Syntheses based on natural α-amino acids. Cyanoethylation of 3-substituted 5-methyl-2-thiohydantoins

Article abstract of DOI:10.1007/s10593-006-0008-3

Starting from α-alanine, the C- and S-cyanoethyl derivatives of 5-methyl-3-phenyl(allyl)-2-thiohydantoins have been synthesized. It was shown that the products of hydrolysis of C-cyanoethyl derivatives, 5-methyl-3-phenyl(allyl)-(β-carboxyethyl)-2-thiohydantoins, are formed in addition. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-006-0008-3

Chemistry of Heterocyclic Compounds, Vol. 41, No. 11, 2005
SYNTHESES BASED ON NATURAL α-AMINO
ACIDS. CYANOETHYLATION OF 3-SUBSTITUTED
5-METHYL-2-THIOHYDANTOINS
A. T. Ayupova and Kh. M. Shakhidoyatov
Starting from α-alanine, the C- and S-cyanoethyl derivatives of 5-methyl-3-phenyl(allyl)-2-
thiohydantoins have been synthesized. It was shown that the products of hydrolysis of C-cyanoethyl
derivatives, 5-methyl-3-phenyl(allyl)-(β-carboxyethyl)-2-thiohydantoins, are formed in addition.
Keywords: acrylonitrile, α-alanine, 2-thiohydantoin, cyanoethylation.
The wide distribution of hydantoins in nature and the presence among them of active regulators of plant
growth [1, 2] has defined the problem of the present work, viz. the synthesis of analogs of these compounds,
substituted 2-thiohydantoins. The closeness of the latter in structure to compounds isolated from a whole family
of plant sources [3], guarantees the safety of their practical use, since degrading enzyme systems exist in plants
preventing an excessive accumulation of both the natural compounds and their analogs [4].
To solve this problem we have studied the cyanoethylation of the known 5-methyl-3-phenyl(allyl)-2-
thiohydantoins 1a,b obtained previously by the interaction of α-alanine with phenyl and allyl isothiocyanates [5].
When using 2-thiohydantoins in synthesis it is necessary to consider the readily occurring isomeric and
tautomeric conversions of these molecules. Its thioamide fragment S=C–NH is a tautomeric triad, in which the
2
equilibrium is displaced in the direction of the NH form [6]. The latter circumstance determines the ambiguity of
the reactivity of anions of compounds of type 1. Investigations showed that predominantly N-alkyl derivatives
are formed on alkylation of 2-thioxoimidazolidines with hard reagents in polar solvents [7, 8]. At the same time
the predominant formation of S-alkylation products is observed in reactions with soft alkylating agents in
solvents of low polarity [9]. In other words, in polar solvents the reaction is directed to the center of basicity, the
N atom of the triad [10-12]. In nonpolar solvents a determining role is played by the polarizability of the reaction
center, which is greater at the sulfur atom than at the nitrogen. It is also known that on alkylation of
imidazolidinethiones the alkylation begins at the more nucleophilic sulfur atom [13], but alkylation of
N-aminoazolinethiones occurs exclusively at the sulfur atom [14] and in this respect they do not differ from
other heterocyclic thiones [15]. In compounds 1a,b there is an additional reaction center at the C(5) atom, at
which alkylation may also occur. Because of this there is undoubted interest in clarifying the direction of
alkylation of thiohydantoins 1a,b.
By cyanoethylating compounds 1a,b with an excess of acrylonitrile in alcohohol in the presence of a
catalytic amount of sodium hydroxide at room temperature, a mixture was obtained in both cases consisting
mainly of products of C and S alkylation 2a,b to 4a,b (overall yield up to 90%, see Table 1), among which the
double alkylation products 3a,b (yields up to 50%) predominated.
_
_________________________________________________________________________________________
S. Yunusov Institute of Chemistry of Plant Substances, Academy of Sciences, Republic of Uzbekistan,
Tashkent 700170; e-mail: Ayup@icps.org.uz. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11,
pp. 1657-1661, November, 2005. Original article submitted February 20, 2002; revision submitted February 14,
2
003.
1
394
0009-3122/05/4111-1394©2005 Springer Science+Business Media, Inc.

R
R
O
N
O
N
N
S
+
CH =CHCN
2
S
CH CH CN
2 2
+
EtOH, NaOH
N
H
Me
Me
1
a,b
2a,b
R
R
R
O
O
O
N
N
N
S
CH CH CN
+
S
+
O
+
2
2
N
N
H
N
H
Me
Me
Me
CH CH CN
2
2
CH CH COOH
2
2
3
a,b
4a,b
5a,b
1
-5 a R = Ph, b R = CH
2
CH=CH
2
The possibility of the reaction occurring at two reactive centers has been described in the literature [16].
It should be mentioned that in the case of products of alkylation only at the carbon atom no corresponding
5
-(β-cyanoethyl) derivatives were obtained, but β-substituted propionic acids 4a,b are formed as a result of
hydrolysis of the latter. Small quantities (up to 10%) of hydantoins 5a,b, products of hydrolytic desulfurization
of the initial compounds 1a,b, were also isolated from the reaction mixtures. The formation of hydantoins on
alkylating thiohydantoins in the presence of alkali has been noted previously [3].
The results obtained indicate that under the conditions studied cyanoethylation occurs at two reactive
centers of the molecule of compounds 1a,b, the sulfur atom and the C atom of the ring.
(
5)
The structures of compounds 2a,b to 5a,b were confirmed by data of elemental analysis (Table 1) and
IR, UV, and NMR spectra (Table 2).
Absorption bands are present in the IR spectra for C=O (2a,b to 5a,b), C≡N (2a,b and 3a,b), NH (4a,b,
5
3
a,b), and OH (4a,b) groups. The disposition of the absorption bands in the UV spectra of compounds 2a,b and
a,b are characteristic of S-alkylation products [17]. In the H NMR spectra of compounds 3a,b and 4a,b the
1
singlet form for the signal of the 5-CH group indicates the absence of proton from position 5, and consequently
3
the presence in this position of a second substituent. The integrated intensity, shape, and position of the proton
TABLE 1. Characteristics of the Synthesized Compounds 2-5
Found, %
Com-
pound
Empirical
formula
——————
Calculated, %
mp, °C
(solvent)
+
R
f
M
Yield, %
15
C
H
N
2
a
C
13
H
13
N
3
OS
60.98
1.66
5.05
5.14
15.9
16.6
200-201
0.27
259
6
(benzene)
2
3
b
a
C
C
10
16
H
13
16
N
3
4
OS
OS
58.39
8.81
5.19
5.83
5.01
5.13
17.19
18.83
17.05
17.95
Oil
0.18
0.60
223
312
25
50
5
H
N
60.95
1.54
140-41
alcohol)
6
(
3
4
b
a
C
C
13
13
H
16
14
N
4
2
OS
56.01
6.32
5.09
5.80
4.98
5.04
19.98
20.29
9.97
10.07
Oil
0.57
0.45
276
278
45
25
5
H
N
O
3
S
S
55.98
6.12
220-221
alcohol)
5
(
4
5
b
a
C
C
10
10
H
14
10
N
2
2
O
3
2
49.02
9.59
5.04
5.79
5.01
5.29
10.98
11.57
14.01
14.74
Oil
0.35
0.75
242
190
22
10
4
H
N
O
62.98
3.16
160-162
alcohol)
6
(
5
b
C
7
H
10
N
2
O
2
54.01
4.55
7.05
7.79
17.98
18.18
95-97
alcohol)
0.27
154
8
5
(
1
395

TABLE 2. Spectral Characteristics of Compounds 2a,b to 4a,b
Com-
pound*
-1
1
IR spectrum, ν, cm
Н NMR spectrum, δ, ppm (J, Hz)
2
2
a
2253 (C≡N), 1749 (C=O), 1.68 (3H, d, J = 7.5, CH
050 (s, C
7.00-7.50 (5H, m, Ar)
2248 (C≡N), 1765 (C=O) 1.75 (3H, d, J = 7.0, CH
.85 (2H, t, J = 7.2, CH
CH cycle); 4.20 (2H, dt, J = 5.6, J = 1.0, N−CH
.03 (2H, t, J = 10.4, =CH ); 5.75 (1H, ddt, J = 15.5,
J = 10.4, J = 5.6, =CH−)
2252 (C≡N), 1750 (C=O), 1.60 (3H, s, CH ); 2.40 (4H, m, CH -α); 3.12 (2H, t, J = 7.0,
3 2
); 2.40 (2H, t, J = 7.0, CH -α);
3
6 5
H )
b
3
); 2.42 (2H, J = 7.2, CH
-β); 4.12 (1H, qd, J = 7.0, J = 1.0,
);
2
-α);
3
2
2
5
2
3
3
a
3
2
3
050 (s, C
6
H
5
)
CH -α); 3.80 (1H, dt, J = 13.0, J = 7.0, CH -β); 4.05 (1H,
2
2
dt, J = 13.0, J = 7.0, CH
2
-β); 7.13-7.55 (5H, m, Ar)
b
2251 (C≡N), 1750 (C=O)
1.70 (3H, s, CH
J = 7.0, CH -α); 3.80 (1H, dt, J = 13.0, J = 7.0, CH
.05 (1H, dt, J = 13.0, J = 7.0, CH
3
); 2.42 (4H, m, CH
2
-α); 3.12 (2H, t,
-β);
-β); 4.20 (2H, dt,
2
2
4
2
J = 5.6, J = 1.0, N−CH
2
2
); 5.03 (2H, t, J = 10.4, =CH );
5.75 (1H, ddt, J = 15.5, J = 10.4, J = 5.6, =CH−)
4
4
a
3753 (NH), 3480 (OH),
1.68 (3H, s, CH
3
); 2.32 (1H, m, CH
2
-α); 2.48 (1H, CH -α);
2
2
1
1
3
755 (C=O), 1630 (C=O), 2.55 (1H, m, CH -β); 2.62 (1H, m, CH -β);
2
080, 1210 (C=S),
050 (s, C
7.45 (2H, m, Ar); 7.65 (3H, m, Ar)
6
5
H )
b
3750 (NH), 3480 (OH),
1.75 (3H, s, CH ); 2.32 (1H, m, CH
3
2
-α); 2.48 (1H, m,
1
1
765 (C=O), 1630 (C=O), CH -α); 2.55 (1H, m, CH -β); 2.62 (1H, m, CH -β);
080-1210 (C=S)
2
2
2
4.40 (2H, dt, J = 5.6, J = 1.0, N−CH ); 5.03 (2H, t,
2
2
J = 10.4, =CH ); 5.75 (1H, ddt, J = 15.5, J = 10.4,
J = 5.6, =CH−)
_
*
2
______
UV spectrum, λmax, nm (log ε): 2a 246 (3.21), 268 (4.01); 2b 248 (3.25),
78 (4.01); 3a 246 (3.25), 278 (4.01); 3b 248 (3.17), 178 (4.01).
signals of the substituents for all compounds 2-5 were in agreement with the proposed structures. There were
peaks in the mass spectra of compounds 2-4 of medium intensity for the molecular ions, the character of the
breakdown of which confirms the structures of these products.
EXPERIMENTAL
The IR spectra (KBr disks) were obtained on a Perkin-Elmer 2000 Fourier spectrometer, the mass
1
spectra on a MX 1303 instrument, and the H NMR spectra on a INM 4-100 instrument in CDCl , internal
3
standard was HMDS (δ 0.05 ppm). The UV spectra of solutions in ethanol were taken on a Hitachi EPS 3T
spectrometer. The purity of the products and the progress of reactions was checked by TLC on Silufol UV 254
plates in the system methanol–benzene, visualizing with iodine vapor.
Interaction of 3-R-5-methyl-2-thiohydantoins 1a,b with Acrylonitrile. Thiohydantoin 1a (1.03 g,
0
0
.005 mol) and a catalytic quantity of sodium hydroxide were added to a solution of acrylonitrile (1.98 g,
.015 mole) in alcohol (20 ml). The mixture obtained was stirred for 1 h forming a transparent solution, from
which a copious white precipitate began to precipitate. The reaction mixture was maintained at room
temperature for 1 h, the solid was filtered off, and recrystallized from alcohol. 5-(β-Cyanoethyl)-2-(β-
cyanoethylthio)-5-methyl-3-phenylhydantoin (3a) (0.78 g) was obtained. The filtrate was evaporated, the
residue, oily crystals of a light yellow color, was treated with 5% sodium hydroxide solution, and further (0.1 g)
product 3a was filtered off. The alkaline mother liquor was neutralized with dilute hydrochloric acid, the
precipitated solid was filtered off, and recrystallized from benzene. 2-(β-Cyanoethylthio)-5-methyl-3-
1
396

phenylhydantoin (2a) (0.19 g) was obtained. The neutral mother liquor was acidified with dilute hydrochloric
acid to pH 3, the precipitated solid was filtered off, and recrystallized from alcohol. 5-(β-Carboxyethyl)-5-
methyl-3-phenyl-2-thiohydantoin (4a) (0.35 g) was obtained. The mother liquor after isolating compound 4a
was acidified with hydrochloric acid to pH 1, the precipitated solid was recrystallized from alcohol (to remove
contamination by starting material 1a), and 5-methyl-3-phenylhydantoin (5a) (0.095 g) was obtained.
The interaction of acrylonitrile with thiohydantoin 1b was carried out analogously and 3-allyl-2-(β-
cyanoethylthio)-5-methylhydantoin (2b), 3-allyl-5-(β-cyanoethyl)-2-(β-cyanoethylthio)-5-methylhydantoin (3b),
3
-allyl-5-(β-carboxyethyl)-5-methyl-2-thiohydantoin (4b), and 3-allyl-5-methylhydantoin (5b) respectively,
were isolated.
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