Synthesis of some new 5-dialkylaminomethylhydantoins and related compounds

Article abstract of DOI:10.3987/COM-12-12592

In this paper, we describe the synthesis of new 5-dialkylaminomethyl- substituted hydantoin derivatives (3 and 9) from β-aminoalanines (1 or 6) and some chemical properties of the synthesized compounds. A synthetic trial for the preparation of a new twin-

Full text of DOI:10.3987/COM-12-12592

HETEROCYCLES, Vol. 87, No. 1, 2013
133
HETEROCYCLES, Vol. 87, No. 1, 2013, pp. 133 - 145. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 21st September, 2012, Accepted, 26th October, 2012, Published online, 31st October, 2012
DOI: 10.3987/COM-12-12592
SYNTHESIS OF SOME NEW
5-DIALKYLAMINOMETHYLHYDANTOINS AND RELATED
COMPOUNDS
Fumiko Fujisaki, Mayu Egami, Keiko Toyofuku, and Kunihiro Sumoto*
Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-Ku,
Fukuoka 814-0180, Japan; E-mail: kunihiro@adm.fukuoka-u.ac.jp
Abstract
–
In this paper, we describe the synthesis of new
5-dialkylaminomethyl-substituted hydantoin derivatives (3 and 9) from
!-aminoalanines (1 or 6) and some chemical properties of the synthesized
compounds. A synthetic trial for the preparation of a new twin-drug type molecule
(12) is also described.
In connection with studies on new antibacterial compounds, many synthetic studies on molecular
modifications have been carried out to find new promising candidates. Many reports on molecular
recognition properties of artificial molecules have appeared, and many chemists are naturally interested in
studying such biologically active substances. We have been interested in
H
substances that interfere with molecular recognition process1-4 in order to find
new leads for antibacterial agents. We have already examined molecular
modification of a bioisosteric replacement of the oxazolidinone ring in
linezolid by a hydantoin nucleus.5-7 Regarding biological activities of
synthesized hydantoin derivatives, we have observed that most of the
R1
N
O
N
R2
N
O
Ar
(A)
5-dialkylaminomethy-3-arylhydantoin derivatives (A) show a wide range of significant antibacterial
activities against either gram-positive or gram-negative strains.7 For this attractive bioactivity of
5-dialkylaminomethyl-substituted hydantoins, further molecular modifications of this class of compounds
seemed to be interesting.
In this article, we describe a novel synthetic route for new 5-dialkylaminomethylhydantoin-related
heterocycles and some chemical properties of the synthesized hydantoin derivatives.

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HETEROCYCLES, Vol. 87, No. 1, 2013
SYNTHESIS OF 5-DIALKYLAMINOMETHYLHYDANTOINS
The new 3-aryl-substituted hydantoins were obtained from methyl ester of !-aminoalanines 1 and
arylisocyanates as starting materials.5,6 Details of the preparation of the new 3-aryl-substituted hydantoin
derivatives (3a—3d) and their physical or spectroscopic data are presented in the Experimental section.
The overall preparation stages (1!2!3) for the new target 5-dialkylaminomethyl-3-arylhydantoins
(3a—d) are shown in Chart 1.
H
R1
N
CO2Me
H2N C
R1
R2
O
CO2Me
R3NCO, NEt3
in CH2Cl2
R1
R2
N
R2
CH2N
R3 HNOCHN C
CH2N
N
R3
H
H
c . HCl
rt
O
• 2HCl
• HCl
(1a, b)
(2a, b)
(3a—d)
R1
R2
R1
Yield
[%]
R3
Compounds
N
Compounds
N
R2
69.8a)
22.7b)
3a =
3b =
N
N
1a, 2a =
1b, 2b =
N
N
86.0b)
74.4b)
3c =
3d =
N
N
(CH2)2 Cl
a) The yield was based on the compound 2a.�b) The
yield was based on the compound 1.
Chart 1
A new N(3)-alkyl-substituted hydantoin derivative 3e was prepared (see Chart 2). The cyclization
reaction of the urea intermediate 2c to the hydantoin derivative 3e was sensitive to reaction temperature.
Room temperature for the cyclization stage is adequate for preparation of the target hydantoin derivative.
By heating the urea intermediate 2c with concentrated HCl, elimination of the corresponding
dialkylamine also occurred easily to give 5-methylenehydantoin 4 together with the formation of a
migration product 5. Compound 5 was probably formed from a tautomeric isomer 4’ (see Chart 2). The
structures of these substituted hydantoins were confirmed by spectroscopic and elemental analyses (see
Experimental).

HETEROCYCLES, Vol. 87, No. 1, 2013
135
HN
H
H
N
Me
N
N
Me
CH2
O
O
O
N
N
N
N
+
O
O
O
Cl
Cl
Cl
4'
4
5
c. HCl
H
O
N
CO2Me
C CH2N
Cl
OCN
NEt3
N
H2N
NH
CO2Me
H
Cl
• 2HCl
1a
2c
H
N
l
C
H
t
.
r
c
O
N
N
O
Cl
3e
Chart 2
Some new N(1)-methyl hydantoin analogues 9a—9c were also prepared from N-methyl-!!aminoalanine
methyl ester derivatives 7 as starting materials (see Chart 3).
Interestingly, compounds 9a—9c having an N(1)-methyl substituent in a hydantoin ring were unstable
even at rt in a commonly used organic solvent, such as CH2Cl2, AcOEt or DMSO, and gradually afforded
a corresponding 5-methylene derivative 108 with elimination of a secondary amine. This characteristic
chemical behavior of some N(1)-unsubstituted 5-dialkylaminomethylhydantoins has been observed
previously in some N(1)-unsubstituted hydantoins.5,6

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HETEROCYCLES, Vol. 87, No. 1, 2013
R1
R2
CO2Me
R1
R2
CO2H
R1
R2
CO2Me
R3NCO, NEt3
in CH2Cl2
R3 HNOCN C CH2N
MeHN C CH2N
MeHN C CH2N
H
H
H
Me
• 2HCl
7
8
6
Me
Me
R1
N
CH2
N
R1
R2
O
O
N
R2
+
HN
N
N
R3
O
O
R3
9a—9c
10
R1
Yielda)
[%]
R3
Compounds
N
R1
R2
Compounds
N
R2
9a:
N
N
Cl
32.2
6a, 7a:
N
9b:
9c:
35.3
25.8
6b, 7b:
N
N
a) The yields were based on the compound 7.
Chart 3
Among the compounds shown in Chart 3, it is expected that bulky 3-naphthyl-substituted
5-dialkylaminomethylhydantoin derivatives (3b and 9c) have two diastereomeric rotational isomers, since
restricted internal rotation of a bulky group in the molecules against the planarity of the 5-substituted
hydantoin ring system has been pointed out in a few derivatives.9,10 NMR data of our compounds (3b and
9c) in DMSO clearly showed the existence of two diastereomeric rotational isomers. The ratio of the two
isomers for the compound 3b was estimated to be ca. 1:1 [from the integration of C(5)-H signals
(4.97—4.99 ppm, 5.12—5.14 ppm) on the hydantoin ring]. Interestingly, compound 9c having
N(1)-methyl and C(5)-piperidinomethyl substituents showed the existence of two rotational isomers in a

HETEROCYCLES, Vol. 87, No. 1, 2013
137
ratio of 7:3 [by comparison of each integration of N(1)-methyl protons in the hydantoin ring] (see
Experimental). Structures of the two rotational isomers are shown in Figure 1. We speculate that the
represented rotational isomer 9c-A is a more stable conformer than 9c-B because the conformer 9c-B has
a more sterically hindered interaction between a bulky C(5)-substituent and a plane of the naphthalene
ring.
O
O
N
Me
N
N
N
Me
N
H
H
O
O
N
9c-A
9c-B
Figure 1
In connection with the synthesis of some identical twin-drug or triplet-drug type symmetrical molecules,11
a twin-drug type symmetrical hydantoin derivative 12 was also prepared for the purpose of comparison of
chemical and biological properties. Twin-drug type compound 12 could be obtained from double
cyclization of the corresponding urea intermediate 11 (see Chart 4). The symmetrical feature in solution
of this compound 12 is elucidated by the 13C-NMR spectrum, showing a magnetically equivalent
spectroscopic signal pattern12 (see Experimental).
CO2Me
O
N
NHCO NHCHCH2N
NH
O
N
rt
c. HCl,
HN
N
N
O
CO2Me
O
CHCH N
NHCONH
11
• 2HCl
2
12
Chart 4
Through these synthetic studies on hydantoin derivatives, we have established conventional procedures
for a few new types of 3-and 5-disubstituted hydantoin derivatives. Assays for antibacterial activity of the
prepared compounds by using gram-negative bacteria and gram-positive bacteria as target organisms are

138
HETEROCYCLES, Vol. 87, No. 1, 2013
now under investigation. Biological results for these compounds will be described in detail in a separate
paper.
EXPERIMENTAL
1
Melting points are uncorrected. IR spectra were measured by a Shimadzu FT/IR-8100 spectrometer. H-
and 13C-NMR spectra were obtained by a JEOL JNM A-500 at rt. The chemical shifts were expressed in !
ppm downfield from an internal tetramethylsilane (TMS) signal. The signal assignments were confirmed
1
1
1
by H - H two-dimensional (2D) correlation spectroscopy (COSY), H -13C heteronuclear multiple
1
quantum coherence (HMQC), and H -13C heteronuclear multiple-bond connectivity (HMBC) spectra.
High FAB-MS spectra were obtained by a JEOL JMS-HX110 mass spectrometer. The following
abbreviations in parentheses were used for pyrrolidine ring (Pyr), piperidine ring (Pip), 1-naphthyl ring
(Np) and hydantoin ring (Hyd).
Synthesis of 2-amino-3-(sec-amino)propanoic acid methyl esters (1a—b)
According to the procedure reported previously, esterification of !-aminoalanine13,14 (0.01 mol) with
methanolic hydrogen chloride (5—10%) (150 mL) gave the corresponding methyl ester (1a—b). The
obtained materials were used for the subsequent reaction stage without further purification.
3-(Biphenyl-4-yl)-5-(pyrrolidin-1-ylmethyl)imidazolidine-2,4-dione Hydrochloride (3a)
TEA (0.90 g, 8.9 mmol) was added to a suspension of methyl 2-amino-3-(pyrrolidin-1-yl)propanoic acid
methyl ester dihydrochloride 1a (1.0 g, 4.08 mmol) in toluene (10 mL) at 0 °C. After 5 min, a solution of
4-biphenylyl isocyanate (0.80 g, 4.10 mmol) in CH2Cl2 was added dropwise to the mixture and stirred for
4 h at rt. Water (25 mL) was added to the mixture and insoluble material was collected by filtration to
give 2-(3-biphenyl-4-ylureido)-3-(pyrrolidin-1-yl)propanoic acid 2a (1.02 g, 70.8%), mp 192 °C (dec). IR
(KBr) cm-1: 1691. HR-FAB-MS (positive) m/z: 354.1817. Calcd for C20H24N3O3: 354.1818. This urea
derivative 2a was used without further purification. Concentrated HCl (15 mL) was added to the urea
derivative (0.75 g, 2.12 mmol) and the mixture was allowed to stand 1 week at rt and then the precipitated
solid material was collected by filtration to give the crude compound (0.55 g, 69.8% from the
corresponding urea derivative). An analytical sample was obtained by recrystallization from EtOH/MeOH
as colorless feathers, mp 183—185 °C (with dec). IR (KBr) cm-1: 1779, 1717. FAB-MS (positive) m/z:
336 (M+H).+ 1H-NMR (DMSO-d6) ": 1.91�1.93 (each 2H, br, Pyr H-3, H-4), 3.10—3.11 (2H, br, Pyr H-2
x1, H-5 x 1), 3.67—3.71 (4H, br, CH2-Pyr and Pyr H-2 x1, H-5 x 1), 4.84—4.86 (1H, m, Hyd H-5),
7.39—7.51 (4H, m, Ar H), 7.69—7.80 (5H, m, Ar H), 8.78 (1H, s, Hyd H-1), 11.05 (1H, br, NH+).
13C-NMR (DMSO-d6) ": 22.5 (Pyr C-3 or C-4), 22.8 (Pyr C-4 or C-3), 53.5 (Pyr C-2 or C-5), 53.8 (Hyd
C-5), 54.1 (Pyr C-5 or C-2), 55.1 (CH2-Pyr), 126.8 x 2 (Ar C), 127.0 x 2 (Ar C), 127.0 (Ar C-4’), 127.7 x
2 (Ar C), 129.0 x 2 (Ar C), 131.1 (Ar C-1), 139.3 (Ar C-4), 139.8 (Ar C-1’), 155.3 (Hyd C-2), 170.1 (Hyd

HETEROCYCLES, Vol. 87, No. 1, 2013
139
C-4). Anal. Calcd for C20H22ClN3O2: C, 64.60; H, 5.96; N, 11.30. Found. C, 64.51; H, 5.98; N, 11.19.
Compound 3b ~ 3d were also obtained by a similar method described above.
3-(Naphthalen-1-yl)-5-(pyrrolidin-1-ylmethyl)imidazolidine-2,4-dione Hydrochloride (3b)
This compound was obtained from compound 1a in 22.7% yield as colorless crystals, mp 195 °C (dec).
The same proportion of two rotational isomers is indicated by 1H-NMR spectrum in DMSO-d6 at 34.6 °C.
IR (KBr) cm-1: 1793, 1725. FAB-MS (positive) m/z: 310 (M+H).+ 1H-NMR (DMSO-d6) !: 1.90—1.96
(4H, m, Pyr H-3, H-4), 3.14—3.17 (2H, br, Pyr H-2, H-5), 3.69—3.94 (4H, m, CH2-Pyr and Pyr H-2,
H-5), 4.97—4.99 (0.5H, m, Hyd H-5), 5.12—5.14 (0.5H, m, Hyd H-5), 7.53—7.65 (4H, m Np H),
7.73—7.74 (0.5H, m, Np H), 7.84—7.86 (0.5H, m, Np H), 8.04—8.08 (2H, m, Np H), 8.85 (0.5H, br s,
13
Hyd H-1), 8.89 (0.5H, br s, Hyd H-1), 11.28—11.31 (1H, m, NH+). C-NMR (DMSO-d6) ": 22.5, (Pyr
C-3, C-4), 22.7 (Pyr C-3, C-4), 53.2, 54.0 (CH2-Pyr), 54.1 and 54.5 (Hyd C-5), 55.1 (Pyr C-2, C-5), 55.6
(Pyr C-2, C-5), 122.4, 122.6, 125.4, 125.5, 126.5 (x 2), 126.9 (x 2), 127.0, 127.1, 128.1, 128.2, 129.4 (x
2) (Np C), 129.6 (x 2) (Np C-8’), 129.7 (x 2) (Np C-4’), 133.6 (x 2) (Np C-1), 155.4 and 155.7 (Hyd C-2),
170.5 and 170.6 (Hyd C-4). Anal. Calcd for C18H20ClN3O2 • 0.3 H2O: C, 61.55; H, 5.91; N, 11.96. Found.
C, 61.51; H, 5.80; N, 11.91.
3-(Biphenyl-4-yl)-5-(piperidin-1-ylmethyl)imidazolidine-2,4-dione Hydrochloride (3c)
This compound was obtained from compound 1b in 86.0% yield as colorless crystals, mp >215 °C (dec).
IR (KBr) cm-1: 1781, 1718. FAB-MS (positive) m/z: 350 (M+H).+ 1H-NMR (DMSO-d6) !: 1.38—1.41
(1H, m, Pip H-4), 1.72—1.75 (1H, m, Pip H-4), 1.81—1.91 (4H, m, Pip H-3, H-5), 2.98—3.07 (2H, m,
Pip H-2 H-6), 3.45—3.48 (1H, m, Pip H-2 or H-6), 3.55—3.56 (2H, m CH2-Pip), 3.66—3.68 (1H, m, Pip
H-6 or H-2), 4.97—4.99 (1H, m, Hyd H-5), 7.38—7.42 (1H, m, Ar H), 7.46—7.51 (4H, m, Ar H),
7.70—7.72 (2H, m, Ar H), 7.77—7.80 (2H, m, Ar H), 8.90 (1H, s, Hyd H-1), 10.76 (1H, br s, NH+).
13C-NMR (DMSO-d6) ": 21.1 (Pip C-4), 22.2 (Pip C-3 or C-5), 22.3 (Pip C-5 or C-3), 51.9 (Pip C-2 or
C-6), 52.3 (Hyd C-5), 53.6 (Pip C-6 or C-2), 58.1 (CH2-Pip), 126.8 (x 2) (Ar C), 127.0 (x 4) (Ar C), 127.7
(Ar C-4’), 129.0 (x 2) (Ar C), 131.1 (Ar C-1), 139.3 (Ar C-4), 139.8 (Ar C-1’), 155.1 (Hyd C-2), 170.2
(Hyd C-4). Anal. Calcd for C21H24ClN3O2: C, 65.36; H, 6.27; N, 10.89. Found. C, 65.22; H, 6.30; N,
10.87.
3-(2-Chloroethyl)-5-(pyrrolidin-1-ylmethyl)imidazolidine-2,4-dione Hydrochloride (3d)
This compound was obtained from compound 1b in 74.4% yield as a white solid, mp 176—182 °C
(EtOH/H+). IR (KBr) cm-1: 1786, 1714. FAB-MS (positive) m/z: 260 (M+H).+ 1H-NMR (DMSO-d6) !:
1.35—1.38 (1H, m, Pip H-4), 1.70—1.86 (5H, m, Pip H-3 x 2, Pip H-4, Pip H-5 x 2), 2.92—3.02 (2H, m,
Pip H-2 x 1, H-6 x 1), 3.30—3.32 (1H, m, CHH-Pip), 3.43—3.47 (2H, m, CHH-Pip + Pip H-2 x 1 or H-6
x 1), 3.55—3.58 (1H, m, Pip H-6 x 1 or H-2 x 1), 3.62—3.79 (4H, m, CH2CH2Cl), 4.88—4.89 (1H, d, J =
9.0 Hz, Hyd H-5), 8.73 (1H, s, Hyd H-1), 10.76 (1H, br s, NH+). 13C-NMR (DMSO-d6) !: 21.1 (Pip C-4),

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HETEROCYCLES, Vol. 87, No. 1, 2013
22.1, 22.3 (Pip C-3, C-5), 39.8 (CH2CH2Cl), 40.9 (CH2CH2Cl), 51.7 (Pip C-2 or C-6), 52.1 (Hyd C-5),
53.4 (Pip C-6 or C-2), 58.0 (CH2-Pip), 155.7 (Hyd C-2), 171.0 (Hyd C-4). Anal. Calcd for
C11H19Cl2N3O2: C, 44.61; H, 6.47; N, 14.19. Found. C, 44.39; H, 6.41; N, 14.21.
3-(2-Chloroethyl)-5-(pyrrolidin-1-ylmethyl)imidazolidine-2,4-dione Hydrochloride (3e)
This compound was obtained from compound 1a in 21.2% yield as a white solid, mp 160—165 °C. IR
(KBr) cm-1: 1784, 1713. FAB-MS (positive) m/z: 246 (M+H).+ 1H-NMR (DMSO-d6) !: 1.90—2.02 (4H,
m, Pyr H-3, H-4), 3.05 (2H, br, Pyr H-2 x 1, H-5 x 1), 3.42—3.46 (1H, m, CHH-Pyr), 3.57—3.68 (3H, m,
CHH-Pyr, Pyr H-2 x 1, and H-5 x 1), 3.70—3.73 (2H, m, CH2CH2Cl), 3.77—3.80 (2H, m, CH2CH2Cl),
4.72 (1H, d, J = 8.0 Hz, Hyd H-5), 8.57 (1H, s, Hyd H-1), 11.02 (1H, br s, NH+). 13C-NMR (DMSO-d6) !:
22.4 (Pyr C-3 or C-4), 22.6 (Pyr C-4 or C-3), 39.8 (CH2CH2Cl), 40.8 (CH2CH2Cl), 53.3 (Pyr C-2 or C-5),
53.6 (Hyd C-5), 54.0 (Pyr C-5 or C-2), 55.1 (CH2-Pyr), 155.8 (Hyd C-2), 170.8 (Hyd C-4). Anal. Calcd
for C10H17Cl2N3O2: C, 42.57; H, 6.07; N, 14.89. Found. C, 42.46; H, 6.04; N, 14.60.
[Preparation of compounds 4 and 5]
A solution of 2-chloroethyl isocyanate (0.22 g, 2.09 mmol) in CH2Cl2 was added to a solution of
compound 1a (0.50 g, 2.04 mmol) and TEA (0.41 g, 4.06 mmol) in CH2Cl2 (10 mL). The mixture was
stirred for 1 h at rt and concentrated in vacuo. Concentrated HCl (4 mL) and water (1 mL) were added to
the residue and the mixture was allowed to stand for 16 h at rt and subsequently heated for 6 min (100 °C).
After removal of the solvent, the residue was dissolved in water and the resulting solution was made
alkaline (ca. pH = 11) with K2CO3. The resulting mixture was extracted with AcOEt and the extract was
washed with brine, dried over Na2SO4, and concentrated in vacuo to give a mixture of compounds 4 and 5.
Separation by centrifugal silica gel chromatography using AcOEt as a solvent gave the two compounds 4
(0.180 g, 50.7%) and 5 (0.043 g, 8.6%) as a white solid. The data for compounds 4 and 5 are shown
below.
3-(2-Chloroethyl)-5-methyleneimidazolidine-2,4-dione (4)
Mp 107—109 °C. IR (KBr) cm-1: 1781, 1725, 1699. FAB-MS (positive) m/z: 175 (M+H).+ 1H-NMR
(DMSO-d6) !: 3.77—3.80 (4H, m, CH2CH2Cl), 4.87 (1H, s, = CHH), 4.88 (1H, s, = CHH), 10.63 (1H, br
13
s, Hyd H-1). C-NMR (DMSO-d6) !: 39.6 (CH2CH2Cl), 41.1 (CH2CH2Cl), 94.7 (=CH2), 134.9 (Hyd
C-5), 153.7 (Hyd C-2), 162.7 (Hyd C-4). HR-FAB-MS (positive) m/z: 175.0272 (Calcd for C6H8ClN2O2:
175.0274).
3-(2-Chloroethyl)-5-(pyrrolidin-1-ylmethyl)imidazolidine-2,4-dione (5)
Mp 103—104 °C. IR (KBr) cm-1: 1787, 1727, 1712. FAB-MS (positive) m/z: 246 (M+H).+ 1H-NMR
(DMSO-d6) !: 1.45 (3H, s, CH3), 1.67 (4H, s, Pyr H-3, H-4), 2.47—2.51 (2H, m, Pyr H-2 x 1, H-5 x 1),
2.62—2.66 (2H, m, Pyr H-2 x 1, H-5 x 1), 3.69—3.72 (2H, m, CH2CH2Cl), 3.78—3.81 (2H, m,
CH2CH2Cl), 8.55 (1H, br s, Hyd H-1). 13C-NMR (DMSO-d6) !: 23.19 (CH3), 23.22 (Pyr C-3, C-4), 39.3

HETEROCYCLES, Vol. 87, No. 1, 2013
141
(CH2CH2Cl), 41.3 (CH2CH2Cl), 45.3 (Pyr C-2, C-5), 75.2 (Hyd C-5), 155.1 (Hyd C-2), 173.9 (Hyd C-4).
Anal. Calcd for C10H16ClN3O2 • 0.2 H2O: C, 48.18; H, 6.63; N, 16.85. Found. C, 48.14; H, 6.45; N,
16.94.
[Preparation of 2-(methylamino)-3-(pyrrolidin-1-yl)propanoic acid (6a)]
Preparation of diethyl 2-(benzyl(methyl)amino)propanedioate. To a solution of diethyl
bromomalonate (0.105 mol) in 40 mL of absolute EtOH was added dropwise methylbenzylamine (0.209
mol). The mixture was refluxed for 1 h, and the solvent was evaporated under reduced pressure. Et2O was
added to the residue and insoluble material was filtered off. The obtained organic layer was washed with
brine and dried over anhydrous Mg2SO4. After concentration of the solvent, the residue was purified with
an aluminum oxide column using AcOEt-n-hexane-Et2O (1:4:5) as a solvent to give diethyl
1
2-(benzyl(methyl)amino)propanedioate as a colorless oil (98.2%). H-NMR (CDCl3) ": 1.30 (6H, t, J =
7.0 Hz, CH2CH3 x 2), 2.46 (3H, s, NCH3), 3.82 (2H, s, NCH2Ph), 4.16 (1H, s, CHCOOCH2CH3), 4.25
(4H, q, J = 7.0 Hz, CH2CH3 x 2), 7.22—7.39 (5H, m, Ar H).
Preparation
of
diethyl
2-(methylamino)propanedioate.
A
solution
of
diethyl
2-(benzyl(methyl)amino)propanedioate (30 g, 0.108 mol) in EtOH (200 mL) was rapidly stirred under
2~3 atmospheric pressure of hydrogen in the presence of 5% Pd-C (12 g). After absorption of hydrogen
ceased, the catalyst was removed by filtration through Celite 545. The filtrate was evaporated to dryness
under reduced pressure. The residue was purified with an aluminum oxide column using n-hexane-Et2O
(1:4:5) as a solvent to give diethyl 2-(methylamino)propanedioate as a colorless oil (17.5 g, 86.1%). The
product gave a single spot on TLC analysis.1H-NMR (DMSO-d6) ": 1.29 (6H, t, J = 7.0 Hz, CH2CH3 x 2),
2.17 (1H, br, NH), 2.45 (3H, s, NCH3), 3.94 (1H, s, CHCOOCH2CH3), 4.25 (4H, q, J = 7.0 Hz, CH2CH3 x
2). HR-FAB-MS (positive) m/z: 190.1071 (Calcd for C7H15NO4: 190.1079).
Preparation of compound 6a. Diethyl 2-(methylamino)propanedioate (34.3 g, 0.181 mol) was added to
a mixture of pyrrolidine (14.1 g, 0.199 mol) and formaldehyde (37%) (16.2 g, 0.200 mol), and the
resulting mixture was stirred at rt for 10 min and then heated in a water bath for a few min. Concentrated
HCl (500 mL) was added to the reaction mixture under cooling and then the mixture was allowed to stand
at rt for 1 month. The resulting mixture was heated at 90 °C in a water bath for 1 h and concentrated in
vacuo. The oily residue was passed through a column packed with ion-exchanged resin (AG 11A8®, Bio
Rad Laboratories) in order to obtain free amino acid. The obtained precipitate was purified with a silica
gel column using (EtOH-NH3 (28% aq) =97/3) as a solvent to give a crude crystalline product. Washing
the crystalline product with EtOH gave 6a (11.98 g, 38.4%). An analytical sample could be obtained by
recrystallization from EtOH as colorless crystals, mp >218 °C (dec). IR (KBr) cm-1: 3453, 2876, 2838,
2778, 1582. FAB-MS m/z: 173 (M+H+). 1H-NMR (D2O) ": 2.00—2.03(4H, m, Pyr H-3, H-4), 2.44 (3H, s,
NCH3), 3.18—3.28 (6H, m, Pyr H-2, H-5 and CH2-Pyr), 3.37 (1H, dd, J = 7.5, 6.5 Hz, CHCOOH).

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13C-NMR (D2O) ": 25.6 (Pyr C-3, C-4), 35.9 (NCH3), 57.3 (Pyr C-2, C-5), 58.9 (CH2-Pyr), 64.2
(CHCOOH), 180.0 (COOH). Anal. Calcd for C8H16N2O2: C, 55.79; H, 9.36; N, 16.27. Found: C, 55.73;
H, 9.08; N, 16.14.
In a similar fashion, compound 6b was also obtained. The data for N-methyl !-aminoalanines 6b is
shown below.
2-(Methylamino)-3-(piperidin-1-yl)propanoic acid (6b)
The yield from diethyl 2-(methylamino)propanedioate was 30.4%. The analytical sample was obtained by
recrystallization from EtOH as colorless crystals, mp >194 °C (dec). IR (KBr) cm-1: 2824, 1648, 1604.
FAB-MS m/z: 187 (M+H+). 1H-NMR (D2O) ": 1.56—1.61 (2H, m, Pip H-4), 1.73—1.78 (4H, m, Pip H-3,
H-5), 2.49 (3H, s, NCH3), 2.95—3.07 (5H. m, CHH-Pip and Pip H-2, H-5), 3.09 (1H, dd, J = 13.5, 6.0 Hz,
13
CHH-Pip), 3.49 (1H, dd, J = 8.0, 6.0 Hz, CHCOOH). C-NMR (D2O) ": 24.7 (Pip C-4), 26.4 (Pip C-3,
C-5), 35.8 (NCH3), 56.7 (Pip C-2, C-6), 60.5 (CH2-Pip), 62.8 (CHCOOH), 178.7 (COOH). Anal. Calcd
for C9H18N2O2: C, 58.04; H, 9.74; N, 15.04. Found: C, 58.00; H, 9.85; N, 14.89.
Preparation of 2-(methylamino)-3-(pyrrolidin-1-yl)propanoic acid methyl esters: 7a—b
Methanolic hydrogen chloride (5—10%) (150 mL) was added to a solution of compounds 6a—b (0.01
mol) in anhydrous MeOH, and the mixture was kept for 3 d at rt under anhydrous conditions and then
evaporated to dryness in vacuo. After treatment with methanolic hydrogen chloride three times, the
residue was used for the subsequent reaction step without further purification.
3-(4-Chlorophenyl)-1-methyl-5-(pyrrolidin-1-ylmethyl)imidazolidine-2,4-dione (9a)
A solution of p-chlorophenyl isocyanate (0.31 g, 2.02 mmol) in CH2Cl2 was added to a solution of
N-methyl amino acid methyl ester dihydrochloride 7a (0.50 g, 1.93 mmol) and TEA (0.82 g, 8.12 mmol)
in CH2Cl2, and the reaction mixture was stirred for 1 h at rt. The mixture was washed with water, dried
over Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column with AcOEt as a
solvent to give compound 9a as a white solid (0.19 g, 32.2%), mp 93—95 °C. IR (KBr) cm-1: 1777, 1716.
FAB-MS (positive) m/z: 308 (M+H).+ 1H-NMR (DMSO-d6) ": 1.63—1.69 (4H, m, Pyr H-3, H-4),
2.45—2.51 (2H, br, Pyr H-2 x 1, H-5 x 1), 2.54—2.59 (2H, br, Pyr H-2 x 1, H-5 x 1), 2.94—2.98 (1H, m,
CHH-Pyr), 2.97 (3H, s, NCH3), 3.01—3.05 (1H, m, CHH-Pyr), 4.24 (1H, dd, J = 4.5, 3.5 Hz, Hyd-H-5),
13
7.35—7.47 (2H, m, Ar H-2, H-6), 7.53—7.57 (2H, m, Ar H-3, H-5). C-NMR (DMSO-d6) ": 23.4 (Pyr
C-3, C-4), 27.9 (NCH3), 53.8 (CH2-Pyr), 54.4 (Pyr C-2, C-5), 61.1 (Hyd C-5), 127.8 x 2 (Ar C-2, C-6),
128.8 x 2 (Ar C-3, C-5), 131.1 (Ar C-4), 132.0 (Ar C-1), 154.8 (Hyd C-2), 171.0 (Hyd C-4). Anal. Calcd
for C15H18ClN3O2: C, 58.54; H, 5.89; N, 13.65. Found. C, 58.44; H, 5.90; N, 13.50.
3-(Biphenyl-4-yl)-1-methyl-5-(pyrrolidin-1-ylmethyl)imidazolidine-2,4-dione (9b)
Compound 9b was prepared in a manner similar to that for 9a in 35.3% yield as a white solid, mp
108—110 °C. IR (KBr) cm-1: 1779, 1708. FAB-MS (positive) m/z: 350 (M+H).+ 1H-NMR (DMSO-d6) ":

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1.65—1.70 (4H, m, Pyr H-3, H-4), 2.47—2.61 (4H, m, Pyr H-2, H-5), 2.99 (3H, s, NCH3), 2.97—3.07
(2H, m, CH2-Pyr), 4.25—4.27 (1H, m, Hyd H-5), 7.37—7.42 (3H, m, Ar H), 7.47—7.52 (2H, m, Ar H),
7.68—7.72 (2H, m, Ar H), 7.75—7.79 (2H, m, Ar H). 13C-NMR (DMSO-d6) !: 23.4 (Pyr C-3, C-4), 27.9
(NCH3), 53.8 (CH2-Pyr), 54.4 (Pyr C-2, C-5), 61.0 (Hyd C-5), 126.6, 126.7 x 2 (Ar C), 126.9, 127.0 (Ar
C), 127.6 (Ar C-4’), 127.7, 128.9 x 2 (Ar C), 131.6 (Ar C-1), 139.3 (Ar C-4), 139.5 (Ar C-1’), 155.1 (Hyd
C-2), 171.2 (Hyd C-4). Anal. Calcd for C21H23N3O2: C, 72.18; H, 6.63; N, 12.03. Found. C, 71.90; H,
6.61; N, 11.64.
1-Methyl-3-(naphthalen-1-yl)-5-(piperidin-1-ylmethyl)imidazolidine-2,4-dione (9c)
This compound was obtained from the reaction of 1-naphthyl isocyanate and compound 7b by a method
similar to that for 9a in 25.8% yield as a white solid, mp 159—160 °C. A ratio of the two rotational
isomers (majorꢀminor) of 7:3 was indicated by the 1H-NMR spectrum in DMSO-d6 at 34.6 °C. IR (KBr)
cm-1: 1774, 1714. FAB-MS (positive) m/z: 338 (M+H).+ 1H-NMR (DMSO-d6) !: 1.39—1.46 (2H, m, Pip
H-4), 1.51—1.60 (4H, m, Pip H-3, Pip H-5), 2.40—2.59 (4H, m, Pip H-2, H-6), 2.86—2.93 (2H, m,
CH2-Pip), 3.01 (3H x 0.7, s, NCH3 for major rotational isomer), 3.04 (3H x 0.3, s, NCH3 for minor
rotational isomer), 4.30 —4.31 (1H x 0.7, m, Hyd H-5 for major rotational isomer), 4.47—4.48 (1H x 0.3,
m, Hyd H-5 for minor rotational isomer), 7.37 (1H x 0.3, d, J = 6.5 Hz, Np H for minor rotational isomer),
7.47 (1H x 0.7, dd J = 7.0, 1.0 Hz, Np H for major rotational isomer), 7.52—7.64 (3H, m, Np H for major
and minor rotational isomers), 7.80 (1H x 0.3, d, J = 8.0 Hz, Np H for minor rotational isomer), 8.00 (1H
x 0.7, d, J = 8.5 Hz, Np H for major rotational isomer), 8.03—8.09 (2H, m, Np H for major and minor
13
rotational isomers). C-NMR (DMSO-d6) !: 23.5 (Pip C-4), 25.7 (Pip C-3, C-5), 28.3 (NCH3), 54.9
(CH2-Pip), 55.8 (Pip C-6, C-2), 62.4 (Hyd C-5), 128.9 (Np C-8’), 129.9 (Np C-4’), 133.7 (Np C-1), 155.9
(Hyd C-2), 171.7 (Hyd C-4). These signals are ascribable to the major rotational isomer. !: 23.6 (Pip C-4),
25.9 (Pip C-3, C-5), 28.5 (NCH3), 55.8 (Pip C-6, C-2), 57.1 (CH2-Pip), 60.6 (Hyd C-5), 129.0 (Np C-8’),
130.0 (Np C-4’), 133.7 (Np C-1), 155.7 (Hyd C-2), 172.0 (Hyd C-4). These signals are ascribable to the
minor rotational isomer. !: 122.9, 123.1, 125.5 (x 2), 126.4, 126.5 (x 2), 126.7, 127.0, 128.1 (x 2), 129.1
(x 2), 129.2 (Np C). These signals are for both rotational isomers. Anal. Calcd for C20H23N3O2: C, 71.19;
H, 6.87; N, 12.45. Found. C, 71.05; H, 6.95; N, 12.17.
3,3'-(4,4'-Methylenebis(4,1-phenylene))bis(5-(piperidin-1-ylmethyl)imidazolidine-2,4-dione)
Dihydrochloride (12)
A solution of 3,4'-methylenebis(isocyanatobenzene) (0.22 g, 0.88 mmol) in CH2Cl2 was added to a
solution of compound 1b (0.50 g, 1.93 mmol) and TEA (0.39 g, 3.86 mmol) in CH2Cl2 (10 mL). The
mixture was stirred for 1 h at rt and washed with water, dried over Na2SO4, and concentrated in vacuo to
give diurea derivative 11 (0.41 g, 65.1%), mp 119 °C (dec). IR (KBr) cm-1: 3338, 1744, 1652.
HR-FAB-MS (positive) m/z: 623.3558. Calcd for C3H47N6O6: 623.3557. Concentrated HCl (3 mL) was

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added to this urea intermediate (0.38 g, 0.61 mmol) and the mixture was allowed to stand for 8 d at rt and
then the solvent was removed under reduced pressure to give compound 12 as a white solid (0.40 g,
97.6% from compound 11). This product was very hygroscopic, mp 178—180 °C. IR (KBr) cm-1: 1782,
1719. FAB-MS (positive) m/z: 559 (M+H).+ 1H-NMR (DMSO-d6) ": 1.36—1.39 (2H, m, Pip H-4),
1.71—1.82 (2H, m, Pip H-4), 1.85—1.91 (8H, m, Pip H-3 x 4, H-5 x 4), 2.95—3.05 (4H, m, Pip H-2 x 2,
H-6 x 2), 3.43—3.53 (6H, m, CHH-Pip x 2, Pip H-2 x 2, and Pip H-6 x 2), 3.64—3.67 ( 2H, m CHH-Pip
x 2), 4.04 (2H, s, Ph-CH2-Ph), 4.95—4.97 (2H, m, Hyd H-5 x 2), 7.28—7.37 (8H, m, Ar H), 8.86 ( 2H, s,
Hyd H-1 x 2), 10.86 (2H, br s, NH+ x 2). 13C-NMR (DMSO-d6) ": 21.1(Pp C-4), 22.1, (Pip C-3 or C-5),
22.3 (Pip C-5 or C-3), 40.1 (Ph-CH2-Ph), 51.8 (Pip C-2 or C-6), 52.2 (Hyd C-5), 53.6 (Pip C-6 or C-2),
58.1 (CH2-Pip), 126.7 (Ar C-2, C-2’, C-6, C-6’), 129.0 (Ar C-3, C-3’, C-5, C-5’), 129.9 (Ar C-, C-1’),
140.9 (Ar C 4, C-4’), 155.1 (Hyd C-2), 170.1 (Hyd C-4). Anal. Calcd for C31H40Cl2N6O4 • 2.3H2O: C,
55.32; H, 6.68; N, 12.49. Found. C, 55.32; H, 6.74; N, 12.22.
REFERENCES AND NOTES
1. A. P. Davis, Org. Biomol. Chem., 2009, 7, 3629.
2. J. B. Locke, J. Finn, M. Hilgers, G. Morales, S. Rahawi, G. C. Kedar, J. J. Picazo, W. Im, K. J. Shaw,
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Fu, B. Plunkett, S.-N. Su, S. Vieths, R. T. Lee, Y. C. Lee, and S.-K. Huang, J. Biol. Chem., 2010,
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4. A. Varki, R. D. Cummings, J. D. Esko, H. H. Freeze, P. Stanley, C. R. Bertozzi, G. W. Hart, and M.
E. Etzler, ‘Essentials of Glycobiology’ 2nd ed. Cold Spring Harbor Laboratory Press, Cold Spring
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6. F. Fujisaki, K. Shoji, and K. Sumoto, Chem. Pharm. Bull., 2009, 57, 1415.
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2010, 58, 1123.
1
8. For example, in the H-NMR spectrum of compound 9b, characteristic methylene signals were
observed at 5.10 (d, J = 2.5 Hz) and 5.37 (d, J = 2.5 Hz) ppm, indicating the corresponding
hydantoin derivative 10.
9. L. D. Colebrook, Can. J. Chem., 1991, 69, 1957.
10. R. Benassi, A. Bregulla, D. Henning, M. Heydenreich, G. Kempter, E. Kleinpeter, and F. Taddei, J.
Mol. Struct., 1999, 475, 105.
11. F. Fujisaki, H. Usami, S. Nakashima, S. Iwashita, Y. Kurose, N. Kashige, F. Miake, and K. Sumoto,

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Heterocycles, 2011, 83, 1843.
12. The cyclization of compound 11 to hydantoin derivative 12 is not stereoselective ring closure, and
the obtained compound 12 can therefore be considered to be a mixture of a meso compound and two
enatiomeric C2-symmetrical molecules that have the same absolute configuration regarding two C(5)
chiral carbons in two hydantoin rings in the molecule 12. With reference to this stereochemistry of
the product 12, we have no experimental data to prove the product to be a mixture of three
stereoisomeric forms.
13. N. Abe, F. Fujisaki, and K. Sumoto, Chem. Pharm. Bull., 1998, 46, 142.
14. F. Fujisaki, N. Abe, and K. Sumoto, Chem. Pharm. Bull., 2002, 50, 129.