Synthesis of 1,3,5-trisubstituted hydantoins by regiospecific domino condensation/aza-Michael/O→N acyl migration of carbodiimides with activated α,β-unsaturated carboxylic acids

Article abstract of DOI:10.1021/jo0480848

(Chemical Equation Presented) Carbodiimides and suitably activated α,β-unsaturated carboxylic acids react effectively to afford a vast array of 1,3,5-trisubstituted hydantoins by means of a regiospecific domino condensation/aza-Michael/N→O acyl migration. The reaction works well in very mild conditions (20°C, dichloromethane) with fumaric acid derivatives bearing an electron-withdrawing group in the β position. Good results have been obtained also with less activated substrates bearing only one electron-withdrawing group in the β position, using more polar solvents (acetonitrile, DMF), and in the presence of a base (2,4,6-trimethylpyridine). Reactions with asymmetric carbodiimides are generally highly chemo- and regioselective, giving rise to the formation of a single regioisomeric hydantoin. However, asymmetric carbodiimides bearing one alkyl group and one aryl group can produce variable amounts of N-acylurea byproducts. The latter could be easily recovered and transformed into the corresponding hydantoins. A detailed study of the influence of key reaction parameters such as solvent, base, and structure of the reactants on the reaction outcome and mechanism is presented. This methodology is particularly convenient for the synthesis of trifluoromethyl-substituted hydantoins, which could be interesting as bioactive compounds in medicinal chemistry, as well as precursors of the corresponding α-amino acids.

Full text of DOI:10.1021/jo0480848

Synthesis of 1,3,5-Trisubstituted Hydantoins by Regiospecific
Domino Condensation/Aza-Michael/OfN Acyl Migration of
Carbodiimides with Activated r,â-Unsaturated Carboxylic Acids†
Alessandro Volonterio,*,‡ Carmen Ramirez de Arellano,§ and Matteo Zanda*,|
Dipartimento di Chimica, Materiali ed Ingegneria Chimica “G. Natta” del Politecnico di Milano,
C.N.R.sIstituto di Chimica del Riconoscimento Molecolare, Sezione “A. Quilico”,
via Mancinelli 7, I-20131 Milano, Italy, and Departamento de Quimica Organica Facultad de Farmacia,
Universidad de Valencia, 46100 Burjassot, Valencia, Spain
alessandro.volonterio@polimi.it
Received October 28, 2004
Carbodiimides and suitably activated R,â-unsaturated carboxylic acids react effectively to afford a
vast array of 1,3,5-trisubstituted hydantoins by means of a regiospecific domino condensation/aza-
Michael/NfO acyl migration. The reaction works well in very mild conditions (20 °C, dichlo-
romethane) with fumaric acid derivatives bearing an electron-withdrawing group in the â position.
Good results have been obtained also with less activated substrates bearing only one electron-
withdrawing group in the â position, using more polar solvents (acetonitrile, DMF), and in the
presence of a base (2,4,6-trimethylpyridine). Reactions with asymmetric carbodiimides are generally
highly chemo- and regioselective, giving rise to the formation of a single regioisomeric hydantoin.
However, asymmetric carbodiimides bearing one alkyl group and one aryl group can produce variable
amounts of N-acylurea byproducts. The latter could be easily recovered and transformed into the
corresponding hydantoins. A detailed study of the influence of key reaction parameters such as
solvent, base, and structure of the reactants on the reaction outcome and mechanism is presented.
This methodology is particularly convenient for the synthesis of trifluoromethyl-substituted
hydantoins, which could be interesting as bioactive compounds in medicinal chemistry, as well as
precursors of the corresponding R-amino acids.
Introduction
convulsants1 and antimuscarinics,2 antiulcers and anti-
arrythmics,3 antivirals, antidiabetics,4 serotonin and
fibrinogen receptor antagonists,5 inhibitors of the glycine
binding site of the NMDA receptor,6 and antagonists of
One of the challenges of medicinal chemistry is the
promotion of the structural diversity of a ligand, which
can be achieved by the attachment of pharmacophoric
groups to the rigidified molecule. Small, substituted
heterocyclic compounds offer a unique possibility of
different kinds and degrees of substitution. In particular,
hydantoins have been widely used in biological screenings
resulting in numerous pharmaceutical applications. In
fact, many derivatives have been identified as anti-
(1) Thenmozhiyal, J. C.; Wong, P. T. H.; Chui, W. K. J. Med. Chem.
2004, 47, 1527-1535.
(2) (a) Bazil, C. W.; Pedley, T. A. Annu. Rev. Med. 1998, 49, 135-
162. (b) Luer, M. S. Neurol. Res. 1998, 20, 178-182.
(3) (a) Matsukura, M.; Daiku, Y.; Ueda, K.; Tanaka, S.; Igarashi,
T.; Minami, N. Chem. Pharm. Bull. 1992, 40, 1823-1827. (b) Knabe,
J.; Baldauf, J.; Ahlhelm, A. Pharmazie 1997, 52, 912-919.
(4) Somsa´k, L.; Kova´cs, L.; To´th, M.; O¨ sz, E.; Szila´gyi, L.; Gyo¨rgy-
dea´k, Z.; Dinya, Z.; Docsa, T.; To´th, B.; Gergely, P. J. Med. Chem. 2001,
44, 2843-2848.
† This paper is dedicated to Prof. Pierfrancesco Bravo on the occasion
of his 70th birthday.
(5) (a) Moloney, G. P.; Robertson, A. D.; Martin, G. R.; MacLennan,
S.; Mathews, N.; Dosworth, S.; Sang, P. Y.; Knight, C.; Glen. R. J. Med.
Chem. 1997, 40, 2347-2362. (b) Moloney, G. P.; Martin, G. R.;
Mathews, N.; Milne, A.; Hobbs, H.; Dosworth, S.; Sang, P. Y.; Knight,
C.; Williams, M.; Maxwell, M.; Glen. R. J. Med. Chem. 1999, 42, 2504-
2526.
‡ Dipartimento di Chimica Materiali ed Ingegneria Chimica “G.
Natta” del Politecnico di Milano.
§ Universidad de Valencia.
| C.N.R.sIstituto di Chimica del Riconoscimento Molecolare.
10.1021/jo0480848 CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/10/2005
J. Org. Chem. 2005, 70, 2161-2170
2161

Volonterio et al.
SCHEME 1. Mechanism of Carbodiimide Activation
leukocyte cell adhesion acting as allosteric inhibitors of
the protein-protein interaction.7 The observed activities
usually do not arise from the heterocycle itself but from
the different ligands that have been attached to it. For
this reason, there is a lot of interest in developing new
strategies for a straightforward synthesis of substituted
hydantoins both in solution and in solid phase. Moreover,
substituted hydantoins are important building blocks for
the synthesis of nonnatural amino acids both in racemic
form by alkaline hydrolytic degradation8 and in an
enantioselective way by enzymatic resolution.9 To date,
the most utilized strategy to prepare substituted hydan-
toins is the strongly acidic or basic cyclization of ureido
acids obtained from reactions of amino acids or amino
nitriles with alkyl, aryl, or chorosulfonyl isocyanates,
respectively, which requires extended reaction time or
high temperature.10 In this way, 3,5-di and 3,5,5-tri-
substituted hydantoins are readily accessible, while for
the synthesis of 1,3,5-tri- and 1,3,5,5-tetrasubstituted
hydantoins it is necessary to perform a preliminary
alkylation of the amino function by reductive amination11
or via Mitsunobu reaction.12 However, different new
methodologies for synthesizing 1,3,5-trisubstituted hyd-
antoins have been recently reported, including a mild
cyclization/cleavage approach to various linear urea
compounds in solid phase,11-13 a novel application of the
Ugi five-component condensation,14 a base-catalyzed
rearrangement of 5-substituted barbituric acids,15 and
palladium-catalyzed carbonylation of aldehydes in the
presence of urea derivatives.16
Carbodiimides17 such as dicyclohexylcarbodiimide (DCC)
and diisopropylcarbodiimide (DIC) are very popular
reagents often used to activate carboxylic acid groups to
nucleophilic substitution.18 The mechanism and kinetics
of reaction of carbodiimides with carboxylic acids have
been extensively investigated.19 The reaction sequence
involves a proton transfer from the carboxylic acid 1
(Scheme 1) to the basic nitrogen of the carbodiimide 2,
followed by addition of the carboxylate to form the O-acyl
isourea 3.
It is known19a that in low dielectric constant solvents
such as CH2Cl2 (DCM), formation of 3 occurs instanta-
neously and, in the absence of a nucleophile or a base, it
can be stable for many hours. The intermediate 3 is a
reactive species and in the presence of a nucleophile
affords the coupling product 4, together with a urea
coproduct 5. However, 3 can undergo a rearrangement,
the so-called OfN acyl migration, to give the N-acylurea
6, which is a frequently found byproduct in these reac-
tions.
Very recently, we have developed a new straightfor-
ward method for the synthesis of 1,3,5-trisubstituted
hydantoins by a one-pot domino20 condensation/aza-
Michael addition/OfN acyl migration of carbodiimides
with activated R,â-unsaturated carboxylic acids, which
proceeds under very mild conditions.21 Different com-
mercially available carbodiimides 2 (Scheme 2) react
smoothly at 20 °C in DCM with fumaric and maleic acid
derivatives 1 to give the intermediate O-acyl isourea 3,
which immediately produces the intermediate 7 through
an intramolecular N-Michael addition.22 The following
(6) Jansen, M.; Potschka, H.; Brandt, C.; Lo¨scher, W.; Dannhardt,
G. J. Med. Chem. 2003, 46, 64-73.
(7) Last-Barney, K.; Davidson, W.; Cardozo, M.; Frye, L. L.; Grygon,
C. A.; Hopkins, J. L.; Jeanfavre, D. D., Pav, S.; Qian, C.; Stevenson, J.
M.; Tong, L.; Zindell, R.; Kelly, T. A. J. Am. Chem. Soc. 2001, 123,
5643-5650.
(8) Sutherland, J. C.; Hess, G. P. Nat. Prod. Rep. 2000, 621-631.
(9) (a) Syldatk, C.; Mu¨ller, R.; Siemann, M.; Krohn, K.; Wagner, F.
In Biocatalytic Production of Amino Acids and Derivatives; Rozzell,
J. D.; Wagner, F., Eds.; Hanser: Mu¨nchen, 1992; p 75. (b) Drauz, K.;
Waldmann, H. Enzyme Catalysis in Organic Synthesis, VCH: Wein-
heim, 1995, p 409.
(16) Beller, M.; Eckert, M.; Moradi, W. A.; Neumann, H. Angew.
Chem., Int. Ed. 1999, 38, 1454-1456.
(17) For a review concerning the synthesis and the structural and
chemical properties of carbodiimides, see: Williams, A.; Ibrahim, I. T.
Chem. Rev. 1981, 81, 589-636.
(10) Lo´pez, C. A.; Trigo, G. G. Adv. Heterocycl. Chem. 1985, 38, 177-
228.
(18) Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067-
1068.
(11) (a) Kim, S. W.; Ahn, S. Y.; Koh, J. S.; Lee, J. H.; Ro, S.; Cho, H.
Y. Tetrahedron Lett. 1997, 38, 4603-4606. (b) Matthews, J.; Rivero,
R. A. J. Org. Chem. 1997, 62, 6090-6092. (c) Sim, M. M.; Ganesan, A.
J. Org. Chem. 1997, 62, 3230-3235.
(12) Boeijen, A.; Kruijtzer, J. A. W.; Liskamp, R. M. J. Bioorg. Med.
Chem. Lett. 1998, 8, 2375-2380.
(19) (a) Klausner, Y. S.; Bodansky, M. Synthesis 1972, 1, 453-463
and references cited therein. (b) Rebek, J.; Fitler, D. J. Am. Chem.
Soc. 1973, 95, 4052-4053.
(20) Tietze, L. F. Chem. Rev. 1996, 96, 115-136.
(21) Volonterio, A.; Zanda, M. Tetrahedron Lett. 2003, 44, 8549-
8551.
(13) (a) Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahedron
Lett. 1996, 37, 937-940. (b) Park, K. H.; Kurth, M. J. Tetrhedron Lett.
2000, 41, 7409-7413. (c) Lamothe, M.; Lannuzel, M.; Perez, M. J.
Comb. Chem. 2002, 4, 73-78. (d) Nefzi, A.; Giulianotti, M.; Troung,
L.; Rattan, S.; Ostresh, J. M.; Houghten, R. A. J. Comb. Chem. 2002,
4, 175-178. (e) Va´zquez, J.; Royo, M.; Albericio, F. Lett. Org. Chem.
2004, 1, 224-226.
(22) For a related process involving an amino group as a nucleophile,
see: (a) Saito, T.; Tsuda, K.; Saito, Y. Tetrahedron Lett. 1996, 37, 209-
212. (b) Molina, P.; Aller, E.; Lorenzo, A. Synthesis 1998, 26, 283-
287. A conceptually related process involving fumaric acid mono-
ethylester and several carbodiimides, in the presence of alcohols or
amines, was reported to produce rearranged urea products via the
intermediates 3 and 7. In that case, the corresponding hydantoins were
occasionally observed as minor byproducts. See: (c) Kishikawa, K.;
Sankhavasi, W.; Yoshizaki, K.; Kohmoto, S.; Yamamoto, M.; Yamada,
K. J. Chem. Soc., Perkin Trans. 1 1994, 1205-1209. In this reference,
no attempts to produce hydantoins and no description of the reaction
course in the absence of alcohols or amines were described.
(14) Hulme, C.; Ma, L.; Romano, J. J.; Morton, G.; Tang, S. Y.;
Cherrier, M. P.; Choi, S.; Salvino, J.; Labaudiniere, R. Tetrahedron
Lett. 2000, 41, 1889-1893.
(15) Meusel, M.; Ambroz˘ ak, A.; Hecker, T. K.; Gu¨tschow, M. J. Org.
Chem. 2003, 68, 4684-4692.
2162 J. Org. Chem., Vol. 70, No. 6, 2005

Synthesis of 1,3,5-Trisubstituted Hydantoins
SCHEME 2 One-Pot Domino Condensation/Aza-Michael Addition/OfN Acyl Migration
Crafts acylation of anisole26 and p-fluorobenzene,27
respectively (eq 3). While 4,4,4-trifluoro-3-trifluoromethyl
(Tfm)-crotonic acid 1f is commercially available, the
methyl ketone 1g was prepared by trapping with the
stabilized ylide 9 the pyruvaldehyde produced by in situ
oxidation of the hydroxy acetone 11 with MnO2 in DCM
(eq 4).28
SCHEME 3. Preparation of Starting Materials
1a-g
Reactions with Symmetric Carbodiimides. When
symmetric carbodiimides such as DIC (2a), DCC (2b),
1,3-di-tert-butylcarbodiimide (2c), and 1,3-p-tolylcarbo-
diimide (2d) were reacted with activated R,â-unsaturated
carboxylic acids 1a-g, N,N′-disubstituted hydantoins
8a-v were cleanly formed in moderate to good yields
(Table 1).
Strongly activated acids 1a (entries 1-5) and 1b
(entries 6-9) reacted smoothly (less than 5 min) in DCM
at 20 °C, producing the corresponding hydantoins 8a-h
in good yields. Even sterically congested 1,3-di-tert-
butylcarbodiimide 2c gave satisfactory results (entries
3 and 8),29 while 1,3-p-tolylcarbodiimide 2d reacted
sluggishly (entries 4 and 9). Acid 1a gave rise to low
diastereoselection both when reacted as an equimolar
mixture of the E/Z isomers (formation of the two
epimeric hydantoins 8a-d in a 1:1 mixture was observed,
entries 1-4) and when reacted as pure (Z)-isomer iso-
lated by flash chromatography (FC) of the mixture (the
epimeric hydantoins 8a formed in a 2.5:1 mixture, entry
5). The stereochemistry of one of the diastereoisomers
8c was unambiguously assigned by X-ray analysis (see
Supporting Information).
Less activated fumaric acid monoethyl ester 1c re-
quired longer reaction times (DCM, overnight, 20 °C);
however, satisfactory results were obtained as well with
2a,b (entries 10 and 11), and even 2d (entry 13), while
sterically congested 2c reacted sluggishly (entry 12),30
affording the N-acylurea 6k, arising from OfN acyl
migration of the intermediate O-acyl isourea, as a major
product (30% yield). Under these conditions, less reactive
aryl γ-oxo-R,â-unsaturated carboxylic acids 1d,e did not
react with carbodiimide 2b (entries 14 and 21). To
increase the reactivity of 1d, we tried to perform the
reaction in the presence of a catalytic amount of a base
OfN acyl migration gives rise to the formation of the
hydantoin 8.
In this paper, we provide a full account on the scope
and limits of this new methodology, which has been
studied in detail by performing the reaction on many
different R,â-unsaturated carboxylic acids having vari-
able degrees of activation and carbodiimides, including
hitherto scarcely investigated asymmetric carbodiimides
having different substituents at the two nitrogen atoms.
The new results dramatically expand the scope of the
process and allow for the preparation of a potentially very
large array of structurally diverse hydantoins.23
Results
Synthesis of R,â-Unsaturated Carboxylic Acids
1a-g. The R,â-unsaturated carboxylic acids 1a,b were
prepared by Wittig reaction of the stabilized ylide 924 with
ethyl trifluoropyruvate and diethyl ketomalonate, re-
spectively (Scheme 3, eq 1). The product 1a was obtained
as an equimolecular mixture of the E/Z isomers and used
in this form.
Starting from maleic anhydride 10, we obtained in
diastereomerically pure (E)-form the fumaric acid mono-
ethyl ester 1c by ethanolysis in the presence of triethyl-
amine25 (eq 2), and the aryl ketones 1d,e by Friedel-
(25) Schoeneker, J. W.; Takemori, A. E.; Portoghese, P. S. J. Med.
Chem. 1986, 29, 1868-1871.
(26) Kameo, K.; Ogawa, K.; Takeshita, K.; Nakaike, S.; Tamisawa,
K.; Sota, K. Chem. Pharm. Bull. 1988, 36, 2050-2060.
(27) Upreti, M.; Pant, S.; Dandia, A.; Pant, U. C. Phosphorus, Sulfur
Silicon Relat. Elem. 1996, 113, 165-172.
(28) Wei, X.; Taylor, R. J. K. J. Org. Chem. 2000, 65, 616-620.
(29) Reaction between 1b and 2c (Table 1, entry 8) was performed
in an NMR tube: neither 1H nor 13C NMR spectroscopy allowed us to
detect any putative intermediate, as the final hydantoin 8g formed
immediately.
(30) Use of a catalytic base did not improve the outcome of the
reactions involving 2c.
(23) For preliminary results on the reaction involving asymmetric
carbodiimides: Volonterio, A.; Zanda, M. Lett. Org. Chem. 2005, 2, 44-
46.
(24) Seuring, B.; Seebach, D. Justus Liebigs Ann. Chem. 1978,
2044-2073.
J. Org. Chem, Vol. 70, No. 6, 2005 2163

Volonterio et al.
TABLE 1. Synthesis of N,N′-Disubstituted Hydantoins 8a-v
a 1a used in nearly equimolar E/Z ratio. b Equimolar mixture of two diastereomers. c Two diastereomers with dr ) 2.5/1.0. d Time ) 5
min. e Overnight. f No reaction observed. g Formation of the corresponding N-acylurea was observed.
2164 J. Org. Chem., Vol. 70, No. 6, 2005

Synthesis of 1,3,5-Trisubstituted Hydantoins
TABLE 2. Reaction with Strongly Asymmetric N-Benzyl-N′-p-methoxyphenylcarbodiimides 2e
a Overnight. b Performed with 1 equiv.
(DMAP, DCM, overnight, 20 °C) obtaining the formation
of the hydantoin 8m in low yield (entry 15). A slight
increase of yield was obtained performing the reaction
in CH3CN instead of DCM (entry 16). An even better
yield of the hydantoin 8n was achieved performing the
reaction in CH3CN with 0.5 equiv of a base (entry 17)
such as sym-collidine (TMP). Finally, good yields of
products 8m-o were achieved using an equimolar amount
of base (entries 18-20), even with the less reactive
carbodiimide 2d. In contrast, the p-fluoro derivative 1e
gave only a moderate yield of the hydantoin 8p (entry
22). Since the reaction was apparently strongly depend-
ent on the polarity of the solvent, we tried to increase
the reactivity of 1e performing the reaction in DMF.
Indeed, satisfactory results were obtained with carbo-
diimides 2a,b (entries 23 and 24). Using CH3CN as a
solvent and 1.0 equiv of base, aliphatic 4-oxo-pent-2-enoic
acid 1f showed good reactivity with carbodiimides 2b,d
providing hydantoins 8r,s, respectively, in good yields
(entries 25 and 26). Finally, despite its two electron-
withdrawing groups in the â position, 4,4,4-trifluoro-3-
Tfm-crotonic acid 1g reacted sluggishly with carbodiimide
2a in the absence of a base (entry 27). However, it showed
a good reactivity with carbodiimides 2b,d in CH3CN in
the presence of an equimolar amount of the base, produc-
ing hydantoins 8u,v in very good yields (entries 28 and
29).
Reactions with Asymmetric Carbodiimides. Next,
to expand the scope of the process, we investigated the
reaction of carboxylic acids 1b-g with asymmetric carbo-
diimides 2e-h (Tables 2-5). The latter were prepared
by dehydration of asymmetric ureas, which were obtained
in turn by reaction of amines with isocyanates, with
bromotriphenylphosphorane prepared in situ from bro-
mine and triphenyl phosphine.31 With the goal of achiev-
ing regioselectivity in the key intramolecular aza-Michael
step, we chose to use asymmetric carbodiimides having
different functionalities at the nitrogen atoms in terms
of nucleophilic character and/or steric bulkiness, depend-
ing on the R3 and R4 appendages.32
For the sake of clarity, carbodiimides having R3 ) alkyl
and R4 ) aryl will be dubbed “strongly asymmetric”, and
J. Org. Chem, Vol. 70, No. 6, 2005 2165

Volonterio et al.
TABLE 3. Reaction with Strongly Asymmetric N-Cyclohexyl-N′-phenylcarbodiimide 2f
a Time ) 5 min. b Overnight. c Performed with 1 equiv.
those having both R3 and R4 ) alkyl or aryl will be
dubbed “weakly asymmetric”. We first investigated the
reactivity of strongly asymmetric N-benzyl-N′-p-meth-
oxyphenyl (PMP) carbodiimide 2e (Table 2).
in 68% total yield was achieved performing the reaction
in CH3CN (entry 10). The structure of hydantoin 12e,
and thus the regiochemical course of the reaction, was
unambiguously determined by X-ray diffraction analysis
(see Supporting Information).
In contrast with symmetric carbodiimides (see above),
formation of a detectable amount of the N-acylurea
byproduct 6 was observed in nearly all cases. The
reaction between fumaric acid monoethyl ester 1c and
2e showed high regioselectivity and scarce chemoselect-
ivity when performed in DCM in the absence of a base.
In fact, a ca. 2:1 mixture of hydantoin 12a and N-acylurea
6a (70% total yield) was obtained (Table 2, entry 1). In
contrast, in CH3CN and in the presence of a base, the
reaction was completely chemoselective but not regio-
selective, producing a 1:1 mixture of the two hydantoins
12a and 13a in 68% yield (entry 2). Less reactive aryl
and alkyl γ-oxo-R,â-unsaturated carboxylic acids 1d-f
reacted smoothly in polar solvents, affording totally
regioselective but poorly chemoselective reactions (except
1f in CH3CN, which gave exclusively the urea 6d) and
producing mixtures of hydantoins 12b-d and N-acyl-
ureas 6b-d, respectively, in good total yields (entries
3-8). Finally, highly reactive 4,4,4-trifluoro-3-Tfm-cro-
tonic acid 1g produced the hydantoin 12e in good yield,
as a unique product, in DCM (entry 9). Formation of an
equimolar mixture of the two hydantoins 12e and 13e
Importantly, N-acylurea byproducts 6b,d, whose struc-
ture was unambiguously assigned by 1H NMR analysis,
could be converted in good yields into the corresponding
hydantoins 12b,d by treatment with NaH in dry DMF
(Scheme 4). Clearly, this strongly improves the synthetic
methodology, as it permits the recycle of a relevant side-
product. It is worth noting that N-acylureas 6 are stable
compounds that do not convert spontaneously into hyd-
antoins 9.
Next, we checked the behavior of more sterically
congested strongly asymmetric N-cyclohexyl-N′-phenyl-
carbodiimide 2f (Table 3).
As expected, highly reactive acid 1b reacted smoothly
with 2f, giving hydantoin 12f as the only product in very
good yield (Table 3, entry 1). The reaction between 2f
and less activated acids 1c-e proved to be less effective
in comparison with 2e probably due to the bulkier
character of the N-cyclohexyl moiety of 2f with respect
to the N-benzyl in 2e, which slows the intramolecular
aza-Michael step. In fact, fumaric acid monoethyl ester
1c reacted with carbodiimide 2f, affording N-acylurea 6g
as a major product and the hydantoin 12g as a minor
product (entries 2 and 3). Aryl γ-oxo-R,â unsaturated
carboxylic acids 1d,e, which were scarcely reactive in
DCM, also produced N-acylureas 6h,i as major products,
even in a very polar solvent such as DMF (entries 4-6).
(31) Palomo, C.; Mestres, R. Synthesis 1981, 373-374.
(32) Examples of regioselective reactions exploiting the reactivity
of asymmetric carbodiimides: (a) Larksarp, C.; Alper, H. J. Org. Chem.
1998, 63, 6229-6233. (b) Heras, M.; Ventura, M.; Linden, A.; Villal-
gordo, J. M. Tetrahedron 2001, 57, 4371-4388.
2166 J. Org. Chem., Vol. 70, No. 6, 2005

Synthesis of 1,3,5-Trisubstituted Hydantoins
TABLE 4. Reaction with Weakly Asymmetric N-tert-Butyl-N′-benzylcarbodiimide 2g
a Time ) 5 min. b Overnight. c Performed with 1 equiv.
Moreover, in these reactions, together with hydantoins
12h,i, we noticed also the formation of a small amount
of the other regioisomeric hydantoins 13h,i derived from
intramolecular aza-Michael addition of the less nucleo-
philic aniline moiety. Also in this case, the N-acylurea
6h could be transformed into the hydantoin 12h (80%)
using the same condition shown above (see Scheme 4).
The reaction between 4,4,4-trifluoro-3-Tfm-crotonic acid
1g and carbodiimide 2f was chemo- and regiospecific in
DCM, giving rise exclusively to the hydantoin 12j in very
good yield (entry 7), whereas the same reaction performed
in CH3CN produced without regioselectivity an equimolar
mixture of the two hydantoins 12j and 13j.
Next, we investigated the behavior of weakly asym-
metric dialkyl carbodiimides. Considering that the key
intramolecular N-Michael step was shown to be remark-
ably sensitive to steric hindrance and hoping to obtain
regioselective reactions, we synthesized a model carbo-
diimide 2g bearing a tertiary alkyl group (tert-butyl) and
a primary alkyl group (benzyl); then, we studied its
reactivity with acids 1b-g (Table 4). In analogy with
symmetric carbodiimides, with 2f we never detected the
formation of N-acylurea byproducts. Fumaric acids 1b,c
with 2g in DCM gave totally selective reactions with just
the formation of the favorite hydantoins 12k,l produced
by the nucleophilic attack of the less hindered benzyl-
amine moiety (entries 1 and 2). Less reactive aryl γ-oxo-
R,â unsaturated carboxylic acids 1d,e, which are scarcely
reactive in DCM, produced an equimolar mixture of
hydantoins 12m,n and 13m,n both in DMF and in less
polar CH3CN (entries 3-5). 4,4,4-Trifluoro-3-Tfm-crotonic
acid 1g gave a completely selective reaction, affording
only the hydantoin 12o both in DCM (entry 6) and in
CH3CN (entry 7). The latter results suggest that, when
the difference of nucleophilicity or bulkiness between the
two alkylic nitrogen substituents on the carbodiimides
is high and the R,â-unsaturated carboxylic acids are
highly activated, the solvent has little or no influence on
the selectivity.
Finally, we tested the reactivity of weakly asymmetric
carbodiimide 2h, which has two different aromatic sub-
stituents (Table 5). In this case, the regioselectivity could
arise from the higher electron density, and therefore
higher nucleophilicity, on the nitrogen atom of the
anisidine moiety with respect to the electron-poor 4-nitro
aniline moiety.
The difference in reactivity of the two amine moieties
turned out to be smaller than expected, and the resulting
regioselectivity was lower than that observed in the
previous cases. However, complete chemoselectivity was
obtained in all cases, and no formation of N-acylurea
byproducts was detected. The best regioselectivity was
achieved with the most activated acid 1b in the presence
of 1 equiv of base (12p:13p ) 5:1, Table 5, entry 2), while
in the absence of base a 3:1 mixture of hydantoins was
obtained (entry 1). As in the case of dialkyl carbodiimide
2g, the regioselectivity of the reaction of 2h with 4,4,4-
trifluoro-3-Tfm-crotonic acid 1g was not affected by the
polarity of the solvent; therefore, the same 4:1 mixture
of hydantoins 9t and 10t was obtained both in DCM
(entry 7) and CH3CN (entry 8). Finally, with less acti-
vated acids 1c-e, no regioselectivity was observed (en-
tries 3-6).
J. Org. Chem, Vol. 70, No. 6, 2005 2167

Volonterio et al.
TABLE 5. Reaction with Weakly Asymmetric N-p-Methoxy-phenyl-N′-p-nitro-phenylcarbodiimide 2h
a Time ) 5 min. b Overnight. c Not determined. d Performed with 1 equiv.
SCHEME 4. Conversion of N-Acylureas 6 into
Hydantoins 9
Since the formation of N-acylureas 6 and hydantoins
8, 12, 13 is under kinetic control, as demonstrated by
the fact that these compounds interconvert neither into
each other nor into the starting materials 1 and 2, the
mechanism above allows for a valid interpretation of the
experimental results.
Concerning the chemoselectivity of the process, namely,
the competition between formation of N-acyl-isoureas 6
and 6′ and hydantoins 12 and 13, the latter becomes
predominant, and even exclusive, with highly activated
carboxylic acids. In those cases, the intramolecular aza-
Michael reaction leading to the intermediates 7 and 7′
(Scheme 5) appears to be faster than the OfN acyl
migrations. On the other hand, the pathway leading to
hydantoins is predominant with symmetric (R3 ) R4) or
weakly asymmetric (both R3 and R4 ) alkyl or aryl)
carbodiimides (Scheme 6). In fact, N-acylurea byproducts
were formed only from strongly asymmetric carbodi-
imides 2e,f, which have one alkyl (R3) and one aryl group
(R4) as N-substituents.34 Moreover, only one of the
regioisomeric forms, namely, 6, was observed, whereas
6′ was never detected. This is in line with previous
examples of OfN acyl migrations involving asymmetric
carbodiimides35 and could be explained by assuming that
in the case of symmetric (R3 ) R4) or weakly asymmetric
carbodiimides, the tautomeric forms 3 and 3′ are simi-
larly populated at the equilibrium, and the O-acyl isourea
Discussion
The reaction sequence with asymmetric carbodiimides
is portrayed in Scheme 5. In the case of symmetric
carbodiimides, only two products can be formed, namely,
the N-acylurea 6 and the hydantoin 8 (see Scheme 2).
For asymmetric carbodiimides, the reaction could provide
four different products: two regioisomeric hydantoins 12
and 13 and two N-acylureas 6 and 6′ (Scheme 5).
The first step involves addition of the carboxylic acid
1 to the carbodiimide 2 to form a reactive intermediate
O-acyl isourea,21 existing in two prototropic tautomeric
forms 3 and 3′. An OfN acyl migration can give rise to
the corresponding N-acylureas 6 and 6′, which are
frequently found byproducts in the condensation reac-
tions of carboxylic acids promoted by carbodiimides.
Although little is known on the mechanism of these OfN
acyl migrations and on the regioselectivity of the forma-
tion of N-acylureas from asymmetric carbodiimides,
Khorana proposed a rearrangement involving the CdN
bond of the intermediate O-acyl isoureas.33 In the case
of asymmetric O-acyl isoureas, this would lead to 6 from
3 and to 6′ from 3′ (Scheme 5).
(34) The only exception was a relatively small amount (30%) of
N-acylurea 6k formed from one of the reactions involving symmetric
tert-butyl carbodiimide 2c. This “abnormal” event could be due to the
exceptional steric hindrance of 2c.
(35) Gru¨nefeld, J.; Zinner, G. Arch. Pharm. (Weinheim, Ger.) 1985,
318, 1062-1069.
(33) Khorana, H. G. J. Chem. Soc. 1952, 2081-2088.
2168 J. Org. Chem., Vol. 70, No. 6, 2005

Synthesis of 1,3,5-Trisubstituted Hydantoins
SCHEME 5. Reaction Sequence with Asymmetric Carbodiimides
SCHEME 6. Proposed Mechanism for the
Interestingly, both the chemoselectivity and the regio-
control of hydantoin formation (but not that of N-acylurea
formation, which is always 100%) are strongly influenced
by experimental factors such as the solvent and the use
of a base. Concerning the solvent, the use of more polar
solvents (DMF > CH3CN > DCM) increases the rate of
the intramolecular aza-Michael step and thus the
chemoselectivity of the process in favor of the hydantoins
but in some cases (see, for example, the formation of 12e
and 13e, Table 2, entries 9 and 10) decreases the
regioselectivity of the process. Clearly, this can be
interpreted in terms of the well-known accelerating effect
of polar solvents on aza-Michael reactions, which gener-
ally involve highly polar (and even zwitterionic) inter-
mediates, whereas the OfN acyl migrations do not. On
the other hand, the lowering of the kinetic activation
energy brought about by the use of polar solvents is
expected to be accompanied by a decrease in regioselect-
ivity, since the less nucleophilic N-R functions become
more competitive in the aza-Michael attack.
Formation of N-Acylureas
N-CdN π-system is highly delocalized (Scheme 6). This
should make less favorable the rearrangement to 6,
which involves the CdN-R4 double bond. On the other
hand, the observed regioselectivity leading exclusively to
the formation of regioisomers 6, which have R4 ) PMP
(N-acylureas 6a-d) and R4 ) Ph (6f-i), should be due
to the predominance of regioisomer 3, which has the
CdN bond conjugated with the aromatic π-system.
The regioselectivity of the hydantoin formation is
regulated by the second reaction pathway involving the
intermediate O-acyl isoureas 3 and 3′ (Scheme 5), which
is an intramolecular aza-Michael reaction leading to the
regioisomeric 2-imino-oxazolidin-2-ones 7 and 7′. Al-
though 2-imino-oxazolidin-2-ones, like 7 and 7′, have been
isolated,36 it is known that such compounds have a strong
proclivity to undergo OfN acyl migration leading to the
final hydantoins 12 and 13, respectively.21c Thus, the
regioselectivity of the hydantoin formation with asym-
metric carbodiimides depends mainly on the difference
of nucleophilicity between the two incipient amine moi-
eties N-R3 and N-R4 on the carbodiimide: the greater
the difference, the higher the regioselectivity. It is
therefore not surprising that weakly asymmetric carbo-
diimides such as 2h afforded lower regiocontrols in
comparison with strongly asymmetric carbodiimides such
as 2e,f. In this respect, both electronic and steric differ-
ences between R3 and R4 appear to be important.
The base has a similar effect, as it is well-known that
bases catalyze aza-Michael reactions.37 Concerning the
effect of the base on regioselectivity, the same arguments
discussed above for the solvent effect should be applied.
Conclusion
In summary, we have developed a general, straight-
forward method for the preparation of 1,3,5-trisubstituted
hydantoins in good to excellent yields by means of a new
domino reaction between carbodiimides and activated
R,â-unsaturated carboxylic acids that takes place under
very mild conditions. Both the regio- and chemoselectivity
of the process are generally very good, although the
nature of reactants, as well as reaction parameters such
as the solvent and the use (or not) of a base promoter,
have strong effects, which have been studied in detail. A
large array of structurally diverse 1,3,5-trisubstituted
hydantoins can be synthesized through this method,
which looks particularly suitable for solid-phase/com-
(37) Molteni, M.; Volonterio, A.; Zanda, M. Org. Lett. 2003, 5, 3887-
3890 and references therein.
(36) Brady, W. T.; Owens, R. A. J. Org. Chem. 1977, 42, 3220-3222.
J. Org. Chem, Vol. 70, No. 6, 2005 2169

Volonterio et al.
NMR (235.4 MHz, CDCl3) δ -63.2 (d, J ) 8.6 Hz, 3F); EIMS
(m/z) 338 [M+ (100)], 323 (64), 223 (80), 83 (78).
binatorial chemistry. Resolution of this issue, as well as
the development of a stereoselective version of the domino
process, is currently in progress in our laboratory.
Synthesis of Hydantoins. Reactions in the Presence
of a Base. General Procedure. To a stirred solution of
carbodiimide 2 (1 equiv) in an organic solvent (0.1 M solution)
was added 1 equiv of TMP followed by a solution of
R,â-unsarurated carboxylic acid 1 (1 equiv) in a minimum
amount of the same organic solvent. The resulting solution
was stirred overnight. The organic solvent was evaporated
under reduced pressure, diluted with AcOEt, and extracted
with 1 M HCl aqueous solution. The combined organic layers
were dried over anhydrous NaSO4, filtered, and concentrated
under vacuum, and the crude was purified by flash chroma-
tography.
Experimental Section
General Methods. Commercially available reagent-grade
solvents were employed without purification. Melting points
(mp) are uncorrected and were obtained on a capillary ap-
1
paratus. H NMR spectra were run on 250, 400, or 500 MHz
spectrometers. Chemical shifts are expressed in parts per
million (δ), using tetramethylsilane (TMS) as an internal
standard for 1H and 13C nuclei (δH and δC ) 0.00), while C6F6
was used as an external standard (δF 162.90) for 19F.
Synthesis of Hydantoins Starting from N-Acylureas
6. General Procedure. To a stirred solution of N-acylurea 6
(1 equiv) in dry DMF (0.1 M solution) was added 1.1 equiv of
NaH (60% in weight oil dispersion) at 0 °C under a nitrogen
atmosphere. After total consumption of starting material (TLC
monitoring), water was added, the organic solvent evaporated
under reduced pressure, and the resulting mixture extracted
with AcOEt. The combined organic layers were dried over
anhydrous NaSO4, filtered, and concentrated under vacuum,
and the crude was purified by flash chromatography.
3-Benzyl-1-(4-methoxy-phenyl)-1-[4-(4-methoxy-phen-
yl)-4-oxo-but-2-enoyl]-urea (6b): Rf ) 0.73 (hexane/AcOEt
) 50:50); mp 145-147 °C; FTIR (microscope) ν 1724, 1663
cm-1; 1H NMR (400 MHz, CDCl3) δ 9.50 (br t, J ) 4.4 Hz, 1H),
7.89 (d, J ) 8.8 Hz, 2H), 7.86 (d, J ) 15.0 Hz, 1H), 7.40-7.25
(m, 5H), 7.15 (d, J ) 8.8 Hz, 2H), 6.96 (d, J ) 8.8 Hz, 2H),
6.93 (d, J ) 8.8 Hz, 2H), 6.75 (d, J ) 15.0 Hz, 1H), 4.56
(d, J ) 5.4 Hz, 2H), 3.87 (s, 3H), 3.84 (s, 3H); 13C NMR (100.6
MHz, CDCl3) δ 187.3, 168.2, 164.2, 160.0, 154.6, 138.1, 135.8,
133.0, 131.2, 130.4, 129.8, 129.7, 128.7, 127.8, 127.5, 115.0,
114.1, 55.5, 55.4, 44.8; EIMS (m/z) 444 [M+ (4)], 311 (58), 133
(45), 123 (57), 91 (100).
General Procedure for the Preparation of 1a. To a
stirred solution of ylide 9 (3.0 g, 8.0 mmol) in DCM (40 mL)
was added dropwise neat ethyl trifluoropyruvate (1.6 g,
9.5 mmol). The solution was stirred for 90 min, the solvent
evaporated in vacuo, and the crude purified through a short
silica gel column. The recovered compounds were dissolved in
a 20% TFA solution in DCM, and after 2 h the solvent was
removed by evaporation. 1a (7.6 mmol, 95% overall yield) was
recovered as a 1:1 mixture of diastereoisomers.
1
(E)-1a: H NMR (400 MHz, CDCl3) δ 9.36 (br s, 1H), 7.31
(s, 1H), 4.36 (q, J ) 7.0 Hz, 2H), 1.36 (t, J ) 7.0 Hz, 3H);
13C NMR (100.6 MHz, CDCl3) δ 168.4, 161.0, 135.0 (q, J ) 3.4
Hz), 128.5 (q, J ) 33.6 Hz), 120.4 (q, J ) 274.3 Hz), 63.0, 13.9;
19F NMR (235.4 MHz, CDCl3) δ -66.7 (s, 3F).
(Z)-1a: FTIR (neat) ν 1743, 1724 cm-1; 1H NMR (400 MHz,
CDCl3) δ 9.70 (br s, 1H), 6.67 (q, J ) 1.3 Hz, 1H), 4.33 (q, J )
7.0 Hz, 2H), 1.30 (t, J ) 7.0 Hz, 3H); 13C NMR (100.6 MHz,
CDCl3) δ 167.6, 161.2, 135.6 (q, J ) 3.1 Hz), 128.9, 120.7
(q, J ) 274.3 Hz), 63.1, 13.4; 19F NMR (235.4 MHz, CDCl3) δ
-62.9 (s, 3F); EIMS (m/z) 212 [M+ (100)].
Synthesis of Hydantoins. Reactions in the Absence of
a Base. General Procedure. To a stirred solution of R,â-
unsaturated carboxylic acid 1 (1 equiv) in DCM (0.1 M
solution) was added 1 equiv of carbodiimide 2. After total
consumption of starting material (TLC monitoring), the or-
ganic solvent was evaporated under reduced pressure and the
crude purified by flash chromatography.
1-Benzyl-3-(4-methoxy-phenyl)-5-[2-(4-methoxy-phen-
yl)-2-oxo-ethyl]-imidazolidine-2,4-dione (12b): Rf ) 0.59
(hexane/AcOEt ) 50:50); mp 107-108 °C; FTIR (microscope)
1
ν 1775, 1727, 1673 cm-1; H NMR (400 MHz, CDCl3) δ 7.75
(d, J ) 8.8 Hz, 2H), 7.44 (d, J ) 8.8 Hz, 2H), 7.30-7.12
(m, 5H), 6.99 (d, J ) 8.8 Hz, 2H), 6.88 (d, J ) 8.8 Hz, 2H),
4.70 (d, J ) 15.3 Hz, 1H), 4.48 (d, J ) 15.3 Hz, 1H), 4.46
(dd, J ) 5.2 and 3.4 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.51
(dd, J ) 17.8 and 3.4 Hz, 1H), 3.33 (dd, J ) 17.8 and 5.2 Hz,
1H); 13C NMR (100.6 MHz, CDCl3) δ 193.5, 172.4, 164.0, 159.3,
156.5, 136.2, 130.3, 128.9, 128.8, 128.6, 128.2, 127.8, 127.7,
125.0, 114.4, 113.8, 55.8, 55.5, 45.8, 37.9; EIMS (m/z) 444
[M+ (23)], 309 (39), 135 (42), 123 (46), 108 (74), 91 (100).
(S,S)-(1,3-Diisopropyl-2,5-dioxo-imidazolidin-4-yl)-3,3,3-
trifluoro-propionic Acid Ethyl Ester (8a): Rf ) 0.30
(hexane/AcOEt ) 90:10); FTIR (microscope) ν 1778, 1748, 1703
1
cm-1; H NMR (400 MHz, CDCl3) δ 4.35-4.18 (m, 4H), 3.92
(dq, J ) 9.6 and 1.8 Hz, 1H), 3.65 (septet, J ) 7.0 Hz, 1H),
1.42 (d, J ) 2.6 Hz, 3H), 1.40 (d, J ) 2.6 Hz, 3H), 1.39
(d, J ) 6.7 Hz, 3H), 1.29 (d, J ) 6.7 Hz, 3H), 1.27 (t, J ) 7.0
Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 170.0, 163.1, 156.3,
123.7 (q, J ) 279.3 Hz), 62.4, 57.1, 51.1 (q, J ) 27.7 Hz,), 48.4,
44.4, 20.6, 19.6, 19.0, 18.9, 14.1; 19F NMR (235.4 MHz, CDCl3)
δ -64.9 (d, J ) 9.5 Hz, 3F); EIMS (m/z) 338 [M+ (100)], 323
(58), 223 (79).
Acknowledgment. Politecnico di Milano and CNR
are gratefully acknowledged for economic support.
(S,R)-(1,3-Diisopropyl-2,5-dioxo-imidazolidin-4-yl)-3,3,3-
trifluoro-propionic Acid Ethyl Ester (8a): Rf ) 0.27
(hexane/AcOEt ) 90:10); FTIR (microscope) ν 1781, 1755, 1713
Supporting Information Available: Copies of 1H or 13
C
NMR spectra for compounds (Z)-1a, 6b-d, 6h-i, 8a-g, 8i-
u, 12a-m, 12o,p, and 13n,q-t; thermal ellipsoid plot of
compounds 8c and 12e; characterization data for compounds
6c,d, 6h-k, 8b-u, 12a,c-t, 13a,e,j,m,n, and 13p-t; and
complete data (excluding structure factor) of the crystal
structure in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
cm-1 1H NMR (400 MHz, CDCl3) δ 4.46 (s, 1H), 4.35-4.22
;
(m, 3H), 3.91 (dq, J ) 9.0 and 1.6 Hz, 1H), 3.64 (septet,
J ) 6.7 Hz, 1H), 1.44 (d, J ) 6.7 Hz, 3H), 1.39 (d, J ) 7.0 Hz,
3H), 1.36 (d, J ) 7.0 Hz, 3H), 1.32 (t, J ) 7.0 Hz, 3H), 1.26
(d, J ) 6.7 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 170.1,
165.1, 156.2, 123.2 (q, J ) 283.8 Hz), 63.0, 56.6, 50.4
(q, J ) 27.2 Hz), 47.9, 44.3, 20.2, 19.4, 19.1, 19.0, 13.9; 19F
JO0480848
2170 J. Org. Chem., Vol. 70, No. 6, 2005