A facile protocol for the preparation of 5-alkylidene and 5-imino substituted hydantoins from N,N′-disubstituted parabanic acids

Article abstract of DOI:10.1016/j.tetlet.2012.06.129

A convenient procedure for the preparation of various substituted (thio)hydantoins is described. The method is based on Wittig and aza-Wittig reactions of parabanic acids with phosphonium ylides. The reactions occurred both regio- and stereo-selectively.

Full text of DOI:10.1016/j.tetlet.2012.06.129

Tetrahedron Letters 53 (2012) 4758–4762
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Tetrahedron Letters
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A facile protocol for the preparation of 5-alkylidene and 5-imino substituted
hydantoins from N,N0-disubstituted parabanic acids
Sßevket Hakan Üngören a, , Ibrahim Kani , Ahmet Günay
⇑
b
a
_
a Department of Chemistry, Faculty of Arts and Sciences, Bozok University, 66200 Yozgat, Turkey
b Department of Chemistry, Faculty of Sciences, Anadolu University, 26470 Eskißsehir, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient procedure for the preparation of various substituted (thio)hydantoins is described. The
method is based on Wittig and aza-Wittig reactions of parabanic acids with phosphonium ylides. The
reactions occurred both regio- and stereo-selectively.
Received 4 May 2012
Revised 9 June 2012
Accepted 27 June 2012
Available online 4 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Wittig reactions
Hydantoins
Imidazolidine
Parabanic acid derivatives
Iminophosphoranes
OH
Five-membered rings containing two heteroatoms are privi-
leged structures with proven utility in medicinal chemistry.1 One
example of such a heterocycle is hydantoin (I), an important phar-
macophore.2 Several hydantoin alkaloids (for example II–IV) have
been extracted from sponges, corals or marine organisms,2,3 and
some synthetic drugs such as phenytoin (V) and nilutamide (VI)
contain a hydantoin skeleton.1,2,4 Due to the interesting features
of hydantoins, recent progress has led to the development of
new methods for the preparation of these compounds.
Many processes have been published for the preparation of sub-
stituted hydantoins including the Bucherer–Bergs synthesis,5a the
Eldman method,5b the Staudinger reaction,5c microwave-assisted
approaches,5d a domino process,5e Ugi reactions5f,g and MCRs or so-
lid-phase techniques.2 Nevertheless, new methods for the rapid
synthesis of structurally varied and functionalized hydantoins re-
main desirable.
O
O
H3C
N
H
N
H2N
H3C
N
O
N
N
N
N
H3C
O
O
OCH3
lucettamine B (III)
IV
)
naamidinene (
H
N
O
H
O
CH3
CH3
N
Ph
Ph
F3C
N
HN
O
O
O2N
nilutamide (VI)
phenytoin (V)
CH3
O
N
H
N
Wittig and aza-Wittig reactions are often used for the synthesis of
acyclic and cyclic carbonyl compounds. In addition, the ability to
perform the reactions in neutral solvents, without catalysts, at mild
temperatures is advantageous.6
As an efficient new process for the preparation of alkylidene-
and imino-substituted hydantoins, the reactions of Wittig reagents
with parabanic acid derivatives are described herein by means of a
two-step synthetic procedure: a cyclization process involving
readily accessible urea and oxalyl chloride producing parabanic
O
N
H3C
HN
O
N
H
O
hydantoin (I)
II
)
3'-deimino-3'-oxaaplysinopsin (
⇑
Corresponding author. Tel.: +90 354 242 1021; fax: +90 354 242 1022.
E-mail address: hungoren@erciyes.edu.tr (Sß.H. Üngören).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.129

Sß.H. Üngören et al. / Tetrahedron Letters 53 (2012) 4758–4762
4759
Scheme 1. Preparation of various substituted hydantoins in the two steps starting from ureas.
Table 1
Synthetic hydantoins 3a–c and 4a–i prepared using Wittig/aza-Wittig reactions
Entry
Substrate
Me
Wittig reagent
Hydantoin (product)
Time (min)
20
Yielda (%)
Mp (°C)
Me
N
O
O
O
S
S
OMe
OEt
Me
N
O
O
O
O
1
Ph3P@CHCOOMe
77
124
58
N
N
N
N
N
N
N
N
Me
Me
2a
2a
2a
2a
O
3a
3b
O
Me
N
Me
N
S
S
2
3
Ph3P@CHCOOEt
Ph3P@CHCOMe
20
20
81
83
Me
Me
O
Me
N
O
Me
N
S
S
73
Me
Me
3c
O
Me
N
O
Me
N
N
Ph3P
S
S
N
N
4
5
20
20
79
81
96
97
Me
Me
O
O
4a
Me
N
N
Me
N
Ph3P
S
S
O
O
Me
N
N
N
N
Me
Me
2a
2a
O
O
Me
4b
Me
N
N
Me
N
Ph3P
S
S
N
Br
6
20
73
148
Me
Me
O
O
Br
4c
4d
4e
Me
N
Me
N
N
N
Ph3P
Ph3P
S
S
O
O
N
N
7
8
20
20
78
65
189
100
N
N
N
N
Me
Me
2a
2a
O
O
Me
N
Me
N
S
S
N
Me
Me
O
O
N

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Sß.H. Üngören et al. / Tetrahedron Letters 53 (2012) 4758–4762
Table 1 (Continued)
Entry
Substrate
Wittig reagent
Hydantoin (product)
Time (min)
Yielda (%)
Mp (°C)
Me
N
N
N
N
Me
Ph3P
Ph3P
Ph3P
O
O
N
O
O
N
Me
N
N
N
N
9
60
75
Oilb
Me
Me
2b
2b
O
O
Me
4f
Me
N
Me
N
O
O
N
Br
10
60
70
100
Me
Me
O
O
Br
4g
O
O
OMe
OMe
N
Me
O
O
N
N
O
11
120
61
142
N
N
Ph
Ph
2c
O
O
Me
4h
O
O
N
Ph3P
OMe
N
OMe
Br
O
O
N
O
N
12
120
56
159
O
N
N
Ph
Ph
2c
O
4i
Br
a
Isolated yield.
b
Lit10 yellow oil.
Figure 1. X-ray crystal structure of 3b.
acids, followed by regio- and stereo-selective Wittig reaction with
the parabanic acids.
Parabanic acid derivatives 2a–c (Scheme 1) have been pre-
viously synthesized using various procedures.7 In this study, com-
pounds 2a–c were prepared via cyclizations of ureas 1a–c with
oxalyl chloride.8
The parabanic acids 2a–c reacted regioselectively with arylimi-
nophosphoranes and acylmethylenephosphoranes in xylene at re-
flux to afford 5-imino 4a–i or 5-methylidene 3a–c substituted
hydantoins (Scheme 1).9 While reactions run in xylene resulted
in moderate to good yields (56–83%) within 2 h, the use of toluene
resulted in very long reaction times and poor yields. In addition,

Sß.H. Üngören et al. / Tetrahedron Letters 53 (2012) 4758–4762
4761
Fig. 2. X-ray crystal structure of 4b.
the Wittig reagents reacted much faster with 2-thioxo substituted
References and notes
imidazolidines than with 2-oxo substituted imidazolidines in xy-
lene (Table 1). All the products 3a–c and 4a–i were purified by col-
umn chromatography.
The Wittig reagents attacked the amide carbonyl of the paraba-
nic acids, but not the urea carbonyl. In addition, with parabanic
acid derivative 2c, which contained different substituents attached
to the nitrogen atoms, the Wittig reagents reacted regioselectively
on the alkyl-N–C@O group.
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3. (a) Guella, G.; Mancini, I.; Zibrowius, H.; Pietra, F. Helv. Chim. Acta 1988, 71,
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The 1H NMR spectrum of 3a showed a methine proton at d 5.98,
methoxy protons at d 3.80 and methyl protons at d 3.84 and d 3.36.
The 13C NMR spectrum exhibited one thione and two carbonyl car-
bons at d 181.5 (urea), d 164.4 and d 163.6 (ester and amide), C@CH
carbons at d 135.9 and d 99.4 and a methoxy and two methyl car-
bons at d 52.2, d 34.6 and d 29.0. In the 1H NMR spectra, the signals
of the methine protons of products 3a–c resonated between 6 and
7 ppm. These observations were consistent with the (Z)-geometry
for the reaction products.
Unambiguous evidence for the structures of both 5-alkylidene
and 5-imino substituted hydantoins was obtained by X-ray ana-
lyses of crystals of 3b and 4b (Figs. 1 and 2).11
6. (a) Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.; de Los Santos, J. M.
Tetrahedron 2007, 63, 523–575; (b) Abdou, V. M. Phosphorus Sulfur Silicon 2002,
177, 325–389.
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Gupte, S. P. Appl. Organomet. Chem. 2010, 24, 402–407; (c) Bogolubsky, A. V.;
Ryabukhin, S. V.; Pakhomov, G. G.; Ostapchuk, E. N.; Shivanyuk, A. N.;
Tolmachev, A. A. Synlett 2008, 2279–2282.
In conclusion, we have described a simple, rapid and catalyst-
free procedure for the synthesis of variously substituted hydantoin
and thiohydantoin derivatives from parabanic acids by regioselec-
tive Wittig reactions.
Acknowledgements
8. Representative procedure for the preparation of parabanic acid derivatives by the
reaction between ureas 1 and oxalyl chloride: To a CH3CN solution of 1a (1.04 g,
10 mmol) was added oxalyl chloride (1.26 g, 10 mmol), and the mixture was
stirred at reflux for 50 min. The solvent was removed on a rotary evaporator
and the residue was recrystallized from cyclohexane to give compound 2a.
Orange crystals, yield 1.45 g, 92%; mp: 98–100 °C. FT–IR (ATR): 1763 (C@O),
The authors are grateful to The Medicinal Plants and Medicine
Research Centre of Anadolu University for the use of the X-ray
diffractometer.
1331 (C@S) cmꢀ1
;
1H NMR (400 MHz, CDCl3): 3.42 (s, 6H, 2 ꢁ Me); 13C NMR
(100 MHz, CDCl3): 181.5 (C@S), 155.3 (2 ꢁ C@O), 28.2 (2 ꢁ Me). Anal. Calcd for
C5H6N2O2S (158 g/mol): C, 37.97; H, 3.82; N, 17.71; S, 20.27. Found: C, 38.11; H,
3.85; N, 17.63; S, 20.06%.
Supplementary data
9. Representative procedure for the preparation of hydantoins from the reaction
between parabanic acids 2 and a Wittig reagent: To a boiling xylene solution of
Supplementary data (1H NMR and 13C NMR spectral data of all
synthesized compounds are reported along with crystallographic
data for compounds 3b and 4b) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.06.129.
2a
(0.158 g,
1 mmol)
was
added
(methoxycarbonylmethylene)
triphenylphosphorane, and the mixture was stirred under reflux for 20 min.
The solvent was removed on a rotary evaporator, and the residue was subjected
to column chromatography on silica gel 60 HF254; elution with CHCl3 afforded

4762
Sß.H. Üngören et al. / Tetrahedron Letters 53 (2012) 4758–4762
10. Sayer, J. M.; DePecol, M. J. Am. Chem. Soc. 1976, 99, 2665–2671.
the product 3a. Orange crystals, yield 0.165 g, 77%; FT–IR (ATR): 1744, 1700
(C@O), 1653 (C@C) cmꢀ1
;
1H NMR (400 MHz, CDCl3): 5.98 (s, 1H, @CH), 3.84 (s,
11. X-ray crystallographic data for structures 3b and 4b have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
numbers CCDC 874366 and 875257, respectively. Copies of these data can be
obtained, free of charge, on application to the CCDC (deposit@ccdc.cam.ac.uk).
3H, N(3)Me), 3.80 (s, 3H, OMe), 3.36 (s, 3H, N(2)Me); 13C NMR (100 MHz,
CDCl3): 181.5 (C@S), 164.4 (COOMe), 163.6 (N–C@O), 135.9 (C@CH), 99.4
(C@CH), 52.3 (OMe), 34.6, 29.0 (2 ꢁ NMe). Anal. Calcd for C8H10N2O3S (214 g/
mol): C, 44.85; H, 4.70; N, 13.08; S, 14.97. Found: C, 44.79; H, 4.72; N, 13.16; S,
14.81%.