Synthesis and reactivity of 5-methylenehydantoins

Article abstract of DOI:10.1016/j.tet.2011.09.034

5-Methylenehydantoin, as well as the N-mono- and N,N-di-protected derivatives, can be obtained by different synthetic routes. These compounds can undergo a large variety of reactions, such as Diels-Alder, epoxidation, methanol addition and conjugate addition reactions of different types of nucleophiles, including carbon (cyanide), nitrogen (piperidine) and sulfur (thiols, thioacetate) nucleophiles. The reactivity with electrophilic reagents, such as m-CPBA or methanol in acidic medium, and the need for Lewis acids to promote the conjugate addition reactions indicate that hydantoin is a poor electron-withdrawing group.

Full text of DOI:10.1016/j.tet.2011.09.034

Tetrahedron 67 (2011) 8639e8647
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journal homepage: www.elsevier.com/locate/tet
Synthesis and reactivity of 5-methylenehydantoins
a
,
b
,
a
,
b
a
,
b
c
*
ꢀ
ꢀ
ꢀ
Jose M. Fraile
, Gustavo Lafuente , Jose A. Mayoral , Antonio Pallares
a
ꢀ
ꢀ
ꢀ
Instituto de Síntesis Química y Catalisis Homogenea (ISQCH), C.S.I.C., Universidad de Zaragoza, Departamento de Química Organica, Pedro Cerbuna 12, E-50009 Zaragoza, Spain
b
ꢀ
ꢀ
ꢀ
Instituto Universitario de Catalisis Homogenea (IUCH), C.S.I.C., Universidad de Zaragoza, Departamento de Química Organica, Pedro Cerbuna 12, E-50009 Zaragoza, Spain
c Deretil, E-04618 Villaricos (Almería), Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2011
Received in revised form 9 September 2011
Accepted 13 September 2011
Available online 16 September 2011
5-Methylenehydantoin, as well as the N-mono- and N,N-di-protected derivatives, can be obtained by
different synthetic routes. These compounds can undergo a large variety of reactions, such as DielseAlder,
epoxidation, methanol addition and conjugate addition reactions of different types of nucleophiles, in-
cluding carbon (cyanide), nitrogen (piperidine) and sulfur (thiols, thioacetate) nucleophiles. The
reactivity with electrophilic reagents, such as m-CPBA or methanol in acidic medium, and the need for
Lewis acids to promote the conjugate addition reactions indicate that hydantoin is a poor electron-
withdrawing group.
Keywords:
Hydantoins
Conjugate additions
DielseAlder
Epoxidation
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
catalysts to obtain 5-aryl-hydantoins from 5-bromohydantoin and
aromatics.18
The hydantoin unit is highly important in pharmaceutical
chemistry for several reasons. On the one hand hydantoins, and in
particular 5-substituted hydantoins, are present in a large variety of
pharmaceuticals, both from natural and synthetic origin. Different
biological properties, such as anticonvulsive,1 antidepressant,2 an-
tiviral,3 or anticoagulant,4 are associated to the presence of
hydantoins. Spirohydantoins have been described for treatment of
chronic diabetes problems.5 Phenytoin (5,5-diphenylhydantoin)
has been used in the treatment of epilepsy,6 nilutamide (5,5-
dimethylhydantoin) was approved for treatment of prostate can-
cer.7 The structure of 5-alkylidenehydantoin is present in several
natural products, such as aplysinopsines,8 axinohydantoins,9 and
mukanadin B.10
Therefore the development of new synthetic approaches for the
preparation of new hydantoins is an area of practical interest. One
synthetic alternative for preparation of structurally complex
hydantoins would be the use of 5-ylidenehydantoins as synthetic
intermediates. Thus a research program was started with the ob-
jective of generating a library, as large as possible, of hydantoin
derivatives with potential pharmaceutical interest. In this paper we
describe the synthesis of 5-ylidenehydantoins, with particular
emphasis on 5-methylenehydantoins, with and without protection
in the nitrogen atoms, and the evaluation of the latest as synthetic
intermediates in different types of reactions, such as DielseAlder,
epoxidation and conjugate additions.
On the other hand, 5-substituted hydantoins are important
from a synthetic point of view, as they are intermediates in the
industrial synthesis of aminoacids.11 Among them 5-aryl-hydan-
toins play a crucial role in the synthesis of semisynthetic antibi-
otics.12 As an example 5-(4-hydroxyphenyl)-hydantoin can be
prepared by direct condensation of phenol, urea, and either
glyoxylic acid13 or methyl 2-hydroxy-2-methoxyacetate,14,15 re-
action of phenol with allantoin,15,16 or reaction of p-hydroxy-
mandelic acid and urea,17 in all cases with homogeneous or het-
erogeneous acids. Heterogeneous Lewis acids can be used as
2. Results and discussion
2.1. Synthesis of 5-ylidenehydantoins
2.1.1. Synthesis from hydantoin. A first alternative is the function-
alization of position 5 of the hydantoin ring. One option is the
condensation of formaldehyde with a phosphorous derivative of
hydantoin (Scheme 1). In the Wittig variation it is necessary to
prepare a phosphonium salt (2). This was possible by bromination
of hydantoin18 in dioxane under reflux and in situ reaction with
triphenylphosphine at 55 ꢀC.19 The Wittig reaction was first tested
with benzaldehyde, using different organic bases (triethylamine,
aminoethanol, N,N-dimethylaminoethanol) with no success. The
* Corresponding author. Tel.: þ34 976 761000x3514; e-mail address: jmfraile@
unizar.es (J.M. Fraile).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.034

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J.M. Fraile et al. / Tetrahedron 67 (2011) 8639e8647
insolubility of the phosphonium salt (2) in any organic solvents
may be the origin for this lack of reactivity.
compatible with the presence of NeCH2eO groups. Neither the
change of solvent by other with different properties and hence
different hydantoin solubility (1,4-dioxane, THF, dichloromethane,
water) nor that of base (piperidine, triethylamine) allowed im-
proving these results.
Scheme 2.
Hydantoin (1) is insoluble in most of organic solvents and NH
groups may interfere in different reactions, as seen above. In order
to solve both problems, it is possible to selectively protect one or
both NH groups with benzyl or trimethylsilyl moieties (Scheme 3).
Scheme 1.
The HornereWadswortheEmmons variation (Scheme 1) was
more efficient, as the phosphonate19 3, also in situ generated from
hydantoin, was much more soluble in organic solvents. NaH and
LiOH19 were tested as bases for the reaction with benzaldehyde.
The best yield was obtained with LiOH, that was used in the re-
action with different aliphatic and aromatic aldehydes, as well as
aliphatic ketones (Table 1), leading to several 5-alkylidene- and 5-
arylidenehydantoins (4) as Z/E mixtures. However, the reaction
failed with formaldehyde and aromatic ketones.
Table 1
Scheme 3.
Results of the reaction between phosphonate substituted hydantoin (3) and differ-
ent aldehydes and ketonesa
R1
R2
Yield (%)
Z/E
Treatment of hydantoin with sodium methoxide in methanol
allows the selective protection of the most acidic NH in position 3.
Reaction with benzyl bromide led to 3-benzylhydantoin (5) with
65% yield. The use of an excess of sodium methoxide and benzyl
bromide did not produce the dibenzylation, showing that a stron-
ger base was needed in order to abstract the NH in position 1. 1,3-
Dibenzylhydantoin (7) can be prepared by two alternative
methods. On the one hand, treatment of 5 with NaH in dioxane and
benzyl bromide led to 7 with 90% yield. It is also possible the direct
dibenzylation from hydantoin using LDA/THF or K2CO3/DMF as
a base. In the first case by-products derived from diisopropylamine
made difficult the purification of 7. In the second one the final yield
was only 20%. In view of these problems the synthesis of 7 was
carried out in two steps.
The selective protection of NH in position 1 was achieved by
silylation with hexamethyldisilazane (Me3SieNHeSiMe3, HMDS) to
obtain 1-trimethylsilylhydantoin (6, Scheme 3). Disilylation was
not possible either by using harder conditions or by treatment with
base. In this case the reactivity of position 1 seems to indicate that N
is acting as a nucleophile, and N in position 3 is not nucleophilic
enough to react with HMDS.
n-C3H7e
i-C3H7e
n-C6H13e
Phe
p-MePhe
2-Furyle
p-MeOPhe
p-ClPhe
p-NO2Phe
p-CHOPhe
o-CHOPhe
He
He
He
He
He
He
He
He
He
He
He
He
He
Mee
32
58
98
72
74
96
54
51
28
42b
78b
0
63:37
38:62
50:50
67:33
67:33
77:23
72:28
54:46
75:25
n.d.c
n.d.c
d
Mee
28
60
25
0
d
eC5H10e
eC4H8e
Phe
d
d
Mee
Phe
d
Phe
0
d
a
Conditions: 2 mmol 16, 2 mmol LiOH, 2 mmol carbonyl compound, 20 ml eth-
anol, rt 24 h.
b
c
Yield of condensation by both aldehydes.
Mixture of ZZ, ZE and EE products. The ratio could not be determined.
The other possibility is the direct condensation of hydantoin
with formaldehyde in basic medium. This method had been de-
scribed for aromatic aldehydes,20 and also for aliphatic aldehydes21
including carbohydrates.22 Reaction with benzaldehyde using
aminoethanol as a base in water led to better results (94% yield of Z
isomer 4, Scheme 2) than the HornereWadswortheEmmons re-
action. Moreover the selectivity was much better, with only Z iso-
mer being detectable by 1H NMR. However only 16% yield was
obtained with acetone, and the reaction with formaldehyde led to
a complex mixture, which 1H NMR spectrum showed the disap-
pearance of NH groups and several signals at 3.8e4.2 ppm
Thus the condensation reaction was carried out with 1,3-
dibenzylhydantoin (7) using aminoethanol as a base in THF. A
mixture of 1,3-dibenzyl-5-hydroxymethylhydantoin (8), 1,3-
dibenzyl-5,5-bis(hydroxymethyl)hydantoin (9) and 1,3-dibenzyl-
5-methylene-hydantoin (10) was obtained (Scheme 4). Attempts to
minimize the formation of the dihydroxyalkylated product 9 by
lowering reaction temperature and time, amount of formaldehyde
led to very low conversion. On the contrary the substitution of THF
by dioxane and the increase in reaction temperature even enhanced
the formation of 9. It seems that once the hydroxymethylhydantoin

J.M. Fraile et al. / Tetrahedron 67 (2011) 8639e8647
8641
8 is formed, it favourably and unavoidably competes with 7 for
hydroxyalkylation. Conversion of 8 into 10, was accomplished by
heating the crude in the presence of MgSO4, leading to 40% yield of
the desired product.
The elimination should be easier in the case of 5-
hydroxymethylhydantoin (15). It can be prepared in quantitative
yield from serine (14a) by reaction with KOCN (Scheme 6).25
However, reactions with sulfonyl chlorides were again unsuccess-
ful, probably due to the low solubility of 15 in most organic sol-
vents. In the case of reaction with acids, conversion was observed at
high temperature and long reaction time, but only unidentified
products were obtained.
Scheme 4.
2.1.2. Simultaneous synthesis of the hydantoin ring. The condensa-
tion of pyruvic acid with acetamide leads to N-acetamidoacrylic
acid.23 Analogously the condensation of pyruvic acid with urea
should give the corresponding ureide, and then the hydantoin by
cyclization (Scheme 5). In fact 5-bromomethylenehydantoins have
been synthesized from 3-bromopyruvic acid and ureas, catalyzed
by BF3.24
Scheme 6.
Protection of hydantoin should help to overcome the solubility
problems. 3-Benzyl-5-hydroxymethylhydantoin (17) was prepared
from serine methyl ester (14b) and benzyl isocyanate in two steps,
first a condensation in basic medium to give the ureide, and then
cyclization in acidic medium with 83% overall yield (Scheme 6).
Elimination was possible with PPh3/diethyl azadicarboxylate
(DIAD)/Et3N/THF26 to produce 3-benzyl-5-methylenehydantoin
(18). The lack of reactivity of 15 under the same conditions seems
to confirm the solubility issue with this reagent.
Another option would be the preparation of 5-methylene-
hydantoin (16) by elimination of 5-chloromethylhydantoin. This
route (Scheme 7) started with the preparation of 3-chloro-2-
hydroxypropionitrile (20) from chloroacetaldehyde (19) and sub-
sequent formation of hydantoin with simultaneous elimination.
The need for purification of the intermediate cyanohydrin by ex-
traction in ether, together with its quite high solubility in water and
its high volatility, make yield remain very low (15%).
Scheme 5.
Starting from pyruvic acid or methyl pyruvate in excess with
continuous water elimination using a DeaneStark, the reaction led
to 5-hydroxy-5-methylhydantoin (12), either in the absence or in
the presence of an acid catalyst. The use of stoichiometric amounts
of both reagents produced the double reaction of the carbonyl
group of the pyruvic derivative to obtain the corresponding diu-
reide 13, showing that nucleophilic attack of urea on the carbonyl
group is the first step whereas cyclization is the second one. The
intermediate hydroxyureide easily reacts with a second molecule of
urea, unless the concentration of pyruvic/pyruvate is much higher.
All the attempts to eliminate the hydroxyl group of 12 were
unsuccessful. One possibility was the conversion into a good leav-
ing group by sulfonation. However 12 was unable to react with
p-toluenesulfonyl chloride/BuLi/DMF and methanesulfonyl chlo-
ride/Et3N/THF, probably due to the steric hindrance around the
tertiary alcohol together with the poor solubility of 12 in organic
solvents and the acidity of the free NH groups. Treatment with acids
(neat acetic, neat phosphoric, hydrochloric/benzene, neat formic/
acetic anhydride) under heating led to complex mixtures of un-
identified compounds, with only traces of 5-methylenehydantoin.
The instability of the carbonium ion in position 5 of hydantoin, due
to the electron-withdrawing character of the neighbour carbonyl
and the presence of other basic centres in the molecule, may ac-
count for this behaviour.
Scheme 7.
2.2. Reactivity
In this work the objective was to test the reactivity of methyl-
enehydantoins as either electron-deficient alkenes, due to the
presence of the carbonyl as electron-withdrawing group, and the
limitations due to the slightly donor character of the nitrogen. As
the idea was the preparation of a large number of molecules, the
synthetic methods were not optimized. Most of methods were
tested with the more soluble 1,3-dibenzyl-5-methylenehydantoin

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J.M. Fraile et al. / Tetrahedron 67 (2011) 8639e8647
(10) and only some of them were tried with the unprotected 5-
methylenehydantoin (16).
methylhydantoin 24 (Scheme 10). Again the poor withdrawing
character of hydantoin seems to be the origin of this behaviour,
allowing the formation of the tertiary carbonium cation in position
5 of the hydantoin ring.
2.2.1. DielseAlder reactions. One example of DielseAlder reaction
with a chirally 1,3-disubstituted-5-methylenehydantoin had been
described in the literature,27 as well as some 1,3-dipolar cycload-
ditions,28 and the use of 5-methylene-4-thiohydantoins as
heterodienes.29
In a first reaction, 1,3-dibenzyl-5-methylenehydantoin (10) was
made react with 2,3-dimethylbuta-1,3-diene (Scheme 8). Under
thermal conditions (toluene under reflux) the reaction did not take
place, but the corresponding spirohydantoin 21 was obtained using
ZnI2 (50% mol) at 80 ꢀC.
Scheme 10.
2.2.4. Conjugate addition of cyanide. The addition of a C1 synthon
would open the way to hydantoin precursors of aspartic ana-
logues. Cyanide was chosen as simple but versatile C1 nucleo-
phile. A Lewis acid was necessary to promote the reaction, in this
case Cu(OTf)2 (15% mol),34 confirming the poor electrophilic
character of the alkene. Reaction of 1,3-dibenzyl-5-
methylenehydantoin with NaCN in the presence of the Lewis
acid in acetonitrile/water at 40 ꢀC, led to quantitative conversion
to the expected 5-cyanomethylhydantoin 25 and another product.
Purification and analysis showed that this product was a spi-
robis(hydantoin) 26, that should come from the addition of the
enolate of 25 to a second molecule of methylenehydantoin and
subsequent cyclization of the intermediate enolate (Scheme 11).
The spirobis(hydantoin) 26 can be obtained as the only product
when using only a slight excess of NaCN (NaCN/10¼1.5) after 14 h,
whereas total selectivity to the cyanomethylhydantoin 25 can be
obtained at low conversion (50%) by using a larger excess of NaCN
(NaCN/10¼15) at rt. Longer reaction times and/or higher tem-
perature (40 ꢀC) always lead to a 25/26 selectivity of 77/23. An
intramolecular attack of the intermediate enolate to a nitrile had
been described in the conjugate addition of malononitrile enolate
to 5-arylidene-2-thiohydantoins,29 but to the best of our knowl-
edge this is the first intermolecular addition described for this
kind of systems.
Scheme 8.
The reaction with cyclopentadiene (Scheme 8) was carried out
at rt with Et2AlCl (100% mol). Both possible spirohydantoin isomers,
22n and 22x, in 75:25 ratio were obtained, being major the one
with the nitrogen in endo position (22n), in agreement with the
result obtained with N-acetyl-dehydroalaninates.30
2.2.2. Epoxidation. The epoxidation of 5-methylenehydantoins
would lead to oxiranic spirohydantoins, which may be interesting
synthetic intermediates. All the attempts to epoxidize 1,3-dibenzyl-
5-methylenehydantoin in basic medium, either with hydrogen
peroxide, using K2CO3 or hydrotalcite31 as a base, or tert-butyl hy-
droperoxide, using KF/alumina as a base,32 were unsuccessful,
probably due to the poor electron-withdrawing character of the
hydantoin group.
Thus the epoxide 23 was obtained in quantitative yield by direct
epoxidation with a typical electrophilic oxidant, such as m-chlor-
operbenzoic acid in CH2Cl2 at rt (Scheme 9). This result opens the
way to the possible use of catalytic epoxidations with alkyl
hydroperoxides.
Scheme 9.
Scheme 11.
2.2.3. Reaction with methanol. The addition of oxygen nucleophiles
would allow obtaining hydantoin precursors of serine analogues,
and methanol was chosen as model compound. 1,3-Dibenzyl-5-
methylenehydantoin (10) was shown to be inert against MeONa/
MeOH/THF, NaOH/MeOH/THF, MeOH/CH3CN/water/Cu(OTf)2, or
MeOH under reflux.33 Only the reaction of methanol in acidic
medium led to reaction, but in this case methoxide was added to
carbon 5 of hydantoin ring, leading to 1,3-dibenzyl-5-methoxy-5-
2.2.5. Conjugate addition of piperidine. Piperidine was chosen as an
example of nitrogen nucleophile (Scheme 12). Quantitative yield of
compound 27 was obtained by addition of piperidine to 1,3-
dibenzyl-5-methylenehydantoin (10) at 40 ꢀC using only 3 equiv
of piperidine in the presence of Cu(OTf)2 (15% mol).34 The lack of

J.M. Fraile et al. / Tetrahedron 67 (2011) 8639e8647
8643
by-products of the same type as 26 may be due to the change from
a charged nucleophiles (cyanide) to a neutral one (piperidine).
methylenehydantoin and, in lower degree, 5-methylenehydantoin
have shown to be valuable intermediates for a wide variety of re-
actions, including DielseAlder cycloadditions, epoxidation and
conjugate additions of thiols (phenylmethanethiol, sodium hydro-
sulfide, potassium thioacetate), amines (piperidine) and cyanide.
Hydantoin precursors of cysteine or aspartic acid can be then pre-
pared, as well as different types of spirohydantoins. In contrast with
the expected behaviour, methylenehydantoins are poorly electro-
philic, due to the low electron-withdrawing character of the
hydantoin ring, and efficiently react as nucleophiles. Electrophi-
licity can be improved by the use of Lewis acids. These results open
the way for future developments in the field.
Scheme 12.
2.2.6. Conjugate addition of sulfur compounds. Due to the interest of
hydantoin precursors of cysteine analogues, several types of sulfur
compounds were tested as nucleophiles (Scheme 13).
4. Experimental section
4.1. General procedure for 5-alkylidenehydantoins (4)
To a solution of hydantoin (956 mg, 5 mmol) in anhydrous di-
oxane (2 ml) heated at 105 ꢀC under inert atmosphere was slowly
added bromine (800 mg, 5 mmol) and the resulting solution was
stirred at the same temperature for 45 min. After cooling at rt,
triethyl phosphite (830 mg, 5 mmol) was slowly added, always
keeping reaction temperature below 45 ꢀC. The mixture was stirred
for 90 min and the solvent was removed under reduced pressure.
The crude was washed with hexane, filtered and dried to obtain 5-
diethylphosphonatehydantoin (3) (1.44 g, 92% yield). 1H NMR
(DMSO-d6,
d ppm): 8.89 (s, 1H), 7.33e7.25 (m, 5H), 4.94 (d, 1H,
J¼14.8 Hz), 4.58 (dd, 1H, J¼14.9 Hz), 4.52 (d, 1H, J¼14.9 Hz), 4.07 (c,
4H, J¼7.0 Hz), 1.21 (t, 6H, J¼7.0 Hz). 13C NMR (DMSO-d6,
d ppm):
167.6, 136.2, 128.3, 127.5, 127.3, 127.1, 55.7, 54.2, 41.2, 16.1. 31P NMR
(DMSO-d6,
d ppm): 12.8.
A solution of 5-diethylphosphonatehydantoin (3) (2 mmol), the
carbonyl compound (2 mmol) and LiOH (48 mg, 2 mmol) in ethanol
(20 ml) was stirred at rt for 24 h. The solid product was filtered,
washed with ethanol and dried.
5-Benzylidenehydantoin (273 mg, 72% yield, Z/E ratio 67/33):
Elemental analysis (C10H8N2O2): theoretical C 63.82, H 4.28, N
14.89; experimental: C 63.73, H 4.41, N 14.77. Z isomer: 1H NMR
Scheme 13.
(DMSO-d6,
6.41 (s, 1H). 13C NMR (DMSO-d6,
128.7, 128.3, 127.9, 108.3. E isomer: 1H NMR (DMSO-d6,
11.15 (s, 1H), 10.30 (s, 1H), 7.62e7.31 (m, 5H), 6.33 (s, 1H). 13C NMR
d
ppm): 11.24 (s, 1H), 10.54 (s, 1H), 7.62e7.31 (m, 5H),
ppm): 165.5, 156.7, 132.9, 129.3,
ppm):
Reaction with phenylmethanethiol was accomplished in meth-
anol with triethylamine as a base, the same conditions used for
dehydroalaninates.35 Yields were quantitative with 5-
methylenehydantoins, even with the poorly soluble unprotected 16.
Reaction with sodium hydrosulfide was not possible with 16,
probably due to the acidic character of the NH groups. On the
contrary, reaction with 10 in methanol/THF (1:1) took place with
100% conversion to produce 30 (Scheme 13).
d
d
(DMSO-d6,
d ppm): 163.5, 153.8, 129.8, 128.7, 128.6, 128.2, 128.0,
115.5.
5-(2-Methylpropylene)hydantoin (179 mg, 58% yield, Z/E ratio 38/
62): Elemental analysis (C7H10N2O2): theoretical C 54.54, H 6.49, N
18.18; experimental: C 54.47, H 6.61, N 18.27. Z isomer: 1H NMR
Potassium thioacetate is less basic and nucleophilic than sodium
hydrosulfide. Reaction did not take place (<5% yield) in water/
acetonitrile in the absence of catalyst. However different Lewis
acids (CuCl2, Cu(OTf)2, YbCl3, Yb(OTf)3) were able to promote the
reaction. After an optimization process, including thioacetate/
hydantoin ratio, type and amount of Lewis acid, and reaction
temperature, 100% yield of either 31 or 32 was obtained with
10 equiv of thioacetate and 60% mol Yb(OTf)3 at 90 ꢀC.
In this case the lack of bis-hydantoin by-products cannot be
ascribed to the use of neutral nucleophiles. A more likely reason
would be the absence of an electrophilic centre (such as nitrile in
the case of the bis-hydantoin enolate intermediate to 26) able to
shift the equilibrium towards a stable bis-hydantoin product.
(DMSO-d6,
d ppm): 10.93 (s, 1H), 10.14 (s, 1H), 5.35 (d, 1H,
J¼10.1 Hz), 2.63 (m, 1H), 0.99 (d, 3H, J¼6.6 Hz). 13C NMR (DMSO-d6,
d
ppm): 164.7, 154.8, 128.6, 118.2, 25.7, 22.1. E isomer: 1H NMR
(DMSO-d6,
d
ppm): 10.93 (s, 1H), 9.92 (s, 1H), 5.23 (d, 1H, J¼10.1 Hz),
3.55 (m, 1H), 0.97 (d, 3H, J¼6.6 Hz). 13C NMR (DMSO-d6,
d ppm):
164.5, 153.9, 127.8, 123.8, 24.4, 22.9.
5-Isopropylidenehydantoin (80 mg, 28% yield): Elemental anal-
ysis (C6H8N2O2): theoretical C 51.42, H 5.75, N 19.99; experimental:
C 51.33, H 5.91, N 20.07. 1H NMR (DMSO-d6,
d ppm): 10.85 (s, 1H),
9.77 (s, 1H), 2.11 (s, 3H), 1.79 (s, 3H). 13C NMR (DMSO-d6,
d ppm):
164.7, 153.9, 124.9, 123.9, 20.6, 17.9.
4.2. Synthesis of 3-benzylhydantoin (5)
3. Conclusions
A solution of hydantoin (6.00 g, 60 mmol) and sodium meth-
oxide (3.66 g, 68 mmol) in anhydrous methanol (60 ml) was heated
at 60 ꢀC for 1 h under inert atmosphere. Benzyl bromide (12.24 g,
72 mmol) was then added and the mixture was stirred at the same
temperature for 14 h. After cooling at rt, the solvent was eliminated
5-Methylenehydantoins, including unprotected, 1- and 3-
monoprotected and 1,3-diprotected ones, can be prepared by dif-
ferent methods, although in low yield. 1,3-Dibenzyl-5-

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J.M. Fraile et al. / Tetrahedron 67 (2011) 8639e8647
under reduced pressure, and the obtained solid was stirred with
water (100 ml) for 12 h, filtered and dried under vacuum. 3-
Benzylhydantoin (7.5 g, 65% yield) was obtained as a white solid.
Elemental analysis (C10H10N2O2): theoretical C 63.15, H 5.30, N
14.73; experimental: C 63.26, H 5.24, N 14.59. 1H NMR (DMSO-d6,
(s, 1H), 6.78 (s, 1H), 1.32 (s, 3H). 13C NMR (DMSO-d6,
d ppm): 175.7,
156.1, 68.7, 24.3.
4.7. Synthesis of 2,2-diureidepropanoic acid (13a)
d
ppm): 8.12 (s, 1H), 7.32e7.26 (m, 5H), 4.53 (s, 2H), 3.98 (s, 2H). 13
C
To a solution of pyruvic acid (3.5 g, 40 mmol) in anhydrous
benzene (56 ml) heated under reflux in a DeaneStark apparatus,
urea (2.5 g, 40 mmol) was added and the resulting solution was
refluxed for 7 h. After cooling at rt, the solid was filtered off, washed
with methanol and dried. 2,2-Diureidepropanoic acid (1.9 g, 25%
NMR (DMSO-d6, d ppm): 171.8, 157.3, 136.7, 128.3, 127.3, 127.2, 45.9,
40.9.
4.3. Synthesis of 1,3-dibenzylhydantoin (7)
yield) was obtained as
a white solid. Elemental analysis
(C5H10N4O4): theoretical C 31.58, H 5.26, N 29.47; experimental: C
A solution of 3-benzylhydantoin (5, 6.80 g, 35.8 mmol) and so-
dium hydride (0.974 g, 40 mmol) in anhydrous dioxane (50 ml) was
heated at 90 ꢀC for 90 min under inert atmosphere. Benzyl bromide
(7.31 g, 43 mmol) was then added and the mixture was stirred at
110 ꢀC for 14 h. After cooling at rt, the solvent was eliminated under
reduced pressure. Dichloromethane (50 ml) was added, the solid
was filtered off, and the solution was concentrated under reduced
pressure. The oil was crystallized in hexane to obtain 1,3-
dibenzylhydantoin (9.02 g, 90% yield) as a white solid. Elemental
analysis (C17H16N2O2): theoretical C 72.84, H 5.75, N 9.99; experi-
31.45, H 5.21, N 29.63. 1H NMR (DMSO-d6,
d ppm): 12.62 (s,1H), 6.63
(s, 2H), 5.70 (s, 4H), 1.58 (s, 3H). 13C NMR (DMSO-d6,
d ppm): 165.8,
156.0, 102.3, 33.2.
4.8. Synthesis of methyl 2,2-diureidepropanoate (13b)
To a solution of methyl pyruvate (11.4 g,100 mmol) in anhydrous
benzene (70 ml) heated under reflux in a DeaneStark apparatus,
urea (2.5 g, 40 mmol) was added and the resulting solution was
refluxed for 20 h. After cooling at rt, the solvent and the excess of
pyruvate were eliminated at reduced pressure. The yellowish solid
was filtered off, washed with acetone and dried. Methyl 2,2-
diureidepropanoate (3.3 g, 81% yield) was obtained as a white
solid. Elemental analysis (C6H12N4O4): theoretical C 35.29, H 5.26, N
27.45; experimental: C 35.41, H 5.11, N 27.52. 1H NMR (DMSO-d6,
mental: C 72.75, H 5.62, N 10.05. 1H NMR (CDCl3,
(m, 10H), 4.61 (s, 2H), 4.47 (s, 2H), 3.64 (s, 2H). 13C NMR (CDCl3,
ppm): 169.2, 156.2, 135.7, 135.0, 128.7, 128.4, 128.3, 127.9, 127.8,
d ppm): 7.34e7.16
d
127.6, 48.8, 46.4, 42.3.
4.4. Synthesis of 1-trimethylsilylhydantoin (6)
d
ppm): 6.82 (s, 2H), 5.71 (s, 4H), 3.61 (s, 3H), 1.64 (s, 3H). 13C NMR
(DMSO-d6, ppm): 172.5, 157.3, 66.3, 52.4, 24.6.
d
A mixture of hydantoin (1.0 g, 10 mmol), hexamethyldisilazane
(3.22 g, 20 mmol) and dichloromethane (5 ml) was heated under
reflux for 72 h under inert atmosphere. After cooling at rt, the
solvent was eliminated under reduced pressure to obtain 1-
trimethylsilylhydantoin (1.66 g, 96% yield). 1H NMR (DMSO-d6,
4.9. Synthesis of 5-hydroxymethylhydantoin (15)
A solution of potassium cyanate (4.0 g, 49.4 mmol) and serine
(4.0 g, 38.1 mmol) in water (50 ml) was heated under reflux for
90 min. After cooling at rt, hydrochloric acid (15 ml, 35% aq solu-
tion) was added and the mixture was heated under reflux for 24 h.
The solvent was removed under reduced pressure, and the result-
ing solid was washed with methanol and dried, leading to 5-
hydroxymethylhydantoin (5.1 g, 99% yield) as a white solid. Ele-
mental analysis (C4H6N2O3): theoretical C 36.93, H 4.65, N 21.53;
d
ppm): 10.60 (s, 1H), 3.92 (s, 2H), 0.23 (s, 9H). 13C NMR (DMSO-d6,
ppm): 174.3, 160.6, 50.2, ꢁ1.3.
d
4.5. Synthesis of 1,3-dibenzyl-5-methylenehydantoin (10)
A mixture of 1,3-dibenzylhydantoin (1.4 g, 5 mmol), ethanol-
amine (0.25 ml), THF (2.5 ml) and formaldehyde (15 ml of 37% aq
solution) was heated in a closed vessel at 80 ꢀC for 24 h. After
cooling at rt the solvent was removed under reduced pressure. The
crude was dissolved using dichloromethane (150 ml) and water
(150 ml). After decantation, the organic phase was dried over
MgSO4, filtered and evaporated under reduced pressure. The oily
residue was purified by column chromatography on silica gel using
dichloromethane as an eluent. 1,3-Dibenzyl-5-methylenehyda-
ntoin (350 mg, 24% yield) was obtained as a white solid. Ele-
mental analysis (C18H16N2O2): theoretical C 73.95, H 5.52, N 9.58;
experimental: C 37.05, H 4.52, N 21.41. 1H NMR (DMSO-d6,
10.51 (s, 1H), 7.77 (s,1H), 5.06 (m,1H), 3.98 (m, 1H), 3.57 (m, 1H). 13C
NMR (DMSO-d6, ppm): 109.0, 164.2, 66.7, 66.2.
d ppm):
d
4.10. Synthesis of 3-benzyl-5-hydroxymethylhydantoin (17)
Benzyl isocyanate (4.51 g, 33.9 mmol) was added to a solution of
serine methyl ester (5.25 g, 33.9 mmol) and triethylamine (3.42 g,
33.9 mmol) in anhydrous acetonitrile (30 ml) under inert atmo-
sphere, and the mixture was heated at 80 ꢀC for 24 h. The solvent
was removed under reduced pressure; the crude was dissolved
with water (200 ml) and then extracted with dichloromethane
(4ꢂ200 ml). The combined organic phases were dried over MgSO4,
filtered and evaporated under reduced pressure. The resulting solid
was washed with diethyl ether (200 ml), filtered, washed, and dried
leading to methyl 2-(3-benzylureide)-3-hydroxypropanoate (7.1 g,
83% yield). Elemental analysis (C12H16N2O4): theoretical C 57.13, H
6.39, N 11.10; experimental: C 57.25, H 6.51, N 11.01. 1H NMR
experimental: C 74.07, H 5.61, N 9.67. 1H NMR (CDCl3,
d ppm):
7.37e7.15 (m, 10H), 5.28 (d, 2H; J¼2.4 Hz), 4.70 (s, 2H), 4.69 (s, 2H),
4.60 (d, 2H; J¼2.4 Hz). 13C NMR (CDCl3,
d ppm): 162.2, 154.2,
135.8, 135.6, 135.0, 128.9, 128.8, 128.7, 128.1, 128.0, 127.3, 95.6, 44.2,
44.6.
4.6. Synthesis of 5-hydroxy-5-methylhydantoin (12)
To a solution of pyruvic acid (8.8 g, 100 mmol) in anhydrous
benzene (56 ml) heated under reflux in a DeaneStark apparatus,
urea (2.5 g, 40 mmol) was added and the resulting solution was
refluxed for 5 h. After cooling at rt, the solid was filtered off, washed
with methanol and dried. 5-Hydroxy-5-methylhydantoin (1.24 g,
27% yield) was obtained as a white solid. Elemental analysis
(C4H6N2O3): theoretical C 36.93, H 4.65, N 21.53; experimental: C
(DMSO-d6,
d
ppm): 7.34e7.19 (m, 5H), 6.75 (t, 1H; J¼5.4 Hz), 6.34 (d,
1H; J¼7.4 Hz), 5.11 (t, 1H; J¼5.1 Hz), 4.24 (m, 1H), 4.21 (d, 2H;
J¼6.0 Hz), 3.78e3.71 (m, 1H), 3.63 (s, 3H), 3.61e3.54 (m, 1H). 13C
NMR (DMSO-d6, d ppm): 172.2, 157.6, 140.6, 128.2, 126.9, 126.5, 61.9,
55.0, 51.7, 42.7.
Hydrochloric acid (2.5 ml of 35% aq solution) was added to
solution of methyl 2-(3-benzylureide)-3-hydroxypropanoate
a
36.82, H 4.57, N 21.42. 1H NMR (DMSO-d6,
d
ppm): 10.35 (s, 1H), 7.93
(7.1 g, 28.2 mmol) in methanol (200 ml), and the mixture was

J.M. Fraile et al. / Tetrahedron 67 (2011) 8639e8647
8645
heated at 80 ꢀC for 24 h. The solvent was removed under reduced
pressure and the resulting solid was washed with diethyl ether
(200 ml), filtered, and dried, leading to 3-benzyl-5-
hydroxymethylhydantoin (6.2 g, 99% yield) as a white solid. Ele-
mental analysis (C11H12N2O3): theoretical C 59.99, H 5.49, N 12.72;
7,8-dimethyl-1,3-diazaspiro[4.5]dec-7-en-2,4-dione (21) (102 mg,
91% yield). Elemental analysis (C24H26N2O2): theoretical C 76.98, H
7.00, N 7.48; experimental: C 77.13, H 7.07, N 7.35. 1H NMR (CDCl3,
d
ppm): 7.34e7.11 (m, 10H), 4.64 (s, 2H), 4.51 (d,1H, J¼15.6 Hz), 4.42
(d, 1H, J¼15.6), 2.26 (m, 1H), 2.13 (m, 1H), 1.85(m, 1H), 1.81 (m, 2H),
1.65 (m,1H),1.55 (s, 3H),1.36 (s, 3H). 13C NMR (CDCl3,
ppm): 175.8,
experimental: C 59.87, H 5.61, N 12.57. 1H NMR (DMSO-d6,
d
ppm):
d
8.19 (s, 1H), 7.30e7.24 (m, 5H), 5.16 (t, 1H; J¼5.1 Hz), 4.56 (d, 1H;
156.5, 138.4, 136.4, 128.7, 128.5, 128.4, 127.8, 127.4, 127.1, 125.4,
122.0, 63.4, 44.3, 42.5, 36.7, 30.1, 28.2, 18.8, 18.7.
J¼15.6 Hz), 4.48 (d, 2H; J¼15.6 Hz), 4.15 (t, 1H, J¼2.3 Hz), 3.65 (m,
2H). 13C NMR (DMSO-d6,
d ppm): 173.0, 157.1, 136.8, 128.4, 127.2,
127.0, 59.8, 59.2, 40.9.
4.14. DielseAlder reaction with cyclopentadiene
4.11. Synthesis of 3-benzyl-5-methylenehydantoin (18)
(a) Thermal reaction:
A
solution of 1,3-dibenzyl-5-
methylenehydantoin (146 mg. 0.5 mmol) and freshly distilled
cyclopentadiene (660 mg, 10 mmol) in toluene (12 ml) was stirred
at 100 ꢀC for 24 h. The reaction was cooled at rt and the solvent was
eliminated under reduced pressure. The crude oil was crystallized
in hexane, leading to product 22n (170 mg, 95% yield). 1H NMR
To a solution of 3-benzyl-5-hydroxymethylhydantoin (3.27 g,
14.8 mmol) and triphenylphosphine (4.32 g, 16.5 mmol) in anhy-
drous THF (40 ml) cooled at 0 ꢀC under inert atmosphere, diiso-
propyl azadicarboxylate (3.25 ml, 16.5 mmol) was slowly added.
The mixture was stirred at rt for 10 min, triethylamine (1.51 g,
15 mmol) was added and the resulting solution was stirred for 14 h.
The solvent was removed under reduced pressure. The resulting oil
was purified by column chromatography on silica gel using hexane/
ethyl acetate (1:1) as an eluent, leading to 3-benzyl-5-
methylenehydantoin (2.95 g, 95% yield). Elemental analysis
(C11H10N2O2): theoretical C 65.34, H 4.95, N 13.86; experimental: C
(CDCl3,
d
ppm): 7.37e7.00 (m, 10H), 6.41 (dd, 1H, J¼5.7, 3.6 Hz), 5.74
(dd, 1H, J¼5.7, 3.6 Hz), 4.75 (s, 2H), 4.66 (d, 1H, J¼12.0 Hz), 4.32 (d,
1H, J¼12.0 Hz), 2.92 (dd, 1H, J¼3.6, 3.6 Hz), 2.91 (d, 1H, J¼3.6 Hz),
2.53 (d, 1H, J¼5.7 Hz), 2.15 (dd, 1H, J¼12.3, 3.6 Hz), 1.35 (d, 1H,
J¼12.3 Hz), 1.26 (d, 1H, J¼5.7 Hz). 13C NMR (CDCl3,
d ppm): 176.0,
155.8, 139.5, 136.7, 135.4, 132.8, 127.9, 127.6, 127.4, 126.7, 126.0,
125.3, 68.6, 52.7, 47.1, 43.7, 41.6, 40.8, 34.0.
65.43, H 4.82, N 13.77. 1H NMR (DMSO-d6,
d
ppm): 8.88 (s, 1H),
(b) Catalytic reaction:
A
solution of 1,3-dibenzyl-5-
7.36e7.24 (m, 5H), 5.18 (d, 1H, J¼2.1 Hz), 4.87 (d, 1H, J¼2.1 Hz), 4.60
methylenehydantoin (292 mg, 1 mmol) and EtAlCl2 (1 mmol) in
anhydrous CH2Cl2 (5 ml) was stirred under inert atmosphere for 1 h
at rt. Then freshly distilled cyclopentadiene (1320 mg, 20 mmol)
was added and the reaction was stirred at rt for 12 h. The solvent
was eliminated under reduced pressure and the crude oil was
crystallized in hexane, leading to a mixture of 22n and 22x in 75/25
ratio (350 mg, 98% yield).
(s, 2H). 13C NMR (CDCl3,
131.6, 127.9, 95.9, 42.1.
d ppm): 163.0, 154.3, 135.9, 134.7, 133.0,
4.12. Synthesis of 5-methylenehydantoin (16)
Chloroacetaldehyde diethyl acetal (15.2 g, 100 mmol) was dis-
solved in an aqueous solution of HCl (30 ml, 5.5 M) and the so-
lution was stirred at rt for 24 h. After cooling at 0 ꢀC, Na2SO3
(18.9 g, 150 mmol) and NaHSO3 (39 g of a 40% aq solution,
150 mmol) were added. After 10 min stirring at 0 ꢀC, the solution
was warmed at rt, KCN (75 ml of 2 M aq solution) was added
dropwise (20 min), the resulting mixture was stirred for 2 h, and
then extracted with diethyl ether (4ꢂ50 ml). The combined or-
ganic phases were dried over MgSO4, filtered and evaporated
under reduced pressure. A solution of (NH4)2CO3 (180 mmol) in
water/methanol (3/2, 200 ml) was added to the residue, and the
mixture was stirred at rt for 14 h. The methanol was evaporated
under reduced pressure and the aqueous solution was extracted
with ethyl acetate (6ꢂ50 ml). The combined organic phases were
dried over MgSO4, filtered and evaporated under reduced pres-
sure. The resulting solid was washed with a small amount of water
and dried, leading to 5-methylenehydantoin (1.0 g, 9% yield) as
a white solid. Elemental analysis (C4H4N2O2): theoretical C 42.86,
H 3.60, N 24.99; experimental: C 42.80, H 3.72, N 24.85. 1H NMR
Spectra of 22x (from the mixture). 1H NMR (CDCl3,
d ppm):
7.37e7.00 (m, 10H), 6.31 (dd, 1H, J¼5.5, 2.9 Hz), 6.09 (dd, 1H, J¼5.5,
3.3 Hz), 4.88 (d, 1H, J¼16.5 Hz), 4.7 (s, 2H), 4.49 (d, 1H, J¼16.5 Hz),
2.94 (m, 2H), 2.66 (m, 1H), 1.83 (m, 1H), 1.81 (m, 1H), 1.59 (m, 1H).
13C NMR (CDCl3,
d ppm): 174.4, 155.3, 138.6, 136.7, 134.5, 132.7,
127.8, 127.6, 127.5, 127.0, 126.2, 125.8, 69.4, 51.1, 48.0, 43.2, 41.9, 41.8,
35.8.
4.15. Epoxidation
A solution of 1,3-dibenzyl-5-methylenehydantoin (87.6 mg.
0.3 mmol) and m-chloroperbenzoic acid (309 mg, 0.9 mmol) in
CH2Cl2 (10 ml) was stirred for 40 h at rt. CH2Cl2 (20 ml) and aqueous
NaOH solution (30 ml, 0.085 M) were added. Once separated, the
organic phase was dried over anhydrous MgSO4, filtered and
evaporated under vacuum, leading to 4,6-dibenzyl-1-oxo-4,6-
diazaspiro[2.4]heptane-5,7-dione (23) (87 mg, 94% yield). 1H
NMR (CDCl3,
d
ppm): 7.51e7.02 (m, 10H), 4.71 (d, 1H, J¼15.6 Hz),
(DMSO-d6,
d
ppm): 11.07 (s, 1H), 10.27 (s, 1H), 5.01 (d, 1H,
4.62 (d, 1H, J¼14.8 Hz), 4.57 (d, 1H, J¼14.8 Hz), 4.37 (d, 1H,
J¼3.3 Hz), 4.72 (d, 1H, J¼3.3 Hz). 13C NMR (DMSO-d6,
d ppm):
J¼11.6 Hz), 4.31 (d, 1H, J¼15.6 Hz), 4.21 (d, 1H, J¼11.6 Hz). 13C NMR
164.1, 154.3, 136.4, 92.7.
(CDCl3, d ppm): 169.7, 156.5, 136.2, 135.6, 128.7, 128.6, 128.2, 128.0,
127.9, 127.7, 87.9, 60.5, 43.3, 43.0.
4.13. DielseAlder reaction with 2,3-dimethylbuta-1,3-diene
4.16. Synthesis of 1,3-dibenzyl-5-methoxy-5-
methylhydantoin (24)
To a solution of 1,3-dibenzyl-5-methylenehydantoin (87.6 mg.
0.3 mmol) and ZnI2 (32 mg, 0.15 mmol, pre-dried for 24 h at 140 ꢀC
under vacuum) in anhydrous toluene (5 ml) under inert atmo-
sphere was added 2,3-dimethylbuta-1,3-diene (738 mg, 9 mmol)
and the mixture was stirred at 80 ꢀC for 40 h. The reaction was
cooled at rt and the solvent was eliminated under reduced pres-
sure. The crude was fractioned with CH2Cl2 (15 ml) and water
(15 ml). Once separated, the organic phase was dried over anhy-
drous MgSO4, filtered and evaporated under vacuum. The resulting
solid was washed with methanol (10 ml) leading to 1,3-dibenzyl-
To a solution of 1,3-dibenzyl-5-methylenehydantoin (29.2 mg.
0.1 mmol) in methanol (5 ml) was added an aqueous solution of HCl
(35%, 0.2 ml) and the resulting mixture was heated at 80 ꢀC for 24 h.
After cooling at rt the solvent was eliminated under reduced
pressure to obtain 1,3-dibenzyl-5-methoxy-5-methylhydantoin in
quantitative yield. Elemental analysis (C19H20N2O3): theoretical C
70.35, H 6.21, N 8.64; experimental: C 70.19, H 6.27, N 8.52. 1H NMR
(CDCl3,
d
ppm): 7.37e7.20 (m, 10H), 4.68 (d, 1H, J¼14.6 Hz), 4.64 (d,

8646
J.M. Fraile et al. / Tetrahedron 67 (2011) 8639e8647
1H, J¼14.6 Hz), 4.57 (d, 1H, J¼15.2 Hz), 4.27 (d, 1H, J¼15.2 Hz), 2.78
(s, 3H), 1.34 (s, 3H). 13C NMR (CDCl3,
ppm): 171.2, 155.5, 137.2,
J¼3.3 Hz), 3.43 (s, 2H), 2.79 (dd, 1H, J¼3.3, 14.1 Hz), 2.72 (dd, 1H,
d
J¼3.3, 14.1 Hz). 13C NMR (CDCl3,
d ppm): 171.5, 156.6, 137.5, 129.0,
136.1, 128.8, 128.7, 128.6, 128.5, 128.0, 127.8, 89.5, 51.2, 42.5 (2ꢂs),
128.6, 128.5 (3ꢂs), 128.2 (2ꢂs), 58.3, 44.8, 42.8, 36.8, 29.8.
21.8.
4.20. Synthesis of 1,3-dibenzyl-5-sulfanylmethylhydantoin (30)
4.17. Addition of sodium cyanide
To a solution of 1,3-dibenzyl-5-methylenehydantoin (58.4 mg,
0.2 mmol) in a mixture of methanol and THF (4 ml, 50:50 v/v) was
added a solution of sodium hydrogenosulfide (17 mg, 0.3 mmol) in
methanol (6 ml). The resulting solution was stirred at rt for 24 h and
the solvent was eliminated under reduced pressure. The crude oil
was partitioned between with CH2Cl2 (10 ml) and a saturated
aqueous solution of NH4Cl (10 ml). The organic phase was dried
over anhydrous MgSO4, filtered and evaporated under vacuum,
leading 1,3-dibenzyl-5-sulfanylmethylhydantoin (52 mg, 80%
A solution of 1,3-dibenzyl-5-methylenehydantoin (29.2 mg.
0.1 mmol), sodium cyanide (74 mg, 1.5 mmol) and Cu(OTf)2 (5.5 mg,
0.015 mmol) in an acetonitrile/water mixture (2 ml, 50:50 v/v) was
heated at 40 ꢀC for 4 h. CH2Cl2 (15 ml) and water (15 ml) were
added to the mixture. Once separated, the organic phase was dried
over anhydrous MgSO4, filtered and evaporated under vacuum,
leading a mixture of 25 and 26 in molar ratio 77:23 with 100%
conversion.
(1,3-Dibenzyl-2,5-dioxoimidazolidin-4-yl)acetonitrile (25): 1H
yield). 1H NMR (CDCl3,
d ppm): 7.37e7.19 (m, 10H), 4.85 (d, 1H,
NMR (CDCl3,
d
ppm): 7.50e7.15 (m, 10H), 4.91 (d, 1H, J¼15.4 Hz),
J¼15.6 Hz), 4.68 (d, 1H, J¼14.8 Hz), 4.62 (d, 1H, J¼14.8 Hz), 4.14 (d,
1H, J¼15.6 Hz), 3.95 (t, 1H, J¼3.6 Hz), 2.90 (m, 1H), 2.71 (m, 1H). 13C
4.70 (d, 1H, J¼15.8 Hz), 4.60 (d, 1H, J¼15.8 Hz), 4.30 (d, 1H,
J¼15.4 Hz), 3.87 (t, 1H, J¼4.8 Hz), 2.67 (t, 2H, J¼4.8 Hz). 13C NMR
NMR (CDCl3,
d ppm): 171.0, 156.9, 135.9, 135.4, 129.1, 128.6, 128.5,
(CDCl3,
d ppm): 169.5, 156.1, 137.7, 136.7, 128.3, 127.8, 127.6, 127.4,
128.4, 128.3, 128.0, 59.9, 45.2, 42.8, 23.4.
127.3, 127.1, 114.8, 55.1, 45.7, 43.1, 19.3.
12-Amino-1,3,8,10-tetrabenzyl-1,3,8,10-tetraazadispiro-[4.1.4.2]
4.21. Synthesis of S-(2,5-dioxoimidazolidin-4-yl)methyl
thioacetate (31)
tridec-12-en-2,4,9,11-tetraone (26): 1H NMR (CDCl3,
d ppm):
7.56e7.20 (m, 20H), 4.80 (d, 1H, J¼15.4 Hz), 4.78 (d, 1H, J¼15.1 Hz),
4.74 (s, 4H), 4.63 (d, 1H, J¼15.4 Hz), 4.58 (d, 1H, J¼15.1 Hz), 4.07 (s,
1H), 2.72 (s, 2H), 2.52 (d, 1H, J¼15.4 Hz), 2.48 (d, 1H, J¼15.4 Hz).
A solution of 5-methylenehydantoin (33.1 mg, 0.3 mmol), po-
tassium thioacetate (339 mg, 3 mmol) and Yb(OTf)3 (102 mg,
0.18 mmol) in an acetonitrile/water mixture (12 ml, 50:50 v/v) was
heated at 90 ꢀC for 14 h. After cooling, CH2Cl2 (10 ml) and water
(10 ml) were added to the mixture. Once separated, the organic
phase was dried over anhydrous MgSO4, filtered and evaporated
under vacuum, leading S-(2,5-dioxoimidazolidin-4-yl)methyl thi-
13C NMR (CDCl3,
d ppm): 175.3, 173.0, 155.8, 155.5, 146.5, 129.1,
128.9, 128.8, 128.7 (2ꢂs), 128.6, 128.5, 128.4 (2ꢂs), 128.3, 128.1,
127.9, 127.8, 127.3, 127.2, 103.2, 74.3, 73.2, 42.9 (2ꢂs), 42.7 (2ꢂs),
39.0.
oacetate (56.3 mg, 99% yield). 1H NMR (DMSO-d6,
d ppm): 4.87 (dd,
4.18. Synthesis of 1,3-dibenzyl-5-(piperdin-1-ylmethyl)
hydantoin (27)
1H, J¼2.9, 4.4 Hz), 3.87 (dd, 1H, J¼4.4, 14.5 Hz), 3.38 (dd, 1H, J¼2.9,
14.5 Hz), 2.32 (s, 3H). 13C NMR (DMSO-d6,
d ppm): 193.4, 169.0,
A solution of 1,3-dibenzyl-5-methylenehydantoin (116.8 mg,
0.4 mmol), piperidine (122 mg, 1.4 mmol) and Cu(OTf)2 (22 mg,
0.06 mmol) in an acetonitrile/water mixture (4 ml, 50:50 v/v) was
heated at 40 ꢀC for 40 h. CH2Cl2 (30 ml) and water (30 ml) were
added to the mixture. Once separated, the organic phase was dried
over anhydrous MgSO4, filtered and evaporated under vacuum,
leading 1,3-dibenzyl-5-(piperdin-1-ylmethyl)hydantoin (68 mg,
90% yield). Elemental analysis (C23H27N3O2): theoretical C 73.18, H
7.21, N 11.13; experimental: C 73.31, H 7.05, N 11.20. 1H NMR
152.4, 59.1, 29.6, 27.7.
4.22. Synthesis of S-(1,3-dibenzyl-2,5-dioxoimidazolidin-4-yl)
methyl thioacetate (32)
From 1,3-dibenzyl-5-methylenehydantoin (29.2 mg, 0.1 mmol),
using the same method described above to obtain 32 mg (87%
yield). Elemental analysis (C20H20N2O3S): theoretical C 65.20, H
5.47, N 7.60, S 8.70; experimental: C 65.08, H 5.51, N 7.49, S 8.58. 1H
(CDCl3,
d
ppm): 7.36e7.17 (m, 10H), 5.04 (d, 1H, J¼14.8 Hz), 4.66 (d,
NMR (CDCl3,
d
ppm): 7.34e7.18 (m, 10H), 4.97 (d, 1H, J¼15.2 Hz),
1H, J¼14.8 Hz), 4.58 (d, 1H, J¼14.8 Hz), 4.27 (d, 1H, J¼14.8 Hz), 3.74
(dd, 1H, J¼3.3, 6.8 Hz), 2.68 (dd, 1H, J¼3.3, 13.9 Hz), 2.59 (dd, 1H,
J¼6.8, 13.9 Hz), 2.31 (m, 2H), 2.29 (m, 2H), 1.37 (m, 4H), 1.29 (m,
4.65 (d, 1H, J¼14.4 Hz), 4.55 (d, 1H, J¼14.4 Hz), 4.01 (d, 1H,
J¼15.2 Hz), 3.95 (dd, 1H, J¼3.0, 4.4 Hz), 3.36 (dd, 1H, J¼4.4, 14.4 Hz),
2.82 (dd, 1H, J¼3.0, 14.4 Hz), 2.19 (s, 3H). 13C NMR (CDCl3,
d ppm):
2H). 13C NMR (CDCl3,
d ppm): 172.0, 156.8, 136.4, 136.2, 128.8,
193.9, 170.9, 156.5, 135.9, 135.4, 129.1, 128.7 (2ꢂs), 128.6 (2ꢂs),
128.6, 128.5, 128.2, 127.9, 127.7, 59.0, 57.5, 55.4, 45.2, 42.5, 26.0,
24.0.
128.4, 128.3, 127.9, 57.6, 44.7, 42.8, 30.6, 27.8.
Acknowledgements
4.19. Addition of phenylmethanethiol
This work was made possible by the generous financial support
A
solution of 5-methylenehydantoin or 1,3-dibenzyl-5-
ꢀ
of Deretil, and the Spanish ‘Ministerio de Ciencia e Innovacion’
methylenehydantoin (1 mmol), phenylmethanethiol (124 mg,
1 mmol) and triethylamine (20.2 mg, 0.2 mmol) in methanol (7 ml)
was stirred at rt for 24 h. The resulting solution was washed with
hexane (3ꢂ7 ml) and the solvent was eliminated under reduced
pressure to obtain the corresponding product.
(CTQ2008-05138 and Consolider Ingenio 2010 INTECAT CSD2006-
0003).
Supplementary data
5-Benzylsulfanylmethylhydantoin (28, 217 mg, 92% yield). 1H
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.09.034.
NMR (DMSO-d6,
d ppm): 10.74 (s, 1H), 8.01 (s, 1H), 7.32e7.31 (m,
5H), 4.31 (m, 1H), 3.77 (s, 2H), 2.72 (m, 2H). 13C NMR (DMSO-d6,
d
ppm): 174.9, 157.6, 138.3, 129.0, 128.4, 127.0, 57.7, 35.9, 32.0.
1,3-Dibenzyl-5-benzylsulfanylmethylhydantoin (29, 395 mg, 95%
References and notes
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d
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