Preparation and chemical properties of 5-dialkylaminomethylhydantoins and 2-thio-analogues

Article abstract of DOI:10.1248/cpb.57.1415

An efficient procedure for the preparation of 5- dialkylaminomethylhydantoins 3, which are easily obtained from cyclization of the corresponding urea derivatives 2 starting with β-aminoalanines 1, is described. Methylenehydantoin and the corresponding 2-t

Full text of DOI:10.1248/cpb.57.1415

December 2009
Notes
Chem. Pharm. Bull. 57(12) 1415—1420 (2009)
1415
Preparation and Chemical Properties of 5-Dialkylaminomethylhydantoins
and 2-Thio-Analogues
Fumiko FUJISAKI, Kaori SHOJI, and Kunihiro SUMOTO*
Faculty of Pharmaceutical Science, Fukuoka University; Nanakuma, Jonan-ku, Fukuoka 814–0180, Japan.
Received July 16, 2009; accepted September 30, 2009
An efficient procedure for the preparation of 5-dialkylaminomethylhydantoins 3, which are easily obtained
from cyclization of the corresponding urea derivatives 2 starting with b-aminoalanines 1, is described. Methyl-
enehydantoin and the corresponding 2-thio analogue (4a, 4b) were obtained from hydantoins 3a and 3b, respec-
tively. Some new chemical properties of these hydantoin derivatives are reported.
Key words hydantoin; methylenehydantoin; b-aminoalanine; dimerization; elimination
Much interest has been shown in hydantoins and related 5.35 ppm) are observed, and a remarkable signal for 13C reso-
compounds from synthetic and biological points of view.1—6) nance (d 97.6 ppm) of an exo-methylene carbon (ꢁCꢀCH2)
In connection with our studies on synthetic applications of a is also confirmed by the 13C-NMR spectrum. We observed
new type of amino acid b-aminoalanines 17—10) and our that this deamination of 2-thiohydantoin 3b to give 5-methyl-
search for biologically active compounds, we have already ene-2-thiohydantoin 4b proceeded more easily than that of
reported that the compounds 1 are useful starting materials to corresponding hydantoin (3a→4a)7) through the above NMR
prepare 5-dialkylaminomethylhydantoins (3: XꢀO, YꢀCH) experiments. 5-Methylene-2-thiohydantoin analogue 4b
via cyclization of corresponding urea derivatives 2, which are could be isolated in good yield (76%, see Experimental).
easily prepared by the addition of a primary amino group in Throughout our repeated trials for the isolation of compound
compounds 1 to aryl isocyanates.7) We carried out further 4b, we found that 5-methylene-2-thiohydantoin is not a sta-
preparation of new analogues of 5-dialkylaminomethylhy- ble species at elevated temperatures (over 80 °C in solution),
dantoins and 2-thio-analogues. In this paper, we report the giving unknown polymerized products. Methylenehydantoin
synthesis of these new derivatives 3 and the chemical proper- 4a or the 2-thio-analogue 4b (by retro-Michael addition of 3a
ties observed in the synthesized compounds.
or 3b) is formed probably via a 6-membered tautomeric in-
The desired compounds 3 were obtained in good yields by termediacy state (A) (shown in Chart 2).
1
cyclization of the corresponding urea derivatives 2 prepared
In H-NMR spectra of 5-methylene-2-thiohydantoin 4b,
by condensation of aryl(thio)isocyanates with b-aminoala- the N–H proton of the hydantoin ring was easily deuterated
nines 1 (Chart 1). Since purification of the intermediates urea by treatment with D2O. Interestingly, two 5-methylene pro-
derivatives (2b and 2h—j) was difficult, compound 3b and tons were further deuterated smoothly at room temperature.
the 2-thio-analogues 3h—j were prepared by a “one-pot” This result obviously indicates that 5-methylene-2-thiohy-
procedure (1→3) without further purification of the corre- dantoin 4b exists in an equilibrium state through keto-enol
sponding intermediate urea derivatives. The results of the re- tautomerism of a thioamido functionality conjugated with a
→
action stages (1→2 and 2→3) are summarized in Tables 1 5-methylene group in the 2-thiohydantoin ring (4b-I 4b-
←
→
→
and 2, respectively. The structures of these new products II 4b-III 4b-IV) (see Chart 3).
←
←
were established by spectroscopic and elemental analyses.
All of the assignments were confirmed by two-dimensional many constituted tautomers that are in equilibrium with each
(2D) -NMR spectroscopic analysis. other and that differ in the location of hydrogen atoms and
The 5-dialkylaminomethylhydantoin system 3 may exist as
By treatment with a large excess amount of H2O, deamina- double bonds. Because of the contribution of these tau-
tion (elimination of dialkylamines 5) of 2-thiohydantoin de- tomeric isomers, compounds 3 show a variety of chemical
rivative 3b took place to give 5-methylene-2-thiohydantoin behaviors depending on the reaction conditions (summarized
1
4b (Chart 2). This behavior was easily confirmed by H- in Chart 4).
1
NMR spectroscopic analysis. Thus, by H-NMR (in DMSO)
Thus, in the case of 3a, the fact that treatment with a large
monitoring, easily detectable and characteristic signals for excess amount of methylamine in MeOH gave 5-methyl-5-
two 5-methylene protons in the compound 4b (d 5.18, and methylamino hydantoin derivative 6 (9%) also supports the
Chart 1
© 2009 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: kunihiro@adm.fukuoka-u.ac.jp

1416
Vol. 57, No. 12
above tautomerism (shown in Chart 3). In this reaction, N- tion to the b-substituted ring-opened urea derivative 8 (Chart
phenylurea 711) was also isolated (8%) together with recovery 6) represented as the general structure 2ꢂ shown in Chart 4
of the starting material 3a (49%) (Chart 5). The formation of (see Experimental). This fact apparently indicates the contri-
N-phenylurea 7 may be ascribable to the hydrolysis of a tau- bution of a tautomeric isomer E and formation of 4 in equi-
tomeric form E shown in Chart 4.
In contrast, by treatment of hydantoin 3a with methyl-
librium.
The fragment b-amino-a-ketoaldehyde such as 9 shown in
amine in water, we also obtained N-phenylurea 7 by scission brackets in Chart 4 could not be isolated in our repeated tri-
of the original amino acid C–N bond in 25% yield in addi- als for isolation. This a-ketoaldehyde 9 is probably an unsta-
ble reactive material that gives unknown polymerized com-
pounds. The formation stages of the ring-opened urea deriva-
tive 8 arising from two subsequent pathways [via path b from
a precursor 4 or path a from a tautomeric form G of methyl-
Chart 2
Chart 3
Chart 4

December 2009
1417
spectroscopic data have already been reported in our previous paper.10)
General Procedure for Urea Derivatives (2) These compounds were
prepared from b-aminoalanines 1 and phenyl isocyanates or phenyl isothio-
cyanates according to the procedure reported previously.7) The preparations
of 2b and 2h—j were carried out at elevated temperatures (ca. 50 °C).
New urea derivatives 2 prepared in this study are shown in Table 1. IR,
FAB-MS, and elemental analysis are also shown in Table 1. Synthesis of 2-
(3-phenylureido)-3-thiomorpholinopropanoic acid 2a has already been re-
ported.7)
Chart 5
2-(3-Phenylthioureido)-3-thiomorpholinopropanoic Acid (2b): 1H-NMR
(DMSO-d6) d: 2.57—2.87 (10H, m, Thi-H and CH2Nꢀ), 3.00—4.50 (1H,
br, COOH), 4.89 (1H, br, CHCH2), 7.10—7.14 (1H, m, Ar H-4), 7.31—7.35
(2H, m, Ar H-3, H-5), 7.49—7.51 (2H, m, Ar H-2, H-6), 7.81—7.82 (1H,
br, Ar–NHCSNH), 10.01 (1H, br, Ar–NHCSNH). 13C-NMR (DMSO-d6) d:
26.7 (Thi C-2, C-6), 54.4 (Thi C-3, C-5) 54.7 (CHCH2Nꢀ), 58.3 (CH2Nꢀ),
122.8 (Ar C-4), 124.2 (Ar C-2, C-6), 128.3 (Ar C-3, C-5), 139.1 (Ar C-1),
172.6 (COOH), 180.0 (CꢀS).
Chart 6
3-(Dimethylamino)-2-(3-phenylureido)propanoic Acid (2c): 1H-NMR
(D2O) d: 2.97 (6H, s, N(CH3)2), 3.40 (1H, dd, Jꢀ13.0, 8.5 Hz, CHHNꢀ),
3.54 (1H, dd, Jꢀ13.0, 6.0 Hz, CHHNꢀ), 4.52—4.55 (1H, m, CHCH2),
7.18—7.21 (1H, m, Ar–H), 7.35—7.43 (4H, m, Ar–H). 13C-NMR (D2O) d:
46.2 (N(CH3)2), 53.4 (CHCH2), 62.5 (CH2Nꢀ), 124.1 (Ar C-2, C-6), 127.1
(Ar C-4), 132.1 (Ar C-3, C-5), 140.7 (Ar C-1), 160.4 (NHCONH), 177.7
(COOH).
2-{3-(4-Chlorophenyl)ureido}-3-(dimethylamino)propanoic Acid (2d):
1H-NMR (DMSO-d6) d: 2.66 (6H, s, N(CH3)2), 2.89—2.93 (1H, m,
CHHNꢀ), 3.12—3.16 (1H, m, CHHNꢀ), 3.5—5.0 (1H, br, COOH), 4.06—
4.08 (1H, m, CHCH2), 6.61—6.62 (1H, m, Ar–NHCONH), 7.24—7.26 (2H,
m, Ar H-3, H-5), 7.44—7.46 (2H, m, Ar H-2, H-6), 9.36 (1H, s,
Ar–NHCONH). 13C-NMR (DMSO-d6) d: 43.2 (Nꢀ(CH3)2), 48.8 (CHCH2),
59.2 (CH2Nꢀ), 118.9 (Ar C-2, C-6), 124.5 (Ar C-4), 128.4 (Ar C-3, C-5),
139.4 (Ar C-1), 154.9 (NHCONH), 171.9 (COOH).
2-{3-(4-Chlorophenyl)ureido}-3-(pyrrolidin-1-yl)propanoic Acid (2e):
1H-NMR (HMPA-d18) d: 1.65—1.67 (4H, m, Pyr H-3, H-4), 2.50—2.58
(4H, m, Pyr H-2, H-5), 2.72—2.80 (2H, m, CH2Nꢀ), 3.3—5.1 (1H, br,
COOH), 4.38—4.42 (1H, m, CHCH2Nꢀ), 6.55—6.57 (1H, m,
Ar–NHCONH), 7.19—7.22 (2H, m, Ar H-3, H-5), 7.50—7.52 (2H, m, Ar
H-2, H-6), 9.90 (1H, s, Ar–NHCONH). 13C-NMR (HMPA-d18) d: 24.0 (Pyr
C-3, C-4), 53.1 (CHCH2Nꢀ), 54.6 (Pyr C-2, C-5), 58.4 (CH2Nꢀ), 118.9
(Ar C-2, C-6), 124.4 (Ar C-4), 128.6 (Ar C-3, C-5), 141.2 (Ar C-1), 155.0
(NHCONH), 172.8 (COOH).
2-{3-(2,4-Dichlorophenyl)ureido}-3-(pyrrolidin-1-yl)propanoic Acid (2f):
1H-NMR (DMSO-d6) d: 1.83—1.86 (4H, m, Pyr H-3, H-4), 2.98—3.00 (1H,
m, CHHNꢀ), 3.01—3.04 (4H, m, Pyr H-2, H-5), 3.11—3.15 (1H, m,
CHHNꢀ), 3.3—5.1 (1H, br, COOH), 4.06—4.10 (1H, m, CHCH2), 7.29—
7.31 (1H, m, Ar H-5), 7.44—7.45 (1H, m, Ar–NHCONH), 7.52 (1H, d,
Jꢀ2.7 Hz, Ar H-3), 8.13—8.15 (1H, m, Ar H-6), 8.65 (1H, br,
Ar–NHCONH). 13C-NMR (DMSO-d6) d: 22.9 (Pyr C-3, C-4), 50.7
(CHCH2Nꢀ), 53.2 (Pyr C-2, C-5), 56.5 (CH2Nꢀ), 122.0 (Ar C-6), 122.2
(Ar C-2), 125.3 (Ar C-4), 127.2 (Ar C-5), 128.3 (Ar C-3), 135.9 (Ar C-1),
154.4 (NHCONH), 171.9 (COOH).
2-{3-(4-Methylphenyl)ureido}-3-(pyrrolidin-1-yl)propanoic Acid (2g):
1H-NMR (DMSO-d6) d: 1.87—1.89 (4H, m, Pyr H-3, H-4), 2.21 (3H, s,
Ar–CH3), 3.03—3.08 (1H, m, CHHNꢀ), 3.10—3.16 (4H, m, Pyr H-2, H-5),
3.21—3.25 (1H, m, CHHNꢀ), 3.3—4.8 (1H, br, COOH), 4.00—4.03 (1H,
m, CHCH2), 6.50—6.51 (1H, m, Ar–NHCONH), 7.00—7.02 (2H, m, Ar H-
3, H-5), 7.28—7.30 (2H, m, Ar H-2, H-6), 9.00 (1H, s, Ar–NHCONH). 13C-
NMR (DMSO-d6) d: 20.2 (Ar–CH3), 22.8 (Pyr C-3, C-4), 50.0 (CHCH2),
53.2 (Pyr C-2, C-5), 56.7 (CH2Nꢀ), 117.5 (Ar C-2, C-6), 128.9 (Ar C-3, C-
5), 129.7 (Ar C-4), 137.8 (Ar C-1), 155.1 (NHCONH), 171.9 (COOH).
2-{3-(2,4-Dichlorophenyl)ureido}-3-(piperidin-1-yl)propanoic Acid (2h):
1H-NMR (DMSO-d6) d: 1.45—1.48 (2H, m, Ppd H-4), 1.58—1.61 (4H, m,
Ppd H-3, H-5), 2.71—2.75 (1H, m, CHHNꢀ), 2.77—2.87 (4H, m, Ppd H-2,
H-6), 2.96—3.00 (1H, m, CHHNꢀ), 3.5—5.3 (1H, br, COOH), 4.15—4.19
(1H, m, CHCH2), 7.29—7.31 (1H, m, Ar H-5), 7.38—7.39 (1H, m,
Ar–NHCONH), 7.52 (1H, d, Jꢀ2.4 Hz, Ar H-3), 8.12—8.14 (1H, m, Ar H-
6), 8.62 (1H, br, Ar–NHCONH). 13C-NMR (DMSO-d6) d: 22.5 (Ppd C-4),
24.3 (Ppd C-3, C-5), 49.0 (CHCH2Nꢀ), 52.7 (Ppd C-2, C-6), 58.3
(CH2Nꢀ), 122.1 (Ar C-6), 125.3 (Ar C-2), 127.2 (Ar C-5), 128.3 (Ar C-3),
135.9 (Ar C-4), 143.8 (Ar C-1), 154.4 (NHCONH), 172.3 (COOH).
2-(3-Phenylthioureido)-3-(pyrrolidin-1-yl)propanoic Acid (2i): 1H-NMR
(DMSO-d6) d: 1.90—1.93 (4H, m, Pyr H-3, H-4), 2.00—5.00 (1H, br,
COOH), 3.14—3.19 (1H, m, CHHNꢀ), 3.26—3.27 (4H, m, Pyr H-2, H-5),
3.51—3.55 (1H, m, CHHNꢀ), 4.58—4.60 (1H, m, CHCH2Nꢀ), 7.10—7.12
Chart 7
enehydantoin, including hydrolysis by water and addition of
MeNH2] can be considered in either of two ways (see Chart
4).
These results clearly indicate the contribution of the
N(1)C(5) double bond in this hydantoin ring system 3 such
as tautamers D and E in Chart 4. The contribution of the tau-
tomers E or a ring-opened intermediate F was substantiated
by the frequent formation of N-phenylurea 7 in many runs
under hydrolytic conditions.
Regarding isolated methylenehydantoin 4a, we found that
compound 4a shows an interesting chemical behavior. Treat-
ment of 4a with p-TsOH in benzene gave a dimeric hydan-
toin derivative 10 as an E/Z isomeric mixture in excellent
yield (90%). The ratio of E/Z isomers of 10 was ca. 1/5 by
1H-NMR spectroscopic analysis (see Experimental). This
dimerized compound 10 was also obtained in good yield
from a similar treatment of 5-hydroxymethylhydantoin 11
prepared by starting with D-serine methyl ester (see Chart 7
and Experimental). The formation of dimerized product 10 is
the first observation as a chemical property of 4a. This
dimerization process can be considered to be an analogous
manner of dimerization of enamines.12,13)
On the basis of the above chemical information, further
detailed synthetic studies of molecular modification and a
search for biologically active new leads in the above hydan-
toin-relating derivatives are underway.
Experimental
Melting points are uncorrected. IR spectra were measured by a Shimadzu
FT/IR-8100 spectrometer. The 1H- and 13C-NMR spectra were obtained by a
JEOL JNM A-500 at 35 °C. The chemical shifts were expressed in d ppm
downfield from an internal tetramethylsilane (TMS) signal. The signal as-
signments were confirmed by 1H–1H two-dimensional (2D) correlation spec-
troscopy (COSY), 1H–13C heteronuclear multiple quantum coherence
(HMQC), and 1H–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 the
thiomorpholine ring (Thi), pyrrolidine ring (Pyr), piperidine ring (Ppd), and
hydantoin ring (Hyd).
Preparation of b-Aminoalanines (1) All of the starting compounds 1
were prepared according to the procedures reported previously. Physical and

1418
Vol. 57, No. 12
Table 1. Preparation and Physical Data of Urea Derivatives (2a—k)
Anal.c)
Compd.
No.
Yield
(%)
mp
(°C)
FAB-MS IR (KBr)
X
Y
R1
R2
R3
Formula
(MꢃH)ꢃ cmꢄ1
Found (Calcd)
2aa)
2b
2c
2d
2e
2f
O
S
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
–(CH2)2–S–(CH2)2–
–(CH2)–S–(CH2)2–
H
H
87
58
43
49
43
10
35
98
57
81
65
170—173 (dec.)
130—133 (dec.)
206.5 (dec.)
C14H19N3O3S
C14H19N3O2S2
310
326
252
286
312
346
292
360
294
308
453
3326
1622
3286
1632
3336
1627
3303
1615
3313
1614
3314
1614
3357
1618
3322
1619
3141
1619
3444
1624
3248
1612
54.13 6.40 13.30
(54.35 6.19 13.58)
326.0993
(326.0997)
O
O
O
O
O
O
S
Me
Me
Me
Me
H
C12H17N3O3
57.21 6.64 16.58
(57.36 6.82 16.72)
49.18 5.59 14.61
(49.20 5.78 14.34)
53.90 5.64 13.35
(53.94 5.82 13.48)
44.00 5.26 10.94
(43.99 5.54 10.29)
59.68 7.22 13.94
(59.63 7.41 13.91)
360.0883
4-Cl
4-Cl
2,4-Cl
4-CH3
2,4-Cl
H
178.8—180 (dec.)
194—196 (dec.)
167.2 (dec.)
C12H16N3O3Cl·0.4H2O
C14H18N3O3Cl
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)5–
–(CH2)4–
–(CH2)5–
–(CH2)4–
C14H17N3O3Cl2·2H2O
C15H21N3O3·0.6H2O
C15H19N3O3Cl2
2g
2h
2i
189—191 (dec.)
b)
—
(360.0882)
294.1278
(294.1276)
308.1433
140—142.5 (dec.)
168 (dec.)
C14H19N3O2S
2j
S
H
C15H21N3O2S·HCl
C13H18N4O2S·0.6H2O
(308.1433)
2K
S
H
155 (dec.)
51.22 6.21 18.23
(51.16 6.34 18.36)
a) Data were taken from ref. 7. b) Hygroscopic amorphous white powder. c) Elemental analysis of compounds 2b, 2h—j was carried out by high-resolution MS spectra.
Table 2. Preparation and Physical Data of Hydantoin Derivatives (3a—k)
Anal.
Compd.
No.
Yield
(%)
mp
(°C)
FAB-MS IR (KBr)
X
Y
R1
R2
R3
Formula
(MꢃH)ꢃ cmꢄ1
Found (Calcd)
3aa)
3b
3c
3d
3e
3f
O
S
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
–(CH2)2–S–(CH2)2–
–(CH2)2–S–(CH2)2–
H
H
85
(84)b)
98
193—196
C14H18N3O2ClS
C14H18N3OClS2·0.2H2O
C12H16N3O2Cl·0.2H2O
C12H15N3O2Cl2
292
308
234
268
294
328
274
342
276
290
277
1779
1704
1759
1726
1789
1725
1781
1733
1775
1713
1974
1726
1774
1712
1797
1729
1757
51.52 5.54 12.76
(51.29 5.53 12.82)
48.43 4.28 12.06
(48.39 5.34 12.09)
52.78 6.01 15.34
(52.73 6.05 15.37)
47.34 4.98 13.84
(47.48 4.97 13.81)
49.83 5.19 12.38
(49.83 5.32 12.45)
45.66 4.39 11.43
(45.66 4.49 11.41)
58.09 6.54 13.54
(58.16 6.51 13.56)
47.55 4.74 11.13
(47.58 4.79 11.10)
53.72 5.90 13.42
(53.92 5.82 13.48)
54.30 6.08 12.66
(54.38 6.27 12.68)
41.93 5.80 15.15
(41.89 5.57 15.03)
168—170 (dec.)
c)
O
O
O
O
O
O
S
Me
Me
Me
Me
H
—
4-Cl
4-Cl
2,4-Cl
4-CH3
2,4-Cl
H
97
180—182
195—197 (dec.)
183—185 (dec.)
188—189
–(CH2)4–
44
C14H17N3O2Cl2·0.4H2O
C14H16N3O2Cl3·0.2H2O
C15H20N3O2Cl
–(CH2)4–
–(CH2)4–
–(CH2)5–
–(CH2)4–
–(CH2)5–
–(CH2)4–
52
3g
3h
3i
99
(79)b)
(74)b)
(79)b)
94
193—195 (dec.)
189 (dec.)
C15H18N3O2Cl3
C14H18N3OClS
3j
S
H
198 (dec.)
C15H20N3OClS·0.3H2O
C13H18N4OSCl2·1.3H2O
1757
1760
3k
S
H
180 (dec.)
a) Data were taken from ref. 7. b) The yield was based on the starting amino acid (1). c) Hygroscopic amorphous white powder.

December 2009
1419
m, Ar H-3), 8.91—8.92 [1H, s, Hyd N(1)-H], 11.23 (1H, br, NHꢃ). 13C-
NMR (DMSO-d6) d: 22.3, 22.5, 22.6, 22.7 (Pyr C-3, C-4), 53.0, 53.3, 53.8,
54.3, 54.9, 55.4 (Pyr C-2, C-5 and Pyr–CH2), 53.9, 54.4 (Hyd C-5), 128.3,
128.4, 128.4, 129.4, 129.4, 132.3 (Ar C-3, C-5, C-6), 132.3, 132.3, 133.0,
133.0, 134.8, 134.9 (Ar C-1, C-2, C-4), 153.8, 154.2 (Hyd C-2), 169.2,169.4
(Hyd C-4).
(1H, m, Ar H-4), 7.30—7.33 (2H, m, Ar H-3, H-5), 7.53—7.55 (2H, m, Ar
H-2, H-6), 7.90 (1H, br, Ar–NHCSNH), 10.25 (1H, s, Ar–NHCSNH). 13C-
NMR (DMSO-d6) d: 22.8 (Pyr C-3, C-4), 53.3 (Pyr C-2, C-5), 53.4
(CHCH2Nꢀ), 55.3 (CH2Nꢀ), 122.7 (Ar C-2, C-6), 124.1 (Ar C-4), 128.5
(Ar C-3, C-5), 139.2 (Ar C-1), 171.3 (COOH), 179.8 (CꢀS).
2-(3-Phenylthioureido)-3-(piperidin-1-yl)propanoic Acid Hydrochloride
(2j): 1H-NMR (DMSO-d6) d: 1.49—1.65 (6H, m, Ppd H-3, H-4, H-5),
2.78—3.03 (5H, m, Ppd H-2, H-6 and CHHNꢀ), 3.37—3.60 (1H, m,
CHHNꢀ), 4.68—4.71 (1H, m, CHCH2Nꢀ), 3.50—6.00 (2H, br,
COOHꢃAr–NHCSNH), 7.10—7.13 (1H, m, Ar H-4), 7.31—7.34 (2H, m,
Ar H-3, H-5), 7.49—7.51 (2H, m, Ar H-2, H-6), 7.73 (1H, br s, NHꢃ), 10.05
(1H, br, Ar–NHCSNH). 13C-NMR (DMSO-d6) d: 22.0 (Ppd C-4), 23.7 (Ppd
C-3, C-5), 52.1 (CH2Nꢀ), 52.3 (Ppd C-2, C-6), 56.6 (CHCH2Nꢀ), 122.3
(Ar C-2, C-6), 124.1 (Ar C-4), 128.5 (Ar C-3, C-5), 139.0 (Ar C-1), 171.6
(COOH), 179.9 (CꢀS).
3-(4-Methylphenyl)-5-(pyrrolidin-1-ylmethyl)hydantoin
Hydrochloride
(3g): 1H-NMR (DMSO-d6) d: 1.91 — 2.04 (4H, m, Pyr H-3, H-4), 2.34 (3H,
s, CH3), 3.08—3.10 (2H, m, Pyr H-2, H-5), 3.63—3.70 (4H, m, CH2-Pyr
and Pyr H-2, H-5), 4.82 (1H, td, Jꢀ6.0, 1.5 Hz, Hyd H-5), 7.23—7.25 (2H,
m, Ar H-2, H-6), 7.28—7.29 (2H, m, Ar H-3, H-5), 8.70 [1H, s, Hyd N(1)-
H], 11.22 (1H, br, NHꢃ). 13C-NMR (DMSO-d6) d: 20.6, 22.7 (Pyr C-3, C-
4), 53.3, 54.1 (Pyr C-2, C-5), 53.7 (Hyd C-5), 55.2 (Pyr–CH2), 126.5 (Ar C-
2, C-6), 129.1 (Ar C-3, C-5), 129.2 (Ar C-1), 137.5 (Ar C-4), 155.3 (Hyd C-
2), 170.0 (Hyd C-4).
2-(3-Pyridin-3-ylthioureido)-3-(pyrrolidin-1-yl)propanoic Acid (2k): 1H-
NMR (DMSO-d6) d: 1.91—2.17 (4H, m, Pyr H-3, H-4), 3.09—3.45 (5H, m,
Pyr H-2, H-5 and CHHNꢀ), 3.51—3.52 (1H, m, CHHNꢀ), 3.00—4.60
(1H, br, COOH), 4.56 (1H, br, CHCH2Nꢀ), 7.32—7.35 (1H, m, Pyridine H-
5), 8.11—8.12 (2H, m, Pyridine H-4, H-6), 8.27—8.29 (1H, m, Pyridine H-
2), 8.69 (1H, d, Jꢀ2.0 Hz, Pyridine-NHCSNH), 10.53 (1H, br, Pyridine-
NHCSNH). 13C-NMR (DMSO-d6) d: 22.8 (Pyr C-3, C-4), 53.3 (Pyr C-2, C-
5), 53.7 (CHCH2Nꢀ), 55.3 (CH2Nꢀ), 123.2 (Pyridine C-5), 129.6 (Pyridine
C-2), 136.4 (Pyridine C-3), 144.0 (Pyridine C-6), 144.6 (Pyridine C-4),
171.3 (COOH), 180.4 (CꢀS).
Preparation of Hydantoin and 2-Thiohydantoin Derivatives (3)
Using the same method as that described in our previous paper,7) hydantoin
derivatives 3 were prepared from corresponding urea derivatives 2. Hydan-
toins (3b, 3h—j) were prepared from urea derivatives (2b, 2h—j) obtained
by the general procedure without purification. Hydantoin 3a has been re-
ported in our preliminary paper.7) The results for new hydantoin and 2-thio
analogues derivatives (3b—k) are summarized in Table 2.
3-(2,4-Dichlorophenyl)-5-(piperidin-1-ylmethyl)hydantoin Hydrochloride
(3h): 1H-NMR (DMSO-d6) d: 1.37—1.42 (1H, m, Ppd H-4), 1.72—1.93
(5H, m, Ppd H-3, H-4, H-5), 2.97—3.09 (2H, m, Ppd H-2, H-6), 3.40—3.67
(4H, m, Ppd H-2, H-6 and CH2-Ppd), 5.04 (0.5H, dd, Jꢀ9.5, 1.5 Hz, Hyd H-
5), 5.18 (0.5H, d, Jꢀ1.5 Hz, Hyd H-5), 7.55—7.63 (2H, m, Ar H-5, H-6),
7.86—7.87 (1H, m, Ar H-3), 9.04—9.05 [1H, s, Hyd N(1)-H], 10.9 (1H, br,
NHꢃ). 13C-NMR (DMSO-d6) d: 21.0 (Ppd C-4), 22.0, 22.1, 22.2, 22.2 (Ppd
C-3, C-5), 51.6, 52.0, 53.4, 53.7 (Ppd C-2, C-6), 52.4, 53.0 (Hyd C-5), 57.9,
53.0 (Ppd–CH2), 127.5, 128.3, 128.4, 129.5, 132.2, 133.0 (Ar C-3, C-5, C-
6), 134.8, 134.9, 134.9 (Ar C-1, C-2, C-4), 153.7, 154.0 (Hyd C-2), 169.4,
169.6 (Hyd C-4).
3-Phenyl-5-(pyrrolidin-1-ylmethyl)-2-thiohydantoin Hydrochloride (3i):
In the case of pyrrolidine derivative (3i), formation of 85% of 2-thiomethyl-
enehydantoin was observed in 1H-NMR spectra (in DMSO-d6) after 10 min.
1H-NMR (DMSO-d6) d: 1.92—2.05 (4H, m, Pyr H-3, H-4), 3.05—3.10 (2H,
m, Pyr H-2, H-5), 3.67—3.77 (4H, m, Pyr H-2, H-5, and CH2-Pyr), 5.05—
5.07 (1H, m, Hyd H-5), 7.31—7.32 (2H, m, Ar H), 7.32—7.33 (3H, m, Ar
H), 10.56 [1H, s, Hyd N(1)-H], 11.22 (1H, s, NHꢃ). 13C-NMR (DMSO-d6)
d: 22.5 (Pyr C-3, C-4), 53.1 (Pyr C-2, C-5), 54.2 (Pyr–CH2), 56.4 (Hyd C-
5), 128.6, 128.7 (Ar C-2—C-6), 133.0 (Ar C-1), 170.9 (CꢀO), 182.7
(CꢀS).
3-Phenyl-5-(piperidin-1-ylmethyl)-2-thiohydantoin Hydrochloride (3j): In
the case of piperidine derivative 3j, formation of 82% of 2-thiomethylenehy-
dantoin was observed in 1H-NMR spectra (in DMSO-d6) after 1 h. 1H-NMR
(DMSO-d6) d: 1.75—1.86 (6H, m, Ppd H-3, H-4, H-5), 3.39—3.60 (6H, m,
Ppd H-2, H-6 and CH2-Ppd), 5.50 (1H, br, Hyd H-5), 7.13—7.51 (5H, m, Ar
H), 8.42 [1H, s, Hyd N(1)-H], 10.34 (1H, br s, NHꢃ). 13C-NMR (DMSO-d6)
d: 21.2, 22.2, 22.2 (Ppd C-3, C-4, C-5), 52.4 (Hyd C-5), 52.7 (Ppd C-2, C-
6), 56.3 (Ppd–CH2), 123.0, 124.5, 128.6 (Ar C-2—C-6), 138.8 (Ar C-1),
170.3 (Hyd CꢀO), 180.7 (Hyd CꢀS).
3-Phenyl-5-(thiomorpholinomethyl)-2-thiohydantoin Hydrochloride (3b):
In the NMR spectroscopic operation (in DMSO-d6), formation of 2-
thiomethylenehydantoin (25%) was observed after 10 min together with
compound 3b. The ratio of this product was based on the methylene signals
of 4b at d 5.18 and d 5.35 against a methyne proton at d 5.24 of compound
1
3b. In the spectrum of H- and 13C-NMR (DMSO-d6), two compounds (4b
and thiomorpholine) were observed in an equilibrium state. 1H-NMR
(DMSO-d6) d: 2.50—3.96 (10H, m, Thi H-2, H-3, H-5, H-6 and CH2-Thi),
5.24 (1H, br, Hyd H-5), 7.30—7.52 (5H, m, Ar H), 10.58 (1H, s, Hyd N(1)-
H), 11.64 (1H, br, NHꢃ). 13C-NMR (DMSO-d6) d: 23.7 (Thi C-2, C-6), 44.5
(Thi C-3, C-5), 54.8 (Hyd C-5), 57.6 (CH2-Thi), 128.6, 128.7 (Ar C-2—C-
6), 133.1 (Ar C-1), 171.0 (CꢀO), 182.5 (CꢀS). Thiomorpholine was also
detected in this spectrum at d: 2.86—2.89 (4H, m, Thi H-2, H-6), 3.24 (4H,
ꢃ
br, Thi H-3, H-5), 9.29 (2H, br s, NH2 in Thi), 13C-NMR (DMSO-d6) d:
3-(Pyridin-3-yl)-5-(pyrrolidin-1-ylmethyl)-2-thiohydantoin Dihydrochlo-
1
ride (3k): H-NMR (CD3OD) d: 2.02—2.22 (4H, m, Pyr H-3, H-4), 3.25—
23.4 (Thi C-2, C-6), 44.5 (Thi C-3, C-5),
5-(Dimethylamino)methyl-3-phenylhydantoin Hydrochloride (3c): 1H-
NMR (DMSO-d6) d: 2.88 [6H, s, N(CH3)2], 3.57—3.58 [2H, m,
CH2N(CH3)2], 4.87—4.89 (1H, m, Hyd H-5), 7.36—7.43 (3H, m, Ar H-3,
H-4, H-5), 7.48—7.51 (2H, m, Ar H-2, H-6), 8.72 [1H, s, Hyd N(1)-H],
10.97 (1H, br, NHꢃ). 13C-NMR (DMSO-d6) d: 42.1, 43.4 (CH3ꢅ2), 52.6
(Hyd C-5), 58.1 [CH2N(CH3)2], 126.6 (Ar C-2, C-6), 128.0 (Ar C-4), 128.7
(Ar C-3, C-5), 131.8 (Ar C-1), 155.2 (Hyd- C-2), 170.6 (Hyd C-4).
3.32 (2H, m, Pyr H-2, H-5), 3.85—3.90 (4H, m, Pyr H-2, H-5, and CH2-
Pyr), 5.12—5.14 (1H, m, Hyd H-5), 8.28—8.31 (1H, m, Pyridine H-5),
8.92—8.94 (1H, m, Pyridine H-4), 8.96—8.98 (1H, m, Pyridine H-6),
9.22—9.29 (1H, m, Pyridine H-2). 13C-NMR (CD3OD) d: 24.1, 24.2 (Pyr C-
3, C-4), 56.9, 56.4 (Pyr C-2, C-5), 55.4 (Pyr–CH2), 58.2 (Hyd C-5), 128.7
(Pyridine C-5), 134.6 (Pyridine C-1), 142.4 (Pyridine C-6), 143.0 (Pyridine
C-2), 147.8 (Pyridine C-4), 171.5 (CꢀO), 182.9 (CꢀS).
5-Methylene-3-phenyl-2-thiohydantoin (4b) A suspension of com-
pound 3b (0.134 g, 0.39 mmol) in water (10 ml) was kept at room tempera-
ture for 3 d. The solid material in the reaction mixture was extracted with
Et2O. The organic layer was washed with 1N-HCl (ꢅ2) and then brine and
dried over anhydrous MgSO4. Concentration of the solvent gave a yellow
solid material 4b (60 mg, 76%), mpꢁ200 °C (dec). IR (KBr) cmꢄ1: 3228,
1716 1657. MS (positive) m/z: 205. 1H-NMR (DMSO-d6) d: 5.18 (1H, d,
Jꢀ1.8 Hz, HydꢀCHH), 5.35 (1H, d, Jꢀ1.8 Hz, HydꢀCHH), 7.34—7.52
(5H, m, Ar H), 12.47 [1H, br s, N(1)-H], 13C-NMR (DMSO-d6) d: 97.6
(HydꢀCHH), 126.6, 128.6, 128.6, 128.7, 128.7 (Ar C-2—C-6), 132.9 (Ar
C-1), 135.2 (Hyd C-5), 162.3 (Hyd C-4), 178.0 (Hyd C-2). Anal. Calcd for
C10H8N2OS: C, 58.8; H, 3.95; N, 13.72. Found: C, 58.80; H, 4.25; N, 13.43.
Treatment of Compound (3a) with Methylamine in Methanol A so-
lution of hydantoin hydrochloride 3a (0.3 g, 9.1ꢅ10ꢄ4 mol) and methyl-
amine (0.43 g, 40% in H2O, 5.5ꢅ10ꢄ3 mol) in methanol (15 ml) was refluxed
for 15 min. After evaporation of the solvent, water (ca. 7 ml) was added to
the mixture and mixture was extracted with AcOEt. The extract was evapo-
rated to give a brownish material. Purification by column chromatography
with SiO2 (with AcOEt–Hexaneꢀ5 : 1 as a solvent) gave three main prod-
ucts [3a (as a free base), 5-methyl-5-methylamino-1-phenylhydantoin 6, and
3-(4-Chlorophenyl)-5-(dimethylamino)methylhydantoin
Hydrochloride
(3d): 1H-NMR (DMSO-d6) d: 2.88 [6H, s, N(CH3)2], 3.57 [2H, d, Jꢀ6.0 Hz,
CH2N(CH3)2], 4.88 (1H, td, Jꢀ6.0, 1.0 Hz, Hyd H-5), 7.43 (2H, d,
Jꢀ8.5 Hz, Ar H-2, H-6), 7.57 (2H, d, Jꢀ8.5 Hz, Ar H-3, H-5), 8.80 [1H, s,
Hyd N(1)-H], 11.2 (1H, br, NHꢃ). 13C-NMR (DMSO-d6) d: 42.1, 43.4
(CH3ꢅ2), 52.7 (Hyd C-5), 58.1 [CH2N(CH3)2], 128.2 (Ar C-2, C-6), 128.7
(Ar C-3, C-5), 130.7 (Ar C-4), 132.3 (Ar C-1), 154.8 (Hyd C-2), 169.8 (Hyd
C-4).
3-(4-Chlorophenyl)-5-(pyrrolidin-1-ylmethyl)hydantoin
Hydrochloride
1
(3e): H-NMR (DMSO-d6) d: 1.92, 2.04 (each 2H, br, Pyr H-3, H-4), 3.09
(2H, br, Pyr H-2, H-5), 3.64—3.69 (4H, m, CH2-Pyr and Pyr H-2, H-5),
4.81—4.83 (1H, m, Hyd H-5), 7.42—7.45 (2H, m, Ar H-2, H-6), 7.55—
7.58 (2H, m, Ar H-3, H-5), 8.78 [1H, s, Hyd N(1)-H], 11.13 (1H, br, NHꢃ).
13C-NMR (DMSO-d6) d: 22.4, 22.7 (Pyr C-3, C-4), 53.4, 54.1 (Pyr C-2, C-
5), 53.7 (Hyd C-5), 55.0 (Pyr-CH2), 128.3 (Ar C-2, C-6), 128.7 (Ar C-3, C-
5), 130.7 (Ar C-4), 132.3 (Ar C-1), 154.9 (Hyd C-2), 167.8 (Hyd C-4).
3-(2,4-Dichlorophenyl)-5-(pyrrolidin-1-ylmethyl)hydantoin Hydrochlo-
1
ride (3f): H-NMR (DMSO-d6) d: 1.92, 2.50 (each 2H, br, Pyr H-3, H-4),
3.11 (2H, br, CH2-Pyr), 3.65—3.72 (4H, m, Pyr H-2, H-5), 4.91 (0.5H, d,
Jꢀ9.0 Hz, Hyd- H-5), 5.04 (0.5H, d, Jꢀ7.5 Hz, Hyd H-5), 7.86—7.87 (1H,

1420
Vol. 57, No. 12
1-phenylurea 7] in 49%, 9%, and 8% yields, respectively. 1-Phenylurea 711)
was shown to be identical to a commercially available authentic sample by
1H-, 13C-NMR and IR spectroscopic analysis.
5-Methyl-5-methylamino-1-phenylhydantoin (6): mp 117—118 °C. IR
(KBr) cmꢄ1: 3311, 1721, 1713 1696. FAB-MS (positive) m/z: 220 (MꢃHꢃ).
1H-NMR (DMSO-d6) d: 1.45 (3H, m, CH3), 2.17 (3H, d, Jꢀ5.0 Hz,
NHCH3), 2.93 (1H, br, NHCH3), 7.32—7.48 (5H, m, Ar H), 8.44 [1H, br,
N(1)-H]. 13C-NMR (DMSO-d6) d: 23.6 (CH3), 28.2 (NHCH3), 73.9 (Hyd C-
5), 126.6 (Ar C–2, C-6), 127.7 (Ar C-4), 128.6 (Ar C-3, C-5), 132.0 (Ar C-
1), 154.1 (Hyd C-2), 174.5 (Hyd C-4). Anal. Calcd for C11H13N3O2·0.1H2O:
C, 59.77; H, 6.02; N, 19.01. Found: C, 59.77; H, 5.90; N, 18.82.
Treatment of Compound (3a) with Methylamine in Water Methyl-
amine (0.43 g, 40% in H2O, 5.5ꢅ10ꢄ3 mol) was added to a solution of 0.3 g
of 3a (9.1ꢅ10ꢄ4 mol) in H2O (10 ml). The mixture was stirred for 40 min at
room temperature. After evaporation of the solvent in vacuo, H2O (2—3 ml)
was added to the residue. The resulting crystallized material was collected
by filtration to give 1-phenylurea 7 (28—32%). After evaporation of the
mother filtrate, purification of the products gave the compound 8 (25—
40%).
3-(Methylamino)-2-(3-phenylureido)propanoic Acid (8): mp 188—189 °C
(dec.). IR (KBr) cmꢄ1: 1701, 1648, 1603. FAB-MS (positive) m/z: 238
(MꢃH)ꢃ. 1H-NMR (D2O) d: 2.79 (3H, s, NHCH3), 3.28—3.32 (1H, m,
NHCHCHHNHCH3), 3.45—3.48 (1H, m, NHCHCHHNHCH3), 4.43—4.46
(1H, m, NHCHCHHNHCH3), 7.17—7.42 (5H, Ar H). 13C-NMR (D2O) d:
36.0 (NHCH3), 54.2 (NHCHCH2), 54.6 (NHCHCH2), 124.0 (Ar C-2, C-6),
127.0 (Ar C-4), 132.1 (Ar C-3, C-5), 140.7 (Ar C-1), 160.5 (NHCONH),
177.6 (COOH). Anal. Calcd for C11H15N3O3·0.5H2O: C, 53.65; H, 6.55; N,
17.06. Found: C, 53.86; H, 6.37; N, 16.96.
stirring at 50 °C for 90 min. After evaporation of the solvent, conc HCl was
added to the residue and the resulting mixture was allowed to stand for 4 d at
room temperature. After evaporation of the solvent, the residue was tritu-
rated with AcOEt and the separated crystal material was filtered to give 5-
hydroxymethylhydantoin derivative 11 (0.98 g in 74% yield). An analytical
sample was obtained by recrystallization from EtOH, mp 167—168 °C
(Lit15) mp 166—167 °C). IR (KBr) cmꢄ1: 3262, 1767, 1693. FAB-MS (posi-
tive) m/z: 207 (MꢃHꢃ). 1H-NMR (DMSO-d6) d: 3.67—3.70 (1H, m,
CHH–OH), 3.75—3.80 (1H, m, CHH–OH), 4.22 (1H, t, Jꢀ3.0 Hz, Hyd H-
5), 5.15 (1H, t, Jꢀ5.0 Hz, OH), 7.35—7.38 (3H, m, Ar H), 7.44—7.48 (2H,
m, Ar H), 8.33 (1H, br s, NH). 13C-NMR (DMSO-d6) d: 59.0 (Hyd C-5),
60.1 (CH2–OH), 126.4 (Ar C-2, C-6), 127.5 (Ar C-4), 128.6 (Ar C-3, C-5),
132.3 (Ar C-1), 156.0 (Hyd C-2), 171.9 (Hyd C-4). Anal. Calcd for
C10H10N2O3·0.1H2O: C, 57.74; H, 4.94; N, 13.47. Found: C, 57.74; H, 4.90;
N, 13.45.
Formation of Dimerized Methylenehydantoin (10) from 5-Hydroxy-
methyl-3-phenylhydantoin (11) A solution of 5-hydroxymethyl-3-phenyl-
hydantoin 11 (0.51 g, 2.48 mmol) obtained above and p-toluenesulfonic acid
(2.5 g, 14.5 mmol) in anhydrous benzene was refluxed for 7 h with a water
separator. After evaporation of the solvent, the residue was dissolved in
AcOEt and washed with water (ꢅ4), washed with brine, and dried over
MgSO4. Evaporation of the solvent gave dimerized methylenehydantoin de-
rivative 10, 0.42 g in 90% yield. The product was identical to a sample ob-
tained from the reaction starting with methylenehydantoin 4a. The isomeric
ratio (E/Z) of the products in this reaction was also ca. 1/5.
References and Notes
1) Shih H.-W., Cheng W.-C., Tetrahedron Lett., 49, 1008—1011 (2008).
2) Kuster G. J. T., Van Berkom L. W. A., Kalmoua M., Van Loevezijn A.,
Sliedregt L. A. J. M., Van Steen B. J., Kruse C. G., Rutjes F. P. J. T.,
Scheeren H. W., J. Comb. Chem., 8, 85—94 (2006).
3) Boeijen A., Kruijtzer J. A. W., Liskamp R. M. J., Bioorg. Med. Chem.
Lett., 8, 2375—2380 (1998).
4) Balavoine F., Malabre P., Alleaume T., Rey A., Cherfils V., Jeanneton
O., Seigneurin-Venin S., Revah F., Bioorg. Med. Chem. Lett., 17,
3754—3759 (2007).
Formation of Dimerized Methylenehydantoin (10) from Methylenehy-
dantoin (4a) A solution of methylenehydantoin 4a (12 mg, 0.06 mmol) in
the presence of p-toluenesulfonic acid (50 mg) in anhydrous benzene (6 ml)
was refluxed for 10 min. After evaporation of the solvent, the residue was
dissolved in AcOEt. The resulting solution was washed with aq.-NaHCO3
(5%, 1 mlꢅ2), washed with brine, and then dried over anhydrous MgSO4.
Evaporation of the solvent gave dimerized product 10 in 90% yield, mp
1
161—162 °C. H- and 13C-NMR spectroscopic results were consistent with
5) Opacic N., Barbaric M., Zorc B., Cetina M., Nagl A., Frkovic D., Kralj
M., Pavelic K., Balzarini J., Andrei G., Snoeck R., Clercq E. D., Raic-
Malic S., Mintas M., J. Med. Chem., 48, 475—482 (2005).
6) El-Barbary A. A., Khodair A. I., Pederson E. B., Nielsen C., J. Med.
Chem., 37, 73—77 (1994).
7) Fujisaki F., Shoji K., Sumoto K., Heterocycles, 78, 213—220 (2009)
and related referances cited herein.
8) Fujisaki F., Abe N., Sumoto K., Chem. Pharm. Bull., 52, 1238—1241
(2004).
9) Fujisaki F., Abe N., Sumoto K., Chem. Pharm. Bull., 50, 129—132
(2002).
10) Abe N., Fujisaki F., Sumoto K., Chem. Pharm. Bull., 46, 142—144
(1998).
11) Dabis T. L., Org. Syn., III, 1923, 95—97 (1923).
12) Singh H., Singh P., Mehta R. K., Chem. Ind., 3, 124 (1977).
13) Swan G. A., Wilcock J. D., J. Chem. Soc. Perkin Trans. 1, 1974, 885—
891 (1974) and related refernces cited herein.
14) Tan S. F., Ang K. P., Fong Y. F., J. Chem. Soc. Perkin Trans. 2, 1986,
1941—1944 (1986).
an E/Z isomeric mixture of 10. This isomeric ratio (E/Zꢀca. 1/5) was easily
estimated by integration values of corresponded vinyl protons at d 5.62 ppm
(E) and at d 5.77 ppm (Z), respectively. This stereochemistry of the two
stereo isomers (E/Z) could be determined on the basis of data reported by
Tan et al.14) and by careful analysis of 2D-NMR spectroscopic data. IR
(KBr) cmꢄ1: 3305, 1777, 1713 1680. FAB-MS (positive) m/z: 377 (MꢃHꢃ).
1H-NMR (DMSO-d6) d: 1.67, 1.73 [3H, m, CH3 (E and Z, respectively)],
5.62, 5.77 [1H, s, HydꢀCH–(E and Z, respectively)], 733—7.52 (10H, m,
Ar H), 8.72, 10.43 (each 1H, br, NH). 13C-NMR (DMSO-d6) d: 24.0, 27.6
[CH3, (Z and E, respectively)], 60.0, 58.2 [Hyd C-5 (Z and E, respectively)],
108.9, 113.8 [methyleneHyd (C-5)ꢀCH-–(Z and E, respectively)], 126.6
126.7, 126.7, 128.0, 128.5, 128.6, 128.7, 128.8, 128.8, 128.9 (Ar C2—C-6),
131.1, 131.2, 131.4, 131.8, 131.8, 132.3 [methyleneHyd C-5 and Ar C-1
(ꢅ2)], 153.3, 152.4 [methyleneHyd C-2 (Z and E, respectively)], 154.2,
154.5 [Hyd C-2 (Z and E, respectively)], 162.3, 160.6 [methyleneHyd C-4
(Z and E, respectively)], 173.4, 174.1 [Hyd C-4 (Z and E, respectively)].
Anal. Calcd for C20H16N4O4·0.3H2O: C, 62.92; H, 4.38; N, 14.68. Found: C,
62.94; H, 4.54; N, 14.41.
5-Hydroxymethyl-3-phenylhydantoin (11) Phenyl isocyanate (1.15 g,
9.66 mmol) was added dropwise to a solution of D-serine methyl ester hy-
drochloride (1 g, 6.43 mmol) in 3 M-sodium hydroxide (3 ml) with vigorous
15) Sprinson D. B., Chargaff E., J. Biol. Chem., 164, 417—432 (1946).