A versatile method for the synthesis of substituted 1-aminohydantoin derivatives

Article abstract of DOI:10.1016/j.tetlet.2003.08.029

An efficient and versatile method has been developed for the synthesis of 1-aminohydantoin derivatives which can be substituted at all the possible positions of the hydantoin ring. The starting materials are aldehydes, ketones, carboxylic acids and hydrazides as well as isocyanates readily available from commercial sources. The semicarbazide-type reaction product of an N-acyl-N′-(1-cyanoalkyl)hydrazine, obtained from the above materials by methods known from the literature, and an isocyanate is cyclized in the presence of a basic catalyst to yield 1-acylamino-4-imino-2-oxoimidazolidine derivatives whose acid catalyzed hydrolysis leads to 1-aminohydantoin derivatives in good to excellent yields. The last two steps are carried out in a single reaction medium.

Full text of DOI:10.1016/j.tetlet.2003.08.029

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7475–7477
A versatile method for the synthesis of substituted
1-aminohydantoin derivatives
Iva´n Be´lai*
Plant Protection Institute, Hungarian Academy of Sciences, PO Box 102, H-1525 Budapest, Hungary
Received 13 May 2003; revised 29 July 2003; accepted 8 August 2003
Abstract—An efficient and versatile method has been developed for the synthesis of 1-aminohydantoin derivatives which can be
substituted at all the possible positions of the hydantoin ring. The starting materials are aldehydes, ketones, carboxylic acids and
hydrazides as well as isocyanates readily available from commercial sources. The semicarbazide-type reaction product of an
N-acyl-N%-(1-cyanoalkyl)hydrazine, obtained from the above materials by methods known from the literature, and an isocyanate
is cyclized in the presence of a basic catalyst to yield 1-acylamino-4-imino-2-oxoimidazolidine derivatives whose acid catalyzed
hydrolysis leads to 1-aminohydantoin derivatives in good to excellent yields. The last two steps are carried out in a single reaction
medium.
© 2003 Elsevier Ltd. All rights reserved.
Although the first 1-aminohydantoin derivatives (1-
aminoimidazolidine-2,4-diones) were synthesized at the
end of the 19th century1 no general and versatile route
has been developed for the synthesis of 1-aminohydan-
toins which can be substituted in any or all of the
possible substituent positions. Many publications2–5
and patents6,7 describe the preparation of 1-aminohy-
dantoins carrying substituents only in certain positions.
Recently a paper has been published describing solid
support synthesis of 1-aminohydantoins.8
The goal of this work was to develop a simple, general
route (Scheme 1) for the synthesis of 1-aminohydan-
toins 4 which can bear substituents at all the possible
ring positions.
The significance of the derivatives containing the 1-
aminohydantoin core structure is exemplified by several
commercially available drugs (Fig. 1), for example the
antimicrobial Nitrofurantoin9 and the sceletal muscle
relaxant Dantrium.10 The diversity in activity of hydan-
toins also bearing 1-methyleneamino groups is shown
by two other compounds, Azimilide and BW68C whose
activity is different from that of the previously men-
tioned two compounds. Azimilide is a candidate drug
against arrhythmia,11 while BW68C is
a potent
inhibitor of platelet aggregation acting as an agonist of
the prostaglandin D-receptor.12 The anthelmintic activ-
ity of 1-aminohydantoins bearing a cinnamoyl moiety
on the amino function (Fig. 1) has also been reported.13
Keywords: 1-aminohydantoin derivatives; intramolecular cyclization;
versatile synthesis method.
* Tel.: +36-1-4877-541; fax: +36-1-4877-555; e-mail: ibel@nki.hu
Figure 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.029

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I. Be´lai / Tetrahedron Letters 44 (2003) 7475–7477
Table 1. Structures, yields and melting points of the 1-
aminohydantoins synthesized
Scheme 1. General synthetic route for the preparation of
1-aminohydantoins.
To obtain 1-aminohydantoins, firstly an isocyanate was
reacted with the amino nitrogen of an N-acyl-N%-(1-
cyanoalkyl)hydrazine 1 resulting in the intermediary
1-acyl-2-(1-cyanoalkyl)-4-substituted-semicarbazides 2.
Intramolecular cyclization via nucleophilic attack of the
amide-nitrogen on the cyano carbon atom produced
imino-compounds 3 the hydrolysis of which gave 1-
aminohydantoins 4 (Table 1). The cyclization and sub-
sequent hydrolysis were conducted in one pot.
Hydrazides of type 1 can be obtained through many
known routes. Such methods include a Strecker-type
reaction using a carboxylic acid hydrazide, a ketone or
an aldehyde and sodium or potassium cyanide,14,15
addition of hydrogen cyanide to N-substituted hydra-
zones,16 acylation of a-cyanoalkyl-hydrazines,17 and
condensation of acid hydrazides with a cyanohy-
drin.18,19 The introduction of a large number of differ-
ent substituents is possible due to availability of a very
large number of starting materials, i.e. aldehydes,
ketones, carboxylic acids, hydrazides and isocyanates,
which are required for the synthesis of 1.
The addition of isocyanates to 1 was carried out in
dichloromethane from which the intermediates 2 were
precipitated. The formation of 3 in solution takes place
by a slow spontaneous cyclization of 2, however, in the
presence of 5–10 mol% of base, cyclization was com-
plete within a few hours. The reactions were carried out
in EtOH where 2 was only partially soluble, but after
the addition of 5 mol% NaOEt in EtOH 2 dissolved
within 2–3 min which was followed by the reappearance
of a precipitate after about 0.5 h. The cyclization
resulting in the formation of 3h (R1=Ph, R2=R3=H,
R4=nBu) occured within 10 min without addition of
base. This is probably due to the lack of steric hin-
drance as the carbon atom next to the cyano function is
not substituted (cf. 3a–g, 3i). The acid-catalyzed hydrol-
ysis of 3 yielding 4 required a reaction time ranging
from a few hours to 2 days.
toin derivatives formed were separated by filtration in
good to excellent yields based on 2.20 All compounds 4,
except 4a, are new, and their structures were confirmed
by 1H and 13C NMR spectroscopy21 as well as by
elemental analyses.21
In both the 1H and 13C NMR spectra the signals
corresponding to the protons and the carbons, respec-
tively, of the two methyl groups of 4c gave two singlets
instead of one and a similar duplication was observed
for the signals corresponding to the methyl and ethyl
groups at the C5 position of 4d. In both compounds the
presence of an ortho substituent resulted in restricted
rotation around the N3(hydantoin)ꢀC1(phenyl) bond.
In the 13C NMR spectrum of 4d, having an optically
active center as well, the signals of most of all the other
carbons were also doubled.
The reaction procedure is as follows. To a suspension
of 2 in EtOH was added 0.05 mol% of NaOEt in
EtOH. Following cyclization, the reaction mixture was
acidified by addition of aqueous 2 M HCl solution and
was allowed to stand for 5–48 h. The 1-aminohydan-

I. Be´lai / Tetrahedron Letters 44 (2003) 7475–7477
7477
In summary, we have elaborated a versatile and general
method for the synthesis of substituted 1-aminohydan-
toin derivatives. The semicarbazide-type products 2,
obtained by the addition reaction of an N-acyl-N%-(1-
as well as elemental analysis data of the new 1-aminohy-
dantoin derivatives.
4b: 1H NMR: l 1.55 (s, 6H), 7.40–7.48 (m, 6H), 7.54–7.58
(m, 1H), 7.95–7.97 (m, 2H), 10.21 (s, 1H). 13C NMR: l
22.08 (2C), 63.37, 127.01 (2C), 127.76 (2C), 128.18 (2C),
128.76 (2C), 129.75, 131.24, 132.21, 133.31, 152.62, 167.40,
173.71. Anal. calcd for C18H16ClN3O3: C, 60.43; H, 4.51;
N, 11.74; Cl 9.91. Found: C, 60.49; H, 4.43; N, 11.69; Cl,
9.98%.
cyanoalkyl)hydrazine
1 and an isocyanate, were
cyclized to yield imino-derivatives 3 which were subse-
quently hydrolyzed in the same medium to 1-aminohy-
dantoin. For the preparation of hydrazines 1, a large
number of potential starting materials, i.e. aldehydes,
ketones, carboxylic acids and hydrazides are available
from commercial sources.
1
4c: H NMR: l 1.51 and 1.54 (2s, 2×3H), 7.25–7.28 (m,
2H), 7.41–7.46 (m, 4H), 7.54–7.57 (m, 1H), 7.65–7.67 (m,
2H), 9.35 (s, 1H). 13C NMR: l 21.64, 22.81, 64.82, 127.41
(2C), 127.93, 128.49, 128.84, 130.17 (2C), 130.32, 130.70,
131.07, 132.44, 132.93, 153.94, 166.64, 173.47. Anal. calcd
for C18H16ClN3O3: C, 60.43; H, 4.51; N, 11.74; Cl 9.91.
Found: C, 60.51; H, 4.47; N, 11.80, Cl, 9.96%.
References
1. Traube, W.; Hoffa, E. Chem. Ber. 1898, 31, 162–169.
2. Bailey, J. R.; Read, W. T. J. Am. Chem. Soc. 1915, 37,
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1
4d: H NMR: l 0.95 and 0.99 (2t, 3H, J=7.41 Hz), 1.49
and 1.52 (2s, 3H), 1.75–1.94 (m, 2H), 3.78 (s, 3H), 6.95–6.99
(m, 1H), 7.15–7.20 (m, 2H), 7.26–7.29 (m, 1H), 7.37–7.46
m (3H), 7.54–7.58 (m, 1H). 13C NMR: l 8.22 and 8.60,
21.23 and 21.44, 28.86 and 29.43, 55.53, 68.90 and 68.99,
111.81 and 111.88, 119.74, 119.85 and 119.91, 128.02 and
128.09, 129.14 and 129.18, 129.71 and 129.73, 130.60 and
130.65, 130.75, 130.96, 131.22 and 131.34, 131.60 and
131.63, 133.00 and 133.59, 154.95 and 155.03, 159.76,
166.64 and 166.74, 173.07 and 173.15. Anal. calcd for
C20H20ClN3O4: C, 59.78; H, 5.02; N, 10.46; Cl, 8.82.
Found: C, 59.69; H, 4.97; N, 10.55; Cl, 8.75%.
5. Milcent, R.; Barbier, G.; Yver, B.; Mazouz, F. J. Hetero-
cycl. Chem. 1991, 28, 1511–1516.
6. Breuer, H.; Treuner, U. D. US Pat. 1977, 4.038.271.
7. Breuer, H.; Treuner, U. D. Ger. Pat. 1976, 2.714.214.
8. Wilson, L. J.; Li, M.; Portlock, D. E. Tetrahedron Lett.
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9. Kenyon, H. US Pat. 1952, 2.610.181.
4e: 1H NMR: l 1.29 (t, 3H, J=7.14 Hz), 1.60–1.78 (m, 6H),
1.84–2.06 (m, 4H), 4.25 (q, 2H, J=7.14 Hz), 7.39–7.40 (m,
5H). 13C NMR: l 14.38, 21.24 (2C), 24.37, 31.34 (2C),
62.92, 64.04, 127.34 (2C), 129.17 (2C), 129.82, 133.88,
153.48, 156.22, 172.72. Anal. calcd for C17H20ClN3O4: C,
55.82; H, 5.51; N, 11.49; Cl, 9.69. Found: C, 55.91; H, 5.47;
N, 11.41; Cl, 9.78%.
10. Davis, C. S.; Snyder, H. R. US Pat. 1965, 3.415.821.
11. Yu, C. N.; Pelosi, S. S.; Calcagno, M. A. US Pat. 1994,
5.462.940.
12. Barraclough, P.; Bolofa, M. L.; Giles, H.; Gillam, J.;
Harris, C. J.; Kelly, M. G.; Leff, P.; McNeill, A.; Robert-
son, A. D.; Stepney, R. J.; Whittle, B. J. R. Bioorg. Med.
Chem. 1996, 4, 81–90.
13. Alaimo, H.; Hatton, C. J. J. Med. Chem. 1976, 19, 349–350.
14. Chi-Tung-Hs, A.; Murphy, R. Eur. Pat. 1987, 234.994.
15. Ziegler, F. E.; Wender, P. A. J. Org. Chem. 1977, 42,
2001–2003.
16. Chiba, T.; Okimoto, M. Synthesis 1990, 209–211.
17. Karady, S.; Ly, M. G.; Pines, S. H.; Sletzinger, M. J. Org.
Chem. 1971, 14, 1946–1948.
4f: 1H NMR: l 3.12 (s, 3H), 3.79 (s, 3H), 5.35 (s, 1H), 6.91
(d, 2H, J=8.89 Hz), 7.23 (d, 2H, J=8.79 Hz), 7.30–7.34
(m, 2H), 7.48 (m, 2H), 7.68 (dd, 1H, J=7.14 and 1.29 Hz).
13C NMR: l 25.43, 55.37, 65.45, 114.62 (2C), 124.15,
127.43 (2C), 128.66 (2C), 128.99 (2C), 130.45, 132.75,
157.78, 160.45, 166.61, 170.02. Anal. calcd for
C18H17N3O4: C, 63.71; H, 5.05; N, 12.38. Found: C, 63.63;
H, 4.99; N, 12.31%.
4g: 1H NMR: l 1.19–1.43 (m, 6H), 1.40 (s, 6H), 1.66–1.86
(m, 2H), 2.08–2.18 (m, 2H), 3.91–3.99 (m, 1H), 7.27–7.31
(m, 2H), 7.43 (t, 2H, J=7.45 Hz), 7.68 (d, 1H, J=7.45 Hz).
13C NMR: l 22.06 (2C), 24.91, 25.72 (2C), 29.45 (2C),
51.91, 63.31, 127.32 (2C), 128.48 (2C), 139.51, 132.33,
155.39, 166.74, 175.01. Anal. calcd for C18H23N3O3: C,
65.63; H, 7.04; N, 12.76. Found: C, 65.73; H, 6.98; N,
12.84%.
18. Ford, M. C.; Rust, R. A. J. Chem. Soc. 1958, 1297–1298.
19. Trivedi, P. B.; Undavia, N. K.; Dave, A. M.; Bhatt, K. M.;
Desai, M. C. Indian J. Chem. 1993, 32B, 497–500.
20. The experimental conditions for the synthesis of 1-amino-
hydantoins is illustrated by the synthesis of N-[3-(4-
chlorophenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]-
benzamide 4b: A solution of 1b (R1=Ph, R2=R3=Me;
2.03 g, 10 mmol) and 4-chlorophenyl isocyanate (1.61 g,
10.5 mmol) in dichloromethane (10 ml) was stirred
overnight, then the precipitated product was filtered by
suction and washed with dichloromethane to obtain pure
2b (R1=Ph, R2=R3=Me, R4=4-ClPh). Yield: 73%; mp
164°C. To a suspension of 2b (1.43 g, 4 mmol) in EtOH
(10 ml) was added a solution of 0.2 M NaOEt in EtOH
(1 ml, 0.2 mmol). The material dissolved within 2–3 min
after which a precipitate appeared. After 2 h, 2N aqueous
HCl (4 ml, 8 mmol) was poured into the reaction mixture
which was then left at rt for 20 h. The resulting solid
material was filtered by suction, washed with water and
dried to give 4b in 95% yield.
4h: 1H NMR: l 0.86 (t, 3H, J=7.2 Hz), 1.22–1.30 (m, 2H),
1.38–1.46 (m, 2H), 3.15–3.20 (m, 2H), 4.58 (brs, 1H), 5.52
(m, 2H), 7.54 (m, 2H), 7.62 (m, 1H), 7.95 (d, 2H, J=7.40
Hz). 13C NMR: l 13.66, 18.83, 31.89, 36.51, 40.68, 116.30,
127.69 (2C), 128.95 (2C), 130.73, 133.19, 156.51, 166.56.
Anal. calcd for C14H17N3O3: C, 61.08; H, 6.22; N, 15.26.
Found: C, 60.99; H, 6.28; N, 15.34%.
1
4i: H NMR: l 1.49 (s, 9H), 1.50 (s, 6H), 6.65 (brs, 1H),
7.40 (s, 4H). 13C NMR: l 22.11 (2C), 28.04 (3C), 62.97,
82.71, 127.15 (2C), 129.15 (2C), 129.89, 133.86, 146.73,
154.91, 173.64. Anal. calcd for C16H20ClN3O4: C, 54.32; H,
5.70; N, 11.88; Cl, 10.02. Found: C, 54.41; H, 5.75; N,
11.81; Cl, 9.95%.
21. 1H NMR (400 MHz, CDCl3, TMS) and 13C NMR spectral,