The aminobarbituric acid-hydantoin rearrangement

Article abstract of DOI:10.1021/jo020761f

A general synthesis protocol for the generation of tri- and tetrasubstituted 5-carbamoylhydantoins is described. Starting from barbituric acids and following bromination and reaction with primary amines, 5-aminobarbituric acids 3a-s and 8 were prepared. C

Full text of DOI:10.1021/jo020761f

Th e Am in oba r bitu r ic Acid -Hyd a n toin Rea r r a n gem en t
Manuela Meusel,† Agnieszka Ambroz˘ ak,† Thomas K. Hecker,‡ and Michael Gu¨tschow*,†
Pharmaceutical Institute, Poppelsdorf, University of Bonn, D-53115 Bonn, Germany, and
Institute of Pharmacy, University of Leipzig, D-04103 Leipzig, Germany
guetschow@uni-bonn.de
Received December 24, 2002
A general synthesis protocol for the generation of tri- and tetrasubstituted 5-carbamoylhydantoins
is described. Starting from barbituric acids and following bromination and reaction with primary
amines, 5-aminobarbituric acids 3a -s and 8 were prepared. Compounds 3 and 8 were subjected to
different conditions of a base-catalyzed rearrangement reaction to yield the 1,5,5-trisubstituted
hydantoins 4a -s and the 1,3,5,5-tetrasubstituted hydantoin 5c, respectively. Alkylation of 4a -s
afforded 1,3,5,5-tetrasubstituted hydantoins 5a -h . Mechanisms that explain the transformation
of corresponding aminobarbituric acids to hydantoins 4a -s and 5c were discussed in terms of the
formation of ring-opened intermediates. Aminobarbituric acids 3a -s unsubstituted at position 3
underwent a ring contraction via intermediate isocyanates which were trapped by the amino
function. A different mechanism involving a carbamate intermediate was concluded for conversion
of the 1,3,5,5-tetrasubstituted aminobarbituric acid 8.
In tr od u ction
hydantocidins from Streptomyces hygroscopicus8 and
aplysinopsins isolated from marine organisms.9
Hydantoins have long been the focus of attention as a
ubiquitous moiety incorporated into compounds with
numerous biological activities and therapeutic applica-
tions,1,2 e.g., as anticonvulsants,3 antiarrhythmics,4 an-
tidiabetics,5 serotonin and fibrinogen receptor antago-
nists.6 Moreover, a class of tetrasubstituted hydantoins
were reported as antagonists of leukocyte cell adhesion
acting as allosteric inhibitors of the protein-protein
interaction.7 Some bioactive natural products were found
which contain a hydantoin or related moiety, such as
Small, substituted heterocyclic compounds play an
important role in the development of biologically active
substances by offering a high structural diversity. Among
such heterocycles, particularly the hydantoin scaffold
opens the possibility of different kinds and degrees of
substitution. A variety of combinatorial approaches have
been described by which pharmacophoric groups were
attached to such a relatively rigid scaffold.10-12 Therefore,
the chemistry of multiple substituted hydantoins has
newly attracted much interest, and traditional ap-
proaches have been combined with recently developed
strategies. General accesses to 5-mono- and 5,5-disub-
stituted hydantoins were provided early by Read syn-
thesis and by Bucherer-Bergs method. The former
comprised the reaction of amino acids and cyanate salts
and the latter the condensation of carbonyl compounds
with potassium cyanide and ammonium carbonate.1,13
The condensation of R-dicarbonyl compounds with ureas
† University of Bonn.
‡ University of Leipzig.
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Houghten, R. A. J . Comb. Chem. 2002, 4, 175-178.
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10.1021/jo020761f CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/20/2003
4684
J . Org. Chem. 2003, 68, 4684-4692

Aminobarbituric Acid-Hydantoin Rearrangement
SCHEME 1
represented another classical methodology that involved
a step similar to the benzilic acid rearrangement.1,14
Hydantoins were prepared by acid-catalyzed cycliza-
tion of ureido acids obtained from reactions of amino
acids or amino nitriles with alkyl, aryl, or chlorosulfonyl
isocyanates, respectively.1,15 This type of cyclization has
widely been used in combinatorial chemistry,11 and
modifications have been applied. For example, N,N-
disubstituted hydantoins have been synthesized by a
route that involved condensation with aromatic alde-
hydes and reduction prior to urea formation to introduce
substituents at position N-1 of the final products.12
1,3,5,5-Tetrasubstituted hydantoins were accessible by
1,3-dipolar cycloaddition reactions of 1-oxa-4-azabuta-
dienes with aryl isocyanates.16,17 The reaction of ureas
with dimethyl acetylenedicarboxylate afforded 5-car-
bomethoxymethylidenehydantoins.18 A one-pot multi-
component reaction was developed to prepare hydantoins
from aldehydes, carbon monoxide, and ureas employing
palladium catalysis.19 Lately, 1,3,5-trisubstituted hydan-
toins were made available using a novel application of
the Ugi five-component condensation.20
In a previous report, it was shown that 5-NH2-
substituted barbituric acids undergo a ring contraction
to give 5,5-disubstituted hydantoins.21 This transforma-
tion was accomplished by treating the barbituric acids
with sodium ethoxide in ethanol. Alkaline hydrolysis of
barbituric acids have been investigated frequently. The
reaction center was found to be that carbonyl carbon close
to the undissociated nitrogen (e.g., 1-methylbarbituric
acids dissociated at N-3 and attacked at C-6). Nucleo-
philic attack resulted in ring opening and irreversible
decarboxylation of the malonuric acids formed. 1,3-
Dialkyl substitution shifted the ring cleavage to the
N-C-2 bonds.22,23 It stands to reason that alcoholysis of
barbituric acids under nonaqueous conditions was rarely
examined, since these were the usual conditions of their
preparation. However, the usage of alkoxide prevents any
decarboxylation and might allow for alternative ring
closure reactions, other than the recyclization to the
parent barbituric acids. Herein we present a novel
application of this concept by converting 5-aminobarbi-
turic acids with alkali alkoxide to hydantoins.
ditional substituted amino group at position 5 and to
investigate their conversion to hydantoins. As antici-
pated, such aminobarbituric acids 3 (Scheme 1) represent
suitable substrates for a rearrangement reaction to 1,5,5-
trisubstituted hydantoins 4. A fourth substituent might
then easily be introduced at position 3 to furnish tetra-
substituted hydantoins. Furthermore, the mechanism of
the rearrangement should be elucidated.
It was the priority objective of the present study to
prepare 1,5-substituted barbituric acids with an ad-
(13) Anteunis, M. J . O.; Spiessens, L.; De Witte, M.; Callens, R.;
Reyniers, F. Bull. Soc. Chim. Belg. 1987, 96, 459-465.
(14) (a) Schwenker, G.; Guo, H. Arch. Pharm. (Weinheim) 1993, 326,
45-50. (b) Lehmann, J . Arch. Pharm. (Weinheim) 1984, 317, 459-
465. (c) Paul, S.; Gupta, M.; Gupta, R.; Loupy, A. Synthesis 2002, 75-
78.
(15) Sarges, R.; Howard, H. R.; Kelbaugh, P. R. J . Org. Chem. 1982,
47, 4081-4085.
Resu lts a n d Discu ssion
(16) Moskal, J .; Moskal, A. Synthesis 1979, 794-797.
(17) (a) Moskal, J .; Moskal, A.; Milart, P. Tetrahedron Lett. 1982,
38, 1787-1792. (b) Moskal, J .; Moskal, A.; Milart, P. Monatsh. Chem.
1984, 115, 187-195.
The synthetic route to 5-aminobarbituric acids 3 is
shown in Scheme 1. 1,5-Disubstituted barbituric acids
1a -g were brominated at position 5 using bromine in
acetic acid. The resulting bromobarbituric acids 2 were
reacted with various primary amines to obtain 3a -s
(Table 1) as the first representatives of this type of
trisubstituted aminobarbituric acids. The nucleophilic
substitution reactions were performed with 2 equiv of the
amine and acetonitrile as the suitable solvent. After
dilution with water, the products were isolated by extrac-
tion with ethyl acetate. This procedure allowed the
(18) Lee, G.-Y.; Lee, Y.-S.; Koo, S. M.; Lee, K.-J . Bull. Korean Chem.
Soc. 1999, 20, 1359-1362.
(19) Beller, M.; Eckert, M.; Moradi, W. A.; Neumann, H. Angew.
Chem., Int. Ed. 1999, 38, 1454-1457.
(20) 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.
(21) Gu¨tschow, M.; Hecker, T.; Eger, K. Synthesis 1999, 410-414.
(22) Barton´, H. J .; Matusik, L.; Bojarski, J . Pol. J . Chem. 1996, 70,
570-577.
(23) Bojarski, J . T.; Mokrosz, J . L.; Barton´, H. J .; Paluchowska, M.
H. Adv. Heterocycl. Chem. 1985, 38, 229-297.
J . Org. Chem, Vol. 68, No. 12, 2003 4685

Meusel et al.
TABLE 1. P r ep a r a tion of Am in oba r bitu r ic Acid s 3 a n d
Rea r r a n gem en t to Hyd a n toin s 4
Constitution of the products 4 and 5 was unambigu-
ously elucidated as 5-carbamoyl hydantoins, which are
ultimately distinguishable from corresponding aminobar-
bituric acids on the basis of spectral data. 13C NMR
spectra of 5-carbamoyl hydantoins showed three distinct
carbonyl signals at 155-157 ppm (C-2), 163-167 ppm
(exocyclic CO), and 170-174 (C-4), the first and the last
being characteristic of the hydantoin scaffold. In contrast,
the first carbonyl resonance of aminobarbituric acids 3
appeared at 150 ppm (C-2), and the 13C NMR shifts of
the two other carbonyl carbons (C-4, C-6) occurred close
together at 170-173 ppm.24 Depending on the nature of
R1, C-5 signals of hydantoins 4 and 5 were observed
either between 69 and 71 ppm for alkyl, or between 75
and 77 ppm for phenyl substitution. These values lay
downfield compared to those of the aminobarbituric acids
at 62-64 ppm and 71-72 ppm, respectively. According
yield,
%
entry R1 R2
R3
3 (yield, %)
3a (71)b
4
conditionsa
1
2
3
Me Me i-Pr
Me Me Bn
4a
B
C
B
E
36b
30b
43c
21b
56c
17b
16b
28b
81c
36b
28c
35b
56c
66c
38b
58c
15c
28b
38b
64c
28c
85b
3b (82)c
4b
4
5
Me Me cyclohexyl 3c (60)b
4c
4d
4e
B
B
B
C
B
B
A
A
D
B
B
B
C
B
B
A
A
A
6
Me Et Pr
3d (68)c
3e (81)b
7
Me Et i-Pr
8
9
Me Et Bn
3f (66)b
4f
4g
4h
4i
10
11
12
13
14
15
16
17
18
19
20
21
22
Me Et cyclohexyl 3g (92)c
Me Ph Bn
3h (59)b
Me Ph cyclohexyl 3i (74)b
Ph Me Pr
Ph Me Bn
Ph Et Pr
3k (70)c
3l (55)b
3m (92)c
4k
4l
4m
1
to H NMR data for compounds 4 and 5, the residue R2
3n (51)b
3o (74)b
3p (72)b
3r (96)c
3s (67)b
4n
4o
4p
4r
was determined as part of the exocyclic carboxamide
moiety. The spectra showed characteristic splitting pat-
terns for the side-chain NH and the attached methyl or
methylene protons. Compared to 5-benzylaminobarbitu-
ric acids, 1-benzylhydantoins showed clearly different
chemical shifts of their diastereotopic benzylic protons.
Ph Et Bn
Ph Pr Bn
Ph Ph Pr
Ph Ph i-Pr
Ph Ph Bn
4s
a
All reactions were performed under an argon atmosphere.
Conditions A: Reactions were performed for 3 h in refluxing EtOH
in the presence of sodium ethoxide (4 equiv, 0.3 M). B: Reactions
were performed for 5 h in a sealed tube at 120 °C with EtOH in
the presence of sodium ethoxide (4 equiv, 0.8 M). C: Reactions
were performed for 5 h in refluxing BuOH in the presence of
sodium butoxide (4 equiv, 0.8 M). D: Reactions were performed
for 3 h at 78 °C in DMF in the presence of sodium hydride (4
equiv). E: Reactions were performed for 5 h at 78 °C in DMF in
the presence of sodium hydride (4 equiv). Refer to the Experimen-
We have analyzed the mass spectra of all aminobar-
bituric acids and hydantoins prepared. Fragmentation
of aminobarbituric acids was not uniform but depended
on the amino residue introduced at position 5.25-28 For
5-carbamoyl hydantoins, the elimination of R2NCO was
the significant fragmentation29,34 accompanied by further
decay that included the substituent at position 1.30-33
b
tal Section for details. Yields refer to products recrystallized or
Aminobarbituric acids 3 and hydantoins 4 could easily
be detected by a color reaction using cobalt(II) nitrate/
piperidine in methanol to give a violet complex.23,35 As
expected in the cases of tetrasubstituted hydantoins 5,
the reaction was negative.36
purified as indicated (Experimental Section). c Yields refer to pure
crude products.
removal of the corresponding ammonium barbiturates.
Such salts had been observed as impurities in certain
cases under other workup conditions.
(24) For 13C NMR data of barbituric acids, see: (a) De Meester, P.;
J ovanovic, M. V.; Chu, S. S. C.; Biehl, E. R. J . Heterocycl. Chem. 1986,
23, 337-341. (b) Cortes, S.; Kohn, H. J . Org. Chem. 1983, 48, 2246-
2254.
(25) MS fragmentation of 5-isopropylaminobarbituric acids (3,
R3 ) i-Pr): (M+ - CH3), (M+ - C3H7N). Relative intensities are noted
in the Experimental Section.
(26) MS fragmentation of 5-benzylaminobarbituric acids (3,
R3 ) Bn; 8): (M+ - C7H7N), 106 (C7H8N+). Relative intensities are
noted in the Experimental Section.
(27) MS fragmentation of 5-cyclohexylaminobarbituric acids (3,
R3 ) cyclohexyl): (M+ - HCNO), 98 (C6H12N+). Relative intensities
are noted in the Experimental Section.
Seventeen aminobarbituric acids 3 were converted to
hydantoins 4, and the ring contraction was examined
under different conditions. The transformations of 1-
phenyl aminobarbituric acids (3, R2 ) Ph) were per-
formed in refluxing ethanol in the presence of 4 equiv of
sodium ethoxide (0.3 M) over 3 h (conditions A, Table 1).
However, to successfully accomplish the conversions of
1-alkyl aminobarbituric acids (3, R2 ) Me, Et, Pr),
stronger conditions were needed. These barbituric acids
were treated in a closed reaction vessel at 120 °C for 5 h
with an 0.8 M solution of sodium ethoxide (4 equiv) in
ethanol (conditions B). It was shown exemplarily that
ethanol could be replaced by higher-boiling 1-butanol,
and thus sodium ethoxide by butoxide, to allow for a
reaction process in an open vessel (conditions C). More-
over, the rearrangement was studied in the absence of a
nucleophilic coreactant with sodium hydride in DMF at
78 °C (conditions D, E, respectively). Under these condi-
tions, hydantoins 4b and 4i were obtained and proved
to be identical with the corresponding products obtained
with sodium ethoxide.
(28) MS fragmentation of 5-propylaminobarbituric acids (3, R3
)
Pr): (M+ - C2H5). Relative intensities are noted in the Experimental
Section.
(29) MS fragmentation of hydantoins 4: (M+ - R2NCO). Relative
intensities are noted in the Experimental Section.
(30) MS fragmentation of 1-isopropylhydantoins (4, R3 ) i-Pr): (M+
- R2NCO - C3H6). Relative intensities are noted in the Experimental
Section.
(31) MS fragmentation of 1-benzylhydantoins (4, 5, R3 ) Bn): (M+
- R2NCO - C7H7), 91 (C7H7+). Relative intensities are noted in the
Experimental Section.
(32) MS fragmentation of 1-cyclohexylhydantoins (4, 5, R3 ) cyclo-
hexyl): (M+ - R2NCO - C6H10). Relative intensities are noted in the
Experimental Section.
(33) MS fragmentation of 1-propylhydantoins (4, 5; R3 ) Pr): (M+
- R2NCO - C3H6). Relative intensities are noted in the Experimental
Section.
As expected, 1,5,5-trisubstituted hydantoins could be
alkylated at the only remaining position 3. This was
shown for the reactions of several hydantoins 4 with
methyl iodide or ethyl bromide. The tetrasubstituted
hydantoins 5a -h are outlined in Scheme 1.
(34) This has also been reported for a few 5-carbamoylhydantoins
known so far: Zanotti, G.; Pinnen, F. J . Heterocycl. Chem. 1981, 18,
1629-1633. See also refs 16, 17, 21.
(35) (a) de Faubert Maunder, M. J . Analyst 1975, 100, 878-883.
(b) Bult, A. Pharm. Weekbl. 1975, 110, 1161-1163.
4686 J . Org. Chem., Vol. 68, No. 12, 2003

Aminobarbituric Acid-Hydantoin Rearrangement
SCHEME 2
The aminobarbituric acid-hydantoin rearrangement
could be envisaged to follow two different mechanisms.
One possible mechanism involved the addition of the
nucleophile, ring opening, and ring closure (ANRORC-
type reaction).37 Ring cleavage might result from a
nucleophilic attack of ethoxide (or butoxide) at one
carbonyl carbon of substrates 3. With such a nucleophilic
displacement being operative in the rearrangement,
intermediates I-IV had to be considered. As it has been
shown for the alkaline hydrolysis of 1,5,5-trisubstituted
barbiturates,23,38 carbon C-6 should preferably be at-
tacked. However, the corresponding ester intermediates
I might recyclize to 3 or undergo an intermolecular
reaction but could not form the hydantoins 4. This is also
true for ester intermediates II which might result from
an attack of ethoxide at C-4. Nucleophilic addition of
ethoxide at C-2 and subsequent cleavage of either the
1,2-bond or the 2,3-bond might afford carbamate inter-
mediates III and IV. Both of them are capable to
generate 5-carbamoyl hydantoins by ring closure reac-
tions. The possible products of these ring transformations
are 4 and V, respectively. At least for 1-alkyl-substituted
aminobarbituric acids 3, intermediates IV and thus
products V should be considered. However, in the course
of our investigations on ethoxide-promoted conversions
of 3, hydantoins V were not isolated. The major products
were always compounds 4 which could surely be distin-
1
guished from V by means of H NMR. These findings
indicated that the ANRORC-type reaction was not opera-
tive in the conversion of aminobarbituric acids 3 to
hydantoins 4.
It was considered that the elimination-addition mech-
anism did not require the presence of ethoxide (or
butoxide). Thus, the rearrangement was performed in the
absence of any nucleophilic coreactant by hydride-
promoted deprotonation of the aminobarbituric acids.
Indeed, the respective hydantoins were formed under
these conditions (conditions D, E; Table 1) to provide final
evidence for the elimination-addition mechanism.
It was intended to study the reaction with a tetrasub-
stituted aminobarbituric acid as substrate. For that
purpose, compound 8 was synthesized by a pathway
outlined in Scheme 2. Initially, 8 was treated with sodium
ethoxide in ethanol under conditions that have been
applied for the conversion of trisubstituted aminobarbi-
turic acids (conditions A, B; Table 1). Unexpectedly, the
treatment of 8 with 4 equiv of sodium ethoxide in
refluxing ethanol yielded the 1,3,5-trisubstituted hydan-
toin 9. Clearly, the formation of 9 from 8 was a result of
a consecutive transformation, and the 1,3,5,5-tetrasub-
stituted hydantoin 5c was assumed as an intermediate
which underwent a decarbamoylation. This was con-
firmed when 5c was subjected to the same conditions and
compound 9 was reobtained.
Alternatively, the formation of hydantoins 4 followed
an elimination-addition mechanism, known from E1cB
processes in acyl transfer reactions.39-41 According to this
elimination-addition mechanism, an initial deprotona-
tion of the aminobarbituric acids 3 was followed by the
ring-opening elimination of the carboxamide moiety.
Thereby, an intermediate isocyanate42 was formed as
shown in Scheme 1. Intramolecular addition of the amino
group completed the rearrangement.
Compound 5c has already been obtained by methyla-
tion of the trisubstituted hydantoin 4l (Scheme 1). It
should be noted that 4l resisted to decarbamoylation
under the stronger conditions of its preparation. An easy
explanation for the different stability is the neutral
(36) N-Substituted compounds 8 and 9 failed to react with cobalt-
(II) nitrate, too.
(37) (a) van der Plas, H. C. Acc. Chem. Res. 1978, 11, 462-468. (b)
Maiboroda, D. A.; Babaev, E. V.; J ug, K. J . Org. Chem. 1997, 62, 7100-
7105.
(38) Garrett, E. R.; Bojarski, J . T.; Yakatan, G. J . J . Pharm. Sci.
1971, 60, 1145-1154.
(42) Intermediate acylisocyanates were generated by phosgenation
of the carboxamide moiety of cyclic imines and underwent a trapping
reaction to fused hydantoin iminium chlorides: J aunin, R.; Arnold,
W. Helv. Chim. Acta 1973, 56, 2569-2583. For further examples to
prepare fused imidazo derivatives by trapping reactions, see ref 43.
(39) Williams, A.; Douglas, K. T. Chem. Rev. 1975, 75, 627-649.
(40) Hegarty, A. F.; Hegarty, C. N.; Scott, F. L. J . Chem. Soc., Perkin
Trans. 2 1974, 1258-1268.
(41) Gu¨tschow, M. J . Org. Chem. 1999, 64, 5109-5115.
J . Org. Chem, Vol. 68, No. 12, 2003 4687

Meusel et al.
hydantoin unit in 5c which served as a better leaving
group compared to the negatively charged hydantoin
moiety in 4l. It was established that decarbamoylation
reactions showed a high sensitivity to the nature of the
leaving group.40 A reaction similar to formation of 9 from
5c has been described for 1,3,5-triaryl-5-arylcarbamoyl-
hydantoins which lost an aryl isocyanate by thermal
elimination.16 Decarbamoylation reactions have also been
reported for other R-acceptor-substituted amides under
conditions of pyrolysis44 or alcoholysis.45 For the cleavage
of the R-acceptor-substituted amide side chain of certain
penicillins, an elimination of an isocyanate was sug-
gested.46
Next, the reaction of compound 8 with sodium ethoxide
in ethanol was studied under various conditions to
prepare 5c and prevent a further degradation to 9 as well
(Scheme 2). This was accomplished by using a catalytic
amount of ethoxide and an explicitly prolonged reaction
time. However, covalent nucleophilic catalysis was neces-
sary for the conversion of 8 since no reaction was
observed in the absence of sodium ethoxide, maintaining
the other conditions. The ring contraction of the tetra-
substituted aminobarbituric acid 8 had to process in a
different way compared to the elimination-addition
mechanism discussed above for the trisubstituted ami-
nobarbituric acids 3. In contrast to 3, N-3 deprotonation
of the substrate 8 is not possible. This led to an enhanced
susceptibility of the carbonyl C-2 to nucleophilic attacks.
Therefore, an ANRORC-type reaction was proposed for
the ring contraction of 8 to produce 5c. This transforma-
tion involved the addition of ethoxide, ring opening to
the carbamate intermediate and ring closure by attack
of the amino group at the carbamate carbon.
Compound 5c was concluded to be the intermediate
in the conversion of 8 to 9, and the further degradation
of 5c was a decarbamoylation reaction. On the other
hand, aminobarbituric acids could be transformed to
corresponding 3-unsubstituted 5-carbamoylhydantoins 4
(Scheme 1) showing a less susceptibility to decarbamoy-
lation. This was also the case for 1,3-unsubstituted
5-carbamoylhydantoins.21 In an earlier report,47 3,5-
dimethyl-1-p-tolylhydantoin was obtained by the treat-
ment of 1,3,5-trimethyl-5-p-tolylaminobarbituric acid
with ethanolic potassium hydroxide, and this reaction can
now be attributed to a ring transformation-decarbam-
oylation pathway similar to that outlined in Scheme 2.
There are some further examples known for ring contrac-
tions of six-membered rings to form hydantoins. Methyl
dihydroorotate underwent a methoxide-catalyzed conver-
sion to methyl hydantoin-5-acetate, and dimethyl 2-urei-
dosuccinate was supposed to be the intermediate; thus,
the exocyclic ester moiety served as an electrophile for
the recyclization.48 However, in the aminobarbituric
acid-hydantoin rearrangement reported herein, a nu-
cleophilic attack of the exocyclic amino function com-
pleted the ring closure. Hydantoins were also prepared
from six-membered heterocyclic compounds without an
exocyclic moiety being incorporated into the newly formed
hydantoin skeleton.49
In summary, an efficient synthetic entry to 1,5,5-
trisubstituted hydantoins 4 based on a conversion of
1,5,5-trisubstituted barbituric acids 3 has been found. To
introduce a 5-amino function into barbituric acids, cor-
responding bromobarbituric acids 2 can be reacted with
primary amines. The nitrogen atom of this functionality
is then incorporated into the newly formed five-mem-
bered ring. Thus, diversity at position 1 of the hydantoins
4 can be attained using different primary amines (defin-
ing R3). In the course of the ring contraction, expulsion
of the cyclic OdC(6)-NR2 moiety of the aminobarbituric
acids generates the exocyclic carbamoyl function of the
hydantoin products. The substitution pattern at position
5 of the hydantoins is derived from the ureas (defining
R2) and dialkyl malonates (defining R1) which can be used
as diverse starting materials for the preparation of the
corresponding barbituric acids 1. The present procedure
enables regioselective introduction of the three substit-
uents into the hydantoin scaffold of 4. Moreover, the
fourth substituent can easily be attached to the unsub-
stituted position 3 to obtain hydantoins 5. It is known
that hydantoins undergo alkylation and acylation reac-
tions preferably at position 3,55 whereas substitution at
position 1 (and 5) occurs under more severe condi-
tions.1,6,48
The aminobarbituric acid-hydantoin rearrangement
follows a deprotonation-elimination-addition mecha-
nism. However, if 1,3-disubstition of the aminobarbituric
acids prevents the formation of an intermediate iso-
cyanate, a mechanism involving nucleophilic addition,
ring opening, and ring closure becomes operative. The
rearrangement will be applied in our ongoing efforts
toward the chemistry of multisubstituted heterocyclic
compounds.
Exp er im en ta l Section
Melting points are not corrected. 1H NMR spectra (500 MHz)
and 13C NMR spectra (125 MHz) were recorded in DMSO-d6,
unless otherwise stated. Mass spectra were obtained from
using electron impact ionization (EI, 70 eV). Thin-layer chro-
matography was performed on Merck aluminum sheets, silica
gel 60 F254. The solvent system used for TLC was toluene/
acetone/methanol (5:3:2). Barbituric acids 1a -g, 6 were
prepared following literature procedures.50-52
Syn th esis of 5-Br om oba r bitu r ic Acid s 2a -g: Gen er a l
P r oced u r e. A solution of barbituric acid 1 (20 mmol) in acetic
(49) (a) Senda, S.; Hirota, K.; Banno, K. Tetrahedron Lett. 1974, 35,
3087-3088. (b) Sayer, J . M.; DePecol, M. J . Am. Chem. Soc. 1977, 99,
2665-2671. (c) Otter, B. A.; Sasson, I. M.; Gagnier, R. P. J . Org. Chem.
1982, 47, 508-513.
(50) (a) Senda, S.; Izumi, H.; Fujimura, H. Drug Res. 1967, 17,
1519-1523. (b) Knabe, J .; Schmitt, W. Arch. Pharm. (Weinheim) 1984,
317, 789-796. (c) Lapachev, V. V.; Stadlbauer, W.; Kappe, T. Monatsh.
Chem. 1988, 119, 97-102.
(51) To´th, G.; Makleit, S. Acta Chim. Acad. Sci. Hung. 1981, 107,
139-145.
(52) Knabe, J .; Reinhardt, J . Arch. Pharm. (Weinheim) 1982, 315,
706-716.
(53) Aspelund, H. Acta Acad. Abo. Ser. B 1939, XII, 5, 1-33.
(54) Saettone, M. F. J . Org. Chem. 1966, 31, 1959-1962.
(55) Mixtures of N-3 and N-1 alkylation products have also been
obtained, see ref 13.
(43) Gu¨tschow, M.; Powers, J . C. J . Org. Chem. 2001, 66, 4723-
4727.
(44) Mukaiyama, T.; Tokizawa, M.; Nohira, H.; Takei, H. J . Org.
Chem. 1961, 26, 4381-4384.
(45) Matoba, K.; Ishigami, E.; Takahata, H.; Yamasaki, T. Chem.
Pharm. Bull. 1981, 29, 651-656.
(46) Guest, A. W.; Milner, P. H. Tetrahedron Lett. 1984, 25, 4845-
4848.
(47) Clarke-Lewis, J . W.; Moody, K. Aust. J . Chem. 1970, 23, 1229-
1248.
(48) Keys, L. D., III; Folting, K.; Streib, W. E.; J ohnston, M. J . Org.
Chem. 1986, 51, 4721-4723.
4688 J . Org. Chem., Vol. 68, No. 12, 2003

Aminobarbituric Acid-Hydantoin Rearrangement
acid (300 mL) was stirred at room temperature. A solution of
bromine in acetic acid (20% solution, 16 g, 20 mmol) was added
dropwise over 20 min. When the addition was completed, the
mixture was stirred for 1 h at room temperature, the solvent
was evaporated under reduced pressure, and the residue was
dissolved in diethyl ether. After addition of charcoal and
filtration into the same amount of petroleum ether, the
mixture was kept at room temperature in an open dish. The
residue after evaporation was suspended in petroleum ether
and filtered off.
5-Bromo-1,5-dimethylbarbituric acid (2a ): yield 78%, mp
119-122 °C, lit.51,52 mp 94-95 °C, 147-148 °C; 1H NMR
(CDCl3) δ 2.08 (s, 3H), 3.33 (s, 3H), 8.48 (s, 1H); 13C NMR
(CDCl3) δ 21.7, 28.9, 45.1, 148.7, 165.6, 167.1.
1-Ethyl-5-methyl-5-propylaminobarbituric acid (3d ): mp
86-89 °C; 1H NMR δ 0.80 (t, J ) 7.4 Hz, 3H), 1.07 (t, J ) 7.1
Hz, 3H), 1.29-1.36 (m, 2H), 1.40 (s, 3H), 2.21 (t, J ) 7.1 Hz,
2H), 3.73 (q, J ) 7.1 Hz, 2H), 11.45 (s, 1H); 13C NMR δ 11.8,
13.2, 23.0, 24.4, 36.0, 46.3, 63.5, 149.9, 171.6, 172.1; EIMS
(m/z)28 226 (M+ - H, 1), 198 (100).
1-Ethyl-5-isopropylamino-5-methylbarbituric acid (3e): mp
96-99 °C (ethyl acetate/petroleum ether); 1H NMR δ 0.84 (d,
J ) 6.3 Hz, 3H), 0.87 (d, J ) 6.3 Hz, 3H), 1.07 (t, J ) 7.1 Hz,
3H), 1.40 (s, 3H), 2.65-2.73 (m, 1H), 3.74 (q, J ) 7.1 Hz, 2H),
11.50 (s, 1H); 13C NMR δ 13.0, 24.0, 26.3, 36.0, 45.5, 62.5,
149.8, 172.1, 172.7; EIMS (m/z)25 226 (M+ - H), 212 (100), 170
(6).
5-Benzylamino-1-ethyl-5-methylbarbituric acid (3f): mp
118-120 °C (MeOH/diethyl ether); 1H NMR δ 1.05 (t, J ) 7.1
Hz, 3H), 1.46 (s, 3H); 3.01-3.12 (m, 1H), 3.43-3.55 (m, 2H),
5-Bromo-1-ethyl-5-methylbarbituric acid (2b): yield 84%,
mp 121-123 °C, lit.51 mp 121-123 °C; 1H NMR (CDCl3) δ 1.21
(t, J ) 7.0 Hz, 3H), 2.07 (s, 3H), 3.87-4.01 (m, 2H), 8.52 (s,
1H); 13C NMR (CDCl3) δ 12.6, 21.5, 37.7, 45.4, 148.4, 165.7,
166.6.
3.69 (q, J ) 7.1 Hz, 2H), 7.18-7.29 (m, 5H), 11.47 (s, 1H); 13
C
NMR δ 13.1, 24.9, 35.9, 48.3, 63.5, 126.8, 128.0, 128.1, 139.8,
149.7, 171.3, 171.8; EIMS (m/z)26 275 (M+, 1), 170 (3), 106
(100).
5-Bromo-5-methyl-1-phenylbarbituric acid (2c): yield 82%,
1
mp 125-126 °C; H NMR (CDCl3) δ 2.14 (s, 3H), 7.22-7.54
5-Cyclohexylamino-1-ethyl-5-methylbarbituric Acid (3g). The
crude product was dried and washed with diethyl ether: mp
(m, 5H), 8.48 (s, 1H); 13C NMR (CDCl3) δ 21.2, 45.8, 128.0,
129.6, 129.6, 133.3, 148.3, 165.4, 166.8.
1
110-113 °C; H NMR δ 0.90-1.65 (m, 10H), 1.06 (t, J ) 7.1
Hz, 3H), 1.45 (s, 3H), 2.28-2.42 (m, 1H), 3.74 (q, J ) 7.1 Hz,
2H), 11.51 (s, 1H); 13C NMR δ 12.9, 23.8, 24.6, 25.4, 26.2, 30.5,
34.0, 36.0, 53.2, 61.2, 149.8, 172.1, 172.7; EIMS (m/z)27 267
(M+, 4), 24 (52), 98 (100).
5-Bromo-1-methyl-5-phenylbarbituric acid (2d ): yield 95%,
mp 124-126 °C, lit.53 mp 128-129 °C; 1H NMR (CDCl3) δ 3.37
(s, 3H), 7.39-7.53 (m, 5H), 8.44 (s, 1H); 13C NMR (CDCl3) δ
29.3, 56.2, 128.3, 128.9, 130.0, 132.6, 148.3, 164.8, 166.4.
5-Bromo-1-ethyl-5-phenylbarbituric Acid (2e). The residue
obtained after evaporation of acetic acid was suspended in
diethyl ether (30 mL), and the product was filtered off: yield
5-Benzylamino-5-methyl-1-phenylbarbituric Acid (3h ). The
crude product was purified by column chromatography (eluent,
1
1:1 ethyl acetate/petroleum ether): mp 86-89 °C; H NMR δ
1
1.60 (s, 3H), 3.17 (s, br, 1H), 3.62 (s, br, 2H), 7.21-7.47 (m,
10H), 11.60 (s, 1H); 13C NMR δ 24.5, 48.4, 64.0, 126.9, 128.2,
128.3, 128.5, 128.9, 129.1, 135.3, 140.2, 150.0, 171.5, 172.1;
EIMS (m/z)26 322 (M+ - H), 218 (5), 106 (100).
93%, mp 158-159 °C; H NMR (CDCl3) δ 1.24 (t, J ) 7.2 Hz,
3H), 3.99 (q, J ) 7.2 Hz, 2H), 7.39-7.52 (m, 5H), 8.43 (s, 1H);
13C NMR (CDCl3) δ 12.8, 38.2, 56.4, 128.3, 128.8, 129.9, 132.6,
148.0, 164.8, 165.9.
5-Cyclohexylamino-5-methyl-1-phenylbarbituric acid (3i):
mp 201-203 °C (toluene); 1H NMR δ 0.96-1.70 (m, 10H), 1.52
(s, 3H), 2.43-2.50 (m, 1H), 7.21-7.26 (m, 2H), 7.40-7.52 (m,
3H), 10.83 (s, br, 1H); 13C NMR δ 24.8, 24.8, 25.5, 25.6, 34.3,
34.3, 53.1, 62.6, 128.6, 129.0, 129.1, 135.2, 150.0, 172.2, 172.9;
EIMS (m/z)27 315 (M+, 14), 272 (86), 98 (100).
1-Methyl-5-phenyl-5-propylaminobarbituric acid (3k ): mp
106-110 °C; 1H NMR δ 0.85 (t, J ) 7.4 Hz, 3H), 1.44 (sext., J
) 7.4 Hz, 2H), 2.34-2.36 (m, 2H), 2.83 (s, br, 1H), 3.17 (s,
3H), 7.32-7.42 (m, 5H), 11.75 (s, 1H); 13C NMR δ 11.8, 23.2,
28.0, 46.6, 71.3, 126.5, 128.8, 128.9, 138.3, 150.1, 169.7, 171.1;
EIMS (m/z)28 275 (M+, 10), 246 (100).
5-Benzylamino-1-methyl-5-phenylbarbituric acid (3l): mp
147-148 °C (EtOH/cyclohexane); 1H NMR δ 3.15 (s, 3H), 3.26-
3.32 (m, 1H), 3.60-3.69 (m, 2H), 7.20-7.49 (m, 10H), 11.73
(s, 1H); 13C NMR δ 28.1, 48.7, 71.2, 126.5, 126.9, 128.2, 128.2,
128.9, 129.0, 138.2, 140.3, 150.2, 170.0, 171.0; EIMS (m/z)26
323 (M+, 3), 218 (16), 106 (100).
5-Bromo-1-propyl-5-phenylbarbituric acid (2f): yield 55%,
mp 87-90 °C, 1H NMR (CDCl3) δ 0.92 (t, J ) 7.5 Hz, 3H),
1.64 (sext., J ) 7.5 Hz, 2H), 3.89 (t, J ) 7.5 Hz, 2H), 7.37-
7.53 (m, 5H), 8.59 (s, 1H); 13C NMR (CDCl3) δ 11.0, 20.9, 44.2,
56.3, 128.3, 128.8, 129.9, 132.6, 148.4, 165.0, 166.2.
5-Bromo-1,5-diphenylbarbituric acid (2g): yield 89%, mp
157-158 °C, lit.53 mp 158-158.5 °C; 1H NMR (CDCl3) δ 7.16-
7.61 (m, 10H), 8.54 (s, 1H); 13C NMR (CDCl3) δ 55.8, 128.1,
128.4, 129.0, 129.6, 129.7, 130.1, 132.3, 133.3, 148.1, 164.6,
166.0.
Syn th esis of 5-Am in oba r bitu r ic Acid s 3a -s: Gen er a l
P r oced u r e. A solution of the appropriate amine (20 mmol)
in cold anhydrous acetonitrile (5 mL) was added dropwise at
0 °C to a stirred solution of 5-bromobarbituric acid 2 (10 mmol)
in cold anhydrous acetonitrile (25 mL). The mixture was
stirred at room temperature for 1 h, diluted with brine (250
mL), and extracted with ethyl acetate (4 × 100 mL). The
combined organic layers were dried (Na2SO4) and evaporated
to dryness. See Table 1 for yields.
1-Ethyl-5-phenyl-5-propylaminobarbituric acid (3m ): mp
1
1,5-Dimethyl-5-isopropylaminobarbituric acid (3a): mp 131-
135 °C (ethyl acetate/petroleum ether); 1H NMR δ 0.84 (d,
J ) 6.3 Hz, 3H), 0.86 (d, J ) 6.3 Hz, 3H), 1.40 (s, 3H), 2.68
(sept., J ) 6.3 Hz, 1H), 3.09 (s, 3H), 11.48 (s, 1H); 13C NMR δ
24.1, 24.1, 26.2, 27.8, 45.6, 62.6, 150.3, 172.2, 173.2; EIMS
(m/z)25 212 (M+ - H, 2), 198 (100), 156 (57).
101-105 °C; H NMR δ 0.85 (t, J ) 7.3 Hz, 3H), 1.08 (t, J )
7.0 Hz, 3H), 1.44 (sext., J ) 7.3 Hz, 2H), 2.32-2.39 (m, 2H),
2.86 (s, br, 1H), 3.73-3.87 (m, 2H), 7.33-7.42 (m, 5H), 11.76
(s, 1H); 13C NMR δ 11.8, 13.1, 23.2, 36.4, 46.6, 71.1, 126.3,
128.8, 128.9, 138.2, 149.7, 169.7, 170.6; EIMS (m/z)28 289 (M+,
6), 260 (64).
5-Benzylamino-1,5-dimethylbarbituric Acid (3b). The crude
product was dried and washed with diethyl ether: mp 139-
142 °C; 1H NMR δ 1.46 (s, 3H), 3.03 (s, 3H), 3.00-3.10 (m,
1H), 3.44-3.53 (m, 2H), 7.18-7.29 (m, 5H), 11.77 (s, br, 1H);
13C NMR δ 25.1, 27.7, 48.5, 63.6, 126.9, 128.1, 128.2, 140.0,
150.3, 171.5, 172.4; EIMS (m/z)26 261 (M+, 2), 156 (5), 106
(100).
5-Benzylamino-1-ethyl-5-phenylbarbituric acid (3n ): mp
133-139 °C (diethyl ether/petroleum ether); H NMR δ 1.08
(t, J ) 6.9 Hz, 3H), 3.28-3.35 (m, 1H), 3.59-3.85 (m, 4H),
7.20-7.47 (m, 10H), 11.78 (s, 1H); 13C NMR δ 13.1, 36.5, 48.6,
71.1, 126.4, 127.0, 128.2, 128.3, 129.0, 129.1, 138.0, 140.2,
149.7, 169.6, 170.5; EIMS (m/z)26 337 (M+, 1), 232 (6), 106
(100).
1
5-Cyclohexylamino-1,5-dimethylbarbituric acid (3c): mp
198-199 °C (ethyl acetate/cyclohexane); 1H NMR δ 0.90-1.60
(m, 10H), 1.40 (s, 3H), 2.28-2.44 (m, 2H); 3.09 (s, 3H), 11.47
(s, br, 1H); 13C NMR δ 24.7, 25.5, 34.1, 34.1, 26.2, 27.8, 53.2,
63.3, 150.3, 172.2, 173.1; EIMS (m/z)27 253 (M+, 11), 210 (100),
98 (53).
5-Benzylamino-5-phenyl-1-propylbarbituric Acid (3o). The
crude product was purified by column chromatography (eluent,
1:2 ethyl acetate/petroleum ether): mp 112-114 °C; 1H NMR
δ 0.77 (t, J ) 7.4 Hz, 3H), 1.49 (sext., J ) 7.4 Hz, 2H), 3.30-
3.33 (m, 1H), 3.59-3.77 (m, 4H), 7.21-7.45 (m, 10H), 11.80
(s, 1H);13C NMR δ 11.1, 20.8, 42.7, 48.6, 71.2, 126.4, 126.9,
J . Org. Chem, Vol. 68, No. 12, 2003 4689

Meusel et al.
128.2, 128.2, 128.9, 129.1, 138.0, 140.2, 150.0, 169.7, 170.6;
1-Isopropyl-5-methyl-5-methylcarbamoylhydantoin (4a ): mp
174-176 °C (ethyl acetate/cyclohexane); 1H NMR δ 1.21 (d, J
) 6.9 Hz, 3H), 1.29 (d, J ) 6.9 Hz, 3H), 1.51 (s, 3H), 2.59 (d,
J ) 4.5 Hz, 3H), 3.44 (sept., J ) 6.9 Hz, 1H), 7.97 (q, J ) 4.5
Hz, 1H), 10.83 (s, 1H); 13C NMR δ 18.9, 20.5, 20.8, 26.6, 45.4,
69.7, 155.1, 166.6, 173.0; MS (FAB) 214 (MH+); EIMS (m/z)29,30
156 (100), 114 (99).
1-Benzyl-5-methyl-5-methylcarbamoylhydantoin (4b): mp
177-182 °C; 1H NMR δ 1.36 (s, 3H), 2.49 (d, J ) 4.6 Hz, 3H),
4.14 (d, J ) 15.9 Hz, 1H), 4.60 (d, J ) 15.9 Hz, 1H), 7.23-
7.34 (m, 5H), 7.99 (q, J ) 4.6 Hz, 1H), 11.16 (s, 1H); 13C NMR
δ 18.8, 26.7, 44.1, 69.9, 127.5, 128.2, 128.6, 137.9, 156.9, 166.1,
173.1; EIMS (m/z)29,31 261(M+, 5), 204 (35), 113 (8), 91 (100).
1-Cyclohexyl-5-methyl-5-methylcarbamoylhydantoin (4c): mp
240-242 °C; 1H NMR δ 1.00-1.77 (m, 10H), 1.53 (s, 3H), 2.58
(d, J ) 4.6 Hz, 3H), 2.70-3.05 (m, 1H), 8.01 (q, J ) 4.6 Hz,
1H), 10.87 (s, 1H); 13C NMR δ 19.0, 25.1, 25.7, 25.8, 26.6, 30.2,
30.4, 53.4, 69.7, 155.2, 166.7, 173.0; EIMS (m/z)29,32 253 (M+,
4), 196 (100), 114 (88).
EIMS (m/z)26 351 (M+, 1), 246 (7), 106 (100).
1,5-Diphenyl-5-propylaminobarbituric acid (3p ): mp 140-
143 °C (diethyl ether); 1H NMR δ 0.87 (t, J ) 7.4 Hz, 3H),
1.42-1.50 (m, 2H), 2.44-2.49 (m, 2H), 2.94 (s, br, 1H), 7.25-
7.54 (m, 10H), 11.90 (s, 1H); 13C NMR δ 11.8, 23.3, 46.6, 71.6,
126.6, 128.8, 128.9, 129.0, 129.0, 129.2, 134.9, 138.0, 149.8,
169.7, 170.8; EIMS (m/z)28 337 (M+, 15), 308 (100).
1,5-Diphenyl-5-isopropylaminobarbituric acid (3r ): mp 44-
48 °C; 1H NMR δ 1.00 (d, J ) 6.3 Hz, 3H), 1.04 (d, J ) 6.3 Hz,
3H), 2.97 (sept., J ) 6.3 Hz, 1H), 7.25-7.56 (m, 10H), 11.97
(s, 1H); 13C NMR δ 24.5, 46.0, 70.9, 126.5, 128.8, 128.8, 128.9,
129.0, 129.3, 134.8, 138.8, 149.7, 170.1, 171.7; EIMS (m/z)25
337 (M+, 12), 322 (100), 280 (34).
5-Benzylamino-1,5-diphenylbarbituric acid (3s): mp 205-
210 °C (MeOH); 1H NMR δ 3.37-3.40 (t, J ) 7.4 Hz, 1H),
3.69-3.79 (m, 2H), 7.22-7.61 (m, 15H), 11.95 (s, 1H); 13C NMR
δ 48.7, 71.7, 126.6, 126.9, 128.2, 128.8, 128.9, 129.1, 129.2,
134.9, 137.8, 140.4, 149.8, 169.6, 170.6; EIMS (m/z)26 385 (M+,
4), 280 (11), 106 (100).
5-Ethylcarbamoyl-5-methyl-1-propylhydantoin (4d): mp 132-
1
138 °C (MeOH); H NMR δ 0.82 (t, J ) 7.4 Hz, 3H), 0.98 (t,
Rea r r a n gem en t of Am in oba r bitu r ic Acid s 3a -s to
Hyd a n toin s 4a -s: Gen er a l P r oced u r es. Con d ition s A.
To a solution of sodium (0.18 g, 8 mmol) in anhydrous ethanol
(27 mL) was added aminobarbituric acid 3 (2 mmol). The
mixture was refluxed for 3 h under an argon atmosphere. The
solution was evaporated to dryness. The residue was taken
up with a small amount of water, and insoluble material was
removed by filtration. The filtrate was acidified with cold
hydrochloric acid (1 N). The precipitate was filtered off and
dried under reduced pressure. Working up was done as
indicated below. Con d ition s B. To a solution of sodium (0.18
g, 8 mmol) in anhydrous ethanol (10 mL) was added amino-
barbituric acid 3 (2 mmol). The mixture was heated in a sealed
tube at 120 °C for 5 h under an argon atmosphere. The solution
was evaporated to dryness under reduced pressure, the residue
was taken up with a small amount of water, and insoluble
material was removed by filtration. The filtrate was acidified
with cold hydrochloric acid (1 N). The precipitate was filtered
off and dried under reduced pressure. Further treatment or
recrystallization of the crude product was performed as
indicated below. Con d ition s C. To a solution of sodium (0.28
g, 12 mmol) in anhydrous butanol (15 mL) was added ami-
nobarbituric acid 3 (3 mmol). The mixture was refluxed for 5
h under an argon atmosphere. Afterward, most of the solvent
was removed under reduced pressure. Water (10 mL) was
added, the mixture was stirred for 2 min, kept at room
temperature for 30 min, and then the organic layer was
removed. The aqueous phase was washed with ethyl acetate
(4 × 5 mL), acidified with hydrochloric acid (2 N) to pH 2, and
cooled. The precipitate was filtered off and dried under reduced
pressure. If no crystallization was observed, the solution was
extracted with ethyl acetate (4 × 5 mL), and the combined
organic layers were dried (Na2SO4) and evaporated to dryness.
Further treatment or recrystallization was performed as
indicated below. Con d ition s D. To a solution of sodium
hydride (95%, dry, 0.20 g, 8 mmol) in anhydrous DMF (26.7
mL) was added aminobarbituric acid 3 (2 mmol). The solution
was heated at 78 °C for 3 h under an argon atmosphere. The
mixture was poured into hydrochloric acid (100 mL, 1 N) and
cooled. The product was filtered off, washed with water, and
dried under reduced pressure. Con d ition s E. To a solution
of sodium hydride (95%, dry, 0.20 g, 8 mmol) in anhydrous
DMF (10 mL) was added aminobarbituric acid 3 (2 mmol). The
solution was heated at 78 °C for 5 h under an argon
atmosphere. The mixture was poured into cold hydrochloric
acid (100 mL, 1 N). The product was isolated by extracting
the aqueous phase with ethyl acetate (4 × 25 mL). The organic
layers were combined, dried (Na2SO4), and evaporated to
dryness. The crude oil was dissolved in diethyl ether. After
the solution was cooled for at least 5 days, pure crystals were
separated by suction filtration and dried. See Table 1 for
methods and yields.
J ) 7.3 Hz, 3H), 1.50 (s, 3H), 1.43-1.50 (m, 2H), 2.93-3.19
(m, 4H), 8.06 (t, J ) 5.4 Hz, 1H), 10.91 (s, 1H); 13C NMR δ
11.4, 14.5, 18.4, 21.8, 34.4, 42.3, 69.4, 156.4, 165.7, 173.0; MS
(FAB) 228 (MH+); EIMS (m/z)29,33 156 (100), 114 (16).
5-Ethylcarbamoyl-1-isopropyl-5-methylhydantoin (4e). In
performing method A, the crude oil was triturated with diethyl
ether, and the product was filtered off: mp 183-186 °C
1
(MeOH); H NMR δ 0.99 (t, J ) 7.2 Hz, 3H), 1.22 (d, J ) 6.8
Hz, 3H), 1.30 (d, J ) 6.8 Hz, 3H), 1.51 (s, 3H), 3.00-3.16 (m,
2H), 3.44 (sept., J ) 6.8 Hz, 1H), 8.04 (t, J ) 5.4 Hz, 1H),
10.81 (s, 1H); 13C NMR δ 15.3, 19.6, 21.2, 21.6, 35.1, 46.1, 70.4,
155.9, 166.6, 173.7; MS (FAB) 228 (MH+); EIMS (m/z)52,30 156
(100), 114 (72).
1-Benzyl-5-ethylcarbamoyl-5-methylhydantoin (4f): mp 154-
159 °C; 1H NMR δ 0.90 (t, J ) 7.3 Hz, 3H), 1.33 (s, 3H), 2.94-
3.00 (m, 2H), 4.10 (d, J ) 16.1 Hz, 1H), 4.59 (d, J ) 16.1 Hz,
1H), 7.21-7.32 (m, 5H), 8.01-8.04 (t, J ) 5.5 Hz, 1H), 11.11
(s, br, 1H); 13C NMR δ 14.4, 18.7, 34.4, 43.9, 69.7, 127.3, 128.0,
128.4, 137.8, 157.0, 165.2, 173.1; EIMS (m/z)29,31 275 (M+, 2),
204 (69), 113 (18), 91 (100).
1-Cyclohexyl-5-ethylcarbamoyl-5-methylhydantoin (4g). The
crude product was dried, triturated with diethyl ether, and
1
filtered off: mp 168-175 °C; H NMR δ 0.98 (t, J ) 7.1 Hz,
3H), 1.03-1.96 (m, 10H), 1.50 (s, 3H), 2.95-3.20 (m, 3H), 8.09
(t, J ) 5.5 Hz, 1H), 10.85 (s, 1H); 13C NMR δ 14.5, 19.0, 25.1,
25.7, 25.8, 30.3, 30.5, 34.4, 53.5, 69.7, 155.2, 165.9, 173.0; EIMS
(m/z)29,32 267 (M+, 4), 196 (83), 114 (100).
1-Benzyl-5-methyl-5-phenylcarbamoylhydantoin (4h ): mp
1
63-68 °C; H NMR δ 1.52 (s, 3H), 4.34 (d, J ) 16.0 Hz, 1H),
4.59 (d, J ) 16.0 Hz, 1H), 7.06-7.46 (m, 10H), 9.64 (s, 1H),
11.23 (s, 1H); 13C NMR δ 19.0, 44.0, 70.4, 121.3, 124.4, 127.3,
128.2, 128.4, 128.5, 137.5, 138.0, 156.8, 164.3, 172.6; EIMS
(m/z)29,31 323 (M+, 4), 204 (100), 113 (10), 91 (57).
1-Cyclohexyl-5-methyl-5-phenylcarbamoylhydantoin (4i): mp
133-137 °C (EtOH/cyclohexane); 1H NMR δ 1.01-1.99 (m,
10H), 1.64 (s, 3H), 3.10-3.17 (m, 1H), 7.07-7.12 (m, 1H),
7.29-7.35 (m, 2H, 3′-H), 7.56-7.61 (m, 2H), 9.81 (s, 1H), 10.98
(s, 1H); 13C NMR δ 19.7, 25.1, 26.6, 25.8, 30.1, 30.7, 53.6, 70.5,
121.1, 124.4, 128.7, 138.2, 155.3, 165.1, 172.6; EIMS (m/z)29,32
315 (M+, 3), 196 (100), 114 (83).
5-Methylcarbamoyl-5-phenyl-1-propylhydantoin (4k ): mp
1
200-204 °C; H NMR δ 0.62 (t, J ) 7.4 Hz, 3H), 1.08-1.29
(m, 2H), 2.67 (d, J ) 4.4 Hz, 3H), 3.10-3.25 (m, 2H), 7.22-
7.45 (m, 5H), 7.81 (q, J ) 4.4 Hz, 1H), 11.25 (s, 1H); 13C NMR
δ 11.2, 21.1, 26.8, 43.5, 75.8, 127.9, 128.9, 129.1, 134.8, 156.0,
165.6, 171.6; MS (FAB) 276 (MH+); EIMS (m/z)29,33 218 (100),
176 (13).
1-Benzyl-5-methylcarbamoyl-5-phenylhydantoin (4l). The
crude product was recrystallized from MeOH/diethyl ether
(yield 32%). An analytic sample was obtained from recrystal-
lization from EtOH: mp 182-189 °C; 1H NMR δ 2.45 (d, J )
4690 J . Org. Chem., Vol. 68, No. 12, 2003

Aminobarbituric Acid-Hydantoin Rearrangement
4.6 Hz, 3H), 4.45 (d, J ) 16.3 Hz, 1H), 4.64 (d, J ) 16.3 Hz,
1H), 6.97-7.38 (m, 10H), 7.77 (q, J ) 4.6 Hz, 1H), 11.38 (s,
1H); 13C NMR δ 26.5, 44.9, 76.1, 126.7, 127.3, 127.9, 128.0,
128.9, 129.0, 134.2, 137.4, 156.5, 165.5, 171.5; EIMS (m/z)29,31
323 (M+, 4), 266 (59), 175 (19), 91 (100).
25.1, 25.5, 25.6, 30.3, 30.7, 53.9, 69.4, 121.2, 121.5, 128. 8,
138.1, 154.9, 164.8, 171.3; EIMS (m/z)29,32 329 (M+, 4), 210
(100), 128 (83).
1-Ben zyl-3-m eth yl-5-m eth ylcar bam oyl-5-ph en ylh ydan -
toin (5c). To a solution of 4l (0.32 g, 1 mmol) in acetone 90%
(45 mL) were added sodium carbonate (0.21 g, 2 mmol) and
methyl iodide (0.57 g, 0.25 mL, 4 mmol). The mixture was
refluxed for 90 min and filtered. The filtrate was evaporated
under reduced pressure. The crude product was recrystallized
from ethanol to give 5c (120 mg, 35%) as colorless crystals:
5-Ethylcarbamoyl-5-phenyl-1-propylhydantoin (4m ): mp
1
148-152 °C; H NMR δ 0.63 (t, J ) 7.4 Hz, 3H), 1.04 (t, J )
7.3 Hz, 3H), 1.07-1.31 (m, 2H), 3.11-3.25 (m, 4H), 7.23-7.46
(m, 5H), 7.86 (t, J ) 5.7 Hz, 1H), 11.25 (s, 1H); 13C NMR δ
11.2, 14.4, 21.2, 34.6, 43.5, 75.8, 127.9, 128.9, 129.0, 134.8,
156.1, 164.9, 171.7; EIMS (m/z)29,33 289 (M+, 1), 218 (100), 176
(24).
1
mp 148-150 °C; H NMR δ 2.45 (d, J ) 4.6 Hz, 3H), 2.98 (s,
3H), 4.49 (d, J ) 16.1 Hz, 1H), 4.72 (d, J ) 16.1 Hz, 1H), 6.99-
7.40 (m, 10H), 7.88 (q, J ) 4.6 Hz, 1H); 13C NMR δ 25.6, 26.7,
45.4, 75.3, 127.1, 127.7, 128.1, 128.4, 129.1, 129.3, 134.2, 137.3,
156.4, 165.4, 170.5; EIMS (m/z)29,31 337 (M+, 1), 280 (100), 189
(25), 91 (35).
1-Benzyl-5-ethylcarbamoyl-5-phenylhydantoin (4n ): mp 132-
133 °C (ethyl acetate/petroleum ether); 1H NMR δ 0.87 (t, J )
7.3 Hz, 3H), 2.90-3.03 (m, 2H), 4.48 (d, J ) 16.2 Hz, 1H), 4.61
(d, J ) 16.2 Hz, 1H), 6.97-7.39 (m, 10H), 7.80 (t, J ) 5.4 Hz,
1H), 11.33 (s, br, 1H); 13C NMR δ 14.1, 34.5, 44.9, 76.1, 126.7,
127.2, 127.9, 128.0, 128.9, 129.0, 134.4, 137.5, 156.6, 164.7,
171.6; EIMS (m/z)29,31 337 (M+, 5), 266 (79), 175 (24), 91 (100).
1-Benzyl-5-phenyl-5-propylcarbamoylhydantoin (4o). The
crude oil was triturated with ethyl acetate/petroleum ether,
and the product was filtered off: mp 102-105 °C (MeOH); 1H
NMR δ 0.75 (t, J ) 7.4 Hz, 3H), 1.29-1.36 (m, 2H), 2.82-2.98
(m, 2H), 4.50 (d, J ) 16.2 Hz, 1H), 4.59 (d, J ) 16.2 Hz, 1H),
6.96-7.40 (m, 10H), 7.78 (t, J ) 5.7 Hz, 1H), 11.38 (s, 1H);
13C NMR δ 11.4, 21.9, 41.3, 44.9, 76.3, 126.7, 127.2, 127.9,
128.1, 128.9, 129.0, 134.4, 137.5, 156.5, 164.9, 171.6; EIMS
(m/z)29,31 351 (M+, 3), 266 (52), 175 (11), 91 (76).
5-Eth ylca r ba m oyl-3-m eth yl-5-p h en yl-1-p r op ylh yd a n -
toin (5d ). To a solution of 4m (0.29 g, 1 mmol) in acetone 90%
(45 mL) were added sodium carbonate (0.21 g, 2 mmol) and
methyl iodide (0.57 g, 0.25 mL, 4 mmol). The mixture was
refluxed for 90 min and filtered. The volume of the solvent
was reduced. After cooling, the precipitate was collected and
recrystallized from EtOH to give 5d (35 mg, 12%) as colorless
1
crystals: mp 68-70 °C; H NMR δ 0.64 (t, J ) 7.4 Hz, 3H),
1.05 (t, J ) 7.3 Hz, 3H), 1.09-1.36 (m, 2H), 2.94 (s, 3H), 3.14-
3.31 (m, 4H), 7.25-7.45 (m, 5H), 7.92 (t, J ) 5.7 Hz, 1H); 13
C
NMR δ 11.1, 14.4, 21.1, 25.2, 34.7, 43.9, 74.8, 128.1, 128.9,
129.1, 134.5, 155.7, 164.6, 170.4; MS (FAB) 304 (MH+); EIMS
(m/z)29,33 232 (100), 190 (11).
5-Phenyl-5-phenylcarbamoyl-1-propylhydantoin (4p ): mp
1
75-79 °C; H NMR δ 0.63 (t, J ) 7.4 Hz, 3H), 1.12-1.19 (m,
3-E t h yl-5-e t h ylca r b a m oyl-5-p h e n yl-1-p r op ylh yd a n -
toin (5e). To a solution of 4m (0.89 g, 3 mmol) in acetone 90%
(135 mL) were added sodium carbonate (0.96 g, 9 mmol) and
ethyl bromide (1.96 g, 1.34 mL, 18 mmol). The mixture was
refluxed for 3 h and filtered. The filtrate was evaporated to
dryness. The crude product was purified by column chroma-
tography (eluent, 5:3 methanol/hexane) to give 5e (156 mg,
1H), 1.25-1.34 (m, 1H), 3.21-3.35 (m, 2H), 7.11-7.60 (m,
10H), 9.69 (s, 1H), 11.38 (s, 1H); 13C NMR δ 11.2, 21.2, 43.4,
76.7, 121.4, 124.8, 128.0, 128.7, 129.1, 129.2, 134.5, 137.8,
156.1, 164.2, 171.3; MS (FAB) 338 (MH+); EIMS (m/z)29,33 218
(100), 176 (10).
1-Isopropyl-5-phenyl-5-phenylcarbamoylhydantoin (4r ): mp
172-174 °C; 1H NMR δ 0.91, (d, J ) 6.9 Hz, 3H), 1.41 (d, J )
6.9 Hz, 3H), 3.50 (sept., J ) 6.9 Hz, 1H), 7.11-7.62 (m, 10H),
9.54 (s, 1H), 11.37 (s, 1H); 13C NMR δ 20.0, 20.3, 46.8, 77.3,
121.2, 124.7, 128.2, 128.8, 129.1, 129.4, 134.8, 137.7, 154.8,
163.9, 171.7; EIMS (m/z)29,30 337 (M+, 2), 218 (100), 176 (43).
1-Benzyl-5-phenyl-5-phenylcarbamoylhydantoin (4s): mp
185-195 °C (EtOH/diethyl ether/cyclohexane); 1H NMR δ 4.39
(d, J ) 16.0 Hz, 1H), 4.56 (d, J ) 16.0 Hz, 1H), 7.02-7.46 (m,
15H), 10.21 (s, 1H). One NH signal did not appear. 13C NMR
δ 45.3, 76.3, 120.3, 124.2, 125.1, 127.4, 127.6, 127.6, 128.3,
128.8, 128.8, 136.9, 137.8, 139.3, 165.6. Two carbonyl signals
did not appear. MS (FAB) 386 (MH+); EIMS (m/z)29,31 385 (M+,
2), 266 (97), 175 (17), 91 (100).
1-Ben zyl-3,5-dim eth yl-5-eth ylcar bam oylh ydan toin (5a).
To a solution of 4f (0.29 g, 1 mmol) in acetone 90% (45 mL)
were added sodium carbonate (0.21 g, 2 mmol) and methyl
iodide (0.57 g, 0.25 mL, 4 mmol). The mixture was refluxed
for 90 min and filtered. The filtrate was evaporated under
reduced pressure. The crude product was purified by column
chromatography (eluent, 2:1 ethyl acetate/petroleum ether) to
give 5a as a colorless oil (60 mg, 21%): 1H NMR δ 0.88 (t, J )
7.2 Hz, 3H), 1.37 (s, 3H), 2.91 (s, 3H), 2.92-2.98 (m, 2H), 4.22
(d, J ) 16.1 Hz, 1H), 4.59 (d, J ) 16.1 Hz, 1H), 7.21-7.31 (m,
5H), 7.98 (t, J ) 5.4 Hz, 1H); 13C NMR δ 14.3, 18.5, 25.2, 34.4,
44.2, 68.6, 127.4, 128.0, 128.3, 137.4, 156.5, 164.9, 171.7; EIMS
(m/z)29,31 289 (M+, 1), 218 (100), 127 (75), 91 (100).
1
16%) as a white solid: mp 86-88 °C; H NMR δ 0.63 (t, J )
7.4 Hz, 3H), 1.03 (t, J ) 7.3 Hz, 3H), 1.10 (t, J ) 7.3 Hz, 3H),
1.10-1.34 (m, 2H), 3.14-3.27 (m, 4H), 3.45-3.51 (m, 2H),
7.22-7.46 (m, 5H), 7.90 (t, J ) 5.7 Hz, 1H); 13C NMR δ 11.1,
13.2, 14.4, 21.1, 33.9, 34.6, 43.8, 74.7, 128.0, 129.0, 129.2, 134.5,
155.4, 164.6, 170.1; MS (FAB) 318 (MH+); EIMS (m/z)29,33 246
(100), 204 (5).
3-Meth yl-5-p h en yl-5-p h en ylca r ba m oyl-1-p r op ylh yd a n -
toin (5f). To a solution of 4p (0.34 g, 1 mmol) in acetone 90%
(45 mL) were added sodium carbonate (0.21 g, 2 mmol) and
methyl iodide (0.57 g, 0.25 mL, 4 mmol). The mixture was
refluxed for 90 min and filtered. The volume of the solvent
was reduced. After cooling, the precipitate was collected by
suction filtration to give 5f (340 mg, 94%) as colorless
crystals: mp 160-163 °C; 1H NMR δ 0.67 (t, J ) 7.4 Hz, 3H),
1.16-1.19 (m, 1H), 1.25-1.33 (m, 1H), 3.00 (s, 3H), 3.27-3.31
(m, 1H), 3.38-3.44 (m, 1H), 7.14-7.62 (m, 10H), 9.75 (s, 1H);
13C NMR δ 11.2, 21.2, 25.4, 43.8, 75.6, 121.3, 124.8, 128.2,
128.8, 129.0, 129.3, 134.2, 137.8, 155.8, 163.9, 170.1; EIMS
(m/z)29,33 351 (M+, 1), 232 (100), 190 (7).
3-Eth yl-5-p h en yl-5-p h en ylca r ba m oyl-1-p r op ylh yd a n -
toin (5g). To a solution of 4p (1.01 g, 3 mmol) in acetone 90%
(135 mL) were added sodium carbonate (0.96 g, 9 mmol) and
ethyl bromide (1.96 g, 1.34 mL, 18 mmol). The mixture was
refluxed for 3 h and filtered. The volume of the filtrate was
reduced and cooled. The precipitate was filtered off and
recrystallized from EtOH to give 5g (781 mg, 71%) as colorless
needles: mp 155-158 °C; 1H NMR δ 0.63 (t, J ) 7.3 Hz, 3H),
1.12 (t, J ) 7.3 Hz, 3H), 1.08-1.19 (m, 1H), 1.24-1.33 (m, 1H),
3.27-3.39 (m, 2H), 3.48-3.57 (m, 2H), 7.11-7.60 (m, 10H),
9.75 (s, 1H); 13C NMR δ 11.2, 13.2, 21.2, 34.1, 43.7, 75.5, 121.4,
124.8, 128.1, 128.8, 129.2, 129.4, 134.2, 137.8, 155.4, 163.9,
169.8; EIMS (m/z)29,33 365 (M+, 1), 246 (100), 204 (15).
1-Cycloh exyl-3,5-d im eth yl-5-p h en ylca r ba m oylh yd a n -
toin (5b). To a solution of 4i (0.32 g, 1 mmol) in acetone 90%
(45 mL) were added sodium carbonate (0.21 g, 2 mmol) and
methyl iodide (0.57 g, 0.25 mL, 4 mmol). The mixture was
refluxed for 90 min and filtered. The filtrate was evaporated
under reduced pressure. The crude product was recrystallized
from ethanol to give 5b (184 mg, 55%) as colorless crystals:
mp 140-141 °C; 1H NMR δ 1.03-2.03 (m, 10H), 1.64 (s, 3H),
2.88 (s, 3H), 3.13-3.20 (m, 1H), 7.08-7.13 (m, 1H), 7.29-7.35
(m, 2H), 7.51-7.57 (m, 2H), 9.76 (s, 1H); 13C NMR δ 19.5, 25.0,
1-Ben zyl-3-m eth yl-5-ph en yl-5-ph en ylcar bam oylh ydan -
toin (5h ). To a solution of 4s (0.41 g, 1 mmol) in acetone 90%
(45 mL) were added sodium carbonate (0.21 g, 2 mmol) and
J . Org. Chem, Vol. 68, No. 12, 2003 4691

Meusel et al.
methyl iodide (0.57 g, 0.25 mL, 4 mmol). The mixture was
refluxed for 90 min and filtered. The filtrate was evaporated
under reduced pressure. The crude product was recrystallized
from ethanol to give 5h (230 mg, 56%) as a colorless solid: mp
mL). The mixture was heated in a sealed tube at 120 °C for
120 h under an argon atmosphere. After cooling for a few days,
the precipitate was collected by suction filtration and dried to
give 5c as colorless crystals (0.19 g, 55%), which was identical
with the material obtained from methylation of 4l.
1
64-66 °C; H NMR δ 3.02 (s, 3H), 4.59 (d, J ) 16.2 Hz, 1H),
4.77 (d, J ) 16.2 Hz, 1H), 6.95-7.12 (m, 6H), 7.22-7.45 (m,
9H), 9.65 (s, 1H); 13C NMR δ 25.4, 45.1, 75.7, 121.3, 124.6,
126.7, 127.3, 127.8, 128.2, 128.4, 128.8, 129.1, 133.7, 136.9,
137.4, 156.0, 163.4, 169.9; EIMS (m/z)29,31 399 (M+, 4), 280 (92),
189 (39), 91 (100).
P r ep a r a tion of 1-Ben zyl-3-m eth yl-5-p h en ylh yd a n toin
(9) fr om 1-Ben zyl-3-m eth yl-5-m eth ylca r ba m oyl-5-p h en -
ylh yd a n toin (5c). To a solution of sodium (0.18 g, 8 mmol)
in anhydrous ethanol (26 mL) was added hydantoin 5c (0.67
g, 2 mmol). The mixture was refluxed for 3 h under an argon
atmosphere. The solution was evaporated to dryness, the
residue was taken up with a small amount of water and
acidified with cold hydrochloric acid (1 N). The precipitate was
cooled, filtered off, and dried under reduced pressure to give
9 (0.44 g, 74%) as colorless crystalls: mp 103-105 °C, lit.54
mp 120-121 °C; 1H NMR δ 2.95 (s, 3H), 3.90 (d, J ) 15.8 Hz,
1H), 4.78 (d, J ) 15.8 Hz, 1H), 4.98 (s, 1H), 7.10-7.40 (m,
10H); 13C NMR δ 25.0, 44.6, 63.6, 127.6, 127.9, 128.1, 128.6,
129.0, 129.1, 133.5, 136.2, 156.6, 171.4; EIMS (m/z) 280 (M+,
100), 91 (C7H7+, 30).
5-Br om o-1,3-d im eth yl-5-p h en ylba r bitu r ic Acid (7). A
solution of barbituric acid 6 (3.07 g, 12 mmol) in acetic acid
(180 mL) was stirred at room temperature. A solution of
bromine in acetic acid (20% solution, 9.6 g, 12 mmol) was
added dropwise over 20 min. When the addition was com-
pleted, it was stirred for 1 h at room temperature, and the
solvent was evaporated under reduced pressure. The residue
was diluted with water (25 mL) and extracted with ethyl
acetate (3 × 25 mL). The combined organic layers were stirred
with charcoal and dried (Na2SO4). The filtrate was evaporated
to dryness to give 7 (2.41 g, 57%) as an oil: 1H NMR (CDCl3)
δ 3.39 (s, 6H), 7.36-7.50 (m, 5H); 13C NMR (CDCl3) δ 29.9,
57.0, 128.1, 128.8, 129.8, 133.4, 149.8, 165.8.
P r ep a r a tion of 1-Ben zyl-3-m eth yl-5-p h en ylh yd a n toin
(9) fr om 5-Ben zyla m in o-1,3-d im eth yl-5-p h en ylba r bitu r ic
Acid (8). Compound 8 (0.67 g, 2 mmol) was reacted with
sodium ethoxide using the procedure described above to give
9 (0.43 g, 72%) which was identical with the material obtained
from the conversion of 5c to 9.
5-Ben zyla m in o-1,3-d im eth yl-5-p h en ylba r bitu r ic Acid
(8). A solution of the benzylamine (1.71 g, 1.75 mL, 16 mmol)
in cold anhydrous acetonitrile (4 mL) was added dropwise at
0 °C to a stirred solution of 7 (2.60 g, 8 mmol) in cold
anhydrous acetonitrile (20 mL). The mixture was stirred at
room temperature for 1 h, diluted with brine (50 mL), and
extracted with ethyl acetate (4 × 25 mL). The combined
organic layers were dried (Na2SO4) and evaporated to dryness.
The crude product was recrystallized from ethyl acetate to give
Ack n ow led gm en t. M.M. and M.G. gratefully ac-
knowledge financial support from the Graduiertenkolleg
804 “Analyse von Zellfunktionen durch kombinatorische
Chemie und Biochemie”. The authors dedicate this work
to Professor Dr. K. Eger on the occasion of his 60th
birthday.
1
8 (1.97 g, 73%) as a white solid: mp 156-157 °C; H NMR δ
3.18 (s, 6H), 3.39 (t, J ) 7.3 Hz, 1H), 3.64 (d, J ) 7.3 Hz, 2H),
7.20-7.46 (m, 10H); 13C NMR δ 29.0, 48.7, 71.2, 126.6, 126.9,
128.2, 128.3, 128.9, 129.0, 138.2, 140.2, 150.7, 170.0; EIMS
(m/z)26 336 (M+ - H, 1), 232 (19), 106 (100).
Su p p or tin g In for m a tion Ava ila ble: Assignments to 1H
1
and 13C NMR data, elemental analyses, and figures giving H
P r ep a r a tion of 1-Ben zyl-3-m eth yl-5-m eth ylca r ba m oyl-
5-p h en ylh yd a n t oin (5c) fr om 5-Ben zyla m in o-1,3-d i-
m eth yl-5-p h en ylba r bitu r ic Acid (8). To a solution of 8 (0.34
g, 1 mmol) in anhydrous ethanol (12 mL) was added a stock
solution of sodium ethoxide in anhydrous ethanol (0.2 M, 1
and 13C NMR spectra for compounds 2a -g, 3a -s, 4a -s,
5a -h , 7, 8, and 9. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O020761F
4692 J . Org. Chem., Vol. 68, No. 12, 2003