Synthesis of new 2,5-diamino-1,3-thiazole and 2-thiohydantoin derivatives by condensation of N-(2-Aryl-1-chloro-2-oxoethyl) carboxamides with thioureas

Article abstract of DOI:10.1134/S1070363208070268

N-(2-Aryl-1-chloro-2-oxoethyl) carboxamides react under mild conditions with thiourea, N-alkyl-and N-arylthioureas, and various N,N′-disubstituted thioureas, following the Hantzsch reaction scheme. The reactions are selective, and the resulting 2,5-diamin

Full text of DOI:10.1134/S1070363208070268

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 7, pp. 1427–1435. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © A.G. Balya, A.N. Chernega, S.A. But, A.N. Vasilenko, V.S. Brovarets, B.S. Drach, 2008, published in Zhurnal Obshchei Khimii,
2008, Vol. 78, No. 7, pp. 1194–1202.
Synthesis of New 2,5-Diamino-1,3-thiazole
and 2-Thiohydantoin Derivatives by Condensation
of N-(2-Aryl-1-chloro-2-oxoethyl) Carboxamides with Thioureas
A. G. Balyaa, A. N. Chernegab, S. A. Butb, A. N. Vasilenkoa, V. S. Brovaretsa, and B. S. Dracha
a Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine
e-mail: drach@bpci.kiev.ua
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 5, Kiev, 02660 Ukraine
Received August 17, 2007
Abstract—N-(2-Aryl-1-chloro-2-oxoethyl) carboxamides react under mild conditions with thiourea, N-alkyl-
and N-arylthioureas, and various N,N′-disubstituted thioureas, following the Hantzsch reaction scheme. The
reactions are selective, and the resulting 2,5-diamino-1,3-thiazole derivatives undergo recyclization acid
followed by hydrolysis to give substituted 2-thiohydantoins on heating with hydrochloric acid in ethanol.
DOI: 10.1134/S1070363208070268
Accessible N-(2-aryl-1-chloro-2-oxoethyl) carbox-
amides of the general formula ArCOCHClNHCOR
may be regarded as most reactive phenacylating
agents; they are readily obtained from the addition
products of carboxylic acid amides and aryl(oxo)
acetaldehydes [1–5]. These compounds turned out to
be suitable for the synthesis of a series of nitrogen-
containing heterocycles [3, 6–10]; however, the scope
of their application has been studied poorly. In the
present work we examined in detail the possibility of
using compounds I and II for the preparation of new
derivatives of 2,5-diamino-1,3-thiazole (III–VIII) and
2-thiohydantoin (IX–XIV) (Scheme 1, Table 1).
COCHCl fragment in I and II and that the N-acyl
moiety remains intact. The IR and H NMR spectra of
condensation products III and IV contained absorption
1
bands and signals assignable to the amide bond and
1
primary amino group. In the H NMR spectra of VII
and VIII we observed only one set of signals from
ptotons in the R1, R3, Ar1, and Ar2 groups, which
indicated high regioselectivity of the condensation of I
and II with unsymmetrically substituted thioureas
having an aryl group at one nitrogen atom and alkyl,
aralkyl, or alkenyl group at the other nitrogen atom.
The structure of products VII and VIII was finally
proved by X-ray analysis of a single crystal of
compound VIIIj obtained by reaction of IIc (Ar1 = 4-
MeC6H4, R1 = 2-furyl) with N-allyl-N′-(4-ethoxy-
phenyl)thiourea. The structure of molecule VIIIj is
shown in Fig. 1. The central five-membered heteroring
S1N1C1C2C3 is planar within 0.009 Å. The benzene
rings C9–C14 and C19–C24 with the S1N1C1C2C3 ring
plane form dihedral angles of 67.7 and 89.5°,
respectively, and the dihedral angle between the
thiazole and furan (O2C5C6C7C8) rings is 29.5°. The N3
atom has a planar–trigonal configuration: the sum of
the bond angles at that atom is 360.0°. Conjugation
between the unshared electron pair on the N3 atom
with the π-electron system of the thiazole ring and
Compounds I and II (Ar1 = Ph, 4-MeC6H4) were
brought into cyclocondensation with thiourea, N-alkyl-
and N-arylthioureas, and various N,N′-disubstituted
thioureas. The direction of such reactions with thiourea
was determined previously [7, 11], while the regio-
selectivity in the condensation involving both
electrophilic centers in the α-chloro carbonyl fragment
of I and II and nitrogen and sulfur nucleophilic centers
in unsymmetrically substituted thioureas was
established only on the basis of a combination of
spectral, X-ray diffraction, and chemical studies
(Scheme 1, Table 2, Fig. 1). The IR and 1H NMR data
showed that the cyclization actually involves the
1427

1428
BALYA et al.
Scheme 1.
R3
HN
H2N
S
NHAr2;
Ar1
O
(1)
NH2;
(1)
O
S
R1
N
H
Cl
(2) NaHCO3
(2) NaHCO3
Iа−Ic, IIа−IIc
H2N
(1)
NHR2;
S
(2) NaHCO3
R3
Ar1
Ar1
Ar1
O
O
O
N
N
N
NHR2
NH2
N
R1
R1
N
R1
N
H
N
S
S
S
Ar2
H
H
III, IV
Vа−Vd, VIа−VId
VIIа−VIIm, VIIIа−VIIIk
HCl, H2O, Δ
HCl, H2O, Δ
HCl, H2O, Δ
R3
Ar1
Ar1
Ar1
N
NH
S
NH
O
S
O
O
S
N
N
N
Ar2
XIIа−XIIh, XIVа−XIVg
R2
XIа−XId, XIIа−XIId
H
IX, X
I, III, V, VII, IX, XI, XIII, Ar1 = C6H5; II, IV, VI, VIII, X, XII, XIV, Ar1 = 4-CH3C6H4; Ia, IIa, III, IV, Va–Vd, VIa–
VId, VIIa–VIIh, VIIIa–VIIIg, R1 = CH3; Ib, IIb, VIIi–VIIk, VIIIh) R1 = C6H5; Ic, IIc, VIIl, VIIm, VIIIi–VIIIk, R1 = 2-
furyl; Va, VIa, XIa, XIIa, R2 = CH3; Vb, VIb, XIb, XIIb, R2 = C6H5CH2; Vc, VIc, XIc, XIIc, R2 = C6H5; Vd, VId, XId,
XIId, R2 = 4-CH3C6H4; VIIa, VIIIa, XIIIa, XIVa, R3 = CH3; VIIb, VIIi, VIIl, VIIIi, XIIIb, R3 = CH3OCH2CH2; VIIc,
VIIj, VIIm, VIIIb, VIIIj, XIIIc, XIVb, R3 = CH2=CHCH2; VIId, VIIIc, XIIId, XIVc, R3 = C6H5CH2; VIIe, VIIId, XIIIe,
XIVd, R3 = 4-CH3OC6H4CH2; VIIf, VIIk, VIIIe, VIIIh, VIIIk, XIIIf, XIVe, R3 = 2-furylmethyl; VIIg, VIIIf, XIIIg,
XIVf, R3 = 4-CH3C6H4; VIIh, VIIIg, XIIIh, XIVg, R3 = 4-C2H5OC6H4; VIIa, VIIb, VIId–VIIf, VIIi, VIIk, VIIl, VIIIa,
VIIIc–VIIIe, VIIIh, VIIIi, VIIIk, XIIIa, XIIIb, XIIId–XIIIf, XIVa, XIVc–XIVe, Ar2 = C6H5; VIIg, VIIIf, XIIIg, XIVf,
Ar2 = 4-CH3C6H4; VIIc, VIIh, VIIj, VIIm, VIIIb, VIIIg, VIIIj, XIIIc, XIIIh, XIVb, XIVg, Ar2 = 4-C2H5OC6H4.
C=O bond (the conformation of molecule VIIIj is
favorable for this interaction) leads to shortening of the
N3–C1 [1.400(5) Å] and N3–C4 bonds [1.349(2) Å]
relative to a purely single N(sp2)–C(sp2) bond (1.43–
1.45 Å) [19, 20].
Cl carbon atom in I and II interacts mainly with the
sulfur center in the thiourea reagent and that the
carbonyl group in the COCHClNH fragment
preferentially interacts with either primary amino
group or (if the latter is lacking) NHAlk,
NHCH2CH=CH2, NHCH2Ar, or NHCH2Ht group
which is more nucleophilic than NHAr group. Thus the
examined condensations occur under very mild
conditions (THF, 20–25°C) in a regioselective fashion
Taking into account the above data, as well as the
results of chemical transformations of compounds III–
VIII (see below), we can state that the electrophilic C–
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SYNTHESIS OF NEW 2,5-DIAMINO-1,3-THIAZOLE
1429
Table 1. Yields, melting points, and elemental analyses of compounds III–XIV
Found, %
Calculated, %
N S
Comp.
no.
Yield, %а
mp, °C (solvent)
Formula
N
S
73
75
232–234 (AcOH)
243–245 (EtOH)
211–213 (EtOH)
158–160 (EtOH)
227–229 (EtOH)
181–183 (MeOH)
215–217 (EtOH)
167–169 (EtOH)
183–185 (EtOH)
159–161 (EtOH)
211–213 (i-PrOH)
125–126 (EtOH)
138–140 (i-PrOH)
167–168 (i-PrOH)
167–169 (EtOH)
166–168 (i-PrOH)
107–109 (i-PrOH)
173–174 (EtOH)
169–171 (CH3CN)
164–166 (MeOH)
137–139 (EtOH)
103–105 (EtOH)
174–176 (i-PrOH)
110–112 (EtOH)
166–168 (i-PrOH)
201–202 (EtOH)
190–192 (EtOH)
179–181 (i-PrOH)
161–163 (CH3CN)
122–124 (EtOH)
143–144 (MeOH)
147–149 (EtOH)
223–224d (EtOH)
247–248 (EtOH)
153–154e (C6H6)
150–151 (EtOH)
227–229f (MeOH)
233–235g (CH3CN)
157–158 (C6H6)
127–129 (EtOH)
232–233 (EtOH)
203–205 (EtOH)
17.93
16.83
16.79
12.81
13.39
12.85
15.99
12.29
12.78
12.29
10.26
10.49
10.53
9.59
13.63
12.79
12.87
9.95
10.29
9.79
12.19
9.31
9.78
9.36
7.84
8.01
7.95
7.29
7.39
7.59
6.67
7.29
6.95
6.99
7.60
6.99
9.41
7.69
7.62
7.79
7.39
6.41
6.80
7.23
6.81
6.93
16.74
15.39
15.37
11.65
11.96
11.19
14.39
10.75
11.19
10.69
C11H11N3OS
C12H13N3OS
C12H13N3OS
C18H17N3OS
C17H15N3OS
C18H17N3OS
C13H15N3OS
C19H19N3OS
C18H17N3OS
C19H19N3OS
C20H22ClN3О2Sb
C22H23N3O2S
C24H21N3OS
C25H23N3O2S
C22H20ClN3O2Sc
C25H23N3OS
C27H27N3O3S
C25H23N3O2S
C27H25N3O2S
C27H21N3O2S
C23H21N3O3S
C25H23N3O3S
C19H19N3OS
C23H25N3O2S
C25H23N3OS
C23H21N3O2S
C26H25N3OS
C28H29N3O3S
C28H23N3O2S
C24H23N3O3S
C26H25N3O3S
C26H21N3O3S
C9H8N2OS
18.01
16.99
16.99
12.99
13.58
12.99
16.07
12.45
12.99
12.45
10.40
10.67
10.51
9.78
13.74
12.96
12.96
9.91
III
IV
77
Va
84
Vb
73
10.36
9.91
Vc
60
Vd
81
12.26
9.50
VIa
80
VIb
71
9.91
VIc
67
9.50
VId
69
7.93
VIIb
VIIc
VIId
VIIe
VIIf
VIIg
VIIh
VIIi
VIIj
VIIk
VIIl
VIIm
VIIIa
VIIIb
VIIIc
VIIIe
VIIIf
VIIIg
VIIIh
VIIIi
VIIIj
VIIIk
IX
81
8.14
67
8.02
63
7.46
68
9.73
9.86
7.52
56
10.01
8.69
10.16
8.87
7.75
61
6.77
77
9.59
9.78
7.46
80
9.09
9.22
7.03
74
9.19
9.30
7.10
81
9.93
10.01
9.43
7.64
71
9.28
7.19
69
12.29
10.16
10.03
10.26
9.63
12.45
10.31
10.16
10.41
9.82
9.50
73
7.86
74
7.75
79
7.94
53
7.50
59
8.49
8.61
6.57
74
8.91
9.02
6.88
79
9.51
9.69
7.39
69
9.03
9.14
6.97
83
9.09
9.22
7.03
76 (81)
71 (75)
88
14.42
13.43
13.41
9.75
14.57
13.58
13.58
9.92
16.68
15.54
15.54
11.35
11.94
11.35
14.55
10.81
11.35
10.81
C10H10N2OS
C10H10N2OS
C16H14N2OS
C15H12N2OS
C16H14N2OS
C11H12N2OS
C17H16N2OS
C16H14N2OS
C17H16N2OS
X
XIа
78
XIb
87
10.40
9.83
10.44
9.92
XIc
86
XId
86
12.53
9.40
12.71
9.45
XIIa
XIIb
XIIc
XIId
78
79
9.85
9.92
83
9.29
9.45
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1430
BALYA et al.
Found, %
Table 1. (Contd.)
Comp.
Calculated, %
N S
Yield, %а
mp, °C (solvent)
Formula
no.
N
S
(69)
81
202–204 (EtOH)
121–122 (EtOH)
140–141 (EtOH)
191–192 (CH3CN)
188–190 (АсOH)
149–150 (EtOH)
180–192h (EtOH)
182–184 (CH3CN)
184–186 (EtOH)
129–131 (EtOH)
201–202 (CH3CN)
185–187 (CH3CN)
169–170 (EtOH)
144–146 (EtOH)
164–166 (EtOH)
9.79
8.43
7.79
7.71
7.15
7.95
7.39
6.31
9.31
7.51
7.45
6.83
7.64
7.11
6.09
11.29
9.73
9.01
8.79
8.09
9.11
8.49
7.35
10.75
8.69
8.53
7.90
8.75
8.19
7.03
C16H14N2OS
C18H18N2O2S
C20H20N2O2S
C22H18N2OS
C23H20N2O2S
C20H16N2O2S
C23H20N2OS
C25H24N2O3S
C17H16N2OS
C21H22N2O2S
C23H20N2OS
C24H22N2O2S
C21H18N2O2S
C24H22N2OS
C26H26N2O3S
9.92
8.58
7.94
7.81
7.21
8.04
7.52
6.47
9.45
7.64
7.52
6.96
7.73
7.24
11.35
9.82
9.09
8.94
8.25
9.20
8.60
7.41
10.81
8.75
8.60
7.96
8.84
8.29
7.18
XIIIа
XIIIb
XIIIc
XIIId
XIIIe
XIIIf
XIIIg
XIIIh
XIVa
XIVb
XIVc
XIVd
XIVe
XIVf
XIVg
79
82 (71)
91 (86)
83
81
83
75 (63)
81
75 (68)
(71)
69
79
76
6.27
a
c
The yields according to method b are given in parentheses. b VIIb·HCl. Found, %: Cl 8.61. Calculated, %: Cl 8.77. VIIf·HCl. Found,
d
%: Cl 8.21. Calculated, %: Cl 8.32. Published data: mp 220°C [12], 227°C [13], 225°C [14]; samples were synthesized from
phenylglycine. Published data [15]: mp 159–160°C. Published data: mp 232–233°C [16], 232.1–233.6°C [17]; samples were
e
f
g
synthesized from phenylglycine. Published data [16]: mp 237–238°C; sample was synthesized from the corresponding amino acid and
phenyl isothiocyanate. h Coincided with the melting point of the condensation product of phenyl(oxo)acetaldehyde with N,N′-bis(p-tolyl)
thiourea [18].
Table 2. IR and 1H NMR spectra of compounds III–XIVa
Comp. no.
III
1H NMR spectrum (DMSO-d6), δ, ppm
1.99 s (3H, CH3), 6.70 br.s (2H, NH2), 7.21–7.68 m (5Harom), 9.80 s (1H, NH)
1.98 s (3H, CH3), 2.32 s (3H, CH3), 6.59 br.s (2H, NH2), 7.14–7.56 m (4H, Harom), 9.64 s (1H, NH)
2.00 s (3H, CH3), 2.83 d (3H, CH3), 7.20 m (1H, NH), 7.23–7.72 m (5H, Harom), 9.76 s (1H, NH)
1.99 s (3H, CH3), 4.44 d (2H, CH2), 7.77 t (1H, NH), 7.21–7.71 m (10H, Harom), 9.73 s (1H, NH)
2.07 s (3H, CH3), 6.95–7.77 m (10H, Harom), 9.95 s (1H, NH), 10.18 s (1H, NH)
IV
Va
Vb
Vc
2.06 s (3H, CH3), 2.28 s (3H, CH3), 7.09–7.76 m (9H, Harom), 9.91 s (1H, NH), 10.14 s (1H, NH)
1.99 s (3H, CH3), 2.31 s (3H, CH3), 4.44 d (2H, CH2), 7.18–7.59 m (9H, Harom), 7.95 t (1H, NH), 9.81 s (1H, NH)
2.05 s (3H, CH3), 2.25 s (3H, CH3), 2.34 s (3H, CH3), 7.10–7.67 m (8H, Harom), 9.89 s (1H, NH), 10.06 s (1H, NH)
1.99 s (3H, CH3), 3.11 s (3H, CH3), 3.49 t (2H, CH2), 4.26 t (2H, CH2), 7.40–7.69 m (10H, Harom), 10.59 s (1H, NH)
Vd
VIb
VId
VIIb
VIIc
1.31 t (3H, CH3), 1.82 s (3H, CH3), 4.00 m (2H, CH2), 4.25 d (2H, CH2), 4.88–5.07 m (2H, CH2), 5.74 m (1H, CH), 6.87–
7.48 m (9H, Harom), 9.42 s (1H, NH)
1.81 s (3H, CH3), 4.92 s (2H, CH2), 6.92–7.41 m (15H, Harom), 9.39 s (1H, NH)
VIId
VIId
1.98 s (3H, CH3), 3.72 s (3H, CH3), 5.36 s (2H, CH2), 6.77–7.56 m (14H, Harom), 10.61 s (1H, NH)
VIIeb
VIIg
VIIh
2.05 s (3H, CH3), 5.41 s (2H, CH2), 6.31–7.56 m (13H, Harom)
1.85 s (3H, CH3), 2.24 s (3H, CH3), 2.26 s (3H, CH3), 6.74–7.22 m (13H, Harom), 9.50 s (1H, NH)
1.31 m (6H, 2CH3), 1.85 s (3H, CH3), 3.95 m (4H, 2CH2), 6.73–7.24 m (13H, Harom), 9.47 s (1H, NH)
3.14 s (3H, CH3), 3.58 m (2H, CH2), 3.89 m (2H, CH2), 6.96–7.71 m (15H, Harom), 9.75 s (1H, NH)
VIIi
VIIj
1.35 t (3H, CH3), 3.97 m (2H, CH2), 4.33 m (2H, CH2), 4.98–5.11 m (2H, CH2), 5.83 m (1H, CH), 6.81–7.70 m (14H, Harom),
9.72 s (1H, NH)
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SYNTHESIS OF NEW 2,5-DIAMINO-1,3-THIAZOLE
1431
Table 2. (Contd.)
Comp. no.
1H NMR spectrum (DMSO-d6), δ, ppm
4.98 s (2H, CH2), 6.01–7.69 m (18H, Harom), 9.91 s (1H, NH)
VIIk
VIIl
3.09 s (3H, CH3), 3.54 t (2H, CH2), 3.88 t (2H, CH2), 6.59–7.84 m (13H, Harom), 9.76 s (1H, NH)
1.32 t (3H, CH3), 3.98 m (2H, CH2), 4.32 d (2H, CH2), 4.93–5.11 m (2H, CH2), 5.79 m (1H, CH), 6.60–7.84 m (12H, Harom),
9.76 s (1H, NH)
VIIm
1.81 s (3H, CH3), 2.39 s (3H, CH3), 6.94–7.31 m (9H, Harom), 9.32 s (1H, NH)
VIIIa
VIIIb
1.31 t (3H, CH3), 1.82 s (3H, CH3), 2.36 s (3H, CH3), 3.99 m (2H, CH2), 4.23 d (2H, CH2), 4.89–5.08 m (2H, CH2), 5.74 m
(1H, CH), 6.82–7.29 m (8H, Harom), 9.43 s (1H, NH)
1.81 s (3H, CH3), 2.35 s (3H, CH3), 4.90 s (2H, CH2), 6.90–7.31 m (14H, Harom), 9.33 s (1H, NH)
1.81 t (3H, CH3), 2.39 s (3H, CH3), 4.83 s (2H, CH2), 6.02–7.41 m (12H, Harom), 9.33 s (1H, NH)
1.85 s (3H, CH3), 2.26 s (9H, 3CH3), 6.72–7.07 m (12H, Harom), 9.43 s (1H, NH)
VIIIc
VIIIe
VIIIf
VIIIh
VIIIi
VIIIj
2.35 s (3H, CH3), 4.93 s (2H, CH2), 6.06–7.71 m (17H, Harom), 9.73 s (1H, NH)
2.34 s (3H, CH3), 3.11 s (3H, CH3), 3.53 t (2H, CH2), 3.86 t (2H, CH2), 6.59–7.83 m (12H, Harom), 9.69 s (1H, NH)
1.31 t (3H, CH3), 2.33 s (3H, CH3), 4.00 m (2H, CH2), 4.31 d (2H, CH2), 4.95–5.12 m (2H, CH2), 5.79 m (1H, CH), 6.59–
7.29 m (11H, Harom), 9.68 s (1H, NH)
2.33 s (3H, CH3), 4.93 s (2H, CH2), 6.04–7.84 m (15H, Harom), 9.74 s (1H, NH)
5.28 s (1H, CH), 7.26–7.43 m (5H, Harom), 10.40 s (1H, NH), 11.75 s (1H, NH)
2.32 s (3H, CH3), 5.20 s (1H, CH), 7.24–7.43 m (4H, Harom), 10.32 s (1H, NH), 11.68 s (1H, NH)
3.12 s (3H, CH3), 5.32 s (1H, CH), 7.28–7.41 m (5H, Harom), 10.69 s (1H, NH)
4.91 s (2H, CH2), 5.41 s (1H, CH), 7.22–7.41 m (10H, Harom), 10.77 s (1H, NH)
5.52 s (1H, CH), 7.26–7.51 m (10H, Harom), 10.94 s (1H, NH)
VIIIk
IX
X
XIa
XIb
XIc
2.37 s (3H, CH3), 5.50 s (1H, CH), 7.13–7.44 m (9H, Harom), 10.92 s (1H, NH)
2.33 s (3H, CH3), 5.55 s (1H, CH), 7.28–7.52 m (9H, Harom), 10.98 s (1H, NH)
XId
XIIc
XIIIa
XIIIb
XIIIc
3.16 s (3H, CH3), 5.53 s (1H, CH), 7.31–7.51 m (10H, Harom
3.25 s (3H, CH3), 3.26–4.31 m (4H, 2CH2), 5.58 s (1H, CH), 7.32–7.51 m (10H, Harom
1.38 t (3H, CH3), 3.72 m, 4.82 m (2H, CH2), 4.07 m (2H, CH2), 5.14 m (2H, CH2), 5.45 s (1H, CH), 5.76 m (1H, CH), 6.95–
7.47 m (9H, Harom
4.26 d and 5.49 d (1H each, CH2, J = 15.3 Hz), 5.36 s (1H, CH), 7.21–7.56 m (15H, Harom
3.74 s (3H, CH3), 4.15 d and 5.46 d (1H each, CH2, J = 15.0 Hz), 5.32 s (1H, CH), 6.82–7.51 m (14H, Harom
4.37 d and 5.39 d (2H, CH2, J = 15.6 Hz), 5.40 s (1H, CH), 6.26–7.52 m (13H, Harom
2.42 s (3H, CH3), 2.38 s (3H, CH3), 6.21 s (1H, CH), 7.15–7.44 m (13H, Harom
1.32 t (3H, CH3), 1.39 t (3H, CH3), 3.95 m (2H, CH2), 4.06 m (2H, CH2), 6.05 s (1H, CH), 6.81–7.38 m (13H, Harom
)
)
)
)
XIIId
XIIIe
XIIIf
XIIIg
XIIIh
)
)
)
)
2.35 s (3H, CH3), 3.13 s (3H, CH3), 5.47 s (1H, CH), 7.20–7.51 m (9H, Harom
1.38 t (3H, CH3), 2.36 s (3H, CH3), 3.68 m, 4.81 m (2H, CH2), 4.08 m (2H, CH2), 5.15 m (2H, CH2), 5.39 s (1H, CH), 5.75 s
(1H, CH), 6.69–7.27 m (8H, Harom
2.36 s (3H, CH3), 4.19 d, 5.51 d (2H, CH2, J = 15.3 Hz), 5.28 s (1H, CH), 7.16–7.51 m (14H, Harom
)
XIVa
XIVb
)
)
XIVc
XIVd
2.37 s (3H, CH3), 3.75 s (3H, CH3), 4.10 d and 5.48 d (1H each, CH2, J = 15.0 Hz), 5.23 s (1H, CH), 6.82–7.51 m (13H,
Harom
)
2.36 s (3H, CH3), 4.29 d and 5.42 d (1H each, CH2, J = 15.6 Hz), 5.33 s (1H, CH), 6.27–7.52 m (12H, Harom
)
XIVe
XIVf
2.27 s (6H, 2CH3), 2.40 s (3H, CH3), 6.07 s (1H, CH), 7.11–7.39 m (12H, Harom
)
a
IR spectra, ν, cm–1: compounds III–VI: 3100–3400 (NHas), 1640–1660 (C=O); VII–VIII: 3100–3400 (NHas), 1610–1660 (band with a
shoulder; C=O, C=N); IX–XII: 3150–3180 (NHas), 1740–1760 (C=O); XIII–XIV: 1740–1760 (C=O). The H NMR spectrum was
b
1
recorded in CF3COOD.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 7 2008

1432
BALYA et al.
in the presence of iodine should be noted; it gives 2-
amino-5-benzoylamino-4-phenyl-1,3-thiazole [23].
C18
N2
C17
C16
C2
However, the scope of application of this simple
synthesis was poorly studied, the yields of substituted
thiazoles like III are considerably lower than in the
reactions with compounds I and II, and derivatives
like V–VIII are quite difficult to obtain due to lower
regioselectivity of the cyclization.
C20
C21
C25
C24
N1
C22
C26
C13 C14
C3
S1
O1
C15
O3
C19
C9
C23
C12
C1
N3
C5
C11 C10
C4
C6
Interestingly, all cyclization products III–VIII were
converted into the corresponding 2-thiohydantoin
derivatives IX–XIV on heating with hydrochloric acid
in ethanol (Scheme 1). Among these transformations,
only the reaction of 2-amino-5-benzoylamino-4-
phenyl-1,3-thiazole with 10% hydrochloric acid has
been reported previously [24]. Thus we have
demonstrated general character of the reaction of
various 2-amino-5-acylamino-1,3-thiazoles III–VI
with hydrochloric acid. Obviously, the transformation
begins with recyclization which is followed by acid
hydrolysis of the acylamino group. A plausible
mechanism of this complex process is ahown in
Scheme 2. Recyclization of III–VI is unlikely to
directly involve the thiazole ring, for the latter is
aromatic and its cleavage is difficult. However, the
presence of an acylamino group in the 5 position of the
thiazole ring could give rise to prototropy, and
structure A can be converted (at least to a small extent)
into nonaromatic structure B which can be readily
cleaved with ethanol in the presence of hydrogen
chloride. The subsequent recyclization C→D and
hydrolysis of the acylamino group D→E seem to be
quite feasible (Scheme 2). Naturally, analogous
transformations could be drawn for substituted 2-
imino-2,3-dihydro-1,3-thiazoles VII and VIII.
O2
C8
C7
Fig. 1. Structure of the molecule of N-[3-methyl-4-(4-
methylphenyl)-2-phenylimino-2,3-dihydro-1,3-thiazol-5-yl]
acetamide (VIIIj) according to the X-ray diffraction data.
Principal bond lengths (Å) and bond angles (deg): S1–C1
1.752(3), S1–C3 1.782(3), N1–C2 1.396(5), N1–C3 1.383(4),
N2–C3 1.269(5), N2–C24 1.427(5), N3–C1 1.400(5), N3–C4
1.349(5), C1–C2 1.334(5), C1S1C3 90.2(2), C2N1C3 114.7(3),
C3N2C24 118.2(3), C1N3C4 125.2(3), S1C1C2 112.8(3),
N1C2C1 113.4(3).
according to the Hantzsch reaction scheme and lead to
the formation of compounds III–VIII. Many simpler
α-halocarbonyl compounds are known [21, 22] to react
with substituted thioureas in a similar way; unlike
these, reagents I and II contain a very labile chlorine
atom, which allows the reaction to occur under mild
conditions ensuring enhanced regioselectivity.
Undoubtedly, selective introduction of an acylamino
substituent into the 5 position of 2-amino-1,3-thiazole
or 2-imino-2,3-dihydro-1,3-thiazole system attracts
strong interest from the preparative viewpoint, for the
above approach is often the only one leading to such
thiazole derivatives. Among other methods, the
reaction of 1-benzoylaminoacetophenone with thiourea
Scheme 2.
Ar
Ar
O
O
N
N
N
H
N
N
N
S
S
H
H
H
А
B
EtOH, H+
Ar
Ar
H
H
Ar
H
O
O
H3O+
N
N
N
Δ
S
−EtOH
N
N
S
O
S
N
N
OC2H5 NH
C
D
E
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 7 2008

SYNTHESIS OF NEW 2,5-DIAMINO-1,3-THIAZOLE
1433
Table 3. Principal correlations in the HMQC and HMBC
spectra of compound IXa
The structure of the products obtained by reactions
of III–VIII with hydrochloric acid in ethanol is
beyond doubt, for some of these were synthesized
previously by independent methods (Table 1), while
the others were identified as substituted 2-
thiohydantoins on the basis of their spectral parameters
and chemical transformations. For example, treatment
of both compound III and 2-amino-5-benzoylamino-4-
phenyl-1,3-thiazole [7] (these compounds differ only
by the N-acyl residues) with hydrochloric acid gave the
same product, 5-phenyl-2-thiohydantoin IX. The latter
was identical in melting point to an authentic sample
of IX prepared by reaction of N-phenylaminoacetic
acid with ammonium thiocyanate (Table 1). The IR
spectrum of the product contained a strong absorption
band at 1750 cm–1, corresponding to stretching vibra-
tions of the C5=O group in the imidazolidine ring (cf.
[16]). The structure of compound IX was finally
proved by heteronuclear 1H–13C NMR correlation
experiments (through 2 and 3 bonds, HMQC and
HMBC techniques). The HMQC and HMBC data
13C chemical shifts δC, ppm
1H chemical
shifts δ, ppm
HMQC
HMBC
127.42 (C2, C6)
7.38 (C4H)
129.27 (C4)
7.42 (C3H, C5H) 129.59 (C3, C5) 129.59 (C3, C5); 135.21 (C1)
7.26 (C2H, C6H) 127.42 (C2, C6) 127.42 (C2, C6); 129.27 (C4)
5.39 (CH)
64.63 (CH)
64.63 (CH); 127.42 (C2, C6);
135.21 (C1); 175.54 (CO);
183.59 (CS)
10.50 (CS–N–H)
11.87 (CO–N–H)
64.63 (CH); 183.59 (CS);
175.54 (CO)
64.63 (CH); 183.59 (CS);
175.54 (CO)
a
For atom numbering, see Fig. 2.
measured on a Varian VXR-300 instrument, and the
1H–13C heteronuclear correlation spectra were obtained
on a Varian Mercury-400 spectrometer; DMSO-d6 was
used as solvent, and tetramethylsilane, as internal
reference.
1
allowed us to assign all H and 13C signals. The
principal correlations are shown in Fig. 2, and their
complete list is given in Table 3.
Thus the formation of 5-phenyl-2-thiohydantoin as
a result of the transformation sequence Ia→III→IX
casts no doubt. Substituted analogs of IX, compounds
XI–XIV, were synthesized by treatment of V–VIII
with hydrochloric acid. These reactions occurred in a
regioselective fashion even under one-pot conditions;
therefore, they provide a useful alternative to the
known method for the preparation of substituted 2-
thiohydantoins from N-arylglycines or their esters [15–
17, 25, 26]. Insofar as the series of accessible reagents
like I and II and their analogs like HtCOCHCl·
NHCOR continuously extends, at least some of these
compounds could appear to be suitable for the
synthesis of 2-thiohydantoin derivatives that are
difficult to obtain by the procedures developed
previously [15–18, 25, 26].
The X-ray diffraction data for compound VIIIj
were obtained from a 0.19×0.25×0.48-mm single
crystal at room temperature on an Enraf–Nonius CAD-
4 automatic four-circle diffractometer (CuKα radia-
tion, λ = 1.54178 Å, scan rate ratio 2θ/ω = 1.2, θmax
=
68°, spherical segment 0 ≤ h ≤ 9, 0 ≤ k ≤ 20, 0 ≤ l ≤
17). A total of 3128 reflections were measured, 2250 of
which were symmetry-independent (Rint = 0.021).
5.39
129.27
H
127.42
129.59
10.50
H
H
S
N
5
6
It should also be noted that the preparative impor-
tance of products of selective cyclocondensation of com-
pounds I and II with thioureas is not limited to their recyc-
lization; these compounds can be involved in some other
interesting transformations (see, e.g., [11]) which will
be reported in detail in our subsequent publications.
183.59
11.87
1
4
7.38
N
3
2
H
O
H
H
7.26
175.54
7.42
64.63
EXPERIMENTAL
Fig. 2. Principal correlations (denoted with arrows) and
signal assignment (δ, δC, ppm) in the 1H and 13C NMR
spectra of 5-phenyl-2-thioxoimidazolidin-4-one (IX).
The IR spectra were recorded in KBr on a Specord
M-80 spectrometer. The 1H NMR spectra were
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 7 2008

1434
BALYA et al.
Rhombic crystals with the following unit cell
parameters: a = 8.933(4), b = 17.567(7), c = 15.166(7)
Å; V = 2380(2) Å3; M 459.6; Z = 4; dcalc = 1.29 g/cm3;
μ = 14.30 cm–1; F(000) = 975.8; space group Pna21
(no. 33). The structure was solved by the direct method
and was refined by the least-squares procedure in full-
matrix anisotropic approximation using CRYSTALS
software package [27]. The refinement procedure was
performed using 1988 reflections with I > 3σ(I) (302
refined parameters, 6.6 reflections per parameter).
About 50% of hydrogen atoms were visualized by
difference syntheses of electron density, and positions
of the other hydrogen atoms were calculated on the
basis of geometry considerations. All hydrogen atoms
were included in the refinement procedure with fixed
positional and thermal parameters. Chebyshev’s weight
scheme [28] with the following four parameters was
applied: 0.72, –0.64, 0.14, and –0.43. The final
divergence factors were R = 0.037 and Rw = 0.037;
goodness of fit 1.139. The residual electron density
from the Fourier difference series was 0.14 and –0.34
e/Å3. Absorption by the crystal was taken into account
using the azimuthal scanning technique [29]. The
absolute configuration of molecule VIIIj was
determined according to Flack [30]: the enantiopole
parameter was refined to 0.02(3) by 2466 unaveraged
Friedel-equivalent reflections. The complete set of
crystallographic data for compound VIIIj was
deposited to the Cambridge Crystallographic Data
Center (entry no. CCDC 653733).
N-[3-Alkyl(aryl)-4-aryl-2-arylimino-2,3-dihydro-
1,3-thiazol-5-yl]carboxamides VII and VIII were
synthesized in a similar way from compounds Ia–Ic
and IIa–IIc and the corresponding N,N′-disubstituted
thioureas. Compounds VIIa and VIIId were brought
into further transformations without additional
purification, while compounds VIIb and VIIf were
isolated as hydrochlorides.
5-Aryl-2-thioxoimidazolidin-4-ones IX and X
(general procedure). a. Concentrated hydrochloric
acid, 15 ml, was added to a solution of 0.006 mol of
compound III or IV in 40 ml of ethanol. The mixture
was heated for 2 h under reflux and cooled, 100 ml of
a saturated aqueous solution of sodium hydrogen
carbonate was added, and the precipitate was filtered
off and recrystallized from appropriate solvent.
b. Compound Ia or IIa, 0.006 mol, was added to a
suspension of 0.006 mol of thiourea in 10 ml of THF,
and the mixture was stirred for 24 h at 20–25°C. The
solvent was removed under reduced pressure, 40 ml of
ethanol was added, the mixture was heated for 1 h
under reflux and cooled, 15 ml of concentrated
hydrochloric acid was added, the mixture was heated
for 2 h under reflux and cooled, 100 ml of a saturated
aqueous solution of sodium hydrogen carbonate was
added, and the precipitate was filtered off and
recrystallized from appropriate solvent. Samples of
compounds IX and X obtained according to methods a
and b showed no depression of the melting point on
mixing, and their IR and 1H NMR spectra were
identical.
N-(2-Aryl-1-chloro-2-oxoethyl) carboxylic acid
amides Ia–Ic and IIa–IIc were synthesized by the
procedure described previously [6].
3-Alkyl(aryl)-5-aryl-2-thioxoimidazolidin-4-ones
XIa–XId and XIIa–XIId were synthesized as
compounds IX and X from substituted thiazoles Va–
Vd and VIa–VId, respectively, according to method a.
N-(2-Amino-4-aryl-1,3-thiazol-5-yl)acetamides III
and IV (general procedure). Compound Ia or IIa,
0.01 mol, was added to a suspension of 0.01 mol of
thiourea in 25 ml of anhydrous THF, and the mixture
was stirred for 24 h at 20–25°C. The solvent was
removed under reduced pressure, 30 ml of anhydrous
methanol was added to the residue, and the mixture
was heated for 1 h under reflux. The solvent was
removed under reduced pressure, the residue was
treated with 100 ml of a saturated aqueous solution of
sodium hydrogen carbonate, and the precipitate was
filtered off, washed with water, and recrystallized from
appropriate solvent.
1-Alkyl(aryl)-3,5-diaryl-2-thioxoimidazolidin-4-
ones XIIIa–XIIIh and XIVa–XIVg were synthesized
in a similar way from substituted thiazoles VIIa–VIIh
and VIIIa–VIIIg, respectively, according to method a
or b (Table 1).
ACKNOWLEDGMENTS
This study was performed under financial support
by the Ukrainian Science and Technology Center
[project no. 3017(R)].
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