A mild, efficient approach for the synthesis of 1,5-disubstituted hydantoins

Article abstract of DOI:10.1002/ejoc.200900868

An efficient and straightforward two-step procedure for the synthesis of N-1 alkyl/aryl-substituted hydantoins was developed, starting from easily available starting materials. The procedure envisages a highly reglospecific domino condensation/aza-Michael

Full text of DOI:10.1002/ejoc.200900868

FULL PAPER
DOI: 10.1002/ejoc.200900868
A Mild, Efficient Approach for the Synthesis of 1,5-Disubstituted Hydantoins
Francesca Olimpieri,[a] Maria Cristina Bellucci,[b] Alessandro Volonterio,*[a] and
Matteo Zanda*[c,d]
Keywords: Domino reactions / Regioselectivity / Nitrogen heterocycles
An efficient and straightforward two-step procedure for the
synthesis of N-1 alkyl/aryl-substituted hydantoins was devel-
oped, starting from easily available starting materials. The
procedure envisages a highly regiospecific domino conden-
sation/aza-Michael (nucleophilic substitution)/OǞN acyl mi-
gration between activated α,β-unsaturated carboxylic acids
or α-haloaryl acetic acids, respectively, and N-tert-butyl- or
N-tritylcarbodiimides, leading to the regioselective formation
of hydantoins bearing the tertiary alkylic substituent in the 3-
position, followed by selective removal the substituent. This
process avoids the use of harsh reaction conditions and toxic
reagents and is high yielding. A detailed study of the influ-
ence of the structure of the reactants on the reaction outcome
is presented. A wide variety of final products having a pri-
mary, secondary, cyclic and aryl substituent at the N-1 posi-
tion were successfully synthesized by this method.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
amino acids or amino nitriles with alkyl, aryl or chlorosul-
fonyl isocyanates, respectively, which requires extended re-
action times or high temperatures.[10] In this way, 3,5-di-
and 3,5,5-trisubstituted hydantoins are readily accessible,
whereas for the synthesis of 1,3,5-tri- and 1,3,5,5-tetrasub-
stituted hydantoins, it is necessary to perform a preliminary
alkylation of the amino function by reductive amination[11]
or by a Mitsunobu reaction.[12] Various different routes/
methods for the synthesis of hydantoins have been recently
developed both in solution and in the solid phase to im-
prove the drawbacks associated with the above strat-
egy.[11–13] In this context, we recently demonstrated that car-
bodiimides 2 when treated with suitable carboxylic acids 1,
namely, activated α,β-unsaturated acids and α-haloaryl-
acetic acids, in the absence of a nucleophile are useful rea-
gents for the straightforward synthesis of 1,3,5-trisubsti-
tuted hydantoins 3 through a regiospecific domino process
consisting of a condensation step between the two reac-
tants, leading to the formation of O-acyl isourea intermedi-
ates that undergo nucleophilic aza-Michael reaction or
halogen displacement, respectively, followed by a final
NǞO acyl migration step (Scheme 1).[14]
Introduction
Hydantoins have been widely used in biological screen-
ings resulting in numerous pharmaceutical applications. In
fact, many derivatives have been identified as anticonvul-
sants[1] and antimuscarinics,[2] antiulcers and antiarrythm-
ics,[3] antivirals, antidiabetics,[4] serotonin and fibrinogen re-
ceptor antagonists,[5] inhibitors of the glycine binding site
of the NMDA receptor[6] and antagonists of leukocyte cell
adhesion acting as allosteric inhibitors of the protein–pro-
tein interaction.[7] The observed activities usually do not
arise from the heterocycle itself but from the different li-
gands that have been attached to it. Moreover, substituted
hydantoins are important building blocks for the synthesis
of nonnatural amino acids both in racemic form by alkaline
degradation[8] and in an enantioselective way by enzymatic
resolution.[9] For this reason, there is a lot of interest in
developing new strategies for a straightforward synthesis of
selectively substituted hydantoins both in solution and in
the solid phase. To date, the most utilized strategy to pre-
pare substituted hydantoins is the strongly acidic or basic
cyclization of ureido acids obtained from reactions of
In some cases, the NǞO acyl migration process was com-
petitive with the nucleophilic step, leading to the corre-
sponding N-acylureas 4 and 5, which are frequently found
byproducts in the condensation reaction of carboxylic acids
promoted by carbodiimides, alone or in a mixture with 3.
It is worth noting that this process is facilitated when the
substituents on the carbodiimides are different in terms of
electronic properties (highly asymmetric carbodiimides)
rather than steric bulkiness (weakly asymmetric carbodi-
imides).[14b] However, N-acylureas 4 or 5 could be easily
cyclized to the target hydantoins by treatment with NaH in
[a] Dipartimento di Chimica, Materiali e Ingegneria Chimica
“Giulio Natta”,
Via Mancinelli 7, 20131 Milano, Italy
Fax: +39-02-23993180
E-mail: alessandro.volonterio@polimi.it
[b] Dipartimento di Scienze Molecolari Agroalimentari, Università
degli Studi di Milano,
Via Celoria 2, 20133 Milano, Italy
[c] Institute of Medicinal Science, University of Aberdeen,
Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK
[d] C.N.R.-I.C.R.M.,
Via Mancinelli 7, 20131 Milano, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900868.
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F. Olimpieri, M. C. Bellucci, A. Volonterio, M. Zanda
FULL PAPER
Scheme 1. One-pot, domino processes leading to 1,3,5-trisubstituted hydantoins.
THF or DMF, or in situ in a one-pot sequential process could be prepared by reaction between cyanate and N-alkyl
with a 2  aqueous NaOH solution, respectively. Despite amino acid esters followed by acid-catalyzed cyclization[16]
the great interest in the development of novel methodolo- or by treatment of freshly prepared aldimines with cyanide,
gies for the synthesis of hydantoins, there are only very few cyanate and aqueous acid, in sequence.[17] Very recently, a
practical methods available in the literature for the synthesis new approach involving a three-step procedure for the syn-
of selectively 1,5-disubstituted hydantoins. The most uti- thesis of N-1 substituted hydantoins was reported, namely,
lized strategy relies on a four-step reaction sequence involv- amination of cyanogen bromide, alkylation of the resulting
ing (1) the synthesis of the 1,3-unsubstituted hydantoin N-substituted cyanamide with methyl bromoacetate and fi-
ring, (2) protection of the more reactive N-3 position, which nal acid-catalyzed cyclization.[18] Although efficient and
usually arises with modest yields, (3) alkylation of the N-1 high yielding, this procedure envisages the use of highly
position and (4) removal of the N-3 protecting group.[15] In toxic cyanogen bromide and leads to the formation of 5-
general, the above strategy reduces the yields, is time con- unsubstituted hydantoins. In this paper, we wish to report
suming and is not applicable for the synthesis of hydantoins a mild and efficient method for the synthesis of selectively
with secondary alkyl groups or aromatic substituents at the 1,5-disubstituted hydantoins starting from easily available
N-1 position. Alternatively, 1,5-disubstituted hydantoins starting materials through a two-step reaction sequence in-
Scheme 2. Retrosynthetic scheme for the synthesis of 1,5-disubstituted hydantoins.
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A Mild, Efficient Approach for the Synthesis of 1,5-Disubstituted Hydantoins
volving (1) the highly regiospecific domino condensation/ slower (overnight; Table 1, Entry 3). Also, less-activated
aza-Michael (nucleophilic substitution)/OǞN acyl mi- monoethyl fumarate 1b when treated with dialkylcarbodi-
gration with N-tert-butyl- or N-tritylcarbodiimides, leading imides 2a,b,d, in DCM led to a regioselective process, pro-
to the regioselective formation of the corresponding N-3- ducing hydantoins 3d,e,f, respectively, bearing the tert-butyl
tert-butyl or -trityl-substituted hydantoins and (2) selective substituent in the 3-position (Table 1,Entries 4–6). When 1b
cleavage of the tertiary alkyl N-3 protecting group was treated with N-phenyl-NЈ-tert-butylcarbodiimide (2c)
(Scheme 2).
we obtained an equimolecular mixture of the expected hy-
dantoin 3g and N-acylurea derivative 4g (Table 1, En-
try 7).[21] The latter result is not surprising, as the two sub-
stituents in 2c (an aryl and an alkyl substituent) possess
different electronic features (strongly asymmetric carbodi-
imide). In order to increase the nucleophilicity of the inter-
mediate O-acylurea, and thus the yield of 3g, we performed
the reaction in the presence of a base such as 2,4,6-trimeth-
ylpyridine (TMP). However, in this case, the base promoted
the OǞN acyl migration process, leading to the formation
of a 3:1 mixture of N-acylurea 4g and 3g (Table 1, Entry 8).
As expected, also 4,4,4-trifluoro-3-trifluoromethyl(Tmf)-
crotonic acid (1c) gave the formation of hydantoins 3h–k
with total regiocontrol when treated with dialkylcarbodi-
imides 2a,d–f in very good yields (Table 1, Entries 9–12) un-
der the optimized conditions for this acid (TMP, CH3CN).
However, with N-phenyl-NЈ-tert-butylcarbodiimide (2c),
acid 1c produced hydantoin 3l only in low yield, although
as the only regioisomer (Table 1, Entry 13). To our surprise,
α-bromophenylacetic acid (1d), which reacted smoothly
(TMP, DCM) with an N-tert-butylcarbodiimide bearing a
primary alkyl group at the other nitrogen atom, such as 2a,
producing only regioisomer 3m (Table 1, Entry 14), did not
react at all under the same conditions with analogous car-
bodiimides bearing a secondary alkyl group (data not
shown).
However, by performing the reaction in more polar diox-
ane, we obtained the selective formation of N-acylisourea
4n as the only regioisomer in very good yield (Table 1, En-
try 15). As expected,[14c] by treating the reaction mixture in
situ with aqueous 2  NaOH for a few minutes we obtained
the selective formation of hydantoin regioisomers 3n,o (3o
in an equimolar ratio of two diastereoisomers) with car-
bodiimides 2e,f, respectively (Table 1, Entries 16 and 17).
When 1d was treated with 2c in dioxane in the presence of
TMP, we obtained a mixture of hydantoin 3p and N-acyl-
urea 4p together with other unidentified byproducts
(Table 1, Entry 18), whereas cyclization with aqueous 2 
NaOH failed, leading to a complex mixture of byproducts
(data not shown). Finally, when dialkylcarbodiimides 2a,b
were treated with poorly reactive aryl γ-oxo-α,β unsaturated
carboxylic acids 1e,f in DMF in the presence of TMP, we
Results and Discussion
In previous work,[14] we demonstrated that asymmetric
carbodiimides, namely, carbodiimides having different func-
tionalities at the nitrogen atoms in terms of nucleophilic
character and/or steric bulkiness, react with suitable carb-
oxylic acids, giving rise to the formation of hydantoins
with total regioselectivity in most cases. In particular, good
results both in terms of regioselectivity and yield were ob-
tained by using N-tert-butyl-substituted carbodiimides
when the substituent at the other nitrogen atom was a pri-
mary alkyl group (benzyl substituent), leading to the forma-
tion of 1,3,5-trisubstituted hydantoins having the imine ni-
trogen atom protected with the removable tert-butyl substit-
uent. Thus, we decided to further explore the reactivity of
such N-tert-butylcarbodiimides to pave the way, after de-
protection, to the selective synthesis of 1,5-disubstituted hy-
dantoins with different substituents at the N-1 position, in-
cluding secondary alkyl and aromatic groups. In particular,
we synthesized suitable N-tert-butylcarbodiimides 2a–f hav-
ing primary, secondary and aryl substituents at the other
nitrogen atom by a Staudinger reaction[19] between alkyl or
aryl azides 6 and commercially available tert-butyl isocyan-
ate (7) (Scheme 3, method A) or by dehydration of the cor-
responding ureas obtained by addition of amines or anilines
8 to 7 (Scheme 3, method B).[20] It is worth noting that these
carbodiimides are quite stable and could be easily recovered
in good yields by short-path flash chromatography (see Ex-
perimental Section).
Highly activated acid 1a reacted smoothly with tert-but-
yl-substituted carbodiimides 2a,b in DCM at room tem-
perature without the need of a base, giving rise in a few
minutes to the formation of N-1 primary alkyl or N-1 sec-
ondary alkyl N-3-tert-butyl-substituted hydantoins 3a,b,
respectively, as the only regioisomers (Table 1, Entries 1 and
2). Despite the fact that nitrogen-bearing aryl substituents
are, in general, less nucleophilic than those bearing an alkyl
group, the process was regioselective also with carbodiimide
2c, which when reacted with 1a under the same conditions,
afforded exclusively hydantoin 3c, although the process was
Scheme 3. Synthesis of N-tert-butyl-substituted carbodiimides.
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Table 1. Synthesis of N-3 tert-butyl-substituted hydantoins.
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A Mild, Efficient Approach for the Synthesis of 1,5-Disubstituted Hydantoins
Table 1. (Conntinued)
[a] See Ref.[14b] [b] Reaction was complete in 5 min. [c] Two diastereoisomers in a ca. 5:1 ratio. [d] See Ref.[14c] [e] Equimolar ratio of two
diastereoisomers. [f] Not determined. [g] Equimolar ratio of regioisomers.
obtained an equimolecular mixture of hydantoin regio- can be obtained by addition of alkyl or arylamines to trityl-
isomers 3q,r and 3s,t, respectively, in very good yields isocyanate, which was synthesized by reaction of commer-
(Table 1, Entries 19 and 20).
cially available tritylamine (9) with triphosgene (Scheme 4).
Next, in order to increase the difference between the two Also in this case, the resulting carbodiimides were easily
nitrogen atoms both in terms of nucleophilic power and recovered by short-path flash chromatography.
steric bulkiness in the O-acylisourea intermediates, we de-
Highly activated acid 1a reacted smoothly also with N-
cided to study the behaviour of related N-trityl-substituted primary and secondary alkyl, NЈ-tritylcarbodiimides 2g,h,
carbodiimides 2g–k with the expectation that the regioselec- leading to hydantoins 3aa,ab as the only regioisomers
tivity of the process would increase in those cases where N- (Table 2, Entries 1 and 2), whereas no reaction occurred
tert-butylcarbodiimides failed (for instance, with acids 1e,f). with N-phenyl-NЈ-tritylcarbodiimide (2i) (Table 2, Entry 3),
Such carbodiimides could be easily obtained by dehy- probably due to the lower reactivity of the carbodiimide
[20]
dration promoted by freshly prepared Ph3PBr2
or by compared with the corresponding tert-butylcarbodiimide
Burgess reagent[22] of the corresponding ureas 10. The latter 2c, which in turn is probably due to lower electrophilicity
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Scheme 4. Synthesis of N-trityl-substituted carbodiimides.
rather than higher steric hindrance. N-Tritylcarbodiimides imides, leading to a clean reaction with carbodiimides bear-
were less reactive than the corresponding N-tert-butyl deriv- ing a primary alkyl group such as 2j (Table 2, Entry 11)
atives also in the intramolecular nucleophilic step. In fact, and a mixture of hydantoin 3ai, N-acylurea 4ai and other
when 2j was treated with carboxylic acid 1b we obtained the byproducts with carbodiimide 2i (Table 2, Entry 12). Unex-
almost exclusive formation of N-acylurea 4ac as the only pectedly, aryl γ-oxo-α,β unsaturated carboxylic acids 1e,f
regioisomer in good yield, whereas when treated with 2h, reacted with N-tritylcarbodiimides in a chemo- and regiose-
which has a nitrogen atom bearing a secondary alkyl group lective way. In fact, reactions of N-primary and secondary
and thus more nucleophilic, we obtained the regioselective alkyl, NЈ-tritylcarbodiimides 2g,h with 1e,f produced the
formation of a 3:1 mixture of N-acylurea 4ad and hydan- formation of hydantoins 3aj and 3al, respectively, as the
toin 3ad (Table 2, Entries 4 and 5).[23] Not surprisingly, the only regioisomers (Table 2, Entries 12 and 14). Also, N-
ratio of hydantoin 3ae versus N-acyl derivative 4ae in- aryl-NЈ-tritylcarbodiimides 2i,k produced completely
creased, becoming the predominant product, when 1b was chemoselective processes when reacted with acids 2g,h,
treated with N-phenyl-NЈ-tritylcarbodiimide (2i). As a mat- leading to the corresponding hydantoins (Table 2, En-
ter of fact, such a carbodiimide is more “symmetric” com- tries 13, 15, and 16) although to achieve good yield the re-
pared with 2h,j as a result of the electronic features of the actions were run for 24 h at 80 °C. However, in the latter
trityl group, which are much closer to those of an aryl sub- cases, the process was not completely regioselective. In fact,
stituent rather than an alkyl one. Acid 1c reacted smoothly when 1e,f were treated with carbodiimide 2k, bearing a
also with N-tritylcarbodiimides 2j,h to produce hydantoins para-methoxyphenyl N-substituent, we still obtained a
3af,ag, respectively, in very good yields and total regioselec- highly regioselective process leading to the formation of hy-
tivity (Table 2, Entries 7 and 8). However, the same acid did dantoins 3ak and 3an as major regioisomers with 82 and
not react at all with 2i, confirming the low reactivity of this 78% regioisomeric excesses, respectively (Table 2, Entries 13
acid with less reactive carbodiimides such 2c and 2i and 16), whereas with less nucleophilic carbodiimide 2i,
(Table 2, Entry 9). The reactivity of α-bromophenylacetic bearing an N-phenyl substituent, the regioselectivity
acid (1d) with N-tritylcarbodiimides was very similar to that dropped down to 60% (Table 2, Entry 15). However, the lat-
observed with the corresponding N-tert-butylcarbodi- ter results strongly improve the synthetic methodology, as
Table 2. Synthesis of N-3 trityl-substituted hydantoins.
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A Mild, Efficient Approach for the Synthesis of 1,5-Disubstituted Hydantoins
Table 2. (Conntinued)
[a] No reaction occurred. [b] Not determined. [c] Reaction performed in 24 h at 80 °C in a sealed tube. [d] A 10:1 mixture of the two
regioisomers was obtained. [e] A 4:1 mixture of the two regioisomers was obtained. [f] An 8:1 mixture of the two regioisomers was
obtained.
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F. Olimpieri, M. C. Bellucci, A. Volonterio, M. Zanda
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aryl γ-oxo-α,β unsaturated carboxylic acids reacted with N- dantoins bearing the tert-butyl substituent were treated
tert-butylcarbodiimides with no regiocontrol in all cases. with a 10% solution of methansulfonic acid in DCM at
Finally, in order to validate our strategy, a series of hy- 60 °C in a sealed tube for several hours, leading to the for-
dantoins 2 were selectively deprotected at the nitrogen atom mation of products 11a–d in very good yields (Table 3, En-
in the 3-position of the ring, leading to a library of the tries 1–4). The corresponding N-trityl derivatives were con-
target 1,3-disubstitued hydantoins 11. For this purpose, hy- verted into target products 11e–j in excellent yield by treat-
ment with a 10% solution of TFA in DCM, in the presence
of Et3SiH at room temperature (Table 3, Entries 5–10).
Table 3. Synthesis of 1,5-disubstituted hydantoins.
Conclusions
In summary, we have developed a general, straightfor-
ward method for the preparation of 1,5-disubstituted hy-
dantoins in good to excellent yields through a two-step
strategy relying on a highly regioselective domino reaction
between N-tert-butyl- or N-trityl-substituted carbodiimides
and activated α,β-unsaturated carboxylic acids or α-haloar-
ylacetic acids followed by selective deprotection of the terti-
ary alkyl substituent at the 3-position of the ring. In gene-
ral, we suggest the use of N-tert-butylcarbodiimides because
they are easier to prepare (by Staudinger reaction) and gave
cleaner reactions. However, in some cases, when the carbox-
ylic acids are less reactive like aryl γ-oxo-α,β unsaturated
carboxylic acids, with such carbodiimides the process is not
selective, producing a mixture of the two hydantoin re-
gioisomers. In these cases, the use of related N-tritylcar-
bodiimides overcame this drawback, leading to the forma-
tion of the desired hydantoins as the only regioisomers
when the other carbodiimide substituent is a primary or
secondary alkyl group, or as major regioisomers with N-
aryl-NЈ-tritylcarbodiimides. A large array of 1,5-disubsti-
tuted hydantoins with primary, secondary, cyclic and aryl
groups at the 1-position can be synthesized through this
method that overcomes the drawbacks of precedent meth-
odologies (harsh conditions or toxic reagents). For these
reasons, our strategy looks particularly suitable for solid-
phase/combinatorial chemistry. The latter issue, as well as
the development of a stereoselective version of the domino
process, are currently in progress in our laboratory.
Experimental Section
General Methods: Commercially available reagent-grade solvents
were employed without purification. 1H NMR spectra were run on
spectrometers at 250, 400 or 500 MHz. Chemical shifts are ex-
pressed in ppm (δ), using tetramethylsilane (TMS) as internal stan-
1
dard for H and 13C nuclei (δH and δC = 0.00 ppm), whereas C6F6
was used as an external standard (δF = 162.90 ppm) for 19F nuclei.
Materials: Carbodiimides were prepared according to the literature
(see in the manuscript). 4,4,4-Trifluoro-3-Tmf-crotonic acid (1c)
and α-bromophenylacetic acid (1d) are commercially available,
whereas acids 1a,b,e,f were prepared as reported in ref.[14b] 1H
NMR and 13C NMR spectroscopic data of carbodiimides 2c,[24]
2i[22] and 2f[25] were in agreement with those previously reported.
General Procedure for the Synthesis of Tetrasubstituted Hydantoins
3: To a stirred solution of acid 1 (1 equiv.) in organic solvent (0.1 
solution) was added carbodiimide 2 (1 equiv. or 1.5 equiv. for acid
1d) followed by TMP (1 equiv.) at room temperature, and the mix-
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A Mild, Efficient Approach for the Synthesis of 1,5-Disubstituted Hydantoins
ture was stirred overnight (unless otherwise noted). When needed
Acknowledgments
(see Tables 1 and 2), aqueous 2  NaOH (10% in volume) was
added, and the mixture was stirred for 15 min. Aqueous 1  HCl
was added until acidic pH, and the resulting mixture was extracted
with DCM. The combined organic layer was dried with anhydrous
Na2SO4, filtered and concentrated under vacuum. The crude was
purified by flash chromatography.
Politecnico di Milano (Progetto Giovani Ricercatori 2007–2008) is
gratefully acknowledged for economic support.
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Diethyl
2-(3-Butyl-2,5-dioxo-1-tritylimidazolidin-4-yl)malonate
(3aa): Rf = 0.39 (hexane/AcOEt, 80:20). 1H NMR (400 MHz,
CDCl3): δ = 7.42 (m, 6 H), 7.16–7.14 (m, 9 H), 4.24 (d, J = 2.6 Hz,
1 H), 4.19–4.12 (m, 4 H), 4.00 (d, J = 2.6 Hz, 1 H), 3.52 (m, 1 H),
2.94 (m, 1 H), 1.36 (m, 2 H), 1.22 (t, J = 7.0 Hz, 3 H), 1.17 (t, J =
7.0 Hz, 3 H), 0.98 (m, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ
= 170.3, 166.9, 165.6, 156.2, 142.4, 128.6, 127.3, 126.5, 74.0, 62.3,
62.1, 57.3, 52.8, 41.5, 29.0, 19.4, 13.95, 13.96, 13.5 ppm. MS (ESI):
m/z (%) = 579.2 (100) [M+ + Na], 557.1 (8) [M+ + H].
General Procedure for N-tert-Butyl Deprotection: A stirred solution
of hydantoin 3 (1 equiv.) and CH3SO3H (10% in volume) in DCM
(0.5  solution) was heated at 60 °C in a sealed tube for 3 h. The
solution was cooled to room temperature, diluted with aqueous
5% NaHCO3 until basic and extracted with DCM. The combined
organic layer was dried with anhydrous Na2SO4, filtered and con-
centrated under vacuum. When necessary, the crude was purified
by flash chromatography.
Diethyl 2-(2,5-Dioxo-3-phenylimidazolidin-4-yl)malonate (11a): Rf =
0.34 (hexane/AcOEt, 60:40). 1H NMR (400 MHz, CDCl3): δ = 8.64
(br. s, 1 H), 7.34–7.28 (m, 5 H), 5.16 (d, J = 4.2 Hz, 1 H), 4.28 (q,
J = 7.0 Hz, 2 H), 4.11 (m, 2 H), 3.92 (d, J = 4.2 Hz, 1 H), 1.30 (t,
J = 7.0 Hz, 3 H), 1.18 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 169.9, 165.5, 165.4, 154.4, 134.4, 129.5,
126.9, 123.8, 62.6, 62.1, 60.3, 50.9, 13.9, 13.8 ppm. MS (ESI): m/z
(%) = 335.0 (6) [M+ + H], 357.0 (100) [M+ + Na].
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General Procedure for N-Trityl Deprotection: A solution of hydan-
toin 3 (1 equiv.), Et3SiH (4 equiv.) and TFA (10% in volume) in
DCM (0.5  solution) was stirred at room temperature until all the
starting material was consumed (TLC monitoring). The solution
was diluted with aqueous 5% NaHCO3 until basic and extracted
with DCM. The combined organic layer was dried with anhydrous
Na2SO4, filtered and concentrated under vacuum, and the crude
was purified by flash chromatography.
1889–1893; g) M. Meusel, A. Ambrozak, T. K. Hecker, M.
˙
Gütschow, J. Org. Chem. 2003, 68, 4684–4692; h) M. Beller, M.
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M. Zanda, Synlett 2008, 3016–3020.
Ethyl 2-(3-Benzyl-2,5-dioxoimidazolidin-4-yl)acetate (11e): Rf
=
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J. P. Wepsic, A. R. Harkness, J. L. Grutsch, R. A. Wright, B. G.
Johnson, S. Andis, L. A. Kingston, R. Tomlinson, R. Lewis,
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0.24 (hexane/AcOEt, 50:50). 1H NMR (400 MHz, CDCl3): δ = 8.54
(br. s, 1 H), 7.33 (m, 5 H), 4.77 (d, J = 15.6 Hz, 1 H),4.30 (d, J =
15.6 Hz, 1 H),4.14 (t, J = 4.8 Hz, 1 H), 4.08 (m, 2 H), 2.78 (d, J =
4.8 Hz, 2 H), 1.19 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR (125.7 MHz,
CDCl3): δ = 172.4, 168.9, 135.8, 129.0, 128.2, 128.1, 61.4, 57.3,
45.1, 34.1, 14.0 ppm. MS (ESI): m/z (%) = 277.2 [M++H, (100)].
Supporting Information (see footnote on the first page of this arti-
cle): The spectroscopic data for all the remaining compounds and
the copies of the 1H and 13C NMR spectra for all new compounds.
Eur. J. Org. Chem. 2009, 6179–6188
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6187

F. Olimpieri, M. C. Bellucci, A. Volonterio, M. Zanda
FULL PAPER
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Received: July 30, 2009
Published Online: November 2, 2009
6188
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6179–6188