65–7.20 (m,
5H), 7.41 (s, 1H), 8.04 (s, 1H), 8.80 (s, 1H); 13C NMR
3
(DMSO-d6) d: 16.69 (d, Jcp = 6.14Hz), 19.42 (d,
2
1Jcp = 142.93Hz), 24.92, 32.12 (d, Jcp = 3.56Hz), 58.70
References and notes
3
2
(d, Jcp = 17.29Hz), 61.53 (d, Jcp = 6.14Hz), 112.50,
120.27, 129.47, 147.15, 154.80, 164.41; Anal. Calcd for
C16H25N4O4P:C, 52.17; H, 6.84; N, 15.21. Found: C,
52.32; H, 6.94; N, 15.21.
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1998, 39, 5135–5138.
´
2. Belai, I. Tetrahedron Lett. 2003, 44, 7475–7477.
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M. S.; DeLorey, T. M.; Brown, G. M. J. Med. Chem.
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1385–1390.
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14. Typical experimental data for compound 5a. Diethyl 2-(5-
methyl-2-oxo-3-phenylaminio-4-thioxo-imidazolidin-5-yl)eth-
ylphosphonate. Colorless solid (85%). Mp 166°C (Et2O/
hexane); IR (KBr): 3100, 1765, 1286, 1213, 1037cmꢀ1; 1H
NMR (DMSO-d6) d: 1.23 (t, J = 7.08Hz, 6H), 1.48 (s,
3H), 1.63–2.01 (m, 4H), 3.93–4.03 (m, 4H), 6.69–7.18 (m,
5H), 8.78 (s, 1H), 9.78 (s, 1H); 13C NMR (DMSO-d6) d:
3
1
16.67 (d, Jcp = 5.37Hz), 19.77 (d, Jcp = 141.09Hz),
27.73, 33.95 (d, Jcp = 2.30Hz), 61.63 (d, Jcp = 6.90Hz),
2
2
3
67.49 (d, Jcp = 19.17Hz), 112.78, 120.41, 129.40,
148.02, 154.29, 207.62; Anal. Calcd for C16H24N3O4PS:C,
49.86; H, 6.28; N, 10.90. Found: C, 49.77; H, 6.37; N,
10.74.
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2409–2416.