Synthesis of 5-hydroxy hydantoins via a tandem process

Article abstract of DOI:10.1016/j.tetlet.2016.08.022

An efficient entry to 5-hydroxyhydantoin derivatives is reported. The reaction of α-ketoacids with commercially available carbodiimides under mild conditions, and in the presence of visible light, induces the rearrangement of an O-acyl urea, and eventuall

Full text of DOI:10.1016/j.tetlet.2016.08.022

Accepted Manuscript
Synthesis of 5-hydroxy hydantoins via a Tandem process
Rosa Luisa Meza León, Sylvain Bernès, Guadalupe Nallely Cortés López,
Virginia M. Mastranzo, Martha Sosa Rivadeneyra, Fernando Sartillo Piscil
PII:
S0040-4039(16)31009-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.022
TETL 47993
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 July 2016
4 August 2016
6 August 2016
Please cite this article as: León, R.L.M., Bernès, S., López, G.N.C., Mastranzo, V.M., Rivadeneyra, M.S., Piscil,
F.S., Synthesis of 5-hydroxy hydantoins via a Tandem process, Tetrahedron Letters (2016), doi: http://dx.doi.org/
10.1016/j.tetlet.2016.08.022
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Synthesis of 5-hydroxy hydantoins via a
tandem process
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Rosa Luisa Meza Leóna,∗ Sylvain Bernèsb, Guadalupe Nallely Cortés López a, Virginia M. Mastranzoc, Martha
Sosa Rivadeneyraa, Fernando Sartillo Piscila

1
Tetrahedron Letters
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Synthesis of 5-hydroxy hydantoins via a Tandem process
Rosa Luisa Meza Leóna,∗ Sylvain Bernèsb, Guadalupe Nallely Cortés López a, Virginia M. Mastranzoc,
Martha Sosa Rivadeneyraa, Fernando Sartillo Piscila
a Benemérita Universidad Autónoma de Puebla (BUAP), Facultad de Ciencias Químicas, 14 Sur Esq. San Claudio, San Manuel. 72570, Puebla, México
b Benemérita Universidad Autónoma de Puebla (BUAP), Instituto de Física, 18 Sur y San Claudio S/N, San Manuel. 72570, Puebla, México
c Universidad Autónoma de Tlaxcala (UAT), Facultad de Ciencias Básicas, Ingeniería y Tecnología Calzada Apizaquito S/N 90300, Apizaco Tlaxcala, México
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient entry to 5-hydroxyhydantoin derivatives is reported. The reaction of α-ketoacids
with commercially available carbodiimides under mild conditions, and in presence of visible
light, induces the rearrangement of an O-acyl urea, and eventually leads to hydantoins in good
yields. Because of economy of atoms, this tandem process can be considered as a green
procedure.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
5-hydroxy hydantoin
carbodiimides
imidazolidine-2,4,5-triones
green process
Introduction
this letter a one-pot tandem synthesis of 5-hydroxyhydantoins,
using α-ketoacids and carbodiimides as starting materials.
Hydantoins are the key structural unit in a broad variety of
natural and synthetic compounds with biological activity, such as
(+)-hydantocidin, which has shown herbicidal and plant growth
regulatory activities.1 Phenytoin, an anticonvulsant which has
been
used
in
treatment
of
epilepsy,2
(Z)-5-(4-
hydroxybenzylidene)imidazolidine-2,4-dione, extracted from the
sponge Hemimycale Arabica, which displays moderate
antiproliferative activity against human cervical carcinoma,3
among many others (Fig. 1).
Of particular interest are the 5-hydroxyhydantoins, because
have been proposed that 5-hydroxy-1-methyl hydantoin for
example is involved in inflammatory processes, as reported by
Lenaga et al.4 5-Hydroxyhydantoin and 5-methyl-5-
hydroxyhydantoin are the major products of cytosine and
thymine oxidative degradation, respectively, and have been
detected in cancer cells, so the damage caused by these
hydantoins could be involved in some mutagenesis and
carcinogenesis processes.5
Figure 1. Some important 5-substituted hydantoins.
Results
Occurrences of new synthetic routes discovered adventitiously
while searching for something else are not uncommon, as has
happened to us, during an attempt to catch carbonyl radicals
generated through the Barton decarboxylation7 method. In the
first step, the Barton ester was obtained by conversion of a
carboxylic acid, in presence of N-hydroxy-2-thiopyridone and
DCC, in dry dichloromethane, and in a flask covered with an
aluminum foil in order to keep the reaction in the dark; then the
Given the importance of this kind of heterocycles, many
approaches to address the synthesis of 5-substituted hydantoins
derivatives have been reported, which are generally based on
multi-steps procedures, and involve strong acidic or basic
conditions. However, modern organic chemistry requires safer
and greener alternatives, strongly oriented toward optimizing
atom economy and fewer steps, and minimizing the amount of
6
pollutants generated as byproducts. Along this line, we present in
———
∗ Corresponding author. Tel.: +52-222-229-5500; fax: +52-222-245-4972; e-mail: rosaluisa@yahoo.com

2
Tetrahedron
radical trap (an electrophilic olefin in our case) was added, the
Given the long reaction times led us to believe that with visible
light was accelerating the reaction, but if in the first reaction we
did not get radical addition to the olefin, and even further in the
dark reaction albeit very slowly it takes place so the reaction does
not proceed by free radicals, therefore the function of the light is
to give to the reaction the activation energy needed to be carried
out thus decreasing the reaction time. The use of DCM as solvent
and visible light requires that the reaction to be carried out at 0 °
C.
aluminum foil removed, and the reaction irradiated at 273 K with
visible light, to generate the radicals. In the process, we used
phenylglyoxylic acid, but to our surprise, the olefin (methyl (Z)-
3-cyanoacrylate) was recovered quantitatively, while the
carboxylic acid had been consumed in full. The reaction afforded
a white solid that was not identified as the expected dicyclohexyl
urea. However, we originally anticipated that a nucleophilic
attack of N-hydroxy-2-thiopyridone on the formed O-acyl urea
would take place. The nucleophilic substitution would then result
in the formation of the Barton ester and dicyclohexylurea
We finally decided to perform the reaction with other α-
ketoacids, at 0°C, in dry DCM, under visible light irradiation
(150 W lamp), over two hours. Results are shown in Table 1; all
derivatives 6a-6e were obtained as racemic mixtures.
(Scheme 1). Instead, we obtained
derivative.
a 5-hydroxyhydantoin
Table1. 5-hydroxyhydantoins 6 produced via scheme 2*
1
R1
R2
6
Yield %
a
b
c
d
e
Ph
H
CH3
H
Cy
Cy
Cy
iPr
iPr
90
85
81
83
85
Ph
* Reaction conditions: 0°C, dry DCM, irradiation with visible light (150
W lamp).
The 5-hydroxyhydantoins 6a and 6b crystallized, and their
structures were confirmed by single crystals X-ray diffraction.8 In
both molecules (Fig. 2), the hydantoin heterocycle is flat, as in
other 1,3-dicyclohexylhydantoin derivatives,9 and the space
groups are consistent with racemic mixtures. In the case of 6b,
the molecule has mirror symmetry, through the m plane in space
group Pnma. As a consequence, substituents at C4 and C5 are
disordered by symmetry. However, bond lengths observed for
these groups corroborate the presence of a carbonyl group [C=O:
1.210(2) Å] and a hydroxyl group [C–OH: 1.395(2) Å].
Scheme1. Barton decarboxylation.
This result may be rationalized if we consider the strong
electrophilic character of the ketocarbonyl group in the O-acyl
urea intermediate 3. An intramolecular nucleophilic addition
allows the formation of an iminooxazolidin-5-one derivative, 5,
which, in turn, undergoes a rearrangement, leading to the
formation of the 5-hydroxyhydantoin derivative 6, in good yield
(Scheme 2). Interestingly, the atom economy is 100 % along this
route.
Figure 2. Molecular structures of 6a (left) and 6b (right).
Volonterio et al. reported a similar reaction to obtain 5-
substituted hydantoins from carbodiimides and using α-halo
carboxylic acid or α,β-unsaturated carboxylic acids as starting
materials. They however had to use a base in order to promote
the ring closure.10 Using our methodology, the desired hydantoins
are obtained in good yields with only two reactants, the α-
ketoacid and a carbodiimide.
Scheme2. Formation of 5-hydroxy-5-subtituted hydantoins 6.
We then tested the reaction without olefin, or N-Hydroxy-2-
thiopiridone, and the flask was kept in the dark during the course
of the reaction, which was monitored by TLC and after
prolonged reaction time, we obtained the same 6a and raw
material unreacted, lowering the yield to 70%. If the reaction is
carried out at room temperature without the foil the reaction time
lengthens, the reaction was followed by TLC for 48 h, the yield
was decreased and raw material was recovered.
Indeed, when the reaction is conducted with chlorooxoacetates
in place of α-ketoacids: by reacting carbodiimides and ethyl
chlorooxoacetate in dry dichloromethane and in presence of a
stoichiometric amount of water, imidazolidine-2,4,5-triones we
obtained in excellent yields (N-substituted parabanic acids, see
Scheme 3).

3
6. (a)Murray, R.G.; Whitehead, D.M.; Strat, F.; Conway, S. J. Org. Biomol.
Chem., 2008, 6, 988–991. (b) Fraile, J. M.; Lafuente, G.; Mayoral, J. A.;
Pallarés, A. Tetrahedron 2011, 67, 8639-8647.(c) Mahmoodi, N. O.;
Khodaee, Z. ARKIVOC 2007, iii, 29-36
7. (a) Barton, D.H.R.; Crich, D.; Motherwell, W.B. J. Chem. Soc., Chem.
Commun. 1983, 939-941; (b) Barton, D.H.R.; Crich, D. J. Chem. Soc. Perkin
Trans. 1 1986, 1603-1611.
8.
1,3-Dicyclohexyl-5-hydroxy-5-phenyl-imidazolidine-2,4-dione
(6a).
C21H28N2O3, orthorhombic, Pna21;
a
= 10.280(3), b = 10.384(3), c =
18.098(5) Å, V = 1932.0(9) Å3, Z = 4, T = 298 K, 2015 independent
reflections for 239 refined parameters (Friedel pairs were merged); R1 = 0.044
for 1386 data with I > 2σ(I) and wR2 = 0.139 for all data. CIF and structure
factors were deposited with the CCDC, deposition number: CCDC-1491223.
1,3-Dicyclohexyl-5-hydroxy-imidazolidine-2,4-dione
(6b).
C15H24N2O3,
Scheme3. Synthesis of imidazolidine-2,4,5-triones.
orthorhombic, Pnma; a = 9.0432(5), b = 26.2181(14), c = 6.2633(3) Å, V =
1485.00(13) Å3, Z = 4, T = 153(2) K, 1547 independent reflections for 107
refined parameters; R1 = 0.038 for 1248 data with I > 2σ(I) and wR2 = 0.105
for all data. CIF and structure factors were deposited with the CCDC,
deposition number: CCDC-1491224.
9. Talhi, O.; Fernandes, J.A.; Pinto, D.C.G.A.; Almeida Paz, F.A.; Silva,
A.S.M. Tetrahedron, 2013, 69, 5413-5420.
10. (a) Olimpieri, F.; Bellucci, M.C.; Marcelli, T.; Volonterio, A. Org.
Biomol. Chem. 2012, 10, 9538-9555; (b) Volonterio, A.; Zanda, M.
Tetrahedron Lett. 2003, 44, 8549-8551; (c) Volonterio, A.; Ramírez de
Arellano, C.; Zanda, M. J. Org. Chem. 2005, 70, 2161-2170.
Conclusion
In summary, we developed an accessible and efficient entry to
the synthesis of 5-hydroxyhydantoins, in one step, via a tandem
process. Visible light is used to accelerate the reaction, and α-
ketoacids proved to be the raw material of choice in this
synthesis. Their reaction with carbodiimides allows reaching a
variety of 5-hydroxyhydantoins under mild conditions and with
good yields. The reported reaction may also be considered as a
good example of atom economy, and meets the criteria for a
green approach for the synthesis of hydantoins.
Acknowledgments
We gratefully acknowledge financial support Benemérita
Universidad Autónoma de Puebla (BUAP-VIEP) MELL-
NAT16-1.
References and notes
1. Haruyama, H.; Takayama, T.; Kinoshita, T.; Kondo, M.; Nakajima, M.;
Haneishi, T. J. Chem. Soc. Perkin Trans. 1 1991, 1637-1640.
2. Merritt, H. H.; Putnam, T.J. J. Am. Med. Assoc. 1938, 111, 1068-1073.
3. Youssef, D.T.A.; Shaala, L.A.; Alshali, K.Z. Mar. Drugs 2015, 13, 6609-
6619.
4. Lenaga, K.; Nakamura, K.; lshii, A.; Taga, T.; Miwa, Y.; Yoneda, F. J.
Chem. Soc. Perkin Trans. 1. 1989, 1153-1156.
5. Le Bihan, Y.-V.; Izquierdo, M.A.; Coste, F.; Aller, P.; Culard, F.; Gehrke,
T.H.; Essalhi, K.; Carell,T.; Castaing, B. Nucleic Acids Research, 2011, 39,
6277–6290.
Supplementary Material
Supplementary data associated with this manuscript
(experimental procedures and copies of 1H and 13C NMR spectra,
X-ray of new compounds) can be found in online version at:

4
Tetrahedron
Graphical Abstract
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template box below.
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Synthesis of 5-hydroxy hydantoins via a
tandem process
Rosa Luisa Meza Leóna,∗ Sylvain Bernèsb, Guadalupe Nallely Cortés López a, Virginia M. Mastranzoc, Martha
Sosa Rivadeneyraa, Fernando Sartillo Piscila
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5
Highlights
•
•
•
Synthesis of 5-hydroxy hydantoins in one pot is
reported
X-ray structures of 5-hydroxy hydantoins 6a
and 6b are reported
an excellent atom economy and good yields
under mild condition reaction is reported