Synthesis of 3-ω-amino-2-thiohydantoins

Article abstract of DOI:10.1002/jhet.5570400417

In the reaction of ethyl isothiocyanatoacetate with diamines, followed by cyclization of the intermediate product, 3-monosubstituted thiohydantoins have been obtained. It was found that the reaction course depends on the purity of the isothiocyanate used and also, in the case of dialkylaminoamines, the self-cyclization occurs. Besides the dialkylamino derivatives of 3-monosubstituted 2-thiohydantoins also new monoalkylamino, amino and heterocyclic derivatives were synthesized. The aryldiazonium derivative of 3-monosubstituted 2-thiohydantoin yielded both respective phenol derivative after hydrolysis and the product of coupling with 2-naphthol.

Full text of DOI:10.1002/jhet.5570400417

Jul-Aug 2003
665
Synthesis of 3-W-Amino-2-Thiohydantoins
Józef Ryczek
·
Department of Chemistry, Pedagogical University , Podchor˛azych 2 St., 30-084 Kraków, Poland
Received July 2, 2002
In the reaction of ethyl isothiocyanatoacetate with diamines, followed by cyclization of the intermediate
product, 3-monosubstituted thiohydantoins have been obtained. It was found that the reaction course
depends on the purity of the isothiocyanate used and also, in the case of dialkylaminoamines, the self-
cyclization occurs. Besides the dialkylamino derivatives of 3-monosubstituted 2-thiohydantoins also new
monoalkylamino, amino and heterocyclic derivatives were synthesized. The aryldiazonium derivative of 3-
monosubstituted 2-thiohydantoin yielded both respective phenol derivative after hydrolysis and the product
of coupling with 2-naphthol.
J. Heterocyclic Chem., 40, 665(2003).
2-Thiohydantoins, in common with their 2-oxo analogs,
Results and Discussion.
have interesting pharmacological activity [1-3], technical
applications [4,5] and properties [6,7]. Investigations on
these compounds is less active in comparison to hydantoins
due to their difficult synthesis and higher toxicity. A rela-
tively small number of 3-monosubstituted 2-thiohydantoins
have been synthesized to date, and only a few among them
possess dialkylamino substituents [8-10]. 2-Thiohydantoins
with amino or hydroxy group in the substituent in 3 position
are not reported in the literature. This is due mainly to diffi-
culty of synthesis, because it is impossible to obtain
aliphatic or aromatic isothiocyanates with a free amino
group, as well as aliphatic ones with hydroxy group. Such
isothiocyanates are pre-requisite in the standard synthesis
[11] of 3-monosubstituted 2-thiohydantoins.
The dialkylamino, amino and hydroxy derivatives of 3-
monosubstituted 2-thiohydantoin described in this paper
were obtained by the literature method [12] using ethyl
isothiocyanatoacetate and respective diamine, aminoalco-
hol or aminophenol. Mass spectrometry investigations
showed that the starting isothiocyanate contains small
amounts of thiophosgene and carbon disulfide. These con-
taminants could not be removed from the reagent obtained
according to literature [13] by standard procedures like
vacuum distillation (an azeotrope was formed).
It was found that these minor contaminants markedly
influence the reaction, yielding tar-like products of uniden-
tified composition. Using highly pure isothiocyanate,
obtained by removal of contaminants by purging with

666
J. Ryczek
Vol. 40
13
gaseous nitrogen for several days, the reaction goes
smoothly yielding high yields and pure products. Using
this approach [12] N-substituted esters of thiohydantoic
acid were obtained from diamines and ethyl isothiocyana-
toacetate. These products were further cyclized in acid
medium (HCl) to 3-monosubstitued 2-thiohydantoins.
Physicochemical data and tlc and ms results of the final
and C nmr data are given in Table 2.
When using dialylaminoalkyl amines and running the
reaction both at room temperature and at –5 °C the inter-
mediate products III, i.e., N-substituted ester of thiohy-
dantoic acid, could not be isolated since these sponta-
neously cyclized to 3-monosubstitued 2-thiohydantoins IV
1-6 in high purity and yield. It was found that for some
dialkylaminoalkyl amines the reaction course depends on
1
products are summarized in Table 1, whereas ir, H nmr
Table 1
Preparative, Physical and Analytical Data for Compounds 1-19
Compound
(Formula)
Yield
(%)
Mp°C
Solvent
Recryst.
Analyses
Found/Calcd
H
m/z
M
TLC
.
+
(UV, I )
2
C
N
1 [a]
99.7
149-51
206-7
75-6
Benzene
EtOH
187
DMF:CHCl
Light petroleum
5:3:15 Rf = 0.50
3
C H N OS
7
13 3
1 a
37.6
37.4
6.3
6.3
18.8
18.5
C H N OS·HCl
7
13 3
2 [a]
C H N OS
99.8
99.6
94.0
94.6
99.8
Cyclohexane +
Benzene
215
201
229
201
219
DMF:CHCl :
9
17
3
3
Light petroleum
5:3:15 Rf = 0.40
2 a
215-17
143-4
EtOH
42.9
42.9
7.2
7.3
16.7
16.7
C H N OS·HCl
9
17 3
3 [a]
C H N OS
Benzene +
Cyclohexane
DMF:CHCl :
3
Light petroleum
5:3:15 Rf = 0.31
8
15 3
3 a [10]
C H N OS·HCl
209-10
103-4
EtOH
40.4
40.6
6.8
6.7
17.7
17.6
8
15 3
4 [a]
Cyclohexane +
Benzene
DMF:CHCl :
3
C
H
N OS
Light petroleum
5:3:15 Rf = 0.30
10 19
3
4 a [10]
N OS·HCl
154-5
EtOH
45.2
45.0
7.6
7.7
15.8
16.0
C
H
10 19
3
5 [a]
149-51
Cyclohexane +
Benzene
DMF:CHCl :
3
C H N OS
Light petroleum
1:2:15 Rf = 0.18
8
15 3
i
5 a
214-15
97-8
Pr OH
40.4
40.0
54.3
54.2
6.8
7.0
8.7
8.6
17.7
17.9
17.3
17.0
C H N OS·HCl
8
15 3
6 [a]
Benzene +
Light petroleum
DMF:CHCl :
3
C
H
N OS
Light petroleum
1:2:15 Rf = 0.39
11 21
3
6 a
245-6
151-2
259-60
233-4
144-5
124-5
222-3
216-17
302-3
234-5
EtOH
C
H N OS·HCl
11 21 3
7
86.7
60.5
24.3
100.0
100.0
96.1
92.1
69.3
40.2
Acetone+
Benzene
EtOH
37.5
37.1
5.0
4.9
17.5
17.4
160
187
Acetone: CHCl
1:1 Rf = 0.42
Acetone: CHCl
1:1 Rf = 0.74
3
C H N O S
5
8 2 2
8 [16]
C H N OS
3
9
8 2
9
EtOH
Benzene
Benzene
EtOH
37.6
37.3
55.5
55.4
58.2
57.8
48.6
48.6
52.1
51.9
51.9
51.9
30.7
30.3
6.3
6.6
6.8
6.7
7.5
7.2
5.2
5.3
6.0
6.0
3.9
3.8
5.1
5.2
18.8
18.8
14.9
14.9
13.6
13.7
15.5
15.4
14.0
13.8
13.4
13.5
21.5
21.0
C H N OS·HCl
7
13 3
10
C
H N O S
13 19 3 2
11
C
H N O S
15 23 3 2
12 [8]
235
263
208
159
anh. EtOH
Rf = 0.67
anh. EtOH
C
H N OS·HCl
11 13 3
13
EtOH
C
H
N OS·HCl
Rf = 0.70
13 17
3
14
H O
Acetone: CHCl
1:1 Rf = 0.51
2
3
C H N O S
9
8 2 2
15
EtOH
C H N OS·HCl
5
9 3

Jul-Aug 2003
667
Synthesis of 3-W-Amino-2-Thiohydantoins
Table 1 (continued)
16
83.4
89.1
54.3
67.0
248-9
269-70
MeOH
AcOH
EtOH
44.3
44.4
63.0
62.6
[b]
4.1
4.1
3.9
17.2
17.1
15.5
5.6
207
362
231
290
C H N OS·HCl
9
9 3
17
Acetone: CHCl
3
1:1 Rf = 0.50
C
H
N O S
3.71
19 14
4 2
18
C H N OS
370 decomp.
MeOH:CH Cl
2
2
1:5 Rf = 0.42
11
9 3
19
> 370
decomp.
DMF +
Benzene
49.6
49.5
3.5
3.4
19.3
19.2
DMF:CHCl :
3
C
H
N O S
Light petroleum
1:2:4 Rf = 0.34
12 10
4 3
[a] Free bases change their composition after some time; [b] Forms coke-like uncombustible residue.
the solvent used. In some cases the use of a more polar sol-
vent, for instance chloroform, gave unsatisfactory results,
affording oligomeric products of undefined composition.
Alternatively, solvents of low polarity (light petroleum)
proved to be an excellent reaction medium. The cycliza-
tion of pure ethyl ester of N-phenylthiohydantoic acid [14]
3-phenyl-2-thiohydantoin 8 [16] (Scheme 2). However, the
yield and purity of the product obtained was inferior to that
when the cyclization was run in acid solution [12]. The reac-
tion course was monitored by tlc. Since in the synthesis with
dialkylaminoalkylamines chloroform or light petroleum was
used as a solvent, it was assumed that the cyclization of inter-
mediate III does not depend on the presence of strongly alka-
line dialkylaminoalkylamine in the reaction medium. This
was confirmed in the reaction of ethyl isothiocyanatoacetate
with ethanolamine where also the intermediate without the
dialkylamino group but having instead the hydroxy sub-
stituent could not be isolated. The only product of this reac-
tion was 3-(2-hydroxyethyl)-2-thiohydantoin 7. This shows
that the process of self-cyclization is an individual property
of some esters of 2-thiohydantoic acid. Analogous esters of
hydantoic acid under the same circumstances do not show
self-cyclization. However, when a monoalkyldiamine such
as N-methyl-1,3-propanediamine was used, the intermediate
III was isolated and without purification cyclized to 2-thio-
hydantoin derivative 9. The analogous reaction with ethyl
isocyanatoacetate yields unidentified products, but not the
monoalkyl derivative of hydantoin. The fact that
in the presence of N(C H ) [15] was run both in chloro-
2
5 3
form and anhydrous ethanol to investigate the effect of sol-
vent on that reaction.
It was found that in chloroform the cyclization does not
occur either after 24 hours at room temperature or after
reflux for 3 hours. In the ethanol solution the reaction was
complete after several hours at room temperature yielding
Table 2
IR, H NMR and C NMR Spectroscopic Data for Compounds 1-19
1
13
-1
Compound
n
(KBr) cm
d
[500 MHz ]
d [125 MHz ]
C
max
H
1
3009 (NH)
1716 (CO)
2.32 (s, 6H, N(CH ) ), 2.66 (t, 2H, J= 6.5 Hz, C(7)H ),
38.96 (C(6)H ), 45.49- (N(CH ) ), 48.67 (C(7)H ),
2 3 2 2
3 2
2
3.39 (t, 2H, J= 6.5Hz, C(6)H ), 4.10 (s, 2H, C(5)H ),
56.24 (C(5)H ), 171.92 (C(2)S), 185.15 (C(4)O)
2
2
2
8,60 ( br s, 1H, N(1)H)
1.04 (t, 6H, J=7.1 Hz, N(CH -CH ) ), 2.60 (q, 4H, J=7.1 Hz,
2
3087 (NH)
1737 (CO)
11.95 (N(CH -CH ) ), 38.98 (C(6)H ), 47.22
3 2 2 2
3
2 2
N(CH -CH ) ), 2.73 (t, 2H, J=7.2 Hz, C(7)H ), 3.90 (t,
(N(CH -CH ) ), 48.47 (C(7)H ), 49.32 (C(5)H ),
3
2 2
2
3 2 2 2 2
2H, J=7.2 Hz, C(6)H ), 4.08 (s, 2H, C(5)H ), 7,95 (br s,
171.61 (C(2)S), 185.08 (C(4)O)
25.98 (C(7)H ), 39.21 (C(6)H ), 44.93 (N(CH ) ),
2
2
H, N(1)H)
1.90 (quint, 2H, J=6.7 Hz and J=7.4 Hz C(7)H ), 2.28 (s,
3
4
3250 (NH)
1726 (CO)
2
2
2
3 2
6H, N(CH ) ), 2.42 (2H, t, 2H, J=7.4 Hz, C(8)H ),
48.69 (C(8)H ), 55.87 (C(5)H ), 172.42 (C(2)S),
184.95 (C(4)O)
3 2
2
2
2
3.82 ( t, 2H, J=6.7 Hz C(6)H ), 4.06 (s, 2H, C(5)H )
2
2
3240 (NH)
1733 (CO)
1.03 (t, 6H, J=7.1 Hz, N(CH -CH ) ), 1.90 (quint, 2H,
10.82 (N(CH -CH ) ), 25.15 (C(7)H ), 39.47
3
2 2
3 2 2 2
J=7.0 Hz and J=7.5 Hz, C(7)H ), 2.60 (t, 2H J=7.5 Hz,
(C(6)H ), 45.89 (N(CH -CH ) ), 48.61 (C(6)H ),
2 3 2 2 2
2
C(8)H ), 2.65 (q, 4H, J=7.1Hz, N(CH -CH ) ), 3.81
49.89 (C(5)H ), 172.18 (C(2)S), 184.88 (C(4)O)
2
3
2 2
2
(t, 2H, J=7.0 Hz, C(6)H ), 4.06 (s, 2H, C(5)H )
2
2
5
1.39 (d, 3H, J= 6.5 Hz, C(7)H ), 2.22 (dd, 1H, J=4.3 Hz and
15.74 (C(7)H ), 45.75 (N(CH ) ), 48.44 (C(6)H),
3 3 2
3
x
y
3100 (NH)
1720 (CO)
J=12.8 Hz C(8)H H ), 2.28 (s, 6H, N(CH ) ), 3.46 (br s,
48.86 (C(5)H ), 60.80 (C(8)H ), 172.23 (C(2)S),
3 2
2
2
y
x
1H, C(8)H H ), 4.07(dd, 2H, J=18.9 Hz, C(5)H ), 4.91(br
185. 99 (C(4)O)
2
s, 1H, C(6)H), 8.49(br s, 1H, N(1)H)

668
J. Ryczek
Vol. 40
Table 2 (continued)
6
1.01 (d, 6H, J=6.4 Hz, N((CH ) -CH) ), 2.67 (t, 2H, J=
20.73 N((CH ) -CH) ), 41.93 N((CH ) -CH) ),
3 2 2 3 2 2
3 2
2
3245 (NH)
1705 (CO)
7.2 Hz, C(7) H ), 3.03 (m, 2H, J=6.4 Hz, N((CH ) -CH) ),
42.16 (C(7)H ), 48.38 (C(6)H ), 48.74
(C(5)H ), 171.47 (C(2)S), 185.33 (C(4)O)
2
2
3 2
2
2 2
3.79 (t, 2H, J=7.2 Hz, C(6)H ), 4.06 (s, 2H, C(5)H ),
2
2
7.48 (br s, 1H, (N(1)H)
3.73 (q, 2H, J=6.2 Hz, C(6)H ), 3.82 (t, 1H, J=6.2 Hz,
7
8
9
3140 (NH)
2475 OH)
1725 (CO)
3145 (NH)
43.69 (C(7)H ), 49.05 (C(6)H ), 59.42 (C(5)H ),
2 2 2
173.19 (C(2)S), 185.78 (C(4)O)
2
OH), 3.88 (t, 2H, J=6.2 Hz, C(7)H ), 4.14 (s, 2H,
2
C(5)H ), 8.90 (br s, 1H, N(1)H)
2
4.34 (s, 2H, C(5)H ), 7.41 (m, 5H, J=7.3 Hz, Ph),
49.71 (C(5)H ), 129.28 (C(7,11)H), 129.43
2
2
2995 (CH )
9.10 (br s, 1H, N(1)H)
(C(9)H), 129.68 (C(8,10)H), 134.93 (C(6)),
172.43 (C(2)S), 185.61 (C(4)O)
2
1755 (CO)
3170 (NH)
1.91 (quint, 2H, J=6.9 Hz and J=7.9 Hz, C(7)H ),
24.16 (C(7)H ), 32.20 (NH-CH ), 39.00
2
2 3
+
2470 (H )
2.88 (t, 2H, J=7.9 Hz, C(8)H ), 3.34 (s, 3H, NH-CH ),
(C(6)H ), 45.72 (C(8)H ), 48.50 (C(5)H ),
2 2 2
2
3
1725 (CO)
3.72 (t, 2H, J=6.9 Hz, C(6)H ), 4.13 (s, 2H, C(5)H ),
172.86 (C(2)S), 183.04 (C(4)O)
2
2
8.85 (br s, 1H, N(1)H)
1.27 (t, 3H, J=7.1 Hz, C(1)
C(1)
14.09 ( H ), 40.45 (C(4)H ), 46.77 (N(CH ) ),
10
11
3350 (NH 1)
3150 (NH 2)
1730 (CO)
H ), 2.98 (s, 6H, N(CH ) ),
3
3 2
3
2
3 2
4.19 (q, 2H, J=7.1 Hz, C(2)H ), 4.41 (d, 2H, J=4.9 Hz,
61.55 (C(2)H ), 113.10 (C(9,13)H), 123.79
(C(8)), 127.28 (C(10,12)H), 149.86
(C(11)), 169.72 C(6)S, 181.33 C(3)O
2
2
C(4)H ), 6.4 (br s, 1H, N(5)H), 6.73 (d, 2H, J= 8.8 Hz,
2
C(10,12)H), 7.12 (d, 2H, J=8.8 Hz, C(9,13)H),
7.75 (br s, 1H, N(7)H)
t, 3H, J=
C(1)
12.40 (N(CH -CH ) ), 14.07 (
3350 (NH 1)
3180 (NH 2)
1735 (CO)
1.17 (t, 6H, J=7.0 Hz, N(CH -CH ) ), 1.27 (
H ), 44,39
3
3
2 2
3
2 2
7.1 Hz, C(1)
H ), 3.36 (q, 4H, J=7.0 Hz, N(CH -CH ) ),
(C(4)H ), 46.75 (N(CH -CH ) ), 61.51
3
3
2 2
2 3 2 2
4.20 (q, 2H, J=7.1 Hz, C(2)H ), 4.43 (d, 2H, J=4.9 Hz,
(C(2)H ), 112.15 (C(9,13)H), 122.43 (C(8)),
2
2
C(4)H ), 6.38 (br s, 1H, N(5)H), 6.60 (d, 2H, J=7.9 Hz,
C(10,12)H), 7.08 (d, 2H, J=7.9 Hz, C(9,13)H),
7.66 (br s, 1H, N(7)H)
127.64 (C(10,12)H), 147.41 (C(11)), 169.69
C(6)S, 181.44 C(3)O
2
12
13
3140 (NH)
2520 (H )
3.06 (s, 6H, N(CH ) ), 4.28 (s, 2H, C(5)H ), 7.30 (m, 4H
C(7,8,10,11)H)
br 44.05 (N(CH ) ), 49.15, (C(5)H ), br 119.24
3 2 2
(C(6)), 129.46 (C(7,8,10,11)H), br 144.91 (C(9)),
172.14 (C(2)S), 183.05 (C(4)O)
3 2
2
+
1730 (CO)
3130 (NH)
1.08 (m, 6H, N(CH -CH ) ), 3.54 (br s, 4H, N(CH -CH ) ),
10.21 (N(CH -CH ) ), 49.30 (C(5)H ), br 51.68
3
2 2
3
2 2
3
2 2
2
+
2520 (H )
4.30 (s, 2H, C(5)H ), 7.52 (br s, 2H C(8, 10)H), 7.94 (br s,
(N(CH -CH ) ), br 122.51 (C(6)), 130.49
2
3 2 2
1725 (CO)
2H, C(7,11)H), 10.49 (br s, 1H, N(1)H)
(C\(7,8,10,11)H), br 138.50 (C(9)), 172.07 (C(2)S),
182.81 (C(4)O)
14
15
16
17
3400 (OH)
3150 (NH)
1740 (CO)
3180 (NH)
4.26 (s, 2H, C(5)H ), 6.83 (d, 2H, J= 8.7 Hz, C(8,10)H),
7.04 (d, 2H, J=8.7 Hz, C(7,11)H), 9.73 (br s, 1H, N(1)H),
10.30 (br s, 1H, OH)
48.93 (C(5)H ), 115.22 (C(8,10)H), 124.51
(C(7,11)H), 129.90 (C(6)), 157.44 (C(9)),
172.42 (C(2)S), 183.90 (C(4)O)
2
2
3.05 (t, 2H, J=6.0 Hz, C(7)H ), 3.90 (t, 2H, J=6.0 Hz,
36.91 (C(7)H ), 37.68 (C(6)H ), 48.80 (C(5)H ),
2
2 2 2
+
2610 (H )
C(6)H ), 4.08 (s, 2H, C(5)H ), 8.20 (br s 2H, NH ), 10.36
173.23 (C(2)S), 182.65 (C(4)O)
2
2
2
1720 (CO)
3150 (NH)
(br s, 1H, N(1)H)
4.92 (d, 2H, J=1.0 Hz, C(5)H ), 7.32 (d, 2H, J=7.8 Hz,
49.16 (C(5)H ), 122.15 (C(8,10)H), 130.09
2
2
+
2550 (H )
C(7,11)H), 7.37 (d, 2H, J=7.8 Hz, C(8,10)H), 9.72
(C(7,11)H), 131.26 (C(6)), 134.57 (C(9)),
172.16 (C(2)S), 183 11 (C(4)O)
1725 (CO)
3140 (NH)
1730 (CO)
(br s, 2H, NH ), 10.46 (br s, 1H, N(1)H)
2
4.33 (s, 2H, C(5)H ), 6.91 (d, 1H, J=9.42 Hz, C(16)H),
49.12 (C(5)H ), 118.70 (C(7,11)H), 121.42 ,
2
2
7.46 (m, 3H, J=8.6 Hz, C(7,11)H and C(19)H), 7.62 (m,
1H, J=7.4 Hz and J=8.0 Hz, C(20)H), 7.79 (d, 1H, J=
7.7 Hz, C(18)H), 7.97 (m, 3H, J=8.0 Hz, C(8,10)H and
C(17)H), 8.56 (d.1H, J=8.0 Hz, C(21)H), 10.48 (br s,
1H, N(1)H)
124.15, 126.03, 127.86, 128.89, 129.13, 129.49,
132.36, 132.69, 140.49, 144.49 (C( 6,9,14,15,16,
17,18,-19, 20,21,22 and 23), 130.11 (C(8,11)H),
172,02 (C(2)S), 183.09 (C(4)O)
18
19
3340 (NH)
1725 (CO)
4.26 (s, 2H, C(5)H ), 6.85 (dd, 1H, J=8.5 Hz and J= 1.8 Hz,
48.85 (C(5)H ), 111.18, 117.89, 119.23, 121.33,
2
2
C(3’)H), 7.17 (br s, 1H, C(7’)H), 7.26 (d, 1H, J=2.5 Hz,
C(6’)H), 7.34 (d, 1H, J=8.5 Hz, C(2’)H), 7.47 (d, 1H,
J=1.7 Hz, C(4’)H), 10.24 (br s, 1H, N(1)H), 10.99 (d,
1H, J=1.8 Hz, N(1’)H)
124.00, 124.23, 126.03, 135.95 (C(2’,3’,4’,
5’,6’ ,7’,8’,9’), 172.5 (C(2)S),
184.44 (C(4)O)
3190 (NH)
1750,
1705 (CO)
4.09 (s, 2H, C(5’)H ), 4.31 (s, 2H, C(5)H ), 7.39 (m, 2H,
46.04 (C(5’)H ), 49.18 (C(5)H ), 126.82 (C(8,10)H),
2 2
2
2
J=8.6 Hz, C(8,10)H), 7.47 (m, 2H, J=8.6 Hz, C(7,11)H),
8.39 (br s, 1H, N(1’)H), 10.46 (br s, 1H, N(1)H),
129.17 (C(7,11)H), 132.22 (C(9)), 132.50 (C(6)),
156.28 (C(2’)O), 171.03 (C(4’)O), 172.19 (C(2)S),
183.07 (C(4)O)
Compounds 1-6 and 10, 11 were measured in CDCl 9, 12-19 in DMSO-d , 7, 8 in acetone-d .
3,
6
6
intermediate III obtained from monoalkylaminoalkylamine
shows no self-cyclization confirms the conclusion that such
self-cyclization depends mainly on the structure of the ester
Syntheses where aromatic diamines are used, (similar to
those with aliphatic diamines having dialkylamine group)
are efficient and lead to 3-monosubstituted 2-thiohydan-
toins of high purity. It was confirmed that the reaction with
aromatic diamines which have dialkylamine group
and not on its basicity (pK of dialkylamines with NH group
b
is higher than that of trialkylamines).

Jul-Aug 2003
669
Synthesis of 3-W-Amino-2-Thiohydantoins
proceeds via an N-substituted ester of thiohydantoic acid
10, 11, that may be isolated. A similar reaction course was
found in the case of reaction of 4-aminophenol with ethyl
isothiocyanatoacetate. The experiments proved that the
self-cyclization takes place only for substituents being an
alkyl group, but not for those with aryl moiety.
containing hydantoin and 2-thiohydantoin rings was
obtained from 3-(4-aminophenyl)-hydantoin and ethyl
isothiocyanatoacetate. This reaction indicates that hetero-
cyclic derivatives of 3-monosubstituted 2-thiohydantoins
may be conveniently prepared by this means.
Derivatives of 3-monosubstituted 2-thiohydantoin with
amine groups as the substituent were obtained by reaction
of an aliphatic or aromatic monoacetyldiamine with ethyl
isothiocyanatoacetate. Due to solubility requirements of
monoacetyldiamines, the reaction was run in anhydrous
ethanol. The intermediate III was cyclized (HCl) to the
respective 3-monosubstituted 2-thiohydantoins 15, 16.
This last compound was diazotized to yield phenyldiazo-
nium salt 16a, which is quite stable in the solution at the
room temperature.
EXPERIMENTAL
Elemental analysis for C,H,N was run on a Perkin Elmer 2400
analyser. The ir spectra were made in KBr discs and registered on
SPECORD 75 IR and JASCO FT/IR-670 spectrometers. Melting
points were measured on a hot stage Boetius apparatus and are
uncorrected. The 1H nmr and 13C nmr spectra were acquired on a
Bruker 500 apparatus, using CDCl3 (for 1 – 6, 10, and 11) or
DMSO-d6 (for 9, 12 – 19) and TMS as internal standard.
Coupling constants are given in Hz. Interpretation of nmr spectra
was assisted by gNMR V3.6 programme. The mass spectra were
recorded using Finnigan INCOS 500 and Varian MAT-112 spec-
trometers at 70 eV. Tlc was performed on aluminum foil covered
with silicagel 60 F254 (Merck). The spots were visualized under
uv light at 254 nm or with iodine vapors. All reagents were from
Aldrich. Reactions with hazardous solvents (benzene, chloro-
form) were run in an efficient fume cupboard.
General procedures
Ethyl Isothiocyanatoacetate II.
Ethyl isothiocyanatoacetate II (123 g) was obtained according
to literature [13] and rectified under vacuum was slowly purged
with oxygen free nitrogen for 10 days. Then the product was dis-
tilled under vacuum yielding 120 g (97.5%) of II free from thio-
phosgene and carbon disulfide.
Synthesis of Compounds 1-7.
To 1 g of II (6.9 mmol) in 20 cm3 of chloroform (1, 6) or 20
cm3 of dichloromethane (5, 7) or 20 cm3 of light petroleum (40-
60 °C) (2-4) was added an equimolar amount of dialkyl-
oaminoalkylamine (1-6) or ethanolamine (7) in 20 cm3 of the
same solvent in which the isothiocyanate was dissolved, drop-
wise at room temperature or at –5 °C. After some time (usually
several minutes) in the case of compounds 2-4 the oily product
was separated and crystallized quickly. For 7 after 1 h a precipi-
tate was formed, whereas for other compounds the solution
stayed homogeneous. After 4 h the reaction mixture was evapo-
rated to dryness under vacuum in rotary evaporator and the
residue was crystallized from the appropriate solvent (see
Table 1). Compounds 1-6 were converted into hydrochlorides
with an ethanol solution of HCl (2 M), the solvent being evapo-
rated under vacuum and the residue was crystallized from appro-
priate solvent (Table 1).
Compound 16a was hydrolyzed to 3-(4-hydroxy-
phenyl)-2-thiohydantoin 14 (identical with that obtained
by synthesis) but in very low yield (ca. 1%) in comparison
to analogous reaction of the hydantoin derivative [17] (ca
45%). The coupling reaction of 16a with 2-naphthol was
run in alkaline solution and yielded azo dye 17 with indi-
cator properties. This reaction did not cause opening of the
thiohydantoin ring although 2-thiohydantoins are more
susceptible to alkaline medium than their 2-oxo analogs
and easily decompose in it.
Synthesis of 3-(5'indolyl)-2-thiohydantoin 18 was
accomplished starting from 5-aminoindole and ethyl
isothiocyanatoacetate. The intermediate III was cyclized
without isolation in acetic acid and HCl medium. In the
case of hydantoin a similar reaction failed. Compound 19,
3-(Phenyl)-2-thioxo-4-imidazolidinone (8) [16] (cyclization with
(C2H5)3N).
Pure N-(phenylthiocarbamoyl)glycine ethyl ester (1.00 g, 4.2
mmol) obtained from ethyl isothiocyanatoacetate and aniline (ir,
1H nmr , 13C nmr, tlc (chloroform (Rf = 0.21); uv, I2, mp 89 °C ),
was dissolved in 25 cm3 of anhydrous ethanol. Then an equimolar
amount (0.424 g) of (C2H5)3N) was added. Afterca. 2 h a precip-
itate started to separate. After 5 h the precipitate was collected by
filtration yielding 0.75 g of 8. After recrystallization from ethanol

670
J. Ryczek
Vol. 40
a yield of 60.5%, mp 259-60 °C was obtained. When chloroform
was used as a solvent instead of ethanol no precipitate was formed
either after 24 h at the room temperature or after 3 h reflux.
3-(4'-Hydroxyphenyl)-2-thioxo-4-imidazolidinone (14).
To diazonium salt 16a (made as described above from 4 g of
amine 16) 40 cm3 of water was added and the mixture was
refluxed for 4 h at 100 °C. The reaction course was monitored by
taking out a small sample and adding alkaline solution of 2-naph-
thol. A red color confirmed the presence of residual diazonium
salt. After completion of reaction the mixture was evaporated
under vacuum, the residue was dried and then extracted twice with
25 cm3 of boiling acetone. The solid was filtered off and the com-
bined acetone filtrates were evaporated to dryness. The residue
was crystallized from ethanol yielding 0.034 g of 14 (ca 1%).
N-(4-Dialkylaminophenylthiocarbamoyl)glycine Ethyl Esters
(10, 11).
To a solution of 1.00 g (6.9 mmol) of ethyl isothiocyanatoac-
etate in 20 cm3 of chloroform an equimolar amount of appropri-
ate 4-dialkylaminophenylamine (methyl or ethyl) in 20 cm3 of
chloroform was added dropwise during 15 min. After 24 h the
solvent was evaporated under vacuum and the solid residue was
crystallized from appropriate solvent (see Table 1)
3-[4-(2-Hydroxy-naphthalen-1-ylazo)-phenyl]-2-thioxo-imida-
zolidin-4-one (17).
Synthesis of Compounds 9, 12-16 and 19.
To 1.00 g (6.9 mmol) of II in 25 cm3 of chloroform (9,12,13)
or 50 cm3 of anhydrous ethanol (14-16,19) an equimolar amount
of diamine (9, 12, 13, 19), monoacetyldiamine (15, 16) or
aminophenol (14) in the same amount of the same solvent was
added dropwise with constant stirring at room temperature. The
reaction mixture was stirred for 4 h and then the solvent was
evaporated under vacuum. The solid residue was dried at 40 °C
under vacuum. In the case of compound 19 the residue was crys-
tallized (72% yield) and the purity was checked by tlc
(acetone:chloroform 1:1, v/v (Rf = 0.40); uv, I2). Mp 208-210 °C.
For other compounds the product was dissolved in 25 cm3 of
ethanol and 25 cm3 of HCl solution (1:1) was added. The solution
was refluxed for 4 h, then the solvent was evaporated and the
solid residue was crystallized from appropriate solvent.
To diazonium salt 16a (made as described above from 2 g of
amine 16) kept at 0 °C an equimolar amount of 2-naphthol (1.18
g) in 5.9 cm3 of 10 % NaOH was quickly added with constant
stirring. A precipitate formed immediately. Then 50 cm3 of water
was added and the mixture was stirred for 0.5 h. The precipitate
was collected by filtration and washed with water until neutral.
The precipitate was dried and crystallized from acetic acid yeld-
ing 2.65 g (89.1%) of 17.
REFERENCES AND NOTES
[1] A. I. Khodair and J. P. Gesson , Phosphorus, Sulfur Silicon
Relat. Elem., 142, 167 (1998).
[2] H. M. Elokdah, S. Y. Chai, T. S. Sulkowski and D. P. Strike ,
US Patent 5,821,372 (1998); Chem. Abstr.,129, 302638a (1998).
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09,090 (2001); Chem. Abstr., 134, 163050r (2001).
[4] T. Ooya, Jpn. Kokai Tokkyo Koho JP 08 43,984 (1996);Chem.
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[5] Q. Zheng, Z. Yao, J. Cheng, Y. Shen and Z. Lu, Chem. Lett.
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[6] P. Dang and A. K. Madan , J. Chem. Inf. Comput. Sci., 34,
1162 (1994).
[7] S. S. Pelosi Jr., Ch. N. Yu and M. A. Calcango, PTC Int. Appl.
WO 93 04,061 (1993); Chem. Abstr., 119, 180776q (1993).
[8] V. Knoppova and L.Drobnica, Chem.Zvesti, 26, 553 (1972).
[9] J. P. Henichart, J. L. Bernier and R. Houssin, Synthesis , 311
(1980).
[10] J. Ryczek and J. Kusowska, Il Farmaco, 38, 383 (1983).
[11] M. Marckwald, N. Neumark and R. Stelzner, Ber., 24, 3278
(1891).
3-(5'-Indolyl)-2-thioxo-4-imidazolidinone (18).
To a solution of 0.22 g of ethyl isothiocyanatoacetate in 20 cm3
of anhydrous ethanol, an equimolar amount (0.20 g) of 5-
aminoindole in 50 cm3 of anhydrous ethanol was added. After 24
h the reaction mixture was evaporated under vacuum, dissolved
in 50 cm3 of glacial acetic acid and refluxed for 3 h. Then the sol-
vent was evaporated and the residue was dissolved in 50 cm3 of
ethanol then 2 M HCl was slowly added until the solution became
opaque. Finally, 20 cm3 of ethanol was added and the solution
was refluxed for 4 h. The solvent was evaporated under vacuum
and the residue was crystallized from diluted ethanol to yield
0.19 g (54.3%) of 18.
4-[3'-(2-Thioxo-4'-imidazolidinonyl-)]benzenediazonium
Chloride (16a).
To a solution of 2.00 g (8.2 mmol) of 3-(4'-aminophenyl)-2-
thiohydantoin hydrochloride 16 in 50 cm3 of water 1.6 cm3 of
conc. HCl was added and the mixture was cooled to 0 °C. Then at
that temperature with constant stirring 0.57 g of NaNO2 (8.3
mmol) in 1.6 cm3 of water was added during 45 min. After addi-
tion of NaNO2 the solution was stirred for 15 min to give a solu-
tion of 16a that was used without purification.
[12] J. Ryczek, Polish Journal of Chem., 68, 2599 (1994).
[13] Houben-Weyl “Methoden der Organischen Chemie” Vol. 9,
876 Thieme Verlag, Stuttgart 1955.
[14] E. Fischer, Ber., 34, 439 (1901).
[15] K. Nowak, Rocz. Chem., 51, 1565 (1977).
[16] P. Edman, Acta Chem. Scand., 4, 277 (1950).
[17] J.Ryczek, J. Heterocyclic Chem., 39, 997 (2002).