3,5,5-Trisubstituted hydantoins from activated (benzyloxycarbonylamino) malonic acids

Article abstract of DOI:10.1055/s-0031-1290974

Diethyl 2-alkyl-2-(benzyloxycarbonylamino)malonates were saponified, activated with oxalyl chloride, and treated with primary aromatic amines. This gave 3,5-disubstituted hydantoin-5-carboxamides. As second products, 2-alkyl-2-formamido-N¹,N

Full text of DOI:10.1055/s-0031-1290974

PAPER
▌1907
p3a,p5er,5-Trisubstituted Hydantoins from Activated (Benzyloxycarbonyl-
amino)malonic Acids
3,5,5-Trisubstituted Hydantoins
Lukáš Hroch,a Marie Hrušková,a Janina Schmitz,a Gregor Schnakenburg,b Michael Gütschow*a
a
Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
Fax +49(228)732567; E-mail: guetschow@uni-bonn.de
b
Institute of Inorganic Chemistry, University of Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany
Received: 21.11.2011; Accepted after revision: 20.03.2012
O
O
R1
R1
NHR3
R1
NHR3
Abstract: Diethyl 2-alkyl-2-(benzyloxycarbonylamino)malonates
were saponified, activated with oxalyl chloride, and treated with
primary aromatic amines. This gave 3,5-disubstituted hydantoin-5-
carboxamides. As second products, 2-alkyl-2-formamido-N1,N3-
bis(aryl)malonamides were isolated. The formation of both types of
products is expected to include a cyclization to 2-alkoxyoxazol-
5(4H)-ones, acting as precursor for the hydantoins, or a further
transformation to N-carboxy anhydrides, their chloride-promoted
ring opening, and subsequent conversion to give the bis(aryl)malon-
amides.
R3
R2
O
R2
CONHR2
O
5
N
N
N
2
H
O
N
H
O
OCN
O
N
H
3
1
2
Scheme 1 Aminobarbituric acid–hydantoin rearrangement2
Cbz-NH-CH(CO2Et)2
4
Key words: hydantoins, malonic acids, oxazolones, nitrogen het-
erocycles, ring closure, ring opening
R1X, NaOEt, EtOH, 87 °C
R1
R1
NaOH, EtOH, r.t.
CO2Et
CO2Et
CO2H
CO2H
Cbz-HN
Cbz-HN
Hydantoins have been the subject of considerable interest
in drug discovery because of their wide range of biologi-
cal activities. With four possible points of diversity, this
heterocyclic structure represents a significant molecular
scaffold in combinatorial chemistry. Indeed, the reported
bioactivities usually arise from the different residues at-
tached to the heterocycle. Moreover, hydantoins are im-
portant building blocks for non-natural amino acids
through chemical or enzymatic synthesis.1 Previously, the
aminobarbituric acid–hydantoin rearrangement has been
reported as an attractive synthetic entry to polysubstituted
5-carbamoylhydantoins.2 For example, 1,5-disubstituted
5-aminobarbituric acids 12,3 undergo a base-catalyzed ring
contraction to 5-carbamoylhydantoins 3 in which the sub-
stituent at the carbamoyl moiety originates from the sub-
stituent at the N1 nitrogen of the parent barbituric acid
(Scheme 1). This elimination–addition process includes
an E1cB mechanism and the recyclization of the interme-
diate 2 due to the nucleophilic attack of the amino group
at the isocyanate moiety.2,4 Besides the attention on 1,5,5-
substituted representatives, such as 3, synthetic efforts to
acquire trisubstituted hydantoins have been focused on
1,3,5-substituted derivatives.5 Herein, we report on a new
synthetic entry to 3,5,5-trisubstituted hydantoins 11
(Scheme 2). As in the case of 3, the N1–C5(CO)–CO por-
tion of 11 originates from an aminomalonic acid precur-
sor.
6a R1 = Me 97%
6b R1 = Et 92%
5a R1 = Me 83%
5b R1 = Et 65%
1. (COCl)2, DMF (cat.), CH2Cl2, r.t.
R1
COCl
COCl
Cbz-HN
7
R1
R1
R1
COCl
O
COCl
O
N
COCl
HN
OHC-HN
5
2
5
2
COCl
Ph
O
O
O
O
8
10
9
2. R2NH2, Et3N, 1,4-dioxane, r.t.
CONHR2
R1
5
HN
R1
2
CONHR2
+
OHC-HN
O
O
N
CONHR2
R2
12a–j 5–35%
11a–j 9–43%
R1
R2
Ph
R1 R2
a
b
c
d
e
Me
Me
Me
Me
Me
f
Et Ph
Et
Et
Et
Et
g
h
i
3-F3CC6H4
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
3-F3CC6H4
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
j
Scheme 2 Synthesis of hydantoins 11 and malonic acid diamides 12
SYNTHESIS 2012, 44, 1907–1914
Advanced online publication: 09.05.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290974; Art ID: SS-2011-T1085-OP
© Georg Thieme Verlag Stuttgart · New York

1908
L. Hroch et al.
PAPER
The preparation of hydantoins 11 is outlined in Scheme 2.
Diethyl 2-aminomalonate was reacted with benzyl chloro-
formate to provide benzyloxycarbonyl-protected diethyl
aminomalonate 4.6 Alkylation of 4 with methyl iodide or
ethyl bromide afforded 5a or 5b, respectively. Malonic es-
ter derivatives 5 were treated with aqueous ethanolic sodi-
um hydroxide solution for four days at room temperature,
acidified under cooling, extracted with ethyl acetate and
evaporated at room temperature. Under the mild condi-
tions of saponification, decarboxylation could be avoided.
Next, the reactions of malonic acids 6 with oxalyl chloride
followed by instantaneous treatment of the activated inter-
mediates with aromatic amines were carried out. The re-
action with oxalyl chloride (4.6 equiv) was performed in
dichloromethane in the presence of N,N-dimethylform-
amide under argon atmosphere. After evaporation of the
volatiles, 1,4-dioxane, aniline or a monosubstituted ani-
line derivative (2 equiv), and triethylamine (2.4 equiv)
were added. After a reaction time of 24 hours at room tem-
perature, the products were purified by column chroma-
tography and obtained after recrystallization in 9–43%
yield. Products 11 were unambiguously identified as 5-
carbamoylhydantoins on the basis of spectroscopic data.
Their 13C NMR spectra showed three distinct carbonyl
signals at δ = 154–159 (C2), 164–166 (exocyclic CO), and
169–172 (C4), the first and the last being characteristic of
the hydantoin scaffold. As expected, multiplets appeared
for the diastereotopic methylene protons in the 1H NMR
spectra of 5-ethylhydantoins 11f–j. The structure of the
hydantoin 11f was further confirmed by X-ray crystallog-
raphy (Figure 1).
Figure 1 Molecular structure of 5-ethyl-3-phenyl-5-(phenylcarbamo-
yl)hydantoin (11f, top) and 2-ethyl-2-formamido-N1,N3-diphenyl-
malonamide (12f, bottom).14 Hydrogen atoms of the phenyl and ethyl
groups have been omitted for clarity. Carbon atoms are shown in gray,
oxygen atoms in light gray, nitrogen atoms in dark gray, and hydro-
gen atoms in white.
mers much larger coupling constants (3J > 10 Hz) have
been detected.9–12 The E/Z ratio, as determined on the ba-
sis of 1H NMR assignments, was reported for several N-
monoalkylated formamides, including those with tert-al-
kyl groups. The proportion of the Z-isomer was generally
higher (≥70%).10,13 In the case of formanilides, the prefer-
ence for the Z-isomer was less pronounced.9,12 In contrast
to the hydantoins 11, the methylene protons of the achiral
malonic acid diamides 12f–j are not diastereotopic, and
their signals appear as quartets.
The following mechanism for the formation of 5-carbam-
oylhydantoins 11 is proposed (Scheme 2): Treatment of 6
with oxalyl chloride leads to a malonyl dichloride deriva-
tive 7, which undergoes cyclocondensation to the 2-alk-
oxyoxazol-5(4H)-one 8.7 This intermediate reacts at the
exocyclic acid chloride group to form the carboxamide
moiety, and is furthermore attacked by the aromatic amine
at either ring carbon C2 or C5. In the latter case, ring
cleavage produces the second carboxamide group of the
resulting 2-(benzyloxycarbonylamino)malonic acid di-
amide. This intermediate undergoes a subsequent ring clo-
sure to 11.8
A single-crystal X-ray analysis was carried out on the 2-
formamidomalonic acid diamide 12f, as an example, con-
firming its structure and the Z-configuration (Figure 1).
The unexpected formation of products 12 could not be ful-
ly rationalized. A possible mechanism is as follows
(Scheme 2): In the course of the activation of the malonic
acid 6a or 6b, the 2-alkoxyoxazol-5(4H)-one 8 is formed.
The activation of the carboxyl groups by means of oxalyl
chloride leads to the release of hydrogen chloride, carbon
dioxide, and carbon monoxide.15 Under these conditions,
a chloride-promoted displacement of the benzyl group is
operative and the N-carboxy anhydride (NCA) 9 is gener-
ated.16 A nucleophilic attack of chloride occurs at the elec-
trophilic C5 carbon of NCA 9,17,18 resulting in the
reopening of the cyclic anhydride and decarboxylation.
The thus generated amino group is formylated, probably
by carbon monoxide or due to the action of N,N-dimethyl-
formamide, activated by oxalyl chloride,19 to produce 10.
When malonyl dichloride 10 is then exposed to the aro-
A second product was observed in each of the ten synthe-
ses, and was isolated by column chromatography, recrys-
tallized, and obtained in 5–35% yield. Its structure was
assigned as the corresponding 2-formamidomalonic acid
diamide 12 (Scheme 2).
Structural assignments of 12a–j were confirmed by NMR
data, which clearly indicated the equivalence of the two
carboxamide portions. The formamido group produces
two 1H NMR signals at δ = 8.12–8.19 and 8.47–9.43, for
the CH and NH resonances, respectively, as assigned by
HSQC experiments. If observed at all, 3J(HH) (HCONH)
coupling occurred with coupling constants smaller than 2
Hz. This clearly indicates that the N-substituted for-
mamides 12 are present as Z-isomers, because for E-iso-
Synthesis 2012, 44, 1907–1914
© Georg Thieme Verlag Stuttgart · New York

PAPER
3,5,5-Trisubstituted Hydantoins
1909
matic amine, it can readily react with the amine to form pected reaction behavior of aminomalonic acid
the corresponding 2-formamidomalonic acid diamide 12. derivatives when activated with oxalyl chloride. Using the
example of 2-(benzyloxycarbonylamino)isobutyric acid,
Next, we addressed the question of whether the hydantoin
the scope of the reaction was found to be rather narrow, as
formation and the formylation reaction would also occur
the monocarboxylic acid derivative did not produce a cor-
with a benzyloxycarbonyl-protected monocarboxylic acid
responding hydantoin.
(Scheme 3). In the 2-aminoisobutyric acid derivative 13,
one carboxyl group of 6a has been replaced by methyl.
TLC was carried out on Merck aluminum sheets, silica gel 60 F254
.
Preparative column chromatography was performed on Acros Or-
ganics silica gel 60A (0.060–0.200 mm). Melting points were deter-
1. (COCl)2, DMF (cat.), CH2Cl2, r.t.
2. PhNH2, Et3N, 1,4-dioxane, r.t.
Cbz-HN
13
1
mined on a Büchi 510 oil bath apparatus and are uncorrected. H
CO2H
and 13C NMR spectra were acquired on a Bruker Avance DRX 500
1
spectrometer operating at 500 MHz for H and 125 MHz for 13C.
HN
+
OHC-HN
Chemical shifts δ are cited in ppm relative to the signal center by us-
ing the solvent peaks of DMSO-d6 (δ =2.49/39.7) as reference.
HRMS (ESI) spectra were recorded on a micrOTOF-Q (Bruker Dal-
tonics) spectrometer. Elemental analyses were carried out with a
Vario EL apparatus.
O
O
N
CONHPh
Ph
14
15 <5% from 13
15% from 18
CDI, HCO2H, DIPEA, CH2Cl2, r.t.
Diethyl 2-(Benzyloxycarbonylamino)malonate (4)
Diethyl 2-aminomalonate hydrochloride (10.6 g, 50 mmol) and
Na2CO3 (6.36 g, 60 mmol) were dissolved in H2O (60 mL). The
soln was cooled (ice bath) and benzyl chloroformate (8.53 g,
50 mmol) was added. After 2 h, the mixture was allowed to warm
to r.t. and stirred overnight. The soln was acidified with 2 M aq HCl
to pH 1–2 and extracted with EtOAc (3 × 30 mL). The
combined organic layers were dried (Na2SO4) and the solvent was
removed under reduced pressure. PE (40 mL) was added to the res-
idue and the mixture was heated. When it started boiling, a suffi-
cient amount of EtOAc was added to dissolve the oily material.
Na2SO4 was added to the soln. After filtration, the soln was kept at
–30 °C overnight. The precipitate was collected by suction filtration
and dried under reduced pressure.
H3+N
MsO–
CONHPh
18
MsOH, THF, 0 °C, r.t.
PhNH2, EDC, DMAP,
CH2Cl2, r.t., Δ
Boc-HN
Boc-HN
CONHPh
CO2H
17 50%
16
Scheme 3 Synthesis of hydantoin 14 and anilide 15
White solid; yield: 14.62 g (95%); mp 35–36 °C (Lit.6 31–32 °C);
Rf = 0.64 (PE–EtOAc, 3:1).
Compound 13 was subjected to the treatment with oxalyl
chloride, N,N-dimethylformamide, and aniline (Scheme
3). The reaction mixture was analyzed with respect to the
formation of the envisaged products 14 and 15. Hydantoin
14 and anilide 15 were independently synthesized as fol-
lows. Compound 14 was prepared from 2-aminoisobutyr-
ic acid and phenyl isocyanate,20 and 15 was obtained by a
route starting from tert-butoxycarbonyl-protected 2-ami-
noisobutyric acid 16. The N-formylation to 15 was
achieved with in situ generated N-formylimidazole.21 For
compound 15, the Z-configuration of the formamido
group was again ascertained. With authentic samples of
14 and 15 in hand, their presence in the product mixture
formed in the reaction of 13 could be verified. After pre-
parative chromatography, the N-formylated product 15
was found in a corresponding fraction and further purified
by recrystallization. Compound 15 was at least produced
in minor quantities, but the hydantoin 14 could not be
identified in the various fractions. The diminished forma-
tion of products 14 and 15, in comparison with 11 and 12
(Scheme 2), may be because of entropic reasons: interme-
diate 7 provides two electrophilic sites for the ring clo-
sure, whereas the acid chloride derived from 13 only one.
1H NMR (500 MHz, DMSO-d6): δ = 1.18 (t, J = 7.3 Hz, 6 H,
OCH2CH3), 4.10–4.21 (m, 4 H, OCH2CH3), 4.90 (d, J = 8.2 Hz,
1 H, CONHCH), 5.06 (s, 2 H, PhCH2O), 7.29–7.38 (m, 5 H, Harom),
8.24 (d, J = 8.2 Hz, 1 H, CONHCH).
13C NMR (125 MHz, DMSO-d6): δ = 13.95 (OCH2CH3), 57.86
(CONHCH), 61.77 (OCH2CH3), 66.11 (PhCH2O), 127.90, 128.04,
128.48, 136.77 (Carom), 156.01 (OCONH), 166.53 (CCOO).
Anal. Calcd for C15H19NO6: C, 58.25; H, 6.19; N, 4.53. Found: C,
58.40; H, 6.07; N, 4.58.
Diethyl 2-Alkyl-2-(benzyloxycarbonylamino)malonates 5; Gen-
eral Procedure
A soln of NaOEt was prepared from Na (460 mg, 20 mmol) and an-
hyd EtOH (40 mL). Malonate 4 (6.19 g, 20 mmol) and MeI (3.12 g,
1.37 mL, 22 mmol) or EtBr (2.28 g, 1.56 mL, 22 mmol) were added.
The soln was stirred at 87 °C for 10 h in an oil bath. CH2Cl2 (62
mL), charcoal (0.80 g), silica gel (0.80 g), and Na2SO4 (2.1 g) were
added. After filtration of the mixture, the solvent was removed un-
der reduced pressure and the oily residue was purified by column
chromatography (silica gel, PE–EtOAc, 3:1).
Diethyl 2-(Benzyloxycarbonylamino)-2-methylmalonate (5a)
Colorless oil; yield: 5.40 g (83%); Rf = 0.79 (PE–EtOAc, 3:1).
1H NMR (500 MHz, DMSO-d6): δ = 1.14 (t, J = 6.8 Hz, 6 H,
OCH2CH3), 1.57 (s, 3 H, 2-CH3), 4.11 (q, J = 6.8 Hz, 4 H,
OCH2CH3), 5.03 (s, 2 H, PhCH2O), 7.28–7.38 (m, 5 H, Harom), 7.72
(s, 1 H, CONHC).
13C NMR (125 MHz, DMSO-d6): δ = 13.86 (OCH2CH3), 21.68 (2-
CH3), 61.71 (OCH2CH3), 63.16, 65.71 (C-2, PhCH2O), 127.77,
127.97, 128.43, 136.90 (Carom), 154.93 (OCONH), 168.52 (CCOO).
In summary, we have developed a synthetic entry to the
new class of 3,5-disubstituted hydantoin-5-carboxamides,
thus extending the availability of these promising hetero-
cyclic compounds. Moreover, we have explored an unex-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1907–1914

1910
L. Hroch et al.
PAPER
Diethyl 2-(Benzyloxycarbonylamino)-2-ethylmalonate (5b)
Colorless oil; yield: 4.38 g (65%); Rf = 0.80 (PE–EtOAc, 3:1).
1H NMR (500 MHz, DMSO-d6): δ = 1.73 (s, 3 H, CH3), 7.09–7.13
(m, 1 H, Harom), 7.31–7.35 (m, 2 H, Harom), 7.38–7.43 (m, 3 H,
1H NMR (500 MHz, DMSO-d6): δ = 0.76 (t, J = 7.6 Hz, 3 H, 2-
CH2CH3), 1.12 (t, J = 7.0 Hz, 6 H, OCH2CH3), 2.09 (q, J = 7.6 Hz,
2 H, 2-CH2CH3), 4.12 (q, J = 7.0 Hz, 4 H, OCH2CH3), 5.04 (s, 2 H,
PhCH2O), 7.28–7.38 (m, 5 H, Harom), 7.49 (s, 1 H, CONHC).
13C NMR (125 MHz, DMSO-d6): δ = 7.85 (2-CH2CH3), 13.88
(OCH2CH3), 26.62 (2-CH2CH3), 61.75 (OCH2CH3), 65.71, 67.09
(C-2, PhCH2O), 127.67, 127.93, 128.41, 136.89 (Carom), 154.62
(OCONH), 167.63 (CCOO).
H
arom), 7.47–7.50 (m, 2 H, Harom), 7.63–7.65 (m, 2 H, Harom), 8.96 (s,
1 H, NH), 9.92 (s, 1 H, 5-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 21.68 (CH3), 65.39 (C-5),
120.95, 124.40, 126.98, 128.15, 128.70, 128.83, 132.08, 138.24
(Carom), 155.12 (C-2), 165.25 (5-CONH), 171.29 (C-4).
HRMS (ESI): m/z [M + Na]+ calcd for C17H15N3O3: 332.1006;
found: 332.1000.
5-Methyl-3-[3-(trifluoromethyl)phenyl]-5-{[3-(trifluorometh-
yl)phenyl]carbamoyl}hydantoin (11b)
White solid; yield: 0.54 g (24%); mp 170–171 °C; Rf = 0.82 (PE–
EtOAc, 1:1).
1H NMR (500 MHz, DMSO-d6): δ = 1.76 (s, 3 H, CH3), 7.46–7.49
(m, 1 H, Harom), 7.59 (t, J = 7.9 Hz, 1 H, Harom), 7.73–7.80 (m, 3 H,
2-Alkyl-2-(benzyloxycarbonylamino)malonic Acids 6; General
Procedure
A soln of 5a (1.62 g, 5 mmol) or 5b (1.69 g, 5 mmol), 2.5 M NaOH
(60 mL), and EtOH (20 mL) was stirred at r.t. for 4 d. The soln was
cooled (ice bath), acidified with ice-cooled 1 M aq HCl to pH 1–2
and extracted with EtOAc (3 × 30 mL). The combined organic lay-
ers were dried (Na2SO4). After filtration, the solvent was removed
under reduced pressure at r.t. The material was used for the next re-
action step without further purification.
H
arom), 7.89 (br s, 1 H, Harom), 7.97–8.00 (m, 1 H, Harom), 8.07 (br s,
1 H, Harom), 9.12 (s, 1 H, NH), 10.23 (s, 1 H, 5-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 21.41 (CH3), 65.56 (C-5),
117.01 (q, 3J = 3.9 Hz, Carom), 120.79 (q, 3J = 3.6 Hz, Carom), 123.61
3
1
2-(Benzyloxycarbonylamino)-2-methylmalonic Acid (6a)
Light-yellow oil; yield: 1.30 g (97%).
(q, J = 3.8 Hz, Carom), 123.93 (q, J = 270.7 Hz, CF3), 124.18 (q,
1J = 270.6 Hz, CF3), 124.39 (Carom), 124.83 (q, 3J = 3.7 Hz, Carom),
129.49 (q, J = 31.5 Hz, Carom), 129.59 (q, J = 32.0 Hz, Carom),
130.08 (Carom), 130.20 (Carom), 130.94 (Carom), 132.81 (Carom),
139.04 (Carom), 154.69 (C-2), 165.63 (5-CONH), 170.74 (C-4).
2
2
1H NMR (500 MHz, DMSO-d6): δ = 1.55 (s, 3 H, CH3), 5.02 (s,
2 H, PhCH2O), 7.12 (s, 1 H, CONHC), 7.28–7.37 (m, 5 H, Harom).
13C NMR (125 MHz, DMSO-d6): δ = 21.45 (2-CH3), 62.67, 65.61
(C-2, PhCH2O), 127.66, 127.90, 128.45, 136.93 (Carom), 154.59
(OCONH), 170.34 (CCOO).
Anal. Calcd for C19H13F6N3O3: C, 51.25; H, 2.94; N, 9.44. Found:
C, 51.65; H, 2.98; N, 9.08.
5-Methyl-3-(4-methylphenyl)-5-[(4-methylphenyl)carbamo-
yl]hydantoin (11c)
Off-white solid; yield: 0.20 g (12%); mp 185–186 °C; Rf = 0.71
(PE–EtOAc, 1:1).
1H NMR (500 MHz, DMSO-d6): δ = 1.71 (s, 3 H, 5-CH3), 2.26, 2.36
(each s, 6 H, CH3Ph), 7.12–7.14 (m, 2 H, Harom), 7.28 (s, 4 H, Harom),
7.50–7.53 (m, 2 H, Harom), 8.90 (s, 1 H, NH), 9.83 (s, 1 H, 5-
CONH).
13C NMR (125 MHz, DMSO-d6): δ = 20.58, 20.83 (CH3Ph), 21.69
(5-CH3), 65.33 (C-5), 120.96, 126.85, 129.07, 129.31, 129.50,
133.40, 135.74, 137.67 (Carom), 155.25 (C-2), 165.10 (5-CONH),
171.42 (C-4).
2-(Benzyloxycarbonylamino)-2-ethylmalonic Acid (6b)
Light-yellow oil; yield: 1.30 g (92%).
1H NMR (500 MHz, DMSO-d6): δ = 0.73 (t, J = 7.4 Hz, 3 H, 2-
CH2CH3), 2.10 (q, J = 7.4 Hz, 2 H, 2-CH2CH3), 5.03 (s, 2 H,
PhCH2O), 6.85 (s, 1 H, CONHC), 7.28–7.37 (m, 5 H, Harom).
13C NMR (125 MHz, DMSO-d6): δ = 8.01 (2-CH2CH3), 25.67 (2-
CH2CH3), 65.60, 66.75 (C-2, PhCH2O), 127.54, 127.89, 128.46,
136.96 (Carom), 154.24 (OCONH), 169.57 (CCOO).
5-Alkyl-3-aryl-5-(arylcarbamoyl)hydantoins 11 and 2-Alkyl-2-
formamido-N1,N3-bis(aryl)malonamides 12; General Proce-
dure
Malonic acid 6a (1.34 g, 5 mmol) or 6b (1.41 g, 5 mmol) was dis-
solved in anhyd CH2Cl2 (100 mL), and four drops of DMF were
added. Oxalyl chloride (2.92 g, 2.00 mL, 23 mmol) was added and
the soln was stirred at r.t. under argon atmosphere until the evolu-
tion of gas had ceased, approximately after 30–60 min. The solvent
was removed under reduced pressure and the residue was diluted
with anhyd 1,4-dioxane (20 mL). An argon atmosphere was again
introduced. A mixture of Et3N (1.21 g, 1.67 mL, 12 mmol), anhyd
1,4-dioxane (5 mL), and the appropriate amine [aniline (1.40 g, 1.37
mL, 15 mmol), 3-aminobenzotrifluoride (2.42 g, 1.88 mL, 15
mmol), p-toluidine (1.61 g, 1.65 mL, 15 mmol), p-anisidine (1.85 g,
15 mmol), or 4-nitroaniline (2.07 g, 15 mmol)] was prepared. This
mixture was injected through a septum over a period of 30 min. The
soln was stirred at r.t. for 24 h. The precipitated [Et3NH]Cl was re-
moved by suction filtration and the filtrate was evaporated to dry-
ness. The oily residue was purified by column chromatography
(silica gel, PE–EtOAc, 1:1). The corresponding fractions were com-
bined and the solvents were removed under reduced pressure. Et2O
was added to the residues, and after storage at –30 °C for 2 h, the
precipitates were collected by suction filtration and dried under re-
duced pressure to provide the corresponding products 11 and 12
from each reaction.
Anal. Calcd for C19H19N3O3: C, 67.64; H, 5.68; N, 12.46. Found: C,
67.47; H, 5.60; N, 12.21.
3-(4-Methoxyphenyl)-5-[(4-methoxyphenyl)carbamoyl]-5-
methylhydantoin (11d)
White solid; yield: 0.34 g (18%); mp 157–158 °C; Rf = 0.38 (PE–
EtOAc, 1:1).
1H NMR (500 MHz, DMSO-d6): δ = 1.70 (s, 3 H, 5-CH3), 3.72, 3.78
(each s, 6 H, CH3OPh), 6.88–6.92 (m, 2 H, Harom), 7.00–7.04 (m,
2 H, Harom), 7.29–7.33 (m, 2 H, Harom), 7.51–7.55 (m, 2 H, Harom),
8.86 (s, 1 H, NH), 9.79 (s, 1 H, 5-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 21.63 (5-CH3), 55.31, 55.51
(CH3OPh), 65.24 (C-5), 113.82, 114.10, 122.54, 124.66, 128.40,
131.27, 155.41, 156.04 (Carom), 158.90 (C-2), 164.96 (5-CONH),
171.57 (C-4).
Anal. Calcd for C19H19N3O5: C, 61.78; H, 5.18; N, 11.38. Found: C,
62.11; H, 5.20; N, 10.98.
5-Methyl-3-(4-nitrophenyl)-5-[(4-nitrophenyl)carbamoyl]hy-
dantoin (11e)
Yellow solid; yield: 0.48 g (24%); mp 208–209 °C; Rf = 0.49 (PE–
EtOAc, 1:1).
5-Methyl-3-phenyl-5-(phenylcarbamoyl)hydantoin (11a)
White solid; yield: 0.14 g (9%); mp 147–148 °C; Rf = 0.64 (PE–
EtOAc, 1:1).
1H NMR (500 MHz, DMSO-d6): δ = 1.78 (s, 3 H, CH3), 7.79–7.83
(m, 2 H, Harom), 7.93–7.97 (m, 2 H, Harom), 8.23–8.27 (m, 2 H,
Harom), 8.35–8.39 (m, 2 H, Harom), 9.23 (s, 1 H, NH), 10.46 (s, 1 H,
5-CONH).
Synthesis 2012, 44, 1907–1914
© Georg Thieme Verlag Stuttgart · New York

PAPER
3,5,5-Trisubstituted Hydantoins
1911
13C NMR (125 MHz, DMSO-d6): δ = 21.50 (CH3), 65.64 (C-5),
120.62, 124.18, 124.80, 127.21, 137.77, 143.19, 144.35, 146.28
(Carom), 154.18 (C-2), 165.82 (5-CONH), 170.38 (C-4).
Harom), 7.00–7.04 (m, 2 H, Harom), 7.25–7.29 (m, 2 H, Harom), 7.51–
7.55 (m, 2 H, Harom), 8.91 (s, 1 H, NH), 9.73 (s, 1 H, 5-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 7.64 (CH2CH3), 27.92
(CH2CH3), 55.33, 55.53 (CH3OPh), 69.35 (C-5), 113.83, 114.23,
122.55, 124.52, 128.31, 131.23, 155.70, 156.06 (Carom), 158.97 (C-
2), 164.30 (5-CONH), 170.76 (C-4).
Anal. Calcd for C17H13N5O7: C, 51.13; H, 3.28; N, 17.54. Found: C,
50.78; H, 3.55; N, 17.02.
5-Ethyl-3-phenyl-5-(phenylcarbamoyl)hydantoin (11f)
White solid; yield: 0.37 g (23%); mp 142–144 °C; Rf = 0.75 (PE–
EtOAc, 1:1).
Anal. Calcd for C20H21N3O5: C, 62.65; H, 5.52; N, 10.96. Found: C,
62.62; H, 5.57; N, 10.85.
The product was recrystallized from PE–EtOAc; this gave crystals
for X-ray analysis.
5-Ethyl-3-(4-nitrophenyl)-5-[(4-nitrophenyl)carbamoyl]hydan-
toin (11j)
Light-yellow solid; yield: 0.53 g (26%); mp 112–114 °C; Rf = 0.64
(PE–EtOAc, 1:1).
1H NMR (500 MHz, DMSO-d6): δ = 0.92 (t, J = 7.4 Hz, 3 H,
CH2CH3), 2.10–2.18 (m, 1 H, CH2CH3), 2.22–2.30 (m, 1 H,
CH2CH3), 7.09–7.13 (m, 1 H, Harom), 7.31–7.43 (m, 5 H, Harom),
7.46–7.51 (m, 2 H, Harom), 7.62–7.65 (m, 2 H, Harom), 9.01 (s, 1 H,
NH), 9.85 (s, 1 H, 5-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 7.63 (CH2CH3), 27.99
(CH2CH3), 69.49 (C-5), 120.95, 124.41, 126.89, 128.25, 128.71,
128.96, 131.93, 138.18 (Carom), 155.40 (C-2), 164.58 (5-CONH),
170.50 (C-4).
1H NMR (500 MHz, DMSO-d6): δ = 0.93 (t, J = 7.4 Hz, 3 H,
CH2CH3), 2.16–2.33 (m, 2 H, CH2CH3), 7.76–7.80 (m, 2 H, Harom),
7.94–7.98 (m, 2 H, Harom), 8.23–8.27 (m, 2 H, Harom), 8.34–8.38 (m,
2 H, Harom), 9.34 (s, 1 H, NH), 10.38 (s, 1 H, 5-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 7.60 (CH2CH3), 20.10
(CH2CH3), 69.74 (C-5), 120.67, 124.32, 124.81, 127.19, 137.51,
143.22, 144.30, 146.39 (Carom), 154.42 (C-2), 165.07 (5-CONH),
169.67 (C-4).
Anal. Calcd for C18H17N3O3: C, 66.86; H, 5.30; N, 13.00. Found: C,
67.01; H, 5.72; N, 13.06.
Anal. Calcd for C18H15N5O7: C, 52.30; H, 3.66; N, 16.94. Found: C,
52.23; H, 4.12; N, 16.29.
5-Ethyl-3-[3-(trifluoromethyl)phenyl]-5-{[3-(trifluorometh-
yl)phenyl]carbamoyl}hydantoin (11g)
White solid; yield: 0.99 g (43%); mp 63–64 °C; Rf = 0.87 (PE–
EtOAc, 1:1).
2-Formamido-2-methyl-N1,N3-diphenylmalonamide (12a)
White solid; yield: 0.08 g (5%); mp 169–171 °C; Rf = 0.57 (PE–
EtOAc, 1:3).
1H NMR (500 MHz, DMSO-d6): δ = 0.94 (t, J = 7.4 Hz, 3 H,
CH2CH3), 2.15–2.31 (m, 2 H, CH2CH3), 7.46–7.49 (m, 1 H, Harom),
7.59 (t, J = 8.0 Hz, 1 H, Harom), 7.73–7.81 (m, 3 H, Harom), 7.83–7.85
(m, 1 H, Harom), 7.97–8.00 (m, 1 H, Harom), 8.08 (br s, 1 H, Harom),
9.23 (s, 1 H, NH), 10.16 (s, 1 H, 5-CONH).
1H NMR (500 MHz, DMSO-d6): δ = 1.78 (s, 3 H, CH3), 7.06–7.11
(m, 2 H, Harom), 7.28–7.33 (m, 4 H, Harom), 7.56–7.60 (m, 4 H,
Harom), 8.14 (d, J = 1.6 Hz, 1 H, HCONH), 8.71 (br s, 1 H,
HCONH), 9.93 (s, 2 H, 2-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 22.11 (CH3), 63.27 (C-2),
120.71, 124.17, 128.73, 138.35 (Carom), 162.04 (HCONH), 168.23
(2-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 7.66 (CH2CH3), 27.98
3
(CH2CH3), 69.63 (C-5), 117.04 (q, J = 3.7 Hz, Carom), 120.79 (q,
3
1
3J = 3.6 Hz, Carom), 123.40 (q, J = 3.7 Hz, Carom), 123.87 (q, J =
HRMS (ESI): m/z [M + Na]+ calcd for C17H17N3O3: 334.1162;
found: 334.1168.
1
270.6 Hz, CF3), 124.18 (q, J = 270.7 Hz, CF3), 124.43 (Carom),
124.92 (q, 3J = 3.7 Hz, Carom), 129.70 (q, 2J = 32.0 Hz, Carom), 129.71
2
2-Formamido-2-methyl-N1,N3-bis[3-(trifluoromethyl)phe-
nyl]malonamide (12b)
White solid; yield: 0.47 g (21%); mp 140–141 °C; Rf = 0.73 (PE–
EtOAc, 1:3).
1H NMR (500 MHz, DMSO-d6): δ = 1.81 (s, 3 H, CH3), 7.42–7.45
(m, 2 H, Harom) 7.55 (t, J = 8.1 Hz, 2 H, Harom), 7.86–7.89 (m, 2 H,
(q, J = 31.5 Hz, Carom), 130.05 (Carom), 130.33 (Carom), 130.78
(Carom), 132.61 (Carom), 138.97 (Carom), 154.88 (C-2), 164.84 (5-
CONH), 169.98 (C-4).
Anal. Calcd for C20H15F6N3O3: C, 52.30; H, 3.29; N, 9.15. Found:
C, 52.56; H, 3.67; N, 9.16.
5-Ethyl-3-(4-methylphenyl)-5-[(4-methylphenyl)carbamoyl]hy-
dantoin (11h)
Off-white solid; yield: 0.44 g (25%); mp 168–170 °C; Rf = 0.80
(PE–EtOAc, 1:1).
1H NMR (500 MHz, DMSO-d6): δ = 0.91 (t, J = 7.4 Hz, 3 H,
CH2CH3), 2.07–2.15 (m, 1 H, CH2CH3), 2.20–2.28 (m, 1 H,
CH2CH3), 2.26, 2.33 (each s, 6 H, CH3Ph), 7.12–7.14 (m, 2 H,
Harom), 8.08 (br s, 2 H, Harom), 8.16 (s, 1 H, HCONH), 8.80 (s, 1 H,
HCONH), 10.20 (s, 2 H, 2-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 21.81 (CH3), 63.68 (C-2),
116.84 (q, 3J = 3.7 Hz, Carom), 120.53 (q, 3J = 3.7 Hz, Carom), 124.22
1
2
(q, J = 270.6 Hz, CF3), 124.27 (Carom), 129.51 (q, J = 31.5 Hz,
Carom), 130.04 (Carom), 139.22 (Carom), 162.12 (HCONH), 168.39 (2-
CONH).
Harom), 7.23–7.29 (m, 4 H, Harom), 7.50–7.53 (m, 2 H, Harom), 8.94 (s,
Anal. Calcd for C19H15F6N3O3: C, 51.01; H, 3.38; N, 9.39. Found:
C, 51.10; H, 3.65; N, 9.15.
1 H, NH), 9.77 (s, 1 H, 5-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 7.62 (CH2CH3), 20.59, 20.83
(CH3Ph), 27.96 (CH2CH3), 69.42 (C-5), 120.96, 126.76, 129.09,
129.35, 129.43, 133.42, 135.68, 137.80 (Carom), 155.54 (C-2),
164.44 (5-CONH), 170.61 (C-4).
2-Formamido-2-methyl-N1,N3-bis(4-methylphenyl)malon-
amide (12c)
Off-white solid; yield: 0.33 g (19%); mp 131–132 °C; Rf = 0.66
(PE–EtOAc, 1:3).
1H NMR (500 MHz, DMSO-d6): δ = 1.76 (s, 3 H, 2-CH3), 2.24 (s,
6 H, CH3Ph), 7.10–7.12 (m, 4 H, Harom), 7.43–7.46 (m, 4 H, Harom),
8.13 (s, 1 H, HCONH), 8.66 (s, 1 H, HCONH), 9.85 (s, 2 H, 2-
CONH).
13C NMR (125 MHz, DMSO-d6): δ = 20.56 (CH3Ph), 22.17 (2-
CH3), 63.11 (C-2), 120.74, 129.10, 133.17, 135.83 (Carom), 161.96
(HCONH), 168.10 (2-CONH).
Anal. Calcd for C20H21N3O3: C, 68.36; H, 6.02; N, 11.96. Found: C,
68.15; H, 6.12; N, 11.65.
5-Ethyl-3-(4-methoxyphenyl)-5-[(4-methoxyphenyl)carbamo-
yl]hydantoin (11i)
Off-white solid; yield: 0.38 g (20%); mp 152–153 °C; Rf = 0.53
(PE–EtOAc, 1:1).
1H NMR (500 MHz, DMSO-d6): δ = 0.90 (t, J = 7.4 Hz, 3 H,
CH2CH3), 2.06–2.15 (m, 1 H, CH2CH3), 2.19–2.27 (m, 1 H,
CH2CH3), 3.72, 3.78 (each s, 6 H, CH3OPh), 6.88–6.92 (m, 2 H,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1907–1914

1912
L. Hroch et al.
PAPER
Anal. Calcd for C19H21N3O3: C, 67.24; H, 6.24; N, 12.38. Found: C,
66.53; H, 6.36; N, 12.21.
2-Ethyl-2-formamido-N1,N3-bis(4-methylphenyl)malonamide
(12h)
Off-white solid; yield: 0.54 g (31%); mp 156–158 °C; Rf = 0.72
(PE–EtOAc, 1:3).
2-Formamido-N1,N3-bis(4-methoxyphenyl)-2-methylmalon-
amide (12d)
1H NMR (500 MHz, DMSO-d6): δ = 0.81 (t, J = 7.4 Hz, 3 H,
CH2CH3), 2.24 (s, 6 H, CH3Ph), 2.34 (q, J = 7.4 Hz, 2 H, CH2CH3),
7.09–7.12 (m, 4 H, Harom) 7.42–7.46 (m, 4 H, Harom), 8.15 (d, J ≈ 1.2
Hz, 1 H, HCONH), 8.47 (d, J ≈ 1.2 Hz, 1 H, HCONH), 9.87 (s, 2 H,
2-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 8.07 (CH2CH3), 20.56
(CH3Ph), 26.88 (CH2CH3), 66.88 (C-2), 120.93, 129.08, 133.27,
135.68 (Carom), 161.73 (HCONH), 167.39 (2-CONH).
White solid; yield: 0.28 g (15%); mp 151–153 °C; Rf = 0.43 (PE–
EtOAc, 1:3).
1H NMR (500 MHz, DMSO-d6): δ = 1.76 (s, 3 H, 2-CH3), 3.71 (s,
6 H, CH3OPh), 6.86–6.90 (m, 4 H, Harom), 7.44–7.49 (m, 4 H,
Harom), 8.12 (s, 1 H, HCONH), 8.61 (s, 1 H, HCONH), 9.79 (s, 2 H,
2-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 22.13 (2-CH3), 55.34
(CH3OPh), 62.95 (C-2), 113.87, 122.38, 131.40, 155.96 (Carom),
161.85 (HCONH), 167.95 (2-CONH).
Anal. Calcd for C20H23N3O3: C, 67.97; H, 6.56; N, 11.89. Found: C,
67.82; H, 6.55; N, 11.57.
Anal. Calcd for C19H21N3O5: C, 61.45; H, 5.70; N, 11.31. Found: C,
60.90; H, 5.72; N, 11.19.
2-Ethyl-2-formamido-N1,N3-bis(4-methoxyphenyl)malon-
amide (12i)
Off-white solid; yield: 0.30 g (16%); mp 142–144 °C; Rf = 0.50
(PE–EtOAc, 1:3).
1H NMR (500 MHz, DMSO-d6): δ = 0.81 (t, J = 7.4 Hz, 3 H,
CH2CH3), 2.34 (q, J = 7.4 Hz, 2 H, CH2CH3), 3.71 (s, 6 H,
CH3OPh), 6.85–6.89 (m, 4 H, Harom), 7.44–7.48 (m, 4 H, Harom),
8.15 (d, J ≈ 1.1 Hz, 1 H, HCONH), 8.43 (d, J ≈ 1.1 Hz, 1 H,
HCONH), 9.81 (s, 2 H, 2-CONH).
2-Formamido-2-methyl-N1,N3-bis(4-nitrophenyl)malonamide
(12e)
Light-yellow solid; yield: 0.65 g (32%); mp 218–219 °C; Rf = 0.41
(PE–EtOAc, 1:3).
1H NMR (500 MHz, DMSO-d6): δ = 1.82 (s, 3 H, CH3), 7.88–7.92
(m, 4 H, Harom) 8.18 (s, 1 H, HCONH), 8.20–8.24 (m, 4 H, Harom),
8.92 (s, 1 H, HCONH), 10.44 (s, 2 H, 2-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 21.70 (CH3), 64.13 (C-2),
120.33, 124.85, 142.96, 144.61 (Carom), 162.38 (HCONH), 168.56
(2-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 8.05 (CH2CH3), 26.73
(CH2CH3), 55.33 (CH3OPh), 66.77 (C-2), 113.84, 122.53, 131.24,
156.00 (Carom), 161.62 (HCONH), 167.23 (2-CONH).
Anal. Calcd for C17H15N5O7: C, 50.88; H, 3.77; N, 17.45. Found: C,
51.02; H, 3.91; N, 17.03.
Anal. Calcd for C20H23N3O5: C, 62.33; H, 6.01; N, 10.90. Found: C,
61.99; H, 5.92; N, 10.78.
2-Ethyl-2-formamido-N1,N3-diphenylmalonamide (12f)
White solid; yield: 0.55 g (34%); mp 189–190 °C; Rf = 0.67 (PE–
EtOAc, 1:3).
2-Ethyl-2-formamido-N1,N3-bis(4-nitrophenyl)malonamide
(12j)
Light-yellow solid; yield: 0.73 g (35%); mp 132–134 °C; Rf = 0.41
(PE–EtOAc, 1:3).
1H NMR (500 MHz, DMSO-d6): δ = 0.85 (t, J = 7.4 Hz, 3 H,
CH2CH3), 2.38 (q, J = 7.4 Hz, 2 H, CH2CH3), 7.89–7.93 (m, 4 H,
The product was recrystallized from EtOAc to obtain crystals for X-
ray analysis.
1H NMR (500 MHz, DMSO-d6): δ = 0.83 (t, J = 7.5 Hz, 3 H,
CH2CH3), 2.36 (q, J = 7.5 Hz, 2 H, CH2CH3), 7.07–7.11 (m, 2 H,
Harom), 7.28–7.33 (m, 4 H, Harom), 7.56–7.59 (m, 4 H, Harom), 8.16 (d,
J = 1.3 Hz, 1 H, HCONH), 8.53 (br s, 1 H, HCONH), 9.96 (s, 2 H,
2-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 8.07 (CH2CH3), 26.84
(CH2CH3), 67.02 (C-2), 120.91, 124.26, 128.71, 138.20 (Carom),
161.78 (HCONH), 167.52 (2-CONH).
Harom) 8.19 (d, J ≈ 1.1 Hz, 1 H, HCONH), 8.20–8.24 (m, 4 H, Harom),
8.74 (d, J ≈ 1.1 Hz, 1 H, HCONH), 10.47 (s, 2 H, 2-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 8.01 (CH2CH3), 26.67
(CH2CH3), 67.75 (C-2), 120.59, 124.81, 143.08, 144.39 (Carom),
162.09 (HCONH), 167.85 (2-CONH).
Anal. Calcd for C18H17N5O7: C, 51.92; H, 4.36; N, 16.82. Found: C,
51.87; H, 4.41; N, 16.51.
Anal. Calcd for C18H19N3O3: C, 66.45; H, 5.89; N, 12.91. Found: C,
66.31; H, 6.01; N, 12.71.
Reaction of 13 with Oxalyl Chloride, N,N-Dimethylformamide,
and Aniline
Isobutyric acid 13 (1.19 g, 5 mmol) was dissolved in anhyd CH2Cl2
(100 mL), and four drops of DMF were added. Oxalyl chloride
(2.92 g, 2.00 mL, 23 mmol) was added and the soln was stirred at
r.t. under an argon atmosphere for 30 min. The solvent was removed
under reduced pressure and the residue was diluted with anhyd 1,4-
dioxane (20 mL). An argon atmosphere was again introduced. A
mixture of Et3N (1.21 g, 1.67 mL, 12 mmol), anhyd 1,4-dioxane (5
mL), and aniline (1.40 g, 1.37 mL, 15 mmol) was prepared. This
mixture was injected through a septum over a period of 30 min. The
soln was stirred at r.t. for 24 h. The precipitated [Et3NH]Cl was re-
moved by suction filtration and the filtrate was evaporated to dry-
ness. Four fractions were obtained from the oily residue after
column chromatography (silica gel, PE–EtOAc, 1:2). An appropri-
ate fraction (Rf ≈ 0.56) was analyzed by 1H and 13C NMR, but did
not contain notable amounts of hydantoin 14. A further fraction
(Rf ≈ 0.19) contained the anilide 15. Pure material of 15 (5 mg) was
obtained by recrystallization (n-hexane–EtOAc).
2-Ethyl-2-formamido-N1,N3-bis[3-(trifluoromethyl)phe-
nyl]malonamide (12g)
White solid; yield: 0.57 g (25%); mp 141–143 °C; Rf = 0.77 (PE–
EtOAc, 1:3).
1H NMR (500 MHz, DMSO-d6): δ = 0.83 (t, J = 7.4 Hz, 3 H,
CH2CH3), 2.39 (q, J = 7.4 Hz, 2 H, CH2CH3), 7.42–7.45 (m, 2 H,
Harom) 7.55 (t, J = 8.0 Hz, 2 H, Harom), 7.88–7.91 (m, 2 H, Harom),
8.08 (br s, 2 H, Harom), 8.17 (d, J = 1.0 Hz, 1 H, HCONH), 8.64 (br
s, 1 H, HCONH), 10.22 (s, 2 H, 2-CONH).
13C NMR (125 MHz, DMSO-d6): δ = 7.95 (CH2CH3), 26.44
3
(CH2CH3), 67.39 (C-2), 116.97 (q, J = 3.7 Hz, Carom), 120.58 (q,
3J = 3.5 Hz, Carom), 124.16 (q, 1J = 270.6 Hz, CF3), 124.40 (Carom),
2
129.45 (q, J = 31.5 Hz, Carom), 129.98 (Carom), 139.03 (Carom),
161.81 (HCONH), 167.62 (2-CONH).
Anal. Calcd for C20H17F6N3O3: C, 52.07; H, 3.71; N, 9.11. Found:
C, 52.16; H, 3.76; N, 8.78.
5,5-Dimethyl-3-phenylimidazolidine-2,4-dione (14)
2-Aminoisobutyric acid (516 mg, 5 mmol) was dissolved in 2 M aq
NaOH (5 mL), and PhNCO (1.79 g, 1.63 mL, 15 mmol) was added.
Synthesis 2012, 44, 1907–1914
© Georg Thieme Verlag Stuttgart · New York

PAPER
3,5,5-Trisubstituted Hydantoins
1913
The mixture was stirred at r.t. for 1 h. The precipitated N,N′-diphe-
nylurea was collected by filtration and the filtrate was acidified with
2 M aq HCl to pH 1. The resulting precipitate was collected by fil-
tration and suspended in 2 M aq HCl (50 mL). The reaction mixture
was stirred at reflux for 2 h. The aqueous suspension was extracted
with CH2Cl2 (3 × 50 mL). The soln was dried (Na2SO4) and evapo-
rated.
mixtures were combined and stirred at r.t. for 3 h. After evaporation
of the solvent, the resulting solid was suspended in H2O (50 mL)
and extracted with CH2Cl2 (3 × 30 mL). The combined organic lay-
ers were washed with 10% aq KHSO4 (2 × 30 mL), sat. aq NaHCO3
(2 × 30 mL), H2O (30 mL), and brine (30 mL). The solvent was
dried (Na2SO4) and evaporated. The crude product was recrystal-
lized from EtOAc.
White solid; yield: 0.66 g (65%); mp 164–167 °C (Lit.20 168–
170 °C); Rf = 0.49 (PE–EtOAc, 1:1), Rf = 0.56 (PE–EtOAc, 1:2).
White solid; yield: 30 mg (15%); mp 184–186 °C; Rf = 0.13 (PE–
EtOAc, 1:1); Rf = 0.19 (PE–EtOAc, 1:2).
1H NMR (500 MHz, DMSO-d6): δ = 1.39 [s, 6 H, C(CH3)2], 7.34–
7.39 (m, 3 H, H-2, H-4, H-6), 7.44–7.48 (m, 2 H, H-3, H-5), 8.50 (s,
1 H, NH).
13C NMR (125 MHz, DMSO-d6): δ = 24.88 [C(CH3)2], 57.83
[C(CH3)2], 126.87, 127.83, 128.77, 132.34 (Carom), 154.32 (C-2),
176.53 (C-4).
1H NMR (500 MHz, DMSO-d6): δ = 1.45 [s, 6 H, C(CH3)2], 7.01–
7.04 (m, 1 H, H-4), 7.25–7.29 (m, 2 H, H-3, H-5), 7.57–7.60 (m,
2 H, H-2, H-6), 7.97 (d, 3J = 1.9 Hz, 1 H, HCONH), 8.19 (br s, 1 H,
HCONH), 9.36 (s, 1 H, NHPh).
13C NMR (125 MHz, DMSO-d6): δ = 25.10 [C(CH3)2], 56.29
[C(CH3)2], 120.35, 123.37, 128.48, 139.23 (Carom), 172.49
[COC(CH3)2], 161.03 (HCO).
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C,
64.33; H, 5.84; N, 13.12.
HRMS (ESI): m/z [M + Na]+ calcd for C11H14N2O2: 229.0947;
found: 229.0948.
2-(tert-Butoxycarbonylamino)-N-phenylisobutyramide (17)
Aniline (1.12 g, 1.10 mL, 12 mmol) was dissolved in anhyd CH2Cl2
(50 mL). Then, 16 (1.22 g, 6 mmol), EDC (1.02 g, 1.16 mL, 6.60
mmol) and DMAP (37 mg, 0.30 mmol) were added. The reaction
mixture was stirred at r.t. for 72 h and refluxed for 6 h. After evap-
oration of the solvent, the resulting solid was suspended in H2O and
extracted with EtOAc (3 × 30 mL). The combined organic layers
were washed with 10% KHSO4 (30 mL), sat. NaHCO3 (2 × 30 mL),
H2O (30 mL), and brine (30 mL). The solvent was dried (Na2SO4)
and evaporated. The product was purified by column chromatogra-
phy (silica gel, PE–EtOAc, 1:2).
Acknowledgment
L.H. thanks Matthias Mertens and Philipp Aaron Ottersbach, Uni-
versity of Bonn, for advice. G.S. thanks Prof. A. C. Filippou for sup-
port. The work was supported by the Lifelong Learning
Programme/ERASMUS of the European Commission.
References
White solid; yield: 0.83 g (50%); mp 157–160 °C; Rf = 0.79 (PE–
EtOAc, 1:1).
(1) Meusel, M.; Gütschow, M. Org. Prep. Proced. Int. 2004, 36,
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1H NMR (500 MHz, DMSO-d6): δ = 1.35–1.37 [m, 15 H, C(CH3)3,
C(CH3)2], 6.86 (br s, 1 H, NHPh), 6.99–7.02 (m, 1 H, H-4), 7.24–
7.28 (m, 2 H, H-3, H-5), 7.58–7.59 (m, 2 H, H-2, H-6), 9.34 [s, 1 H,
NHC(CH3)2].
13C NMR (125 MHz, DMSO-d6): δ = 25.16 [C(CH3)2], 28.22
[C(CH3)3], 56.56 [C(CH3)2], 78.34 [C(CH3)3], 120.02, 123.07,
128.48, 139.51 (Carom), 154.40 [COOC(CH3)3], 173.40 (CONHPh).
(2) Meusel, M.; Ambrożak, A.; Hecker, T. K.; Gütschow, M.
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(3) Gütschow, M.; Hecker, T.; Thiele, A.; Hauschildt, S.; Eger,
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(6) Jacob, L. A.; Chen, B. L.; Stec, D. Synthesis 1993, 611.
(7) For the formation of 2-alkoxyoxazol-5(4H)-ones through
activation of N-protected amino acids, see, for example:
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Anal. Calcd for C15H22N2O3: C, 64.73; H, 7.97; N, 10.06. Found: C,
64.83; H, 8.38; N, 11.23.
N-Phenylisobutyramide-2-aminium Methanesulfonate (18)
Compound 17 (835 mg, 3 mmol) was dissolved in anhyd THF (15
mL). Under ice cooling, anhyd methanesulfonic acid (1.73 g, 1.17
mL, 18 mmol) was added, and the mixture was stirred at r.t. over-
night. The precipitate was collected by filtration, washed with cold
EtOAc and PE and dried.
White solid; yield: 0.60 g (73%); mp 180–198 °C; Rf = 0.11 (PE–
EtOAc, 1:1).
1H NMR (500 MHz, DMSO-d6): δ = 1.59 [s, 6 H, C(CH3)2], 2.30 (s,
–
3 H, CH3SO3 ), 7.12–7.15 (m, 1 H, H-4), 7.34–7.38 (m, 2 H, H-3,
+
H-5), 7.60–7.62 (m, 2 H, H-2, H-6), 8.22 (s, 3 H, NH3 ), 9.88 (s,
1 H, NHPh).
13C NMR (125 MHz, DMSO-d6): δ = 23.50 [C(CH3)2], 57.23
[C(CH3)2], 120.69, 124.56, 128.93, 138.10 (Carom), 170.35
(CONHPh).
(8) For the hydantoin cyclization of (alkoxycarbonyl-
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Anal. Calcd for C11H18N2O4S: C, 48.16; H, 6.61; N, 10.21. Found:
C, 47.33; H, 6.92; N, 10.90.
2-Formamido-N-phenylisobutyramide (15)
1,1′-Carbonyldiimidazole (CDI; 178 mg, 1.1 mmol) was dissolved
in anhyd CH2Cl2 (2.2 mL), and formic acid (51 mg, 42 μL, 1.1
mmol) was added. The mixture was stirred at r.t. for 10 min. Com-
pound 18 (274 mg, 1 mmol) was suspended in anhyd CH2Cl2 (25
mL), and DIPEA (129 mg, 174 μL, 1.00 mmol) was added. Both
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© Georg Thieme Verlag Stuttgart · New York
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© Georg Thieme Verlag Stuttgart · New York